Final Results From a Phase I Trial and Expansion Cohorts of Cabozantinib and Nivolumab Alone or With Ipilimumab for Advanced/Metastatic Genitourinary Tumors.

PURPOSE: Cabozantinib and nivolumab (CaboNivo) alone or with ipilimumab (CaboNivoIpi) have shown promising efficacy and safety in patients with metastatic urothelial carcinoma (mUC), metastatic renal cell carcinoma (mRCC), and rare genitourinary (GU) tumors in a dose-escalation phase I study. We report the final data analysis of the safety, overall response rate (ORR), progression-free survival (PFS), and overall survival (OS) of the phase I patients and seven expansion cohorts. METHODS: This is an investigator-initiated, multicenter, phase I trial. CaboNivo doublet expansion cohorts included (1) mUC, (2) mRCC, and (3) adenocarcinoma of the bladder/urachal; CaboNivoIpi triplet expansion cohorts included (1) mUC, (2) mRCC, (3) penile cancer, and (4) squamous cell carcinoma of the bladder and other rare GU tumors (ClinicalTrials.gov identifier: NCT02496208). RESULTS: The study enrolled 120 patients treated with CaboNivo (n = 64) or CaboNivoIpi (n = 56), with a median follow-up of 49.2 months. In 108 evaluable patients (CaboNivo n = 59; CaboNivoIpi n = 49), the ORR was 38% (complete response rate 11%) and the median duration of response was 20 months. The ORR was 42.4% for mUC, 62.5% for mRCC (n = 16), 85.7% for squamous cell carcinoma of the bladder (n = 7), 44.4% for penile cancer (n = 9), and 50.0% for renal medullary carcinoma (n = 2). Grade ≥ 3 treatment-related adverse events occurred in 84% of CaboNivo patients and 80% of CaboNivoIpi patients. CONCLUSION: CaboNivo and CaboNivoIpi demonstrated clinical activity and safety in patients with multiple GU malignancies, especially clear cell RCC, urothelial carcinoma, and rare GU tumors such as squamous cell carcinoma of the bladder, small cell carcinoma of the bladder, adenocarcinoma of the bladder, renal medullary carcinoma, and penile cancer.

A novel multiplex score to predict outcomes of partial nephrectomy for multiple tumors.

BACKGROUND: The RENAL nephrometry score (RNS) is widely used to describe renal mass complexity and inform patient counseling for partial nephrectomy (PN). However, in cases with multiple tumors, it is unknown which features drive perioperative outcomes. OBJECTIVE: To employ a novel scoring equation (multiplex score [MS]) derived from RNS to assess outcomes of multiplex PN at our institution. DESIGN, SETTING, AND PARTICIPANTS: A total of 62 consecutive multiplex PN (median (range) # tumors = 4(2-11), 65% robotic) were performed by a single surgeon. The MS was defined a priori as a weighted score derived from RNS (# low risk ([LR] lesions) + 2*(# intermediate risk [IR]) + 4*(# high risk [HR]) based on published complication rates. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: MS was dichotomized into favorable/unfavorable based on median score. Patient outcomes were maintained prospectively. MS was compared with other potential RNS derived scoring systems. RESULTS AND LIMITATION: A total of 249 tumors were scored. Median (range) MS was 6(range 2-20, IQR 3-8). Complications occurred in 10 patients (16.1%). Only 1 complication occurred in the favorable MS(<6) group, and MS was associated with perioperative complication (P = 0.02) and blood loss (P < .001). When compared to other potential scoring systems, MS had the best area under the curve (AUC) to predict operative complications (0.75). CONCLUSIONS: The novel MS was associated with complications and blood loss. This tool may facilitate standardized reporting of complexity for multiplex series, with special relevance for hereditary cancer syndromes. PATIENT SUMMARY: For patients who have one kidney tumor, there are established scoring systems to help patients and surgeons decide on the surgical plan. However currently, for patients with more than one renal tumor, there is no such scoring system. Here, we present the "Multiplex Score" to aid shared-decision-making in cases with more than one renal tumor.

