Amy Karon

The immune-related adverse effects of inhibitors of programmed cell death protein 1 (PD-1) and its ligand varied by tumor type in a large systematic review and meta-analysis.

Patients with melanoma were significantly more likely to develop colitis (odds ratio, 4.2; 95% confidence interval, 1.3 to 14.0), diarrhea (OR, 1.9), pruritus (OR, 2.4), and rash (OR, 1.8) compared with patients with non–small cell lung cancer, who were significantly more likely to develop pneumonitis, reported Leila Khoja, MBChB, PhD, of AstraZeneca UK, Melbourn, England, and associates. Patients with melanoma also were significantly more likely to develop arthralgia, hypothyroidism, rash, pruritus, and diarrhea compared with patients with renal cell carcinoma, who were more likely to develop pneumonitis and dyspnea.

“In light of this study, we should be mindful that different tumor types may have different immune-related adverse effect patterns when treated with the same immune checkpoint inhibitor,” the reviewers noted (Ann Oncol. 2017 Aug 8. doi: 10.1093/annonc/mdx286).

The review included 48 trials of nearly 7,000 patients with solid tumors who received CTLA-4 inhibitors (26 studies), PD-1 inhibitors (17 studies), PD-1 ligand (PD-L1) inhibitors (two trials), or both CTLA-4 and PD-1 inhibitors (three trials). The reviewers identified the studies by searching the Medline, EMBASE, and COCHRANE databases for prospective trials published from 2003 through November 2015.

Severe or life-threatening immune-related adverse effects developed in 31% of patients who received CTLA-4 inhibitors and 10% of patients who received PD-1 inhibitors. Inhibitors of CTLA-4 were significantly more likely to cause all grades of colitis (OR, 8.7), hypophysitis (OR, 6.5), and rash (OR, 2.0), while PD-1 inhibitors were more strongly linked with pneumonitis (OR 6.4), hypothyroidism (OR 4.3), arthralgia (OR, 3.5), and vitiligo (OR, 3.5).

The reviewers also looked for significant predictors of immune-related colitis and pneumonitis, because these are potentially fatal. They found that pneumonitis was significantly linked to PD-1/PD-L1 inhibitor therapy (P less than .001) and colitis to CTLA-4 treatment (P = .04), even after accounting for therapeutic dose and tumor type. No other factors reached significance in this multivariable model.

“Clearly, a more thorough understanding of the mechanisms of immune-related adverse effects is needed, which may lead to the identification of biomarkers to predict the occurrence of toxicity in patients or predict those who have immune-related adverse effects that are unlikely to respond to corticosteroids,” the reviewers concluded. Researchers should also study whether clinical factors such as treatment history or comorbidities affect the risk of immune-related adverse effects from immune checkpoint inhibitors, they said.

The reviewers reported having no funding sources and no relevant conflicts of interest.

The immune-related adverse effects of inhibitors of programmed cell death protein 1 (PD-1) and its ligand varied by tumor type in a large systematic review and meta-analysis.

Patients with melanoma were significantly more likely to develop colitis (odds ratio, 4.2; 95% confidence interval, 1.3 to 14.0), diarrhea (OR, 1.9), pruritus (OR, 2.4), and rash (OR, 1.8) compared with patients with non–small cell lung cancer, who were significantly more likely to develop pneumonitis, reported Leila Khoja, MBChB, PhD, of AstraZeneca UK, Melbourn, England, and associates. Patients with melanoma also were significantly more likely to develop arthralgia, hypothyroidism, rash, pruritus, and diarrhea compared with patients with renal cell carcinoma, who were more likely to develop pneumonitis and dyspnea.

“In light of this study, we should be mindful that different tumor types may have different immune-related adverse effect patterns when treated with the same immune checkpoint inhibitor,” the reviewers noted (Ann Oncol. 2017 Aug 8. doi: 10.1093/annonc/mdx286).

The review included 48 trials of nearly 7,000 patients with solid tumors who received CTLA-4 inhibitors (26 studies), PD-1 inhibitors (17 studies), PD-1 ligand (PD-L1) inhibitors (two trials), or both CTLA-4 and PD-1 inhibitors (three trials). The reviewers identified the studies by searching the Medline, EMBASE, and COCHRANE databases for prospective trials published from 2003 through November 2015.

Severe or life-threatening immune-related adverse effects developed in 31% of patients who received CTLA-4 inhibitors and 10% of patients who received PD-1 inhibitors. Inhibitors of CTLA-4 were significantly more likely to cause all grades of colitis (OR, 8.7), hypophysitis (OR, 6.5), and rash (OR, 2.0), while PD-1 inhibitors were more strongly linked with pneumonitis (OR 6.4), hypothyroidism (OR 4.3), arthralgia (OR, 3.5), and vitiligo (OR, 3.5).

The reviewers also looked for significant predictors of immune-related colitis and pneumonitis, because these are potentially fatal. They found that pneumonitis was significantly linked to PD-1/PD-L1 inhibitor therapy (P less than .001) and colitis to CTLA-4 treatment (P = .04), even after accounting for therapeutic dose and tumor type. No other factors reached significance in this multivariable model.

“Clearly, a more thorough understanding of the mechanisms of immune-related adverse effects is needed, which may lead to the identification of biomarkers to predict the occurrence of toxicity in patients or predict those who have immune-related adverse effects that are unlikely to respond to corticosteroids,” the reviewers concluded. Researchers should also study whether clinical factors such as treatment history or comorbidities affect the risk of immune-related adverse effects from immune checkpoint inhibitors, they said.

The reviewers reported having no funding sources and no relevant conflicts of interest.

The immune-related adverse effects of inhibitors of programmed cell death protein 1 (PD-1) and its ligand varied by tumor type in a large systematic review and meta-analysis.

Patients with melanoma were significantly more likely to develop colitis (odds ratio, 4.2; 95% confidence interval, 1.3 to 14.0), diarrhea (OR, 1.9), pruritus (OR, 2.4), and rash (OR, 1.8) compared with patients with non–small cell lung cancer, who were significantly more likely to develop pneumonitis, reported Leila Khoja, MBChB, PhD, of AstraZeneca UK, Melbourn, England, and associates. Patients with melanoma also were significantly more likely to develop arthralgia, hypothyroidism, rash, pruritus, and diarrhea compared with patients with renal cell carcinoma, who were more likely to develop pneumonitis and dyspnea.

“In light of this study, we should be mindful that different tumor types may have different immune-related adverse effect patterns when treated with the same immune checkpoint inhibitor,” the reviewers noted (Ann Oncol. 2017 Aug 8. doi: 10.1093/annonc/mdx286).

The review included 48 trials of nearly 7,000 patients with solid tumors who received CTLA-4 inhibitors (26 studies), PD-1 inhibitors (17 studies), PD-1 ligand (PD-L1) inhibitors (two trials), or both CTLA-4 and PD-1 inhibitors (three trials). The reviewers identified the studies by searching the Medline, EMBASE, and COCHRANE databases for prospective trials published from 2003 through November 2015.

Severe or life-threatening immune-related adverse effects developed in 31% of patients who received CTLA-4 inhibitors and 10% of patients who received PD-1 inhibitors. Inhibitors of CTLA-4 were significantly more likely to cause all grades of colitis (OR, 8.7), hypophysitis (OR, 6.5), and rash (OR, 2.0), while PD-1 inhibitors were more strongly linked with pneumonitis (OR 6.4), hypothyroidism (OR 4.3), arthralgia (OR, 3.5), and vitiligo (OR, 3.5).

The reviewers also looked for significant predictors of immune-related colitis and pneumonitis, because these are potentially fatal. They found that pneumonitis was significantly linked to PD-1/PD-L1 inhibitor therapy (P less than .001) and colitis to CTLA-4 treatment (P = .04), even after accounting for therapeutic dose and tumor type. No other factors reached significance in this multivariable model.

“Clearly, a more thorough understanding of the mechanisms of immune-related adverse effects is needed, which may lead to the identification of biomarkers to predict the occurrence of toxicity in patients or predict those who have immune-related adverse effects that are unlikely to respond to corticosteroids,” the reviewers concluded. Researchers should also study whether clinical factors such as treatment history or comorbidities affect the risk of immune-related adverse effects from immune checkpoint inhibitors, they said.

The reviewers reported having no funding sources and no relevant conflicts of interest.

Supplemental oxygen did not prevent mortality or rehospitalization among patients with suspected myocardial infarction whose oxygen saturation on room air exceeded 90%, investigators reported.

Rates of all-cause mortality at 1 year were 5% among patients who received supplemental oxygen through an open face mask (6 liters per minute for 6-12 hours) and 5.1% among patients who breathed room air, said Robin Hofmann, MD, of Karolinska Institutet, Stockholm, and his associates. In addition, rehospitalization for MI occurred in 3.8% of patients who received supplemental oxygen and 3.3% of those breathed room air. The findings of the randomized registry-based trial of 6,629 patients were presented at the annual congress of the European Society of Cardiology and published simultaneously in the New England Journal of Medicine.

