Hemoglobin A1c Is a Predictor of New Insulin Dependence After Partial Pancreatectomy: A Multi-Institutional Analysis.

BACKGROUND: Pancreatic diseases have long been associated with impaired glucose control. This study sought to identify the incidence of new insulin-dependent diabetes mellitus (IDDM) after pancreatectomy and the predictive accuracy of hemoglobin A1c (HbA1c) or blood glucose. METHODS: Patients who underwent partial pancreatectomy and had preoperative HbA1c available at two academic institutions were assessed for new IDDM on discharge in relation to complication rates and survival. RESULTS: Of the 267 patients analyzed, 67% had abnormal HbA1c levels prior to surgery (mean 6.8%, glucose 135 mg/dL). Two hundred eight (77.9%) were not insulin-dependent prior to surgery, and 35 (16.8%) developed new IDDM after resection. On multivariable regression, increasing HbA1c and preoperative glucose were the only significant predictors for new IDDM. Optimal predictive cutoffs (HbA1c of 6.25% and glucose of 121 mg/dL) were determined in a discovery group (n = 143) and confirmed in a validation group (n = 124) with a diagnostic sensitivity of 72.7% and specificity of 84.8%. Patients with new IDDM after resection had higher rates of severe complications (OR 3.39), increased TPN at discharge (OR 4.32), and increased rates of discharge to nursing facilities (OR 2.57) (all P < 0.05). New IDDM was also associated with a decreased cancer-specific survival. CONCLUSION: Preoperative HbA1c ≥ 6.25% and blood glucose ≥ 121 mg/dL can accurately identify patients at increased risk of IDDM. These diagnostics may help identify patients in a preoperative setting that may benefit from interventions such as diabetes education or enhanced glucose control preoperatively.

Delayed Processing of Secretin-Induced Pancreas Fluid Influences the Quality and Integrity of Proteins and Nucleic Acids.

OBJECTIVES: Endoscopic pancreatic function tests are used to diagnose pancreatic diseases and are a viable source for the discovery of biomarkers to better characterize pancreatic disorders. However, pancreatic fluid (PF) contains active enzymes that degrade biomolecules. Therefore, we tested how preservation methods and time to storage influence the integrity and quality of proteins and nucleic acids. METHODS: We obtained PF from 9 subjects who underwent an endoscopic pancreatic function test. Samples were snap frozen at the time of collection; after 1, 2, and 4 hours on ice; or after storage overnight at 4°C with or without RNase or protease inhibitors (PIs). Electrophoresis and mass spectrometry analysis determined protein abundance and quality, whereas nucleic acid integrity values determined DNA and RNA degradation. RESULTS: Protein degradation increased after 4 hours on ice and DNA degradation after 2 hours on ice. Adding PIs delayed degradation. RNA was significantly degraded under all conditions compared with the snap frozen samples. Isolated RNA from PF-derived exosomes exhibited similar poor quality as RNA isolated from matched PF samples. CONCLUSIONS: Adding PIs immediately after collecting PF and processing the fluid within 4 hours of collection maintains the protein and nucleic acid integrity for use in downstream molecular analyses.

Long-Term Assessment of Pancreatic Function After Pancreatectomy for Cystic Neoplasms.