Cabozantinib plus Nivolumab Phase I Expansion Study in Patients with Metastatic Urothelial Carcinoma Refractory to Immune Checkpoint Inhibitor Therapy.

PURPOSE: This study investigated the efficacy and tolerability of cabozantinib plus nivolumab (CaboNivo) in patients with metastatic urothelial carcinoma (mUC) that progressed on checkpoint inhibition (CPI). PATIENTS AND METHODS: A phase I expansion cohort of patients with mUC who received prior CPI was treated with cabozantinib 40 mg/day and nivolumab 3 mg/kg every 2 weeks until disease progression/unacceptable toxicity. The primary goal was objective response rate (ORR) per RECIST v.1.1. Secondary objectives included progression-free survival (PFS), duration of response (DoR), overall survival (OS), safety, and tolerability. RESULTS: Twenty-nine out of 30 patients enrolled were evaluable for efficacy. Median follow-up was 22.2 months. Most patients (86.7%) received prior chemotherapy and all patients received prior CPI (median seven cycles). ORR was 16.0%, with one complete response and three partial responses (PR). Among 4 responders, 2 were primary refractory, 1 had a PR, and 1 had stable disease on prior CPI. Median DoR was 33.5 months [95% confidence interval (CI), 3.7-33.5], median PFS was 3.6 months (95% CI, 2.1-5.5), and median OS was 10.4 months (95% CI, 5.8-19.5). CaboNivo decreased immunosuppressive subsets such as regulatory T cells (Tregs) and increased potential antitumor immune subsets such as nonclassical monocytes and effector T cells. A lower percentage of monocytic myeloid-derived suppressor cells (M-MDSC) and polymorphonuclear MDSCs, lower CTLA-4 and TIM-3 expression on Tregs, and higher effector CD4+ T cells at baseline were associated with better PFS and/or OS. CONCLUSIONS: CaboNivo was clinically active, well tolerated, and favorably modulated peripheral blood immune subsets in patients with mUC refractory to CPI.

Clinical value of 18FDG PET/MRI in muscle-invasive, locally advanced, and metastatic bladder cancer.

OBJECTIVE: Metastatic bladder cancer is an aggressive disease that can often be difficult to diagnose and stage with conventional cross-sectional imaging. The primary objective of this study was to determine the clinical value of fluorine-18 2-fluoro-2-deoxy-D-glucose (18F-FDG) PET/MRI for surveillance and restaging of patients with muscle-invasive, locally advanced, and metastatic bladder cancer compared to conventional imaging methods. MATERIALS AND METHODS: This retrospective study enrolled patients with muscle-invasive, locally advanced and metastatic bladder cancer in a single institute evaluated with 18F-FDG PET/MRI. All patients also underwent conventional imaging with CT. Additional imaging may also have included 18F-FDG PET/CT (18F-FDG PET), or sodium fluoride (NaF) PET/CT in some patients. Images were reviewed by a diagnostic radiologist/nuclear medicine physician. Number of lesions and sites of disease were captured and compared between 18F-FDG PET/MRI and conventional imaging. Lesions were confirmed by sequential imaging or lesion biopsy. All patients were followed for survival. RESULTS: Fifteen patients (4 for surveillance; 11 for restaging) underwent 34 18F-FDG PET/MRI scans. Each patient received a corresponding conventional CT around the time of the 18F-FDG PET/MRI (median 6 days). The 15 patients (11 male; 4 female) had a median age of 61.5 years (range 37-73) and histologies of urothelial carcinoma (n = 13) and small-cell carcinoma of the bladder (n = 2) diagnosed as stage 4 (n = 13), stage 3 (n = 1), or stage 2 (n = 1). 18F-FDG PET/MRI detected 82 metastatic malignant lesions involving lymph nodes (n = 22), liver (n = 10), lung (n = 34), soft tissue (n = 12), adrenal glands (n = 1), prostate (n = 1), and bone (n = 2) with a resultant advantage of 36% for lesion visibility in comparison with CT. Serial imaging or biopsy confirmed these lesions as malignant. CONCLUSION: 18F-FDG PET/MRI can detect metastatic lesions which cannot be identified on conventional CT, and this can allow for better treatment planning and improved disease monitoring during therapy.