Guidelines recommend oxygen supplementation in MI, and the practice has persisted for more than a century, but adequately powered trials of hard clinical endpoints are lacking. Above-normal oxygen saturation can potentially worsen reperfusion injury by causing coronary vasoconstriction and increasing production of reactive oxygen species, the researchers noted.

Notably, the Australian Air Versus Oxygen in Myocardial Infarction (AVOID) trial found that oxygen supplementation was associated with larger infarct sizes in patients with ST-segment elevation myocardial infarction, and a recent Cochrane report did not support routine oxygen supplementation for MI.

The current trial enrolled patients aged 30 years and older who had chest pain or shortness of breath lasting less than 6 hours, an oxygen saturation of at least 90% on pulse oximetry, and either electrocardiographic evidence of ischemia or elevated cardiac troponin T or I levels (N Engl J Med. 2017 Aug 28. doi: 10.1056/NEJMoa1706222).

Oxygen therapy lasted a median of 11.6 hours, after which median oxygen saturation levels were 99% in the intervention group and 97% in the control group.

A total of 62 patients (2%) who received oxygen developed hypoxemia, as did 254 patients (8%) who breathed room air. Median highest troponin levels during hospitalization were 946.5 ng per L and 983.0 ng per L, respectively. A total of 166 (5%) patients in the oxygen group and 168 (5.1%) control patients died from any cause by a year after treatment (hazard ratio, 0.97; P = .8). Likewise, supplemental oxygen did not prevent rehospitalization with MI within 1 year (HR, 1.13; P = .3).

“Because power for evaluation of the primary endpoint was lower than anticipated, we cannot completely rule out a small beneficial or detrimental effect of oxygen on mortality,” the researchers wrote. But clinical differences were unlikely, based on the superimposable time-to-event curves through 12 months, the consistent results across subgroups, and the neutral findings on secondary clinical endpoints, they added.

The Swedish Research Council, the Swedish Heart-Lung Foundation, and the Swedish Foundation for Strategic Research funded the study. Dr. Hofmann disclosed research grants from these entities.

Supplemental oxygen did not prevent mortality or rehospitalization among patients with suspected myocardial infarction whose oxygen saturation on room air exceeded 90%, investigators reported.

Rates of all-cause mortality at 1 year were 5% among patients who received supplemental oxygen through an open face mask (6 liters per minute for 6-12 hours) and 5.1% among patients who breathed room air, said Robin Hofmann, MD, of Karolinska Institutet, Stockholm, and his associates. In addition, rehospitalization for MI occurred in 3.8% of patients who received supplemental oxygen and 3.3% of those breathed room air. The findings of the randomized registry-based trial of 6,629 patients were presented at the annual congress of the European Society of Cardiology and published simultaneously in the New England Journal of Medicine.

Guidelines recommend oxygen supplementation in MI, and the practice has persisted for more than a century, but adequately powered trials of hard clinical endpoints are lacking. Above-normal oxygen saturation can potentially worsen reperfusion injury by causing coronary vasoconstriction and increasing production of reactive oxygen species, the researchers noted.

Notably, the Australian Air Versus Oxygen in Myocardial Infarction (AVOID) trial found that oxygen supplementation was associated with larger infarct sizes in patients with ST-segment elevation myocardial infarction, and a recent Cochrane report did not support routine oxygen supplementation for MI.

The current trial enrolled patients aged 30 years and older who had chest pain or shortness of breath lasting less than 6 hours, an oxygen saturation of at least 90% on pulse oximetry, and either electrocardiographic evidence of ischemia or elevated cardiac troponin T or I levels (N Engl J Med. 2017 Aug 28. doi: 10.1056/NEJMoa1706222).

Oxygen therapy lasted a median of 11.6 hours, after which median oxygen saturation levels were 99% in the intervention group and 97% in the control group.

A total of 62 patients (2%) who received oxygen developed hypoxemia, as did 254 patients (8%) who breathed room air. Median highest troponin levels during hospitalization were 946.5 ng per L and 983.0 ng per L, respectively. A total of 166 (5%) patients in the oxygen group and 168 (5.1%) control patients died from any cause by a year after treatment (hazard ratio, 0.97; P = .8). Likewise, supplemental oxygen did not prevent rehospitalization with MI within 1 year (HR, 1.13; P = .3).

“Because power for evaluation of the primary endpoint was lower than anticipated, we cannot completely rule out a small beneficial or detrimental effect of oxygen on mortality,” the researchers wrote. But clinical differences were unlikely, based on the superimposable time-to-event curves through 12 months, the consistent results across subgroups, and the neutral findings on secondary clinical endpoints, they added.

The Swedish Research Council, the Swedish Heart-Lung Foundation, and the Swedish Foundation for Strategic Research funded the study. Dr. Hofmann disclosed research grants from these entities.

Supplemental oxygen did not prevent mortality or rehospitalization among patients with suspected myocardial infarction whose oxygen saturation on room air exceeded 90%, investigators reported.

Rates of all-cause mortality at 1 year were 5% among patients who received supplemental oxygen through an open face mask (6 liters per minute for 6-12 hours) and 5.1% among patients who breathed room air, said Robin Hofmann, MD, of Karolinska Institutet, Stockholm, and his associates. In addition, rehospitalization for MI occurred in 3.8% of patients who received supplemental oxygen and 3.3% of those breathed room air. The findings of the randomized registry-based trial of 6,629 patients were presented at the annual congress of the European Society of Cardiology and published simultaneously in the New England Journal of Medicine.

Guidelines recommend oxygen supplementation in MI, and the practice has persisted for more than a century, but adequately powered trials of hard clinical endpoints are lacking. Above-normal oxygen saturation can potentially worsen reperfusion injury by causing coronary vasoconstriction and increasing production of reactive oxygen species, the researchers noted.

Notably, the Australian Air Versus Oxygen in Myocardial Infarction (AVOID) trial found that oxygen supplementation was associated with larger infarct sizes in patients with ST-segment elevation myocardial infarction, and a recent Cochrane report did not support routine oxygen supplementation for MI.

The current trial enrolled patients aged 30 years and older who had chest pain or shortness of breath lasting less than 6 hours, an oxygen saturation of at least 90% on pulse oximetry, and either electrocardiographic evidence of ischemia or elevated cardiac troponin T or I levels (N Engl J Med. 2017 Aug 28. doi: 10.1056/NEJMoa1706222).

Oxygen therapy lasted a median of 11.6 hours, after which median oxygen saturation levels were 99% in the intervention group and 97% in the control group.

A total of 62 patients (2%) who received oxygen developed hypoxemia, as did 254 patients (8%) who breathed room air. Median highest troponin levels during hospitalization were 946.5 ng per L and 983.0 ng per L, respectively. A total of 166 (5%) patients in the oxygen group and 168 (5.1%) control patients died from any cause by a year after treatment (hazard ratio, 0.97; P = .8). Likewise, supplemental oxygen did not prevent rehospitalization with MI within 1 year (HR, 1.13; P = .3).

“Because power for evaluation of the primary endpoint was lower than anticipated, we cannot completely rule out a small beneficial or detrimental effect of oxygen on mortality,” the researchers wrote. But clinical differences were unlikely, based on the superimposable time-to-event curves through 12 months, the consistent results across subgroups, and the neutral findings on secondary clinical endpoints, they added.

The Swedish Research Council, the Swedish Heart-Lung Foundation, and the Swedish Foundation for Strategic Research funded the study. Dr. Hofmann disclosed research grants from these entities.

Over an 18-month period, small, insertable cardiac monitors detected atrial fibrillation in 29% of previously undiagnosed patients who were at high risk of both AF and stroke, and in 40% of patients over 30 months, according to investigators. The study was presented at the annual congress of the European Society of Cardiology and simultaneously published in JAMA Cardiology.

More than half (56%) of patients consequently started oral anticoagulation therapy, noted James A. Reiffel, MD, of Columbia University College of Physicians and Surgeons, New York, with his associates, for the REVEAL AF investigators.

“The incidence of previously undiagnosed atrial fibrillation may be substantial in patients with risk factors for AF and stroke,” they concluded. “Atrial fibrillation would have gone undetected in most patients had monitoring been limited to 30 days. Further trials regarding the value of detecting subclinical AF and of prophylactic therapies are warranted.”

Atrial fibrillation affects millions worldwide and is associated with older age, hypertension, diabetes, and heart failure, all of which also independently increase the risk of stroke. Minimally invasive prolonged electrocardiographic monitoring with insertable cardiac monitors might help hasten detection and treatment of AF, but diagnostic yield in high-risk patients has been unclear.

