Jonathan A. Coleman

The Effect of Tumor Location on Prognosis in Patients Treated with Radical Nephroureterectomy at Memorial Sloan-Kettering Cancer Center

BACKGROUNDnThe prognostic impact of primary tumor location on outcomes for patients with upper-tract urothelial carcinoma (UTUC) is still contentious.nnnOBJECTIVEnTo test the association between tumor location and disease recurrence and cancer-specific survival (CSS) in patients treated with radical nephroureterectomy (RNU) for UTUC.nnnDESIGN, SETTING, AND PARTICIPANTSnProspectively collected data were retrospectively reviewed from 324 consecutive patients treated with RNU between 1995 and 2008 at a single tertiary referral center. Patients who had previous radical cystectomy, preoperative chemotherapy, previous contralateral UTUC, or metastatic disease at presentation were excluded. This left 253 patients for analysis. Tumor location was categorized as renal pelvis or ureter based on the location of the dominant tumor. Recurrences in the bladder only, in nonbladder sites, and in any site were analyzed.nnnINTERVENTIONnAll patients were treated with RNU.nnnMEASUREMENTSnRecurrence-free survival and CSS probabilities were estimated using Kaplan-Meier and Cox regression analyses.nnnRESULTS AND LIMITATIONSnMedian follow-up for survivors was 48 mo. The 5-yr recurrence-free probability (including bladder recurrence) and CSS estimates were 32% and 78%, respectively. On multivariable analysis, pathologic stage was the only predictor for disease recurrence (p=0.01). Tumor location was not an independent predictor for recurrence (hazard ratio: 1.19; p=0.3), and there was no difference in the probability of disease recurrence between ureteral and renal pelvic tumors (p=0.18). On survival analysis, we also found no differences between ureteral and renal pelvic tumors on probability of CSS (p=0.2). On multivariate analysis, pathologic stage (p<0.0001) and nodal status (p=0.01) were associated with worse CSS. This study is limited by its retrospective nature.nnnCONCLUSIONSnOur study did not show any differences in recurrence and CSS rates between patients with ureteral and renal pelvic tumors treated with RNU.

Comparison Between Laparoscopic and Open Radical Nephroureterectomy in a Contemporary Group of Patients: Are Recurrence and Disease-Specific Survival Associated with Surgical Technique?

BACKGROUNDnOpen radical nephroureterectomy (ORN) is the current standard of care for upper tract urothelial carcinoma (UTUC), but laparoscopic radical nephroureterectomy (LRN) is emerging as a minimally invasive alternative. Questions remain regarding the oncologic safety of LRN and its relative equivalence to ORN.nnnOBJECTIVEnOur aim was to compare recurrence-free and disease-specific survival between ORN and LRN.nnnDESIGN, SETTING, AND PARTICIPANTSnWe retrospectively analyzed data from 324 consecutive patients treated with radical nephroureterectomy (RN) between 1995 and 2008 at a major cancer center. Patients with previous invasive bladder cancer or contralateral UTUC were excluded. Descriptive data are provided for 112 patients who underwent ORN from 1995 to 2001 (pre-LRN era). Comparative analyses were restricted to patients who underwent ORN (n=109) or LRN (n=53) from 2002 to 2008. Median follow-up for patients without disease recurrence was 23 mo.nnnINTERVENTIONnAll patients underwent RN.nnnMEASUREMENTSnRecurrence was categorized as bladder-only recurrence or any recurrence (bladder, contralateral kidney, operative site, regional lymph nodes, or distant metastasis). Recurrence-free probabilities were estimated using Kaplan-Meier methods. A multivariable Cox model was used to evaluate the association between surgical approach and disease recurrence. The probability of disease-specific death was estimated using the cumulative incidence function.nnnRESULTS AND LIMITATIONSnClinical and pathologic characteristics were similar for all patients. The recurrence-free probabilities were similar between ORN and LRN (2-yr estimates: 38% and 42%, respectively; p=0.9 by log-rank test). On multivariable analysis, the surgical approach was not significantly associated with disease recurrence (hazard ratio [HR]: 0.88 for LRN vs ORN; 95% confidence interval [CI], 0.57-1.38; p=0.6). There was no significant difference in bladder-only recurrence (HR: 0.78 for LRN vs ORN; 95% CI, 0.46-1.34; p=0.4) or disease-specific mortality (p=0.9). This study is limited by its retrospective nature.nnnCONCLUSIONSnBased on the results of this retrospective study, no evidence indicates that oncologic control is compromised for patients treated with LRN in comparison with ORN.

