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

DOI： 10.14740/wjon1691

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

DOI： 10.14740/wjon1694

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Language：English  

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：English   Publishing type：Research paper (scientific journal)  

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

DOI： 10.1002/ccr3.7537

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

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

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Language：English  

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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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：English   Publishing type：Research paper (scientific journal)  

OBJECTIVE: Neoadjuvant chemotherapy (NAC) is essential for surgical downstaging of early-stage breast cancer, but taxane administration is associated with neuropathy. We investigated whether eribulin induces less neuropathy than paclitaxel. METHODS: In this multicentre, randomised study (UMIN000012817), patients diagnosed with invasive breast cancer between December 2013 and April 2016 were randomly assigned to group E (eribulin followed by fluorouracil, epirubicin, and cyclophosphamide; FEC) or group P (paclitaxel followed by FEC). The primary endpoint was incidence of grade 1 or higher peripheral neuropathy according to the Common Terminology Criteria for Adverse Events (CTCAE). Secondary endpoints were pathological complete response (pCR), clinical response, breast-conserving surgery, adverse events, disease-free survival (DFS), and patient neurotoxicity questionnaire (PNQ) analysis. RESULTS: One hundred and eighteen cases were analyzed for safety and 115 were evaluated for efficacy. Peripheral sensory neuropathy was significantly lower in group E after week 6, while peripheral motor neuropathy in group E was significantly lower at weeks 9, 12, and 15. pCR in groups E and P was 20.7% and 29.8% (P = .289), respectively, and clinical response was 55.2% and 77.2% (P = .017), respectively. Three-year DFS was 89.7% in group E and 86.0% in group P (P = .561). Neutropenia was more frequent and more severe in group E. PNQ was evaluated for 4 years, and item 1 (sensory) was consistently lower in group E. CONCLUSION: Neuropathy was significantly less frequent and less severe in patients who received eribulin compared with paclitaxel. Thus, eribulin could be a good alternative to paclitaxel in patients suffering severe neuropathy.

DOI： 10.1016/j.clbc.2022.08.007

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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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Background: Combination therapy with cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors and hormonal therapy as the first-line and second-line treatments has already been shown to be effective in patients with hormone receptor-positive (HR+) human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer (MBC) in clinical trials. On the other hand, in clinical practice, CDK4/6 inhibitors are used not only as first-/second-line but also as later-line hormonal therapies, or for patients receiving prior chemotherapy in metastatic setting. However, the efficacy and safety of combination therapy in these patients remain unclear. In this study, we evaluate the clinical efficacy and safety of combination therapy with abemaciclib and hormonal therapy for chemotherapy-treated patients with HR+ HER2- MBC. Methods: This multi-institutional prospective cohort study will involve a total of 300 chemotherapy-treated patients with HR+ HER2- MBC. The primary endpoint is progression-free survival (PFS). Secondary endpoints include overall survival, time to treatment failure, response rate, clinical benefit rate, and adverse events. The preplanned subpopulation analysis is the number of chemotherapy regimens for HR+ HER2- MBC (two or less vs. three or more), prior treatment history with CDK4/6 inhibitors other than abemaciclib (presence vs. absence) and menopausal status (pre vs. post). We also planned to determine PFS of the subpopulation treated with abemaciclib as maintenance therapy after chemotherapy. Discussion: In this multi-institutional prospective cohort study, we evaluate the clinical efficacy and safety of combination therapy with abemaciclib and hormonal therapy for chemotherapy-treated patients with HR+ HER2- MBC. We also evaluate this combination therapy as maintenance therapy in patients who respond to early-line chemotherapy.

DOI： 10.14740/wjon1511

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

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ABSTRACT: Intraductal papilloma (IDP) is a benign tumor of the breast. However, IDP has been reported to show high uptake of 18F-FDG using whole-body PET. We experienced IDP with low-grade ductal carcinoma in situ using dedicated breast PET, which is more sensitive than whole-body PET. The 18F-FDG uptake of the whole tumor was high, and differentiation between the carcinoma and the residual benign lesion was difficult. This is the first report of IDP detected with dedicated breast PET. Diagnosis of IDP is sometimes controversial; papilloma may show glucose uptake similar to that of low-grade carcinoma.

DOI： 10.1097/RLU.0000000000004086

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PURPOSE: Patients with breast cancer may develop cognitive impairment as a result of hormone therapy and aging. This study aimed to describe older patients' experience of cognitive impairment related to hormone therapy for breast cancer. METHODS: A qualitative and descriptive design was used. Semi-structured interviews were conducted with 11 patients asking about their experience in daily life related to their cognitive impairment. Study participants were evaluated by cancer-specific geriatric assessment. Inductive content analysis was conducted using the interview records. RESULTS: Three themes emerged from the patients' narrative data: recognizing of cognitive impairments, impacts on mental health, and coping with cognitive impairments. Recognizing of cognitive function consisted of two categories: perception of cognitive changes and acknowledging their cognitive function status through interacting with others. Impacts on mental health consisted of six categories: decreased motivation for social activities, upset by perception of cognitive decline, concerns about impacts of cognitive impairment on treatment of breast cancer, concerns about the care burden of their family, concerns about progression of cognitive impairments, and feeling secure that their cognitive impairment is not unusual. Coping with cognitive impairments consisted of two categories: coping with problems related to cognitive impairment and trying to maintain and improve cognitive function. CONCLUSION: Oncology nurses should assess cognitive function and complete a comprehensive evaluation of older patients receiving hormone therapy for breast cancer. An evaluation of cognitive function would enable a tailored approach to education and support to enhance coping ability in the longer term.

DOI： 10.1016/j.ejon.2022.102115

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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

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

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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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Triple-negative breast cancer (TNBC) lacks an effective treatment target and is usually treated with chemotherapy. Treatment of older patients with TNBC, however, should be decided carefully because of the side effects of chemotherapy in this population. Some forms of TNBC are associated with a favorable prognosis and do not require chemotherapy. To optimize the treatment of older patients with TNBC, it is important to know the clinicopathological characteristics and a prognostic marker. In this study, classic clinicopathological factors, immunohistochemical characteristics (androgen receptor [AR], cytokeratin 5/6 [CK5/6], epidermal growth factor receptor), tumor-infiltrating lymphocytes (TILs), and the clinical outcome based on the status of each biomarker were compared among a consecutive series of female patients with TNBC aged ≥75 years (n = 75) and among those aged 55-64 years matched for the pathological stage (n = 47) who underwent surgery without neoadjuvant therapy. TNBC with special histology (particularly apocrine carcinoma, pleomorphic invasive lobular carcinoma, and metaplastic carcinoma) was more frequent in the older group than in the younger group (35/75, 57% versus 11/47, 23%, P = 0.010). The AR positivity rate was higher in older patients than in younger patients, whereas TILs and CK5/6 exhibited the opposite results. In multivariate analyses, AR positivity was an independent predictor of a favorable outcome in older patients (lower recurrence rate), whereas the high level of TILs was favorable in younger patients (lower recurrence and mortality rates). AR positivity or apocrine morphology was frequent and predicts a favorable clinical outcome in older patients with TNBC, suggesting the importance of AR examination in this population.

DOI： 10.1016/j.humpath.2021.01.005

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

DOI： 10.21873/invivo.12522

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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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BACKGROUND/AIM: Aldehyde dehydrogenase 1 (ALDH1) is known as a breast cancer stem cell (CSC) marker. This study aimed to identify genes associated with ALDH1. MATERIALS AND METHODS: ALDH1-positive and -negative breast cancer cells were isolated using laser capture microdissection from five tissue samples of ALDH1-positive breast cancer patients. Messenger RNA expression levels were compared between ALDH1-positive and -negative cells. RESULTS: We found 104 differentially expressed genes between ALDH1-positive and -negative cells. Gene ontology and pathway analysis revealed that these genes were correlated with CSC functions and pathways. Network analyses identified 10 genes that were closely associated with ALDH1. We validated these 10 genes utilizing The Cancer Genome Atlas and the Molecular Taxonomy of Breast Cancer International Consortium cohort, and found that they were associated with ALDH1 expression and correlated with Wnt pathway signaling. CONCLUSION: The 10 genes we identified could be potential targets for CSC therapy of breast cancer.

DOI： 10.21873/anticanres.14696

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

DOI： 10.1007/s12282-020-01188-8

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Other Link： http://link.springer.com/article/10.1007/s12282-020-01188-8/fulltext.html

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BACKGROUND: Pathological complete response (pCR) is often achieved by neoadjuvant chemotherapy (NAC), particularly in hormone receptor-negative breast cancer. Contrast-enhanced magnetic resonance imaging (cMRI) is the most reliable imaging modality to evaluate the pathological effect of NAC. Ultrasonography is indispensable to collect representative specimens from the target lesion by core needle biopsy (CNB). This study aimed to evaluate the accuracy of predicting pCR by adding CNB after NAC, in cases with complete clinical response (cCR) diagnosed by cMRI. METHODS: In this prospective multicentre study, we evaluated patients diagnosed with cCR by cMRI after NAC. Ultrasound-guided CNB (uCNB) using a 14G needle was performed without clip markers under general anaesthesia as planned surgery. Specimens collected by uCNB were compared to those resected surgically and were categorized as (i) no carcinoma (ypT0), (ii) no invasive carcinoma and only residual carcinoma in situ (ypTis) and (iii) residual invasive carcinoma. The concordance of pathological results between the uCNB and surgical specimens was evaluated. RESULTS: Of the 83 patients evaluated, 41 (49.4%) and 17 (20.5%) of them had ypT0 and ypTis, respectively. The false negative rates (FNR), sensitivity and specificity for predicting ypT0 by uCNB were 50.0%, 50.0%, 100%, respectively, and those for predicting ypT0+ypTis were 28.0%, 72.0% and 98.3%, respectively. The concordance rates were 74.7% (62/83) for ypT0 and 90.4% (75/83) for ypT0+ypTis. CONCLUSION: In cCR cases diagnosed by cMRI, uCNB was not accurate enough to predict pCR. Additional modalities like clip placements and/or thicker core needles may be required for better prediction.

