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Changing attitudes, perceived norms promote safe sleep in mothers
related to these practices, according to a new study.
In the past, the American Academy of Pediatrics has made safe sleep recommendations regarding infant sleep position and location. According to the new study’s authors, Rachel Y. Moon, MD, and her colleagues, parents had poorly adhered to these recommendations in several studies. However, some improvements with adherence were seen when a mobile health intervention was used in the Social Media and Risk Reduction Training Study (JAMA. 2017;318[4]:351-9). The new study, published in Pediatrics, used the same intervention described in that JAMA paper.
The more recent mobile health project sought to identify which factors, as outlined by a theory of planned behavior, were affected by a mobile health intervention through analysis of survey responses. Of the 1,600 women who provided written consent, 1,263 (78.9%) completed the survey.
According to the results, the intervention did more to affect attitudes (adjusted odds ratio, 2.35; 95% confidence interval, 1.72-3.20) than it did to affect perceived norms (aOR, 1.75; 95% CI, 1.27-2.36) regarding supine sleeping position. It had similar effects on attitudes (aOR, 1.91; 95% CI, 1.54-2.36) versus perceived norms (aOR, 1.37; 95% CI, 1.13-1.66) regarding sleep location as well. The intervention had no significant effect on perceived maternal control regarding either sleeping position or location.
While levels of safe sleep adherence were lower in African Americans and subgroups of low economic status at baseline, the intervention improved the rates of adherence in these groups to levels comparable with other groups included in the study.
“Recognition that these attitudes and social norms may be the main drivers of mothers’ choices regarding infant-sleep practices should inform health messaging strategies, including the use of [mobile heath], to promote [safe sleep],” the researchers concluded.
The study was funded by grants from the Eunice Kennedy Shriver National Institute of Child Health and Human Development and the CJ foundation for sudden infant death syndrome. The National Institutes of Health also provided funding.
SOURCE: Moon RY et al. Pediatrics. 2019. doi: 10.1542/peds.2018-2799.
related to these practices, according to a new study.
In the past, the American Academy of Pediatrics has made safe sleep recommendations regarding infant sleep position and location. According to the new study’s authors, Rachel Y. Moon, MD, and her colleagues, parents had poorly adhered to these recommendations in several studies. However, some improvements with adherence were seen when a mobile health intervention was used in the Social Media and Risk Reduction Training Study (JAMA. 2017;318[4]:351-9). The new study, published in Pediatrics, used the same intervention described in that JAMA paper.
The more recent mobile health project sought to identify which factors, as outlined by a theory of planned behavior, were affected by a mobile health intervention through analysis of survey responses. Of the 1,600 women who provided written consent, 1,263 (78.9%) completed the survey.
According to the results, the intervention did more to affect attitudes (adjusted odds ratio, 2.35; 95% confidence interval, 1.72-3.20) than it did to affect perceived norms (aOR, 1.75; 95% CI, 1.27-2.36) regarding supine sleeping position. It had similar effects on attitudes (aOR, 1.91; 95% CI, 1.54-2.36) versus perceived norms (aOR, 1.37; 95% CI, 1.13-1.66) regarding sleep location as well. The intervention had no significant effect on perceived maternal control regarding either sleeping position or location.
While levels of safe sleep adherence were lower in African Americans and subgroups of low economic status at baseline, the intervention improved the rates of adherence in these groups to levels comparable with other groups included in the study.
“Recognition that these attitudes and social norms may be the main drivers of mothers’ choices regarding infant-sleep practices should inform health messaging strategies, including the use of [mobile heath], to promote [safe sleep],” the researchers concluded.
The study was funded by grants from the Eunice Kennedy Shriver National Institute of Child Health and Human Development and the CJ foundation for sudden infant death syndrome. The National Institutes of Health also provided funding.
SOURCE: Moon RY et al. Pediatrics. 2019. doi: 10.1542/peds.2018-2799.
related to these practices, according to a new study.
In the past, the American Academy of Pediatrics has made safe sleep recommendations regarding infant sleep position and location. According to the new study’s authors, Rachel Y. Moon, MD, and her colleagues, parents had poorly adhered to these recommendations in several studies. However, some improvements with adherence were seen when a mobile health intervention was used in the Social Media and Risk Reduction Training Study (JAMA. 2017;318[4]:351-9). The new study, published in Pediatrics, used the same intervention described in that JAMA paper.
The more recent mobile health project sought to identify which factors, as outlined by a theory of planned behavior, were affected by a mobile health intervention through analysis of survey responses. Of the 1,600 women who provided written consent, 1,263 (78.9%) completed the survey.
According to the results, the intervention did more to affect attitudes (adjusted odds ratio, 2.35; 95% confidence interval, 1.72-3.20) than it did to affect perceived norms (aOR, 1.75; 95% CI, 1.27-2.36) regarding supine sleeping position. It had similar effects on attitudes (aOR, 1.91; 95% CI, 1.54-2.36) versus perceived norms (aOR, 1.37; 95% CI, 1.13-1.66) regarding sleep location as well. The intervention had no significant effect on perceived maternal control regarding either sleeping position or location.
While levels of safe sleep adherence were lower in African Americans and subgroups of low economic status at baseline, the intervention improved the rates of adherence in these groups to levels comparable with other groups included in the study.
“Recognition that these attitudes and social norms may be the main drivers of mothers’ choices regarding infant-sleep practices should inform health messaging strategies, including the use of [mobile heath], to promote [safe sleep],” the researchers concluded.
The study was funded by grants from the Eunice Kennedy Shriver National Institute of Child Health and Human Development and the CJ foundation for sudden infant death syndrome. The National Institutes of Health also provided funding.
SOURCE: Moon RY et al. Pediatrics. 2019. doi: 10.1542/peds.2018-2799.
FROM PEDIATRICS
Restricting opioids after knee surgery did not increase refills
according to a study in the Journal of Arthroplasty.
Contrary to concerns that restrictive opioid prescribing might increase the number of patient call-ins and refill requests, one academic institution had significantly fewer call-ins and refills after it implemented a strict postoperative opioid prescribing protocol on Jan. 1, 2018.
“Orthopedic surgeons might be reluctant to change practice without evidence that new, more-restrictive practice will not impede patient care,” the researchers wrote. “As the current study demonstrates, there is room to significantly decrease postoperative opioid prescriptions in total joint arthroplasty. This places patients at lower risk of opioid abuse and diversion without significantly altering the risk of postoperative complications or compromising postoperative pain control.”
Opioid overuse is a major public health concern, and orthopedic surgeons may overprescribe opioids after surgery. The University of Iowa Hospitals and Clinics in Iowa City implemented strict postoperative opioid prescription guidelines that are based on the American Academy of Orthopedic Surgeons Clinical Practice Guidelines. As part of the protocol, patients receive a preoperative education session that emphasizes risks associated with opioid use. Before initiating this protocol, postoperative drug choice and quantity had not been standardized.
To examine changes in opioid prescriptions and the number of call-ins, postoperative complications, and prescription refill requests after the implementation of the restrictive opioid prescribing protocol, investigators at the institution conducted a retrospective study.
Andrew J. Holte, a researcher in the department of orthopedics and rehabilitation, and his colleagues reviewed cases from June 2017 to February 2018. Their analysis included 399 patients who underwent total hip arthroplasty or total knee arthroplasty.
In all, 282 patients underwent surgery before the restrictive protocol (the historical cohort) and 117 after (the restrictive cohort). In the historical cohort, about 48% of the patients underwent total knee arthroplasty. In the restrictive cohort, about 44% underwent total knee arthroplasty. Patients had an average age of about 61 years, and approximately 52% were women.
According to comparisons of morphine mg equivalents (MME), the historical cohort received significantly larger mean initial opioid prescriptions (752 MME vs. 387 MME), significantly more refills per patient (0.5 vs. 0.3), and significantly more medication through refills (253 MME vs. 84 MME).
“For reference, 50 pills of 5 mg oxycodone is equivalent to 300 MMEs,” the authors noted.
A multivariable model found that younger age and total knee arthroplasty, compared with total hip arthroplasty, were associated with increased likelihood of requests for refills and patient call-ins.
“Surprisingly, there were significantly more patient call-ins and requests for refills of opioids in the historical cohort,” Mr. Holte and his colleagues said. “Although this study did not collect direct data on patient pain scores, we believe that call-ins and requests for refills are sufficient surrogate markers for inadequate pain control.”
The study does not account for prescriptions from other providers or whether patients took none, some, or all of their filled prescriptions. Future studies are needed to assess how reduced opioid prescriptions affect pain and functional outcomes in the long term, the researchers said.
One or more study authors disclosed potential conflicts of interest. The disclosures can be found in Appendix A, Supplementary Data, at the end of the journal article.
SOURCE: Holte AJ et al. J Arthroplasty. 2019 Feb 20. doi: 10.1016/j.arth.2019.02.022.
according to a study in the Journal of Arthroplasty.
Contrary to concerns that restrictive opioid prescribing might increase the number of patient call-ins and refill requests, one academic institution had significantly fewer call-ins and refills after it implemented a strict postoperative opioid prescribing protocol on Jan. 1, 2018.
“Orthopedic surgeons might be reluctant to change practice without evidence that new, more-restrictive practice will not impede patient care,” the researchers wrote. “As the current study demonstrates, there is room to significantly decrease postoperative opioid prescriptions in total joint arthroplasty. This places patients at lower risk of opioid abuse and diversion without significantly altering the risk of postoperative complications or compromising postoperative pain control.”
Opioid overuse is a major public health concern, and orthopedic surgeons may overprescribe opioids after surgery. The University of Iowa Hospitals and Clinics in Iowa City implemented strict postoperative opioid prescription guidelines that are based on the American Academy of Orthopedic Surgeons Clinical Practice Guidelines. As part of the protocol, patients receive a preoperative education session that emphasizes risks associated with opioid use. Before initiating this protocol, postoperative drug choice and quantity had not been standardized.
To examine changes in opioid prescriptions and the number of call-ins, postoperative complications, and prescription refill requests after the implementation of the restrictive opioid prescribing protocol, investigators at the institution conducted a retrospective study.
