From the AGA Journals

A scoring model encompassing just four traits accurately predicted which patients with Barrett’s esophagus were most likely to develop high-grade dysplasia or esophageal adenocarcinoma, researchers reported in the April issue of Gastroenterology (2017 Dec 19. doi: 10.1053/j.gastro.2017.12.009).

Those risk factors included sex, smoking, length of Barrett’s esophagus, and the presence of baseline low-grade dysplasia, said Sravanthi Parasa, MD, of Swedish Medical Center, Seattle, and her associates. For example, a male with a history of smoking found to have a 5-cm, nondysplastic Barrett’s esophagus on histology during his index endoscopy would fall into the model’s intermediate risk category, with a 0.7% annual risk of progression to high-grade dysplasia or esophageal adenocarcinoma, they explained. “This model has the potential to complement molecular biomarker panels currently in development,” they wrote.

Barrett’s esophagus increases the risk of esophageal adenocarcinoma by anywhere from 30 to 125 times, a range that reflects the multifactorial nature of progression and the hypothesis that not all patients with Barrett’s esophagus should undergo the same frequency of endoscopic surveillance, said the researchers. To incorporate predictors of progression into a single model, they analyzed prospective data from nearly 3,000 patients with Barrett’s esophagus who were followed for a median of 6 years at five centers in the United States and one center in the Netherlands. At baseline, patients were an average of 55 years old (standard deviation, 20 years), 84% were men, 88% were white, and the average Barrett’s esophagus length was 3.7 cm (SD, 3.2 cm).

The researchers created the model by starting with many demographic and clinical candidate variables and then using backward selection to eliminate those that did not predict progression with a P value of .05 or less. This is the same method used in the Framingham Heart Study, they noted. In all, 154 (6%) patients with Barrett’s esophagus developed high-grade dysplasia or esophageal adenocarcinoma, with an annual progression rate of about 1%. The significant predictors of progression included male sex, smoking, length of Barrett’s esophagus, and low-grade dysplasia at baseline. A model that included only these four variables distinguished progressors from nonprogressors with a c statistic of 0.76 (95% confidence interval, 0.72 to 0.80; P less than .001). Using 30% of patients as an internal validation cohort, the model’s calibration slope was 0.99 and its calibration intercept was -0.09 cohort (perfectly calibrated models have a slope of 1.0 and an intercept of 0.0).

Therefore, the model was well calibrated and did an appropriate job of identifying risk groups, the investigators concluded. Considering that the overall risk of Barrett’s esophagus progression is low, using this model could help avoid excess costs and burdens of unnecessary surveillance, they added. “We recognize that there is a key interest in contemporary medical research whether a marker (e.g. molecular, genetic) could add to incremental value of a risk progression score,” they wrote. “This can be an area of future research.”

There were no funding sources. Dr. Parasa had no disclosures. One coinvestigator disclosed ties to Cook Medical, CDx Diagnostics, and Cosmo Pharmaceuticals.

SOURCE: Parasa S et al. Gastroenterology. 2017 Dec 19. doi: 10.1053/j.gastro.2017.12.009.

A scoring model encompassing just four traits accurately predicted which patients with Barrett’s esophagus were most likely to develop high-grade dysplasia or esophageal adenocarcinoma, researchers reported in the April issue of Gastroenterology (2017 Dec 19. doi: 10.1053/j.gastro.2017.12.009).

Those risk factors included sex, smoking, length of Barrett’s esophagus, and the presence of baseline low-grade dysplasia, said Sravanthi Parasa, MD, of Swedish Medical Center, Seattle, and her associates. For example, a male with a history of smoking found to have a 5-cm, nondysplastic Barrett’s esophagus on histology during his index endoscopy would fall into the model’s intermediate risk category, with a 0.7% annual risk of progression to high-grade dysplasia or esophageal adenocarcinoma, they explained. “This model has the potential to complement molecular biomarker panels currently in development,” they wrote.

Barrett’s esophagus increases the risk of esophageal adenocarcinoma by anywhere from 30 to 125 times, a range that reflects the multifactorial nature of progression and the hypothesis that not all patients with Barrett’s esophagus should undergo the same frequency of endoscopic surveillance, said the researchers. To incorporate predictors of progression into a single model, they analyzed prospective data from nearly 3,000 patients with Barrett’s esophagus who were followed for a median of 6 years at five centers in the United States and one center in the Netherlands. At baseline, patients were an average of 55 years old (standard deviation, 20 years), 84% were men, 88% were white, and the average Barrett’s esophagus length was 3.7 cm (SD, 3.2 cm).

The researchers created the model by starting with many demographic and clinical candidate variables and then using backward selection to eliminate those that did not predict progression with a P value of .05 or less. This is the same method used in the Framingham Heart Study, they noted. In all, 154 (6%) patients with Barrett’s esophagus developed high-grade dysplasia or esophageal adenocarcinoma, with an annual progression rate of about 1%. The significant predictors of progression included male sex, smoking, length of Barrett’s esophagus, and low-grade dysplasia at baseline. A model that included only these four variables distinguished progressors from nonprogressors with a c statistic of 0.76 (95% confidence interval, 0.72 to 0.80; P less than .001). Using 30% of patients as an internal validation cohort, the model’s calibration slope was 0.99 and its calibration intercept was -0.09 cohort (perfectly calibrated models have a slope of 1.0 and an intercept of 0.0).

Therefore, the model was well calibrated and did an appropriate job of identifying risk groups, the investigators concluded. Considering that the overall risk of Barrett’s esophagus progression is low, using this model could help avoid excess costs and burdens of unnecessary surveillance, they added. “We recognize that there is a key interest in contemporary medical research whether a marker (e.g. molecular, genetic) could add to incremental value of a risk progression score,” they wrote. “This can be an area of future research.”

There were no funding sources. Dr. Parasa had no disclosures. One coinvestigator disclosed ties to Cook Medical, CDx Diagnostics, and Cosmo Pharmaceuticals.

SOURCE: Parasa S et al. Gastroenterology. 2017 Dec 19. doi: 10.1053/j.gastro.2017.12.009.

A scoring model encompassing just four traits accurately predicted which patients with Barrett’s esophagus were most likely to develop high-grade dysplasia or esophageal adenocarcinoma, researchers reported in the April issue of Gastroenterology (2017 Dec 19. doi: 10.1053/j.gastro.2017.12.009).

Those risk factors included sex, smoking, length of Barrett’s esophagus, and the presence of baseline low-grade dysplasia, said Sravanthi Parasa, MD, of Swedish Medical Center, Seattle, and her associates. For example, a male with a history of smoking found to have a 5-cm, nondysplastic Barrett’s esophagus on histology during his index endoscopy would fall into the model’s intermediate risk category, with a 0.7% annual risk of progression to high-grade dysplasia or esophageal adenocarcinoma, they explained. “This model has the potential to complement molecular biomarker panels currently in development,” they wrote.

Barrett’s esophagus increases the risk of esophageal adenocarcinoma by anywhere from 30 to 125 times, a range that reflects the multifactorial nature of progression and the hypothesis that not all patients with Barrett’s esophagus should undergo the same frequency of endoscopic surveillance, said the researchers. To incorporate predictors of progression into a single model, they analyzed prospective data from nearly 3,000 patients with Barrett’s esophagus who were followed for a median of 6 years at five centers in the United States and one center in the Netherlands. At baseline, patients were an average of 55 years old (standard deviation, 20 years), 84% were men, 88% were white, and the average Barrett’s esophagus length was 3.7 cm (SD, 3.2 cm).

The researchers created the model by starting with many demographic and clinical candidate variables and then using backward selection to eliminate those that did not predict progression with a P value of .05 or less. This is the same method used in the Framingham Heart Study, they noted. In all, 154 (6%) patients with Barrett’s esophagus developed high-grade dysplasia or esophageal adenocarcinoma, with an annual progression rate of about 1%. The significant predictors of progression included male sex, smoking, length of Barrett’s esophagus, and low-grade dysplasia at baseline. A model that included only these four variables distinguished progressors from nonprogressors with a c statistic of 0.76 (95% confidence interval, 0.72 to 0.80; P less than .001). Using 30% of patients as an internal validation cohort, the model’s calibration slope was 0.99 and its calibration intercept was -0.09 cohort (perfectly calibrated models have a slope of 1.0 and an intercept of 0.0).

Therefore, the model was well calibrated and did an appropriate job of identifying risk groups, the investigators concluded. Considering that the overall risk of Barrett’s esophagus progression is low, using this model could help avoid excess costs and burdens of unnecessary surveillance, they added. “We recognize that there is a key interest in contemporary medical research whether a marker (e.g. molecular, genetic) could add to incremental value of a risk progression score,” they wrote. “This can be an area of future research.”

There were no funding sources. Dr. Parasa had no disclosures. One coinvestigator disclosed ties to Cook Medical, CDx Diagnostics, and Cosmo Pharmaceuticals.

SOURCE: Parasa S et al. Gastroenterology. 2017 Dec 19. doi: 10.1053/j.gastro.2017.12.009.

Increased donor liver perfusate levels of an underglycosylated glycoprotein predicted primary transplant nonfunction with 100% accuracy in two prospective cohorts, researchers reported in Gastroenterology.

SOURCE: AMERICAN GASTROENTEROLOGICAL ASSOCIATION

Glycomic alterations of immunoglobulin G “represent inflammatory disturbances in the liver that [mean it] will fail after transplantation,” wrote Xavier Verhelst, MD, of Ghent (Belgium) University Hospital, and his associates. The new glycomarker “could be a tool to safely select high-risk organs for liver transplantation that otherwise would be discarded from the donor pool based on a conventional clinical assessment,” and also could help prevent engraftment failures. “To our knowledge, not a single biomarker has demonstrated the same accuracy today,” they wrote in the April issue of Gastroenterology.

Chronic shortages of donor livers contribute to morbidity and death worldwide. However, relaxing donor criteria is controversial because of the increased risk of primary nonfunction, which affects some 2%-10% of liver transplantation patients, and early allograft dysfunction, which is even more common. Although no reliable scoring systems or biomarkers have been able to predict these outcomes prior to transplantation, clinical glycomics of serum has proven useful for diagnosing hepatic fibrosis, cirrhosis, and hepatocellular carcinoma, and for distinguishing hepatic steatosis from nonalcoholic steatohepatitis. “Perfusate biomarkers are an attractive alternative [to] liver biopsy or serum markers, because perfusate is believed to represent the condition of the entire liver parenchyma and is easy to collect in large volumes,” the researchers wrote.