In this single-arm, multicenter, prospective study, researchers inserted Reveal XT or Reveal LINQ (Medtronic) cardiac monitors in 385 adults who had either CHAD2 scores of 3, or CHAD2 scores of 2 and one additional risk factor for AF, such as coronary artery disease, sleep apnea, chronic obstructive pulmonary disease, or renal insufficiency. The primary endpoint was AF lasting at least 6 minutes (JAMA Cardiol. 2017 Aug 26. doi: 10.1001/jamacardio.2017.3180). Median follow-up time was 22.5 months. Rates of detecting AF were 6% at 30 days compared with 20% at 6 months, 27% at 12 months, 34% at 24 months, and 40% at 30 months. Patients typically had their first AF episode about 4 months (median, 123 days) after the device was inserted. Among patients who had experienced AF by 18 months, 10% had one or more episodes lasting at least 24 hours, and 72 (56%) were prescribed oral anticoagulation therapy.

The recent PREDATE AF and ASSERT-II studies also found that previously undiagnosed AF was common among high-risk patients, the researchers noted. However, whether anticoagulating patients who have only brief episodes of AF significantly reduces their risk of stroke remains unclear, they added. Three trials (ARTESiA, NOAH, and LOOP) are underway to assess whether oral anticoagulation therapy improves outcomes in patients with device-detected AF.

Medtronic funded the study. Dr. Reiffel and five coinvestigators disclosed consulting for and receiving “modest honoraria” from Medtronic. Two other coinvestigators reported employment with and stock ownership in Medtronic.

Over an 18-month period, small, insertable cardiac monitors detected atrial fibrillation in 29% of previously undiagnosed patients who were at high risk of both AF and stroke, and in 40% of patients over 30 months, according to investigators. The study was presented at the annual congress of the European Society of Cardiology and simultaneously published in JAMA Cardiology.

More than half (56%) of patients consequently started oral anticoagulation therapy, noted James A. Reiffel, MD, of Columbia University College of Physicians and Surgeons, New York, with his associates, for the REVEAL AF investigators.

“The incidence of previously undiagnosed atrial fibrillation may be substantial in patients with risk factors for AF and stroke,” they concluded. “Atrial fibrillation would have gone undetected in most patients had monitoring been limited to 30 days. Further trials regarding the value of detecting subclinical AF and of prophylactic therapies are warranted.”

Atrial fibrillation affects millions worldwide and is associated with older age, hypertension, diabetes, and heart failure, all of which also independently increase the risk of stroke. Minimally invasive prolonged electrocardiographic monitoring with insertable cardiac monitors might help hasten detection and treatment of AF, but diagnostic yield in high-risk patients has been unclear.

In this single-arm, multicenter, prospective study, researchers inserted Reveal XT or Reveal LINQ (Medtronic) cardiac monitors in 385 adults who had either CHAD2 scores of 3, or CHAD2 scores of 2 and one additional risk factor for AF, such as coronary artery disease, sleep apnea, chronic obstructive pulmonary disease, or renal insufficiency. The primary endpoint was AF lasting at least 6 minutes (JAMA Cardiol. 2017 Aug 26. doi: 10.1001/jamacardio.2017.3180). Median follow-up time was 22.5 months. Rates of detecting AF were 6% at 30 days compared with 20% at 6 months, 27% at 12 months, 34% at 24 months, and 40% at 30 months. Patients typically had their first AF episode about 4 months (median, 123 days) after the device was inserted. Among patients who had experienced AF by 18 months, 10% had one or more episodes lasting at least 24 hours, and 72 (56%) were prescribed oral anticoagulation therapy.

The recent PREDATE AF and ASSERT-II studies also found that previously undiagnosed AF was common among high-risk patients, the researchers noted. However, whether anticoagulating patients who have only brief episodes of AF significantly reduces their risk of stroke remains unclear, they added. Three trials (ARTESiA, NOAH, and LOOP) are underway to assess whether oral anticoagulation therapy improves outcomes in patients with device-detected AF.

Medtronic funded the study. Dr. Reiffel and five coinvestigators disclosed consulting for and receiving “modest honoraria” from Medtronic. Two other coinvestigators reported employment with and stock ownership in Medtronic.

Over an 18-month period, small, insertable cardiac monitors detected atrial fibrillation in 29% of previously undiagnosed patients who were at high risk of both AF and stroke, and in 40% of patients over 30 months, according to investigators. The study was presented at the annual congress of the European Society of Cardiology and simultaneously published in JAMA Cardiology.

More than half (56%) of patients consequently started oral anticoagulation therapy, noted James A. Reiffel, MD, of Columbia University College of Physicians and Surgeons, New York, with his associates, for the REVEAL AF investigators.

“The incidence of previously undiagnosed atrial fibrillation may be substantial in patients with risk factors for AF and stroke,” they concluded. “Atrial fibrillation would have gone undetected in most patients had monitoring been limited to 30 days. Further trials regarding the value of detecting subclinical AF and of prophylactic therapies are warranted.”

Atrial fibrillation affects millions worldwide and is associated with older age, hypertension, diabetes, and heart failure, all of which also independently increase the risk of stroke. Minimally invasive prolonged electrocardiographic monitoring with insertable cardiac monitors might help hasten detection and treatment of AF, but diagnostic yield in high-risk patients has been unclear.

In this single-arm, multicenter, prospective study, researchers inserted Reveal XT or Reveal LINQ (Medtronic) cardiac monitors in 385 adults who had either CHAD2 scores of 3, or CHAD2 scores of 2 and one additional risk factor for AF, such as coronary artery disease, sleep apnea, chronic obstructive pulmonary disease, or renal insufficiency. The primary endpoint was AF lasting at least 6 minutes (JAMA Cardiol. 2017 Aug 26. doi: 10.1001/jamacardio.2017.3180). Median follow-up time was 22.5 months. Rates of detecting AF were 6% at 30 days compared with 20% at 6 months, 27% at 12 months, 34% at 24 months, and 40% at 30 months. Patients typically had their first AF episode about 4 months (median, 123 days) after the device was inserted. Among patients who had experienced AF by 18 months, 10% had one or more episodes lasting at least 24 hours, and 72 (56%) were prescribed oral anticoagulation therapy.

The recent PREDATE AF and ASSERT-II studies also found that previously undiagnosed AF was common among high-risk patients, the researchers noted. However, whether anticoagulating patients who have only brief episodes of AF significantly reduces their risk of stroke remains unclear, they added. Three trials (ARTESiA, NOAH, and LOOP) are underway to assess whether oral anticoagulation therapy improves outcomes in patients with device-detected AF.

Medtronic funded the study. Dr. Reiffel and five coinvestigators disclosed consulting for and receiving “modest honoraria” from Medtronic. Two other coinvestigators reported employment with and stock ownership in Medtronic.

Global mortality due to rheumatic heart disease fell by about 48% during a recent 25-year-period, but some of the poorest areas of the world were left behind, according to a report in the New England Journal of Medicine.

Those regions included Oceania, South Asia, and central sub-Saharan Africa, where rheumatic heart disease remains endemic, wrote David A. Watkins, MD, MPH, of the University of Washington, Seattle, and his coinvestigators. “We estimate that 10 persons per 1,000 population living in South Asia and central sub-Saharan Africa and 15 persons per 1,000 population in Oceania were living with rheumatic heart disease in the year 2015,” they wrote. “Improvements in the measurement of the burden of rheumatic heart disease will assist in planning for its control and will help identify countries where further investments are needed.”

Global mortality due to rheumatic heart disease fell by about 48% during a recent 25-year-period, but some of the poorest areas of the world were left behind, according to a report in the New England Journal of Medicine.

Those regions included Oceania, South Asia, and central sub-Saharan Africa, where rheumatic heart disease remains endemic, wrote David A. Watkins, MD, MPH, of the University of Washington, Seattle, and his coinvestigators. “We estimate that 10 persons per 1,000 population living in South Asia and central sub-Saharan Africa and 15 persons per 1,000 population in Oceania were living with rheumatic heart disease in the year 2015,” they wrote. “Improvements in the measurement of the burden of rheumatic heart disease will assist in planning for its control and will help identify countries where further investments are needed.”

Global mortality due to rheumatic heart disease fell by about 48% during a recent 25-year-period, but some of the poorest areas of the world were left behind, according to a report in the New England Journal of Medicine.

Those regions included Oceania, South Asia, and central sub-Saharan Africa, where rheumatic heart disease remains endemic, wrote David A. Watkins, MD, MPH, of the University of Washington, Seattle, and his coinvestigators. “We estimate that 10 persons per 1,000 population living in South Asia and central sub-Saharan Africa and 15 persons per 1,000 population in Oceania were living with rheumatic heart disease in the year 2015,” they wrote. “Improvements in the measurement of the burden of rheumatic heart disease will assist in planning for its control and will help identify countries where further investments are needed.”

Rates of phlebitis associated with peripheral venous catheters (PVC) ranged from less than 1% to 34% depending on which assessment tool researchers used in a large cross-sectional study.

