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First treat-to-target gout trial supports allopurinol dose escalation
Gradual dose escalation of allopurinol achieved target serum urate levels without causing excess adverse effects in patients with gout who tolerated but responded inadequately to creatinine clearance–based dosing, including in patients with chronic kidney disease, investigators reported in Annals of the Rheumatic Diseases.
The study is the first randomized, controlled trial to examine treat-to-target allopurinol dose escalation in gout. “We believe this approach can be undertaken in all patients who tolerate allopurinol,” lead investigator Lisa Stamp, MD, said in an interview. However, it is important to monitor kidney and liver function.”
To help settle these debates, Dr. Stamp and her associates recruited 183 patients with gout whose serum urate levels averaged 7.15 mg/dL (standard deviation, 1.6 mg/dL) despite at least 1 month of at least a creatinine clearance–based allopurinol dose (average, 269 mg/day). For the next 12 months, patients either continued this dose or increased it monthly until serum urate fell below 6 mg/dL (Ann Rheum Dis. 2017 March 17. doi: 10.1136/annrheumdis-2016-210872).
At month 12, 69% of dose-escalation patients and 32% of controls reached this target (P less than .001; odds ratio, 4.3; 95% confidence interval, 2.4-7.9). Serum urate levels dropped by a mean of 1.5 mg/dL with dose escalation and by 0.34 mg/dL in controls (P less than .001). Thus, dose escalation cut serum urate levels by an additional 1.2 mg/dL (95% CI, 0.67-1.5 mg/dL; P less than .001). The average final daily allopurinol dose was 413 mg (range, 0-900 mg) with dose escalation and 288 mg (0-600 mg) for controls.
Notably, renal function measures did not differ between arms. “There has been long-standing concern about whether it is safe to escalate allopurinol doses in persons with chronic kidney disease,” said Kenneth Saag, MD, of the University of Alabama at Birmingham, who was not involved in the trial. “This study contributes to the limited literature supporting the practice of treating to serum urate targets, even in patients with underlying kidney disease.”
Fully 52% of trial participants had chronic kidney disease, and 44% had tophi. “Thus, our population is representative of people with gout, represents real-life clinical practice, and the results are generalizable to other gout populations,” the investigators wrote.
The findings support the ACR recommendation to gradually titrate urate-lowering therapy while performing close laboratory monitoring, said Tuhina Neogi, MD, of Boston University, who was not involved in the study. This approach is “efficacious and relatively safe for patients who have already tolerated lower doses of allopurinol, but have not yet achieved their serum urate target,” she said. “This is akin to finding the right regimen and titrating doses of medications for patients with diabetes or hypertension in a patient-centered manner.”
Patients in both groups developed mild increases in liver function tests, and a few in the dose escalation group developed more pronounced rises in gamma glutamyl transferase (GGT), as previously reported in the LASSO trial (Semin Arthritis Rheum. 2015 Oct;45[2]:174-83). Allopurinol has been linked to liver enzyme abnormalities, and the GGT finding is of unclear significance, but laboratory monitoring is important, Dr. Neogi said. If primary care providers who treat gout cannot routinely measure serum urate and other relevant laboratory measures, they should consider referring patients to a rheumatologist, she added.
Gradual dose escalation meant that patients did not reach the serum urate target until month 7, Dr. Neogi added. “Since the trial was 12 months long, the time over which serum urate was less than 6 mg/dL was not long enough to demonstrate the benefits on flares and tophi,” she said. The open-label extension phase of the trial should shed more insight on these important questions, she added.
For now, providers should know that “patients with gout are not well served if their serum urate levels remain elevated, as that means they are at ongoing risk for flares and tophi,” Dr. Neogi said. “This trial provides evidence and further support for the feasibility, efficacy, and relative safety of escalating allopurinol beyond creatinine-clearance dosing to achieve this important and critical goal for gout management.”
The Health Research Council of New Zealand funded the study. Dr. Stamp and two coinvestigators disclosed grant support from the Health Research Council of New Zealand. Dr. Stamp also disclosed grants from Ardea Biosciences and the Health Research Council of New Zealand outside the submitted work, and her coinvestigators disclosed grants and personal fees from AstraZeneca, Ardea Biosciences, Takeda, and several other pharmaceutical companies. Dr. Neogi had no disclosures. Dr. Saag has received meal compensation from Eli Lilly.
Gradual dose escalation of allopurinol achieved target serum urate levels without causing excess adverse effects in patients with gout who tolerated but responded inadequately to creatinine clearance–based dosing, including in patients with chronic kidney disease, investigators reported in Annals of the Rheumatic Diseases.
The study is the first randomized, controlled trial to examine treat-to-target allopurinol dose escalation in gout. “We believe this approach can be undertaken in all patients who tolerate allopurinol,” lead investigator Lisa Stamp, MD, said in an interview. However, it is important to monitor kidney and liver function.”
To help settle these debates, Dr. Stamp and her associates recruited 183 patients with gout whose serum urate levels averaged 7.15 mg/dL (standard deviation, 1.6 mg/dL) despite at least 1 month of at least a creatinine clearance–based allopurinol dose (average, 269 mg/day). For the next 12 months, patients either continued this dose or increased it monthly until serum urate fell below 6 mg/dL (Ann Rheum Dis. 2017 March 17. doi: 10.1136/annrheumdis-2016-210872).
At month 12, 69% of dose-escalation patients and 32% of controls reached this target (P less than .001; odds ratio, 4.3; 95% confidence interval, 2.4-7.9). Serum urate levels dropped by a mean of 1.5 mg/dL with dose escalation and by 0.34 mg/dL in controls (P less than .001). Thus, dose escalation cut serum urate levels by an additional 1.2 mg/dL (95% CI, 0.67-1.5 mg/dL; P less than .001). The average final daily allopurinol dose was 413 mg (range, 0-900 mg) with dose escalation and 288 mg (0-600 mg) for controls.
Notably, renal function measures did not differ between arms. “There has been long-standing concern about whether it is safe to escalate allopurinol doses in persons with chronic kidney disease,” said Kenneth Saag, MD, of the University of Alabama at Birmingham, who was not involved in the trial. “This study contributes to the limited literature supporting the practice of treating to serum urate targets, even in patients with underlying kidney disease.”
Fully 52% of trial participants had chronic kidney disease, and 44% had tophi. “Thus, our population is representative of people with gout, represents real-life clinical practice, and the results are generalizable to other gout populations,” the investigators wrote.
The findings support the ACR recommendation to gradually titrate urate-lowering therapy while performing close laboratory monitoring, said Tuhina Neogi, MD, of Boston University, who was not involved in the study. This approach is “efficacious and relatively safe for patients who have already tolerated lower doses of allopurinol, but have not yet achieved their serum urate target,” she said. “This is akin to finding the right regimen and titrating doses of medications for patients with diabetes or hypertension in a patient-centered manner.”
Patients in both groups developed mild increases in liver function tests, and a few in the dose escalation group developed more pronounced rises in gamma glutamyl transferase (GGT), as previously reported in the LASSO trial (Semin Arthritis Rheum. 2015 Oct;45[2]:174-83). Allopurinol has been linked to liver enzyme abnormalities, and the GGT finding is of unclear significance, but laboratory monitoring is important, Dr. Neogi said. If primary care providers who treat gout cannot routinely measure serum urate and other relevant laboratory measures, they should consider referring patients to a rheumatologist, she added.
Gradual dose escalation meant that patients did not reach the serum urate target until month 7, Dr. Neogi added. “Since the trial was 12 months long, the time over which serum urate was less than 6 mg/dL was not long enough to demonstrate the benefits on flares and tophi,” she said. The open-label extension phase of the trial should shed more insight on these important questions, she added.
For now, providers should know that “patients with gout are not well served if their serum urate levels remain elevated, as that means they are at ongoing risk for flares and tophi,” Dr. Neogi said. “This trial provides evidence and further support for the feasibility, efficacy, and relative safety of escalating allopurinol beyond creatinine-clearance dosing to achieve this important and critical goal for gout management.”
The Health Research Council of New Zealand funded the study. Dr. Stamp and two coinvestigators disclosed grant support from the Health Research Council of New Zealand. Dr. Stamp also disclosed grants from Ardea Biosciences and the Health Research Council of New Zealand outside the submitted work, and her coinvestigators disclosed grants and personal fees from AstraZeneca, Ardea Biosciences, Takeda, and several other pharmaceutical companies. Dr. Neogi had no disclosures. Dr. Saag has received meal compensation from Eli Lilly.
Gradual dose escalation of allopurinol achieved target serum urate levels without causing excess adverse effects in patients with gout who tolerated but responded inadequately to creatinine clearance–based dosing, including in patients with chronic kidney disease, investigators reported in Annals of the Rheumatic Diseases.
The study is the first randomized, controlled trial to examine treat-to-target allopurinol dose escalation in gout. “We believe this approach can be undertaken in all patients who tolerate allopurinol,” lead investigator Lisa Stamp, MD, said in an interview. However, it is important to monitor kidney and liver function.”
To help settle these debates, Dr. Stamp and her associates recruited 183 patients with gout whose serum urate levels averaged 7.15 mg/dL (standard deviation, 1.6 mg/dL) despite at least 1 month of at least a creatinine clearance–based allopurinol dose (average, 269 mg/day). For the next 12 months, patients either continued this dose or increased it monthly until serum urate fell below 6 mg/dL (Ann Rheum Dis. 2017 March 17. doi: 10.1136/annrheumdis-2016-210872).
At month 12, 69% of dose-escalation patients and 32% of controls reached this target (P less than .001; odds ratio, 4.3; 95% confidence interval, 2.4-7.9). Serum urate levels dropped by a mean of 1.5 mg/dL with dose escalation and by 0.34 mg/dL in controls (P less than .001). Thus, dose escalation cut serum urate levels by an additional 1.2 mg/dL (95% CI, 0.67-1.5 mg/dL; P less than .001). The average final daily allopurinol dose was 413 mg (range, 0-900 mg) with dose escalation and 288 mg (0-600 mg) for controls.
Notably, renal function measures did not differ between arms. “There has been long-standing concern about whether it is safe to escalate allopurinol doses in persons with chronic kidney disease,” said Kenneth Saag, MD, of the University of Alabama at Birmingham, who was not involved in the trial. “This study contributes to the limited literature supporting the practice of treating to serum urate targets, even in patients with underlying kidney disease.”
Fully 52% of trial participants had chronic kidney disease, and 44% had tophi. “Thus, our population is representative of people with gout, represents real-life clinical practice, and the results are generalizable to other gout populations,” the investigators wrote.
The findings support the ACR recommendation to gradually titrate urate-lowering therapy while performing close laboratory monitoring, said Tuhina Neogi, MD, of Boston University, who was not involved in the study. This approach is “efficacious and relatively safe for patients who have already tolerated lower doses of allopurinol, but have not yet achieved their serum urate target,” she said. “This is akin to finding the right regimen and titrating doses of medications for patients with diabetes or hypertension in a patient-centered manner.”
Patients in both groups developed mild increases in liver function tests, and a few in the dose escalation group developed more pronounced rises in gamma glutamyl transferase (GGT), as previously reported in the LASSO trial (Semin Arthritis Rheum. 2015 Oct;45[2]:174-83). Allopurinol has been linked to liver enzyme abnormalities, and the GGT finding is of unclear significance, but laboratory monitoring is important, Dr. Neogi said. If primary care providers who treat gout cannot routinely measure serum urate and other relevant laboratory measures, they should consider referring patients to a rheumatologist, she added.
Gradual dose escalation meant that patients did not reach the serum urate target until month 7, Dr. Neogi added. “Since the trial was 12 months long, the time over which serum urate was less than 6 mg/dL was not long enough to demonstrate the benefits on flares and tophi,” she said. The open-label extension phase of the trial should shed more insight on these important questions, she added.
For now, providers should know that “patients with gout are not well served if their serum urate levels remain elevated, as that means they are at ongoing risk for flares and tophi,” Dr. Neogi said. “This trial provides evidence and further support for the feasibility, efficacy, and relative safety of escalating allopurinol beyond creatinine-clearance dosing to achieve this important and critical goal for gout management.”
The Health Research Council of New Zealand funded the study. Dr. Stamp and two coinvestigators disclosed grant support from the Health Research Council of New Zealand. Dr. Stamp also disclosed grants from Ardea Biosciences and the Health Research Council of New Zealand outside the submitted work, and her coinvestigators disclosed grants and personal fees from AstraZeneca, Ardea Biosciences, Takeda, and several other pharmaceutical companies. Dr. Neogi had no disclosures. Dr. Saag has received meal compensation from Eli Lilly.
FROM ANNALS OF THE RHEUMATIC DISEASES
Key clinical point:
Major finding: At month 12, 69% of dose escalation patients and 32% of controls had serum urate levels below 6 mg/dL (P less than .001). Dose escalation did not increase the risk of serious adverse effects.
Data source: A 12-month, open-label, randomized, controlled, parallel-group, comparative trial of 186 patients with gout.
Disclosures: The Health Research Council of New Zealand funded the study. Dr. Stamp and two coinvestigators disclosed grant support from Health Research Council of New Zealand. Dr. Stamp also disclosed grants from Ardea Biosciences and Health Research Council of New Zealand outside the submitted work, and her coinvestigators disclosed grants and personal fees from AstraZeneca, Ardea Biosciences, Takeda, and several other pharmaceutical companies. Dr. Neogi had no disclosures. Dr. Saag has received meal compensation from Eli Lilly.
Elbasvir, grazoprevir beat HCV despite compensated cirrhosis
Twelve weeks of combination therapy with elbasvir and grazoprevir (EBR/GZR) achieved sustained virologic response in 98% of treatment-naive patients with compensated cirrhosis and chronic hepatitis C (HCV) genotype 1, 4, or 6 infections, and in 89% of treatment-experienced patients, according to a pooled analysis of six industry-sponsored trials.
Concomitant ribavirin offered “no incremental benefit” for treatment-naive patients, while 16 or 18 weeks of EBR and GZR with ribavirin achieved SVR12 in 100% of treatment-experienced patients, wrote Ira M. Jacobson, MD, of Mount Sinai Beth Israel and Icahn School of Medicine at Mount Sinai, New York, and his associates. The report was published in the May issue of Gastroenterology (doi: 10.1053/j.gastro.2017.01.050).
Regardless of treatment history, genotype 1a patients with resistance-associated variants (RAV) in HCV nonstructural protein 5A (NS5A) needed ribavirin to achieve sustained virologic response (SVR) rates above 90%, the researchers emphasized. “Both patients with HCV genotype 1a infection with baseline RAVs who received 16 or 18 weeks of EBR/GZR and ribavirin achieved SVR12,” the researchers noted. Elbasvir is an HCV NS5A inhibitor, and GZR is an HCV NS3/4A protease inhibitor. In 2016, the Food and Drug Administration approved them in combination (Zepatier) for chronic genotype 1 and genotype 4 HCV. Studies have confirmed the benefits of treating HCV even when patients have cirrhosis, but they can be challenging to treat, especially if they have already failed a regimen that included a direct-acting antiviral agent, the investigators noted.
