Pediatrics

Photo by Petr Kratochvil

Patients who develop B-cell precursor acute lymphoblastic leukemia (BCP-ALL) in childhood may have dysregulated immune function at birth, according to a study published in Cancer Research.

Investigators evaluated neonatal concentrations of inflammatory markers and found significant differences between children who were later diagnosed with BCP-ALL and leukemia-free control subjects.

“Our findings suggest that children who develop ALL are immunologically disparate already at birth,” said study author Signe Holst Søegaard, a PhD student at Statens Serum Institut in Copenhagen, Denmark.

“This may link to other observations suggesting that children who develop ALL respond differently to infections in early childhood, potentially promoting subsequent genetic events required for transformation to ALL, or speculations that they are unable to eliminate preleukemic cells.”

“Importantly, our study does not inform about the nature of the associations observed—i.e., whether they are causal or consequential. Accordingly, further studies are needed both to confirm the findings and to identify the underlying mechanisms.”

For this study, Søegaard and her colleagues measured concentrations of 10 inflammatory markers on neonatal dried blood spots from 178 patients with BCP-ALL and 178 matched controls. The patients were diagnosed with BCP-ALL at ages 1 to 9.

The inflammatory markers assessed were interleukin (IL)-6, its soluble receptor sIL-6Rα, IL-8, IL-10, IL-12, IL-17, IL-18, transforming growth factor (TGF)-β1, monocyte chemotactic protein (MCP)-1, and C-reactive protein (CRP).

Results

Compared to controls, children who later developed BCP-ALL had significantly different neonatal concentrations of eight inflammatory markers.

Concentrations of sIL-6Rα, IL-8, TGF-β1, MCP-1, and CRP were significantly lower among the BCP-ALL patients. The adjusted odds ratios (adjusted for birth weight and maternal age) of BCP-ALL were 0.82 for sIL-6Rα, 0.84 for IL-8, 0.83 for TGF-β1, 0.68 for MCP-1, and 0.83 for CRP.

On the other hand, concentrations of IL-6, IL-17, and IL-18 were significantly higher among BCP-ALL patients than controls. The adjusted odds ratios were 1.19 for IL-6, 1.12 for IL-17, and 1.08 for IL-18.

The investigators noted that IL-10 concentrations were too low for accurate measurement in all patients and controls. Additionally, a “large proportion” of patients and controls (31% to 61%) had IL-6 and IL-17 concentrations that were below the limit of detection.

“We also demonstrated that several previously shown ALL risk factors—namely, birth order, gestational age, and sex—were associated with the neonatal concentrations of inflammatory markers,” Søegaard said. “These findings raise the interesting possibility that the effects of some known ALL risk factors partly act through prenatal programming of immune function.”

The investigators found that increasing birth order was associated with significantly higher IL-18 and lower CRP concentrations.

Increasing gestational age was associated with significantly lower sIL-6Rα and TGF-β1 concentrations and higher CRP concentrations. And males had significantly lower sIL-6Rα and IL-8 concentrations and higher CRP concentrations than females.

However, none of the following factors were significantly associated with concentrations of inflammatory biomarkers: maternal age at delivery, maternal hospital contact due to infection during pregnancy, maternal prescription for antimicrobials during pregnancy, birth weight, and mode of delivery.

“Our findings underline the role the child’s baseline immune characteristics may play in the development of ALL,” Søegaard said. “However, we cannot yet use our research results to predict who will develop childhood ALL. In future studies, we will further characterize the relation between immune constitution at birth and risk of childhood ALL with the ultimate goal of developing preventive strategies targeting predisposed children.”

Søegaard noted that this study had its limitations, including the small number of inflammatory markers studied. In addition, the limited sample size made it impossible to detect potential differences between BCP-ALL subtypes.

The study was sponsored by the Dagmar Marshall Foundation, the A.P. Møller Foundation, the Danish Childhood Cancer Foundation, the Arvid Nilsson Foundation, and the Danish Cancer Research Foundation. There were no conflicts of interest disclosed.

Photo by Petr Kratochvil

Patients who develop B-cell precursor acute lymphoblastic leukemia (BCP-ALL) in childhood may have dysregulated immune function at birth, according to a study published in Cancer Research.

Investigators evaluated neonatal concentrations of inflammatory markers and found significant differences between children who were later diagnosed with BCP-ALL and leukemia-free control subjects.

“Our findings suggest that children who develop ALL are immunologically disparate already at birth,” said study author Signe Holst Søegaard, a PhD student at Statens Serum Institut in Copenhagen, Denmark.

“This may link to other observations suggesting that children who develop ALL respond differently to infections in early childhood, potentially promoting subsequent genetic events required for transformation to ALL, or speculations that they are unable to eliminate preleukemic cells.”

“Importantly, our study does not inform about the nature of the associations observed—i.e., whether they are causal or consequential. Accordingly, further studies are needed both to confirm the findings and to identify the underlying mechanisms.”

For this study, Søegaard and her colleagues measured concentrations of 10 inflammatory markers on neonatal dried blood spots from 178 patients with BCP-ALL and 178 matched controls. The patients were diagnosed with BCP-ALL at ages 1 to 9.

The inflammatory markers assessed were interleukin (IL)-6, its soluble receptor sIL-6Rα, IL-8, IL-10, IL-12, IL-17, IL-18, transforming growth factor (TGF)-β1, monocyte chemotactic protein (MCP)-1, and C-reactive protein (CRP).

Results

Compared to controls, children who later developed BCP-ALL had significantly different neonatal concentrations of eight inflammatory markers.

Concentrations of sIL-6Rα, IL-8, TGF-β1, MCP-1, and CRP were significantly lower among the BCP-ALL patients. The adjusted odds ratios (adjusted for birth weight and maternal age) of BCP-ALL were 0.82 for sIL-6Rα, 0.84 for IL-8, 0.83 for TGF-β1, 0.68 for MCP-1, and 0.83 for CRP.

On the other hand, concentrations of IL-6, IL-17, and IL-18 were significantly higher among BCP-ALL patients than controls. The adjusted odds ratios were 1.19 for IL-6, 1.12 for IL-17, and 1.08 for IL-18.

The investigators noted that IL-10 concentrations were too low for accurate measurement in all patients and controls. Additionally, a “large proportion” of patients and controls (31% to 61%) had IL-6 and IL-17 concentrations that were below the limit of detection.

“We also demonstrated that several previously shown ALL risk factors—namely, birth order, gestational age, and sex—were associated with the neonatal concentrations of inflammatory markers,” Søegaard said. “These findings raise the interesting possibility that the effects of some known ALL risk factors partly act through prenatal programming of immune function.”

The investigators found that increasing birth order was associated with significantly higher IL-18 and lower CRP concentrations.

Increasing gestational age was associated with significantly lower sIL-6Rα and TGF-β1 concentrations and higher CRP concentrations. And males had significantly lower sIL-6Rα and IL-8 concentrations and higher CRP concentrations than females.

However, none of the following factors were significantly associated with concentrations of inflammatory biomarkers: maternal age at delivery, maternal hospital contact due to infection during pregnancy, maternal prescription for antimicrobials during pregnancy, birth weight, and mode of delivery.

“Our findings underline the role the child’s baseline immune characteristics may play in the development of ALL,” Søegaard said. “However, we cannot yet use our research results to predict who will develop childhood ALL. In future studies, we will further characterize the relation between immune constitution at birth and risk of childhood ALL with the ultimate goal of developing preventive strategies targeting predisposed children.”

Søegaard noted that this study had its limitations, including the small number of inflammatory markers studied. In addition, the limited sample size made it impossible to detect potential differences between BCP-ALL subtypes.

The study was sponsored by the Dagmar Marshall Foundation, the A.P. Møller Foundation, the Danish Childhood Cancer Foundation, the Arvid Nilsson Foundation, and the Danish Cancer Research Foundation. There were no conflicts of interest disclosed.

Photo by Petr Kratochvil

Patients who develop B-cell precursor acute lymphoblastic leukemia (BCP-ALL) in childhood may have dysregulated immune function at birth, according to a study published in Cancer Research.

Investigators evaluated neonatal concentrations of inflammatory markers and found significant differences between children who were later diagnosed with BCP-ALL and leukemia-free control subjects.

“Our findings suggest that children who develop ALL are immunologically disparate already at birth,” said study author Signe Holst Søegaard, a PhD student at Statens Serum Institut in Copenhagen, Denmark.

“This may link to other observations suggesting that children who develop ALL respond differently to infections in early childhood, potentially promoting subsequent genetic events required for transformation to ALL, or speculations that they are unable to eliminate preleukemic cells.”

“Importantly, our study does not inform about the nature of the associations observed—i.e., whether they are causal or consequential. Accordingly, further studies are needed both to confirm the findings and to identify the underlying mechanisms.”

For this study, Søegaard and her colleagues measured concentrations of 10 inflammatory markers on neonatal dried blood spots from 178 patients with BCP-ALL and 178 matched controls. The patients were diagnosed with BCP-ALL at ages 1 to 9.

The inflammatory markers assessed were interleukin (IL)-6, its soluble receptor sIL-6Rα, IL-8, IL-10, IL-12, IL-17, IL-18, transforming growth factor (TGF)-β1, monocyte chemotactic protein (MCP)-1, and C-reactive protein (CRP).

Results

Compared to controls, children who later developed BCP-ALL had significantly different neonatal concentrations of eight inflammatory markers.

Concentrations of sIL-6Rα, IL-8, TGF-β1, MCP-1, and CRP were significantly lower among the BCP-ALL patients. The adjusted odds ratios (adjusted for birth weight and maternal age) of BCP-ALL were 0.82 for sIL-6Rα, 0.84 for IL-8, 0.83 for TGF-β1, 0.68 for MCP-1, and 0.83 for CRP.

On the other hand, concentrations of IL-6, IL-17, and IL-18 were significantly higher among BCP-ALL patients than controls. The adjusted odds ratios were 1.19 for IL-6, 1.12 for IL-17, and 1.08 for IL-18.

The investigators noted that IL-10 concentrations were too low for accurate measurement in all patients and controls. Additionally, a “large proportion” of patients and controls (31% to 61%) had IL-6 and IL-17 concentrations that were below the limit of detection.

“We also demonstrated that several previously shown ALL risk factors—namely, birth order, gestational age, and sex—were associated with the neonatal concentrations of inflammatory markers,” Søegaard said. “These findings raise the interesting possibility that the effects of some known ALL risk factors partly act through prenatal programming of immune function.”

The investigators found that increasing birth order was associated with significantly higher IL-18 and lower CRP concentrations.

Increasing gestational age was associated with significantly lower sIL-6Rα and TGF-β1 concentrations and higher CRP concentrations. And males had significantly lower sIL-6Rα and IL-8 concentrations and higher CRP concentrations than females.

However, none of the following factors were significantly associated with concentrations of inflammatory biomarkers: maternal age at delivery, maternal hospital contact due to infection during pregnancy, maternal prescription for antimicrobials during pregnancy, birth weight, and mode of delivery.

“Our findings underline the role the child’s baseline immune characteristics may play in the development of ALL,” Søegaard said. “However, we cannot yet use our research results to predict who will develop childhood ALL. In future studies, we will further characterize the relation between immune constitution at birth and risk of childhood ALL with the ultimate goal of developing preventive strategies targeting predisposed children.”

