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Is It Possible to Reprogram Adult Pancreatic Exocrine Into β Cells?

In Vivo Reprogramming of Adult Pancreatic Exocrine Cells to β-Cells.

Zhou Q, Brown J, et al:

Nature 2008; 455 (October 2): 627-632

Ngn3, Pdx1, and Mafa transcription factors delivered via an adenovirus vector can transform pancreatic exocrine cells in vivo into insulin-producing β cells.

Objective: To determine if adult pancreatic exocrine cells could be reprogrammed into pancreatic β cells in vivo. Design: Prospective, controlled basic science study. Methods: 2-month-old adult immune-deficient Rag1-strain rats were used as experimental animals to avoid immune response complications. Adenoviruses that express transcription factors responsible for cell reprogramming were prepared and injected into the pancreata of the mice. Insulin-positive cells were detected using immunochemical techniques. Results: 3 of 9 possible transcription factors in concert were found to be able to reprogram exocrine cells into β cells and were absolutely required: Ngn3, Pdx1, and Mafa. Insulin was detected by 3 days after transfection, reaching a peak similar to native β cells by 10 days post-injection. Of exocrine cells, 20% were reprogrammed to express insulin. Insulin production was still detectable up to 3 months into the experimental period. Conclusions: Adenoviral vectors containing 3 transcription factors (Ngn3, Pdx1, and Mafa) were capable of reprogramming mouse pancreatic exocrine cells into β cells in vivo. Reviewer's Comments: A fascinating study suggesting that cells do not have to be dedifferentiated to be reprogrammed to express new functions. Furthermore, no stem cells were required for gene expression in these experiments. One limitation is that this study may not be generalizable to human biology as the host mice are an immunodeficient strain, and adenoviral vectors are directly injected into the pancreas. In addition, the transfection process does not reprogram cells 100% of the time, so its efficiency is suboptimal. Hopefully, future developments in cell biology will allow for newer techniques that may render these approaches feasible in actual patients. (Reviewer-Ingram M. Roberts, MD). © 2009, Oakstone Medical Publishing

Keywords: Reprogramming Adult Pancreatic Exocrine Cells Into β-Cells

Print Tag: Refer to original journal article

"Diet" Mixers Increase Alcohol Absorption

Artificially Sweetened Versus Regular Mixers Increase Gastric Emptying and Alcohol Absorption.

Wu K-L, Chaikomin R, et al:

Am J Med 2006; 119 (September): 802-804

A small, randomized, blinded crossover study demonstrates that gastric emptying is faster and blood alcohol levels higher when alcohol is mixed with artificially sweetened mixers as opposed to regular, calorie-containing mixers.

Background: A major determinant of alcohol absorption is the rate of gastric emptying, which is dependent on the nutrient (or calorie) content in the stomach; gastric emptying is closely regulated by feedback mechanisms to release 2 to 3 calories per minute. Because of the popularity of "low carb" diets and the popularity of sweetened drinks, pre-mixed alcoholic drinks have appeared in "diet" varieties, sweetened with artificial sweeteners rather than sucrose. Objective: To determine if sugar-free mixed alcohol drinks would empty more rapidly from the stomach and increase the rate of alcohol absorption. Design: Randomised, crossover, blinded human physiologic study. Participants: 8 healthy, young non-obese males. Methods: Subjects imbibed 600-mL orange-flavored vodka drinks, containing 30 g of alcohol and sweetened with either sucrose or artificial sweetener. Each subject ingested both drinks in a randomized, crossover fashion, with an appropriate washout period in-between sessions. Blood alcohol levels were assessed at baseline and at intervals up to 3 hours after ingestion. Gastric emptying was assessed using ultrasound techniques, which the authors claim correlates with scintigraphic emptying of liquids. Results: Baseline values were the same for both testing periods. Antral area decreased significantly more rapidly after the diet drink, and the gastric half-emptying time was significantly less in the diet drink group compared to the regularly flavored drink group (21.1 ± 9.5 minutes vs 36.3 ± 15.3 minutes). Both peak and area under the curve blood ethanol concentrations were significantly greater after the diet drink as compared to the regular drink (0.053 ± 0.006 vs 0.034 ± 0.008 g% and 5.2 ± 0.7 vs 3.2 ± 0.7 units, respectively). The ethanol level achieved with the diet drink, but not the regular drink, would characterize subjects as legally drunk for driving. Conclusions: Alcoholic drinks made with diet mixers empty more rapidly from the stomach and result in markedly increased blood ethanol levels when compared to drinks containing sucrose mixers. The authors note that alcohol content alone is an unreliable measure when comparing the intoxicating potential of mixed or, in fact, any alcoholic beverage. Reviewer's Comments: The old adage to eat something before you drink would appear to hold true. Just be sure to eat something with calories. (Reviewer-Timothy O. Lipman, MD). © 2009, Oakstone Medical Publishing

Keywords: Gastric Emptying


Maintenance ADAL Decreases Need for Hospitalization, Surgery in Crohn's Disease

Effects of Adalimumab Therapy on Incidence of Hospitalization and Surgery in Crohn's Disease: Results From the

CHARM Study.

Feagan BG, Panaccione R, et al:

Gastroenterology 2008; 135 (November): 1493-1499

Crohn's disease patients treated with adalimumab have a decreased risk of hospitalization and surgery at 1 year, compared to placebo-treated patients.