DOI： 10.1016/j.suronc.2020.10.002

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

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

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

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

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BACKGROUND: Nipple-areola complex (NAC) reconstruction is a technique used in breast reconstructive surgery, which is performed during the final stage of breast reconstruction after total mastectomy of primary breast cancer. Composite nipple grafts utilizing the contralateral NAC are common; however, to our knowledge, there are no reports of new primary invasive ductal carcinoma development within the graft. Here, we describe one such case for the first time. CASE PRESENTATION: A 54-year-old woman was referred to us by the Department of Plastic and Reconstructive Surgery in our medical center for further evaluation of right nipple erosion. She had undergone total mastectomy of the right breast following a breast cancer diagnosis 15 years ago, at which time tumor biological profiling revealed the following: estrogen receptor (ER), positive; progesterone receptor (PgR), negative; and human epidermal growth factor receptor 2 (HER2), undetermined. She received adjuvant chemotherapy and endocrine therapy. She defaulted endocrine therapy for a few years, and 7 years after surgery, she underwent autologous breast reconstruction with a deep inferior epigastric perforator (DIEP) flap. In the following year, NAC reconstruction was performed using a composite graft technique. Seven years after the NAC reconstruction, erosion appeared on the nipple grafted from its contralateral counterpart; scrape cytology revealed malignancy. The skin on the right side of her chest around the NAC and subcutaneous fat tissue consisted of transferred tissue from the abdomen, as the DIEP flap and grafted nipple were located on the graft skin. The right nipple carcinoma arose from the tissue taken from the left nipple. Magnetic resonance imaging (MRI) or computed tomography showed no malignant findings in the left breast. As the malignant lesion seemed limited to the area around the grafted right nipple on MRI, surgical resection with sufficient lateral and deep margins was performed around the right nipple. Pathological findings revealed invasive ductal carcinoma with comedo ductal components infiltrating the graft skin and underlying adipose tissue. Immunohistochemistry revealed positive for ER, PgR, and HER2. CONCLUSIONS: To our knowledge, this is the first case involving the development of invasive ductal carcinoma in a nipple graft constructed on the skin of a DIEP flap, with the origin from the contralateral breast's nipple.

DOI： 10.1186/s40792-020-00962-2

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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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BACKGROUND: There is limited information on the oncological outcomes of immediate autologous breast reconstruction in the Asian population. This study aimed to evaluate the oncological outcomes of immediate one-stage autologous breast reconstruction using a free perforator flap for breast cancer patients at a single institution in Japan. METHODS: We retrospectively reviewed 239 patients who underwent immediate one-stage autologous breast reconstruction using a free perforator flap after skin- or nipple-sparing mastectomy. The whole breast was pathologically analyzed in 5-mm sections. Clinical and pathological data were collected from medical records. RESULTS: For tumor stage among the 239 patients, 101 (42.3%) had stage 0, 127 (53.1%) had stage I and II, and 11 (4.6%) had stage III. Twenty-three patients (9.6%) had margin involvement in the surgical specimen. Adjuvant chemotherapy was performed in 75 patients (30%), and endocrine therapy was administered in 153 patients (64%). Radiation therapy was performed in 15 patients (6.3%) because of multiple lymph node metastases or margin involvement. With a median follow-up time of 73 mo, local recurrence was found in 3.3%, distant metastases in 2.5%, and contralateral breast cancer in 3.7%. All patients with local recurrence did not receive radiation therapy as adjuvant treatment. CONCLUSIONS: Among the patients who underwent immediate one-stage autologous reconstruction after breast surgery, 3.3% had local recurrence. For patients with margin involvement, radiation therapy is a promising option.

DOI： 10.1016/j.jss.2020.01.010

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BACKGROUND: A subgroup of triple-negative breast cancer (TNBC) shows impaired BRCA1 function owing to causes other than mutation, which is called "BRCAness." DNA-damaging agents are known to have more efficacy in BRCA1-mutant tumors than mitotic poisons. We conducted a prospective single-arm clinical trial of neoadjuvant chemotherapy (NAC) using an anthracycline-based regimen without taxanes for BRCAness TNBCs. MATERIALS AND METHODS: BRCAness was examined using the multiplex ligation-dependent probe amplification (MLPA) method in TNBC cases. For BRCAness cases, NAC was performed with anthracycline-based regimens without additional taxanes. RESULTS: A total of 30 patients with TNBC were enrolled. MLPA was successfully performed in 25 patients. Eighteen patients (72%) showed BRCAness. Twenty-three patients received NAC as per the protocol. On analysis, the clinical response rate (complete response plus partial response) was 76.4%, and the pathological complete response rate was 35.3%. CONCLUSIONS: The interim analysis revealed that the pathological complete response rate was lower than estimated. Therefore, BRCAness by MLPA was not sufficient to predict the therapeutic response to anthracycline-based regimens in TNBC.

DOI： 10.1016/j.jss.2019.12.047

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If familial hereditary tumor is suspected, diagnosis and treatment should always be performed considering the presence of familial hereditary tumors irrespective of whether genetic testing is performed.

DOI： 10.1002/ccr3.2698

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INTRODUCTION: Despite the excellent prognosis associated with pathological complete response (pCR) to neoadjuvant chemotherapy (NAC), some patients still develop recurrence. Here, we investigated the outcomes of breast cancer patients with pCR, as well as the clinical and pathological predictors of cancer recurrence in these patients. MATERIALS AND METHODS: Of the 1599 breast cancer patients treated with NAC, we evaluated 394 patients who achieved pCR between January 2007 and December 2016. pCR was defined as no evidence of invasive cancer in breast. Residual in situ ductal and axillary lymph node diseases were not considered. We analyzed the outcomes using the Kaplan-Meier method. We assessed the association of clinical and pathological predictors with cancer recurrence using the cox proportional hazards regression model. RESULTS: The median follow-up time was 63 months. The 5-year disease-free survival rate was 92.3%. Cancer recurrence was observed in 28 patients (7.1%): local recurrence 8 patients (2.0%), visceral metastasis 10 patients (2.5%), and brain metastasis 10 patients (2.5%). Brain metastases were found in patients with HER2 type breast cancer. The significant predictors of cancer recurrence were HER2 positivity (p = 0.04), clinical tumor size (p < 0.01), and lymph node metastasis (p < 0.01) before NAC on univariate analysis and only lymph node metastasis on multivariate analysis. CONCLUSION: Patients achieving pCR to NAC showed excellent outcomes. Advanced clinical stage, large tumor size, presence of lymph node metastasis, and HER2 positivity before NAC were identified as significant predictors of cancer recurrence. Residual in situ ductal and lymph node diseases after NAC were not significant predictors.

DOI： 10.1016/j.ejso.2019.08.001

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BACKGROUND: It is important to determine whether anthracycline-containing regimens or taxane-containing regimens are more effective in individual patients. The present study compared the efficacy of six cycles of docetaxel and cyclophosphamide (TC6) with that of three cycles of 5-fluorouracil, epirubicin and cyclophosphamide followed by docetaxel (FEC-D) in Japanese patients with hormone receptor (HR)-negative breast cancer (BC) to identify subtypes requiring anthracycline treatment. METHODS: The study included 103 patients with operable HR-negative BC. Of these patients 53 received FEC-D and 50 received TC6. The primary endpoint was pathological complete response (pCR). The secondary endpoints were safety, breast-conserving surgery, disease-free survival (DFS) and overall survival (OS). The predictive factors for each regimen were evaluated. RESULTS: Of the 103 patients, 97 completed the study (FEC-D, 50 patients; TC6, 47 patients). The pCR rate was higher with FEC-D (36%) than with TC6 (25.5%); however, the difference was not significant (P = 0.265). TC6 was safer than FEC-D, as the adverse events with docetaxel in the FEC-D regimen were similar to those with the TC6 regimen. Among patients with basal BC, the pCR rate was significantly higher with FEC-D (42.9%) than with TC6 (13.6%; P = 0.033). Among patients with triple-negative breast cancer (TNBC), the DFS and OS were significantly better with FEC-D than with TC6 (P = 0.016 and P = 0.034, respectively). CONCLUSION: TC6 was not as effective as FEC-D for treating HR-negative BC, as TC6 was not sufficient to treat TNBC, particularly the basal subtype. Our findings suggest that anthracyclines are better treatment options than taxanes for basal BC.

DOI： 10.1016/j.breast.2019.06.003

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BACKGROUND: Breast matrix-producing carcinomas (MPCs) are rare, and usually triple-negative (TNBC; i.e. oestrogen receptor-, progesterone receptor-, and human epidermal growth factor receptor 2-negative). This study evaluated the clinical features, immunohistochemical profiles, and pathological response to neoadjuvant chemotherapy (NAC) of patients with MPCs. PATIENTS AND METHODS: Five MPCs were identified among 247 patients with TNBC receiving anthracycline- and taxane-based NAC. Pathological response was assessed using surgical specimens. RESULTS: All tumours were histological grade 3 according to pre-treatment core biopsies. Mean Ki-67 and p53 positivity were 65% and 90%, respectively. All tumours were TNBC, and epidermal growth factor receptor-, cytokeratin 5/6-, and vimentin-positive. Grade 3 (pathological complete response) was achieved in 0% (0/5) and 32% (77/242) of those with MPCs and with TNBCs of no specific histological type, respectively, and grade 1a (poor response) in 80% (4/5) and 13% (31/242), respectively. CONCLUSION: MPCs are basal-type TNBCs expressing epithelial-mesenchymal transition markers, with a poor response to standard NAC. Further studies are needed to improve the treatment of this rare but aggressive tumour.

DOI： 10.21873/anticanres.13536

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DOI： 10.1186/s40792-019-0585-x

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PURPOSE: Aldehyde dehydrogenase1 (ALDH1) is widely accepted as a stem cell marker for normal breast as well as in breast cancer. Although the clinical impact of ALDH1 was observed in our previous study, we do not know how ALDH1 affects stem cell features resulting in worsening of prognosis in breast cancer. The purpose of this study is to explore ALDH1-related gene and its function on cancer stem cell (CSC). METHODS: In five cases of ALDH1-positive triple-negative breast cancer, mRNA expression profile was compared between ALDH1-positive and ALDH1-negative cells by Affymetrix microarray analysis after microdissection. Among the genes modulated in ALDH1-positive cells, we focused on H19, which encodes a long non-coding RNA, in this study. An in-vitro study was conducted with H19 siRNA in HCC1934 and iCSCL10A cell lines. The association of H19 with prognosis was examined in 180 breast cancer cases. RESULTS: Network analysis revealed the existence of five genes related with H19, including miR-103, miR-107, let-7, miR-29b-1, and Trx. In-vitro analysis showed that suppression of H19 using siRNA reduces sphere formation capacity in both HCC1934 and iCSCL10A cell lines. In clinical studies, H19 expression was associated with hormone negativity, tumor size, and nodal status. Patients with H19 expression had significantly poor disease-free survival (DFS) (26.3 vs. 64.8% at 5 years, p = 0.001) and overall survival (OS) (28.9 vs. 68.3% at 5 years, p = 0.004). The effect of H19 expression on prognosis was the most significant in triple-negative breast cancer compared to that in other subtypes (20.0 vs. 65.4% at 5 years DFS, p = 0.012, 20.0 vs. 69.2% at 5 years OS, p = 0.016). CONCLUSION: This study indicated that H19 was associated with stem cell phenotype in ALDH1-positive breast cancer. H19 regulates CSC and is associated with poor prognosis in breast cancer patients, particularly in triple-negative subtype.

DOI： 10.1007/s10549-018-4793-z

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：American Association for Cancer Research Inc.  

