From the AGA Journals

In patients with Barrett’s esophagus and low-grade dysplasia confirmed by repeat endoscopy, endoscopic eradication therapy is the optimal cost-effective management strategy, according to an analysis of population-based models. For patients with nondysplastic Barrett’s esophagus, the optimal surveillance interval is every 3 years for men and every 5 years for women, according to the study, which was published in Clinical Gastroenterology and Hepatology.

Clinical guidelines recommend surveillance or treatment of patients with Barrett’s esophagus, a precursor lesion for esophageal adenocarcinoma, depending on the presence and grade of dysplasia. For high-grade dysplasia, guidelines recommend endoscopic eradication therapy. For low-grade dysplasia, the optimal strategy is unclear, said first study author Amir-Houshang Omidvari, MD, MPH, a researcher at Erasmus MC University Medical Center Rotterdam (the Netherlands) and colleagues. In addition, the ideal surveillance interval for patients with nondysplastic Barrett’s esophagus is unknown.

Simulated cohorts

To identify optimal management strategies, the investigators simulated cohorts of 60-year-old patients with Barrett’s esophagus in the United States using three independent population-based models. They followed each cohort until death or age 100 years. The study compared disease progression without surveillance or treatment with 78 management strategies. The cost-effectiveness analyses used a willingness-to-pay threshold of $100,000 per quality-adjusted life year (QALY).

For low-grade dysplasia, the researchers assessed various surveillance intervals, endoscopic eradication therapy with confirmation of low-grade dysplasia by a repeat endoscopy after 2 months of high-dose acid suppression, and endoscopic eradication therapy without confirmatory testing. For nondysplastic Barrett’s esophagus, the researchers evaluated no surveillance and surveillance intervals of 1, 2, 3, 4, 5, or 10 years. The researchers made assumptions based on published data about rates of misdiagnosis, treatment efficacy, recurrence, complications, and other outcomes. They used Centers for Medicare & Medicaid Services reimbursement rates to evaluate costs. For all management strategies, the researchers assumed surveillance would stop at age 80 years.

In a simulated cohort of men with Barrett’s esophagus who did not receive surveillance or endoscopic eradication therapy, the models predicted an average esophageal adenocarcinoma cumulative incidence of 111 cases per 1,000 patients and mortality of 77 deaths per 1,000 patients, with a total cost of $5.7 million for their care. Management strategies “prevented 23%-75% of [esophageal adenocarcinoma] cases and decreased mortality by 31%-88% while increasing costs to $6.2-$17.3 million depending on the management strategy,” the authors said. The optimal cost-effective strategy – endoscopic eradication therapy for patients with low-grade dysplasia after endoscopic confirmation, and surveillance every 3 years for patients with nondysplastic Barrett’s esophagus – decreased esophageal adenocarcinoma incidence to 38 cases (–66%) and mortality to 15 deaths (–81%) per 1,000 patients, compared with natural history. This approach increased costs to $9.8 million and gained 358 QALYs.

The models predicted fewer esophageal adenocarcinoma cases in women without surveillance or treatment (75 cases per 1,000 patients). “Because of the higher incremental costs per QALY gained in women, the optimal strategy was surveillance every 5 years for [nondysplastic Barrett’s esophagus],” the researchers reported.

Avoiding misdiagnosis

“Despite the potential harms and cost of endoscopic therapy, [endoscopic eradication therapy of low-grade dysplasia] reduces the number of endoscopies required for surveillance ... because of prolonged surveillance intervals after successful treatment, and [it] generally prevents more [esophageal adenocarcinoma] cases than strategies using only surveillance,” wrote Dr. Omidvari and colleagues. Confirmation of low-grade dysplasia with repeat testing before treatment was more cost-effective than treatment without confirmatory testing. Although this approach requires one more endoscopy per patient, a decrease in inappropriate treatment of patients with false-positive low-grade dysplasia diagnoses compensates for the additional testing costs, they said.

The researchers noted that available data on long-term outcomes are limited. Nevertheless, the analysis may have important implications for patients with Barrett’s esophagus without dysplasia or with low-grade dysplasia, the authors said.

The National Institutes of Health/National Cancer Institute supported the study and provided funding for the authors.

[email protected]

SOURCE: Omidvari A-H et al. Clin Gastroenterol Hepatol. 2019 Dec 6. doi: 10.1016/j.cgh.2019.11.058.

In patients with Barrett’s esophagus and low-grade dysplasia confirmed by repeat endoscopy, endoscopic eradication therapy is the optimal cost-effective management strategy, according to an analysis of population-based models. For patients with nondysplastic Barrett’s esophagus, the optimal surveillance interval is every 3 years for men and every 5 years for women, according to the study, which was published in Clinical Gastroenterology and Hepatology.

Clinical guidelines recommend surveillance or treatment of patients with Barrett’s esophagus, a precursor lesion for esophageal adenocarcinoma, depending on the presence and grade of dysplasia. For high-grade dysplasia, guidelines recommend endoscopic eradication therapy. For low-grade dysplasia, the optimal strategy is unclear, said first study author Amir-Houshang Omidvari, MD, MPH, a researcher at Erasmus MC University Medical Center Rotterdam (the Netherlands) and colleagues. In addition, the ideal surveillance interval for patients with nondysplastic Barrett’s esophagus is unknown.

Simulated cohorts

To identify optimal management strategies, the investigators simulated cohorts of 60-year-old patients with Barrett’s esophagus in the United States using three independent population-based models. They followed each cohort until death or age 100 years. The study compared disease progression without surveillance or treatment with 78 management strategies. The cost-effectiveness analyses used a willingness-to-pay threshold of $100,000 per quality-adjusted life year (QALY).

For low-grade dysplasia, the researchers assessed various surveillance intervals, endoscopic eradication therapy with confirmation of low-grade dysplasia by a repeat endoscopy after 2 months of high-dose acid suppression, and endoscopic eradication therapy without confirmatory testing. For nondysplastic Barrett’s esophagus, the researchers evaluated no surveillance and surveillance intervals of 1, 2, 3, 4, 5, or 10 years. The researchers made assumptions based on published data about rates of misdiagnosis, treatment efficacy, recurrence, complications, and other outcomes. They used Centers for Medicare & Medicaid Services reimbursement rates to evaluate costs. For all management strategies, the researchers assumed surveillance would stop at age 80 years.

In a simulated cohort of men with Barrett’s esophagus who did not receive surveillance or endoscopic eradication therapy, the models predicted an average esophageal adenocarcinoma cumulative incidence of 111 cases per 1,000 patients and mortality of 77 deaths per 1,000 patients, with a total cost of $5.7 million for their care. Management strategies “prevented 23%-75% of [esophageal adenocarcinoma] cases and decreased mortality by 31%-88% while increasing costs to $6.2-$17.3 million depending on the management strategy,” the authors said. The optimal cost-effective strategy – endoscopic eradication therapy for patients with low-grade dysplasia after endoscopic confirmation, and surveillance every 3 years for patients with nondysplastic Barrett’s esophagus – decreased esophageal adenocarcinoma incidence to 38 cases (–66%) and mortality to 15 deaths (–81%) per 1,000 patients, compared with natural history. This approach increased costs to $9.8 million and gained 358 QALYs.

The models predicted fewer esophageal adenocarcinoma cases in women without surveillance or treatment (75 cases per 1,000 patients). “Because of the higher incremental costs per QALY gained in women, the optimal strategy was surveillance every 5 years for [nondysplastic Barrett’s esophagus],” the researchers reported.

Avoiding misdiagnosis

“Despite the potential harms and cost of endoscopic therapy, [endoscopic eradication therapy of low-grade dysplasia] reduces the number of endoscopies required for surveillance ... because of prolonged surveillance intervals after successful treatment, and [it] generally prevents more [esophageal adenocarcinoma] cases than strategies using only surveillance,” wrote Dr. Omidvari and colleagues. Confirmation of low-grade dysplasia with repeat testing before treatment was more cost-effective than treatment without confirmatory testing. Although this approach requires one more endoscopy per patient, a decrease in inappropriate treatment of patients with false-positive low-grade dysplasia diagnoses compensates for the additional testing costs, they said.

The researchers noted that available data on long-term outcomes are limited. Nevertheless, the analysis may have important implications for patients with Barrett’s esophagus without dysplasia or with low-grade dysplasia, the authors said.

The National Institutes of Health/National Cancer Institute supported the study and provided funding for the authors.

[email protected]

SOURCE: Omidvari A-H et al. Clin Gastroenterol Hepatol. 2019 Dec 6. doi: 10.1016/j.cgh.2019.11.058.

In patients with Barrett’s esophagus and low-grade dysplasia confirmed by repeat endoscopy, endoscopic eradication therapy is the optimal cost-effective management strategy, according to an analysis of population-based models. For patients with nondysplastic Barrett’s esophagus, the optimal surveillance interval is every 3 years for men and every 5 years for women, according to the study, which was published in Clinical Gastroenterology and Hepatology.

Clinical guidelines recommend surveillance or treatment of patients with Barrett’s esophagus, a precursor lesion for esophageal adenocarcinoma, depending on the presence and grade of dysplasia. For high-grade dysplasia, guidelines recommend endoscopic eradication therapy. For low-grade dysplasia, the optimal strategy is unclear, said first study author Amir-Houshang Omidvari, MD, MPH, a researcher at Erasmus MC University Medical Center Rotterdam (the Netherlands) and colleagues. In addition, the ideal surveillance interval for patients with nondysplastic Barrett’s esophagus is unknown.

Simulated cohorts

To identify optimal management strategies, the investigators simulated cohorts of 60-year-old patients with Barrett’s esophagus in the United States using three independent population-based models. They followed each cohort until death or age 100 years. The study compared disease progression without surveillance or treatment with 78 management strategies. The cost-effectiveness analyses used a willingness-to-pay threshold of $100,000 per quality-adjusted life year (QALY).

For low-grade dysplasia, the researchers assessed various surveillance intervals, endoscopic eradication therapy with confirmation of low-grade dysplasia by a repeat endoscopy after 2 months of high-dose acid suppression, and endoscopic eradication therapy without confirmatory testing. For nondysplastic Barrett’s esophagus, the researchers evaluated no surveillance and surveillance intervals of 1, 2, 3, 4, 5, or 10 years. The researchers made assumptions based on published data about rates of misdiagnosis, treatment efficacy, recurrence, complications, and other outcomes. They used Centers for Medicare & Medicaid Services reimbursement rates to evaluate costs. For all management strategies, the researchers assumed surveillance would stop at age 80 years.

In a simulated cohort of men with Barrett’s esophagus who did not receive surveillance or endoscopic eradication therapy, the models predicted an average esophageal adenocarcinoma cumulative incidence of 111 cases per 1,000 patients and mortality of 77 deaths per 1,000 patients, with a total cost of $5.7 million for their care. Management strategies “prevented 23%-75% of [esophageal adenocarcinoma] cases and decreased mortality by 31%-88% while increasing costs to $6.2-$17.3 million depending on the management strategy,” the authors said. The optimal cost-effective strategy – endoscopic eradication therapy for patients with low-grade dysplasia after endoscopic confirmation, and surveillance every 3 years for patients with nondysplastic Barrett’s esophagus – decreased esophageal adenocarcinoma incidence to 38 cases (–66%) and mortality to 15 deaths (–81%) per 1,000 patients, compared with natural history. This approach increased costs to $9.8 million and gained 358 QALYs.

The models predicted fewer esophageal adenocarcinoma cases in women without surveillance or treatment (75 cases per 1,000 patients). “Because of the higher incremental costs per QALY gained in women, the optimal strategy was surveillance every 5 years for [nondysplastic Barrett’s esophagus],” the researchers reported.

Avoiding misdiagnosis

“Despite the potential harms and cost of endoscopic therapy, [endoscopic eradication therapy of low-grade dysplasia] reduces the number of endoscopies required for surveillance ... because of prolonged surveillance intervals after successful treatment, and [it] generally prevents more [esophageal adenocarcinoma] cases than strategies using only surveillance,” wrote Dr. Omidvari and colleagues. Confirmation of low-grade dysplasia with repeat testing before treatment was more cost-effective than treatment without confirmatory testing. Although this approach requires one more endoscopy per patient, a decrease in inappropriate treatment of patients with false-positive low-grade dysplasia diagnoses compensates for the additional testing costs, they said.

The researchers noted that available data on long-term outcomes are limited. Nevertheless, the analysis may have important implications for patients with Barrett’s esophagus without dysplasia or with low-grade dysplasia, the authors said.

The National Institutes of Health/National Cancer Institute supported the study and provided funding for the authors.

[email protected]

SOURCE: Omidvari A-H et al. Clin Gastroenterol Hepatol. 2019 Dec 6. doi: 10.1016/j.cgh.2019.11.058.

For patients with chronic hepatitis B virus (HBV) infection, up to 10 years of treatment with entecavir was safe and produced a superior rate of sustained virologic response, compared with other HBV nucleoside or nucleotide analogues in a global randomized clinical trial.

Virologic responses were confirmed and maintained in 80% of entecavir patients and 61% of patients who received other therapies, said Jin-Lin Hou, MD, of Southern Medical University in Guangzhou, China, and associates. Regardless of which treatment patients received, a sustained virologic response was associated with a significantly lower rate of liver-related hepatitis B virus (HBV) disease progression and hepatocellular carcinoma. Rates of serious treatment-related adverse events were 0.2% in the entecavir arm and 0.8% in the nonentecavir arm. Moreover, the primary outcome of time-to-adjudicated clinical outcome events “showed that entecavir treatment, compared with nonentecavir, was not associated with an increased risk of malignant neoplasms, including hepatocellular carcinoma, nonhepatocellular carcinoma malignancies, and overall malignancies,” they wrote in Clinical Gastroenterology and Hepatology.

Entecavir is approved for the treatment of adults with chronic HBV infection, and its long-term use has been linked to the regression of hepatic fibrosis and cirrhosis. In treatment-naive patients, genotypic resistance and virologic breakthrough are rare even after up to 5 years of entecavir therapy. Although human studies have not linked this treatment duration with an increased risk of adverse events, murine studies have identified benign and malignant tumors of the brain, lung, and liver in entecavir-treated mice and rats. “With the exception of lung tumors, which were limited to male mice, rodent tumors occurred only at entecavir exposures [that were] significantly higher than those achieved in human beings with standard approved doses,” the researchers wrote.

