Bladder-preserving radiation therapy for patients with locally advanced and node-positive bladder cancer.

Purpose: Trimodality therapy for muscle-invasive bladder cancer (MIBC) yields similar oncologic outcomes compared to radical cystectomy in appropriately selected patients; however, data regarding locally advanced MIBC (LA-MIBC) is limited. We explored our experience with LA-MIBC undergoing radiation therapy (RT). Methods: We retrospectively identified 30 patients from an institutional prospectively collated database with non-metastatic, LA-MIBC. Patients with T3-4 N0 or T2-4 N + treated from 2012 to 2022 with definitive-intent RT, who were not candidates for cystectomy were included. Kaplan-Meier analysis was used to estimate time-to-event outcomes, and multivariate analyses were conducted using Cox proportional hazards modeling. Results: 43 % had T3N0 disease, 30 % had T4N0 disease, and 27 % had node positive disease.. Neoadjuvant chemotherapy/systemic therapy was administered in 63 % of patients. Median dose and fractionation of RT was 60 Gy in 30 fractions. 23 % of patients received hypofractionated RT, 57 % received nodal RT.At a median follow-up of 20 (range, 1-75) months after RT, estimated 1- and 2-year OS was 73 % and 61 %, respectively. Estimated 1-year progression-free survival was 50 %. Local bladder failure was a component of progression in 17 % of patients, and all local bladder failure events occurred within the first 12 months following RT. Lymph node or distant metastases occurred in 23 % of patients. Estimated 1-year OS was 83 % with pure urothelial histology but only 58 % with variant histology (P = 0.001). Late grade 3 + GU and GI toxicity occurred in 7 % and 5 % of patients, respectively. Conclusions: In this cohort with LA-MIBC treated with RT, distant failures predominate, local failures are less common, and toxicity was minimal. Survival outcomes remain encouraging for RT in this challenging patient population. Further investigation is warranted to identify biomarkers for patient selection and strategies to improve distant control.

Epithelioid trophoblastic tumor in male patients with germ cell tumor: A clinicopathologic analysis of five cases.

Epithelioid trophoblastic tumor (ETT) is an extremely rare chorionic-type neoplasm in the testis, with only seven cases reported in the literature. Here, we report five cases of testicular ETT from a single institution, constituting the largest series of this rare tumor to date. The patients had a mean age of 44 years (range, 20-68 years). Four patients had a previous history of testicular germ cell tumor (GCT) treated with chemotherapy, and they developed ETT in metastatic sites in a mean of 11 years (range, 3-15 years) after the initial diagnosis of testicular GCT. Only one patient had ETT in the testis. Three patients had a normal serum beta-human chorionic gonadotropin (ß-hCG) level, and two patients had a level that was slightly elevated, but far below that typically seen in patients with choriocarcinoma. ETT was characterized by a proliferation of intermediate trophoblastic cells with abundant eosinophilic cytoplasm, and the tumors frequently had coagulative necrosis with eosinophilic debris, mimicking keratinizing squamous cell carcinoma. The trophoblastic phenotype of ETT was supported by its immunoreactivity for trophoblastic markers, including GATA-3 (3 of 3 cases tested), α-inhibin (3/4), p63 (3/5), and ß-hCG (3/4). ETT was also positive for cytokeratin (4/4) and GCT marker SALL4 (3/3). Despite surgery and chemotherapy, two patients died of disease 17 months after ETT diagnosis, and three patients were alive with metastatic disease at a mean of 20 months (range, 15-28 months). Our results demonstrate that ETT may be an aggressive disease associated with distinct pathologic features and poor clinical outcome.

Bladder-sparing Therapy for Bacillus Calmette-Guérin-unresponsive Non-muscle-invasive Bladder Cancer: International Bladder Cancer Group Recommendations for Optimal Sequencing and Patient Selection.