Objective: To determine the effects of maintenance therapy with adalimumab (ADAL) on risks of hospitalization and risks of surgery in Crohn's disease (CD) patients. Design: Double-blind, randomized placebo-controlled trial. Participants: 778 patients with active CD (Crohn's Disease Activity Index score of 220 to 450). Methods: 778 patients from the CHARM (Crohn's Trial of the Fully Human Antibody Adalimumab for Remission Maintenance) trial were studied after induction therapy with 80 mg ADAL at baseline and 40 mg at 2 weeks. Of 778 patients, 499 were responders at week 4 and 279 were non-responders. All 778 patients (4-week responders and non-responders) were randomized to ADAL 40 mg every other week (n=260), ADAL 40 mg weekly (n=257), or placebo (n=261) for 56 weeks. All-cause hospitalizations, CD-related hospitalizations, and CD-related surgeries were compared at 3 and 12 months between the placebo group and the ADAL groups, individually and combined. Results: All-cause and CD-related hospitalizations were significantly less in the ADAL groups (every other week, weekly, and combined) at 3 and 12 months when compared to placebo. Hazard ratios for all-cause hospitalizations were 0.45, 0.36, and 0.40 for ADAL every other week, weekly, and combined, respectively (P <0.01), compared to placebo. Similar results were seen with hazard ratios for CD-related hospitalizations (0.5, 0.34, and 0.42, respectively, for ADAL groups compared to placebo (P <0.05). Fewer CD-related operations were performed in the ADAL groups every other week, weekly, and combined (0.4, 0.8, and 0.6 surgeries, respectively, vs 3.8 per 100 patients in the placebo group). Conclusions: Rates of hospitalization and rates of surgery are reduced by more than half in CD patients treated for 1 year with ADAL. Reviewer's Comments: Maintenance therapy with ADAL for 1 year reduced the risk of hospitalization and surgery in CD patients. The inclusion of 279 patients who did not exhibit improvement after induction therapy did not affect the significance of the data. A direct comparison of hazard ratios for hospitalization or surgery between patients who responded to induction therapy at 4 weeks and those who did not was not presented. (Reviewer-Allen L. Ginsberg, MD). © 2009, Oakstone Medical Publishing

Keywords: Crohn's Disease


Patients With EmA, Other Factors May Benefit From a Gluten Free Diet

Diagnosing Mild Enteropathy Celiac Disease: A Randomized, Controlled Clinical Study.

Kurppa K, Collin P, et al:

Gastroenterology 2009; 136 (March): 816-823

Patients who have positive anti-endomysial antibodies and biopsies and who do not demonstrate celiac disease may benefit from a gluten-free diet.

Background: At present, criteria for diagnosis of celiac disease are small bowel mucosal atrophy and crypt hyperplasia (Marsh III). It is generally believed that damage to the mucosa develops gradually and, thus, patients may develop symptoms before florid histologic changes take place. In view of the fact that endomysial antibodies (EmA) are indicative of forthcoming villous atrophy, it is speculated that patients having these antibodies and mild histologic changes may respond to a gluten-free diet (GFD). Objective: To ascertain if patients with EmA who have mild histologic changes in their small bowel mucosa might respond to a GFD. Participants/Methods: 70 consecutive patients found to have EmA had small bowel biopsies. Of those biopsied, 23 had only mild enteropathy (Marsh I to II) and were randomized to be put on a GFD or to stay on a diet containing gluten. At 1 year, clinical, histologic, and serologic studies were repeated. The remaining 47 patients in the original study had lesions compatible with celiac disease and served as controls. Results: In those patients who continued to consume gluten (Marsh I to II), all had deterioration in their mucosal villous architecture. In addition, all remained symptomatic, and endomysial antibodies persisted. In those patients who were on a GFD, symptoms improved, antibody levels decreased, and mucosal inflammation diminished similar to those who had been diagnosed with celiac disease (Marsh III). Conclusions: Patients with EmA who have mild histologic changes in their small bowel and who do not meet criteria for diagnosis of celiac disease appear to benefit from a GFD. Diagnostic criteria for celiac disease need to be re-evaluated, and those having EmA and only mild histologic changes belong in the spectrum of genetic gluten intolerance and should be tried on a GFD. Reviewer's Comments: This very interesting and important paper should encourage clinicians who see patients who have EmA but lack histologic criteria for celiac disease to put these patients on a GFD, as they are very likely to benefit from it. (Reviewer-Michael M. Phillips, MD). © 2009, Oakstone Medical Publishing

Keywords: Celiac Disease


IV PPI Use Has Escalated Dramatically in Patients Without High-Risk Indicators

Intravenous Proton Pump Inhibition Utilization and Prescribing Patterns Escalation: A Comparison Between Early and

Current Trends in Use.

Law J, Andrews CN, Enns R:

Gastrointest Endosc 2009; 69 (January): 3-9

IV proton pump inhibitor use in patients without a high risk of non-variceal upper gastrointestinal bleeding has escalated over the last several years in the absence of high-risk indicators.

Background: Use of IV proton pump inhibitors (PPIs) and endoscopy are well-accepted treatment methods for patients at high risk for continued bleeding. Objective: To evaluate the expansion of use of IV PPIs in a single institution over 2 study periods. Design: Retrospective case series. Participants: Consecutive patients receiving IV PPIs from November 1999 to June 2001 and from June 2003 to May 2004 at a single Canadian medical center. Data were gathered by retrospective hospital record review. Methods: The Charlson index was used to measure severity of comorbidity in the second study period; the earlier period comorbidity score was derived from assessing the number of systems involved. High-risk ulcer stigmata were noted, and the Forrest classification was calculated for each patient. Rebleeding, surgery, ICU care, and death were all noted. Results: In the early study group, 217 patients received IV PPIs on 218 occasions, compared to 516 receiving 613 episodes of IV PPI use in the late group. In the early group, 93% of 217 patients received IV PPI therapy for non-variceal gastrointestinal bleeding, compared to 56% of 516 patients in the late group. Also noted was that 18% of patients received IV PPIs for NPO status and 13% for abdominal pain in the late group. Seventy percent of patients in the early group underwent upper endoscopy versus 25% in the late group. In the early group, 55% of patients were on IV PPIs before endoscopy compared to 92% in the late group. These results were all statistically significant. Conclusions: IV PPI use has escalated at this hospital and is being used in patients before endoscopy or identification of high-risk endoscopic stigmata. Reviewer's Comments: Reviewer's Comments: I think this study's findings mirror what has occurred in most institutions - a creeping escalation of IV PPI use in non-high-risk patients. Pharmaceutical companies initially pitched the equal drug cost of oral and IV formulations of PPI therapy but did not account for the significant ancillary expense associated with IV medication use. This study also demonstrated that IV PPI use has expanded from treatment of non-variceal gastrointestinal bleeding to a number of other indications. These drugs are most helpful in preventing rebleeding of high-risk lesions after endoscopic evaluation and treatment. Utilization review programs are being instituted to address some issues related to escalation of IV PPI use. (Reviewer-J. Mark Lawson, MD). © 2009, Oakstone Medical Publishing

Keywords: IV Proton Pump Inhibitor Use


Latinos With HCV GT1 Have Lower SVRs Compared to Non-Latino Whites

Peginterferon Alfa-2a and Ribavirin in Latino and Non-Latino Whites With Hepatitis C.

