Effect of HLA Genotype on Anti-PD-1 Antibody Treatment for Advanced Renal Cell Carcinoma in the SNiP-RCC Study.

Immune checkpoint blockade therapies are widely used for cancer treatment, including advanced renal cell carcinoma (RCC). This study aimed to investigate the impact of zygosity in HLA genes and individual HLA genotypes on the efficacy of an anti-PD-1 Ab, nivolumab, in treating advanced RCC. Patient enrollment was conducted across 23 institutions in Japan from August 19, 2019, to September 30, 2020, with follow-up concluding on March 31, 2021. HLA genotype imputation of HLA-A, B, and C, DQB1, and DRB1 loci was performed. Among 222 patients, the presence of at least one homozygosity of the HLA-II allele significantly improved the best objective response (hazard ratio, 0.34; 95% confidence interval, 0.21-0.96; p = 0.042). The HLA evolutionary divergence (HED) of the HLA-A and HLA-B loci was higher than the HLA-C (p < 0.0001 and p < 0.0001, respectively), with high HED of the HLA-B locus correlating to clinical benefits in nivolumab treatment (hazard ratio, 0.44; 95% confidence interval, 0.21-0.90; p = 0.024) and improving cancer-specific survival compared with the low group (p = 0.0202). Additionally, high HED of the HLA-B locus was correlated with the number of infiltrated CD8+ cells in the tumor microenvironment (correlation coefficient, 0.4042). These findings indicate that the diversity of the HLA-B locus plays a significant role in the anti-tumor effect of nivolumab treatment in advanced RCC, potentially offering insights for improved risk stratification in nivolumab treatment and leading to better medical management of advanced RCC.

Clinicopathological characteristics of adrenocortical carcinoma in the Kyushu-Okinawa area of Japan.

OBJECTIVE: Adrenocortical carcinoma is a rare condition, with limited comprehensive reports from Japan. This study aimed to review Japan's data on adrenocortical carcinoma by assessing information from 46 patients-with adrenocortical carcinoma across 10 Japanese university hospitals. METHODS: We conducted a retrospective multi-institutional analysis of the clinical characteristics of adrenocortical carcinoma in Japan. We evaluated data from 46 patients across 10 university hospitals over 10 years and analyzed the relationship between clinicopathological characteristics and overall survival. RESULTS: Five- and 10-year overall survival rates were 59% and 53%, respectively. Overall survival was significantly different among the tumor-node-metastasis system for adrenocortical carcinoma of the American Joint Committee on Cancer/International Union Against Cancer, with the worst prognosis in stage IV (p = 0.0044). In our cohort, neither the Weiss score nor the Ki-67 proliferation index correlated with overall survival. Adjuvant treatment did not yield improved overall survival, whereas resection of the primary tumor in stage IV disease was significantly associated with improved overall survival (p = 0.0262). Out of the cases evaluated for plasma hormones, plasma cortisol, aldosterone, testosterone, and DHEA-S levels were measured at 23%, 42%, 29%, and 62%, respectively, demonstrating higher levels than the upper normal limits. CONCLUSION: Patients with stage IV adrenocortical carcinoma had a poor prognosis; however, resection of the primary tumor in stage IV disease was associated with prolonged survival. The results of this study are expected to contribute to future treatment of adrenocortical carcinoma in Japan.

Effect of genetic polymorphisms on outcomes following nivolumab for advanced renal cell carcinoma in the SNiP-RCC trial.

