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This is the first case report in which computed tomography (CT) images of a patient with emphysematous pyelonephritis (EPN) capture the time course of emphysema from onset to resolution through conservative treatment. To re-evaluate EPN, including refractory urinary tract infections, CT scans after 72 h might be helpful., Competing Interests: The authors declare no conflict of interest., (© 2024 The Author(s). Clinical Case Reports published by John Wiley & Sons Ltd.)

Objectives: The current study aimed to examine the incidence of perioperative infections and graft viability in ABO-compatible and ABO-incompatible renal transplant recipients., Methods: We included 643 living donor renal transplant recipients registered in the Michinoku Renal Transplant Network from 1998 to 2021. Patients were divided into the ABO-compatible and ABO-incompatible kidney transplantation groups. We compared the characteristics of the two groups and evaluated the incidence of postoperative viral infections (cytomegalovirus and BK virus), graft loss-free survival, and overall survival between the two groups., Results: Of 643 patients, 485 (75%) and 158 (25%) were ABO-compatible and ABO-incompatible renal transplant recipients, respectively. Postoperative viral infections, rituximab use, and plasma exchange were significantly more common in ABO-incompatible than in ABO-compatible transplant recipients. However, there were no significant differences in terms of other background characteristics. The ABO-incompatible group was more likely to develop viral infections than the ABO-compatible group. Graft loss-free survival and overall survival did not significantly differ between the two groups. According to the multivariate Cox regression analysis, ABO compatibility was not significantly associated with graft loss-free survival and overall survival., Conclusion: Although the incidence of postoperative viral infections in ABO-incompatible renal transplant recipients increased, there was no significant difference in terms of rejection events, graft loss-free survival, and overall survival., (© 2024. The Author(s), under exclusive licence to Springer Nature B.V.)

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.)

Most recently, the antibody-drug conjugate, enfortumab vedotin, has been covered by insurance for the treatment of unresectable or metastatic urothelial carcinoma after chemotherapy and immune checkpoint inhibitors, and has significantly changed the pharmacotherapy for urothelial carcinoma in clinical practice. Recently, several reports demonstarated the efficacy and safety of enfortumab vedotin in real-world clinical practice, highlighting its current status and challenges. In addition, the combination of enfortumab vedotin and pembrolizumab for the treatment of untreated unresectable or metastatic urothelial carcinoma has received expedited approval by the FDA and is expected to become a key drug in urothelial carcinoma.

Background: Enfortumab vedotin (EV) was approved for patients with metastatic urothelial carcinoma (mUC) who progressed after anticancer therapy on September 2021 in Japan. The association between the occurrence of EV-related side effects and clinical outcome remains to be elucidated., Methods: We identified 97 mUC patients treated with EV therapy at our five institutions from the date of approval to March 2023. The median follow-up period was 7.0 months. We retrospectively analyzed the efficacy and safety of EV., Results: The median age of the patients was 71 years old, 39% had PS of 1 or more, and 56.7% had primary tumor in upper urinary tract. Overall response rate (ORR) to EV therapy, median progression-free survival (PFS), and overall survival (OS) were 43.3%, 7.52 months, and 12.78 months, respectively. Any grade of treatment-related skin disorder, dysgeusia, peripheral neuropathy, gastrointestinal disorder, and hyperglycemia occurred in 61 (62.9%), 36 (37.1%), 34 (35.1%), 29 (29.9%), and 18 (18.6%) patients, respectively. The patients with EV-associated peripheral neuropathy had significantly higher ORR (58.8% vs. 34.9%, P = .032) and longer median PFS (8.05 vs. 6.31 months, P = .017) and OS (not reached vs. 11.57 months, P = .008, respectively) than those without. The occurrence of peripheral neuropathy after EV treatment and the presence of peritoneal dissemination were factors independently associated with PFS (hazard ratio = 0.46, P = .008 and hazard raito = 3.83, P = .004, respectively) and OS (hazard ratio = 0.30, P = .005 and hazard raito = 4.53, P = .002, respectively)., Conclusions: The occurrence of EV-related peripheral neuropathy might be associated with the efficacy of EV therapy in mUC patients., (© The Author(s) 2024. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Introduction Decreased renal function after radical nephroureterectomy is one of the most important complications because it contributes to the decision to initiate adjuvant chemotherapy. This study aimed to investigate clinical factors associated with changes in renal function after radical nephroureterectomy in elderly patients. Methodology A total of 145 patients who underwent radical nephroureterectomy for upper tract urothelial carcinoma were evaluated. The renal function was calculated preoperatively, postoperatively, and one month postoperatively, and the long-term change in renal function was investigated once a year. The association between clinical factors and changes in renal function following radical nephroureterectomy in univariate and multivariate analyses was stratified by age ≥75 years and <75 years. Results The median age of the patients was 71 years, with 94 patients (65%) aged <75 years and 51 patients (35%) aged ≥75 years. The median estimated glomerular filtration rates (eGFRs) were 57.1 (21.8-100) preoperatively, 36.1 (9.1-100) postoperatively, and 42.4 (19.5-100) in one month after radical nephroureterectomy. The median eGFRs in elderly patients were 50.8 (21.8-85.4) preoperatively. In the elderly group, only 8% had an eGFR of ≥50 as cisplatin-eligible at one month postoperatively. The long-term renal function in the elderly may decline further than during the stable postoperative periods. In the multivariate analysis, hydronephrosis (HN) was a significant predictor of decreased renal function in patients aged ≥75 years between the pre- and postoperative periods. Conclusions Elderly patients with HN who have upper tract urothelial carcinoma have a lower risk of decreased renal function after radical nephroureterectomy. This result may be useful in determining adjuvant therapy., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. Iwate Medical University issued approval 2019-083. Animal subjects: All authors have confirmed that this study did not involve animal subjects or tissue. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Kawamura et al.)

