Philip Abbosh

Is anatomic complexity associated with renal tumor growth kinetics under active surveillance

INTRODUCTION Linear growth rate (LGR) is the most commonly employed trigger for definitive intervention in patients with renal masses managed with an initial period of active surveillance (AS). Using our institutional cohort, we explored the association between tumor anatomic complexity at presentation and LGR in patients managed with AS. METHODS AND MATERIALS Enhancing renal masses managed expectantly for at least 6 months were included for analysis. The association between Nephrometry Score and LGR was assessed using generalized estimating equations, adjusting for the age, Charlson score, race, sex, and initial tumor size. RESULTS Overall, 346 patients (401 masses) met the inclusion criteria (18% ≥ cT1b), with a median follow-up of 37 months (range: 6-169). Of these, 44% patients showed progression to definitive intervention with a median duration of 27 months (range: 6-130). On comparing patients managed expectantly to those requiring intervention, no difference was seen in median tumor size at presentation (2.2 vs. 2.2 cm), whereas significant differences in median age (74 vs. 65 y, P < 0.001), Charlson comorbidity score (3 vs. 2, P<0.001), and average LGR (0.23 vs. 0.49 cm/y, P < 0.001) were observed between groups. Following adjustment, for each 1-point increase in Nephrometry Score sum, the average tumor LGR increased by 0.037 cm/y (P = 0.002). Of the entire cohort, 6 patients (1.7%) showed progression to metastatic disease. CONCLUSIONS The demonstrated association between anatomic tumor complexity at presentation and renal masses of LGR of clinical stage 1 under AS may afford a clinically useful cue to tailor individual patient radiographic surveillance schedules and warrants further evaluation.

Surgical Apgar Score Predicts an Increased Risk of Major Complications and Death after Renal Mass Excision

PURPOSE Tailoring perioperative management to minimize the postoperative complication rates depends on reliable prognostication of patients most at risk. The Surgical Apgar Score is an objective measure of the operative course validated to predict major complications and death after general/vascular surgery. We assessed the ability of the Surgical Apgar Score to identify patients most at risk for postoperative morbidity and mortality after renal mass excision. MATERIALS AND METHODS Data for 886 patients undergoing renal mass excision via radical or partial nephrectomy from 2010 to 2013 were extracted from a prospectively collected database. The Surgical Apgar Score was calculated using electronic anesthesia records. Major postoperative complications, readmission and reoperation within 30 days of surgery as well as 90-day mortality were examined. RESULTS Overall 13.2% of patients experienced major postoperative complications at 30 days. Clavien grade I, II, III, IV and V complications were experienced by 1.7%, 2.9%, 5.8%, 1.9% and 0.9%, respectively. The 90-day all cause mortality rate was 1.4%. The Surgical Apgar Score was significantly lower in patients experiencing major complications (mean 7.3 vs 7.8, p=0.004) and death (6.3 vs 7.7, p=0.03). Patients with a Surgical Apgar Score of 4 or less were 3.7 times more likely to experience a major complication (p=0.01) and 24 times more likely to die within 90 days of surgery (p=0.0007) compared to patients with a Surgical Apgar Score greater than 8. CONCLUSIONS The Surgical Apgar Score is an easily collected metric that can identify patients at higher risk for major complications and death after renal mass excision. A prospective trial to help further delineate the optimal use of this tool in an adjusted perioperative management approach with patients undergoing renal mass excision is warranted.

Lymphopenia is an independent predictor of inferior outcome in papillary renal cell carcinoma

PURPOSE Lymphopenia as a likely index of poor systemic immunity is an independent predictor of inferior outcome in patients with clear cell renal cell carcinoma (RCC). We sought to evaluate the prognostic relevance of preoperative absolute lymphocyte count (ALC) in a cohort of patients with papillary RCC (PRCC). MATERIALS AND METHODS A prospectively maintained, renal cancer database was analyzed. Patients with preoperative ALC, within 3 months before surgery, were eligible for the study. Those with multifocal or bilateral renal tumors were excluded. Correlations between ALC and age, gender, smoking, Charlson comorbidity index, pathologic T category, PRCC subtype, and TNM stage were evaluated. Differences in overall survival (OS) and cancer-specific survival by ALC status were assessed using the log-rank test and cumulative incident estimators, respectively. Cox proportional hazards model was used for multivariable analyses. RESULTS A total of 192 patients met the inclusion criteria. As a continuous variable, preoperative ALC was associated with higher TNM stage (P = 0.001) and older age (P = 0.01). As a dichotomous variable, lymphopenia (<1,300 cells/µl) was associated with higher TNM stage (P = 0.003). On multivariable analyses, controlling for covariates, after a median follow-up of 37.3 months, lymphopenia was associated with inferior OS (hazard ratio = 2.3 [95% CI: 1.2-4.3], P = 0.011) and trended to significance for cancer-specific survival (P = 0.071). Among patients with nonmetastatic disease and lymphopenia, OS at 37.5 months was shorter compared with those with normal ALC (83% vs. 93%, P = 0.0006). CONCLUSIONS In patients with PRCC, lymphopenia is associated with lower survival independent of TNM stage, age, and histology. ALC may provide an additional preoperative prognostic factor.