Accordingly, they studied 66 patients who underwent liver transplantation at a single center in Belgium and a separate validation cohort of 56 transplantation recipients from two centers. The most common reason for liver transplantation was decompensated cirrhosis secondary to alcoholism, followed by chronic hepatitis C or B virus infection, acute liver failure, and polycystic liver disease. Donor grafts were transported using cold static storage (21° C), and hepatic veins were flushed to collect perfusate before transplantation. Protein-linked N-glycans was isolated from these perfusate samples and analyzed with a multicapillary electrophoresis-based ABI3130 sequencer.

The four patients in the primary study cohort who developed primary nonfunction resembled the others in terms of all clinical and demographic parameters except that they had a markedly increased concentration (P less than .0001) of a single-glycan, agalacto core-alpha-1,6-fucosylated biantennary glycan, dubbed NGA2F. The single patient in the validation cohort who developed primary nonfunction also had a significantly increased concentration of NGA2F (P = .037). There were no false positives in either cohort, and a 13% cutoff for perfusate NGA2F level identified primary nonfunction with 100% accuracy, the researchers said. In a multivariable model of donor risk index and perfusate markers, only NGA2F was prognostic for developing primary nonfunction (P less than .0001).

The researchers found no specific glycomic signature for early allograft dysfunction, perhaps because it is more complex and multifactorial, they wrote. Although electrophoresis testing took 48 hours, work is underway to shorten this to a “clinically acceptable time frame,” they added. They recommended multicenter studies to validate their findings.

Funders included the Research Fund – Flanders and Ghent University. The researchers reported having no conflicts of interest.

SOURCE: Verhelst X et al. Gastroenterology 2018 Jan 6. doi: 10.1053/j.gastro.2017.12.027.

Increased donor liver perfusate levels of an underglycosylated glycoprotein predicted primary transplant nonfunction with 100% accuracy in two prospective cohorts, researchers reported in Gastroenterology.

SOURCE: AMERICAN GASTROENTEROLOGICAL ASSOCIATION

Glycomic alterations of immunoglobulin G “represent inflammatory disturbances in the liver that [mean it] will fail after transplantation,” wrote Xavier Verhelst, MD, of Ghent (Belgium) University Hospital, and his associates. The new glycomarker “could be a tool to safely select high-risk organs for liver transplantation that otherwise would be discarded from the donor pool based on a conventional clinical assessment,” and also could help prevent engraftment failures. “To our knowledge, not a single biomarker has demonstrated the same accuracy today,” they wrote in the April issue of Gastroenterology.

Chronic shortages of donor livers contribute to morbidity and death worldwide. However, relaxing donor criteria is controversial because of the increased risk of primary nonfunction, which affects some 2%-10% of liver transplantation patients, and early allograft dysfunction, which is even more common. Although no reliable scoring systems or biomarkers have been able to predict these outcomes prior to transplantation, clinical glycomics of serum has proven useful for diagnosing hepatic fibrosis, cirrhosis, and hepatocellular carcinoma, and for distinguishing hepatic steatosis from nonalcoholic steatohepatitis. “Perfusate biomarkers are an attractive alternative [to] liver biopsy or serum markers, because perfusate is believed to represent the condition of the entire liver parenchyma and is easy to collect in large volumes,” the researchers wrote.

Accordingly, they studied 66 patients who underwent liver transplantation at a single center in Belgium and a separate validation cohort of 56 transplantation recipients from two centers. The most common reason for liver transplantation was decompensated cirrhosis secondary to alcoholism, followed by chronic hepatitis C or B virus infection, acute liver failure, and polycystic liver disease. Donor grafts were transported using cold static storage (21° C), and hepatic veins were flushed to collect perfusate before transplantation. Protein-linked N-glycans was isolated from these perfusate samples and analyzed with a multicapillary electrophoresis-based ABI3130 sequencer.

The four patients in the primary study cohort who developed primary nonfunction resembled the others in terms of all clinical and demographic parameters except that they had a markedly increased concentration (P less than .0001) of a single-glycan, agalacto core-alpha-1,6-fucosylated biantennary glycan, dubbed NGA2F. The single patient in the validation cohort who developed primary nonfunction also had a significantly increased concentration of NGA2F (P = .037). There were no false positives in either cohort, and a 13% cutoff for perfusate NGA2F level identified primary nonfunction with 100% accuracy, the researchers said. In a multivariable model of donor risk index and perfusate markers, only NGA2F was prognostic for developing primary nonfunction (P less than .0001).

The researchers found no specific glycomic signature for early allograft dysfunction, perhaps because it is more complex and multifactorial, they wrote. Although electrophoresis testing took 48 hours, work is underway to shorten this to a “clinically acceptable time frame,” they added. They recommended multicenter studies to validate their findings.

Funders included the Research Fund – Flanders and Ghent University. The researchers reported having no conflicts of interest.

SOURCE: Verhelst X et al. Gastroenterology 2018 Jan 6. doi: 10.1053/j.gastro.2017.12.027.

Increased donor liver perfusate levels of an underglycosylated glycoprotein predicted primary transplant nonfunction with 100% accuracy in two prospective cohorts, researchers reported in Gastroenterology.

SOURCE: AMERICAN GASTROENTEROLOGICAL ASSOCIATION

Glycomic alterations of immunoglobulin G “represent inflammatory disturbances in the liver that [mean it] will fail after transplantation,” wrote Xavier Verhelst, MD, of Ghent (Belgium) University Hospital, and his associates. The new glycomarker “could be a tool to safely select high-risk organs for liver transplantation that otherwise would be discarded from the donor pool based on a conventional clinical assessment,” and also could help prevent engraftment failures. “To our knowledge, not a single biomarker has demonstrated the same accuracy today,” they wrote in the April issue of Gastroenterology.

Chronic shortages of donor livers contribute to morbidity and death worldwide. However, relaxing donor criteria is controversial because of the increased risk of primary nonfunction, which affects some 2%-10% of liver transplantation patients, and early allograft dysfunction, which is even more common. Although no reliable scoring systems or biomarkers have been able to predict these outcomes prior to transplantation, clinical glycomics of serum has proven useful for diagnosing hepatic fibrosis, cirrhosis, and hepatocellular carcinoma, and for distinguishing hepatic steatosis from nonalcoholic steatohepatitis. “Perfusate biomarkers are an attractive alternative [to] liver biopsy or serum markers, because perfusate is believed to represent the condition of the entire liver parenchyma and is easy to collect in large volumes,” the researchers wrote.

Accordingly, they studied 66 patients who underwent liver transplantation at a single center in Belgium and a separate validation cohort of 56 transplantation recipients from two centers. The most common reason for liver transplantation was decompensated cirrhosis secondary to alcoholism, followed by chronic hepatitis C or B virus infection, acute liver failure, and polycystic liver disease. Donor grafts were transported using cold static storage (21° C), and hepatic veins were flushed to collect perfusate before transplantation. Protein-linked N-glycans was isolated from these perfusate samples and analyzed with a multicapillary electrophoresis-based ABI3130 sequencer.

The four patients in the primary study cohort who developed primary nonfunction resembled the others in terms of all clinical and demographic parameters except that they had a markedly increased concentration (P less than .0001) of a single-glycan, agalacto core-alpha-1,6-fucosylated biantennary glycan, dubbed NGA2F. The single patient in the validation cohort who developed primary nonfunction also had a significantly increased concentration of NGA2F (P = .037). There were no false positives in either cohort, and a 13% cutoff for perfusate NGA2F level identified primary nonfunction with 100% accuracy, the researchers said. In a multivariable model of donor risk index and perfusate markers, only NGA2F was prognostic for developing primary nonfunction (P less than .0001).

The researchers found no specific glycomic signature for early allograft dysfunction, perhaps because it is more complex and multifactorial, they wrote. Although electrophoresis testing took 48 hours, work is underway to shorten this to a “clinically acceptable time frame,” they added. They recommended multicenter studies to validate their findings.

Funders included the Research Fund – Flanders and Ghent University. The researchers reported having no conflicts of interest.

SOURCE: Verhelst X et al. Gastroenterology 2018 Jan 6. doi: 10.1053/j.gastro.2017.12.027.

Pioglitazone therapy given for 18 months benefited patients with nonalcoholic steatohepatitis (NASH) similarly regardless of whether they had type 2 diabetes mellitus or prediabetes, according to the results of a randomized prospective trial.

SOURCE: AMERICAN GASTROENTEROLOGICAL ASSOCIATION

The primary outcome, at least a 2-point reduction in nonalcoholic fatty liver disease activity score compared with placebo, without worsening fibrosis, was met by 48% of NASH patients with T2DM and by 46% of those with prediabetes, reported Fernando Bril, MD, of the division of endocrinology, diabetes, and metabolism at the University of Florida, Gainesville, and his associates. The report was published in Clinical Gastroenterology and Hepatology.
 

NASH resolved completely in 44% with T2DM and 26% of patients without it, respectively, perhaps indicating that pioglitazone acts slightly differently when patients with NASH have T2DM, according to the investigators. “Although the effects on fibrosis appear to be similar in both groups, pioglitazone may contribute to halting [its] rapid progression [in T2DM],” they wrote. “These differences will deserve further exploration in larger clinical trials.”

The trial (NCT00994682) enrolled 101 patients with biopsy-confirmed NASH, of whom 52 had T2DM and 49 had prediabetes based on clinical history, baseline fasting plasma glucose, hemoglobin A_1c, and an oral glucose tolerance test, as per American Diabetes Association guidelines. After a 4-week run-in period, patients were randomly assigned to receive either pioglitazone (45 mg per day) or placebo for 18 months. All patients received lifestyle counseling and a hypocaloric (500-kcal reduced) diet.

Compared with placebo, pioglitazone improved most secondary outcomes similarly regardless of whether patients were T2DM or prediabetes. The two exceptions were fibrosis and insulin sensitivity of adipose tissue. Patients with T2DM only experienced improved fibrosis in the setting of pioglitazone therapy (P = .035 vs. baseline). In prediabetic patients, fibrosis lessened moderately over time, regardless of whether they received pioglitazone or placebo. Insulin sensitivity of adipose tissue improved much more markedly with treatment in patients with T2DM (P less than .001 vs. baseline) than in those with prediabetes (P = .002 for T2DM vs. prediabetes).

Compared with placebo, pioglitazone improved hepatic and skeletal muscle insulin sensitivity similarly, regardless of diabetes status. Likewise, intrahepatic triglyceride content, as measured by proton magnetic resonance spectroscopy, fell by 11% in pioglitazone recipients with T2DM and by 9% of those with prediabetes, a nonsignificant difference. Pioglitazone also led to a statistically similar decrease in plasma alanine aminotransferase level regardless of whether patients had T2DM (50 U/L) or were prediabetic (36 U/L).