BACKGROUND: With advances in cross-sectional imaging, pancreatic cysts are more frequently diagnosed and have become a common indication for pancreatectomy. The impact of pancreatectomy in these patients is important. The purpose of this study was to assess short-term outcomes, long-term nutritional status, quality of life (QOL), and pancreas function after pancreatectomy for cystic neoplasms. MATERIALS AND METHODS: At a single institution, patients at least 3 y post-pancreatectomy for benign cystic neoplasms were identified. Using a validated questionnaire, short-term outcomes, long-term outcomes including endocrine and exocrine insufficiency, long-term nutritional status, and preoperative and postoperative QOL were compared based on operation and indication for resection. RESULTS: Among 102 eligible patients, 70 had valid contact information and 51 (72.9%) agreed to participate. Median follow-up was 6 (4-8) y. Patients undergoing pancreatoduodenectomy for benign cysts had higher morbidity than a similar cohort resected for pancreatic adenocarcinoma (patients with at least 1 ≥ grade 2 complication [49.0% versus 31.6%, P = 0.038]). After long-term follow-up, pancreatectomy did not significantly affect perceived QOL. Half of patients had mild-moderate or severe malnourishment, but pancreatic enzyme replacement was reported by only 4 (7.8%) patients. New-onset diabetes was present in 15 (29.4%) patients with median time-to-diagnosis of 6 (1-12) mo after resection. CONCLUSIONS: Pancreatectomy for benign cysts did not negatively impact patients' perceived QOL. However, after long-term follow-up, malnutrition and pancreatic insufficiency occurred in a significant percentage and may be greater than previously estimated. Consideration of short- and long-term outcomes should factor into preoperative counseling, especially in cysts with minimal risk of progression to malignancy.

Evidence Versus Practice in Early Drain Removal After Pancreatectomy.

BACKGROUND: Early drain removal when postoperative day (POD) one drain fluid amylase (DFA) was ≤5000 U/L reduced complications in a previous randomized controlled trial. We hypothesized that most surgeons continue to remove drains late and this is associated with inferior outcomes. METHODS: We assessed the practice of surgeons in a prospectively maintained pancreas surgery registry to determine the association between timing of drain removal with demographics, comorbidities, and complications. We selected patients with POD1 DFA ≤5000 U/L and excluded those without drains, and subjects without data on POD1 DFA or timing of drain removal. Early drain removal was defined as ≤ POD5. RESULTS: Two hundred and forty four patients met inclusion criteria. Only 90 (37%) had drains removed early. Estimated blood loss was greater in the late removal group (190 mL versus 100 mL, P = 0.005) and pathological findings associated with soft gland texture were more frequent (97 [63%] versus 35 [39%], P < 0.0001). Patients in the late drain removal group had more complications (84 [55%] versus 30 [33%], P = 0.001) including pancreatic fistula (55 [36%] versus 4 [4%], P < 0.0001), delayed gastric emptying (27 [18%] versus 3 [3%], P = 0.002), and longer length of stay (7 d versus 5 d, P < 0.0001). In subset analysis for procedure type, complications and pancreatic fistula remained significant for both pancreatoduodenectomy and distal pancreatectomy. CONCLUSIONS: Despite level one data suggesting improved outcomes with early removal when POD1 DFA is ≤ 5000 U/L, experienced pancreas surgeons more frequently removed drains late. This practice was associated with known risk factors (estimated blood loss, soft pancreas) and may be associated with inferior outcomes suggesting potential for improvement.

SRC-3 inhibition blocks tumor growth of pancreatic ductal adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) is a highly malignant and lethal disease with few treatment options. Steroid receptor coactivator-3 (SRC-3, also known as NCOA3, AIB1, pCIP, ACTR, RAC3, TRAM1) sits at the nexus of many growth signaling pathways and has been pursued as a therapeutic target for breast, prostate and lung cancers. In this study, we find that SRC-3 is overexpressed in PDAC and inversely correlates with patient overall survival. Knockdown of SRC-3 reduces pancreatic cancer cell proliferation, migration and invasion in vitro. Additionally, inhibition of SRC-3 using either shRNA or a small molecule inhibitor can significantly inhibit tumor growth in orthotopic pancreatic cancer mouse models. Collectively, this study establishes SRC-3 as a promising therapeutic target for pancreatic cancer treatment.

Standard Operating Procedures for Biospecimen Collection, Processing, and Storage: From the Consortium for the Study of Chronic Pancreatitis, Diabetes, and Pancreatic Cancer.