Rodriguez-Torres M, Jeffers LJ, et al:

N Engl J Med 2009; 360 (January 15): 257-267

Latinos with naïve genotype 1 hepatitis C virus have lower sustained virologic response rates compared to non-Latino whites.

Background: Hepatitis C virus (HCV) is common in Latinos and may be associated with more aggressive disease. However, because they have been underrepresented in most clinical trials, their response compared to non-Latino whites is not defined. Objective: To examine the effect of Latino ethnicity on response to peginterferon alfa-2a (PEG) plus ribavirin (RVN) for treatment of naïve genotype (GT) 1 chronic HCV. Design: Prospective, multicenter non-randomized study. Participants: Latino and non-Latino whites with HCV GT1. Non-whites were excluded. Methods: All patients received PEG 180 μg/week and RVN 1000 to 1200 mg/day for 48 weeks. Response was assessed at weeks 4 (for rapid virologic response [RVR]), 12 (for early virologic response [EVR]), 24, 48 (for end of treatment response [ETR]), and 72 (for sustained virologic response [SVR]). The primary end point was SVR. Secondary end points were RVR, EVR, and ETR. Safety, tolerability, dose reductions, and histologic responses were also assessed. Results: Of 569 patients enrolled, 269 were Latino and 300 were non-Latino whites. Although groups were comparable, Latinos were slightly younger (45 vs 48 years), had higher body mass indices (30 vs 28) and alanine aminotransferase levels, and had more cirrhosis (13% vs 10%). SVR rates were lower in Latinos compared to non-Latinos (34% vs 49%; P <0.001). Corresponding rates for RVR, EVR, and ETR were 14% versus 20% (P =0.04), 48% versus 63% (P <0.001), 56% versus 73% (P <0.001) in Latinos compared to non-Latinos, respectively, while relapse rates were similar (19% vs 17%). Multivariate analysis adjusted for baseline demographic, laboratory, and virologic parameters found that non-Latino ethnicity (odds ratio [OR], 6.93) and low baseline viral load (<400,000 IU/mL; OR, 2.92) were the only independent predictors of SVR. Adherence to treatment, dose modification, and adverse events were similar in both groups, while fewer Latinos discontinued therapy because of adverse events. Conclusions: Latinos with HCV GT1 have lower SVR rates compared to non-Latino whites. Reviewer's Comments: Similar to studies in blacks compared to whites, Latinos have lower RVR, EVR, and ETR rates than do non-Latino whites, which results in lower SVRs even after controlling for body mass index, histologic severity, dose reductions, and compliance. Whether this is due to other factors such as steatosis, insulin resistance, or genetic factors remains unknown. Hopefully, the addition of antiviral agents (such as Telaprevir or Boceprevir) to PEG and RVN will improve SVRs in minorities. (Reviewer-Richard K. Sterling, MD). © 2009, Oakstone Medical Publishing

Keywords: Peginterferon Alfa-2a + Ribavirin


AFP-L3%, DCP Correlate Better With Absence of HCC

Utility of Lens culinaris Agglutinin-Reactive Fraction of Alpha-Fetoprotein and Des-Gamma-Carboxy Prothrombin, Alone

or in Combination, as Biomarkers for Hepatocellular Carcinoma.

Sterling RK, Jeffers L, et al:

Clin Gastroenterol Hepatol 2009; 7 (January): 104-113

The Lens culinaris agglutinin-reactive fraction of alpha-fetoprotein (AFP) and the des-gamma-carboxy prothrombin correlate better in the absence of hepatocellular carcinoma; in combination they had higher specificity than total AFP.

Background: Because alpha-fetoprotein (AFP) has poor sensitivity in the surveillance of hepatocellular carcinoma (HCC), other biomarkers, such as Lens culinaris agglutinin-reactive fraction of AFP (AFP-L3) and des-gamma-carboxy prothrombin (DCP) are increasingly used in Asia. However, their utility in North America is unknown. Objective: To evaluate the clinical utility of AFP-L3 and DCP, alone or in combination, in a North American population. Design: Prospective multicenter study. Participants: Patients with hepatitis C virus (HCV)-related cirrhosis from 7 sites in the U.S. and Canada. Methods: After baseline clinical and laboratory data were collected, patients were followed every 3 to 6 months for up to 2 years. At each visit, total AFP, AFP-L3%, and DCP were obtained (Wako Diagnostics; Richmond, VA). Liver imaging was performed at entry and every 6 to 12 months at each center. Diagnosis of HCC was made by histology or imaging (European Associated for the Study of the Liver criteria). HCC stage was based on United Network of Organ Sharing criteria. AFP-L3% and DCP results were unknown to clinical centers. Results: Of 372 patients, 34 of 298 developed HCC who were free of HCC at entry (annual incidence, 4.3%). The overall sensitivity, specificity, and positive- and negative-predictive values were 61%, 71%, 34%, and 88% for AFP >20 ng/mL, respectively; 37%, 92%, 52%, and 85% for AFP-L3% >10, respectively; 39%, 90%, 48%, and 86% for DCP >7.5 ng/mL when used alone, respectively; and higher at 77%, 59%, 32%, and 91% when AFP was combined with AFP-L3% and DCP, respectively. In those with AFP between 20 and 200 ng/mL, AFP-L3% and DCP exhibited high specificities of 86.6% and 90.2%, respectively. Of 29 HCC patients with AFP <20 ng/mL, 13 (45%) exhibited elevation of AFP-L3% or DCP. Increased alanine aminotransferase was associated with increased total AFP but not AFP-L3% or DCP. The HCC-free survival was lower in those with increased AFP-L3% and DCP. Conclusions: AFP-L3% and DCP correlated better with absence of HCC; in combination, they had a higher specificity than total AFP. Reviewer's Comments: Although AFP-L3% and DCP provided only marginal benefit in surveillance for early HCC, their clinical utility is in identifying those with negative imaging who might benefit from enhanced follow-up, and in their strong predictability to exclude HCC if both are negative. However, caution in using these biomarkers alone without imaging is warranted as approximately 23% of those with HCC had normal results, while 40% of those without HCC had at least 1 positive test. (Reviewer-Richard K. Sterling, MD). © 2009, Oakstone Medical Publishing

Keywords: Hepatocellular Carcinoma


Esophageal Cancer Incidence Lower in Barrett's After Ablation

Esophageal Adenocarcinoma in Barrett's Esophagus After Endoscopic Ablative Therapy: A Meta-Analysis and Systematic

Review.