This trial’s key takeaway is that pioglitazone improves liver histology in NASH whether or not patients are diabetic, said the researchers. “We believed that it was essential to compare its efficacy in patients with [and] without T2DM because of the vast number of patients with prediabetes and NASH and given the significant metabolic and cardioprotective effects of pioglitazone among patients without T2DM,” they wrote. The natural history of NASH is worse in the presence of T2DM, which might explain pioglitazone’s superior effects on fibrosis and insulin sensitivity of adipose tissue in this population, they added.

The Burroughs Wellcome Fund, the American Diabetes Association, and the Veteran’s Affairs Merit Award supported the work. Senior author Kenneth Cusi, MD, disclosed nonfinancial support from Takeda Pharmaceuticals, grants from Novartis and Janssen Research and Development, and consulting relationships with Eli Lilly, Tobira Therapeutics, and Pfizer. The other authors had no conflicts.

Source: Bril F, et al. Clin Gastroenterol Hepatol. 2018 Feb 24. doi: 10.1016/j.cgh.2017.12.001.

Pioglitazone therapy given for 18 months benefited patients with nonalcoholic steatohepatitis (NASH) similarly regardless of whether they had type 2 diabetes mellitus or prediabetes, according to the results of a randomized prospective trial.

SOURCE: AMERICAN GASTROENTEROLOGICAL ASSOCIATION

The primary outcome, at least a 2-point reduction in nonalcoholic fatty liver disease activity score compared with placebo, without worsening fibrosis, was met by 48% of NASH patients with T2DM and by 46% of those with prediabetes, reported Fernando Bril, MD, of the division of endocrinology, diabetes, and metabolism at the University of Florida, Gainesville, and his associates. The report was published in Clinical Gastroenterology and Hepatology.
 

NASH resolved completely in 44% with T2DM and 26% of patients without it, respectively, perhaps indicating that pioglitazone acts slightly differently when patients with NASH have T2DM, according to the investigators. “Although the effects on fibrosis appear to be similar in both groups, pioglitazone may contribute to halting [its] rapid progression [in T2DM],” they wrote. “These differences will deserve further exploration in larger clinical trials.”

The trial (NCT00994682) enrolled 101 patients with biopsy-confirmed NASH, of whom 52 had T2DM and 49 had prediabetes based on clinical history, baseline fasting plasma glucose, hemoglobin A_1c, and an oral glucose tolerance test, as per American Diabetes Association guidelines. After a 4-week run-in period, patients were randomly assigned to receive either pioglitazone (45 mg per day) or placebo for 18 months. All patients received lifestyle counseling and a hypocaloric (500-kcal reduced) diet.

Compared with placebo, pioglitazone improved most secondary outcomes similarly regardless of whether patients were T2DM or prediabetes. The two exceptions were fibrosis and insulin sensitivity of adipose tissue. Patients with T2DM only experienced improved fibrosis in the setting of pioglitazone therapy (P = .035 vs. baseline). In prediabetic patients, fibrosis lessened moderately over time, regardless of whether they received pioglitazone or placebo. Insulin sensitivity of adipose tissue improved much more markedly with treatment in patients with T2DM (P less than .001 vs. baseline) than in those with prediabetes (P = .002 for T2DM vs. prediabetes).

Compared with placebo, pioglitazone improved hepatic and skeletal muscle insulin sensitivity similarly, regardless of diabetes status. Likewise, intrahepatic triglyceride content, as measured by proton magnetic resonance spectroscopy, fell by 11% in pioglitazone recipients with T2DM and by 9% of those with prediabetes, a nonsignificant difference. Pioglitazone also led to a statistically similar decrease in plasma alanine aminotransferase level regardless of whether patients had T2DM (50 U/L) or were prediabetic (36 U/L).

This trial’s key takeaway is that pioglitazone improves liver histology in NASH whether or not patients are diabetic, said the researchers. “We believed that it was essential to compare its efficacy in patients with [and] without T2DM because of the vast number of patients with prediabetes and NASH and given the significant metabolic and cardioprotective effects of pioglitazone among patients without T2DM,” they wrote. The natural history of NASH is worse in the presence of T2DM, which might explain pioglitazone’s superior effects on fibrosis and insulin sensitivity of adipose tissue in this population, they added.

The Burroughs Wellcome Fund, the American Diabetes Association, and the Veteran’s Affairs Merit Award supported the work. Senior author Kenneth Cusi, MD, disclosed nonfinancial support from Takeda Pharmaceuticals, grants from Novartis and Janssen Research and Development, and consulting relationships with Eli Lilly, Tobira Therapeutics, and Pfizer. The other authors had no conflicts.

Source: Bril F, et al. Clin Gastroenterol Hepatol. 2018 Feb 24. doi: 10.1016/j.cgh.2017.12.001.

Pioglitazone therapy given for 18 months benefited patients with nonalcoholic steatohepatitis (NASH) similarly regardless of whether they had type 2 diabetes mellitus or prediabetes, according to the results of a randomized prospective trial.

SOURCE: AMERICAN GASTROENTEROLOGICAL ASSOCIATION

The primary outcome, at least a 2-point reduction in nonalcoholic fatty liver disease activity score compared with placebo, without worsening fibrosis, was met by 48% of NASH patients with T2DM and by 46% of those with prediabetes, reported Fernando Bril, MD, of the division of endocrinology, diabetes, and metabolism at the University of Florida, Gainesville, and his associates. The report was published in Clinical Gastroenterology and Hepatology.
 

NASH resolved completely in 44% with T2DM and 26% of patients without it, respectively, perhaps indicating that pioglitazone acts slightly differently when patients with NASH have T2DM, according to the investigators. “Although the effects on fibrosis appear to be similar in both groups, pioglitazone may contribute to halting [its] rapid progression [in T2DM],” they wrote. “These differences will deserve further exploration in larger clinical trials.”

The trial (NCT00994682) enrolled 101 patients with biopsy-confirmed NASH, of whom 52 had T2DM and 49 had prediabetes based on clinical history, baseline fasting plasma glucose, hemoglobin A_1c, and an oral glucose tolerance test, as per American Diabetes Association guidelines. After a 4-week run-in period, patients were randomly assigned to receive either pioglitazone (45 mg per day) or placebo for 18 months. All patients received lifestyle counseling and a hypocaloric (500-kcal reduced) diet.

Compared with placebo, pioglitazone improved most secondary outcomes similarly regardless of whether patients were T2DM or prediabetes. The two exceptions were fibrosis and insulin sensitivity of adipose tissue. Patients with T2DM only experienced improved fibrosis in the setting of pioglitazone therapy (P = .035 vs. baseline). In prediabetic patients, fibrosis lessened moderately over time, regardless of whether they received pioglitazone or placebo. Insulin sensitivity of adipose tissue improved much more markedly with treatment in patients with T2DM (P less than .001 vs. baseline) than in those with prediabetes (P = .002 for T2DM vs. prediabetes).

Compared with placebo, pioglitazone improved hepatic and skeletal muscle insulin sensitivity similarly, regardless of diabetes status. Likewise, intrahepatic triglyceride content, as measured by proton magnetic resonance spectroscopy, fell by 11% in pioglitazone recipients with T2DM and by 9% of those with prediabetes, a nonsignificant difference. Pioglitazone also led to a statistically similar decrease in plasma alanine aminotransferase level regardless of whether patients had T2DM (50 U/L) or were prediabetic (36 U/L).

This trial’s key takeaway is that pioglitazone improves liver histology in NASH whether or not patients are diabetic, said the researchers. “We believed that it was essential to compare its efficacy in patients with [and] without T2DM because of the vast number of patients with prediabetes and NASH and given the significant metabolic and cardioprotective effects of pioglitazone among patients without T2DM,” they wrote. The natural history of NASH is worse in the presence of T2DM, which might explain pioglitazone’s superior effects on fibrosis and insulin sensitivity of adipose tissue in this population, they added.

The Burroughs Wellcome Fund, the American Diabetes Association, and the Veteran’s Affairs Merit Award supported the work. Senior author Kenneth Cusi, MD, disclosed nonfinancial support from Takeda Pharmaceuticals, grants from Novartis and Janssen Research and Development, and consulting relationships with Eli Lilly, Tobira Therapeutics, and Pfizer. The other authors had no conflicts.

Source: Bril F, et al. Clin Gastroenterol Hepatol. 2018 Feb 24. doi: 10.1016/j.cgh.2017.12.001.

Psychogastroenterology is the science of applying psychological principles and techniques to alleviate the burden of chronic digestive diseases. This burden includes digestive symptoms and disease severity, as well as patients’ ability to cope with them. Chronic digestive diseases, such as irritable bowel syndrome, gastroesophageal reflux disease, and inflammatory bowel diseases, cannot be disentangled from their psychosocial context. In this regard, the role of gastroenterologists in promoting best practices for the assessment and referral of patients across the spectrum of disease to brain-gut psychotherapies is crucial.

A review by Laurie Keefer, PhD, AGAF, and her coauthors, published in the April issue of Gastroenterology, provided a clinical update on the structure and efficacy of two major classes of psychogastroenterology – cognitive-behavioral therapy (CBT) and gut-directed hypnotherapy (HYP). The review discussed the effects of these therapies on GI symptoms and the patients’ ability to improve coping, resilience, and self-regulation. The review also provided a framework to understand the scientific rationale and best practices associated with incorporating brain-gut psychotherapies into routine GI care. Furthermore, it presented recommendations on how to address psychological issues and make effective referrals in routine practice.

Previous studies had highlighted that the burden of chronic digestive diseases is amplified by psychosocial factors, including poor coping, depression, and poor social support. Mental health professionals specializing in psychogastroenterology integrate the use of brain-gut psychotherapies into GI practice settings, which may help reduce health care utilization and symptom burden.

The article contains best practice advice based on a review of the literature, including existing systematic reviews and expert opinions. These best practices include the following:

• Gastroenterologists routinely should assess health-related quality of life, symptom-specific anxieties, early-life adversity, and functional impairment related to a patient’s digestive complaints.
• Gastroenterologists should master patient-friendly language to help explain the brain-gut pathway and how this pathway can become dysregulated by any number of factors, the psychosocial risks perpetuating and maintaining factors of GI diseases, and why the gastroenterologist is referring a patient to a mental health provider.
• Gastroenterologists should know the structure and core features of the most effective brain-gut psychotherapies.
• Gastroenterologists should establish a direct referral and ongoing communication pathway with one or two qualified mental health providers and assure patients that he/she will remain a part of the care team.
• Gastroenterologists should familiarize themselves with one or two neuromodulators that can be used to augment behavioral therapies when necessary.