Introduction: We aimed to determine whether unfractionated heparin (UH) and low molecular weight heparin (LH) contribute to aberrant carnitine metabolism in patients receiving hemodialysis., Methods: The rate of increase in serum free fatty acids (FFAs) and the ratio of acylcarnitine to free carnitine (AC/FC) from before to after hemodialysis were determined in patients receiving UH and LH. Additionally, the effect of switching patients to UH from LH was examined., Results: AC/FC was significantly higher in the UH group. In addition, serum FFAs in that group increased to 0.825 ± 0.270 after dialysis from 0.172 ± 0.160 before dialysis, showing a positive correlation with AC/FC. Furthermore, AC/FC was observed to be significantly higher in patients who were switched to UH from LH at 3 months after the change., Conclusion: Compared with UH, LH has a lesser effect on lipid metabolism, suggesting that it also has a lesser effect on carnitine metabolism., (© 2023 International Society for Apheresis and Japanese Society for Apheresis.)

Introduction: Secondary eosinophilia due to solid tumors is a rare case. This is the first study to report secondary eosinophilia due to renal cancer in a patient on dialysis., Case Presentation: A 70-year-old man, on long-term hemodialysis was incidentally detected with right renal cancer, and workup performed revealed eosinophilia. Allergic symptoms caused by hemodialysis were initially considered; however, treatment did not lead to any improvement in eosinophilia. Therefore, nephrectomy for renal cancer was performed. The resolution of symptoms and eosinophilia after surgery suggested renal cancer as the cause of eosinophilia., Conclusion: As demonstrated in this patient with dialysis-related renal cancer, eosinophilia associated with solid tumors may be addressed by treating the tumor., Competing Interests: The authors declare no conflict of interest., (© 2024 The Authors. IJU Case Reports published by John Wiley & Sons Australia, Ltd on behalf of Japanese Urological Association.)

Objective: The companion diagnosis for olaparib, a poly (ADP-ribose) polymerase inhibitor for prostate cancer, aims to detect BRCA1/2 gene variants. In clinical practice, the frequency of germline BRCA1/2 variants in patients receiving castration-resistant prostate cancer treatment is unknown. We aimed to evaluate the prevalence of germline BRCA1/2 variants and their relationship to prognosis and treatment efficacy in castration-resistant prostate cancer., Methods: Between June 2021 and 2023, 92 patients receiving castration-resistant prostate cancer treatment were examined for germline BRCA1/2 variants using BRACAnalysis CDx®. Furthermore, the associations between BRCA1/2 pathogenic variants and clinical outcomes were assessed., Results: Of the 92 patients referred for genetic testing, 6 (6.5%) carried germline pathogenic variants in BRCA1/2. The BRCA2 variant was the most frequent (n = 5), followed by BRCA1 variant (n = 1). Among the five variants in BRCA2, the p.Asp427Thrfs*3 variant was identified for the first time in prostate cancer. Overall survival from castration-resistant prostate cancer for patients with BRCA1/2 variants was significantly shorter than for patients without BRCA1/2 variants (P = 0.043). Progression-free survival of androgen receptor signaling inhibitors for patients with BRCA1/2 variants was significantly shorter than for those without (P = 0.003). Progression-free survival of taxane chemotherapy was significantly shorter in patients with BRCA1/2 variants than in those without (P = 0.0149)., Conclusions: In clinical practice, 6.5% of patients treated with castration-resistant prostate cancer carried germline BRCA1/2 pathogenic variants. Japanese castration-resistant prostate cancer patients with germline BRCA1/2 mutants have a poor prognosis and may be less responsive to treatment with androgen receptor signaling inhibitors and taxane-based chemotherapy for castration-resistant prostate cancer., (© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

We evaluated the efficacy and safety of TAS0313, a multi-epitope long peptide vaccine, plus pembrolizumab in post-chemotherapy immune checkpoint inhibitor-naïve patients with locally advanced/metastatic urothelial carcinoma (la/mUC). TAS0313 9 mg was administered subcutaneously followed by pembrolizumab 200 mg on Day 1, and as monotherapy on Day 8 and 15 of Cycles 1 and 2, and Day 1 of subsequent cycles in 21-day cycles. The primary endpoint was the objective response rate (ORR). Secondary endpoints included progression-free survival (PFS), overall survival (OS), and safety. Biomarkers of response were assessed. In 36 patients enrolled, the ORR was 33.3% (complete response: 7 patients; partial response: 5 patients). Median PFS was 5.0 months; 6- and 12-month progression-free rates were 46.4% and 36.5%, respectively. Median OS was not reached; 6-, 12-, and 24-month OS rates were 83.3%, 72.2%, and 55.1%, respectively. In post hoc analysis, patients with a tumor infiltrating CD8+ lymphocyte (CD8+ TIL) count ≥99 and/or programmed cell death ligand 1 (PD-L1) combined positive score (CPS) ≥50 and lymphocyte count >1,380 cells/μL had higher ORRs and prolonged PFS versus patients with a CD8+ TIL count <99, PD-L1 CPS <50, and lymphocyte count ≤1,380 cells/μL. Thirty-four (94.4%) patients receiving combination therapy experienced treatment-related adverse events (AE), with pyrexia (n = 15, 41.7%), injection-site reactions (n = 15, 41.7%), injection-site induration (n = 6, 16.7%), and malaise (n = 6, 16.7%) the most common. No grade ≥3 treatment-related AEs occurred in ≥10% of patients. TAS0313 plus pembrolizumab combination therapy showed promising efficacy and manageable safety in la/mUC. Clinical Trial Registration: JapicCTI-183824., (©2023 The Authors; Published by the American Association for Cancer Research.)

