Publications by authors named "George Van Buren"

42 Publications

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

J Gastrointest Surg 2021 May 4. Epub 2021 May 4.

Division of Surgical Oncology, Department of Surgery, The Ohio State University Wexner Medical Center, Arthur G. James Cancer Hospital and Solove Research Institute, 395 W. 12th Avenue, Suite 670, Columbus, OH, 43210-1267, USA.

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.
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http://dx.doi.org/10.1007/s11605-021-05014-0DOI Listing
May 2021

Diagnostic Laparoscopy Improves Staging of Malignant Pleural Mesothelioma with Routine PET Imaging.

Ann Thorac Surg 2020 Dec 1. Epub 2020 Dec 1.

The Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, Texas.

Background: With a multimodal treatment strategy, cytoreductive surgery extends survival in malignant pleural mesothelioma. Improving the accuracy of staging can refine patient selection. Our objective was to determine whether diagnostic laparoscopy (DL) improves staging for patients with malignant pleural mesothelioma with routine use of positron emission tomography.

Methods: We performed a retrospective review of our prospectively maintained database from February 2014 until May 2019. Inclusion criteria were patients who had disease in the chest that was deemed potentially resectable by radiographic criteria and who underwent DL as part of staging evaluation prior to surgery.

Results: 187 patients (71% male, 80% epithelial) underwent DL during staging. 76% proceeded to surgery. 22% were unresectable at exploratory thoracotomy and 78% underwent resection (Pleurectomy and decortication, 68%; extrapleural pneumonectomy, 32%). 89% had a position-emission tomography-computed tomographic scan (PET-CT) and 11% had a pre-operative CT without PET. DL revealed peritoneal disease in 17%. Among patients with pathologically proven disease at DL, 77% had negative PET-CT imaging. Based upon the pathologic findings at DL, the sensitivity, specificity, positive predictive value, and negative predictive value of PET-CT were 23%, 78%, 17%, and 83%, respectively. The accuracy of PET-CT was 68%.

Conclusions: PET-CT has low sensitivity and diagnostic accuracy to identify peritoneal disease in malignant pleural mesothelioma. DL as part of pre-operative staging defines an important subset of patients with bicavitary disease. We recommend DL as a component of staging prior to surgery.
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http://dx.doi.org/10.1016/j.athoracsur.2020.08.113DOI Listing
December 2020

The Landmark Series: Mitigation of the Postoperative Pancreatic Fistula.

Ann Surg Oncol 2021 Feb 21;28(2):1052-1059. Epub 2020 Oct 21.

Department of Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.

Pancreatic fistula has been the defining complication and challenge of pancreatic surgery. Better awareness and mitigation of postoperative pancreatic fistulas has led to significant improvements in morbidity and mortality of pancreatic surgery. The definition and management of pancreatic fistulas has sequentially progressed over the last three decades; the literature ranges from retrospective, observational studies to prospective multicenter randomized controlled trials. The landmark literature contributions driving the perioperative management of pancreatic fistulas are detailed in this article.
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http://dx.doi.org/10.1245/s10434-020-09251-6DOI Listing
February 2021

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

J Surg Res 2020 03 15;247:547-555. Epub 2019 Nov 15.

Michael E DeBakey Department of Surgery, Baylor College of Medicine, Houston, Texas. Electronic address:

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.
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http://dx.doi.org/10.1016/j.jss.2019.09.045DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8094044PMC
March 2020

Novel Methylated DNA Markers Discriminate Advanced Neoplasia in Pancreatic Cysts: Marker Discovery, Tissue Validation, and Cyst Fluid Testing.

Am J Gastroenterol 2019 09;114(9):1539-1549

Division of Gastroenterology & Hepatology, Mayo Clinic, Rochester, Minnesota, USA.

