Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: The choice between 22-gauge endoscopic ultrasound-guided fine-needle biopsy (EUS-FNB) and EUS-guided fine-needle aspiration (EUS-FNA) for histological diagnosis of type 1 autoimmune pancreatitis (AIP) is unclear. We retrospectively examined the detection rate of histological findings for AIP using EUS-FNA/FNB. METHODS: Patients diagnosed with type 1 AIP using EUS-FNB (Franseen needle) or EUS-FNA (conventional needle) with 22-gauge needles at our hospital between 2012 and 2023 were included in this study. AIP was diagnosed according to International Consensus Diagnostic Criteria (ICDC). The detection rates of level 1 findings, which included storiform fibrosis and/or obliterative phlebitis, and level 2 histological findings were evaluated according to the ICDC. RESULTS: The EUS-FNB and EUS-FNA groups included 25 and 24 patients, respectively. No significant differences in patient background were noted between the two groups. The detection rates of prominent filtration of lymphocytes and plasma cells along with fibrosis were 56.0% in the EUS-FNB group and 12.5% in the EUS-FNA group (p = .001). The detection rates of more than 10 IgG4-positive plasma cells per high-power microscopic field were 68.0% and 29.2% in the EUS-FNB and EUS-FNA groups, respectively (p = .007). The histological findings for levels 1 and 2 were significantly higher in the EUS-FNB group (56.0% vs. 12.5%; p = .001). Mild pancreatitis was observed in the EUS-FNB group; however, no other serious adverse events occurred. CONCLUSION: The 22-gauge EUS-FNB yielded a higher rate of histological findings than 22-gauge EUS-FNA, suggesting that 22-gauge EUS-FNB is suitable and safe for the histological diagnosis of type 1 AIP.

DOI： 10.1002/jhbp.12095

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Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND/PURPOSE: This study clarifies the short- and long-term outcomes of liver resection with hepatic vein (HV) reconstruction for liver tumors and identifies the risk factors for poor outcome. METHODS: We contacted 263 specialized centers in Japan and collected data on this surgical procedure. Patient characteristics, surgical procedures, and outcomes were then analyzed. RESULTS: A total of 187 patients were enrolled from 36 institutions. Grade C post-hepatectomy liver failure (PHLF) and in-hospital mortality were 3.2% and 1.6%, respectively. The median overall survival (OS) and recurrence-free survival (RFS) were 49.9 and 9.8 months, respectively. Surgical outcomes, OS and RFS did not differ among three types of liver tumors, colorectal liver metastasis (CRLM) (n = 127), hepatocellular carcinoma (n = 27), and intrahepatic cholangiocarcinoma (n = 27). Patients with CRLM and seven or more courses of preoperative chemotherapy had significantly worse OS. Compared with HV reconstruction for securing liver remnant (LR) function (n = 148), reconstruction of the only main HV remaining in the LR (n = 39) had significantly worse short-term outcomes, but did not result in increased mortality, and showed equivalent OS and RFS. CONCLUSIONS: Liver resection with HV reconstruction can be achieved safely and contributes to a relatively good long-term outcome for patients with advanced liver malignancies.

DOI： 10.1002/jhbp.12077

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Language：English   Publishing type：Research paper (scientific journal)  

Neuroendocrine carcinoma (NEC) of the colon and rectum is a rare malignancy with a poor prognosis that is characterized by distinct clinical and histopathological features that differ significantly from those of more prevalent adenocarcinomas. Poorly differentiated colorectal adenocarcinoma (PDC) is also rare and carries a poor prognosis. Considering the morphological similarities between these two rare, poorly differentiated cancers of the colon and rectum, it is plausible that certain cases of colorectal cancer (CRC) diagnosed as PDC may contain NEC as well. In the present study, cases of CRC that were diagnosed as PDC at our institution were investigated, searching for patients who exhibited NEC characteristics based on the expression of neuroendocrine markers (NEMs), including chromogranin A, synaptophysin and insulinoma-associated 1 (INSM1), and the loss of retinoblastoma 1 (Rb). Of 816 total CRC cases, 74 cases (9.1%) were identified as PDC. These were further divided into 13 (17.5%) cases that were positive for NEMs and others. Of these 13 cases, the expression rates for chromogranin A and synaptophysin were 69.2% each, while that of INSM1 was 100%. Upon re-examination of the 13 PDC cases, two cases were morphologically identified as NEC, including one large- and one small-cell NEC. A total of two cases showed loss of Rb in their PDC lesions. NEM positivity was considered an independent prognostic factor in the 74 PDC cases. Among these cases, some may exhibit characteristics of NEC. Unraveling the molecular mechanisms using CRC that harbors both PDC and NEC will be a task for future research.

DOI： 10.3892/mco.2024.2789

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Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: Methionine restriction (MR) has been demonstrated to exhibit anti-tumor effects in various types of cancer, including pancreatic cancer (PC). However, the detailed mechanism induced by MR remains still unclear. This study aims to reveal the underlying mechanism of MR on PC by proteomic analysis. MATERIAL & METHODS: Human PC cell lines were cultured in both standard and MR media to evaluate the effect of MR. The differences in protein expression were evaluated through proteomic analysis. Ingenuity Pathway Analysis (IPA) was performed to identify proteins potentially associated with tumor growth in vitro. The proteins associated with the anti-tumor effect were validated using western blotting, real-time PCR, and ELISA. An experimental model involving subcutaneous PC mice was established for the assessment of the effectiveness of the MR diet and the expression of target proteins through immunohistochemical staining. RESULTS: Cell proliferation was suppressed in the MR media compared to the standard media. IPA analysis showed that STAT3 was decreased in the Apoptotic Pathway of Pancreatic Cancer Cell lines in the MR group. Western blotting showed MR decreased STAT3 expression. Real-time PCR showed that MR decreased JAK2 and STAT3 mRNA expression in Panc-1 and Mia-PaCa 2, but not in Capan-1. ELISA revealed that NF-kB expression was decreased in the MR group. In the in vivo study, the final estimated tumor volume in the MR group was significantly lower than the control group (p < 0.01). Immunostaining of resected specimens showed that STAT3 expression was suppressed in the MR group. CONCLUSION: MR suppressed the JAK2/STAT3 pathway and decreased NF-kB in some PC cell lines.

DOI： 10.1016/j.pan.2024.11.023

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Publishing type：Research paper (scientific journal)   Publisher：Springer Science and Business Media LLC  

DOI： 10.1245/s10434-024-16455-7

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Other Link： https://link.springer.com/article/10.1245/s10434-024-16455-7/fulltext.html

Publishing type：Research paper (scientific journal)  

Background/Objectives: Endoscopic ultrasound-guided hepaticogastrostomy (EUS-HGS) often requires fistula dilation owing to the placement of a large diameter of the delivery stent. The recently developed delivery devices, which are as thin as 5.9/6.0 Fr, may save the need for fistula dilation. Therefore, we investigated whether large fistula dilation would be required or not in the case of this newly developed thin-diameter delivery stents. Methods: We conducted a retrospective study involving 33 patients implemented with a self-expandable metal stent (SEMS) during EUS-HGS. The patients were categorized based on the delivery device diameter into thin (n = 13; delivery device diameter: 5.9/6.0 Fr) and thick (n = 20; delivery device diameter: 8.5 Fr) groups. We compared the initial rate of success, technical success, and clinical success between the thin and thick groups. The initial rate of success was defined as successful stent placement without a balloon or large diameter mechanical dilation. Results: The rate of the initial stenting success was significantly higher in the thin group (100% [13/13]) compared with that in the thick group (65.0% [13/20]) (p = 0.027). In the thick group, seven cases with technical difficulty in terms of stent placement could be successfully completed with additional fistula dilation with a 9 Fr bougie dilator or 4 mm balloon dilator; this resulted in a technical success of 100% in both groups ultimately. The rate of clinical success was 100% and 95.0% in the thin and thick groups, respectively (p = 1.00). Conclusions: Thin delivery stents may facilitate stent placement without the need for a balloon fistula or large-diameter mechanical dilation.

DOI： 10.3390/jcm13216328

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Publishing type：Research paper (scientific journal)   Publisher：Elsevier BV  

DOI： 10.1016/j.esmoop.2024.103737

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Language：English   Publishing type：Research paper (scientific journal)  

Background/Objectives: Endoscopic ultrasound-guided hepaticogastrostomy (EUS-HGS) often requires fistula dilation owing to the placement of a large diameter of the delivery stent. The recently developed delivery devices, which are as thin as 5.9/6.0 Fr, may save the need for fistula dilation. Therefore, we investigated whether large fistula dilation would be required or not in the case of this newly developed thin-diameter delivery stents. Methods: We conducted a retrospective study involving 33 patients implemented with a self-expandable metal stent (SEMS) during EUS-HGS. The patients were categorized based on the delivery device diameter into thin (n = 13; delivery device diameter: 5.9/6.0 Fr) and thick (n = 20; delivery device diameter: 8.5 Fr) groups. We compared the initial rate of success, technical success, and clinical success between the thin and thick groups. The initial rate of success was defined as successful stent placement without a balloon or large diameter mechanical dilation. Results: The rate of the initial stenting success was significantly higher in the thin group (100% [13/13]) compared with that in the thick group (65.0% [13/20]) (p = 0.027). In the thick group, seven cases with technical difficulty in terms of stent placement could be successfully completed with additional fistula dilation with a 9 Fr bougie dilator or 4 mm balloon dilator; this resulted in a technical success of 100% in both groups ultimately. The rate of clinical success was 100% and 95.0% in the thin and thick groups, respectively (p = 1.00). Conclusions: Thin delivery stents may facilitate stent placement without the need for a balloon fistula or large-diameter mechanical dilation.

DOI： 10.3390/jcm13216328

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Language：English   Publishing type：Research paper (scientific journal)  

Background/Objectives: The usefulness of dual-energy computed tomography (DECT) for low absorption in the parenchymal phase and contrast effects in the delayed phase for pancreatic cancer is not clear. Therefore, the diagnostic capability of low-KeV images obtained using DECT for pancreatic cancer in the pancreatic parenchymal and delayed phases was evaluated quantitatively and qualitatively. Methods: Twenty-five patients with pancreatic cancer who underwent contrast-enhanced DECT were included. A total of 50 and 70 KeV CT images, classified as low-keV and conventional CT-equivalent images, were produced, respectively. The tumor-to-pancreas contrast (Hounsfield units [HU]) in the pancreatic parenchymal and delayed phases was calculated by subtracting the CT value of the pancreatic tumor from that of normal parenchyma. Results: The median tumor-to-pancreas contrast on 50 KeV CT in the pancreatic parenchymal phase (133 HU) was higher than that on conventional CT (68 HU) (p < 0.001). The median tumor-to-pancreas contrast in the delayed phase was -28 HU for 50 KeV CT and -9 HU for conventional CT (p = 0.545). For tumors < 20 mm, the tumor-to-pancreas contrast of 50 KeV CT (-39 HU) had a significantly clearer contrast effect than that of conventional CT (-16.5 HU), even in the delayed phase (p = 0.034). Conclusions: These 50 KeV CT images may clarify the low-absorption areas of pancreatic cancer in the pancreatic parenchymal phase. A good contrast effect was observed in small pancreatic cancers on 50 KeV delayed-phase images, suggesting that DECT is useful for the visualization of early pancreatic cancer with a small tumor diameter.

DOI： 10.3390/tomography10100117

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Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: The aim of this study was to determine the optimal treatment for patients with pancreatic cancer (PaCa) having positive peritoneal cytology (PPC). METHODS: This multicenter retrospective study included patients with PPC treated at 78 high-volume centers between January 2012 and December 2020. Prognoses after resection (S-group) and initiation of nonsurgical treatment (N-group) were compared. Prognostic factors for survival in both groups were analyzed. Detailed characteristics of conversion surgery (CS) in the N-group were evaluated. RESULTS: In total, 568 enrolled patients were classified into an S-group (n = 445) or an N-group (n = 123). Median survival times (MSTs) were 19.0 months and 19.3 months, respectively, with no significant difference in prognosis (p = .845). The intervenable prognostic factors for survival were adjuvant treatment in the S-group (p < .001) and CS in the N-group (p < .001). Following CS, the MST was prolonged to 45.6 months, and peritoneal or liver recurrence decreased considerably. CS can be expected if PPC is diagnosed before neoadjuvant treatment and when combination treatment is initiated. CONCLUSION: Surgical resection may not be beneficial for improving survival when PPC is evident. Chemotherapy aiming for CS may be the optimal treatment for such patients.

DOI： 10.1002/jhbp.12074

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Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: Post-colectomy pan-enteritis in ulcerative colitis (UC) is very rare, but it is often severe and fatal. We present a case of massive bleeding and perforation due to post-colectomy pan-enteritis, which showed a significant response to biologics in a UC patient. CASE PRESENTATION: A 30-year-old woman with a 5-month history of pancolitis UC underwent subtotal colectomy with ileostomy and mucosal fistula for refractory UC. She was diagnosed with small bowel obstruction on postoperative day (POD) 8 and bowel bleeding was observed on POD18. Reoperation was performed for bowel obstruction and bleeding on POD20. Intraoperatively, adhesive small bowel obstruction in the ileum and multiple erosions and ulcers with perforation were observed throughout the small bowel. We diagnosed post-colectomy pan-enteritis, and jejunostomy, lavage, adhesiolysis, and a simple closure of the perforated ileum were performed. High-dose steroid therapy for pan-enteritis was administered immediately after reoperation, and infliximab was administered because of worsening bleeding on day 3 after reoperation. Bleeding decreased one day after biologic administration and bleeding completely disappeared on day 10 after biologic administration. Specimens obtained from the terminal ileum at colectomy showed a normal ileum without inflammation and villus atrophy, while specimens from the perforated ileum showed congestion, villous atrophy, epithelial erosion, and mononuclear cell infiltration. No cryptitis, crypt distortion, or basal plasmacytosis (common characteristics in UC) were observed in either specimen. CONCLUSION: An early diagnosis and intervention are important for post-colectomy pan-enteritis, and infliximab may be effective. Post-colectomy pan-enteritis with a multiple ulcer phenotype has different histological characteristics from UC and may have a different pathogenesis.

DOI： 10.1186/s40792-024-02003-8

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Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: The real-world efficacy, prognostic factors, and adverse events of second-line nivolumab monotherapy and subsequent third-line therapy for unresectable or metastatic esophageal cancer have not been fully evaluated. METHODS: This multi-institutional retrospective cohort study evaluated 184 consecutive patients treated with second-line nivolumab monotherapy for esophageal cancer between March 2021 and December 2022. We assessed tumor response, adverse events, long-term survival, and prognostic factors. RESULTS: Among 128 patients with measurable lesions, the response rate was 23% and the disease control rate for all enrolled patients was 45%. The incidence of grade 3 or higher adverse events was 14%, but no treatment-related deaths presented. Median progression-free survival was 5.1 months and overall survival was 14 months, respectively. C-reactive protein level and performance status were identified as significant prognostic factors of overall survival through Cox proportional hazards analysis. The group with two favorable prognostic factors showed better overall survival than the groups with either one or zero prognostic factors (median overall survival: 22, 15, and 4.4 months, respectively). Among 69 patients who received third-line taxane anticancer agents, the progression-free survival was 6.7 months. CONCLUSIONS: Our study demonstrated that the real-world outcomes of second-line nivolumab monotherapy were comparable to those of previous randomized clinical trials in terms of tumor response, safety, and long-term survival. Furthermore, a good performance status and low C-reactive protein levels may identify patients who are likely to benefit from therapy. Third-line chemotherapy after nivolumab treatment may have an enhanced effect; however, further prospective studies are required to confirm this finding.

DOI： 10.1007/s00535-024-02141-8

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Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: The Delphi consensus study was carried out under the auspices of the International and Asia-Pacific Hepato-Pancreato-Biliary Associations (IHPBA-APHPBA) to develop practice guidelines for management of gallbladder cancer (GBC) globally. METHOD: GBC experts from 17 countries, spanning 6 continents, participated in a hybrid four-round Delphi consensus development process. The methodology involved email, online consultations, and in-person discussions. Sixty eight clinical questions (CQs) covering various domains related to GBC, were administered to the experts. A consensus recommendation was accepted only when endorsed by more than 75% of the participating experts. RESULTS: Out of the sixty experts invited initially to participate in the consensus process 45 (75%) responded to the invitation. The consensus was achieved in 92.6% (63/68) of the CQs. Consensus covers epidemiological aspects of GBC, early, incidental and advanced GBC management, definitions for radical GBC resections, the extent of liver resection, lymph node dissection, and definitions of borderline resectable and locally advanced GBC. CONCLUSIONS: This is the first international Delphi consensus on GBC. These recommendations provide uniform terminology and practical clinical guidelines on the current management of GBC. Unresolved contentious issues like borderline resectable/locally advanced GBC need to be addressed by future clinical studies.

DOI： 10.1016/j.hpb.2024.07.411

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Publishing type：Research paper (scientific journal)   Publisher：Springer Science and Business Media LLC  

DOI： 10.1007/s10549-024-07434-3

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Publishing type：Research paper (scientific journal)   Publisher：Ovid Technologies (Wolters Kluwer Health)  

Objective:

This study aimed to clarify the molecular mechanism of remnant pancreatic cancer (PC) development after primary PC resection.

Summary Background Data:

Molecular mechanisms of the development of remnant PCs following primary PC resection are largely unknown.

Methods:

Forty-three patients undergoing remnant PC resection after primary PC resection between 2001 and 2017 at 26 institutes were retrospectively analyzed. Clinicopathological features and molecular alterations detected by targeted amplicon sequencing of 36 PC-associated genes were evaluated.

Results:

These patients showed significantly lower body mass indices and higher hemoglobin A1c values at remnant PC resection than at primary PC resection. A comparison of the molecular features between primary and remnant PCs indicated that remnant PCs were likely to develop via three different molecular pathways: successional, showing identical and accumulated alterations (n=14); phylogenic, showing identical and distinct alterations (n=26); and distinct, showing independent distinctive alterations (n=3). The similarity of gene alterations was associated with time to the remnant PC development (r=－0.384, P=0.0173). Phylogenic pathways were significantly associated with the intraductal spread of carcinoma (P=0.007). Patient survival did not differ significantly depending on these molecular pathways.

Conclusion:

Molecular profiling uncovered three pathways for the development of remnant PCs, namely, successional, phylogenic, and distinct pathways. The vast majority of remnant PCs are likely to be molecularly associated with primary PCs either in the successional or phylogenic way. This information could impact the design of a strategy for monitoring and treating remnant PCs.

DOI： 10.1097/sla.0000000000006444

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Publishing type：Research paper (scientific journal)   Publisher：Springer Science and Business Media LLC  

DOI： 10.1007/s10549-024-07421-8

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Language：Japanese   Publisher：(一社)日本消化器外科学会  

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Language：Japanese   Publisher：(公社)神奈川県医師会  

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Language：Japanese   Publisher：(一社)日本消化器外科学会  

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Publishing type：Research paper (scientific journal)   Publisher：Ovid Technologies (Wolters Kluwer Health)  

Objective:

To investigate the clinical relevance of common myeloid progenitor (CMP) cells in breast tumor microenvironment (TME).

Background:

The role of rare cells in TME is less studied. In Silico transcriptomic analyses of real-world data enable us to detect and quantify rare cells, including CMP cells.

Methods:

A total of 5176 breast cancer (BC) patients from SCAN-B, METABRIC, and 5 single-cell sequence cohorts were analyzed using the xCell algorithm. The high group was defined as more than two-thirds of the CMP scores in each cohort.

Results:

CMP cells consist of 0.07% to 0.25% of bulk breast tumor cells, more in estrogen receptor-positive (ER+) compared with triple-negative (TN) subtype (0.1% to 0.75%, 0.18% to 0.33% of immune cells, respectively). CMP cells did not correlate with any of the myeloid lineages or stem cells in TME. CMP infiltration was higher in smaller tumors, with lower Nottingham grade, and in ER+/HER2− than in TNBC consistently in both SCAN-B and METABRIC cohorts. High CMP was significantly associated with a lower risk of brain metastasis and with better survival, particularly in ER+/HER2−. High CMP enriched epithelial-to-mesenchymal transition and angiogenesis pathways, and less cell proliferation and DNA repair gene sets. High CMP ER+/HER2- was associated with less immune cell infiltration and cytolytic activity (P&lt;0.001). CMP infiltration correlated with neoadjuvant chemoimmunotherapy response for both ER+/HER2- and TNBC in the ISPY-2 cohort (AUC=0.69 and 0.74, respectively).

Conclusions:

CMP in BC is inversely associated with cell proliferation and brain metastasis, better response to immunotherapy, and survival. This is the first to report the clinical relevance of CMP infiltration in BC.

DOI： 10.1097/sla.0000000000006428

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Publishing type：Research paper (scientific journal)   Publisher：Springer Science and Business Media LLC  

DOI： 10.1007/s12072-024-10678-2

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Publishing type：Research paper (scientific journal)   Publisher：Wiley  

Abstract

Aim

Lymph node metastasis is an adverse prognostic factor in pancreatic ductal adenocarcinoma. However, it remains a challenge to predict lymph node metastasis using preoperative imaging alone. We used machine learning (combining preoperative imaging findings, tumor markers, and clinical information) to create a novel prediction model for lymph node metastasis in resectable pancreatic ductal adenocarcinoma.

Methods

The data of patients with resectable pancreatic ductal adenocarcinoma who underwent surgery between September 1991 and October 2022 were retrospectively examined. Machine‐learning software (Statistical Package for the Social Sciences Modeler) was used to create a prediction model, and parameter tuning was performed to improve the model's accuracy. We also analyzed the contribution of each feature to prediction using individual conditional expectation and partial dependence plots.

Results

Of the 331 cases included in the study, 241 comprised the training cohort and 90 comprised the test cohort. After parameter tuning, the areas under the receiver operating characteristic curves for the training and test cohorts were 0.780 and 0.795, respectively. Individual conditional expectation and partial dependence plots showed that larger tumor size and carbohydrate antigen 19–9 and Duke pancreatic monoclonal antigen type 2 levels were associated with positive lymph node metastasis prediction in this model; neoadjuvant treatment was associated with negative lymph node metastasis prediction.

Conclusion

Machine learning may contribute to the creation of an effective predictive model of lymph node metastasis in pancreatic ductal adenocarcinoma. Prediction models using machine learning may contribute to the development of new treatment strategies in resectable pancreatic ductal adenocarcinoma.

DOI： 10.1002/ags3.12836

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Publishing type：Research paper (scientific journal)   Publisher：Elsevier BV  

DOI： 10.1016/j.pan.2024.05.530

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Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: There is little established evidence regarding treatment strategies for unresectable biliary tract cancer (BTC). This study aimed to clarify the situation of multidisciplinary treatment for unresectable BTC in the 2000s when there was no international standard first-line therapy. METHODS: We retrospectively reviewed 315 consecutive patients with unresectable BTC who had been treated at seven tertiary institutions in Kanagawa Prefecture, Japan between 1999 and 2008. RESULTS: The unresectable factors were as follows: locally advanced, 101 cases (32.1%); hematogenous metastases, 80 cases (25.4%); and peritoneal dissemination, 30 cases (9.5%). Chemotherapy or radiation therapy was administered to 218 patients (69.2%). The best supportive care was provided in 97 cases (30.8%). The most common regimen was gemcitabine monotherapy, followed by gemcitabine combination therapy and S-1 monotherapy. The 1- and 2-year survival rates of all patients were 34.6% and 12.2%, respectively. The median survival time (MST) was 8 months in all patients. The 1-year survival rate was 65%, and the MST was 12 months among the locally advanced patients, whereas patients with peritoneal dissemination had the worst outcome; the 1-year survival rate was 7%, and the MST was 5 months. Among treated 90 cases of perihilar cholangiocarcinoma, patients who received chemoradiotherapy (n = 24) had a significantly better outcome than those who received chemotherapy alone (MST: 20 vs. 11 months, P < 0.001). CONCLUSIONS: Unresectable BTC has heterogeneous treatment outcomes depending on the mode of tumor extension and location. Multidisciplinary treatment seems useful for patients with locally advanced BTC, whereas patients with metastatic disease still have a poor prognosis.

DOI： 10.14740/wjon1821

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Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: Although surgical resection is the only curative treatment for biliary tract cancer, in some cases, the disease is diagnosed as unresectable at initial presentation. There are few reports of conversion surgery after the initial treatment for unresectable locally advanced biliary tract cancer. This study aimed to evaluate the efficacy and safety of conversion surgery in patients with initially unresectable locally advanced biliary tract cancer. METHODS: We retrospectively collected clinical data from groups of patients in multiple centers belonging to the Japanese Society of Hepato-Biliary-Pancreatic Surgery and Korean Association of Hepato-Biliary-Pancreatic Surgery. We analyzed two groups of prognostic factors (pretreatment and surgical factors) and their relation to the treatment outcomes. RESULTS: A total of 56 patients with initially unresectable locally advanced biliary tract cancer were enrolled in this study of which 55 (98.2%) patients received chemotherapy, and 16 (28.6%) patients received additional radiation therapy. The median time from the start of the initial treatment to resection was 6.4 months. Severe postoperative complications of Clavien-Dindo grade III or higher occurred in 34 patients (60.7%), and postoperative mortality occurred in five patients (8.9%). Postoperative histological results revealed CR in eight patients (14.3%). The median survival time from the start of the initial treatment in all 56 patients who underwent conversion surgery was 37.7 months, the 3-year survival rate was 53.9%, and the 5-year survival rate was 39.1%. CONCLUSIONS: Conversion surgery for initially unresectable locally advanced biliary tract cancer may lead to longer survival in selected patients. However, more precise preoperative safety evaluation and careful postoperative management are required.

DOI： 10.1002/jhbp.1437

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Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: The real-world efficacy, feasibility, and prognostic factors of immune-checkpoint inhibitor combination therapy for unresectable or metastatic esophageal cancer are not fully established. METHODS: This multi-institutional retrospective cohort study evaluated 71 consecutive patients treated with immune-checkpoint inhibitor combination therapy for esophageal cancer between March 2021 and December 2022. We assessed tumor response, safety, and long-term survival. RESULTS: In patients with measurable lesions, the response rate was 58%, and the disease control rate for all enrolled patients was 80%. Five patients (7.0%) underwent successful conversion surgery. Grade 3 or higher immune-related adverse events occurred in 13% of patients, and one patient (1.4%) died due to cholangitis. Median progression-free survival was 9.7 (95% confidence interval: 6.5-not reached). C-reactive protein levels and performance status were identified as significant predictors of progression-free survival through Cox proportional hazards analysis. CONCLUSIONS: Immune-checkpoint inhibitor combination therapy for esophageal cancer demonstrated comparable tumor response, safety, and long-term survival to previous randomized clinical trials. Patients with good performance status and low C-reactive protein levels may be suitable candidates for this treatment.

DOI： 10.1007/s10147-024-02532-0

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Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: Although curative resection with vascular reconstruction improves the prognosis of blood-invading locally advanced hepatobiliary tumors, the mortality and morbidity of the procedure remains unclear. This study aimed to clarify the risk factors associated with mortality and morbidity in patients undergoing liver resection with vascular reconstruction. METHODS: This retrospective observational study included 1215 patients undergoing hepatectomy of more than one section with vascular reconstruction, except for left lateral sectionectomy registered in the National Clinical Database (NCD) between 2015 and 2019. The rates of surgical mortality and relevant clinical factors were evaluated. RESULTS: Among the four types of vascular reconstruction, portal venous reconstruction was frequently performed in 724 patients (59.6% of the enrolled patients). Surgical mortality was 8.1%. Patients with hepatic artery reconstruction had the highest surgical mortality rate of 15.8%. In other types of reconstruction, surgical mortality was 9.1% in the portal vein, 5.2% in inferior vena cava, and 4.9% in hepatic vein. Factors significantly associated with surgical mortality include age, sex (male), preoperative comorbidity (American Society of Anesthesiologists grade >3, respiratory distress, diabetes, preoperative pneumonia, weight loss, and obstructive jaundice), poorer liver functional reserve (indocyanine green retention rate at 15 min and prothrombin time/international normalized ratio >1.1) and accompanying biliary reconstruction. CONCLUSIONS: The NCD revealed the detailed status of liver resection combined with vascular reconstruction in Japan. Based on the results of this analysis, understanding the factors that influence the outcome and postoperative course of each procedure will provide patients with accurate information and opportunities to improve future outcomes.

DOI： 10.1002/jhbp.1435

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Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND & AIMS: Despite previously reported treatment strategies for nonfunctioning small (≤20 mm) pancreatic neuroendocrine neoplasms (pNENs), uncertainties persist. We aimed to evaluate the surgically resected cases nonfunctioning small pNENs (NF-spNENs) in a large Japanese cohort to elucidate an optimal treatment strategy for NF-spNENs. METHODS: In this Japanese multicenter study, data were retrospectively collected from patients who underwent pancreatectomy between January 1996 and December 2019, were pathologically diagnosed with pNEN, and were treated according to the WHO 2019 classification. Overall, 1,490 patients met the eligibility criteria, and 1,014 were included in the analysis cohort. RESULTS: In the analysis cohort, 606 patients (59.8%) had NF-spNENs, with 82% classified as grade 1 (NET-G1) and 18% as grade 2 (NET-G2) or higher. The incidence of lymph node metastasis (N1) by grade was significantly higher in NET-G2 (G1: 3.1% vs. G2: 15.0%). Independent factors contributing to N1 were NET-G2 or higher and tumor diameter ≥15 mm. The predictive ability of tumor size for N1 was high. Independent factors contributing to recurrence included multiple lesions, NET-G2 or higher, tumor diameter ≥15 mm, and N1. However, the independent factor contributing to survival was tumor grade (NET-G2 or higher). The appropriate timing for surgical resection of NET-G1 and NET-G2 or higher was when tumors were >20 and >10 mm, respectively. For neoplasms with unknown preoperative grades, tumor size >15 mm was considered appropriate. CONCLUSIONS: NF-spNENs are heterogeneous with varying levels of malignancy. Therefore, treatment strategies based on tumor size alone can be unreliable; personalized treatment strategies that consider tumor grading are preferable.

DOI： 10.1016/j.cgh.2024.03.029

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Publishing type：Research paper (scientific journal)   Publisher：Elmer Press, Inc.  

DOI： 10.14740/wjon1732

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Language：Japanese   Publisher：(一社)日本外科学会  

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Publishing type：Research paper (scientific journal)   Publisher：Elmer Press, Inc.  

DOI： 10.14740/wjon1751

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Language：Japanese   Publisher：(一社)日本外科学会  

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Language：Japanese   Publisher：(一社)日本外科学会  

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Language：Japanese   Publisher：(一社)日本外科学会  

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Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: Recent advancements in systemic therapy for hepatocellular carcinoma (HCC) necessitate the establishment of resectability criteria for advanced HCC. METHODS: A questionnaire survey sought to clarify the perspectives of Japanese expert hepatobiliary surgeons regarding surgical indications for HCC. Thirty-one questions were used to determine when surgery is strongly recommended (resectable: R) or not recommended (unresectable: UR). RESULTS: A total of 351 responses were obtained. While 64.7% of the respondents considered solitary tumors as being R, irrespective of size, opinions diverged on the upper limit of the number of tumors/tumor size for R: (1) up to three nodules with no size limit (27.9%), (2) up to three nodules ≤5 cm in diameter each (21.4%) and (3) up to three nodules ≤3 cm in diameter each (19.4%). Vp1, Vp2, Vp3, and Vp4 were considered as being R by 90.9%, 70.7%, 39.0%, and 8.0% of respondents, respectively. Half of the respondents indicated they would consider resection even for cases with extrahepatic spread under limited conditions. CONCLUSIONS: The current views of Japanese expert surgeons on the resectability criteria for HCC were clarified for the first time. The findings could serve as a basis for preparing expert consensus statements on the resectability criteria for HCC.

DOI： 10.1002/jhbp.1408

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AIM: We explored institutional factors in Japan associated with lower operative mortality and failure-to-rescue (FTR) rates for eight major gastrointestinal procedures. METHODS: A 22-item online questionnaire was sent to 2119 institutional departments (IDs) to examine the association between institutional factors and operative mortality and FTR rates. IDs were classified according to the number of annual surgeries, board certification status, and locality. In addition, the top 20% and bottom 20% of IDs were identified based on FTR rates and matched with the results of the questionnaire survey. Factors associated with operative mortality were selected by multivariate analysis. RESULTS: Of the 1083 IDs that responded to the questionnaire, 568 (213 382 patients) were included in the analysis. Operative morbidity, operative mortality, and FTR rates in the top 20% and bottom 20% of IDs were 13.1% and 8.4% (p < 0.001), 0.52% and 4.3% (p < 0.001), and 4.0% and 51.2% (p < 0.001), respectively. Based on the patients' background characteristics, the top 20% of IDs handled more advanced cases. No significant difference in locality was seen between better or worse hospital FTR rates, but fewer esophagectomies, hepatectomies, and pancreatoduodenectomies were performed in depopulated areas. Six items were found to be associated with operative mortality by multivariate logistic analysis. Only 50 (8.8%) IDs met all five factors related to better FTR rates. CONCLUSIONS: The present findings indicate that several hospital factors surrounding surgical treatment, characterized by abundant human resources, are closely related to better postoperative recovery from severe complications.

DOI： 10.1002/ags3.12745

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AIM: Obstructive colon cancer is locally advanced colon cancer with poor prognosis. However, the effect of neoadjuvant chemotherapy (NAC) on obstructive colon cancer remains unclear. Therefore, this study aimed to investigate the safety and efficacy of NAC in patients with obstructive colon cancer. METHODS: From January 2012 to December 2017, we collected patient data for clinical stage II/III obstructive colon cancer at seven Yokohama Clinical Oncology Group (YCOG) institutions. The long-term outcomes of the NAC and non-NAC groups were analyzed retrospectively after adjusting for patients' background characteristics using propensity score matching. RESULTS: Among the 202 eligible patients, propensity score matching extracted 51 patients each for the NAC and non-NAC groups. After matching, the groups showed no marked differences in the background factors. All the patients in the NAC group underwent diverting stoma construction. Nineteen patients (37.3%) experienced grade 3-4 adverse events during NAC. The incidence of postoperative complications was similar between groups. The 5-year progression-free survival rates were 75.8% in the NAC group and 63.0% in the non-NAC group (p = 0.22, log-rank test). The 5-year overall survival rates were 88.5% in the NAC group and 78.8% in the non-NAC group (p = 0.09, log-rank test). CONCLUSION: Although NAC was feasible for obstructive colon cancer after diverting stoma construction, its effects on long-term outcomes could not be proven.

DOI： 10.1002/ags3.12736

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BACKGROUND: Immune checkpoint inhibitor (ICI) combinations represent an emerging treatment strategies in cancer. However, their efficacy in microsatellite stable (MSS) or mismatch repair-proficient (pMMR) colorectal cancer (CRC) is variable. Here, a multiomic characterization was performed to identify predictive biomarkers associated with patient response to ICI combinations in MSS/pMMR CRC for the further development of ICI combinations. METHODS: Whole-exome sequencing, RNA sequencing, and multiplex fluorescence immunohistochemistry of tumors from patients with MSS/pMMR CRC, who received regorafenib plus nivolumab (REGONIVO) or TAS-116 plus nivolumab (TASNIVO) in clinical trials were conducted. Twenty-two and 23 patients without prior ICI from the REGONIVO and TASNIVO trials were included in this study. A biomarker analysis was performed using samples from each of these studies. RESULTS: The epithelial-mesenchymal transition pathway and genes related to cancer-associated fibroblasts were upregulated in the REGONIVO responder group, and the G2M checkpoint pathway was upregulated in the TASNIVO responder group. The MYC pathway was upregulated in the REGONIVO non-responder group. Consensus molecular subtype 4 was significantly associated with response (p=0.035) and longer progression-free survival (p=0.006) in the REGONIVO trial. CD8+ T cells, regulatory T cells, and M2 macrophages density was significantly higher in the REGONIVO trial responders than in non-responders. Mutations in the POLE gene and patient response were significantly associated in the TASNIVO trial; however, the frequencies of other mutations or tumor mutational burden were not significantly different between responders and non-responders in either trial. CONCLUSIONS: We identified molecular features associated with the response to the REGONIVO and TASNIVO, particularly those related to tumor microenvironmental factors. These findings are likely to contribute to the development of biomarkers to predict treatment efficacy for MSS/pMMR CRC and future immunotherapy combinations for treatment.

