Use of the recently updated AJCC Cancer Staging Manual, 8th edition, produced about 10% better accuracy when interpreting T1a invasive melanomas in a national study.

For stage T1b or greater cases, using the AJCC 8 instead of the AJCC 7 yielded about 6% higher concordance between interpretations and consensus reference diagnoses, said Joann G. Elmore, MD, MPH, of the David Geffen School of Medicine at the University of California, Los Angeles, and her associates. “Intraobserver reproducibility of diagnoses also improved,” but “concordance and reproducibility remain low,” the researchers wrote. The report was published in JAMA Open Network.

For the study, 187 pathologists each interpreted one of five glass slide sets of melanocytic skin biopsies. At least 8 months later, they interpreted the same set again, both times recording their interpretations on the online Pathology Assessment Tool and Hierarchy for Diagnosis (MPATH-Dx). Researchers then used AJCC 7 and AJCC 8 criteria to group these interpretations into one of five MPATH-Dx classes. The final analysis included only the 116 cases of invasive melanoma, because changes in the AJCC 8 criteria affected only MPATH-Dx classes IV (T1a) and V (T1b and higher), the investigators explained.

For T1a invasive melanomas, overall concordance between interpretations and consensus diagnoses rose from 44% (95% confidence interval, 41%-48%) under the AJCC 7 criteria to 54% (95% CI, 51%-57%) under the AJCC 8 criteria. For stage T1b or higher lesions, concordance rose from 72% to 78%. Intrapathologist reproducibility improved from 59% to 64% for T1a cases and from 74% to 77% for T1b or higher cases. Thus, the AJCC 8 produced “modest” improvements in concordance and reproducibility over the AJCC 7, the researchers said.

One of the most likely explanations is that the AJCC 8 eliminated dermal mitotic activity as a criterion for T1b melanomas, which is “potentially unreliable” in thin lesions, they added. Persistently low concordance and reproducibility “suggest that conventional histopathology has been parsed to a degree that falls below the limits of reliability,” they concluded.

The National Cancer Institute provided funding. Dr. Elmore disclosed ties to Myriad Genetics, SciBase, and the National Institutes of Health.

SOURCE: Elmore JG et al. JAMA Network Open. 2018 May 18. doi: 10.1001/jamanetworkopen.2018.0083.

Use of the recently updated AJCC Cancer Staging Manual, 8th edition, produced about 10% better accuracy when interpreting T1a invasive melanomas in a national study.

For stage T1b or greater cases, using the AJCC 8 instead of the AJCC 7 yielded about 6% higher concordance between interpretations and consensus reference diagnoses, said Joann G. Elmore, MD, MPH, of the David Geffen School of Medicine at the University of California, Los Angeles, and her associates. “Intraobserver reproducibility of diagnoses also improved,” but “concordance and reproducibility remain low,” the researchers wrote. The report was published in JAMA Open Network.

For the study, 187 pathologists each interpreted one of five glass slide sets of melanocytic skin biopsies. At least 8 months later, they interpreted the same set again, both times recording their interpretations on the online Pathology Assessment Tool and Hierarchy for Diagnosis (MPATH-Dx). Researchers then used AJCC 7 and AJCC 8 criteria to group these interpretations into one of five MPATH-Dx classes. The final analysis included only the 116 cases of invasive melanoma, because changes in the AJCC 8 criteria affected only MPATH-Dx classes IV (T1a) and V (T1b and higher), the investigators explained.

For T1a invasive melanomas, overall concordance between interpretations and consensus diagnoses rose from 44% (95% confidence interval, 41%-48%) under the AJCC 7 criteria to 54% (95% CI, 51%-57%) under the AJCC 8 criteria. For stage T1b or higher lesions, concordance rose from 72% to 78%. Intrapathologist reproducibility improved from 59% to 64% for T1a cases and from 74% to 77% for T1b or higher cases. Thus, the AJCC 8 produced “modest” improvements in concordance and reproducibility over the AJCC 7, the researchers said.

One of the most likely explanations is that the AJCC 8 eliminated dermal mitotic activity as a criterion for T1b melanomas, which is “potentially unreliable” in thin lesions, they added. Persistently low concordance and reproducibility “suggest that conventional histopathology has been parsed to a degree that falls below the limits of reliability,” they concluded.

The National Cancer Institute provided funding. Dr. Elmore disclosed ties to Myriad Genetics, SciBase, and the National Institutes of Health.

SOURCE: Elmore JG et al. JAMA Network Open. 2018 May 18. doi: 10.1001/jamanetworkopen.2018.0083.

Use of the recently updated AJCC Cancer Staging Manual, 8th edition, produced about 10% better accuracy when interpreting T1a invasive melanomas in a national study.

For stage T1b or greater cases, using the AJCC 8 instead of the AJCC 7 yielded about 6% higher concordance between interpretations and consensus reference diagnoses, said Joann G. Elmore, MD, MPH, of the David Geffen School of Medicine at the University of California, Los Angeles, and her associates. “Intraobserver reproducibility of diagnoses also improved,” but “concordance and reproducibility remain low,” the researchers wrote. The report was published in JAMA Open Network.

For the study, 187 pathologists each interpreted one of five glass slide sets of melanocytic skin biopsies. At least 8 months later, they interpreted the same set again, both times recording their interpretations on the online Pathology Assessment Tool and Hierarchy for Diagnosis (MPATH-Dx). Researchers then used AJCC 7 and AJCC 8 criteria to group these interpretations into one of five MPATH-Dx classes. The final analysis included only the 116 cases of invasive melanoma, because changes in the AJCC 8 criteria affected only MPATH-Dx classes IV (T1a) and V (T1b and higher), the investigators explained.

For T1a invasive melanomas, overall concordance between interpretations and consensus diagnoses rose from 44% (95% confidence interval, 41%-48%) under the AJCC 7 criteria to 54% (95% CI, 51%-57%) under the AJCC 8 criteria. For stage T1b or higher lesions, concordance rose from 72% to 78%. Intrapathologist reproducibility improved from 59% to 64% for T1a cases and from 74% to 77% for T1b or higher cases. Thus, the AJCC 8 produced “modest” improvements in concordance and reproducibility over the AJCC 7, the researchers said.

One of the most likely explanations is that the AJCC 8 eliminated dermal mitotic activity as a criterion for T1b melanomas, which is “potentially unreliable” in thin lesions, they added. Persistently low concordance and reproducibility “suggest that conventional histopathology has been parsed to a degree that falls below the limits of reliability,” they concluded.

The National Cancer Institute provided funding. Dr. Elmore disclosed ties to Myriad Genetics, SciBase, and the National Institutes of Health.

SOURCE: Elmore JG et al. JAMA Network Open. 2018 May 18. doi: 10.1001/jamanetworkopen.2018.0083.

Patients with inflammatory bowel disease were about 22% more likely to develop Parkinson’s disease than were unaffected peers in a population-based cohort study spanning more than 3 decades.

The finding “strengthens the theory of a ‘gut-brain axis,’ in which the intestinal environment influences the functioning of the central nervous system and intestinal imbalance may precede Parkinson’s disease,” wrote Marie Villumsen, PhD, of Bispebjerg and Frederiksberg Hospital in Copenhagen, with her associates.

Thus, clinicians should be vigilant for parkinsonism in patients with inflammatory bowel disease (IBD), the researchers wrote on May 21 in Gut. “Although the absolute risk of Parkinson’s disease [among patients with IBD] remains low, our study points to overlapping pathogenic mechanisms which merit further investigation, as they may represent targets for future therapeutic interventions.”

Gastrointestinal dysfunction can be one of the earliest manifestations of Parkinson’s disease, the researchers noted. Both neurodegenerative disorders and IBD involve chronic inflammation, and both Crohn’s disease and Parkinson’s disease have been linked to aberrations of the LRRK2 gene, which helps regulate inflammation and clearance of alpha-sinuclein, a key component of neuronal Lewy bodies in Parkinson’s disease.

To assess whether IBD directly increases the risk of Parkinson’s disease, the investigators studied individuals from the Danish National Patient Register, which covers all hospitalizations and outpatient visits in Denmark. They matched 76,477 patients with IBD with 7.5 million unaffected individuals of the same sex and age during 1977-2014. Patients with IBD had significantly more comorbidities (P less than .001) than individuals without IBD, so the researchers also controlled for Charlson Comorbidity Index.

In the adjusted analyses, IBD significantly increased the risk of developing Parkinson’s disease among both men (hazard ratio, 1.2) and women (HR, 1.23), irrespective of follow-up time and regardless of whether patients were less than 40 years old (HR, 1.22), 40-65 years old (HR, 1.25), or older than 65 years (HR, 1.30). The association between IBD and Parkinson’s disease also held up after accounting for the possibility that early gut symptoms of Parkinson’s disease were sometimes misdiagnosed as IBD, the researchers wrote.

Interestingly, stratifying by IBD subtype showed that the statistically significant risk factor was ulcerative colitis (HR, 1.35; 95% confidence interval, 1.20-1.52), not Crohn’s disease (HR, 1.12; 95% CI, 0.89-1.40). Prior studies have found that cigarette smoking reduces the risk of both Parkinson’s disease and ulcerative colitis, the investigators noted. They called for additional studies of intestinal inflammation in Parkinson’s disease and the role of the brain-gut axis in the etiology of parkinsonism.

Parkinsonforeningen, Landsforeningen Multipel System Atrofi, and Aage og Johanne Louis-Hansens Fond provided support. The investigators declared no competing interests.

SOURCE: Villumsen M et al. Gut. 2018 May 21. doi: 10.1136/gutjnl-2017-315666.

Patients with inflammatory bowel disease were about 22% more likely to develop Parkinson’s disease than were unaffected peers in a population-based cohort study spanning more than 3 decades.

The finding “strengthens the theory of a ‘gut-brain axis,’ in which the intestinal environment influences the functioning of the central nervous system and intestinal imbalance may precede Parkinson’s disease,” wrote Marie Villumsen, PhD, of Bispebjerg and Frederiksberg Hospital in Copenhagen, with her associates.

