The Effect of Immunonutrition on Veterans Undergoing Major Surgery for Gastrointestinal Cancer.

A randomized controlled trial found that providing immunonutrition supplementation before surgery reduced the rate of postoperative complications and the length of hospital stays.

Diet-induced obesity associated with steatosis, oxidative stress, and inflammation in liver.

BACKGROUND: Obesity induces steatosis and increases oxidative stress, as well as chronic inflammation in the liver. The balance between lipogenesis and lipolysis is disrupted in obese animals. At a cellular level, the changes in metabolic sensors and energy regulators are poorly understood. We hypothesized that diet-induced steatosis increases oxidative stress, inflammation, and changes the metabolic regulators to promote energy storage in mice. The setting was a university-affiliated basic science research laboratory. METHODS: Four-week-old C57BL mice were fed a high-fat diet (n = 8) or regular chow (n = 8) for 7 weeks. The liver sections were stained for fat content and immunofluorescence. Liver homogenates were used for protein analysis by immunoblotting and mRNA analysis by reverse transcriptase-polymerase chain reaction. The gels were quantified using densitometry P ≤ .05 was considered significant. RESULTS: The high-fat diet upregulated protein kinase-C atypical isoforms ζ and λ and decreased glucose tolerance and the interaction of insulin receptor substrate 2 with phosphoinositide kinase-3. The high-fat diet increased the transcriptional factors liver X receptor (4321 ± 98 versus 2981 ± 80) and carbohydrate response element-binding protein (5132 ± 135 versus 3076 ± 91), the lipogenesis genes fatty acid binding protein 5, stearoyl-co-enzyme A desaturase-1, and acetyl-co-enzyme A carboxylase protein, and fatty acid synthesis. The high-fat diet decreased 5'-adenosine monophosphate-activated protein kinase (2561 ± 78 versus 1765 ± 65), glucokinase-3ß (2.214 ± 34 versus 3356 ± 86), and SIRT1 (2015 ± 76 versus 3567 ± 104) and increased tumor necrosis factor-α (3415 ± 112 versus 2042 ± 65), nuclear factor kappa B (5123 ± 201 versus 2562 ± 103), cyclooxygenase-2 (4230 ± 113 versus 2473 ± 98), nicotinamide-adenine dinucleotide phosphate oxidase (3501 ± 106 versus 1600 ± 69) and reactive oxygen species production (all P < .001, obese mice versus lean mice). CONCLUSION: A high-fat diet impairs glucose tolerance and hepatic insulin signaling, upregulates transcriptional and translational activities that promote lipogenesis, cytokine production, proinflammatory signaling, and oxidative stress, and downregulates lipolysis. Understanding the complex cellular signals triggered by obesity might have profound clinical implications.

Roux-en-Y gastric bypass alters tumor necrosis factor-α but not adiponectin signaling in immediate postoperative period in obese rats.

BACKGROUND: Adiponectin has anti-inflammatory properties and is increased with weight loss. Tumor necrosis factor (TNF)-α is a pro-inflammatory cytokine that negatively regulates adiponectin. Previously, we have demonstrated that Roux-en-Y gastric bypass (RYGB) induces weight loss and improves steatosis in obese rats. We hypothesized that RYGB would alter the interplay of TNF-α and adiponectin signaling in the postoperative period. METHODS: Obese Sprague-Dawley male rats that had undergone RYGB (n = 5) or sham (n = 4) were euthanatized at 9 weeks postoperatively. The adiponectin levels from serial serum samples were measured by enzyme-linked immunosorbent assay. Adiponectin, adiponectin receptor 2, and TNF-α mRNA from adipose and liver samples were quantified by reverse transcriptase-polymerase chain reaction. Data are presented as mean ± standard deviation; using a t test, P <.05 was significant. RESULTS: RYGB did not change the serum adiponectin, adipose tissue adiponectin mRNA, or hepatic adiponectin receptor 2 levels compared with the levels in the sham-operated rats (P >.05). However, the TNF-α mRNA levels had decreased in the adipose tissue (P >.05) but remained unchanged in the liver compared with the sham controls (P >.05). CONCLUSION: Surgically-induced weight loss in a rat model of RYGB did not increase adiponectin signaling in the immediate postoperative period but was associated with decreased pro-inflammatory signaling in the adipose tissue. During this period, pro-inflammatory signaling might play a more important role than adiponectin. Additional studies with longer follow-up are necessary to determine whether adiponectin plays a role in weight loss and improvement of steatosis after RYGB.