Rates also varied within individual instruments because they included several possible case definitions, Katarina Göransson, PhD, and her associates reported in Lancet Haematology. “We find it concerning that our study shows variation of the proportion of PVCs causing phlebitis both within and across the instruments investigated,” they wrote. “How to best measure phlebitis outcomes is still unclear, since no universally accepted instrument exists that has had rigorous testing. From a work environment and patient safety perspective, clinical staff engaged in PVC management should be aware of the absence of adequately validated instruments for phlebitis assessment.”

There are many tools to measure PVC-related phlebitis, but no consensus on which to use, and past studies have reported rates of anywhere from 2% to 62%. Hypothesizing that instrument variability contributed to this discrepancy, the researchers tested 17 instruments in 1,032 patients who had 1,175 PVCs placed at 12 inpatient units in Sweden. Eight tools used clinical definitions, seven used severity rating systems, and two used scoring systems (Lancet Haematol. 2017 doi: 10.1016/S2352-3026[17]30122-9).

Rates of PVC-induced phlebitis reached 12% (137 cases) when the researchers used case definition tools, up to 31% when they used scoring systems (P less than .0001), and up to 34% when they used severity rating systems (P less than .0001, compared with the 12% rate). “The proportion within instruments ranged from less than 1% to 28%,” they added. “We [also] identified face validity issues, such as use of indistinct or complex measurements and inconsistent measurements or definitions.”

The investigators did not perform a systematic review to identify these instruments, and they did not necessarily use the most recent versions, they noted. Nevertheless, the findings have direct implications for hospital quality control measures, which require using a single validated instrument over time to generate meaningful results, they said. Hence, the investigators recommended developing a joint research program to develop reliable measures of PVC-related adverse events and better support clinicians who are trying to decide whether to remove PVCs.

The investigators reported having no funding sources and no competing interests.

[email protected]

Rates of phlebitis associated with peripheral venous catheters (PVC) ranged from less than 1% to 34% depending on which assessment tool researchers used in a large cross-sectional study.

Rates also varied within individual instruments because they included several possible case definitions, Katarina Göransson, PhD, and her associates reported in Lancet Haematology. “We find it concerning that our study shows variation of the proportion of PVCs causing phlebitis both within and across the instruments investigated,” they wrote. “How to best measure phlebitis outcomes is still unclear, since no universally accepted instrument exists that has had rigorous testing. From a work environment and patient safety perspective, clinical staff engaged in PVC management should be aware of the absence of adequately validated instruments for phlebitis assessment.”

There are many tools to measure PVC-related phlebitis, but no consensus on which to use, and past studies have reported rates of anywhere from 2% to 62%. Hypothesizing that instrument variability contributed to this discrepancy, the researchers tested 17 instruments in 1,032 patients who had 1,175 PVCs placed at 12 inpatient units in Sweden. Eight tools used clinical definitions, seven used severity rating systems, and two used scoring systems (Lancet Haematol. 2017 doi: 10.1016/S2352-3026[17]30122-9).

Rates of PVC-induced phlebitis reached 12% (137 cases) when the researchers used case definition tools, up to 31% when they used scoring systems (P less than .0001), and up to 34% when they used severity rating systems (P less than .0001, compared with the 12% rate). “The proportion within instruments ranged from less than 1% to 28%,” they added. “We [also] identified face validity issues, such as use of indistinct or complex measurements and inconsistent measurements or definitions.”

The investigators did not perform a systematic review to identify these instruments, and they did not necessarily use the most recent versions, they noted. Nevertheless, the findings have direct implications for hospital quality control measures, which require using a single validated instrument over time to generate meaningful results, they said. Hence, the investigators recommended developing a joint research program to develop reliable measures of PVC-related adverse events and better support clinicians who are trying to decide whether to remove PVCs.

The investigators reported having no funding sources and no competing interests.

[email protected]

Rates of phlebitis associated with peripheral venous catheters (PVC) ranged from less than 1% to 34% depending on which assessment tool researchers used in a large cross-sectional study.

Rates also varied within individual instruments because they included several possible case definitions, Katarina Göransson, PhD, and her associates reported in Lancet Haematology. “We find it concerning that our study shows variation of the proportion of PVCs causing phlebitis both within and across the instruments investigated,” they wrote. “How to best measure phlebitis outcomes is still unclear, since no universally accepted instrument exists that has had rigorous testing. From a work environment and patient safety perspective, clinical staff engaged in PVC management should be aware of the absence of adequately validated instruments for phlebitis assessment.”

There are many tools to measure PVC-related phlebitis, but no consensus on which to use, and past studies have reported rates of anywhere from 2% to 62%. Hypothesizing that instrument variability contributed to this discrepancy, the researchers tested 17 instruments in 1,032 patients who had 1,175 PVCs placed at 12 inpatient units in Sweden. Eight tools used clinical definitions, seven used severity rating systems, and two used scoring systems (Lancet Haematol. 2017 doi: 10.1016/S2352-3026[17]30122-9).

Rates of PVC-induced phlebitis reached 12% (137 cases) when the researchers used case definition tools, up to 31% when they used scoring systems (P less than .0001), and up to 34% when they used severity rating systems (P less than .0001, compared with the 12% rate). “The proportion within instruments ranged from less than 1% to 28%,” they added. “We [also] identified face validity issues, such as use of indistinct or complex measurements and inconsistent measurements or definitions.”

The investigators did not perform a systematic review to identify these instruments, and they did not necessarily use the most recent versions, they noted. Nevertheless, the findings have direct implications for hospital quality control measures, which require using a single validated instrument over time to generate meaningful results, they said. Hence, the investigators recommended developing a joint research program to develop reliable measures of PVC-related adverse events and better support clinicians who are trying to decide whether to remove PVCs.

The investigators reported having no funding sources and no competing interests.

[email protected]

Inotuzumab ozogamicin therapy significantly increased the risk of sinusoidal obstruction syndrome (veno-occlusive disease) among adults with relapsed or refractory B-cell precursor acute lymphoblastic leukemia (ALL), especially when they also received follow-up hematopoietic stem cell transplantation, according to a safety analysis from the INO-VATE trial.

After a median of 9 weeks of treatment, 13% of 164 patients who received inotuzumab ozogamicin (Besponsa, Wyeth/Pfizer) developed sinusoidal obstruction syndrome, compared with less than 1% of 143 patients who received standard care, reported Hagop M. Kantarjian, MD, of the University of Texas MD Anderson Cancer Center in Houston, and his associates (Lancet Haematol. 2017 Jul 4. doi: 10.1016/ S2352-3026[17]30103-5).

Follow-up treatment with HSCT increased the risk of sinusoidal obstruction syndrome in both the intervention (22%) and standard-care (3%) groups. Among patients who did not undergo HSCT, rates of this adverse event were 3% and 0%, respectively. Five patients died from sinusoidal obstruction syndrome, all of whom received both inotuzumab ozogamicin and HSCT. The findings earned the newly approved regimen a boxed warning for severe hepatotoxicity.

The open-label, phase 3, multicenter INO-VATE study included 326 adults with CD22-positive, Philadelphia chromosome–negative or Philadelphia chromosome–positive relapsed or refractory B-cell precursor ALL. The safety analysis included 305 patients. Rates of treatment-emergent hepatotoxicities, of all grades, were 51% with inotuzumab ozogamicin and 34% with standard care. Most adverse hepatic events were grade 1-2 liver-related laboratory abnormalities, but 8% of inotuzumab ozogamicin recipients developed grade 3 or higher sinusoidal obstruction syndrome, versus less than 1% of the control group.

“After follow-up HSCT, the frequency of sinusoidal obstruction syndrome was 50% or higher in the following subgroups: patients aged 65 years or older, patients with last available pre-HSCT serum bilirubin concentration more than or equal to the upper limit of normal, and patients who received conditioning regimens with two alkylating agents,” Dr. Kantarjian and his fellow investigators wrote. Conditioning regimens that included thiotepa markedly increased the risk of sinusoidal obstruction syndrome. Additional risk factors included HSCT before study enrollment, history of liver disease, and a final pre-HSCT platelet count of less than 100 × 109 platelets per L.

Rates of sinusoidal obstruction syndrome were 42% with four to six cycles of inotuzumab ozogamicin, 23% with three cycles, 19% with two cycles, and 8% with one cycle, said the investigators. In multivariate analysis, conditioning with two alkylating agents (P = .02 compared with one alkylating agent) and pre-HSCT bilirubin of at least the upper limit of normal (P = .01) significantly increased the risk of sinusoidal obstruction syndrome during or after treatment with inotuzumab ozogamicin.