Thus, clinicians should be vigilant for parkinsonism in patients with inflammatory bowel disease (IBD), the researchers wrote on May 21 in Gut. “Although the absolute risk of Parkinson’s disease [among patients with IBD] remains low, our study points to overlapping pathogenic mechanisms which merit further investigation, as they may represent targets for future therapeutic interventions.”

Gastrointestinal dysfunction can be one of the earliest manifestations of Parkinson’s disease, the researchers noted. Both neurodegenerative disorders and IBD involve chronic inflammation, and both Crohn’s disease and Parkinson’s disease have been linked to aberrations of the LRRK2 gene, which helps regulate inflammation and clearance of alpha-sinuclein, a key component of neuronal Lewy bodies in Parkinson’s disease.

To assess whether IBD directly increases the risk of Parkinson’s disease, the investigators studied individuals from the Danish National Patient Register, which covers all hospitalizations and outpatient visits in Denmark. They matched 76,477 patients with IBD with 7.5 million unaffected individuals of the same sex and age during 1977-2014. Patients with IBD had significantly more comorbidities (P less than .001) than individuals without IBD, so the researchers also controlled for Charlson Comorbidity Index.

In the adjusted analyses, IBD significantly increased the risk of developing Parkinson’s disease among both men (hazard ratio, 1.2) and women (HR, 1.23), irrespective of follow-up time and regardless of whether patients were less than 40 years old (HR, 1.22), 40-65 years old (HR, 1.25), or older than 65 years (HR, 1.30). The association between IBD and Parkinson’s disease also held up after accounting for the possibility that early gut symptoms of Parkinson’s disease were sometimes misdiagnosed as IBD, the researchers wrote.

Interestingly, stratifying by IBD subtype showed that the statistically significant risk factor was ulcerative colitis (HR, 1.35; 95% confidence interval, 1.20-1.52), not Crohn’s disease (HR, 1.12; 95% CI, 0.89-1.40). Prior studies have found that cigarette smoking reduces the risk of both Parkinson’s disease and ulcerative colitis, the investigators noted. They called for additional studies of intestinal inflammation in Parkinson’s disease and the role of the brain-gut axis in the etiology of parkinsonism.

Parkinsonforeningen, Landsforeningen Multipel System Atrofi, and Aage og Johanne Louis-Hansens Fond provided support. The investigators declared no competing interests.

SOURCE: Villumsen M et al. Gut. 2018 May 21. doi: 10.1136/gutjnl-2017-315666.

Patients with inflammatory bowel disease were about 22% more likely to develop Parkinson’s disease than were unaffected peers in a population-based cohort study spanning more than 3 decades.

The finding “strengthens the theory of a ‘gut-brain axis,’ in which the intestinal environment influences the functioning of the central nervous system and intestinal imbalance may precede Parkinson’s disease,” wrote Marie Villumsen, PhD, of Bispebjerg and Frederiksberg Hospital in Copenhagen, with her associates.

Thus, clinicians should be vigilant for parkinsonism in patients with inflammatory bowel disease (IBD), the researchers wrote on May 21 in Gut. “Although the absolute risk of Parkinson’s disease [among patients with IBD] remains low, our study points to overlapping pathogenic mechanisms which merit further investigation, as they may represent targets for future therapeutic interventions.”

Gastrointestinal dysfunction can be one of the earliest manifestations of Parkinson’s disease, the researchers noted. Both neurodegenerative disorders and IBD involve chronic inflammation, and both Crohn’s disease and Parkinson’s disease have been linked to aberrations of the LRRK2 gene, which helps regulate inflammation and clearance of alpha-sinuclein, a key component of neuronal Lewy bodies in Parkinson’s disease.

To assess whether IBD directly increases the risk of Parkinson’s disease, the investigators studied individuals from the Danish National Patient Register, which covers all hospitalizations and outpatient visits in Denmark. They matched 76,477 patients with IBD with 7.5 million unaffected individuals of the same sex and age during 1977-2014. Patients with IBD had significantly more comorbidities (P less than .001) than individuals without IBD, so the researchers also controlled for Charlson Comorbidity Index.

In the adjusted analyses, IBD significantly increased the risk of developing Parkinson’s disease among both men (hazard ratio, 1.2) and women (HR, 1.23), irrespective of follow-up time and regardless of whether patients were less than 40 years old (HR, 1.22), 40-65 years old (HR, 1.25), or older than 65 years (HR, 1.30). The association between IBD and Parkinson’s disease also held up after accounting for the possibility that early gut symptoms of Parkinson’s disease were sometimes misdiagnosed as IBD, the researchers wrote.

Interestingly, stratifying by IBD subtype showed that the statistically significant risk factor was ulcerative colitis (HR, 1.35; 95% confidence interval, 1.20-1.52), not Crohn’s disease (HR, 1.12; 95% CI, 0.89-1.40). Prior studies have found that cigarette smoking reduces the risk of both Parkinson’s disease and ulcerative colitis, the investigators noted. They called for additional studies of intestinal inflammation in Parkinson’s disease and the role of the brain-gut axis in the etiology of parkinsonism.

Parkinsonforeningen, Landsforeningen Multipel System Atrofi, and Aage og Johanne Louis-Hansens Fond provided support. The investigators declared no competing interests.

SOURCE: Villumsen M et al. Gut. 2018 May 21. doi: 10.1136/gutjnl-2017-315666.

CAMBRIDGE, MASS. – In the era of biologics, physical therapy still has a place in the treatment of patients with ankylosing spondylitis, according to Angelo Papachristos, an advanced physiotherapist at St. Michaels Hospital in Toronto.

Speaking in an education session at the annual meeting of the Spondyloarthritis Research and Treatment Network (SPARTAN), Mr. Papachristos said that therapy should be introduced at diagnosis, individualized, and constantly reevaluated.

“There is no one recommendation,” he said. “Therapy should be monitored and adjusted over time depending on how the patient responds.”

Mr. Papachristos drew attention to two portions of recommendations from the American College of Sports Medicine (ACSM).

First, that scientific evidence demonstrates that the beneficial effects of exercise are indisputable and that the benefits far outweigh the risks.

Second, that a program of regular exercise that includes cardiorespiratory, resistance, flexibility, and neuromotor aspects to improve and maintain fitness and health is essential for most adults.

How much exercise to prescribe and when to introduce exercise remains a question.

[email protected]

CAMBRIDGE, MASS. – In the era of biologics, physical therapy still has a place in the treatment of patients with ankylosing spondylitis, according to Angelo Papachristos, an advanced physiotherapist at St. Michaels Hospital in Toronto.

Speaking in an education session at the annual meeting of the Spondyloarthritis Research and Treatment Network (SPARTAN), Mr. Papachristos said that therapy should be introduced at diagnosis, individualized, and constantly reevaluated.

“There is no one recommendation,” he said. “Therapy should be monitored and adjusted over time depending on how the patient responds.”

Mr. Papachristos drew attention to two portions of recommendations from the American College of Sports Medicine (ACSM).

First, that scientific evidence demonstrates that the beneficial effects of exercise are indisputable and that the benefits far outweigh the risks.

Second, that a program of regular exercise that includes cardiorespiratory, resistance, flexibility, and neuromotor aspects to improve and maintain fitness and health is essential for most adults.

How much exercise to prescribe and when to introduce exercise remains a question.

[email protected]

CAMBRIDGE, MASS. – In the era of biologics, physical therapy still has a place in the treatment of patients with ankylosing spondylitis, according to Angelo Papachristos, an advanced physiotherapist at St. Michaels Hospital in Toronto.

Speaking in an education session at the annual meeting of the Spondyloarthritis Research and Treatment Network (SPARTAN), Mr. Papachristos said that therapy should be introduced at diagnosis, individualized, and constantly reevaluated.

“There is no one recommendation,” he said. “Therapy should be monitored and adjusted over time depending on how the patient responds.”

Mr. Papachristos drew attention to two portions of recommendations from the American College of Sports Medicine (ACSM).

First, that scientific evidence demonstrates that the beneficial effects of exercise are indisputable and that the benefits far outweigh the risks.

Second, that a program of regular exercise that includes cardiorespiratory, resistance, flexibility, and neuromotor aspects to improve and maintain fitness and health is essential for most adults.

How much exercise to prescribe and when to introduce exercise remains a question.

[email protected]

SAN DIEGO – Among patients with idiopathic pulmonary fibrosis (IPF), an improvement in 4-meter gait speed with pulmonary rehabilitation is an independent predictor of all-cause mortality at 1 year, suggest results from a multicenter study presented at an international conference of the American Thoracic Society.

The authors of the study found that patients who improved their gait speed had a longer survival time. In all, 11% of patients died within 1 year of completing pulmonary rehabilitation.

Doug Brunk/MDedge News

“Mortality is an attractive endpoint in IPF clinical research but requires large sample sizes and long follow-up duration, making clinical trials expensive and challenging to undertake,” lead study author Claire M. Nolan, MSc, said at the conference.

“Consequently, there is much interest in surrogate endpoints of mortality. In the elderly population, a lot of work has been done on performance measures, in particular the 4-meter gait test. It’s a simple test to do from the assessor’s perspective, because you just need a 4-meter corridor and a stopwatch. From the patient’s perspective, they only have to walk at their usual speed, making it feasible in most settings.”

The study by Ms. Nolan, a National Institute for Health Research fellow, and her associates, involved recruiting 90 IPF patients referred to three outpatient pulmonary rehabilitation programs in London. All patients underwent the following assessments before and after 8 weeks of pulmonary rehabilitation: spirometry; Medical Research Council dyspnea score; anthropometry; 4-meter gait speed; incremental shuttle walk test, and King’s Brief Interstitial Lung Disease questionnaire. Ms. Nolan, a respiratory physiotherapist with the Harefield Pulmonary Rehabilitation and Muscle Research Group, Royal Brompton and Harefield NHS Foundation Trust, Harefield, London, and her associates drew from national databases to obtain data on all-cause mortality 1 year following pulmonary rehabilitation.

