Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

Birt-Hogg-Dubé (BHD) syndrome is a hereditary kidney cancer syndrome, which predisposes patients to develop kidney cancer, cutaneous fibrofolliculomas and pulmonary cysts. The responsible gene FLCN is a tumor suppressor for kidney cancer, which plays an important role in energy homeostasis through the regulation of mitochondrial oxidative metabolism. However, the process by which FLCN-deficiency leads to renal tumorigenesis is unclear. In order to clarify molecular pathogenesis of BHD-associated kidney cancer, we conducted whole-exome sequencing analysis using next-generation sequencing technology as well as metabolite analysis using liquid chromatography-mass spectrometry and gas chromatography-mass spectrometry. Whole-exome sequencing analysis of BHD-associated kidney cancer revealed that copy number variations of BHD-associated kidney cancer are considerably different from those already reported in sporadic cases. In somatic variant analysis, very few variants were commonly observed in BHD-associated kidney cancer; however, variants in chromatin remodeling genes were frequently observed in BHD-associated kidney cancer (17/29 tumors, 59%). Metabolite analysis of BHD-associated kidney cancer revealed metabolic reprogramming toward upregulated redox regulation which may neutralize reactive oxygen species potentially produced from mitochondria with increased respiratory capacity under FLCN-deficiency. BHD-associated kidney cancer displays unique molecular characteristics that are completely different from sporadic kidney cancer, providing mechanistic insight into tumorigenesis under FLCN-deficiency as well as a foundation for development of novel therapeutics for kidney cancer.

DOI： 10.1093/hmg/ddy181

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Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

Although hereditary kidney cancer syndrome accounts for approximately five percent of all kidney cancers, the mechanistic insight into tumor development in these rare conditions has provided the foundation for the development of molecular targeting agents currently used for sporadic kidney cancer. In the late 1980s, the comprehensive study for hereditary kidney cancer syndrome was launched in the National Cancer Institute, USA and the first kidney cancer-associated gene, VHL, was identified through kindred analysis of von Hippel-Lindau (VHL) syndrome in 1993. Subsequent molecular studies on VHL function have elucidated that the VHL protein is a component of E3 ubiquitin ligase complex for hypoxia-inducible factor (HIF), which provided the basis for the development of tyrosine kinase inhibitors targeting the HIF-VEGF/PDGF pathway. Recent whole-exome sequencing analysis of sporadic kidney cancer exhibited the recurrent mutations in chromatin remodeling genes and the later study has revealed that several chromatin remodeling genes are altered in kidney cancer kindred at the germline level. To date, more than 10 hereditary kidney cancer syndromes together with each responsible gene have been characterized and most of the causative genes for these genetic disorders are associated with either metabolism or epigenome regulation. In this review article, we describe the molecular mechanisms of how an alteration of each kidney cancer-associated gene leads to renal tumorigenesis as well as denote therapeutic targets elicited by studies on hereditary kidney cancer.

DOI： 10.1111/cas.13503

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Germline H255Y and K508R missense mutations in the folliculin (FLCN) gene have been identified in patients with bilateral multifocal (BMF) kidney tumours and clinical manifestations of Birt-Hogg-Dubé (BHD) syndrome, or with BMF kidney tumours as the only manifestation; however, their impact on FLCN function remains to be determined. In order to determine if FLCN H255Y and K508R missense mutations promote aberrant kidney cell proliferation leading to pathogenicity, we generated mouse models expressing these mutants using BAC recombineering technology and investigated their ability to rescue the multi-cystic phenotype of Flcn-deficient mouse kidneys. Flcn H255Y mutant transgene expression in kidney-targeted Flcn knockout mice did not rescue the multi-cystic kidney phenotype. However, expression of the Flcn K508R mutant transgene partially, but not completely, abrogated the phenotype. Notably, expression of the Flcn K508R mutant transgene in heterozygous Flcn knockout mice resulted in development of multi-cystic kidneys and cardiac hypertrophy in some mice. These results demonstrate that both FLCN H255Y and K508R missense mutations promote aberrant kidney cell proliferation, but to different degrees. Based on the phenotypes of our preclinical models, the FLCN H255Y mutant protein has lost it tumour suppressive function leading to the clinical manifestations of BHD, whereas the FLCN K508R mutant protein may have a dominant negative effect on the function of wild-type FLCN in regulating kidney cell proliferation and, therefore, act as an oncoprotein. These findings may provide mechanistic insight into the role of FLCN in regulating kidney cell proliferation and facilitate the development of novel therapeutics for FLCN-deficient kidney cancer.

DOI： 10.1093/hmg/ddw392

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Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

Birt-Hogg-Dubé syndrome is an autosomal dominantly inherited disease that predisposes patients to develop fibrofolliculoma, lung cysts and bilateral multifocal renal tumors, histologically hybrid oncocytic/chromophobe tumors, chromophobe renal cell carcinoma, oncocytoma, papillary renal cell carcinoma and clear cell renal cell carcinoma. The predominant forms of Birt-Hogg-Dubé syndrome-associated renal tumors, hybrid oncocytic/chromophobe tumors and chromophobe renal cell carcinoma are typically less aggressive, and a therapeutic principle for these tumors is a surgical removal with nephron-sparing. The timing of surgery is the most critical element for postoperative renal function, which is one of the important prognostic factors for Birt-Hogg-Dubé syndrome patients. The folliculin gene (FLCN) that is responsible for Birt-Hogg-Dubé syndrome was isolated as a novel tumor suppressor for kidney cancer. Recent studies using murine models for FLCN, a protein encoded by the FLCN gene, and its two binding partners, folliculin-interacting protein 1 (FNIP1) and folliculin-interacting protein 2 (FNIP2), have uncovered important roles for FLCN, FNIP1 and FNIP2 in cell metabolism, which include AMP-activated protein kinase-mediated energy sensing, Ppargc1a-driven mitochondrial oxidative phosphorylation and mTORC1-dependent cell proliferation. Birt-Hogg-Dubé syndrome is a hereditary hamartoma syndrome, which is triggered by metabolic alterations under a functional loss of FLCN/FNIP1/FNIP2 complex, a critical regulator of kidney cell proliferation rate; a mechanistic insight into the FLCN/FNIP1/FNIP2 pathway could provide us a basis for developing new therapeutics for kidney cancer.

DOI： 10.1111/iju.13015

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Folliculin (FLCN)-interacting proteins 1 and 2 (FNIP1, FNIP2) are homologous binding partners of FLCN, a tumor suppressor for kidney cancer. Recent studies have revealed potential functions for Flcn in kidney; however, kidney-specific functions for Fnip1 and Fnip2 are unknown. Here we demonstrate that Fnip1 and Fnip2 play critical roles in kidney tumor suppression in cooperation with Flcn. We observed no detectable phenotype in Fnip2 knockout mice, whereas Fnip1 deficiency produced phenotypes similar to those seen in Flcn-deficient mice in multiple organs, but not in kidneys. We found that absolute Fnip2 mRNA copy number was low relative to Fnip1 in organs that showed phenotypes under Fnip1 deficiency but was comparable to Fnip1 mRNA copy number in mouse kidney. Strikingly, kidney-targeted Fnip1/Fnip2 double inactivation produced enlarged polycystic kidneys, as was previously reported in Flcn-deficient kidneys. Kidney-specific Flcn inactivation did not further augment kidney size or cystic histology of Fnip1/Fnip2 double-deficient kidneys, suggesting pathways dysregulated in Flcn-deficient kidneys and Fnip1/Fnip2 double-deficient kidneys are convergent. Heterozygous Fnip1/homozygous Fnip2 double-knockout mice developed kidney cancer at 24 mo of age, analogous to the heterozygous Flcn knockout mouse model, further supporting the concept that Fnip1 and Fnip2 are essential for the tumor-suppressive function of Flcn and that kidney tumorigenesis in human Birt-Hogg-Dubé syndrome may be triggered by loss of interactions among Flcn, Fnip1, and Fnip2. Our findings uncover important roles for Fnip1 and Fnip2 in kidney tumor suppression and may provide molecular targets for the development of novel therapeutics for kidney cancer.

DOI： 10.1073/pnas.1419502112

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BACKGROUND: Birt-Hogg-Dubé (BHD) syndrome is a hereditary hamartoma syndrome that predisposes patients to develop hair follicle tumors, lung cysts, and kidney cancer. Genetic studies of BHD patients have uncovered the causative gene, FLCN, but its function is incompletely understood. METHODS: Mice with conditional alleles of FLCN and/or peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PPARGC1A), a transcriptional coactivator that regulates mitochondrial biogenesis, were crossbred with mice harboring either muscle creatine kinase (CKM) -Cre or myogenin (MYOG) -Cre transgenes to knock out FLCN and/or PPARGC1A in muscle, or cadherin 16 (CDH16)- Cre transgenes to knock out FLCN and/or PPARGC1A in kidney. Real-time polymerase chain reaction, immunoblotting, electron microscopy, and metabolic profiling assay were performed to evaluate mitochondrial biogenesis and function in muscle. Immunoblotting, electron microscopy, and histological analysis were used to investigate expression and the pathological role of PPARGC1A in FLCN-deficient kidney. Real-time polymerase chain reaction, oxygen consumption measurement, and flow cytometry were carried out using a FLCN-null kidney cancer cell line. All statistical analyses were two-sided. RESULTS: Muscle-targeted FLCN knockout mice underwent a pronounced metabolic shift toward oxidative phosphorylation, including increased mitochondrial biogenesis (FLCN ( f/f ) vs FLCN ( f/f ) /CKM-Cre: % mitochondrial area mean = 7.8% vs 17.8%; difference = 10.0%; 95% confidence interval = 5.7% to 14.3%; P < .001), and the observed increase in mitochondrial biogenesis was PPARGC1A dependent. Reconstitution of FLCN-null kidney cancer cells with wild-type FLCN suppressed mitochondrial metabolism and PPARGC1A expression. Kidney-targeted PPARGC1A inactivation partially rescued the enlarged kidney phenotype and abrogated the hyperplastic cells observed in the FLCN-deficient kidney. CONCLUSION: FLCN deficiency and subsequent increased PPARGC1A expression result in increased mitochondrial function and oxidative metabolism as the source of cellular energy, which may give FLCN-null kidney cells a growth advantage and drive hyperplastic transformation.

DOI： 10.1093/jnci/djs418

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Birt-Hogg-Dube' syndrome characterized by increased risk for renal neoplasia is caused by germline mutations in the BHD/FLCN gene encoding a novel tumor suppressor protein, folliculin(FLCN), which interacts with FNIP1 and 5'-AMP-activated protein kinase(AMPK). Here we report the identification and characterization of a novel FNIP1 homolog FNIP2 that also interacts with FLCN and AMPK. C-terminally-deleted FLCN mutants, similar to those produced by naturally-occurring germline mutations in BHD patients, were unable to bind FNIP2. These data taken together with our previous results that demonstrated FNIP1 binding to the C-terminus of FLCN suggest that FLCN tumor suppressor function may be facilitated by interactions with both FNIP1 and FNIP2 through its C-terminus. Furthermore, we demonstrate that FNIP1 and FNIP2 are able to form homo- or heteromeric multimers suggesting that they may function independently or cooperatively with FLCN. Differential expression of FNIP1 and FNIP2 transcripts in some normal tissues may indicate tissue specificity for these homologs. Interestingly FNIP1 and FNIP2 were oppositely expressed in human clear cell renal cell carcinoma (RCC), and coordinately expressed in chromophobe RCC and oncocytoma, suggesting their differential function in different histologic variants of RCC.

DOI： 10.1016/j.gene.2008.02.022

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INTRODUCTION: Lenvatinib plus pembrolizumab is a standard first-line therapy for advanced renal cell carcinoma (RCC), and acute acalculous cholecystitis is a rare adverse event. CASE PRESENTATION: A 60-year-old woman with metastatic TFE3-positive non-clear cell RCC, classified as poor risk by the International Metastatic RCC Database Consortium (IMDC) criteria, started pembrolizumab plus lenvatinib after palliative radiotherapy for cervical spine metastasis. Lenvatinib was initiated at 8 mg and escalated to 12 mg, achieving tumor shrinkage. Nine days after starting cycle 4, she developed fever and right upper quadrant pain. Computed tomography demonstrated gallbladder distension and wall thickening without gallstones, consistent with acute acalculous cholecystitis. Lenvatinib was interrupted, and intravenous piperacillin/tazobactam was administered; her symptoms improved without drainage. Lenvatinib was resumed at 8 mg with pembrolizumab, and no recurrence occurred. CONCLUSION: Early recognition and temporary interruption of lenvatinib with antibiotics may allow cautious rechallenge.

DOI： 10.1002/iju5.70203

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Bone marrow represents a unique microenvironment enriched with both immunosuppressive cells and immune-activating functions. However, its role in metastasis and response to immunotherapy remains poorly understood. We report a case of sarcomatoid clear cell renal cell carcinoma with systemic bone marrow metastasis that achieved a complete response to ipilimumab plus nivolumab. Using matched pretreatment and post-treatment bone marrow samples, we performed integrative immune profiling. Pretreatment analyses showed abundant CD14+ myeloid cells, phenotypically consistent with myeloid-derived suppressor cell (MDSC)-like populations, together with CD8+ T cells. RNA-seq-based deconvolution revealed a predominance of monocytic-MDSC-like cells, which were selectively reduced after treatment with a shift toward monocyte and neutrophil-associated cells. Paired single-sample gene set enrichment analysis demonstrated that immunosuppressive (MDSC-like populations and TGF-β), and immune-activating (CD8+ T cell, interferon-gamma) pathways coexisted at baseline and were broadly attenuated following treatment. These findings suggest that the bone marrow microenvironment harbored a hybrid immune state characterized by concurrent inflammatory and immunosuppressive programs. The subsequent global contraction of both programs suggests that immune remodeling primarily reflects the resolution of tumor-driven immune activation following tumor eradication, rather than the effect from immune checkpoint inhibitors. This case highlights that even in an immune-restrictive niche, latent but functional antitumor immunity can be unleashed by immune checkpoint blockade.

DOI： 10.1136/jitc-2025-013940

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DOI： 10.1016/j.neo.2026.101296

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OBJECTIVE: The objective of this study is to evaluate the correlation between erectile dysfunction (ED) and lower urinary tract symptoms (LUTSs) using the International Index of Erectile Function-5 (IIEF-5) and the International Prostate Symptom Score (IPSS). METHODS: An online survey was conducted among 4800 Japanese men using the International Index of Erectile Function-5 (IIEF-5), International Prostate Symptom Score (IPSS) and Overactive Bladder Symptom Score (OABSS). After excluding one incomplete response, data from 4799 participants were analysed. Participants were grouped by ED severity according to IIEF-5 score. The total and subcategory scores of the IPSS and OABSS were compared among the groups. LUTSs were categorized as post-micturition, storage, voiding symptoms and incontinence. An additional analysis was conducted by age group: younger (40s-50s) and older (≥70s). RESULTS: Lower ED severity was associated with significantly lower IPSS and OABSS total scores (p < 0.001). Voiding symptoms and incontinence scores increased with ED severity (p < 0.001). Severe ED (IIEF-5 to <8) was significantly associated with worse scores across all the LUTS domains. Younger men without ED had significantly lower scores in all LUTS categories (p < 0.001). However, among older men, no significant differences in LUTS scores were observed according to ED status. CONCLUSION: ED severity is positively correlated with LUTS severity, particularly voiding symptoms and incontinence. This relationship was more prominent in younger men.

DOI： 10.1002/bco2.70219

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BACKGROUND: Salivary gland carcinomas are uncommon malignancies with various histological subtypes harboring fusion genes. The EWSR1::ATF1 fusion gene, resulting from a translocation between chromosomes 12 and 22, is frequently observed in hyalinizing clear cell carcinoma (HCCC). However, the role of this fusion gene in HCCC oncogenesis remains unclear. METHODS: We generated EWSR1::ATF1 transgenic mice by introducing an EWSR1::ATF1 fusion gene with a breakpoint in HCCC. These mice were crossed with Lama parotid secretory protein (PSP)-Cre transgenic mice, expressing Cre recombinase in salivary glands, to produce salivary gland-specific EWSR1::ATF1 transgenic mice. Tumor samples were analyzed using Western blotting, histopathology, and RNA sequencing. RESULTS: We generated salivary gland-specific EWSR1::ATF1 transgenic mice, and tumors developed in major salivary glands in three mice. These tumors exhibited more malignant characteristics than human HCCC. CONCLUSIONS: These results suggest that salivary gland-specific expression of EWSR1::ATF1 plays an important role in malignant tumor formation in major salivary glands.

DOI： 10.1002/hed.70289

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DOI： 10.1007/s11701-025-03115-5

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UNLABELLED: Hereditary leiomyomatosis and renal cell carcinoma syndrome (HLRCC) is an autosomal dominant disorder caused by germline loss-of-function mutations in the fumarate hydratase (FH) gene. It is characterized by cutaneous and uterine leiomyomas and an increased risk of highly aggressive renal cell carcinoma (RCC), often associated with poor prognosis. We report the case of a 31-year-old Japanese woman diagnosed with unresectable RCC with nodal and adrenal metastases. Histopathological analysis of a biopsy specimen suggested papillary RCC; however, cancer genome profiling revealed a presumed germline pathogenic variant in FH. Subsequent germline testing confirmed the FH mutation, establishing the diagnosis of HLRCC-associated RCC. Cascade genetic testing identified several asymptomatic relatives carrying the same germline FH variant. Immunohistochemistry (IHC) revealed unexpected positivity for FH and S-(2-succinyl) cysteine in tumor cells. Although FH loss is a hallmark of HLRCC-associated renal cell carcinoma, rare cases, such as this one, may exhibit retained FH expression on IHC. The patient was treated with a combination of lenvatinib and pembrolizumab, achieving a sustained partial response for 18 months following treatment initiation. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s13691-025-00811-9.