Notably, inotuzumab ozogamicin did not significantly increase the chances of survival compared with standard care among patients who also received follow-up HSCT (hazard ratio, 1.3; 97.5% confidence interval, 0.66 to 2.3; P = 0.77). Among HSCT recipients, the chances of surviving to 24 months were 39% (95% CI, 28%-50%) with inotuzumab ozogamicin and 29% (11%-49%) with standard care. Nonetheless, HSCT “offers possibility of cure in the relapsed or recurrent [ALL] setting,” the researchers wrote. Clinicians should be especially wary of sinusoidal obstruction syndrome if patients are 65 years or older, received HSCT before inotuzumab ozogamicin treatment, or have a baseline history of liver disease, they said. Strategies to minimize risk include shortening the duration of inotuzumab ozogamicin treatment and avoiding conditioning regimens that contain two alkylating agents.

Pfizer funded and collaborated in the trial. Dr. Kantarjian disclosed ties to Pfizer and numerous other pharmaceutical companies.

Inotuzumab ozogamicin therapy significantly increased the risk of sinusoidal obstruction syndrome (veno-occlusive disease) among adults with relapsed or refractory B-cell precursor acute lymphoblastic leukemia (ALL), especially when they also received follow-up hematopoietic stem cell transplantation, according to a safety analysis from the INO-VATE trial.

After a median of 9 weeks of treatment, 13% of 164 patients who received inotuzumab ozogamicin (Besponsa, Wyeth/Pfizer) developed sinusoidal obstruction syndrome, compared with less than 1% of 143 patients who received standard care, reported Hagop M. Kantarjian, MD, of the University of Texas MD Anderson Cancer Center in Houston, and his associates (Lancet Haematol. 2017 Jul 4. doi: 10.1016/ S2352-3026[17]30103-5).

Follow-up treatment with HSCT increased the risk of sinusoidal obstruction syndrome in both the intervention (22%) and standard-care (3%) groups. Among patients who did not undergo HSCT, rates of this adverse event were 3% and 0%, respectively. Five patients died from sinusoidal obstruction syndrome, all of whom received both inotuzumab ozogamicin and HSCT. The findings earned the newly approved regimen a boxed warning for severe hepatotoxicity.

The open-label, phase 3, multicenter INO-VATE study included 326 adults with CD22-positive, Philadelphia chromosome–negative or Philadelphia chromosome–positive relapsed or refractory B-cell precursor ALL. The safety analysis included 305 patients. Rates of treatment-emergent hepatotoxicities, of all grades, were 51% with inotuzumab ozogamicin and 34% with standard care. Most adverse hepatic events were grade 1-2 liver-related laboratory abnormalities, but 8% of inotuzumab ozogamicin recipients developed grade 3 or higher sinusoidal obstruction syndrome, versus less than 1% of the control group.

“After follow-up HSCT, the frequency of sinusoidal obstruction syndrome was 50% or higher in the following subgroups: patients aged 65 years or older, patients with last available pre-HSCT serum bilirubin concentration more than or equal to the upper limit of normal, and patients who received conditioning regimens with two alkylating agents,” Dr. Kantarjian and his fellow investigators wrote. Conditioning regimens that included thiotepa markedly increased the risk of sinusoidal obstruction syndrome. Additional risk factors included HSCT before study enrollment, history of liver disease, and a final pre-HSCT platelet count of less than 100 × 109 platelets per L.

Rates of sinusoidal obstruction syndrome were 42% with four to six cycles of inotuzumab ozogamicin, 23% with three cycles, 19% with two cycles, and 8% with one cycle, said the investigators. In multivariate analysis, conditioning with two alkylating agents (P = .02 compared with one alkylating agent) and pre-HSCT bilirubin of at least the upper limit of normal (P = .01) significantly increased the risk of sinusoidal obstruction syndrome during or after treatment with inotuzumab ozogamicin.

Notably, inotuzumab ozogamicin did not significantly increase the chances of survival compared with standard care among patients who also received follow-up HSCT (hazard ratio, 1.3; 97.5% confidence interval, 0.66 to 2.3; P = 0.77). Among HSCT recipients, the chances of surviving to 24 months were 39% (95% CI, 28%-50%) with inotuzumab ozogamicin and 29% (11%-49%) with standard care. Nonetheless, HSCT “offers possibility of cure in the relapsed or recurrent [ALL] setting,” the researchers wrote. Clinicians should be especially wary of sinusoidal obstruction syndrome if patients are 65 years or older, received HSCT before inotuzumab ozogamicin treatment, or have a baseline history of liver disease, they said. Strategies to minimize risk include shortening the duration of inotuzumab ozogamicin treatment and avoiding conditioning regimens that contain two alkylating agents.

Pfizer funded and collaborated in the trial. Dr. Kantarjian disclosed ties to Pfizer and numerous other pharmaceutical companies.

Inotuzumab ozogamicin therapy significantly increased the risk of sinusoidal obstruction syndrome (veno-occlusive disease) among adults with relapsed or refractory B-cell precursor acute lymphoblastic leukemia (ALL), especially when they also received follow-up hematopoietic stem cell transplantation, according to a safety analysis from the INO-VATE trial.

After a median of 9 weeks of treatment, 13% of 164 patients who received inotuzumab ozogamicin (Besponsa, Wyeth/Pfizer) developed sinusoidal obstruction syndrome, compared with less than 1% of 143 patients who received standard care, reported Hagop M. Kantarjian, MD, of the University of Texas MD Anderson Cancer Center in Houston, and his associates (Lancet Haematol. 2017 Jul 4. doi: 10.1016/ S2352-3026[17]30103-5).

Follow-up treatment with HSCT increased the risk of sinusoidal obstruction syndrome in both the intervention (22%) and standard-care (3%) groups. Among patients who did not undergo HSCT, rates of this adverse event were 3% and 0%, respectively. Five patients died from sinusoidal obstruction syndrome, all of whom received both inotuzumab ozogamicin and HSCT. The findings earned the newly approved regimen a boxed warning for severe hepatotoxicity.

The open-label, phase 3, multicenter INO-VATE study included 326 adults with CD22-positive, Philadelphia chromosome–negative or Philadelphia chromosome–positive relapsed or refractory B-cell precursor ALL. The safety analysis included 305 patients. Rates of treatment-emergent hepatotoxicities, of all grades, were 51% with inotuzumab ozogamicin and 34% with standard care. Most adverse hepatic events were grade 1-2 liver-related laboratory abnormalities, but 8% of inotuzumab ozogamicin recipients developed grade 3 or higher sinusoidal obstruction syndrome, versus less than 1% of the control group.

“After follow-up HSCT, the frequency of sinusoidal obstruction syndrome was 50% or higher in the following subgroups: patients aged 65 years or older, patients with last available pre-HSCT serum bilirubin concentration more than or equal to the upper limit of normal, and patients who received conditioning regimens with two alkylating agents,” Dr. Kantarjian and his fellow investigators wrote. Conditioning regimens that included thiotepa markedly increased the risk of sinusoidal obstruction syndrome. Additional risk factors included HSCT before study enrollment, history of liver disease, and a final pre-HSCT platelet count of less than 100 × 109 platelets per L.

Rates of sinusoidal obstruction syndrome were 42% with four to six cycles of inotuzumab ozogamicin, 23% with three cycles, 19% with two cycles, and 8% with one cycle, said the investigators. In multivariate analysis, conditioning with two alkylating agents (P = .02 compared with one alkylating agent) and pre-HSCT bilirubin of at least the upper limit of normal (P = .01) significantly increased the risk of sinusoidal obstruction syndrome during or after treatment with inotuzumab ozogamicin.

Notably, inotuzumab ozogamicin did not significantly increase the chances of survival compared with standard care among patients who also received follow-up HSCT (hazard ratio, 1.3; 97.5% confidence interval, 0.66 to 2.3; P = 0.77). Among HSCT recipients, the chances of surviving to 24 months were 39% (95% CI, 28%-50%) with inotuzumab ozogamicin and 29% (11%-49%) with standard care. Nonetheless, HSCT “offers possibility of cure in the relapsed or recurrent [ALL] setting,” the researchers wrote. Clinicians should be especially wary of sinusoidal obstruction syndrome if patients are 65 years or older, received HSCT before inotuzumab ozogamicin treatment, or have a baseline history of liver disease, they said. Strategies to minimize risk include shortening the duration of inotuzumab ozogamicin treatment and avoiding conditioning regimens that contain two alkylating agents.

Pfizer funded and collaborated in the trial. Dr. Kantarjian disclosed ties to Pfizer and numerous other pharmaceutical companies.

Adults with nonalcoholic steatohepatitis (NASH) fared as well on key outcome measures as other liver transplant recipients, despite having significantly more comorbidities, according to the results of a single-center retrospective cohort study.

Major morbidity, mortality, and rates of graft survival after 90 days were similar between patients who underwent transplantation for NASH and those who underwent it for another cirrhotic liver condition, wrote Eline H. van den Berg, MD, of University Medical Center Groningen (the Netherlands) with her associates. “These results are comforting, considering the expected increase of patients with NASH cirrhosis in the near future,” the researchers concluded. “Future analysis regarding the recurrence of nonalcoholic fatty liver disease, development of long-term complications, long-term graft patency, and occurrence of comorbid diseases after LT [liver transplantation] is mandatory to better understand the natural history and risk profile of NASH patients and to prevent and treat its complications.” The findings were published online in Digestive and Liver Disease (Dig Liver Dis. 2017 Aug 11. doi: 10.1016/j.dld.2017.08.022).