DOI： 10.1136/jitc-2023-008210

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Language：Japanese   Publisher：日本臨床外科学会  

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AIM: We evaluated the safety of robotic surgery for right-sided colon cancer in Japan. METHODS: This was a prospective, open-label, single-arm phase II trial conducted at two institutions. Patients ≥20 years old with stage I-III right-sided colon cancer and scheduled for radical resection with ≥D2 lymph node dissection were eligible. The criterion for surgeons was experience performing robot-assisted rectal resection in ≥40 cases. The primary endpoint was the postoperative complication rate ≤30 days after surgery. RESULTS: From August 2021 to February 2023, 42 patients were enrolled; three were excluded, with 39 analyzed as the full analysis set. The median age was 72 years, and the median body mass index was 23.2. The tumor was located in the cecum in 13 cases (33.3%), ascending colon in 20 cases (51.3%), and transverse colon in six cases (15.4%). Ileocolic resection was performed in 17 cases (43.5%) and right hemicolectomy in 22 cases (56.5%), both with D3 lymph node dissection. The median console time was 109 min, and the operative time was 170 min. The mean blood loss was 7.7 mL. Intracorporeal anastomosis was performed in 28 patients (71.8%). There were no conversions and no intraoperative adverse events. The median postoperative stay was 5 days. Postoperative complications occurred in four patients (10.2%; paralytic ileus [n = 3] and pneumonia [n = 1]). All postoperative complications were grade 1 or 2, with no mortalities noted. R0 resection was achieved in all patients. CONCLUSIONS: This study demonstrated the safety and feasibility of robotic surgery for right-sided colon cancer.

DOI： 10.1002/ags3.12718

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Language：Japanese   Publisher：(公社)神奈川県医師会  

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Language：Japanese   Publisher：(公社)神奈川県医師会  

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OBJECTIVES: Hand-assisted laparoscopic surgery (HALS) combines the benefits of laparoscopic surgery with the tactile feedback from open surgery. In the current era of laparoscopic surgery, the significance of HALS as a technical transition has diminished. This study clarified the usefulness of HALS in restorative proctocolectomy (RPC) for ulcerative colitis (UC) in the era of laparoscopic surgery. METHODS: The 212 patients who underwent RPC with ileal pouch-anal anastomosis between 2007 and 2023 were included in this study. The patients were divided into three groups, open surgery (OS), HALS, and conventional laparoscopic surgery (LAP), and their characteristics, surgical outcomes, surgical complications, and functional outcomes were compared. RESULTS: The number of surgical techniques was OS in 21 cases, HALS in 184 cases, and LAP in 7 cases. The number of surgeons was two for OS and HALS, and four for LAP, with OS and HALS having fewer surgeons than LAP. The length of the skin incision was 13, 7, and 3 cm for OS, HALS, and LAP, respectively, and the operation times was 250, 286, and 576 minutes for OS, HALS, and LAP, respectively, with LAP having the longest operation time. The postoperative complications and function did not differ markedly among the three groups. CONCLUSIONS: In RPC for UC, HALS involved fewer surgeons and a shorter operative time than LAP. Even in the era of laparoscopic surgery, HALS remains a useful option, especially when a shorter operation time is required or when the number of available surgeons is insufficient.

DOI： 10.23922/jarc.2024-024

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BACKGROUND: The risk and prognosis of pancreatobiliary cancer and in patients with autoimmune pancreatitis (AIP) and IgG4-related sclerosing cholangitis (IgG4-SC) remain unclear. Therefore, we retrospectively investigated the risk of pancreatobiliary cancer and prognosis in patients with AIP and IgG4-SC. METHODS: Patients with AIP and IgG4-SC at seven centers between 1998 and 2022 were investigated. The following data were evaluated: (1) the number of cancers diagnosed and standardized incidence ratio (SIR) for pancreatobiliary and other cancers during the observational period and (2) prognosis after diagnosis of AIP and IgG4-SC using standardized mortality ratio (SMR). RESULTS: This study included 201 patients with AIP and IgG4-SC. The mean follow-up period was 5.7 years. Seven cases of pancreatic cancer were diagnosed, and the SIR was 8.11 (95% confidence interval [CI]: 7.29-9.13). Three cases of bile duct cancer were diagnosed, and the SIR was 6.89 (95% CI: 6.20-7.75). The SMR after the diagnosis of AIP and IgG4-SC in cases that developed pancreatobiliary cancer were 4.03 (95% CI: 2.83-6.99). CONCLUSIONS: Patients with autoimmune pancreatitis and IgG4-SC were associated with a high risk of pancreatic and bile duct cancer. Patients with AIP and IgG4-SC have a worse prognosis when they develop pancreatobiliary cancer.

DOI： 10.1002/jhbp.1404

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BACKGROUND AND AIMS: Fully covered self-expandable metallic stents (SEMS) are laser-cut (L) or braided (B); however, which is more effective for distal malignant biliary obstruction (DMBO) has been unclear. We compared the clinical outcomes of using L- type and B-type stents because we believe that recurrent biliary obstruction (RBO) is less likely to occur with L-type stents. METHODS: Patients diagnosed with unresectable DMBO were randomly assigned to groups L and B in a stratified block fashion, and outcomes were compared. The primary outcome was the rate of RBO within 1 year; secondary outcomes were adverse events, clinical success rate, time to RBO (TRBO), and overall survival. RESULTS: Of the 60 enrolled participants, 56 (group L: 27, group B: 29) were included. The rates of RBO within 1 year were 44.4% and 17.2% in groups L and B, respectively (odds ratio 2.57 [95% confidence interval {CI}: 1.045-6.353]). Early adverse events, which improved with conservative treatment, included pancreatitis (n=4) in group L and pancreatitis (n=3) and cholecystitis (n=1) in group B (p=0.913). The median TRBO (220 days [95% CI: 56-272] versus 418 days [95% CI: 232-454]) was significantly longer in group B than in group L (log-rank test, p=0.0118). The median overall survival (L: 158 days, B: 204 days) after stenting was not significantly different between the groups (p=0.8544). CONCLUSIONS: In the setting of DMBO, braided (B)-type stents are associated with less recurrent obstruction than laser-cut-type (L) stents, although there was no difference in safety.

DOI： 10.1016/j.gie.2023.11.057

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Publishing type：Research paper (scientific journal)   Publisher：Elmer Press, Inc.  

DOI： 10.14740/wjon1694

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Purpose: The present study aimed to determine whether concomitant extrahepatic bile duct resection (EHBDR) improves the prognosis of patients with T2 gallbladder cancer (GBC). Methods: Between 2014 and 2018, 4947 patients with GBC were registered in the National Biliary Tract Cancer Registry in Japan. This included 3804 patients (76.9%) who underwent curative-intent surgical resection; 1609 of these patients had pT2 GBC with no distant metastasis. Of the 1609 patients with GBC, 520 underwent EHBDR and 1089 did not. We compared the patients' backgrounds and disease-specific survival rates between the groups. Results: The frequency of lymph node metastasis was significantly higher in the EHBDR group than in the non-EHBDR group (38.2% vs. 20.7%, p <.001). In the entire cohort, however, there was no significant difference in disease-specific survival between the two groups (76% vs. 79%, p =.410). The EHBDR group had a significantly higher incidence of postoperative complications (Clavien–Dindo classification grade = 3) (32.4% vs. 11.7%, p <.001). When we focused on the survival of only T2N1 patients who underwent gallbladder bed resection, the prognosis was significantly improved for the EHBDR group (5-year survival rate: 64% vs. 54%, p =.017). The non-EHBDR group was subcategorized into two groups: D2 dissection and D1 dissection or sampling, and survival curves were compared between these subgroups. Although the EHBDR group tended to have a favorable prognosis compared to the D2 group, this difference was not significant (p =.167). However, the EHBDR group had a significantly greater prognosis than the D1 dissection or sampling group (5 year-survival rate: 64 vs. 49%, p =.027). Conclusions: The EHBDR may improve the prognosis of patients with T2 gall bladder cancer with lymph node metastases; however, its indication should be carefully determined because of the increased risk of postoperative complications.

DOI： 10.1002/jhbp.1379

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BACKGROUND/AIM: Ramucirumab plus paclitaxel has been widely used as a second-line chemotherapy for treating advanced gastric cancer. However, the real-world data of this regimen for older patients with gastric cancer (GC) remains unrevealed. The aim of this study was to clarify the feasibility and efficacy of this regimen for older patients with GC in a single-arm, phase II study. PATIENTS AND METHODS: Patients aged ≥70 years having unresectable or recurrent GC who met the eligible criteria were enrolled. Paclitaxel was administered at a dose of 80 mg/m2 on days 1, 8, and 15, and ramucirumab was administered at a dose of 8 mg/kg on day 1 and day 15 of a 4-week cycle. Primary endpoint was the incidence of adverse events and secondary endpoints were response rate, progression-free survival, and overall survival. A total of 25 patients were enrolled in the full-set analysis. RESULTS: Grade 3 or more adverse events were observed in 21 patients (84.0%). Neutropenia was most frequently observed (68.0%), followed by peripheral sensory neuropathy (12.0%), and febrile neutropenia (12.0%). Median progression-free survival and overall survival were 6.9 months and 13.4 months, respectively. Disease control rate was 88.0%, and response rate of patients with measurable lesions was 52.9%. Notably, no treatment-related deaths occurred. CONCLUSION: Ramucirumab plus paclitaxel as a second-line chemotherapy demonstrated acceptable oncological outcomes, despite the occurrence of frequent adverse events. It is necessary to carefully select patients and adjust treatment regimens in older patients with GC to safely administer chemotherapy and subsequently achieve satisfactory long-term outcomes.

DOI： 10.21873/anticanres.16771

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Publishing type：Research paper (scientific journal)   Publisher：Elmer Press, Inc.  

DOI： 10.14740/wjon1691

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Language：Japanese   Publisher：(一社)日本内視鏡外科学会  

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Language：Japanese   Publisher：(一社)日本内視鏡外科学会  

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BACKGROUND/PURPOSE: There is currently no consensus on the use of endoscopic papillectomy (EP) for early stage duodenal ampullary adenocarcinoma. This study aimed to evaluate the feasibility of EP for patients with early stage duodenal ampullary adenocarcinoma. METHODS: Patients who underwent EP for ampullary adenocarcinomas were investigated. Complete and clinical complete resection rates were evaluated. Clinical complete resection was defined as either complete resection or resection with positive or unknown margins but no cancer in the surgically resected specimen, or no recurrence on endoscopy after at least a 1-year follow-up. RESULTS: Adenocarcinoma developed in 30 patients (carcinoma in situ [Tis]: 21, mucosal tumors [T1a(M)]: 4, tumors in the sphincter of Oddi [T1a(OD)]: 5). The complete resection rate was 60.0% (18/30) (Tis: 66.7% [14/21], T1a[M]: 50.0% [2/4], and T1a[OD]: 40.0% [2/5]). The mean follow-up period was 46.8 months. The recurrence rate for all patients was 6.7% (2/30). The clinical complete resection rates of adenocarcinoma were 89.2% (25/28); rates for Tis, T1a(M), and T1a(OD) were 89.4% (17/19), 100% (4/4), and 80% (4/5), respectively. CONCLUSIONS: EP may potentially achieve clinical complete resection of early stage (Tis and T1a) duodenal ampullary adenocarcinomas.

DOI： 10.1002/jhbp.1398

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Language：Japanese   Publisher：(一社)日本消化器外科学会  

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Language：Japanese   Publisher：(一社)日本消化器外科学会  

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Language：Japanese   Publisher：(一社)日本消化器外科学会  

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Language：Japanese   Publisher：(一社)日本消化器外科学会  

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OBJECTIVE: To investigate the clinical relevance of intratumoral tumor infiltrating lymphocytes (TILs) in breast cancer as measured by computational deconvolution of bulk tumor transcriptomes. SUMMARY BACKGROUND DATA: Commonly assessed TILs, located in tumor stroma without direct contact with cancer cells (stromal TILs), correlate with breast cancer treatment response and survival. The clinical relevance of intratumoral TILs has been less studied partly due to their rarity; however, they may have nonnegligible effects given their direct contact with cancer cells. METHODS: In all, 5870 breast cancer patients from TCGA, METABRIC, GSE96058, GSE25066, GSE163882, GSE123845, and GSE20271 cohorts were analyzed and validated. RESULTS: The intratumoral TIL score was established by the sum of all types of lymphocytes using the xCell algorithm. This score was the highest in triple-negative breast cancer (TNBC) and the lowest in the ER-positive/HER2-negative subtype. It correlated with cytolytic activity and infiltrations of dendritic cells, macrophages, and monocytes, and uniformly enriched immune-related gene sets regardless of subtype. Intratumoral TIL-high tumors correlated with higher mutation rates and significant cell proliferation on biological, pathological, and molecular analyses only in the ER-positive/HER2-negative subtype. It was significantly associated with pathological complete response after anthracycline- and taxane-based neoadjuvant chemotherapy in about half of the cohorts, regardless of the subtype. Intratumoral TIL-high tumors correlated with better overall survival in HER2-positive and TNBC subtypes consistently in 3 cohorts. CONCLUSIONS: Intratumoral TILs estimated by transcriptome computation were associated with increased immune response and cell proliferation in ER-positive/HER2-negative and better survival in HER2-positive and TNBC subtypes, but not always with pathological complete response after neoadjuvant chemotherapy.

DOI： 10.1097/SLA.0000000000005954

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Language：Japanese   Publisher：日本臨床外科学会  

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Language：Japanese   Publisher：(公社)日本生化学会  

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BACKGROUND: The aim of this study was to analyze the nationwide surgical outcome of a left trisectionectomy (LT) and to identify the perioperative risk factors associated with its morbidity. METHODS: Cases of LT for hepato-biliary malignancies registered at the Japanese National Clinical Database between 2013 and 2019 were retrospectively reviewed. Statistical analyses were performed to identify the perioperative risk factors associated with a morbidity of Clavien-Dindo classification (CD) ≥III. RESULTS: Left trisectionectomy was performed on 473 and 238 cases of biliary and nonbiliary cancers, respectively. Morbidity of CD ≥III and V occurred in 45% and 5% of cases with biliary cancer, respectively, compared with 26% and 2% of cases with nonbiliary cancer, respectively. In multivariable analyses, biliary cancer was significantly associated with a morbidity of CD ≥III (odds ratio, 1.87; p = .018). In subgroup analyses for biliary cancer, classification of American Society of Anesthesiologists physical status (ASA-PS) 2, portal vein resection (PVR), and intraoperative blood loss ≥30 mL/kg were significantly associated with a morbidity of CD ≥III. CONCLUSIONS: Biliary cancer induces severe morbidity after LT. The ASA-PS classification, PVR, and intraoperative blood loss indicate severe morbidity after LT for biliary cancer.

DOI： 10.1002/jhbp.1358

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DOI： 10.1093/bjs/znad263

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BACKGROUND: We previously reported an association between antithrombotic therapy and an increased risk of postpancreatectomy hemorrhage (PPH). To validate our findings, we conducted a large-scale multicenter retrospective study from 63 high-volume centers in Japan. METHODS: Between 2015 and 2018, 7116 patients who underwent pancreatectomy were enrolled. The antithrombotic group consisted of 920 patients (12.9%) who received preoperative antithrombotic agents including aspirin, clopidogrel, ticlopidine, prasugrel, warfarin, and direct oral anticoagulants. RESULTS: PPH occurred in 235 (3.3%) of the patients. The incidence of PPH and mortality were significantly higher in the antithrombotic group than in the control group (5.7 vs. 3.0% and 2.2 vs. 0.9%, respectively; both p < .001). In multivariate analysis, a history of antithrombotic use was an independent risk factor for grade C PPH (p = .036). In the antithrombotic group, PPH tended to be delayed in the patients with restarting antithrombotic therapy. Notably, the occurrence of delayed PPH after restarting antithrombotic therapy was observed only when antithrombotic therapy was restarted within 10 days after pancreatectomy. CONCLUSIONS: This multicenter study demonstrated that a history of antithrombotic use was a significant risk factor for PPH and mortality. In particular, the resumption of antithrombotic therapy in the early postoperative period should be done with caution.

DOI： 10.1002/jhbp.1349

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BACKGROUND/PURPOSE: Little is known about the features of T1 pancreatic ductal adenocarcinoma (PDAC) and its definition in the eighth edition of the American Joint Committee on Cancer (AJCC) staging system needs validation. The aims were to analyze the clinicopathologic features of T1 PDAC and investigate the validity of its definition. METHOD: Data from 1506 patients with confirmed T1 PDAC between 2000 and 2019 were collected and analyzed. The results were validated using 3092 T1 PDAC patients from the Surveillance, Epidemiology, and End Results (SEER) database. RESULTS: The median survival duration of patients was 50 months, and the 5-year survival rate was 45.1%. R0 resection was unachievable in 10.0% of patients, the nodal metastasis rate was 40.0%, and recurrence occurred in 55.2%. The current T1 subcategorization was not feasible for PDAC, tumors with extrapancreatic extension (72.8%) had worse outcomes than those without extrapancreatic extension (median survival 107 vs. 39 months, p < .001). Extrapancreatic extension was an independent prognostic factor whereas the current T1 subcategorization was not. The results of this study were reproducible with data from the SEER database. CONCLUSION: Despite its small size, T1 PDAC displayed aggressive behavior warranting active local and systemic treatment. The subcategorization by the eighth edition of the AJCC staging system was not adequate for PDAC, and better subcategorization methods need to be explored. In addition, the role of extrapancreatic extension in the staging system should be reconsidered.

DOI： 10.1002/jhbp.1316

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The Japanese Society of Gastroenterology first published evidence-based clinical practice guidelines for cholelithiasis in 2010, followed by a revision in 2016. Currently, the revised third edition was published to reflect recent evidence on the diagnosis, treatment, and prognosis of cholelithiasis conforming to the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system. Following this revision, the present English version of the guidelines was updated and published herein. The clinical questions (CQ) in the previous version were reviewed and rearranged into three newly divided categories: background questions (BQ) dealing with basic background knowledge, CQ, and future research questions (FRQ), which refer to issues that require further accumulation of evidence. Finally, 52 questions (29 BQs, 19 CQs, and 4 FRQs) were adopted to cover the epidemiology, pathogenesis, diagnosis, treatment, complications, and prognosis. Based on a literature search using MEDLINE, Cochrane Library, and Igaku Chuo Zasshi databases for the period between 1983 and August 2019, along with a manual search of new information reported over the past 5 years, the level of evidence was evaluated for each CQ. The strengths of recommendations were determined using the Delphi method by the committee members considering the body of evidence, including benefits and harms, patient preference, and cost-benefit balance. A comprehensive flowchart was prepared for the diagnosis and treatment of gallbladder stones, common bile duct stones, and intrahepatic stones, respectively. The current revised guidelines are expected to be of great assistance to gastroenterologists and general physicians in making decisions on contemporary clinical management for cholelithiasis patients.

DOI： 10.1007/s00535-023-02014-6

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Language：Japanese   Publisher：(一社)日本大腸肛門病学会  

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Publishing type：Research paper (scientific journal)   Publisher：Frontiers Media SA  

Sequencing-based interrogation of gut microbiota is a valuable approach for detecting microbes associated with colorectal cancer (CRC); however, such studies are often confounded by the effect of bowel preparation. In this study, we evaluated the viability of identifying CRC-associated mucosal bacteria through centimeter-scale profiling of the microbiota in tumors and adjacent noncancerous tissue from eleven patients who underwent colonic resection without preoperative bowel preparation. High-throughput 16S rRNA gene sequencing revealed that differences between on- and off-tumor microbiota varied considerably among patients. For some patients, phylotypes affiliated with genera previously implicated in colorectal carcinogenesis, as well as genera with less well-understood roles in CRC, were enriched in tumor tissue, whereas for other patients, on- and off-tumor microbiota were very similar. Notably, the enrichment of phylotypes in tumor-associated mucosa was highly localized and no longer apparent even a few centimeters away from the tumor. Through short-term liquid culturing and metagenomics, we further generated more than one-hundred metagenome-assembled genomes, several representing bacteria that were enriched in on-tumor samples. This is one of the first studies to analyze largely unperturbed mucosal microbiota in tissue samples from the resected colons of unprepped CRC patients. Future studies with larger cohorts are expected to clarify the causes and consequences of the observed variability in the emergence of tumor-localized microbiota among patients.

DOI： 10.3389/fcimb.2023.1216024

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BACKGROUND: A score derived from the concentrations of α-fetoprotein (AFP) and des-γ-carboxy prothrombin (DCP) and tumor volume (TV), called ADV score, has been shown to be prognostic of hepatocellular carcinoma (HCC) recurrence following hepatic resection (HR) or liver transplantation. METHODS: This multicenter, multinational validation study included 9200 patients who underwent HR from 2010 to 2017 at 10 Korean and 73 Japanese centers, and were followed up until 2020. RESULTS: AFP, DCP, and TV showed weak correlations (ρ ≤ .463, r ≤ .189, p < .001). Disease-free survival (DFS), overall survival (OS), and post-recurrence survival rates were dependent on 1.0 log and 2.0 log intervals of ADV scores (p < .001). Receiver operating characteristic (ROC) curve analysis showed that ADV score cutoffs of 5.0 log for DFS and OS yielded the areas under the curve ≥ .577, with both being significantly prognostic of tumor recurrence and patient mortality at 3 years. ADV score cutoffs of ADV 4.0 log and 8.0 log, derived through K-adaptive partitioning method, showed higher prognostic contrasts in DFS and OS. ROC curve analysis showed that an ADV score cutoff of 4.2 log was suggestive of microvascular invasion, with both microvascular invasion and an ADV score cutoff of 4.2 log showing similar DFS rates. CONCLUSIONS: This international validation study demonstrated that ADV score is an integrated surrogate biomarker for post-resection prognosis of HCC. Prognostic prediction using ADV score can provide reliable information that can assist in planning treatment of patients with different stages of HCC and guide individualized post-resection follow-up based on the relative risk of HCC recurrence.

DOI： 10.1002/jhbp.1319

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Language：Japanese   Publisher：(一社)日本胆道学会  

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Since the popularization of cancer screening and an improvement in treatment over the last two decades, multiple primary malignant neoplasms (MPMNs) have been increasingly reported. We report a patient who developed metachronous MPMNs in the breast, the endometrium, and the pancreas over a period of 13 years. A 42-year-old woman was first diagnosed with breast cancer and underwent breast-conserving surgery with adjuvant radiation therapy and endocrine therapy. Four years after breast surgery, she was diagnosed with endometrial cancer and underwent a laparoscopic modified radical hysterectomy with bilateral oophorectomy with pelvic lymph node dissection followed by adjuvant chemotherapy. However, there was peritoneal dissemination of endometrial cancer 1 year after surgery, which could be removed laparoscopically followed by adjuvant chemotherapy. Ten years after breast cancer surgery, pleural metastasis of breast cancer was diagnosed and treated by endocrine therapy. Thirteen years after breast cancer surgery, a pancreatic tumor with multiple liver masses emerged. It was difficult to diagnose whether primary or metastasis cancer by the results of the pathological analysis. Finally, we diagnosed primary pancreatic cancer with liver metastasis by clinical examination with the BRCA2-pathogenic variant. These tumors were well responded to chemotherapy and the patient survived during a follow-up period of 8 months. According to MPMNs, breast cancer patients should be followed-up carefully for the possibility of BRCA pathogenic variant and development of different primary malignant neoplasms.

DOI： 10.14740/wjon1658

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Language：Japanese   Publisher：(一社)日本胆道学会  

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BACKGROUND: Colorectal cancer liver metastasis (CCLM) is the most frequent cause of death of colorectal cancer. Development of novel new effective therapy is needed for CCLM patients to improve outcome. The aim of the present study was to investigate the efficacy of recombinant methioninase (rMETase) on a CCLM orthotopic mouse model of liver metastasis established using the human colon cancer cell line HT29 expressing red fluorescent protein (RFP). MATERIALS AND METHODS: Orthotopic CCLM nude mouse models were randomized into two groups: control group (n = 6, PBS 200 µl, i.p., daily); rMETase group (n = 6, 100 units/200 µl, i.p., daily). Tumor volume was measured on day 0 and day 15. Body weight was measured twice a week. All mice were sacrificed on day 15. RESULTS: rMETase significantly inhibited the increase of the liver metastasis as determined by RFP fluorescence area and intensity (p = 0.016 and 0.015, respectively). There was no significant difference of body weight between either group on any day. CONCLUSIONS: The present study suggests that rMETase has future potential therapy for CCLM in the clinic.

DOI： 10.1016/j.tice.2023.102125

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It is well established that genetic information differs amongst the adolescent and young adult population (AYA) and older patients. Although several studies on genetic information have been conducted, no current prognostic biomarker exists to help differentiate survival outcomes amongst AYA patients. The GALNT family of genes have been associated with several cancer etiologies, such as the Tn antigen and epithelial-mesenchymal transition (EMT); however, the clinical significance of GALNT1 expression in breast cancer (BC) remains unclear. We investigated the clinical relevance of GALNT1 expression in BC using two large independent cohorts. We found that, although triple-negative BC (TNBC) had the highest GALNT1 expression compared to ER-positive/HER2-negative BC, GALNT1 levels in BC were not associated with clinical aggressiveness, including histological grade, AJCC stage and N-category, and patient survival, consistently in both the METABRIC and GSE96058 cohorts. There was also no biological difference between low- and high-GALNT1 expression BC, as analyzed by hallmark gene sets via gene set enrichment analysis (GSEA). Further, no significant difference was found in GALNT1 expression levels among AYAs and older patients. However, high GALNT1 expression was associated with significantly worse survival in AYA patients, in both cohorts. Furthermore, high GALNT1 expression was found to be an independent factor among several clinical features, including subtype, histological grade, AJCC T and N-category, in AYA patients. In both cohorts, BC with high GALNT1 expression demonstrated low levels of CD8+ T-cell infiltration, but not other anti-cancerous or pro-cancerous immune cells. Finally, high levels of GALNT1 BC demonstrated increased EMT, angiogenesis, and protein secretion in the AYA population, but not in older patients. In conclusion, our findings demonstrate that GALNT1 expression was found to be associated with angiogenesis and EMT, and may have potential as prognostic biomarker, specifically in AYA patients.

DOI： 10.3390/cancers15133489

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BACKGROUND: Although previous studies have noted the potential benefit of early drain removal (EDR) after pancreatoduodenectomy (PD), there is a paucity of data on the timing of drain removal utilizing a national database that reflect the "real world" setting. Given the ongoing controversy related to PD drain use and management, we sought to define trends in drain use among a large national cohort, as well as identify factors associated with EDR following PD. METHODS: The ACS NSQIP targeted pancreatectomy database was used to identify patients who underwent PD between 2014 and 2020. The trend in proportion of patients with EDR (removal ≤ POD3) as well as predictors of EDR were assessed. Risk-adjusted postoperative outcomes were evaluated by multivariable regression analysis. RESULTS: Among 14,356 patients, 16.2% of patients (N = 2324) experienced EDR, and the proportion of patients with EDR increased by 68% over the study period (2014: 10.9% vs. 2020: 18.3%, p < 0.001). Higher drain fluid amylase on POD1-3 [LogWorth (LW) = 44.3], operative time (LW = 33.2), and use of minimally invasive surgery (LW = 14.0) were associated with EDR. Additionally, EDR was associated with decreased risk of overall and serious morbidity, PD-related morbidity (e.g., pancreatic fistula), reoperation, prolonged length of stay and readmission (all p < 0.05). CONCLUSIONS: Routine drain placement remains a common practice among most surgeons. EDR following PD increased over time was associated with lower post-operative complications and shorter LOS. Despite evidence that EDR was safe and may even be associated with lower complications, only 1 in 6 patients were managed with EDR.

DOI： 10.1007/s00268-023-06966-x

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BACKGROUND: Centralization of complex surgeries has made little progress when it only considers the minimum number of surgical procedures. We aim to assess the impact of certification system of Japanese Society of Hepato-Biliary-Pancreatic Surgery (JSHBPS) on centralization and surgical quality of advanced hepato-pancreatic-biliary (HPB) surgery. METHODS: The National Clinical Database was used to review 20 111 patients who underwent pancreatoduodenectomy (PD) and 9666 who underwent advanced hepatectomy defined as hepatectomy of more than one section during 2019 and 2020. JSHPBS certifies hospitals based on the annual number of advanced HPB surgeries and the surgical quality. Minimum numbers of surgeries for board-certified A and B institutions are 50 and 30, respectively. Short-term outcomes were compared among institutions. RESULTS: In 2020, 69.4% (7007/10090) and 72.9% (3433/4710) of patients underwent PD and advanced hepatectomy at board-certified institutions. In-hospital mortality rates after PD was 0.9% at certified A institutions, 1.4% at B institutions, and 2.7% at non-certified institutions (p < .001). The odds ratio (OR) of risk-adjusted mortality after PD compared with non-certified institutions was 0.39 (confidence interval [CI]: 0.30-0.50, p < .001) at certified A institutions, and 0.54 at certified B institutions (CI: 0.40-0.73, p < .001). In-hospital mortality rates after advanced hepatectomy was 1.7% at certified A institutions, 2.3% at B institutions, and 3.2% at non-certified institutions (p < .001). The OR of risk-adjusted mortality after advanced hepatectomy compared with non-certified institutions was 0.57 at certified A institutions (CI: 0.41-0.78, p < .001). CONCLUSION: The volume- and quality-controlled certification system of JSHBPS reduces surgical mortality after advanced HPB surgeries.

DOI： 10.1002/jhbp.1307

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Language：Japanese   Publisher：(一社)日本消化器外科学会  

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Publishing type：Research paper (scientific journal)   Publisher：Wiley  

DOI： 10.1002/ccr3.7537

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BACKGROUND: The role of recurrence-free survival (RFS) as a valid surrogate endpoint for overall survival (OS) in patients who underwent upfront surgery for colorectal liver metastases remains uncertain. The aim of the study was to compare the two survival measures in a nationwide cohort of upfront resected colorectal liver metastasis. METHODS: Data from patients with colorectal liver metastases without extrahepatic metastases who underwent curative surgery for liver metastases were retrieved from the Japanese nationwide database (data collection 2005-2007 and 2013-2014). RFS, OS, and survival after recurrence were estimated using the Kaplan-Meier method. The correlation (ρ) between RFS and OS was assessed using the rank correlation method combined with iterative multiple imputation, to account for censoring. As a secondary analysis, the correlation was evaluated according to adjuvant chemotherapy regimen. In sensitivity analysis, the pairwise correlation between RFS and OS was calculated. RESULTS: A total of 2385 patients with colorectal liver metastases were included. In the primary analysis, there was a moderately strong correlation between RFS and OS (ρ = 0.73, 95 per cent c.i. 0.70 to 0.76). The strength of the correlation was similar regardless of the adjuvant treatment regimen (oxaliplatin plus 5-fluorouracil: ρ = 0.72, 0.67 to 0.77; 5-fluorouracil alone: ρ = 0.72, 0.66 to 0.76; observation: ρ = 0.74, 0.69 to 0.78). The mean(s.d.) pairwise correlation coefficient between 3-year RFS and 5-year OS was 0.87(0.06). CONCLUSION: In surgically treated patients with colorectal liver metastases, there was a moderately strong correlation between RFS and OS, which was unaffected by the treatment regimen. Further validation using a trial-level analysis is required.

DOI： 10.1093/bjs/znad127

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BACKGROUND/AIM: In the previous phase I/II study, we established neoadjuvant chemotherapy (NAC) using bi-weekly docetaxel, cisplatin, and S-1 (DCS) for clinical stage III gastric cancer. This study aimed to clarify long-term outcomes of this treatment. PATIENTS AND METHODS: Relapse-free survival (RFS) and overall survival (OS) were calculated by the Kaplan-Meier method and prognostic factors for RFS and OS were identified by univariate analysis. RESULTS: A total of 47 patients with clinical stage III gastric cancer were enrolled in this study. The 5-year RFS and OS rates were 69.8% and 74.3%, respectively, in all registered patients. Moreover, the 5-year OS and RFS rates in patients receiving R0 gastrectomy were 68.0% and 79.4%, respectively. Neutrophil-lymphocyte ratio (NLR) before NAC ≥2.41, prognostic nutritional index (PNI) before NAC ≤50.4, Glasgow prognostic score before NAC classification 2, NLR after NAC ≥1.43, PNI after NAC <48.0, and Grade 1a/1b pathological response significantly worsened RFS. NLR after NAC ≥1.43, PNI before NAC ≤50.4, NLR after NAC ≥1.43, and body weight loss >5 kg after NAC significantly worsened OS. CONCLUSION: Although bi-weekly DCS therapy as neoadjuvant setting showed acceptable long-term outcomes, poor immune-nutritional status before and after NAC caused worse long-term survival in stage III gastric cancer patients. It is warranted to conduct a well-designed prospective randomized control study to compare long-term outcomes using the bi-weekly DCS regimen between patients with and without immune-nutritional support during peri-NAC.

DOI： 10.21873/anticanres.16453

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Language：Japanese   Publisher：医学図書出版(株)  

胆道癌における遠隔転移はStage IVに分類され,たとえそれが限局,少数個の転移であっても積極的な切除の対象とされてこなかった。実際これまでのStage IV胆道癌の切除成績は現在行われている胆道癌化学療法の治療効果と同等であり,あえて高侵襲の胆道癌外科切除を選択するメリットは全くなかったと言える。一方で近年,乳癌などの領域では少数の遠隔転移の切除成績が良好であることから"oligometastases"という概念が広まり,乳癌を含めた一部の癌腫領域では少数の遠隔転移であれば切除が行われている。今回教室で経験した胆道癌遠隔転移症例の切除例について検討すると,1臓器5個以内のいわゆるoligometastases状態であっても一期的に転移巣と原発巣を切除した症例の予後は非常に不良であった。一方,down staging chemotherapyを行いconversion surgeryが施行できた症例の予後は良好であり,現時点で胆道癌の少数遠隔転移に対する切除術はdown staging chemotherapyを前提とすれば,その意義は高いと思われる。一方oligometastases状態は原発巣の癌悪性度の表現型とも言われており,実際には数だけで規定できるものではない。悪性度の高い胆道癌でoligometastases状態を定義するためには原発巣の病理学的因子や転移巣の数だけでなく,より癌の性質を特定するバイオマーカーの探索が必要である。(著者抄録)

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Language：Japanese   Publisher：日本外科系連合学会  

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Language：Japanese   Publisher：日本外科系連合学会  

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To improve treatment outcomes in patients with colorectal liver metastasis (CRLM), the Joint Committee for Nationwide Survey on CRLM was established by the Japanese Society for Cancer of the Colon and Rectum and the Japanese Society of Hepato-Biliary-Pancreatic Surgery. The aim of the study was to evaluate transition in the characteristics and treatment strategy in CRLM patients and analyze prognostic factors using large-scale data. The present study summarizes the data of patients newly diagnosed between 2015 and 2017 and presents prognostic data of patients newly diagnosed in 2013 and 2014. Survival curves were generated by the Kaplan-Meier method and compared by log-rank test. Multivariate analyses were carried out using Cox proportional hazard modeling. The data of 4502 patients newly diagnosed with CRLM between 2015 and 2017 and the prognostic data of 2427 patients diagnosed in 2013 and 2014 are included. Regarding the 2013 and 2014 prognostic data, the 5-year overall survival (OS) rates of patients who underwent hepatectomy alone was 59.8%. Multivariate analyses identified age at diagnosis of CRLM ≥70 years, concomitant extrahepatic metastasis at diagnosis of CRLM, tumor depth of primary lesion ≥subserosa/pericolic or perirectal tissue, mutant KRAS status, number of CRLM ≥5, maximum diameter of CRLM >5 cm, and surgical curability R1/R2 as independent predictors of OS. Analysis of the latest nationwide database of patients diagnosed with CRLM revealed changes in patients and oncological characteristics, a transition in treatment strategy, and different independent prognosticators to those reported previously.

DOI： 10.1002/jhbp.1252

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Language：Japanese   Publisher：日本外科系連合学会  

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Language：Japanese   Publisher：日本外科系連合学会  

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Publishing type：Research paper (scientific journal)   Publisher：Wiley  

Abstract

Introduction

Conventionally, the recommended duration of adjuvant chemotherapy of colon cancer had been 6 months. The IDEA Collaboration suggested that shortening capecitabin and oxaliplatin (CAPOX) adjuvant chemotherapy may be possible. S‐1 and oxaliplatin (SOX) treatment is standard treatment in metastatic colorectal cancer in Japan. The aim of this study was to optimize treatment dosage and duration of adjuvant SOX in stage III colon cancer.

