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Background: The aim of this study is to find a novel molecular target based on chromosomal alteration and array-based gene expression analyses in bladder cancer (BC). We investigated a cancer testis antigen, LY6K, which is located on chromosome 8q24.3.Methods: Five BC cell lines were subjected to high-resolution array-comparative genomic hybridisation with 244 000 probes. The expression levels of LY6K mRNA were evaluated in BC cell lines and clinical BC specimens by real-time reverse transcription-PCR. The cell lines were subjected to fluorescence in situ hybridisation of LY6K. Cell viability was evaluated by cell growth, wound healing, and matrigel invasion assays.Results: Typical gained loci (P<0.0001) at 6p21.33-p21.32, 8q24.3, 9q34.13, 11q13.1-q14.1, 12q13.12-q13.13, 16p13.3, and 20q11.21-q13.33 were observed in all of the cell lines. We focused on 8q24.3 locus where LY6K gene harbours, and it was the top upregulated one in the gene profile from the BC cell line. LY6K mRNA expression was significantly higher in 91 BCs than in 37 normal bladder epitheliums (P<0.0001). Fluorescence in situ hybridisation validated that the high LY6K mRNA expression was due to gene amplification in the region where the gene harbours. Cell viability assays demonstrated that significant inhibitions of cell growth, migration, and invasion occured in LY6K knock down BC cell lines; converse phenomena were observed in a stable LY6K transfectant; and LY6K knockdown of the transfectant retrieved the original phenotype from the LY6K transfectant.Conclusion: Upregulation of the oncogenic LY6K gene located on the gained locus at 8q24.3 may contribute BC development. [ABSTRACT FROM AUTHOR]

Background: Chemotherapy including cisplatin is recommended for the treatment of advanced bladder cancer, but its effectiveness is limited due to the acquisition of drug resistance. Although several mechanisms of cisplatin resistance have been reported, there are still many unknowns, and treatment of cisplatin-resistant bladder cancer remains difficult. Accordingly, in this study, we aimed to identify and characterize microRNAs involved in cisplatin resistance., Methods: Small RNA sequencing analysis was performed to search for microRNAs related to cisplatin resistance. The identified microRNAs were then characterized using gain-of-function studies, sensitivity analysis, target gene analysis, and cellular assays., Results: We identified miR-424-5p as a candidate microRNA that was downregulated in cisplatin-resistant strains compared with parental strains. Notably, in gain-of-function studies, miR-424-5p suppressed the proliferative ability of cisplatin-resistant bladder cancer (CDDP-R BC). Furthermore, miR-424-5p restored sensitivity to cisplatin. RNA sequence analysis revealed seven candidate genes targeted by this microRNA. Among them, cyclin E1 (CCNE1) was chosen for subsequent analyses because its expression was upregulated in cisplatin-resistant cells compared with parental cells and because recent studies have shown that CCNE1 amplification is synthetic lethal with PKMYT1 kinase inhibition. Therefore, we performed functional analysis using the PKMYT1 inhibitor RP-6306 and demonstrated that RP-6306 inhibited cell growth through suppression of mitotic entry and restored cisplatin sensitivity in CDDP-R BC., Conclusions: Overall, our findings provided insights into the development of novel therapeutic strategies for CDDP-R BC., (© 2024. The Author(s).)

Background: Radical cystectomy in women generally includes the removal of the uterus, ovaries, and anterior vaginal wall, but the criteria for reproductive organ sparing are not clear., Methods: A total of 2674 patients with bladder cancer were retrospectively reviewed, having undergone cystectomy at this nationwide multicenter from January 2013 to December 2019. We evaluated the incidence of malignancy in reproductive organs in a cohort of 417 women and analyzed the clinicopathological features of reproductive organ involvement. Recurrence-free survival and overall survival were reported using Kaplan-Meier survival curves., Results: Median follow-up was 36.9 months. Of the 417 patients with urothelial carcinoma of the bladder, 325 underwent hysterectomy, and 92 had a spared uterus and anterior wall of the vagina. Twenty-nine (8.9%) patients exhibited reproductive organ involvement; this consisted of 22 (6.8%) uteri, 16 (4.9%) vaginas, and two (0.6%) ovaries. Incidental primary reproductive malignancies were found in only two (0.6%) patients. Recurrence-free survival and overall survival were significantly shorter in patients with reproductive organ involvement than in those without. Patients with reproductive organ involvement were more likely to have tumors with ≥ cT3 or sub-localization at the posterior/trigone/bladder neck., Conclusions: The risk of reproductive organ involvement cannot be ignored in women undergoing radical cystectomy for urothelial carcinoma of the bladder, therefore, the eligibility criteria for reproductive organ preservation should be considered carefully., (© 2024. The Author(s) under exclusive licence to Japan Society of Clinical Oncology.)

