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Background: Nivolumab has been approved for treating ≥ 10 cancer types. However, there is limited information on the incidence of rare, but potentially serious, treatment-related adverse events (TRAEs), as well as notable TRAEs in patients with certain medical disorders or older patients in Japan. Methods: We performed pooled analyses of data from published post-marketing surveillance in Japan of nivolumab monotherapy for patients with malignant melanoma, non-small cell lung cancer, renal cell carcinoma, head and neck cancer, and gastric cancer to determine the frequencies of 20 categories of TRAEs of special interest overall and in patient groups with higher perceived safety risks (history of autoimmune disease, interstitial lung disease, tuberculosis, or hepatitis B/C; patients vaccinated during nivolumab treatment; and older patients [≥ 75 years]). Results: The overall population comprised 7421 patients treated with nivolumab. TRAEs were reported in 49.1% of patients, with grade ≥ 3 TRAEs in 16.7%. Endocrine disorders (14.4%), hepatobiliary disorders (10.9%), and interstitial lung disease (7.0%) were the three most common categories (any grade). The incidences of rare TRAEs with high risk of becoming serious, which occurred in < 1% of patients, were consistent with those in previous reports. The frequencies of TRAEs were not markedly increased in the specified patient groups relative to the overall population. Conclusion: To our knowledge, this is the largest study examining the safety of nivolumab-treated patients in real-world clinical practice including rare but potentially serious TRAEs. We found no new signals in the safety of nivolumab among the patient groups relative to the overall population, and no additional safety measures are required in these groups. Trial registration UMIN000048892 (overall analysis), JapicCTI-163272 (melanoma), Japic-163271 (non-small cell lung cancer), JapicCTI-184071 (head and neck cancer), JapicCTI-184070 (gastric cancer), and JapicCTI-184069 (renal cell cancer). [ABSTRACT FROM AUTHOR]

Objective: To achieve patient‐centricity in metastatic renal cell carcinoma (mRCC) treatment, it is essential to clarify the differences in perspectives between patients and physicians. This cross‐sectional analysis of a web survey aimed to clarify the differences in expectations and concerns between mRCC patients and physicians regarding systemic mRCC therapy in Japan. Methods: Surveys from 83 patients and 165 physicians were analyzed. Results: The top three most significant differences in expectations of systemic therapy between patients and physicians (patient‐based physician value) were "Chance of achieving treatment‐free status" (−30.1%, p < 0.001), "Longer survival" (+25.8%, p < 0.001), and "Chance of eliminating all evidence of disease" (−25.6%, p < 0.001). The top three most significant differences in concerns for systemic therapy between patients and physicians (patient‐based physician value) were "Lack of efficacy" (+36.1%, p < 0.001), "Lack of knowledge of treatment" (−28.2%, p < 0.001), and "Daily activities affected by side effects" (+22.3%, p < 0.001). Diarrhea, fatigue/malaise, and nausea/vomiting were patients' most distressing adverse events; 50.6% of patients had difficulty telling their physicians about adverse events such as fatigue, anxiety, and depression. Conclusions: This study demonstrated a gap between patients with mRCC and physicians in their expectations and concerns for systemic therapy. Japanese patients with mRCC suffer from a number of adverse events, some of which are not shared with physicians. This study highlights the importance of communicating well with patients in clinical practice to achieve patient‐centricity in systemic treatment for mRCC. [ABSTRACT FROM AUTHOR]

Simple Summary: We investigated financial toxicity in Japanese patients with metastatic renal cell carcinoma using the COST tool. Despite universal coverage, patients in Japan had similar levels of financial toxicity as in other countries. There was a positive correlation between the FACT-G total score and the COST score. Age < 65 years and not having private health insurance were associated with higher financial toxicity. Information on the financial toxicity experienced by Japanese patients with metastatic renal cell carcinoma (mRCC) is lacking, even though Japan has its own unique public health insurance system. Thus, a web-based survey was conducted to evaluate the financial toxicity experienced by Japanese mRCC patients using the COmprehensive Score for financial Toxicity (COST) tool. This study enrolled Japanese patients who underwent, or were undergoing, systemic therapy for mRCC. The outcomes evaluated were the distribution of COST scores, the correlation between COST and quality of life (QOL) assessed by the Functional Assessment of Cancer Therapy-General (FACT-G) scale, and demographic factors associated with financial toxicity. The median (range) COST score was 19.0 (3.0–36.0). The Pearson correlation coefficient for COST and FACT-G total scores was 0.40. Univariate analysis revealed that not having private health insurance and lower household income per year were significantly associated with lower COST scores. Multivariate analyses showed that age < 65 years and not having private health insurance were significantly associated with lower COST scores. This study revealed that Japanese mRCC patients experience adverse financial impacts even under the universal health insurance coverage system available in Japan, and financial toxicity negatively affects their QOL. [ABSTRACT FROM AUTHOR]

Purpose: Our study aimed to compare the surgical outcomes of robot-assisted partial nephrectomy (RAPN) between younger and older patients after adjusting for their background differences. We particularly assessed RAPN outcomes and safety in older patients. Methods: We retrospectively evaluated 559 patients clinically diagnosed with T1 renal cell carcinoma (RCC) and treated with RAPN between 2013 and 2022 at five institutions in Japan. The patients were classified into two groups according to their age during surgery (younger group: < 75 years, older group: ≥ 75 years). Propensity score matching (PSM) was performed to adjust for the differences in the backgrounds between younger and older patients, and surgical outcomes were compared. Results: Among the 559 patients, 422 (75.5%) and 137 (24.5%) were classified into the younger and older groups, respectively; 204 and 102 patients from the younger and older groups were matched according to PSM, respectively. Subsequently, patient characteristics other than age were not significantly different between the two groups. In the matched cohort, the older group had more patients with major complications (younger, 3.0%; older, 8.8%; P = 0.045). Conclusion: Surgical outcomes of RAPN in older patients with RCC were comparable with those in younger patients, although older patients experiencedsignificantly more complications than younger patients. These results suggest the need for further detailed preoperative evaluation and appropriate postoperative management in older patients receiving RAPN. [ABSTRACT FROM AUTHOR]

Objectives: In the phase 3 JAVELIN Renal 101 trial in patients with advanced renal cell carcinoma (aRCC), objective response rate (ORR) and progression‐free survival (PFS) were significantly improved in patients treated with first‐line avelumab plus axitinib vs sunitinib. Here we evaluate real‐world outcomes with first‐line avelumab plus axitinib in Japanese patients with aRCC. Methods: In this multicenter, noninterventional, retrospective study, clinical data from patients with aRCC treated with first‐line avelumab plus axitinib between December 2019 and December 2020 in Japan were reviewed. Endpoints included ORR and PFS per investigator assessment, and time to treatment discontinuation (TTD). Results: Data from 48 patients (median age, 69 years) from 12 sites were analyzed. Median follow‐up was 10.4 months (range, 2.6–16.5), and median duration of treatment was 7.4 months (range, 0.5–16.5). International Metastatic RCC Database Consortium risk category was favorable, intermediate, or poor in 16.7%, 54.2%, and 29.2% of patients, respectively. The ORR was 48.8% (95% CI, 33.3%–64.5%), including complete response in 3/43 patients (7.0%). Thirteen patients (27.1%) had disease progression or died, and median PFS was 15.3 months (95% CI, 9.7 months – not estimable). At data cutoff, 24 patients (50.0%) were still receiving avelumab plus axitinib, and median TTD was 15.2 months (95% CI, 7.4 months – not estimable). Three patients (6.3%) received high‐dose corticosteroid treatment for immune‐related adverse events, and 8 (16.7%) received treatment for infusion‐related reactions. Conclusions: We report the first real‐world evidence of the effectiveness and tolerability of first‐line avelumab plus axitinib in Japanese patients with aRCC. Results were comparable with the JAVELIN Renal 101 trial. [ABSTRACT FROM AUTHOR]

