Soluble Immune Checkpoint Molecules as Predictors of Efficacy in Immuno-Oncology Combination Therapy in Advanced Renal Cell Carcinoma.

Immuno-oncology (IO) combination therapy is the first-line treatment for advanced renal cell carcinoma (RCC). However, biomarkers for predicting the response to IO combination therapy are lacking. Here, we investigated the association between the expression of soluble immune checkpoint molecules and the therapeutic efficacy of IO combination therapy in advanced RCC. The expression of soluble programmed cell death-1 (sPD-1), soluble programmed cell death ligand-1 (sPD-L1), soluble PD-L2 (sPD-L2), and lymphocyte activation gene-3 (sLAG-3) was assessed in plasma samples from 42 patients with advanced RCC who received first-line IO combination therapy. All IMDC risk classifications were represented among the patients, including 14.3, 57.1, and 28.6% with favorable, intermediate, and poor risk, respectively. Univariate analysis revealed that prior nephrectomy, sPD-L2 levels, and sLAG-3 levels were significant factors affecting progression-free survival (PFS), whereas multivariate analyses suggested that sPD-L2 and sLAG-3 levels were independent prognostic factors for PFS. In a univariate analysis of the overall survival, prior nephrectomy and sPD-L2 levels were significant factors; no significant differences were observed in the multivariate analysis. No significant correlation was observed between the sPD-L2 and sLAG-3 levels and PD-L2 and LAG-3 expression via immunohistochemistry. In conclusion, sPD-L2 and sLAG-3 expression may serve as a potential biomarker for predicting IO combination therapy efficacy.

Sarcopenia and the Therapeutic Effects of Androgen Receptor-axis-targeted Therapies in Patients With Castration-resistant Prostate Cancer.

BACKGROUND/AIM: Sarcopenia is a syndrome characterized by the progressive and generalized loss of skeletal muscle mass and has been reported to be a poor prognostic factor for taxane-treated castration-resistant prostate cancer (CRPC). However, whether sarcopenia affects androgen receptor axis-targeted therapies (ARATs) remains unknown. In the present study, we investigated the association between sarcopenia in CRPC and treatment outcomes of ARATs. PATIENTS AND METHODS: From January 2015 to September 2022, 127 patients who received ARATs as 1st-line treatment for CRPC at our two hospitals were included in the study. We retrospectively evaluated sarcopenia using computed tomography images and investigated whether sarcopenia affects the progression-free survival (PFS) and overall survival (OS) of patients with CRPC treated with ARATs. RESULTS: Out of 127 patients, 99 were diagnosed with sarcopenia. The PFS of the sarcopenic group administered ARATs was significantly better than that of the non-sarcopenic group. Furthermore, in the multivariate analysis of PFS, sarcopenia was an independent favourable prognostic factor. However, there was no significant difference in the OS between the sarcopenic and non-sarcopenia groups. CONCLUSION: ARATs could more effectively treat patients with CRPC and sarcopenia than patients with CRPC without sarcopenia. Sarcopenia may positively influence the therapeutic effects of ARATs.

Prognostic Value of Absolute Lymphocyte Count in Patients with Advanced Renal Cell Carcinoma Treated with Nivolumab Plus Ipilimumab.

Nivolumab and ipilimumab (NIVO + IPI) is standard therapy for patients with advanced renal cell carcinoma (RCC). Absolute lymphocyte count (ALC) is a valuable prognostic factor in patients with various cancers treated with immune checkpoint inhibitors. Herein, we determined the prognostic value of pretreatment ALC in advanced RCC patients treated with NIVO + IPI as first-line therapy. Data from 46 advanced RCC patients treated with NIVO + IPI between September 2018 and August 2022 were retrospectively reviewed and analyzed. Median progression-free survival (PFS) and overall survival (OS) were significantly shorter in patients with low than high ALC (PFS: p = 0.0095; OS: p = 0.0182). Multivariate analysis suggested that prior nephrectomy [hazard ratio (HR) = 3.854, 95% confidence interval (CI) = 1.433-10.359, p = 0.0075] and pretreatment ALC (HR = 2.513, 95% CI = 1.119-5.648, p = 0.0257) were independent factors for PFS. Our new prognostic ALNx model based on ALC and prior nephrectomy suggested that the poor-risk group was a predictor of significantly worse PFS (p < 0.0001) and OS (p = 0.0016). Collectively, the developed ALNx model may be a novel predictor of response in advanced RCC patients treated with NIVO + IPI.