Circulating Tumor Cell and Circulating Tumor DNA Assays Reveal Complementary Information for Patients with Metastatic Urothelial Cancer.

Despite considerable advances in the management of urothelial carcinoma (UC), better risk stratification and enhanced detection of minimal residual disease are still urgent priorities to prolong survival while avoiding the morbidity of overtreatment. Circulating tumor cells and DNA (CTCs, ctDNA) are two biologically distinct "liquid biopsies" that may potentially address this need, although they have been understudied in UC to date and their relative utility is unknown. To this end, matched CTC and ctDNA samples were collected for a head-to-head comparison in a pilot study of 16 patients with metastatic UC. CTCs were defined as cytokeratin- and/or EpCAM-positive using the RareCyte direct imaging platform. ctDNA was assayed using the PlasmaSelect64 probe-capture assay. 75% of patients had detectable CTCs, and 73% had detectable somatic mutations, with no correlation between CTC count and ctDNA. 91% of patients had tissue confirmation of at least one plasma mutation and, importantly, several clinically actionable mutations were detected in plasma that were not found in the matching tumor. A ctDNA fraction of >2% was significantly associated with worse overall survival (p=0.039) whereas CTC detection was not (p=0.46). Notably, using a predefined gene panel for ctDNA detection had a high but not complete detection rate in metastatic UC, similar to what has been described for a custom tissue-personalized assay approach. In sum, both liquid biopsies show promise in UC and deserve further investigation. PATIENT SUMMARY: New "liquid biopsy" blood tests are emerging for urothelial cancer aimed at early detection and avoiding overtreatment. Our results suggest that two such tests provide complementary information: circulating tumor cells may be best for studying the biological features of a person's cancer, whereas circulating tumor DNA may be better for early detection.

Circulating Tumor Cell Subtypes and T-cell Populations as Prognostic Biomarkers to Combination Immunotherapy in Patients with Metastatic Genitourinary Cancer.

PURPOSE: Circulating tumor cells (CTC) are under investigation as a minimally invasive liquid biopsy that may improve risk stratification and treatment selection. CTCs uniquely allow for digital pathology of individual malignant cell morphology and marker expression. We compared CTC features and T-cell counts with survival endpoints in a cohort of patients with metastatic genitourinary cancer treated with combination immunotherapy. EXPERIMENTAL DESIGN: Markers evaluated included pan-CK/CD45/PD-L1/DAPI for CTCs and CD4/CD8/Ki-67/DAPI for T cells. ANOVA was used to compare CTC burden and T-cell populations across timepoints. Differences in survival and disease progression were evaluated using the maximum log-rank test. RESULTS: From December 2016 to January 2019, 183 samples from 81 patients were tested. CTCs were found in 75% of patients at baseline. CTC burden was associated with shorter overall survival (OS) at baseline (P = 0.022), but not on-therapy. Five morphologic subtypes were detected, and the presence of two specific subtypes with unique cellular features at baseline and on-therapy was associated with worse OS (0.9-2.3 vs. 28.2 months; P < 0.0001-0.013). Increasing CTC heterogeneity on-therapy had a trend toward worse OS (P = 0.045). PD-L1+ CTCs on-therapy were associated with worse OS (P < 0.01, cycle 2). Low baseline and on-therapy CD4/CD8 counts were also associated with poor OS and response category. CONCLUSIONS: Shorter survival may be associated with high CTC counts at baseline, presence of specific CTC morphologic subtypes, PD-L1+ CTCs, and low %CD4/8 T cells in patients with metastatic genitourinary cancer. A future study is warranted to validate the prognostic utility of CTC heterogeneity and detection of specific CTC morphologies.

Phase I Study of Cabozantinib and Nivolumab Alone or With Ipilimumab for Advanced or Metastatic Urothelial Carcinoma and Other Genitourinary Tumors.