Sphingosine-1-phosphate (S1P), a bioactive sphingolipid mediator, has been implicated in regulation of many processes important for breast cancer progression. Previously, we observed that S1P is exported out of human breast cancer cells by ATPbinding cassette (ABC) transporter ABCC1, but not by ABCB1, both known multidrug resistance proteins that efflux chemotherapeutic agents. However, the pathologic consequences of these events to breast cancer progression and metastasis have not been elucidated. Here, it is demonstrated that high expression of ABCC1, but not ABCB1, is associated with poor prognosis in breast cancer patients. Overexpression of ABCC1, but not ABCB1, in human MCF7 and murine 4T1 breast cancer cells enhanced S1P secretion, proliferation, and migration of breast cancer cells. Implantation of breast cancer cells overexpressing ABCC1, but not ABCB1, into the mammary fat pad markedly enhanced tumor growth, angiogenesis, and lymphangiogenesis with a concomitant increase in lymph node and lung metastases as well as shorter survival of mice. Interestingly, S1P exported via ABCC1 from breast cancer cells upregulated transcription of sphingosine kinase 1 (SPHK1), thus promoting more S1P formation. Finally, patients with breast cancers that express both activated SPHK1 and ABCC1 have significantly shorter disease-free survival. These findings suggest that export of S1P via ABCC1 functions in a malicious feed-forward manner to amplify the S1P axis involved in breast cancer progression and metastasis, which has important implications for prognosis of breast cancer patients and for potential therapeutic targets. Implication: Multidrug resistant transporter ABCC1 and activation of SPHK1 in breast cancerworsen patient's survival by export of S1P to the tumor microenvironment to enhance key processes involved in cancer progression. Mol Cancer Res
16(6)
1059-70.

DOI： 10.1158/1541-7786.MCR-17-0353

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Although obesity with associated inflammation is now recognized as a risk factor for breast cancer and distant metastases, the functional basis for these connections remain poorly understood. Here, we show that in breast cancer patients and in animal breast cancer models, obesity is a sufficient cause for increased expression of the bioactive sphingolipid mediator sphingosine-1-phosphate (S1P), which mediates cancer pathogenesis. A high-fat diet was sufficient to upregulate expression of sphingosine kinase 1 (SphK1), the enzyme that produces S1P, along with its receptor S1PR1 in syngeneic and spontaneous breast tumors. Targeting the SphK1/S1P/S1PR1 axis with FTY720/fingolimod attenuated key proinflammatory cytokines, macrophage infiltration, and tumor progression induced by obesity. S1P produced in the lung premetastatic niche by tumor-induced SphK1 increased macrophage recruitment into the lung and induced IL6 and signaling pathways important for lung metastatic colonization. Conversely, FTY720 suppressed IL6, macrophage infiltration, and S1P-mediated signaling pathways in the lung induced by a high-fat diet, and it dramatically reduced formation of metastatic foci. In tumor-bearing mice, FTY720 similarly reduced obesity-related inflammation, S1P signaling, and pulmonary metastasis, thereby prolonging survival. Taken together, our results establish a critical role for circulating S1P produced by tumors and the SphK1/S1P/S1PR1 axis in obesity-related inflammation, formation of lung metastatic niches, and breast cancer metastasis, with potential implications for prevention and treatment.Significance: These findings offer a preclinical proof of concept that signaling by a sphingolipid may be an effective target to prevent obesity-related breast cancer metastasis. Cancer Res; 78(7); 1713-25. ©2018 AACR.

DOI： 10.1158/0008-5472.CAN-17-1423

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PURPOSE: Although association studies of genetic variations with the clinical outcomes of breast cancer patients treated with tamoxifen have been reported, genetic factors which could determine individual response to tamoxifen are not fully clarified. We performed a genome-wide association study (GWAS) to identify novel genetic markers for response to tamoxifen. EXPERIMENTAL DESIGN: We prospectively collected 347 blood samples from patients with hormone receptor-positive and human epidermal growth factor receptor 2-negative, invasive breast cancer receiving preoperative tamoxifen monotherapy for 14 to 28 days. We used Ki-67 response in breast cancer tissues after preoperative short-term tamoxifen therapy as a surrogate marker for response to tamoxifen. We performed GWAS and genotype imputation using 275 patients, and an independent set of 72 patients was used for replication study. RESULTS: The combined result of GWAS and the replication study, and subsequent imputation analysis indicated possible association of three loci with Ki-67 response after tamoxifen therapy (rs17198973 on chromosome 4q34.3, rs4577773 on 6q12, and rs7087428 on 10p13, Pcombined = 5.69 x 10-6, 1.64 x 10-5, and 9.77 x 10-6, respectively). When patients were classified into three groups by the scoring system based on the genotypes of the three SNPs, patients with higher scores showed significantly higher after/before ratio of Ki-67 compared to those with lower scores (P = 1.8 x 10-12), suggesting the cumulative effect of the three SNPs. CONCLUSION: We identified three novel loci, which could be associated with clinical response to tamoxifen. These findings provide new insights into personalized hormonal therapy for the patients with breast cancer.

DOI： 10.1371/journal.pone.0201606

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Language：English   Publisher：SPRINGER JAPAN KK  

DOI： 10.1007/s12282-017-0792-x

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My arguments regarding postmastectomy radiotherapy (PMRT) for this case are based on the following 4 reasons: (1) high rate of local recurrence in the no PMRT group in the Early Breast Cancer Trialists' Collaborative Group meta-analysis on which the present guideline is based, (2) stage migration by sentinel node biopsy, (3) possible adverse events of radiotherapy, and (4) problems on extrapolation of data from western countries.

DOI： 10.1007/s12282-016-0749-5

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER ASSOC CANCER RESEARCH  

Purpose: CYP2D6 is the key enzyme responsible for the generation of the potent active metabolite of tamoxifen, "endoxifen." There are still controversial reports questioning the association between CYP2D6 genotype and tamoxifen efficacy. Hence, we performed a prospective multicenter study to evaluate the clinical effect of CYP2D6 genotype on tamoxifen therapy.
Experimental Design: We enrolled 279 patients with hormone receptor-positive and human epidermal growth factor receptor 2-egative, invasive breast cancer receiving preoperative tamoxifen monotherapy for 14 to 28 days. Ki-67 response in breast cancer tissues after tamoxifen therapy was used as a surrogate marker for response to tamoxifen. We prospectively investigated the effects of allelic variants of CYP2D6 on Ki-67 response, pathological response, and hot flushes.
Results: Ki-67 labeling index in breast cancer tissues significantly decreased after preoperative tamoxifen monotherapy (P = 0.0000000000000013). Moreover, proportion and Allred scores of estrogen receptor-positive cells in breast cancer tissues were significantly associated with Ki-67 response (P = 0.0076 and 0.0023, respectively). Although CYP2D6 variants were not associated with pathologic response nor hot flushes, they showed significant association wyith Ki-67 response after preoperative tamoxifen therapy (P = 0.018; between two groups, one with at least one wild-type allele and the other without a wild-type allele).
Conclusions: This is the first prospective study evaluating the relationship between CYP2D6 variants and Ki-67 response after tamoxifen therapy. Our results suggest that genetic variation in CYP2D6 is a key predictor for the response to tamoxifen in patients with breast cancer. (C) 2016 AACR.

DOI： 10.1158/1078-0432.CCR-16-1779

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Despite the dramatic advances in breast cancer treatment over the past two decades, it is still the most common malignancies in women. One of the reasons patients succumb to breast cancer is treatment resistance leading to metastasis and recurrence. Recently, cancer stem cells (CSCs) have been suggested as a cause of metastasis and recurrence in several cancers because of their unique characteristics, including self-renewal, pluripotency, and high proliferative ability. Increasing evidence has implicated breast cancer stem cells (BCSCs) as essential for tumor development, progression, recurrence, and treatment resistance. BCSCs exhibit resistance to treatment owing to several inter-related factors, including overexpression of ATP-binding cassette (ABC) transporters and increased aldehyde dehydrogenase (ALDH) activity, DNA repair, and reactive oxygen species (ROS) scavenging. In addition, the Notch, Hedgehog, and Wnt signaling pathways have been suggested as the major pathways involved in the self-renewal and differentiation of BCSCs. Despite growing evidence suggesting the importance of BCSCs in progression and metastasis, clear criteria for the identification of BCSCs in clinical practice have yet to be established. Several potential markers have been suggested, including CD44+/CD24-/low, ALDH1, EpCAM/ESA, and nestin
however, there is no standard method to detect BCSCs. Triple-negative breast cancer, which shows initial chemosensitivity, demonstrates worsened prognosis due to therapy resistance, which might be related to the presence of BCSCs. Several clinical trials aimed at the identification of BCSCs or the development of BCSC-targeted therapy are in progress. Determining the clinical relevance of BCSCs may provide clues for overcoming therapy resistance in breast cancer.

DOI： 10.21037/gs.2016.08.03

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

Background Sphingosine-1-phosphate (S1P) is a pleiotropic bioactive lipid mediator that regulates many physiological and pathological processes. It has been suggested that S1P gradient with high concentrations in the blood and lymphatic fluid and low concentrations in the peripheral tissue plays important roles in immune cell trafficking and potentially cancer progression. However, only a few reports have assessed S1P levels in the lymphatic fluid due to lack of an established easy-to-use method. Here, we report a simple technique for collection of lymphatic fluid to determine S1P. Materials and methods Lymphatic fluid was collected directly with a catheter needle (classical method) or was absorbed onto filter paper after incision of cisterna chyli (new method) in murine models. Blood, lymphatic fluid and mesenteric lymph nodes were corrected from wild type and sphingosine kinase 2 (SphK2) knockout mice to determine S1P levels by mass spectrometry. Results The volume of lymphatic fluid collected by the new method was at least three times greater than those collected by the classical method. S1P concentrations in lymphatic fluid are lower than in blood and higher than in lymph nodes. Interestingly, S1P levels in lymphatic fluid from SphK2 knockout mice were significantly higher than those in wild type, suggesting an important role of SphK2 and/or SphK1 to regulate S1P levels in lymphatic fluid. Conclusions In agreement with the previous theory, our results confirm “S1P gradient” among blood, lymphatic fluid and peripheral lymphatic tissues. Convenient methods for collection and measurement of sphingolipids in lymphatic fluid are expected to provide new insights on functions of sphingolipids.