Patient education about the referral to a mental health provider is difficult and requires attention to detail and fostering a good physician-patient relationship. It is important to help patients understand why they are being referred to a psychologist for a gastrointestinal complaint and that their physical symptoms are not being discounted. Failure to properly explain the reason for referral may lead to poor follow-through and even lead the patient to seek care with another provider.

In order to foster widespread integration of these services, research and clinical gaps need to be addressed. Research gaps include the lack of prospective trials that compare the relative effectiveness of brain-gut psychotherapies with each other and/or with that of psychotropic medications. Other promising brain-gut therapies, such as mindfulness meditation or acceptance-based approaches, lack sufficient research to be included in clinical practice. Limited evidence supports the effect of psychotherapies have in accelerating or enhancing the efficacy of pharmacologic therapies and on improving disease course or inflammation in conditions such as Crohn’s and ulcerative colitis.

SOURCE: Keefer L et al. Gastroenterology. doi: 10.1053/j.gastro.2018.01.045.

Psychogastroenterology is the science of applying psychological principles and techniques to alleviate the burden of chronic digestive diseases. This burden includes digestive symptoms and disease severity, as well as patients’ ability to cope with them. Chronic digestive diseases, such as irritable bowel syndrome, gastroesophageal reflux disease, and inflammatory bowel diseases, cannot be disentangled from their psychosocial context. In this regard, the role of gastroenterologists in promoting best practices for the assessment and referral of patients across the spectrum of disease to brain-gut psychotherapies is crucial.

A review by Laurie Keefer, PhD, AGAF, and her coauthors, published in the April issue of Gastroenterology, provided a clinical update on the structure and efficacy of two major classes of psychogastroenterology – cognitive-behavioral therapy (CBT) and gut-directed hypnotherapy (HYP). The review discussed the effects of these therapies on GI symptoms and the patients’ ability to improve coping, resilience, and self-regulation. The review also provided a framework to understand the scientific rationale and best practices associated with incorporating brain-gut psychotherapies into routine GI care. Furthermore, it presented recommendations on how to address psychological issues and make effective referrals in routine practice.

Previous studies had highlighted that the burden of chronic digestive diseases is amplified by psychosocial factors, including poor coping, depression, and poor social support. Mental health professionals specializing in psychogastroenterology integrate the use of brain-gut psychotherapies into GI practice settings, which may help reduce health care utilization and symptom burden.

The article contains best practice advice based on a review of the literature, including existing systematic reviews and expert opinions. These best practices include the following:

• Gastroenterologists routinely should assess health-related quality of life, symptom-specific anxieties, early-life adversity, and functional impairment related to a patient’s digestive complaints.
• Gastroenterologists should master patient-friendly language to help explain the brain-gut pathway and how this pathway can become dysregulated by any number of factors, the psychosocial risks perpetuating and maintaining factors of GI diseases, and why the gastroenterologist is referring a patient to a mental health provider.
• Gastroenterologists should know the structure and core features of the most effective brain-gut psychotherapies.
• Gastroenterologists should establish a direct referral and ongoing communication pathway with one or two qualified mental health providers and assure patients that he/she will remain a part of the care team.
• Gastroenterologists should familiarize themselves with one or two neuromodulators that can be used to augment behavioral therapies when necessary.

Patient education about the referral to a mental health provider is difficult and requires attention to detail and fostering a good physician-patient relationship. It is important to help patients understand why they are being referred to a psychologist for a gastrointestinal complaint and that their physical symptoms are not being discounted. Failure to properly explain the reason for referral may lead to poor follow-through and even lead the patient to seek care with another provider.

In order to foster widespread integration of these services, research and clinical gaps need to be addressed. Research gaps include the lack of prospective trials that compare the relative effectiveness of brain-gut psychotherapies with each other and/or with that of psychotropic medications. Other promising brain-gut therapies, such as mindfulness meditation or acceptance-based approaches, lack sufficient research to be included in clinical practice. Limited evidence supports the effect of psychotherapies have in accelerating or enhancing the efficacy of pharmacologic therapies and on improving disease course or inflammation in conditions such as Crohn’s and ulcerative colitis.

SOURCE: Keefer L et al. Gastroenterology. doi: 10.1053/j.gastro.2018.01.045.

Psychogastroenterology is the science of applying psychological principles and techniques to alleviate the burden of chronic digestive diseases. This burden includes digestive symptoms and disease severity, as well as patients’ ability to cope with them. Chronic digestive diseases, such as irritable bowel syndrome, gastroesophageal reflux disease, and inflammatory bowel diseases, cannot be disentangled from their psychosocial context. In this regard, the role of gastroenterologists in promoting best practices for the assessment and referral of patients across the spectrum of disease to brain-gut psychotherapies is crucial.

A review by Laurie Keefer, PhD, AGAF, and her coauthors, published in the April issue of Gastroenterology, provided a clinical update on the structure and efficacy of two major classes of psychogastroenterology – cognitive-behavioral therapy (CBT) and gut-directed hypnotherapy (HYP). The review discussed the effects of these therapies on GI symptoms and the patients’ ability to improve coping, resilience, and self-regulation. The review also provided a framework to understand the scientific rationale and best practices associated with incorporating brain-gut psychotherapies into routine GI care. Furthermore, it presented recommendations on how to address psychological issues and make effective referrals in routine practice.

Previous studies had highlighted that the burden of chronic digestive diseases is amplified by psychosocial factors, including poor coping, depression, and poor social support. Mental health professionals specializing in psychogastroenterology integrate the use of brain-gut psychotherapies into GI practice settings, which may help reduce health care utilization and symptom burden.

The article contains best practice advice based on a review of the literature, including existing systematic reviews and expert opinions. These best practices include the following:

• Gastroenterologists routinely should assess health-related quality of life, symptom-specific anxieties, early-life adversity, and functional impairment related to a patient’s digestive complaints.
• Gastroenterologists should master patient-friendly language to help explain the brain-gut pathway and how this pathway can become dysregulated by any number of factors, the psychosocial risks perpetuating and maintaining factors of GI diseases, and why the gastroenterologist is referring a patient to a mental health provider.
• Gastroenterologists should know the structure and core features of the most effective brain-gut psychotherapies.
• Gastroenterologists should establish a direct referral and ongoing communication pathway with one or two qualified mental health providers and assure patients that he/she will remain a part of the care team.
• Gastroenterologists should familiarize themselves with one or two neuromodulators that can be used to augment behavioral therapies when necessary.

Patient education about the referral to a mental health provider is difficult and requires attention to detail and fostering a good physician-patient relationship. It is important to help patients understand why they are being referred to a psychologist for a gastrointestinal complaint and that their physical symptoms are not being discounted. Failure to properly explain the reason for referral may lead to poor follow-through and even lead the patient to seek care with another provider.

In order to foster widespread integration of these services, research and clinical gaps need to be addressed. Research gaps include the lack of prospective trials that compare the relative effectiveness of brain-gut psychotherapies with each other and/or with that of psychotropic medications. Other promising brain-gut therapies, such as mindfulness meditation or acceptance-based approaches, lack sufficient research to be included in clinical practice. Limited evidence supports the effect of psychotherapies have in accelerating or enhancing the efficacy of pharmacologic therapies and on improving disease course or inflammation in conditions such as Crohn’s and ulcerative colitis.

SOURCE: Keefer L et al. Gastroenterology. doi: 10.1053/j.gastro.2018.01.045.

Among patients with inflammatory bowel disease (IBD), opioid prescriptions tripled during a recent 20-year period, and heavy use of strong opioids was a significant predictor of all-cause mortality, according to a large cohort study reported in the April issue of Clinical Gastroenterology and Hepatology.

Because this study was retrospective, it could not establish causality, said Nicholas E. Burr, MD, of the University of Leeds (England) and his associates. But “[de]signing and conducting a large-scale randomized controlled trial may not be feasible,” they wrote. “Despite the limitations of observational data, population data sets may be the best method to investigate a potential effect.”

Liderina/Thinkstock

The gastrointestinal side effects of many analgesics complicate pain management for patients with IBD, who not only live with chronic abdominal pain but also can develop arthropathy-related musculoskeletal pain, chronic widespread pain, and fibromyalgia. In addition to the risk of narcotic bowel associated with opioid use in IBD, opioids can mask flares in IBD or can cause toxic dilatation if administered during acute flares, the researchers noted. Because few studies had examined opioid use in IBD, the investigators retrospectively studied 3,517 individuals with Crohn’s disease and 5,349 patients with ulcerative colitis from ResearchOne, a primary care electronic health records database that covers about 10% of patients in England. The data set excluded patients with indeterminate colitis or who underwent colectomy for ulcerative colitis.

From 1990 through 1993, only 10% of patients with IBD were prescribed opioids, vs. 30% from 2010 through 2013 (P less than .005). After the investigators controlled for numerous demographic and clinical variables, being prescribed a strong opioid (morphine, oxycodone, fentanyl, buprenorphine, methadone, hydromorphone, or pethidine) more than three times per year significantly correlated with all-cause mortality in both Crohn’s disease (hazard ratio, 2.2; 95% confidence interval, 1.2-4.0) and ulcerative colitis (HR, 3.3; 95% CI, 1.8-6.2), the researchers reported.Among patients with ulcerative colitis, more moderate use of strong opioids (one to three prescriptions annually) also significantly correlated with all-cause mortality (HR, 2.4; 95% CI, 1.2-5.2), as did heavy use of codeine (HR, 1.8; 95% CI, 1.1-3.1), but these associations did not reach statistical significance among patients with Crohn’s disease. Tramadol was not linked to mortality in either IBD subtype when used alone or in combination with codeine.

Dr. Burr and his associates said they could not control for several important potential confounders, including fistulating disease, quality of life, mental illness, substance abuse, and history of abuse, all of which have been linked to opioid use in IBD. Nonetheless, they found dose-dependent correlations with mortality that highlight a need for pharmacovigilance of opioids in IBD, particularly given dramatic increases in prescriptions, they said. These were primary care data, which tend to accurately reflect long-term medication use, they noted.

Crohn’s and Colitis U.K. and the Leeds Teaching Hospitals NHS Trust Charitable Foundation provided funding. The investigators reported having no conflicts of interest.

SOURCE: Burr NE et al. Clin Gastroenterol Hepatol. doi: 10.1016/j.cgh.2017.10.022.

Among patients with inflammatory bowel disease (IBD), opioid prescriptions tripled during a recent 20-year period, and heavy use of strong opioids was a significant predictor of all-cause mortality, according to a large cohort study reported in the April issue of Clinical Gastroenterology and Hepatology.