Wani S, Puli SR, et al:

Am J Gastroenterol 2009; 104 (February): 502-513

This meta-analysis showed that ablative therapy for Barrett's esophagus with or without dysplasia results in a reduced rate of esophageal cancer, with the most benefit noted in Barrett's high-grade dysplasia.

Objective: To determine the incidence of cancer following Barrett's ablative therapy and to compare these rates to the incidence of cancer in a non-ablated cohort. Design/Methods: Systematic review of all published articles that would provide data concerning the incidence of esophageal adenocarcinoma (EAC) in Barrett's esophagus (BE) and also similar data concerning EAC following ablative therapy for BE. Extensive databases were searched in MEDLINE, ie, PubMed, Ovid, ACP Journal Club, Cochrane CENTRAL, AGA, ACG abstracts. Keywords were used to identify this condition, and all information used represented standards proposed by the Meta-Analysis of Observational Studies in Epidemiology study group. Patients had to have histologically proven BE or dysplasia, follow-up of at least 6 months, and, in the case of ablation, follow-up histology of at least 6 months' duration. Results: (1) The search identified 4427 reference articles, of which 65 met inclusion criteria for ablation studies and 53 for natural history data. (2) The incidence of EAC in non-dysplastic BE (NDBE) in surveillance studies was 5.98/1000 patient-years. The incidence of cancer in this group of patients undergoing ablative therapy was 1.68/1000. (3) In patients with low-grade dysplasia undergoing surveillance, the incidence of cancer was 16.98/1000 patient-years. Patients in this group undergoing ablative therapy had a EAC rate of 1.58/1000 patient-years. (4) The incidence of cancer in patients undergoing surveillance for high-grade dysplasia was 65.8/1000 patient-years. Patients undergoing ablative therapy in this group had an EAC rate of 16.76/1000 patient-years. Conclusions: These studies indicate that ablation of BE tissue probably decreases the likelihood of future development of EAC. This decrement in the likelihood of developing EAC following BE ablation is best seen in patients with BE high-grade dysplasia. Reviewer's Comments: Because this study is a compilation of patients from the literature, and most patients were not in randomized controlled studies comparing ablative techniques versus placebo, many parameters could not be controlled for. Calculations from this study suggest that the number needed to treat to save 1 EAC in NDBE would be 250, and for BE high-grade dysplasia, 20. This would suggest that if ablative therapy were to be used for NDBE, it would have to be extremely safe and inexpensive. On the other hand, in high-grade dysplasia patients, BE ablation significantly decreases the risk of cancer with significantly fewer patients. Ablative therapy in this group seems to be the best course of therapy. (Reviewer-Roy K.H. Wong, MD). © 2009, Oakstone Medical Publishing

Keywords: Esophageal Adenocarcinoma


Type III or IV Hilar Strictures May Fare Better With Percutaneous Stenting

Palliative Treatment With Self-Expandable Metallic Stents in Patients With Advanced Type III or IV Hilar

Cholangiocarcinoma: A Percutaneous Versus Endoscopic Approach.

Paik WH, Park YS, et al:

Gastrointest Endosc 2009; 69 (January): 55-62

Percutaneous stenting of high-grade hilar biliary strictures has a higher initial success rate compared to endoscopic therapy.

Background: Hilar malignant biliary strictures represent a significant management problem. Biliary drainage results in a number of clinically beneficial outcomes in this group of patients. Objective: To compare percutaneous versus endoscopic methods to treat high-grade hilar biliary obstruction. Design: Multicenter retrospective study. Participants: Medical reports of 466 patients with hilar biliary obstruction were reviewed, and 85 patients with Bismuth III or IV lesions treated solely with percutaneous or endoscopic expandable metallic stents made up the study population. Methods: Initial outcomes were assessed for the 2 types of drainage procedures, including success rates and complications. Long-term outcomes were noted, particularly stent patency and survival. Standard procedural techniques were used. Interventions: Percutaneous or endoscopic biliary drainage using self-expandable metallic stents. Results: The 2 groups were clinically similar. A statistically higher rate of initial success in biliary drainage was noted with the percutaneous approach, with a 92% success rate versus 77% with the endoscopic approach. Procedure-related complications were similar in the 2 groups, with only 1 death. Importantly, median survival in the 2 groups in which the procedure was initially successful was similar but was markedly better compared to those who had failed biliary drainage (8.7 vs 1.8 months). Conclusions: In patients with type III or IV hilar strictures, percutaneous stenting achieves a higher initial success rate with a low procedure complication rate. Reviewer's Comments: Reviewer's Comments: The key issues pointed out in this retrospective trial are that percutaneous stenting at this institution had a high rate of success and reasonable complication rate as compared to the endoscopic approach at this institution. In addition, the dramatic increase in median survival with successful stenting is further evidence that stenting has a significant palliative effect in these patients. The endoscopic approach to hilar strictures is challenging and, in my opinion, should in general be left to high-volume centers specializing in complicated procedures when interventional radiology expertise is available. (Reviewer-J. Mark Lawson, MD). © 2009, Oakstone Medical Publishing

Keywords: Hilar Bile Duct Obstructions


Nut Consumption Associated With Reduced Hypertension Risk

Nut Consumption and Risk of Hypertension in U.S. Male Physicians.