Objectives: When primary treatment has been inadequate, nivolumab and axitinib are often used as a secondary treatments for patients with metastatic renal cell carcinoma (mRCC). However, there have been few reports comparing the efficacy and safety of these drugs. Methods: We retrospectively investigated 58 patients treated with nivolumab and 57 patients treated with axitinib as secondary treatment between April 2013 and December 2019. We then assessed the clinical efficacy and safety of the treatments in both groups. Results: The most common primary therapy was sunitinib (61.7%). Both nivolumab and axitinib groups showed no significant differences in terms of the objective response rate and disease control rate (p = 0.280 and p = 0.518, respectively). Importantly, progression‐free survival (PFS) and overall survival (OS) seemed to be similar in patients treated with nivolumab and axitinib (p = 0.527 and p = 0.266, respectively), irrespective of the objective response to primary therapy. Furthermore, a Cox proportional hazards model showed that pretreatment Karnofsky Performance Status was significantly associated with PFS and OS. Although the incidence of adverse events was significantly higher in the patients treated with axitinib, there was no significant difference in time to treatment failure between the two groups. Conclusions: Nivolumab and axitinib showed similar clinical benefits as secondary treatment in patients with mRCC; thus, they should be an option in sequential therapy following treatment with tyrosine kinase inhibitors (TKIs). Future studies and feasible therapeutic biomarkers would help predict the clinical response to TKIs or immune checkpoint inhibitors in patients with mRCC. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Although five immune‐oncologic‐drug‐based combination therapies, such as ipilimumab plus nivolumab, avelumab plus axitinib, pembrolizumab plus axitinib, nivolumab plus cabozantinib, and pembrolizumab plus lenvatinib, have been approved for advanced renal cell carcinoma (RCC) in Japan, the optimal therapy for advanced RCC has not been determined. Without head‐to‐head comparison, several network meta‐analyses using phase 3 clinical trials presented the highest likelihood of maximal overall survival, progression‐free survival, and objective response rate according to several categories such as the International Metastatic Renal Cell Carcinoma Database Consortium risk group, programmed cell death 1‐ligand 1 expression, sarcomatoid features, or the safety profile of treatment‐related adverse events; however, they did not include the results of additional long‐term follow‐up data in each clinical trial. In the real world, advanced RCC treatment depends on several factors, such as age, comorbidity, tumor burden, or the presence of symptoms that affect daily life. To relieve tumor‐related symptoms, tumor burden reduction is required, which may lead to the use of therapies with high response rates and low risk of disease progression. Moreover, patients with comorbidities, such as uncontrolled diabetes, are required to avoid steroid therapy for adverse events, which may necessitate the use of therapies with a low incidence of adverse events that are needed for high‐dose steroids or permanent steroid replacement therapy. Moreover, novel drugs, such as the hypoxia‐inducible factor 2a inhibitor (belzutifan) or immunostimulatory interleukin‐2 cytokine prodrug (bempegaldesleukin) have been developed, and phase 3 clinical trials of combination therapy using these drugs for treatment‐naïve advanced RCC are ongoing. Further development of systemic therapies for advanced RCC is required. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

This document is an editorial comment published in the International Journal of Urology. It discusses the need for more data on the therapeutic benefits of third-line therapy, specifically with the use of EV, in real-world patients with advanced urothelial carcinoma (UC) in Japan. The authors state that the present data increase our knowledge about real-world practices regarding subsequent systemic therapy in Japanese patients with advanced UC. The authors are affiliated with the Department of Urology at Tokyo Women's Medical University in Tokyo, Japan. [Extracted from the article]

A multicenter retrospective study was conducted to evaluate the efficacy and safety of cabozantinib in patients with advanced or metastatic renal cell carcinoma (mRCC). We enrolled 53 patients with mRCC who received cabozantinib at eight institutions in Japan. The primary endpoint was overall survival (OS). The secondary endpoints were objective response rate (ORR), disease control rate (DCR), and progression-free survival (PFS). In addition, we analyzed prognostic factors in patients with mRCC treated with cabozantinib. The median follow-up period was 8 months, and the median OS was 20.0 months. The ORR and DCR were 39.6% and 83.0%, respectively. The median PFS was 11.0 months. PFS was significantly shorter in patients previously treated with at least two tyrosine kinase inhibitors and in those with C-reactive protein (CRP) ≥ 1.27 mg/dL (p = 0.021 and p = 0.029, respectively). Adverse events of any grade and grades ≥3 occurred in 42 (79.2%) and 10 (18.9%) patients, respectively. Cabozantinib is a useful treatment option for patients with mRCC and may benefit from earlier use. In this study, CRP ≥ 1.27 mg/dL is a poor prognostic factor in patients treated with cabozantinib, and careful follow-up may be required in treating patients with high CRP. [ABSTRACT FROM AUTHOR]

Background: The association between the combination of platelet count and neutrophil-lymphocyte ratio (COP-NLR) at the time of adverse events during sunitinib treatment and prognosis is unclear, and prognostic models combining the prognostic factors of sunitinib have not been well studied. Thus, we developed a prognostic model that includes the COP-NLR to predict the prognosis of patients with metastatic renal cell carcinoma (mRCC) treated with sunitinib.Methods: We performed a retrospective cohort study of 102 patients treated with sunitinib for mRCC between 2008 and 2020 in three hospitals associated with Showa University, Japan. The primary outcome was overall survival (OS). The collected data included baseline patient characteristics, adverse events, laboratory values, and COP-NLR scores within the first 6 weeks of sunitinib treatment. Prognostic factors of OS were analyzed using the Cox proportional hazards model. The integer score was derived from the beta-coefficient (β) of these factors and was divided into three groups. The survival curves were visualized using the Kaplan-Meier method and estimated using a log-rank test.Results: The median OS was 32.3 months. Multivariable analysis showed that the number of metastatic sites, Memorial Sloan Kettering Cancer Center risk group, number of metastases, non-hypertension, modified Glasgow Prognostic Score, and 6-week COP-NLR were significantly associated with OS. A higher 6-week COP-NLR was significantly associated with a shorter OS (p < 0.001). The β values of the five factors for OS were scored (non-hypertension, mGPS, and 6-week COP-NLR = 1 point; number of metastatic sites = 2 points; MSKCC risk group = 3 points) and patients divided into three groups (≤ 1, 2-3, and ≥ 4). The low-risk (≤ 1) group had significantly longer OS than the high-risk (≥ 4) group (median OS: 99.0 vs. 6.2 months, p < 0.001).Conclusions: This study showed that the COP-NLR within the first 6 weeks of sunitinib treatment had a greater impact on OS than the COP-NLR at the start of sunitinib treatment. The developed prognostic model for OS, including the 6-week COP-NLR, will be useful in decision-making to continue sunitinib in the early treatment stage of patients with mRCC. [ABSTRACT FROM AUTHOR]

Background: In metastatic renal-cell carcinoma (mRCC), recent clinical trials have shown efficacy of first-line combination therapy, as evidenced by better clinical outcome over target therapy. However, there are insufficient real-world evidences in mRCC patients in Japan. Methods: We performed a multicenter retrospective study of 72 mRCC patients who received nivolumab plus ipilimumab as first-line treatment between September 2018 and July 2021. Patient's characteristics, clinical outcomes and safety were retrospectively reviewed. We analyzed overall response rate (ORR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS) in patients treated with combination therapy. Results: Of all patients, the median age was 70 years (range, 36–86) and the major type of histology was clear cell RCC (n = 55; 76.4%). Progressive disease (n = 25; 34.8%) and irAEs (n = 22; 30.6%) were the most common causes for discontinuing treatment. Median PFS and OS seemed similar between patients who discontinued treatment because of irAEs and for patients who did not (p = 0.360 and p = 0.069, respectively). Importantly, for patients with synchronous metastatic disease at diagnosis (n = 56), nephrectomy before initiating nivolumab plus ipilimumab had a significantly positive impact on better OS when compared to that in patients without nephrectomy (p = 0.028). Conclusion: This study confirms efficacy and safety of nivolumab plus ipilimumab for mRCC patients in real-world settings. Furthermore, nivolumab plus ipilimumab was associated with a better outcome in patients who had undergone nephrectomy at diagnosis for synchronous mRCC. [ABSTRACT FROM AUTHOR]