Andrew J. Holte, a researcher in the department of orthopedics and rehabilitation, and his colleagues reviewed cases from June 2017 to February 2018. Their analysis included 399 patients who underwent total hip arthroplasty or total knee arthroplasty.
In all, 282 patients underwent surgery before the restrictive protocol (the historical cohort) and 117 after (the restrictive cohort). In the historical cohort, about 48% of the patients underwent total knee arthroplasty. In the restrictive cohort, about 44% underwent total knee arthroplasty. Patients had an average age of about 61 years, and approximately 52% were women.
According to comparisons of morphine mg equivalents (MME), the historical cohort received significantly larger mean initial opioid prescriptions (752 MME vs. 387 MME), significantly more refills per patient (0.5 vs. 0.3), and significantly more medication through refills (253 MME vs. 84 MME).
“For reference, 50 pills of 5 mg oxycodone is equivalent to 300 MMEs,” the authors noted.
A multivariable model found that younger age and total knee arthroplasty, compared with total hip arthroplasty, were associated with increased likelihood of requests for refills and patient call-ins.
“Surprisingly, there were significantly more patient call-ins and requests for refills of opioids in the historical cohort,” Mr. Holte and his colleagues said. “Although this study did not collect direct data on patient pain scores, we believe that call-ins and requests for refills are sufficient surrogate markers for inadequate pain control.”
The study does not account for prescriptions from other providers or whether patients took none, some, or all of their filled prescriptions. Future studies are needed to assess how reduced opioid prescriptions affect pain and functional outcomes in the long term, the researchers said.
One or more study authors disclosed potential conflicts of interest. The disclosures can be found in Appendix A, Supplementary Data, at the end of the journal article.
SOURCE: Holte AJ et al. J Arthroplasty. 2019 Feb 20. doi: 10.1016/j.arth.2019.02.022.
according to a study in the Journal of Arthroplasty.
Contrary to concerns that restrictive opioid prescribing might increase the number of patient call-ins and refill requests, one academic institution had significantly fewer call-ins and refills after it implemented a strict postoperative opioid prescribing protocol on Jan. 1, 2018.
“Orthopedic surgeons might be reluctant to change practice without evidence that new, more-restrictive practice will not impede patient care,” the researchers wrote. “As the current study demonstrates, there is room to significantly decrease postoperative opioid prescriptions in total joint arthroplasty. This places patients at lower risk of opioid abuse and diversion without significantly altering the risk of postoperative complications or compromising postoperative pain control.”
Opioid overuse is a major public health concern, and orthopedic surgeons may overprescribe opioids after surgery. The University of Iowa Hospitals and Clinics in Iowa City implemented strict postoperative opioid prescription guidelines that are based on the American Academy of Orthopedic Surgeons Clinical Practice Guidelines. As part of the protocol, patients receive a preoperative education session that emphasizes risks associated with opioid use. Before initiating this protocol, postoperative drug choice and quantity had not been standardized.
To examine changes in opioid prescriptions and the number of call-ins, postoperative complications, and prescription refill requests after the implementation of the restrictive opioid prescribing protocol, investigators at the institution conducted a retrospective study.
Andrew J. Holte, a researcher in the department of orthopedics and rehabilitation, and his colleagues reviewed cases from June 2017 to February 2018. Their analysis included 399 patients who underwent total hip arthroplasty or total knee arthroplasty.
In all, 282 patients underwent surgery before the restrictive protocol (the historical cohort) and 117 after (the restrictive cohort). In the historical cohort, about 48% of the patients underwent total knee arthroplasty. In the restrictive cohort, about 44% underwent total knee arthroplasty. Patients had an average age of about 61 years, and approximately 52% were women.
According to comparisons of morphine mg equivalents (MME), the historical cohort received significantly larger mean initial opioid prescriptions (752 MME vs. 387 MME), significantly more refills per patient (0.5 vs. 0.3), and significantly more medication through refills (253 MME vs. 84 MME).
“For reference, 50 pills of 5 mg oxycodone is equivalent to 300 MMEs,” the authors noted.
A multivariable model found that younger age and total knee arthroplasty, compared with total hip arthroplasty, were associated with increased likelihood of requests for refills and patient call-ins.
“Surprisingly, there were significantly more patient call-ins and requests for refills of opioids in the historical cohort,” Mr. Holte and his colleagues said. “Although this study did not collect direct data on patient pain scores, we believe that call-ins and requests for refills are sufficient surrogate markers for inadequate pain control.”
The study does not account for prescriptions from other providers or whether patients took none, some, or all of their filled prescriptions. Future studies are needed to assess how reduced opioid prescriptions affect pain and functional outcomes in the long term, the researchers said.
One or more study authors disclosed potential conflicts of interest. The disclosures can be found in Appendix A, Supplementary Data, at the end of the journal article.
SOURCE: Holte AJ et al. J Arthroplasty. 2019 Feb 20. doi: 10.1016/j.arth.2019.02.022.
FROM THE JOURNAL OF ARTHROPLASTY
New consensus recommendations on vaccination in hemophilia
New consensus statements, released by a panel of 11 experts, provide 27 specific recommendations related to the use of vaccines in patients with hemophilia.
The recommendations from the Italian Haemophilia and Vaccinations (HEVA) project were authored by an 11-member committee with expertise in both hemophilia and immunization. The authors reviewed 20 relevant studies published before August 30, 2017.
“Vaccination of patients with severe congenital bleeding disorders remains a challenge, and clinicians are often uncertain about immunization recommendations for these patients,” wrote Elena Santagostino, MD, PhD, of the Centro Emofilia e Trombosi Angelo Bianchi Bonomi in Milan, Italy, and her colleagues. The report is published in Haemophilia.
The statements were also validated by separate groups of clinicians at hemophilia treatment centers across Italy.
The key issues described included vaccination schedule, route of administration, vaccination of patients with antibodies that impede coagulation factor VIII inhibitors, and risk of inhibitor formation with vaccination.
In general, committee members agreed on the majority of statements, with the exception of those related to the possible links between vaccination and inhibitor formation. There were a total of five statements on which no consensus was reached.
Vaccinations in both adults and children with hemophilia should be provided in accordance with the institutional schedule for those without bleeding disorders, according to the recommendations.
“The only difference is that vaccination of patients with haemophilia requires comprehensive planning, taking into account disease severity, type and route of vaccination, and bleeding risk,” the experts wrote.
The panel also reported that current data suggest that vaccination timing is not affected by the timing of factor VIII replacement.
The authors acknowledged that the recommendations were formed by a group of experts from Italy using a specific consensus framework. As a result, they may not be applicable to all patient populations.
The manuscript was supported by Sobi. The authors reported financial relationships with Bayer, Bioverativ, CSL Behring, Grifols, Kedrion, Novo Nordisk, Pfizer, and other companies.
SOURCE: Santagostino E et al. Haemophilia. 2019 Apr 16. doi: 10.1111/hae.13756.
New consensus statements, released by a panel of 11 experts, provide 27 specific recommendations related to the use of vaccines in patients with hemophilia.
The recommendations from the Italian Haemophilia and Vaccinations (HEVA) project were authored by an 11-member committee with expertise in both hemophilia and immunization. The authors reviewed 20 relevant studies published before August 30, 2017.
“Vaccination of patients with severe congenital bleeding disorders remains a challenge, and clinicians are often uncertain about immunization recommendations for these patients,” wrote Elena Santagostino, MD, PhD, of the Centro Emofilia e Trombosi Angelo Bianchi Bonomi in Milan, Italy, and her colleagues. The report is published in Haemophilia.
The statements were also validated by separate groups of clinicians at hemophilia treatment centers across Italy.
The key issues described included vaccination schedule, route of administration, vaccination of patients with antibodies that impede coagulation factor VIII inhibitors, and risk of inhibitor formation with vaccination.
In general, committee members agreed on the majority of statements, with the exception of those related to the possible links between vaccination and inhibitor formation. There were a total of five statements on which no consensus was reached.
Vaccinations in both adults and children with hemophilia should be provided in accordance with the institutional schedule for those without bleeding disorders, according to the recommendations.
“The only difference is that vaccination of patients with haemophilia requires comprehensive planning, taking into account disease severity, type and route of vaccination, and bleeding risk,” the experts wrote.
The panel also reported that current data suggest that vaccination timing is not affected by the timing of factor VIII replacement.
The authors acknowledged that the recommendations were formed by a group of experts from Italy using a specific consensus framework. As a result, they may not be applicable to all patient populations.
The manuscript was supported by Sobi. The authors reported financial relationships with Bayer, Bioverativ, CSL Behring, Grifols, Kedrion, Novo Nordisk, Pfizer, and other companies.
SOURCE: Santagostino E et al. Haemophilia. 2019 Apr 16. doi: 10.1111/hae.13756.
New consensus statements, released by a panel of 11 experts, provide 27 specific recommendations related to the use of vaccines in patients with hemophilia.
The recommendations from the Italian Haemophilia and Vaccinations (HEVA) project were authored by an 11-member committee with expertise in both hemophilia and immunization. The authors reviewed 20 relevant studies published before August 30, 2017.
“Vaccination of patients with severe congenital bleeding disorders remains a challenge, and clinicians are often uncertain about immunization recommendations for these patients,” wrote Elena Santagostino, MD, PhD, of the Centro Emofilia e Trombosi Angelo Bianchi Bonomi in Milan, Italy, and her colleagues. The report is published in Haemophilia.
The statements were also validated by separate groups of clinicians at hemophilia treatment centers across Italy.
The key issues described included vaccination schedule, route of administration, vaccination of patients with antibodies that impede coagulation factor VIII inhibitors, and risk of inhibitor formation with vaccination.
In general, committee members agreed on the majority of statements, with the exception of those related to the possible links between vaccination and inhibitor formation. There were a total of five statements on which no consensus was reached.
Vaccinations in both adults and children with hemophilia should be provided in accordance with the institutional schedule for those without bleeding disorders, according to the recommendations.
“The only difference is that vaccination of patients with haemophilia requires comprehensive planning, taking into account disease severity, type and route of vaccination, and bleeding risk,” the experts wrote.