Søegaard noted that this study had its limitations, including the small number of inflammatory markers studied. In addition, the limited sample size made it impossible to detect potential differences between BCP-ALL subtypes.

The study was sponsored by the Dagmar Marshall Foundation, the A.P. Møller Foundation, the Danish Childhood Cancer Foundation, the Arvid Nilsson Foundation, and the Danish Cancer Research Foundation. There were no conflicts of interest disclosed.

The Food and Drug Administration has approved the subcutaneous formulation of Actemra (tocilizumab) for systemic juvenile idiopathic arthritis (SJIA) for patients aged 2 years and older, according to a press release from its developer, Genentech. The intravenous formulation was approved in 2011 for this indication.

The approval is based on data the JIGSAW-118 study. This 52-week, open-label, multicenter, phase 1b pharmacokinetic/pharmacodynamic bridging study was designed to determine the appropriate dosing regimen by treating 51 patients with SJIA according to body weight.

The safety profile of subcutaneous tocilizumab was similar to that seen with intravenous tocilizumab, although there were more injection-site reactions seen with the subcutaneous formulation. Its efficacy was extrapolated based on the drug’s pharmacokinetic profile seen with IV tocilizumab in SJIA patients and with subcutaneous tocilizumab in patients with rheumatoid arthritis.

SJIA is a rare disease with limited treatment options, according to the press release. In general, JIA affects almost 300,000 children in the United States, and about 10% of those cases are SJIA.

cpalmer@mdedge.com

The Food and Drug Administration has approved the subcutaneous formulation of Actemra (tocilizumab) for systemic juvenile idiopathic arthritis (SJIA) for patients aged 2 years and older, according to a press release from its developer, Genentech. The intravenous formulation was approved in 2011 for this indication.

The approval is based on data the JIGSAW-118 study. This 52-week, open-label, multicenter, phase 1b pharmacokinetic/pharmacodynamic bridging study was designed to determine the appropriate dosing regimen by treating 51 patients with SJIA according to body weight.

The safety profile of subcutaneous tocilizumab was similar to that seen with intravenous tocilizumab, although there were more injection-site reactions seen with the subcutaneous formulation. Its efficacy was extrapolated based on the drug’s pharmacokinetic profile seen with IV tocilizumab in SJIA patients and with subcutaneous tocilizumab in patients with rheumatoid arthritis.

SJIA is a rare disease with limited treatment options, according to the press release. In general, JIA affects almost 300,000 children in the United States, and about 10% of those cases are SJIA.

cpalmer@mdedge.com

The Food and Drug Administration has approved the subcutaneous formulation of Actemra (tocilizumab) for systemic juvenile idiopathic arthritis (SJIA) for patients aged 2 years and older, according to a press release from its developer, Genentech. The intravenous formulation was approved in 2011 for this indication.

The approval is based on data the JIGSAW-118 study. This 52-week, open-label, multicenter, phase 1b pharmacokinetic/pharmacodynamic bridging study was designed to determine the appropriate dosing regimen by treating 51 patients with SJIA according to body weight.

The safety profile of subcutaneous tocilizumab was similar to that seen with intravenous tocilizumab, although there were more injection-site reactions seen with the subcutaneous formulation. Its efficacy was extrapolated based on the drug’s pharmacokinetic profile seen with IV tocilizumab in SJIA patients and with subcutaneous tocilizumab in patients with rheumatoid arthritis.

SJIA is a rare disease with limited treatment options, according to the press release. In general, JIA affects almost 300,000 children in the United States, and about 10% of those cases are SJIA.

cpalmer@mdedge.com

Fetal alcohol spectrum disorder should be screened for, diagnosed, and managed in an integrated pediatric medical home, providing early intervention and accessing community resources, according to a clinical report from the American Academy of Pediatrics.

NIH/National Institute on Alcohol Abuse and Alcoholism//CCSA 3.0

After the AAP released its guidelines on fetal alcohol spectrum disorder (FASD) in 2015, some pediatricians asked for further guidance on how to care for patients with FASD within the medical home, as many had a knowledge gap on how to best manage these patients.

“For some pediatricians, it can seem like a daunting task to care for an individual with an FASD, but there are aspects of integrated care and providing a medical home that can be instituted as with all children with complex medical diagnoses,” wrote Renee M. Turchi, MD, MPH, of the department of pediatrics at St. Christopher’s Hospital for Children and Drexel Dornsife School of Public Health in Philadelphia, and her colleagues on the AAP Committee on Substance Abuse and the Council on Children with Disabilities. Their report is in Pediatrics. “In addition, not recognizing an FASD can lead to inadequate treatment and less-than-optimal outcomes for the patient and family.”

Dr. Turchi and her colleagues released the FASD clinical report with “strategies to support families who are interacting with early intervention services, the educational system, the behavioral and/or mental health system, other community resources, and the transition to adult-oriented heath care systems when appropriate.” They noted the prevalence of FASD is increasing, with 1 in 10 pregnant women using alcohol within the past 30 days and 1 in 33 pregnant women reporting binge drinking in the past 30 days. They reaffirmed the AAP’s endorsement from the 2015 clinical report on FASD regarding abstinence of alcohol for pregnant women, emphasizing that there is no amount or kind of alcohol that is risk free during pregnancy, nor is there a time in pregnancy when drinking alcohol is risk free.

Providers in a medical home should communicate any prenatal alcohol exposure (PAE) to obstetric providers so they can review risk factors, optimize screening, and monitor children, Dr. Turchi and her colleagues said. They also should understand the diagnostic criteria and classifications for FASDs, including physical features such as low weight, short palpebral features, smooth philtrum, a thin upper lip, abnormalities in the central nervous system, and any alcohol use during pregnancy. Any child – regardless of age – is a candidate for universal PAE screening at initial visits or when “additional cognitive and behavioral concerns arise.”

The federal Child Abuse Prevention and Treatment Act “does not require clinicians to report to child protective services if a child has been exposed prenatally to alcohol (i.e., for a positive PAE screening result). Referral to child protective services is required if the child has been diagnosed with an FASD in the period between birth and 3 years. The intent of this referral is to develop safe care and possible treatment plans for the infant and caregiver if needed, not to initiate punitive actions,” according to the report. States have their own definitions about child abuse and neglect, so the report encourages providers to know the mandates and reporting laws in the states where they practice.

Monitoring children in a medical home for the signs and symptoms of FASD is important, the authors said, because research has shown an increased chance at reducing adverse life outcomes if a child is diagnosed before age 6 and is in a stable home with access to support services.

Management of children with FASD is individual, as symptoms for each child will uniquely present not just in terms of physical issues such as growth or congenital defects affecting the heart, eyes, kidneys, or bones, but also as developmental, cognitive, and behavioral problems. Children with FASD also may receive a concomitant diagnosis when evaluated, such as ADHD or depression, that will require additional accommodation. The use of evidence-based diagnostic and standard screening approaches and referring when necessary will help reevaluate whether a child has a condition such as ADHD, oppositional defiant disorder, or another diagnosis, or is displaying symptoms of FASD such as a receptive or expressive language disorder.

Pediatricians must work together with the families, educational professionals, the mental health community, and therapists to help manage FASD in children. In cases where a child is in foster care, partnering with the foster care partners and child welfare agencies to gain access to the medical information of the biological parents is important to determine whether there is parental history of substance abuse and to provide appropriate treatment and interventions.

“Given the complex array of systems and services requiring navigation and coordination for children with an FASD and their families, a high-quality primary care medical home with partnerships with families, specialists, therapists, mental and/or behavioral health professionals, and community partners is critical, as it is for all children with special health care needs,” Dr. Turchi and her colleagues said.

The authors reported no relevant conflicts of interest.
 

SOURCE: Turchi RM et al. Pediatrics. 2018 Sept 10. doi:10.1542/peds.2018-2333.

Fetal alcohol spectrum disorder should be screened for, diagnosed, and managed in an integrated pediatric medical home, providing early intervention and accessing community resources, according to a clinical report from the American Academy of Pediatrics.

NIH/National Institute on Alcohol Abuse and Alcoholism//CCSA 3.0

After the AAP released its guidelines on fetal alcohol spectrum disorder (FASD) in 2015, some pediatricians asked for further guidance on how to care for patients with FASD within the medical home, as many had a knowledge gap on how to best manage these patients.

“For some pediatricians, it can seem like a daunting task to care for an individual with an FASD, but there are aspects of integrated care and providing a medical home that can be instituted as with all children with complex medical diagnoses,” wrote Renee M. Turchi, MD, MPH, of the department of pediatrics at St. Christopher’s Hospital for Children and Drexel Dornsife School of Public Health in Philadelphia, and her colleagues on the AAP Committee on Substance Abuse and the Council on Children with Disabilities. Their report is in Pediatrics. “In addition, not recognizing an FASD can lead to inadequate treatment and less-than-optimal outcomes for the patient and family.”

Dr. Turchi and her colleagues released the FASD clinical report with “strategies to support families who are interacting with early intervention services, the educational system, the behavioral and/or mental health system, other community resources, and the transition to adult-oriented heath care systems when appropriate.” They noted the prevalence of FASD is increasing, with 1 in 10 pregnant women using alcohol within the past 30 days and 1 in 33 pregnant women reporting binge drinking in the past 30 days. They reaffirmed the AAP’s endorsement from the 2015 clinical report on FASD regarding abstinence of alcohol for pregnant women, emphasizing that there is no amount or kind of alcohol that is risk free during pregnancy, nor is there a time in pregnancy when drinking alcohol is risk free.

Providers in a medical home should communicate any prenatal alcohol exposure (PAE) to obstetric providers so they can review risk factors, optimize screening, and monitor children, Dr. Turchi and her colleagues said. They also should understand the diagnostic criteria and classifications for FASDs, including physical features such as low weight, short palpebral features, smooth philtrum, a thin upper lip, abnormalities in the central nervous system, and any alcohol use during pregnancy. Any child – regardless of age – is a candidate for universal PAE screening at initial visits or when “additional cognitive and behavioral concerns arise.”

The federal Child Abuse Prevention and Treatment Act “does not require clinicians to report to child protective services if a child has been exposed prenatally to alcohol (i.e., for a positive PAE screening result). Referral to child protective services is required if the child has been diagnosed with an FASD in the period between birth and 3 years. The intent of this referral is to develop safe care and possible treatment plans for the infant and caregiver if needed, not to initiate punitive actions,” according to the report. States have their own definitions about child abuse and neglect, so the report encourages providers to know the mandates and reporting laws in the states where they practice.

Monitoring children in a medical home for the signs and symptoms of FASD is important, the authors said, because research has shown an increased chance at reducing adverse life outcomes if a child is diagnosed before age 6 and is in a stable home with access to support services.

Management of children with FASD is individual, as symptoms for each child will uniquely present not just in terms of physical issues such as growth or congenital defects affecting the heart, eyes, kidneys, or bones, but also as developmental, cognitive, and behavioral problems. Children with FASD also may receive a concomitant diagnosis when evaluated, such as ADHD or depression, that will require additional accommodation. The use of evidence-based diagnostic and standard screening approaches and referring when necessary will help reevaluate whether a child has a condition such as ADHD, oppositional defiant disorder, or another diagnosis, or is displaying symptoms of FASD such as a receptive or expressive language disorder.

