Near-infrared fluorescent cholangiography facilitates identification of biliary anatomy during laparoscopic cholecystectomy.

BACKGROUND: Intraoperative cholangiography (IOC) is the current gold standard for biliary imaging during laparoscopic cholecystectomy (LC). However, utilization of IOC remains low. Near-infrared fluorescence cholangiography (NIRF-C) is a novel, noninvasive method for real-time, intraoperative biliary mapping. Our aims were to assess the safety and efficacy of NIRF-C for identification of biliary anatomy during LC. METHODS: Patients were administered indocyanine green (ICG) prior to surgery. NIRF-C was used to identify extrahepatic biliary structures before and after partial and complete dissection of Calot's triangle. Routine IOC was performed in each case. Identification of biliary structures using NIRF-C and IOC, and time required to complete each procedure were collected. RESULTS: Eighty-two patients underwent elective LC with NIRF-C and IOC. Mean age and body mass index (BMI) were 42.6 ± 13.7 years and 31.5 ± 8.2 kg/m(2), respectively. ICG was administered 73.8 ± 26.4 min prior to incision. NIRF-C was significantly faster than IOC (1.9 ± 1.7 vs. 11.8 ± 5.3 min, p < 0.001). IOC was unobtainable in 20 (24.4 %) patients while NIRF-C did not visualize biliary structures in 4 (4.9 %) patients. After complete dissection, the rates of visualization of the cystic duct, common bile duct, and common hepatic duct using NIRF-C were 95.1, 76.8, and 69.5 %, respectively, compared to 72.0, 75.6, and 74.3 % for IOC. In 20 patients where IOC could not be obtained, NIRF-C successfully identified biliary structures in 80 % of the cases. Higher BMI was not a deterrent to visualization of anatomy with NIRF-C. No adverse events were observed with NIRF-C. CONCLUSIONS: NIRF-C is a safe and effective alternative to IOC for imaging extrahepatic biliary structures during LC. This technique should be evaluated further under a variety of acute and chronic gallbladder inflammatory conditions to determine its usefulness in biliary ductal identification.

Obstructive jaundice expands intrahepatic regulatory T cells, which impair liver T lymphocyte function but modulate liver cholestasis and fibrosis.

Although obstructive jaundice has been associated with a predisposition toward infections, the effects of bile duct ligation (BDL) on bulk intrahepatic T cells have not been clearly defined. The aim of this study was to determine the consequences of BDL on liver T cell phenotype and function. After BDL in mice, we found that bulk liver T cells were less responsive to allogeneic or syngeneic Ag-loaded dendritic cells. Spleen T cell function was not affected, and the viability of liver T cells was preserved. BDL expanded the number of CD4(+)CD25(+)Foxp3(+) regulatory T cells (Treg), which were anergic to direct CD3 stimulation and mediated T cell suppression in vitro. Adoptively transferred CD4(+)CD25(-) T cells were converted into Treg within the liver after BDL. In vivo depletion of Treg after BDL restored bulk liver T cell function but exacerbated the degrees of inflammatory cytokine production, cholestasis, and hepatic fibrosis. Thus, BDL expands liver Treg, which reduce the function of bulk intrahepatic T cells yet limit liver injury.

Advances in the surgical management of gastrointestinal stromal tumor.

Imatinib mesylate has revolutionized the treatment of GIST. Dramatic changes in clinical practice have been observed in the past decade. Nonetheless, time has also revealed the limitations of treating GIST with a single agent alone, as resistance to imatinib has become a significant clinical dilemma. Surgical resection still remains the only chance for a cure. However, it is clear that GIST is a complex disease and requires effective integration of surgery and targeted therapy to reduce recurrence after resection of primary GIST or to prolong survival in metastatic disease. Recent studies have begun to delineate the feasibility of multimodal treatment of this disease. Knowledge gained thus far, along with ongoing and future investigations of GIST, will be extremely relevant to the potential use of molecular targeted therapy for other solid neoplasms.

Combined stimulation with interleukin-18 and CpG induces murine natural killer dendritic cells to produce IFN-gamma and inhibit tumor growth.