For the trial, they assigned more than 12,000 patients with chronic HBV infection to receive long-term treatment with entecavir or investigators’ choice of another HBV nucleoside or nucleotide analogue. Patients were from 229 centers in Asia, Europe, and North and South America, and a total of 6,216 received entecavir, while 6,162 received another therapy.

Compared with other HBV nucleoside and nucleotide analogues, long-term treatment with entecavir “provided a high margin of safety” and was not tied to higher rates of liver or nonliver malignancies, the researchers found. The carcinogenicity of entecavir in rodents did not appear to extend to humans. Furthermore, among 5,305 trial participants in China, a sustained virologic response was associated with a clinically and statistically significant reduction in the risk of liver-related HBV disease progression (hazard ratio, 0.09; 95% CI, 0.04-0.22) and hepatocellular carcinoma (HR, 0.03; 95% CI, 0.009-0.113).

The results confirm the appropriateness of long-term entecavir therapy for chronic HBV infection, as recommended by current guidelines, Dr. Hou and associates concluded. However, patients in this trial were relatively young, with a median age of only 39 years. Therefore, the risk of entecavir-associated malignancies in older age cohorts could not be evaluated.

Bristol-Myers Squibb designed the study, performed statistical analyses, and funded the study and manuscript preparation. The Ministry of Science and Technology of China and the Local Innovative and Research Teams Project of Guangdong Pearl River Talents Program provided partial support. Dr. Hou disclosed grants and personal fees from Bristol-Myers Squibb, GlaxoSmithKline, and Novartis. Several coinvestigators also disclosed ties to Bristol-Myers Squibb and to several other pharmaceutical companies.

SOURCE: Hou J-L et al. Clin Gastroenterol Hepatol. 2019 Jul 12. doi: 10.1016/j.cgh.2019.07.010.

For patients with chronic hepatitis B virus (HBV) infection, up to 10 years of treatment with entecavir was safe and produced a superior rate of sustained virologic response, compared with other HBV nucleoside or nucleotide analogues in a global randomized clinical trial.

Virologic responses were confirmed and maintained in 80% of entecavir patients and 61% of patients who received other therapies, said Jin-Lin Hou, MD, of Southern Medical University in Guangzhou, China, and associates. Regardless of which treatment patients received, a sustained virologic response was associated with a significantly lower rate of liver-related hepatitis B virus (HBV) disease progression and hepatocellular carcinoma. Rates of serious treatment-related adverse events were 0.2% in the entecavir arm and 0.8% in the nonentecavir arm. Moreover, the primary outcome of time-to-adjudicated clinical outcome events “showed that entecavir treatment, compared with nonentecavir, was not associated with an increased risk of malignant neoplasms, including hepatocellular carcinoma, nonhepatocellular carcinoma malignancies, and overall malignancies,” they wrote in Clinical Gastroenterology and Hepatology.

Entecavir is approved for the treatment of adults with chronic HBV infection, and its long-term use has been linked to the regression of hepatic fibrosis and cirrhosis. In treatment-naive patients, genotypic resistance and virologic breakthrough are rare even after up to 5 years of entecavir therapy. Although human studies have not linked this treatment duration with an increased risk of adverse events, murine studies have identified benign and malignant tumors of the brain, lung, and liver in entecavir-treated mice and rats. “With the exception of lung tumors, which were limited to male mice, rodent tumors occurred only at entecavir exposures [that were] significantly higher than those achieved in human beings with standard approved doses,” the researchers wrote.

For the trial, they assigned more than 12,000 patients with chronic HBV infection to receive long-term treatment with entecavir or investigators’ choice of another HBV nucleoside or nucleotide analogue. Patients were from 229 centers in Asia, Europe, and North and South America, and a total of 6,216 received entecavir, while 6,162 received another therapy.

Compared with other HBV nucleoside and nucleotide analogues, long-term treatment with entecavir “provided a high margin of safety” and was not tied to higher rates of liver or nonliver malignancies, the researchers found. The carcinogenicity of entecavir in rodents did not appear to extend to humans. Furthermore, among 5,305 trial participants in China, a sustained virologic response was associated with a clinically and statistically significant reduction in the risk of liver-related HBV disease progression (hazard ratio, 0.09; 95% CI, 0.04-0.22) and hepatocellular carcinoma (HR, 0.03; 95% CI, 0.009-0.113).

The results confirm the appropriateness of long-term entecavir therapy for chronic HBV infection, as recommended by current guidelines, Dr. Hou and associates concluded. However, patients in this trial were relatively young, with a median age of only 39 years. Therefore, the risk of entecavir-associated malignancies in older age cohorts could not be evaluated.

Bristol-Myers Squibb designed the study, performed statistical analyses, and funded the study and manuscript preparation. The Ministry of Science and Technology of China and the Local Innovative and Research Teams Project of Guangdong Pearl River Talents Program provided partial support. Dr. Hou disclosed grants and personal fees from Bristol-Myers Squibb, GlaxoSmithKline, and Novartis. Several coinvestigators also disclosed ties to Bristol-Myers Squibb and to several other pharmaceutical companies.

SOURCE: Hou J-L et al. Clin Gastroenterol Hepatol. 2019 Jul 12. doi: 10.1016/j.cgh.2019.07.010.

For patients with chronic hepatitis B virus (HBV) infection, up to 10 years of treatment with entecavir was safe and produced a superior rate of sustained virologic response, compared with other HBV nucleoside or nucleotide analogues in a global randomized clinical trial.

Virologic responses were confirmed and maintained in 80% of entecavir patients and 61% of patients who received other therapies, said Jin-Lin Hou, MD, of Southern Medical University in Guangzhou, China, and associates. Regardless of which treatment patients received, a sustained virologic response was associated with a significantly lower rate of liver-related hepatitis B virus (HBV) disease progression and hepatocellular carcinoma. Rates of serious treatment-related adverse events were 0.2% in the entecavir arm and 0.8% in the nonentecavir arm. Moreover, the primary outcome of time-to-adjudicated clinical outcome events “showed that entecavir treatment, compared with nonentecavir, was not associated with an increased risk of malignant neoplasms, including hepatocellular carcinoma, nonhepatocellular carcinoma malignancies, and overall malignancies,” they wrote in Clinical Gastroenterology and Hepatology.

Entecavir is approved for the treatment of adults with chronic HBV infection, and its long-term use has been linked to the regression of hepatic fibrosis and cirrhosis. In treatment-naive patients, genotypic resistance and virologic breakthrough are rare even after up to 5 years of entecavir therapy. Although human studies have not linked this treatment duration with an increased risk of adverse events, murine studies have identified benign and malignant tumors of the brain, lung, and liver in entecavir-treated mice and rats. “With the exception of lung tumors, which were limited to male mice, rodent tumors occurred only at entecavir exposures [that were] significantly higher than those achieved in human beings with standard approved doses,” the researchers wrote.

For the trial, they assigned more than 12,000 patients with chronic HBV infection to receive long-term treatment with entecavir or investigators’ choice of another HBV nucleoside or nucleotide analogue. Patients were from 229 centers in Asia, Europe, and North and South America, and a total of 6,216 received entecavir, while 6,162 received another therapy.

Compared with other HBV nucleoside and nucleotide analogues, long-term treatment with entecavir “provided a high margin of safety” and was not tied to higher rates of liver or nonliver malignancies, the researchers found. The carcinogenicity of entecavir in rodents did not appear to extend to humans. Furthermore, among 5,305 trial participants in China, a sustained virologic response was associated with a clinically and statistically significant reduction in the risk of liver-related HBV disease progression (hazard ratio, 0.09; 95% CI, 0.04-0.22) and hepatocellular carcinoma (HR, 0.03; 95% CI, 0.009-0.113).

The results confirm the appropriateness of long-term entecavir therapy for chronic HBV infection, as recommended by current guidelines, Dr. Hou and associates concluded. However, patients in this trial were relatively young, with a median age of only 39 years. Therefore, the risk of entecavir-associated malignancies in older age cohorts could not be evaluated.

Bristol-Myers Squibb designed the study, performed statistical analyses, and funded the study and manuscript preparation. The Ministry of Science and Technology of China and the Local Innovative and Research Teams Project of Guangdong Pearl River Talents Program provided partial support. Dr. Hou disclosed grants and personal fees from Bristol-Myers Squibb, GlaxoSmithKline, and Novartis. Several coinvestigators also disclosed ties to Bristol-Myers Squibb and to several other pharmaceutical companies.

SOURCE: Hou J-L et al. Clin Gastroenterol Hepatol. 2019 Jul 12. doi: 10.1016/j.cgh.2019.07.010.

Hepatocellular carcinoma (HCC) tissue contains several unique populations of tumor infiltrating cells, including some exhausted effector T cells that regain normal function when treated with the immunotherapy drug nivolumab, according to researchers.

The unique populations of recently activated CD4+, CD8+, and CD4-CD8 double-negative cells identified in the tumors expressed specific activation markers and inhibitor receptors, according to investigators, who have published the results of their immune profiling analyses in Cellular and Molecular Gastroenterology and Hepatology.

“Importantly, these cells expressed markers of activation and tissue residence, possibly suggesting activation within the tumor,” said Daniela Di Blasi, PhD, and the others researchers, of the University of Basel in Switzerland.

A further look at tumor histology revealed an accumulation of those activated T cells in immune-inflamed HCC, according to the investigators, who added that enumeration of specific tumor-infiltrating lymphocytes could represent “a prognostic indicator of therapy responsiveness.”

However, they advised caution in interpreting the results to date: “We are aware that the analysis described here is based on a small number of patients and that validation of its prognostic value requires ad hoc prospective studies that include more patients,” they said in their report.

The researcher’s findings were based on analysis of HCC biopsies before and after treatment with the immune checkpoint inhibitor nivolumab, nontumor liver tissue biopsies, and peripheral blood samples from 36 patients, most of whom were male, and about half of whom had cirrhosis. Investigators used multiparametric flow cytometry to characterize expression of activation markers including CD137, CD150, and ICOS, among others, as well as expression of inhibitory receptors including TIGIT and PD1.

Compared with nonneoplastic liver tissue, tumor tissue was enriched with T cells expressing the activation marker CD137 and the inhibitory receptor ICOS, indicating that HCC tumor-infiltrating lymphocytes “are different from liver-resident T cells and might have immunologic relevance,” Dr. Di Blasi and coauthors said in their report.

Further analysis revealed several cell populations unique to HCC samples, the authors said, including CD4+ T cells coexpressing ICOS and TIGIT, which tended to accumulate in tumor tissue, compared with nontumor tissue and peripheral blood mononuclear cells. Those CD4+ tumor-infiltrating T cells were functionally impaired, they added, as shown by a lack of cytokine production.

Activated CD8+ T cells likewise preferentially accumulated in tumor tissue, and most of those tumor-infiltrating cells expressed CD38 and PD1. The presence of these proliferating and functional cells may contribute to local inflammation and antitumor response, according to the investigators, who also identified two unique populations of double-negative T cells, including some that expressed CD137, which they said was a marker of recent T-cell activation.

The investigators also looked at the presence of tumor-infiltrating lymphocytes correlated to the presence of mononuclear cell infiltrate in tumor tissue. They found that immune-inflamed tumors had significantly increased proliferation of unique CD4+, CD8+, and double-negative T cell populations.

Nivolumab treatment appeared to substantially reduce the proportion of impaired CD4+ T cells, while increasing the percentage of interferon gamma–producing CD38+ CD4+ T cells and also promoting enrichment of interferon gamma–producing CD38+ CD8+ cells. Those increases in release of interferon gamma may have a positive influence on antitumor immunity via modulation of immune and tumor cell functions, according to the investigators.

Not all immune-inflamed tumors responded to nivolumab treatment, suggesting that an immune-inflamed profile is “necessary but not sufficient” for clinical response to an anti-PD1 agent, noted Dr. Di Blasi and colleagues.

Taken together, the researchers said their investigations suggest the presence of unique populations of T cells that might be providing effective anti-tumor immunity.

“These studies set the point for the identification of the tumor antigens stimulating these T cells and their possible exploitation as immunotherapeutic targets in HCC,” they concluded in the report.

The study was supported by grants from the European Research Council and the Swiss Initiative in Systems Biology, among others. Dr. Di Blasi and coauthors disclosed no conflicts of interest.

SOURCE: Di Blasi D et al. Cell Mol Gastroenterol Hepatol. 2019 Aug 22. doi: 10.1016/j.jcmgh.2019.08.004.

Hepatocellular carcinoma (HCC) tissue contains several unique populations of tumor infiltrating cells, including some exhausted effector T cells that regain normal function when treated with the immunotherapy drug nivolumab, according to researchers.

The unique populations of recently activated CD4+, CD8+, and CD4-CD8 double-negative cells identified in the tumors expressed specific activation markers and inhibitor receptors, according to investigators, who have published the results of their immune profiling analyses in Cellular and Molecular Gastroenterology and Hepatology.

“Importantly, these cells expressed markers of activation and tissue residence, possibly suggesting activation within the tumor,” said Daniela Di Blasi, PhD, and the others researchers, of the University of Basel in Switzerland.

A further look at tumor histology revealed an accumulation of those activated T cells in immune-inflamed HCC, according to the investigators, who added that enumeration of specific tumor-infiltrating lymphocytes could represent “a prognostic indicator of therapy responsiveness.”

However, they advised caution in interpreting the results to date: “We are aware that the analysis described here is based on a small number of patients and that validation of its prognostic value requires ad hoc prospective studies that include more patients,” they said in their report.

The researcher’s findings were based on analysis of HCC biopsies before and after treatment with the immune checkpoint inhibitor nivolumab, nontumor liver tissue biopsies, and peripheral blood samples from 36 patients, most of whom were male, and about half of whom had cirrhosis. Investigators used multiparametric flow cytometry to characterize expression of activation markers including CD137, CD150, and ICOS, among others, as well as expression of inhibitory receptors including TIGIT and PD1.

Compared with nonneoplastic liver tissue, tumor tissue was enriched with T cells expressing the activation marker CD137 and the inhibitory receptor ICOS, indicating that HCC tumor-infiltrating lymphocytes “are different from liver-resident T cells and might have immunologic relevance,” Dr. Di Blasi and coauthors said in their report.