BACKGROUND AND OBJECTIVE: There has been a recent surge in the development of agents for bacillus Calmette-Guérin-unresponsive (BCG-U) non-muscle-invasive bladder cancer (NMIBC). Critical assessment of these agents and practical recommendations for optimal selection of patients and therapies are urgently needed, especially in the absence of randomized trials on bladder-sparing treatment (BST) options. METHODS: A global committee of bladder cancer experts was assembled to develop recommendations on BST for BCG-U NMIBC. Working groups reviewed the literature and developed draft recommendations, which were then voted on by International Bladder Cancer Group (IBCG) members using a modified Delphi process. During a live meeting in August 2023, voting results and supporting evidence were presented, and recommendations were refined on the basis of meeting discussions. Final recommendations achieved >75% agreement during the meeting, and some were further refined via web conferences and e-mail discussions. KEY FINDINGS AND LIMITATIONS: There is currently no single optimal agent for patients with BCG-U disease who seek to avoid radical cystectomy (RC). BST selection should be personalized, taking into account individual patient characteristics and preferences, tumor attributes, and efficacy/toxicity data for the agents available. For patients with BCG-U carcinoma in situ (CIS), gemcitabine/docetaxel (GEM/DOCE), nadofaragene firadenovec (NFF), and nogapendekin alfa inbakicept-pmln (NAI) + BCG are recommended; because of its systemic toxicity, pembrolizumab should only be offered after other options are exhausted. For patients with BCG-U papillary-only tumors, GEM/DOCE, NFF, NAI + BCG, single-agent chemotherapy, hyperthermic mitomycin C, and pembrolizumab are recommended. Given the modest efficacy of available options, clinical trial participation is encouraged. For unapproved agents with reported data, IBCG recommendations await the final results of pivotal trials. CONCLUSIONS AND CLINICAL IMPLICATIONS: The IBCG consensus recommendations provide practical guidance on BST for BCG-U NMIBC.

A Pilot Study of the CD38 Antagonist Daratumumab in Patients with Metastatic Renal Cell Carcinoma or Muscle-Invasive Bladder Cancer.

PURPOSE: We performed a pilot study of daratumumab (an mAb directed against CD38) in muscle-invasive bladder cancer (MIBC) and treatment-refractory metastatic renal cell carcinoma (mRCC). EXPERIMENTAL DESIGN: Patients with MIBC underwent baseline transurethral resection of the bladder tumor followed by four weekly doses of daratumumab prior to cystectomy. Patients with mRCC underwent baseline and sequential biopsies after eight weekly doses. The primary endpoint was safety. The secondary endpoints were pathologic complete response rate for the MIBC cohort and objective response rate and progression-free survival for the mRCC cohort. Exploratory analyses included immune monitoring and overall survival. A Bayesian sequential monitoring design for toxicity was used for excessive toxicity. RESULTS: In both the MIBC (n = 8) and mRCC (n = 8) cohorts, no toxicity events were encountered. In the MIBC cohort, one patient experienced pathologic complete response rate. In the mRCC cohort, no objective responses were reported, and the median progression-free survival was 1.5 months (95% confidence interval, 1.1-1.8 months). Immune monitoring found significant reductions in NK cells in circulation in both cohorts after treatment. In the tissue analysis, IHC found evidence of diminished CD38 presence in mRCC with treatment, whereas the baseline levels in MIBC were low. CONCLUSION: Treatment with daratumumab was safe. No signal of efficacy was detected in mRCC, and conclusions on the activity in MIBC were limited. Evidence of daratumumab targeting CD38 was detected in circulating immune cells and within the tumor microenvironment of mRCC and MIBC. SIGNIFICANCE: In this prospective clinical trial of daratumumab, treatment in patients with MIBC and mRCC was safe. Limited efficacy was observed. Treatment with daratumumab resulted in CD38-expressing immune cell subsets to be targeted both in circulation and within the tumor microenvironment.

Diagnostic accuracy of upper tract urothelial carcinoma using biopsy, urinary cytology, and nephroureterectomy specimens: A tertiary cancer center experience.

OBJECTIVES: We studied the diagnostic accuracy and discordance of upper tract urothelial carcinoma (UTUC) by comparing biopsy and urinary cytology with matched nephroureterectomy specimens. METHODS: Sixty-nine patients with UTUC without neoadjuvant treatment were retrospectively identified who had matched biopsy and nephroureterectomy specimens. Twenty patients had concurrent upper tract cytology. H&E and cytology slides were re-reviewed. Statistical analysis was performed. RESULTS: Patients included 48 men and 21 women with a mean age of 69 years. A concordant grade between biopsy and surgical specimen was present in 49 (71%) patients. The mean size of biopsy specimens in the discordant group was significantly smaller than that in the concordant group. Invasion was evaluated in 48 biopsy cases that had adequate subepithelial tissue, and 33 of them were diagnosed with concordant invasion status. Mean tumor size in both tumor grade and invasion discordant groups was significantly larger than that in the concordant group. High-grade urothelial carcinoma was detected in 84% of cases using urinary cytology. CONCLUSIONS: Our study demonstrates the diagnostic challenges of UTUC on small biopsy specimens. Biopsy specimen size and tumor size are significantly associated with the diagnostic discordance. Upper tract cytology showed high diagnostic accuracy and should be complementary to the biopsy.