DOI： 10.1007/s13691-025-00811-9

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BACKGROUND: We examined the clinical significance of the distance between the tumor and collecting system or sinus (DTCS), representing the nearness (N) score in the RENAL nephrometry score, on outcomes of robotic-assisted partial nephrectomy (RAPN). METHODS: We retrospectively analyzed 425 patients who underwent RAPN between 2016 and 2021. Multivariate binary logistic regression was used to assess predictive preoperative clinical factors. Receiver operating characteristic (ROC) curve analysis determined the optimal DTCS cutoff point for each outcome. RESULTS: The mean DTCS was 4.0 mm (SD 4.6), and 79 were N1, 97 N2, and 249 N3. DTCS was significantly associated with opening of the collecting system (p < 0.001) and trifecta achievement (p = 0.085), but not with pentafecta achievement. Optimal DTCS cutoff values were 4 and 7 mm for opening of the collecting system, and 0 mm for trifecta achievement. CONCLUSIONS: While the DTCS cutoff value of 4 and 7 mm may indicate surgical technical difficulty, the 0 mm appears to be the more clinically relevant cutoff value for perioperative outcome risk stratification.

DOI： 10.1186/s12885-025-15315-1

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Language：Japanese   Publisher：日本唾液腺学会  

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Language：Japanese   Publisher：日本唾液腺学会  

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OBJECTIVES: Cystic renal tumors (cRT) pose technical challenges during robot-assisted partial nephrectomy (RAPN) due to the risk of cyst rupture, yet their true impact on perioperative outcomes remains unclear. This study aimed to evaluate the surgical and pathological outcomes of RAPN for cRT compared with solid renal tumors (sRT). MATERIALS AND METHODS: We retrospectively analyzed 694 consecutive RAPN cases (2016-2023) at a high-volume center. Tumors were categorized as sRT (n = 609), partially cystic renal tumors with < 50% cystic component (pcRT), and cRT with ≥ 50% cystic component. Patient background, perioperative outcomes, resection techniques, and oncological results were compared. The SIB score was used as a surrogate measure for tumor resection method, distinguishing between enucleation, enucleoresection, and resection. RESULTS: Among these 694 cases, 609 (88%), 36 (5%) and 49 (7%) cases were classified into sRT, pcRT and cRT groups, respectively. Age, BMI, RENAL score, or clinical stage showed no differences among the three groups, and tumor size of pcRT and cRT was significantly larger than that of sRT (P = 0.067). No significant differences were observed in operative time, warm ischemia time, blood loss, trifecta achievement, or positive surgical margins. Pathologic up-grade was noted in 28 cases (2.6%) in sRT, while none were noted in pcRT and cRT. Multivariate analysis of predictive factors for WIT, trifecta, and pentafecta, showed that cystic tumor was not identified as predictive factors. CONCLUSIONS: RAPN for cystic renal tumors is safe and feasible, with perioperative, pathological, and functional outcomes comparable to solid tumors. The proportion of cystic components did not adversely influence outcomes, supporting the application of standard resection techniques for both cystic and solid tumors. RAPN should be considered a reliable first-line surgical option for cystic tumors when technically feasible.

DOI： 10.1007/s11701-025-03001-0

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Approximately 5% of all colorectal cancers have a strong genetic component and are classified as hereditary colorectal cancer (HCRC). Some of the unique features commonly seen in HCRC cases include early age of onset, synchronous/metachronous cancer occurrence, and multiple cancers in other organs. These characteristics require different management approaches, including diagnosis, treatment or surveillance, from those used in the management of sporadic colorectal cancer. Accurate diagnosis of HCRC is essential because it enables targeted surveillance and risk reduction strategies that improve patient outcomes. Recent genetic advances revealed several causative genes for polyposis and non-polyposis syndromes. The Japanese Society for Cancer of the Colon and Rectum (JSCCR) first published guidelines for the management of HCRC in 2012, with subsequent revisions every 4 years. The 2024 update to the JSCCR guidelines for HCRC was developed by meticulously reviewing evidence from systematic reviews and the consensus of the JSCCR HCRC Guidelines Committee, which includes representatives from patient advocacy groups for FAP and Lynch syndrome. These guidelines provide an up-to-date summary of HCRC, along with clinical recommendations for managing FAP and Lynch syndrome.

DOI： 10.1007/s10147-025-02892-1

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Introduction: Bladder cancer is associated with a high recurrence rate, and outcomes for muscle-invasive and metastatic disease remain poor. New targeted therapies, such as the FGFR inhibitor erdafitinib, have been introduced, but the progression from non-muscle-invasive to muscle-invasive disease remains a major clinical challenge. Methods: In this study, we performed immunohistochemical staining for FGFR1-FGFR4 on surgical specimens from 192 cases of urothelial carcinoma. We also conducted various functional assays on human bladder cancer cell lines to assess protein/gene expression, cell proliferation, migration, invasion, and colony formation. Results: FGFR2 and FGFR3 expressions were found to be significantly down-regulated in high-grade (0.014) and muscle-invasive (0.002) tumors, respectively. Functionally, the FGFR inhibitor erdafitinib suppressed cell proliferation and migration, and FGFR3 silencing also markedly reduced proliferation, migration, invasion, and colony formation in cancer cell lines. Conclusions: The down-regulation of FGFR3 in muscle-invasive bladder cancer, coupled with the inhibitory effect of its inactivation on cell growth, suggests a significant role for FGFR3 in bladder cancer progression.

DOI： 10.3390/cancers17213588

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OBJECTIVE: To compare complications, perioperative outcomes, postoperative renal function, and recurrence-free survival (RFS) between robot-assisted partial nephrectomy (RAPN) for hilar and non-hilar tumors. METHODS: We retrospectively analyzed the medical records of patients who underwent RAPN between March 2016 and August 2023. Patient demographic characteristics were adjusted using 1:1 propensity score matching. RESULTS: A total of 618 patients (524 with non-hilar tumors and 94 with hilar tumors) were analyzed. Hilar tumors exhibited a larger tumor size, higher RENAL nephrometry score (RNS), and greater complexity than non-hilar tumors pre-matching (all p < 0.05). Propensity score matching resulted in 77 patients per group, with no significant baseline differences except for the L factor of the RNS. Before propensity score matching, hilar tumors were associated with a higher frequency of renal artery/vein clamping and intraperitoneal approaches, as well as significantly longer operative and warm ischemia times than non-hilar tumors. However, after matching, these differences were no longer significant. The adverse event rate was not significantly different between the hilar and non-hilar tumor groups. Trifecta achievement rates were significantly lower in hilar tumors before matching (p < 0.001) but were comparable after matching (p = 0.325). No significant differences were observed in the postoperative eGFR, preservation at 1, 3, and 12 months, or pentafecta rates. Before matching, RFS was significantly lower in hilar tumors (p = 0.015); however, this difference was not significant after matching (p = 0.186). CONCLUSION: Hilar tumors showed similar complications, renal function, and recurrence-free survival rates as non-hilar tumors, indicating that RAPN is safe and feasible for hilar tumors.

DOI： 10.1111/iju.70156

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

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Language：Japanese   Publisher：(一社)日本泌尿器内視鏡・ロボティクス学会  

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Language：Japanese   Publisher：(一社)日本泌尿器内視鏡・ロボティクス学会  

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

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BACKGROUND: Non-metastatic castration-resistant prostate cancer (nmCRPC) is often asymptomatic but carries a risk of progression to metastatic disease. Apalutamide (APA) and darolutamide (DARO) have been shown to improve metastasis-free survival (MFS). This study evaluated the real-world efficacy and safety of APA and DARO in Japanese patients with nmCRPC. METHODS: We retrospectively analyzed 67 nmCRPC patients treated with APA (n = 32) or DARO (n = 35). Outcomes included time to treatment discontinuation or mCRPC progression, time to mCRPC, PSA response rate, treatment-related adverse events (TRAEs), post-mCRPC treatment patterns, and predictors of progression. RESULTS: In patients with prostate-specific antigen doubling time (PSADT) < 10 months, no significant difference was observed between the APA and DARO groups in the time to progression to mCRPC. PSA response and MFS were comparable between groups. TRAEs were significantly more frequent with APA (75.0% vs. 25.7%), with rash being the most common. High PSA at treatment initiation (≥ 3.6 ng/mL) and PSA response < 90% were independent predictors of progression. Abiraterone was the most common first-line agent after mCRPC. CONCLUSIONS: DARO was associated with a lower incidence of TRAEs compared to APA. Rash was more prevalent with APA. Elevated baseline PSA and suboptimal PSA response were associated with progression.

DOI： 10.1186/s12894-025-01919-z

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INTRODUCTION: There are no previous reports of solitary renal metastases from urothelial carcinoma with trophoblastic differentiation, a rare bladder cancer subtype that is pathologically hCGβ positive. CASE PRESENTATION: A 77-year-old male with urothelial carcinoma with trophoblastic differentiation underwent robot-assisted radical cystectomy following neoadjuvant chemotherapy. Pathological examination revealed urothelial carcinoma, classified as ypT2b and ypN0 with detection of focal hCGβ positivity. Postoperatively, serum hCGβ levels decreased from 1.6 to < 0.2 mIU/mL. At the 9-month follow-up, serum hCGβ was elevated to 20.1 mIU/mL with no recurrence on PET-CT. Gemcitabine-cisplatin chemotherapy was initiated; however, a solitary renal tumor was detected. Partial nephrectomy confirmed that the tumor was a renal metastasis of bladder cancer. Serum hCGβ levels decreased and remained < 0.2 mIU/mL, even 20 months after partial nephrectomy. CONCLUSION: We report a case of urothelial carcinoma with trophoblastic differentiation and elevated serum hCGβ levels, in which a solitary renal metastasis was successfully resected by robot-assisted partial nephrectomy.

DOI： 10.1002/iju5.70072

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The objective of this study is to evaluate mechanical tension on the renal parenchyma during partial nephrectomy using a novel index and compare the effects of different suture techniques on strain in a simulated model. A kidney-shaped urethane resin model with surface markers was created to measure deformation. Three-dimensional scanning assessed deformation before and after suturing. Strain values were calculated using finite-element shape functions on a triangular mesh. Distance from the centerline of the suture was also measured. The standard suturing method was defined as continuous stitches using self-retaining barbed sutures. Based on this standard, variations were introduced in suture material, suturing technique (continuous or interrupted), number of stitches, and the distance from the defect edge. Seven suture patterns were tested. Deformation values were higher when sutures were placed farther from the defect margin and lower when placed closer. Interrupted, tight, sparse, and multifilament suture patterns produced strain values similar to those of the standard technique. Narrow suture pattern tended to have longer distances from the centerline than the wide suture pattern. Interrupted and multifilament suture patterns also showed slightly longer distances than the standard pattern. This is the first study to visualize and quantify strain distribution during renorrhaphy using deformation values. The findings suggest that the distance of suture placement from the limbus may impact parenchymal strain. Despite limitations such as a small sample size and use of simulated models, these results offer insights into optimizing renorrhaphy techniques to minimize tissue stress. Future studies with larger sample sizes are warranted.

DOI： 10.1007/s11701-025-02580-2

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The significance of "L" score in the radius (R), exophytic/endophytic (E), nearness (N), anterior/posterior (A), location (L); RENAL nephrometry scoring system remains unestablished compared to other subscores. This study assessed the influence of the "L" score on surgical and functional outcomes of RAPN, dividing renal tumors into medial and lateral relative to the kidney's central line, to explore its impact on "L" score utility. A retrospective analysis was conducted on 668 RAPN patients, with 405 having medial and 263 lateral renal tumors. Patients who underwent RAPN were retrospectively analyzed, including 405 with medial renal tumors and 263 with lateral renal tumors. In medial tumors, the "L" score independently predicted non-achievement of trifecta (P = 0.011) and pentafecta (P = 0.032). In lateral tumors, the "L" score did not predict non-achievement of these outcomes. In conclusion, significance of the "L" score on surgical outcomes differs between medial and lateral tumors and it is strongly associated with outcomes in medial tumors, whereas its predictive value in lateral tumors is less marked. The RENAL nephrometry score lacks differentiation between medial and lateral tumors; therefore, surgeons should interpret "L" scores with caution.

DOI： 10.1038/s41598-025-08647-2

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Language：Japanese   Publisher：(一社)腎癌研究会  

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Language：Japanese   Publisher：(一社)腎癌研究会  

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

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Language：Japanese   Publisher：(一社)腎癌研究会  

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

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Lower urinary tract symptoms (LUTS) significantly affect patient quality of life. Treatment options for bladder outlet obstruction (BOO) due to benign prostatic hyperplasia (BPH) (a common cause of LUTS) are insufficient to relieve discomfort. As the incidence of BPH is increasing, new pharmacological targets for LUTS treatment are required. Corticotropin-releasing hormone (CRH) is a neuropeptide that controls normal micturition in rodents. Herein, we investigated the role of spinal CRH in regulating micturition in sham and BOO rats, and evaluated CRH as a therapeutic target for bladder dysfunction in BOO model Sprague-Dawley rats. Histological analysis, cystometry with intrathecal administration of CRH agonists/antagonists, western blotting, and real-time PCR assessed the role of CRH and its receptors (CRHR1 and CRHR2) in micturition in sham and BOO rats. CRH administration shortened the voiding interval, while pretreatment with antagonists against CRHR2 (but not CRHR1) suppressed CRH-induced frequent voiding. Western blotting confirmed CRHR1 expression in the dorsal root ganglia (DRG) and bladder, but not the spinal cord, of rats. Real-time PCR showed higher CRHR2 mRNA expression in the spinal cord and DRG than in the bladder in both groups. Overall, spinal CRH facilitates the micturition reflex via CRHR2, and is a promising therapeutic target for LUTS.

DOI： 10.1038/s41598-025-87990-w

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

Tumor development often requires cellular adaptation to a unique, high metabolic state; however, the molecular mechanisms that drive such metabolic changes in TFE3-rearranged renal cell carcinoma (TFE3-RCC) remain poorly understood. TFE3-RCC, a rare subtype of RCC, is defined by the formation of chimeric proteins involving the transcription factor TFE3. In this study, we analyzed cell lines and genetically engineered mice, demonstrating that the expression of the chimeric protein PRCC-TFE3 induced a hypoxia-related signature by transcriptionally upregulating HIF1α and HIF2α. The upregulation of HIF1α by PRCC-TFE3 led to increased cellular ATP production by enhancing glycolysis, which also supplied substrates for the TCA cycle while maintaining mitochondrial oxidative phosphorylation. We crossed TFE3-RCC mouse models with Hif1α and/or Hif2α knockout mice and found that Hif1α, rather than Hif2α, is essential for tumor development in vivo. RNA-seq and metabolomic analyses of the kidney tissues from these mice revealed that ketone body production is inversely correlated with tumor development, whereas de novo lipid synthesis is upregulated through the HIF1α/SREBP1-dependent mechanism in TFE3-RCC. Our data suggest that the coordinated metabolic shift via the PRCC-TFE3/HIF1α/SREBP1 axis is a key mechanism by which PRCC-TFE3 enhances cancer cell metabolism, promoting tumor development in TFE3-RCC.

DOI： 10.1111/gtc.13195

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

A 79-year-old male patient with urothelial carcinoma with squamous differentiation, pT2N0M0, was referred to our hospital. A computed tomography (CT) scan showed left hydronephrosis associated with the bladder tumor and reticular shadows in the lung fields. After neoadjuvant chemotherapy with gemcitabine and cisplatin, the patient underwent robot-assisted radical cystectomy and cutaneous ureterostomy for bladder cancer on March X. On postoperative day 2, SpO2 decreased with increased oxygen demand, and a CT scan revealed a diffuse reticular shadow in both lungs. The patient was diagnosed with acute exacerbation of interstitial pneumonia (IP). Steroid pulse therapy with 1,000 mg/day methylprednisolone (mPSL) was initiated immediately, and nasal high-flow (NHF) oxygen was introduced. After a positive response to mPSL was confirmed, the patient was weaned from NHF on postoperative day 9. As the IP did not worsen, he was discharged after receiving home oxygen therapy. Six months after the acute exacerbation of IP, CT showed no tumor recurrence or progression.

DOI： 10.5980/jpnjurol.116.37

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

TFE3-rearranged Renal Cell Carcinoma (TFE3-RCC) is an aggressive subtype of RCC characterized by Xp11.2 rearrangement, leading to TFE3 fusion proteins with oncogenic potential. Despite advances in understanding its molecular biology, effective therapies for advanced cases remain elusive. This study investigates the role of ARID2, a component of the SWI/SNF chromatin remodeling complex, in TFE3-RCC. Through a series of in vitro and in vivo experiments, we confirmed that ARID2 acts as a tumor suppressor in TFE3-RCC. ARID2 knockout (KO) enhanced TFE3-RCC cell migration, proliferation, and tumor growth. Transcriptomic analysis revealed ERBB3 as a key target gene regulated by both PRCC-TFE3 and ARID2. Chromatin immunoprecipitation (ChIP) assays demonstrated that PRCC-TFE3 directly binds to and upregulates ERBB3 expression, with ARID2 KO further enhancing this effect. TFE3-RCC ARID2 KO cells exhibited significant gene expression enrichment in MAPK and ERBB3 signaling pathways. These cells also showed increased activation of ERBB3, EGFR, and selective activation of SRC and MAPK. TFE3-RCC ARID2 KO cells demonstrated heightened sensitivity to the ERBB3 inhibitor AZD8931 compared to their wild-type counterparts, exhibiting significantly reduced migration and proliferation rates. These findings suggest that the PRCC-TFE3-ARID2-ERBB3 axis plays a critical role in TFE3-RCC pathogenesis and highlights the potential of targeting ERBB3 in ARID2-deficient TFE3-RCC as a therapeutic strategy. This study provides new insights into the molecular mechanisms of TFE3-RCC and suggests avenues for precision treatment of this aggressive cancer.