Further analysis revealed several cell populations unique to HCC samples, the authors said, including CD4+ T cells coexpressing ICOS and TIGIT, which tended to accumulate in tumor tissue, compared with nontumor tissue and peripheral blood mononuclear cells. Those CD4+ tumor-infiltrating T cells were functionally impaired, they added, as shown by a lack of cytokine production.

Activated CD8+ T cells likewise preferentially accumulated in tumor tissue, and most of those tumor-infiltrating cells expressed CD38 and PD1. The presence of these proliferating and functional cells may contribute to local inflammation and antitumor response, according to the investigators, who also identified two unique populations of double-negative T cells, including some that expressed CD137, which they said was a marker of recent T-cell activation.

The investigators also looked at the presence of tumor-infiltrating lymphocytes correlated to the presence of mononuclear cell infiltrate in tumor tissue. They found that immune-inflamed tumors had significantly increased proliferation of unique CD4+, CD8+, and double-negative T cell populations.

Nivolumab treatment appeared to substantially reduce the proportion of impaired CD4+ T cells, while increasing the percentage of interferon gamma–producing CD38+ CD4+ T cells and also promoting enrichment of interferon gamma–producing CD38+ CD8+ cells. Those increases in release of interferon gamma may have a positive influence on antitumor immunity via modulation of immune and tumor cell functions, according to the investigators.

Not all immune-inflamed tumors responded to nivolumab treatment, suggesting that an immune-inflamed profile is “necessary but not sufficient” for clinical response to an anti-PD1 agent, noted Dr. Di Blasi and colleagues.

Taken together, the researchers said their investigations suggest the presence of unique populations of T cells that might be providing effective anti-tumor immunity.

“These studies set the point for the identification of the tumor antigens stimulating these T cells and their possible exploitation as immunotherapeutic targets in HCC,” they concluded in the report.

The study was supported by grants from the European Research Council and the Swiss Initiative in Systems Biology, among others. Dr. Di Blasi and coauthors disclosed no conflicts of interest.

SOURCE: Di Blasi D et al. Cell Mol Gastroenterol Hepatol. 2019 Aug 22. doi: 10.1016/j.jcmgh.2019.08.004.

Hepatocellular carcinoma (HCC) tissue contains several unique populations of tumor infiltrating cells, including some exhausted effector T cells that regain normal function when treated with the immunotherapy drug nivolumab, according to researchers.

The unique populations of recently activated CD4+, CD8+, and CD4-CD8 double-negative cells identified in the tumors expressed specific activation markers and inhibitor receptors, according to investigators, who have published the results of their immune profiling analyses in Cellular and Molecular Gastroenterology and Hepatology.

“Importantly, these cells expressed markers of activation and tissue residence, possibly suggesting activation within the tumor,” said Daniela Di Blasi, PhD, and the others researchers, of the University of Basel in Switzerland.

A further look at tumor histology revealed an accumulation of those activated T cells in immune-inflamed HCC, according to the investigators, who added that enumeration of specific tumor-infiltrating lymphocytes could represent “a prognostic indicator of therapy responsiveness.”

However, they advised caution in interpreting the results to date: “We are aware that the analysis described here is based on a small number of patients and that validation of its prognostic value requires ad hoc prospective studies that include more patients,” they said in their report.

The researcher’s findings were based on analysis of HCC biopsies before and after treatment with the immune checkpoint inhibitor nivolumab, nontumor liver tissue biopsies, and peripheral blood samples from 36 patients, most of whom were male, and about half of whom had cirrhosis. Investigators used multiparametric flow cytometry to characterize expression of activation markers including CD137, CD150, and ICOS, among others, as well as expression of inhibitory receptors including TIGIT and PD1.

Compared with nonneoplastic liver tissue, tumor tissue was enriched with T cells expressing the activation marker CD137 and the inhibitory receptor ICOS, indicating that HCC tumor-infiltrating lymphocytes “are different from liver-resident T cells and might have immunologic relevance,” Dr. Di Blasi and coauthors said in their report.

Further analysis revealed several cell populations unique to HCC samples, the authors said, including CD4+ T cells coexpressing ICOS and TIGIT, which tended to accumulate in tumor tissue, compared with nontumor tissue and peripheral blood mononuclear cells. Those CD4+ tumor-infiltrating T cells were functionally impaired, they added, as shown by a lack of cytokine production.

Activated CD8+ T cells likewise preferentially accumulated in tumor tissue, and most of those tumor-infiltrating cells expressed CD38 and PD1. The presence of these proliferating and functional cells may contribute to local inflammation and antitumor response, according to the investigators, who also identified two unique populations of double-negative T cells, including some that expressed CD137, which they said was a marker of recent T-cell activation.

The investigators also looked at the presence of tumor-infiltrating lymphocytes correlated to the presence of mononuclear cell infiltrate in tumor tissue. They found that immune-inflamed tumors had significantly increased proliferation of unique CD4+, CD8+, and double-negative T cell populations.

Nivolumab treatment appeared to substantially reduce the proportion of impaired CD4+ T cells, while increasing the percentage of interferon gamma–producing CD38+ CD4+ T cells and also promoting enrichment of interferon gamma–producing CD38+ CD8+ cells. Those increases in release of interferon gamma may have a positive influence on antitumor immunity via modulation of immune and tumor cell functions, according to the investigators.

Not all immune-inflamed tumors responded to nivolumab treatment, suggesting that an immune-inflamed profile is “necessary but not sufficient” for clinical response to an anti-PD1 agent, noted Dr. Di Blasi and colleagues.

Taken together, the researchers said their investigations suggest the presence of unique populations of T cells that might be providing effective anti-tumor immunity.

“These studies set the point for the identification of the tumor antigens stimulating these T cells and their possible exploitation as immunotherapeutic targets in HCC,” they concluded in the report.

The study was supported by grants from the European Research Council and the Swiss Initiative in Systems Biology, among others. Dr. Di Blasi and coauthors disclosed no conflicts of interest.

SOURCE: Di Blasi D et al. Cell Mol Gastroenterol Hepatol. 2019 Aug 22. doi: 10.1016/j.jcmgh.2019.08.004.

An implanted gastric electrical stimulation device significantly improved refractory vomiting but not quality of life in a randomized, multicenter, double-blind crossover trial of 172 patients.

After 4 months of electrical stimulation, frequency of vomiting was significantly improved from baseline in the intervention arm, compared with the control arm, in patients with both delayed (P less than .01) and normal (P = .05) gastric emptying. There was also an improvement in nausea with gastric stimulation. In contrast, there was no significant improvement in the coprimary endpoint of quality of life. Based on these findings, “a limited number of medically resistant patients may benefit from gastroelectric stimulation to relieve nausea and vomiting,” wrote Philippe Ducrotté, MD, of Rouen (France) University Hospital and associates in Gastroenterology.

High-frequency gastric electrical stimulation with the surgically implanted Enterra device is regarded as a treatment option for chronic refractory vomiting in patients with or without gastroparesis. However, only moderate evidence supports the use of this therapy, with level 1 evidence limited to a single study, according to the researchers. For the study, they enrolled 172 adults with at least 12 months of nausea or vomiting that was refractory to antiemetic or prokinetic therapy and was either idiopathic or related to type 1 or 2 diabetes mellitus or surgery (partial gastric resection or vagotomy). Symptoms “had to be severe enough to affect the general condition of the patient, including [causing] weight loss, or the need to change dietary intake to control diabetes,” said the researchers.

The study started with a 4-month run-in period, after which all patients had the device implanted and left off for one month. Patients in the intervention arm then had the device turned on and programmed at standard parameters (5 mA, 14 Hz, 330 micros, cycle on 0.1s, cycle off 5s). Both groups were assessed at 4 months, and 149 patients then crossed over to the other arm and were assessed again at 4 months. Vomiting was evaluated on a 5-point scale ranging from 0 (most severe) to 5 (symptom absent), while quality of life was assessed by means of the 36-question, self-administered Gastrointestinal Quality of Life Index (GIQLI).

During the intervention, 30.6% of patients reported at least a 1-point improvement on the vomiting frequency scale, while 53% reported no change. With the device turned off, 16.5% of patients reported an improvement in vomiting. During both phases of the trial, median vomiting frequency score was improved in the intervention arm compared with the control arm (P less than .001) in patients with (42%) and without (58%) diabetes. “Gastric emptying was not accelerated during the on period compared with the off period,” the investigators wrote. 

A total of 133 (77%) patients in the study had gastroparesis. Most patients were women in their 40s who vomited several times per day. Among 45 device-related events, the most common was abdominal pain at the implantation site (62%), followed by “infectious problems” at the abdominal pouch level (36%) and hematoma (2%). Three of these events “were serious enough to prompt device removal,” the researchers wrote.

The French government funded the study. The investigators reported having no conflicts of interest. They dedicated the paper to the memory of Dr. Ducrotté, who died during the course of the study.

*This story was updated on January 13, 2020.

SOURCE: Ducrotté P et al. Gastroenterology. 2019 Oct 1. https://doi.org/10.1053/j.gastro.2019.10.018

An implanted gastric electrical stimulation device significantly improved refractory vomiting but not quality of life in a randomized, multicenter, double-blind crossover trial of 172 patients.

After 4 months of electrical stimulation, frequency of vomiting was significantly improved from baseline in the intervention arm, compared with the control arm, in patients with both delayed (P less than .01) and normal (P = .05) gastric emptying. There was also an improvement in nausea with gastric stimulation. In contrast, there was no significant improvement in the coprimary endpoint of quality of life. Based on these findings, “a limited number of medically resistant patients may benefit from gastroelectric stimulation to relieve nausea and vomiting,” wrote Philippe Ducrotté, MD, of Rouen (France) University Hospital and associates in Gastroenterology.

High-frequency gastric electrical stimulation with the surgically implanted Enterra device is regarded as a treatment option for chronic refractory vomiting in patients with or without gastroparesis. However, only moderate evidence supports the use of this therapy, with level 1 evidence limited to a single study, according to the researchers. For the study, they enrolled 172 adults with at least 12 months of nausea or vomiting that was refractory to antiemetic or prokinetic therapy and was either idiopathic or related to type 1 or 2 diabetes mellitus or surgery (partial gastric resection or vagotomy). Symptoms “had to be severe enough to affect the general condition of the patient, including [causing] weight loss, or the need to change dietary intake to control diabetes,” said the researchers.

The study started with a 4-month run-in period, after which all patients had the device implanted and left off for one month. Patients in the intervention arm then had the device turned on and programmed at standard parameters (5 mA, 14 Hz, 330 micros, cycle on 0.1s, cycle off 5s). Both groups were assessed at 4 months, and 149 patients then crossed over to the other arm and were assessed again at 4 months. Vomiting was evaluated on a 5-point scale ranging from 0 (most severe) to 5 (symptom absent), while quality of life was assessed by means of the 36-question, self-administered Gastrointestinal Quality of Life Index (GIQLI).

During the intervention, 30.6% of patients reported at least a 1-point improvement on the vomiting frequency scale, while 53% reported no change. With the device turned off, 16.5% of patients reported an improvement in vomiting. During both phases of the trial, median vomiting frequency score was improved in the intervention arm compared with the control arm (P less than .001) in patients with (42%) and without (58%) diabetes. “Gastric emptying was not accelerated during the on period compared with the off period,” the investigators wrote. 

A total of 133 (77%) patients in the study had gastroparesis. Most patients were women in their 40s who vomited several times per day. Among 45 device-related events, the most common was abdominal pain at the implantation site (62%), followed by “infectious problems” at the abdominal pouch level (36%) and hematoma (2%). Three of these events “were serious enough to prompt device removal,” the researchers wrote.

The French government funded the study. The investigators reported having no conflicts of interest. They dedicated the paper to the memory of Dr. Ducrotté, who died during the course of the study.

*This story was updated on January 13, 2020.

SOURCE: Ducrotté P et al. Gastroenterology. 2019 Oct 1. https://doi.org/10.1053/j.gastro.2019.10.018

An implanted gastric electrical stimulation device significantly improved refractory vomiting but not quality of life in a randomized, multicenter, double-blind crossover trial of 172 patients.

After 4 months of electrical stimulation, frequency of vomiting was significantly improved from baseline in the intervention arm, compared with the control arm, in patients with both delayed (P less than .01) and normal (P = .05) gastric emptying. There was also an improvement in nausea with gastric stimulation. In contrast, there was no significant improvement in the coprimary endpoint of quality of life. Based on these findings, “a limited number of medically resistant patients may benefit from gastroelectric stimulation to relieve nausea and vomiting,” wrote Philippe Ducrotté, MD, of Rouen (France) University Hospital and associates in Gastroenterology.

High-frequency gastric electrical stimulation with the surgically implanted Enterra device is regarded as a treatment option for chronic refractory vomiting in patients with or without gastroparesis. However, only moderate evidence supports the use of this therapy, with level 1 evidence limited to a single study, according to the researchers. For the study, they enrolled 172 adults with at least 12 months of nausea or vomiting that was refractory to antiemetic or prokinetic therapy and was either idiopathic or related to type 1 or 2 diabetes mellitus or surgery (partial gastric resection or vagotomy). Symptoms “had to be severe enough to affect the general condition of the patient, including [causing] weight loss, or the need to change dietary intake to control diabetes,” said the researchers.

The study started with a 4-month run-in period, after which all patients had the device implanted and left off for one month. Patients in the intervention arm then had the device turned on and programmed at standard parameters (5 mA, 14 Hz, 330 micros, cycle on 0.1s, cycle off 5s). Both groups were assessed at 4 months, and 149 patients then crossed over to the other arm and were assessed again at 4 months. Vomiting was evaluated on a 5-point scale ranging from 0 (most severe) to 5 (symptom absent), while quality of life was assessed by means of the 36-question, self-administered Gastrointestinal Quality of Life Index (GIQLI).

During the intervention, 30.6% of patients reported at least a 1-point improvement on the vomiting frequency scale, while 53% reported no change. With the device turned off, 16.5% of patients reported an improvement in vomiting. During both phases of the trial, median vomiting frequency score was improved in the intervention arm compared with the control arm (P less than .001) in patients with (42%) and without (58%) diabetes. “Gastric emptying was not accelerated during the on period compared with the off period,” the investigators wrote. 