Objectives: Pancreatic cystic lesions (PCLs) may be precancerous. Those likely to harbor high-grade dysplasia (HGD) or pancreatic cancer (PC) are targets for surgical resection. Current algorithms to predict advanced neoplasia (HGD/PC) in PCLs lack diagnostic accuracy. In pancreatic tissue and cyst fluid (CF) from PCLs, we sought to identify and validate novel methylated DNA markers (MDMs) that discriminate HGD/PC from low-grade dysplasia (LGD) or no dysplasia (ND).

Methods: From an unbiased whole-methylome discovery approach using predefined selection criteria followed by multistep validation on case (HGD or PC) and control (ND or LGD) tissues, we identified discriminant MDMs. Top candidate MDMs were then assayed by quantitative methylation-specific polymerase chain reaction on archival CF from surgically resected PCLs.

Results: Of 25 discriminant MDMs identified in tissue, 13 were selected for validation in 134 CF samples (21 cases [8 HGD, 13 PC], 113 controls [45 ND, 68 LGD]). A tree-based algorithm using 2 CF-MDMs (TBX15, BMP3) achieved sensitivity and specificity above 90%. Discrimination was significantly better by this CF-MDM panel than by mutant KRAS or carcinoembryonic antigen, with areas under the receiver operating characteristic curve of 0.93 (95% confidence interval: 0.86-0.99), 0.71 (0.57-0.85), and 0.72 (0.60-0.84), respectively. Cutoffs for the MDM panel applied to an independent CF validation set (31 cases, 56 controls) yielded similarly high discrimination, areas under the receiver operating characteristic curve = 0.86 (95% confidence interval: 0.77-0.94, P = 0.2).

Discussion: Novel MDMs discovered and validated in tissue accurately identify PCLs harboring HGD/PC. A panel of 2 MDMs assayed in CF yielded results with potential to enhance current risk prediction algorithms. Prospective studies are indicated to optimize and further evaluate CF-MDMs for clinical use.
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http://dx.doi.org/10.14309/ajg.0000000000000284DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7294458PMC
September 2019

Mutant p53 promotes cancer initiation in the pancreas by stabilizing HSP70.

Cancer Lett 2019 07 1;453:122-130. Epub 2019 Apr 1.

Division of Gastroenterology and Hepatology, Department of Internal Medicine, The University of Texas McGovern Medical School, Houston, TX, 77030, USA. Electronic address:

Pancreatic cancer remains a highly lethal malignancy. We have recently shown that simultaneous expression of Kras and mutant Tp53 promotes invasive ductal adenocarcinoma from pancreatic ductal cells. We hypothesized specific mutations in TP53 have divergent mechanisms of transforming ductal cells. In order to understand the role of mutant TP53 in transforming pancreatic ductal cells, we used a lentiviral system to express mutant TP53 and TP53, two of the most frequently mutated TP53 alleles in pancreatic cancer patients, in immortalized, but not transformed, pancreatic ductal epithelial cells carrying a KRAS mutation (HPNE:KRAS). Mutant TP53 expression enhanced colony formation and an RPPA assay results revealed TP53 uniquely induced HSP70 expression in HPNE:KRAS cells. In the context of TP53 expression; we observed nuclear localization of HSP70. We performed immunoprecipitation experiments to show mutant p53 binds to HSP70. We also provide evidence mutant p53 is important for HSP70 stability and, more importantly, HSP70 is required for mutant p53 stability. These data are critical in the context of events leading to cellular transformation in the pancreas.
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http://dx.doi.org/10.1016/j.canlet.2019.03.047DOI Listing
July 2019

Mesothelin and TGF-α predict pancreatic cancer cell sensitivity to EGFR inhibitors and effective combination treatment with trametinib.

PLoS One 2019 28;14(3):e0213294. Epub 2019 Mar 28.

Michael E. DeBakey Department of Surgery, Division of Surgical Research, Baylor College of Medicine, Houston, Texas, United States of America.

