WASHINGTON – The three approaches to distal pancreatectomy – open, laparoscopic, and robotic – are equally safe and oncologically sound methods in properly selected patients, findings from a NSQIP database study show.

“The three approaches have specific indications for use and advantages in well-selected patients; therefore, demonstrating the superiority of one technique over another remains challenging,” said Dimitrios Xourafas, MD, in his presentation at the annual clinical congress of the American College of Surgeons.

[email protected]

On Twitter @Alz_Gal

WASHINGTON – The three approaches to distal pancreatectomy – open, laparoscopic, and robotic – are equally safe and oncologically sound methods in properly selected patients, findings from a NSQIP database study show.

“The three approaches have specific indications for use and advantages in well-selected patients; therefore, demonstrating the superiority of one technique over another remains challenging,” said Dimitrios Xourafas, MD, in his presentation at the annual clinical congress of the American College of Surgeons.

[email protected]

On Twitter @Alz_Gal

WASHINGTON – The three approaches to distal pancreatectomy – open, laparoscopic, and robotic – are equally safe and oncologically sound methods in properly selected patients, findings from a NSQIP database study show.

“The three approaches have specific indications for use and advantages in well-selected patients; therefore, demonstrating the superiority of one technique over another remains challenging,” said Dimitrios Xourafas, MD, in his presentation at the annual clinical congress of the American College of Surgeons.

[email protected]

On Twitter @Alz_Gal

Adding low-dose metronomic chemotherapy (oral cyclophosphamide and methotrexate) to standard methotrexate, adriamycin, and platinum (MAP) maintenance treatment did not extend event-free survival in adolescents and young adults with high-grade, resectable osteosarcoma of the extremities, according to investigators.

“In pediatric tumors such as localized osteosarcomas, in situ tumor angiogenesis and levels of circulating angiogenic factors correlate with metastatic disease and a poor prognosis,” noted Andreza A. Senerchia, MD, of the Institute of Pediatric Oncology/Support Group for Adolescents and Children With Cancer, Federal University of Sao Paulo (Brazil), and her associates.

Since metronomic chemotherapy can prevent tumor angiogenesis and is a readily available, low-cost treatment with low toxicity, it could serve as a useful add-on to established MAP maintenance therapy in this patient population, they speculated.

The investigators assessed this approach in a prospective clinical trial involving 296 patients aged younger than 30 (mean age, 14 years; range, 0-29 years) who were treated at 27 medical centers in Brazil, Argentina, and Uruguay. All the study participants had high-grade but nonmetastatic operable osteosarcomas of the extremities, and all underwent preoperative chemotherapy followed by surgical resection, with limb salvage whenever possible.

A total of 139 patients were then randomly assigned to receive MAP plus metronomic chemotherapy (intervention group) and 157 to receive MAP alone (control group). However, 35% of the intervention group never started metronomic chemotherapy for a variety of reasons, and another 10% stopped the treatment very early.

At 5 years, cumulative event-free survival was 61% with MAP plus metronomic chemotherapy and 64% with MAP alone, a nonsignificant difference. When the analysis was restricted to only the patients in the intervention group who actually received metronomic chemotherapy, there still was no evidence that the add-on treatment made any difference in event-free survival. Similarly, mean overall survival was not significantly different between the two study groups, at 76% and 73%, respectively, Dr. Senerchia and her associates wrote (Cancer 2016 Nov 7. doi: 10.1002/cncr.30411).

There were 27 deaths (19%) in the intervention group, 81% of which were due to disease progression and 11% of which were due to treatment-related toxicity. Similarly, there were 24 deaths (15%) in the control group, of which 83% were due to disease progression and 17% to treatment-related toxicity.

These findings “do not support the routine use of cyclophosphamide and methotrexate as metronomic agents after standard chemotherapy for nonmetastatic osteosarcoma. However, our results should not preclude further investigation into the potential of maintenance for patients with osteosarcoma ... The combination tested here may not be optimal. In addition, adding a targeted-like effect through drug repositioning could allow more potent treatment with the addition of, for instance, valproic acid or beta-blockers,” the investigators said.

Adding low-dose metronomic chemotherapy (oral cyclophosphamide and methotrexate) to standard methotrexate, adriamycin, and platinum (MAP) maintenance treatment did not extend event-free survival in adolescents and young adults with high-grade, resectable osteosarcoma of the extremities, according to investigators.

“In pediatric tumors such as localized osteosarcomas, in situ tumor angiogenesis and levels of circulating angiogenic factors correlate with metastatic disease and a poor prognosis,” noted Andreza A. Senerchia, MD, of the Institute of Pediatric Oncology/Support Group for Adolescents and Children With Cancer, Federal University of Sao Paulo (Brazil), and her associates.

Since metronomic chemotherapy can prevent tumor angiogenesis and is a readily available, low-cost treatment with low toxicity, it could serve as a useful add-on to established MAP maintenance therapy in this patient population, they speculated.

The investigators assessed this approach in a prospective clinical trial involving 296 patients aged younger than 30 (mean age, 14 years; range, 0-29 years) who were treated at 27 medical centers in Brazil, Argentina, and Uruguay. All the study participants had high-grade but nonmetastatic operable osteosarcomas of the extremities, and all underwent preoperative chemotherapy followed by surgical resection, with limb salvage whenever possible.

A total of 139 patients were then randomly assigned to receive MAP plus metronomic chemotherapy (intervention group) and 157 to receive MAP alone (control group). However, 35% of the intervention group never started metronomic chemotherapy for a variety of reasons, and another 10% stopped the treatment very early.

At 5 years, cumulative event-free survival was 61% with MAP plus metronomic chemotherapy and 64% with MAP alone, a nonsignificant difference. When the analysis was restricted to only the patients in the intervention group who actually received metronomic chemotherapy, there still was no evidence that the add-on treatment made any difference in event-free survival. Similarly, mean overall survival was not significantly different between the two study groups, at 76% and 73%, respectively, Dr. Senerchia and her associates wrote (Cancer 2016 Nov 7. doi: 10.1002/cncr.30411).

There were 27 deaths (19%) in the intervention group, 81% of which were due to disease progression and 11% of which were due to treatment-related toxicity. Similarly, there were 24 deaths (15%) in the control group, of which 83% were due to disease progression and 17% to treatment-related toxicity.

These findings “do not support the routine use of cyclophosphamide and methotrexate as metronomic agents after standard chemotherapy for nonmetastatic osteosarcoma. However, our results should not preclude further investigation into the potential of maintenance for patients with osteosarcoma ... The combination tested here may not be optimal. In addition, adding a targeted-like effect through drug repositioning could allow more potent treatment with the addition of, for instance, valproic acid or beta-blockers,” the investigators said.

Adding low-dose metronomic chemotherapy (oral cyclophosphamide and methotrexate) to standard methotrexate, adriamycin, and platinum (MAP) maintenance treatment did not extend event-free survival in adolescents and young adults with high-grade, resectable osteosarcoma of the extremities, according to investigators.

“In pediatric tumors such as localized osteosarcomas, in situ tumor angiogenesis and levels of circulating angiogenic factors correlate with metastatic disease and a poor prognosis,” noted Andreza A. Senerchia, MD, of the Institute of Pediatric Oncology/Support Group for Adolescents and Children With Cancer, Federal University of Sao Paulo (Brazil), and her associates.

Since metronomic chemotherapy can prevent tumor angiogenesis and is a readily available, low-cost treatment with low toxicity, it could serve as a useful add-on to established MAP maintenance therapy in this patient population, they speculated.

The investigators assessed this approach in a prospective clinical trial involving 296 patients aged younger than 30 (mean age, 14 years; range, 0-29 years) who were treated at 27 medical centers in Brazil, Argentina, and Uruguay. All the study participants had high-grade but nonmetastatic operable osteosarcomas of the extremities, and all underwent preoperative chemotherapy followed by surgical resection, with limb salvage whenever possible.

A total of 139 patients were then randomly assigned to receive MAP plus metronomic chemotherapy (intervention group) and 157 to receive MAP alone (control group). However, 35% of the intervention group never started metronomic chemotherapy for a variety of reasons, and another 10% stopped the treatment very early.

At 5 years, cumulative event-free survival was 61% with MAP plus metronomic chemotherapy and 64% with MAP alone, a nonsignificant difference. When the analysis was restricted to only the patients in the intervention group who actually received metronomic chemotherapy, there still was no evidence that the add-on treatment made any difference in event-free survival. Similarly, mean overall survival was not significantly different between the two study groups, at 76% and 73%, respectively, Dr. Senerchia and her associates wrote (Cancer 2016 Nov 7. doi: 10.1002/cncr.30411).

There were 27 deaths (19%) in the intervention group, 81% of which were due to disease progression and 11% of which were due to treatment-related toxicity. Similarly, there were 24 deaths (15%) in the control group, of which 83% were due to disease progression and 17% to treatment-related toxicity.

These findings “do not support the routine use of cyclophosphamide and methotrexate as metronomic agents after standard chemotherapy for nonmetastatic osteosarcoma. However, our results should not preclude further investigation into the potential of maintenance for patients with osteosarcoma ... The combination tested here may not be optimal. In addition, adding a targeted-like effect through drug repositioning could allow more potent treatment with the addition of, for instance, valproic acid or beta-blockers,” the investigators said.