Djoussé L, Rudich T, Gaziano JM:

Clin Nutr 2009; 28 (February): 10-14

In a secondary data analysis of the Physicians Health Study 1, daily nut consumption was associated with reduced risk of hypertension in lean male U.S. physicians.

Background: Hypertension is a major risk factor for cardiovascular and renal disease. Modifiable lifestyle factors such as sodium intake, type of diet, weight control, and exercise could play a role in hypertension prevention. Nut consumption may lower the risk of hypertension. Objective: To examine whether nut consumption is associated with a lower risk of incident hypertension, and to determine whether overweight or obesity modifies any potential associations between nut consumption and hypertension. Design: Secondary data analysis of participants in a randomized controlled trial. Participants/Methods: 22,071 U.S. male physicians in the Physicians Health Study1 (PHS1) were randomized to low-dose aspirin and/or β-carotene or placebo for the primary prevention of cardiovascular disease and cancer. Twelve months after randomization, participants completed a food frequency questionnaire, which included questions on nut consumption. Newly diagnosed hypertension was ascertained by self-reporting. A variety of other variables were collected and assessed. Results: After exclusions for missing data and hypertension at baseline, 15,966 participants were available for analysis. Using the strictest model that accounted for potential confounding variables (age, body mass index, smoking, alcohol consumption, history of diabetes, exercise, fruit and vegetable intake, breakfast cereal and type, red meat, fish, dairy, multivitamin use, PHS1 treatment assignment, and lipid status) as compared with no or rare intake of nuts, intake of ≥1 ounces of nuts daily was associated with a significant 18% reduction in hypertension risk (hazard ratio, 0.82; 95% CI, 0.71 to 0.94). When stratified by BMI (< or >25kg/m2), the significant inverse association between nut consumption and hypertension was seen only in lean male physicians. Results: A lowered incidence of hypertension among lean U.S. male physicians is associated with consuming ≥1 ounces of nuts per day. Reviewer's Comments: Why might nuts be beneficial? Nuts are low in sodium and contain nutrients, which may have beneficial influences on blood pressure; these potentially beneficial nutrients include mono- and polyunsaturated fatty acids, magnesium, potassium, fiber, antioxidants, and vitamins. What are the limitations of this information? The positive association evolved only after extensive secondary analysis in a cohort assembled to ask a different question. Such is the nature of epidemiologic and much of nutrition research. The findings are in sync with other purported health benefits of nut consumption. Obviously, confirmation from other cohorts is needed. It is highly unlikely that we are ever going to see a long-term, randomized controlled trial evaluating the health effects of nuts. (Reviewer-Timothy O. Lipman, MD). © 2009, Oakstone Medical Publishing

Keywords: Nut Consumption


Endoscopic Full-Thickness Plication Now Possible

Endoscopic Full-Thickness Plication for the Treatment of GERD by Application of Multiple Plicator Implants: A Multicenter

Study.

von Renteln D, Schiefke I, et al:

Gastrointest Endosc 2008; 68 (November): 833-844

Endoscopic full-thickness plication was safe and effective in reducing GERD symptoms in a recent pilot study.

Background: Treatment of reflux frequently involves lifelong therapy. Endoscopic therapy with a single Plicator has been effective in reducing reflux. Researchers have speculated that multiple Plicator placement may be more beneficial. Objective: To evaluate the effectiveness of multiple endoscopic Plicator placement in patients with chronic reflux symptoms. Design: Open-label, prospective multicenter study. Participants: Patients aged >18 years with >6 months of gastroesophageal reflux disease (GERD) symptoms requiring daily proton pump inhibitor therapy and a hiatal hernia (HH) <3 cm in size. Methods: Efficacy of therapy was based on GERD health-related quality-of-life (HRQL) questionnaire at 6 months after treatment, visual analog scale (VAS) score, medication use, esophageal pH/manometry, and esophagitis. Exclusions included those with HH >3 cm, grade 3 to 4 esophagitis, Barrett's epithelium, dysphagia, esophageal bleeding, vomiting, or bloating. Propofol and midazolam were used for sedation. Atropine and antibiotics were given. After upper endoscopy, the endoscope was passed through the center of the Plicator. After retroflexion, the tissue retractor was placed 1 cm below the gastroesophageal junction (GEJ) and tissue was drawn back, and the arms then closed, deploying the suture with a pledget. This was repeated in the remaining quadrants with incremental advancements toward the GEJ with each placement. Results: 41 patients were enrolled. Six-month post-procedure HRQL improved 76% for reflux symptoms as compared to baseline score while off medication. Seventy percent were off daily therapy; 80% had improved reflux symptoms compared to baseline. Median esophagitis scores improved 75% compared with baseline, and pH testing showed a 38% drop in acid exposure. Manometry was also improved statistically. Conclusions: Multiple serially placed implants using an endoscopic full-thickness Plicator was safe and effective in reducing reflux symptoms, antireflux medications, acid exposure, and esophagitis. Reviewer's Comments: I reviewed this article to point out several important issues in dealing with the evaluation of new medical devices. While obviously this study is relatively small in size, not randomized, and not blinded, there are other, even greater issues we need to consider. As pointed out in the accompanying editorial, FDA clearance of a medical device can be made with virtually no rigorous data on efficacy or long-term safety. This is well demonstrated by the sham controlled randomized trials of 2 other techniques, Enteryx and the Stretta procedure. While benefit was shown in some areas of reflux control, there was no change in measured acid exposure after the procedure with the use of Enteryx; with the Stretta procedure, there was no change in either medication use or level of acid exposure. Careful long-term randomized controlled trials versus medical and standard surgical therapy should be required before exposing our patients to these exciting but untested procedures. (Reviewer-J. Mark Lawson, MD). © 2009, Oakstone Medical Publishing

Keywords: Endoscopic Plication


Complete Endoscopic Eradication of Intestinal Metaplasia Possible

Endoscopic Ablation of Barrett's Esophagus: A Multicenter Study With 2.5-Year Follow-Up.

Fleischer DE, Overholt BF, et al:

Gastrointest Endosc 2008; 68 (November): 867-876

Radiofrequency ablation makes complete eradication of Barrett's esophagus possible.