High-quality and well-annotated biorepositories are needed to better understand the pathophysiology and biologic mechanisms of chronic pancreatitis (CP) and its consequences. We report a methodology for the development of a robust standard operating procedure (SOP) for a biorepository based on the experience of the clinical centers within the consortium to study Chronic Pancreatitis, Diabetes and Pancreas Cancer Clinical Centers (CPDPC), supported by the National Cancer Institute and the National Institute for Diabetes and Digestive and Kidney Diseases as a unique multidisciplinary model to study CP, diabetes, and pancreatic cancer in both children and adults. Standard operating procedures from the CPDPC centers were evaluated and consolidated. The literature was reviewed for standard biorepository operating procedures that facilitated downstream molecular analysis. The existing literature on biobanking practices was harmonized with the SOPs from the clinical centers to produce a biorepository for pancreatic research. This article reports the methods and basic principles behind the creation of SOPs to develop a biorepository for the CPDPC. These will serve as a guide for investigators developing biorepositories in pancreas research. Rigorous and meticulous adherence to standardized biospecimen collection will facilitate investigations to better understand the pathophysiology and biologic mechanisms of CP, diabetes, and pancreatic cancer.

Venous thrombosis following pancreaticoduodenectomy with venous resection.

BACKGROUND: Addition of en bloc segmental venous reconstruction (VR) to pancreaticoduodenectomy (PD) for venous involvement of pancreatic tumors increases the complexity of the operation and may increase complications. The long-term mesenteric venous patency rate and oncologic outcome has not been well defined. METHODS: Our prospective database was reviewed to assess 90-day postoperative outcomes for patients who underwent PD or PD + VR (September 2004-June 2016). Two independent observers reviewed CT scans to determine long-term vein patency. In patients with pancreatic ductal adenocarcinoma, the impact of VR on 5-year overall survival was assessed using multivariate Cox proportional hazards regression. Student's t-test was used to evaluate continuous variables and the chi-square test for categorical variables. RESULTS: Three hundred ninety-three patients underwent PD (51 PD + VR). Patients undergoing PD + VR had longer operations (561 ± 119 versus 433 ± 89 min, P < 0.00001) and greater blood loss (768 ± 812 versus 327 ± 423 cc, P < 0.00001). There was no difference in 90-day mortality, overall postoperative complication rates, complication severity grades, reoperation, readmission, or length of stay. 26.7% experienced venous thrombosis. Most thromboses occurred in the first year after surgery, but we also observed late thrombosis in 1 patient after 89-month follow-up. Among 135 patients with pancreatic ductal adenocarcinoma, survival was significantly longer in the PD-alone group (31.3 months [95% confidence interval: 22.9-40.0] versus 17.0 [95% confidence interval: 13.0-19.1], plog-rank = 0.013). CONCLUSIONS: PD + VR does not increase short-term morbidity, but venous thrombosis is frequent and can occur long after surgery. Survival is inferior when VR is required especially in the absence of neoadjuvant chemotherapy.

Sequential drain amylase to guide drain removal following pancreatectomy.

BACKGROUND: Although used as criterion for early drain removal, postoperative day (POD) 1 drain fluid amylase (DFA) ≤ 5000 U/L has low negative predictive value for clinically relevant postoperative pancreatic fistula (CR-POPF). It was hypothesized that POD3 DFA ≤ 350 could provide further information to guide early drain removal. METHODS: Data from a pancreas surgery consortium database for pancreatoduodenectomy and distal pancreatectomy patients were analyzed retrospectively. Those patients without drains or POD 1 and 3 DFA data were excluded. Patients with POD1 DFA ≤ 5000 were divided into groups based on POD3 DFA: Group A (≤350) and Group B (>350). Operative characteristics and 60-day outcomes were compared using chi-square test. RESULTS: Among 687 patients in the database, all data were available for 380. Fifty-five (14.5%) had a POD1 DFA > 5000. Among 325 with POD1 DFA ≤ 5000, 254 (78.2%) were in Group A and 71 (21.8%) in Group B. Complications (35 (49.3%) vs 87 (34.4%); p = 0.021) and CR-POPF (13 (18.3%) vs 10 (3.9%); p < 0.001) were more frequent in Group B. CONCLUSIONS: In patients with POD1 DFA ≤ 5000, POD3 DFA ≤ 350 may be a practical test to guide safe early drain removal. Further prospective testing may be useful.