Methods

This trial was as open‐label multi‐center randomized phase II study. Patients with stage III colon cancer were randomly assigned to 3 months or 6 months of adjuvant SOX treatment in different doses: 130 mg/m² (3 months) or 100 mg/m² (6 months) of oxaliplatin. The primary endpoint was 3‐year disease‐free survival (DFS) and the null hypothesis for the primary endpoint was that the 3‐year DFS was ≤72% in each arm and was tested with a one‐sided significance level of 10%.

Results

Eighty‐two patients were assigned to the 6 months arm and 81 to the 3 months arm. The 3‐year DFS was 75.0% (80% CI 67.95–80.72, p = 0.282) in the 6 months arm and 76.9% (80% CI 70.1–82.38, p = 0.171) in the 3 months arm. Treatment completion rate and relative dose intensity (RDI) were higher in 3 months than 6 months arm. The adverse events (AE) were similar in both arms.

Conclusions

The 3‐year DFS was not significantly superior to null hypothesis in both 3 months and 6 months arms for the stage III colon cancer. Primary endpoint was not achieved. The SOX regimen was not feasible in long‐term outcomes.

DOI： 10.1002/ags3.12687

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Background: Although surgery is the mainstay of curative-intent treatment for extrahepatic biliary tract cancer (EBTC), recurrence following surgery can be high and prognosis poor. The impact of neoadjuvant therapy (NAT) relative to upfront surgery (US) among patients with EBTC remains unclear. Methods: The Surveillance, Epidemiology, and End Results (SEER) databases was utilized to identify patients who underwent surgery from 2006 to 2017 for EBTC, including gallbladder cancer (GBC) and extrahepatic cholangiocarcinoma (ECC). Trends in NAT utilization were investigated, and the impact of NAT on prognosis was compared with US using a propensity score-matched (PSM) analysis. Results: Among 6582 EBTC patients (GBC, n = 4467, ECC, n = 2215), 1.6% received NAT; the utilization of NAT for EBTC increased over time (Ptrend = 0.03). Among patients with lymph node metastasis, the lymph node ratio was lower among patients with NAT (0.18 vs. 0.40, p < 0.01). After PSM, there was no difference in overall survival (OS) and cancer-specific survival (CSS) among patients treated with NAT versus US (5-year OS: 24.0% vs. 24.6%, p = 0.14, 5-year CSS: 38.0% vs. 36.1%, p = 0.21). A subgroup analysis revealed that NAT was associated with improved OS and CSS among patients with stages III-IVA of the disease (OS: HR 0.65, 95%CI 0.46-0.92, p = 0.02, CSS: HR 0.62, 95%CI 0.41-0.92, p = 0.01). Conclusions: While NAT did not provide an overall benefit to patients undergoing surgery for EBTC, individuals with advanced-stage disease had improved OS and CSS with NAT. An individualized approach to NAT use among patients with EBTC may provide a survival benefit.

DOI： 10.3390/jcm12072654

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Language：Japanese   Publisher：(一社)日本外科学会  

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Language：Japanese   Publisher：医学図書出版(株)  

膵癌の随伴徴候である耐糖能低下,凝固能亢進を惹起する因子について述べる。糖尿病は膵癌のリスクファクターとして広く知られているが,新規発症の糖尿病の膵癌に対する相対的リスクの高さや,膵切除後に糖尿病が改善する例があることから,膵癌自体が耐糖能低下を引き起こすことが指摘されている。その中でadrenomedullinは膵癌患者で多く発現し,インスリン分泌を抑制するとされ,注目を集めている。がん関連血栓症(cancer associated thrombosis:CAT)の中でも膵癌はとくにリスクの高い癌腫とされ,凝固能亢進においては,外因系凝固カスケードのinitiation factorである組織因子(tissue factor:TF)が膵癌患者で多く発現し,血栓形成を促す重要な役割を担っているとされる。(著者抄録)

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Language：Japanese   Publisher：(一社)日本外科学会  

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Language：Japanese   Publisher：(一社)日本外科学会  

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Language：Japanese   Publisher：日本消化器病学会-関東支部  

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Language：Japanese   Publisher：(一社)日本外科学会  

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Language：Japanese   Publisher：(一社)日本外科学会  

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Language：Japanese   Publisher：(一社)日本外科学会  

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Language：Japanese   Publisher：(一社)日本外科学会  

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Language：Japanese   Publisher：(一社)日本外科学会  

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Granulomatous mastitis (GM) is a rare disease, particularly among men. Herein, we present a case of GM diagnosed in a 63-year-old male patient who showed reduction in the tumor size during 3 months of observation.

DOI： 10.1002/ccr3.7048

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Language：Japanese   Publisher：金原出版(株)  

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PURPOSE: This study aimed to evaluate the frequency and grade of anastomotic leakage (AL) in stapled ileal pouch-anal anastomosis (IPAA) and its long-term impact on the pouch functions. METHODS: A longitudinal cohort study was conducted on UC patients who underwent stapled IPAA at Yokohama City University Medical Center between 2007 and 2018. The diagnosis and grading of AL were performed in accordance with the recommendations of the International Study Group of Rectal Cancer. We assessed the functional pouch rate, late complication, pouch survival rate, bowel function (bowel movements per day, soiling, spotting, difficulty in distinguishing feces from flatus) and pouch inflammation (pouchitis disease activity index; PDAI) in the long-term period. RESULTS: Two hundred seventy-six patients were analyzed. Twenty-three (8.3%; grade B/C; 13/10) patients were diagnosed with AL, but a functional pouch was achieved in all the twenty-three patients. Anastomotic stricture was significantly more common in patients with AL (AL group) than in patients without AL (non-AL group; AL/non-AL: 13.0/3.2%, p = 0.020). There were no differences in other late complications. Furthermore, the pouch survival rate did not differ between the AL and non-AL groups (100.0/97.9%/10 years, p = 0.494). There were no differences between the groups in bowel movements per day, spotting, soling, difficulty in distinguishing feces from flatus, or PDAI postoperatively. CONCLUSIONS: Curable AL may not affect late complications (except anastomotic stricture), pouch survival, the bowel function, or pouch inflammation over the long term. Perioperative management to prevent the severity of AL is as important as preventing its occurrence.

DOI： 10.1007/s00384-023-04339-3

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BACKGROUND: Double-stapled ileal pouch-anal anastomosis (DS-IPAA) is easy to construct and has a good functional outcome in patients with ulcerative colitis (UC). However, retention of the anorectal mucosa may lead to a subsequent risk of inflammation and neoplasia. This study aimed to identify factors associated with the retention of a large amount of anorectal mucosa after DS-IPAA. METHODS: The medical records of 163 patients who had undergone one-stage total proctocolectomy and DS-IPAA for UC between 2007 and 2020 were retrospectively reviewed. The patients were divided into two groups according to the length of the retained mucosa. The high anastomosis group was defined as having a retained mucosal length of ≥ 30 mm in the anterior or posterior wall. Clinical factors were compared between the high and low anastomosis groups. RESULTS: The high anastomosis group showed a significantly higher body mass index (BMI) (high vs. low: 23.2 vs. 19.0), longer operation time (304 vs. 263) and greater blood loss (357 vs. 240). In the multivariate analysis, high BMI was the only factor significantly associated with high anastomosis (odds ratio 1.32). There was a positive correlation between BMI and the length of the retained mucosa. CONCLUSIONS: In DS-IPAA, BMI showed the strongest association with the retention of a large amount of the anorectal mucosa. In high BMI patients, although the risk of inability of anastomosis is little than that of IPAA with mucosectomy, the possible retention of a large amount of mucosa should be considered.

DOI： 10.1186/s12876-023-02667-w

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Gastric cancer is highly malignant and recalcitrant to first line chemotherapies that include 5-fluorouracil (5-FU). Cancer cells are addicted to methionine for their proliferation and survival. Methionine addiction of cancer is known as the Hoffman effect. Methionine restriction with recombinant methioninase (rMETase) has been shown to selectively starve cancer cells and has shown synergy with cytotoxic chemotherapy including 5-FU. The present study aimed to investigate the efficacy of rMETase alone and the combination with 5-FU on poorly differentiated human gastric cancer cell lines (MKN45, NUGC3, and NUGC4) in vitro and vivo. rMETase suppressed the tumor growth of 3 kinds of poorly differentiated gastric cancer cells in vitro. The fluorescence ubiquitination-based cell cycle indicator (FUCCI) demonstrated cancer cells treated with rMETase were selectively trapped in the S/G2 phase of the cell cycle. In the present study, subcutaneous MKN45 gastric cancer models were randomized into four groups when the tumor volume reached 100 mm3: G1: untreated control; G2: 5-FU (i.p., 50 mg/kg, weekly, three weeks); G3: oral-rMETase (o-rMETase) (p.o., 100 units/body, daily, three weeks); G4: 5-FU with o-rMETase (5-FU; i.p., 50 mg/kg, weekly, three weeks o-rMETase; p.o., 100 units/body, daily, three weeks). All mice were sacrificed on day 22. Body weight and estimated tumor volume were measured twice a week. 5-FU and o-rMETase suppressed tumor growth as monotherapies on day 18 (p = 0.044 and p = 0.044). However, 5-FU combined with o-rMETase was significantly superior to each monotherapy (p < 0.001 and p < 0.001, respectively) and induced extensive necrosis compared to other groups. The combination of 5-FU and o-rMETase shows promise for transformative therapy for poorly differentiated gastric cancer in the clinic.

DOI： 10.1016/j.bbrc.2022.12.062

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PURPOSE: This study aimed to analyze treatment outcomes and prognostic markers, including immune and inflammatory factors, of postoperative radiation therapy (RT) administered to patients with cholangiocarcinoma (CCA). METHODS: We retrospectively included 59 patients with CCA who underwent surgery and postoperative RT with curative intent from 2004 to 2019. Patients received external irradiation (50 Gy in 25 fractions) using three-dimensional RT. We analyzed prognostic factors of inflammation, such as pre-RT platelet count, hemoglobin, lymphocyte count ratio (LCR) of the leukocyte count, platelet-to-lymphocyte ratio (PLR), and neutrophil-to-lymphocyte ratio (NLR). RESULTS: Tumor stages were distributed as follows: I (n = 8), II (n = 25), III (n = 15), and IVA (n = 11). The median follow-up was 24 months. Two-year overall survival (OS), cause-specific survival (CSS), progression-free survival (PFS), and locoregional control (LRC) rates were 59.5%, 62.0%, 40.1%, and 66.7%, respectively. Univariate analysis revealed that lower LCR was significantly associated with shorter PFS (p = 0.0446). There was no significant difference between the median baseline values of PLR and NLR; and age ≥75, positive regional lymph node metastases (N+), and chemotherapy after RT were significantly associated with poor OS. Multivariate analysis revealed a significant association of N+ with worse OS, PFS, and CSS and that lower LCR was significantly associated with better PFS (p = 0.0234). Among late toxicity events, two patients (3.38%) were suspected with therapy-related liver toxicity. CONCLUSIONS: Lower LCR before RT was a better prognostic factor for postoperative RT of patients with CCA.

DOI： 10.1111/ajco.13809

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INTRODUCTION: This study aimed to compare the prognostic impact of laparoscopic left hepatectomy (LLH) with that of open left hepatectomy (OLH) on patient survival after resection of left hepatocellular carcinoma (HCC). METHODS: Among the 953 patients who received initial treatment for primary HCC that was resectable by either LLH or OLH from 2013 to 2017 in Japan and Korea, 146 patients underwent LLH and 807 underwent OLH. The inverse probability of treatment weighting approach based on propensity scoring was used to address the potential selection bias inherent in the recurrence and survival outcomes between the LLH and OLH groups. RESULTS: The occurrence rate of postoperative complications and hepatic decompensation was significantly lower in the LLH group than in the OLH group. Recurrence-free survival (RFS) was better in the LLH group than in the OLH group (hazard ratio, 1.33; 95% confidence interval, 1.03-1.71; p = 0.029), whereas overall survival (OS) was not significantly different. Subgroup analyses of RFS and OS revealed an almost consistent trend in favor of LLH over OLH. In patients with tumor sizes of ≥4.0 cm or those with single tumors, both RFS and OS were significantly better in the LLH group than in the OLH group. CONCLUSIONS: LLH decreases the risk of tumor recurrence and improves OS in patients with primary HCC located in the left liver.

DOI： 10.1159/000527294

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Language：Japanese   Publisher：(一社)日本胃癌学会  

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Language：Japanese   Publisher：(株)南江堂  

＜文献概要＞肝門部胆管癌に対する肝右三区域+尾状葉切除術は,もっとも大量の肝切除を伴う術式である.肝右三区域切除は肝不全をはじめとした術後合併症発生率が非常に高率であり,血行再建を伴う場合その手術難易度はさらに高度となるため,慎重な症例選択のもとに限られた専門施設で施行されるべき術式である.本稿では,肝門部胆管癌に対する肝右三区域+尾状葉切除術の適応,周術期管理,手術手技に関して,当科で経験した症例を提示しながら概説する.

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Other Link： https://search.jamas.or.jp/default/link?pub_year=2023&ichushi_jid=J00393&link_issn=&doc_id=20230302110006&doc_link_id=10.15106%2Fj_geka85_135&url=https%3A%2F%2Fdoi.org%2F10.15106%2Fj_geka85_135&type=%E5%8C%BB%E6%9B%B8.jp_%E3%82%AA%E3%83%BC%E3%83%AB%E3%82%A2%E3%82%AF%E3%82%BB%E3%82%B9&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00024_2.gif

Language：Japanese   Publisher：日本消化器病学会-関東支部  

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Language：Japanese   Publisher：(一社)日本大腸肛門病学会  

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Language：English   Publishing type：Research paper (scientific journal)  

OBJECTIVE: To clarify the short- and long-term postoperative outcomes and surgical indications for patients accompanied by hepatocellular carcinoma (HCC) with tumor thrombus (TT) in the inferior vena cava (IVC) or right atrium (RA). SUMMARY BACKGROUND DATA: These patients are known to have an extremely poor prognosis; however, the postoperative outcomes have not been fully verified because of the rarity of this disease. METHODS: We contacted 211 specialized centers in Japan and collected data on liver resection for HCC with TT in the IVC or RA from centers with experience performing surgery for such patients. The patient characteristics, operative procedures, and surgical outcomes were then analyzed. RESULTS: A total of 119 patients from 23 institutions were enrolled; 49 patients had TT in the IVC below the diaphragm (type I), 42 had TT in the IVC above the diaphragm (type II), and 28 had TT entering the RA (type III). The severity and frequency of postoperative complications did not differ among the three groups. There was one surgery-related death in the type III group. The median survival times were 2.47 years in the type I group, 1.77 years in the type II group, and 1.02 years in the type III group. A multivariate analysis identified an indocyanine green retention rate at 15 min >15% and ≥3 tumors as prognostic factors affecting survival, while the use of cardiopulmonary bypass and ≥3 tumors were risk factors for recurrence. CONCLUSION: As the postoperative prognosis of patients with type I or type II disease and of patients with no risk factors is relatively good, surgery should be considered for these patient populations.

DOI： 10.1097/SLA.0000000000005789

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Language：Japanese   Publisher：(株)へるす出版  

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Language：Japanese   Publisher：(公社)神奈川県医師会  

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Language：English   Publishing type：Research paper (scientific journal)  

Metabolic reprogramming to sustain immortality is a hallmark of cancer and glycolysis is an important way to attain this. Thus, we investigate the association of glycolysis and associated pathways in the survival of breast cancer. A total of 5,176 breast cancer patients from multiple independent cohorts were analyzed. We determined the glycolytic signaling score by the degree of enrichment by Gene Set Variant Analysis and the median was used to divide each cohort into high vs low score groups. Glycolysis high breast cancer significantly enriched the hallmark cell proliferation-related gene sets (E2F targets, G2M checkpoint, and MYC targets v1 and v2) and was associated with high MKI67 expression. In all cohorts, triple-negative breast cancer (TNBC) was associated with the highest glycolysis score. It was found that in TNBC, glycolysis high breast cancer was associated with worse survival but in ER-positive/HER2-negative breast cancer this was not observed consistently. The glycolysis high TNBC enriched multiple pro-cancerous gene sets and was infiltrated with a low level of B-cells and anti-cancerous immune cells, and significantly associated with a decreased level of cytolytic activity. It was also observed that the glycolysis was higher in the metastatic sites than in the primary breast cancer and the survival was not affected by the metastatic sites. In conclusion, accelerated glycolysis is associated with cancer cell proliferation and worse survival in TNBC.

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Language：Japanese   Publisher：(一社)日本内視鏡外科学会  

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Language：Japanese   Publisher：(一社)日本内視鏡外科学会  

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Language：Japanese   Publisher：(一社)日本内視鏡外科学会  

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Language：Japanese   Publisher：(一社)日本内視鏡外科学会  

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Language：Japanese   Publisher：(一社)日本内視鏡外科学会  

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Language：Japanese   Publisher：(一社)日本内視鏡外科学会  

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Language：Japanese   Publisher：(一社)日本内視鏡外科学会  

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Language：Japanese   Publisher：(一社)日本内視鏡外科学会  

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Language：Japanese   Publisher：(一社)日本内視鏡外科学会  

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Language：English   Publishing type：Research paper (scientific journal)  

Why inflammation is common in ileal pouches with ulcerative colitis (UC) is unclear. We therefore clarified the morphological changes in pouches and afferent limbs (AL) of patients with UC and explored the relationship between these findings. We evaluated the morphological findings (histological and endoscopic inflammation as the Pouchitis Disease Activity Index [PDAI] histology subscore [hPDAI] and endoscopy subscore [ePDAI], inflammatory bowel disease [IBD]-specific findings using the IBD score [SIBD], colonic metaplasia using the colonic metaplasia score [CMS], and goblet cell [GC] ratio) in the pouch and AL of patients with UC. A total of 261 pouchoscopies were analyzed. The pouch body had a higher hPDAI (p < 0.001), SIBD (p < 0.001), CMS (p < 0.001), GC ratio (p < 0.001), and ePDAI (p < 0.001) than the AL. The hPDAI was correlated with the SIBD (Spearman's coefficient r = 0.538; p < 0.001), CMS (r = 0.687; p < 0.001), and the ePDAI (r = 0.552; p < 0.001), but not with GC ratio (r = 0.175; p < 0.001) or the pouch usage duration (r = -0.057; p = 0.107). The incidence of histological inflammation was higher in specimens showing basal plasmacytosis with severe mononuclear cell infiltration (BP) than in those without BP (odds ratio [OR] 6.790, p < 0.001), BP was commonly found with crypt hyperplasia (OR 3.414, p < 0.001) and the crypt length correlated with neutrophil infiltration (r = 0.469; p < 0.001). Histological inflammation, colonic metaplasia, the GC ratio, endoscopic inflammation, and IBD-specific findings were commonly present in the pouch than in the AL. Histological inflammation occurs with IBD-specific findings and colonic metaplasia, and these signify endoscopic inflammation.

DOI： 10.1038/s41598-022-24708-2

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Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: BRCAness is a characteristic feature of homologous recombination deficiency (HRD) mimicking BRCA gene mutation in breast cancer. We hypothesized that a measure to quantify BRCAness that causes synthetic lethality in BRCA mutated tumors will identify responders to PARP inhibitors. METHODS: A total of 6753 breast cancer patients from 3 large independent cohorts were analyzed. A score was generated by transcriptomic profiling using gene set variation analysis algorithm on 34 BRCA1-mutation related genes selected by high AUC levels in ROC curve between BRCA1 mutation and wildtype breast cancer. RESULTS: The score was significantly associated with BRCA1 mutation, high mutation load and intratumoral heterogeneity as expected, as well as with high HRD, DNA repair and MKi67 expression regardless of BRCA mutations. High BRCAness tumors enriched not only DNA repair, but also all five Hallmark cell proliferation-related gene sets. High BRCAness tumors were significantly associated with higher cytolytic activity and with higher anti-cancerous immune cell infiltration. Not only did the breast cancer cell lines with BRCA-mutation show high score, but even the other cells in human breast cancer tumor microenvironment were contributing to the score. The BRCAness score was the highest in triple-negative breast cancer consistently in all 3 cohorts. BRCAness was associated with response to chemotherapy and correlated strongly with response to PARP inhibitor in both triple-negative and ER-positive/HER2-negative breast cancer. CONCLUSIONS: We established a novel BRCAness score using BRCA-mutation-related gene expressions and found that it associates with DNA repair and predicts response to PARP inhibitors regardless of BRCA mutation.

DOI： 10.1186/s40364-022-00427-8

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Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND/PURPOSE: This study aimed to investigate the efficacy of intensive fluid-loading therapy post-endoscopic retrograde cholangiopancreatography (ERCP) for the prevention of post-ERCP pancreatitis (PEP) in at-risk patients. METHODS: In this retrospective study, data of 1200 patients at risk for PEP were investigated. After propensity score matching, 404 patients were included in the normal (n = 202) and hydration (n = 202) groups. On the day of ERCP, patients in both groups were infused with 2000 ml/24 h of fluid before ERCP. Meanwhile, the hydration group received an additional 1000 ml/10 h of lactated Ringer's solution postoperatively. RESULTS: The incidence of PEP was lower in the hydration group (12.4%) than in the normal group (24.3%) (odds ratio [OR]: 0.44; 95% CI: 0.26-0.75, p = .003). The incidence of severe PEP was 2.0% and 6.9% in the hydration and normal groups (OR: 0.27; 95% CI: 0.09-0.84, p = .027), respectively. The incidence of fatal PEP was 0% and 2.0% in the hydration and normal groups (OR: N.A.: p = .123), respectively. CONCLUSIONS: Post-ERCP hydration may be an effective method of preventing PEP, including severe PEP, in at-risk patients.

DOI： 10.1002/jhbp.1267

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Publishing type：Research paper (scientific journal)   Publisher：Wiley  

DOI： 10.1002/jhbp.1256

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Other Link： https://onlinelibrary.wiley.com/doi/full-xml/10.1002/jhbp.1256

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1245/s10434-022-12269-7

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Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND/AIM: Routine use of adjuvant chemotherapy (AC) following hepatectomy for colorectal liver metastases (CRLM) is not universally practiced because of the lack of supporting evidence. Therefore, we investigated the efficacy of AC following curative CRLM resection. PATIENTS AND METHODS: Among the 742 patients who underwent their first hepatectomy for CRLM at our institution, 335 were stratified into surgery alone (SA; n=162) and AC (n=173) groups. Poor prognostic factors for SA were identified using multivariate logistic regression analysis. Propensity score matching was used to compare the clinical outcomes between SA and AC groups according to the number of prognostic factors. RESULTS: Multivariate analysis showed that preoperative carcinoembryonic antigen (CEA) levels (≥10 ng/ml; p=0.01), primary lymph node metastases (≥1; p=0.0001), and the number (n≥4; p=0.01) and maximum diameter (≥5 cm; p=0.00001) of CRLM tumours were independent poor prognostic factors for overall survival (OS) in the SA group. Patients with ≥3 risk factors were categorized as being high risk. After propensity score matching, the 5-year OS rate was significantly higher in the AC group (n=13) than that in the SA group (n=15; 47.9% vs. 7.3%; p=0.03) among high-risk patients. CONCLUSION: Adjuvant chemotherapy after curative CRLM resection may improve the prognosis of patients with three or more risk factors including preoperative CEA levels ≥10 g/ml, primary lymph node metastases ≥1, number (≥4) and maximum diameter (≥5 cm) of CRLM tumours.

DOI： 10.21873/anticanres.16055

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Language：Japanese   Publisher：(一社)日本外科学会  

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Language：Japanese   Publisher：(一社)日本創傷治癒学会  

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Language：Japanese   Publisher：医学図書出版(株)  

高齢化社会が進むにつれ,高齢胆管癌患者の数も増加傾向である。胆管癌に対する外科的切除術は,肝門部領域胆管癌に対する肝切除術と遠位胆管癌に対する膵頭十二指腸切除術に大別され,いずれも複雑で高侵襲,術後合併症も多い術式である。これまでの報告では,高齢者に対する膵頭十二指腸切除術は非高齢者と比べても,同等の安全性で施行できるとの報告が多い。しかし,高齢者肝門部領域胆管癌に対する肝切除術の安全性に関する報告は少ない。限られた報告の中でも,高齢者と非高齢者で短期・長期成績で差がないとする報告もあれば,その真逆の報告もあり,手術適応に対する客観的指標や医学的根拠が存在しない。本稿ではこれまでの報告と自施設の成績を交えて,肝門部領域胆管癌を中心に高齢者胆管癌に対する手術について概説した。高齢者であっても慎重に評価した上で手術を行えば,非高齢者と同等の予後を期待できることから,手術の意義が大きいと考える。(著者抄録)

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Language：Japanese   Publisher：日本臨床外科学会  

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Language：Japanese   Publisher：日本臨床外科学会  

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Language：Japanese   Publisher：(一社)日本消化器外科学会  

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Language：Japanese   Publisher：日本臨床外科学会  

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Language：Japanese   Publisher：日本臨床外科学会  

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Language：Japanese   Publisher：(一社)日本消化器外科学会  

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Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: The efficacy of multidisciplinary treatment, including neoadjuvant treatment, in borderline resectable pancreatic cancer (BRPC) remains unclear. We assessed the efficacy of neoadjuvant chemoradiotherapy with gemcitabine and tegafu/gimearcil/oteracil (S-1) for BRPC. METHODS: In a single-center, non-randomized prospective study, neoadjuvant chemoradiotherapy (NACRT) with gemcitabine plus S-1 was administered for BRPC (no. B090312028) in 122 patients enrolled between 2009-2015. Gemcitabine plus S-1 comprised gemcitabine on days 8 and 15, and daily S-1 on days 1-14. After two courses of gemcitabine plus S-1, 30 Gy radiotherapy was administered in 10 fractions with S-1. RESULTS: Eighty-four and 38 patients had BR-PV and BR-A, respectively. No deaths occurred during NACRT. Ninety-four patients (77%) underwent resection with curative intent. R0 resection was performed in 91% of resected cases. Patients who underwent post-NACRT resection had better overall survival than did patients without resection (mean survival time [MST]: 24.7 vs. 9.6 months, 5-year-survival rate (5ysr): 30.3% vs. 0%, p<0.001). Adjuvant chemotherapy was administered in 73% of patients. MST and 5ysr of the patients treated with NACRT followed by resection and adjuvant chemotherapy were 29.6 months and 34.3%, respectively. CONCLUSIONS: Neoadjuvant chemoradiotherapy with gemcitabine and S-1 can be safely administered in BRPC and may require adjuvant chemotherapy.

DOI： 10.1002/jhbp.1245

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Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND AND PURPOSE: During endoscopic ultrasound-guided hepaticogastrostomy (EUS-HGS), tract dilation is one of the most important steps, and the placement of conventional metal stents with 8.5 Fr delivery devices is difficult due to the large outer shape of the device. Fine-gauge balloon catheters have become popular because of their stricture penetration ability and ease of dilation. This study aimed to evaluate the utility of fine-gauge balloon catheters. PATIENTS AND METHODS: This retrospective study involved 38 patients who underwent conventional metal stent placement. The patients were classified into two groups: those who underwent dilation with a fine-gauge balloon catheter before initial metal stenting (balloon dilation group) and those who underwent bougie dilation only (non-balloon dilation group). We evaluated the stenting success rate after initial dilation and adverse events. RESULTS: Seventeen and twenty-one patients were included in the balloon dilation and non-balloon dilation groups, respectively. The stenting success rate after initial dilation was 100% (17/17) in the balloon dilation group and 71.4% (15/21) in the non-balloon dilation group (p = 0.024). As adverse events, peritonitis was observed in one case (4.8%) in the balloon dilation group, and in three cases (14.3%) in the non-balloon dilation group (p = 0.613). CONCLUSIONS: Dilation using a fine-gauge balloon catheter before conventional metal stent with 8.5 Fr delivery device placement is considered effective in EUS-HGS.

DOI： 10.3390/jcm11195681

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Language：Japanese   Publisher：(一社)日本大腸肛門病学会  

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Language：Japanese   Publisher：日本消化器病学会-関東支部  

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Language：Japanese   Publisher：医学図書出版(株)  

胆道再建を伴う肝切除術後の胆汁漏は、本術式の約1/3の症例に発症し、比較的多く遭遇する術後合併症である。胆汁漏そのものが致死的になることは少ないものの、感染のフォーカスとなり、コントロールできない場合には出血や、肝不全などの致死的合併症の引き金となることがあるため、早期に適切な対応が必要である。胆道再建を伴う肝切除術後の胆汁漏は肝切離面もしくは胆管空腸吻合の縫合不全が原因となる。いずれの場合においてもドレナージが基本治療となる。適切なドレナージを継続することでcavityの縮小をはかり、治癒をめざす。肝切離面からの非交通型胆汁漏は難治性となることもあるため、予防には術前の胆管走行の理解などの注意も必要である。(著者抄録)

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Language：Japanese   Publisher：日本臨床外科学会  

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Language：Japanese   Publisher：(一社)日本大腸肛門病学会  

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Language：Japanese   Publisher：(一社)日本大腸肛門病学会  

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Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: In IgG4-related sclerosing cholangitis (IgG4-SC), the necessity of biliary drainage (BD) is unclear. In this study, we aimed to retrospectively investigate the improvement of liver damage and jaundice in cases of IgG4-SC with and without BD, before starting steroids. METHODS: Fifty-two patients with IgG4-SC were investigated in the study. The study endpoints were the normalization rate of alkaline phosphatase (ALP)/total bilirubin (T-Bil) after 8 weeks of steroids, with and without BD. RESULTS: Propensity score matching was performed based on ALP and T-Bil, and 28 patients were included. There were 14 patients each in the BD and non-BD groups. Before initiation of steroids, the mean ALP in the BD group and the non-BD group was 378/461 (p = 0.541); the mean T-Bil was 2.5/1.8 (p = 0.401). Eight weeks after initiation of steroids, ALP improvement rate in BD group/non-BD group was 69.2%/61.5% (p = 1.000), and T-Bil improvement rate was 100%/100% (p = Ns). CONCLUSIONS: Steroids for IgG4-SC could prove effective in improving liver damage and jaundice, regardless of the presence or absence of BD. BD for IgG4-SC aimed to improve jaundice may not be necessary.

DOI： 10.1002/jhbp.1230

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Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: In this study, we aimed to develop and validate a nomogram to predict overall survival (OS) and recurrence-free survival (RFS) in patients who underwent curative resection of ampulla of Vater (AOV) cancer. This is the first study for nomograms in AOV cancer patients using retrospective data based on an international multicenter study. METHODS: A total of 2007 patients with AOV adenocarcinoma who received operative therapy between 2002 January and 2015 December in Korea and Japan were retrospectively assessed to develop a prediction model. Nomograms for 5-year OS and 3-year RFS were constructed by dividing the patients who received and who did not receive adjuvant therapy after surgery, respectively. Significant risk factors were identified by univariate and multivariate Cox analyses. Performance assessment of the four prediction models was conducted by the Harrell's concordance index (C-index) and calibration curves using bootstrapping. RESULTS: A total of 2007 and 1873 patients were collected for nomogram construction to predict 5-year OS and 3-year RFS. We developed four types of nomograms, including models for 5-year OS and 3-year RFS in patients who did not receive postoperative adjuvant therapy, and 5-year OS and 3-year RFS in patients who received postoperative adjuvant therapy. The C-indices of these nomograms were 0.795 (95% confidence interval [CI]: 0.766-0.823), 0.712 (95% CI: 0.674-0.750), 0.804 (95% CI: 0.7778-0.829), and 0.703 (95% CI: 0.669-0.737), respectively. CONCLUSIONS: This predictive model could help clinicians to choose optimal treatment and precisely predict prognosis in AOV cancer patients.

DOI： 10.1002/jhbp.1229

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Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1093/bjs/znac147

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Language：English   Publishing type：Research paper (scientific journal)  

Importance: In patients with resectable colorectal cancer liver metastases (CRLM), the choice of surgical technique and resection margin are the only variables that are under the surgeon's direct control and may influence oncologic outcomes. There is currently no consensus on the optimal margin width. Objective: To determine the optimal margin width in CRLM by using artificial intelligence-based techniques developed by the Massachusetts Institute of Technology and to assess whether optimal margin width should be individualized based on patient characteristics. Design, Setting, and Participants: The internal cohort of the study included patients who underwent curative-intent surgery for KRAS-variant CRLM between January 1, 2000, and December 31, 2017, at Johns Hopkins Hospital, Baltimore, Maryland, Memorial Sloan Kettering Cancer Center, New York, New York, and Charité-University of Berlin, Berlin, Germany. Patients from institutions in France, Norway, the US, Austria, Argentina, and Japan were retrospectively identified from institutional databases and formed the external cohort of the study. Data were analyzed from April 15, 2019, to November 11, 2021. Exposures: Hepatectomy. Main Outcomes and Measures: Patients with KRAS-variant CRLM who underwent surgery between 2000 and 2017 at 3 tertiary centers formed the internal cohort (training and testing). In the training cohort, an artificial intelligence-based technique called optimal policy trees (OPTs) was used by building on random forest (RF) predictive models to infer the margin width associated with the maximal decrease in death probability for a given patient (ie, optimal margin width). The RF component was validated by calculating its area under the curve (AUC) in the testing cohort, whereas the OPT component was validated by a game theory-based approach called Shapley additive explanations (SHAP). Patients from international institutions formed an external validation cohort, and a new RF model was trained to externally validate the OPT-based optimal margin values. Results: This cohort study included a total of 1843 patients (internal cohort, 965; external cohort, 878). The internal cohort included 386 patients (median [IQR] age, 58.3 [49.0-68.7] years; 200 men [51.8%]) with KRAS-variant tumors. The AUC of the RF counterfactual model was 0.76 in both the internal training and testing cohorts, which is the highest ever reported. The recommended optimal margin widths for patient subgroups A, B, C, and D were 6, 7, 12, and 7 mm, respectively. The SHAP analysis largely confirmed this by suggesting 6 to 7 mm for subgroup A, 7 mm for subgroup B, 7 to 8 mm for subgroup C, and 7 mm for subgroup D. The external cohort included 375 patients (median [IQR] age, 61.0 [53.0-70.0] years; 218 men [58.1%]) with KRAS-variant tumors. The new RF model had an AUC of 0.78, which allowed for a reliable external validation of the OPT-based optimal margin. The external validation was successful as it confirmed the association of the optimal margin width of 7 mm with a considerable prolongation of survival in the external cohort. Conclusions and Relevance: This cohort study used artificial intelligence-based methodologies to provide a possible resolution to the long-standing debate on optimal margin width in CRLM.

DOI： 10.1001/jamasurg.2022.1819

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BACKGROUND/PURPOSE: Laparoscopic (repeat) liver resection (LRLR) is a well-established liver tumor treatment. However, since its outcomes and comparison with open repeat liver resection (ORLR) in recurrent liver cancer remain inadequately studied, this study then aimed to compare their short-term outcomes for liver cancers (hepatocellular carcinoma, intrahepatic cholangiocellular carcinoma, and metastatic liver cancer). METHODS: Repeat liver resection cases between 2013 and 2017 from Japan's National Clinical Database were extracted. We used propensity score matching (PSM) to compare the proportion of patients with postoperative complications of Clavien-Dindo classification grade II or higher (CD2+) (primary endpoint), as well as the operative time, intraoperative bleeding volume, and intraoperative transfusion implementation rate (secondary endpoints). RESULTS: Of 2902 patients (ORLR, 2476; LRLR, 426), 712 (356 per type) with comparable backgrounds remained via PSM. Before and after PSM, the postoperative CD2+ complication rate was significantly lower in the LRLR group, who had shorter operative time, smaller intraoperative bleeding volume, and lower intraoperative transfusion rate, than in the ORLR group (after matching, 7.6% vs 18.3%, P < 0.0001). CONCLUSIONS: LRLR showed better short-term outcomes than ORLR, making it a safer and more effective liver cancer treatment.