Improved Survival of Real-world Japanese Patients With Advanced Renal Cell Carcinoma Treated With Immuno-oncology Combination Therapy.

BACKGROUND/AIM: Immuno-oncology (IO) combination therapy has become the standard of treatment for advanced renal cell carcinoma (RCC). In this retrospective study, we compared the efficacy of first-line molecular targeted therapy (MTT), administered as monotherapy, and IO combination therapy using real-world data of Japanese patients. PATIENTS AND METHODS: The clinical information of 202 patients with RCC who received MTT (n=144) or IO combination therapy (n=58) at the Kurume University Hospital from May 2008 to May 2022 was collected and retrospectively analyzed. The Cox proportional hazards model was used for univariate and multivariate analyses, with hazard ratios (HRs) and 95% confidence intervals (CIs) calculated. RESULTS: The patients treated with IO combination therapy had a prolonged progression-free survival (PFS) compared with those treated with MTT (p=0.0038). IO combination therapy was significantly associated with a better PFS in patients with intermediate (p=0.0072) and poor risk (p=0.0411) but not in those with favorable risk (p=0.5434). Furthermore, overall survival with IO combination therapy was significantly better in patients at poor risk (p=0.0335). Multivariate analyses suggested that prior nephrectomy (HR=1.501, 95%CI=1.048-2.150, p=0.0268) and first-line therapy (HR=1.962, 95%CI=1.288-2.986, p=0.0017) were independent prognostic factors for PFS. CONCLUSION: IO combination therapy significantly improved the PFS of patients with advanced RCC, especially those with intermediate- and poor-risk disease. Further investigations focusing on the improvement of survival are warranted.

Immediate Prostate-specific Antigen Decline After Enzalutamide Following Abiraterone Predicts Survival in Castration-resistant Disease.

BACKGROUND/AIM: Although the sequential use of abiraterone and enzalutamide is not recommended because of possible cross-resistance, many patients with metastatic castration-resistant prostate cancer (mCRPC) are receiving sequential abiraterone and enzalutamide in the real world, and a subset of patients can benefit from sequential therapy with these drugs. This study aimed to identify patients who could benefit from the sequential use of enzalutamide after abiraterone use. PATIENTS AND METHODS: We included 70 patients with mCRPC who received enzalutamide sequentially following abiraterone treatment. Decline in the prostatespecific antigen (PSA) levels at 4 weeks after enzalutamide initiation and the association between decline in PSA levels and survival were analyzed. RESULTS: Sixteen men (22.9%) achieved a decline of >50% in PSA levels after 4 weeks of enzalutamide administration. Overall survival (OS) after enzalutamide among men with >50% decline at 4 weeks was significantly better than that among men with a PSA decline <50% (not reached vs. 34 months, p=0.008). OS after first-line abiraterone treatment for men with PSA decline >50% and <50% was not reached and 46 months, respectively (p=0.007). A PSA decline of >50% at 4 weeks of enzalutamide administration was an independent predictor of longer OS. CONCLUSION: A PSA decline of >50% at 4 weeks after the start of sequential enzalutamide treatment following abiraterone treatment predicted long-term survival in patients with mCRPC. Early PSA decline can identify patients who benefit from second-line enzalutamide after abiraterone treatment and can be useful as a decision-making tool regarding treatment.

Survival outcomes of non-definitive therapy for muscle-invasive bladder cancer.

To analyze the risks and survival outcomes of non-definitive therapy (nDT) for muscle-invasive bladder cancer (MIBC), which may provide useful information for future treatment selection, the present study analyzed 124 patients who were diagnosed with MIBC (cT2-4aN1-2M0) and treated at Kurume University Hospital (Kurume, Japan) with definitive therapy (DT; including radical cystectomy and trimodal therapy) or nDT [transurethral resection of bladder tumor (TURBT) monotherapy or TURBT plus chemotherapy]. Differences in survival outcomes between the two groups were estimated using the Kaplan-Meier method and analyzed using the log-rank test. Cox proportional hazards regression models were used for multivariate analysis of each survival outcome. Of the 124 patients, 45% were treated with nDT, and among these, 50% were treated with TURBT monotherapy and 50% were treated with TURBT plus chemotherapy. Of the patients who chose definitive treatment, 69% were treated with radical cystectomy. The median age in the nDT group was 77 years, which was significantly higher than that in the DT group. Additionally, the proportion of patients with poor performance status, high Charlson comorbidity index and high neutrophil-lymphocyte ratio values was significantly higher in the nDT group. nDT was associated with significantly reduced overall survival, cancer-specific survival and progression-free survival rates, and was a poor prognostic factor for all survival outcomes compared with DT. In conclusion, nDT was associated with a high cancer-related mortality risk. The most appropriate treatment method should be discussed with the patients after providing them with sufficient information on the risks and benefits of each treatment method.

