Explore the vast range of titles available.

After cystectomy, patients with muscle-invasive bladder cancer were randomly assigned to pembrolizumab or observation for 1 year. The pembrolizumab group had a median disease-free survival twice as long as the observation group.

PurposeThe value of bladder cancer (BC) substaging into macroscopic (pT3b) and microscopic (pT3a) perivesical fat extension in lymph node (Ln)-negative patients is controversially discussed and limited evidence for prognostic relevance of additional histopathological factors in pT3 BC exists. We evaluated the prognostic value of pT3 substaging and established pathological and clinical parameters with focus on tumor invasive front (TIF) and tumor size.MethodsSpecimens of 52 patients treated with radical cystectomy (RC) for pT3 a/b muscle-invasive BC were reviewed and re-evaluated by a pathologist specialized in uropathology. Clinical variables and standard histopathologic characteristics were assessed including TIF and tumor size. Their value as prognosticators for overall survival (OS) and recurrence-free survival (RFS) was evaluated.ResultsMean age of patients was 67.55 years. Tumors were staged pT3a in 28 patients (53.8%) and pT3b in 24 (46.8%). Median OS was 34.51 months. Median tumor size was 3.2 cm, median TIF was 11.0 mm. Differences in OS between pT3a and pT3b were not significant (p = 0.45). Carcinoma in situ (CIS) and lymphovascular invasion (LVI) were significantly associated with pT3b tumors. Univariate analysis could not identify pathological prognosticators like TIF or tumor size for OS and RFS (p for all > 0.05).ConclusionNo significant differences in OS or RFS were observed comparing Ln-negative pT3 BC following radical cystectomy. Additional pathologic variables like TIF could not be identified as prognosticator. Relevance of pT3 BC substaging needs reevaluation in larger prospective cohorts.

PD-1 and PD-L1 inhibitors are active in metastatic urothelial carcinoma, but positive randomised data supporting their use as a first-line treatment are lacking. In this study we assessed outcomes with first-line pembrolizumab alone or combined with chemotherapy versus chemotherapy for patients with previously untreated advanced urothelial carcinoma. KEYNOTE-361 is a randomised, open-label, phase 3 trial of patients aged at least 18 years, with untreated, locally advanced, unresectable, or metastatic urothelial carcinoma, with an Eastern Cooperative Oncology Group performance status of up to 2. Eligible patients were enrolled from 201 medical centres in 21 countries and randomly allocated (1:1:1) via an interactive voice-web response system to intravenous pembrolizumab 200 mg every 3 weeks for a maximum of 35 cycles plus intravenous chemotherapy (gemcitabine [1000 mg/m2] on days 1 and 8 and investigator's choice of cisplatin [70 mg/m2] or carboplatin [area under the curve 5] on day 1 of every 3-week cycle) for a maximum of six cycles, pembrolizumab alone, or chemotherapy alone, stratified by choice of platinum therapy and PD-L1 combined positive score (CPS). Neither patients nor investigators were masked to the treatment assignment or CPS. At protocol-specified final analysis, sequential hypothesis testing began with superiority of pembrolizumab plus chemotherapy versus chemotherapy alone in the total population (all patients randomly allocated to a treatment) for the dual primary endpoints of progression-free survival (p value boundary 0·0019), assessed by masked, independent central review, and overall survival (p value boundary 0·0142), followed by non-inferiority and superiority of overall survival for pembrolizumab versus chemotherapy in the patient population with CPS of at least 10 and in the total population (also a primary endpoint). Safety was assessed in the as-treated population (all patients who received at least one dose of study treatment). This study is completed and is no longer enrolling patients, and is registered at ClinicalTrials.gov, number NCT02853305. Between Oct 19, 2016 and June 29, 2018, 1010 patients were enrolled and allocated to receive pembrolizumab plus chemotherapy (n=351), pembrolizumab monotherapy (n=307), or chemotherapy alone (n=352). Median follow-up was 31·7 months (IQR 27·7–36·0). Pembrolizumab plus chemotherapy versus chemotherapy did not significantly improve progression-free survival, with a median progression-free survival of 8·3 months (95% CI 7·5–8·5) in the pembrolizumab plus chemotherapy group versus 7·1 months (6·4–7·9) in the chemotherapy group (hazard ratio [HR] 0·78, 95% CI 0·65–0·93; p=0·0033), or overall survival, with a median overall survival of 17·0 months (14·5–19·5) in the pembrolizumab plus chemotherapy group versus 14·3 months (12·3–16·7) in the chemotherapy group (0·86, 0·72–1·02; p=0·0407). No further formal statistical hypothesis testing was done. In analyses of overall survival with pembrolizumab versus chemotherapy (now exploratory based on hierarchical statistical testing), overall survival was similar between these treatment groups, both in the total population (15·6 months [95% CI 12·1–17·9] with pembrolizumab vs 14·3 months [12·3–16·7] with chemotherapy; HR 0·92, 95% CI 0·77–1·11) and the population with CPS of at least 10 (16·1 months [13·6–19·9] with pembrolizumab vs 15·2 months [11·6–23·3] with chemotherapy; 1·01, 0·77–1·32). The most common grade 3 or 4 adverse event attributed to study treatment was anaemia with pembrolizumab plus chemotherapy (104 [30%] of 349 patients) or chemotherapy alone (112 [33%] of 342 patients), and diarrhoea, fatigue, and hyponatraemia (each affecting four [1%] of 302 patients) with pembrolizumab alone. Six (1%) of 1010 patients died due to an adverse event attributed to study treatment; two patients in each treatment group. One each occurred due to cardiac arrest and device-related sepsis in the pembrolizumab plus chemotherapy group, one each due to cardiac failure and malignant neoplasm progression in the pembrolizumab group, and one each due to myocardial infarction and ischaemic colitis in the chemotherapy group. The addition of pembrolizumab to first-line platinum-based chemotherapy did not significantly improve efficacy and should not be widely adopted for treatment of advanced urothelial carcinoma. Merck Sharp and Dohme, a subsidiary of Merck, Kenilworth, NJ, USA.

