Natural History and Genomic Landscape of Chemotherapy-Resistant Muscle-Invasive Bladder Cancer.

PURPOSE: Patients with residual invasive bladder cancer after neoadjuvant chemotherapy (NAC) and radical cystectomy have a poor prognosis. Data on adjuvant therapy for these patients are conflicting. We sought to evaluate the natural history and genomic landscape of chemotherapy-resistant bladder cancer to inform patient management and clinical trials. METHODS: Data were collected on patients with clinically localized muscle-invasive urothelial bladder cancer treated with NAC and cystectomy at our institution between May 15, 2001, and August 15, 2019, and completed four cycles of gemcitabine and cisplatin NAC, excluding those treated with adjuvant therapies. Survival was estimated using the Kaplan-Meier method, and multivariable Cox proportional hazards models were used to identify predictors of recurrence-free survival (RFS). Genomic alterations were identified in targeted exome sequencing (Memorial Sloan Kettering Integrated Mutation Profiling of Actionable Cancer Targets) data from post-NAC specimens from a subset of patients. RESULTS: Lymphovascular invasion (LVI) was the strongest predictor of RFS (hazard ratio, 2.15 [95% CI, 1.37 to 3.39]) on multivariable analysis. Patients with ypT2N0 disease without LVI had a significantly prolonged RFS compared with those with LVI (70% RFS at 5 years). Lymph node yield did not affect RFS. Among patients with sequencing data (n = 101), chemotherapy-resistant tumors had fewer alterations in DNA damage response genes compared with tumors from a publicly available chemotherapy-naïve cohort (15% v 29%; P = .021). Alterations in CDKN2A/B were associated with shorter RFS. PIK3CA alterations were associated with LVI. Potentially actionable alterations were identified in more than 75% of tumors. CONCLUSION: Although chemotherapy-resistant bladder cancer generally portends a poor prognosis, patients with organ-confined disease without LVI may be candidates for close observation without adjuvant therapy. The genomic landscape of chemotherapy-resistant tumors is similar to chemotherapy-naïve tumors. Therapeutic opportunities exist for targeted therapies as adjuvant treatment in chemotherapy-resistant disease.

Incidence and management of prostatic urethra recurrence in a cohort of 21 patients who received BCG induction for non-muscle invasive bladder cancer.

PURPOSE: To describe the incidence and management of patients who develop a prostatic urethral (PU) urothelial carcinoma recurrence after Bacillus Calmette-Guerin (BCG) induction for non-muscle invasive bladder cancer (NMIBC). MATERIALS AND METHODS: We performed a retrospective cohort study of all patients who received BCG induction at our institution from 1996 to 2021 (N = 642) for NMIBC. All patients with pathologically confirmed PU involvement following BCG induction with no known PU involvement pre-BCG were included. We describe the presentation, management, and outcomes for PU recurrence. RESULTS: Among the 642 patients, 21 (3.3%) patients had a PU recurrence after BCG induction. 8 (38%) patients received >2 cycles of BCG induction prior to the recurrence. Median time from induction to PU recurrence was 21 months and 12 (57.1%) patients had concurrent bladder recurrence. At the time of their PU recurrence, 14/21 (67%) of patients were deemed BCG Unresponsive. Nearly all (18/21) were high grade, and 10 were stage Tis, 7 Ta, and 3 T1, and 1 T2. 19/21 (90%) patients received bladder sparing treatment: 6 with TURBT and BCG, 6 with TURBT and intravesical chemotherapy, 5 with TURBT only, and 2 did not receive immediate treatment of their PU recurrence due to advanced stage of disease. 2/21 (9.5%) received a radical cystectomy for initial treatment of the post-BCG PU recurrence, of which all were >pT2. Median follow-up time from BCG induction to the patient's last visit was 64.5 months. Following treatment of PU recurrence, 15/18 patients had another recurrence at a median of 5 months: about 47% of recurrences were bladder only and 14% recurred only in the PU as well. About 1 patient received a RC after the second recurrence and was pT2. CONCLUSION: Patients with PU recurrences following intravesical BCG have a high-risk disease phenotype with a significant risk of recurrence. Conservative management may be appropriate for well-selected patients who do not desire a cystoprostatectomy.

Clinical and Genomic Landscape of FGFR3-Altered Urothelial Carcinoma and Treatment Outcomes with Erdafitinib: A Real-World Experience.