“We also identified a cutpoint, so if patients improved their walking speed by 0.009 meters per second or above, that was associated with a longer survival time at 1 year (area under the curve of 0.76, for sensitivity of 69.6% and a specificity of 70%; P less than 0.01),” she said.* “Among patients who achieved that cutpoint or exceeded it, only 5% of them died in the 1-year follow-up period, compared with 23% in the group that didn’t achieve that cutpoint. That’s quite a big difference, but this requires external validation in another population.”

To determine the 4-meter gait speed change cut-off that best discriminated between patients who died and survived, the investigators plotted receiver operating characteristic curves. For validation, they conducted a Kaplan-Meier analysis to assess time to death, with significance assessed via the log-rank test. Finally, they used a multivariate Cox proportional hazards model to characterize the relationship between 4-meter gait speed change and all-cause mortality, adjusting for independent predictors of mortality (age, previous respiratory hospitalizations in the past year, forced vital capacity percent predicted) and baseline 4-meter gait speed.

At baseline, 70% of the 90 patients were male, mean age was 74 years, mean forced vital capacity was 72.8% predicted, and mean Medical Research Council dyspnea score was 3. In addition, mean body mass index was 27.2 kg/m², mean 4-meter gait speed was 0.92 meters per second, mean incremental shuttle walk test measurement was 271 meters, and mean King’s Brief Interstitial Lung Disease total score was 56.4. Following 8 weeks of pulmonary rehabilitation, the patients’ 4-meter gait speed improved significantly by a mean of 0.15 meters per second (P less than .001). All other variables also improved significantly, with the exception of forced vital capacity.

In an interview, Ms. Nolan characterized the results as “one piece of the puzzle in answering whether 4-meter gait speed is a useful test for clinicians and researchers. It needs to be taken in the context of 4-meter gait speed in other populations as well as with what we’re finding in patients with IPF. We know that this test is reliable, valid, and responsive to treatment. Now we know that it has predictive capacity as well.”

During her presentation, she cited potential reasons why change in gait speed is associated with survival. “Firstly, gait speed has been described as a clinical indicator of multisystem well-being and the ‘sixth vital sign,’ ”she said. “Walking ability and speed rely on multiple factors and the integration of many systems, cardiovascular and otherwise. We know that pulmonary rehab has multiple benefits and improves these systems, and it’s plausible that change in gait speed may be a surrogate marker for, say, improvement in exercise capacity or health status. But the precise mechanism requires verification.”

Ms. Nolan acknowledged certain limitations of the study, including the fact that contemporaneous measurement of full lung function testing and pulmonary hypertension diagnosis were not available at the time of the study. “Therefore, we were unable to account for [diffusing capacity of the lung for carbon monoxide] and pulmonary hypertension diagnosis,” she said. “Secondly, we were unable to identify the precise cause of death from the national database of harm and care records, but this corroborates previous data which suggest that it’s difficult to reliably discern if a death is IPF- or non-IPF related. Lastly, we know that the benefits of pulmonary rehab experienced by IPF patients tend to wane after 6 months. It would be interesting to compare the short-term improvements in gait speed that we observed to more sustained improvements, to identify whether this impacts prognostability.”

National Institute for Health Research funded the study. Ms. Nolan reported having no financial disclosures.

*Correction, 5/23/18: An earlier version of this article misstated the 4-meter gait speed cutoff point. 

[email protected]

SOURCE: Nolan CM et al. ATS 2018, Abstract A2456.

SAN DIEGO – Among patients with idiopathic pulmonary fibrosis (IPF), an improvement in 4-meter gait speed with pulmonary rehabilitation is an independent predictor of all-cause mortality at 1 year, suggest results from a multicenter study presented at an international conference of the American Thoracic Society.

The authors of the study found that patients who improved their gait speed had a longer survival time. In all, 11% of patients died within 1 year of completing pulmonary rehabilitation.

Doug Brunk/MDedge News

“Mortality is an attractive endpoint in IPF clinical research but requires large sample sizes and long follow-up duration, making clinical trials expensive and challenging to undertake,” lead study author Claire M. Nolan, MSc, said at the conference.

“Consequently, there is much interest in surrogate endpoints of mortality. In the elderly population, a lot of work has been done on performance measures, in particular the 4-meter gait test. It’s a simple test to do from the assessor’s perspective, because you just need a 4-meter corridor and a stopwatch. From the patient’s perspective, they only have to walk at their usual speed, making it feasible in most settings.”

The study by Ms. Nolan, a National Institute for Health Research fellow, and her associates, involved recruiting 90 IPF patients referred to three outpatient pulmonary rehabilitation programs in London. All patients underwent the following assessments before and after 8 weeks of pulmonary rehabilitation: spirometry; Medical Research Council dyspnea score; anthropometry; 4-meter gait speed; incremental shuttle walk test, and King’s Brief Interstitial Lung Disease questionnaire. Ms. Nolan, a respiratory physiotherapist with the Harefield Pulmonary Rehabilitation and Muscle Research Group, Royal Brompton and Harefield NHS Foundation Trust, Harefield, London, and her associates drew from national databases to obtain data on all-cause mortality 1 year following pulmonary rehabilitation.

“We also identified a cutpoint, so if patients improved their walking speed by 0.009 meters per second or above, that was associated with a longer survival time at 1 year (area under the curve of 0.76, for sensitivity of 69.6% and a specificity of 70%; P less than 0.01),” she said.* “Among patients who achieved that cutpoint or exceeded it, only 5% of them died in the 1-year follow-up period, compared with 23% in the group that didn’t achieve that cutpoint. That’s quite a big difference, but this requires external validation in another population.”

To determine the 4-meter gait speed change cut-off that best discriminated between patients who died and survived, the investigators plotted receiver operating characteristic curves. For validation, they conducted a Kaplan-Meier analysis to assess time to death, with significance assessed via the log-rank test. Finally, they used a multivariate Cox proportional hazards model to characterize the relationship between 4-meter gait speed change and all-cause mortality, adjusting for independent predictors of mortality (age, previous respiratory hospitalizations in the past year, forced vital capacity percent predicted) and baseline 4-meter gait speed.

At baseline, 70% of the 90 patients were male, mean age was 74 years, mean forced vital capacity was 72.8% predicted, and mean Medical Research Council dyspnea score was 3. In addition, mean body mass index was 27.2 kg/m², mean 4-meter gait speed was 0.92 meters per second, mean incremental shuttle walk test measurement was 271 meters, and mean King’s Brief Interstitial Lung Disease total score was 56.4. Following 8 weeks of pulmonary rehabilitation, the patients’ 4-meter gait speed improved significantly by a mean of 0.15 meters per second (P less than .001). All other variables also improved significantly, with the exception of forced vital capacity.

In an interview, Ms. Nolan characterized the results as “one piece of the puzzle in answering whether 4-meter gait speed is a useful test for clinicians and researchers. It needs to be taken in the context of 4-meter gait speed in other populations as well as with what we’re finding in patients with IPF. We know that this test is reliable, valid, and responsive to treatment. Now we know that it has predictive capacity as well.”

During her presentation, she cited potential reasons why change in gait speed is associated with survival. “Firstly, gait speed has been described as a clinical indicator of multisystem well-being and the ‘sixth vital sign,’ ”she said. “Walking ability and speed rely on multiple factors and the integration of many systems, cardiovascular and otherwise. We know that pulmonary rehab has multiple benefits and improves these systems, and it’s plausible that change in gait speed may be a surrogate marker for, say, improvement in exercise capacity or health status. But the precise mechanism requires verification.”

Ms. Nolan acknowledged certain limitations of the study, including the fact that contemporaneous measurement of full lung function testing and pulmonary hypertension diagnosis were not available at the time of the study. “Therefore, we were unable to account for [diffusing capacity of the lung for carbon monoxide] and pulmonary hypertension diagnosis,” she said. “Secondly, we were unable to identify the precise cause of death from the national database of harm and care records, but this corroborates previous data which suggest that it’s difficult to reliably discern if a death is IPF- or non-IPF related. Lastly, we know that the benefits of pulmonary rehab experienced by IPF patients tend to wane after 6 months. It would be interesting to compare the short-term improvements in gait speed that we observed to more sustained improvements, to identify whether this impacts prognostability.”

National Institute for Health Research funded the study. Ms. Nolan reported having no financial disclosures.

*Correction, 5/23/18: An earlier version of this article misstated the 4-meter gait speed cutoff point. 

[email protected]

SOURCE: Nolan CM et al. ATS 2018, Abstract A2456.

SAN DIEGO – Among patients with idiopathic pulmonary fibrosis (IPF), an improvement in 4-meter gait speed with pulmonary rehabilitation is an independent predictor of all-cause mortality at 1 year, suggest results from a multicenter study presented at an international conference of the American Thoracic Society.

The authors of the study found that patients who improved their gait speed had a longer survival time. In all, 11% of patients died within 1 year of completing pulmonary rehabilitation.

Doug Brunk/MDedge News

“Mortality is an attractive endpoint in IPF clinical research but requires large sample sizes and long follow-up duration, making clinical trials expensive and challenging to undertake,” lead study author Claire M. Nolan, MSc, said at the conference.

“Consequently, there is much interest in surrogate endpoints of mortality. In the elderly population, a lot of work has been done on performance measures, in particular the 4-meter gait test. It’s a simple test to do from the assessor’s perspective, because you just need a 4-meter corridor and a stopwatch. From the patient’s perspective, they only have to walk at their usual speed, making it feasible in most settings.”

The study by Ms. Nolan, a National Institute for Health Research fellow, and her associates, involved recruiting 90 IPF patients referred to three outpatient pulmonary rehabilitation programs in London. All patients underwent the following assessments before and after 8 weeks of pulmonary rehabilitation: spirometry; Medical Research Council dyspnea score; anthropometry; 4-meter gait speed; incremental shuttle walk test, and King’s Brief Interstitial Lung Disease questionnaire. Ms. Nolan, a respiratory physiotherapist with the Harefield Pulmonary Rehabilitation and Muscle Research Group, Royal Brompton and Harefield NHS Foundation Trust, Harefield, London, and her associates drew from national databases to obtain data on all-cause mortality 1 year following pulmonary rehabilitation.