A total of 133 (77%) patients in the study had gastroparesis. Most patients were women in their 40s who vomited several times per day. Among 45 device-related events, the most common was abdominal pain at the implantation site (62%), followed by “infectious problems” at the abdominal pouch level (36%) and hematoma (2%). Three of these events “were serious enough to prompt device removal,” the researchers wrote.

The French government funded the study. The investigators reported having no conflicts of interest. They dedicated the paper to the memory of Dr. Ducrotté, who died during the course of the study.

*This story was updated on January 13, 2020.

SOURCE: Ducrotté P et al. Gastroenterology. 2019 Oct 1. https://doi.org/10.1053/j.gastro.2019.10.018

The American Gastroenterological Association recently released a clinical practice update for endoscopic treatment of Barrett’s esophagus with dysplasia and/or early esophageal adenocarcinoma.

The update offers best practice advice for a range of clinical scenarios based on published evidence, including guidelines and recent systematic reviews, reported lead author Prateek Sharma, MD, of the University of Kansas, Kansas City. Dr. Sharma was accompanied on the authoring review team by three other expert gastroenterologists from the United States and the Netherlands.

Beyond practice advice, the investigators highlighted a research focus for the future.

“Given the expense and time required for careful and continual surveillance after Barrett’s endoscopic therapy, the future must define improved means of risk-stratifying patients for therapy who are at highest risk for cancer development and for risk of recurrence after complete eradication of intestinal metaplasia,” they wrote in Gastroenterology. “Potentially, we may use a panel of patient characteristics (such as the [Progression in Barrett’s] score), preablation tissue characteristics (e.g., baseline grade of dysplasia) and the posttherapy molecular makeup of the epithelium to help risk stratify our patients.”

For now, many of the treatment principles in the update depend upon histologic features.

For instance, either endoscopic therapy or continued surveillance are reasonable options for patients with Barrett’s esophagus who have confirmed and persistent low-grade dysplasia. In contrast, the update recommends that all patients with high-grade dysplasia or esophageal adenocarcinoma (T1a) undergo endoscopic therapy, highlighting that this method is preferred over esophagectomy for patients with T1a cancer. Along the same lines, the investigators noted that endoscopic therapy is a “reasonable alternative” to esophagectomy in cases of T1b esophageal adenocarcinoma in the presence of minimal invasion and good to moderate differentiation, particularly in patients who are poor candidates for surgery.

During the decision-making process, patients with dysplasia should be advised that not undergoing endoscopic therapy may increase cancer risk, the investigators wrote, adding that patients should also be informed about endoscopic therapy–related risks of bleeding and perforation, which occur in less than 1% of patients, and the risk of postprocedural stricture formation, which occurs in approximately 6% of patients.

If endoscopic therapy is elected, the update suggests that the procedure be done by experts who perform at least 10 new cases per year.

Concerning specifics of therapy, the investigators advised that mucosal ablation be applied to all visible esophageal columnar mucosa, 5-10 mm proximal to the squamocolumnar junction, and 5-10 mm distal to the gastroesophageal junction. Ablation should only be performed in cases of flat Barrett’s esophagus in which no visible abnormalities or signs of inflammation are present, the review team wrote.

The investigators went on to lay out some “practical ground rules” for endoscopic therapy, including a potential pitfall.

“Ablation therapy may consist of multiple 2-3 monthly ablation sessions that may extend over a period of more than a year,” the investigators wrote. “The worst adverse outcome during the treatment period is failing to recognize and treat an invasive cancer while continuing the ablation sessions. This occurrence may place the patient outside of the window of opportunity for curative endoscopic treatment. Therefore, every ablation session starts with careful endoscopic inspection using [high-definition white-light endoscopy] and preferably optical chromoendoscopy to exclude the presence of visible abnormalities that require an endoscopic resection instead of the scheduled ablation. Routine biopsies of flat Barrett’s esophagus are not necessary or recommended prior to ablation at these sessions, as the blood may inhibit optimal energy transfer to the tissue.”

Following successfully achieved complete endoscopic and histologic eradication of intestinal metaplasia, the update calls for surveillance endoscopy with biopsies at intervals of 1 and 3 years for cases of low-grade dysplasia and at intervals of 3, 6, and 12 months for high-grade dysplasia or esophageal adenocarcinoma, followed by annual checks thereafter.

The investigators disclosed relationships with Olympus, Ironwood, Erbe, and others.

SOURCE: Sharma P et al. Gastroenterology. 2019 Nov 12. doi: 10.1053/j.gastro.2019.09.051.

The American Gastroenterological Association recently released a clinical practice update for endoscopic treatment of Barrett’s esophagus with dysplasia and/or early esophageal adenocarcinoma.

The update offers best practice advice for a range of clinical scenarios based on published evidence, including guidelines and recent systematic reviews, reported lead author Prateek Sharma, MD, of the University of Kansas, Kansas City. Dr. Sharma was accompanied on the authoring review team by three other expert gastroenterologists from the United States and the Netherlands.

Beyond practice advice, the investigators highlighted a research focus for the future.

“Given the expense and time required for careful and continual surveillance after Barrett’s endoscopic therapy, the future must define improved means of risk-stratifying patients for therapy who are at highest risk for cancer development and for risk of recurrence after complete eradication of intestinal metaplasia,” they wrote in Gastroenterology. “Potentially, we may use a panel of patient characteristics (such as the [Progression in Barrett’s] score), preablation tissue characteristics (e.g., baseline grade of dysplasia) and the posttherapy molecular makeup of the epithelium to help risk stratify our patients.”

For now, many of the treatment principles in the update depend upon histologic features.

For instance, either endoscopic therapy or continued surveillance are reasonable options for patients with Barrett’s esophagus who have confirmed and persistent low-grade dysplasia. In contrast, the update recommends that all patients with high-grade dysplasia or esophageal adenocarcinoma (T1a) undergo endoscopic therapy, highlighting that this method is preferred over esophagectomy for patients with T1a cancer. Along the same lines, the investigators noted that endoscopic therapy is a “reasonable alternative” to esophagectomy in cases of T1b esophageal adenocarcinoma in the presence of minimal invasion and good to moderate differentiation, particularly in patients who are poor candidates for surgery.

During the decision-making process, patients with dysplasia should be advised that not undergoing endoscopic therapy may increase cancer risk, the investigators wrote, adding that patients should also be informed about endoscopic therapy–related risks of bleeding and perforation, which occur in less than 1% of patients, and the risk of postprocedural stricture formation, which occurs in approximately 6% of patients.

If endoscopic therapy is elected, the update suggests that the procedure be done by experts who perform at least 10 new cases per year.

Concerning specifics of therapy, the investigators advised that mucosal ablation be applied to all visible esophageal columnar mucosa, 5-10 mm proximal to the squamocolumnar junction, and 5-10 mm distal to the gastroesophageal junction. Ablation should only be performed in cases of flat Barrett’s esophagus in which no visible abnormalities or signs of inflammation are present, the review team wrote.

The investigators went on to lay out some “practical ground rules” for endoscopic therapy, including a potential pitfall.

“Ablation therapy may consist of multiple 2-3 monthly ablation sessions that may extend over a period of more than a year,” the investigators wrote. “The worst adverse outcome during the treatment period is failing to recognize and treat an invasive cancer while continuing the ablation sessions. This occurrence may place the patient outside of the window of opportunity for curative endoscopic treatment. Therefore, every ablation session starts with careful endoscopic inspection using [high-definition white-light endoscopy] and preferably optical chromoendoscopy to exclude the presence of visible abnormalities that require an endoscopic resection instead of the scheduled ablation. Routine biopsies of flat Barrett’s esophagus are not necessary or recommended prior to ablation at these sessions, as the blood may inhibit optimal energy transfer to the tissue.”

Following successfully achieved complete endoscopic and histologic eradication of intestinal metaplasia, the update calls for surveillance endoscopy with biopsies at intervals of 1 and 3 years for cases of low-grade dysplasia and at intervals of 3, 6, and 12 months for high-grade dysplasia or esophageal adenocarcinoma, followed by annual checks thereafter.

The investigators disclosed relationships with Olympus, Ironwood, Erbe, and others.

SOURCE: Sharma P et al. Gastroenterology. 2019 Nov 12. doi: 10.1053/j.gastro.2019.09.051.

The American Gastroenterological Association recently released a clinical practice update for endoscopic treatment of Barrett’s esophagus with dysplasia and/or early esophageal adenocarcinoma.

The update offers best practice advice for a range of clinical scenarios based on published evidence, including guidelines and recent systematic reviews, reported lead author Prateek Sharma, MD, of the University of Kansas, Kansas City. Dr. Sharma was accompanied on the authoring review team by three other expert gastroenterologists from the United States and the Netherlands.

Beyond practice advice, the investigators highlighted a research focus for the future.

“Given the expense and time required for careful and continual surveillance after Barrett’s endoscopic therapy, the future must define improved means of risk-stratifying patients for therapy who are at highest risk for cancer development and for risk of recurrence after complete eradication of intestinal metaplasia,” they wrote in Gastroenterology. “Potentially, we may use a panel of patient characteristics (such as the [Progression in Barrett’s] score), preablation tissue characteristics (e.g., baseline grade of dysplasia) and the posttherapy molecular makeup of the epithelium to help risk stratify our patients.”

For now, many of the treatment principles in the update depend upon histologic features.

For instance, either endoscopic therapy or continued surveillance are reasonable options for patients with Barrett’s esophagus who have confirmed and persistent low-grade dysplasia. In contrast, the update recommends that all patients with high-grade dysplasia or esophageal adenocarcinoma (T1a) undergo endoscopic therapy, highlighting that this method is preferred over esophagectomy for patients with T1a cancer. Along the same lines, the investigators noted that endoscopic therapy is a “reasonable alternative” to esophagectomy in cases of T1b esophageal adenocarcinoma in the presence of minimal invasion and good to moderate differentiation, particularly in patients who are poor candidates for surgery.

During the decision-making process, patients with dysplasia should be advised that not undergoing endoscopic therapy may increase cancer risk, the investigators wrote, adding that patients should also be informed about endoscopic therapy–related risks of bleeding and perforation, which occur in less than 1% of patients, and the risk of postprocedural stricture formation, which occurs in approximately 6% of patients.

If endoscopic therapy is elected, the update suggests that the procedure be done by experts who perform at least 10 new cases per year.

Concerning specifics of therapy, the investigators advised that mucosal ablation be applied to all visible esophageal columnar mucosa, 5-10 mm proximal to the squamocolumnar junction, and 5-10 mm distal to the gastroesophageal junction. Ablation should only be performed in cases of flat Barrett’s esophagus in which no visible abnormalities or signs of inflammation are present, the review team wrote.

The investigators went on to lay out some “practical ground rules” for endoscopic therapy, including a potential pitfall.

“Ablation therapy may consist of multiple 2-3 monthly ablation sessions that may extend over a period of more than a year,” the investigators wrote. “The worst adverse outcome during the treatment period is failing to recognize and treat an invasive cancer while continuing the ablation sessions. This occurrence may place the patient outside of the window of opportunity for curative endoscopic treatment. Therefore, every ablation session starts with careful endoscopic inspection using [high-definition white-light endoscopy] and preferably optical chromoendoscopy to exclude the presence of visible abnormalities that require an endoscopic resection instead of the scheduled ablation. Routine biopsies of flat Barrett’s esophagus are not necessary or recommended prior to ablation at these sessions, as the blood may inhibit optimal energy transfer to the tissue.”

Following successfully achieved complete endoscopic and histologic eradication of intestinal metaplasia, the update calls for surveillance endoscopy with biopsies at intervals of 1 and 3 years for cases of low-grade dysplasia and at intervals of 3, 6, and 12 months for high-grade dysplasia or esophageal adenocarcinoma, followed by annual checks thereafter.

The investigators disclosed relationships with Olympus, Ironwood, Erbe, and others.

SOURCE: Sharma P et al. Gastroenterology. 2019 Nov 12. doi: 10.1053/j.gastro.2019.09.051.

The American Gastroenterological Association (AGA) recently published clinical practice guidelines for managing gastric intestinal metaplasia (GIM).

The guidelines are the first of their kind to be published in the United States, according to lead author Samir Gupta, MD, of the University of California San Diego, and colleagues. The panelists suggested that the guidelines may help standardize decision making in a common clinical scenario.

“GIM has been considered as one specific marker to identify patients who might benefit from surveillance because it has been associated with increased risk for gastric cancer and is routinely encountered in clinical practice,” the panelists wrote in Gastroenterology.

The guideline panel was composed of three gastroenterologists, two guideline methodologist trainees, and three GRADE experts. Recommendations were based on the AGA guideline development process, the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology, best practices set forth by the Academy of Medicine, and a technical review.

“Given the paucity of robust direct data on GIM in the U.S., evidence from all regions of the world was considered relevant in the evidence-gathering phase,” the panelists wrote (Gastroenterology. 2019 Dec 6. doi: 10.1053/j.gastro.2019.12.003).

Based on available evidence, the expert panel developed three clinical recommendations.

First, the panelists recommended that clinicians test all patients with GIM for Helicobacter pylori, followed by eradication, over no testing and eradication. This recommendation was strong and based on moderate quality evidence from 22 studies, including 7 randomized controlled trials. These studies showed that, compared with placebo, eradication of H. pylori was associated with a 32% pooled relative risk reduction in gastric cancer and a 33% pooled relative risk reduction in gastric cancer mortality among patients with or without GIM. The pooled relative risk reduction rate was similar in analyses solely composed of individuals with GIM, the panelists noted, whereas mortality data restricted to individuals with GIM were lacking.

“Overall, the known strong association of H. pylori with risk for incident gastric cancer and the technical review’s findings, which reinforce the evidence of reduced risk for incident gastric cancer after H. pylori eradication, supports the AGA recommendation to test for and eradicate H. pylori,” the panelists wrote.

The second recommendation, which was conditional and based on very low quality evidence, advised against routine use of endoscopic surveillance for patients with GIM. Still, surveillance may be considered for patients with higher risk of gastric cancer, including those with incomplete and/or extensive GIM, a family history of gastric cancer, racial/ethnic minorities, and immigrants from high incidence regions, the panelists wrote.

