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Study supports multigene germline testing in colorectal cancer
About 10% of patients with colorectal cancer had at least one germline mutation known to increase the risk of cancer, according to results from a large single-center retrospective cohort study published in Journal of Clinical Oncology.
The findings “raise the provocative question of whether all patients with colorectal cancer (CRC) should undergo multigene germline testing for inherited cancer susceptibility,” especially because the results have implications for both patients and family members, said Matthew B. Yurgelun, MD, of Dana-Farber Cancer Institute in Boston, and his associates.
Hereditary factors long have been known to play a role in CRC, but clinicians have routinely limited genetic testing to phenotypically high-risk patients and to specific syndromes. For example, all patients with CRC are now typically tested for microsatellite instability (MSI) and mismatch repair deficiency (MRD) to identify the 2%-4% with Lynch syndrome. Likewise, patients with colorectal polyposis are routinely tested for familial adenomatous polyposis (FAP) and MUTYH-associated polyposis (MAP), the researchers noted.
To explore the prevalence of germline mutations among unselected patients with CRC, they studied 1,058 consecutive cases treated at Dana-Farber Institute between December 2008 and March 2014. The researchers tested blood samples for 25 genes linked to inherited cancer risk, reviewed medical records, and sifted through questionnaires to assess personal and family cancer histories, tumor locations, and the results of tests for MSI, MMR, and KRAS/NRAS and BRAF mutations. They also categorized each gene as high or moderate penetrance based on published estimates of the lifetime risk of cancer associated with pathogenic mutations of that gene.
Pathogenic germline mutations were found in 105 patients (9.9%; 95% confidence interval, 8.2%-11.9%). Lynch syndrome was the most common single mutational genotype, affecting 33 patients (3.1%). Twenty-eight of 29 (97%) MSI/MMR tests were abnormal, confirming the reliability of MSI/MMR testing for diagnosing Lynch syndrome, the researchers noted
Among 74 (7%) patients with mutations besides Lynch syndrome, 23 (2%) patients had mutations in high-penetrance genes, including 11 (1%) with BRCA1/2 mutations, five with APC, three with biallelic MUTYH, two with PALB2, one with CDKN2A, and one with TP53.
Notably, 15 of these patients had no clinical history that would have suggested an underlying mutation, the researchers noted. Another 38 (3.6%) patients had moderate-penetrance CRC risk gene mutations, including 19 patients with monoallelic MUTYH, 17 patients with APC*I1307K, and two patients with CHEK2 mutations, they said.
Additional analysis failed to link pathogenic mutations to age at CRC diagnosis, family history of CRC, or personal history of other cancers. Thus, clinicians should not skip comprehensive germline testing in CRC just because patients lack these characteristics, the researchers said. Indeed, the findings “clearly illustrate that genetic factors that underlie CRC extend beyond [the] well-recognized familial CRC syndromes, are markedly more common than previously appreciated, frequently occur in patients with CRC who lack classic high-risk features, and are found predominantly in genes for which specialized risk-reducing interventions are recommended,” they emphasized.
The National Cancer Institute and Myriad Genetics supported the work. Dr. Yurgelun disclosed research funding from Myriad Genetics.
About 10% of patients with colorectal cancer had at least one germline mutation known to increase the risk of cancer, according to results from a large single-center retrospective cohort study published in Journal of Clinical Oncology.
The findings “raise the provocative question of whether all patients with colorectal cancer (CRC) should undergo multigene germline testing for inherited cancer susceptibility,” especially because the results have implications for both patients and family members, said Matthew B. Yurgelun, MD, of Dana-Farber Cancer Institute in Boston, and his associates.
Hereditary factors long have been known to play a role in CRC, but clinicians have routinely limited genetic testing to phenotypically high-risk patients and to specific syndromes. For example, all patients with CRC are now typically tested for microsatellite instability (MSI) and mismatch repair deficiency (MRD) to identify the 2%-4% with Lynch syndrome. Likewise, patients with colorectal polyposis are routinely tested for familial adenomatous polyposis (FAP) and MUTYH-associated polyposis (MAP), the researchers noted.
To explore the prevalence of germline mutations among unselected patients with CRC, they studied 1,058 consecutive cases treated at Dana-Farber Institute between December 2008 and March 2014. The researchers tested blood samples for 25 genes linked to inherited cancer risk, reviewed medical records, and sifted through questionnaires to assess personal and family cancer histories, tumor locations, and the results of tests for MSI, MMR, and KRAS/NRAS and BRAF mutations. They also categorized each gene as high or moderate penetrance based on published estimates of the lifetime risk of cancer associated with pathogenic mutations of that gene.
Pathogenic germline mutations were found in 105 patients (9.9%; 95% confidence interval, 8.2%-11.9%). Lynch syndrome was the most common single mutational genotype, affecting 33 patients (3.1%). Twenty-eight of 29 (97%) MSI/MMR tests were abnormal, confirming the reliability of MSI/MMR testing for diagnosing Lynch syndrome, the researchers noted
Among 74 (7%) patients with mutations besides Lynch syndrome, 23 (2%) patients had mutations in high-penetrance genes, including 11 (1%) with BRCA1/2 mutations, five with APC, three with biallelic MUTYH, two with PALB2, one with CDKN2A, and one with TP53.
Notably, 15 of these patients had no clinical history that would have suggested an underlying mutation, the researchers noted. Another 38 (3.6%) patients had moderate-penetrance CRC risk gene mutations, including 19 patients with monoallelic MUTYH, 17 patients with APC*I1307K, and two patients with CHEK2 mutations, they said.
Additional analysis failed to link pathogenic mutations to age at CRC diagnosis, family history of CRC, or personal history of other cancers. Thus, clinicians should not skip comprehensive germline testing in CRC just because patients lack these characteristics, the researchers said. Indeed, the findings “clearly illustrate that genetic factors that underlie CRC extend beyond [the] well-recognized familial CRC syndromes, are markedly more common than previously appreciated, frequently occur in patients with CRC who lack classic high-risk features, and are found predominantly in genes for which specialized risk-reducing interventions are recommended,” they emphasized.
The National Cancer Institute and Myriad Genetics supported the work. Dr. Yurgelun disclosed research funding from Myriad Genetics.
About 10% of patients with colorectal cancer had at least one germline mutation known to increase the risk of cancer, according to results from a large single-center retrospective cohort study published in Journal of Clinical Oncology.
The findings “raise the provocative question of whether all patients with colorectal cancer (CRC) should undergo multigene germline testing for inherited cancer susceptibility,” especially because the results have implications for both patients and family members, said Matthew B. Yurgelun, MD, of Dana-Farber Cancer Institute in Boston, and his associates.
Hereditary factors long have been known to play a role in CRC, but clinicians have routinely limited genetic testing to phenotypically high-risk patients and to specific syndromes. For example, all patients with CRC are now typically tested for microsatellite instability (MSI) and mismatch repair deficiency (MRD) to identify the 2%-4% with Lynch syndrome. Likewise, patients with colorectal polyposis are routinely tested for familial adenomatous polyposis (FAP) and MUTYH-associated polyposis (MAP), the researchers noted.
To explore the prevalence of germline mutations among unselected patients with CRC, they studied 1,058 consecutive cases treated at Dana-Farber Institute between December 2008 and March 2014. The researchers tested blood samples for 25 genes linked to inherited cancer risk, reviewed medical records, and sifted through questionnaires to assess personal and family cancer histories, tumor locations, and the results of tests for MSI, MMR, and KRAS/NRAS and BRAF mutations. They also categorized each gene as high or moderate penetrance based on published estimates of the lifetime risk of cancer associated with pathogenic mutations of that gene.
Pathogenic germline mutations were found in 105 patients (9.9%; 95% confidence interval, 8.2%-11.9%). Lynch syndrome was the most common single mutational genotype, affecting 33 patients (3.1%). Twenty-eight of 29 (97%) MSI/MMR tests were abnormal, confirming the reliability of MSI/MMR testing for diagnosing Lynch syndrome, the researchers noted
Among 74 (7%) patients with mutations besides Lynch syndrome, 23 (2%) patients had mutations in high-penetrance genes, including 11 (1%) with BRCA1/2 mutations, five with APC, three with biallelic MUTYH, two with PALB2, one with CDKN2A, and one with TP53.
Notably, 15 of these patients had no clinical history that would have suggested an underlying mutation, the researchers noted. Another 38 (3.6%) patients had moderate-penetrance CRC risk gene mutations, including 19 patients with monoallelic MUTYH, 17 patients with APC*I1307K, and two patients with CHEK2 mutations, they said.
Additional analysis failed to link pathogenic mutations to age at CRC diagnosis, family history of CRC, or personal history of other cancers. Thus, clinicians should not skip comprehensive germline testing in CRC just because patients lack these characteristics, the researchers said. Indeed, the findings “clearly illustrate that genetic factors that underlie CRC extend beyond [the] well-recognized familial CRC syndromes, are markedly more common than previously appreciated, frequently occur in patients with CRC who lack classic high-risk features, and are found predominantly in genes for which specialized risk-reducing interventions are recommended,” they emphasized.
The National Cancer Institute and Myriad Genetics supported the work. Dr. Yurgelun disclosed research funding from Myriad Genetics.
FROM THE JOURNAL OF CLINICAL ONCOLOGY
Key clinical point: Consider comprehensive germline testing in all patients with colorectal cancer.
Major finding: A total of 9.9% of patients had pathogenic germline mutations.
Data source: A single-center retrospective cohort study of 1,058 unselected patients with colorectal cancer.
Disclosures: The National Cancer Institute and Myriad Genetics supported the work. Dr. Yurgelun disclosed research funding from Myriad Genetics.
AGA Clinical Practice Update: Clostridium difficile in IBD
Inflammatory bowel disease (IBD) increases the risk and severity of Clostridium difficile infection (CDI) while CDI tends to complicate and worsen the clinical course of IBD, experts note in a clinical practice update.
Thus, it is crucial that clinicians pursue stool testing for toxigenic C. difficile infection whenever a patient with IBD presents with a colitis flare, regardless of the recent antibiotic history, wrote Sahil Khanna, MBBS, of the Mayo Clinic, Rochester, Minn., and his associates (Clin Gastroenterol Hepatol. 2016 Feb. doi: 10.1016/j.cgh.2016.10.024). Clinicians should also test for recurrent CDI if symptoms of colitis persist or return after antibiotic therapy for CDI, they emphasized.
CDI can present atypically in IBD. Underlying colitis leads to colonic dysbiosis and loss of resistance to bacterial colonization, which permits CDI to develop even when patients have not recently received antibiotics. Patients with IBD also tend to develop CDI starting at younger ages, more often acquire it from community settings, and may lack the typical colonoscopic features of CDI. Simple colonization of C. difficile without infection also is more common in patients with IBD than in those without IBD, the experts note.
The authors contradict guidelines from both the American College of Gastroenterology and Infectious Diseases Society of America by recommending consideration of vancomycin over metronidazole for treatment of CDI. Not only are C. difficile treatment failures with metronidazole rising, but vancomycin was more effective than was metronidazole in a recent post hoc analysis (Clin Infect Dis. 2014;59[3]:345-54) of two large multicenter phase III trials. Furthermore, another phase III trial (N Engl J Med. 2011;364:422-31) found vancomycin noninferior to fidaxomicin for CDI.
The experts recommend “strong consideration” of hospitalization if patients with IBD and CDI present with profuse diarrhea, severe abdominal pain, a markedly increased peripheral blood leukocyte count, or other signs and symptoms of sepsis. Aggressive monitoring and treatment are especially important because it can be difficult to distinguish an IBD flare, which merits immunosuppression, from superimposed CDI, which might exacerbate the underlying infection, they noted. Few studies are available to help guide the decision about when to intensify steroids and other immunosuppressives in IBD patients with acute CDI. Thus, the experts suggest delaying this step until after starting therapy for CDI, but note that this decision should be individualized pending more robust data.
The authors emphasized the potential role of fecal microbiota transplantation (FMT), which has been shown to be very effective in both immunocompetent patients with CDI and those who are immunosuppressed, including because of IBD therapies. They recommend considering referral for FMT as early as the first recurrence of CDI in patients with IBD, particularly because of the strong safety and efficacy profile of FMT, the risk of complications from CDI in IBD patients, and scarce data on antibiotic therapy for recurrent CDI in the setting of IBD.
Dr. Khanna disclosed consulting relationships with Rebiotix. and Summit Pharmaceuticals. Senior author Ciaran P. Kelly, MD, disclosed serving as a consultant to Merck, Seres Therapeutics, Summit Pharmaceuticals, and Takeda Pharmaceuticals. The third author, Andrea Shin, MD, had no relevant disclosures.
