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Survey: Palliative care blocked by many barriers in end-stage liver disease
results of a recent survey show.
Cultural factors, unrealistic expectations of the patient, lack of reimbursement, and competing demands for physicians’ time were some of the barriers to palliative care cited most frequently in the survey, said the researchers, in their report on the survey results that appears in Clinical Gastroenterology and Hepatology.
Moreover, most responding physicians said they felt end-of-life advance care planning discussions take place too late in the course of illness, according to Nneka N. Ufere, MD, of the Gastrointestinal Unit, Department of Medicine, Massachusetts General Hospital, Boston, and co-authors of the report.
“Multiple interventions targeted at patients, caregivers, institutions, and clinicians are needed to overcome barriers to improve the delivery of high-quality palliative and end-of-life care for patients with end-stage liver disease,” the researchers said.
Specialty palliative care can improve quality of life for patients with life-limiting conditions such as end-stage liver disease, which is associated with poor quality of life and a median survival of just two years without liver transplant, the authors said.
Advance care planning, in which patients discuss goals and care preferences in light of the expected course of illness, was a “critical component” of palliative care that can improve the quality of end-of-life care, Dr. Ufere and co-authors said.
Unfortunately, palliative care planning services are underutilized in end-stage liver disease, studies show, while rates of timely advance care planning discussions are low.
To find out why, Dr. Ufere and colleagues asked 1,238 physicians to fill out a web-based questionnaire designed to assess their perceptions of barriers to use of palliative care and barriers to timely advance care planning discussions. A total of 396 physicians (32%) completed the survey between February and April 2018.
Sixty percent were transplant hepatologists, and 79% of the survey participants said they worked in a teaching hospital, according to Dr. Ufere and co-authors, who added that no respondents had formal palliative care training.
Almost all respondents (95%) agreed that centers providing care for end-stage liver disease patients should have palliative care services, and most (86%) said they thought such patients would benefit from palliative care earlier in the course of disease.
While most (84%) agreed that a hepatologist was the best provider to discuss advance care planning with the patient, only about one-quarter (27%) said the hepatologist was best suited to provide palliative care, while most (88%) said the palliative care specialist was best for that role.
When asked about patient and caregiver barriers, nearly all respondents (95%) agreed that cultural factors that influenced palliative care perception was an issue, while 93% said patients’ unrealistic expectations was an issue.
Clinician barriers that respondents perceived included competing demands for clinicians’ time, cited by 91%, fear that palliative care might destroy the patient’s hope, cited by 82%, and the misperception that palliative care starts when active treatment ends, cited by 81%.
One potential solution to the competing demands on clinicians’ time would be development of “collaborative care models” between palliative care and hepatology services, according to Dr. Ufere and co-authors.
“Outpatient specialty palliative care visits, ideally temporally coordinated with the hepatology visits, can play a role not only in attending to symptom assessment and ACP, but also in addressing important psychosocial aspects of care, such as patient coping and well-being,” they said in their report on the survey.
Institutional barriers of note included limited reimbursement for time spent providing palliative care, cited by 76% and lack of a palliative care service, cited by nearly half (46%).
Some of the most commonly affirmed barriers to timely advance care planning discussions included insufficient training in end-of-life communication issues, and insufficient training in cultural competency issues related to the discussions.
In terms of timeliness, only 17% said advance care planning discussions happen at the right time, while 81% said they happen too late, investigators found.
Funding for the research came from the National Institutes of Health. The authors had no disclosures or conflicts of interest related to the report.
SOURCE: Ufere NN, et al. Clin Gastroenterol Hepatol. 2019 Mar 15. doi: 10.1016/j.cgh.2019.03.022.
results of a recent survey show.
Cultural factors, unrealistic expectations of the patient, lack of reimbursement, and competing demands for physicians’ time were some of the barriers to palliative care cited most frequently in the survey, said the researchers, in their report on the survey results that appears in Clinical Gastroenterology and Hepatology.
Moreover, most responding physicians said they felt end-of-life advance care planning discussions take place too late in the course of illness, according to Nneka N. Ufere, MD, of the Gastrointestinal Unit, Department of Medicine, Massachusetts General Hospital, Boston, and co-authors of the report.
“Multiple interventions targeted at patients, caregivers, institutions, and clinicians are needed to overcome barriers to improve the delivery of high-quality palliative and end-of-life care for patients with end-stage liver disease,” the researchers said.
Specialty palliative care can improve quality of life for patients with life-limiting conditions such as end-stage liver disease, which is associated with poor quality of life and a median survival of just two years without liver transplant, the authors said.
Advance care planning, in which patients discuss goals and care preferences in light of the expected course of illness, was a “critical component” of palliative care that can improve the quality of end-of-life care, Dr. Ufere and co-authors said.
Unfortunately, palliative care planning services are underutilized in end-stage liver disease, studies show, while rates of timely advance care planning discussions are low.
To find out why, Dr. Ufere and colleagues asked 1,238 physicians to fill out a web-based questionnaire designed to assess their perceptions of barriers to use of palliative care and barriers to timely advance care planning discussions. A total of 396 physicians (32%) completed the survey between February and April 2018.
Sixty percent were transplant hepatologists, and 79% of the survey participants said they worked in a teaching hospital, according to Dr. Ufere and co-authors, who added that no respondents had formal palliative care training.
Almost all respondents (95%) agreed that centers providing care for end-stage liver disease patients should have palliative care services, and most (86%) said they thought such patients would benefit from palliative care earlier in the course of disease.
While most (84%) agreed that a hepatologist was the best provider to discuss advance care planning with the patient, only about one-quarter (27%) said the hepatologist was best suited to provide palliative care, while most (88%) said the palliative care specialist was best for that role.
When asked about patient and caregiver barriers, nearly all respondents (95%) agreed that cultural factors that influenced palliative care perception was an issue, while 93% said patients’ unrealistic expectations was an issue.
Clinician barriers that respondents perceived included competing demands for clinicians’ time, cited by 91%, fear that palliative care might destroy the patient’s hope, cited by 82%, and the misperception that palliative care starts when active treatment ends, cited by 81%.
One potential solution to the competing demands on clinicians’ time would be development of “collaborative care models” between palliative care and hepatology services, according to Dr. Ufere and co-authors.
“Outpatient specialty palliative care visits, ideally temporally coordinated with the hepatology visits, can play a role not only in attending to symptom assessment and ACP, but also in addressing important psychosocial aspects of care, such as patient coping and well-being,” they said in their report on the survey.
Institutional barriers of note included limited reimbursement for time spent providing palliative care, cited by 76% and lack of a palliative care service, cited by nearly half (46%).
Some of the most commonly affirmed barriers to timely advance care planning discussions included insufficient training in end-of-life communication issues, and insufficient training in cultural competency issues related to the discussions.
In terms of timeliness, only 17% said advance care planning discussions happen at the right time, while 81% said they happen too late, investigators found.
Funding for the research came from the National Institutes of Health. The authors had no disclosures or conflicts of interest related to the report.
SOURCE: Ufere NN, et al. Clin Gastroenterol Hepatol. 2019 Mar 15. doi: 10.1016/j.cgh.2019.03.022.
results of a recent survey show.
Cultural factors, unrealistic expectations of the patient, lack of reimbursement, and competing demands for physicians’ time were some of the barriers to palliative care cited most frequently in the survey, said the researchers, in their report on the survey results that appears in Clinical Gastroenterology and Hepatology.
Moreover, most responding physicians said they felt end-of-life advance care planning discussions take place too late in the course of illness, according to Nneka N. Ufere, MD, of the Gastrointestinal Unit, Department of Medicine, Massachusetts General Hospital, Boston, and co-authors of the report.
“Multiple interventions targeted at patients, caregivers, institutions, and clinicians are needed to overcome barriers to improve the delivery of high-quality palliative and end-of-life care for patients with end-stage liver disease,” the researchers said.
Specialty palliative care can improve quality of life for patients with life-limiting conditions such as end-stage liver disease, which is associated with poor quality of life and a median survival of just two years without liver transplant, the authors said.
Advance care planning, in which patients discuss goals and care preferences in light of the expected course of illness, was a “critical component” of palliative care that can improve the quality of end-of-life care, Dr. Ufere and co-authors said.
Unfortunately, palliative care planning services are underutilized in end-stage liver disease, studies show, while rates of timely advance care planning discussions are low.
To find out why, Dr. Ufere and colleagues asked 1,238 physicians to fill out a web-based questionnaire designed to assess their perceptions of barriers to use of palliative care and barriers to timely advance care planning discussions. A total of 396 physicians (32%) completed the survey between February and April 2018.
Sixty percent were transplant hepatologists, and 79% of the survey participants said they worked in a teaching hospital, according to Dr. Ufere and co-authors, who added that no respondents had formal palliative care training.
Almost all respondents (95%) agreed that centers providing care for end-stage liver disease patients should have palliative care services, and most (86%) said they thought such patients would benefit from palliative care earlier in the course of disease.
While most (84%) agreed that a hepatologist was the best provider to discuss advance care planning with the patient, only about one-quarter (27%) said the hepatologist was best suited to provide palliative care, while most (88%) said the palliative care specialist was best for that role.
When asked about patient and caregiver barriers, nearly all respondents (95%) agreed that cultural factors that influenced palliative care perception was an issue, while 93% said patients’ unrealistic expectations was an issue.
Clinician barriers that respondents perceived included competing demands for clinicians’ time, cited by 91%, fear that palliative care might destroy the patient’s hope, cited by 82%, and the misperception that palliative care starts when active treatment ends, cited by 81%.
One potential solution to the competing demands on clinicians’ time would be development of “collaborative care models” between palliative care and hepatology services, according to Dr. Ufere and co-authors.
“Outpatient specialty palliative care visits, ideally temporally coordinated with the hepatology visits, can play a role not only in attending to symptom assessment and ACP, but also in addressing important psychosocial aspects of care, such as patient coping and well-being,” they said in their report on the survey.
Institutional barriers of note included limited reimbursement for time spent providing palliative care, cited by 76% and lack of a palliative care service, cited by nearly half (46%).
Some of the most commonly affirmed barriers to timely advance care planning discussions included insufficient training in end-of-life communication issues, and insufficient training in cultural competency issues related to the discussions.
In terms of timeliness, only 17% said advance care planning discussions happen at the right time, while 81% said they happen too late, investigators found.
Funding for the research came from the National Institutes of Health. The authors had no disclosures or conflicts of interest related to the report.
SOURCE: Ufere NN, et al. Clin Gastroenterol Hepatol. 2019 Mar 15. doi: 10.1016/j.cgh.2019.03.022.
FROM CLINICAL GASTROENTEROLOGY AND HEPATOLOGY
Tailoring the Mediterranean diet for NAFLD
Adults with nonalcoholic fatty liver disease (NAFLD) were more likely to implement the Mediterranean diet when they had greater nutritional knowledge and skills, family support, nutritional care, and positive reinforcement in the media, according to an in-depth study of 19 patients.
Barriers to adopting the diet included “an obesogenic environment, life stressors, and demand for convenience. Poor understanding of the causes and significance of NAFLD adversely affected readiness to change dietary habits,” wrote Laura Haigh of Newcastle University in Newcastle Upon Tyne, England, and associates. The study, which included both standard quantitative methods and semistructured interviews, was published in Clinical Gastroenterology and Hepatology.
The Mediterranean diet emphasizes vegetables, legumes, fish, fruits, whole grains, nuts, and olive oil in lieu of processed foods, sweets, saturated fats, and red meat. This diet has been definitively shown to improve insulin sensitivity and steatosis, even when patients do not lose weight. This has sparked interest in its use for NAFLD disease, but keys to its successful adoption in Northern Europe are not well understood.
Therefore, the researchers recruited 19 NAFLD patients from a tertiary care center in the United Kingdom for a 12-week Mediterranean diet intervention. Most were female, white, in their late 50s, obese, and had type 2 diabetes. “Participants were taught behavioral strategies through the provision of shopping lists, meal planners, and recipes. No advice was given on calorie allowances or physical activities,” the investigators noted.
By using a 14-point assessment tool, they found that dietary adherence rose significantly at 12 weeks, compared with baseline (P = .006). In all, 79% of patients lost weight (mean, 2.4 kg; P = .001 versus baseline), and 72% significantly increased their serum level of HDL cholesterol. Interviews linked successful adoption of the diet with diverse factors, such as believing that NAFLD is lifestyle associated, realizing that healthier nutrition can improve health outcomes, and having access to transportation and budget grocery stories. Patients generally saw the Mediterranean diet as flexible and affordable, but they struggled to adopt it if they worked irregular hours, experienced substantial life stress or were very busy, or tended to eat for self-reward or self-comfort.
Other cited barriers included “diet saboteurs” (including spouses), the plethora of unhealthy foods available in patients’ environments, low nutritional or medical knowledge, and cultural, social, or taste incompatibility, the researchers reported. Taken together, the findings underscore “the futility of a one-size-fits-all approach” when implementing the Mediterranean diet in this population, they concluded. Instead, their patients valued a collaborative, tailored approach – ideally one that incorporated in-person and group-based treatment, as well as online support.
Funders included the North East of England hub of the Allied Health Professions Research Network, the Elucidating Pathways of Steatohepatitis consortium, the Horizon 2020 Framework Program of the European Union, and the Newcastle NIHR Biomedical Research Centre. The researchers reported having no conflicts of interest.
SOURCE: Haigh L et al. Clin Gastroenterol Hepatol. 2018 Oct 31. doi: 10.1016/j.cgh.2018.10.044.
Adults with nonalcoholic fatty liver disease (NAFLD) were more likely to implement the Mediterranean diet when they had greater nutritional knowledge and skills, family support, nutritional care, and positive reinforcement in the media, according to an in-depth study of 19 patients.
Barriers to adopting the diet included “an obesogenic environment, life stressors, and demand for convenience. Poor understanding of the causes and significance of NAFLD adversely affected readiness to change dietary habits,” wrote Laura Haigh of Newcastle University in Newcastle Upon Tyne, England, and associates. The study, which included both standard quantitative methods and semistructured interviews, was published in Clinical Gastroenterology and Hepatology.
The Mediterranean diet emphasizes vegetables, legumes, fish, fruits, whole grains, nuts, and olive oil in lieu of processed foods, sweets, saturated fats, and red meat. This diet has been definitively shown to improve insulin sensitivity and steatosis, even when patients do not lose weight. This has sparked interest in its use for NAFLD disease, but keys to its successful adoption in Northern Europe are not well understood.
Therefore, the researchers recruited 19 NAFLD patients from a tertiary care center in the United Kingdom for a 12-week Mediterranean diet intervention. Most were female, white, in their late 50s, obese, and had type 2 diabetes. “Participants were taught behavioral strategies through the provision of shopping lists, meal planners, and recipes. No advice was given on calorie allowances or physical activities,” the investigators noted.
By using a 14-point assessment tool, they found that dietary adherence rose significantly at 12 weeks, compared with baseline (P = .006). In all, 79% of patients lost weight (mean, 2.4 kg; P = .001 versus baseline), and 72% significantly increased their serum level of HDL cholesterol. Interviews linked successful adoption of the diet with diverse factors, such as believing that NAFLD is lifestyle associated, realizing that healthier nutrition can improve health outcomes, and having access to transportation and budget grocery stories. Patients generally saw the Mediterranean diet as flexible and affordable, but they struggled to adopt it if they worked irregular hours, experienced substantial life stress or were very busy, or tended to eat for self-reward or self-comfort.