DOI： 10.1016/j.heliyon.2016.e00219

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ACADEMIC PRESS INC ELSEVIER SCIENCE  

Background: The standard of care for elderly women with breast cancer remains controversial. The aim of this study was to clarify the management of elderly breast cancer patients who undergo surgery.
Materials and methods: This retrospective single-center cohort study included 2276 breast cancer patients who underwent surgery between 1993 and 2014. The patients were divided into three groups according to age: &lt;= 64 y (young), 65-74 y (older), and &gt;= 75 y (elderly).
Results: The elderly had more advanced stage disease at diagnosis (stage III and IV, 16.2%, 17.5%, and 22.1% for the young, older, and elderly groups, respectively). The elderly were more likely to undergo mastectomy (43.3%, 41.4%, and 50.7%, respectively), omit axillary operation (0.6%, 1.1%, and 9.3%, respectively), and skip radiotherapy after breast-conserving surgery (93.1%, 86.8%, and 29.1%, respectively). Endocrine therapy was widely used in all the groups (94.4%, 93.8%, and 90.1%, respectively), but frequency of chemotherapy was lower in the elderly regardless of hormone receptor (HR) status (40.8%, 25.5%, and 9.3% in HR(+), 87.2%, 75.3%, and 39.5% in HR(-), respectively). Although the locoregional recurrence rate was higher in the elderly (4.2%, 3.4%, and 7.0% at 5 y, respectively; P = 0.028), there were no differences among groups in distant metastasis-free survival or breast cancerespecific survival.
Conclusions: Although elderly patients had more advanced stages of cancer and received less treatment, there were no differences in survival. Omission of axillary dissection, radiation, and chemotherapy after operation may be an option for breast cancer patients aged &gt;= 75 y. (C) 2016 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.jss.2016.05.031

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：FEDERATION AMER SOC EXP BIOL  

The bioactive sphingolipid sphingosine-1-phosphate (S1P) and the kinase that produces it have been implicated in inflammatory bowel diseases in mice and humans; however, little is known about the role of the 2 S1P-specific phosphohydrolase isoforms, SGPP1 and SGPP2, which catalyze dephosphorylation of S1P to sphingosine. To elucidate their functions, we generated specific knockout mice. Deletion of Sgpp2, which is mainly expressed in the gastrointestinal tract, significantly reduced dextran sodium sulfate (DSS)-induced colitis severity, whereas deletion of ubiquitously expressed Sgpp1 slightly worsened colitis. Moreover, Sgpp1 deletion enhanced expression of multifunctional proin-flammatory cytokines, IL-6, TNF-alpha, and IL-1 beta, activation of the transcription factor signal transducer and activator of transcription 3, and immune cell infiltration into the colon. Conversely, Sgpp2-nullmice failed to mount a DSS-induced systemic inflammatory response. Of interest, Sgpp2 deficiency suppressed DSS-induced intestinal epithelial cell apoptosis and improved mucosal barrier integrity. Furthermore, down-regulation of Sgpp2 attenuated LPS-induced para-cellular permeability in cultured cells and enhanced expression of the adherens junction protein E-cadherin. Finally, in patients with ulcerative colitis, SGPP2 expression was elevated in colitis tissues relative to that in uninvolved tissues. These results indicate that induction of SGPP2 expression contributes to the pathogenesis of colitis by promoting disruption of the mucosal barrier function. SGPP2 may represent a novel therapeutic target in inflammatory bowel disease.

DOI： 10.1096/fj.201600394R

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Aim: Triple negative breast cancer (TNBC) is a heterogeneous disease and is associated with the cancer stem cell (CSC), basal-like, and BRCA1 function deficient (BRCAness) subtypes. We examined these 3 subtypes in TNBC and compared their chemosensitivity against anthracycline or taxane with a special attention to BRCAness.
Methods: Sixty-six TNBC cases were obtained from a randomized phase II trial comparing TCx6 (TC6) with PEC-Docetaxel (FEC-D) as neoadjuvant chemotherapy. The core needle specimens before chemotherapy were used for subtyping. The basal-like and CSC subtypes were identified by immunohistochemistry; CK5/6 and EGFR staining for the basal-like subtype and ALDH1 staining for the CSC subtype. The BRCAness subtype was examined by Multiplex Ligation-dependent Probe Amplification (MLPA). Correlations between subgroups and pCR rates according to each regimen and subtype were examined.
Results: The basal-like and BRCAness subtypes were significantly associated (p = 0.010) with the other subtypes, but not the CSC subtype. The pCR rates were higher with 1-EC-D than with TC6 in the basal-like (54.5% vs 14.3%, p = 0.081) and BRCAness (56.2% vs 16.7%, p = 0.030) subtypes. Both were not effective in the CSC subtype (18.2% vs 11.8%, p = 1.00).
Conclusion: BRCAness identified by MLPA was practically useful for treatment selection for avoiding taxane. ALDH1 may be considered as a marker for the CSC subtype requiring novel agents. (C) 2016 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.ejso.2016.02.246

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The tumor microenvironment is a determining factor for cancer biology and progression. Sphingosine-1-phosphate (S1P), produced by sphingosine kinases (SphKs), is a bioactive lipid mediator that regulates processes important for cancer progression. Despite its critical roles, the levels of S1P in interstitial fluid (IF), an important component of the tumor microenvironment, have never previously been measured due to a lack of efficient methods for collecting and quantifying IF. The purpose of this study is to clarify the levels of S1P in the IF from murine mammary glands and its tumors utilizing our novel methods. We developed an improved centrifugation method to collect IF. Sphingolipids in IF, blood, and tissue samples were measured by mass spectrometry. In mice with a deletion of SphK1, but not SphK2, levels of S1P in IF from the mammary glands were greatly attenuated. Levels of S1P in IF from mammary tumors were reduced when tumor growth was suppressed by oral administration of FTY720/fingolimod. Importantly, sphingosine, dihydro-sphingosine, and S1P levels, but not dihydro-S1P, were significantly higher in human breast tumor tissue IF than in the normal breast tissue IF. To our knowledge, this is the first reported S1P IF measurement in murine normal mammary glands and mammary tumors, as well as in human patients with breast cancer. S1P tumor IF measurement illuminates new aspects of the role of S1P in the tumor microenvironment.

DOI： 10.1007/s10911-016-9354-7

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Aldehyde dehydrogenase 1 (ALDH1) has been identified as a breast cancer stem cell marker, but its value as a predictor of prognosis and chemoresistance is controversial. This study investigated the effect of ALDH1 on prognosis and chemoresponse by breast cancer subtype. We immunohistochemically analyzed 653 invasive breast cancer specimens and evaluated correlations among clinicopathological factors, survival status, response to neoadjuvant chemotherapy, and ALDH1 expression. Of 653 specimens, 139 (21.3 %) expressed ALDH1 in tumor cells. ALDH1 expression was correlated significantly with larger tumor size, node metastasis, higher nuclear grade, and with HER2(+) and progesterone/estrogen receptor (HR)(-) subtypes. ALDH1 expression was significantly observed in HER2 type and triple-negative breast cancer (TNBC). Patients with ALDH1(+) cancers had significantly shorter disease-free survival (P &lt; 0001) and overall survival (P = 0.044). ALDH1 expression significantly affected prognosis of luminal types, but not TNBC and HER2-enriched types. For the 234 patients treated with neoadjuvant chemotherapy, pathological complete response (pCR) rate was significantly lower in ALDH1(+) cases (13.5 vs. 30.3 %, P = 0.003). pCR and ALDH1 expression were significantly correlated in TNBC patients (P = 0.003). ALDH1(+) breast cancers tended to be aggressive, with poor prognoses. Although ALDH1(+) TNBC showed higher chemoresistance, ALDH1 had significant impact on prognosis in the luminal type but not in TNBC.

DOI： 10.1007/s10549-016-3738-7

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Background: The objective of this study was to examine the clinical outcomes of immediate breast reconstruction using perforator flaps from different donor sites, and to characterize the trends among these flaps.
Methods: We retrospectively reviewed 136 consecutive patients who underwent immediate breast reconstruction using free flaps after skin sparing mastectomy (SSM) or nipple-sparing mastectomy (NSM). The whole breast was pathologically analyzed in 5-mm sections. Breast reconstruction was performed using the deep inferior epigastric perforator (DIEP) flap, gluteal artery perforator (GAP) flap, and posterior medial thigh perforator (PMTP) flap. Patient characteristics were compared among donor sites.
Results: NSM was converted to SSM because of intraoperative subareolar tumor positivity in 7 of 107 patients. Eleven patients had positive margins in permanent sections. All but one patient had a positive horizontal margin in the peripheral direction. The 5-year recurrence-free survival rate was 91.9%. The locoregional recurrence rate was 5.1% with a mean follow-up observation period of 75 months. DRIP, GAP, and PMTP flaps were used in 64 (47.1%), 38 (27.9%), and 34 (25.0%) patients, retrospectively. DIEP flaps were used in older patients and those with a higher body mass index. GAP flaps were used in younger patients. DIEP and GAP flaps were used for larger breasts, and PMTP flaps for smaller breasts.
Conclusion: NSM or SSM with immediate perforator flap breast reconstruction is an oncologically acceptable surgical option. We believe that age, desire to have children, body mass index, and excised breast volume are valuable factors for selecting the optimal donor site. (C) 2015 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.ejso.2015.12.002

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Background: It has now become clear that the complex interplay of cancer and the immune responses against it plays a critical role in the tumor microenvironment during cancer progression. As new targets for cancer treatment are being discovered and investigated, murine models used for preclinical studies need to include intact immune responses to provide a closer correlation with human cancer. We have recently developed a modified syngeneic orthotopic murine colon cancer model that mimics human colon cancer progression with consistent results.
Materials and methods: Tumors were created using the murine colon adenocarcinoma cell line, CT26, modified to overexpress the firefly luciferase gene (CT26-luc1), which allowed real-time in vivo monitoring of tumor burden when the substrate, D-luciferin, was injected intraperitoneally using the In Vivo Imaging System. Mice are Balb/c (Harlan), syngeneic with the CT26-luc1 cells. Cells are injected submucosally, suspended in Matrigel, into the cecum wall under direct visualization.
Results: The model has demonstrated consistent implantation in the cecum. In vivo bioluminescence allowed real-time monitoring of total tumor burden. Perioperative preparation had a significant impact on reproducibility of the model. Finally, total tumor burden quantified with bioluminescence enabled estimation of lymph node metastasis ex vivo.
Conclusions: This method maintains an intact immune response and closely approximates the clinical tumor microenvironment. It is expected to provide an invaluable murine metastatic colon cancer model particularly in preclinical studies for drug development targeting those mechanisms. (C) 2015 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.jss.2015.04.030

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DOI： 10.1158/1538-7445.AM2015-4247

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DOI： 10.1158/1538-7445.AM2015-5272

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DOI： 10.1158/1538-7445.SABCS14-P2-06-16

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY-BLACKWELL  

Bile acids are important hormones during the feed/fast cycle, allowing the liver to coordinately regulate nutrient metabolism. How they accomplish this has not been fully elucidated. Conjugated bile acids activate both the ERK1/2 and AKT signaling pathways via sphingosine 1-phosphate receptor 2 (S1PR2) in rodent hepatocytes and in vivo. Here, we report that feeding mice a high-fat diet, infusion of taurocholate into the chronic bile fistula rat, or overexpression of the gene encoding S1PR2 in mouse hepatocytes significantly upregulated hepatic sphingosine kinase 2 (SphK2) but not SphK1. Key genes encoding nuclear receptors/enzymes involved in nutrient metabolism were significantly downregulated in livers of S1PR2(-/-) and SphK2(-/-) mice. In contrast, overexpression of the gene encoding S1PR2 in primary mouse hepatocytes differentially increased SphK2, but not SphK1, and mRNA levels of key genes involved in nutrient metabolism. Nuclear levels of sphingosine-1-phosphate, an endogenous inhibitor of histone deacetylases 1 and 2, as well as the acetylation of histones H3K9, H4K5, and H2BK12 were significantly decreased in hepatocytes prepared from S1PR2(-/-) and SphK2(-/-) mice. Conclusion: Both S1PR2(-/-) and SphK2(-/-) mice rapidly developed fatty livers on a high-fat diet, suggesting the importance of conjugated bile acids, S1PR2, and SphK2 in regulating hepatic lipid metabolism. (Hepatology 2015;61:1216-1226)