Clinical trials of EGFR inhibitors in combination with gemcitabine for the treatment of pancreatic ductal adenocarcinoma (PDAC) have generated mixed results partially due to the poorly defined effectiveness of EGFR inhibitors in PDAC. Here, we studied a panel of PDAC cell lines to compare the IC50s of the EGFR inhibitors gefitinib and cetuximab. We found that gefitinib induced biphasic inhibition in over 50% of PDAC cells, with the initial growth inhibition occurring at nanomolar concentrations and a second growth inhibition occurring outside the clinical range. In contrast to gefitinib, cetuximab produced a single phase growth inhibition in a subset of PDAC cells. Using this sensitivity data, we screened for correlations between cell morphology proteins and EGFR ligands to EGFR inhibitor sensitivity, and found that mesothelin and the EGFR ligand TGF-α have a strong correlation to gefitinib and cetuximab sensitivity. Analysis of downstream signaling pathways indicated that plc-γ1 and c-myc were consistently inhibited by EGFR inhibitor treatment in sensitive cell lines. While an inconsistent additive effect was observed with either cetuximab or gefitinib in combination with gemcitabine, the cell pathway data indicated consistent ERK activation, leading us to pursue EGFR inhibitors in combination with trametinib, a MEK1/2 inhibitor. Both cetuximab and gefitinib in combination with trametinib produced an additive effect in all EGFR sensitive cell lines. Our results indicate that mesothelin and TGF-α can predict PDAC sensitivity to EGFR inhibitors and a combination of EGFR inhibitors with trametinib could be a novel effective treatment for PDAC.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0213294PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6438513PMC
December 2019

Evidence Versus Practice in Early Drain Removal After Pancreatectomy.

J Surg Res 2019 04 4;236:332-339. Epub 2019 Jan 4.

Baylor College of Medicine, Michael E. DeBakey Department of Surgery, Houston, TX. Electronic address:

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.
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http://dx.doi.org/10.1016/j.jss.2018.11.048DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6377814PMC
April 2019

Pancreatic Incidentalomas: A Management Algorithm for Identifying Ectopic Spleens.

J Surg Res 2019 04 17;236:144-152. Epub 2018 Dec 17.

Elkins Pancreas Center, Michael E DeBakey Department of Surgery, Baylor College of Medicine, Houston, Texas. Electronic address:

Background: Identification of incidental pancreatic lesions is increasing because of advancements in imaging. Diagnosis remains a challenge for clinicians, with intrapancreatic accessory spleens (IPAS) posing a unique dilemma. IPAS are frequently resected because of inability to exclude alternate diagnoses, subjecting patients to unnecessary risk. The purpose of this study was to examine our institutional experience with IPAS and develop a multidisciplinary algorithm to improve preoperative diagnosis.

Materials And Methods: Patients who underwent a distal pancreatectomy at a single institution from 2005 to 2018 were identified from a prospectively maintained database. Examination of final pathology for a diagnosis of IPAS yielded the final cohort. Demographics, preoperative workup, and operative course were reviewed and analyzed. A diagnostic algorithm was composed based on the consensus of a panel of expert pancreatic surgeons, a radiologist, and a pathologist.

Results: Ten patients of 303 patients who underwent a distal pancreatectomy were identified with a final pathology of IPAS. The average age was 54 y, 80% were white, and 60% were male. Lesions ranged in size from 7 mm to 5.1 cm in largest diameter (mean 2.2 cm). Lesions were described as round, well-marginated, and enhancing masses within the pancreatic tail. Preoperative workup was variable in terms of imaging and laboratory testing. Diagnostic workups were examined and combined with multidisciplinary input to create a diagnostic algorithm.

Conclusions: Incidental pancreatic lesions like IPAS remain a diagnostic challenge for clinicians. Employing a diagnostic algorithm as proposed may aid in the distinction of malignant and premalignant pathology and prevent unwarranted pancreatic resections.
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http://dx.doi.org/10.1016/j.jss.2018.11.032DOI Listing
April 2019

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

Cancer Lett 2019 02 10;442:310-319. Epub 2018 Nov 10.