Immune-related adverse events are clinical biomarkers to predict favorable outcomes in advanced renal cell carcinoma treated with nivolumab plus ipilimumab.

BACKGROUND: Immune checkpoint inhibitors cause various immune-related adverse events. The present study examined the association between the incidence of immune-related adverse events and survival outcomes in patients treated with nivolumab plus ipilimumab for patients with advanced renal cell carcinoma. In addition, we compared the effect of adverse event profiles on survival for patients receiving nivolumab plus ipilimumab. METHODS: A total of 35 patients with advanced renal cell carcinoma who were treated with nivolumab plus ipilimumab from August 2018 to August 2021 were retrospectively reviewed and analyzed. Cox proportional hazards models were used for univariate and multivariate analyses, and hazard ratio and 95% confidence intervals were calculated. RESULTS: Of the 35 patients, 22 (62.9%) experienced immune-related adverse events. The median progression-free survival (P = 0.0012) and overall survival (P = 0.0147) were significantly longer in patients with immune-related adverse events than in those without immune-related adverse events. Multivariate analysis showed that the incidence of immune-related adverse events was an independent factor for progression-free survival (hazard ratio = 4.940, 95% confidence interval: 1.558-15.664, P = 0.0067). Skin reaction was a positive predictive immune-related adverse events for progression-free survival (hazard ratio = 9.322, 95% confidence interval: 1.954-44.475, P = 0.0051). CONCLUSION: Patients with advanced renal cell carcinoma with immune-related adverse events had superior clinical outcomes of nivolumab plus ipilimumab treatment than those without immune-related adverse events. Skin immune-related adverse events may be effective biomarkers in patients with advanced renal cell carcinoma treated with nivolumab plus ipilimumab.

Absolute lymphocyte count is an independent predictor of survival in patients with metastatic renal cell carcinoma treated with nivolumab.

OBJECTIVE: Programmed cell death-1 antibody therapy has demonstrated improved progression-free survival and overall survival in patients with metastatic renal cell carcinoma. However, there are limited studies on biomarkers that can predict the efficacy of immune checkpoint inhibitors. We examined the influence of peripheral inflammatory biomarkers on the clinical outcomes of patients with metastatic renal cell carcinoma treated with nivolumab. METHODS: Data of 38 patients with metastatic renal cell carcinoma, who were treated with nivolumab monotherapy after receiving at least one molecular targeted therapy from November 2016 to February 2021, were retrospectively reviewed and analyzed. RESULTS: Median progression-free survival and overall survival were significantly shorter in patients with low absolute lymphocyte count (<1300/µl) versus those with high absolute lymphocyte count (progression-free survival: P = 0.0102; overall survival: P = 0.0026). Median overall survival was shorter in patients with high neutrophil-lymphocyte ratio (≥3.0) versus those with low neutrophil-lymphocyte ratio (P = 0.0344). Multivariate analysis showed that absolute lymphocyte count was an independent factor for progression-free survival (hazard ratio = 2.332, 95% confidence interval = 1.012-5.375, P = 0.0468) and overall survival (hazard ratio = 4.153, 95% confidence interval = 1.108-15.570, P = 0.0347). Increased absolute lymphocyte count, 1 month after nivolumab initiation, was a positive predictive factor for progression-free survival (hazard ratio = 0.419, 95% confidence interval = 0.189-0.926, P = 0.0317) and overall survival (hazard ratio = 0.285, 95% confidence interval = 0.091-0.890, P = 0.0308). CONCLUSION: Our study indicates that peripheral absolute lymphocyte count, before nivolumab initiation, is a predictor of poor response in metastatic renal cell carcinoma. Additionally, increased absolute lymphocyte count, 1 month post-nivolumab initiation, can be a predictor of the effects of nivolumab.

Distribution, shape, and immunohistochemical characteristics of serotonin-immunoreactive neuroendocrine cells in the urethra and periurethral genital organs in mice.

