Machine learning analysis for detecting late recurrence and loss to follow-up after renal cell carcinoma surgery.

Objectives: Renal cell carcinoma (RCC) is shown to have a tendency for late recurrence, occurring 5 or more years after curative surgery. Imaging diagnosis is required for follow-up, and there is no definitive answer as to how long this should continue. Some patients discontinue follow-up visits at their own discretion. How best to predict late recurrence and loss to follow-up (LF) remains unclear. Patients and methods: This study targeted patients diagnosed with non-metastatic RCC who underwent either radical or partial nephrectomy at Chiba University Hospital between 1988 and 2021. Follow-up for patients with RCC is typically lifelong. We used random survival forests (RSFs), a machine learning-based survival analysis method, to predict late recurrence and LF. For verification of prediction accuracy, we applied the time-dependent area under the receiver operating characteristic curve (t-AUC). To analyse the risks of late recurrence and LF, SurvSHAP(t) and partial dependence plots were used. Results: We analysed 1051 cases in this study. Median follow-up was 58.5 (range: 0-376) months. The predictive accuracy of recurrence using RSF was t-AUC 0.806, 0.761, 0.674 and 0.566 at 60, 120, 180 and 240 months postoperatively, respectively. The recurrence risk impact showed a time-dependent increase up to approximately 50 months postoperatively. Beyond 50 months, there were no distinct risk factors characteristic of late recurrence. The predictive accuracy of LF using RSF was t-AUC 0.542, 0.699, 0.685, 0.628 and 0.674 at 60, 120, 180, 240 and 300 months postoperatively, respectively. The risk of LF increased with advancing age beyond 70 years. Conclusion: It is difficult to identify factors that predict late recurrence. For long-term follow-up observation, it is essential to pay particular attention to patients with RCC aged 70 years and above. Establishing frameworks to facilitate collaboration with local hospitals near patients' residences and providing care within the community is necessary.

Association Between Residual Urine Volume and Recurrence Among Patients at High Risk of Non-Muscle-Invasive Bladder Carcinoma With Versus Without Bacillus Calmette-Guérin Treatment.

Non-muscle-invasive bladder carcinoma often occurs in older adults, who often also have urinary dysfunction. The residual urine volume is an important indicator of urinary dysfunction. However, the impact of the residual urine volume on intravesical recurrence remains unclear. In the present study, we analyzed the data of 372 patients at high or very high risk of cancer progression according to the Japanese Urological Association classification who had undergone transurethral resection of a bladder tumor. In univariate analysis, postoperative absence of intravesical Bacillus Calmette-Guérin (BCG) induction was an independent risk factor for intravesical recurrence (hazard ratio 1.94, absence versus presence, p = 0.0019). The incidence of intravesical recurrence did not significantly differ between the mild, intermediate, and severe residual urine groups in the total cohort. Among the BCG-treated cohort, the three groups showed similar trends. Among the non-BCG-treated cohort, although the patients with more than 100 ml of residual urine tended to have more intravesical recurrence than patients with a smaller residual urine volume, this difference did not reach statistical significance. BCG treatment is recommended for patients at high risk of bladder carcinoma. Patients with a large residual urine volume without BCG treatment may be at high risk of intravesical recurrence.

TNFSF9 Is Associated with Favorable Tumor Immune Microenvironment in Patients with Renal Cell Carcinoma Who Are Treated with the Combination Therapy of Nivolumab and Ipilimumab.

Combination therapy of nivolumab and ipilimumab (NIVO + IPI) for metastatic renal cell carcinoma (mRCC) has shown efficacy, but approximately 20% of patients experience disease progression in the early stages of treatment. No useful biomarkers have been reported to date. Therefore, it is desirable to identify biomarkers to predict treatment responses in advance. We examined the tumor microenvironment (TME)-related gene expression in mRCC patients treated with NIVO + IPI, between the response and non-response groups, using tumor tissues, before administering NIVO + IPI. In TME-related genes, TNFSF9 expression was identified as a candidate for the predictive biomarker. Its expression discriminated between the response and non-response groups with 88.89% sensitivity and 87.50% specificity (AUC = 0.9444). We further analyzed the roles of TNFSF9 in TME using bioinformatics from The Cancer Genome Atlas (TCGA) cohort. An adaptive immune response was activated in the TNFSF9-high-expression tumors. Indeed, T follicular helper cells, plasma B cells, and tumor-infiltrating CD8+ T cells were increased in the tumors, which indicates the promotion of humoral immunity due to enhanced T-B interactions. However, as the number of regulatory T cells (Treg) increased in the tumors, the percentage of dysfunctional T cells also increased. This suggests that not only PD-1 but also CTLA-4 inhibition may have suppressed Treg activation and improved the therapeutic effect in the TNFSF9 high-expression tumors. Therefore, TNFSF9 may predict the therapeutic efficacy of NIVO + IPI for mRCC and allow more appropriate patient selection.

