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

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

Oxidative stress in peroxisomes induced by androgen receptor inhibition through peroxisome proliferator-activated receptor promotes enzalutamide resistance in prostate cancer.

Androgen receptor (AR)-targeting therapy induces oxidative stress in prostate cancer. However, the mechanism of oxidative stress induction by AR-targeting therapy remains unclear. This study investigated the mechanism of oxidative stress induction by AR-targeting therapy, with the aim to develop novel therapeutics targeting oxidative stress induced by AR-targeting therapy. Intracellular reactive oxygen species (ROS) was examined by fluorescence microscopy and flow cytometry analysis. The effects of silencing gene expression and small molecule inhibitors on gene expression and cytotoxic effects were examined by quantitative real-time PCR and cell proliferation assay. ROS induced by androgen depletion co-localized with peroxisomes in prostate cancer cells. Among peroxisome-related genes, PPARA was commonly induced by AR inhibition and involved in ROS production via PKC signaling. Inhibition of PPARα by specific siRNA and a small molecule inhibitor suppressed cell proliferation and increased cellular sensitivity to the antiandrogen enzalutamide in prostate cancer cells. This study revealed a novel pathway by which AR inhibition induced intracellular ROS mainly in peroxisomes through PPARα activation in prostate cancer. This pathway is a promising target for the development of novel therapeutics for prostate cancer in combination with AR-targeting therapy such as antiandrogen enzalutamide.

Importance of 3ß-hydroxysteroid dehydrogenases and their clinical use in prostate cancer.

Androgen receptor signaling is crucial for the development of treatment resistance in prostate cancer. Among steroidogenic enzymes, 3ß-hydroxysteroid dehydrogenases (3ßHSDs) play critical roles in extragonadal androgen synthesis, especially 3ßHSD1. Increased expression of 3ßHSDs is observed in castration-resistant prostate cancer tumors compared with primary prostate tumors, indicating their involvement in castration resistance. Recent studies link 3ßHSD1 to resistance to androgen receptor signaling inhibitors. The regulation of 3ßHSD1 expression involves various factors, including transcription factors, microenvironmental influences, and posttranscriptional modifications. Additionally, the clinical significance of HSD3B1 genotypes, particularly the rs1047303 variant, has been extensively studied. The impact of HSD3B1 genotypes on treatment outcomes varies according to the therapy administered, suggesting the potential of HSD3B1 genotyping for personalized medicine. Targeting 3ßHSDs may be a promising strategy for prostate cancer management. Overall, understanding the roles of 3ßHSDs and their genetic variations may enable the development and optimization of novel treatments for prostate cancer.

Validation study on the 2 mm diameter cutoff in lymph node-positive cases following radical prostatectomy in accordance with the AJCC/UICC TNM 8th edition: Real-world data analysis from a Japanese cohort.

OBJECTIVES: The American Joint Committee on Cancer (AJCC)/Union for International Cancer Control (UICC) 8th edition has proposed micrometastasis as a lymph node metastasis (LN+) of diameter ≤2 mm in prostate cancer. However, supporting evidence has not described. We evaluated LN+ patients' survival after radical prostatectomy (RP) based on the LN maximum tumor diameter (MTD). METHODS: Data from 561 LN+ patients after RP and pelvic LN dissection (PLND) treated between 2006 and 2019 at 33 institutions were retrospectively investigated. Patients were stratified by a LN+ MTD cutoff of 2 mm. Outcomes included castration resistance-free survival (CRFS), metastasis-free survival (MFS), cancer-specific survival (CSS), and overall survival (OS). RESULTS: In total, 282 patients were divided into two groups (LN+ MTD >2 mm [n = 206] and ≤2 mm [n = 76]). Patients of LN+ status >2 mm exhibited significantly decreased CRFS and MFS, and poorer CSS and OS. No patients developed CRPC in the LN+ status ≤2 mm group when the PLND number was ≥14. Multivariate analysis showed the number of LN removed, RP Gleason pattern 5, and MTD in LN+ significantly predicted CRFS. CONCLUSIONS: Patients of LN+ status ≤2 mm showed better prognoses after RP. In all the patients in the ≤2-mm group, the progression to CRPC could be prevented with appropriate interventions, particularly when PLND is performed accurately. Our findings support the utility of the pN substaging proposed by the AJCC/UICC 8th edition; this will facilitate precision medicine for patients with advanced prostate cancer.