Inflammatory bowel disease (IBD) increases the risk and severity of Clostridium difficile infection (CDI) while CDI tends to complicate and worsen the clinical course of IBD, experts note in a clinical practice update.
Thus, it is crucial that clinicians pursue stool testing for toxigenic C. difficile infection whenever a patient with IBD presents with a colitis flare, regardless of the recent antibiotic history, wrote Sahil Khanna, MBBS, of the Mayo Clinic, Rochester, Minn., and his associates (Clin Gastroenterol Hepatol. 2016 Feb. doi: 10.1016/j.cgh.2016.10.024). Clinicians should also test for recurrent CDI if symptoms of colitis persist or return after antibiotic therapy for CDI, they emphasized.
CDI can present atypically in IBD. Underlying colitis leads to colonic dysbiosis and loss of resistance to bacterial colonization, which permits CDI to develop even when patients have not recently received antibiotics. Patients with IBD also tend to develop CDI starting at younger ages, more often acquire it from community settings, and may lack the typical colonoscopic features of CDI. Simple colonization of C. difficile without infection also is more common in patients with IBD than in those without IBD, the experts note.
The authors contradict guidelines from both the American College of Gastroenterology and Infectious Diseases Society of America by recommending consideration of vancomycin over metronidazole for treatment of CDI. Not only are C. difficile treatment failures with metronidazole rising, but vancomycin was more effective than was metronidazole in a recent post hoc analysis (Clin Infect Dis. 2014;59[3]:345-54) of two large multicenter phase III trials. Furthermore, another phase III trial (N Engl J Med. 2011;364:422-31) found vancomycin noninferior to fidaxomicin for CDI.
The experts recommend “strong consideration” of hospitalization if patients with IBD and CDI present with profuse diarrhea, severe abdominal pain, a markedly increased peripheral blood leukocyte count, or other signs and symptoms of sepsis. Aggressive monitoring and treatment are especially important because it can be difficult to distinguish an IBD flare, which merits immunosuppression, from superimposed CDI, which might exacerbate the underlying infection, they noted. Few studies are available to help guide the decision about when to intensify steroids and other immunosuppressives in IBD patients with acute CDI. Thus, the experts suggest delaying this step until after starting therapy for CDI, but note that this decision should be individualized pending more robust data.
The authors emphasized the potential role of fecal microbiota transplantation (FMT), which has been shown to be very effective in both immunocompetent patients with CDI and those who are immunosuppressed, including because of IBD therapies. They recommend considering referral for FMT as early as the first recurrence of CDI in patients with IBD, particularly because of the strong safety and efficacy profile of FMT, the risk of complications from CDI in IBD patients, and scarce data on antibiotic therapy for recurrent CDI in the setting of IBD.
Dr. Khanna disclosed consulting relationships with Rebiotix. and Summit Pharmaceuticals. Senior author Ciaran P. Kelly, MD, disclosed serving as a consultant to Merck, Seres Therapeutics, Summit Pharmaceuticals, and Takeda Pharmaceuticals. The third author, Andrea Shin, MD, had no relevant disclosures.
Inflammatory bowel disease (IBD) increases the risk and severity of Clostridium difficile infection (CDI) while CDI tends to complicate and worsen the clinical course of IBD, experts note in a clinical practice update.
Thus, it is crucial that clinicians pursue stool testing for toxigenic C. difficile infection whenever a patient with IBD presents with a colitis flare, regardless of the recent antibiotic history, wrote Sahil Khanna, MBBS, of the Mayo Clinic, Rochester, Minn., and his associates (Clin Gastroenterol Hepatol. 2016 Feb. doi: 10.1016/j.cgh.2016.10.024). Clinicians should also test for recurrent CDI if symptoms of colitis persist or return after antibiotic therapy for CDI, they emphasized.
CDI can present atypically in IBD. Underlying colitis leads to colonic dysbiosis and loss of resistance to bacterial colonization, which permits CDI to develop even when patients have not recently received antibiotics. Patients with IBD also tend to develop CDI starting at younger ages, more often acquire it from community settings, and may lack the typical colonoscopic features of CDI. Simple colonization of C. difficile without infection also is more common in patients with IBD than in those without IBD, the experts note.
The authors contradict guidelines from both the American College of Gastroenterology and Infectious Diseases Society of America by recommending consideration of vancomycin over metronidazole for treatment of CDI. Not only are C. difficile treatment failures with metronidazole rising, but vancomycin was more effective than was metronidazole in a recent post hoc analysis (Clin Infect Dis. 2014;59[3]:345-54) of two large multicenter phase III trials. Furthermore, another phase III trial (N Engl J Med. 2011;364:422-31) found vancomycin noninferior to fidaxomicin for CDI.
The experts recommend “strong consideration” of hospitalization if patients with IBD and CDI present with profuse diarrhea, severe abdominal pain, a markedly increased peripheral blood leukocyte count, or other signs and symptoms of sepsis. Aggressive monitoring and treatment are especially important because it can be difficult to distinguish an IBD flare, which merits immunosuppression, from superimposed CDI, which might exacerbate the underlying infection, they noted. Few studies are available to help guide the decision about when to intensify steroids and other immunosuppressives in IBD patients with acute CDI. Thus, the experts suggest delaying this step until after starting therapy for CDI, but note that this decision should be individualized pending more robust data.
The authors emphasized the potential role of fecal microbiota transplantation (FMT), which has been shown to be very effective in both immunocompetent patients with CDI and those who are immunosuppressed, including because of IBD therapies. They recommend considering referral for FMT as early as the first recurrence of CDI in patients with IBD, particularly because of the strong safety and efficacy profile of FMT, the risk of complications from CDI in IBD patients, and scarce data on antibiotic therapy for recurrent CDI in the setting of IBD.
Dr. Khanna disclosed consulting relationships with Rebiotix. and Summit Pharmaceuticals. Senior author Ciaran P. Kelly, MD, disclosed serving as a consultant to Merck, Seres Therapeutics, Summit Pharmaceuticals, and Takeda Pharmaceuticals. The third author, Andrea Shin, MD, had no relevant disclosures.
FROM CLINICAL GASTROENTEROLOGY AND HEPATOLOGY
AGA Guideline: Acute liver failure
Physicians should avoid routinely testing patients with acute liver failure for Wilson’s disease unless there is “high clinical suspicion” for the disorder, according to a new guideline from the AGA Institute.
Wilson’s disease so rarely accompanies acute liver failure that a positive test will have low predictive value, Steven L. Flamm, MD, of Northwestern University, Chicago, and his associates wrote in the February issue of Gastroenterology (doi: 10.1053/j.gastro.2016.12.026). Diagnosing Wilson’s disease also is unlikely to change treatment “because liver transplantation is the ultimate outcome,” they emphasize.
The guideline grades seven recommendations as “conditional” based on “very-low” quality evidence. These include the statement on Wilson’s disease testing, plus suggestions to test and treat patients with ALF for herpes simplex virus (HSV) infection, to test pregnant patients for hepatitis E virus infection, and to perform autoantibody testing for autoimmune hepatitis. Case series report only about a 1% prevalence of HSV infection in ALF, and there is little information on diagnostic accuracy or treatment in this setting, the guidelines state. Although acyclovir is relatively safe and inexpensive, data on efficacy is limited to “a suggestion on a case-report level that patients with acute hepatitis secondary to HSV do better with treatment than without.”
The guideline also conditionally recommends against routine testing for varicella zoster virus infection and routine liver biopsy in ALF. The authors note only about 10 case reports of varicella zoster–associated ALF and few data on how liver biopsy results in ALF alter treatment plan, outcome, or the choice to seek liver transplantation. The experts do recommend prognostic scoring with Model for End-Stage Liver Disease, which pooled analyses have found to be more sensitive than King’s College Criteria, they wrote.
The guideline conditionally recommends against empirically treating elevated intracranial pressure in ALF, on the basis of five randomized trials that found no overall mortality benefit of moderate hypothermia, hypertonic saline, L-ornithine, L-aspartate, intravenous mannitol, or hyperventilation.
The experts cite insufficient evidence to recommend using N-acetyl cysteine in patients whose ALF is not associated with acetaminophen exposure. Likewise, they find inadequate data to make any recommendation about using extracorporeal liver support systems outside of the setting of clinical trials. Although such systems can “potentially” buy time for patients to either spontaneously recover without transplant or survive longer on the transplantation list, three systematic reviews found “no clear effect on mortality,” and randomized trials reported either null results or a “marginally significant survival benefit” in the face of steep costs and potentially significant toxicities, the authors emphasize.
None of the experts had relevant financial disclosures.
Physicians should avoid routinely testing patients with acute liver failure for Wilson’s disease unless there is “high clinical suspicion” for the disorder, according to a new guideline from the AGA Institute.
Wilson’s disease so rarely accompanies acute liver failure that a positive test will have low predictive value, Steven L. Flamm, MD, of Northwestern University, Chicago, and his associates wrote in the February issue of Gastroenterology (doi: 10.1053/j.gastro.2016.12.026). Diagnosing Wilson’s disease also is unlikely to change treatment “because liver transplantation is the ultimate outcome,” they emphasize.
The guideline grades seven recommendations as “conditional” based on “very-low” quality evidence. These include the statement on Wilson’s disease testing, plus suggestions to test and treat patients with ALF for herpes simplex virus (HSV) infection, to test pregnant patients for hepatitis E virus infection, and to perform autoantibody testing for autoimmune hepatitis. Case series report only about a 1% prevalence of HSV infection in ALF, and there is little information on diagnostic accuracy or treatment in this setting, the guidelines state. Although acyclovir is relatively safe and inexpensive, data on efficacy is limited to “a suggestion on a case-report level that patients with acute hepatitis secondary to HSV do better with treatment than without.”
The guideline also conditionally recommends against routine testing for varicella zoster virus infection and routine liver biopsy in ALF. The authors note only about 10 case reports of varicella zoster–associated ALF and few data on how liver biopsy results in ALF alter treatment plan, outcome, or the choice to seek liver transplantation. The experts do recommend prognostic scoring with Model for End-Stage Liver Disease, which pooled analyses have found to be more sensitive than King’s College Criteria, they wrote.
The guideline conditionally recommends against empirically treating elevated intracranial pressure in ALF, on the basis of five randomized trials that found no overall mortality benefit of moderate hypothermia, hypertonic saline, L-ornithine, L-aspartate, intravenous mannitol, or hyperventilation.
The experts cite insufficient evidence to recommend using N-acetyl cysteine in patients whose ALF is not associated with acetaminophen exposure. Likewise, they find inadequate data to make any recommendation about using extracorporeal liver support systems outside of the setting of clinical trials. Although such systems can “potentially” buy time for patients to either spontaneously recover without transplant or survive longer on the transplantation list, three systematic reviews found “no clear effect on mortality,” and randomized trials reported either null results or a “marginally significant survival benefit” in the face of steep costs and potentially significant toxicities, the authors emphasize.
None of the experts had relevant financial disclosures.
Physicians should avoid routinely testing patients with acute liver failure for Wilson’s disease unless there is “high clinical suspicion” for the disorder, according to a new guideline from the AGA Institute.
Wilson’s disease so rarely accompanies acute liver failure that a positive test will have low predictive value, Steven L. Flamm, MD, of Northwestern University, Chicago, and his associates wrote in the February issue of Gastroenterology (doi: 10.1053/j.gastro.2016.12.026). Diagnosing Wilson’s disease also is unlikely to change treatment “because liver transplantation is the ultimate outcome,” they emphasize.
The guideline grades seven recommendations as “conditional” based on “very-low” quality evidence. These include the statement on Wilson’s disease testing, plus suggestions to test and treat patients with ALF for herpes simplex virus (HSV) infection, to test pregnant patients for hepatitis E virus infection, and to perform autoantibody testing for autoimmune hepatitis. Case series report only about a 1% prevalence of HSV infection in ALF, and there is little information on diagnostic accuracy or treatment in this setting, the guidelines state. Although acyclovir is relatively safe and inexpensive, data on efficacy is limited to “a suggestion on a case-report level that patients with acute hepatitis secondary to HSV do better with treatment than without.”
The guideline also conditionally recommends against routine testing for varicella zoster virus infection and routine liver biopsy in ALF. The authors note only about 10 case reports of varicella zoster–associated ALF and few data on how liver biopsy results in ALF alter treatment plan, outcome, or the choice to seek liver transplantation. The experts do recommend prognostic scoring with Model for End-Stage Liver Disease, which pooled analyses have found to be more sensitive than King’s College Criteria, they wrote.