Department of Pharmacology and Chemical Biology, Baylor College of Medicine, Houston, TX, 77030, USA; Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, 77030, USA. Electronic address:

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.
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http://dx.doi.org/10.1016/j.canlet.2018.11.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6311429PMC
February 2019

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

Pancreas 2018 Nov/Dec;47(10):1213-1221

Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, and Comprehensive Cancer Center, The Ohio State University Wexner Medical Center, Columbus, OH.

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.
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http://dx.doi.org/10.1097/MPA.0000000000001171DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6197069PMC
March 2019

Understaging of clinical stage I pancreatic cancer and the impact of multimodality therapy.

Surgery 2019 02 20;165(2):307-314. Epub 2018 Sep 20.

Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, TX; Center for Innovations in Quality, Effectiveness and Safety, Michael E. DeBakey VA Medical Center, Houston, TX. Electronic address:

Background: Although current guidelines recommend multimodal therapy for all patients with pancreatic ductal adenocarcinoma, it is unclear the extent to which clinical stage I patients are accurately staged and how this may affect management.

Methods: In this retrospective cohort study of 4,404 patients aged 18-79 years with clinical stage 1 (ie, T1N0 or T2N0) pancreatic ductal adenocarcinoma treated with upfront resection in the National Cancer Database (2004-2014), understaging was ascertained by comparing pretreatment clinical stage with pathologic stage. The association between adjuvant treatment and overall risk of death among true stage I and understaged patients was evaluated using multivariable Cox regression.

Results: Upstaging was identified in 72.6% of patients (62.8% T3/4, 53.9% N1) of whom 69.7% received adjuvant therapy compared with 47.0% with true stage I disease. Overall survival at 5 years among those with true stage I disease was significantly higher than those who had been clinically understaged (42.9% vs 16.6%; log-rank, p < 0.001). For true stage I patients, adjuvant therapy was not associated with risk of death (hazard ratio: 1.07, 95% confidence interval: 0.89-1.29). For understaged patients, adjuvant therapy significantly decreased risk of death (hazard ratio: 0.64, 95% confidence interval: 0.55-0.74).

Conclusion: The majority of clinical stage I pancreatic ductal adenocarcinoma patients actually have higher-stage disease and benefit from multimodal therapy; however, one third of understaged patients do not receive any adjuvant treatment. Clinicians should discuss all potential treatment strategies with patients (in the context of the acknowledged risks and benefits), including the utilization of neoadjuvant approaches in those presenting with potentially resectable disease.
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http://dx.doi.org/10.1016/j.surg.2018.08.003DOI Listing
February 2019

Venous thrombosis following pancreaticoduodenectomy with venous resection.

J Surg Res 2018 08 13;228:271-280. Epub 2018 Apr 13.

Baylor College of Medicine, The Elkins Pancreas Center, Michael E. DeBakey Department of Surgery, Houston, Texas. Electronic address:

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], p = 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.
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http://dx.doi.org/10.1016/j.jss.2018.02.006DOI Listing
August 2018

Sequential drain amylase to guide drain removal following pancreatectomy.

HPB (Oxford) 2018 06 23;20(6):514-520. Epub 2018 Feb 23.

Baylor College of Medicine, Michael E. DeBakey Department of Surgery, One Baylor Plaza Suite 404D, Houston, TX 77030, USA. Electronic address:

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.
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http://dx.doi.org/10.1016/j.hpb.2017.11.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5995628PMC
June 2018

Evidence-Based Management of Drains Following Pancreatic Resection: A Systematic Review.

Pancreas 2018 01;47(1):12-17

From the Elkins Pancreas Center and the Department of Surgery at Baylor College of Medicine, Houston TX.