The Role of Adipocytokines and their Receptors in Prostate Cancer: Adiponectin May Protect Against Progression.

BACKGROUND/AIM: Obesity is correlated with an increased risk of developing malignancies, including prostate cancer. Adipocytokines, such as leptin and adiponectin, are a family of hormones derived from adipose tissue that are involved not only in metabolism, but also in the development and progression of various malignancies. However, little is known about their role in prostate cancer. This study aimed to determine how leptin, adiponectin, and their receptors impact the spread of prostate cancer. MATERIALS AND METHODS: We first performed immunohistochemical analysis of prostate cancer tissue microarrays to detect leptin, leptin receptor (Ob-R), adiponectin, and adiponectin receptors 1 and 2 (AdipoR1 and AdipoR2). Wound healing assays and western blot analysis were then performed in human prostate cancer cell lines. RESULTS: Immunohistochemistry showed that prostate tissue was not significantly positive for adiponectin. However, its expression tended to decrease according to the International Society of Urological Pathology (ISUP) grade of prostate cancer (p=0.056). In prostate cancer cell lines, administration of the synthetic adiponectin AdipoRon suppressed cell migration as well as the expression of phospho-NF-[Formula: see text]B and cyclooxygenase-2, whereas leptin stimulated these effects. CONCLUSION: Adiponectin expression tended to be suppressed according to ISUP grade in prostate cancer tissues. In vitro, tumor cell migration was induced by leptin but suppressed by adiponectin. Targeting adipocytokines could be a novel treatment strategy for prostate cancer.

Prognostication in Lymph Node-Positive Prostate Cancer with No PSA Persistence After Radical Prostatectomy.

BACKGROUND: This study aimed to create a prognostic model to predict disease recurrence among patients with lymph node involvement but no prostate-specific antigen (PSA) persistence and to explore its clinical utility. METHODS: The study analyzed patients with lymph node involvement after pelvic lymph node dissection with radical prostatectomy in whom no PSA persistence was observed between 2006 and 2019 at 33 institutions. Prognostic factors for recurrence-free survival (RFS) were analyzed by the Cox proportional hazards model. RESULTS: Among 231 patients, 127 experienced disease recurrence. The factors prognostic for RFS were PSA level at diagnosis (≥ 20 vs. < 20 ng/mL: hazard ratio [HR], 1.66; 95% confidence interval [CI], 1.09-2.52; P = 0.017), International Society of Urological Pathology grade group at radical prostatectomy (RP) specimen (group ≥ 4 vs. ≤ 3: HR, 1.63; 95% CI 1.12-2.37; P = 0.010), pathologic T-stage (pT3b/4 vs. pT2/3a: HR, 1.70; 95% CI 1.20-2.42; P = 0.0031), and surgical margin status (positive vs. negative: HR, 1.60; 95% CI 1.13-2.28; P = 0.0086). The prognostic model using four parameters were associated with RFS and metastasis-free survival. CONCLUSION: The prognostic model in combination with postoperative PSA value and number of lymph nodes is clinically useful for discussing treatment choice with patients.

The effect of human leukocyte antigen genotype on survival in advanced prostate cancer treated with primary androgen deprivation therapy: the KYUCOG-1401-A study.

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

Clinical features and oncological outcomes of bladder cancer microsatellite instability.

OBJECTIVES: Excellent anticancer effect for solid tumors with microsatellite instability (MSI)-high by anti-PD-1 antibody has been reported. In this study, we investigated the clinical impact of MSI status in bladder cancer. METHODS: This study included 205 Japanese patients who underwent transurethral resection for bladder cancer between 2005 and 2021. The prevalence rates of microsatellite stable (MSS), MSI-low (MSI-L), and MSI-high (MSI-H) were determined using molecular testing. We examined the association of MSI status (MSS versus MSI-L/H) with clinicopathological characteristics and oncological outcomes. RESULTS: MSI-L/H tumors were associated with higher T-category in non-muscle invasive bladder cancer (NMIBC). Additionally, MSI-L/H tumors were associated with a higher risk of intravesical recurrence in NMIBC patients treated with intravesical bacillus Calmette-Guérin (BCG) but not with non-BCG therapy. CONCLUSIONS: This study suggested that the MSI status might serve as a predictive marker for intravesical recurrence after BCG intravesical therapy in NMIBC and highlighted an unmet need for an alternative treatment in patients with MSI-L/H tumors.

