No increase in cardiovascular risks for obese kids who become normal-weight adults

November 17, 2011

ST LOUIS (MD Consult) - Among children who are overweight or obese, cardiovascular risk factors are not increased for those are nonobese in adulthood, according to a study in the November 17, 2011, issue of The New England Journal of Medicine.

The researchers analyzed data from 4 prospective studies of cardiovascular risk factors involving children with follow-up into adulthood. The analysis included a total of 6,328 participants, with a mean follow-up of 23 years. All underwent assessment of body mass index (BMI) in childhood and adulthood.

Cardiovascular risk factors at follow-up were compared for participants who were normal-weight in both childhood and adulthood (4,742 participants), overweight or obese in childhood but nonobese in adulthood (274 participants), overweight or obese in childhood and obese in adulthood (500 participants), and normal-weight in childhood but obese in adulthood (812 participants). The lead author was Dr Markus Juonala of University of Turku and Turku University Hospital, Finland.

Cardiovascular risk factors were significantly increased for participants who had high adiposity in both childhood and adulthood, compared to those who had normal BMI in childhood and were nonobese in adulthood. Relative risks were 5.4 for type 2 diabetes, 2.7 for hypertension. 1.8 for elevated low-density lipoprotein cholesterol, 2.1 for reduced high-density lipoprotein cholesterol, 3.0 for elevated triglycerides, and 1.7 for increased carotid artery intima-media thickness.

In contrast, none of these risks was increased for participants who had high BMI in childhood but were nonobese in adulthood. For obese adults who had been normal-weight in childhood, risks were similar to those who had been overweight or obese in childhood.

Childhood obesity has been linked to an increased risk of cardiovascular disease and death. It is unclear whether childhood obesity increases risks independently of the effects of obesity in adulthood.

The new study confirms the increased rates of cardiovascular risk factors among overweight or obese children who become obese adults. However, for children who have high BMI but are not obese as adults, risks are similar to those with normal BMI at both times. Although no clinical recommendations can be made from the observational study, the researchers write, "[W]e hypothesize that reducing BMI in children and adolescents who are overweight or obese could reduce their cardiovascular risk."

NSAIDs Can Raise Risk for Crohn's Disease

November 2, 2011 (National Harbor, Maryland/Washington, DC) — High doses of nonsteroidal anti-inflammatory drugs (NSAIDs), longer duration of use, or greater frequency of use are all associated with an increased risk for Crohn's disease and ulcerative colitis, according to findings of a study presented here at the American College of Gastroenterology (ACG) 2011 Annual Scientific Meeting.

In contrast, although both aspirin and NSAIDs are associated with ulcerations in the gastrointestinal tract, dose, duration, and frequency of aspirin use were not associated with risk for Crohn's disease or ulcerative colitis. The authors distinguished between aspirin and other NSAIDs in their study.

"So this suggests that there may be pathways uniquely affected by NSAIDs and not by aspirin," Ashwin Ananthakrishnan, MD, MPH, a gastroenterologist on staff at Massachusetts General Hospital, Boston, and an instructor at Harvard Medical School, told Medscape Medical News. "Such pathways could potentially be important in explaining why some people get Crohn's and ulcerative colitis."

Compared with nonusers, women who used NSAIDs for more than 15 days a month faced a greater risk for Crohn's disease and ulcerative colitis. Women who used more than 5 tablets of NSAIDs per week also saw an elevated risk for Crohn's disease compared with women with more than 6 years of NSAID use.

Although significant advances have been made in understanding the genetics of Crohn's disease and ulcerative colitis, with up to 99 genetic variations associated with the 2 conditions, genetic changes explain only about one third of the risk for the diseases, suggesting that environment has a big influence on why someone gets either Crohn's disease or ulcerative colitis, said Dr. Ananthakrishnan, who was lead author on the study.

The researchers conducted a prospective cohort study of 76,814 women enrolled in the Nurses' Health Study (NHS). Since 1990, the NHS has captured data on aspirin and NSAID use. Gastroenterologists subsequently confirmed diagnoses of Crohn's disease or ulcerative colitis.

The data drew upon more than 18 years of data, including 123 confirmed incident cases of Crohn's disease and 117 cases of ulcerative colitis. The mean age of the cohort in 1990 was 57 years. The researchers used Cox proportional hazards models to examine the relative risks for Crohn's disease and ulcerative colitis after adjusting for possible confounders, including smoking, menopausal status, and hormone use. In all, 44% of women reported regular use of aspirin and 37% said they regularly used NSAIDs at baseline.

Dr. Ananthakrishnan cautioned against overinterpreting the results of the study. "It's very important to recognize you have to weigh the risks and benefits," he said. For someone who doesn't have Crohn's or ulcerative colitis, the absolute risk is fairly small. Perhaps 15 in 100,000 people risk getting the conditions.

More studies are needed to compare the safety of these agents, he said, noting that people are more likely to take high-dose NSAIDs and take NSAIDs more frequently for pain relief. Those who take aspirin for cardiac protection tend to take low doses. "We don't know if you take the same dose of NSAIDs or aspirin, if they are equally safe or equally dangerous," he said.

Bruce Sands, MD, MS, chief of the Division of Gastroenterology and Burrill B. Crohn professor of medicine at Mount Sinai Hospital in New York, New York, said he found the study "a very provocative, interesting, and well-done work."

"The risk of NSAIDS for IBD [inflammatory bowel disease] has long been speculated due to their effects in decreasing barrier function of the gut epithelium. This is the first study to prospectively assess that risk in advance of onset of disease to my knowledge," he told Medscape Medical News.