Cytoprotective Small Compound M109S Attenuated Retinal Ganglion Cell Degeneration Induced by Optic Nerve Crush in Mice.

BAX plays an essential role in retinal ganglion cell (RGC) death induced by optic nerve injury. Recently, we developed M109S, an orally bioactive and cytoprotective small compound (CPSC) that inhibits BAX-mediated cell death. We examined whether M109S can protect RGC from optic nerve crush (ONC)-induced apoptosis. M109S was administered starting 5 h after ONC for 7 days. M109S was orally administered in two groups (5 mg/kg twice a day or 7.5 mg/kg once a day). The retina was stained with anti-BRN3A and cleaved Caspase-3 (active Caspase-3) that are the markers of RGC and apoptotic cells, respectively. ONC decreased the number of BRN3A-positive RGC and increased the number of active Caspase-3-expressing apoptotic cells. In ONC-treated retina, there were cells that were double stained with anti-BRN3A and ant-cleaved Caspase-3, indicating that apoptosis in BRN3A-positive RGCs occurred. M109S inhibited the decrease of BRN3A-positive cells whereas it inhibited the increase of active Caspase-3-positive cells in the retina of ONC-treated mice, suggesting that M109S inhibited apoptosis in RGCs. M109S did not induce detectable histological damage to the lungs or kidneys in mice, suggesting that M109S did not show toxicities in the lung or kidneys when the therapeutic dose was used. The present study suggests that M109S is effective in rescuing damaged RGCs. Since M109S is an orally bioactive small compound, M109S may become the basis for a portable patient-friendly medicine that can be used to prevent blindness by rescuing damaged optic nerve cells from death.

Germ Cell Tumor of the Testis: Lethal Subtypes of a Curable Cancer.

Germ cell tumor of the testis (GCT) is a curable cancer even when it is widely metastatic; however, outcomes can differ based on tumor histology. Chemo-resistance in certain phenotypes, such as teratoma and yolk sac tumor, contributes to poor clinical outcomes in some patients with GCT. Despite this resistance to S-YSTemic therapy, many of these tumor subtypes remain amenable to surgical resection and possible cure. In this study, we report on a series of seven patients highlighting two chemo-resistant subtypes of nonseminomatous germ cell tumor (NSGCT), sarcomatoid yolk sac tumor (S-YST), and epithelioid trophoblastic tumor (ETT) for which early resection rather than additional salvage chemotherapy or high-dose intense chemotherapy might provide a superior clinical outcome and enhance cure rate.

Inferring Bladder Cancer Evolution from Mucosal field Effects by Whole-Organ Spatial Mutational, Proteomic, and Metabolomic Mapping.

Multi-platform mutational, proteomic, and metabolomic spatial mapping was used on the whole-organ scale to identify the molecular evolution of bladder cancer from mucosal field effects. We identified complex proteomic and metabolomic dysregulations in microscopically normal areas of bladder mucosa adjacent to dysplasia and carcinoma in situ. The mutational landscape developed in a background of complex defects of protein homeostasis which included dysregulated nucleocytoplasmic transport, splicesome, ribosome biogenesis, and peroxisome. These changes were combined with altered urothelial differentiation which involved lipid metabolism and protein degradations controlled by PPAR. The complex alterations of proteome were accompanied by dysregulation of gluco-lipid energy-related metabolism. The analysis of mutational landscape identified three types of mutations based on their geographic distribution and variant allele frequencies. The most common were low frequency α mutations restricted to individual mucosal samples. The two other groups of mutations were associated with clonal expansion. The first of this group referred to as ß mutations occurred at low frequencies across the mucosa. The second of this group called γ mutations increased in frequency with disease progression. Modeling of the mutations revealed that carcinogenesis may span nearly 30 years and can be divided into dormant and progressive phases. The α mutations developed gradually in the dormant phase. The progressive phase lasted approximately five years and was signified by the advent of ß mutations, but it was driven by γ mutations which developed during the last 2-3 years of disease progression to invasive cancer. Our study indicates that the understanding of complex alterations involving mucosal microenvironment initiating bladder carcinogenesis can be inferred from the multi-platform whole-organ mapping.