Does LKB1 mediate activation of hepatic AMP-protein kinase (AMPK) and sirtuin1 (SIRT1) after Roux-en-Y gastric bypass in obese rats?

INTRODUCTION: Roux-en-Y gastric bypass (RYGB) improves steatosis and reduces liver triglycerides in obese rats. Sirtuin1 (SIRT1) and AMP-activated protein kinase (AMPK) are key metabolic regulators that reduce lipogenesis and increase fatty acid oxidation. LKB1 phosphorylates AMPK and may activate SIRT1. We hypothesize that RYGB in obese rats is associated with an upregulation of the LKB1-AMPK-SIRT1 signaling pathway. METHODS: Obese Sprague-Dawley male rats underwent RYGB or sham. Liver tissue was obtained at 9 weeks postoperatively. Protein levels of SIRT1, LKB1, p-LKB1, AMPKalpha, p-AMPKalpha, and p-protein kinase C-zeta (PKC-zeta ) were determined. Protein associations of LKB1 with each of SIRT1, AMPKalpha, and PKC-zeta were determined by coimmunoprecipitation.Data are mean +/- SD; for t test, p<0.05 was significant. RESULTS: RYGB increased protein levels of hepatic AMPKalpha, p-AMPKalpha, and SIRT1 (all p<0.001 vs. sham); p-LKB1 but not LKB1 increased after RYGB (p<0.001 vs. sham). Physical interactions of LKB1-AMPK and LKB1-SIRT1 increased after RYGB (p<0.001 vs. sham). Although PKC-zeta mRNA and p-PKC-zeta did not change, interactions between LKB1 and PKC-zeta increased after RYGB (p<0.001 vs. sham). CONCLUSION: RYGB increases hepatic levels of SIRT1, AMPK, and p-AMPK as well as increasing interactions of LKB1 with AMPK or SIRT1. p-PKC-zeta may play an intermediary role in the interaction between AMPK and SIRT. These findings demonstrate key signaling changes in powerful metabolic regulators that may account for the resolution of steatosis after RYGB.

Downregulation of adiponectin/AdipoR2 is associated with steatohepatitis in obese mice.

BACKGROUND: Recent evidence suggests that obesity is associated with hypo-adiponectinmia and chronic inflammation. Adiponectin regulates fat storage, energy expenditure, and inflammation. We propose that high fat diet induces steatohepatitis, reduces serum adiponectin, and liver adiponectin receptors. METHODS: A 4-week-old C57BL male mice were fed high fat diet (n = 8) or regular chow (control; n = 6) for 7 weeks. Body weight, liver weight, and serum adiponectin were measured. Liver sections were stained with hematoxylin and eosin and oil red for fat content. Liver homogenates were used for protein (immunoblotting) and mRNA (reverse transcription PCR) of Toll-like receptor 4 (TLR4), tumor necrosis factor alpha (TNF-alpha), interleukin (IL)-6, sterol regulatory element-binding proteins (SREBP)-1c, and adiponectin receptors (AdipoR1/AdipoR2) in addition to nuclear phorsphorylated p65NF-kappaB. Gels were quantified using densitometry; t test was used, and p < 0.05 was significant. RESULTS: High fat diet increased body (50%) and liver weight (33%), as well as hepatocyte fat content and ballooning. Mice fed high fat diet exhibited reduced serum adiponectin and liver AdipoR2. High fat diet increased hepatic levels of SREBP-1c, TLR4, TNF-alpha, and IL-6 protein and mRNA and increased activation of p65NF-kappaB. CONCLUSIONS: Diet-induced liver steatosis is associated with increased lipogensis, upregulation of pro-inflammatory cytokines, and transcription factors as well as downregulation of AdipoR2. Reduction in serum adiponectin suggests that adiponectin signaling may be the crosslink between high fat diet, hepatic inflammation, and nonalcoholic fatty liver disease.