Patients with multiple sclerosis (MS) treated with interferon beta or glatiramer acetate who are age 45 or older and have no evidence of clinical disease activity for more than four years have a high likelihood of remaining relapse-free after treatment cessation, according to research published online ahead of print October 20 in Multiple Sclerosis.

The study conducted by Gabriel Bsteh, MD, a neurologist at the Medical University of Innsbruck in Austria, and his colleagues provides evidence in the absence of randomized trials that may help guide discussions with patients—particularly those who have not had a relapse recently—when they ask whether they could discontinue disease-modifying treatment (DMT).

The current study involved 221 patients with relapsing-remitting MS who discontinued DMT after more than a year and had documented follow-up at two years. After a median follow-up period of 3.8 years, 98 patients (44.3%) had a relapse. Confirmed disability progression occurred in 46 patients (20.8%), and 15 patients (6.8%) converted to secondary progressive MS.

The independent predictors of absence of relapse after discontinuing treatment included age 45 or older at discontinuation (hazard ratio [HR], 0.47), absence of relapses for four or more years on DMT before discontinuation (HR, 0.29), and absence of contrast-enhancing lesions (HR, 0.46). A combination of age 45 or older and absence of relapses after four or more years on DMT was associated with a very low risk of having a relapse after discontinuation, regardless of MRI results (HR, 0.06).

Higher Expanded Disability Status Scale (EDSS) scores at discontinuation, age older than 45 at discontinuation, and longer disease duration were the only significant independent predictors of disability progression after discontinuation, irrespective of the presence of relapses on DMT or gadolinium-enhancing lesions.

“This [result] underlines the concept of a window of opportunity in the treatment of MS, in the sense that once a certain extent of disability is reached, the impact of relapses, and therefore the effect of anti-inflammatory treatment, is drastically reduced,” said the investigators.

The study is limited by its observational, retrospective nature, but the results emphasized the importance of regular, thorough clinical evaluation of patients with relapsing-remitting MS, said the researchers. “While MRI may have a role in aiding decision making regarding DMT discontinuation, our data clearly show that demographic factors and clinical monitoring go a long way in risk stratification,” they said.

The authors received no financial support for the study, but several of the authors reported participating in meetings or receiving honoraria from various pharmaceutical companies.

—Nicola Garrett

Suggested Reading

Bsteh G, Feige J, Ehling R, et al. Discontinuation of disease-modifying therapies in multiple sclerosis - Clinical outcome and prognostic factors. Mult Scler. 2016 Oct 20 [Epub ahead of print].

Patients with multiple sclerosis (MS) treated with interferon beta or glatiramer acetate who are age 45 or older and have no evidence of clinical disease activity for more than four years have a high likelihood of remaining relapse-free after treatment cessation, according to research published online ahead of print October 20 in Multiple Sclerosis.

The study conducted by Gabriel Bsteh, MD, a neurologist at the Medical University of Innsbruck in Austria, and his colleagues provides evidence in the absence of randomized trials that may help guide discussions with patients—particularly those who have not had a relapse recently—when they ask whether they could discontinue disease-modifying treatment (DMT).

The current study involved 221 patients with relapsing-remitting MS who discontinued DMT after more than a year and had documented follow-up at two years. After a median follow-up period of 3.8 years, 98 patients (44.3%) had a relapse. Confirmed disability progression occurred in 46 patients (20.8%), and 15 patients (6.8%) converted to secondary progressive MS.

The independent predictors of absence of relapse after discontinuing treatment included age 45 or older at discontinuation (hazard ratio [HR], 0.47), absence of relapses for four or more years on DMT before discontinuation (HR, 0.29), and absence of contrast-enhancing lesions (HR, 0.46). A combination of age 45 or older and absence of relapses after four or more years on DMT was associated with a very low risk of having a relapse after discontinuation, regardless of MRI results (HR, 0.06).

Higher Expanded Disability Status Scale (EDSS) scores at discontinuation, age older than 45 at discontinuation, and longer disease duration were the only significant independent predictors of disability progression after discontinuation, irrespective of the presence of relapses on DMT or gadolinium-enhancing lesions.

“This [result] underlines the concept of a window of opportunity in the treatment of MS, in the sense that once a certain extent of disability is reached, the impact of relapses, and therefore the effect of anti-inflammatory treatment, is drastically reduced,” said the investigators.

The study is limited by its observational, retrospective nature, but the results emphasized the importance of regular, thorough clinical evaluation of patients with relapsing-remitting MS, said the researchers. “While MRI may have a role in aiding decision making regarding DMT discontinuation, our data clearly show that demographic factors and clinical monitoring go a long way in risk stratification,” they said.

The authors received no financial support for the study, but several of the authors reported participating in meetings or receiving honoraria from various pharmaceutical companies.

—Nicola Garrett

Suggested Reading

Bsteh G, Feige J, Ehling R, et al. Discontinuation of disease-modifying therapies in multiple sclerosis - Clinical outcome and prognostic factors. Mult Scler. 2016 Oct 20 [Epub ahead of print].

Patients with multiple sclerosis (MS) treated with interferon beta or glatiramer acetate who are age 45 or older and have no evidence of clinical disease activity for more than four years have a high likelihood of remaining relapse-free after treatment cessation, according to research published online ahead of print October 20 in Multiple Sclerosis.

The study conducted by Gabriel Bsteh, MD, a neurologist at the Medical University of Innsbruck in Austria, and his colleagues provides evidence in the absence of randomized trials that may help guide discussions with patients—particularly those who have not had a relapse recently—when they ask whether they could discontinue disease-modifying treatment (DMT).

The current study involved 221 patients with relapsing-remitting MS who discontinued DMT after more than a year and had documented follow-up at two years. After a median follow-up period of 3.8 years, 98 patients (44.3%) had a relapse. Confirmed disability progression occurred in 46 patients (20.8%), and 15 patients (6.8%) converted to secondary progressive MS.

The independent predictors of absence of relapse after discontinuing treatment included age 45 or older at discontinuation (hazard ratio [HR], 0.47), absence of relapses for four or more years on DMT before discontinuation (HR, 0.29), and absence of contrast-enhancing lesions (HR, 0.46). A combination of age 45 or older and absence of relapses after four or more years on DMT was associated with a very low risk of having a relapse after discontinuation, regardless of MRI results (HR, 0.06).

Higher Expanded Disability Status Scale (EDSS) scores at discontinuation, age older than 45 at discontinuation, and longer disease duration were the only significant independent predictors of disability progression after discontinuation, irrespective of the presence of relapses on DMT or gadolinium-enhancing lesions.

“This [result] underlines the concept of a window of opportunity in the treatment of MS, in the sense that once a certain extent of disability is reached, the impact of relapses, and therefore the effect of anti-inflammatory treatment, is drastically reduced,” said the investigators.

The study is limited by its observational, retrospective nature, but the results emphasized the importance of regular, thorough clinical evaluation of patients with relapsing-remitting MS, said the researchers. “While MRI may have a role in aiding decision making regarding DMT discontinuation, our data clearly show that demographic factors and clinical monitoring go a long way in risk stratification,” they said.

The authors received no financial support for the study, but several of the authors reported participating in meetings or receiving honoraria from various pharmaceutical companies.

—Nicola Garrett

Suggested Reading

Bsteh G, Feige J, Ehling R, et al. Discontinuation of disease-modifying therapies in multiple sclerosis - Clinical outcome and prognostic factors. Mult Scler. 2016 Oct 20 [Epub ahead of print].

BALTIMORE—Lack of evidence for disease-modifying therapies (DMTs) in children presents a significant challenge in pediatric multiple sclerosis (MS). Forty percent of children with pediatric MS discontinue DMTs for inefficacy or side effects, according to an overview presented at the 141st Annual Meeting of the American Neurological Association.

“We need to keep working on clinical trials in kids and not shy away from investigating the stronger agents,” said Jennifer Graves, MD, PhD, Assistant Professor of Neurology at the University of California, San Francisco School of Medicine. Future studies should incorporate comprehensive outcomes that include measures of cognition, brain volume, and retinal integrity, she added. National and international collaborations currently under way may help achieve sample sizes that could provide conclusive evidence.

Pediatric MS Has Distinctive Features

Nearly 5% of patients with MS have pediatric onset of symptoms; 20%–30% of these patients have onset before age 11. The mean age of onset for pediatric MS is 13. In several ways, the course of MS is different in children than in adults. Children typically have higher relapse rates than adults and are less likely to develop primary or secondary progressive MS in their childhood. Neurologists are concerned, however, about the possibility that these children will develop secondary progression in their 20s or 30s.

“A lot of these kids drop off the map between seeing us in pediatric centers and moving to adult MS centers. Often, these are the people that show up at [age] 30 with significant disability and high lesion burdens because they dropped out of care when they left their parents’ homes,” said Dr. Graves.

Unlike in adult MS, the gender ratio is approximately equal in prepubertal pediatric MS. There is a near 1:1 ratio of females to males in children who present before age 11, but the ratio increases over time to 2:1 or 3:1 in adolescents and adults. Postpubertal and adult patients with MS have similar features, but prepubertal patients have features distinct from those of adult MS. For example, prepubertal patients have a lower prevalence of oligoclonal bands. Their MRI lesions tend to be larger and less distinct and sometimes resolve completely. In addition, children tend to have better motor, visual, and cerebellar recovery from relapses than adults.