The panel also reported that current data suggest that vaccination timing is not affected by the timing of factor VIII replacement.
The authors acknowledged that the recommendations were formed by a group of experts from Italy using a specific consensus framework. As a result, they may not be applicable to all patient populations.
The manuscript was supported by Sobi. The authors reported financial relationships with Bayer, Bioverativ, CSL Behring, Grifols, Kedrion, Novo Nordisk, Pfizer, and other companies.
SOURCE: Santagostino E et al. Haemophilia. 2019 Apr 16. doi: 10.1111/hae.13756.
FROM HAEMOPHILIA
Research, clinical practice come together at transgender care symposium
NEW ORLEANS – A well-attended afternoon symposium on transgender medicine gave participants at the annual meeting of the Endocrine Society a solid grounding in transgender care, from prepubescence through adulthood. Here, Joshua Safer, MD, and Michael Irwig, MD, discuss highlights of the symposium, which brought together research, best practices, and clinical practice pearls.
In his presentation, Dr. Safer focused on The basics, he said, begin with presenting well-established, scientific principles supporting current standards of transgender care.
Dr. Safer, executive director of the Mount Sinai Center for Transgender Medicine and Surgery, New York, pointed out the critical role of gonadotropin-releasing hormone antagonists in delaying puberty for transgender girls. Blockade of puberty – and elevated testosterone – can forestall otherwise irreversible male secondary sex characteristics. These include laryngeal enlargement and bony changes of facial structure, for example.
Dr. Irwig, director of andrology at George Washington University, Washington, laid out the basics of transgender hormone therapy, including clinical pearls, such as avoiding ethinyl estradiol because of the heightened risk of venous thromboembolism.
Dr. Safer is a member of the editorial advisory board of Clinical Endocrinology News. He reported that he has received consulting fees from Endo Pharmaceuticals and that his spouse is an employee of Parexel. Dr. Irwig reported no relevant conflicts of interest or financial disclosures.
NEW ORLEANS – A well-attended afternoon symposium on transgender medicine gave participants at the annual meeting of the Endocrine Society a solid grounding in transgender care, from prepubescence through adulthood. Here, Joshua Safer, MD, and Michael Irwig, MD, discuss highlights of the symposium, which brought together research, best practices, and clinical practice pearls.
In his presentation, Dr. Safer focused on The basics, he said, begin with presenting well-established, scientific principles supporting current standards of transgender care.
Dr. Safer, executive director of the Mount Sinai Center for Transgender Medicine and Surgery, New York, pointed out the critical role of gonadotropin-releasing hormone antagonists in delaying puberty for transgender girls. Blockade of puberty – and elevated testosterone – can forestall otherwise irreversible male secondary sex characteristics. These include laryngeal enlargement and bony changes of facial structure, for example.
Dr. Irwig, director of andrology at George Washington University, Washington, laid out the basics of transgender hormone therapy, including clinical pearls, such as avoiding ethinyl estradiol because of the heightened risk of venous thromboembolism.
Dr. Safer is a member of the editorial advisory board of Clinical Endocrinology News. He reported that he has received consulting fees from Endo Pharmaceuticals and that his spouse is an employee of Parexel. Dr. Irwig reported no relevant conflicts of interest or financial disclosures.
NEW ORLEANS – A well-attended afternoon symposium on transgender medicine gave participants at the annual meeting of the Endocrine Society a solid grounding in transgender care, from prepubescence through adulthood. Here, Joshua Safer, MD, and Michael Irwig, MD, discuss highlights of the symposium, which brought together research, best practices, and clinical practice pearls.
In his presentation, Dr. Safer focused on The basics, he said, begin with presenting well-established, scientific principles supporting current standards of transgender care.
Dr. Safer, executive director of the Mount Sinai Center for Transgender Medicine and Surgery, New York, pointed out the critical role of gonadotropin-releasing hormone antagonists in delaying puberty for transgender girls. Blockade of puberty – and elevated testosterone – can forestall otherwise irreversible male secondary sex characteristics. These include laryngeal enlargement and bony changes of facial structure, for example.
Dr. Irwig, director of andrology at George Washington University, Washington, laid out the basics of transgender hormone therapy, including clinical pearls, such as avoiding ethinyl estradiol because of the heightened risk of venous thromboembolism.
Dr. Safer is a member of the editorial advisory board of Clinical Endocrinology News. He reported that he has received consulting fees from Endo Pharmaceuticals and that his spouse is an employee of Parexel. Dr. Irwig reported no relevant conflicts of interest or financial disclosures.
EXPERT ANALYSIS FROM ENDO 2019
Researchers to be honored at ASPHO
Several hematology and oncology researchers will receive awards at the 2019 conference of the American Society of Pediatric Hematology/Oncology (ASPHO), which takes place May 1-4.
Loretta Li, MD, of Boston Children’s Hospital/Dana-Farber Cancer Institute, and Akshay Sharma, MBBS, of St. Jude Children’s Research Hospital in Memphis, will receive Young Investigator awards at the conference.
Dr. Sharma is conducting research investigating the genetic regulation of fetal hemoglobin and developing transplant and gene therapy trials for patients with sickle cell disease. Dr. Li is studying the activity of JAK2 inhibitors, as well as mechanisms of response and resistance to these drugs, in leukemias.
Elliott Vichinsky, MD, of UCSF Benioff Children’s Hospital Oakland in California, will receive ASPHO’s Distinguished Career Award. Dr. Vichinsky has helped implement newborn screening programs for blood diseases, developed techniques to make blood safer for chronically transfused patients, and conducted research that furthered the development of drugs used to treat iron overload.
Wilbur Lam, MD, PhD, of Aflac Cancer & Blood Disorders Center/Emory University in Atlanta, has won the Frank A. Oski Memorial Lectureship. He will present “Development and Clinical Translation of Engineered Microsystems for Hematologic Applications” on May 2.
Dr. Lam’s research has focused on using nanomechanical and microfluidic engineering approaches to study blood cells, endothelial cells, and thrombosis. Dr. Lam and his lab have created “microvasculature-on-a-chip” models of blood diseases and a smartphone app that can detect and monitor anemia.
Kenneth McClain, MD, PhD, of Texas Children’s Hospital/Baylor University in Houston, has won the 2019 George R. Buchanan Lectureship. Dr. McClain will present “An Oncogene-Driven Orphan Disease: A Short History of Langerhans Cell Histiocytosis” on May 2.
Dr. McClain’s research has focused on Langerhans cell histiocytosis and related disorders. He has served as a founding member and president of the Histiocyte Society, and he organizes yearly events to provide information on Langerhans cell histiocytosis to patients and their families.
Smita Bhatia, MD, of University of Alabama, Birmingham, has won the Childhood Cancer Survivorship Award for Excellence. Her research has focused on health‐related outcomes in cancer survivors and the pathogenesis of these outcomes. Dr. Bhatia has developed models that can identify high-risk cancer survivors and interventions that can reduce complications among cancer survivors.
Movers in Medicine highlights career moves and personal achievements by hematologists and oncologists. Did you switch jobs, take on a new role, climb a mountain? Tell us all about it at [email protected], and you could be featured in Movers in Medicine.
Several hematology and oncology researchers will receive awards at the 2019 conference of the American Society of Pediatric Hematology/Oncology (ASPHO), which takes place May 1-4.
Loretta Li, MD, of Boston Children’s Hospital/Dana-Farber Cancer Institute, and Akshay Sharma, MBBS, of St. Jude Children’s Research Hospital in Memphis, will receive Young Investigator awards at the conference.
Dr. Sharma is conducting research investigating the genetic regulation of fetal hemoglobin and developing transplant and gene therapy trials for patients with sickle cell disease. Dr. Li is studying the activity of JAK2 inhibitors, as well as mechanisms of response and resistance to these drugs, in leukemias.
Elliott Vichinsky, MD, of UCSF Benioff Children’s Hospital Oakland in California, will receive ASPHO’s Distinguished Career Award. Dr. Vichinsky has helped implement newborn screening programs for blood diseases, developed techniques to make blood safer for chronically transfused patients, and conducted research that furthered the development of drugs used to treat iron overload.
Wilbur Lam, MD, PhD, of Aflac Cancer & Blood Disorders Center/Emory University in Atlanta, has won the Frank A. Oski Memorial Lectureship. He will present “Development and Clinical Translation of Engineered Microsystems for Hematologic Applications” on May 2.
Dr. Lam’s research has focused on using nanomechanical and microfluidic engineering approaches to study blood cells, endothelial cells, and thrombosis. Dr. Lam and his lab have created “microvasculature-on-a-chip” models of blood diseases and a smartphone app that can detect and monitor anemia.
Kenneth McClain, MD, PhD, of Texas Children’s Hospital/Baylor University in Houston, has won the 2019 George R. Buchanan Lectureship. Dr. McClain will present “An Oncogene-Driven Orphan Disease: A Short History of Langerhans Cell Histiocytosis” on May 2.
Dr. McClain’s research has focused on Langerhans cell histiocytosis and related disorders. He has served as a founding member and president of the Histiocyte Society, and he organizes yearly events to provide information on Langerhans cell histiocytosis to patients and their families.
Smita Bhatia, MD, of University of Alabama, Birmingham, has won the Childhood Cancer Survivorship Award for Excellence. Her research has focused on health‐related outcomes in cancer survivors and the pathogenesis of these outcomes. Dr. Bhatia has developed models that can identify high-risk cancer survivors and interventions that can reduce complications among cancer survivors.
Movers in Medicine highlights career moves and personal achievements by hematologists and oncologists. Did you switch jobs, take on a new role, climb a mountain? Tell us all about it at [email protected], and you could be featured in Movers in Medicine.
Several hematology and oncology researchers will receive awards at the 2019 conference of the American Society of Pediatric Hematology/Oncology (ASPHO), which takes place May 1-4.
Loretta Li, MD, of Boston Children’s Hospital/Dana-Farber Cancer Institute, and Akshay Sharma, MBBS, of St. Jude Children’s Research Hospital in Memphis, will receive Young Investigator awards at the conference.
