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Unresectable, metastatic, advanced urothelial carcinoma (aUC) is an aggressive disease and is treated with platinum-containing first-line chemotherapy, followed by immune checkpoint inhibitors and antibody–drug conjugates. Response to first-line chemotherapy is a vital priority in sequential treatment strategies because a better response to first-line chemotherapy is associated with a better response to subsequent therapies. Gemcitabine plus carboplatin chemotherapy is conventionally recommended for cisplatin-ineligible patients. This multicenter, single-arm prospective trial will investigate whether dose-dense methotrexate, vinblastine, doxorubicin, and carboplatin (DD-MVACarbo) chemotherapy is superior to gemcitabine plus carboplatin chemotherapy in terms of efficacy in platinum-naïve, cisplatin-ineligible patients with aUC. After screening and registration, a total of 46 patients will be treated with this novel chemotherapy regimen. The primary endpoint is the objective response rate. The secondary endpoints include disease control rate, patient-reported outcomes, and adverse events. No evidence of this novel intervention is available as of July 2024. The results are expected to change the standard of care and improve the management of patients with aUC. [ABSTRACT FROM AUTHOR]

Simple Summary: This study investigated the efficacy of complete metastasectomy (CM) in metastatic renal cell carcinoma (mRCC) during the tyrosine kinase inhibitor (TKI) and immune checkpoint inhibitor (ICI) era. Analyzing data from a multi-institutional database with 367 mRCC patients, the CM group exhibited significantly longer overall survival than the non-CM group in unadjusted cohorts (p < 0.001, hazard ratio 0.49, 95% confidence interval 0.35–0.69). However, this superiority was not sustained in adjusted cohorts. The median disease-free survival (DFS) after CM was 24 months, with no significant differences noted based on the time of relapse. This study supports CM's potential in mRCC management during the TKI/ICI era, acknowledging limitations such as sample size and selection bias. Complete metastasectomy (CM) in metastatic renal cell carcinoma (mRCC) has demonstrated efficacy in the cytokine era, but its effectiveness in the era of tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors (ICIs) remains unclear. A multi-institutional database included clinicopathological data of 367 patients with mRCC. Patients were divided into two groups: the CM group and the non-CM group. These two groups were compared before and after propensity score matching (PSM). Cox proportional hazard models were used to detect factors associated with disease-free survival (DFS) and overall survival (OS) from mRCC diagnosis. The CM group showed a significant association with longer overall survival compared to the non-CM group in the PSM-unadjusted cohorts (p < 0.001, hazard ratio 0.49, 95% confidence interval 0.35–0.69), but no superiority was noted in the adjusted cohorts. The median DFS after CM was 24 months, with no significant differences based on relapse timing. Notably, the international metastatic RCC database consortium risk categories and metastatic burden were associated with DFS. This study supports the potential of CM in mRCC management during the TKI/ICI era, although limitations including sample size and selection bias need to be considered. [ABSTRACT FROM AUTHOR]