DOI： 10.3390/cimb46120817

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

A 28-year-old male presented to his physician with a chief complaint of fever and cough. Contrastenhanced computed tomography revealed a 17×16×8 cm heterogeneous tumor in the anterior mediastinum, as well as right heart and inferior vena cava compression due to the tumor. He was referred to our hospital for close examination and treatment. Alpha fetoprotein (AFP) was 24,769 ng/ml, and percutaneous needle biopsy revealed a germ cell tumor with a York sac tumor component; therefore, Bleomycin, Etoposide and Cisplatin (BEP) therapy was started. Although AFP tended to decrease with BEP therapy, the tumor size remained unchanged, and right heart failure due to right heart system decompression led to cardiogenic shock. Consequently, veno-arterial extracorporeal membrane oxygenation (VA-ECMO) was introduced on Day 25. Since cardiogenic shock continued even after VA-ECMO, anterior mediastinal tumor resection was attempted on Day 30 following consultation with the respiratory surgery, cardiovascular surgery, cardiology, and intensive care units. Because the tumor was strongly adherent, tumor resection was abandoned, and tumor reduction surgery was performed. Postoperatively, his cardiovascular status improved quickly, and he was weaned off VA-ECMO the day after surgery. AFP decreased to 22 ng/ml but re-elevated; therefore, EP therapy was introduced on Day 97 when AFP was 600 ng/ml. We report a case of a primary mediastinal germ cell tumor with circulatory disturbance due to cardiopulmonary compression. In cases similar to ours, multidisciplinary treatment in collaboration with multiple departments is necessary.

DOI： 10.14989/ActaUrolJap_70_12_451

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

Renal and ovarian clear cell carcinoma (CCC) are both characterized by a clear cytoplasm and exhibit similar genomic alterations and clinical characteristics. We hypothesized that both CCCs may share clinical biomarker. Tissue factor pathway inhibitor 2 (TFPI2), a serine protease inhibitor, has emerged as a promising serum biomarker for ovarian CCC, and we evaluated the efficacy of TFPI2 as a biomarker for renal cell carcinoma (RCC). Serum samples were collected from patients with RCC and healthy volunteers, and TFPI2 levels were measured. Expression of TFPI2 in each cell type was evaluated using single-cell RNA sequencing. Survival analyses according to TFPI2 expression levels were performed based on publicly available databases. Serum TFPI2 was significantly elevated in patients with RCC compared to healthy volunteers, particularly those with clear cell histology. Metastatic RCC tumors exhibited higher TFPI2 than localized RCCs. Moreover, higher TFPI2 correlated with higher Fuhrman grades in clear cell RCC. Publicly available databases showed an association between TFPI2 expression and overall survival, particularly in clear cell RCC. Single-cell RNA sequencing confirmed TFPI2 expression in clear cell RCC and normal kidney tubular epithelial cells. TFPI2 has emerged as a potential serum biomarker for RCC, offering avenues for improved detection and prognostication.

DOI： 10.1038/s41598-024-80248-x

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

DOI： 10.3390/tomography10110130

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

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A regulatory mechanism for SLC family transporters, critical transporters for sodium and glucose reabsorptions in renal tubule, is incompletely understood. Here, we report an important regulation of SLC family transporter by SETD2, a chromatin remodeling gene whose alterations have been found in a subset of kidney cancers. Kidney-specific inactivation of Setd2 resulted in hypovolemia with excessive urine excretion in mouse and interestingly, RNA-sequencing analysis of Setd2-deficient murine kidney exhibited decreased expressions of SLC family transporters, critical transporters for sodium and glucose reabsorptions in renal tubule. Importantly, inactivation of Setd2 in murine kidney displayed attenuated dapagliflozin-induced diuresis and glucose excretion, further supporting that SETD2 might regulate SLCfamily transporter-mediated sodium and glucose reabsorptions in renal tubule. These data uncover an important regulation of SLC family transporter by SETD2, which may illuminate a crosstalk between metabolism and epigenome in renal tubule.

DOI： 10.1016/j.bbrc.2024.150730

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OBJECTIVE: Artery and vein (AV) clamps can control venous bleeding in the surgical field and prevent carbon dioxide embolism, especially when large veins are expected to open. However, whether AV clamps cause more renal damage than artery-only (AO) clamps remains unclear. This study aimed to compare renal function and blood loss in surgeries using AO and AV clamps based on high RENAL nephrometry scores (RNS) in robot-assisted partial nephrectomy (RAPN). METHODS: We retrospectively analyzed the medical records of 500 patients who underwent RAPN between March 2016 and December 2021. We performed 1:1 propensity matching for these patients. RESULTS: A total of 340 patients with pathological malignancies who were followed up for at least 12 months were included in this analysis. A total of 291 patients with AO clamping and 49 patients with AV clamping were included. Overall, the AV clamp group had higher total RNSs and larger diameters than the AO clamp group. Propensity score-matched analysis included 37 patients in each clamp group. The median warm ischemia times of the AV and AO clamps were 25 and 22 min, respectively, with no significant difference. There were no statistically significant differences between the groups in the amount of blood loss, rate of acute kidney injury (AKI), or renal function at 1, 3, or 12 months post-RAPN. CONCLUSION: Compared with the AO clamp, the AV clamp did not have a detrimental impact on blood loss or renal dysfunction. Consequently, AV clamps may be considered for patients presenting with moderate-to-high-complexity RNSs.

DOI： 10.1111/iju.15567

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Language：English   Publisher：(一社)日本癌学会  

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Language：Japanese   Publisher：泌尿器科紀要刊行会  

症例1(17歳男性)。肉眼的血尿を主訴に、前医のCT検査にて右腎腫瘤が指摘され、精査加療目的で当科へ紹介となった。症例2(61歳女性)。当院でHBVフォロー中に撮影したCTで偶発的に右腎下極の腫瘤が認められ、当科へ紹介となった。両症例とも、画像所見から乳頭状腎細胞癌が疑われ、Robot-assisted partial nephrectomyが施行された。病理組織学的に後腎性腺腫と確定診断され、いずれも経過良好で術後8日目に退院となった。

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Other Link： https://search.jamas.or.jp/default/link?pub_year=2024&ichushi_jid=J01269&link_issn=&doc_id=20240903440004&doc_link_id=1390865409046350976&url=https%3A%2F%2Fcir.nii.ac.jp%2Fcrid%2F1390865409046350976&type=CiNii&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00003_2.gif

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

Metanephric adenoma is an extremely rare disease. We describe two cases of metanephric adenoma. Case 1 : A 17-year-old male adolescent developed gross hematuria, and urinalysis revealed positive protein and occult blood. He was referred to our department for further evaluation and likely tumor removal. Contrast-enhanced computed tomography (CT) showed a neoplasm (23 mm) with poor contrast effect during the early as well as the late contrast phase. Case 2 : A 61-year-old woman presented with an incidentally detected tumor in the lower pole of the right kidney ; contrast-enhanced CT revealed a large neoplasm (10 mm) with poor contrast effect during the early as well as late contrast phase. Both patients underwent robot-assisted partial nephrectomy (RAPN) under the preoperative diagnosis of papillary renal cell carcinoma. Metanephric adenoma is histopathologically indistinguishable from papillary renal cell carcinoma preoperatively, and histopathology and immunostaining are neceaasry for accurate diasnosis.

DOI： 10.14989/ActaUrolJap_70_8_247

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Language：Japanese   Publisher：(一社)腎癌研究会  

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Language：Japanese   Publisher：(一社)腎癌研究会  

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Language：Japanese   Publisher：(一社)腎癌研究会  

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Language：Japanese   Publisher：(一社)腎癌研究会  

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Language：Japanese   Publisher：(一社)腎癌研究会  

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Language：Japanese   Publisher：(一社)腎癌研究会  

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

Abstract

Application of physical forces, ranging from ultrasound to electric fields, is recommended in various clinical practice guidelines, including those for treating cancers and bone fractures. However, the mechanistic details of such treatments are often inadequately understood, primarily due to the absence of comprehensive study models. In this study, we demonstrate that an alternating magnetic field (AMF) inherently possesses a direct anti‐cancer effect by enhancing oxidative phosphorylation (OXPHOS) and thereby inducing metabolic reprogramming. We observed that the proliferation of human glioblastoma multiforme (GBM) cells (U87 and LN229) was inhibited upon exposure to AMF within a specific narrow frequency range, including around 227 kHz. In contrast, this exposure did not affect normal human astrocytes (NHA). Additionally, in mouse models implanted with human GBM cells in the brain, daily exposure to AMF for 30 min over 21 days significantly suppressed tumor growth and prolonged overall survival. This effect was associated with heightened reactive oxygen species (ROS) production and increased manganese superoxide dismutase (MnSOD) expression. The anti‐cancer efficacy of AMF was diminished by either a mitochondrial complex IV inhibitor or a ROS scavenger. Along with these observations, there was a decrease in the extracellular acidification rate (ECAR) and an increase in the oxygen consumption rate (OCR). This suggests that AMF‐induced metabolic reprogramming occurs in GBM cells but not in normal cells. Our results suggest that AMF exposure may offer a straightforward strategy to inhibit cancer cell growth by leveraging oxidative stress through metabolic reprogramming.

DOI： 10.1111/cas.16243

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Publishing type：Research paper (scientific journal)   Publisher：Oxford University Press (OUP)  

Abstract

Background

PET/CT imaging with Zirconium-89 labeled [89Zr]Zr-DFO-girentuximab, which targets tumor antigen CAIX, may aid in the differentiation and characterization of clear cell renal cell carcinomas (RCC) and other renal and extrarenal lesions, and has been studied in European and American cohorts. We report results from a phase I study that evaluated the safety profile, biodistribution, and dosimetry of [89Zr]Zr-DFO-girentuximab in Japanese patients with suspected RCC.

Methods

Eligible adult patients received 37 MBq (± 10%; 10 mg mass dose) of intravenous [89Zr]Zr-DFO-girentuximab. Safety and tolerability profile was assessed based on adverse events, concomitant medications, physical examination, vital signs, hematology, serum chemistry, urinalysis, human anti-chimeric antibody measurement, and 12-lead electrocardiograms at predefined intervals. Biodistribution and normal organ and tumor dosimetry were evaluated with PET/CT images acquired at 0.5, 4, 24, 72 h and Day 5 ± 2 d after administration.

Results

[89Zr]Zr-DFO-girentuximab was administered in six patients as per protocol. No treatment-emergent adverse events were reported. Dosimetry analysis showed that radioactivity was widely distributed in the body, and that the absorbed dose in healthy organs was highest in the liver (mean ± standard deviation) (1.365 ± 0.245 mGy/MBq), kidney (1.126 ± 0.190 mGy/MBq), heart wall (1.096 ± 0.232 mGy/MBq), and spleen (1.072 ± 0.466 mGy/MBq). The mean effective dose, adjusted by the radioactive dose administered, was 0.470 mSv/MBq. The radiation dose was highly accumulated in the targeted tumor, while any abnormal accumulation in other organs was not reported.

Conclusions

This study demonstrates that [89Zr]Zr-DFO-girentuximab administered to Japanese patients with suspected RCC has a favorable safety profile and is well tolerated and has a similar dosimetry profile to previously studied populations.

DOI： 10.1093/jjco/hyae075

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

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

Objective: Complete endophytic renal tumors (CERTs) are the most challenging for robot-assisted partial nephrectomy (RAPN). This study aimed to determine the impact of CERT on outcomes of RAPN. Methods: All RAPN cases for localized renal tumor undertaken at Yokohama City University Hospital between 2016 and 2023 were enrolled. Tumor characteristics and surgical, functional, and oncologic outcomes of RAPN were compared between CERT and non-CERT groups. Results: Consecutive 666 patients were enrolled, and 76 (11.4%) were identified as CERT (3 points of "E" score). CERT showed smaller tumor diameters (p < 0.001), more predominant hilar tumor (p = 0.029), higher "N" scores (p < 0.001) and "L" scores (p = 0.006) than non-CERT. The CERT group showed longer warm ischemia times (p < 0.001), more frequent positive surgical margins (p = 0.028), and relatively lower trifecta achievement rates (p = 0.101) than the non-CERT group. In multivariable analysis, the CERT was an independent predictor for trifecta achievement but not for pentafecta achievement. Conclusions: CERT was associated with longer warm ischemia time, positive surgical margin, and lower trifecta achievement, but not with surgical complication and pentafecta achievement in RAPN. This study suggested that CERT had limited influence on long-term renal functional preservation; however, it had strong impacts on short-term surgical outcome.

DOI： 10.1089/end.2023.0608

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INTRODUCTION: The number of facilities adopting intracorporeal urinary diversion (ICUD) using robots instead of extracorporeal urinary diversion (ECUD) is increasing. However, guidance on how to introduce robot-assisted radical cystectomy (RARC) + ICUD in each urological institute remains unclear. This study aimed to verify the feasibility of the transition from laparoscopic radical cystectomy (LRC) + ECUD to RARC + ICUD. METHODS: We retrospectively analyzed 26 consecutive patients who underwent ICUD with an ileal conduit after RARC between 2018 and 2020 (RARC + ICUD early group). We then compared these patients with 26 consecutive patients who underwent ECUD with an ileal conduit after LRC between 2012 and 2019 (LRC + ECUD late group) at Yokohama City University Hospital. RESULTS: In the RARC + ICUD early group compared with the LRC + ECUD late group, the median total operation time was 516 versus 532.5 min (P = .217); time to cystectomy, 191 versus 206.5 min (P = .234); time of urinary diversion with an ileal conduit, 198 versus 220 min (P = .016); postoperative maximum C-reactive protein levels, 6.98 versus 12.46 mg/L (P = .001); number of days to oral intake, 3 versus 5 days (P = .003); length of hospital stay, 17 versus 32 days (P < .001). The postoperative complication rates (within 90 days) were 23.1% and 42.3% in the RARC + ICUD early and LRC + ECUD late groups, respectively (P = .237). Clavien-Dindo classification ≥3 was noted in 1 and 4 patients in the RARC + ICUD early and LRC + ECUD late groups, respectively (P = .350). CONCLUSION: Regarding perioperative outcomes, the RARC + ICUD early group was not inferior to the LRC + ECUD late group. This study suggests the feasibility of a transition from LRC + ECUD to RARC + ICUD.

DOI： 10.1111/ases.13289

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

The influence of chronic kidney disease stage on robot-assisted partial nephrectomy outcomes remains underexplored. This study aimed to assess the impact of chronic kidney disease stage on functional and surgical outcomes of robot-assisted partial nephrectomy and identify preoperative predictors of significant postoperative 1-year renal-function loss (RFL). Clinical data of 408 patients who underwent robot-assisted partial nephrectomy at Yokohama City University Hospital between 2016 and 2023 were retrospectively reviewed. The da Vinci Surgical System was applied in all patients, and outcomes assessed included surgical parameters, postoperative estimated glomerular filtration rate, trifecta and pentafecta achievements, and complications. Significant RFL was defined as estimated glomerular filtration rate reduction ≥ 25% from baseline. Higher chronic kidney disease stages correlated with older age, hypertension, diabetes, and solitary kidneys. Postoperative estimated glomerular filtration rate decline was most pronounced in patients with chronic kidney disease stages 4-5. Although the chronic kidney disease stage did not significantly affect most surgical parameters, pentafecta achievement was higher in patients with chronic kidney disease stage 3 than in those with stages 4-5. Two patients required hemodialysis after robot-assisted partial nephrectomy. Multivariable logistic regression analysis showed that preoperative hemoglobin level and maximum tumor diameter were significant predictive factors for significant RFL. In conclusion, preoperative CKD stage did not influence on surgical outcome except for pentafecta achievement. RAPN may be feasible for patients with CKD stages 4-5 because of no rapid progression to hemodialysis induction and no procedure-related mortality. Preoperative hemoglobin levels and tumor diameter emerged as predictors of significant RFL.

DOI： 10.1007/s11701-024-01873-2

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

OBJECTIVE: In December 2021, enfortumab vedotin (EV), an antibody-drug conjugate directed against nectin-4, was approved in Japan as a new treatment after platinum-containing chemotherapy and PD-1/PD-L1 inhibitors. This study evaluated, using real-world data, the efficacy and safety of EV therapy in patients with metastatic urothelial carcinoma (mUC). MATERIALS AND METHODS: Fifty-five patients with mUC who discontinued pembrolizumab therapy due to disease progression between June 2018 and April 2023 at Yokohama City University Hospital were evaluated retrospectively. Of the 55 patients, 25 received EV therapy (EV group) and 30 did not (non-EV group). All patients who underwent EV therapy were diagnosed with disease progression after the approval of EV in Japan. RESULTS: The median (range) follow-up period after pembrolizumab discontinuation was 6.3 (0.7-31.1) months. There were eight (32.0%) deaths due to cancer in the EV group and 27 (90.0%) in the non-EV group. The overall survival (OS) after pembrolizumab discontinuation was not reached in the EV group versus 2.6 months in the non-EV group (p < 0.001). A multivariate analysis revealed that EV therapy (EV vs. non-EV group; hazard ratio 0.26; 95% confidence interval 0.16-0.41; p < 0.001) was an independent prognostic factor for OS. CONCLUSION: EV prolonged OS in mUC following pembrolizumab therapy in real-world data.

