David B. Lautz

Immunologic and clinical effects of antibody blockade of cytotoxic T lymphocyte-associated antigen 4 in previously vaccinated cancer patients

Cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) functions as a negative regulator of endogenous and vaccine-induced antitumor immunity. The administration of fully human anti-CTLA-4 blocking monoclonal antibodies to advanced-cancer patients increases immune-mediated tumor destruction in some subjects. Nonetheless, patients that respond also frequently manifest serious inflammatory pathologies, raising the possibility that the therapeutic and toxic effects of CTLA-4 blockade might be linked. Here we show that periodic infusions of anti-CTLA-4 antibodies after vaccination with irradiated, autologous tumor cells engineered to secrete GM-CSF (GVAX) generate clinically meaningful antitumor immunity without grade 3 or 4 toxicity in a majority of metastatic melanoma patients. The application of this sequential immunotherapy to advanced ovarian carcinoma patients also revealed that tumor destruction and severe inflammatory pathology could be dissociated, although further refinements are required to increase clinical responses and to minimize toxicity in this population. The extent of therapy-induced tumor necrosis was linearly related to the natural logarithm of the ratio of intratumoral CD8+ effector T cells to FoxP3+ regulatory T cells (Tregs) in posttreatment biopsies. Together, these findings help clarify the immunologic and clinical effects of CTLA-4 antibody blockade in previously vaccinated patients and raise the possibility that selective targeting of antitumor Tregs may constitute a complementary strategy for combination therapy.

Growth Hormone, Glutamine, and an Optimal Diet Reduces Parenteral Nutrition in Patients With Short Bowel Syndrome: A Prospective, Randomized, Placebo-Controlled, Double-Blind Clinical Trial

Objective:To determine if growth hormone (GH) and glutamine (Gln) might allow for a reduction in parenteral nutrition (PN) in individuals with short bowel syndrome. Background Data:Following massive intestinal resection, patients frequently sustain severe nutrient malabsorption and are dependent on PN for life. GH treatment with or without Gln might allow for a reduction in PN. Methods:A prospective, double-blind, randomized, placebo-controlled clinical trial performed in 41 adults dependent on PN. Following screening, patients were admitted to an in-house facility for 6 weeks. After 2 weeks of stabilization and dietary optimization, patients were randomized to one of 3 treatment arms (1:2:2 ratio): oral Gln (30 g/day) + GH placebo (control group, n = 9), Gln placebo + GH (0.1 mg/kg per day, n = 16), or Gln + GH (n = 16). Standard criteria based on clinical and laboratory measurements were followed to determine PN volume and content. After 4 weeks of treatment, patients were discharged and monitored; GH and GH placebo were discontinued, but the diet with Gln or Gln placebo was continued for 3 months. Results:Patients receiving GH + Gln placebo + diet showed greater reductions in PN volume (5.9 ± 3.8 L/wk, mean ± SD), PN calories (4338 ± 1858 calories/wk), and PN infusions (3 ± 2 infusions/wk) than corresponding reductions in the Gln + diet group (3.8 ± 2.4 L/wk; 2633 ± 1341 calories/wk; 2 ± 1 infusions/wk, P < 0.05). Patients who received GH + Gln + diet showed the greatest reductions (7.7 ± 3.2 L/wk; 5751 ± 2082 calories/wk; 4 ± 1 infusions/wk, P < 0.001 versus Gln + diet). At the 3-month follow-up, only patients who had received GH + Gln + diet maintained significant reductions in PN (P < 0.005) compared with the Gln + diet. Conclusions:Treatment with GH + diet or GH + Gln + diet initially permitted significantly more weaning from PN than Gln + diet. Only subjects receiving GH + Gln + diet maintained this effect for at least 3 months.