Dr. Sharma is conducting research investigating the genetic regulation of fetal hemoglobin and developing transplant and gene therapy trials for patients with sickle cell disease. Dr. Li is studying the activity of JAK2 inhibitors, as well as mechanisms of response and resistance to these drugs, in leukemias.
Elliott Vichinsky, MD, of UCSF Benioff Children’s Hospital Oakland in California, will receive ASPHO’s Distinguished Career Award. Dr. Vichinsky has helped implement newborn screening programs for blood diseases, developed techniques to make blood safer for chronically transfused patients, and conducted research that furthered the development of drugs used to treat iron overload.
Wilbur Lam, MD, PhD, of Aflac Cancer & Blood Disorders Center/Emory University in Atlanta, has won the Frank A. Oski Memorial Lectureship. He will present “Development and Clinical Translation of Engineered Microsystems for Hematologic Applications” on May 2.
Dr. Lam’s research has focused on using nanomechanical and microfluidic engineering approaches to study blood cells, endothelial cells, and thrombosis. Dr. Lam and his lab have created “microvasculature-on-a-chip” models of blood diseases and a smartphone app that can detect and monitor anemia.
Kenneth McClain, MD, PhD, of Texas Children’s Hospital/Baylor University in Houston, has won the 2019 George R. Buchanan Lectureship. Dr. McClain will present “An Oncogene-Driven Orphan Disease: A Short History of Langerhans Cell Histiocytosis” on May 2.
Dr. McClain’s research has focused on Langerhans cell histiocytosis and related disorders. He has served as a founding member and president of the Histiocyte Society, and he organizes yearly events to provide information on Langerhans cell histiocytosis to patients and their families.
Smita Bhatia, MD, of University of Alabama, Birmingham, has won the Childhood Cancer Survivorship Award for Excellence. Her research has focused on health‐related outcomes in cancer survivors and the pathogenesis of these outcomes. Dr. Bhatia has developed models that can identify high-risk cancer survivors and interventions that can reduce complications among cancer survivors.
Movers in Medicine highlights career moves and personal achievements by hematologists and oncologists. Did you switch jobs, take on a new role, climb a mountain? Tell us all about it at [email protected], and you could be featured in Movers in Medicine.
When to transition heart failure patient to alternative loop diuretic
PHILADELPHIA – While many internists might think a switch to spironolactone would be warranted for a heart failure patient with inadequate response to oral furosemide (Lasix), transitioning to an alternative loop diuretic may be the preferable approach, a cardiologist said at the annual meeting of the American College of Physicians.
“Lasix is associated with very high variability in terms of absorption, so torsemide and bumetanide should be considered in patients who have a poor response,” said Paul McKie, MD, MPH, a cardiologist and internist with Mayo Clinic, Rochester, Minn., in a session at the meeting.
When polled, only 22% of attendees at the session picked “transition to torsemide” as the best approach for restoring fluid balance with the lowest adverse potential in a 74-year-old woman with nonischemic cardiomyopathy on furosemide 80 mg twice daily who has been hospitalized for fluid overload three times in the year.
The majority of attendees (41%) said they would have added spironolactone. Dr. McKie disagreed with this approach. Instead, Dr. McKie said he would have transitioned this person to an alternative loop diuretic.
he added.
The rationale for considering an alternative loop diuretic in this patient hinges on bioavailability, which is “highly variable” for oral furosemide, at 10%-100%, while by contrast, torsemide and bumetanide have a very consistent bioavailability of 80%-100%, according to Dr. McKie.
“For this reason, I think about using torsemide or bumetanide in patients who are not responding to oral Lasix,” he said.
Dr. McKie described an algorithm that he and his colleagues use in clinic to intensify outpatient therapy for patients not achieving diuresis.
The first step is to ensure adherence and ask patients whether they are following sodium and fluid restriction: “I always ask about that first,” he said. “I tell patients, ‘You can out-eat and out-drink any diuretic regimen.’ ”
The next step is to double the dose of the loop diuretic and, sometimes, triple the dose if the double dose is not effective.
“If they’re diuresing but it’s just not adequate, then I’ll move to twice-daily dosing,” he said. “A practical tip is I tell patients to take their first dose as soon as they wake up and the second dose around 1:00 PM so that they’re not urinating all night.”
If twice-daily dosing doesn’t help, then that’s the point where an alternative loop diuretic would be warranted, according to Dr. McKie’s algorithm.
“Then I add a thiazide like metolazone, but I only do that after I’ve increased the dose of the loop diuretic,” he added.
If all else fails, then outpatient IV diuretics can be considered, according to the algorithmic approach.
Dr. McKie reported no relevant disclosures.
PHILADELPHIA – While many internists might think a switch to spironolactone would be warranted for a heart failure patient with inadequate response to oral furosemide (Lasix), transitioning to an alternative loop diuretic may be the preferable approach, a cardiologist said at the annual meeting of the American College of Physicians.
“Lasix is associated with very high variability in terms of absorption, so torsemide and bumetanide should be considered in patients who have a poor response,” said Paul McKie, MD, MPH, a cardiologist and internist with Mayo Clinic, Rochester, Minn., in a session at the meeting.
When polled, only 22% of attendees at the session picked “transition to torsemide” as the best approach for restoring fluid balance with the lowest adverse potential in a 74-year-old woman with nonischemic cardiomyopathy on furosemide 80 mg twice daily who has been hospitalized for fluid overload three times in the year.
The majority of attendees (41%) said they would have added spironolactone. Dr. McKie disagreed with this approach. Instead, Dr. McKie said he would have transitioned this person to an alternative loop diuretic.
he added.
The rationale for considering an alternative loop diuretic in this patient hinges on bioavailability, which is “highly variable” for oral furosemide, at 10%-100%, while by contrast, torsemide and bumetanide have a very consistent bioavailability of 80%-100%, according to Dr. McKie.
“For this reason, I think about using torsemide or bumetanide in patients who are not responding to oral Lasix,” he said.
Dr. McKie described an algorithm that he and his colleagues use in clinic to intensify outpatient therapy for patients not achieving diuresis.
The first step is to ensure adherence and ask patients whether they are following sodium and fluid restriction: “I always ask about that first,” he said. “I tell patients, ‘You can out-eat and out-drink any diuretic regimen.’ ”
The next step is to double the dose of the loop diuretic and, sometimes, triple the dose if the double dose is not effective.
“If they’re diuresing but it’s just not adequate, then I’ll move to twice-daily dosing,” he said. “A practical tip is I tell patients to take their first dose as soon as they wake up and the second dose around 1:00 PM so that they’re not urinating all night.”
If twice-daily dosing doesn’t help, then that’s the point where an alternative loop diuretic would be warranted, according to Dr. McKie’s algorithm.
“Then I add a thiazide like metolazone, but I only do that after I’ve increased the dose of the loop diuretic,” he added.
If all else fails, then outpatient IV diuretics can be considered, according to the algorithmic approach.
Dr. McKie reported no relevant disclosures.
PHILADELPHIA – While many internists might think a switch to spironolactone would be warranted for a heart failure patient with inadequate response to oral furosemide (Lasix), transitioning to an alternative loop diuretic may be the preferable approach, a cardiologist said at the annual meeting of the American College of Physicians.
“Lasix is associated with very high variability in terms of absorption, so torsemide and bumetanide should be considered in patients who have a poor response,” said Paul McKie, MD, MPH, a cardiologist and internist with Mayo Clinic, Rochester, Minn., in a session at the meeting.
When polled, only 22% of attendees at the session picked “transition to torsemide” as the best approach for restoring fluid balance with the lowest adverse potential in a 74-year-old woman with nonischemic cardiomyopathy on furosemide 80 mg twice daily who has been hospitalized for fluid overload three times in the year.
The majority of attendees (41%) said they would have added spironolactone. Dr. McKie disagreed with this approach. Instead, Dr. McKie said he would have transitioned this person to an alternative loop diuretic.
he added.
The rationale for considering an alternative loop diuretic in this patient hinges on bioavailability, which is “highly variable” for oral furosemide, at 10%-100%, while by contrast, torsemide and bumetanide have a very consistent bioavailability of 80%-100%, according to Dr. McKie.
“For this reason, I think about using torsemide or bumetanide in patients who are not responding to oral Lasix,” he said.
Dr. McKie described an algorithm that he and his colleagues use in clinic to intensify outpatient therapy for patients not achieving diuresis.
The first step is to ensure adherence and ask patients whether they are following sodium and fluid restriction: “I always ask about that first,” he said. “I tell patients, ‘You can out-eat and out-drink any diuretic regimen.’ ”
The next step is to double the dose of the loop diuretic and, sometimes, triple the dose if the double dose is not effective.
“If they’re diuresing but it’s just not adequate, then I’ll move to twice-daily dosing,” he said. “A practical tip is I tell patients to take their first dose as soon as they wake up and the second dose around 1:00 PM so that they’re not urinating all night.”
If twice-daily dosing doesn’t help, then that’s the point where an alternative loop diuretic would be warranted, according to Dr. McKie’s algorithm.
“Then I add a thiazide like metolazone, but I only do that after I’ve increased the dose of the loop diuretic,” he added.
If all else fails, then outpatient IV diuretics can be considered, according to the algorithmic approach.
Dr. McKie reported no relevant disclosures.
REPORTING FROM INTERNAL MEDICINE 2019
First North American clinical guidelines for hidradenitis suppurativa released
Rigorous evidence is unavailable for most interventions for treating hidradenitis suppurativa (HS), so management needs to be individualized, according to the
The guidelines were published in the Journal of the American Academy of Dermatology.
In an interview, Christopher Sayed, MD, cochair of the guidelines committee, of the department of dermatology at the University of North Carolina, Chapel Hill, said in an interview that the North American guidelines vary from the British Association of Dermatologists (Br J Dermatol. 2018 Dec 15. doi: 10.1111/bjd.17537) and European guidelines (J Eur Acad Dermatol Venereol. 2015 Apr;29[4]:619-44). For example, surgery is an active treatment option for various stages of the disorder in the North American guidelines, whereas surgery is considered a last-ditch effort in the British and European guidelines.