The guideline conditionally recommends against empirically treating elevated intracranial pressure in ALF, on the basis of five randomized trials that found no overall mortality benefit of moderate hypothermia, hypertonic saline, L-ornithine, L-aspartate, intravenous mannitol, or hyperventilation.
The experts cite insufficient evidence to recommend using N-acetyl cysteine in patients whose ALF is not associated with acetaminophen exposure. Likewise, they find inadequate data to make any recommendation about using extracorporeal liver support systems outside of the setting of clinical trials. Although such systems can “potentially” buy time for patients to either spontaneously recover without transplant or survive longer on the transplantation list, three systematic reviews found “no clear effect on mortality,” and randomized trials reported either null results or a “marginally significant survival benefit” in the face of steep costs and potentially significant toxicities, the authors emphasize.
None of the experts had relevant financial disclosures.
FROM GASTROENTEROLOGY
BOS beat placebo for eosinophilic esophagitis
Budesonide oral suspension (BOS) was safe and significantly outperformed placebo on validated measures of eosinophilic esophagitis, according to a first-in-kind, multicenter, randomized, double-blind, phase II trial presented in the March issue of Gastroenterology (doi: 10.1053/j.gastro.2016.11.021).
The novel topical corticosteroid formulation yielded a significant histologic response and was associated with 3 fewer days of dysphagia over 2 weeks compared with placebo, reported Evan S. Dellon, MD, MPH, of University of North Carolina, Chapel Hill, and his associates. “There were no unexpected safety signals, and compliance with medication was high, suggesting that this formulation can be reliably used,” they wrote. Their findings earned BOS (SHP621) an FDA Breakthrough Therapy Designation in June 2016. Although corticosteroids are first-line therapy for eosinophilic esophagitis, symptom response in other studies has been mixed, and the Food and Drug Administration had approved neither fluticasone nor budesonide for this disease, the researchers noted. They formulated BOS to adhere better to the esophageal mucosa in order to enhance esophageal delivery while decreasing unwanted pulmonary deposition.
For the study, they randomly assigned 93 patients aged 11-40 years with eosinophilic esophagitis to receive either placebo or 2 mg BOS twice daily. By week 12, Dysphagia Symptom Questionnaire scores had fallen by 14.3 points with BOS group and by 7.5 points with placebo (P = .001). Endoscopic severity scores dropped by 3.8 points with BOS and rose by 0.4 points with placebo (P less than .0001). Rates of histologic response were 39% and 3%, respectively (P less than .0001). Nonresponders averaged 10 kg more body weight than responders, and had been diagnosed about 21 months earlier (average disease duration, 46 months and 25 months, respectively).
Rates of reported adverse effects were similar with BOS (47%) and placebo (50%). Individual rates of nasopharyngitis, upper respiratory infections, and oropharyngeal pain also were comparable between groups, but one patient stopped BOS after developing dyspnea, nausea, and vomiting that were considered treatment related. Esophageal candidiasis developed in two BOS recipients – a rate similar rate to that in a prior study of BOS (Clin Gastroenterol Hepatol. 2015 Jan 13. doi: 10.1016/j.cgh.2014.05.02), and a lower percentage than in other studies of topical steroids for eosinophilic esophagitis, according to the researchers. Morning cortisol levels were similar between groups, and there were no adverse laboratory effects, they added.
Patients in this trial had severe symptoms and histology and were highly compliant with treatment. They filled out at least 70% of their symptom diary, had at least 15 eosinophils per high-power frame from at least two esophageal levels on screening endoscopy, and reported at least 4 days of dysphagia during the second half of a 4-week, blinded placebo run-in period. Researchers should consider using these strict inclusion criteria in future trials of eosinophilic esophagitis, especially because previous studies have failed to show a treatment benefit for topical steroid therapy, the investigators noted.
Meritage Pharma, which is now a part of the Shire group, makes budesonide oral suspension and sponsored the study. Dr. Dellon disclosed ties to Meritage, Receptos, Regeneron, Aptalis, Banner Life Sciences, Novartis, and Roche. All five coinvestigators disclosed ties to industry, including Meritage, Shire, Receptos, Regeneron, and Biogen Idec.
Budesonide oral suspension (BOS) was safe and significantly outperformed placebo on validated measures of eosinophilic esophagitis, according to a first-in-kind, multicenter, randomized, double-blind, phase II trial presented in the March issue of Gastroenterology (doi: 10.1053/j.gastro.2016.11.021).
The novel topical corticosteroid formulation yielded a significant histologic response and was associated with 3 fewer days of dysphagia over 2 weeks compared with placebo, reported Evan S. Dellon, MD, MPH, of University of North Carolina, Chapel Hill, and his associates. “There were no unexpected safety signals, and compliance with medication was high, suggesting that this formulation can be reliably used,” they wrote. Their findings earned BOS (SHP621) an FDA Breakthrough Therapy Designation in June 2016. Although corticosteroids are first-line therapy for eosinophilic esophagitis, symptom response in other studies has been mixed, and the Food and Drug Administration had approved neither fluticasone nor budesonide for this disease, the researchers noted. They formulated BOS to adhere better to the esophageal mucosa in order to enhance esophageal delivery while decreasing unwanted pulmonary deposition.
For the study, they randomly assigned 93 patients aged 11-40 years with eosinophilic esophagitis to receive either placebo or 2 mg BOS twice daily. By week 12, Dysphagia Symptom Questionnaire scores had fallen by 14.3 points with BOS group and by 7.5 points with placebo (P = .001). Endoscopic severity scores dropped by 3.8 points with BOS and rose by 0.4 points with placebo (P less than .0001). Rates of histologic response were 39% and 3%, respectively (P less than .0001). Nonresponders averaged 10 kg more body weight than responders, and had been diagnosed about 21 months earlier (average disease duration, 46 months and 25 months, respectively).
Rates of reported adverse effects were similar with BOS (47%) and placebo (50%). Individual rates of nasopharyngitis, upper respiratory infections, and oropharyngeal pain also were comparable between groups, but one patient stopped BOS after developing dyspnea, nausea, and vomiting that were considered treatment related. Esophageal candidiasis developed in two BOS recipients – a rate similar rate to that in a prior study of BOS (Clin Gastroenterol Hepatol. 2015 Jan 13. doi: 10.1016/j.cgh.2014.05.02), and a lower percentage than in other studies of topical steroids for eosinophilic esophagitis, according to the researchers. Morning cortisol levels were similar between groups, and there were no adverse laboratory effects, they added.
Patients in this trial had severe symptoms and histology and were highly compliant with treatment. They filled out at least 70% of their symptom diary, had at least 15 eosinophils per high-power frame from at least two esophageal levels on screening endoscopy, and reported at least 4 days of dysphagia during the second half of a 4-week, blinded placebo run-in period. Researchers should consider using these strict inclusion criteria in future trials of eosinophilic esophagitis, especially because previous studies have failed to show a treatment benefit for topical steroid therapy, the investigators noted.
Meritage Pharma, which is now a part of the Shire group, makes budesonide oral suspension and sponsored the study. Dr. Dellon disclosed ties to Meritage, Receptos, Regeneron, Aptalis, Banner Life Sciences, Novartis, and Roche. All five coinvestigators disclosed ties to industry, including Meritage, Shire, Receptos, Regeneron, and Biogen Idec.
Budesonide oral suspension (BOS) was safe and significantly outperformed placebo on validated measures of eosinophilic esophagitis, according to a first-in-kind, multicenter, randomized, double-blind, phase II trial presented in the March issue of Gastroenterology (doi: 10.1053/j.gastro.2016.11.021).
The novel topical corticosteroid formulation yielded a significant histologic response and was associated with 3 fewer days of dysphagia over 2 weeks compared with placebo, reported Evan S. Dellon, MD, MPH, of University of North Carolina, Chapel Hill, and his associates. “There were no unexpected safety signals, and compliance with medication was high, suggesting that this formulation can be reliably used,” they wrote. Their findings earned BOS (SHP621) an FDA Breakthrough Therapy Designation in June 2016. Although corticosteroids are first-line therapy for eosinophilic esophagitis, symptom response in other studies has been mixed, and the Food and Drug Administration had approved neither fluticasone nor budesonide for this disease, the researchers noted. They formulated BOS to adhere better to the esophageal mucosa in order to enhance esophageal delivery while decreasing unwanted pulmonary deposition.
For the study, they randomly assigned 93 patients aged 11-40 years with eosinophilic esophagitis to receive either placebo or 2 mg BOS twice daily. By week 12, Dysphagia Symptom Questionnaire scores had fallen by 14.3 points with BOS group and by 7.5 points with placebo (P = .001). Endoscopic severity scores dropped by 3.8 points with BOS and rose by 0.4 points with placebo (P less than .0001). Rates of histologic response were 39% and 3%, respectively (P less than .0001). Nonresponders averaged 10 kg more body weight than responders, and had been diagnosed about 21 months earlier (average disease duration, 46 months and 25 months, respectively).
Rates of reported adverse effects were similar with BOS (47%) and placebo (50%). Individual rates of nasopharyngitis, upper respiratory infections, and oropharyngeal pain also were comparable between groups, but one patient stopped BOS after developing dyspnea, nausea, and vomiting that were considered treatment related. Esophageal candidiasis developed in two BOS recipients – a rate similar rate to that in a prior study of BOS (Clin Gastroenterol Hepatol. 2015 Jan 13. doi: 10.1016/j.cgh.2014.05.02), and a lower percentage than in other studies of topical steroids for eosinophilic esophagitis, according to the researchers. Morning cortisol levels were similar between groups, and there were no adverse laboratory effects, they added.
Patients in this trial had severe symptoms and histology and were highly compliant with treatment. They filled out at least 70% of their symptom diary, had at least 15 eosinophils per high-power frame from at least two esophageal levels on screening endoscopy, and reported at least 4 days of dysphagia during the second half of a 4-week, blinded placebo run-in period. Researchers should consider using these strict inclusion criteria in future trials of eosinophilic esophagitis, especially because previous studies have failed to show a treatment benefit for topical steroid therapy, the investigators noted.
Meritage Pharma, which is now a part of the Shire group, makes budesonide oral suspension and sponsored the study. Dr. Dellon disclosed ties to Meritage, Receptos, Regeneron, Aptalis, Banner Life Sciences, Novartis, and Roche. All five coinvestigators disclosed ties to industry, including Meritage, Shire, Receptos, Regeneron, and Biogen Idec.
FROM GASTROENTEROLOGY
Key clinical point: Budesonide oral suspension (BOS) (2 mg twice daily) was safe and significantly outperformed placebo on validated measures of eosinophilic esophagitis.
Major finding: Dysphagia Symptom Questionnaire scores decreased by 14.3 points with BOS and by 7.5 points with placebo (P = .001). Endoscopic severity scores decreased by 3.8 points and rose by 0.4 points, respectively (P less than .0001).
Data source: A 12-week, double-blind, placebo-controlled, parallel-group, phase II trial of 93 adolescents and adults with eosinophilic esophagitis.
Disclosures: Meritage Pharma, which is now a part of the Shire group, makes budesonide oral suspension and sponsored the study. Dr. Dellon disclosed ties to Meritage, Receptos, Regeneron, Aptalis, Banner Life Sciences, Novartis, and Roche. All five coinvestigators disclosed ties to industry, including Meritage, Shire, Receptos, Regeneron, and Biogen Idec.
VIDEO: Sofosbuvir with velpatasvir beat other HCV GT3 regimens
Regimens containing sofosbuvir and velpatasvir were most effective for treating both cirrhotic and noncirrhotic genotype 3 hepatitis C virus infection (HCV GT3), according to a meta-analysis reported in the March issue of Clinical Gastroenterology and Hepatology (doi: 10.1016/j.cgh.2016.10.03).
“Our analyses indicated that ribavirin significantly increases SVR [sustained viral response] rates and should be considered, if tolerated,” added Floor A.C. Berden, MD, of Radboud University Medical Center, Nijmegen, the Netherlands, and her associates.
SOURCE: AMERICAN GASTROENTEROLOGICAL ASSOCIATION
Direct-acting antiviral regimens successfully treat chronic HCV infection, but tend to perform suboptimally in HCV GT3, especially when patients are treatment experienced and have cirrhosis. Options for HCV GT3 infection include sofosbuvir combined with ribavirin, daclatasvir, or velpatasvir. But head-to-head trials of these regimens are lacking, and are unlikely to occur, in part because the Food and Drug Administration permits single-arm trials with historical controls as the comparator, the investigators said.