Survival and variceal rehemorrhage after shunting support small-diameter prosthetic H-graft portacaval shunt.

This study was undertaken to report variceal rebleeding and survival after small-diameter prosthetic H-graft portacaval shunts (HGPCS) and to compare actual to predicted survival after shunting. Since 1987 we have prospectively followed patients after undergoing HGPCS to treat bleeding varices failing/not amenable to sclerotherapy/banding. One hundred and seventy patients underwent shunting. Cirrhosis was because of alcohol in 56%, hepatitis in 12%, both in 11%, and other causes in 21%. Child class was A for 10%, B for 28%, and C for 62%. Thirty-three patients died by 6 months, 54 by 24 months, 87 by 60 months, and 112 by 10 years, generally because of liver failure. Fifty-one patients are alive at a median of 48.3 months, 76 months +/- 57.8 (mean +/- SD). Variceal rehemorrhage was documented in 3 (2%) patients. By child class, 5-year/10-year survival rates were as follows: A 66.7/33.3%, B 48.6/15.6%, and C 29.2/7.0%. Actual survival was superior to predicted survival (Model for End-Stage Liver Disease [MELD]), (p < 0.001). Variceal rehemorrhage in patients undergoing small-diameter prosthetic H-graft portacaval shunting was very uncommon. Actual survival was superior to predicted survival (MELD). Long-term survival paralleled degree of hepatic function, although long-term survival was possible even with very advanced cirrhosis. Application of HGPCS is encouraged.

Results after laparoscopic fundoplication: does age matter?

Antireflux fundoplications are undertaken with hesitation in older patients because of presumed higher morbidity and poorer outcomes. This study was undertaken to determine if symptoms of gastroesophageal reflux disease (GERD) could be safely abrogated in a high-risk/reward popu lation of older patients. One hundred eight patients more than 70 years of age (range, 70-90 years) underwent laparoscopic Nissen fundoplications undertaken between 1992 and 2005 and were compared with 108 concurrent patients less than 60 years of age (range, 18-59 years) to determine relative outcomes. Before and after fundoplication, patients scored the severity of reflux and dysphagia on a Likert Scale (0 = minor, 10 = severe). Before fundoplication, older patients had lower reflux scores (P < 0.01), but not lower dysphagia scores or DeMeester scores. One patient (86 years old) died from myocardial infarction; otherwise, complications occurred infrequently, inconsequentially, and regardless of age. At similar durations of follow-up, reflux and dysphagia scores significantly improved (P < 0.01) for older and younger patients. After fundoplication, older patients had lower dysphagia scores (P < 0.01) and lower reflux scores (P < 0.01). At the most recent follow-up, 82 per cent of older patients rated their relief of symptoms as good or excellent. Similarly, 81 per cent of the younger patients reported good or excellent results. Ninety-one per cent of patients 70 years of age or more versus 85 per cent of patients less than 60 years would undergo laparoscopic Nissen fundoplication again, if necessary. With fundoplication, symptoms of GERD improve for older and younger patients, with less symptomatic dysphagia and reflux in older patients after fundoplication. Laparoscopic fundoplication safely ameliorates symptoms of GERD in elderly patients with symptomatic outcomes superior to those seen in younger patients.

Laparoscopic Nissen fundoplication offers high patient satisfaction with relief of extraesophageal symptoms of gastroesophageal reflux disease.