PURPOSE: We assessed the safety and efficacy of cabozantinib and nivolumab (CaboNivo) and CaboNivo plus ipilimumab (CaboNivoIpi) in patients with metastatic urothelial carcinoma (mUC) and other genitourinary (GU) malignances. PATIENTS AND METHODS: Patients received escalating doses of CaboNivo or CaboNivoIpi. The primary objective was to establish a recommended phase II dose (RP2D). Secondary objectives included objective response rate (ORR), progression-free survival (PFS), duration of response (DoR), and overall survival (OS). RESULTS: Fifty-four patients were enrolled at eight dose levels with a median follow-up time of 44.6 months; data cutoff was January 20, 2020. Grade 3 or 4 treatment-related adverse events (AEs) occurred in 75% and 87% of patients treated with CaboNivo and CaboNivoIpi, respectively, and included fatigue (17% and 10%, respectively), diarrhea (4% and 7%, respectively), and hypertension (21% and 10%, respectively); grade 3 or 4 immune-related AEs included hepatitis (0% and 13%, respectively) and colitis (0% and 7%, respectively). The RP2D was cabozantinib 40 mg/d plus nivolumab 3 mg/kg for CaboNivo and cabozantinib 40 mg/d, nivolumab 3 mg/kg, and ipilimumab 1 mg/kg for CaboNivoIpi. ORR was 30.6% (95% CI, 20.0% to 47.5%) for all patients and 38.5% (95% CI, 13.9% to 68.4%) for patients with mUC. Median DoR was 21.0 months (95% CI, 5.4 to 24.1 months) for all patients and not reached for patients with mUC. Median PFS was 5.1 months (95% CI, 3.5 to 6.9 months) for all patients and 12.8 months (95% CI, 1.8 to 24.1 months) for patients with mUC. Median OS was 12.6 months (95% CI, 6.9 to 18.8 months) for all patients and 25.4 months (95% CI, 5.7 to 41.6 months) for patients with mUC. CONCLUSION: CaboNivo and CaboNivoIpi demonstrated manageable toxicities with durable responses and encouraging survival in patients with mUC and other GU tumors. Multiple phase II and III trials are ongoing for these combinations.

Characterization of Urothelial Cancer Circulating Tumor Cells with a Novel Selection-Free Method.

OBJECTIVE: To investigate circulating tumor cells (CTCs) as biomarkers of urothelial carcinoma (UC). To date, the majority of work on this topic has utilized the CellSearch test, which has limited sensitivity due to reliance on positive selection for the cell surface protein epithelial cell adhesion molecule (EpCAM). We used a novel selection-free method to enumerate and characterize CTCs across a range of UC stages. MATERIALS AND METHODS: Blood samples from 38 patients (9 controls, 8 nonmuscle invasive bladder cancer [NMIBC], 12 muscle-invasive bladder cancer [MIBC], and 9 metastatic UC) were processed with the AccuCyte-CyteFinder system. Slides were stained for the white blood cell markers CD45 and CD66b and the epithelial markers EpCAM and pancytokeratin. CTCs were defined as any cytokeratin postive and white blood cell marker negative cell. Separately, the more restrictive CellSearch definition was applied, with the additional requirement of EpCAM positivity. The Kruskal-Wallis ANOVA test compared CTC counts by stage. RESULTS: Greater than or equal to 1 CTC was detected in 2 of 8 (25%) patients with NMIBC, 7 of 12 (58%) with MIBC, and 6of 9 (67%) with metastatic disease. No control had CTCs. Comparing CTC counts between groups, the only statistically significant comparison was between controls and patients with metastatic UC (P = .009). With EpCAM positivity as a CTC requirement, no CTCs were detected in any patient with NMIBC, and only 2 (17%) patients with MIBC had CTCs. CTCs tended to be larger in metastatic patients. CONCLUSION: CTCs were detected at all UC stages and exhibited phenotypic diversity of cell size and EpCAM expression. EpCAM negative CTCs that would be missed with the CellSearch test were detected in patients with NMIBC and patients with MIBC.

Prostate Cancer Disseminated Tumor Cells are Rarely Detected in the Bone Marrow of Patients with Localized Disease Undergoing Radical Prostatectomy across Multiple Rare Cell Detection Platforms.