DOI： 10.1002/jhbp.1156

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Language：Japanese   Publisher：日本外科系連合学会  

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Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: The liver is the most common metastatic site of colorectal cancer. Hepatectomy is the mainstay of treatment for patients with colorectal liver metastases (CRLMs). However, there are cases of early recurrence after upfront hepatectomy alone. In selected high-risk patients, neoadjuvant chemotherapy (NAC) may improve long-term survival. AIM: To determine the efficacy of NAC for initially resectable CRLMs. METHODS: Among 644 patients who underwent their first hepatectomy for CRLMs at our institution, 297 resectable cases were stratified into an upfront hepatectomy group (238 patients) and a NAC group (59 patients). Poor prognostic factors for upfront hepatectomy were identified using multivariate logistic regression analysis. Propensity score matching was used to compare clinical outcomes between the upfront hepatectomy and NAC groups, according to the number of poor prognostic factors. Survival curves were estimated using the Kaplan-Meier method and compared using the log-rank test. RESULTS: Preoperative carcinoembryonic antigen levels (≥ 10 ng/mL) (P = 0.003), primary histological type (other than well/moderately differentiated) (P = 0.04), and primary lymph node metastases (≥ 1) (P = 0.04) were identified as independent poor prognostic factors for overall survival (OS) in the upfront hepatectomy group. High-risk status was defined as the presence of two or more risk factors. After propensity score matching, 50 patients were matched in each group. Among high-risk patients, the 5-year OS rate was significantly higher in the NAC group (13 patients) than in the upfront hepatectomy group (18 patients) (100% vs 34%; P = 0.02). CONCLUSION: NAC may improve the prognosis of high-risk patients with resectable CRLMs who have two or more risk factors.

DOI： 10.4251/wjgo.v14.i7.1281

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Endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) is useful in diagnosing subepithelial lesions (SELs), and adequate tissue sampling is necessary to differentiate between benign and malignant diseases to determine therapeutic strategies. This study aimed to evaluate sampling adequacy and diagnostic performance of EUS-FNA for SELs with Franseen needles. This retrospective study enrolled 130 patients who underwent EUS-FNA with a 22-gauge needle for SELs from January 2010 to March 2021. We compared sampling adequacy and predictive factors influencing the sampling adequacy of EUS-FNA for SELs between Franseen and conventional needles. The sampling adequacy rates were 95.0% (38/40) with Franseen needles and 76.7% (69/90) with conventional needles (p = 0.011). The mean number of punctures with Franseen needles (2.80) was significantly less than that with conventional needles (3.42) (p &lt; 0.001). In the multivariate analysis, the use of Franseen needles (p = 0.029; odds ratio [OR], 5.37; 95% confidence interval [CI], 1.18-23.36) was an independent factor influencing the sampling adequacy. Compared to conventional needles, the Franseen needle could play a vital role in accurately diagnosing SELs by yielding better sampling adequacy and reducing the number of passes.

DOI： 10.3390/diagnostics12071667

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DOI： 10.1245/s10434-022-12105-y

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BACKGROUND: The examination of the efficacy of near-infrared imaging using indocyanine green in laparoscopic lateral pelvic lymph node dissection remains insufficient. OBJECTIVE: The aim of this study was to examine whether near-infrared imaging contributed to an increase in the total number of harvested lateral pelvic lymph nodes in laparoscopic lateral pelvic lymph node dissection. DESIGN: This was a retrospective, multi-institutional study with propensity score matching. SETTINGS: We conducted this study within the framework of the Yokohama Clinical Oncology Group in Japan. PATIENTS: The study population included consecutive patients with middle-low rectal cancer (clinical stage II to III) who underwent laparoscopic lateral pelvic lymph node dissection between January 2013 and February 2018. MAIN OUTCOME MEASURES: The total number of harvested lateral pelvic lymph nodes was compared in laparoscopic lateral pelvic lymph node dissection with and without near-infrared imaging. RESULTS: A total of 172 eligible patients were included; 84 of these patients underwent laparoscopic surgery with near-infrared imaging. After propensity score matching, 58 patients were matched in each of the near-infrared and the non-near-infrared groups. The operation time in the near-infrared group was significantly longer than that in the non-near-infrared group (426 vs 369 min), and the amount of intraoperative blood loss in the near-infrared group was significantly smaller than that in the non-near-infrared group (13 vs 110 mL). The total number of harvested lateral pelvic lymph nodes in the near-infrared group was significantly higher than that in the non-near-infrared group (14 vs 9). There were no significant differences in the postoperative complication rates of the 2 groups. LIMITATIONS: The limitations of the present study include its retrospective design. CONCLUSIONS: This study revealed that laparoscopic lateral pelvic lymph node dissection combined with near-infrared imaging could increase the total number of harvested lateral pelvic lymph nodes without impairing functional preservation. See Video Abstract at http://links.lww.com/DCR/B800.This study was registered with the Japanese Clinical Trials Registry as UMIN000041372 (http://www.umin.ac.jp/ctr/index.htm).IMÁGENES CASI-INFRARROJAS UTILIZANDO VERDE DE INDOCIANINA EN LA DISECCIÓN LAPAROSCÓPICA DE GANGLIOS LINFÁTICOS PÉLVICOS LATERALES EN CASOS DE CÁNCER DE RECTO MEDIO-INFERIOR DE ESTADIO CLÍNICO II / III: ESTUDIO DE COHORTES CON PUNTUACIÓN DE PROPENSIÓNANTECEDENTES:El examen de la eficacia de las imágenes casi-infrarrojas utilizando le verde de indocianina en la disección laparoscópica de los ganglios linfáticos pélvicos laterales sigue siendo insuficiente.OBJETIVO:El objetivo de este estudio fue examinar si las imágenes casi-infrarrojas contribuyeron a un aumento en el número total de ganglios linfáticos pélvicos laterales recolectados durante su disección laparoscópica.DISEÑO:Estudio retrospectivo, multi-institucional con emparejamiento por puntuación de propensión.AJUSTES:Estudio realizado dentro el marco establecido por el Grupo de Oncología Clínica de Yokohama, Japón.PACIENTES:La población estudiada incluyó pacientes consecutivos con cáncer de recto medio-bajo (estadio clínico II a III) que se sometieron a una disección laparoscópica de los ganglios linfáticos pélvicos laterales entre enero de 2013 y febrero de 2018.PRINCIPALES RESULTADOS MEDIDAS:El número total de ganglios linfáticos pélvicos laterales extraídos se comparó en la disección laparoscópica de ganglios linfáticos pélvicos laterales con y sin imágenes casi-infrarrojas.RESULTADOS:Se incluyeron un total de 172 pacientes elegibles; 84 de estos pacientes se sometieron a cirugía laparoscópica con imágenes casi-infrarrojas. Después del emparejamiento por puntuación de propensión, 58 pacientes fueron emparejados en cada uno de los grupos de luz casi-infrarroja y los sin luz. El tiempo de operación en el grupo de luz casi-infrarroja fue significativamente más largo que en el grupo sin luz (426 frente a 369 min), y la cantidad de pérdida de sangre intraoperatoria en el grupo de luz casi-infrarroja fue significativamente menor que en el grupo sin luz (13 frente a 110 ml). El número total de ganglios linfáticos pélvicos laterales recolectados en el grupo de luz casi-infrarroja fue significativamente mayor que en el grupo sin luz (14 frente a 9). No hubo diferencias significativas en las tasas de complicaciones posoperatorias de los dos grupos.LIMITACIONES:Las limitaciones del presente estudio incluyen su diseño retrospectivo.CONCLUSIONES:Este estudio reveló que la disección laparoscópica de los ganglios linfáticos pélvicos laterales combinada con imágenes casi-infrarrojas podría aumentar el número total de ganglios linfáticos pélvicos laterales recolectados sin afectar la preservación funcional. Consulte Video Resumen en http://links.lww.com/DCR/B800. (Traducción-Dr. Xavier Delgadillo)Este estudio se registró en el Registro de Ensayos Clínicos de Japón como UMIN000041372 (http://www.umin.ac.jp/ctr/index.htm).

DOI： 10.1097/DCR.0000000000002156

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Language：Japanese   Publisher：(一社)日本消化器外科学会  

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Language：Japanese   Publisher：(一社)日本消化器外科学会  

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Language：Japanese   Publisher：(一社)日本消化器外科学会  

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Language：Japanese   Publisher：(公社)神奈川県医師会  

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Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: Previous studies have reported contrasting results regarding the advantages of spleen preservation during laparoscopic distal pancreatectomy (LDP) for preventing infectious complications. METHODS: A total of 3787 patients who underwent LDP for benign or low-grade malignant pancreatic disease in 92 centers across Korea and Japan were included in this retrospective study. Postoperative infectious complications and other complications were compared between LDP with splenectomy (LDPS) and LDP with spleen preservation (LSPDP) by propensity score matching (PSM) analysis. RESULTS: After PSM, the LSPDP group had a lower rate of overall infectious complications (P = .079) and a significantly lower rate of intra-abdominal abscess (P = .014) compared with the LDPS group. Within the LSPDP group, the vessel preservation subgroup had a significantly higher rate of infectious complications (P = .002) compared with the vessel resection subgroup. Low-volume centers had a higher rate of intra-abdominal abscess than high-volume centers in the LSPDP group (P = .001) and the splenic vessel preservation subgroup (P = .003). CONCLUSIONS: Spleen preservation in LDP for benign or borderline malignant pancreatic diseases was advantageous in lowering the risk of infectious complications, specifically intra-abdominal abscess. However, the risk of intra-abdominal abscess may differ according to the level of surgeon's experience.

DOI： 10.1002/jhbp.1213

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BACKGROUND: We sought to define the association of the systemic immune inflammation index (SII) with prognosis and adjuvant therapy benefit among patients undergoing resection of extrahepatic cholangiocarcinoma (eCCA). METHODS: The impact of SII on overall (OS) and recurrence-free survival (RFS) following resection of eCCA was assessed and compared with other inflammatory markers and traditional prognostic factors. Propensity score matching (PSM) was used to determine the impact of adjuvant therapy (AT) on OS and RFS relative to low versus high SII. RESULTS: Patients with high versus low SII had worse 5-year OS (15.9% vs. 27.9%) and RFS (12.4% vs. 20.9%) (both p < 0.01). On multivariate analysis, high SII remained associated with worse OS (HR = 1.50, 95% CI 1.20-1.87) and RFS (HR = 1.46, 95% CI 1.18-1.81). Patients with T1/2 disease and a high-SII had worse 5-year OS versus individuals with T3/4 disease and low-SII (5-year OS: T1/2 & low-SII 35.6%, T1/2 & high-SII 16.4%, T3/4 & low-SII 22.1%, T3/4 & high-SII 15.6%, p < 0.01). Similarly, 5-year OS was comparable among individuals with N0 and high-SII versus N1 and low-SII (5-year OS: N0 & high-SII 23.2%, N1 and low-SII 19.8%, p = 0.95). On PSM, AT improved OS and RFS among patients with high SII (5-year OS: 22.5% vs. 12.3%, p < 0.01, 5-year RFS: 19.0% vs. 12.5%; p = 0.01) but not individuals with low SII (5-year OS: 22.9% vs. 26.9%; p = 0.98, 5-year RFS: 18.5% vs. 19.9%; p = 0.94). CONCLUSIONS: SII was independently associated with postoperative OS and RFS following curative-intent resection of eCCA. High SII up-staged patients relative T- and N-categories and identified patients with high SII as the most likely to benefit from AT.

DOI： 10.1245/s10434-022-12058-2

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Publishing type：Research paper (scientific journal)   Publisher：Springer Science and Business Media LLC  

DOI： 10.1245/s10434-022-11939-w

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Other Link： https://link.springer.com/article/10.1245/s10434-022-11939-w/fulltext.html

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AIM: Postmastectomy radiotherapy (PMRT) is the standard treatment for locally advanced breast cancer. However, the effectiveness of PMRT in patients with pT1-2 and N1 tumours remains controversial. Therefore, this study aimed to determine the prognostic impact of PMRT in patients with breast cancer and with pT1-2 and 1-3 lymph node metastases. METHODS: Using data from the Japanese National Clinical Database from 2004 to 2012, we evaluated the association of PMRT with locoregional recurrence (LRR), any recurrence, and mortality. We enrolled patients who had undergone mastectomy and axillary node dissection and were diagnosed with pT1-2 and N1. We compared clinicopathological factors and prognosis between patients who received (PMRT group) and those who did not receive (No-PMRT group) PMRT. RESULTS: Among 8914 patients enrolled, 492 patients belonged to the PMRT group and 8422 to the No-PMRT group. The median observation time was 6.3 years. There was no significant difference in the incidences of LRR (4.0% versus 5.0%, P = 0.61), recurrence (13.8% versus 11.8%, P = 0.23) and breast cancer death (6.0% versus 4.3%, P = 0.08) at 5 years between the groups. Multivariable analysis revealed that LRR was significantly associated with tumour size, number of node metastases and triple-negative subtype but not with PMRT. CONCLUSIONS: The LRR rate in the No-PMRT group was 5.0% at 5 years among patients with T1-2 and N1. PMRT did not significantly influence LRR in patients with T1-2 and N1. However, PMRT administration should be tailored considering the individual risks of tumour size, 3 node metastases and triple-negative subtype.

DOI： 10.1016/j.ejca.2022.05.017

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Objective The effectiveness of everolimus for the management of pancreatic neuroendocrine neoplasms (PNENs), including the G3/NEC types, remains unclear. We therefore investigated the effectiveness of the drug for the management of PNENs. Methods We analyzed the progression-free survival (PFS) and overall survival (OS) associated with everolimus and factors influencing the PFS and OS. Results One hundred patients were evaluated. The PFS associated with the G1/G2 types tended to be significantly longer than that associated with the G3/NEC types (hazard ratio [HR], 0.45; p =0.005). A multivariate analysis showed that the significant factors influencing the PFS were age (<65 years old; HR, 0.44; p =0.002), grade (G1/G2; HR, 0.42; p =0.006), everolimus treatment line (≤2nd; HR, 0.55; p =0.031), and presence of treatment with metformin (yes; HR, 0.29; p =0.044). The median OS was 63.8 months. In the multivariate analysis, the significant factors influencing the OS were grade (G1/G2; HR, 0.21; p <0.001), volume of liver metastasis (≤25%; HR, 0.27; p <0.001), everolimus treatment line (≤2nd; HR, 0.27; p <0.001), and presence of primary tumor resection (yes; HR, 0.33; p =0.005). Conclusions The effectiveness of everolimus in the management of G3/NEC types and prognoses tended to be poorer than those associated with the G1/G2 types. Everolimus combined with metformin and early-line treatment with everolimus may be effective for managing advanced PNENs.

DOI： 10.2169/internalmedicine.9416-22

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BACKGROUND: Prognostic stratification of patients with colorectal cancer liver metastasis based solely on tumor-related factors has only moderate discriminatory ability. We hypothesized that the inclusion of nontumor related factors can improve prediction of long-term prognosis of patients with colorectal cancer liver metastasis. METHODS: Nontumor related laboratory markers were assessed utilizing a training cohort from 2 U.S. institutions (n = 1,205). Factors independently associated with prognosis were used to develop a nontumor related prognostic score. The discriminatory ability, assessed by Harrell's C-statistics (C-index) and net reclassification improvement, was validated and compared with 3 commonly used tumor-related clinical risk scores: Fong clinical risk scores, m-clinical risk scores, and Genetic and Morphological Evaluation (GAME) score in an external validation cohort from 5 Asian (n = 1,307) and 3 European (n = 1,058) institutions. The discriminatory ability of nontumor related prognostic score combined with each of these 3 tumor-related prognostic scores was also estimated. RESULTS: Alkaline phosphatase (hazard ratio 1.43; 95% confidence interval, 1.11-1.84), albumin (hazard ratio 0.71; 95% confidence interval, 0.57-0.89), and mean corpuscular volume (hazard ratio 19.0, per log unit; 95% confidence interval, 4.79-75.0) were each independently associated with increased risk of death after resection of colorectal cancer liver metastasis (all P < .05). In turn, alkaline phosphatase, albumin, and mean corpuscular volume were combined to form a nontumor related prognostic score (2.942 × mean corpuscular volume + 0.399 × alkaline phosphatase-0.339 × albumin-12) × 10 (median, 16; range, 1-30). The nontumor related prognostic score had good-to-modest discriminatory ability in the external cohort (C-index = 0.58), which was comparable to the 3 established tumor-related prognostic scores (C-index: Fong clinical risk scores, 0.53, m-clinical risk scores, 0.55, GAME, 0.58). The addition of the nontumor related prognostic score to the tumor-related prognostic scores enhanced the discriminatory ability in the entire study cohort (C-index: nontumor related score+Fong, 0.60, nontumor related score+m-clinical risk scores, 0.61, nontumor related score+GAME, 0.64), as well reclassification improvement (42.5, 42.7%, and 21.2%, respectively). CONCLUSION: Nontumor related prognostic information may help improve the prognostic stratification of patients after resection of colorectal cancer liver metastasis. The nontumor related prognostic score may be combined with tumor-related prognostic tools to enhance prognostic stratification of patients with colorectal cancer liver metastasis.

DOI： 10.1016/j.surg.2022.01.030

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Language：Japanese   Publisher：日本ストーマ・排泄リハビリテーション学会  

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BACKGROUND: To ensure that highly advanced hepatobiliary-pancreatic surgery (HBPS) is performed safely, the Japanese Society of Hepato-Biliary-Pancreatic Surgery (JSHBPS) board certification system for expert surgeons established a safety committee to monitor surgical safety. METHODS: We investigated postoperative mortality rates based on summary reports of numbers and outcomes of highly advanced HBPS submitted annually by the board-certified training institutions from 2012 to 2019. We also analyzed summary reports on mortality cases submitted by institutions with high 90-day post-HBPS mortality rates and recommended site visits and surveys as necessary. RESULTS: Highly advanced HBPS was performed in 121,518 patients during the 8-year period. Thirty-day mortality rates from 2012 to 2019 were 0.92%, 0.8%, 0.61%, 0.63%, 0.70%, 0.59%, 0.48%, and 0.52%, respectively (p < .001). Ninety-day mortality rates were 2.1%, 1.82%, 1.62%, 1.28%, 1.46%, 1.22%, 1.19%, and 0.98%, respectively (p < .001). Summary reports were submitted by 20 hospitals between 2015 and 2019. Mortality rates before and after the start of report submission and audit were 5.72% and 2.79%, respectively, (odds ratio 0.690, 95% confidence interval 0.487-0.977; p = .037). CONCLUSIONS: Development of a system for designation of board-certified expert surgeons and safety management improved the mortality rate associated with highly advanced HBPS.

DOI： 10.1002/jhbp.1186

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BACKGROUND/PURPOSE: Whether organ-preserving pancreatic surgery has an advantage in postoperative short- and long-term outcomes or not is still unknown because only small case series studies have been available to date. In this multicenter retrospective study, we aimed to elucidate the clinical advantage and disadvantage of organ-preserving pancreatectomy among patients with low-grade malignant pancreatic tumors and benign pancreatic diseases. METHODS: We included patients diagnosed with benign or low-malignant pancreatic tumor who underwent pancreaticoduodenectomy (PD) in 621 cases, duodenum-preserving pancreatic head resection (DPPHR) in 31 cases, middle pancreatectomy (MP) in 148 cases, distal pancreatectomy (DP) in 814 cases, and spleen-preserving distal pancreatectomy (SPDP) in 259 cases between January 1, 2013, and December 31, 2017. Preoperative backgrounds, surgical outcomes and pre- and postoperative (3, 6, 12, 24, and 36 months) nutritional status were compared between these procedures. RESULTS: In terms of short-term outcomes, the incidence of pancreatic fistula in patients who underwent MP was significantly higher than in patients with standard pancreatectomy. As for the long-term pancreatic functions in the cases of head or body lesion, both exocrine and endocrine functions after MP were significantly favorable compared with the PD group from 3 to 36 months after surgery. In pancreatic body or tail lesion, significant advantage of endocrine function, but not exocrine function, was found in the MP group compared to standard DP at all time points. CONCLUSIONS: MP may contribute to the improvement of postoperative quality of life for patients with pancreatic body low-malignant tumors, rather than PD or DP; however, reducing the incidence of short-term complications such as pancreatic fistula is a future challenge.

DOI： 10.1002/jhbp.1154

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Methionine addiction, found in all types of cancer investigated, is because of the overuse of methionine by cancer cells for excess transmethylation reactions. In the present study, we compared the histone H3 lysine-methylation status and degree of malignancy between methionine-addicted cancer cells and their isogenic methionine-independent revertants, selected by their growth in low concentration of methionine. The methionine-independent revertans can grow on low levels of methionine or independently of exogenous methionine using methionine precursors, as do normal cells. In the methionine-independent revertants, the excess levels of trimethylated histone H3 lysine marks found in the methionine-addicted parental cancer cells were reduced or lost, and their tumorigenicity and experimental metastatic potential in nude mice were also highly reduced. Methionine addiction of cancer is linked with malignancy and hypermethylation of histone H3 lysines. The results of the present study thus provide a unique framework to further understand a fundamental basis of malignancy.

DOI： 10.1016/j.isci.2022.104162

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BACKGROUND/PURPOSE: The detection ability and role of different imaging modalities to detect pancreatic neuroendocrine neoplasms (PNENs) including small lesions is unclear. This study aimed to compare the ability of endoscopic ultrasound (EUS) and computed tomography (CT) to detect PNENs. METHODS: Data of patients who underwent EUS and contrast-enhanced CT and were diagnosed with PNENs were analyzed. The detection rates of pancreatic lesions with EUS and CT based on tumor size and influencing factors were investigated. RESULTS: For 256 PNEN lesions, the detection rate of EUS was better than that of CT (94.5% vs. 86.3%; p < 0.001). EUS was significantly superior to CT for PNENs ≤ 5 mm (58.3% vs 16.7%; p = 0.006) and 5-10 mm (97.7% vs 79.5%; p = 0.008). There was no significant difference in the detection rate between EUS and CT for PNENs > 10 mm (98.4% vs 96.4%; p = 0.375). Size (≤ 5 mm) and insulinoma were independent factors associated with poor EUS and CT detection rates. CONCLUSIONS: EUS exhibited better detection ability than CT, with an excellent detection rate for PNENs > 5 mm, except for insulinomas. CT could detect PNENs > 10 mm, which are amenable to treatment.

DOI： 10.1002/jhbp.1144

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Language：Japanese   Publisher：(一社)日本外科学会  

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Language：Japanese   Publisher：(一社)日本外科学会  

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Language：Japanese   Publisher：(一社)日本外科学会  

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Language：Japanese   Publisher：(一社)日本外科学会  

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Language：English   Publishing type：Research paper (scientific journal)  

PURPOSE: Transcriptomic profiling was performed for microsatellite instability-high (MSI-H)/mismatch repair-deficient (dMMR) gastrointestinal (GI) tumors to determine the predictors of response to PD-1 blockade. EXPERIMENTAL DESIGN: Thirty-six patients with MSI-H/dMMR GI tumors, including gastric cancer, colorectal cancer (CRC), cholangiocarcinoma, small intestine cancer, and pancreatic cancer, being treated with PD-1 blockade were analyzed. We conducted the transcriptomic analysis of GI tumors using RNA sequencing data, including the consensus molecular subtypes (CMS) of CRC. RESULTS: Gene set enrichment analysis (GSEA) demonstrated that non-responders had upregulations of epithelial mesenchymal transition, angiogenesis, hypoxia, mTORC1, TNF-α, KRAS, Wnt/β-catenin, TGF-β, and various metabolism-related signaling pathways. Meanwhile, the IFN-γ pathway was enriched in responders. Based on the leading-edge analysis of GSEA, VEGF-A was significantly correlated with enriched pathways in non-responders. Patients with high VEGF-A expression, compared to those with low expression, had significantly shorter progression-free survival (PFS) (median 4.8 months vs. not reached [NR], P = 0.032) and overall survival (median 11.1 months vs. NR, P = 0.045). Among 13 patients with CRC evaluable for CMS classification, the objective response rate was 100%, 0%, 0%, and 16.7% in CMS1, CMS2, CMS3 and CMS4, respectively. Patients with CMS1 had significantly longer PFS (NR vs. 4.8 months, P = 0.017) than those with CMS2, CMS3, or CMS4. CONCLUSIONS: Several transcriptomic features, including CMS classification and related genes, were associated with response to PD-1 blockade in MSI-H/dMMR GI tumors. These findings can help develop predictive biomarkers or combination immunotherapies.

DOI： 10.1158/1078-0432.CCR-22-0041

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PURPOSE: The present study explored preoperative risk factors (predictors) of incisional surgical site infection (I-SSI) in severe or intractable ulcerative colitis (UC). METHODS: This was a retrospective study of 230 consecutive patients who underwent primary surgery for UC. Patients whose surgical indications were UC with cancer or dysplasia were excluded. SSI was defined as an infection according to the Centers for Disease Control and Prevention Guidelines. Preoperative variables were examined by univariate, receiver operating characteristic curve, and multivariate analyses. RESULTS: We analyzed 208 patients in this study. In a multivariate logistic analysis, C-reactive protein (CRP) ≥ 1.7 mg/dl [odds ratio (OR) 5.35; 95% confidence interval (CI) 1.50-19.06; p = 0.01), albumin ≤ 2.4 g/dl (OR 5.77; 95% CI 1.41-23.57; p = 0.02), and preoperative blood transfusion (OR 3.21; 95% CI 1.04-9.96; p = 0.04) were predictors of I-SSI. Patients with all predictors had a more than 50% incidence of I-SSI, a higher incidence of all severe complications (13.6% vs. 3.2%; p = 0.02), and a longer postoperative hospital stay (19.5 vs. 17.0 days, p = 0.04) than the other patients. CONCLUSIONS: CRP ≥ 1.7 mg/dl, albumin ≤ 2.4 g/dl, and transfusion are predictors of I-SSI in severe or intractable UC. Clinician should carefully evaluate the surgical options before these predictors appear.

DOI： 10.1007/s00595-021-02354-x

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PURPOSE: To determine the selection criteria, postoperative complications, bowel function, and prognosis of stapled ileal pouch-anal anastomosis (IPAA) and hand-sewn IPAA for ulcerative colitis (UC). METHODS: We defined our surgical indications and strategy, and compared the postoperative complications, bowel function, and prognoses between patients who underwent stapled and hand-sewn IPAA for UC at the Yokohama City University Medical Center between 2004 and 2017. RESULTS: Among 320 patients enrolled, 298 patients underwent stapled IPAA while 22 underwent hand-sewn IPAA. There was no significant difference in the postoperative complications between the two groups. Regarding postoperative bowel function, stapled IPAA caused significantly less soiling (stapled vs hand-sewn: 9.1% vs 41.0%, odds ratio (OR) = 0.14, p < 0.0002), spotting (stapled vs hand-sewn: 23.2% vs 63.6%, OR = 0.17, p < 0.0001), and difficulty in distinguishing feces from flatus (stapled vs hand-sewn: 39.9% vs 63.6%, OR = 0.36, p < 0.026). No postoperative neoplasia was observed at the final follow-up in all patients. CONCLUSION: In this study, there was no clear difference in the postoperative complications between stapled and hand-sewn IPAA, but stapled IPAA resulted in better postoperative bowel function. Postoperative oncogenesis from the residual mucosa is rare. However, future cancer risk remains; thus, careful follow-up is required.

DOI： 10.1007/s00384-021-04059-6

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BACKGROUND: Although distant metastasis from pancreatic ductal adenocarcinoma (PDAC) has a dismal prognosis, some single center studies reported that lung metastasis has a favorable prognosis. The aim of this study is to evaluate the prognostic value of site-specific metastasis after pancreatectomy for PDAC, with a focus on lung metastasis. METHODS: Data from 117 cases of lung metastasis after pancreatectomy were collected retrospectively from 23 institutions in Japan. To compare the sites of metastasis we also collected the data of 134 patients with liver only metastasis, 67 patients with peritoneal only metastasis and 121 patients with locoregional recurrence alone. RESULTS: In patients with lung only metastasis, the median time from recurrence to death (RTD) was 23.1 months, which was better in comparison to other sites of recurrence. In lung metastasis group, the patients who underwent pulmonary resection had better long-term outcomes in comparison to those who did not. (RTD: 29.2 vs 15.2, P < .001). In the multivariate analysis, solitary metastasis (HR 5.03; 95% CI 1.195-21.144, P = .022) and postoperative chemotherapy (HR 14.089; 95% CI 1.729-114.77, P = .023) were identified as significant prognostic factors after lung resection. CONCLUSIONS: Surgical resection is a favorable option for selected patients with a solitary lung metastasis and for whom adjuvant chemotherapy can be administrated.

DOI： 10.1002/jhbp.1127

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PURPOSE: The purpose of this study was to clarify the perioperative deep-vein thrombosis (DVT) prevalence and its risk factors in surgical ulcerative colitis (UC) patients by comparing the results with those in surgical colorectal cancer (CRC) patients at a high risk of perioperative venous thrombosis. METHODS: This retrospective, observational study included patients who underwent surgery for UC or CRC between January 2013 and October 2019. Consecutive surgical patients with a positive D-dimer assay result (≥ 1.0 µg/ml) underwent lower-extremity venous ultrasonography. The prevalence and risk factors for preoperative DVT were examined in UC patients. RESULTS: A total of 101 UC patients and 593 CRC patients were deemed eligible. Among the D-dimer positive cases, there were no significant differences between the two groups in the preoperative DVT prevalence (UC: 21.8% vs. CRC: 28.8%, p = 0.151), distal type (18.8% vs. 27.2%, p = 0.086), or proximal type (5.9% vs. 4.2%, p = 0.434). Furthermore, multivariate analyses showed that an older age, overweight status, poor ASA status, and a high preoperative dose of steroid were independent risk factors for preoperative DVT in UC surgical patients. CONCLUSIONS: The risk of perioperative thrombosis in UC patients was considered similar to that in CRC, so active thromboprophylaxis should be administered to UC patients while paying attention to bleeding. TRIAL REGISTRATION: This study was registered with the Japanese Clinical Trials Registry as UMIN000042004 ( http://www.umin.ac.jp/ctr/index.htm ).

DOI： 10.1007/s00595-021-02335-0

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BACKGROUND/AIM: We previously observed higher prevalence of high-grade pancreatic intraepithelial neoplasia (PanIN) in LSL-KrasG12D/+; Pdx1Cre/+ (KC-Crmp4wild) mice than LSL-KrasG12D/+; Pdx1Cre/+; Crmp4-/- (KC-Crmp4-/-) mice. This study investigated the relationship between collapsin response mediator protein 4 (CRMP4) and immune cell infiltration in pancreatic cancer. MATERIALS AND METHODS: PanIN was induced by intraperitoneal injection of caerulein into KC-Crmp4wild and KC-Crmp4-/- mice, and immune cells in PanIN lesions were compared. Subcutaneous tumors were created by injecting Pan02 cells, and tumor diameter was compared between Crmp4wild and Crmp4-/- mice every 7 days. Peritumoral immune cells were examined immunohisto chemically. RESULTS: High-grade PanIN in KC mice showed statistically significantly high expression of CD163 (p=0.031) and CD11b (p=0.027). Following subcutaneous injection of Pan02 cells, tumor diameter was greater in Crmp4wild mice than Crmp4-/- mice. Crmp4wild mice exhibited higher CD163 and CD11b expression than Crmp4-/- mice in tumors (p<0.001). CONCLUSION: CRMP4 might promote pancreatic cancer by up-regulating M2 macrophages and myeloid-derived suppressor cells.

DOI： 10.21873/anticanres.15537

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PURPOSE: Sentinel lymph node biopsy is omitted in older women (≥ 70 years old) with clinical lymph node (LN)-negative hormone receptor-positive breast cancer as it does not influence adjuvant treatment decision-making. However, older women are heterogeneous in frailty while the chance of recurrence increase with improving longevity. Therefore, a biomarker that identifies LN metastasis may facilitate treatment decision-making. RUFY3 is associated with cancer progression. We evaluated RUFY3 expression level as a biomarker for LN-positive breast cancer in older women. METHODS: Clinical and transcriptomic data of breast cancer patients were obtained from the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC, n = 1903) and The Cancer Genome Atlas (TCGA, n = 1046) Pan-cancer study cohorts. RESULTS: A total of 510 (METABRIC) and 211 (TCGA) older women were identified. LN-positive breast cancer, which represented 51.4% (METABRIC) and 48.4% (TCGA), demonstrated worse disease-free, disease-specific, and overall survival. RUFY3 levels were significantly lower in LN-positive tumors regardless of age. The area under the curve for the receiver operator characteristic (AUC-ROC) curves showed RUFY3-predicted LN metastasis. Low RUFY3 enriched oxidative phosphorylation, DNA repair, MYC targets, unfolded protein response, and mtorc1 signaling gene sets, was associated with T helper type 1 cell infiltration, and with intratumor heterogeneity and fraction altered. Low RUFY3 expression was associated with LN-positive breast cancer and with worse disease-specific survival among older women. CONCLUSION: Older women with breast cancers who had low expression level of RUFY3 were more frequently diagnosed with LN-positive tumors, which translated into worse prognosis.

DOI： 10.1007/s10549-021-06482-3

PubMed

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Language：English   Publisher：AMER ASSOC CANCER RESEARCH  

DOI： 10.1158/1538-7445.SABCS21-P3-19-27

Web of Science

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Language：Japanese   Publisher：(公社)神奈川県医師会  

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Although miR-99b is a known suppressive microRNA (miRNA) in several cancers, its role in breast cancer has not been elucidated. In this study, we examined the clinical relevance of miR-99b expression in breast cancer. We analyzed miRNA and mRNA expression and their relationships with clinical parameters in 1,961 breast cancer samples from two independent large cohorts, the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) and The Cancer Genome Atlas (TCGA). Several algorithms, including gene set enrichment analysis (GSEA) and xCell, have been used to investigate biological functions and the tumor microenvironment. High miR-99b expression significantly enriched the mTORC1 signaling gene set in breast cancer (NES = 1.63, FDR = 0.03, and NES = 1.58, FDR = 0.10, in METABRIC and TCGA, respectively). No other mechanisms, including the epithelial mesenchymal transition, NFκB, and TGF-β signaling, were consistently enriched in both cohorts. MiR-99b-high breast cancer was associated with high homologous recombination deficiencies, intratumor heterogeneity, and high rates of mutation and neoantigens. In agreement, miR-99b-high breast cancer was associated with increased cell proliferation, correlating with Nottingham histological grade, and significant enrichment of E2F targets, G2/M checkpoint, and mitotic spindle gene sets consistently in both cohorts (P = 0.01, P < 0.001). High miR-99b levels were also associated with low stromal cell fractions in the tumor microenvironment, including adipocytes, keratinocytes, and lymphatic endothelial cells (P < 0.001). However, in both cohorts, miR-99b expression was not associated with significant infiltration of immune cells, except dendritic cells (P = 0.006, 0.020). Finally, in both cohorts, breast cancer with high miR-99b expression was significantly associated with worse disease-free survival (DSS) and overall survival (OS), particularly in estrogen receptor (ER)-positive/human epidermal growth factor (HER)2-negative breast cancer (DSS hazard ratio (HR) 1.29, 95% confidence interval (CI) 1.10-1.51, P < 0.001 in the METABRIC cohort and HR 1.82, 95% CI 1.12-2.98, P = 0.017 in the TCGA cohort). In conclusion, breast cancer with high miR-99b expression was significantly associated with mTORC1 signaling, cell proliferation, and decreased patient survival, particularly in the ER-positive/HER2-negative subtype.

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Publishing type：Research paper (scientific journal)   Publisher：Anticancer Research USA Inc.  

DOI： 10.21873/cgp.20299

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The apolipoprotein B mRNA-editing enzyme catalytic polypeptide-like (APOBEC) causes a point mutation from cytidine to uracil in DNA and/or RNA. The role of APOBEC3A and APOBEC3B in breast cancer has been well described, whereas that of APOBEC3F remains unknown. To investigate the clinical relevance of APOBEC3F expression, we analyzed a total of 3000 breast cancer cases from multiple independent large patient cohorts including METABRIC, TCGA, GSE75688, and GSE114725. High expression of APOBEC3F was associated with improved disease-specific and overall survival in triple negative breast cancer (TNBC). APOBEC3F is not usually a reflection of cancer cell biology in TNBC or luminal breast cancer, except for homologous recombination deficiency in TNBC. In the TNBC homologous recombination deficiency group, APOBEC3F expression was not consistently associated with intratumor heterogeneity, mutation rates, or neoantigens. APOBEC3F expression did not correlate with response to any of the drugs tested in breast cancer cell lines in vitro. However, high APOBEC3F expression was associated with enrichment of several immune-related gene sets and immune activity. High APOBEC3F expression also accompanied higher infiltration of anti-cancer immune cell infiltration in TNBC. However, in luminal breast cancer, high APOBEC3F tumor significantly enriched not only immune-related gene sets, but also cell proliferation-, metastasis-, and apoptosis-related gene sets. Analysis of single-cell transcriptomes showed APOBEC3F exclusively expressed in immune cells and significantly associated with cytolytic activity of the immune cells, immune response, and immune cell proliferation. Expression of immune checkpoint genes was uniformly elevated in APOBEC3F-high tumors. We conclude that APOBEC3F is exclusively expressed in immune cells and this expression is associated with enhanced anti-cancer immune response as well as improved survival in TNBC.

