Galen Cortina

Autopsy Findings Following Gastric Bypass Surgery for Morbid Obesity

BACKGROUND Roux-en-Y gastric bypass, currently the most frequently performed surgical procedure for morbid obesity, has a low but significant mortality rate. There are limited data documenting the findings at necropsy in patients who have died following this procedure. OBJECTIVE To determine cause of death and pathologic processes present in obese subjects dying after gastric bypass surgery. PATIENTS We studied 10 patients who underwent autopsy following gastric bypass surgery for morbid obesity between the years 1994 and 2000. RESULTS There were 6 men and 4 women. The mean age of the patients was 48 years (range, 28-62 years). The mean preoperative weight was 162 kg (range, 112-245 kg), and the mean body mass index was 54 kg/m(2) (range, 39-76 kg/m(2)), similar to all patients undergoing gastric bypass at our institution during the same period. Five deaths were directly attributable to technical complications. Five deaths were attributed to underlying comorbid conditions. One patient died of cirrhosis and one of pulmonary hemorrhage. Three patients died from pulmonary embolism. However, 8 of 10 patients had microscopic evidence of pulmonary emboli, despite prophylaxis for deep vein thrombosis. Most patients had some degree of steatohepatitis and hepatic fibrosis (80% and 70%, respectively). There were no deaths from primary cardiac events. CONCLUSIONS In patients who die after Roux-en-Y gastric bypass, half die due to technical complications, whereas the other half die of complications of their obesity. Clinically, only 20% of patients were suspected to have pulmonary emboli, yet at autopsy, 80% of patients had pulmonary emboli. In morbidly obese patients undergoing Roux-en-Y gastric bypass, there is an unexpectedly high rate of clinically silent pulmonary emboli contributing to morbidity and mortality.

Randomized trial of argon plasma coagulation vs. multipolar electrocoagulation for ablation of Barrett's esophagus

BACKGROUND Endoscopic ablation of Barretts esophagus has been described in which various thermocoagulation modalities are used in combination with a high dose of a proton pump inhibitor. No randomized comparison of ablation strategies has been published. METHODS Referred patients were screened to identify those with Barretts esophagus 2 to 7 cm in length, without high-grade dysplasia or cancer. Included patients received pantoprazole (40 mg twice a day), followed by randomization to treatment with argon plasma coagulation (APC) or multipolar electrocoagulation (MPEC). The primary outcome measure was the number of treatment sessions required for endoscopic ablation. RESULTS Of 235 patients screened, 52 were randomized. The mean length of Barretts esophagus was 3.1 cm in the MPEC group vs. 4.0 cm in the APC group (p = 0.03). Otherwise, the treatment groups were similar with regard to baseline characteristics. The mean number of treatment sessions required for endoscopic ablation was 2.9 for MPEC vs. 3.8 for APC (p = 0.04) in an intention-to-treat analysis (p = 0.249, after adjustment for the difference in length of Barretts esophagus). The proportion of patients in which ablation was endoscopically achieved proximal to the gastroesophageal junction was 88% for the MPEC group vs. 81% for the APC group (p = 0.68) and histologically achieved in 81% for MPEC vs. 65% for APC (p = 0.21). The mean time required for the first treatment session was 6 minutes with MPEC vs. 10 minutes with APC (p = 0.01) in per protocol analysis. There was no serious adverse event, but transient moderate to severe upper-GI symptoms occurred after MPEC in 8% vs. 13% after APC (p = 0.64). Conclusions Although there were no statistically significant differences, ablation of Barretts esophagus with pantoprazole and MPEC required numerically fewer treatment sessions, and endoscopic and histologic ablation was achieved in a greater proportion of patients compared with treatment with pantoprazole and APC.