To explore the efficacy of EBR/GZR in compensated, Child-Pugh A cirrhosis, they studied 402 such patients with HCV genotype 1, 4, or 6 infections whose baseline HCV RNA level exceeded 10,000 IU. Patients had participated in one of six phase II/III clinical trials and had received EBR/GZR 50 mg/100 mg once daily for 12-18 weeks, with or without ribavirin (800-1400 mg/day based on body weight). Treatment-naive patients received 12 weeks of treatment, while treatment-experienced patients received 12, 16, or 18 weeks of treatment.
Twelve weeks of ribavirin did not boost SVR for either treatment-naive (90%) or treatment-experienced patients (91%), the researchers said. However, all 49 treatment-experienced patients who received EBR/GZR plus ribavirin for 16 or 18 weeks achieved SVR12, compared to 94% of patients who received EBR/GZR without ribavirin for 16 or 18 weeks.
Virologic failure was more common with HCV genotype 1a infections than with genotype 1b or 4 infection, especially if patients previously had not responded to interferon, the researchers noted. Eight of 11 (73%) patients with HCV genotype 1a infection and baseline NS5A RAVs achieved SVR12, compared with 98% of GT1a-infected patients without RAVs at baseline. But EBR/GZR was effective in various other subgroups, including patients with less than 100,000 platelets per microL, serum albumin below 3.5 g/dL, and FibroScan scores below 25 kPa. These findings suggest that EBR/GZR remains effective in patients with advanced compensated cirrhosis, the investigators said.
Most patients tolerated therapy, but six stopped treatment because of adverse events, including one episode of severe, possibly treatment-related abdominal pain. Also, four patients had late, asymptomatic rises in alanine aminotransferase (ALT) after first normalizing on treatment, and one patient stopped treatment because of grade 4 ALT elevation with eosinophilia. “There were no decompensation events in this generally healthy cirrhotic population, and no other evidence of declining liver function while on treatment,” the researchers added.
The integrated analysis was not prespecified, nor was it powered to compare outcomes between treatment arms. Only three patients had genotype 6 infection, and all were treatment-experienced. Only 23 patients had genotype 4 infection. Also, most patients had well-compensated cirrhosis. Finally, the trials varied in terms of how they defined cirrhosis, the investigators noted.
Merck, which funded the study, makes elbasvir and grazoprevir. The investigators acknowledged medical writing and editorial assistance from ApotheCom, which Merck funded. Dr. Jacobson disclosed consulting relationships and grant funding from Merck, AbbVie, Bristol-Myers Squibb, Gilead, Intercept, Janssen, and Trek.
Twelve weeks of combination therapy with elbasvir and grazoprevir (EBR/GZR) achieved sustained virologic response in 98% of treatment-naive patients with compensated cirrhosis and chronic hepatitis C (HCV) genotype 1, 4, or 6 infections, and in 89% of treatment-experienced patients, according to a pooled analysis of six industry-sponsored trials.
Concomitant ribavirin offered “no incremental benefit” for treatment-naive patients, while 16 or 18 weeks of EBR and GZR with ribavirin achieved SVR12 in 100% of treatment-experienced patients, wrote Ira M. Jacobson, MD, of Mount Sinai Beth Israel and Icahn School of Medicine at Mount Sinai, New York, and his associates. The report was published in the May issue of Gastroenterology (doi: 10.1053/j.gastro.2017.01.050).
Regardless of treatment history, genotype 1a patients with resistance-associated variants (RAV) in HCV nonstructural protein 5A (NS5A) needed ribavirin to achieve sustained virologic response (SVR) rates above 90%, the researchers emphasized. “Both patients with HCV genotype 1a infection with baseline RAVs who received 16 or 18 weeks of EBR/GZR and ribavirin achieved SVR12,” the researchers noted. Elbasvir is an HCV NS5A inhibitor, and GZR is an HCV NS3/4A protease inhibitor. In 2016, the Food and Drug Administration approved them in combination (Zepatier) for chronic genotype 1 and genotype 4 HCV. Studies have confirmed the benefits of treating HCV even when patients have cirrhosis, but they can be challenging to treat, especially if they have already failed a regimen that included a direct-acting antiviral agent, the investigators noted.
To explore the efficacy of EBR/GZR in compensated, Child-Pugh A cirrhosis, they studied 402 such patients with HCV genotype 1, 4, or 6 infections whose baseline HCV RNA level exceeded 10,000 IU. Patients had participated in one of six phase II/III clinical trials and had received EBR/GZR 50 mg/100 mg once daily for 12-18 weeks, with or without ribavirin (800-1400 mg/day based on body weight). Treatment-naive patients received 12 weeks of treatment, while treatment-experienced patients received 12, 16, or 18 weeks of treatment.
Twelve weeks of ribavirin did not boost SVR for either treatment-naive (90%) or treatment-experienced patients (91%), the researchers said. However, all 49 treatment-experienced patients who received EBR/GZR plus ribavirin for 16 or 18 weeks achieved SVR12, compared to 94% of patients who received EBR/GZR without ribavirin for 16 or 18 weeks.
Virologic failure was more common with HCV genotype 1a infections than with genotype 1b or 4 infection, especially if patients previously had not responded to interferon, the researchers noted. Eight of 11 (73%) patients with HCV genotype 1a infection and baseline NS5A RAVs achieved SVR12, compared with 98% of GT1a-infected patients without RAVs at baseline. But EBR/GZR was effective in various other subgroups, including patients with less than 100,000 platelets per microL, serum albumin below 3.5 g/dL, and FibroScan scores below 25 kPa. These findings suggest that EBR/GZR remains effective in patients with advanced compensated cirrhosis, the investigators said.
Most patients tolerated therapy, but six stopped treatment because of adverse events, including one episode of severe, possibly treatment-related abdominal pain. Also, four patients had late, asymptomatic rises in alanine aminotransferase (ALT) after first normalizing on treatment, and one patient stopped treatment because of grade 4 ALT elevation with eosinophilia. “There were no decompensation events in this generally healthy cirrhotic population, and no other evidence of declining liver function while on treatment,” the researchers added.
The integrated analysis was not prespecified, nor was it powered to compare outcomes between treatment arms. Only three patients had genotype 6 infection, and all were treatment-experienced. Only 23 patients had genotype 4 infection. Also, most patients had well-compensated cirrhosis. Finally, the trials varied in terms of how they defined cirrhosis, the investigators noted.
Merck, which funded the study, makes elbasvir and grazoprevir. The investigators acknowledged medical writing and editorial assistance from ApotheCom, which Merck funded. Dr. Jacobson disclosed consulting relationships and grant funding from Merck, AbbVie, Bristol-Myers Squibb, Gilead, Intercept, Janssen, and Trek.
Twelve weeks of combination therapy with elbasvir and grazoprevir (EBR/GZR) achieved sustained virologic response in 98% of treatment-naive patients with compensated cirrhosis and chronic hepatitis C (HCV) genotype 1, 4, or 6 infections, and in 89% of treatment-experienced patients, according to a pooled analysis of six industry-sponsored trials.
Concomitant ribavirin offered “no incremental benefit” for treatment-naive patients, while 16 or 18 weeks of EBR and GZR with ribavirin achieved SVR12 in 100% of treatment-experienced patients, wrote Ira M. Jacobson, MD, of Mount Sinai Beth Israel and Icahn School of Medicine at Mount Sinai, New York, and his associates. The report was published in the May issue of Gastroenterology (doi: 10.1053/j.gastro.2017.01.050).
Regardless of treatment history, genotype 1a patients with resistance-associated variants (RAV) in HCV nonstructural protein 5A (NS5A) needed ribavirin to achieve sustained virologic response (SVR) rates above 90%, the researchers emphasized. “Both patients with HCV genotype 1a infection with baseline RAVs who received 16 or 18 weeks of EBR/GZR and ribavirin achieved SVR12,” the researchers noted. Elbasvir is an HCV NS5A inhibitor, and GZR is an HCV NS3/4A protease inhibitor. In 2016, the Food and Drug Administration approved them in combination (Zepatier) for chronic genotype 1 and genotype 4 HCV. Studies have confirmed the benefits of treating HCV even when patients have cirrhosis, but they can be challenging to treat, especially if they have already failed a regimen that included a direct-acting antiviral agent, the investigators noted.
To explore the efficacy of EBR/GZR in compensated, Child-Pugh A cirrhosis, they studied 402 such patients with HCV genotype 1, 4, or 6 infections whose baseline HCV RNA level exceeded 10,000 IU. Patients had participated in one of six phase II/III clinical trials and had received EBR/GZR 50 mg/100 mg once daily for 12-18 weeks, with or without ribavirin (800-1400 mg/day based on body weight). Treatment-naive patients received 12 weeks of treatment, while treatment-experienced patients received 12, 16, or 18 weeks of treatment.
Twelve weeks of ribavirin did not boost SVR for either treatment-naive (90%) or treatment-experienced patients (91%), the researchers said. However, all 49 treatment-experienced patients who received EBR/GZR plus ribavirin for 16 or 18 weeks achieved SVR12, compared to 94% of patients who received EBR/GZR without ribavirin for 16 or 18 weeks.
Virologic failure was more common with HCV genotype 1a infections than with genotype 1b or 4 infection, especially if patients previously had not responded to interferon, the researchers noted. Eight of 11 (73%) patients with HCV genotype 1a infection and baseline NS5A RAVs achieved SVR12, compared with 98% of GT1a-infected patients without RAVs at baseline. But EBR/GZR was effective in various other subgroups, including patients with less than 100,000 platelets per microL, serum albumin below 3.5 g/dL, and FibroScan scores below 25 kPa. These findings suggest that EBR/GZR remains effective in patients with advanced compensated cirrhosis, the investigators said.
Most patients tolerated therapy, but six stopped treatment because of adverse events, including one episode of severe, possibly treatment-related abdominal pain. Also, four patients had late, asymptomatic rises in alanine aminotransferase (ALT) after first normalizing on treatment, and one patient stopped treatment because of grade 4 ALT elevation with eosinophilia. “There were no decompensation events in this generally healthy cirrhotic population, and no other evidence of declining liver function while on treatment,” the researchers added.
The integrated analysis was not prespecified, nor was it powered to compare outcomes between treatment arms. Only three patients had genotype 6 infection, and all were treatment-experienced. Only 23 patients had genotype 4 infection. Also, most patients had well-compensated cirrhosis. Finally, the trials varied in terms of how they defined cirrhosis, the investigators noted.
Merck, which funded the study, makes elbasvir and grazoprevir. The investigators acknowledged medical writing and editorial assistance from ApotheCom, which Merck funded. Dr. Jacobson disclosed consulting relationships and grant funding from Merck, AbbVie, Bristol-Myers Squibb, Gilead, Intercept, Janssen, and Trek.
FROM GASTROENTEROLOGY
Key clinical point: Twelve weeks of combination therapy with elbasvir and grazoprevir was relatively well tolerated and achieved sustained viral response for most patients with chronic genotype 1, 4, or 6 hepatitis C virus infections and compensated cirrhosis.
Major finding: Rates of sustained virologic response were 98% for treatment-naive patients and 89% for treatment-experienced patients.
Data source: An integrated analysis of 402 patients with treatment-naive or treatment-experienced HCV GT1, 4, or 6 infection and compensated, Child-Pugh A cirrhosis.
Disclosures: Merck, which funded the study, makes elbasvir and grazoprevir. The investigators acknowledged medical writing and editorial assistance from ApotheCom, which Merck funded. Dr. Jacobson disclosed consulting relationships and grant funding from Merck, AbbVie, Bristol-Myers Squibb, Gilead, Intercept, Janssen, and Trek.
VIDEO: Study estimates prevalence of pediatric celiac disease, autoimmunity
By age 15 years, 3.1% of adolescents in Denver developed celiac disease, and another 2% developed a lesser degree of celiac disease autoimmunity, according to a 20-year prospective longitudinal study.
“Although more than 5% of children may experience a period of celiac disease autoimmunity [CDA], not all develop celiac disease [CD] or require gluten-free diets,” Edwin Liu, MD, of University of Colorado School of Medicine and Children’s Hospital Colorado (Aurora, Colo.), wrote with his associates in the May issue of Gastroenterology (doi: 10.1053/j.gastro.2017.02.002). Most celiac autoimmunity probably develops before age 10, “which informs future efforts for universal screening,” they added.
Source: American Gastroenterological Association
About 40% of the general population has the HLA-DQ2 or DQ8 risk genotypes for celiac disease [CD], but little is known about rates of celiac disease among children in the United States, the researchers said. To help fill this gap, they analyzed celiac-risk HLA genotypes for 31,766 infants born between 1993 and 2004 from the Diabetes Autoimmunity Study in the Young. The 1,339 children with HLA risk genotypes were followed for up to 20 years.
By age 15 years, 66 of these children (4.9%) had developed tissue transglutaminase autoantibodies (tTGA) consistent with CDA, and also met criteria for CD, the researchers said. Another 46 (3.4%) children developed only CDA, of whom 46% experienced spontaneous resolution of tTGA seropositivity without treatment. By using genotype-specific risk weighting for population frequencies of HLA, the researchers estimated that 2.4% of the general population of Denver had CDA by age 5 years, 4.3% had CDA by age 10 years, and 5.1% had CDA by age 15 years. Estimated rates of CD were 1.6%, 2.8%, and 3.1%, respectively.
These findings suggest a significant rise in the incidence of CD compared with historical estimates in the United States, and reflect recent studies “using different approaches in North America,” the researchers said. Reasons for the “dramatic increase” are unknown, but environmental causes seem likely, especially given the absence of identified genetic differences and marked changes in the prevalence of CD during the past 2 decades, they added.
Several other reports have documented fluctuating and transient tTGA antibodies in children, the researchers noted. Awareness of transient CD autoantibodies might limit public acceptance of universal screening programs for CD, they said. “Continued long-term follow-up will identify whether the autoimmunity in these subjects truly abates and tolerance develops, or if CDA will recur in time, possibly in response to additional stimulating events,” they added. “At present, low positive tTGA results should be interpreted with caution, and do not necessarily indicate need for biopsy or for treatment.”
The study did not include the DR5/DR7 risk genotype, which accounts for less than 5% of CD cases. The study also did not account for the estimated 2.5% of the general population that has DR3/DR7, which can be considered high risk, the researchers said. Thus, the study is conservative and might underestimate the real incidence of CD or CDA, they added.
The National Institutes of Health provided funding. The investigators reported having no conflicts of interest.