Because this study was retrospective, it could not establish causality, said Nicholas E. Burr, MD, of the University of Leeds (England) and his associates. But “[de]signing and conducting a large-scale randomized controlled trial may not be feasible,” they wrote. “Despite the limitations of observational data, population data sets may be the best method to investigate a potential effect.”

Liderina/Thinkstock

The gastrointestinal side effects of many analgesics complicate pain management for patients with IBD, who not only live with chronic abdominal pain but also can develop arthropathy-related musculoskeletal pain, chronic widespread pain, and fibromyalgia. In addition to the risk of narcotic bowel associated with opioid use in IBD, opioids can mask flares in IBD or can cause toxic dilatation if administered during acute flares, the researchers noted. Because few studies had examined opioid use in IBD, the investigators retrospectively studied 3,517 individuals with Crohn’s disease and 5,349 patients with ulcerative colitis from ResearchOne, a primary care electronic health records database that covers about 10% of patients in England. The data set excluded patients with indeterminate colitis or who underwent colectomy for ulcerative colitis.

From 1990 through 1993, only 10% of patients with IBD were prescribed opioids, vs. 30% from 2010 through 2013 (P less than .005). After the investigators controlled for numerous demographic and clinical variables, being prescribed a strong opioid (morphine, oxycodone, fentanyl, buprenorphine, methadone, hydromorphone, or pethidine) more than three times per year significantly correlated with all-cause mortality in both Crohn’s disease (hazard ratio, 2.2; 95% confidence interval, 1.2-4.0) and ulcerative colitis (HR, 3.3; 95% CI, 1.8-6.2), the researchers reported.Among patients with ulcerative colitis, more moderate use of strong opioids (one to three prescriptions annually) also significantly correlated with all-cause mortality (HR, 2.4; 95% CI, 1.2-5.2), as did heavy use of codeine (HR, 1.8; 95% CI, 1.1-3.1), but these associations did not reach statistical significance among patients with Crohn’s disease. Tramadol was not linked to mortality in either IBD subtype when used alone or in combination with codeine.

Dr. Burr and his associates said they could not control for several important potential confounders, including fistulating disease, quality of life, mental illness, substance abuse, and history of abuse, all of which have been linked to opioid use in IBD. Nonetheless, they found dose-dependent correlations with mortality that highlight a need for pharmacovigilance of opioids in IBD, particularly given dramatic increases in prescriptions, they said. These were primary care data, which tend to accurately reflect long-term medication use, they noted.

Crohn’s and Colitis U.K. and the Leeds Teaching Hospitals NHS Trust Charitable Foundation provided funding. The investigators reported having no conflicts of interest.

SOURCE: Burr NE et al. Clin Gastroenterol Hepatol. doi: 10.1016/j.cgh.2017.10.022.

Among patients with inflammatory bowel disease (IBD), opioid prescriptions tripled during a recent 20-year period, and heavy use of strong opioids was a significant predictor of all-cause mortality, according to a large cohort study reported in the April issue of Clinical Gastroenterology and Hepatology.

Because this study was retrospective, it could not establish causality, said Nicholas E. Burr, MD, of the University of Leeds (England) and his associates. But “[de]signing and conducting a large-scale randomized controlled trial may not be feasible,” they wrote. “Despite the limitations of observational data, population data sets may be the best method to investigate a potential effect.”

Liderina/Thinkstock

The gastrointestinal side effects of many analgesics complicate pain management for patients with IBD, who not only live with chronic abdominal pain but also can develop arthropathy-related musculoskeletal pain, chronic widespread pain, and fibromyalgia. In addition to the risk of narcotic bowel associated with opioid use in IBD, opioids can mask flares in IBD or can cause toxic dilatation if administered during acute flares, the researchers noted. Because few studies had examined opioid use in IBD, the investigators retrospectively studied 3,517 individuals with Crohn’s disease and 5,349 patients with ulcerative colitis from ResearchOne, a primary care electronic health records database that covers about 10% of patients in England. The data set excluded patients with indeterminate colitis or who underwent colectomy for ulcerative colitis.

From 1990 through 1993, only 10% of patients with IBD were prescribed opioids, vs. 30% from 2010 through 2013 (P less than .005). After the investigators controlled for numerous demographic and clinical variables, being prescribed a strong opioid (morphine, oxycodone, fentanyl, buprenorphine, methadone, hydromorphone, or pethidine) more than three times per year significantly correlated with all-cause mortality in both Crohn’s disease (hazard ratio, 2.2; 95% confidence interval, 1.2-4.0) and ulcerative colitis (HR, 3.3; 95% CI, 1.8-6.2), the researchers reported.Among patients with ulcerative colitis, more moderate use of strong opioids (one to three prescriptions annually) also significantly correlated with all-cause mortality (HR, 2.4; 95% CI, 1.2-5.2), as did heavy use of codeine (HR, 1.8; 95% CI, 1.1-3.1), but these associations did not reach statistical significance among patients with Crohn’s disease. Tramadol was not linked to mortality in either IBD subtype when used alone or in combination with codeine.

Dr. Burr and his associates said they could not control for several important potential confounders, including fistulating disease, quality of life, mental illness, substance abuse, and history of abuse, all of which have been linked to opioid use in IBD. Nonetheless, they found dose-dependent correlations with mortality that highlight a need for pharmacovigilance of opioids in IBD, particularly given dramatic increases in prescriptions, they said. These were primary care data, which tend to accurately reflect long-term medication use, they noted.

Crohn’s and Colitis U.K. and the Leeds Teaching Hospitals NHS Trust Charitable Foundation provided funding. The investigators reported having no conflicts of interest.

SOURCE: Burr NE et al. Clin Gastroenterol Hepatol. doi: 10.1016/j.cgh.2017.10.022.

Bioengineered liver models have enabled recapitulation of liver architecture with precise control over cellular microenvironments, resulting in stabilized liver functions for several weeks in vitro. Studies have focused on using these models to investigate cell responses to drugs and other stimuli (for example, viruses and cell differentiation cues) to predict clinical outcomes. Gregory H. Underhill, PhD, from the department of bioengineering at the University of Illinois at Urbana-Champaign and Salman R. Khetani, PhD, from the department of bioengineering at the University of Illinois in Chicago presented a comprehensive review of the these advances in bioengineered liver models in Cellular and Molecular Gastroenterology and Hepatology (doi: 10.1016/j.jcmgh.2017.11.012).

Drug-induced liver injury (DILI) is a leading cause of drug attrition in the United States, with some marketed drugs causing cell necrosis, hepatitis, cholestasis, fibrosis, or a mixture of injury types. Although the Food and Drug Administration requires preclinical drug testing in animal models, differences in species-specific drug metabolism pathways and human genetics may result in inadequate identification of potential for human DILI. Some bioengineered liver models for in vitro studies are based on tissue engineering using high-throughput microarrays, protein micropatterning, microfluidics, specialized plates, biomaterial scaffolds, and bioprinting.

High-throughput cell microarrays enable systematic analysis of a large number of drugs or compounds at a relatively low cost. Several culture platforms have been developed using multiple sources of liver cells, including cancerous and immortalized cell lines. These platforms show enhanced capabilities to evaluate combinatorial effects of multiple signals with independent control of biochemical and biomechanical cues. For instance, a microchip platform for transducing 3-D liver cell cultures with genes for drug metabolism enzymes featuring 532 reaction vessels (micropillars and corresponding microwells) was able to provide information about certain enzyme combinations that led to drug toxicity in cells. The high-throughput cell microarrays are, however, primarily dependent on imaging-based readouts and have a limited ability to investigate cell responses to gradients of microenvironmental signals.

Liver development, physiology, and pathophysiology are dependent on homotypic and heterotypic interactions between parenchymal and nonparenchymal cells (NPCs). Cocultures with both liver- and nonliver-derived NPC types, in vitro, can induce liver functions transiently and have proven useful for investigating host responses to sepsis, mutagenesis, xenobiotic metabolism and toxicity, response to oxidative stress, lipid metabolism, and induction of the acute-phase response. Micropatterned cocultures (MPCCs) are designed to allow the use of different NPC types without significantly altering hepatocyte homotypic interactions. Cell-cell interactions can be precisely controlled to allow for stable functions for up to 4-6 weeks, whereas more randomly distributed cocultures have limited stability. Unlike randomly distributed cocultures, MPCCs can be infected with HBV, HCV, and malaria. Potential limitations of MPCCs include the requirement for specialized equipment and devices for patterning collagen for hepatocyte attachment.

Randomly distributed spheroids or organoids enable 3-D establishment of homotypic cell-cell interactions surrounded by an extracellular matrix. The spheroids can be further cocultured with NPCs that facilitate heterotypic cell-cell interactions and allow the evaluation of outcomes resulting from drugs and other stimuli. Hepatic spheroids maintain major liver functions for several weeks and have proven to be compatible with multiple applications within the drug development pipeline.

These spheroids showed greater sensitivity in identifying known hepatotoxic drugs than did short-term primary human hepatocyte (PHH) monolayers. PHHs secreted liver proteins, such as albumin, transferrin, and fibrinogen, and showed cytochrome-P450 activities for 77-90 days when cultured on a nylon scaffold containing a mixture of liver NPCs and PHHs.

Nanopillar plates can be used to create induced pluripotent stem cell–derived human hepatocyte-like cell (iHep) spheroids; although these spheroids showed some potential for initial drug toxicity screening, they had lower overall sensitivity than conventional PHH monolayers, which suggests that further maturation of iHeps is likely required.

Potential limitations of randomly distributed spheroids include necrosis of cells in the center of larger spheroids and the requirement for expensive confocal microscopy for high-content imaging of entire spheroid cultures. To overcome the limitation of disorganized cell type interactions over time within the randomly distributed spheroids/organoids, bioprinted human liver organoids are designed to allow precise control of cell placement.

Yet another bioengineered liver model is based on perfusion systems or bioreactors that enable dynamic fluid flow for nutrient and waste exchange. These so called liver-on-a-chip devices contain hepatocyte aggregates adhered to collagen-coated microchannel walls; these are then perfused at optimal flow rates both to meet the oxygen demands of the hepatocytes and deliver low shear stress to the cells that’s similar to what would be the case in vivo. Layered architectures can be created with single-chamber or multichamber, microfluidic device designs that can sustain cell functionality for 2-4 weeks.

Some of the limitations of perfusion systems include the potential binding of drugs to tubing and materials used, large dead volume requiring higher quantities of novel compounds for the treatment of cell cultures, low throughput, and washing away of built-up beneficial molecules with perfusion.

The ongoing development of more sophisticated engineering tools for manipulating cells in culture will lead to continued advances in bioengineered livers that will show improving sensitivity for the prediction of clinically relevant drug and disease outcomes.