Salvage robot-assisted radical prostatectomy after carbon ion radiotherapy to the prostate.

PURPOSE: This study presents the surgical and oncological outcomes of salvage robot-assisted radical prostatectomy (RARP) after carbon ion radiotherapy at a single institution. METHODS: Patients who underwent salvage RARP for local recurrence after carbon ion radiotherapy at Kyushu University Hospital between 2020 and 2023 were included. A single surgeon performed salvage RARP with extended pelvic lymph node dissection. Clinicopathological characteristics and perioperative and postoperative outcomes were prospectively collected and electronically recorded. RESULTS: Ten cases were included. The preoperative clinical T-stage was T2, except for one case with T3a. The median console time was 171 min (range, 135-226 min). No severe perioperative or postoperative complications were noted. The pathological T-stage was T2, T3a, and T3b in four, four, and two cases, respectively. Biochemical recurrence was observed in one patient at 31.2 months after surgery. For patients with more than 1 year of follow-up, urinary continence recovery with ≤1 pad was achieved in two cases within 1 year, whereas four cases did not recover urinary continence within 1 year. CONCLUSIONS: This case series demonstrated the feasibility of salvage RARP after carbon ion radiotherapy. Although the urinary continence recovery was modest, short-term disease control was favorable.

Field experiment of a telesurgery system using a surgical robot with haptic feedback.

PURPOSE: To verify the usefulness of haptic feedback in telesurgery and improve the safety of telerobotic surgery. METHODS: The surgeon's console was installed at two sites (Fukuoka and Beppu; 140 km apart), and the patient cart was installed in Fukuoka. During the experiment, the surgeon was blinded to the haptic feedback levels and asked to grasp the intestinal tract in an animal model. The surgeon then performed the tasks at each location. RESULTS: No marked differences in task accuracy or average grasping force were observed between the surgeon locations. However, the average task completion time was significantly longer, and the system usability scale (SUS) was significantly lower rating for remote operations than for local ones. No marked differences in task accuracy or task completion time were observed between the haptic feedback levels. However, with haptic feedback, the organ was grasped with a significantly weaker force than that without it. Furthermore, with haptic feedback, experienced surgeons in robotic surgery tended to perform an equivalent task with weaker grasping forces than inexperienced surgeons. CONCLUSION: The haptic feedback function is a tool that allows the surgeon to perform surgery with an appropriate grasping force, both on site and remotely. Improved safety is necessary in telesurgery; haptic feedback will thus be an essential technology in robotic telesurgery going forward.

Adverse Events of Cabozantinib Plus Nivolumab Versus Ipilimumab Plus Nivolumab.

INTRODUCTION: Recently, many agents and combinations for metastatic and advanced renal cell carcinoma have been approved. This study aims to highlight the comprehensive differences in adverse events (AEs) between cabozantinib (CAB) plus nivolumab (NIVO) and ipilimumab (IPI) plus NIVO based on a real-world big dataset. MATERIAL AND METHODS: We downloaded AE datasets of IPI + NIVO and CAB + NIVO from the Food and Drug Administration Adverse Event Reporting System database. We used the Medical Dictionary for Regulatory Activities to treat each AE as a preferred term and grouped it into the System Organ Class (SOC). We performed logistic regression analyses to compare IPI + NIVO and CAB + NIVO. RESULTS: The incidence rates of 7 types of toxicities were higher for CAB + NIVO than for IPI + NIVO. On the other hand, the incidence rates of 3 types of toxicities were higher for IPI + NIVO than for CAB + NIVO. Serious AEs were higher in patients receiving IPI + NIVO. CONCLUSION: Our findings suggest that both combination therapies presented a disproportionate distribution of toxicities in several SOC. These findings may help clinicians select suitable therapy for the individual and improve the safety profile in patients with advanced renal cell carcinoma receiving NIVO + IPI and NIVO + CAB in a real-world setting.

Comprehensive genomic profiling testing in Japanese castration-resistant prostate cancer patients: results of a single-center retrospective cohort study.