This study calls into question the incidence of celiac disease in the modern pediatric population and, by extension, future prevalence in adults. This is a unique prospective cohort study that followed children over a decade and a half and estimated a cumulative incidence of celiac disease of 3.1% by age 15. In sharp contrast, previous retrospective population-based studies estimated a prevalence of approximately 0.75%-1% in adult and pediatric populations. A recent publication by the United States Preventive Services Task Force used the previously accepted prevalence estimates to recommend against routine screening for celiac disease in the asymptomatic general population as well as targeted screening in those at higher risk. Increases in disease incidence as reported by the current study may call these recommendations into question, particularly in young children where cumulative incidence was high and potential for treatment benefit is substantial.
Dawn Wiese Adams, MD, MS, is assistant professor, director of celiac clinic, in the department of gastroenterology, hepatology, and nutrition, Vanderbilt University Medical Center, Nashville, Tenn. She has no conflicts of interest.
This study calls into question the incidence of celiac disease in the modern pediatric population and, by extension, future prevalence in adults. This is a unique prospective cohort study that followed children over a decade and a half and estimated a cumulative incidence of celiac disease of 3.1% by age 15. In sharp contrast, previous retrospective population-based studies estimated a prevalence of approximately 0.75%-1% in adult and pediatric populations. A recent publication by the United States Preventive Services Task Force used the previously accepted prevalence estimates to recommend against routine screening for celiac disease in the asymptomatic general population as well as targeted screening in those at higher risk. Increases in disease incidence as reported by the current study may call these recommendations into question, particularly in young children where cumulative incidence was high and potential for treatment benefit is substantial.
Dawn Wiese Adams, MD, MS, is assistant professor, director of celiac clinic, in the department of gastroenterology, hepatology, and nutrition, Vanderbilt University Medical Center, Nashville, Tenn. She has no conflicts of interest.
This study calls into question the incidence of celiac disease in the modern pediatric population and, by extension, future prevalence in adults. This is a unique prospective cohort study that followed children over a decade and a half and estimated a cumulative incidence of celiac disease of 3.1% by age 15. In sharp contrast, previous retrospective population-based studies estimated a prevalence of approximately 0.75%-1% in adult and pediatric populations. A recent publication by the United States Preventive Services Task Force used the previously accepted prevalence estimates to recommend against routine screening for celiac disease in the asymptomatic general population as well as targeted screening in those at higher risk. Increases in disease incidence as reported by the current study may call these recommendations into question, particularly in young children where cumulative incidence was high and potential for treatment benefit is substantial.
Dawn Wiese Adams, MD, MS, is assistant professor, director of celiac clinic, in the department of gastroenterology, hepatology, and nutrition, Vanderbilt University Medical Center, Nashville, Tenn. She has no conflicts of interest.
By age 15 years, 3.1% of adolescents in Denver developed celiac disease, and another 2% developed a lesser degree of celiac disease autoimmunity, according to a 20-year prospective longitudinal study.
“Although more than 5% of children may experience a period of celiac disease autoimmunity [CDA], not all develop celiac disease [CD] or require gluten-free diets,” Edwin Liu, MD, of University of Colorado School of Medicine and Children’s Hospital Colorado (Aurora, Colo.), wrote with his associates in the May issue of Gastroenterology (doi: 10.1053/j.gastro.2017.02.002). Most celiac autoimmunity probably develops before age 10, “which informs future efforts for universal screening,” they added.
Source: American Gastroenterological Association
About 40% of the general population has the HLA-DQ2 or DQ8 risk genotypes for celiac disease [CD], but little is known about rates of celiac disease among children in the United States, the researchers said. To help fill this gap, they analyzed celiac-risk HLA genotypes for 31,766 infants born between 1993 and 2004 from the Diabetes Autoimmunity Study in the Young. The 1,339 children with HLA risk genotypes were followed for up to 20 years.
By age 15 years, 66 of these children (4.9%) had developed tissue transglutaminase autoantibodies (tTGA) consistent with CDA, and also met criteria for CD, the researchers said. Another 46 (3.4%) children developed only CDA, of whom 46% experienced spontaneous resolution of tTGA seropositivity without treatment. By using genotype-specific risk weighting for population frequencies of HLA, the researchers estimated that 2.4% of the general population of Denver had CDA by age 5 years, 4.3% had CDA by age 10 years, and 5.1% had CDA by age 15 years. Estimated rates of CD were 1.6%, 2.8%, and 3.1%, respectively.
These findings suggest a significant rise in the incidence of CD compared with historical estimates in the United States, and reflect recent studies “using different approaches in North America,” the researchers said. Reasons for the “dramatic increase” are unknown, but environmental causes seem likely, especially given the absence of identified genetic differences and marked changes in the prevalence of CD during the past 2 decades, they added.
Several other reports have documented fluctuating and transient tTGA antibodies in children, the researchers noted. Awareness of transient CD autoantibodies might limit public acceptance of universal screening programs for CD, they said. “Continued long-term follow-up will identify whether the autoimmunity in these subjects truly abates and tolerance develops, or if CDA will recur in time, possibly in response to additional stimulating events,” they added. “At present, low positive tTGA results should be interpreted with caution, and do not necessarily indicate need for biopsy or for treatment.”
The study did not include the DR5/DR7 risk genotype, which accounts for less than 5% of CD cases. The study also did not account for the estimated 2.5% of the general population that has DR3/DR7, which can be considered high risk, the researchers said. Thus, the study is conservative and might underestimate the real incidence of CD or CDA, they added.
The National Institutes of Health provided funding. The investigators reported having no conflicts of interest.
By age 15 years, 3.1% of adolescents in Denver developed celiac disease, and another 2% developed a lesser degree of celiac disease autoimmunity, according to a 20-year prospective longitudinal study.
“Although more than 5% of children may experience a period of celiac disease autoimmunity [CDA], not all develop celiac disease [CD] or require gluten-free diets,” Edwin Liu, MD, of University of Colorado School of Medicine and Children’s Hospital Colorado (Aurora, Colo.), wrote with his associates in the May issue of Gastroenterology (doi: 10.1053/j.gastro.2017.02.002). Most celiac autoimmunity probably develops before age 10, “which informs future efforts for universal screening,” they added.
Source: American Gastroenterological Association
About 40% of the general population has the HLA-DQ2 or DQ8 risk genotypes for celiac disease [CD], but little is known about rates of celiac disease among children in the United States, the researchers said. To help fill this gap, they analyzed celiac-risk HLA genotypes for 31,766 infants born between 1993 and 2004 from the Diabetes Autoimmunity Study in the Young. The 1,339 children with HLA risk genotypes were followed for up to 20 years.
By age 15 years, 66 of these children (4.9%) had developed tissue transglutaminase autoantibodies (tTGA) consistent with CDA, and also met criteria for CD, the researchers said. Another 46 (3.4%) children developed only CDA, of whom 46% experienced spontaneous resolution of tTGA seropositivity without treatment. By using genotype-specific risk weighting for population frequencies of HLA, the researchers estimated that 2.4% of the general population of Denver had CDA by age 5 years, 4.3% had CDA by age 10 years, and 5.1% had CDA by age 15 years. Estimated rates of CD were 1.6%, 2.8%, and 3.1%, respectively.
These findings suggest a significant rise in the incidence of CD compared with historical estimates in the United States, and reflect recent studies “using different approaches in North America,” the researchers said. Reasons for the “dramatic increase” are unknown, but environmental causes seem likely, especially given the absence of identified genetic differences and marked changes in the prevalence of CD during the past 2 decades, they added.
Several other reports have documented fluctuating and transient tTGA antibodies in children, the researchers noted. Awareness of transient CD autoantibodies might limit public acceptance of universal screening programs for CD, they said. “Continued long-term follow-up will identify whether the autoimmunity in these subjects truly abates and tolerance develops, or if CDA will recur in time, possibly in response to additional stimulating events,” they added. “At present, low positive tTGA results should be interpreted with caution, and do not necessarily indicate need for biopsy or for treatment.”
The study did not include the DR5/DR7 risk genotype, which accounts for less than 5% of CD cases. The study also did not account for the estimated 2.5% of the general population that has DR3/DR7, which can be considered high risk, the researchers said. Thus, the study is conservative and might underestimate the real incidence of CD or CDA, they added.
The National Institutes of Health provided funding. The investigators reported having no conflicts of interest.
Key clinical point: The presence of celiac disease autoimmunity does not predict universal progression to celiac disease.
Major finding: By age 15 years, an estimated 3.1% of children in Denver developed celiac disease, and another 2% developed a lesser degree of celiac disease autoimmunity that often resolved spontaneously without treatment.
Data source: A 20-year prospective study of 1,339 children with genetic risk factors for celiac disease, with extrapolation based on the prevalence of human leukocyte antigen genotypes in the general population.
Disclosures: The National Institutes of Health provided funding. The investigators reported having no conflicts of interest.
VIDEO: Occult cancers contribute to GI bleeding in anticoagulated patients
Occult cancers accounted for one in about every 12 major gastrointestinal bleeding events among patients taking warfarin or dabigatran for atrial fibrillation, according to a retrospective analysis of data from a randomized prospective trial reported in the May issue of Clinical Gastroenterology and Hepatology (2017. doi: org/10.1016/j.cgh.2016.10.011).
These bleeding events caused similarly significant morbidity among patients taking either drug, Kathryn F. Flack, MD, of Icahn School of Medicine at Mount Sinai in New York and her associates wrote. “Patients bleeding from cancer required a mean of approximately 10 nights in the hospital, and approximately one-fourth required intensive care, but 0 of 44 died as a direct result of the bleeding,” the researchers reported. They hoped the specific dabigatran reversal agent, idarucizumab (Praxbind), will improve bleeding outcomes in patients receiving dabigatran.
Source: American Gastroenterological Association
Major gastrointestinal bleeding (MGIB) is the first sign of occult malignancy in certain patients receiving anticoagulation therapy. Starting an anticoagulant is a type of “stress test” that can reveal an occult cancer, the researchers said. Although dabigatran etexilate (Pradaxa) is generally safe and effective, a twice-daily, 150-mg dose of this direct oral anticoagulant slightly increased MGIB, compared with a lower dose in the international, multicenter RE-LY (Randomized Evaluation of Long Term Anticoagulant Therapy) trial (N Engl J Med. 2009;361:1139-51). Furthermore, unlike warfarin, dabigatran therapy places active anticoagulant within the luminal gastrointestinal tract, which “might promote bleeding from friable gastrointestinal cancers,” the investigators noted. To explore this possibility, they evaluated 546 unique MGIB events among RE-LY patients.
Medical chart reviews identified 44 (8.1%) MGIB events resulting from occult gastrointestinal cancers. Cancer accounted for similar proportions of MGIB among warfarin and dabigatran recipients (8.5% and 6.8%; P = .6). Nearly all cancers were colorectal or gastric, except for one case each of ampullary cancer, renal cell carcinoma, and melanoma that had metastasized to the luminal gastrointestinal tract. Colorectal cancer accounted for 80% of cancer-related MGIB overall, including 88% in the dabigatran group and 50% in the warfarin group (P = .02). Conversely, warfarin recipients had more MGIB associated with gastric cancer (50%) than did dabigatran recipients (2.9%; P = .001).
Short-term outcomes of MGIB associated with cancer did not vary by anticoagulant, the investigators said. There were no deaths, but two (4.5%) MGIB events required emergency endoscopic treatment, one (2.3%) required emergency surgery, and 33 (75%) required at least one red blood cell transfusion. Compared with patients whose MGIB was unrelated to cancer, those with cancer were more likely to bleed for more than 7 days (27.3% vs. 63.6%; P less than .001). Patients with occult cancer also developed MGIB sooner after starting anticoagulation (223 vs. 343 days; P = .003), but time to bleeding did not significantly vary by type of anticoagulant.
“Most prior studies on cancer bleeding have been case reports and case series in patients receiving warfarin,” the investigators wrote. “Our study is relevant because of the increasing prevalence of atrial fibrillation and anticoagulation in the aging global population, the increasing prescription of direct oral anticoagulants, and the morbidity, mortality, and complex decision making associated with MGIB and especially cancer-related MGIB in patients receiving anticoagulation therapy.”
The RE-LY trial was sponsored by Boehringer Ingelheim . Dr. Flack reported no conflicts of interest. Senior author James Aisenberg, MD, disclosed advisory board and consulting relationships with Boehringer Ingelheim and Portola Pharmaceuticals. Five other coinvestigators disclosed ties to several pharmaceutical companies, and two coinvestigators reported employment with Boehringer Ingelheim. The other coinvestigators had no conflicts.
Dr. Flack and her colleagues should be congratulated for providing important data as they reviewed 546 major GI bleeding events from a large randomized prospective trial of long-term anticoagulation in subjects with AF. They found that 1 in every 12 major GI bleeding events in patients on warfarin or dabigatran was associated with an occult cancer; colorectal cancer being the most common.
How will these results help us in clinical practice? First, when faced with GI bleeding in AF subjects on anticoagulants, a proactive diagnostic approach is needed for the search for a potential luminal GI malignancy; whether screening for GI malignancy before initiating anticoagulants is beneficial requires prospective studies with cost analysis. Second, cancer-related GI bleeding in dabigatran users occurs earlier than noncancer-related bleeding. Given that a fraction of GI bleeding events were not investigated, one cannot exclude the possibility of undiagnosed luminal GI cancers in the comparator group. Third, cancer-related bleeding is associated with prolonged hospital stay. We should seize the opportunity to study the effects of this double-edged sword; anticoagulants may help us reveal occult malignancy, but more importantly, we need to determine whether dabigatranreversal agent idarucizumab can improve bleeding outcomes in patients on dabigatran presenting with cancer-related bleeding.
Siew C. Ng, MD, PhD, AGAF, is professor at the department of medicine and therapeutics, Institute of Digestive Disease, Chinese University of Hong Kong. She has no conflicts of interest.
Dr. Flack and her colleagues should be congratulated for providing important data as they reviewed 546 major GI bleeding events from a large randomized prospective trial of long-term anticoagulation in subjects with AF. They found that 1 in every 12 major GI bleeding events in patients on warfarin or dabigatran was associated with an occult cancer; colorectal cancer being the most common.
How will these results help us in clinical practice? First, when faced with GI bleeding in AF subjects on anticoagulants, a proactive diagnostic approach is needed for the search for a potential luminal GI malignancy; whether screening for GI malignancy before initiating anticoagulants is beneficial requires prospective studies with cost analysis. Second, cancer-related GI bleeding in dabigatran users occurs earlier than noncancer-related bleeding. Given that a fraction of GI bleeding events were not investigated, one cannot exclude the possibility of undiagnosed luminal GI cancers in the comparator group. Third, cancer-related bleeding is associated with prolonged hospital stay. We should seize the opportunity to study the effects of this double-edged sword; anticoagulants may help us reveal occult malignancy, but more importantly, we need to determine whether dabigatranreversal agent idarucizumab can improve bleeding outcomes in patients on dabigatran presenting with cancer-related bleeding.
Siew C. Ng, MD, PhD, AGAF, is professor at the department of medicine and therapeutics, Institute of Digestive Disease, Chinese University of Hong Kong. She has no conflicts of interest.