“Although the technical review did not find evidence supporting increased risk for gastric cancer among racial/ethnic minorities or immigrants with documented GIM, an overall increased risk for gastric cancer (irrespective of presence/absence of GIM) has been established among these groups, and may be considered as part of decision making regarding surveillance,” the panelists wrote.

The third and final recommendation was also conditional and based on very weak evidence; the panelists recommended against routine short-interval repeat endoscopy for the purpose of risk stratification.

“The technical review found no direct evidence to support the impact of short-interval (less than 12 months) repeat upper endoscopy among patients with incidental GIM on patient-important outcomes,” the panelists wrote.

However, the guidelines note that patients with potentially elevated risk profiles, such as patients with a family history of gastric cancer, “may reasonably elect for repeat endoscopy within 1 year for risk stratification.”

Comparing these guidelines with those from other organizations, such as the European Society of Gastrointestinal Endoscopy (ESGE), the panelists concluded that recommendations across organizations are “generally similar.”

Finally, the panelists outlined relevant knowledge gaps and pointed to future research topics. For instance, data are scarce comparing outcomes in relation to surveillance versus no surveillance among patients with GIM; and biomarkers such as pepsinogen levels, which are used in Asian countries for risk stratification of gastric cancer, have been studied minimally in the United States.

Guideline development was funded by the AGA. The panelists disclosed no conflicts of interest.

The American Gastroenterological Association (AGA) recently published clinical practice guidelines for managing gastric intestinal metaplasia (GIM).

The guidelines are the first of their kind to be published in the United States, according to lead author Samir Gupta, MD, of the University of California San Diego, and colleagues. The panelists suggested that the guidelines may help standardize decision making in a common clinical scenario.

“GIM has been considered as one specific marker to identify patients who might benefit from surveillance because it has been associated with increased risk for gastric cancer and is routinely encountered in clinical practice,” the panelists wrote in Gastroenterology.

The guideline panel was composed of three gastroenterologists, two guideline methodologist trainees, and three GRADE experts. Recommendations were based on the AGA guideline development process, the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology, best practices set forth by the Academy of Medicine, and a technical review.

“Given the paucity of robust direct data on GIM in the U.S., evidence from all regions of the world was considered relevant in the evidence-gathering phase,” the panelists wrote (Gastroenterology. 2019 Dec 6. doi: 10.1053/j.gastro.2019.12.003).

Based on available evidence, the expert panel developed three clinical recommendations.

First, the panelists recommended that clinicians test all patients with GIM for Helicobacter pylori, followed by eradication, over no testing and eradication. This recommendation was strong and based on moderate quality evidence from 22 studies, including 7 randomized controlled trials. These studies showed that, compared with placebo, eradication of H. pylori was associated with a 32% pooled relative risk reduction in gastric cancer and a 33% pooled relative risk reduction in gastric cancer mortality among patients with or without GIM. The pooled relative risk reduction rate was similar in analyses solely composed of individuals with GIM, the panelists noted, whereas mortality data restricted to individuals with GIM were lacking.

“Overall, the known strong association of H. pylori with risk for incident gastric cancer and the technical review’s findings, which reinforce the evidence of reduced risk for incident gastric cancer after H. pylori eradication, supports the AGA recommendation to test for and eradicate H. pylori,” the panelists wrote.

The second recommendation, which was conditional and based on very low quality evidence, advised against routine use of endoscopic surveillance for patients with GIM. Still, surveillance may be considered for patients with higher risk of gastric cancer, including those with incomplete and/or extensive GIM, a family history of gastric cancer, racial/ethnic minorities, and immigrants from high incidence regions, the panelists wrote.

“Although the technical review did not find evidence supporting increased risk for gastric cancer among racial/ethnic minorities or immigrants with documented GIM, an overall increased risk for gastric cancer (irrespective of presence/absence of GIM) has been established among these groups, and may be considered as part of decision making regarding surveillance,” the panelists wrote.

The third and final recommendation was also conditional and based on very weak evidence; the panelists recommended against routine short-interval repeat endoscopy for the purpose of risk stratification.

“The technical review found no direct evidence to support the impact of short-interval (less than 12 months) repeat upper endoscopy among patients with incidental GIM on patient-important outcomes,” the panelists wrote.

However, the guidelines note that patients with potentially elevated risk profiles, such as patients with a family history of gastric cancer, “may reasonably elect for repeat endoscopy within 1 year for risk stratification.”

Comparing these guidelines with those from other organizations, such as the European Society of Gastrointestinal Endoscopy (ESGE), the panelists concluded that recommendations across organizations are “generally similar.”

Finally, the panelists outlined relevant knowledge gaps and pointed to future research topics. For instance, data are scarce comparing outcomes in relation to surveillance versus no surveillance among patients with GIM; and biomarkers such as pepsinogen levels, which are used in Asian countries for risk stratification of gastric cancer, have been studied minimally in the United States.

Guideline development was funded by the AGA. The panelists disclosed no conflicts of interest.

The American Gastroenterological Association (AGA) recently published clinical practice guidelines for managing gastric intestinal metaplasia (GIM).

The guidelines are the first of their kind to be published in the United States, according to lead author Samir Gupta, MD, of the University of California San Diego, and colleagues. The panelists suggested that the guidelines may help standardize decision making in a common clinical scenario.

“GIM has been considered as one specific marker to identify patients who might benefit from surveillance because it has been associated with increased risk for gastric cancer and is routinely encountered in clinical practice,” the panelists wrote in Gastroenterology.

The guideline panel was composed of three gastroenterologists, two guideline methodologist trainees, and three GRADE experts. Recommendations were based on the AGA guideline development process, the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology, best practices set forth by the Academy of Medicine, and a technical review.

“Given the paucity of robust direct data on GIM in the U.S., evidence from all regions of the world was considered relevant in the evidence-gathering phase,” the panelists wrote (Gastroenterology. 2019 Dec 6. doi: 10.1053/j.gastro.2019.12.003).

Based on available evidence, the expert panel developed three clinical recommendations.

First, the panelists recommended that clinicians test all patients with GIM for Helicobacter pylori, followed by eradication, over no testing and eradication. This recommendation was strong and based on moderate quality evidence from 22 studies, including 7 randomized controlled trials. These studies showed that, compared with placebo, eradication of H. pylori was associated with a 32% pooled relative risk reduction in gastric cancer and a 33% pooled relative risk reduction in gastric cancer mortality among patients with or without GIM. The pooled relative risk reduction rate was similar in analyses solely composed of individuals with GIM, the panelists noted, whereas mortality data restricted to individuals with GIM were lacking.

“Overall, the known strong association of H. pylori with risk for incident gastric cancer and the technical review’s findings, which reinforce the evidence of reduced risk for incident gastric cancer after H. pylori eradication, supports the AGA recommendation to test for and eradicate H. pylori,” the panelists wrote.

The second recommendation, which was conditional and based on very low quality evidence, advised against routine use of endoscopic surveillance for patients with GIM. Still, surveillance may be considered for patients with higher risk of gastric cancer, including those with incomplete and/or extensive GIM, a family history of gastric cancer, racial/ethnic minorities, and immigrants from high incidence regions, the panelists wrote.

“Although the technical review did not find evidence supporting increased risk for gastric cancer among racial/ethnic minorities or immigrants with documented GIM, an overall increased risk for gastric cancer (irrespective of presence/absence of GIM) has been established among these groups, and may be considered as part of decision making regarding surveillance,” the panelists wrote.

The third and final recommendation was also conditional and based on very weak evidence; the panelists recommended against routine short-interval repeat endoscopy for the purpose of risk stratification.

“The technical review found no direct evidence to support the impact of short-interval (less than 12 months) repeat upper endoscopy among patients with incidental GIM on patient-important outcomes,” the panelists wrote.

However, the guidelines note that patients with potentially elevated risk profiles, such as patients with a family history of gastric cancer, “may reasonably elect for repeat endoscopy within 1 year for risk stratification.”

Comparing these guidelines with those from other organizations, such as the European Society of Gastrointestinal Endoscopy (ESGE), the panelists concluded that recommendations across organizations are “generally similar.”

Finally, the panelists outlined relevant knowledge gaps and pointed to future research topics. For instance, data are scarce comparing outcomes in relation to surveillance versus no surveillance among patients with GIM; and biomarkers such as pepsinogen levels, which are used in Asian countries for risk stratification of gastric cancer, have been studied minimally in the United States.

Guideline development was funded by the AGA. The panelists disclosed no conflicts of interest.

Currently available fibrosis scoring systems appear to have only a modest predictive ability for development of severe liver disease in the general population, according to authors of a large, retrospective cohort study.

Of five noninvasive scoring systems evaluated, all did have high negative predictive value in the general population, according to authors of the study, which included data on more than 800,000 individuals in Sweden. However, their sensitivities were low, with most of the individuals who developed severe liver disease over a 10-year follow-up period initially classified as being at low risk for advanced fibrosis, according to the study authors, led by Hannes Hagström, MD, PhD, of the division of hepatology, Karolinska University Hospital, Stockholm.

The scoring systems tended to perform better in patients at higher risk for nonalcoholic fatty liver disease (NAFLD) at baseline, suggesting the best use of the tools is in patients at increased risk or who have liver disease indications, Dr. Hagström and coauthors wrote in a report on the study.

“Although useful in populations with a high prevalence of advanced fibrosis, current scores lack precision for usage in the general population for which the prevalence of advanced fibrosis is much lower,” Dr. Hagström and colleagues said.

The scoring systems were derived from high-risk cohorts with liver diseases, the authors noted, stating that the disease prevalence in any given population will affect the performance of a test that’s intended to diagnose that specific disease.

“New and improved” scoring systems should be developed to more effectively pinpoint patients with NAFLD who are at higher risk of a severe liver event, they added in the report, which appears in Gastroenterology.

The population-based cohort study by Dr. Hagström and colleagues was based on data from 812,073 patients enrolled in the Swedish Apolipoprotein Mortality Risk (AMORIS) cohort between 1985 and 1996. Investigators said they excluded patients under 35 and over 79 years of age, patients with severe liver disease at baseline, and those with a prior diagnosis of alcohol or drug abuse.

Investigators used available data to calculate five scores, including the AST to Platelet Ratio Index (APRI); the body mass index, AST/ALT ratio, and diabetes (BARD) score; the Fibrosis-4 (FIB-4) score; Forns Index; and NAFLD Fibrosis Score (NFS).

At baseline, 0.5%-8.0% of patients were considered to be at high risk for advanced fibrosis, depending on the test used, investigators said. With up to 10 years of follow-up, the proportion of individuals who developed severe liver diseases (cirrhosis, liver failure, hepatocellular carcinoma, liver transplantation, or decompensated liver disease) was 0.3%-0.6%, and with the maximum 27 years of follow-up, the incidence ranged from 1.0% to 1.4%.

There was a “strong association” between baseline risk of fibrosis and development of severe liver diseases; however, the majority of cases occurred in patients deemed low risk at baseline, Dr. Hagström and colleagues noted in their report.

For example, 12.4% of individuals classified as high risk by APRI developed severe liver diseases over 10 years, compared to just 0.4% of the low-risk group, yet out of 723 cases, 502 (69%) occurred in the low-risk patients, the data show.

Hazard ratios did increase with risk level, and at the high-risk level, adjusted hazard ratios ranged from 1.7 (95% confidence interval [CI], 1.1-2.5) for the high-risk BARD patients to 45.9 (95% CI, 36.1-58.3) for the high-risk APRI patients, investigators reported.

Taken together, results of this study demonstrate that the performance of all scores was low in an unselected population, according to investigators.

Of all tests, APRI was least likely to falsely classify patients who never developed severe liver diseases and had an intermediate-risk group of 4%, the lowest of any test, which are findings that may have implications for routine primary care, according to investigators.

“APRI could be the currently best score to exclude a high risk of liver-related events in the near future, and thereby reduce unnecessary testing in a general population,” they said in a discussion of their results.

The study was supported by an independent grant from AstraZeneca. Dr. Hagström reported disclosures related to that company, as well as Novo Nordisk, Gilead Sciences, IQVIA, Intercept, and Bristol Myers-Squibb.

SOURCE: Hagström H et al. Gastroenterology. 2019 Sep 26. doi: 10.1053/j.gastro.2019.09.008.

Currently available fibrosis scoring systems appear to have only a modest predictive ability for development of severe liver disease in the general population, according to authors of a large, retrospective cohort study.

Of five noninvasive scoring systems evaluated, all did have high negative predictive value in the general population, according to authors of the study, which included data on more than 800,000 individuals in Sweden. However, their sensitivities were low, with most of the individuals who developed severe liver disease over a 10-year follow-up period initially classified as being at low risk for advanced fibrosis, according to the study authors, led by Hannes Hagström, MD, PhD, of the division of hepatology, Karolinska University Hospital, Stockholm.

The scoring systems tended to perform better in patients at higher risk for nonalcoholic fatty liver disease (NAFLD) at baseline, suggesting the best use of the tools is in patients at increased risk or who have liver disease indications, Dr. Hagström and coauthors wrote in a report on the study.

“Although useful in populations with a high prevalence of advanced fibrosis, current scores lack precision for usage in the general population for which the prevalence of advanced fibrosis is much lower,” Dr. Hagström and colleagues said.

The scoring systems were derived from high-risk cohorts with liver diseases, the authors noted, stating that the disease prevalence in any given population will affect the performance of a test that’s intended to diagnose that specific disease.

“New and improved” scoring systems should be developed to more effectively pinpoint patients with NAFLD who are at higher risk of a severe liver event, they added in the report, which appears in Gastroenterology.

The population-based cohort study by Dr. Hagström and colleagues was based on data from 812,073 patients enrolled in the Swedish Apolipoprotein Mortality Risk (AMORIS) cohort between 1985 and 1996. Investigators said they excluded patients under 35 and over 79 years of age, patients with severe liver disease at baseline, and those with a prior diagnosis of alcohol or drug abuse.

Investigators used available data to calculate five scores, including the AST to Platelet Ratio Index (APRI); the body mass index, AST/ALT ratio, and diabetes (BARD) score; the Fibrosis-4 (FIB-4) score; Forns Index; and NAFLD Fibrosis Score (NFS).