The aim of this study was to evaluate the clinical validity of monitoring urine pellet DNA (upDNA) of bladder cancer (BC) by digital PCR (dPCR) as a biomarker for early recurrence prediction, treatment efficacy evaluation, and no-recurrence corroboration. Tumor panel sequencing was first performed to select patient-unique somatic mutations to monitor both upDNA and circulating tumor DNA (ctDNA) by dPCR. For longitudinal monitoring using upDNA as well as plasma ctDNA, an average of 7.2 (range, 2 to 12) time points per case were performed with the dPCR assay for 32 previously treated and untreated patients with BC. Clinical recurrence based on imaging and urine cytology was compared using upDNA variant allele frequency (VAF) dynamics. A continuous increasing trend of upDNA VAF ≥1% was considered to indicate molecular recurrence. Most (30/32; 93.8%) cases showed at least one traceable somatic mutation. In 5 of 7 cases (71.4%) with clinical recurrence, upDNA VAF >1% was detected 7 to 15 months earlier than the imaging diagnosis. The upDNA VAF remained high after initial treatment for locally recurrent cases. The clinical validity of upDNA monitoring was confirmed with the observation that 26 of 30 cases (86.7%) were traceable. Local recurrences were not indicated by ctDNA alone. The results support the clinical validity of upDNA monitoring in the management of recurrent BC., (Copyright © 2024 Association for Molecular Pathology and American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Objectives: Nocturnal polyuria (NP) is one of the causes of nocturia that impairs quality of life. It is necessary to consider that NP is latent when the initial treatment for nocturia is unsatisfactory. Therefore, it is important to establish a treatment for NP based on the pathophysiology. We have previously reported the relationship between NP and fluctuation in blood pressure. The present study aimed to investigate the association between NP and 24-h blood pressure fluctuations in a multicenter prospective study., Methods: This study included male patients with lower urinary tract symptoms. We categorized the patients into the nonnocturnal polyuria (non-NP) group (≤0.33) and the NP group (>0.33) based on the nocturnal polyuria index from the frequency volume chart. We measured the 24-h diurnal blood pressure and compared the two groups., Results: Among 90 patients, 46 in the non-NP group and 44 in the NP group were included. There was no significant difference in the systolic and diastolic blood pressure during waking time between the two groups; however, the degree of systolic blood pressure reduction during sleep time in the NP group was significantly less than that in the non-NP group (p = 0.039). In the multivariate analysis, systolic BP during sleep was significantly associated with NP (OR 0.970, p = 0.028)., Conclusion: NP is associated with inadequate nocturnal blood pressure reduction in males, suggesting that reduction in nocturnal blood pressure may lead to improvement in nocturia., (© 2023 The Japanese Urological Association.)

Pancreatic injury is a rare, but noted complication of nephrectomy. We report a case involving a 56-year-old man who presented with cT3bN0M0 left locally advanced renal cell carcinoma with an inferior vena cava thrombus. Nephrectomy with thrombectomy was performed given the remarkable shrinkage of the primary tumor and thrombus following lenvatinib plus pembrolizumab administration. The patient developed postoperative pancreatitis associated with unrecognized minor pancreatic injury, which was treated conservatively. To our knowledge, this has been the first case that underwent nephrectomy for RCC with an IVC thrombus after presurgical lenvatinib plus pembrolizumab and received conservative treatment for postoperative pancreatitis., Competing Interests: Conflict of interestThe authors declare that they have no conflict of interest., (© The Author(s) under exclusive licence to The Japan Society of Clinical Oncology 2024. Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.)

Biomarkers that could detect the postoperative recurrence of upper tract urothelial carcinoma (UTUC) have not been established. In this prospective study, we aim to evaluate the utility of individualized circulating tumor DNA (ctDNA) monitoring using digital PCR (dPCR) as a tumor recurrence biomarker for UTUC in the perioperative period. Twenty-three patients who underwent radical nephroureterectomy (RNU) were included. In each patient, whole exome sequencing by next-generation sequencing and TERT promoter sequencing of tumor DNA were carried out. Case-specific gene mutations were selected from sequencing analysis to examine ctDNA by dPCR analysis. We also prospectively collected plasma and urine ctDNA from each patient. The longitudinal variant allele frequencies of ctDNA during the perioperative period were plotted. Case-specific gene mutations were detected in 22 cases (96%) from ctDNA in the preoperative samples. Frequently detected genes were TERT (39%), FGFR3 (26%), TP53 (22%), and HRAS (13%). In all cases, we obtained plasma and urine samples for 241 time points and undertook individualized ctDNA monitoring for 2 years after RNU. Ten patients with intravesical recurrence had case-specific ctDNA detected in urine at the time of recurrence. The mean lead time of urinary ctDNA in intravesical recurrence was 60 days (range, 0-202 days). Two patients with distal metastasis had case-specific ctDNA in plasma at the time of metastasis. In UTUC, tumor-specific gene mutations can be monitored postoperatively as ctDNA in plasma and urine. Individualized ctDNA might be a minimally invasive biomarker for the early detection of postoperative recurrence., (© 2023 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

