Gregory Veillette

Implications and Management of Pancreatic Fistulas Following Pancreaticoduodenectomy: The Massachusetts General Hospital Experience

OBJECTIVE To describe the management and impact of pancreatic fistulas in a high-volume center. DESIGN Retrospective case series. SETTING Tertiary academic center. PATIENTS Five hundred eighty-one consecutive patients who underwent pancreaticoduodenectomy from January 2001 through June 2006. MAIN OUTCOME MEASURES Development of a pancreatic fistula (defined as > 30 mL of amylase-rich fluid from drains on or after postoperative day 7, or discharge with surgical drains in place, regardless of amount); the need for additional interventions or total parenteral nutrition; other morbidity; and mortality. RESULTS Seventy-five patients (12.9%) developed a pancreatic fistula. Fistulas were managed with gradual withdrawal of surgical drains. This allowed for patient discharge and eventual closure at a mean of 18 days in 38.7% of cases; these were classified as low-impact fistulas. The remaining 46 patients (61.3%) had an associated abscess, required percutaneous drainage or total parenteral nutrition, or developed bleeding; these were classified as high-impact fistulas and closed a mean of 35 days after surgery. Standard 30-day in-hospital mortality was 1.9% for all pancreaticoduodenectomies and 6.7% for those who developed a pancreatic fistula. The overall fistula-related mortality was 9.3% (7 patients), all but 1 of which was related to major hemorrhage. CONCLUSIONS More than one-third of pancreatic fistulas are clinically insignificant (low impact). The remaining 60% of fistulas have a high clinical impact and nearly an 8-fold increase in overall mortality.

Up to 9-day survival and control of thrombocytopenia following alpha1,3-galactosyl transferase knockout swine liver xenotransplantation in baboons.

Kim K, Schuetz C, Elias N, Veillette GR, Wamala I, Varma M, Smith RN, Robson SC, Cosimi AB, Sachs DH, Hertl M. Up to 9‐day survival and control of thrombocytopenia following GalT‐KO swine liver xenotransplantation in baboons. Xenotransplantation 2012; 19: 256–264..

Early Drain Removal--The Middle Ground Between the Drain Versus No Drain Debate in Patients Undergoing Pancreaticoduodenectomy: A Prospective Validation Study.

OBJECTIVE To perform an unbiased assessment of first postoperative day (POD 1) drain amylase level and pancreatic fistula (PF) after pancreaticoduodenectomy (PD). BACKGROUND Recent evidence demonstrated that drain abandonment in PD is unsafe. Early drain amylase levels have been proposed as predictors of PF after PD, allowing for selection of patients for early drain removal. METHODS Daily drain amylase levels were correlated with the development of PF in 2 independent cohorts of patients undergoing PD: training cohort (n = 126; year 2008) and validation cohort (n = 369; years 2009-2012). RESULTS POD 1 drain amylase level had the highest predictive ability (concordance index: 0.911) for PF in the training cohort. An amylase level of 612 U/L or higher showed the best accuracy (86%), sensitivity (93%), and specificity (79%). Thus, a cutoff value of 600 U/L was utilized. In the validation cohort, 229 (62.1%) patients had a POD 1 drain amylase level of lower than 600 U/L, and PF developed in only 2 (0.9%) cases; whereas in patients with POD 1 drain amylase level of 600 U/L or higher (n = 140) the PF rate was 31.4% (odds ratio [OR] = 52, P < 0.0001). On multivariate analysis, POD 1 drain amylase level of lower than 600 U/L (OR = 0.0192, P < 0.0001) was a stronger predictor of the absence of PF than pancreatic gland texture (OR = 0.193, P = 0.002) and duct diameter (OR = 0.861, P = 0.835). CONCLUSIONS After PD, the risk of PF is less than 1% if POD 1 drain amylase level is lower than 600 U/L. We propose that in this group, which comprise more than 60% of patients, drains should be removed on POD 1.