Plasmacytoid urothelial carcinoma of the urinary bladder-A clinicopathological and molecular analysis of 52 cases.

Plasmacytoid urothelial carcinoma (UC) is a rare histologic subtype of bladder cancer that is associated with an aggressive clinical behavior. We analyzed the clinicopathologic and molecular features of plasmacytoid UC in 52 patients from a single institute. The patients included 44 men and 8 women, with a mean age of 64 years (range, 41-91 years). All bladder cancers were high-grade UC, and plasmacytoid component accounted for a mean of 47% of bladder tumors (range, 5-100%). Distinct gene mutations were found in most plasmacytoid UCs (n = 49); the most common mutations were TP53 (n = 30), followed by TERT (n = 20), and CDH1 (n = 18). Copy number analysis was performed in 34 patients, and 13 of them showed copy number variations. Expression of HER2 was analyzed in 18 patients by immunohistochemistry, and 3 of them showed HER2 overexpression, which was confirmed by fluorescence in situ hybridization analysis. Thirty-two patients died of disease in a median of 15 months (range, 1-45 months). No individual gene mutations were significantly associated with clinical outcome, but mutations in the mammalian target of rapamycin (mTOR) pathway, including PICK3CA and PIK3R1 mutations, were associated with a significantly shorter survival duration (p < 0.05). Plasmacytoid UC is an aggressive histologic subtype that demonstrates frequent somatic gene mutations and CNVs, which may underlie its oncogenesis and progression. Gene mutations of the mTOR pathway are associated with poor outcome in a subset of patients with plasmacytoid UC.

Phase 1b Trial Evaluating Tolerability and Activity of Targeted Fibroblast Growth Factor Receptor Inhibition in Localized Upper Tract Urothelial Carcinoma.

PURPOSE: We initiated a biomarker-informed preoperative study of infigratinib, a fibroblast growth factor receptor (FGFR) inhibitor, in patients with localized upper tract urothelial carcinoma (UTUC), a population with high unmet needs and tumor with a high frequency of FGFR3 alterations. MATERIALS AND METHODS: Patients with localized UTUC undergoing ureteroscopy or nephroureterectomy/ureterectomy were enrolled on a phase 1b trial (NCT04228042). Once-daily infigratinib 125 mg by mouth × 21 days (28-day cycle) was given for 2 cycles. Tolerability was monitored by Bayesian design and predefined stopping boundaries. The primary endpoint was tolerability, and the secondary endpoint was objective response based on tumor mapping, done after endoscopic biopsy and post-trial surgery. Total planned enrollment: 20 patients. Targeted sequencing performed using a NovaSeq 6000 solid tumor panel. RESULTS: From May 2021 to November 2022, 14 patients were enrolled, at which point the trial was closed due to termination of all infigratinib oncology trials. Two patients (14.3%) had treatment-terminating toxicities, well below the stopping threshold. Responses occurred in 6 (66.7%) of 9 patients with FGFR3 alterations. Responders had median tumor size reduction of 67%, with 3 of 5 patients initially planned for nephroureterectomy/ureterectomy converted to ureteroscopy. Median follow-up in responders was 24.7 months (14.9-28.9). CONCLUSIONS: In this first trial of targeted therapy for localized UTUC, FGFR inhibition was well tolerated and had significant activity in FGFR3 altered tumors. Renal preservation was enabled in a substantial proportion of participants. These data support the design of a biomarker-driven phase 2 trial of FGFR3 inhibition in this population with significant unmet clinical needs.

Loss of LPAR6 and CAB39L dysregulates the basal-to-luminal urothelial differentiation program, contributing to bladder carcinogenesis.

We describe a strategy that combines histologic and molecular mapping that permits interrogation of the chronology of changes associated with cancer development on a whole-organ scale. Using this approach, we present the sequence of alterations around RB1 in the development of bladder cancer. We show that RB1 is not involved in initial expansion of the preneoplastic clone. Instead, we found a set of contiguous genes that we term "forerunner" genes whose silencing is associated with the development of plaque-like field effects initiating carcinogenesis. Specifically, we identified five candidate forerunner genes (ITM2B, LPAR6, MLNR, CAB39L, and ARL11) mapping near RB1. Two of these genes, LPAR6 and CAB39L, are preferentially downregulated in the luminal and basal subtypes of bladder cancer, respectively. Their loss of function dysregulates urothelial differentiation, sensitizing the urothelium to N-butyl-N-(4-hydroxybutyl)nitrosamine-induced cancers, which recapitulate the luminal and basal subtypes of human bladder cancer.