Roux-en-Y Gastric Bypass Surgery or Lifestyle With Intensive Medical Management in Patients With Type 2 Diabetes: Feasibility and 1-Year Results of a Randomized Clinical Trial

IMPORTANCE Emerging data support bariatric surgery as a therapeutic strategy for management of type 2 diabetes mellitus. OBJECTIVE To test the feasibility of methods to conduct a larger multisite trial to determine the long-term effect of Roux-en-Y gastric bypass (RYGB) surgery compared with an intensive diabetes medical and weight management (Weight Achievement and Intensive Treatment [Why WAIT]) program for type 2 diabetes. DESIGN, SETTING, AND PARTICIPANTS A 1-year pragmatic randomized clinical trial was conducted in an academic medical institution. Participants included persons aged 21 to 65 years with type 2 diabetes diagnosed more than 1 year before the study; their body mass index was 30 to 42 (calculated as weight in kilograms divided by height in meters squared) and hemoglobin A1c (HbA1c) was greater than or equal to 6.5%. All participants were receiving antihyperglycemic medications. INTERVENTIONS RYGB (n = 19) or Why WAIT (n = 19) including 12 weekly multidisciplinary group lifestyle, medical, and educational sessions with monthly follow-up thereafter. MAIN OUTCOMES AND MEASURES Proportion of patients with fasting plasma glucose levels less than 126 mg/dL and HbA1c less than 6.5%, measures of cardiometabolic health, and patient-reported outcomes. RESULTS At 1 year, the proportion of patients achieving HbA1c below 6.5% and fasting glucose below 126 mg/dL was higher following RYGB than Why WAIT (58% vs 16%, respectively; P = .03). Other outcomes, including HbA1c, weight, waist circumference, fat mass, lean mass, blood pressure, and triglyceride levels, decreased and high-density lipoprotein cholesterol increased more after RYGB compared with Why WAIT. Improvement in cardiovascular risk scores was greater in the surgical group. At baseline the participants exhibited moderately low self-reported quality-of-life scores reflected by Short Form-36 total, physical health, and mental health, as well as high Impact of Weight on Quality of Life-Lite and Problem Areas in Diabetes health status scores. At 1 year, improvements in Short Form-36 physical and mental health scores and Problem Areas in Diabetes scores did not differ significantly between groups. The Impact of Weight on Quality of Life-Lite score improved more with RYGB and correlated with greater weight loss compared with Why WAIT. CONCLUSIONS AND RELEVANCE In obese patients with type 2 diabetes, RYGB produces greater weight loss and sustained improvements in HbA1c and cardiometabolic risk factors compared with medical management, with emergent differences over 1 year. Both treatments improve general quality-of-life measures, but RYGB provides greater improvement in the effect of weight on quality of life. These differences may help inform therapeutic decisions for diabetes and weight loss strategies in obese patients with type 2 diabetes until larger randomized trials are performed. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01073020.

Gastrojejunal Stoma Diameter Predicts Weight Regain after Roux-en-Y Gastric Bypass

BACKGROUND & AIMS Weight regain after Roux-en-Y gastric bypass (RYGB) is associated with reductions in health status and quality of life. We evaluated whether gastrojejunal stoma diameter is a risk factor for weight regain after RYGB. METHODS We examined data collected over 4 years from consecutive patients referred to a tertiary care bariatric center for upper endoscopy after RYGB. We used linear regression analysis to determine the association between the gastrojejunal stoma diameter and weight regain. We applied a logistic regression model using clinical and endoscopic parameters to develop a prediction rule for weight gain after RYGB. RESULTS Among 165 patients included in our study, 59% had significant weight regain (≥ 20% of maximum weight lost after the RYGB) and 41% did not. The mean percentage of maximal weight lost after RYGB that was regained in the entire cohort was 30% ± 22%. Gastrojejunal stoma diameter was associated significantly with weight regain after RYGB surgery in univariate analysis (β = .31, P < .0001). This association remained significant after adjusting for several known or purported risk factors for weight regain (β = .19, P = .003). We developed a simple prediction rule for weight regain after RYGB using a 7-point scoring system that includes the gastrojejunal stoma diameter, race, and percentage of maximal body weight lost after RYGB; a cut-off score of 4 or more points had an area under receiver operating characteristic curve of 0.76 and a positive predictive value of 75%. CONCLUSIONS Increased gastrojejunal stoma diameter is a risk factor for weight regain after RYGB and can be incorporated in a novel prediction rule.

Endoscopic repair of gastrogastric fistula after Roux-en-Y gastric bypass: a less-invasive approach.

