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Mutations found in almost 4% of pancreatic cancer patients
In a registry-based study, 3.8% of patients with pancreatic cancer had germline mutations in genes known to significantly increase cancer risk, researchers reported in the March issue of Gastroenterology.
“A small but clinically important proportion of pancreatic cancer is associated with mutations in known predisposition genes. The heterogeneity of mutations identified in this study shows the value of using a multiple-gene panel in pancreatic cancer,” said Robert Grant of the Ontario Institute for Cancer Research in Toronto and his associates.
Source: American Gastroenterological Association
Some patients had mutations in the BRCA and MMR genes, about which enough is known to help guide preventive measures and treatment decisions, the researchers noted. “Furthermore, all mutation carriers represent a high-risk subgroup of patients for pancreatic cancer researchers to consider for screening studies and for experimental targeted therapies,” the investigators wrote (Gastroenterology 2014 Dec. 2 [doi:10.1053/j.gastro.2014.11.042]).
For the study, the investigators carried out multigene next-generation sequencing of DNA from the blood and saliva of 290 patients with pancreatic cancer. The patients were randomly chosen from a population-based pancreatic cancer registry in Ontario. The researchers looked for mutations in 13 genes that have been previously linked to cancers: APC, ATM, BRCA1, BRCA2, CDKN2A, MLH1, MSH2, MSH6, PALB2, PMS2, PRSS1, STK11, and TP53. They found a total of 11 pathogenic germline mutations in seven of these genes, including 3 in the ATM gene, 1 in BRCA1,2 in BRCA2, 1 in MLH1, 2 in MSH2, 1 in MSH6, and 1 in TP53, they reported.
A total of 3.8% (95% confidence interval, 2.1%-5.6%) of the patients carried mutations, or about 1 in every 26 patients, said the researchers. Most mutations were linked to breast or colorectal cancer. Mutation carriers were significantly more likely to have been diagnosed with breast cancer or colorectal cancer themselves, or to have an affected first-degree relative (P < .01 for both), compared with other patients in the study.
Furthermore, the prevalence of mutations jumped to 10.7% (95% CI, 4.4%-11.1%) when the researchers looked only at patients with a personal or family history of breast cancer, and to 11.1% (95% CI, 3.0%-19.1%) in the subgroup of patients with a personal or family history of colorectal cancer, the investigators reported.
But mutation status was not linked with familial pancreatic cancer, nor with age at diagnosis, which “raises questions with important clinical implications,” said the researchers. “With decreasing sequencing costs, which patients should be referred for multiple-gene panel sequencing? What is the relevance of mutations in [patients] with atypical personal and family histories?”
Answering those questions would require studying many genes from large groups of patients with pancreatic cancer, they emphasized. For now, although multiple-gene panels cost about the same amount as single-gene tests, “the added value of simultaneously sequencing many genes remains uncertain, and likely depends on the clinical setting,” they said. Nonetheless, the analysis uncovered so many mutations in the cohort that the researchers would recommend multiple-gene testing of patients with pancreatic cancer, they said.
Patients were recruited into the registry based on pathology results, which would have excluded those with advanced pancreatic cancer who never had pathology testing, said the investigators. Also, study patients tended to be younger, to have been treated in academic centers, and to have resectable disease more often than other patients in Ontario with pancreatic cancer.
The work was funded by the Weston Garfield Foundation, Pancreatic Cancer Canada, National Cancer Institute, Mount Sinai Hospital Biospecimen Repository, and Teresa Bianco. The investigators declared having no conflicts of interest.
In a registry-based study, 3.8% of patients with pancreatic cancer had germline mutations in genes known to significantly increase cancer risk, researchers reported in the March issue of Gastroenterology.
“A small but clinically important proportion of pancreatic cancer is associated with mutations in known predisposition genes. The heterogeneity of mutations identified in this study shows the value of using a multiple-gene panel in pancreatic cancer,” said Robert Grant of the Ontario Institute for Cancer Research in Toronto and his associates.
Source: American Gastroenterological Association
Some patients had mutations in the BRCA and MMR genes, about which enough is known to help guide preventive measures and treatment decisions, the researchers noted. “Furthermore, all mutation carriers represent a high-risk subgroup of patients for pancreatic cancer researchers to consider for screening studies and for experimental targeted therapies,” the investigators wrote (Gastroenterology 2014 Dec. 2 [doi:10.1053/j.gastro.2014.11.042]).
For the study, the investigators carried out multigene next-generation sequencing of DNA from the blood and saliva of 290 patients with pancreatic cancer. The patients were randomly chosen from a population-based pancreatic cancer registry in Ontario. The researchers looked for mutations in 13 genes that have been previously linked to cancers: APC, ATM, BRCA1, BRCA2, CDKN2A, MLH1, MSH2, MSH6, PALB2, PMS2, PRSS1, STK11, and TP53. They found a total of 11 pathogenic germline mutations in seven of these genes, including 3 in the ATM gene, 1 in BRCA1,2 in BRCA2, 1 in MLH1, 2 in MSH2, 1 in MSH6, and 1 in TP53, they reported.
A total of 3.8% (95% confidence interval, 2.1%-5.6%) of the patients carried mutations, or about 1 in every 26 patients, said the researchers. Most mutations were linked to breast or colorectal cancer. Mutation carriers were significantly more likely to have been diagnosed with breast cancer or colorectal cancer themselves, or to have an affected first-degree relative (P < .01 for both), compared with other patients in the study.
Furthermore, the prevalence of mutations jumped to 10.7% (95% CI, 4.4%-11.1%) when the researchers looked only at patients with a personal or family history of breast cancer, and to 11.1% (95% CI, 3.0%-19.1%) in the subgroup of patients with a personal or family history of colorectal cancer, the investigators reported.
But mutation status was not linked with familial pancreatic cancer, nor with age at diagnosis, which “raises questions with important clinical implications,” said the researchers. “With decreasing sequencing costs, which patients should be referred for multiple-gene panel sequencing? What is the relevance of mutations in [patients] with atypical personal and family histories?”
Answering those questions would require studying many genes from large groups of patients with pancreatic cancer, they emphasized. For now, although multiple-gene panels cost about the same amount as single-gene tests, “the added value of simultaneously sequencing many genes remains uncertain, and likely depends on the clinical setting,” they said. Nonetheless, the analysis uncovered so many mutations in the cohort that the researchers would recommend multiple-gene testing of patients with pancreatic cancer, they said.
Patients were recruited into the registry based on pathology results, which would have excluded those with advanced pancreatic cancer who never had pathology testing, said the investigators. Also, study patients tended to be younger, to have been treated in academic centers, and to have resectable disease more often than other patients in Ontario with pancreatic cancer.
The work was funded by the Weston Garfield Foundation, Pancreatic Cancer Canada, National Cancer Institute, Mount Sinai Hospital Biospecimen Repository, and Teresa Bianco. The investigators declared having no conflicts of interest.
In a registry-based study, 3.8% of patients with pancreatic cancer had germline mutations in genes known to significantly increase cancer risk, researchers reported in the March issue of Gastroenterology.
“A small but clinically important proportion of pancreatic cancer is associated with mutations in known predisposition genes. The heterogeneity of mutations identified in this study shows the value of using a multiple-gene panel in pancreatic cancer,” said Robert Grant of the Ontario Institute for Cancer Research in Toronto and his associates.
Source: American Gastroenterological Association
Some patients had mutations in the BRCA and MMR genes, about which enough is known to help guide preventive measures and treatment decisions, the researchers noted. “Furthermore, all mutation carriers represent a high-risk subgroup of patients for pancreatic cancer researchers to consider for screening studies and for experimental targeted therapies,” the investigators wrote (Gastroenterology 2014 Dec. 2 [doi:10.1053/j.gastro.2014.11.042]).
For the study, the investigators carried out multigene next-generation sequencing of DNA from the blood and saliva of 290 patients with pancreatic cancer. The patients were randomly chosen from a population-based pancreatic cancer registry in Ontario. The researchers looked for mutations in 13 genes that have been previously linked to cancers: APC, ATM, BRCA1, BRCA2, CDKN2A, MLH1, MSH2, MSH6, PALB2, PMS2, PRSS1, STK11, and TP53. They found a total of 11 pathogenic germline mutations in seven of these genes, including 3 in the ATM gene, 1 in BRCA1,2 in BRCA2, 1 in MLH1, 2 in MSH2, 1 in MSH6, and 1 in TP53, they reported.
A total of 3.8% (95% confidence interval, 2.1%-5.6%) of the patients carried mutations, or about 1 in every 26 patients, said the researchers. Most mutations were linked to breast or colorectal cancer. Mutation carriers were significantly more likely to have been diagnosed with breast cancer or colorectal cancer themselves, or to have an affected first-degree relative (P < .01 for both), compared with other patients in the study.
Furthermore, the prevalence of mutations jumped to 10.7% (95% CI, 4.4%-11.1%) when the researchers looked only at patients with a personal or family history of breast cancer, and to 11.1% (95% CI, 3.0%-19.1%) in the subgroup of patients with a personal or family history of colorectal cancer, the investigators reported.
But mutation status was not linked with familial pancreatic cancer, nor with age at diagnosis, which “raises questions with important clinical implications,” said the researchers. “With decreasing sequencing costs, which patients should be referred for multiple-gene panel sequencing? What is the relevance of mutations in [patients] with atypical personal and family histories?”
Answering those questions would require studying many genes from large groups of patients with pancreatic cancer, they emphasized. For now, although multiple-gene panels cost about the same amount as single-gene tests, “the added value of simultaneously sequencing many genes remains uncertain, and likely depends on the clinical setting,” they said. Nonetheless, the analysis uncovered so many mutations in the cohort that the researchers would recommend multiple-gene testing of patients with pancreatic cancer, they said.
Patients were recruited into the registry based on pathology results, which would have excluded those with advanced pancreatic cancer who never had pathology testing, said the investigators. Also, study patients tended to be younger, to have been treated in academic centers, and to have resectable disease more often than other patients in Ontario with pancreatic cancer.
The work was funded by the Weston Garfield Foundation, Pancreatic Cancer Canada, National Cancer Institute, Mount Sinai Hospital Biospecimen Repository, and Teresa Bianco. The investigators declared having no conflicts of interest.
FROM GASTROENTEROLOGY
Key clinical point: In a registry-based study, 3.8% of patients with pancreatic cancer had mutations in seven genes known to substantially increase cancer risk.
Major finding: Eleven pathogenic mutations were found in the ATM, BRCA1, BRCA2, MLH1, MSH2, MSH6, and TP53 genes.
Data source: Multiple-gene sequencing of 290 patients with pancreatic cancer.
Disclosures: The work was funded by the Weston Garfield Foundation, Pancreatic Cancer Canada, National Cancer Institute, Mount Sinai Hospital Biospecimen Repository, and Teresa Bianco. The investigators declared having no conflicts of interest.
Stress independently predicts peptic ulcers
High levels of psychological stress more than doubled the odds of peptic ulcers, and the link remained statistically significant even after controlling for factors such as Helicobacter pylori infection and cigarette smoking, according to a prospective study published in the March issue of Clinical Gastroenterology and Hepatology.
The findings contradict the widely accepted view that stress does not cause peptic ulcers, said Dr. Susan Levenstein of Aventino Medical Group in Rome and her associates. “Clinicians treating ulcer patients should investigate potential psychological stress among other risk factors,” they said.
Source: American Gastroenterological Association
Although “a vast literature links peptic ulcer to stress,” past studies suffered so many methodologic weaknesses that groups such as the U.S. National Institute of Diabetes and Digestive and Kidney Diseases rejected the evidence outright, Dr. Levenstein and her associates noted. Many studies were cross-sectional, for example, or did not control for confounders such as helicobacteriosis, they said.
To further study the effects of stress on ulcer risk, the researchers analyzed historical data from 76 patients who lacked a history of gastric and duodenal ulcers in 1982, but by 1994 had developed “distinct breach[es] in the mucosa” that were confirmed by endoscopy or contrast radiology. The researchers did not count erosions that lacked appreciable depth as ulcers, they noted (Clin. Gastroenterol. Hepatol. 2014 Aug. 8 [doi:10.1016/j.cgh.2014.07.052]).
Study subjects answered 12 questions about their stress levels, such as, “Do your hands easily shake?” “Do you often suffer from fits of dizziness?” “Do you constantly have thoughts that trouble and worry you?” and “Do you usually feel misunderstood by other people?” They answered these questions at baseline in 1982-1983, again in 1987-1988, and again in 1993-1994.
Respondents who scored in the top tertile for psychological stress had an ulcer incidence of 3.5%, compared with 1.6% for those in the lowest tertile (odds ratio, 2.2; 95% confidence interval, 1.2-3.9; P < .01), reported the investigators. And controlling for smoking, helicobacteriosis, use of nonsteroidal anti-inflammatory drugs, and low socioeconomic status only partially weakened the relationship between stress and ulcers, they said. After accounting for those risk factors, every one-point increase on the stress questionnaire still upped the odds of peptic ulcer by 12% (odds ratio, 1.12; 95% confidence interval, 1.01-1.23)they reported.
Helicobacteri pylori infection was the strongest independent predictor of ulcers (OR, 3.3; 95% CI, 2.02-5.69), while cigarette smoking came in a close second (OR, 2.91; 95% CI, 1.38-6.16), said the researchers. Notably, stress and helicobacteriosis did not seem to synergistically increase the chances of ulcers, they reported. “Stress affected H. pylori–related ulcers at least as much as those related to neither H. pylori nor nonsteroidal anti-inflammatory drugs,” they said.
Several factors might explain the stress-ulcer link, such as increased acid load, activation of the hypothalamic-pituitary-adrenal axis, shifts in blood flow, and cytokine activation that might impair gastrointestinal mucosal defenses, said the investigators. Although the baseline data in their study were more than 2 decades old, that meant that patients likely had not been treated to eradicate H. pylori and were less likely to have taken proton pump inhibitors than the current population that has over-the-counter access to PPIs, they added. They also noted that past studies found a particularly strong link between stress and bleeding or perforated ulcers, which have not declined as much as other types of ulcers. “These results support a multicausal model of peptic ulcer etiology, with intertwined biological and psychosocial components,” they concluded.
The Kirby Family Foundation funded the statistical analysis. The researchers reported no conflicts of interest.
Stress was the most frequently cited cause of ulcer disease before Helicobacter pylori was discovered. The harried executive who developed an ulcer was a widely accepted profile of an ulcer diathesis. When the role of H. pylori infection and NSAIDs became clear, the role of stress was downplayed and some articles and textbooks dismissed stress as a potential cause for ulcer disease.
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Dr. Nimish Vakil |
Studies of New York City residents suggest a higher incidence of ulcer disease after the 9-11 attacks and studies from Japan have shown an increase in the incidence of ulcer disease after the nuclear reactor disaster. In this issue of Clinical Gastroenterology and Hepatology, Dr. Levenstein and her colleagues report the results of a study of stress and the incidence of ulcer disease in Danish subjects. In 1982-1983, a population-based study in Denmark collected sera and psychological data in over 3000 subjects and reinterviewed them in 1987-1988 and 1993-1994. An ad-hoc, unvalidated scale developed by the authors measured stress. It included a psychological scale used by the Danish military to identify recruits unsuitable for military service but also included tranquilizer use, working more than 40 hours a week, and unemployment. In multivariate analysis, they found that stress increased the risk for both gastric and duodenal ulcers, with an adjusted odds ratio of 1.19 per point increase in the stress scale for gastric ulcers (95% confidence interval, 1.03-1.37) and a odds ratio of 1.1 per point increase in the stress index for duodenal ulcers (95% CI, 0.98-1.27).
There are obvious limitations with this study: a historical cohort, an unvalidated stress scale, the inclusion of items that may not represent stress in some cultures (e.g., working more than 40 hours/week) and the lower bound of confidence intervals for risk which are very close to one. However, studies such as this tell us that we have been too quick to dismiss the role of stress in ulcer pathogenesis. With declining H. pylori prevalence and the development of safer NSAIDs, stress will undergo a renaissance in the pathogenesis of ulcer disease.
Dr. Nimish Vakil, AGAF, FASGE, FACP, is a physician specializing in gastroenterology at the Aurora Wilkinson Medical Clinic in Summit, Wisc. He is a consultant for Astra Zeneca, Ironwood, and Baxter Pharmaceuticals.
Stress was the most frequently cited cause of ulcer disease before Helicobacter pylori was discovered. The harried executive who developed an ulcer was a widely accepted profile of an ulcer diathesis. When the role of H. pylori infection and NSAIDs became clear, the role of stress was downplayed and some articles and textbooks dismissed stress as a potential cause for ulcer disease.
|
Dr. Nimish Vakil |
Studies of New York City residents suggest a higher incidence of ulcer disease after the 9-11 attacks and studies from Japan have shown an increase in the incidence of ulcer disease after the nuclear reactor disaster. In this issue of Clinical Gastroenterology and Hepatology, Dr. Levenstein and her colleagues report the results of a study of stress and the incidence of ulcer disease in Danish subjects. In 1982-1983, a population-based study in Denmark collected sera and psychological data in over 3000 subjects and reinterviewed them in 1987-1988 and 1993-1994. An ad-hoc, unvalidated scale developed by the authors measured stress. It included a psychological scale used by the Danish military to identify recruits unsuitable for military service but also included tranquilizer use, working more than 40 hours a week, and unemployment. In multivariate analysis, they found that stress increased the risk for both gastric and duodenal ulcers, with an adjusted odds ratio of 1.19 per point increase in the stress scale for gastric ulcers (95% confidence interval, 1.03-1.37) and a odds ratio of 1.1 per point increase in the stress index for duodenal ulcers (95% CI, 0.98-1.27).