Therefore, they searched PubMed, Embase, and the Web of Science database through March 15, 2016, for randomized trials and real-world studies of at least one direct-acting antiviral agent in adults with chronic HCV GT3 infection. They also manually searched abstracts presented at the 2015 conferences of the European Association for the Study of the Liver and the American Association for the Study of Liver Diseases. This work yielded 27 studies: 16 randomized controlled trials, 6 single-arm studies, and 5 observational cohort studies. The researchers used a Bayesian analysis based on Markov chain Monte Carlo methods.
For patients without cirrhosis, sofosbuvir and velpatasvir with ribavirin yielded the highest estimated likelihood of SVR (99%; 95% confidence interval, 98%-100%), followed by sofosbuvir and velpatasvir without ribavirin (97%; 95% CI, 95%-99%), sofosbuvir and daclatasvir with ribavirin (96%; 95% CI, 92%-98%), and sofosbuvir and peginterferon with ribavirin (95%; 95% CI, 91%-98%), all for 12 weeks, the investigators reported.
For patients with cirrhosis, the most effective regimen was sofosbuvir with velpatasvir for 24 weeks (estimated SVR, 96%; 95% CI, 92%-99%), followed by sofosbuvir and daclatasvir with ribavirin for 24 weeks (94%; 95% CI, 87%-98%), sofosbuvir and velpatasvir and ribavirin for 12 weeks (94%; 95% CI, 86%-98%). The estimated efficacy of sofosbuvir and velpatasvir held up in sensitivity analyses that honed in on studies with a low risk of bias, approved regimens, or those under regulatory evaluation, patients without decompensated cirrhosis, and patients without HIV coinfection.
Adding ribavirin to a direct-acting antiviral regimen improved the odds of SVR about 2.6-fold (95% CI, 1.3-4.7) among noncirrhotic patients and by about 4.5 times in cirrhotic patients (95% CI, 2.5-7.7), the investigators reported. “In clinical practice, choice of treatment may depend on several factors, such as availability and price of direct-acting antivirals, tolerance of ribavirin, risk of adverse events or drug-drug interactions, and the presence of resistance-associated substitutions,” they added. Nonetheless, these findings can help prioritize therapies for HCV GT3 infection in both clinical guidelines and practice, they emphasized.
Dr. Berden and four coinvestigators had no relevant financial disclosures. Senior author Joost Drenth, MD, PhD, disclosed serving on advisory boards and receiving research grants from several pharmaceutical companies.
The rapid development of direct-acting antiviral agents (DAAs) to treat hepatitis C has yielded many surprises and left some gaps in our knowledge.
One of the surprises was that genotype 3, previously considered “easier to treat,” proved quite resistant to the first generation of DAAs. One of the gaps in knowledge was a lack of randomized and head-to-head trials for current medications. One could argue that randomized trials have limited utility in a disease with essentially no spontaneous cures, and that head-to-head trials are pointless in a rapidly evolving field where regimens may be obsolete by the time the study is completed.
On the bright side, a hard endpoint like sustained virologic response (SVR) makes comparison between trials possible. The paper by Bergen et al. offers some guidance in closing the knowledge gap. Their meta-analysis using Bayesian Markov Chain Monte Carlo methods examined the effectiveness of currently available antiviral agents in 27 studies that focused entirely on genotype 3. All studies used antiviral agents that are currently available in the United States, and effectiveness was tested in both noncirrhotic and cirrhotic patients.
The evolution of antiviral therapy has been amazing. After decades of incremental gains, we entered an era of dizzying progress. Genotype 3 went from great news to bad news, and genotype 1 went from a scourge to a piece of cake.
Norman L. Sussman, MD, is associate professor of surgery, Baylor College of Medicine, Houston; director, Project ECHO. He has received speaking and consulting fees for AbbVie, BMS, Gilead, and Merck.
The rapid development of direct-acting antiviral agents (DAAs) to treat hepatitis C has yielded many surprises and left some gaps in our knowledge.
One of the surprises was that genotype 3, previously considered “easier to treat,” proved quite resistant to the first generation of DAAs. One of the gaps in knowledge was a lack of randomized and head-to-head trials for current medications. One could argue that randomized trials have limited utility in a disease with essentially no spontaneous cures, and that head-to-head trials are pointless in a rapidly evolving field where regimens may be obsolete by the time the study is completed.
On the bright side, a hard endpoint like sustained virologic response (SVR) makes comparison between trials possible. The paper by Bergen et al. offers some guidance in closing the knowledge gap. Their meta-analysis using Bayesian Markov Chain Monte Carlo methods examined the effectiveness of currently available antiviral agents in 27 studies that focused entirely on genotype 3. All studies used antiviral agents that are currently available in the United States, and effectiveness was tested in both noncirrhotic and cirrhotic patients.
The evolution of antiviral therapy has been amazing. After decades of incremental gains, we entered an era of dizzying progress. Genotype 3 went from great news to bad news, and genotype 1 went from a scourge to a piece of cake.
Norman L. Sussman, MD, is associate professor of surgery, Baylor College of Medicine, Houston; director, Project ECHO. He has received speaking and consulting fees for AbbVie, BMS, Gilead, and Merck.
The rapid development of direct-acting antiviral agents (DAAs) to treat hepatitis C has yielded many surprises and left some gaps in our knowledge.
One of the surprises was that genotype 3, previously considered “easier to treat,” proved quite resistant to the first generation of DAAs. One of the gaps in knowledge was a lack of randomized and head-to-head trials for current medications. One could argue that randomized trials have limited utility in a disease with essentially no spontaneous cures, and that head-to-head trials are pointless in a rapidly evolving field where regimens may be obsolete by the time the study is completed.
On the bright side, a hard endpoint like sustained virologic response (SVR) makes comparison between trials possible. The paper by Bergen et al. offers some guidance in closing the knowledge gap. Their meta-analysis using Bayesian Markov Chain Monte Carlo methods examined the effectiveness of currently available antiviral agents in 27 studies that focused entirely on genotype 3. All studies used antiviral agents that are currently available in the United States, and effectiveness was tested in both noncirrhotic and cirrhotic patients.
The evolution of antiviral therapy has been amazing. After decades of incremental gains, we entered an era of dizzying progress. Genotype 3 went from great news to bad news, and genotype 1 went from a scourge to a piece of cake.
Norman L. Sussman, MD, is associate professor of surgery, Baylor College of Medicine, Houston; director, Project ECHO. He has received speaking and consulting fees for AbbVie, BMS, Gilead, and Merck.
Regimens containing sofosbuvir and velpatasvir were most effective for treating both cirrhotic and noncirrhotic genotype 3 hepatitis C virus infection (HCV GT3), according to a meta-analysis reported in the March issue of Clinical Gastroenterology and Hepatology (doi: 10.1016/j.cgh.2016.10.03).
“Our analyses indicated that ribavirin significantly increases SVR [sustained viral response] rates and should be considered, if tolerated,” added Floor A.C. Berden, MD, of Radboud University Medical Center, Nijmegen, the Netherlands, and her associates.
SOURCE: AMERICAN GASTROENTEROLOGICAL ASSOCIATION
Direct-acting antiviral regimens successfully treat chronic HCV infection, but tend to perform suboptimally in HCV GT3, especially when patients are treatment experienced and have cirrhosis. Options for HCV GT3 infection include sofosbuvir combined with ribavirin, daclatasvir, or velpatasvir. But head-to-head trials of these regimens are lacking, and are unlikely to occur, in part because the Food and Drug Administration permits single-arm trials with historical controls as the comparator, the investigators said.
Therefore, they searched PubMed, Embase, and the Web of Science database through March 15, 2016, for randomized trials and real-world studies of at least one direct-acting antiviral agent in adults with chronic HCV GT3 infection. They also manually searched abstracts presented at the 2015 conferences of the European Association for the Study of the Liver and the American Association for the Study of Liver Diseases. This work yielded 27 studies: 16 randomized controlled trials, 6 single-arm studies, and 5 observational cohort studies. The researchers used a Bayesian analysis based on Markov chain Monte Carlo methods.
For patients without cirrhosis, sofosbuvir and velpatasvir with ribavirin yielded the highest estimated likelihood of SVR (99%; 95% confidence interval, 98%-100%), followed by sofosbuvir and velpatasvir without ribavirin (97%; 95% CI, 95%-99%), sofosbuvir and daclatasvir with ribavirin (96%; 95% CI, 92%-98%), and sofosbuvir and peginterferon with ribavirin (95%; 95% CI, 91%-98%), all for 12 weeks, the investigators reported.
For patients with cirrhosis, the most effective regimen was sofosbuvir with velpatasvir for 24 weeks (estimated SVR, 96%; 95% CI, 92%-99%), followed by sofosbuvir and daclatasvir with ribavirin for 24 weeks (94%; 95% CI, 87%-98%), sofosbuvir and velpatasvir and ribavirin for 12 weeks (94%; 95% CI, 86%-98%). The estimated efficacy of sofosbuvir and velpatasvir held up in sensitivity analyses that honed in on studies with a low risk of bias, approved regimens, or those under regulatory evaluation, patients without decompensated cirrhosis, and patients without HIV coinfection.
Adding ribavirin to a direct-acting antiviral regimen improved the odds of SVR about 2.6-fold (95% CI, 1.3-4.7) among noncirrhotic patients and by about 4.5 times in cirrhotic patients (95% CI, 2.5-7.7), the investigators reported. “In clinical practice, choice of treatment may depend on several factors, such as availability and price of direct-acting antivirals, tolerance of ribavirin, risk of adverse events or drug-drug interactions, and the presence of resistance-associated substitutions,” they added. Nonetheless, these findings can help prioritize therapies for HCV GT3 infection in both clinical guidelines and practice, they emphasized.
Dr. Berden and four coinvestigators had no relevant financial disclosures. Senior author Joost Drenth, MD, PhD, disclosed serving on advisory boards and receiving research grants from several pharmaceutical companies.
Regimens containing sofosbuvir and velpatasvir were most effective for treating both cirrhotic and noncirrhotic genotype 3 hepatitis C virus infection (HCV GT3), according to a meta-analysis reported in the March issue of Clinical Gastroenterology and Hepatology (doi: 10.1016/j.cgh.2016.10.03).
“Our analyses indicated that ribavirin significantly increases SVR [sustained viral response] rates and should be considered, if tolerated,” added Floor A.C. Berden, MD, of Radboud University Medical Center, Nijmegen, the Netherlands, and her associates.
SOURCE: AMERICAN GASTROENTEROLOGICAL ASSOCIATION
Direct-acting antiviral regimens successfully treat chronic HCV infection, but tend to perform suboptimally in HCV GT3, especially when patients are treatment experienced and have cirrhosis. Options for HCV GT3 infection include sofosbuvir combined with ribavirin, daclatasvir, or velpatasvir. But head-to-head trials of these regimens are lacking, and are unlikely to occur, in part because the Food and Drug Administration permits single-arm trials with historical controls as the comparator, the investigators said.
Therefore, they searched PubMed, Embase, and the Web of Science database through March 15, 2016, for randomized trials and real-world studies of at least one direct-acting antiviral agent in adults with chronic HCV GT3 infection. They also manually searched abstracts presented at the 2015 conferences of the European Association for the Study of the Liver and the American Association for the Study of Liver Diseases. This work yielded 27 studies: 16 randomized controlled trials, 6 single-arm studies, and 5 observational cohort studies. The researchers used a Bayesian analysis based on Markov chain Monte Carlo methods.
For patients without cirrhosis, sofosbuvir and velpatasvir with ribavirin yielded the highest estimated likelihood of SVR (99%; 95% confidence interval, 98%-100%), followed by sofosbuvir and velpatasvir without ribavirin (97%; 95% CI, 95%-99%), sofosbuvir and daclatasvir with ribavirin (96%; 95% CI, 92%-98%), and sofosbuvir and peginterferon with ribavirin (95%; 95% CI, 91%-98%), all for 12 weeks, the investigators reported.
For patients with cirrhosis, the most effective regimen was sofosbuvir with velpatasvir for 24 weeks (estimated SVR, 96%; 95% CI, 92%-99%), followed by sofosbuvir and daclatasvir with ribavirin for 24 weeks (94%; 95% CI, 87%-98%), sofosbuvir and velpatasvir and ribavirin for 12 weeks (94%; 95% CI, 86%-98%). The estimated efficacy of sofosbuvir and velpatasvir held up in sensitivity analyses that honed in on studies with a low risk of bias, approved regimens, or those under regulatory evaluation, patients without decompensated cirrhosis, and patients without HIV coinfection.