Objectives: Robot‐assisted partial nephrectomy is widely performed for small renal masses, achieving excellent perioperative and intermediate oncological outcomes. However, long‐term oncological, functional, and quality of life outcomes after robot‐assisted partial nephrectomy remain unclear. In this study, we aimed to evaluate quality of life at 1 year and oncological and functional outcomes of robot‐assisted partial nephrectomy after a minimum follow‐up of 5 years. Methods: Personal, perioperative, postoperative, functional, oncological, and quality of life data were evaluated. The EQ‐5D‐5L tool, which incorporates health profiles and a EuroQol Visual Analog Scale, was used to assess quality of life preoperatively and 365 days postoperatively. Regarding oncological and functional outcomes, overall survival, recurrence‐free survival, and changes in estimated glomerular filtration rate were calculated. Results: There were few changes in levels between the two time points for all EQ‐5D dimensions. The mean change in EQ‐5D‐5L was 0.020 (95% confidence interval 0.006–0.033, P = 0.006), and in EuroQol Visual Analog Scale score 4.60 (95% confidence interval 2.17–7.02, P = 0.0003). Overall and recurrence‐free survival 5 years after robot‐assisted partial nephrectomy were 97.9% and 92.8%, respectively. After an early postoperative decrease, the estimated glomerular filtration rate remained stable over time. Conclusions: Robot‐assisted partial nephrectomy in patients with a T1 renal tumor is safe, feasible, and effective from the perspective of quality of life and survival, even after 5 years. When making treatment decisions, perioperative and quality of life outcomes should be considered together with long‐term oncological outcomes. [ABSTRACT FROM AUTHOR]

Objective: To clarify the frequency of deficient mismatch repair (dMMR) in Japanese ovarian cancer patients, we examined microsatellite instability (MSI) status and immunohistochemistry (IHC) subtypes, including endometrioid carcinoma (EMC), clear cell carcinoma (CCC), or a mixture of both (Mix). Methods: We registered 390 patients who were diagnosed with EMC/CCC/Mix between 2006 and 2015 and treated at seven participating facilities. For 339 patients confirmed eligible by the Central Pathological Review Board, MSI, IHC, and MutL homolog 1 methylation analyses were conducted. The tissues of patients with Lynch syndrome (LS)-related cancer histories, such as colorectal and endometrial cancer, were also investigated. Results: MSI-high (MSI-H) status was observed in 2/217 CCC (0.9%), 10/115 EMC (8.7%), and 1/4 Mix (25%). Additionally, loss of MMR protein expression (LoE-MMR) was observed in 5/219 (2.3%), 16/115 (14.0%), and 1/4 (25%) patients with CCC, EMC, and Mix, respectively. Both MSI-H and LoE-MMR were found significantly more often in EMC (p<0.001). The median (range) ages of patients with MMR expression and LoE-MMR were 54 (30-90) and 46 (22-76) (p=0.002), respectively. In the multivariate analysis, advanced stage and histological type were identified as prognostic factors. Conclusion: The dMMR rate for EMC/CCC was similar to that reported in Western countries. In Japan, it is assumed that the dMMR frequency is higher because of the increased proportion of CCC. [ABSTRACT FROM AUTHOR]

Summary: What is known and objectives: As for adverse events (AEs) caused by everolimus, findings from clinical trials and post‐marketing surveillance have reported interstitial lung disease, hyperglycaemia, cardiovascular disease, etc. However, these reports are limited to incidence, and detailed studies on the risk of occurrence, time to onset and post‐event clinical outcomes are only related to hyperglycaemia. The purpose of this study was to perform a comprehensive analysis of adverse events during everolimus therapy in patients with renal cell carcinoma (RCC) using the Japanese Adverse Event Report database. Methods: Data reported between April 2004 and June 2021 in the Japanese Adverse Drug Event Report database were extracted for use. The reported odds ratio, time to onset and post‐event course were analysed for the top 30 adverse events reported. Results and discussion: Among the top 30 adverse events, 23 adverse event signals were detected and classified into seven categories: lung‐related AEs, haematological‐related AEs, cancer progression, blood glucose‐related AEs, hepatic‐related AEs, renal‐related AEs and others. The lung‐related adverse events category was the most common, and the proportion of fatal outcomes after the occurrence of two adverse events related to infectious pneumonia was more than 10%. What is new and conclusion: A comprehensive survey of adverse events associated with everolimus administration using the pharmacovigilance database revealed that pulmonary and haematological AEs are frequently reported. The results suggest that attention should be paid to the occurrence of lung disorders because they may lead to fatal outcomes. [ABSTRACT FROM AUTHOR]

Simple Summary: The drug sunitinib is used in metastatic renal cell carcinoma, but patients respond very differently to this drug. To better tailor sunitinib treatment to the individual patient, clinically useful markers are needed. We explored the DNA of patients with metastatic renal cell cancer to detect variations that determine how a patient would respond to sunitinib treatment. We investigated >8 million genetic variants in large patient cohorts from Europe (n = 550) and Japan (n = 204) and found novel genetic variants in PDLIM3 and DSCAM that are related to survival in sunitinib-treated patients. The mechanistic role of these variants in the action of sunitinib needs to be further explored to define its clinical potential. Our findings are a major step towards achieving personalized treatment for patients with metastatic renal cell carcinoma. Individual response to sunitinib in metastatic renal cell carcinoma (mRCC) patients is highly variable. Earlier, sunitinib outcome was related to single nucleotide polymorphisms (SNPs) in CYP3A5 and ABCB1. Our aim is to provide novel insights into biological mechanisms underlying sunitinib action. We included mRCC patients from the European EuroTARGET consortium (n = 550) and the RIKEN cohort in Japan (n = 204) which were analysed separately and in a meta-analysis of genome-wide association studies (GWAS). SNPs were tested for association with progression-free survival (PFS) and overall survival (OS) using Cox regression. Summary statistics were combined using a fixed effect meta-analysis. SNP rs28520013 in PDLIM3 and the correlated SNPs rs2205096 and rs111356738 both in DSCAM, showed genome-wide significance (p < 5 × 10−8) with PFS and OS in the meta-analysis. The variant T-allele of rs28520013 associated with an inferior PFS of 5.1 months compared to 12.5 months in non-carriers (p = 4.02 × 10−10, HR = 7.26). T-allele carriers of rs28520013 showed an inferior OS of 6.9 months versus 30.2 months in non-carriers (p = 1.62 × 10−8, HR = 5.96). In this GWAS we identified novel genetic variants in PDLIM3 and DSCAM that impact PFS and OS in mRCC patients receiving sunitinib. The underlying link between the identified genes and the molecular mechanisms of sunitinib action needs to be elucidated. [ABSTRACT FROM AUTHOR]

Background: This all-case post-marketing surveillance (PMS) evaluated the real-world safety and effectiveness of nivolumab monotherapy in Japanese patients with un-resectable or metastatic renal cell carcinoma (RCC). Methods: This multicenter, open-label, non-interventional, observational PMS study (registered from August 2016 to January 2017) was conducted in patients who were newly initiated on nivolumab monotherapy. Assessments included treatment-related adverse events (TRAEs) of special interest, patient characteristics affecting safety, and effectiveness over 12 months. Results: Overall, 580 patients were enrolled; 555 and 554 patients comprised the safety and effectiveness analysis sets, respectively. The median (range) age of the population was 66 (14–90) years. Nivolumab was initiated as 1st-, 2nd-, and ≥ 3rd-line treatment in 0.2%, 42.0%, and 57.8% of patients, respectively. TRAEs were reported in 275 (49.5%) patients. The most common TRAEs of special interest included thyroid dysfunction (9.5%), hepatic dysfunction (8.6%), and interstitial lung disease (6.7%). The incidence of TRAEs was significantly higher in elderly patients (≥ 65 vs < 65 years; ≥ 75 vs < 75 years); patients with lower C-reactive protein levels (< 5 vs ≥ 5 mg/dL); and patients with vs without a past medical history, including hepatic, thyroid, and autoimmune diseases. The 6- and 12-month survival rates were 71.8% and 57.9%, respectively. Conclusion: The safety profile of nivolumab monotherapy in Japanese patients with advanced RCC was similar to that in the phase 3 CheckMate 025 trial. No new safety signals were observed in this study. [ABSTRACT FROM AUTHOR]