A Prospective Randomized Multicenter Trial of Distal Pancreatectomy With and Without Routine Intraperitoneal Drainage.

OBJECTIVE: The objective of this study was to test the hypothesis that distal pancreatectomy (DP) without intraperitoneal drainage does not affect the frequency of grade 2 or higher grade complications. BACKGROUND: The use of routine intraperitoneal drains during DP is controversial. Prior to this study, no prospective trial focusing on DP without intraperitoneal drainage has been reported. METHODS: Patients undergoing DP for all causes at 14 high-volume pancreas centers were preoperatively randomized to placement of a drain or no drain. Complications and their severity were tracked for 60 days and mortality for 90 days. The study was powered to detect a 15% positive or negative difference in the rate of grade 2 or higher grade complications. All data were collected prospectively and source documents were reviewed at the coordinating center to confirm completeness and accuracy. RESULTS: A total of 344 patients underwent DP with (N = 174) and without (N = 170) the use of intraperitoneal drainage. There were no differences between cohorts in demographics, comorbidities, pathology, pancreatic duct size, pancreas texture, or operative technique. There was no difference in the rate of grade 2 or higher grade complications (44% vs. 42%, P = 0.80). There was no difference in clinically relevant postoperative pancreatic fistula (18% vs 12%, P = 0.11) or mortality (0% vs 1%, P = 0.24). DP without routine intraperitoneal drainage was associated with a higher incidence of intra-abdominal fluid collection (9% vs 22%, P = 0.0004). There was no difference in the frequency of postoperative imaging, percutaneous drain placement, reoperation, readmission, or quality of life scores. CONCLUSIONS: This prospective randomized multicenter trial provides evidence that clinical outcomes are comparable in DP with or without intraperitoneal drainage.

Delayed gastric emptying following pancreaticoduodenectomy: Incidence, risk factors, and healthcare utilization.

AIM: To characterize incidence and risk factors for delayed gastric emptying (DGE) following pancreaticoduodenectomy and examine its implications on healthcare utilization. METHODS: A prospectively-maintained database was reviewed. DGE was classified using International Study Group of Pancreatic Surgery criteria. Patients who developed DGE and those who did not were compared. RESULTS: Two hundred and seventy-six patients underwent pancreaticoduodenectomy (PD) (> 80% pylorus-preserving, antecolic-reconstruction). DGE developed in 49 patients (17.8%): 5.1% grade B, 3.6% grade C. Demographic, clinical, and operative variables were similar between patients with DGE and those without. DGE patients were more likely to present multiple complications (32.6% vs 4.4%, ≥ 3 complications, P < 0.001), including postoperative pancreatic fistula (POPF) (42.9% vs 18.9%, P = 0.001) and intra-abdominal abscess (IAA) (16.3% vs 4.0%, P = 0.012). Patients with DGE had longer hospital stay (median, 12 d vs 7 d, P < 0.001) and were more likely to require transitional care upon discharge (24.5% vs 6.6%, P < 0.001). On multivariate analysis, predictors for DGE included POPF [OR = 3.39 (1.35-8.52), P = 0.009] and IAA [OR = 1.51 (1.03-2.22), P = 0.035]. CONCLUSION: Although DGE occurred in < 20% of patients after PD, it was associated with increased healthcare utilization. Patients with POPF and IAA were at risk for DGE. Anticipating DGE can help individualize care and allocate resources to high-risk patients.

Nutritional and Metabolic Derangements in Pancreatic Cancer and Pancreatic Resection.