Other cited barriers included “diet saboteurs” (including spouses), the plethora of unhealthy foods available in patients’ environments, low nutritional or medical knowledge, and cultural, social, or taste incompatibility, the researchers reported. Taken together, the findings underscore “the futility of a one-size-fits-all approach” when implementing the Mediterranean diet in this population, they concluded. Instead, their patients valued a collaborative, tailored approach – ideally one that incorporated in-person and group-based treatment, as well as online support.
Funders included the North East of England hub of the Allied Health Professions Research Network, the Elucidating Pathways of Steatohepatitis consortium, the Horizon 2020 Framework Program of the European Union, and the Newcastle NIHR Biomedical Research Centre. The researchers reported having no conflicts of interest.
SOURCE: Haigh L et al. Clin Gastroenterol Hepatol. 2018 Oct 31. doi: 10.1016/j.cgh.2018.10.044.
Adults with nonalcoholic fatty liver disease (NAFLD) were more likely to implement the Mediterranean diet when they had greater nutritional knowledge and skills, family support, nutritional care, and positive reinforcement in the media, according to an in-depth study of 19 patients.
Barriers to adopting the diet included “an obesogenic environment, life stressors, and demand for convenience. Poor understanding of the causes and significance of NAFLD adversely affected readiness to change dietary habits,” wrote Laura Haigh of Newcastle University in Newcastle Upon Tyne, England, and associates. The study, which included both standard quantitative methods and semistructured interviews, was published in Clinical Gastroenterology and Hepatology.
The Mediterranean diet emphasizes vegetables, legumes, fish, fruits, whole grains, nuts, and olive oil in lieu of processed foods, sweets, saturated fats, and red meat. This diet has been definitively shown to improve insulin sensitivity and steatosis, even when patients do not lose weight. This has sparked interest in its use for NAFLD disease, but keys to its successful adoption in Northern Europe are not well understood.
Therefore, the researchers recruited 19 NAFLD patients from a tertiary care center in the United Kingdom for a 12-week Mediterranean diet intervention. Most were female, white, in their late 50s, obese, and had type 2 diabetes. “Participants were taught behavioral strategies through the provision of shopping lists, meal planners, and recipes. No advice was given on calorie allowances or physical activities,” the investigators noted.
By using a 14-point assessment tool, they found that dietary adherence rose significantly at 12 weeks, compared with baseline (P = .006). In all, 79% of patients lost weight (mean, 2.4 kg; P = .001 versus baseline), and 72% significantly increased their serum level of HDL cholesterol. Interviews linked successful adoption of the diet with diverse factors, such as believing that NAFLD is lifestyle associated, realizing that healthier nutrition can improve health outcomes, and having access to transportation and budget grocery stories. Patients generally saw the Mediterranean diet as flexible and affordable, but they struggled to adopt it if they worked irregular hours, experienced substantial life stress or were very busy, or tended to eat for self-reward or self-comfort.
Other cited barriers included “diet saboteurs” (including spouses), the plethora of unhealthy foods available in patients’ environments, low nutritional or medical knowledge, and cultural, social, or taste incompatibility, the researchers reported. Taken together, the findings underscore “the futility of a one-size-fits-all approach” when implementing the Mediterranean diet in this population, they concluded. Instead, their patients valued a collaborative, tailored approach – ideally one that incorporated in-person and group-based treatment, as well as online support.
Funders included the North East of England hub of the Allied Health Professions Research Network, the Elucidating Pathways of Steatohepatitis consortium, the Horizon 2020 Framework Program of the European Union, and the Newcastle NIHR Biomedical Research Centre. The researchers reported having no conflicts of interest.
SOURCE: Haigh L et al. Clin Gastroenterol Hepatol. 2018 Oct 31. doi: 10.1016/j.cgh.2018.10.044.
FROM CLINICAL GASTROENTEROLOGY AND HEPATOLOGY
MicroRNA-375 may be key to fibrolamellar carcinoma
Up-regulation of microRNA-375 may be a future therapeutic strategy for patients with fibrolamellar carcinoma (FLC), according to investigators.
Analysis of primary FLC tumors showed that microRNA-375 was the most abnormal microRNA, down-regulated 27-fold, reported lead author Timothy A. Dinh, MD, of the University of North Carolina at Chapel Hill and his colleagues. Overexpression of microRNA-375 in an FLC cell line suppressed cell migration and proliferation, hinting at therapeutic potential.
“Overall, our results show that miR-375 [microRNA-375] functions as a tumor suppressor in FLC and points toward future therapies based on miR-375 mimics that may provide a viable option for patients,” the investigators wrote in a Cellular and Molecular Gastroenterology and Hepatology.
FLC is an uncommon liver cancer in adolescents and young adults. Currently, surgery is the only effective treatment; unfortunately, many patients have metastatic disease at the time of diagnosis, disallowing surgical cure.
“The lack of knowledge of underlying disease mechanisms has hindered our understanding of this cancer and the development of novel therapeutics for FLC patients,” the investigators wrote.
Previous research has shown that almost all patients with FLC (80%-100%) have a heterozygous deletion mutation on chromosome 19. However, it is not a loss of genetic information that incites neoplasia; instead, the deletion causes a fusion of genes DNAJB1 and PRKACA. This fusion is capable of triggering liver tumors, a phenomenon confirmed through mouse models. The present study built on these findings, along with recent awareness that several microRNAs are dysregulated in FLC, compared with normal liver tissue.
First, the investigators performed small RNA-sequencing in six primary FLC tumors from The Cancer Genome Atlas (TCGA). They found that 30 microRNAs were up-regulated and 46 microRNAs were down-regulated. Among these, microRNA-375 was the most significantly down-regulated, at 27-fold (P = .009). To confirm these findings, the same process was repeated in 18 independent samples, with the same result.
The investigators explained that, in addition to magnitude of down-regulation, microRNA-375 deserved attention for at least three other reasons: It is down-regulated in numerous cancer types, it directly targets known oncogenes, and it is suppressed by the cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA) signaling axis, which is overactive in FLC.
Further testing confirmed that microRNA-375 was consistently more down-regulated in samples of FLC, by up to 20-fold, than it was in nonmalignant liver tissue. To confirm that loss of microRNA-375 expression occurred in FLC tumor cells instead of other cell types, such as stromal cells, a patient-derived xenograft of FLC was compared with liver lineage cells, including adult hepatocytes, hepatoblasts, hepatic stem cells, and biliary tree stem cells. Again, microRNA-375 was down-regulated most in the FLC cells. Additional comparisons within the TCGA showed that microRNA-375 was more down-regulated in FLC than 21 out of 22 other tumor types (second only to melanoma).
“Taken together with our findings from primary tumor tissue, our results strongly suggest that miR-375 may function as a tumor suppressor in FLC,” the investigators wrote.
Having confirmed the ubiquity of microRNA-375 down-regulation in FLC, the investigators turned to the relationship between the DNAJB1-PRKACA fusion and microRNA-375. Using two methods – gene deletion with CRISPR/Cas9 and transposon injection – the investigators found that creating the DNAJB1-PRKACA fusion in cells of mice was sufficient to suppress microRNA-375 expression, which supports a downstream relationship.
Finally, the investigators showed that treating an FLC cell line with an microRNA-375 mimic suppressed the Hippo signaling pathway, including connective tissue growth factor (CTGF) and yes-associated protein 1 (YAP1). These events translated to reduced cellular activity, which suggests that up-regulating microRNA-375 could, indeed, control FLC.
“Importantly, introduction of a miR-375 mimic significantly reduced colony formation, EdU incorporation, and migration, indicative of reduced survival, proliferation, and metastatic potential, respectively,” the investigators wrote.
“With RNA-based therapies showing increasing promise, miR-375–based therapies merit future consideration for FLC therapeutics,” they concluded.
The study was funded by the National Institute of Diabetes and Digestive and Kidney Diseases, the National Institute on Alcohol Abuse and Alcoholism, and the Fibrolamellar Cancer Foundation. The investigators declared no conflicts of interest.
SOURCE: Dinh TA et al. Cell Mol Gastroenterol Hepatol. 2019 Feb 11. doi: 10.1016/j.jcmgh.2019.01.008.
For several decades, fibrolamellar carcinoma was the enigmatic liver cancer. Neither etiology nor molecular causes were known. The breakthrough came when tumor sequencing identified a hitherto undescribed fusion gene in 15 out of 15 patients analyzed: A small portion of the heat shock protein DNAJB1 was fused to the catalytic subunit of protein kinase A (PKA, or PRKACA), which retained full kinase activity.
Underscoring the significance of this finding, the DNAJB1-PRKACA fusion gene was shown to be sufficient to elicit tumors similar to human fibrolamellar carcinoma when engineered in mice. The absence of conspicuous codriver genes makes DNAJB1-PRKACA a primary candidate for therapeutic target. However, PKA inhibitors would be problematic in the clinic because of the vital physiological functions of PKA. Consequently, the hunt is on to decipher the oncogenic signaling pathways emanating from DNAJB1-PRKACA with the hope to identify alternative targets among its downstream mediators.
In this work, the Sethupathy lab performed a thorough study on abnormally regulated microRNAs in fibrolamellar carcinoma tumors. Intriguingly, they identified several microRNAs controlled by DNAJB1-PRKACA that have oncogenic or tumor suppressor function in other cancers. In particular, the tumor suppressor microRNA-375 was massively down-regulated by DNAJB1-PRKACA. Furthermore, introducing a microRNA-375 mimic in fibrolamellar cancer cells suppressed proliferation and motility. Important studies like this open up new avenues aiming to manipulate cancer microRNAs as alternative or complementary approaches for targeting DNAJB1-PRKACA signaling in the highly fatal fibrolamellar carcinoma.
Morten Frödin, MSc, PhD, is an associate professor and group leader of the Biotech Research and Innovation Centre, University of Copenhagen.
For several decades, fibrolamellar carcinoma was the enigmatic liver cancer. Neither etiology nor molecular causes were known. The breakthrough came when tumor sequencing identified a hitherto undescribed fusion gene in 15 out of 15 patients analyzed: A small portion of the heat shock protein DNAJB1 was fused to the catalytic subunit of protein kinase A (PKA, or PRKACA), which retained full kinase activity.
Underscoring the significance of this finding, the DNAJB1-PRKACA fusion gene was shown to be sufficient to elicit tumors similar to human fibrolamellar carcinoma when engineered in mice. The absence of conspicuous codriver genes makes DNAJB1-PRKACA a primary candidate for therapeutic target. However, PKA inhibitors would be problematic in the clinic because of the vital physiological functions of PKA. Consequently, the hunt is on to decipher the oncogenic signaling pathways emanating from DNAJB1-PRKACA with the hope to identify alternative targets among its downstream mediators.
In this work, the Sethupathy lab performed a thorough study on abnormally regulated microRNAs in fibrolamellar carcinoma tumors. Intriguingly, they identified several microRNAs controlled by DNAJB1-PRKACA that have oncogenic or tumor suppressor function in other cancers. In particular, the tumor suppressor microRNA-375 was massively down-regulated by DNAJB1-PRKACA. Furthermore, introducing a microRNA-375 mimic in fibrolamellar cancer cells suppressed proliferation and motility. Important studies like this open up new avenues aiming to manipulate cancer microRNAs as alternative or complementary approaches for targeting DNAJB1-PRKACA signaling in the highly fatal fibrolamellar carcinoma.
Morten Frödin, MSc, PhD, is an associate professor and group leader of the Biotech Research and Innovation Centre, University of Copenhagen.
For several decades, fibrolamellar carcinoma was the enigmatic liver cancer. Neither etiology nor molecular causes were known. The breakthrough came when tumor sequencing identified a hitherto undescribed fusion gene in 15 out of 15 patients analyzed: A small portion of the heat shock protein DNAJB1 was fused to the catalytic subunit of protein kinase A (PKA, or PRKACA), which retained full kinase activity.
Underscoring the significance of this finding, the DNAJB1-PRKACA fusion gene was shown to be sufficient to elicit tumors similar to human fibrolamellar carcinoma when engineered in mice. The absence of conspicuous codriver genes makes DNAJB1-PRKACA a primary candidate for therapeutic target. However, PKA inhibitors would be problematic in the clinic because of the vital physiological functions of PKA. Consequently, the hunt is on to decipher the oncogenic signaling pathways emanating from DNAJB1-PRKACA with the hope to identify alternative targets among its downstream mediators.
In this work, the Sethupathy lab performed a thorough study on abnormally regulated microRNAs in fibrolamellar carcinoma tumors. Intriguingly, they identified several microRNAs controlled by DNAJB1-PRKACA that have oncogenic or tumor suppressor function in other cancers. In particular, the tumor suppressor microRNA-375 was massively down-regulated by DNAJB1-PRKACA. Furthermore, introducing a microRNA-375 mimic in fibrolamellar cancer cells suppressed proliferation and motility. Important studies like this open up new avenues aiming to manipulate cancer microRNAs as alternative or complementary approaches for targeting DNAJB1-PRKACA signaling in the highly fatal fibrolamellar carcinoma.
Morten Frödin, MSc, PhD, is an associate professor and group leader of the Biotech Research and Innovation Centre, University of Copenhagen.
Up-regulation of microRNA-375 may be a future therapeutic strategy for patients with fibrolamellar carcinoma (FLC), according to investigators.
Analysis of primary FLC tumors showed that microRNA-375 was the most abnormal microRNA, down-regulated 27-fold, reported lead author Timothy A. Dinh, MD, of the University of North Carolina at Chapel Hill and his colleagues. Overexpression of microRNA-375 in an FLC cell line suppressed cell migration and proliferation, hinting at therapeutic potential.
“Overall, our results show that miR-375 [microRNA-375] functions as a tumor suppressor in FLC and points toward future therapies based on miR-375 mimics that may provide a viable option for patients,” the investigators wrote in a Cellular and Molecular Gastroenterology and Hepatology.
FLC is an uncommon liver cancer in adolescents and young adults. Currently, surgery is the only effective treatment; unfortunately, many patients have metastatic disease at the time of diagnosis, disallowing surgical cure.
“The lack of knowledge of underlying disease mechanisms has hindered our understanding of this cancer and the development of novel therapeutics for FLC patients,” the investigators wrote.
Previous research has shown that almost all patients with FLC (80%-100%) have a heterozygous deletion mutation on chromosome 19. However, it is not a loss of genetic information that incites neoplasia; instead, the deletion causes a fusion of genes DNAJB1 and PRKACA. This fusion is capable of triggering liver tumors, a phenomenon confirmed through mouse models. The present study built on these findings, along with recent awareness that several microRNAs are dysregulated in FLC, compared with normal liver tissue.
First, the investigators performed small RNA-sequencing in six primary FLC tumors from The Cancer Genome Atlas (TCGA). They found that 30 microRNAs were up-regulated and 46 microRNAs were down-regulated. Among these, microRNA-375 was the most significantly down-regulated, at 27-fold (P = .009). To confirm these findings, the same process was repeated in 18 independent samples, with the same result.