Background and objectives: This study aimed to evaluate the association between warm ischemic time (WIT) and postoperative renal function using Trifecta achievement in patients with renal cell carcinoma (RCC) who underwent robotic (RAPN) or laparoscopic partial nephrectomy (LPN). Materials and Methods: We conducted a retrospective multicenter cohort study of patients with RCC who underwent RAPN (RAPN group) or LPN (LPN group) at three institutions in Japan between March 2012 and October 2021. The primary endpoints were the rate of trifecta achievement in both surgical techniques and the association between WIT and recovery of postoperative renal function surgical outcomes. Results: The rate of trifecta achievement was significantly lower in patients with LPN than in those with RAPN (p < 0.001). WIT ≥ 25 min were 18 patients (18%) in the RAPN group and 89 (52.7%) in the LPN group. The postoperative estimated glomerular filtration rate (eGFR) was almost the same. However, 13 patients (7.7%) had a decreased in eGFR ≥ 15% at 3 months after LPN compared with the preoperative eGFR. Conclusions: The rate of trifecta achievement in the RAPN group was significantly higher than that in the LPN group. However, eGFR was identified as relatively better preserved after PN in both groups. [ABSTRACT FROM AUTHOR]

The incidence of uterine corpus cancer has been increasing globally due to increase in obesity. However, a detailed analysis of long‐term epidemiological trends of corpus cancer in Japan, where obesity is relatively minimal, has not been conducted. In this retrospective, population‐based study using the Osaka Cancer Registry, we analyzed 15 255 cases of corpus neoplasia registered between 1977 and 2016. We determined the age‐standardized incidence, mortality, relative survival and conditional survival rates, and the treatment trends for corpus cancer over the last 40 years in Japan. The age‐standardized incidence rate of corpus neoplasia increased sharply in 2000‐2011 (APC = 9.9, 95% CI: 8.4‐11.3), whereas the mortality rate trended to a much more modest increase (APC = 3.3, 95% CI: 2.7‐3.8). Compared to 1977‐2000, 10‐year survival rates for post‐2000 cases of localized and regional corpus cancers significantly improved (from 87.7% [95% CI: 85.8‐89.4] to 94.2% [95% CI: 92.7‐95.7] and from 47.5% [95% CI: 43.3‐51.6] to 64.4% [95% CI: 61.0‐67.6], respectively). This was largely associated with the significant increase in the percentage of localized and regional patients who received chemotherapy instead of radiation as an adjuvant therapy combined to surgery (P <.001 for both). We found that each histological type (endometrioid carcinoma, serous carcinoma, clear cell carcinoma and carcinosarcoma) has different characteristics of trend of age‐standardized incidence rate, relative survival and distribution of extent of disease. In endometrioid carcinoma, the age‐standardized incidence rate increased consistently after 1990, but the rate of increase was decreasing after 1997. What's new? For the past 40 years, age‐standardized incidence of corpus cancer in Japan, similar to other countries worldwide, has been increasing. However, whereas global increases in corpus cancer are linked to increasing obesity, obesity rates in Japan remain uniquely low. This population‐based study, drawing on data from the Osaka Cancer Registry, reveals a sharp increase in age‐standardized incidence of corpus neoplasia from 2000‐2011 in Japan. Each histological cancer type differed in incidence trend, relative survival, and distribution of extent of disease. Additional analyses indicate that recent changes in adjuvant therapy, particularly increased use of chemotherapy over radiation, have improved prognosis. [ABSTRACT FROM AUTHOR]

Background: In the phase III open-label KEYNOTE-426 (NCT02853331) study, first-line pembrolizumab and axitinib improved overall survival (OS) and progression-free survival (PFS) versus sunitinib for metastatic renal cell carcinoma (mRCC). KEYNOTE-426 evaluated patients enrolled from 25 sites in Japan. Methods: Patients enrolled in Japan were included in this post hoc subgroup analysis. Adults with clear cell mRCC were randomly assigned 1:1 to receive intravenous pembrolizumab 200 mg every 3 weeks plus oral axitinib 5 mg twice daily or oral sunitinib 50 mg once daily (4 weeks on/2 weeks off). Dual primary endpoints were OS and PFS as assessed by blinded independent central review. Objective response rate (ORR) and safety were secondary endpoints. Results: The Japanese subgroup comprised 94 patients (pembrolizumab–axitinib, n = 44; sunitinib, n = 50; 11% of the intent-to-treat population). Median time from randomization to data cutoff (January 6, 2020) was 29.5 months (range 24.6–37.3). Consistent with the intent-to-treat population, the OS, PFS, and ORR suggested improvement with pembrolizumab–axitinib versus sunitinib in the Japanese subgroup. Grade ≥ 3 treatment-related adverse events (TRAEs) occurred in 70% of patients receiving pembrolizumab–axitinib versus 78% receiving sunitinib; 11 (25%) patients receiving pembrolizumab–axitinib and 13 (27%) patients receiving sunitinib discontinued the study medication due to AEs. TRAEs led to the discontinuation of pembrolizumab, axitinib, pembrolizumab–axitinib, or sunitinib in 32%, 34%, 14%, and 20%, respectively. No deaths from TRAEs occurred. Conclusions: Efficacy outcomes for the Japanese subgroup were consistent with those of the global population. Safety in Japanese patients was consistent with the results from the global population. [ABSTRACT FROM AUTHOR]

Objective: To investigate whether robot‐assisted partial nephrectomy compared with laparoscopic partial nephrectomy is effective for renal hilar tumor removal. Methods: This was a prospective, multicenter, single‐arm, open‐label trial with a 2‐year enrollment period. A total of 22 academic hospitals in Japan participated in the present study. Comparison with historical control values from reported studies of laparoscopic partial nephrectomy was carried out. The warm ischemia time and positive surgical margin rate were set as primary perioperative and oncological outcomes. In the historical control group, these were 27.7 min and 13%, respectively. Results: The analysis population included 105 participants. The mean warm ischemia time was 20.2 (95% confidence interval 16.7–21.8; P < 0.0001 vs 27.7). Two of 103 participants (1.9%) had a positive surgical margin (95% confidence interval 0.5–6.8%). Both results satisfy the prespecified decision criteria for the superiority of robot‐assisted partial nephrectomy over the historical control of laparoscopic partial nephrectomy. Resected weight and preoperative estimated glomerular filtration rate were predictive factors of functional loss of the partially nephrectomized kidney after robot‐assisted partial nephrectomy. Conclusion: Robot‐assisted partial nephrectomy for clinical T1 renal hilar tumors results in shorter warm ischemia time than and comparable positive surgical margin rate to those reported for laparoscopic partial nephrectomy. [ABSTRACT FROM AUTHOR]