Dr. Flack and her colleagues should be congratulated for providing important data as they reviewed 546 major GI bleeding events from a large randomized prospective trial of long-term anticoagulation in subjects with AF. They found that 1 in every 12 major GI bleeding events in patients on warfarin or dabigatran was associated with an occult cancer; colorectal cancer being the most common.
How will these results help us in clinical practice? First, when faced with GI bleeding in AF subjects on anticoagulants, a proactive diagnostic approach is needed for the search for a potential luminal GI malignancy; whether screening for GI malignancy before initiating anticoagulants is beneficial requires prospective studies with cost analysis. Second, cancer-related GI bleeding in dabigatran users occurs earlier than noncancer-related bleeding. Given that a fraction of GI bleeding events were not investigated, one cannot exclude the possibility of undiagnosed luminal GI cancers in the comparator group. Third, cancer-related bleeding is associated with prolonged hospital stay. We should seize the opportunity to study the effects of this double-edged sword; anticoagulants may help us reveal occult malignancy, but more importantly, we need to determine whether dabigatranreversal agent idarucizumab can improve bleeding outcomes in patients on dabigatran presenting with cancer-related bleeding.
Siew C. Ng, MD, PhD, AGAF, is professor at the department of medicine and therapeutics, Institute of Digestive Disease, Chinese University of Hong Kong. She has no conflicts of interest.
Occult cancers accounted for one in about every 12 major gastrointestinal bleeding events among patients taking warfarin or dabigatran for atrial fibrillation, according to a retrospective analysis of data from a randomized prospective trial reported in the May issue of Clinical Gastroenterology and Hepatology (2017. doi: org/10.1016/j.cgh.2016.10.011).
These bleeding events caused similarly significant morbidity among patients taking either drug, Kathryn F. Flack, MD, of Icahn School of Medicine at Mount Sinai in New York and her associates wrote. “Patients bleeding from cancer required a mean of approximately 10 nights in the hospital, and approximately one-fourth required intensive care, but 0 of 44 died as a direct result of the bleeding,” the researchers reported. They hoped the specific dabigatran reversal agent, idarucizumab (Praxbind), will improve bleeding outcomes in patients receiving dabigatran.
Source: American Gastroenterological Association
Major gastrointestinal bleeding (MGIB) is the first sign of occult malignancy in certain patients receiving anticoagulation therapy. Starting an anticoagulant is a type of “stress test” that can reveal an occult cancer, the researchers said. Although dabigatran etexilate (Pradaxa) is generally safe and effective, a twice-daily, 150-mg dose of this direct oral anticoagulant slightly increased MGIB, compared with a lower dose in the international, multicenter RE-LY (Randomized Evaluation of Long Term Anticoagulant Therapy) trial (N Engl J Med. 2009;361:1139-51). Furthermore, unlike warfarin, dabigatran therapy places active anticoagulant within the luminal gastrointestinal tract, which “might promote bleeding from friable gastrointestinal cancers,” the investigators noted. To explore this possibility, they evaluated 546 unique MGIB events among RE-LY patients.
Medical chart reviews identified 44 (8.1%) MGIB events resulting from occult gastrointestinal cancers. Cancer accounted for similar proportions of MGIB among warfarin and dabigatran recipients (8.5% and 6.8%; P = .6). Nearly all cancers were colorectal or gastric, except for one case each of ampullary cancer, renal cell carcinoma, and melanoma that had metastasized to the luminal gastrointestinal tract. Colorectal cancer accounted for 80% of cancer-related MGIB overall, including 88% in the dabigatran group and 50% in the warfarin group (P = .02). Conversely, warfarin recipients had more MGIB associated with gastric cancer (50%) than did dabigatran recipients (2.9%; P = .001).
Short-term outcomes of MGIB associated with cancer did not vary by anticoagulant, the investigators said. There were no deaths, but two (4.5%) MGIB events required emergency endoscopic treatment, one (2.3%) required emergency surgery, and 33 (75%) required at least one red blood cell transfusion. Compared with patients whose MGIB was unrelated to cancer, those with cancer were more likely to bleed for more than 7 days (27.3% vs. 63.6%; P less than .001). Patients with occult cancer also developed MGIB sooner after starting anticoagulation (223 vs. 343 days; P = .003), but time to bleeding did not significantly vary by type of anticoagulant.
“Most prior studies on cancer bleeding have been case reports and case series in patients receiving warfarin,” the investigators wrote. “Our study is relevant because of the increasing prevalence of atrial fibrillation and anticoagulation in the aging global population, the increasing prescription of direct oral anticoagulants, and the morbidity, mortality, and complex decision making associated with MGIB and especially cancer-related MGIB in patients receiving anticoagulation therapy.”
The RE-LY trial was sponsored by Boehringer Ingelheim . Dr. Flack reported no conflicts of interest. Senior author James Aisenberg, MD, disclosed advisory board and consulting relationships with Boehringer Ingelheim and Portola Pharmaceuticals. Five other coinvestigators disclosed ties to several pharmaceutical companies, and two coinvestigators reported employment with Boehringer Ingelheim. The other coinvestigators had no conflicts.
Occult cancers accounted for one in about every 12 major gastrointestinal bleeding events among patients taking warfarin or dabigatran for atrial fibrillation, according to a retrospective analysis of data from a randomized prospective trial reported in the May issue of Clinical Gastroenterology and Hepatology (2017. doi: org/10.1016/j.cgh.2016.10.011).
These bleeding events caused similarly significant morbidity among patients taking either drug, Kathryn F. Flack, MD, of Icahn School of Medicine at Mount Sinai in New York and her associates wrote. “Patients bleeding from cancer required a mean of approximately 10 nights in the hospital, and approximately one-fourth required intensive care, but 0 of 44 died as a direct result of the bleeding,” the researchers reported. They hoped the specific dabigatran reversal agent, idarucizumab (Praxbind), will improve bleeding outcomes in patients receiving dabigatran.
Source: American Gastroenterological Association
Major gastrointestinal bleeding (MGIB) is the first sign of occult malignancy in certain patients receiving anticoagulation therapy. Starting an anticoagulant is a type of “stress test” that can reveal an occult cancer, the researchers said. Although dabigatran etexilate (Pradaxa) is generally safe and effective, a twice-daily, 150-mg dose of this direct oral anticoagulant slightly increased MGIB, compared with a lower dose in the international, multicenter RE-LY (Randomized Evaluation of Long Term Anticoagulant Therapy) trial (N Engl J Med. 2009;361:1139-51). Furthermore, unlike warfarin, dabigatran therapy places active anticoagulant within the luminal gastrointestinal tract, which “might promote bleeding from friable gastrointestinal cancers,” the investigators noted. To explore this possibility, they evaluated 546 unique MGIB events among RE-LY patients.
Medical chart reviews identified 44 (8.1%) MGIB events resulting from occult gastrointestinal cancers. Cancer accounted for similar proportions of MGIB among warfarin and dabigatran recipients (8.5% and 6.8%; P = .6). Nearly all cancers were colorectal or gastric, except for one case each of ampullary cancer, renal cell carcinoma, and melanoma that had metastasized to the luminal gastrointestinal tract. Colorectal cancer accounted for 80% of cancer-related MGIB overall, including 88% in the dabigatran group and 50% in the warfarin group (P = .02). Conversely, warfarin recipients had more MGIB associated with gastric cancer (50%) than did dabigatran recipients (2.9%; P = .001).
Short-term outcomes of MGIB associated with cancer did not vary by anticoagulant, the investigators said. There were no deaths, but two (4.5%) MGIB events required emergency endoscopic treatment, one (2.3%) required emergency surgery, and 33 (75%) required at least one red blood cell transfusion. Compared with patients whose MGIB was unrelated to cancer, those with cancer were more likely to bleed for more than 7 days (27.3% vs. 63.6%; P less than .001). Patients with occult cancer also developed MGIB sooner after starting anticoagulation (223 vs. 343 days; P = .003), but time to bleeding did not significantly vary by type of anticoagulant.
“Most prior studies on cancer bleeding have been case reports and case series in patients receiving warfarin,” the investigators wrote. “Our study is relevant because of the increasing prevalence of atrial fibrillation and anticoagulation in the aging global population, the increasing prescription of direct oral anticoagulants, and the morbidity, mortality, and complex decision making associated with MGIB and especially cancer-related MGIB in patients receiving anticoagulation therapy.”
The RE-LY trial was sponsored by Boehringer Ingelheim . Dr. Flack reported no conflicts of interest. Senior author James Aisenberg, MD, disclosed advisory board and consulting relationships with Boehringer Ingelheim and Portola Pharmaceuticals. Five other coinvestigators disclosed ties to several pharmaceutical companies, and two coinvestigators reported employment with Boehringer Ingelheim. The other coinvestigators had no conflicts.
FROM CLINICAL GASTROENTEROLOGY AND HEPATOLOGY
Key clinical point: Occult cancers accounted for about 1 in every 12 major gastrointestinal bleeding events among patients receiving warfarin or dabigatran for atrial fibrillation.
Major finding: A total of 44 (8.1%) major gastrointestinal bleeds were associated with occult cancers.Data source: A retrospective analysis of 546 unique major gastrointestinal bleeding events from the Randomized Evaluation of Long Term Anticoagulant Therapy (RE-LY) trial.
Disclosures: RE-LY was sponsored by Boehringer Ingleheim. Dr. Flack had no conflicts of interest. Senior author James Aisenberg, MD, disclosed advisory board and consulting relationships with Boehringer Ingelheim and Portola Pharmaceuticals. Five other coinvestigators disclosed ties to several pharmaceutical companies, and two coinvestigators reported employment with Boehringer Ingelheim. The other coinvestigators had no conflicts.
Psyllium cut frequency of abdominal pain in pediatric IBS trial
Consuming psyllium fiber significantly reduced the frequency, but not the severity, of abdominal pain in children with irritable bowel syndrome in a randomized, double-blind, placebo-controlled trial reported in the May issue of Clinical Gastroenterology and Hepatology (2016 Nov;14[11]:1667).
Psyllium therapy did not reduce the self-reported severity of abdominal pain, Robert J. Shulman, MD, of Baylor College of Medicine in Houston reported with his associates in Clinical Gastroenterology and Hepatology. Psyllium was associated with shifts in intestinal microbiota, compared with baseline, although the changes did not reach statistical significance when compared with placebo, the researchers added. “Further studies are needed to investigate the potential mechanism whereby psyllium decreases abdominal pain frequency in children with irritable bowel syndrome [IBS],” they wrote.
IBS affects up to 20% of school-aged children. Consuming psyllium is thought to improve abdominal pain and stooling symptoms in adults with IBS, but data are inconclusive, and few randomized trials have evaluated fiber in childhood IBS. Therefore, the investigators randomly assigned 103 children (average age, 13 years; standard deviation, 3 years) with IBS who had responded inadequately to an 8-day carbohydrate elimination diet to receive a single daily dose of either psyllium or placebo maltodextrin for 6 weeks. Children aged 7-11 years received 6 g of fiber, while those aged 12-18 years received 12 g of fiber. Patients filled out a daily pain and stool diary during a 2-week baseline assessment period and again during the final 2 weeks of the trial. They also underwent breath hydrogen and methane testing, gut permeability testing, and a stool microbiota assessment during the final weekend of treatment.
At baseline, the trial arms resembled each other in terms of frequency and severity of abdominal pain, psychological characteristics, percentage of normal stools, baseline hydrogen production, and gastrointestinal permeability, the researchers said. During the final 2 weeks of treatment, the psyllium arm reported an average of 8.2 (standard deviation, 1.2) fewer episodes of abdominal pain, compared with baseline, while the control arm reported a mean reduction of 4.1 (SD, 1.3) episodes of abdominal pain (P = .03). At the end of treatment, the arms did not significantly differ in percentage of breath hydrogen or methane production, gastrointestinal permeability, or percentage of normal stools or diarrhea. However, controls had a significantly greater reduction in constipation compared with the psyllium group (P = .048).
Stool microbiome assessments of 33 children revealed a trend toward a greater increase in Bacteroidetes and a greater decrease in Firmicutes bacteria in the fiber group, compared with the control group (P = .068). The fiber group was also “marginally enriched” in bacteria of class Bacteroidia, while the placebo group was enriched in bacteria of class Clostridia (P = .094). However, the groups did not differ at narrower taxonomic levels, the researchers said. A larger sample size might have facilitated better detection of differences between groups, such as in breath hydrogen production or interactions between abdominal pain and psychological symptoms, they added.
The study was supported in part by the National Institutes of Health, the Daffy’s Foundation, and the USDA/ARS. The investigators reported having no conflicts of interest.
Consuming psyllium fiber significantly reduced the frequency, but not the severity, of abdominal pain in children with irritable bowel syndrome in a randomized, double-blind, placebo-controlled trial reported in the May issue of Clinical Gastroenterology and Hepatology (2016 Nov;14[11]:1667).
Psyllium therapy did not reduce the self-reported severity of abdominal pain, Robert J. Shulman, MD, of Baylor College of Medicine in Houston reported with his associates in Clinical Gastroenterology and Hepatology. Psyllium was associated with shifts in intestinal microbiota, compared with baseline, although the changes did not reach statistical significance when compared with placebo, the researchers added. “Further studies are needed to investigate the potential mechanism whereby psyllium decreases abdominal pain frequency in children with irritable bowel syndrome [IBS],” they wrote.
IBS affects up to 20% of school-aged children. Consuming psyllium is thought to improve abdominal pain and stooling symptoms in adults with IBS, but data are inconclusive, and few randomized trials have evaluated fiber in childhood IBS. Therefore, the investigators randomly assigned 103 children (average age, 13 years; standard deviation, 3 years) with IBS who had responded inadequately to an 8-day carbohydrate elimination diet to receive a single daily dose of either psyllium or placebo maltodextrin for 6 weeks. Children aged 7-11 years received 6 g of fiber, while those aged 12-18 years received 12 g of fiber. Patients filled out a daily pain and stool diary during a 2-week baseline assessment period and again during the final 2 weeks of the trial. They also underwent breath hydrogen and methane testing, gut permeability testing, and a stool microbiota assessment during the final weekend of treatment.
At baseline, the trial arms resembled each other in terms of frequency and severity of abdominal pain, psychological characteristics, percentage of normal stools, baseline hydrogen production, and gastrointestinal permeability, the researchers said. During the final 2 weeks of treatment, the psyllium arm reported an average of 8.2 (standard deviation, 1.2) fewer episodes of abdominal pain, compared with baseline, while the control arm reported a mean reduction of 4.1 (SD, 1.3) episodes of abdominal pain (P = .03). At the end of treatment, the arms did not significantly differ in percentage of breath hydrogen or methane production, gastrointestinal permeability, or percentage of normal stools or diarrhea. However, controls had a significantly greater reduction in constipation compared with the psyllium group (P = .048).