Surgical intervention is often needed “for patients to be the best they can be, and it can be difficult for medicine alone to fix [certain] patients,” Dr. Sayed said. This point that “using medical treatment alone or just surgical treatment alone often doesn’t lead to the best outcome” is stressed in the North American guidelines, he noted.
Limited evidence for high-level recommendations
Adalimumab (Humira), a tumor necrosis factor blocker, was the only therapy for which level 1A evidence is available, and this is because of its study in large-scale randomized controlled trials. (The Food and Drug Administration approved adalimumab in 2015 for treating moderate to severe HS.) Other biologic therapies such as infliximab, anakinra, and ustekinumab carry level 2B recommendations, which Dr. Sayed said will likely influence the availability of these therapies.
Similarly, Nd:YAG laser carries a level 2B recommendation, as does wide excision surgical intervention.
Many of the other treatment modalities explored in the guidelines are not well supported by the literature, according to Dr. Sayed . “The vast majority ... had category C recommendations,” he said. “Some things we tried to evaluate that, really, we can’t give any recommendation on at all because there was no evidence.” He noted that changes in lifestyle and dietary practices are issues patients with HS frequently bring up, but they carry very little evidence of benefit in the literature.
“Even things we use very commonly in HS are often supported by weak evidence because we have to rely on clinical experience. ... There’s just not funding for trials of older drugs or lifestyle interventions,” he said. Treatment mainstays such as tetracycline-class antibiotics, for example, similarly have no large-scale randomized controlled trials to support their use.
Consider comorbidity screening
Treatment is frequently complicated by patient comorbidities, including type 2 diabetes, metabolic syndrome, polycystic ovary syndrome (PCOS), and impaired sexual health, said Dr. Sayed.
“The disease leads to scarring and disfigurement, and can [have a] higher impact on quality of life than almost any other dermatologic disease if you compare them side by side using quality of life measures,” he noted. “We know these patients are more likely to have depression, there are high rates of suicide among these patients. A lot of that has to do with the fact that it’s a chronic disease where there is pain and disfigurement, and patients often grow very, very frustrated in part due to the disease.”
He advised consistent follow-up to ensure patients are not frustrated because of lack of perceived progress.
No one-size-fits-all approach
Dr. Sayed said individualized management is one of the most important parts of taking care of a patient with HS. For example, patients with Hurley stage 1 and Hurley stage 2 variations of the disease may present very differently, and that is the reason why the guidelines do not offer a stepwise treatment algorithm for the disease.
“[The guidelines] have many treatments that may overlap different stages of disease, where those things might need to be used together,” he said. “It takes a lot of discussion with patients about their treatment preferences and listening to whether their disease is progressing or not, whether or not it’s stable, and then trying to figure out whether things like surgery fit into the treatment strategy.”
Despite these recommendations, there may be situations where the answer is not listed in the guidelines. “The guidelines are based on evidence that’s available at the time we review the literature,” he said. “For many patients, they may fail every treatment that’s recommended within the guidelines. There will be times where you have to be creative for patients and go beyond what the guidelines can currently recommend and give patients the treatment that they need even when it seems like all options have been exhausted.”
The authors report relationships with 3M, AbbVie, Adelphi Values, Amgen, BSN, Celgene, Chemocentryx, Coloplast, Galderma, Hidramed Solutions, Hollister, the HS Foundation, Incyte, InflaRx, Integra, Janssen, KCI Inc., Lenicura, Leo, Lilly, The Microdermis Corporation, Novartis, Pfizer, UCB, Valeant, and XBiotech both inside and outside the supported work.
SOURCES: Alikhan A et al. J Am Acad Dermatol. 2019. doi: 10.1016/j.jaad.2019.02.067; Alikhan A et al. J Am Acad Dermatol. 2019. doi: 10.1016/j.jaad.2019.02.068.
Rigorous evidence is unavailable for most interventions for treating hidradenitis suppurativa (HS), so management needs to be individualized, according to the
The guidelines were published in the Journal of the American Academy of Dermatology.
In an interview, Christopher Sayed, MD, cochair of the guidelines committee, of the department of dermatology at the University of North Carolina, Chapel Hill, said in an interview that the North American guidelines vary from the British Association of Dermatologists (Br J Dermatol. 2018 Dec 15. doi: 10.1111/bjd.17537) and European guidelines (J Eur Acad Dermatol Venereol. 2015 Apr;29[4]:619-44). For example, surgery is an active treatment option for various stages of the disorder in the North American guidelines, whereas surgery is considered a last-ditch effort in the British and European guidelines.
Surgical intervention is often needed “for patients to be the best they can be, and it can be difficult for medicine alone to fix [certain] patients,” Dr. Sayed said. This point that “using medical treatment alone or just surgical treatment alone often doesn’t lead to the best outcome” is stressed in the North American guidelines, he noted.
Limited evidence for high-level recommendations
Adalimumab (Humira), a tumor necrosis factor blocker, was the only therapy for which level 1A evidence is available, and this is because of its study in large-scale randomized controlled trials. (The Food and Drug Administration approved adalimumab in 2015 for treating moderate to severe HS.) Other biologic therapies such as infliximab, anakinra, and ustekinumab carry level 2B recommendations, which Dr. Sayed said will likely influence the availability of these therapies.
Similarly, Nd:YAG laser carries a level 2B recommendation, as does wide excision surgical intervention.
Many of the other treatment modalities explored in the guidelines are not well supported by the literature, according to Dr. Sayed . “The vast majority ... had category C recommendations,” he said. “Some things we tried to evaluate that, really, we can’t give any recommendation on at all because there was no evidence.” He noted that changes in lifestyle and dietary practices are issues patients with HS frequently bring up, but they carry very little evidence of benefit in the literature.
“Even things we use very commonly in HS are often supported by weak evidence because we have to rely on clinical experience. ... There’s just not funding for trials of older drugs or lifestyle interventions,” he said. Treatment mainstays such as tetracycline-class antibiotics, for example, similarly have no large-scale randomized controlled trials to support their use.
Consider comorbidity screening
Treatment is frequently complicated by patient comorbidities, including type 2 diabetes, metabolic syndrome, polycystic ovary syndrome (PCOS), and impaired sexual health, said Dr. Sayed.
“The disease leads to scarring and disfigurement, and can [have a] higher impact on quality of life than almost any other dermatologic disease if you compare them side by side using quality of life measures,” he noted. “We know these patients are more likely to have depression, there are high rates of suicide among these patients. A lot of that has to do with the fact that it’s a chronic disease where there is pain and disfigurement, and patients often grow very, very frustrated in part due to the disease.”
He advised consistent follow-up to ensure patients are not frustrated because of lack of perceived progress.
No one-size-fits-all approach
Dr. Sayed said individualized management is one of the most important parts of taking care of a patient with HS. For example, patients with Hurley stage 1 and Hurley stage 2 variations of the disease may present very differently, and that is the reason why the guidelines do not offer a stepwise treatment algorithm for the disease.
“[The guidelines] have many treatments that may overlap different stages of disease, where those things might need to be used together,” he said. “It takes a lot of discussion with patients about their treatment preferences and listening to whether their disease is progressing or not, whether or not it’s stable, and then trying to figure out whether things like surgery fit into the treatment strategy.”
Despite these recommendations, there may be situations where the answer is not listed in the guidelines. “The guidelines are based on evidence that’s available at the time we review the literature,” he said. “For many patients, they may fail every treatment that’s recommended within the guidelines. There will be times where you have to be creative for patients and go beyond what the guidelines can currently recommend and give patients the treatment that they need even when it seems like all options have been exhausted.”
The authors report relationships with 3M, AbbVie, Adelphi Values, Amgen, BSN, Celgene, Chemocentryx, Coloplast, Galderma, Hidramed Solutions, Hollister, the HS Foundation, Incyte, InflaRx, Integra, Janssen, KCI Inc., Lenicura, Leo, Lilly, The Microdermis Corporation, Novartis, Pfizer, UCB, Valeant, and XBiotech both inside and outside the supported work.
SOURCES: Alikhan A et al. J Am Acad Dermatol. 2019. doi: 10.1016/j.jaad.2019.02.067; Alikhan A et al. J Am Acad Dermatol. 2019. doi: 10.1016/j.jaad.2019.02.068.
Rigorous evidence is unavailable for most interventions for treating hidradenitis suppurativa (HS), so management needs to be individualized, according to the
The guidelines were published in the Journal of the American Academy of Dermatology.
In an interview, Christopher Sayed, MD, cochair of the guidelines committee, of the department of dermatology at the University of North Carolina, Chapel Hill, said in an interview that the North American guidelines vary from the British Association of Dermatologists (Br J Dermatol. 2018 Dec 15. doi: 10.1111/bjd.17537) and European guidelines (J Eur Acad Dermatol Venereol. 2015 Apr;29[4]:619-44). For example, surgery is an active treatment option for various stages of the disorder in the North American guidelines, whereas surgery is considered a last-ditch effort in the British and European guidelines.
Surgical intervention is often needed “for patients to be the best they can be, and it can be difficult for medicine alone to fix [certain] patients,” Dr. Sayed said. This point that “using medical treatment alone or just surgical treatment alone often doesn’t lead to the best outcome” is stressed in the North American guidelines, he noted.
Limited evidence for high-level recommendations
Adalimumab (Humira), a tumor necrosis factor blocker, was the only therapy for which level 1A evidence is available, and this is because of its study in large-scale randomized controlled trials. (The Food and Drug Administration approved adalimumab in 2015 for treating moderate to severe HS.) Other biologic therapies such as infliximab, anakinra, and ustekinumab carry level 2B recommendations, which Dr. Sayed said will likely influence the availability of these therapies.
Similarly, Nd:YAG laser carries a level 2B recommendation, as does wide excision surgical intervention.
Many of the other treatment modalities explored in the guidelines are not well supported by the literature, according to Dr. Sayed . “The vast majority ... had category C recommendations,” he said. “Some things we tried to evaluate that, really, we can’t give any recommendation on at all because there was no evidence.” He noted that changes in lifestyle and dietary practices are issues patients with HS frequently bring up, but they carry very little evidence of benefit in the literature.