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Regulatory T cells (Tregs) are a subset of CD4+ T lymphocytes known to dampen the host immune response against cancer cells. Within the tumor microenvironment, Tregs are potent facilitators of immune tolerance, and a higher proportion of Tregs compared to cytotoxic T cells predicts a worse outcome in most solid tumors. We studied the association between Treg density, and cancer biology and clinical outcome in colorectal cancer (CRC). We used xCell to estimate intratumoral Tregs in total of 898 CRC patients in the Cancer Genome Atlas (TCGA) and GCE39582 cohorts. High-Treg CRCs enriched immune response-related gene sets; inflammatory response, IFN-γ and IFN-α response, IL2/IL6 signaling, and allograft rejection, and had significantly high infiltration of CD8, CD4, M1 and M2 macrophage, and dendritic cells in both cohorts. While high-Treg CRCs enriched multiple pro-cancer signaling pathways compared to low-Treg CRCs, such as Epithelial Mesenchymal Transition, K-ras, Hypoxia, TGF-β, TNF-α, and angiogenesis, Treg infiltration was surprisingly associated with earlier CRC stage in TCGA. Notably, in two separate cohorts a higher proportion of Tregs predicted an improved response to chemotherapy. In the GSE28702 cohort, metastatic CRCs with more Tregs showed a significantly better response to mFOLFOX6 versus low-Treg CRC metastases (88.9% response vs. 16.7%, P<0.001). In the GSE72970 cohort, high-Treg CRCs were found to have a 68.8% response to FOLFOX/FOLFIRI without bevacizumab, compared to 44% response in the low-Treg CRCs. Additionally, high-Treg CRCs were associated with increased expression of immune checkpoint molecules PD-L1/PD-L2, CTLA4, TIGIT and BTLA, implying susceptibility to immunotherapy. We also found that CRCs with higher proportions of Tregs were associated with lower amounts of three microorganisms in the tumor: Lachnoclostridium, flavivirus, and Ornithobacterium. In conclusion, we show that amount of Treg in the tumor is a predictor of host immune response and chemotherapy response in CRC.

PubMed

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Language：English   Publishing type：Research paper (scientific journal)  

AIM: To examine the role of the Modified Glasgow Prognostic Score (mGPS) and Prognostic Nutritional Index (PNI) as prognostic markers for patients with metastatic breast cancer (MBC). PATIENTS AND METHODS: We investigated the associations of clinico-pathological factors with time-to-treatment failure (TTF) and overall survival (OS) in 110 patients with MBC treated with eribulin. RESULTS: C-Reactive protein >1 mg/dl, albumin <3.5 g/dl, mGPS=2, and PNI <40 were significant predictors of shorter TTF in univariate analyses. PNI <40 remained a significant and independent predictor of shorter TTF in multivariate analyses. De novo tumor, visceral metastases, C-reactive protein >1 mg/dl, albumin <3.5 g/dl, mGPS=2, and PNI <40 were significant predictors of poor OS at the univariate level. A PNI <40 was a significant and independent predictor of poor OS in multivariate analyses. CONCLUSION: PNI is a reliable predictor of TTF and OS in patients with MBC treated with eribulin.

DOI： 10.21873/invivo.12903

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Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND/AIM: There are few models predicting breast cancer prognosis among patients receiving neoadjuvant chemotherapy (NAC) for estrogen receptor (ER)-positive/human epidermal growth factor receptor 2 (HER2)-negative (luminal) breast cancer. We examined whether biological features (BFs) of residual tumors are prognostic factors following NAC. PATIENTS AND METHODS: We enrolled patients with remnant tumors following NAC for luminal breast cancer and evaluated clinical stage, pathological stage, BFs prior to NAC, and BFs following NAC as prognostic factors. BFs were divided into high and low risk using the previously reported YR-IHC4 model calculated according to ER, progesterone receptor (PgR), HER2, and the proliferation marker Ki-67. RESULTS: A total of 57 patients were enrolled in the current study. We observed a statistically significant difference in relapse-free survival (RFS) between the BF risk categories via YR-IHC4 predictions following NAC (p=0.044). The 5-year RFS rates of the BF low- and high-risk groups following NAC were 84.2% and 52.5%, respectively. CONCLUSION: BFs of residual tumors following NAC may be important prognostic factors in luminal breast cancer.

DOI： 10.21873/invivo.12774

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Language：Japanese   Publishing type：Research paper (scientific journal)  

This is a case implying a serious infectious complication risk during intensive severe ulcerative colitis treatment. A 26-year-old man developed diarrhea and bloody stool who was diagnosed with ulcerative colitis in 2018. He was managed with 5-aminosalicylic acid, but intolerance reaction resulted in discontinuation of treatment. He relapsed with severe abdominal pain and bloody stools in February 2019. He was referred to our department for intensive therapy. He had been treated with steroids, tacrolimus, granulocyte and monocyte apheresis, infliximab or tofacitinib, which temporarily improved his clinical symptoms. However, his medical condition could not be controlled. Hand-assisted laparoscopic subtotal colectomy was then performed in October 2019. He developed intermittent fever on postoperative day 3. Enhanced computed tomography (CT) revealed multiple deep vein thromboses and pulmonary embolism. Antibiotics and anticoagulation therapy were initiated, but postoperative day 13 CT showed multiple pulmonary cavities containing fluids and air, which were diagnosed as pulmonary abscess. His intermittent fever was over 38.0°C. Severe cough and hemoptysis lasted 3 weeks, the clinical symptoms and laboratory data then gradually improved after the fourth week.

DOI： 10.11405/nisshoshi.119.1029

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OBJECTIVE: To investigate the safety and survival benefits of portal vein and/or superior mesenteric vein (PV/SMV) resection with jejunal vein resection (JVR) for pancreatic ductal adenocarcinoma (PDAC). SUMMARY BACKGROUND DATA: Few studies have shown the surgical outcome and survival of pancreatic resection with JVR, and treatment strategies for patients with PDAC suspected of jejunal vein (JV) infiltration remain unclear. METHODS: In total, 1260 patients who underwent pancreatectomy with PV/SMV resection between 2013 and 2016 at 50 facilities were included; treatment outcomes were compared between the PV/SMV group (PV/SMV resection without JVR; n = 824), PV/SMV-J1 V group (PV/SMV resection with first jejunal vein resection; n = 394), and PV/SMV-J2,3 V group (PV/SMV resection with second jejunal vein or later branch resection; n = 42). RESULTS: Postoperative complications and mortality did not differ between the three groups. The postoperative complication rate associated with PV/SMV reconstruction was 11.9% in PV/SMV group, 8.6% in PV/SMV-J1 V group, and 7.1% in PV/SMV-J2,3 V group; there were no significant differences among the three groups. Overall survival did not differ between PV/SMV and PV/SMV-J1 V groups (median survival; 29.2 months vs. 30.9 months. p = 0.60). Although PV/SMV-J2,3 V group had significantly shorter survival than PV/SMV group who underwent upfront surgery (p = 0.05), no significant differences in overall survival of patients who received preoperative therapy. Multivariate survival analysis revealed that adjuvant therapy and R0 resection were independent prognostic factors in all groups. CONCLUSIONS: PV/SMV resection with JVR can be safely performed and may provide satisfactory overall survival with the pre-and postoperative adjuvant therapy.

DOI： 10.1097/SLA.0000000000005330

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：International Institute of Anticancer Research  

Background/ Aim: Currently, there is no classification system specializing in recurrent inguinal hernia (RIH) after open-surgery. For this reason, in this study we proposed one so as to understand the causes of RIH. Patients and Methods: Recurrence of IH after suturerepair was classified either as the tissue-loosening (TL) or the tissue-disruption (TD) type. Recurrence after open-meshrepair was classified according to the locational relation between the hernia-defect and the mesh, as follows: i) meshdistant (MD), ii) para-mesh (PM), iii) mesh-migration (MM), and iv) unclassifiable (UC). Fifty-two RIHs in 48 patients were classified, using this system, and analyzed. Results: This system-based classification led to the identification of: i) MM in 11 lesions, ii) PM in 11, iii) MD in 10, iv) TL in 7, v) TD in 5, and vi) UC in 8 lesions. The median time to recurrence (MTR) was significantly shorter in patients who had previously undergone a mesh-repair (n=34) compared to those who had undergone a suture-repair (n=13) [Meshrepair vs. suture-repair MTR: 1.6 years (0.1-20) vs. 30 years (15-72), p&lt
0.001]. MTR was significantly shorter in the following order: i) MM [0.5(0.1-2.0)]), ii) PM [2.6(0.2-15)]), iii) MD [11(0.5-20)], iv) TD [20(15-30)], and v) TL [40(30- 72)] (p&lt
0.001). Conclusion: This classification system helps understand the causes of RIH, leading to improved outcomes following open-surgery in the future.

DOI： 10.21873/invivo.12652

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Springer Science and Business Media Deutschland GmbH  

Background: There are few randomized controlled trials on the efficacy of spray-type anti-adhesion material during diverting ileostomy in laparoscopic rectal cancer surgery. Purpose: This study will assess whether or not spraying an anti-adhesion material during diverting ileostomy could reduce the surgeon's multifaceted workload in ileostomy closure. Methods: Patients with laparoscopic or robotic surgery for rectal cancer scheduled for low anterior resection and diverting ileostomy will be enrolled in the ADOBARRIER study (multicenter, single-blind, randomized controlled trial). The target sample size is set at 120 cases, which will be randomly divided into an anti-adhesion material-using group and a non-using group at a ratio of 1:1. The primary endpoint is the multifaceted workload of the surgeon of ileostomy closure using SURG-TLX between groups with and without usage of the anti-adhesion material during diverting ileostomy construction
the secondly endpoint is the operative time, amount of intraoperative blood loss, degree of adhesions, and extent of intra-abdominal adhesions when the ileostomy is closed. Conclusions: This RCT will evaluate the efficacy and safety of spray-type anti-adhesion material for diverting ileostomy construction. The results of this study are expected to facilitate decision-making regarding the use of anti-adhesion material. Trial registration: This trial was registered with the Japan Registry of Clinical Trials (jRCT) in October 2020 as jRCTs032200155.

DOI： 10.1007/s00384-021-04032-3

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BACKGROUND: Recent studies have clarified that near-infrared observation using indocyanine green has the advantage of evaluating perfusion of the anastomotic site, especially in rectal cancer surgery, resulting in a reduction in anastomotic leak. OBJECTIVE: The aim of this study was to evaluate the efficacy of near-infrared observation for reducing the anastomotic leak after stapled side-to-side anastomosis in colon cancer surgery. DESIGN: This was a retrospective propensity score case-matched study. SETTINGS: The study was conducted at 3 institutions in the Yokohama Clinical Oncology Group. PATIENTS: From January 2011 to December 2019, patients who underwent colon cancer surgery with stapled side-to-side anastomosis were included. MAIN OUTCOME MEASURES: The main outcome was the percentage of anastomotic leak within 30 days after surgery. RESULTS: A total of 1034 patients were collected. There were 532 patients who underwent near-infrared observation and 502 who did not. A total of 370 patients were matched to the near-infrared and non-near-infrared groups. In the near-infrared group, 12 patients (3.2%) were judged to have poor perfusion (4 patients) and no perfusion (8 patients), so the planned transection point was changed. There were no cases of anastomotic leak among these 12 patients. The anastomotic leak rates were 3.5% (13/370) in the non-near-infrared group and 0.8% (3/370) in the near-infrared group. The anastomotic leak and reoperation rates were significantly lower in the near-infrared group than in the non-near-infrared group (OR, 0.224; 95% CI, 0.063-0.794, p = 0.001; OR, 0.348; 95% CI, 0.124-0.977, p = 0.036). LIMITATIONS: Although we reduced selection bias by performing propensity score matching, this was a retrospective study and was not randomized. CONCLUSION: This large-scale case-matched study showed that assessing perfusion by near-infrared observation significantly reduced the anastomotic leak and reoperation rates after stapled side-to-side anastomosis in colon cancer surgery and may be better suited to colo-colonic anastomosis. Video Abstract at http://links.lww.com/DCR/B513.Japanese Clinical Trials Registry: UMIN-CTR000039977. EVALUACIN DEL EFECTO DE LA OBSERVACIN INTRAOPERATORIA CON INFRARROJO CERCANO SOBRE LA FUGA ANASTOMTICA DESPUS DE UNA ANASTOMOSIS LATEROLATERAL CON ENGRAPADORA EN LA CIRUGA DE CNCER DE COLON MEDIANTE EL EMPAREJAMIENTO POR PUNTAJES DE PROPENSIN: ANTECEDENTES:Estudios recientes han aclarado que la observación con infrarrojo cercano con verde de indocianina tiene la ventaja de evaluar la perfusión del sitio anastomótico, especialmente en la cirugía de cáncer de recto, lo que resulta en una reducción de la fuga anastomótica.OBJETIVO:El objetivo de este estudio fue evaluar la eficacia de la observación con infrarrojo cercano para reducir la fuga anastomótica después de una anastomosis latero-lateral con engrapadora en la cirugía de cáncer de colon.DISEÑO:Este fue un estudio retrospectivo emparejado con puntaje de propensión.AJUSTE:El estudio se llevó a cabo en tres instituciones del Grupo de Oncología Clínica de Yokohama.PACIENTES:Desde enero de 2011 hasta diciembre de 2019, se incluyeron pacientes que se sometieron a cirugía de cáncer de colon con anastomosis latero-lateral con engrapadora.PRINCIPALES MEDIDAS DE RESULTADO:El resultado principal fue el porcentaje de fuga anastomótica dentro de los 30 días posteriores a la cirugía.RESULTADOS:Se recogió un total de 1034 pacientes. Hubo 532 pacientes que se sometieron a observación con infrarrojo cercano y 502 que no. Un total de 370 pacientes fueron emparejados con los grupos de infrarrojo cercano y no infrarrojo cercano. En el grupo de infrarrojo cercano, se consideró que 12 casos (3,2%) tenían mala perfusión (4 casos) y ninguna perfusión (8 casos), por lo que se cambió el punto de transección planificado. No hubo casos de fuga anastomótica entre estos 12 casos. Las tasas de fuga anastomótica fueron del 3,5% (13/370) en el grupo sin infrarrojo cercano y del 0,8% (3/370) en el grupo con infrarrojo cercano. Las tasas de fuga anastomótica y de reintervención fueron significativamente menores en el grupo con infrarrojo cercano que en el grupo sin infrarrojo cercano (razón de posibilidades 0,224, intervalo de confianza del 95% 0,063-0,794, p = 0,001; razón de posibilidades 0,348, intervalo de confianza del 95% 0,124 -0,977, p = 0,036, respectivamente).LIMITACIONES:Aunque se redujo el sesgo de selección al realizar el emparejamiento por puntaje de propensión, este fue un estudio retrospectivo y no fue aleatorio.CONCLUSIÓN:Este estudio de casos emparejados a gran escala demostró que la evaluación de la perfusión mediante la observación con infrarrojo cercano redujo significativamente la fuga anastomótica y las tasas de reintervención después de la anastomosis latero-lateral con engrapadora en la cirugía de cáncer de colon y puede ser más adecuada para la anastomosis colo-colónica. Consulte Video Resumen en http://links.lww.com/DCR/B513.Registro japonés de ensayos clínicos: UMIN-CTR000039977.

DOI： 10.1097/DCR.0000000000001960

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Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：日本臨床外科学会  

症例は36歳,男性.海外出張中に,左側腹部痛を主訴に前医へ搬送された.上腸間膜動脈血栓症と診断され,精査されたが原因不明であった.腹痛は軽快傾向であったため,高血圧に対して降圧治療をされ帰国した.しかし,疼痛が持続していたため当院を受診した.腹部造影CTでは上腸間膜動脈解離,左結腸動脈瘤と周囲の血腫を認めた.下腸間膜動脈の血管造影では脾彎曲の辺縁動脈の動脈瘤と,口側に連続する不整な血管拡張を認めた.腸管虚血の可能性が高いことから動脈塞栓(transcatheter arterial embolization;以下,TAE)は施行せず,準緊急手術を行う方針とした.術中所見では腹腔内出血を認め,脾彎曲近傍では腸間膜,後腹膜に広範に血腫を認めた.腹腔鏡下に脾彎曲の授動を行い,腸間膜内血腫のため小開腹創から切除範囲を決定し結腸左半切除術とした.病理診断は分節性動脈中膜融解症(segmental arterial mediolysis;以下,SAM)であった.上腸間膜動脈解離は保存的加療を行い,1ヵ月後には偽腔の血栓化を認めた.SAMによる左結腸動脈瘤破裂に対して腹腔鏡補助下手術を施行した1例を経験したので報告する.(著者抄録)

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Language：Japanese   Publisher：(一社)日本内視鏡外科学会  

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Language：Japanese   Publisher：(一社)日本内視鏡外科学会  

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Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: Prevention of bile duct injury and vasculo-biliary injury while performing laparoscopic cholecystectomy (LC) is an unsolved problem. Clarifying the surgical difficulty using intraoperative findings can greatly contribute to the pursuit of best practices for acute cholecystitis. In this study, multiple evaluators assessed surgical difficulty items in unedited videos and then constructed a proposed surgical difficulty grading. METHODS: We previously assembled a library of typical video clips of the intraoperative findings for all LC surgical difficulty items in acute cholecystitis. Fifty-one experts on LC assessed unedited surgical videos. Inter-rater agreement was assessed by Fleiss's κ and Gwet's agreement coefficient (AC). RESULTS: Except for one item ("edematous change"), κ or AC exceeded 0.5, so the typical videos were judged to be applicable. The conceivable surgical difficulty gradings were analyzed. According to the assessment of difficulty factors, we created a surgical difficulty grading system (agreement probability = 0.923, κ = 0.712, 90% CI: 0.587-0.837; AC2  = 0.870, 90% CI: 0.768-0.972). CONCLUSION: The previously published video clip library and our novel surgical difficulty grading system should serve as a universal objective tool to assess surgical difficulty in LC.

DOI： 10.1002/jhbp.1068

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Springer Science and Business Media Deutschland GmbH  

Background: The impact of tumor burden score (TBS) on conditional survival (CS) among patients undergoing curative-intent resection of hepatocellular carcinoma (HCC) has not been examined to date. Methods: Patients who underwent liver resection of HCC between 2000 and 2017 were identified from a multi-institutional database. The impact of TBS and other clinicopathologic factors on 3-year conditional survival (CS3) was examined. Results: Among 1,040 patients, 263 (25.3%) patients had low TBS, 668 (64.2%) had medium TBS and 109 (10.5%) had high TBS. TBS was strongly associated with OS
5-year OS was 39.0% among patients with high TBS compared with 61.1% and 79.4% among patients with medium and low TBS, respectively (p &lt
0.001). While actuarial survival decreased as time elapsed from resection, CS increased over time irrespective of TBS. The largest differences between 3-year actuarial survival and CS3 were noted among patients with high TBS (5-years postoperatively
CS3: 78.7% vs. 3-year actuarial survival: 30.7%). The effect of adverse clinicopathologic factors including high TBS, poor/undifferentiated tumor grade, microvascular invasion, liver capsule involvement, and positive margins on prognosis decreased over time. Conclusions: CS rates among patients who underwent resection for HCC increased as patients survived additional years, irrespective of TBS. CS estimates can be used to provide important dynamic information relative to the changing survival probability after resection of HCC.

DOI： 10.1007/s00268-021-06265-3

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Springer Science and Business Media Deutschland GmbH  

Introduction: Although preoperative α-fetoprotein (AFP) has been recognized as an important tumor marker among patients with hepatocellular carcinoma (HCC), the predictive value of AFP levels at the time of recurrence (rAFP) on post-recurrence outcomes has not been well examined. Methods: Patients undergoing curative-intent resection of HCC between 2000 and 2017 were identified using a multi-institutional database. The impact of rAFP on post-recurrence survival, as well as the impact of rAFP relative to the timing and treatment of HCC recurrence were examined. Results: Among 852 patients who underwent resection of HCC, 307 (36.0%) individuals developed a recurrence. The median rAFP level was 8 ng/mL (interquartile range 3–100). Among the 307 patients who developed recurrence, 3-year post-recurrence survival was 48.5%. Patients with rAFP &gt
10 ng/mL had worse 3-year post-recurrence survival compared with individuals with rAFP &lt
10 ng/mL (28.7% vs. 65.5%, p &lt
0.001). rAFP correlated with survival among patients who had early (3-year survival
rAFP &gt
10 vs. &lt
10 ng/mL: 30.1% vs. 60.2%, p &lt
0.001) or late (18.0% vs. 78.7%, p = 0.03) recurrence. Furthermore, rAFP levels predicted 3-year post-recurrence survival among patients independent of the therapeutic modality used to treat the recurrent HCC (rAFP &gt
10 vs. &lt
10 ng/mL
ablation: 41.1% vs. 76.0%
intra-arterial therapy: 12.9% vs. 46.1%
resection: 37.5% vs. 100%
salvage transplantation: 60% vs. 100%
all p &lt
0.05). After adjusting for competing risk factors, patients with rAFP &gt
10 ng/mL had a twofold higher hazard of death in the post-recurrence setting (hazard ratio 1.96, 95% confidence interval 1.26–3.04). Conclusion: AFP levels at the time of recurrence following resection of HCC predicted post-recurrence survival independent of the secondary treatment modality used. Evaluating AFP levels at the time of recurrence can help inform post-recurrence risk stratification of patients with recurrent HCC.

DOI： 10.1245/s10434-021-09977-x

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Springer Science and Business Media Deutschland GmbH  

Background: Mutations of BRCA genes are the most studied in breast cancer, but the clinical relevance of BRCA2 gene expression has been less well studied. Given that BRCA2 is a DNA repair gene, we hypothesized that high BRCA2 expression is associated with highly proliferative and aggressive biology in breast cancer. Materials and Methods: A total of 4342 breast cancer patients were analyzed from The Cancer Genome Atlas (TCGA, n = 1069) as the testing cohort and Gene Expression Omnibus (GEO) dataset GSE96058 (n = 3273) as a validation cohort. Results: There was no relationship between BRCA2 mutation and BRCA2 gene expression. BRCA2 high expression breast cancer was associated with higher Nottingham grade (p &lt
0.001), with high proliferation (MKI-67, p &lt
0.001), and with higher intratumor heterogeneity, homologous recombination deficiency, mutation rate, fraction altered, and neoantigens (all p &lt
0.001). BRCA2 high expression was associated with E2F1, RB1, PALB2, and PARP, as well as cell proliferation-related gene sets, E2F targets, G2M checkpoints, and mitotic spindle, and with less ESR1 and ER response early and late gene sets. They were associated with significantly reduced number of stroma cells and with high infiltration of both favorable and unfavorable immune cells. BRCA2 high expression significantly correlated with response to olaparib, a PARP inhibitor, and inversely with cyclophosphamide in ER-positive/HER2-negative tumors, but not in TNBC. Conclusions: BRCA2 high gene expression was associated with highly proliferative and aggressive breast cancer that was highly immunogenic with better response to PARP inhibitors in ER-positive patients. BRCA2 gene expression may become a candidate marker for aggressive biology and to tailor specific treatment strategies in the future.

DOI： 10.1245/s10434-021-10063-5

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Backgrounds: Extrahepatic recurrence of hepatocellular carcinoma (HCC) after surgical resection is associated with unfavorable prognosis. The objectives of the current study were to identify the risk factors and develop a nomogram for the prediction of extrahepatic recurrence after initial curative surgery. Methods: A total of 635 patients who underwent curative-intent resection for HCC between 2000 and 2017 were identified from an international multi-institutional database. The clinicopathological characteristics, risk factors, and long-term survival of patients with extrahepatic recurrence were analyzed. A nomogram for the prediction of extrahepatic recurrence was established and validated in 144 patients from an external cohort. Results: Among the 635 patients in the derivative cohort, 283 (44.6%) experienced recurrence. Among patients who recurred, 80 (28.3%) patients had extrahepatic ± intrahepatic recurrence, whereas 203 (71.7%) had intrahepatic recurrence only. Extrahepatic recurrence was associated with more advanced initial tumor characteristics, early recurrence, and worse prognosis versus non-extrahepatic recurrence. A nomogram for the prediction of extrahepatic recurrence was developed using the β-coefficients from the identified risk factors, including neutrophil-to-lymphocyte ratio, multiple lesions, tumor size, and microvascular invasion. The nomogram demonstrated good ability to predict extrahepatic recurrence (c-index: training cohort 0.786
validation cohort: 0.845). The calibration plots demonstrated good agreement between estimated and observed extrahepatic recurrence (p = 0.658). Conclusions: An externally validated nomogram was developed with good accuracy to predict extrahepatic recurrence following curative-intent resection of HCC. This nomogram may help identify patients at high risk of extrahepatic recurrence and guide surveillance protocols as well as adjuvant treatments.

DOI： 10.1245/s10434-021-10142-7

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BACKGROUND: Mutations of BRCA genes are the most studied in breast cancer, but the clinical relevance of BRCA2 gene expression has been less well studied. Given that BRCA2 is a DNA repair gene, we hypothesized that high BRCA2 expression is associated with highly proliferative and aggressive biology in breast cancer. MATERIALS AND METHODS: A total of 4342 breast cancer patients were analyzed from The Cancer Genome Atlas (TCGA, n = 1069) as the testing cohort and Gene Expression Omnibus (GEO) dataset GSE96058 (n = 3273) as a validation cohort. RESULTS: There was no relationship between BRCA2 mutation and BRCA2 gene expression. BRCA2 high expression breast cancer was associated with higher Nottingham grade (p < 0.001), with high proliferation (MKI-67, p < 0.001), and with higher intratumor heterogeneity, homologous recombination deficiency, mutation rate, fraction altered, and neoantigens (all p < 0.001). BRCA2 high expression was associated with E2F1, RB1, PALB2, and PARP, as well as cell proliferation-related gene sets, E2F targets, G2M checkpoints, and mitotic spindle, and with less ESR1 and ER response early and late gene sets. They were associated with significantly reduced number of stroma cells and with high infiltration of both favorable and unfavorable immune cells. BRCA2 high expression significantly correlated with response to olaparib, a PARP inhibitor, and inversely with cyclophosphamide in ER-positive/HER2-negative tumors, but not in TNBC. CONCLUSIONS: BRCA2 high gene expression was associated with highly proliferative and aggressive breast cancer that was highly immunogenic with better response to PARP inhibitors in ER-positive patients. BRCA2 gene expression may become a candidate marker for aggressive biology and to tailor specific treatment strategies in the future.

DOI： 10.1245/s10434-021-10063-5

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Sulphur-containing compounds have been linked to colorectal cancer by factors such as the presence of methyl mercaptan in intestinal gas and long-term dietary intake associated with sulphur-metabolizing microbiota. Therefore, this current case report hypothesized that active sulphur metabolism in colorectal cancer results in the formation of sulphur compounds in the intestine and, thus, examined sulphur metabolites possibly associated with sulphur respiration in colon cancer tissues. The patient was a 73-year-old female that underwent laparoscopic right hemicolectomy for ascending colon cancer. During the surgery, colon cancer tissues and normal intestinal mucosa samples were collected. After optimizing the sample concentrations for homogenization (pre-treatment), the samples were stabilized using a hydroxyphenyl-containing derivative and the relevant metabolites were quantified using liquid chromatography with tandem mass spectrometry. The results showed that cysteine persulfide and cysteine trisulfide levels were higher in colon cancer tissues than in normal mucosal tissues. Thus, sulphur metabolism, possibly sulphur respiration, is enhanced in colon cancer tissues.

DOI： 10.1177/03000605211059936

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Background: Real-world outcomes of nivolumab treatment for gastric cancer and associated prognostic factors remain unclear; the present study aimed to evaluate both items. Methods: A total of 278 consecutive patients treated with nivolumab for gastric cancer during 2017-2019 were enrolled in this multi-institutional retrospective cohort study. The impact of laboratory findings, immune-related adverse events (irAEs), and clinicopathological factors on long-term survival was evaluated using the Cox proportional hazards model. Results: The response rate was 11.7% in patients with measurable lesions. The overall and progression-free survival estimates were 6.77 and 2.53 months, respectively. The incidence of irAEs was 30.6% (6.8% for grade ≥3). There were no treatment-related deaths. Multivariate analysis revealed that C-reactive protein level of ≤0.5 mg/dL (hazard ratio = 0.476, P < .001), irAE occurrence (hazard ratio = 0.544, P < .001), albumin level of >3.5 g/dL (hazard ratio = 0.688, P = .045), performance status 0 (hazard ratio = 0.711, P = .028), lymphocyte count >1000/μL (hazard ratio = 0.686, P = .027), and differentiated histological type (hazard ratio = 0.740, P = .046) were independently associated with improved survival. The median survival of patients with four or more good prognostic factors was 18.3 months. Conclusion: Nivolumab showed safety and survival benefits in patients with previously treated unresectable or recurrent gastric cancer. Low C-reactive protein level, irAE occurrence, high albumin level, high lymphocyte count, and differentiated histological type may affect outcomes. The presence of four or more good prognostic factors may help identify likely long-term survivors.

DOI： 10.1002/ags3.12489

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DOI： 10.1245/s10434-021-10135-6

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Language：Japanese   Publisher：(一社)日本消化器外科学会  

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BACKGROUND: The prognostic implication of mutant KRAS (mKRAS) among patients with primary disease in the rectum remains unknown. METHODS: From 2000 to 2018, patients undergoing hepatectomy for colorectal liver metastases at 10 collaborating international institutions with documented KRAS status were surveyed. RESULTS: A total of 834 (65.8%) patients with primary colon cancer and 434 (34.2%) patients with primary rectal cancer were included. In patients with primary colon cancer, mKRAS served as a reliable prognostic biomarker of poor overall survival (OS) (hazard ratio [HR]: 1.58, 95% CI 1.28-1.95) in the multivariable analysis. Although a trend towards significance was noted, mKRAS was not found to be an independent predictor of OS in patients with primary rectal tumors (HR 1.34, 95% CI 0.98-1.80). For colon cancer, the specific codon impacted in mKRAS appears to reflect underlying disease biology and oncologic outcomes, with codon 13 being associated with particularly poor OS in patients with left-sided tumors (codon 12, HR 1.56, 95% CI 1.22-1.99; codon 13, HR 2.10 95% CI 1.43-3.08;). Stratifying the rectal patient population by codon mutation did not confer prognostic significance following hepatectomy. CONCLUSIONS: While the left-sided colonic disease is frequently grouped with rectal disease, our analysis suggests that there exist fundamental biologic differences that drive disparate outcomes. Although there was a trend toward significance of KRAS mutations for patients with primary rectal cancers, it failed to achieve statistical significance.

DOI： 10.1002/jhbp.1054

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：NLM (Medline)  

DOI： 10.1097/DCR.0000000000002042

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Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：(一社)日本消化器外科学会  

症例は55歳の男性で,肝腫瘍精査にて前医を受診し,経皮肝生検でadenocarcinomaを認め肝内胆管癌の診断となった.ERCPでは右肝管から肝門部に至る狭窄を認めた.CTでは肝右葉に45mm大の不整形な乏血性腫瘤を認め,右肝動脈を含めた右グリソン鞘への浸潤を認めた.また,肝門リンパ節腫大を認めた.以上より,肝内胆管癌(T3N1M0 cStage IVA)と診断され,前医では切除不能と判断された.GEM+CDDP療法を計10コース施行したところ治療効果判定SDであったため切除の可否を含め当科紹介となった.当科では治癒切除可能と判断し,肝右葉尾状葉切除,肝外胆管切除,胆嚢摘出術,D2郭清を施行した.病理学的には腫瘤形成型の中分化型腺癌であり,門脈浸潤・右肝管浸潤を認め,傍大動脈リンパ節を含めリンパ節転移を認めた.また,胆嚢粘膜にも癌を認め,肝内胆管癌の胆嚢転移と診断した.(著者抄録)

DOI： 10.5833/jjgs.2020.0104

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The symposium "New criteria of resectability for pancreatic cancer" was held during the 33nd meeting of the Japanese Society of Hepato-Biliary-Pancreatic Surgery (JSHBPS) in 2021 to discuss the potential modifications that could be made in the current resectability classification. The meeting focused on setting the foundation for developing a new prognosis-based resectability classification that is based on the tumor biology and the response to neoadjuvant treatment (NAT). The symposium included selected experts from Western and Eastern high-volume centers who have discussed their concept of resectability status through published literature. During the symposium, presenters reported new resectability classifications from their respective institutions based on tumor biology, conditional status, pathology, and genetics, in addition to anatomical tumor involvement. Interestingly, experts from all the centers reached the agreement that anatomy alone is insufficient to define resectability in the current era of effective NAT. On behalf of the JSHBPS, we would like to summarize the content of the conference in this position paper. We also invite global experts as internal reviewers of this paper for intercontinental cooperation in creating an up-to-date, prognosis-based resectability classification that reflects the trends of contemporary clinical practice.

DOI： 10.1002/jhbp.1049

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Language：Japanese   Publisher：日本臨床外科学会  

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Hepatocellular carcinoma is a leading cause of cancer death worldwide. The unfolded protein response (UPR) has been revealed to confer tumorigenic capacity in cancer cells. We hypothesized that a quantifiable score representative of the UPR could be used as a biomarker for cancer progression in HCC. In this study, a total of 655 HCC patients from 4 independent HCC cohorts were studied to examine the relationships between enhancement of the UPR and cancer biology and patient survival in HCC utilizing an UPR score. The UPR correlated with carcinogenic sequence and progression of HCC consistently in two cohorts. Enhanced UPR was associated with the clinical parameters of HCC progression, such as cancer stage and multiple parameters of cell proliferation, including histological grade, mKI67 gene expression, and enrichment of cell proliferation-related gene sets. The UPR was significantly associated with increased mutational load, but not with immune cell infiltration or angiogeneis across independent cohorts. The UPR was consistently associated with worse survival across independent cohorts of HCC. In conclusion, the UPR score may be useful as a biomarker to predict prognosis and to better understand HCC.

DOI： 10.3390/cancers13174443

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Elsevier B.V.  

Background: To improve the prognostic accuracy of the 8th edition of the American Joint Committee on Cancer (AJCC) staging system for intrahepatic cholangiocarcinoma (ICC) with establishment and validation of a modified TNM (mTNM) staging system. Methods: Data on patients who underwent curative-intent resection for ICC was collected from 15 high-volume centers worldwide (n = 643). An external validation dataset was obtained from the SEER registry (n = 797). The mTNM staging system was proposed by redefining T categories, and incorporating the recently proposed N status as N0 (no lymph node metastasis [LNM]), N1 (1–2 LNM) and N2 (≥3 LNM). Results: The 8th AJCC TNM staging system failed to stratify overall survival (OS) of stage II versus IIIA, stage IIIB versus IV, as well as overall stage III versus IV among all patients from the two databases, as well as stage I versus II, and stage III versus III among patients who had ≥6 LNs examined. There was a monotonic decrement in survival based on the proposed mTNM staging classification among patients derived from both the multi-institutional (Median OS, stage I 69.8 vs. II 37.1 vs. III 18.9 vs. IV 16.4 months, all p &lt
0.05), and SEER (Median OS, stage I 87.0 vs. II 29.3 vs. III 17.7 vs. IV 14.2 months, all p &lt
0.05) datasets, which was also verified among patients who had ≥6 lymph node harvested from both databases. Conclusion: The modified TNM staging system for ICC using the new T and N definitions provided an improved means to stratify patients relative to long-term OS versus the 8th AJCC staging.

DOI： 10.1016/j.hpb.2021.02.009

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Language：Japanese   Publisher：(一社)日本大腸肛門病学会  

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AIM: This study aimed at investigating the real-world prognostic impact of systemic treatment in older patients with stage II/III breast cancer (BC). METHODS: This retrospective cohort study included patients with stage II/III primary BC, aged ≥55 years, and registered in the Japanese Breast Cancer Registry from 2004 to 2011. The clinicopathological characteristics, treatments, and prognosis of patients aged ≥75 years (older) were compared to those of younger patients. RESULTS: In total, 56,093 patients (12,727, ≥75 years; 17,860, 65-74 years; 25,506, 55-64 years) were enrolled. In the older group, 9.2% with a luminal (hormone receptor [HR]+/human epidermal growth factor receptor 2 [HER2]-), 32.9% with a triple-negative (TN, HR-/HER2-), and 27.4% with a HER2-positive (any-HR/HER2+) receptor were administered chemotherapy. In those with luminal cancer, the 5-year breast cancer-specific survival (BCSS) was approximately 95% in all age groups. Meanwhile, among those with TN and HER2-positive BC, the older group had a poorer BCSS. The 5-year overall survival (OS) was also poorer in the older group across all subtypes. Among older patients matched using clinicopathological factors, chemotherapy use was associated with improved OS in the luminal and HER2-positive subtypes. CONCLUSIONS: Chemotherapy use was lower among older patients with stage II/III breast cancer. Those with TN and HER2-positive BC had a lower BCSS than their younger counterparts. Chemotherapy may be beneficial in improving the OS in older patients with luminal and HER2-positive BCs. Treatment for older patients should be individualized, based on tumor-related factors, quality of life, and the patient's health status.