Dr. Ananthakrishnan has disclosed no relevant financial relationships. Dr. Sands has financial relationships with Abbott Immunology, Avaxia Biologics, Bristol-Myers Squibb, Elan Pharmaceuticals, Emmi Solutions, GlaxoSmithKline, Novartis Pharmaceuticals, Pfizer, and Prometheus Laboratories.

American College of Gastroenterology (ACG) 2011 Annual Scientific Meeting and Postgraduate Course. Abstract #6. Presented October 31, 2011.

Combination Therapy Gives Patients With IBD Another Option

November 4, 2011 (National Harbor/Washington, DC) — Combination therapy with allopurinol and low-dose thiopurines is an effective and well-tolerated treatment for inflammatory bowel disease (IBD), according to a study presented here at the American College of Gastroenterology 2011 Annual Scientific Meeting and Postgraduate Course.

This combination therapy gives another treatment option for patients with IBD who fail conventional thiopurine therapy, lead author Frank Hoentjen, MD, PhD, told Medscape Medical News. He is assistant professor of medicine at Raboud University Medical Center in Nijmegen, the Netherlands.

The researchers wanted to see whether they could lower the discontinuation rate for thiopurine by optimizing therapy before increasing the dosage.

"In patients with a skewed thiopurine metabolism who have either adverse reactions or an inability to achieve remission, allopurinol plus low-dose thiopurines should be considered before escalating maintenance therapy," Dr. Hoentjen said.

The "long-term effectiveness and tolerability of allopurinol and thiopurine combination therapy in inflammatory bowel disease patients" confirm previous small studies, which have shown the benefit of combination therapy, he said. The cohort size and follow-up time in this study were double those of the largest previous study.

Physicians have puzzled over the problems associated with thiopurines for a few decades, but only in the past 10 years have they learned that levels of metabolites correlate with efficacy and adverse effects, Dr. Hoentjen explained. Some of the adverse reactions that have caused patients to discontinue thiopurine therapy are nausea, vomiting, headaches, muscle aches, leucopenia, transaminitis, and pancreatitis.

The study looked at 85 patients with an average follow-up time of 20.4 months. Most of the patients were diagnosed with Crohn's disease or ulcerative colitis. Patients started combination therapy because of previous thiopurine refractoriness (54%), an inability to achieve or maintain remission despite optimized thiopurine therapy, hepatotoxicity (47%), nonhepatic adverse reactions (8%), or for other reasons (5%).

Participants were adults with IBD from 2 tertiary referral IBD centers who failed monotherapy with thiopurines; they were subsequently treated with allopurinol plus low-dose thiopurine. Therapeutic effectiveness was assessed by calculating the cumulative number of patients still using combination therapy at 6, 12, 24, and 60 months and who were still in clinical remission, based on Physician's Global Assessment and on laboratory, radiologic, and/or endoscopic findings.

The percentage of patients still using combination therapy at 6, 12, 24, and 60 months was 88%, 84%, 76%, and 73%, respectively.

The genetic background in this subgroup of patients might be an area for future research, Dr. Hoentjen said. If researchers can genetically identify patients who will develop a skewed thiopurine metabolism (and possibly the consequences, like hepatotoxicity or lack of clinical remission), they will be able to start combination therapy without trying monotherapy with thiopurines first, he said. Although physicians already use thiopurine methyltransferase genotyping in clinical practice, it is not 100% predictive.

James Lewis, MD, MSCE, chair elect of the National Scientific Advisory Committee of the Crohn's and Colitis Foundation of America, told Medscape Medical News that he finds the study "very interesting."

Although thiopurines are commonly used to treat IBD, data on the use of allopurinol to modify thiopurine metabolism toward the production of 6-thioguanine nucleotides are limited, and long-term data on the combination are even harder to come by. "These data suggest that in selected patients who preferentially metabolize mercaptopurine to 6-methylmercaptopurine, this may be an effective long-term strategy," he said.

Dr. Lewis, who is also associate professor of medicine and epidemiology at the University of Pennsylvania in Philadelphia, offered up some warnings. Patients and physicians who consider using this combination need to be aware of the risks for bone marrow suppression and perhaps liver injury, he cautioned. Leukopenia occurred in 13% of these patients. We know that it is challenging to closely monitor patients treated with azathioprine or 6-mercaptopurine for bone marrow suppression, he said. "This combination raises the stakes even higher, and an optimal monitoring frequency has not been established."

Dr. Hoentjen has disclosed no relevant financial relationships. Dr. Lewis reports providing consulting/research support services to Roche, Amgen, Centocor, Dark Canyon Laboratories, Millennium Pharmaceuticals, Pfizer, Shire, Takeda, and United Biosource Corporation.

American College of Gastroenterology (ACG) 2011 Annual Scientific Meeting and Postgraduate Course. Abstract 27. Presented November 1, 2011.

Turmeric Enema May Equal Vancomycin for C. Difficile Colitis

NEW YORK (Reuters Health) Nov 03 - Turmeric enemas may be as tolerable and effective as vancomycin enemas for treating Clostridium difficile colitis, a small new study suggests.

Turmeric, a plant belonging to the ginger family, produces a bright yellow spice that has been used for thousands of years in food and as medicine. Curcumin is its major component.

Turmeric is known to have antioxidant, anti-inflammatory and anti-microbial properties, and it also slows cell proliferation, according to Dr. P. Patrick Basu of North Shore Forest Hills Hospital and Columbia University College of Physicians and Surgeons in New York.

Dr. Basu told Reuters Health that after reading about the use of turmeric enemas for ulcerative colitis, he hoped to find a similar benefit for patients with moderate to severe C. difficile colitis.