The progression of prostate cancer (PCa) relies on the activation of the androgen receptor (AR) by androgens. Despite efforts to block this pathway through androgen deprivation therapy, resistance can occur through several mechanisms, including the abnormal activation of AR, resulting in castration-resistant PCa following the introduction of treatment. Mutations, amplifications, and splicing variants in AR-related genes have garnered attention in this regard. Furthermore, recent large-scale next-generation sequencing analysis has revealed the critical roles of AR and AR-related genes, as well as the DNA repair, PI3K, and cell cycle pathways, in the onset and progression of PCa. Moreover, research on epigenomics and microRNA has increasingly become popular; however, it has not translated into the development of effective therapeutic strategies. Additionally, treatments targeting homologous recombination repair mutations and the PI3K/Akt pathway have been developed and are increasingly accessible, and multiple clinical trials have investigated the efficacy of immune checkpoint inhibitors. In this comprehensive review, we outline the status of PCa research in genomics and briefly explore potential future developments in the field of epigenetic modifications and microRNAs.

The prognosis for patients who achieve a pathologic complete response in bladder cancer is excellent, but the association between their prognosis and the tumor microenvironment is unclear. We investigated the tumor immune microenvironment of those with pathological complete response after platinum-based neoadjuvant chemotherapy for cT2-4aN0M0 bladder cancer using multiplex fluorescence immunohistochemistry. Our retrospective study included 12 patients with pathological complete response who underwent radical cystectomy following neoadjuvant chemotherapy for cT2-4aN0M0 muscle-invasive bladder cancer. We assessed the density of several immune cell types in pretreatment and posttreatment tissues via multiplex fluorescence immunohistochemical analysis. The median age was 67 years; 10 patients were male. Nine (75%) and 3 (25%) patients were cT2 and cT3, respectively. The 5-year progression-free and overall survivals were 90% and 100%, respectively. The densities of regulatory T cells (Treg; CD3 + CD4 + FoxP3 + cell) were significantly decreased and almost disappeared in the tumor microenvironment of posttreatment tissue compared with pretreatment tissue. Other immune cells, such as effector T cells or M2 macrophages, were not significantly changed between posttreatment and pretreatment tissues. In pathological complete response, Tregs in the tumor immune microenvironment were significantly decreased after platinum-based chemotherapy for muscle-invasive bladder cancer. The temporary arresting of immune response in the tumor microenvironment may reflect a favorable prognosis due to the decrease of Tregs with tumor shrinkage and improve the host tumor immune response., (© 2024. The Author(s).)

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.

Background: Prostate cancer in the anterior region may be missed on a transrectal systematic biopsy (SBx). Therefore, this study aimed to evaluate the performance of magnetic resonance imaging-transrectal ultrasound (MRI-TRUS) fusion targeted biopsy (TBx) in detecting anterior region cancer in patients with a history of SBxs., Methods: Prostate biopsies were performed in 224 patients after multiparametric MRI, among whom 119 patients with prostate imaging reporting and data system (PI-RADS version 2) scores of 3 to 5 underwent MRI-TRUS fusion TBxs. Afterward, cancer detection rates (CDRs) and TBx-positive core regions were compared by categorizing patients into those with or without a history of SBxs., Results: Total CDR was 68.8% (44/64 cases) in the initial biopsy group (Initial-Bx group) and 47.3% (26/55 cases) in the previous-negative-systematic biopsy group (Pre-Neg-SBx group) ( P  = 0.018). Interestingly, both TBx- and SBx-core positive cases were more common in the Initial-Bx group than in the Pre-Neg-SBx group (Initial-Bx group: 75% [33/44 cases] vs. Pre-Neg-SBx group: 42.3% [11/26 cases], P  = 0.006). However, only TBx-core positive cases were more common in the Pre-Neg-SBx group than in the Initial-Bx group (Initial-Bx group: 11.4% [5/44 cases] vs. Pre-Neg-SBx group: 30.8% [8/26 cases], P  = 0.043). In addition, the proportion of anterior lesions detected by TBx cores was higher in the Pre-Neg-SBx group than in the Initial-Bx group (Initial-Bx group: 26.3% [10/38 cases] vs. Pre-Neg-SBx group: 52.6% [10/19 cases], P  = 0.049)., Conclusion: Using MRI-TRUS fusion TBx in the evaluation of previously negative SBx cases improved the detection rate of anterior lesions, which might have been missed in previous SBxs. Especially in patients with a history of SBxs mpMRI should be performed to screen for anterior lesions., (© 2023 The Asian Pacific Prostate Society. Published by Elsevier B.V.)