We conducted a multicenter, retrospective study to evaluate the efficacy and safety of combination nivolumab plus ipilimumab (NIVO+IPI) in 35 patients with advanced or metastatic renal cell carcinoma (mRCC). In this study, we focused on patients who received NIVO+IPI and were stratified into intermediate- or poor-risk disease according to the International Metastatic Renal Cell Carcinoma Database Consortium model at five institutions in Japan. The primary endpoint was overall survival (OS). Secondary endpoints were disease control rate (DCR), best overall response (BOR), objective response rate (ORR), and progression-free survival (PFS). In addition, we evaluated the role of inflammatory cell ratios, namely neutrophil-to-lymphocyte ratio (NLR) and platelet-tolymphocyte ratio (PLR), as predictive biomarkers in patients with mRCC. The median follow-up period was 1 year, and the 1-year OS rate was 95.8%. The ORR and DCR were 34.3% and 80.0%, respectively. According to BOR, four patients (11.4%) achieved complete response. According to NLR stratification, the 1-year PFS rates were 82.6% and 23.7% when the NLR was ≤4.6 and >4.6, respectively (p = 0.04). Based on PLR stratification, the 1-year PFS rates were 81.7% and 34.3% when the PLR was ≤188.1 and >188.1, respectively (p = 0.033). Although 71.4% of the patients experienced treatment-related adverse events (TRAEs) with NIVO+IPI, only four patients discontinued NIVO+IPI due to grade 3/4 TRAEs. Patients treated with NIVO+IPI as a first-line therapy for advanced or mRCC achieved relatively better oncological outcomes. Therefore, NIVO+IPI may have potential advantages and may lead to a treatment effect compared to those receiving targeted therapies. In addition, PLR >188.1 may be a useful predictive marker for mRCC patients who received NIVO+IPI. [ABSTRACT FROM AUTHOR]

The article discusses the effectiveness and tolerability of the combination of avelumab and axitinib as a first-line treatment for advanced renal cell carcinoma (mRCC) in a real-world setting. The study, named "J-DART," demonstrated outcomes that were comparable to those of the JAVELIN Renal 101 trial. The article also highlights the need for developing standards of care for patients who do not meet trial eligibility criteria, particularly those with non-clear cell RCC. The authors express hope for obtaining evidence regarding the real-world outcomes of using avelumab and axitinib for trial-unfit patients with mRCC in the future. [Extracted from the article]

Background: We assessed the prognostic value of body mass index (BMI) in Asian patients with localized RCC who underwent nephrectomy.Methods: A total of 665 patients who underwent nephrectomy for localized RCC were enrolled in the present study and divided into the two BMI groups: i.e., BMI < 25 in 463 (69.6%) and BMI > 25 in 202 (30.4%) patients.Results: In total, there were 482 (72.5%) males and 183 (27.5%) females. Five-year cancer-specific survival (CSS) rates were significantly higher in increased BMI than the lower BMI group (97.1 and 92.5%: P = 0.007). When stratified by sex, significantly longer CSS in higher BMI was confirmed in males (5-year CSS of 92.7% in BMI < 25 and 98.1% in BMI > 25, p = 0.005), while there was no difference in CSS between BMI groups for female patients. Multivariable analysis exhibited that higher BMI was an independent predictor for favorable CSS in male (cox model: p = 0.041, Fine & Gray regression model: p = 0.014), but not in the female. Subgroup analysis for CSS revealed that favorable CSS with higher BMI was observed in patient subgroups of age < 65 (p = 0.019), clear cell histology (p = 0.018), and tumor size > 4 cm, p = 0.020) as well as male (p = 0.020).Conclusion: Our findings collected from the multi-institutional Japanese dataset demonstrated longer survival in patients with higher BMI than lower BMI for non-metastatic RCC treated with nephrectomy. Intriguingly, this finding was restricted to males, but not to females. [ABSTRACT FROM AUTHOR]

The human T cell lymphotropic virus type 1 (HTLV-1) is the first human retrovirus discovered. Since then, it has spread worldwide and is mainly associated with adult T cell leukemia/lymphoma (ATLL) and HTLV1-associated myelopathy (HAM). Its relationship, however, with other types of cancer is controversial. We describe the case of a patient presenting with small cells lung epidermoid carcinoma who had recently developed HAM, and a review of the literature related to these conditions. This is the first case of this type of lung cancer, the same of the first description in the literature, associated with HAM outside Japan. [ABSTRACT FROM AUTHOR]

Thus, we should wait for the final analyses of other regimens to determine whether the short-term benefits of IO + TKI regimens in terms of PFS or ORR are really associated with the prolongation of OS in patients. Immune oncology (IO) agent-based combination therapy is a mainstay of first-line therapy for patients with metastatic renal cell carcinoma (mRCC). Editorial Comment to Efficacy and safety of pembrolizumab and axitinib as first-line treatment for patients with advanced renal cell carcinoma: Real-world experience in Japan. [Extracted from the article]

Objectives: To evaluate the efficacy and safety of cabozantinib, through a bridging study to METEOR, in Japanese patients with advanced renal cell carcinoma who had progressed after prior tyrosine kinase inhibitor therapy. Methods: This phase II, open-label, single-arm study (ClinicalTrials.gov registration number: NCT03339219) included adult Japanese patients with advanced renal cell carcinoma and measurable disease who had received one or more tyrosine kinase inhibitors. Patients received cabozantinib 60 mg orally once daily while there was clinical benefit, or until unacceptable toxicity or disease progression. The primary end-point was objective response rate per Response Evaluation Criteria in Solid Tumors Version 1.1. Secondary end-points included clinical benefit rate (complete or partial response, or ≥8- week stable disease), progression-free survival, overall survival and safety. Results: Of the 35 patients enrolled, 68.6%, 22.9% and 8.6% had previously received one, two and three prior tyrosine kinase inhibitors, respectively. The median duration of cabozantinib exposure was 27.0 weeks (range 5.1--43.0 weeks). The objective response rate was 20.0% (90% confidence interval 9.8--34.3%), and the clinical benefit rate was 85.7% (95% confidence interval 69.7--95.2%). The 6-month estimated progression-free survival was 72.3% (95% confidence interval 53.3--84.6%); the median progression-free survival and overall survival were not reached. All patients reported adverse events, which were manageable by supportive treatment or dose modification; two patients (5.7%) discontinued therapy due to adverse events. Conclusions: The results showed that findings from METEOR can be extrapolated, and that cabozantinib 60 mg/day is a viable treatment option in Japanese patients with advanced renal cell carcinoma who had progressed after prior tyrosine kinase inhibitor therapy. [ABSTRACT FROM AUTHOR]

Background: In a phase III clinical trial, CheckMate 025, treatment of metastatic renal cell carcinoma (mRCC) with nivolumab demonstrated superior efficacy over everolimus. However, as the clinical trial excluded patients with specific complications and poor performance status (PS), the effectiveness and safety of nivolumab in clinical practice, in which patients with various clinical complications are treated, is unclear. This study explored real-world nivolumab treatment in Japanese mRCC patients. Methods: This is an interim analysis of a multicenter, non-interventional, medical record review study (minimum follow-up: 9 months). All eligible Japanese mRCC patients who first received nivolumab between February and October 2017 were included; data cut-off was April 2019. We analyzed nivolumab treatment patterns, efficacy (including overall survival, progression-free survival, objective response rate, and duration of response) and safety (including immune-related adverse events). Results: Of 208 evaluable patients, 31.7% received nivolumab as fourth- or later line of treatment. At data cut-off, 26.9% of patients were continuing nivolumab treatment. The major reason for discontinuation was disease progression (n = 100, 65.8%). Median overall survival was not reached; the 12-month survival rate was 75.6%. Median progression-free survival was 7.1 months, the objective response rate was 22.6%, and median duration of response was 13.3 months. Patients who were excluded or limited in number in CheckMate 025, such as those with non-clear cell RCC or poor PS, also received benefits from nivolumab treatment. Immune-related adverse events occurred in 27.4% of patients (grade ≥ 3, 10.1%). Conclusion: Nivolumab was effective and well-tolerated in real-world Japanese mRCC patients. Trial registration: UMIN000033312 [ABSTRACT FROM AUTHOR]

