This Month in Gastroenterology

Article Outline

• Endotherapy or Surgery for Mucosal Esophageal Adenocarcinoma
• N-Acetylcysteine in Acute Liver Failure
• A Nonpathogenic Probiotic Yeast Inhibits Intestinal Neoplasia
• An Acidic Trigger for Zymogen Induction of Acute Pancreatitis
• Copyright

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Endotherapy or Surgery for Mucosal Esophageal Adenocarcinoma 

Esophageal adenocarcinoma, associated with reflux disease and Barrett's esophagus, is the malignancy with the fastest growing incidence. Traditionally, esophagectomy was the treatment of choice for curative intent, but this intervention is not without morbidity and mortality. More recently, endoscopic mucosal resection (EMR) has been advocated for mucosally confined adenocarcinomas of the esophagus, based on the observation that these have a low rate of metastatic lymphadenopathy. However, the currently available case series are limited by small numbers of patients and a relatively short duration of follow-up. In addition, it remains unclear how endoscopic treatment of mucosally confined esophageal adenocarcinoma compares with modern-day esophagectomy in the same indication.

In this issue of Gastroenterology, Prasad et al report on the outcome of patients with esophageal mucosal adenocarcinoma treated endoscopically or by conventional esophagectomy at the Mayo Clinic over the previous decade. This retrospective study identified 132 patients who underwent endoscopic therapy and 46 patients who underwent esophagectomy for mucosal esophageal adenocarcinoma between 1998 and 2007. In these nonrandomized cohorts, patients treated operatively were significantly younger (68 ± 1 vs 71 ± 1 years), had longer Barrett's esophagus length (7.3 ± 0.8 vs 5.5 ± 0.4 cm), and had fewer medical comorbidities than those treated endoscopically. All endoscopically treated patients underwent EMR; in 43%, additional photodynamic therapy was performed.

After EMR with or without photodynamic therapy, remission (defined as the absence of carcinoma on histology from 2 consecutive surveillance endoscopies) was achieved in 124 patients (94%). Eight patients from the endotherapy group elected surgery after detection of esophageal adenocarcinoma on the first surveillance endoscopy. Endoscopic therapy was done in an outpatient setting with no procedure-related mortality. Complications of endotherapy, in 18 patients, included strictures (n = 8; all had received photodynamic therapy), bleeding requiring hospitalization (n = 5), or photosensitization (n = 5; all had received photodynamic therapy).

In the surgical esophagectomy group, 4 had evidence of metastatic lymphadenopathy (8.6%) and 1 patient received postoperative chemoradiation. The median hospital stay was 8 days and postoperative morbidity occurred in 34% of the patients. There was 1 postoperative death and 3 readmissions within 90 days.

At a median follow-up of 465 person-years in the endoscopy group and 244 person-years in the surgery group, cumulative mortality did not differ between both groups (17% vs 20%, respectively). Overall survival (83% v. 95%, respectively) was comparable between the 2 groups (Figure 1). One patient in each group died from recurrent or metastatic esophageal adenocarcinoma. Cancer-free survival was significantly higher in the surgical group (80% vs 7%; P < .01). Recurrent carcinoma was detected during follow-up in 16 (12%) of the endoscopically treated patients compared with 1 in the surgical group. All recurrences were intramucosal carcinomas, appearing as small nodular lesions, and all except 1 patient (who chose to undergo esophagectomy) were managed by EMR. Residual dysplastic Barrett's esophagus was a significant predictor of recurrent carcinoma in univariate analysis. Additional photodynamic therapy did not affect recurrence rates.

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• Figure 1. 

  (A) Overall survival in endotherapy (blue line) and surgical (red line) groups (Kaplan–Meier curves; not significant). (B) Cancer-free survival in endotherapy (blue line) and surgical (red line) groups (Kaplan–Meier curves; P = .01).

This retrospective comparison of 2 treatment cohorts of patients with mucosal esophageal adenocarcinoma shows that overall survival and cumulative mortality rates were comparable between the 2 cohorts (endotherapy and surgical), despite the older age and higher comorbidity in the endotherapy group. There was a 12% recurrence rate in the endotherapy group, which was significantly greater than in the surgical group, but this was eligible for endoscopic retreatment.

Limitations of the study are the retrospective and, therefore, nonrandomized setting, and the rapid evolution of endotherapy for esophageal mucosa adenocarcinoma, where radiofrequency ablation is rapidly becoming a major treatment modality, which was not addressed in the present cohort. However, this study demonstrates that endoscopic management seems to be a viable alternative to esophagectomy for patients with mucosal esophageal adenocarcinoma.