Natural killer dendritic cells (NKDC) are a novel subtype of dendritic cells with natural killer (NK) cell properties. IFN-gamma is a pleiotropic cytokine that plays an important role in the innate immune response to tumors. Based on our previous finding that the combination of Toll-like receptor 9 ligand CpG and interleukin (IL)-4 stimulates NKDC to produce IFN-gamma, we hypothesized that NKDC are the major IFN-gamma-producing dendritic cell subtype and may play a significant role in the host antitumor response. We found that under several conditions in vitro and in vivo NKDC accounted for the majority of IFN-gamma production by murine spleen CD11c(+) cells. IL-18 alone induced NKDC to secrete IFN-gamma, and the combination of IL-18 and CpG resulted in a synergistic increase in IFN-gamma production, both in vitro and in vivo. NK cells made 26-fold less IFN-gamma under the same conditions in vitro, whereas dendritic cells produced a negligible amount. The mechanism of IFN-gamma secretion by NKDC depended on IL-12. NKDC selectively proliferated in vitro and in vivo in response to the combination of IL-18 and CpG. Systemic treatment with IL-18 and CpG reduced the number of B16F10 melanoma lung metastases. The mechanism depended on NK1.1(+) cells, as their depletion abrogated the effect. IL-18 and CpG activated NKDC provided greater tumor protection than NK cells in IFN-gamma(-/-) mice. Thus, NKDC are the major dendritic cell subtype to produce IFN-gamma. The combined use of IL-18 and CpG is a viable strategy to potentiate the antitumor function of NKDC.

In vivo overexpression of Flt3 ligand expands and activates murine spleen natural killer dendritic cells.

Natural killer dendritic cells (NKDC) are a unique class of murine immune cells that possess the characteristics of both natural killer (NK) cells and dendritic cells (DC). Because NKDC are able to secrete IFN-gamma, directly lyse tumor cells, and present antigen to naïve T cells, they have immunotherapeutic potential. The relative paucity of NKDC, however, impedes their detailed study. We have found that in vivo, overexpression of the hematopoietic cytokine Flt3 ligand (Flt3L) expands NKDC in various organs from 2-18 fold. Flt3L expanded splenic NKDC retain the ability to lyse tumor cells and become considerably more potent at activating naïve allogeneic and antigen-specific T cells. Compared to normal splenic NKDC, Flt3L-expanded splenic NKDC have a more mature phenotype, a slightly increased ability to capture and process antigen, and a similar cytokine profile. In vivo, we found that Flt3L-expanded splenic NKDC are more effective than normal splenic NKDC in stimulating antigen-specific CD8 T cells. Additionally, we show that NKDC are able to cross-present antigen in vivo. The ability to expand NKDC in vivo using Flt3L will facilitate further analysis of their unique biology. Moreover, Flt3L-expanded NKDC may have enhanced immunotherapeutic potential, given their increased ability to stimulate T cells.

Laparoscopic Nissen fundoplication controls reflux symptoms and improves disease-specific quality of life in patients with class I and II obesity.

BACKGROUND: Patients with class I obesity and refractory gastroesophageal reflux disease may not qualify for bariatric surgery, and the effectiveness of laparoscopic Nissen fundoplication remains controversial. This study evaluates the early efficacy of laparoscopic Nissen fundoplication in patients with class I and II obesity. METHODS: Data for patients who underwent laparoscopic Nissen fundoplication between 2009 and 2014 were collected prospectively. Cohorts were stratified based on body mass index at the time of surgery: Nonobese (body mass index <30 kg/m2), class I obese (body mass index 30-34.9 kg/m2), and class II obese (body mass index 35-39.9 kg/m2). Primary outcome measures were symptoms assessed using the gastroesophageal reflux symptom scale and the gastroesophageal reflux disease health-related quality of life questionnaires. RESULTS: One hundred seventy-six patients underwent laparoscopic Nissen fundoplication during the study period: 76 nonobese (body mass index 26.2 ± 2.9 kg/m2), 53 class I obese (body mass index 32.4 ± 1.5 kg/m2), and 47 class II obese (body mass index 37.7 ± 2.5 kg/m2). Baseline gastroesophageal reflux symptom scale scores were 35.5 (6-72), 37.0 (5-72), and 45.0 (5-72) in nonobese, class I obese, and class II obese groups, respectively. Six weeks postoperatively, scores decreased to 6.5 (0-72), 4.0 (0-27), and 9.0 (0-64), respectively (P < .001). After 18-months, scores remained improved at 8.0 (0-72), 5 (0-48), and 4 (0-62), respectively (P < .001). A similar trend was seen in gastroesophageal reflux disease-health-related quality of life scores. Overall, 86%, 83%, and 79% remained free of proton-pump inhibitor medications, respectively. CONCLUSION: Laparoscopic Nissen fundoplication provides similar symptom control and quality of life 18-months postoperatively in nonobese and class I and II obese patients. Thus, laparoscopic Nissen fundoplication represents a viable surgical option for patients with class I and II obesity.