DOI： 10.1111/iju.15437

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

Central nervous system hemangioblastoma (CNS-HB) is the most common manifestation of von Hippel-Lindau disease (VHL). The main axis of the CNS-HB pathway is the VHL-HIF signaling pathway. Recently, we proposed an alternative VHL-JAK-STAT pathway in CNS-HB. In contrast, the VHL substrate transcription factor zinc fingers and homeoboxes 2 (ZHX2) have been identified as the oncogenic drivers in VHL-deficient clear cell renal cell carcinoma (RCC). However, ZHX2 expression in CNS-HB has not been previously reported. Furthermore, the VHL-ZXH2-NF-κB signaling pathway in CNS-HB remains unresolved. In this study, we aimed to investigate ZHX2 expression and VHL gene alteration in CNS-HB and propose the role of ZHX2 in CNS-HB. Using the MACS method, Scl+ hemangioblastoma-like cells were isolated from multipotent nestin-expressing stem cells. The ubiquitination of ZHX2 in these cells and the immunoprecipitation between ZHX2 and VHL were investigated. In addition, the VHL genes of patients with hemangioblastoma were analyzed. ZHX2 expression in CNS-HB tissues was examined by immunohistochemistry and western blotting. In addition, VHL gene mutations in CNS-HB were analyzed by sequencing. The association between ZHX2 expression and VHL gene mutation was analyzed. ZHX2 was ubiquitinated in Scl+hemangioblastoma-like cells after the transfer of the VHL expression vector into these cells. ZHX2 expression in these cells was well detected before transfer but disappeared after the transfer. ZHX2 expression was detected in 18 of the 21 CNS-HB tissues by immunoblotting and/or immunohistochemistry. Sporadic CNS-HB showed weak expression, whereas VHL-related CNS-HB showed moderate or strong expression. In particular, CNS-HB with severe VHL gene mutations, including large deletions, showed strong or moderate ZHX2 expression. The association between VHL gene mutation and ZHX2 expression revealed a significant correlation between VHL gene alteration severity and the level of immunoblotting (P < 0.05). In conclusion, the severity of VHL gene alteration correlates with the level of ZHX2 expression. ZHX2 is predominantly expressed in CNS-HB, especially in VHL-related cases with severe VHL gene alterations, suggesting a potential role in tumorigenesis and proliferation of CNS-HB.

DOI： 10.15586/jkcvhl.v11i4.355

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The human mitochondrial genome (mtDNA) is a circular DNA molecule with a length of 16.6 kb, which contains a total of 37 genes. Somatic mtDNA mutations accumulate with age and environmental exposure, and some types of mtDNA variants may play a role in carcinogenesis. Recent studies observed mtDNA variants not only in kidney tumors but also in adjacent kidney tissues, and mtDNA dysfunction results in kidney injury, including chronic kidney disease (CKD). To investigate whether a relationship exists between heteroplasmic mtDNA variants and kidney function, we performed ultra-deep sequencing (30,000×) based on long-range PCR of DNA from 77 non-tumor kidney tissues of kidney cancer patients with CKD (stages G1 to G5). In total, this analysis detected 697 single-nucleotide variants (SNVs) and 504 indels as heteroplasmic (0.5% ≤ variant allele frequency (VAF) < 95%), and the total number of detected SNVs/indels did not differ between CKD stages. However, the number of deleterious low-level heteroplasmic variants (pathogenic missense, nonsense, frameshift and tRNA) significantly increased with CKD progression (p < 0.01). In addition, mtDNA copy numbers (mtDNA-CNs) decreased with CKD progression (p < 0.001). This study demonstrates that mtDNA damage, which affects mitochondrial genes, may be involved in reductions in mitochondrial mass and associated with CKD progression and kidney dysfunction.

DOI： 10.3390/ijms242417212

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BACKGROUND: Late-onset hypogonadism (LOH) is a condition caused by the decline of testosterone levels with aging and is associated with various symptoms, including lower urinary tract symptoms (LUTSs). Although some reports have shown that testosterone replacement treatment for LOH improves LUTSs, no large study has revealed a correlation between LUTSs and LOH. This study investigated the correlation between the severity of LOH and LUTSs in Japanese males >40 years of age using a web-based questionnaire with the Aging Males' Symptoms (AMS) scale. METHODS: We asked 2000 Japanese males to answer both the AMS and IPSS/QOL questionnaires using a web-based survey. Among these 2000 individuals, 500 individuals were assigned to each age group. RESULTS: The IPSS total score was positively correlated with the severity of AMS (shown as median [mean ± SD]): no/little group, 2 (3.67 ± 5.36); mild group, 6 (7.98 ± 6.91); moderate group, 11 (12.49 ± 8.63); and severe group, 16 (14.83 ± 9.24) (p < 0.0001). CONCLUSIONS: Individuals with higher AMS values, representing cases with severe LOH symptoms, had a higher risk of experiencing nocturia and LUTSs than those with lower AMS values.

DOI： 10.3390/jcm12247528

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OBJECTIVES: To investigate the predictive factors for pentafecta achievement of robot-assisted partial nephrectomy (RAPN) for intermediate highly complex renal tumors (RENAL score ≥ 7). METHODS: We retrospectively analyzed the data of 247 patients with renal tumors with a RENAL score ≥ 7 who underwent RAPN. Baseline characteristics and perioperative outcomes were compared between the pentafecta achieved group and the unachieved group. A multivariable logistic regression model was used to identify the predictive factors for pentafecta achievement for cT1 renal tumors with a RENAL score ≥ 7. RESULTS: Of the 247 patients, 75 (30.3%) patients were in the achieved group and 172 (69.7%) patients were in the unachieved group. The median warm ischemia time and total operation time were 18 min versus 23 min (p < 0.001) and 179 min versus 201 min (p < 0.001) in the achieved and unachieved groups, respectively. In the unachieved group, six patients (3.4%) had major perioperative complications (Clavien-Dindo classification system ≥3). The median preservation rates of estimated GFR at the 1-year postoperative period were 96.5% versus 83.0% (p < 0.001) in the achieved and unachieved groups. Multivariable logistic regression models revealed that age and tumor size were independent predictive factors for pentafecta achievement for cT1 renal tumors with a RENAL score ≥ 7. There were no significant differences in cancer-free survival between the two groups (p = 0.456). CONCLUSION: Age and tumor size were independent predictive factors for pentafecta achievement, although there was no difference in oncological outcomes between the pentafecta achieved group and the unachieved group in RAPN for cT1 renal tumors with a RENAL score ≥ 7.

DOI： 10.1111/iju.15274

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

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

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Language：Japanese   Publisher：日本唾液腺学会  

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Language：Japanese   Publisher：(一社)日本泌尿器内視鏡・ロボティクス学会  

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Language：Japanese   Publisher：(一社)日本泌尿器内視鏡・ロボティクス学会  

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Language：Japanese   Publisher：(一社)日本泌尿器内視鏡・ロボティクス学会  

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Language：Japanese   Publisher：(一社)日本泌尿器科学会  

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

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

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Language：English   Publisher：(一社)日本癌学会  

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

BACKGROUND: Enfortumab vedotin shows promise as a targeted therapy for advanced urothelial carcinoma, particularly in patients who have previously received platinum-based chemotherapy and an immune-checkpoint inhibitor. The EV-301 phase III trial demonstrated significantly improved overall survival and response rates compared to standard chemotherapy. However, more data, especially from larger real-world studies, are needed to further assess its effectiveness in Japanese patients. METHODS: A total of 6007 urothelial cancer patients inducted with pembrolizumab as a second-line treatment were analyzed. Among them, 563 patients received enfortumab vedotin after pembrolizumab, while 443 patients received docetaxel or paclitaxel after pembrolizumab, and all were included in the study for efficacy as a life prolonging agent. RESULTS: The enfortumab vedotin group showed a longer overall survival than the paclitaxel/docetaxel group (p = 0.013, HR: 0.71). In multivariate analysis, enfortumab vedotin induction was the independent risk factor for overall survival (p = 0.013, HR: 0.70). There were no significant differences in cancer-specific survival. CONCLUSIONS: Enfortumab vedotin prolonged the overall survival for Japanese advanced or metastatic urothelial carcinoma patients compared to paclitaxel or docetaxel after pembrolizumab treatment.

DOI： 10.3390/cancers15174227

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

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

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

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Language：Japanese   Publisher：(一社)腎癌研究会  

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Language：Japanese   Publisher：(一社)腎癌研究会  

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Language：Japanese   Publisher：(一社)腎癌研究会  

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Language：Japanese   Publisher：(一社)腎癌研究会  

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Language：Japanese   Publisher：(一社)腎癌研究会  

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Language：Japanese   Publisher：(一社)腎癌研究会  

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

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

OBJECTIVE: Radical prostatectomy can be performed more safely and with fewer com- plications since the advent of robot-assisted surgery. However, increased bleeding is a concern when robot-assisted radical prostatectomy includes lymph node dissection and nerve sparing. In real-world clinical practice, inexperienced surgeons sometimes perform robot-assisted radical prostatectomy. In this study, we investigated the effec- tiveness of microporous polysaccharide hemospheres as a local hemostatic agent in robot-assisted radical prostatectomy. METHODS: We retrospectively evaluated 301 patients who underwent robot-assisted radical prostatectomy at our institution between December 2017 and November 2020. The patients were divided into 2 groups according to whether their surgery was per- formed after the introduction of microporous polysaccharide hemospheres as a local hemostatic agent (group A, n = 140) or before it (group B, n = 161: historical control). RESULTS: Preoperative androgen deprivation therapy was significantly more common in group A than in group B (23 vs. 11, P = .009). Furthermore, surgeons were significantly less experienced (P < .001) and the operation time was significantly longer (260 min- utes vs. 229 minutes; P < .001) in group A than in group B. There was no significant difference in any other patient background characteristics or in the surgical outcomes between the groups. CONCLUSION: The use of microporous polysaccharide hemospheres allowed even inex- perienced surgeons to perform robot-assisted radical prostatectomy without compro- mising surgical outcomes.

DOI： 10.5152/tud.2023.22242

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Language：Japanese   Publisher：(一社)腎癌研究会  

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Language：Japanese   Publisher：(一社)腎癌研究会  

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Language：English   Publisher：(一社)日本泌尿器科学会総会事務局  

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Language：English   Publisher：(一社)日本泌尿器科学会総会事務局  

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Language：English   Publisher：(一社)日本泌尿器科学会総会事務局  

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Language：English   Publisher：(一社)日本泌尿器科学会総会事務局  

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Language：English   Publisher：(一社)日本泌尿器科学会総会事務局  

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

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Language：Japanese   Publisher：(一社)日本泌尿器科学会  

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

(Objective) To compare the initial results of robot-assisted laparoscopic pyeloplasty (RALP) and laparoscopic pyeloplasty (LP) for uretero-pelvic junction obstruction (UPJO). (Methods) Between April 2008 to October 2021, we identified 104 cases of UPJO where LP was performed and 18 cases where RALP was performed at our hospital. We retrospectively analyzed their perioperative outcomes. Furthermore, we recorded the operative times for each cases of LP and RALP. (Results) The median operative time for RALP was 141 minutes, which was significantly shorter than that for LP (204 minutes). No patient in the RALP group demonstrated any Clavien-Dindo complications (≥grade 3). During the observation period, improvement of symptoms was observed in all cases. The median suturing time in RALP was 38 minutes. Compared with the last 20 cases of LP, the time to expose the uretero-pelvic junction, the time of renal pelvis incision, and suturing time were significantly shorter in RALP. In addition, the console and suturing times were stable since the initial stage. In cases with a high grade of hydronephrosis, there was a large variation in the time to expose the uretero-pelvic junction and suture the renal pelvis and ureter in LP; however, this variation was smaller in RALP. (Conclusion) At our hospital, RALP for UPJO is considered to be a safe procedure. In the future, it is necessary to consider the long-term results and effectiveness of RALP.

DOI： 10.5980/jpnjurol.114.1

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

A 57-years-old woman was referred to our urological department due to a 7.2-cm tumor in the left kidney, detected on computed tomography (CT). Dynamic CT of the kidney confirmed the diagnosis of left renal cancer, with lung metastasis (cT2aN0M1). The patient had a poor prognosis (IMDC classification), given the following risk factors: Time from initial diagnosis to initiation of systemic therapy < 1year, hemoglobin of 8.4 g/dL, calcium of 10.7 mg/dL, and platelet of 74.2×104/mm3. Laparoscopic left radical nephrectomy was performed before systemic drug treatment because the solitary lung metastasis was relatively small (10 mm) and the patient had symptoms of hematuria and fever. The pathological diagnosis was a clear cell carcinoma with renal sinus invasion (pT3a). Four days postoperatively, the patient developed lymphatic leakage, and was unresponsive to diet and conservative treatment. Lymphatic embolization with iodized poppy oil fatty acid ethyl ester was performed 22 days postoperatively. Contrast material leakage from the left renal hilar lymph node was observed before embolization. Post-embolization CT confirmed no contrast leakage. The patient resumed oral feeding on the 28th postoperative day, and the drain was successfully removed the next day. She was discharged on the 35th postoperative day. On follow-up, increased lung metastases were observed on CT. She was treated with the combination of ipilimumab and nivolumab. After one course of treatment, a CT scan showed a further increased in lung metastases (RECIST: PD). Thus, she was initiated on cabozantinib monotherapy. Lymphatic embolization may be a safe and effective treatment for lymphatic leakage that does not improve with conservative treatment.

DOI： 10.5980/jpnjurol.114.133

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

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Language：Japanese   Publisher：(一社)日本泌尿器内視鏡・ロボティクス学会  

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Language：Japanese   Publisher：(一社)日本泌尿器内視鏡・ロボティクス学会  

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Language：Japanese   Publisher：(一社)日本泌尿器内視鏡・ロボティクス学会  

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Language：Japanese   Publisher：(一社)西日本泌尿器科学会  

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

BACKGROUND: The ALSYMPCA trial revealed radium-223 (Ra-223) to be a life-prolonging agent for bone metastatic castration-resistant prostate cancer (CRPC). However, only 2.8% of enrolled patients in that clinical trial were Asian, and no Japanese patients were enrolled. Several retrospective studies have been published concerning Japanese bone metastatic CRPC patients receiving Ra-223. However, no study has yet reported the correlation between Ra-223 induction and the survival in Japanese bone metastatic CRPC patients. This study investigated the effect of Ra-223 as a life-prolonging agent in a large Japanese healthcare fee database. METHODS: A total of around 410 000 prostate cancer patients were extracted from this database, and 25 934 were diagnosed with CRPC. In these patients, the age, date of the CRPC diagnosis, date of Ra-223 induction, and prognosis were analyzed. RESULTS: A total of 1628 patients received Ra-223, and 6693 patients were diagnosed with bone metastasis CRPC, with the remaining 17 613 patients diagnosed with CRPC without bone metastasis. The patients who completed six courses of Ra-223 showed a significantly more favorable overall and cancer-specific survival than those who received ≤5 courses (p < 0.0001 and p < 0.0001, respectively). For time from CRPC diagnosis date to death, the Ra-223 induction group showed a significantly more favorable prognosis with regard to both the overall and cancer-specific survival than the bone metastatic CRPC patients without Ra-223 (p < 0.0001 and p < 0.0001, respectively). CONCLUSIONS: Bone metastatic CRPC patients who received Ra-223 showed a significantly better prognosis than bone metastatic CPRC patients who did not receive Ra-223.

DOI： 10.1111/iju.15008

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Language：Japanese   Publisher：(一社)腎癌研究会  

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Language：Japanese   Publisher：(一社)腎癌研究会  

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Language：Japanese   Publisher：(一社)腎癌研究会  

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Language：Japanese   Publisher：(一社)腎癌研究会  

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

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

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

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

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Language：Japanese   Publisher：(一社)腎癌研究会  

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

Renal cell carcinoma with Xp11.2 translocation involving the TFE3 gene (TFE3-RCC) is a recently identified subset of RCC with unique morphology and clinical presentation. The chimeric PRCC-TFE3 protein produced by Xp11.2 translocation has been shown to transcriptionally activate its downstream target genes that play important roles in carcinogenesis and tumor development of TFE3-RCC. However, the underlying molecular mechanisms remain poorly understood. Here we show that in TFE3-RCC cells, PRCC-TFE3 controls heme oxygenase 1 (HMOX1) expression to confer chemoresistance. Inhibition of HMOX1 sensitized the PRCC-TFE3 expressing cells to genotoxic reagents. We screened for a novel chlorambucil-polyamide conjugate (Chb) to target PRCC-TFE3-dependent transcription, and identified Chb16 as a PRCC-TFE3-dependent transcriptional inhibitor of HMOX1 expression. Treatment of the patient-derived cancer cells with Chb16 exhibited senescence and growth arrest, and increased sensitivity of the TFE3-RCC cells to the genotoxic reagent etoposide. Thus, our data showed that the TFE3-RCC cells acquired chemoresistance through HMOX1 expression and that inhibition of HMOX1 by Chb16 may be an effective therapeutic strategy for TFE3-RCC.

