Vimal K. Narula

Natural-orifice transgastric endoscopic peritoneoscopy in humans: Initial clinical trial

BackgroundNatural-orifice translumenal endoscopic surgery (NOTES) is a possible advancement for surgical interventions. We initiated a pilot study in humans to investigate feasibility and develop the techniques and technology necessary for NOTES. Reported herein is the first human clinical trial of NOTES, performing transoral transgastric diagnostic peritoneoscopy.MethodsPatients were scheduled to undergo diagnostic laparoscopic evaluation of a pancreatic mass. The findings of traditional laparoscopy were recorded by anatomical abdominal quadrant. A second surgeon, blinded to the laparoscopic findings, performed transgastric peritoneoscopy. Diagnostic findings between the two methods were compared and operative times and clinical course were recorded. Definitive care was based on findings at diagnostic laparoscopy.ResultsTen patients completed the protocol with an average age of 67.6 years. All patients underwent diagnostic laparoscopy followed by successful transgastric access and diagnostic endoscopic peritoneoscopy. The average time of diagnostic laparoscopy was 12.3 minutes compared to 24.8 minutes for the transgastric route. Transgastric abdominal exploration corroborated the decision to proceed to open exploration made during traditional laparoscopic exploration in 9 of 10 patients. Peritoneal or liver biopsies were obtained in four patients by traditional laparoscopy and in one patient by the transgastric access route. Findings were confirmed by laparotomy in nine patients. Eight patients underwent pancreaticoduodenectomy and two underwent palliative gastrojejunostomy and/or hepaticojejunostomy.ConclusionsTransgastric diagnostic peritoneoscopy is safe and feasible. This study demonstrates the initial steps of NOTES in humans, providing a potential platform for incisionless surgery. Technical issues, including instrumentation, visualization, intra-abdominal manipulation, and gastric closure need further development.

Visceral Adipose Inflammation in Obesity Is Associated with Critical Alterations in Tregulatory Cell Numbers

Background The development of insulin resistance (IR) in mouse models of obesity and type 2 diabetes mellitus (DM) is characterized by progressive accumulation of inflammatory macrophages and subpopulations of T cells in the visceral adipose. Regulatory T cells (Tregs) may play a critical role in modulating tissue inflammation via their interactions with both adaptive and innate immune mechanisms. We hypothesized that an imbalance in Tregs is a critical determinant of adipose inflammation and investigated the role of Tregs in IR/obesity through coordinated studies in mice and humans. Methods and Findings Foxp3-green fluorescent protein (GFP) “knock-in” mice were randomized to a high-fat diet intervention for a duration of 12 weeks to induce DIO/IR. Morbidly obese humans without overt type 2 DM (n = 13) and lean controls (n = 7) were recruited prospectively for assessment of visceral adipose inflammation. DIO resulted in increased CD3+CD4+, and CD3+CD8+ cells in visceral adipose with a striking decrease in visceral adipose Tregs. Treg numbers in visceral adipose inversely correlated with CD11b+CD11c+ adipose tissue macrophages (ATMs). Splenic Treg numbers were increased with up-regulation of homing receptors CXCR3 and CCR7 and marker of activation CD44. In-vitro differentiation assays showed an inhibition of Treg differentiation in response to conditioned media from inflammatory macrophages. Human visceral adipose in morbid obesity was characterized by an increase in CD11c+ ATMs and a decrease in foxp3 expression. Conclusions Our experiments indicate that obesity in mice and humans results in adipose Treg depletion. These changes appear to occur via reduced local differentiation rather than impaired homing. Our findings implicate a role for Tregs as determinants of adipose inflammation.

Transgastric instrumentation and bacterial contamination of the peritoneal cavity

IntroductionNatural orifice transluminal endoscopic surgery (NOTES) is a rapidly evolving technique providing access to the peritoneum utilizing an endoscope via a natural orifice. One of the most significant requirements of this technique is the need to minimize the risk of clinically significant peritoneal contamination. We report the bacterial load and contamination of the peritoneal cavity in patients requiring a gastrotomy Roux-en-Y gastric bypass (LSRYGB).MethodsWe prospectively studied 50 patients undergoing a gastrotomy with creation of a gastrojejunostomy during LSRYGB. We recorded the patient’s proton-pump inhibitor (PPI) utilization preoperatively and sampled gastric contents without lavage. We also sampled peritoneal fluid prior to and after gastrotomy, noting the length of time the gastrotomy was open to the peritoneum. Each of the three samples was sent for bacterial colony counts, and culture with identification of species.ResultsFifty patients underwent LSRYGB with a mean operative time of 93 min. The gastrotomy was open to the peritoneal cavity for an average of 18 min. Seventeen of 50 patients were on PPIs preoperatively, resulting in a significant difference in postgastrostomy peritoneal bacterial counts. The average number of colony-forming units (CFU) of the gastric aspirate was 22,303 CFU/ml. Peritoneal aspirates obtained for examination prior to creation of a gastrotomy showed no CFUs in 44 of 50 patients. Peritoneal sampling after gastrotomy showed contamination of the abdomen with an average of 1102 CFU/ml. There was no correlation between the bacterial load in the stomach and peritoneal load after gastrotomy. No infectious complications or leaks developed. One complication of rhabdomyolysis in a patient with no peritoneal bacterial contamination developed.ConclusionsTransgastric instrumentation does contaminate the abdominal cavity but pathogens are clinically insignificant due to species or bacterial load. Patients on PPIs do have an increased bacterial load in the gastric aspirate, with no clinical significant infection.