The investigators explained that, in addition to magnitude of down-regulation, microRNA-375 deserved attention for at least three other reasons: It is down-regulated in numerous cancer types, it directly targets known oncogenes, and it is suppressed by the cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA) signaling axis, which is overactive in FLC.
Further testing confirmed that microRNA-375 was consistently more down-regulated in samples of FLC, by up to 20-fold, than it was in nonmalignant liver tissue. To confirm that loss of microRNA-375 expression occurred in FLC tumor cells instead of other cell types, such as stromal cells, a patient-derived xenograft of FLC was compared with liver lineage cells, including adult hepatocytes, hepatoblasts, hepatic stem cells, and biliary tree stem cells. Again, microRNA-375 was down-regulated most in the FLC cells. Additional comparisons within the TCGA showed that microRNA-375 was more down-regulated in FLC than 21 out of 22 other tumor types (second only to melanoma).
“Taken together with our findings from primary tumor tissue, our results strongly suggest that miR-375 may function as a tumor suppressor in FLC,” the investigators wrote.
Having confirmed the ubiquity of microRNA-375 down-regulation in FLC, the investigators turned to the relationship between the DNAJB1-PRKACA fusion and microRNA-375. Using two methods – gene deletion with CRISPR/Cas9 and transposon injection – the investigators found that creating the DNAJB1-PRKACA fusion in cells of mice was sufficient to suppress microRNA-375 expression, which supports a downstream relationship.
Finally, the investigators showed that treating an FLC cell line with an microRNA-375 mimic suppressed the Hippo signaling pathway, including connective tissue growth factor (CTGF) and yes-associated protein 1 (YAP1). These events translated to reduced cellular activity, which suggests that up-regulating microRNA-375 could, indeed, control FLC.
“Importantly, introduction of a miR-375 mimic significantly reduced colony formation, EdU incorporation, and migration, indicative of reduced survival, proliferation, and metastatic potential, respectively,” the investigators wrote.
“With RNA-based therapies showing increasing promise, miR-375–based therapies merit future consideration for FLC therapeutics,” they concluded.
The study was funded by the National Institute of Diabetes and Digestive and Kidney Diseases, the National Institute on Alcohol Abuse and Alcoholism, and the Fibrolamellar Cancer Foundation. The investigators declared no conflicts of interest.
SOURCE: Dinh TA et al. Cell Mol Gastroenterol Hepatol. 2019 Feb 11. doi: 10.1016/j.jcmgh.2019.01.008.
Up-regulation of microRNA-375 may be a future therapeutic strategy for patients with fibrolamellar carcinoma (FLC), according to investigators.
Analysis of primary FLC tumors showed that microRNA-375 was the most abnormal microRNA, down-regulated 27-fold, reported lead author Timothy A. Dinh, MD, of the University of North Carolina at Chapel Hill and his colleagues. Overexpression of microRNA-375 in an FLC cell line suppressed cell migration and proliferation, hinting at therapeutic potential.
“Overall, our results show that miR-375 [microRNA-375] functions as a tumor suppressor in FLC and points toward future therapies based on miR-375 mimics that may provide a viable option for patients,” the investigators wrote in a Cellular and Molecular Gastroenterology and Hepatology.
FLC is an uncommon liver cancer in adolescents and young adults. Currently, surgery is the only effective treatment; unfortunately, many patients have metastatic disease at the time of diagnosis, disallowing surgical cure.
“The lack of knowledge of underlying disease mechanisms has hindered our understanding of this cancer and the development of novel therapeutics for FLC patients,” the investigators wrote.
Previous research has shown that almost all patients with FLC (80%-100%) have a heterozygous deletion mutation on chromosome 19. However, it is not a loss of genetic information that incites neoplasia; instead, the deletion causes a fusion of genes DNAJB1 and PRKACA. This fusion is capable of triggering liver tumors, a phenomenon confirmed through mouse models. The present study built on these findings, along with recent awareness that several microRNAs are dysregulated in FLC, compared with normal liver tissue.
First, the investigators performed small RNA-sequencing in six primary FLC tumors from The Cancer Genome Atlas (TCGA). They found that 30 microRNAs were up-regulated and 46 microRNAs were down-regulated. Among these, microRNA-375 was the most significantly down-regulated, at 27-fold (P = .009). To confirm these findings, the same process was repeated in 18 independent samples, with the same result.
The investigators explained that, in addition to magnitude of down-regulation, microRNA-375 deserved attention for at least three other reasons: It is down-regulated in numerous cancer types, it directly targets known oncogenes, and it is suppressed by the cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA) signaling axis, which is overactive in FLC.
Further testing confirmed that microRNA-375 was consistently more down-regulated in samples of FLC, by up to 20-fold, than it was in nonmalignant liver tissue. To confirm that loss of microRNA-375 expression occurred in FLC tumor cells instead of other cell types, such as stromal cells, a patient-derived xenograft of FLC was compared with liver lineage cells, including adult hepatocytes, hepatoblasts, hepatic stem cells, and biliary tree stem cells. Again, microRNA-375 was down-regulated most in the FLC cells. Additional comparisons within the TCGA showed that microRNA-375 was more down-regulated in FLC than 21 out of 22 other tumor types (second only to melanoma).
“Taken together with our findings from primary tumor tissue, our results strongly suggest that miR-375 may function as a tumor suppressor in FLC,” the investigators wrote.
Having confirmed the ubiquity of microRNA-375 down-regulation in FLC, the investigators turned to the relationship between the DNAJB1-PRKACA fusion and microRNA-375. Using two methods – gene deletion with CRISPR/Cas9 and transposon injection – the investigators found that creating the DNAJB1-PRKACA fusion in cells of mice was sufficient to suppress microRNA-375 expression, which supports a downstream relationship.
Finally, the investigators showed that treating an FLC cell line with an microRNA-375 mimic suppressed the Hippo signaling pathway, including connective tissue growth factor (CTGF) and yes-associated protein 1 (YAP1). These events translated to reduced cellular activity, which suggests that up-regulating microRNA-375 could, indeed, control FLC.
“Importantly, introduction of a miR-375 mimic significantly reduced colony formation, EdU incorporation, and migration, indicative of reduced survival, proliferation, and metastatic potential, respectively,” the investigators wrote.
“With RNA-based therapies showing increasing promise, miR-375–based therapies merit future consideration for FLC therapeutics,” they concluded.
The study was funded by the National Institute of Diabetes and Digestive and Kidney Diseases, the National Institute on Alcohol Abuse and Alcoholism, and the Fibrolamellar Cancer Foundation. The investigators declared no conflicts of interest.
SOURCE: Dinh TA et al. Cell Mol Gastroenterol Hepatol. 2019 Feb 11. doi: 10.1016/j.jcmgh.2019.01.008.
FROM CELLULAR AND MOLECULAR GASTROENTEROLOGY AND HEPATOLOGY
Look for functional esophageal disorders if GERD patients fail PPIs
In a small, first-in-kind study, functional heartburn or reflux hypersensitivity affected fully 75% of patients whose gastroesophageal reflux disease symptoms had not improved with once-daily proton pump inhibitor therapy.
At the same time, proton pump inhibitor (PPI) responders and nonresponders had similar impedance and pH parameters, reported Jason Abdallah, MD, of Case Western Reserve University, Cleveland, and his associates. The findings show “the important role of esophageal hypersensitivity in this patient population.” For these patients, the investigators suggested adding a neuromodulator and possibly psychotherapy, such as cognitive-behavioral therapy, hypnotherapy, relaxation techniques, mindfulness, and biofeedback.
Symptoms in up to 45% of patients with gastroesophageal reflux disease (GERD) persist despite once-daily PPI therapy, Dr. Abdallah and his associates wrote in Clinical Gastroenterology and Hepatology. For the study, they compared reflux characteristics and patterns between 13 patients whose GERD symptoms had fully resolved on standard once-daily PPIs and 16 patients who reported at least twice-weekly heartburn, regurgitation, or both for at least 3 months, despite treatment. Patients in both groups continued PPIs and underwent upper endoscopy and combined esophageal impedance–pH monitoring.
The average age of patients in this study was 54.5 years, with a standard deviation of 14.5 years. Demographic and clinical characteristics were similar between groups, and patients in both groups were receiving omeprazole, esomeprazole, or pantoprazole. Four (31%) PPI responders had abnormal pH test results, as did four (25%) nonresponders. Responders and nonresponders had similar numbers of reflux events; proportions of events that were acidic, weakly acidic, or alkaline; and mean total time with pH less than 4.0.
Additionally, most patients in both groups had normal endoscopic findings. One PPI responder had Los Angeles grade A erosive esophagitis, and two PPI responders had short-segment Barrett’s esophagus. Three PPI responders and two PPI nonresponders had nonobstructive Schatzki rings, and one PPI nonresponder had an esophageal stricture. Finally, five PPI responders (38%) and three nonresponders (19%) had hiatal hernias (P = .41).
In patients with GERD, “PPI failure” does not reflect a unique pattern of reflux events, acid exposure, or nonacidic reflux parameters, Dr. Abdallah and his associates concluded. The fact that most PPI nonresponders had a concurrent functional esophageal disorder – either reflux hypersensitivity or functional heartburn – “support[s] the hypothesis that PPI failure is primarily driven by esophageal hypersensitivity.”
This was a small study – recruitment “was hampered by the invasive nature of some of the procedures,” they wrote. “In addition, it is our experience that many patients who have responded to PPI [therapy] are reluctant to undergo invasive testing as part of a study protocol. Therefore, we believe that these types of prospective, invasive studies are rather difficult to perform but, at the same time, provide essential insight into the understanding of refractory GERD.”
No external funding sources were acknowledged. The senior author reported ties to Ironwood Pharmaceuticals, Mederi Therapeutics, Ethicon, AstraZeneca, and Takeda. The other researchers reported no conflicts of interest.
SOURCE: Abdallah J et al. Clin Gastroenterol Hepatol. 2018 Jun 15. doi: 10.1016/j.cgh.2018.09.006.
In a small, first-in-kind study, functional heartburn or reflux hypersensitivity affected fully 75% of patients whose gastroesophageal reflux disease symptoms had not improved with once-daily proton pump inhibitor therapy.
At the same time, proton pump inhibitor (PPI) responders and nonresponders had similar impedance and pH parameters, reported Jason Abdallah, MD, of Case Western Reserve University, Cleveland, and his associates. The findings show “the important role of esophageal hypersensitivity in this patient population.” For these patients, the investigators suggested adding a neuromodulator and possibly psychotherapy, such as cognitive-behavioral therapy, hypnotherapy, relaxation techniques, mindfulness, and biofeedback.
Symptoms in up to 45% of patients with gastroesophageal reflux disease (GERD) persist despite once-daily PPI therapy, Dr. Abdallah and his associates wrote in Clinical Gastroenterology and Hepatology. For the study, they compared reflux characteristics and patterns between 13 patients whose GERD symptoms had fully resolved on standard once-daily PPIs and 16 patients who reported at least twice-weekly heartburn, regurgitation, or both for at least 3 months, despite treatment. Patients in both groups continued PPIs and underwent upper endoscopy and combined esophageal impedance–pH monitoring.
The average age of patients in this study was 54.5 years, with a standard deviation of 14.5 years. Demographic and clinical characteristics were similar between groups, and patients in both groups were receiving omeprazole, esomeprazole, or pantoprazole. Four (31%) PPI responders had abnormal pH test results, as did four (25%) nonresponders. Responders and nonresponders had similar numbers of reflux events; proportions of events that were acidic, weakly acidic, or alkaline; and mean total time with pH less than 4.0.
Additionally, most patients in both groups had normal endoscopic findings. One PPI responder had Los Angeles grade A erosive esophagitis, and two PPI responders had short-segment Barrett’s esophagus. Three PPI responders and two PPI nonresponders had nonobstructive Schatzki rings, and one PPI nonresponder had an esophageal stricture. Finally, five PPI responders (38%) and three nonresponders (19%) had hiatal hernias (P = .41).
In patients with GERD, “PPI failure” does not reflect a unique pattern of reflux events, acid exposure, or nonacidic reflux parameters, Dr. Abdallah and his associates concluded. The fact that most PPI nonresponders had a concurrent functional esophageal disorder – either reflux hypersensitivity or functional heartburn – “support[s] the hypothesis that PPI failure is primarily driven by esophageal hypersensitivity.”
This was a small study – recruitment “was hampered by the invasive nature of some of the procedures,” they wrote. “In addition, it is our experience that many patients who have responded to PPI [therapy] are reluctant to undergo invasive testing as part of a study protocol. Therefore, we believe that these types of prospective, invasive studies are rather difficult to perform but, at the same time, provide essential insight into the understanding of refractory GERD.”
No external funding sources were acknowledged. The senior author reported ties to Ironwood Pharmaceuticals, Mederi Therapeutics, Ethicon, AstraZeneca, and Takeda. The other researchers reported no conflicts of interest.
SOURCE: Abdallah J et al. Clin Gastroenterol Hepatol. 2018 Jun 15. doi: 10.1016/j.cgh.2018.09.006.
In a small, first-in-kind study, functional heartburn or reflux hypersensitivity affected fully 75% of patients whose gastroesophageal reflux disease symptoms had not improved with once-daily proton pump inhibitor therapy.
At the same time, proton pump inhibitor (PPI) responders and nonresponders had similar impedance and pH parameters, reported Jason Abdallah, MD, of Case Western Reserve University, Cleveland, and his associates. The findings show “the important role of esophageal hypersensitivity in this patient population.” For these patients, the investigators suggested adding a neuromodulator and possibly psychotherapy, such as cognitive-behavioral therapy, hypnotherapy, relaxation techniques, mindfulness, and biofeedback.
Symptoms in up to 45% of patients with gastroesophageal reflux disease (GERD) persist despite once-daily PPI therapy, Dr. Abdallah and his associates wrote in Clinical Gastroenterology and Hepatology. For the study, they compared reflux characteristics and patterns between 13 patients whose GERD symptoms had fully resolved on standard once-daily PPIs and 16 patients who reported at least twice-weekly heartburn, regurgitation, or both for at least 3 months, despite treatment. Patients in both groups continued PPIs and underwent upper endoscopy and combined esophageal impedance–pH monitoring.
The average age of patients in this study was 54.5 years, with a standard deviation of 14.5 years. Demographic and clinical characteristics were similar between groups, and patients in both groups were receiving omeprazole, esomeprazole, or pantoprazole. Four (31%) PPI responders had abnormal pH test results, as did four (25%) nonresponders. Responders and nonresponders had similar numbers of reflux events; proportions of events that were acidic, weakly acidic, or alkaline; and mean total time with pH less than 4.0.
Additionally, most patients in both groups had normal endoscopic findings. One PPI responder had Los Angeles grade A erosive esophagitis, and two PPI responders had short-segment Barrett’s esophagus. Three PPI responders and two PPI nonresponders had nonobstructive Schatzki rings, and one PPI nonresponder had an esophageal stricture. Finally, five PPI responders (38%) and three nonresponders (19%) had hiatal hernias (P = .41).
In patients with GERD, “PPI failure” does not reflect a unique pattern of reflux events, acid exposure, or nonacidic reflux parameters, Dr. Abdallah and his associates concluded. The fact that most PPI nonresponders had a concurrent functional esophageal disorder – either reflux hypersensitivity or functional heartburn – “support[s] the hypothesis that PPI failure is primarily driven by esophageal hypersensitivity.”