Background: Cardiovascular diseases are still highly prevalent after kidney transplantation. However, little is known about the impact of the timing of rejection episodes on cardiovascular disease. The study aimed to analyze the influence of the timing of rejection episodes on cardiovascular events in recipients of living donor kidney transplantation., Methods: We studied 572 living donor kidney transplant recipients from the Michinoku Renal Transplant Network (MRTN), which includes 6 centers in the Tohoku region of Japan. Fine-Gray proportional hazards regression analysis with time-dependent variables was used to assess the effect of rejection episode on cardiovascular events. Recipients were divided into three groups: those without rejection (non-rejection, 370 patients), rejection within 6 months after transplantation (early rejection, 99 patients), and rejection after 6 months (late rejection, 103 patients). The effect of timing on cardiovascular events was evaluated using Fine-Gray proportional hazards regression analysis., Results: During a median follow-up of 77 months, 70 patients experienced cardiovascular events. Rejection episodes were significantly associated with cardiovascular events (hazard ratio [HR]: 2.08, 95% confidence interval [CI]: 1.26-3.43, P = 0.004), along with age and dialysis vintage. The 5-year cumulative incidence of cardiovascular events was significantly higher in the late rejection group than in the early rejection group (15% vs. 3.3%, P = 0.021). However, no significant difference in 5-year cumulative cardiovascular event incidence was observed between the early rejection and non-rejection groups. Late rejection was significantly associated with cardiovascular events (HR: 2.40, 95% CI: 1.38-4.18, P = 0.002), whereas early rejection was not significantly correlated with cardiovascular event risk (HR: 1.18, P = 0.670)., Conclusions: Rejections occurring more than 6 months after transplantation is significantly associated with risk of cardiovascular events., Trial Registration Number: 2019-099-1, date of registration; 3 Dec. 2019, retrospectively registered., (© 2023. The Author(s) under exclusive licence to Italian Society of Nephrology.)

Objectives: To investigate the efficacy of pharmacotherapy for metastatic non-clear cell renal cell carcinoma (nccRCC) in Japanese population., Methods: In this retrospective analysis, we compared the time to treatment failure (TTF) for molecular-targeted agents as first-line therapy, or nivolumab therapy as sequential therapy between ccRCC and nccRCC using the data of Japanese metastatic RCC patients registered in the Michinoku Japan Urological Cancer Study Group database., Results: In total, 511 cases of ccRCC and 77 cases of nccRCC were treated with pharmacotherapy. After excluding the patients who received cytokine therapy, chemotherapy, or others, there were 391 ccRCC patients and 60 nccRCC patients who were treated with tyrosine kinase inhibitors (TKIs), and 7 ccRCC patients and 7 nccRCC patients who were treated with mammalian-target of rapamycin inhibitors (mTORIs). In addition, 132 ccRCC patients and 16 nccRCC patients received nivolumab. There was no significant difference in IMDC risk classification before first-line therapy between ccRCC and nccRCC groups, or in each subgroup within the nccRCC group. TTF for TKIs (161 days, 95% CI: 75-212 days) and mTORIs (21 days, 95% CI: 9-31 days) didn't differ significantly between nccRCC and ccRCC groups (205 days, 95% CI: 174-243 days and 33 days, 95% CI: 8-113 days, respectively). TTF for TKIs was significantly longer than that for mTORIs in nccRCC group (p<0.01). There was no significant difference in TTF between the different TKIs in nccRCC group. In addition, no significant difference in TTF for nivolumab was seen between ccRCC and nccRCC groups., Conclusions: The results showed that the efficacy of molecular-targeted agents as first-line therapy was similar oncological outcomes between metastatic nccRCC and ccRCC in Japanese patients. TKIs may be more effective than mTORIs in metastatic nccRCC patients. Nivolumab administration might also be as effective in nccRCC patients as in ccRCC patients in Japanese population., (© 2023 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Background: The Modified International Metastatic Renal Cell Carcinoma Dataset Consortium model (mIMDC) is a preoperative prognostic model for pT3cN0M0 renal cell carcinoma (RCC). This study aimed to validate the mIMDC and to construct a new model in a localized and locally advanced RCC (LLRCC)., Methods: A database was established (the Michinoku Japan Urological Cancer Study Group database) consisting of 79 patients who were clinically diagnosed with LLRCC (cT3b/c/4NanyM0) and underwent radical nephrectomy from December 2007 to May 2018. Using univariable and multivariable analyses, we retrospectively analyzed disease-free survival (DFS) and overall survival (OS) in this database, constructed a new prognostic model according to these results, and estimated the model fit using c-index on the new and mIMDC models., Results: Independent poorer prognostic factors for both DFS and OS include the following: ≥ 1 Eastern Cooperative Oncology Group performance status, 2.0 mg/dL C-reactive protein, and > upper normal limit of white blood cell count. The median DFS in the favorable (no factor), intermediate (one factor), and poor-risk group (two or three factors) was 76.1, 14.3, and 4.0 months, respectively (P < 0.001). The 3-year OS in the favorable, intermediate, and poor-risk group were 92%, 44%, and 0%, respectively (P < 0.001). The c-indices of the new and mIMDC models were 0.67 and 0.60 for DFS (P = 0.060) and 0.74 and 0.63 for OS (P = 0.012), respectively., Conclusion: The new preoperative prognostic model in LLRCC can be used in patient care and clinical trials., (© 2023. The Author(s) under exclusive licence to Japan Society of Clinical Oncology.)

