Faculty Bibliography

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.

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.

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.

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.

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.