Search

In locally advanced and metastatic malignancies, antibiotic (ATB) therapy has a negative effect on immunotherapy efficacy. Therefore, we aimed to evaluate whether ATB therapy and use of specific ATB classes with concomitant neoadjuvant pembrolizumab affected pathologic complete response (ypT0N0) and relapse-free survival (RFS) for patients with clinical T2–4N0M0 bladder cancer enrolled in the PURE-01 study. Of the 149 patients evaluated, 48 (32%) received any concomitant ATB therapy. The ATB class most commonly administered was fluoroquinolones (16 patients; 33%). In the ATB cohort, seven patients (15%) achieved ypT0N0 status, compared to 50 (50%; p < 0.001) in the untreated group. Moreover, ATB use was negatively associated with ypT0N0 status (odds ratio 0.18, 95% confidence interval [CI] 0.05–0.48; p = 0.001). The 24-mo RFS rate was 63% (95% CI 48-83%) in the ATB group versus 90% (95% CI 83–97) in the untreated group. We found that ATB use was associated with a higher recurrence rate (hazard ratio [HR] 2.64, 95% CI 1.08–6.50; p = 0.03). Exploratory analyses showed that fluoroquinolone use was associated with a higher recurrence rate (HR 3.28, 95% CI 1.12–9.60; p = 0.03). Our study revealed an association between ATB use and neoadjuvant immunotherapy efficacy in an intention-to-cure population, highlighting the need for future studies to better investigate this relationship. Patient summary: The efficacy of immunotherapy for cancer is influenced by several patient and tumor factors, including the use of antibiotics. We found that antibiotics taken at the same time as immunotherapy drugs were associated with lower rates of complete response and of recurrence-free survival among patients with muscle-invasive bladder cancer. These findings need to be confirmed in future studies.

Background In patients with muscle-invasive urothelial bladder cancer (MIBC), molecular alterations in immunotherapy-resistant tumors found at radical cystectomy (RC) remain largely unstudied. Objective To investigate the biology of pembrolizumab-resistant tumors in comparison to an RC cohort treated without any systemic therapy and a cohort of neoadjuvant chemotherapy (NAC)-treated tumors. Design, setting, and participants Transcriptome-wide expression profiling was performed on 26 RC samples from patients with ypT2–4 disease after pembrolizumab treatment, of which 22 had matched pretherapy samples. Unsupervised consensus clustering (CC) was performed to compare 26 post-pembrolizumab samples with 94 RC samples without neoadjuvant treatment and 21 samples collected from the former tumor bed of NAC-treated patients (scar tissue). Clusters were investigated for their biological and clinical characteristics and were compared to a cohort of post-NAC tumors (n = 133). Outcome measurements and statistical analysis Patient and tumor characteristics were compared between subgroups using χ2 tests and two-sided Wilcoxon rank-sum tests. The primary endpoint was recurrence-free survival. Results and limitations Molecular subtyping of pre- and post-pembrolizumab samples revealed significant differences: only 36% of samples had a concordant subtype according to the consensus classifier. Unsupervised CC revealed three distinct post-pembrolizumab clusters (basal, luminal, and scar-like). A scar-like subtype was present in 50% of the post-pembrolizumab cases (n = 13) and expressed genes associated with wound healing/scarring. This subtype had higher luminal marker expression in the post-pembrolizumab setting compared to CC scar-like tumors from the other cohorts. Patients with the scar-like subtype showed favorable prognosis after systemic therapy, but not in the RC-only setting. The small numbers in each subgroup represents the major study limitation. Conclusions This study expands our understanding of the biology of pembrolizumab-resistant MIBC and provides a framework for defining molecular subtypes after treatment. The results further support the hypothesis that luminal-type tumors may be resistant to immunotherapy or that this treatment may select for, or induce, a luminal phenotype. Patient summary We carried out genetic analysis for bladder cancer tumors from patients who had received an immunotherapy agent called pembrolizumab and compared them to tumors treated with standard chemotherapy or just bladder removal. We found differences in gene expression between the treatment types and between tumor tissue from the same patient before and after treatment. These results may be helpful in personalizing therapy strategies for patients with bladder cancer.

The similar clinical behavior, overlapping therapeutic patterns, and several clinical trials addressing the neoadjuvant and first-line therapy settings for bladder cancer support the call for a more uniform definition of "locally advanced" disease. We highlight the diverse therapeutic opportunities that patients with locally advanced bladder cancer may receive at present. Multimodal management, and post-therapy surgery in particular, may still have a role in selected patients.

Cytoreductive radical prostatectomy (CRP) may offer a survival advantage, according to several retrospective analyses. However, few data are available regarding the morbidity of radical prostatectomy in the metastatic setting. We addressed intra- and postoperative complications of CRP relative to radical prostatectomy for nonmetastatic prostate cancer (nmRP). Within the National Inpatient Sample database (2008–2013), we identified patients who underwent CRP versus nmRP. Propensity score matching to reduce the effect of inherent differences between CRP and nmRP patients, multivariable logistic regression models, Poisson regression models, and linear regression models were used. Of 76 378 patients, 1.2% (n = 953) underwent CRP. CRP resulted in higher rates of overall (odds ratio [OR]: 1.34, p = 0.01), intraoperative (OR: 2.61, p = 0.005), and miscellaneous surgical complications (OR: 1.69, p = 0.02). Moreover, CRP was associated with longer stay (OR: 1.07, p = 0.01) and higher total hospital charges ($810 more per surgery, p = 0.0004). Intra- and postoperative complications associated with CRP are higher than those of nmRP. Similarly, an increase in total hospital charges is associated with CRP. Nonetheless, CRP complication profile validates its safety and feasibility. Patient summary: In this population-based study, we recorded higher intra- and postoperative complications rates for CRP versus nmRP. Nonetheless, CRP complication rates appear manageable but require explicit discussion at counseling. Perioperative complications associated with cytoreductive radical prostatectomy are moderately higher than those of radical prostatectomy in nonmetastatic prostate cancer patients. Similarly, total hospital charges are marginally higher. Nonetheless, the complication profile of cytoreductive radical prostatectomy validates its safety and feasibility in highly selected patients.