This was a small study – recruitment “was hampered by the invasive nature of some of the procedures,” they wrote. “In addition, it is our experience that many patients who have responded to PPI [therapy] are reluctant to undergo invasive testing as part of a study protocol. Therefore, we believe that these types of prospective, invasive studies are rather difficult to perform but, at the same time, provide essential insight into the understanding of refractory GERD.”
No external funding sources were acknowledged. The senior author reported ties to Ironwood Pharmaceuticals, Mederi Therapeutics, Ethicon, AstraZeneca, and Takeda. The other researchers reported no conflicts of interest.
SOURCE: Abdallah J et al. Clin Gastroenterol Hepatol. 2018 Jun 15. doi: 10.1016/j.cgh.2018.09.006.
FROM CLINICAL GASTROENTEROLOGY AND HEPATOLOGY
No biopsy for 21% of adults with celiac disease
Patients with celiac disease often do not receive a biopsy or nutritional recommendations at diagnosis, according to the findings of a large survey study.
Strikingly, 21% of respondents did not have a confirmatory duodenal biopsy, reported Andrew M. Joelson, MD, of Columbia University Medical Center, New York, and his associates. Gastroenterologists diagnosed 66% of biopsied patients but only 31% of nonbiopsied patients (P less than .001). “Patients require more education about management of celiac disease and referral to gastroenterologists for duodenal biopsy confirmation,” the researchers wrote in the May issue of Clinical Gastroenterology and Hepatology.
Classic small-bowel findings in celiac disease (intraepithelial lymphocytes, crypt hyperplasia, and villous atrophy) are not pathognomonic, making serology important for diagnosis. European guidelines discuss forgoing biopsy in children whose antitissue transglutaminase antibody titers are at least 10-fold above the upper limit of normal. However, the American College of Gastroenterology and the American Gastroenterological Association continue to recommend combining serology with confirmatory small bowel biopsy. The extent to which physicians follow this advice is unclear, the researchers noted.
Therefore, they analyzed data from a questionnaire posted on the Celiac Disease Foundation website during a 7-month period in 2016. Among 982 adults with self-reported celiac disease, 780 said their diagnosis included both serology and biopsy and 202 said they received serology only. Only 40% of these nonbiopsied respondents said they sought nutritional counseling at diagnosis, compared with 59% of biopsied patients (P less than .001). Patients diagnosed by serology alone also were more likely to report using dietary supplements to aid gluten digestion (20% vs. 9% of biopsied respondents; P less than .001).
These associations remained statistically significant after adjustment for age and sex, said the researchers. Nonbiopsied patients had a significantly lower odds of having been diagnosed by a gastroenterologist (odds ratio, 0.16; 95% confidence interval, 0.07-0.37) and seeking nutritional counseling (OR, 0.45; 95% CI, 0.33-0.63) and were significantly more likely to use digestive supplements (OR, 2.61; 95%, CI 1.62-4.19).
Fully 87% of respondents always followed a strict gluten-free diet, but symptoms persisted in 65% of those who were not biopsied, compared with only 51% of those who were biopsied. There were too few responses to this question for the difference between groups to reach statistical significance, but the finding might reflect the greater diagnostic accuracy of biopsy, the researchers said. However, they cautioned that none of the associations in this study were necessarily causal, diagnoses were not independently validated, and the reliability of self-reported celiac diagnosis remains unclear.
Survey respondents also were self-selected – for example, 91% self-identified as white and 60% reported having a bachelor’s degree, compared with only about 77% and one-third of adults captured by U.S. Census Bureau data from 2017.
“Although these characteristics may limit the generalizability of our findings, this study nevertheless reflects a population of celiac disease that is not typically studied, such as those not attending large academic celiac disease centers, and those diagnosed without the involvement of a gastroenterologist,” the researchers wrote. “Future studies are warranted to further characterize this population regarding the long-term consequences of forgoing the duodenal biopsy, and to develop educational interventions to promote evidence-based diagnosis and management of celiac disease.”
SOURCE: Joelson AM et al. Clin Gastroenterol Hepatol. 2018 Sep 10. doi: 10.1016/j.cgh.2018.09.006.
Self-reported celiac disease diagnosis is not validated and perhaps more inaccurate now with the rise of other gluten-related disorders. Although misdiagnosis is possible, the finding in this study by Joelson et al. that 21% of self-reported celiac adults said they never had a confirmatory biopsy is remarkable. Another important observation is the low-quality celiac care among nonbiopsed adults, with less formal nutritional counseling and high use of gluten digestive supplements and persistent symptoms.
Nowadays, biopsy confirmation may not be necessary for all. There is strong evidence for nonbiopsy diagnosis in selected symptomatic children with high titers of tissue transglutaminase antibodies (more than 10 times the upper limit of normal) and a positive endomysial antibody in a second sample. Whether the nonbiopsy approach could be applicable also in adults remains controversial. Current guidelines recommend biopsy confirmation in all adults. However, emerging evidence favors celiac disease diagnosis without use of biopsy in selected adults.
Although the debate regarding pros and cons of nonbiopsy diagnosis is far from an end, this approach is here to stay. In the future, regardless of the method selected to confirm celiac disease diagnosis, the overall quality of celiac care should be ensured.
Alberto Rubio-Tapia, MD, is an assistant professor of medicine at the Mayo Clinic, Rochester, Minn. He has no conflicts of interest.
Self-reported celiac disease diagnosis is not validated and perhaps more inaccurate now with the rise of other gluten-related disorders. Although misdiagnosis is possible, the finding in this study by Joelson et al. that 21% of self-reported celiac adults said they never had a confirmatory biopsy is remarkable. Another important observation is the low-quality celiac care among nonbiopsed adults, with less formal nutritional counseling and high use of gluten digestive supplements and persistent symptoms.
Nowadays, biopsy confirmation may not be necessary for all. There is strong evidence for nonbiopsy diagnosis in selected symptomatic children with high titers of tissue transglutaminase antibodies (more than 10 times the upper limit of normal) and a positive endomysial antibody in a second sample. Whether the nonbiopsy approach could be applicable also in adults remains controversial. Current guidelines recommend biopsy confirmation in all adults. However, emerging evidence favors celiac disease diagnosis without use of biopsy in selected adults.
Although the debate regarding pros and cons of nonbiopsy diagnosis is far from an end, this approach is here to stay. In the future, regardless of the method selected to confirm celiac disease diagnosis, the overall quality of celiac care should be ensured.
Alberto Rubio-Tapia, MD, is an assistant professor of medicine at the Mayo Clinic, Rochester, Minn. He has no conflicts of interest.
Self-reported celiac disease diagnosis is not validated and perhaps more inaccurate now with the rise of other gluten-related disorders. Although misdiagnosis is possible, the finding in this study by Joelson et al. that 21% of self-reported celiac adults said they never had a confirmatory biopsy is remarkable. Another important observation is the low-quality celiac care among nonbiopsed adults, with less formal nutritional counseling and high use of gluten digestive supplements and persistent symptoms.
Nowadays, biopsy confirmation may not be necessary for all. There is strong evidence for nonbiopsy diagnosis in selected symptomatic children with high titers of tissue transglutaminase antibodies (more than 10 times the upper limit of normal) and a positive endomysial antibody in a second sample. Whether the nonbiopsy approach could be applicable also in adults remains controversial. Current guidelines recommend biopsy confirmation in all adults. However, emerging evidence favors celiac disease diagnosis without use of biopsy in selected adults.
Although the debate regarding pros and cons of nonbiopsy diagnosis is far from an end, this approach is here to stay. In the future, regardless of the method selected to confirm celiac disease diagnosis, the overall quality of celiac care should be ensured.
Alberto Rubio-Tapia, MD, is an assistant professor of medicine at the Mayo Clinic, Rochester, Minn. He has no conflicts of interest.
Patients with celiac disease often do not receive a biopsy or nutritional recommendations at diagnosis, according to the findings of a large survey study.
Strikingly, 21% of respondents did not have a confirmatory duodenal biopsy, reported Andrew M. Joelson, MD, of Columbia University Medical Center, New York, and his associates. Gastroenterologists diagnosed 66% of biopsied patients but only 31% of nonbiopsied patients (P less than .001). “Patients require more education about management of celiac disease and referral to gastroenterologists for duodenal biopsy confirmation,” the researchers wrote in the May issue of Clinical Gastroenterology and Hepatology.
Classic small-bowel findings in celiac disease (intraepithelial lymphocytes, crypt hyperplasia, and villous atrophy) are not pathognomonic, making serology important for diagnosis. European guidelines discuss forgoing biopsy in children whose antitissue transglutaminase antibody titers are at least 10-fold above the upper limit of normal. However, the American College of Gastroenterology and the American Gastroenterological Association continue to recommend combining serology with confirmatory small bowel biopsy. The extent to which physicians follow this advice is unclear, the researchers noted.
Therefore, they analyzed data from a questionnaire posted on the Celiac Disease Foundation website during a 7-month period in 2016. Among 982 adults with self-reported celiac disease, 780 said their diagnosis included both serology and biopsy and 202 said they received serology only. Only 40% of these nonbiopsied respondents said they sought nutritional counseling at diagnosis, compared with 59% of biopsied patients (P less than .001). Patients diagnosed by serology alone also were more likely to report using dietary supplements to aid gluten digestion (20% vs. 9% of biopsied respondents; P less than .001).
These associations remained statistically significant after adjustment for age and sex, said the researchers. Nonbiopsied patients had a significantly lower odds of having been diagnosed by a gastroenterologist (odds ratio, 0.16; 95% confidence interval, 0.07-0.37) and seeking nutritional counseling (OR, 0.45; 95% CI, 0.33-0.63) and were significantly more likely to use digestive supplements (OR, 2.61; 95%, CI 1.62-4.19).
Fully 87% of respondents always followed a strict gluten-free diet, but symptoms persisted in 65% of those who were not biopsied, compared with only 51% of those who were biopsied. There were too few responses to this question for the difference between groups to reach statistical significance, but the finding might reflect the greater diagnostic accuracy of biopsy, the researchers said. However, they cautioned that none of the associations in this study were necessarily causal, diagnoses were not independently validated, and the reliability of self-reported celiac diagnosis remains unclear.
Survey respondents also were self-selected – for example, 91% self-identified as white and 60% reported having a bachelor’s degree, compared with only about 77% and one-third of adults captured by U.S. Census Bureau data from 2017.
“Although these characteristics may limit the generalizability of our findings, this study nevertheless reflects a population of celiac disease that is not typically studied, such as those not attending large academic celiac disease centers, and those diagnosed without the involvement of a gastroenterologist,” the researchers wrote. “Future studies are warranted to further characterize this population regarding the long-term consequences of forgoing the duodenal biopsy, and to develop educational interventions to promote evidence-based diagnosis and management of celiac disease.”
SOURCE: Joelson AM et al. Clin Gastroenterol Hepatol. 2018 Sep 10. doi: 10.1016/j.cgh.2018.09.006.
Patients with celiac disease often do not receive a biopsy or nutritional recommendations at diagnosis, according to the findings of a large survey study.
Strikingly, 21% of respondents did not have a confirmatory duodenal biopsy, reported Andrew M. Joelson, MD, of Columbia University Medical Center, New York, and his associates. Gastroenterologists diagnosed 66% of biopsied patients but only 31% of nonbiopsied patients (P less than .001). “Patients require more education about management of celiac disease and referral to gastroenterologists for duodenal biopsy confirmation,” the researchers wrote in the May issue of Clinical Gastroenterology and Hepatology.
Classic small-bowel findings in celiac disease (intraepithelial lymphocytes, crypt hyperplasia, and villous atrophy) are not pathognomonic, making serology important for diagnosis. European guidelines discuss forgoing biopsy in children whose antitissue transglutaminase antibody titers are at least 10-fold above the upper limit of normal. However, the American College of Gastroenterology and the American Gastroenterological Association continue to recommend combining serology with confirmatory small bowel biopsy. The extent to which physicians follow this advice is unclear, the researchers noted.
Therefore, they analyzed data from a questionnaire posted on the Celiac Disease Foundation website during a 7-month period in 2016. Among 982 adults with self-reported celiac disease, 780 said their diagnosis included both serology and biopsy and 202 said they received serology only. Only 40% of these nonbiopsied respondents said they sought nutritional counseling at diagnosis, compared with 59% of biopsied patients (P less than .001). Patients diagnosed by serology alone also were more likely to report using dietary supplements to aid gluten digestion (20% vs. 9% of biopsied respondents; P less than .001).
These associations remained statistically significant after adjustment for age and sex, said the researchers. Nonbiopsied patients had a significantly lower odds of having been diagnosed by a gastroenterologist (odds ratio, 0.16; 95% confidence interval, 0.07-0.37) and seeking nutritional counseling (OR, 0.45; 95% CI, 0.33-0.63) and were significantly more likely to use digestive supplements (OR, 2.61; 95%, CI 1.62-4.19).
Fully 87% of respondents always followed a strict gluten-free diet, but symptoms persisted in 65% of those who were not biopsied, compared with only 51% of those who were biopsied. There were too few responses to this question for the difference between groups to reach statistical significance, but the finding might reflect the greater diagnostic accuracy of biopsy, the researchers said. However, they cautioned that none of the associations in this study were necessarily causal, diagnoses were not independently validated, and the reliability of self-reported celiac diagnosis remains unclear.
Survey respondents also were self-selected – for example, 91% self-identified as white and 60% reported having a bachelor’s degree, compared with only about 77% and one-third of adults captured by U.S. Census Bureau data from 2017.
“Although these characteristics may limit the generalizability of our findings, this study nevertheless reflects a population of celiac disease that is not typically studied, such as those not attending large academic celiac disease centers, and those diagnosed without the involvement of a gastroenterologist,” the researchers wrote. “Future studies are warranted to further characterize this population regarding the long-term consequences of forgoing the duodenal biopsy, and to develop educational interventions to promote evidence-based diagnosis and management of celiac disease.”
SOURCE: Joelson AM et al. Clin Gastroenterol Hepatol. 2018 Sep 10. doi: 10.1016/j.cgh.2018.09.006.
FROM CLINICAL GASTROENTEROLOGY AND HEPATOLOGY
AGA Clinical Practice Update: Switching between biologics and biosimilars in inflammatory bowel disease
Patients with inflammatory bowel disease (IBD) will soon have access to new biosimilars to infliximab, adalimumab, and other monoclonal antibodies, experts wrote in an American Gastroenterological Association clinical practice update.
“It is anticipated that biosimilars for IBD are here to stay,” wrote Laura E. Raffals, MD, of the Mayo Clinic in Rochester, Minn., and her associates in Clinical Gastroenterology and Hepatology. “Provided that the regulatory pathway remains rigorous and postmarketing surveillance is performed adequately, clinicians and patients can be reassured that these agents will provide the same well-described effectiveness for moderate to severe Crohn’s disease and ulcerative colitis, without new safety concerns.”