He reported Monday at the American College of Gastroenterology's annual meeting in Washington, DC that he and his colleagues randomly assigned 36 patients to twice-daily enemas containing either vancomycin (250 mg), turmeric (1 g), or placebo, for 10 days. Patients also took 500 mg metronidazole orally three times a day for two weeks.

The infection was eradicated in similar proportions of patients in the vancomycin and turmeric groups (83% and 76%, respectively), compared to 66% in the placebo group.

At 21 days after the end of treatment, the ATLAS score for clinical severity (Age, Temperature, Leukocytes, Albumin, and Systemic antibiotics) was reduced by 60% in the vancomycin and turmeric groups, compared to 38% in the placebo group. In addition, the endoscopic appearance of luminal ulcers was improved with vancomycin and turmeric compared to placebo.

Recurrence developed in 10% of patients treated with vancomycin, 9% of those in the turmeric group, and 29% of patients who received the placebo.

While the treatment was generally tolerable, two patients given the turmeric enema complained of stained fomites. Dr. Basu and his team addressed the issue of leakage by giving patients non-medical suppositories after the enema was administered.

"The people who got vancomycin, they did very well, and curcumin, they did equally well," Dr. Basu said. "The beauty of it was that the curcumin was much, much less expensive." He estimated the cost of the turmeric enemas at $150 for 14 days of twice-daily enemas.

Dr. Basu said he and his colleagues are running a larger trial with 120 patients, which they plan to submit for publication next year.

Many different cancers show increased risk after organ transplantation

November 2, 2011

ST LOUIS (MD Consult) - Organ transplant recipients are at increased risk of a wide range of cancers, including cancers unrelated to infection, reports a study in the November 2, 2011, issue of The Journal of the American Medical Association.

National, regional, and state cancer registries were used to evaluate overall patterns of cancer risk after solid organ transplantation. The linked registries provided data on 175,732 solid organ transplant recipients—about 58% received kidney transplants, 22% liver transplants, 10% heart transplants, and 4% lung transplants.

Relative and absolute risks of cancers associated with organ transplantation were assessed, compared to the general population. The analysis included the risks of 32 cancers known to be associated with infections, such as anal cancer and Kaposi sarcoma; as well as cancers with no known relationship to infections. The lead author was Dr Eric A. Engels of the National Cancer Institute.

Organ transplant recipients had an increased overall cancer risk, with an incidence of 1,375 per 100,000 person-years. The standardized incidence ratio (SIR) was 2.0, with an excess absolute risk of 719.3 per 100,000 person-years.

The most common cancers occurring at increased rates in organ transplant recipients were non-Hodgkin lymphoma, SIR 7.54; lung cancer, SIR 1.97; liver cancer, SIR 11.56; and kidney cancer, SIR 4.65. Excess absolute risks were 168.3, 85.3, 109.6, and 76.1 per 100,000 person-years, respectively.

Lung transplant recipients had the greatest increase in lung cancer risk, SIR 6.14. However, lung cancer risk was also significantly increased for other groups of transplant recipients. The increase in liver cancer risk was limited to liver recipients: SIR 43.83. This risk was extremely high in the first 6 months after liver transplantation, SIR 508.97; but much lower with long-term follow-up of 10 to 15 years, SIR 2.22.

Kidney cancer risk was increased for kidney recipients: SIR 6.66, with a bimodal pattern in onset time. Liver and heart transplant recipients were also at increased risk of kidney cancer: SIR 1.80 and 2.90, respectively.

Because of immunosuppression and oncogenic viral infections, organ transplant recipients are at increased risk of cancer. Most studies of this issue have focused on kidney transplant recipients. There are also questions about the risks of non-infection-related cancers.

The new study shows an overall increase in cancer risk after solid organ transplantation, including kidney, liver, heart, and lung recipients. Significant increases are observed for both infection and non-infection related cancers. The researchers conclude, "The elevated risk for a broad range of malignancies among transplant recipients, coupled with improvements in long-term survival, should encourage further development of approaches to prevention and early detection of cancer targeted to this population."

JAMA. 2011;306:1891-1901.

Comparison of Endoscopic and Surgical Resection of Intramucosal Carcinoma in Barrett's Esophagus

Wesley D Leung; Jennifer Chennat
Posted: 10/27/2011; Expert Rev Gastroenterol Hepatol. 2011;5(5):575-578. © 2011 Expert Reviews Ltd.
Abstract and Introduction

Abstract

Evaluation of: Pech O, Bollschweiler E, Manner H et al. Comparison between endoscopic and surgical resection of mucosal esophageal adenocarcinoma in Barrett's esophagus at two high-volume centers. Ann. Surg. 254(1), 67–72 (2011).
The optimal management of intramucosal carcinoma in Barrett's esophagus continues to be controversial. To date, there has not been a lot of research directly comparing endoscopic versus surgical management of intramucosal carcinoma. Previous studies have shown that both modalities to have excellent outcomes. The reviewed article is a matched retrospective cohort study from two high-volume centers, which shows both modalities to be effective, but an associated higher morbidity rate and risk for procedure-related mortality in the surgical group, and higher recurrence rate in the endoscopic therapy group. The study is discussed in the context of the current state of knowledge regarding Barrett's esophagus and intramucosal carcinoma, in particular outcomes and limitations of the present study.

Barrett's Esophagus & Intramucosal Carcinoma

The annual incidence of adenocarcinoma from Barrett's esophagus (BE) is approximately 0.5% and appears to be rising.[1–3] Identification of different stages of BE (intestinal metaplasia to low-grade dysplasia, high-grade dysplasia (HGD), intramucosal carcinoma (IMC) and invasive adenocarcinoma) can be clinically challenging, and has profound treatment implications owing to the different prognostic profiles between early neoplasia and more advanced stages.