PURPOSE: Prostate circulating tumor cells escape into peripheral blood and enter bone marrow as disseminated tumor cells, representing an early step before conventionally detectable metastasis. It is unclear how frequently this occurs in localized disease and existing detection methods rely on epithelial markers with low specificity and sensitivity. We used multiple methodologies of disseminated tumor cell detection in bone marrow harvested at radical prostatectomy. MATERIALS AND METHODS: Bone marrow was harvested from 208 clinically localized cases, 16 controls and 5 metastatic cases with peripheral blood obtained from 37 metastatic cases. Samples were evaluated at 4 centers with 4 distinct platforms using antibody enrichment with the AdnaTest (Qiagen®) or VERSA (versatile exclusion based rare sample analysis), or whole sample interrogation with the RareCyte platform (Seattle, Washington) or HD-SCA (high definition single cell assay) using traditional epithelial markers and prostate specific markers. We investigated the sensitivity and specificity of these markers by evaluating expression levels in control and metastatic cases. RESULTS: EpCAM, NKX3.1 and AR were nonspecifically expressed in controls and in most samples using AdnaTest with no relation to perioperative variables. Only 1 patient with localized disease showed positive results for the prostate specific marker PSA. With the VERSA platform no localized case demonstrated disseminated tumor cells. With the RareCyte and HD-SCA platforms only a single patient had 1 disseminated tumor cell. CONCLUSIONS: Evaluation across multiple platforms revealed that epithelial markers are nonspecific in bone marrow and, thus, not suitable for disseminated tumor cell detection. Using prostate specific markers disseminated tumor cells were typically not detected in patients with localized prostate cancer.

Analogous detection of circulating tumor cells using the AccuCyte® -CyteFinder® system and ISET system in patients with locally advanced and metastatic prostate cancer.

INTRODUCTION: Circulating tumor cells (CTCs) can provide important information on patient's prognosis and treatment efficacy. Currently, a plethora of methods is available for the detection of these rare cells. We compared the outcomes of two of those methods to enumerate and characterize CTCs in patients with locally advanced and metastatic prostate cancer (PCa). First, the selection-free AccuCyte® - CyteFinder® system (RareCyte® , Inc., Seattle, WA) and second, the ISET system (Rarecells Diagnostics, France), a CTC detection method based on cell size-exclusion. METHODS: Peripheral blood samples were obtained from 15 patients with metastatic PCa and processed in parallel, using both methods according to manufacturer's protocol. CTCs were identified by immunofluorescence, using commercially available antibodies to pancytokeratin (PanCK), EpCAM, CD45/CD66b/CD34/CD11b/CD14 (AccuCyte® - CyteFinder® system), and pancytokeratin, vimentin (Vim) and CD45 (ISET system). RESULTS: The median CTC count was 5 CTCs/7.5 mL (range, 0-20) for the AccuCyte® - CyteFinder® system and 37 CTCs/7.5 mL (range, 8-139) for the ISET system (P < 0.001). Total CTC counts obtained for the two methods were correlated (r = 0.750, P = 0.001). When separating the total CTC count obtained with the ISET system in PanCK+/Vim- and PanCK+/Vim+ CTCs, the total CTC count obtained with the AccuCyte® - CyteFinder® system was moderately correlated with the PanCK+/Vim- CTCs, and strongly correlated with the PanCK+/Vim+ CTCs (r = 0.700, P = 0.004 and r = 0.810, P < 0.001, respectively). CONCLUSION: Our results highlight significant disparities in the enumeration and phenotype of CTCs detected by both techniques. Although the median amount of CTCs/7.5 mL differed significantly, total CTC counts of both methods were strongly correlated. For future studies, a more uniform approach to the isolation and definition of CTCs based on immunofluorescent stains is needed to provide reproducible results that can be correlated with clinical outcomes.

Hospital Charges and Length of Stay Following Radical Cystectomy in the Enhanced Recovery After Surgery Era.