This work was funded by National Institutes of Health grants. The author Dr. Khetani disclosed a conflict of interest with Ascendance Biotechnology, which has licensed the micropatterned coculture and related systems from Massachusetts Institute of Technology, Cambridge, and Colorado State University, Fort Collins, for commercial distribution. Dr. Underhill disclosed no conflicts.

SOURCE: Underhill GH and Khetani SR. Cell Molec Gastro Hepatol. 2017. doi: org/10.1016/j.jcmgh.2017.11.012.

Bioengineered liver models have enabled recapitulation of liver architecture with precise control over cellular microenvironments, resulting in stabilized liver functions for several weeks in vitro. Studies have focused on using these models to investigate cell responses to drugs and other stimuli (for example, viruses and cell differentiation cues) to predict clinical outcomes. Gregory H. Underhill, PhD, from the department of bioengineering at the University of Illinois at Urbana-Champaign and Salman R. Khetani, PhD, from the department of bioengineering at the University of Illinois in Chicago presented a comprehensive review of the these advances in bioengineered liver models in Cellular and Molecular Gastroenterology and Hepatology (doi: 10.1016/j.jcmgh.2017.11.012).

Drug-induced liver injury (DILI) is a leading cause of drug attrition in the United States, with some marketed drugs causing cell necrosis, hepatitis, cholestasis, fibrosis, or a mixture of injury types. Although the Food and Drug Administration requires preclinical drug testing in animal models, differences in species-specific drug metabolism pathways and human genetics may result in inadequate identification of potential for human DILI. Some bioengineered liver models for in vitro studies are based on tissue engineering using high-throughput microarrays, protein micropatterning, microfluidics, specialized plates, biomaterial scaffolds, and bioprinting.

High-throughput cell microarrays enable systematic analysis of a large number of drugs or compounds at a relatively low cost. Several culture platforms have been developed using multiple sources of liver cells, including cancerous and immortalized cell lines. These platforms show enhanced capabilities to evaluate combinatorial effects of multiple signals with independent control of biochemical and biomechanical cues. For instance, a microchip platform for transducing 3-D liver cell cultures with genes for drug metabolism enzymes featuring 532 reaction vessels (micropillars and corresponding microwells) was able to provide information about certain enzyme combinations that led to drug toxicity in cells. The high-throughput cell microarrays are, however, primarily dependent on imaging-based readouts and have a limited ability to investigate cell responses to gradients of microenvironmental signals.

Liver development, physiology, and pathophysiology are dependent on homotypic and heterotypic interactions between parenchymal and nonparenchymal cells (NPCs). Cocultures with both liver- and nonliver-derived NPC types, in vitro, can induce liver functions transiently and have proven useful for investigating host responses to sepsis, mutagenesis, xenobiotic metabolism and toxicity, response to oxidative stress, lipid metabolism, and induction of the acute-phase response. Micropatterned cocultures (MPCCs) are designed to allow the use of different NPC types without significantly altering hepatocyte homotypic interactions. Cell-cell interactions can be precisely controlled to allow for stable functions for up to 4-6 weeks, whereas more randomly distributed cocultures have limited stability. Unlike randomly distributed cocultures, MPCCs can be infected with HBV, HCV, and malaria. Potential limitations of MPCCs include the requirement for specialized equipment and devices for patterning collagen for hepatocyte attachment.

Randomly distributed spheroids or organoids enable 3-D establishment of homotypic cell-cell interactions surrounded by an extracellular matrix. The spheroids can be further cocultured with NPCs that facilitate heterotypic cell-cell interactions and allow the evaluation of outcomes resulting from drugs and other stimuli. Hepatic spheroids maintain major liver functions for several weeks and have proven to be compatible with multiple applications within the drug development pipeline.

These spheroids showed greater sensitivity in identifying known hepatotoxic drugs than did short-term primary human hepatocyte (PHH) monolayers. PHHs secreted liver proteins, such as albumin, transferrin, and fibrinogen, and showed cytochrome-P450 activities for 77-90 days when cultured on a nylon scaffold containing a mixture of liver NPCs and PHHs.

Nanopillar plates can be used to create induced pluripotent stem cell–derived human hepatocyte-like cell (iHep) spheroids; although these spheroids showed some potential for initial drug toxicity screening, they had lower overall sensitivity than conventional PHH monolayers, which suggests that further maturation of iHeps is likely required.

Potential limitations of randomly distributed spheroids include necrosis of cells in the center of larger spheroids and the requirement for expensive confocal microscopy for high-content imaging of entire spheroid cultures. To overcome the limitation of disorganized cell type interactions over time within the randomly distributed spheroids/organoids, bioprinted human liver organoids are designed to allow precise control of cell placement.

Yet another bioengineered liver model is based on perfusion systems or bioreactors that enable dynamic fluid flow for nutrient and waste exchange. These so called liver-on-a-chip devices contain hepatocyte aggregates adhered to collagen-coated microchannel walls; these are then perfused at optimal flow rates both to meet the oxygen demands of the hepatocytes and deliver low shear stress to the cells that’s similar to what would be the case in vivo. Layered architectures can be created with single-chamber or multichamber, microfluidic device designs that can sustain cell functionality for 2-4 weeks.

Some of the limitations of perfusion systems include the potential binding of drugs to tubing and materials used, large dead volume requiring higher quantities of novel compounds for the treatment of cell cultures, low throughput, and washing away of built-up beneficial molecules with perfusion.

The ongoing development of more sophisticated engineering tools for manipulating cells in culture will lead to continued advances in bioengineered livers that will show improving sensitivity for the prediction of clinically relevant drug and disease outcomes.

This work was funded by National Institutes of Health grants. The author Dr. Khetani disclosed a conflict of interest with Ascendance Biotechnology, which has licensed the micropatterned coculture and related systems from Massachusetts Institute of Technology, Cambridge, and Colorado State University, Fort Collins, for commercial distribution. Dr. Underhill disclosed no conflicts.

SOURCE: Underhill GH and Khetani SR. Cell Molec Gastro Hepatol. 2017. doi: org/10.1016/j.jcmgh.2017.11.012.

Bioengineered liver models have enabled recapitulation of liver architecture with precise control over cellular microenvironments, resulting in stabilized liver functions for several weeks in vitro. Studies have focused on using these models to investigate cell responses to drugs and other stimuli (for example, viruses and cell differentiation cues) to predict clinical outcomes. Gregory H. Underhill, PhD, from the department of bioengineering at the University of Illinois at Urbana-Champaign and Salman R. Khetani, PhD, from the department of bioengineering at the University of Illinois in Chicago presented a comprehensive review of the these advances in bioengineered liver models in Cellular and Molecular Gastroenterology and Hepatology (doi: 10.1016/j.jcmgh.2017.11.012).

Drug-induced liver injury (DILI) is a leading cause of drug attrition in the United States, with some marketed drugs causing cell necrosis, hepatitis, cholestasis, fibrosis, or a mixture of injury types. Although the Food and Drug Administration requires preclinical drug testing in animal models, differences in species-specific drug metabolism pathways and human genetics may result in inadequate identification of potential for human DILI. Some bioengineered liver models for in vitro studies are based on tissue engineering using high-throughput microarrays, protein micropatterning, microfluidics, specialized plates, biomaterial scaffolds, and bioprinting.

High-throughput cell microarrays enable systematic analysis of a large number of drugs or compounds at a relatively low cost. Several culture platforms have been developed using multiple sources of liver cells, including cancerous and immortalized cell lines. These platforms show enhanced capabilities to evaluate combinatorial effects of multiple signals with independent control of biochemical and biomechanical cues. For instance, a microchip platform for transducing 3-D liver cell cultures with genes for drug metabolism enzymes featuring 532 reaction vessels (micropillars and corresponding microwells) was able to provide information about certain enzyme combinations that led to drug toxicity in cells. The high-throughput cell microarrays are, however, primarily dependent on imaging-based readouts and have a limited ability to investigate cell responses to gradients of microenvironmental signals.

Liver development, physiology, and pathophysiology are dependent on homotypic and heterotypic interactions between parenchymal and nonparenchymal cells (NPCs). Cocultures with both liver- and nonliver-derived NPC types, in vitro, can induce liver functions transiently and have proven useful for investigating host responses to sepsis, mutagenesis, xenobiotic metabolism and toxicity, response to oxidative stress, lipid metabolism, and induction of the acute-phase response. Micropatterned cocultures (MPCCs) are designed to allow the use of different NPC types without significantly altering hepatocyte homotypic interactions. Cell-cell interactions can be precisely controlled to allow for stable functions for up to 4-6 weeks, whereas more randomly distributed cocultures have limited stability. Unlike randomly distributed cocultures, MPCCs can be infected with HBV, HCV, and malaria. Potential limitations of MPCCs include the requirement for specialized equipment and devices for patterning collagen for hepatocyte attachment.

Randomly distributed spheroids or organoids enable 3-D establishment of homotypic cell-cell interactions surrounded by an extracellular matrix. The spheroids can be further cocultured with NPCs that facilitate heterotypic cell-cell interactions and allow the evaluation of outcomes resulting from drugs and other stimuli. Hepatic spheroids maintain major liver functions for several weeks and have proven to be compatible with multiple applications within the drug development pipeline.

These spheroids showed greater sensitivity in identifying known hepatotoxic drugs than did short-term primary human hepatocyte (PHH) monolayers. PHHs secreted liver proteins, such as albumin, transferrin, and fibrinogen, and showed cytochrome-P450 activities for 77-90 days when cultured on a nylon scaffold containing a mixture of liver NPCs and PHHs.

Nanopillar plates can be used to create induced pluripotent stem cell–derived human hepatocyte-like cell (iHep) spheroids; although these spheroids showed some potential for initial drug toxicity screening, they had lower overall sensitivity than conventional PHH monolayers, which suggests that further maturation of iHeps is likely required.

Potential limitations of randomly distributed spheroids include necrosis of cells in the center of larger spheroids and the requirement for expensive confocal microscopy for high-content imaging of entire spheroid cultures. To overcome the limitation of disorganized cell type interactions over time within the randomly distributed spheroids/organoids, bioprinted human liver organoids are designed to allow precise control of cell placement.

Yet another bioengineered liver model is based on perfusion systems or bioreactors that enable dynamic fluid flow for nutrient and waste exchange. These so called liver-on-a-chip devices contain hepatocyte aggregates adhered to collagen-coated microchannel walls; these are then perfused at optimal flow rates both to meet the oxygen demands of the hepatocytes and deliver low shear stress to the cells that’s similar to what would be the case in vivo. Layered architectures can be created with single-chamber or multichamber, microfluidic device designs that can sustain cell functionality for 2-4 weeks.

