Early cardiac complications after bariatric surgery: does the type of procedure matter?

BACKGROUND: Major adverse cardiac events (MACE) can be a cause of postoperative mortality. This is specifically important in bariatric surgery due to obesity-related cardiovascular risk factors. OBJECTIVE: To assess postoperative cardiac adverse events after bariatric surgery and its independent predictors. SETTING: A retrospective analysis of 2011-2015 Healthcare Cost and Utilization Project-National Inpatient Sample. METHODS: Data on patients who underwent laparoscopic sleeve gastrectomy (SG) or Roux-en-Y gastric bypass (RYGB) were retrieved. MACE was identified as a composite variable including myocardial infarction, acute ischemic heart disease without myocardial infarction, and acute heart failure. Dysrhythmia (excluding premature beats) was identified as a separate outcome. Multivariate regression analysis for MACE was performed using demographic factors, co-morbidities, and type of surgery. RESULTS: The analysis included 108,432 patients (SG: 54.6%, RYGB: 45.4%). MACE was found in 116 patients (.1%), and dysrhythmia occurred in 3670 patients (3.4%). Median length of stay in patients with MACE was 4.5 versus 2 days in others (P < .001). There were 43 deaths overall, and 31 were in patients with MACE or dysrhythmia (P < .001). Age ≥ 50 years, male sex, congestive heart failure, chronic pulmonary disease, ischemic heart disease, history of pulmonary emboli, and fluid or electrolyte disorders were independent predictors of MACE based on multivariate analysis. Type of surgery (SG versus RYGB) was not an independent predictor for MACE (odds ratio 1.41, 95% confidence interval: .77-2.55). CONCLUSIONS: While cardiac complications are rare after bariatric surgery, their occurrence is associated with increased length of stay, hospital charges, and mortality. Older age, male sex, cardiopulmonary co-morbidities, and fluid or electrolyte disorders are predictive of MACE. RYGB does not increase the risk of MACE compared with SG.

Mortality in open abdominal aortic surgery in patients with morbid obesity.

BACKGROUND: Open abdominal aortic surgery is among procedures with high morbidity and mortality. Adverse postoperative complications may be more common in morbidly obese patients. OBJECTIVES: This study compared the outcomes of open abdominal aortic surgeries in patients with and without morbid obesity. SETTING: A retrospective analysis of 2007-2014 Healthcare Cost and Utilization Project-Nationwide Inpatient Sample. METHODS: We included patients who underwent open abdominal aortic aneurysm (AAA) repair or open aorta-iliac-femoral (AIF) bypass. Demographic factors, morbid obesity, co-morbidities, and emergent versus elective surgery were considered for univariate and multivariate analyses. RESULTS: A total of 29,340 patients (13,443 AAA repair and 15,897 AIF bypass) were included (age 66.3 ± 10.8 years, 65.7% male). The mortality was 9.1% in 536 patients with morbid obesity compared with 7.1% in patients without morbid obesity. Based on multivariate analysis, age, existing co-morbidities, emergent versus elective setting, and morbid obesity were found to be independent predictors of mortality. Patients with morbid obesity had an odds ratio of 3.61 (95% CI, 1.50-8.68; P = .004) for mortality, longer mean length of stay (11.2 versus 9.3 days, P < .001), and higher total hospital charges ($99,500 versus $73,700, P < .001). CONCLUSIONS: Morbid obesity is an independent risk factor of mortality in patients undergoing open AAA repair and AIF bypass. Weight loss strategies should be considered for morbidly obese patients with an anticipation of open abdominal aortic procedures.

Outcomes of Bariatric Surgery Versus Medical Management for Type 2 Diabetes Mellitus: a Meta-Analysis of Randomized Controlled Trials.