OBJECTIVE: To report our center's experience with enhanced recovery after surgery (ERAS) pathway for radical cystectomy (RC), specifically evaluating complications, LOS, 30- and 90-day readmissions, and hospital charges. Pathways of this type have been shown to decrease the length of stay (LOS) and postoperative ileus. However, concerns persist that ERAS is costly and increases readmissions. To date, limited studies have evaluated these concerns. MATERIALS AND METHODS: Our ERAS protocol was implemented for RC in December 2015. Outcomes in ERAS patients were compared with those in RC patients from the time period before ERAS. Patients were excluded if they underwent concomitant nephroureterectomy. RESULTS: Fifty-six consecutive ERAS patients were compared with 54 pre-ERAS patients. The median charge for index hospitalization was $31,090 in the ERAS group and $35,489 in the pre-ERAS group (P = .036). The median LOS was 5.0 days in the ERAS group and 8.5 days in the pre-ERAS group (P = < .001). The pre-ERAS group had a significantly increased use of nasogastric tube (13.8% vs 30.0%) and parenteral nutrition (6.9% vs 20.4%). The overall complication rate (including infectious, renal, deep vein thrombosis and pulmonary embolism, myocardial infarction and stroke, and respiratory and gastrointestinal-related complications) was similar between the 2 groups (51.7% in the ERAS group and 62.0% in the pre-ERAS group, P = .28). Thirty- and 90-day readmissions also remained similar (19.0% vs 14.8%, P = .55, and 31.0% vs 27.7%, P = .64). The most common readmission reason was infection, specifically urinary tract infection. CONCLUSION: Implementation of the ERAS pathway at our center resulted in significantly reduced LOS and total hospital charge, with comparable rates of complication and readmission, highlighting the need for ERAS pathways in patients undergoing RC.

Nucleolin Staining May Aid in the Identification of Circulating Prostate Cancer Cells.

INTRODUCTION: Circulating tumor cells (CTCs) have great potential as circulating biomarkers for solid malignancies. Currently available assays for CTC detection rely on epithelial markers with somewhat limited sensitivity and specificity. We found that the staining pattern of nucleolin, a common nucleolar protein in proliferative cells, separates CTCs from white blood cells (WBCs) in men with metastatic prostate cancer. PATIENTS AND METHODS: Whole peripheral blood from 3 men with metastatic prostate cancer was processed with the AccuCyte CTC system (RareCyte, Seattle, WA). Slides were immunostained with 4',6-diamidino-2-phenylindole (DAPI), anti-pan-cytokeratin, anti-CD45/CD66b/CD11b/CD14/CD34, and anti-nucleolin antibodies and detected using the CyteFinder system. DAPI nucleolin colocalization and staining pattern wavelet entropy were measured with novel image analysis software. RESULTS: A total of 33,718 DAPI-positive cells were analyzed with the novel imaging software, of which 45 (0.13%) were known CTCs based on the established AccuCyte system criteria. Nucleolin staining pattern for segmentable CTCs demonstrated greater wavelet entropy than that of WBCs (median wavelet entropy, 6.86 × 107 and 3.03 × 106, respectively; P = 2.92 × 10-22; approximated z statistic = 9.63). Additionally, the total nucleolin staining of CTCs was greater than that of WBCs (median total pixel intensity, 1.20 × 105 and 2.55 × 104 integrated pixel units, respectively; P = 2.40 × 10-21; approximated z statistic = 9.41). CONCLUSION: Prostate cancer CTCs displayed unique nucleolin expression and localization compared to WBCs. This finding has the potential to serve as the basis for a sensitive and specific CTC detection method.

Patterns of Pelvic Lymph Node Dissection at the Time of Radical Prostatectomy for Low-risk Men.