OBJECTIVE: Comprehensive genomic profiling testing using a hybrid-capture next-generation sequencing is commonly used in clinical practice to employ precision medicine in cancer treatment worldwide. In this study, we aimed to analyze the profiles obtained using comprehensive genomic profiling testing that was performed in Japanese castration-resistant prostate cancer patients and to discuss the genetic findings in a real-world setting. METHODS: A total of 60 cases and 57 castration-resistant prostate cancer patients underwent comprehensive genomic profiling testing between 1 January 2021 and 31 December 2022. Four types of comprehensive genomic profiling testing were selected, and clinically significant cancer-specific gene alterations were identified. RESULTS: The median age of patients was 74 years, and the median prostate-specific antigen value at the time of submission was 18.6 ng/ml. Fifty-seven (95%) of 60 cases were metastatic castration-resistant prostate cancers, and 3 cases (5%) were non-metastatic. Among all genetic alterations, androgen-receptor alteration was the most frequently detected in 17 cases (28.3%), followed by 15 cases of TP53 (25.0%), 14 cases of CDK12 (23.3%), 10 cases of phosphatase and tensin homolog (16.7%) and 9 cases of ATM (15.0%) mutations. A total of 13 patients (21.7%) received systemic therapy according to the comprehensive genomic profiling testing results. Overall, the survival rate was significantly greater in the group treated through systemic therapy based on comprehensive genomic profiling testing compared with the group without new therapeutic treatment (P = 0.041). CONCLUSIONS: Comprehensive genomic profiling testing is recommended in castration-resistant prostate cancer patients identified as resistant to standard therapy as this can provide a new therapeutic option.

GnRH antagonist monotherapy versus a GnRH agonist plus bicalutamide for advanced hormone-sensitive prostate cancer; KYUCOG-1401.

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

Validation of schedules for optimal prostate-specific antigen monitoring after radical prostatectomy.

BACKGROUND: Early detection of biochemical recurrence (BCR) after radical prostatectomy (RP) is crucial for early treatment and improving survival outcomes. The optimal prostate-specific antigen (PSA) monitoring remains unclear, and several models have been proposed. We aimed to externally validate four models for optimal PSA monitoring after RP and propose modifications to improve them. METHODS: We reviewed the clinicopathological data of 896 patients who underwent robot-assisted RP between 2009 and 2022. We examined all PSA values and estimated the PSA value for four monitoring schedules at each time point in the virtual follow-up. We defined the ideal PSA for BCR detection between 0.2 and 0.4 ng/mL. RESULTS: During the median follow-up of 21.4 months, 128 (14.3%) patients presented BCR. The original and modified Keio models, National Cancer Center Hospital model, and American Urological Association/American Society for Radiation Oncology model detected BCR in 14 (10.9%), three (2.3%), 12 (9.4%), and 11 (8.6%) patients with PSA >0.4 ng/mL. Most patients experienced BCR detected with PSA >0.4 ng/mL during the first year postoperative. The modification of interval within 6 months postoperative avoided BCR detection with PSA >0.4 ng/mL within the first year postoperative in 8/9 (88.9%), 1/2 (50.0%), 5/6 (83.3%), and 4/4 (100%) for the original and modified Keio models, National Cancer Center Hospital model, and American Urological Association/American Society for Radiation Oncology model, respectively. CONCLUSION: We validated four models for PSA monitoring after RP to detect BCR and suggested modifications to avoid detections out of the desired range of PSA. These modifications could help to establish an optimal PSA monitoring schedule after RP.

Current status and future perspective of immunotherapy for renal cell carcinoma.

In the last decade, the standard treatment for advanced renal cell carcinoma (RCC) has evolved, mainly driven by the development and approval of immune checkpoint inhibitors (ICIs). Currently, ICI monotherapy and ICI-based combinations with tyrosine kinase inhibitors and targeted therapies against mammalian target of rapamycin or vascular endothelial growth factor have become new standard treatments for first-line and subsequent-line therapies. ICIs play an important role as an adjuvant postoperative therapy, and this field is the subject of active research. Furthermore, ongoing randomized controlled trials are investigating the clinical value of more intense treatments by combining multiple effective treatments for RCC. Additionally, novel biomarkers for prognosis have been investigated. This study reviews the current evidence on immunotherapy as a treatment for RCC patients, randomized controlled trials, and ongoing studies including RCC patients and recent findings, and discusses future perspectives.

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

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