Nonalcoholic fatty liver disease begins as steatosis and can progress to NASH, fibrosis, and cirrhosis. The global obesity epidemic is amplifying its incidence, and about 26% of patients who develop NASH ultimately develop cirrhosis. Cirrhosis itself increases the risk of in-hospital death or prolonged length of postoperative stay, but patients with NASH also have obesity and cardiovascular disease, which might “tremendously increase” the risk of poor postoperative outcomes, the researchers said. Because prior research had focused mainly on mortality and had reported conflicting results, they used the Clavien-Dindo classification system to retrospectively study rates of complications among 169 adults who underwent liver transplantation at their center from 2009 through 2015, including 34 (20%) patients with NASH cirrhosis.

Patients with NASH were significantly older than other transplant recipients (59 versus 55 years, P = .01) and had markedly higher rates of obesity (62% versus 8%; P less than .01), diabetes mellitus (74% versus 20%; P less than .01), metabolic syndrome (83% versus 38%; P less than .01), hypertension (61% versus 30%; P less than .01), and cardiovascular disease (29% versus 11%; P less than .01). Despite these differences, the groups had statistically similar rates of postoperative mortality (3% in both groups), 90-day graft survival posttransplantation (94% and 90%, respectively), and major postoperative complications, including biopsy-proven acute cellular rejection (3% and 7%), hepatic artery thrombosis (0% and 7%), relaparotomy (15% and 24%), primary nonfunction (0% and 1.6%), retransplantation (6% and 7%), sepsis (12% and 13%), gastrointestinal infection (24% and 36%), fever of unknown origin (18% and 14%), and renal replacement therapy (15% and 24%).

After accounting for age, sex, transplant year, and donor characteristics, NASH patients were at significantly increased risk of grade 2 urogenital infections, compared with other patients (odds ratio, 3.4; 95% confidence interval, 1.1 to 10.6; P = .03). Grade 1 complications also were more common with NASH than otherwise (77% versus 59%), and the difference remained statistically significant in the multivariable analysis (OR, 1.6; 95% CI, 1.03 to 2.63; P = .04).

The study used a strict, internationally accepted definition of NASH – all patients either had cases confirmed by biopsy, had metabolic syndrome, or had obesity and type 2 diabetes mellitus, and, further, none had hepatitis or alcoholic liver disease. None of the patients in the study received transplants for acute liver failure or noncirrhotic liver disease, and none were 70 years or older, which is the cutoff age for liver transplantation in the Netherlands.

The investigators received no funding for the study and reported having no conflicts of interest.

Adults with nonalcoholic steatohepatitis (NASH) fared as well on key outcome measures as other liver transplant recipients, despite having significantly more comorbidities, according to the results of a single-center retrospective cohort study.

Major morbidity, mortality, and rates of graft survival after 90 days were similar between patients who underwent transplantation for NASH and those who underwent it for another cirrhotic liver condition, wrote Eline H. van den Berg, MD, of University Medical Center Groningen (the Netherlands) with her associates. “These results are comforting, considering the expected increase of patients with NASH cirrhosis in the near future,” the researchers concluded. “Future analysis regarding the recurrence of nonalcoholic fatty liver disease, development of long-term complications, long-term graft patency, and occurrence of comorbid diseases after LT [liver transplantation] is mandatory to better understand the natural history and risk profile of NASH patients and to prevent and treat its complications.” The findings were published online in Digestive and Liver Disease (Dig Liver Dis. 2017 Aug 11. doi: 10.1016/j.dld.2017.08.022).

Nonalcoholic fatty liver disease begins as steatosis and can progress to NASH, fibrosis, and cirrhosis. The global obesity epidemic is amplifying its incidence, and about 26% of patients who develop NASH ultimately develop cirrhosis. Cirrhosis itself increases the risk of in-hospital death or prolonged length of postoperative stay, but patients with NASH also have obesity and cardiovascular disease, which might “tremendously increase” the risk of poor postoperative outcomes, the researchers said. Because prior research had focused mainly on mortality and had reported conflicting results, they used the Clavien-Dindo classification system to retrospectively study rates of complications among 169 adults who underwent liver transplantation at their center from 2009 through 2015, including 34 (20%) patients with NASH cirrhosis.

Patients with NASH were significantly older than other transplant recipients (59 versus 55 years, P = .01) and had markedly higher rates of obesity (62% versus 8%; P less than .01), diabetes mellitus (74% versus 20%; P less than .01), metabolic syndrome (83% versus 38%; P less than .01), hypertension (61% versus 30%; P less than .01), and cardiovascular disease (29% versus 11%; P less than .01). Despite these differences, the groups had statistically similar rates of postoperative mortality (3% in both groups), 90-day graft survival posttransplantation (94% and 90%, respectively), and major postoperative complications, including biopsy-proven acute cellular rejection (3% and 7%), hepatic artery thrombosis (0% and 7%), relaparotomy (15% and 24%), primary nonfunction (0% and 1.6%), retransplantation (6% and 7%), sepsis (12% and 13%), gastrointestinal infection (24% and 36%), fever of unknown origin (18% and 14%), and renal replacement therapy (15% and 24%).

After accounting for age, sex, transplant year, and donor characteristics, NASH patients were at significantly increased risk of grade 2 urogenital infections, compared with other patients (odds ratio, 3.4; 95% confidence interval, 1.1 to 10.6; P = .03). Grade 1 complications also were more common with NASH than otherwise (77% versus 59%), and the difference remained statistically significant in the multivariable analysis (OR, 1.6; 95% CI, 1.03 to 2.63; P = .04).

The study used a strict, internationally accepted definition of NASH – all patients either had cases confirmed by biopsy, had metabolic syndrome, or had obesity and type 2 diabetes mellitus, and, further, none had hepatitis or alcoholic liver disease. None of the patients in the study received transplants for acute liver failure or noncirrhotic liver disease, and none were 70 years or older, which is the cutoff age for liver transplantation in the Netherlands.

The investigators received no funding for the study and reported having no conflicts of interest.

Adults with nonalcoholic steatohepatitis (NASH) fared as well on key outcome measures as other liver transplant recipients, despite having significantly more comorbidities, according to the results of a single-center retrospective cohort study.

Major morbidity, mortality, and rates of graft survival after 90 days were similar between patients who underwent transplantation for NASH and those who underwent it for another cirrhotic liver condition, wrote Eline H. van den Berg, MD, of University Medical Center Groningen (the Netherlands) with her associates. “These results are comforting, considering the expected increase of patients with NASH cirrhosis in the near future,” the researchers concluded. “Future analysis regarding the recurrence of nonalcoholic fatty liver disease, development of long-term complications, long-term graft patency, and occurrence of comorbid diseases after LT [liver transplantation] is mandatory to better understand the natural history and risk profile of NASH patients and to prevent and treat its complications.” The findings were published online in Digestive and Liver Disease (Dig Liver Dis. 2017 Aug 11. doi: 10.1016/j.dld.2017.08.022).

Nonalcoholic fatty liver disease begins as steatosis and can progress to NASH, fibrosis, and cirrhosis. The global obesity epidemic is amplifying its incidence, and about 26% of patients who develop NASH ultimately develop cirrhosis. Cirrhosis itself increases the risk of in-hospital death or prolonged length of postoperative stay, but patients with NASH also have obesity and cardiovascular disease, which might “tremendously increase” the risk of poor postoperative outcomes, the researchers said. Because prior research had focused mainly on mortality and had reported conflicting results, they used the Clavien-Dindo classification system to retrospectively study rates of complications among 169 adults who underwent liver transplantation at their center from 2009 through 2015, including 34 (20%) patients with NASH cirrhosis.

Patients with NASH were significantly older than other transplant recipients (59 versus 55 years, P = .01) and had markedly higher rates of obesity (62% versus 8%; P less than .01), diabetes mellitus (74% versus 20%; P less than .01), metabolic syndrome (83% versus 38%; P less than .01), hypertension (61% versus 30%; P less than .01), and cardiovascular disease (29% versus 11%; P less than .01). Despite these differences, the groups had statistically similar rates of postoperative mortality (3% in both groups), 90-day graft survival posttransplantation (94% and 90%, respectively), and major postoperative complications, including biopsy-proven acute cellular rejection (3% and 7%), hepatic artery thrombosis (0% and 7%), relaparotomy (15% and 24%), primary nonfunction (0% and 1.6%), retransplantation (6% and 7%), sepsis (12% and 13%), gastrointestinal infection (24% and 36%), fever of unknown origin (18% and 14%), and renal replacement therapy (15% and 24%).