BACKGROUND Gastrogastric fistulas (GGFs) are a well-known complication of Roux-en-Y gastric bypass. Surgical repair of such fistulas is technically difficult, with significant associated morbidity. The aim of the present study was to evaluate the efficacy of endoscopic GGF closure at a university hospital in the United States. METHODS Patients with Roux-en-Y gastric bypass and confirmed GGFs on esophagogastroduodenoscopy or barium study. Endoscopic repair was performed with the EndoCinch suturing system (group 1) or clips (group 2). All patients were followed up in the outpatient clinic or interviewed by telephone at 1, 6, and 18 months after the procedure, then as indicated by symptoms. RESULTS A total of 95 patients were included in the present series (group 1, n = 71, 75%; group 2, n = 24, 25%). The mean GGF size was significantly larger in group 1 than in group 2 (14.5 +/- 8.7 versus 7.7 +/- 6, P = .01). An average of 2.2 sutures or 3 clips (range 2-7) was used. Complete initial GGF closure was achieved in 90 patients (95%), with reopening in 59 (65%) an average of 177 +/- 202 days. The average follow-up was 395 +/- 49 days, with 22 patients lost to follow-up. Two significant complications were reported (bleeding and an esophageal tear). None of the GGFs with an initial size >20 mm remained closed during the follow-up period compared with 10 (32%) of the 31 fistulas <or=10 mm in diameter remained closed. CONCLUSION Peroral endoscopic repair of postbariatric GGFs is technically feasible and safe but with limited durability. The fistula size predicted for long-term outcomes, with the best results seen in fistulas <or=10 mm in diameter.

Treatment of weight regain after gastric bypass surgery when using a new endoscopic platform: initial experience and early outcomes (with video)

BACKGROUND Some patients are thought to regain weight after gastric bypass surgery because of dilation of the gastrojejunal anastomosis (GJA) and/or gastric pouch. OBJECTIVE To assess the technical success and safety of an endoscopic procedure, Revision Obesity Surgery Endoscopic (ROSE), using an endoscopic operating system for the placement of tissue anchors to reduce the diameter of the GJA and size of the gastric pouch. DESIGN Prospective case series. SETTING Brigham and Womens Hospital, Boston, Massachusetts. PATIENTS AND INTERVENTIONS A total of 20 patients who had regained a mean of 13 kg after gastric bypass, with a dilated pouch and GJA on screening endoscopy, underwent the ROSE procedure. MAIN OUTCOME MEASUREMENTS Technical success, reduction in size of the GJA and gastric pouch, and early complications. Early weight loss was also assessed. RESULTS Technical success was achieved in 17 of 20 (85%) patients with an average reduction in stoma diameter of 16 mm (65% reduction) and an average reduction in pouch length of 2.5 cm (36% reduction). The mean weight loss in successful cases was 8.8 kg at 3 months. There were no major complications. LIMITATIONS Single-center case series with a relatively small number of patients and short duration of follow-up, which was inadequate for assessing durable long-term weight loss. CONCLUSION The ROSE procedure is technically feasible and appears safe. Data from this series suggest that the ROSE procedure is effective in reducing not only the size of the GJA but also the gastric pouch and may provide an endoscopic alternative for weight regain in gastric bypass patients.

Evaluation of an endoscopic suturing device for transoral outlet reduction in patients with weight regain following Roux-en-Y gastric bypass

BACKGROUND AND STUDY AIMS A dilated gastrojejunal anastomosis (GJA) is thought to be associated with weight regain in patients with Roux-en-Y gastric bypass (RYGB). Due to a high rate of perioperative morbidity, surgical revision is not generally performed. The aim of this study was to assess the technical feasibility, safety, and early outcomes of a procedure using a commercially available endoscopic suturing device to reduce the diameter of the GJA. PATIENTS AND METHODS This was a retrospective analysis of 25 consecutive patients who underwent transoral outlet reduction (TORe) for dilated GJA and weight regain. An endoscopic suturing device was used to place sutures at the margin of the GJA in order to reduce its aperture. On chart review, clinical data were available at 3, 6, and 12 months. RESULTS Patients had regained a mean of 24 kg from their weight loss nadir and had a mean body mass index of 43 kg/m2 at the time of endoscopic revision. Average anastomosis diameter was 26.4 mm. Technical success was achieved in all patients (100 %) with a mean reduction in anastomosis diameter to 6 mm (range 3 - 10 mm), representing a 77.3 % reduction. The mean weight loss in successful cases was 11.5 kg, 11.7 kg, and 10.8 kg at 3, 6, and 12 months, respectively. There were no major complications. CONCLUSION This case series demonstrated the technical feasibility, safety, and efficacy of performing gastrojejunostomy reduction using a commercially available endoscopic suturing device. This technique may represent an effective and minimally invasive option for the management of weight regain in patients with RYGB.