Serum and Colonic Mucosal Immune Markers in Irritable Bowel Syndrome

OBJECTIVES:Low-grade colonic mucosal inflammation has been postulated to have an important role in the pathophysiology of irritable bowel syndrome (IBS). The objectives of this study were (i) to identify serum and tissue-based immunological and neuroendocrine markers associated with mucosal inflammation in male (M) and female (F) patients with non-post-infectious IBS (non-PI-IBS) compared with healthy controls and (ii) to assess possible correlations of such markers with IBS symptoms.METHODS:Sigmoid mucosal biopsies were obtained from 45 Rome II positive IBS patients without a history of PI-IBS (26 F, 35.5% IBS-C, 33.3% IBS-D, 31.1% IBS-A/M) and 41 healthy controls (22 F) in order to measure immunological markers (serum cytokine levels, colonic mucosal mRNA levels of cytokines, mucosal immune cell counts) and neuroendocrine markers associated with mucosal inflammation (corticotropin releasing factor- and neurokinin (NK)-related ligands and receptors, enterochromaffin cells). Symptoms were measured using validated questionnaires.RESULTS:Of all the serum and mucosal cytokines measured, only interleukin-10 (IL-10) mRNA expression showed a group difference, with female, but not male, patients showing lower levels compared with female controls (18.0±2.9 vs. 29.5±4.0, P=0.006). Mucosal mRNA expression of NK-1 receptor was significantly lower (1.15±0.19 vs. 2.66±0.56, P=0.008) in female, but not male, patients compared with healthy controls. No other significant differences were observed.CONCLUSIONS:Immune cell counts and levels of cytokines and neuropeptides that are associated with inflammation were not significantly elevated in the colonic mucosa of non-PI-IBS patients, and did not correlate with symptoms. Thus, these findings do not support that colonic mucosal inflammation consistently has a primary role in these patients. However, the finding of decreased IL-10 mRNA expression may be a possible biomarker of IBS and warrants further investigation.

First Phase 1 Double-Blind, Placebo-Controlled, Randomized Rectal Microbicide Trial Using UC781 Gel with a Novel Index of Ex Vivo Efficacy

Objectives Successful control of the HIV/AIDS pandemic requires reduction of HIV-1 transmission at sexually-exposed mucosae. No prevention studies of the higher-risk rectal compartment exist. We report the first-in-field Phase 1 trial of a rectally-applied, vaginally-formulated microbicide gel with the RT-inhibitor UC781 measuring clinical and mucosal safety, acceptability and plasma drug levels. A first-in-Phase 1 assessment of preliminary pharmacodynamics was included by measuring changes in ex vivo HIV-1 suppression in rectal biopsy tissue after exposure to product in vivo. Methods HIV-1 seronegative, sexually-abstinent men and women (N = 36) were randomized in a double-blind, placebo-controlled trial comparing UC781 gel at two concentrations (0.1%, 0.25%) with placebo gel (1∶1∶1). Baseline, single-dose exposure and a separate, 7-day at-home dosing were assessed. Safety and acceptability were primary endpoints. Changes in colorectal mucosal markers and UC781 plasma drug levels were secondary endpoints; ex vivo biopsy infectibility was an ancillary endpoint. Results All 36 subjects enrolled completed the 7–14 week trial (100% retention) including 3 flexible sigmoidoscopies, each with 28 biopsies (14 at 10 cm; 14 at 30 cm). There were 81 Grade 1 adverse events (AEs) and 8 Grade 2; no Grade 3, 4 or procedure-related AEs were reported. Acceptability was high, including likelihood of future use. No changes in mucosal immunoinflammatory markers were identified. Plasma levels of UC781 were not detected. Ex vivo infection of biopsies using two titers of HIV-1BaL showed marked suppression of p24 in tissues exposed in vivo to 0.25% UC781; strong trends of suppression were seen with the lower 0.1% UC781 concentration. Conclusions Single and 7-day topical rectal exposure to both concentrations of UC781 were safe with no significant AEs, high acceptability, no detected plasma drug levels and no significant mucosal changes. Ex vivo biopsy infections demonstrated marked suppression of HIV infectibility, identifying a potential early biomarker of efficacy. (Registered at ClinicalTrials.gov; #NCT00408538)

Improved Survival Following Pancreaticoduodenectomy to Treat Adenocarcinoma of the Pancreas: The Influence of Operative Blood Loss