DOI： 10.1111/cas.15364

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

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

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

INTRODUCTION: Preoperative prediction of surgical difficulty of partial nephrectomy (PN) is essential to minimize the perioperative complications and to achieve a good surgical outcome. Recently, various scoring systems have been used to evaluate the difficulty of PN including R.E.N.A.L (Radius, Exophytic/Endophytic, Nearness, Anterior/Posterior, Location) nephrometry score. There were no scoring systems evaluating the roughness of the renal tumor surface and we hypothesized that the roughness of the renal tumor surface might affect the surgical difficulty of robot-assisted partial nephrectomy (RAPN). This study aimed to evaluate the impact of roughness of the renal tumor surface on the surgical outcome of RAPN. METHODS: Overall, 161 patients underwent RAPN performed by the same surgeon between May 2016 and April 2019. We divided those tumors into two groups, like "roughness positive (tumor with roughness of tumor surface)" and "roughness negative (tumor without roughness of tumor surface)" according to the roughness of the endophytic region on preoperative computed tomography images. Clinical and pathological outcomes were compared between the two groups. RESULTS: Eighty-five and 78 tumors were identified roughness negative and positive, respectively. Cases with roughness positive showed a significantly longer operative time, console time, and ischemia time and had greater blood loss than those with roughness negative. Significant and independent predictors of ischemia time and estimated glomerular filtration rate (eGFR) decrease were roughness of tumor surface, tumor size (not for eGFR decrease), and N score of the R.E.N.A.L nephrometry score. CONCLUSION: Roughness of renal tumor surface was significantly and positively associated with ischemia time and the eGFR decrease rate.

DOI： 10.1111/ases.13058

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Language：Japanese   Publisher：(一社)日本泌尿器科学会総会事務局  

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Language：Japanese   Publisher：(一社)日本泌尿器科学会総会事務局  

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Language：Japanese   Publisher：(一社)日本泌尿器科学会総会事務局  

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Language：Japanese   Publisher：(一社)日本泌尿器科学会総会事務局  

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Language：Japanese   Publisher：(一社)日本泌尿器内視鏡・ロボティクス学会  

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Language：Japanese   Publisher：(一社)日本泌尿器内視鏡・ロボティクス学会  

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Language：Japanese   Publisher：(一社)日本泌尿器内視鏡・ロボティクス学会  

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Other Link： https://search.jamas.or.jp/default/link?pub_year=2021&ichushi_jid=J05817&link_issn=&doc_id=20210924460024&doc_link_id=%2Fcs5jjend%2F2021%2F003402%2F028%2F0300-0306%26dl%3D0&url=https%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fcs5jjend%2F2021%2F003402%2F028%2F0300-0306%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

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

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

OBJECTIVES: To assess the correlation of urine loss rate after catheter removal with long-term continence after robot-assisted radical prostatectomy. METHODS: We enrolled 163 patients on whom robot-assisted radical prostatectomy was carried out and whose urine loss rate we were able to evaluate after catheter removal. Urinary incontinence was evaluated from immediately after removal of the catheter to the date of discharge, and at 1, 3, 6 and 12 months after surgery. Urine loss rate was defined as the urine loss volume divided by the total urine volume. RESULTS: The continence rates of patients with ≤1% urine loss rate on the day of catheter removal were 100% at 6 and 12 months after surgery. A multivariate analysis proved that ≤10% urine loss rate on the day of catheter removal was a significant predictor of continence at 3 months after surgery. Furthermore, the continence rate at 12 months of patients who did not achieve ≤10% urine loss rate on the day of catheter removal was 79.5%. Among them, the continence rate at 12 months of patients who achieved ≥15% urine loss rate improvement from the day of catheter removal to the next day was 95.2%; the factor differed significantly between the continence and incontinence groups at 12 months after surgery. CONCLUSIONS: The urine loss rate on the day of catheter removal is significantly related to the acquisition of urinary continence. Furthermore, our findings suggest that long-term urinary continence can be expected, even in the event of poor urine loss rate on the day of catheter removal, if it improves on the next day.

DOI： 10.1111/iju.14488

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

Hereditary leiomyomatosis and renal cell cancer (HLRCC) is a rare autosomal dominant disorder that results from a germline mutation in the fumarate hydratase gene (FH). Individuals with FH mutations are at risk of developing renal cell carcinoma (RCC). Patients with HLRCC-associated RCC (HLRCC-RCC) have aggressive clinical courses, but there is as yet no standardized therapy for advanced HLRCC-RCC. We report an aggressive RCC case in a 49-year-old man. Nine weeks after undergoing a total nephroureterectomy of the right kidney, he had a metastasectomy at port site. Within 14 weeks of the initial surgery, multiple recurrent tumors developed in the right retroperitoneal space. The pathological diagnosis was FH-deficient RCC. Genetic testing identified a heterozygous germline mutation of FH (c.641_642delTA), which confirmed the diagnosis of HLRCC-RCC. He received combination therapy with the immune checkpoint inhibitors (ICIs) nivolumab and ipilimumab as the first-line therapy. After 31 weeks of ICI treatment, a complete response was achieved. The disease-free condition has been prolonged for 24 months since the initial surgical treatment. This is the first case report of successful treatment of HLRCC-RCC with nivolumab plus ipilimumab. This combination immunotherapy is expected to be an effective approach to treat patients with advanced-stage HLRCC-RCC.

DOI： 10.1007/s10689-020-00195-0

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

Blood and lymphatic vessels structurally bear a strong resemblance but never share a lumen, thus maintaining their distinct functions. Although lymphatic vessels initially arise from embryonic veins, the molecular mechanism that maintains separation of these two systems has not been elucidated. Here, we show that genetic deficiency of Folliculin, a tumor suppressor, leads to misconnection of blood and lymphatic vessels in mice and humans. Absence of Folliculin results in the appearance of lymphatic-biased venous endothelial cells caused by ectopic expression of Prox1, a master transcription factor for lymphatic specification. Mechanistically, this phenotype is ascribed to nuclear translocation of the basic helix-loop-helix transcription factor Transcription Factor E3 (TFE3), binding to a regulatory element of Prox1, thereby enhancing its venous expression. Overall, these data demonstrate that Folliculin acts as a gatekeeper that maintains separation of blood and lymphatic vessels by limiting the plasticity of committed endothelial cells.

DOI： 10.1038/s41467-020-20156-6

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Language：Japanese   Publisher：(一社)日本泌尿器科学会総会事務局  

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

AIMS: Hereditary leiomyomatosis and renal cell cancer (HLRCC) is an autosomal dominant disorder caused by germline mutations in fumarate hydratase (FH). Affected families have an increased risk of renal cell carcinoma (RCC). HLRCC-associated RCC (HLRCC-RCC) is highly aggressive. Clinicopathological information of genetically diagnosed patients with HLRCC-RCC contributes to the establishment of effective therapies. METHODS: Ten Japanese patients with HLRCC-RCC were enrolled in the study. Genetic testing for FH was carried out. Somatic mutations in FH and immunohistochemical analyses of FH and B7 family ligands (PD-L1 and B7-H3) were investigated in 13 tumours. Copy number variations were evaluated in two tumours. RESULTS: All patients had FH germline mutations. Regarding histology, most tumours had type 2 papillary architecture or tubulocystic pattern or both. All tumours were FH deficient by immunohistochemistry. Ten tumours were positive for PD-L1, and 12 tumours were positive for B7-H3. Somatic mutation analysis demonstrated loss of heterozygosity of FH in 10 tumours. Copy number variation analysis revealed uniparental disomy between 1q24.2 and 1q44 encompassing FH; gain of chromosome 2 p was also common. All patients had either metastases or residual tumours. Three patients died of HLRCC-RCC and one of colon cancer, whereas the other six are currently alive, including two without recurrence. CONCLUSIONS: HLRCC-RCCs appear to have unique molecular profiles, including PD-L1 expression. One patient had complete response to immunotherapy, which may be an option for HLRCC-RCC.

DOI： 10.1136/jclinpath-2020-206548

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Language：Japanese   Publisher：(一社)日本泌尿器内視鏡・ロボティクス学会  

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Language：Japanese   Publisher：(一社)日本泌尿器内視鏡・ロボティクス学会  

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Language：Japanese   Publisher：(一社)日本泌尿器内視鏡・ロボティクス学会  

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Language：Japanese   Publisher：(一社)日本泌尿器内視鏡・ロボティクス学会  

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

OBJECTIVES: To compare the outcomes of radical prostatectomy (RP), intensity-modulated radiation therapy (IMRT), and low-dose-rate brachytherapy (BT) using propensity score matching analysis in patients with clinically localized prostate cancer. METHODS: A group of 2273 patients with clinically localized prostate cancer between January 2004 and December 2015 at the Yokohama City University hospital were identified. The records of 1817 of these patients, who were followed up for a minimum of 2 years, were reviewed; 462 were treated with RP, 319 with IMRT, and 1036 with BT. The patients were categorized according to the National Comprehensive Cancer Network risk classification criteria, and biochemical outcomes and overall survival rates were examined. Biochemical failure for RP was defined as prostate-specific antigen (PSA) levels > 0.2 ng/ml, and for IMRT and BT as nadir PSA level + 2 ng/ml. Propensity scores were calculated using multivariable logistic regression based on covariates, including the patient's age, preoperative PSA, Gleason score, number of positive cores, and clinical T stage. RESULTS: Median follow-up was 77 months for the RP, 54 months for IMRT, and 66 months for BT patients. After the propensity scores were adjusted, a total of 372 (186 each) and 598 (299 each) patients were categorized into RP vs IMRT and RP vs BT groups, respectively. Kaplan-Meier analysis did not show any statistically significant differences in terms of overall survival rate between these groups (RP vs IMRT: p = 0.220; RP vs BT: p = 0.429). IMRT was associated with improved biochemical failure-free survival compared to RP in all risk groups (high-risk: p < 0.001; intermediate-risk: p = 0.009; low-risk: p = 0.001), whereas significant differences were observed only in the intermediate-risk group (p = 0.003) within the RP vs BT group. CONCLUSION: The results of our propensity score analysis of mid-term localized prostate cancer treatment outcomes demonstrated no significant differences in the overall survival rate. Despite the difference in biochemical failure definition between surgery and radiotherapeutic approaches, the results of this study demonstrate improved biochemical control favoring IMRT and BT as compared to RP.

DOI： 10.1007/s00345-019-03056-3

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

DOI： 10.1002/bco2.36

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Other Link： https://onlinelibrary.wiley.com/doi/full-xml/10.1002/bco2.36

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

PURPOSE: Nivolumab is part of the standard therapy for mRCC. Although deep and long-lasting responses are seen in some patients, the benefit of treatment is limited to some patients and the majority of patients will experience disease progression. PD-L1 is still under evaluation as a predictive biomarker and there is an urgent need to establish biomarkers for the treatment of nivolumab. Here, we investigate C-reactive protein (CRP) at 1 month after treatment of nivolumab as a target to predict the response of patients with metastatic renal cell carcinoma (mRCC) to nivolumab. METHODS: After approval of the study by our institutional review board, 64 patients with mRCC who underwent nivolumab treatment at Kanagawa Cancer Center and Yokohama City University Hospital were enrolled. The patient characteristics, blood examination data at start of nivolumab treatment and 1 month after treatment, response to treatment and progression-free survival (PFS) were evaluated. Tumour responses were assessed according to both the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 and the immune RECIST (iRECIST) criteria. Moreover, in 12 patients who agreed to an additional blood examination, several serum inflammatory factors were investigated and their correlation with CRP level was examined. RESULTS: The median follow-up was 8.3 months (range 0.2-29.8 months). The median PFS period was 4.5 months and the median immune-PFS (iPFS) period was 5.3 months. RECIST 1.1 criteria underestimated the benefits of nivolumab in four (6.4%) cases. Multivariate analyses showed that an Eastern Cooperative Oncology Group performance status (≥ 2) at start of treatment and CRP level at 1 month after treatment (≥ 1.5 mg/dL) were independent risk factors for a poor iPFS of nivolumab. The CRP level at baseline was not an independent prognostic factor for iPFS. When compared with the responder group (iCR + iPR + iSD), the non-responder group (iPD) had a significantly higher CRP levels at 1 month after treatment (p < 0.001). In the responder group, there was significant decrease in the CRP level after nivolumab treatment when compared with the baseline (p = 0.002), whereas there was a significant increase in the non-responder group (p = 0.019). Even patients with high baseline CRP (≥ 1.5 mg/dL) obtained good iPFS if CRP was decreased (< 1.5 mg/dL) 1 month after treatment. In addition, the classification of Glasgow prognostic score (GPS), which is a cumulative prognostic score based on CRP and albumin, was a significant predictor for iPFS. A strong correlation (|r| > 0.7) with CRP level at 1 month after treatment was seen for sCD163, IL-34, MMP-1, MMP-2, osteopontin, sTNF-R1 and sTNF-R2. Of these, MMP-1 and MMP-2 were not correlated at baseline. CONCLUSION: Our results indicated that the CRP level at 1 month after treatment with nivolumab appears to be a promising predictive biomarker for response to nivolumab treatment in patients with mRCC. It is clinically useful to be able to predict the effect within a short period. Further prospective trials are needed to prove these preliminary findings.

DOI： 10.1007/s00280-020-04088-y

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PURPOSE: The PROPHET (Prostate Cancer: Prostate Health Index Trial) is a prospective study to clarify the diagnostic impact of laboratory based and prostate volume adjusted p2PSA ([-2] proenzyme prostate specific antigen) related indexes on prostate cancer and clinically significant prostate cancer with prostate specific antigen less than 10 ng/ml. MATERIALS AND METHODS: Between April 2015 and March 2017, 421 men 50 to 79 years old in the prostate specific antigen range above age specific cutoffs and below 10 ng/ml were registered in the PROPHET. We investigated the diagnostic impacts of various clinical laboratory based free prostate specific antigen related and p2PSA related indexes on any grade and high Gleason grade group prostate cancer. RESULTS: Of the 363 eligible participants 179, 141 and 80 were diagnosed with any grade, and Gleason Grade Group 2-5 and 3-5 prostate cancer, respectively. The AUC-ROCs distinguishing nonprostate cancer vs prostate cancer, nonprostate cancer plus low Gleason Grade Group and low volume vs remaining prostate cancer with a higher Gleason Grade group or a higher volume on the PHI (Prostate Health Index) were significantly superior to the AUC-ROCs of prostate specific antigen and free-to-total prostate specific antigen. At 90% sensitivity in all investigated p2PSA related indexes the false-positive rate was superior to that of prostate specific antigen and free-to-total prostate specific antigen in any group comparison in terms of the Gleason Grade Group and positive biopsy cores. In 35% to 42% of men without prostate cancer and/or those with less aggressive prostate cancer the PHI would avoid unnecessary biopsy. CONCLUSIONS: Laboratory based p2PSA related indexes were significantly superior for detecting clinically significant prostate cancer compared to free-to-total prostate specific antigen. The indexes those would avoid up to 42% of prostate biopsies in men without aggressive cancer while maintaining 90% sensitivity.

DOI： 10.1097/JU.0000000000000495

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Birt-Hogg-Dubé (BHD) syndrome is associated with the development of hereditary renal cell carcinoma (RCC) and is caused by a germline mutation in the folliculin gene. Most cases of BHD syndrome-associated RCC (BHD-RCC) are less aggressive than sporadic clear cell RCC and multifocal. Therefore, it is critical to distinguish BHD-RCC from its sporadic counterparts to identify and monitor affected families and to preserve renal function for as long as possible. The World Health Organization/International Society of Urological Pathology consensus classification defined distinct entities for certain hereditary RCC; however, BHD-RCC was not included in this classification. Although the clinical features and molecular mechanisms of BHD-RCC have been investigated intensively over the last two decades, pathologists and urologists occasionally face difficulties in the diagnosis of BHD-RCC that require genetic testing. Affected patients usually have miscellaneous benign disorders that often precede renal carcinogenesis. In the present review, we summarize the current understanding of the histopathological features of BHD-RCC based on our epidemiological studies of Japanese families and a literature review. Pathological diagnostic clues and differential diagnosis of BHD-RCC from other hereditary RCC are also briefly discussed.

DOI： 10.1111/cas.14255

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Language：Japanese   Publisher：(一社)腎癌研究会  

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Language：Japanese   Publisher：(一社)腎癌研究会  

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Language：Japanese   Publisher：(一社)日本泌尿器内視鏡・ロボティクス学会  

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Language：Japanese   Publisher：(一社)日本泌尿器内視鏡・ロボティクス学会  

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Language：Japanese   Publisher：(一社)日本泌尿器内視鏡・ロボティクス学会  

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Language：Japanese   Publisher：(一社)日本泌尿器内視鏡・ロボティクス学会  

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Renal cell carcinoma (RCC) associated with Xp11.2 translocation (TFE3-RCC) has been recently defined as a distinct subset of RCC classified by characteristic morphology and clinical presentation. The Xp11 translocations involve the TFE3 transcription factor and produce chimeric TFE3 proteins retaining the basic helix-loop-helix leucine zipper structure for dimerization and DNA binding suggesting that chimeric TFE3 proteins function as oncogenic transcription factors. Diagnostic biomarkers and effective forms of therapy for advanced cases of TFE3-RCC are as yet unavailable. To facilitate the development of molecular based diagnostic tools and targeted therapies for this aggressive kidney cancer, we generated a translocation RCC mouse model, in which the PRCC-TFE3 transgene is expressed specifically in kidneys leading to the development of RCC with characteristic histology. Expression of the receptor tyrosine kinase Ret was elevated in the kidneys of the TFE3-RCC mice, and treatment with RET inhibitor, vandetanib, significantly suppressed RCC growth. Moreover, we found that Gpnmb (Glycoprotein nonmetastatic B) expression was notably elevated in the TFE3-RCC mouse kidneys as seen in human TFE3-RCC tumors, and confirmed that GPNMB is the direct transcriptional target of TFE3 fusions. While GPNMB IHC staining was positive in 9/9 cases of TFE3-RCC, Cathepsin K, a conventional marker for TFE3-RCC, was positive in only 67% of cases. These data support RET as a potential target and GPNMB as a diagnostic marker for TFE3-RCC. The TFE3-RCC mouse provides a preclinical in vivo model for the development of new biomarkers and targeted therapeutics for patients affected with this aggressive form of RCC. IMPLICATIONS: Key findings from studies with this preclinical mouse model of TFE3-RCC underscore the potential for RET as a therapeutic target for treatment of patients with TFE3-RCC, and suggest that GPNMB may serve as diagnostic biomarker for TFE3 fusion RCC.