Pancreatic cancer is an aggressive malignancy with a poor prognosis. The disease and its treatment can cause significant nutritional impairments that often adversely impact patient quality of life (QOL). The pancreas has both exocrine and endocrine functions and, in the setting of cancer, both systems may be affected. Pancreatic exocrine insufficiency (PEI) manifests as weight loss and steatorrhea, while endocrine insufficiency may result in diabetes mellitus. Surgical resection, a central component of pancreatic cancer treatment, may induce or exacerbate these dysfunctions. Nutritional and metabolic dysfunctions in patients with pancreatic cancer lack characterization, and few guidelines exist for nutritional support in patients after surgical resection. We reviewed publications from the past two decades (1995-2016) addressing the nutritional and metabolic status of patients with pancreatic cancer, grouping them into status at the time of diagnosis, status at the time of resection, and status of nutritional support throughout the diagnosis and treatment of pancreatic cancer. Here, we summarize the results of these investigations and evaluate the effectiveness of various types of nutritional support in patients after pancreatectomy for pancreatic adenocarcinoma (PDAC). We outline the following conservative perioperative strategies to optimize patient outcomes and guide the care of these patients: (1) patients with albumin < 2.5 mg/dL or weight loss > 10% should postpone surgery and begin aggressive nutrition supplementation; (2) patients with albumin < 3 mg/dL or weight loss between 5% and 10% should have nutrition supplementation prior to surgery; (3) enteral nutrition (EN) should be preferred as a nutritional intervention over total parenteral nutrition (TPN) postoperatively; and, (4) a multidisciplinary approach should be used to allow for early detection of symptoms of endocrine and exocrine pancreatic insufficiency alongside implementation of appropriate treatment to improve the patient's quality of life.

Pancreatic endometrial cyst mimics mucinous cystic neoplasm of the pancreas.

Pancreatic cysts include a variety of benign, premalignant, and malignant lesions. Endometrial cysts in the pancreas are exceedingly rare lesions that are difficult to diagnose pre-operatively. This report describes the findings in a 43-year-old patient with a recent episode of acute pancreatitis who presented with a large cyst in the tail of the pancreas. Imaging demonstrated a loculated pancreatic cyst, and cyst fluid aspiration revealed an elevated amylase and carcinoembryonic antigen. The patient experienced an interval worsening of abdominal pain, fatigue, diarrhea, and a 15-pound weight loss 3 mo after the initial episode of pancreatitis. With concern for a possible pre-malignant lesion, the patient underwent a laparoscopic distal pancreatectomy with splenectomy, which revealed a 16 cm × 12 cm × 4 cm lesion. Final histopathology was consistent with an intra-pancreatic endometrial cyst. Here we discuss the overlapping imaging and laboratory features of pancreatic endometrial cysts and mucinous cystic neoplasms of the pancreas.

Incorporation of Procedure-specific Risk Into the ACS-NSQIP Surgical Risk Calculator Improves the Prediction of Morbidity and Mortality After Pancreatoduodenectomy.

OBJECTIVE: This multicenter study sought to evaluate the accuracy of the American College of Surgeons National Surgical Quality Improvement Program's (ACS-NSQIP) surgical risk calculator for predicting outcomes after pancreatoduodenectomy (PD) and to determine whether incorporating other factors improves its predictive capacity. BACKGROUND: The ACS-NSQIP surgical risk calculator has been proposed as a decision-support tool to predict complication risk after various operations. Although it considers 21 preoperative factors, it does not include procedure-specific variables, which have demonstrated a strong predictive capacity for the most common and morbid complication after PD - clinically relevant pancreatic fistula (CR-POPF). The validated Fistula Risk Score (FRS) intraoperatively predicts the occurrence of CR-POPF and serious complications after PD. METHODS: This study of 1480 PDs involved 47 surgeons at 17 high-volume institutions. Patient complication risk was calculated using both the universal calculator and a procedure-specific model that incorporated the FRS and surgeon/institutional factors. The performance of each model was compared using the c-statistic and Brier score. RESULTS: The FRS was significantly associated with 30-day mortality, 90-day mortality, serious complications, and reoperation (all P < 0.0001). The procedure-specific model outperformed the universal calculator for 30-day mortality (c-statistic: 0.79 vs 0.68; Brier score: 0.020 vs 0.021), 90-day mortality, serious complications, and reoperation. Neither surgeon experience nor institutional volume significantly predicted mortality; however, surgeons with a career PD volume >450 were less likely to have serious complications (P < 0.001) or perform reoperations (P < 0.001). CONCLUSIONS: Procedure-specific complication risk influences outcomes after pancreatoduodenectomy; therefore, risk adjustment for performance assessment and comparative research should consider these preoperative and intraoperative factors along with conventional ACS-NSQIP preoperative variables.

