Plasma metabolomics profiling of 580 patients from an Early Detection Research Network prostate cancer cohort.

Prostate cancer is the second most common cancer in men and affects 1 in 9 men in the United States. Early screening for prostate cancer often involves monitoring levels of prostate-specific antigen (PSA) and performing digital rectal exams. However, a prostate biopsy is always required for definitive cancer diagnosis. The Early Detection Research Network (EDRN) is a consortium within the National Cancer Institute aimed at improving screening approaches and early detection of cancers. As part of this effort, the Weill Cornell EDRN Prostate Cancer has collected and biobanked specimens from men undergoing a prostate biopsy between 2008 and 2017. In this report, we describe blood metabolomics measurements for a subset of this population. The dataset includes detailed clinical and prospective records for 580 patients who underwent prostate biopsy, 287 of which were subsequentially diagnosed with prostate cancer, combined with profiling of 1,482 metabolites from plasma samples collected at the time of biopsy. We expect this dataset to provide a valuable resource for scientists investigating prostate cancer metabolism.

Randomized phase II trial of MRI-guided salvage radiotherapy for prostate cancer in 4 weeks versus 2 weeks (SHORTER).

BACKGROUND: Ultra-hypofractionated image-guided stereotactic body radiotherapy (SBRT) is increasingly used for definitive treatment of localized prostate cancer. Magnetic resonance imaging-guided radiotherapy (MRgRT) facilitates improved visualization, real-time tracking of targets and/or organs-at-risk (OAR), and capacity for adaptive planning which may translate to improved targeting and reduced toxicity to surrounding tissues. Given promising results from NRG-GU003 comparing conventional and moderate hypofractionation in the post-operative setting, there is growing interest in exploring ultra-hypofractionated post-operative regimens. It remains unclear whether this can be done safely and whether MRgRT may help mitigate potential toxicity. SHORTER (NCT04422132) is a phase II randomized trial prospectively evaluating whether salvage MRgRT delivered in 5 fractions versus 20 fractions is non-inferior with respect to gastrointestinal (GI) and genitourinary (GU) toxicities at 2-years post-treatment. METHODS: A total of 136 patients will be randomized in a 1:1 ratio to salvage MRgRT in 5 fractions or 20 fractions using permuted block randomization. Patients will be stratified according to baseline Expanded Prostate Cancer Index Composite (EPIC) bowel and urinary domain scores as well as nodal treatment and androgen deprivation therapy (ADT). Patients undergoing 5 fractions will receive a total of 32.5 Gy over 2 weeks and patients undergoing 20 fractions will receive a total of 55 Gy over 4 weeks, with or without nodal coverage (25.5 Gy over 2 weeks and 42 Gy over 4 weeks) and ADT as per the investigator's discretion. The co-primary endpoints are change scores in the bowel and the urinary domains of the EPIC. The change scores will reflect the 2-year score minus the pre-treatment (baseline) score. The secondary endpoints include safety endpoints, including change in GI and GU symptoms at 3, 6, 12 and 60 months from completion of treatment, and efficacy endpoints, including time to progression, prostate cancer specific survival and overall survival. DISCUSSION: The SHORTER trial is the first randomized phase II trial comparing toxicity of ultra-hypofractionated and hypofractionated MRgRT in the salvage setting. The primary hypothesis is that salvage MRgRT delivered in 5 fractions will not significantly increase GI and GU toxicities when compared to salvage MRgRT delivered in 20 fractions. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04422132. Date of registration: June 9, 2020.

A multidisciplinary approach to optimize primary prostate cancer biobanking.

