Faculty Bibliography

PURPOSE:SARS-CoV-2 (COVID-19) is a systemic infection. Patients with cancer are immunocompromised and may be vulnerable to COVID-related morbidity and mortality. The objectives of this study were to determine if patients with cancer have worse outcomes compared with patients without cancer and to identify demographic and clinical predictors of morbidity and mortality among patients with cancer. METHODS:We used data from adult patients who tested positive for COVID-19 and were admitted to two New York-Presbyterian hospitals between March 3 and May 15, 2020. Patients with cancer were matched 1:4 to controls without cancer in terms of age, sex, and number of comorbidities. Using Kaplan-Meier curves and the log-rank test, we compared morbidity (intensive care unit admission and intubation) and mortality outcomes between patients with cancer and controls. Among those with cancer, we identified demographic and clinical predictors of worse outcomes using Cox proportional hazard models. RESULTS:= .894) between patients with and without cancer. CONCLUSION:We observed that patients with COVID-19 and cancer had similar outcomes compared with matched patients without cancer. This finding suggests that a diagnosis of active cancer alone and recent anticancer therapy do not predict worse COVID-19 outcomes and therefore, recommendations to limit cancer-directed therapy must be considered carefully in relation to cancer-specific outcomes and death.

PURPOSE/OBJECTIVE:The neutrophil-to-lymphocyte ratio (NLR) is associated with decreased overall survival in patients with pancreatic adenocarcinoma (PAC) in studies including few minority patients. We investigated the association between NLR and survival in patients with advanced PAC in an ethnically diverse population. METHODS:We retrospectively evaluated 226 patients with advanced PAC treated at Montefiore Medical Center between 2006 and 2015. Adjusted Cox proportion hazard regression models were utilized to derive effect estimates for survival duration. RESULTS:Patients with a NLR ≤ 5 (126 patients, median age 66 years) were more likely to be non-Hispanic Black (30.8% vs. 20%), while patients with a NLR > 5 (70 patients, median age 66 years) were more likely to be non-Hispanic White (21.4% vs. 12.2%) or Hispanic (44.3% vs. 34%). A NLR > 5 compared with a NLR ≤ 5 was significantly associated with a worse overall survival when adjusted for a priori and exploratory variables from the univariate analysis (median survival 7.4 vs. 12 months, HR 1.650, 95% CI 1.139, 2.390). CONCLUSIONS:In an ethnically diverse population, elevated NLR is an independent marker of poor prognosis and a potentially valuable factor in driving therapeutic decisions and defining prognosis for patients in the locally advanced or metastatic for PAC setting, meriting investigation in prospective clinical trials.

Sarcomatoid urothelial carcinoma (SUC) is a rare subtype of urothelial carcinoma (UC) that typically presents at an advanced stage compared to more common variants of UC. Locally advanced and metastatic UC have a poor long-term survival following progression on first-line platinum-based chemotherapy. Antibodies directed against the programmed cell death 1 protein (PD-1) or its ligand (PD-L1) are now approved to be used in these scenarios. The need for reliable biomarkers for treatment stratification is still under research. Here, we present a novel case report of the first Imaging Mass Cytometry (IMC) analysis done in SUC to investigate the immune cell repertoire and PD-L1 expression in a patient who presented with metastatic SUC and experienced a prolonged response to the anti-PD1 immune checkpoint inhibitor pembrolizumab after progression on first-line chemotherapy. This case report provides an important platform for translating these findings to a larger cohort of UC and UC variants.

BACKGROUND:Non-Hispanic blacks (NHB) with renal cell carcinoma (RCC) are more likely to have papillary RCC (pRCC) than non-Hispanic whites (NHW). Data on histologic subtypes in RCC in Hispanics (H) are also sparse. Previous studies have shown that pRCC is more prevalent in NHB than in NHW, but they analyzed predominantly NHW populations. The Montefiore-Einstein Center for Cancer Care (MECC) serves a predominantly NHB and H population in the Bronx, NY. We investigated histologic subtype specific associations with established RCC risk factors in this population. PATIENTS AND METHODS:The MECC tumor registry was used to identify patients ≥ 18 years of age treated with partial or radical nephrectomy between January 2000 and December 2015. An institutional software program and individual chart review were used to obtain demographic data (including self-reported race, age, and sex), pathology data, and RCC risk factors (hypertension, diabetes, renal function, weight). Data were modeled by multinomial logistic regression to estimate odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS:A total of 1010 RCC cases were identified. Of these, 232 (23.0%) occurred in NHW, 383 (37.9%) NHB, 181 (17.9%) H, and 214 (21.2%) other. A total of 530 cases (52.5%) were clear cell (ccRCC) histology, 257 (25.4%) pRCC, 100 (9.9%) chromophobe (cRCC), and 123 (12.2%) other. Individuals with pRCC compared to ccRCC were more likely to be NHB than NHW (OR, 4.41; 95% CI, 2.81-6.93) but were less likely to be female (OR, 0.50; 95% CI, 0.35-0.72). Individuals with pRCC were also less likely to be H than NHW (OR, 0.52; 95% CI, 0.27-0.99). Patients with cRCC were also more likely to be NHB than NHW (OR, 2.23; 95% CI, 1.06-4.67). CONCLUSION:In the MECC data set, histology of RCC varies by race, confirming earlier reports that non-ccRCC is more common in NHB than NHW. We also report that pRCC is less common in H than NHW.