PSA doubling time 4.65 months as an optimal cut-off of Japanese nonmetastatic castration-resistant prostate cancer.

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

Implications of unconventional histological subtypes on magnetic resonance imaging and oncological outcomes in patients who have undergone radical prostatectomy.

The prognostic significance of unconventional histology (UH) subtypes including intraductal carcinoma of the prostate (IDC-P), ductal adenocarcinoma, and cribriform pattern has been investigated for prostate cancer (PCa). However, little is known about magnetic resonance imaging (MRI) features and the oncological impact of tumor localization in localized PCa with UH. Clinical data of 211 patients with acinar adenocarcinoma (conventional histology [CH]) and 82 patients with UH who underwent robotic-assisted radical prostatectomy (RARP) were reviewed. Patients with UH are more likely to be older and have higher Gleason grade group, higher Prostate Imaging-Reporting and Data System (PI-RADS) v2.1 score, and larger tumor volume (TV) than those with CH. Multivariate analysis identified the presence of UH as an independent prognostic factor for progression-free survival (PFS) (hazard ration (HR) 2.41, 95% confidence interval (CI) 0.22-0.79, P = 0.0073). No significant difference in PFS was seen regarding tumor localization (transition zone [TZ] or peripheral zone [PZ]) in patients with UH (P = 0.8949), whereas PZ cancer showed shorter PFS in patients with CH (P = 0.0174). PCa with UH was associated with higher progression than PCa with CH among resection margin (RM)-negative cases (P < 0.0001). Further, increased PI-RADS v2.1 score did not correlate with larger TV in UH (P = 0.991), whereas a significant difference in TV was observed in CH (P < 0.0001). The prognostic significance of UH tumor was independent of tumor localization, and shorter PFS was observed even in RM-negative cases, indicating an aggressive subtype with micro-metastatic potential. Furthermore, UH tumors are more likely to harbor a large TV despite PI-RADS v2.1 score ≤ 3. These findings will help optimal perioperative management for PCa with UH.

The LAT1 inhibitor JPH203 suppresses the growth of castration-resistant prostate cancer through a CD24-mediated mechanism.

L-type amino acid transporter 1 (LAT1) is specifically expressed in many malignancies, contributes to the transport of essential amino acids, such as leucine, and regulates the mammalian target of rapamycin (mTOR) signaling pathway. We investigated the expression profile and functional role of LAT1 in prostate cancer using JPH203, a specific inhibitor of LAT1. LAT1 was highly expressed in castration-resistant prostate cancer (CRPC) cells, including C4-2 and PC-3 cells, but its expression level was low in castration-sensitive LNCaP cells. JPH203 significantly inhibited [14C] leucine uptake in CRPC cells but had no effect in LNCaP cells. JPH203 inhibited the proliferation, migration, and invasion of CRPC cells but not of LNCaP cells. In C4-2 cells, Cluster of differentiation (CD) 24 was identified by RNA sequencing as a novel downstream target of JPH203. CD24 was downregulated in a JPH203 concentration-dependent manner and suppressed activation of the Wnt/ß-catenin signaling pathway. Furthermore, an in vivo study showed that JPH203 inhibited the proliferation of C4-2 cells in a castration environment. The results of this study indicate that JPH203 may exert its antitumor effect in CRPC cells via mTOR and CD24.

Chromatin activation with H3K36me2 and compartment shift in metastatic castration-resistant prostate cancer.