A Potential Role for Dendritic Cell/Macrophage-Expressing DPP4 in Obesity-Induced Visceral Inflammation

Dipeptidyl peptidase-4 (DDP4) inhibitors target the enzymatic degradation of incretin peptides and represent a major advance in the treatment of type 2 diabetes. DPP4 has a number of nonenzymatic functions that involve its interaction with adenosine deaminase (ADA) and other extracellular matrix proteins. Here, we assessed the nonenzymatic role of DPP4 in regulating dendritic cell (DC)/macrophage–mediated adipose inflammation in obesity. Both obese humans and rodents demonstrated increased levels of DPP4 expression in DC/macrophage cell populations from visceral adipose tissue (VAT). The DPP4 expression increased during monocyte differentiation to DC/macrophages and with lipopolysaccharide (LPS)-induced activation of DC/macrophages. The DPP4 colocalized with membrane-bound ADA on human DCs and enhanced the ability of the latter to stimulate T-cell proliferation. The DPP4 interaction with ADA in human DC/macrophages was competitively inhibited by the addition of exogenous soluble DPP4. Knockdown of DPP4 in human DCs, but not pharmacologic inhibition of their enzymatic function, significantly attenuated the ability to activate T cells without influencing its capacity to secrete proinflammatory cytokines. The nonenzymatic function of DPP4 on DC may play a role in potentiation of inflammation in obesity by interacting with ADA. These findings suggest a novel role for the paracrine regulation of inflammation in adipose tissue by DPP4.

Robotic and laparoscopic pancreaticoduodenectomy: A hybrid approach

Objectives: Minimally invasive surgery is beneficial for complex operations; robotics may improve performance in these procedures; however, robotic pancreaticoduodenectomy (PD) has been plagued by long operative times. We describe a small series (n = 5) of patients who underwent a hybrid PD for treatment of obstructive jaundice and pancreatic mass. Methods: After diagnostic laparoscopy, the gallbladder was retracted cephalad and the porta hepatis was dissected. The lesser sac was opened to expose the superior mesenteric vein below the pancreas. Once the vein was cleared, the bile duct, stomach, pancreas, and jejunum were transected. After the uncinate process was cleared, the specimen was removed. The da Vinci S Surgical Robotic System was docked to perform a mucosa-to-mucosa pancreaticojejunostomy and an end-to-side choledochojejunostomy. A stapled gastrojejunostomy and drain placement completed the operation. Results: Five patients underwent hybrid PD between May 2006 and June 2007. All patients had a history of pancreatitis and presented with obstructive jaundice and a pancreatic mass. The operations were completed with 5 ports. The mean operative time was 7 hours. The mean hospital stay was 9.6 days. At 6 months after the operation, all patients were disease-free. Conclusions: Complex procedures such as PD can be accomplished with minimally invasive surgical techniques using robotic instrumentation.

T-Cell Costimulation Protects Obesity-Induced Adipose Inflammation and Insulin Resistance

A key pathophysiologic role for activated T-cells in mediating adipose inflammation and insulin resistance (IR) has been recently postulated. However, mechanisms underlying their activation are poorly understood. In this study, we demonstrated a previously unrecognized homeostatic role for the costimulatory B7 molecules (CD80 and CD86) in preventing adipose inflammation. Instead of promoting inflammation, which was found in many other disease conditions, B7 costimulation reduced adipose inflammation by maintaining regulatory T-cell (Treg) numbers in adipose tissue. In both humans and mice, expression of CD80 and CD86 was negatively correlated with the degree of IR and adipose tissue macrophage infiltration. Decreased B7 expression in obesity appeared to directly impair Treg proliferation and function that lead to excessive proinflammatory macrophages and the development of IR. CD80/CD86 double knockout (B7 KO) mice had enhanced adipose macrophage inflammation and IR under both high-fat and normal diet conditions, accompanied by reduced Treg development and proliferation. Adoptive transfer of Tregs reversed IR and adipose inflammation in B7 KO mice. Our results suggest an essential role for B7 in maintaining Tregs and adipose homeostasis and may have important implications for therapies that target costimulation in type 2 diabetes.

A review of 130 humans enrolled in transgastric NOTES protocols at a single institution.