A study published in the July issue of Pediatrics described the demographic and clinical characteristics of patients with pediatric MS in the United States. Of the 490 children and adolescents enrolled, 28% developed symptoms before age 12. Sixty-seven percent of participants identified as white, 21% as African-American, and 70% as non-Hispanic. Thirty-nine percent of patients had one or two foreign-born parents. Approximately 31% of patients had a prodrome (often infectious), which occurred mostly in children under age 12. Researchers observed a difference in the type of relapses in children under 12, compared with adolescents and adults. Young children tended to have more cerebellar symptoms, encephalopathy, and greater lesion burden in the posterior fossa.

Perinatal Risk Factors in Pediatric MS

In work from the US Network of Pediatric MS Centers presented at the 68th Annual Meeting of the American Academy of Neurology, Cesarean section (C-section) was associated with a 60% reduced odds of having pediatric-onset MS. The association remained statistically significant after the researchers adjusted for socioeconomic status and other maternal variables such as BMI, age, gestational diabetes, pre-eclampsia, and birth complications. While the mechanism of the association remains unknown, it is of interest in light of the new insights regarding the microbiome and MS. Children born by C-section typically have different gut flora for at least the first year of life, said Dr. Graves. When the data were adjusted for C-section result, maternal illness was independently associated with a twofold increase in the risk of pediatric MS.

The mechanism of maternal illness effects on MS risk have yet to be elucidated, but in animal models of MS, exposure during pregnancy to certain bacterial antigens can result in a pro­inflammatory Th17 phenotype and may cause long-term effects in offspring. An exploratory analysis in this perinatal risk factor study revealed that variables associated with agricultural work by the parent and home use of pesticides and insecticides were associated with a twofold increased risk of pediatric MS.

Diet, BMI, and Exercise

Diets high in salt have been associated with high relapse rate in adults. This association has not been found in pediatric MS, however. High fat intake is associated with high relapse rate in children with MS, according to research presented at the 32nd Congress of the European Committee for Treatment and Research in MS. Diets rich in fruits and vegetables are linked to a lower relapse rate, even after adjusting for fat intake.

In addition, data indicate that BMI is directly proportional to the risk for pediatric MS. Vigorous activity, however, is associated with decreased risk of pediatric MS, a decreased number of T2 lesions, and a decreased relapse rate, according to a Canadian study.

Role of Risk Genes and Genetic Ancestry in Pediatric MS

Genetics may play a key role in the development of early-onset pediatric MS. Researchers are analyzing data in the United States for people of multiple genetic ancestries. Of 110 nonhuman leukocyte antigen (HLA) risk variants for adult MS, 36 may increase the risk of pediatric MS, either at the level of single-nucleotide polymorphisms (SNPs) or as an aggregate genetic risk factor. The effect size of each SNP is greater in children than in adults; each SNP may increase the risk of MS by twofold or more.

Imaging Efforts

Imaging could improve understanding of pediatric MS. National and international efforts to standardize protocols for 3-T imaging, volumetric scans, and diffusion tensor imaging (DTI) are under way. DTI already has revealed abnormal fractional anisotropy in pediatric MS, and this abnormality is associated with cognitive difficulty. MRI and optical coherence tomography (OCT) help to distinguish between MS, neuromyelitis optica (NMO), and acute disseminated encephalomyelitis (ADEM).

OCT imaging in children indicates similar levels of neuronal and axonal injury as in adults, despite better visual recovery in children. In a study published in the Multiple Sclerosis Journal, boys with pediatric MS were found to have greater axonal loss than girls with pediatric MS.

Testing DMTs’ Efficacy

Several studies of DMTs in pediatric MS are under way. PARADIGMS is an ongoing, 24-month, double-blind, double-randomized trial investigating the effect of fingolimod on relapse rate in pediatric MS. The control group is receiving interferons, and 3% of patients to date are prepubertal. Enrollment remains open, and the investigators hope to recruit more prepubertal patients. Studies were also launched for the two other oral disease-modifying agents, teriflunomide and dimethyl fumarate.

Observational registries are studying the safety and clinical experience with disease modifying agents in children. Investigators recently published data for 100 children in an Italian registry of patients with MS treated with natalizumab. The treatment decreased relapse rate to 0.1. Approximately 28% of the population had no evidence of disease activity. The drug appeared to be well tolerated in children and to be efficacious.

—Erica Tricarico

Suggested Reading

Belman AL, Krupp LB, Olsen CS, et al. Characteristics of children and adolescents with multiple sclerosis. Pediatrics. 2016;138(1).

BALTIMORE—Lack of evidence for disease-modifying therapies (DMTs) in children presents a significant challenge in pediatric multiple sclerosis (MS). Forty percent of children with pediatric MS discontinue DMTs for inefficacy or side effects, according to an overview presented at the 141st Annual Meeting of the American Neurological Association.

“We need to keep working on clinical trials in kids and not shy away from investigating the stronger agents,” said Jennifer Graves, MD, PhD, Assistant Professor of Neurology at the University of California, San Francisco School of Medicine. Future studies should incorporate comprehensive outcomes that include measures of cognition, brain volume, and retinal integrity, she added. National and international collaborations currently under way may help achieve sample sizes that could provide conclusive evidence.

Pediatric MS Has Distinctive Features

Nearly 5% of patients with MS have pediatric onset of symptoms; 20%–30% of these patients have onset before age 11. The mean age of onset for pediatric MS is 13. In several ways, the course of MS is different in children than in adults. Children typically have higher relapse rates than adults and are less likely to develop primary or secondary progressive MS in their childhood. Neurologists are concerned, however, about the possibility that these children will develop secondary progression in their 20s or 30s.

“A lot of these kids drop off the map between seeing us in pediatric centers and moving to adult MS centers. Often, these are the people that show up at [age] 30 with significant disability and high lesion burdens because they dropped out of care when they left their parents’ homes,” said Dr. Graves.

Unlike in adult MS, the gender ratio is approximately equal in prepubertal pediatric MS. There is a near 1:1 ratio of females to males in children who present before age 11, but the ratio increases over time to 2:1 or 3:1 in adolescents and adults. Postpubertal and adult patients with MS have similar features, but prepubertal patients have features distinct from those of adult MS. For example, prepubertal patients have a lower prevalence of oligoclonal bands. Their MRI lesions tend to be larger and less distinct and sometimes resolve completely. In addition, children tend to have better motor, visual, and cerebellar recovery from relapses than adults.

A study published in the July issue of Pediatrics described the demographic and clinical characteristics of patients with pediatric MS in the United States. Of the 490 children and adolescents enrolled, 28% developed symptoms before age 12. Sixty-seven percent of participants identified as white, 21% as African-American, and 70% as non-Hispanic. Thirty-nine percent of patients had one or two foreign-born parents. Approximately 31% of patients had a prodrome (often infectious), which occurred mostly in children under age 12. Researchers observed a difference in the type of relapses in children under 12, compared with adolescents and adults. Young children tended to have more cerebellar symptoms, encephalopathy, and greater lesion burden in the posterior fossa.

Perinatal Risk Factors in Pediatric MS

In work from the US Network of Pediatric MS Centers presented at the 68th Annual Meeting of the American Academy of Neurology, Cesarean section (C-section) was associated with a 60% reduced odds of having pediatric-onset MS. The association remained statistically significant after the researchers adjusted for socioeconomic status and other maternal variables such as BMI, age, gestational diabetes, pre-eclampsia, and birth complications. While the mechanism of the association remains unknown, it is of interest in light of the new insights regarding the microbiome and MS. Children born by C-section typically have different gut flora for at least the first year of life, said Dr. Graves. When the data were adjusted for C-section result, maternal illness was independently associated with a twofold increase in the risk of pediatric MS.

The mechanism of maternal illness effects on MS risk have yet to be elucidated, but in animal models of MS, exposure during pregnancy to certain bacterial antigens can result in a pro­inflammatory Th17 phenotype and may cause long-term effects in offspring. An exploratory analysis in this perinatal risk factor study revealed that variables associated with agricultural work by the parent and home use of pesticides and insecticides were associated with a twofold increased risk of pediatric MS.

Diet, BMI, and Exercise

Diets high in salt have been associated with high relapse rate in adults. This association has not been found in pediatric MS, however. High fat intake is associated with high relapse rate in children with MS, according to research presented at the 32nd Congress of the European Committee for Treatment and Research in MS. Diets rich in fruits and vegetables are linked to a lower relapse rate, even after adjusting for fat intake.

In addition, data indicate that BMI is directly proportional to the risk for pediatric MS. Vigorous activity, however, is associated with decreased risk of pediatric MS, a decreased number of T2 lesions, and a decreased relapse rate, according to a Canadian study.

Role of Risk Genes and Genetic Ancestry in Pediatric MS

Genetics may play a key role in the development of early-onset pediatric MS. Researchers are analyzing data in the United States for people of multiple genetic ancestries. Of 110 nonhuman leukocyte antigen (HLA) risk variants for adult MS, 36 may increase the risk of pediatric MS, either at the level of single-nucleotide polymorphisms (SNPs) or as an aggregate genetic risk factor. The effect size of each SNP is greater in children than in adults; each SNP may increase the risk of MS by twofold or more.

