Sally E. Hodges

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.

Pancreatic resection without routine intraperitoneal drainage

BACKGROUND Most surgeons routinely place intraperitoneal drains at the time of pancreatic resection but this practice has recently been challenged. OBJECTIVE Evaluate the outcome when pancreatic resection is performed without operatively placed intraperitoneal drains. METHODS In all, 226 consecutive patients underwent pancreatic resection. In 179 patients drains were routinely placed at the time of surgery and in 47 no drains were placed. Outcomes for these two cohorts were recorded in a prospective database and compared using the χ(2) - /Fishers exact test for categorical variables, and Wilcoxons test for continuous variables. RESULTS Demographic, surgical and pathological details were similar between the two cohorts. Elimination of routine intraperitoneal drainage did not increase the frequency or severity of serious complications. However, when all grades of complications were considered, the number of patients that experienced any complication (65% vs. 47%, P= 0.020) and the median complication severity grade (1 vs. 0, P= 0.027) were increased in the group that had drains placed at the time of surgery. Eliminating intra-operative drains was associated with decreased delayed gastric emptying (24% vs. 9%, P= 0.020) and a trend towards decreased wound infection (12% vs. 2%, P= 0.054). The readmission rate (9% vs. 17% P= 0.007) and number of patients requiring post-operative percutaneous drains (2% vs. 11%, P= 0.001) was higher in patients who did not have operatively placed drains but there was no difference in the re-operation rate (4% vs. 0%, P= 0.210). CONCLUSION Abandoning the practice of routine intraperitoneal drainage after pancreatic resection may not increase the incidence or severity of severe post-operative complications.

Intra-abdominal Fat Predicts Survival in Pancreatic Cancer

BackgroundBody mass index (BMI) has proven unreliable in predicting survival following pancreaticoduodenectomy for cancer. While measures of intra-abdominal fat correlate with medical and postoperative complications of obesity, the impact of intra-abdominal fat on pancreatic cancer survival is uncertain. We hypothesized that the quantity of intra-abdominal fat would predict survival following resection of pancreatic cancer.MethodsPreoperative CT imaging was used to measure intra-abdominal fat. Cox regression analyses were used to identify independent predictors of survival.ResultsSixty-one patients from 2000–2009 underwent pancreaticoduodenectomy for exocrine pancreatic adenocarcinoma. After adjusting for age and perineural invasion status, preoperative BMI did not predict overall survival (p < 0.827). Unlike BMI, quartile of intra-abdominal fat predicted survival. Relative to patients with the least intra-abdominal fat (lowest quartile), those with more intra-abdominal fat demonstrated worse overall survival, but in a non-linear fashion. Individuals in the second quartile showed a fourfold increase in likelihood of death (HR 4.018, 95% CI 1.099–14.687, p < 0.035) relative to the lowest quartile. Patients in the third (HR 2.124, 95% CI 0.278–16.222, p < 0.468) and fourth quartile (HR 1.354, 95% CI 0.296–6.190, p < 0.696) also showed greater risk of death.ConclusionsMeasuring intra-abdominal fat identifies a subset of patients with worse prognosis in pancreatic cancer.

A novel epigenetic CREB‐miR‐373 axis mediates ZIP4‐induced pancreatic cancer growth

Changes in the intracellular levels of the essential micronutrient zinc have been implicated in multiple diseases including pancreatic cancer; however, the molecular mechanism is poorly understood. Here, we report a novel mechanism where increased zinc mediated by the zinc importer ZIP4 transcriptionally induces miR‐373 in pancreatic cancer to promote tumour growth. Reporter, expression and chromatin immunoprecipitation assays demonstrate that ZIP4 activates the zinc‐dependent transcription factor CREB and requires this transcription factor to increase miR‐373 expression through the regulation of its promoter. miR‐373 induction is necessary for efficient ZIP4‐dependent enhancement of cell proliferation, invasion, and tumour growth. Further analysis of miR‐373 in vivo oncogenic function reveals that it is mediated through its negative regulation of TP53INP1, LATS2 and CD44. These results define a novel ZIP4‐CREB‐miR‐373 signalling axis promoting pancreatic cancer growth, providing mechanistic insights explaining in part how a zinc transporter functions in cancer cells and may have broader implications as inappropriate regulation of intracellular zinc levels plays an important role in many other diseases.