Some of the limitations of perfusion systems include the potential binding of drugs to tubing and materials used, large dead volume requiring higher quantities of novel compounds for the treatment of cell cultures, low throughput, and washing away of built-up beneficial molecules with perfusion.

The ongoing development of more sophisticated engineering tools for manipulating cells in culture will lead to continued advances in bioengineered livers that will show improving sensitivity for the prediction of clinically relevant drug and disease outcomes.

This work was funded by National Institutes of Health grants. The author Dr. Khetani disclosed a conflict of interest with Ascendance Biotechnology, which has licensed the micropatterned coculture and related systems from Massachusetts Institute of Technology, Cambridge, and Colorado State University, Fort Collins, for commercial distribution. Dr. Underhill disclosed no conflicts.

SOURCE: Underhill GH and Khetani SR. Cell Molec Gastro Hepatol. 2017. doi: org/10.1016/j.jcmgh.2017.11.012.

Recently, exciting clinical progress has been made in the study of hepatotropic pathogens in the context of liver-dependent infectious diseases. Tissue engineering has been applied to authentically recapitulate human liver biology, facilitating the study of host-pathogen interactions during the entire pathogen life cycle. This is crucial for the development and validation of therapeutic interventions, such as drug and vaccine candidates that may act on the liver cells. The engineered models range from two-dimensional (2-D) cultures of primary human hepatocytes (HH) and stem cell–derived progeny to three-dimensional (3-D) organoid cultures and humanized rodent models. A review by Nil Gural and colleagues, published in Cellular and Molecular Gastroenterology and Hepatology, described these unique models. Furthermore, the progress made in combining individual approaches and pairing the most appropriate model system and readout modality was discussed.

The major human hepatotropic pathogens include hepatitis C virus (HCV), hepatitis B virus (HBV), and the protozoan parasites Plasmodium falciparum and P. vivax. While HBV and HCV can cause chronic liver diseases such as cirrhosis and hepatocellular carcinoma, Plasmodium parasites cause malaria. The use of cancer cell lines and animal models to study host-pathogen interactions is limited by uncontrolled proliferation, abnormal liver-specific functions, and stringent host dependency of the hepatotropic pathogens. HHs are thus the only ideal system to study these pathogens, however, maintaining these cells ex vivo is challenging.

For instance, 2D monolayers of human hepatoma-derived cell lines (such as HepG2-A16 and HepaRG) are easier to maintain, to amplify for scaling up, and to use for drug screening, thus representing a renewable alternative to primary hepatocytes. These model systems have been useful to study short-term infections of human Plasmodium parasites (P. vivax and P. falciparum); other hepatotropic pathogens such as Ebola, Lassa, human cytomegalovirus, and dengue viruses; and to generate virion stocks (HCV, HBV). For long-term scientific analyses and cultures, as well as clinical isolates of pathogens that do not infect hepatoma cells, immortalized cell lines have been engineered to differentiate and maintain HH functions for a longer duration. Additionally, cocultivation of primary hepatocytes with nonparenchymal cells or hepatocytes with mouse fibroblasts preserves hepatocyte phenotype. The latter is a self-assembling coculture system that could potentially maintain an infection for over 30 days and be used for testing anti-HBV drugs. A micropatterned coculture system, in which hepatocytes are positioned in “islands” via photolithographic patterning of collagen, surrounded by mouse embryonic fibroblasts, can maintain hepatocyte phenotypes for 4-6 weeks, and remain permissive to P. falciparum, P. vivax, HBV, and HCV infections. Furthermore, micropatterned coculture systems support full developmental liver stages of both P. falciparum and P. vivax, with the release of merozoites from hepatocytes and their subsequent infection of overlaid human red blood cells.

Alternatively, embryonic stem cells and induced pluripotent stem cells of human origin can be differentiated into hepatocytelike cells that enable investigation of host genetics within the context of host-pathogen interactions, and can also be used for target identification for drug development. However, stem cell cultures require significant culture expertise and may not represent a fully differentiated adult hepatocyte phenotype.

Recently, exciting clinical progress has been made in the study of hepatotropic pathogens in the context of liver-dependent infectious diseases. Tissue engineering has been applied to authentically recapitulate human liver biology, facilitating the study of host-pathogen interactions during the entire pathogen life cycle. This is crucial for the development and validation of therapeutic interventions, such as drug and vaccine candidates that may act on the liver cells. The engineered models range from two-dimensional (2-D) cultures of primary human hepatocytes (HH) and stem cell–derived progeny to three-dimensional (3-D) organoid cultures and humanized rodent models. A review by Nil Gural and colleagues, published in Cellular and Molecular Gastroenterology and Hepatology, described these unique models. Furthermore, the progress made in combining individual approaches and pairing the most appropriate model system and readout modality was discussed.

The major human hepatotropic pathogens include hepatitis C virus (HCV), hepatitis B virus (HBV), and the protozoan parasites Plasmodium falciparum and P. vivax. While HBV and HCV can cause chronic liver diseases such as cirrhosis and hepatocellular carcinoma, Plasmodium parasites cause malaria. The use of cancer cell lines and animal models to study host-pathogen interactions is limited by uncontrolled proliferation, abnormal liver-specific functions, and stringent host dependency of the hepatotropic pathogens. HHs are thus the only ideal system to study these pathogens, however, maintaining these cells ex vivo is challenging.

For instance, 2D monolayers of human hepatoma-derived cell lines (such as HepG2-A16 and HepaRG) are easier to maintain, to amplify for scaling up, and to use for drug screening, thus representing a renewable alternative to primary hepatocytes. These model systems have been useful to study short-term infections of human Plasmodium parasites (P. vivax and P. falciparum); other hepatotropic pathogens such as Ebola, Lassa, human cytomegalovirus, and dengue viruses; and to generate virion stocks (HCV, HBV). For long-term scientific analyses and cultures, as well as clinical isolates of pathogens that do not infect hepatoma cells, immortalized cell lines have been engineered to differentiate and maintain HH functions for a longer duration. Additionally, cocultivation of primary hepatocytes with nonparenchymal cells or hepatocytes with mouse fibroblasts preserves hepatocyte phenotype. The latter is a self-assembling coculture system that could potentially maintain an infection for over 30 days and be used for testing anti-HBV drugs. A micropatterned coculture system, in which hepatocytes are positioned in “islands” via photolithographic patterning of collagen, surrounded by mouse embryonic fibroblasts, can maintain hepatocyte phenotypes for 4-6 weeks, and remain permissive to P. falciparum, P. vivax, HBV, and HCV infections. Furthermore, micropatterned coculture systems support full developmental liver stages of both P. falciparum and P. vivax, with the release of merozoites from hepatocytes and their subsequent infection of overlaid human red blood cells.

Alternatively, embryonic stem cells and induced pluripotent stem cells of human origin can be differentiated into hepatocytelike cells that enable investigation of host genetics within the context of host-pathogen interactions, and can also be used for target identification for drug development. However, stem cell cultures require significant culture expertise and may not represent a fully differentiated adult hepatocyte phenotype.

Recently, exciting clinical progress has been made in the study of hepatotropic pathogens in the context of liver-dependent infectious diseases. Tissue engineering has been applied to authentically recapitulate human liver biology, facilitating the study of host-pathogen interactions during the entire pathogen life cycle. This is crucial for the development and validation of therapeutic interventions, such as drug and vaccine candidates that may act on the liver cells. The engineered models range from two-dimensional (2-D) cultures of primary human hepatocytes (HH) and stem cell–derived progeny to three-dimensional (3-D) organoid cultures and humanized rodent models. A review by Nil Gural and colleagues, published in Cellular and Molecular Gastroenterology and Hepatology, described these unique models. Furthermore, the progress made in combining individual approaches and pairing the most appropriate model system and readout modality was discussed.

The major human hepatotropic pathogens include hepatitis C virus (HCV), hepatitis B virus (HBV), and the protozoan parasites Plasmodium falciparum and P. vivax. While HBV and HCV can cause chronic liver diseases such as cirrhosis and hepatocellular carcinoma, Plasmodium parasites cause malaria. The use of cancer cell lines and animal models to study host-pathogen interactions is limited by uncontrolled proliferation, abnormal liver-specific functions, and stringent host dependency of the hepatotropic pathogens. HHs are thus the only ideal system to study these pathogens, however, maintaining these cells ex vivo is challenging.

For instance, 2D monolayers of human hepatoma-derived cell lines (such as HepG2-A16 and HepaRG) are easier to maintain, to amplify for scaling up, and to use for drug screening, thus representing a renewable alternative to primary hepatocytes. These model systems have been useful to study short-term infections of human Plasmodium parasites (P. vivax and P. falciparum); other hepatotropic pathogens such as Ebola, Lassa, human cytomegalovirus, and dengue viruses; and to generate virion stocks (HCV, HBV). For long-term scientific analyses and cultures, as well as clinical isolates of pathogens that do not infect hepatoma cells, immortalized cell lines have been engineered to differentiate and maintain HH functions for a longer duration. Additionally, cocultivation of primary hepatocytes with nonparenchymal cells or hepatocytes with mouse fibroblasts preserves hepatocyte phenotype. The latter is a self-assembling coculture system that could potentially maintain an infection for over 30 days and be used for testing anti-HBV drugs. A micropatterned coculture system, in which hepatocytes are positioned in “islands” via photolithographic patterning of collagen, surrounded by mouse embryonic fibroblasts, can maintain hepatocyte phenotypes for 4-6 weeks, and remain permissive to P. falciparum, P. vivax, HBV, and HCV infections. Furthermore, micropatterned coculture systems support full developmental liver stages of both P. falciparum and P. vivax, with the release of merozoites from hepatocytes and their subsequent infection of overlaid human red blood cells.

Alternatively, embryonic stem cells and induced pluripotent stem cells of human origin can be differentiated into hepatocytelike cells that enable investigation of host genetics within the context of host-pathogen interactions, and can also be used for target identification for drug development. However, stem cell cultures require significant culture expertise and may not represent a fully differentiated adult hepatocyte phenotype.

Endoscopic treatment of T1a esophageal adenocarcinoma outperformed esophagectomy across a range of ages and comorbidity levels in a Markov model.

Esophagectomy produced 0.16 more unadjusted life-years, but led to 0.27 fewer quality-adjusted life-years (QALYs), in the hypothetical case of a 75-year-old man with T1aN0M0 esophageal adenocarcinoma (EAC) and a Charlson comorbidity index score of 0, reported Jacqueline N. Chu, MD, of Massachusetts General Hospital, Boston, and her associates. “[We] believe QALYs are a more important endpoint because of the significant morbidity associated with esophagectomy,” they wrote in the March issue of Clinical Gastroenterology and Hepatology.