Stool microbiome assessments of 33 children revealed a trend toward a greater increase in Bacteroidetes and a greater decrease in Firmicutes bacteria in the fiber group, compared with the control group (P = .068). The fiber group was also “marginally enriched” in bacteria of class Bacteroidia, while the placebo group was enriched in bacteria of class Clostridia (P = .094). However, the groups did not differ at narrower taxonomic levels, the researchers said. A larger sample size might have facilitated better detection of differences between groups, such as in breath hydrogen production or interactions between abdominal pain and psychological symptoms, they added.
The study was supported in part by the National Institutes of Health, the Daffy’s Foundation, and the USDA/ARS. The investigators reported having no conflicts of interest.
Consuming psyllium fiber significantly reduced the frequency, but not the severity, of abdominal pain in children with irritable bowel syndrome in a randomized, double-blind, placebo-controlled trial reported in the May issue of Clinical Gastroenterology and Hepatology (2016 Nov;14[11]:1667).
Psyllium therapy did not reduce the self-reported severity of abdominal pain, Robert J. Shulman, MD, of Baylor College of Medicine in Houston reported with his associates in Clinical Gastroenterology and Hepatology. Psyllium was associated with shifts in intestinal microbiota, compared with baseline, although the changes did not reach statistical significance when compared with placebo, the researchers added. “Further studies are needed to investigate the potential mechanism whereby psyllium decreases abdominal pain frequency in children with irritable bowel syndrome [IBS],” they wrote.
IBS affects up to 20% of school-aged children. Consuming psyllium is thought to improve abdominal pain and stooling symptoms in adults with IBS, but data are inconclusive, and few randomized trials have evaluated fiber in childhood IBS. Therefore, the investigators randomly assigned 103 children (average age, 13 years; standard deviation, 3 years) with IBS who had responded inadequately to an 8-day carbohydrate elimination diet to receive a single daily dose of either psyllium or placebo maltodextrin for 6 weeks. Children aged 7-11 years received 6 g of fiber, while those aged 12-18 years received 12 g of fiber. Patients filled out a daily pain and stool diary during a 2-week baseline assessment period and again during the final 2 weeks of the trial. They also underwent breath hydrogen and methane testing, gut permeability testing, and a stool microbiota assessment during the final weekend of treatment.
At baseline, the trial arms resembled each other in terms of frequency and severity of abdominal pain, psychological characteristics, percentage of normal stools, baseline hydrogen production, and gastrointestinal permeability, the researchers said. During the final 2 weeks of treatment, the psyllium arm reported an average of 8.2 (standard deviation, 1.2) fewer episodes of abdominal pain, compared with baseline, while the control arm reported a mean reduction of 4.1 (SD, 1.3) episodes of abdominal pain (P = .03). At the end of treatment, the arms did not significantly differ in percentage of breath hydrogen or methane production, gastrointestinal permeability, or percentage of normal stools or diarrhea. However, controls had a significantly greater reduction in constipation compared with the psyllium group (P = .048).
Stool microbiome assessments of 33 children revealed a trend toward a greater increase in Bacteroidetes and a greater decrease in Firmicutes bacteria in the fiber group, compared with the control group (P = .068). The fiber group was also “marginally enriched” in bacteria of class Bacteroidia, while the placebo group was enriched in bacteria of class Clostridia (P = .094). However, the groups did not differ at narrower taxonomic levels, the researchers said. A larger sample size might have facilitated better detection of differences between groups, such as in breath hydrogen production or interactions between abdominal pain and psychological symptoms, they added.
The study was supported in part by the National Institutes of Health, the Daffy’s Foundation, and the USDA/ARS. The investigators reported having no conflicts of interest.
FROM CLINICAL GASTROENTEROLOGY AND HEPATOLOGY
Key clinical point: Compared with placebo maltodextrin, consuming psyllium fiber significantly reduced the self-reported frequency of abdominal pain in children with irritable bowel syndrome.
Major finding: Children who received psyllium reported an average of 8.2 fewer pain episodes, compared with baseline, while controls reported a mean reduction of 4.1 pain episodes (P = .03).
Data source: A randomized, double-blind trial of 103 children aged 12-18 years of age with irritable bowel syndrome.
Disclosures: The study was supported in part by the National Institutes of Health, the Daffy’s Foundation, and the USDA/ARS. The investigators reported having no conflicts of interest.
Study supports NCCN recommendations on risk-reducing salpingo-oophorectomy
NATIONAL HARBOR, MD – A large hereditary cancer study supports National Comprehensive Cancer Network guidance to consider risk-reducing salpingo-oophorectomy (RRSO) between ages 45 and 50 years for women with BRIP1, RAD51C, or RAD51D mutations, Lydia Usha, MD, said at the annual meeting of the Society of Gynecologic Oncology.
The average ages for an ovarian cancer diagnosis were 56 years for women with RAD51D mutations, 61 years for RAD51C mutations, and 64 years for BRIP1 mutations, said Dr. Usha of Rush Medical College, Chicago. When appropriate, delaying RRSO “avoids the psychosocial and medical complications of premature menopause,” she said.
Among all women, mutation prevalence was 0.3% for BRIP1, 0.1% for RAD51C and RAD51D, 1.2% for BRCA1, and 1.3% for BRCA2 mutations, Dr. Usha reported. Among 18,719 women who had a personal history of ovarian cancer, the most common mutation was BRCA1 (3.5%), followed by BRCA2 (2.7%). In contrast, the combined prevalence of BRIP1, RAD51C, and RAD51D mutations among cancer patients was only 1.6%.
Cancer prevalence was highest among women who had mutations of RAD51C (22%), followed by RAD51D (19%), BRCA1 and BRIP1 (16% in each case), and BRCA2 (11%). Thus, while BRIP1 and RAD51D mutations were uncommon, their presence signified an ovarian cancer risk that was similar to that with BRCA1 mutations, and a greater risk than with BRCA2, Dr. Usha said.
The average ages for ovarian cancer diagnosis were 64 years for BRIP1, 61 years for RAD51C, 60 years for BRCA2, 56 years for RAD51C, and 54 years for BRCA1. “More than 80% of women with ovarian cancer who had a mutation in BRIP1, RAD51C, or BRCA2 were diagnosed after age 50,” Dr. Usha noted. These findings support considering RRSO closer to age 45 years for RAD51D mutation carriers and closer to age 50 years for women with pathogenic variants of BRIP1, added discussant Kari Ring, MD, of the University of Virginia, Charlottesville.
Mutation type did not significantly correlate with ethnicity or type of ovarian cancer, Dr. Usha noted. “Collectively, these findings may aid clinical decisions about the medical management of women with mutations in these genes,” she said. “Our data may also assist with reproductive decisions, such as age of childbearing.”
Dr. Usha did not report external funding sources, but disclosed travel expenses from Myriad Genetics.
NATIONAL HARBOR, MD – A large hereditary cancer study supports National Comprehensive Cancer Network guidance to consider risk-reducing salpingo-oophorectomy (RRSO) between ages 45 and 50 years for women with BRIP1, RAD51C, or RAD51D mutations, Lydia Usha, MD, said at the annual meeting of the Society of Gynecologic Oncology.
The average ages for an ovarian cancer diagnosis were 56 years for women with RAD51D mutations, 61 years for RAD51C mutations, and 64 years for BRIP1 mutations, said Dr. Usha of Rush Medical College, Chicago. When appropriate, delaying RRSO “avoids the psychosocial and medical complications of premature menopause,” she said.
Among all women, mutation prevalence was 0.3% for BRIP1, 0.1% for RAD51C and RAD51D, 1.2% for BRCA1, and 1.3% for BRCA2 mutations, Dr. Usha reported. Among 18,719 women who had a personal history of ovarian cancer, the most common mutation was BRCA1 (3.5%), followed by BRCA2 (2.7%). In contrast, the combined prevalence of BRIP1, RAD51C, and RAD51D mutations among cancer patients was only 1.6%.
Cancer prevalence was highest among women who had mutations of RAD51C (22%), followed by RAD51D (19%), BRCA1 and BRIP1 (16% in each case), and BRCA2 (11%). Thus, while BRIP1 and RAD51D mutations were uncommon, their presence signified an ovarian cancer risk that was similar to that with BRCA1 mutations, and a greater risk than with BRCA2, Dr. Usha said.
The average ages for ovarian cancer diagnosis were 64 years for BRIP1, 61 years for RAD51C, 60 years for BRCA2, 56 years for RAD51C, and 54 years for BRCA1. “More than 80% of women with ovarian cancer who had a mutation in BRIP1, RAD51C, or BRCA2 were diagnosed after age 50,” Dr. Usha noted. These findings support considering RRSO closer to age 45 years for RAD51D mutation carriers and closer to age 50 years for women with pathogenic variants of BRIP1, added discussant Kari Ring, MD, of the University of Virginia, Charlottesville.
Mutation type did not significantly correlate with ethnicity or type of ovarian cancer, Dr. Usha noted. “Collectively, these findings may aid clinical decisions about the medical management of women with mutations in these genes,” she said. “Our data may also assist with reproductive decisions, such as age of childbearing.”
Dr. Usha did not report external funding sources, but disclosed travel expenses from Myriad Genetics.
NATIONAL HARBOR, MD – A large hereditary cancer study supports National Comprehensive Cancer Network guidance to consider risk-reducing salpingo-oophorectomy (RRSO) between ages 45 and 50 years for women with BRIP1, RAD51C, or RAD51D mutations, Lydia Usha, MD, said at the annual meeting of the Society of Gynecologic Oncology.
The average ages for an ovarian cancer diagnosis were 56 years for women with RAD51D mutations, 61 years for RAD51C mutations, and 64 years for BRIP1 mutations, said Dr. Usha of Rush Medical College, Chicago. When appropriate, delaying RRSO “avoids the psychosocial and medical complications of premature menopause,” she said.
Among all women, mutation prevalence was 0.3% for BRIP1, 0.1% for RAD51C and RAD51D, 1.2% for BRCA1, and 1.3% for BRCA2 mutations, Dr. Usha reported. Among 18,719 women who had a personal history of ovarian cancer, the most common mutation was BRCA1 (3.5%), followed by BRCA2 (2.7%). In contrast, the combined prevalence of BRIP1, RAD51C, and RAD51D mutations among cancer patients was only 1.6%.
Cancer prevalence was highest among women who had mutations of RAD51C (22%), followed by RAD51D (19%), BRCA1 and BRIP1 (16% in each case), and BRCA2 (11%). Thus, while BRIP1 and RAD51D mutations were uncommon, their presence signified an ovarian cancer risk that was similar to that with BRCA1 mutations, and a greater risk than with BRCA2, Dr. Usha said.
The average ages for ovarian cancer diagnosis were 64 years for BRIP1, 61 years for RAD51C, 60 years for BRCA2, 56 years for RAD51C, and 54 years for BRCA1. “More than 80% of women with ovarian cancer who had a mutation in BRIP1, RAD51C, or BRCA2 were diagnosed after age 50,” Dr. Usha noted. These findings support considering RRSO closer to age 45 years for RAD51D mutation carriers and closer to age 50 years for women with pathogenic variants of BRIP1, added discussant Kari Ring, MD, of the University of Virginia, Charlottesville.
Mutation type did not significantly correlate with ethnicity or type of ovarian cancer, Dr. Usha noted. “Collectively, these findings may aid clinical decisions about the medical management of women with mutations in these genes,” she said. “Our data may also assist with reproductive decisions, such as age of childbearing.”
Dr. Usha did not report external funding sources, but disclosed travel expenses from Myriad Genetics.
AT THE ANNUAL MEETING ON WOMEN'S CANCER
Key clinical point: A large hereditary cancer study supports National Comprehensive Cancer Network guidance to consider risk-reducing salpingo-oophorectomy between age 45 and 50 years for women with BRIP1, RAD51C, or RAD51D mutations.
Major finding: Average ages for an ovarian cancer diagnosis were 56 years for women with RAD51D mutations, 61 years for RAD51C mutations, and 64 years for BRIP1 mutations.
Data source: Analyses of a 25-gene hereditary panel performed in 345,667 women.
Disclosures: Dr. Usha did not report external funding sources, but disclosed travel expenses from Myriad Genetics.
Study nixed magnesium for infants with acute bronchiolitis
Intravenous magnesium does not benefit, and may harm, infants with moderate to severe acute bronchiolitis, investigators reported.
Compared with placebo, adding a single intravenous dose of magnesium sulfate (100 mg/kg) to usual care did not reduce time to medical readiness for discharge, even when patients had eczema or a family history of asthma, and was tied to more than a threefold rise in the rate of short-term readmissions, Khalid Al Ansari, MD, of Hamad Medical Corp. in Doha, Qatar, and his associates wrote in Chest. “To our knowledge, this is the first randomized study to investigate the effect of intravenous magnesium in a bronchiolitis population,” they added.
Bronchiolitis lacks new, inexpensive, readily available treatments, despite being a common reason for hospital admission, the researchers noted. For older children with moderate to severe exacerbations of asthma, a meta-analysis found that the addition of magnesium to usual care appeared to cut readmissions and shorten lengths of stay, compared with placebo. To explore magnesium therapy in younger children, the investigators enrolled 162 previously healthy infants up to 18 months old who had been admitted to the short-stay unit of a pediatric emergency center with a diagnosis of moderate to severe viral bronchiolitis. Patients received usual care with oral dexamethasone and nebulized 5% hypertonic saline in 1 mL of 1:1000 epinephrine, plus an intravenous 60-minute infusion with a blinded syringe of either 0.9% saline placebo or magnesium sulfate (100 mg/kg) (Chest. 2017 Mar 9. doi: 10.1016/j.chest.2017.03.002).
The primary endpoint, time to medical readiness for discharge, did not statistically differ between groups, averaging 24.1 (95% confidence interval, 20.0-29.1) hours with magnesium and 25.3 (95% CI, 20.3-31.5) hours with placebo (P = .91). Among patients with a history of eczema or a family history of asthma, mean times to readiness for discharge resembled those for the entire cohort and did not statistically differ based on treatment. Average Wang bronchiolitis severity scores also were similar between groups, as were rates of outpatient clinic visits (33.8% with magnesium and 27.2% with placebo). Thus, the trial identified “no benefit in adding intravenous magnesium for infant bronchiolitis, even in patients characterized to be at a higher risk for asthma,” the researchers concluded.
Strikingly, 2-week readmission rates were 19.5% with magnesium (95% CI, 11.3-30.1) and 6.2% with placebo (95% CI, 0.02-13.8; P = .016). Among patients with eczema or a family history of asthma, 2-week readmission rates also were significantly higher with magnesium (26.3%; 95% CI, 13.4-43.1) than with placebo (7.5%; 95% CI, 1.6-20.4; P = .034) These might have been chance findings, or magnesium might have masked worse bronchiolitis, prolonged the disease course, or interacted with 5% hypertonic saline or systemic corticosteroids, the investigators said. Intravenous magnesium might contribute to secondary relapse, especially among patients with eczema or a family history of asthma, they added.