Mutational patterns in chemotherapy resistant muscle-invasive bladder cancer

Despite continued widespread use, the genomic effects of cisplatin-based chemotherapy and implications for subsequent treatment are incompletely characterized. Here, we analyze whole exome sequencing of matched pre- and post-neoadjuvant cisplatin-based chemotherapy primary bladder tumor samples from 30 muscle-invasive bladder cancer patients. We observe no overall increase in tumor mutational burden post-chemotherapy, though a significant proportion of subclonal mutations are unique to the matched pre- or post-treatment tumor, suggesting chemotherapy-induced and/or spatial heterogeneity. We subsequently identify and validate a novel mutational signature in post-treatment tumors consistent with known characteristics of cisplatin damage and repair. We find that post-treatment tumor heterogeneity predicts worse overall survival, and further observe alterations in cell-cycle and immune checkpoint regulation genes in post-treatment tumors. These results provide insight into the clinical and genomic dynamics of tumor evolution with cisplatin-based chemotherapy, suggest mechanisms of clinical resistance, and inform development of clinically relevant biomarkers and trials of combination therapies.The impact of cisplatin-based chemotherapy on tumor genomes is complex. Here, the authors study matched pre- and post-chemotherapy primary samples in muscle-invasive bladder cancer, finding a cisplatin-based mutational signature, and highlighting the impact of intratumor heterogeneity on survival.

Is extended pharmacologic venous thromboembolism prophylaxis uniformly safe after radical cystectomy

OBJECTIVE To quantitate the risk of clinically significant renal function deterioration after radical cystectomy (RC), which could result in supratherapeutic levels of low-molecular-weight heparin (LMWH) and increased risk of bleeding events with the use of extended pharmacologic venous thromboembolism prophylaxis (EPVTEP) after hospital discharge. METHODS Patients undergoing RC between 2006 and 2011 were identified from the institutional registry. Estimated glomerular filtration rate (eGFR) was calculated and categorized as preoperative, discharge, and nadir. Perioperative eGFR trends in patients who would have been candidates for EPVTEP were evaluated. RESULTS Three hundred four patients with eGFR >30 mL/min/1.73 m(2) at the time of hospital discharge were included in the analysis as potentially eligible for EPVTEP. Large portion of patients (43%) exhibited decline in eGFR after discharge. Importantly, 13.0% of patients (n = 40), who would have qualified for EPVTEP at discharge, experienced nadir GFR below the 30-mL/min/1.73 m(2) threshold value at which LMWH would have become supratherapeutic. The odds ratio for developing a GFR <30 mL/min/1.73 m(2) was 9.1 (95% confidence interval, 4.3-19.3; P <.001), comparing those with a discharge GFR ≥60 mL/min/1.73 m(2) with those with a discharge GFR <60 mL/min/1.73 m(2). CONCLUSION More than 10% experienced an eGFR, which would have rendered LMWH supratherapeutic and potentially would have placed the patient at risk for clinically significant bleeding. Although postoperative venous thromboembolic event after RC is a recognized concern, a better understanding of the risks of EPVTEP is needed before this strategy is universally adopted in patients undergoing RC.

Perioperative Outcomes Following Partial Nephrectomy Performed on Patients Remaining on Antiplatelet Therapy

Purpose: We evaluated the risk of bleeding complications in patients undergoing partial nephrectomy in whom perioperative antiplatelet therapy was continued, as antiplatelet therapy is increasingly used and hemorrhage is a significant concern in partial nephrectomy. Materials and Methods: In this 2‐center retrospective analysis 1,097 patients underwent partial nephrectomy between 2000 and 2014. The cohort was split into 3 groups of perioperative continuation of antiplatelet therapy (group 1—67), antiplatelet therapy stopped preoperatively (group 2—254) and no chronic antiplatelet therapy (group 3—776). Bleeding complications were defined as any transfusion, or any hospital readmission or secondary procedure performed for hemorrhage. Multivariable analysis was performed to elucidate independent risk factors for bleeding complications. Results: Patients in group 1 were older (median age 66 years vs 64 and 57 years in groups 2/3, p <0.0001), and had greater comorbidity (median ASA classification score 3 vs 2 and 2, p <0.0001). Group 1 had a higher rate of bleeding complications (20.9% vs 7.1% and 6.4%, p <0.0001) and transfusions (16.4% vs 5.9% and 5.4%, p=0.002). Multivariable analysis revealed continued antiplatelet therapy was an independent predictor of bleeding complications (OR 2.19, 95% CI 1.06–4.51, p=0.03). These findings appear attributable to intraoperative clopidogrel use. On multivariable analysis the use of aspirin alone was not associated with bleeding complications (OR 1.64, 95% CI 0.72–3.75, p=0.24). Conclusions: The risk of bleeding complications due to antiplatelet therapy use at partial nephrectomy may be due to clopidogrel. The need to continue perioperative aspirin alone does not appear to be a contraindication to the safe performance of partial nephrectomy.