PURPOSE: Biobanking tissue of high quality and fidelity is imperative for cancer genomics research. Since it is a challenging process, we sought to develop a protocol that improves the fidelity and quantity of biobanked primary prostate cancer (CaP) tissue. MATERIALS AND METHODS: We conducted a pilot study evaluating pathologic concordance of biobanked tissue and the radical prostatectomy specimen using either standard protocol (SP) vs. next-generation protocol (NGP). RESULTS: There were no significant differences in clinical and pathologic characteristics (age, BMI, preoperative PSA, prostate weight, race, final prostatectomy Gleason score, or pathologic tumor and nodal stages) between the two protocol arms. Utilization of the NGP compared to the standard protocol resulted in a significantly higher rate of pathologic concordance between the biobanked and RP specimens (61.8% vs. 37.9%, P = 0.0231) as well as a nearly two-fold increase in the amount of biobanked tumor tissue (330 mm3 vs. 174 mm3, P < 0.001). When looking at relevant clinical and pathologic characteristics, NGP was associated with pathologic concordance on both univariate [OR 2.65 (95% CI 1.13-6.21), P = 0.025] and multivariate analysis [OR 3.11 (95% CI 1.09-8.88), P = 0.034]. CONCLUSIONS: Our study validates the NGP as a multidisciplinary approach for improving the fidelity and amount of biobanked primary CaP tissue for future studies. Given the challenges to banking tissue from primary CaP as tumors are often difficult to visualize grossly and are frequently multifocal, optimizing the fidelity and volume of biobanked tissue is an important step forward to improve the generalizability of genomic data as we move towards precision medicine.

Collision tumors revealed by prospectively assessing subtype-defining molecular alterations in 904 individual prostate cancer foci.

BACKGROUNDProstate cancer is multifocal with distinct molecular subtypes. The utility of genomic subtyping has been challenged due to inter- and intrafocal heterogeneity. We sought to characterize the subtype-defining molecular alterations of primary prostate cancer across all tumor foci within radical prostatectomy (RP) specimens and determine the prevalence of collision tumors.METHODSFrom the Early Detection Research Network cohort, we identified 333 prospectively collected RPs from 2010 to 2014 and assessed ETS-related gene (ERG), serine peptidase inhibitor Kazal type 1 (SPINK1), phosphatase and tensin homolog (PTEN), and speckle type BTB/POZ protein (SPOP) molecular status. We utilized dual ERG/SPINK1 immunohistochemistry and fluorescence in situ hybridization to confirm ERG rearrangements and characterize PTEN deletion, as well as high-resolution melting curve analysis and Sanger sequencing to determine SPOP mutation status.RESULTSBased on index focus alone, ERG, SPINK1, PTEN, and SPOP alterations were identified in 47.5%, 10.8%, 14.3%, and 5.1% of RP specimens, respectively. In 233 multifocal RPs with ERG/SPINK1 status in all foci, 139 (59.7%) had discordant molecular alterations between foci. Collision tumors, as defined by discrepant ERG/SPINK1 status within a single focus, were identified in 29 (9.4%) RP specimens.CONCLUSIONInterfocal molecular heterogeneity was identified in about 60% of multifocal RP specimens, and collision tumors were present in about 10%. We present this phenomenon as a model for the intrafocal heterogeneity observed in previous studies and propose that future genomic studies screen for collision tumors to better characterize molecular heterogeneity.FUNDINGEarly Detection Research Network US National Cancer Institute (NCI) 5U01 CA111275-09, Center for Translational Pathology at Weill Cornell Medicine (WCM) Department of Pathology and Laboratory Medicine, US NCI (WCM SPORE in Prostate Cancer, P50CA211024-01), R37CA215040, Damon Runyon Cancer Research Foundation, US MetLife Foundation Family Clinical Investigator Award, Norwegian Cancer Society (grant 208197), and South-Eastern Norway Regional Health Authority (grant 2019016 and 2020063).

Novel nomograms to predict muscle invasion and lymph node metastasis in upper tract urothelial carcinoma.