There are obvious limitations with this study: a historical cohort, an unvalidated stress scale, the inclusion of items that may not represent stress in some cultures (e.g., working more than 40 hours/week) and the lower bound of confidence intervals for risk which are very close to one. However, studies such as this tell us that we have been too quick to dismiss the role of stress in ulcer pathogenesis. With declining H. pylori prevalence and the development of safer NSAIDs, stress will undergo a renaissance in the pathogenesis of ulcer disease.
Dr. Nimish Vakil, AGAF, FASGE, FACP, is a physician specializing in gastroenterology at the Aurora Wilkinson Medical Clinic in Summit, Wisc. He is a consultant for Astra Zeneca, Ironwood, and Baxter Pharmaceuticals.
Stress was the most frequently cited cause of ulcer disease before Helicobacter pylori was discovered. The harried executive who developed an ulcer was a widely accepted profile of an ulcer diathesis. When the role of H. pylori infection and NSAIDs became clear, the role of stress was downplayed and some articles and textbooks dismissed stress as a potential cause for ulcer disease.
|
Dr. Nimish Vakil |
Studies of New York City residents suggest a higher incidence of ulcer disease after the 9-11 attacks and studies from Japan have shown an increase in the incidence of ulcer disease after the nuclear reactor disaster. In this issue of Clinical Gastroenterology and Hepatology, Dr. Levenstein and her colleagues report the results of a study of stress and the incidence of ulcer disease in Danish subjects. In 1982-1983, a population-based study in Denmark collected sera and psychological data in over 3000 subjects and reinterviewed them in 1987-1988 and 1993-1994. An ad-hoc, unvalidated scale developed by the authors measured stress. It included a psychological scale used by the Danish military to identify recruits unsuitable for military service but also included tranquilizer use, working more than 40 hours a week, and unemployment. In multivariate analysis, they found that stress increased the risk for both gastric and duodenal ulcers, with an adjusted odds ratio of 1.19 per point increase in the stress scale for gastric ulcers (95% confidence interval, 1.03-1.37) and a odds ratio of 1.1 per point increase in the stress index for duodenal ulcers (95% CI, 0.98-1.27).
There are obvious limitations with this study: a historical cohort, an unvalidated stress scale, the inclusion of items that may not represent stress in some cultures (e.g., working more than 40 hours/week) and the lower bound of confidence intervals for risk which are very close to one. However, studies such as this tell us that we have been too quick to dismiss the role of stress in ulcer pathogenesis. With declining H. pylori prevalence and the development of safer NSAIDs, stress will undergo a renaissance in the pathogenesis of ulcer disease.
Dr. Nimish Vakil, AGAF, FASGE, FACP, is a physician specializing in gastroenterology at the Aurora Wilkinson Medical Clinic in Summit, Wisc. He is a consultant for Astra Zeneca, Ironwood, and Baxter Pharmaceuticals.
High levels of psychological stress more than doubled the odds of peptic ulcers, and the link remained statistically significant even after controlling for factors such as Helicobacter pylori infection and cigarette smoking, according to a prospective study published in the March issue of Clinical Gastroenterology and Hepatology.
The findings contradict the widely accepted view that stress does not cause peptic ulcers, said Dr. Susan Levenstein of Aventino Medical Group in Rome and her associates. “Clinicians treating ulcer patients should investigate potential psychological stress among other risk factors,” they said.
Source: American Gastroenterological Association
Although “a vast literature links peptic ulcer to stress,” past studies suffered so many methodologic weaknesses that groups such as the U.S. National Institute of Diabetes and Digestive and Kidney Diseases rejected the evidence outright, Dr. Levenstein and her associates noted. Many studies were cross-sectional, for example, or did not control for confounders such as helicobacteriosis, they said.
To further study the effects of stress on ulcer risk, the researchers analyzed historical data from 76 patients who lacked a history of gastric and duodenal ulcers in 1982, but by 1994 had developed “distinct breach[es] in the mucosa” that were confirmed by endoscopy or contrast radiology. The researchers did not count erosions that lacked appreciable depth as ulcers, they noted (Clin. Gastroenterol. Hepatol. 2014 Aug. 8 [doi:10.1016/j.cgh.2014.07.052]).
Study subjects answered 12 questions about their stress levels, such as, “Do your hands easily shake?” “Do you often suffer from fits of dizziness?” “Do you constantly have thoughts that trouble and worry you?” and “Do you usually feel misunderstood by other people?” They answered these questions at baseline in 1982-1983, again in 1987-1988, and again in 1993-1994.
Respondents who scored in the top tertile for psychological stress had an ulcer incidence of 3.5%, compared with 1.6% for those in the lowest tertile (odds ratio, 2.2; 95% confidence interval, 1.2-3.9; P < .01), reported the investigators. And controlling for smoking, helicobacteriosis, use of nonsteroidal anti-inflammatory drugs, and low socioeconomic status only partially weakened the relationship between stress and ulcers, they said. After accounting for those risk factors, every one-point increase on the stress questionnaire still upped the odds of peptic ulcer by 12% (odds ratio, 1.12; 95% confidence interval, 1.01-1.23)they reported.
Helicobacteri pylori infection was the strongest independent predictor of ulcers (OR, 3.3; 95% CI, 2.02-5.69), while cigarette smoking came in a close second (OR, 2.91; 95% CI, 1.38-6.16), said the researchers. Notably, stress and helicobacteriosis did not seem to synergistically increase the chances of ulcers, they reported. “Stress affected H. pylori–related ulcers at least as much as those related to neither H. pylori nor nonsteroidal anti-inflammatory drugs,” they said.
Several factors might explain the stress-ulcer link, such as increased acid load, activation of the hypothalamic-pituitary-adrenal axis, shifts in blood flow, and cytokine activation that might impair gastrointestinal mucosal defenses, said the investigators. Although the baseline data in their study were more than 2 decades old, that meant that patients likely had not been treated to eradicate H. pylori and were less likely to have taken proton pump inhibitors than the current population that has over-the-counter access to PPIs, they added. They also noted that past studies found a particularly strong link between stress and bleeding or perforated ulcers, which have not declined as much as other types of ulcers. “These results support a multicausal model of peptic ulcer etiology, with intertwined biological and psychosocial components,” they concluded.
The Kirby Family Foundation funded the statistical analysis. The researchers reported no conflicts of interest.
High levels of psychological stress more than doubled the odds of peptic ulcers, and the link remained statistically significant even after controlling for factors such as Helicobacter pylori infection and cigarette smoking, according to a prospective study published in the March issue of Clinical Gastroenterology and Hepatology.
The findings contradict the widely accepted view that stress does not cause peptic ulcers, said Dr. Susan Levenstein of Aventino Medical Group in Rome and her associates. “Clinicians treating ulcer patients should investigate potential psychological stress among other risk factors,” they said.
Source: American Gastroenterological Association
Although “a vast literature links peptic ulcer to stress,” past studies suffered so many methodologic weaknesses that groups such as the U.S. National Institute of Diabetes and Digestive and Kidney Diseases rejected the evidence outright, Dr. Levenstein and her associates noted. Many studies were cross-sectional, for example, or did not control for confounders such as helicobacteriosis, they said.
To further study the effects of stress on ulcer risk, the researchers analyzed historical data from 76 patients who lacked a history of gastric and duodenal ulcers in 1982, but by 1994 had developed “distinct breach[es] in the mucosa” that were confirmed by endoscopy or contrast radiology. The researchers did not count erosions that lacked appreciable depth as ulcers, they noted (Clin. Gastroenterol. Hepatol. 2014 Aug. 8 [doi:10.1016/j.cgh.2014.07.052]).
Study subjects answered 12 questions about their stress levels, such as, “Do your hands easily shake?” “Do you often suffer from fits of dizziness?” “Do you constantly have thoughts that trouble and worry you?” and “Do you usually feel misunderstood by other people?” They answered these questions at baseline in 1982-1983, again in 1987-1988, and again in 1993-1994.
Respondents who scored in the top tertile for psychological stress had an ulcer incidence of 3.5%, compared with 1.6% for those in the lowest tertile (odds ratio, 2.2; 95% confidence interval, 1.2-3.9; P < .01), reported the investigators. And controlling for smoking, helicobacteriosis, use of nonsteroidal anti-inflammatory drugs, and low socioeconomic status only partially weakened the relationship between stress and ulcers, they said. After accounting for those risk factors, every one-point increase on the stress questionnaire still upped the odds of peptic ulcer by 12% (odds ratio, 1.12; 95% confidence interval, 1.01-1.23)they reported.
Helicobacteri pylori infection was the strongest independent predictor of ulcers (OR, 3.3; 95% CI, 2.02-5.69), while cigarette smoking came in a close second (OR, 2.91; 95% CI, 1.38-6.16), said the researchers. Notably, stress and helicobacteriosis did not seem to synergistically increase the chances of ulcers, they reported. “Stress affected H. pylori–related ulcers at least as much as those related to neither H. pylori nor nonsteroidal anti-inflammatory drugs,” they said.
Several factors might explain the stress-ulcer link, such as increased acid load, activation of the hypothalamic-pituitary-adrenal axis, shifts in blood flow, and cytokine activation that might impair gastrointestinal mucosal defenses, said the investigators. Although the baseline data in their study were more than 2 decades old, that meant that patients likely had not been treated to eradicate H. pylori and were less likely to have taken proton pump inhibitors than the current population that has over-the-counter access to PPIs, they added. They also noted that past studies found a particularly strong link between stress and bleeding or perforated ulcers, which have not declined as much as other types of ulcers. “These results support a multicausal model of peptic ulcer etiology, with intertwined biological and psychosocial components,” they concluded.
The Kirby Family Foundation funded the statistical analysis. The researchers reported no conflicts of interest.
FROM CLINICAL GASTROENTEROLOGY AND HEPATOLOGY
Key clinical point: High stress levels independently predicted peptic ulcers.
Major finding: After adjustment for other risk factors, every one-point increase on a 12-item stress questionnaire increased the odds of peptic ulcers by 12% (OR, 1.12; 95% CI, 1.01-1.23).
Data source: Prospective, population-based study of 76 patients with peptic ulcers.
Disclosures: The Kirby Family Foundation funded the statistical analysis. The researchers reported no conflicts of interest.
Study linked gastric phenotypes, hormone levels to obesity
A prospective study linked obesity to faster gastric emptying time, higher fasted stomach volume, lower postprandial levels of the appetite-modifying hormone peptide tyrosine tyrosine, and higher postprandial levels of glucagonlike peptide–1, researchers reported in the March issue of Gastroenterology.
By understanding how patients’ obesity relates to these types of specific, quantifiable measures, clinicians might better tailor treatments based on their mechanisms of action, said Dr. Andres Acosta and his associates at Mayo Medical School, Rochester, Minn. “This observation has public health relevance, as it would usher in a new era of matching patients based on quantitative traits to pharmacotherapy, potentially enhancing drug efficacy in treatment of obesity, and reducing expenditures for both validating the efficacy of such medications and prescribing them to obese individuals in clinical practice,” the researchers said.
Source: American Gastroenterological Association
Extended-release phentermine-topiramate and other prescription weight-loss therapies vary from patient to patient in terms of efficacy, the researchers noted. For example, only about half of patients treated with phentermine-topiramate ER have been found to lose more than 10% of their body weight, while 30% lose less than 5% of body weight on the drug, they said. Furthermore, past studies have yielded conflicting data on whether gastric functions, such as emptying time and volume, predict body mass index (BMI), they noted (Gastroenterology 2014 Dec. 2 [doi:10.1053/j.gastro.2014.11.020]).
To explore these relationships, the investigators prospectively studied 328 adults and found that obese individuals had higher stomach volume when fasting (P = .03), faster gastric emptying (P < .001 for solids and P < .011 for liquids), lower levels of peptide tyrosine tyrosine (PYY) after eating (P = .003), and higher postprandial levels of glucagonlike peptide–1 (GLP-1) (P < .001), compared with normal-weight individuals.
Next, they carried out an expanded analysis that added retrospective data from another 181 adults. Among the 509 total subjects in that analysis, 85 were of normal weight (BMI, 18-24.9 kg/m2), 158 were overweight (BMI, 25-29.9 kg/m2), 135 fell within the obesity class I definition (BMI, 30-34.9 kg/m2), and 131 met the criteria for obesity class II (BMI greater than 35 kg/m2), the researchers reported. This study found that obese subjects ate more before feeling full (P = .038), compared with normal-weight individuals, as did patients whose waist circumference was abnormally high (P = .016), compared with subjects of normal girth, they added. In fact, for every 5 kg per m2 increase in BMI, individuals consumed about 50 calories more, and those with abnormal waist circumference consumed about 100 calories more at a buffet meal, compared with individuals whose waist circumference was normal (P = 0.016), they added.
The researchers also studied the effects of phentermine-topiramate ER on weight loss in 24 of the obese individuals, of whom half were randomized to the drug and half to placebo. The treatment group lost an average of 1.4 kg (standard deviation, 0.4 kg), compared with a 0.23-kg average loss for the placebo group (SD, 0.4 kg; P = 0.03), the investigators said. The treatment group also consumed fewer calories and had slower gastric emptying than the placebo group, they added. Furthermore, the amount of calories that individuals had previously consumed at a buffet meal was significantly linked with their response to phentermine-topiramate ER, they reported. Based on those results, obese individuals who tend to consume more than 1,000 calories at buffets could be expected to lose more than 1 kg per week on phentermine-topiramate ER, at least in the short term, they added.
Finally, factors related to satiety were found to explain 21% of differences among overweight and obese individuals, while gastric capacity explained 14% and psychological factors such as anxiety and depression explained 13%, the investigators said. Such measures “can serve as biomarkers to enrich selection of patients for treatment, based on the pharmacological effects of the medication,” they added. Just as satiety predicted response to phentermine-topiramate ER, other biomarkers might predict response to amylin agonists or GLP-1 agonists, they said.
The National Institutes of Health supported the study, and Vivus provided medication. The researchers reported having no conflicts of interest.
The last 2 decades have witnessed a dramatic rise in surgical as well as less invasive procedures to combat obesity and insulin resistance. However, it is clear that bariatric medicine/surgery has a long way to go. We have little or no knowledge about predictors of outcome and optimal selection for response to medical, surgical, or endoscopic interventions, leading to a "one-size-fits-all" approach, which may not be the most appropriate for treating obesity.
Perhaps an even more important problem is that therapies (such as drugs or balloons) may be ignored or even dismissed on the basis of overall disappointing results in large cohort studies, even though they may have the potential to produce much more significant weight loss in yet to be identified subgroups of patients.
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| Dr. Pankaj Jay Pasricha |
With the expected proliferation of less invasive procedures with better patient acceptance, it becomes even more imperative, therefore, to start phenotyping patients across several dimensions including, but not limited, to the individual's gastrointestinal physiology and pathophysiology. In this article, Acosta et al. have taken a preliminary step in that direction, with a focus on gastric physiology and associated parameters of eating and satiety in a large group of obese patients. Their initial classification of "gastric phenotypes" needs to be validated further but provides a valuable framework to start building a more nuanced and tailored approach to interventions, particularly those that act predominantly on the stomach such as balloons, a dazzling variety of which are expected to appear on the market in the near future.
Dr. Pankaj Jay Pasricha, AGAF, is director of the Johns Hopkins Center for Neurogastroenterology; director of the Food Body and Mind Center at Johns Hopkins; professor of medicine and neurosciences, Johns Hopkins School of Medicine; and professor of innovation management, Johns Hopkins Carey School of Business, Baltimore. He has no conflicts of interest.
The last 2 decades have witnessed a dramatic rise in surgical as well as less invasive procedures to combat obesity and insulin resistance. However, it is clear that bariatric medicine/surgery has a long way to go. We have little or no knowledge about predictors of outcome and optimal selection for response to medical, surgical, or endoscopic interventions, leading to a "one-size-fits-all" approach, which may not be the most appropriate for treating obesity.
Perhaps an even more important problem is that therapies (such as drugs or balloons) may be ignored or even dismissed on the basis of overall disappointing results in large cohort studies, even though they may have the potential to produce much more significant weight loss in yet to be identified subgroups of patients.
|
| Dr. Pankaj Jay Pasricha |
With the expected proliferation of less invasive procedures with better patient acceptance, it becomes even more imperative, therefore, to start phenotyping patients across several dimensions including, but not limited, to the individual's gastrointestinal physiology and pathophysiology. In this article, Acosta et al. have taken a preliminary step in that direction, with a focus on gastric physiology and associated parameters of eating and satiety in a large group of obese patients. Their initial classification of "gastric phenotypes" needs to be validated further but provides a valuable framework to start building a more nuanced and tailored approach to interventions, particularly those that act predominantly on the stomach such as balloons, a dazzling variety of which are expected to appear on the market in the near future.