INTRODUCTION: Bariatric surgery improves type 2 diabetes (T2D) in obese patients. The sustainability of these effects and the long-term results have been under question. OBJECTIVE: To compare bariatric surgery versus medical management (MM) for T2D based on a meta-analysis of randomized controlled trials (RCTs) with 2 years of follow-up. MATERIAL AND METHODS: Seven RCTs with at least 2-year follow-up were identified. The primary endpoint was remission of T2D (full or partial). Four hundred sixty-three patients with T2D and body mass index > 25 kg/m2 were evaluated. RESULTS: After 2 years, T2D remission was observed in 138 of 263 patients (52.5%) with bariatric surgery compared to seven of 200 patients (3.5%) with MM (risk ratio (RR) = 10, 95% CI 5.5-17.9, p < 0.001). Subgroup analysis of the Roux-en-Y gastric bypass (RYGB) showed a significant effect size at 2 years in favor of RYGB over MM for a higher decrease of HbA1C (0.9 percentage points, 95% CI 0.6-1.1, p < 0.001), decrease of fasting blood glucose (35.3 mg/dl, 95% CI 13.3-57.3, p = 0.002), increase of high-density lipoprotein (HDL) (12.2 mg/dl, 95% CI 7.6-16.8, p < 0.001), and decrease of triglycerides (32.4 mg/dl, 95% CI 4.5-60.3, p = 0.02). Four studies followed patients up to 5 years and showed 62 of 225 patients (27.5%) with remission after surgery, compared to six of 156 patients (3.8%) with MM (RR = 6, 95% CI 2.7-13, p < 0.001). CONCLUSION: This meta-analysis shows a superior and persistent effect of bariatric surgery versus MM for inducement of remission of T2D. This benefit of bariatric surgery was significant at 2 years and superior to MM even after 5 years. Compared with MM, patients with RYGB had better glycemic control and improved levels of HDL and triglycerides.

Predictors of mortality after elective ventral hernia repair: an analysis of national inpatient sample.

PURPOSE: Deciding between surgery and non-operative management of a non-obstructive ventral hernia (VH) in a high-risk patient often poses a clinical challenge. The aim of this study is to evaluate a national series of open and laparoscopic ventral hernia repair (VHR), and to assess predictors of mortality after elective VHR. METHODS: A retrospective analysis of 2008-2014 data from the Healthcare Cost and Utilization Project-Nationwide Inpatient Sample was performed. All patients with a primary diagnosis of abdominal wall hernia were included. Inguinal, femoral, or diaphragmatic hernias were excluded. Patients were stratified by elective versus emergent repair. Factors associated with mortality after elective VHR were analyzed. RESULTS: 103,635 patients were studied, including 14,787 (14.3%) umbilical, 63,685 (61.5%) incisional, and 25,163 (24.3%) other ventral hernias. Operative procedures included 59,993 (57.9%) elective and 43,642 (42.1%) emergent VHR. 21.3% elective VHRs were laparoscopic versus 13% in emergent cases (P < 0.001). Mesh was used in 52,642 (87.7%) elective versus 27,734 (63.5%) emergent VHR (P < 0.001). Median (interquartile range) length of stay was 2(3) days in laparoscopic and 3(3) days in open group (P < 0.001). Mortality was 0.2% (n = 135) in elective and 0.6% (n = 269) in emergent group (P < 0.001). In elective group, mortality rates were equal among laparoscopic and open VHR (0.2%), while in emergent group, it was lower in laparoscopic VHR (0.4% vs 0.6%, P = 0.028). Multivariate analysis of elective VHR showed that the following factors were associated with mortality during hospitalization: age > 50 years [Odds ratio (OR) = 1.96], male gender (OR = 2.37), congestive heart failure (OR = 2.15), pulmonary circulation disorders (OR = 5.26), coagulopathy (OR = 3.93), liver disease (OR = 1.89), fluid and electrolyte disturbances (OR = 8.66), metastatic cancer (OR = 4.66), neurological disorders (OR = 2.31), and paralysis (OR = 5.29). CONCLUSIONS: VHR has a low mortality, especially when performed laparoscopically. In patients undergoing elective VHR, higher age and some comorbidities are predictors of mortality. These include congestive heart failure, pulmonary circulation disorders, coagulopathy, liver disease, metastatic cancer, neurological disorders, and paralysis. Conservative management should be considered for these high-risk subgroups in context of the overall clinical presentation.

The cost of robotics: an analysis of the added costs of robotic-assisted versus laparoscopic surgery using the National Inpatient Sample.