Genomic Characterization of Upper Tract Urothelial Carcinoma

BACKGROUNDnDespite a similar histologic appearance, upper tract urothelial carcinoma (UTUC) and urothelial carcinoma of the bladder (UCB) tumors have distinct epidemiologic and clinicopathologic differences.nnnOBJECTIVEnTo investigate whether the differences between UTUC and UCB result from intrinsic biological diversity.nnnDESIGN, SETTING, AND PARTICIPANTSnTumor and germline DNA from patients with UTUC (n=83) and UCB (n=102) were analyzed using a custom next-generation sequencing assay to identify somatic mutations and copy number alterations in 300 cancer-associated genes.nnnOUTCOME MEASUREMENTS AND STATISTICAL ANALYSISnWe described co-mutation patterns and copy number alterations in UTUC. We also compared mutation frequencies in high-grade UTUC (n=59) and high-grade UCB (n=102).nnnRESULTS AND LIMITATIONSnComparison of high-grade UTUC and UCB revealed significant differences in the prevalence of somatic alterations. Genes altered more commonly in high-grade UTUC included FGFR3 (35.6% vs 21.6%; p=0.065), HRAS (13.6% vs 1.0%; p=0.001), and CDKN2B (15.3% vs 3.9%; p=0.016). Genes less frequently mutated in high-grade UTUC included TP53 (25.4% vs 57.8%; p<0.001), RB1 (0.0% vs 18.6%; p<0.001), and ARID1A (13.6% vs 27.5%; p=0.050). Because our assay was restricted to genomic alterations in a targeted panel, rare mutations and epigenetic changes were not analyzed.nnnCONCLUSIONSnHigh-grade UTUC tumors display a spectrum of genetic alterations similar to high-grade UCB. However, there were significant differences in the prevalence of several recurrently mutated genes including HRAS, TP53, and RB1. As relevant targeted inhibitors are being developed and tested, these results may have important implications for the site-specific management of patients with urothelial carcinoma.nnnPATIENT SUMMARYnComparison of next-generation sequencing of upper tract urothelial carcinoma (UTUC) with urothelial bladder cancer identified that similar mutations were present in both cancer types but at different frequencies, indicating a potential need for unique management strategies. UTUC tumors were found to have a high rate of mutations that could be targeted with novel therapies.

Ultrasonic tissue characterization of uveal melanoma and prediction of patient survival after enucleation and brachytherapy

We performed survival studies on 136 patients with uveal malignant melanoma who were examined with ultrasonic tissue characterization before treatment with cobalt-60 brachytherapy (74 patients) or enucleation (62 patients). Mean follow-up time was 58.7 months for the brachytherapy group and 59.0 months for the enucleated group. The maximal follow-up time was nearly ten years. Univariate survival analysis showed that patients with small tumors (less than 250 mm3, 49 patients) had a higher five-year survival when treated with brachytherapy than when treated with enucleation. No patients in this study with tumor volumes greater than 1,500 mm3 (13 patients) were treated with brachytherapy. For tumors of intermediate size (74 patients), survival analysis did not indicate appreciable differences between the treatment options. However, multivariate models including two ultrasonic tissue characterization variables, scatterer size and concentration, showed appreciable intergroup differences in the dependence of survival on these factors. Results suggest that tissue properties detectable with ultrasonic techniques are related to differences in patient survival and may be used for treatment planning for tumors of intermediate size.

Mutation Detection in Patients With Advanced Cancer by Universal Sequencing of Cancer-Related Genes in Tumor and Normal DNA vs Guideline-Based Germline Testing

Importance Guidelines for cancer genetic testing based on family history may miss clinically actionable genetic changes with established implications for cancer screening or prevention. Objective To determine the proportion and potential clinical implications of inherited variants detected using simultaneous sequencing of the tumor and normal tissue (“tumor-normal sequencing”) compared with genetic test results based on current guidelines. Design, Setting, and Participants From January 2014 until May 2016 at Memorial Sloan Kettering Cancer Center, 10 336 patients consented to tumor DNA sequencing. Since May 2015, 1040 of these patients with advanced cancer were referred by their oncologists for germline analysis of 76 cancer predisposition genes. Patients with clinically actionable inherited mutations whose genetic test results would not have been predicted by published decision rules were identified. Follow-up for potential clinical implications of mutation detection was through May 2017. Exposure Tumor and germline sequencing compared with the predicted yield of targeted germline sequencing based on clinical guidelines. Main Outcomes and Measures Proportion of clinically actionable germline mutations detected by universal tumor-normal sequencing that would not have been detected by guideline-directed testing. Results Of 1040 patients, the median age was 58 years (interquartile range, 50.5-66 years), 65.3% were male, and 81.3% had stage IV disease at the time of genomic analysis, with prostate, renal, pancreatic, breast, and colon cancer as the most common diagnoses. Of the 1040 patients, 182 (17.5%; 95% CI, 15.3%-19.9%) had clinically actionable mutations conferring cancer susceptibility, including 149 with moderate- to high-penetrance mutations; 101 patients tested (9.7%; 95% CI, 8.1%-11.7%) would not have had these mutations detected using clinical guidelines, including 65 with moderate- to high-penetrance mutations. Frequency of inherited mutations was related to case mix, stage, and founder mutations. Germline findings led to discussion or initiation of change to targeted therapy in 38 patients tested (3.7%) and predictive testing in the families of 13 individuals (1.3%), including 6 for whom genetic evaluation would not have been initiated by guideline-based testing. Conclusions and Relevance In this referral population with selected advanced cancers, universal sequencing of a broad panel of cancer-related genes in paired germline and tumor DNA samples was associated with increased detection of individuals with potentially clinically significant heritable mutations over the predicted yield of targeted germline testing based on current clinical guidelines. Knowledge of these additional mutations can help guide therapeutic and preventive interventions, but whether all of these interventions would improve outcomes for patients with cancer or their family members requires further study. Trial Registration clinicaltrials.gov Identifier: NCT01775072