HYPOTHESIS Although the safety of pancreaticoduodenectomy has notably improved over the past several decades, the reported survival of patients with pancreatic cancer remains poor. We hypothesized that, in recent years, the survival of patients with pancreatic adenocarcinoma following pancreaticoduodenectomy has substantially improved. DESIGN Retrospective case series. SETTING Major academic medical and pancreatic surgery center. PATIENTS A total of 182 consecutive patients underwent pancreaticoduodenectomy for various diagnoses between 1987 and 2005. Patients from 1987-1995 were compared with patients from 1996-2005. INTERVENTIONS Pancreaticoduodenectomy for patients with a diagnosis of pancreatic adenocarcinoma. MAIN OUTCOME MEASURES Survival after pancreaticoduodenectomy and patient outcomes. RESULTS During the time period analyzed, 182 patients underwent pancreaticoduodenectomy to treat ductal adenocarcinoma. There were no operative deaths, and 86.3% of patients had an R0 resection. The 5-year survival rate for the entire group was 27.4%. However, survival improved from 15.8% to 35.5% during the study period. Both groups had equivalent demographic and pathological characteristics, and the only predictors of poor survival in multivariate analysis were operative blood loss of more than 400 mL (hazard ratio, 2.17), poorly differentiated tumors (3.03), lymph node metastases (1.92), perineural invasion (2.66), and undergoing an operation before 1996 (1.42). CONCLUSIONS The survival rate for patients undergoing pancreaticoduodenectomy to treat pancreatic cancer has substantially improved. This finding is partially owing to improved operative technique and limited operative blood loss.

An Orthotopic Nude Mouse Model for Evaluating Pathophysiology and Therapy of Pancreatic Cancer

Introduction Orthotopic, clinically relevant animal models are necessary for the study of pathophysiology and therapy for pancreatic cancer. Aims To develop a minimally traumatic technique of orthotopic tumor induction, to develop a scoring system to quantify local and systemic tumor spread, and to provide a model with a broad range of well-differentiated to undifferentiated pancreatic cancers. Methodology Orthotopic tumors were induced in nude mice by atraumatic pancreatic implantation of two fragments from subcutaneous donor tumors or intrapancreatic injection of human tumor cells (MIAPaCa-2, AsPC-1, HPAF-2, Capan-1). Animals were monitored for 14 weeks or until death. Primary tumor volume, local infiltration, and systemic metastasis were assessed and analyzed at autopsy. Macroscopic findings were confirmed by histologic evaluation. Results Tumor take rate in the implantation group was 100% for all four cell lines. Marked differences with regard to tumor size, metastatic spread, and survival were found depending on the grade of differentiation. Less differentiated cells (MIAPaCa-2, AsPC-1) caused higher dissemination scores and mortality than better-differentiated cells (HPAF-2, Capan-1). Clinical features included cachexia, jaundice, and malignant ascites. Orthotopic tumor cell injection resulted in an incomplete tumor take rate. Moreover, early artificial abdominal tumor spread was found in injected animals due to microscopic cell loss during the injection procedure. Conclusions Orthotopic implantation of donor tumor fragments into nude mice is technically feasible and is superior to the cell injection technique. It results in reproducible local and systemic development of pancreatic cancer that mimics the human disease. A dissemination score may help to better quantify therapeutic effects in future studies.

Pretransplant Predictors of Survival After Intestinal Transplantation: Analysis of a Single-center Experience of More Than 100 Transplants

Introduction. Outcomes after intestinal transplantation (ITx) have steadily improved. There are few studies that assess factors associated with these enhanced results. The purpose of this study was to examine peri-ITx variables and survival. Methods. A review of a prospectively maintained database was undertaken and included all patients undergoing ITx from 1991 to 2010. The study endpoints were patient and graft survival. Data collection included 44 variables. Survival was computed using Kaplan-Meier methods. Univariate analysis was conducted (log-rank test) with significance set at P less than or equal to 0.20. Multivariate analysis of significant variables was conducted using model reduction by backward elimination variable selection method with significance set at P less than 0.05. Results. Eighty-eight patients received 106 ITx. The majority of recipients were male, Latino, and children. The leading causes of intestinal and liver failure were gastroschisis and parenteral nutrition. Grafts transplanted were isolated intestine (24%), liver-intestine (62%), and multivisceral (14%). Overall 1- and 5-year patient and graft survival were 80% and 65%, and 74% and 64%, respectively. Significant univariate survival predictors were weight less than 20 kg, children, liver-inclusive allograft, panel reactive antibody less than 20%, absence of donor-specific antibody, negative crossmatch, warm ischemia time less than 60 min, absence of recipient splenectomy, interleukin-2 receptor antagonist induction, and era. Significant multivariate survival predictors were absence of donor-specific antibody, absence of recipient splenectomy, and liver-inclusive graft type. Conclusion. This large, single-center ITx experience confirms a marked improvement in outcome over time. Several important factors were associated with survival, and these factors can potentially be adjusted before ITx. These findings should refocus future efforts on strategies to improve treatment and prevent graft loss.