Evidence supports the use of biosimilars in IBD, but switching patients in stable remission on infliximab (Remicade) to a biosimilar, namely infliximab-dyyb (Inflectra), should remain a case-by-case choice, according to an AGA clinical practice update. Pending more safety data, the update’s authors recommended against nonmedical switches during pregnancy and urge special attention when considering whether to switch children.
Biologics have revolutionized IBD treatment, but at a steep price. As patents expire, companies have developed biosimilar agents that aim to conserve safety and efficacy at lower cost. Studies support this idea, although whether initiating or switching to biosimilars will save patients (versus hospitals or payers) money “remains to be seen,” the practice update states.
The FDA approval process for biosimilars is more rigorous than that for generics, but it skips the multiple phases of clinical trials required to approve reference biologics. Instead, the FDA requires robust evidence that the biosimilar has comparable structure, function, immunogenicity, animal toxicity, pharmacokinetics and pharmacodynamics, and clinical safety and efficacy in humans. Under U.S. law, a biosimilar cannot be FDA approved if its clinically active components differ from the reference product or it shows clinically meaningful differences in safety, potency, or purity.
So far, five biosimilars have been approved by the FDA for use in IBD, although not all are on the market yet: infliximab-dyyb (Inflectra), adalimumab-atta (Amjevita), infliximab-abda (Renflexis), adalimumab-adbm (Cyltezo), and infliximab-qbtx (Ixifi). Most postmarketing studies of their use involved patients on stable doses of Remicade who switched to biosimilar infliximab-dyyb (Inflectra).
The best known of these studies is the double-blind, randomized NOR-SWITCH trial, in which patients with Crohn’s disease, ulcerative colitis, spondyloarthritis, rheumatoid arthritis, psoriatic arthritis, or chronic plaque psoriasis on Remicade either continued it or switched to biosimilar infliximab-dyyb (Inflectra). At week 52, both safety and the likelihood of worsening disease activity were similar regardless of treatment randomization. The study was not powered to assess subgroup outcomes in Crohn’s disease or ulcerative colitis, the practice update notes.
More recently, the results of the 16-week SECURE trial also indicated that switching to infliximab-dyyb (Inflectra) was safe and well tolerated by patients with remitted IBD. However, the FDA has not yet designated any biosimilar as “interchangeable” with an approved biologic confirmed safe in multiple switches, the practice update notes. As a result, state laws prohibit patients from being switched to a biosimilar without notification. Both the NOR-SWITCH and SECURE trials were done in Europe.
Clinicians also must understand that antidrug antibodies to originator and biosimilar infliximab cross-react with each other, the experts emphasized. Switching patients with antibodies to Remicade or a biosimilar to the other product therefore risks an immediate hypersensitivity reaction, including life-threatening anaphylaxis.
The authors disclosed no external funding sources. One author disclosed ties to AbbVie, Janssen, Pfizer, Merck, Samsung Bioepis, and Amgen. The rest reported having no conflicts of interest.
SOURCE: Raffals LA et al. Clin Gastroenterol Hepatol. 2018 Sep 6. doi: 10.1016/j.cgh.2018.08.064.
Patients with inflammatory bowel disease (IBD) will soon have access to new biosimilars to infliximab, adalimumab, and other monoclonal antibodies, experts wrote in an American Gastroenterological Association clinical practice update.
“It is anticipated that biosimilars for IBD are here to stay,” wrote Laura E. Raffals, MD, of the Mayo Clinic in Rochester, Minn., and her associates in Clinical Gastroenterology and Hepatology. “Provided that the regulatory pathway remains rigorous and postmarketing surveillance is performed adequately, clinicians and patients can be reassured that these agents will provide the same well-described effectiveness for moderate to severe Crohn’s disease and ulcerative colitis, without new safety concerns.”
Evidence supports the use of biosimilars in IBD, but switching patients in stable remission on infliximab (Remicade) to a biosimilar, namely infliximab-dyyb (Inflectra), should remain a case-by-case choice, according to an AGA clinical practice update. Pending more safety data, the update’s authors recommended against nonmedical switches during pregnancy and urge special attention when considering whether to switch children.
Biologics have revolutionized IBD treatment, but at a steep price. As patents expire, companies have developed biosimilar agents that aim to conserve safety and efficacy at lower cost. Studies support this idea, although whether initiating or switching to biosimilars will save patients (versus hospitals or payers) money “remains to be seen,” the practice update states.
The FDA approval process for biosimilars is more rigorous than that for generics, but it skips the multiple phases of clinical trials required to approve reference biologics. Instead, the FDA requires robust evidence that the biosimilar has comparable structure, function, immunogenicity, animal toxicity, pharmacokinetics and pharmacodynamics, and clinical safety and efficacy in humans. Under U.S. law, a biosimilar cannot be FDA approved if its clinically active components differ from the reference product or it shows clinically meaningful differences in safety, potency, or purity.
So far, five biosimilars have been approved by the FDA for use in IBD, although not all are on the market yet: infliximab-dyyb (Inflectra), adalimumab-atta (Amjevita), infliximab-abda (Renflexis), adalimumab-adbm (Cyltezo), and infliximab-qbtx (Ixifi). Most postmarketing studies of their use involved patients on stable doses of Remicade who switched to biosimilar infliximab-dyyb (Inflectra).
The best known of these studies is the double-blind, randomized NOR-SWITCH trial, in which patients with Crohn’s disease, ulcerative colitis, spondyloarthritis, rheumatoid arthritis, psoriatic arthritis, or chronic plaque psoriasis on Remicade either continued it or switched to biosimilar infliximab-dyyb (Inflectra). At week 52, both safety and the likelihood of worsening disease activity were similar regardless of treatment randomization. The study was not powered to assess subgroup outcomes in Crohn’s disease or ulcerative colitis, the practice update notes.
More recently, the results of the 16-week SECURE trial also indicated that switching to infliximab-dyyb (Inflectra) was safe and well tolerated by patients with remitted IBD. However, the FDA has not yet designated any biosimilar as “interchangeable” with an approved biologic confirmed safe in multiple switches, the practice update notes. As a result, state laws prohibit patients from being switched to a biosimilar without notification. Both the NOR-SWITCH and SECURE trials were done in Europe.
Clinicians also must understand that antidrug antibodies to originator and biosimilar infliximab cross-react with each other, the experts emphasized. Switching patients with antibodies to Remicade or a biosimilar to the other product therefore risks an immediate hypersensitivity reaction, including life-threatening anaphylaxis.
The authors disclosed no external funding sources. One author disclosed ties to AbbVie, Janssen, Pfizer, Merck, Samsung Bioepis, and Amgen. The rest reported having no conflicts of interest.
SOURCE: Raffals LA et al. Clin Gastroenterol Hepatol. 2018 Sep 6. doi: 10.1016/j.cgh.2018.08.064.
Patients with inflammatory bowel disease (IBD) will soon have access to new biosimilars to infliximab, adalimumab, and other monoclonal antibodies, experts wrote in an American Gastroenterological Association clinical practice update.
“It is anticipated that biosimilars for IBD are here to stay,” wrote Laura E. Raffals, MD, of the Mayo Clinic in Rochester, Minn., and her associates in Clinical Gastroenterology and Hepatology. “Provided that the regulatory pathway remains rigorous and postmarketing surveillance is performed adequately, clinicians and patients can be reassured that these agents will provide the same well-described effectiveness for moderate to severe Crohn’s disease and ulcerative colitis, without new safety concerns.”
Evidence supports the use of biosimilars in IBD, but switching patients in stable remission on infliximab (Remicade) to a biosimilar, namely infliximab-dyyb (Inflectra), should remain a case-by-case choice, according to an AGA clinical practice update. Pending more safety data, the update’s authors recommended against nonmedical switches during pregnancy and urge special attention when considering whether to switch children.
Biologics have revolutionized IBD treatment, but at a steep price. As patents expire, companies have developed biosimilar agents that aim to conserve safety and efficacy at lower cost. Studies support this idea, although whether initiating or switching to biosimilars will save patients (versus hospitals or payers) money “remains to be seen,” the practice update states.
The FDA approval process for biosimilars is more rigorous than that for generics, but it skips the multiple phases of clinical trials required to approve reference biologics. Instead, the FDA requires robust evidence that the biosimilar has comparable structure, function, immunogenicity, animal toxicity, pharmacokinetics and pharmacodynamics, and clinical safety and efficacy in humans. Under U.S. law, a biosimilar cannot be FDA approved if its clinically active components differ from the reference product or it shows clinically meaningful differences in safety, potency, or purity.
So far, five biosimilars have been approved by the FDA for use in IBD, although not all are on the market yet: infliximab-dyyb (Inflectra), adalimumab-atta (Amjevita), infliximab-abda (Renflexis), adalimumab-adbm (Cyltezo), and infliximab-qbtx (Ixifi). Most postmarketing studies of their use involved patients on stable doses of Remicade who switched to biosimilar infliximab-dyyb (Inflectra).
The best known of these studies is the double-blind, randomized NOR-SWITCH trial, in which patients with Crohn’s disease, ulcerative colitis, spondyloarthritis, rheumatoid arthritis, psoriatic arthritis, or chronic plaque psoriasis on Remicade either continued it or switched to biosimilar infliximab-dyyb (Inflectra). At week 52, both safety and the likelihood of worsening disease activity were similar regardless of treatment randomization. The study was not powered to assess subgroup outcomes in Crohn’s disease or ulcerative colitis, the practice update notes.
More recently, the results of the 16-week SECURE trial also indicated that switching to infliximab-dyyb (Inflectra) was safe and well tolerated by patients with remitted IBD. However, the FDA has not yet designated any biosimilar as “interchangeable” with an approved biologic confirmed safe in multiple switches, the practice update notes. As a result, state laws prohibit patients from being switched to a biosimilar without notification. Both the NOR-SWITCH and SECURE trials were done in Europe.
Clinicians also must understand that antidrug antibodies to originator and biosimilar infliximab cross-react with each other, the experts emphasized. Switching patients with antibodies to Remicade or a biosimilar to the other product therefore risks an immediate hypersensitivity reaction, including life-threatening anaphylaxis.
The authors disclosed no external funding sources. One author disclosed ties to AbbVie, Janssen, Pfizer, Merck, Samsung Bioepis, and Amgen. The rest reported having no conflicts of interest.
SOURCE: Raffals LA et al. Clin Gastroenterol Hepatol. 2018 Sep 6. doi: 10.1016/j.cgh.2018.08.064.
FROM CLINICAL GASTROENTEROLOGY AND HEPATOLOGY
Study eyes biomarkers of regorafenib response in hepatocellular carcinoma
.
“In the absence of established or predefined biomarkers for regorafenib, we performed a broad exploratory biomarker analyses at the DNA, RNA, and protein level that represents a much more comprehensive approach than previous studies of regorafenib or sorafenib,” wrote Michael Teufel, PhD, of Bayer Healthcare Pharmaceuticals in Whippany, N.J., and his associates. The preplanned, retrospective analysis of data from the phase 3 RESOURCE trial was reported in Gastroenterology.
The randomized trial included 567 patients whose hepatocellular carcinoma had progressed on sorafenib. Regorafenib significantly outperformed placebo with regard to overall survival (OS). Dr. Teufel and his associates performed next-generation sequencing on 17 archived tumor samples containing sufficient tissue (all from regorafenib recipients). They also performed immune profiling on 46 tumor samples (32 from regorafenib recipients and 14 from placebo recipients), protein analysis on 499 plasma samples (332 from regorafenib recipients and 167 from placebo recipients), and microRNA analysis on 343 plasma samples (234 regorafenib recipients and 109 placebo recipients).
Among 266 proteins tested, decreased levels of 5 proteins correlated with significantly longer OS on regorafenib therapy. These proteins are involved in inflammation or hepatocellular carcinogenesis, the researchers noted. Importantly, none were associated with survival independent of treatment. These five proteins included angiopoietin 1 (hazard ratio for OS, 0.53; 95% confidence interval, 0.38-0.73), cystatin B (hazard ratio, 0.47; 95% CI, 0.34-0.64); the latency-associated peptide of transforming growth factor beta (HR, 0.46; 95% CI, 0.33-0.64), oxidized low-density lipoprotein receptor 1 (HR, 0.54; 95% CI, 0.41-0.72), and C-C motif chemokine ligand 3 (HR, 0.54; 95% CI, 0.39-0.74).
Additionally, baseline concentrations of 47 of the 266 proteins correlated with a time to progression (TPP) benefit on regorafenib therapy (adjusted P less than or equal to .05 for each). The 47 proteins included all 5 that predicted an OS benefit. All but two proteins (calbindin and gelsolin) showed the same directional effect as for OS (that is, low expression predicted response).
Nine plasma microRNA’s levels correlated with improved OS on regorafenib (adjusted P less than or equal to .05): MIR30A, MIR122, MIR125B, MIR200A, MIR374B, MIR15B, MIR107, MIR320, and MIR645. Notably, expression was linked to longer OS specifically among patients with the Hoshida S3 subtype of hepatocellular carcinoma. Next-generation sequencing of tumor samples also identified 49 variants in 27 oncogenes or tumor-suppressor genes. Mutations in CTNNB1 were found in 3 of 10 patients who progressed on regorafenib, and VEGFA amplification was found in 1 of 7 regorafenib responders.
“Thus far, rational biomarker selection has been unsuccessful in identifying predictive markers for regorafenib in colorectal cancer and gastrointestinal stromal tumors,” the researchers commented. “The broader approach used in this study is not only biologically warranted considering the heterogeneity of hepatocellular carcinoma tumors, but is also needed due to the multiple targets and pathways affected by MKIs such as regorafenib. Levels of these circulating biomarkers and genetic features of tumors might be used to identify patients with hepatocellular carcinoma most likely to respond to regorafenib.”
Bayer funded the study, provided the study drug, and was involved in all aspects of the study. Dr. Teufel and three coinvestigators are Bayer employees. Dr. Teufel and two coinvestigators own stock in Bayer. Three other coinvestigators disclosed ties to Bayer and other pharmaceutical companies.
SOURCE: Teufel M et al. Gastroenterology. 2019 Jan 30. doi: 10.1053/j.gastro.2019.01.261.
.
“In the absence of established or predefined biomarkers for regorafenib, we performed a broad exploratory biomarker analyses at the DNA, RNA, and protein level that represents a much more comprehensive approach than previous studies of regorafenib or sorafenib,” wrote Michael Teufel, PhD, of Bayer Healthcare Pharmaceuticals in Whippany, N.J., and his associates. The preplanned, retrospective analysis of data from the phase 3 RESOURCE trial was reported in Gastroenterology.
The randomized trial included 567 patients whose hepatocellular carcinoma had progressed on sorafenib. Regorafenib significantly outperformed placebo with regard to overall survival (OS). Dr. Teufel and his associates performed next-generation sequencing on 17 archived tumor samples containing sufficient tissue (all from regorafenib recipients). They also performed immune profiling on 46 tumor samples (32 from regorafenib recipients and 14 from placebo recipients), protein analysis on 499 plasma samples (332 from regorafenib recipients and 167 from placebo recipients), and microRNA analysis on 343 plasma samples (234 regorafenib recipients and 109 placebo recipients).