Increasing awareness of the risk of cancer from BE and enhanced and novel endoscopic imaging techniques have led to earlier detection of early curable esophageal adenocarcinoma. However, optimal management of patients with IMC from BE continues to be controversial and is still evolving.

Traditionally, esophagectomy has been the gold-standard treatment for BE with HGD, owing to the suspected risk of harboring occult invasive carcinoma, which has been estimated to be as high as 40%.[4,5] Our previous analysis of the published literature demonstrated that the true prevalence of submucosal invasive carcinoma in the setting of HGD was actually 12%, which was much lower than the pooled reported historical rate of 40%.[6] Esophagectomy has also been routinely performed for BE with IMC, despite the low incidence of lymph node metastasis of less than 1% that is associated with noninvasive disease limited to the mucosa (T1a).[7] In addition, esophagectomy is associated with significant morbidity and mortality rates even in high-volume centers.[8,9]

In contrast, endoscopic therapies have entered the clinical forefront as acceptable nonsurgical alternatives for HGD and IMC. The goal of endoscopic therapy for HGD or IMC is to ablate all BE epithelium (both dysplastic and nondysplastic) owing to the risk of synchronous/metachronous lesion development in the remaining BE segment.[7] Endoscopic therapies can be further subdivided into tissue-acquiring and nontissue-acquiring modalities. Tissue acquisition can be achieved through endoscopic mucosal resection (EMR), while photodynamic therapy, radiofrequency ablation and cryotherapy all ablate tissue without the benefit of histological specimen retrieval. Modalities such as argon plasma coagulation, multipolar electrocoagulation and laser therapies are thought to have more limited utility owing to high BE relapse rates, infrequent usage or significant risk of buried gland development.[10]

Summary of Methods & Results

The article by Pech and colleagues is a retrospective cohort study examining the outcomes of surgical versus endoscopic resection (ER) among patients with IMC.[11] The primary outcome of the study was to determine the complete remission rate in surgical and endoscopic groups.

A total of 114 patients with Barrett's IMC between 1996 and 2009 were included in the study. Patients having neoadjuvant chemoradiation or chemotherapy were excluded. A total of 38 patients were treated surgically at an expert center in Cologne University (Cologne, Germany; 26 direct referrals and 12 with unsuccessful endoscopic treatment). Of the 967 patients, 76 were treated with ER at Wiesbaden Hospital (Wiesbaden, Germany). They were randomly matched in a 2:1 fashion to the surgically treated patients with blinding to therapeutic outcome. Matching criteria included age, gender, tumor infiltration depth (pT1m1–3), tumor differentiation grade (G1/2 vs G3) and duration of follow-up. Circumferential EMR was not performed according to the authors, so the ER specimens were acquired from focal regions.

The endoscopic group had a pretreatment workup consisting of endoscopy with biopsies, CT scans of the chest and abdomen, and endoscopic ultrasound for lymph node staging. Complete remission was confirmed by two negative follow-up endoscopies and was followed by ablation of remaining nondysplastic BE using argon plasma coagulation and a strict follow-up surveillance program.

The surgical group had en-bloc esophagectomy after open or laparoscopic gastric mobilization and two-field lymphadenectomy of mediastinal and abdominal lymph nodes. Histopathologic examination of all resected specimens for the 38 surgical patients was re-evaluated by two experienced pathologists. Surgical patients also underwent a standardized follow-up.

The endoscopic and surgical resection cohorts were matched in a 2:1 fashion by the prespecified matching criteria. This resulted in no significant differences between the two cohorts regarding age, gender, Charlson index of comorbidity grade, infiltration depth, tumor differentiation grade or follow-up period. The only significant difference was that the ER group had a shorter Barrett's length (3 cm) than those treated surgically (6 cm; p < 0.02). There were no lymphovascular invasion or lymph node metastases in either group. Complete remission of neoplasia was achieved in all but one endoscopically treated patient (98.7%) versus all patients in the surgical group (100%).

Median follow-up in the ER and surgical groups were 4.1 years and 3.7 years, respectively. There was a trend towards increased overall rate of recurrence/metachronous neoplasia in the ER group versus the surgical group (6.6 vs 0%), but the difference was not significant (p = 0.17). Patients with metachronous neoplasia in the ER cohort all had long-segment BE (mean: 8.0 cm) versus those without (mean: 3.7 cm; p = 0.08).

The rate of minor complications in the ER group was 17%. Significantly more major complications were seen in the surgical versus ER cohort (32 vs 0%; p < 0.001), for example, anastomatic leakage, pneumonia, cardiac problems and sepsis. There was no tumor-related mortality in either group but surgery was associated with a procedure-related mortality rate of 2.6% and zero in the ER group, however, there was no significant difference between these groups (p = 0.333).

Multivariate analysis of survival revealed that only age was an independent prognostic factor for survival (hazard ratio: 1.13; p = 0.005). Multivariate analysis of disease-free survival could not identify risk factors for recurrence/metachronous neoplasia.

Discussion & Significance

There have been few published studies that have compared outcomes of endoscopic and surgical resection of Barrett's-related IMC. This paper is the first study comparing single treatment modalities, ER and transthoracic esophageal resection in this population. Because the study design matched the two treatment cohorts by various criteria, this made them more amenable to comparison than previous studies.

Traditionally, radical esophageal resection has been regarded as the treatment of choice in patients with BE-related IMC. Recent publications by various groups, including the author's and our own group, have reported excellent long-term results with endoscopic treatment and very low complication rates.[7,12–15]

Endoscopic resection is an important therapeutic option for removal of BE-related IMC because, unlike ablative methods, ER allows complete pathologic assessment of the resected specimen, including depth of cancer invasion, cellular differentiation and lymphovascular involvement. This pathological staging allows prediction of risk of lymph node metastasis and guides whether the patient can be cured endoscopically or should proceed towards surgical treatment (e.g., when there is deep submucosal or lymphovascular infiltration).