Molecular profile of bladder cancer progression to clinically aggressive subtypes.

Bladder cancer is a histologically and clinically heterogenous disease. Most bladder cancers are urothelial carcinomas, which frequently develop distinct histological subtypes. Several urothelial carcinoma histological subtypes, such as micropapillary, plasmacytoid, small-cell carcinoma and sarcomatoid, show highly aggressive behaviour and pose unique challenges in diagnosis and treatment. Comprehensive genomic characterizations of the urothelial carcinoma subtypes have revealed that they probably arise from a precursor subset of conventional urothelial carcinomas that belong to different molecular subtypes - micropapillary and plasmacytoid subtypes develop along the luminal pathway, whereas small-cell and sarcomatoid subtypes evolve along the basal pathway. The subtypes exhibit distinct genomic alterations, but in most cases their biological properties seem to be primarily determined by specific gene expression profiles, including epithelial-mesenchymal transition, urothelial-to-neural lineage plasticity, and immune infiltration with distinct upregulation of immune regulatory genes. These breakthrough studies have transformed our view of bladder cancer histological subtype biology, generated new hypotheses for therapy and chemoresistance, and facilitated the discovery of new therapeutic targets.

Influence of lamina propria invasion extension on T1 high-grade non-muscle-invasive bladder cancer in patients undergoing BCG or radical cystectomy.

OBJECTIVE: To evaluate the prognostic value of T1 substaging in patients treated with bacillus Calmette-Guérin (BCG) or immediate radical cystectomy (iRC). MATERIALS AND METHODS: We performed an institutional review board-approved retrospective study analysing non-muscle-invasive bladder cancer (NMIBC) patients with pT1 disease treated with either BCG or iRC between 2000 and 2020. Lamina propria (LP) invasion characteristics were extracted from the pathology report. The Kaplan-Meier method was used to calculate overall survival (OS), cancer-specific survival (CSS) and metastasis-free survival (MFS). Multivariable Cox models were used to determine the association between progression-free survival (PFS) and characteristics in the BCG cohort. A logistic regression model explored the relationship between T1 substaging and upstaging to >pT2 at iRC. RESULTS: A total of 411 T1 high-grade patients were identified. LP invasion characteristics were as follows: not specified: 115 (28%); focal/superficial (F/S): 147 (35.8%); and extensive/multifocal (E/M): 149 (36.2%). Overall, 303 patients (73.7%) received BCG, and 108 patients (26.3%) underwent iRC. The median (interquartile range) follow-up was 53 (32-96) months. Patients with E/M LP invasion were significantly more likely to undergo iRC (34% vs. 19%; P = 0.003). Patients with E/M LP invasion showed poorer MFS and CSS compared to those with F/S LP invasion when treated with BCG but not when treated with iRC. Among BCG-treated patients, progression occurred in 41 patients and E/M LP invasion was independently associated with progression after BCG (hazard ratio 5.3, 95% confidence interval [CI] 2.2-13.1; P < 0.001). T1 substaging was not associated with upstaging at RC (odds ratio 3.15, 95% CI 0.82-12.12; P = 0.095). CONCLUSIONS: Extensive/multifocal LP invasion was associated with poor PFS, MFS and CSS in patients treated with BCG. T1 substaging provides valuable prognostic information and should be reported in pathology reports.

Impact of age >70 years on oncological outcomes in patients with non-muscle-invasive bladder cancer treated with Bacillus Calmette-Guérin.