BACKGROUND: Anti-PD-1 antibodies are widely used for cancer treatment including advanced renal cell carcinoma (RCC). However, their therapeutic and adverse effects vary among patients. This study aimed to identify genetic markers that predict outcome after nivolumab anti-PD-1 antibody treatment for advanced RCC. METHODS: This study was registered on the website of the University Hospital Medical Information Network (protocol ID, UMIN000037739). Patient enrollment was conducted at 23 institutions in Japan between August 19, 2019, and September 30, 2020. Patient follow-up ended on March 31, 2021. Patients were treated with nivolumab for advanced clear cell RCC. A genome-wide association study was performed in the development set, while genotyping of target regions in the validation set was undertaken. Single nucleotide polymorphisms (SNPs) in genes of interest CD274, PDCD1LG2 and PDCD1 were genotyped in the combined set. The primary endpoint was the association of SNPs with objective response following nivolumab treatment. As secondary endpoints, the associations of SNPs with radiographic progression-free survival (rPFS) and treatment-related grade ≥ 3 adverse events (AEs) were evaluated. RESULTS: A genome-wide association study followed by a validation study identified that SNPs in FARP1 (rs643896 and rs685736) were associated with objective response and rPFS but not AEs following nivolumab treatment. Furthermore, SNPs in PDCD1LG2 (rs822339 and rs1411262) were associated with objective response, rPFS, and AEs following nivolumab treatment. Genetic risk category determined according to the number of risk alleles in SNPs (rs643896 in FARP1 and rs4527932 in PDCD1LG2) excellently predicted objective response and rPFS in nivolumab treatment. CONCLUSION: This study revealed that SNPs in FARP1 and PDCD1LG2 were correlated with outcome in nivolumab treatment. The use of these SNPs may be beneficial in selecting appropriate treatment for individual patients and may contribute to personalized medicine.

UTX deficiency in neural stem/progenitor cells results in impaired neural development, fetal ventriculomegaly, and postnatal death.

Recent studies have demonstrated that epigenetic modifications are deeply involved in neurogenesis; however, the precise mechanisms remain largely unknown. To determine the role of UTX (also known as KDM6A), a demethylase of histone H3K27, in neural development, we generated Utx-deficient mice in neural stem/progenitor cells (NSPCs). Since Utx is an X chromosome-specific gene, the genotypes are sex-dependent; female mice lose both Utx alleles (UtxΔ/Δ ), and male mice lose one Utx allele yet retain one Uty allele, the counterpart of Utx on the Y chromosome (UtxΔ/Uty ). We found that UtxΔ/Δ mice exhibited fetal ventriculomegaly and died soon after birth. Immunofluorescence staining and EdU labeling revealed a significant increase in NSPCs and a significant decrease in intermediate-progenitor and differentiated neural cells. Molecular analyses revealed the downregulation of pathways related to DNA replication and increased H3K27me3 levels around the transcription start sites in UtxΔ/Δ NSPCs. These results indicate that UTX globally regulates the expression of genes required for proper neural development in NSPCs, and UTX deficiency leads to impaired cell cycle exit, reduced differentiation, and neonatal death. Interestingly, although UtxΔ/Uty mice survived the postnatal period, most died of hydrocephalus, a clinical feature of Kabuki syndrome, a congenital anomaly involving UTX mutations. Our findings provide novel insights into the role of histone modifiers in neural development and suggest that UtxΔ/Uty mice are a potential disease model for Kabuki syndrome.

Protocadherin B9 Is Associated with Human Esophageal Squamous Cell Carcinoma Progression.

INTRODUCTION: Esophageal cancer is the sixth leading cause of cancer-related death worldwide. However, molecular targeted therapy and novel therapeutic targets are needed for esophageal squamous cell cancer (ESCC). In a previous study, we reported that protocadherin (PCDH) B9 plays an important role in several cancers. Therefore, in this study, we examined the clinical significance of PCDHB9 expression in ESCC. METHODS: PCDHB9 expression was examined using immunohistochemistry in 128 cases and using quantitative reverse transcription-polymerase chain reaction in 16 cases of ESCC. PCDHB9 function in ESCC cells was examined using RNA interference. RESULTS: High PCDHB9 expression was identified in 5 of 16 (31.3%). In total, 51 (40%) ESCC cases showed strong PCDHB9 expression, whereas nonneoplastic mucosa rarely showed its expression. High PCDHB9 expression was significantly associated with T classification, N grade, and stage in ESCC. In ESCC cell lines, PCDHB9 knockdown affected cell growth, migration, and adhesion. Further, the expression of integrin (ITG) A3, ITGA4, ITGA5, ITGB1, ITGB6, vimentin, snail family transcriptional repressor 1, and cadherin 2 (NCAD) was significantly reduced and cadherin 1 was significantly increased in PCDHB9 knockdown ESCC cells. CONCLUSION: These results suggest that PCDHB9 plays a tumor-promoting role and is a potential biomarker and therapeutic target in ESCC.

