A west African ancestry-associated SNP on 8q24 predicts a positive biopsy in African American men with suspected prostate cancer following PSA screening.

BACKGROUND: African American (AA) men have the highest incidence and mortality rates of prostate cancer (PCa) among all racial groups in the United States. While race is a social construct, for AA men, this overlaps with west African ancestry. Many of the PCa susceptibility variants exhibit distinct allele frequencies and risk estimates across different races and contribute substantially to the large disparities of PCa incidence among races. We previously reported that a single-nucleotide polymorphism (SNP) in 8q24, rs7824364, was strongly associated with west African ancestry and increased risks of PCa in both AA and Puerto Rican men. In this study, we determined whether this SNP can predict biopsy positivity and detection of clinically significant disease (Gleason score [GS] ≥ 7) in a cohort of AA men with suspected PCa. METHODS: SNP rs7824364 was genotyped in 199 AA men with elevated total prostate-specific antigen (PSA) (>2.5 ng/mL) or abnormal digital rectal exam (DRE) and the associations of different genotypes with biopsy positivity and clinically significant disease were analyzed. RESULTS: The variant allele carriers were significantly over-represented in the biopsy-positive group compared to the biopsy-negative group (44% vs. 25.7%, p = 0.011). In the multivariate logistic regression analyses, variant allele carriers were at a more than a twofold increased risk of a positive biopsy (odds ratio [OR] = 2.14, 95% confidence interval [CI] = 1.06-4.32). Moreover, the variant allele was a predictor (OR = 2.26, 95% CI = 1.06-4.84) of a positive biopsy in the subgroup of patients with PSA < 10 ng/mL and normal DRE. The variant allele carriers were also more prevalent in cases with GS ≥ 7 compared to cases with GS < 7 and benign biopsy. CONCLUSIONS: This study demonstrated that the west African ancestry-specific SNP rs7824364 on 8q24 independently predicted a positive prostate biopsy in AA men who were candidates for prostate biopsy subsequent to PCa screening.

The role of metastatic burden in cytoreductive/consolidative radical cystectomy.

PURPOSE: To describe our institutional experience with cytoreductive/consolidative radical cystectomy (CCRC) for metastatic urothelial carcinoma (UC) and to investigate clinicopathologic features predicting prolonged cancer specific survival (CSS) following CCRC. METHODS: We performed IRB-approved review of our cystectomy database, and identified 43 patients with metastatic UC who underwent CCRC. Baseline demographics, chemotherapy regimen, clinicopathologic features, and perioperative complications were collected. Progression-free survival (PFS) and CSS were estimated from the time of CCRC. Univariate and multivariate Cox regression models were used to identify predictors of improved CSS after CCRC. RESULTS: Of the 43 patients, 32 (74.4%) had clinical evidence of distant metastases, while 11 harbored occult metastases on the surgical specimen. The most common site of metastasis was the retroperitoneal lymph nodes, found in 30 patients. Solitary metastases were found in 22 patients (51.1%). Forty-one (95%) patients received chemotherapy prior to CCRC. Disease progression was detected in 35 patients after CCRC (median PFS 5.9 months), and 34 died of metastatic cancer (median CSS 12.3 months). On multivariate analysis, patients with solitary metastases were found to have improved CSS compared to those with multiple metastases (HR 2.62, 95% CI 1.16-5.90, p = 0.02), with median CSS of 26.0 months vs. 7.9 months (p < 0.001). Median postoperative length of stay was 10 days. Overall, 56% suffered postoperative complications, including one perioperative mortality. CONCLUSIONS: CCRC is feasible in the setting of metastatic UC. Patients with solitary metastasis demonstrated longer CSS than those with multiple metastases, and should be considered candidates for future trials evaluating the role of CCRC for metastatic UC.

Robotic or open superficial inguinal lymph node dissection as staging procedures for clinically node negative high risk penile cancer.