PURPOSE: Erdafitinib is the only FDA-approved targeted therapy for FGFR2/3-altered metastatic urothelial cancer. We characterized the genetic landscape of FGFR-altered urothelial carcinoma and real-world clinical outcomes with erdafitinib, including on-treatment genomic evolution. EXPERIMENTAL DESIGN: Prospectively collected clinical data were integrated with institutional genomic data to define the landscape of FGFR2/3-altered urothelial carcinoma. To identify mechanisms of erdafitinib resistance, a subset of patients underwent prospective cell-free (cf) DNA assessment. RESULTS: FGFR3 alterations predictive of erdafitinib sensitivity were identified in 39% (199/504) of patients with non-muscle invasive, 14% (75/526) with muscle-invasive, 43% (81/187) with localized upper tract, and 26% (59/228) with metastatic specimens. One patient had a potentially sensitizing FGFR2 fusion. Among 27 FGFR3-altered cases with a primary tumor and metachronous metastasis, 7 paired specimens (26%) displayed discordant FGFR3 status. Erdafitinib achieved a response rate of 40% but median progression-free and overall survival of only 2.8 and 6.6 months, respectively (n = 32). Dose reductions (38%, 12/32) and interruptions (50%, 16/32) were common. Putative resistance mutations detected in cfDNA involved TP53 (n = 5), AKT1 (n = 1), and second-site FGFR3 mutations (n = 2). CONCLUSIONS: FGFR3 mutations are common in urothelial carcinoma, whereas FGFR2 alterations are rare. Discordance of FGFR3 mutational status between primary and metastatic tumors occurs frequently and raises concern over sequencing archival primary tumors to guide patient selection for erdafitinib therapy. Erdafitinib responses were typically brief and dosing was limited by toxicity. FGFR3, AKT1, and TP53 mutations detected in cfDNA represent putative mechanisms of acquired erdafitinib resistance.

Survival outcomes in patients with muscle invasive bladder cancer undergoing radical vs. partial cystectomy.

PURPOSE: While radical cystectomy (RC) is the standard of care for muscle invasive bladder cancer (MIBC), partial cystectomy (PC) is an effective alternative in select patients. We sought to examine differences in survival for RC and PC in a hospital-based registry. MATERIAL AND METHODS: We identified patients diagnosed with cT2-4 bladder cancer who underwent RC or PC from 2003 to 2015 in the National Cancer Database (NCDB). Using inverse probability treatment weighting (IPTW) to control for known confounders, we compared the primary outcome of overall survival (OS) in patients who underwent RC vs. PC. Kaplan-Meier survival analysis, univariable and multivariable Cox proportional hazards modeling were used. We performed a secondary survival analysis for a subcohort of patients with cT2, cN0, tumor size ≤5 cm, and no concurrent carcinoma in situ (CIS), who may be optimal candidates for PC. RESULTS: A total of 22,534 patients met inclusion criteria, of which 6.9% (1,457) underwent PC. RC had longer median OS than PC (67.8 vs. 54.1 months) and on Cox regression analysis (HR 0.88, 95% CI, 0.80-0.95, P = 0.002). However, in our subcohort, there was no difference in OS between RC and PC (HR 1.02, 95% CI, 0.9-1.2, P = 0.74). PC was associated with increased time from surgery to any systemic therapy or death in the subcohort. CONCLUSIONS: Among patients with clinically organ-confined MIBC, PC appears to afford similar survival outcomes to RC in a large national data set. The safety and tolerability of PC may warrant consideration in highly selected patients.

Readmissions after radical nephrectomy in a national cohort.

OBJECTIVE: To analyze the factors and costs associated with 30-day readmissions for patients undergoing radical nephrectomy. MATERIALS AND METHODS: We used the 2014 Nationwide Readmission Database to identify adults who underwent radical nephrectomy for renal cancer, stratified by surgical approach. We determined patient factors associated with readmission rates, diagnoses, and costs using multivariate logistic regression. RESULTS: Among 19,523 individuals, the 30-day readmission rate was 7.7% (n = 1,506). On multivariate regression, odds of readmission were significantly increased with age ≥75 in those who underwent open nephrectomy (OR: 1.35; 95%CI: 1.03-1.78). Subjects with a Charlson comorbidity score ≥3 had significantly higher rates of readmission regardless of surgical approach (Open RN - OR: 1.85; 95%CI: 1.33-2.56; Lap RN - OR: 1.99; 95%CI 1.10-3.59; Robotic RN - OR: 2.18; 95%CI: 1.23-3.86). Common reasons for readmission were gastrointestinal, cardiovascular, urinary tract infections, and wound complications across all surgical approaches. The mean cost per readmission was as high as 126% ($20,357) of the mean index admission cost. CONCLUSION: One in 13 adults undergoing radical nephrectomy is readmitted within 30 days of discharge. Associated readmission cost is up to 1.26 times the cost of index admission. Our findings may inform efforts aiming to reduce hospital readmissions and curtail healthcare costs.