Assessment of the learning curve for pancreaticoduodenectomy

BACKGROUND Experience with the Whipple procedure has been associated with improved outcomes, but the learning curve for this complex procedure is not well defined. METHODS Outcomes with 162 consecutive Whipple procedures during the 1st 11.5 years of practice was documented in a prospective database. A period of low (≤11/y) and high (≥23/y) case volume was compared using the Wilcoxon rank-sum test and Fisher exact test. RESULTS With low case volume, blood loss was higher (800 vs 400 mL, P = .001), more patients were transfused (44% vs 18%, P = .027), there were more complications (58% vs 46%, P = .0337), and a longer length of stay (10 vs 7 days, P = .006). There was only 1 mortality (.7%). CONCLUSIONS Frequent repetition of the Whipple procedure is associated with an improvement in quantifiable quality benchmarks, and improvement continues with extensive experience. However, with proper training and the right environment, this procedure can be performed during the learning curve with acceptable outcomes.

Engineered T cells for pancreatic cancer treatment

OBJECTIVE Conventional chemotherapy and radiotherapy produce marginal survival benefits in pancreatic cancer, underscoring the need for novel therapies. The aim of this study is to develop an adoptive T cell transfer approach to target tumours expressing prostate stem cell antigen (PSCA), a tumour-associated antigen that is frequently expressed by pancreatic cancer cells. METHODS Expression of PSCA on cell lines and primary tumour samples was confirmed by immunohistochemistry. Healthy donor- and patient-derived T cells were isolated, activated in vitro using CD3/CD28, and transduced with a retroviral vector encoding a chimeric antigen receptor (CAR) targeting PSCA. The ability of these cells to kill tumour cells was analysed by chromium-51 (Cr(51)) release. RESULTS Prostate stem cell antigen was expressed on >70% of the primary tumour samples screened. Activated, CAR-modified T cells could be readily generated in clinically relevant numbers and were specifically able to kill PSCA-expressing pancreatic cancer cell lines with no non-specific killing of PSCA-negative target cells, thus indicating the potential efficacy and safety of this approach. CONCLUSIONS Prostate stem cell antigen is frequently expressed on pancreatic cancer cells and can be targeted for immune-mediated destruction using CAR-modified, adoptively transferred T cells. The safety and efficacy of this approach indicate that it deserves further study and may represent a promising novel treatment for patients with pancreatic cancer.

A tumorigenic factor interactome connected through tumor suppressor microRNA-198 in human pancreatic cancer.

Purpose: The majority of pancreatic cancers overexpress mesothelin (MSLN), which contributes to enhanced proliferation, invasion, and migration. However, the MSLN regulatory network is still unclear. Here, we investigated the regulation of a panel of tumorigenic factors and explored the potential of MSLN-regulated miR-198 treatment in vivo. Experimental Design: The expression and functional regulation of the tumorigenic factors MSLN, NF-κB, and the homeobox transcription factors (TF) POU2F2 (OCT-2), Pre-B-cell leukemia homeobox factor 1 (PBX-1), valosin-containing protein (VCP), and miR-198 were studied in pancreatic cancer cell lines, patient tumor samples, and xenograft pancreatic cancer mouse models. Results: We found that miR-198 is downregulated in pancreatic cancer and is involved in an intricate reciprocal regulatory loop with MSLN, which represses miR-198 through NF-κB–mediated OCT-2 induction. Furthermore, miR-198 repression leads to overexpression of PBX-1 and VCP. The dysregulated PBX-1/VCP axis leads to increased tumorigenicity. Reconstitution of miR-198 in pancreatic cancer cells results in reduced tumor growth, metastasis, and increased survival through direct targeting MSLN, PBX-1, and VCP. Most interestingly, reduced levels of miR-198 in human tissue samples are associated with upregulation of these tumorigenic factors (MSLN, OCT-2, PBX-1, VCP) and predict poor survival. Reduced miR-198 expression links this tumor network signature and prognosticates poor patient outcome. High miR-198 disrupts the network and predicts better prognosis and increased survival. Conclusions: miR-198 acts as a central tumor suppressor and modulates the molecular makeup of a critical interactome in pancreatic cancer, indicating a potential prognostic marker signature and the therapeutic potential of attacking this tumorigenic network through a central vantage point. Clin Cancer Res; 19(21); 5901–13. ©2013 AACR.