At baseline, 0.5%-8.0% of patients were considered to be at high risk for advanced fibrosis, depending on the test used, investigators said. With up to 10 years of follow-up, the proportion of individuals who developed severe liver diseases (cirrhosis, liver failure, hepatocellular carcinoma, liver transplantation, or decompensated liver disease) was 0.3%-0.6%, and with the maximum 27 years of follow-up, the incidence ranged from 1.0% to 1.4%.

There was a “strong association” between baseline risk of fibrosis and development of severe liver diseases; however, the majority of cases occurred in patients deemed low risk at baseline, Dr. Hagström and colleagues noted in their report.

For example, 12.4% of individuals classified as high risk by APRI developed severe liver diseases over 10 years, compared to just 0.4% of the low-risk group, yet out of 723 cases, 502 (69%) occurred in the low-risk patients, the data show.

Hazard ratios did increase with risk level, and at the high-risk level, adjusted hazard ratios ranged from 1.7 (95% confidence interval [CI], 1.1-2.5) for the high-risk BARD patients to 45.9 (95% CI, 36.1-58.3) for the high-risk APRI patients, investigators reported.

Taken together, results of this study demonstrate that the performance of all scores was low in an unselected population, according to investigators.

Of all tests, APRI was least likely to falsely classify patients who never developed severe liver diseases and had an intermediate-risk group of 4%, the lowest of any test, which are findings that may have implications for routine primary care, according to investigators.

“APRI could be the currently best score to exclude a high risk of liver-related events in the near future, and thereby reduce unnecessary testing in a general population,” they said in a discussion of their results.

The study was supported by an independent grant from AstraZeneca. Dr. Hagström reported disclosures related to that company, as well as Novo Nordisk, Gilead Sciences, IQVIA, Intercept, and Bristol Myers-Squibb.

SOURCE: Hagström H et al. Gastroenterology. 2019 Sep 26. doi: 10.1053/j.gastro.2019.09.008.

Currently available fibrosis scoring systems appear to have only a modest predictive ability for development of severe liver disease in the general population, according to authors of a large, retrospective cohort study.

Of five noninvasive scoring systems evaluated, all did have high negative predictive value in the general population, according to authors of the study, which included data on more than 800,000 individuals in Sweden. However, their sensitivities were low, with most of the individuals who developed severe liver disease over a 10-year follow-up period initially classified as being at low risk for advanced fibrosis, according to the study authors, led by Hannes Hagström, MD, PhD, of the division of hepatology, Karolinska University Hospital, Stockholm.

The scoring systems tended to perform better in patients at higher risk for nonalcoholic fatty liver disease (NAFLD) at baseline, suggesting the best use of the tools is in patients at increased risk or who have liver disease indications, Dr. Hagström and coauthors wrote in a report on the study.

“Although useful in populations with a high prevalence of advanced fibrosis, current scores lack precision for usage in the general population for which the prevalence of advanced fibrosis is much lower,” Dr. Hagström and colleagues said.

The scoring systems were derived from high-risk cohorts with liver diseases, the authors noted, stating that the disease prevalence in any given population will affect the performance of a test that’s intended to diagnose that specific disease.

“New and improved” scoring systems should be developed to more effectively pinpoint patients with NAFLD who are at higher risk of a severe liver event, they added in the report, which appears in Gastroenterology.

The population-based cohort study by Dr. Hagström and colleagues was based on data from 812,073 patients enrolled in the Swedish Apolipoprotein Mortality Risk (AMORIS) cohort between 1985 and 1996. Investigators said they excluded patients under 35 and over 79 years of age, patients with severe liver disease at baseline, and those with a prior diagnosis of alcohol or drug abuse.

Investigators used available data to calculate five scores, including the AST to Platelet Ratio Index (APRI); the body mass index, AST/ALT ratio, and diabetes (BARD) score; the Fibrosis-4 (FIB-4) score; Forns Index; and NAFLD Fibrosis Score (NFS).

At baseline, 0.5%-8.0% of patients were considered to be at high risk for advanced fibrosis, depending on the test used, investigators said. With up to 10 years of follow-up, the proportion of individuals who developed severe liver diseases (cirrhosis, liver failure, hepatocellular carcinoma, liver transplantation, or decompensated liver disease) was 0.3%-0.6%, and with the maximum 27 years of follow-up, the incidence ranged from 1.0% to 1.4%.

There was a “strong association” between baseline risk of fibrosis and development of severe liver diseases; however, the majority of cases occurred in patients deemed low risk at baseline, Dr. Hagström and colleagues noted in their report.

For example, 12.4% of individuals classified as high risk by APRI developed severe liver diseases over 10 years, compared to just 0.4% of the low-risk group, yet out of 723 cases, 502 (69%) occurred in the low-risk patients, the data show.

Hazard ratios did increase with risk level, and at the high-risk level, adjusted hazard ratios ranged from 1.7 (95% confidence interval [CI], 1.1-2.5) for the high-risk BARD patients to 45.9 (95% CI, 36.1-58.3) for the high-risk APRI patients, investigators reported.

Taken together, results of this study demonstrate that the performance of all scores was low in an unselected population, according to investigators.

Of all tests, APRI was least likely to falsely classify patients who never developed severe liver diseases and had an intermediate-risk group of 4%, the lowest of any test, which are findings that may have implications for routine primary care, according to investigators.

“APRI could be the currently best score to exclude a high risk of liver-related events in the near future, and thereby reduce unnecessary testing in a general population,” they said in a discussion of their results.

The study was supported by an independent grant from AstraZeneca. Dr. Hagström reported disclosures related to that company, as well as Novo Nordisk, Gilead Sciences, IQVIA, Intercept, and Bristol Myers-Squibb.

SOURCE: Hagström H et al. Gastroenterology. 2019 Sep 26. doi: 10.1053/j.gastro.2019.09.008.

Serum lipid increases seen after 8-61 weeks of tofacitinib treatment for ulcerative colitis are modest, reversible, and correlated with reduced systemic inflammation, according to results of an analysis including more than 1,000 patients.

Major adverse cardiac events (MACE) were “infrequent” following treatment, according to the authors of the analysis, with an incidence rate similar to what has been reported for tofacitinib in rheumatoid arthritis and for other agents in ulcerative colitis.

That said, the period of observation in the analysis is “relatively short,” and so may not provide an accurate risk estimate for MACE, noted the investigators, led by Bruce E. Sands, MD, of the division of gastroenterology at the Icahn School of Medicine at Mount Sinai, New York.

“Longer-term studies, involving a larger number of patients, will be needed to further assess MACE risk in patients with ulcerative colitis,” Dr. Sands and coinvestigators wrote in their report on the observational analysis, which appears in Clinical Gastroenterology and Hepatology.

“It is noteworthy that no increase in MACE risk and no dose relationship with tofacitinib have been observed in a larger rheumatoid arthritis cohort with over 8.5 years of observation and more than 19,000 patient-years of collective exposure,” they continued.

The present analysis included 1,157 patients with ulcerative colitis who participated in 8-week phase 2 and 3 tofacitinib induction studies, a phase 3 maintenance study, and a long-term extension study that is ongoing.

Reversible and dose-dependent increases in both LDL cholesterol and HDL cholesterol were observed after 8 weeks of treatment with tofacitinib at the recommended induction dose of 10 mg twice daily, the investigators found.

Increases in LDL cholesterol, HDL cholesterol, and total cholesterol correlated with decreases in high-sensitivity C-reactive protein, suggesting any potential impact of lipid increases on cardiovascular events might be offset by reduced inflammation, according to the investigators.

“Previous studies in RA and inflammatory bowel disease have shown an inverse relationship between active inflammation and serum lipid profiles, suggesting that inflammation lowers lipid concentrations, and that treatment of the underlying inflammatory disease may, therefore, increase them,” Dr. Sands and colleagues wrote.

The lipid changes also correlated with increases in body mass index, possibly because of better nutrition, reduced protein loss, and less catabolism following tofacitinib treatment, along with the corticosteroid taper required in these studies of the drug, they added.

Lipid increases generally stayed elevated through 61 weeks of treatment, while in patients randomized to placebo after 8 weeks of tofacitinib treatment, lipid levels fell back toward baseline, which suggests a reversal of the increases after tofacitinib withdrawal, the investigators wrote.

A total of 4 MACEs were seen among the 1,157 patients in the analysis, for an incidence rate of 0.24 (95% confidence interval, 0.07-0.62), according to the report. Those events included an acute coronary syndrome, an MI, an aortic dissection, and a hemorrhagic stroke. All four occurred in tofacitinib-treated patients, though the investigators noted that the aortic dissection and hemorrhagic stroke are events typically associated with genetics or other nonlipid factors.

In any case, that MACE incidence rate was “similar” to infliximab (Remicade) for what has been observed in tumor necrosis factor antagonist treatment of ulcerative colitis within a U.S. claims database study. In that analysis, including patients treated with infliximab, golimumab, and adalimumab, the incidence rate was 0.51 (95% CI, 0.31-0.79), the investigators noted.

These findings, taken together, support recommendations in tofacitinib prescribing information that call for monitoring of lipid concentrations 4-8 weeks after treatment is started, according to Dr. Sands and coauthors.

Funding for the study came from Pfizer. The study authors disclosed potential conflicts of interest related to Pfizer, AbbVie, Amgen, Bristol-Myers Squibb, Celgene, Janssen, MedImmune (AstraZeneca), Millennium Pharmaceuticals, Prometheus Laboratories, Takeda, and 4D Pharma, among others.

SOURCE: Sands BE et al. Clin Gastroenterol Hepatol. 2019 May 8. doi: 10.1016/j.cgh.2019.04.059.

Serum lipid increases seen after 8-61 weeks of tofacitinib treatment for ulcerative colitis are modest, reversible, and correlated with reduced systemic inflammation, according to results of an analysis including more than 1,000 patients.

Major adverse cardiac events (MACE) were “infrequent” following treatment, according to the authors of the analysis, with an incidence rate similar to what has been reported for tofacitinib in rheumatoid arthritis and for other agents in ulcerative colitis.

That said, the period of observation in the analysis is “relatively short,” and so may not provide an accurate risk estimate for MACE, noted the investigators, led by Bruce E. Sands, MD, of the division of gastroenterology at the Icahn School of Medicine at Mount Sinai, New York.

“Longer-term studies, involving a larger number of patients, will be needed to further assess MACE risk in patients with ulcerative colitis,” Dr. Sands and coinvestigators wrote in their report on the observational analysis, which appears in Clinical Gastroenterology and Hepatology.

“It is noteworthy that no increase in MACE risk and no dose relationship with tofacitinib have been observed in a larger rheumatoid arthritis cohort with over 8.5 years of observation and more than 19,000 patient-years of collective exposure,” they continued.

The present analysis included 1,157 patients with ulcerative colitis who participated in 8-week phase 2 and 3 tofacitinib induction studies, a phase 3 maintenance study, and a long-term extension study that is ongoing.

Reversible and dose-dependent increases in both LDL cholesterol and HDL cholesterol were observed after 8 weeks of treatment with tofacitinib at the recommended induction dose of 10 mg twice daily, the investigators found.

Increases in LDL cholesterol, HDL cholesterol, and total cholesterol correlated with decreases in high-sensitivity C-reactive protein, suggesting any potential impact of lipid increases on cardiovascular events might be offset by reduced inflammation, according to the investigators.

“Previous studies in RA and inflammatory bowel disease have shown an inverse relationship between active inflammation and serum lipid profiles, suggesting that inflammation lowers lipid concentrations, and that treatment of the underlying inflammatory disease may, therefore, increase them,” Dr. Sands and colleagues wrote.

The lipid changes also correlated with increases in body mass index, possibly because of better nutrition, reduced protein loss, and less catabolism following tofacitinib treatment, along with the corticosteroid taper required in these studies of the drug, they added.

Lipid increases generally stayed elevated through 61 weeks of treatment, while in patients randomized to placebo after 8 weeks of tofacitinib treatment, lipid levels fell back toward baseline, which suggests a reversal of the increases after tofacitinib withdrawal, the investigators wrote.

A total of 4 MACEs were seen among the 1,157 patients in the analysis, for an incidence rate of 0.24 (95% confidence interval, 0.07-0.62), according to the report. Those events included an acute coronary syndrome, an MI, an aortic dissection, and a hemorrhagic stroke. All four occurred in tofacitinib-treated patients, though the investigators noted that the aortic dissection and hemorrhagic stroke are events typically associated with genetics or other nonlipid factors.

In any case, that MACE incidence rate was “similar” to infliximab (Remicade) for what has been observed in tumor necrosis factor antagonist treatment of ulcerative colitis within a U.S. claims database study. In that analysis, including patients treated with infliximab, golimumab, and adalimumab, the incidence rate was 0.51 (95% CI, 0.31-0.79), the investigators noted.

These findings, taken together, support recommendations in tofacitinib prescribing information that call for monitoring of lipid concentrations 4-8 weeks after treatment is started, according to Dr. Sands and coauthors.

Funding for the study came from Pfizer. The study authors disclosed potential conflicts of interest related to Pfizer, AbbVie, Amgen, Bristol-Myers Squibb, Celgene, Janssen, MedImmune (AstraZeneca), Millennium Pharmaceuticals, Prometheus Laboratories, Takeda, and 4D Pharma, among others.

SOURCE: Sands BE et al. Clin Gastroenterol Hepatol. 2019 May 8. doi: 10.1016/j.cgh.2019.04.059.

Serum lipid increases seen after 8-61 weeks of tofacitinib treatment for ulcerative colitis are modest, reversible, and correlated with reduced systemic inflammation, according to results of an analysis including more than 1,000 patients.

Major adverse cardiac events (MACE) were “infrequent” following treatment, according to the authors of the analysis, with an incidence rate similar to what has been reported for tofacitinib in rheumatoid arthritis and for other agents in ulcerative colitis.

That said, the period of observation in the analysis is “relatively short,” and so may not provide an accurate risk estimate for MACE, noted the investigators, led by Bruce E. Sands, MD, of the division of gastroenterology at the Icahn School of Medicine at Mount Sinai, New York.