Background: The therapeutic role of pelvic lymph node dissection (PLND) during radical prostatectomy (RP) for prostate cancer is not established. In clinical practice, PLND is primarily performed in cases of high-risk prostate cancer. The detection of lymph node metastasis plays a crucial role in determining the need for subsequent treatments. This study aims to evaluate the prognosis of prostate cancer patients with lymph node involvement (LNI) by stratifying them based on postoperative prostate-specific antigen (PSA) levels to identify biomarkers that can guide postoperative treatment strategies., Methods: Analysis was conducted on 383 patients, selected from 572 initially eligible, who underwent RP with LNI across 33 Japanese Urological Oncology Group institutions from 2006 to 2019. Patients were grouped according to postoperative PSA levels and salvage treatments received. Follow-up focused on castration resistance-free survival (CRFS), metastasis-free survival (MFS), and overall survival (OS)., Results: In the persistent PSA group (PSA ≥ 0.1 ng/mL), CRFS and MFS were significantly shorter compared to the non-persistent PSA group (PSA < 0.1 ng/mL), and there was a tendency for shorter OS. In the persistent PSA group, patients with postoperative PSA values above the median (PSA ≥ 0.52 ng/mL) showed shorter CRFS and MFS. Furthermore, in the PSA ≥ 0.52 group, androgen deprivation therapy (ADT) plus radiotherapy (RT) combination had prolonged CRFS and MFS compared with ADT alone., Conclusions: This study provides valuable insights into stratifying patients based on postoperative PSA levels to tailor postoperative treatment strategies, potentially improving the prognosis of prostate cancer patients with LNI., (© 2024. The Author(s) under exclusive licence to Japan Society of Clinical Oncology.)

Purpose: Metastatic non-clear cell renal cell carcinoma (nccRCC) is a heterogeneous disease with a poor prognosis and is treated with immunotherapy (IO)-based combinations according to the clear cell renal cell carcinoma. Tyrosine-kinase inhibitors (TKIs), such as cabozantinib and axitinib, are commonly used as the 2nd line therapy after 1st line IO combination therapy, but their efficacy as 2nd line TKI therapy for nccRCC is unknown. In this study, we performed a retrospective multicenter analysis of nccRCC patients who were previously treated with IO combination therapy and received 2nd line TKIs., Methods: Among 254 patients enrolled in the Japanese multicenter retrospective study, 52 patients with nccRCC histology who received second-line TKIs were included in this study. Progression-free survival and overall survival (OS) from 2nd line TKIs were analyzed by log-rank test and Cox-proportional hazard model. Objective response rate (ORR) of 2nd line TKIs were analyzed., Results: The 1-year PFS and OS rates were 25.0% (95% CI = 13.1-36.8) and 63.8% (95% CI, 48.0-75.9), respectively. No patients had a complete response, 11 had a partial response, and 18 had stable disease. ORR was 21.1%. IMDC poor risk and sunitinib as the 2nd line therapy were significantly associated with poor PFS., Conclusion: The 2nd-line TKI was effective for a small group of nccRCC patients previously treated with IO combination therapy, although this study was retrospectively analyzed with a small number of cases., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background and Objective: Robotic adrenalectomy (RA) has attracted interest as an alternative to laparoscopic adrenalectomy (LA) for patients with pheochromocytoma, although its beneficial effects are uncertain. Our aim was to compare RA and LA outcomes for these patients., Methods: Data for patients who underwent RA or LA for pheochromocytoma in 46 international centers between 2012 and 2022 were reviewed. We analyzed baseline characteristics and postoperative complications at discharge, 90 d, and 1 yr. We conducted propensity score matching (PSM; 1:1 ratio) and multivariable analyses to evaluate outcomes and risk factors for the occurrence of complications and higher Comprehensive Complication Index (CCI)., Key Findings and Limitations: Of 1755 patients, 1613 (91.9%) underwent LA and 142 (8.1%) underwent RA. Estimated blood loss, conversion rate, complication rate, and CCI at discharge, 90 d, and 1 yr were similar between the groups. However, RA was associated with a longer operative time in comparison to LA (100 vs 123 min; p < 0.001), but not after PSM (p = 0.120). Multivariable analysis revealed that Charlson comorbidity index (odds ratio [OR] 1.17, 95% confidence interval [CI] 1.07-1.29; p = 0.001), and tumor size per 1-cm increment (OR 1.13, 95% CI 1.07-1.21; p < 0.001) were independently associated with the incidence of complications, but there was no significant difference in complication rates between the LA and RA groups (OR 1.09, 95% CI 0.63-1.87; p = 0.767). After PSM, RA was associated with a lower rate of severe (grade ≥3a) complications in comparison to LA (p = 0.023)., Conclusions and Clinical Implications: RA is a safe alternative to LA and yields similar outcomes for patients with pheochromocytoma. RA may be associated with a lower likelihood of severe complications. Further studies are warranted to determine the role of robotic surgery in pheochromocytoma., Patient Summary: Pheochromocytoma is a rare tumor in the adrenal gland and the gold-standard treatment is surgical removal. We assessed patient outcomes after robot-assisted surgery compared with laparoscopic surgery and found that outcomes are similar, but the rate of severe complications may be lower if a surgical robot is used., (Copyright © 2024 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Gemcitabine plus cisplatin (GC) combination chemotherapy is the primary treatment for advanced bladder cancer (BC) with unresectable or metastatic disease. However, most cases develop resistance to this therapy. We investigated whether drug resistance could be targeted through metabolic reprogramming therapies. Metabolomics analyses in our lab's gemcitabine- and cisplatin-resistant cell lines revealed increased phosphoglycerate dehydrogenase (PHGDH) expression in gemcitabine-resistant cells compared with parental cells. Isocitrate dehydrogenase 2 (IDH2) gain of function stabilized hypoxia-inducible factor1α (HIF1α) expression, stimulating aerobic glycolysis. In gemcitabine-resistant cells, elevated fumaric acid suppressed prolyl hydroxylase domain-containing protein 2/Egl nine homolog 1 (PHD2) and stabilized HIF1α expression. PHGDH downregulation or inhibition in gemcitabine-resistant BC cells inhibited their proliferation, migration, and invasion. Cisplatin-resistant cells showed elevated fatty acid metabolism, upregulating fatty acid synthase (FASN) downstream of tyrosine kinase. Using the fibroblast growth factor receptor (FGFR) tyrosine kinase inhibitor erdafitinib, we inhibited malonyl-CoA production, which is crucial for fatty acid synthesis, and thereby suppressed upregulated HIF1α expression. Combination treatment with NCT503 and erdafitinib synergistically suppressed tumor cell proliferation and induced apoptosis in vitro and in vivo. Understanding these mechanisms could enable innovative BC therapeutic strategies to be developed., (© 2024 The Author(s). Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.)