BACKGROUND: Robotic-assisted surgery (RAS) with its advantages continues to gain popularity among surgeons. This study analyzed the increased costs of RAS in common surgical procedures using the National Inpatient Sample. METHODS: Retrospective analysis of the 2012-2014 Healthcare Cost and Utilization Project-NIS was performed for the following laparoscopic/robotic procedures: cholecystectomy, ventral hernia repair, right and left hemicolectomy, sigmoidectomy, abdominoperineal resection, and total abdominal hysterectomy (TAH). Patients with additional concurrent procedures were excluded. Costs were compared between the laparoscopic procedures and their RAS counterparts. Total costs and charges for cholecystectomy (the most common procedure in the dataset) were compared based on the payer and characteristics of hospital (region, rural/urban, bed size, and ownership). RESULTS: A total of 91,630 surgeries (87,965 laparoscopic, 3665 robotic) were analyzed. The average cost for the laparoscopic group was $10,227 ± $4986 versus $12,340 ± $5880 for the robotic cases (p < 0.001). The overall and percentage increases for laparoscopic versus robotic for each procedure were as follows: cholecystectomy $9618 versus $10,944 (14%), ventral hernia repair $10,739 versus $13,441 (25%), right colectomy $12,516 versus $15,027 (20%), left colectomy $14,157 versus $17,493 (24%), sigmoidectomy $13,504 versus $16,652 (23%), abdominoperineal resection $17,708 versus $19,605 (11%), and TAH $9368 versus $9923 (6%). Hysterectomy was the only procedure performed primarily using RAS and it was found to have the lowest increase in costs. Increased costs were associated with even higher increases in charges, especially in investor-owned private hospitals. CONCLUSION: RAS is more costly when compared to conventional laparoscopic surgery. Additional costs may be lower in centers that perform a higher volume of RAS. Further analysis of long-term outcomes (including reoperations and readmissions) is needed to better compare the life-long treatment costs for both surgical approaches.

Cost of bariatric surgery and factors associated with increased cost: an analysis of national inpatient sample.

BACKGROUND: In the current healthcare environment, bariatric surgery centers need to be cost-effective while maintaining quality. OBJECTIVE: The aim of this study was to evaluate national cost of bariatric surgery to identify the factors associated with a higher cost. SETTING: A retrospective analysis of 2012-2013 Healthcare Cost and Utilization Project - Nationwide Inpatient Sample (HCUP-NIS). METHOD: We included all patients with a diagnosis of morbid obesity (ICD9 278.01) and a Diagnosis Related Group code related to procedures for obesity, who underwent Roux-en-Y gastric bypass (RYGB), sleeve gastrectomy (SG), or adjustable gastric banding (AGB) as their primary procedure. We converted "hospital charges" to "cost," using hospital specific cost-to-charge ratio. Inflation was adjusted using the annual consumer price index. Increased cost was defined as the top 20th percentile of the expenditure and its associated factors were analyzed using the logistic regression multivariate analysis. RESULTS: A total of 45,219 patients (20,966 RYGBs, 22,380 SGs, and 1,873 AGBs) were included. The median (interquartile range) calculated costs for RYGB, SG, and AGB were $12,543 ($9,970-$15,857), $10,531 ($8,248-$13,527), and $9,219 ($7,545-$12,106), respectively (P<.001). Robotic-assisted procedures had the highest impact on the cost (odds ratio 3.6, 95% confidence interval 3.2-4). Hospital cost of RYGB and SG increased linearly with the length of hospital stay and almost doubled after 7 days. Furthermore, multivariate analysis showed that certain co-morbidities and concurrent procedures were associated with an increased cost. CONCLUSION: Factors contributing to the cost variation of bariatric procedures include co-morbidities, robotic platform, complexity of surgery, and hospital length of stay.

Prediction of pancreatic anastomotic failure after pancreatoduodenectomy: the use of preoperative, quantitative computed tomography to measure remnant pancreatic volume and body composition.