OBJECTIVE: To evaluate the impact of age on oncological outcomes in a large contemporary cohort of patients with non-muscle-invasive bladder cancer (NMIBC) treated with adequate Bacillus Calmette-Guérin (BCG). PATIENTS AND METHODS: We performed an Institutional Review Board-approved retrospective study analysing patients with NMIBC treated with adequate BCG at our institution from 2000 to 2020. Adequate BCG was defined as per United States Food and Drug Administration (FDA) guidelines as being receipt of at least five of six induction BCG instillations with a minimum of two additional doses (of planned maintenance or of re-induction) of BCG instillations within a span of 6 months. The study's primary outcome was to determine if age >70 years was associated with progression to MIBC cancer or distant metastasis. The cumulative incidence method and the competing-risk regression analyses were used to investigate the association of advanced age (>70 years) with progression, high-grade (HG) recurrence and cancer-specific mortality (CSM). RESULTS: Overall, data from 632 patients were analysed: 355 patients (56.2%) were aged ≤70 years and 277 (43.8%) were >70 years. Age >70 years did not adversely affect either cumulative incidence of progression or HG recurrence (P = 0.067 and P = 0.644, respectively). On competing-risk regression analyses, age >70 years did not emerge as an independent predictor of progression or HG recurrence (sub-standardised hazard ratio [SHR] 1.57, 95% confidence interval [CI] 0.87-2.81, P = 0.134; and SHR 1.05, 95% CI 0.77-1.44, P = 0.749). Not unexpectedly, patients in the older group did have higher overall mortality (P < 0.001) but not CSM (P = 0.057). CONCLUSION: Age >70 years was not associated with adverse oncological outcomes in a large contemporary cohort of patients receiving adequate intravesical BCG for NMIBC. BCG should not be withheld from older patients seeking for bladder sparing options.

Contemporary Issues in Urothelial Carcinoma of Upper Urinary Tract.

Upper urinary tract urothelial carcinoma (UTUC) is an uncommon malignancy involving the renal pelvis and ureter. Careful pathologic analysis plays a critical role in the diagnosis and clinical management of UTUC. In combination with clinical and radiologic evaluation, pathologic features can be used to stratify patients into low-risk and high-risk groups. This risk stratification can help clinicians select the optimal treatment for patients with UTUC, such as kidney-sparing (conservative) treatment, radical nephroureterectomy or ureterectomy, and perioperative systemic therapy. However, due to the technical difficulty of obtaining sufficient tissue from the upper urinary tract, it is often challenging for pathologists to accurately grade the tumor and assess tumor invasion in small biopsy specimens. Although the majority of UTUCs are pure urothelial carcinoma, a considerable subset of UTUCs show histologic subtypes or divergent differentiation. Recent studies have identified genetically distinct molecular subtypes of UTUC by examining DNA, RNA, and protein expression profiles. The prognosis of pT3 UTUC, particularly renal pelvic UC, remains controversial, and several studies have proposed subclassification of pT3 UTUC. Lynch syndrome is a significant risk factor for UTUC, and screening tests may be considered in young patients and those with familial histories of the disease. Despite significant progress in recent years, several issues remain to be addressed in the pathologic diagnosis, molecular classification, and treatment of UTUC.

Long-Term Oncological Outcomes in Patients Diagnosed With Nonmetastatic Plasmacytoid Variant of Bladder Cancer: A 20-Year University of Texas MD Anderson Cancer Center Experience.

PURPOSE: The treated natural history of nonmetastatic plasmacytoid variant of bladder cancer (PV-BCa) is poorly understood owing to its rarity. We sought to examine the disease recurrence and metastasis patterns in this select group of patients in order to identify opportunities for intervention. MATERIALS AND METHODS: We conducted a natural language processing algorithm-augmented retrospective chart review of 56 consecutive patients who were treated with curative intent for nonmetastatic PV-BCa at our institution between 1998 and 2018. Kaplan-Meier and multivariable Cox regression methods were used for survival analyses. RESULTS: The stage at presentation was: ≤ cT2N0 in 22 (39.3%), cT3N0 in 15 (26.8%), cT4N0 in 13 (23.2%), and ≥ cN1 in 6 patients (10.7%). Forty-nine patients (87.5%) received chemotherapy, and 42 (75%) were able to undergo the planned surgery. Notably, only 4 patients (7.2%) had pT0 stage, while 22 (52.4%) had pN+ disease at the time of surgery. At 36-month follow-up, 28.4% of patients (95% CI: 22.1%-34.5%) were alive and 22.2% (95% CI: 16.1%-28.5%) were free of metastatic disease. The benefit of surgical extirpation was stage specific: successful completion of surgery was associated with improved metastasis-free survival (at 36 months 32.4% vs 0%, log-rank P < .001) in patients with localized or locally advanced disease (≤cT2N0/cT3N0); however, in patients with regionally advanced disease (cT4N0/≥cN1), consolidative surgery following chemotherapy was not associated with improved metastasis-free survival (12.5% vs 10% at 36 months, log-rank P = .49). The median time to metastasis from primary treatment end was 6.5 months (IQR: 2.9-14.7). The predominant site of recurrence/metastasis was the peritoneum (76.1%), either in isolation or along with extraperitoneal lesions. Salvage immunotherapy in these patients significantly reduced the risk of death (HR = 0.11, P = .001). CONCLUSIONS: PV-BCa is a disease with high lethality. Despite multimodal treatment, a vast majority of patients develop atypical intraperitoneal metastasis soon after therapy and rapidly succumb to it. Clinical trials evaluating utility of hyperthermic intraperitoneal chemotherapy and/or immunotherapy may be warranted in this high-risk population.