Objective: To analyse the impact of histological discordance of subtypes (subtypes or divergent differentiation [DD]) in specimens from transurethral resection (TUR) and radical cystectomy (RC) on the outcome of the patients with bladder cancer receiving RC., Patients and Methods: We analysed data for 2570 patients from a Japanese nationwide cohort with bladder cancer treated with RC between January 2013 and December 2019 at 36 institutions. The non-urinary tract recurrence-free survival (NUTR-FS) and overall survival (OS) stratified by TUR or RC specimen histology were determined. We also elucidated the predictive factors for OS in patients with subtype/DD bladder cancer., Results: At median follow-up of 36.9 months, 835 (32.4%) patients had NUTR, and 691 (26.9%) died. No statistically significant disparities in OS or NUTR-FS were observed when TUR specimens were classified as pure-urothelial carcinoma (UC), subtypes, DD, or non-UC. Among 2449 patients diagnosed with pure-UC or subtype/DD in their TUR specimens, there was discordance between the pathological diagnosis in TUR and RC specimens. Histological subtypes in RC specimens had a significant prognostic impact. When we focused on 345 patients with subtype/DD in TUR specimens, a multivariate Cox regression analysis identified pre-RC neutrophil-lymphocyte ratio and pathological stage as independent prognostic factors for OS (P = 0.016 and P = 0.001, respectively). The presence of sarcomatoid subtype in TUR specimens and lymphovascular invasion in RC specimens had a marginal effect (P = 0.069 and P = 0.056, respectively)., Conclusion: This study demonstrated that the presence of subtype/DD in RC specimens but not in TUR specimens indicated a poor prognosis. In patients with subtype/DD in TUR specimens, pre-RC neutrophil-lymphocyte ratio and pathological stage were independent prognostic factors for OS., (© 2024 BJU International.)

Background: Pelvic exenteration (PE) is the last resort for achieving a complete cure for pelvic cancer; however, it is burdensome for patients. Minimally invasive surgeries, including robot-assisted surgery, have been widely used to treat malignant tumors and have also recently been used in PE. This study aimed to evaluate the safety and efficacy of robot-assisted PE (RPE) by comparing the outcomes of open PE (OPE) with those of conventional laparoscopic PE (LPE) for treating pelvic tumors., Methods: Following the ethics committee approval, a multicenter retrospective analysis of patients who underwent pelvic exenteration between January 2012 and October 2022 was conducted. Data on patient demographics, tumor characteristics, and perioperative outcomes were collected. A 1:1 propensity score-matched analysis was performed to minimize group selection bias., Results: In total, 261 patients met the study criteria, of whom 61 underwent RPE, 90 underwent OPE, and 110 underwent LPE. After propensity score matching, 50 pairs were created for RPE and OPE and 59 for RPE and LPE. RPE was associated with significantly less blood loss (RPE vs. OPE: 408 mL vs. 2385 ml, p < 0.001), lower transfusion rate (RPE vs. OPE: 32% vs. 82%, p < 0.001), and lower rate of complications over Clavien-Dindo grade II (RPE vs. OPE: 48% vs. 74%, p = 0.013; RPE vs. LPE: 48% vs. 76%, p = 0.002)., Conclusion: This multicenter study suggests that RPE reduces blood loss and transfusion compared with OPE and has a lower rate of complications compared with OPE and LPE in patients with locally advanced and recurrent pelvic tumors., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