Imaging Efforts

Imaging could improve understanding of pediatric MS. National and international efforts to standardize protocols for 3-T imaging, volumetric scans, and diffusion tensor imaging (DTI) are under way. DTI already has revealed abnormal fractional anisotropy in pediatric MS, and this abnormality is associated with cognitive difficulty. MRI and optical coherence tomography (OCT) help to distinguish between MS, neuromyelitis optica (NMO), and acute disseminated encephalomyelitis (ADEM).

OCT imaging in children indicates similar levels of neuronal and axonal injury as in adults, despite better visual recovery in children. In a study published in the Multiple Sclerosis Journal, boys with pediatric MS were found to have greater axonal loss than girls with pediatric MS.

Testing DMTs’ Efficacy

Several studies of DMTs in pediatric MS are under way. PARADIGMS is an ongoing, 24-month, double-blind, double-randomized trial investigating the effect of fingolimod on relapse rate in pediatric MS. The control group is receiving interferons, and 3% of patients to date are prepubertal. Enrollment remains open, and the investigators hope to recruit more prepubertal patients. Studies were also launched for the two other oral disease-modifying agents, teriflunomide and dimethyl fumarate.

Observational registries are studying the safety and clinical experience with disease modifying agents in children. Investigators recently published data for 100 children in an Italian registry of patients with MS treated with natalizumab. The treatment decreased relapse rate to 0.1. Approximately 28% of the population had no evidence of disease activity. The drug appeared to be well tolerated in children and to be efficacious.

—Erica Tricarico

Suggested Reading

Belman AL, Krupp LB, Olsen CS, et al. Characteristics of children and adolescents with multiple sclerosis. Pediatrics. 2016;138(1).

BALTIMORE—Lack of evidence for disease-modifying therapies (DMTs) in children presents a significant challenge in pediatric multiple sclerosis (MS). Forty percent of children with pediatric MS discontinue DMTs for inefficacy or side effects, according to an overview presented at the 141st Annual Meeting of the American Neurological Association.

“We need to keep working on clinical trials in kids and not shy away from investigating the stronger agents,” said Jennifer Graves, MD, PhD, Assistant Professor of Neurology at the University of California, San Francisco School of Medicine. Future studies should incorporate comprehensive outcomes that include measures of cognition, brain volume, and retinal integrity, she added. National and international collaborations currently under way may help achieve sample sizes that could provide conclusive evidence.

Pediatric MS Has Distinctive Features

Nearly 5% of patients with MS have pediatric onset of symptoms; 20%–30% of these patients have onset before age 11. The mean age of onset for pediatric MS is 13. In several ways, the course of MS is different in children than in adults. Children typically have higher relapse rates than adults and are less likely to develop primary or secondary progressive MS in their childhood. Neurologists are concerned, however, about the possibility that these children will develop secondary progression in their 20s or 30s.

“A lot of these kids drop off the map between seeing us in pediatric centers and moving to adult MS centers. Often, these are the people that show up at [age] 30 with significant disability and high lesion burdens because they dropped out of care when they left their parents’ homes,” said Dr. Graves.

Unlike in adult MS, the gender ratio is approximately equal in prepubertal pediatric MS. There is a near 1:1 ratio of females to males in children who present before age 11, but the ratio increases over time to 2:1 or 3:1 in adolescents and adults. Postpubertal and adult patients with MS have similar features, but prepubertal patients have features distinct from those of adult MS. For example, prepubertal patients have a lower prevalence of oligoclonal bands. Their MRI lesions tend to be larger and less distinct and sometimes resolve completely. In addition, children tend to have better motor, visual, and cerebellar recovery from relapses than adults.

A study published in the July issue of Pediatrics described the demographic and clinical characteristics of patients with pediatric MS in the United States. Of the 490 children and adolescents enrolled, 28% developed symptoms before age 12. Sixty-seven percent of participants identified as white, 21% as African-American, and 70% as non-Hispanic. Thirty-nine percent of patients had one or two foreign-born parents. Approximately 31% of patients had a prodrome (often infectious), which occurred mostly in children under age 12. Researchers observed a difference in the type of relapses in children under 12, compared with adolescents and adults. Young children tended to have more cerebellar symptoms, encephalopathy, and greater lesion burden in the posterior fossa.

Perinatal Risk Factors in Pediatric MS

In work from the US Network of Pediatric MS Centers presented at the 68th Annual Meeting of the American Academy of Neurology, Cesarean section (C-section) was associated with a 60% reduced odds of having pediatric-onset MS. The association remained statistically significant after the researchers adjusted for socioeconomic status and other maternal variables such as BMI, age, gestational diabetes, pre-eclampsia, and birth complications. While the mechanism of the association remains unknown, it is of interest in light of the new insights regarding the microbiome and MS. Children born by C-section typically have different gut flora for at least the first year of life, said Dr. Graves. When the data were adjusted for C-section result, maternal illness was independently associated with a twofold increase in the risk of pediatric MS.

The mechanism of maternal illness effects on MS risk have yet to be elucidated, but in animal models of MS, exposure during pregnancy to certain bacterial antigens can result in a pro­inflammatory Th17 phenotype and may cause long-term effects in offspring. An exploratory analysis in this perinatal risk factor study revealed that variables associated with agricultural work by the parent and home use of pesticides and insecticides were associated with a twofold increased risk of pediatric MS.

Diet, BMI, and Exercise

Diets high in salt have been associated with high relapse rate in adults. This association has not been found in pediatric MS, however. High fat intake is associated with high relapse rate in children with MS, according to research presented at the 32nd Congress of the European Committee for Treatment and Research in MS. Diets rich in fruits and vegetables are linked to a lower relapse rate, even after adjusting for fat intake.

In addition, data indicate that BMI is directly proportional to the risk for pediatric MS. Vigorous activity, however, is associated with decreased risk of pediatric MS, a decreased number of T2 lesions, and a decreased relapse rate, according to a Canadian study.

Role of Risk Genes and Genetic Ancestry in Pediatric MS

Genetics may play a key role in the development of early-onset pediatric MS. Researchers are analyzing data in the United States for people of multiple genetic ancestries. Of 110 nonhuman leukocyte antigen (HLA) risk variants for adult MS, 36 may increase the risk of pediatric MS, either at the level of single-nucleotide polymorphisms (SNPs) or as an aggregate genetic risk factor. The effect size of each SNP is greater in children than in adults; each SNP may increase the risk of MS by twofold or more.

Imaging Efforts

Imaging could improve understanding of pediatric MS. National and international efforts to standardize protocols for 3-T imaging, volumetric scans, and diffusion tensor imaging (DTI) are under way. DTI already has revealed abnormal fractional anisotropy in pediatric MS, and this abnormality is associated with cognitive difficulty. MRI and optical coherence tomography (OCT) help to distinguish between MS, neuromyelitis optica (NMO), and acute disseminated encephalomyelitis (ADEM).

OCT imaging in children indicates similar levels of neuronal and axonal injury as in adults, despite better visual recovery in children. In a study published in the Multiple Sclerosis Journal, boys with pediatric MS were found to have greater axonal loss than girls with pediatric MS.

Testing DMTs’ Efficacy

Several studies of DMTs in pediatric MS are under way. PARADIGMS is an ongoing, 24-month, double-blind, double-randomized trial investigating the effect of fingolimod on relapse rate in pediatric MS. The control group is receiving interferons, and 3% of patients to date are prepubertal. Enrollment remains open, and the investigators hope to recruit more prepubertal patients. Studies were also launched for the two other oral disease-modifying agents, teriflunomide and dimethyl fumarate.

Observational registries are studying the safety and clinical experience with disease modifying agents in children. Investigators recently published data for 100 children in an Italian registry of patients with MS treated with natalizumab. The treatment decreased relapse rate to 0.1. Approximately 28% of the population had no evidence of disease activity. The drug appeared to be well tolerated in children and to be efficacious.

—Erica Tricarico

Suggested Reading

Belman AL, Krupp LB, Olsen CS, et al. Characteristics of children and adolescents with multiple sclerosis. Pediatrics. 2016;138(1).

WASHINGTON – Myeloablative autologous hematopoietic stem cell transplantation was superior to monthly intravenous cyclophosphamide in patients with severe scleroderma with internal organ involvement in the randomized, multicenter Scleroderma: Cyclophosphamide or Transplantation (SCOT) trial.

At both 54 and 48 months, a comparison of global rank composite scores favored myeloablation followed by CD34+-selected autologous hematopoietic stem cell transplantation (HSCT) over 12 monthly pulses of 750 mg/m² cyclophosphamide in the intention-to-treat population of 36 and 39 subjects with diffuse cutaneous systemic sclerosis and high-risk lung and/or renal involvement who were randomized to the groups, respectively (P = .013 at 54 months and P = .008 at 48 months). In subjects who actually underwent HSCT or received at least nine cyclophosphamide doses, the effect was even stronger (P = .004 at 54 months and P = .003 at 48 months), Keith M. Sullivan, MD, reported at the annual meeting of the American College of Rheumatology.

The global rank composite scores were derived based on a hierarchy of outcomes including – in rank order – death, event-free survival, forced vital capacity, scleroderma health assessment questionnaire score, and modified Rodnan skin score (mRSS); each patient was compared, based on the hierarchy, with every other patient in the study.

HSCT was superior overall and within each of the components of the score, Dr. Sullivan said.