An assessment of the necessity of transfusion during pancreatoduodenectomy

INTRODUCTION Perioperative transfusion of packed red blood cells (PRBC) has been associated with negative side effects. We hypothesized that a majority of transfusions in our series of patients who underwent pancreaticoduodenectomy (PD) were unnecessary. A retrospective analysis was performed to determine whether transfusions were indicated based on pre-determined criteria, and the impact of perioperative transfusions on postoperative outcomes was assessed. METHODS Our prospectively maintained database was queried for patients who underwent PD between 2004 and 2011. 200 patients were divided into Cohort 1 (no transfusion) and Cohort 2 (transfusion). Rates of various graded 90-day postoperative complications were compared. Categorical values were compared according to the Common Terminology Criteria for Adverse Events. All cases involving intraoperative blood transfusion were reviewed for associated blood loss, intraoperative vital signs, urine output, hemoglobin values, and presence or absence of EKG changes to determine whether the transfusion was indicated based on these criteria. RESULTS There were 164 patients (82%) in Cohort 1 (no transfusion) and 36 patients (18%) in Cohort 2 (transfused). Both groups had similar demographics. Patients in Cohort 2 had lesser median preoperative values of hemoglobin (12.3 vs 13.1, P = .002), a greater incidence of vein resection (33% vs. 16%, P = .021), longer operative times (518 vs 440 minutes, P < .0001), a greater estimated blood loss (850 vs. 300 mL, P < .001), and greater intraoperative fluid resuscitation (6,550 vs. 5,300 mL, P = .002). Ninety-day mortality was similar between the 2 groups (3% vs 1%, P = .328). Patients in Cohort 2 (transfused) had increased rates of delayed gastric emptying (36% vs. 20%, P = .031), wound infection (28% vs. 7%, P = .031), pulmonary complications (6% vs. 0%, P = .032), and urinary retention (6% vs. 0%, P = .032). A greater incidence of any complication of grade II severity (67% vs. 35%, P = .0005) or grade III severity (36% vs. 17%, P = .010) was also noted in Cohort 2. Of the 33 intraoperative transfusions, 15 (46%) did not meet any of the predetermined criteria: intraoperative hypotension (<90/60 mmHg), tachycardia (>110 beats per minute), low urine output (<10 mL/hour), decreased oxygen saturation (<95%), excessive blood loss (>1,000 mL), EKG changes, and low hemoglobin (<7.0 g/dL). CONCLUSION Perioperative transfusions among patients with PD were associated with increased rates of various postoperative complications. A substantive portion (∼46%) of perioperative transfusions in this patient population did not meet predetermined criteria, indicating a potential opportunity for improved blood product use. Further prospective studies are required to determine whether the implementation of these criteria may a positive impact on perioperative outcomes.

Routine nasogastric suction may be unnecessary after a pancreatic resection

BACKGROUND Most surgeons routinely place a nasogastric tube at the time of a pancreatic resection. The goal of the present study was to evaluate the outcome when a pancreatic resection is performed without routine post-operative nasogastric suction. METHODS One hundred consecutive patients underwent a pancreatic resection (64 a pancreaticoduodenectomy, 98% pylorus sparing and 36 a distal pancreatectomy). In the first cohort (50 patients), a nasogastric tube was routinely placed at the time of surgery and in the second cohort (50 patients) the nasogastric was removed in the operating room. Outcomes for these two cohorts were recorded in a prospective database and compared using the χ(2) or Fishers exact test and Wilcoxons rank-sum test. RESULTS Demographical, surgical and pathological details were similar between the two cohorts. A post-operative complication occurred in 22 (44%) in each group (P= 1.000). There were no statistically significant differences in the frequency or severity of complications, or length of stay between groups. The spectrum of complications experienced by the two cohorts was similar including complications that could potentially be related to the use of nasogastric suction such as delayed gastric emptying, anastomotic leak, wound dehiscence and pneumonia. There was no difference between the two groups in the number of patients who required post-operative nasogastric tube placement (or replacement) [2 (4%) vs. 4 (8%), P= 0.678]. CONCLUSION It may be safe to place a nasogastric tube post-operatively in a minority of patients after a pancreatic resection and spare the majority the discomfort associated with routine post-operative nasogastric suction.

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 β-catenin in clinical trials, suggests future treatment decisions for these patients may be guided by genomic analysis.