OBJECTIVE: To examine nationwide patterns of lymph node dissection (LND) in men with D'Amico low-risk prostate cancer, including the rate of detected lymph node metastasis and factors associated with the decision to perform LND. Existing guidelines recommend against LND at the time of radical prostatectomy (RP) in low-risk men, yet this is still a common practice. MATERIALS AND METHODS: The 2013 National Cancer Database includes 1,208,180 cases of prostate cancer diagnosed between 2004 and 2013. Of these, 50,245 met D'Amico low-risk criteria, had complete clinicopathologic data, and underwent RP. Mixed effects multivariable logistic regression models were used to identify hospital and treatment characteristics independently associated with LND, extended LND, and the detection of lymph node metastasis. RESULTS: A total of 20,556 men (40.9%) underwent LND and 4360 (8.7%) had extended LND. Lymph node metastasis was present in 76 cases (0.37%). On multivariable analysis, robotic vs open RP had odds ratio (OR) = 0.16 (0.14-0.17), P < .0001, for LND, and surgery at an academic center had OR = 1.76 (1.33-2.33), P < .0001, for LND. Men on Medicaid were less likely than the privately insured to undergo LND, and the highest earners were most likely to undergo LND. In multivariable analysis, race was significantly associated with lymph node metastasis, with black men having the highest rates (P < .0001). CONCLUSION: LND is performed in nearly half of low-risk men, more commonly during open surgery at academic centers, yet metastasis is discovered less than 1% of the time. Guidelines suggest that percentage core involvement should be considered, but if the overall risk of metastasis is low, LND should not be performed.

The Impact of Downgrading from Biopsy Gleason 7 to Prostatectomy Gleason 6 on Biochemical Recurrence and Prostate Cancer Specific Mortality.

PURPOSE: Gleason score is one of the most important prognostic indicators for prostate cancer. Downgrading from biopsy Gleason score 7 to radical prostatectomy Gleason score 6 occurs commonly and yet to our knowledge the impact on survival outcomes is unknown. We examined biochemical recurrence and prostate cancer specific mortality risk in a large cohort evaluated by a single group of expert urological pathologists. MATERIALS AND METHODS: Of 23,918 men who underwent radical prostatectomy at our institution between 1984 and 2014, 10,236 with biopsy and radical prostatectomy Gleason score 6 or 7 without upgrading were included in analysis. The cohort was divided into 3 groups, including group 1-biopsy and radical prostatectomy Gleason score 6 in 6,923 patients (67.6%), group 2-Gleason score 7 downgraded to radical prostatectomy Gleason score 6 in 648 (6.3%) and group 3-biopsy and radical prostatectomy Gleason score 7 in 2,665 (26.0%). Biochemical recurrence and prostate cancer specific mortality risks were compared using Cox regression and competing risk analyses adjusting for clinicopathological variables. RESULTS: At a median followup of 5 years (range 1 to 29), 992 men experienced biochemical recurrence and 95 had died of prostate cancer. Biochemical recurrence-free survival in downgraded cases (group 2) was better than in group 3 cases, which had Gleason score 7 on biopsy and radical prostatectomy (p <0.001), but worse than group 1 cases, which had Gleason score 6 on biopsy and radical prostatectomy (p <0.001). Downgrading was independently associated with biochemical recurrence (adjusted HR 1.87, p <0.0001) but not with prostate cancer specific mortality (adjusted HR 1.65, p = 0.636). CONCLUSIONS: Downgrading from biopsy Gleason score 7 to radical prostatectomy Gleason score 6 was an independent predictor of biochemical recurrence but not prostate cancer specific mortality, likely due to the presence of minor amounts of Gleason pattern 4.

New Prostate Cancer Grading System Predicts Long-term Survival Following Surgery for Gleason Score 8-10 Prostate Cancer.