Simple Summary: The clinical utility of urine nectins in bladder cancer (BCa) is unclear. We investigated the potential diagnostic and prognostic values of Nectin-2 and Nectin-4. This study included 122 patients with BCa, including 78 with non-muscle-invasive BCa, 44 with muscle-invasive BCa, and ten healthy controls. The detection sensitivities of urine Nectin-2, urine Nectin-4, NMP-22, and cytology were 84%, 98%, 52%, and 47%, respectively. Their specificities were 40%, 80%, 100%, and 100%, respectively. Urine Nectin-2 and Nectin-4, but not NMP-22, were significantly more sensitive than cytology alone. A four-titer grouping based on levels of urine Nectin-2/Nectin-4 had a high capability for discriminating between NMIBC and MIBC. Urine levels correlated with tumor expression and serum levels in the Nectin-4 analysis. Urine nectins are potential diagnostic biomarkers for BCa. The clinical utility of urine nectins in bladder cancer (BCa) is unclear. We investigated the potential diagnostic and prognostic values of urine Nectin-2 and Nectin-4. Levels of urine Nectin-2, Nectin-4, and NMP-22 were quantified using an enzyme-linked immunosorbent assay in 122 patients with BCa, consisting of 78 with non-muscle-invasive BCa (NMIBC) and 44 with muscle-invasive BCa (MIBC), and ten healthy controls. Tumor nectin expression in MIBC was evaluated with immunohistochemical staining of transurethral resection specimens. The level of urine Nectin-4 (mean: 18.3 ng/mL) was much higher than that of urine Nectin-2 (mean: 0.40 ng/mL). The sensitivities of Nectin-2, Nectin-4, NMP-22, and cytology assays were 84%, 98%, 52%, and 47%, respectively; their specificities were 40%, 80%, 100%, and 100%, respectively. Both urine Nectin-2 and Nectin-4, though not NMP-22, were found to be significantly more sensitive than cytology. A four-titer grouping based on levels of urine Nectin-2/Nectin-4 (low/high, high/high, low/low, and high/low) showed a high capability for discriminating between NMIBC and MIBC. Neither urine Nectin-2 nor Nectin-4 levels had a significant prognostic value in NMIBC or MIBC. Urine levels correlated with tumor expression and serum levels in the Nectin-4 analysis, but not in the Nectin-2 analysis. Urine nectins are potential diagnostic biomarkers for BCa. [ABSTRACT FROM AUTHOR]

Simple Summary: To investigate the organ-specific responses and clinical outcomes of mixed responses (MRs) to treatment with pembrolizumab for unresectable or metastatic urothelial carcinoma (ur/mUC), 136 patients were analyzed retrospectively. The total objective response rate (ORR) and organ-specific ORR were determined according to RECIST version 1.1 as follows: (i) CR, (ii) PR, (iii) SD, and (ⅳ) PD. MR was defined as when PD occurred in one lesion plus either CR or PR in other lesion simultaneously, and 12 cases were applicable. Most of the organ-specific ORR was 30–40%, but bone metastasis was only 5%. Compared to non-responders, responders to locally advanced lesions and lymph node, lung, or liver metastases were involved in OS, but local recurrence and bone metastases were not involved in OS. In MR, patients who continued pembrolizumab experienced longer survival times compared to patients who discontinued pembrolizumab and received standard treatment. To investigate the organ-specific response and clinical outcomes of mixed responses (MRs) to immune checkpoint inhibitors (ICIs) for unresectable or metastatic urothelial carcinoma (ur/mUC), we retrospectively analyzed 136 patients who received pembrolizumab. The total objective response rate (ORR) and organ-specific ORR were determined for each lesion according to the Response Evaluation Criteria in Solid Tumors version 1.1 as follows: (i) complete response (CR), (ii) partial response (PR), (iii) stable disease (SD), and (iv) progressive disease (PD). Most of the organ-specific ORR was 30–40%, but bone metastasis was only 5%. There was a significant difference in overall survival (OS) between responders and non-responders with locally advanced lesions and lymph node, lung, or liver metastases (HR 9.02 (3.63–22.4) p < 0.0001; HR 3.63 (1.97–6.69), p < 0.0001; HR 2.75 (1.35–5.59), p = 0.0053; and HR 3.17 (1.00–10.0), p = 0.049, respectively). MR was defined as occurring when PD happened in one lesion plus either CR or PR occurred in another lesion simultaneously, and 12 cases were applicable. MR was significantly associated with a poorer prognosis than that of the responder group (CR or PR; HR 0.09 (0.02–0.35), p = 0.004). Patients with bone metastases benefitted less. Care may be needed to treat patients with MR as well as patients with pure PD. Further studies should be conducted in the future. [ABSTRACT FROM AUTHOR]

