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Postoperative pulmonary complications are a common cause of postoperative morbidity in patients undergoing hepatectomy. This study aimed to identify risk factors, define severity, and evaluate the impact of postoperative pulmonary complications on postoperative morbidity after hepatectomy.We used a prospective database in identifying all hepatectomies from 2013 to 2018. The database was then augmented using extensive review of medical records. The Strasburg system was used in categorizing resections per complexity: major hepatic resection and minor hepatic resection, whereas the Clavien-Dindo system was used in defining postoperative pulmonary complications per severity. Potential confounders were controlled for on multiple regression models.A total of 702 cases were identified: major hepatic resection 413 (60%) and minor hepatic resection 289 (40%). Patients demonstrated comparable characteristics, but the postoperative pulmonary complications group was more likely to have chronic obstructive pulmonary disease (10% vs 5%; P = .02). Severe postoperative pulmonary complications among major hepatectomy was observed in 38 patients (13%). Predictors for severe postoperative pulmonary complications requiring intervention included postoperative liver failure (odds ratio = 2.8; P = .002) and biliary fistula (odds ratio = 3.5; P = .001). In addition, the occurrence of severe postoperative pulmonary complications markedly hindered recovery, increasing length of stay by 4.4-fold and readmission rates by 3-fold (P.001). On multivariable analysis, postoperative pulmonary complications significantly increase postoperative length of stay (8 vs 5 days; P.001) and readmission (odds ratio = 3.2; P = .001). Mortality was similar (1% vs 4%; P = .066).Postoperative pulmonary complications are a major cause of delayed recovery and worse outcomes after hepatectomy. Further, postoperative liver failure and biliary fistula can predict the occurrence of severe postoperative pulmonary complications among major hepatic resection and the associated need for readmission with these complications.

CA9 protein levels are increased under hypoxia, but APE1 levels are not

APE1/Ref-1 protein expression affects CA9 mRNA levels in additional PDAC cell lines

Confirmation of HIF-1 deletion in MEF cells

APE1/Ref-1 interactions with STAT3 and NFκB are stimulated by IL-6 and TNFα (respectively) under normoxic conditions

Cell viability analysis used for normalization of pH data

Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer-related mortality in the United States. Aggressive treatment regimens have not changed the disease course, and the median survival has just recently reached a year. Several mechanisms are proposed to play a role in PDAC therapeutic resistance, including hypoxia, which creates a more aggressive phenotype with increased metastatic potential and impaired therapeutic efficacy. AP Endonuclease-1/Redox Effector Factor 1 (APE1/Ref-1) is a multifunctional protein possessing a DNA repair function in base excision repair and the ability to reduce oxidized transcription factors, enabling them to bind to their DNA target sequences. APE1/Ref-1 regulates several transcription factors involved in survival mechanisms, tumor growth, and hypoxia signaling. Here, we explore the mechanisms underlying PDAC cell responses to hypoxia and modulation of APE1/Ref-1 redox signaling activity, which regulates the transcriptional activation of hypoxia-inducible factor 1 alpha (HIF1α). Carbonic anhydrase IX (CA9) is regulated by HIF1α and functions as a part of the cellular response to hypoxia to regulate intracellular pH, thereby promoting cell survival. We hypothesized that modulating APE1/Ref-1 function will block activation of downstream transcription factors, STAT3 and HIF1α, interfering with the hypoxia-induced gene expression. We demonstrate APE1/Ref-1 inhibition in patient-derived and established PDAC cells results in decreased HIF1α–mediated induction of CA9. Furthermore, an ex vivo three-dimensional tumor coculture model demonstrates dramatic enhancement of APE1/Ref-1–induced cell killing upon dual targeting of APE1/Ref-1 and CA9. Both APE1/Ref-1 and CA9 are under clinical development; therefore, these studies have the potential to direct novel PDAC therapeutic treatment. Mol Cancer Ther; 15(11); 2722–32. ©2016 AACR.

APE1 expression correlates with decreased survival in PDAC and CA9 is upregulated in PDAC

Additional methods including synthesis information for one of the inhibitors used and methods used for TCGA survival analysis found in supplemental figure 7.

APE1/Ref-1 interactions with HIF1α and STAT3 are stimulated by hypoxia in Cancer-Associated Fibroblast (CAF) cells