Pharmacotherapy in Conjunction with a Diet and Exercise Program for the Treatment of Weight Recidivism or Weight Loss Plateau Post-bariatric Surgery: a Retrospective Review.

BACKGROUND: Bariatric surgery is an effective therapeutic option for management of obesity. However, weight recidivism (WR) and weight loss plateau (WLP) are common problems. We present our experience with the use of two pharmacotherapies in conjunction with our standard diet and exercise program in those patients who experienced WR or WLP. METHODS: From June 2010 to April 2014, bariatric surgery patients who experienced WR or WLP after undergoing Roux-en-Y gastric bypass (RYGB) or laparoscopic adjustable gastric banding (LAGB), and who were treated with phentermine (Ph) or phentermine-topiramate (PhT), were reviewed retrospectively. Generalized estimating equations were used to compare patient weights through 90 days between initial surgery type and medication type. Patient weights, medication side effect, and co-morbidities were collected during the first 90 days of therapy. RESULTS: Fifty-two patients received Ph while 13 patients received PhT. Overall, patients in both groups lost weight. Among those whose weights were recorded at 90 days, patients on Ph lost 6.35 kg (12.8% excess weight loss (EWL); 95% confidence interval (CI) 4.25, 8.44) and those prescribed PhT lost 3.81 kg (12.9% EWL; CI 1.08, 6.54). Adjusting for baseline weight, time since surgery, and visit through 90 days, patients treated with Ph weighed significantly less than those on PhT throughout the course of this study (1.35 kg lighter; 95% CI 0.17, 2.53; p = 0.025). There were no serious side effects reported. CONCLUSIONS: Phentermine and phentermine-topirimate in addition to diet and exercise appear to be viable options for weight loss in post-RYGB and LAGB patients who experience WR or WLP.

Laparoscopic sleeve gastrectomy in morbidly obese patients with end-stage heart failure and left ventricular assist device: medium-term results.

BACKGROUND: Morbid obesity precludes patients with end-stage heart failure from becoming cardiac transplant candidates. This study evaluates the safety and efficacy of laparoscopic sleeve gastrectomy (LSG) as a means to transplant candidacy in such patients. METHODS: Morbidly obese patients with end-stage heart failure, who were ineligible for cardiac transplantation and underwent LSG between 2008 and 2013, were reviewed retrospectively. Demographic characteristics, perioperative details, percentage of excess weight loss (%EWL), and status of transplant candidacy were analyzed. RESULTS: Six patients (3 men) with end-stage heart failure and morbid obesity underwent LSG. Three patients (50%) had a left ventricular assist device (LVAD) in place at the time of surgery. Median age was 34 (31-66) years and mean preoperative body mass index (BMI) was 47.6±3.0 kg/m2. Median operative time was 90 (66-141) minutes, with a median length of stay of 7 (4-16) days. There were no perioperative deaths. One patient suffered a spontaneous flank hematoma. The same patient also had thrombosis of the LVAD pump at 3 weeks postoperatively, requiring an uneventful device exchange. At median follow-up of 22 (12-70) months, the mean %EWL was 51.4±10.3% with a decrease in BMI to 34.3±2.4 kg/m2 (P<.05). All patients had lost sufficient weight to become transplant eligible within 12 months of surgery. Two patients had undergone successful transplantation and another 2 were on the transplant list. CONCLUSION: LSG appears to be a safe, technically feasible, and effective method for obtaining adequate weight loss in morbidly obese patients with end-stage heart failure and mechanical circulatory support, subsequently improving their access to cardiac transplantation. This is the largest case series to date of this high-risk group of patients undergoing LSG.

Laparoscopic adjustable gastric banded plication: case-matched study from a single U.S. center.