Real-world treatment outcomes of patients with penile cancer in the Kyushu-Okinawa area of Japan in the pre-guideline era.

OBJECTIVES: To understand the real-world outcomes for patients with penile cancer in the Kyushu-Okinawa area before the introduction of practice guidelines in Japan. METHODS: We retrospectively collected medical information on patients with penile squamous cell carcinoma and penile intraepithelial neoplasia at 12 university hospitals and their affiliated hospitals in the Kyushu-Okinawa area from January 2009 to December 2020. Patients with unknown clinical stage were excluded. Patient background characteristics and survival, as well as pretreatment factors involved in survival, were investigated. RESULTS: A total of 196 patients were included. Patients with clinical stage 0, I, IIA, IIB, IIIA, IIIB and IV comprised 9.7, 26.0, 22.4, 2.6, 10.7, 14.3 and 14.3%, respectively. The median follow-up was 26 months, and the mean 5-year overall survival and cancer-specific survival rates were 74.3 and 79.8%, respectively. On univariate analysis, tumor diameter ≥ 30 mm, penile shaft tumor, Eastern Cooperative Oncology Group performance status ≥ 1, cT ≥ 3, cN ≥ 2 and cM1 were associated with significantly poorer cancer-specific survival. On multivariate analysis, pretreatment factors of cN ≥ 2 (hazard ratio, 32.5; 95% confidence interval, 5.08-208; P = 0.0002), Eastern Cooperative Oncology Group performance status ≥ 1 (4.42; 1.79-10.9; P = 0.0012) and cT ≥ 3 (3.34; 1.11-10.1; P = 0.0319) were identified as independent prognostic factors. CONCLUSIONS: The study revealed basic data for future penile cancer treatment and research, including survival rates according to clinical stages, and identified cN ≥ 2, Eastern Cooperative Oncology Group performance status ≥ 1 and cT ≥ 3 at initial diagnosis as independent prognostic factors. Evidence for penile cancer in Japan is particularly scarce, and future large-scale prospective studies are warranted.

Clinical factors for tumor response, progression, and survival in nivolumab for advanced renal cell carcinoma in the SNiP-RCC study.

BACKGROUND: This study is part of the SNPs in Nivolumab PD-1 inhibitor for RCC (SNiP-RCC). Here we aimed to reveal clinical factors for tumor response, progression, and survival in nivolumab for advanced clear cell renal cell carcinoma (RCC) in Japanese patients. METHODS: We included patients from 23 institutions in Japan. We evaluated the objective response, radiographic progression-free survival (PFS), overall survival (OS), and treatment-related grade ≥ 3 (serious adverse events [SAEs]). RESULTS: We included 222 patients. The median age was 69 years (interquartile range 62-74 years), and 71% of the patients were male. Pancreas metastasis, lung metastases, prior cytokine therapy, and SAEs, were associated with objective response. The median PFS was 18 months. Liver metastases (hazard ratio [HR], 1.61), age ≥ 75 (HR, 0.48), previous resection of primary sites (HR, 0.47), and SAEs (HR, 0.47) were independent prognostic factors for PFS. Karnofsky Performance Status <70 (HR, 2.90), high platelets (HR, 4.48), previous resection of primary sites (HR, 0.23), and pathological grade (HR, 0.19 for grade 2 and HR, 0.12 for grade 3) were independent prognostic factors for OS. SAEs were reported in 45 (20.3%) cases. In the group of patients with prior nephrectomy, SAEs were associated with objective response, PFS, and OS. CONCLUSION: The SNiP-RCC study identified clinical parameters correlated with treatment outcomes in Japanese patients with priorly treated advanced clear cell RCC undergoing nivolumab monotherapy.