Objective: International Federation of Gynecology and Obstetrics (FIGO) staging for ovarian, fallopian tube, and peritoneal cancers was revised in 2014. The aim of this study is to clarify whether the revised FIGO2014 staging reflects the prognosis of patients with ovarian cancer by histological type in Japan. Methods: We extracted 9,747 patients who were diagnosed with ovarian cancer since 2004 until 2008 and who could be classified into appropriate stages from the Gynecologic Cancer Registry of Japan Society of Obstetrics and Gynecology. These cases were analyzed after revision to FIGO2014 based on the pTNM classification. Results: Among stage I, the 5-year overall survival rate (5y-OS) in FIGO2014 was 94.9% in stage IA, 92.3% in stage IC1, 86.1% in IC2, and 84.9% in IC3 with significant differences between stages IA and IC1 (p=0.012), IC1 and IC2 (p<0.001). There was a significant difference between stages IA and IC1 in clear cell and mucinous carcinoma but not in serous and endometrioid carcinoma. Among stage III, the 5y-OS was 75.6% in stage IIIA1, 68.9% in IIIA2, 58.6% in IIIB, and 44.4% in IIIC, with significant differences between stages IIIA2 and IIIB (p=0.009), IIIB and IIIC (p<0.001). Among stage IV, the 5y-OS was Conclusion: The results suggest that changes in classification for stage III and stage IV are appropriate, but the subclassification for stage IC might be too detailed. There was a discrepancy of prognosis by histological type between stage IA and IC143.1% in stage IVA* and 32.1% in IVB with a significant difference (p=0.002). [ABSTRACT FROM AUTHOR]

Objectives: To assess whether the clinical outcome of advanced/metastatic renal cell carcinoma (mRCC) treated with sorafenib, in real-world conditions, differs in patients with cardiovascular disease (CVD).Methods: mRCC patients (n = 2256 before matching) were matched by propensity score into CVD (n = 560) and non-CVD groups (n = 560), followed by safety and effectiveness analyzes.Results: After matching, patients' features used for matching were balanced between the CVD and non-CVD groups, except for age (p = 0.0049). Renal comorbidity occurred more frequently in the CVD group. Exposure to sorafenib and objective response rate (25.4% [CVD], 28.5% [non-CVD]) were comparable in both groups. Median progression-free survival (PFS; 7.1 months, 95% CI: 6.4-8.6 [CVD]; 6.7 months, 6.3-8.3 [non-CVD]), and hazard ratios for PFS (0.954, 0.821-1.108) and overall survival (0.889, 0.683-1.156), were similar in the matched population. The incidences of adverse drug reactions (ADR, ≥10%) were generally similar between groups, although hypertension (42.1% vs 34.5%), diarrhea (26.3% vs 19.6%), decreased appetite (11.3% vs 7.5%), and non-serious and serious renal failure/dysfunction (3.6% vs 1.4% and 1.8% vs 0.4%), occurred more frequently in the CVD group.Conclusion: This analyzes suggests that sorafenib has clinical benefit for mRCC patients regardless of baseline CVD. Serious ADRs increased for renal dysfunction.Clinical Trial Registration: www.clinicaltrials.gov identifier is NCT01411423. [ABSTRACT FROM AUTHOR]

Introduction and Objectives The animal models for renal carcinogenesis have allowed researchers to better understand the physiopathological, genetic, molecular, and immunological mechanisms underlying the development of human renal cancers from the induction of precancerous lesions to the metastatic process. Our study aimed to review and discuss the characteristics of all the spontaneous animal models of renal carcinogenesis described in scientific literature to date and see how they could address future challenges in the field of personalized medicine. Methods and Materials We reviewed all the papers on PubMed which focus on spontaneous animal models of renal carcinogenesis. To do so, we used the keywords "spontaneous" AND "animal model" AND "renal cancer" in the PubMed search engine. We also conducted a search using the keywords "spontaneous" AND "animal model" AND "kidney cancer." PRISMA recommendations were used for the literature review. Results A total of 213 publications were found on PubMed with the keywords "spontaneous" AND "animal model" AND "kidney cancer." 219 publications were found on PubMed with the keywords "spontaneous" AND "animal model" AND "renal cancer." After pooling these 2 searches and removing the duplicate publications, 233 publications remained. Among these, 220 full-text articles were assessed for eligibility; 160 were removed because they were irrelevant to our topic, and the remaining 60 studies were included in our qualitative synthesis. Conclusions Many spontaneous animal models have been developed to study renal cancer. So far, these models have enabled the understanding of pathophysiological mechanisms underlying renal cancer. Though less appropriate than patient xenografts from the perspective of personalized medicine, we believe animal models can help medical professionals better understand the hows and whys of the genetic events underlying the intratumoral heterogeneity and spatial distribution of metastatic subclones. [ABSTRACT FROM AUTHOR]

Renal cell carcinoma unclassified with medullary phenotype (RCCU‐MP) is a rare variant of renal medullary carcinoma (RMC) characterized by loss of SMARCB1 (INI1 / SNF5 / BAF47) protein expression in patients without sickle cell trait. Here, we report a case of RCCU‐MP in a Japanese patient who had experienced colon cancer 13 years ago, gastric cancer 11 years ago and lung cancer 9 years ago and had received hemodialysis for 15 years. This is the first report of RCCU‐MP in Japan. The patient was not of African descent, and did not have SCT or any other hereditary blood abnormality typical of RMC. The tumor was located in the left kidney, and was composed histologically of rhabdoid cells with marked lymphocyte infiltration; it was immunohistochemically negative for SMARCB1. We were, however, unable to detect mutation in the SMARCB1 gene, reduced messengerRNA expression, or deletion or translocation of chromosome 22, where the SMARCB1 gene is located. These results suggest that RCCU‐MP may not involve the hemizygous loss of this gene noted in typical RMC cases. [ABSTRACT FROM AUTHOR]

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.)

To evaluate the efficacy and safety of anti-PD1 therapy (nivolumab) in advanced renal cell carcinoma (RCC) in a clinical setting. Between March 2013 and January 2018, 33 patients with RCC (27 men and 6 women) were treated with nivolumab. Before anti-PD1 treatment, 12, 9 and 12 patients received one, two, and three or more therapies, respectively. Objective response, survival rate, and clinical adverse events were evaluated by the revised RECIST criteria (version 1.1). The median patient age was 68 years (range: 37–79). In total, 14 (42%) patients had an Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 while 17 (52%) and two (6%) had an ECOG PS of 1 and 2 or higher, respectively. One (3%), 24 (73%) and eight (24%) were classified as having favorable, intermediate, and poor risk, respectively. The median follow-up duration after nivolumab initiation was 26 months (range: 1–131). The median progression-free and overall survival were 10.3 months and 45.9 months, respectively. Nivolumab was associated with a disease control rate of 58%, with an objective response of 24% (complete response, 1; partial response, 7; stable disease, 11; progressive disease, 10; not assessed, 4). A total of 15 (46%) patients experienced adverse events, of which six were severe (grade 3 or more) and 10 were immunotherapy-related. This study examined the initial experience of nivolumab administration in Japanese patients with advanced RCC. Our results suggest that nivolumab can achieve acceptable outcomes in a real clinical setting, with outcomes that are comparable to those of clinical trials. [ABSTRACT FROM AUTHOR]

Objective: To report the outcomes of laparoscopic radical nephrectomy with inferior vena cava thrombectomy for right renal cell carcinoma at Kobe City Medical Center General Hospital, Kobe, Hyogo, Japan. Method: A retrospective review of the clinical records of five patients who underwent laparoscopic radical nephrectomy with inferior vena cava thrombectomy for right renal cell carcinoma between 2013 and 2017 was carried out. The surgical procedure included ligation and cutting of the right renal artery, followed by kidney mobilization. The left renal vein, and the caudal and cephalad sides of the inferior vena cava thrombus were clamped using laparoscopic vascular clamps, and the inferior vena cava was incised. The free kidney and tumor thrombus were placed en bloc in a retrieval bag. Subsequently, the inferior vena cava was laparoscopically closed using a continuous suture. Results: The median operative time, pneumoperitoneum time, blood loss and postoperative hospital stay were 316 min, 266 min, 400 mL and 7 days, respectively. The median clamp time was 28 min (range 13–105 min). One patient (20%) required a perioperative blood transfusion. The surgical margin was negative in all patients. Only one patient experienced a major complication (Clavien–Dindo grade ≥3), namely a postoperative hemorrhage requiring transarterial embolism. Conclusion: En bloc laparoscopic radical nephrectomy with inferior vena cava thrombectomy is a challenging yet feasible procedure for experienced surgeons in carefully selected patients. Further studies of this surgical procedure are required for standardization and safe application. [ABSTRACT FROM AUTHOR]