Pediatricians must work together with the families, educational professionals, the mental health community, and therapists to help manage FASD in children. In cases where a child is in foster care, partnering with the foster care partners and child welfare agencies to gain access to the medical information of the biological parents is important to determine whether there is parental history of substance abuse and to provide appropriate treatment and interventions.

“Given the complex array of systems and services requiring navigation and coordination for children with an FASD and their families, a high-quality primary care medical home with partnerships with families, specialists, therapists, mental and/or behavioral health professionals, and community partners is critical, as it is for all children with special health care needs,” Dr. Turchi and her colleagues said.

The authors reported no relevant conflicts of interest.
 

SOURCE: Turchi RM et al. Pediatrics. 2018 Sept 10. doi:10.1542/peds.2018-2333.

Fetal alcohol spectrum disorder should be screened for, diagnosed, and managed in an integrated pediatric medical home, providing early intervention and accessing community resources, according to a clinical report from the American Academy of Pediatrics.

NIH/National Institute on Alcohol Abuse and Alcoholism//CCSA 3.0

After the AAP released its guidelines on fetal alcohol spectrum disorder (FASD) in 2015, some pediatricians asked for further guidance on how to care for patients with FASD within the medical home, as many had a knowledge gap on how to best manage these patients.

“For some pediatricians, it can seem like a daunting task to care for an individual with an FASD, but there are aspects of integrated care and providing a medical home that can be instituted as with all children with complex medical diagnoses,” wrote Renee M. Turchi, MD, MPH, of the department of pediatrics at St. Christopher’s Hospital for Children and Drexel Dornsife School of Public Health in Philadelphia, and her colleagues on the AAP Committee on Substance Abuse and the Council on Children with Disabilities. Their report is in Pediatrics. “In addition, not recognizing an FASD can lead to inadequate treatment and less-than-optimal outcomes for the patient and family.”

Dr. Turchi and her colleagues released the FASD clinical report with “strategies to support families who are interacting with early intervention services, the educational system, the behavioral and/or mental health system, other community resources, and the transition to adult-oriented heath care systems when appropriate.” They noted the prevalence of FASD is increasing, with 1 in 10 pregnant women using alcohol within the past 30 days and 1 in 33 pregnant women reporting binge drinking in the past 30 days. They reaffirmed the AAP’s endorsement from the 2015 clinical report on FASD regarding abstinence of alcohol for pregnant women, emphasizing that there is no amount or kind of alcohol that is risk free during pregnancy, nor is there a time in pregnancy when drinking alcohol is risk free.

Providers in a medical home should communicate any prenatal alcohol exposure (PAE) to obstetric providers so they can review risk factors, optimize screening, and monitor children, Dr. Turchi and her colleagues said. They also should understand the diagnostic criteria and classifications for FASDs, including physical features such as low weight, short palpebral features, smooth philtrum, a thin upper lip, abnormalities in the central nervous system, and any alcohol use during pregnancy. Any child – regardless of age – is a candidate for universal PAE screening at initial visits or when “additional cognitive and behavioral concerns arise.”

The federal Child Abuse Prevention and Treatment Act “does not require clinicians to report to child protective services if a child has been exposed prenatally to alcohol (i.e., for a positive PAE screening result). Referral to child protective services is required if the child has been diagnosed with an FASD in the period between birth and 3 years. The intent of this referral is to develop safe care and possible treatment plans for the infant and caregiver if needed, not to initiate punitive actions,” according to the report. States have their own definitions about child abuse and neglect, so the report encourages providers to know the mandates and reporting laws in the states where they practice.

Monitoring children in a medical home for the signs and symptoms of FASD is important, the authors said, because research has shown an increased chance at reducing adverse life outcomes if a child is diagnosed before age 6 and is in a stable home with access to support services.

Management of children with FASD is individual, as symptoms for each child will uniquely present not just in terms of physical issues such as growth or congenital defects affecting the heart, eyes, kidneys, or bones, but also as developmental, cognitive, and behavioral problems. Children with FASD also may receive a concomitant diagnosis when evaluated, such as ADHD or depression, that will require additional accommodation. The use of evidence-based diagnostic and standard screening approaches and referring when necessary will help reevaluate whether a child has a condition such as ADHD, oppositional defiant disorder, or another diagnosis, or is displaying symptoms of FASD such as a receptive or expressive language disorder.

Pediatricians must work together with the families, educational professionals, the mental health community, and therapists to help manage FASD in children. In cases where a child is in foster care, partnering with the foster care partners and child welfare agencies to gain access to the medical information of the biological parents is important to determine whether there is parental history of substance abuse and to provide appropriate treatment and interventions.

“Given the complex array of systems and services requiring navigation and coordination for children with an FASD and their families, a high-quality primary care medical home with partnerships with families, specialists, therapists, mental and/or behavioral health professionals, and community partners is critical, as it is for all children with special health care needs,” Dr. Turchi and her colleagues said.

The authors reported no relevant conflicts of interest.
 

SOURCE: Turchi RM et al. Pediatrics. 2018 Sept 10. doi:10.1542/peds.2018-2333.

To the Editor:

A 17-year-old adolescent boy presented with dark spots on the legs and back of 2 months’ duration. He was not taking any medications and the spots could not be washed away by scrubbing with soap and water. He denied symptoms, except occasional itching. Family history revealed a maternal uncle with protein C deficiency and a maternal grandmother with systemic lupus erythematosus. Review of systems was negative; the patient denied joint pain and contact with heating pads or laptop computers. Based on the initial presentation, an underlying systemic condition was suspected. Physical examination revealed reticulate, nonblanching, brown patches on the bilateral arms, legs, and back in an apparent livedoid pattern (Figure). The patient’s history and physical examination suggested terra firma-forme dermatosis, livedo racemosa, or another vasculopathic process. However, gentle rubbing of the skin with an alcohol swab removed the discoloration completely, leading to the diagnosis of terra firma-forme dermatosis.

Livedo racemosa appears as an irregular, focal, reticulated discoloration of the skin.¹ The reticulated pattern of livedo racemosa has a branched or broken-up appearance.² Livedo racemosa indicates a disruption in the vasculature due to inflammation or occlusion.¹ The change is pathologic and does not blanch or resolve with warming.^1,2 The condition can progress to pigmentation and ulceration.¹ Livedo racemosa is a cutaneous manifestation of underlying vascular pathology. Due to a variety of causes, skin biopsy is nondiagnostic. Livedo racemosa can be caused by conditions such as systemic lupus erythematosus, syphilis, tuberculosis, polycythemia rubra vera, and Sneddon syndrome, among others.^3-5

Terra firma-forme dermatosis was reported in 1987 by Duncan et al.⁶ The condition classically presents with an exasperated mother who is unable to clean the “dirt” off her child’s skin despite multiple vigorous scrubbing attempts. The condition most commonly occurs in the summer months on the neck, face, and ankles.^7,8 Duncan et al⁶ reported that when the affected area was prepared for a biopsy, clean skin was revealed after wiping with an alcohol swab. No other cleansing agent has been reported to effectively remove the discoloration of terra firma-forme dermatosis. Hoping to elucidate a cause, Duncan et al⁶ performed both bacteriologic and fungal studies. The bacterial skin culture grew only normal flora, and fungal culture grew only normal contaminants consistent with the potassium hydroxide preparation of skin scraping. Histopathologic examination showed hyperkeratosis and orthokeratosis but not parakeratosis. Staining revealed melanin in the hyperkeratotic areas.⁶ Although the cause of this condition largely is unknown, it is thought that the epidermis in the affected areas could undergo altered maturation, resulting in trapping melanin that causes the skin to appear hyperkeratotic and hyperpigmented.¹ In our case, wiping the skin revealed the unsuspected diagnosis of terra firma-forme dermatosis displaying an unusual pseudolivedoid pattern. With apparently hyperpigmented processes, rubbing the skin with alcohol may help avoid unnecessary aggressive workup.

To the Editor:

A 17-year-old adolescent boy presented with dark spots on the legs and back of 2 months’ duration. He was not taking any medications and the spots could not be washed away by scrubbing with soap and water. He denied symptoms, except occasional itching. Family history revealed a maternal uncle with protein C deficiency and a maternal grandmother with systemic lupus erythematosus. Review of systems was negative; the patient denied joint pain and contact with heating pads or laptop computers. Based on the initial presentation, an underlying systemic condition was suspected. Physical examination revealed reticulate, nonblanching, brown patches on the bilateral arms, legs, and back in an apparent livedoid pattern (Figure). The patient’s history and physical examination suggested terra firma-forme dermatosis, livedo racemosa, or another vasculopathic process. However, gentle rubbing of the skin with an alcohol swab removed the discoloration completely, leading to the diagnosis of terra firma-forme dermatosis.

Livedo racemosa appears as an irregular, focal, reticulated discoloration of the skin.¹ The reticulated pattern of livedo racemosa has a branched or broken-up appearance.² Livedo racemosa indicates a disruption in the vasculature due to inflammation or occlusion.¹ The change is pathologic and does not blanch or resolve with warming.^1,2 The condition can progress to pigmentation and ulceration.¹ Livedo racemosa is a cutaneous manifestation of underlying vascular pathology. Due to a variety of causes, skin biopsy is nondiagnostic. Livedo racemosa can be caused by conditions such as systemic lupus erythematosus, syphilis, tuberculosis, polycythemia rubra vera, and Sneddon syndrome, among others.^3-5

Terra firma-forme dermatosis was reported in 1987 by Duncan et al.⁶ The condition classically presents with an exasperated mother who is unable to clean the “dirt” off her child’s skin despite multiple vigorous scrubbing attempts. The condition most commonly occurs in the summer months on the neck, face, and ankles.^7,8 Duncan et al⁶ reported that when the affected area was prepared for a biopsy, clean skin was revealed after wiping with an alcohol swab. No other cleansing agent has been reported to effectively remove the discoloration of terra firma-forme dermatosis. Hoping to elucidate a cause, Duncan et al⁶ performed both bacteriologic and fungal studies. The bacterial skin culture grew only normal flora, and fungal culture grew only normal contaminants consistent with the potassium hydroxide preparation of skin scraping. Histopathologic examination showed hyperkeratosis and orthokeratosis but not parakeratosis. Staining revealed melanin in the hyperkeratotic areas.⁶ Although the cause of this condition largely is unknown, it is thought that the epidermis in the affected areas could undergo altered maturation, resulting in trapping melanin that causes the skin to appear hyperkeratotic and hyperpigmented.¹ In our case, wiping the skin revealed the unsuspected diagnosis of terra firma-forme dermatosis displaying an unusual pseudolivedoid pattern. With apparently hyperpigmented processes, rubbing the skin with alcohol may help avoid unnecessary aggressive workup.

To the Editor:

A 17-year-old adolescent boy presented with dark spots on the legs and back of 2 months’ duration. He was not taking any medications and the spots could not be washed away by scrubbing with soap and water. He denied symptoms, except occasional itching. Family history revealed a maternal uncle with protein C deficiency and a maternal grandmother with systemic lupus erythematosus. Review of systems was negative; the patient denied joint pain and contact with heating pads or laptop computers. Based on the initial presentation, an underlying systemic condition was suspected. Physical examination revealed reticulate, nonblanching, brown patches on the bilateral arms, legs, and back in an apparent livedoid pattern (Figure). The patient’s history and physical examination suggested terra firma-forme dermatosis, livedo racemosa, or another vasculopathic process. However, gentle rubbing of the skin with an alcohol swab removed the discoloration completely, leading to the diagnosis of terra firma-forme dermatosis.