Adding ribavirin to a direct-acting antiviral regimen improved the odds of SVR about 2.6-fold (95% CI, 1.3-4.7) among noncirrhotic patients and by about 4.5 times in cirrhotic patients (95% CI, 2.5-7.7), the investigators reported. “In clinical practice, choice of treatment may depend on several factors, such as availability and price of direct-acting antivirals, tolerance of ribavirin, risk of adverse events or drug-drug interactions, and the presence of resistance-associated substitutions,” they added. Nonetheless, these findings can help prioritize therapies for HCV GT3 infection in both clinical guidelines and practice, they emphasized.
Dr. Berden and four coinvestigators had no relevant financial disclosures. Senior author Joost Drenth, MD, PhD, disclosed serving on advisory boards and receiving research grants from several pharmaceutical companies.
FROM CLINICAL GASTROENTEROLOGY AND HEPATOLOGY
Key clinical point. Regimens containing sofosbuvir and velpatasvir were more effective than were other direct-acting antiviral combinations for treating genotype 3 hepatitis C virus infection, regardless of cirrhosis status.
Major finding: For patients without cirrhosis, sofosbuvir and velpatasvir with ribavirin for 12 weeks yielded the highest estimated likelihood of sustained viral response (99%). For patients with cirrhosis, the most effective regimen was sofosbuvir with velpatasvir for 24 weeks (estimated SVR, 96%).
Data source: A systematic review and meta-analysis of 27 studies: 16 randomized controlled trials, 6 single-arm studies, and 5 observational cohort studies.
Disclosures: Dr. Berden and four coinvestigators had no relevant financial disclosures. Senior author Joost Drenth, MD, PhD, disclosed serving on advisory boards and receiving research grants from several pharmaceutical companies.
Sterile fecal filtrate effectively treated recurrent CDI
Sterile fecal filtrate transplantation (FFT) effectively treated five cases of symptomatic chronic-relapsing Clostridium difficile infection, investigators reported.
The procedure restored normal bowel habits and eliminated symptoms through the end of the study – that is, for at least 6 months – in all patients, Stephan J. Ott, MD, and his associates wrote (Gastroenterology. 2019. doi: 10.1053/j.gastro.2016.11.010).
Proteome analyses did not identify proteins likely to explain this efficacy, but 16S rRNA gene sequencing did demonstrate diverse bacterial DNA signatures in the filtrates, and tests of virus-like particles yielded “a complex signature of macrophages,” Dr. Ott and his associates reported. Additional tests suggested that recipients’ microbiomes continued to change weeks after FFT. “This open-label series strongly suggests that FFT should be evaluated in a controlled setting in comparison with standard fecal microbiota transplantation,” the researchers concluded.
Fecal microbiota transplantation (FMT) effectively treats recurrent Clostridium difficile infection (CDI), but even “the most rigorous and costly donor screening procedures, or defined panels of bacteria, cannot exclude the risk of transferring unknown pathogens or undetectable functional characteristics within the living microorganisms to the recipient, including bacterial or viral risk factors for metabolic diseases, cancer, atopy, or autoimmunity,” the investigators wrote.
Therefore, they performed sterile FFT in five patients who were positive on at least two of three tests: enzyme-linked immunosorbent assay for C. difficile–specific glutamate dehydrogenase; C. difficile toxin enzyme-linked immunosorbent assay; and culture of toxin-producing C. difficile. Patients chose their own stool donors, who were then screened based on published guidelines (Clin Gastroenterol Hepatol. 2011;9[12]:1044-49). Next, “slurries” were prepared from donor stool and filtered with a custom-built air pressure filtration system, yielding a “light brown, clear liquid with a subjectively less unpleasant and intensive odor” than conventional FMT stool preparations. Bacterial cultures of these filtrates yielded no growth, whereas donor stool cultures showed profuse growth of aerobic and anaerobic bacterial colonies, Dr. Ott and his associates said.
Patients became symptom-free 2-4 days after undergoing FFT. Notably, one patient had previously undergone FMT, which led to acute fever and diarrhea and recurrence of baseline symptoms after 3 months. This patient did not develop fever or diarrhea after FFT, was symptom-free after 3 days, and remained symptom-free until the study ended 2 years later, the researchers said. All other patients also remained symptom-free through the end of the study, that is, for 6 months to more than 2 years.
Analyses of 16S rRNA revealed substantial longitudinal shifts after FFT that often were present by week 1 and remained stable until week 6, the investigators said. Further tests confirmed marked shifts in bacterial phylotypes and in their relative abundance over time. Repeated virus analyses of one patient also showed that the phageome shifted over time to resemble that of the donor.
Patients were between 49 and 75 years old, three were female and two were male, and all had received more than one antibiotic before their first episode of CDI. Antibiotics for CDI had included metronidazole, vancomycin, and rifaximin. Comorbidities included pseudomembranous colitis, renal failure, HIV infection, epilepsy, and chronic heart failure, and medical histories included recurrent diverticulitis with sigmoid resection, gastric carcinoma, and colon cancer.
“It is important to keep in mind that, in contrast to conventional FMT, transferring sterile FFT filtrates cannot be expected to establish a microbiota similar to that of the donor in the receiving patient,” Dr. Ott and his associates noted. Instead, bacterial DNA in the filtrate might trigger the re-establishment of the recipient microbiome, they said. Bacterial cell wall fragments or bacteriophages also might play a role, they added.
The German Excellence Cluster and CONARIS Research Institute AG supported the work. Dr. Ott reported having lectured for Allergosan. Two coinvestigators reported employment with CONARIS. A third coinvestigator reported shareholder relationships with CONARIS, Allergosan, Danone, and Nestle and lectureship compensation from Allergosan. The other eight coinvestigators had no relevant conflicts of interest.
The remarkable efficacy of fecal microbial transplant in recurrent C. difficile infection provides a compelling example of ecologic microbiome-based therapy. Its mechanism is widely considered to be the restoration of select microbial species that suppress C. difficile colonization and virulence in healthy individuals. Identification of such suppressive microbiota is still at an early stage, with empirical studies revealing effective synthetic microbial consortia, and evidence of some modes of action, such as bile salt metabolism (Nature 2015;517:205-8; PLoS Pathog. 2012;8:e1002995).
Clouding this elegant concept is the provocative new study of Dr. Ott and his colleagues. Prompted by long-term safety concerns, they evaluated the efficacy of a donor fecal microfiltrate lacking viable intact organisms. Indeed, in five patients, long-term eradication of C. difficile was achieved with a single dose. This observation indicates that the initial action of fecal transplant may not require restoration of viable organisms into the antibiotic-damaged ecosystem.
What mechanisms might account for the therapeutic action of organism-free fecal microfiltrate? First, this material is laden with a complex, potentially distinct mix of microbial products and particulates (Cell. 2016;165[5]:1106-19) from donor origin or ex vivo processing. These biologicals may induce immune processes to promote control of C. difficile directly or via changes in other commensals of the patient's microbiome. Second, the microfiltrate retains abundant and diverse bacteria-targeting viruses of the fecal stream. Perhaps certain viruses, deficient in patients, target C. difficile and/or beneficially reshape microbial composition (Cell Mol Gastroenterol Hepatol. 2015;1[1]:28-40). So, C. difficile challenges us once more into the breach with new insights ahead for the principles and practice of ecologic microbiome therapy.
Jonathan Braun, MD, PhD, is professor and chair of pathology and laboratory medicine at the University of California, Los Angeles. He has no conflicts of interest.
The remarkable efficacy of fecal microbial transplant in recurrent C. difficile infection provides a compelling example of ecologic microbiome-based therapy. Its mechanism is widely considered to be the restoration of select microbial species that suppress C. difficile colonization and virulence in healthy individuals. Identification of such suppressive microbiota is still at an early stage, with empirical studies revealing effective synthetic microbial consortia, and evidence of some modes of action, such as bile salt metabolism (Nature 2015;517:205-8; PLoS Pathog. 2012;8:e1002995).
Clouding this elegant concept is the provocative new study of Dr. Ott and his colleagues. Prompted by long-term safety concerns, they evaluated the efficacy of a donor fecal microfiltrate lacking viable intact organisms. Indeed, in five patients, long-term eradication of C. difficile was achieved with a single dose. This observation indicates that the initial action of fecal transplant may not require restoration of viable organisms into the antibiotic-damaged ecosystem.
What mechanisms might account for the therapeutic action of organism-free fecal microfiltrate? First, this material is laden with a complex, potentially distinct mix of microbial products and particulates (Cell. 2016;165[5]:1106-19) from donor origin or ex vivo processing. These biologicals may induce immune processes to promote control of C. difficile directly or via changes in other commensals of the patient's microbiome. Second, the microfiltrate retains abundant and diverse bacteria-targeting viruses of the fecal stream. Perhaps certain viruses, deficient in patients, target C. difficile and/or beneficially reshape microbial composition (Cell Mol Gastroenterol Hepatol. 2015;1[1]:28-40). So, C. difficile challenges us once more into the breach with new insights ahead for the principles and practice of ecologic microbiome therapy.
Jonathan Braun, MD, PhD, is professor and chair of pathology and laboratory medicine at the University of California, Los Angeles. He has no conflicts of interest.
The remarkable efficacy of fecal microbial transplant in recurrent C. difficile infection provides a compelling example of ecologic microbiome-based therapy. Its mechanism is widely considered to be the restoration of select microbial species that suppress C. difficile colonization and virulence in healthy individuals. Identification of such suppressive microbiota is still at an early stage, with empirical studies revealing effective synthetic microbial consortia, and evidence of some modes of action, such as bile salt metabolism (Nature 2015;517:205-8; PLoS Pathog. 2012;8:e1002995).
Clouding this elegant concept is the provocative new study of Dr. Ott and his colleagues. Prompted by long-term safety concerns, they evaluated the efficacy of a donor fecal microfiltrate lacking viable intact organisms. Indeed, in five patients, long-term eradication of C. difficile was achieved with a single dose. This observation indicates that the initial action of fecal transplant may not require restoration of viable organisms into the antibiotic-damaged ecosystem.
What mechanisms might account for the therapeutic action of organism-free fecal microfiltrate? First, this material is laden with a complex, potentially distinct mix of microbial products and particulates (Cell. 2016;165[5]:1106-19) from donor origin or ex vivo processing. These biologicals may induce immune processes to promote control of C. difficile directly or via changes in other commensals of the patient's microbiome. Second, the microfiltrate retains abundant and diverse bacteria-targeting viruses of the fecal stream. Perhaps certain viruses, deficient in patients, target C. difficile and/or beneficially reshape microbial composition (Cell Mol Gastroenterol Hepatol. 2015;1[1]:28-40). So, C. difficile challenges us once more into the breach with new insights ahead for the principles and practice of ecologic microbiome therapy.
Jonathan Braun, MD, PhD, is professor and chair of pathology and laboratory medicine at the University of California, Los Angeles. He has no conflicts of interest.
Sterile fecal filtrate transplantation (FFT) effectively treated five cases of symptomatic chronic-relapsing Clostridium difficile infection, investigators reported.
The procedure restored normal bowel habits and eliminated symptoms through the end of the study – that is, for at least 6 months – in all patients, Stephan J. Ott, MD, and his associates wrote (Gastroenterology. 2019. doi: 10.1053/j.gastro.2016.11.010).
Proteome analyses did not identify proteins likely to explain this efficacy, but 16S rRNA gene sequencing did demonstrate diverse bacterial DNA signatures in the filtrates, and tests of virus-like particles yielded “a complex signature of macrophages,” Dr. Ott and his associates reported. Additional tests suggested that recipients’ microbiomes continued to change weeks after FFT. “This open-label series strongly suggests that FFT should be evaluated in a controlled setting in comparison with standard fecal microbiota transplantation,” the researchers concluded.
Fecal microbiota transplantation (FMT) effectively treats recurrent Clostridium difficile infection (CDI), but even “the most rigorous and costly donor screening procedures, or defined panels of bacteria, cannot exclude the risk of transferring unknown pathogens or undetectable functional characteristics within the living microorganisms to the recipient, including bacterial or viral risk factors for metabolic diseases, cancer, atopy, or autoimmunity,” the investigators wrote.
Therefore, they performed sterile FFT in five patients who were positive on at least two of three tests: enzyme-linked immunosorbent assay for C. difficile–specific glutamate dehydrogenase; C. difficile toxin enzyme-linked immunosorbent assay; and culture of toxin-producing C. difficile. Patients chose their own stool donors, who were then screened based on published guidelines (Clin Gastroenterol Hepatol. 2011;9[12]:1044-49). Next, “slurries” were prepared from donor stool and filtered with a custom-built air pressure filtration system, yielding a “light brown, clear liquid with a subjectively less unpleasant and intensive odor” than conventional FMT stool preparations. Bacterial cultures of these filtrates yielded no growth, whereas donor stool cultures showed profuse growth of aerobic and anaerobic bacterial colonies, Dr. Ott and his associates said.