Objectives: To clarify treatment patterns and outcomes for patients with unresectable or metastatic renal cell carcinoma in the molecular target therapy era in Japan. Methods: A multicenter, retrospective medical chart review study was carried out. Patients diagnosed with unresectable or metastatic renal cell carcinoma between January 2012 and August 2015 were enrolled. Data extracted from medical records included treatment duration, grade ≥3 adverse events, reason for discontinuation for each targeted therapy and survival data until August 2016. Results: Of 277 eligible patients, 266, 170 and 77 received first‐, second‐ and third‐line systemic treatment, respectively. Tyrosine kinase inhibitors were the most common first‐line therapy (72.2%), followed by mammalian target of rapamycin inhibitors (14.3%) and cytokines (13.5%). Among 170 patients who received second‐line treatment, tyrosine kinase inhibitor–tyrosine kinase inhibitor was the most common sequence (58.8%), followed by tyrosine kinase inhibitor–mammalian target of rapamycin inhibitor (14.1%) and cytokine–tyrosine kinase inhibitor (14.1%). With a median follow‐up period of 19.8 months, median overall survival was not reached at 48 months. Patients who discontinued first‐line tyrosine kinase inhibitors in <6 months showed poorer overall survival compared with patients who received first‐line tyrosine kinase inhibitors for ≥6 months. Conclusions: The present analysis illustrates the contemporary treatment patterns and prognosis for patients with unresectable or metastatic renal cancer in a real‐world setting in Japan. Tyrosine kinase inhibitor–tyrosine kinase inhibitor represents the most commonly used sequence. Shorter treatment duration of first‐line tyrosine kinase inhibitors is associated with poorer prognosis, suggesting the need for better treatment options. [ABSTRACT FROM AUTHOR]

Introduction: There is limited data on the efficacy of sequential targeted therapy for metastatic renal cell carcinoma (mRCC) beyond the second line, especially for Asian patients. We evaluated the efficacy and side effects of targeted therapy beyond the second line. Materials and Methods: We retrospectively reviewed 69 patients who were administered targeted therapy for mRCC at our institution between 2008 and 2016. Sunitinib, pazopanib, sorafenib, axitinib, everolimus, and temsirolimus were available in Japan in 2016, and treatment had been conducted with those six agents. Twenty-four patients underwent therapy beyond the second line. The progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method. In addition, a survey on patients' attitudes toward cancer treatment was conducted. Twenty-five of the 69 patients responded to the question with their opinions on the continuation of treatment after standard therapy failure. Results: The median PFS was 7.6 and 2.5 months for third- and fourth-line therapy. The median OS calculated from the initiation of third-line therapy was 14.2 months. The rates of serious toxicities with third- and fourth-line regimens were not markedly increased compared with first- and second-line therapies. Forty percent of patients hoped to continue treatment after exhausting standard care. Conclusions: Our retrospective study indicates the efficacy and safety of third- and fourth-line targeted therapies. In addition to the efficacy, a patient can also influence treatment continuation. [ABSTRACT FROM AUTHOR]

Background: A high incidence of severe hematological adverse events during sunitinib treatment complicates decision making on dose and treatment cycle. We identified the characteristics of early-onset hematotoxicity of sunitinib in Japanese patients with renal cell carcinoma (RCC).Methods: Seventy-nine patients were treated with sunitinib as 6-week cycles of "4-week on 2-week off" schedule. To evaluate early-onset hematotoxicity, we compared patients with dose reduction during the first cycle (dose-reduced group, n = 57) and those who maintained the initial dose (dose-maintained group, n = 22). ABCG2 and FLT3 genotypes were analyzed for association between hematotoxicity and reported gene polymorphisms.Results: Mean relative dose intensity (RDI) was similar in the two groups during the first 2 weeks of dosing in the first cycle, but was significantly lower in the dose-reduced group during the last 2 weeks. Lymphocytopenia and thrombocytopenia were observed in the dose-reduced group within the first 2 weeks. Genetic analysis indicated a significantly higher frequency of FLT3 738 T/C polymorphism in the dose-reduced group, but no significant difference in the ABCG2 421 C/A polymorphism.Conclusions: This study showed a high incidence of sunitinib-induced hematotoxicity in Japanese patients with RCC, many of whom need dose adjustment during the first cycle. Further studies should verify whether dose adjustment based on early-onset thrombocytopenia prolongs sunitinib treatment. [ABSTRACT FROM AUTHOR]

The safety and efficacy of robot-assisted partial nephrectomy (RAPN) has been reported in Western countries. However, there are no similar reported studies of RAPN in Japan. Although common medical services are covered by public health insurance in Japan, RAPN had not been approved as a listed treatment for public insurance. We conducted a prospective clinical trial to confirm the efficacy and safety of RAPN in Japan. The aim of the present review article is to describe current status of RAPN in Japan and to introduce a part of clinical results obtained from the clinical trial. Based on the favorable results obtained in this clinical trial, RAPN was approved in April 2016 by the Japanese Ministry of Health, Labour and Welfare to be covered by public health insurance. This change allows access to RAPN to everyone in Japan, regardless of wealth. The RAPN techniques used in Japan are also reviewed. [ABSTRACT FROM AUTHOR]

Aims: The treatment landscape of renal cell carcinoma has changed with the introduction of targeted therapies. While the clinical benefit of cabozantinib is well-established for Japanese patients who have received prior treatment, the economic benefit remains unclear. The objective of this study was to assess the cost-effectiveness of cabozantinib compared with everolimus, axitinib, and nivolumab in patients with advanced renal cell carcinoma who have failed at least one prior therapy in Japan., Methods: A cost-effectiveness model was developed using a partitioned survival approach and a public healthcare payer's perspective. Over a lifetime horizon, clinical and economic implications were estimated according to a three-health-state structure: progression-free, post-progression, and death. Key clinical inputs and utilities were derived from the METEOR trial, and a de novo network meta-analysis and cost data were obtained from publicly available Japanese data sources. Costs, quality-adjusted life-years, and incremental cost-effectiveness ratios were estimated. Costs and health benefits were discounted annually at 2%., Results: Cabozantinib was more costly and effective compared with everolimus and axitinib, with deterministic incremental cost-effectiveness ratios of ¥5,375,559 and ¥2,223,138, respectively. Compared to nivolumab, cabozantinib was predicted to be less costly and more effective. Sensitivity and scenario analyses demonstrated that the key drivers of cost-effectiveness results were the estimation of overall survival and treatment duration, relative efficacy, drug costs, and subsequent treatment costs., Limitations: METEOR was an international trial but did not enroll any patients from Japan. Efficacy and safety data from METEOR were used as a proxy for the Japanese population following validation by clinical experts, and alternative assumptions specific to clinical practice in Japan were evaluated in scenario analyses., Conclusions: In Japan, cabozantinib is a cost-effective alternative to everolimus, axitinib, and nivolumab for the treatment of patients with advanced renal cell carcinoma who have received at least one prior line of therapy.