DOI： 10.1016/j.ejca.2021.06.006

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BACKGROUND: The significance of the dimensional factors (tumor diameter, area and volume) as the prognostic factor has not been precisely evaluated in pT1 gastric cancer. OBJECTIVES: This study aimed to identify the clinical impact and to confirm the clinical feasibility of the dimensional factors as prognostic factors in pT1 gastric cancer. METHODS: We analyzed prognostic factors for disease-specific survival (DSS), overall survival (OS) using clinicopathological factors by univariate and multivariate analyses and the pattern of recurrence in 2011 pT1 gastric cancer (mucosal and submucosal cancers) undergoing R0 gastrectomy. The cut-off values of each dimensional factor was decided by the ROC curve. RESULTS: Cox proportional hazard regression model showed that older age (≥75) and more advanced pN stage were adverse independent prognostic factors for DSS, and revealed that older age (≥75), greater preoperative co-morbid diseases, proximal and total gastrectomy, operative method and Clavien-Dindo classification (≥grade III) were independent adverse factors for OS. Any dimensional factors were not independent prognostic factors for any survival. CONCLUSIONS: The dimensional factors do not influence both OS and DSS in pT1 gastric cancer patients and so it is difficult to apply these dimensional factors for conducting therapeutic strategies.

DOI： 10.1016/j.suronc.2021.101584

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Background: We aimed to present the 2019 annual report of the gastroenterological section of the National Clinical Database (NCD). Methods: We reviewed 609,589 cases recorded in 2019 and 5,029,764 cases registered from 2011 to 2019 for the 115 selected gastroenterological surgical procedures. Results: The main features of gastroenterological surgery in Japan were similar to those described in the 2018 annual report, namely, that 1) operative numbers gradually increased in all procedures, except gastrectomy and hepatectomy, which decreased in these years; 2) in all eight major gastroenterological surgeries, the age distribution tended toward older patients; 3) the morbidity of esophagectomy, hepatectomy, and pancreaticoduodenectomy increased, but mortality was minimized in all procedures; 4) all eight major gastroenterological procedures have increasingly been performed under laparoscopy; and 5) board-certified surgeons were increasingly involved. These trends in recent years were more prominent in 2019. Conclusions: Thanks to the continuous cooperation and dedication of the surgeons, medical staff, and surgical clinical reviewers who registered the clinical data into the NCD, it is possible to understand the comprehensive landscape of surgery in Japan and to disclose new evidence in this field. The Japanese Society of Gastroenterological Surgery will continue to promote the value of this database and encourage the use of feedback and clinical studies using the NCD, now and in the future. Generating further approaches to surgical quality improvement are important directions for future research.

DOI： 10.1002/ags3.12462

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Language：Japanese   Publisher：日本臨床外科学会  

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Obstructive jaundice is a major symptom of pancreatic head cancer, and although its amelioration is required before scheduling chemotherapy, the decision to perform biliary drainage for resectable pancreatic cancer has remained controversial. In recent years, the effectiveness of neoadjuvant therapy for pancreatic cancer has been reported. Preoperative biliary drainage has become increasingly necessary, making the choice of stent an important one; thus, the longer the waiting period extends through neoadjuvant chemotherapy, the more durable stents - such as self-expandable metallic stents, rather than plastic stents - would be desired as an option. Still, there is insufficient evidence regarding surgical outcomes and long-term prognosis, and further confirmatory studies are needed. Through this review, we aim to provide an update on the characteristics of biliary stents and preoperative biliary drainage for potentially resectable pancreatic cancer.

DOI： 10.1111/den.14107

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BACKGROUND: Although multidisciplinary treatments including the use of adjuvant therapy (AT) have been adopted for biliary tract cancers, patients with distal cholangiocarcinoma (DCC) can still experience recurrence. We sought to characterize the incidence and predictors of early recurrence (ER) that occurred within 12 months following surgery for DCC. PATIENTS AND METHODS: Patients who underwent resection for DCC between 2000 and 2015 were identified from the US multi-institutional database. Cox regression analysis was used to identify clinicopathological factors to develop an ER risk score, and the predictive model was validated in an external dataset. RESULTS: Among 245 patients included in the analysis, 67 patients (27.3%) developed ER. No difference was noted in ER rates between patients who did and did not receive AT (28.7% vs. 25.0%, p = 0.55). Multivariable analysis revealed that neutrophil-to-lymphocyte ratio (NLR), peak total bilirubin (T-Bil), major vascular resection (MVR), lymphovascular invasion, and R1 surgical margin status were associated with a higher ER risk. A DIstal Cholangiocarcinoma Early Recurrence Score was developed according to each factor available prior to surgery [NLR > 9.0 (2 points); peak T-bil > 1.5 mg/dL (1 points); MVR (2 points)]. Cumulative ER rates incrementally increased among patients who were low (0 points; 10.6%), intermediate (1-2 points; 26.8%), or high (3-5 points; 57.6%) risk (p < 0.001) in the training dataset, as well as in the validation dataset [low (0 points); 3.4%, intermediate (1-2 points); 32.7%, or high risk (3-5 points); 55.6% (p < 0.001)]. CONCLUSIONS: Among patients undergoing resection for DCC, 1 in 4 patients experienced an ER. Alternative treatment strategies such as neoadjuvant chemotherapy may be considered especially among individuals deemed to be at high risk for ER.

DOI： 10.1245/s10434-021-09811-4

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BACKGROUND: Sentinel lymph node (SLN) biopsy has been the standard modality for breast cancer patients with clinically node negative disease. In patients who undergo axillary lymph node dissection (ALND) due to SLN metastasis, the harvested nodes (non-SLNs) often contain no metastasis. Here, we evaluated the predictive factors associated with non-SLN metastasis in breast cancer patients. MATERIALS AND METHODS: This was a retrospective study of patients with operable cT1-3, cN0 invasive breast cancer who underwent SLN biopsy followed by ALND due to SLN metastasis. The clinicopathologic factors and predictive factors of non-SLN metastasis were analyzed. The optimal cutoff for the Ki67 index and the number of positive and negative SLNs that were predictive of non-SLN metastasis were evaluated using receiver operating characteristic curves. RESULTS: The median number of SLN and non-SLN was 3 and 11, respectively. Of the 150 patients, 52 (35.0%) had metastases in non-SLNs. The optimal cutoffs for the Ki67 index and the number of positive and negative SLNs were of 12%, 2, and 1, respectively. In the univariate analysis, the Ki67 index and the number of positive SLNs≥2 and negative SLNs≤1 were higher in the non-SLN + group than that in the non-SLN - group. The number of negative SLNs was as a predictive factor for non-SLNs metastasis in the multivariate analysis. CONCLUSIONS: The number of negative SLNs predicts the risk of non-SLN metastasis in breast cancer. When deciding on whether to omit ALND, the number of positive and negative SLNs should be considered.

DOI： 10.1016/j.jss.2021.01.047

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PURPOSE: Surgery in elderly patients with esophageal cancer is challenging due to high mortality and limited survival. This study aimed to evaluate the safety and effectiveness of curative esophagectomy in elderly patients with esophageal cancer. METHODS: This study included 77 and 112 patients with esophageal cancer aged ≥ 70 and 40-64 years, respectively, who underwent R0 esophagectomy between January 1998 and December 2016. Patient characteristics, intraoperative outcomes, postoperative complications, and long-term survival were compared. RESULTS: The proportions of comorbid diseases (85.7% vs. 57.1%; P < 0.001), the American Society of Anesthesiologists score (1/2/3; 2.6%/94.8%/2.6% vs. 42.9%/57.1%/0%; P < 0.001), the preoperative systemic inflammation score (SIS) (0/1/2; 20.8%/48.1%/31.2% vs. 38.4%/38.4%/23.2%; P = 0.036), and postoperative complications (Clavien-Dindo grade ≥ III) (33.8% vs. 20.5%; P = 0.041) were significantly higher in the elderly group than those in the non-elderly group. However, long-term overall survival (OS) and relapse-free survival were not significantly different between the groups. On multivariate analysis, SIS (hazard ratio, 3.06; P = 0.037) and severe postoperative complications (hazard ratio, 2.01; P = 0.039) were significantly correlated with OS in the elderly group. CONCLUSIONS: As SIS and severe postoperative complications lead to poor prognosis after R0 esophagectomy in elderly patients, selecting appropriate patients for esophagectomy and preventing severe postoperative complications is essential.

DOI： 10.1007/s00423-021-02271-0

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PURPOSE: This study performed a comprehensive molecular characterization of microsatellite instability-high (MSI-H)/mismatch repair-deficient (dMMR) gastrointestinal (GI) tumors to elucidate predictors of response to PD-1 blockade. EXPERIMENTAL DESIGN: Forty-five patients with MSI-H/dMMR GI tumors, including gastric cancer, colorectal cancer, cholangiocarcinoma, small intestine cancer, pancreatic cancer, and duodenal cancer, receiving PD-1 blockade were analyzed. We conducted the genomic profiling of GI tumors by whole-exome sequencing or targeted next-generation sequencing. The tumor microenvironment was evaluated by transcriptomic analysis and multiplex fluorescence IHC. RESULTS: Patients with low tumor mutational burdens (TMBs) had lower objective response rates (ORRs; 0% vs. 48.8%) and a significantly shorter progression-free survival (PFS; 2.3 vs. 15.6 months; HR, 6.20; P = 0.002) than those with high TMBs. Among common gene alterations in GI tumors, only PTEN mutations, which were mutually exclusive with a low TMB, were significantly associated with a lower ORRs than wild-type PTEN (21.4 vs. 54.8%; odds, 4.45; P = 0.045). Compared with wild-type PTEN, PTEN mutations in the phosphatase domain were associated with significantly lower ORRs (12.5 vs. 54.8%; P = 0.049), shorter PFS (2.6 vs. 15.6 months; HR, 5.04; P < 0.001), lower intratumoral CD8+ T-cell levels, higher intratumoral CD204+ macrophage levels, and PI3K/AKT/mTOR pathway enrichment, whereas PTEN mutations in the C2 domain were not. CONCLUSIONS: Low TMBs and PTEN mutations, especially mutations in the phosphatase domain associated with an immunosuppressive environment, were mutually exclusive and might be negative predictors of PD-1 blockade responses in patients with MSI-H/dMMR GI tumors.

DOI： 10.1158/1078-0432.CCR-21-0401

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Language：Japanese   Publisher：(一社)日本乳癌学会  

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INTRODUCTION: Two novel clinical risk scores (CRS) that incorporate KRAS mutation status were developed: modified CRS (mCRS) and GAME score. However, they have not been tested in large national and international cohorts. The aim of this study was to validate the prognostic discrimination utility and determine the clinical usefulness of the two novel CRS. METHODS: Patients undergoing hepatectomy for CRLM (2000-2018) in 10 centers were included. The discriminatory abilities of mCRS, GAME, and Fong CRS were evaluated using Harrell's C-index and Akaike's Information Criterion. RESULTS: In the entire cohort, the C-index of the GAME score (0.61) was significantly higher than those of Fong score (0.57) and mCRS (0.54), while the C-Index of mCRS was significantly lower than that of Fong score. When we compared the models in the various geographical regions, the C-index of GAME score was significantly higher than that of mCRS in North America, Europe, and South America. The AIC of Fong score, mCRS, and GAME score were 14 405, 14 447, and 14 319, respectively. CONCLUSION: In conclusion, using the largest and most heterogenous population of CRLM patients with known KRAS status, this independent, external validation demonstrated that the GAME score outperforms both the traditional Fong score and mCRS.

DOI： 10.1002/jhbp.963

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AIM: To evaluate the association between bromodomain-containing protein 4 (BRD4) expression and clinicopathological factors and prognosis in human breast cancer specimens. PATIENTS AND METHODS: We used tissue microarrays constructed from samples of patients (n=183) who underwent surgery. We validated the association between BRD4 expression and prognosis in solid tumours, including breast cancer, using The Cancer Genome Atlas (TCGA) database. RESULTS: Immunohistochemical staining showed that BRD4 was widely distributed in breast cancer tissues. BRD4 was strongly expressed in 19.7% of patients but BRD4 staining intensity was not correlated with other clinicopathological factors. Most importantly, patients with a strong BRD4 expression had a significantly longer disease-specific survival than those with a weak BRD4 expression (100.0% vs. 91.3% at 5 years, p=0.027). mRNA expression analysis showed similar results (91.2% vs. 80.2% at 6 years, p=0.047). CONCLUSION: Strong BRD4 expression was associated with a significantly better prognosis in breast cancer tumours.

DOI： 10.21873/anticanres.15148

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INTRODUCTION: The ACS NSQIP Surgical Risk Calculator (SRC) assesses risk to support goal-concordant care. While it accurately predicts US outcomes, its performance internationally is unknown. This study evaluates SRC accuracy in predicting mortality following low anterior resection (LAR) and pancreaticoduodenectomy (PD) in NSQIP patients and accuracy retention when applied to native Japanese patients (National Clinical Database, NCD). METHODS: NSQIP (41,260 LAR; 15,114 PD) and NCD cases (61,220 LAR; 27,901 PD) from 2015 to 2017 were processed through the SRC mortality model. Country-specific calibration and discrimination were assessed with and without an intercept correction applied to the Japanese data. RESULTS: The SRC exhibited acceptable calibration for LAR and PD when applied to NSQIP data but miscalibration for NCD data. A simple correction to the model intercept, motivated by lower mortality rates in the Japanese data, successfully remediated the miscalibration. CONCLUSIONS: The SRC may inaccurately predict surgical risk when applied to the native Japanese population. An intercept correction method is suggested when miscalibration is encountered; it is simple to implement and may permit effective international use of the SRC.

DOI： 10.1016/j.amjsurg.2021.06.008

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BACKGROUND: Long-term outcomes in gastric cancer patients with positive lavage cytology (CY1) are generally poor. This multi-institutional retrospective cohort study aims to evaluate the clinical significance of the neutrophil-lymphocyte ratio (NLR) and the lymphocyte-monocyte ratio (LMR) in CY1 gastric cancer patients. METHODS: A total of 121 CY1 gastric cancer patients without other non-curative factors, who underwent macroscopically curative resection, were enrolled in this study. The cutoff values of preoperative NLR (pre-NLR), postoperative NLR (post-NLR), preoperative LMR (pre-LMR), and postoperative LMR (post-LMR) were defined by the Contal and O'Quigley method as 2.3, 3.0, 2.5, and 3.2, respectively. A Cox proportional hazard model was used to identify the independent prognostic factors among NLR, LMR, and other clinicopathological factors. RESULTS: There were significant differences in the overall survival (OS) between the two groups: high post-NLR groups vs. low post-NLR group (median survival time, months) (10.9 vs. 22.8, P = 0.006) and high pre-LMR group vs. low pre-LMR group (21.3 vs. 11.0, P = 0.001). The LMR value elevated significantly after gastrectomy (P = 0.020), although not in the NLR value (P = 0.733). On multivariate analysis, high post-NLR (hazard ratio = 1.506; 95% confidence interval = 1.047-2.167; P = 0.027), low pre-LMR (1.773; 1.135-2.769, 0.012), and no postoperative chemotherapy (1.558; 1.053-2.305, 0.027) were found to be independent prognostic factors for adverse OS. CONCLUSIONS: Because a combination of high post-NLR and low pre-LMR may be an adverse prognostic marker in resectable CY1 gastric cancer patients, it is necessary to conduct a prospective trial to confirm a useful perioperative chemotherapeutic regimen for these patients.

DOI： 10.1007/s00423-021-02233-6

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Cancer-associated adipocytes are known to cause inflammation; however, the role of adipogenesis, the formation of adipocytes, in breast cancer is unclear. We hypothesized that intra-tumoral adipogenesis reflects a different cancer biology than abundance of intra-tumoral adipocytes. The Molecular Signatures Database Hallmark adipogenesis gene set of gene set variant analysis was used to quantify adipogenesis. Total of 5,098 breast cancer patients in multiple cohorts (training; GSE96058 (n = 3273), validation; TCGA (n = 1069), treatment response; GSE25066 (n = 508) and GSE20194 (n = 248)) were analyzed. Adipogenesis did not correlate with abundance of adipocytes. Adipogenesis was significantly lower in triple negative breast cancer (TNBC). Elevated adipogenesis was significantly associated with worse survival in TNBC, but not in the other subtypes. High adipogenesis TNBC was significantly associated with low homologous recombination deficiency, but not with mutation load. High adipogenesis TNBC enriched metabolism-related gene sets, but neither of cell proliferation- nor inflammation-related gene sets, which were enriched to adipocytes. High adipogenesis TNBC was infiltrated with low CD8+ T cells and high M2 macrophages. Although adipogenesis was not associated with neoadjuvant chemotherapy response, high adipogenesis TNBC was significantly associated with low expression of PD-L1 and PD-L2 genes, and immune checkpoint molecules index. In conclusion, adipogenesis in TNBC was associated with cancer metabolism and unfavorable tumor immune microenvironment, which is different from abundance of adipocytes.

DOI： 10.1038/s41598-021-91897-7

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Elderly patients are known to have a worse prognosis for breast cancer. This is commonly blamed on their medical comorbidities and access to care. However, in addition to these social issues, we hypothesized that the extreme elderly (octogenarians-patients over 80 years old) have biologically worse cancer with unfavorable tumor immune microenvironment. The Cancer Genomic Atlas (TCGA) and the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) breast cancer cohorts were analyzed. The control (aged 40-65) and octogenarians numbered 668 and 53 in TCGA and 979 and 118 in METABRIC, respectively. Octogenarians had significantly worse breast cancer-specific survival in both cohorts (p < 0.01). Octogenarians had a higher ER-positive subtype rate than controls in both cohorts. Regarding PAM50 classification, luminal-A and -B subtypes were significantly higher in octogenarians, whereas basal and claudin-low subtypes were significantly lower (p < 0.05) in octogenarians. There was no difference in tumor mutation load, intratumor heterogeneity, or cytolytic activity by age. However, the octogenarian cohort was significantly associated with high infiltration of pro-cancer immune cells, M2 macrophage, and regulatory T cells in both cohorts (p < 0.05). Our results demonstrate that octogenarians' breast cancer is associated with worse survival and with an unfavorable tumor immune microenvironment.

DOI： 10.3390/cancers13122933

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BACKGROUND: In addition to the direct power of anticancer drugs, the effectiveness of anticancer therapy depends on the host immune function. The present study investigated whether or not the reduction rate and histological response of preoperative chemotherapy were related to the immune microenvironment surrounding a primary tumor of the rectum. METHODS: Sixty-five patients received preoperative chemotherapy followed by resection from 2012 to 2014; all of these patients were retrospectively analyzed. CD3, CD8, and FoxP3 were immunohistochemically examined as markers for T lymphocytes, cytotoxic T lymphocytes, and regulatory T lymphocytes (Treg), respectively. The correlation between the tumor-infiltrating lymphocyte composition and the tumor reduction rate and histological response to neoadjuvant chemotherapy was investigated. RESULTS: The average tumor reduction rate was 41.5% ± 18.8%. According to RECIST, 47 patients (72.3%) achieved a partial response (PR), and 1 patient (1.5%) achieved a complete response (CR). Eight patients (12.3%) showed a grade 2 histological response, and 2 (3.1%) showed a grade 3 response. A multivariate analysis demonstrated that a low Treg infiltration in stromal cell areas was significantly associated with the achievement of a PR or CR [odds ratio (OR) 7.69; 95% confidence interval (CI) 1.96-33.33; p < 0.01] and a histological grade 2 or 3 response (OR 11.11; 95% CI 1.37-98.04; p = 0.02). CONCLUSION: A low Treg infiltration in the stromal cell areas may be a marker of a good response to neoadjuvant chemotherapy in patients with locally advanced rectal cancer.

DOI： 10.1007/s00595-021-02311-8

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Springer Science and Business Media Deutschland GmbH  

Purpose: This study evaluated the results of laparoscopic surgery (LAP) compared to open surgery (OP) for locally advanced mid-to-lower rectal cancer. Methods: From February 2008 to December 2014, we collected patient data with clinical stage II/III mid-to-lower rectal cancer who underwent resection with LAP or OP at 13 institutions associated with the Yokohama Clinical Oncology Group (YCOG). The short-term outcomes and long-term prognoses associated with LAP and OP were analyzed after adjusting for the patients’ backgrounds using propensity score matching. Results: Among 1091 eligible cases, a propensity score matching with six covariates—age, sex, body mass index, American Society of Anesthesiologists physical status category, tumor location, and clinical stage—extracted 237 cases each for the LAP and OP groups, respectively. After matching, there were no differences in background factors between the two groups except for the presence or absence of preoperative treatment. Operative time was significantly longer in the LAP group than that in the OP group (p &lt
0.001), while the amount of bleeding and the length of postoperative hospital stay were significantly lower in the LAP group than that in the OP group (p &lt
0.001 and p = 0.001, respectively). There were no significant differences between groups in the incidence of postoperative complications. The 3-year overall survival and relapse-free survival rates were 90.5% and 88.6% and 78.3% and 71.6% in the LAP and OP groups, respectively, which did not differ significantly. Conclusions: The short-term outcomes and long-term prognoses of LAP in this cohort study indicated that LAP could be a therapeutic option for locally advanced rectal cancer. Trial Registration: UMIN000040406

DOI： 10.1007/s00384-021-03871-4

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A malignant tumor in the breast may not be conclusive of breast cancer. It is important to keep the possibility of primary breast lymphoma in rare scenarios. For the diagnosis of primary breast lymphoma, immunohistochemical staining is necessary.

DOI： 10.1002/ccr3.4189

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Tissue biopsy is the gold standard for diagnosis and morphological and immunohistochemical analyses to characterize cancer. However, tissue biopsy usually requires an invasive procedure, and it can be challenging depending on the condition of the patient and the location of the tumor. Even liquid biopsy analysis of body fluids such as blood, saliva, gastric juice, sweat, tears and cerebrospinal fluid may require invasive procedures to obtain samples. Liquid biopsy can be applied to circulating tumor cells (CTCs) or nucleic acids (NAs) in blood. Recently, urine has gained popularity due to its less invasive sampling, ability to easily repeat samples, and ability to follow tumor evolution in real-time, making it a powerful tool for diagnosis and treatment monitoring in cancer patients. With the development and advancements in extraction methods of urinary substances, urinary NAs have been found to be closely related to carcinogenesis, metastasis, and therapeutic response, not only in urological cancers but also in non-urological cancers. This review mainly highlights the components of urine liquid biopsy and their utility and limitations in oncology, especially in non-urological cancers.

DOI： 10.3390/cancers13112652

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Although triple-negative breast cancer (TNBC) typically responds better to neoadjuvant chemotherapy (NAC) compared to the other subtypes, a pathological complete response (pCR) is achieved in less than half of the cases. We established a novel three-gene score using genes based on the E2F target gene set that identified pCR after NAC, which showed robust performance in both training and validation cohorts (total of n = 3862 breast cancer patients). We found that the three-gene score was elevated in TNBC compared to the other subtypes. A high score was associated with Nottingham histological grade 3 in TNBC. Across multiple cohorts, high-score TNBC enriched not only E2F targets but also G2M checkpoint and mitotic spindle, which are all cell proliferation-related gene sets. High-score TNBC was associated with homologous recombination deficiency, high mutation load, and high infiltration of Th1, Th2, and gamma-delta T cells. However, the score did not correlate with drug sensitivity for paclitaxel, 5-fluorouracil, cyclophosphamide, and doxorubicin in TNBC human cell lines. High-score TNBC was significantly associated with a high rate of pCR not only in the training cohort but also in the validation cohorts. High-score TNBC was significantly associated with better survival in patients who received chemotherapy but not in patients who did not receive chemotherapy. The three-gene score is associated with a high mutation rate, immune cell infiltration, and predicts response to NAC in TNBC.

DOI： 10.3390/cancers13102401

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Publishing type：Research paper (scientific journal)   Publisher：Elsevier {BV}  

DOI： 10.1016/j.regen.2021.100042

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BACKGROUND/PURPOSE: The relationship between autoimmune pancreatitis (AIP) and malignancy has been reported. However, the potential risk for cancer in patients with immunoglobulin 4 (IgG4)-related sclerosing cholangitis (IgG4-SC) is unclear. The present study aimed to evaluate the incidence of cancer in IgG4-SC patients. METHODS: We retrospectively collected clinical data for 121 patients diagnosed with IgG4-SC from 7 hospitals. We calculated the standardized incidence ratio (SIR) of cancer in IgG4-SC patients based on the national cancer rates. The SIR of the period after the diagnosis of IgG4-SC were calculated. RESULTS: The mean follow-up period was 6.4 years, with 121 IgG4-SC patients. During the follow-up period, 26 patients had cancer, and 29 cancers were diagnosed. The SIR of cancer after the diagnosis of IgG4-SC was 1.90 (95% confidence interval [CI] 1.67-2.21). The SIR of pancreatic and bile duct cancer was 10.30 and 8.88, respectively. The SIR of cancer in <1 year, 1-5 years, and >5 years after diagnosis of IgG4-SC were 2.58, 1.01, and 2.44, respectively. CONCLUSIONS: IgG4-SC patients have a high risk of cancer including pancreatic and bile duct cancer. The risk of cancer was high less <1 year and >5 years after diagnosis of IgG4-SC. Therefore, IgG4-SC patients may require careful long-term follow-up.

DOI： 10.1002/jhbp.957

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Springer Science and Business Media Deutschland GmbH  

Introduction: While tumor burden (TB) has been associated with outcomes among patients with hepatocellular carcinoma, the role of overall TB in intrahepatic cholangiocarcinoma (ICC) remains poorly defined. Methods: Patients undergoing curative-intent resection of ICC between 2000 and 2017 were identified from a multi-institutional database. The impact of TB on overall (OS) and disease-free survival (DFS) was evaluated in the multi-institutional database and validated externally. Results: Among 1101 patients who underwent curative-intent resection of ICC, 624 (56.7%) had low TB, 346 (31.4%) medium TB, and 131 (11.9%) high TB. OS incrementally worsened with higher TB (5-year OS
low TB: 48.3% vs medium TB: 29.8% vs high TB: 17.3%, p &lt
0.001). Similarly, patients with low TB had better DFS compared with medium and high TB patients (5-year DFS: 38.3% vs 18.7% vs 6.9%, p &lt
0.001). On multivariable analysis, TB was independently associated with OS (medium TB: HR = 1.40, 95% CI 1.14–1.71
high TB: HR = 1.89, 95% CI 1.46–2.45) and DFS (medium TB, HR = 1.61, 95% CI 1.33–1.96
high TB: HR = 2.03, 95% CI 1.56–2.64). Survival analysis revealed an excellent prognostic discrimination using the TB among the external validation cohort (3-year OS
low TB: 44.8%, medium TB: 29.3%
high TB: 23.3%, p = 0.03
3-year DFS: low TB: 32.7%, medium TB: 10.7%
high TB: 0%, p &lt
0.001). While neoadjuvant chemotherapy was not associated with survival across the TB groups, receipt of adjuvant chemotherapy was associated with increased survival among patients with high TB (5-year OS: 24.4% vs 13.4%, p = 0.02). Conclusion: Overall TB dictated prognosis among patients with resectable ICC. TB may be used as a tool to help guide post-resection treatment strategies.

DOI： 10.1245/s10434-020-09393-7

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Objective Neuroendocrine neoplasms (NENs) are rare and indolent diseases, but the efficacy of treatment without surgical resection is temporary and limited. Targeted immunotherapy is an important treatment strategy in several cancers. However, the tumor and host immune reactions in the NEN microenvironment are poorly understood. Therefore, we investigated the immune checkpoint system and host immune response in pathological NEN specimens. Methods The expression of the mismatch repair proteins MSH2, MSH6, PMS2, and MLH1 was immunohistochemically detected in archival tissue samples obtained from 20 patients with gastroenteropancreatic NENs. We additionally assessed the expression of programmed death (PD)-1, PD-L1, and the tumor-infiltrating lymphocyte (TIL) markers CD8 and family of transcription factor P3 (FOXP3). Results All 20 NENs expressed the mismatch repair proteins MSH2, MSH6, PMS2, and MLH1. The PD-L1 and/or PD-1 expression in the tumor cells and/or TILs was confirmed in 75% of the cases. PD-1-, CD8-, and FOXP3-positive TILs were more frequently associated with PD-L1-positive tumors than with PD-L1 negative tumors (PD-1: 19.5 vs. 7.3, CD8: 18.1 vs. 7.1, FOXP3: 13.2 vs. 3.2, p=0.438, p=0.419, P=0.603, respectively). The number of cells positive for PD-1 tended to gradually increase in increasing grade of NENs but did not reach significance (Grade 1: 5.8, Grade 2: 10.2, NEC: 18.1, p=0.903). Conclusion NENs consistently express mismatch repair proteins but have a high expression of PD-L1 and/or PD-1 in the tumor microenvironment. NEC and PD-L1-positive NENs may be immunologically "hot" tumors, so an immunological approach may be an appropriate treatment strategy for these tumors.

DOI： 10.2169/internalmedicine.5648-20

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The Japanese Society of Hepato-Biliary-Pancreatic Surgery launched the clinical practice guidelines for the management of biliary tract cancers (cholangiocarcinoma, gallbladder cancer, and ampullary cancer) in 2007, then published the 2nd version in 2014. In this 3rd version, clinical questions (CQs) were proposed on six topics. The recommendation, grade for recommendation, and statement for each CQ were discussed and finalized by an evidence-based approach. Recommendations were graded as grade 1 (strong) or grade 2 (weak) according to the concepts of the grading of recommendations assessment, development, and evaluation system. The 31 CQs covered the six topics: (1) prophylactic treatment, (2) diagnosis, (3) biliary drainage, (4) surgical treatment, (5) chemotherapy, and (6) radiation therapy. In the 31 CQs, 14 recommendations were rated strong and 14 recommendations weak. The remaining three CQs had no recommendation. Each CQ includes a statement of how the recommendations were graded. This latest guideline provides recommendations for important clinical aspects based on evidence. Future collaboration with the cancer registry will be key for assessing the guidelines and establishing new evidence.

DOI： 10.3760/cma.j.cn115610-20210303-00107

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Publishing type：Research paper (scientific journal)   Publisher：Elsevier BV  

DOI： 10.1016/j.asjsur.2021.03.034

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BACKGROUND: The high operative mortality rate after hepatopancreatoduodenectomy (HPD) is still a major issue. The present study explored why operative mortality differs significantly due to hospital volume. METHOD: Surgical case data were extracted from the National Clinical Database (NCD) in Japan from 2011 to 2014. Surgical procedures were categorized as major (≥2 sections) and minor (<2 sections) hepatectomy. Hospitals were categorized according to the certification system by the Japanese Society of Hepato-Biliary-Pancreatic Surgery (JSHBPS) based on the number of major hepato-biliary-pancreatic surgeries performed per year. The FTR rate was defined as death in a patient with at least one postoperative complication. RESULTS: A total of 422 patients who underwent HPD were analyzed. The operative mortality rates in board-certified A training institutions, board-certified B training institutions, and non-certified institution were 7.2%, 11.6%, and 21.4%, respectively. Multiple logistic regression showed that certified A institutions, major hepatectomy, and blood transfusion were the predictors of operative mortality. Failure to rescue rates were lowest in certified A institutions (9.3%, 17.0%, and 33.3% in certified A, certified B, and non-certified, respectively). CONCLUSIONS: To reduce operative mortality after HPD, further centralization of this procedure is desirable. Future studies should clarify specific ways to improve the failure-to-rescue rates in certified institutions.

DOI： 10.1002/jhbp.918

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Language：Japanese   Publisher：(一社)日本外科学会  

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BACKGROUND/PURPOSE: The role of endoscopic preoperative biliary drainage for pancreatic head cancer is controversial because of the high incidence of stent occlusion before surgery. We sought to validate a suitable stent for biliary drainage in patients with pancreatic cancer undergoing neoadjuvant chemotherapy (NAC)/neoadjuvant chemoradiotherapy (NAC-RT). METHODS: We evaluated patients who received preoperative neoadjuvant therapy for pancreatic head cancer between January 2013 and December 2019. A covered metal (CMS) or plastic stent (PS) was inserted in symptomatic patients for biliary drainage. Recurrent biliary obstruction (RBO), success rate of endoscopic drainage, adverse events, and surgical outcomes were compared between the CMS and PS groups. RESULTS: Occurrence rate of RBO was significantly higher with PS (97%) vs CMS (15%, P < .001), and time to RBO was significantly longer with CMS vs PS (not reached vs 40.5 days, P < .001). Delayed schedule associated with RBO for neoadjuvant chemotherapy was significantly lower in CMS vs PS (14% vs 50%, P < .05). There was no difference in postoperative bleeding, operation time, complications, and rate of a microscopically margin-negative resection between groups. CONCLUSIONS: Use of CMS during NAC/NAC-RT allows for safe chemotherapy without causing cholangitis or biliary obstruction and for surgery to be performed.

DOI： 10.1002/jhbp.958

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The generation of pathologic, immature, and dysfunctional vessels by angiogenesis is a mechanism of metastasis that has been a therapeutic target for colorectal cancer (CRC). In this study, we investigated the clinical relevance of intra-tumoral microvascular endothelial (mvE) cells in CRC using the xCell algorithm on transcriptome. A total of 1244 CRC patients in discovery and validation cohorts were analyzed. We found that an abundance of mvE cells did not mirror angiogenesis but reflected mature blood vessels because it was significantly associated with a high expression of vascular stability-related genes, including sphingosine-1-phosphate receptor genes and pericytes. Epithelial-mesenchymal transition and myogenesis gene sets were enriched in mvE cell abundant CRC, while mvE cell-less CRC enriched cell proliferation, oxidative phosphorylation, and protein secretion gene sets. mvE cell abundant CRC was associated with infiltration of M2 macrophages, dendritic cells, and less gamma-delta T cells (all p < 0.001), but not with the interferon-γ response. mvE cell abundant CRC was significantly associated with worse patient survival in CRC. Interestingly, mvE cell abundant CRC was significantly associated with a high response rate to chemotherapy (p = 0.012) and worse patient survival for those that did not receive chemotherapy. However, there was no survival difference in patients who underwent chemotherapy. In conclusion, we estimated the abundance of mvE cells using the xCell algorithm on tumor transcriptome finding its association with the number of mature blood vessels in a tumor microenvironment and its ability to predict response to chemotherapy, thereby patient survival in CRC.

DOI： 10.3390/cancers13061477

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Publishing type：Research paper (scientific journal)   Publisher：Wiley  

DOI： 10.1002/jhbp.920

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Annexin A1 (ANXA1) is a calcium-dependent phospholipid-binding protein overexpressed in pancreatic cancer (PC). ANXA1 expression has been shown to take part in a wide variety of cancer biology, including carcinogenesis, cell proliferation, invasion, apoptosis, and metastasis, in addition to the initially identified anti-inflammatory effect in experimental settings. We hypothesized that ANXA1 expression is associated with cell proliferation and survival in PC patients. To test this hypothesis, we analyzed 239 PC patients in The Cancer Genome Atlas (TCGA) and GSE57495 cohorts. ANXA1 expression correlated with epithelial-mesenchymal transition (EMT) but weakly with angiogenesis in PC patients. ANXA1-high PC was significantly associated with a high fraction of fibroblasts and keratinocytes in the tumor microenvironment. ANXA1 high PC enriched multiple malignant gene sets, including hypoxia, tumor necrosis factor (TNF)-α signaling via nuclear factor-kappa B (NF-kB), and MTORC1, as well as apoptosis, protein secretion, glycolysis, and the androgen response gene sets consistently in both cohorts. ANXA1 expression was associated with TP53 mutation alone but associated with all KRAS, p53, E2F, and transforming growth factor (TGF)-β signaling pathways and also associated with homologous recombination deficiency in the TCGA cohort. ANXA1 high PC was associated with a high infiltration of T-helper type 2 cells in the TME, with advanced histological grade and MKI67 expression, as well as with a worse prognosis regardless of the grade. ANXA1 expression correlated with a sensitivity to gemcitabine, doxorubicin, and 5-fluorouracil in PC cell lines. In conclusion, ANXA1 expression is associated with EMT, cell proliferation, survival, and the drug response in PC.