Recent Advances in Genitourinary Tumors Updates From the 5th Edition of the World Health Organization Blue Book Series.

CONTEXT.­: Urinary and Male Genital Tumours is the 8th volume of the World Health Organization Classification of Tumours series, 5th edition. Released in hard copy in September 2022, it presents an update to the classification of male genital and urinary tumors in the molecular age. Building upon previous volumes in this series, significant effort has been made to harmonize terminology across organ systems for biologically similar tumors (eg, neuroendocrine tumors). Genomic terminology has been standardized and genetic syndromes covered more comprehensively. This review presents a concise summary of this volume highlighting new entities, notable modifications relative to the 4th edition, and elements of relevance to routine clinical practice. OBJECTIVE.­: To provide a comprehensive update on the World Health Organization classification of urinary and male genital tumors, highlighting updated diagnostic criteria and terminology. DATA SOURCES.­: The 4th and 5th editions of the World Health Organization Classification of Tumours: Urinary and Male Genital Tumours. CONCLUSIONS.­: The World Health Organization has made several changes in the 5th edition of the update on urinary and male genital tumors that pathologists need to be aware of for up-to-date clinical practice.

Comparative Effectiveness Analysis of Treatment Strategies for Surgically Resectable Neuroendocrine Carcinoma of the Urinary Tract.

BACKGROUND: Neoadjuvant chemotherapy (neoCTX) has been recommended as the optimal strategy in surgically resectable neuroendocrine carcinoma (NEC) of the urinary tract (NEC-URO). OBJECTIVE: To determine the systemic therapy regimen and timing, which are most active against NEC-URO. DESIGN, SETTING, AND PARTICIPANTS: We used our institutional historical clinical and pathological database to study 203 patients (cT2, 74%; cT3/4a, 22%; and cTx, 4%) with surgically resectable NEC-URO between November 1985 and May 2020. A total of 141 patients received neoCTX and 62 underwent initial radical surgery, 24 of whom received adjuvant CTX (adjCTX). INTERVENTION: Neoadjuvant CTX with etoposide/cisplatin (EP), an alternating doublet of ifosfamide/doxorubicin (IA) and EP, dose-dense methotrexate/vinblastine/doxorubicin/cisplatin (MVAC), gemcitabine/cisplatin (GC), or others. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Overall survival (OS), downstaging rate, and pathological complete response using a multivariable model adjusting for tumor- and patient-related factors. RESULTS AND LIMITATIONS: Downstaging rate was significantly improved with neoCTX versus initial surgery (49.6% vs 14.5%, p < 0.0001), stage cT2N0 versus cT3/4N0 (44% vs 25%, p = 0.01), or presence of carcinoma in situ (47% vs 28%, p = 0.01). Downstaging was greatest with IA/EP (65%) versus EP (39%), MVAC/GC (27%), or others (36%, p = 0.04). After adjusting for age and Eastern Cooperative Oncology Group performance status, IA/EP was still associated with improved downstaging (odds ratio = 3.7 [1.3-10.2], p = 0.01). At a median follow-up of 59.7 mo, 5-yr OS rates for neoCTX followed by surgery, surgery alone, and surgery followed by adjCTX were 57%, 22%, and 30%, respectively. An NEC regimen (IA/EP or EP) versus a urothelial regimen (MVAC/GC or others) was associated with improved survival (145.4 vs 42.5 mo, hazard ratio = 0.49, 95% confidence interval: 0.25-0.94). CONCLUSIONS: Neoadjuvant CTX remains the standard-of-care treatment for NEC-URO with an advantage for NEC regimens over traditional urothelial regimens. IA/EP improves pathological downstaging at the time of surgery compared with EP, but is reserved for younger and higher function patients. PATIENT SUMMARY: In this report, we looked at the outcomes from invasive neuroendocrine carcinoma of the urinary tract in a large US population. We found that the outcomes varied with treatment strategy. We conclude that the best outcomes are seen in patients treated with chemotherapy prior to surgery and regimens tailored to histology and tolerance.