Simple Summary: The 2016 World Health Organization classification system distinguishes between urothelial carcinomas (UCs) with divergent differentiation (DD) and those with variant morphologies (VMs), which until now had been considered to indicate highest-risk cases. Intravesical Bacillus Calmette–Guérin (BCG) treatment is an alternative therapeutic and adjuvant option after transurethral resection of a bladder tumor. However, data comparing oncological outcomes after intravesical BCG treatment among pure UC, UC with DD, and UC with VMs are sparse. This is a retrospective study to investigate the outcomes of bladder-preservation therapy using intravesical BCG treatment on cases of bladder UCs with DD or VMs. We followed the outcomes of 1490 patients with pure UCs, UC with DD, or UC with VM. We found that concomitant VMs, not DD, was more likely to result in cancer-specific death. The VM-associated risk was significant for cancer-specific mortality only, not for recurrence-free or progression-free survival rates. The 2016 World Health Organization classification newly described infiltrating urothelial carcinoma (UC) with divergent differentiation (DD) or variant morphologies (VMs). Data comparing oncological outcomes after bladder-preservation therapy using intravesical Bacillus Calmette–Guérin (BCG) treatment among T1 bladder pure UC (pUC), UC with DD (UC-DD), and UC with VMs (UC-VM) are limited. We evaluated 1490 patients with T1 high-grade bladder UC who received intravesical BCG during 2000–2019. They were classified into three groups: 93.6% with pUC, 4.4% with UC-DD, and 2.0% with UC-VM. Recurrence-free, progression-free, and cancer-specific survival following intravesical BCG were compared among the groups using multivariate Cox regression analysis, also used to estimate inverse probability of treatment weighting-adjusted hazard ratio and 95% confidence interval for the outcomes. Glandular differentiation and micropapillary variant were the most common forms in the UC-DD and UC-VM groups, respectively. Of 1490 patients, 31% and 13% experienced recurrence and progression, respectively, and 5.0% died of bladder cancer. Survival analyses revealed the impact of concomitant VMs was significant for cancer-specific survival, but not recurrence-free and progression-free survival compared with that of pUC. Our analysis clearly demonstrated that concomitant VMs were associated with aggressive behavior in contrast to concomitant DD in patients treated with intravesical BCG. [ABSTRACT FROM AUTHOR]

Clinical evidence regarding risk reduction of repeated bladder recurrence after initial photodynamic diagnosis (PDD)-assisted transurethral resection of bladder tumor (TURBT) is still limited in patients with non-muscle-invasive bladder cancer (NMIBC). We analyzed patients with primary NMIBC undergoing TURBT without any adjuvant treatment to compare the risk of cumulative recurrence between the conventional white-light (WL)-TURBT and PDD-TURBT. Out of 430 patients diagnosed with primary NMIBC from 2010 to 2019, 40 undergoing WL-TURBT and 60 undergoing PDD-TURBT were eligible. Multivariate Cox regression analysis for time to the first recurrence demonstrated that PDD assistance was an independent prognostic factor with better outcome (p = 0.038, hazard ratio = 0.39, and 95% confidence interval 0.16–0.95). While no patient experienced more than one recurrence within 1000 postoperative days in the PDD-TURBT group, five out of 40 patients treated by WL-TURBT experienced repeated recurrence. The comparison of cumulative incidence per 10,000 person-days between the two groups revealed that PDD assistance decreased by 6.6 recurrences per 10,000 person-days (exact p = 0.011; incidence rate ratio 0.37, Clopper–Pearson confidence interval 0.15–0.82). This is the first study addressing PDD assistance-induced risk reduction of repeated bladder recurrence using the person-time method. Our findings could support clinical decision making, especially on adjuvant therapy after TURBT. [ABSTRACT FROM AUTHOR]