OBJECTIVES: To develop accurate preoperative nomograms for prediction of muscle-invasive disease and lymph node metastasis in upper tract urothelial carcinoma (UTUC), to assist surgeons in risk stratifying patients and help guide treatment decisions. MATERIALS/METHODS: The National Cancer Database was used to identify all patients from 2004 to 2016 with UTUC who underwent extirpative surgery and lymphadenectomy. Univariate and multivariate logistic regression was performed to identify variables predicting muscle-invasive and node-positive disease. The data set was split 80:20 into a derivation and validation cohort and used to generate and test two nomograms. Nomograms were assessed using area under the curve (AUC) and calibration plots. RESULTS: A total of 6,143 patients met inclusion criteria. Predictors of muscle-invasive disease were age, grade, lymphovascular invasion (LVI), tumor size, and positive clinical lymph node status. Predictors of node-positive disease were grade, LVI, tumor size, and positive clinical lymph node status. The accuracy of the final nomogram predicting muscle-invasive disease was 80.0% (AUC 0.800, corrected C-index 0.813), and the accuracy of the nomogram predicting node-positive disease was 87.8% (AUC 0.878, corrected C-index 0.887). CONCLUSIONS: With data readily available after imaging and biopsy (age, tumor grade, LVI status, tumor size, and clinical lymph node status), we developed the first preoperative nomograms to quantitatively predict muscle-invasive disease and lymph node metastasis in UTUC, with an accuracy of 80.0% and 87.8% respectively. This information could be helpful to assist surgeons with pre-operative risk stratification.

Sociodemographic Disparities in Access to Chemotherapy for Bladder Cancer.

BACKGROUND: We sought to evaluate sociodemographic disparities in access to neoadjuvant (NAC) and adjuvant (AC) chemotherapy in the United States and their effect on survival. METHODS: The National Cancer Database was used to identify all patients from 2004 to 2016 eligible for NAC and AC. Univariate and multivariate logistic regression was performed to identify sociodemographic predictors associated with receipt of NAC and AC. Kaplan-Meier and Cox proportional hazard models were used for survival analysis. RESULTS: A total of 17,121 patients were eligible for NAC, and 18,962 for AC. Older (OR 0.94, P < .001), Medicare (OR 0.88, P = .047), Medicaid (OR 0.66, P = .001), uninsured (OR 0.47, P < .001), rural (OR 0.70, P = .042), and community hospital patients (OR 0.72, P < .001) were less likely to receive NAC. Older, (OR 0.95, P < .001), female (OR 0.79, P < .001), Medicaid (OR 0.71, P = .003), uninsured (OR 0.60, P = .001), and lower income patients (OR 0.86, P = .017) were less likely to receive AC. In NAC-eligible patients, older (HR 1.02, P < .001), Medicare (HR 1.11, P = .024), Medicaid (HR 1.25, P = .012), and community hospital patients (HR 1.09, P = .021) were at an increased risk of death. In AC-eligible patients, older (HR 1.01, P < .001), Black (HR 1.15, P = .011), Medicaid (HR 1.14, P = .042), lower income (HR 1.07, P = .038) and community hospital patients (HR 1.07, P = .021) were at an increased risk of death. CONCLUSIONS: Significant sociodemographic disparities currently exist in the United States in access to neoadjuvant and adjuvant chemotherapy for bladder cancer. Uninsured and Medicaid insurance status are the strongest predictors of not receiving chemotherapy. Efforts must be made to deliver this critical standard-of-care treatment to these patients.

Pilot study of the diagnostic utility of 89 Zr-df-IAB2M and 68 Ga-PSMA-11 PET imaging and multiparametric MRI in localized prostate cancer.