Figure Legends for Supplemental Figures

Supplemental Digital Content is available in the text, Objective: The aim of this study was to clarify the role of pancreatic surgery during the COVID-19 pandemic to optimize patients’ and clinicians’ safety and safeguard health care capacity. Summary Background Data: The COVID-19 pandemic heavily impacts health care systems worldwide. Cancer patients appear to have an increased risk for adverse events when infected by COVID-19, but the inability to receive oncological care seems may be an even larger threat, particularly in case of pancreatic cancer. Methods: An online survey was submitted to all members of seven international pancreatic associations and study groups, investigating the impact of the COVID-19 pandemic on pancreatic surgery using 21 statements (April, 2020). Consensus was defined as >80% agreement among respondents and moderate agreement as 60% to 80% agreement. Results: A total of 337 respondents from 267 centers and 37 countries spanning 5 continents completed the survey. Most respondents were surgeons (n = 302, 89.6%) and working in an academic center (n = 286, 84.9%). The majority of centers (n = 166, 62.2%) performed less pancreatic surgery because of the COVID-19 pandemic, reducing the weekly pancreatic resection rate from 3 [interquartile range (IQR) 2–5] to 1 (IQR 0–2) (P < 0.001). Most centers screened for COVID-19 before pancreatic surgery (n = 233, 87.3%). Consensus was reached on 13 statements and 5 statements achieved moderate agreement. Conclusions: This global survey elucidates the role of pancreatic surgery during the COVID-19 pandemic, regarding patient selection for the surgical and oncological treatment of pancreatic diseases to support clinical decision-making and creating a starting point for further discussion.

Background and Hypothesis: Diagnosis of chronic pancreatitis (CP) is challenging and controversial. Magnetic Resonance Imaging (MRI) offers a noninvasive modality to diagnose CP, but its findings have been rarely correlated with histopathology. We aimed to assess the correlation of T1 signal intensity ratio of pancreas to spleen (T1 SIRp/s) and arterio-venous ratio (AVR) of the parenchyma on MRI and Cambridge score on MRCP with surgical histopathology in patients who underwent pancreatic resection. Methods: We identified 160 pancreatic resections performed in adults between 2017 and 2019 by searching our institution’s surgery database. Seventy-one of them had surgical pathology specimens available and 59 of them had MRI/MRCP within 3 months prior to the surgery. Histologic grading was performed by a gastrointestinal pathologist using Ammann’s fibrosis score. Two image analysts blinded to the clinical information and fibrosis score measured T1 SIRp/s from unenhanced T1-weighted fat-saturated gradient-echo images and arterio-venous ratio (AVR) from post-contrast dynamic phase. Cambridge score was also recorded from MRCP. Statistical analysis included Pearson’s correlation coefficient of the T1 SIRp/s, AVR, and Cambridge score with the fibrosis score and weighted kappa for interobserver agreement. Results: Correlations between T1 SIRp/s and AVR with the fibrosis score were (r= -0.30, p=0.02, 95%CI: -0.51 to -0.04 and r= -0.36, p=0.01, 95%CI: -0.58 to -0.09, respectively). In comparison, there is less correlation between the Cambridge grade and the fibrosis (r= 0.17, p=0.15, 95% CI for r= -0.07 to 0.39). Interobserver agreement was good (kappa=0.80). Conclusion: There is moderate correlation between the T1 signal intensity and enhancement ratio of the pancreas with pancreatic fibrosis. This is higher than the correlation between the Cambridge grade and fibrosis. Multi-institutional, prospective studies are needed to verify T1 SIR and AVR as potential imaging biomarkers of pancreatic fibrosis.

Aggregation is a characteristic of extensively oxidized (ox-) LDL. We wished to determine whether this structural change contributed even more to the documented poor degradation in macrophages of ox-LDL than the chemical changes. When protein degradation of the soluble and insoluble portions of extensively ox-LDL was compared to that of acetyl LDL in mouse peritoneal macrophages (MPM), we found that the percent of internalized LDL that was degraded was lowest for the insoluble portion (insol. ox-LDL), intermediate for the soluble portion (sol. ox-LDL), and highest for the acetyl LDL, regardless of whether the binding and uptake mechanisms had been excluded, e.g., by performing appropriate pulse-chase studies. As the same order of degradation was found after long-term degradation under cell-free conditions by a mixture of cathepsin B and D, it is likely that poor degradation of ox-LDL by lysosomal proteases is partially responsible for the deficient processing of ox-LDL in MPM. However, when MPM were incubated in a pulse-chase design with LDL that was induced to aggregate by vortexing without oxidizing (vx-LDL), degradation over an 18-h interval of accumulated vx-LDL was almost as low (25%) as that of insol. ox-LDL (18%), in contrast to sol. ox-LDL (60%). Yet, in a cell-free system cathepsin degradation of vx-LDL was as efficient as that of acetyl LDL and LDL. Also, the differences in degradation between sol. and insol. ox-LDL were smaller than in MPM. Thus, it appears that alternative mechanisms to poor proteolysis of substrate were responsible for poor intracellular processing of such aggregated lipoproteins. These results suggest that, although the poorer processing of insol. ox-LDL than sol. ox-LDL may be due, in part, to more deficient proteolytic degradation, particle aggregation per se may play at least as important a role in such deficiencies. This may occur by such mechanisms as altered intracellular trafficking leading to poorer fusion in macrophages of phagosomes containing aggregated lipoproteins with lysosomes.