BackgroundThe methodology of Natural Orifice Translumenal Endoscopic Surgery (NOTES) has been validated in both human and animal models. Herein is a discussion of our experience gained from the initial 130 patients enrolled in transgastric pre-NOTES and NOTES protocols at our institution.MethodsA retrospective review of our research database was performed for all patients enrolled in NOTES protocols. The infectious risk of a gastrotomy with and without a NOTES procedure was assessed in 100 patients. Eighty patients completed a true NOTES protocol looking at staging, access, and insufflation with select patients evaluating the potential for bacterial contamination of the abdominal compartment.ResultsA total of 130 patients have completed pre-NOTES and NOTES protocols at our institution. We observed no clinically significant contamination of the abdomen secondary to transgastric procedures in 100 patients. Diagnostic transgastric endoscopic peritoneoscopy (DTEP) was completed in 20 patients with pancreatic head masses and found to have a 95% concordance with laparoscopic exploration for assessment of peritoneal metastases. Blind endoscopic gastrotomy and DTEP were evaluated in 40 patients who underwent laparoscopic Roux-en-Y gastric bypass procedures (LSRYGB) and were found to be safe, reliable, and without a clinically significant risk of contamination. Endoscopic peritoneal insufflation was successfully established and correlated with standard laparoscopic insufflation in 20 patients.ConclusionsTransgastric NOTES is a safe alternative approach to accessing the peritoneal cavity in humans. The risk of bacterial contamination secondary to peroral and transgastric access is clinically insignificant. A device for the facile closure of the gastric defect is the sole factor limiting institution of this methodology as a standalone technique.

Gastrotomy closure using bioabsorbable plugs in a canine model.

The repair of gastric perforation commonly involves simple suture closure using an open or laparoscopic approach. An endolumenal approach using prosthetic materials may be beneficial. The role of bioprosthetics in this instance has not been thoroughly investigated, thus the authors evaluated the feasibility of gastric perforation repair using a bioabsorbable device and quantified gross and histological changes at the injury site. Twelve canines were anesthetized and underwent open gastrotomy. A 1-cm-diameter perforation was created in the anterior wall of the stomach and plugged with a bioabsorbable device. Intralumenal pH was recorded. Canines were sacrificed at one, four, six, eight, and 12 weeks. The stomach was explanted followed by gross and histological examination. The injury site was examined. The relative ability of the device to seal the perforation was recorded, as were postoperative changes. Tissue samples were analyzed for gross and microscopic tissue growth and compared to normal gastric tissue in the same animal as an internal control. A scoring system of −2 to +2 was used to measure injury site healing (−2= leak, −1= no leak and minimal ingrowth, 0= physiologic healing, +1= mild hypertrophic tissue, +2= severe hypertrophic tissue). In all canines, the bioprosthesis successfully sealed the perforation without leak under ex vivo insufflation. At one week, the device maintained its integrity but there was no tissue ingrowth. Histological healing score was −1. At 4–12 weeks, gross examination revealed a healed injury site in all animals. The lumenal portion of the plug was completely absorbed. The gross and histological healing score ranged from −1 to +1. The application of a bioabsorbable device results in durable closure of gastric perforation with physiologic healing of the injury site. This method of gastrotomy closure may aid in the evolution of advanced endoscopic approaches to perforation closure of hollow viscera.

Laparoscopic Distal Pancreatectomy with Splenic Conservation: An Operation without Increased Morbidity

Objectives. The advent of minimally invasive techniques was marked by a paradigm shift towards the use of laparoscopy for benign distal pancreatic masses. Herein we describe one centers experience with laparoscopic distal pancreatectomy. Methods. A retrospective chart review was performed for all distal pancreatectomies completed laparoscopically from 1999 to 2009. Outcomes from those cases completed with a concurrent splenectomy were compared to the spleen-preserving procedures. Results. Twenty-four patients underwent laparoscopic distal pancreatectomy. Seven had spleen-conserving operations. There was no difference in the mean estimated blood loss (316 versus 285 mL, P = .5) or operative time (179 versus 170 minutes, P = .9). The mean tumor size was not significantly different (3.1 versus 2.2 cm, P = .9). There was no difference in the average hospital stay (7.1 versus 7.0 days, P = .7). Complications in the spleen-preserving group included one iatrogenic colon injury, two pancreatic fistulas, and two cases of iatrogenic diabetes. In the splenectomy group, two developed respiratory failure, three acquired iatrogenic diabetes, and two suffered pancreatic fistulas (71% versus 41%, P = .4). Conclusions. The laparoscopic distal pancreatectomy is a safe operation with a low morbidity. Splenic conservation does not significantly increase the morbidity of the procedure.

A computerized analysis of robotic versus laparoscopic task performance

IntroductionRobotic technology has been postulated to improve performance in advanced surgical skills. We utilized a novel computerized assessment system to objectively describe the technical enhancement in task performance comparing robotic and laparoscopic instrumentation.Methods and proceduresAdvanced laparoscopic surgeons (2–10 yrs experience) performed three unique task modules using laparoscopic and Telerobotic surgical instrumentation (Intuitive Surgical, Sunnyvale, CA). Performance was evaluated using a computerized assessment system (ProMIS, Dublin, Ireland) and results were recorded as time (s), path (mm) and precision. Each surgeon had an initial training session followed by two testing sessions for each module. A paired Student’s t-test was used to analyze the data.ResultsTen surgeons completed the study. 8/10 surgeons had significant technical enhancement utilizing robotic technology.ConclusionsThe ProMIS computerized assessment system can be modified to objectively obtain task performance data with robotic instrumentation. All the tasks were performed faster and with more precision using the robotic technology than standard laparoscopy.