Dr. Pankaj Jay Pasricha, AGAF, is director of the Johns Hopkins Center for Neurogastroenterology; director of the Food Body and Mind Center at Johns Hopkins; professor of medicine and neurosciences, Johns Hopkins School of Medicine; and professor of innovation management, Johns Hopkins Carey School of Business, Baltimore. He has no conflicts of interest.
The last 2 decades have witnessed a dramatic rise in surgical as well as less invasive procedures to combat obesity and insulin resistance. However, it is clear that bariatric medicine/surgery has a long way to go. We have little or no knowledge about predictors of outcome and optimal selection for response to medical, surgical, or endoscopic interventions, leading to a "one-size-fits-all" approach, which may not be the most appropriate for treating obesity.
Perhaps an even more important problem is that therapies (such as drugs or balloons) may be ignored or even dismissed on the basis of overall disappointing results in large cohort studies, even though they may have the potential to produce much more significant weight loss in yet to be identified subgroups of patients.
|
| Dr. Pankaj Jay Pasricha |
With the expected proliferation of less invasive procedures with better patient acceptance, it becomes even more imperative, therefore, to start phenotyping patients across several dimensions including, but not limited, to the individual's gastrointestinal physiology and pathophysiology. In this article, Acosta et al. have taken a preliminary step in that direction, with a focus on gastric physiology and associated parameters of eating and satiety in a large group of obese patients. Their initial classification of "gastric phenotypes" needs to be validated further but provides a valuable framework to start building a more nuanced and tailored approach to interventions, particularly those that act predominantly on the stomach such as balloons, a dazzling variety of which are expected to appear on the market in the near future.
Dr. Pankaj Jay Pasricha, AGAF, is director of the Johns Hopkins Center for Neurogastroenterology; director of the Food Body and Mind Center at Johns Hopkins; professor of medicine and neurosciences, Johns Hopkins School of Medicine; and professor of innovation management, Johns Hopkins Carey School of Business, Baltimore. He has no conflicts of interest.
A prospective study linked obesity to faster gastric emptying time, higher fasted stomach volume, lower postprandial levels of the appetite-modifying hormone peptide tyrosine tyrosine, and higher postprandial levels of glucagonlike peptide–1, researchers reported in the March issue of Gastroenterology.
By understanding how patients’ obesity relates to these types of specific, quantifiable measures, clinicians might better tailor treatments based on their mechanisms of action, said Dr. Andres Acosta and his associates at Mayo Medical School, Rochester, Minn. “This observation has public health relevance, as it would usher in a new era of matching patients based on quantitative traits to pharmacotherapy, potentially enhancing drug efficacy in treatment of obesity, and reducing expenditures for both validating the efficacy of such medications and prescribing them to obese individuals in clinical practice,” the researchers said.
Source: American Gastroenterological Association
Extended-release phentermine-topiramate and other prescription weight-loss therapies vary from patient to patient in terms of efficacy, the researchers noted. For example, only about half of patients treated with phentermine-topiramate ER have been found to lose more than 10% of their body weight, while 30% lose less than 5% of body weight on the drug, they said. Furthermore, past studies have yielded conflicting data on whether gastric functions, such as emptying time and volume, predict body mass index (BMI), they noted (Gastroenterology 2014 Dec. 2 [doi:10.1053/j.gastro.2014.11.020]).
To explore these relationships, the investigators prospectively studied 328 adults and found that obese individuals had higher stomach volume when fasting (P = .03), faster gastric emptying (P < .001 for solids and P < .011 for liquids), lower levels of peptide tyrosine tyrosine (PYY) after eating (P = .003), and higher postprandial levels of glucagonlike peptide–1 (GLP-1) (P < .001), compared with normal-weight individuals.
Next, they carried out an expanded analysis that added retrospective data from another 181 adults. Among the 509 total subjects in that analysis, 85 were of normal weight (BMI, 18-24.9 kg/m2), 158 were overweight (BMI, 25-29.9 kg/m2), 135 fell within the obesity class I definition (BMI, 30-34.9 kg/m2), and 131 met the criteria for obesity class II (BMI greater than 35 kg/m2), the researchers reported. This study found that obese subjects ate more before feeling full (P = .038), compared with normal-weight individuals, as did patients whose waist circumference was abnormally high (P = .016), compared with subjects of normal girth, they added. In fact, for every 5 kg per m2 increase in BMI, individuals consumed about 50 calories more, and those with abnormal waist circumference consumed about 100 calories more at a buffet meal, compared with individuals whose waist circumference was normal (P = 0.016), they added.
The researchers also studied the effects of phentermine-topiramate ER on weight loss in 24 of the obese individuals, of whom half were randomized to the drug and half to placebo. The treatment group lost an average of 1.4 kg (standard deviation, 0.4 kg), compared with a 0.23-kg average loss for the placebo group (SD, 0.4 kg; P = 0.03), the investigators said. The treatment group also consumed fewer calories and had slower gastric emptying than the placebo group, they added. Furthermore, the amount of calories that individuals had previously consumed at a buffet meal was significantly linked with their response to phentermine-topiramate ER, they reported. Based on those results, obese individuals who tend to consume more than 1,000 calories at buffets could be expected to lose more than 1 kg per week on phentermine-topiramate ER, at least in the short term, they added.
Finally, factors related to satiety were found to explain 21% of differences among overweight and obese individuals, while gastric capacity explained 14% and psychological factors such as anxiety and depression explained 13%, the investigators said. Such measures “can serve as biomarkers to enrich selection of patients for treatment, based on the pharmacological effects of the medication,” they added. Just as satiety predicted response to phentermine-topiramate ER, other biomarkers might predict response to amylin agonists or GLP-1 agonists, they said.
The National Institutes of Health supported the study, and Vivus provided medication. The researchers reported having no conflicts of interest.
A prospective study linked obesity to faster gastric emptying time, higher fasted stomach volume, lower postprandial levels of the appetite-modifying hormone peptide tyrosine tyrosine, and higher postprandial levels of glucagonlike peptide–1, researchers reported in the March issue of Gastroenterology.
By understanding how patients’ obesity relates to these types of specific, quantifiable measures, clinicians might better tailor treatments based on their mechanisms of action, said Dr. Andres Acosta and his associates at Mayo Medical School, Rochester, Minn. “This observation has public health relevance, as it would usher in a new era of matching patients based on quantitative traits to pharmacotherapy, potentially enhancing drug efficacy in treatment of obesity, and reducing expenditures for both validating the efficacy of such medications and prescribing them to obese individuals in clinical practice,” the researchers said.
Source: American Gastroenterological Association
Extended-release phentermine-topiramate and other prescription weight-loss therapies vary from patient to patient in terms of efficacy, the researchers noted. For example, only about half of patients treated with phentermine-topiramate ER have been found to lose more than 10% of their body weight, while 30% lose less than 5% of body weight on the drug, they said. Furthermore, past studies have yielded conflicting data on whether gastric functions, such as emptying time and volume, predict body mass index (BMI), they noted (Gastroenterology 2014 Dec. 2 [doi:10.1053/j.gastro.2014.11.020]).
To explore these relationships, the investigators prospectively studied 328 adults and found that obese individuals had higher stomach volume when fasting (P = .03), faster gastric emptying (P < .001 for solids and P < .011 for liquids), lower levels of peptide tyrosine tyrosine (PYY) after eating (P = .003), and higher postprandial levels of glucagonlike peptide–1 (GLP-1) (P < .001), compared with normal-weight individuals.
Next, they carried out an expanded analysis that added retrospective data from another 181 adults. Among the 509 total subjects in that analysis, 85 were of normal weight (BMI, 18-24.9 kg/m2), 158 were overweight (BMI, 25-29.9 kg/m2), 135 fell within the obesity class I definition (BMI, 30-34.9 kg/m2), and 131 met the criteria for obesity class II (BMI greater than 35 kg/m2), the researchers reported. This study found that obese subjects ate more before feeling full (P = .038), compared with normal-weight individuals, as did patients whose waist circumference was abnormally high (P = .016), compared with subjects of normal girth, they added. In fact, for every 5 kg per m2 increase in BMI, individuals consumed about 50 calories more, and those with abnormal waist circumference consumed about 100 calories more at a buffet meal, compared with individuals whose waist circumference was normal (P = 0.016), they added.
The researchers also studied the effects of phentermine-topiramate ER on weight loss in 24 of the obese individuals, of whom half were randomized to the drug and half to placebo. The treatment group lost an average of 1.4 kg (standard deviation, 0.4 kg), compared with a 0.23-kg average loss for the placebo group (SD, 0.4 kg; P = 0.03), the investigators said. The treatment group also consumed fewer calories and had slower gastric emptying than the placebo group, they added. Furthermore, the amount of calories that individuals had previously consumed at a buffet meal was significantly linked with their response to phentermine-topiramate ER, they reported. Based on those results, obese individuals who tend to consume more than 1,000 calories at buffets could be expected to lose more than 1 kg per week on phentermine-topiramate ER, at least in the short term, they added.
Finally, factors related to satiety were found to explain 21% of differences among overweight and obese individuals, while gastric capacity explained 14% and psychological factors such as anxiety and depression explained 13%, the investigators said. Such measures “can serve as biomarkers to enrich selection of patients for treatment, based on the pharmacological effects of the medication,” they added. Just as satiety predicted response to phentermine-topiramate ER, other biomarkers might predict response to amylin agonists or GLP-1 agonists, they said.
The National Institutes of Health supported the study, and Vivus provided medication. The researchers reported having no conflicts of interest.
Key clinical point: Obesity was linked to lower satiety levels, faster gastric emptying, greater fasted gastric volume, and lower levels of PYY.
Major finding: Obese individuals had larger stomach volume when fasting (P = .03), faster gastric emptying (P < .001 for solids and P < .011 for liquids), lower levels of PYY after eating (P = .003), and higher postprandial levels of GLP-1 (P < .001), compared with normal-weight individuals.
Data source: Prospective study of 328 adults, expanded study of 509 adults, and nested randomized, controlled clinical trial of 24 obese adults.
Disclosures: The National Institutes of Health supported the study, and Vivus provided medication. The researchers reported having no conflicts of interest.
Human liver cells can induce antiviral reaction against hepatitis C
Immunity against the hepatitis C virus can be induced by cultured primary human liver sinusoidal endothelial cells, according to a study published in the February issue of Gastroenterology (doi:10.1053/j.gastro.2014.10.040).
“We found HLSECs [primary human LSECs] express many of the receptors implicated in HCV [hepatitis C virus] attachment and entry and HLSEC-to-hepatocyte contact was dispensable for uptake,” wrote lead author Dr. Silvia M. Giugliano of the University of Colorado, Denver, and her associates.
In a cohort study, investigators exposed HLSECs and immortalized liver endothelial cells (TMNK-1) to several variants of HCV: full-length transmitted/founder virus, sucrose-purified Japanese fulminant hepatitis–1 (JFH-1), a virus encoding a luciferase reporter, and the HCV-specific pathogen-associated molecular pattern molecules (PAMP, substrate for RIG-I). Cells were analyzed by using polymerase chain reaction (PCR), immunofluorescence, and immunohistochemical assays.
Results showed that HLSECs, regardless of contact between cells, were able to internalize HCV when exposed to it and replicate, though not translate HCV RNA. The HCV RNA “induced consistent and broad transcription of multiple interferons (IFNs) [via] pattern recognition receptors (TLR7 and retinoic acid-inducible gene 1).” Furthermore, supernatants from primary HLSECs transfected with HCV-specific PAMP molecules had larger inductions of IFNs and IFN-stimulated genes in HLSECs.
“Conditioned media from IFN-stimulated HLSECs induced expression of antiviral genes by uninfected primary human hepatocytes,” wrote Dr. Giugliano and her coauthors. “Exosomes, derived from HLSECs following stimulation with either type I or type III IFNs, controlled HCV replication in a dose-dependent manner.”
However, the investigators say that more study is required to understand why HCV is able to present so persistently if the means to combat the virus are so apparent in the immune system.
“These results raise a number of intriguing questions, for example, how the use of exogenous IFN to treat viral hepatitis could be expected to induce additional, previously unrecognized antiviral mechanisms involving HLSECs,” says the study. “Further work is warranted to understand why despite these innate immune responses, HCV is able to establish persistence and fail eradication with IFN-based antiviral therapy.”
The study supported by grants R21-AI103361 and U19 AI 1066328; Dr. Rosen received a Merit Review grant and Dr. Shaw received grant R21-AI 106000. The authors reported no financial conflicts of interest.
Liver sinusoidal endothelial cells (LSECs) are a large component of the liver immune system but are not very well characterized for their role in diseases like chronic hepatitis C virus (HCV) infection. Dr. Giugliano and her associates tested the antiviral activity of primary human LSECs and an immortalized LSEC cell line (TMNK-1), following exposure to several viral variants. These included naturally
 |
| Dr. Arash Grakoui |
occurring founder genotype 1a virus, a JFH-1 infectious clone (cloned originally from a patient with fulminant hepatitis), a modified cell culture of adaptive JFH-1 virus expressing luciferase reporter, and HCV-specific pathogen-associated molecular pattern poly UC RNA that is a substrate for RIG-I. They found LSECs were able to acquire HCV in an LSEC-to-hepatocyte–contact independent manner but that these cells were not permissive for productive infection (replication). Importantly, viral RNA through HCV uptake induced robust transcription of type I and III interferon (IFN) by LSECs via TLR7 and RIG-I pathways. LSEC-derived IFN had antiviral effects on HCV-infected human hepatoma cell line, Huh7.5 cells in vitro, and this effect was mediated through the production of exosomes. The authors concluded that LSECs likely have an important antiviral role in HCV infection through bystander induction of an antiviral state. This study highlights the idea that these cells can function similarly to other innate/phagocytic cells like monocytes/macrophages and furthers the idea that innate activation of LSECs may have protective effects on the antiviral state of hepatocytes. Mechanisms of antiviral immunity by LSECs, whether it occurs through exosomes or IFN, will have a significant impact in the field as the answers will have relevance to numerous facets of liver immunology, including gene transfer, organ transplant, and response to other hepatotropic infections.
Dr. Arash Grakoui is an associate professor jointly appointed in the departments of medicine, division of infectious diseases and Yerkes National Primate Research Center, department of microbiology and immunology at Emory University, Atlanta. He has no conflicts of interest.
Liver sinusoidal endothelial cells (LSECs) are a large component of the liver immune system but are not very well characterized for their role in diseases like chronic hepatitis C virus (HCV) infection. Dr. Giugliano and her associates tested the antiviral activity of primary human LSECs and an immortalized LSEC cell line (TMNK-1), following exposure to several viral variants. These included naturally
|
| Dr. Arash Grakoui |
occurring founder genotype 1a virus, a JFH-1 infectious clone (cloned originally from a patient with fulminant hepatitis), a modified cell culture of adaptive JFH-1 virus expressing luciferase reporter, and HCV-specific pathogen-associated molecular pattern poly UC RNA that is a substrate for RIG-I. They found LSECs were able to acquire HCV in an LSEC-to-hepatocyte–contact independent manner but that these cells were not permissive for productive infection (replication). Importantly, viral RNA through HCV uptake induced robust transcription of type I and III interferon (IFN) by LSECs via TLR7 and RIG-I pathways. LSEC-derived IFN had antiviral effects on HCV-infected human hepatoma cell line, Huh7.5 cells in vitro, and this effect was mediated through the production of exosomes. The authors concluded that LSECs likely have an important antiviral role in HCV infection through bystander induction of an antiviral state. This study highlights the idea that these cells can function similarly to other innate/phagocytic cells like monocytes/macrophages and furthers the idea that innate activation of LSECs may have protective effects on the antiviral state of hepatocytes. Mechanisms of antiviral immunity by LSECs, whether it occurs through exosomes or IFN, will have a significant impact in the field as the answers will have relevance to numerous facets of liver immunology, including gene transfer, organ transplant, and response to other hepatotropic infections.
Dr. Arash Grakoui is an associate professor jointly appointed in the departments of medicine, division of infectious diseases and Yerkes National Primate Research Center, department of microbiology and immunology at Emory University, Atlanta. He has no conflicts of interest.
Liver sinusoidal endothelial cells (LSECs) are a large component of the liver immune system but are not very well characterized for their role in diseases like chronic hepatitis C virus (HCV) infection. Dr. Giugliano and her associates tested the antiviral activity of primary human LSECs and an immortalized LSEC cell line (TMNK-1), following exposure to several viral variants. These included naturally
|
| Dr. Arash Grakoui |
occurring founder genotype 1a virus, a JFH-1 infectious clone (cloned originally from a patient with fulminant hepatitis), a modified cell culture of adaptive JFH-1 virus expressing luciferase reporter, and HCV-specific pathogen-associated molecular pattern poly UC RNA that is a substrate for RIG-I. They found LSECs were able to acquire HCV in an LSEC-to-hepatocyte–contact independent manner but that these cells were not permissive for productive infection (replication). Importantly, viral RNA through HCV uptake induced robust transcription of type I and III interferon (IFN) by LSECs via TLR7 and RIG-I pathways. LSEC-derived IFN had antiviral effects on HCV-infected human hepatoma cell line, Huh7.5 cells in vitro, and this effect was mediated through the production of exosomes. The authors concluded that LSECs likely have an important antiviral role in HCV infection through bystander induction of an antiviral state. This study highlights the idea that these cells can function similarly to other innate/phagocytic cells like monocytes/macrophages and furthers the idea that innate activation of LSECs may have protective effects on the antiviral state of hepatocytes. Mechanisms of antiviral immunity by LSECs, whether it occurs through exosomes or IFN, will have a significant impact in the field as the answers will have relevance to numerous facets of liver immunology, including gene transfer, organ transplant, and response to other hepatotropic infections.