See page 815.

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N-Acetylcysteine in Acute Liver Failure 

Acute liver failure is a severe and difficult-to-manage medical condition, which may rapidly progress and require liver transplantation. For acetaminophen poisoning, the most common cause of acute liver failure in the Western world, administration of N-acetylcysteine (NAC) within the first 24 hours is able to prevent or limit liver damage. NAC may exert a number of favorable effects, such as improving systemic hemodynamics and tissue oxygen delivery, which may also be beneficial to patients with other forms of acute liver failure. However, clinical trials evaluating the use of NAC in nonacetaminophen acute liver failure are lacking.

In this issue of Gastroenterology, Lee et al report on a prospective, randomized, double-blind, placebo-controlled, multicenter trial of NAC for acute liver failure not from acetaminophen toxicity. Patients received dextrose 5% or dextrose 5% with NAC (initial loading dose of 150 mg/kg per hour of NAC over 1 hour followed by 12.5 mg/kg per hour for 4 hours, then continuous infusions and 6.25 mg/kg for the remaining 67 hours). Patients with nonacetaminophen acute liver failure were eligible for the trial. Patients were excluded if they had known or suspected acetaminophen overdose, if they had previously received NAC, or if they had hepatic ischemia, liver failure owing to pregnancy, or cancer. Randomization was stratified by the standard hepatic encephalopathy (coma) categories (I–II and III–IV). The primary end point was the overall number of patients surviving at 3 weeks after study admission. The secondary end point was the number of patients surviving without transplantation after 3 weeks.

A total of 173 patients were recruited; 92 were randomized to placebo and 81 to receive NAC. The main causes of acute liver failure were drug-induced liver injury (n = 45), autoimmune hepatitis (n = 26), hepatitis B (n = 37), and indeterminate (n = 41). Early discontinuations of therapy owing to death or withdrawal of consent, transplantation, or side effects occurred with similar incidence in both groups. Survival at 3 weeks did not differ between both groups (70% for NAC vs 66% for placebo). Overall transplantation rates were 32% for NAC versus 45% for placebo (P = .09). Transplant-free survival was significantly higher in the treatment group compared with placebo (40% vs 27%; P = .04). The greatest difference was observed in patients with coma grades I–I (52% vs 30%). Patients in the NAC coma category I–II group had significantly longer transplant-free survival time than the other 3 groups (Figure 2). NAC-treated patients tended to have shorter hospital stays compared with placebo treated patients (median of 9 vs 13 days; P = .056). High-sensitivity analysis of the presence of acetaminophen in blood samples identified 6 patients with potentially unrecognized acetaminophen intoxication, but excluding these did not alter the results. Except for a higher prevalence of nausea and vomiting in NAC-treated patients (14% vs 4%; P = .03), the adverse event profile did not differ between the groups.

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• Figure 2. 

  Kaplan–Meier curves for each group (treatment by coma category) showing transplant-free survival to 365 days. Patients in the NAC I–II group demonstrated significantly greater transplant-free survival than the other 3 groups (largest P = .017).

This study shows that transplant-free survival is improved by administration of NAC in nonacetaminophen acute liver failure. This was mainly the case for patients with early stage hepatic encephalopathy, whereas advanced coma grade patients showed no significant benefit from NAC in the present study. Based on the present study and its favorable safety profile, IV NAC should be considered for patients with early stage nonacetaminophen acute liver failure. Future studies are needed to establish the optimal dose and duration of NAC therapy, predictors of response to NAC, and underlying mechanisms.

See page 856.

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A Nonpathogenic Probiotic Yeast Inhibits Intestinal Neoplasia 

The nonpathogenic yeast Saccharomyces boulardii has been used as a probiotic, and has been demonstrated to possess anti-inflammatory activity, as well as enzymatic, antimicrobial, and antitoxin activity. In particular, S boulardii inhibits the mitogenic ERK/MAPK pathway, but it is unclear how it drives this inhibition, and whether this yeast can reduce neoplastic growth as a result of the inhibition.