BACKGROUND: Accurate diagnosis of localized prostate cancer (PCa) is limited by inadequacy of multiparametric (mp) MRI to fully identify and differentiate localized malignant tissue from benign pathologies. Prostate-specific membrane antigen (PSMA) represents an excellent target for molecular imaging. IAB2M, an 85-kD minibody derived from a de-immunized monoclonal antibody directed at the extracellular domain of human PSMA (huJ591), and PSMA-11, a small molecule ligand have been previously tested as probes for visualization of recurrent/metastatic PCa with PET/CT. This pilot, non-randomized trial studied their diagnostic utility in patients (pts) with localized PCa. METHODS: Pts planned for radical prostatectomy (RP) were enrolled and underwent mpMRI and PET/CT imaging with 89 Zr-df-IAB2M and/or 68 Ga-PSMA-PET/CT. Image results were read by a radiologist blinded to clinical information and pathology results, mapped and compared to corresponding histopathology findings from all lesions, both clinically significant and nonsignificant. The detection rates of all three imaging modalities were measured and correlated. RESULTS: 20 pts with median age of 64.5 (46-79) years and PSA level of 7.5 (1.6-36.56) ng/ml were enrolled. 19 pts underwent RP and were imaged pre-operatively with 89 Zr-Df-IAB2M PET/CT and mpMRI. Nine of those were imaged using 68 Ga-PSMA-11 as well. Out of 48 intraprostatic lesions verified on surgical pathology, IAB2M PET/CT was able to detect 36 (75%). A similar proportion of pathologically confirmed, clinically significant lesions (22/29, 76%) was detected. IAB2M PET/CT was also able to identify 14/19 (74%) extraprostatic lesions. The performance of mpMRI was inferior, with 24/48 detectable lesions (50%) and 18/29 clinically significant intraprostatic lesions (62%). Compared to the current standard (mpMRI), IAB2M PET/CT had a sensitivity of 88%, specificity 38%, positive predictive value 58%, and accuracy 63%. In 9 pts who underwent Ga-PSMA-11 as well, the latter yielded a detection rate of 70% (14/20), which was also seen in clinically significant lesions (10/14, 71%). Ga-PSMA-11 PET/CT also detected 4/6 (67%) extraprostatic lesions. CONCLUSIONS: In this pilot study, the performance of 89 Zr-df-IAB2M was superior to mpMRI and similar to 68 Ga-PSMA-11 PET/CT. The higher detection rate of PSMA-PET supports its use as a diagnostic tool with consequent management change implications in men with localized PCa.

Does neoadjuvant chemotherapy diminish the sex disparity in bladder cancer survival after radical cystectomy?

INTRODUCTION: Sex-specific survival disparities for bladder cancer outcomes after radical cystectomy (RC) have been demonstrated in several studies. However, these studies predate the widespread adoption of neoadjuvant chemotherapy (NAC). We evaluated the differences in sex-specific survival between patients who received NAC with those who did not, using a contemporary national outcomes database. METHODS: The National Cancer Data Base was queried from 2004 to 2015 to identify subjects who underwent RC. Kaplan-Meier method with log-rank test was performed to compare all-cause mortality between men and women at each pathologic (p) TNM stage group: T1-4N0, N+ and M+ disease. Associations for all-cause mortality were identified using an adjusted Cox regression analysis, and our findings were confirmed with a subgroup analysis. RESULTS: A total of 9,835 subjects (7,483 men and 2,532 women) were included in the analysis. Kaplan-Meier survival curves and Cox regression analysis demonstrated female sex was not associated with worse overall survival compared to males (HR 0.947, 95%CI 0.852-1.053, P = 0.947) in the overall cohort. Stratified by pT stage and node positivity, worse overall survival was seen in women with pT4 disease who did not receive NAC compared to men (5-year OS 9.6% women vs. 15.2% men, P < 0.001), but no sex-specific difference was seen across all groups in patients who received NAC. Subgroup multivariable analysis showed that female sex conferred a survival disadvantage for pT4 (HR 1.369, P = 0.026) disease only in patients who did not receive NAC. CONCLUSIONS: In a contemporary cohort of subjects who underwent RC, administration of NAC narrows the sex survival-gap in advanced stage bladder cancer. Strategies to improve NAC usage in women should be adopted to overcome potential sex-specific differences such as delayed diagnosis, anatomic differences in higher stage disease, or altered tumor biology which may contribute to differences in oncologic outcomes.

Phase II multi-center trial of optical coherence tomography as an adjunct to white light cystoscopy for intravesical real time imaging and staging of bladder cancer.