Immune-related adverse events in urothelial cancer patients: Adjustment for immortal time bias.

To investigate the association between the onset, severity, and type of immune-related adverse events (irAEs) and the efficacy of pembrolizumab in patients with platinum-pretreated advanced urothelial carcinoma (UC), we retrospectively collected clinical datasets of 755 patients and conducted landmark analysis. Patients who survived for fewer than 3 months were excluded from the evaluation to reduce the immortal time bias. In total, 620 patients were evaluated, of whom 220 patients (35.5%) experienced grade ≥2 irAEs, including 134 patients with grade 2 irAEs and 86 with grade ≥3 irAEs. Propensity score matching extracted 198 patients with and without grade ≥2 irAEs. The onset of grade ≥2 irAEs was associated with longer median progression-free survival (PFS) (8.3 months vs. 4.5 months, p = 0.003) and overall survival (OS) (20.4 months vs. 14.3 months, p = 0.031) and a higher objective response rate (ORR) (44.8% vs. 30.2%, p = 0.004). Patients with grade 2 irAEs had significantly better oncological outcomes (PFS, OS, and ORR) than grade ≤1 and ≥3 irAEs. Patients with grade ≥3 irAEs had worse outcomes than grade 2 irAEs. Endocrine and skin irAEs were related with better survival outcomes, and the rate of severities was lower in these categories. In conclusion, the occurrence of irAEs, particularly low-grade irAEs, was predictive of pembrolizumab efficacy in patients with platinum-pretreated advanced UC.

Pre-pembrolizumab neutrophil-to-lymphocyte ratio (NLR) predicts the efficacy of second-line pembrolizumab treatment in urothelial cancer regardless of the pre-chemo NLR.

Neutrophil-to-lymphocyte ratio (NLR) was reported to be associated with prognosis of urothelial cancer (UC) patients receiving systemic chemotherapy or immunotherapy. However, it has not been elucidated how preceding first-line chemotherapy affects NLR and subsequent second-line pembrolizumab treatment. This multicenter study analyzed 458 patients with metastatic UC who received first-line chemotherapy and second-line pembrolizumab with regard to pre-chemotherapy and pre-pembrolizumab NLR in association with the efficacy of chemotherapy and pembrolizumab treatment. NLR was increased in 47% while decreased in 53% of patients before and after first-line chemotherapy. High pre-chemotherapy NLR (≥ 3) was significantly associated with unfavorable overall (OS, P = 0.0001) and progression-free (P < 0.0001) survivals after first-line chemotherapy. However, pre-chemotherapy NLR showed only modest influence on radiological response and survival after second-line pembrolizumab treatment, whereas pre-pembrolizumab NLR showed higher association. NLR decrease was associated with partial response or greater objective response by first-line chemotherapy, while NLR increase was associated with higher patient age. In conclusion, immediate pre-chemotherapy and pre-pembrolizumab NLR was significantly associated with efficacy of the following treatment, respectively. However, even patients with high pre-chemotherapy NLR achieved favorable OS if they had their NLR reduced by chemotherapy, whereas those with high pre-chemotherapy NLR yielded unfavorable OS if they had their NLR remained high after chemotherapy, suggesting that chemotherapy may have differential effect on the efficacy of subsequent pembrolizumab treatment in UC patients.

Prediction of anastomotic leakage after left-sided colorectal cancer surgery: a pilot study utilizing quantitative near-infrared spectroscopy.