“Even things we use very commonly in HS are often supported by weak evidence because we have to rely on clinical experience. ... There’s just not funding for trials of older drugs or lifestyle interventions,” he said. Treatment mainstays such as tetracycline-class antibiotics, for example, similarly have no large-scale randomized controlled trials to support their use.
Consider comorbidity screening
Treatment is frequently complicated by patient comorbidities, including type 2 diabetes, metabolic syndrome, polycystic ovary syndrome (PCOS), and impaired sexual health, said Dr. Sayed.
“The disease leads to scarring and disfigurement, and can [have a] higher impact on quality of life than almost any other dermatologic disease if you compare them side by side using quality of life measures,” he noted. “We know these patients are more likely to have depression, there are high rates of suicide among these patients. A lot of that has to do with the fact that it’s a chronic disease where there is pain and disfigurement, and patients often grow very, very frustrated in part due to the disease.”
He advised consistent follow-up to ensure patients are not frustrated because of lack of perceived progress.
No one-size-fits-all approach
Dr. Sayed said individualized management is one of the most important parts of taking care of a patient with HS. For example, patients with Hurley stage 1 and Hurley stage 2 variations of the disease may present very differently, and that is the reason why the guidelines do not offer a stepwise treatment algorithm for the disease.
“[The guidelines] have many treatments that may overlap different stages of disease, where those things might need to be used together,” he said. “It takes a lot of discussion with patients about their treatment preferences and listening to whether their disease is progressing or not, whether or not it’s stable, and then trying to figure out whether things like surgery fit into the treatment strategy.”
Despite these recommendations, there may be situations where the answer is not listed in the guidelines. “The guidelines are based on evidence that’s available at the time we review the literature,” he said. “For many patients, they may fail every treatment that’s recommended within the guidelines. There will be times where you have to be creative for patients and go beyond what the guidelines can currently recommend and give patients the treatment that they need even when it seems like all options have been exhausted.”
The authors report relationships with 3M, AbbVie, Adelphi Values, Amgen, BSN, Celgene, Chemocentryx, Coloplast, Galderma, Hidramed Solutions, Hollister, the HS Foundation, Incyte, InflaRx, Integra, Janssen, KCI Inc., Lenicura, Leo, Lilly, The Microdermis Corporation, Novartis, Pfizer, UCB, Valeant, and XBiotech both inside and outside the supported work.
SOURCES: Alikhan A et al. J Am Acad Dermatol. 2019. doi: 10.1016/j.jaad.2019.02.067; Alikhan A et al. J Am Acad Dermatol. 2019. doi: 10.1016/j.jaad.2019.02.068.
FROM THE JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY
Plant-based diet lowers risk of heart failure
according to an analysis published online in the Journal of the American College of Cardiology.
Conversely, a Southern diet, defined as favoring fried and processed foods, is associated with an increased risk of heart failure. The results support a population-based dietary strategy for decreasing the risk of incident heart failure, according to the investigators.
Campaigns to prevent heart failure often emphasize the maintenance of a healthy diet and weight; however, little research has examined the relationship between dietary patterns and incident heart failure in patients without coronary heart disease.
Kyla M. Lara, MD, postgraduate fellow of cardiology and general internal medicine at the Icahn School of Medicine at Mount Sinai, New York, and colleagues sought to analyze the associations between five dietary patterns and incident hospitalizations for heart failure among adults in the United States. They examined data from the REGARDS (Reasons for Geographic and Racial Differences in Stroke) trial, a prospective study of black and white adults who were followed from 2003-2007 to 2014. Eligible participants completed a food frequency questionnaire and had no coronary heart disease or heart failure at baseline.
The REGARDS researchers’ principal component analysis identified the following five dietary patterns: convenience (for example, Mexican and Chinese dishes and fast food), plant based (for example, vegetables, fruit, and fish), sweets (for example, desserts, breads, and candy), Southern (for example, fried food, processed meats, and sugary beverages), and alcohol/salads. Dr. Lara and colleagues chose incident heart failure hospitalization as their primary endpoint.
The investigators included 16,068 participants in their analysis. Mean age was 64 years, roughly 59% of the sample were women, and 34% were black.
After a median 8.7 years of follow-up, 363 participants had incident heart failure hospitalizations. The highest quartile of adherence to the plant-based dietary pattern was associated with a 41% lower risk of heart failure in multivariate models, compared with the lowest quartile. The highest adherence to the Southern dietary pattern was linked with a 72% higher risk of heart failure after adjustments for age, sex, race, and other potential confounders such as education, income, smoking, and physical activity.
After further adjustments for body mass index, waist circumference, hypertension, dyslipidemia, diabetes mellitus, atrial fibrillation, and chronic kidney disease, the association was attenuated and no longer statistically significant. Dr. Lara and colleagues found no statistically significant associations between incident heart failure with reduced or preserved ejection fraction hospitalizations and the dietary patterns. They also found no associations with the other three dietary patterns.
One researcher reported receiving research funding from Amgen and has consulted for Novartis. The other researchers reported no relevant conflicts.
SOURCE: Lara KM et al. J Am Coll Cardiol. 2019 Apr 30;73(16):2036-45.
This analysis of the REGARDS study contributes toward creating a strong evidence base for the prevention of heart failure through dietary measures, wrote Dong D. Wang, SCD, MD, a visiting scientist at Harvard School of Public Health, Boston, in an accompanying editorial. Empirically derived dietary patterns, such as those described in this study, can form the basis for recommendations easily, he added. “We usually have greater confidence when interpreting the associations with dietary patterns as causal than we have for the associations with specific nutrients or foods. Furthermore, the findings are particularly useful for making recommendations to a general population because of their use of a baseline coronary heart disease–free study population and the inclusion of black participants with greater susceptibility to heart failure. Thus, this study possesses a great potential of informing the population-level strategies for the prevention of heart failure.”
Nutritional epidemiologic studies examining subtypes of heart failure are valuable in light of the disease’s phenotypic and pathophysiological heterogeneity, Dr. Wang wrote. “These findings, if confirmed in future studies, will not only contribute to in-depth biological understanding and phenotypic refinement of heart failure, but also inform dietary prevention approaches customized for specific heart failure phenotypes. In addition, they perfectly fit into key missions of precision medicine [i.e., understanding large variability between individuals in both the development and the clinical manifestations of the specific disease, as well as variability in individual’s response to dietary, lifestyle, and pharmacological interventions].”
Dr. Wang reported no relationships relevant to the contents of this paper.
This analysis of the REGARDS study contributes toward creating a strong evidence base for the prevention of heart failure through dietary measures, wrote Dong D. Wang, SCD, MD, a visiting scientist at Harvard School of Public Health, Boston, in an accompanying editorial. Empirically derived dietary patterns, such as those described in this study, can form the basis for recommendations easily, he added. “We usually have greater confidence when interpreting the associations with dietary patterns as causal than we have for the associations with specific nutrients or foods. Furthermore, the findings are particularly useful for making recommendations to a general population because of their use of a baseline coronary heart disease–free study population and the inclusion of black participants with greater susceptibility to heart failure. Thus, this study possesses a great potential of informing the population-level strategies for the prevention of heart failure.”
Nutritional epidemiologic studies examining subtypes of heart failure are valuable in light of the disease’s phenotypic and pathophysiological heterogeneity, Dr. Wang wrote. “These findings, if confirmed in future studies, will not only contribute to in-depth biological understanding and phenotypic refinement of heart failure, but also inform dietary prevention approaches customized for specific heart failure phenotypes. In addition, they perfectly fit into key missions of precision medicine [i.e., understanding large variability between individuals in both the development and the clinical manifestations of the specific disease, as well as variability in individual’s response to dietary, lifestyle, and pharmacological interventions].”
Dr. Wang reported no relationships relevant to the contents of this paper.
This analysis of the REGARDS study contributes toward creating a strong evidence base for the prevention of heart failure through dietary measures, wrote Dong D. Wang, SCD, MD, a visiting scientist at Harvard School of Public Health, Boston, in an accompanying editorial. Empirically derived dietary patterns, such as those described in this study, can form the basis for recommendations easily, he added. “We usually have greater confidence when interpreting the associations with dietary patterns as causal than we have for the associations with specific nutrients or foods. Furthermore, the findings are particularly useful for making recommendations to a general population because of their use of a baseline coronary heart disease–free study population and the inclusion of black participants with greater susceptibility to heart failure. Thus, this study possesses a great potential of informing the population-level strategies for the prevention of heart failure.”
Nutritional epidemiologic studies examining subtypes of heart failure are valuable in light of the disease’s phenotypic and pathophysiological heterogeneity, Dr. Wang wrote. “These findings, if confirmed in future studies, will not only contribute to in-depth biological understanding and phenotypic refinement of heart failure, but also inform dietary prevention approaches customized for specific heart failure phenotypes. In addition, they perfectly fit into key missions of precision medicine [i.e., understanding large variability between individuals in both the development and the clinical manifestations of the specific disease, as well as variability in individual’s response to dietary, lifestyle, and pharmacological interventions].”
Dr. Wang reported no relationships relevant to the contents of this paper.
according to an analysis published online in the Journal of the American College of Cardiology.
Conversely, a Southern diet, defined as favoring fried and processed foods, is associated with an increased risk of heart failure. The results support a population-based dietary strategy for decreasing the risk of incident heart failure, according to the investigators.
Campaigns to prevent heart failure often emphasize the maintenance of a healthy diet and weight; however, little research has examined the relationship between dietary patterns and incident heart failure in patients without coronary heart disease.
Kyla M. Lara, MD, postgraduate fellow of cardiology and general internal medicine at the Icahn School of Medicine at Mount Sinai, New York, and colleagues sought to analyze the associations between five dietary patterns and incident hospitalizations for heart failure among adults in the United States. They examined data from the REGARDS (Reasons for Geographic and Racial Differences in Stroke) trial, a prospective study of black and white adults who were followed from 2003-2007 to 2014. Eligible participants completed a food frequency questionnaire and had no coronary heart disease or heart failure at baseline.
The REGARDS researchers’ principal component analysis identified the following five dietary patterns: convenience (for example, Mexican and Chinese dishes and fast food), plant based (for example, vegetables, fruit, and fish), sweets (for example, desserts, breads, and candy), Southern (for example, fried food, processed meats, and sugary beverages), and alcohol/salads. Dr. Lara and colleagues chose incident heart failure hospitalization as their primary endpoint.