The authors report excellent complete remission rates in both treatment modalities for BE–IMC with no differences with regards to overall survival and disease-free follow-up. These rates are comparable to rates seen in other studies. However, there was a trend towards more recurrences in the ER group; however, the ablation modality used – argon plasma coagulation – has fallen out of favor in most centers. Thus, if more current therapies, such as radiofrequency ablation (RFA), were used in this study, the recurrence rates in the ER group might even be lower, as suggested by study by Pouw, where 41 patients with BE with early neoplasia underwent RFA with or without ER had 98% eradication of all BE tissue/dysplasia and no dysplasia after a mean 21 months follow-up.[16] Similar results have been seen for early neoplasia in BE longer than 10 cm.[17] In a more recent study, Pouw and colleagues also showed pre-RFA ER for visible lesions and serial RFA with focal escape ER for post-RFA residual tissue achieved 100% eradication of BE tissue after a median 22 months follow-up.[18]

In addition, the ER used in this study was not circumferential and may have left remaining neoplastic tissue behind to contribute to the higher recurrence rate in this subgroup. Lack of circumferential ER (or piecemeal resection) has been demonstrated to be a risk factor frequently associated with BE tissue recurrence.[7] Our group and other select centers have utilized complete Barrett's eradication EMR with the curative intent of removing all Barrett's epithelium with HGD or IMC to potentially reduce the risk of developing synchronous and metachronous lesions. Our center reported a 96.9% remission rate from Barrett's epithelium and no reported synchronous or metachronous lesions over a mean of 22.9 months.[14] As mentioned by the authors, the BE length in the ER group was lower than the surgical group and a higher recurrence rate of carcinoma may have been observed in the ER group if the patients had a comparable length to the surgical group.[11]

The complication rates of ER were similar to those that have been reported in other studies. Complication rates include perforation (<0.5%), bleeding (14%; usually easily controlled with epinephrine and/or metal clips) and esophageal stenosis (0–30%).[19] However, the complication rates from esophagectemy in this study appear higher than other centers. There is a major difference between resections performed for advanced esophageal cancer and those performed for T1 lesions. In fact, many series have shown that the mortality rate for early cancer is close to 0% and that after the immediate postoperative period, the quality of life is excellent.[20,21] For instance, the Luketich group has shown that esophagectomy for T1 lesions can be performed with a 0% mortality rate.[20] In addition, the use of minimally invasive techniques has brought about an improvement in the immediate postoperative course because it is associated with less postoperative pain, a shorter hospital stay and a faster recovery time. Chang and colleagues showed that postoperative symptoms caused by esophagectomy are common but mild, and do not interfere with quality of life, which is excellent and similar to that of the general population.[19]

Another argument favoring ER over esophagectemy for BE-related IMC was put forth in a decision analysis by Pohl et al..[22] Concerning BE-related early cancer (T1 with mucosal or minimal submucosal infiltration), a decision tree model compared EMR of the cancerous lesion with RFA of the remaining Barrett's segment to esophagectomy. During the 5-year interval of the study, endoscopic therapy cost US$17,000 and yielded 4.88 quality-adjusted life years, compared with US$28,000 and 4.59, respectively, for esophagectomy. The overall outcome was not changed by varying the recurrence rates of cancer or BE metaplasia after endoscopic therapy.

The study remains observational and contrasts with prior reports comparing the two modalities. In a study by the Mayo group, the ER and surgical groups were difficult to compare, but showed a higher recurrence rate in the ER compared with the surgical group (12 vs 2%) and lower cancer-free survival.[23] Overall survival was similar in the two groups. In a study by Schembre et al., two heterogeneous populations of HGD and IMC were treated by ER and surgery.[24] The ER group had a higher tumor progression rate and the surgical group had higher complication rates and was more expensive than the ER group.

There were a number of limitations to this study. For example, the follow-up time in this study may not have been long enough to detect differences between the two groups. Furthermore, despite using two separate centers and matching criteria to minimize selection bias between the two groups, selection bias could still have influenced the results. Finally, the study remains retrospective and observational, thus making it difficult to draw definitive conclusions from the study, and a randomized trial might still be required.

Expert Commentary & Five-year View

While observational studies can be useful, more definitive data will require randomized controlled trials. However, implementing this type of research methodology would be challenging to accomplish in the BE-related IMC population, as it would be difficult to persuade patients to be randomized to esophagectemy given the already excellent published results in patients that have undergone ER. In addition, blinding treatment groups would be impossible in a randomized trial and placebo treatment would be unethical. As a result of these and other factors, randomized placebo-controlled studies are difficult to achieve in BE-related IMC.

Future studies should include outcome and cost-analysis data comparing endoscopic treatment combining EMR and ablation therapies such as RFA or complete Barrett's eradication EMR, compared with esophagectemy. Despite the excellent efficacy of ER seen in this study, esophagectemy should still be considered in patients with IMC with lymph node involvement seen by endoscopic ultrasound, patients that are young and healthy (making 20–40 year surveillance less feasible or desired), patients not willing to be compliant with rigorous endoscopic follow-up, patients with multifocal disease and long-segment BE, and esophageal adenocarcinoma extending into and beyond the submucosa.