Livedo racemosa appears as an irregular, focal, reticulated discoloration of the skin.¹ The reticulated pattern of livedo racemosa has a branched or broken-up appearance.² Livedo racemosa indicates a disruption in the vasculature due to inflammation or occlusion.¹ The change is pathologic and does not blanch or resolve with warming.^1,2 The condition can progress to pigmentation and ulceration.¹ Livedo racemosa is a cutaneous manifestation of underlying vascular pathology. Due to a variety of causes, skin biopsy is nondiagnostic. Livedo racemosa can be caused by conditions such as systemic lupus erythematosus, syphilis, tuberculosis, polycythemia rubra vera, and Sneddon syndrome, among others.^3-5

Terra firma-forme dermatosis was reported in 1987 by Duncan et al.⁶ The condition classically presents with an exasperated mother who is unable to clean the “dirt” off her child’s skin despite multiple vigorous scrubbing attempts. The condition most commonly occurs in the summer months on the neck, face, and ankles.^7,8 Duncan et al⁶ reported that when the affected area was prepared for a biopsy, clean skin was revealed after wiping with an alcohol swab. No other cleansing agent has been reported to effectively remove the discoloration of terra firma-forme dermatosis. Hoping to elucidate a cause, Duncan et al⁶ performed both bacteriologic and fungal studies. The bacterial skin culture grew only normal flora, and fungal culture grew only normal contaminants consistent with the potassium hydroxide preparation of skin scraping. Histopathologic examination showed hyperkeratosis and orthokeratosis but not parakeratosis. Staining revealed melanin in the hyperkeratotic areas.⁶ Although the cause of this condition largely is unknown, it is thought that the epidermis in the affected areas could undergo altered maturation, resulting in trapping melanin that causes the skin to appear hyperkeratotic and hyperpigmented.¹ In our case, wiping the skin revealed the unsuspected diagnosis of terra firma-forme dermatosis displaying an unusual pseudolivedoid pattern. With apparently hyperpigmented processes, rubbing the skin with alcohol may help avoid unnecessary aggressive workup.

Children’s Research Hospital

An extensive analysis of mixed phenotype acute leukemia (MPAL) has led to new insights that may have implications for disease classification and treatment.

Researchers believe they have identified new subtypes of MPAL that should be included in the World Health Organization (WHO) classification for acute leukemia.

Each of these subtypes shares genomic characteristics with other acute leukemias, which suggests the new subtypes might respond to treatments that are already in use.

This research has also shed light on how MPAL evolves and appears to provide an explanation for why MPAL displays characteristics of both acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL).

“ALL and AML have very different treatments, but MPAL has features of both, so the question of how best to treat patients with MPAL has been challenging the leukemia community worldwide, and long-term survival of patients has been poor,” said Charles Mullighan, MBBS, MD, of St. Jude Children’s Research Hospital in Memphis, Tennessee.

With these issues in mind, Dr. Mullighan and his colleagues conducted their study of MPAL and described their findings in Nature.

New classifications

The researchers used whole-genome, whole-exome, and RNA sequencing to analyze 115 samples from pediatric patients with MPAL.

The analysis revealed mutations that define the two most common subtypes of MPAL—B/myeloid and T/myeloid—and suggested these subtypes share similarities with other leukemia subtypes.

The researchers found that 48% of B/myeloid MPAL cases carried rearrangements in ZNF384, a characteristic that is also found in cases of B-cell ALL. In fact, the team said the gene expression profiles of ZNF384r B-ALL and ZNF384r MPAL were indistinguishable.

“That is biologically and clinically important,” Dr. Mullighan said. “The findings suggest the ZNF384 rearrangement defines a distinct leukemia subtype, and the alteration should be used to guide treatment.”

The researchers noted that patients with ZNF384r exhibited higher FLT3 expression than patients with other types of B/myeloid or T/myeloid MPAL, so patients with ZNF384r MPAL might respond well to treatment with a FLT3 inhibitor.

This study also showed that cases of B/myeloid MPAL without ZNF384r shared genomic features with other B-ALL subtypes, such as Ph-like B-ALL, which may have implications for treatment.

Another of the researchers’ discoveries was that T/myeloid MPAL and early T-cell precursor ALL have similar gene expression profiles.

The team identified several genes that were mutated at similar frequencies in T/myeloid MPAL and early T-cell precursor ALL, including WT1, ETV6, EZH2, and FLT3. WT1 was the most frequently mutated transcription factor gene in T/myeloid MPAL.

Based on these findings, the researchers said the WHO classification of acute leukemia should be updated to include:

• ZNF384r acute leukemia (either B-ALL or MPAL)
• WT1-mutant T/myeloid MPAL
• Ph-like B/myeloid MPAL.

Evolution of MPAL

The researchers’ analyses also revealed leukemia-initiating genetic alterations in early hematopoietic progenitors.

The team said this and other findings—including the common genomic features of ZNF384r MPAL and B-ALL—suggest the ambiguous phenotype of MPAL results from alterations in immature hematopoietic progenitors.

“These findings suggest that the founding mutation occurs early in blood cell development, in some cases in hematopoietic stem cells, and results in an acute leukemia with features of both myeloid and lymphoid cells,” said study author Thomas Alexander, MD, of the University of North Carolina at Chapel Hill.

“One previous theory was that the reason you have two different cancer types within the same patient is that they acquire different mutations that drive them to become AML or ALL, with genomically distinct tumors within the same patient. That doesn’t seem to be the case from our data. Our proposed model is that the mutations occur earlier in development in cells that retain the potential to acquire myeloid or lymphoid features.”

This research was supported by the National Cancer Institute, the National Institutes of Health, Cookies for Kids’ Cancer, and other organizations.

Children’s Research Hospital

An extensive analysis of mixed phenotype acute leukemia (MPAL) has led to new insights that may have implications for disease classification and treatment.

Researchers believe they have identified new subtypes of MPAL that should be included in the World Health Organization (WHO) classification for acute leukemia.

Each of these subtypes shares genomic characteristics with other acute leukemias, which suggests the new subtypes might respond to treatments that are already in use.

This research has also shed light on how MPAL evolves and appears to provide an explanation for why MPAL displays characteristics of both acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL).

“ALL and AML have very different treatments, but MPAL has features of both, so the question of how best to treat patients with MPAL has been challenging the leukemia community worldwide, and long-term survival of patients has been poor,” said Charles Mullighan, MBBS, MD, of St. Jude Children’s Research Hospital in Memphis, Tennessee.

With these issues in mind, Dr. Mullighan and his colleagues conducted their study of MPAL and described their findings in Nature.

New classifications

The researchers used whole-genome, whole-exome, and RNA sequencing to analyze 115 samples from pediatric patients with MPAL.

The analysis revealed mutations that define the two most common subtypes of MPAL—B/myeloid and T/myeloid—and suggested these subtypes share similarities with other leukemia subtypes.

The researchers found that 48% of B/myeloid MPAL cases carried rearrangements in ZNF384, a characteristic that is also found in cases of B-cell ALL. In fact, the team said the gene expression profiles of ZNF384r B-ALL and ZNF384r MPAL were indistinguishable.

“That is biologically and clinically important,” Dr. Mullighan said. “The findings suggest the ZNF384 rearrangement defines a distinct leukemia subtype, and the alteration should be used to guide treatment.”

The researchers noted that patients with ZNF384r exhibited higher FLT3 expression than patients with other types of B/myeloid or T/myeloid MPAL, so patients with ZNF384r MPAL might respond well to treatment with a FLT3 inhibitor.

This study also showed that cases of B/myeloid MPAL without ZNF384r shared genomic features with other B-ALL subtypes, such as Ph-like B-ALL, which may have implications for treatment.

Another of the researchers’ discoveries was that T/myeloid MPAL and early T-cell precursor ALL have similar gene expression profiles.

The team identified several genes that were mutated at similar frequencies in T/myeloid MPAL and early T-cell precursor ALL, including WT1, ETV6, EZH2, and FLT3. WT1 was the most frequently mutated transcription factor gene in T/myeloid MPAL.

Based on these findings, the researchers said the WHO classification of acute leukemia should be updated to include:

• ZNF384r acute leukemia (either B-ALL or MPAL)
• WT1-mutant T/myeloid MPAL
• Ph-like B/myeloid MPAL.

Evolution of MPAL

The researchers’ analyses also revealed leukemia-initiating genetic alterations in early hematopoietic progenitors.

The team said this and other findings—including the common genomic features of ZNF384r MPAL and B-ALL—suggest the ambiguous phenotype of MPAL results from alterations in immature hematopoietic progenitors.

“These findings suggest that the founding mutation occurs early in blood cell development, in some cases in hematopoietic stem cells, and results in an acute leukemia with features of both myeloid and lymphoid cells,” said study author Thomas Alexander, MD, of the University of North Carolina at Chapel Hill.

“One previous theory was that the reason you have two different cancer types within the same patient is that they acquire different mutations that drive them to become AML or ALL, with genomically distinct tumors within the same patient. That doesn’t seem to be the case from our data. Our proposed model is that the mutations occur earlier in development in cells that retain the potential to acquire myeloid or lymphoid features.”

This research was supported by the National Cancer Institute, the National Institutes of Health, Cookies for Kids’ Cancer, and other organizations.

Children’s Research Hospital

An extensive analysis of mixed phenotype acute leukemia (MPAL) has led to new insights that may have implications for disease classification and treatment.

Researchers believe they have identified new subtypes of MPAL that should be included in the World Health Organization (WHO) classification for acute leukemia.

Each of these subtypes shares genomic characteristics with other acute leukemias, which suggests the new subtypes might respond to treatments that are already in use.

This research has also shed light on how MPAL evolves and appears to provide an explanation for why MPAL displays characteristics of both acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL).

“ALL and AML have very different treatments, but MPAL has features of both, so the question of how best to treat patients with MPAL has been challenging the leukemia community worldwide, and long-term survival of patients has been poor,” said Charles Mullighan, MBBS, MD, of St. Jude Children’s Research Hospital in Memphis, Tennessee.

With these issues in mind, Dr. Mullighan and his colleagues conducted their study of MPAL and described their findings in Nature.

New classifications

The researchers used whole-genome, whole-exome, and RNA sequencing to analyze 115 samples from pediatric patients with MPAL.

The analysis revealed mutations that define the two most common subtypes of MPAL—B/myeloid and T/myeloid—and suggested these subtypes share similarities with other leukemia subtypes.

The researchers found that 48% of B/myeloid MPAL cases carried rearrangements in ZNF384, a characteristic that is also found in cases of B-cell ALL. In fact, the team said the gene expression profiles of ZNF384r B-ALL and ZNF384r MPAL were indistinguishable.

“That is biologically and clinically important,” Dr. Mullighan said. “The findings suggest the ZNF384 rearrangement defines a distinct leukemia subtype, and the alteration should be used to guide treatment.”

The researchers noted that patients with ZNF384r exhibited higher FLT3 expression than patients with other types of B/myeloid or T/myeloid MPAL, so patients with ZNF384r MPAL might respond well to treatment with a FLT3 inhibitor.

This study also showed that cases of B/myeloid MPAL without ZNF384r shared genomic features with other B-ALL subtypes, such as Ph-like B-ALL, which may have implications for treatment.