BACKGROUND: Anastomotic leakage (AL) occurs with some frequency in all types of colorectal cancer surgery and is associated with increased morbidity, mortality and recurrence rates. Complications might be prevented by monitoring intra-operative bowel perfusion at the anastomotic site. A pilot study concerning the objective and quantitative measurement of tissue perfusion by monitoring regional tissue saturation of oxygen (rSO2) was conducted, using the In Vivo Optical Spectroscopy (INVOS™) system (Medtronic, Minneapolis, MN, USA). METHODS: This study evaluated the ability of the INVOS™ system to predict AL after left-sided colorectal cancer surgery. rSO2 measurements of the oral side of the site of bowel anastomosis were taken before anastomosis in 73 patients. Clinical factors, including rSO2, were analyzed to identify risk factors for AL. RESULTS: Among 73 patients, 6 (8.2%) experienced AL. The rSO2 values of the oral anastomotic site were significantly lower in AL patients than in non-AL patients. In the multivariate analysis, the rSO2 value of the oral anastomotic site was an independent risk factor for AL. CONCLUSION: Monitoring the rSO2 at the anastomotic site enabled the prediction of AL. A prospective study to evaluate the efficacy of the INVOS™ system for monitoring intestinal rSO2 is in progress.

Omnidirectional camera and head-mount display contribute to the safety of laparoscopic surgery.

BACKGROUND: We focused on the availability of an omnidirectional camera and head-mount display (HMD). If the laparoscope is an omnidirectional camera, captured images are sent to the HMD worn by the operator in real time. The operator can thus view the image as they like without moving the camera and obtain a 360° view intuitively. However, the surgical system that can be used for actual laparoscopic operations has not yet been developed. In this study, we aimed to show that an omnidirectional camera and HMD would be useful in laparoscopic surgery. MATERIAL AND METHODS: Eleven medical students and twelve surgical residents (Surgeons group) participated in this study. We created an experimental box with five marks randomly attached inside the box, and the inside cannot be seen from the outside. We measured the time it took to identify all marks between conventional laparoscope and substitute system in each group. RESULTS: In the substitute system, the time required for the task was significantly shorter than with conventional laparoscopy in each group. CONCLUSION: An omnidirectional camera and HMD may be a useful new device for laparoscopic surgery. This system may help improve the safety of laparoscopic surgery.

Clinical indicators for the incidence of postoperative ileus after elective surgery for colorectal cancer.

BACKGROUND: The occurrence of postoperative ileus leads to increased patient morbidity, longer hospitalization, and higher healthcare costs. No clear policy on postoperative ileus prevention exists. Therefore, we aim to evaluate the clinical factors involved in the development of postoperative ileus after elective surgery for colorectal cancer. METHODS: We retrospectively analyzed patients who underwent elective surgery involving bowel resection with or without re-anastomosis for colon cancer between April 2015 and March 2020. The primary readout was the presence or absence of postoperative ileus. Univariate and multivariate analyses were used to identify pre- and intraoperative risk factors, and the incidence of postoperative ileus was assessed using independent factors. RESULTS: Postoperative ileus occurred in 48 out of 356 patients (13.5%). In multivariate analysis, male sex poor performance status, and intraoperative in-out balance per body weight were independently associated with postoperative ileus development. The incidence of postoperative ileus was 2.5% in the cases with no independent factors; however, it increased to 36.1% when two factors were observed and 75.0% when three factors were matched. CONCLUSIONS: We discovered that male gender, poor performance status, and intraoperative in-out balance per body weight were associated with the development of postoperative ileus. Of these, intraoperative in-out balance per body weight is a controllable factor. Hence it is important to control the intraoperative in-out balance to lower the risk for postoperative ileus.

[A Case of Stauffer Syndrome-Like Findings Associated with Metastatic Renal Cell Cancer Improved by Molecular Targeted Therapy].

We report a case of Stauffer syndrome-like findings in a patient with metastatic renal carcinoma treated by surgery and molecular targeted therapy. The patient was a 58-year-old woman diagnosed with renal carcinoma with multiple metastases. She had hepatosplenomegaly and hepatic dysfunction with elevated serum liver enzyme and IL-6 levels. Treatment with temsirolimus and axitinib reduced the size of the local and metastatic tumors and simultaneously improved the hepatosplenomegaly. The local tumor was excised by laparoscopic nephrectomy, treated with axitinib and then with nivolumab. With the reduction in the metastatic tumor size, serum liver enzyme and IL-6 levels decreased. It was suggested that molecular targeted therapy is an effective treatment when the findings of metastatic renal cell carcinoma, are similar to those of Stauffer syndrome.