Sidebar

Key Issues

The incidence of esophageal adenocarcinoma has increased eightfold in the last 30 years and is thought to be secondary to gastroesophageal reflux disease through the development of Barrett's esophagus (BE).
The study by Pech and colleagues is a retrospective observational cohort study examining the outcomes of endoscopic and surgical resection in patients with BE-related intramucosal carcinoma. The primary outcome of the study was complete remission of cancer after treatment.
Both treatment groups had excellent complete remission rates.
The authors observed a higher morbidity rate and a risk for procedure-related mortality in the surgical group and a trend towards higher recurrence rate in the endoscopic group.
This study supports the role of endoscopic treatment of BE-related intramucosal carcinoma as an excellent alternative to esophagectemy and suggests a better safety profile, but confirmation from other studies may be required.

H. pylori on the hook for diabetes risk

H. pylori on the hook for diabetes risk


October 26, 2011

BY NEIL OSTERWEIL
BOSTON – Already convicted for its role in causing peptic ulcers, Helicobacter pylori is also being indicted as a possible co-conspirator in the development of diabetes, investigators from two separate studies said at the annual meeting of the Infectious Diseases Society of America.

In a study of nearly 1,800 older Latinos in California, H. pylori infection was associated with a more than twofold greater risk for diabetes, reported Dr. Christine Y. Jeon of the Columbia University School of Nursing, New York.

In addition, a separate study of National Health and Nutrition Examination Survey (NHANES) data found that, after excluding for diabetes and controlling for other risk factors, H. pylori seropositivity was positively associated with hemoglobin A1c (HbA1c) levels – suggesting that the bacterium may play a role in impaired glucose tolerance, said Dr. Yu Chen of New York University Langone Medical Center, New York.

Dr. Jeon noted that, although the mechanism for the association between H. pylori infection and diabetes is unknown, it does not appear to be mediated by either the inflammatory pathway or insulin resistance.

“This highlights the need for future studies on how the timing and severity of H. pylori infection affect glucose control in younger individuals, and how H. pylori alters gut microbiota and subsequent host gene expression and energy uptake,” she said.

Dr. Jeon and her colleagues conducted a study to examine whether risk of diabetes changes with various common chronic infections, including herpes simplex virus 1, varicella virus, cytomegalovirus, Toxoplasma gondii, and H. pylori.

The study and its focus on H. pylori in particular were motivated in part by observation of a racial gradient in both diabetes prevalence and H. pylori infection in the United States, with Mexican Americans having a higher prevalence of both than either whites or non-Hispanic blacks.

In addition, studies have found evidence of association between periodontal bacteria and increased diabetes risk, as well as links between decreased insulin sensitivity and higher antibody titers to herpes simplex virus 2 and Chlamydia pneumoniae.

Other studies, however, have not shown an association between common infections and insulin resistance or diabetes.

The study investigators analyzed data on 1,789 men and women older than 60 years who were enrolled in the Sacramento Area Latino Study on Aging (SALSA). Of that group, 782 people did not have diabetes and had available baseline pathogen data.

During the 10-year study, 144 of those 782 people developed diabetes (18% incidence rate), with diabetes defined as self-report of a physician’s diagnosis of diabetes or of taking hypoglycemic medication, including insulin, at semiannual interviews; fasting glucose of at least 126 mg/dL at four follow-up visits; or death certificate inclusion of diabetes as a cause of death.

In bivariate analysis adjusted for gender and education, none of the pathogens reached statistical significance for an association with diabetes.

In multivariate analysis, however, the only significant association seen with diabetes was H. pylori (hazard ratio, 2.69). The association was stronger than that for either vascular disease (HR, 1.78) or being a former smoker (HR of 1.34 in bivariate analysis).

Possible explanations for the association include H. pylori–induced alterations in gut microbiota, changes in nutrient metabolism in the gut, increased energy harvesting, or altered host gene expression, Dr. Jeon said.

In the second study, Dr. Chen and her colleague Dr. Martin Blaser looked at data from NHANES III (1988-1994) and IV (1999-2004).

In NHANES III, they found a positive association between H. pylori and HbA1c in the overall cohort and in people with body mass indices (BMI) both below 25 and 25 and higher (P for interaction for each comparison less than .01).

They also saw a synergistic interaction between H. pylori and higher levels of BMI in both NHANES III and IV (P for interaction less than .01), suggesting that H. pylori exacerbated the rise in HbA1c often seen with weight increase.

In addition, in NHANES III but not NHANES IV, the synergistic effect was seen among patients seropositive for the cagA strain of H. pylori, which has been associated with virulence.

The investigators did not, however, find an association between self-reported diabetes and H. pylori infection.

Dr. Jeon’s study was supported by grants from the National Institutes of Health. Dr. Chen did not disclose a funding source. Both investigators reported that they had no relevant financial disclosures.

Perspective: GERD management update

October 20, 2011

BY WILLIAM E. GOLDEN, M.D., AND ROBERT H. HOPKINS, M.D.

Background. Gastroesphageal reflux disease (GERD) is one of the most common conditions affecting adults. One study of an employed population showed a prevalence of about 4%, costing employers more than $3,000 per employee-year over 3 years, more than half of which is due to pharmacy costs. The Agency for Healthcare Research and Quality has recently published a comparative effectiveness review on this topic, which updates their last systematic review from 2005.

Conclusions. Cohort studies suggest that patients with morbid obesity, typical GERD symptoms, and more severe esophagitis have worse treatment outcomes with medical therapy, and that older patients achieve better symptom control with medical treatment.

Medical treatment with proton pump inhibitor (PPI) therapy and antireflux surgery are similarly effective in reducing symptoms and decreasing esophageal exposure to acid. However, the surgical literature is limited by low follow-up rates, with 33%-56% of patients ending up lost to follow-up in long-term studies.

Evidence remains insufficient to assess the effectiveness of the available endoscopic interventions for treatment of GERD compared with other endoscopic techniques, medical therapy, and/or surgery.