DOI： 10.1002/hep.27592

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BACKGROUND: The impact of neoadjuvant chemotherapy (NACT) on immediate free flap breast reconstruction remains controversial. Furthermore, the oncological outcomes of immediate free flap breast reconstruction after skin-sparing mastectomy (SSM) following NACT remain unclear. This study aimed to investigate the surgical complications and oncological outcomes of immediate perforator flap reconstruction after SSM following NACT. METHODS: A total of 201 consecutive patients with indications for immediate perforator flap reconstruction after SSM were included between 2004 and 2012. Surgical and oncological outcomes were compared between patients with and without NACT. RESULTS: There were 38 patients in the NACT group and 163 in the non-NACT control group. The median age of the NACT group was 39.5 years, which was significantly younger than the control group (43.0 years; P < 0.05). Patients in the NACT group also had more advanced and aggressive disease (P < 0.05). There was no significant difference in the frequency of surgical complications between the groups, no difference in the type of complications, and no significant difference in the frequencies of major and minor complications. No patients in the NACT group had delayed adjuvant therapy. Eight patients (4%) developed recurrences, with a median follow-up time of 3.0 years. Local recurrences occurred in three control patients but no patients in the NACT group. CONCLUSION: NACT does not affect short-term or interim outcomes after immediate perforator flap reconstruction and may thus represent a safe and practical treatment option for the multidisciplinary treatment of breast cancer.

DOI： 10.1016/j.ejso.2014.09.001

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：W.B. Saunders Ltd  

Background: Although sentinel lymph node biopsy (SLNB) is a standard staging method for assessing nodal status of breast cancer patients, SLNB after neoadjuvant chemotherapy (NAC) remains controversial. The aim of this study was to validate the practicality and accuracy of SLNB by our modified Indigocarmine blue dye methods following NAC. Methods: One hundred consecutive cases with breast cancers treated by NAC were enrolled in this study. After NAC, all patients underwent SLNB performed by our modified Indigocarmine blue dye methods without radioisotope, followed by back-up axillary lymph node dissection (ALND). Results: Sentinel nodes (SNs) were identified in 94 cases (identification rate, 94%)
the accuracy was 94.7% (89/94 cases)
and the false negative rate (FNR) 13.5% (5/37 cases). For cases with vs. without clinically evident metastatic nodes before NAC, the identification rate was 92.4% (61/66 cases) vs. 97.1% (33/34 cases)
the accuracy 91.8% (56/61 cases) vs. 97.0% (32/33 cases) and the FNR 16.1% (5/31 cases) vs. 0% (0/6 case), respectively. There were six patients without identified SNs, three of them had metastatic nodes. False negatives occurred in five cases
in four, fewer than two sentinel nodes had been removed. Conclusion: Following NAC, the accuracy of SLNB by modified Indigocarmine blue dye methods is adequate compared with other tracers. In patients in whom no SNs have been identified, lymphatic metastasis is likely and therefore ALND is recommended. For patients with cN0 prior to NAC, SLNB by modified Indigocarmine blue dye methods is clinically feasible, though controversial for patients with positive nodes.

DOI： 10.1016/j.ejso.2014.10.066

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BACKGROUND: HER2-positive breast cancer sensitivity to anthracyclines is enhanced when topoisomerase IIα (TOP2A) is co-amplified under both adjuvant and metastatic settings. However, the relationship between anthracycline sensitivity and TOP2A amplification in HER2-positive breast cancers in neoadjuvant settings is not known. METHODS: The TOP2A gene status was examined by FISH in biopsies from 18 patients who received anthracycline and cyclophosphamide before surgery. RESULTS: The TOP2A gene was amplified in 6/17 patients and was significantly associated with pathological response to the chemotherapy regimen. CONCLUSIONS: TOP2A amplification could predict anthracycline-sensitivity. Thus, the HER2/TOP2A co-amplified subtype may be effectively treated by anthracycline-containing regimens alone.

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DOI： 10.1158/1538-7445.AM2014-1890

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Breast cancer drug development costs nearly $610 million and 37 months in preclinical mouse model trials with minimal success rates. Despite these inefficiencies, there are still no consensus breast cancer preclinical models. Murine mammary adenocarcinoma 4T1-luc2 cells were implanted subcutaneous (SQ) or orthotopically percutaneous (OP) injection in the area of the nipple, or surgically into the chest 2nd mammary fat pad under direct vision (ODV) in Balb/c immunocompetent mice. Tumor progression was followed by in vivo bioluminescence and direct measurements, pathology and survival determined, and tumor gene expression analyzed by genome-wide microarrays. ODV produced less variable-sized tumors and was a reliable method of implantation. ODV implantation into the chest 2nd mammary pad rather than into the abdominal 4th mammary pad, the most common implantation site, better mimicked human breast cancer progression pattern, which correlated with bioluminescent tumor burden and survival. Compared to SQ, ODV produced tumors that differentially expressed genes whose interaction networks are of importance in cancer research. qPCR validation of 10 specific target genes of interest in ongoing clinical trials demonstrated significant differences in expression. ODV implantation into the chest 2nd mammary pad provides the most reliable model that mimics human breast cancer compared from subcutaneous implantation that produces tumors with different genome expression profiles of clinical significance. Increased understanding of the limitations of the different preclinical models in use will help guide new investigations and may improve the efficiency of breast cancer drug development .

DOI： 10.1007/s10549-014-3118-0

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：NATURE PUBLISHING GROUP  

Although interleukin 1 (IL-1) induces expression of the transcription factor IRF1 (interferon-regulatory factor 1), the roles of IRF1 in immune and inflammatory responses and mechanisms of its activation remain elusive. Here we found that IRF1 was essential for IL-1-induced expression of the chemokines CXCL10 and CCL5, which recruit mononuclear cells into sites of sterile inflammation. Newly synthesized IRF1 acquired Lys63 (K63)-linked polyubiquitination mediated by the apoptosis inhibitor cIAP2 that was enhanced by the bioactive lipid SIP. In response to IL-1, cIAP2 and the sphingosine kinase SphK1 (the enzyme that generates S1P) formed a complex with IRF1, which led to its activation. Thus, IL-1 triggered a hitherto unknown signaling cascade that controlled the induction of IRF1-dependent genes that encode molecules important for sterile inflammation.

DOI： 10.1038/ni.2810

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Background: Two most commonly used animal models for studying breast cancer lung metastasis are: lung metastasis after orthotopic implantation of cells into the mammary gland, and lung implantations produced after tail vein (TV) injection of cells. Tail vein injection can produce lung lesions faster, but little has been studied regarding the differences between these tumors, thus, we examined their morphology and gene expression profiles.
Methods: Syngeneic murine mammary adenocarcinoma, 4T1-luc2 cells, were implanted either subcutaneously (Sq), orthotopically (OS), or injected via TV in Balb/c mice. Genome-wide microarray analyses of cultured 4T1 cells, Sq tumor, OS tumor, lung metastases after OS (LMet), and lung tumors after TV (TVt) were performed 10 days after implantation.
Results: Bioluminescence analysis demonstrated different morphology of metastases between LMet and TVt, confirmed by histology. Gene expression profile of cells were significantly different from tumors, OS, Sq, TVt or LMet (10,350 probe sets; FDR &lt;= 1%; P&lt;0.0001). Sq tumors were significantly different than OS tumors (700 probe sets; FDR &lt;= 15%; P&lt;0.01), and both tumor types (Sq and OS) were significantly different than LMet (1,247 probe sets; &gt;1.5-fold-change; P&lt;0.01), with no significant difference between TVt and LMet.
Conclusions: There were significant differences between the gene profiles of cells in culture and OS versus LMet, but there were no differences between LMet versus TVt. Therefore, the lung tumor generated by TVt can be considered genetically similar to those produced after OS, and thus TVt is a relevant model for breast cancer lung metastasis.

DOI： 10.3978/j.issn.2072-1439.2013.06.17

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Background. Although many retrospective studies suggest that resection of the primary tumor improves survival in metastatic breast cancer animal studies suggest that resection induces metastasis. Moreover, there has been no critical evaluation of how well animal studies actually model metastatic breast cancer. We used our newly established orthotopic cancer implantation under direct vision model to evaluate the hypothesis that primary tumor resection improves survival in metastatic breast cancer by reducing overall tumor burden and improving immune responsiveness.
Methods. Murine mammary adenocarcinoma 4T1-luc2 cells that can be visualized by bioluminescence were implanted orthotopically into BALB/c mice under direct vision. Resection of the primary tumors at days 6, 10, and 28 were compared to sham resection of the contralateral normal mammary gland and observation alone. Tumor burden was quantified by bioluminescence. Taimor-draining lymph nodes were identified by intradermal injection of lymphazurin, and primary tumors, lymph nodes, and lungs.were examined pathologically. Kaplan-Meier survival analyses were performed. Splenocyte myeloid-derived suppressor cells (MDSCs) and CD4 or CD8 single positive T lymphocytes were quantified by flow cytometry.
Results. Tumors invaded locally, metastasized to regional lymph nodes, and then metastasized to distant organs, with subsequent mortality. Surgical stress increased tumor burden only transiently without affecting survival. When primary tumor resection decreased overall tumor burden substantially, further growth of metastatic lesions did not increase the overall tumor burden compared to observation, and survival was improved, which was not the case when resection did not significantly reduce the overall tumor burden. Decreasing overall tumor burden through resection of the primary tumor resulted in decreased splenic MDSC numbers and increased CD4 and CD8 cells, suggesting 'the potential for an improved immunologic response to cancer.
Conclusion. Decreasing overall tumor burden through resection of the primary breast tumor decreased MDSCs, increased CD4 and CD8 cells, and improved survival.