Another of the researchers’ discoveries was that T/myeloid MPAL and early T-cell precursor ALL have similar gene expression profiles.

The team identified several genes that were mutated at similar frequencies in T/myeloid MPAL and early T-cell precursor ALL, including WT1, ETV6, EZH2, and FLT3. WT1 was the most frequently mutated transcription factor gene in T/myeloid MPAL.

Based on these findings, the researchers said the WHO classification of acute leukemia should be updated to include:

• ZNF384r acute leukemia (either B-ALL or MPAL)
• WT1-mutant T/myeloid MPAL
• Ph-like B/myeloid MPAL.

Evolution of MPAL

The researchers’ analyses also revealed leukemia-initiating genetic alterations in early hematopoietic progenitors.

The team said this and other findings—including the common genomic features of ZNF384r MPAL and B-ALL—suggest the ambiguous phenotype of MPAL results from alterations in immature hematopoietic progenitors.

“These findings suggest that the founding mutation occurs early in blood cell development, in some cases in hematopoietic stem cells, and results in an acute leukemia with features of both myeloid and lymphoid cells,” said study author Thomas Alexander, MD, of the University of North Carolina at Chapel Hill.

“One previous theory was that the reason you have two different cancer types within the same patient is that they acquire different mutations that drive them to become AML or ALL, with genomically distinct tumors within the same patient. That doesn’t seem to be the case from our data. Our proposed model is that the mutations occur earlier in development in cells that retain the potential to acquire myeloid or lymphoid features.”

This research was supported by the National Cancer Institute, the National Institutes of Health, Cookies for Kids’ Cancer, and other organizations.

Photo by Bill Branson

In a phase 3 study, levofloxacin prophylaxis significantly reduced bacteremia in children with acute leukemias who received intensive chemotherapy.

However, the risk of bacteremia was not significantly reduced with levofloxacin in another cohort of children who underwent hematopoietic stem cell transplant (HSCT).

Sarah Alexander, MD, of the Hospital for Sick Children in Toronto, Ontario, Canada, and her colleagues reported these findings in JAMA.

This multicenter, randomized trial (ACCL0934) enrolled patients aged 6 months to 21 years.

There were 200 patients with acute leukemias (acute myeloid leukemia or relapsed acute lymphoblastic leukemia) who were set to receive chemotherapy and 424 patients who were to receive a myeloablative autologous or allogeneic HSCT.

The acute leukemia patients were randomized to receive no prophylaxis (n=100) or levofloxacin prophylaxis (n=100) for two consecutive cycles of chemotherapy.

The HSCT recipients were randomized to receive no prophylaxis (n=214) or levofloxacin prophylaxis (n=210) during one HSCT procedure.

Results

In the primary analysis of the acute leukemia group (n=195), the incidence of bacteremia was 21.9% for those randomized to levofloxacin and 43.4% for those who did not receive prophylaxis (P=0.001).

In the primary analysis of the HSCT group (n=418), the incidence of bacteremia was 11.0% in the levofloxacin arm and 17.3% in the control arm (P=0.06).

However, a post hoc analysis accounting for time at risk showed a significant difference in favor of prophylaxis in both the acute leukemia and HSCT groups and a similar effect size between groups.

For the acute leukemia group, the rate of bacteremic episodes in the post hoc analysis was 4.9 versus 9.4 per 1,000 patient-days in the prophylaxis and control arms, respectively (P=0.008).

In the HSCT group, the rate of bacteremic episodes was 5.3 versus 10.0 per 1,000 patient-days in the prophylaxis and control arms, respectively (P=0.02).

The researchers said it is possible that the effect of prophylaxis was similar between the HSCT and acute leukemia groups, but there was reduced power to detect a significant difference because of fewer events among HSCT recipients.

However, the differences between the HSCT and acute leukemia groups in the primary analysis might also be explained by differences in supportive care measures or infections with pathogens that had differential sensitivity to levofloxacin.

The researchers noted that levofloxacin-resistant pathogens, such as viridans group streptococcal isolates and several gram-negative isolates, often were detected in patients who had bacteremia events despite prophylaxis. This suggests other interventions in combination with levofloxacin prophylaxis are probably needed to further decrease risk.

Dr. Alexander and her colleagues also said further randomized studies are needed to better understand the risks of levofloxacin in relation to its benefits.

In the current study, there were 23 serious adverse events reported in 8 patients. Twelve of these events, occurring in two patients, may have been related to levofloxacin.

This research was supported by grants from the Community Clinical Oncology Program and National Cancer Institute. Dr. Alexander reported no disclosures. Coauthors reported disclosures related to Bristol-Myers Squibb, Chimerix, Jazz Pharmaceuticals, and the Children’s Oncology Group.

Photo by Bill Branson

In a phase 3 study, levofloxacin prophylaxis significantly reduced bacteremia in children with acute leukemias who received intensive chemotherapy.

However, the risk of bacteremia was not significantly reduced with levofloxacin in another cohort of children who underwent hematopoietic stem cell transplant (HSCT).

Sarah Alexander, MD, of the Hospital for Sick Children in Toronto, Ontario, Canada, and her colleagues reported these findings in JAMA.

This multicenter, randomized trial (ACCL0934) enrolled patients aged 6 months to 21 years.

There were 200 patients with acute leukemias (acute myeloid leukemia or relapsed acute lymphoblastic leukemia) who were set to receive chemotherapy and 424 patients who were to receive a myeloablative autologous or allogeneic HSCT.

The acute leukemia patients were randomized to receive no prophylaxis (n=100) or levofloxacin prophylaxis (n=100) for two consecutive cycles of chemotherapy.

The HSCT recipients were randomized to receive no prophylaxis (n=214) or levofloxacin prophylaxis (n=210) during one HSCT procedure.

Results

In the primary analysis of the acute leukemia group (n=195), the incidence of bacteremia was 21.9% for those randomized to levofloxacin and 43.4% for those who did not receive prophylaxis (P=0.001).

In the primary analysis of the HSCT group (n=418), the incidence of bacteremia was 11.0% in the levofloxacin arm and 17.3% in the control arm (P=0.06).

However, a post hoc analysis accounting for time at risk showed a significant difference in favor of prophylaxis in both the acute leukemia and HSCT groups and a similar effect size between groups.

For the acute leukemia group, the rate of bacteremic episodes in the post hoc analysis was 4.9 versus 9.4 per 1,000 patient-days in the prophylaxis and control arms, respectively (P=0.008).

In the HSCT group, the rate of bacteremic episodes was 5.3 versus 10.0 per 1,000 patient-days in the prophylaxis and control arms, respectively (P=0.02).

The researchers said it is possible that the effect of prophylaxis was similar between the HSCT and acute leukemia groups, but there was reduced power to detect a significant difference because of fewer events among HSCT recipients.

However, the differences between the HSCT and acute leukemia groups in the primary analysis might also be explained by differences in supportive care measures or infections with pathogens that had differential sensitivity to levofloxacin.

The researchers noted that levofloxacin-resistant pathogens, such as viridans group streptococcal isolates and several gram-negative isolates, often were detected in patients who had bacteremia events despite prophylaxis. This suggests other interventions in combination with levofloxacin prophylaxis are probably needed to further decrease risk.

Dr. Alexander and her colleagues also said further randomized studies are needed to better understand the risks of levofloxacin in relation to its benefits.

In the current study, there were 23 serious adverse events reported in 8 patients. Twelve of these events, occurring in two patients, may have been related to levofloxacin.

This research was supported by grants from the Community Clinical Oncology Program and National Cancer Institute. Dr. Alexander reported no disclosures. Coauthors reported disclosures related to Bristol-Myers Squibb, Chimerix, Jazz Pharmaceuticals, and the Children’s Oncology Group.

Photo by Bill Branson

In a phase 3 study, levofloxacin prophylaxis significantly reduced bacteremia in children with acute leukemias who received intensive chemotherapy.

However, the risk of bacteremia was not significantly reduced with levofloxacin in another cohort of children who underwent hematopoietic stem cell transplant (HSCT).

Sarah Alexander, MD, of the Hospital for Sick Children in Toronto, Ontario, Canada, and her colleagues reported these findings in JAMA.

This multicenter, randomized trial (ACCL0934) enrolled patients aged 6 months to 21 years.

There were 200 patients with acute leukemias (acute myeloid leukemia or relapsed acute lymphoblastic leukemia) who were set to receive chemotherapy and 424 patients who were to receive a myeloablative autologous or allogeneic HSCT.

The acute leukemia patients were randomized to receive no prophylaxis (n=100) or levofloxacin prophylaxis (n=100) for two consecutive cycles of chemotherapy.

The HSCT recipients were randomized to receive no prophylaxis (n=214) or levofloxacin prophylaxis (n=210) during one HSCT procedure.

Results

In the primary analysis of the acute leukemia group (n=195), the incidence of bacteremia was 21.9% for those randomized to levofloxacin and 43.4% for those who did not receive prophylaxis (P=0.001).

In the primary analysis of the HSCT group (n=418), the incidence of bacteremia was 11.0% in the levofloxacin arm and 17.3% in the control arm (P=0.06).

However, a post hoc analysis accounting for time at risk showed a significant difference in favor of prophylaxis in both the acute leukemia and HSCT groups and a similar effect size between groups.

For the acute leukemia group, the rate of bacteremic episodes in the post hoc analysis was 4.9 versus 9.4 per 1,000 patient-days in the prophylaxis and control arms, respectively (P=0.008).

In the HSCT group, the rate of bacteremic episodes was 5.3 versus 10.0 per 1,000 patient-days in the prophylaxis and control arms, respectively (P=0.02).

The researchers said it is possible that the effect of prophylaxis was similar between the HSCT and acute leukemia groups, but there was reduced power to detect a significant difference because of fewer events among HSCT recipients.

However, the differences between the HSCT and acute leukemia groups in the primary analysis might also be explained by differences in supportive care measures or infections with pathogens that had differential sensitivity to levofloxacin.

The researchers noted that levofloxacin-resistant pathogens, such as viridans group streptococcal isolates and several gram-negative isolates, often were detected in patients who had bacteremia events despite prophylaxis. This suggests other interventions in combination with levofloxacin prophylaxis are probably needed to further decrease risk.

Dr. Alexander and her colleagues also said further randomized studies are needed to better understand the risks of levofloxacin in relation to its benefits.

In the current study, there were 23 serious adverse events reported in 8 patients. Twelve of these events, occurring in two patients, may have been related to levofloxacin.

This research was supported by grants from the Community Clinical Oncology Program and National Cancer Institute. Dr. Alexander reported no disclosures. Coauthors reported disclosures related to Bristol-Myers Squibb, Chimerix, Jazz Pharmaceuticals, and the Children’s Oncology Group.

Photo by Nina Matthews

A nationwide cohort study suggests an association between a woman’s use of hormonal contraceptives and leukemia in her offspring.

Children of mothers who used hormonal contraception, either during pregnancy or in the 3 months beforehand, had a 1.5-fold greater risk of leukemia, when compared to children of mothers who had never used hormonal contraception.

This increased risk translated to one additional case of leukemia per about 50,000 children exposed to hormonal contraceptives.

The increased risk appeared limited to non-lymphoid leukemia.

Marie Hargreave, PhD, of the Danish Cancer Society Research Center in Copenhagen, Denmark, and her colleagues reported these findings in The Lancet Oncology.