Epigenetic modifiers are upregulated during the process of prostate cancer, acquiring resistance to castration therapy and becoming lethal metastatic castration-resistant prostate cancer (CRPC). However, the relationship between regulation of histone modifications and chromatin structure in CRPC has yet not fully been validated. Here, we reanalyzed publicly available clinical transcriptome and clinical outcome data and identified NSD2, a histone methyltransferase that catalyzes H3K36me2, as an epigenetic modifier that was upregulated in CRPC and whose increased expression in prostate cancer correlated with higher recurrence rate. We performed ChIP-seq, RNA-seq, and Hi-C to conduct comprehensive epigenomic and transcriptomic analyses to identify epigenetic reprogramming in CRPC. In regions where H3K36me2 was increased, H3K27me3 was decreased, and the compartment was shifted from inactive to active. In these regions, 68 aberrantly activated genes were identified as candidate downstream genes of NSD2 in CRPC. Among these genes, we identified KIF18A as critical for CRPC growth. Under NSD2 upregulation in CRPC, epigenetic alteration with H3K36me2-gain and H3K27me3-loss occurs accompanying with an inactive-to-active compartment shift, suggesting that histone modification and chromatin structure cooperatively change prostate carcinogenesis.

Copy Number Gain in Androgen Receptors Predicts the Poor Prognosis in Japanese Castration-resistant Prostate Cancer.

BACKGROUND/AIM: The prognostic significance of androgen receptor amplification (AR amp) in cell-free DNA (cfDNA) was studied in Japanese patients with castration-resistant prostate cancer (CRPC). PATIENTS AND METHODS: A total of 120 serum samples were obtained from 38 patients with CRPC. Serum cfDNA was purified and the AR copy number was determined. Factors associated with progression-free survival (PFS) and overall survival (OS) were statistically investigated. RESULTS: The number of patients administered enzalutamide (Enza)/abiraterone (Abi)/docetaxel (DTX) was 33/25/11, respectively. The median PSA was 16.5 ng/ml. Thirty patients (79%) had bone metastases and three patients (7.9%) had lung metastases. The median follow-up was 655 days. The median initial AR copy number was 1.27 (1.10-11.50); an AR copy number of 1.27 or higher was defined as an AR-amp. Regarding PFS, the presence of AR-amp, Gleason score (GS), and ALP were significant factors in univariate analysis. In multivariate analysis, AR amplification was an independent prognostic factor (hazard ratio=7.7, p=0.0035). For OS, PSA and AR-amp were significant factors. In multivariate analysis, AR-amp (hazard ratio=4.65, p=0.0188) was the only independent prognostic factor. CONCLUSION: AR-amp was associated with high nadir PSA and low iPSA/PSA ratio. AR-amp was significantly associated with poor prognosis in Japanese patients with CRPC.

Testosterone bounce predicts favorable prognoses for prostate cancer patients treated with degarelix.

BACKGROUND: To clarify the clinical roles of changes in testosterone (T) levels with a cut-off level of 20 ng/dL as predictive factors for prostate cancer patients treated with degarelix acetate. METHODS: A total of 120 prostate cancer patients who received hormone therapies with gonadotropin-releasing hormone antagonist degarelix acetate were retrospectively analyzed. The predictive values of nadir T levels, max T levels, T bounce, and other clinical factors were evaluated for overall survival (OS), cancer-specific survival (CSS), and progression-free survival (PFS). T bounce was defined as satisfying both nadir serum T levels of <20 ng/dL and max serum T levels of ≥20 ng/dL during hormone therapies. RESULTS: In 120 prostate cancer patients, 16 (13%) patients did not achieve nadir T < 20 ng/dL, and 76 (63%) patients had max T ≥ 20 ng/dL. The median times to nadir T and max T are 108 and 312 days, respectively. T bounce was shown in 60 (50%) patients and is associated with favorable prognoses both for OS (p = 0.0019) and CSS (p = 0.0013) but not for PFS (p = 0.92). While in the subgroup analyses of the patients with the progression of the first-line hormone therapies, T bounce predicts favorable OS (p = 0.0015) and CSS (p = 0.0013) after biochemical recurrence. CONCLUSIONS: The present study revealed that T bounce with cut-off levels of 20 ng/dL is a promising biomarker that predicts OS and CSS for prostate cancer patients treated with degarelix acetate.

Beyond 2D: A scalable and highly sensitive method for a comprehensive 3D analysis of kidney biopsy tissue.