DOI： 10.1016/j.surg.2013.02.002

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Sphingosine-1-phosphate (S1P), a ligand for 5 specific receptors, is a potent lipid mediator that plays important roles in lymphocyte trafficking and immune responses. S1P is produced inside cells and therefore must be secreted to exert its effects through these receptors. Spinster 2 (Spns2) is one of the cell surface transporters thought to secrete S1P. We have shown that Spns2 can export endogenous S1P from cells and also dihydro-S1P, which is active at all cell surface S1P receptors. Moreover, Spns(2-/-) mice have decreased levels of both of these phosphorylated sphingoid bases in blood, accompanied by increases in very long chain ceramide species, and have defective lymphocyte trafficking. Surprisingly, levels of S1P and dihydro-S1P were increased in lymph from Spns(2-/-) mice as well as in specific tissues, including lymph nodes, and interstitial fluid. Moreover, lymph nodes from Spns(2-/-) mice have aberrant lymphatic sinus that appeared collapsed, with reduced numbers of lymphocytes. Our data suggest that Spns2 is an S1P transporter in vivo that plays a role in regulation not only of blood S1P but also lymph node and lymph S1P levels and consequently influences lymphocyte trafficking and lymphatic vessel network organization.-Nagahashi, M., Kim, E. Y., Yamada, A., Ramachandran, S., Allegood, J. C., Hait, N. C., Maceyka, M., Milstien, S., Takabe, K., Spiegel, S. Spns2, a transporter of phosphorylated sphingoid bases, regulates their blood and lymph levels and the lymphatic network. FASEB J. 27, 1001-1011 (2013). www.fasebj.org

DOI： 10.1096/fj.12-219618

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The effect of UVC irradiation wasinvestigated on a model of brain cancer and a model of experimental brain metastasis. For the brain cancer model, brain cancer cells were injected stereotactically into the brain. For the brain metastasis model, lung cancer cells were injected intra-carotidally or stereotactically. The U87 human glioma cell line was used for the brain cancer model, and the Lewis lung carcinoma (LLC) was used for the experimental brain metastasis model. Both cancer cell types were labeled with GFP in the nucleus and RFP in the cytoplasm. A craniotomy open window was used to image single cancer cells in the brain. This double labeling of the cancer cells withGFP and RFP enabled apoptosis of single cells to be imaged at the subcellular level through the craniotomy open window. UVC irradiation, beamed through the craniotomy open window, induced apoptosis in the cancer cells. UVC irradiation was effective on LLC and significantly extended survival of the mice with experimental brain metastasis. In contrast, the U87 glioma was relatively resistant to UVC irradiation. The results of this study suggest the use of UVC for treatment of superficial brain cancer or metastasis.

DOI： 10.1002/jcb.24381

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY-BLACKWELL  

The effect of UVC irradiation was investigated on a model of brain cancer and a model of experimental brain metastasis. For the brain cancer model, brain cancer cells were injected stereotactically into the brain. For the brain metastasis model, lung cancer cells were injected intra-carotidally or stereotactically. The U87 human glioma cell line was used for the brain cancer model, and the Lewis lung carcinoma (LLC) was used for the experimental brain metastasis model. Both cancer cell types were labeled with GFP in the nucleus and RFP in the cytoplasm. A craniotomy open window was used to image single cancer cells in the brain. This double labeling of the cancer cells with GFP and RFP enabled apoptosis of single cells to be imaged at the subcellular level through the craniotomy open window. UVC irradiation, beamed through the craniotomy open window, induced apoptosis in the cancer cells. UVC irradiation was effective on LLC and significantly extended survival of the mice with experimental brain metastasis. In contrast, the U87 glioma was relatively resistant to UVC irradiation. The results of this study suggest the use of UVC for treatment of superficial brain cancer or metastasis. J. Cell. Biochem. 114: 428434, 2013. (c) 2012 Wiley Periodicals, Inc.

DOI： 10.1002/jcb.24381

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ATP-binding cassette (ABC) transporters are membrane proteins that efflux various compounds from cells, including chemotherapeutic agents, and are known to affect multidrug resistance. Recent reports disagree on whether ABCC11 is a risk factor for breast tumorigenesis, but its expression in breast cancer is poorly investigated. We hypothesized that both frequency and expression levels of ABC transporters in breast tumors would vary by cancer subtype, and be associated with prognosis. Here, we constructed a tissue microarray breast tumor samples from 281 patients, and analyzed expressions of ABCB1, ABCC1, ABCC11, and ABCG2 immunohistochemically. Breast cancer subtypes were determined by immunohistochemistry of estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 (HER2). Protein expression was correlated to clinicopathological characteristics, clinical follow-up, and pathological complete response to neoadjuvant chemotherapy. The tissue microarray comprised 191 luminal A (68.0 %), 17 luminal B (6.0 %), 27 HER2 (9.6 %), and 46 triple-negative (16.4 %) samples. ABCC1 and ABCC11 expressions were associated with significantly shorter disease-free survival (P = 0.027 and P = 0.003, respectively). ABCC1, ABCC11, and ABCG2, but not ABCB1, were expressed significantly more, and more frequently, in aggressive subtypes. Patients with HER2+ and triple-negative tumor subtypes that expressed high levels of ABCC11 had significantly worse disease-free survival (P = 0.017 and P &lt; 0.001, respectively). We have shown, for the first time, that ABCC1, ABCC11, and ABCG2 are highly expressed in aggressive breast cancer subtypes, and that tumor ABCC11 expression is associated with poor prognosis.

File： 2013 BCRT ABCC11.pdf

DOI： 10.1007/s10549-012-2398-5

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DOI： 10.1016/j.ccr.2012.11.013

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Breast cancer is the most common type of cancer in women. However, it is very rarely manifested as hematologic disorders. A 35-year-old woman was admitted because of disseminated intravascular coagulation. Examinations revealed the presence of breast cancer in her left breast; therefore, paclitaxel was administered weekly. Although disseminated intravascular coagulation was controlled, pulmonary dysfunction due to lymphangitis carcinomatosa suddenly occurred 10 weeks after treatment. Pulmonary dysfunction was effectively treated with epirubicin and cyclophosphamide. Twenty-three weeks after treatment, the patient developed liver dysfunction accompanied with jaundice due to progressive metastatic lesions in the liver; liver dysfunction improved after the administration of vinorelbine. Subsequently, because of the recurrence of pulmonary dysfunction, rechallenge with epirubicin and cyclophosphamide was performed and was effective; however, this therapy was discontinued because of its adverse effects. She expired of liver failure 33 weeks after the occurrence of disseminated intravascular coagulation. Metastatic tumors in the bone marrow, lung, and liver showed different sensitivities to different anti-cancer agents. We report a case of breast cancer manifested by hematologic disorders which was treated by a sequential chemotherapy.

DOI： 10.3978/j.issn.2072-1439.2012.10.17

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DOI： 10.3978/j.issn.2227-684X.2012.10.05

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：BAISHIDENG PUBL GRP CO LTD  

Meckel's diverticulum is a common asymptomatic congenital gastrointestinal anomaly, but rarely it can present with hemorrhage. Over the last few years inverted Meckel's diverticulum has been reported in the literature with increasing frequency as an occult source of lower gastrointestinal hemorrhage. Here, we report a case of a 54-year-old male, who was referred for surgical evaluation with persistent anemia and occult blood per rectum after a work up which failed to localize the source over 12 mo, including upper and capsule endoscopy, colonoscopy, enteroclysis, Meckel scan, and tagged nuclear red blood cell scan. An abdominal computed tomography scan showed a possible mid-ileal intussusception and intraluminal mass. During the abdominal exploration, inverted Meckel's diverticulum was diagnosed and resected. We review the literature, discuss the forms in which the disease presents, the diagnostic modalities utilized, pathological findings, and treatment. Although less than 40 cases have been reported in the English literature from 1978 to 2005, 19 cases have been reported in the last 6 years alone (2006-2012) due to improved diagnostic modalities. Successful diagnosis and treatment of this disease requires a high index of clinical suspicion, which is becoming increasingly relevant to general gastroenterologists. (C) 2012 Baishideng. All rights reserved.

DOI： 10.3748/wjg.v18.i42.6155

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Cancer cells, with and without fluorescent protein expression, were irradiated with various doses of UVC (100, 400, and600 J/m(2)). Dual-color Lewis lung carcinoma cells (LLC) and U87 human glioma cells, expressing GFP in the nucleus and RFP in the cytoplasm and non-colored LLC and U87 cells were cultured in 96-well plates. Eight hours after seeding, the cells were irradiated with the various doses of UVC. The resulting cell number was determined after 24 hours. Compared to non-coloredLLC cells, the number of dual-color LLC cells decreased significantly due to UVC irradiation with 100 J/m(2) (p=0.003). Although there was no significant difference in the number of dual-color and non-colored U87 cells after 100 J/m(2) UVC irradiation (p=0.852), the number of dual-color U87 cells decreased significantly with respect to non-colored cells due to UVC irradiation with400 J/m(2) and 600 J/m(2) (p=0.011 and p=0.009, respectively). Thus, both dual-color LLC and dual-color U87 cells were more sensitive to UVC light than non-colored LLC and U87 cells. These results suggest that the expression of fluorescent proteins in cancer cells can enhance photodynamic therapy (PDT) using UVC and possibly

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：INT INST ANTICANCER RESEARCH  

Cancer cells, with and without fluorescent protein expression, were irradiated with various doses of UVC (100, 400, and 600 J/m(2)). Dual-color Lewis lung carcinoma cells (LLC) and U87 human glioma cells, expressing GFP in the nucleus and REP in the cytoplasm and non-colored LLC and U87 cells were cultured in 96-well plates. Eight hours after seeding, the cells were irradiated with the various doses of UVC. The resulting cell number was determined after 24 hours. Compared to non-colored LLC cells, the number of dual-color LLC cells decreased significantly due to UVC irradiation with 100 J/m(2) (p=0.003). Although there was no significant difference in the number of dual-color and non-colored U87 cells after 100 J/m(2) UVC irradiation (p=0.852), the number of dual-color U87 cells decreased significantly with respect to non-colored cells due to UVC irradiation with 400 J/m(2) and 600 J/m(2) (p=0.011 and p=0.009, respectively). Thus, both dual-color LLC and dual-color U87 cells were more sensitive to UVC light than non-colored LLC and U87 cells. These results suggest that the expression of fluorescent proteins in cancer cells can enhance photodynamic therapy (PDT) using UVC and possibly with other wavelengths of light as well.

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DOI： 10.3978/j.issn.2227-684X.2012.07.01

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DOI： 10.1158/1538-7445.AM2012-5350

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Language：English   Publisher：FUTURE MEDICINE LTD  

Breast cancer is a major health concern for many women, but despite the current standard therapies, many women still die of metastatic disease. Angiogenesis has been evaluated as a possible target for therapy and bevacizumab (Avastin (R), Genentech/Roche, CA, USA), a monoclonal antibody against VEGF-A, has been developed to target this. Current clinical trials utilizing bevacizumab have shown an increase in progression-free survival, but this has not translated to an increase in overall survival in breast cancer patients. In this article, we summarize the currently published trials utilizing bevacizumab in the treatment of breast cancer and describe various methods of measuring angiogenesis In vitro and In vivo. We also describe the related process of lymphangiogenesis, as this may contribute to the mechanism of cancer progression and may be a potential target for therapy in the future. Understanding these processes may help us develop new treatments for breast cancer.