The study included 1,185,157 children born between 1996 and 2014 and followed for a median of 9.3 years. Data on these children were collected from the Danish Medical Birth Registry and the Danish Cancer Registry.

The researchers looked at redeemed prescriptions from the Danish National Prescription Registry to determine the mothers’ contraceptive use and divided the women into three categories:

• Mothers who had never used hormonal contraceptives
• Those with previous hormonal contraceptive use, defined as greater than 3 months before the start of pregnancy
• Mothers with recent contraceptive use, defined as during or within 3 months of pregnancy.

Results

There were 606 children diagnosed with leukemia in the study cohort—465 with lymphoid leukemia and 141 with non-lymphoid leukemia.

Overall, children born to mothers with previous or recent use of hormonal contraceptives had a significantly increased risk of developing any leukemia. The hazard ratios (HRs) were as follows:

• Previous use of hormonal contraceptives—HR=1.25 (P=0.039)
• Recent use—HR=1.46 (P=0.011)
• Use within 3 months of pregnancy—HR=1.42 (P=0.025)
• Use during pregnancy—HR=1.78 (P=0.070).

The risk of lymphoid leukemia did not increase significantly with maternal use of hormonal contraceptives. The HRs were as follows:

• Previous use of hormonal contraceptives—HR=1.23 (P=0.089)
• Recent use—HR=1.27 (P=0.167)
• Use within 3 months of pregnancy—HR=1.28 (P=0.173)
• Use during pregnancy—HR=1.22 (P=0.635).

However, the risk of non-lymphoid leukemia was significantly increased in children born to mothers with recent hormonal contraceptive use. The HRs were as follows:

• Previous use of hormonal contraceptives—HR=1.33 (P=0.232)
• Recent use—HR=2.17 (P=0.008)
• Use within 3 months of pregnancy—HR=1.95 (P=0.033)
• Use during pregnancy—HR=3.87 (P=0.006).

The association between recent contraceptive use and any leukemia was strongest in children ages 6 to 10 years. The researchers said this was not surprising because the incidence of non-lymphoid leukemia increases after the age of 6.

The researchers estimated that a mother’s recent use of hormonal contraceptives would have resulted in about one additional case of leukemia per 47,170 children; in other words, 25 additional cases of leukemia over the study period.

This low risk of leukemia “is not a major concern with regard to the safety of hormonal contraceptives,” the researchers said.

However, the findings do suggest the intrauterine hormonal environment affects leukemia development in children, and this should be explored in future research.

This study was supported by the Danish Cancer Research Foundation and other foundations. One author reported grants from the sponsoring foundations, and another author reported speaking fees from Jazz Pharmaceuticals and Shire Pharmaceuticals.

Photo by Nina Matthews

A nationwide cohort study suggests an association between a woman’s use of hormonal contraceptives and leukemia in her offspring.

Children of mothers who used hormonal contraception, either during pregnancy or in the 3 months beforehand, had a 1.5-fold greater risk of leukemia, when compared to children of mothers who had never used hormonal contraception.

This increased risk translated to one additional case of leukemia per about 50,000 children exposed to hormonal contraceptives.

The increased risk appeared limited to non-lymphoid leukemia.

Marie Hargreave, PhD, of the Danish Cancer Society Research Center in Copenhagen, Denmark, and her colleagues reported these findings in The Lancet Oncology.

The study included 1,185,157 children born between 1996 and 2014 and followed for a median of 9.3 years. Data on these children were collected from the Danish Medical Birth Registry and the Danish Cancer Registry.

The researchers looked at redeemed prescriptions from the Danish National Prescription Registry to determine the mothers’ contraceptive use and divided the women into three categories:

• Mothers who had never used hormonal contraceptives
• Those with previous hormonal contraceptive use, defined as greater than 3 months before the start of pregnancy
• Mothers with recent contraceptive use, defined as during or within 3 months of pregnancy.

Results

There were 606 children diagnosed with leukemia in the study cohort—465 with lymphoid leukemia and 141 with non-lymphoid leukemia.

Overall, children born to mothers with previous or recent use of hormonal contraceptives had a significantly increased risk of developing any leukemia. The hazard ratios (HRs) were as follows:

• Previous use of hormonal contraceptives—HR=1.25 (P=0.039)
• Recent use—HR=1.46 (P=0.011)
• Use within 3 months of pregnancy—HR=1.42 (P=0.025)
• Use during pregnancy—HR=1.78 (P=0.070).

The risk of lymphoid leukemia did not increase significantly with maternal use of hormonal contraceptives. The HRs were as follows:

• Previous use of hormonal contraceptives—HR=1.23 (P=0.089)
• Recent use—HR=1.27 (P=0.167)
• Use within 3 months of pregnancy—HR=1.28 (P=0.173)
• Use during pregnancy—HR=1.22 (P=0.635).

However, the risk of non-lymphoid leukemia was significantly increased in children born to mothers with recent hormonal contraceptive use. The HRs were as follows:

• Previous use of hormonal contraceptives—HR=1.33 (P=0.232)
• Recent use—HR=2.17 (P=0.008)
• Use within 3 months of pregnancy—HR=1.95 (P=0.033)
• Use during pregnancy—HR=3.87 (P=0.006).

The association between recent contraceptive use and any leukemia was strongest in children ages 6 to 10 years. The researchers said this was not surprising because the incidence of non-lymphoid leukemia increases after the age of 6.

The researchers estimated that a mother’s recent use of hormonal contraceptives would have resulted in about one additional case of leukemia per 47,170 children; in other words, 25 additional cases of leukemia over the study period.

This low risk of leukemia “is not a major concern with regard to the safety of hormonal contraceptives,” the researchers said.

However, the findings do suggest the intrauterine hormonal environment affects leukemia development in children, and this should be explored in future research.

This study was supported by the Danish Cancer Research Foundation and other foundations. One author reported grants from the sponsoring foundations, and another author reported speaking fees from Jazz Pharmaceuticals and Shire Pharmaceuticals.

Photo by Nina Matthews

A nationwide cohort study suggests an association between a woman’s use of hormonal contraceptives and leukemia in her offspring.

Children of mothers who used hormonal contraception, either during pregnancy or in the 3 months beforehand, had a 1.5-fold greater risk of leukemia, when compared to children of mothers who had never used hormonal contraception.

This increased risk translated to one additional case of leukemia per about 50,000 children exposed to hormonal contraceptives.

The increased risk appeared limited to non-lymphoid leukemia.

Marie Hargreave, PhD, of the Danish Cancer Society Research Center in Copenhagen, Denmark, and her colleagues reported these findings in The Lancet Oncology.

The study included 1,185,157 children born between 1996 and 2014 and followed for a median of 9.3 years. Data on these children were collected from the Danish Medical Birth Registry and the Danish Cancer Registry.

The researchers looked at redeemed prescriptions from the Danish National Prescription Registry to determine the mothers’ contraceptive use and divided the women into three categories:

• Mothers who had never used hormonal contraceptives
• Those with previous hormonal contraceptive use, defined as greater than 3 months before the start of pregnancy
• Mothers with recent contraceptive use, defined as during or within 3 months of pregnancy.

Results

There were 606 children diagnosed with leukemia in the study cohort—465 with lymphoid leukemia and 141 with non-lymphoid leukemia.

Overall, children born to mothers with previous or recent use of hormonal contraceptives had a significantly increased risk of developing any leukemia. The hazard ratios (HRs) were as follows:

• Previous use of hormonal contraceptives—HR=1.25 (P=0.039)
• Recent use—HR=1.46 (P=0.011)
• Use within 3 months of pregnancy—HR=1.42 (P=0.025)
• Use during pregnancy—HR=1.78 (P=0.070).

The risk of lymphoid leukemia did not increase significantly with maternal use of hormonal contraceptives. The HRs were as follows:

• Previous use of hormonal contraceptives—HR=1.23 (P=0.089)
• Recent use—HR=1.27 (P=0.167)
• Use within 3 months of pregnancy—HR=1.28 (P=0.173)
• Use during pregnancy—HR=1.22 (P=0.635).

However, the risk of non-lymphoid leukemia was significantly increased in children born to mothers with recent hormonal contraceptive use. The HRs were as follows:

• Previous use of hormonal contraceptives—HR=1.33 (P=0.232)
• Recent use—HR=2.17 (P=0.008)
• Use within 3 months of pregnancy—HR=1.95 (P=0.033)
• Use during pregnancy—HR=3.87 (P=0.006).

The association between recent contraceptive use and any leukemia was strongest in children ages 6 to 10 years. The researchers said this was not surprising because the incidence of non-lymphoid leukemia increases after the age of 6.

The researchers estimated that a mother’s recent use of hormonal contraceptives would have resulted in about one additional case of leukemia per 47,170 children; in other words, 25 additional cases of leukemia over the study period.

This low risk of leukemia “is not a major concern with regard to the safety of hormonal contraceptives,” the researchers said.

However, the findings do suggest the intrauterine hormonal environment affects leukemia development in children, and this should be explored in future research.

This study was supported by the Danish Cancer Research Foundation and other foundations. One author reported grants from the sponsoring foundations, and another author reported speaking fees from Jazz Pharmaceuticals and Shire Pharmaceuticals.

©Raimond Spekking

In a prospective study, Hispanic pediatric patients with acute lymphoblastic leukemia (ALL) had a risk of methotrexate-induced neurotoxicity that was more than twice the risk observed in non-Hispanic white patients.

However, there was no significant difference in methotrexate neurotoxicity between non-Hispanic black patients and non-Hispanic white patients.

There were no cases of neurotoxicity among patients of other races/ethnicities.

Michael E. Scheurer, PhD, of Baylor College of Medicine in Houston, Texas, and his colleagues conducted this study and detailed the results in Clinical Cancer Research.

The study included 280 patients with newly diagnosed ALL. Most patients (85.7%) had B-ALL, 10.7% had T-ALL, and 3.6% had lymphoblastic lymphoma.

Nearly half of the patients (48.2%) were Hispanic, 36.2% were non-Hispanic white, 8.3% were non-Hispanic black, and 7.3% were non-Hispanic “other.”

The patients, who had a mean age of 8.4 years at diagnosis, were treated with modern ALL protocols and were followed from diagnosis to the start of maintenance/continuation therapy.

Methotrexate neurotoxicity was seen in 39 patients at the time of the analysis. Of those patients, 29 (74.4%) were Hispanic.

Compared with non-Hispanic whites, Hispanics had a high risk of methotrexate neurotoxicity, even after the researchers accounted for age, sex, ALL risk stratification, and other factors. The adjusted hazard ratio (HR) was 2.43 (P=0.036).

“We had observed that our Hispanic patients tended to experience neurotoxicity more often than other groups, but we were surprised to see the magnitude of the difference,” Dr. Scheurer said.

There was no significant difference in methotrexate neurotoxicity between non-Hispanic black patients and non-Hispanic white patients. The adjusted HR for non-Hispanic black patients was 1.23 (P=0.80).

Patients in the “other” racial/ethnic group did not experience any neurotoxic events.

All nine patients who experienced a second neurotoxic event were Hispanic.

Patients who had neurotoxicity received an average of 2.25 fewer doses of intrathecal methotrexate (P<0.01) and 1.81 fewer doses of intravenous methotrexate (P=0.084) than patients without neurotoxicity.

About three-quarters (74.4%) of patients experiencing methotrexate neurotoxicity received leucovorin rescue, according to the investigators, who noted that leucovorin may interact with methotrexate and reduce its efficacy.