A case-mix-adjusted comparison of early oncological outcomes of open and robotic prostatectomy performed by experienced high volume surgeons

Radical prostatectomy provides local‐regional control of prostate cancer and is the most common treatment for prostate cancer in the United States. Over the past decade there has been a shift in the surgical approach used to treat this disease, moving from open retropubic approach to robot‐assisted laparoscopic prostatectomy. While robotic prostatectomy has been demonstrated to result in less blood loss, fewer transfusions and shorter hospital duration, it has never been demonstrated in a meaningful prospective manner to result in improved or even equivalent oncological outcomes. Prior attempts to address this question have been hampered by methodological issues with study design, differences in case mix, or differences in surgical learning curve between surgeons. In this retrospective study we compared the oncological outcomes of open radical prostatectomy and robotic prostatectomy limiting our analysis to expert surgeons in their respective surgical approaches. Importantly, the patient cohort contained a majority of patients with intermediate‐ and high‐risk features and all surgeons attempted to adhere to strict oncological principles, including performing complete pelvic lymph node dissections in almost all of the patients in the study. The results demonstrate that oncological outcomes show no significant difference with respect to surgical approach, even for patients with higher risk features, and that there is more variation between individual surgeons than between surgical approaches.

Pilot Study to Assess Safety and Clinical Outcomes of Irreversible Electroporation for Partial Gland Ablation in Men with Prostate Cancer

PURPOSEnPartial prostate gland ablation is a strategy to manage localized prostate cancer. Irreversible electroporation can ablate localized soft tissues. We describe 30 and 90-day complications and intermediate term functional outcomes in men undergoing prostate gland ablation using irreversible electroporation.nnnMATERIALS AND METHODSnWe reviewed the charts of 25 patients with prostate cancer who underwent prostate gland ablation using irreversible electroporation as a primary procedure and who were followed for at least 6 months.nnnRESULTSnMedian followup was 10.9 months. Grade 3 complications occurred in 2 patients including epididymitis (1) and urinary tract infection (1). Fourteen patients experienced grade 2 or lower complications, mainly transient urinary symptoms, hematuria and urinary tract infections. Of 25 patients 4 (16%) had cancer in the zone of ablation on routine followup biopsy at 6 months. Of those with normal urinary function at baseline 88% and 94% reported normal urinary function at 6 and 12 months after prostate gland ablation, respectively. By 12 months only 1 patient with normal erectile function at baseline reported new difficulty with potency and only 2 patients (8%) required a pad for urinary incontinence.nnnCONCLUSIONSnProstate gland ablation with irreversible electroporation is feasible and safe in selected men with localized prostate cancer. Intermediate term urinary and erectile function outcomes appear reasonable. Irreversible electroporation is effective in the ablation of tumor bearing prostate tissue as a majority of men had no evidence of residual cancer on biopsy 6 months after prostate gland ablation.

Genomic Biomarkers for the Prediction of Stage and Prognosis of Upper Tract Urothelial Carcinoma

PURPOSEnGenomic characterization of radical nephroureterectomy specimens in patients with upper tract urothelial carcinoma may allow for thoughtful integration of systemic and targeted therapies. We sought to determine whether genomic alterations in upper tract urothelial carcinoma are associated with adverse pathological and clinical outcomes.nnnMATERIALS AND METHODSnNext generation exon capture sequencing of 300 cancer associated genes was performed in 83 patients with upper tract urothelial carcinoma. Genomic alterations were assessed individually and also grouped into core signal transduction pathways or canonical cell functions for association with clinicopathological outcomes. Binary outcomes, including grade (high vs low), Txa0stage (pTa/T1/T2 vs pT3/T4) and organ confined status (pT2 or less and N0/Nx vs greater than pT2 or N+) were assessed with the Kruskal-Wallis and Fisher exact tests as appropriate. Associations between alterations and survival were estimated using the Kaplan-Meier method and Cox regression.nnnRESULTSnOf the 24 most commonly altered genes in 9 pathways TP53/MDM2 alterations and FGFR3 mutations were the only 2 alterations uniformly associated with high grade, advanced stage, nonorgan confined disease, and recurrence-free and cancer specific survival. TP53/MDM2 alterations were associated with adverse clinicopathological outcomes whereas FGFR3 mutations were associated with favorable outcomes. We created a risk score using TP53/MDM2 and FGFR3 status that was able to discriminate between adverse pathological and clinical outcomes, including in the subset of patients with high grade disease. The study is limited by small numbers and lack of validation.nnnCONCLUSIONSnOur data indicate that specific genomic alterations in radical nephroureterectomy specimens correlate with tumor grade, stage and cancer specific survival outcomes.