OBJECTIVE: To determine whether remnant pancreatic volume (RPV), subcutaneous/visceral adipose tissue(SAT/VAT) area, and skeletal muscle (SM) area calculated from preoperative computed tomography (CT) can predict the occurrence of pancreatic anastomotic failure (PAF) after pancreatoduodenectomy (PD). BACKGROUND: Increased body mass index, small main pancreatic duct, and soft pancreatic texture are well-established predictors of PAF after PD. The impact on PAF of anthropomorphic measurements, such as RPV and body composition, is unknown. METHODS: In 173 patients undergoing PD from 2004 to 2009, cross sections of SAT/VAT/SM area were quantitated volumetrically, respectively, from preoperative CT. RPV was calculated from the CT as the sum of pancreatic tissue area to the left of the presumed pancreatic transection site. The predictive ability for multiple models using combinations of body mass index, RPV, SAT/VAT area, SM area, main pancreatic duct size, and pancreatic gland texture was described using a concordance index (c-index). RESULTS: Clinically relevant PAF occurred in 22 patients (13%). Multivariate logistic regression analysis identified RPV (P = 0.0012), VAT area (P = 0.0003), and SM area (P = 0.0006) as independent predictors of PAF. Using previously identified risk factors, the best 2-predictor model (body mass index and pancreatic duct size) resulted in a c-index of 0.748. Using anthropomorphic factors, however, the 2-predictor model using VAT and SM areas revealed a superior c-index of 0.959. CONCLUSIONS: Our 2-predictor model using VAT area and SM area based on volumetric quantification using preoperative CT may offer clinical benefit as an objective prognostic measure to predict clinically relevant PAF after PD.

Frequency of subtypes of biliary intraductal papillary mucinous neoplasm and their MUC1, MUC2, and DPC4 expression patterns differ from pancreatic intraductal papillary mucinous neoplasm.

BACKGROUND: Biliary intraductal papillary mucinous neoplasm (B-IPMN) has been proposed as a unique clinicopathologic disease with distinct histopathologic features, although wide acceptance remains controversial. A recent consensus conference classified pancreatic IPMN (P-IPMN) into 4 subtypes (ie, gastric, intestinal, pancreatobiliary, oncocytic) based on morphologic appearance and mucin (MUC) staining properties. The aim of this study was to determine whether B-IPMN has similar histopathologic and immunologic subtypes to P-IPMN. STUDY DESIGN: Specific immunostaining for MUC1, MUC2, and deleted for pancreas cancer, locus 4 were performed on specimens from 19 patients with a histopathologic diagnosis of B-IPMN. Immunostaining patterns of B-IPMN were correlated with histopathology. RESULTS: Based on histopathology, the following subtypes of B-IPMN were identified: pancreatobiliary n = 9 (47%), intestinal n = 8 (42%), oncocytic n = 2 (11%), and gastric n = 0 (0%). Pancreatobiliary and oncocytic subtypes of B-IPMN were positive for MUC1 and negative for MUC2, and intestinal subtypes were positive for MUC2 and negative for MUC1. Thirteen of the 19 B-IPMN were associated with invasive carcinoma; loss of deleted for pancreas cancer, locus 4 was found in 6 of 13 invasive components and in 3 of 19 noninvasive components of B-IPMN. Five-year survival for patients with resected B-IPMN and invasive carcinoma was 38%, which is similar to that for resected P-IPMN with invasive carcinoma. CONCLUSIONS: Histopathologic subtypes and type-specific MUC expression patterns of B-IPMN resemble those of P-IPMN. MUC1 expression and/or absence of MUC2 expression, which correlate with aggressive features of P-IPMN, were found in B-IPMN and correlate with invasive B-IPMN. Loss of deleted for pancreas cancer, locus 4 parallels the findings observed in P-IPMN. These findings provide additional support that B-IPMN is a unique entity with similarities to main duct P-IPMN.

Dual-phase computed tomography for assessment of pancreatic fibrosis and anastomotic failure risk following pancreatoduodenectomy.

INTRODUCTION: Delayed or decreased computed tomography (CT) enhancement characteristics in pancreatic fibrosis have been described. METHODS: A review of 157 consecutive patients with preoperative dual-phase CT between 2004 and 2009 was performed. Pancreatic CT attenuation upstream from the tumor was measured in the pancreatic and hepatic imaging phases. The ratio of the mean CT attenuation value [hepatic to pancreatic phase; late/early (L/E) ratio] and histological grade of pancreatic fibrosis was correlated with the development of a clinically relevant pancreatic anastomotic failure (PAF) and other clinical parameters. RESULTS: A clinically relevant PAF was observed in 21 patients (13.4%) with morbidity and mortality of 39.5% and 0%, respectively. The PAF group showed maximum enhancement in the pancreatic and washout in the hepatic CT phase, while the no PAF group showed a delayed enhancement pattern. Degree of pancreatic fibrosis and L/E ratio were significantly lower for the PAF group than the no PAF group (0.86 ± 0.14 vs. 1.09 ± 0.24; P < 0.0001 and 21.0 ± 17.9 vs. 40.4 ± 29.8; P < 0.0001); fewer PAF patients showed an atrophic histological pattern (14% vs. 39%; P = 0.046). The L/E ratio was positively correlated with pancreatic fibrosis. Pancreatic fibrosis and L/E ratio increased with larger duct size (P < 0.001), the presence of diabetes (P < 0.05), and the surgeon's assessment of pancreas firmness (P < 0.001). In multivariate analyses, L/E ratio and body mass index were significant predictors for the development of a clinically relevant PAF; a 0.1-U increase of L/E ratio decreased the odds of a PAF by 54%. CONCLUSION: Pancreatic CT enhancement pattern can accurately assess pancreatic fibrosis and is a powerful tool to predict the risk of developing a clinically relevant PAF following PD.