The investigators included 16,068 participants in their analysis. Mean age was 64 years, roughly 59% of the sample were women, and 34% were black.
After a median 8.7 years of follow-up, 363 participants had incident heart failure hospitalizations. The highest quartile of adherence to the plant-based dietary pattern was associated with a 41% lower risk of heart failure in multivariate models, compared with the lowest quartile. The highest adherence to the Southern dietary pattern was linked with a 72% higher risk of heart failure after adjustments for age, sex, race, and other potential confounders such as education, income, smoking, and physical activity.
After further adjustments for body mass index, waist circumference, hypertension, dyslipidemia, diabetes mellitus, atrial fibrillation, and chronic kidney disease, the association was attenuated and no longer statistically significant. Dr. Lara and colleagues found no statistically significant associations between incident heart failure with reduced or preserved ejection fraction hospitalizations and the dietary patterns. They also found no associations with the other three dietary patterns.
One researcher reported receiving research funding from Amgen and has consulted for Novartis. The other researchers reported no relevant conflicts.
SOURCE: Lara KM et al. J Am Coll Cardiol. 2019 Apr 30;73(16):2036-45.
according to an analysis published online in the Journal of the American College of Cardiology.
Conversely, a Southern diet, defined as favoring fried and processed foods, is associated with an increased risk of heart failure. The results support a population-based dietary strategy for decreasing the risk of incident heart failure, according to the investigators.
Campaigns to prevent heart failure often emphasize the maintenance of a healthy diet and weight; however, little research has examined the relationship between dietary patterns and incident heart failure in patients without coronary heart disease.
Kyla M. Lara, MD, postgraduate fellow of cardiology and general internal medicine at the Icahn School of Medicine at Mount Sinai, New York, and colleagues sought to analyze the associations between five dietary patterns and incident hospitalizations for heart failure among adults in the United States. They examined data from the REGARDS (Reasons for Geographic and Racial Differences in Stroke) trial, a prospective study of black and white adults who were followed from 2003-2007 to 2014. Eligible participants completed a food frequency questionnaire and had no coronary heart disease or heart failure at baseline.
The REGARDS researchers’ principal component analysis identified the following five dietary patterns: convenience (for example, Mexican and Chinese dishes and fast food), plant based (for example, vegetables, fruit, and fish), sweets (for example, desserts, breads, and candy), Southern (for example, fried food, processed meats, and sugary beverages), and alcohol/salads. Dr. Lara and colleagues chose incident heart failure hospitalization as their primary endpoint.
The investigators included 16,068 participants in their analysis. Mean age was 64 years, roughly 59% of the sample were women, and 34% were black.
After a median 8.7 years of follow-up, 363 participants had incident heart failure hospitalizations. The highest quartile of adherence to the plant-based dietary pattern was associated with a 41% lower risk of heart failure in multivariate models, compared with the lowest quartile. The highest adherence to the Southern dietary pattern was linked with a 72% higher risk of heart failure after adjustments for age, sex, race, and other potential confounders such as education, income, smoking, and physical activity.
After further adjustments for body mass index, waist circumference, hypertension, dyslipidemia, diabetes mellitus, atrial fibrillation, and chronic kidney disease, the association was attenuated and no longer statistically significant. Dr. Lara and colleagues found no statistically significant associations between incident heart failure with reduced or preserved ejection fraction hospitalizations and the dietary patterns. They also found no associations with the other three dietary patterns.
One researcher reported receiving research funding from Amgen and has consulted for Novartis. The other researchers reported no relevant conflicts.
SOURCE: Lara KM et al. J Am Coll Cardiol. 2019 Apr 30;73(16):2036-45.
FROM THE JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY
Key clinical point: Plant-based and Southern diets influence the risk of heart failure.
Major finding: Adherence to a plant-based diet reduces the risk of heart failure by 41%.
Study details: An analysis of data for 16,068 participants in the REGARDS study.
Disclosures: One coauthor reported receiving research funding from Amgen and has consulted for Novartis.
Source: Lara KM et al. J Am Coll Cardiol. 2019 Apr 30;73(16):2036-45.
Factors emerge for mitigating CD19 CAR T toxicity
HOUSTON – Cytokine release syndrome and neurotoxicity frequently occur with CD19-directed chimeric antigen receptor (CAR) T-cell immunotherapies, but targetable factors for mitigating the risk and effects of these complications are emerging, according to Cameron Turtle, MBBS, PhD.
These factors include infused CAR T-cell dose, bone marrow disease burden, immune response, and the lymphodepletion regimen used, Dr. Turtle, of Fred Hutchinson Cancer Research Center, Seattle, said at the Transplantation & Cellular Therapies Meetings. This list is based on an analysis of several studies that included a total of 195 patients with B-cell malignancies who were treated with defined-composition CD19 CAR T cells.
In a 2016 study included in the analysis, for instance, Dr. Turtle and his colleagues found that CD19 CAR T cells administered to adults with B-cell acute lymphoblastic leukemia (B-ALL) after lymphodepletion chemotherapy were “remarkably potent.” Remission was achieved in 27 of 29 patients (J Clin Invest. 2016 Jun 1;126[6]:2123-38).
However, the study also established that high CAR T-cell doses and tumor burden increased the risk of severe cytokine release syndrome (CRS) and neurotoxicity, Dr. Turtle said at the meeting, held by the American Society for Blood and Marrow Transplantation and the Center for International Blood and Marrow Transplant Research. At its meeting, the American Society for Blood and Marrow Transplantation announced a new name for the society: American Society for Transplantation and Cellular Therapy (ASTCT).
“Importantly, we identified serum biomarkers that allow testing of early intervention strategies in the patients who have the highest risk of toxicity,” he said.
Dr. Turtle explained that significantly higher peak interleuken-6 (IL-6) and interferon (IFN)-gamma levels were seen after CAR T-cell infusion in patients with high bone marrow tumor burden and in patients requiring treatment in an intensive care unit (ICU).
ICU care correlated with a higher percentage of bone marrow blasts before lymphodepletion chemotherapy, he added.
Elevations of serum C-reactive protein (CRP) and ferritin also correlated with bone marrow disease burden and with the occurrence of severe CRS requiring ICU care, he said, noting that ferritin and CRP levels declined after tocilizumab or corticosteroid therapy.
In addition, all patients in the study who developed neurotoxicity had evidence of CRS. Peak levels of IL-6, IFN-gamma, ferritin, and CRP were significantly higher in those who developed grade 3 or higher neurotoxicity. Further, serum IL-6 and IFN-gamma concentrations on day 1 after infusion were significantly higher in those who required ICU care and in those who subsequently developed grade 4 neurotoxicity than in patients who developed grade 3 neurotoxicity.
Multivariate analysis indicated that serum IL-6 concentration of more than 30 pg/mL on day 1 and the total number of CD19+ cells in bone marrow before therapy were independent predictors of subsequent development of grade 3 or higher neurotoxicity.
Notably, serum IL-6 of more than 30 pg/mL on day 1 identified all patients in the study who subsequently developed grade 4 or higher neurotoxicity, Dr. Turtle and his colleagues noted.
“The findings suggested that evaluation of serum IL-6 concentration early after CAR T-cell infusion might be useful for identifying patients at high risk of severe neurotoxicity and to evaluate early intervention approaches,” he said.
Neurotoxicity
In a 2017 study from Juliane Gust, MD, PhD, and her colleagues, bone marrow disease burden, lymphodepletion regimen, and CAR T-cell dose were found to be significantly associated with neurotoxicity during multivariate analysis (Cancer Discov. 2017 Dec;7[12]:1404-19).
Patients with severe neurotoxicity in that study demonstrated evidence of endothelial activation, including disseminated intravascular coagulation, capillary leak, and increased blood-brain barrier permeability – with the latter leading to a failure to protect the cerebrospinal fluid from high concentrations of systemic cytokines, including IFN-gamma. These high levels of cytokines may cause vascular pericyte activation and stress, Dr. Turtle explained.
Patients who subsequently developed grade 4 or higher neurotoxicity had higher pretreatment levels of endothelial activation biomarkers.
“Endothelial cells and pericytes contribute to the integrity of the blood-brain barrier; this suggests a potential role for IL-6 and vascular endothelial growth factor from pericytes to augment endothelial permeability,” Dr. Turtle said.
CRS
In another 2017 study, from Kevin A. Hay, MD, and his colleagues, similar factors were found to be associated with CRS (Blood. 2017 Nov 23;130[21]:2295-306).
Multivariable analysis identified high marrow tumor burden, lymphodepletion using cyclophosphamide and fludarabine, higher CAR T-cell dose, thrombocytopenia before lymphodepletion, and manufacturing of CAR T cells without selection of CD8+ central memory T cells as independent predictors of CRS.
Severe CRS was characterized by hemodynamic instability, capillary leak, and consumptive coagulopathy. As in the study by Dr. Gust and her colleagues, biomarkers of endothelial activation, including angiopoietin-2 and von Willebrand factor, were increased during severe CRS and before lymphodepletion in patients who subsequently developed CRS.
Potential modifications
The findings to date suggest that risk stratification, prophylaxis, early intervention and therapeutic intervention are among potential strategies for mitigating the risk of CD19-directed CAR T toxicity, Dr. Turtle said. Steroids, tocilizumab, siltuximab, anakinra, anti-GM-CSF, small molecules, plasma exchange, angiopoietin-1, and hypertransfusion are among candidates under consideration for such interventions, he noted.
Other approaches that have been tested in small studies, and which may reduce toxicity and improve the therapeutic index of CD19 CAR T-cell therapy for B-ALL, include split dosing and risk-adapted dosing.
“These approaches do appear to mitigate toxicity, but larger studies are needed to confirm that treatment efficacy is maintained,” Dr. Turtle said.
Toxicity prediction and early intervention to maintain the CAR T-cell dose while avoiding grade 4 or greater toxicities would be helpful and is within reach, he said, noting that the findings by Dr. Hay and his colleagues led to the development of “day-1 cytokine combination algorithms that predict grade 4-5 CRS and could direct preemptive intervention.”