There is insufficient evidence to determine whether medical therapy or surgery for GERD is more effective for the prevention of long-term complications, including Barrett’s esophagus and esophageal adenocarcinoma.

There also is insufficient evidence to assess the benefits of treating extraesophageal manifestations (chronic cough, laryngeal symptoms, and asthma) of GERD with surgery or medications. The lack of specificity in attributing these manifestations to GERD makes this issue difficult to study specifically.

Implementation

• Goals of treatment: Usual treatment goals for GERD include improvement of symptoms and quality of life, achieving/maintaining healing of esophageal erosions, and prevention of long-term complications such as Barrett’s esophagus. There is not a consensus approach to achieving these goals.

• Drug therapy: PPIs are more effective than H₂-receptor antagonists for achievement of symptomatic control within 4 weeks and for healing of reflux esophagitis by 8 weeks. Maintenance treatment with PPIs also has been shown to be superior for sustaining symptom control.

Continuous treatment with PPIs is associated with better GERD symptom control and quality of life than is intermittent “on demand” treatment over 6 months with each of the PPI regimens evaluated.

In older patients, daily pantoprazole (40 mg) and rabeprazole (20 mg) have been shown to provide better symptom control and healing of esophagitis compared with over-the-counter omeprazole (20 mg) at 8 weeks. Daily esomeprazole (20 mg) has been shown to result in better endoscopic remission rates than OTC lansoprazole (15 mg) daily for 6 months. It is unclear whether these trial differences reflect clinically significant differences in practice.

Studies have not demonstrated a consistent difference in symptom relief/control or esophagitis healing rates between the following medications and doses: esomeprazole (10-40 mg), lansoprazole (15-30 mg), pantoprazole (20-40 mg), and deslansoprazole (30-90 mg). There is some evidence that rabeprazole (10 mg) may provide better symptom control than esomeprazole (40 mg) at 4 weeks, and that pantoprazole (40 mg) may improve symptoms better than esomeprazole (40 mg) at 24 weeks.

• Role of surgery: There are few to no comparative data on which to base recommendations for any particular antireflux surgical procedure for the treatment of GERD.

For patients with GERD symptoms that are controlled with medical treatment, laparoscopic fundoplication provides symptom control at least equivalent to that provided by continued medical treatment for at least the first year after the procedure, if it is performed by an experienced surgeon at a high-volume center. Ten percent or more of patients treated surgically may require the addition of medical treatment in the long term.

Patients undergoing antireflux surgery in trials were found to have a variety of adverse outcomes, including perioperative infections, incisional hernias, dysphagia, and bloating. The frequency of these events is not predictable by easily identifiable preoperative factors such as patient sex, morbid obesity, degree of esophagitis, presence of hiatal hernias, and/or baseline symptoms. Reoperation rates ranged from 3% to 35% of patients in surgical trials.

• Long-term treatment: Long-term use of PPIs is associated with headache, GI symptoms, increased risk of pneumonia, and infections due to Clostridium difficile and campylobacter. Recent studies have also demonstrated an increased risk of fractures with long-term PPI treatment, although the strength of this association is unclear.

Successful treatment of GERD in patients whose symptoms are poorly controlled with medical treatment remains a challenge. There is limited evidence from two uncontrolled cohort studies of laparoscopic fundoplication demonstrating symptomatic improvement at 5 years.

Despite the large number of medications and interventions available and the numerous clinical trials conducted, GERD remains a significant clinical problem. A number of major questions remain unstudied or, as yet, unanswered.

تعليمات ونصائح لمرضى ارتداد محتويات المعدة للمريء

1. رفع رأس السرير حوالي 15 – 20 سم عن مستوى أرض الغرفة بواسطة قوالب خشبية أو غيره.

2. النوم على الجانب الأيسر.

3. إنقاص الوزن في المرضى الذين يعانون من السمنة (الوزن الزائد).

4. عدم ارتداء الملابس الضيقة أو إحكام شد الحزام .

5. حاول أن تعدل في أكل بعض المأكولات والمشروبات:

· حاول أن تأكل وجبات قليلة الدهون وكثيرة البروتينات.

· تجنب المهيجات والمثيرات مثل :

- العصائر الحامضة مثل عصير الليمون.

- الأغذية التي تحتوي على البندورة ومشتقاتها.

- القهوة.

- المشروبات الغازية.

- المشروبات الكحولية.

- الشوكولاتة.

6. تجنب الأكل قبل النوم بثلاث ساعات على الأقل.

7. الامتناع الكلي عن التدخين.

8. تجنب الأدوية التي قد تزيد من احتمال ارتداد الحامض من المعدة إلى المريء ومنها:

· أدوية المغص Anticholinergics

· المهدئات Sedatives / Tranquilizers

· علاجات توسيع القصبات الهوائية Theophylline

· علاجات الضغط الموسعة للأوعية الدموية Calcium Channel Blockers

· البروستاجلاندين Prostaglandins

· الندرونيت ( علاج لهشاشة العظام ) Alendronate

9. لا مانع من تناول مضادات الحموضة عند نفاذ الدواء.

DVT, PE risk increased in surgery patients with IBD

October 18, 2011

BY SHARON WORCESTER

Patients with inflammatory bowel disease who undergo surgery have a twofold increase in the risk of deep vein thrombosis or pulmonary embolism, compared with those without IBD, and the risk is even greater among those with IBD who undergo nonintestinal surgery, according to findings from the American College of Surgeons National Surgical Quality Improvement Program.