Among 266 proteins tested, decreased levels of 5 proteins correlated with significantly longer OS on regorafenib therapy. These proteins are involved in inflammation or hepatocellular carcinogenesis, the researchers noted. Importantly, none were associated with survival independent of treatment. These five proteins included angiopoietin 1 (hazard ratio for OS, 0.53; 95% confidence interval, 0.38-0.73), cystatin B (hazard ratio, 0.47; 95% CI, 0.34-0.64); the latency-associated peptide of transforming growth factor beta (HR, 0.46; 95% CI, 0.33-0.64), oxidized low-density lipoprotein receptor 1 (HR, 0.54; 95% CI, 0.41-0.72), and C-C motif chemokine ligand 3 (HR, 0.54; 95% CI, 0.39-0.74).
Additionally, baseline concentrations of 47 of the 266 proteins correlated with a time to progression (TPP) benefit on regorafenib therapy (adjusted P less than or equal to .05 for each). The 47 proteins included all 5 that predicted an OS benefit. All but two proteins (calbindin and gelsolin) showed the same directional effect as for OS (that is, low expression predicted response).
Nine plasma microRNA’s levels correlated with improved OS on regorafenib (adjusted P less than or equal to .05): MIR30A, MIR122, MIR125B, MIR200A, MIR374B, MIR15B, MIR107, MIR320, and MIR645. Notably, expression was linked to longer OS specifically among patients with the Hoshida S3 subtype of hepatocellular carcinoma. Next-generation sequencing of tumor samples also identified 49 variants in 27 oncogenes or tumor-suppressor genes. Mutations in CTNNB1 were found in 3 of 10 patients who progressed on regorafenib, and VEGFA amplification was found in 1 of 7 regorafenib responders.
“Thus far, rational biomarker selection has been unsuccessful in identifying predictive markers for regorafenib in colorectal cancer and gastrointestinal stromal tumors,” the researchers commented. “The broader approach used in this study is not only biologically warranted considering the heterogeneity of hepatocellular carcinoma tumors, but is also needed due to the multiple targets and pathways affected by MKIs such as regorafenib. Levels of these circulating biomarkers and genetic features of tumors might be used to identify patients with hepatocellular carcinoma most likely to respond to regorafenib.”
Bayer funded the study, provided the study drug, and was involved in all aspects of the study. Dr. Teufel and three coinvestigators are Bayer employees. Dr. Teufel and two coinvestigators own stock in Bayer. Three other coinvestigators disclosed ties to Bayer and other pharmaceutical companies.
SOURCE: Teufel M et al. Gastroenterology. 2019 Jan 30. doi: 10.1053/j.gastro.2019.01.261.
.
“In the absence of established or predefined biomarkers for regorafenib, we performed a broad exploratory biomarker analyses at the DNA, RNA, and protein level that represents a much more comprehensive approach than previous studies of regorafenib or sorafenib,” wrote Michael Teufel, PhD, of Bayer Healthcare Pharmaceuticals in Whippany, N.J., and his associates. The preplanned, retrospective analysis of data from the phase 3 RESOURCE trial was reported in Gastroenterology.
The randomized trial included 567 patients whose hepatocellular carcinoma had progressed on sorafenib. Regorafenib significantly outperformed placebo with regard to overall survival (OS). Dr. Teufel and his associates performed next-generation sequencing on 17 archived tumor samples containing sufficient tissue (all from regorafenib recipients). They also performed immune profiling on 46 tumor samples (32 from regorafenib recipients and 14 from placebo recipients), protein analysis on 499 plasma samples (332 from regorafenib recipients and 167 from placebo recipients), and microRNA analysis on 343 plasma samples (234 regorafenib recipients and 109 placebo recipients).
Among 266 proteins tested, decreased levels of 5 proteins correlated with significantly longer OS on regorafenib therapy. These proteins are involved in inflammation or hepatocellular carcinogenesis, the researchers noted. Importantly, none were associated with survival independent of treatment. These five proteins included angiopoietin 1 (hazard ratio for OS, 0.53; 95% confidence interval, 0.38-0.73), cystatin B (hazard ratio, 0.47; 95% CI, 0.34-0.64); the latency-associated peptide of transforming growth factor beta (HR, 0.46; 95% CI, 0.33-0.64), oxidized low-density lipoprotein receptor 1 (HR, 0.54; 95% CI, 0.41-0.72), and C-C motif chemokine ligand 3 (HR, 0.54; 95% CI, 0.39-0.74).
Additionally, baseline concentrations of 47 of the 266 proteins correlated with a time to progression (TPP) benefit on regorafenib therapy (adjusted P less than or equal to .05 for each). The 47 proteins included all 5 that predicted an OS benefit. All but two proteins (calbindin and gelsolin) showed the same directional effect as for OS (that is, low expression predicted response).
Nine plasma microRNA’s levels correlated with improved OS on regorafenib (adjusted P less than or equal to .05): MIR30A, MIR122, MIR125B, MIR200A, MIR374B, MIR15B, MIR107, MIR320, and MIR645. Notably, expression was linked to longer OS specifically among patients with the Hoshida S3 subtype of hepatocellular carcinoma. Next-generation sequencing of tumor samples also identified 49 variants in 27 oncogenes or tumor-suppressor genes. Mutations in CTNNB1 were found in 3 of 10 patients who progressed on regorafenib, and VEGFA amplification was found in 1 of 7 regorafenib responders.
“Thus far, rational biomarker selection has been unsuccessful in identifying predictive markers for regorafenib in colorectal cancer and gastrointestinal stromal tumors,” the researchers commented. “The broader approach used in this study is not only biologically warranted considering the heterogeneity of hepatocellular carcinoma tumors, but is also needed due to the multiple targets and pathways affected by MKIs such as regorafenib. Levels of these circulating biomarkers and genetic features of tumors might be used to identify patients with hepatocellular carcinoma most likely to respond to regorafenib.”
Bayer funded the study, provided the study drug, and was involved in all aspects of the study. Dr. Teufel and three coinvestigators are Bayer employees. Dr. Teufel and two coinvestigators own stock in Bayer. Three other coinvestigators disclosed ties to Bayer and other pharmaceutical companies.
SOURCE: Teufel M et al. Gastroenterology. 2019 Jan 30. doi: 10.1053/j.gastro.2019.01.261.
FROM GASTROENTEROLOGY
Mucosal impedance contour rapidly distinguished GERD, non-GERD, and eosinophilic esophagitis
.
Source: American Gastroenterological Association
Each group showed a significantly different (P less than .01) pattern of mucosal impedance (MI), or disruption of mucosal integrity, along the esophageal axis, wrote Dhyanesh A. Patel, MD, of Vanderbilt University Medical Center in Nashville, Tenn., and his associates. Patients without GERD had higher MI values along all esophageal segments, while GERD was characterized by below-normal values in the distal esophagus only, and eosinophilic esophagitis led to low values throughout the esophagus.
The findings were validated in a separate patient cohort, and the only reported adverse event was an episode of mild chest pain. “This contour heatmap could easily be employed to establish a diagnosis during endoscopy, independent of biopsy or pH monitoring,” the investigators wrote in Gastroenterology. They cautioned that the balloon catheter cannot be safely used in patients with severe fibrostenotic disease.
Current definitive diagnostics for GERD leave much to be desired. Transnasal probes are imprecise and uncomfortable, and they can be insensitive if discomfort causes patients to vary normal activity or skip meals. Wireless ambulatory pH monitoring is more tolerable but unreliable and measures only acidity of refluxed material at a single point along the esophagus. These tests also “fail to account for day-to-day variability of reflux, as they only provide a 24- to 48-hour snapshot of a disease process that is chronic in nature,” the researchers wrote. Eosinophilic esophagitis is becoming more common and usually requires proximal and distal biopsies for diagnosis.
Mucosal impedance contour pattern testing is based on the fact that both GERD and eosinophilic esophagitis involve increased distance between esophageal epithelial cells. The amount of intercellular dilatation correlates inversely with MI values. In proof-of-concept studies, individuals with GERD, non-GERD, eosinophilic esophagitis, and achalasia had distinct MI patterns. However, these studies tested a single-channel catheter system that took only point measurements and was subject to interoperator variability. To improve on this concept, Dr. Patel and his associates mounted radial and axial sensors on a balloon catheter to measure MI at 180-degree intervals along a 10-cm esophageal segment.
They tested the new device prospectively in 69 patients undergoing esophagogastroduodenoscopy with or without pH monitoring (which was used as the standard). In all, 24 patients had GERD, 21 had eosinophilic esophagitis, and 24 had normal findings. By using the intercept and slope of the balloon MI measurements, the researchers detected GERD with an area under the receiver operating characteristic curve (AUC) of 0.67, eosinophilic esophagitis with an AUC of 0.84, and non-GERD with an AUC of 0.83.
These findings held up in a separate validation cohort of 36 patients (28 with GERD and eight with eosinophilic esophagitis) from three tertiary care centers. The probability of eosinophilic esophagitis was highest in patients with low distal MI values (that is, a low intercept) and a low slope (showing that MI values remained low proximally). A low distal MI intercept with a steeper positive slope suggested GERD, while a higher distal MI intercept with a steep slope signified non-GERD.
The system “potentially obviates the need for 24- to 48-hour ambulatory wireless pH monitoring or esophageal biopsies for histopathology,” the researchers concluded. “This can help reduce diagnostic and treatment latency and might allow for monitoring disease activity over time.”
The National Institutes of Health funded the external validation analysis. Diversatek Healthcare, which patented the device together with Vanderbilt University, gave research funding to four coinvestigators, including the senior author. Dr. Patel and the other five coinvestigators reported having no conflicts of interest.
SOURCE: Patel DA et al. Gastroenterology. 2019 Jan 31. doi: 10.1053/j.gastro.2019.01.253.
Evaluating esophageal disorders such as GERD or eosinophilic esophagitis can be time consuming for patients in clinical practice and requires multiple visits to complete testing and obtain results. Other than visualizing complications of reflux such as erosive esophagitis or Barrett’s esophagus, there has been no immediate option to diagnose GERD in standard practice during routine endoscopy. Furthermore, the decision to pursue long-term medication or surgery for GERD relies on a brief pH assessment to be truly representative of a patient’s everyday symptoms. Follow-up of eosinophilic esophagitis requires repeated upper endoscopies with biopsies after every incremental change in medication or diet, which unsurprisingly, can reduce compliance with ongoing management for what is often a readily treatable condition.
Both GERD and eosinophilic esophagitis can be characterized by changes in esophageal mucosal impedance. Rather than directly measuring the pH or eosinophil counts, Dr. Patel and associates prospectively validated the diagnostic test performance of an add-on endoscopic mucosal impedance device that might enable the gastroenterologist to rule out GERD or rule in eosinophilic esophagitis during the index endoscopy with reasonable accuracy (AUC above 0.8 to rule out GERD or rule in eosinophilic esophagitis) while adding 2-3 minutes of procedure time. One patient was admitted for chest pain after use of the device but was discharged without complication, and the authors caution against use in severe fibrostenotic disease.
While work to refine a clinical prediction model with this technology is ongoing, the promise of diagnosing and following common esophageal conditions of GERD and eosinophilic esophagitis during endoscopy would have clear value in expediting care and enhancing compliance with treatment.
Eric D. Shah, MD, MBA, is assistant professor of medicine, director of gastrointestinal motility, esophageal, and swallowing disorders center, Geisel School of Medicine, Dartmouth College, Hanover, N.H. He has no disclosures.
Evaluating esophageal disorders such as GERD or eosinophilic esophagitis can be time consuming for patients in clinical practice and requires multiple visits to complete testing and obtain results. Other than visualizing complications of reflux such as erosive esophagitis or Barrett’s esophagus, there has been no immediate option to diagnose GERD in standard practice during routine endoscopy. Furthermore, the decision to pursue long-term medication or surgery for GERD relies on a brief pH assessment to be truly representative of a patient’s everyday symptoms. Follow-up of eosinophilic esophagitis requires repeated upper endoscopies with biopsies after every incremental change in medication or diet, which unsurprisingly, can reduce compliance with ongoing management for what is often a readily treatable condition.
Both GERD and eosinophilic esophagitis can be characterized by changes in esophageal mucosal impedance. Rather than directly measuring the pH or eosinophil counts, Dr. Patel and associates prospectively validated the diagnostic test performance of an add-on endoscopic mucosal impedance device that might enable the gastroenterologist to rule out GERD or rule in eosinophilic esophagitis during the index endoscopy with reasonable accuracy (AUC above 0.8 to rule out GERD or rule in eosinophilic esophagitis) while adding 2-3 minutes of procedure time. One patient was admitted for chest pain after use of the device but was discharged without complication, and the authors caution against use in severe fibrostenotic disease.
While work to refine a clinical prediction model with this technology is ongoing, the promise of diagnosing and following common esophageal conditions of GERD and eosinophilic esophagitis during endoscopy would have clear value in expediting care and enhancing compliance with treatment.
Eric D. Shah, MD, MBA, is assistant professor of medicine, director of gastrointestinal motility, esophageal, and swallowing disorders center, Geisel School of Medicine, Dartmouth College, Hanover, N.H. He has no disclosures.
Evaluating esophageal disorders such as GERD or eosinophilic esophagitis can be time consuming for patients in clinical practice and requires multiple visits to complete testing and obtain results. Other than visualizing complications of reflux such as erosive esophagitis or Barrett’s esophagus, there has been no immediate option to diagnose GERD in standard practice during routine endoscopy. Furthermore, the decision to pursue long-term medication or surgery for GERD relies on a brief pH assessment to be truly representative of a patient’s everyday symptoms. Follow-up of eosinophilic esophagitis requires repeated upper endoscopies with biopsies after every incremental change in medication or diet, which unsurprisingly, can reduce compliance with ongoing management for what is often a readily treatable condition.
Both GERD and eosinophilic esophagitis can be characterized by changes in esophageal mucosal impedance. Rather than directly measuring the pH or eosinophil counts, Dr. Patel and associates prospectively validated the diagnostic test performance of an add-on endoscopic mucosal impedance device that might enable the gastroenterologist to rule out GERD or rule in eosinophilic esophagitis during the index endoscopy with reasonable accuracy (AUC above 0.8 to rule out GERD or rule in eosinophilic esophagitis) while adding 2-3 minutes of procedure time. One patient was admitted for chest pain after use of the device but was discharged without complication, and the authors caution against use in severe fibrostenotic disease.
While work to refine a clinical prediction model with this technology is ongoing, the promise of diagnosing and following common esophageal conditions of GERD and eosinophilic esophagitis during endoscopy would have clear value in expediting care and enhancing compliance with treatment.
Eric D. Shah, MD, MBA, is assistant professor of medicine, director of gastrointestinal motility, esophageal, and swallowing disorders center, Geisel School of Medicine, Dartmouth College, Hanover, N.H. He has no disclosures.
.
Source: American Gastroenterological Association
Each group showed a significantly different (P less than .01) pattern of mucosal impedance (MI), or disruption of mucosal integrity, along the esophageal axis, wrote Dhyanesh A. Patel, MD, of Vanderbilt University Medical Center in Nashville, Tenn., and his associates. Patients without GERD had higher MI values along all esophageal segments, while GERD was characterized by below-normal values in the distal esophagus only, and eosinophilic esophagitis led to low values throughout the esophagus.