Relapse occurred in 15.4% (6/39) of patients with neurotoxicity and 2.1% (13/241) of patients with no neurotoxicity (P=0.0038).

The investigators said these findings add to the growing body of evidence that Hispanics and other minority pediatric patients with ALL experience “significant disparities” in treatment outcomes.

It remains unclear why Hispanic patients would have a higher risk of methotrexate neurotoxicity, and that must be explored in future studies, the investigators said.

The team is currently investigating whether biomarkers could be used to identify patients at risk of methotrexate neurotoxicity.

“Biomarkers may someday allow us to identify patients upfront, before even beginning therapy, who might be at risk for such outcomes,” Dr. Scheurer said. “If we can identify these at-risk patients, we can potentially employ strategies to either fully prevent or mitigate these toxicities.”

This research was supported by the National Institutes of Health and Reducing Ethnic Disparities in Acute Leukemia (REDIAL) Consortium, a St. Baldrick’s Foundation Consortium Research Grant. The researchers said they had no potential conflicts of interest.

©Raimond Spekking

In a prospective study, Hispanic pediatric patients with acute lymphoblastic leukemia (ALL) had a risk of methotrexate-induced neurotoxicity that was more than twice the risk observed in non-Hispanic white patients.

However, there was no significant difference in methotrexate neurotoxicity between non-Hispanic black patients and non-Hispanic white patients.

There were no cases of neurotoxicity among patients of other races/ethnicities.

Michael E. Scheurer, PhD, of Baylor College of Medicine in Houston, Texas, and his colleagues conducted this study and detailed the results in Clinical Cancer Research.

The study included 280 patients with newly diagnosed ALL. Most patients (85.7%) had B-ALL, 10.7% had T-ALL, and 3.6% had lymphoblastic lymphoma.

Nearly half of the patients (48.2%) were Hispanic, 36.2% were non-Hispanic white, 8.3% were non-Hispanic black, and 7.3% were non-Hispanic “other.”

The patients, who had a mean age of 8.4 years at diagnosis, were treated with modern ALL protocols and were followed from diagnosis to the start of maintenance/continuation therapy.

Methotrexate neurotoxicity was seen in 39 patients at the time of the analysis. Of those patients, 29 (74.4%) were Hispanic.

Compared with non-Hispanic whites, Hispanics had a high risk of methotrexate neurotoxicity, even after the researchers accounted for age, sex, ALL risk stratification, and other factors. The adjusted hazard ratio (HR) was 2.43 (P=0.036).

“We had observed that our Hispanic patients tended to experience neurotoxicity more often than other groups, but we were surprised to see the magnitude of the difference,” Dr. Scheurer said.

There was no significant difference in methotrexate neurotoxicity between non-Hispanic black patients and non-Hispanic white patients. The adjusted HR for non-Hispanic black patients was 1.23 (P=0.80).

Patients in the “other” racial/ethnic group did not experience any neurotoxic events.

All nine patients who experienced a second neurotoxic event were Hispanic.

Patients who had neurotoxicity received an average of 2.25 fewer doses of intrathecal methotrexate (P<0.01) and 1.81 fewer doses of intravenous methotrexate (P=0.084) than patients without neurotoxicity.

About three-quarters (74.4%) of patients experiencing methotrexate neurotoxicity received leucovorin rescue, according to the investigators, who noted that leucovorin may interact with methotrexate and reduce its efficacy.

Relapse occurred in 15.4% (6/39) of patients with neurotoxicity and 2.1% (13/241) of patients with no neurotoxicity (P=0.0038).

The investigators said these findings add to the growing body of evidence that Hispanics and other minority pediatric patients with ALL experience “significant disparities” in treatment outcomes.

It remains unclear why Hispanic patients would have a higher risk of methotrexate neurotoxicity, and that must be explored in future studies, the investigators said.

The team is currently investigating whether biomarkers could be used to identify patients at risk of methotrexate neurotoxicity.

“Biomarkers may someday allow us to identify patients upfront, before even beginning therapy, who might be at risk for such outcomes,” Dr. Scheurer said. “If we can identify these at-risk patients, we can potentially employ strategies to either fully prevent or mitigate these toxicities.”

This research was supported by the National Institutes of Health and Reducing Ethnic Disparities in Acute Leukemia (REDIAL) Consortium, a St. Baldrick’s Foundation Consortium Research Grant. The researchers said they had no potential conflicts of interest.

©Raimond Spekking

In a prospective study, Hispanic pediatric patients with acute lymphoblastic leukemia (ALL) had a risk of methotrexate-induced neurotoxicity that was more than twice the risk observed in non-Hispanic white patients.

However, there was no significant difference in methotrexate neurotoxicity between non-Hispanic black patients and non-Hispanic white patients.

There were no cases of neurotoxicity among patients of other races/ethnicities.

Michael E. Scheurer, PhD, of Baylor College of Medicine in Houston, Texas, and his colleagues conducted this study and detailed the results in Clinical Cancer Research.

The study included 280 patients with newly diagnosed ALL. Most patients (85.7%) had B-ALL, 10.7% had T-ALL, and 3.6% had lymphoblastic lymphoma.

Nearly half of the patients (48.2%) were Hispanic, 36.2% were non-Hispanic white, 8.3% were non-Hispanic black, and 7.3% were non-Hispanic “other.”

The patients, who had a mean age of 8.4 years at diagnosis, were treated with modern ALL protocols and were followed from diagnosis to the start of maintenance/continuation therapy.

Methotrexate neurotoxicity was seen in 39 patients at the time of the analysis. Of those patients, 29 (74.4%) were Hispanic.

Compared with non-Hispanic whites, Hispanics had a high risk of methotrexate neurotoxicity, even after the researchers accounted for age, sex, ALL risk stratification, and other factors. The adjusted hazard ratio (HR) was 2.43 (P=0.036).

“We had observed that our Hispanic patients tended to experience neurotoxicity more often than other groups, but we were surprised to see the magnitude of the difference,” Dr. Scheurer said.

There was no significant difference in methotrexate neurotoxicity between non-Hispanic black patients and non-Hispanic white patients. The adjusted HR for non-Hispanic black patients was 1.23 (P=0.80).

Patients in the “other” racial/ethnic group did not experience any neurotoxic events.

All nine patients who experienced a second neurotoxic event were Hispanic.

Patients who had neurotoxicity received an average of 2.25 fewer doses of intrathecal methotrexate (P<0.01) and 1.81 fewer doses of intravenous methotrexate (P=0.084) than patients without neurotoxicity.

About three-quarters (74.4%) of patients experiencing methotrexate neurotoxicity received leucovorin rescue, according to the investigators, who noted that leucovorin may interact with methotrexate and reduce its efficacy.

Relapse occurred in 15.4% (6/39) of patients with neurotoxicity and 2.1% (13/241) of patients with no neurotoxicity (P=0.0038).

The investigators said these findings add to the growing body of evidence that Hispanics and other minority pediatric patients with ALL experience “significant disparities” in treatment outcomes.

It remains unclear why Hispanic patients would have a higher risk of methotrexate neurotoxicity, and that must be explored in future studies, the investigators said.

The team is currently investigating whether biomarkers could be used to identify patients at risk of methotrexate neurotoxicity.

“Biomarkers may someday allow us to identify patients upfront, before even beginning therapy, who might be at risk for such outcomes,” Dr. Scheurer said. “If we can identify these at-risk patients, we can potentially employ strategies to either fully prevent or mitigate these toxicities.”

This research was supported by the National Institutes of Health and Reducing Ethnic Disparities in Acute Leukemia (REDIAL) Consortium, a St. Baldrick’s Foundation Consortium Research Grant. The researchers said they had no potential conflicts of interest.

The two most common reasons for pediatric emergency department visits exhibit considerable and opposing seasonal variations, according to the Agency for Healthcare Research and Quality.

Of the 30 million ED visits by children aged 18 years and younger during fiscal year 2015, about 9.6 million, or just under 24%, were for respiratory disorders, making it the most common diagnosis by body system. The second-most common reason, injuries, was associated with approximately 7.9 million visits in 2015, the AHRQ reported recently in a statistical brief.

Over the 4-year period from 2011 to 2015, pediatric ED visits for respiratory disorders peaked during the months from October to March and dropped during April-September. In 2015, for example, there was a 43% difference between October-December, which was the highest-volume quarter, and July-September, which had the lowest volume of visits, the report showed.

The opposite pattern of seasonality was seen with visits for injury-related visits: The high point each year occurs in April-September, with the low in October-March. In 2015, there was a 30% difference between the lowest-volume quarter of January-March and the highest-volume quarter of July-September, based on the analysis of data from the Nationwide Emergency Department Sample.

rfranki@mdedge.com

The two most common reasons for pediatric emergency department visits exhibit considerable and opposing seasonal variations, according to the Agency for Healthcare Research and Quality.

Of the 30 million ED visits by children aged 18 years and younger during fiscal year 2015, about 9.6 million, or just under 24%, were for respiratory disorders, making it the most common diagnosis by body system. The second-most common reason, injuries, was associated with approximately 7.9 million visits in 2015, the AHRQ reported recently in a statistical brief.

Over the 4-year period from 2011 to 2015, pediatric ED visits for respiratory disorders peaked during the months from October to March and dropped during April-September. In 2015, for example, there was a 43% difference between October-December, which was the highest-volume quarter, and July-September, which had the lowest volume of visits, the report showed.

The opposite pattern of seasonality was seen with visits for injury-related visits: The high point each year occurs in April-September, with the low in October-March. In 2015, there was a 30% difference between the lowest-volume quarter of January-March and the highest-volume quarter of July-September, based on the analysis of data from the Nationwide Emergency Department Sample.

rfranki@mdedge.com

The two most common reasons for pediatric emergency department visits exhibit considerable and opposing seasonal variations, according to the Agency for Healthcare Research and Quality.

Of the 30 million ED visits by children aged 18 years and younger during fiscal year 2015, about 9.6 million, or just under 24%, were for respiratory disorders, making it the most common diagnosis by body system. The second-most common reason, injuries, was associated with approximately 7.9 million visits in 2015, the AHRQ reported recently in a statistical brief.

Over the 4-year period from 2011 to 2015, pediatric ED visits for respiratory disorders peaked during the months from October to March and dropped during April-September. In 2015, for example, there was a 43% difference between October-December, which was the highest-volume quarter, and July-September, which had the lowest volume of visits, the report showed.

The opposite pattern of seasonality was seen with visits for injury-related visits: The high point each year occurs in April-September, with the low in October-March. In 2015, there was a 30% difference between the lowest-volume quarter of January-March and the highest-volume quarter of July-September, based on the analysis of data from the Nationwide Emergency Department Sample.

rfranki@mdedge.com

Levofloxacin prophylaxis significantly reduced bacteremia in children with acute leukemias receiving intensive chemotherapy, according to results of a multicenter, randomized phase 3 trial.

Risk of bacteremia was not significantly reduced with levofloxacin in another cohort of children undergoing hematopoietic stem cell transplantation (HSCT), although a post hoc analysis accounting for time at risk did show a significant difference, according to results of this Children’s Oncology Group (COG) trial.

The reduction in risk for children with acute leukemias was similar to findings of adult studies showing the benefit of prophylactic antibiotics in patients with cancer-related neutropenia, said Sarah Alexander, MD, of the division of hematology/oncology, the Hospital for Sick Children, Toronto, and her coinvestigators.