Many pancreatic surgeons continue to use intraperitoneal drains, but others have limited or avoided their use, believing this improves outcomes. We conducted a systematic review and meta-analysis of the literature assessing outcomes in pancreatectomy without drains, selective drainage, and early drain removal. We searched PubMed, Embase, and the Cochrane Library databases and conducted a systematic review of randomized and nonrandomized studies comparing routine intra-abdominal drainage versus no drainage, selective drain use, and early versus late drain removal after pancreatectomy, with major complications as the primary outcome. A meta-analysis of the literature assessing routine use of drains was conducted using the random-effects model. A total of 461 articles met search criteria from PubMed (168 articles), Embase (263 articles), and the Cochrane Library (30 articles). After case reports and articles without primary data on complications were excluded, 14 studies were identified for systematic review. Definitive evidence-based recommendations cannot be made regarding the management of drains following pancreatectomy because of limitations in the available literature. Based on available evidence, the most conservative approach, pending further data, is routine placement of a drain and early removal unless the patient's clinical course or drain fluid amylase concentration suggests a developing fistula.
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http://dx.doi.org/10.1097/MPA.0000000000000961DOI Listing
January 2018

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

Ann Surg 2017 09;266(3):421-431

*Michael E. DeBakey Department of Surgery, Baylor College of Medicine, The Elkins Pancreas Center, Houston, TX †Dan L. Duncan Cancer Center, Houston, TX ‡Department of Surgery, The Ohio State University, Columbus, OH §Department of Surgery, Baptist Memorial Hospital, University of Tennessee Health Science Center, Memphis, TN ¶Department of Surgery, Indiana University, Indianapolis, IN ||Department of Surgery, University of Calgary, Calgary, Alberta, Canada **Department of Surgery, Medical University of South Carolina, Charleston, SC ††Department of Surgery, University of Florida, Gainesville, FL ‡‡Department of Surgery, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada §§Department of Surgery, Winthrop University Hospital, Mineola, NY ¶¶Department of Surgery, University of Pennsylvania, Philadelphia, PA ||||Department of Surgery, University of Nebraska Medical Center, Omaha, NE ***Department of Surgery, The University of Texas Medical Branch, Galveston, TX †††Department of Surgery, University of South Florida, Tampa, FL ‡‡‡Department of Surgery, Thomas Jefferson University, Philadelphia, PA.

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.
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http://dx.doi.org/10.1097/SLA.0000000000002375DOI Listing
September 2017

Value of lymph node positivity in treatment planning for early stage pancreatic cancer.

Surgery 2017 09 27;162(3):557-567. Epub 2017 Jun 27.

Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, TX; VA HSR&D Center for Innovations in Quality, Effectiveness, and Safety, Michael E. DeBakey VA Medical Center, Houston, TX.

Background: Multimodal therapy is recommended for early stage pancreatic cancer, although whether all patients benefit and the optimal timing of chemotherapy remain unclear.

Methods: Retrospective cohort study of patients aged 18-79 years with stage I-II pancreatic ductal adenocarcinoma in the National Cancer Database (2004-2012). Patients were grouped based on treatment strategy as surgery only, adjuvant, and preoperative. Accuracy of nodal staging and rate of nodal downstaging were ascertained using pretreatment clinical and postresection pathologic nodal status data. Association between overall risk of death and treatment strategy was evaluated with multivariable Cox regression.

Results: Among 19,031 patients, 31.1% underwent surgery only, 59.6% received adjuvant, and 9.3% preoperative therapy. Based on patients receiving upfront surgery, clinical nodal staging bore sensitivity, specificity, positive predictive value, and negative predictive value of 46.2%, 95.7%, 95.1%, and 49.8%, respectively. Preoperative therapy downstaged 38% of cN1 patients to ypN0; 5-year overall survival for this group was 27.2% vs 12.3% for ypN1 patients (P < .001). Relative to surgery only, adjuvant (HR 0.75, 95% CI [0.71-0.78]) and preoperative therapy (HR 0.66 [0.60-0.73]) were associated with lower risk of death among patients with pN1, but not pN0 (adjuvant-HR 1.01 [0.94-1.09]; preoperative-HR 1.10 [0.99-1.22]), disease.