Major venous resection during total laparoscopic pancreaticoduodenectomy.

BACKGROUND: The feasibility of total laparoscopic pancreaticoduodenectomy (TLPD) has been established. Laparoscopic major venous resection during TLPD has not been reported. The aim of the present study was to describe the technique and outcomes of patients undergoing TLPD with major venous resection. METHODS: Retrospective review of all consecutive patients undergoing TLPD and major venous resection from July 2007 to December 2010 was performed. Patient demographics and peri-operative outcomes were retrieved. Data are presented as mean ± standard deviation (SD) or median with range. RESULTS: Out of 129 patients undergoing TLPD, major venous resection was performed in 11 patients with a mean age of 71 years. Median operative time and blood loss was 413 (301-666) min and 500 (75-2800) ml, respectively. Venous resection included tangential (n= 10) and segmental resection (n = 1). Venous reconstruction included patch (n = 4), suture (n = 4), stapled (n = 2) and a left renal vein interposition graft (n = 1). Median mesoportal clamp time was 35 (10-82) min. There was no 30-day or in-hospital mortality. Post-operative imaging was available in 10 patients with 100% patency at the venous reconstruction site. CONCLUSIONS: Laparoscopic major venous resection during TLPD is feasible in selected patients. Extensive experience with complex laparoscopic pancreatic resection and reconstruction is advocated before attempting this procedure.

Prosthetic graft reconstruction after portal vein resection in pancreaticoduodenectomy: a multicenter analysis.

BACKGROUND: Use of prosthetic grafts for reconstruction after portal vein (PV) resection during pancreaticoduodenectomy is controversial. We examined outcomes in patients who underwent vein reconstruction using polytetrafluoroethylene (PTFE). STUDY DESIGN: Review of prospectively maintained databases at 3 centers identified all patients who underwent pancreaticoduodenectomy (PD) with vein resection and reconstruction using PTFE grafts between 1994 and 2009. Patient, operative, and outcomes variables were studied. Graft patency and survival were assessed using the Kaplan-Meier technique. RESULTS: Thirty-three patients underwent segmental vein resection with interposition PTFE graft reconstruction. Median age was 67 years; median Eastern Cooperative Oncology Group score was 1. Most operations were performed for pancreatic adenocarcinoma (n = 28, 85%); 96% were T3 lesions or greater. Standard PD was performed in 12 (36%) patients, pylorus-preservation in 17 (52%), and total pancreatectomy in 4 (12%). Combined resection of portal and superior mesenteric veins (SMV) was required in 49%, with resection isolated to PV in 12% and SMV in 39%. Splenic vein ligation was necessary in 30%. Median graft diameter was 12 mm (range 8 to 20 mm), with the majority being ring-enforced (73%). Median operative and vascular clamp times were 463 and 41 minutes, respectively, with median blood loss of 1,500 mL. The negative margin rate was 64%. Overall morbidity rate was 46%, and 30-day mortality was 6%. No patients developed irreversible hepatic necrosis or graft infection. Pancreatic fistulas occurred in 3 (9.1%). With mean follow-up of 14 months, overall graft patency was 76%. Estimated median duration of graft patency was 21 months. Median survival was 12 months for pancreatic adenocarcinoma. CONCLUSIONS: With careful patient selection, PTFE graft reconstruction of resected PV/SMV during pancreaticoduodenectomy is possible with minimal risk of hepatic necrosis or graft infection. Comparison studies to primary anastomosis and autologous vein reconstruction are necessary.

LY2109761, a novel transforming growth factor beta receptor type I and type II dual inhibitor, as a therapeutic approach to suppressing pancreatic cancer metastasis.