Dr. Arash Grakoui is an associate professor jointly appointed in the departments of medicine, division of infectious diseases and Yerkes National Primate Research Center, department of microbiology and immunology at Emory University, Atlanta. He has no conflicts of interest.
Immunity against the hepatitis C virus can be induced by cultured primary human liver sinusoidal endothelial cells, according to a study published in the February issue of Gastroenterology (doi:10.1053/j.gastro.2014.10.040).
“We found HLSECs [primary human LSECs] express many of the receptors implicated in HCV [hepatitis C virus] attachment and entry and HLSEC-to-hepatocyte contact was dispensable for uptake,” wrote lead author Dr. Silvia M. Giugliano of the University of Colorado, Denver, and her associates.
In a cohort study, investigators exposed HLSECs and immortalized liver endothelial cells (TMNK-1) to several variants of HCV: full-length transmitted/founder virus, sucrose-purified Japanese fulminant hepatitis–1 (JFH-1), a virus encoding a luciferase reporter, and the HCV-specific pathogen-associated molecular pattern molecules (PAMP, substrate for RIG-I). Cells were analyzed by using polymerase chain reaction (PCR), immunofluorescence, and immunohistochemical assays.
Results showed that HLSECs, regardless of contact between cells, were able to internalize HCV when exposed to it and replicate, though not translate HCV RNA. The HCV RNA “induced consistent and broad transcription of multiple interferons (IFNs) [via] pattern recognition receptors (TLR7 and retinoic acid-inducible gene 1).” Furthermore, supernatants from primary HLSECs transfected with HCV-specific PAMP molecules had larger inductions of IFNs and IFN-stimulated genes in HLSECs.
“Conditioned media from IFN-stimulated HLSECs induced expression of antiviral genes by uninfected primary human hepatocytes,” wrote Dr. Giugliano and her coauthors. “Exosomes, derived from HLSECs following stimulation with either type I or type III IFNs, controlled HCV replication in a dose-dependent manner.”
However, the investigators say that more study is required to understand why HCV is able to present so persistently if the means to combat the virus are so apparent in the immune system.
“These results raise a number of intriguing questions, for example, how the use of exogenous IFN to treat viral hepatitis could be expected to induce additional, previously unrecognized antiviral mechanisms involving HLSECs,” says the study. “Further work is warranted to understand why despite these innate immune responses, HCV is able to establish persistence and fail eradication with IFN-based antiviral therapy.”
The study supported by grants R21-AI103361 and U19 AI 1066328; Dr. Rosen received a Merit Review grant and Dr. Shaw received grant R21-AI 106000. The authors reported no financial conflicts of interest.
Immunity against the hepatitis C virus can be induced by cultured primary human liver sinusoidal endothelial cells, according to a study published in the February issue of Gastroenterology (doi:10.1053/j.gastro.2014.10.040).
“We found HLSECs [primary human LSECs] express many of the receptors implicated in HCV [hepatitis C virus] attachment and entry and HLSEC-to-hepatocyte contact was dispensable for uptake,” wrote lead author Dr. Silvia M. Giugliano of the University of Colorado, Denver, and her associates.
In a cohort study, investigators exposed HLSECs and immortalized liver endothelial cells (TMNK-1) to several variants of HCV: full-length transmitted/founder virus, sucrose-purified Japanese fulminant hepatitis–1 (JFH-1), a virus encoding a luciferase reporter, and the HCV-specific pathogen-associated molecular pattern molecules (PAMP, substrate for RIG-I). Cells were analyzed by using polymerase chain reaction (PCR), immunofluorescence, and immunohistochemical assays.
Results showed that HLSECs, regardless of contact between cells, were able to internalize HCV when exposed to it and replicate, though not translate HCV RNA. The HCV RNA “induced consistent and broad transcription of multiple interferons (IFNs) [via] pattern recognition receptors (TLR7 and retinoic acid-inducible gene 1).” Furthermore, supernatants from primary HLSECs transfected with HCV-specific PAMP molecules had larger inductions of IFNs and IFN-stimulated genes in HLSECs.
“Conditioned media from IFN-stimulated HLSECs induced expression of antiviral genes by uninfected primary human hepatocytes,” wrote Dr. Giugliano and her coauthors. “Exosomes, derived from HLSECs following stimulation with either type I or type III IFNs, controlled HCV replication in a dose-dependent manner.”
However, the investigators say that more study is required to understand why HCV is able to present so persistently if the means to combat the virus are so apparent in the immune system.
“These results raise a number of intriguing questions, for example, how the use of exogenous IFN to treat viral hepatitis could be expected to induce additional, previously unrecognized antiviral mechanisms involving HLSECs,” says the study. “Further work is warranted to understand why despite these innate immune responses, HCV is able to establish persistence and fail eradication with IFN-based antiviral therapy.”
The study supported by grants R21-AI103361 and U19 AI 1066328; Dr. Rosen received a Merit Review grant and Dr. Shaw received grant R21-AI 106000. The authors reported no financial conflicts of interest.
FROM GASTROENTEROLOGY
Key clinical point: Cultured primary human liver sinusoidal endothelial cells (HLSECs) induce self-amplifying interferon-mediated responses and release of exosomes with antiviral activity, thus allowing it to mediate immunity against the hepatitis C virus (HCV).
Major finding: HLSECs and CV-specific PAMP molecules induced IFNs and replicated HCV RNA when exposed to various forms of HCV.
Data source: Cohort study
Disclosures: Study supported by grants R21-AI103361 and U19 AI 1066328; Dr. Rosen received a Merit Review grant and Dr. Shaw received grant R21-AI 106000. The authors reported no financial conflicts of interest.
Increased prevalence of chronic narcotic use in children with IBD
The prevalence of chronic narcotic use among pediatric patients with inflammatory bowel disease is abnormally high and should be curbed to prevent further adverse effects from taking hold, according to a new study published in the February issue of Clinical Gastroenterology and Hepatology.
“Although pain control is an important aspect of disease management in pediatric IBD [inflammatory bowel disease], little is known about chronic narcotic use in children,” wrote the investigators, led by Dr. Jessie P. Buckley of the University of North Carolina at Chapel Hill. They added that “although children with Crohn’s disease are at increased risk of anxiety and depression, the relationship between narcotic use and psychiatric conditions has not yet been assessed in the pediatric IBD population (Clin. Gastroenterol. Hepatol. 2015 February [doi:10.1016/j.cgh.2014.07.057].”
In a retrospective, cross-sectional study, Dr. Buckley and her associates counted all 4,911,286 patients aged 18 years or younger with continuous health plan enrollment and pharmacy benefits in the MarketScan Commercial Claims and Encounters database between January 1, 2010 and December 31, 2011. Children were defined as having IBD if they had either three or more health care visits for Crohn’s disease or ulcerative colitis during the study’s time frame, or “at least one health care contact for Crohn’s disease or ulcerative colitis and at least one pharmacy claim for any of the following medications: mesalamine, olsalazine, balsalazide, sulfasalazine, 6-mercaptopurine, azathioprine, methotrexate, enteral budesonide, or biologics (infliximab, adalimumab, certolizumab,or natalizumab).”
From this population, the authors used diagnosis codes based on data from the U.S. National Drug Code system, the European Pharmaceutical Market Research Association, and the Pharmaceutical Business Intelligence and Research Group Anatomical Classification System drug classes, along with information on dispensation of IBD medications, to select 4,344 IBD patients, each of whom was subsequently matched with 5 other patients without IBD based on age, sex, and geographic region within the United States (Northeast, North Central, South, or West), yielding 21,720 in this population. Subjects were defined as chronic users if they “had at least three narcotic drug claims during the 2-year study period.” Within the IBD population, 2,737 (63%) of subjects had Crohn’s disease and 1,607 (37%) had ulcerative colitis.
Investigators found that 5.6% (241 individuals) of the 4,344 subjects with IBD were chronic narcotic users, significantly higher than the 2.3% rate (489 subjects) of chronic narcotic use found in the non-IBD population (prevalence odds ratio, 2.59; 95% confidence interval, 2.21–3.04). Furthermore, chronic narcotic use was more prevalent in IBD patients with psychological impairment than those without: 15.7% (POR, 6.8; 95% CI, 4.3–10.6) versus 3.2% (POR, 2.3; 95% CI, 1.9–2.7), respectively. In children with IBD, older age and chronic narcotic use were also more highly associated with “increased health care utilization [and] fracture.”
“Children with IBD had more than twice the prevalence of chronic narcotic use as children without, and associations between IBD status and narcotic use indicate particularly high burden among those with concomitant anxiety or depression,” Dr. Buckley and her associates wrote, adding that “psychiatric diagnoses have also been associated with increased risk of narcotic use among adult patients with IBD. Greater attention to the complex relationships between pain and psychological impairment is warranted because children with IBD are at increased risk of anxiety and depression, compared with their peers, and other cofactors are not easily intervened on (e.g., age, region, fracture).”
The authors disclosed that financial support for this study was provided, at least in part, by GlaxoSmithKline (GSK). Dr. Buckley received funding through a research assistantship at GSK, coauthors Dr. Suzanne F. Cook and Dr. Jeffery K. Allen are employees of GSK, and coauthor Dr. Michael D. Kappelman is a consultant to GSK, among other companies.
The prevalence of chronic narcotic use among pediatric patients with inflammatory bowel disease is abnormally high and should be curbed to prevent further adverse effects from taking hold, according to a new study published in the February issue of Clinical Gastroenterology and Hepatology.
“Although pain control is an important aspect of disease management in pediatric IBD [inflammatory bowel disease], little is known about chronic narcotic use in children,” wrote the investigators, led by Dr. Jessie P. Buckley of the University of North Carolina at Chapel Hill. They added that “although children with Crohn’s disease are at increased risk of anxiety and depression, the relationship between narcotic use and psychiatric conditions has not yet been assessed in the pediatric IBD population (Clin. Gastroenterol. Hepatol. 2015 February [doi:10.1016/j.cgh.2014.07.057].”
In a retrospective, cross-sectional study, Dr. Buckley and her associates counted all 4,911,286 patients aged 18 years or younger with continuous health plan enrollment and pharmacy benefits in the MarketScan Commercial Claims and Encounters database between January 1, 2010 and December 31, 2011. Children were defined as having IBD if they had either three or more health care visits for Crohn’s disease or ulcerative colitis during the study’s time frame, or “at least one health care contact for Crohn’s disease or ulcerative colitis and at least one pharmacy claim for any of the following medications: mesalamine, olsalazine, balsalazide, sulfasalazine, 6-mercaptopurine, azathioprine, methotrexate, enteral budesonide, or biologics (infliximab, adalimumab, certolizumab,or natalizumab).”
From this population, the authors used diagnosis codes based on data from the U.S. National Drug Code system, the European Pharmaceutical Market Research Association, and the Pharmaceutical Business Intelligence and Research Group Anatomical Classification System drug classes, along with information on dispensation of IBD medications, to select 4,344 IBD patients, each of whom was subsequently matched with 5 other patients without IBD based on age, sex, and geographic region within the United States (Northeast, North Central, South, or West), yielding 21,720 in this population. Subjects were defined as chronic users if they “had at least three narcotic drug claims during the 2-year study period.” Within the IBD population, 2,737 (63%) of subjects had Crohn’s disease and 1,607 (37%) had ulcerative colitis.
Investigators found that 5.6% (241 individuals) of the 4,344 subjects with IBD were chronic narcotic users, significantly higher than the 2.3% rate (489 subjects) of chronic narcotic use found in the non-IBD population (prevalence odds ratio, 2.59; 95% confidence interval, 2.21–3.04). Furthermore, chronic narcotic use was more prevalent in IBD patients with psychological impairment than those without: 15.7% (POR, 6.8; 95% CI, 4.3–10.6) versus 3.2% (POR, 2.3; 95% CI, 1.9–2.7), respectively. In children with IBD, older age and chronic narcotic use were also more highly associated with “increased health care utilization [and] fracture.”
“Children with IBD had more than twice the prevalence of chronic narcotic use as children without, and associations between IBD status and narcotic use indicate particularly high burden among those with concomitant anxiety or depression,” Dr. Buckley and her associates wrote, adding that “psychiatric diagnoses have also been associated with increased risk of narcotic use among adult patients with IBD. Greater attention to the complex relationships between pain and psychological impairment is warranted because children with IBD are at increased risk of anxiety and depression, compared with their peers, and other cofactors are not easily intervened on (e.g., age, region, fracture).”
The authors disclosed that financial support for this study was provided, at least in part, by GlaxoSmithKline (GSK). Dr. Buckley received funding through a research assistantship at GSK, coauthors Dr. Suzanne F. Cook and Dr. Jeffery K. Allen are employees of GSK, and coauthor Dr. Michael D. Kappelman is a consultant to GSK, among other companies.
The prevalence of chronic narcotic use among pediatric patients with inflammatory bowel disease is abnormally high and should be curbed to prevent further adverse effects from taking hold, according to a new study published in the February issue of Clinical Gastroenterology and Hepatology.
“Although pain control is an important aspect of disease management in pediatric IBD [inflammatory bowel disease], little is known about chronic narcotic use in children,” wrote the investigators, led by Dr. Jessie P. Buckley of the University of North Carolina at Chapel Hill. They added that “although children with Crohn’s disease are at increased risk of anxiety and depression, the relationship between narcotic use and psychiatric conditions has not yet been assessed in the pediatric IBD population (Clin. Gastroenterol. Hepatol. 2015 February [doi:10.1016/j.cgh.2014.07.057].”
In a retrospective, cross-sectional study, Dr. Buckley and her associates counted all 4,911,286 patients aged 18 years or younger with continuous health plan enrollment and pharmacy benefits in the MarketScan Commercial Claims and Encounters database between January 1, 2010 and December 31, 2011. Children were defined as having IBD if they had either three or more health care visits for Crohn’s disease or ulcerative colitis during the study’s time frame, or “at least one health care contact for Crohn’s disease or ulcerative colitis and at least one pharmacy claim for any of the following medications: mesalamine, olsalazine, balsalazide, sulfasalazine, 6-mercaptopurine, azathioprine, methotrexate, enteral budesonide, or biologics (infliximab, adalimumab, certolizumab,or natalizumab).”
From this population, the authors used diagnosis codes based on data from the U.S. National Drug Code system, the European Pharmaceutical Market Research Association, and the Pharmaceutical Business Intelligence and Research Group Anatomical Classification System drug classes, along with information on dispensation of IBD medications, to select 4,344 IBD patients, each of whom was subsequently matched with 5 other patients without IBD based on age, sex, and geographic region within the United States (Northeast, North Central, South, or West), yielding 21,720 in this population. Subjects were defined as chronic users if they “had at least three narcotic drug claims during the 2-year study period.” Within the IBD population, 2,737 (63%) of subjects had Crohn’s disease and 1,607 (37%) had ulcerative colitis.
Investigators found that 5.6% (241 individuals) of the 4,344 subjects with IBD were chronic narcotic users, significantly higher than the 2.3% rate (489 subjects) of chronic narcotic use found in the non-IBD population (prevalence odds ratio, 2.59; 95% confidence interval, 2.21–3.04). Furthermore, chronic narcotic use was more prevalent in IBD patients with psychological impairment than those without: 15.7% (POR, 6.8; 95% CI, 4.3–10.6) versus 3.2% (POR, 2.3; 95% CI, 1.9–2.7), respectively. In children with IBD, older age and chronic narcotic use were also more highly associated with “increased health care utilization [and] fracture.”
“Children with IBD had more than twice the prevalence of chronic narcotic use as children without, and associations between IBD status and narcotic use indicate particularly high burden among those with concomitant anxiety or depression,” Dr. Buckley and her associates wrote, adding that “psychiatric diagnoses have also been associated with increased risk of narcotic use among adult patients with IBD. Greater attention to the complex relationships between pain and psychological impairment is warranted because children with IBD are at increased risk of anxiety and depression, compared with their peers, and other cofactors are not easily intervened on (e.g., age, region, fracture).”
The authors disclosed that financial support for this study was provided, at least in part, by GlaxoSmithKline (GSK). Dr. Buckley received funding through a research assistantship at GSK, coauthors Dr. Suzanne F. Cook and Dr. Jeffery K. Allen are employees of GSK, and coauthor Dr. Michael D. Kappelman is a consultant to GSK, among other companies.
FROM CLINICAL GASTROENTEROLOGY AND HEPATOLOGY
Key clinical point: Chronic narcotic use in pediatric patients with inflammatory bowel disease has become increasingly prevalent.
Major finding: Prevalence of chronic narcotic use was 5.6% among children with IBD vs. 2.3% in the general population (OR, 2.6).
Data source: Retrospective, cross-sectional study.