Conclusion: Our data provide strong support for preoperative chemotherapy for patients with node-positive pancreatic cancer, one third of whom may be downstaged. Among those with seemingly node-negative disease, half will be understaged with current clinical staging modalities. These results should be considered when planning treatment for patients with early stage pancreatic cancer.
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http://dx.doi.org/10.1016/j.surg.2017.05.003DOI Listing
September 2017

Nutritional and Metabolic Derangements in Pancreatic Cancer and Pancreatic Resection.

Nutrients 2017 Mar 7;9(3). Epub 2017 Mar 7.

The Elkins Pancreas Center, Michael E. DeBakey Department of Surgery, and Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA.

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.
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http://dx.doi.org/10.3390/nu9030243DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5372906PMC
March 2017

Whole-genome landscape of pancreatic neuroendocrine tumours.

Nature 2017 03 15;543(7643):65-71. Epub 2017 Feb 15.

QIMR Berghofer Medical Research Institute, Herston Road, Brisbane 4006, Australia.

The diagnosis of pancreatic neuroendocrine tumours (PanNETs) is increasing owing to more sensitive detection methods, and this increase is creating challenges for clinical management. We performed whole-genome sequencing of 102 primary PanNETs and defined the genomic events that characterize their pathogenesis. Here we describe the mutational signatures they harbour, including a deficiency in G:C > T:A base excision repair due to inactivation of MUTYH, which encodes a DNA glycosylase. Clinically sporadic PanNETs contain a larger-than-expected proportion of germline mutations, including previously unreported mutations in the DNA repair genes MUTYH, CHEK2 and BRCA2. Together with mutations in MEN1 and VHL, these mutations occur in 17% of patients. Somatic mutations, including point mutations and gene fusions, were commonly found in genes involved in four main pathways: chromatin remodelling, DNA damage repair, activation of mTOR signalling (including previously undescribed EWSR1 gene fusions), and telomere maintenance. In addition, our gene expression analyses identified a subgroup of tumours associated with hypoxia and HIF signalling.
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http://dx.doi.org/10.1038/nature21063DOI Listing
March 2017

Overexpression of Semaphorin-3E enhances pancreatic cancer cell growth and associates with poor patient survival.

Oncotarget 2016 Dec;7(52):87431-87448

Michael E. DeBakey Department of Surgery, Division of Surgical Research, Baylor College of Medicine, Houston, TX, USA.

Semaphorin-3E (Sema3E) is a member of an axon guidance gene family, and has recently been reported to contribute to tumor progression and metastasis. However, its role in pancreatic cancer is yet unknown and uncharacterized. In this study, we showed that Sema3E is overexpressed in human pancreatic cancer, and that high Sema3E levels are associated with tumor progression and poor survival. Interestingly, we also observed Sema3E expression in the nucleus, even though Sema3E is reported to be a secreted protein. Overexpression of Sema3E in pancreatic cancer cells promoted cell proliferation and migration in vitro, and increased tumor incidence and growth in vivo. Conversely, knockout of Sema3E suppressed cancer cell proliferation and migration in vitro, and reduced tumor incidence and size in vivo. Moreover, Sema3E induced cell proliferation via acting through the MAPK/ERK pathway. Collectively, these results reveal an undiscovered role of Sema3E in promoting pancreatic cancer pathogenesis, suggesting that Sema3E may be a suitable prognostic marker and therapeutic target for pancreatic cancer.
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http://dx.doi.org/10.18632/oncotarget.13704DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5349999PMC
December 2016

Reply.

Authors:
George Van Buren

Pancreas 2016 08;45(7):e34-5

The Elkins Pancreas Center Michael E. DeBakey Department of Surgery and Dan L. Duncan Cancer Center Baylor College of Medicine Houston, TX

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http://dx.doi.org/10.1097/MPA.0000000000000627DOI Listing
August 2016

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

Cell Rep 2016 Feb 21;14(4):907-919. Epub 2016 Jan 21.