DOI： 10.1158/1541-7786.MCR-18-1235

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Photodynamic diagnosis (PDD) can improve diagnostic accuracy by using PDD agents such as 5-aminolevulinic acid (ALA). However, the weakness and photobleaching of fluorescence of PDD agents may lead to insufficient fluorescence visibility for the detection of cancer during resection operations. We focused on the "fluorescence enhancement effect" resulting from the addition of polyethylene glycol-modified titanium dioxide nanoparticles (TiO2-PEG NPs) to address these problems. The results showed that the combined administration of TiO2-PEG NPs and ALA could enhance and prolong fluorescence in bladder cancer cells, similar to in the mixture alone. It was suggested that the fluorescence enhancement was related to the accumulation of TiO2-PEG NPs in cells via endocytosis, causing the light scattering and enhancement of fluorescence. This fluorescence enhancement effect could be applicable for PDD.

DOI： 10.3390/ijms20153698

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BACKGROUND: We reported previously the usefulness of 18F-2-fluoro-2-deoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) to predict prognosis of renal cell carcinoma (RCC) treated with molecular targeted agents. Herein we describe a preliminary research of nine patients who underwent FDG-PET/CT before and after initiation of nivolumab. METHODS: Patients with metastatic RCC who were treated by nivolumab from October 2016 to March 2017 were enrolled in this study. All patients underwent FDG-PET/CT at baseline and 1 month as a first response assessment, and contrast-enhanced or non-contrast-enhanced CT scan at 4 month as a second response assessment. Logistic regression analysis was performed to assess the association of potential predictors, including age, gender, baseline diameter, baseline maximum standardized uptake value (SUVmax), lung or not lung metastasis, elevation of SUVmax at 1st assessment, and decrease in diameter at 1st assessment with the response at 2nd assessment (decrease in the diameter ≥ 30% or not). RESULTS: There were 9 patients and 30 lesions. Mean days of first assessment with FDG-PET/CT and second assessment by CT scan from initiation of treatment were 32.3 ± 6.4, 115.5 ± 14.9, respectively. Lesions whose diameter decreased ≥30% at second assessment were defined as responding, and lesions whose diameter did not decrease ≥30% were defined as non-responding. There were 18 responding lesions, and 12 non-responding lesions. We compared change in diameter and SUVmax at first assessment with FDG-PET/CT, respectively. All lesions with decreased diameter and elevated SUVmax at first assessment with FDG-PET/CT showed responding at second assessment by CT scan, while most lesions with increased diameter and declined SUVmax at first assessment showed non-responding at second assessment. The multivariate logistic regression analyses revealed that only the elevation of SUVmax at 1 month was an independent predictor (P = 0.025, OR: 13.087, 95%CI: 1.373-124.716). CONCLUSION: Our findings suggest that the early assessment using FDG-PET/CT can be effective to predict the response of RCC to nivolumab. However, larger prospective studies are needed to confirm these preliminary results. TRIAL REGISTRATION: Registered in University Hospital Medical Information Network in JAPAN [ UMIN0000008141 ], registration date: 11 Jun 2012.

DOI： 10.1186/s12885-019-5510-y

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Introduction and Objectives: The neutrophil-to-lymphocyte ratio (NLR) has been suggested as a simple marker of the systemic inflammatory response in critical care patients. The NLR can be easily calculated from routine complete blood counts in the peripheral blood. This parameter has been reported to be an independent prognosticator for some solid malignancies. In the present study, we examined the importance of the NLR as a prognostic marker for castration-resistant prostate cancer (CRPC) patients who received docetaxel- (DOC-) based chemotherapy. Methods: We analyzed a total of 73 patients who received DOC chemotherapy for CRPC in Yokohama City University Medical Center and affiliated hospitals. Complete blood cell counts were performed, and the NLR was calculated using the neutrophil and lymphocyte counts obtained on the same day or a few days before the initiation of DOC chemotherapy. We determined the NLR cutoff value based on the sensitivity and specificity levels derived from area under the receiver operator characteristic curves for death. Results: The median overall survival (OS) after DOC was 21.0 months (range: 2.0-51.0). The median OS was shorter in patients with a high NLR (≥2.59) than in those with a low NLR (<2.59) (12.0 versus 31.6 months, p=0.001). In the multivariate analysis, the NLR and lymph node (LN) metastasis were independent predictors of the OS (hazard ratio 3.643, p=0.001; hazard ratio 2.184, p=0.038, respectively). Conclusions: The higher NLR group showed a significantly poorer OS than the lower NLR group. Pre-DOC NLR might be a new marker for predicting the prognosis of patients who receive DOC chemotherapy.

DOI： 10.1155/2019/2535270

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BACKGROUND: Bladder cancers have been characterized as a tumor group in which the immunological response is relatively well preserved. Programmed death ligand 1 (PD-L1, B7-H1, CD274) has been shown to be expressed in several malignancies, including bladder cancer. However, the clinicopathological impact of this biomarker has not yet been established. In the present study, a quantitative real-time polymerase chain reaction (qPCR) was performed using paired normal and cancerous bladder cancer tissue to investigate PD-1/PD-L1 gene expression. METHODS: We examined the mRNA expression of PD-1/PD-L1 by a qPCR using 58 pairs of normal and cancerous human bladder tissue specimens. We also examined the correlation with the expressions of the STAT1 and NFAT genes, which are thought to be upstream and downstream of the PD-L1 pathway, respectively. RESULTS: There were no significant differences between normal and cancerous tissue in the expression of the PD-1 and PD-L1 genes (p = 0.724 and p = 0.102, respectively). However, PD-1 and PD-L1 were both more highly expressed in high-grade bladder cancer than in low-grade bladder cancer (p < 0.050 and p < 0.010). PD-L1 was positively correlated with the expressions of both the STAT1 (r = 0.681, p < 0.001) and the NFATc1 genes (r = 0.444. p < 0.001). CONCLUSIONS: PD-1 and PD-L1 might be a new biomarker that correlates with the pathological grade of bladder cancer. PD-L1 might function as a mediator of stage progression in bladder cancer and STAT1-NFAT pathway might associate this function.

DOI： 10.1186/s12894-018-0414-8

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Language：Japanese   Publisher：(一社)日本泌尿器内視鏡・ロボティクス学会  

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Language：Japanese   Publisher：(一社)日本泌尿器内視鏡・ロボティクス学会  

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Language：Japanese   Publisher：(一社)日本泌尿器内視鏡・ロボティクス学会  

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Language：Japanese   Publisher：(一社)日本泌尿器内視鏡・ロボティクス学会  

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Osteoclast differentiation is a dynamic differentiation process, which is accompanied by dramatic changes in metabolic status as well as in gene expression. Recent findings have revealed an essential connection between metabolic reprogramming and dynamic gene expression changes during osteoclast differentiation. However, the upstream regulatory mechanisms that drive these metabolic changes in osteoclastogenesis remain to be elucidated. Here, we demonstrate that induced deletion of a tumor suppressor gene, Folliculin (Flcn), in mouse osteoclast precursors causes severe osteoporosis in 3 weeks through excess osteoclastogenesis. Flcn-deficient osteoclast precursors reveal cell autonomous accelerated osteoclastogenesis with increased sensitivity to receptor activator of NF-κB ligand (RANKL). We demonstrate that Flcn regulates oxidative phosphorylation and purine metabolism through suppression of nuclear localization of the transcription factor Tfe3, thereby inhibiting expression of its target gene Pgc1. Metabolome studies revealed that Flcn-deficient osteoclast precursors exhibit significant augmentation of oxidative phosphorylation and nucleotide production, resulting in an enhanced purinergic signaling loop that is composed of controlled ATP release and autocrine/paracrine purinergic receptor stimulation. Inhibition of this purinergic signaling loop efficiently blocks accelerated osteoclastogenesis in Flcn-deficient osteoclast precursors. Here, we demonstrate an essential and novel role of the Flcn-Tfe3-Pgc1 axis in osteoclastogenesis through the metabolic reprogramming of oxidative phosphorylation and purine metabolism. © 2018 The Authors Journal of Bone and Mineral Research published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research (ASBMR).

DOI： 10.1002/jbmr.3477

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Hereditary leiomyomatosis and renal cell cancer (HLRCC) is a rare genetic disorder characterized by cutaneous and uterine leiomyomatosis with RCC. This disorder is caused by a germline mutation in the fumarate hydratase (FH) gene, which encodes an important enzyme of the tricarboxylic acid (TCA) cycle. This mutation distinguishes HLRCC from sporadic RCCs. Herein, we investigated a case of HLRCC in a 32-year-old man who underwent nephrectomy for treatment of a solid-cystic tumor in the left kidney. Histopathology demonstrated a variegated architecture of papillary, tubulocystic and cribriform patterns composed of high-grade tumor cells with enlarged nuclei and eosinophilic nucleoli. Immunostaining and western blotting revealed no FH expression in the tumor. Genomic DNA sequencing identified a heterozygous mutation involving deletion of the 3' end of exon 2 and intron 2 of the FH gene (c.251_267+7delTGACAGAACGCATGCCAGTAAGTG), and RT-PCR confirmed exon 2 skipping in FH mRNA. The somatic FH gene status of the tumor showed only the mutated allele, indicating loss of heterozygosity as the "second hit" of tumor suppressor gene inactivation. These data support that an FH mutation involving the splice site causes exon skipping, changing the conformation of the protein and accelerating carcinogenic cascades under impaired FH functioning in the TCA cycle.

DOI： 10.1111/pin.12684

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PURPOSE: We investigated prospectively whether 18F-2-fluoro-2-deoxyglucose positron emission tomography/computed tomography (FDG PET/CT) can predict the overall survival (OS) of patients with advanced renal cell carcinoma (RCC) previously treated by molecular targeted therapies. METHODS: Between 2009 and 2016, 81 patients who had received single molecular targeted therapies (43 sorafenib, 27 sunitinib, 8 temsirolimus and others) and were scheduled for second line molecular targeted therapies for advanced RCC were enrolled in this prospective study. FDG PET/CT was performed after first line molecular targeted therapies, the max SUVmax (highest standardized uptake value for each patient) recorded, and its association with OS compared with those of known risk factors. The median follow-up was 15.4 months (range 0.9-97.4 months). RESULTS: The max SUVmax of the 81 subjects ranged from undetectable to 23.0 (median 7.1). Patients with high max SUVmax had a poor prognosis and multivariate analysis with established risk factors showed that it was an independent predictor of survival (p < 0.001; hazard ratio 1.156; 95% confidence interval 1.080-1.239). Subclassification of patients by max SUVmax showed that the median OS of patients with max SUVmax < 7.0 (39), 7.0-12.0 (30), and ≥ 12.0 (12) were 32.8, 15.2, and 6.0 months, respectively. These differences are statistically significant (< 7.0 versus 7.0-12.0: p = 0.0333, 7.0-12.0 versus ≥ 12.0: p = 0.0235). CONCLUSIONS: The max SUVmax by FDG PET/CT of patients with RCC evaluated after their first molecular targeted therapy predicts OS. FDG PET/CT is a useful "imaging biomarker" for patients with advanced RCC planning sequential molecular targeted therapies.

DOI： 10.1007/s00280-018-3542-7

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OBJECTIVE: More accurate diagnostic procedures for prostate cancer are needed to avoid unnecessary biopsy due to the low specificity of prostate-specific antigen (PSA). Recent studies showed that the percentage of serum isoform [-2]proPSA (p2PSA) to free PSA (%p2PSA), the Prostate Health Index (PHI) and magnetic resonance imaging (MRI) were more accurate than PSA. The aim of this study was to test the accuracy of %p2PSA, PHI and MRI in discriminating patients with and without prostate cancer. MATERIALS AND METHODS: The subjects were 50 consecutive men with a PSA level of 2.0-10.0 ng/ml, who underwent prostate biopsy from October 2012 to July 2014. These patients underwent multiparametric MRI before biopsy, and their serum samples were measured for PSA, free PSA and p2PSA. The sensitivity, specificity and accuracy of PHI, %p2PSA and MRI were compared with PSA in the diagnosis of biopsy-confirmed prostate cancer. RESULTS: In a univariate analysis, %p2PSA [area under the curve (AUC): 0.811] and PHI (AUC 0.795) were more accurate than MRI (AUC: 0.583) and PSA (AUC: 0.554) for prostate cancer detection. At 60% sensitivity, the specificity of PHI (76.5%) was higher than that of MRI (52.9%). For significant cancer detection, %p2PSA (AUC: 0.745), PHI (AUC: 0.791) and MRI (AUC: 0.739) were marginally more accurate than PSA (AUC: 0.696). At 85% sensitivity, the specificity of MRI (62.1%) was higher than that of PHI (34.5%). CONCLUSION: PHI and %p2PSA can be used for screening the general population and MRI can be used for detection of significant cancer in patients suspected, from screening tests, of having prostate cancer.

DOI： 10.1080/21681805.2017.1298155

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PURPOSE: We evaluated 18F-2-fluoro-2-deoxyglucose positron emission tomography/computed tomography (FDG PET/CT) results as outcome predictors for patients with metastatic renal cell carcinoma (RCC) treated by everolimus (EVL), an inhibitor of mammalian target of rapamycin. METHODS: We retrospectively reviewed 30 patients who were treated with EVL for metastatic RCC between May 2010 and March 2015, by evaluating their FDG PET/CT result before and 1 month after starting EVL treatment. We examined the relationships between each patient's maximum standardized uptake value (max SUVmax) assessed by FDG PET/CT on progression-free survival (PFS) and overall survival (OS). RESULTS: Median PFS for all 30 patients was 3.77 months (range 0.72-24.56 months) and median OS after EVL treatment of all 30 patients was 11.67 months (range 1.0-62.98 months). Enrolled patients were divided into two groups by max SUVmax prior to EVL (median = 7.6) and at 1 month after EVL treatment (median = 5.7). PFS were significantly shorter in higher max SUVmax prior to EVL (<7.6, PFS 7.8 vs 3.5 months, log-rank P = 0.017) and at 1 month after EVL (<5.7, PFS 10.6 vs 2.7 months, log-rank P = 0.002) than lower max SUVmax. OS were also significantly shorter in higher max SUVmax prior to EVL (<7.6, OS 18.1 vs 7.5 months, log-rank P = 0.010) and at 1 month after EVL (<5.7, OS 17.2 vs 7.5 months, log-rank P = 0.009) than lower max SUVmax. Multivariate Cox hazard regression analysis indicated that max SUVmax at 1 month after EVL is an independent predictor of both PFS and OS in patients treated with EVL although univariate regression analysis showed max SUVmax before EVL is a possible predictor. CONCLUSIONS: Max SUVmax assessed by FDG PET/CT prior to EVL and at 1 month after EVL treatment can accurately predict PFS and can guide decisions on whether to continue or change treatments for patients with EVL-treated RCC who suffer from adverse events.

DOI： 10.1007/s00280-017-3275-z

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Hereditary renal cell carcinomas (RCCs) are life-threatening disorders not only for the patients but also for their relatives. Birt-Hogg-Dubé syndrome (BHD) is an autosomal dominant disorder caused by germline mutations in the folliculin gene (FLCN). The protein product, FLCN, functions as a tumor suppressor, and the affected patients have high risks of developing multiple RCCs. The carcinogenic mechanisms stemming from FLCN dysfunction have been investigated using rodent models and human RCC tissues. However, very limited information has been available about in vitro signaling of human renal cells with genetically mutant FLCN. Herein, we established a new cell line, BHD-F59RSVT, from a BHD patient's chromophobe RCC by transfecting SV40 large T antigen. We investigated FLCN mutations, chromosome profiles, and cytopathologic characteristics of the cell line. BHD-F59RSVT reflected the patient's FLCN germline mutation, a 3-nt deletion in exon 13 (c.1528_1530delGAG). Neither somatic mutation nor loss of heterozygosity of FLCN was detectable. Chromosome 17p11.2 of the FLCN proximal region demonstrated a trimodal pattern. Genome-wide chromosomal analysis revealed a loss of chromosome 16 and mosaic segmental gains in chromosome 7. BHD-F59RSVT cells were positive when immunostained for cytokeratin 7, supporting their origin from distal convoluted tubules. Western blotting analysis demonstrated severely suppressed FLCN expression at the protein level. The collective findings indicate that the established cell line will be suitable for functional analysis of the typical phenotype of BHD-associated RCC with suppressed FLCN expression.

DOI： 10.1038/labinvest.2016.137

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Folliculin-interacting protein 1 and 2 (FNIP1 and FNIP2) play critical roles in preventing renal malignancy through their association with the tumor suppressor FLCN. Mutations in FLCN are associated with Birt-Hogg-Dubé (BHD) syndrome, a rare disorder with increased risk of renal cancer. Recent studies indicated that FNIP1/FNIP2 double knockout mice display enlarged polycystic kidneys and renal carcinoma, which phenocopies FLCN knockout mice, suggesting that these two proteins function together to suppress renal cancer. However, the molecular mechanism functionally linking FNIP1/FNIP2 and FLCN remains largely elusive. Here, we demonstrated that FNIP2 protein is unstable and subjected to proteasome-dependent degradation via β-TRCP and Casein Kinase 1 (CK1)-directed ubiquitination in a nutrition-dependent manner. Degradation of FNIP2 leads to lysosomal dissociation of FLCN and subsequent lysosomal association of mTOR, which in turn promotes the proliferation of renal cancer cells. These results indicate that SCFβ-TRCP negatively regulates the FLCN complex by promoting FNIP degradation and provide molecular insight into the pathogenesis of BHD-associated renal cancer.