Ampullary Cancers Harbor ELF3 Tumor Suppressor Gene Mutations and Exhibit Frequent WNT Dysregulation.

The ampulla of Vater is a complex cellular environment from which adenocarcinomas arise to form a group of histopathologically heterogenous tumors. To evaluate the molecular features of these tumors, 98 ampullary adenocarcinomas were evaluated and compared to 44 distal bile duct and 18 duodenal adenocarcinomas. Genomic analyses revealed mutations in the WNT signaling pathway among half of the patients and in all three adenocarcinomas irrespective of their origin and histological morphology. These tumors were characterized by a high frequency of inactivating mutations of ELF3, a high rate of microsatellite instability, and common focal deletions and amplifications, suggesting common attributes in the molecular pathogenesis are at play in these tumors. The high frequency of WNT pathway activating mutation, coupled with small-molecule inhibitors of ß-catenin in clinical trials, suggests future treatment decisions for these patients may be guided by genomic analysis.

The Characterization and Prediction of ISGPF Grade C Fistulas Following Pancreatoduodenectomy.

INTRODUCTION: International Study Group of Pancreatic Fistula (ISGPF) grade C postoperative pancreatic fistulas (POPF) are the greatest contributor to major morbidity and mortality following pancreatoduodenectomy (PD); however, their infrequent occurrence has hindered deeper analysis. This study sought to develop a predictive algorithm, which could facilitate effective management of this challenging complication. METHODS: Data were accrued from 4301 PDs worldwide. Demographics, postoperative management, and microbiological characteristics of grade C POPFs were evaluated. American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP) preoperative and intraoperative variables were compared between grade C POPFs and a 639-case sample of non-grade C POPFs. Risk factors for grade C POPF formation were identified using regression analysis. RESULTS: Grade C POPFs developed in 79 patients (1.8 %). Deaths (90 days) occurred in 2.0 % (N = 88) of the overall series, with 35 % (N = 25) occurring in the presence of a grade C POPF. Reoperations occurred 72.2 % of the time. The rates of single- and multi-system organ failure were 28.2 and 39.7 %, respectively. Mortality rates escalated with pulmonary, renal, and neurologic organ failure, but they were unaffected by reoperation(s). The median number of complications incurred was four (IQR: 2-5), and the median duration of hospital stay was 32 (IQR: 21-54) days. Warning signs for impending grade C POPFs most often presented on postoperative day (POD) 6. Adjuvant chemotherapy might have benefited 55.7 % of grade C POPF patients, yet it was delayed in 25.6 % and never delivered in 67.4 % of these patients. Predictive models for grade C POPF occurrence based on preoperative factors alone and preoperative and intraoperative factors yielded areas under the receiver operating characteristic curve of 0.73 and 0.84 (both P < 0.000001), respectively. CONCLUSION: This global study represents the largest analysis of grade C POPFs following PD. It describes the severe burden that grade C POPFs incur on patients, with high rates of reoperation and infection, while also potentially worsening overall survival by causing death and delay/omission of adjuvant therapy. Additionally, aggressive clinical management for these POPFs did not improve or worsen 90-day mortality. Predictive tools developed through these data may provide value in managing this difficult complication.

The value of drains as a fistula mitigation strategy for pancreatoduodenectomy: something for everyone? Results of a randomized prospective multi-institutional study.