Gene-based Confirmatory Germline Testing Following Tumor-only Sequencing of Prostate Cancer.

BACKGROUND: Tumor-only genomic profiling is an important tool in therapeutic management of men with prostate cancer. Since clinically actionable germline variants may be reflected in tumor profiling, it is critical to identify which variants have a higher risk of being germline in origin to better counsel patients and prioritize genetic testing. OBJECTIVE: To determine when variants found on tumor-only sequencing of prostate cancers should prompt confirmatory germline testing. DESIGN, SETTING, AND PARTICIPANTS: Men with prostate cancer who underwent both tumor and germline sequencing at Memorial Sloan Kettering Cancer Center from January 1, 2015 to January 31, 2020 were evaluated. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Tumor and germline profiles were analyzed for pathogenic and likely pathogenic ("pathogenic") variants in 60 moderate- or high-penetrance genes associated with cancer predisposition. The germline probability (germline/germline + somatic) of a variant was calculated for each gene. Clinical and pathologic factors were analyzed as potential modifiers of germline probability. RESULTS AND LIMITATIONS: Of the 1883 patients identified, 1084 (58%) had a somatic or germline pathogenic variant in one of 60 cancer susceptibility genes, and of them, 240 (22%) had at least one germline variant. Overall, the most frequent variants were in TP53, PTEN, APC, BRCA2, RB1, ATM, and CHEK2. Variants in TP53, PTEN, or RB1 were identified in 746 (40%) patients and were exclusively somatic. Variants with the highest germline probabilities were in PALB2 (69%), MITF (62%), HOXB13 (60%), CHEK2 (55%), BRCA1 (55%), and BRCA2 (47%), and the overall germline probability of a variant in any DNA damage repair gene was 40%. Limitations were that most of the men included in the cohort had metastatic disease, and different thresholds for pathogenicity exist for somatic and germline variants. CONCLUSIONS: Of patients with pathogenic variants found on prostate tumor sequencing, 22% had clinically actionable germline variants, for which the germline probabilities varied widely by gene. Our results provide an evidenced-based clinical framework to prioritize referral to genetic counseling following tumor-only sequencing. PATIENT SUMMARY: Patients with advanced prostate cancer are recommended to have germline genetic testing. Genetic sequencing of a patient's prostate tumor may also identify certain gene variants that are inherited. We found that patients who had variants in certain genes, such as ones that function in DNA damage repair, identified in their prostate tumor sequencing, had a high risk for having an inherited cancer syndrome.

Genomic heterogeneity as a barrier to precision oncology in urothelial cancer.

Precision oncology relies on the accurate molecular characterization of individual patients with cancer at the time of treatment initiation. However, tumor molecular profiles are not static, and cancers continually evolve because of ongoing mutagenesis and clonal selection. Here, we performed genomic analyses of primary tumors, metastases, and plasma collected from individual patients to define the concordance of actionable genomic alterations and to identify drivers of metastatic disease progression. We observed a high degree of discordance of actionable genomic alterations, with 23% discordant between primary and metastatic disease sites. Among chromatin-modifying genes, ARID1A mutations, when discordant, were exclusive to the metastatic tumor samples. Our findings indicate that the high degree of lesion-to-lesion genomic heterogeneity may be a barrier to precision oncology approaches for bladder cancer and that circulating tumor DNA profiling may be preferred to tumor sequencing for a subset of patients.

FOXA1 repression drives lineage plasticity and immune heterogeneity in bladder cancers with squamous differentiation.