Patients in this study had a median age of 3.7 months (range, 22 days to 17.6 months), about half had eczema or a family history of asthma, and 86% had positive nasopharyngeal virus swabs. Cardiopulmonary monitoring revealed no acute events during treatment. Of 16 readmissions in the magnesium group, 11 entered the infirmary and 4 entered the hospital. The five placebo readmissions included four to the infirmary and one to the hospital.
“As with other ‘negative studies,’ we may have failed to identify a benefit from intravenous magnesium in a patient subgroup because of our limited sample size,” the investigators wrote. “But we think our findings are generalizable to a similarly heterogeneous group of patients presenting for bronchiolitis care in a busy urban emergency department.”
Hamad Medical Corp. sponsored the study. The investigators reported having no conflicts of interest.
The study authors are correct that there isn’t a “new” treatment for infant bronchiolitis. But the American Academy of Pediatrics published a Clinical Practice Guidelines in 2014 (Pediatrics. Vol 134, Number 5, November 2014).
This study included patients admitted to a short-stay unit within the emergency room and they were receiving both of these therapies as “usual care.” Therefore, it is difficult to say if this may have confounded the results. In any case, intravenous magnesium sulfate doesn’t make sense as an intervention for bronchiolitis.
The study authors are correct that there isn’t a “new” treatment for infant bronchiolitis. But the American Academy of Pediatrics published a Clinical Practice Guidelines in 2014 (Pediatrics. Vol 134, Number 5, November 2014).
This study included patients admitted to a short-stay unit within the emergency room and they were receiving both of these therapies as “usual care.” Therefore, it is difficult to say if this may have confounded the results. In any case, intravenous magnesium sulfate doesn’t make sense as an intervention for bronchiolitis.
The study authors are correct that there isn’t a “new” treatment for infant bronchiolitis. But the American Academy of Pediatrics published a Clinical Practice Guidelines in 2014 (Pediatrics. Vol 134, Number 5, November 2014).
This study included patients admitted to a short-stay unit within the emergency room and they were receiving both of these therapies as “usual care.” Therefore, it is difficult to say if this may have confounded the results. In any case, intravenous magnesium sulfate doesn’t make sense as an intervention for bronchiolitis.
Intravenous magnesium does not benefit, and may harm, infants with moderate to severe acute bronchiolitis, investigators reported.
Compared with placebo, adding a single intravenous dose of magnesium sulfate (100 mg/kg) to usual care did not reduce time to medical readiness for discharge, even when patients had eczema or a family history of asthma, and was tied to more than a threefold rise in the rate of short-term readmissions, Khalid Al Ansari, MD, of Hamad Medical Corp. in Doha, Qatar, and his associates wrote in Chest. “To our knowledge, this is the first randomized study to investigate the effect of intravenous magnesium in a bronchiolitis population,” they added.
Bronchiolitis lacks new, inexpensive, readily available treatments, despite being a common reason for hospital admission, the researchers noted. For older children with moderate to severe exacerbations of asthma, a meta-analysis found that the addition of magnesium to usual care appeared to cut readmissions and shorten lengths of stay, compared with placebo. To explore magnesium therapy in younger children, the investigators enrolled 162 previously healthy infants up to 18 months old who had been admitted to the short-stay unit of a pediatric emergency center with a diagnosis of moderate to severe viral bronchiolitis. Patients received usual care with oral dexamethasone and nebulized 5% hypertonic saline in 1 mL of 1:1000 epinephrine, plus an intravenous 60-minute infusion with a blinded syringe of either 0.9% saline placebo or magnesium sulfate (100 mg/kg) (Chest. 2017 Mar 9. doi: 10.1016/j.chest.2017.03.002).
The primary endpoint, time to medical readiness for discharge, did not statistically differ between groups, averaging 24.1 (95% confidence interval, 20.0-29.1) hours with magnesium and 25.3 (95% CI, 20.3-31.5) hours with placebo (P = .91). Among patients with a history of eczema or a family history of asthma, mean times to readiness for discharge resembled those for the entire cohort and did not statistically differ based on treatment. Average Wang bronchiolitis severity scores also were similar between groups, as were rates of outpatient clinic visits (33.8% with magnesium and 27.2% with placebo). Thus, the trial identified “no benefit in adding intravenous magnesium for infant bronchiolitis, even in patients characterized to be at a higher risk for asthma,” the researchers concluded.
Strikingly, 2-week readmission rates were 19.5% with magnesium (95% CI, 11.3-30.1) and 6.2% with placebo (95% CI, 0.02-13.8; P = .016). Among patients with eczema or a family history of asthma, 2-week readmission rates also were significantly higher with magnesium (26.3%; 95% CI, 13.4-43.1) than with placebo (7.5%; 95% CI, 1.6-20.4; P = .034) These might have been chance findings, or magnesium might have masked worse bronchiolitis, prolonged the disease course, or interacted with 5% hypertonic saline or systemic corticosteroids, the investigators said. Intravenous magnesium might contribute to secondary relapse, especially among patients with eczema or a family history of asthma, they added.
Patients in this study had a median age of 3.7 months (range, 22 days to 17.6 months), about half had eczema or a family history of asthma, and 86% had positive nasopharyngeal virus swabs. Cardiopulmonary monitoring revealed no acute events during treatment. Of 16 readmissions in the magnesium group, 11 entered the infirmary and 4 entered the hospital. The five placebo readmissions included four to the infirmary and one to the hospital.
“As with other ‘negative studies,’ we may have failed to identify a benefit from intravenous magnesium in a patient subgroup because of our limited sample size,” the investigators wrote. “But we think our findings are generalizable to a similarly heterogeneous group of patients presenting for bronchiolitis care in a busy urban emergency department.”
Hamad Medical Corp. sponsored the study. The investigators reported having no conflicts of interest.
Intravenous magnesium does not benefit, and may harm, infants with moderate to severe acute bronchiolitis, investigators reported.
Compared with placebo, adding a single intravenous dose of magnesium sulfate (100 mg/kg) to usual care did not reduce time to medical readiness for discharge, even when patients had eczema or a family history of asthma, and was tied to more than a threefold rise in the rate of short-term readmissions, Khalid Al Ansari, MD, of Hamad Medical Corp. in Doha, Qatar, and his associates wrote in Chest. “To our knowledge, this is the first randomized study to investigate the effect of intravenous magnesium in a bronchiolitis population,” they added.
Bronchiolitis lacks new, inexpensive, readily available treatments, despite being a common reason for hospital admission, the researchers noted. For older children with moderate to severe exacerbations of asthma, a meta-analysis found that the addition of magnesium to usual care appeared to cut readmissions and shorten lengths of stay, compared with placebo. To explore magnesium therapy in younger children, the investigators enrolled 162 previously healthy infants up to 18 months old who had been admitted to the short-stay unit of a pediatric emergency center with a diagnosis of moderate to severe viral bronchiolitis. Patients received usual care with oral dexamethasone and nebulized 5% hypertonic saline in 1 mL of 1:1000 epinephrine, plus an intravenous 60-minute infusion with a blinded syringe of either 0.9% saline placebo or magnesium sulfate (100 mg/kg) (Chest. 2017 Mar 9. doi: 10.1016/j.chest.2017.03.002).
The primary endpoint, time to medical readiness for discharge, did not statistically differ between groups, averaging 24.1 (95% confidence interval, 20.0-29.1) hours with magnesium and 25.3 (95% CI, 20.3-31.5) hours with placebo (P = .91). Among patients with a history of eczema or a family history of asthma, mean times to readiness for discharge resembled those for the entire cohort and did not statistically differ based on treatment. Average Wang bronchiolitis severity scores also were similar between groups, as were rates of outpatient clinic visits (33.8% with magnesium and 27.2% with placebo). Thus, the trial identified “no benefit in adding intravenous magnesium for infant bronchiolitis, even in patients characterized to be at a higher risk for asthma,” the researchers concluded.
Strikingly, 2-week readmission rates were 19.5% with magnesium (95% CI, 11.3-30.1) and 6.2% with placebo (95% CI, 0.02-13.8; P = .016). Among patients with eczema or a family history of asthma, 2-week readmission rates also were significantly higher with magnesium (26.3%; 95% CI, 13.4-43.1) than with placebo (7.5%; 95% CI, 1.6-20.4; P = .034) These might have been chance findings, or magnesium might have masked worse bronchiolitis, prolonged the disease course, or interacted with 5% hypertonic saline or systemic corticosteroids, the investigators said. Intravenous magnesium might contribute to secondary relapse, especially among patients with eczema or a family history of asthma, they added.
Patients in this study had a median age of 3.7 months (range, 22 days to 17.6 months), about half had eczema or a family history of asthma, and 86% had positive nasopharyngeal virus swabs. Cardiopulmonary monitoring revealed no acute events during treatment. Of 16 readmissions in the magnesium group, 11 entered the infirmary and 4 entered the hospital. The five placebo readmissions included four to the infirmary and one to the hospital.
“As with other ‘negative studies,’ we may have failed to identify a benefit from intravenous magnesium in a patient subgroup because of our limited sample size,” the investigators wrote. “But we think our findings are generalizable to a similarly heterogeneous group of patients presenting for bronchiolitis care in a busy urban emergency department.”
Hamad Medical Corp. sponsored the study. The investigators reported having no conflicts of interest.
Key clinical point: Intravenous magnesium does not benefit, and may harm, infants with acute bronchiolitis.
Major finding: Time to medical readiness for discharge averaged 24.1 hours (95% CI, 20.0-29.1) in the magnesium group and 25.3 hours (95% CI, 20.3-31.5) in the placebo group (P = .91). Rates of 2-week readmission were 19.5% with magnesium and 6.2% with placebo (P = .016).
Data source: A single-center, randomized, double-blind, placebo-controlled trial of 162 previously healthy infants diagnosed with viral bronchiolitis.
Disclosures: Hamad Medical Corp. sponsored the study. The investigators reported having no conflicts of interest.
Complete resection tied to improved survival in low-grade serous ovarian cancer
NATIONAL HARBOR, MD. – Surgical resection to the point of no residual macroscopic disease significantly improved survival among patients with low-grade serous ovarian carcinoma, based on the findings of a large multicenter retrospective cohort study.
Adjuvant platinum-based therapy, however, did not appear to boost survival in the analysis, Tamayaa May, MD, MSc, said at the annual meeting of the Society of Gynecologic Oncology. “Genotyping and targeted sequencing of low-grade serous ovarian carcinoma often identifies actionable mutations, and treatment with MEK-based combination therapy might be a viable therapeutic strategy in patients with KRAS or NRAS mutations,” added Dr. May of Princess Margaret Cancer Center at the University of Toronto. She and her associates plan to examine more subgroups to determine if genomic alterations predict systemic response, she said.
Low-grade (Silverberg grade 1) serous ovarian tumors are slow growing but tend to resist chemotherapy, making optimal debulking a crucial part of treatment. In past studies, debulking that eliminated macroscopic evidence of disease was associated with a median survival time of about 115 months, compared with about 43 months if patients had residual disease, Dr. May noted.
To further explore outcomes after surgical resection, and to help clarify the role of systemic platinum-based therapy in low-grade serous ovarian carcinoma, she and her associates analyzed clinical data from 714 patients with low-grade serous ovarian carcinomas, including 40 from her institution and 674 from the Ovarian Cancer Association Consortium Registry. Most (60%) patients had stage III disease at diagnosis.
Complete data on surgical outcomes were available for 382 patients, of whom 202 (53%) had residual macroscopic disease and 43% did not. Among 439 patients with complete treatment data, 170 (39%) received first-line platinum-based chemotherapy. For the 391 patients with complete data on progression-free survival (PFS), the median follow-up was 4.9 years and median PFS was 3.1 years (95% confidence interval, 2.6-4.5 years). Residual macroscopic disease correlated with shorter PFS (P less than .001), as did higher tumor stage and baseline CA125 (P less than .001), but platinum-based therapy did not (P = .1).
A multivariable analysis of 333 patients confirmed these findings, Dr. May said. Independent correlates of death or disease progression included residual macroscopic disease (hazard ratio, 2.38; 95% CI, 1.68-3.37; P less than .001), older age (HR, 1.15; 95% CI, 1.02-1.30; P = .02), and stage III (HR, 3.28; 95% CI, 1.87-5.76; P less than .001) or stage IV disease (HR, 5.68; 95% CI, 2.73-11.83; P less than .001), compared with stage I disease. In contrast, platinum-based therapy did not correlate with survival (HR, 0.94; 95% CI, 0.69-1.28; P = .69).
The overall survival analysis also linked mortality with higher tumor stage, increased baseline CA125, and residual disease (P less than .001 for each association), but not with platinum-based therapy (P = .2). The multivariable analysis independently tied mortality to older age (HR, 1.25; P less than .001), stage III (HR, 2.31; P = .006) or IV disease (HR, 3.86; P less than .001), and residual disease (HR, 2.53; P less than .001), but not to platinum-based therapy (HR, 1.05; P = .77).
Data consistency and completeness were issues in this study: most notably, 45% of patients had no PFS data, Dr. May commented. Nonetheless, this type of large retrospective multicenter analysis is one of the best ways to study rare tumors, including low-grade serous ovarian carcinoma, she said.
The Ovarian Cancer Research Fund provides financial support for OCAC. Dr. May reported having no conflicts of interest.
NATIONAL HARBOR, MD. – Surgical resection to the point of no residual macroscopic disease significantly improved survival among patients with low-grade serous ovarian carcinoma, based on the findings of a large multicenter retrospective cohort study.
Adjuvant platinum-based therapy, however, did not appear to boost survival in the analysis, Tamayaa May, MD, MSc, said at the annual meeting of the Society of Gynecologic Oncology. “Genotyping and targeted sequencing of low-grade serous ovarian carcinoma often identifies actionable mutations, and treatment with MEK-based combination therapy might be a viable therapeutic strategy in patients with KRAS or NRAS mutations,” added Dr. May of Princess Margaret Cancer Center at the University of Toronto. She and her associates plan to examine more subgroups to determine if genomic alterations predict systemic response, she said.
Low-grade (Silverberg grade 1) serous ovarian tumors are slow growing but tend to resist chemotherapy, making optimal debulking a crucial part of treatment. In past studies, debulking that eliminated macroscopic evidence of disease was associated with a median survival time of about 115 months, compared with about 43 months if patients had residual disease, Dr. May noted.
To further explore outcomes after surgical resection, and to help clarify the role of systemic platinum-based therapy in low-grade serous ovarian carcinoma, she and her associates analyzed clinical data from 714 patients with low-grade serous ovarian carcinomas, including 40 from her institution and 674 from the Ovarian Cancer Association Consortium Registry. Most (60%) patients had stage III disease at diagnosis.