The findings were validated in a separate patient cohort, and the only reported adverse event was an episode of mild chest pain. “This contour heatmap could easily be employed to establish a diagnosis during endoscopy, independent of biopsy or pH monitoring,” the investigators wrote in Gastroenterology. They cautioned that the balloon catheter cannot be safely used in patients with severe fibrostenotic disease.
Current definitive diagnostics for GERD leave much to be desired. Transnasal probes are imprecise and uncomfortable, and they can be insensitive if discomfort causes patients to vary normal activity or skip meals. Wireless ambulatory pH monitoring is more tolerable but unreliable and measures only acidity of refluxed material at a single point along the esophagus. These tests also “fail to account for day-to-day variability of reflux, as they only provide a 24- to 48-hour snapshot of a disease process that is chronic in nature,” the researchers wrote. Eosinophilic esophagitis is becoming more common and usually requires proximal and distal biopsies for diagnosis.
Mucosal impedance contour pattern testing is based on the fact that both GERD and eosinophilic esophagitis involve increased distance between esophageal epithelial cells. The amount of intercellular dilatation correlates inversely with MI values. In proof-of-concept studies, individuals with GERD, non-GERD, eosinophilic esophagitis, and achalasia had distinct MI patterns. However, these studies tested a single-channel catheter system that took only point measurements and was subject to interoperator variability. To improve on this concept, Dr. Patel and his associates mounted radial and axial sensors on a balloon catheter to measure MI at 180-degree intervals along a 10-cm esophageal segment.
They tested the new device prospectively in 69 patients undergoing esophagogastroduodenoscopy with or without pH monitoring (which was used as the standard). In all, 24 patients had GERD, 21 had eosinophilic esophagitis, and 24 had normal findings. By using the intercept and slope of the balloon MI measurements, the researchers detected GERD with an area under the receiver operating characteristic curve (AUC) of 0.67, eosinophilic esophagitis with an AUC of 0.84, and non-GERD with an AUC of 0.83.
These findings held up in a separate validation cohort of 36 patients (28 with GERD and eight with eosinophilic esophagitis) from three tertiary care centers. The probability of eosinophilic esophagitis was highest in patients with low distal MI values (that is, a low intercept) and a low slope (showing that MI values remained low proximally). A low distal MI intercept with a steeper positive slope suggested GERD, while a higher distal MI intercept with a steep slope signified non-GERD.
The system “potentially obviates the need for 24- to 48-hour ambulatory wireless pH monitoring or esophageal biopsies for histopathology,” the researchers concluded. “This can help reduce diagnostic and treatment latency and might allow for monitoring disease activity over time.”
The National Institutes of Health funded the external validation analysis. Diversatek Healthcare, which patented the device together with Vanderbilt University, gave research funding to four coinvestigators, including the senior author. Dr. Patel and the other five coinvestigators reported having no conflicts of interest.
SOURCE: Patel DA et al. Gastroenterology. 2019 Jan 31. doi: 10.1053/j.gastro.2019.01.253.
.
Source: American Gastroenterological Association
Each group showed a significantly different (P less than .01) pattern of mucosal impedance (MI), or disruption of mucosal integrity, along the esophageal axis, wrote Dhyanesh A. Patel, MD, of Vanderbilt University Medical Center in Nashville, Tenn., and his associates. Patients without GERD had higher MI values along all esophageal segments, while GERD was characterized by below-normal values in the distal esophagus only, and eosinophilic esophagitis led to low values throughout the esophagus.
The findings were validated in a separate patient cohort, and the only reported adverse event was an episode of mild chest pain. “This contour heatmap could easily be employed to establish a diagnosis during endoscopy, independent of biopsy or pH monitoring,” the investigators wrote in Gastroenterology. They cautioned that the balloon catheter cannot be safely used in patients with severe fibrostenotic disease.
Current definitive diagnostics for GERD leave much to be desired. Transnasal probes are imprecise and uncomfortable, and they can be insensitive if discomfort causes patients to vary normal activity or skip meals. Wireless ambulatory pH monitoring is more tolerable but unreliable and measures only acidity of refluxed material at a single point along the esophagus. These tests also “fail to account for day-to-day variability of reflux, as they only provide a 24- to 48-hour snapshot of a disease process that is chronic in nature,” the researchers wrote. Eosinophilic esophagitis is becoming more common and usually requires proximal and distal biopsies for diagnosis.
Mucosal impedance contour pattern testing is based on the fact that both GERD and eosinophilic esophagitis involve increased distance between esophageal epithelial cells. The amount of intercellular dilatation correlates inversely with MI values. In proof-of-concept studies, individuals with GERD, non-GERD, eosinophilic esophagitis, and achalasia had distinct MI patterns. However, these studies tested a single-channel catheter system that took only point measurements and was subject to interoperator variability. To improve on this concept, Dr. Patel and his associates mounted radial and axial sensors on a balloon catheter to measure MI at 180-degree intervals along a 10-cm esophageal segment.
They tested the new device prospectively in 69 patients undergoing esophagogastroduodenoscopy with or without pH monitoring (which was used as the standard). In all, 24 patients had GERD, 21 had eosinophilic esophagitis, and 24 had normal findings. By using the intercept and slope of the balloon MI measurements, the researchers detected GERD with an area under the receiver operating characteristic curve (AUC) of 0.67, eosinophilic esophagitis with an AUC of 0.84, and non-GERD with an AUC of 0.83.
These findings held up in a separate validation cohort of 36 patients (28 with GERD and eight with eosinophilic esophagitis) from three tertiary care centers. The probability of eosinophilic esophagitis was highest in patients with low distal MI values (that is, a low intercept) and a low slope (showing that MI values remained low proximally). A low distal MI intercept with a steeper positive slope suggested GERD, while a higher distal MI intercept with a steep slope signified non-GERD.
The system “potentially obviates the need for 24- to 48-hour ambulatory wireless pH monitoring or esophageal biopsies for histopathology,” the researchers concluded. “This can help reduce diagnostic and treatment latency and might allow for monitoring disease activity over time.”
The National Institutes of Health funded the external validation analysis. Diversatek Healthcare, which patented the device together with Vanderbilt University, gave research funding to four coinvestigators, including the senior author. Dr. Patel and the other five coinvestigators reported having no conflicts of interest.
SOURCE: Patel DA et al. Gastroenterology. 2019 Jan 31. doi: 10.1053/j.gastro.2019.01.253.
FROM GASTROENTEROLOGY
One-time, universal hepatitis C testing cost effective, researchers say
Universal one-time screening for hepatitis C virus infection is cost effective, compared with birth cohort screening alone, according to the results of a study published in Clinical Gastroenterology and Hepatology.
The Centers for Disease Control and Prevention and the U.S. Preventive Services Task Force recommend testing all individuals born between 1945 and 1965 in addition to injection drug users and other high-risk individuals. But so-called birth cohort screening does not reflect the recent spike in hepatitis C virus (HCV) cases among younger persons in the United States, nor the current recommendation to treat nearly all chronic HCV cases, wrote Mark H. Eckman, MD, of the University of Cincinnati, and his associates.
Using a computer program called Decision Maker, they modeled the cost-effectiveness of universal one-time testing, birth cohort screening, and no screening based on quality-adjusted life-years (QALYS) and 2017 U.S. dollars. They assumed that all HCV-infected patients were treatment naive, treatment eligible, and asymptomatic (for example, had no decompensated cirrhosis). They used efficacy data from the ASTRAL trials of sofosbuvir-velpatasvir as well as the ENDURANCE, SURVEYOR, and EXPEDITION trials of glecaprevir-pibrentasvir. In the model, patients who did not achieve a sustained viral response to treatment went on to complete a 12-week triple direct-acting antiviral (DAA) regimen (sofosbuvir, velpatasvir, and voxilaprevir).
Based on these assumptions, universal one-time screening and treatment of infected individuals cost less than $50,000 per QALY gained, making it highly cost effective, compared with no screening, the investigators wrote. Universal screening also was highly cost effective when compared with birth cohort screening, costing $11,378 for each QALY gained.
“Analyses performed during the era of first-generation DAAs and interferon-based treatment regimens found birth-cohort screening to be ‘cost effective,’ ” the researchers wrote. “However, the availability of a new generation of highly effective, non–interferon-based oral regimens, with fewer side effects and shorter treatment courses, has altered the dynamic around the question of screening.” They pointed to another recent study in which universal one-time HCV testing was more cost effective than birth cohort screening.
Such findings have spurred experts to revisit guidelines on HCV screening, but universal testing is controversial when some states, counties, and communities have a low HCV prevalence. In the model, universal one-time HCV screening was cost effective (less than $50,000 per QALY gained), compared with birth cohort screening as long as prevalence exceeded 0.07% among adults not born between 1945 and 1965. The current prevalence estimate in this group is 0.29%, which is probably low because it does not account for the rising incidence among younger adults, the researchers wrote. In an ideal world, all clinics and hospitals would implement an HCV testing program, but in the real world of scarce resources, “data regarding the cost-effectiveness threshold can guide local policy decisions by directing testing services to settings in which they generate sufficient benefit for the cost.”
Partial funding came from the National Foundation for the Centers for Disease Control and Prevention (CDC Foundation), with funding provided through multiple donors to the CDC Foundation’s Viral Hepatitis Action Coalition. Dr. Eckman reported grant support from Merck and one coinvestigator reported ties to AbbVie, Gilead, Merck, and several other pharmaceutical companies.
SOURCE: Eckman MH et al. Clin Gastroenterol Hepatol. 2018 Sep 7. doi: 10.1016/j.cgh.2018.08.080.
Universal one-time screening for hepatitis C virus infection is cost effective, compared with birth cohort screening alone, according to the results of a study published in Clinical Gastroenterology and Hepatology.
The Centers for Disease Control and Prevention and the U.S. Preventive Services Task Force recommend testing all individuals born between 1945 and 1965 in addition to injection drug users and other high-risk individuals. But so-called birth cohort screening does not reflect the recent spike in hepatitis C virus (HCV) cases among younger persons in the United States, nor the current recommendation to treat nearly all chronic HCV cases, wrote Mark H. Eckman, MD, of the University of Cincinnati, and his associates.
Using a computer program called Decision Maker, they modeled the cost-effectiveness of universal one-time testing, birth cohort screening, and no screening based on quality-adjusted life-years (QALYS) and 2017 U.S. dollars. They assumed that all HCV-infected patients were treatment naive, treatment eligible, and asymptomatic (for example, had no decompensated cirrhosis). They used efficacy data from the ASTRAL trials of sofosbuvir-velpatasvir as well as the ENDURANCE, SURVEYOR, and EXPEDITION trials of glecaprevir-pibrentasvir. In the model, patients who did not achieve a sustained viral response to treatment went on to complete a 12-week triple direct-acting antiviral (DAA) regimen (sofosbuvir, velpatasvir, and voxilaprevir).
Based on these assumptions, universal one-time screening and treatment of infected individuals cost less than $50,000 per QALY gained, making it highly cost effective, compared with no screening, the investigators wrote. Universal screening also was highly cost effective when compared with birth cohort screening, costing $11,378 for each QALY gained.
“Analyses performed during the era of first-generation DAAs and interferon-based treatment regimens found birth-cohort screening to be ‘cost effective,’ ” the researchers wrote. “However, the availability of a new generation of highly effective, non–interferon-based oral regimens, with fewer side effects and shorter treatment courses, has altered the dynamic around the question of screening.” They pointed to another recent study in which universal one-time HCV testing was more cost effective than birth cohort screening.
Such findings have spurred experts to revisit guidelines on HCV screening, but universal testing is controversial when some states, counties, and communities have a low HCV prevalence. In the model, universal one-time HCV screening was cost effective (less than $50,000 per QALY gained), compared with birth cohort screening as long as prevalence exceeded 0.07% among adults not born between 1945 and 1965. The current prevalence estimate in this group is 0.29%, which is probably low because it does not account for the rising incidence among younger adults, the researchers wrote. In an ideal world, all clinics and hospitals would implement an HCV testing program, but in the real world of scarce resources, “data regarding the cost-effectiveness threshold can guide local policy decisions by directing testing services to settings in which they generate sufficient benefit for the cost.”
Partial funding came from the National Foundation for the Centers for Disease Control and Prevention (CDC Foundation), with funding provided through multiple donors to the CDC Foundation’s Viral Hepatitis Action Coalition. Dr. Eckman reported grant support from Merck and one coinvestigator reported ties to AbbVie, Gilead, Merck, and several other pharmaceutical companies.
SOURCE: Eckman MH et al. Clin Gastroenterol Hepatol. 2018 Sep 7. doi: 10.1016/j.cgh.2018.08.080.
Universal one-time screening for hepatitis C virus infection is cost effective, compared with birth cohort screening alone, according to the results of a study published in Clinical Gastroenterology and Hepatology.
The Centers for Disease Control and Prevention and the U.S. Preventive Services Task Force recommend testing all individuals born between 1945 and 1965 in addition to injection drug users and other high-risk individuals. But so-called birth cohort screening does not reflect the recent spike in hepatitis C virus (HCV) cases among younger persons in the United States, nor the current recommendation to treat nearly all chronic HCV cases, wrote Mark H. Eckman, MD, of the University of Cincinnati, and his associates.
Using a computer program called Decision Maker, they modeled the cost-effectiveness of universal one-time testing, birth cohort screening, and no screening based on quality-adjusted life-years (QALYS) and 2017 U.S. dollars. They assumed that all HCV-infected patients were treatment naive, treatment eligible, and asymptomatic (for example, had no decompensated cirrhosis). They used efficacy data from the ASTRAL trials of sofosbuvir-velpatasvir as well as the ENDURANCE, SURVEYOR, and EXPEDITION trials of glecaprevir-pibrentasvir. In the model, patients who did not achieve a sustained viral response to treatment went on to complete a 12-week triple direct-acting antiviral (DAA) regimen (sofosbuvir, velpatasvir, and voxilaprevir).
Based on these assumptions, universal one-time screening and treatment of infected individuals cost less than $50,000 per QALY gained, making it highly cost effective, compared with no screening, the investigators wrote. Universal screening also was highly cost effective when compared with birth cohort screening, costing $11,378 for each QALY gained.
“Analyses performed during the era of first-generation DAAs and interferon-based treatment regimens found birth-cohort screening to be ‘cost effective,’ ” the researchers wrote. “However, the availability of a new generation of highly effective, non–interferon-based oral regimens, with fewer side effects and shorter treatment courses, has altered the dynamic around the question of screening.” They pointed to another recent study in which universal one-time HCV testing was more cost effective than birth cohort screening.
Such findings have spurred experts to revisit guidelines on HCV screening, but universal testing is controversial when some states, counties, and communities have a low HCV prevalence. In the model, universal one-time HCV screening was cost effective (less than $50,000 per QALY gained), compared with birth cohort screening as long as prevalence exceeded 0.07% among adults not born between 1945 and 1965. The current prevalence estimate in this group is 0.29%, which is probably low because it does not account for the rising incidence among younger adults, the researchers wrote. In an ideal world, all clinics and hospitals would implement an HCV testing program, but in the real world of scarce resources, “data regarding the cost-effectiveness threshold can guide local policy decisions by directing testing services to settings in which they generate sufficient benefit for the cost.”