DOI： 10.2217/FON.12.22

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER ASSOC CANCER RESEARCH  

Sphingosine-1-phosphate (S1P) is a pleiotropic bioactive lipid mediator that promotes breast cancer progression by diverse mechanisms that remain somewhat unclear. Here we report pharmacologic evidence of a critical role for sphingosine kinase 1 (SphK1) in producing S1P and mediating tumor-induced hemangiogenesis and lymphangiogenesis in a murine model of breast cancer metastasis. S1P levels increased both in the tumor and the circulation. In agreement, serum S1P levels were significantly elevated in stage IIIA human breast cancer patients, compared with age/ ethnicity-matched healthy volunteers. However, treatment with the specific SphK1 inhibitor SK1-I suppressed S1P levels, reduced metastases to lymph nodes and lungs, and decreased overall tumor burden of our murine model. Both S1P and angiopoietin 2 (Ang2) stimulated hemangiogenesis and lymphangiogenesis in vitro, whereas SK1-I inhibited each process. We quantified both processes in vivo from the same specimen by combining directed in vivo angiogenesis assays with fluorescence-activated cell sorting, thereby confirming the results obtained in vitro. Notably, SK1-I decreased both processes not only at the primary tumor but also in lymph nodes, with peritumoral lymphatic vessel density reduced in SK1-I-treated animals. Taken together, our findings show that SphK1-produced S1P is a crucial mediator of breast cancer-induced hemangiogenesis and lymphangiogenesis. Our results implicate SphK1 along with S1P as therapeutic targets in breast cancer. Cancer Res; 72(3); 726-35. (C) 2012 AACR.

DOI： 10.1158/0008-5472.CAN-11-2167

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

A 50-year-old man with primary biliary cirrhosis underwent living-donor liver transplantation (LDLT) using a graft of a left hemiliver with a left caudate lobe and duct-to-duct hepaticocholedochostomy. Postoperative bile leakage necessitated percutaneous drainage 22 days after LDLT. The patient presented to our hospital 205 days after the LDLT with abdominal distension and fever. Computed tomography showed ascites and a diffusely mottled pattern in the graft. The caudate lobe was swollen, and its bile ducts were dilated. The inferior vena cava was forced to the right by the swollen caudate lobe, and the root of the hepatic vein was stretched. The hepatic vein was not contrasted. Endoscopic retrograde cholangiography showed a biliary anastomotic stricture. Based on these findings, we diagnosed a severe outflow block of the hepatic vein and biliary anastomotic stricture. We performed balloon dilation of the biliary anastomosis and implanted a metallic stent in the hepatic vein. Thereafter, his clinical symptoms improved dramatically.

DOI： 10.1007/s00595-011-0037-0

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：MARY ANN LIEBERT, INC  

Sphingosine-1-phosphate (S1P) is a potent sphingolipid metabolite that regulates a number of biological processes critical for cancer. S1P produced inside cancer cells is exported and exerts its extracellular functions by binding to its specific receptors in an autocrine, paracrine, and/or endocrine manner, which is known as inside-out signaling. S1P is also known to exert its intracellular functions especially in the inflammatory process, but its relevance to cancer biology remains to be elucidated. Recently, there have been growing interests in the role of S1P in breast cancer progression, including angiogenesis and lymphangiogenesis. Our group demonstrated that activation of sphingosine kinase 1, the enzyme that catalyzes the phosphorylation of sphingosine to S1P, is a key step of this process. In this review, we will cover our current knowledge on the role of S1P signaling pathway in breast cancer progression with an emphasis on its role in tumor-induced lymphangiogenesis.

DOI： 10.1089/lrb.2012.0010

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：COGNIZANT COMMUNICATION CORP  

Breast cancer is not a single entity. This study therefore aimed to identify differences in the impacts of anticancer agents and predictive factors between different breast cancer subtypes. A total of 234 patients with luminal (n = 109), luminal-HER2 (L-H, n = 29), HER-2 (n = 35), or triple negative (TN, n = 61) breast cancer subtypes were treated with standard neoadjuvant chemotherapy consisting of an anthracycline and/or taxane. Pathological response and prognosis were examined in each subtype. Expression levels of estrogen and progesterone receptors, HER-2, nuclear grade, MIB-1, p53, topoisomerase II alpha (topoII alpha), cytokeratin (CK) 5/6, and epidermal growth factor receptor (EGER) were examined in association with quasipathological complete response (QpCR). QpCR rates were 9.1% (10/109) in luminal, 45% (13/29) in L-H, 37% (13/35) in HER2, and 54.1% (33/61) in TN. Non-QpCR patients showed significantly poorer 3-year disease-free survival than QpCR patients in TN, but not in patients with other subtypes. No factors were associated with QpCR in luminal patients. Patients with higher nuclear grade were more likely to achieve QpCR in L-H. The proliferative markers MIB-1 and topolla had opposite impacts on pathological response in HER-2 and TN. The QpCR rate was significantly higher in TN lacking CK5/6 and/or EGFR expression, defined as nonbasal subtype, compared with basal subtype (p = 0.049). Cytotoxic anticancer agents were associated with different responses in different breast cancer subtypes. Identifying basal-type cancer and further subdivision of nonbasal types is important for treating TN patients.

DOI： 10.3727/096504012X13473664562565

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Language：English   Publisher：AMER ASSOC CANCER RESEARCH  

DOI： 10.1158/0008-5472.SABCS11-P5-13-23

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DOI： 10.1158/1538-7445.AM2011-1695

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Language：English   Publisher：AMER ASSOC CANCER RESEARCH  

DOI： 10.1158/0008-5472.SABCS10-P1-01-16

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DOI： 10.1158/0008-5472.SABCS10-P1-12-01

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Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：Japanese Journal of Cancer and Chemotherapy Publishers Inc.  

We report a long-term survival case of metastatic breast cancer treated with trastuzumab and paclitaxel. The patient was a 64-year-old female. She underwent right quadrantectomy with axillary lymphadenectomy for advanced breast cancer. Histological examination showed papillotubular carcinoma, f, t2, n1 (6/14), ER (-), PgR (-), HER2 (3+). CMF and radiation were performed as adjuvant therapy. One year after the operation she was diagnosed to have liver metastasis and initiated trastuzumab treatment. Paclitaxel was also intermittently administered when the tumor marker was elevated. Four years after the operation, she experienced obstructive jaundice and was diagnosed as hepatic portal region metastasis. Obstructive jaundice was promptly alleviated after receiving trastuzumab and vinorelbin. No adverse events were reported over sixty-eight months of trastuzumab treatment. Long-term trastuzumab and intermittent chemotherapy would be one of the optimal treatments for HER2-positive breast cancer.

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

Adult rhabdomyosarcoma rupture is rare. A 21-year-old man seen for abdominal pain and constipation was found in abdominal computed tomography (CT) and magnetic resonance imaging (MRI) to have a large pelvic tumor with abdominal pain and distension rapidly worsening. CT showed considerable ascites and laboratory findings indicated anemia. In emergency surgery based on a diagnosis of tumor rupture, we found in-traabdominal hemorrhaging and mucinous discharge and conducted abdominoperineal resection. Parts of the tumor adhering to the prostate and urinary bladder had to remain in the abdomen. The histopathological diagnosis was embryonal rhabdomyosarcoma. One month after surgery, metastases detected in the liver and lung have completely disappeared after chemotherapy and radiation. At present, 15 months after surgery, the man remains alive without disease recurrence.. © 2010 The Japanese Society of Gastroenterological Surgery.

DOI： 10.5833/jjgs.43.1082

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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  

Li-Fraumeni症候群(LFS)は,TP53遺伝子の生殖細胞系列における病的バリアントにより乳癌,軟部組織肉腫,骨肉腫,脳腫瘍,白血病,肺癌,副腎皮質癌,消化器癌等種々の悪性腫瘍を発症する常染色体優性遺伝形式の遺伝性疾患であり,Chompretの診断基準が用いられる.放射線による二次発癌の恐れがあるため,治療法の選択や術後フォローを含むサーベイランスには注意が必要である.症例は27歳の女性.18歳時に右脛骨傍骨性骨肉腫,27歳時に左上顎軟骨肉腫に罹患.術後3ヵ月フォローCTで右乳房外側に造影結節を認め,針生検で非浸潤性乳管癌(DCIS)と診断した.Chompret基準を満たすため,LFSを疑い遺伝学的検査を提案したが希望はなく,術前に確定診断には至らなかったもののLFSに準じて治療方針を決定した.右乳輪乳頭温存乳房切除術とセンチネルリンパ節生検,組織拡張器挿入術を施行した.術後1年半で遺伝学的検査に同意し,(NM000546.5(TP53):c.476C>A:p.Ala159Asp,de novo)を同定した.現在,毎年の胸部MRIでフォローしている.(著者抄録)

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：AMER ASSOC CANCER RESEARCH  

DOI： 10.1158/1538-7445.SABCS19-P2-14-06

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

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Language：English   Publisher：(一社)日本癌治療学会  

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Language：Japanese   Publisher：神奈川県医師会  

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Language：Japanese   Publisher：(NPO)日本乳癌検診学会  

ステレオガイド下吸引式乳房組織生検は侵襲的な検査であり、検査時間の短縮に努める必要がある。検査技術の習得のためには穿刺ファントムを用いた穿刺実習が有用と考えるが、市販の穿刺ファントムは高価で頻回の購入は困難である。そこでわれわれは、実習用の穿刺ファントムの自作を検討した。穿刺ファントムの素材には、作成する観点および実用性の観点から、軽量粘土およびウレタン樹脂が選択された。さらに使用感について検討し、ウレタン樹脂を採用した。ウレタン樹脂の主剤(主成分ポリエーテルポリオール)と硬化剤(主成分ジイソシアネート)の配合割合についても検討を行った。模擬石灰化の深さは、中央部、表層部、深部の3段階に意図的に配置することが可能であった。柔らかい乳房を想定した配合割合で、3層の模擬石灰化を含むウレタン樹脂のファントム(直径7cm、高さ5cm円柱型)を作成したところ、作成日数30日、作成費用約2,000円であった。安価かつ容易に教育用穿刺ファントムを自作することが可能であったので報告する。(著者抄録)

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Other Link： http://search.jamas.or.jp/link/ui/2017406625

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

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Language：Japanese   Publisher：神奈川県医師会  

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Language：Japanese   Publisher：(NPO)日本乳腺甲状腺超音波医学会  

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

症例は64歳,女性.右乳癌T2N0M0(ER陽性,PgR境界域,HER2未検)に対して右乳房切除とセンチネルリンパ節生検を施行した.術後3年で傍胸骨リンパ節再発を認め,切除した.免疫染色ではER陽性,PgR陰性,HER2陽性(3+)であった.術後5年で胸骨転移を認め,ゾレドロン酸の投与を開始した.以降,左腋窩リンパ節再発と胸骨転移に対して,ホルモン療法,化学療法および抗HER2療法を続行し,ゾレドロン酸も継続投与した.投与開始から8年経過時に,右大腿の動揺を自覚し転倒した.右大腿骨骨幹部非定型骨折(atypical femoral fracture:AFF)の診断で入院,患側の骨折治療と,対側の骨折予防のために,両側大腿骨の髄内釘固定を行った.BP製剤によるAFF発症は極めて稀であるが,骨転移治療においてBP製剤を長期に用いる際は,AFF発症の可能性を念頭に置くべきと考えられた.(著者抄録)