Bladder-sparing Treatment in Patients with Bacillus Calmette-Guerin-unresponsive Non-muscle-invasive Bladder Cancer: An Analysis of Long-term Survival Outcomes.

Background: Data for bladder-sparing treatment (BST) in bacillus Calmette-Guerin (BCG)-unresponsive non-muscle-invasive bladder cancer (NMIBC) patients report short-term outcomes limited to 1-2 yr. Objective: To assess long-term survival outcomes of BCG-unresponsive NMIBC patients treated with BST. Design setting and participants: BCG-unresponsive NMIBC patients diagnosed between January 2000 and September 2021 from an institutional NMIBC registry were evaluated. Intervention: Long-term survival outcomes for patients receiving BST, early radical cystectomy (RC), and delayed RC were compared. Outcome measurements and statistical analysis: The primary endpoints were overall survival (OS) and cancer-specific survival (CSS). Results and limitations: In total, 114 patients with a median follow-up of 71.2 mo (interquartile range: 32.6-132.2) were analyzed. There were no significant differences in OS (hazard ratio [HR]: 1.40, 95% confidence interval [CI]: 0.68-2.89, p = 0.4) or CSS (HR: 0.88, 95% CI: 0.22-3.55, p = 0.9) between patients undergoing early RC (n = 38) and BST (n = 76). At 60 mo, BST patients had a high-grade recurrence-free rate, muscle-invasive disease/metastasis progression-free rate, and avoidance of RC rate of 37%, 83%, and 58%, respectively. Current smoker status (HR: 4.44, 95% CI: 1.41-13.97, p = 0.011) was the only variable predictive of high-grade recurrence following a multivariable analysis. The median time to RC from BCG-unresponsive date was 2.1 and 11.7 mo for those undergoing early RC and delayed RC (after BST), respectively. Patients treated with early RC had a higher incidence of cT1 disease (53% vs 36%, p = 0.049) and lymphovascular invasion (LVI; 11% vs 0%, p = 0.011) compared to patients treated with BST. Survival outcomes were similar between groups: 10-yr OS-58% versus 50% (HR: 1.40, 95% CI: 0.68-2.89, p = 0.4), and 10-yr CSS-81% versus 85% (HR: 0.88, 95% CI: 0.22-3.55, p = 0.9). Conclusions: An analysis of long-term survival of BCG-unresponsive NMIBC patients receiving BST suggests that it may be safe in patients without LVI and/or variant histology and nonsmokers. Survival outcomes for patients treated with BST may not be inferior to those receiving early RC. Patient summary: Bladder-sparing treatment can be offered to appropriately selected patients who have bacillus Calmette-Guerin (BCG)-unresponsive non-muscle-invasive bladder cancer. Long-term outcomes may not be inferior to those for patients who opt for early radical cystectomy.

Reprint of: somatic-type malignancies in testicular germ cell tumors.

The development of somatic-type malignancy (SM) in testicular germ cell tumor represents a major challenge in the diagnosis and treatment of testicular cancer. Most SMs are derived from teratoma, and the remainder is associated with yolk sac tumor. They occur more frequently in metastases than in primary testicular tumors. SMs demonstrate a variety of histologic types, including sarcoma, carcinoma, embryonic-type neuroectodermal tumor, nephroblastoma-like tumor, and hematologic malignancy. Sarcoma, particularly rhabdomyosarcoma, accounts for the majority of SMs in the primary testicular tumors, whereas carcinoma, particularly adenocarcinoma, is the most common SM in metastases. Although SMs derived from testicular germ cell tumors mimic their histologic counterparts in other organs with overlapping immunohistochemical profiles, isochromosome 12p is present in most SMs, which can be useful in the differential diagnosis. The presence of SM in the primary testicular tumor may not worsen the outcome, but the development of SM in metastasis is associated with a poor prognosis. Furthermore, somatic-type carcinoma is likely associated with a worse prognosis than somatic-type sarcoma. Although SMs respond poorly to the cisplatin-based chemotherapy, timely surgical resection is an effective treatment for most patients.