BACKGROUND: Optical coherence tomography (OCT) is a novel imaging modality that provides microstructural information of different tissue layers using near-infrared light. This prospective, multicenter phase II trial aimed to assess the accuracy of OCT-assisted cystoscopy for bladder tumor staging. METHODS: Patients with primary or recurrent bladder tumors (Ta,T1) identified by outpatient cystoscopy were included. The primary objective was to assess the accuracy and positive predictive value of for determining tumor stage ≥T1 correlated by histopathology. 72 suspicious lesions from 63 patients were eligible to analyze in the study. All suspected lesions were evaluated with conventional cystoscopy, interpreted in real-time using OCT, and then resected. All results were compared to pathology. A total of 363 OCT images of tumor and normal mucosa in 25 patients were obtained to evaluate diagnostic efficacy of the computer-aided texture analysis algorithm. RESULTS: Sensitivity and specificity for predicting invasive tumors (≥ T1, n = 17) were 58.8% and 92.7% for cystoscopy, 64.7% and 100% for OCT-assisted cystoscopy, respectively. Accuracy of cystoscopy and OCT-assisted cystoscopy for predicting invasive tumor was 84.7% and 91.7% (P = 0.063), respectively. Cystoscopy and OCT-assisted cystoscopy correctly predicted T stage in 52/72 and 59/72 cases, respectively (P = 0.016). Cystoscopy missed 2 more invasive tumors than OCT-assisted cystoscopy. Cystoscopy (14.3%, 1/7) and OCT-assisted cystoscopy (28.6%, 2/7) showed relatively low sensitivity in detecting muscle invasion. Computer aided texture analysis demonstrated 75.1% sensitivity, 64.0% specificity, and 74.4% accuracy for differentiating tumor and normal urothelium. CONCLUSION: OCT-assisted cystoscopy is a real time noninvasive and simple procedure that enhanced the accuracy of staging bladder tumors and prediction of any tumor invasion. Though the study did not meet the prespecified primary endpoint, OCT imaging is a promising adjunct to cystoscopy that may supplement intraoperative decision-making during transurethral resection of bladder tumors and additional prospective studies are warranted.

Changes in Urologic Operative Practice at the Beginning of the COVID-19 Pandemic in a Large, National Cohort.

OBJECTIVE: To analyze population-level changes in operative practice since the onset of the COVID-19 pandemic to contextualize observations made by individual practices and optimize future responses. MATERIALS AND METHODS: This US retrospective analysis used the Premier Perspectives Database. We investigated changes in operative volume through March 2020. Baseline operative volume for urologic surgery was calculated using data from the preceding 12 months and compared on a total and by procedure basis. Multivariable linear regression was used to identify hospital-level predictors of change in response to the pandemic. RESULTS: At baseline, we captured 23,788 urologic procedural encounters per month as compared with 19,071 during March 2020- a 19.9% decrease. Urologic oncology-related cases were relatively preserved as compared to others (average change in March 2020: +1.1% versus -32.2%). Northeastern (ß = -5.66, 95% confidence interval [CI]: -10.2 to -1.18, p = 0.013) and Midwestern hospitals (ß = -4.17, 95% CI: -7.89 to -0.45, p = 0.027; both with South as reference region), and those with an increasing percentage of patients insured by Medicaid (ß= -0.17 per percentage point, 95% CI: -0.33 to -0.01, p = 0.04) experienced a significantly larger decrease in volume. CONCLUSIONS: There was a 20% decline in urologic operative volume in March 2020, compared with baseline, that preferentially affected hospitals serving Medicaid patients, and those in Northeast and Midwest. In the face of varying mandates on elective surgery, widespread declines in operative volume may also represent hesitancy on behalf of patients to interface with healthcare during the pandemic.

Robotic Radical Cystectomy in the Contemporary Management of Bladder Cancer.

"The robotic approach for radical cystectomy has become increasingly adopted by the urologic oncology community, as it has been shown to have equivalent oncologic outcomes with shorter hospital stay and fewer perioperative transfusions. Consensus guidelines from expert surgeons have been published to provide guidance on all aspects of how to implement the robotic approach in the urologic oncology clinic."

The role of surgical experience in patient selection, surgical quality, and outcomes in robot-assisted radical cystectomy.