Background: Surveillance endoscopy is in widespread use to detect and monitor Barrett's esophagus. Radiofrequency ablation (RFA) has recently been reported to be helpful. Objective: To evaluate long-term safety and efficacy of RFA of Barrett's esophagus. Design: Prospective multicenter trial. Participants: Patients were aged 18 to 75 years and were found to have biopsy-proven intestinal metaplasia with segment length of 2 to 6 cm. Prior therapy, dysplasia, active esophagitis, stricture, or varices were disqualifying. Methods: This paper was derived from data from the Ablation of Intestinal Metaplasia trial. Ablation was performed with the circumferential ablation device known as the HALO system, which includes a sizing balloon and a balloon-based ablation catheter. The ablation procedure is detailed and has been previously reported in this journal series. Results: Complete remission at 12 months occurred in 70% of patients (48 of 69); at 30 months with additional therapy, complete remission occurred in 98% (60 of 61). There was no buried metaplastic tissue discovered, no stricturing, and no serious complications. Conclusions: The use of stepwise RFA of intestinal metaplasia is highly effective in achieving complete eradication. Reviewer's Comments: This technique has been reported previously by me in this audio series and appears to be standing the test of time with a reasonable complication rate and a high success rate. RFA appears to be a more effective technique in completely destroying superficial and deep metaplastic tissue. Typically 2 treatment sessions were needed. The number of patients in this uncontrolled trial was relatively small, which should make us cautious in implementing treatment when this device becomes available. Keep in mind that FDA clearance on a device is typically made with minimal documentation of safety and efficacy. (Reviewer-J. Mark Lawson, MD). © 2009, Oakstone Medical Publishing

Keywords: Barrett's Eradication


Older Age Males Have Increased Risk of Colonoscopy-Related Bleeding, Perforation

Bleeding and Perforation After Outpatient Colonoscopy and Their Risk Factors in Usual Clinical Practice.

Rabeneck L, Paszat LF, et al:

Gastroenterology 2008; 135 (December): 1899-1906

Factors that increase the risk of bleeding and perforation during colonoscopy include older age, male gender, higher comorbidity, and polypectomy by a low-volume endoscopist.

Objective: To determine the risk of bleeding, perforation, and death following outpatient colonoscopy and to identify factors associated with these risks. Design/Participants: Population-based cohort of individuals undergoing outpatient colonoscopy in 4 Canadian provinces. Methods: Data were collected from April 2002 until March 2003 using the Canadian Institute for Health Information (CIHI) Discharge Abstract Database, which contains information on all patients discharged from the hospital or same-day surgery units. Patient demographics, diagnosis, procedures, and discharge status were contained in this database. Using the information from this database, exclusion criteria were developed to try to estimate a cohort having a screening colonoscopy. Algorithms were developed to identify bleeding, perforations, and death 30 days following index colonoscopy. Risk factors included patient age, sex, comorbidity, and polypectomy and endoscopist specialty (GI, surgeon, internist, FP, GP) and experience (# colonoscopies/year). These were categorized into volume, quintile, and setting (hospital, private office, and clinic). Algorithms were validated via kappa statistics. Results: Overall, the bleeding and perforation rates were 1.64/1000 and 0.85/1000, respectively, with a risk of death of 1 in 14,000. Older age (60 to 75 years) was associated with an increase in bleeding (OR, 1.61; P <0.001), perforation (OR, 2.06; P <0.0001), and perforation plus bleeding (OR, 1.72; P <0.0005). Females had a lower risk of bleeding (OR, 0.52; P <0.0003) and bleeding plus perforation (OR, 0.67; P <0.009). Comorbidity was associated with an increased risk of perforation (OR, 3.73; P <0.003) and bleeding plus perforation (OR, 2.29; P <0.008). Polypectomy was associated with an increased risk of bleeding (OR, 10.32; P <0.0001), perforation (OR, 2.96; P <0.0001), and bleeding plus perforation (OR, 6.78; P <0.0001). Low-volume endoscopists had increased odds of having bleeding and perforation. Conclusions: Factors associated with an increased risk of bleeding and perforation during colonoscopy included older age, male, higher comorbidity, and undergoing polypectomy by a low-volume endoscopist. Reviewer's Comments: The major advantage of this study is that it is population-based and reflects the practice in the general population and not the practice of a single specialty care institution. These data are consistent with other population-based studies and the complications noted in this study are higher than in single-center, gastroenterologist-performed studies. It also indicates that the complications of colonoscopy are not negligible, especially when performed in older patients by non-gastroenterologists. The disadvantages of this study are the fact that one could not specifically determine whether all colonoscopies were screening or diagnostic colonoscopies and how many polyps were retrieved in each patient. (Reviewer-Roy K.H. Wong, MD). © 2009, Oakstone Medical Publishing

Keywords: Bleeding & Perforation


Increased Weight Linked to Increased Liver Cancer Risk in HBV Carriers

Body-Mass Index and Progression of Hepatitis B: A Population-Based Cohort Study in Men.

Yu M-W, Shih W-L, et al:

J Clin Oncol 2008; 26 (December 1): 5576-5582

In a 16-year prospective Taiwanese cohort of carriers of the hepatitis B virus, excess weight was associated with an increased risk of hepatocellular carcinoma and liver disease-associated death.