A multicenter study of nonmetastatic castration-resistant prostate cancer (nmCRPC) was conducted to identify the optimal cut-off value of prostate-specific antigen (PSA) doubling time (PSADT) that correlated with the prognosis in Japanese nmCRPC. Of the 515 patients diagnosed and treated for nmCRPC at 25 participating Japanese Urological Oncology Group centers, 450 patients with complete clinical information were included. The prognostic values of clinical factors were evaluated with respect to prostate specific antigen progression-free (PFS), cancer-specific survival (CSS), and overall survival (OS). The optimal cutoff value of PSADT was identified using survival tree analysis by Python. The Median PSA and PSADT at diagnosis of nmCRPC were 3.3 ng/ml, and 5.2 months, respectively. Patients treated with novel hormonal therapy (NHT) showed significantly longer PFS (HR: hazard ratio 0.38, p < 0.0001) and PFS2 (HR 0.45, p < 0.0001) than those treated with vintage nonsteroidal antiandrogen agent (Vintage). The survival tree identified 4.65 months as the most prognostic PSADT cutoff point. Among the clinical and pathological factors PSADT of < 4.65 months remained an independent prognostic factor for OS (HR 2.96, p = 0.0003) and CSS (HR 3.66, p < 0.0001). Current data represented optimal cut-off of PSADT 4.65 months for a Japanese nmCRPC., (© 2024. The Author(s).)

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., (Copyright © 2024 by The American Association of Immunologists, Inc.)

Background: To date, no studies have compared the treatment outcomes of second-line therapies in patients with metastatic clear cell renal cell carcinoma (ccRCC). This study retrospectively evaluated the efficacy of cabozantinib and axitinib as second-line treatments in patients with metastatic ccRCC who previously received immune-oncology combination therapy., Patients and Methods: Patients with metastatic ccRCC treated with cabozantinib and axitinib as second-line therapy after nivolumab-ipilimumab treatment were identified among 243 patients with RCC treated between August 1, 2018 and January 31, 2022 at 34 institutions belonging to the Japanese Urological Oncology Group. Patients were assessed for treatment outcomes, including progression-free survival (PFS), overall survival, objective response rate (ORR), and incidence rate of treatment-related adverse events (AEs)., Results: Forty-eight patients treated with cabozantinib and 60 treated with axitinib as second-line therapy after nivolumab-ipilimumab treatment for metastatic ccRCC were identified. The median PFS (95% confidence interval) was 11.0 months (9.0-16.0) with cabozantinib and 9.5 months (6.0-13.0) with axitinib. The ORRs were 37.5% (cabozantinib) and 38.3% (axitinib). The rates of any-grade AEs and grade ≥3 AEs were 79.2% (cabozantinib) versus 63.3% (axitinib; P = .091) and 35.4% (cabozantinib) versus 23.3% (axitinib; P = .202), respectively. In the poor-risk group, PFS was longer in the cabozantinib group than in the axitinib group (P = .033)., Conclusion: The efficacy and safety of cabozantinib and axitinib were comparable. In the poor-risk group, cabozantinib was more effective than axitinib. These findings provide valuable insights into the selection of second-line treatment options after nivolumab-ipilimumab treatment in patients with metastatic ccRCC., Competing Interests: Disclosure HK: Honoraria, Advisory, or Research support: Bristol-Myers Squibb and Takeda. HM: Honoraria: Takeda, MSD, Pfizer, and Ono. JF: Honoraria: Takeda, MSD, and Ono., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Bladder cancer (BC) is a common genitourinary malignancy that exhibits silent morbidity and high mortality rates because of a lack of diagnostic markers and limited effective treatments. Here, we evaluated the role of the lncRNA brain cytoplasmic RNA 1 ( BCYRN1 ) in BC. We performed loss-of-function assays to examine the effects of BCYRN1 downregulation in T24 and BOY BC cells. We found that BCYRN1 downregulation significantly inhibited the proliferation, migration, invasion, and three-dimensional spheroid formation ability and induced apoptosis in BC cells. Additionally, gene set enrichment analysis (GSEA) using RNA sequences from tumor fractions showed that BCYRN1 downregulation decreased the expression of mRNAs associated with the cell cycle. These findings were supported by observations of G 2 /M arrest in flow cytometry assays. Finally, we examined the expression of serum exosomal BCYRN1 as a biomarker. Clinically, BCYRN1 expression in serum exosomes from patients with BC ( n = 31) was significantly higher than that in healthy donors ( n = 19; mean difference: 4.1-fold higher, p < 0.01). Moreover, in patients who had undergone complete resection of BC, serum exosomal BCYRN1 levels were significantly decreased ( n = 8). Thus, serum exosomal BCYRN1 may be a promising diagnostic marker and therapeutic target in patients with BC.