Disclosures: Support for this study was provided by GlaxoSmithKline; all of the study’s coauthors are either employed by or otherwise affiliated with the company.
Transoral fundoplication can be effective against GERD symptoms
Transoral esophagogastric fundoplication can be an effective treatment for patients seeking to alleviate symptoms associated with gastroesophageal reflux disease, particularly in individuals with persistent regurgitation despite prior treatment with proton pump inhibitor therapy, according to the results of a new study published in the February issue of Gastroenterology (doi:10.1053/j.gastro.2014.10.009).
“Gastroesophageal reflux disease (GERD) remains one of the most common conditions for which Americans take daily medication, and PPI use has more than doubled in the last decade,” wrote lead authors Dr. John G. Hunter of Oregon Health & Science University in Portland, and Dr. Peter J. Kahrilas of Northwestern University in Chicago, and their associates. “Despite this, up to 40% of proton pump inhibitor (PPI)–dependent GERD patients have troublesome symptoms of GERD, despite PPI therapy.”
In the Randomized EsophyX vs Sham, Placebo-Controlled Transoral Fundoplication (RESPECT) trial, investigators screened 696 patients who were experiencing “troublesome regurgitation” despite daily PPI treatment. These subjects were evaluated via three validated GERD-specific symptom scales, and were either on or off PPI use at the time of trial commencement. Post trial, patients were blinded to therapy and were reassessed at intervals of 2, 12, and 26 weeks. All patients underwent 48-hour esophageal pH monitoring and esophagogastroduodenoscopy at 66 months after the trial ended.
Regurgitation severity was based on the Montreal definition, which was used to measure efficacy of treatments given as part of the study. The Montreal definition of reflux is described by the authors as “either mucosal damage or troublesome symptoms attributable to reflux.” Those with “least troublesome” regurgitation while on PPIs “underwent barium swallow, esophagogastroduodenoscopy, 48-hour esophageal pH monitoring (off PPIs), and high-resolution esophageal manometry analyses.”
Eighty-seven subjects with GERD and hiatal hernias of at least 2 centimeters were randomly assigned to groups that underwent transoral fundoplication (TF) followed by placebo treatment after 6 months, while 42 subjects, who made up the control group, underwent a “sham surgery” and began regimens of once- or twice-daily omeprazole medication for 6 months.
Results showed that 67% of patients who received TF treatment experienced elimination of adverse regurgitation vs. 45% of those treated with PPI (P = .023). Control of esophageal pH also improved noticeably in patients who received TF treatment versus those who did not (9.3% vs. 6.3% on average, respectively, P < .001), but not in patients who received the “sham surgery” (8.6% preop vs. 8.9% postop on average). Fewer patients who received TF treatment recorded having “no response” after 3 months compared with those in the control group (11% vs. 36%, respectively, P = .004).
“Transoral fundoplication may fill the ‘therapeutic gap’ that exists between PPI and laparoscopic fundoplication,” wrote the authors. “Considering the virtual absence of dysphagia and bloating after TF, which may be problematic with LINX [LINX Reflux Management System], it would appear that TF is an option for patients with troublesome regurgitation, as well as for patients with troublesome GERD symptoms who wish not to take PPI over a protracted period of time.”
Several coauthors disclosed ties with the study sponsor EndoGastric Solutions of Redmond, Wash., as well as individual potential conflicts of interest.
Transoral esophagogastric fundoplication can be an effective treatment for patients seeking to alleviate symptoms associated with gastroesophageal reflux disease, particularly in individuals with persistent regurgitation despite prior treatment with proton pump inhibitor therapy, according to the results of a new study published in the February issue of Gastroenterology (doi:10.1053/j.gastro.2014.10.009).
“Gastroesophageal reflux disease (GERD) remains one of the most common conditions for which Americans take daily medication, and PPI use has more than doubled in the last decade,” wrote lead authors Dr. John G. Hunter of Oregon Health & Science University in Portland, and Dr. Peter J. Kahrilas of Northwestern University in Chicago, and their associates. “Despite this, up to 40% of proton pump inhibitor (PPI)–dependent GERD patients have troublesome symptoms of GERD, despite PPI therapy.”
In the Randomized EsophyX vs Sham, Placebo-Controlled Transoral Fundoplication (RESPECT) trial, investigators screened 696 patients who were experiencing “troublesome regurgitation” despite daily PPI treatment. These subjects were evaluated via three validated GERD-specific symptom scales, and were either on or off PPI use at the time of trial commencement. Post trial, patients were blinded to therapy and were reassessed at intervals of 2, 12, and 26 weeks. All patients underwent 48-hour esophageal pH monitoring and esophagogastroduodenoscopy at 66 months after the trial ended.
Regurgitation severity was based on the Montreal definition, which was used to measure efficacy of treatments given as part of the study. The Montreal definition of reflux is described by the authors as “either mucosal damage or troublesome symptoms attributable to reflux.” Those with “least troublesome” regurgitation while on PPIs “underwent barium swallow, esophagogastroduodenoscopy, 48-hour esophageal pH monitoring (off PPIs), and high-resolution esophageal manometry analyses.”
Eighty-seven subjects with GERD and hiatal hernias of at least 2 centimeters were randomly assigned to groups that underwent transoral fundoplication (TF) followed by placebo treatment after 6 months, while 42 subjects, who made up the control group, underwent a “sham surgery” and began regimens of once- or twice-daily omeprazole medication for 6 months.
Results showed that 67% of patients who received TF treatment experienced elimination of adverse regurgitation vs. 45% of those treated with PPI (P = .023). Control of esophageal pH also improved noticeably in patients who received TF treatment versus those who did not (9.3% vs. 6.3% on average, respectively, P < .001), but not in patients who received the “sham surgery” (8.6% preop vs. 8.9% postop on average). Fewer patients who received TF treatment recorded having “no response” after 3 months compared with those in the control group (11% vs. 36%, respectively, P = .004).
“Transoral fundoplication may fill the ‘therapeutic gap’ that exists between PPI and laparoscopic fundoplication,” wrote the authors. “Considering the virtual absence of dysphagia and bloating after TF, which may be problematic with LINX [LINX Reflux Management System], it would appear that TF is an option for patients with troublesome regurgitation, as well as for patients with troublesome GERD symptoms who wish not to take PPI over a protracted period of time.”
Several coauthors disclosed ties with the study sponsor EndoGastric Solutions of Redmond, Wash., as well as individual potential conflicts of interest.
Transoral esophagogastric fundoplication can be an effective treatment for patients seeking to alleviate symptoms associated with gastroesophageal reflux disease, particularly in individuals with persistent regurgitation despite prior treatment with proton pump inhibitor therapy, according to the results of a new study published in the February issue of Gastroenterology (doi:10.1053/j.gastro.2014.10.009).
“Gastroesophageal reflux disease (GERD) remains one of the most common conditions for which Americans take daily medication, and PPI use has more than doubled in the last decade,” wrote lead authors Dr. John G. Hunter of Oregon Health & Science University in Portland, and Dr. Peter J. Kahrilas of Northwestern University in Chicago, and their associates. “Despite this, up to 40% of proton pump inhibitor (PPI)–dependent GERD patients have troublesome symptoms of GERD, despite PPI therapy.”
In the Randomized EsophyX vs Sham, Placebo-Controlled Transoral Fundoplication (RESPECT) trial, investigators screened 696 patients who were experiencing “troublesome regurgitation” despite daily PPI treatment. These subjects were evaluated via three validated GERD-specific symptom scales, and were either on or off PPI use at the time of trial commencement. Post trial, patients were blinded to therapy and were reassessed at intervals of 2, 12, and 26 weeks. All patients underwent 48-hour esophageal pH monitoring and esophagogastroduodenoscopy at 66 months after the trial ended.
Regurgitation severity was based on the Montreal definition, which was used to measure efficacy of treatments given as part of the study. The Montreal definition of reflux is described by the authors as “either mucosal damage or troublesome symptoms attributable to reflux.” Those with “least troublesome” regurgitation while on PPIs “underwent barium swallow, esophagogastroduodenoscopy, 48-hour esophageal pH monitoring (off PPIs), and high-resolution esophageal manometry analyses.”
Eighty-seven subjects with GERD and hiatal hernias of at least 2 centimeters were randomly assigned to groups that underwent transoral fundoplication (TF) followed by placebo treatment after 6 months, while 42 subjects, who made up the control group, underwent a “sham surgery” and began regimens of once- or twice-daily omeprazole medication for 6 months.
Results showed that 67% of patients who received TF treatment experienced elimination of adverse regurgitation vs. 45% of those treated with PPI (P = .023). Control of esophageal pH also improved noticeably in patients who received TF treatment versus those who did not (9.3% vs. 6.3% on average, respectively, P < .001), but not in patients who received the “sham surgery” (8.6% preop vs. 8.9% postop on average). Fewer patients who received TF treatment recorded having “no response” after 3 months compared with those in the control group (11% vs. 36%, respectively, P = .004).
“Transoral fundoplication may fill the ‘therapeutic gap’ that exists between PPI and laparoscopic fundoplication,” wrote the authors. “Considering the virtual absence of dysphagia and bloating after TF, which may be problematic with LINX [LINX Reflux Management System], it would appear that TF is an option for patients with troublesome regurgitation, as well as for patients with troublesome GERD symptoms who wish not to take PPI over a protracted period of time.”
Several coauthors disclosed ties with the study sponsor EndoGastric Solutions of Redmond, Wash., as well as individual potential conflicts of interest.
FROM GASTROENTEROLOGY
Key clinical point: Transoral esophagogastric fundoplication (TF) is an effective treatment for gastroesophageal reflux disease symptoms, particularly in patients with persistent regurgitation despite proton pump inhibitor therapy (PPI).
Major finding: Of patients who received TF, 67% experienced elimination of adverse regurgitation, compared with 45% of those treated with PPI (P = .023).
Data source: Randomized EsophyX vs Sham, Placebo-Controlled Transoral Fundoplication (RESPECT) trial.
Disclosures: Several coauthors disclosed ties with the study sponsor EndoGastric Solutions of Redmond, Wash., as well as individual potential conflicts of interest.
Sofosbuvir and ribavirin critical to preventing posttransplantation HCV recurrence
Sofosbuvir and ribavirin treatments should be administered to patients with hepatitis C virus who undergo liver transplantations in order to significantly decrease the risks of posttransplant HCV recurrence, according to two new studies published in the January issue of Gastroenterology (10.1053/j.gastro.2014.09.023 and 10.1053/j.gastro.2014.10.001).
“In clinical trials, administration of sofosbuvir with ribavirin was associated with rapid decreases of HCV RNA to undetectable levels in patients with HCV genotype 1, 2, 3, 4, and 6 infections,” wrote lead author Dr. Michael P. Curry of the Beth Israel Deaconess Medical Center in Boston, and his coauthors on the first of these two studies. “In more than 3,000 patients treated to date, sofosbuvir has been shown to be safe, viral breakthrough during treatment has been rare (and associated with nonadherence), and few drug interactions have been observed.”
In a phase II, open-label study, Dr. Curry and his coinvestigators enrolled 61 patients with HCV of any genotype, and cirrhosis with a Child-Turcotte-Pugh score no greater than 7, who were all wait-listed to receive liver transplantations. Subjects received up to 48 weeks of treatment with 400 mg of sofosbuvir, and a separate dose of ribavirin prior to liver transplantation, while 43 patients received transplantations alone. The primary outcome sought by investigators was HCV-RNA levels less than 25 IU/mL at 12 weeks after transplantation among patients that had this level prior to the operation.
The investigators found that 43 subjects had the desired HCV-RNA levels; of that population, 49% had a posttransplantation virologic response, with the most frequent side effects reported by subjects being fatigue (38%), headache (23%), and anemia (21%). Of the 43 applicable subjects, 30 (70% of the population) had a posttransplantation virologic response at 12 weeks, 10 (23%) had recurrent infection, and 3 (7%) died.
“This study provides proof of concept that virologic suppression without interferon significantly can reduce the rate of recurrent HCV after liver transplantation,” the study says, adding that the results “compare favorably with those observed in other trials of pretransplantation antiviral therapy.”
In the second study, the authors ascertained that combination therapy consisting of sofosbuvir and ribavirin for 24 weeks is effective at preventing hepatitis C virus recurrence in patients who undergo liver transplantations.
“Recurrent HCV infection is the most common cause of mortality and graft loss following transplantation, and up to 30% of patients with recurrent infection develop cirrhosis within 5 years,” wrote the study’s authors, led by Dr. Michael Charlton of the Mayo Clinic in Rochester, Minn.
Using a prospective, multicenter, open-label pilot study, investigators enrolled and treated 40 patients with a 24-week regimen of 400 mg sofosbuvir and ribavirin starting at 400 mg, which was subsequently adjusted per patient based on individual creatinine clearance and hemoglobin levels. Subjects were 78% male and 85% white, with 83% having HCV genotype 1, 40% having cirrhosis, and 88% having been previously treated with interferon. The primary outcome investigators looked for was “sustained virologic response 12 weeks after treatment (SVR12).”
Data showed that SVR12 was achieved by 28 of the 40 subjects that received treatment, or 70%. The most commonly reported adverse effects were fatigue (30%), diarrhea (28%), headache (25%), and anemia (20%). No patients exhibited detectable viral resistance during or after treatment, and although two patients terminated their treatment because of adverse events, investigators reported no deaths, graft losses, or episodes of rejection.
“In contrast,” Dr. Charlton and his coauthors noted, “interferon-based treatments have been associated with posttreatment immunological dysfunction (particularly plasma cell hepatitis) and even hepatic decompensation in LT [liver transplant] recipients.”
The authors of the first study disclosed that Dr. Curry has received grants from and been affiliated with Gilead, which was a sponsor of the study. The authors of the second study reported no relevant financial disclosures.
Sofosbuvir and ribavirin treatments should be administered to patients with hepatitis C virus who undergo liver transplantations in order to significantly decrease the risks of posttransplant HCV recurrence, according to two new studies published in the January issue of Gastroenterology (10.1053/j.gastro.2014.09.023 and 10.1053/j.gastro.2014.10.001).
“In clinical trials, administration of sofosbuvir with ribavirin was associated with rapid decreases of HCV RNA to undetectable levels in patients with HCV genotype 1, 2, 3, 4, and 6 infections,” wrote lead author Dr. Michael P. Curry of the Beth Israel Deaconess Medical Center in Boston, and his coauthors on the first of these two studies. “In more than 3,000 patients treated to date, sofosbuvir has been shown to be safe, viral breakthrough during treatment has been rare (and associated with nonadherence), and few drug interactions have been observed.”
In a phase II, open-label study, Dr. Curry and his coinvestigators enrolled 61 patients with HCV of any genotype, and cirrhosis with a Child-Turcotte-Pugh score no greater than 7, who were all wait-listed to receive liver transplantations. Subjects received up to 48 weeks of treatment with 400 mg of sofosbuvir, and a separate dose of ribavirin prior to liver transplantation, while 43 patients received transplantations alone. The primary outcome sought by investigators was HCV-RNA levels less than 25 IU/mL at 12 weeks after transplantation among patients that had this level prior to the operation.
The investigators found that 43 subjects had the desired HCV-RNA levels; of that population, 49% had a posttransplantation virologic response, with the most frequent side effects reported by subjects being fatigue (38%), headache (23%), and anemia (21%). Of the 43 applicable subjects, 30 (70% of the population) had a posttransplantation virologic response at 12 weeks, 10 (23%) had recurrent infection, and 3 (7%) died.
“This study provides proof of concept that virologic suppression without interferon significantly can reduce the rate of recurrent HCV after liver transplantation,” the study says, adding that the results “compare favorably with those observed in other trials of pretransplantation antiviral therapy.”
In the second study, the authors ascertained that combination therapy consisting of sofosbuvir and ribavirin for 24 weeks is effective at preventing hepatitis C virus recurrence in patients who undergo liver transplantations.
“Recurrent HCV infection is the most common cause of mortality and graft loss following transplantation, and up to 30% of patients with recurrent infection develop cirrhosis within 5 years,” wrote the study’s authors, led by Dr. Michael Charlton of the Mayo Clinic in Rochester, Minn.
Using a prospective, multicenter, open-label pilot study, investigators enrolled and treated 40 patients with a 24-week regimen of 400 mg sofosbuvir and ribavirin starting at 400 mg, which was subsequently adjusted per patient based on individual creatinine clearance and hemoglobin levels. Subjects were 78% male and 85% white, with 83% having HCV genotype 1, 40% having cirrhosis, and 88% having been previously treated with interferon. The primary outcome investigators looked for was “sustained virologic response 12 weeks after treatment (SVR12).”
Data showed that SVR12 was achieved by 28 of the 40 subjects that received treatment, or 70%. The most commonly reported adverse effects were fatigue (30%), diarrhea (28%), headache (25%), and anemia (20%). No patients exhibited detectable viral resistance during or after treatment, and although two patients terminated their treatment because of adverse events, investigators reported no deaths, graft losses, or episodes of rejection.
“In contrast,” Dr. Charlton and his coauthors noted, “interferon-based treatments have been associated with posttreatment immunological dysfunction (particularly plasma cell hepatitis) and even hepatic decompensation in LT [liver transplant] recipients.”