Most pancreatic cancer patients present with inoperable disease or develop metastases after surgery. Conventional therapies are usually ineffective in treating metastatic disease. It is evident that novel therapies remain to be developed. Transforming growth factor beta (TGF-beta) plays a key role in cancer metastasis, signaling through the TGF-beta type I/II receptors (TbetaRI/II). We hypothesized that targeting TbetaRI/II kinase activity with the novel inhibitor LY2109761 would suppress pancreatic cancer metastatic processes. The effect of LY2109761 has been evaluated on soft agar growth, migration, invasion using a fibroblast coculture model, and detachment-induced apoptosis (anoikis) by Annexin V flow cytometric analysis. The efficacy of LY2109761 on tumor growth, survival, and reduction of spontaneous metastasis have been evaluated in an orthotopic murine model of metastatic pancreatic cancer expressing both luciferase and green fluorescence proteins (L3.6pl/GLT). To determine whether pancreatic cancer cells or the cells in the liver microenvironment were involved in LY2109761-mediated reduction of liver metastasis, we used a model of experimental liver metastasis. LY2109761 significantly inhibited the L3.6pl/GLT soft agar growth, suppressed both basal and TGF-beta1-induced cell migration and invasion, and induced anoikis. In vivo, LY2109761, in combination with gemcitabine, significantly reduced the tumor burden, prolonged survival, and reduced spontaneous abdominal metastases. Results from the experimental liver metastasis models indicate an important role for targeting TbetaRI/II kinase activity on tumor and liver microenvironment cells in suppressing liver metastasis. Targeting TbetaRI/II kinase activity on pancreatic cancer cells or the cells of the liver microenvironment represents a novel therapeutic approach to prevent pancreatic cancer metastasis.

Mechanisms of synthetic serine protease inhibitor (FUT-175)-mediated cell death.

BACKGROUND: Constitutive activation of nuclear factor-kappaB (NF-kappaB) is a frequent molecular alteration in pancreatic cancer and a number of studies have suggested that constitutive NF-kappaB activity plays a key role in the aggressive behavior of this disease. In an attempt to identify an effective therapeutic agent for pancreatic cancer, the authors studied the role of FUT-175, a synthetic serine protease inhibitor, in the inhibition of NF-kappaB activation and the induction of apoptotic responses. METHODS: To examine the effect of FUT-175 on the inhibition of NF-kappaB and the induction of apoptosis in pancreatic cancer cell lines, Western and Northern blot analyses, electromobility shift (EMSA), luciferase reporter gene, DNA fragmentation, immunoprecipitation, in vitro kinase, small interfering RNA (siRNA), and chromatin immunoprecipitation (ChIP) assays were performed. RESULTS: In a time-dependent and dose-dependent manner, FUT-175 inhibited IkappaBalpha phosphorylation and NF-kappaB activation, thereby inhibiting the antiapoptotic activity of NF-kappaB. Simultaneously, FUT-175 up-regulated the expression of tumor necrosis factor receptor-1 (TNFR1), which in turn activated the proapoptotic caspase-8 and Bid pathways and induced apoptosis in pancreatic cancer cells. FUT-175-induced activation of Fas-associated death domain (FADD) and caspase-8 was suppressed by RNA interference-mediated inhibition of TNFR1 expression. Furthermore, expression of the transcription factor PEA3 was up-regulated by FUT-175 and was involved in FUT-175-mediated TNFR1 expression. CONCLUSIONS: These results suggested a possible mechanism by which FUT-175 may disrupt interconnected signaling pathways by both suppressing the NF-kappaB antiapoptotic activity and inducing TNFR-mediated apoptosis. Supported by this unique function as a NF-kappaB inhibitor and apoptosis inducer, this well-established synthetic serine protease inhibitor with as-of-yet poorly understood mechanisms of actions appears to be a potentially therapeutic agent for pancreatic cancer.

Endoluminal methods for gastrotomy closure in natural orifice transenteric surgery (NOTES).