DOI： 10.18632/oncotarget.14221

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Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：一般社団法人 日本泌尿器科学会  

A 45-year-old woman with dyspnea and appetite and weight loss was admitted to our hospital. Computed tomography (CT) revealed a right hypovascular renal tumor with tumor thrombus in the inferior vena cava and metastases in the liver, stomach, and left kidney. The renal tumor was diagnosed as a mucinous tubular and spindle cell carcinoma (MTSCC) by pathological examination of a percutaneous needle biopsy specimen. She was treated with temsirolimus (25 mg per week). Five weeks after initiation of this treatment, her liver metastases had clearly decreased in size and her appetite had been restored. However, progressive disease was diagnosed by CT scan revealing expansion of tumor thrombus after 7 weeks, prompting a switch in treatment to axitinib. Approximately 6 months after the diagnosis, she died of cancer. MTSCC is considered to have relative good prognosis, however, many cases with poor prognoses have been reported recently. Our experience with this patient suggests that temsirolimus may be effective treatment for metastatic MTSCC.

DOI： 10.5980/jpnjurol.108.149

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DOI： 10.1016/j.ijscr.2016.11.042

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Xanthogranulomatous pyelonephritis (XGP) is a type of chronic suppurative renal inflammation. We present an extremely rare case of XGP concomitant with chromophobe renal cell carcinoma (RCC). A-39-year-old woman presented with transient fever and left lower abdominal pain during steroid pulse therapy for thyroid eye disease. Imaging studies including contrast-enhanced computed tomography, magnetic resonance imaging, and doppler ultrasonography, showed a 40 mm unusual mass lesion in the upper pole of the left kidney, and we could not rule out the possibility of malignancy.A left open partial nephrectomy for the renal mass was performed. Pathological examination revealed a 5 mm chromophobe RCC located beside a 30 mm XGP. The patient presented a favorable course without inflammatory episodes or tumor recurrence during the 9-month follow-up. This is the first case report of the coexistent XGP and chromophobe RCC.

DOI： 10.5980/jpnjurol.108.154

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Birt-Hogg-Dubé syndrome (BHD) is a rare genetic disorder characterized by fibrofolliculomas, pulmonary cysts and renal cell carcinomas (RCCs). The affected individuals inherit germline mutations in the folliculin gene (FLCN). We investigated the mutation spectrum and clinicopathologic findings of 312 patients from 120 different families (119 Japanese and 1 Taiwanese). A total of 31 different FLCN sequence variants were identified. The majority were c.1285dupC (n = 34), c.1533_1536delGATG (n = 25), and c.1347_1353dupCCACCCT (n = 19). Almost all patients presented with pulmonary cysts. The incidence of RCCs in FLCN mutation carriers over the age of 40 was 34.8% (40/115). Fifty-five RCC lesions were surgically resected; most were either chromophobe RCC (n = 24; 43.6%) or hybrid oncocytic/chromophobe tumors (19; 34.5%). Seventy-six of 156 FLCN mutation carriers (120 probands and 36 sibs, 48.7%) had skin papules; however, cutaneous manifestations were so subtle that only one patient voluntarily consulted dermatologists. Japanese Asian BHD families have three FLCN mutational hotspots. Recurrent episodes of pneumothoraces are the major symptoms suggestive of a BHD diagnosis in our cohort. Characteristic features of lung and kidney lesions may be more informative than fibrofolliculomas as diagnostic criteria for BHD in the Japanese Asian population.

DOI： 10.1111/cge.12807

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BACKGROUND: Osteoporosis is a common consequence of androgen deprivation therapy (ADT) for prostate cancer. Up to 20 % of men on ADT have suffered from fractures within 5 years. The WHO Fracture Risk Assessment Tool (FRAX) has been utilized to predict the 10-year probability of major osteoporotic and hip fracture. However, to date, no large studies assessing the utility of the FRAX score in prostate cancer patients with or without ADT have been performed. We herein evaluated the impact of ADT on the FRAX score in prostate cancer patients. METHODS: The assessment of the FRAX score was performed in a total of 1220 prostate cancer patients, including patients who underwent brachytherapy (n = 547), radical prostatectomy (n = 200), external beam radiation therapy (n = 264) and hormonal therapy alone (n = 187) at Yokohama City University Hospital (Yokohama, Japan). We evaluated the effect of ADT on the FRAX score. RESULTS: Using the FRAX model, the median and mean 10-year probability of a major osteoporotic fracture according to the clinical risk factors alone was 7.9 % (8.8 ± 4.3 %), while the 10-year probability of hip fracture risk was 2.7 % (3.5 ± 3.1 %). In the ADT group, the duration of ADT was correlated with both major osteoporotic risk and hip fracture risk (R(2) = 0.141, p < 0.001 and R(2) = 0.166, p < 0.001, respectively). A comparison between the ADT (n = 187) and non-ADT (n = 399) groups demonstrated that the major fracture risk was > 20 % higher and the hip fracture risk was > 3 % higher in the ADT group than in the non-ADT group (ADT: 10 (5.3 %) and 118 (63.1 %), non-ADT 13 (3.3 %) and 189 (47.4 %), p < 0.001 and p < 0.001, respectively). CONCLUSIONS: These results suggested that the longer duration of ADT led to an increased FRAX score, and the FRAX score may be a predictor of bone management treatment, particularly in prostate cancer patients.

DOI： 10.1186/s12894-016-0151-9

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Birt-Hogg-Dubé syndrome (BHD) is a familial disorder associated with a germline mutation of FLCN that is a tumor suppressor gene. Patients with BHD have high risks for developing multiple renal cell carcinomas (RCCs). The frequent histological types are hybrid oncocytic/chromophobe tumors (HOCTs) and chromophobe RCCs. The morphology of HOCTs could alert pathologists to the possibility of BHD. On the other hand, chromophobe RCCs occurring in BHD patients demonstrate positive immunostaining for cytokeratin-7, CD82, and Ksp-cadherin similar to their sporadic counterparts. Highly reliable markers for BHD-associated chromophobe RCCs have not been identified. In the present study, we analyzed the state of chromosome 17 in 18 renal tumors composed of 8 chromophobe RCCs, 7 HOCTs, and 3 papillary RCCs obtained from BHD patients using fluorescent and chromogenic in situ hybridization probes for the centromeric region of chromosome 17 long arm. All chromophobe RCCs and HOCTs were disomic except for 1 chromophobe RCC that showed monosomy. On the other hand, 12 of 14 sporadic chromophobe RCCs were monosomic (P = .0008). The state of chromosomes 2 and 6 were also statistically different (P = .0074 and P = .0007, respectively). Three BHD-associated papillary RCCs demonstrated either trisomy (n = 2) or disomy (n = 1). Three of 5 sporadic papillary RCCs showed trisomy. The results indicate that fluorescent and chromogenic in situ hybridization of the centromeric region of chromosome 17 long arm should be a potent useful marker for chromophobe RCCs in patients who have not been diagnosed with BHD and thereby help to determine whether the cases should be considered for genetic testing.

DOI： 10.1016/j.humpath.2016.01.004

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Folliculin (FLCN) is an autosomal dominant tumor suppressor gene that modulates diverse signaling pathways required for growth, proliferation, metabolism, survival, motility, and adhesion. FLCN is an essential protein required for murine embryonic development, embryonic stem cell (ESC) commitment, and Drosophila germline stem cell maintenance, suggesting that Flcn may be required for adult stem cell homeostasis. Conditional inactivation of Flcn in adult hematopoietic stem/progenitor cells (HSPCs) drives hematopoietic stem cells (HSC) into proliferative exhaustion resulting in the rapid depletion of HSPC, loss of all hematopoietic cell lineages, acute bone marrow (BM) failure, and mortality after 40 days. HSC that lack Flcn fail to reconstitute the hematopoietic compartment in recipient mice, demonstrating a cell-autonomous requirement for Flcn in HSC maintenance. BM cells showed increased phosphorylation of Akt and mTorc1, and extramedullary hematopoiesis was significantly reduced by treating mice with rapamycin in vivo, suggesting that the mTorc1 pathway was activated by loss of Flcn expression in hematopoietic cells in vivo. Tfe3 was activated and preferentially localized to the nucleus of Flcn knockout (KO) HSPCs. Tfe3 overexpression in HSPCs impaired long-term hematopoietic reconstitution in vivo, recapitulating the Flcn KO phenotype, and supporting the notion that abnormal activation of Tfe3 contributes to the Flcn KO phenotype. Flcn KO mice develop an acute histiocytic hyperplasia in multiple organs, suggesting a novel function for Flcn in macrophage development. Thus, Flcn is intrinsically required to maintain adult HSC quiescence and homeostasis, and Flcn loss leads to BM failure and mortality in mice.

DOI： 10.1002/stem.2293

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BACKGROUND: Various molecular-targeting therapies have become available for the treatment of advanced renal cell carcinoma (RCC). Accurate prognostication is desirable for choosing the appropriate treatment for individual patients. (18)F-2-fluoro-2-deoxyglucose positron-emission tomography/computed tomography (FDG PET/CT) is a non-invasive tool for evaluating glucose accumulation, which can be an index of biological characteristics of cancer. We prospectively evaluated FDG PET/CT as a prognostic indicator in patients with advanced RCC. METHODS: A total of 101 patients slated for different systematic therapies for advanced RCC were enrolled between 2008 and 2014. A total of 61 patients had recurrent RCC (58 metastatic and 3 regional) and 40 patients had stage IV RCC (36 metastatic and 4 locoregional). Sixteen patients had not undergone nephrectomy. Pre-treatment FDG PET/CT was performed, and the max SUVmax (the highest SUV measurement in each patient) was recorded. The max SUVmax was compared with different clinical risk factors as prognostic indicators. The median observation period was 18 months (range 1-70 months). RESULTS: The max SUVmax of the 101 subjects ranged from undetectable to 23.0 (median 6.9). Patients with high max SUVmax had a poor prognosis. Multivariate analysis with standard risk factors revealed that max SUVmax was an independent predictor of survival (p < 0.001; hazard ratio 1.265; 95% confidence interval 1.159-1.380). A cutoff of 8.8 for max SUVmax advocated in our previous report was highly significant (p < 0.0001). When we subclassified the max SUVmax values, the median overall survival of subjects with max SUVmax < 7.0 was 41.9 months. That of subjects with max SUVmax between 7.0 and 12.0 was 20.6 months. That of subjects with max SUVmax ≥ 12.0 was 4.2 months. The differences were statistically significant. CONCLUSIONS: Pretreatment max SUVmax assessed by FDG PET/CT is a useful prognostic marker for patients with advanced RCC, providing helpful information for clinical decision making.

DOI： 10.1186/s12885-016-2097-4

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BACKGROUND: Obesity is known to be associated with prostate cancer development and progression, but the detailed mechanism is not clear. Monocyte chemotactic protein-1 (MCP-1) is secreted from cancer cells, stromal cells, and adipocytes, and it is involved in prostate cancer progression. Here we investigated the biological role of MCP-1 secreted from adipocytes for prostate cancer cells. METHODS: Human pre-adipocytes (HPAds) were cultured and differentiated to mature adipocytes. Conditioned medium (CM) from HPAd cells was obtained using phenol red-free RPMI1640 medium. We performed a cytokine membrane array analysis to detect cytokines in the CM. To characterize the physiological function of MCP-1 in the CM, we performed an MTT-assay, a wound-healing and invasion assay with anti-MCP-1 antibody using three prostate cancer cell lines: DU145, LNCaP, and PC-3. Matrix metalloproteinase (MMP)-2 and MMP-9 activities were evaluated by gelatin zymography. A qPCR and Western blotting were used to examine the mRNA and protein expression levels of MMP-2. RESULTS: The cytokine membrane array of the CM showed a strong signal of MCP-1compared to the control medium, and we thus focused our attention on MCP-1 in the CM. The CM up-regulated the cancer cell proliferation, and the neutralization by anti-MCP-1 antibody inhibited the proliferative effect of the prostate cancer cell lines. The CM greatly increased the invasive activity in the prostate cancer cell lines, and anti-MCP-1 antibody decreased the invasiveness. Gelatin zymography revealed that the CM markedly enhanced the enzymatic activity of MMP-2, and anti-MCP-1 antibody down-regulated its effect. MMP-2 mRNA expression was undetected and the MMP-2 protein level was unchanged between the control medium and CM in DU145 cells. CONCLUSIONS: MCP-1 from adipocytes enhances the growth and invasion activity of prostate cancer cells. The inhibition of MCP-1 derived from adipocytes might be an effective treatment for prostate cancer.

DOI： 10.1002/pros.22972

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Cardiac hypertrophy, an adaptive process that responds to increased wall stress, is characterized by the enlargement of cardiomyocytes and structural remodeling. It is stimulated by various growth signals, of which the mTORC1 pathway is a well-recognized source. Here, we show that loss of Flcn, a novel AMPK-mTOR interacting molecule, causes severe cardiac hypertrophy with deregulated energy homeostasis leading to dilated cardiomyopathy in mice. We found that mTORC1 activity was upregulated in Flcn-deficient hearts, and that rapamycin treatment significantly reduced heart mass and ameliorated cardiac dysfunction. Phospho-AMP-activated protein kinase (AMPK)-alpha (T172) was reduced in Flcn-deficient hearts and nonresponsive to various stimulations including metformin and AICAR (5-amino-1-β-D-ribofuranosyl-imidazole-4-carboxamide). ATP levels were elevated and mitochondrial function was increased in Flcn-deficient hearts, suggesting that excess energy resulting from up-regulated mitochondrial metabolism under Flcn deficiency might attenuate AMPK activation. Expression of Ppargc1a, a central molecule for mitochondrial metabolism, was increased in Flcn-deficient hearts and indeed, inactivation of Ppargc1a in Flcn-deficient hearts significantly reduced heart mass and prolonged survival. Ppargc1a inactivation restored phospho-AMPK-alpha levels and suppressed mTORC1 activity in Flcn-deficient hearts, suggesting that up-regulated Ppargc1a confers increased mitochondrial metabolism and excess energy, leading to inactivation of AMPK and activation of mTORC1. Rapamycin treatment did not affect the heart size of Flcn/Ppargc1a doubly inactivated hearts, further supporting the idea that Ppargc1a is the critical element leading to deregulation of the AMPK-mTOR-axis and resulting in cardiac hypertrophy under Flcn deficiency. These data support an important role for Flcn in cardiac homeostasis in the murine model.

DOI： 10.1093/hmg/ddu286

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High serum calcium (Ca) due to aberrant secretion of tumor parathyroid hormone-like hormone (PTHLH) is a well-known paraneoplastic sign and is associated with poor prognosis in patients with renal cell carcinoma (RCC). However, the status of serum Ca and tumor PTHLH expression have not been verified using the 2004 World Health Organization (WHO) renal tumor classification. We retrospectively reviewed corrected serum Ca levels at initial onset (n = 683) and/or as of recurrence (n = 71) in patients with RCC. We also examined a total of 623 renal parenchymal tumor samples for PTHLH mRNA expressions by quantitative real-time PCR. High serum Ca concomitant with PTHLH overexpression in tumors was observed exclusively in clear cell RCC but not in other non clear cell subtype tumors, including papillary, chromophobe, collecting-duct, unclassified, and other rare subtype RCCs or in benign oncocytomas and angiomyolipomas. In clear cell RCC, PTHLH expression was significantly high in male patients, and was associated with a symptomatic presentation, higher grade, and higher stage cases, whereas it was not associated with VHL gene status. Univariate analyses demonstrated that high PTHLH expression was strongly associated with poor outcome both in overall survival (OS) and disease-free survival (DFS) for patients who underwent standard nephrectomy. Further multivariate Cox analyses revealed that the PTHLH expressions remained as independent prognostic parameters for OS but not for DFS. These data suggest that the previously characterized tumor signatures of high serum Ca due to high PTHLH expression and poor prognosis are clear cell RCC-specific features, whereas these characteristics are rare in non clear cell RCCs.

DOI： 10.1002/cam4.270

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TRAP1 (TNF receptor-associated protein), a member of the HSP90 chaperone family, is found predominantly in mitochondria. TRAP1 is broadly considered to be an anticancer molecular target. However, current inhibitors cannot distinguish between HSP90 and TRAP1, making their utility as probes of TRAP1-specific function questionable. Some cancers express less TRAP1 than do their normal tissue counterparts, suggesting that TRAP1 function in mitochondria of normal and transformed cells is more complex than previously appreciated. We have used TRAP1-null cells and transient TRAP1 silencing/overexpression to show that TRAP1 regulates a metabolic switch between oxidative phosphorylation and aerobic glycolysis in immortalized mouse fibroblasts and in human tumor cells. TRAP1-deficiency promotes an increase in mitochondrial respiration and fatty acid oxidation, and in cellular accumulation of tricarboxylic acid cycle intermediates, ATP and reactive oxygen species. At the same time, glucose metabolism is suppressed. TRAP1-deficient cells also display strikingly enhanced invasiveness. TRAP1 interaction with and regulation of mitochondrial c-Src provide a mechanistic basis for these phenotypes. Taken together with the observation that TRAP1 expression is inversely correlated with tumor grade in several cancers, these data suggest that, in some settings, this mitochondrial molecular chaperone may act as a tumor suppressor.