The spatial organization of various cell populations is critical for the major physiological and pathological processes in the kidneys. Most evaluation of these processes typically comes from a conventional 2D tissue cross-section, visualizing a limited amount of cell organization. Therefore, the 2D analysis of kidney biopsy introduces selection bias. The 2D analysis potentially omits key pathological findings outside a 1- to 10-µm thin-sectioned area and lacks information on tissue organization, especially in a particular irregular structure such as crescentic glomeruli. In this study, we introduce an easy-to-use and scalable method for obtaining high-quality images of molecules of interest in a large tissue volume, enabling a comprehensive evaluation of the 3D organization and cellular composition of kidney tissue, especially the glomerular structure. We show that CUBIC and ScaleS clearing protocols could allow a 3D analysis of the kidney tissues in human and animal models of kidney disease. We also demonstrate that the paraffin-embedded human biopsy specimens previously examined via 2D evaluation could be applicable to 3D analysis, showing a potential utilization of this method in kidney biopsy tissue collected in the past. In summary, the 3D analysis of kidney biopsy provides a more comprehensive analysis and a minimized selection bias than 2D tissue analysis. Additionally, this method enables a quantitative evaluation of particular kidney structures and their surrounding tissues, with the potential utilization from basic science investigation to applied diagnostics in nephrology.

L-type amino acid transporter 1 inhibitor JPH203 prevents the growth of cabazitaxel-resistant prostate cancer by inhibiting cyclin-dependent kinase activity.

L-type amino acid transporter 1 (LAT1, SLC7A5) is an amino acid transporter expressed in various carcinomas, and it is postulated to play an important role in the proliferation of cancer cells through the uptake of essential amino acids. Cabazitaxel is a widely used anticancer drug for treating castration-resistant prostate cancer (CRPC); however, its effectiveness is lost when cancer cells acquire drug resistance. In this study, we investigated the expression of LAT1 and the effects of a LAT1-specific inhibitor, JPH203, in cabazitaxel-resistant prostate cancer cells. LAT1 was more highly expressed in the cabazitaxel-resistant strains than in the normal strains. Administration of JPH203 inhibited the growth, migration, and invasive ability of cabazitaxel-resistant strains in vitro. Phosphoproteomics using liquid chromatography-mass spectrometry to comprehensively investigate changes in phosphorylation due to JPH203 administration revealed that cell cycle-related pathways were affected by JPH203, and that JPH203 significantly reduced the kinase activity of cyclin-dependent kinases 1 and 2. Moreover, JPH203 inhibited the proliferation of cabazitaxel-resistant cells in vivo. Taken together, the present study results suggest that LAT1 might be a valuable therapeutic target in cabazitaxel-resistant prostate cancer.

Novel nerve-sparing robot-assisted radical prostatectomy with endopelvic fascia preservation and long-term outcomes for a single surgeon.

Although novel techniques for avoiding incontinence during robot-assisted radical prostatectomy have been developed, long-term oncological outcomes are unknown. The objective of this study was to determine the long-term oncological outcomes and functional outcomes of novel nerve-sparing robot-assisted radical prostatectomy with endopelvic fascia preservation for a single surgeon. Data from 100 patients who underwent structure-preserving prostatectomies performed by a single surgeon were retrospectively analyzed. The median console time was 123 min. Bilateral nerve-sparing was performed in 43% of patients underwent, and 57% underwent unilateral nerve-sparing surgery. Most patients (96%) reached complete pad-zero urinary continence by one year after surgery. Satisfactory erectile function was achieved in 97% of patients who underwent bilateral nerve-sparing surgery, and 80% of patients who underwent unilateral nerve-sparing surgery. The surgical margin was positive for 25% of patients, and the biochemical recurrence-free rate at 5 years was 77%. The cancer-specific survival rate was 100% during the median follow-up period of 4.5 years. Clavien-Dindo grade III complications occurred in 1% of cases. The outcomes for novel nerve-sparing robot-assisted radical prostatectomy with endopelvic fascia preservation were similar to previously reported oncological outcomes, with satisfactory functional outcomes. This operative method may be useful for patients who are eligible for nerve-sparing surgery.

Summary of the Clinical Practice Guidelines for Upper Tract Urothelial Carcinoma 2023 by the Japanese Urological Association.