Partial funding came from the National Foundation for the Centers for Disease Control and Prevention (CDC Foundation), with funding provided through multiple donors to the CDC Foundation’s Viral Hepatitis Action Coalition. Dr. Eckman reported grant support from Merck and one coinvestigator reported ties to AbbVie, Gilead, Merck, and several other pharmaceutical companies.
SOURCE: Eckman MH et al. Clin Gastroenterol Hepatol. 2018 Sep 7. doi: 10.1016/j.cgh.2018.08.080.
FROM CLINICAL GASTROENTEROLOGY AND HEPATOLOGY
High-calorie diet may worsen Wilson disease
A high-calorie diet may cause earlier onset of more severe Wilson disease, according to a rodent study.
If translatable to humans, the results could explain “striking phenotype-genotype discrepancies” between patients with Wilson disease, and may give reason to monitor nutrition more closely, particularly dietary levels of fat and sugar, reported lead author Claudia Einer, a PhD candidate at the German Research Center for Environmental Health in Neuherberg, Germany, and her colleagues. Their findings clarify an association between impaired copper metabolism, which defines Wilson disease, and liver steatosis, a common finding in affected patients.
“Indeed, Wilson disease often may be misdiagnosed as nonalcoholic fatty liver disease (NAFLD),” the investigators wrote in Cellular and Molecular Gastroenterology and Hepatology. They noted that previous reports showed similar mitochondrial alterations in the livers of patients with NAFLD and those with Wilson disease. Furthermore, in a case report of two twins with Wilson disease, the twin with bulimia nervosa developed severe liver disease, whereas the other twin, who was undernourished, had mild liver disease. Considering these observations and other supportive evidence, the investigators tested this apparent relationship between a high-fat diet and liver damage in Wilson disease.
“The rationale of this study was that both enriched copper and fatty acids cause bioenergetic defects and therefore synergistically and detrimentally may coincide on hepatic mitochondria, which was found to be dramatically the case,” the investigators wrote.
The study involved homozygous Atp7b–/– rats, which mirror Wilson disease, and heterozygous Atp7b+/– rats, which served as control subjects because they lack copper accumulation. The high-calorie diet contained high fat and sugar levels to mirror “the eating habits in Western society, causing the ‘American-lifestyle-induced-obesity syndrome.’ ”
Within several weeks of starting the high-calorie diet, both control and Wilson disease rats showed higher liver triglyceride levels and visceral fat mass compared with rats on the normal diet, with liver histology also showing macrosteatosis and increased NAFLD Activity Score (NAS). Control rats maintained similar body and liver weights regardless of diet; in contrast, Wilson disease rats on the high-calorie diet showed increased liver weight, compared with Wilson disease rats on the normal diet. In addition, Wilson disease rats fed the high-calorie diet had clinical liver injury, supported by elevated aspartate aminotransferase (AST) levels and gross hepatic damage. Under the microscope, histology revealed widespread necrosis, apoptosis, inflammation, and fibrosis; findings were sufficient to constitute nonalcoholic steatohepatitis in all Wilson disease rats fed the high-calorie diet, compared with just one-third of the control rats receiving high calories. Additional testing showed that Wilson disease rats fed the high-calorie diet had disease onset 20 days sooner than did Wilson disease rats fed the normal diet.
“This is a remarkable disease acceleration,” the investigators noted, highlighting the median survival of 106 days in Wilson disease rats fed a normal diet.
Copper testing showed that Wilson disease rats fed the high-calorie diet had high serum levels of non–ceruloplasmin-bound copper, which is a sign of overt liver damage; based on histologic findings, the copper likely came from destroyed hepatocytes. Regardless of diet type, Wilson disease rats developed high levels of copper within the liver, suggesting comparable copper consumption via water sources. Regardless of genotype, the high-calorie diet led to higher mitochondrial copper levels than those of the normal diet, but Wilson disease rats showed the highest levels of copper sequestration in mitochondria, to an extreme degree.
“Importantly,” the investigators wrote, “such increased mitochondrial copper significantly correlated with a higher NAS and a progressive Histologic Activity Index score.”
Closer inspection showed that the mitochondria of Wilson disease rats were abnormal regardless of diet, but those fed the high-calorie diet had “a most severe mitochondrial phenotype,” including detached membranes and ballooned cristae.
“These structural impairments were paralleled by remarkable mitochondrial functional deficits,” the investigators reported, referring to a significant decrease in adenosine triphosphate production and an increase in mitochondrial H2O2. In response to these mitochondrial abnormalities, cholesterol-related enzymes quadrupled, most prominently for biliary excretion. The investigators summed up these hepatic events as a “toxic triad of adenosine triphosphate depletion, increased reactive oxygen species, and increased bile salts [that led] to an earlier onset of the disease and to enhanced disease progression.”
To complete the set of experiments, rats were given the copper chelator methanobactin. This treatment effectively mitigated structural and functional abnormalities in mitochondria, which drove serum levels of AST, copper, and bile salts toward normalcy. Although treatment halted overt liver damage, histology revealed that resolution was incomplete.
“We conclude that lipid accumulation in copper-burdened hepatocytes may represent a ‘second-hit’ in Wilson disease, inducing liver damage, and suggest that further research should establish whether dietary counseling of Wilson disease patients may be of therapeutic benefit,” the investigators concluded.
The study was funded by Deutsche Forschungsgemeinschaft and the WiFoMed Society. The investigators reported no conflicts of interest.
SOURCE: Einer et al. Cell Mol Gastroenterol Hepatol. 2019 Jan 11. doi: 10.1016/j.jcmgh.2018.12.005.
A high-calorie diet may cause earlier onset of more severe Wilson disease, according to a rodent study.
If translatable to humans, the results could explain “striking phenotype-genotype discrepancies” between patients with Wilson disease, and may give reason to monitor nutrition more closely, particularly dietary levels of fat and sugar, reported lead author Claudia Einer, a PhD candidate at the German Research Center for Environmental Health in Neuherberg, Germany, and her colleagues. Their findings clarify an association between impaired copper metabolism, which defines Wilson disease, and liver steatosis, a common finding in affected patients.
“Indeed, Wilson disease often may be misdiagnosed as nonalcoholic fatty liver disease (NAFLD),” the investigators wrote in Cellular and Molecular Gastroenterology and Hepatology. They noted that previous reports showed similar mitochondrial alterations in the livers of patients with NAFLD and those with Wilson disease. Furthermore, in a case report of two twins with Wilson disease, the twin with bulimia nervosa developed severe liver disease, whereas the other twin, who was undernourished, had mild liver disease. Considering these observations and other supportive evidence, the investigators tested this apparent relationship between a high-fat diet and liver damage in Wilson disease.
“The rationale of this study was that both enriched copper and fatty acids cause bioenergetic defects and therefore synergistically and detrimentally may coincide on hepatic mitochondria, which was found to be dramatically the case,” the investigators wrote.
The study involved homozygous Atp7b–/– rats, which mirror Wilson disease, and heterozygous Atp7b+/– rats, which served as control subjects because they lack copper accumulation. The high-calorie diet contained high fat and sugar levels to mirror “the eating habits in Western society, causing the ‘American-lifestyle-induced-obesity syndrome.’ ”
Within several weeks of starting the high-calorie diet, both control and Wilson disease rats showed higher liver triglyceride levels and visceral fat mass compared with rats on the normal diet, with liver histology also showing macrosteatosis and increased NAFLD Activity Score (NAS). Control rats maintained similar body and liver weights regardless of diet; in contrast, Wilson disease rats on the high-calorie diet showed increased liver weight, compared with Wilson disease rats on the normal diet. In addition, Wilson disease rats fed the high-calorie diet had clinical liver injury, supported by elevated aspartate aminotransferase (AST) levels and gross hepatic damage. Under the microscope, histology revealed widespread necrosis, apoptosis, inflammation, and fibrosis; findings were sufficient to constitute nonalcoholic steatohepatitis in all Wilson disease rats fed the high-calorie diet, compared with just one-third of the control rats receiving high calories. Additional testing showed that Wilson disease rats fed the high-calorie diet had disease onset 20 days sooner than did Wilson disease rats fed the normal diet.
“This is a remarkable disease acceleration,” the investigators noted, highlighting the median survival of 106 days in Wilson disease rats fed a normal diet.
Copper testing showed that Wilson disease rats fed the high-calorie diet had high serum levels of non–ceruloplasmin-bound copper, which is a sign of overt liver damage; based on histologic findings, the copper likely came from destroyed hepatocytes. Regardless of diet type, Wilson disease rats developed high levels of copper within the liver, suggesting comparable copper consumption via water sources. Regardless of genotype, the high-calorie diet led to higher mitochondrial copper levels than those of the normal diet, but Wilson disease rats showed the highest levels of copper sequestration in mitochondria, to an extreme degree.
“Importantly,” the investigators wrote, “such increased mitochondrial copper significantly correlated with a higher NAS and a progressive Histologic Activity Index score.”
Closer inspection showed that the mitochondria of Wilson disease rats were abnormal regardless of diet, but those fed the high-calorie diet had “a most severe mitochondrial phenotype,” including detached membranes and ballooned cristae.
“These structural impairments were paralleled by remarkable mitochondrial functional deficits,” the investigators reported, referring to a significant decrease in adenosine triphosphate production and an increase in mitochondrial H2O2. In response to these mitochondrial abnormalities, cholesterol-related enzymes quadrupled, most prominently for biliary excretion. The investigators summed up these hepatic events as a “toxic triad of adenosine triphosphate depletion, increased reactive oxygen species, and increased bile salts [that led] to an earlier onset of the disease and to enhanced disease progression.”
To complete the set of experiments, rats were given the copper chelator methanobactin. This treatment effectively mitigated structural and functional abnormalities in mitochondria, which drove serum levels of AST, copper, and bile salts toward normalcy. Although treatment halted overt liver damage, histology revealed that resolution was incomplete.
“We conclude that lipid accumulation in copper-burdened hepatocytes may represent a ‘second-hit’ in Wilson disease, inducing liver damage, and suggest that further research should establish whether dietary counseling of Wilson disease patients may be of therapeutic benefit,” the investigators concluded.
The study was funded by Deutsche Forschungsgemeinschaft and the WiFoMed Society. The investigators reported no conflicts of interest.
SOURCE: Einer et al. Cell Mol Gastroenterol Hepatol. 2019 Jan 11. doi: 10.1016/j.jcmgh.2018.12.005.
A high-calorie diet may cause earlier onset of more severe Wilson disease, according to a rodent study.
If translatable to humans, the results could explain “striking phenotype-genotype discrepancies” between patients with Wilson disease, and may give reason to monitor nutrition more closely, particularly dietary levels of fat and sugar, reported lead author Claudia Einer, a PhD candidate at the German Research Center for Environmental Health in Neuherberg, Germany, and her colleagues. Their findings clarify an association between impaired copper metabolism, which defines Wilson disease, and liver steatosis, a common finding in affected patients.
“Indeed, Wilson disease often may be misdiagnosed as nonalcoholic fatty liver disease (NAFLD),” the investigators wrote in Cellular and Molecular Gastroenterology and Hepatology. They noted that previous reports showed similar mitochondrial alterations in the livers of patients with NAFLD and those with Wilson disease. Furthermore, in a case report of two twins with Wilson disease, the twin with bulimia nervosa developed severe liver disease, whereas the other twin, who was undernourished, had mild liver disease. Considering these observations and other supportive evidence, the investigators tested this apparent relationship between a high-fat diet and liver damage in Wilson disease.
“The rationale of this study was that both enriched copper and fatty acids cause bioenergetic defects and therefore synergistically and detrimentally may coincide on hepatic mitochondria, which was found to be dramatically the case,” the investigators wrote.
The study involved homozygous Atp7b–/– rats, which mirror Wilson disease, and heterozygous Atp7b+/– rats, which served as control subjects because they lack copper accumulation. The high-calorie diet contained high fat and sugar levels to mirror “the eating habits in Western society, causing the ‘American-lifestyle-induced-obesity syndrome.’ ”
Within several weeks of starting the high-calorie diet, both control and Wilson disease rats showed higher liver triglyceride levels and visceral fat mass compared with rats on the normal diet, with liver histology also showing macrosteatosis and increased NAFLD Activity Score (NAS). Control rats maintained similar body and liver weights regardless of diet; in contrast, Wilson disease rats on the high-calorie diet showed increased liver weight, compared with Wilson disease rats on the normal diet. In addition, Wilson disease rats fed the high-calorie diet had clinical liver injury, supported by elevated aspartate aminotransferase (AST) levels and gross hepatic damage. Under the microscope, histology revealed widespread necrosis, apoptosis, inflammation, and fibrosis; findings were sufficient to constitute nonalcoholic steatohepatitis in all Wilson disease rats fed the high-calorie diet, compared with just one-third of the control rats receiving high calories. Additional testing showed that Wilson disease rats fed the high-calorie diet had disease onset 20 days sooner than did Wilson disease rats fed the normal diet.
“This is a remarkable disease acceleration,” the investigators noted, highlighting the median survival of 106 days in Wilson disease rats fed a normal diet.
Copper testing showed that Wilson disease rats fed the high-calorie diet had high serum levels of non–ceruloplasmin-bound copper, which is a sign of overt liver damage; based on histologic findings, the copper likely came from destroyed hepatocytes. Regardless of diet type, Wilson disease rats developed high levels of copper within the liver, suggesting comparable copper consumption via water sources. Regardless of genotype, the high-calorie diet led to higher mitochondrial copper levels than those of the normal diet, but Wilson disease rats showed the highest levels of copper sequestration in mitochondria, to an extreme degree.
“Importantly,” the investigators wrote, “such increased mitochondrial copper significantly correlated with a higher NAS and a progressive Histologic Activity Index score.”
Closer inspection showed that the mitochondria of Wilson disease rats were abnormal regardless of diet, but those fed the high-calorie diet had “a most severe mitochondrial phenotype,” including detached membranes and ballooned cristae.
“These structural impairments were paralleled by remarkable mitochondrial functional deficits,” the investigators reported, referring to a significant decrease in adenosine triphosphate production and an increase in mitochondrial H2O2. In response to these mitochondrial abnormalities, cholesterol-related enzymes quadrupled, most prominently for biliary excretion. The investigators summed up these hepatic events as a “toxic triad of adenosine triphosphate depletion, increased reactive oxygen species, and increased bile salts [that led] to an earlier onset of the disease and to enhanced disease progression.”
To complete the set of experiments, rats were given the copper chelator methanobactin. This treatment effectively mitigated structural and functional abnormalities in mitochondria, which drove serum levels of AST, copper, and bile salts toward normalcy. Although treatment halted overt liver damage, histology revealed that resolution was incomplete.
“We conclude that lipid accumulation in copper-burdened hepatocytes may represent a ‘second-hit’ in Wilson disease, inducing liver damage, and suggest that further research should establish whether dietary counseling of Wilson disease patients may be of therapeutic benefit,” the investigators concluded.
The study was funded by Deutsche Forschungsgemeinschaft and the WiFoMed Society. The investigators reported no conflicts of interest.
SOURCE: Einer et al. Cell Mol Gastroenterol Hepatol. 2019 Jan 11. doi: 10.1016/j.jcmgh.2018.12.005.
FROM CELLULAR AND MOLECULAR GASTROENTEROLOGY AND HEPATOLOGY