Pharmacologic ascorbate treatment (P-AscH À , high-dose, intravenous vitamin C) results in a transient short-term increase in the flux of hydrogen peroxide that is preferentially cytotoxic to cancer cells versus normal cells. This study examines whether an increase in hydrogen peroxide is sustained posttreatment and potential mechanisms involved in this process. Cellular bioenergetic profiling following treatment with P-AscH À was examined in tumorigenic and nontumorigenic cells. P-AscH À resulted in sustained increases in the rate of cellular oxygen consumption (OCR) and reactive oxygen species (ROS) in tumor cells, with no changes in nontumorigenic cells. Sources for this increase in ROS and OCR were DUOX 1 and 2, which are silenced in pancreatic ductal adenocarcinoma, but upregulated with P-AscH À treatment. An inducible catalase system, to test causality for the role of hydrogen peroxide, reversed the P-AscH À -induced increases in DUOX, whereas DUOX inhibition partially rescued P-AscH Àinduced toxicity. In addition, DUOX was significantly downregulated in pancreatic cancer specimens compared with normal pancreas tissues. Together, these results suggest that P-AscH Àinduced toxicity may be enhanced by late metabolic shifts in tumor cells, resulting in a feed-forward mechanism for generation of hydrogen peroxide and induction of metabolic stress through enhanced DUOX expression and rate of oxygen consumption.Significance: A high dose of vitamin C, in addition to delivering an acute exposure of H 2 O 2 to tumor cells, activates DUOX in pancreatic cancer cells, which provide sustained production of H 2 O 2 .

Introduction The use of bariatric surgery in the management of obesity and its related morbidity has significantly increased in the US over the past decade. There is a lack of data on the impact of optimal preoperative glycemic control on the morbidity and mortality following bariatric surgery. The aim of this study was to analyze the impact of hemoglobin (Hb) A1c > 7 on outcomes among patients undergoing Roux-en-Y gastric bypass (RYGB) or sleeve gastrectomy (SG). Methods Data were extracted from the Metabolic and Bariatric Surgery Accreditation and Quality Improvement Program (2017) and limited to patients undergoing an elective laparoscopic RYGB or SG. Multivariable logistic regression was conducted to adjust for other preoperative variables. Results A total number of 31,060 (69.3%) patients underwent SG, while 13,754 (30.7%) received RYGB. Patients who were older, male, non-Hispanic, smokers, and those with a higher American Society of Anesthesiologist Classification (ASA) score were more likely to have elevated HbA1c levels. Compared to individuals with normal HbA1c levels, patients with elevated levels had no significant difference in mortality (p = 0.902) but did have a difference in composite morbidity and mortality (p < 0.001). On multivariable analysis, elevated HbA1c, older age, increasing body mass index (BMI), elevated creatinine, longer operations, African American race, receiving RYGB, and having a trainee as surgical assistant were found to increase the odds of having an adverse outcome. No significant difference was found within smoking status, sex, ASA Classification, robotic vs laparoscopic, or if a second attending surgeon was assisting. Conclusions HbA1c levels and presence of trainees in the OR are modifiable preoperative risk factors for adverse events following bariatric surgery. Improving preoperative glycemic control may be an effective and achievable quality improvement measure.

The current obesity pandemic has a clear impact on quality of life and health resource utilization; hence it has become a significant global health concern. Multiple obesity-related comorbidities such as gastroesophageal reflux disease (GERD) are frequently observed among this patient population. GERD is a complex disease with multiple elements contributing to the failure of the anti-reflux barrier. If left untreated, the excessive reflux of gastric contents into the esophagus can give rise to multiple complications such as esophagitis, strictures, metaplasia, and cancer. When surgical treatment of GERD is indicated in an obese patient, adequate preoperative evaluation and treatment are critical to achieve durable resolution of symptoms attributed to GERD as well as other obesity related comorbidities. To maximize the potential for a positive outcome, when suitable, gastric bypass surgery rather than sleeve gastrectomy or fundoplication should be strongly considered in the obese patient with GERD.

Reactive oxygen species (ROS) are a normal byproduct of cellular metabolism and are required components in cell signaling and immune responses. However, an imbalance of ROS can lead to oxidative stress in various pathological states. Increases in oxidative stress are one of the hallmarks in cancer cells, which display an altered metabolism when compared to corresponding normal cells. Extracellular superoxide dismutase (EcSOD) is an antioxidant enzyme that catalyzes the dismutation of superoxide anion (O2−) in the extracellular environment. By doing so, this enzyme provides the cell with a defense against oxidative damage by contributing to redox balance. Interestingly, EcSOD expression has been found to be decreased in a variety of cancers, and this loss of expression may contribute to the development and progression of malignancies. In addition, recent compounds can increase EcSOD activity and expression, which has the potential for altering this redox signaling and cellular proliferation. This review will explore the role that EcSOD expression plays in cancer in order to better understand its potential as a tool for the detection, predicted outcomes and potential treatment of malignancies.

ObjectivesPharmacological ascorbate (P-AscH−, high-dose, intravenous vitamin C) has shown promise as an adjuvant therapy for pancreatic ductal adenocarcinoma (PDAC) treatment. The objective of this study was to determine the effects of P-AscH− when combined with PDAC chemotherapies.MethodsClonogenic survival, combination indices, and DNA damage were determined in human PDAC cell lines treated with P-AscH− in combination with 5-fluorouracil, paclitaxel, or FOLFIRINOX (combination of leucovorin, 5-fluorouracil, irinotecan, oxaliplatin). Tumor volume changes, overall survival, blood analysis, and plasma ascorbate concentration were determined in vivo in mice treated with P-AscH− with or without FOLFIRINOX.ResultsP-AscH− combined with 5-fluorouracil, paclitaxel, or FOLFIRINOX significantly reduced clonogenic survival in vitro. The DNA damage, measured by γH2AX protein expression, was increased after treatment with P-AscH−, FOLFIRINOX, and their combination. In vivo, tumor growth rate was significantly reduced by P-AscH−, FOLFIRINOX, and their combination. Overall survival was significantly increased by the combination of P-AscH− and FOLFIRINOX. Treatment with P-AscH− increased red blood cell and hemoglobin values but had no effect on white blood cell counts. Plasma ascorbate concentrations were significantly elevated in mice treated with P-AscH− with or without FOLFIRINOX.ConclusionsThe addition of P-AscH− to standard of care chemotherapy has the potential to be an effective adjuvant for PDAC treatment.