Patients became symptom-free 2-4 days after undergoing FFT. Notably, one patient had previously undergone FMT, which led to acute fever and diarrhea and recurrence of baseline symptoms after 3 months. This patient did not develop fever or diarrhea after FFT, was symptom-free after 3 days, and remained symptom-free until the study ended 2 years later, the researchers said. All other patients also remained symptom-free through the end of the study, that is, for 6 months to more than 2 years.
Analyses of 16S rRNA revealed substantial longitudinal shifts after FFT that often were present by week 1 and remained stable until week 6, the investigators said. Further tests confirmed marked shifts in bacterial phylotypes and in their relative abundance over time. Repeated virus analyses of one patient also showed that the phageome shifted over time to resemble that of the donor.
Patients were between 49 and 75 years old, three were female and two were male, and all had received more than one antibiotic before their first episode of CDI. Antibiotics for CDI had included metronidazole, vancomycin, and rifaximin. Comorbidities included pseudomembranous colitis, renal failure, HIV infection, epilepsy, and chronic heart failure, and medical histories included recurrent diverticulitis with sigmoid resection, gastric carcinoma, and colon cancer.
“It is important to keep in mind that, in contrast to conventional FMT, transferring sterile FFT filtrates cannot be expected to establish a microbiota similar to that of the donor in the receiving patient,” Dr. Ott and his associates noted. Instead, bacterial DNA in the filtrate might trigger the re-establishment of the recipient microbiome, they said. Bacterial cell wall fragments or bacteriophages also might play a role, they added.
The German Excellence Cluster and CONARIS Research Institute AG supported the work. Dr. Ott reported having lectured for Allergosan. Two coinvestigators reported employment with CONARIS. A third coinvestigator reported shareholder relationships with CONARIS, Allergosan, Danone, and Nestle and lectureship compensation from Allergosan. The other eight coinvestigators had no relevant conflicts of interest.
Sterile fecal filtrate transplantation (FFT) effectively treated five cases of symptomatic chronic-relapsing Clostridium difficile infection, investigators reported.
The procedure restored normal bowel habits and eliminated symptoms through the end of the study – that is, for at least 6 months – in all patients, Stephan J. Ott, MD, and his associates wrote (Gastroenterology. 2019. doi: 10.1053/j.gastro.2016.11.010).
Proteome analyses did not identify proteins likely to explain this efficacy, but 16S rRNA gene sequencing did demonstrate diverse bacterial DNA signatures in the filtrates, and tests of virus-like particles yielded “a complex signature of macrophages,” Dr. Ott and his associates reported. Additional tests suggested that recipients’ microbiomes continued to change weeks after FFT. “This open-label series strongly suggests that FFT should be evaluated in a controlled setting in comparison with standard fecal microbiota transplantation,” the researchers concluded.
Fecal microbiota transplantation (FMT) effectively treats recurrent Clostridium difficile infection (CDI), but even “the most rigorous and costly donor screening procedures, or defined panels of bacteria, cannot exclude the risk of transferring unknown pathogens or undetectable functional characteristics within the living microorganisms to the recipient, including bacterial or viral risk factors for metabolic diseases, cancer, atopy, or autoimmunity,” the investigators wrote.
Therefore, they performed sterile FFT in five patients who were positive on at least two of three tests: enzyme-linked immunosorbent assay for C. difficile–specific glutamate dehydrogenase; C. difficile toxin enzyme-linked immunosorbent assay; and culture of toxin-producing C. difficile. Patients chose their own stool donors, who were then screened based on published guidelines (Clin Gastroenterol Hepatol. 2011;9[12]:1044-49). Next, “slurries” were prepared from donor stool and filtered with a custom-built air pressure filtration system, yielding a “light brown, clear liquid with a subjectively less unpleasant and intensive odor” than conventional FMT stool preparations. Bacterial cultures of these filtrates yielded no growth, whereas donor stool cultures showed profuse growth of aerobic and anaerobic bacterial colonies, Dr. Ott and his associates said.
Patients became symptom-free 2-4 days after undergoing FFT. Notably, one patient had previously undergone FMT, which led to acute fever and diarrhea and recurrence of baseline symptoms after 3 months. This patient did not develop fever or diarrhea after FFT, was symptom-free after 3 days, and remained symptom-free until the study ended 2 years later, the researchers said. All other patients also remained symptom-free through the end of the study, that is, for 6 months to more than 2 years.
Analyses of 16S rRNA revealed substantial longitudinal shifts after FFT that often were present by week 1 and remained stable until week 6, the investigators said. Further tests confirmed marked shifts in bacterial phylotypes and in their relative abundance over time. Repeated virus analyses of one patient also showed that the phageome shifted over time to resemble that of the donor.
Patients were between 49 and 75 years old, three were female and two were male, and all had received more than one antibiotic before their first episode of CDI. Antibiotics for CDI had included metronidazole, vancomycin, and rifaximin. Comorbidities included pseudomembranous colitis, renal failure, HIV infection, epilepsy, and chronic heart failure, and medical histories included recurrent diverticulitis with sigmoid resection, gastric carcinoma, and colon cancer.
“It is important to keep in mind that, in contrast to conventional FMT, transferring sterile FFT filtrates cannot be expected to establish a microbiota similar to that of the donor in the receiving patient,” Dr. Ott and his associates noted. Instead, bacterial DNA in the filtrate might trigger the re-establishment of the recipient microbiome, they said. Bacterial cell wall fragments or bacteriophages also might play a role, they added.
The German Excellence Cluster and CONARIS Research Institute AG supported the work. Dr. Ott reported having lectured for Allergosan. Two coinvestigators reported employment with CONARIS. A third coinvestigator reported shareholder relationships with CONARIS, Allergosan, Danone, and Nestle and lectureship compensation from Allergosan. The other eight coinvestigators had no relevant conflicts of interest.
FROM GASTROENTEROLOGY
Key clinical point: Sterile fecal filtrate transplantation effectively treated symptomatic chronic-relapsing Clostridium difficile infection.
Major finding: For all patients, transplantation restored normal bowel habits within 2-4 days and eliminated symptoms for at least 6 months.
Data source: A single-center cases series of five patients with recurrent symptomatic CDI.
Disclosures: The German Excellence Cluster and CONARIS Research Institute AG supported the work. Dr. Ott reported having lectured for Allergosan. Two coinvestigators reported employment with CONARIS. A third coinvestigator reported shareholder relationships with CONARIS, Allergosan, Danone, and Nestle and lectureship compensation from Allergosan. The other eight coinvestigators had no relevant conflicts of interest.
Endoscopic resection alone sufficed in many T1 colorectal cancers
Patients with T1 colorectal cancer might not benefit from additional surgery after endoscopic resection unless they have positive or indeterminate resection margins or high-risk histology, according to a retrospective, population-based study of 1,315 patients.
After a median follow-up of 6.6 years, the rates of colorectal cancer (CRC) recurrence were 6.2% in patients who underwent endoscopic resection only and 6.4% in patients who also had additional surgery (P = .9), reported Tim D.G. Belderbos, MD, of University Medical Center Utrecht (the Netherlands). Rates of local recurrence also were similar between these groups (4.1% and 3.7%, P = .3), he and his associates reported in the March issue of Clinical Gastroenterology and Hepatology (doi: 10.1016/j.cgh.2016.08.041).
Among high-risk patients, however, the rates of overall recurrence were 14% with endoscopic resection only and 7% with endoscopic resection plus additional surgery (P = .06), and the rates of local recurrence were 12% and 1%, respectively (P = .004). “Based on our study, we recommend performing additional surgery after initial endoscopic resection in cases of high-risk T1 CRC, determined by high-risk histology and/or positive resection margins,” the researchers concluded. Invasive CRCs confined to the colonic submucosa (T1 CRC) present a treatment dilemma – they are usually cured by complete endoscopic resection, but up to 13% involve lymph node metastases and need additional surgery, the investigators noted. To identify predictors of recurrence and metastasis, they studied all patients diagnosed with T1 CRC in the Southeast Netherlands from 1995 through 2011. A total of 370 patients (28%) underwent endoscopic resection only, 220 (17%) underwent endoscopic resection with additional surgery, and 725 (55%) had an initial surgical resection.
Surgery after endoscopic resection was more likely when patients had positive or doubtful resection margins (P less than .001), and this link remained significant after high-risk histology, tumor location, time period, age, sex, and comorbidities were controlled for. Endoscopic resection plus surgery did not reduce the risk of recurrence, compared with endoscopic resection only (P = .3), after the investigators accounted for age, sex, year of procedure, tumor location, and margin characteristics. Initial surgery was associated with significantly lower rates of overall and local recurrence, compared with endoscopic resection only, but the differences also lost significance in the multivariable analysis (P = .2).
Only the presence of positive resection margins significantly predicted recurrence among patients undergoing endoscopic resection (hazard ratio, 6.9; 95% confidence interval, 2.3-20.9). Positive or doubtful resection margins also predicted recurrence after initial surgery, with hazard ratios of 13.2 and 3.4, respectively. High-risk histology – that is, poor differentiation, deep submucosal invasion, or lymphangioinvasion – was significantly associated with lymph node metastasis (OR, 2.2; 95% CI, 1.3-3.7; P less than .002), but not with recurrence after resection margins were accounted for. This might result from missing histology data or the fact that patients with high-risk histology tended to undergo surgical rather than endoscopic resection, the researchers said.
They noted several other study limitations, including a lack of details about lesions and procedures. Also, endoscopic submucosal resection was not practiced in the Netherlands during the study period, they said.
The investigators did not report funding sources and had no disclosures.
Patients with T1 colorectal cancer might not benefit from additional surgery after endoscopic resection unless they have positive or indeterminate resection margins or high-risk histology, according to a retrospective, population-based study of 1,315 patients.
After a median follow-up of 6.6 years, the rates of colorectal cancer (CRC) recurrence were 6.2% in patients who underwent endoscopic resection only and 6.4% in patients who also had additional surgery (P = .9), reported Tim D.G. Belderbos, MD, of University Medical Center Utrecht (the Netherlands). Rates of local recurrence also were similar between these groups (4.1% and 3.7%, P = .3), he and his associates reported in the March issue of Clinical Gastroenterology and Hepatology (doi: 10.1016/j.cgh.2016.08.041).
Among high-risk patients, however, the rates of overall recurrence were 14% with endoscopic resection only and 7% with endoscopic resection plus additional surgery (P = .06), and the rates of local recurrence were 12% and 1%, respectively (P = .004). “Based on our study, we recommend performing additional surgery after initial endoscopic resection in cases of high-risk T1 CRC, determined by high-risk histology and/or positive resection margins,” the researchers concluded. Invasive CRCs confined to the colonic submucosa (T1 CRC) present a treatment dilemma – they are usually cured by complete endoscopic resection, but up to 13% involve lymph node metastases and need additional surgery, the investigators noted. To identify predictors of recurrence and metastasis, they studied all patients diagnosed with T1 CRC in the Southeast Netherlands from 1995 through 2011. A total of 370 patients (28%) underwent endoscopic resection only, 220 (17%) underwent endoscopic resection with additional surgery, and 725 (55%) had an initial surgical resection.
Surgery after endoscopic resection was more likely when patients had positive or doubtful resection margins (P less than .001), and this link remained significant after high-risk histology, tumor location, time period, age, sex, and comorbidities were controlled for. Endoscopic resection plus surgery did not reduce the risk of recurrence, compared with endoscopic resection only (P = .3), after the investigators accounted for age, sex, year of procedure, tumor location, and margin characteristics. Initial surgery was associated with significantly lower rates of overall and local recurrence, compared with endoscopic resection only, but the differences also lost significance in the multivariable analysis (P = .2).
Only the presence of positive resection margins significantly predicted recurrence among patients undergoing endoscopic resection (hazard ratio, 6.9; 95% confidence interval, 2.3-20.9). Positive or doubtful resection margins also predicted recurrence after initial surgery, with hazard ratios of 13.2 and 3.4, respectively. High-risk histology – that is, poor differentiation, deep submucosal invasion, or lymphangioinvasion – was significantly associated with lymph node metastasis (OR, 2.2; 95% CI, 1.3-3.7; P less than .002), but not with recurrence after resection margins were accounted for. This might result from missing histology data or the fact that patients with high-risk histology tended to undergo surgical rather than endoscopic resection, the researchers said.
They noted several other study limitations, including a lack of details about lesions and procedures. Also, endoscopic submucosal resection was not practiced in the Netherlands during the study period, they said.
The investigators did not report funding sources and had no disclosures.