OBJECTIVE: To evaluate perioperative and oncologic outcomes of a cohort of clinically node negative high-risk penile cancer patients undergoing robotic assisted inguinal lymph node dissection (RAIL) compared to patients undergoing open superficial inguinal lymph node dissection (OSILND). PATIENTS AND METHODS: We retrospectively reviewed the clinical characteristics and outcomes of clinically node negative high-risk penile cancer patients undergoing RAIL at MDACC from 2013-2019. We sought to compare this to a contemporary open cohort of clinically node negative patients treated from 1999 to 2019 at MDACC and Moffit Cancer Center (MCC) with an OSILND. Descriptive statistics were used to characterize the study cohorts. Comparison analysis between operative variables was performed using Fisher's exact test and Wilcoxon's rank-sum test. The Kaplan-Meier method was used to estimate survival endpoints. RESULTS: There were 24 patients in the RAIL cohort, and 35 in the OSILND cohort. Among the surgical variables, operative time (348.5 minutes vs. 239.0 minutes, P < 0.01) and the duration of operative drain (37 vs. 22 days P = 0.017) were both significantly longer in the RAIL cohort. Complication incidences were similar for both cohorts (34.3% for OSILND vs. 33.3% for RAIL), with wound complications making up 33% of all complications for RAIL and 31% of complications for OSILND. No inguinal recurrences were noted in either cohort. The median follow-up was 40 months for RAIL and 33 months for OSILND. CONCLUSIONS: We observed similar complication rates and surgical variable outcomes in our analysis apart from operative time and operative drain duration. Oncological outcomes were similar between the two cohorts. RAIL was a reliable staging and potentially therapeutic procedure among clinically node negative patients with penile squamous cell carcinoma with comparable outcomes to an OSILND cohort.

Robotic Postchemotherapy Retroperitoneal Lymph Node Dissection for Testicular Cancer.

BACKGROUND: Postchemotherapy retroperitoneal lymph node dissection (pcRPLND) is mandated in patients with nonseminomatous germ cell tumor found to have residual masses after chemotherapy. Performed via the open approach, pcRPLND can incur significant perioperative morbidity. OBJECTIVE: To demonstrate the feasibility of robotic pcRPLND (r-pcRPLND) and provide evidence for its selection criteria. DESIGN, SETTING, AND PARTICIPANTS: A retrospective search identified 93 patients undergoing pcRPLND between April 2007 and March 2018, comprising 30 r-pcRPLND and 63 open pcRPLND (o-pcRPLND) procedures performed by a single surgeon. INTERVENTION: r-pcRPLND and o-pcRPLND. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Baseline clinicopathologic characteristics and intraoperative variables including operating room (OR) time, estimated blood loss (EBL), resection of adjacent organs, and intraoperative consultation with other surgical services were recorded. Hospital length of stay (LOS) and perioperative complications were assessed as per the Clavien-Dindo classification, and oncologic outcomes such as nodal yield, histologic distribution, pathologic staging, time to recurrence, and cancer-specific survival were compared. RESULTS AND LIMITATIONS: r-pcRPLND was performed in a well-selected cohort with lower clinical stage (p=0.006), favorable International Germ Cell Cancer Collaborative Group classification (p=0.01), and smaller retroperitoneal mass (p=0.001). o-pcRPLND required more frequent bilateral template dissection (88.9% vs 43.3%; p<0.001), resection of adjacent organs (36.5% vs 10%; p=0.007), consultation with other surgical services (46% vs 2%; p<0.001), and auxiliary procedures (54.0% vs 20%; p=0.003) to achieve complete oncologic control. OR time was similar between the two groups (o-pcRPLND 375min vs r-pcRPLND 388min; p=0.16) and EBL was significantly lower in r-pcRPLND (234 vs 825ml; p<0.001). Median LOS was significantly shorter after r-pcRPLND (2 vs 7d; p<0.001). A total of 31 patients (33%) suffered postoperative complications, of whom 18 (19.4%) had major complications. Nodal yield was similar (o-pcRPLND 23 vs r-pcRPLND 24; p=0.8). The distribution of lesion histology (necrosis/teratoma/GCT) was also similar pcRPLND (o-pcRPLND 25.4%/57.1%/17.4% vs r-pcPLND 33.3%/50%/16.7%; p=0.51). Overall, tumor recurred in 15 patients (16.1%), including three following r-pcRPLND (10%), all outside the operative field. On univariate analysis, surgical approach was not a significant predictor of time to recurrence (p=0.34). One limitation was that antegrade ejaculation was not assessed. CONCLUSIONS: With rigorous patient selection, r-pcRPLND can be safely performed and may reduce perioperative morbidity while maintaining oncologic proficiency. PATIENT SUMMARY: Resection of residual retroperitoneal mass after chemotherapy in patients with metastatic testicular cancer can be performed safely via a robotic approach. Robotic surgery can reduce the morbidity of the procedure.