Cancers arising from the bladder urothelium often exhibit lineage plasticity with regions of urothelial carcinoma adjacent to or admixed with regions of divergent histomorphology, most commonly squamous differentiation. To define the biologic basis for and clinical significance of this morphologic heterogeneity, here we perform integrated genomic analyses of mixed histology bladder cancers with separable regions of urothelial and squamous differentiation. We find that squamous differentiation is a marker of intratumoral genomic and immunologic heterogeneity in patients with bladder cancer and a biomarker of intrinsic immunotherapy resistance. Phylogenetic analysis confirms that in all cases the urothelial and squamous regions are derived from a common shared precursor. Despite the presence of marked genomic heterogeneity between co-existent urothelial and squamous differentiated regions, no recurrent genomic alteration exclusive to the urothelial or squamous morphologies is identified. Rather, lineage plasticity in bladder cancers with squamous differentiation is associated with loss of expression of FOXA1, GATA3, and PPARG, transcription factors critical for maintenance of urothelial cell identity. Of clinical significance, lineage plasticity and PD-L1 expression is coordinately dysregulated via FOXA1, with patients exhibiting morphologic heterogeneity pre-treatment significantly less likely to respond to immune checkpoint inhibitors.

Targeted Therapies in Advanced and Metastatic Urothelial Carcinoma.

This review describes the current landscape of targeted therapies in urothelial carcinoma. The standard of care for advanced urothelial carcinoma patients remains platinum-based combination chemotherapy followed by immunotherapy. However, median overall survival for these patients is still <1 year and there is an urgent need for alternative therapies. The advent of next-generation sequencing has allowed widespread comprehensive molecular characterization of urothelial tumors and, subsequently, the development of therapies targeting specific molecular pathways implicated in carcinogenesis such as FGFR inhibition, Nectin-4, Trop-2, and HER2 targeting. As these therapies are demonstrated to be effective in the second-line setting, they will be advanced in the treatment paradigm to localized and even non-muscle invasive disease.

Clinical and Genomic Characterization of Bladder Carcinomas With Glandular Phenotype.

PURPOSE: To compare oncologic outcomes and genomic alteration profiles in patients with bladder and urachal adenocarcinoma, urothelial carcinoma (UC) with glandular differentiation, and UC, not otherwise specified (NOS) undergoing surgical resection, with emphasis on response to systemic therapy. METHODS: We identified patients with bladder cancer with glandular variants who underwent surgical resection at Memorial Sloan Kettering from 1995 to 2018 (surgical cohort) and/or patients who had tumor sequencing using a targeted next-generation sequencing platform (genomics cohort). Pathologic complete and partial response rates to neoadjuvant chemotherapy (NAC) and recurrence-free and cancer-specific survival were measured. Alteration frequencies between histologic subtypes were compared. RESULTS: Thirty-seven patients with bladder adenocarcinoma, 46 with urachal adenocarcinoma, 84 with UC with glandular differentiation, and 1,049 with UC, NOS comprised the surgical cohort. Despite more advanced disease in patients with bladder and urachal adenocarcinoma, no significant differences in recurrence or cancer-specific survival by histology were observed after adjusting for stage. In patients with UC with glandular differentiation, NAC resulted in partial (≤ pT1N0) and complete (pT0N0) responses in 28% and 17%, respectively. Bladder and urachal adenocarcinoma genomic profiles resembled colorectal adenocarcinoma with frequent TP53, KRAS, and PIK3CA alterations while the genomic profile of UC with glandular differentiation more closely resembled UC, NOS. Limitations include retrospective nature of analysis and small numbers of nonurothelial histology specimens. CONCLUSION: The genomic profile of bladder adenocarcinomas resembled colorectal adenocarcinomas, whereas UC with glandular differentiation more closely resembled UC, NOS. Differences in outcomes among patients with glandular bladder cancer variants undergoing surgical resection were largely driven by differences in stage. Cisplatin-based NAC demonstrated activity in UC with glandular differentiation, suggesting NAC should be considered for this histologic variant.

Prostate-specific Membrane Antigen Positron Emission Tomography/Computed Tomography Compared with Conventional Imaging for Initial Staging of Treatment-naïve Intermediate- and High-risk Prostate Cancer: A Retrospective Single-center Study.