Molecular and Genomic Profiling to Identify Actionable Targets in Chromophobe Renal Cell Cancer

Metastatic chromophobe renal cell cancer (chRCC) is a rare subtype of RCC with no standard treatment. We performed molecular profiling of 12 chRCC cases to identify alterations predictive of response to therapy. Tests included immunohistochemistry assays, fluorescence in situ hybridization, and next-generation sequencing. Analysis identified c-KIT overexpression in 6/9 (67%) samples analyzed, and loss of protein expression of RRM1 and MGMT in 11/12 (92%) and of PTEN in 7/12 samples (58%). Mutations of TP53, PTEN, APC, and VHL genes were identified. In summary, molecular profiling of chRCC identified alterations in genes and protein expression that might provide a mechanistic rationale for off-label use of approved therapies in advanced chRCC, and could guide the design of molecularly targeted clinical trials. PATIENT SUMMARY: In this study, we evaluated samples of a rare type of kidney cancer (chromophobe type) and identified potential genetic markers that could be used to individualize treatment and possibly improve treatment outcomes.

Bcl-2 Protein Targeting by the p53/p21 Complex—Letter

Kim and colleagues reported a p53/p21 complex regulates cancer cell invasion and apoptosis by targeting the Bcl-2 family ([1][1]). Interaction of overexpressed p53 and p21 proteins in p53-null H1299 cells correlated with decreased cell invasion. No coimmunoprecipitation experiments documenting

MP88-11 IMMUNE CORRELATES OF PATHOLOGIC RESPONSE IN BLADDER CANCER PATIENTS UNDERGOING NEOADJUVANT CHEMOTHERAPY

RESULTS: High LASP1 expression correlated with metastatic recurrence rate between patients. The LASP1 expression is higher in UC1 and T24 cells than in UC13 and UC6 cells. Knockdown of LASP1 using siRNA inhibited cell growth, and was accompanied by an increase in p21 and p27, and a decreased of cyclin D1. Flow cytometry revealed that LASP1 knockdown induced G1 arrest. Conversely, stable LASP1 overexpression drove cell growth with an increase of cyclin D1 in UC6 and UC3 cells. The treatment of CDDP and GEM induced LASP1 expression in Western Blotting. Furthermore, compared with parental cell line, LASP1 is higher in T24 CDDP-R and RT112 CDDP-R cells than in parental cells. LASP1 ASO inhibited cell growth in RT112 CDDP-R and T24 CDDP-R cells. In the orthotopic bladder cancer model, systemic LASP1 ASO administration to athymic nude mice delayed tumor progression in T24 CDDP-R cells. CONCLUSIONS: These data revealed that LASP1 inhibition might be as a promising novel therapeutics modality in the treatment of chemoresistant bladder cancer.

Abstract B14: Neoantigen burden associates with chemoresponse in muscle-invasive bladder cancer patients receiving neoadjuvant chemotherapy

Background: The basis of response to chemotherapy is incompletely characterized. The immune system is increasingly recognized as both a key player in cancer control and as druggable target. We hypothesized that the immune system impacts pathologic response in patients undergoing cisplatin-based neoadjuvant chemotherapy (NAC) for muscle-invasive (≥pT2) bladder cancer though neoantigens present in tumors. Methods: Whole exome sequencing (WES) was performed on tumor DNA from patients in two independent cohorts who underwent cisplatin-based NAC. Pathologic response was defined in the cystectomy specimen. The Memorial Sloan Kettering/Dana Farber Cancer institute (MSKCC/DFCI) cohort (n=50; 25 ≤ pTis responders) and Philadelphia cohorts (n=48; 20 ≤ pTis responders) were treated with gemcitabine/ cisplatin or methotrexate/ vinblastine/ doxorubicin/ cisplatin. Mutation analysis was performed using standard analytical pipelines. Macrohistocompatibility complex (MHC)-restricted neoantigens were identified with netMHCpan and PolySolver. Wilcoxon rank sum test was used to test for significance and all tests were two-sided. Results: In both cohorts, mutation rate associated with pathologic response (p Conclusions: Mutational load and neoantigen burden correlate strongly with pathologic response to NAC. Chemotherapy may therefore exert tumor cell autonomous effects through apoptotic mechanisms and a tumor cell extrinsic effect by alerting the immune system via neoantigen presentation on dying cells. Mutation rate is likely directly correlated to neoantigen burden and both may impact patient selection for chemotherapy alone or in combination with immunotherapy agents, and development of antitumor vaccines. Experiments are underway to more directly characterize the impact of the immune system in the response to chemotherapy. Citation Format: Philip H. Abbosh, David Liu, Michael H. Johnson, Wafik S. El-Deiry, Elizabeth R. Plimack, Jonathan E. Rosenberg, Eliezer M. Van Allen. Neoantigen burden associates with chemoresponse in muscle-invasive bladder cancer patients receiving neoadjuvant chemotherapy. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Targeting the Vulnerabilities of Cancer; May 16-19, 2016; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(1_Suppl):Abstract nr B14.