The findings were supported by secondary analyses showing that at 54 months, event-free survival was 79% in the HSCT group vs. 50% in the cyclophosphamide group, and overall survival was 91% vs. 77% in the groups, respectively; the differences between the groups were statistically significant, said Dr. Sullivan of Duke University, Durham, N.C.

“In advanced scleroderma, that is a remarkable finding,” he said of the nearly 30-point difference in event-free survival rates between the groups.

Further, disease-modifying antirheumatic drugs were initiated by 54 months in 9% of the HSCT recipients vs. 44% of those in the cyclophosphamide group, he noted.

The rate of serious adverse events was similar in the two groups, although grade 3 or greater adverse events, including treatment-related cytopenias, were more common in the HSCT group, as was herpes zoster. Remarkably, most serious adverse events and adverse events occurred in the first 14 months, Dr. Sullivan noted.

Treatment-related mortality at 54 months was 3% in the HSCT group, and 0% in the cyclophosphamide group, he said.

Study subjects were adults aged 18-69 years with mean baseline modified Rodnan skin score of 30, mean baseline forced vital capacity of 74%, and mean diffusing capacity of the lung for carbon monoxide (DLCO) of 53% of predicted. All but two had lung involvement.

“So [there was] significant skin and pulmonary impairment,” he said.

There are, unquestionably, risks with transplant, but the SCOT findings support myeloablative autologous HSCT as a significant advance in the care of diffuse cutaneous systemic scleroderma with internal organ involvement, as this approach provided superior long-term outcomes, compared with 12 months of IV cyclophosphamide, he said, adding that the global rank composite score developed for this study was a useful measure of scleroderma outcomes.

“Therefore it would be prudent to consider early referral to the transplant center for consultation, which would allow patients, earlier in their disease – before the mRSS hit 30 and the DLCOs hit 50 – to make informed decisions,” he concluded.

The SCOT trial was funded by the National Institute of Allergy and Infectious Diseases. The authors reported having no disclosures.

[email protected]

WASHINGTON – Myeloablative autologous hematopoietic stem cell transplantation was superior to monthly intravenous cyclophosphamide in patients with severe scleroderma with internal organ involvement in the randomized, multicenter Scleroderma: Cyclophosphamide or Transplantation (SCOT) trial.

At both 54 and 48 months, a comparison of global rank composite scores favored myeloablation followed by CD34+-selected autologous hematopoietic stem cell transplantation (HSCT) over 12 monthly pulses of 750 mg/m² cyclophosphamide in the intention-to-treat population of 36 and 39 subjects with diffuse cutaneous systemic sclerosis and high-risk lung and/or renal involvement who were randomized to the groups, respectively (P = .013 at 54 months and P = .008 at 48 months). In subjects who actually underwent HSCT or received at least nine cyclophosphamide doses, the effect was even stronger (P = .004 at 54 months and P = .003 at 48 months), Keith M. Sullivan, MD, reported at the annual meeting of the American College of Rheumatology.

The global rank composite scores were derived based on a hierarchy of outcomes including – in rank order – death, event-free survival, forced vital capacity, scleroderma health assessment questionnaire score, and modified Rodnan skin score (mRSS); each patient was compared, based on the hierarchy, with every other patient in the study.

HSCT was superior overall and within each of the components of the score, Dr. Sullivan said.

The findings were supported by secondary analyses showing that at 54 months, event-free survival was 79% in the HSCT group vs. 50% in the cyclophosphamide group, and overall survival was 91% vs. 77% in the groups, respectively; the differences between the groups were statistically significant, said Dr. Sullivan of Duke University, Durham, N.C.

“In advanced scleroderma, that is a remarkable finding,” he said of the nearly 30-point difference in event-free survival rates between the groups.

Further, disease-modifying antirheumatic drugs were initiated by 54 months in 9% of the HSCT recipients vs. 44% of those in the cyclophosphamide group, he noted.

The rate of serious adverse events was similar in the two groups, although grade 3 or greater adverse events, including treatment-related cytopenias, were more common in the HSCT group, as was herpes zoster. Remarkably, most serious adverse events and adverse events occurred in the first 14 months, Dr. Sullivan noted.

Treatment-related mortality at 54 months was 3% in the HSCT group, and 0% in the cyclophosphamide group, he said.

Study subjects were adults aged 18-69 years with mean baseline modified Rodnan skin score of 30, mean baseline forced vital capacity of 74%, and mean diffusing capacity of the lung for carbon monoxide (DLCO) of 53% of predicted. All but two had lung involvement.

“So [there was] significant skin and pulmonary impairment,” he said.

There are, unquestionably, risks with transplant, but the SCOT findings support myeloablative autologous HSCT as a significant advance in the care of diffuse cutaneous systemic scleroderma with internal organ involvement, as this approach provided superior long-term outcomes, compared with 12 months of IV cyclophosphamide, he said, adding that the global rank composite score developed for this study was a useful measure of scleroderma outcomes.

“Therefore it would be prudent to consider early referral to the transplant center for consultation, which would allow patients, earlier in their disease – before the mRSS hit 30 and the DLCOs hit 50 – to make informed decisions,” he concluded.

The SCOT trial was funded by the National Institute of Allergy and Infectious Diseases. The authors reported having no disclosures.

[email protected]

WASHINGTON – Myeloablative autologous hematopoietic stem cell transplantation was superior to monthly intravenous cyclophosphamide in patients with severe scleroderma with internal organ involvement in the randomized, multicenter Scleroderma: Cyclophosphamide or Transplantation (SCOT) trial.

At both 54 and 48 months, a comparison of global rank composite scores favored myeloablation followed by CD34+-selected autologous hematopoietic stem cell transplantation (HSCT) over 12 monthly pulses of 750 mg/m² cyclophosphamide in the intention-to-treat population of 36 and 39 subjects with diffuse cutaneous systemic sclerosis and high-risk lung and/or renal involvement who were randomized to the groups, respectively (P = .013 at 54 months and P = .008 at 48 months). In subjects who actually underwent HSCT or received at least nine cyclophosphamide doses, the effect was even stronger (P = .004 at 54 months and P = .003 at 48 months), Keith M. Sullivan, MD, reported at the annual meeting of the American College of Rheumatology.

The global rank composite scores were derived based on a hierarchy of outcomes including – in rank order – death, event-free survival, forced vital capacity, scleroderma health assessment questionnaire score, and modified Rodnan skin score (mRSS); each patient was compared, based on the hierarchy, with every other patient in the study.

HSCT was superior overall and within each of the components of the score, Dr. Sullivan said.

The findings were supported by secondary analyses showing that at 54 months, event-free survival was 79% in the HSCT group vs. 50% in the cyclophosphamide group, and overall survival was 91% vs. 77% in the groups, respectively; the differences between the groups were statistically significant, said Dr. Sullivan of Duke University, Durham, N.C.

“In advanced scleroderma, that is a remarkable finding,” he said of the nearly 30-point difference in event-free survival rates between the groups.

Further, disease-modifying antirheumatic drugs were initiated by 54 months in 9% of the HSCT recipients vs. 44% of those in the cyclophosphamide group, he noted.

The rate of serious adverse events was similar in the two groups, although grade 3 or greater adverse events, including treatment-related cytopenias, were more common in the HSCT group, as was herpes zoster. Remarkably, most serious adverse events and adverse events occurred in the first 14 months, Dr. Sullivan noted.

Treatment-related mortality at 54 months was 3% in the HSCT group, and 0% in the cyclophosphamide group, he said.

Study subjects were adults aged 18-69 years with mean baseline modified Rodnan skin score of 30, mean baseline forced vital capacity of 74%, and mean diffusing capacity of the lung for carbon monoxide (DLCO) of 53% of predicted. All but two had lung involvement.

“So [there was] significant skin and pulmonary impairment,” he said.

There are, unquestionably, risks with transplant, but the SCOT findings support myeloablative autologous HSCT as a significant advance in the care of diffuse cutaneous systemic scleroderma with internal organ involvement, as this approach provided superior long-term outcomes, compared with 12 months of IV cyclophosphamide, he said, adding that the global rank composite score developed for this study was a useful measure of scleroderma outcomes.

“Therefore it would be prudent to consider early referral to the transplant center for consultation, which would allow patients, earlier in their disease – before the mRSS hit 30 and the DLCOs hit 50 – to make informed decisions,” he concluded.

The SCOT trial was funded by the National Institute of Allergy and Infectious Diseases. The authors reported having no disclosures.

[email protected]

Almost a third of doctors blamed overprescribing for the opioid crisis, according to a survey of 225 U.S. primary care, emergency department, and pain management physicians by InCrowd, an online physician survey company.

Respondents said their own and other physicians’ overprescribing is the single biggest factor fueling the leap in opioid abuse over the past 5 years.

©Liderina/Thinkstock

[email protected]

Almost a third of doctors blamed overprescribing for the opioid crisis, according to a survey of 225 U.S. primary care, emergency department, and pain management physicians by InCrowd, an online physician survey company.

Respondents said their own and other physicians’ overprescribing is the single biggest factor fueling the leap in opioid abuse over the past 5 years.

©Liderina/Thinkstock

[email protected]

Almost a third of doctors blamed overprescribing for the opioid crisis, according to a survey of 225 U.S. primary care, emergency department, and pain management physicians by InCrowd, an online physician survey company.

Respondents said their own and other physicians’ overprescribing is the single biggest factor fueling the leap in opioid abuse over the past 5 years.