After accounting for age, sex, transplant year, and donor characteristics, NASH patients were at significantly increased risk of grade 2 urogenital infections, compared with other patients (odds ratio, 3.4; 95% confidence interval, 1.1 to 10.6; P = .03). Grade 1 complications also were more common with NASH than otherwise (77% versus 59%), and the difference remained statistically significant in the multivariable analysis (OR, 1.6; 95% CI, 1.03 to 2.63; P = .04).

The study used a strict, internationally accepted definition of NASH – all patients either had cases confirmed by biopsy, had metabolic syndrome, or had obesity and type 2 diabetes mellitus, and, further, none had hepatitis or alcoholic liver disease. None of the patients in the study received transplants for acute liver failure or noncirrhotic liver disease, and none were 70 years or older, which is the cutoff age for liver transplantation in the Netherlands.

The investigators received no funding for the study and reported having no conflicts of interest.

Digital droplet PCR (ddPCR) was an accurate and noninvasive method to detect mutations leading to hemophilia A and B in maternal plasma DNA in 15 at-risk pregnancies of 8 to 42 weeks’ gestation, researchers reported.

Additionally, the researchers showed for the first time that targeted massively parallel sequencing (MPS) accurately detected the clinically important int22h-related inversion mutations in maternal plasma DNA from pregnant hemophilia carriers from three families with the disorder.

As costs of sequencing continue to fall, larger studies of pregnant carriers of F8 int22h-related inversions can help make MPS “an essential part in noninvasive prenatal testing of hemophilia carriers,” Irena Hudecova, PhD, of Li Ka Shing Institute of Health Sciences, Hong Kong, and her associates wrote (Blood. 2017 Jul 20;130[3]:340-7).

Diagnosing hemophilia during pregnancy helps optimize care and allows mothers to make informed decisions about whether to terminate pregnancies. But for male fetuses, invasive testing has been the only option. In a prior small study, researchers used noninvasive microfluidics PCR to detect sequence variants of F8, which encodes factor VIII, and F9, which encodes Factor IX. The assay uses a chip that can accommodate about 9,000 reaction wells, making noninvasive screening much more feasible and affordable. But technical difficulties had precluded detection of int22h-related inversions, the inversion mutations of intron 22 in F8 on chromosome X that affect about half of individuals with severe hemophilia (Blood. 2011 Mar 31;117[13]:3684-91).

For the current study, the researchers first designed family-specific ddPCR assays to test for relevant maternal sequence variants scattered across the F8 and F9 genes. Tests of 15 male singleton fetuses produced three unclassified samples, but no misclassifications.

“Because of the scalability of ddPCR, the protocol performed reliably even in cases with fetal DNA fraction lower than 10%,” the researchers wrote. “When an unclassified result is encountered, one either performs more digital analyses on the sample to accumulate more data points, or when the sample is consumed, one may resort to an additional blood draw, possibly at a later gestational age with higher fetal DNA fraction.”

Next, the investigators used MPS to create detailed fetal haplotype maps of the 7.6-Md region of F8 where int22h-related inversions occur. This approach yielded an “accurate and robust measurement of maternally inherited fetal haplotypes,” they wrote. “Our data suggest it is feasible to apply targeted MPS to interrogate maternally inherited F8 int22h-related inversions, whereas ddPCR [is] an affordable approach for the identification of F8 and F9 sequence variants in maternal plasma.”

The study was funded by the Research Grants Council of the Hong Kong SAR Government and the Vice Chancellor’s One-Off Discretionary Fund of The Chinese University of Hong Kong. Dr. Hudecova reported having no financial disclosures. Several coauthors disclosed patents for plasma nucleic acid analysis and ties to Sequenom, Illumina, Xcelom, and Cirina.

Digital droplet PCR (ddPCR) was an accurate and noninvasive method to detect mutations leading to hemophilia A and B in maternal plasma DNA in 15 at-risk pregnancies of 8 to 42 weeks’ gestation, researchers reported.

Additionally, the researchers showed for the first time that targeted massively parallel sequencing (MPS) accurately detected the clinically important int22h-related inversion mutations in maternal plasma DNA from pregnant hemophilia carriers from three families with the disorder.

As costs of sequencing continue to fall, larger studies of pregnant carriers of F8 int22h-related inversions can help make MPS “an essential part in noninvasive prenatal testing of hemophilia carriers,” Irena Hudecova, PhD, of Li Ka Shing Institute of Health Sciences, Hong Kong, and her associates wrote (Blood. 2017 Jul 20;130[3]:340-7).

Diagnosing hemophilia during pregnancy helps optimize care and allows mothers to make informed decisions about whether to terminate pregnancies. But for male fetuses, invasive testing has been the only option. In a prior small study, researchers used noninvasive microfluidics PCR to detect sequence variants of F8, which encodes factor VIII, and F9, which encodes Factor IX. The assay uses a chip that can accommodate about 9,000 reaction wells, making noninvasive screening much more feasible and affordable. But technical difficulties had precluded detection of int22h-related inversions, the inversion mutations of intron 22 in F8 on chromosome X that affect about half of individuals with severe hemophilia (Blood. 2011 Mar 31;117[13]:3684-91).

For the current study, the researchers first designed family-specific ddPCR assays to test for relevant maternal sequence variants scattered across the F8 and F9 genes. Tests of 15 male singleton fetuses produced three unclassified samples, but no misclassifications.

“Because of the scalability of ddPCR, the protocol performed reliably even in cases with fetal DNA fraction lower than 10%,” the researchers wrote. “When an unclassified result is encountered, one either performs more digital analyses on the sample to accumulate more data points, or when the sample is consumed, one may resort to an additional blood draw, possibly at a later gestational age with higher fetal DNA fraction.”

Next, the investigators used MPS to create detailed fetal haplotype maps of the 7.6-Md region of F8 where int22h-related inversions occur. This approach yielded an “accurate and robust measurement of maternally inherited fetal haplotypes,” they wrote. “Our data suggest it is feasible to apply targeted MPS to interrogate maternally inherited F8 int22h-related inversions, whereas ddPCR [is] an affordable approach for the identification of F8 and F9 sequence variants in maternal plasma.”

The study was funded by the Research Grants Council of the Hong Kong SAR Government and the Vice Chancellor’s One-Off Discretionary Fund of The Chinese University of Hong Kong. Dr. Hudecova reported having no financial disclosures. Several coauthors disclosed patents for plasma nucleic acid analysis and ties to Sequenom, Illumina, Xcelom, and Cirina.

Digital droplet PCR (ddPCR) was an accurate and noninvasive method to detect mutations leading to hemophilia A and B in maternal plasma DNA in 15 at-risk pregnancies of 8 to 42 weeks’ gestation, researchers reported.

Additionally, the researchers showed for the first time that targeted massively parallel sequencing (MPS) accurately detected the clinically important int22h-related inversion mutations in maternal plasma DNA from pregnant hemophilia carriers from three families with the disorder.

As costs of sequencing continue to fall, larger studies of pregnant carriers of F8 int22h-related inversions can help make MPS “an essential part in noninvasive prenatal testing of hemophilia carriers,” Irena Hudecova, PhD, of Li Ka Shing Institute of Health Sciences, Hong Kong, and her associates wrote (Blood. 2017 Jul 20;130[3]:340-7).

Diagnosing hemophilia during pregnancy helps optimize care and allows mothers to make informed decisions about whether to terminate pregnancies. But for male fetuses, invasive testing has been the only option. In a prior small study, researchers used noninvasive microfluidics PCR to detect sequence variants of F8, which encodes factor VIII, and F9, which encodes Factor IX. The assay uses a chip that can accommodate about 9,000 reaction wells, making noninvasive screening much more feasible and affordable. But technical difficulties had precluded detection of int22h-related inversions, the inversion mutations of intron 22 in F8 on chromosome X that affect about half of individuals with severe hemophilia (Blood. 2011 Mar 31;117[13]:3684-91).

For the current study, the researchers first designed family-specific ddPCR assays to test for relevant maternal sequence variants scattered across the F8 and F9 genes. Tests of 15 male singleton fetuses produced three unclassified samples, but no misclassifications.

“Because of the scalability of ddPCR, the protocol performed reliably even in cases with fetal DNA fraction lower than 10%,” the researchers wrote. “When an unclassified result is encountered, one either performs more digital analyses on the sample to accumulate more data points, or when the sample is consumed, one may resort to an additional blood draw, possibly at a later gestational age with higher fetal DNA fraction.”

Next, the investigators used MPS to create detailed fetal haplotype maps of the 7.6-Md region of F8 where int22h-related inversions occur. This approach yielded an “accurate and robust measurement of maternally inherited fetal haplotypes,” they wrote. “Our data suggest it is feasible to apply targeted MPS to interrogate maternally inherited F8 int22h-related inversions, whereas ddPCR [is] an affordable approach for the identification of F8 and F9 sequence variants in maternal plasma.”