Background: Kidney transplant recipients (KTRs) are at risk of severe coronavirus disease 2019 (COVID-19), and even now that Omicron subvariants have become dominant, cases of severe disease are certain to occur. The aims of this retrospective study were to evaluate the efficacy of antiviral treatment for COVID-19 and to identify risk factors for severe disease in KTRs during Omicron subvariant-dominant periods., Methods: A total of 65 KTRs diagnosed with COVID-19 who received antiviral treatment between July 2022 and September 2023 were analyzed. Mild cases received oral molnupiravir (MP) as outpatient therapy, while moderate or worse cases received intravenous remdesivir (RDV) as inpatient therapy. In principle, mycophenolate mofetil was withdrawn and switched to everolimus. We investigated the efficacy of antiviral treatment and compared the clinical parameters of mild/moderate and severe/critical cases to identify risk factors for severe COVID-19., Results: Among 65 cases, 49 were mild, 6 were moderate, 9 were severe, and 1 was of critical severity. MP was administered to 57 cases; 49 (86%) improved and 8 (14%) progressed. RDV was administered to 16 cases; 14 (87%) improved and 2 (13%) progressed. Seventeen (26%) cases required hospitalization, and none died. Comparisons of the severe/critical group (n = 10) with the mild/moderate group (n = 55) demonstrated that the severe/critical group had a significantly higher median age (64 vs. 53 years, respectively; p = 0.0252), prevalence of diabetes (70% vs. 22%, respectively; p = 0.0047) and overweight/obesity (40% vs. 11%, respectively; p = 0.0393), as well as a significantly longer median time from symptom onset to initial antiviral therapy (3 days vs. 1 day, respectively; p = 0.0026). Multivariate analysis showed that a longer time from symptom onset to initial antiviral treatment was an independent risk factor for severe COVID-19 (p = 0.0196, odds ratio 1.625, 95% confidence interval 1.081-2.441)., Conclusion: These findings suggest that a longer time from symptom onset to initial antiviral treatment is associated with a higher risk of severe COVID-19 in KTRs. Initiating antiviral treatment as early as possible is crucial for preventing severe outcomes; this represents a valuable insight into COVID-19 management in KTRs., (© 2024. The Author(s).)

Objectives: To compare the effectiveness and safety of gonadotropin-releasing hormone (GnRH) antagonist monotherapy to combined androgen blockade (CAB) with a GnRH agonist and bicalutamide in patients with advanced hormone-sensitive prostate cancer (HSPC)., Methods: The study was conducted as KYUCOG-1401 trial (UMIN000014243) and enrolled 200 patients who were randomly assigned to either group A (GnRH antagonist monotherapy followed by the addition of bicalutamide) or group B (CAB by a GnRH agonist and bicalutamide). The primary endpoint was PSA progression-free survival. The secondary endpoints were the time to CAB treatment failure, radiographic progression-free survival, overall survival, changes in serum parameters, including PSA, hormones, and bone and lipid metabolic markers, and adverse events., Results: PSA progression-free survival was significantly longer in group B (hazard ratio [HR], 95% confidence interval [CI]; 1.40, 1.01-1.95, p = 0.041). The time to CAB treatment failure was slightly longer in group A (HR, 95% CI; 0.80, 0.59-1.08, p = 0.146). No significant differences were observed in radiographic progression-free survival or overall survival. The percentage of patients with serum testosterone that did not reach the castration level was higher at 60 weeks (p = 0.046) in group A. No significant differences were noted in the serum levels of bone metabolic or lipid markers between the two groups. An injection site reaction was more frequent in group A., Conclusions: The present results support the potential of CAB using a GnRH agonist and bicalutamide as a more effective treatment for advanced HSPC than GnRH antagonist monotherapy., (© 2023 The Japanese Urological Association.)

Background: Immune editing, in which human leukocyte antigens (HLA) have critical roles, has been suggested to shape the landscape of human cancer. This study prospectively investigated whether HLA gene zygosity is associated with the prognosis of primary androgen deprivation therapy in advanced prostate cancer., Methods: KYUCOG-1401-A was conducted in conjunction with a prospective clinical trial (KYUCOG-1401). Among the patients enrolled in KYUCOG-1401 and treated with primary androgen deprivation therapy, only Japanese patients were included. HLA genotypes of HLA-A, B, C, DRB1, DQB1, and DPB1 were determined. The effect of divergence of HLA genotypes on time to progression, prostate cancer-specific survival, and overall survival was evaluated., Results: Among 127 patients, homozygosity for HLA-DRB1 (HR, 95% CI; 4.05, 1.54-10.7, P = 0.0047) and HLA-DQB1 (HR, 95% CI; 3.75, 1.47-9.58, P = 0.0058) was associated with an increased risk of prostate cancer-specific mortality. Patients with higher HLA evolutionary divergence scores at HLA-DQB1 (HR, 95% CI; 0.90, 0.82-0.97, P = 0.0093) had lower risks of prostate cancer-specific mortality. Androgen-responsive gene sets were upregulated in CD4low and CD8low tumors in the prostate cancer cohort, but not in the bladder and kidney cancer cohorts., Conclusions: This study suggested that the diversity of HLA-II loci including HLA-DRB1 and HLA-DQB1 plays an important role in advanced prostate cancer survival, contributing to improved risk stratification in advanced prostate cancer. Moreover, it was shown that CD4 + T cells play an important role in androgen deprivation therapy, suggesting that immunotherapy targeting CD4 + T cells is promising for prostate cancer., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