This article is an English translation of the Clinical Practice Guidelines for Upper Tract Urothelial Carcinoma (2nd edition) published in June 2023. The Japanese Urological Association's (JUA) Guidelines Committee on Upper Tract Urothelial Carcinoma (UTUC) created a 2023 update guideline to support clinicians' current evidence-based management of UTUC and to incorporate its recommendations into clinical practice. The new guideline adhered as closely as possible to the Minds Manual for Guideline Development 2020 ver. 3.0. Findings related to epidemiological, pathological, diagnosis, treatment, and follow-up were reviewed. In addition, seven clinical questions (CQs) were set to determine the grade of recommendation and level of evidence. Preconceptions and biases were removed from the preparation process, the overall evidence was evaluated appropriately, and recommendations were made after fully considering the balance between benefits and harms. Although the evidence is still insufficient to be taken up as a CQ, the latest important information is described in seven columns, and clinical issues that should be resolved in the future related to the CQ are described as recommendations for tomorrow. We hope that these guidelines will help medical professionals, patients, and their families involved in the treatment of UTUC in their decision-making, and hope that a critical review of these guidelines will lead to further refinements in the next edition.

Challenges in the diagnosis of the enigmatic primary adrenal leiomyosarcoma: two case reports and review of the literature.

BACKGROUND: Primary adrenal leiomyosarcoma is a rare and aggressive mesenchymal tumor derived from the smooth muscle wall of a central adrenal vein or its tributaries; therefore, tumors tend to invade the inferior vena cava and cause thrombosis. The great majority of tumors grow rapidly, which makes the disease difficult to diagnose in its early clinical stages and needs differentiation from adrenocortical carcinomas for the selection of chemotherapy including mitotane which causes adrenal insufficiency. CASE PRESENTATION: We presented two patients with adrenal leiomyosarcoma who were referred to our hospital with abdominal pain and harboring large adrenal tumors and inferior vena cava thrombosis. The endocrine findings, including serum catecholamine levels, were unremarkable. These two patients were considered clinically inoperable, and CT-guided core needle biopsy was performed to obtain the definitive histopathological diagnosis and determine the modes of therapy. The masses were subsequently diagnosed as primary adrenal leiomyosarcoma based on the histological features and positive immunoreactivity for SMA (smooth muscle actin), desmin, and vimentin. CONCLUSIONS: Adrenal leiomyosarcoma derived from the smooth muscle wall of a central adrenal vein or its tributaries is rare but should be considered a differential diagnosis in the case of nonfunctioning adrenal tumors extending directly to the inferior vena cava. CT-guided biopsy is considered useful for histopathological diagnosis and clinical management of patients with inoperable advanced adrenal tumors without any hormone excess.

Preoperative PI-RADS v2.1 Scoring System Improves Risk Classification in Patients Undergoing Radical Prostatectomy.

BACKGROUND/AIM: The purpose of this study was to examine the prognostic value of Prostate imaging-reporting and data system (PI-RADS) v2.1 scoring system in patients who underwent radical prostatectomy (RP). PATIENTS AND METHODS: Clinical data of 294 patients who received RP between 2006 and 2018 were reviewed and multiple parameters including PI-RADS v2.1 score were employed to identify predictive factors for biochemical recurrence (BCR). Tumor volume was calculated from prostatectomy specimens. RESULTS: Median age at operation and initial PSA level were 67 years old and 7.68 ng/ml, respectively. 44.9 and 24.8% of patients were diagnosed with PI-RADS score 4 and 5 prior to biopsies, respectively. BCR was observed in 17% of patients and median observation period was 63.43 months. After multivariate analysis, PI-RADS v2.1 score 5 [hazard ratio (HR)=2.24, p=0.0124] was an independent predictive factor of BCR in addition to clinical T stage (≥2c) (HR=2.32, p=0.0093) and biopsy Gleason score (≥8) (HR=2.81, p=0.0007). Furthermore, PI-RADS score 5 significantly stratified the prognosis in D'Amico intermediate- and high-risk groups (p=0.0174 and p=0.0013, respectively). We established novel risk classifications including PI-RADS v2.1 score and found that prognostic capabilities were improved as compared to the D'Amico classification. CONCLUSION: The PI-RADS v2.1 score exhibited significant prognostic value in patients with localized prostate cancer following RP. Risk classifications based on PI-RADS v2.1 score might provide better ability for predicting oncological outcomes as compared to the D'Amico classification system.

Cushing's syndrome in pregnancy in which laparoscopic adrenalectomy was safely performed by a retroperitoneal approach.