The authors of the first study disclosed that Dr. Curry has received grants from and been affiliated with Gilead, which was a sponsor of the study. The authors of the second study reported no relevant financial disclosures.
Sofosbuvir and ribavirin treatments should be administered to patients with hepatitis C virus who undergo liver transplantations in order to significantly decrease the risks of posttransplant HCV recurrence, according to two new studies published in the January issue of Gastroenterology (10.1053/j.gastro.2014.09.023 and 10.1053/j.gastro.2014.10.001).
“In clinical trials, administration of sofosbuvir with ribavirin was associated with rapid decreases of HCV RNA to undetectable levels in patients with HCV genotype 1, 2, 3, 4, and 6 infections,” wrote lead author Dr. Michael P. Curry of the Beth Israel Deaconess Medical Center in Boston, and his coauthors on the first of these two studies. “In more than 3,000 patients treated to date, sofosbuvir has been shown to be safe, viral breakthrough during treatment has been rare (and associated with nonadherence), and few drug interactions have been observed.”
In a phase II, open-label study, Dr. Curry and his coinvestigators enrolled 61 patients with HCV of any genotype, and cirrhosis with a Child-Turcotte-Pugh score no greater than 7, who were all wait-listed to receive liver transplantations. Subjects received up to 48 weeks of treatment with 400 mg of sofosbuvir, and a separate dose of ribavirin prior to liver transplantation, while 43 patients received transplantations alone. The primary outcome sought by investigators was HCV-RNA levels less than 25 IU/mL at 12 weeks after transplantation among patients that had this level prior to the operation.
The investigators found that 43 subjects had the desired HCV-RNA levels; of that population, 49% had a posttransplantation virologic response, with the most frequent side effects reported by subjects being fatigue (38%), headache (23%), and anemia (21%). Of the 43 applicable subjects, 30 (70% of the population) had a posttransplantation virologic response at 12 weeks, 10 (23%) had recurrent infection, and 3 (7%) died.
“This study provides proof of concept that virologic suppression without interferon significantly can reduce the rate of recurrent HCV after liver transplantation,” the study says, adding that the results “compare favorably with those observed in other trials of pretransplantation antiviral therapy.”
In the second study, the authors ascertained that combination therapy consisting of sofosbuvir and ribavirin for 24 weeks is effective at preventing hepatitis C virus recurrence in patients who undergo liver transplantations.
“Recurrent HCV infection is the most common cause of mortality and graft loss following transplantation, and up to 30% of patients with recurrent infection develop cirrhosis within 5 years,” wrote the study’s authors, led by Dr. Michael Charlton of the Mayo Clinic in Rochester, Minn.
Using a prospective, multicenter, open-label pilot study, investigators enrolled and treated 40 patients with a 24-week regimen of 400 mg sofosbuvir and ribavirin starting at 400 mg, which was subsequently adjusted per patient based on individual creatinine clearance and hemoglobin levels. Subjects were 78% male and 85% white, with 83% having HCV genotype 1, 40% having cirrhosis, and 88% having been previously treated with interferon. The primary outcome investigators looked for was “sustained virologic response 12 weeks after treatment (SVR12).”
Data showed that SVR12 was achieved by 28 of the 40 subjects that received treatment, or 70%. The most commonly reported adverse effects were fatigue (30%), diarrhea (28%), headache (25%), and anemia (20%). No patients exhibited detectable viral resistance during or after treatment, and although two patients terminated their treatment because of adverse events, investigators reported no deaths, graft losses, or episodes of rejection.
“In contrast,” Dr. Charlton and his coauthors noted, “interferon-based treatments have been associated with posttreatment immunological dysfunction (particularly plasma cell hepatitis) and even hepatic decompensation in LT [liver transplant] recipients.”
The authors of the first study disclosed that Dr. Curry has received grants from and been affiliated with Gilead, which was a sponsor of the study. The authors of the second study reported no relevant financial disclosures.
FROM GASTROENTEROLOGY
Visible light spectrography should be used in diagnosing chronic gastrointestinal ischemia
Using visible light spectrography in the diagnosis of patients with suspected chronic gastrointestinal ischemia can lead to more accurate diagnoses, more-effective treatment regimens, and, ultimately, longer-lasting positive results, according to a new study published in the January issue of Clinical Gastroenterology and Hepatology (doi: 10.1016/j.cgh.2014.07.012).
“Medical history and physical examination were poor predictors for the presence of CGI [chronic gastrointestinal ischemia] [but] addition of radiologic evaluation [and] functional testing by means of tonometry substantially improved the accuracy of diagnosis,” said study leader Dr. Aria Sana of Utrecht University in the Netherlands.
The authors added that “VLS [Visible light spectrography] has recently been introduced as a new minimally invasive technique to detect mucosal hypoxia by means of measurement of mucosal capillary hemoglobin oxygen saturation during endoscopy in patients clinically suspected of CGI.”
In a prospective study, Dr. Sana and her associates gathered data on 212 patients referred to their medical center between November 2008 through January 2011 for suspected CGI. Subjects underwent visualization of gastrointestinal arteries and assessments of mucosal perfusion via VLS; those found to have occlusive CGI were followed-up after a median 13 months’ time to assess their response to treatment.
Of the 212 subjects initially screened, 107 (50%) were found to have occlusive CGI. Of that population, 96 (90%) were offered treatment, of which 89 (93%) were available to provide follow-up data after the median time of 13 months.
Investigators found that 62 subjects (70% of the 89 who reported after the follow-up period) had sustained responses to treatment that they were prescribed as a result of VLS and visualization-based diagnoses. Furthermore, patients who displayed weight loss, abdominal bruit, and low corpus mucosal saturation were found most likely to respond to treatment, particularly the latter – corpus saturation level of less than 56% was “one of the strongest predictors of a positive treatment response” investigators found.
“The presence of [at least] two predictors or the absence of any predictor was of discriminative value with [greater than] 85% vs. [less than] 50% response rate, respectively, suggesting patients with a predicted response rate of < 50% should primarily be considered for conservative management,” Dr. Sana and her coinvestigators noted.
The authors disclosed no conflicts of any kind.
In this study from the Netherlands, the authors used visible light spectroscopy (VLS) to diagnose chronic gastrointestinal ischemia (CGI) and to predict its response to surgical or endoscopic treatment; a challenging task indeed. Diagnosis of CGI is difficult because the classic symptom complex of meal-precipitated abdominal pain leading to weight loss is nonspecific; asymptomatic splanchnic vascular obstruction is not uncommon in the general population with autopsy series showing significant stenosis of the celiac, superior mesenteric, and inferior mesenteric arteries of 50%, 30%, and 30%, respectively; radiologic imaging tests conventionally used to diagnose CGI evaluate only vascular anatomy and not physiologic parameters of ischemia, i.e., intracellular acidosis (which can be evaluated by balloon tonometry) nor mucosal hemoglobin oxygen saturation, which is determined by VLS.
The authors evaluated 212 patients referred for suspected CGI and in all performed radiologic imaging of the splanchnic vessels and assessment of mucosal perfusion by VLS. Obstructive CGI (OCGI)was diagnosed by a multidisciplinary team and required clinical agreement, significant stenosis of at least one splanchnic artery and mucosal ischemia as determined by VLS. OCGI was classified as single- or multivessel and patients were offered surgical or endovascular revascularization. Response to treatment was then evaluated in patients with OCGI. A total of 107 patients were diagnosed with OCGI and data on response to treatment was available in 89 with a median follow-up of 13 months. Sustained symptomatic response was seen in 62 (70%) and most strongly predicted by the presence of weight loss, an abdominal bruit, and a gastric corpus mucosal saturation level of < 56%. This is an important study because it stresses the value of a team approach to diagnosis and the use of a combination of techniques to evaluate vascular obstruction and its functional significance.
There were several shortcomings of the study, in my opinion, although these do not lessen the importance of the study’s message. Most important, the study was not blinded. Spontaneous resolution of symptoms was noted in 19 patients without OCGI and in an additional 9 patients treated with a variety of medical and surgical means. Celiac artery compression release relieved symptoms in 17 patients, although the ischemic nature of this entity is arguable. Repeat VLS was not performed in all patients. Finally, clinical follow-up was relatively short and long-term follow-up was mainly by questionnaire, leading to another source of bias. To perform fiber-optic catheter-based VLS oximetry during esophagogastroduodenoscopy in a consistent fashion is technically challenging but probably worthwhile to learn. The authors continue to shine light on this relatively dark and poorly illuminated subject matter; let it shine, let it shine, let it shine.
Dr. Lawrence J. Brandt, MACG, AGAF, FASGE, is a professor of medicine and surgery at the Albert Einstein College of Medicine, N.Y., and emeritus chief, division of gastroenterology, Montefiore Medical Center, Bronx, N.Y.
In this study from the Netherlands, the authors used visible light spectroscopy (VLS) to diagnose chronic gastrointestinal ischemia (CGI) and to predict its response to surgical or endoscopic treatment; a challenging task indeed. Diagnosis of CGI is difficult because the classic symptom complex of meal-precipitated abdominal pain leading to weight loss is nonspecific; asymptomatic splanchnic vascular obstruction is not uncommon in the general population with autopsy series showing significant stenosis of the celiac, superior mesenteric, and inferior mesenteric arteries of 50%, 30%, and 30%, respectively; radiologic imaging tests conventionally used to diagnose CGI evaluate only vascular anatomy and not physiologic parameters of ischemia, i.e., intracellular acidosis (which can be evaluated by balloon tonometry) nor mucosal hemoglobin oxygen saturation, which is determined by VLS.
The authors evaluated 212 patients referred for suspected CGI and in all performed radiologic imaging of the splanchnic vessels and assessment of mucosal perfusion by VLS. Obstructive CGI (OCGI)was diagnosed by a multidisciplinary team and required clinical agreement, significant stenosis of at least one splanchnic artery and mucosal ischemia as determined by VLS. OCGI was classified as single- or multivessel and patients were offered surgical or endovascular revascularization. Response to treatment was then evaluated in patients with OCGI. A total of 107 patients were diagnosed with OCGI and data on response to treatment was available in 89 with a median follow-up of 13 months. Sustained symptomatic response was seen in 62 (70%) and most strongly predicted by the presence of weight loss, an abdominal bruit, and a gastric corpus mucosal saturation level of < 56%. This is an important study because it stresses the value of a team approach to diagnosis and the use of a combination of techniques to evaluate vascular obstruction and its functional significance.
There were several shortcomings of the study, in my opinion, although these do not lessen the importance of the study’s message. Most important, the study was not blinded. Spontaneous resolution of symptoms was noted in 19 patients without OCGI and in an additional 9 patients treated with a variety of medical and surgical means. Celiac artery compression release relieved symptoms in 17 patients, although the ischemic nature of this entity is arguable. Repeat VLS was not performed in all patients. Finally, clinical follow-up was relatively short and long-term follow-up was mainly by questionnaire, leading to another source of bias. To perform fiber-optic catheter-based VLS oximetry during esophagogastroduodenoscopy in a consistent fashion is technically challenging but probably worthwhile to learn. The authors continue to shine light on this relatively dark and poorly illuminated subject matter; let it shine, let it shine, let it shine.
Dr. Lawrence J. Brandt, MACG, AGAF, FASGE, is a professor of medicine and surgery at the Albert Einstein College of Medicine, N.Y., and emeritus chief, division of gastroenterology, Montefiore Medical Center, Bronx, N.Y.
In this study from the Netherlands, the authors used visible light spectroscopy (VLS) to diagnose chronic gastrointestinal ischemia (CGI) and to predict its response to surgical or endoscopic treatment; a challenging task indeed. Diagnosis of CGI is difficult because the classic symptom complex of meal-precipitated abdominal pain leading to weight loss is nonspecific; asymptomatic splanchnic vascular obstruction is not uncommon in the general population with autopsy series showing significant stenosis of the celiac, superior mesenteric, and inferior mesenteric arteries of 50%, 30%, and 30%, respectively; radiologic imaging tests conventionally used to diagnose CGI evaluate only vascular anatomy and not physiologic parameters of ischemia, i.e., intracellular acidosis (which can be evaluated by balloon tonometry) nor mucosal hemoglobin oxygen saturation, which is determined by VLS.
The authors evaluated 212 patients referred for suspected CGI and in all performed radiologic imaging of the splanchnic vessels and assessment of mucosal perfusion by VLS. Obstructive CGI (OCGI)was diagnosed by a multidisciplinary team and required clinical agreement, significant stenosis of at least one splanchnic artery and mucosal ischemia as determined by VLS. OCGI was classified as single- or multivessel and patients were offered surgical or endovascular revascularization. Response to treatment was then evaluated in patients with OCGI. A total of 107 patients were diagnosed with OCGI and data on response to treatment was available in 89 with a median follow-up of 13 months. Sustained symptomatic response was seen in 62 (70%) and most strongly predicted by the presence of weight loss, an abdominal bruit, and a gastric corpus mucosal saturation level of < 56%. This is an important study because it stresses the value of a team approach to diagnosis and the use of a combination of techniques to evaluate vascular obstruction and its functional significance.
There were several shortcomings of the study, in my opinion, although these do not lessen the importance of the study’s message. Most important, the study was not blinded. Spontaneous resolution of symptoms was noted in 19 patients without OCGI and in an additional 9 patients treated with a variety of medical and surgical means. Celiac artery compression release relieved symptoms in 17 patients, although the ischemic nature of this entity is arguable. Repeat VLS was not performed in all patients. Finally, clinical follow-up was relatively short and long-term follow-up was mainly by questionnaire, leading to another source of bias. To perform fiber-optic catheter-based VLS oximetry during esophagogastroduodenoscopy in a consistent fashion is technically challenging but probably worthwhile to learn. The authors continue to shine light on this relatively dark and poorly illuminated subject matter; let it shine, let it shine, let it shine.
Dr. Lawrence J. Brandt, MACG, AGAF, FASGE, is a professor of medicine and surgery at the Albert Einstein College of Medicine, N.Y., and emeritus chief, division of gastroenterology, Montefiore Medical Center, Bronx, N.Y.
Using visible light spectrography in the diagnosis of patients with suspected chronic gastrointestinal ischemia can lead to more accurate diagnoses, more-effective treatment regimens, and, ultimately, longer-lasting positive results, according to a new study published in the January issue of Clinical Gastroenterology and Hepatology (doi: 10.1016/j.cgh.2014.07.012).
“Medical history and physical examination were poor predictors for the presence of CGI [chronic gastrointestinal ischemia] [but] addition of radiologic evaluation [and] functional testing by means of tonometry substantially improved the accuracy of diagnosis,” said study leader Dr. Aria Sana of Utrecht University in the Netherlands.
The authors added that “VLS [Visible light spectrography] has recently been introduced as a new minimally invasive technique to detect mucosal hypoxia by means of measurement of mucosal capillary hemoglobin oxygen saturation during endoscopy in patients clinically suspected of CGI.”
In a prospective study, Dr. Sana and her associates gathered data on 212 patients referred to their medical center between November 2008 through January 2011 for suspected CGI. Subjects underwent visualization of gastrointestinal arteries and assessments of mucosal perfusion via VLS; those found to have occlusive CGI were followed-up after a median 13 months’ time to assess their response to treatment.
Of the 212 subjects initially screened, 107 (50%) were found to have occlusive CGI. Of that population, 96 (90%) were offered treatment, of which 89 (93%) were available to provide follow-up data after the median time of 13 months.
Investigators found that 62 subjects (70% of the 89 who reported after the follow-up period) had sustained responses to treatment that they were prescribed as a result of VLS and visualization-based diagnoses. Furthermore, patients who displayed weight loss, abdominal bruit, and low corpus mucosal saturation were found most likely to respond to treatment, particularly the latter – corpus saturation level of less than 56% was “one of the strongest predictors of a positive treatment response” investigators found.
“The presence of [at least] two predictors or the absence of any predictor was of discriminative value with [greater than] 85% vs. [less than] 50% response rate, respectively, suggesting patients with a predicted response rate of < 50% should primarily be considered for conservative management,” Dr. Sana and her coinvestigators noted.
The authors disclosed no conflicts of any kind.
Using visible light spectrography in the diagnosis of patients with suspected chronic gastrointestinal ischemia can lead to more accurate diagnoses, more-effective treatment regimens, and, ultimately, longer-lasting positive results, according to a new study published in the January issue of Clinical Gastroenterology and Hepatology (doi: 10.1016/j.cgh.2014.07.012).
“Medical history and physical examination were poor predictors for the presence of CGI [chronic gastrointestinal ischemia] [but] addition of radiologic evaluation [and] functional testing by means of tonometry substantially improved the accuracy of diagnosis,” said study leader Dr. Aria Sana of Utrecht University in the Netherlands.
The authors added that “VLS [Visible light spectrography] has recently been introduced as a new minimally invasive technique to detect mucosal hypoxia by means of measurement of mucosal capillary hemoglobin oxygen saturation during endoscopy in patients clinically suspected of CGI.”
In a prospective study, Dr. Sana and her associates gathered data on 212 patients referred to their medical center between November 2008 through January 2011 for suspected CGI. Subjects underwent visualization of gastrointestinal arteries and assessments of mucosal perfusion via VLS; those found to have occlusive CGI were followed-up after a median 13 months’ time to assess their response to treatment.