Patients with T1 colorectal cancer might not benefit from additional surgery after endoscopic resection unless they have positive or indeterminate resection margins or high-risk histology, according to a retrospective, population-based study of 1,315 patients.
After a median follow-up of 6.6 years, the rates of colorectal cancer (CRC) recurrence were 6.2% in patients who underwent endoscopic resection only and 6.4% in patients who also had additional surgery (P = .9), reported Tim D.G. Belderbos, MD, of University Medical Center Utrecht (the Netherlands). Rates of local recurrence also were similar between these groups (4.1% and 3.7%, P = .3), he and his associates reported in the March issue of Clinical Gastroenterology and Hepatology (doi: 10.1016/j.cgh.2016.08.041).
Among high-risk patients, however, the rates of overall recurrence were 14% with endoscopic resection only and 7% with endoscopic resection plus additional surgery (P = .06), and the rates of local recurrence were 12% and 1%, respectively (P = .004). “Based on our study, we recommend performing additional surgery after initial endoscopic resection in cases of high-risk T1 CRC, determined by high-risk histology and/or positive resection margins,” the researchers concluded. Invasive CRCs confined to the colonic submucosa (T1 CRC) present a treatment dilemma – they are usually cured by complete endoscopic resection, but up to 13% involve lymph node metastases and need additional surgery, the investigators noted. To identify predictors of recurrence and metastasis, they studied all patients diagnosed with T1 CRC in the Southeast Netherlands from 1995 through 2011. A total of 370 patients (28%) underwent endoscopic resection only, 220 (17%) underwent endoscopic resection with additional surgery, and 725 (55%) had an initial surgical resection.
Surgery after endoscopic resection was more likely when patients had positive or doubtful resection margins (P less than .001), and this link remained significant after high-risk histology, tumor location, time period, age, sex, and comorbidities were controlled for. Endoscopic resection plus surgery did not reduce the risk of recurrence, compared with endoscopic resection only (P = .3), after the investigators accounted for age, sex, year of procedure, tumor location, and margin characteristics. Initial surgery was associated with significantly lower rates of overall and local recurrence, compared with endoscopic resection only, but the differences also lost significance in the multivariable analysis (P = .2).
Only the presence of positive resection margins significantly predicted recurrence among patients undergoing endoscopic resection (hazard ratio, 6.9; 95% confidence interval, 2.3-20.9). Positive or doubtful resection margins also predicted recurrence after initial surgery, with hazard ratios of 13.2 and 3.4, respectively. High-risk histology – that is, poor differentiation, deep submucosal invasion, or lymphangioinvasion – was significantly associated with lymph node metastasis (OR, 2.2; 95% CI, 1.3-3.7; P less than .002), but not with recurrence after resection margins were accounted for. This might result from missing histology data or the fact that patients with high-risk histology tended to undergo surgical rather than endoscopic resection, the researchers said.
They noted several other study limitations, including a lack of details about lesions and procedures. Also, endoscopic submucosal resection was not practiced in the Netherlands during the study period, they said.
The investigators did not report funding sources and had no disclosures.
FROM CLINICAL GASTROENTEROLOGY AND HEPATOLOGY
Key clinical point. Patients with T1 colorectal cancer might not benefit from additional surgery after endoscopic resection unless they have positive or indeterminate resection margins or high-risk histology.
Major finding: After a median follow-up of 6.6 years, rates of CRC recurrence were 6.2% in patients who underwent endoscopic resection only, and 6.4% in patients who also had additional surgery (P = .9). Among high-risk patients, these rates were 14% and 7%, respectively (P = .06).
Data source: A retrospective population-based study of 1,315 patients who underwent endoscopic or surgical resection of T1 colorectal cancer.
Disclosures: The investigators did not report funding sources and had no disclosures.
Rituximab after ASCT boosted survival in mantle cell lymphoma
SAN DIEGO – Maintenance therapy every other month with rituximab significantly prolonged event-free and overall survival after autologous stem cell transplantation among younger patients with mantle cell lymphoma, based on results from a multicenter, randomized, phase 3 trial.
After a median follow-up period of 50 months, 79% of the rituximab maintenance arm remained alive and free of progression, relapse, and severe infection, compared with 61% of the no-maintenance arm (P = .001), said Steven Le Gouill, MD, PhD, at the 2016 meeting of the American Society of Hematology.
This is the first study linking rituximab maintenance after ASCT to improved survival in younger patients with mantle cell lymphoma, said Dr. Le Gouill of Nantes University Hospital in Nantes, France.
The trial “demonstrates for the first time that rituximab maintenance after ASCT prolongs event-free survival, progression-free survival, and overall survival” in younger patients with treatment-naïve mantle cell lymphoma, Dr. Le Gouill said. The findings confirm rituximab maintenance as “a new standard of care” in younger patients with mantle cell lymphoma, he concluded.
Prior research http://www.nejm.org/doi/full/10.1056/NEJMoa1200920#t=abstract supports maintenance therapy with rituximab rather than interferon alfa for older patients whose mantle cell lymphoma responded to induction with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP), noted Dr. Le Gouill. To examine outcomes in younger patients with treatment-naïve mantle cell lymphoma, he and his associates treated 299 individuals aged 65 years and younger (median age, 57 years) with standard induction consisting of 4 courses of rituximab, dexamethasone, high-dose cytarabine, and salt platinum (R-DHAP) every 21 days, followed by conditioning with rituximab plus BiCNU, etoposide, cytarabine, and melphalan (R-BEAM) and ASCT. Patients without at least a partial response to R-DHAP received 4 additional courses of R-CHOP-14 before ASCT. Patients then were randomized either to no maintenance or to infusions of 375 mg R per m2 every 2 months for 3 years.
A total of 53% of patients were mantle cell lymphoma international prognostic index (MIPI) low risk, 27% were intermediate and 19% were high-risk. Rituximab maintenance was associated with a 60% lower risk of progression (HR, 0.4; 95% CI, 0.23 to 0.68; P = .0007) and a 50% lower risk of death (HR, 0.5; 95% CI, 0.25 to 0.98; P = .04).
The French Innovative Leukemia Organisation sponsored the trial. Dr. Le Gouill disclosed ties to Roche, Janssen-Cilag, and Celgene.
SAN DIEGO – Maintenance therapy every other month with rituximab significantly prolonged event-free and overall survival after autologous stem cell transplantation among younger patients with mantle cell lymphoma, based on results from a multicenter, randomized, phase 3 trial.
After a median follow-up period of 50 months, 79% of the rituximab maintenance arm remained alive and free of progression, relapse, and severe infection, compared with 61% of the no-maintenance arm (P = .001), said Steven Le Gouill, MD, PhD, at the 2016 meeting of the American Society of Hematology.
This is the first study linking rituximab maintenance after ASCT to improved survival in younger patients with mantle cell lymphoma, said Dr. Le Gouill of Nantes University Hospital in Nantes, France.
The trial “demonstrates for the first time that rituximab maintenance after ASCT prolongs event-free survival, progression-free survival, and overall survival” in younger patients with treatment-naïve mantle cell lymphoma, Dr. Le Gouill said. The findings confirm rituximab maintenance as “a new standard of care” in younger patients with mantle cell lymphoma, he concluded.
Prior research http://www.nejm.org/doi/full/10.1056/NEJMoa1200920#t=abstract supports maintenance therapy with rituximab rather than interferon alfa for older patients whose mantle cell lymphoma responded to induction with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP), noted Dr. Le Gouill. To examine outcomes in younger patients with treatment-naïve mantle cell lymphoma, he and his associates treated 299 individuals aged 65 years and younger (median age, 57 years) with standard induction consisting of 4 courses of rituximab, dexamethasone, high-dose cytarabine, and salt platinum (R-DHAP) every 21 days, followed by conditioning with rituximab plus BiCNU, etoposide, cytarabine, and melphalan (R-BEAM) and ASCT. Patients without at least a partial response to R-DHAP received 4 additional courses of R-CHOP-14 before ASCT. Patients then were randomized either to no maintenance or to infusions of 375 mg R per m2 every 2 months for 3 years.
A total of 53% of patients were mantle cell lymphoma international prognostic index (MIPI) low risk, 27% were intermediate and 19% were high-risk. Rituximab maintenance was associated with a 60% lower risk of progression (HR, 0.4; 95% CI, 0.23 to 0.68; P = .0007) and a 50% lower risk of death (HR, 0.5; 95% CI, 0.25 to 0.98; P = .04).
The French Innovative Leukemia Organisation sponsored the trial. Dr. Le Gouill disclosed ties to Roche, Janssen-Cilag, and Celgene.
SAN DIEGO – Maintenance therapy every other month with rituximab significantly prolonged event-free and overall survival after autologous stem cell transplantation among younger patients with mantle cell lymphoma, based on results from a multicenter, randomized, phase 3 trial.
After a median follow-up period of 50 months, 79% of the rituximab maintenance arm remained alive and free of progression, relapse, and severe infection, compared with 61% of the no-maintenance arm (P = .001), said Steven Le Gouill, MD, PhD, at the 2016 meeting of the American Society of Hematology.
This is the first study linking rituximab maintenance after ASCT to improved survival in younger patients with mantle cell lymphoma, said Dr. Le Gouill of Nantes University Hospital in Nantes, France.
The trial “demonstrates for the first time that rituximab maintenance after ASCT prolongs event-free survival, progression-free survival, and overall survival” in younger patients with treatment-naïve mantle cell lymphoma, Dr. Le Gouill said. The findings confirm rituximab maintenance as “a new standard of care” in younger patients with mantle cell lymphoma, he concluded.
Prior research http://www.nejm.org/doi/full/10.1056/NEJMoa1200920#t=abstract supports maintenance therapy with rituximab rather than interferon alfa for older patients whose mantle cell lymphoma responded to induction with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP), noted Dr. Le Gouill. To examine outcomes in younger patients with treatment-naïve mantle cell lymphoma, he and his associates treated 299 individuals aged 65 years and younger (median age, 57 years) with standard induction consisting of 4 courses of rituximab, dexamethasone, high-dose cytarabine, and salt platinum (R-DHAP) every 21 days, followed by conditioning with rituximab plus BiCNU, etoposide, cytarabine, and melphalan (R-BEAM) and ASCT. Patients without at least a partial response to R-DHAP received 4 additional courses of R-CHOP-14 before ASCT. Patients then were randomized either to no maintenance or to infusions of 375 mg R per m2 every 2 months for 3 years.
A total of 53% of patients were mantle cell lymphoma international prognostic index (MIPI) low risk, 27% were intermediate and 19% were high-risk. Rituximab maintenance was associated with a 60% lower risk of progression (HR, 0.4; 95% CI, 0.23 to 0.68; P = .0007) and a 50% lower risk of death (HR, 0.5; 95% CI, 0.25 to 0.98; P = .04).
The French Innovative Leukemia Organisation sponsored the trial. Dr. Le Gouill disclosed ties to Roche, Janssen-Cilag, and Celgene.
AT ASH 2016
Key clinical point: Maintenance therapy with rituximab after autologous stem cell transplantation was associated with significantly increased survival among younger patients with mantle cell lymphoma.
Major finding: After a median follow-up time of 50 months, 79% of patients who received rituximab maintenance remained alive and free of progression, relapse, and severe infection, compared with 61% of those who received no maintenance therapy (P = .001).
Data source: A multicenter randomized phase 3 trial of 299 adults up to 65 years old with mantle cell lymphoma.
Disclosures: The French Innovative Leukemia Organisation sponsored the trial. Dr. Le Gouill disclosed ties to Roche, Janssen-Cilag, and Celgene.
Ultrashort course antibiotics may be enough in stable VAP
Ultrashort courses of antibiotics led to similar outcomes as longer durations of therapy among adults with suspected ventilator-associated pneumonia but minimal and stable ventilator settings, according to a large retrospective observational study.
The duration of antibiotic therapy did not significantly affect the time to extubation alive (hazard ratio, 1.2; 95% CI, 1.0-1.4), time to hospital discharge (HR, 1.1; 95% CI, 0.9-1.3), rates of ventilator death (HR, 0.8; 95% CI, 0.6-1.2), or rates of hospital death (HR, 1.0; 95% CI, 0.8-1.31).), said Michael Klompas, MD, and his associates at Harvard Medical School in Boston. If confirmed, the findings would support surveillance of serial ventilator settings to “identify candidates for early antibiotic discontinuation,” the investigators reported (Clin Infect Dis. 2016 Dec 29. doi: 10.1093/cid/ciw870).