The development of diabetes mellitus (DM) after living donor kidney transplantation (KT) is a risk factor for worsening transplant kidney function, cardiac disease, and cerebrovascular disease, which may affect prognosis after KT. At our institution, all patients' glucose tolerance is evaluated perioperatively by oral glucose tolerance tests (OGTTs) at pre-KT, and 3, 6, and 12 month (mo.) after KT. We analyzed the insulinogenic index (ISI) and homeostasis model assessment beta cell (HOMA-β) based on the immunoreactive insulin (IRI) levels to determine how glucose tolerance changed after KT in 214 patients who had not been diagnosed with DM before KT. In addition, we analyzed the body mass index (BMI) which may also influence glucose tolerance after KT. The concentration of tacrolimus (TAC) in blood was also measured as the area under the curve (AUC) to examine its effects at each sampling point. The preoperative-OGTTs showed that DM was newly diagnosed in 22 of 214 patients (10.3%) who had not been given a diagnosis of DM by the pre-KT fasting blood sugar (FBS) tests. The glucose tolerance was improved in 15 of 22 DM patients at 12 mo. after KT. ISI and IRI deteriorated only at 3 mo. after KT but improved over time. There was a trend of an inverse correlation between HOMA-β and TAC-AUC. We also found inverse correlations between IRI and an increase in BMI from 3 to 12 mo. after KT. Early corticosteroid withdrawal or the steroid minimization protocol with tacrolimus to maintain a low level of diabetogenic tacrolimus and BMI decrease after KT used by our hospital individualizes lifestyle interventions for each patient might contribute to an improvement in post-KT glucose tolerance., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Mitsuke et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Multitargeted receptor tyrosine kinase inhibitors, including vascular endothelial growth factor (VEGF) inhibitors, such as sunitinib, have been used as the primary targeted agents for patients with recurrent or distant metastasis of advanced renal cell carcinoma (RCC). However, endogenous or acquired sunitinib resistance has become a significant therapeutic problem. Therefore, we focused on mechanisms of sunitinib resistance in RCC. First, we undertook RNA sequencing analysis using previously established sunitinib-resistant RCC (SUR-Caki1, SUR-ACHN, and SUR-A498) cells. The results showed increased expression of secretogranin II (SCG2, chromogranin C) in SUR-RCC cells compared to parental cells. The Cancer Genome Atlas database showed that SCG2 expression was increased in RCC compared to normal renal cells. In addition, the survival rate of the SCG2 high-expression group was significantly lower than that of the RCC low-expression group. Thus, we investigated the involvement of SCG2 in sunitinib-resistant RCC. In vitro analysis showed that migratory and invasive abilities were suppressed by SCG2 knockdown SUR cells. As SCG2 was previously reported to be associated with angiogenesis, we undertook a tube formation assay. The results showed that suppression of SCG2 inhibited angiogenesis. Furthermore, coimmunoprecipitation assays revealed a direct interaction between SCG2 and hypoxia-inducible factor 1α (HIF1α). Expression levels of VEGF-A and VEGF-C downstream of HIF1α were found to be decreased in SCG2 knockdown SUR cells. In conclusion, SCG2 could be associated with sunitinib resistance through VEGF regulation in RCC cells. These findings could lead to a better understanding of the VHL/HIF/VEGF pathway and the development of new therapeutic strategies for sunitinib-resistant RCC., (© 2023 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

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., (© 2023 The Japanese Urological Association.)

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., (© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

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., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Androgen-deprivation therapy (ADT) has been widely used for the treatment of advanced prostate cancer. However, prognosis and adverse events (AEs) vary among patients. This study aimed to identify genetic markers able to predict the outcome of ADT. Japanese patients treated with primary ADT for advanced prostate cancer in the KYUCOG-1401 trial were enrolled as a development set. A distinct population of advanced prostate cancer cases treated with ADT was included as a validation set. Single-nucleotide polymorphisms (SNPs) associated with radiographic progression-free survival (rPFS) at 1 year and AEs including de novo diabetes mellitus (DM), arthralgia, and de novo dyslipidemia were identified in the development set by a genome-wide association study (GWAS). The SNPs associated with rPFS in the development study were then genotyped in the validation set. GWAS followed by validation identified SNPs (rs76237622 in PRR27 and rs117573572 in MTAP) that were associated with overall survival (OS) in ADT. A genetic prognostic model using these SNPs showed excellent predictive efficacy for PFS and OS in ADT. In addition, GWAS showed that several SNPs were associated with de novo DM, arthralgia, and de novo dyslipidemia in ADT. This study identified novel multiple SNPs that correlated with outcomes in ADT. Future studies on correlations affecting the therapeutic efficacy of ADT-based combination therapies would make a valuable contribution to the development of personalized medicine.

Combination chemotherapy with gemcitabine and cisplatin (GC) is recommended as the primary treatment for advanced bladder cancer (BC). However, the benefits of this approach are limited owing to the acquisition of drug resistance. Here, we found that gemcitabine-resistant and cisplatin-resistant BCs do not exhibit cross-resistance, and that these BCs exhibit different mRNA patterns, as revealed using RNA sequence analysis. To overcome drug resistance, we used the newly developed pan-RAS inhibitor Compound 3144. Compound 3144 inhibited cell viability through suppression of RAS-dependent signaling in gemcitabine- and cisplatin-resistant BCs. RNA sequencing revealed that several genes and pathways, particularly those related to the cell cycle, were significantly downregulated in Compound 3144-treated BCs. These findings provide insights into potential therapeutic strategies for treating BC., (© 2023 The Authors. FEBS Open Bio published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.)