Repetitive Gastric Aspiration Leads to Augmented Indirect Allorecognition after Lung Transplantation in Miniature Swine

Introduction. Lung transplant recipients with documented gastroesophageal reflux disease (GERD) are at increased risk for graft dysfunction. Here, we present the first large-animal model of gastric aspiration after allogeneic lung transplantation and some preliminary data demonstrating the effect of chronic aspiration on the direct and indirect pathways of allorecognition. Methods. Left orthotopic lung transplants (n=3) were performed in miniature swine across a major histocompatibility complex class I disparity, followed by 12 days of high-dose cyclosporine A. At the time of transplantation, a transtracheal catheter was placed at the carina, above the bronchial anastomosis. A gastrostomy tube was placed for daily aspiration of gastric contents. Subsequently, graft lungs were instilled with gastric aspirate daily (3 mL/hr×8 hr/day) for 50 days. Recipients were followed up with daily complete blood count, scheduled chest radiographs, and biopsies. In vitro studies, including cell-mediated lympholysis, mixed lymphocyte reactions, and peptide proliferation assays, were performed. Results from these three recipients were compared with those of historical controls (n=6) who were treated identically, except for the tracheal cannulation and simulated gastric aspiration. Results. Two of the experimental animals were euthanized with nonviable lungs soon after the postoperative day 50 biopsy. In both cases the native lung was normal. The third animal survived over 180 days without the evidence of chronic rejection. After immunosuppressive treatment, all animals demonstrated donor-specific hyporesponsiveness by assays of direct alloresponse (cell-mediated lympholysis, mixed lymphocyte reaction). A significant response to synthetic donor-derived class I peptide, however, was seen in all animals. A more pronounced and diffuse response was seen in the animals rejecting their grafts. The historical controls showed medium-term graft survival with evidence of chronic rejection in the majority of animals, as previously reported. Conclusion. In a model of GERD after lung transplantation, a spectrum of clinical outcomes was observed. The in vitro data suggest that acid reflux enhances the indirect alloresponse to processed donor class I antigen, giving mechanistic insight into the manner in which GERD may be deleterious to the transplanted lung.

Distal Biliary Malignancy

Distal cholangiocarcinoma (malignancy in the common bile duct from the cystic duct to the ampulla) remains a rare diagnosis. Most of these lesions are adenocarcinomas, and typically present with painless jaundice. If suspected, a high-quality CT scan and endoscopic retrograde cholangiopancreatography are required for diagnosis and staging. In addition, identification of risk factors, use of tumor markers, and advanced molecular testing may enhance diagnostic and prognostic capabilities. The treatment of choice for resectable disease is pancreaticoduodenectomy and the overall 5-year survival for resected distal cholangiocarcinoma remains 20% to 30%.

Autoimmune sensitization to cardiac myosin leads to acute rejection of cardiac allografts in miniature swine

Background. Recent studies in mice and patients suggest that posttransplantation induction of autoimmune responses to tissue-specific antigens contributes to the rejection of major histocompatibility complex mismatched allotransplants. The relevance of this phenomenon to the rejection of major and minor histocompatibility-mismatched allografts performed in large-animal models remains to be established. Methods. Miniature swine were immunized with cardiac myosin (CM) in Freunds adjuvant and received heterotopic, minor antigen-mismatched heart transplants. T-cell (proliferation and delayed type hypersensitivity [DTH]) and B-cell (antibody) responses specific to CM were measured. The rejection of heart transplants was assessed histologically. Results. Three of four swine that were immunized with CM before receiving a minor antigen-mismatched heart transplant exhibited potent DTH, T-cell proliferation and antibody responses to CM and rejected their grafts acutely. The fourth swine, which failed to mount a significant DTH response to CM and displayed low and transient anti-CM antibody titers, demonstrated long-term allograft survival. Conclusions. This large-animal study supports the relevance of autoimmunity to CM in the rejection of minor antigen disparate cardiac allotransplants.

Donor Brain Death Inhibits Tolerance Induction in Miniature Swine Recipients of Fully MHC‐Disparate Pulmonary Allografts

We have previously shown that a short course of high‐dose tacrolimus induces long‐term tolerance to fully mismatched lung allografts procured from healthy MHC‐inbred miniature swine. Here, we investigate whether donor brain death affects tolerance induction. Four recipient swine were transplanted with fully mismatched lung grafts from donors that were rendered brain dead and mechanically ventilated for 4 h before procurement (Group 1). These recipients were compared to two control groups (Group 2: 4 h of donor ventilation without brain death [n = 5]; and Group 3: no donor brain death with <1 h of ventilation [n = 6]). All recipients were treated with a 12‐day course of tacrolimus. In contrast to both groups of control animals, the swine transplanted with lung allografts from brain dead donors all rejected their grafts by postoperative day 45 and showed persistent responsiveness to donor antigen by MLR. Several additional swine underwent brain death induction and/or mechanical ventilation alone to determine the effects of these procedures on the expression of proinflammatory molecules. Significant increases in serum concentrations of IL‐1, TNF‐α and IL‐10 were seen after brain death. Upregulation of IL‐1 and IL‐6 gene expression was also observed.