[A Cohort Study on the Prognosis of Patients with Urothelial Carcinoma Using the Miyazaki Urological Cancer Database (MUCD)].

Miyazaki Urological Cancer Database (MUCD) is a web-based database containing background, treatment, and prognosis of patients with prostate, renal, and urothelial cancers diagnosed in Miyazaki. We entered information on patients diagnosed with urothelial carcinoma from 2014 to 2018 at 4 of the 17 facilities that diagnose urothelial carcinoma in Miyazaki Prefecture. We analyzed the overall survival for bladder cancer and upper urinary tract cancer, and examined its correlation with the presence of symptoms, urine cytology, and clinical TNM classification. There were 487 patients with urothelial carcinoma, comprising 372 (76%) with bladder cancer and 115 (24%) with upper tract urinary cancer. In the bladder cancer group, 301 (81%) patients had symptomatic disease and 119 (32%) had positive urine cytology. The stage according to the TNM classification was Ta-1N0, T2-4N0, N1-2M0 and M1 in 248 (67%), 94 (26%), 19 (5%) and 11 (3%) patients, respectively. In the upper urinary tract cancers group, 89 (76%) had symptomatic disease and 41 (36%) had positive urine cytology. The stage according to the TNM classification was Ta-1N0, T2-4N0, N1-2M0 and M1 in 45 (39%), 37 (32%), 11 (10%) and 22 (19%) patients, respectively. The 3-year survival rates for bladder and upper urinary tract cancer were 83.4% and 67.8%, respectively. TNM classification (≤T1 vs ≥T2≥) was significantly associated with overall survival (bladder cancer : HR＝7.07, 95% CI＝3.13-16.0, p＜0.0001 ; upper tract urinary cancer : HR＝6.33, 95% CI＝2.13-18.8, p＝0.0009). The prognosis of patients with urothelial carcinoma diagnosed in multiple institutions could be evaluated using MUCD. The clinical T stage was significantly associated with overall survival in patients with bladder cancer and patients with upper urinary tract cancer.

Feasibility of laparoscopic adrenalectomy for metastatic adrenal tumors in selected patients: a retrospective multicenter study of Japanese populations.

BACKGROUND: Because of the small numbers of cases in single centers, the indications for and survival benefits of adrenalectomy for adrenal metastasis remain unclear. We evaluated the outcomes of laparoscopic adrenalectomy for patients with adrenal metastasis. METHODS: We retrospectively analyzed the records of 67 patients who underwent laparoscopic adrenalectomy for metastatic disease from 2003 to 2017 at 11 hospitals. Associations of clinical, surgical, and pathologic features with overall survival (OS) and positive surgical margins were evaluated using univariate and multivariate Cox regression analyses and univariate logistic regression analysis. RESULTS: Lung cancer (30%) and renal cell carcinoma (30%) were the most common primary tumor types. Intraoperative complications were observed in seven patients (10%) and postoperative complications in seven (10%). The surgical margin was positive in 10 patients (15%). The median OS was 3.8 years. Univariate analysis showed that the tumor size, episodes of extra-adrenal metastasis before adrenalectomy, extra-adrenal metastasis at the time of adrenalectomy, and positive surgical margins were significantly associated with shorter OS (p = 0.022, p = 0.005, p < 0.001, and p = 0.022, respectively). Multivariate analysis showed that extra-adrenal metastasis at the time of adrenalectomy and positive surgical margins remained statistically significant (p = 0.022 and p = 0.049, respectively). In the univariate analysis, the tumor size was significantly associated with positive surgical margins (p = 0.039). CONCLUSIONS: Laparoscopic adrenalectomy for adrenal metastasis can be safely performed in selected patients, and patients with isolated adrenal metastasis and negative surgical margins seem to have more favorable outcomes.

Preoperative incremental maximum squeeze pressure as a predictor of fecal incontinence after very low anterior resection for low rectal cancer.