Simple Summary: Two host-dependent biological characteristics, "avoiding immune destruction" and "tumor-promoting inflammation" have been added to cancer hallmarks in 2011. The interaction and cross-talk among tumor cells and several immune cells in a tumor microenvironment are dynamic and complex processes. The purpose of this review is to discuss the prognostic impact of tumor-infiltrating lymphocytes and predictive biomarkers for immune checkpoint inhibitors in four urological solid tumors, the urothelial carcinoma, renal cell carcinoma, prostate cancer, and retroperitoneal sarcoma, through summarizing the findings of observation studies and clinical trials. Over the past decade, an "immunotherapy tsunami", more specifically that involving immune checkpoint inhibitors (ICIs), has overtaken the oncological field. The interaction and cross-talk among tumor cells and several immune cells in the tumor microenvironment are dynamic and complex processes. As immune contexture can vary widely across different types of primary tumors and tumor microenvironments, there is still a significant lack of clinically available definitive biomarkers to predict patient response to ICIs, especially in urogenital malignancies. An increasing body of evidence evaluating urological malignancies has proven that tumor-infiltrating lymphocytes (TILs) are a double-edged sword in cancer. There is an urgent need to shed light on the functional heterogeneity in the tumor-infiltrating immune system and to explore its prognostic impact following surgery and other treatments. Notably, we emphasized the difference in the immunological profile among urothelial carcinomas arising from different primary origins, the bladder, renal pelvis, and ureter. Significant differences in the density of FOXP3-positive TILs, CD204-positive tumor-infiltrating macrophages, PD-L1-positive cells, and colony-stimulating factors were observed. This review discusses two topics: (i) the prognostic impact of TILs and (ii) predictive biomarkers for ICIs, to shed light on lymphocyte migration in four solid tumors, the urothelial carcinoma, renal cell carcinoma, prostate cancer, and retroperitoneal sarcoma. [ABSTRACT FROM AUTHOR]

Chemotherapy-induced adverse effects can reduce the relative dose intensity and quality of life. In this study, we investigated the potential benefit of supplementary anamorelin and 5-aminolevulinic acid (5-ALA) as preventive interventions against a gemcitabine and cisplatin (GC) combination chemotherapy-induced adverse effects in a mouse model. Non-cancer-bearing C3H mice were randomly allocated as follows and treated for 2 weeks—(1) non-treated control, (2) oral anamorelin alone, (3) oral 5-ALA alone, (4) gemcitabine and cisplatin (GC) chemotherapy, (5) GC plus anamorelin, and (6) GC plus 5-ALA. GC chemotherapy significantly decreased body weight, food intake, skeletal muscle mass and induced severe gastric mucositis, which resulted in decreased ghrelin production and blood ghrelin level. The supplementation of oral anamorelin to GC chemotherapy successfully mitigated decrease of food intake during the treatment period and body weight loss at day 8. In addition, analysis of the resected muscles and stomach revealed that anamorelin suppressed chemotherapy-induced skeletal muscle atrophy by mediating the downregulation of forkhead box protein O-1 (FOXO1)/atrogin-1 signaling and gastric damage. Our findings suggest the preventive effect of anamorelin against GC combination chemotherapy, which was selected for patients with some types of advanced malignancies in clinical practice. [ABSTRACT FROM AUTHOR]

Heparan sulfate proteoglycan syndecan-1, CD138, is known to be associated with cell proliferation, adhesion, and migration in malignancies. We previously reported that syndecan-1 (CD138) may contribute to urothelial carcinoma cell survival and progression. We investigated the role of heparanase, an enzyme activated by syndecan-1 in human urothelial carcinoma. Using human urothelial cancer cell lines, MGH-U3 and T24, heparanase expression was reduced with siRNA and RK-682, a heparanase inhibitor, to examine changes in cell proliferation activity, induction of apoptosis, invasion ability of cells, and its relationship to autophagy. A bladder cancer development mouse model was treated with RK-682 and the bladder tissues were examined using immunohistochemical analysis for Ki-67, E-cadherin, LC3, and CD31 expressions. Heparanase inhibition suppressed cellular growth by approximately 40% and induced apoptosis. The heparanase inhibitor decreased cell activity in a concentration-dependent manner and suppressed invasion ability by 40%. Inhibition of heparanase was found to suppress autophagy. In N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN)-induced bladder cancer mice, treatment with heparanase inhibitor suppressed the progression of cancer by 40%, compared to controls. Immunohistochemistry analysis showed that heparanase inhibitor suppressed cell growth, and autophagy. In conclusion, heparanase suppresses apoptosis and promotes invasion and autophagy in urothelial cancer. [ABSTRACT FROM AUTHOR]