Background: Obesity has been associated with an increased risk of a number of gastrointestinal malignancies, including hepatocellular carcinoma (HCC). The potential relationship between obesity and other risk factors for HCC, such as hepatitis B virus (HBV), is unclear. Objective: To assess the potential relationship between excess body mass index (BMI) and liver-related morbidity and mortality in healthy male HBV carriers. Design: Prospective cohort study. Participants: Healthy Taiwanese males aged ≥30 years infected with HBV. Methods: Subjects were recruited during routine physical exam from 1989 to 1992. Multiple baseline parameters were obtained. Subjects were followed through 2005. BMI was divided into 4 categories: underweight (<18.5 kg/m2), normal (18.5 to 24.9 kg/m2), overweight (25.0 to 29.9 kg/m2), and obese (≥30 kg/m2). Outcomes were assessed. Results: 2903 HBV+ males free of cancer at baseline were followed for a mean of 14.7 years. During this time, 218 deaths occurred, including 92 attributable to liver-related disease (HCC in 71, cirrhosis in 21). In Cox proportional models adjusting for age, diabetes, number of visits, smoking, and alcohol, compared with normal weight men, increased hazard ratios (HRs) for incident HCC were observed for overweight men (HR, 1.48; 95% CI, 1.04 to 2.12) and obese men (HR, 1.96; 95% CI, 0.72 to 5.38). Liver-related mortality had adjusted HRs of 1.74 (95% CI, 1.15 to 2.65) in overweight men and 1.50 (95% CI, 0.36 to 6.19) in obese men. Conclusions: Over a mean of 14.7 years, increased weight may increase the risk of liver-related mortality and HCC in males with HBV. Reviewer's Comments: These data support other observational findings suggesting an association between increased body weight and cancer incidence or mortality. By themselves, however, these data are less than overwhelming, as significant associations were seen only in overweight men but not in obese men. Hopefully, data confirming or refuting these findings will appear from other cohorts in the future. (Reviewer-Timothy O. Lipman, MD). © 2009, Oakstone Medical Publishing

Keywords: Obesity


LARS Outcomes Similar to Those of Medical Tx for GERD

Comparing Laparoscopic Antireflux Surgery With Esomeprazole in the Management of Patients With Chronic Gastro-

Oesophageal Reflux Disease: A 3-Year Interim Analysis of the LOTUS Trial.

Lundell L, Attwood S, et al:

Gut 2008; 57 (September): 1207-1213

Results after laparoscopic antireflux surgery are similar to those after medical therapy for treatment of reflux disease over a 3-year follow-up period.

Objective: To compare the results of a trial of medical therapy with esomeprazole with those of laparoscopic antireflux surgery (LARS). Design: Prospective, parallel-group, randomized controlled design. Participants: 554 patients with gastroesophageal reflux disease (GERD) were randomized to either LARS (288 patients) or esomeprazole 20 mg that could be increased to 40 mg daily if necessary (266 patients). Patients were recruited from 6 European countries and 40 different institutions. Methods: Patients received endoscopy at 1 and 3 years after initial endoscopy when enrolled in the study. All patients underwent a 3-month run-in period during which time patients received 40 mg esomeprazole daily to produce baseline healing. The primary end point of the study was treatment failure as defined by relapse of symptoms requiring treatment measures beyond those in the study protocol. The study was 3 years in duration. Results: 90% of LARS patients remained in remission after 3 years of study versus 93% for esomeprazole patients (P =0.25). Significant adverse effects occurred in 21.0% of LARS patients and 14.3% of esomeprazole patients. The study was discontinued in 0.8% of LARS patients and in 3.8% of esomeprazole patients. Conclusions: Patients with GERD treated with either LARS or esomeprazole had similar clinical outcomes over a 3-year period of treatment. Reviewer's Comments: The majority of patients (>90%) in this study had grade B Los Angeles endoscopic esophagitis and mild clinical symptoms. It is possible that these results in patients with grade C to D esophagitis may not be similar to those found by these investigators. One might conclude from this research that mild endoscopic esophagitis should always be treated medically unless the patient refuses to take medications and specifically requests LARS therapy. These patients should be continued to be followed to see if there are any differences in long-term results between groups. (Reviewer-Ingram M. Roberts, MD). © 2009, Oakstone Medical Publishing

Keywords: Gastroesophageal Reflux Disease


What Factors Accelerate Endoscopic Esophagitis Stage Progression?

The Effect of Metabolic Risk Factors on the Natural Course of Gastro-Oesophageal Reflux Disease.

Lee Y-C, Yen AM-F, et al:

Gut 2009; 58 (February): 174-181

Progression of the stage of endoscopic esophagitis may be accelerated by male sex, the metabolic syndrome, and cigarette smoking.

Objective: To determine if certain metabolic risk factors influence the natural history of gastroesophageal reflux disease (GERD). Design: Prospective cohort of patients from a single medical center. Participants: 3669 patients who underwent at least 2 upper endoscopies between June 2003 and December 2006 comprised the study population. Methods: The study was divided into 3 "epochs" spanning the total time of the research period. Data were analyzed with a 3-state Markov model for the natural history of GERD. State 1 was non-erosive endoscopy, state 2 was Los Angeles classification A to B, and state 3 was Los Angeles classification C to D. Results: During the course of the study, 12.2%, 14.9%, and 17.9% of patients, respectively, progressed from non-erosive to erosive stages, while 42.5%, 37.3%, and 34.6%, respectively, regressed to a non-erosive endoscopy. Male sex (relative risk [RR], 4.31), smoking (RR,1.2), and metabolic syndrome (RR, 1.75) were independent factors that increased the likelihood that a patient would progress from a non-erosive stage to an erosive stage. Acid suppression therapies increased the likelihood of regression from erosive to non-erosive esophagitis (RR, 0.54). Conclusions: Endoscopic esophageal damage is a process that exhibits dynamic characteristics that are subject to modification. Male gender, active smoking, and presence of the metabolic syndrome accelerated the progression of GERD from non-erosive to erosive stages. Reviewer's Comments: The patient population consisted of 68% Asian men, so it is unclear if the natural history of GERD in other patient populations would be similar. Of interest is the fact that only 0.06% of patients screened for this study had Barrett's esophagus, and these patients were not included for analysis in this research. (Reviewer-Ingram M. Roberts, MD). © 2009, Oakstone Medical Publishing

Keywords: Metabolic Risk Factors


PEG Alpha-2b, Alpha-2a Response Rates Similar in HIV-HCV Coinfection

Randomized Trial Comparing Pegylated Interferon Alpha-2b Versus Pegylated Interferon Alpha-2a, Both Plus Ribavirin, to

Treat Chronic Hepatitis C in Human Immunodeficiency Virus Patients.

Laguno M, Cifuentes C, et al:

Hepatology 2009; 49 (January): 22-31

In patients with HIV and hepatitis C virus coinfection, response rates are similar between pegylated interferon alpha-2b and alpha-2a when combined with ribavirin.