In the study by Chen et al, S boulardii was used to study signaling pathway effects in colorectal cancer cells and its effect in Apc^min mice. S boulardii markedly reduced phosphorylation of the epithelial growth factor receptor (EGFR) in colon cancer cells within 1 minute of exposure, with concomitant loss of downstream phosho-ERK1/2 and phospho-MEK1/2 activation. Additionally, S boulardii inhibited phosphorylation of the tyrosine kinase insulin-like growth factor-1 receptor and other members of the ErbB family such as HER-2 and HER-3, but did not inhibit other signaling kinases such as CamKII and PKC family members, indicating selectivity of S boulardii for signaling pathway inhibition. The inhibition of EGFR by S boulardii blocked EGF-induced cell proliferation, reduced cell colony formation, inactivated phospho-Akt, and increased apoptosis. Oral intake of S boulardii by Apc^min mice fed daily between ages 7 and 16 weeks reduced the number, diameter, and total surface area of intestinal tumors when compared with untreated Apc^min mice (Figure 3). Polyps from treated Apc^min mice showed lower dysplasia scores, lower proliferation indices, increased apoptosis, and reduced phospho-EGFR–stained cells compared with controls.

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• Figure 3. 

  Oral intake of S boulardii inhibits tumor growth in Apc^Min mice. After 9 weeks of oral administration of S boulardii, Apc^Min mice were humanely killed and the 10-cm section of the distal small intestine was harvested, from which was measured the number and size of intestinal tumors. Tumor number is significantly reduced in Apc^Min mice treated with S boulardii (n = 8) compared with control Apc^Min mice (n = 6; P = .03). Tumor size was also significantly reduced in the treated group (P = .03), as well as total tumor surface area (P = .02). Bars represent mean values ± standard error.

The study indicates that the nonpathogenic yeast S boulardii inhibits EGFR-induced proliferative signals to affect neoplastic growth in vivo. This yeast should be studied in humans to assess prevention and treatment of human colon neoplasia.

See page 914.

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An Acidic Trigger for Zymogen Induction of Acute Pancreatitis 

Acute pancreatitis is mediated by premature activation of proteases released by pancreatic acini to cause autolysis of this organ. Before protease activation, acini sensitization may occur, enhancing the injury by the proteases. Clinical evidence suggests that low pH environments may be required to initiate or enhance the severity of acute pancreatitis, but this has not been evaluated experimentally.

In the study by Bhoomagoud et al, the effect of low pH was studied in dispersed pancreatic acini and in vivo in rats. In dispersed acini, lowering the extracellular pH (pHe) from 7.4 to 7.0 had no effect on intrinsic zymogen activation, but in the presence of cerulein (a cholecystokinin [CCK] analog), trypsin, and chymotrypsin activity was greatly enhanced (2.5- to 5-fold), indicating that acid sensitization increased the protease activity. This effect could be blocked with a CCKA receptor antagonist (blocking cerulein), and reversed by increasing pHe back to 7.4 (Figure 4). Reducing pHe (acid sensitization) allowed for lower dosages of cerulein to have an effect. Other mechanisms for acidification, such as lactate or sodium propionate acidosis, also sensitized acini to cerulein-induced zymogen activation, and also enhanced zymogen-induced acinar injury as measured by lactate dehydrogenase release and by microscopy with the observance of basolateral cell membrane blebbing and appearance of large cytoplasmic vacuoles. Pharmacologic inhibition of proton-transporting vacuolar (v) ATPase blocked the effect of lowering pHe and subsequent cerulein-induced zymogen activation, indicating that vATPase mediates the pH-induced sensitization. Rat pancreata examined 1 hour after an acid load infusion and treated with cerulein demonstrated a 20-fold increase in trypsin activity over untreated controls and was associated with acute pancreatic edema, compared with a 7-fold increase in trypsin activity with cerulein treatment alone without any acid infusion.

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• Figure 4. 

  The effects of low extracellular pH (pHe) on cerulein-induced zymogen activation are reversible. Acini were exposed to different pHe conditions: group 1, pHe 7.4; group 2, pHe 7.0 for 30 minutes before cerulein hyperstimulation and maintained at pHe 7.0 for the remainder of the experiment; and group 3, pHe 7.0 for 15 minutes and then pHe was reversed to pH 7.4 and was allowed to equilibrate for another 15 minutes before treatment with or without cerulein (100 nmol/L) for 1 hour. Acini were collected and assayed for (A) trypsin and (B) chymotrypsin activity. Data are the mean values ± standard error of the mean of ≥4 individual experiments. *P < .05 compared with analogous treatment at pHe 7.4. ^#P < .05 compared with analogous treatment at pHe 7.0.

This study indicates that an extracellular acid load sensitizes pancreatic acinar cells to CCK-induced zymogen secretion, activation, and injury. Prevention of acid sensitization may reduce iatrogenic and other inducers of pancreatitis.

See page 1083.