BACKGROUND: Laparoscopic adjustable gastric banded plication (LAGBP) is a novel technique for weight loss surgery. This study evaluates the safety and short-term efficacy of LAGBP in a U.S. population. The setting was an academic medical center in the United States. METHODS: Patients who underwent LAGBP between 2012 and 2013 were reviewed retrospectively. Demographic characteristics, pre and perioperative details, body mass index (BMI), and percent excess weight loss (%EWL) were analyzed and compared to case-matched cohorts that had laparoscopic adjustable gastric banding (LAGB) or laparoscopic sleeve gastrectomy (LSG) during the same time period. RESULTS: Seventeen patients (14 females) underwent LAGBP during the study period and were case-matched based on age, sex, race, and preoperative BMI with patients having LAGB and LSG. Mean age and preoperative BMI for LAGBP cohort were 42.5±11.6 years and 47.7±6.5 kg/m2, respectively. Mean operative time and estimated blood loss were 72±16 minutes and 23±23 mL, respectively, compared to 49±16 minutes (P=.002) and 15±23 mL for LAGB, and 66±18 minutes and 36±22 mL for LSG. There were no perioperative deaths. Hospital length of stay was 1.1±.3 days for LAGBP, versus .7±.3 days (P=.004) for LAGB, and 2.7±1.4 days (P<.001) for LSG. At 12-month follow-up, patients in the LAGBP and LAGB groups had undergone similar number of band adjustments (4.7 versus 5.1; P=.68). The %EWL was 46.1±14.8% for the LAGBP cohort, compared to 38.9±20.6% for LAGB, and 57.7±16% for LSG. CONCLUSION: LAGBP is technically feasible and safe, and offers weight loss results positioned between LAGB and LSG at 1 year. To date, this is the largest U.S. series to compare this novel technique to more traditional weight loss procedures.

Bioabsorbable hernia plugs in laparoscopic inguinal herniorraphy: short-term and long-term results.

PURPOSE: To report our short-term and long-term experience with laparoscopic inguinal hernia repair (LIHR) using a bioabsorbable plug. METHODS: Patients who underwent LIHR from 2009 to 2011 using a bioabsorbable plug and synthetic mesh patch were reviewed retrospectively. Short-term follow-up information was obtained within 30 days of surgery, whereas long-term follow-up was obtained in 2014. Quality of life was assessed using the Carolinas Comfort Scale. RESULTS: Forty-four patients (43 male), including 6 (13.6%) with recurrent disease, underwent 52 LIHR with a bioabsorbable plug. Mean age and body mass index were 60.9 ± 10.5 years and 27.9 ± 4.7 kg/m, respectively. Among 39 (88.6%) patients available for short-term follow-up, early postoperative complications were seen in 10 (25.6%) patients, all of which resolved spontaneously. Mean long-term follow-up duration was 41.6 ± 4.1 months, among 30 (68.2%) patients (40 hernia repairs). There were 2 (5%) hernia recurrences, with 1 requiring a reoperation 12 months after initial repair. Only 2 (6.7%) patients reported moderate or bothersome chronic pain. CONCLUSIONS: Bioabsorbable plug combined with a synthetic mesh is safe and effective for use during LIHR. The technique offers an acceptable incidence of chronic pain and recurrence.

Laparoscopy in trauma: An overview of complications and related topics.

The introduction of laparoscopy has provided trauma surgeons with a valuable diagnostic and, at times, therapeutic option. The minimally invasive nature of laparoscopic surgery, combined with potentially quicker postoperative recovery, simplified wound care, as well as a growing number of viable intraoperative therapeutic modalities, presents an attractive alternative for many traumatologists when managing hemodynamically stable patients with selected penetrating and blunt traumatic abdominal injuries. At the same time, laparoscopy has its own unique complication profile. This article provides an overview of potential complications associated with diagnostic and therapeutic laparoscopy in trauma, focusing on practical aspects of identification and management of laparoscopy-related adverse events.

Laparoscopic Roux-en-Y gastric bypass for treatment of symptomatic paraesophageal hernia in the morbidly obese: medium-term results.

BACKGROUND: The ideal surgical approach for treatment of symptomatic paraesophageal hernias (PEH) in obese patients remains elusive. The objective of this study was to assess the safety, feasibility, and effectiveness of combined laparoscopic PEH repair and Roux-en-Y gastric bypass (RYGB) for the management of symptomatic PEH in morbidly obese patients. METHODS: Fourteen patients with symptomatic PEH and morbid obesity (body mass index [BMI]>35 kg/m(2)) underwent laparoscopic PEH repair with RYGB between 2008 and 2011. Demographic characteristics and preoperative and perioperative details were analyzed. Patients were contacted in October 2013 for follow-up. BMI, reflux symptoms, and disease-specific quality of life (QoL) data were obtained. RESULTS: There were 11 females (79%). Median age and preoperative BMI were 48 years and 42 kg/m(2), respectively. Mean operative time was 180 minutes, with median length-of-stay of 4 days. There were no perioperative deaths, and 5 patients experienced postoperative complications including 1 gastrojejunostomy leak. Complete follow-up with a median follow-up interval of 35 months was available in 9 (64%) patients. The median % excess weight loss was 67.9%. Thirty-three percent required antisecretory medications for reflux control, compared to 89% preoperatively. Seventy-eight percent of patients reported good to excellent QoL outcomes assessed by the Gastroesophageal Reflux Disease Health-Related Quality of Life questionnaire. Overall, 89% of patients were satisfied with their operation and would undergo the procedure again. CONCLUSION: Combined laparoscopic PEH repair and RYGB is a safe, feasible, and effective treatment option for morbidly obese patients with symptomatic PEH, and offers good to excellent disease-specific quality-of-life outcomes at medium-term follow-up. To date, this is the largest series with the longest follow-up in this unique patient population.