In a prospective, randomized trial involving patients with urothelial carcinoma who had undergone radical surgery, adjuvant nivolumab was compared with placebo. The median disease-free survival was 20.8 months with nivolumab and 10.8 months with placebo. Treatment-related adverse events of grade 3 or higher were noted in 17.9% of patients in the nivolumab group.

Neoadjuvant chemotherapy followed by radical cystectomy is the standard treatment for cisplatin-eligible patients with muscle-invasive bladder cancer. Adding perioperative immunotherapy may improve outcomes. In this phase 3, open-label, randomized trial, we assigned, in a 1:1 ratio, cisplatin-eligible patients with muscle-invasive bladder cancer to receive neoadjuvant durvalumab plus gemcitabine-cisplatin every 3 weeks for four cycles, followed by radical cystectomy and adjuvant durvalumab every 4 weeks for eight cycles (durvalumab group), or to receive neoadjuvant gemcitabine-cisplatin followed by radical cystectomy alone (comparison group). Event-free survival was one of two primary end points. Overall survival was the key secondary end point. In total, 533 patients were assigned to the durvalumab group and 530 to the comparison group. The estimated event-free survival at 24 months was 67.8% (95% confidence interval [CI], 63.6 to 71.7) in the durvalumab group and 59.8% (95% CI, 55.4 to 64.0) in the comparison group (hazard ratio for progression, recurrence, not undergoing radical cystectomy, or death from any cause, 0.68; 95% CI, 0.56 to 0.82; P<0.001 by stratified log-rank test). The estimated overall survival at 24 months was 82.2% (95% CI, 78.7 to 85.2) in the durvalumab group and 75.2% (95% CI, 71.3 to 78.8) in the comparison group (hazard ratio for death, 0.75; 95% CI, 0.59 to 0.93; P = 0.01 by stratified log-rank test). Treatment-related adverse events of grade 3 or 4 in severity occurred in 40.6% of the patients in the durvalumab group and in 40.9% of those in the comparison group; treatment-related adverse events leading to death occurred in 0.6% in each group. Radical cystectomy was performed in 88.0% of the patients in the durvalumab group and in 83.2% of those in the comparison group. Perioperative durvalumab plus neoadjuvant chemotherapy led to significant improvements in event-free survival and overall survival as compared with neoadjuvant chemotherapy alone. (Funded by AstraZeneca; NIAGARA ClinicalTrials.gov number, NCT03732677; EudraCT number, 2018-001811-59.).