“We also identified a cutpoint, so if patients improved their walking speed by 0.009 meters per second or above, that was associated with a longer survival time at 1 year (area under the curve of 0.76, for sensitivity of 69.6% and a specificity of 70%; P less than 0.01),” she said.* “Among patients who achieved that cutpoint or exceeded it, only 5% of them died in the 1-year follow-up period, compared with 23% in the group that didn’t achieve that cutpoint. That’s quite a big difference, but this requires external validation in another population.”

To determine the 4-meter gait speed change cut-off that best discriminated between patients who died and survived, the investigators plotted receiver operating characteristic curves. For validation, they conducted a Kaplan-Meier analysis to assess time to death, with significance assessed via the log-rank test. Finally, they used a multivariate Cox proportional hazards model to characterize the relationship between 4-meter gait speed change and all-cause mortality, adjusting for independent predictors of mortality (age, previous respiratory hospitalizations in the past year, forced vital capacity percent predicted) and baseline 4-meter gait speed.

At baseline, 70% of the 90 patients were male, mean age was 74 years, mean forced vital capacity was 72.8% predicted, and mean Medical Research Council dyspnea score was 3. In addition, mean body mass index was 27.2 kg/m², mean 4-meter gait speed was 0.92 meters per second, mean incremental shuttle walk test measurement was 271 meters, and mean King’s Brief Interstitial Lung Disease total score was 56.4. Following 8 weeks of pulmonary rehabilitation, the patients’ 4-meter gait speed improved significantly by a mean of 0.15 meters per second (P less than .001). All other variables also improved significantly, with the exception of forced vital capacity.

In an interview, Ms. Nolan characterized the results as “one piece of the puzzle in answering whether 4-meter gait speed is a useful test for clinicians and researchers. It needs to be taken in the context of 4-meter gait speed in other populations as well as with what we’re finding in patients with IPF. We know that this test is reliable, valid, and responsive to treatment. Now we know that it has predictive capacity as well.”

During her presentation, she cited potential reasons why change in gait speed is associated with survival. “Firstly, gait speed has been described as a clinical indicator of multisystem well-being and the ‘sixth vital sign,’ ”she said. “Walking ability and speed rely on multiple factors and the integration of many systems, cardiovascular and otherwise. We know that pulmonary rehab has multiple benefits and improves these systems, and it’s plausible that change in gait speed may be a surrogate marker for, say, improvement in exercise capacity or health status. But the precise mechanism requires verification.”

Ms. Nolan acknowledged certain limitations of the study, including the fact that contemporaneous measurement of full lung function testing and pulmonary hypertension diagnosis were not available at the time of the study. “Therefore, we were unable to account for [diffusing capacity of the lung for carbon monoxide] and pulmonary hypertension diagnosis,” she said. “Secondly, we were unable to identify the precise cause of death from the national database of harm and care records, but this corroborates previous data which suggest that it’s difficult to reliably discern if a death is IPF- or non-IPF related. Lastly, we know that the benefits of pulmonary rehab experienced by IPF patients tend to wane after 6 months. It would be interesting to compare the short-term improvements in gait speed that we observed to more sustained improvements, to identify whether this impacts prognostability.”

National Institute for Health Research funded the study. Ms. Nolan reported having no financial disclosures.

*Correction, 5/23/18: An earlier version of this article misstated the 4-meter gait speed cutoff point. 

[email protected]

SOURCE: Nolan CM et al. ATS 2018, Abstract A2456.

On the advent of this year’s Society for Vascular Surgery’s (SVS) Vascular Annual Meeting (VAM), I would like to welcome you to the 2018 ­annual spring meeting for VESS, which convenes in conjunction with VAM on June 20 at the Hynes Convention Center in Boston. Our Wednesday program looks very diverse and outstanding, covering key topics in aortic and branch aortic, cerebrovascular, lower extremity, venous disease, hemodialysis, physician wellness/burnout, academic issues, and the medical management of vascular disease. Thank you to Matthew Smeds and the rest of the program committee for putting together such an engaging lineup for this year’s spring meeting! I would also encourage you to visit our industry sponsors for this event; exhibits will be available for perusal June 21-22 within the convention center. Finally, we will be cosponsoring an event Thursday, June 21, at 7 p.m. in the Independence West Room of the Sheraton Hotel as a Networking Reception for Women, Diversity, and Young Surgeons. All residents and students are invited to attend this networking reception hosted by SVS and VESS. Thanks also to the SVS for hosting this meeting and for the ongoing collaboration we have enjoyed between our societies!

VESS members and leadership have continued to elevate the practice of vascular surgery and the research that has defined it. The more than 40-year history of this society is well outlined by Dr. Vik Kashyap in J Vasc Surg 2014;60(4):1123-4. VESS remains focused on engaging vascular trainees and vascular surgeons within a framework of collegial academic excellence. We continue to support research through grant funding at both the trainee and young investigator levels, and our presenters at both the spring VESS/VAM and Winter Annual Meetings enjoy a very high acceptance rate for publication of their findings. For more information about VESS, just visit vesurgery.org. The leadership for this society is proud of what it stands for. We are committed to exploring relevant and educational topics in vascular surgery. We hope this year’s spring meeting enhances your understanding and practice of vascular surgery. See you June 20th! 

Jon Eliason, MD
VESS President

On the advent of this year’s Society for Vascular Surgery’s (SVS) Vascular Annual Meeting (VAM), I would like to welcome you to the 2018 ­annual spring meeting for VESS, which convenes in conjunction with VAM on June 20 at the Hynes Convention Center in Boston. Our Wednesday program looks very diverse and outstanding, covering key topics in aortic and branch aortic, cerebrovascular, lower extremity, venous disease, hemodialysis, physician wellness/burnout, academic issues, and the medical management of vascular disease. Thank you to Matthew Smeds and the rest of the program committee for putting together such an engaging lineup for this year’s spring meeting! I would also encourage you to visit our industry sponsors for this event; exhibits will be available for perusal June 21-22 within the convention center. Finally, we will be cosponsoring an event Thursday, June 21, at 7 p.m. in the Independence West Room of the Sheraton Hotel as a Networking Reception for Women, Diversity, and Young Surgeons. All residents and students are invited to attend this networking reception hosted by SVS and VESS. Thanks also to the SVS for hosting this meeting and for the ongoing collaboration we have enjoyed between our societies!

VESS members and leadership have continued to elevate the practice of vascular surgery and the research that has defined it. The more than 40-year history of this society is well outlined by Dr. Vik Kashyap in J Vasc Surg 2014;60(4):1123-4. VESS remains focused on engaging vascular trainees and vascular surgeons within a framework of collegial academic excellence. We continue to support research through grant funding at both the trainee and young investigator levels, and our presenters at both the spring VESS/VAM and Winter Annual Meetings enjoy a very high acceptance rate for publication of their findings. For more information about VESS, just visit vesurgery.org. The leadership for this society is proud of what it stands for. We are committed to exploring relevant and educational topics in vascular surgery. We hope this year’s spring meeting enhances your understanding and practice of vascular surgery. See you June 20th! 

Jon Eliason, MD
VESS President

On the advent of this year’s Society for Vascular Surgery’s (SVS) Vascular Annual Meeting (VAM), I would like to welcome you to the 2018 ­annual spring meeting for VESS, which convenes in conjunction with VAM on June 20 at the Hynes Convention Center in Boston. Our Wednesday program looks very diverse and outstanding, covering key topics in aortic and branch aortic, cerebrovascular, lower extremity, venous disease, hemodialysis, physician wellness/burnout, academic issues, and the medical management of vascular disease. Thank you to Matthew Smeds and the rest of the program committee for putting together such an engaging lineup for this year’s spring meeting! I would also encourage you to visit our industry sponsors for this event; exhibits will be available for perusal June 21-22 within the convention center. Finally, we will be cosponsoring an event Thursday, June 21, at 7 p.m. in the Independence West Room of the Sheraton Hotel as a Networking Reception for Women, Diversity, and Young Surgeons. All residents and students are invited to attend this networking reception hosted by SVS and VESS. Thanks also to the SVS for hosting this meeting and for the ongoing collaboration we have enjoyed between our societies!

VESS members and leadership have continued to elevate the practice of vascular surgery and the research that has defined it. The more than 40-year history of this society is well outlined by Dr. Vik Kashyap in J Vasc Surg 2014;60(4):1123-4. VESS remains focused on engaging vascular trainees and vascular surgeons within a framework of collegial academic excellence. We continue to support research through grant funding at both the trainee and young investigator levels, and our presenters at both the spring VESS/VAM and Winter Annual Meetings enjoy a very high acceptance rate for publication of their findings. For more information about VESS, just visit vesurgery.org. The leadership for this society is proud of what it stands for. We are committed to exploring relevant and educational topics in vascular surgery. We hope this year’s spring meeting enhances your understanding and practice of vascular surgery. See you June 20th! 

Jon Eliason, MD
VESS President

It seems fitting, said Tiffany Street, President of the Society for Vascular Nursing, that SVN and SVS have their conferences in the same location and with overlapping times.

Joanna Bronson/SVS

“It parallels what we do every day in clinical practice,” she said. “Recently, we have focused our attention on the emphasis of the clinical vascular care team. Physicians and nurses collaborate daily on the care of vascular patients so collaboration in the learning environment is imperative.”

SVN’s 36th Annual Conference, SVN @SVS, will be held June 20 to 21, coinciding with the opening two days of VAM. The SVN conference registration fee permits entrance to VAM, as well.

Both organizations are emphasizing the team approach to vascular care this year, with SVN also stressing vascular education and the holistic approach to vascular patient care, Ms. Street said. An abstract session Thursday will focus on “The Vascular Team Connections,” with two abstract presentations plus a panel discussion on “How Collaboration Changes a Patient.” Speakers include surgeon and SVS President R. Clement Darling III, MD; a physician assistant, Erin Hanlon, PA-PAC; and two nurses, Marie Rossi, BS, RN, and Karen Fitzgerald, MSN, RN, NP.