DOI： 10.3390/cells10030653

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：International Institute of Anticancer Research  

Background/Aim: Current expert consensus recommends re-resection for incidental gallbladder cancer (IGBC) of pT1b-3. This study examined whether this consensus was reasonably applicable to patients with IGBC in one Japanese region. Patients and Methods: This was a multicenter, retrospective analysis of cholecystectomies for presumed benign diseases between January 2000 and December 2009. Results: IGBC was diagnosed in 70 (1.0%) out of 6,775 patients undergoing cholecystectomy. Five-year disease-specific cumulative survival was 100% in 19 patients with pT1a, 80.0% in five with pT1b, 49.5% in 33 with pT2, and 23.1% in 13 with pT3. Re-resection was not performed for the 24 patients with pT1a/1b disease, whereas 24 out of 46 patients with pT2/3 underwent re-resection. Regardless of re-resection, independent factors associated with a poor prognosis on multivariate analysis were grade 2 or poorer disease and bile spillage at prior cholecystectomy. In the 24 patients with pT2/3 re-resection, 11 patients without either of these two factors had significantly better 5-year disease-specific cumulative survival than the 13 patients with one or two independent factors associated with a poor prognosis (72.7% vs. 30.8%, p=0.009). Conclusion: This Japanese regional study suggests that indication of re-resection for IGBC should not be determined by pT-factor alone and that much more attention should be paid to pathological and intraoperative findings at prior cholecystectomy.

DOI： 10.21873/INVIVO.12372

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Language：Japanese   Publisher：(一社)日本内視鏡外科学会  

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BACKGROUND AND OBJECTIVES: Despite the long-standing consensus on the importance of tumor size, tumor number and carcinoembryonic antigen (CEA) levels as predictors of long-term outcomes among patients with colorectal liver metastases (CRLM), optimal prognostic cut-offs for these variables have not been established. METHODS: Patients who underwent curative-intent resection of CRLM and had available data on at least one of the three variables of interest above were selected from a multi-institutional dataset of patients with known KRAS mutational status. The resulting cohort was randomly split into training and testing datasets and recursive partitioning analysis was employed to determine optimal cut-offs. The concordance probability estimates (CPEs) for these optimal cut offs were calculated and compared to CPEs for the most widely used cut-offs in the surgical literature. RESULTS: A total of 1643 patients who met eligibility criteria were identified. Following recursive partitioning analysis in the training dataset, the following cut-offs were identified: 2.95 cm for tumor size, 1.5 for tumor number and 6.15 ng/ml for CEA levels. In the entire dataset, the calculated CPEs for the new tumor size (0.52), tumor number (0.56) and CEA (0.53) cut offs exceeded CPEs for other commonly employed cut-offs. CONCLUSION: The current study was able to identify optimal cut-offs for the three most commonly employed prognostic factors in CRLM. While the per variable gains in discriminatory power are modest, these novel cut-offs may help produce appreciable increases in prognostic performance when combined in the context of future risk scores.

DOI： 10.1002/jso.26361

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BACKGROUND: To explore best practices for acute cholecystitis, it is necessary to construct a system to assess the difficulty of laparoscopic cholecystectomy (LC) based on intraoperative findings. In this study, multiple evaluators assessed videos of LC to assemble a library of typical video clips for 25 intraoperative findings. METHODS: We have previously identified 25 items that contribute to surgical difficulty in LC. For each item, roughly 30-second video clips were submitted from videos of LC performed at member institutions. We then selected one typical video from the collected clips based on simple tabulation of the instances of agreement. Inter-rater agreement was assessed with Fleiss's κ and Gwet's agreement coefficient (AC). RESULTS: Except in the case of two assessment items ("edematous change" and "easy bleeding"), κ or AC significantly exceeded 0.5 and the typical videos were judged to be applicable. For the two remaining items, the evaluation was repeated after clarifying the definitions of positive and negative findings. Eventually, they were recognized as typical. The completed video clip library contains 31 clips and is divided into five categories (http://www.jshbps.jp/modules/project/index.php?content_id=13). CONCLUSIONS: This clip library may be highly useful in clinical settings as a more objective standard for assessing surgical difficulty in LC.

DOI： 10.1002/jhbp.871

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BACKGROUND/AIM: This study aimed to investigate the efficacy of first-line gemcitabine monotherapy for metastatic breast cancer (MBC) and its effect on health-related quality of life (HRQoL) compared with treatment of physician's choice (TPC). PATIENTS AND METHODS: We enrolled 96 patients into the first-line gemcitabine group (n=47) or other treatment of physician's choice (TPC) group (n=49) from May 2010 to April 2013. HRQoL was evaluated every 4 weeks. RESULTS: There was no significant difference in the median time to treatment failure (5.3 vs. 4.6 months, hazard ratio=0.87, p=0.546) and the incidence rates of grade 3/4 haematological toxicity (10.6% vs. 8.1%, p=0.677) and grade 3/4 non-haematological toxicity (4.2% vs. 8.1%, p=0.429) between the gemcitabine and TPC groups. Changes in HRQoL from baseline to 12 weeks were not significantly different. CONCLUSION: Gemcitabine achieves similar efficacy and HRQoL benefit to other chemotherapy and can be used as first-line treatment for MBC.

DOI： 10.21873/anticanres.14930

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AIM: The significance of sarcopenia in cancers has been widely recognized. However, few studies have focused on chronological changes in sarcopenia in cancer patients. This study aimed to clarify the clinical significance of changes in the psoas muscle area before and after preoperative chemotherapy. METHODS: This study included 39 patients who underwent gastrectomy followed by preoperative chemotherapy for advanced gastric cancer between January 2010 and December 2016 in our hospital. The psoas muscle area was measured at the umbilical level before and after chemotherapy, and the relationship between its chronological changes and the long-term prognosis was examined. RESULTS: Patients were classified into two groups according to changes in the psoas muscle area before and after preoperative chemotherapy: remarkable muscle depletion and normal groups. No significant differences were observed in clinicopathological factors. Notably, the remarkable muscle depletion group included significantly more male patients (P = .018) and showed a high weight loss rate (P < .001). Although no significant difference was observed in the recurrence-free survival between the two groups (P = .484), overall survival was significantly worse in the remarkable muscle depletion group (P < .001). Multivariate analysis for prognosis revealed that pathological stage III or higher (P = .022) and decreased psoas muscle area (P = .038) were independent prognostic factors. CONCLUSIONS: The present findings suggest that psoas muscle depletion during preoperative chemotherapy is a prognostic factor for poor long-term outcomes in patients who underwent gastrectomy followed by preoperative chemotherapy for advanced gastric cancer.

DOI： 10.1111/ajco.13514

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BACKGROUND: Cirrhosis-associated portal vein thrombosis (CA-PVT) has been reportedly observed in 5-30% of cirrhotic patients. Moreover, the acute exacerbation of CA-PVT is likely to occur after certain situations, such as a status after abdominal surgery. Safety and efficacy of the direct-acting oral anticoagulant (DOAC) used for cirrhotic patients have been being confirmed. However, use of the DOAC as an initial treatment for CA-PVT appears still challenging especially in the early postoperative period after major surgery in terms of unestablished efficacy and safety in such occasion. CASE PRESENTATION: We herein report a case of the acute exacerbation of CA-PVT in the early postoperative period after abdominal surgery, which was successfully treated with DOAC, edoxaban used as an initial treatment. The patient was a 79-year-old Japanese male with alcoholic cirrhosis. The patient suffered choledocholithiasis and had a mural chronic CA-PVT extending from the superior mesenteric vein to the portal trunk. He underwent open cholecystectomy and choledochotomy. Early postoperative clinical course was uneventful except for abdominal distension due to ascites diagnosed on postoperative day (POD)7 when hospital discharge was planned. Contrast enhancement computed tomography (CE-CT) taken on POD 7 revealed the exacerbation of the CA-PVT. Despite recommendation for extension of hospital admission with low molecular weight heparin treatment, the patient strongly hoped to be discharged. Unwillingly, we selected DOAC, edoxaban, as an initial treatment, which was commenced the day after discharge (POD8). As a result, the remarkable improvement of the exacerbated CA-PVT was confirmed by the CE-CT taken on POD21. Any bleeding complications were not observed. Although a slight residue of the CA-PVT remains, the patient is currently doing well 4 years after surgery and is still receiving edoxaban. Any adverse effects of edoxaban have not been observed for 4 years. CONCLUSIONS: A case of successful treatment of the acute exacerbation of CA-PVT with edoxaban was reported. Moreover, edoxaban has been safely administered in a cirrhotic patient for 4 years. The findings obtained from the present case suggest that DOAC can be used as an initial treatment for CA-PVT even in early postoperative period after major abdominal surgery.

DOI： 10.1186/s13256-020-02651-y

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We herein report a woman who was suffering from type 1 diabetes and hearing impairment and whose mother had mitochondrial disease. Abdominal ultrasound identified a hepatic tumour, and a further examination led to the diagnosis of rectal cancer with synchronous multiple liver metastases. A genetic test led to the diagnosis of mitochondrial disease with a mitochondrial gene 3243A&gt
G mutation. After neoadjuvant chemotherapy, we performed hepatectomy and low anterior resection in one stage. Hepatic vascular exclusion was not performed in order to prevent damage to hepatocytes due to liver ischaemia, and Ringer's lactate solution was not used to prevent lactic acidosis. The postoperative course was uneventful. Only one other case involving hepatectomy being performed in a patient with mitochondrial disease has been reported. Considering the extreme rarity of such cases and the importance of perioperative management, we report this case here.

DOI： 10.1136/bcr-2020-238653

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BACKGROUND: Minimally invasive pancreatoduodenectomy (MIPD) has recently gained popularity. Several international meetings focusing on the existing literature on MIPD were held; however, the precise surgical anatomy of the pancreas for the safe use of MIPD has not yet been fully discussed. The aim of this study was to carry out a systematic review of available articles and to show the importance of identifying the anatomical variation in pancreatoduodenectomy. METHODS: In this review, we described variations in surgical anatomy related to MIPD. A systematic search of PubMed (MEDLINE) was conducted, and the references were identified manually. RESULTS: The search strategy yielded 272 articles, with 77 retained for analysis. The important anatomy to be considered during MIPD includes the aberrant right hepatic artery, first jejunal vein, first jejunal artery, and dorsal pancreatic artery. Celiac artery stenosis and a circumportal pancreas are also important to recognize. CONCLUSIONS: We conclude that only certain anatomical variations are associated directly with perioperative outcomes and that identification of these particular variations is important for safe performance of MIPD.

DOI： 10.1002/jhbp.901

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Publishing type：Research paper (scientific journal)   Publisher：Ovid Technologies (Wolters Kluwer Health)  

DOI： 10.1097/sle.0000000000000906

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：MDPI AG  

Introduction: The prognostic role of tumor burden score (TBS) relative to pre‐operative α ‐fetoprotein (AFP) levels among patients undergoing curative‐intent resection of HCC has not been examined. Methods: Patients who underwent curative‐intent resection of HCC between 2000 and 2017 were identified from a multi‐institutional database. The impact of TBS on overall survival (OS) and cumulative recurrence relative to serum AFP levels was assessed. Results: Among 898 patients, 233 (25.9%) patients had low TBS, 572 (63.7%) had medium TBS and 93 (10.4%) had high TBS. Both TBS (5‐year OS
low TBS: 76.9%, medium TBS: 60.9%, high TBS: 39.1%) and AFP (&gt
400 ng/mL vs. &lt
400 ng/mL: 48.5% vs. 66.1%) were strong predictors of outcomes (both p &lt
0.001). Lower TBS was associated with better OS among patients with both low (5‐year OS, low–medium TBS: 68.0% vs. high TBS: 47.7%, p &lt
0.001) and high AFP levels (5‐year OS, low–medium TBS: 53.7% vs. high TBS: not reached, p &lt
0.001). Patients with low–medium TBS/high AFP had worse OS compared with individuals with low–medium TBS/low AFP (5‐year OS, 53.7% vs. 68.0%, p = 0.003). Similarly, patients with high TBS/high AFP had worse outcomes compared with patients with high TBS/low AFP (5‐year OS, not reached vs. 47.7%, p = 0.015). Patients with high TBS/low AFP and low TBS/high AFP had comparable outcomes (5‐year OS, 47.7% vs. 53.7%, p = 0.24). The positive predictive value of certain TBS groups relative to the risk of early recurrence and 5‐year mortality after HCC resection increased with higher AFP levels. Conclusion: Both TBS and serum AFP were important predictors of prognosis among patients with resectable HCC. Serum AFP and TBS had a synergistic impact on prognosis following HCC resection with higher serum AFP predicting worse outcomes among patients with HCC of a certain TBS class.

DOI： 10.3390/cancers13040747

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Publishing type：Research paper (scientific journal)   Publisher：Springer Science and Business Media LLC  

DOI： 10.1007/s00384-021-03869-y

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Springer Science and Business Media Deutschland GmbH  

Background: The impact of tumor necrosis relative to prognosis among patients undergoing curative-intent resection for hepatocellular carcinoma (HCC) remains ill-defined. Methods: Patients who underwent curative-intent resection for HCC without any prior treatment between 2000 and 2017 were identified from an international multi-institutional database. Tumor necrosis was graded as absent, moderate (&lt
50% area), or extensive (≥ 50% area) on histological examination. The relationship between tumor necrosis, clinicopathologic characteristics, and long-term survival were analyzed. Results: Among 919 patients who underwent curative-intent resection for HCC, the median tumor size was 5.0 cm (IQR, 3.0–8.5). Tumor necrosis was present in 367 (39.9%) patients (no necrosis: n = 552, 60.1% vs &lt
50% necrosis: n = 256, 27.9% vs ≥ 50% necrosis: n = 111, 12.1%). Extent of tumor necrosis was also associated with more advanced tumor characteristics. HCC necrosis was associated with OS (median OS: no necrosis, 84.0 months vs &lt
50% necrosis, 73.6 months vs ≥ 50% necrosis: 59.3 months
p &lt
0.001) and RFS (median RFS: no necrosis, 49.6 months vs &lt
50% necrosis, 38.3 months vs ≥ 50% necrosis: 26.5 months
p &lt
0.05). Patients with T1 tumors with extensive ≥ 50% necrosis had an OS comparable to patients with T2 tumors (median OS, 62.9 vs 61.8 months
p = 0.645). In addition, patients with T2 disease with necrosis had long-term outcomes comparable to patients with T3 disease (median OS, 61.8 vs 62.4 months
p = 0.713). Conclusion: Tumor necrosis was associated with worse OS and RFS, as well as T-category upstaging of patients. A modified AJCC T classification that incorporates tumor necrosis should be considered in prognostic stratification of HCC patients.

DOI： 10.1245/s10434-020-09390-w

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：John Wiley and Sons Inc  

Background: The impact of a prolonged time-to-surgery (TTS) among patients with resectable hepatocellular carcinoma (HCC) is not well defined. Methods: Patients who underwent curative-intent hepatectomy for BCLC-0, A and B HCC between 2000 and 2017 were identified using a multi-institutional database. The impact of prolonged TTS on overall survival (OS) and disease-free survival (DFS) was examined. Results: Among 775 patients who underwent resection for HCC, 537 (69.3%) had early surgery (TTS &lt
90 days) and 238 (30.7%) patients had a delayed surgery (TTS ≥ 90 days). Patient- and tumor-related characteristics were similar between the two groups except for a higher proportion of patients undergoing major liver resection in the early surgery group (31.3% vs. 23.8%, p =.04). The percentage of patients with delayed surgery varied from 8.8% to 59.1% among different centers (p &lt
.001). Patients with TTS &lt
90 days had similar 5-year OS (63.7% vs. 64.9
p =.79) and 5-year DFS (33.5% vs. 42.4
p =.20) with that of patients with TTS ≥ 90 days. On multivariable analysis, delayed surgery was not associated with neither worse OS (BCLC-0/A: adjusted hazards ratio [aHR] = 0.90
95% confidence interval [CI]: 0.65–1.25 and BCLC-B: aHR = 0.72
95%CI: 0.30–1.74) nor DFS (BCLC-0/A: aHR = 0.78
95%CI: 0.60–1.01 and BCLC-B: aHR = 0.67
95% CI: 0.36–1.25). Conclusion: Approximately one in three patients diagnosed with resectable HCC had a prolonged TTS. Delayed surgery was not associated with worse outcomes among patients with resectable HCC.

DOI： 10.1002/jso.26297

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BACKGROUND/AIM: We evaluated the impact of the relative dose intensity (RDI) of neoadjuvant chemotherapy (NAC) on the survival of patients with breast cancer (BC). PATIENTS AND METHODS: This randomized phase II trial included 188 patients with human epidermal growth factor receptor 2 (HER2)-negative BC treated with anthracycline followed by paclitaxel as NAC. We grouped patients using a relative dose intensity (RDI) threshold of 85% and evaluated clinicopathological features and clinical outcomes. RESULTS: The 5-year overall survival rate was 91.2% and 76.3%, when RDI ≥85% and <85%, respectively (p=0.015). Age, tumor, and node status, and the RDI were significantly different on univariate analysis, but not on multivariate analysis. An exploratory subgroup analysis revealed that a low RDI was associated with low overall survival of patients with obesity, T1/2 disease, and lymph node metastases. CONCLUSION: Maintaining the RDI of NAC is crucial for achieving the survival benefit in selected patients with HER2-negative BC.

DOI： 10.21873/anticanres.14863

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BACKGROUND/AIM: Methionine addiction, a fundamental and general hallmark of cancer, is due to the excess use of methionine for transmethylation, and is described as the Hoffman-effect. Methionine-addicted cancer cells can revert at low frequency to methionine independence when selected under methionine-restriction. We report here that highly-malignant methionine-addicted H460 human lung-cancer cells, when selected for methionine independence, have greatly-reduced tumorigenic potential. MATERIALS AND METHODS: Methionine-addicted H460 parental cancer cells and methionine-independent revertant H460-R1 cells were injected in nude mice subcutaneously. RESULTS: When the parental H460 methionine-addicted cells were injected in nude mice at 2.5×105, 1×105 and 5×104, the cells could form tumors. In contrast, the H460-R1 methionine-independent revertant cells could not form tumors when the above-listed cell numbers were injected in nude mice. CONCLUSION: There is a tight linkage between methionine addiction and malignancy.

DOI： 10.21873/anticanres.14815

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PURPOSE: The objective of the current study was to assess the therapeutic benefit of lymphadenectomy according to the extent of lymphadenectomy. METHODS: Patients undergoing colectomy for right-sided colon cancer were identified. Distribution of lymph node metastases (DLNM) of 1, 2 and 3 were defined as lymph node metastasis (LNM) in the pericolic nodes, the intermediate nodes and the front of the SMV near the origin of the major artery, respectively. The therapeutic index (TI) was calculated based on the frequency of LNM and the 5 year overall survival (OS) rate of patients with LNM. RESULTS: Among 344 patients who met the inclusion criteria, roughly half had LNM (n = 150, 43.7%). While 107 (31.1%) and 30 (8.7%) patients had DLNM1 and DLNM2, respectively, only 13 patients (3.8%) were defined as DLNM3. However, there was no significant difference in 5 year OS by DLNM (DLNM1 71.1%, DLNM2 78.7%, DLNM3 50.4%, p = 0.61). Overall, the TI of lymphadenectomy for D3 area was approximately 1/10 of the TI for D1 (1.9 vs.22.1), given the low frequency of LNM (3.8%) and poor 5 year OS of patients with LNM (50.4%). This trend was consistent irrespective of primary tumor locations. CONCLUSION: The survival benefit from central lymphadenectomy namely D3 was low among patients with right-sided colon cancers.

DOI： 10.1007/s00595-020-02084-6

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BACKGROUND: Extrahepatic cholangiocarcinoma requires invasive surgery and is associated with poor prognosis; thus, a prognostic biomarker is highly needed. Extrahepatic cholangiocarcinoma is sub-classified into two types based on their location, namely perihilar and distal. Perihilar cholangiocarcinoma requires lobectomy as curative surgical resection, whereas the distal requires pancreatoduodenectomy. HMGA2 overexpression is reported to correlate with progression, aggressiveness, dissemination and poor prognosis in several types of cancers. Although its association with extrahepatic cholangiocarcinoma has been reported, none of the previous studies assessed its significance in each subtype. METHODS: We assessed the expression of HMGA2 protein in surgical specimens after curative intent surgery in 80 patients including 41 with perihilar cholangiocarcinoma and 39 with distal cholangiocarcinoma by immunohistochemistry. We then examined its association with clinicopathological findings and patient survival outcomes. RESULTS: We found that HMGA2 was expressed in 51% (21 of 41) of perihilar cholangiocarcinoma and 41% (16 of 39) of distal cholangiocarcinoma samples. In perihilar cholangiocarcinoma, we found significant correlations between expression and vascular invasion and perineural invasion. In distal cholangiocarcinoma, we found that protein levels correlated with tumor grade. Univariate and multivariate analyses demonstrated that HMGA2 expression was an independent poor prognostic factor for patients with both subtypes of disease. CONCLUSIONS: Our results revealed that HMGA2 expression as an independent prognostic marker for both perihilar and distal cholangiocarcinoma that were resected with curative intent.

DOI： 10.1016/j.ejso.2020.08.005

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OBJECTIVE: The aim of this study was to evaluate the long-term outcomes that were the secondary endpoints of a RCT of multi-port laparoscopic colectomy (MPC) versus SILC in colon cancer surgery. SUMMARY OF BACKGROUND DATA: The actual long-term outcomes, such as the 5-year RFS, OS, and recurrence patterns after surgery, have not been evaluated by a RCT. METHODS: Patients with histologically proven colon carcinoma located in the cecum, ascending, sigmoid or rectosigmoid colon clinically diagnosed as stage 0-III were eligible for this study. Patients were preoperatively randomized and underwent complete mesocolic excision. The 5-year RFS, OS, and recurrence patterns were analyzed (UMIN-CTR 000007220). RESULTS: Between March 1, 2012, and March 31, 2015, a total of 200 patients were randomly assigned to either the MPC arm (n = 100) or SILC arm (n = 100). The median follow-up for all patients was 61.0 months. An intention-to-treat analysis showed that the 5-year RFS was 91.0% [95% confidence interval (CI) 85.1%-96.9%] in the MPC arm and 88.0% (95% CI 82.1%-93.9%) in the SILC arm (hazard ratio: 1.37; 95% CI 0.58-3.24; P = 0.479). The 5-year OS was 95.0% (95% CI 91.1%-98.9%) in the MPC arm and 93.0% (87.1%-98.9%) in the SILC arm (hazard ratio: 1.39; 95% CI 0.44-4.39; P = 0.568). There were no significant differences in the recurrence patterns between the 2 arms. CONCLUSIONS: Even though the results of the 5-year OS and RFS in this trial were exploratory and underpowered, there were no statistically significant differences between the SILC and MPC arms. SILC may be an acceptable treatment option for select patients with colon cancer.

DOI： 10.1097/SLA.0000000000004252

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Hepatocellular carcinoma (HCC) is one of the most common malignancies and a leading cause of cancer-related deaths worldwide. In this study, a total of 749 HCC patients from 5 cohorts were studied to examine the relationships between enhancement of DNA repair and cancer aggressiveness, tumor immune microenvironment, and patient survival in HCC, utilizing a DNA repair pathway score. Our findings suggest that the DNA repair pathway was not only enhanced by the stepwise carcinogenic process of HCC, but also significantly enhanced in grade 3 HCC compared with grade 1 and 2 tumors. DNA repair high HCC was associated with worse survival, elevated intratumor heterogeneity, and mutation load, but not with the fraction of immune cell infiltration nor immune response. HCC tumors with a DNA repair high score enriched the cell proliferation- and other cancer aggressiveness-related gene sets. Interestingly, these features were more pronounced in grade 1 and 2 HCC compared to grade 3 HCC. To our knowledge, this is the first study to use DNA repair pathway-related gene set expression data to examine and validate the clinical relevance of DNA repair pathway activity in HCC. The DNA repair score may be used to better understand and predict prognosis in HCC.

DOI： 10.3390/cancers13020323

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Publishing type：Research paper (scientific journal)   Publisher：Springer Science and Business Media LLC  

DOI： 10.1007/s00595-020-02213-1

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Blackwell Publishing Ltd  

Aim: The present study aimed to examine the effect of continuing antiplatelet therapy in the perioperative period for patients undergoing laparoscopic resection for colorectal cancer who had received preoperative antiplatelet therapy. Methods: This retrospective, multicenter, observational study included patients who underwent laparoscopic surgery for colorectal cancer between January 2011 and May 2020. The study population was limited to patients who used antiplatelet therapy preoperatively. Results: A total of 214 colorectal cancer patients who received antiplatelet therapy preoperatively were included in the present study. Eighty-nine patients underwent surgery under the continuation of antiplatelet therapy, and 125 patients underwent surgery under the discontinuation of antiplatelet therapy before surgery. There were no significant differences between the two groups with regard to intraoperative blood loss (P =.889), intraoperative blood transfusion (P = 1.000), and conversion to laparotomy (P = 1.000). There were no significant differences between the two groups in the incidence of postoperative hemorrhagic complications (Clavien-Dindo Grade ≥II, P =.453
Grade ≥III, P =.572) or three-point major adverse cardiovascular events (P =.268). However, there were two cases of postoperative non-fatal stroke in the discontinued antiplatelet therapy group. Conclusions: The present study revealed that there were no significant differences in the surgical outcomes and postoperative complications between colorectal cancer patients who underwent laparoscopic resection with the continuation of antiplatelet therapy in the perioperative period and those in whom antiplatelet therapy was discontinued during the perioperative period. From the viewpoint of cardiovascular and cerebrovascular risk, it may be better for patients undergoing laparoscopic surgery for colorectal cancer to continue antiplatelet therapy. This study was registered with the Japanese Clinical Trials Registry as UMIN000038707 (http://www.umin.ac.jp/ctr/index.htm).

DOI： 10.1002/ags3.12387

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Publishing type：Research paper (scientific journal)   Publisher：SAGE Publications  

Colorectal anastomotic leakage is one of the most feared and fatal complications of colorectal surgery. To date, no external coating material that can prevent anastomotic leakage has been developed. As myoblasts possess anti-inflammatory capacity and improve wound healing, we developed a multilayered human skeletal muscle myoblast (HSMM) sheet by periodic exposure to supraphysiological hydrostatic pressure during repeated cell seeding. We assessed whether the application of an HSMM sheet can promote the healing process after colonic anastomosis. Partial colectomy and insufficient suturing were employed to create a high-risk colo-colonic anastomosis model in 60 nude rats. Rats were divided into a control group ( n = 30) and an HSMM sheet group ( n = 30). Macroscopic findings, anastomotic bursting pressure, and histology at the colonic anastomotic site were evaluated on postoperative day (POD) 3, 5, 7, 14, and 28. The application of an HSMM sheet significantly suppressed abscess formation at the anastomotic site compared to the control group on POD3 and 5. The anastomotic bursting pressure in the HSMM sheet group was higher than that in the control group on POD3 and 5. Inflammatory cell infiltration in the HSMM sheet group was significantly suppressed compared to that in the control group throughout the time course. Collagen deposition in the HSMM sheet group on POD3 was significantly abundant compared to that in the control group. Regeneration of the mucosa at the colonic anastomotic site was promoted in the HSMM sheet group compared to that in the control group on POD14 and 28. Immunohistochemical analysis demonstrated that surviving cells in the HSMM sheet gradually decreased with postoperative time and none were detected on POD14. These results suggest that the application of a multilayered HSMM sheet may prevent postoperative colonic anastomotic leakage.

DOI： 10.1177/09636897211009559

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Language：Japanese   Publishing type：Research paper (scientific journal)  

A 66-year-old male underwent colonoscopy, which identified an 0-Is polyp in the rectum. Endoscopic resection was then performed, and the histopathological examination showed SM massive, unknown vertical margin, and venous invasion. He was thus referred to our department for the purpose of additional resection. However, follow-up every 6 months was performed because of his wish to avoid additional resection. He underwent contrast-enhanced CT 2 years after the start of follow-up, and a swollen pararectal lymph node was found. Based on this examination, he was diagnosed with recurrent lymph node metastasis and underwent laparoscopic ultra-low anterior resection and diverting ileostomy. Histopathological examination showed well to moderately differentiated tubular adenocarcinoma in the mesorectum and metastasis in a pararectal lymph node. After 8 courses of XELOX therapy as postoperative adjuvant chemotherapy, he underwent stoma closure. He is alive without recurrence 4 years after surgery. Patients should be informed of the expected course of pT1 colorectal cancer along with factors that should be considered for additional resection, and they should be followed carefully.

DOI： 10.15015/00002118

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BACKGROUND: The optimal time interval to define early recurrence (ER) among patients who underwent resection of gallbladder cancer (GBC) is not well defined. We sought to develop and validate a novel GBC recurrence risk (GBRR) score to predict ER among patients undergoing resection for GBC. PATIENTS AND METHODS: Patients who underwent curative-intent resection for GBC between 2000 and 2018 were identified from the US Extrahepatic Biliary Malignancy Consortium database. A minimum p value approach in the log-rank test was used to define the optimal cutoff for ER. A risk stratification model was developed to predict ER based on relevant clinicopathological factors and was externally validated. RESULTS: Among 309 patients, 103 patients (33.3%) had a recurrence at a median follow-up period of 15.1 months. The optimal cutoff for ER was defined at 12 months (p = 3.04 × 10-18). On multivariable analysis, T3/T4 disease (HR: 2.80; 95% CI 1.58-5.11) and poor tumor differentiation (HR: 1.91; 95% CI 1.11-3.25) were associated with greater hazards of ER. The GBRR score was developed using β-coefficients of variables in the final model, and patients were classified into three distinct groups relative to the risk for ER (12-month RFS; low risk: 88.4%, intermediate risk: 77.9%, high risk: 37.0%, p < 0.001). The external validation demonstrated good model generalizability with good calibration (n = 102: 12-month RFS; low risk: 94.2%, intermediate risk: 59.8%, high risk: 42.0%, p < 0.001). The GBRR score is available online at https://ktsahara.shinyapps.io/GBC_earlyrec/ . CONCLUSIONS: A novel online calculator was developed to help clinicians predict the probability of ER after curative-intent resection for GBC. The proposed web-based tool may help in the optimization of surveillance intervals and the counselling of patients about their prognosis.

DOI： 10.1245/s10434-020-09108-y

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Background: High infiltration of Th2 is linked to breast cancer progression and metastasis through the induction of cytokine release and T-cell anergy. The estrogen receptor (ER)-positive subtype, which accounts for 70% of breast cancer, is known to respond less to neoadjuvant chemotherapy (NAC) due to its low potential for proliferation. We hypothesized that Th2 high tumors are highly proliferative, and thus more likely to respond to NAC in ER-positive breast cancer. Methods: We obtained clinicopathological data and overall survival information on 1,069 breast cancer patients from The Cancer Genome Atlas (TCGA). Computational algorithms and CIBERSORT were used to estimate immune cell infiltration. Additionally, xCell was used for validation. Results: Th2 high tumors did not consistently associate with an unfavorable immune cell composition and tumor immune microenvironment but were found to be significantly elevated in the cancer stage. Th2 high tumors also correlated with high Nottingham pathological grade, as well as with Ki-67 and proliferation score in ER-positive subtypes. High Th2 tumors achieved a pathological complete response (pCR) significantly higher in ER-positive breast cancer. Conclusions: In conclusion, high levels of Th2 are associated with aggressive features of breast cancer. Th2 levels may be a biomarker in patient selection for NAC in ER-positive breast cancer.

DOI： 10.21037/gs-20-571

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BACKGROUND: The Japanese Society of Hepato-Biliary-Pancreatic Surgery launched the clinical practice guidelines for the management of biliary tract cancers (cholangiocarcinoma, gallbladder cancer, and ampullary cancer) in 2007, then published the 2nd version in 2014. METHODS: In this 3rd version, clinical questions (CQs) were proposed on six topics. The recommendation, grade for recommendation, and statement for each CQ were discussed and finalized by an evidence-based approach. Recommendations were graded as Grade 1 (strong) or Grade 2 (weak) according to the concepts of the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system. RESULTS: The 31 CQs covered the six topics: (a) prophylactic treatment, (b) diagnosis, (c) biliary drainage, (d) surgical treatment, (e) chemotherapy, and (f) radiation therapy. In the 31 CQs, 14 recommendations were rated strong and 14 recommendations weak. The remaining three CQs had no recommendation. Each CQ includes a statement of how the recommendations were graded. CONCLUSIONS: This latest guideline provides recommendations for important clinical aspects based on evidence. Future collaboration with the cancer registry will be key for assessing the guidelines and establishing new evidence.

DOI： 10.1002/jhbp.870

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Springer Science and Business Media Deutschland GmbH  

Purpose: This study aimed to evaluate the short- and long-term outcomes in obese patients with gastric cancer undergoing totally laparoscopic total gastrectomy (TLTG) to clarify its feasibility in this population. Methods: We examined 136 consecutive patients who underwent TLTG for gastric cancer (GC) between 2013 and 2018. A total of 45 patients with a body mass index (BMI) ≥ 25 kg/m2 were defined as the obese group (obese and overweight patients by the WHO classification), and 91 patients with a BMI &lt
25 kg/m2 were defined as the non-obese group. Short- and long-term outcomes were compared, and the correlation between obesity and postoperative complications was examined in patients who underwent TLTG. Results: Although the operation time (min) was significantly longer in the obese group than in the non-obese group (329 vs 307, p = 0.002), there were no significant differences in the total volume of blood loss (mL) (118 vs 60, p = 0.059) or the rate of conversion to laparotomy between the two groups (2 vs 2, p = 0.466). Moreover, there was no significant difference in the incidence of postoperative complications between the two groups (16% vs 19%, p = 0.653). In the multivariate analysis, obesity was not identified as a risk factor for postoperative complications among patients who underwent TLTG. The rate of overall survival was not significantly different between the groups (p = 0.512). Conclusion: TLTG is feasible for obese Japanese patients with GC. To validate the results of the present study, it is necessary to conduct a prospective study of a large population of patients with GC.

DOI： 10.1007/s00423-021-02369-5

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BACKGROUND: The adoption of spleen-preserving distal pancreatectomy (SPDP) for malignant disease such as pancreatic neuroendocrine tumors (pNETs) has been controversial. The objective of the current study was to assess the impact of SPDP on outcomes of patients with pNETs. METHODS: Patients undergoing a distal pancreatectomy for pNET between 2002 and 2016 were identified in the US Neuroendocrine Tumor Study Group database. Propensity score matching (PSM) was used to compare short- and long-term outcomes of patients undergoing SPDP versus distal pancreatectomy with splenectomy (DPS). RESULTS: Among 621 patients, 103 patients (16.6%) underwent an SPDP. Patients who underwent SPDP were more likely to have lower BMI (median, 27.5 [IQR 24.0-31.2] vs. 28.7 [IQR 25.7-33.6]; p = 0.005) and have undergone minimally invasive surgery (n = 56, 54.4% vs. n = 185, 35.7%; p < 0.001). After PSM, while the median total number of lymph nodes examined among patients who underwent an SPDP was lower compared with DPS (3 [IQR 1-8] vs. 9 [5-13]; p < 0.001), 5-year overall survival (OS) and recurrence-free survival (RFS) were comparable (OS: 96.8 vs. 92.0%, log-rank p = 0.21, RFS: 91.1 vs. 84.7%, log-rank p = 0.93). In addition, patients undergoing SPDP had less intraoperative blood loss (median, 100 mL [IQR 10-250] vs. 150 mL [IQR 100-400]; p = 0.001), lower incidence of serious complications (n = 13, 12.8% vs. n = 28, 27.5%; p = 0.014), and shorter length of stay (median: 5 days [IQR 4-7] vs. 6 days [IQR 5-13]; p = 0.049) compared with patients undergoing DPS. CONCLUSION: SPDP for pNET was associated with acceptable perioperative and long-term outcomes that were comparable to DPS. SPDP should be considered for patients with pNET.