Introduction: The aim is to clarify the hepatitis C virus (HCV) status of hemodialysis (HD) patients and patient management after HCV elimination., Methods: Questionnaire survey was conducted in Iwate prefecture, Japan from 2016 to 2021., Results: Patients underwent HD was 2944, including 132 anti-HCV antibody-positive patients, with 91 HCV RNA-positive patients. Of the 91 HCV RNA-positive patients, 51 received antiviral treatment. Sustained virological response (SVR) rate was 94%. The patients treated with direct antiviral agents had significantly lower mortality rate than the untreated patients, and no liver-related deaths occurred in patients who achieved SVR or in HCV RNA-negative patients. The HCV RNA-positive prevalence was finally 0.79%. Approximately 40% of the facilities had dedicated beds and dialysis-related items for patients who achieved an SVR., Conclusion: To eliminate HCV in HD facilities, it is necessary to promote HCV RNA testing for anti-HCV antibody-positive patients and to provide antiviral treatment for HCV RNA-positive patients. Additionally, collaboration among hepatologists and HD specialists are essential., (© 2023 The Authors. Therapeutic Apheresis and Dialysis published by John Wiley & Sons Australia, Ltd on behalf of International Society for Apheresis and Japanese Society for Apheresis.)

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.)

A 73-year-old man with renal cell carcinoma underwent a left-sided open radical nephrectomy at our center. The pathological diagnosis was Fuhrman Grade 2, stage pT3a, clear cell renal cell carcinoma. A follow-up computed tomography (CT) scan revealed lung metastases 9 months after the surgery. The patient was started on ipilimumab with nivolumab combination therapy; however, after two cycles of administration, he developed arthralgia and swelling of the knee. Furthermore, he developed diarrhea almost simultaneously, resulting in the interruption of the ipilimumab plus nivolumab treatment. We diagnosed arthritis and colitis with immune-related adverse events (irAE) and initiated steroid therapy with rehabilitation. His condition improved dramatically, and nivolumab treatment could be resumed after 3 months of treatment interruption.

To assess the safety and efficacy of proton beam therapy (PBT) for muscle-invasive bladder cancer (MIBC), we examined the outcomes of 36 patients with MIBC (cT2-4aN0M0) who were enrolled in the Proton-Net prospective registry study and received PBT with concurrent chemotherapy from May 2016 to June 2018. PBT was also compared with X-ray chemoradiotherapy in a systematic review (X-ray (photon) radiotherapy). The radiotherapy consisted of 40-41.4 Gy (relative biological effectiveness (RBE) delivered in 20-23 fractions to the pelvic cavity or the entire bladder using X-rays or proton beams, followed by a boost of 19.8-36.3 Gy (RBE) delivered in 10-14 fractions to all tumor sites in the bladder. Concurrently, radiotherapy was given with intra-arterial or systemic chemotherapy of cisplatin alone or in combination with methotrexate or gemcitabine. Overall survival (OS), progression-free survival (PFS) and local control (LC) rates were 90.8, 71.4 and 84.6%, respectively, after 3 years. Only one case (2.8%) experienced a treatment-related late adverse event of Grade 3 urinary tract obstruction, and no severe gastrointestinal adverse events occurred. According to the findings of the systematic review, the 3-year outcomes of XRT were 57-84.8% in OS, 39-78% in PFS and 51-68% in LC. The weighted mean frequency of adverse events of Grade 3 or higher in the gastrointestinal and genitourinary systems was 6.2 and 2.2%, respectively. More data from long-term follow-up will provide us with the appropriate use of PBT and validate its efficacy for MIBC., (© The Author(s) 2023. Published by Oxford University Press on behalf of The Japanese Radiation Research Society and Japanese Society for Radiation Oncology.)

The feasibility and efficacy of particle beam therapy (PBT) using protons or carbon ions were compared with those of photon-based stereotactic body radiotherapy (SBRT) for primary renal cell carcinoma (RCC) via a systematic review and nationwide registry for PBT (Japanese Society for Radiation Oncology [JASTRO] particle therapy committee). Between July 2016 and May 2019, 20 patients with non-metastatic RCC who were treated at six Japanese institutes (using protons at three, using carbon ions at the other three) were registered in the nationwide database and followed up prospectively. The 20 patients comprised 15 men and had a median age of 67 (range: 57-88) years. The total radiation dose was 66-79.6 Gy (relative biological effectiveness [RBE]). Over a median follow up of 31 months, the 3-year rates of overall survival (OS) and local control (LC) were 100% and 94.4%, respectively. No grade ≥ 3 toxicities were observed. Based on a random effects model, a meta-analysis including the present results revealed 3-year OS rates after SBRT and PBT of 75.3% (95% CI: 57.3-86.6) and 94.3% (95% CI: 86.8-97.6), respectively (P = 0.005), but the difference in LC rates between the two methods was not observed (P = 0.63). PBT is expected to have similar if not better treatment results compared with SBRT for primary renal cancer. In particular, PBT was shown to be effective even for large RCC and could provide a therapeutic option when SBRT is not indicated., (© The Author(s) 2023. Published by Oxford University Press on behalf of The Japanese Radiation Research Society and Japanese Society for Radiation Oncology.)