Sarcopenia is a muscle loss syndrome known as a risk factor of various carcinomas. The impact of sarcopenia and sarcopenia-related inflammatory/nutritional markers in metastatic urothelial carcinoma (mUC) treated with pembrolizumab was unknown, so this retrospective study of 27 patients was performed. Psoas muscle mass index (PMI) was calculated by bilateral psoas major muscle area at the L3 with computed tomography. The cut-off PMI value for sarcopenia was defined as ≤6.36 cm2/m2 for men and ≤3.92 cm2/m2 for women. Neutrophil-to-lymphocyte ratio (NLR) ≥ 4.0 and sarcopenia correlated with significantly shorter progression-free survival (PFS) (hazard ratio (HR) 3.81, p = 0.020; and HR 2.99, p = 0.027, respectively). Multivariate analyses identified NLR ≥ 4.0 and sarcopenia as independent predictors for PFS (HR 2.89, p = 0.025; and HR 2.79, p = 0.030, respectively). Prognostic nutrition index < 45, NLR ≥ 4.0 and sarcopenia were correlated with significantly worse for overall survival (OS) (HR 3.44, p = 0.046; HR 4.26, p = 0.024; and HR 3.92, p = 0.012, respectively). Multivariate analyses identified sarcopenia as an independent predictor for OS (HR 4.00, p = 0.026). Furthermore, a decrease in PMI ≥ 5% in a month was an independent predictor of PFS and OS (HR 12.8, p = 0.008; and HR 6.21, p = 0.036, respectively). Evaluation of sarcopenia and inflammatory/nutritional markers may help in the management of mUC with pembrolizumab. [ABSTRACT FROM AUTHOR]

We aimed to determine the oncological outcomes of patients with clinical T1 renal cell carcinoma (RCC) upstaged to pathological T3a and to identify the preoperative predictive factors for upstaging. We retrospectively reviewed 272 patients with clinical T1 RCC who underwent surgical treatment. Thirty-three patients (12%) were upstaged to pathological T3a. These patients had a significantly larger tumor size on computed tomography (p < 0.0001), a higher aspartate aminotransferase (AST)/alanine aminotransferase (ALT) ratio (p = 0.037), and an elevated c-reactive protein (CRP) level (p = 0.014) preoperatively compared with those with pathological T1 RCC. On multivariate analysis, tumor diameter was the only significant preoperative predictive factor for upstaging [hazard ratio (HR), 3.61; 95% confidence interval (CI), 1.32–9.84; p = 0.01]. The AST/ALT ratio tended to be a preoperative predictive factor for upstaging, although it was not significant (HR, 2.14; 95% CI, 0.97–4.73; p = 0.06). Pathological T3a upstaging occurred in 25% of those with a tumor diameter ≥30 mm and a preoperative AST/ALT ratio ≥1.1. There was a significant correlation between pathological T3a upstaging and the number of preoperative risk factors (p = 0.0002). The preoperative tumor diameter and serum AST/ALT ratio can be predictive factors for pathological T3a upstaging in patients with clinical T1 RCC. [ABSTRACT FROM AUTHOR]

The detection of carcinoma in situ (CIS) is essential for the management of high-risk non-muscle invasive bladder cancers. Here, we focused on dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) combined with photodynamic diagnosis (PDD) for the detection of CIS. A total of 45 patients undergoing pre-surgical DCE-MRI and PDD-assisted endoscopic surgery accompanied by biopsies of the eight segmentations were analyzed. Immunohistochemical analysis of the biopsies revealed hypervascularity of CIS lesions, a cause of strong submucosal contrast-enhancement. It was found that 56 (16.2%) of 344 biopsies had pathologically proven CIS. In the DCE-MRI, the overall sensitivity and specificity for detecting CIS were 48.2% and 81.9%, respectively. We set out two different combinations of PDD and DCE-MRI for detecting CIS. Combination 1 was positive when either the PDD or DCE-MRI were test-positive. Combination 2 was positive only when both PDD and DCE-MRI were test-positive. The overall sensitivity of combinations 1 and 2 were 75.0% and 37.5%, respectively (McNemar test, vs PDD alone; p = 0.041 and p < 0.001, respectively). However, the specificity was 74.0% and 91.7%, respectively (vs PDD alone; both p < 0.001). Our future goal is to establish 'MRI-PDD fusion transurethral resction of the bladder tumor (TURBT), which could be an effective therapeutic and diagnostic approach in the clinical management of high-risk disease. [ABSTRACT FROM AUTHOR]