Complete data on surgical outcomes were available for 382 patients, of whom 202 (53%) had residual macroscopic disease and 43% did not. Among 439 patients with complete treatment data, 170 (39%) received first-line platinum-based chemotherapy. For the 391 patients with complete data on progression-free survival (PFS), the median follow-up was 4.9 years and median PFS was 3.1 years (95% confidence interval, 2.6-4.5 years). Residual macroscopic disease correlated with shorter PFS (P less than .001), as did higher tumor stage and baseline CA125 (P less than .001), but platinum-based therapy did not (P = .1).
A multivariable analysis of 333 patients confirmed these findings, Dr. May said. Independent correlates of death or disease progression included residual macroscopic disease (hazard ratio, 2.38; 95% CI, 1.68-3.37; P less than .001), older age (HR, 1.15; 95% CI, 1.02-1.30; P = .02), and stage III (HR, 3.28; 95% CI, 1.87-5.76; P less than .001) or stage IV disease (HR, 5.68; 95% CI, 2.73-11.83; P less than .001), compared with stage I disease. In contrast, platinum-based therapy did not correlate with survival (HR, 0.94; 95% CI, 0.69-1.28; P = .69).
The overall survival analysis also linked mortality with higher tumor stage, increased baseline CA125, and residual disease (P less than .001 for each association), but not with platinum-based therapy (P = .2). The multivariable analysis independently tied mortality to older age (HR, 1.25; P less than .001), stage III (HR, 2.31; P = .006) or IV disease (HR, 3.86; P less than .001), and residual disease (HR, 2.53; P less than .001), but not to platinum-based therapy (HR, 1.05; P = .77).
Data consistency and completeness were issues in this study: most notably, 45% of patients had no PFS data, Dr. May commented. Nonetheless, this type of large retrospective multicenter analysis is one of the best ways to study rare tumors, including low-grade serous ovarian carcinoma, she said.
The Ovarian Cancer Research Fund provides financial support for OCAC. Dr. May reported having no conflicts of interest.
NATIONAL HARBOR, MD. – Surgical resection to the point of no residual macroscopic disease significantly improved survival among patients with low-grade serous ovarian carcinoma, based on the findings of a large multicenter retrospective cohort study.
Adjuvant platinum-based therapy, however, did not appear to boost survival in the analysis, Tamayaa May, MD, MSc, said at the annual meeting of the Society of Gynecologic Oncology. “Genotyping and targeted sequencing of low-grade serous ovarian carcinoma often identifies actionable mutations, and treatment with MEK-based combination therapy might be a viable therapeutic strategy in patients with KRAS or NRAS mutations,” added Dr. May of Princess Margaret Cancer Center at the University of Toronto. She and her associates plan to examine more subgroups to determine if genomic alterations predict systemic response, she said.
Low-grade (Silverberg grade 1) serous ovarian tumors are slow growing but tend to resist chemotherapy, making optimal debulking a crucial part of treatment. In past studies, debulking that eliminated macroscopic evidence of disease was associated with a median survival time of about 115 months, compared with about 43 months if patients had residual disease, Dr. May noted.
To further explore outcomes after surgical resection, and to help clarify the role of systemic platinum-based therapy in low-grade serous ovarian carcinoma, she and her associates analyzed clinical data from 714 patients with low-grade serous ovarian carcinomas, including 40 from her institution and 674 from the Ovarian Cancer Association Consortium Registry. Most (60%) patients had stage III disease at diagnosis.
Complete data on surgical outcomes were available for 382 patients, of whom 202 (53%) had residual macroscopic disease and 43% did not. Among 439 patients with complete treatment data, 170 (39%) received first-line platinum-based chemotherapy. For the 391 patients with complete data on progression-free survival (PFS), the median follow-up was 4.9 years and median PFS was 3.1 years (95% confidence interval, 2.6-4.5 years). Residual macroscopic disease correlated with shorter PFS (P less than .001), as did higher tumor stage and baseline CA125 (P less than .001), but platinum-based therapy did not (P = .1).
A multivariable analysis of 333 patients confirmed these findings, Dr. May said. Independent correlates of death or disease progression included residual macroscopic disease (hazard ratio, 2.38; 95% CI, 1.68-3.37; P less than .001), older age (HR, 1.15; 95% CI, 1.02-1.30; P = .02), and stage III (HR, 3.28; 95% CI, 1.87-5.76; P less than .001) or stage IV disease (HR, 5.68; 95% CI, 2.73-11.83; P less than .001), compared with stage I disease. In contrast, platinum-based therapy did not correlate with survival (HR, 0.94; 95% CI, 0.69-1.28; P = .69).
The overall survival analysis also linked mortality with higher tumor stage, increased baseline CA125, and residual disease (P less than .001 for each association), but not with platinum-based therapy (P = .2). The multivariable analysis independently tied mortality to older age (HR, 1.25; P less than .001), stage III (HR, 2.31; P = .006) or IV disease (HR, 3.86; P less than .001), and residual disease (HR, 2.53; P less than .001), but not to platinum-based therapy (HR, 1.05; P = .77).
Data consistency and completeness were issues in this study: most notably, 45% of patients had no PFS data, Dr. May commented. Nonetheless, this type of large retrospective multicenter analysis is one of the best ways to study rare tumors, including low-grade serous ovarian carcinoma, she said.
The Ovarian Cancer Research Fund provides financial support for OCAC. Dr. May reported having no conflicts of interest.
AT THE ANNUAL MEETING ON WOMEN’S CANCER
Key clinical point: Unlike platinum-based chemotherapy, resection to the point of no residual disease was associated with improved survival among patients with low-grade serous ovarian carcinoma.
Major finding: Independent correlates of death or disease progression included residual macroscopic disease (hazard ratio, 2.38; P less than .001), older age (HR, 1.15; P = .02), and stage III (HR, 3.28; P less than .001) or stage IV (HR, 5.68; P less than .001) disease, compared with stage I disease. Platinum-based therapy was not associated with improved survival (HR, 0.94; P = 69).
Data source: A retrospective cohort study of 714 patients with low-grade (Silverberg grade 1) serous tumors from the Ovarian Cancer Association Consortium Registry.
Disclosures: The Ovarian Cancer Research Fund provides financial support for OCAC. Dr. May reported having no conflicts of interest.
Adding Pap to plasma testing boosted detection of ovarian tumors
NATIONAL HARBOR, MD. – Combining a liquid-based Pap smear and cell-free DNA plasma testing can boost the sensitivity of screening for primary ovarian tumors, based on the results of a prospective study of 201 patients.
The approach, however, was most sensitive when women already had late-stage disease, Amanda Nickles Fader, MD, said at the annual meeting of the Society of Gynecologic Oncology. Nonetheless, she called combined Pap and plasma testing “a promising step toward a broadly applicable screening methodology for the early detection of ovarian cancer.”
Ovarian cancer is a “legal malignancy,” and detecting it at “earlier, more curable stages is a clinical imperative,” said Dr. Fader of the Johns Hopkins Kelly Gynecologic Oncology Service in Baltimore, Md.
Routine screening with ultrasound or the CA-125 test has not been shown to reduce deaths from ovarian cancer and can lead to unnecessary diagnostic surgeries. Therefore, population-based screening is not recommended by the U.S. Preventive Services Task Force, the American Cancer Society, the American Congress of Obstetricians and Gynecologists, or the National Comprehensive Cancer Network, Dr. Fader noted.
This paradigm, however, is starting to change with the advent of DNA-based tests for ovarian cancer, including the PapGene test and assays for circulating DNA released by apoptotic tumor cells (ctDNA), Dr. Fader said. In a previous pilot study, Pap testing identified oncogenic driver mutations in 41% of primary ovarian tumors. In another study, polymerase chain reaction (PCR) testing detected ctDNA in more than 75% of metastatic solid tumors.
Might combining Pap and plasma testing for ctDNA further boost sensitivity? To test this idea, Dr. Fader and her associates performed liquid-based Pap tests and collected plasma from patients just before they underwent surgery for primary ovarian cancer.
They purified DNA from the Pap tests and used a Safe SeqS assay to amplify for 18 genes with known driver mutations in ovarian cancer: AKT1, APC, BRAF, CDKN2A, CTNNB1, EGFR, FBXW7, FGFR2, KRAS, MAPK1, NRAS, PIK3CA, PIK3R1, POLE, PPP2R1A, PTEN, RN F43, and TP53. Plasma DNA was purified and amplified for 16 genes of interest: AKT1, APC, BRAF, CDKN2A, CTNNB1, EGFR, FBXW7, FGFR2, GNAS, HRAS, KRAS, NRAS, PIK3CA, PPP2R1A, PTEN, and TP53. Tests were considered positive if they identified at least one driver mutation.
By itself, the Pap test identified only 34% of cases of stage I or stage II ovarian cancer and only 37% of cases of stage III/IV cancers, for an overall sensitivity of 36%, Dr. Fader reported. Likewise, ctDNA plasma testing yielded sensitivity values of 34% in stage I/II disease and 54% in stage III/IV disease. But combining these assays yielded sensitivities of 64% for stage I/II ovarian cancer and 97% for stage III/IV cancer, for an overall sensitivity of 76%.
Driver mutations most often involved the TP53 gene, followed by PIK3CA and CDKN2A. Rarer mutations included those of PTEN, KRAS, NRAS, APC, POLE, and PPP2RIA, Dr. Fader said. Study participants were 20-79 years old, with a median age of 61, and about 70% had stage III or stage IV disease. Nearly three-quarters of tumors were serous adenocarcinomas, of which 65% were high grade. Other tumors were mucinous (10%), clear cell (5%), germ cell (3%), carcinosarcomas (2%), or sex cord stromal (1%).
There was less detection of early-stage disease in this study, even though the investigators used a sensitive test that identified relatively rare driver mutations, Dr. Fader said. So far, ctDNA testing seems to be more effective for detecting metastatic ovarian cancer, she said. Future studies should further refine DNA detection by adding Tao Brush testing and should evaluate Pap and plasma testing in a larger cohort of women with early-stage ovarian cancer or precursor lesions, including carriers of BRCA mutations, she added.
Dr. Fader did not acknowledge external funding sources. She reported having no conflicts of interest.
NATIONAL HARBOR, MD. – Combining a liquid-based Pap smear and cell-free DNA plasma testing can boost the sensitivity of screening for primary ovarian tumors, based on the results of a prospective study of 201 patients.
The approach, however, was most sensitive when women already had late-stage disease, Amanda Nickles Fader, MD, said at the annual meeting of the Society of Gynecologic Oncology. Nonetheless, she called combined Pap and plasma testing “a promising step toward a broadly applicable screening methodology for the early detection of ovarian cancer.”
Ovarian cancer is a “legal malignancy,” and detecting it at “earlier, more curable stages is a clinical imperative,” said Dr. Fader of the Johns Hopkins Kelly Gynecologic Oncology Service in Baltimore, Md.
Routine screening with ultrasound or the CA-125 test has not been shown to reduce deaths from ovarian cancer and can lead to unnecessary diagnostic surgeries. Therefore, population-based screening is not recommended by the U.S. Preventive Services Task Force, the American Cancer Society, the American Congress of Obstetricians and Gynecologists, or the National Comprehensive Cancer Network, Dr. Fader noted.
This paradigm, however, is starting to change with the advent of DNA-based tests for ovarian cancer, including the PapGene test and assays for circulating DNA released by apoptotic tumor cells (ctDNA), Dr. Fader said. In a previous pilot study, Pap testing identified oncogenic driver mutations in 41% of primary ovarian tumors. In another study, polymerase chain reaction (PCR) testing detected ctDNA in more than 75% of metastatic solid tumors.
Might combining Pap and plasma testing for ctDNA further boost sensitivity? To test this idea, Dr. Fader and her associates performed liquid-based Pap tests and collected plasma from patients just before they underwent surgery for primary ovarian cancer.
They purified DNA from the Pap tests and used a Safe SeqS assay to amplify for 18 genes with known driver mutations in ovarian cancer: AKT1, APC, BRAF, CDKN2A, CTNNB1, EGFR, FBXW7, FGFR2, KRAS, MAPK1, NRAS, PIK3CA, PIK3R1, POLE, PPP2R1A, PTEN, RN F43, and TP53. Plasma DNA was purified and amplified for 16 genes of interest: AKT1, APC, BRAF, CDKN2A, CTNNB1, EGFR, FBXW7, FGFR2, GNAS, HRAS, KRAS, NRAS, PIK3CA, PPP2R1A, PTEN, and TP53. Tests were considered positive if they identified at least one driver mutation.
By itself, the Pap test identified only 34% of cases of stage I or stage II ovarian cancer and only 37% of cases of stage III/IV cancers, for an overall sensitivity of 36%, Dr. Fader reported. Likewise, ctDNA plasma testing yielded sensitivity values of 34% in stage I/II disease and 54% in stage III/IV disease. But combining these assays yielded sensitivities of 64% for stage I/II ovarian cancer and 97% for stage III/IV cancer, for an overall sensitivity of 76%.
Driver mutations most often involved the TP53 gene, followed by PIK3CA and CDKN2A. Rarer mutations included those of PTEN, KRAS, NRAS, APC, POLE, and PPP2RIA, Dr. Fader said. Study participants were 20-79 years old, with a median age of 61, and about 70% had stage III or stage IV disease. Nearly three-quarters of tumors were serous adenocarcinomas, of which 65% were high grade. Other tumors were mucinous (10%), clear cell (5%), germ cell (3%), carcinosarcomas (2%), or sex cord stromal (1%).
There was less detection of early-stage disease in this study, even though the investigators used a sensitive test that identified relatively rare driver mutations, Dr. Fader said. So far, ctDNA testing seems to be more effective for detecting metastatic ovarian cancer, she said. Future studies should further refine DNA detection by adding Tao Brush testing and should evaluate Pap and plasma testing in a larger cohort of women with early-stage ovarian cancer or precursor lesions, including carriers of BRCA mutations, she added.
Dr. Fader did not acknowledge external funding sources. She reported having no conflicts of interest.
NATIONAL HARBOR, MD. – Combining a liquid-based Pap smear and cell-free DNA plasma testing can boost the sensitivity of screening for primary ovarian tumors, based on the results of a prospective study of 201 patients.
The approach, however, was most sensitive when women already had late-stage disease, Amanda Nickles Fader, MD, said at the annual meeting of the Society of Gynecologic Oncology. Nonetheless, she called combined Pap and plasma testing “a promising step toward a broadly applicable screening methodology for the early detection of ovarian cancer.”
Ovarian cancer is a “legal malignancy,” and detecting it at “earlier, more curable stages is a clinical imperative,” said Dr. Fader of the Johns Hopkins Kelly Gynecologic Oncology Service in Baltimore, Md.
Routine screening with ultrasound or the CA-125 test has not been shown to reduce deaths from ovarian cancer and can lead to unnecessary diagnostic surgeries. Therefore, population-based screening is not recommended by the U.S. Preventive Services Task Force, the American Cancer Society, the American Congress of Obstetricians and Gynecologists, or the National Comprehensive Cancer Network, Dr. Fader noted.