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.)

It remains unknown whether the early response to vascular endothelial growth factor receptor tyrosine kinase inhibitor (VEGFR-TKI) management in malignancies links to long-term survival. The objective of this study was to investigate the survival rates and predictive factors of early response in patients with metastatic renal cell carcinoma (mRCC) managed by VEGFR-TKIs. From Jan. 2008 to Oct. 2018, 496 patients were treated with VEGFR-TKIs as first-line treatment at the eight Japanese hospitals (Michinoku RCC). Early cessation was defined as VEGFR-TKIs being given up within 3 months after their initiation. The number of patients in early cessation VEGFR-TKIs (Cohort I) was 173 (34.9%), and in long-term use (Cohort II) was 323 (65.1%). The cancer-specific survival (CSS) and overall survival (OS) were better in Cohort II. IMDC Poor-risk was at risk of early cessation of a first-line VEGFR-TKI. Axitinib was the most preferred drug for long-term treatment. On closer examination, both Cohort I and II were divided into two groups, the patients ceased VEGFR-TKI due to adverse events (Group A [67 from Cohort I] and Group C [51 from Cohort II]) and disease progression (Group B [106 from Cohort I] and Group D [272 from Cohort II]). Despite that the cessation was adverse events, CSS and OS in Group A were worse than both Group C and D. Axitinib was administered with the safer profile. IMDC Poor risk was the risk factor for the early disease progression. Managing early adverse events may contribute to a better prognosis in mRCC patients treated VEGFR-TKIs., (© 2022 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Patients with end-stage renal disease (ESRD) or receiving dialysis have a much higher risk for renal cell carcinoma (RCC), but carcinogenic mechanisms and genomic features remain little explored and undefined. This study's goal was to identify the genomic features of ESRD RCC and characterize them for associations with tumor histology and dialysis exposure. In this study, we obtained 33 RCCs, with various histological subtypes, that developed in ESRD patients receiving dialysis and performed whole-genome sequencing and transcriptome analyses. Driver events, copy-number alteration (CNA) analysis and mutational signature profiling were performed using an analysis pipeline that integrated data from germline and somatic SNVs, Indels and structural variants as well as CNAs, while transcriptome data were analyzed for differentially expressed genes and through gene set enrichment analysis. ESRD related clear cell RCCs' driver genes and mutations mirrored those in sporadic ccRCCs. Longer dialysis periods significantly correlated with a rare mutational signature SBS23, whose etiology is unknown, and increased mitochondrial copy number. All acquired cystic disease (ACD)-RCCs, which developed specifically in ESRD patients, showed chromosome 16q amplification. Gene expression analysis suggests similarity between certain ACD-RCCs and papillary RCCs and in TCGA papillary RCCs with chromosome 16 gain identified enrichment for genes related to DNA repair, as well as pathways related to reactive oxygen species, oxidative phosphorylation and targets of Myc. This analysis suggests that ESRD or dialysis could induce types of cellular stress that impact some specific types of genomic damage leading to oncogenesis., (© The Author(s) 2022. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

A male patient in his 70s was referred to our hospital with the chief complaint of anorexia. Abdominal computed tomography (CT) showed a 20 cm large homogeneous mass in the retroperitoneum, and contrast-enhanced CT revealed uniform staining throughout the inside of the mass. Soluble interleukin-2 receptor and lactate dehydrogenase tumor markers were elevated. Hence, malignant lymphoma was suspected, and ultrasonography-guided biopsy was performed. Histopathological findings showed large lymphocytes with poorly differentiated cytoplasmic nucleoli and positivity for CD20 and CD79a via immunohistochemical analysis, which was consistent with diffuse large B-cell lymphoma. The patient received R-THP-COP therapy which consisted of rituximab, pirarubicin, cyclophosphamide, vincristine and prednisolone. After four chemotherapy courses, a partial response according to the the response evaluation criteria in solid tumors was obtained. The patient was discharged with no signs of recurrence.