Suspected respiratory infections account for up to 70% of ICU antibiotic prescriptions, a “substantial fraction” of which may be unnecessary, the researchers said. “The predilection to overprescribe antibiotics for patients with possible ventilator-associated pneumonia (VAP) is not due to poor clinical skills per se, but rather the tension between practice guidelines that encourage early and aggressive prescribing [and] the difficulty [of] accurately diagnosing VAP,” they wrote. While withholding antibiotics in suspected VAP is “unrealistic” and can contribute to mortality, observing clinical trajectories and stopping antibiotics early when appropriate “may be more promising,” they added.
To test that idea, the researchers studied 1,290 cases of suspected VAP treated at Brigham and Women’s Hospital between 2006 and 2014. On the day antibiotics were started and during each of the next 2 days, all patients had a daily minimum positive end-expiratory pressure (PEEP) of no more than 5 cm H2O and a daily minimum fraction of inspired oxygen (FiO2) of no more than 40%.
A total of 259 patients received 1-3 days of antibiotics, while 1,031 patients received more than 3 days of therapy. These two groups were similar demographically, clinically, and in terms of comorbidities. Point estimates tended to favor ultrashort course antibiotics, but no association reached statistical significance in the overall analysis or in subgroups based on confirmed VAP diagnosis, confirmed pathogenic infection, or propensity-matched pairs.
The results suggest “that patients with suspected VAP but minimal and stable ventilator settings can be adequately managed with very short courses of antibiotics,” Dr. Klompas and his associates concluded. “If these findings are confirmed, assessing ventilator settings may prove to be a simple and objective strategy to identify potential candidates for early antibiotic discontinuation.”
The work was supported by the Centers for Disease Control and Prevention’s Prevention Epicenters Program. The investigators had no relevant financial disclosures.
Ultrashort courses of antibiotics led to similar outcomes as longer durations of therapy among adults with suspected ventilator-associated pneumonia but minimal and stable ventilator settings, according to a large retrospective observational study.
The duration of antibiotic therapy did not significantly affect the time to extubation alive (hazard ratio, 1.2; 95% CI, 1.0-1.4), time to hospital discharge (HR, 1.1; 95% CI, 0.9-1.3), rates of ventilator death (HR, 0.8; 95% CI, 0.6-1.2), or rates of hospital death (HR, 1.0; 95% CI, 0.8-1.31).), said Michael Klompas, MD, and his associates at Harvard Medical School in Boston. If confirmed, the findings would support surveillance of serial ventilator settings to “identify candidates for early antibiotic discontinuation,” the investigators reported (Clin Infect Dis. 2016 Dec 29. doi: 10.1093/cid/ciw870).
Suspected respiratory infections account for up to 70% of ICU antibiotic prescriptions, a “substantial fraction” of which may be unnecessary, the researchers said. “The predilection to overprescribe antibiotics for patients with possible ventilator-associated pneumonia (VAP) is not due to poor clinical skills per se, but rather the tension between practice guidelines that encourage early and aggressive prescribing [and] the difficulty [of] accurately diagnosing VAP,” they wrote. While withholding antibiotics in suspected VAP is “unrealistic” and can contribute to mortality, observing clinical trajectories and stopping antibiotics early when appropriate “may be more promising,” they added.
To test that idea, the researchers studied 1,290 cases of suspected VAP treated at Brigham and Women’s Hospital between 2006 and 2014. On the day antibiotics were started and during each of the next 2 days, all patients had a daily minimum positive end-expiratory pressure (PEEP) of no more than 5 cm H2O and a daily minimum fraction of inspired oxygen (FiO2) of no more than 40%.
A total of 259 patients received 1-3 days of antibiotics, while 1,031 patients received more than 3 days of therapy. These two groups were similar demographically, clinically, and in terms of comorbidities. Point estimates tended to favor ultrashort course antibiotics, but no association reached statistical significance in the overall analysis or in subgroups based on confirmed VAP diagnosis, confirmed pathogenic infection, or propensity-matched pairs.
The results suggest “that patients with suspected VAP but minimal and stable ventilator settings can be adequately managed with very short courses of antibiotics,” Dr. Klompas and his associates concluded. “If these findings are confirmed, assessing ventilator settings may prove to be a simple and objective strategy to identify potential candidates for early antibiotic discontinuation.”
The work was supported by the Centers for Disease Control and Prevention’s Prevention Epicenters Program. The investigators had no relevant financial disclosures.
Ultrashort courses of antibiotics led to similar outcomes as longer durations of therapy among adults with suspected ventilator-associated pneumonia but minimal and stable ventilator settings, according to a large retrospective observational study.
The duration of antibiotic therapy did not significantly affect the time to extubation alive (hazard ratio, 1.2; 95% CI, 1.0-1.4), time to hospital discharge (HR, 1.1; 95% CI, 0.9-1.3), rates of ventilator death (HR, 0.8; 95% CI, 0.6-1.2), or rates of hospital death (HR, 1.0; 95% CI, 0.8-1.31).), said Michael Klompas, MD, and his associates at Harvard Medical School in Boston. If confirmed, the findings would support surveillance of serial ventilator settings to “identify candidates for early antibiotic discontinuation,” the investigators reported (Clin Infect Dis. 2016 Dec 29. doi: 10.1093/cid/ciw870).
Suspected respiratory infections account for up to 70% of ICU antibiotic prescriptions, a “substantial fraction” of which may be unnecessary, the researchers said. “The predilection to overprescribe antibiotics for patients with possible ventilator-associated pneumonia (VAP) is not due to poor clinical skills per se, but rather the tension between practice guidelines that encourage early and aggressive prescribing [and] the difficulty [of] accurately diagnosing VAP,” they wrote. While withholding antibiotics in suspected VAP is “unrealistic” and can contribute to mortality, observing clinical trajectories and stopping antibiotics early when appropriate “may be more promising,” they added.
To test that idea, the researchers studied 1,290 cases of suspected VAP treated at Brigham and Women’s Hospital between 2006 and 2014. On the day antibiotics were started and during each of the next 2 days, all patients had a daily minimum positive end-expiratory pressure (PEEP) of no more than 5 cm H2O and a daily minimum fraction of inspired oxygen (FiO2) of no more than 40%.
A total of 259 patients received 1-3 days of antibiotics, while 1,031 patients received more than 3 days of therapy. These two groups were similar demographically, clinically, and in terms of comorbidities. Point estimates tended to favor ultrashort course antibiotics, but no association reached statistical significance in the overall analysis or in subgroups based on confirmed VAP diagnosis, confirmed pathogenic infection, or propensity-matched pairs.
The results suggest “that patients with suspected VAP but minimal and stable ventilator settings can be adequately managed with very short courses of antibiotics,” Dr. Klompas and his associates concluded. “If these findings are confirmed, assessing ventilator settings may prove to be a simple and objective strategy to identify potential candidates for early antibiotic discontinuation.”
The work was supported by the Centers for Disease Control and Prevention’s Prevention Epicenters Program. The investigators had no relevant financial disclosures.
Key clinical point: Ultrashort antibiotic courses yielded outcomes that were similar to those with longer courses in patients with suspected ventilator-associated pneumonia but minimal and stable ventilator settings.
Major finding: The groups did not significantly differ based on time to extubation alive (hazard ratio, 1.2), time to hospital discharge (HR, 1.1; 95% CI, 0.9-1.3), rates of ventilator death (HR, 0.8; 95% CI, 0.6-1.2), or rates of hospital death (HR, 1.0; 95% CI, 0.8-1.31).
Data source: A single-center retrospective observational study of 1,290 patients with suspected ventilator-associated pneumonia.
Disclosures: The work was supported by the Centers for Disease Control and Prevention’s Prevention Epicenters Program. The investigators had no relevant financial disclosures.
VIDEO: Despite toxicities, ibrutinib is beneficial for treatment-resistant graft-vs.-host disease
SAN DIEGO – An oral regimen of 420 mg ibrutinib achieved complete response in one-third of allogeneic stem cell recipients with chronic graft-vs.-host disease, David Miklos, MD, reported during a late-breaker session at the annual meeting of the American Society of Hematology.
Fully 79% of patients in this open-label phase II study were considered responders when first assessed, 71% of responses lasted at least 5 months, and patients whose disease involved multiple organs generally showed responses in at least two organs, said Dr. Miklos of Stanford (Calif.) University.
Ibrutinib is a first-in-class Bruton’s tyrosine kinase (BTK) inhibitor. Cardiotoxicities have been a concern with ibrutinib, but were not observed in this cohort of 42 patients whose graft-vs.-host disease had not benefited from frontline therapy, Dr. Miklos said during a video interview. However, 52% of patients in this study developed other serious adverse events that are typical with ibrutinib, including pneumonia, septic shock, and fever, he said.
Chronic graft-vs.-host disease is the most common morbidity after allogeneic transplant. This is an “orphan disease” – there are no approved therapies for patients for whom corticosteroids are ineffective, Dr. Miklos noted. Based on these results, investigators are planning a randomized, placebo-controlled, phase III study, he added.
Ibrutinib is jointly commercialized and developed by Janssen Biotech and by Pharmacyclics LLC, an Abbvie company. Dr. Miklos disclosed a consulting relationship, travel and expenses reimbursements, and research funding from Pharmacyclics.
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SAN DIEGO – An oral regimen of 420 mg ibrutinib achieved complete response in one-third of allogeneic stem cell recipients with chronic graft-vs.-host disease, David Miklos, MD, reported during a late-breaker session at the annual meeting of the American Society of Hematology.
Fully 79% of patients in this open-label phase II study were considered responders when first assessed, 71% of responses lasted at least 5 months, and patients whose disease involved multiple organs generally showed responses in at least two organs, said Dr. Miklos of Stanford (Calif.) University.
Ibrutinib is a first-in-class Bruton’s tyrosine kinase (BTK) inhibitor. Cardiotoxicities have been a concern with ibrutinib, but were not observed in this cohort of 42 patients whose graft-vs.-host disease had not benefited from frontline therapy, Dr. Miklos said during a video interview. However, 52% of patients in this study developed other serious adverse events that are typical with ibrutinib, including pneumonia, septic shock, and fever, he said.
Chronic graft-vs.-host disease is the most common morbidity after allogeneic transplant. This is an “orphan disease” – there are no approved therapies for patients for whom corticosteroids are ineffective, Dr. Miklos noted. Based on these results, investigators are planning a randomized, placebo-controlled, phase III study, he added.
Ibrutinib is jointly commercialized and developed by Janssen Biotech and by Pharmacyclics LLC, an Abbvie company. Dr. Miklos disclosed a consulting relationship, travel and expenses reimbursements, and research funding from Pharmacyclics.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
SAN DIEGO – An oral regimen of 420 mg ibrutinib achieved complete response in one-third of allogeneic stem cell recipients with chronic graft-vs.-host disease, David Miklos, MD, reported during a late-breaker session at the annual meeting of the American Society of Hematology.
Fully 79% of patients in this open-label phase II study were considered responders when first assessed, 71% of responses lasted at least 5 months, and patients whose disease involved multiple organs generally showed responses in at least two organs, said Dr. Miklos of Stanford (Calif.) University.
Ibrutinib is a first-in-class Bruton’s tyrosine kinase (BTK) inhibitor. Cardiotoxicities have been a concern with ibrutinib, but were not observed in this cohort of 42 patients whose graft-vs.-host disease had not benefited from frontline therapy, Dr. Miklos said during a video interview. However, 52% of patients in this study developed other serious adverse events that are typical with ibrutinib, including pneumonia, septic shock, and fever, he said.
Chronic graft-vs.-host disease is the most common morbidity after allogeneic transplant. This is an “orphan disease” – there are no approved therapies for patients for whom corticosteroids are ineffective, Dr. Miklos noted. Based on these results, investigators are planning a randomized, placebo-controlled, phase III study, he added.
Ibrutinib is jointly commercialized and developed by Janssen Biotech and by Pharmacyclics LLC, an Abbvie company. Dr. Miklos disclosed a consulting relationship, travel and expenses reimbursements, and research funding from Pharmacyclics.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
AT ASH 2016
Key clinical point: Ibrutinib (420 mg) led to complete responses in one-third of patients with chronic, treatment-resistant graft-vs-host disease.
Major finding: No cardiotoxicities were observed, but 52% of patients had other serious adverse effects, such as sepsis, pyrexia, and pneumonia.
Data source: An open-label phase II study of 42 patients who developed chronic, treatment-resistant graft-vs.-host disease after undergoing allogeneic stem cell transplantation.
Disclosures: Ibrutinib is jointly commercialized and developed by Janssen Biotech and by Pharmacyclics LLC, an Abbvie company. Dr. Miklos disclosed a consulting relationship, reimbursement for travel and expenses, and research funding from Pharmacyclics.