PURPOSE: Very low anterior resection (VLAR) is performed widely, but some patients are left with fecal incontinence (FI), which compromises their quality of life (QOL) severely. This study sought to identify the predictive factors of postoperative FI after VLAR, which remain unclear. METHODS: We evaluated the anorectal manometry data of patients who underwent VLAR to identify the risk factors for postoperative FI among the various clinicopathological factors and manometric characteristics. FI and QOL were analyzed using the Wexner score and EORTC QLQ-C30, respectively. RESULTS: The subjects of this study were 40 patients who underwent VLAR for low rectal cancer between April, 2015 and May, 2018. There were 11 (27%) patients in the major-FI group and 29 (73%) in the minor-FI group. Multivariate analysis revealed that low preoperative incremental maximum squeeze pressure (iMSP) was an independent risk factor for postoperative major-FI. Postoperative QOL tended to be worse in the major-FI group. CONCLUSIONS: Preoperative low iMSP increases the risk of major-FI and impaired QOL after VLAR. This highlights the importance of performing preoperative anorectal manometry to evaluate the patient's anal function as well as to select the most appropriate operative procedure and early multifaceted treatment such as medication, rehabilitation, and biofeedback for postoperative FI.

Dysregulation of Type II Transmembrane Serine Proteases and Ligand-Dependent Activation of MET in Urological Cancers.

Unlike in normal epithelium, dysregulated overactivation of various proteases have been reported in cancers. Degradation of pericancerous extracellular matrix leading to cancer cell invasion by matrix metalloproteases is well known evidence. On the other hand, several cell-surface proteases, including type II transmembrane serine proteases (TTSPs), also induce progression through activation of growth factors, protease activating receptors and other proteases. Hepatocyte growth factor (HGF) known as a multifunctional growth factor that upregulates cancer cell motility, invasiveness, proliferative, and anti-apoptotic activities through phosphorylation of MET (a specific receptor of HGF). HGF secreted as inactive zymogen (pro-HGF) from cancer associated stromal fibroblasts, and the proteolytic activation by several TTSPs including matriptase and hepsin is required. The activation is strictly regulated by HGF activator inhibitors (HAIs) in physiological condition. However, downregulation is frequently observed in cancers. Indeed, overactivation of MET by upregulation of matriptase and hepsin accompanied by the downregulation of HAIs in urological cancers (prostate cancer, renal cell carcinoma, and bladder cancer) are also reported, a phenomenon observed in cancer cells with malignant phenotype, and correlated with poor prognosis. In this review, we summarized current reports focusing on TTSPs, HAIs, and MET signaling axis in urological cancers.

[A Case of Neuroendcrine Carcinoma of the Prostate Diagnosed by Prostate Re-Biopsy during Hormonal Treatment and Effectively Treated by Multidisciplinary Therapy].

A 73-year-old Japanese man visited the urology clinic with the chief complaint of gross hematuria in June 2015. His prostate specific antigen (PSA) level was 146.7 ng/ml and he was diagnosed with prostate adenocarcinoma with a Gleason Score of 5+4. With bone metastasis in the right femur (cT3aN0M1), he was treated by orchiectomy and bicalutamide. He had gross hematuria in October 2017 and a prostate tumor was detected by computed tomography (CT) and magnetic resonance imaging without increasing PSA levels. Prostate re-biopsy showed prostate neuroendocrine carcinoma and local radiation therapy (74 Gy) was performed. Follow-up CT revealed a left adrenal tumor with a positive positron emission tomographic scan in October 2018. Under the diagnosis of metastatic neuroendocrine carcinoma, chemotherapy using cisplatinum and etoposide was performed. The tumor shrunk after five courses of treatment, followed by regrowth in April 2019. Radiation therapy (50 Gy) was added to the left adrenal tumor and it shrunk again. However, a left retroperitoneal tumor was detected in July 2019 and it was resected under laparoscopic surgery and diagnosed as metastatic neuroendocrine carcinoma. Since then, no recurrence has been observed.

Protocadherin B9 promotes resistance to bicalutamide and is associated with the survival of prostate cancer patients.