An international study of interobserver variability of "string sign" of pancreatic cysts among experienced endosonographers.

BACKGROUND AND OBJECTIVES: No single optimal test reliably determines the pancreatic cyst subtype. Following EUS-FNA, the "string sign" test can differentiate mucinous from nonmucinous cysts. However, the interobserver variability of string sign results has not been studied. METHODS: An experienced endosonographer performed EUS-FNA of pancreatic cysts on different patients and was recorded on video performing the string sign test for each. The videos were shared internationally with 14 experienced endosonographers, with a survey for each video: "Is the string sign positive?" and "If the string sign is positive, what is the length of the formed string?" Also asked "What is the cutoff length for string sign to be considered positive?" Interobserver variability was assessed using the kappa statistic (κ). RESULTS: A total of 112 observations were collected from 14 endosonographers. Regarding string sign test positivity, κ was 0.6 among 14 observers indicating good interrater agreement (P < 0.001) while κ was 0.38 when observers were compared to the index endosonographer demonstrating marginal agreement (P < 0.001). Among observations of the length of the string in positive samples, 89.8% showed >5 mm of variability (P < 0.001), indicating marked variability. There was poor agreement on the cutoff length for a string to be considered positive. CONCLUSION: String sign of pancreatic cysts has a good interobserver agreement regarding its positivity that can help in differentiating mucinous from nonmucinous pancreatic cysts. However, the agreement is poor on the measured length of the string and the cutoff length of the formed string to be considered a positive string sign.

Temsirolimus versus Pazopanib (TemPa) in Patients with Advanced Clear-cell Renal Cell Carcinoma and Poor-risk Features: A Randomized Phase II Trial.

BACKGROUND: Temsirolimus has level 1 evidence for initial treatment of poor-risk patients with advanced renal cell carcinoma (mRCC), but its efficacy has not been directly compared with an antiangiogenic tyrosine kinase inhibitor (vascular endothelial growth factor receptor tyrosine kinase inhibitor [VEGFR TKi]) in this setting. OBJECTIVE: To evaluate temsirolimus versus pazopanib as first-line therapy in patients with mRCC, predominant clear-cell features, and clinical characteristics of a poor prognosis. DESIGN, SETTING, AND PARTICIPANTS: A randomized (1:1) phase II trial in 69 treatment-naïve mRCC patients and with three or more predictors of short survival for temsirolimus was conducted during 2012-2017 in a single academic cancer center. Crossover to the alternative treatment upon discontinuation of the first-line agent was permitted. INTERVENTION: Mechanistic target of rapamycin inhibitor temsirolimus and VEGFR TKi pazopanib. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary endpoint was progression-free survival (PFS), and the secondary endpoints were overall survival (OS), objective response rate (ORR), safety, and patient-reported outcomes (PROs). Radiographic response was assessed by blinded radiologists. Efficacy outcomes were adjusted by prior nephrectomy status, prior interleukin-2 treatment, and the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) score. RESULTS AND LIMITATIONS: Thirty-five patients received temsirolimus and 34 received pazopanib upfront; 72% overall had poor risk by IMDC. Median PFS in the first line was 2.7mo with temsirolimus and 5.2mo with pazopanib (adjusted hazard ratio [HR] 1.36, 95% confidence interval [CI] 0.84-2.22; p=0.210). Median OS was 7.1mo with temsirolimus and 11.9mo with pazopanib (adjusted HR 1.16, 95% CI 0.70-1.93; p=0.558), and ORRs were 5.9% and 21.2%, respectively (adjusted odds ratio 5.2, 95% CI 0.9-29.3; p=0.062). PRO measures favored pazopanib. Five patients discontinued first-line therapy due to adverse events. CONCLUSIONS: Temsirolimus and pazopanib had modest activity in patients with poor-risk clear-cell mRCC, and therefore their use should be discouraged in this setting. PATIENT SUMMARY: We evaluated outcomes of advanced renal cell carcinoma patients presenting with aggressive features when treated with temsirolimus or pazopanib as first-line therapy. Survival was <1yr for most, suggesting that more efficacious alternative treatments should be favored for these patients.

