Proteostasis Dysregulation in Pancreatic Cancer

The most common form of pancreatic cancer, pancreatic ductal adenocarcinoma (PDAC), has a dismal 5-year survival rate of less than 5%. Radical surgical resection, in combination with adjuvant chemotherapy, provides the best option for long-term patient survival. However, only approximately 20% of patients are resectable at the time of diagnosis, due to locally advanced or metastatic disease. There is an urgent need for the identification of new, specific, and more sensitive biomarkers for diagnosis, prognosis, and prediction to improve the treatment options for pancreatic cancer patients. Dysregulation of proteostasis is linked to many pathophysiological conditions, including various types of cancer. In this review, we report on findings relating to the main cellular protein degradation systems, the ubiquitin-proteasome system (UPS) and autophagy, in pancreatic cancer. The expression of several components of the proteolytic network, including E3 ubiquitinligases and deubiquitinating enzymes, are dysregulated in PDAC, which accounts for approximately 90% of all pancreatic malignancies. In the future, a deeper understanding of the emerging role of proteostasis in pancreatic cancer has the potential to provide clinically relevant biomarkers and new strategies for combinatorial therapeutic options to better help treat the patients.Peer reviewe

CA19-9 Normalization During Pre-operative Treatment Predicts Longer Survival for Patients with Locally Progressed Pancreatic Cancer

BACKGROUND: Compared to the widely-adopted 2–4 months of pre-operative therapy for patients with borderline resectable (BR) or locally advanced (LA) pancreatic ductal adenocarcinoma (PDAC), our institution tends to administer a longer duration before considering surgical resection. Using this unique approach, the aim of this study was to determine preoperative variables associated with survival. METHODS: Records from patients with BR/LA PDAC who underwent attempt at surgical resection from 1992–2014 were reviewed. RESULTS: After a median duration of 6 months of pre-operative treatment, 109 patients with BR/LA PDAC (BR 63, LA 46) were explored; 93 (85.3%) underwent pancreatectomy. Those who received at least 6 months of pre-operative treatment had longer median overall survival (OS) than those who received less (52.8 vs. 32.1 months, P=0.044). On multivariate analysis, pre-operative treatment duration was the strongest predictor of survival (hazard ratio (HR) 4.79, P=0.043). However, OS was similar in those whose CA19-9 normalized regardless of whether they received more or less than 6 months of chemotherapy (71.4 vs. 101.8 months, P=0.930). CONCLUSIONS: Pre-operative CA19-9 decline can guide treatment duration in patients with BR/LA PDAC. We endorse 6 months of therapy except in those patients whose values normalize, where surgery can be considered after a shorter course

Predictors of Short-Term Diabetes Remission After Laparoscopic Roux-en-Y Gastric Bypass

A remission of type 2 diabetes mellitus (T2DM) is one of the major goals of the contemporary bariatric surgery. The goal of our study is to identify predictors of short-term postoperative diabetes remission in order to facilitate preoperative patient selection. Two hundred forty-five obese (body mass index (BMI) ≥35 kg/m2) T2DM subjects who underwent laparoscopic Roux-en-Y gastric bypass (RYGB) were followed up to 1 year after bariatric surgery. Diabetes remission was defined as hemoglobin A1c (HbA1c) ≤6 % and fasting blood glucose (FBG) <100 mg/dl in absence of all diabetic medications. Twenty-six percent of the patients seen in f/u achieved complete remission at 1 year. Average Hba1c decreased from 8 to 6.7% and 6.4% after 6 and 12 months, respectively. Regression analysis showed that age (p = 0.01), number of diabetes complications (p = 0.03), family history of diabetes (p = 0.04), preoperative use of insulin (p = 0.04), and peri- and postoperative weight loss (p = 0.05, for both) were the best preoperative predictors of diabetes remission at 6 and 12 months (R(2) = 0.3). Younger patients, with fewer diabetic complications, no family history of diabetes, not using insulin, and with greater peri- and postoperative weight loss were the best candidates to achieve a rapid diabetes remission after RYGB