Natural orifice transenteric surgery (NOTES) is a new and rapidly evolving concept for intra-abdominal operations that offers the potential for a revolutionary advance in patient care. Conceptually, operations that currently require an open or laparoscopic approach could be performed without incisions in the abdomen, with their concomitant pain and scarring. A recent consensus statement by a joint group of gastrointestinal surgeons and gastroenterologists has identified several technical and technologic hurdles that would need to be overcome before NOTES becomes a clinical reality. One of the most significant requirements identified is the need for a very secure closure of the gastrotomy site that is required for scope passage and specimen removal. Although a rapidly expanding variety of transgastric procedures has been reported, only a few reports address the basic problem of gastrotomy closure. Availability of a safe and simple gastrotomy closure device, however, will be essential for the widespread adoption of the new field of NOTES. Unless new safe and simple devices for endoscopic gastrotomy closure are available and have proven efficacy, NOTES will remain in the hands of a few specialists at centers of excellence because the risk of complications due to insufficient gastrotomy closure will not be acceptable for the surgeon and gastroenterologist in general practice. In this article, we describe three new devices in development or newly on the market that are targeted to advance the safe endoscopic closure of gastrotomy from NOTES.

The Bernese ankle rules: a fast, reliable test after low-energy, supination-type malleolar and midfoot trauma.

BACKGROUND: Trauma of the midfoot and ankle joint are among the most commonly treated injuries in the emergency unit. The "Ottawa ankle rules" were introduced in 1992 to lower the amount of radiographs based on a standardized clinical examination. The weakness of the "rules" is the low specificity reported in several clinical studies. METHOD: We introduced a new indirect stress technique to examine the ankle and the midfoot after low-energy, supination-type trauma, avoiding direct palpation of the injured region. RESULTS: In 354 prospectively documented patients, the Bernese ankle test produced a sensitivity of 100% and a specificity of 91%. CONCLUSION: Compared with the original Ottawa ankle rules, the number of false-positive findings could be significantly reduced, resulting in a reduction of 84% in radiographs after low-energy, supination-type trauma ankle and midfoot trauma. Further investigations have to be performed to prove whether these findings are reproducible within other clinical settings, which could result in major cost savings for the health care system.

Induction of apoptosis in tumor-associated endothelial cells and therapy of orthotopic human pancreatic carcinoma in nude mice.

Although gemcitabine has been accepted as the first-line chemotherapeutic reagent for advanced pancreatic cancer, improvement of response rate and survival is not sufficient and patients often develop resistance. We hypothesized that the inhibition of phosphorylation of epidermal growth factor receptor (EGFR) and vascular endothelial growth factor receptor (VEGFR) on tumor cells and tumor-associated endothelial cells, combined with gemcitabine, would overcome the resistance to gemcitabine in orthotopic pancreatic tumor animal model. L3.6pl, human pancreatic cancer cells growing in the pancreas, and tumor-associated endothelial cells in microorgan environment highly expressed phosphorylated EGFR, VEGFR, and Akt, which regulates antiapoptotic mechanism. Oral administration of AEE788 (dual tyrosine kinase inhibitor against EGFR and VEGFR) inhibited the phosphorylation of EGFR, VEGFR, and Akt on tumor-associated endothelial cells as well as tumor cells. Although intraperitoneal (i.p.) injection of gemcitabine showed limited inhibitory effect on tumor growth, combination with AEE788 and gemcitabine produced nearly 95% inhibition of tumor growth in parallel with a high level of apoptosis on tumor cells and tumor-associated endothelial cells, and decreased microvascular density and proliferation rate. Collectively, these data indicate that dual inhibition of phosphorylation of EGFR and VEGFR, in combination with gemcitabine, produces apoptosis of tumor-associated endothelial cells and significantly suppresses human pancreatic cancer in nude mice.

Nuclear factor kappa B activation is a potential target for preventing pancreatic carcinoma by aspirin.