Prognostic Implication of the United States Food and Drug Administration-defined BCG-unresponsive Disease.

The category "BCG-unresponsive disease", formulated by experts at the request of the United States Food and Drug Administration, denotes a group of patients with recurrent non-muscle-invasive bladder cancer for whom continued BCG treatment is unlikely to provide benefit. Although quickly adopted for trial design, many of the nuances within the definition lack validation. In this study, we evaluated the prognostic value of BCG unresponsive designation (i.e. recurrence after induction plus at least 1 maintenance course of BCG) by comparing the oncologic outcomes of these patients with those recurring after induction BCG alone. We confirm that appropriately defined, BCG-unresponsive patients are more likely to require salvage radical cystectomy (54.5% vs 17.9%, p=0.002). Moreover, those opting for second-line bladder-sparing therapies are less likely to remain free of tumor recurrence (23% vs 69.2%, p=0.003). On multivariate analysis, BCG-unresponsive disease independently predicts inferior high-grade recurrence-free survival (hazard ratio [HR]: 6.25, 95% confidence interval [CI]: 2.27-16.67; p<0.001) and cystectomy-free survival (HR: 3.85, 95% CI: 1.49-10.0; p=0.006). Our data confirm the prognostic implication of the BCG unresponsive definition i.e. recurrence of high grade disease after induction and one course of maintenance BCG, and support its use in counseling and risk stratification of patients with tumor recurrence after BCG. Patient summary: Patients who have BCG-unresponsive disease, that is, high-grade non-muscle-invasive bladder cancer recurring after BCG induction and maintenance, have a low likelihood to respond to further BCG treatment and should consider radical cystectomy or clinical trial enrollment.

Results of the Phase I Trial of RG7112, a Small-Molecule MDM2 Antagonist in Leukemia.

PURPOSE: RG7112 is a small-molecule MDM2 antagonist. MDM2 is a negative regulator of the tumor suppressor p53 and frequently overexpressed in leukemias. Thus, a phase I study of RG7112 in patients with hematologic malignancies was conducted. EXPERIMENTAL DESIGN: Primary study objectives included determination of the dose and safety profile of RG7112. Secondary objectives included evaluation of pharmacokinetics; pharmacodynamics, such as TP53-mutation status and MDM2 expression; and preliminary clinical activity. Patients were divided into two cohorts: Stratum A [relapsed/refractory acute myeloid leukemia (AML; except acute promyelocytic leukemia), acute lymphoblastic leukemia, and chronic myelogenous leukemia] and Stratum B (relapsed/refractory chronic lymphocytic leukemia/small cell lymphocytic leukemia; CLL/sCLL). Some Stratum A patients were treated at the MTD to assess clinical activity. RESULTS: RG7112 was administered to 116 patients (96 patients in Stratum A and 20 patients in Stratum B). All patients experienced at least 1 adverse event, and 3 dose-limiting toxicities were reported. Pharmacokinetic analysis indicated that twice-daily dosing enhanced daily exposure. Antileukemia activity was observed in the 30 patients with AML assessed at the MTD, including 5 patients who met International Working Group (IWG) criteria for response. Exploratory analysis revealed TP53 mutations in 14% of Stratum A patients and in 40% of Stratum B patients. Two patients with TP53 mutations exhibited clinical activity. p53 target genes were induced only in TP53 wild-type leukemic cells. Baseline expression levels of MDM2 correlated positively with clinical response. CONCLUSIONS: RG7112 demonstrated clinical activity against relapsed/refractory AML and CLL/sCLL. MDM2 inhibition resulted in p53 stabilization and transcriptional activation of p53-target genes. We provide proof-of-concept that MDM2 inhibition restores p53 function and generates clinical responses in hematologic malignancies.