Band revision versus Roux-en-Y gastric bypass conversion as salvage operation after laparoscopic adjustable gastric banding

BACKGROUND With the increasing popularity of laparoscopic adjustable banding (LAGB), reoperations to treat band complications have become increasingly more common. Few studies, however, have documented the outcomes of such revisional procedures. The purpose of the present study was to compare the different reoperative approaches after LAGB placement. The present study was conducted at a tertiary referral academic medical center in the United States. METHODS We reviewed our bariatric database to identify patients who had undergone LAGB from 2004 to 2007 and had undergone either revision of their original band or conversion to Roux-en-Y gastric bypass. RESULTS Of the 66 patients who met our inclusion criteria, 47 (71.2%) had undergone revision and 19 (28.8%) conversion. The patient demographics were similar between the 2 groups. The interval to revision or conversion was 22 and 28 months, respectively. Band slippage was the most common surgical indication in the revision group, and inadequate weight loss was the most common in the conversion group. Although patients in the revision group had experienced good weight loss before their reoperation, the conversion group had not. However, the conversion group experienced good weight loss after their reoperation, with an average excess body weight loss of 48%. CONCLUSION Patients who have experienced successful weight loss with LAGB and experience band complications will have satisfactory outcomes with band revision, maintaining their excess body weight loss. These data suggest that patients with inadequate weight loss after LAGB can do well after conversion to Roux-en-Y gastric bypass.

Endoscopic sclerotherapy for the treatment of weight regain after Roux-en-Y gastric bypass: outcomes, complications, and predictors of response in 575 procedures.

BACKGROUND Weight regain after Roux-en-Y gastric bypass (RYGB) is common. Endoscopic sclerotherapy is increasingly used to treat this weight regain. OBJECTIVES To report safety, outcomes, durability, and predictors of response to sclerotherapy in a large prospective cohort. DESIGN Retrospective analysis of a prospective cohort study of patients with weight regain after RYGB. PATIENTS A total of 231 consecutive patients undergoing 575 sclerotherapy procedures between September 2008 and March 2011. INTERVENTIONS Single or multiple sclerotherapy procedures to inject sodium morrhuate into the rim of the gastrojejunal anastomosis. MAIN OUTCOME MEASUREMENTS We report weight loss, complications, and predictors of response. We also used Kaplan-Meier survival analysis and log-rank test to compare time to continuation of weight regain after sclerotherapy in patients undergoing a single versus multiple sclerotherapy procedures. RESULTS At 6 and 12 months from the last sclerotherapy procedure, weight regain stabilized in 92% and 78% of the cohort, respectively. Those who underwent 2 or 3 sclerotherapy sessions had significantly higher rates of weight regain stabilization than those who underwent a single session (90% vs 60% at 12 months; P = .003). The average weight loss at 6 months from the last sclerotherapy session for the entire cohort was 10 lb (standard deviation 16), representing 18% of the weight regained after RYGB. A subset of 73 patients (32% of the cohort) had greater weight loss at 6 months (26 lb, standard deviation 12), representing 61% of the weight regained. Predictors of a favorable outcome included greater weight regain and the number of sclerotherapy procedures. Bleeding was reported in 2.4% of procedures and transient diastolic blood pressure increases in 15%, without adverse health outcomes. No GI perforations were reported. CONCLUSIONS Endoscopic sclerotherapy appears to be a safe and effective tool for the management of weight regain after RYGB.

Obesity Overview: Epidemiology, Health and Financial Impact, and Guidelines for Qualification for Surgical Therapy

The aim of this article is to describe the context in which this issue of Gastrointestinal Endoscopy Clinics of North America is established. The authors review the current worldwide dimensions and trends of the obesity epidemic; associated mortality and comorbid diseases including diabetes, cancer, cardiovascular disease and obstructive sleep apnea; the financial impact of obesity; and current national and international guidelines for referral and qualification for surgical treatment of obesity.