DOI： 10.1073/pnas.1220659110

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Birt-Hogg-Dubé (BHD) syndrome is an autosomal dominant disorder characterized by cutaneous fibrofolliculomas, pulmonary cysts, and kidney malignancies. Affected individuals carry germ line mutations in folliculin (FLCN), a tumor suppressor gene that becomes biallelically inactivated in kidney tumors by second-hit mutations. Similar to other factors implicated in kidney cancer, FLCN has been shown to modulate activation of mammalian target of rapamycin (mTOR). However, its precise in vivo function is largely unknown because germ line deletion of Flcn results in early embryonic lethality in animal models. Here, we describe mice deficient in the newly characterized folliculin-interacting protein 1 (Fnip1). In contrast to Flcn, Fnip1(-/-) mice develop normally, are not susceptible to kidney neoplasia, but display a striking pro-B cell block that is entirely independent of mTOR activity. We show that this developmental arrest results from rapid caspase-induced pre-B cell death, and that a Bcl2 transgene reconstitutes mature B-cell populations, respectively. We also demonstrate that conditional deletion of Flcn recapitulates the pro-B cell arrest of Fnip1(-/-) mice. Our studies thus demonstrate that the FLCN-FNIP complex deregulated in BHD syndrome is absolutely required for B-cell differentiation, and that it functions through both mTOR-dependent and independent pathways.

DOI： 10.1182/blood-2012-02-410407

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Germline mutations in the BHD/FLCN tumor suppressor gene predispose patients to develop renal tumors in the hamartoma syndrome, Birt-Hogg-Dubé (BHD). BHD encodes folliculin, a protein with unknown function that may interact with the energy- and nutrient-sensing AMPK-mTOR signaling pathways. To clarify BHD function in the mouse, we generated a BHD knockout mouse model. BHD homozygous null (BHD(d/d)) mice displayed early embryonic lethality at E5.5-E6.5, showing defects in the visceral endoderm. BHD heterozygous knockout (BHDd(/+)) mice appeared normal at birth but developed kidney cysts and solid tumors as they aged (median kidney-lesion-free survival = 23 months, median tumor-free survival = 25 months). As observed in human BHD kidney tumors, three different histologic types of kidney tumors developed in BHD(d/+) mice including oncocytic hybrid, oncocytoma, and clear cell with concomitant loss of heterozygosity (LOH), supporting a tumor suppressor function for BHD in the mouse. The PI3K-AKT pathway was activated in both human BHD renal tumors and kidney tumors in BHD(d/+) mice. Interestingly, total AKT protein was elevated in kidney tumors compared to normal kidney tissue, but without increased levels of AKT mRNA, suggesting that AKT may be regulated by folliculin through post translational or post-transcriptional modification. Finally, BHD inactivation led to both mTORC1 and mTORC2 activation in kidney tumors from BHD(d/+) mice and human BHD patients. These data support a role for PI3K-AKT pathway activation in kidney tumor formation caused by loss of BHD and suggest that inhibitors of both mTORC1 and mTORC2 may be effective as potential therapeutic agents for BHD-associated kidney cancer.

DOI： 10.1073/pnas.0908853106

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Out of 132 prostate cancer (Pca) patients who underwent radical prostatectomy 31 (mean age 65 +/- 5 years) had prostate specific antigen (PSA) levels of 4.0 ng/ml or less (low PSA group). The average PSA level was 3.3 +/- 0.5 ng/ml in the low PSA group and 8.5 +/- 5.5 ng/ml in patients with a higher PSA (high PSA group). The pT2 ratio of the radical prostatectomy specimens was 74% (23/31) in the low PSA group and 55% (55/101) in the high PSA group, pT3a was 16% (5/31) and 31% (31/101), pT3b was 10% (3/31) and 10% (10/101), pN1 was 0% and 5% (5/101), respectively. The digital rectal examination (DRE) gave a positive result significantly (p = 0.026) less frequently in the low PSA group (6/31 : 20%), than in the high PSA group (44/101 : 44%). However all three pT3b patients with a low PSA were positive in DRE. This suggests the importance of DRE to detect significant Pca with PSA < or = 4.0. PSA was measured at least three times for more than one year in 19 of the 31 patients with a low PSA level before diagnosis. In 14 of these 19 cases (74%), PSA velocity was more than 0.5 ng/ml/ year and PSA doubling time was less than 4 years. Some patients with significant Pca can not be detected with a PSA cutoff level at 4.0 ng/ml. We recommend that individuals have their own PSA levels, and that long-term changes of PSA are sometimes very important to detect cases of Pca with lower PSA.

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BACKGROUND: The aim of this study was to perform a comprehensive evaluation of the renin-angiotensin system (RAS) in prostate cancer. METHODS: We investigated the expression of RAS components in prostate cancer cells treated with hormonal agents. Real-time PCR data showed the expression of the AT1 receptor, angiotensin I converting enzyme (ACE), and angiotensin I/II (Ang-I/II) precursor in all 87 prostate tissue samples. RESULTS: Expression of these genes in hormone refractory prostate cancer (HRPC) was significantly higher than that in normal prostate tissue and untreated prostate cancer tissue. Western blot showed that protein expression of the AT1 receptor and Ang-I/II was enhanced in LNCaP cells cultivated in steroid-free medium. When LNCaP cells were stimulated with dihydrotestosterone (DHT), estradiol (E2), dexamethasone (DEX), or anti-androgen drugs, protein expression of the AT1 receptor and Ang-I/II was augmented. CONCLUSIONS: The present data suggest that prostatic RAS is overexpressed in HRPC tissue, and expression of its components is influenced by several kinds of hormonal stimulation.

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DOI： 10.5980/jpnjurol1989.97.649

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BACKGROUND: In order to assess whether the prostate-specific antigen (PSA) nadir obtained with an ultrasensitive PSA assay can be used as a prognostic indicator for patients undergoing radical prostatectomy, we investigated it retrospectively. METHODS: Between October 1997 and July 2003, 46 patients underwent radical prostatectomy for prostate cancer at our institution. None of them received preoperative treatment. Levels of PSA were measured with an ultrasensitive PSA assay every 1-3 months after prostatectomy. Biochemical recurrence was defined as a PSA level of 0.2 ng/mL or higher. RESULTS: There was a significant difference in PSA nadir between the biochemical recurrence group and the no recurrence group (P < 0.001). The receiver operating characteristics (ROC) curve gave an optimal cut-off value for PSA nadir of 0.01 ng/mL, demonstrating a significant difference in biochemical recurrence after radical prostatectomy. No patient with a PSA nadir level <0.01 ng/mL showed biochemical failure, while 15 out of 22 patients with PSA nadir levels >or=0.01 ng/mL showed biochemical failure. CONCLUSION: The PSA nadir level obtained using an ultrasensitive PSA assay is an excellent predictor of biochemical recurrence after radical prostatectomy. Early detection of recurrence offers the possibility of early salvage therapy.

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BACKGROUND: We previously demonstrated that an angiotensin II receptor blocker (ARB) had the potential to inhibit cell proliferation of prostate cancer. In this study, we examined whether an ARB could elicit an antiproliferative effect on hormone-refractory prostate cancer, clinically. METHODS: Twenty-three patients with advanced hormone-refractory prostate cancer who had already received secondary hormonal therapy using dexamethasone, and who were no longer receiving conventional therapy, were enrolled. All of the patients received candesartan 8 mg once daily per os and, simultaneously, androgen ablation. Change in prostate-specific antigen (PSA) was determined as the primary endpoint. The secondary end-point was change in performance status (PS). To investigate angiotensin II type 1 (AT1) receptor expression in prostate cancer tissue, real-time quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) was performed, using specimens, from untreated patients with prostate cancer. RESULTS: Eight patients (34.8%) showed responsive PSA changes; six showed a decrease immediately after starting administration and two showed a stable level of PSA. Six men with a PSA decline of more than 50% showed an improvement in PS. The mean time to PSA progression (TTPP) in responders was 8.3 months (range, 1-24 months). Half of the patients showed stable or improved PS during treatment. With regard to toxic effects, only one patient showed hypotension during treatment. The RT-PCR showed that AT1 receptor expression in well-differentiated adenocarcinoma was higher than that in poorly differentiated adenocarcinoma. CONCLUSION: These data showed that an ARB had potential biological effects on prostate cancer, suggesting the usefulness of the cytostatic activity of such agents on recurrent prostate cancer.

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We showed previously that angiotensin II activated the proliferation of prostate cancer cells and that angiotensin II receptor blockers (ARB) could inhibit it. Here, we investigated whether angiotensin II exerts mitogenic effects on the cross-talk between stromal and cancer cells and whether an ARB can inhibit tumor growth through actions on stromal cells. Cell proliferation and interleukin-6 secretion of prostate stromal PrSC cells stimulated with angiotensin II, tumor necrosis factor-alpha, or epidermal growth factor were examined in the absence and presence of ARB. We examined the effect of ARB on mitogen-activated protein kinase (MAPK) phosphorylation of PrSC and PC-3 cells treated with conditioned medium of PrSC cells and determined the effect of ARB on tumor growth induced by paracrine factors from PrSC cells. Angiotensin II activated the cell proliferation and interleukin-6 secretion of PrSC cells, and ARB inhibited it. Angiotensin II, tumor necrosis factor-alpha, or epidermal growth factor induced MAPK phosphorylation in PrSC cells, and this phosphorylation was inhibited by ARB. Conditioned medium of PrSC cells with angiotensin II activated MAPK phosphorylation in PC-3 cells, and ARB-treated conditioned medium of PrSC cells inhibited it. The tumor growth and angiogenesis of a mixture of PC-3 with PrSC were inhibited by ARB administration, whereas those of PC-3 xenografts were not inhibited. ARB exerted an antiproliferative effect on prostate cancer through paracrine factors from stromal cells. Because prostate stromal cells are thought to be involved in the initiation and development of prostate cancer, the present data suggest the possibility that ARBs are a novel therapeutic class of agents for prostate cancer.

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We carried out Genechip analysis using prostate cancer and non-malignant tissue to identify specific genes related to prostate cancer. We focused on neuroserpin (PI-12), which has been identified as one of the genes with high expression in prostate cancer. We analyzed the relationship between its expression pattern and clinical characteristics. Prostate cancer and normal prostate tissue were analyzed by Affymetrix GeneChip technology. We carried out real-time quantitative PCR on a total of 102 specimens: 45 of normal prostate, 45 of previously untreated prostate cancer (constituting 45 pairs of samples obtained at radical prostatectomy, with each pair dissected from the same prostate specimen) and 12 of recurrent hormone refractory prostate cancer (HRPC). Results showed that the neuroserpin gene was more highly expressed in prostate cancer than in normal prostate tissue. Neuroserpin expression in untreated prostate cancer was significantly higher than that in normal prostate. In HRPC it was significantly higher than that in untreated prostate cancer and normal prostate. In untreated prostate cancer, neuroserpin expression was significantly higher in high grade tumors such as poorly differentiated adenocarcinoma than in lower grade tumors such as well or moderately differentiated adenocarcinoma. Higher neuroserpin expression was associated with shorter recurrence-free survival after radical prostatectomy, shorter recurrence-free survival in HRPC patients and shorter overall survival in HRPC patients. The neuroserpin gene may be associated with the development, progression and aggressiveness of prostate cancer. Our present data suggests that higher neuroserpin expression may predict an unfavorable outcome after radical prostatectomy or hormone therapy.

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BACKGROUND: Although patients with prostate cancer with metastatic lesions initially respond to androgen ablation therapy, most patients ultimately develop a hormone-refractory state. Effective treatment for men with hormone-refractory prostate cancer (HRPC) has not been established. We performed a clinical study of docetaxel in HRPC patients, and evaluated its efficacy. METHODS: Nine patients with HRPC were administered 55 mg/m2 docetaxel, every 3 weeks, simultaneously with hormonal therapy, with a luteinizing hormone-releasing hormone analog, and daily oral dexamethasone. Change in serum prostate-specific antigen (PSA) was determined as the primary endpoint. RESULTS: The mean age of the patients was 64 years (range, 49 to 76 years). Median follow-up time was 8.5 months (range, 5.3 to 16.7 months). In eight patients whose pretreatment serum PSA was elevated, six patients (75.0%) had a PSA decline of more than 50%, and four (50.0%) had a PSA decline of more than 75%. Median time to progression for all patients was 7.9 months (range, 0.0 to 11.6 months; 95% confidence interval [CI], 0.0 to 26.3). The median overall survival was 8.5 months (range, 5.3 to 16.7 months; 95% CI, 8.1 to 13.8). Four of six patients (66.7%) with pain before treatment obtained pain relief and were able to discontinue analgesic agents. This regimen was well tolerated. Grade 3 or 4 neutropenia or leukocytopenia without fever was seen in three patients (33.3%). Only one patient required administration of granulocyte-colony stimulating factor because of neutropenia. No other grade 3 or 4 toxicity was observed. CONCLUSION: Docetaxel was an active agent in Japanese HRPC patients, and was well tolerated in this population. To establish its efficacy and safety in Japanese HRPC patients, a large-scale study in Japan is warranted.

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DOI： 10.5980/jpnjurol1989.96.442

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BACKGROUND: The aim of this study was to identify predictors that can increase the accuracy of detecting prostate cancer on subsequent biopsies. METHODS: Between 1998 and 2003, a total of 235 men with prostate specific antigen (PSA) levels between 4.0 and 20 ng/mL underwent one or more systematic needle biopsies of the prostate. Of these men, 73 (31.1%) underwent one repeat biopsy and 26 (11.1%) underwent two or more repeat biopsies. We evaluated the results of prostate biopsies in relation to the morbidity of prostate cancer detected on repeat biopsies. RESULTS: Of the 73 men who underwent repeat biopsy, 16 (21.9%) had prostate cancer. Twenty-six men with one negative re-biopsy underwent two or more repeat biopsies, and five of these patients were found to have early stage prostate cancer. On repeat biopsy, there was a significant difference in percent free PSA between the cancer-detected group and the no-cancer-detected group (P < 0.01). A receiver operating characteristics (ROC) curve gave an optimal cut-off value for percent free PSA of 11%, demonstrating a significant difference in the cancer detection rate on repeat biopsy (P = 0.0009). Analysis of the data for re-biopsies showed that cancer-detected cases showed a raised PSA value and a simultaneously reduced percent free PSA (these differences were statistically significant). CONCLUSIONS: A low percent free PSA level increased the probability of a positive result in repeat biopsy. An increase in the accuracy of detecting cancer, especially on repeat biopsy, will promote the detection of more early stage prostate cancer.

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DOI： 10.1158/1538-7445.AM2017-3527

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Language：Japanese   Publisher：(一社)日本泌尿器科学会  

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

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

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

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

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

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

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

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

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

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Language：Japanese   Publisher：(一社)日本泌尿器科学会総会事務局  

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Language：Japanese   Publisher：(一社)日本泌尿器科学会総会事務局  

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Language：Japanese   Publisher：(一社)日本泌尿器科学会総会事務局  

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Language：Japanese   Publisher：(一社)日本泌尿器科学会総会事務局  

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Language：Japanese   Publisher：(一社)日本泌尿器科学会総会事務局  

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Language：English   Publishing type：Research paper, summary (international conference)  

Web of Science

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Language：Japanese   Publisher：(一社)日本泌尿器科学会総会事務局  

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

症例1は66歳男性で、経尿道的膀胱腫瘍切除術(TUR-BT)を施行した。膀胱注入療法を計6回施行した。膀胱鏡で膀胱内全体に黄白色の物質が付着し、膀胱粘膜の観察が困難となった。Mycobacterium bovis感染疑いの診断で、イソニアジド+リファンピシン+エタンブトール(INH+RFP+EB)を2ヵ月間、INH+RFPを4ヵ月間投与した。内服1ヵ月後で尿培養は陰性化した。膀胱癌の再発は認めていない。症例2は69歳男性で、TUR-BTを施行した。BCG膀注療法を6回施行し、維持療法を行ったが、頻尿と排尿時痛にて2回で終了した。MRIで前立腺右葉に前立腺癌疑いの所見があり、前立腺針生検+膀胱鏡を施行した。BCG膀注療法に伴う類上皮細胞肉芽腫と診断した。抗結核薬は使用せず対症療法で経過観察中である。膀胱癌の再発は認めていない。症例3は68歳男性で、TUR-BTを施行した。BCG膀注療法を6回、維持療法を2回施行した。排尿時痛が悪化し、MRIはBCG膀注療法後肉芽腫性膀胱炎+前立腺炎疑いの所見であった。現在対症療法で経過観察中である。膀胱癌の再発は認めていない。

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Language：Japanese   Publisher：(一社)日本泌尿器科学会総会事務局  

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Language：Japanese   Publisher：(一社)日本泌尿器科学会総会事務局  

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Language：Japanese   Publisher：(一社)日本泌尿器科学会総会事務局  

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Language：Japanese   Publisher：(一社)日本泌尿器科学会総会事務局  

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Language：Japanese   Publisher：(一社)日本泌尿器科学会総会事務局  

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

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Language：Japanese   Publisher：神奈川県医師会  

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Language：Japanese   Publisher：(一社)日本泌尿器内視鏡学会  

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Language：Japanese   Publisher：日本泌尿器内視鏡学会  

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

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Language：Japanese   Publisher：(一社)日本泌尿器内視鏡学会  

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Language：English   Publisher：日本癌学会  

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Language：Japanese   Publisher：西日本泌尿器科学会  

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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：English   Publisher：日本癌学会  

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Language：Japanese   Publisher：西日本泌尿器科学会  

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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：English   Publisher：日本癌学会  

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Language：English   Publishing type：Research paper, summary (international conference)  

Web of Science

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Language：Japanese   Publisher：腎癌研究会  

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Language：Japanese   Publisher：腎癌研究会  

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Language：Japanese   Publisher：(株)医学書院  

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Language：Japanese   Publisher：腎癌研究会  

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Language：Japanese   Publisher：腎癌研究会  

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

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

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

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

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

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

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