Nissen fundoplication is applied for patients with gastroesophageal reflux disease (GERD), usually because of symptoms of esophageal injury. When presenting symptoms are extraesophageal, there is less enthusiasm for operative control of reflux because of concerns of etiology and efficacy. This study was undertaken to evaluate the efficacy of laparoscopic Nissen fundoplication in palliating extraesophageal symptoms of GERD. Patients were asked to score their symptoms before and after laparoscopic Nissen fundoplication on a Likert scale (0 = never/none to 5 = always/every time I eat). A total of 322 patients with extraesophageal symptoms (asthma, cough, gas/bloat, chest pain, and odynophagia) of 4 to 5 were identified and analyzed. After fundoplication, all extraesophageal symptom scores improved (P < 0.0001 for all, Wilcoxon matched-pairs test). Likewise, postoperative symptoms were noted to be greatly improved or resolved in 67 per cent to 82 per cent of patients for each symptom. Furthermore, after fundoplication, patients were less likely to modify their dietary (82% vs 49%) or sleeping habits (70% vs 28%) to avoid initiating/ exacerbating symptoms. Although extraesophageal symptoms are conventionally thought to be inadequately palliated by surgery, this study documents excellent relief of extraesophageal symptoms after laparoscopic Nissen fundoplication, denotes high patient satisfaction, and encourages application of laparoscopic Nissen fundoplication.

Esophagography predicts favorable outcomes after laparoscopic Nissen fundoplication for patients with esophageal dysmotility.

BACKGROUND: We undertook this study to determine if clearance of a food bolus at preoperative esophagography predicts acceptable outcomes after laparoscopic Nissen fundoplication for patients with manometrically abnormal esophageal motility. STUDY DESIGN: Patients with gastroesophageal reflux disease (GERD) or symptomatic hiatal hernia with evidence of esophageal dysmotility by stationary manometry underwent videoesophagography to document the ability of their esophagus to clear food boluses of varying consistencies. Sixty-six patients were identified who had manometric dysmotility yet were able to clear a food bolus at esophagography, and subsequently underwent laparoscopic Nissen fundoplication. These patients were compared with 100 randomly selected patients with normal motility who underwent laparoscopic Nissen fundoplication. Symptom reduction and satisfaction were assessed through followup. Patients with normal motility were compared with those with manometrically moderate and severe dysmotility. RESULTS: Preoperative patient demographic data, symptoms, and symptom scores were similar among patients with normal motility and moderate or severe dysmotility. After fundoplication, symptom reduction was notable for all patients regardless of preoperative motility (p < 0.01, paired Student's t-test). There was no notable difference in postoperative symptom scores (p = NS, Kruskal-Wallis ANOVA) or in patient satisfaction (p = NS, chi-square analysis) among patients stratified by esophageal motility. CONCLUSIONS: Patients with esophageal dysmotility documented by manometry who are able to clear a food bolus at contrast esophagography, have functional results after laparoscopic Nissen fundoplication similar to patients with normal motility. Preoperative esophagography predicts successful outcomes after laparoscopic Nissen fundoplication for patients with manometric esophageal dysmotility.

Age affects presenting symptoms of achalasia and outcomes after myotomy.

Older patients with achalasia presumably have had a longer, more indolent course than younger patients. This study was undertaken to determine the impact of patient age and duration of symptoms on symptom severity and outcome after Heller myotomy. Two hundred sixty-two patients (142 men and 120 women), of average age 49 years +/- 17.7 (SD), have undergone laparoscopic Heller myotomy. Patients scored their symptoms using a Likert scale and subjectively rated their overall outcome. Data are presented as median, mean +/- SD, when appropriate. Follow-up is 25 months, 32 months +/- 28.7. Symptom severity scores improved after myotomy (P < 0.001 for all, paired Student's t test). Before myotomy, older patients had less dysphagia, regurgitation, choking, and chest pain (P < 0.05). Duration of preoperative symptoms did not correlate with frequency of symptoms. After myotomy, older patients had lower scores for dysphagia, chest pain, choking, and heartburn (P < 0.01); patients with prolonged durations of symptoms had lower dysphagia and choking scores. Neither age nor duration of symptoms had a significant effect on overall subjective outcomes. All patients should expect significant reductions in symptoms of achalasia following myotomy. Age and duration of symptoms impact symptoms before and after myotomy, but neither seem to impact subjective measure of outcome.