BACKGROUND: The role of prostate-specific membrane antigen (PSMA) positron emission tomography/computed tomography (PET/CT) imaging in the initial staging of men with prostate cancer (PCa) has yet to be evaluated adequately. OBJECTIVE: To investigate the concordance of PSMA PET/CT with conventional imaging (CI) with cross-sectional abdominopelvic and/or radionuclide bone imaging in the initial staging of patients with treatment-naïve PCa. DESIGN, SETTING, AND PARTICIPANTS: We performed a post hoc retrospective cohort study of patients enrolled in a prospective single-arm trial (NCT03368547). We included patients with intermediate-risk (IR) and high-risk (HR) PCa who underwent PSMA PET/CT within 6 mo of CI. Patients with any treatment prior to PSMA PET/CT were excluded. Patient- and tumor-specific data, and imaging findings were obtained. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Our primary outcome measurement was the concordance rate of PSMA PET/CT with CI for the identification of N, M1a, M1b, and M1c disease. Descriptive statistics were used. RESULTS AND LIMITATIONS: A total of 168 patients with treatment-naïve IR and HR PCa met the inclusion criteria. HR disease accounted for 124/168 (73.8%) patients. The median prostate-specific antigen was 11.4 (6.8-24.6)ng/ml. The rates of nonconcordance between PSMA PET/CT and CI were 34/162 (21.0%), 5/70 (7.1%), 8/92 (8.7%), and 1/71 (1.4%) for N, M1a, M1b, and M1c disease, respectively. PSMA PET/CT assigned a higher stage in 37/168 (22.0%) patients and a lower stage in 12/170 (7.1%) patients. In a subset of 50 patients treated with radical prostatectomy and pelvic lymph node dissection, the prevalence of PSMA PET/CT-positive and that of CI-positive nodal disease were 14% and 4%, and the false negative rates were 30% and 32%, respectively. The principal limitations of this study include the heterogeneity in CI modalities and the 6-mo time frame between CI and PSMA PET. CONCLUSIONS: PSMA PET/CT imaging may serve as a valuable tool in the initial staging of treatment-naïve IR and HR PCa. PATIENT SUMMARY: We evaluated how prostate-specific membrane antigen (PSMA) positron emission tomography/computed tomography (PET/CT) compared with standard imaging (such as computed tomography, bone scan, and prostate magnetic resonance imaging) for initial staging of patients with prostate cancer. Our findings suggest that PSMA PET/CT may detect and rule out more metastatic lesions, which could prove valuable in guiding treatment.

Head-to-Head Comparison of 68Ga-PSMA-11 PET/CT and mpMRI with a Histopathology Gold Standard in the Detection, Intraprostatic Localization, and Determination of Local Extension of Primary Prostate Cancer: Results from a Prospective Single-Center Imaging Trial.

The role of prostate-specific membrane antigen (PSMA)-targeted PET in comparison to multiparametric MRI (mpMRI) in the evaluation of intraprostatic cancer foci is not well defined. The aim of our study was to compare the diagnostic performance of 68Ga-PSMA-11 PET/CT (PSMA PET/CT), mpMRI, and PSMA PET/CT + mpMRI using 3 independent masked readers for each modality and with histopathology as the gold standard in the detection, intraprostatic localization, and determination of local extension of primary prostate cancer. Methods: Patients with intermediate- or high-risk prostate cancer who underwent PSMA PET/CT as part of a prospective trial (NCT03368547) and mpMRI before radical prostatectomy were included. Each imaging modality was interpreted by 3 independent readers who were unaware of the other modality result. A central majority rule was applied (2:1). Pathologic examination of whole-mount slices was used as the gold standard. Imaging scans and whole-mount slices were interpreted using the same standardized approach on a segment level and a lesion level. A "neighboring" approach was used to define imaging-pathology correlation for the detection of individual prostate cancer foci. Accuracy in determining the location, extraprostatic extension (EPE), and seminal vesicle invasion (SVI) of prostate cancer foci was assessed using receiver-operating-characteristic curve analysis. Interreader agreement was calculated using intraclass correlation coefficient analysis. Results: The final analysis included 74 patients (14 [19%] with intermediate risk and 60 [81%] with high risk). The cancer detection rate (lesion-based analysis) was 85%, 83%, and 87% for PSMA PET/CT, mpMRI, and PSMA PET/CT + mpMRI, respectively. The change in AUC was statistically significant between PSMA PET/CT + mpMRI and the 2 imaging modalities alone for delineation of tumor localization (segment-based analysis) (P < 0.001) but not between PSMA PET/CT and mpMRI (P = 0.093). mpMRI outperformed PSMA PET/CT in detecting EPE (P = 0.002) and SVI (P = 0.001). In the segment-level analysis, intraclass correlation coefficient analysis showed moderate reliability among PSMA PET/CT and mpMRI readers using a 5-point Likert scale (range, 0.53-0.64). In the evaluation of T staging, poor reliability was found among PSMA PET/CT readers and poor to moderate reliability was found for mpMRI readers. Conclusion: PSMA PET/CT and mpMRI have similar accuracy in the detection and intraprostatic localization of prostate cancer foci. mpMRI performs better in identifying EPE and SVI. For the T-staging evaluation of intermediate to high-risk prostate cancer, mpMRI should still be considered the imaging modality of reference. Whenever available, PSMA PET/MRI or the coregistration or fusion of PSMA PET/CT and mpMRI (PSMA PET/CT + mpMRI) should be used as it improves tumor extent delineation.

