• Avinoam Nevler, Samantha Z Brown, David Nauheim, Carla Portocarrero, Ulrich Rodeck, Jonathan Bassig, Christopher W Schultz, Grace A McCarthy, Harish Lavu, Theresa P Yeo, Charles J Yeo, and Jonathan R Brody.
• Jefferson Pancreas, Biliary, and Related Cancer Center, Department of Surgery, Thomas Jefferson University, Philadelphia, PA. Electronic address: Avinoam.nevler@jefferson.edu.
• J. Am. Coll. Surg. 2020 Apr 1; 230 (4): 659-667.

BackgroundChronic obstructive respiratory disorders (ORDs) are linked to increased rates of cancer-related deaths. Little is known about the effects of hypercapnia (elevated CO2) on development of pancreatic ductal adenocarcinoma (PDAC) and drug resistance.Study DesignTwo PDAC cell lines were exposed to normocapnic (5% CO2) and hypercapnic (continuous/intermittent 10% CO2) conditions, physiologically similar to patients with active ORD. Cells were assessed for proliferation rate, colony formation, and chemo-/radiotherapeutic efficacy. In a retrospective clinical study design, patients with PDAC who had undergone pancreatic resection between 2002 and 2014 were reviewed. Active smokers were excluded to remove possible smoking-related protumorigenic influence. Clinical data, pathologic findings, and survival end points were recorded. Kaplan-Meier and Cox regression analyses were performed.ResultsExposure to hypercapnia resulted in increased colony formation and proliferation rates in vitro in both cell lines (MIA-PaCa-2: 111% increase and Panc-1: 114% increase; p < 0.05). Hypercapnia exposure induced a 2.5-fold increase in oxaliplatin resistance (p < 0.05) in both cell lines and increased resistance to ionizing radiation in MIA-PaCa-2 cells (p < 0.05). Five hundred and seventy-eight patients were included (52% were male, median age was 68.7 years [interquartile range 60.6 to 76.8 years]). Cox regression analysis, assessing TNM staging, age, sex, and ORD status, identified ORD as an independent risk factor for both overall survival (hazard ratio 1.64; 95% CI, 1.2 to 2.3; p < 0.05) and disease-free survival (hazard ratio 1.68; 95% CI, 1.06 to 2.67).ConclusionsPDAC cells exposed to hypercapnic environments, which is common in patients with ORD, showed tumor proliferation, radioresistance, and chemoresistance. Patients with a history of ORD had a worse overall prognosis, suggesting that hypercapnic conditions play a role in the development and progression of PDAC and stressing the need for patient-tailored care.Copyright © 2020 American College of Surgeons. Published by Elsevier Inc. All rights reserved.

28 keywords...

hide…