DOI： 10.3919/jjsa.76.2930

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Other Link： http://search.jamas.or.jp/link/ui/2016108263

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Language：Japanese   Publisher：横浜市立大学医学会  

医療者ががん患者に死の話題を詳細に告げることは困難を伴うとされ、根治不能ながん患者の最期の場面で蘇生処置をするべきか否かについての確認は、患者本人からではなく、患者の家族との話し合いの中で決定されていることが多い。今回我々は横浜市立大学附属病院の医療スタッフに対して根治不能ながん患者に対するDNR確認の要否に関するアンケート調査を施行した。その結果を報告する。横浜市立大学附属病院でがん診療に関わる医師、看護師、薬剤師521人を対象とし、回収率は92.1%であった。内訳は医師171人、看護師285人、薬剤師24人であった。根治不能ながん患者本人からDNRの確認が必要であるかという質問には、医師、看護師の98%が必要と回答し、不要の解答は1%に過ぎなかった。医療者の70%以上がDNRを「患者自身が医療者に向けた命令」であると捉えており、患者自身からのDNR確認の実現に向けて医療者自身の努力がなされなければならない。(著者抄録)

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：AMER ASSOC CANCER RESEARCH  

DOI： 10.1158/1538-7445.AM2015-407

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DOI： 10.1158/1538-7445.AM2015-112

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Language：Japanese   Publishing type：Book review, literature introduction, etc.   Publisher：Medical Association of Yokohama City University  

In Japan, it has been considered difficult for medical staff to talk with advanced cancer patients in detail about the patient's death, and decision-making regarding "do not resuscitate" (DNR) or cardiopulmonary resuscitation (CPR) at the time of cardiopulmonary arrest. Therefore, whether to perform CPR is decided by the patient's family without consideration of the patient's wishes. This report provides results from a questionnaire completed by medical staff at Yokohama City University Hospital regarding whether decision making for DNR was confirmed by cancer patients themselves. Survey slips were sent to 521 medical staff involved in the treatment of cancer patients at Yokohama City University Hospital, and the response rate was 92.1%. Ninety-eight percent of medical doctors and nurses replied that DNR should be confirmed by the individual patient. Over 70% of medical staff recognized DNR as an order from patients to medical staff, and that medical staff have to make efforts to talk with patients themselves about DNR decisions.

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J-GLOBAL

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD  

DOI： 10.1016/j.cyto.2014.07.114

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DOI： 10.1158/1538-7445.AM2014-2695

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DOI： 10.1158/1538-7445.AM2014-4884

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CiNii Books

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

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Language：English   Publisher：日本癌学会  

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

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

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：AMER ASSOC CANCER RESEARCH  

DOI： 10.1158/1538-7445.AM2013-4887

Web of Science

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Language：English   Publishing type：Rapid communication, short report, research note, etc. (scientific journal)  

DOI： 10.1007/s10549-013-2450-0

Scopus

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：AMER ASSOC CANCER RESEARCH  

DOI： 10.1158/1538-7445.AM2013-5000

Web of Science

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Language：Japanese   Publisher：一般社団法人日本外科学会  

CiNii Books

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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, summary (international conference)   Publisher：AMER ASSOC CANCER RESEARCH  

DOI： 10.1158/1538-7445.AM2012-4364

Web of Science

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：AMER ASSOC CANCER RESEARCH  

DOI： 10.1158/1538-7445.AM2012-5280

Web of Science

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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：日本臨床外科学会  

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Language：Japanese   Publisher：(NPO)日本乳癌検診学会  

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

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

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

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Language：English   Publisher：日本癌学会  

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

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

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Language：Japanese   Publisher：(一社)日本肝胆膵外科学会  

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Language：Japanese   Publisher：(一社)日本肝胆膵外科学会  

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

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

症例は21歳の男性で,腹痛,便通異常を主訴に来院した.大腸内視鏡検査で直腸の壁外性圧迫を認め,CT,MRIで膀胱直腸窩を中心に,径10cmの境界明瞭な腫瘍を認めた.急速に腹痛,腹部膨満感が増悪し,超音波で多量の腹水を認め,腫瘍の破裂が疑われたため,緊急手術となった.術中所見では,骨盤内腫瘍の頂部が破裂し,同部からの出血による多量の血性腹水とムチン様内容物の流出を認めた.出血コントロールのために腫瘍の摘出が必要と判断し,腹会陰式直腸切断術を施行したが,腫瘍は膀胱から前立腺にかけて強固に癒着しており,骨盤内に腫瘍組織の一部が残存した.組織学的には胎児型横紋筋肉腫で,消化管・前立腺に浸潤を認めた.術後肺・肝転移が出現したため,放射線化学療法を施行し,画像上完全寛解となり,術後15ヵ月生存中である.横紋筋肉腫破裂は検索しうる限りで自験例が5例目であり,きわめてまれな症例であるため,文献的考察を交え報告する.(著者抄録)

CiNii Books

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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：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：(NPO)日本乳癌検診学会  

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Language：Japanese   Publisher：(一社)日本癌治療学会  

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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：(株)癌と化学療法社  

症例は64歳、女性。右乳癌に対し乳房部分切除術、腋窩郭清を施行した。病理診断は乳頭腺管癌、t2、n1(6/14)、ER(-)、PgR(-)、HER2(3+)であった。術後補助療法としてCMF療法と放射線照射を実施した。術後1年で肝転移が判明しtrastuzumab投与を開始した。腫瘍マーカーが上昇した際は、paclitaxelを間欠的に併用することで病勢制御が可能であった。術後4年で肝門部転移による閉塞性黄疸が出現し、胆管ステントを留置したが減黄が不良であった。患者の同意の下、trastuzumabとvinorelbineの併用療法を施行したところ黄疸は改善し腫瘍マーカーも正常範囲内に低下した。trastuzumabは累計5年8ヵ月使用したが有害事象はみられず、いまだに効果を有していると考えられた。HER2陽性転移・再発乳癌では、trastuzumab単剤の長期投与と化学療法の併用によって病勢を制御するという治療戦略が可能であると考えられた。(著者抄録)

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Language：Japanese   Publisher：(一社)日本肝胆膵外科学会  

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Language：Japanese   Publisher：(一社)日本肝胆膵外科学会  

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Language：Japanese   Publisher：(一社)日本肝胆膵外科学会  

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Language：Japanese   Publisher：(一社)日本肝胆膵外科学会  

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Language：Japanese   Publisher：(一社)日本肝胆膵外科学会  

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：AMER ASSOC CANCER RESEARCH  

DOI： 10.1158/1538-7445.AM10-4633

Web of Science

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Language：Japanese   Publisher：一般社団法人日本外科学会  

CiNii Books

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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)日本腹部救急医学会  

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Language：Japanese   Publisher：(株)篠原出版新社  

乳癌スクリーニングとして血漿中アミノ酸バランスの変化に基づいて導出した診断式「アミノインデックス」の有用性について検討した。その結果、1)「アミノインデックス」の判別能は、訓練データでROC曲線下面積0.73、感度70%、特異度67%、検証用データでROC曲線下面積0.64、感度55%、特異度67%を示した。2)「アミノインデックス」による病期別の診断能については、早期癌、進行癌いずれに対しても同等の診断能が得られ、早期乳癌スクリーニングに有用であることが示唆された。

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Language：Japanese   Publisher：(一社)日本腹部救急医学会  

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

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Language：Japanese   Publisher：(一社)日本腹部救急医学会  

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Language：Japanese   Publisher：神奈川県医師会  

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Language：Japanese   Publisher：神奈川県医師会  

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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：English   Publisher：日本癌学会  

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

CiNii Books

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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  

CiNii Books

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Language：Japanese   Publisher：(一社)日本マイクロサージャリー学会  

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

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

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

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Language：Japanese   Publisher：(一社)日本病理学会  

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Language：Japanese   Publisher：(NPO)日本乳癌検診学会  

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Language：Japanese   Publisher：(NPO)日本乳癌検診学会  

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Language：Japanese   Publisher：(NPO)日本乳癌検診学会  

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Language：Japanese   Publisher：日本臨床検査医学会  

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Language：Japanese   Publisher：(NPO)日本乳癌検診学会  

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Language：Japanese   Publisher：(NPO)日本乳癌検診学会  

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Language：English   Publisher：日本癌学会  

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Language：English   Publisher：日本癌学会  

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Language：Japanese   Publisher：神奈川県医師会  

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Language：Japanese   Publisher：神奈川県医師会  

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Language：Japanese   Publisher：(一社)日本腹部救急医学会  

症例は49歳,男性。下腹部痛を主訴に来院。右下腹部に腹膜刺激症状を認め,血液検査では高度の炎症所見を認めた。CTにて骨盤内膿瘍が存在し,膿瘍内には線状異物陰影を認めた。綿密な問診を行ったところ,7日前に鯛を摂取した際,喉につかえたが飲み込んだという記憶があった。このため魚骨による消化管穿孔を疑い,手術を施行した。手術では膿瘍内に魚骨,さらに虫垂先端に穿孔部を認めた。魚骨による虫垂穿孔と診断し,虫垂切除術,腹腔ドレナージ術を行った。魚骨による虫垂穿孔はまれで,術前診断のついた症例は少なく,悪性腫瘍を疑われ過大な検査,手術をうけた症例もある。腹部CTにて本症のような線状石灰化を認めた症例では異物による消化管穿孔を念頭に置いて,慎重な読影と,発症前の食生活の詳細な問診を行うことが重要である。(著者抄録)

CiNii Books

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Language：Japanese   Publisher：(NPO)日本肺癌学会  

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Language：Japanese   Publisher：国家公務員共済組合連合会  

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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：国家公務員共済組合連合会  

胆嚢結石症に併存する総胆管結石症の治療成績を検討した。対象は過去3年間に治療を行った総胆管結石症併存胆嚢結石症85例(男性51例、女性4例・平均年齢64.4歳)で、各治療法ごとの在院日数、入院費用などを比較した。その結果、1)治療法は術前内視鏡的切石後腹腔鏡下胆嚢摘出術34例(うち開腹移行4例)、内視鏡的切石後開腹胆嚢摘出術1例、開腹または腹腔鏡下胆嚢摘出術+総胆管切開切石術35例、開腹または腹腔鏡下胆嚢摘出術+経胆嚢管的切石術15例であった。2)腹腔鏡下切石は13例に行なわれ、9例で完遂された。また術前総胆管結石症の非診断例は25例(29.4%)あった。3)平均入院期間は総胆管切開25.4日、内視鏡的切石術24.1日、経総胆管的切石術17.0日と統計的有意差は認めなかった。4)2005年度の治療法による入院費に有意差は認めず、1日あたりの診療報酬に換算してもほとんど差はなかった。5)総胆管結石症の術前診断能は腹部超音波30%未満、CT 66.2%、MRCP 94.1%であった。

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Language：Japanese   Publisher：(一社)日本腹部救急医学会  

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Language：Japanese   Publisher：(一社)日本腹部救急医学会  

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Language：Japanese   Publisher：(一社)日本消化器内視鏡学会-関東支部  

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