In a retrospective cohort study of nearly 269,000 patients from the National Surgical Quality Improvement Program (NSQIP) 2008, 2,249 (0.8%) had IBD. Deep vein thrombosis (DVT) or pulmonary embolism (PE) occurred in 1% of those without IBD, in 2.5% of those with IBD, and in 5% of those with IBD who underwent nonintestinal surgery.

Dr. Andrea Merrill of Massachusetts General Hospital and Dr. Frederick Millham of Newton Wellesley Hospital, both in Boston, reported the research online in the Oct. 17 issue of Archives of Surgery. The findings suggest that the standard DVT and PE prophylaxis for patients undergoing surgery should be reconsidered for those with IBD, they concluded.

After adjustment for more than 30 possible confounders available in the NSQIP that add to the power to predict DVT or PE, a significant association remained between IBD and DVT or PE overall (odds ratio, 2.03) and among those undergoing nonintestinal surgery (OR, 4.45), the investigators found (Arch. Surg. 2011 Oct. 17 [doi:10.1001/archsurg.2011.297]).

No difference was seen between the patients with and without IBD in regard to the occurrence of cerebrovascular accident or myocardial infarction, with 0.4% of patients in both groups experiencing such events.

Although IBD has long been known to be associated with an increased risk of thromboembolic events, data on those undergoing surgery has been scarce, and standard DVT and PE prophylaxis guidelines in the IBD population have not been adjusted to include enhanced prophylaxis.

In light of one recent study suggesting a very high risk of postoperative DVT in those undergoing surgery, the investigators sought to evaluate the risk among IBD patients in the NSQIP, which collected data from 170 hospitals in 2008, resulting in a Participant Use Data File (PUF). The de-identified research database is made available to the participating hospitals.

“As such, the NSQIP PUF data set presents an opportunity to examine the relationship of DVT and PE with IBD in a large group of patients for whom data on comorbid conditions and other potential confounding variables are available and well defined. Furthermore, hospitals participating in the NSQIP, having invested in quality improvement, might be expected to treat patients with best practices, at least with respect to DVT prophylaxis,” the investigators said, explaining that this would reduce the opportunity for treatment bias between centers.

The finding of an increased risk of DVT or PE in IBD patients was consistent with others in both surgical and nonsurgical IBD patients, they found.

An exception is with the lethality of DVT or PE in the setting of IBD. One prior study demonstrated an increased risk of death among IBD patients with DVT or PE, but the investigators of the current study found no support for this finding. Mortality occurred in 8.6% and 8.8% of those without IBD who had DVT or PE, and those with IBD who had DVT or PE, respectively.

They also found no support for one prior study’s finding of an increased risk of arterial thromboembolic events in patients with IBD, but they noted that the current study may have been limited by the lack of data on arterial thrombotic events not involving the coronary or cerebral vessels.

“It may be that if arterial thromboembolism were a reported NSQIP complication, such a relationship would appear,” they said.

Although this study is limited by the fact that the NSQIP was designed to compare overall outcomes across many hospitals rather than to answer specific research questions regarding specific diseases or procedures, its strengths – namely the fact that the data were gathered by specially trained nurses who were accountable to a rigid quality-assurance program, and who were working from a well-defined data dictionary – likely outweigh any potential sources of bias, they said.

The authors reported that they had no disclosures.

Meta-analysis links reduced fracture rate to high vitamin D supplement

Meta-analysis links reduced fracture rate to high vitamin D supplement

October 28, 2010

BY MITCHEL L. ZOLER

TORONTO (EGMN) – A daily vitamin D dose of at least 792 IU was linked with significantly reduced rates of nonvertebral fractures and hip fractures in a meta-analysis of data from 11 randomized, controlled trials.

But the benefit from vitamin D appeared blunted when combined with a higher calcium dose, or when patients received vitamin D once yearly, Dr. Heike A. Bischoff-Ferrari reported.

In the meta-analysis, patients in the highest quartile for daily vitamin D intake, 792-2000 IU, had a statistically significant 14% reduced rate of any nonvertebral fracture, and a significant 30% reduced rate of hip fractures, in an analysis that adjusted for age, gender, and type of dwelling, said Dr. Bischoff-Ferrari, a rheumatologist at the University of Zurich.

Her meta-analysis pooled individual participant data from 12 double-blind, randomized, controlled trials that examined the impact of vitamin D supplements on fracture rate in people aged 65 years or older published through June 2010, and for which she could obtain individual participant data. The primary analysis focused on the 11 studies of the 12 in which participants received the supplement at least monthly, with 31,022 people enrolled. The twelfth study tested once annual dosing, and the researchers included those data in a separate analysis. The participants’ average age was 76 years, and about 90% were women.

The analysis divided the study subjects into the control group, with more than 15,000 people, and then into quartiles of their received amount of vitamin D, including both their study-treatment dose and any additional vitamin D intake. The analysis also took into account adherence to treatment. Each vitamin D quartile contained nearly 4,000 people, with a daily dose range of 792-2,000 mg forming the top quartile. Only the top quartile of vitamin intake linked with statistically significant differences, compared with the controls, for any nonvertebral fracture and for hip fracture.

Adding the data from the one trial that tested annual vitamin D treatment to the meta-analysis eliminated the statistically significant effect on fracture rates, suggesting that yearly administration of vitamin D produces a different effect than daily, weekly, or monthly treatment.

An additional analysis that looked at the interaction of calcium supplements along with vitamin D showed that with a daily calcium dose below 1,000 mg/day a high-dose vitamin D supplement (792-2,000 mg/day) linked with a statistically significant reduction in nonvertebral fractures, but when the daily calcium supplement delivered 1,000 mg or more, this amount of vitamin D did not associate with any significant change in fracture rate, suggesting an adverse effect from higher calcium intake.

Dr. Bischoff-Ferrari said that she had no disclosures.