The team approach is vitally important, Ms. Street said. “Vascular nursing is responsible for the care of the patient across the continuum in collaboration with the surgeon,” she said.

Undergoing a surgical procedure affects not only the patient but also the patient’s family, she pointed out. “Because the family support system is vital to good postoperative outcomes, vascular nurses support the family as well.” Nurses cover with the patient and family what they all might expect during the patient’s recovery, helping them think through the various issues and how best to manage them, she said. “It’s all part of the team approach.”

Abstract sessions at SVN @SVS will focus on CLI, AAA, carotid artery, PAD, venous and arterial compression, and vascular team connections. Concurrent sessions will target both the novice and experienced nurse, plus include other emphases, as well. Several SVS members will be presenters at SVN sessions.

The keynote address will cover the care of patients from the Boston Marathon bombing in 2013. Jonathan Gates, MD, who was Medical Director of Trauma Services at Brigham and Women’s Hospital at the time of the bombing and operated on bombing victims that day, will present the address. Other sessions at the Vascular Annual Meeting also stress the vascular team and patient benefits, including “Team Forum: Improving Metrics in Clinical Practice,” from 1:30 to 3 p.m. Friday. Nurses are sure to find topics of interest at VAM, said Dr. Darling. “I find the team approach integral to optimal patient outcomes,” he said. “I could not be happier at including all members of the team at this year’s VAM, from the special programming for physician assistants on Thursday afternoon to SVN @SVS.

“When we work together,” he said, “everyone benefits, especially the patient.”

Visit vsweb.org/SVN18conference or the VAM Planner (vsweb.org/VAMPlanner) for the complete schedule and more information. 

It seems fitting, said Tiffany Street, President of the Society for Vascular Nursing, that SVN and SVS have their conferences in the same location and with overlapping times.

Joanna Bronson/SVS

“It parallels what we do every day in clinical practice,” she said. “Recently, we have focused our attention on the emphasis of the clinical vascular care team. Physicians and nurses collaborate daily on the care of vascular patients so collaboration in the learning environment is imperative.”

SVN’s 36th Annual Conference, SVN @SVS, will be held June 20 to 21, coinciding with the opening two days of VAM. The SVN conference registration fee permits entrance to VAM, as well.

Both organizations are emphasizing the team approach to vascular care this year, with SVN also stressing vascular education and the holistic approach to vascular patient care, Ms. Street said. An abstract session Thursday will focus on “The Vascular Team Connections,” with two abstract presentations plus a panel discussion on “How Collaboration Changes a Patient.” Speakers include surgeon and SVS President R. Clement Darling III, MD; a physician assistant, Erin Hanlon, PA-PAC; and two nurses, Marie Rossi, BS, RN, and Karen Fitzgerald, MSN, RN, NP.

The team approach is vitally important, Ms. Street said. “Vascular nursing is responsible for the care of the patient across the continuum in collaboration with the surgeon,” she said.

Undergoing a surgical procedure affects not only the patient but also the patient’s family, she pointed out. “Because the family support system is vital to good postoperative outcomes, vascular nurses support the family as well.” Nurses cover with the patient and family what they all might expect during the patient’s recovery, helping them think through the various issues and how best to manage them, she said. “It’s all part of the team approach.”

Abstract sessions at SVN @SVS will focus on CLI, AAA, carotid artery, PAD, venous and arterial compression, and vascular team connections. Concurrent sessions will target both the novice and experienced nurse, plus include other emphases, as well. Several SVS members will be presenters at SVN sessions.

The keynote address will cover the care of patients from the Boston Marathon bombing in 2013. Jonathan Gates, MD, who was Medical Director of Trauma Services at Brigham and Women’s Hospital at the time of the bombing and operated on bombing victims that day, will present the address. Other sessions at the Vascular Annual Meeting also stress the vascular team and patient benefits, including “Team Forum: Improving Metrics in Clinical Practice,” from 1:30 to 3 p.m. Friday. Nurses are sure to find topics of interest at VAM, said Dr. Darling. “I find the team approach integral to optimal patient outcomes,” he said. “I could not be happier at including all members of the team at this year’s VAM, from the special programming for physician assistants on Thursday afternoon to SVN @SVS.

“When we work together,” he said, “everyone benefits, especially the patient.”

Visit vsweb.org/SVN18conference or the VAM Planner (vsweb.org/VAMPlanner) for the complete schedule and more information. 

It seems fitting, said Tiffany Street, President of the Society for Vascular Nursing, that SVN and SVS have their conferences in the same location and with overlapping times.

Joanna Bronson/SVS

“It parallels what we do every day in clinical practice,” she said. “Recently, we have focused our attention on the emphasis of the clinical vascular care team. Physicians and nurses collaborate daily on the care of vascular patients so collaboration in the learning environment is imperative.”

SVN’s 36th Annual Conference, SVN @SVS, will be held June 20 to 21, coinciding with the opening two days of VAM. The SVN conference registration fee permits entrance to VAM, as well.

Both organizations are emphasizing the team approach to vascular care this year, with SVN also stressing vascular education and the holistic approach to vascular patient care, Ms. Street said. An abstract session Thursday will focus on “The Vascular Team Connections,” with two abstract presentations plus a panel discussion on “How Collaboration Changes a Patient.” Speakers include surgeon and SVS President R. Clement Darling III, MD; a physician assistant, Erin Hanlon, PA-PAC; and two nurses, Marie Rossi, BS, RN, and Karen Fitzgerald, MSN, RN, NP.

The team approach is vitally important, Ms. Street said. “Vascular nursing is responsible for the care of the patient across the continuum in collaboration with the surgeon,” she said.

Undergoing a surgical procedure affects not only the patient but also the patient’s family, she pointed out. “Because the family support system is vital to good postoperative outcomes, vascular nurses support the family as well.” Nurses cover with the patient and family what they all might expect during the patient’s recovery, helping them think through the various issues and how best to manage them, she said. “It’s all part of the team approach.”

Abstract sessions at SVN @SVS will focus on CLI, AAA, carotid artery, PAD, venous and arterial compression, and vascular team connections. Concurrent sessions will target both the novice and experienced nurse, plus include other emphases, as well. Several SVS members will be presenters at SVN sessions.

The keynote address will cover the care of patients from the Boston Marathon bombing in 2013. Jonathan Gates, MD, who was Medical Director of Trauma Services at Brigham and Women’s Hospital at the time of the bombing and operated on bombing victims that day, will present the address. Other sessions at the Vascular Annual Meeting also stress the vascular team and patient benefits, including “Team Forum: Improving Metrics in Clinical Practice,” from 1:30 to 3 p.m. Friday. Nurses are sure to find topics of interest at VAM, said Dr. Darling. “I find the team approach integral to optimal patient outcomes,” he said. “I could not be happier at including all members of the team at this year’s VAM, from the special programming for physician assistants on Thursday afternoon to SVN @SVS.

“When we work together,” he said, “everyone benefits, especially the patient.”

Visit vsweb.org/SVN18conference or the VAM Planner (vsweb.org/VAMPlanner) for the complete schedule and more information. 

Federal Practitioner is inviting VA, DoD, and PHS health care providers and researchers to contribute to a special issue that will be published in October 2018 and will examine series mental health and substance use disorders. Articles that address serious mental illnesses, including schizophrenia, bipolar disorder, major depressive disorder, and alcohol or opioid misuse are especially desired. Articles may include new research, review articles, case studies, quality improvement/quality assurance programs, and patient-centered care best practices.

The full text of all accepted Federal Practitioner articles are now included in the PubMed Central database and are part of any PubMed search result.

Interested authors can submit articles at http://www.editorialmanager.com/fedprac or submit a brief 2 to 3 sentence abstract to [email protected] by July 15, 2018. The updated and complete submission guidelines, including details about the style and format, can be found here:

http://www.mdedge.com/fedprac/page/submission-guidelines

Federal Practitioner uses Editorial Manager, a web-based manuscript submission and review system. All manuscripts must be submitted through this system.

All manuscripts submitted to Federal Practitioner for both special and regular issues will be subject to peer review. Peer reviews are conducted in a double-blind fashion, and the reviewers are asked to comment on the manuscript’s importance, accuracy, relevance, clarity, timeliness, balance, and reference citation. Final decisions on all submitted manuscripts are made by the Editor-in-Chief (or, in the event of a potential conflict of interest, a designated surrogate from the journal’s Editorial Advisory Association).

Federal Practitioner is inviting VA, DoD, and PHS health care providers and researchers to contribute to a special issue that will be published in October 2018 and will examine series mental health and substance use disorders. Articles that address serious mental illnesses, including schizophrenia, bipolar disorder, major depressive disorder, and alcohol or opioid misuse are especially desired. Articles may include new research, review articles, case studies, quality improvement/quality assurance programs, and patient-centered care best practices.

The full text of all accepted Federal Practitioner articles are now included in the PubMed Central database and are part of any PubMed search result.

Interested authors can submit articles at http://www.editorialmanager.com/fedprac or submit a brief 2 to 3 sentence abstract to [email protected] by July 15, 2018. The updated and complete submission guidelines, including details about the style and format, can be found here:

http://www.mdedge.com/fedprac/page/submission-guidelines

Federal Practitioner uses Editorial Manager, a web-based manuscript submission and review system. All manuscripts must be submitted through this system.

All manuscripts submitted to Federal Practitioner for both special and regular issues will be subject to peer review. Peer reviews are conducted in a double-blind fashion, and the reviewers are asked to comment on the manuscript’s importance, accuracy, relevance, clarity, timeliness, balance, and reference citation. Final decisions on all submitted manuscripts are made by the Editor-in-Chief (or, in the event of a potential conflict of interest, a designated surrogate from the journal’s Editorial Advisory Association).