“Longer-term studies, involving a larger number of patients, will be needed to further assess MACE risk in patients with ulcerative colitis,” Dr. Sands and coinvestigators wrote in their report on the observational analysis, which appears in Clinical Gastroenterology and Hepatology.

“It is noteworthy that no increase in MACE risk and no dose relationship with tofacitinib have been observed in a larger rheumatoid arthritis cohort with over 8.5 years of observation and more than 19,000 patient-years of collective exposure,” they continued.

The present analysis included 1,157 patients with ulcerative colitis who participated in 8-week phase 2 and 3 tofacitinib induction studies, a phase 3 maintenance study, and a long-term extension study that is ongoing.

Reversible and dose-dependent increases in both LDL cholesterol and HDL cholesterol were observed after 8 weeks of treatment with tofacitinib at the recommended induction dose of 10 mg twice daily, the investigators found.

Increases in LDL cholesterol, HDL cholesterol, and total cholesterol correlated with decreases in high-sensitivity C-reactive protein, suggesting any potential impact of lipid increases on cardiovascular events might be offset by reduced inflammation, according to the investigators.

“Previous studies in RA and inflammatory bowel disease have shown an inverse relationship between active inflammation and serum lipid profiles, suggesting that inflammation lowers lipid concentrations, and that treatment of the underlying inflammatory disease may, therefore, increase them,” Dr. Sands and colleagues wrote.

The lipid changes also correlated with increases in body mass index, possibly because of better nutrition, reduced protein loss, and less catabolism following tofacitinib treatment, along with the corticosteroid taper required in these studies of the drug, they added.

Lipid increases generally stayed elevated through 61 weeks of treatment, while in patients randomized to placebo after 8 weeks of tofacitinib treatment, lipid levels fell back toward baseline, which suggests a reversal of the increases after tofacitinib withdrawal, the investigators wrote.

A total of 4 MACEs were seen among the 1,157 patients in the analysis, for an incidence rate of 0.24 (95% confidence interval, 0.07-0.62), according to the report. Those events included an acute coronary syndrome, an MI, an aortic dissection, and a hemorrhagic stroke. All four occurred in tofacitinib-treated patients, though the investigators noted that the aortic dissection and hemorrhagic stroke are events typically associated with genetics or other nonlipid factors.

In any case, that MACE incidence rate was “similar” to infliximab (Remicade) for what has been observed in tumor necrosis factor antagonist treatment of ulcerative colitis within a U.S. claims database study. In that analysis, including patients treated with infliximab, golimumab, and adalimumab, the incidence rate was 0.51 (95% CI, 0.31-0.79), the investigators noted.

These findings, taken together, support recommendations in tofacitinib prescribing information that call for monitoring of lipid concentrations 4-8 weeks after treatment is started, according to Dr. Sands and coauthors.

Funding for the study came from Pfizer. The study authors disclosed potential conflicts of interest related to Pfizer, AbbVie, Amgen, Bristol-Myers Squibb, Celgene, Janssen, MedImmune (AstraZeneca), Millennium Pharmaceuticals, Prometheus Laboratories, Takeda, and 4D Pharma, among others.

SOURCE: Sands BE et al. Clin Gastroenterol Hepatol. 2019 May 8. doi: 10.1016/j.cgh.2019.04.059.

While initial case reports and series provided preliminarily encouraging results, a larger retrospective study has provided no clear-cut evidence of biochemical response to vedolizumab in patients with primary sclerosing cholangitis (PSC) and inflammatory bowel disease, investigators report.

A subset of patients in the retrospective analysis did experience a substantial drop in alkaline phosphatase (ALP), according to investigators with the International Primary Sclerosing Cholangitis Study Group.

Overall, however, levels of that cholestasis marker rose by a small but statistically significant amount in this study, which included more than 100 patients with PSC and inflammatory bowel disease (IBD).

Responses were more likely in patients with cirrhosis and in those with elevated ALP at baseline, both of which are indicators of more aggressive disease, according to investigator Kate D. Lynch, MD, PhD, of the University of Oxford (England) and her coauthors.

The rate of liver outcomes was in line with the natural history of the disease, according to Dr. Lynch and coinvestigators, who added that most patients had an endoscopic IBD response, as might be expected based on studies of IBD-only patients treated with vedolizumab.

“Despite the disappointment with lack of a uniform response, further evaluation of vedolizumab as a beneficial treatment in PSC may be warranted in a subset of patients via a stratified randomized clinical trial,” Dr. Lynch and coauthors said in their report, which was published in Clinical Gastroenterology and Hepatology.

Vedolizumab, a monoclonal antibody against integrin alpha4beta7, is effective in Crohn’s disease and ulcerative colitis, according to investigators, who added that the “gut-homing pathway” it targets has also been implicated in the pathophysiology of PSC.

“It is possible that vedolizumab may play a role in reducing lymphocyte infiltration into the liver in patients with PSC and thereby in reducing hepatic and biliary inflammation, authors of the retrospective analysis said.

Their analysis included 102 patients with PSC and IBD at 20 centers in Europe and North America. All patients had received at least three doses of vedolizumab for their IBD, given according to the usual dosing schedule. Most of the patients were male (64 patients, or 62.8%) and about 90% had classical large-duct PSC. About one-fifth had cirrhosis, and the majority (about 65%) had ulcerative colitis. Patients were followed until death, liver transplant, or 56 days after the last vedolizumab dose.

The median ALP increased from 1.53 times the upper limit of normal at baseline to 1.64 times the upper limit of normal by the last follow-up, an increase that was statistically significant (P = .018) but not clinically significant, according to investigators. Likewise, they said, statistically significant increases were seen overall in median alanine transaminase and aspartate aminotransferase levels.

However, 21 patients (20.6%) had a drop in ALP of at least 20% from baseline to last follow-up, and another 39 patients (38.2%) had stable ALP over that period, data show, while the remaining 42 (41.2%) had an increase of 20% or more.

Cirrhosis was associated with a near fivefold odds of a 20% or greater ALP drop from baseline to follow-up (odds ratio, 4.70, 95% confidence interval, 1.61-13.76), according to results of univariate analysis, which investigators said were “reproduced” in multivariate analysis.

While no other variables were so clearly linked to a 20% or greater drop in ALP, Dr. Lynch and colleagues said there was a “trend toward an association” in patients with ALP raised at baseline, and in those who had Crohn’s disease or IBD-unspecified instead of ulcerative colitis.

Endoscopic IBD responses were seen in 42 out of 74 patients (56.8%) for whom those data were available, investigators added.

A total of 22 patients (20.9%) had a liver-related outcome over median follow-up of 561 days; however, that outcome may be “slightly overrepresented” by an incidence of cholangitis in 8.8%, which in and of itself is not necessarily an indicator of advanced liver disease, said Dr. Lynch and coauthors in their report.

“This proportion of liver-related outcomes is consistent with the natural history of PSC and does not by itself indicate that vedolizumab treatment is harmful in PSC,” they said, adding that the findings were similar to a study of simtuzumab, a monoclonal antibody directed against lysyl oxidase-like 2, in patients with PSC, of whom 20.1% had a PSC-related event and the incidence of cholangitis was 13.2%.

The retrospective study was supported by the Birmingham National Institute for Health Research (NIHR) Biomedical Research Centre in the United Kingdom. Authors of the report provided disclosures related to Takeda, AbbVie, Dr. Falk Pharma, Intercept, MSD, Janssen, Vifor, Gilead, and Novartis, among others.

SOURCE: Lynch KD et al. Clin Gastroenterol Hepatol. 2019 May 14. doi: 10.1016/j.cgh.2019.05.013.

While initial case reports and series provided preliminarily encouraging results, a larger retrospective study has provided no clear-cut evidence of biochemical response to vedolizumab in patients with primary sclerosing cholangitis (PSC) and inflammatory bowel disease, investigators report.

A subset of patients in the retrospective analysis did experience a substantial drop in alkaline phosphatase (ALP), according to investigators with the International Primary Sclerosing Cholangitis Study Group.

Overall, however, levels of that cholestasis marker rose by a small but statistically significant amount in this study, which included more than 100 patients with PSC and inflammatory bowel disease (IBD).

Responses were more likely in patients with cirrhosis and in those with elevated ALP at baseline, both of which are indicators of more aggressive disease, according to investigator Kate D. Lynch, MD, PhD, of the University of Oxford (England) and her coauthors.

The rate of liver outcomes was in line with the natural history of the disease, according to Dr. Lynch and coinvestigators, who added that most patients had an endoscopic IBD response, as might be expected based on studies of IBD-only patients treated with vedolizumab.

“Despite the disappointment with lack of a uniform response, further evaluation of vedolizumab as a beneficial treatment in PSC may be warranted in a subset of patients via a stratified randomized clinical trial,” Dr. Lynch and coauthors said in their report, which was published in Clinical Gastroenterology and Hepatology.

Vedolizumab, a monoclonal antibody against integrin alpha4beta7, is effective in Crohn’s disease and ulcerative colitis, according to investigators, who added that the “gut-homing pathway” it targets has also been implicated in the pathophysiology of PSC.

“It is possible that vedolizumab may play a role in reducing lymphocyte infiltration into the liver in patients with PSC and thereby in reducing hepatic and biliary inflammation, authors of the retrospective analysis said.

Their analysis included 102 patients with PSC and IBD at 20 centers in Europe and North America. All patients had received at least three doses of vedolizumab for their IBD, given according to the usual dosing schedule. Most of the patients were male (64 patients, or 62.8%) and about 90% had classical large-duct PSC. About one-fifth had cirrhosis, and the majority (about 65%) had ulcerative colitis. Patients were followed until death, liver transplant, or 56 days after the last vedolizumab dose.

The median ALP increased from 1.53 times the upper limit of normal at baseline to 1.64 times the upper limit of normal by the last follow-up, an increase that was statistically significant (P = .018) but not clinically significant, according to investigators. Likewise, they said, statistically significant increases were seen overall in median alanine transaminase and aspartate aminotransferase levels.

However, 21 patients (20.6%) had a drop in ALP of at least 20% from baseline to last follow-up, and another 39 patients (38.2%) had stable ALP over that period, data show, while the remaining 42 (41.2%) had an increase of 20% or more.

Cirrhosis was associated with a near fivefold odds of a 20% or greater ALP drop from baseline to follow-up (odds ratio, 4.70, 95% confidence interval, 1.61-13.76), according to results of univariate analysis, which investigators said were “reproduced” in multivariate analysis.

While no other variables were so clearly linked to a 20% or greater drop in ALP, Dr. Lynch and colleagues said there was a “trend toward an association” in patients with ALP raised at baseline, and in those who had Crohn’s disease or IBD-unspecified instead of ulcerative colitis.

Endoscopic IBD responses were seen in 42 out of 74 patients (56.8%) for whom those data were available, investigators added.

A total of 22 patients (20.9%) had a liver-related outcome over median follow-up of 561 days; however, that outcome may be “slightly overrepresented” by an incidence of cholangitis in 8.8%, which in and of itself is not necessarily an indicator of advanced liver disease, said Dr. Lynch and coauthors in their report.

“This proportion of liver-related outcomes is consistent with the natural history of PSC and does not by itself indicate that vedolizumab treatment is harmful in PSC,” they said, adding that the findings were similar to a study of simtuzumab, a monoclonal antibody directed against lysyl oxidase-like 2, in patients with PSC, of whom 20.1% had a PSC-related event and the incidence of cholangitis was 13.2%.

The retrospective study was supported by the Birmingham National Institute for Health Research (NIHR) Biomedical Research Centre in the United Kingdom. Authors of the report provided disclosures related to Takeda, AbbVie, Dr. Falk Pharma, Intercept, MSD, Janssen, Vifor, Gilead, and Novartis, among others.

SOURCE: Lynch KD et al. Clin Gastroenterol Hepatol. 2019 May 14. doi: 10.1016/j.cgh.2019.05.013.

While initial case reports and series provided preliminarily encouraging results, a larger retrospective study has provided no clear-cut evidence of biochemical response to vedolizumab in patients with primary sclerosing cholangitis (PSC) and inflammatory bowel disease, investigators report.

A subset of patients in the retrospective analysis did experience a substantial drop in alkaline phosphatase (ALP), according to investigators with the International Primary Sclerosing Cholangitis Study Group.

Overall, however, levels of that cholestasis marker rose by a small but statistically significant amount in this study, which included more than 100 patients with PSC and inflammatory bowel disease (IBD).

Responses were more likely in patients with cirrhosis and in those with elevated ALP at baseline, both of which are indicators of more aggressive disease, according to investigator Kate D. Lynch, MD, PhD, of the University of Oxford (England) and her coauthors.

The rate of liver outcomes was in line with the natural history of the disease, according to Dr. Lynch and coinvestigators, who added that most patients had an endoscopic IBD response, as might be expected based on studies of IBD-only patients treated with vedolizumab.

“Despite the disappointment with lack of a uniform response, further evaluation of vedolizumab as a beneficial treatment in PSC may be warranted in a subset of patients via a stratified randomized clinical trial,” Dr. Lynch and coauthors said in their report, which was published in Clinical Gastroenterology and Hepatology.

Vedolizumab, a monoclonal antibody against integrin alpha4beta7, is effective in Crohn’s disease and ulcerative colitis, according to investigators, who added that the “gut-homing pathway” it targets has also been implicated in the pathophysiology of PSC.

“It is possible that vedolizumab may play a role in reducing lymphocyte infiltration into the liver in patients with PSC and thereby in reducing hepatic and biliary inflammation, authors of the retrospective analysis said.

Their analysis included 102 patients with PSC and IBD at 20 centers in Europe and North America. All patients had received at least three doses of vedolizumab for their IBD, given according to the usual dosing schedule. Most of the patients were male (64 patients, or 62.8%) and about 90% had classical large-duct PSC. About one-fifth had cirrhosis, and the majority (about 65%) had ulcerative colitis. Patients were followed until death, liver transplant, or 56 days after the last vedolizumab dose.

The median ALP increased from 1.53 times the upper limit of normal at baseline to 1.64 times the upper limit of normal by the last follow-up, an increase that was statistically significant (P = .018) but not clinically significant, according to investigators. Likewise, they said, statistically significant increases were seen overall in median alanine transaminase and aspartate aminotransferase levels.