It is extremely rare for a patient with prostate cancer (PCa) to have palpable lymph nodes at the initial presentation. In fact, only 4 case reports of palpable superficial lymph nodes at the first visit led to the diagnosis of PCa. Moreover, no such cases are reported in kidney transplantation (KT) patients. A 72-year-old man who started hemodialysis due to diabetic nephropathy was referred to our hospital for a KT in 2018. Before the KT, he had a negative screen for cancer, including PCa. The postoperative course was good. He felt a lump in the left inguinal region three years after the KT. A computed tomography scan revealed abdominal and left inguinal lymphadenopathy, which was consistent with a post-transplant lymphoproliferative disorder. However, a biopsy of an inguinal lymph node revealed adenocarcinoma with positive prostate-specific antigen (PSA) staining, suggesting lymph node metastasis of PCa. The blood PSA level was 1674.23 ng/mL. A prostate biopsy was performed, the pathologic diagnosis of which was PCa, with a Gleason score of 10. In conclusion, even though the standardized incidence ratio of PCa is not known to increase in KT patients, PCa should be included in the differential diagnosis, along with the possibility of post-transplant lymphoproliferative disorder. We also suggest the importance of regular screening for malignant tumors after organ transplantation., Competing Interests: Declaration of Competing Interest All the authors declare no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Exosomes are 40-100 nm nano-sized extracellular vesicles and are receiving increasing attention as novel structures that participate in intracellular communication. We previously found that miRNA-1 (miR-1) functions as a tumor suppressor in renal cell carcinoma (RCC). In this study, we investigated the function of exosomal miR-1 and the possibility that the exosome constitutes a tumor maker in RCC. First, we established the method to collect exosomes from cell lysates and human serum by a spin column-based method. Next, we assessed exosomes using Nanosight nanoparticle tracking analysis and Western blot analysis with exosome marker CD63. We confirmed that exosomes labeled with PKH26 fused with recipient cells. Moreover, miR-1 expression was elevated in RCC cells treated with exosomes derived from miR-1-transfected cells. Functional analyses showed that exosomal miR-1 significantly inhibited cell proliferation, migration and invasion compared to control treatment. Our analyses with TCGA database of RCCs showed that miR-1 expression was significantly downregulated in clinical RCC samples compared to that in normal kidney samples, and patients with low miR-1 expression had poorer overall survival in comparison to patients with high expression. Furthermore, RNA sequence analyses showed that expression levels of several genes were altered by exposure to exosomal miR-1. The analyses with TCGA database indicated that high expression of MYO15A was associated with a poorer outcome in RCC. In addition, RT-qPCR analysis of exosomes from clinical patients' sera showed that MYO15A was significantly upregulated in RCC patients compared to that in healthy controls. This study showed that treatment with exosomal miR-1 might be an effective approach to treating RCCs. In addition, exosomal MYO15A could be a diagnostic tumor marker in RCCs., Competing Interests: Declaration of competing interest None of the authors has any direct or indirect commercial financial incentives associated with the publication of this article entitled “Exosomal microRNA-1 and MY6O15A as a target for therapy and diagnosis in renal cell carcinoma”., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Objectives: Pembrolizumab, an anti-PD-1 monoclonal antibody, revolutionized the treatment of advanced urothelial carcinoma. However, the tolerability and outcomes of pembrolizumab in patients with severe renal dysfunction [creatinine clearance (CrCl) <30 ml/min] are unclear because no clinical trials included such patients. We analyzed the safety profile and outcomes of these patients in the real world., Methods: We extracted data for 739 pembrolizumab-treated patients from a Japanese nationwide cohort of platinum-refractory metastatic urothelial carcinoma. Using propensity score matching, the overall survival (OS) and adverse events (AEs) of patients with CrCl <30 and ≥30 were compared., Results: Ninety-two patients (12.4%) had CrCl <30 ml/min. The median number of doses was similar between the CrCl ≥ 30 and CrCl <30 groups (5 and 4, respectively), and there was no difference in the frequency of grade ≥2 treatment-related AEs between the groups (35.5% vs. 35.7%). The overall response rate was similar between the groups (27.2% vs. 29.7%, P = 0.184). Using propensity score matching, the median OS times in the CrCl ≥30 and CrCl <30 groups were 10.3 (95% confidence interval [CI] = CI 7.3-13.0) and 8.1 months (95% CI = 5.4-14.6, P = 0.626), respectively. The 1-year OS rates in these groups were 41.5% and 38.2%, respectively, and the 2-year OS rates were 21.3% and 20.2%, respectively. In multivariate Cox regression analysis, performance status ≥2 (hazard ratio [HR] = 5.56, 95% CI = 2.64-11.71, P < 0.0001) and neutrophil-to-lymphocyte ratio ≥3 (HR = 2.20, 95% CI =1.15-4.19, P = 0.013) were independently associated with patient prognosis in the CrCl <30 group., Conclusions: This report illustrated that pembrolizumab can be safely administered to patients with severe renal dysfunction, who had similar outcomes as patients without severe renal dysfunction., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Objectives: We analyzed the clinical outcomes of laparoscopic adrenalectomy for pheochromocytomas in hemodialysis compared with nonhemodialysis patients., Methods: Fifty-seven patients (7 hemodialysis and 50 nonhemodialysis) were included in the study. We analyzed the differences in clinical parameters and outcomes between the hemodialysis patient groups and nonhemodialysis patient groups as well as identified predictors for an intraoperative hypertensive spike., Results: The increasing intravascular volume before surgery in hemodialysis patients made perioperative hemodynamic management safer. No significant difference in clinical parameters between the two groups was observed except for the length of hospitalization that was significantly longer in the hemodialysis patients (9 vs. 6 days, P =0.005). An increase in systolic blood pressure at CO 2 insufflation was an independent predictor of a hypertensive spike with a cutoff value of 22.5 mmHg (odds ratio 1.038, 95% confidence interval 1.012-1.078)., Conclusion: Laparoscopic adrenalectomy for pheochromocytomas in hemodialysis was safe and feasible. An increase in systolic blood pressure at CO 2 insufflation was a predictor of the intraoperative hypertensive spike. The research in this manuscript is not registered. This is a retrospective study., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2022 Shuichi Tatarano et al.)