Management of resectable gastrointestinal stromal tumor.

Gastrointestinal stromal tumor (GIST) is a rare neoplasm that recently has become an intense focus of scientific investigation, as it serves as a model for the molecular therapy for cancer. Although surgery remains the principle treatment of primary localized GIST, imatinib mesylate, a selective inhibitor of KIT protein, achieves dramatic responses in metastatic GIST. Multimodality therapy integrating surgery and molecular therapy has shown promise. This article summarizes the epidemiology, clinicopathologic features, natural history, and clinical management of GIST.

Murine liver plasmacytoid dendritic cells become potent immunostimulatory cells after Flt-3 ligand expansion.

UNLABELLED: The liver has unique immunological properties. Although dendritic cells (DCs) are central mediators of immune regulation, little is known about liver DCs. Plasmacytoid DCs (pDCs) are a recently identified subtype of murine liver DC. We sought to define the function of freshly isolated murine liver pDCs. We found that normal liver pDCs were weak in stimulating T cells, yet they possessed a proinflammatory cytokine profile with high tumor necrosis factor-alpha and low IL-10 secretion. To facilitate the investigation of murine liver pDCs, we expanded them in vivo with fms-like tyrosine kinase 3 ligand (Flt3L). After Toll-like receptor-9 ligation, expanded liver pDCs secreted high levels of IFN-alpha and were able to stimulate NK cells, NKT cells, and antigen-specific CD8+ T cells in vitro. In addition, Flt3L expansion alone generated pDCs capable of activating antigen-specific CD8+ T cells in vivo. CONCLUSION: Unstimulated liver pDCs exist in a latent state with the potential to become potent activators of the innate and adaptive immune systems through their interactions with other immune effectors. Our findings have implications for understanding the role of the liver in tolerance and immunity.

NK dendritic cells are innate immune responders to Listeria monocytogenes infection.

NK dendritic cells (NKDC) are recently described immunologic cells that possess both lytic and Ag-presenting function and produce prolific quantities of IFN-gamma. The role of NKDC in innate immunity to bacterial infection is unknown. Because IFN-gamma is important in the immune response to Listeria monocytogenes (LM), we hypothesized that NKDC play a critical role during LM infection in mice. We found that LM increased the frequency and activation state of NKDC in vivo. Using in vivo intracellular cytokine analysis, we demonstrated that NKDC are a major source of early IFN-gamma during infection with LM. Adoptive transfer of wild-type NKDC into IFN-gamma-deficient recipients that were subsequently infected with LM decreased bacterial burden in the liver and spleen and prolonged survival. In contrast, NK cells were depleted early during LM infection, produced less IFN-gamma, and conferred less protection upon adoptive transfer into IFN-gamma-deficient mice. In vitro, LM induction of IFN-gamma secretion by NKDC depended on TLR9, in addition to IL-18 and IL-12. Our study establishes NKDC as innate immune responders to bacterial infection by virtue of their ability to secrete IFN-gamma.

NK dendritic cells expanded in IL-15 exhibit antitumor responses in vivo.

NK dendritic cells (NKDC) are a novel subtype of DC with NK cell properties. IL-15 is a pleiotropic cytokine that plays an obligate role in the proliferation and survival of NK cells. We hypothesized that IL-15 is also essential for NKDC development. NKDC were nearly absent in IL-15(-/-) mice, but restored by administration of exogenous IL-15. Treatment of wild-type mice with IL-15 caused a 2- to 3-fold expansion of both NK cells and NKDC. After 7 days of culture with IL-15, sorted splenic NKDC expanded 10-fold while NK cells increased 5-fold. NKDC expanded in IL-15 retained their cytolytic capacity but lost the ability to stimulate naive T cells. Meanwhile, NKDC expanded in IL-15 produced 10 times more IFN-gamma as fresh NKDC and conferred protection in a tumor prevention model. Thus, IL-15 is essential to the proliferation and survival of NKDC and IL-15 expanded NKDC possess antitumor properties.