Erdafitinib is a pan-fibroblast growth factor receptor (FGFR) inhibitor approved for the treatment of locally advanced or metastatic urothelial carcinoma in adults with susceptible alterations who have progression after platinum-containing chemotherapy. The effects of erdafitinib in patients with -altered metastatic urothelial carcinoma who have progression during or after treatment with checkpoint inhibitors (anti-programmed cell death protein 1 [PD-1] or anti-programmed death ligand 1 [PD-L1] agents) are unclear. We conducted a global phase 3 trial of erdafitinib as compared with chemotherapy in patients with metastatic urothelial carcinoma with susceptible alterations who had progression after one or two previous treatments that included an anti-PD-1 or anti-PD-L1. Patients were randomly assigned in a 1:1 ratio to receive erdafitinib or the investigator's choice of chemotherapy (docetaxel or vinflunine). The primary end point was overall survival. A total of 266 patients underwent randomization: 136 to the erdafitinib group and 130 to the chemotherapy group. The median follow-up was 15.9 months. The median overall survival was significantly longer with erdafitinib than with chemotherapy (12.1 months vs. 7.8 months; hazard ratio for death, 0.64; 95% confidence interval [CI], 0.47 to 0.88; P = 0.005). The median progression-free survival was also longer with erdafitinib than with chemotherapy (5.6 months vs. 2.7 months; hazard ratio for progression or death, 0.58; 95% CI, 0.44 to 0.78; P<0.001). The incidence of grade 3 or 4 treatment-related adverse events was similar in the two groups (45.9% in the erdafitinib group and 46.4% in the chemotherapy group). Treatment-related adverse events that led to death were less common with erdafitinib than with chemotherapy (in 0.7% vs. 5.4% of patients). Erdafitinib therapy resulted in significantly longer overall survival than chemotherapy among patients with metastatic urothelial carcinoma and alterations after previous anti-PD-1 or anti-PD-L1 treatment. (Funded by Janssen Research and Development; THOR ClinicalTrials.gov number, NCT03390504.).

BackgroundImmunotherapy is becoming a standard of care for non-metastatic muscle-invasive bladder cancer (MIBC). The optimal chemotherapy partner for chemo-immunotherapy combinations remains unknown. We evaluated the efficacy and safety of neoadjuvant avelumab-based regimens in patients with MIBC.MethodsThe multicenter phase 2 AURA trial (NCT03674424) enrolled patients with non-metastatic MIBC undergoing radical cystectomy. Cisplatin-eligible patients were randomized to receive avelumab with either dose-dense methotrexate-vinblastine-doxorubicin-cisplatin (ddMVAC-A) or gemcitabine-cisplatin (GC-A). Cisplatin-ineligible patients received either avelumab alone (A) or combined with paclitaxel-gemcitabine (PG-A). The primary endpoint was pathological complete response (pCR). Secondary endpoints included safety, event-free survival, and overall survival (OS).ResultsBetween July 2018 and September 2021, 137 eligible patients were enrolled in the trial. In the cisplatin-eligible cohort (n=79), pCR rates were 58% (95% CI: 42% to 72%) in the ddMVAC-A arm and 53% (95% CI: 37% to 68%) in the GC-A arm. The 36-month OS rates were 87% (95% CI: 76% to 98%) for ddMVAC-A and 67% (95% CI: 53% to 84%) for GC-A. In the cisplatin-ineligible cohort (n=58), pCR rates were 14% (95% CI: 6% to 31%) in the PG-A arm and 32% (95% CI: 18% to 51%) in the A arm. The 36-month OS rates were 48% (95% CI: 33% to 71%) for PG-A and 42% (95% CI: 27% to 65%) for A. Overall, 51 (38%) patients experienced grade 3–4 treatment-related adverse events.ConclusionsAvelumab combined with cisplatin-based neoadjuvant chemotherapy showed promising efficacy in MIBC with a favorable safety profile, also with the ddMVAC regimen. Among cisplatin-ineligible patients, avelumab monotherapy showed encouraging activity, with no additional benefit observed from the PG-A regimen. These results support the use of the ddMVAC regimen as a potential chemotherapy partner for neoadjuvant chemo-immunotherapy combinations in future phase 3 trials, providing an alternative to the GC regimen currently under investigation.Trial registration number NCT03674424.