BACKGROUND: Robot-assisted radical cystectomy (RARC) remains one of the most complex urological procedures. Due to regionalization of bladder cancer care, there is likely an imbalance in experience among urologists performing RARC. We sought to describe changes in patient selection, surgical quality surrogates and rates of complications in relation to surgical experience. METHODS: We retrospectively reviewed 409 consecutive patients with bladder cancer who underwent RARC between 2006 and 2017 by a single surgeon. The cohort was divided into 4 quartiles (Q1-Q4) according to surgical experience, based on the chronologic order at which RARC was performed. Baseline, perioperative and pathologic characteristics of patients were compared among the 4 groups. 30-day and 90-day complications were assessed using the Clavien-Dindo system. The association between surgical experience (quartile) and complications was assessed using multivariable logistic regression analyses. RESULTS: Median age (interquartile range [IQR] from 70-73 years), body mass index (IQR from 25 to 27 kg/m2) and preoperative glomerular filtration rate (IQR from 59 to 65 ml/min) were similar among all quartiles (all P > 0.05). Patients in Q4 had higher rates of previous abdominopelvic surgery (46.1% vs. 30.4%, P = 0.031) and American Society of Anesthesiologists score of 3 to 4 (72.3% vs. 47.1%, P = 0.003) compared to patients in Q1. Patients who underwent RARC in Q4 compared to Q1, had less estimated blood loss (250 ml vs. 350 ml, P < 0.001), shorter operative time (346 vs. 360 minutes, P < 0.001), and higher lymph node yield (22 vs. 17 nodes, P < 0.001). The 30-day and 90-day complication rates were 53% and 62%, respectively. Thirty-day complication rates were similar among all 4 quartiles (P > 0.05), but higher among patients in Q4 compared to Q1 within 90 days (74% vs. 54%, P = 0.01). On multivariable analysis, patients in Q4 were more likely to experience any 90-day complication (OR 2.03, 95%Cl 1.11-3.70) compared to Q1. CONCLUSION: Our results show that with surgical experience, more complex cases can be performed while continuing to improve surgical quality. Nonetheless, there appears to be a trade-off between the increase in complexity of cases performed with experience and accepting higher rates of complications.

Impact of Neoadjuvant Chemotherapy for Upper Tract Urothelial Carcinoma: A Population Based Analysis.

BACKGROUND AND OBJECTIVES: We examined pathologic complete response (pCR) and pathologic downstaging (pDS) rates after neoadjuvant chemotherapy (NAC) in high-risk upper tract urothelial carcinoma, as well as their predictors. We further sought to determine their effects on overall survival and examine prognosticators of survival after NAC. METHODS: The National Cancer Database was used to identify all patients from 2004 to 2016 with nonmetastatic high grade upper tract urothelial carcinoma who received NAC followed by nephroureterectomy. pCR and pDS rates were examined, and univariate and multivariate logistic regression was performed to identify clinical predictors. Kaplan-Meier and Cox proportional hazard methods were used to estimate overall survival. RESULTS: 309 patients met inclusion criteria. 27 patients (8.74%) had pCR, and 92 (29.77%) had pDS. pCR and pDS rates for N+ subgroup were 6.82% and 47.73% respectively, and for N0 subgroup, 9.50% and 22.62%. Female sex (OR 2.94, p = 0.010) was the only predictor of pCR. Node-positive disease (cN1 vs. cN0: OR 6.40, p < 0.001; cN2 vs. cN0: OR 7.46, p < 0.001) was a positive predictor of pDS, and the presence of lymphovascular invasion (LVI) (OR 0.14, p < 0.001) was a negative predictor of pDS. The median OS for all patients was 45.5 months. pCR and pDS were both associated with improved OS, (p < 0.001 for both); median was 99.1 months for both. LVI was the strongest negative prognostic factor for OS (HR 2.85, p < 0.001). CONCLUSIONS: Overall pathological complete response and downstaging rates were 8.74% and 29.77% respectively after multi-agent neoadjuvant chemotherapy. Node-negative and node-positive disease had equivalent rates of complete response, but node-positive disease had a significantly higher rate of downstaging. The presence of LVI was associated with worse overall survival.