However, 21 patients (20.6%) had a drop in ALP of at least 20% from baseline to last follow-up, and another 39 patients (38.2%) had stable ALP over that period, data show, while the remaining 42 (41.2%) had an increase of 20% or more.

Cirrhosis was associated with a near fivefold odds of a 20% or greater ALP drop from baseline to follow-up (odds ratio, 4.70, 95% confidence interval, 1.61-13.76), according to results of univariate analysis, which investigators said were “reproduced” in multivariate analysis.

While no other variables were so clearly linked to a 20% or greater drop in ALP, Dr. Lynch and colleagues said there was a “trend toward an association” in patients with ALP raised at baseline, and in those who had Crohn’s disease or IBD-unspecified instead of ulcerative colitis.

Endoscopic IBD responses were seen in 42 out of 74 patients (56.8%) for whom those data were available, investigators added.

A total of 22 patients (20.9%) had a liver-related outcome over median follow-up of 561 days; however, that outcome may be “slightly overrepresented” by an incidence of cholangitis in 8.8%, which in and of itself is not necessarily an indicator of advanced liver disease, said Dr. Lynch and coauthors in their report.

“This proportion of liver-related outcomes is consistent with the natural history of PSC and does not by itself indicate that vedolizumab treatment is harmful in PSC,” they said, adding that the findings were similar to a study of simtuzumab, a monoclonal antibody directed against lysyl oxidase-like 2, in patients with PSC, of whom 20.1% had a PSC-related event and the incidence of cholangitis was 13.2%.

The retrospective study was supported by the Birmingham National Institute for Health Research (NIHR) Biomedical Research Centre in the United Kingdom. Authors of the report provided disclosures related to Takeda, AbbVie, Dr. Falk Pharma, Intercept, MSD, Janssen, Vifor, Gilead, and Novartis, among others.

SOURCE: Lynch KD et al. Clin Gastroenterol Hepatol. 2019 May 14. doi: 10.1016/j.cgh.2019.05.013.

Loss of pancreatic E-cadherin may interfere with normal growth and maintenance of the pancreas while contributing to multiple pathological processes, based on evidence from mouse models.

In the presence of an oncogene, E-cadherin may play a pivotal role in pancreatic tumor formation, according to lead author Yoshihiro Kaneta, of Yokohama (Japan) City University in Japan, and colleagues. These findings could lead to new treatment strategies for patients with pancreatic cancer who lack E-cadherin, they noted.

Previous studies have shown that E-cadherin is involved in tissue homeostasis, although exact mechanisms vary by organ, and have remained unclear in the pancreas, the investigators explained in Cellular and Molecular Gastroenterology and Hepatology.

According to the investigators, E-cadherin expression is up-regulated in chemically induced acute pancreatitis, while in chronic pancreatitis, which is associated with an increased risk of pancreatic adenocarcinoma, E-cadherin expression is either low or absent. Other research has pointed to a link between dysregulated E-cadherin expression and cancer progression, with a loss of E-cadherin implicated in development of diffuse-type gastric cancer; however, evidence of a similar process in pancreatic cancer has not been reported, the investigators wrote.

To determine the role of E-cadherin in pancreatic function and tumor development, the investigators conducted experiments with knockout mice lacking pancreatic E-cadherin.

For the first 2 days after birth, knockout mice were similar both phenotypically and histologically to control mice. But over time, differences became apparent. Starting at day 3, control mice were comparatively larger than knockout mice, and by day 12, knockout mice began to die, with none surviving beyond day 28. Starting at day 6, histologic changes were observed in the pancreatic tissue of knockout mice, specifically, with aberrant epithelial tubules that resembled acinar-to-ductal metaplasia (ADM). Moreover, acinar cells were dilated and lacked surface expression of E-cadherin.

“These results suggested that E-cadherin was not required for pancreatic development at the embryonic stage but was required for growth and maintenance of the pancreas in the postnatal stage,” the investigators wrote.

Additional analyses revealed further differences between pancreatic tissue from knockout mice and control mice. A variety of aberrant processes were observed in knockout mice, including replacement of acini with alpha-smooth muscle actin–positive fibrotic cells, an increased number of ductal-like structures, a reduced number of amylase-positive cells, and an increased number of cytokeratin-19–positive and CD45-positive cells. Messenger RNA expression levels were also abnormal in pancreatic tissue of knockout mice, with shifts across a variety of cytokines and chemokines. These trends toward inflammation and fibrosis were described by the investigators as pancreatitis-like changes, although they observed no pancreatic intraepithelial neoplasia (PanIN), which is a precursor of pancreatic ductal adenocarcinoma.

In the presence of an oncogene, however, loss of pancreatic E-cadherin did contribute to the development of pancreatic cancer. In the presence of a Kras mutation, knockout mice began to develop PanINs and ADMs as soon as day 4. By day 7, PanINs stained partially positive for E-cadherin, showed structural abnormalities, and exhibited decreased amylase and increased cytokeratin-19. Within a similar time frame, pancreatic tissue began to adhere to the intestine, resulting in ascites and death. No metastases to other organs were observed.

Further testing showed that pancreatic stroma contained tumor cells. While DNA double-strand breaks were scarce, the investigators pointed out that chemotherapy and radiotherapy are typically responsible for DNA damage. Based on previous research linking stem cell conversion with Kras-acquired resistance, the investigators tested markers of stem cells in pancreatic tissue of knockout mice, finding that CD44, KLF4, and KLF5 were increased.

“These observations suggested that loss of E-cadherin provided tumorigenic activity to pancreatic cells and contributed to PanIN formation,” the investigators wrote.

Additional experiments with cell lines supported the above results and added further insight. Of clinical relevance, the investigators suggested that targeting Hdac1 with histone deacetylase inhibitors may be a viable treatment strategy for patients lacking pancreatic E-cadherin.

The study was funded by the Japan Society for the Promotion of Science KAKENHI grant JP17K09465 and the Yokohama City University Kamome project. The investigators declared no conflicts of interest.

SOURCE: Kaneta Y et al. Cell Mol Gastroenterol Hepatol. 2019 Sep 14. doi: 10.1016/j.jcmgh.2019.09.001.

Loss of pancreatic E-cadherin may interfere with normal growth and maintenance of the pancreas while contributing to multiple pathological processes, based on evidence from mouse models.

In the presence of an oncogene, E-cadherin may play a pivotal role in pancreatic tumor formation, according to lead author Yoshihiro Kaneta, of Yokohama (Japan) City University in Japan, and colleagues. These findings could lead to new treatment strategies for patients with pancreatic cancer who lack E-cadherin, they noted.

Previous studies have shown that E-cadherin is involved in tissue homeostasis, although exact mechanisms vary by organ, and have remained unclear in the pancreas, the investigators explained in Cellular and Molecular Gastroenterology and Hepatology.

According to the investigators, E-cadherin expression is up-regulated in chemically induced acute pancreatitis, while in chronic pancreatitis, which is associated with an increased risk of pancreatic adenocarcinoma, E-cadherin expression is either low or absent. Other research has pointed to a link between dysregulated E-cadherin expression and cancer progression, with a loss of E-cadherin implicated in development of diffuse-type gastric cancer; however, evidence of a similar process in pancreatic cancer has not been reported, the investigators wrote.

To determine the role of E-cadherin in pancreatic function and tumor development, the investigators conducted experiments with knockout mice lacking pancreatic E-cadherin.

For the first 2 days after birth, knockout mice were similar both phenotypically and histologically to control mice. But over time, differences became apparent. Starting at day 3, control mice were comparatively larger than knockout mice, and by day 12, knockout mice began to die, with none surviving beyond day 28. Starting at day 6, histologic changes were observed in the pancreatic tissue of knockout mice, specifically, with aberrant epithelial tubules that resembled acinar-to-ductal metaplasia (ADM). Moreover, acinar cells were dilated and lacked surface expression of E-cadherin.

“These results suggested that E-cadherin was not required for pancreatic development at the embryonic stage but was required for growth and maintenance of the pancreas in the postnatal stage,” the investigators wrote.

Additional analyses revealed further differences between pancreatic tissue from knockout mice and control mice. A variety of aberrant processes were observed in knockout mice, including replacement of acini with alpha-smooth muscle actin–positive fibrotic cells, an increased number of ductal-like structures, a reduced number of amylase-positive cells, and an increased number of cytokeratin-19–positive and CD45-positive cells. Messenger RNA expression levels were also abnormal in pancreatic tissue of knockout mice, with shifts across a variety of cytokines and chemokines. These trends toward inflammation and fibrosis were described by the investigators as pancreatitis-like changes, although they observed no pancreatic intraepithelial neoplasia (PanIN), which is a precursor of pancreatic ductal adenocarcinoma.

In the presence of an oncogene, however, loss of pancreatic E-cadherin did contribute to the development of pancreatic cancer. In the presence of a Kras mutation, knockout mice began to develop PanINs and ADMs as soon as day 4. By day 7, PanINs stained partially positive for E-cadherin, showed structural abnormalities, and exhibited decreased amylase and increased cytokeratin-19. Within a similar time frame, pancreatic tissue began to adhere to the intestine, resulting in ascites and death. No metastases to other organs were observed.

Further testing showed that pancreatic stroma contained tumor cells. While DNA double-strand breaks were scarce, the investigators pointed out that chemotherapy and radiotherapy are typically responsible for DNA damage. Based on previous research linking stem cell conversion with Kras-acquired resistance, the investigators tested markers of stem cells in pancreatic tissue of knockout mice, finding that CD44, KLF4, and KLF5 were increased.

“These observations suggested that loss of E-cadherin provided tumorigenic activity to pancreatic cells and contributed to PanIN formation,” the investigators wrote.

Additional experiments with cell lines supported the above results and added further insight. Of clinical relevance, the investigators suggested that targeting Hdac1 with histone deacetylase inhibitors may be a viable treatment strategy for patients lacking pancreatic E-cadherin.

The study was funded by the Japan Society for the Promotion of Science KAKENHI grant JP17K09465 and the Yokohama City University Kamome project. The investigators declared no conflicts of interest.

SOURCE: Kaneta Y et al. Cell Mol Gastroenterol Hepatol. 2019 Sep 14. doi: 10.1016/j.jcmgh.2019.09.001.

Loss of pancreatic E-cadherin may interfere with normal growth and maintenance of the pancreas while contributing to multiple pathological processes, based on evidence from mouse models.

In the presence of an oncogene, E-cadherin may play a pivotal role in pancreatic tumor formation, according to lead author Yoshihiro Kaneta, of Yokohama (Japan) City University in Japan, and colleagues. These findings could lead to new treatment strategies for patients with pancreatic cancer who lack E-cadherin, they noted.

Previous studies have shown that E-cadherin is involved in tissue homeostasis, although exact mechanisms vary by organ, and have remained unclear in the pancreas, the investigators explained in Cellular and Molecular Gastroenterology and Hepatology.

According to the investigators, E-cadherin expression is up-regulated in chemically induced acute pancreatitis, while in chronic pancreatitis, which is associated with an increased risk of pancreatic adenocarcinoma, E-cadherin expression is either low or absent. Other research has pointed to a link between dysregulated E-cadherin expression and cancer progression, with a loss of E-cadherin implicated in development of diffuse-type gastric cancer; however, evidence of a similar process in pancreatic cancer has not been reported, the investigators wrote.

To determine the role of E-cadherin in pancreatic function and tumor development, the investigators conducted experiments with knockout mice lacking pancreatic E-cadherin.

For the first 2 days after birth, knockout mice were similar both phenotypically and histologically to control mice. But over time, differences became apparent. Starting at day 3, control mice were comparatively larger than knockout mice, and by day 12, knockout mice began to die, with none surviving beyond day 28. Starting at day 6, histologic changes were observed in the pancreatic tissue of knockout mice, specifically, with aberrant epithelial tubules that resembled acinar-to-ductal metaplasia (ADM). Moreover, acinar cells were dilated and lacked surface expression of E-cadherin.

“These results suggested that E-cadherin was not required for pancreatic development at the embryonic stage but was required for growth and maintenance of the pancreas in the postnatal stage,” the investigators wrote.

Additional analyses revealed further differences between pancreatic tissue from knockout mice and control mice. A variety of aberrant processes were observed in knockout mice, including replacement of acini with alpha-smooth muscle actin–positive fibrotic cells, an increased number of ductal-like structures, a reduced number of amylase-positive cells, and an increased number of cytokeratin-19–positive and CD45-positive cells. Messenger RNA expression levels were also abnormal in pancreatic tissue of knockout mice, with shifts across a variety of cytokines and chemokines. These trends toward inflammation and fibrosis were described by the investigators as pancreatitis-like changes, although they observed no pancreatic intraepithelial neoplasia (PanIN), which is a precursor of pancreatic ductal adenocarcinoma.

In the presence of an oncogene, however, loss of pancreatic E-cadherin did contribute to the development of pancreatic cancer. In the presence of a Kras mutation, knockout mice began to develop PanINs and ADMs as soon as day 4. By day 7, PanINs stained partially positive for E-cadherin, showed structural abnormalities, and exhibited decreased amylase and increased cytokeratin-19. Within a similar time frame, pancreatic tissue began to adhere to the intestine, resulting in ascites and death. No metastases to other organs were observed.

Further testing showed that pancreatic stroma contained tumor cells. While DNA double-strand breaks were scarce, the investigators pointed out that chemotherapy and radiotherapy are typically responsible for DNA damage. Based on previous research linking stem cell conversion with Kras-acquired resistance, the investigators tested markers of stem cells in pancreatic tissue of knockout mice, finding that CD44, KLF4, and KLF5 were increased.

“These observations suggested that loss of E-cadherin provided tumorigenic activity to pancreatic cells and contributed to PanIN formation,” the investigators wrote.

Additional experiments with cell lines supported the above results and added further insight. Of clinical relevance, the investigators suggested that targeting Hdac1 with histone deacetylase inhibitors may be a viable treatment strategy for patients lacking pancreatic E-cadherin.

The study was funded by the Japan Society for the Promotion of Science KAKENHI grant JP17K09465 and the Yokohama City University Kamome project. The investigators declared no conflicts of interest.

SOURCE: Kaneta Y et al. Cell Mol Gastroenterol Hepatol. 2019 Sep 14. doi: 10.1016/j.jcmgh.2019.09.001.