Source: American Gastroenterological Association

In contrast, the model portrayed the management of T1b EAC as “an individualized decision” – esophagectomy was preferable in 60- to 70-year-old patients with T1b EAC, but serial endoscopic treatment was better when patients were older, with more comorbidities, the researchers said. “For the sickest patients, those aged 80 and older with comorbidity index of 2, endoscopic treatment not only provided more QALYs but more unadjusted life years as well.”

Treatment of T1a EAC is transitioning from esophagectomy to serial endoscopic resection, which physicians still tend to regard as too risky in T1b EAC. The Markov model evaluated the efficacy and cost efficacy of the two approaches in hypothetical T1a and T1b patients of various ages and comorbidities, using cancer death data from the Surveillance, Epidemiology, and End Results (SEER) Medicare database and published cost data converted to 2017 U.S. dollars based on the U.S. Bureau of Labor Statistics’ Consumer Price Index.

SOURCE: Chu JN et al. Clin Gastroenterol Hepatol. 2017 Nov 24. doi: 10.1016/j.cgh.2017.10.024.

Endoscopic treatment of T1a esophageal adenocarcinoma outperformed esophagectomy across a range of ages and comorbidity levels in a Markov model.

Esophagectomy produced 0.16 more unadjusted life-years, but led to 0.27 fewer quality-adjusted life-years (QALYs), in the hypothetical case of a 75-year-old man with T1aN0M0 esophageal adenocarcinoma (EAC) and a Charlson comorbidity index score of 0, reported Jacqueline N. Chu, MD, of Massachusetts General Hospital, Boston, and her associates. “[We] believe QALYs are a more important endpoint because of the significant morbidity associated with esophagectomy,” they wrote in the March issue of Clinical Gastroenterology and Hepatology.

Source: American Gastroenterological Association

In contrast, the model portrayed the management of T1b EAC as “an individualized decision” – esophagectomy was preferable in 60- to 70-year-old patients with T1b EAC, but serial endoscopic treatment was better when patients were older, with more comorbidities, the researchers said. “For the sickest patients, those aged 80 and older with comorbidity index of 2, endoscopic treatment not only provided more QALYs but more unadjusted life years as well.”

Treatment of T1a EAC is transitioning from esophagectomy to serial endoscopic resection, which physicians still tend to regard as too risky in T1b EAC. The Markov model evaluated the efficacy and cost efficacy of the two approaches in hypothetical T1a and T1b patients of various ages and comorbidities, using cancer death data from the Surveillance, Epidemiology, and End Results (SEER) Medicare database and published cost data converted to 2017 U.S. dollars based on the U.S. Bureau of Labor Statistics’ Consumer Price Index.

SOURCE: Chu JN et al. Clin Gastroenterol Hepatol. 2017 Nov 24. doi: 10.1016/j.cgh.2017.10.024.

Endoscopic treatment of T1a esophageal adenocarcinoma outperformed esophagectomy across a range of ages and comorbidity levels in a Markov model.

Esophagectomy produced 0.16 more unadjusted life-years, but led to 0.27 fewer quality-adjusted life-years (QALYs), in the hypothetical case of a 75-year-old man with T1aN0M0 esophageal adenocarcinoma (EAC) and a Charlson comorbidity index score of 0, reported Jacqueline N. Chu, MD, of Massachusetts General Hospital, Boston, and her associates. “[We] believe QALYs are a more important endpoint because of the significant morbidity associated with esophagectomy,” they wrote in the March issue of Clinical Gastroenterology and Hepatology.

Source: American Gastroenterological Association

In contrast, the model portrayed the management of T1b EAC as “an individualized decision” – esophagectomy was preferable in 60- to 70-year-old patients with T1b EAC, but serial endoscopic treatment was better when patients were older, with more comorbidities, the researchers said. “For the sickest patients, those aged 80 and older with comorbidity index of 2, endoscopic treatment not only provided more QALYs but more unadjusted life years as well.”

Treatment of T1a EAC is transitioning from esophagectomy to serial endoscopic resection, which physicians still tend to regard as too risky in T1b EAC. The Markov model evaluated the efficacy and cost efficacy of the two approaches in hypothetical T1a and T1b patients of various ages and comorbidities, using cancer death data from the Surveillance, Epidemiology, and End Results (SEER) Medicare database and published cost data converted to 2017 U.S. dollars based on the U.S. Bureau of Labor Statistics’ Consumer Price Index.

SOURCE: Chu JN et al. Clin Gastroenterol Hepatol. 2017 Nov 24. doi: 10.1016/j.cgh.2017.10.024.

Between 70% and 80% of patients with ulcerative colitis relapsed within 10 years of diagnosis and 10%-15% had aggressive disease in a meta-analysis of 17 population-based cohorts spanning 1935 to 2016.

However, “contemporary population-based cohorts of patients diagnosed in the biologic era are lacking,” [and they] “may inform us of the population-level impact of paradigm shifts in approach to ulcerative colitis management during the last decade, such as early use of disease-modifying biologic therapy and treat-to-target [strategies],” wrote Mathurin Fumery, MD, of the University of California San Diego, La Jolla. The report was published in Clinical Gastroenterology and Hepatology (2017 Jun 16. doi: 10.1016/j.cgh.2017.06.016).

Population-based observational cohort studies follow an entire group in a geographic area over an extended time, which better characterizes the true natural history of disease outside highly controlled settings of clinical trials, the reviewers noted. They searched MEDLINE for population-based longitudinal studies of adults with newly diagnosed ulcerative colitis, whose medical records were reviewed, and who were followed for at least a year. They identified 60 such studies of 17 cohorts that included 15,316 patients in southern and northern Europe, Australia, Israel, the United States, Canada, China, Hong Kong, Indonesia, Sri Lanka, Macau, Malaysia, Singapore, and Thailand.

Left-sided colitis was most common (median, 40%; interquartile range, 33%-45%) and about 10%-30% of patients had disease extension. Patients tended to have mild to moderate disease that was most active at diagnosis and subsequently alternated between remission and mild activity. However, nearly half of patients were hospitalized at some point because of ulcerative colitis, and about half of that subgroup was rehospitalized within 5 years. Furthermore, up to 15% of patients with ulcerative colitis underwent colectomy within 10 years, a risk that mucosal healing helped mitigate. Use of corticosteroids dropped over time as the prevalence of immunomodulators and anti–tumor necrosis factor therapy rose.

SOURCE: Fumery M et al. Clin Gastroenterol Hepatol. 2017 Jun 16. doi: 10.1016/j.cgh.2017.06.016.

Between 70% and 80% of patients with ulcerative colitis relapsed within 10 years of diagnosis and 10%-15% had aggressive disease in a meta-analysis of 17 population-based cohorts spanning 1935 to 2016.

However, “contemporary population-based cohorts of patients diagnosed in the biologic era are lacking,” [and they] “may inform us of the population-level impact of paradigm shifts in approach to ulcerative colitis management during the last decade, such as early use of disease-modifying biologic therapy and treat-to-target [strategies],” wrote Mathurin Fumery, MD, of the University of California San Diego, La Jolla. The report was published in Clinical Gastroenterology and Hepatology (2017 Jun 16. doi: 10.1016/j.cgh.2017.06.016).

Population-based observational cohort studies follow an entire group in a geographic area over an extended time, which better characterizes the true natural history of disease outside highly controlled settings of clinical trials, the reviewers noted. They searched MEDLINE for population-based longitudinal studies of adults with newly diagnosed ulcerative colitis, whose medical records were reviewed, and who were followed for at least a year. They identified 60 such studies of 17 cohorts that included 15,316 patients in southern and northern Europe, Australia, Israel, the United States, Canada, China, Hong Kong, Indonesia, Sri Lanka, Macau, Malaysia, Singapore, and Thailand.

Left-sided colitis was most common (median, 40%; interquartile range, 33%-45%) and about 10%-30% of patients had disease extension. Patients tended to have mild to moderate disease that was most active at diagnosis and subsequently alternated between remission and mild activity. However, nearly half of patients were hospitalized at some point because of ulcerative colitis, and about half of that subgroup was rehospitalized within 5 years. Furthermore, up to 15% of patients with ulcerative colitis underwent colectomy within 10 years, a risk that mucosal healing helped mitigate. Use of corticosteroids dropped over time as the prevalence of immunomodulators and anti–tumor necrosis factor therapy rose.

SOURCE: Fumery M et al. Clin Gastroenterol Hepatol. 2017 Jun 16. doi: 10.1016/j.cgh.2017.06.016.

Between 70% and 80% of patients with ulcerative colitis relapsed within 10 years of diagnosis and 10%-15% had aggressive disease in a meta-analysis of 17 population-based cohorts spanning 1935 to 2016.

However, “contemporary population-based cohorts of patients diagnosed in the biologic era are lacking,” [and they] “may inform us of the population-level impact of paradigm shifts in approach to ulcerative colitis management during the last decade, such as early use of disease-modifying biologic therapy and treat-to-target [strategies],” wrote Mathurin Fumery, MD, of the University of California San Diego, La Jolla. The report was published in Clinical Gastroenterology and Hepatology (2017 Jun 16. doi: 10.1016/j.cgh.2017.06.016).

Population-based observational cohort studies follow an entire group in a geographic area over an extended time, which better characterizes the true natural history of disease outside highly controlled settings of clinical trials, the reviewers noted. They searched MEDLINE for population-based longitudinal studies of adults with newly diagnosed ulcerative colitis, whose medical records were reviewed, and who were followed for at least a year. They identified 60 such studies of 17 cohorts that included 15,316 patients in southern and northern Europe, Australia, Israel, the United States, Canada, China, Hong Kong, Indonesia, Sri Lanka, Macau, Malaysia, Singapore, and Thailand.

Left-sided colitis was most common (median, 40%; interquartile range, 33%-45%) and about 10%-30% of patients had disease extension. Patients tended to have mild to moderate disease that was most active at diagnosis and subsequently alternated between remission and mild activity. However, nearly half of patients were hospitalized at some point because of ulcerative colitis, and about half of that subgroup was rehospitalized within 5 years. Furthermore, up to 15% of patients with ulcerative colitis underwent colectomy within 10 years, a risk that mucosal healing helped mitigate. Use of corticosteroids dropped over time as the prevalence of immunomodulators and anti–tumor necrosis factor therapy rose.

SOURCE: Fumery M et al. Clin Gastroenterol Hepatol. 2017 Jun 16. doi: 10.1016/j.cgh.2017.06.016.