©Liderina/Thinkstock

[email protected]

PORTLAND, OR—Most patients with advanced Parkinson’s disease who received levodopa–carbidopa intestinal gel in an open-label, continued-access-to-treatment study had, at five years, transitioned to using the therapy outside of the study when it became commercially available or continued to participate in the extension study, according to data presented at the Fourth World Parkinson Congress.

Forty-two percent of the patients in the phase III extension study transitioned to a commercially available drug (designated as carbidopa–levodopa enteral suspension in the United States), and 24% of patients remained in the multinational study, said Hubert H. Fernandez, MD, Head of Movement Disorders at the Center for Neurological Restoration at the Cleveland Clinic, and colleagues. Patients may remain in the extension study until a commercially available product is available in the country where they live.

Levodopa–carbidopa intestinal gel is infused continuously directly to the jejunum using a portable pump during approximately 16 hours of wakefulness. The therapy is designed to overcome some of the limitations of oral levodopa, which may lose effectiveness as Parkinson’s disease progresses.

Although investigators observed a high incidence of adverse events, long-term use of levodopa–carbidopa intestinal gel was well tolerated, the researchers said. The average discontinuation rate of 9.6% per year, including all causes of death, was relatively low, Dr. Fernandez and colleagues said.

The most frequently reported adverse events were associated with complications related to percutaneous gastrojejunostomy, such as stoma site maintenance. Other adverse events were associated with advanced Parkinson’s disease, aging, or levodopa. Most patients experienced device malfunctions and required pump replacement during the study.

The extension study began in November 2009. Data through September 30, 2015, were used in the present study. The study enrolled 262 patients with advanced Parkinson’s disease from 11 countries who had completed a 12-week double-blind study and its 52-week open-label extension or who had completed a separate 54-week open-label study. Participants attended scheduled study visits every six months.

Patients had a mean age of 64, 62% were male, and mean disease duration was 11.4 years. Mean exposure to levodopa–carbidopa intestinal gel was 3.1 years in the present study. Patients’ mean total exposure to the treatment was 4.1 years. Fifty-six percent of patients were exposed to the treatment for at least five years.

Adverse events led to discontinuation in 62 patients (24%). Device complaints occurred in 244 patients (93%). The most common device complaints included device malfunction (85%), device occlusion (57%), and device dislocation (56%). Thirty-eight patients died during the study. Two patients died as a result of intestinal dilatation and cardiac arrest, which an investigator considered possibly related to the treatment.

As part of an amended study protocol, patients in the United States began completing efficacy assessments in December 2013 (ie, Parkinson’s disease diary, Unified Parkinson’s Disease Rating Scale, and the Parkinson’s Disease Questionnaire). Patients in the United States showed sustained and clinically meaningful benefits of treatment that were demonstrated by decreased off time and increased on time without troublesome dyskinesia, the researchers concluded.

—Jake Remaly

PORTLAND, OR—Most patients with advanced Parkinson’s disease who received levodopa–carbidopa intestinal gel in an open-label, continued-access-to-treatment study had, at five years, transitioned to using the therapy outside of the study when it became commercially available or continued to participate in the extension study, according to data presented at the Fourth World Parkinson Congress.

Forty-two percent of the patients in the phase III extension study transitioned to a commercially available drug (designated as carbidopa–levodopa enteral suspension in the United States), and 24% of patients remained in the multinational study, said Hubert H. Fernandez, MD, Head of Movement Disorders at the Center for Neurological Restoration at the Cleveland Clinic, and colleagues. Patients may remain in the extension study until a commercially available product is available in the country where they live.

Levodopa–carbidopa intestinal gel is infused continuously directly to the jejunum using a portable pump during approximately 16 hours of wakefulness. The therapy is designed to overcome some of the limitations of oral levodopa, which may lose effectiveness as Parkinson’s disease progresses.

Although investigators observed a high incidence of adverse events, long-term use of levodopa–carbidopa intestinal gel was well tolerated, the researchers said. The average discontinuation rate of 9.6% per year, including all causes of death, was relatively low, Dr. Fernandez and colleagues said.

The most frequently reported adverse events were associated with complications related to percutaneous gastrojejunostomy, such as stoma site maintenance. Other adverse events were associated with advanced Parkinson’s disease, aging, or levodopa. Most patients experienced device malfunctions and required pump replacement during the study.

The extension study began in November 2009. Data through September 30, 2015, were used in the present study. The study enrolled 262 patients with advanced Parkinson’s disease from 11 countries who had completed a 12-week double-blind study and its 52-week open-label extension or who had completed a separate 54-week open-label study. Participants attended scheduled study visits every six months.

Patients had a mean age of 64, 62% were male, and mean disease duration was 11.4 years. Mean exposure to levodopa–carbidopa intestinal gel was 3.1 years in the present study. Patients’ mean total exposure to the treatment was 4.1 years. Fifty-six percent of patients were exposed to the treatment for at least five years.

Adverse events led to discontinuation in 62 patients (24%). Device complaints occurred in 244 patients (93%). The most common device complaints included device malfunction (85%), device occlusion (57%), and device dislocation (56%). Thirty-eight patients died during the study. Two patients died as a result of intestinal dilatation and cardiac arrest, which an investigator considered possibly related to the treatment.

As part of an amended study protocol, patients in the United States began completing efficacy assessments in December 2013 (ie, Parkinson’s disease diary, Unified Parkinson’s Disease Rating Scale, and the Parkinson’s Disease Questionnaire). Patients in the United States showed sustained and clinically meaningful benefits of treatment that were demonstrated by decreased off time and increased on time without troublesome dyskinesia, the researchers concluded.

—Jake Remaly

PORTLAND, OR—Most patients with advanced Parkinson’s disease who received levodopa–carbidopa intestinal gel in an open-label, continued-access-to-treatment study had, at five years, transitioned to using the therapy outside of the study when it became commercially available or continued to participate in the extension study, according to data presented at the Fourth World Parkinson Congress.

Forty-two percent of the patients in the phase III extension study transitioned to a commercially available drug (designated as carbidopa–levodopa enteral suspension in the United States), and 24% of patients remained in the multinational study, said Hubert H. Fernandez, MD, Head of Movement Disorders at the Center for Neurological Restoration at the Cleveland Clinic, and colleagues. Patients may remain in the extension study until a commercially available product is available in the country where they live.

Levodopa–carbidopa intestinal gel is infused continuously directly to the jejunum using a portable pump during approximately 16 hours of wakefulness. The therapy is designed to overcome some of the limitations of oral levodopa, which may lose effectiveness as Parkinson’s disease progresses.

Although investigators observed a high incidence of adverse events, long-term use of levodopa–carbidopa intestinal gel was well tolerated, the researchers said. The average discontinuation rate of 9.6% per year, including all causes of death, was relatively low, Dr. Fernandez and colleagues said.

The most frequently reported adverse events were associated with complications related to percutaneous gastrojejunostomy, such as stoma site maintenance. Other adverse events were associated with advanced Parkinson’s disease, aging, or levodopa. Most patients experienced device malfunctions and required pump replacement during the study.

The extension study began in November 2009. Data through September 30, 2015, were used in the present study. The study enrolled 262 patients with advanced Parkinson’s disease from 11 countries who had completed a 12-week double-blind study and its 52-week open-label extension or who had completed a separate 54-week open-label study. Participants attended scheduled study visits every six months.

Patients had a mean age of 64, 62% were male, and mean disease duration was 11.4 years. Mean exposure to levodopa–carbidopa intestinal gel was 3.1 years in the present study. Patients’ mean total exposure to the treatment was 4.1 years. Fifty-six percent of patients were exposed to the treatment for at least five years.

Adverse events led to discontinuation in 62 patients (24%). Device complaints occurred in 244 patients (93%). The most common device complaints included device malfunction (85%), device occlusion (57%), and device dislocation (56%). Thirty-eight patients died during the study. Two patients died as a result of intestinal dilatation and cardiac arrest, which an investigator considered possibly related to the treatment.

As part of an amended study protocol, patients in the United States began completing efficacy assessments in December 2013 (ie, Parkinson’s disease diary, Unified Parkinson’s Disease Rating Scale, and the Parkinson’s Disease Questionnaire). Patients in the United States showed sustained and clinically meaningful benefits of treatment that were demonstrated by decreased off time and increased on time without troublesome dyskinesia, the researchers concluded.

—Jake Remaly

WASHINGTON – The recombinant fusion protein atacicept, which targets B-cell stimulating factors BLyS and APRIL, had a favorable safety profile and showed some evidence of efficacy in systemic lupus erythematosus patients – particularly those with high disease activity and serologically active disease – in the randomized, phase IIb ADDRESS II study.

Although the primary endpoint of the study – percentage of patients achieving SLE responder index-4 (SRI-4) response at 24 weeks – was not met, a reduction in both disease activity and severe flares was observed in patients in the multicenter study who received atacicept vs. placebo, Joan T. Merrill, MD, of the Oklahoma Medical Research Foundation, Oklahoma City, reported in a late-breaking poster at the annual meeting of the American College of Rheumatology.

[email protected]

WASHINGTON – The recombinant fusion protein atacicept, which targets B-cell stimulating factors BLyS and APRIL, had a favorable safety profile and showed some evidence of efficacy in systemic lupus erythematosus patients – particularly those with high disease activity and serologically active disease – in the randomized, phase IIb ADDRESS II study.