Background: The aim of this study is to evaluate the clinical impact of intravesical Bacillus Calmette-Guérin (BCG)-induced changes in blood/urinary immune markers. Methods: Time-course changes in blood/urinary clinical parameters and mRNA expression of 13 genes in urine sediment taken eight times during the treatment course of intravesical BCG (before, every 2 weeks for 8 weeks, and after) in 24 patients with non-muscle invasive bladder cancer. The genes examined include cellular markers of four immune checkpoint proteins (PD-L1, PD-L2, PD-1, and CTLA-4), immunosuppressive cells (regulatory T cells, tumor-associated macrophages, and myeloid-derived suppressor cells), pan-T lymphocytes, B lymphocytes, and neutrophils. Results: Significant transient increase in gene expression was observed for PD-L1, PD-1, FOXP3, and CD204 at 6–8 doses of BCG. The patients were stratified into two groups depending on the number of genes with increased mRNA expression. Fourteen (58%) had 0–1 genes upregulated, while 10 (42%) had 2–4 genes with increased expression. No patient in the 0–1 group experienced recurrence, while 70% of patients in the 2–4 group experienced recurrence (p value = 0.037, hazard ratio = 5.93). Conclusions: Our findings suggested that increases in more than one of PD-L1, PD-1, FOXP3, and CD204, expression in the urine sediments was associated with resistance to BCG treatment. [ABSTRACT FROM AUTHOR]

The evidence of association between sexually transmitted infection and prostatic inflammation in human prostate cancer (PCa) is limited. Here, we sought to examine the potential association of prostatic infection with the inflammatory environment and prostate carcinogenesis. We screened surgical and biopsy specimens from 45 patients with PCa against a panel of sexually transmitted infection-related organisms using polymerase chain reaction and examined the severity of intraprostatic inflammation by pathologic examination. Among tested organisms, the rate of Mycoplasma genitalium (Mg) infection was significantly different between the prostate cancer cohort and benign prostate hyperplasia (BPH) cohort (P = 0.03). Mg infection in the surgical specimens was associated with younger patients. The rate of extensive disease (pT2c–3b) was higher in Mg-positive patients than in Mg-negative patients (P = 0.027). No significant correlation was observed between Mg infection status and the grade of intraprostatic inflammation. The detection sensitivity of biopsy specimens was 61% for Mg and 60% for human papillomavirus (HPV)18, indicating possible clinical application of this material. A comprehensive understanding of the correlation between the urogenital microbiome and inflammation would facilitate the development of strategies for PCa prevention. Further studies are required to explore its clinical utility in recommendations of early re-biopsy, close follow-up, and treatment by antibiotics. [ABSTRACT FROM AUTHOR]

The clinical significance of regulatory T cells (Treg) and tumor-associated macrophages (TAM) in the tumor microenvironment of human bladder cancer remains unclear. The aim of this study is to explore their relevance to oncological features in non-muscle invasive bladder cancer (NMIBC). We carried out immunohistochemical analysis of forkhead box P3 (FOXP3, Treg maker), CD204 (TAM marker), and interleukin-6 (IL6) using surgical specimens obtained from 154 NMIBC patients. The Treg and TAM counts surrounding the cancer lesion and IL6-positive cancer cell counts were evaluated against clinicopathological variables. We focused on the ability of the Treg and TAM counts around the cancer lesion to predict outcomes after adjuvant intravesical Bacille Calmette-Guérin (BCG) treatment. High Treg counts were associated with female patients, older age, T1 category, and high tumor grade. TAM count was significantly correlated with Treg count and with IL6-positive cancer cell count. In our analysis of 71 patients treated with BCG, high counts of Treg and TAM were associated with shorter recurrence-free survival, and the former was an independent predictor of recurrence. Poor response to intravesical BCG was associated with Treg and TAM in the tumor microenvironment. Disrupting the immune network can be a supplementary therapeutic approach for NMIBC patients receiving intravesical BCG., Competing Interests: The authors declare no conflicts of interest.