Sydney Medical School, University of Sydney, Sydney, NSW 2006, Australia; Department of Surgery, Royal North Shore Hospital, St Leonards, Sydney, NSW 2065, Australia.

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.
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http://dx.doi.org/10.1016/j.celrep.2015.12.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4982376PMC
February 2016

Pancreaticoduodenectomy Without Drains: Interpretation of the Evidence.

Ann Surg 2016 Feb;263(2):e20-1

The Elkins Pancreas Center, Michael E. DeBakey Department of Surgery, Baylor College of Medicine and Dan L. Duncan Cancer Center, Houston, TX.

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http://dx.doi.org/10.1097/SLA.0000000000001242DOI Listing
February 2016

Pancreatic cancer disparities in African Americans.

Pancreas 2015 May;44(4):522-7

From the *Michael E. DeBakey Department of Surgery, †The Elkins Pancreas Center, ‡Dan L. Duncan Cancer Center, and §Department of Medicine, Baylor College of Medicine, Houston, TX.

Objectives: Pancreatic cancer is the fourth leading cause of cancer-related deaths in the United States. The incidence of pancreatic cancer in African Americans is 50% to 90% higher than the incidence in other racial groups. African Americans also have the worst prognosis. This is an evidence-based review of pancreatic cancer in African Americans with particular emphasis on baseline characteristics, treatment, and survival.

Methods: We queried PubMed in search for articles describing racial disparities in pancreatic cancer. Two categories of terms were "anded" together: pancreatic cancer terms and race terms. The last search was performed on November 14, 2013.

Results: We summarized the data on pancreatic cancer baseline characteristics, treatment, and survival for African Americans that we obtained from the following databases: (1) Surveillance, Epidemiology, and End Results, 1988-2008; (2) California Cancer Registry 1988-1998; (3) Cancer Survivor Program of Orange County/San Diego Imperial Organization for Cancer Control, 1988-1998; and (4) Harris County, 1998-2010.

Conclusions: Overall, pancreatic cancer survival of African Americans has not significantly improved over the past several decades despite advances in multimodality therapy; African Americans continue to face worse outcomes than whites. Although baseline characteristics, treatment, and biological factors offer some explanation, they do not completely explain the disparities in incidence and survival.
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http://dx.doi.org/10.1097/MPA.0000000000000323DOI Listing
May 2015

Pancreaticoduodenectomy Without Drains: Interpretation of the Evidence.

Ann Surg 2016 May;263(5):e74-6

The Elkins Pancreas Center, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, TX.

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http://dx.doi.org/10.1097/SLA.0000000000001152DOI Listing
May 2016

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

J Gastrointest Surg 2015 Jan 3;19(1):21-30; discussion 30-1. Epub 2014 Sep 3.

Department of Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.

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.
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http://dx.doi.org/10.1007/s11605-014-2640-zDOI Listing
January 2015

Pancreatic cancer: advances in treatment.

World J Gastroenterol 2014 Jul;20(28):9354-60

Somala Mohammed, George Van Buren II, William E Fisher, The Elkins Pancreas Center, Michael E DeBakey Department of Surgery, and Dan L Duncan Cancer Center, Baylor College of Medicine, Houston, TX 77030, United States.

Pancreatic cancer is a leading cause of cancer mortality and the incidence of this disease is expected to continue increasing. While patients with pancreatic cancer have traditionally faced a dismal prognosis, over the past several years various advances in diagnosis and treatment have begun to positively impact this disease. Identification of effective combinations of existing chemotherapeutic agents, such as the FOLFIRINOX and the gemcitabine + nab-paclitaxel regimen, has improved survival for selected patients although concerns regarding their toxicity profiles remain. A better understanding of pancreatic carcinogenesis has identified several pre-malignant precursor lesions, such as pancreatic intraepithelial neoplasias, intraductal papillary mucinous neoplasms, and cystic neoplasms. Imaging technology has also evolved dramatically so as to allow early detection of these lesions and thereby facilitate earlier management. Surgery remains a cornerstone of treatment for patients with resectable pancreatic tumors, and advances in surgical technique have allowed patients to undergo resection with decreasing perioperative morbidity and mortality. Surgery has also become feasible in selected patients with borderline resectable tumors as a result of neoadjuvant therapy. Furthermore, pancreatectomy involving vascular reconstruction and pancreatectomy with minimally invasive techniques have demonstrated safety without significantly compromising oncologic outcomes. Lastly, a deeper understanding of molecular aberrations contributing to the development of pancreatic cancer shows promise for future development of more targeted and safe therapeutic agents.
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http://dx.doi.org/10.3748/wjg.v20.i28.9354DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4110567PMC
July 2014