Although the primary endpoint of the study – percentage of patients achieving SLE responder index-4 (SRI-4) response at 24 weeks – was not met, a reduction in both disease activity and severe flares was observed in patients in the multicenter study who received atacicept vs. placebo, Joan T. Merrill, MD, of the Oklahoma Medical Research Foundation, Oklahoma City, reported in a late-breaking poster at the annual meeting of the American College of Rheumatology.

[email protected]

WASHINGTON – The recombinant fusion protein atacicept, which targets B-cell stimulating factors BLyS and APRIL, had a favorable safety profile and showed some evidence of efficacy in systemic lupus erythematosus patients – particularly those with high disease activity and serologically active disease – in the randomized, phase IIb ADDRESS II study.

Although the primary endpoint of the study – percentage of patients achieving SLE responder index-4 (SRI-4) response at 24 weeks – was not met, a reduction in both disease activity and severe flares was observed in patients in the multicenter study who received atacicept vs. placebo, Joan T. Merrill, MD, of the Oklahoma Medical Research Foundation, Oklahoma City, reported in a late-breaking poster at the annual meeting of the American College of Rheumatology.

[email protected]

Among patients of European descent, higher latitude regions are associated with an earlier age at onset of multiple sclerosis (MS), according to data published online ahead of print November 3 in the Journal of Neurology, Neurosurgery and Psychiatry. Age at MS onset also is lower among people with less exposure to ultraviolet radiation.

Bruce V. Taylor, MBBS, Professorial Research Fellow at the University of Tasmania, Australia, and his collaborators examined data for 22,162 eligible patients participating in the international MSBase Registry. Eligible participants had MS, were age 16 or older, and came from centers of largely European descent. The investigators defined age at onset as the year of the first symptom suggestive of inflammatory CNS demyelination. They evaluated predictors of age at onset using linear regression.

Most patients in the sample were women (70.4%) and had relapsing-remitting MS (91.5%). In addition, most participants were from the northern hemisphere (81.4%), particularly Europe (67.2%), and a large proportion (15.7%) were from Australia. The sample’s mean age at MS onset was 32.3.

In the univariable analysis, latitude as a continuous linear factor was significantly negatively associated with age at onset. Every 10° increment of latitude was associated with a 0.3-year earlier onset. After adjustment for relevant covariates, patients of the highest latitude stratum had MS onset nearly 1.9 years earlier than patients of the lowest latitude stratum. In an evaluation of latitude as a continuous variable in the multivariable analysis, a 10° increase in latitude was associated with a 0.82-year earlier onset.

A similar pattern emerged for exposure to ultraviolet light. After adjustment for confounders, the investigators found a dose-dependent association between ultraviolet B and age at MS onset. In the multivariable analysis, people with the lowest ultraviolet B exposure had MS onset nearly two years earlier than people with the highest ultraviolet B exposure.

After adjustment for variables, age at MS onset was 0.43 years lower among women than among men. The latitudinal gradient of age at onset was not significantly different between men and women. Birth dates were evenly distributed in all four seasons, and the researchers found no association between season of birth and age at onset.

—Erik Greb

Suggested Reading

Tao C, Simpson S Jr, van der Mei I, et al. Higher latitude is significantly associated with an earlier age of disease onset in multiple sclerosis. J Neurol Neurosurg Psychiatry. 2016 Nov 3 [Epub ahead of print].

Among patients of European descent, higher latitude regions are associated with an earlier age at onset of multiple sclerosis (MS), according to data published online ahead of print November 3 in the Journal of Neurology, Neurosurgery and Psychiatry. Age at MS onset also is lower among people with less exposure to ultraviolet radiation.

Bruce V. Taylor, MBBS, Professorial Research Fellow at the University of Tasmania, Australia, and his collaborators examined data for 22,162 eligible patients participating in the international MSBase Registry. Eligible participants had MS, were age 16 or older, and came from centers of largely European descent. The investigators defined age at onset as the year of the first symptom suggestive of inflammatory CNS demyelination. They evaluated predictors of age at onset using linear regression.

Most patients in the sample were women (70.4%) and had relapsing-remitting MS (91.5%). In addition, most participants were from the northern hemisphere (81.4%), particularly Europe (67.2%), and a large proportion (15.7%) were from Australia. The sample’s mean age at MS onset was 32.3.

In the univariable analysis, latitude as a continuous linear factor was significantly negatively associated with age at onset. Every 10° increment of latitude was associated with a 0.3-year earlier onset. After adjustment for relevant covariates, patients of the highest latitude stratum had MS onset nearly 1.9 years earlier than patients of the lowest latitude stratum. In an evaluation of latitude as a continuous variable in the multivariable analysis, a 10° increase in latitude was associated with a 0.82-year earlier onset.

A similar pattern emerged for exposure to ultraviolet light. After adjustment for confounders, the investigators found a dose-dependent association between ultraviolet B and age at MS onset. In the multivariable analysis, people with the lowest ultraviolet B exposure had MS onset nearly two years earlier than people with the highest ultraviolet B exposure.

After adjustment for variables, age at MS onset was 0.43 years lower among women than among men. The latitudinal gradient of age at onset was not significantly different between men and women. Birth dates were evenly distributed in all four seasons, and the researchers found no association between season of birth and age at onset.

—Erik Greb

Suggested Reading

Tao C, Simpson S Jr, van der Mei I, et al. Higher latitude is significantly associated with an earlier age of disease onset in multiple sclerosis. J Neurol Neurosurg Psychiatry. 2016 Nov 3 [Epub ahead of print].

Among patients of European descent, higher latitude regions are associated with an earlier age at onset of multiple sclerosis (MS), according to data published online ahead of print November 3 in the Journal of Neurology, Neurosurgery and Psychiatry. Age at MS onset also is lower among people with less exposure to ultraviolet radiation.

Bruce V. Taylor, MBBS, Professorial Research Fellow at the University of Tasmania, Australia, and his collaborators examined data for 22,162 eligible patients participating in the international MSBase Registry. Eligible participants had MS, were age 16 or older, and came from centers of largely European descent. The investigators defined age at onset as the year of the first symptom suggestive of inflammatory CNS demyelination. They evaluated predictors of age at onset using linear regression.

Most patients in the sample were women (70.4%) and had relapsing-remitting MS (91.5%). In addition, most participants were from the northern hemisphere (81.4%), particularly Europe (67.2%), and a large proportion (15.7%) were from Australia. The sample’s mean age at MS onset was 32.3.

In the univariable analysis, latitude as a continuous linear factor was significantly negatively associated with age at onset. Every 10° increment of latitude was associated with a 0.3-year earlier onset. After adjustment for relevant covariates, patients of the highest latitude stratum had MS onset nearly 1.9 years earlier than patients of the lowest latitude stratum. In an evaluation of latitude as a continuous variable in the multivariable analysis, a 10° increase in latitude was associated with a 0.82-year earlier onset.

A similar pattern emerged for exposure to ultraviolet light. After adjustment for confounders, the investigators found a dose-dependent association between ultraviolet B and age at MS onset. In the multivariable analysis, people with the lowest ultraviolet B exposure had MS onset nearly two years earlier than people with the highest ultraviolet B exposure.

After adjustment for variables, age at MS onset was 0.43 years lower among women than among men. The latitudinal gradient of age at onset was not significantly different between men and women. Birth dates were evenly distributed in all four seasons, and the researchers found no association between season of birth and age at onset.

—Erik Greb

Suggested Reading

Tao C, Simpson S Jr, van der Mei I, et al. Higher latitude is significantly associated with an earlier age of disease onset in multiple sclerosis. J Neurol Neurosurg Psychiatry. 2016 Nov 3 [Epub ahead of print].

Technique

The patient is positioned on a radiolucent table, and a mobile fluoroscopy unit is available. A tourniquet is applied to the upper thigh but typically is not inflated during the percutaneous hardware removal portion of the operation. It is crucial to have information on retained implants so the correct screwdrivers for screw removal can be selected. In addition, provisions for stripped screws should be made. In each of the 3 cases we managed, the Synthes Screw Removal Set was available. Presence of an implant system known to have problems with cold welding of screws (eg, Less Invasive Stabilization System; Synthes) may necessitate additional preparations, such as making conical extraction devices available.¹

After preoperative administration of antibiotics, the surgeon typically removes only those proximal tibia screws that are preventing insertion of the tibial base plate. Fluoroscopic guidance is used to locate these screws and then remove them with percutaneous stab incisions. (Retained plates are not removed.) The exact method of localizing and removing the screws percutaneously is crucial. A small stab incision is made in the dermal layer. The number of stab incisions to be made depends on the number of screws to be removed. One small incision is needed for each screw hole. Occasionally mobilizing the skin and redirecting the screwdriver in the deep tissues can allow 2 screws to be removed through a single skin wound. The screwdriver head can be inserted through the muscle and fascial layers without the need for deep dissection. The plate is then felt with the screwdriver and the screw head located. It is very important that the screw head be adequately engaged to prevent stripping. The surgeon should not rush this step. The C-arm can be helpful here. Fluoroscopy not only can guide the screwdriver to the screw hole but can confirm the screwdriver is at right angles to the plate, not oblique. Only when the surgeon is completely satisfied that the screw head is well engaged should the attempt to back out the screw be made. If the screw strips, the screwdriver can be removed, and an attempt can be made to insert a percutaneous stripped screw removal device.¹ If this fails, then the technique must be abandoned for a more traditional approach.

