We have found that intestinal bacteria and their metabolites, short‐chain fatty acids (SCFAs), promote cancer growth in prostate cancer (PCa) mouse models. To clarify the association between gut microbiota and PCa in humans, we analyzed the gut microbiota profiles of men with suspected PCa. One hundred and fifty‐two Japanese men undergoing prostate biopsies (96 with cancer and 56 without cancer) were included in the study and randomly divided into two cohorts: a discovery cohort (114 samples) and a test cohort (38 samples). The gut microbiota was compared between two groups, a high‐risk group (men with Grade group 2 or higher PCa) and a negative + low‐risk group (men with negative biopsy or Grade group 1 PCa), using 16S rRNA gene sequencing. The relative abundances of Rikenellaceae, Alistipes, and Lachnospira, all SCFA‐producing bacteria, were significantly increased in high‐risk group. In receiver operating characteristic curve analysis, the index calculated from the abundance of 18 bacterial genera which were selected by least absolute shrinkage and selection operator regression detected high‐risk PCa in the discovery cohort with higher accuracy than the prostate specific antigen test (area under the curve [AUC] = 0.85 vs 0.74). Validation of the index in the test cohort showed similar results (AUC = 0.81 vs 0.67). The specific bacterial taxa were associated with high‐risk PCa. The gut microbiota profile could be a novel useful marker for the detection of high‐risk PCa and could contribute to the carcinogenesis of PCa.

Enfortumab vedotin is a novel antibody–drug conjugate targeting Nectin-4, which is highly expressed in urothelial carcinoma. However, the expression status of Nectin-4 in upper tract urothelial carcinoma (UTUC) remains unclear. The relationship between Nectin-4 and Programmed Death Ligand 1 (PD-L1) in UTUC is also ambiguous. We performed immunohistochemical analysis of 99 UTUC tissue microarray to assess the expression of Nectin-4 and PD-L1 in UTUC. Nectin-4-positivity was detected in 65 (65.7%) samples, and PD-L1 was detected in 24 (24.2%) samples. There was no correlation between the expression of Nectin-4 and PD-L1. Patients with strong Nectin-4-expressing tumors had a significantly higher risk of progression (p = 0.031) and cancer-specific mortality (p = 0.036). Strong Nectin-4 expression was also an independent predictor of disease progression in the high-risk group (pT3 ≤ or presence of lymphovascular invasion or lymph node metastasis) (Hazard ratio, 3.32 [95% confidence interval, 1.20–7.98; p = 0.027]). In conclusion, we demonstrated that Nectin-4 expression rate in UTUC was 65.7% and independent of PD-L1 expression. Strong Nectin-4 expression was associated with worse progression-free survival in high-risk UTUC. These findings suggested that enfortumab vedotin may be effective in a broad range of patients with UTUC, regardless of PD-L1 expression.

It is well known that the prognosis of castration-resistant prostate cancer (CRPC) is poor, and several immunotherapeutic strategies have been applied to the clinical trials. Research on immunotherapy has been of special interest for the treatment of CRPC for years. To evaluate the safety of personalized peptide vaccine (PPV) immunotherapy and its clinical outcomes. A phase 2 randomized controlled trial of PPV immunotherapy with low-dose dexamethasone versus dexamethasone alone for chemotherapy-naive CRPC began in 2008. Eligible patients (prostate-specific antigen [PSA] <10 ng/ml) were human leukocyte antigen (HLA) A02, A24, or A03 superfamily positive and had asymptomatic or minimally symptomatic CRPC. Patients were allocated (1:1) to PPV plus dexamethasone (1mg/d) or to dexamethasone (1mg/d) alone. A maximum of four HLA-matched peptides (each 3mg) was selected based on the preexisting immunoglobulin G responses against the 24 warehouse peptides and administered every 2 wk. PSA, progression-free survival (PFS), time to initiation of chemotherapy, and overall survival (OS) were analyzed using the Kaplan-Meier method, a log-rank test, and proportional hazard analysis. Overall, 37 patients received peptide vaccinations and 35 received dexamethasone alone. The primary end point was PSA PFS, which was significantly longer in the vaccination group than in the dexamethasone group (22.0 vs 7.0 mo; p=0.0076). Median OS was also significantly longer in the vaccination group (73.9 vs 34.9 mo; p=0.00084). The relatively small number of patients enrolled is the major limitation of the study. PPV immunotherapy was well tolerated and associated with longer PSA PFS and OS in men with chemotherapy-naive CRPC. A larger phase 3 study is needed to confirm our findings. We compared clinical outcomes of the treatment with personalized peptide vaccine plus dexamethasone versus dexamethasone alone. Our data provide promising evidence of clinical benefit for peptide vaccines. UMIN-CTR: 000000959.

Purpose: A phase I peptide vaccination trial was done in patients with progressive cytokine-refractory metastatic renal cell carcinoma (RCC) to assess both the toxicity and capability to induce immune responses of three peptides (CA9p219-227, p288-296, and p323-331) derived from CA9, a tumor-associated antigen ubiquitously expressed in RCC. Experimental Design: Twenty-three patients positive for human leukocyte antigen (HLA)-A24 with histologically confirmed RCC were enrolled. Eligibility included progressive disease after standard cytokine therapy with interleukin-2 and/or IFN-α. Patients were vaccinated s.c. with the three peptides emulsified in incomplete Freund's adjuvant at 2-week intervals. Pre- and post-vaccination blood samples were obtained for toxicity assessment and immunologic studies. Patients were monitored for clinical responses on a 3-monthly basis. Results: Vaccinations were well tolerated without any major adverse event. Most of the patients developed peptide-specific CTLs and/or immunoglobulin G reactive to the peptides after the 6th or 9th vaccination, followed by a gradual increase in both CTL frequency and levels of peptide-reactive serum IgG. Three patients with multiple lung metastases showed partial responses with disappearance and shrinking of metastatic lesions. Additionally, stable disease for >6 months was observed in six patients (median duration, 12.2 months). Moreover, the median survival time of all patients who were progressive at trial enrollment after failing immunotherapy was 21.0 months (5-35 months). Conclusions: These results suggest that vaccination of these peptides is safe and recommended for further trials for HLA-A24-positive metastatic RCC patients.

Bladder cancer is a common urological cancer with a high recurrence rate that requires long‐term follow‐up, and early detection positively affects prognosis. To date, the initial diagnosis and follow‐up for bladder cancer rely on cystoscopy, which is an invasive and expensive procedure. Therefore, urinary markers for the detection of bladder cancer have attracted research attention for decades to reduce unnecessary cystoscopies. Urine, which is in continuous contact with bladder cancer, is considered a suitable fluid for providing tumor information. Urinary cytology is the only widely used urinary marker in clinical practice; however, it has poor sensitivity for low‐grade tumors; indicating the need for novel urinary markers. Considerable research has been conducted on this topic over the years, resulting in a complex landscape with a wide range of urinary markers, including protein‐, exfoliated cell‐, RNA‐, DNA‐, and extracellular vesicle‐based markers. Although some of these markers have been approved by the U.S. Food and Drug Administration and are commercially available, their use in clinical practice is limited. To facilitate clinical application, potential urinary markers must withstand prospective clinical trials and be easy for patients and clinicians to understand and utilize in a clinical context. This review provides a comprehensive overview of currently available and recently reported promising urinary markers for bladder cancer. Additionally, the challenges and the prospects of these urinary markers for clinical implementation in bladder cancer treatment were discussed.