Before this COG study, data on prophylactic antibiotics in children with cancer were limited to several small, single-group observational studies, Dr. Alexander and her coauthors wrote in JAMA.

Bacteremia was the primary outcome of the COG study, according to the investigators, because of its link to sepsis, increased health care utilization, and infection-related mortality. “Consequently, this outcome is meaningful to both clinicians and patients,” the investigators noted.

The multicenter, randomized, open-label phase 3 trial (ACCL0934) enrolled patients aged 6 months to 21 years, including 200 with acute leukemias (acute myeloid leukemia or relapsed acute lymphoblastic leukemia) who were to receive at least two intensive chemotherapy cycles, and 424 who were to receive a myeloablative autologous or allogeneic HSCT.

In the final analysis of the acute leukemias group, which included 195 patients, likelihood of bacteremia was 21.9% for those randomized to levofloxacin prophylaxis, versus 43.4% for no prophylaxis (P = 0.001).

In the final analysis of the HSCT group, which included 418 patients, likelihood of bacteremia was not significantly different, at 11.0% for levofloxacin prophylaxis, versus 17.3% for no prophylaxis (P = 0.06).

“Levofloxacin prophylaxis was effective at reducing the risk of bacteremia among patients with acute leukemia, but not among patients undergoing HSCT,” Dr. Armstrong and her coauthors said.

A post hoc analysis accounting for time at risk, however, showed a significant difference in favor of prophylaxis in both groups and a similar effect size between groups, according to investigators.

For the acute leukemias group, the rate of bacteremic episodes in that post hoc analysis was 4.9 versus 9.4 per 1,000 patient-days in the prophylaxis and no prophylaxis arms, respectively (P = 0.008). In the HSCT group, the rate was 5.3 versus 10.0 bacteremias per 1,000 patient-days in the prophylaxis and no prophylaxis arms (P = .02).

The similar effect size suggests that in the primary analysis, there was reduced power to detect a significant difference in the HSCT group because of fewer events, driven partly by a shorter duration of neutropenia in that group, Dr. Armstrong and her associates said.

“However, it is also plausible that the leukemia and HSCT groups had different supportive care measures or were infected with pathogens that had differential sensitivity to levofloxacin resulting in different efficacy of levofloxacin in the 2 groups,” they added.

Levofloxacin-resistant pathogens, such as viridans group streptococcal isolates and several Gram-negative isolates, often were detected in patients who had bacteremia events despite prophylaxis. This suggests that other interventions in combination with levofloxacin prophylaxis are probably needed to further decrease risk, the investigators said.

Further randomized studies are needed to better understand the risks of levofloxacin in relation to its benefits, according to the investigators, who reported 23 serious adverse events in 8 patients, 11 of which were considered unrelated or unlikely to be related to levofloxacin.

“The adoption of antibacterial prophylaxis is tempered by potential negative consequences including Clostridium difficile-associated diarrhea, bacterial resistance, and musculoskeletal toxicities,” Dr. Armstrong and her colleagues noted.

The research was supported by grants from the Community Clinical Oncology Program and National Cancer Institute. Dr. Alexander reported no disclosures. Coauthors reported disclosures related to Bristol-Myers Squibb, Chimerix, Jazz Pharmaceuticals, and the Children’s Oncology Group.

SOURCE: Alexander S, et al . JAMA. 2018;320(10):995-1004.

Levofloxacin prophylaxis significantly reduced bacteremia in children with acute leukemias receiving intensive chemotherapy, according to results of a multicenter, randomized phase 3 trial.

Risk of bacteremia was not significantly reduced with levofloxacin in another cohort of children undergoing hematopoietic stem cell transplantation (HSCT), although a post hoc analysis accounting for time at risk did show a significant difference, according to results of this Children’s Oncology Group (COG) trial.

The reduction in risk for children with acute leukemias was similar to findings of adult studies showing the benefit of prophylactic antibiotics in patients with cancer-related neutropenia, said Sarah Alexander, MD, of the division of hematology/oncology, the Hospital for Sick Children, Toronto, and her coinvestigators.

Before this COG study, data on prophylactic antibiotics in children with cancer were limited to several small, single-group observational studies, Dr. Alexander and her coauthors wrote in JAMA.

Bacteremia was the primary outcome of the COG study, according to the investigators, because of its link to sepsis, increased health care utilization, and infection-related mortality. “Consequently, this outcome is meaningful to both clinicians and patients,” the investigators noted.

The multicenter, randomized, open-label phase 3 trial (ACCL0934) enrolled patients aged 6 months to 21 years, including 200 with acute leukemias (acute myeloid leukemia or relapsed acute lymphoblastic leukemia) who were to receive at least two intensive chemotherapy cycles, and 424 who were to receive a myeloablative autologous or allogeneic HSCT.

In the final analysis of the acute leukemias group, which included 195 patients, likelihood of bacteremia was 21.9% for those randomized to levofloxacin prophylaxis, versus 43.4% for no prophylaxis (P = 0.001).

In the final analysis of the HSCT group, which included 418 patients, likelihood of bacteremia was not significantly different, at 11.0% for levofloxacin prophylaxis, versus 17.3% for no prophylaxis (P = 0.06).

“Levofloxacin prophylaxis was effective at reducing the risk of bacteremia among patients with acute leukemia, but not among patients undergoing HSCT,” Dr. Armstrong and her coauthors said.

A post hoc analysis accounting for time at risk, however, showed a significant difference in favor of prophylaxis in both groups and a similar effect size between groups, according to investigators.

For the acute leukemias group, the rate of bacteremic episodes in that post hoc analysis was 4.9 versus 9.4 per 1,000 patient-days in the prophylaxis and no prophylaxis arms, respectively (P = 0.008). In the HSCT group, the rate was 5.3 versus 10.0 bacteremias per 1,000 patient-days in the prophylaxis and no prophylaxis arms (P = .02).

The similar effect size suggests that in the primary analysis, there was reduced power to detect a significant difference in the HSCT group because of fewer events, driven partly by a shorter duration of neutropenia in that group, Dr. Armstrong and her associates said.

“However, it is also plausible that the leukemia and HSCT groups had different supportive care measures or were infected with pathogens that had differential sensitivity to levofloxacin resulting in different efficacy of levofloxacin in the 2 groups,” they added.

Levofloxacin-resistant pathogens, such as viridans group streptococcal isolates and several Gram-negative isolates, often were detected in patients who had bacteremia events despite prophylaxis. This suggests that other interventions in combination with levofloxacin prophylaxis are probably needed to further decrease risk, the investigators said.

Further randomized studies are needed to better understand the risks of levofloxacin in relation to its benefits, according to the investigators, who reported 23 serious adverse events in 8 patients, 11 of which were considered unrelated or unlikely to be related to levofloxacin.

“The adoption of antibacterial prophylaxis is tempered by potential negative consequences including Clostridium difficile-associated diarrhea, bacterial resistance, and musculoskeletal toxicities,” Dr. Armstrong and her colleagues noted.

The research was supported by grants from the Community Clinical Oncology Program and National Cancer Institute. Dr. Alexander reported no disclosures. Coauthors reported disclosures related to Bristol-Myers Squibb, Chimerix, Jazz Pharmaceuticals, and the Children’s Oncology Group.

SOURCE: Alexander S, et al . JAMA. 2018;320(10):995-1004.

Levofloxacin prophylaxis significantly reduced bacteremia in children with acute leukemias receiving intensive chemotherapy, according to results of a multicenter, randomized phase 3 trial.

Risk of bacteremia was not significantly reduced with levofloxacin in another cohort of children undergoing hematopoietic stem cell transplantation (HSCT), although a post hoc analysis accounting for time at risk did show a significant difference, according to results of this Children’s Oncology Group (COG) trial.

The reduction in risk for children with acute leukemias was similar to findings of adult studies showing the benefit of prophylactic antibiotics in patients with cancer-related neutropenia, said Sarah Alexander, MD, of the division of hematology/oncology, the Hospital for Sick Children, Toronto, and her coinvestigators.

Before this COG study, data on prophylactic antibiotics in children with cancer were limited to several small, single-group observational studies, Dr. Alexander and her coauthors wrote in JAMA.

Bacteremia was the primary outcome of the COG study, according to the investigators, because of its link to sepsis, increased health care utilization, and infection-related mortality. “Consequently, this outcome is meaningful to both clinicians and patients,” the investigators noted.

The multicenter, randomized, open-label phase 3 trial (ACCL0934) enrolled patients aged 6 months to 21 years, including 200 with acute leukemias (acute myeloid leukemia or relapsed acute lymphoblastic leukemia) who were to receive at least two intensive chemotherapy cycles, and 424 who were to receive a myeloablative autologous or allogeneic HSCT.

In the final analysis of the acute leukemias group, which included 195 patients, likelihood of bacteremia was 21.9% for those randomized to levofloxacin prophylaxis, versus 43.4% for no prophylaxis (P = 0.001).

In the final analysis of the HSCT group, which included 418 patients, likelihood of bacteremia was not significantly different, at 11.0% for levofloxacin prophylaxis, versus 17.3% for no prophylaxis (P = 0.06).

“Levofloxacin prophylaxis was effective at reducing the risk of bacteremia among patients with acute leukemia, but not among patients undergoing HSCT,” Dr. Armstrong and her coauthors said.

A post hoc analysis accounting for time at risk, however, showed a significant difference in favor of prophylaxis in both groups and a similar effect size between groups, according to investigators.

For the acute leukemias group, the rate of bacteremic episodes in that post hoc analysis was 4.9 versus 9.4 per 1,000 patient-days in the prophylaxis and no prophylaxis arms, respectively (P = 0.008). In the HSCT group, the rate was 5.3 versus 10.0 bacteremias per 1,000 patient-days in the prophylaxis and no prophylaxis arms (P = .02).

The similar effect size suggests that in the primary analysis, there was reduced power to detect a significant difference in the HSCT group because of fewer events, driven partly by a shorter duration of neutropenia in that group, Dr. Armstrong and her associates said.

“However, it is also plausible that the leukemia and HSCT groups had different supportive care measures or were infected with pathogens that had differential sensitivity to levofloxacin resulting in different efficacy of levofloxacin in the 2 groups,” they added.

Levofloxacin-resistant pathogens, such as viridans group streptococcal isolates and several Gram-negative isolates, often were detected in patients who had bacteremia events despite prophylaxis. This suggests that other interventions in combination with levofloxacin prophylaxis are probably needed to further decrease risk, the investigators said.

Further randomized studies are needed to better understand the risks of levofloxacin in relation to its benefits, according to the investigators, who reported 23 serious adverse events in 8 patients, 11 of which were considered unrelated or unlikely to be related to levofloxacin.

“The adoption of antibacterial prophylaxis is tempered by potential negative consequences including Clostridium difficile-associated diarrhea, bacterial resistance, and musculoskeletal toxicities,” Dr. Armstrong and her colleagues noted.

The research was supported by grants from the Community Clinical Oncology Program and National Cancer Institute. Dr. Alexander reported no disclosures. Coauthors reported disclosures related to Bristol-Myers Squibb, Chimerix, Jazz Pharmaceuticals, and the Children’s Oncology Group.

SOURCE: Alexander S, et al . JAMA. 2018;320(10):995-1004.