Primary brain tumors, both benign and malignant, pose a high risk of perioperative venous thromboembolism (VTE) due to the development of a prothrombotic state. Perioperative pharmacologic thromboprophylaxis with subcutaneous (SC) unfractionated heparin (UFH) has significantly reduced VTE associated morbidity. Recent reports suggest an association between prolonged activated partial thromboplastin time (aPTT) due to prophylactic SC UFH and increased bleeding risk. We present three patients with normal baseline coagulation parameters in whom pharmacologic thromboprophylaxis with SC UFH resulted in a marked prolongation of the aPTT, leading to adverse outcomes in two patients. These cases demonstrate the uncertain kinetics of SC UFH and effect on aPTT, suggesting the significance of routine aPTT monitoring in high-risk settings. Given the wide variation in presentations of therapeutic or supratherapeutic values of aPTT in the perioperative neurosurgical setting, we propose a practical standardized approach to the evaluation and management of aPTT prolongation following prophylactic SC UFH administration.

The majority of colorectal cancers show hyperactivated WNT signaling due to inactivating mutations in the adenomatous polyposis coli (APC) tumor suppressor. Genetically restoring APC suppresses WNT and induces rapid and sustained tumor regression, implying that reengaging this endogenous tumor-suppressive mechanism may be an effective therapeutic strategy. Here, using new animal models, human cell lines, and ex vivo organoid cultures, we show that tankyrase (TNKS) inhibition can control WNT hyperactivation and provide long-term tumor control in vivo, but that effective responses are critically dependent on how APC is disrupted. Mutant APC proteins truncated within the mutation cluster region physically engage the destruction complex and suppress the WNT transcriptional program, while APC variants with early truncations (e.g., Apc^Min) show limited interaction with AXIN1 and β-catenin, and do not respond to TNKS blockade. Together, this work shows that TNKS inhibition, like APC restoration, can reestablish endogenous control of WNT/β-catenin signaling, but that APC genotype is a crucial determinant of this response. SIGNIFICANCE: This study reveals how subtle changes to the mutations in a critical colorectal tumor suppressor, APC, influence the cellular response to a targeted therapy. It underscores how investigating the specific genetic alterations that occur in human cancer can identify important biological mechanisms of drug response and resistance.This article is highlighted in the In This Issue feature, p. 1325.

Tankyrase (TNKS) 1/2 are positive regulators of WNT signaling by controlling the activity of the ß-catenin destruction complex. TNKS inhibitors provide an opportunity to suppress hyperactive WNT signaling in tumors, however, they have shown limited anti-proliferative activity as a monotherapy in human cancer cell lines. Here we perform a kinome-focused CRISPR screen to identify potential effective drug combinations with TNKS inhibition. We show that the loss of CDK4, but not CDK6, synergizes with TNKS1/2 blockade to drive G1 cell cycle arrest and senescence. Through precise modelling of cancer-associated mutations using cytidine base editors, we show that this therapeutic approach is absolutely dependent on suppression of canonical WNT signaling by TNKS inhibitors and is effective in cells from multiple epithelial cancer types. Together, our results suggest that combined WNT and CDK4 inhibition might provide a potential therapeutic strategy for difficult-to-treat epithelial tumors.

Objectives Although non-O blood type is an established risk factor for venous thromboembolism in the general population, the impact of ABO blood type (ABO) on venous thromboembolism risk in individuals with persistent antiphospholipid antibodies (aPL) has not been studied. We sought to investigate the relationship between ABO and venous thromboembolism in aPL-positive individuals. We also sought to explore potential interactions between ABO and sex or race to determine whether ABO contributes to race or sex differences with respect to the development of venous thromboembolism. Methods We identified all patients over 18 years old followed at a tertiary medical center between January 2000 and January 2015 with serological aPL criteria and ABO data. Episodes of venous thromboembolism were recorded. Logistic regression models were fitted to estimate odds ratios (ORs) of venous thromboembolism for non-O (A, B, or AB blood types) versus O blood type. Results There were 226 patients included in the final analysis, of whom 75 (33%) had reported venous thromboembolism. In the overall sample, there was a non-significant difference between venous thromboembolism in patients with non-O blood type compared to O blood type (OR 1.64, 95% confidence interval (CI) 0.94, 2.88; P = 0.08). Men with non-O blood type had a significantly higher risk of venous thromboembolism as compared to men with O-type blood (OR 4.94, 95% CI 1.37, 17.85; P = 0.02), but there was no significant association between ABO and venous thromboembolism among women (OR 0.96, 95% CI 0.50, 1.83; P = 0.52). Conclusions Non-O blood type may be an under-recognized risk factor for venous thromboembolism among men with persistent aPL antibodies, whereas the risk associated with non-O blood type seen in the general population may be attenuated in aPL-positive women.