Introduction: Laparoscopic adrenalectomy is the standard treatment for adrenal tumors caused by Cushing's syndrome. However, few pregnant women have undergone adrenalectomy because of the risk of general anesthesia and surgery. Case presentation: A 28-year-old woman presented with gradually worsening Cushing's signs at around 12 weeks of pregnancy. Magnetic resonance imaging displayed a 38-mm left adrenal tumor, which was the cause of the adrenal Cushing's syndrome. Metyrapone was started, which increased androgen levels. Since the management of Cushing's syndrome by medication alone is challenging, unilateral laparoscopic adrenalectomy by a retroperitoneal approach was performed at 23 weeks of the pregnancy. No perioperative complications were noted. Conclusion: Adrenalectomy is considered safe in pregnant women with Cushing's syndrome. Laparoscopic adrenalectomy by retroperitoneal approach should be chosen and performed between 14 and 30 weeks of pregnancy to prevent mother and fetal complications.

A case of ipsilateral three simultaneous renal cell carcinomas with different histologic types.

Introduction: Few reports have presented sporadic multifocal renal cell carcinomas of different histologic types occurring simultaneously in a single kidney. Here, we present a case of three ipsilateral renal cell carcinomas with three histologic types. Case presentation: A 44-year-old man with end-stage renal disease due to nephrosclerosis was referred to our hospital for an incidental renal tumor. Following the introduction of hemodialysis, enhanced computed tomography revealed a renal tumor suggestive of clear-cell renal cell carcinoma with a cystic component. With a preoperative diagnosis of one renal tumor, he underwent laparoscopic radical nephrectomy. However, pathological examination revealed three renal cell carcinomas with three histological diagnoses: clear-cell, papillary, and clear-cell papillary renal cell carcinomas. Conclusion: Preoperative imaging may not detect all synchronous ipsilateral multifocal renal cell carcinomas. Patients with severe renal function impairment may have synchronous multifocal renal cell carcinomas.

A case of bladder cancer after bilateral lung transplantation following bone marrow transplantation.

Introduction: The incidence of bladder cancer following transplantation is high; however, no previous studies have reported the development of bladder cancer following bone marrow and bilateral lung transplantations. Case presentation: A 42-year-old man who was followed for bilateral lung transplantation due to chronic graft-versus-host disease following bone marrow transplantation complained of gross hematuria. Transurethral resection of the bladder tumor was performed for cT1N0M0 bladder cancer. On the following night, he experienced severe respiratory failure and was intubated. He was discharged on postoperative day 32 with the introduction of home oxygen therapy. The pathological diagnosis was invasive urothelial carcinoma, high-grade, pT1, with urothelial carcinoma in situ. Further treatment could not be performed because of his poor performance status and immunosuppressive state. Conclusion: Vigorous screening for bladder cancer coexisting with other malignancies should be performed for transplant recipients for the early diagnosis and prompt treatment of a relatively aggressive bladder cancer.

Efficacy and safety of second-line cabozantinib after immuno-oncology combination therapy for advanced renal cell carcinoma: Japanese multicenter retrospective study.

Immuno-oncology (IO) combination therapy is utilized as a first-line systemic treatment for advanced renal cell carcinoma. However, evidence supporting the use of cabozantinib after IO combination therapy is lacking. We retrospectively analyzed patients who received second-line cabozantinib after IO combination therapy using the Japanese Urological Oncology Group (JUOG) database. In total, 254 patients were enrolled in the JUOG global study, and 118 patients who received second-line cabozantinib comprised the study cohort. The objective response rate, disease control rate, second-line cabozantinib progression-free survival (PFS), and overall survival from second-line for overall were 32%, 75%, 10.5 months, and not reached, respectively, for first-line IO-IO therapy were 37%, 77%, 11.1 months, and not reached, respectively, versus 24%, 71%, 8.3 months, and not reached, respectively, for first-line IO-tyrosine kinase inhibitor therapy. In univariate and multivariate analyses, discontinuation of first-line treatment because of progressive disease and liver metastasis were independent risk factors for PFS. All-grade adverse events occurred in 72% of patients, and grade 3 or higher adverse events occurred in 28% of patients. Second line-cabozantinib after first-line IO combination therapy for advanced renal cell carcinoma was expected to be effective after either IO-IO or IO-TKI treatment and feasible in real-world practice.