BACKGROUND: A recent randomized, controlled trial investigating intraperitoneal drain use during pancreatoduodenectomy (PD) had a primary goal of assessing overall morbidity. It was terminated early with findings that routine elimination of drains in PD increases mortality and the severity and frequency of overall complications. Here, we provide a follow-up analysis of drain value in reference to clinically relevant postoperative pancreatic fistula (CR-POPF). METHODS: Nine institutions performed 137 PDs, with patients randomized to intraperitoneal drainage (N = 68) or no drainage (N = 69). The Fistula Risk Score (FRS), a 10-point scale derived from four validated risk factors for CR-POPF, facilitated risk adjustment between treatment groups. RESULTS: There was no difference in fistula risk between the two cohorts. Overall, CR-POPF rates were higher in the no drain group compared to the drain group (20.3 vs. 13.2%; p = 0.269). Patients with negligible/low FRS risk had higher rates of CR-POPF when drains were used (14.8 vs. 4.0%; p = 0.352). Conversely, there were significantly fewer CR-POPFs (12.2 vs. 29.5%; p = 0.050) when drains were used with moderate/high risk patients. Lastly, moderate/high risk patients who suffered a CR-POPF had reduced 90-day mortality (22.2 vs. 42.9%) when a drain was used. CONCLUSION: The results of this analysis suggest that drains diminish the rate and severity of CR-POPF in patients with moderate/high risk, but they could possibly be avoided in the roughly one third of patients with negligible/low risk.

Antiproliferative effects and mechanisms of liver X receptor ligands in pancreatic ductal adenocarcinoma cells.

Pancreatic ductal adenocarcinoma (PDAC) is difficult to detect early and is often resistant to standard chemotherapeutic options, contributing to extremely poor disease outcomes. Members of the nuclear receptor superfamily carry out essential biological functions such as hormone signaling and are successfully targeted in the treatment of endocrine-related malignancies. Liver X receptors (LXRs) are nuclear receptors that regulate cholesterol homeostasis, lipid metabolism, and inflammation, and LXR agonists have been developed to regulate LXR function in these processes. Intriguingly, these compounds also exhibit antiproliferative activity in diverse types of cancer cells. In this study, LXR agonist treatments disrupted proliferation, cell-cycle progression, and colony-formation of PDAC cells. At the molecular level, treatments downregulated expression of proteins involved in cell cycle progression and growth factor signaling. Microarray experiments further revealed changes in expression profiles of multiple gene networks involved in biological processes and pathways essential for cell growth and proliferation following LXR activation. These results establish the antiproliferative effects of LXR agonists and potential mechanisms of action in PDAC cells and provide evidence for their potential application in the prevention and treatment of PDAC.

A randomized prospective multicenter trial of pancreaticoduodenectomy with and without routine intraperitoneal drainage.

OBJECTIVE: To test by randomized prospective multicenter trial the hypothesis that pancreaticoduodenectomy (PD) without the use of intraperitoneal drainage does not increase the frequency or severity of complications. BACKGROUND: Some surgeons have abandoned the use of drains placed during pancreas resection. METHODS: We randomized 137 patients to PD with (n = 68, drain group) and without (n = 69, no-drain group) the use of intraperitoneal drainage and compared the safety of this approach and spectrum of complications between the 2 groups. RESULTS: There were no differences between drain and no-drain cohorts in demographics, comorbidities, pathology, pancreatic duct size, pancreas texture, baseline quality of life, or operative technique. PD without intraperitoneal drainage was associated with an increase in the number of complications per patient [1 (0-2) vs 2 (1-4), P = 0.029]; an increase in the number of patients who had at least 1 ≥grade 2 complication [35 (52%) vs 47 (68%), P = 0.047]; and a higher average complication severity [2 (0-2) vs 2 (1-3), P = 0.027]. PD without intraperitoneal drainage was associated with a higher incidence of gastroparesis, intra-abdominal fluid collection, intra-abdominal abscess (10% vs 25%, P = 0.027), severe (≥grade 2) diarrhea, need for a postoperative percutaneous drain, and a prolonged length of stay. The Data Safety Monitoring Board stopped the study early because of an increase in mortality from 3% to 12% in the patients undergoing PD without intraperitoneal drainage. CONCLUSIONS: This study provides level 1 data, suggesting that elimination of intraperitoneal drainage in all cases of PD increases the frequency and severity of complications.