Background Prostate cancer (PCa) is a common malignancy worldwide and is the second leading cause of cancer death in men. The standard therapy for advanced PCa is androgen deprivation therapy (ADT). Although ADT, including bicalutamide treatment, is initially effective, resistance to bicalutamide frequently occurs and leads to the development of castration-resistant PCa. Thus, clarifying the mechanisms of bicalutamide resistance is urgently needed. We designed this study to assess the expression and function of PCDHB9, which encodes the protocadherin B9 protein. Methods The expression of PCDHB9 was determined using immunohistochemistry and a qRT-PCR. The effects of the overexpression or knockdown of PCDHB9 on cell growth, migration, adhesion were evaluated. To evaluate the PCDHB9-mediated effects in PCa, we performed a gene expression analysis using DU145 transfected with PCDHB9. We examined the effects of PCDHB9 inhibition on bicalutamide resistance. Results The qRT-PCR revealed that the expression of PCDHB9 was much higher in PCa than that in non-neoplastic prostate tissues. In 152 clinically localized PCa cases immunohistochemistry showed that 59% of PCa cases were positive for protocadherin B9. A Kaplan-Meier analysis showed that the high expression of protocadherin B9 was associated with PSA recurrence after radical prostatectomy. A functional analysis showed that PCDHB9 modulated cell migration and adhesion. We also found that PCDHB9 induced the expression of ITGB6 based on a gene expression analysis. The effect of PCDHB9 inhibition on bicalutamide sensitivity was examined using MTT assays. The IC50 value of PCDHB9 siRNA-transfected PCa cells was significantly lower than that of negative control siRNA-transfected cells. Furthermore, immunohistochemical staining of protocadherin B9 in 74 PCa patients who were treated with androgen depletion therapy, including bicalutamide treatment, demonstrated that the high expression of protocadherin B9 was significantly associated with poor overall survival. Conclusions PCDHB9 plays an important role in the progression of PCa and bicalutamide resistance. Collectively, our results suggest that PCDHB9 targeted therapy may be more effective than bicalutamide alone.

The efficacy and toxicity of cabazitaxel for treatment of docetaxel-resistant prostate cancer correlating with the initial doses in Japanese patients.

BACKGROUND: We analyzed the efficacy and toxicity of cabazitaxel (CBZ) at high and low initial doses in Japanese patients with docetaxel-resistant castration-resistant prostate cancer (CRPC). METHODS: We retrospectively evaluated 118 patients who received CBZ for docetaxel-resistant CRPC in 10 university hospitals in Japan between 2014 and 2016. The rate of decrease of prostate-specific antigen (PSA), adverse events, progression-free survival (PFS), and overall survival (OS) were compared between patients receiving initially high (≥22.5 mg/m2, n = 36) and low (≤20 mg/m2, n = 80) CBZ doses. Factors associated with survival and grade 4 neutropenia were evaluated. RESULTS: PSA values decreased by > 50% in 22 patients (19%), with a higher frequency in the high-dose group than in the low-dose group (29 and 14%, P = 0.073). The median PFS time for the all-patient, high- and low-dose groups was 2.8 months (95% confidence interval [CI] 1.9-4.4), 2.1 months (1.2-5.5), and 3.0 months (2.0-4.4), respectively (P = 0.904). The median OS times were 16.3 months (95% CI 9.7-30.9), 30.9 months (11.8-47.4), and 10.2 months (8.6-20), respectively (P = 0.020). In multivariate analyses, PFS was significantly associated with existing bone metastasis at diagnosis (P = 0.005) and OS with PSA > 100 ng/ml (P = 0.007), hemoglobin < 12 g/dl (P = 0.030), and low initial CBZ dose (P = 0.030). Grade 4 neutropenia occurred in 53 patients (45%) and was associated with a low CBZ dose (hazard ratio 0.21, 95% CI 0.08-0.59, P = 0.002). CONCLUSIONS: CBZ at a higher initial dose may have similar response rate and response duration, but longer survival duration after treatment with higher toxicity than a lower initial dose for docetaxel-resistant CRPC in Japanese patients.