Federal Practitioner is inviting VA, DoD, and PHS health care providers and researchers to contribute to a special issue that will be published in October 2018 and will examine series mental health and substance use disorders. Articles that address serious mental illnesses, including schizophrenia, bipolar disorder, major depressive disorder, and alcohol or opioid misuse are especially desired. Articles may include new research, review articles, case studies, quality improvement/quality assurance programs, and patient-centered care best practices.

The full text of all accepted Federal Practitioner articles are now included in the PubMed Central database and are part of any PubMed search result.

Interested authors can submit articles at http://www.editorialmanager.com/fedprac or submit a brief 2 to 3 sentence abstract to [email protected] by July 15, 2018. The updated and complete submission guidelines, including details about the style and format, can be found here:

http://www.mdedge.com/fedprac/page/submission-guidelines

Federal Practitioner uses Editorial Manager, a web-based manuscript submission and review system. All manuscripts must be submitted through this system.

All manuscripts submitted to Federal Practitioner for both special and regular issues will be subject to peer review. Peer reviews are conducted in a double-blind fashion, and the reviewers are asked to comment on the manuscript’s importance, accuracy, relevance, clarity, timeliness, balance, and reference citation. Final decisions on all submitted manuscripts are made by the Editor-in-Chief (or, in the event of a potential conflict of interest, a designated surrogate from the journal’s Editorial Advisory Association).

The E. Stanley Crawford Critical Issues Forum – marking 25 years under that name this year – is a mainstay of the Vascular Annual Meeting.

But who was E. Stanley Crawford?

He was a “cardiovascular surgeon extraordinare,” according to the late Calvin Ernst, MD, writing after Dr. Crawford’s death in late 1992. Dr. Crawford developed new techniques for treating AAA; was a coinventor of the Baylor (College of Medicine, where he worked from 1956 until his death) Rapid Autologus Transfusion System, a machine that recycles a patient’s red blood cells during surgery; and wrote more than 300 peer-reviewed publications and book chapters. With his son, Dr. John Lloyd Crawford II, he wrote the “Diseases of the Aorta” textbook, which Dr. Ernst called “a standard reference text on aortic surgery.”

Dr. Crawford also helped develop the SVS Forum on Critical Issues, convening the first session during the 1988 VAM. It was decided the forum should address socioeconomic and research issues, as they impact vascular surgery, and be led by that year’s president-elect.

Dr. Ernst said Dr. Crawford believed the vascular surgery specialty had become “increasingly vague, its mission ill-defined, and its future membership uncertain. The big question: 'Who would want to go into vascular surgery today with the uncertainties of tomorrow and how can those already committed remain dominant?’ ” Dr. Ernst wrote.

Dr. Crawford felt the SVS needed to take a leadership role in this and other questions; he believed the SVS and its members were eminently qualified to do so successfully.

After his death, the SVS Executive Council unanimously agreed to rename the Critical Issues Forum for Dr. Crawford. The first such named forum was held 25 years ago, at the 1993 VAM.

This year’s Crawford Forum will focus on the vascular surgery workforce, addressing challenges and solutions. President-Elect Michel S. Makaroun, MD, who spearheaded a survey of SVS members on workforce data in late December 2017, will moderate.

The E. Stanley Crawford Critical Issues Forum – marking 25 years under that name this year – is a mainstay of the Vascular Annual Meeting.

But who was E. Stanley Crawford?

He was a “cardiovascular surgeon extraordinare,” according to the late Calvin Ernst, MD, writing after Dr. Crawford’s death in late 1992. Dr. Crawford developed new techniques for treating AAA; was a coinventor of the Baylor (College of Medicine, where he worked from 1956 until his death) Rapid Autologus Transfusion System, a machine that recycles a patient’s red blood cells during surgery; and wrote more than 300 peer-reviewed publications and book chapters. With his son, Dr. John Lloyd Crawford II, he wrote the “Diseases of the Aorta” textbook, which Dr. Ernst called “a standard reference text on aortic surgery.”

Dr. Crawford also helped develop the SVS Forum on Critical Issues, convening the first session during the 1988 VAM. It was decided the forum should address socioeconomic and research issues, as they impact vascular surgery, and be led by that year’s president-elect.

Dr. Ernst said Dr. Crawford believed the vascular surgery specialty had become “increasingly vague, its mission ill-defined, and its future membership uncertain. The big question: 'Who would want to go into vascular surgery today with the uncertainties of tomorrow and how can those already committed remain dominant?’ ” Dr. Ernst wrote.

Dr. Crawford felt the SVS needed to take a leadership role in this and other questions; he believed the SVS and its members were eminently qualified to do so successfully.

After his death, the SVS Executive Council unanimously agreed to rename the Critical Issues Forum for Dr. Crawford. The first such named forum was held 25 years ago, at the 1993 VAM.

This year’s Crawford Forum will focus on the vascular surgery workforce, addressing challenges and solutions. President-Elect Michel S. Makaroun, MD, who spearheaded a survey of SVS members on workforce data in late December 2017, will moderate.

The E. Stanley Crawford Critical Issues Forum – marking 25 years under that name this year – is a mainstay of the Vascular Annual Meeting.

But who was E. Stanley Crawford?

He was a “cardiovascular surgeon extraordinare,” according to the late Calvin Ernst, MD, writing after Dr. Crawford’s death in late 1992. Dr. Crawford developed new techniques for treating AAA; was a coinventor of the Baylor (College of Medicine, where he worked from 1956 until his death) Rapid Autologus Transfusion System, a machine that recycles a patient’s red blood cells during surgery; and wrote more than 300 peer-reviewed publications and book chapters. With his son, Dr. John Lloyd Crawford II, he wrote the “Diseases of the Aorta” textbook, which Dr. Ernst called “a standard reference text on aortic surgery.”

Dr. Crawford also helped develop the SVS Forum on Critical Issues, convening the first session during the 1988 VAM. It was decided the forum should address socioeconomic and research issues, as they impact vascular surgery, and be led by that year’s president-elect.

Dr. Ernst said Dr. Crawford believed the vascular surgery specialty had become “increasingly vague, its mission ill-defined, and its future membership uncertain. The big question: 'Who would want to go into vascular surgery today with the uncertainties of tomorrow and how can those already committed remain dominant?’ ” Dr. Ernst wrote.

Dr. Crawford felt the SVS needed to take a leadership role in this and other questions; he believed the SVS and its members were eminently qualified to do so successfully.

After his death, the SVS Executive Council unanimously agreed to rename the Critical Issues Forum for Dr. Crawford. The first such named forum was held 25 years ago, at the 1993 VAM.

This year’s Crawford Forum will focus on the vascular surgery workforce, addressing challenges and solutions. President-Elect Michel S. Makaroun, MD, who spearheaded a survey of SVS members on workforce data in late December 2017, will moderate.

Photo by Petr Kratochvil

Childhood acute lymphoblastic leukemia (ALL) may be preventable, according to a researcher.

Mel Greaves, PhD, of The Institute of Cancer Research in London, UK, reviewed more than 30 years of research and concluded that ALL develops in 2 steps—genetic mutation before birth and further genetic change after birth triggered by infection.

The evidence suggests that infection early in life is beneficial to prime the immune system, but later infection without earlier priming can trigger ALL.

So priming the immune system in the first year of life could potentially prevent childhood ALL, according to Dr Greaves.

He outlined this theory in Nature Reviews Cancer.

Dr Greaves compiled more than 30 years of research into genetics, cell biology, immunology, epidemiology, and animal modelling of ALL.

The evidence led him to conclude that ALL begins with a genetic mutation that occurs before birth and predisposes a child to leukemia.

The disease is triggered later, in childhood, by exposure to one or more common infections. This primarily occurs in children who experienced “clean” childhoods in their first year of life, without much interaction with other infants or older children.

Dr Greaves challenged previous reports of possible environmental causes for ALL, such as ionizing radiation, electromagnetic waves, or man-made chemicals. He argued that none of these reports are supported by robust evidence.

Instead, he believes there is strong evidence suggesting that infection later in childhood, in the absence of earlier priming, can trigger ALL.

Dr Greaves’ studies of identical twins with ALL showed that 2 mutations were required for ALL development. The first arises in one twin in the womb but produces a population of pre-malignant cells that spread to the other twin via their shared blood supply. The second mutation arises after birth and is different in the twins.

Population studies and animal experiments suggest this second genetic hit can be triggered by infection, probably by a range of common viruses and bacteria. In one unique cluster of cases investigated by Dr Greaves and his colleagues, all cases were infected with flu virus.

In other work, researchers engineered mice with an active leukemia-initiating gene. When the team moved the mice from an ultra-clean, germ-free environment to one that had common microbes, the mice developed ALL.

Population studies have indicated that early exposure to infection in infancy, such as via day care attendance and breast feeding, can protect against ALL, probably by priming the immune system. This suggests childhood ALL may be preventable.

Dr Greaves is now investigating whether earlier exposure to harmless microbes could prevent leukemia in mice.

“I have spent more than 40 years researching childhood leukemia, and, over that time, there has been huge progress in our understanding of its biology and its treatment . . . ,” Dr Greaves said. “But it has always struck me that something big was missing, a gap in our knowledge [that failed to explain] why or how otherwise healthy children develop leukemia and whether this cancer is preventable.”

“This body of research is a culmination of decades of work and at last provides a credible explanation for how the major type of childhood leukemia develops. The research strongly suggests that ALL has a clear biological cause and is triggered by a variety of infections in predisposed children whose immune systems have not been properly primed. It also busts some persistent myths about the causes of leukemia, such as the damaging but unsubstantiated claims that the disease is commonly caused by exposure to electro-magnetic waves or pollution.”

“I hope this research will have a real impact on the lives of children. The most important implication is that most cases of childhood leukemia are likely to be preventable. It might be done in the same way that is currently under consideration for autoimmune disease or allergies, perhaps with simple and safe interventions to expose infants to a variety of common and harmless ‘bugs.’”

Photo by Petr Kratochvil

Childhood acute lymphoblastic leukemia (ALL) may be preventable, according to a researcher.

Mel Greaves, PhD, of The Institute of Cancer Research in London, UK, reviewed more than 30 years of research and concluded that ALL develops in 2 steps—genetic mutation before birth and further genetic change after birth triggered by infection.