In patients with urothelial carcinoma, the addition of nivolumab to platinum-based chemotherapy resulted in longer median overall survival than platinum-based chemotherapy alone (21.7 months vs. 18.9 months).

Erdafitinib, a pan-fibroblast growth factor receptor (FGFR) tyrosine kinase inhibitor, was shown to be clinically active and tolerable in patients with advanced urothelial carcinoma and prespecified FGFR alterations in the primary analysis of the BLC2001 study at median 11 months of follow-up. We aimed to assess the long-term efficacy and safety of the selected regimen of erdafitinib determined in the initial part of the study. The open-label, non-comparator, phase 2, BLC2001 study was done at 126 medical centres in 14 countries across Asia, Europe, and North America. Eligible patients were aged 18 years or older with locally advanced and unresectable or metastatic urothelial carcinoma, at least one prespecified FGFR alteration, an Eastern Cooperative Oncology Group performance status of 0–2, and progressive disease after receiving at least one systemic chemotherapy or within 12 months of neoadjuvant or adjuvant chemotherapy or were ineligible for cisplatin. The selected regimen determined in the initial part of the study was continuous once daily 8 mg/day oral erdafitinib in 28-day cycles, with provision for pharmacodynamically guided uptitration to 9 mg/day (8 mg/day UpT). The primary endpoint was investigator-assessed confirmed objective response rate according to Response Evaluation Criteria In Solid Tumors version 1.1. Efficacy and safety were analysed in all treated patients who received at least one dose of erdafitinib. This is the final analysis of this study. This study is registered with ClinicalTrials.gov, NCT02365597. Between May 25, 2015, and Aug 9, 2018, 2328 patients were screened, of whom 212 were enrolled and 101 were treated with the selected erdafitinib 8 mg/day UpT regimen. The data cutoff date for this analysis was Aug 9, 2019. Median efficacy follow-up was 24·0 months (IQR 22·7–26·6). The investigator-assessed objective response rate for patients treated with the selected erdafitinib regimen was 40 (40%; 95% CI 30–49) of 101 patients. The safety profile remained similar to that in the primary analysis, with no new safety signals reported with longer follow-up. Grade 3–4 treatment-emergent adverse events of any causality occurred in 72 (71%) of 101 patients. The most common grade 3–4 treatment-emergent adverse events of any cause were stomatitis (in 14 [14%] of 101 patients) and hyponatraemia (in 11 [11%]). There were no treatment-related deaths. With longer follow-up, treatment with the selected regimen of erdafitinib showed consistent activity and a manageable safety profile in patients with locally advanced or metastatic urothelial carcinoma and prespecified FGFR alterations. Janssen Research & Development.

The human urinary bladder is subject to a unique and extraordinarily diverse array of congenital, inflammatory, metaplastic, and neoplastic abnormalities.  This book provides contemporary, comprehensive, and evidence-based practice information for pathologists, urologists, oncologists, and other medical professionals. In Bladder Pathology, a full spectrum of pathologic conditions that afflict the bladder and urothelium are described and lavishly illustrated. With its emphasis on diagnostic criteria and differential diagnoses, this book is of particular value to practicing pathologists-assisting in the pathologist's recognition, understanding, and accurate interpretation of the light microscopic findings in bladder specimens. Features and benefits of this new volume include: 1,741 high-quality, color illustrations and 112 tables to illustrate the wide range of pathologic and clinical features in the urinary tract An evidence-based approach to diagnosis and patient management for infectious, nonneoplastic, and neoplastic conditions Recent advances in the molecular genetics of the urinary bladder with discussion of their current or potential impact on diagnosis and personalized patient care With emphasis on the scientific validation of current diagnostic methods and their direct application in clinical practice, Bladder Pathology is a cutting-edge resource that not only offers comprehensive research and  clinical information for practicing surgical pathologists, urologists, oncologists, and their clinical colleagues, but also captures a genuine sense of excitement about recent advances in this vital, ever-evolving field.