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

Ann Surg 2014 Apr;259(4):605-12

*Baylor College of Medicine, The Elkins Pancreas Center, Michael E. DeBakey Department of Surgery, and The Dan L. Duncan Cancer Center, Houston, TX †Department of Surgery, The Ohio State University, Columbus, OH ‡Department of Surgery, University of Florida, Gainesville, FL §Department of Surgery, Jefferson Medical College, Philadelphia, PA ¶Department of Surgery, Baptist Memorial Hospital/The University of Tennessee Health Science Center, Memphis, TN ‖Department of Surgery, Indiana University, Indianapolis, IN **Department of Surgery, University of Pennsylvania, Philadelphia, PA ††Department of Surgery, University of South Florida, Tampa, FL; and ‡‡Department of Surgery, The University of Texas Medical Branch, Galveston, TX.

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.
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http://dx.doi.org/10.1097/SLA.0000000000000460DOI Listing
April 2014

Phase II study of induction fixed-dose rate gemcitabine and bevacizumab followed by 30 Gy radiotherapy as preoperative treatment for potentially resectable pancreatic adenocarcinoma.

Ann Surg Oncol 2013 Nov 1;20(12):3787-93. Epub 2013 Aug 1.

Division of Surgical Oncology, UPMC Pancreatic Cancer Center, Pittsburgh, PA, USA.

Background: Eighty percent of patients with resected pancreatic ductal carcinoma (PDC) experience treatment failure within 2 years. We hypothesized that preoperative fixed-dose rate (FDR) gemcitabine (GEM) combined with the angiogenesis inhibitor bevacizumab (BEV) and accelerated 30 Gy radiotherapy (RT) would improve outcomes among patients with potentially resectable PDC.

Methods: This phase II trial tested induction FDR GEM (1,500 mg/m(2)) plus BEV (10 mg/kg IV) every 2 weeks for three cycles followed by accelerated RT (30 Gy in 10 fractions) plus BEV directed at gross tumor volume plus a 1-2 cm vascular margin. Subjects underwent laparoscopy and resection after day 85. Therapy was considered effective if the complete pathologic response rate exceeded 10 % and the margin-negative resection rate exceeded 80%.

Results: Fifty-nine subjects were enrolled; 29 had potential portal vein involvement. Two grade 4 (3.4%) and 19 grade 3 toxicities (32.8%) occurred. Four subjects manifested radiographic progression, and 10 had undetected carcinomatosis. Forty-three pancreatic resections (73%) were performed, including 19 portal vein resections (44%). Margin-negative outcomes were observed in 38 (88%, 95% confidence interval [CI] 75-96), with one complete pathologic response (2.3%; 95% CI 0.1-12). There were seven (6 grade 3; 1 grade 4) wound complications (13%). Median overall survival for the entire cohort was 16.8 months (95% CI 14.9-21.3) and 19.7 months (95% CI 16.5-28.2) after resection.

Conclusions: Induction therapy with FDR GEM and BEV, followed by accelerated BEV/RT to 30 Gy, was well tolerated. Although both effectiveness criteria were achieved, survival outcomes were equivalent to published regimens.
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http://dx.doi.org/10.1245/s10434-013-3161-9DOI Listing
November 2013