BACKGROUND: The newly proposed five-tiered prostate cancer grading system (PCGS) divides Gleason score (GS) 8-10 disease into GS 8 and GS 9-10 on the basis of biochemical recurrence (BCR) following radical prostatectomy (RP) as an outcome. However, BCR does not necessarily portend worse survival outcomes. OBJECTIVE: To assess the significance of distinguishing GS 8 versus 9-10 disease in terms of long-term survival outcomes for both the preoperative setting using biopsy (Bx) GS and the postoperative setting with RP GS. DESIGN, SETTING, AND PARTICIPANTS: Of 23918 men who underwent RP between 1984 and 2014, there were 721 men with biopsy GS 8-10, and 1047 men with RP GS 8-10. OUTCOME MEASURES AND STATISTICAL ANALYSIS: Clinicopathologic characteristics were compared between men with GS 8 and those with GS 9-10. We compared all-cause mortality (ACM) and prostate cancer-specific mortality (PCSM) risk between the groups using Cox regression and competing-risks analyses, adjusting for other perioperative variables and death from other causes as the competing event. RESULTS AND LIMITATIONS: Compared to men with GS 8, men with GS 9-10 had later RP year and higher pathologic stage. Among men with Bx GS 8-10, 115 died (82 due to PC) with median follow-up of 3 yr (interquartile range [IQR] 1-7) for both overall and cancer-specific survival. Of men with RP GS 8-10, 221 died (151 due to PC) with median follow-up of 4 yr (IQR 2-8) and 4 yr (IQR 2-9) for overall and cancer-specific survival, respectively. PC-specific survival rates were significantly lower for men with GS 9-10 compared to men with GS 8 for both Bx (hazard ratio [HR] 2.13, 95% confidence interval [CI] 1.37-3.30; p<0.01) and RP GS (HR 2.38, 95% CI 1.74-3.28; p<0.01). This association persisted in multivariable models after adjusting for perioperative variables. CONCLUSIONS: Men with GS 9-10 had higher ACM and PCSM rates compared to those with GS 8. GS 8 and GS 9-10 PC should be considered separately in both the preoperative and postoperative setting as suggested by the new PCGS. PATIENT SUMMARY: The prostate cancer grading system can predict mortality risk after radical prostatectomy (RP) for men with Gleason score 8-10 disease based on both biopsy and RP Gleason scores. There are significant differences in all-cause mortality and prostate cancer-specific mortality following surgery between men with Gleason score 8 and those with Gleason score 9-10 disease.

Longer average blood storage duration is associated with increased risk of infection and overall morbidity following radical cystectomy.

BACKGROUND: Patients with bladder cancer undergoing radical cystectomy (RC) experience high rates of perioperative blood transfusions (PBTs) and morbidity. The aim of this study was to evaluate the effect of blood storage duration on the risk of adverse perioperative outcomes in this high-risk patient population. MATERIALS AND METHODS: In a retrospective review of RC patients from 2010 to 2014 who received PBTs, the average storage duration for all units transfused was used to classify patients as receiving older blood using 3 different definitions (≥21 days,≥28 days, and≥35 days). Multivariable Poisson regression models were used to determine the adjusted relative risk of perioperative infections and overall morbidity in those given older blood compared to fresher blood. RESULTS: Of the 451 patients undergoing RC, 205 (45%) received nonirradiated PBTs. In multivariable modeling, increasing average blood storage duration, as a continuous variable, was associated with an increased risk of infections (risk ratio [RR] = 1.08 per day, 95% CI: 1.01-1.17) and overall morbidity (RR = 1.08 per day, 95% CI: 1.01-1.15). Furthermore, ≥28-day blood storage (vs.<28) was associated with increased infections (RR = 2.69, 95% CI: 1.18-6.14) and morbidity (RR = 2.54, 95% CI: 1.31-4.95), and ≥35-day blood storage (vs.<35) was also associated with increased infections (RR = 2.83, 95% CI: 1.42-5.66) and morbidity (RR = 3.35, 95% CI: 1.95-5.77). CONCLUSIONS: Although blood is stored up to 42 days, storage≥28 days may expose RC patients to increased perioperative infections and overall morbidity compared with storage<28 days. Prospective cohort studies are warranted in cystectomy and other high-risk surgical oncology patients to better determine the effect of blood storage duration.

Role of biobanking in urology: a review.

In the current era of individualized medicine, a biorepository of human samples is essential to support clinical and translational research. There have been limited efforts in this arena within the field of urology, as cost, logistical and ethical issues represent significant deterrents to biobanking. The Johns Hopkins Brady Urological Institute Biorepository was founded in 1994 as a resource to facilitate discovery. Since its inception, the biorepository has enabled numerous research endeavours including pivotal trials leading to the regulatory approval of four diagnostic tests for prostate cancer. In the present review, we discuss the current state of biobanking within urology, outline the specific ethical and financial challenges to biobanking as well as solutions, and describe the operations of a successful urological biorepository.