Laparoscopic Heller myotomy provides durable relief from achalasia and salvages failures after botox or dilation.

OBJECTIVE: To report outcome after laparoscopic Heller myotomy in a large number of patients. SUMMARY BACKGROUND DATA: Laparoscopic Heller myotomy has been undertaken for over a decade, but most studies involve small numbers of patients with limited follow-up. METHODS: Since 1992, 262 patients have undergone laparoscopic Heller myotomy and been prospectively followed. Concomitant fundoplication was undertaken for a patulous hiatus or large hiatal hernia or to buttress the repair of an esophagotomy until recently when it became routinely applied. With mean follow-up at 32 months, symptoms were scored by patients on a Likert scale (frequency: 0 = Never to 10 = Every time I eat/always; severity: 0 = Not bothersome to 10 = Very bothersome). RESULTS: Before myotomy, 79% received Botox or bag dilation: 52% had Botox, 59% underwent dilation, and 36% had both. Inadvertent esophagotomy occurred in 5%. Concomitant diverticulectomy was undertaken in 4%, and fundoplication was undertaken in 30%. Complications were infrequent. Median length of stay was 1 day. After myotomy, the frequency and severity of symptoms of achalasia and reflux significantly decreased. Eighty-eight percent of patients felt their symptoms were greatly improved or resolved, and 90% felt their outcome was satisfying or better. Ninety-three percent felt they would undergo myotomy again, if necessary. CONCLUSIONS: Laparoscopic Heller myotomy can safely and durably relieve symptoms of dysphagia while also reducing symptoms of reflux. Length of stay is short and patient satisfaction is very high with extended follow-up. Laparoscopic Heller myotomy is strongly encouraged for patients with symptomatic achalasia and is efficacious even after failures of dilation and/or Botox therapy.

Esophagotomy during laparoscopic Heller myotomy cannot be predicted by preoperative therapies and does not influence long-term outcome.

The conventional wisdom is that inadvertent esophagotomy complicates laparoscopic Heller myotomy. This study was undertaken to determine if esophagotomy at myotomy can be predicted by preoperative therapy, and if esophagotomy and/or its repair jeopardizes outcomes. Of 222 laparoscopic Heller myotomies undertaken since 1992, inadvertent esophagotomy occurred in 16 patients (7%); 60 patients who underwent myotomy without esophagotomy were utilized for comparison. Dysphagia and reflux before/after myotomy were scored by patients on a Likert scale (0-5). The median (mean +/- SD) follow-up after myotomy with esophagotomy was 38.8 months (31.6 +/- 21.9 months) versus 46.3 months (51.0 +/- 21.2 months) after myotomy alone. All esophagotomies were immediately recognized and repaired. Patients who experienced esophagotomy were similar to those who did not in application of Botox (56% vs. 77%) or dilation (44% vs. 65%), years of dysphagia (7.3 +/- 5.4 vs. 7.4 +/- 6.0), and mean preoperative dysphagia score (4.9 +/- 0.4 vs. 4.8 +/- 0.4). Esophagotomy led to longer hospitalizations (5.2 days +/- 2.5 days vs. 1.5 days +/- 0.7 days, P < 0.05) but not different postoperative dysphagia scores (1.5 +/- 1.7 vs. 2.1 +/- 1.4), reflux scores (1.4 +/- 1.7 vs. 2.3 +/- 1.3), or good or excellent outcomes (86% vs 84%). Esophagotomy during laparoscopic Heller myotomy is infrequent and cannot be predicted by preoperative therapy or duration or severity of dysphagia. Furthermore, complications after esophagotomy are infrequent and outcomes are indistinguishable from those of patients undergoing uneventful myotomy.