Plating complex tibial plateau fractures through a separate posteromedial approach is now popular.² The deep location and screw orientation of posteromedial hardware make percutaneous removal unfeasible. In these cases, a separate posteromedial incision may be needed—usually posterior enough so it minimally compromises the anterior soft tissues. The incision typically uses the old posteromedial surgical scar but may not need to be as large as the original approach, as only selected screws need be removed. The saphenous neurovascular bundle may still be at risk, depending on the location of these incisions. The plate is not removed.

After the necessary screws are removed, the tourniquet can be inflated, if desired. The total knee arthroplasty (TKA) then proceeds in usual fashion through a single incision and a medial parapatellar arthrotomy.

Results

Between January 2009 and February 2014, Dr. Georgiadis converted 3 cases of retained tibial hardware and severe knee arthrosis to a TKA in a single operation. These cases were reviewed after Institutional Review Board approval was obtained. One patient underwent a closing-wedge high tibial osteotomy 14 years earlier, and the other 2 sustained tibial plateau fractures. Clinical details of the 3 cases are presented in the Table.

In 2 of the cases, anterolateral surgical scars were present. New, separate percutaneous stab incisions were used to remove screws, which meant less of the original skin incision could be used for the TKA (Figures 1A, 1B).

Discussion

If the decision is made to proceed with TKA after previous knee surgery, careful preoperative planning is needed.

For young patients with knee arthrosis and angular deformity, it has been recommended that proximal tibial osteotomy be performed to delay the need for joint replacement.^3,4 Although a wide variety of osteotomy techniques is available, plates and screws are often used. With long-term follow-up, knee arthrosis can be expected to progress, and some of these cases will be converted to knee arthroplasty.^3,4Displaced tibial plateau fractures are intra-articular injuries. Treatment requires surgery.

Am J Orthop. 2016;45(7):E481-E486. Copyright Frontline Medical Communications Inc. 2016. All rights reserved.

Technique

The patient is positioned on a radiolucent table, and a mobile fluoroscopy unit is available. A tourniquet is applied to the upper thigh but typically is not inflated during the percutaneous hardware removal portion of the operation. It is crucial to have information on retained implants so the correct screwdrivers for screw removal can be selected. In addition, provisions for stripped screws should be made. In each of the 3 cases we managed, the Synthes Screw Removal Set was available. Presence of an implant system known to have problems with cold welding of screws (eg, Less Invasive Stabilization System; Synthes) may necessitate additional preparations, such as making conical extraction devices available.¹

After preoperative administration of antibiotics, the surgeon typically removes only those proximal tibia screws that are preventing insertion of the tibial base plate. Fluoroscopic guidance is used to locate these screws and then remove them with percutaneous stab incisions. (Retained plates are not removed.) The exact method of localizing and removing the screws percutaneously is crucial. A small stab incision is made in the dermal layer. The number of stab incisions to be made depends on the number of screws to be removed. One small incision is needed for each screw hole. Occasionally mobilizing the skin and redirecting the screwdriver in the deep tissues can allow 2 screws to be removed through a single skin wound. The screwdriver head can be inserted through the muscle and fascial layers without the need for deep dissection. The plate is then felt with the screwdriver and the screw head located. It is very important that the screw head be adequately engaged to prevent stripping. The surgeon should not rush this step. The C-arm can be helpful here. Fluoroscopy not only can guide the screwdriver to the screw hole but can confirm the screwdriver is at right angles to the plate, not oblique. Only when the surgeon is completely satisfied that the screw head is well engaged should the attempt to back out the screw be made. If the screw strips, the screwdriver can be removed, and an attempt can be made to insert a percutaneous stripped screw removal device.¹ If this fails, then the technique must be abandoned for a more traditional approach.

Plating complex tibial plateau fractures through a separate posteromedial approach is now popular.² The deep location and screw orientation of posteromedial hardware make percutaneous removal unfeasible. In these cases, a separate posteromedial incision may be needed—usually posterior enough so it minimally compromises the anterior soft tissues. The incision typically uses the old posteromedial surgical scar but may not need to be as large as the original approach, as only selected screws need be removed. The saphenous neurovascular bundle may still be at risk, depending on the location of these incisions. The plate is not removed.

After the necessary screws are removed, the tourniquet can be inflated, if desired. The total knee arthroplasty (TKA) then proceeds in usual fashion through a single incision and a medial parapatellar arthrotomy.

Results

Between January 2009 and February 2014, Dr. Georgiadis converted 3 cases of retained tibial hardware and severe knee arthrosis to a TKA in a single operation. These cases were reviewed after Institutional Review Board approval was obtained. One patient underwent a closing-wedge high tibial osteotomy 14 years earlier, and the other 2 sustained tibial plateau fractures. Clinical details of the 3 cases are presented in the Table.

In 2 of the cases, anterolateral surgical scars were present. New, separate percutaneous stab incisions were used to remove screws, which meant less of the original skin incision could be used for the TKA (Figures 1A, 1B).

Discussion

If the decision is made to proceed with TKA after previous knee surgery, careful preoperative planning is needed.

For young patients with knee arthrosis and angular deformity, it has been recommended that proximal tibial osteotomy be performed to delay the need for joint replacement.^3,4 Although a wide variety of osteotomy techniques is available, plates and screws are often used. With long-term follow-up, knee arthrosis can be expected to progress, and some of these cases will be converted to knee arthroplasty.^3,4Displaced tibial plateau fractures are intra-articular injuries. Treatment requires surgery.

Am J Orthop. 2016;45(7):E481-E486. Copyright Frontline Medical Communications Inc. 2016. All rights reserved.

Technique

The patient is positioned on a radiolucent table, and a mobile fluoroscopy unit is available. A tourniquet is applied to the upper thigh but typically is not inflated during the percutaneous hardware removal portion of the operation. It is crucial to have information on retained implants so the correct screwdrivers for screw removal can be selected. In addition, provisions for stripped screws should be made. In each of the 3 cases we managed, the Synthes Screw Removal Set was available. Presence of an implant system known to have problems with cold welding of screws (eg, Less Invasive Stabilization System; Synthes) may necessitate additional preparations, such as making conical extraction devices available.¹

After preoperative administration of antibiotics, the surgeon typically removes only those proximal tibia screws that are preventing insertion of the tibial base plate. Fluoroscopic guidance is used to locate these screws and then remove them with percutaneous stab incisions. (Retained plates are not removed.) The exact method of localizing and removing the screws percutaneously is crucial. A small stab incision is made in the dermal layer. The number of stab incisions to be made depends on the number of screws to be removed. One small incision is needed for each screw hole. Occasionally mobilizing the skin and redirecting the screwdriver in the deep tissues can allow 2 screws to be removed through a single skin wound. The screwdriver head can be inserted through the muscle and fascial layers without the need for deep dissection. The plate is then felt with the screwdriver and the screw head located. It is very important that the screw head be adequately engaged to prevent stripping. The surgeon should not rush this step. The C-arm can be helpful here. Fluoroscopy not only can guide the screwdriver to the screw hole but can confirm the screwdriver is at right angles to the plate, not oblique. Only when the surgeon is completely satisfied that the screw head is well engaged should the attempt to back out the screw be made. If the screw strips, the screwdriver can be removed, and an attempt can be made to insert a percutaneous stripped screw removal device.¹ If this fails, then the technique must be abandoned for a more traditional approach.

Plating complex tibial plateau fractures through a separate posteromedial approach is now popular.² The deep location and screw orientation of posteromedial hardware make percutaneous removal unfeasible. In these cases, a separate posteromedial incision may be needed—usually posterior enough so it minimally compromises the anterior soft tissues. The incision typically uses the old posteromedial surgical scar but may not need to be as large as the original approach, as only selected screws need be removed. The saphenous neurovascular bundle may still be at risk, depending on the location of these incisions. The plate is not removed.

After the necessary screws are removed, the tourniquet can be inflated, if desired. The total knee arthroplasty (TKA) then proceeds in usual fashion through a single incision and a medial parapatellar arthrotomy.

Results

Between January 2009 and February 2014, Dr. Georgiadis converted 3 cases of retained tibial hardware and severe knee arthrosis to a TKA in a single operation. These cases were reviewed after Institutional Review Board approval was obtained. One patient underwent a closing-wedge high tibial osteotomy 14 years earlier, and the other 2 sustained tibial plateau fractures. Clinical details of the 3 cases are presented in the Table.

In 2 of the cases, anterolateral surgical scars were present. New, separate percutaneous stab incisions were used to remove screws, which meant less of the original skin incision could be used for the TKA (Figures 1A, 1B).

Discussion

If the decision is made to proceed with TKA after previous knee surgery, careful preoperative planning is needed.

For young patients with knee arthrosis and angular deformity, it has been recommended that proximal tibial osteotomy be performed to delay the need for joint replacement.^3,4 Although a wide variety of osteotomy techniques is available, plates and screws are often used. With long-term follow-up, knee arthrosis can be expected to progress, and some of these cases will be converted to knee arthroplasty.^3,4Displaced tibial plateau fractures are intra-articular injuries. Treatment requires surgery.

Am J Orthop. 2016;45(7):E481-E486. Copyright Frontline Medical Communications Inc. 2016. All rights reserved.