DOI： 10.1159/000506399

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BACKGROUND: The predictive factors for discontinuation of S-1 administration and prognostic factors in elderly patients with pStage II/III gastric cancer receiving S-1 adjuvant chemotherapy remain unclear. METHODS: Between January 2004 and December 2016, 80 elderly gastric cancer patients (≥70 years) undergoing curative D2 gastrectomy were enrolled in this study. Predictive factors for completion of S-1 administration over 1 year, adverse events due to S-1 administration, and prognostic factors for overall survival (OS) and relapse-free survival (RFS) were evaluated. RESULTS: Twenty-eight patients (35%) completed 8 courses of S-1. The median relative dose intensity was 82.1% (IQR 31.1-100%). The incidence rates of hematological and nonhematological adverse events were acceptable. Distal gastrectomy was an independent predictive factor for completion of S-1 administration (odds ratio [OR] 0.364; 95% confidence interval [CI] 0.141-0.939; p = 0.037). Higher postoperative neutrophil count/lymphocyte count (N/L) ratio and more advanced stage adversely influenced OS. Multivariate analysis revealed that a higher postoperative N/L ratio and more advanced stage adversely affected RFS. CONCLUSION: To complete adjuvant S-1 administration to elderly patients with pStage II/III gastric cancer, total gastrectomy should be avoided if possible. A new regimen for elderly gastric cancer patients with higher postoperative N/L ratios and more advanced stage should be established.

DOI： 10.1159/000515175

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Publishing type：Research paper (scientific journal)   Publisher：Anticancer Research USA Inc.  

DOI： 10.21873/invivo.12522

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DOI： 10.21873/cgp.20292

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Some may think that prediction of metastasis is meaningless since metastatic breast cancer is currently incurable. We argue that effective identification of developing metastasis will enable us to design and conduct clinical trials specifically targeting those patients at high risk. The current study sought to generate the KAM score by 4 genes (BRSK2, EYA1, SIGLEC15, and AGTR1) overexpressed in primary breast cancer that developed metastasis to bone compared with matched controls without metastasis longer than 10 years. A high KAM score was prognostic of poor overall (OS), disease free survival (DFS), and disease specific survival (DSS) in the METABRIC, and OS in the GSE96058 cohorts. A high KAM score was significantly associated with clinical aggressiveness, such as high American Joint Committee Cancer (AJCC) stage, lymph node metastasis, Nottingham pathological grade, and triple negative breast cancer (TNBC). Subgroup analysis revealed that a high KAM score was associated with worse OS in ER-positive/HER2-negative breast cancer in both cohorts. A high KAM breast cancer enriched all 5 cell proliferation-related gene sets of the Hallmark collection and interferon (IFN)-γ response gene sets. Furthermore, a high KAM breast cancer was significantly infiltrated with a high fraction of not only anti-cancer but also pro-cancer immune cells and associated with high level of cytolytic activity. Finally, a high KAM breast cancer was significantly associated with lung metastasis. In conclusion, we developed KAM score using 4 gene expressions that predict lung metastasis and patient survival in breast cancer.

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Colon cancer stem cells (CSC) identified by cell surface markers CD133, CD24, and CD44, have been shown to be involved with tumor formation, chemotherapy resistance, and the progression of metastatic disease. Using an in silico translational approach, we hypothesize that a combination of these CSC markers has prognostic value in a large cohort of patients with colorectal cancer. Clinicopathologic and RNA expression data from a total of 594 colorectal cancer (CRC) patients from TCGA were analyzed. The expression of CD133, CD24, and CD44 was individually defined as "high" or "low" based on the median expression. Disease specific survival (DSS) and overall survival (OS) were not associated with tumors that are CD133-high or CD44-high alone. Patients with CD24-high tumors have significantly better DSS (P<0.001) and OS (P = 0.043). CD24-high, CD44-high and CD133-high tumors were associated with significantly greater EGFR, KRAS and Ki67 expression (all P<0.001). CD133, CD24 and CD44-high tumors were independently enriched for conventional stemness-related signaling pathways such as Wnt/β-catenin and Hedgehog signaling pathways. There was no survival difference linked to CD133-high/CD44-low patients, but CD44-high/CD24-low patients have worse DSS (P = 0.005) compared with CD44-low/CD24-high patients. CD133-high/CD24-low tumors show significant negative enrichment of MYC targets, E2F targets, G2M checkpoint and mitotic spindle gene sets, suggesting less cell proliferation in these tumors. Patients with CD133-high/CD24-low tumors have worse DSS (P = 0.004) and OS (P = 0.044), and are more likely to have early and late recurrences. In conclusion, we demonstrated that CD133-high/CD24-low tumors may predict colorectal cancer prognosis.

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Epidermal growth factor receptor (EGFR) is one of the receptors that belong to the epidermal growth factor family of receptor tyrosine kinases (ErbBs). Several malignancies including breast cancer that express EGFR have poor prognosis. Our study examined the EGFR expression among 5176 breast cancer patients from GSE96058 and METABRIC cohorts and the contribution of tumor immune microenvironment in different subtypes. We found that among different breast cancer subtypes, EGFR expression in TNBC was the highest compared to other subtypes. EGFR high ER-positive/HER2-negative breast cancer had significantly higher survival compared to EGFR low ER-positive/HER2-negative breast cancer. It was also associated with high level of intratumor heterogeneity and homologous recombination defects (HRD). This group was also enriched in immune-related gene sets. On the other hand, low EGFR tumor was enriched in cell proliferation-related gene sets. However, these findings were not observed in TNBC. Interestingly, there was a greater infiltration of anti-cancer immune cells in high EGFR ER-positive/HER2-negative breast cancers, while, TNBC with higher EGFR expression had lower fraction of immune cells along with low level of cytolytic activity. Tumor cells have significantly higher EGFR expression compared to immune cells in single cell sequencing data. There was higher expression of immune checkpoint molecules in high EGFR ER-positive/HER2-negative breast cancer but lower expression in TNBC. High EGFR metastatic tumor was significantly associated with worse survival, but no association with infiltrating immune cells was observed. Our study shows that higher EGFR expression in ER-positive/HER2-negative breast cancer is associated with improved outcomes and an anti-cancer immune microenvironment.

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In experimental settings, maternal embryonic leucine zipper kinase (MELK), an apical member of the snf1/AMPK serine-threonine kinases family, plays a role in tumor growth. We investigated the clinical relevance of MELK expression by performing silico analyses of 7,135 breast cancer patients using multiple independent large cohorts. In triple negative breast cancer (TNBC) found that elevated MELK expression significantly correlates with Nottingham histologic grade and tumor growth according to American Joint Committee Cancer (AJCC) stage. High MELK tumor enriched cell proliferation-related gene sets as well as DNA repair, unfolded protein response, and MTORC signaling gene sets. In two independent cohorts a high mutation rate and worse survival was significantly associated with high MELK tumor. In immune-related gene sets including, allograft rejection, interferon (IFN)-α response, and IFN-γ response, high MELK tumor significantly enriched. Pro-cancer regulatory T cells, T helper type 2 cells and anti-cancer immune cells including CD4+ memory T cells, T helper type1 cells, CD8+ T cells, M1 macrophages, gamma-delta T cells, and dendritic cells with high levels of cytolytic activity (CYT) were highly infiltrated. MELK expression did not correlate with the responses to any of the drugs tested in cell lines. However, pathologic complete response was significantly associated with high MELK following NAC in both TNBC and ER-positive plus HER2-negative breast cancer. In conclusion, cell proliferation, immune response, and NAC breast cancer response was associated with MELK expression.

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Metaplastic breast cancer (MBC) constitutes a rare but unique histologic entity with poor prognosis. We hypothesized that MBC possesses unique genetic profile and tumor immune microenvironment. MBC cases were identified from a total of 10827 breast cancer entries in the Cancer Genome Atlas Data Set (TCGA) and the AACR-GENIE (Genomics Evidence Neoplasia Information Exchange) cohorts. Tumor infiltrated immune cells were estimated by xCell. Baseline clinical characteristics were compared, and gene set enrichment analysis (GSEA) was performed. MBC comprised 0.66% of the cohorts (1.2% of TCGA and 0.6% of GENIE). MBC cases were predominantly triple-negative (TNBC) (8 (61.5%) vs 151 (14.4%), P<0.001), and high Nottingham histological grade (8 (61.5%) vs 222 (21.1%), P=0.02) compared to non-MBC in the TCGA cohort. Increased infiltration of M1 macrophages (P=0.012), dendritic cells (P<0.001) and eosinophils (P=0.036) was noted in the MBC cohort however there was no difference in cytolytic activity (P=0.806), CD4 memory (P=0.297) or CD8 T-cells (P=0.864). Tumor mutation burden was lower in the MBC compared to the non-MBC, median: 0.4 vs 1.6/Mb in the TCGA-TNBC cohort (P=0.67) and 3.0 vs 4.0/Mb (P=0.1) in the GENIE-cohort. MBC had increased intratumor heterogeneity (P<0.001), macrophage regulation (P=0.008) and TGF-beta response (P<0.001). Disease-specific survival was decreased in MBC (P=0.018). Angiogenesis and epithelial-to-mesenchymal transition pathways were enriched in triple-negative MBC by GSEA (P=0.004 and P<0.001, respectively). Our results suggest that high intratumor heterogeneity, enriched angiogenesis and EMT pathway expression represent possible mechanisms leading to worse disease-specific survival found in metaplastic breast cancer.

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Sphingosine-1-Phosphate (S1P) is produced by Sphingosine Kinase 1 (SphK1) in the cell and is transported out of the cells by ABCC1 transporter. S1P induces inflammation, angiogenesis and modulates tumor immune microenvironment (TIME) in autocrine and paracrine manner. We hypothesized that high S1P export is associated with hepatocellular carcinoma (HCC) progression and worse survival. Transcriptome linked with clinical data were obtained from a total of 533 patients from TCGA (The Cancer Genome Atlas)-HCC (n = 350), GSE6764 (n = 75), and GSE89377 (n = 108) cohorts. Both SphK1 and ABCC1 were expressed higher in aggressive HCC than normal liver or cirrhosis and correlated with MKi67 expression. High S1P export by high expression of both SphK1 and ABCC1 enriched gene sets related with cell proliferation (E2F targets, G2M checkpoint, MYC targets), inflammation (Inflammatory response, TNFα, IL6), angiogenesis, metastasis (TGF-β, epithelial-mesenchymal transition), and immune response (allograft rejection, complement, interferon-gamma) in gene set enrichment analysis. High S1P export was associated with elevation of HGF, HSP90AA1, TRAF2, and AKR1B10. It was also associated with high intratumor heterogeneity, leucocyte fraction, macrophage regulation and lymphocyte infiltration, as well as T helper type2 cells, macrophages, dendritic cells, CD4+ T memory activated cells, B-cells and cytolytic activity score in TIME. High S1P export was associated with significantly worse disease specific survival (P = 0.034) and overall survival (P = 0.004) compared to low S1P export group. In conclusion, simultaneous high expression of SphK1 and ABCC1 that reflect S1P export is associated with enhancement of both HCC progression and immune response. Given that S1P export was also associated with worse survival, we cannot help but speculate that pro-cancer pathways activated by S1P may overwhelm the anti-cancer immune response mediated by S1P.

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Tumor infiltrating immune cells plays a critical role in cancer progression. Apoptosis is an autonomous cell death that counteracts tumor growth. To this end, we hypothesized that increased apoptosis in breast cancer is associated with immune cell killing. Apoptosis score of MSigDB Hallmark collection was used to analyze METABRIC cohort (n=1904) and TCGA (n=1069) as validation cohort. High apoptosis tumors enriched cancer promoting signaling pathways; hypoxia, KRAS, TGF-β, PI3K signaling, and was associated with low MKI67 expression and less cell proliferation gene sets, less homologous recombination defects, and less altered fraction. High apoptosis tumors also enriched angiogenesis and high infiltration of vascular endothelial cells, pericytes and stromal cells and significantly enriched inflammation and immune response-related gene sets and high infiltration of CD8, CD4 memory, dendritic cells, M1 and M2 macrophages and significant elevation of cytolytic activity and immune checkpoint molecules, consistently in both cohorts. In conclusion, breast cancer patients with high apoptosis are associated with angiogenesis, immune response, high immune cell infiltration and cytolytic activity. To the best of our knowledge, this is the first study to utilize in silico translational approach to demonstrate the clinical relevance of apoptosis in breast cancer patients in large cohorts.

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Evaluation of the functional aspects if the tumor immune microenvironment (TIME), such as the recently introduced cytolytic activity score (CYT) index have been under the spotlight in cancer research; however, clinical relevance of immune cell killing activity in breast cancer has never been analyzed in large patient cohorts. We hypothesized that CYT reflects the immune activity of TIME and can predict patient survival. A total of 7533 breast cancer patients were analyzed as both discovery and validation cohorts. We found that high CYT was associated with advanced histological grade and triple-negative breast cancer (TNBC). High CYT in tumors was significantly associated with better survival in TNBC, but unexpectedly, not in other breast cancer subtypes. High CYT TNBC included both favorable immune-related, as well as unfavorable (suppressive) inflammation-related gene sets, and characterized by high infiltration with T cells and B cells. High CYT TNBC was associated with high homologous recombination deficiency and low somatic copy number alteration score and less mutant allele tumor heterogeneity, but not with tumor mutation burden (TMB). Although CYT was not associated with pathological complete response after neoadjuvant chemotherapy, it was significantly associated with high expression of multiple immune checkpoint molecules. In conclusion, CYT of TNBC is associated with enhanced anti-cancer immunity, less intra-tumoral heterogeneity, and with better survival.

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Neoadjuvant Chemotherapy (NAC) is not frequently used in ER-positive/HER2-negative breast cancer (BC) because around 10% patients achieve pathological complete response (pCR). Since NAC can result in cancer downstaging both in the breast and axilla and prevent a morbid surgery, thus a score to predict pCR in this population will be crucial to identify patients who can benefit from this approach. A total of 4038 patients from cohorts; GSE25066, GSE20194, Hess, GSE20181, TCGA-BRCA and METBRIC were analyzed. The score was generated by the 5 most highly expressed genes in the Hallmark E2F targets gene set amongst patients in the GSE25066 cohort with ER-positive/HER2-negative BC who achieved pCR. The area under the curve was significantly higher in the score than that for the E2F targets score. High score ER-positive/HER2-negative BCs were significantly associated with higher Nottingham pathological grade, AJCC cancer stage, MKI67 expression levels, intratumor heterogeneity, homologous recombination defects, mutation burden, neoantigen load, and infiltration of anti-cancer immune cells (CD4+, T helper type1, plasmacytoid dendritic cells, M1 macrophages). They also expressed lower abundance of stromal cells including fibroblasts, lymphatic endothelial cells, pericytes and adipocytes consistently in GSE25066, TCGA and METABRIC cohorts. All cell proliferation-related gene sets, G2M checkpoint, E2F targets, MYC targets v1 and v2, Mitotic Spindle, were strongly enriched in high score BCs consistently in 3 cohorts. The gene score was significantly associated with high pCR rate consistently in the GSE25066 (38%, P < 0.001), GSE20194 (16%, P = 0.006), and Hess cohort (23%, P = 0.037). In conclusion, the 5-gene score reflects cancer cell proliferation and immune cell infiltration, and predicts pCR after NAC in ER-positive/HER2-negative breast cancer.

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Given the severe side effects of the treatments and poor survival, prognostic and predictive biomarkers to guide management of pancreatic cancer are in critical need. We hypothesized that cell proliferation-related pathways are associated with drug response and survival in pancreatic cancer. Six Hallmark cell proliferation-related gene sets (G2M Checkpoint, E2F Targets, MYC Targets V1 and V2, Mitotic Spindle, p53 pathway) defined by MSigDB in gene set variant analysis were evaluated in 3 independent cohorts- TCGA-PAAD (n = 176), GSE57495 (n = 63), and GSE62452 (n = 69). G2M and E2F, as well as Mitotic and p53 pathway correlated highly with other gene sets. All pathways were significantly correlated with MKI67 expression and its proliferation score, but none with cytolytic activity and the rate of pathologically complete resection (R0). All pathways were significantly associated with high alteration and expression of KRAS gene except for MYC v1. G2M, E2F, and p53 pathway were significantly associated with high alteration of TP53 gene. Interestingly, different pathways correlated with the AUC of different cancer therapeutics, such as Gemcitabine (Mitotic: r = 0.706 [P = 0.01]), Paclitaxel (MYC v2: r = -0.636 [P < 0.05]), Apatinib (Mitotic: r = -0.556 [P = 0.03]), Palbociclib (E2F: r = 0.675 [P < 0.01]), and Sorafenib (G2M: r = -0.593 [P = 0.03]). Among all six pathways, only G2M was consistently associated with worse patient survival in all three cohorts. In conclusion, each cell proliferation-related pathway was predictive of a unique agent, and the G2M score alone predicts survival in pancreatic cancer.

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Angiogenesis is a cornerstone of cancer as it allows tumors to receive oxygen and nutrients. A high level of angiogenesis within a tumor may therefore be indicative of its aggressiveness. In this study, we examined this hypothesis in gastric cancer. Gene set variation analysis was used to measure the level of angiogenesis in tumors in 1,348 gastric cancer patients using the Hallmark_angiogenesis gene set to score tumor transcriptomes. As we predicted, there was a significant correlation between angiogenesis score and expression of angiogenesis-related genes. The score moderately correlated with abundance of vessel-related stromal cells, fibroblasts and chondrocytes in the tumor microenvironment (TME). Tumors with high score had low infiltration of T helper type 1 and 2 cells but a greater infiltration of M1 macrophages and dendritic cells. They also had enriched expression of gene sets for coagulation, hypoxia, epithelial mesenchymal transition (EMT), and TGF-β signaling. High angiogenesis score was significantly associated with advanced AJCC stage and higher T- but not N-parameters in the TNM staging system. Patients with a high score also had shorter survival. In conclusion, bulk tumor transcriptome-based quantification of tumor angiogenesis using a computational algorithm may serve to identify patients with worse survival in gastric cancer.

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Background: The C-TASK-FORCE phase I/II and Danish randomized phase II trials reported the promising efficacy of trifluridine/tipiracil (TAS102) plus bevacizumab (BEV) in patients with chemorefractory metastatic colorectal cancer (mCRC). However, there had been no direct comparative phase III trial to compare the efficacy between TAS102 plus BEV and standard therapy with either TAS102 or regorafenib monotherapy. Methods: We retrospectively reviewed the medical records of patients with mCRC who received TAS102 plus BEV, TAS102 monotherapy, or regorafenib monotherapy after standard chemotherapies during 2013-2019. Results: Patients received TAS102 plus BEV (n = 139), TAS102 monotherapy (n = 153), or regorafenib monotherapy (n = 133). With a median follow-up of 25.3 months, median overall survival (OS) was 11.5 months [95% confidence interval (CI), 9.9-13.9] for TAS102 plus BEV, 8.1 months (95% CI, 6.8-9.2) for TAS102 monotherapy, and 6.8 months (95% CI, 5.7-8.5) for regorafenib monotherapy. The hazard ratios were 0.67 (95% CI, 0.51-0.88) for TAS102 plus BEV versus TAS102 monotherapy and 0.71 (95% CI, 0.54-0.94) for TAS102 plus BEV versus regorafenib monotherapy. Median progression-free survival (PFS) was 4.4 months (95% CI, 3.7-5.4) for TAS102 plus BEV, 2.5 months (95% CI, 1.6-2.3) for TAS102 monotherapy, and 2.1 months (95% CI, 1.6-2.3) for regorafenib monotherapy. The hazard ratios were 0.57 (95% CI, 0.45-0.73) for TAS102 plus BEV versus TAS102 monotherapy and 0.44 (95% CI, 0.34-0.58) for TAS102 plus BEV versus regorafenib monotherapy. On multivariate analysis, TAS102 plus BEV was independently correlated with better OS and PFS. No unexpected adverse events were observed in any group. Conclusion: Our study shows that OS and PFS are longer in patients treated with TAS102 plus BEV than in those treated with TAS102 or regorafenib monotherapy.

DOI： 10.1177/17588359211009143

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Blackwell Publishing Asia  

Background: The Glissonean approach has been widely validated for both open and minimally invasive anatomic liver resection (MIALR). However, the possible advantages compared to the conventional hilar approach are still under debate. The aim of this systematic review was to evaluate the application of the Glissonean approach in MIALR. Methods: A systematic review of the literature was conducted on PubMed and Ichushi databases. Articles written in English or Japanese were included. From 2,390 English manuscripts evaluated by title and abstract, 43 were included. Additionally, 23 out of 463 Japanese manuscripts were selected. Duplicates were removed, including the most recent manuscript. Results: The Glissonean approach is reported for both major and minor MIALR. The 1st, 2nd and 3rd order divisions of both right and left portal pedicles can be reached following defined anatomical landmarks. Compared to the conventional hilar approach, the Glissonean approach is associated with shorter operative time, lower blood loss, and better peri-operative outcomes. Conclusions: Glissonean approach is safe and feasible for MIALR with several reported advantages compared to the conventional hilar approach. Clear knowledge of Laennec's capsule anatomy is necessary and serves as a guide for the dissection. However, the best surgical approach to be performed depends on surgeon experience and patients’ characteristics. Standardization of the Glissonean approach for MIALR is important.

DOI： 10.1002/jhbp.908

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Blackwell Publishing Asia  

Background: The main aim of this survey was to analyze how liver surgeons perform liver resections and to define their conception of anatomic procedures within the incorporation of minimally invasive liver surgery (MILS). Methods: The survey was distributed among liver surgeons. It mainly focused on personal experience on open and MILS, methods and landmarks, and experience on anatomic resections and Glissonean approach. Results: A total of 445 valid answers from 54 countries was obtained. Surgeons performing MILS mainly have below 10 years of experience (81.8% of responders) and one third has never done complex MILS. New techniques, including indocyanine green demarcation are marginally used (&lt
25%). More than 60% of surgeons do not make a full exposure of hepatic veins during MILS, mainly due to the risk of injury or not considering it to be of utility. Although 88% of responders agreed with the concept of anatomic resection as the “resection along the border/watersheds of each order division identified by the portal vein flow”, only 55% of surgeons have ever performed MILS Glissonean approaches. Conclusions: Liver anatomy is not a static concept. Anatomic resections need training and precision. Standardization of complex anatomic resections by a minimally invasive approach should be encouraged.

DOI： 10.1002/jhbp.959

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Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：Japanese Society of Gastroenterological Surgery  

An 80-year-old man visited another doctor with a complaint of fever. A blood test showed hepatic dysfunction and abdominal contrast-enhanced CT revealed dilatation of the common bile duct and intrahepatic bile ducts and a poorly contrasted mass in the distal bile duct. He was referred to our department for surgical treatment. Endoscopic retrograde cholangiography revealed a 5 cm stenosis in the distal bile duct and bile juice cytology showed class IV. The patient was diagnosed with distal cholangiocarcinoma cT2N0M0 cStage IB and underwent pancreaticoduodenectomy and regional lymph node dissection. Histopathological findings revealed a spindle cell-dominated, circumferential tumor in the distal bile duct. Immunohistological staining showed that the tumor cells were positive for epithelial markers (CK and CAM5.2) and a mesenchymal marker (vimentin), and the final diagnosis was “socalled sarcomatoid carcinoma”. The patient received gemcitabine as adjuvant chemotherapy for six months and has been alive without recurrence for one year postoperatively.

DOI： 10.5833/jjgs.2020.0061

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Springer Science and Business Media Deutschland GmbH  

Background: Postoperative infectious complications may be associated with a worse long-term prognosis for patients undergoing surgery for a malignant indication. The current study aimed to characterize the impact of postoperative infectious complications on long-term oncologic outcomes among patients undergoing resection for hepatocellular carcinoma (HCC). Methods: Patients who underwent curative-intent resection for HCC between 2000 and 2017 were identified from an international multi-institutional database. The relationship between postoperative infectious complications, overall survival (OS), and recurrence-free survival (RFS) was analyzed. Results: Among 734 patients who underwent HCC resection, 269 (36.6%) experienced a postoperative complication (Clavien–Dindo grade 1 or 2 [n = 197, 73.2%] vs grade 3 and 4 [n = 69, 25.7%]). An infectious complication was noted in 81 patients (11.0%) and 188 patients (25.6%) had non-infectious complications. The patients with infectious complications had worse OS (median: infectious complications [46.5 months] vs no complications [106.4 months] [p &lt
0.001] and non-infectious complications [85.7 months] [p &lt
0.05]) and RFS (median: infectious complications [22.1 months] vs no complications [45.5 months] [p &lt
0.05] and non-infectious complications [38.3 months] [p = 0.139]) than the patients who had no complication or non-infectious complications. In the multivariable analysis, infectious complications remained an independent risk factor for OS (hazard ratio [HR], 1.7
p = 0.016) and RFS (HR, 1.6
p = 0.013). Among the patients with infectious complications, patients with non-surgical-site infection (SSI) had even worse OS and RFS than patients with SSI (median OS: 19.5 vs 70.9 months [p = 0.010]
median RFS: 12.8 vs 33.9 months [p = 0.033]). Conclusion: Infectious complications were independently associated with an increased long-term risk of tumor recurrence and death. Patients with non-SSI versus SSI had a particularly worse oncologic outcome.

DOI： 10.1245/s10434-021-10565-2

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Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：Japanese Society of Gastroenterological Surgery  

A 43-year-old male presented with dizziness due to severe anemia. Gastrointestinal endoscopy revealed a large submucosal tumor with bleeding from the ulcer in the anterior wall of the upper stomach. A biopsy specimen indicated a gastrointestinal stromal tumor (GIST). Abdominal enhanced CT revealed an extraluminal growth type GIST of 11.0 cm in diameter and a contrast defect in the left gastric vein extending to the splenic vein and portal vein trunk. FDG-PET/CT showed abnormal accumulation in the gastric main tumor (SUVmax 9.9) and intravascular contrast defect (SUVmax 5.6). These findings led to diagnosis of GIST with a tumor embolus in the portal vein. The patient underwent total gastrectomy with distal pancreatomy with splenectomy and removal of the tumor embolus in the portal vein. Pathological examination of the resected specimen revealed proliferation of spindle cells. Immunohistochemical staining was positive for CD117 (c-kit), DOG1 and CD34, and negative for S-100. Anticoagulant therapy was administered for postoperative portal thrombus. The patient was discharged on the 38th hospital day. Postoperative chemotherapy with imatinib mesylate was started, and the patient is presently alive without recurrence 12 months after surgery.

DOI： 10.5833/jjgs.2020.0105

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：International College of Surgeons  

The aim of this prospective study was to evaluate the safety of preoperative amino acid plus carbohydrate drink (Elental) loading in colon cancer surgery. Prolonged preoperative fasting increases insulin resistance, and current evidence recommends carbohydrate drinks 2 hours before surgery. We prospectively enrolled consecutive patients with a preoperative diagnosis of colon cancer who underwent surgery. The patients received 600 mL of Elental the night before surgery and 300 mL of Elental 3 hours prior to induction of anesthesia. Primary end point was the safety of preoperative amino acid (Elental) loading in colon cancer surgery. Safety measurement was anastomotic leakage and aspiration pneumonia. Secondary end points were incidence rate of incisional surgical site infection, recovery of bowel movement, length of hospital stay, postoperative nutritional status, and insulin resistance. A total of 80 consecutive patients were enrolled in this study from February 2013 to January 2014. The incidence of anastomotic leakage was 3 patients (3.8%), and there was no aspiration pneumonia. The incidence of incisional surgical site infection was 2 patients (2.5%). The median times of first flatus, defecation after surgery, and postoperative hospital stay were 1 day, 2 days, and 6 days, respectively. The insulin resistance recovered to a preoperative level after 3 days after surgery. The preoperative amino acid plus carbohydrate drink (Elental) loading 3 hours prior to induction of anesthesia in colon cancer surgery is safe, and incisional surgical site infection rate and recovery of bowel movement and insulin resistance are feasible.

DOI： 10.9738/INTSURG-D-16-00088.1

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Nuclear factor erythroid 2-related factor 2 (NRF2) is a key modifier in breast cancer. It is unclear whether NRF2 suppresses or promotes breast cancer progression. We studied the clinical relevance of NRF2 expression by conducting in silico analyses in 5443 breast cancer patients from several large patient cohorts (METABRIC, GSE96058, GSE25066, GSE20194, and GSE75688). NRF2 expression was significantly associated with better survival, low Nottingham pathological grade, and ER-positive/HER2-negative and triple negative breast cancer (TNBC). High NRF2 ER-positive/HER2-negative breast cancer enriched inflammation- and immune-related gene sets by GSEA. NRF2 expression was elevated in immune, stromal, and cancer cells. High NRF2 tumors were associated with high infiltration of immune cells (CD8+, CD4+, and dendritic cells (DC)) and stromal cells (adipocyte, fibroblasts, and keratinocytes), and with low fraction of Th1 cells. NRF2 expression significantly correlated with area under the curve (AUC) of several drug response in multiple ER-positive breast cancer cell lines, however, there was no significant association between NRF2 and pathologic complete response (pCR) rate after neoadjuvant chemotherapy in human samples. Finally, high NRF2 breast cancer was associated with high expression of immune checkpoint molecules. In conclusion, NRF2 expression was associated with enhanced tumor-infiltrating lymphocytes in ER-positive/HER2-negative breast cancer.

DOI： 10.3390/cancers12123856

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PURPOSE: This study aimed to investigate gender-dependent antitumor immune response to neoadjuvant chemoradiotherapy (NACRT) in pancreatic ductal adenocarcinoma (PDAC) patients. METHODS: This study enrolled 58 patients (25 females and 33 males) with borderline resectable PDAC who underwent R0 surgical resection after NACRT. The resected tumor specimens were analyzed for tumor-associated macrophages (TAMs); tumor-infiltrating lymphocytes (CD8+ and CD4+ T cells); regulatory T cells; and IRF-5-expressing cells using immunohistochemical staining for CD163, CD204, CD8, CD4, Foxp3, and IRF-5 antigen. The relationship between clinicopathological features and clinical outcomes was evaluated using multivariate Cox proportional hazard analysis. RESULTS: Females had longer overall survival (P = .044) and relapse-free survival (P = .044) than males. The CD204+ TAM number was significantly lower in females than in males (P = .009). No significant difference occurred between female and male patients in other tumor-infiltrating immune cells. IRF-5+ cell number was significantly higher in female patients (P = .002). Negative correlation occurred between CD204+ cells and IRF-5-positive cells (P = .003, r = -.385). CONCLUSIONS: Female gender was an independent prognostic factor possibly due to the greater reduction in CD204+ TAM infiltration in tumors after NACRT. The beneficial effects of NACRT on TAMs' infiltration might be associated with gender-dependent IRF-5 expression.

DOI： 10.1002/jhbp.883

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Pathologically complete (R0) resection is essential for prolonged survival in pancreatic cancer. Survival depends not only on surgical technique, but also on cancer biology. A biomarker to predict survival is a critical need in pancreatic treatment. We hypothesized that this 4-gene score, which was reported to reflect cell proliferation, is a translatable predictive biomarker for pancreatic cancer. A total of 954 pancreatic cancer patients from multiple cohorts were analyzed and validated. Pancreatic cancer had the 10th highest median score of 32 cancers in The Cancer Genome Atlas (TCGA) cohort. The four-gene score significantly correlated with pathological grade and MKI67 expression. The high four-gene score enriched cell proliferation-related and cancer aggressiveness-related gene sets. The high score was associated with activation of KRAS, p53, transforming growth factor (TGF)-β, and E2F pathways, and with high alteration rate of KRAS and CDKN2A genes. The high score was also significantly associated with reduced CD8+ T cell infiltration of tumors, but with high levels of interferon-γ and cytolytic activity in tumors. The four-gene score correlated with the area under the curve of irinotecan and sorafenib in primary pancreatic cancer, and with paclitaxel and doxorubicin in metastatic pancreatic cancer. The high four-gene score was associated with significantly fewer R0 resections and worse survival. The novelty of the study is in the application of the four-gene score to pancreatic cancer, rather than the bioinformatics technique itself. Future analyses of inoperable lesions are expected to clarify the utility of our score as a predictive biomarker of systemic treatments.

DOI： 10.3390/cancers12123635

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INTRODUCTION: While tumor burden (TB) has been associated with outcomes among patients with hepatocellular carcinoma, the role of overall TB in intrahepatic cholangiocarcinoma (ICC) remains poorly defined. METHODS: Patients undergoing curative-intent resection of ICC between 2000 and 2017 were identified from a multi-institutional database. The impact of TB on overall (OS) and disease-free survival (DFS) was evaluated in the multi-institutional database and validated externally. RESULTS: Among 1101 patients who underwent curative-intent resection of ICC, 624 (56.7%) had low TB, 346 (31.4%) medium TB, and 131 (11.9%) high TB. OS incrementally worsened with higher TB (5-year OS; low TB: 48.3% vs medium TB: 29.8% vs high TB: 17.3%, p < 0.001). Similarly, patients with low TB had better DFS compared with medium and high TB patients (5-year DFS: 38.3% vs 18.7% vs 6.9%, p < 0.001). On multivariable analysis, TB was independently associated with OS (medium TB: HR = 1.40, 95% CI 1.14-1.71; high TB: HR = 1.89, 95% CI 1.46-2.45) and DFS (medium TB, HR = 1.61, 95% CI 1.33-1.96; high TB: HR = 2.03, 95% CI 1.56-2.64). Survival analysis revealed an excellent prognostic discrimination using the TB among the external validation cohort (3-year OS; low TB: 44.8%, medium TB: 29.3%; high TB: 23.3%, p = 0.03; 3-year DFS: low TB: 32.7%, medium TB: 10.7%; high TB: 0%, p < 0.001). While neoadjuvant chemotherapy was not associated with survival across the TB groups, receipt of adjuvant chemotherapy was associated with increased survival among patients with high TB (5-year OS: 24.4% vs 13.4%, p = 0.02). CONCLUSION: Overall TB dictated prognosis among patients with resectable ICC. TB may be used as a tool to help guide post-resection treatment strategies.

DOI： 10.1245/s10434-020-09393-7

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Springer  

Objectives: To assess conditional survival (CS) according to recurrence status, as well as conditional disease-free survival (cDFS) among patients with intrahepatic cholangiocarcinoma (ICC). Methods: CS and cDFS were evaluated among ICC patients who underwent curative-intent resection for ICC by using a multi-institutional database. Five-year CS (CS5) at “x” years was calculated separately for patients who did and did not experience recurrence. The cDFS3 at “x” years was defined as the chance to be disease-free for an additional 3 years after not having experienced a recurrence for “x” years postoperatively. Results: Among 1221 patients, median OS was 36.8 months. While estimated actuarial OS decreased over time, CS5 increased as patients survived over longer periods of time and reached 93.9% at 4 years among 139 patients who did not experience a recurrence. Among the 725 (59.4%) patients who did experience a tumor recurrence, CS5 decreased to 17.7% the first postoperative year
however, CS5 subsequently increased to 79.7% for 81 patients who had survived 4 years after surgery. While actuarial DFS decreased from 54.6% at 1 year to 28.2% at 5 years, estimated cDFS3 following liver resection increased over time. Of note, patients with known risk factors for recurrence had even more marked improvements in cDFS3 over subsequent years versus patients without risk factors for recurrence. Conclusion: CS and cDFS changed over time according to the presence of disease-specific risk factors, as well as the presence of recurrence.

DOI： 10.1007/s11605-019-04472-x

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Blackwell Publishing Asia  

Background/Purpose: Early drain removal (EDR) based on drain fluid amylase level (DFA) after pancreaticoduodenectomy excluded 15%-40% patients from EDR because of inappropriate DFA. Methods: Of 198 pancreatoduodenectomy cases, we used the first 105 cases as an exploration cohort to construct the optimal criteria for EDR on postoperative day (POD)4 that were applied to the subsequent 93 cases used as the validation cohort. After that, we examined another 142 patients to further assess the efficacy of the new EDR criteria. Results: Of the four independent predictors of clinically relevant postoperative pancreatic fistula (CR-POPF) ([1] soft pancreas, [2] positive drain fluid culture on POD1, and [3] serum C-reactive protein [CRP] ≥13 mg/dL on POD4) in the exploration cohort, EDR was applied to cases in the validation cohort meeting the [2] and/or [3], enabling 96% (89/93) applicability of EDR. Outcomes were improved in the validation cohort compared to the exploration cohort
CR-POPF: 8.6% vs 25.7%, P =.005
Dindo-Clavien grade ≥ 3 complications: 23.7% vs 41.9%, P =.007
and median hospital stay (day): 21 vs 27, P =.005. The subsequent 142 patients showed 92% (131/142) applicability of EDR and 5.6% (8/142) incidence of CR-POPF. Conclusions: Our new criteria for EDR, without DFA, enabled ≥ 90% applicability of EDR and reduced CR-POPF.

DOI： 10.1002/jhbp.746

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