In recent years, cancer metabolism has attracted attention as a therapeutic target, and glutamine metabolism is considered one of the most important metabolic processes in cancer. Solute carrier family 1 member 5 (SLC1A5) is a sodium channel that functions as a glutamine transporter. In various cancer types, SLC1A5 gene expression is enhanced, and cancer cell growth is suppressed by inhibition of SLC1A5. However, the involvement of SLC1A5 in clear cell renal cell carcinoma (ccRCC) is unclear. Therefore, in this study, we evaluated the clinical importance of SLC1A5 in ccRCC using The Cancer Genome Atlas database. Our findings confirmed that SLC1A5 was a prognosis factor for poor survival in ccRCC. Furthermore, loss-of-function assays using small interfering RNAs or an SLC1A5 inhibitor (V9302) in human ccRCC cell lines (A498 and Caki1) showed that inhibition of SLC1A5 significantly suppressed tumor growth, invasion, and migration. Additionally, inhibition of SLC1A5 by V9302 in vivo significantly suppressed tumor growth, and the antitumor effects of SLC1A5 inhibition were related to cellular senescence. Our findings may improve our understanding of ccRCC and the development of new treatment strategies for ccRCC., Competing Interests: Declaration of competing interest None of the authors has any direct or indirect commercial financial incentives associated with the publication of this article entitled “Targeting of the glutamine transporter SLC1A5 induces cellular senescence in clear cell renal cell carcinoma”., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Patients with advanced bladder cancer are generally treated with a combination of chemotherapeutics, including gemcitabine, but the effect is limited due to acquisition of drug resistance. Thus, in this study, we investigated the mechanism of gemcitabine resistance. First, gemcitabine-resistant cells were established and resistance confirmed in vitro and in vivo. Small RNA sequencing analyses were performed to search for miRNAs involved in gemcitabine resistance. miR-99a-5p, selected as a candidate miRNA, was downregulated compared to its parental cells. In gain-of-function studies, miR-99a-5p inhibited cell viabilities and restored sensitivity to gemcitabine. RNA sequencing analysis was performed to find the target gene of miR-99a-5p. SMARCD1 was selected as a candidate gene. Dual-luciferase reporter assays showed that miR-99a-5p directly regulated SMARCD1. Loss-of-function studies conducted with si-RNAs revealed suppression of cell functions and restoration of gemcitabine sensitivity. miR-99a-5p overexpression and SMARCD1 knockdown also suppressed gemcitabine-resistant cells in vivo. Furthermore, β-galactosidase staining showed that miR-99a-5p induction and SMARCD1 suppression contributed to cellular senescence. In summary, tumor-suppressive miR-99a-5p induced cellular senescence in gemcitabine-resistant bladder cancer cells by targeting SMARCD1., (© 2022 The Authors. Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.)

Objectives: To investigate the impact of the number of cycles and objective response to chemotherapy on overall survival in patients with metastatic urothelial carcinoma treated with pembrolizumab., Methods: This multicenter, retrospective study included 755 patients from 59 institutions with advanced, chemoresistant urothelial carcinoma who received pembrolizumab. The associations of the overall survival with the number of cycles and best objective response were investigated using Cox multiple regression analysis., Results: Overall, 391 patients received standard first-line chemotherapy and pembrolizumab as a second-line treatment, and were included in the final analysis. Of the 391 patients, 185 received less than four cycles, 134 received four to six cycles and 72 received more than six cycles of first-line chemotherapy. An objective response (complete or partial response) to chemotherapy was observed in 145 patients (37.1%). Univariate analysis showed that the overall survival of patients who received more than six cycles or responded to chemotherapy (complete or partial response) was significantly longer than that of patients who received less than four cycles or did not respond to chemotherapy (stable or progressive disease). At multivariate levels, no correlations were observed between overall survival and the number of cycles of or the response to chemotherapy., Conclusions: Therapeutic benefit of pembrolizumab can be expected irrespective of the objective response to and number of cycles of platinum-based first-line chemotherapy., (© 2021 The Japanese Urological Association.)