Germline Variants Identified in Patients with Early-onset Renal Cell Carcinoma Referred for Germline Genetic Testing.

BACKGROUND: Despite guidelines recommending genetic counseling for patients with early-onset renal cell carcinoma (RCC), studies interrogating the spectrum of germline mutations and clinical associations in patients with early-onset RCC are lacking. OBJECTIVE: To define the germline genetic spectrum and clinical associations for patients with early-onset RCC diagnosed at age ≤46 yr who underwent genetic testing. DESIGN, SETTING, AND PARTICIPANTS: We retrospectively identified patients with early-onset RCC who underwent germline testing at our institution from February 2003 to June 2020. OUTCOME MEASUREMENT AND STATISTICAL ANALYSIS: The frequency and spectrum of pathogenic/likely pathogenic (P/LP) variants were determined. Clinical characteristics associated with mutation status were analyzed using two-sample comparison (Fisher's exact or χ2 test). RESULTS AND LIMITATIONS: Of 232 patients with early-onset RCC, 50% had non-clear-cell histology, including unclassified RCC (12.1%), chromophobe RCC (9.7%), FH-deficient RCC (7.0%), papillary RCC (6.6%), and translocation-associated RCC (4.3%). Overall, 43.5% had metastatic disease. Germline P/LP variants were identified in 41 patients (17.7%), of which 21 (9.1%) were in an RCC-associated gene and 20 (8.6%) in a non-RCC-associated gene, including 17 (7.3%) in DNA damage repair genes such as BRCA1/2, ATM, and CHEK2. Factors associated with RCC P/LP variants include bilateral/multifocal renal tumors, non-clear-cell histology, and additional extrarenal primary malignancies. In patients with only a solitary clear-cell RCC, the prevalence of P/LP variants in RCC-associated and non-RCC-associated genes was 0% and 9.9%, respectively. CONCLUSIONS: Patients with early-onset RCC had high frequencies of germline P/LP variants in genes associated with both hereditary RCC and other cancer predispositions. Germline RCC panel testing has the highest yield when patients have clinical phenotypes suggestive of underlying RCC gene mutations. Patients with early-onset RCC should undergo comprehensive assessment of personal and family history to guide appropriate genetic testing. PATIENT SUMMARY: In this study of 232 patients with early-onset kidney cancer who underwent genetic testing, we found a high prevalence of mutations in genes that increase the risk of cancer in both kidneys and other organs for patients and their at-risk family members. Our study suggests that patients with early-onset kidney cancer should undergo comprehensive genetic risk assessment.

When is a Seminoma not a Seminoma? The Incidence, Risk Factors and Management of Patients With Testicular Seminoma With Discordant Elevated Serum Alpha-fetoprotein.

OBJECTIVE: To describe the incidence, clinical and demographic factors, and treatment patterns associated with discordant elevated alpha-fetoprotein (AFP) findings in patients with pure seminomatous histology. METHODS: We queried the National Cancer Database to identify patients with testicular germ cell tumors (GCT) diagnosed in 2011-2015. Patients were grouped based on histologic diagnosis and pre-operative serum AFP level. RESULTS: Of 18,616 patients diagnosed with testicular GCT, 53% (N = 9,849) had pure seminomatous histology, of whom 8.3% (N = 821) had an elevated serum AFP pre-operatively. Non-white patients with seminoma were more likely to have a pre-op elevated AFP (OR 1.42; 95% CI: 1.10-1.83); patients treated at higher volume centers were less likely to have a pre-op elevated AFP (0.66, 95% CI: 0.53-0.83). Patients with seminoma with elevated AFP received adjuvant radiation more frequently than those with NSGCT (Stage I: 15% vs 0.2%, P <.01; Stage II: 21.9% vs 0.1%, P <.01) and less frequently underwent retroperitoneal lymph node dissection (RPLND) (Stage 1: 1.9% vs 11.1% P <.01; Stage II: 8.8% vs 17.4%, P <.01). CONCLUSION: The detection of elevated serum alpha-fetoprotein (AFP) in patients with pure seminomatous testicular germ cell tumors (GCT) is a discordant finding that implies the presence of occult non-seminomatous GCT (NSGCT) elements. 8% of patients with pure seminomatous GCTs had diagnostically discordant elevated pre-operative AFP levels. Despite recommendations to manage these patients as NSGCT, patients with seminoma and elevated AFP were managed in a fashion comparable to those with seminoma and normal AFP levels.