Human leukocyte antigen class I (HLA-I) genotypes are suggested to influence the cancer response to checkpoint blockade immunotherapy. This study assessed the impact of germline HLA genotypes on clinical outcomes in patients with chemoresistant advanced urothelial cancer (UC) treated with pembrolizumab. Zygosity, supertypes, evolutionary divergency, and specific alleles of germline HLA-I and -II were evaluated using the Luminex technique in 108 patients with chemoresistant metastatic or locally advanced UC treated with pembrolizumab. Among the 108 patients, 69 died and 83 showed radiographic progression during follow-up. Homozygous for at least one HLA-I locus, absence of the HLA-A03 supertype, and high HLA-I evolutionary divergence were associated with a radiographic response, but were not associated with survival outcomes. Patients with the HLA-DQB1*03:01 allele had significantly lower disease control rates than patients without the allele (17.4% vs. 53.8%, p = 0.002); its presence was also an independent risk factor for progressive disease (hazard ratio 4.35, 95% confidence interval 1.03-18.46). Furthermore, patients with the HLA-DQB1*03:01 allele had significantly worse progression-free survival than patients without the allele (median progression-free survival 3.1 vs. 4.8 months, p = 0.035). There was no significant relationship between any HLA status and the incidence of severe adverse events. Several germline HLA genotypes, especially HLA-DQB1*03:01, may be associated with radiographic progression. However, their impact on treatment response is limited, and germline HLA genotypes was not independently associated with survival outcomes. Further prospective studies are needed to confirm the relationship between germline HLA genotypes and clinical outcomes in patients with chemoresistant advanced UC treated with pembrolizumab., (© 2022 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Objective: This study aimed to identify patterns of early response to nivolumab and ipilimumab combination therapy (Nivo+Ipi) in primary and metastatic sites of advanced renal cell carcinoma (RCC)., Method: RCC patients treated with Nivo+Ipi or tyrosine-kinase inhibitors (TKIs) as first-line therapy were included. To exclude selection bias due to patient characteristics, baseline clinical data was adjusted by inverse probability of treatment weighting (IPTW). Overall response rate (ORR) and lesional response rates (LRR) in primary and metastatic sites were determined by measuring tumor diameters on serial CT images according to Response Evaluation Criteria in Solid Tumors, version 1.1., Results: 33 patients were treated with Nivo+Ipi and 39 with TKIs as first-line therapy. After IPTW-adjusted analysis, ORR during the first 24 weeks of treatment was significantly higher in Nivo+Ipi group than in TKIs group (45.5% versus 21.7%, p < 0.01). LRR of the primary tumor tended to be higher in Nivo+Ipi group than in TKI group (14.8% versus 4.4%, p = 0.06). Mean LRR of all metastatic sites was not significantly different between the two groups, but tumor shrinkage rate of lung metastasis was significantly higher in Nivo+Ipi group than in TKIs group (68.5% versus -12.7%, p < 0.01). Univariate and multivariate analyses identified lung metastasis as the independent factor associated with prolonged progression-free survival and with higher ORR., Conclusion: Our study found that lung metastasis of advanced RCC exhibited early response to Nivo+Ipi therapy. Further studies are warranted to verify whether site-specific early response predicts overall survival benefit in advanced RCC patients treated with Nivo+Ipi., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: Nivolumab plus ipilimumab combination therapy is one of the standard therapies for untreated renal cell carcinoma patients with an International Metastatic Renal Cell Carcinoma Database Consortium intermediate/poor risk. We have previously reported the 1-year analysis results of the effectiveness and safety of nivolumab plus ipilimumab combination therapy in the real-world setting in Japan. Here, we report the effectiveness of nivolumab plus ipilimumab combination therapy and of second-line therapy, using 2-year analysis., Methods: This retrospective observational study enrolled Japanese patients with previously untreated metastatic renal cell carcinoma who initiated nivolumab plus ipilimumab combination therapy between August 2018 and January 2019. Data were collected from patients' medical records at baseline and at 3 months, 1 year and 2 years after the last enrollment., Results: Of the 45 patients enrolled, 10 patients (22.2%) each had non-clear cell renal cell carcinoma and Eastern Cooperative Oncology Group performance status ≥2 at baseline. Median follow-up period was 24.0 months; objective response rate was 41.5%, with 6 patients achieving complete response; median progression-free survival was 17.8 months and 24-month progression-free survival and overall survival rates were 41.6 and 59.1%, respectively. Second-line therapy achieved an objective response rate of 20%; median progression-free survival was 9.8 months. Median progression-free survival 2 was 26.4 months., Conclusions: The effectiveness of nivolumab plus ipilimumab combination therapy at 2-year analysis in the real-world setting in Japan was comparable to that reported in CheckMate 214. The current analysis also demonstrated the effectiveness of second-line therapy after nivolumab plus ipilimumab combination therapy., (© The Author(s) 2022. Published by Oxford University Press.)

Objectives: This study aims to investigate whether a cribriform pattern on prostate biopsy may be a factor in suspicion of intraductal carcinoma of the prostate after radical prostatectomy., Methods: This retrospective study assessed 100 men who underwent prostatectomy from 2015 to 2019. Participants were grouped as 76 patients with Gleason pattern 4 and 24 patients without this pattern. All 100 participants underwent retrograde radical prostatectomy and limited lymph node dissection. The same pathologist evaluated all specimens. The cribriform pattern was evaluated with haematoxylin and eosin counterstaining, and intraductal carcinoma of the prostate was evaluated with immunohistochemical analysis of cytokeratin 34βE12., Results: Patients with intraductal carcinoma of the prostate on immunohistochemical analysis showed a significant tendency to relapse in the postoperative period, and those with the cribriform pattern on biopsy had a significant recurrence rate. In univariate and multivariate analyses, intraductal carcinoma of the prostate confirmed in biopsy tissue was an independent predictor of biochemical recurrence after prostatectomy. The rate of intraductal carcinoma of the prostate confirmation was 28% of cases with a cribriform pattern in biopsy tissue, which was increased to 62% in prostatectomy tissues., Conclusion: The cribriform pattern in the biopsy tissue may be a predictor for intraductal carcinoma of the prostate., Competing Interests: We declare that we have no conflicts of interest.Approval of the research protocol by an Institutional Reviewer Board and the approval number: R2‐24. Informed consent: NA. Registry and the registration no. of the study/trial: NA. Animal studies: NA., (© 2022 The Authors. BJUI Compass published by John Wiley & Sons Ltd on behalf of BJU International Company.)