Background: Coinfection with hepatitis C virus (HCV) is common in patients with HIV. Although 2 formulations of pegylated interferon (PEG) exist, there have been no head-to-head comparisons in HIV-HCV coinfection. Objective: To compare the efficacy and safety of PEG alpha-2b and alpha-2a, both plus weight-based ribavirin (RVN), for HCV treatment in naïve patients coinfected with HIV. Design: Prospective, randomized, multicenter open-label study. Participants: 182 coinfected patients from 5 Spanish centers who were HCV-RNA-positive, had elevated alanine aminotransferase (1.5 x ULN) levels, and had controlled HIV (CD4 >250 cells/mm3 and HIV RNA <50,000 copies/mL). Methods: Patients were randomly assigned to PEG alpha-2b (80 to 150 μg/week adjusted for weight; n=96) or PEG alpha-2a (180 μg/week; n=86) plus RVN (800 to 1200 mg/day) for 48 weeks. Response was assessed at weeks 4 (rapid virologic response [RVR]), 12 (early virologic response [EVR]), 24, 48 (end of treatment response [ETR]), and 72 (sustained virologic response [SVR]). Those who were positive at week 24 discontinued therapy. The primary end point was SVR. Secondary end points were tolerability and adverse events, RVR, EVR, biochemical response, relapse, and positive- and negative-predictive values (PPVs and NPVs) to achieve SVR in those with RVR and EVR. Results: Groups were well matched (age, 41 years; 73% male; genotype [GT] 1 (45%), 3 (34%), and 4 (17%); advanced fibrosis (29%); and controlled HIV). Overall SVRs were similar in those who received PEG alpha-2b compared to PEG alpha-2a (42% vs 46%). SVR rates were also similar when stratified by GT: 28% vs 32% for GT 1 and 4, and 62% vs 71% in those with GT 2 or 3. RVR (35% vs 35%) and EVR (69% vs 80%) were also similar between groups. PPVs and NPVs were 81% and 74%, respectively, in those with RVR and 64% and 100%, respectively, in those with EVR, and were similar between the 2 PEG formulations. Treatment discontinuation rates were also similar (10%). Multivariate analysis identified younger age (P =0.007), male gender (0.013), and GT 2 or 3 (P <0.0001) as predictors of SVR. Among those with an SVR, 18% did not have biochemical response. Conclusions: In patients with HIV-HCV coinfection, response rates were similar between PEG alpha-2b and alpha-2a combined with RVN. Reviewer's Comments: Although PEG alpha-2a is the only approved PEG in the treatment of HCV in those with coinfection, these data suggest that PEG alpha-2b has similar safety and efficacy. Whether these data translate to North American coinfected patients, a significant proportion of whom are black, remains to be determined. (Reviewer-Richard K. Sterling, MD). © 2009, Oakstone Medical Publishing

Keywords: HIV Coinfection


Increased Portal Inflammation Is Associated With Disease Progression in NAFLD

Portal Chronic Inflammation in Nonalcoholic Fatty Liver Disease (NAFLD): A Histologic Marker of Advanced NAFLD--

Clinicopathologic Correlations From the Nonalcoholic Steatohepatitis Clinical Research Network.

Brunt EM, Kleiner DE, et al:

Hepatology 2009; 49 (March): 809-820

Increased portal inflammation is associated with both clinical and pathologic features of disease progression but not with alanine aminotransferase levels or lobular inflammation.

Background: Non-alcoholic fatty liver disease (NAFLD) is characterized by >5% steatosis with or without lobular inflammation in the absence of significant alcohol intake. When combined with hepatocytes ballooning and pericellular fibrosis, it is non-alcoholic steatohepatitis (NASH). Although portal chronic inflammation (CI) is often seen, its significance is not clear. Objective: To analyze clinical and biopsy data in adult and pediatric patients with NAFLD ,with a focus on portal CI. Design: Retrospective study. Participants: 728 adult and 205 pediatric patients enrolled in the NASH Clinical Research Network (CRN). Methods: Demographics, laboratory studies, comorbid conditions, and medications were recorded. Histology was assessed by the Pathology Committee of the NASH CRN for steatosis, inflammation, and fibrosis (Kleiner 2005). Portal CI was graded as none, mild (few lymphocytes in >1 portal tract), or more than mild (moderate to severe inflammation or lymphoid aggregate). Steatohepatitis was graded as definite, borderline, or definitely not. Adults and children were analyzed separately. Results: Mild, more than mild, and no CI were found in 60%, 23%, and 16%, respectively, of adult biopsies and in 76%, 14%, and 10%, respectively, of pediatric biopsies. In adults, clinical features associated with more than mild portal CI were older age (P <0.0001), female (P =0.001), higher body mass index (P <0.0001), higher insulin levels (P =0.001), higher homeostasis model assessment of insulin resistance (HOMA-IR) score (P <0.0001), and use of medications for NAFLD (P =0.0004), diabetes (P <0.0001), and hypertension (P <0.0001), while histologic features were steatosis amount (P =0.01) and location (P <0.0001), hepatocytes ballooning (P <0.0001), and advanced fibrosis (P <0.0001). In the pediatric population, clinical features associated with more than mild portal CI were younger age (P =0.01) but not body mass index, insulin, or HOMA-IR, while histologic features were steatosis location (P =0.0008) and fibrosis (P <0.0001). In both groups, portal CI did not correlate with lobular inflammation, autoantibodies, or serum alanine aminotransferase (ALT) levels. Conclusions: Increased portal CI is associated with both clinical and pathologic features of disease progression in both adults and children but not with ALT levels or lobular inflammation. Reviewer's Comments: We often see portal CI in patients with NAFLD in the absence of other causes of liver disease. This interesting study describes the association of portal inflammation with clinical and histologic characteristics. However, because this is not a prospective study of paired biopsies, we still do not know if portal CI is the result or the cause of more advanced disease or, importantly, how it is affected by therapy. (Reviewer-Richard K. Sterling, MD). © 2009, Oakstone Medical Publishing

Keywords: Non-Alcoholic Fatty Liver Disease


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