Of the 212 subjects initially screened, 107 (50%) were found to have occlusive CGI. Of that population, 96 (90%) were offered treatment, of which 89 (93%) were available to provide follow-up data after the median time of 13 months.
Investigators found that 62 subjects (70% of the 89 who reported after the follow-up period) had sustained responses to treatment that they were prescribed as a result of VLS and visualization-based diagnoses. Furthermore, patients who displayed weight loss, abdominal bruit, and low corpus mucosal saturation were found most likely to respond to treatment, particularly the latter – corpus saturation level of less than 56% was “one of the strongest predictors of a positive treatment response” investigators found.
“The presence of [at least] two predictors or the absence of any predictor was of discriminative value with [greater than] 85% vs. [less than] 50% response rate, respectively, suggesting patients with a predicted response rate of < 50% should primarily be considered for conservative management,” Dr. Sana and her coinvestigators noted.
The authors disclosed no conflicts of any kind.
FROM CLINICAL GASTROENTEROLOGY AND HEPATOLOGY
Key clinical point: Diagnosis of chronic gastrointestinal ischemia (CGI) via visible light spectrography (VLS) can lead to more effective treatment methods that yield longer-term results.
Major finding: Of patients diagnosed with CGI via VLS, 70% reported sustained responses to treatment after 13 months.
Data source: A prospective study.
Disclosures: The authors reported no conflicts.
Identification of subtypes, mutations in CRC and colon cancer greatly increases survival rates
Identifying subtypes and tumor mutations in patients with colorectal and stage III colon cancer can significantly improve survival rates, according to two new studies published in the January issue of Gastroenterology (doi:10.1053/j.gastro.2014.09.038 and doi:10.1053/j.gastro.2014.09.041).
In the first study, researchers found that etiologically defined subtypes of colorectal cancer are characterized by marked differences in survival rates and confirmed the clinical importance of studying the molecular heterogeneity of the disease.
“Increasing evidence indicates that colorectal cancer (CRC) is a biologically heterogeneous disease that can develop via a number of distinct pathways involving different combinations of genetic and epigenetic changes,” wrote Amanda Phipps, Ph.D, of the University of Washington in Seattle, and her coinvestigators, adding that “the biologic distinctions between CRC subtypes resulting from different etiologic pathways may plausibly translate to differences in survival.”
Between 1998 and 2007, 2,706 participants were enrolled for this study through the population-based Seattle Colon Cancer Family Registry and followed for survival through 2012. Of those, 2,050 had tumor samples collected from them, each of which was classified into one of five subtypes based on tumor markers: type 1 (microsatellite instability [MSI] high, CpG island methylator phenotype [CIMP] positive, positive for BRAF mutation, negative for KRAS mutation); type 2 (microsatellite stable [MSS] or MSI-low, CIMPpositive, positive for BRAF mutation, negative for KRAS mutation); type 3 (MSS or MSI-low, non-CIMP, negative for BRAF mutation, positive for KRAS mutation); type 4 (MSS or MSI-low, non-CIMP, negative for mutations in BRAF and KRAS); and type 5 (MSI-high, non-CIMP, negative for mutations in BRAF and KRAS).
To analyze data, Cox regression models were used to estimate hazard ratios, 95% confidence intervals, and associations for each subtype with specific diseases and overall mortality, all of which were adjusted for age, sex, body mass, diagnosis year, and smoking history.
Results indicated that type 4 tumors were the most predominant, but subjects with type 2 tumors had the highest disease-specific mortality (hazard ratio = 2.20) and subjects with type 3 tumors also had unusually high disease-specific mortality (HR = 1.32). Type 5 tumors were associated with the lowest disease-specific mortality (HR = 0.30). Associations with overall mortality were similar to those with disease-specific mortality.
“These findings contribute to a small but growing literature supporting the significance of CRC-subtype classifications defined by combinations of these tumor markers,” the authors noted.
The second study’s results indicate that patients suffering from stage III colon cancer who have MMR-proficient tumors and mutations in BRAF (V600E) or KRAS had shorter survival times than patients whose tumors lacked these specific mutations.
“Defining [CRC] tumor subtypes based upon pathway-driven alterations has the potential to improve prognostication and guide targeted therapy,” wrote Dr. Frank Sinicrope of the Mayo Clinic in Rochester, Minn., and his associates.
Investigators collected 2,720 tumor samples from stage III cancer patients and detected mutations in BRAF (V600E) and KRAS using a polymerase chain reaction–based assay, and tumors deficient or proficient in DNA mismatch repair (MMR) via detection of MLH1, MSH2, and MSH6 proteins and methylation of the MLH1 promoter. Investigators used a separate sample of tumors, taken from 783 stage III cancer patients, to validate their findings, and employed the Cox proportional hazards model to evaluate associations between tumors and 5-year disease-free survival rates.
Tumors were divided into five subtypes, three of which were MMR proficient – those with BRAFV600E (6.9% of samples), mutations in KRAS (35%), or tumors lacking either BRAFV600E or mutations in KRAS (49%) – and two of which were MMR deficient: the sporadic type (6.8%) with BRAFV600E or hypermethylation of MLH1, and the familial type (2.6%), which lacked BRAFV600E or hypermethylation of MLH1.
The data accumulated by Dr. Sinicrope and his coinvestigators showed that more MMR-proficient tumors with BRAFV600E than MMR-proficient tumors without BRAFV600E or mutations in KRAS were proximal, high grade, N2, and prevalent in female subjects: 76% vs. 33%, 44% vs. 19%, 59% vs. 41%, and 59% vs. 42%, respectively (overall P < .0001).
Furthermore, a “significantly lower proportion” of patients having MMR-proficient tumors with BRAFV600E (HR 1.43; adjusted P = .0065) or mutant KRAS (HR 1.48; adjusted P < .0001) survived disease free for 5 years, compared with those whose MMR-proficient tumors lacked mutations in either gene.
“We found that a biomarker-based classifier can identify prognostically distinct subtypes within stage III colon cancer patients that was externally validated,” the authors wrote, adding that “taken together, our biomarker classifier provides important prognostic information in stage III colon cancers with implications for patient management.”
The investigators for both studies reported no relevant financial disclosures.
It is now recognized that colon cancer is quite heterogeneous on a genetic level, and the clinical features associated with each of these genetic subtypes are equally heterogeneous. The two current studies addressed the question of whether long-term prognosis differs among these genetic subtypes. Colon tumors were first divided into five distinct categories, based upon a panel of multiple molecular markers. One study analyzed more than 2,700 colon cancers of all stages, whereas the other examined more than 2,700 stage III tumors from a North Central Cancer Treatment Group adjuvant chemotherapy trial.
Similar patterns emerged. Tumors with the least favorable prognosis were the so-called “serrated” tumors that are DNA mismatch-repair (MMR) proficient and are positive for a BRAF mutation. Tumors with deficient MMR (MSI-H), whether sporadic or associated with Lynch syndrome, consistently exhibited the most favorable prognosis and highest rates of long-term survival.
These studies provide strong evidence that links survival with specific tumor genotypes, regardless of stage or treatment, and establish the significance of molecular genotyping for prognostic purposes. There are other important reasons to perform tumor genotyping, including the identification of unrecognized Lynch syndrome. However, the therapeutic implications of tumor genotyping remain less clear, as meaningful targeted therapies for each of the specific subgroups are still lacking. In particular, effective targeting of the BRAF oncogene in serrated tumors remains an important priority. More refined molecular classifications are likely to emerge in the future, and the opportunities to offer more precise and personalized approaches to management should increase in parallel.
Dr. Daniel C. Chung is associate professor, department of medicine, Harvard Medical School, Boston, and director, Hi-Risk Gastrointestinal Cancer Clinic, Massachusetts General Hospital, also in Boston. He had no conflicts of interest.
It is now recognized that colon cancer is quite heterogeneous on a genetic level, and the clinical features associated with each of these genetic subtypes are equally heterogeneous. The two current studies addressed the question of whether long-term prognosis differs among these genetic subtypes. Colon tumors were first divided into five distinct categories, based upon a panel of multiple molecular markers. One study analyzed more than 2,700 colon cancers of all stages, whereas the other examined more than 2,700 stage III tumors from a North Central Cancer Treatment Group adjuvant chemotherapy trial.
Similar patterns emerged. Tumors with the least favorable prognosis were the so-called “serrated” tumors that are DNA mismatch-repair (MMR) proficient and are positive for a BRAF mutation. Tumors with deficient MMR (MSI-H), whether sporadic or associated with Lynch syndrome, consistently exhibited the most favorable prognosis and highest rates of long-term survival.
These studies provide strong evidence that links survival with specific tumor genotypes, regardless of stage or treatment, and establish the significance of molecular genotyping for prognostic purposes. There are other important reasons to perform tumor genotyping, including the identification of unrecognized Lynch syndrome. However, the therapeutic implications of tumor genotyping remain less clear, as meaningful targeted therapies for each of the specific subgroups are still lacking. In particular, effective targeting of the BRAF oncogene in serrated tumors remains an important priority. More refined molecular classifications are likely to emerge in the future, and the opportunities to offer more precise and personalized approaches to management should increase in parallel.
Dr. Daniel C. Chung is associate professor, department of medicine, Harvard Medical School, Boston, and director, Hi-Risk Gastrointestinal Cancer Clinic, Massachusetts General Hospital, also in Boston. He had no conflicts of interest.
It is now recognized that colon cancer is quite heterogeneous on a genetic level, and the clinical features associated with each of these genetic subtypes are equally heterogeneous. The two current studies addressed the question of whether long-term prognosis differs among these genetic subtypes. Colon tumors were first divided into five distinct categories, based upon a panel of multiple molecular markers. One study analyzed more than 2,700 colon cancers of all stages, whereas the other examined more than 2,700 stage III tumors from a North Central Cancer Treatment Group adjuvant chemotherapy trial.
Similar patterns emerged. Tumors with the least favorable prognosis were the so-called “serrated” tumors that are DNA mismatch-repair (MMR) proficient and are positive for a BRAF mutation. Tumors with deficient MMR (MSI-H), whether sporadic or associated with Lynch syndrome, consistently exhibited the most favorable prognosis and highest rates of long-term survival.
These studies provide strong evidence that links survival with specific tumor genotypes, regardless of stage or treatment, and establish the significance of molecular genotyping for prognostic purposes. There are other important reasons to perform tumor genotyping, including the identification of unrecognized Lynch syndrome. However, the therapeutic implications of tumor genotyping remain less clear, as meaningful targeted therapies for each of the specific subgroups are still lacking. In particular, effective targeting of the BRAF oncogene in serrated tumors remains an important priority. More refined molecular classifications are likely to emerge in the future, and the opportunities to offer more precise and personalized approaches to management should increase in parallel.
Dr. Daniel C. Chung is associate professor, department of medicine, Harvard Medical School, Boston, and director, Hi-Risk Gastrointestinal Cancer Clinic, Massachusetts General Hospital, also in Boston. He had no conflicts of interest.
Identifying subtypes and tumor mutations in patients with colorectal and stage III colon cancer can significantly improve survival rates, according to two new studies published in the January issue of Gastroenterology (doi:10.1053/j.gastro.2014.09.038 and doi:10.1053/j.gastro.2014.09.041).
In the first study, researchers found that etiologically defined subtypes of colorectal cancer are characterized by marked differences in survival rates and confirmed the clinical importance of studying the molecular heterogeneity of the disease.
“Increasing evidence indicates that colorectal cancer (CRC) is a biologically heterogeneous disease that can develop via a number of distinct pathways involving different combinations of genetic and epigenetic changes,” wrote Amanda Phipps, Ph.D, of the University of Washington in Seattle, and her coinvestigators, adding that “the biologic distinctions between CRC subtypes resulting from different etiologic pathways may plausibly translate to differences in survival.”
Between 1998 and 2007, 2,706 participants were enrolled for this study through the population-based Seattle Colon Cancer Family Registry and followed for survival through 2012. Of those, 2,050 had tumor samples collected from them, each of which was classified into one of five subtypes based on tumor markers: type 1 (microsatellite instability [MSI] high, CpG island methylator phenotype [CIMP] positive, positive for BRAF mutation, negative for KRAS mutation); type 2 (microsatellite stable [MSS] or MSI-low, CIMPpositive, positive for BRAF mutation, negative for KRAS mutation); type 3 (MSS or MSI-low, non-CIMP, negative for BRAF mutation, positive for KRAS mutation); type 4 (MSS or MSI-low, non-CIMP, negative for mutations in BRAF and KRAS); and type 5 (MSI-high, non-CIMP, negative for mutations in BRAF and KRAS).
To analyze data, Cox regression models were used to estimate hazard ratios, 95% confidence intervals, and associations for each subtype with specific diseases and overall mortality, all of which were adjusted for age, sex, body mass, diagnosis year, and smoking history.
Results indicated that type 4 tumors were the most predominant, but subjects with type 2 tumors had the highest disease-specific mortality (hazard ratio = 2.20) and subjects with type 3 tumors also had unusually high disease-specific mortality (HR = 1.32). Type 5 tumors were associated with the lowest disease-specific mortality (HR = 0.30). Associations with overall mortality were similar to those with disease-specific mortality.
“These findings contribute to a small but growing literature supporting the significance of CRC-subtype classifications defined by combinations of these tumor markers,” the authors noted.
The second study’s results indicate that patients suffering from stage III colon cancer who have MMR-proficient tumors and mutations in BRAF (V600E) or KRAS had shorter survival times than patients whose tumors lacked these specific mutations.
“Defining [CRC] tumor subtypes based upon pathway-driven alterations has the potential to improve prognostication and guide targeted therapy,” wrote Dr. Frank Sinicrope of the Mayo Clinic in Rochester, Minn., and his associates.
Investigators collected 2,720 tumor samples from stage III cancer patients and detected mutations in BRAF (V600E) and KRAS using a polymerase chain reaction–based assay, and tumors deficient or proficient in DNA mismatch repair (MMR) via detection of MLH1, MSH2, and MSH6 proteins and methylation of the MLH1 promoter. Investigators used a separate sample of tumors, taken from 783 stage III cancer patients, to validate their findings, and employed the Cox proportional hazards model to evaluate associations between tumors and 5-year disease-free survival rates.
Tumors were divided into five subtypes, three of which were MMR proficient – those with BRAFV600E (6.9% of samples), mutations in KRAS (35%), or tumors lacking either BRAFV600E or mutations in KRAS (49%) – and two of which were MMR deficient: the sporadic type (6.8%) with BRAFV600E or hypermethylation of MLH1, and the familial type (2.6%), which lacked BRAFV600E or hypermethylation of MLH1.
The data accumulated by Dr. Sinicrope and his coinvestigators showed that more MMR-proficient tumors with BRAFV600E than MMR-proficient tumors without BRAFV600E or mutations in KRAS were proximal, high grade, N2, and prevalent in female subjects: 76% vs. 33%, 44% vs. 19%, 59% vs. 41%, and 59% vs. 42%, respectively (overall P < .0001).
Furthermore, a “significantly lower proportion” of patients having MMR-proficient tumors with BRAFV600E (HR 1.43; adjusted P = .0065) or mutant KRAS (HR 1.48; adjusted P < .0001) survived disease free for 5 years, compared with those whose MMR-proficient tumors lacked mutations in either gene.
“We found that a biomarker-based classifier can identify prognostically distinct subtypes within stage III colon cancer patients that was externally validated,” the authors wrote, adding that “taken together, our biomarker classifier provides important prognostic information in stage III colon cancers with implications for patient management.”
The investigators for both studies reported no relevant financial disclosures.
Identifying subtypes and tumor mutations in patients with colorectal and stage III colon cancer can significantly improve survival rates, according to two new studies published in the January issue of Gastroenterology (doi:10.1053/j.gastro.2014.09.038 and doi:10.1053/j.gastro.2014.09.041).
In the first study, researchers found that etiologically defined subtypes of colorectal cancer are characterized by marked differences in survival rates and confirmed the clinical importance of studying the molecular heterogeneity of the disease.
“Increasing evidence indicates that colorectal cancer (CRC) is a biologically heterogeneous disease that can develop via a number of distinct pathways involving different combinations of genetic and epigenetic changes,” wrote Amanda Phipps, Ph.D, of the University of Washington in Seattle, and her coinvestigators, adding that “the biologic distinctions between CRC subtypes resulting from different etiologic pathways may plausibly translate to differences in survival.”
Between 1998 and 2007, 2,706 participants were enrolled for this study through the population-based Seattle Colon Cancer Family Registry and followed for survival through 2012. Of those, 2,050 had tumor samples collected from them, each of which was classified into one of five subtypes based on tumor markers: type 1 (microsatellite instability [MSI] high, CpG island methylator phenotype [CIMP] positive, positive for BRAF mutation, negative for KRAS mutation); type 2 (microsatellite stable [MSS] or MSI-low, CIMPpositive, positive for BRAF mutation, negative for KRAS mutation); type 3 (MSS or MSI-low, non-CIMP, negative for BRAF mutation, positive for KRAS mutation); type 4 (MSS or MSI-low, non-CIMP, negative for mutations in BRAF and KRAS); and type 5 (MSI-high, non-CIMP, negative for mutations in BRAF and KRAS).