Characterization of baseline intestinal mucosal indices of injury and inflammation in men for use in rectal microbicide trials (HIV Prevention Trials Network-056).

Objectives:The purpose of this study was to evaluate the biologic stability of mucosal parameters that might be used as endpoints in phase 1 rectal safety studies. Methods:Sixteen male participants were enrolled into 4 groups defined by HIV status, viral load, and sexual activity. Each participant underwent 3 flexible sigmoidoscopies at 2-week intervals with collection of blood, intestinal biopsies, and rectal secretions. Intestinal histology, phenotypic characterization of mucosal mononuclear cells, cytokine messenger RNA (mRNA) profiles (RANTES, interferon-γ [IFNγ], and interleukin-10), and immunoglobulin secretion were assessed. Intraclass correlation (ICC) was calculated to assess endpoint stability. Results:Qualitative histology demonstrated minimal inflammation in >95% of biopsies and remained stable throughout the study period. ICC for the tissue cytokine mRNA measurements and several T-cell phenotypic markers was >0.7, indicating stability over time. Mucosal CD4 lymphopenia was seen in the HIV-positive participants and was more pronounced in those with higher viral loads. Modest differences were observed for cytokine expression (IFNγ) and T-cell phenotype (CD3, CD4, CD8, CD19, CD4/CCR5, and CD4/CD38) between the tissue samples collected at 10 and 30 cm. Conclusions:These data help to provide a rationale for the selection of endpoints for future phase 1 rectal safety studies.

Clinical and Pathologic Overlap in Nonsteroidal Anti-inflammatory Drug-related Small Bowel Diaphragm Disease and the Neuromuscular and Vascular Hamartoma of the Small Bowel

Diaphragm disease (DD) is a radiographically subtle cause of small bowel obstruction and is part of the spectrum of diseases associated with nonsteroidal anti-inflammatory drug injury. The neuromuscular and vascular hamartoma (NMVH) is a nonepithelial hamartomatous, submucosally based proliferation of mature submucosal elements capable of causing small bowel obstruction. The authors report two patients in whom the clinical setting and gross pathology are that of DD, but the histologic characterization is identical to that described for NMVH. It is probable that in some patients the two diseases overlap so that some patients readily fit the criteria for both entities.

An improved clinical model of orthotopic pancreatic cancer in immunocompetent Lewis rats

The study of pancreatic cancer (PaCa) requires orthotopic, clinically relevant animal models. The aims of this study were to establish an orthotopic model of ductal pancreatic adenocarcinoma in immunocompetent Lewis rats and to develop a scoring system to quantify local tumor infiltration and distant metastasis. Cells (107) of the rat ductal PaCa cell line DSL-6A/C1 were injected s.c. into donor rats. After 8 weeks, either three (IPL-3) or five (IPL-5) fragments (1 mm3) of the resulting s.c. tumors were microsurgically implanted into the pancreas of recipient rats. In another series of animals, 107 DSL-6A/C1 cells were directly injected (INJ) into the pancreas. All animals were monitored daily until death or for 16 weeks. At autopsy, volume of primary tumors and ascites, local and systemic tumor spread, and histologic phenotype were assessed. IPL-5 resulted in significantly larger tumors (12,224 ± 1,933 mm3), more local infiltration and systemic spread (score: 18.3 ± 2.0 points), severe clinical tumor disease, and lethality (50%) in comparison to the other induction techniques (IPL-3: 283 ± 115 mm3/3.5 ± 0.8 points/0; INJ: 752 ± 207 mm3/4.3 ± 0.8 points/8%). Histologic examination revealed moderately to well-differentiated ductal tumors, surrounded by dense stroma. Intraperitoneal tumor dissemination in the INJ group occurred simultaneous with primary tumor growth, indicating PaCa cell spread during injection. Orthotopic implantation of five DSL-6A/C1 tumor fragments into the rat pancreas provides a valid clinical model of ductal pancreatic adenocarcinoma in immunocompetent rodents for preclinical treatment studies. The dissemination score we used permitted quantification of local and systemic tumor spread.