Background: The prognostic significance of early tumor shrinkage (ETS) under second-line targeted therapy for metastatic renal cell carcinoma (mRCC) has not been fully documented. Aims: The objective of this study was to evaluate the impact of ETS induced by a second-line targeted agent on overall survival (OS) in mRCC patients. Patients and Methods: This study retrospectively included 271 consecutive Japanese patients with mRCC who received second-line targeted therapy for at least 3 months. ETS was defined as the degree of tumor shrinkage at the first post-baseline radiological evaluation conducted 4-8 weeks after initiating second-line targeted therapy. Results: Of the 271 patients, 26 had ETS from −100 to −50 %, 70 from −49 to −25 %, 84 from −24 to 0 %, and the remaining 91 failed to achieve a reduction in the tumor size. The median OS following the initiation of second-line targeted therapy stratified according to ETS was 45.8, 30.9, 22.1 and 14.2 months, respectively. Univariate analysis identified prior nephrectomy, the Memorial Sloan-Kettering Cancer Center (MSKCC) risk classification, C-reactive protein (CRP) level, number of metastatic organs, sarcomatoid feature, introduced second-line agent and ETS induced by a second-line agent as parameters significantly associated with OS, of which, only the MSKCC classification, CRP level and ETS appeared to have independent impacts on OS on multivariate analysis. Conclusions: These findings suggest that ETS at the first post-baseline assessment under treatment with a second-line targeted agent could serve as a useful parameter with an independent impact on OS in mRCC patients receiving second-line targeted therapy. [ABSTRACT FROM AUTHOR]

Purpose: This multicenter phase I/II study evaluated the safety, feasibility, and initial efficacy of radiofrequency ablation (RFA) for small malignant renal tumors.Methods: Thirty-three patients were enrolled in the study. A single session of RFA was performed in patients with a renal tumor of 1-3 cm in greatest diameter, with the exception of lesions adjacent to the renal hilum. The primary endpoint was the safety of renal RFA, and the secondary endpoints were its feasibility and initial efficacy for local control, as well as the incidence and grade of adverse events. Clinical efficacy was evaluated by CT scans within 1 week and at a further 4 weeks after the procedure using the criteria adapted from the Response Evaluation Criteria in Solid Tumors.Results: The RFA procedure was completed in 100% (95% confidence interval [CI] 89-100%) of all 33 patients. There were no severe adverse events (0% [95% CI 0-11%]). Among the 33 patients, a complete response, partial response, progressive disease, and stable disease were seen in 28 (85%), 0 (0%), one (3%), and one (3%) patient(s), respectively, with a tumor response rate of 85% [95% CI 68-95%]). Three patients (9%), including one ineligible patient (3%), were not evaluable. Out of 30 evaluable patients, a complete response was achieved in 28 (93%).Conclusion: The current multicenter trial revealed that RFA is a safe, feasible, and effective treatment for small malignant renal tumors in patients who are not candidates for surgery. [ABSTRACT FROM AUTHOR]

The standard treatment for advanced renal cell carcinoma has changed dramatically in the past decade, from cytokine therapy to targeted therapy. Since sorafenib was approved in April 2008, four tyrosine kinase inhibitors and two mammalian target of rapamycin inhibitors have become available in Japan. Most Japanese renal cell carcinoma patients are treated by urologists who are involved in not only kidney surgeries, but also targeted therapy using tyrosine kinase inhibitors, as well as mammalian target of rapamycin inhibitors. Optimal treatment methods are selected from theoretically-based global recommendations, such as the National Comprehensive Cancer Network and European Society for Medical Oncology guidelines; however, real-world clinical practice might be different from that in non-Asian countries. This might be because of different practical conditions; for example, different adverse events and efficacy profiles, different healthcare system, and so on. In the present review, we examine current pharmacotherapy for renal cell carcinoma from evidence-based global data, and compare the reality of Japanese clinical practice to explore the importance of individualized patient therapy. [ABSTRACT FROM AUTHOR]

Background: To improve antitumor effects against metastatic renal cell carcinoma (mRCC), use of molecular target-based drugs in sequential or combination therapy has been advocated. In combination therapy, interferon (IFN)-α amplified the effect of sorafenib in our murine model (J Urol 184:2549, 2010), and cytokine-treated mRCC patients in Japan had good prognoses (Eur Urol 57:317, 2010). We thus conducted a phase II clinical trial of sorafenib plus IFN-α for untreated mRCC patients in Japan.Methods: In this multicenter, prospective study, provisionally registered patients with histologically confirmed metastatic clear cell RCC received natural IFN-α (3 dosages of 3 million U per week) for 2 weeks. Only IFN-α-tolerant patients were registered to this trial, and treated additionally with oral sorafenib (400 mg, bid). The primary end point of the study was rate of response (CR + PR) to sorafenib plus IFN-α treatment assessed using RECIST v1.0. The secondary end points were disease control rate (CR + PR + SD), progression free survival (PFS), overall survival (OS), and safety of the combined treatment. PFS and OS curves were plotted using the Kaplan-Meier method.Results: From July 2009 to July 2012, a total of 53 untreated patients were provisionally registered, and 51 patients were finally registered. Rate of Response to the combined therapy of sorafenib plus IFN-α was 26.2 % (11/42) (CR 1, PR 10). The median PFS was 10.1 months (95 % CI, 6.4 to 18.5 months), and the median OS has not been reached yet. The combined therapy increased neither the incidence of adverse effects (AE) nor the incidence of unexpected AE. A limitation was that a relatively high number of patients (9 patients) were excluded for eligibility criteria violations.Conclusion: Our data have demonstrated that sorafenib plus IFN-α treatment is safe and effective for untreated mRCC patients.Trial Registration: UMIN000002466 , 9(th) September, 2009. [ABSTRACT FROM AUTHOR]

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.)

Background: To evaluate experience of the use of temsirolimus for metastatic renal cell carcinoma (mRCC) in a single center in Japan. Methods: This study included 55 consecutive patients with mRCC who received temsirolimus in a routine clinical setting, and retrospectively reviewed the comprehensive outcomes of these patients. Results: Of the 55 patients, 20 had a Karnofsky performance status of ≤80, and 5, 41 and 9 were classified into favorable, intermediate and poor risk groups, respectively, according to the Memorial Sloan-Kettering Cancer Center model. Initially, 25 mg of temsirolimus was applied weekly; however, dose modification was required in 19 patients, resulting in a relative dose intensity of 90.5 % throughout this series. As the best responses to temsirolimus, 4, 44 and 7 were judged to have a partial response, stable disease and progressive disease, respectively. The median progression-free survival (PFS) and overall survival (OS) of these patients following the introduction of temsirolimus was 7.0 and 25.0 months, respectively. Of several factors examined, only the pretreatment C-reactive protein level was shown to be independently associated with both PFS and OS. The common adverse events related to temsirolimus corresponding to ≥grade 3 were anemia in 4, thrombocytopenia in 3, stomatitis in 3 and hyperglycemia in 3. Quality of life analysis using 36-Item Short Form showed that there were no significant differences in any scale scores between surveys performed before and 3 months after the introduction of temsirolimus. Conclusions: Temsirolimus was well tolerated and facilitated comparatively favorable cancer control in Japanese patients with mRCC. [ABSTRACT FROM AUTHOR]

OBJECTIVE: To investigate the relationship between gender differences in fatty acid-binding protein7 (FABP7) and BRN2 (POU class 3 homeobox 2) expression in renal cell carcinoma (RCC) and the prognosis of patients with RCC. MATERIALS AND METHOD: immunohistochemical (IHC) staining as well as reverse transcription-polymerase chain reaction (RT-PCR) was per-formed in renal tissues from 103 patients (83 men, mean age = 63.6 years old; 20 women, mean age = 63.1 years old) underwent radical nephrectomy from January 1, 2001 through December 31, 2010. The probability of overall patient survival was estimated using the Kaplan-Meier method. RESULTS: FABP7 mRNA expression was more frequent in men (P = 0.07) while BRN2 protein expression was significantly more frequent in women (P = 0.029). In particular, FABP7 was expressed in 100% of G1 renal cell carcinoma both in mRNA and protein levels. In women, FABP7 (-) and BRN2 (+) groups had a worse prognosis both in mRNA level (P = 0.038) and protein level (P = 0.058). BRN2 was expressed 100% of papillary RCC both in mRNA and protein levels. CONCLUSIONS: Our results demonstrated that gender was a key factor in FABP7 and BRN2 expression in RCC, and the combination with FABP7 and BRN2 stratified by gender could be a new potential prognostic factor in patients with RCC. [ABSTRACT FROM AUTHOR]