To analyze data, Cox regression models were used to estimate hazard ratios, 95% confidence intervals, and associations for each subtype with specific diseases and overall mortality, all of which were adjusted for age, sex, body mass, diagnosis year, and smoking history.
Results indicated that type 4 tumors were the most predominant, but subjects with type 2 tumors had the highest disease-specific mortality (hazard ratio = 2.20) and subjects with type 3 tumors also had unusually high disease-specific mortality (HR = 1.32). Type 5 tumors were associated with the lowest disease-specific mortality (HR = 0.30). Associations with overall mortality were similar to those with disease-specific mortality.
“These findings contribute to a small but growing literature supporting the significance of CRC-subtype classifications defined by combinations of these tumor markers,” the authors noted.
The second study’s results indicate that patients suffering from stage III colon cancer who have MMR-proficient tumors and mutations in BRAF (V600E) or KRAS had shorter survival times than patients whose tumors lacked these specific mutations.
“Defining [CRC] tumor subtypes based upon pathway-driven alterations has the potential to improve prognostication and guide targeted therapy,” wrote Dr. Frank Sinicrope of the Mayo Clinic in Rochester, Minn., and his associates.
Investigators collected 2,720 tumor samples from stage III cancer patients and detected mutations in BRAF (V600E) and KRAS using a polymerase chain reaction–based assay, and tumors deficient or proficient in DNA mismatch repair (MMR) via detection of MLH1, MSH2, and MSH6 proteins and methylation of the MLH1 promoter. Investigators used a separate sample of tumors, taken from 783 stage III cancer patients, to validate their findings, and employed the Cox proportional hazards model to evaluate associations between tumors and 5-year disease-free survival rates.
Tumors were divided into five subtypes, three of which were MMR proficient – those with BRAFV600E (6.9% of samples), mutations in KRAS (35%), or tumors lacking either BRAFV600E or mutations in KRAS (49%) – and two of which were MMR deficient: the sporadic type (6.8%) with BRAFV600E or hypermethylation of MLH1, and the familial type (2.6%), which lacked BRAFV600E or hypermethylation of MLH1.
The data accumulated by Dr. Sinicrope and his coinvestigators showed that more MMR-proficient tumors with BRAFV600E than MMR-proficient tumors without BRAFV600E or mutations in KRAS were proximal, high grade, N2, and prevalent in female subjects: 76% vs. 33%, 44% vs. 19%, 59% vs. 41%, and 59% vs. 42%, respectively (overall P < .0001).
Furthermore, a “significantly lower proportion” of patients having MMR-proficient tumors with BRAFV600E (HR 1.43; adjusted P = .0065) or mutant KRAS (HR 1.48; adjusted P < .0001) survived disease free for 5 years, compared with those whose MMR-proficient tumors lacked mutations in either gene.
“We found that a biomarker-based classifier can identify prognostically distinct subtypes within stage III colon cancer patients that was externally validated,” the authors wrote, adding that “taken together, our biomarker classifier provides important prognostic information in stage III colon cancers with implications for patient management.”
The investigators for both studies reported no relevant financial disclosures.
FROM GASTROENTEROLOGY
Cathelicidins might help prevent, treat colonic fibrosis
Peptides known as cathelicidins directly inhibited collagen synthesis in human colonic fibroblasts and in mice with colitis, authors of a controlled, prospective study reported. The findings appeared Nov. 11 in Cellular and Molecular Gastroenterology and Hepatology.
“Our results strongly suggest that cathelicidin administration may be a novel approach to prevent or treat inflammatory bowel disease and IBD-related colonic fibrosis,” said Dr. Jun Hwan Yoo at the University of California, Los Angeles, and his associates.
Cathelicidins are endogenous antimicrobial peptides that exhibit “potent” anti-inflammatory effects against acute colitis, and inhibit colonic fibrosis in mice with chronic or infectious colitis, the investigators said. In past studies, cathelicidin-deficient mice were more susceptible to infections, had poorer wound healing, and developed worse colitis, compared with mice that were not cathelicidin deficient, they added. Cathelicidins also inhibit collagen synthesis in human dermal fibroblasts, they said (Cellular and Molecular Gastroenterology and Hepatology 2014 Nov. 11 10.1016/j.jcmgh.2014.08.001 [doi:10.1016/j.jcmgh.2014.08.001]).
To further explore the role of cathelicidins in intestinal fibrosis, Dr. Yoo and associates created two murine models of intestinal inflammation by infecting mice with Salmonella or by administering trinitrobenzene sulfonic acid enemas. Then they administered either intracolonic mCRAMP peptide at a dose of 5 mg/kg every 3 days, or intravenous injections of a lentivirus that overexpressed the cathelicidin gene. The researchers also exposed human intestinal fibroblasts and human colonic CCD-18Co fibroblasts to transforming growth factor beta1 (TGF-beta1) or to insulinlike growth factor 1, which induced collagen protein and mRNA expression that mimicked intestinal fibrosis. Then they exposed these cells to 3-5 mcm of the human cathelicidin LL-37.
The groups of mice with colitis had significantly higher colonic expression of collagen mRNA and significantly more colon tissue damage than did the normal controls, said the researchers. Mice with colitis that received mCRAMP or lentivirus-overexpressing cathelicidin gene had significantly lower collagen mRNA levels and less cecal and colonic collagen deposition, compared with mice that received only the vehicle control, they added (all P values less than .05). Intracolonic mCRAMP also restored body weight (P = .0178) in mice with colitis, compared with untreated controls, they added. Furthermore, LL-37 inhibited collagen synthesis in human intestinal and colonic fibroblasts (P = .0001), they said.
The research was supported by the UCLA CURE Center, the Crohn’s and Colitis Foundation of America, the National Institutes of Health, the Blinder Research Foundation for Crohn’s Disease, the Eli and Edythe Broad Chair, and the U.S. Public Health Service. The authors declared no conflicts of interest.
Fibrosis is a major complication of Crohn’s disease that can lead to strictures and intestinal obstruction. While biologic therapies have revolutionized medical treatment of Crohn’s disease and may reduce the incidence of recurrent stricturing disease, as many as 20% of Crohn’s disease patients treated with these agents still develop strictures.
One attractive therapeutic target could be TGF-beta, which induces fibroblasts to synthesize collagen and is upregulated in Crohn’s disease strictures. Unfortunately, anti-TGF-beta1 antibody therapy failed to work in other fibrotic diseases. In addition, toxicity might be expected in Crohn’s disease, as TGF-beta has pleiotropic functions in the gut, some of which are critical to homeostasis.
Recent work in extraintestinal organs has elucidated the involvement of cathelicidins, antimicrobial cationic peptides, in fibrosis. For example, LL-37, the cleaved form of human cathelicidin, can reduce TGF-beta–induced collagen synthesis by human keloid fibroblasts. However, the ability of cathelicidins to limit intestinal fibrosis has not been explored.
The study by Yoo et al. is important because it demonstrates that cathelicidins may be a powerful therapy for intestinal fibrosis. Importantly, cathelicidin therapy does not appear to affect TGF-beta signaling, as LL-37 therapy did not affect TGF-beta1 expression in vivo, but did inhibit TGF-beta–induced collagen production by primary Crohn’s disease intestinal fibroblasts in vitro.
It is also important to recognize that cathelicidins are already being developed as therapy to limit fibrosis in extra-intestinal diseases. Thus, much in the same way Crohn’s disease patients benefited from the development of anti-TNF-beta biologics for rheumatoid arthritis, it may be possible to take advantage of ongoing studies to reduce the cost and time involved in delivering a new therapeutic agent to patients.
Dr. Stefania Vetrano is a research associate at the IBD Center, Humanitas Clinical and Research Center, Rozzano, Milan. She has no conflicts of interest.
Fibrosis is a major complication of Crohn’s disease that can lead to strictures and intestinal obstruction. While biologic therapies have revolutionized medical treatment of Crohn’s disease and may reduce the incidence of recurrent stricturing disease, as many as 20% of Crohn’s disease patients treated with these agents still develop strictures.
One attractive therapeutic target could be TGF-beta, which induces fibroblasts to synthesize collagen and is upregulated in Crohn’s disease strictures. Unfortunately, anti-TGF-beta1 antibody therapy failed to work in other fibrotic diseases. In addition, toxicity might be expected in Crohn’s disease, as TGF-beta has pleiotropic functions in the gut, some of which are critical to homeostasis.
Recent work in extraintestinal organs has elucidated the involvement of cathelicidins, antimicrobial cationic peptides, in fibrosis. For example, LL-37, the cleaved form of human cathelicidin, can reduce TGF-beta–induced collagen synthesis by human keloid fibroblasts. However, the ability of cathelicidins to limit intestinal fibrosis has not been explored.
The study by Yoo et al. is important because it demonstrates that cathelicidins may be a powerful therapy for intestinal fibrosis. Importantly, cathelicidin therapy does not appear to affect TGF-beta signaling, as LL-37 therapy did not affect TGF-beta1 expression in vivo, but did inhibit TGF-beta–induced collagen production by primary Crohn’s disease intestinal fibroblasts in vitro.
It is also important to recognize that cathelicidins are already being developed as therapy to limit fibrosis in extra-intestinal diseases. Thus, much in the same way Crohn’s disease patients benefited from the development of anti-TNF-beta biologics for rheumatoid arthritis, it may be possible to take advantage of ongoing studies to reduce the cost and time involved in delivering a new therapeutic agent to patients.
Dr. Stefania Vetrano is a research associate at the IBD Center, Humanitas Clinical and Research Center, Rozzano, Milan. She has no conflicts of interest.
Fibrosis is a major complication of Crohn’s disease that can lead to strictures and intestinal obstruction. While biologic therapies have revolutionized medical treatment of Crohn’s disease and may reduce the incidence of recurrent stricturing disease, as many as 20% of Crohn’s disease patients treated with these agents still develop strictures.
One attractive therapeutic target could be TGF-beta, which induces fibroblasts to synthesize collagen and is upregulated in Crohn’s disease strictures. Unfortunately, anti-TGF-beta1 antibody therapy failed to work in other fibrotic diseases. In addition, toxicity might be expected in Crohn’s disease, as TGF-beta has pleiotropic functions in the gut, some of which are critical to homeostasis.
Recent work in extraintestinal organs has elucidated the involvement of cathelicidins, antimicrobial cationic peptides, in fibrosis. For example, LL-37, the cleaved form of human cathelicidin, can reduce TGF-beta–induced collagen synthesis by human keloid fibroblasts. However, the ability of cathelicidins to limit intestinal fibrosis has not been explored.
The study by Yoo et al. is important because it demonstrates that cathelicidins may be a powerful therapy for intestinal fibrosis. Importantly, cathelicidin therapy does not appear to affect TGF-beta signaling, as LL-37 therapy did not affect TGF-beta1 expression in vivo, but did inhibit TGF-beta–induced collagen production by primary Crohn’s disease intestinal fibroblasts in vitro.
It is also important to recognize that cathelicidins are already being developed as therapy to limit fibrosis in extra-intestinal diseases. Thus, much in the same way Crohn’s disease patients benefited from the development of anti-TNF-beta biologics for rheumatoid arthritis, it may be possible to take advantage of ongoing studies to reduce the cost and time involved in delivering a new therapeutic agent to patients.
Dr. Stefania Vetrano is a research associate at the IBD Center, Humanitas Clinical and Research Center, Rozzano, Milan. She has no conflicts of interest.
Peptides known as cathelicidins directly inhibited collagen synthesis in human colonic fibroblasts and in mice with colitis, authors of a controlled, prospective study reported. The findings appeared Nov. 11 in Cellular and Molecular Gastroenterology and Hepatology.
“Our results strongly suggest that cathelicidin administration may be a novel approach to prevent or treat inflammatory bowel disease and IBD-related colonic fibrosis,” said Dr. Jun Hwan Yoo at the University of California, Los Angeles, and his associates.
Cathelicidins are endogenous antimicrobial peptides that exhibit “potent” anti-inflammatory effects against acute colitis, and inhibit colonic fibrosis in mice with chronic or infectious colitis, the investigators said. In past studies, cathelicidin-deficient mice were more susceptible to infections, had poorer wound healing, and developed worse colitis, compared with mice that were not cathelicidin deficient, they added. Cathelicidins also inhibit collagen synthesis in human dermal fibroblasts, they said (Cellular and Molecular Gastroenterology and Hepatology 2014 Nov. 11 10.1016/j.jcmgh.2014.08.001 [doi:10.1016/j.jcmgh.2014.08.001]).
To further explore the role of cathelicidins in intestinal fibrosis, Dr. Yoo and associates created two murine models of intestinal inflammation by infecting mice with Salmonella or by administering trinitrobenzene sulfonic acid enemas. Then they administered either intracolonic mCRAMP peptide at a dose of 5 mg/kg every 3 days, or intravenous injections of a lentivirus that overexpressed the cathelicidin gene. The researchers also exposed human intestinal fibroblasts and human colonic CCD-18Co fibroblasts to transforming growth factor beta1 (TGF-beta1) or to insulinlike growth factor 1, which induced collagen protein and mRNA expression that mimicked intestinal fibrosis. Then they exposed these cells to 3-5 mcm of the human cathelicidin LL-37.
The groups of mice with colitis had significantly higher colonic expression of collagen mRNA and significantly more colon tissue damage than did the normal controls, said the researchers. Mice with colitis that received mCRAMP or lentivirus-overexpressing cathelicidin gene had significantly lower collagen mRNA levels and less cecal and colonic collagen deposition, compared with mice that received only the vehicle control, they added (all P values less than .05). Intracolonic mCRAMP also restored body weight (P = .0178) in mice with colitis, compared with untreated controls, they added. Furthermore, LL-37 inhibited collagen synthesis in human intestinal and colonic fibroblasts (P = .0001), they said.
The research was supported by the UCLA CURE Center, the Crohn’s and Colitis Foundation of America, the National Institutes of Health, the Blinder Research Foundation for Crohn’s Disease, the Eli and Edythe Broad Chair, and the U.S. Public Health Service. The authors declared no conflicts of interest.
Peptides known as cathelicidins directly inhibited collagen synthesis in human colonic fibroblasts and in mice with colitis, authors of a controlled, prospective study reported. The findings appeared Nov. 11 in Cellular and Molecular Gastroenterology and Hepatology.
“Our results strongly suggest that cathelicidin administration may be a novel approach to prevent or treat inflammatory bowel disease and IBD-related colonic fibrosis,” said Dr. Jun Hwan Yoo at the University of California, Los Angeles, and his associates.
Cathelicidins are endogenous antimicrobial peptides that exhibit “potent” anti-inflammatory effects against acute colitis, and inhibit colonic fibrosis in mice with chronic or infectious colitis, the investigators said. In past studies, cathelicidin-deficient mice were more susceptible to infections, had poorer wound healing, and developed worse colitis, compared with mice that were not cathelicidin deficient, they added. Cathelicidins also inhibit collagen synthesis in human dermal fibroblasts, they said (Cellular and Molecular Gastroenterology and Hepatology 2014 Nov. 11 10.1016/j.jcmgh.2014.08.001 [doi:10.1016/j.jcmgh.2014.08.001]).
To further explore the role of cathelicidins in intestinal fibrosis, Dr. Yoo and associates created two murine models of intestinal inflammation by infecting mice with Salmonella or by administering trinitrobenzene sulfonic acid enemas. Then they administered either intracolonic mCRAMP peptide at a dose of 5 mg/kg every 3 days, or intravenous injections of a lentivirus that overexpressed the cathelicidin gene. The researchers also exposed human intestinal fibroblasts and human colonic CCD-18Co fibroblasts to transforming growth factor beta1 (TGF-beta1) or to insulinlike growth factor 1, which induced collagen protein and mRNA expression that mimicked intestinal fibrosis. Then they exposed these cells to 3-5 mcm of the human cathelicidin LL-37.
The groups of mice with colitis had significantly higher colonic expression of collagen mRNA and significantly more colon tissue damage than did the normal controls, said the researchers. Mice with colitis that received mCRAMP or lentivirus-overexpressing cathelicidin gene had significantly lower collagen mRNA levels and less cecal and colonic collagen deposition, compared with mice that received only the vehicle control, they added (all P values less than .05). Intracolonic mCRAMP also restored body weight (P = .0178) in mice with colitis, compared with untreated controls, they added. Furthermore, LL-37 inhibited collagen synthesis in human intestinal and colonic fibroblasts (P = .0001), they said.
The research was supported by the UCLA CURE Center, the Crohn’s and Colitis Foundation of America, the National Institutes of Health, the Blinder Research Foundation for Crohn’s Disease, the Eli and Edythe Broad Chair, and the U.S. Public Health Service. The authors declared no conflicts of interest.
Key clinical point: Cathelicidins might help prevent or reverse intestinal fibrosis in patients with inflammatory bowel disease.
Major finding: Cathelicidins inhibited colonic fibrosis in mice with colitis and in human intestinal fibroblasts (P = .0001).
Data source: Controlled prospective study of the effects of cathelicidins in laboratory mice with colitis and in human intestinal fibroblasts.
Disclosures: The research was supported by the UCLA CURE Center, the Crohn’s and Colitis Foundation of America, the National Institutes of Health, the Blinder Research Foundation for Crohn’s Disease, the Eli and Edythe Broad Chair, and the U.S. Public Health Service. The authors declared no conflicts of interest.