The aim of this study is to clarify the disibution, shape, and immunohistochemical characteristics of serotonin-immunoreactive neuroendocrine cells (SIR-NECs) in mouse prostate and in the surrounding genital organs by histological and immunohistochemical analysis of the light microscopic serial sections of urethra. We collected lower urinary tracts from 13-week-old mice and observed the distribution pattern and shape of the SIR-NECs by serial light microscopy. The organs on the sections were divided into three anatomical zones to clarify the distribution pattern of SIR-NECs: (1) zone A, the ducts near the prostatic urethra; (2) zone B, the ducts outside the urethral sphincter; and (3) zone C, the acinus areas. Sections were double immune-stained with antibodies against serotonin and one of neuroendocrine-related factors (NRFs), including 10 neural cell markers and eight neurotransmitters, and also 4',6-diamino-2-phenylindole (DAPI). In addition, SIR-NECs were double immune-stained with antibodies against cytokeratin 5 (CK5) and p63, together with DAPI. SIR-NECs were mostly localized in zone A, and no SIR-NECs were observed in zone C. The proportion of flask-shaped SIR-NECs was approximately 15% in zones A and B. No flask-shaped SIR-NECs were observed in urethral epithelia. The NRFs co-localized with SIR-NEC were calcitonin gene-related peptide, CD56, chromogranin A, neuron-specific enolase, neuron cytoplastic protein 9.5, and synaptophysin (72.3%, 73.2%, 88.9%, 92.3%, 91.7%, and 81.9%, respectively). CK5 and p63 were not co-localized with SIR-NECs.　In this study, SIR-NEC of the urethra and the surrounding genital organs was ubiquitous in the urethra and the ducts near the urethra and co-expressed specific nerve-related NRFs.

Baseline prostate-specific antigen levels following treatment with abiraterone acetate as a prognostic factor in castration-resistant prostate cancer.

The aim of the present study was to investigate the prognostic factors associated with progression-free survival (PFS) and overall survival (OS) times in patients with castration-resistant prostate cancer (CRPC) who received treatment with abiraterone acetate (AA) in routine clinical settings. A total of 93 patients treated with AA between September 2014 and February 2017 were selected and their medical records were analyzed retrospectively. The median PFS time of docetaxel (DTX)-naïve patients was 171 days, and that of post-DTX patients was 56 days. The OS time of DTX-naïve patients did not reach the median. The median OS time of post-DTX patients was 761 days. Multivariate analyses identified baseline prostate-specific antigen (PSA) level prior to treatment with AA and the PSA response rate as independent prognostic factors for PFS time, and baseline PSA prior to treatment with AA as the only independent prognostic factor for OS time. The results of the present study indicate that the baseline PSA level prior to treatment with AA is a notable prognostic factor in patients with CRPC.

Prostate cancer with disseminated carcinomatosis of the bone marrow: Two case reports.

Disseminated carcinomatosis of the bone marrow (DCBM) is caused by cancer metastasis to the bone marrow and is often accompanied by disseminated intravascular coagulation (DIC), with rapid clinical progression. We herein report two cases receiving treatment with combined androgen blockade (CAB) and denosumab for prostate cancer with DCBM. The patient in case 1 was an 80-year-old man who was admitted with a 3-day history of melena and was diagnosed with prostate cancer with DCBM by bone marrow biopsy. Despite receiving therapy with CAB and denosumab, the patient developed castration-resistant prostate cancer (CRPC) with accompanying relapse of DIC and succumbed to the disease 7 months later. The patient in case 2 was a 64-year-old man who was admitted with bleeding after a tooth extraction. After a diagnosis of prostate cancer with DCBM, CAB therapy was administered. Enzalutamide was administered following development of CRPC, and the patient has not since experienced an increase in prostate-specific antigen, recurrence of anemia or DIC. To the best of our knowledge, these are the first documented cases in which DCBM was treated with denosumab and enzalutamide.

Transarterial embolization for pelvic hematoma following laparoscopic radical prostatectomy: A case report and review of the literature.

The present study reports a case of hemorrhage from branches of the right obturator artery following laparoscopic radical prostatectomy. On post-operative day 9, the patient complained of lower abdominal pain, and the hemoglobin and hematocrit levels had decreased. Emergency computed tomography angiography showed a large pelvic hematoma suggesting active bleeding. Transarterial embolization (TAE) was performed using microcoils. There were no post-procedure complications. At 3 months post-surgery, using computed tomography, the pelvic hematoma was shown to have been absorbed. To the best of our knowledge, TAE for a hemorrhage from the obturator artery following laparoscopic prostatectomy has not previously been described. TAE is a safe and minimally invasive treatment compared with surgical intervention, and should be considered as a treatment for post-operative arterial hemorrhage.