Chemotherapy-Induced Inflammatory Gene Signature and Protumorigenic Phenotype in Pancreatic CAFs via Stress-Associated MAPK.

UNLABELLED: Pancreatic ductal adenocarcinoma (PDAC) has a characteristically dense stroma comprised predominantly of cancer-associated fibroblasts (CAF). CAFs promote tumor growth, metastasis, and treatment resistance. This study aimed to investigate the molecular changes and functional consequences associated with chemotherapy treatment of PDAC CAFs. Chemoresistant immortalized CAFs (R-CAF) were generated by continuous incubation in gemcitabine. Gene expression differences between treatment-naïve CAFs (N-CAF) and R-CAFs were compared by array analysis. Functionally, tumor cells (TC) were exposed to N-CAF- or R-CAF-conditioned media and assayed for migration, invasion, and viability in vitro Furthermore, a coinjection (TC and CAF) model was used to compare tumor growth in vivo R-CAFs increased TC viability, migration, and invasion compared with N-CAFs. In vivo, TCs coinjected with R-CAFs grew larger than those accompanied by N-CAFs. Genomic analysis demonstrated that R-CAFs had increased expression of various inflammatory mediators, similar to the previously described senescence-associated secretory phenotype (SASP). In addition, SASP mediators were found to be upregulated in response to short duration treatment with gemcitabine in both immortalized and primary CAFs. Inhibition of stress-associated MAPK signaling (P38 MAPK or JNK) attenuated SASP induction as well as the tumor-supportive functions of chemotherapy-treated CAFs in vitro and in vivo These results identify a negative consequence of chemotherapy on the PDAC microenvironment that could be targeted to improve the efficacy of current therapeutic regimens. IMPLICATIONS: Chemotherapy treatment of pancreatic cancer-associated fibroblasts results in a proinflammatory response driven by stress-associated MAPK signaling that enhances tumor cell growth and invasiveness. Mol Cancer Res; 14(5); 437-47. ©2016 AACR.

Limitations of ACS-NSQIP in reporting complications for patients undergoing pancreatectomy: underscoring the need for a pancreas-specific module.

BACKGROUND: Large centralized databases are used with increasing frequency for reporting hospital-specific and nationwide trends and outcomes after various surgical procedures in order to improve quality of surgical care. American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP) is a risk-adjusted, case-weighted complication tracking initiative that reports 30-day outcomes from more than 400 academic and community institutions in the US. However, the accuracy of event reporting specific to pancreatic surgery has never been examined in depth. METHODS: We retrospectively reviewed medical records of patients, the information on whose postoperative course was originally reported through ACS-NSQIP between 2006 and 2010. Preoperative characteristics, operative data, and postoperative events were recorded after review of electronic medical records including physician and nursing notes, operative room records and anesthesiologist reports. Fidelity of reported clinical events was assessed. Accuracy, sensitivity, and specificity were calculated for each variable of interest. RESULTS: Two hundred and forty-nine pancreatectomies were reviewed, including 145 (58.2 %) Whipple procedures, 19 (7.6 %) total pancreatectomies, 65 (26.1 %) distal pancreatectomies, and 15 (6.0 %) central or partial resections. Median age was 65.7, males comprised 41.5 % of the group, and 74.3 % of patients were Caucasian. The overall rate of complications reported by NSQIP was 44.0 %, compared with 45.0 % in our review, however discordance was observed in 27.3 % of the time, including 34 cases of reporting a complication where there was not one, and 34 cases of missed complication. The most frequently reported event was postoperative bleeding requiring transfusion, however this was also the event most commonly misclassified. Additionally, three procedures unrelated to the index operation were recorded as reoperation events. While a pancreas-specific module does not yet exist, ACS-NSQIP reports a 7.6 % rate of organ-space surgical site infections; when compared with our institutional rate of Grades B and C postoperative fistula (10.4 %), we observed discordance 4.4 % of the time. Delayed gastric emptying, a common post-pancreatectomy morbidity, was not captured at all. Additionally, there were significant inaccuracies in reporting urinary tract infections, postoperative pneumonia, wound complications, and postoperative sepsis, with discordance rates of 4.4, 3.2, 3.6, and 6.8 %, respectively. CONCLUSIONS: ACS-NSQIP data are an important and valuable tool for evaluating quality of surgical care, however pancreatectomy-specific postoperative events are often misclassified, underscoring the need for a hepatopancreatobiliary-specific module to better capture key outcomes in this complex and unique patient population.

Short-term but not long-term loss of patency of venous reconstruction during pancreatic resection is associated with decreased survival.

BACKGROUND: Pancreatic surgery with vascular reconstruction is increasingly performed to offer the benefits of surgical resection to patients with locally advanced disease. The short- and long-term patency rates and the clinical significance of thrombosis of such reconstructions are unknown. METHODS: We reviewed pancreatectomies requiring venous reconstruction from 1994 to 2011. We sought to identify predictors of acute (within 30 days) and late thrombosis. We compared survival of patients with thrombosis to patients with patent reconstructions. RESULTS: Of 203 pancreatectomies requiring venous reconstruction, acute thrombosis occurred in nine (4.4 %) cases and was associated with increased perioperative mortality (22.2 versus 4.6 %, p = 0.023). Even when nonfatal, acute thrombosis was associated with decreased median survival (7.1 versus 15.9 months, p = 0.011) and increased hazard of death (hazard ratio 8.6, confidence interval 3.7-19.9, p < 0.001). A late loss of patency was seen in 31.2 % of cases at a median of 9.5 months. Later loss of patency was not associated with decreased median survival or increased hazard of death. CONCLUSIONS: Acute thrombosis of the portal venous reconstructions after pancreatectomy is associated with increased perioperative mortality and, even when nonfatal, is associated with decreased survival. Late loss of patency occurs in one-third of patients but does not affect survival.

Readmission after pancreatic resection is not an appropriate measure of quality.

BACKGROUND: Hospital readmission has been proposed as a metric for quality of medical and surgical care. We examined our institutional experience with readmission after pancreatic resection, and assessed factors predictive of readmission. METHODS: We reviewed 787 pancreatic resections performed at a single institution between 2006 and 2010. Univariate and multivariate logistic regression models were used to assess the relationships between preoperative and postoperative characteristics and readmission. Reasons for hospital readmission were examined in detail. RESULTS: We found the 30-day readmission rate after pancreatic resection to be 11.6 %. In univariate analysis, young age, pancreaticoduodenectomy versus other operations, open versus laparoscopic technique, fistula formation, the need for reoperation, and any complication during the index hospitalization were predictive of readmission. In multivariate analysis, only young age and postoperative complication were predictive of readmission. Vascular resection, postoperative ICU care, length of stay, and discharge disposition were not associated with readmission. The most common reasons for readmission were leaks, fistulas, abscesses, and wound infections (45.1 %), delayed gastric emptying (12.1 %), venous thrombosis (7.7 %), and GI bleeding (7.7 %). CONCLUSIONS: We found the vast majority of readmissions after pancreatic resection were to manage complications related to the operation and were not due to poor coordination of care or poor discharge planning. Because evidence-based measures to prevent these surgical complications do not exist, we cannot support the use of readmission rates themselves as a quality indicator after pancreatic surgery.