Factors That Affect Proportional Glomerular Filtration Rate After Minimally Invasive Partial Nephrectomy

BACKGROUND AND PURPOSEnSeveral factors have been shown to impact the overall glomerular filtration (GFR) rate after partial nephrectomy. Change in overall GFR, however, does not necessarily reflect the impact of these factors on the operated kidney. Using preoperative and postoperative renal scintigraphy, we sought to assess the impact of patient, tumor, and operative factors on GFR of the affected kidney (proportional GFR).nnnPATIENTS AND METHODSnWe identified 73 patients who underwent minimally invasive partial nephrectomy with preoperative and postoperative renal scans from two institutions. Patient, tumor, and operative characteristics were recorded. We used multiple linear regression to determine the patient and clinical factors predictive of postoperative proportional GFR in the operated kidney. We tested for an interaction between preoperative proportional GFR and nephrometry score and ischemia. We further fitted two separate linear models to compare the proportion of variance (R(2)) explained by ischemia time in change in renal function in the operated kidney with the change in renal function in both kidneys.nnnRESULTSnSurgical parameters (procedure approach, ischemia time, and estimated blood loss) and preoperative proportional GFR were significantly associated with postoperative proportional GFR. Preoperative proportional GFR (β=5.93, 95% confidence interval [CI]: 3.88, 7.97, P<0.0005) and procedure approach (β=8.67, 95% CI: 4.50, 12.80, P<0.0005) were strongly associated with outcome while ischemia time (β=-1.80, 95% CI: -3.48, -0.11, P=0.04) and estimated blood loss (β=-1.15, 95% CI: -0.29, -0.01, P=0.04) just reached statistical significance. The interaction term between preoperative proportional GFR and nephrometry score or ischemia time was not statistically significant (nephrometry, P=0.2 continuous or P=0.6 categorical, and ischemia, P=0.7, respectively).nnnCONCLUSIONnLower preoperative proportional GFR, longer ischemia times, and higher blood loss all negatively impact postoperative proportional GFR while tumor complexity as gauged by morphometry scoring does not. Larger studies are needed to determine whether renal scintigraphy is a more accurate method of measuring the impact of the ischemia time on postoperative proportional GFR.

Systemic antitumor immunity by PD-1/PD-L1 inhibition is potentiated by vascular-targeted photodynamic therapy of primary tumors.

Purpose: PD-1/PD-L1 pathway inhibition is effective against advanced renal cell carcinoma, although results are variable and may depend on host factors, including the tumor microenvironment. Vascular-targeted photodynamic (VTP) therapy with the photosensitizer WST11 induces a defined local immune response, and we sought to determine whether this could potentiate the local and systemic antitumor response to PD-1 pathway inhibition. Experimental Design: Using an orthotopic Renca murine model of renal cell carcinoma that develops lung metastases, we treated primary renal tumors with either VTP alone, PD-1/PD-L1 antagonistic antibodies alone, or a combination of VTP and antibodies and then examined treatment responses, including immune infiltration in primary and metastatic sites. Modulation of PD-L1 expression by VTP in human xenograft tumors was also assessed. Results: Treatment of renal tumors with VTP in combination with systemic PD-1/PD-L1 pathway inhibition, but neither treatment alone, resulted in regression of primary tumors, prevented growth of lung metastases, and prolonged survival in a preclinical mouse model. Analysis of tumor-infiltrating lymphocytes revealed that treatment effect was associated with increased CD8+:regulatory T cell (Treg) and CD4+FoxP3-:Treg ratios in primary renal tumors and increased T-cell infiltration in sites of lung metastasis. Furthermore, PD-L1 expression is induced following VTP treatment of human renal cell carcinoma xenografts. Conclusions: Our results demonstrate a role for local immune modulation with VTP in combination with PD-1/PD-L1 pathway inhibition for generation of potent local and systemic antitumor responses. This combined modality strategy may be an effective therapy in cancers resistant to PD-1/PD-L1 pathway inhibition alone. Clin Cancer Res; 24(3); 592–9. ©2017 AACR.