The study was funded by the Research Grants Council of the Hong Kong SAR Government and the Vice Chancellor’s One-Off Discretionary Fund of The Chinese University of Hong Kong. Dr. Hudecova reported having no financial disclosures. Several coauthors disclosed patents for plasma nucleic acid analysis and ties to Sequenom, Illumina, Xcelom, and Cirina.

Mutations that disrupt de novo synthesis of nicotinamide adenine dinucleotide (NAD) were associated with multiple congenital malformations in humans and mice, and supplementing niacin during gestation prevented these malformations in mice, new research suggests.

The malformations include vertebral defects, anal atresia, cardiac defects, tracheoesophageal fistula, renal anomalies, and limb abnormalities (VACTERL), “a nonrandom combination of congenital defects without a known cause,” wrote Hongjun Shi, PhD, of Victor Chang Cardiac Research Institute, New South Wales, Australia, and colleagues (N Engl J Med. 2017;377:544-52).

Numerous genetic and environmental factors can potentially cause NAD deficiency during gestation and the investigators suggested collectively referring to the resulting malformations as “congenital NAD deficiency disorders.”

Congenital defects can occur together in newborns more often than would be expected by chance, but “in many such cases, it has proved difficult to identify a genetic cause,” the investigators noted. Using genomic sequencing, they looked for possible pathogenic gene variants within four unrelated families in which a person was born with multiple congenital malformations. Next, they evaluated the function of the variants by testing in vitro enzyme activity and measuring relevant plasma metabolites. Finally, they used the CRISPR (clustered regularly interspaced short palindromic repeats)–Cas9 system to create mouse models with similar variants.

This approach identified variants in two genes encoding enzymes of the kynurenine pathway: 3-hydroxyanthranilic acid 3,4-dioxygenase (HAAO) and kynureninase (KYNU). Three patients had homozygous variants associated with loss-of-function changes in these proteins. A fourth patient had heterozygous variants in the gene encoding KYNU.

“The mutant enzymes had greatly reduced activity in vitro,” the researchers wrote. Patients had decreased circulating levels of NAD, which tryptophan synthesizes through the kynurenine pathway. Notably, mouse embryos lacking the mouse equivalents of HAAO or KYNU also had congenital defects associated with NAD deficiency. Preventing NAD deficiency during gestation averted these defects in mice.

“The NAD de novo synthesis pathway catabolizes tryptophan,” the researchers added. “Although metabolite levels upstream of the block are elevated, and the metabolites have postnatal functions, we found that it is the deficiency in embryonic NAD, downstream of the block, that is disrupting embryogenesis.”

The study was supported by the Australian and New South Wales governments and foundations. The investigators reported having no other financial disclosures.

Mutations that disrupt de novo synthesis of nicotinamide adenine dinucleotide (NAD) were associated with multiple congenital malformations in humans and mice, and supplementing niacin during gestation prevented these malformations in mice, new research suggests.

The malformations include vertebral defects, anal atresia, cardiac defects, tracheoesophageal fistula, renal anomalies, and limb abnormalities (VACTERL), “a nonrandom combination of congenital defects without a known cause,” wrote Hongjun Shi, PhD, of Victor Chang Cardiac Research Institute, New South Wales, Australia, and colleagues (N Engl J Med. 2017;377:544-52).

Numerous genetic and environmental factors can potentially cause NAD deficiency during gestation and the investigators suggested collectively referring to the resulting malformations as “congenital NAD deficiency disorders.”

Congenital defects can occur together in newborns more often than would be expected by chance, but “in many such cases, it has proved difficult to identify a genetic cause,” the investigators noted. Using genomic sequencing, they looked for possible pathogenic gene variants within four unrelated families in which a person was born with multiple congenital malformations. Next, they evaluated the function of the variants by testing in vitro enzyme activity and measuring relevant plasma metabolites. Finally, they used the CRISPR (clustered regularly interspaced short palindromic repeats)–Cas9 system to create mouse models with similar variants.

This approach identified variants in two genes encoding enzymes of the kynurenine pathway: 3-hydroxyanthranilic acid 3,4-dioxygenase (HAAO) and kynureninase (KYNU). Three patients had homozygous variants associated with loss-of-function changes in these proteins. A fourth patient had heterozygous variants in the gene encoding KYNU.

“The mutant enzymes had greatly reduced activity in vitro,” the researchers wrote. Patients had decreased circulating levels of NAD, which tryptophan synthesizes through the kynurenine pathway. Notably, mouse embryos lacking the mouse equivalents of HAAO or KYNU also had congenital defects associated with NAD deficiency. Preventing NAD deficiency during gestation averted these defects in mice.

“The NAD de novo synthesis pathway catabolizes tryptophan,” the researchers added. “Although metabolite levels upstream of the block are elevated, and the metabolites have postnatal functions, we found that it is the deficiency in embryonic NAD, downstream of the block, that is disrupting embryogenesis.”

The study was supported by the Australian and New South Wales governments and foundations. The investigators reported having no other financial disclosures.

Mutations that disrupt de novo synthesis of nicotinamide adenine dinucleotide (NAD) were associated with multiple congenital malformations in humans and mice, and supplementing niacin during gestation prevented these malformations in mice, new research suggests.

The malformations include vertebral defects, anal atresia, cardiac defects, tracheoesophageal fistula, renal anomalies, and limb abnormalities (VACTERL), “a nonrandom combination of congenital defects without a known cause,” wrote Hongjun Shi, PhD, of Victor Chang Cardiac Research Institute, New South Wales, Australia, and colleagues (N Engl J Med. 2017;377:544-52).

Numerous genetic and environmental factors can potentially cause NAD deficiency during gestation and the investigators suggested collectively referring to the resulting malformations as “congenital NAD deficiency disorders.”

Congenital defects can occur together in newborns more often than would be expected by chance, but “in many such cases, it has proved difficult to identify a genetic cause,” the investigators noted. Using genomic sequencing, they looked for possible pathogenic gene variants within four unrelated families in which a person was born with multiple congenital malformations. Next, they evaluated the function of the variants by testing in vitro enzyme activity and measuring relevant plasma metabolites. Finally, they used the CRISPR (clustered regularly interspaced short palindromic repeats)–Cas9 system to create mouse models with similar variants.

This approach identified variants in two genes encoding enzymes of the kynurenine pathway: 3-hydroxyanthranilic acid 3,4-dioxygenase (HAAO) and kynureninase (KYNU). Three patients had homozygous variants associated with loss-of-function changes in these proteins. A fourth patient had heterozygous variants in the gene encoding KYNU.

“The mutant enzymes had greatly reduced activity in vitro,” the researchers wrote. Patients had decreased circulating levels of NAD, which tryptophan synthesizes through the kynurenine pathway. Notably, mouse embryos lacking the mouse equivalents of HAAO or KYNU also had congenital defects associated with NAD deficiency. Preventing NAD deficiency during gestation averted these defects in mice.

“The NAD de novo synthesis pathway catabolizes tryptophan,” the researchers added. “Although metabolite levels upstream of the block are elevated, and the metabolites have postnatal functions, we found that it is the deficiency in embryonic NAD, downstream of the block, that is disrupting embryogenesis.”

The study was supported by the Australian and New South Wales governments and foundations. The investigators reported having no other financial disclosures.

Physicians should perform reactive therapeutic drug monitoring to guide changes in anti–tumor necrosis factor (TNF) therapy in patients with active inflammatory bowel disease and should consider target trough concentrations of at least 5 mcg/mL for infliximab, at least 7.5 mcg/mL for adalimumab, and at least 20 mcg/mL for certolizumab pegol, according to a guideline from the AGA Institute, published in the September 2017 issue of Gastroenterology (Gastroenterology. doi: 10.1053/j.gastro.2017.07.032).

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Physicians should perform reactive therapeutic drug monitoring to guide changes in anti–tumor necrosis factor (TNF) therapy in patients with active inflammatory bowel disease and should consider target trough concentrations of at least 5 mcg/mL for infliximab, at least 7.5 mcg/mL for adalimumab, and at least 20 mcg/mL for certolizumab pegol, according to a guideline from the AGA Institute, published in the September 2017 issue of Gastroenterology (Gastroenterology. doi: 10.1053/j.gastro.2017.07.032).

copyright varaphoto/Thinkstock

Physicians should perform reactive therapeutic drug monitoring to guide changes in anti–tumor necrosis factor (TNF) therapy in patients with active inflammatory bowel disease and should consider target trough concentrations of at least 5 mcg/mL for infliximab, at least 7.5 mcg/mL for adalimumab, and at least 20 mcg/mL for certolizumab pegol, according to a guideline from the AGA Institute, published in the September 2017 issue of Gastroenterology (Gastroenterology. doi: 10.1053/j.gastro.2017.07.032).

copyright varaphoto/Thinkstock