Molecular classification and diagnostics of upper urinary tract urothelial carcinoma.

Upper urinary tract urothelial carcinoma (UTUC) is one of the common urothelial cancers. Its molecular pathogenesis, however, is poorly understood, with no useful biomarkers available for accurate diagnosis and molecular classification. Through an integrated genetic study involving 199 UTUC samples, we delineate the landscape of genetic alterations in UTUC enabling genetic/molecular classification. According to the mutational status of TP53, MDM2, RAS, and FGFR3, UTUC is classified into five subtypes having discrete profiles of gene expression, tumor location/histology, and clinical outcome, which is largely recapitulated in an independent UTUC cohort. Sequencing of urine sediment-derived DNA has a high diagnostic value for UTUC with 82.2% sensitivity and 100% specificity. These results provide a solid basis for better diagnosis and management of UTUC.

The role of neoadjuvant chemotherapy, lymph node dissection, and treatment delay in patients with muscle-invasive bladder cancer undergoing partial cystectomy.

OBJECTIVES: To investigate treatment patterns of partial cystectomy (PC), neoadjuvant chemotherapy (NAC), lymph node dissection (LND), and treatment delays, and the associations with overall survival (OS) among patients with muscle-invasive bladder cancer. PATIENTS AND METHODS: We identified patients with cT2-4cN0cM0 urothelial carcinoma of the bladder in the National Cancer Database who underwent PC from 2007 through 2015. We performed descriptive statistics and assessed temporal trends using the Cochrane-Armitage test. Our outcomes of interest were NAC, LND, and treatment delay defined as ≥8 or ≥12 weeks for patients who underwent NAC or upfront surgery, respectively. We used logistic regression and multivariable Cox proportional hazards models to evaluate predictors and associations with OS, respectively. RESULTS: A total of 9,199 patients met inclusion criteria. Over the study period, PC utilization decreased from 9% to 7% (P = 0.06). Compared with patients who underwent radical cystectomy, patients treated with PC less frequently received NAC (7% vs. 17%, P < 0.01) and LND (57% vs. 91%, P < 0.01), but were less likely to experience treatment delays (25% vs. 31%, P < 0.01). Only 4.1% (27/655) of patients treated with PC received the combination of NAC, LND, and no treatment delay. In a Cox model, adequacy of LND was associated with improved OS (<10 nodes: HR 0.62, 95% CI 0.48-0.81 and ≥10 nodes: HR 0.48, 95% Cl 0.32-0.72). CONCLUSION: PC is uncommon and associated with poorer utilization of NAC and LND, but fewer treatment delays. The adequacy of LND was associated with improved OS while NAC and treatment delay were not.

Peripherally Acting µ-Opioid Receptor Antagonists in the Management of Postoperative Ileus: a Clinical Review.

Postoperative ileus (POI) and constipation are common secondary effects of opioids and carry significant clinical and economic impacts. µ-Opioid receptors mediate opioid analgesia in the central nervous system (CNS) and gastrointestinal-related effects in the periphery. Peripherally acting µ-opioid receptor antagonists (PAMORAs) block the peripheral effects of opioids in the gastrointestinal tract, while maintaining opioid analgesia in the CNS. While most are not approved for POI or postoperative opioid-induced constipation (OIC), PAMORAs have a potential role in these settings via their selective effects on the µ-opioid receptor. This review will discuss recent clinical trials evaluating the safety and efficacy of PAMORAs, with a focus on alvimopan (Entereg®) and methylnaltrexone (Relistor®) in patients with POI or postoperative OIC. We will characterize potential factors that may have impacted the efficacy observed in phase 3 trials and discuss future directions for the management and treatment of POI.