The evidence suggests that infection early in life is beneficial to prime the immune system, but later infection without earlier priming can trigger ALL.

So priming the immune system in the first year of life could potentially prevent childhood ALL, according to Dr Greaves.

He outlined this theory in Nature Reviews Cancer.

Dr Greaves compiled more than 30 years of research into genetics, cell biology, immunology, epidemiology, and animal modelling of ALL.

The evidence led him to conclude that ALL begins with a genetic mutation that occurs before birth and predisposes a child to leukemia.

The disease is triggered later, in childhood, by exposure to one or more common infections. This primarily occurs in children who experienced “clean” childhoods in their first year of life, without much interaction with other infants or older children.

Dr Greaves challenged previous reports of possible environmental causes for ALL, such as ionizing radiation, electromagnetic waves, or man-made chemicals. He argued that none of these reports are supported by robust evidence.

Instead, he believes there is strong evidence suggesting that infection later in childhood, in the absence of earlier priming, can trigger ALL.

Dr Greaves’ studies of identical twins with ALL showed that 2 mutations were required for ALL development. The first arises in one twin in the womb but produces a population of pre-malignant cells that spread to the other twin via their shared blood supply. The second mutation arises after birth and is different in the twins.

Population studies and animal experiments suggest this second genetic hit can be triggered by infection, probably by a range of common viruses and bacteria. In one unique cluster of cases investigated by Dr Greaves and his colleagues, all cases were infected with flu virus.

In other work, researchers engineered mice with an active leukemia-initiating gene. When the team moved the mice from an ultra-clean, germ-free environment to one that had common microbes, the mice developed ALL.

Population studies have indicated that early exposure to infection in infancy, such as via day care attendance and breast feeding, can protect against ALL, probably by priming the immune system. This suggests childhood ALL may be preventable.

Dr Greaves is now investigating whether earlier exposure to harmless microbes could prevent leukemia in mice.

“I have spent more than 40 years researching childhood leukemia, and, over that time, there has been huge progress in our understanding of its biology and its treatment . . . ,” Dr Greaves said. “But it has always struck me that something big was missing, a gap in our knowledge [that failed to explain] why or how otherwise healthy children develop leukemia and whether this cancer is preventable.”

“This body of research is a culmination of decades of work and at last provides a credible explanation for how the major type of childhood leukemia develops. The research strongly suggests that ALL has a clear biological cause and is triggered by a variety of infections in predisposed children whose immune systems have not been properly primed. It also busts some persistent myths about the causes of leukemia, such as the damaging but unsubstantiated claims that the disease is commonly caused by exposure to electro-magnetic waves or pollution.”

“I hope this research will have a real impact on the lives of children. The most important implication is that most cases of childhood leukemia are likely to be preventable. It might be done in the same way that is currently under consideration for autoimmune disease or allergies, perhaps with simple and safe interventions to expose infants to a variety of common and harmless ‘bugs.’”

Photo by Petr Kratochvil

Childhood acute lymphoblastic leukemia (ALL) may be preventable, according to a researcher.

Mel Greaves, PhD, of The Institute of Cancer Research in London, UK, reviewed more than 30 years of research and concluded that ALL develops in 2 steps—genetic mutation before birth and further genetic change after birth triggered by infection.

The evidence suggests that infection early in life is beneficial to prime the immune system, but later infection without earlier priming can trigger ALL.

So priming the immune system in the first year of life could potentially prevent childhood ALL, according to Dr Greaves.

He outlined this theory in Nature Reviews Cancer.

Dr Greaves compiled more than 30 years of research into genetics, cell biology, immunology, epidemiology, and animal modelling of ALL.

The evidence led him to conclude that ALL begins with a genetic mutation that occurs before birth and predisposes a child to leukemia.

The disease is triggered later, in childhood, by exposure to one or more common infections. This primarily occurs in children who experienced “clean” childhoods in their first year of life, without much interaction with other infants or older children.

Dr Greaves challenged previous reports of possible environmental causes for ALL, such as ionizing radiation, electromagnetic waves, or man-made chemicals. He argued that none of these reports are supported by robust evidence.

Instead, he believes there is strong evidence suggesting that infection later in childhood, in the absence of earlier priming, can trigger ALL.

Dr Greaves’ studies of identical twins with ALL showed that 2 mutations were required for ALL development. The first arises in one twin in the womb but produces a population of pre-malignant cells that spread to the other twin via their shared blood supply. The second mutation arises after birth and is different in the twins.

Population studies and animal experiments suggest this second genetic hit can be triggered by infection, probably by a range of common viruses and bacteria. In one unique cluster of cases investigated by Dr Greaves and his colleagues, all cases were infected with flu virus.

In other work, researchers engineered mice with an active leukemia-initiating gene. When the team moved the mice from an ultra-clean, germ-free environment to one that had common microbes, the mice developed ALL.

Population studies have indicated that early exposure to infection in infancy, such as via day care attendance and breast feeding, can protect against ALL, probably by priming the immune system. This suggests childhood ALL may be preventable.

Dr Greaves is now investigating whether earlier exposure to harmless microbes could prevent leukemia in mice.

“I have spent more than 40 years researching childhood leukemia, and, over that time, there has been huge progress in our understanding of its biology and its treatment . . . ,” Dr Greaves said. “But it has always struck me that something big was missing, a gap in our knowledge [that failed to explain] why or how otherwise healthy children develop leukemia and whether this cancer is preventable.”

“This body of research is a culmination of decades of work and at last provides a credible explanation for how the major type of childhood leukemia develops. The research strongly suggests that ALL has a clear biological cause and is triggered by a variety of infections in predisposed children whose immune systems have not been properly primed. It also busts some persistent myths about the causes of leukemia, such as the damaging but unsubstantiated claims that the disease is commonly caused by exposure to electro-magnetic waves or pollution.”

“I hope this research will have a real impact on the lives of children. The most important implication is that most cases of childhood leukemia are likely to be preventable. It might be done in the same way that is currently under consideration for autoimmune disease or allergies, perhaps with simple and safe interventions to expose infants to a variety of common and harmless ‘bugs.’”

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GLASGOW—Final results from the HAVEN 3 study suggest emicizumab prophylaxis can reduce bleeding in hemophilia A patients without factor VIII inhibitors.

Compared to patients who did not receive prophylaxis, those who received emicizumab prophylaxis had a 96% to 97% reduction in treated bleeds and a 94% to 95% reduction in all bleeds.

An intra-patient comparison showed a 68% reduction in treated bleeds with once-weekly emicizumab, compared to prior factor VIII prophylaxis.

“[Emicizumab] is the first medicine to show superior efficacy to prior factor VIII prophylaxis, the current standard of care therapy, as demonstrated by a statistically significant reduction in treated bleeds in the HAVEN 3 study intra-patient comparison,” said Johnny Mahlangu, MB BCh, of the University of the Witwatersrand in Johannesburg, South Africa.

Dr Mahlangu presented these results at the World Federation of Hemophilia (WFH) 2018 World Congress during the late-breaking abstract session on Monday. HAVEN 3 was sponsored by Hoffmann-La Roche.

Patients and treatment

In this phase 3 trial, researchers evaluated emicizumab in patients with hemophilia A without factor VIII inhibitors. The study included 152 patients who were 12 years of age or older and were previously treated with factor VIII therapy on-demand or as prophylaxis.

Patients previously treated with on-demand factor VIII were randomized in a 2:2:1 fashion to receive:

• Emicizumab prophylaxis at 3 mg/kg/wk for 4 weeks, followed by 1.5 mg/kg/wk until the end of study (arm A, n=36)
• Emicizumab prophylaxis at 3 mg/kg/wk for 4 weeks, followed by 3 mg/kg/2wks for at least 24 weeks (arm B, n=35)
• No prophylaxis, only episodic/on-demand factor VIII treatment (arm C, n=18).

Patients previously treated with factor VIII prophylaxis received emicizumab prophylaxis at 3 mg/kg/wk for 4 weeks, followed by 1.5 mg/kg/wk until the end of study (arm D, n=63).

Episodic treatment of breakthrough bleeds with factor VIII therapy was allowed per protocol.

Emicizumab vs no prophylaxis

The model-based (negative binomial regression model) annualized bleeding rate (ABR) for treated bleeds was 1.5 in arm A, 1.3 in arm B, and 38.2 in arm C. The median ABR for treated bleeds was 0 in arms A and B and 40.4 in arm C.

Compared to patients in arm C, those in arm A had a 96% (P<0.0001) reduction in treated bleeds, and those in arm B had a 97% (P<0.0001) reduction in treated bleeds.

None of the patients in arm C had 0 treated bleeds, compared to 55.6% of patients in arm A and 60% of patients in arm B.

The model-based ABR for all bleeds was 2.5 in arm A, 2.6 in arm B, and 47.6 in arm C.

Patients in arm A had a 95% reduction in all bleeds (P<0.0001), and patients in arm B had a 94% reduction in all bleeds (P<0.0001), compared to patients in arm C.

Fifty percent of patients in arm A had 0 total bleeds, as did 40% of patients in arm B and 0% of patients in arm C.

Intra-patient comparison

The researchers compared previous prophylaxis to once-weekly emicizumab prophylaxis in 48 patients from arm D.

The model-based ABR for treated bleeds was 4.8 with prior prophylaxis and 1.5 with emicizumab. The median ABR for treated bleeds was 1.8 and 0.0, respectively.

Patients had a 68% reduction in treated bleeds with emicizumab (P<0.0001).

With prior prophylaxis, 39.6% of patients had 0 treated bleeds. With emicizumab, 54.2% of patients had 0 treated bleeds.

Safety

There were no serious adverse events (AEs) related to emicizumab, no anti-drug antibodies detected, and none of the patients on emicizumab developed de novo factor VIII inhibitors.

Injection-site reactions occurred in 25.3% of all patients (38/150), 25% of patients in arm A (9/36), 20% in arm B (7/35), 12.5% in arm C (2/16), and 31.7% in arm D (20/63).