BACKGROUND: Pancreatic carcinoma exhibits a unique genetic profile of mutations that may play key roles in its progression to malignant phenotypes. Constitutive activation of transcription factor nuclear factor kappa B (NF-kappaB) is a frequent molecular alteration in pancreatic carcinoma, suggesting a possible link between inflammation and cancer. The aims of the current study were to determine the effects of aspirin on pancreatic carcinoma prevention and to reveal a possible mechanism of aspirin-mediated cancer chemoprevention. METHODS: An orthotopic mouse model with human pancreatic carcinoma cell lines PANC-1, PANC-1/Puro, and PANC-1/IkappaBalphaM was used to study the inhibitory effects of aspirin on pancreatic tumor formation. RESULTS: Aspirin inhibited constitutive NF-kappaB activity in culture and, in turn, decreased the expression of the NF-kappaB downstream target gene, Cox-2, in PANC-1 or PANC-1/Puro cells, without significantly inhibiting the in vitro growth of PANC-1/Puro cells. All animals inoculated with either PANC-1 or PANC-1/Puro cells, and not given aspirin, developed pancreatic tumors, whereas none of the mice injected with PANC-1/IkappaBalphaM cells showed any evidence of pancreatic tumor formation. Animals given aspirin for 6 days before, or at the time of, orthotopic tumor cell injection showed a significantly lower incidence of tumor formation compared with those receiving aspirin 2 weeks after inoculation and controls receiving no aspirin. CONCLUSIONS: Aspirin repressed tumor formation by PANC-1 cells in vivo in a prophylactic setting, suggesting a possible mechanism for aspirin's preventive effect in pancreatic carcinoma through inhibition of NF-kappaB activation and a mechanistic link between inflammation and tumorigenesis. Aspirin-mediated antiinflammatory approaches might be an effective strategy to prevent pancreatic carcinoma.

The value of computed tomographic scanning in the diagnosis and management of orbital fractures associated with head trauma: a prospective, consecutive study at a level I trauma center.

BACKGROUND: Orbital fractures associated with head trauma are not always easy to diagnose. The real incidence of such fractures is unknown. The aim of this study was to evaluate the usefulness of routine primary computed tomographic (CT) scanning for diagnosis of orbital fractures in head trauma patients. METHODS: Over a 3-year period, 600 consecutive patients admitted with head trauma were examined clinically; these patients then underwent cranial helical CT scanning, irrespective of severity of head injuries and presence or absence of fracture-related symptoms. RESULTS: Orbital fractures were diagnosed on CT scan in 118 cases (19.7%). All patients with symptoms directly related to an orbital fracture had radiologically diagnosed fractures, compared with 58.3% of patients with isolated blepharohematoma and 3.8% of asymptomatic patients. CONCLUSION: CT scan of the orbits is indicated for any head trauma patient who presents either one or more symptoms directly related to an orbital fracture or just isolated blepharohematoma. CT scan of the orbits is not indicated in asymptomatic head trauma patients. Inclusion of the orbits in the scanning is recommendable only if a CT scan is already being obtained for a head injury. Clinical follow-up is important to detect any late-appearing symptoms. Accurate clinical examination still plays a crucial role in the diagnosis of orbital fractures.

Overexpression of tropomysin-related kinase B in metastatic human pancreatic cancer cells.

PURPOSE: Pancreatic adenocarcinoma is currently the fourth leading cause of cancer death in the United States, and most pancreatic cancers develop locally advanced disease or metastasis at the time of diagnosis. The mechanisms by which it invades and metastasizes are not known. EXPERIMENTAL DESIGN: To identify the genes involved in pancreatic cancer metastasis, we analyzed the gene expression profiles between highly metastatic Colo357L3.6pl and parental Colo357FG pancreatic cancer cell lines using cDNA microarrays and confirmed differential gene expression by reverse transcription-PCR, Western blotting, and immunologic analysis of 54 samples from pancreatic cancer patients. The correlation with clinical outcome was also examined. The possible signaling pathways involved with tropomyosin-related kinase B (TrkB) were analyzed. RESULTS: Our findings showed that TrkB was overexpressed in the highly metastatic Colo357L3.6pl cells, which correlated with perineural invasion (P = 0.026), positive retroperitoneal margin (P = 0.0005), and shorter latency to development of liver metastasis (Cox proportional hazard ratio, 0.3; 95% confidence interval, 0.1-0.8; P = 0.01) in patient samples. Extracellular signal-regulated kinases 1 and 2 were activated and Elk-1 and AP-1 DNA binding activity was induced in Colo357L3.6pl cells. Furthermore, interleukin 8 and vascular endothelial growth factor were more strongly expressed in Colo357L3.6pl than Colo357FG cells, and these findings were confirmed in Colo357L3.6pl and Colo357FG orthotopic tumors. CONCLUSION: These results suggest that overexpression of TrkB and activation of mitogen-activated protein kinase and AP-1, which may in turn induce the expression of vascular endothelial growth factor and interleukin 8, may mediate the cardinal clinical features of locally aggressive growth and metastasis of pancreatic cancer. Our results also imply that TrkB receptor may be a novel therapeutic target for pancreatic cancer.