This paradigm, however, is starting to change with the advent of DNA-based tests for ovarian cancer, including the PapGene test and assays for circulating DNA released by apoptotic tumor cells (ctDNA), Dr. Fader said. In a previous pilot study, Pap testing identified oncogenic driver mutations in 41% of primary ovarian tumors. In another study, polymerase chain reaction (PCR) testing detected ctDNA in more than 75% of metastatic solid tumors.
Might combining Pap and plasma testing for ctDNA further boost sensitivity? To test this idea, Dr. Fader and her associates performed liquid-based Pap tests and collected plasma from patients just before they underwent surgery for primary ovarian cancer.
They purified DNA from the Pap tests and used a Safe SeqS assay to amplify for 18 genes with known driver mutations in ovarian cancer: AKT1, APC, BRAF, CDKN2A, CTNNB1, EGFR, FBXW7, FGFR2, KRAS, MAPK1, NRAS, PIK3CA, PIK3R1, POLE, PPP2R1A, PTEN, RN F43, and TP53. Plasma DNA was purified and amplified for 16 genes of interest: AKT1, APC, BRAF, CDKN2A, CTNNB1, EGFR, FBXW7, FGFR2, GNAS, HRAS, KRAS, NRAS, PIK3CA, PPP2R1A, PTEN, and TP53. Tests were considered positive if they identified at least one driver mutation.
By itself, the Pap test identified only 34% of cases of stage I or stage II ovarian cancer and only 37% of cases of stage III/IV cancers, for an overall sensitivity of 36%, Dr. Fader reported. Likewise, ctDNA plasma testing yielded sensitivity values of 34% in stage I/II disease and 54% in stage III/IV disease. But combining these assays yielded sensitivities of 64% for stage I/II ovarian cancer and 97% for stage III/IV cancer, for an overall sensitivity of 76%.
Driver mutations most often involved the TP53 gene, followed by PIK3CA and CDKN2A. Rarer mutations included those of PTEN, KRAS, NRAS, APC, POLE, and PPP2RIA, Dr. Fader said. Study participants were 20-79 years old, with a median age of 61, and about 70% had stage III or stage IV disease. Nearly three-quarters of tumors were serous adenocarcinomas, of which 65% were high grade. Other tumors were mucinous (10%), clear cell (5%), germ cell (3%), carcinosarcomas (2%), or sex cord stromal (1%).
There was less detection of early-stage disease in this study, even though the investigators used a sensitive test that identified relatively rare driver mutations, Dr. Fader said. So far, ctDNA testing seems to be more effective for detecting metastatic ovarian cancer, she said. Future studies should further refine DNA detection by adding Tao Brush testing and should evaluate Pap and plasma testing in a larger cohort of women with early-stage ovarian cancer or precursor lesions, including carriers of BRCA mutations, she added.
Dr. Fader did not acknowledge external funding sources. She reported having no conflicts of interest.
AT THE ANNUAL MEETING ON WOMEN’S CANCER
Key clinical point: Adding a liquid-based Pap smear to cell-free DNA plasma testing increased the sensitivity of screening for primary ovarian cancer.
Major finding: This combined approach detected 64% of stage I/II cases and 97% of stage III/IV cases, for an overall sensitivity of 76%. In the same cohort, Pap or plasma testing alone detected between 34% and 54% of cases.
Data source: A prospective study of 201 patients undergoing surgery for primary ovarian cancer.
Disclosures: Dr. Fader did not acknowledge external funding sources. She reported having no conflicts of interest.
Peptide vaccine shows early promise in ovarian, endometrial cancers
NATIONAL HARBOR, MD. – The folate-binding protein vaccine E39+GM-CSF was well tolerated and exhibited a statistically significant, dose-dependent effect on recurrence and disease-free survival among patients with remitted primary ovarian or endometrial cancer, according to the results of a small prospective controlled phase I/IIa trial.
After a median follow-up of 12 months, cancer recurred in 41% of all vaccine recipients and 55% of controls (P = .41), G. Larry Maxwell, MD, reported at the annual meeting of the Society of Gynecologic Oncology. However, cancer recurred in only 13% of patients who received the highest (1,000 mcg) dose of peptide in the vaccine (P = .01 compared with the control group). A closer look showed that this survival benefit was limited to patients with primary disease, indicating that this vaccine has potential as an adjuvant to standard therapy for primary endometrial or ovarian cancer, he added.
Mortality from these cancers continues to rise in the United States despite conventional treatment with chemotherapy and radiation, noted Dr. Maxwell, who is chairman of the department of obstetrics and gynecology of Inova Fairfax Hospital in Annandale, Va.
“Targeted therapies have been evaluated, but durable response remains limited. Novel agents are needed,” he emphasized. He and his coinvestigators have focused on folate-binding protein, which is overexpressed by 20- to 80-fold in endometrial and ovarian tumors, compared with healthy tissue. To develop the vaccine, they combined E39, an immunogenic peptide of folate receptor 1 that amplifies the lymphocytic tumor response, with the immune adjuvant, granulocyte macrophage-colony stimulating factor (GM-CSF).
The trial included 51 patients, of whom 40 had primary ovarian or endometrial cancer and 11 had recurrent cancer. The 29 patients who were HLA-A2 positive were allocated to the vaccine group, receiving six intradermal inoculations of either 100-mcg, 500-mcg, or 1,000-mcg E39 plus 250-mcg GM-CSF, spaced by 21-28 days. Fifteen of these patients received 1,000-mcg E39, while 14 received 500- or 100-mcg doses. The treatment group also received two booster vaccines spaced 6 months apart. The 22 HLA-A2–negative patients were followed as controls. The intervention and control groups resembled each other clinically and demographically, Dr. Maxwell said.
Estimated rates of 2-year disease-free survival were 77% for patients in the 1,000 mcg–dose group, 44% for controls (P = .05), and 23% for patients who received less than 1,000 mcg vaccine (P = .005). Adverse events mainly included grade 1 or grade 2 myalgias, headaches, or reactions at the vaccination site. Mild adverse events were significantly more common at the 1,000-mcg E39 dose than at lower doses (P = .04). There was one grade 3 toxicity, and no grade 4 or 5 adverse events.
Delayed-type hypersensitivity reactions were more pronounced after vaccination, compared with baseline (5.7 ± 1.5 mm versus 10.3 ± 3.0 mm; P = .06), particularly in the 1,000-mcg group (3.8 ± 2.0 mm vs. 9.5 ± 3.5 mm, P = .03), Dr. Maxwell reported. Among patients whose cancer did not recur, delayed-type hypersensitivity was markedly higher after vaccination than at baseline (P = .06). “Our functional immunologic data show that vaccination is associated with delayed type hypersensitivity, but more important, it is associated with clinical outcome,” Dr. Maxwell said.
Low levels of folate-binding protein expression correlated with better disease-free survival, he also reported. “Possibly, this is because high levels of expression are associated with disease aggressiveness, which may outpace the immune response,” he said.
A phase Ib trial of the E39 folate-binding protein peptide vaccine is underway. Dr. Maxwell did not cite external funding sources and reported having no conflicts of interest.
NATIONAL HARBOR, MD. – The folate-binding protein vaccine E39+GM-CSF was well tolerated and exhibited a statistically significant, dose-dependent effect on recurrence and disease-free survival among patients with remitted primary ovarian or endometrial cancer, according to the results of a small prospective controlled phase I/IIa trial.
After a median follow-up of 12 months, cancer recurred in 41% of all vaccine recipients and 55% of controls (P = .41), G. Larry Maxwell, MD, reported at the annual meeting of the Society of Gynecologic Oncology. However, cancer recurred in only 13% of patients who received the highest (1,000 mcg) dose of peptide in the vaccine (P = .01 compared with the control group). A closer look showed that this survival benefit was limited to patients with primary disease, indicating that this vaccine has potential as an adjuvant to standard therapy for primary endometrial or ovarian cancer, he added.
Mortality from these cancers continues to rise in the United States despite conventional treatment with chemotherapy and radiation, noted Dr. Maxwell, who is chairman of the department of obstetrics and gynecology of Inova Fairfax Hospital in Annandale, Va.
“Targeted therapies have been evaluated, but durable response remains limited. Novel agents are needed,” he emphasized. He and his coinvestigators have focused on folate-binding protein, which is overexpressed by 20- to 80-fold in endometrial and ovarian tumors, compared with healthy tissue. To develop the vaccine, they combined E39, an immunogenic peptide of folate receptor 1 that amplifies the lymphocytic tumor response, with the immune adjuvant, granulocyte macrophage-colony stimulating factor (GM-CSF).
The trial included 51 patients, of whom 40 had primary ovarian or endometrial cancer and 11 had recurrent cancer. The 29 patients who were HLA-A2 positive were allocated to the vaccine group, receiving six intradermal inoculations of either 100-mcg, 500-mcg, or 1,000-mcg E39 plus 250-mcg GM-CSF, spaced by 21-28 days. Fifteen of these patients received 1,000-mcg E39, while 14 received 500- or 100-mcg doses. The treatment group also received two booster vaccines spaced 6 months apart. The 22 HLA-A2–negative patients were followed as controls. The intervention and control groups resembled each other clinically and demographically, Dr. Maxwell said.
Estimated rates of 2-year disease-free survival were 77% for patients in the 1,000 mcg–dose group, 44% for controls (P = .05), and 23% for patients who received less than 1,000 mcg vaccine (P = .005). Adverse events mainly included grade 1 or grade 2 myalgias, headaches, or reactions at the vaccination site. Mild adverse events were significantly more common at the 1,000-mcg E39 dose than at lower doses (P = .04). There was one grade 3 toxicity, and no grade 4 or 5 adverse events.
Delayed-type hypersensitivity reactions were more pronounced after vaccination, compared with baseline (5.7 ± 1.5 mm versus 10.3 ± 3.0 mm; P = .06), particularly in the 1,000-mcg group (3.8 ± 2.0 mm vs. 9.5 ± 3.5 mm, P = .03), Dr. Maxwell reported. Among patients whose cancer did not recur, delayed-type hypersensitivity was markedly higher after vaccination than at baseline (P = .06). “Our functional immunologic data show that vaccination is associated with delayed type hypersensitivity, but more important, it is associated with clinical outcome,” Dr. Maxwell said.
Low levels of folate-binding protein expression correlated with better disease-free survival, he also reported. “Possibly, this is because high levels of expression are associated with disease aggressiveness, which may outpace the immune response,” he said.
A phase Ib trial of the E39 folate-binding protein peptide vaccine is underway. Dr. Maxwell did not cite external funding sources and reported having no conflicts of interest.
NATIONAL HARBOR, MD. – The folate-binding protein vaccine E39+GM-CSF was well tolerated and exhibited a statistically significant, dose-dependent effect on recurrence and disease-free survival among patients with remitted primary ovarian or endometrial cancer, according to the results of a small prospective controlled phase I/IIa trial.
After a median follow-up of 12 months, cancer recurred in 41% of all vaccine recipients and 55% of controls (P = .41), G. Larry Maxwell, MD, reported at the annual meeting of the Society of Gynecologic Oncology. However, cancer recurred in only 13% of patients who received the highest (1,000 mcg) dose of peptide in the vaccine (P = .01 compared with the control group). A closer look showed that this survival benefit was limited to patients with primary disease, indicating that this vaccine has potential as an adjuvant to standard therapy for primary endometrial or ovarian cancer, he added.
Mortality from these cancers continues to rise in the United States despite conventional treatment with chemotherapy and radiation, noted Dr. Maxwell, who is chairman of the department of obstetrics and gynecology of Inova Fairfax Hospital in Annandale, Va.
“Targeted therapies have been evaluated, but durable response remains limited. Novel agents are needed,” he emphasized. He and his coinvestigators have focused on folate-binding protein, which is overexpressed by 20- to 80-fold in endometrial and ovarian tumors, compared with healthy tissue. To develop the vaccine, they combined E39, an immunogenic peptide of folate receptor 1 that amplifies the lymphocytic tumor response, with the immune adjuvant, granulocyte macrophage-colony stimulating factor (GM-CSF).
The trial included 51 patients, of whom 40 had primary ovarian or endometrial cancer and 11 had recurrent cancer. The 29 patients who were HLA-A2 positive were allocated to the vaccine group, receiving six intradermal inoculations of either 100-mcg, 500-mcg, or 1,000-mcg E39 plus 250-mcg GM-CSF, spaced by 21-28 days. Fifteen of these patients received 1,000-mcg E39, while 14 received 500- or 100-mcg doses. The treatment group also received two booster vaccines spaced 6 months apart. The 22 HLA-A2–negative patients were followed as controls. The intervention and control groups resembled each other clinically and demographically, Dr. Maxwell said.
Estimated rates of 2-year disease-free survival were 77% for patients in the 1,000 mcg–dose group, 44% for controls (P = .05), and 23% for patients who received less than 1,000 mcg vaccine (P = .005). Adverse events mainly included grade 1 or grade 2 myalgias, headaches, or reactions at the vaccination site. Mild adverse events were significantly more common at the 1,000-mcg E39 dose than at lower doses (P = .04). There was one grade 3 toxicity, and no grade 4 or 5 adverse events.
Delayed-type hypersensitivity reactions were more pronounced after vaccination, compared with baseline (5.7 ± 1.5 mm versus 10.3 ± 3.0 mm; P = .06), particularly in the 1,000-mcg group (3.8 ± 2.0 mm vs. 9.5 ± 3.5 mm, P = .03), Dr. Maxwell reported. Among patients whose cancer did not recur, delayed-type hypersensitivity was markedly higher after vaccination than at baseline (P = .06). “Our functional immunologic data show that vaccination is associated with delayed type hypersensitivity, but more important, it is associated with clinical outcome,” Dr. Maxwell said.
Low levels of folate-binding protein expression correlated with better disease-free survival, he also reported. “Possibly, this is because high levels of expression are associated with disease aggressiveness, which may outpace the immune response,” he said.
A phase Ib trial of the E39 folate-binding protein peptide vaccine is underway. Dr. Maxwell did not cite external funding sources and reported having no conflicts of interest.
AT THE ANNUAL MEETING ON WOMEN’S CANCER
Key clinical point: The folate-binding protein vaccine E39+GM-CSF was well tolerated and exhibited a statistically significant, dose-dependent effect on recurrence and disease-free survival among patients with remitted primary ovarian or endometrial cancer.
Major finding: Most adverse events were of grade 1 or grade 2 severity and were local, not systemic. After a median follow-up of 12 months, cancer recurred in 13% of patients who received the highest (1,000 mcg) dose of peptide in the vaccine, versus 55% controls (P = .01 compared with the control group).
Data source: A prospective controlled phase I/IIa trial of 51 patients with primary or recurrent ovarian or endometrial cancer.
Disclosures: Dr. Maxwell did not cite external funding sources and reported having no conflicts of interest.