An additional patient in arm D (who was included in the total) reported an “injection-site erythema,” not an “injection-site reaction.”

Upper respiratory tract infections occurred in 10.7% of all patients (n=16), 11.1% (n=4) of those in arm A, 11.4% (n=4) of those in arm B, 0% of those in arm C, and 12.7% (n=8) of those in arm D.

Other AEs occurring in at least 5% of patients were arthralgia (19%), nasopharyngitis (12%), headache (11%), and influenza (6%).

One patient in arm B discontinued emicizumab due to multiple mild AEs—insomnia, hair loss, nightmare, lethargy, depressed mood, headache, and pruritus.

Two patients were lost to follow-up—1 in arm A and 1 in arm C.

Photo from Business Wire

GLASGOW—Final results from the HAVEN 3 study suggest emicizumab prophylaxis can reduce bleeding in hemophilia A patients without factor VIII inhibitors.

Compared to patients who did not receive prophylaxis, those who received emicizumab prophylaxis had a 96% to 97% reduction in treated bleeds and a 94% to 95% reduction in all bleeds.

An intra-patient comparison showed a 68% reduction in treated bleeds with once-weekly emicizumab, compared to prior factor VIII prophylaxis.

“[Emicizumab] is the first medicine to show superior efficacy to prior factor VIII prophylaxis, the current standard of care therapy, as demonstrated by a statistically significant reduction in treated bleeds in the HAVEN 3 study intra-patient comparison,” said Johnny Mahlangu, MB BCh, of the University of the Witwatersrand in Johannesburg, South Africa.

Dr Mahlangu presented these results at the World Federation of Hemophilia (WFH) 2018 World Congress during the late-breaking abstract session on Monday. HAVEN 3 was sponsored by Hoffmann-La Roche.

Patients and treatment

In this phase 3 trial, researchers evaluated emicizumab in patients with hemophilia A without factor VIII inhibitors. The study included 152 patients who were 12 years of age or older and were previously treated with factor VIII therapy on-demand or as prophylaxis.

Patients previously treated with on-demand factor VIII were randomized in a 2:2:1 fashion to receive:

• Emicizumab prophylaxis at 3 mg/kg/wk for 4 weeks, followed by 1.5 mg/kg/wk until the end of study (arm A, n=36)
• Emicizumab prophylaxis at 3 mg/kg/wk for 4 weeks, followed by 3 mg/kg/2wks for at least 24 weeks (arm B, n=35)
• No prophylaxis, only episodic/on-demand factor VIII treatment (arm C, n=18).

Patients previously treated with factor VIII prophylaxis received emicizumab prophylaxis at 3 mg/kg/wk for 4 weeks, followed by 1.5 mg/kg/wk until the end of study (arm D, n=63).

Episodic treatment of breakthrough bleeds with factor VIII therapy was allowed per protocol.

Emicizumab vs no prophylaxis

The model-based (negative binomial regression model) annualized bleeding rate (ABR) for treated bleeds was 1.5 in arm A, 1.3 in arm B, and 38.2 in arm C. The median ABR for treated bleeds was 0 in arms A and B and 40.4 in arm C.

Compared to patients in arm C, those in arm A had a 96% (P<0.0001) reduction in treated bleeds, and those in arm B had a 97% (P<0.0001) reduction in treated bleeds.

None of the patients in arm C had 0 treated bleeds, compared to 55.6% of patients in arm A and 60% of patients in arm B.

The model-based ABR for all bleeds was 2.5 in arm A, 2.6 in arm B, and 47.6 in arm C.

Patients in arm A had a 95% reduction in all bleeds (P<0.0001), and patients in arm B had a 94% reduction in all bleeds (P<0.0001), compared to patients in arm C.

Fifty percent of patients in arm A had 0 total bleeds, as did 40% of patients in arm B and 0% of patients in arm C.

Intra-patient comparison

The researchers compared previous prophylaxis to once-weekly emicizumab prophylaxis in 48 patients from arm D.

The model-based ABR for treated bleeds was 4.8 with prior prophylaxis and 1.5 with emicizumab. The median ABR for treated bleeds was 1.8 and 0.0, respectively.

Patients had a 68% reduction in treated bleeds with emicizumab (P<0.0001).

With prior prophylaxis, 39.6% of patients had 0 treated bleeds. With emicizumab, 54.2% of patients had 0 treated bleeds.

Safety

There were no serious adverse events (AEs) related to emicizumab, no anti-drug antibodies detected, and none of the patients on emicizumab developed de novo factor VIII inhibitors.

Injection-site reactions occurred in 25.3% of all patients (38/150), 25% of patients in arm A (9/36), 20% in arm B (7/35), 12.5% in arm C (2/16), and 31.7% in arm D (20/63).

An additional patient in arm D (who was included in the total) reported an “injection-site erythema,” not an “injection-site reaction.”

Upper respiratory tract infections occurred in 10.7% of all patients (n=16), 11.1% (n=4) of those in arm A, 11.4% (n=4) of those in arm B, 0% of those in arm C, and 12.7% (n=8) of those in arm D.

Other AEs occurring in at least 5% of patients were arthralgia (19%), nasopharyngitis (12%), headache (11%), and influenza (6%).

One patient in arm B discontinued emicizumab due to multiple mild AEs—insomnia, hair loss, nightmare, lethargy, depressed mood, headache, and pruritus.

Two patients were lost to follow-up—1 in arm A and 1 in arm C.

Photo from Business Wire

GLASGOW—Final results from the HAVEN 3 study suggest emicizumab prophylaxis can reduce bleeding in hemophilia A patients without factor VIII inhibitors.

Compared to patients who did not receive prophylaxis, those who received emicizumab prophylaxis had a 96% to 97% reduction in treated bleeds and a 94% to 95% reduction in all bleeds.

An intra-patient comparison showed a 68% reduction in treated bleeds with once-weekly emicizumab, compared to prior factor VIII prophylaxis.

“[Emicizumab] is the first medicine to show superior efficacy to prior factor VIII prophylaxis, the current standard of care therapy, as demonstrated by a statistically significant reduction in treated bleeds in the HAVEN 3 study intra-patient comparison,” said Johnny Mahlangu, MB BCh, of the University of the Witwatersrand in Johannesburg, South Africa.

Dr Mahlangu presented these results at the World Federation of Hemophilia (WFH) 2018 World Congress during the late-breaking abstract session on Monday. HAVEN 3 was sponsored by Hoffmann-La Roche.

Patients and treatment

In this phase 3 trial, researchers evaluated emicizumab in patients with hemophilia A without factor VIII inhibitors. The study included 152 patients who were 12 years of age or older and were previously treated with factor VIII therapy on-demand or as prophylaxis.

Patients previously treated with on-demand factor VIII were randomized in a 2:2:1 fashion to receive:

• Emicizumab prophylaxis at 3 mg/kg/wk for 4 weeks, followed by 1.5 mg/kg/wk until the end of study (arm A, n=36)
• Emicizumab prophylaxis at 3 mg/kg/wk for 4 weeks, followed by 3 mg/kg/2wks for at least 24 weeks (arm B, n=35)
• No prophylaxis, only episodic/on-demand factor VIII treatment (arm C, n=18).

Patients previously treated with factor VIII prophylaxis received emicizumab prophylaxis at 3 mg/kg/wk for 4 weeks, followed by 1.5 mg/kg/wk until the end of study (arm D, n=63).

Episodic treatment of breakthrough bleeds with factor VIII therapy was allowed per protocol.

Emicizumab vs no prophylaxis

The model-based (negative binomial regression model) annualized bleeding rate (ABR) for treated bleeds was 1.5 in arm A, 1.3 in arm B, and 38.2 in arm C. The median ABR for treated bleeds was 0 in arms A and B and 40.4 in arm C.

Compared to patients in arm C, those in arm A had a 96% (P<0.0001) reduction in treated bleeds, and those in arm B had a 97% (P<0.0001) reduction in treated bleeds.

None of the patients in arm C had 0 treated bleeds, compared to 55.6% of patients in arm A and 60% of patients in arm B.

The model-based ABR for all bleeds was 2.5 in arm A, 2.6 in arm B, and 47.6 in arm C.

Patients in arm A had a 95% reduction in all bleeds (P<0.0001), and patients in arm B had a 94% reduction in all bleeds (P<0.0001), compared to patients in arm C.

Fifty percent of patients in arm A had 0 total bleeds, as did 40% of patients in arm B and 0% of patients in arm C.

Intra-patient comparison

The researchers compared previous prophylaxis to once-weekly emicizumab prophylaxis in 48 patients from arm D.

The model-based ABR for treated bleeds was 4.8 with prior prophylaxis and 1.5 with emicizumab. The median ABR for treated bleeds was 1.8 and 0.0, respectively.

Patients had a 68% reduction in treated bleeds with emicizumab (P<0.0001).

With prior prophylaxis, 39.6% of patients had 0 treated bleeds. With emicizumab, 54.2% of patients had 0 treated bleeds.

Safety

There were no serious adverse events (AEs) related to emicizumab, no anti-drug antibodies detected, and none of the patients on emicizumab developed de novo factor VIII inhibitors.

Injection-site reactions occurred in 25.3% of all patients (38/150), 25% of patients in arm A (9/36), 20% in arm B (7/35), 12.5% in arm C (2/16), and 31.7% in arm D (20/63).

An additional patient in arm D (who was included in the total) reported an “injection-site erythema,” not an “injection-site reaction.”

Upper respiratory tract infections occurred in 10.7% of all patients (n=16), 11.1% (n=4) of those in arm A, 11.4% (n=4) of those in arm B, 0% of those in arm C, and 12.7% (n=8) of those in arm D.

Other AEs occurring in at least 5% of patients were arthralgia (19%), nasopharyngitis (12%), headache (11%), and influenza (6%).

One patient in arm B discontinued emicizumab due to multiple mild AEs—insomnia, hair loss, nightmare, lethargy, depressed mood, headache, and pruritus.

Two patients were lost to follow-up—1 in arm A and 1 in arm C.