One algorithm based on three cytokines had high sensitivity and specificity, but would require screening of all patients.
Early intervention in patients in whom toxicity is predicted has not been extensively evaluated in clinical studies, he said.
Dr. Hay and his colleagues did, however, develop a “classification tree model of early intervention strategies” using their findings.
A complicating factor in predicting risk and intervening is that each CAR T-cell product is associated with differing levels of toxicity risk. The varying rates of toxicity suggest that promising approaches for addressing CAR T toxicity require validation for each product with respect to cutpoints, efficacy, and maintenance of response, Dr. Turtle said.
“The findings to date are encouraging and show that potentially targetable factors for mitigating the toxicity of CAR T-cell therapy can be identified,” he said. “But clinical studies have yet to convincingly establish the best approach.”
Dr. Turtle has served on advisory boards for Juno/Celgene, Kite/Gilead, Novartis, Precision Biosciences, Eureka Therapeutics, Caribou Biosciences, Nektar Therapeutics, Humanigen, and Aptevo; has intellectual property rights licensed to Juno; has stock options with Precision Biosciences, Eureka Therapeutics, and Caribou Biosciences; and has received research funding from Juno and Nektar Therapeutics.
HOUSTON – Cytokine release syndrome and neurotoxicity frequently occur with CD19-directed chimeric antigen receptor (CAR) T-cell immunotherapies, but targetable factors for mitigating the risk and effects of these complications are emerging, according to Cameron Turtle, MBBS, PhD.
These factors include infused CAR T-cell dose, bone marrow disease burden, immune response, and the lymphodepletion regimen used, Dr. Turtle, of Fred Hutchinson Cancer Research Center, Seattle, said at the Transplantation & Cellular Therapies Meetings. This list is based on an analysis of several studies that included a total of 195 patients with B-cell malignancies who were treated with defined-composition CD19 CAR T cells.
In a 2016 study included in the analysis, for instance, Dr. Turtle and his colleagues found that CD19 CAR T cells administered to adults with B-cell acute lymphoblastic leukemia (B-ALL) after lymphodepletion chemotherapy were “remarkably potent.” Remission was achieved in 27 of 29 patients (J Clin Invest. 2016 Jun 1;126[6]:2123-38).
However, the study also established that high CAR T-cell doses and tumor burden increased the risk of severe cytokine release syndrome (CRS) and neurotoxicity, Dr. Turtle said at the meeting, held by the American Society for Blood and Marrow Transplantation and the Center for International Blood and Marrow Transplant Research. At its meeting, the American Society for Blood and Marrow Transplantation announced a new name for the society: American Society for Transplantation and Cellular Therapy (ASTCT).
“Importantly, we identified serum biomarkers that allow testing of early intervention strategies in the patients who have the highest risk of toxicity,” he said.
Dr. Turtle explained that significantly higher peak interleuken-6 (IL-6) and interferon (IFN)-gamma levels were seen after CAR T-cell infusion in patients with high bone marrow tumor burden and in patients requiring treatment in an intensive care unit (ICU).
ICU care correlated with a higher percentage of bone marrow blasts before lymphodepletion chemotherapy, he added.
Elevations of serum C-reactive protein (CRP) and ferritin also correlated with bone marrow disease burden and with the occurrence of severe CRS requiring ICU care, he said, noting that ferritin and CRP levels declined after tocilizumab or corticosteroid therapy.
In addition, all patients in the study who developed neurotoxicity had evidence of CRS. Peak levels of IL-6, IFN-gamma, ferritin, and CRP were significantly higher in those who developed grade 3 or higher neurotoxicity. Further, serum IL-6 and IFN-gamma concentrations on day 1 after infusion were significantly higher in those who required ICU care and in those who subsequently developed grade 4 neurotoxicity than in patients who developed grade 3 neurotoxicity.
Multivariate analysis indicated that serum IL-6 concentration of more than 30 pg/mL on day 1 and the total number of CD19+ cells in bone marrow before therapy were independent predictors of subsequent development of grade 3 or higher neurotoxicity.
Notably, serum IL-6 of more than 30 pg/mL on day 1 identified all patients in the study who subsequently developed grade 4 or higher neurotoxicity, Dr. Turtle and his colleagues noted.
“The findings suggested that evaluation of serum IL-6 concentration early after CAR T-cell infusion might be useful for identifying patients at high risk of severe neurotoxicity and to evaluate early intervention approaches,” he said.
Neurotoxicity
In a 2017 study from Juliane Gust, MD, PhD, and her colleagues, bone marrow disease burden, lymphodepletion regimen, and CAR T-cell dose were found to be significantly associated with neurotoxicity during multivariate analysis (Cancer Discov. 2017 Dec;7[12]:1404-19).
Patients with severe neurotoxicity in that study demonstrated evidence of endothelial activation, including disseminated intravascular coagulation, capillary leak, and increased blood-brain barrier permeability – with the latter leading to a failure to protect the cerebrospinal fluid from high concentrations of systemic cytokines, including IFN-gamma. These high levels of cytokines may cause vascular pericyte activation and stress, Dr. Turtle explained.
Patients who subsequently developed grade 4 or higher neurotoxicity had higher pretreatment levels of endothelial activation biomarkers.
“Endothelial cells and pericytes contribute to the integrity of the blood-brain barrier; this suggests a potential role for IL-6 and vascular endothelial growth factor from pericytes to augment endothelial permeability,” Dr. Turtle said.
CRS
In another 2017 study, from Kevin A. Hay, MD, and his colleagues, similar factors were found to be associated with CRS (Blood. 2017 Nov 23;130[21]:2295-306).
Multivariable analysis identified high marrow tumor burden, lymphodepletion using cyclophosphamide and fludarabine, higher CAR T-cell dose, thrombocytopenia before lymphodepletion, and manufacturing of CAR T cells without selection of CD8+ central memory T cells as independent predictors of CRS.
Severe CRS was characterized by hemodynamic instability, capillary leak, and consumptive coagulopathy. As in the study by Dr. Gust and her colleagues, biomarkers of endothelial activation, including angiopoietin-2 and von Willebrand factor, were increased during severe CRS and before lymphodepletion in patients who subsequently developed CRS.
Potential modifications
The findings to date suggest that risk stratification, prophylaxis, early intervention and therapeutic intervention are among potential strategies for mitigating the risk of CD19-directed CAR T toxicity, Dr. Turtle said. Steroids, tocilizumab, siltuximab, anakinra, anti-GM-CSF, small molecules, plasma exchange, angiopoietin-1, and hypertransfusion are among candidates under consideration for such interventions, he noted.
Other approaches that have been tested in small studies, and which may reduce toxicity and improve the therapeutic index of CD19 CAR T-cell therapy for B-ALL, include split dosing and risk-adapted dosing.
“These approaches do appear to mitigate toxicity, but larger studies are needed to confirm that treatment efficacy is maintained,” Dr. Turtle said.
Toxicity prediction and early intervention to maintain the CAR T-cell dose while avoiding grade 4 or greater toxicities would be helpful and is within reach, he said, noting that the findings by Dr. Hay and his colleagues led to the development of “day-1 cytokine combination algorithms that predict grade 4-5 CRS and could direct preemptive intervention.”
One algorithm based on three cytokines had high sensitivity and specificity, but would require screening of all patients.
Early intervention in patients in whom toxicity is predicted has not been extensively evaluated in clinical studies, he said.
Dr. Hay and his colleagues did, however, develop a “classification tree model of early intervention strategies” using their findings.
A complicating factor in predicting risk and intervening is that each CAR T-cell product is associated with differing levels of toxicity risk. The varying rates of toxicity suggest that promising approaches for addressing CAR T toxicity require validation for each product with respect to cutpoints, efficacy, and maintenance of response, Dr. Turtle said.
“The findings to date are encouraging and show that potentially targetable factors for mitigating the toxicity of CAR T-cell therapy can be identified,” he said. “But clinical studies have yet to convincingly establish the best approach.”
Dr. Turtle has served on advisory boards for Juno/Celgene, Kite/Gilead, Novartis, Precision Biosciences, Eureka Therapeutics, Caribou Biosciences, Nektar Therapeutics, Humanigen, and Aptevo; has intellectual property rights licensed to Juno; has stock options with Precision Biosciences, Eureka Therapeutics, and Caribou Biosciences; and has received research funding from Juno and Nektar Therapeutics.
HOUSTON – Cytokine release syndrome and neurotoxicity frequently occur with CD19-directed chimeric antigen receptor (CAR) T-cell immunotherapies, but targetable factors for mitigating the risk and effects of these complications are emerging, according to Cameron Turtle, MBBS, PhD.
These factors include infused CAR T-cell dose, bone marrow disease burden, immune response, and the lymphodepletion regimen used, Dr. Turtle, of Fred Hutchinson Cancer Research Center, Seattle, said at the Transplantation & Cellular Therapies Meetings. This list is based on an analysis of several studies that included a total of 195 patients with B-cell malignancies who were treated with defined-composition CD19 CAR T cells.
In a 2016 study included in the analysis, for instance, Dr. Turtle and his colleagues found that CD19 CAR T cells administered to adults with B-cell acute lymphoblastic leukemia (B-ALL) after lymphodepletion chemotherapy were “remarkably potent.” Remission was achieved in 27 of 29 patients (J Clin Invest. 2016 Jun 1;126[6]:2123-38).
However, the study also established that high CAR T-cell doses and tumor burden increased the risk of severe cytokine release syndrome (CRS) and neurotoxicity, Dr. Turtle said at the meeting, held by the American Society for Blood and Marrow Transplantation and the Center for International Blood and Marrow Transplant Research. At its meeting, the American Society for Blood and Marrow Transplantation announced a new name for the society: American Society for Transplantation and Cellular Therapy (ASTCT).
“Importantly, we identified serum biomarkers that allow testing of early intervention strategies in the patients who have the highest risk of toxicity,” he said.
Dr. Turtle explained that significantly higher peak interleuken-6 (IL-6) and interferon (IFN)-gamma levels were seen after CAR T-cell infusion in patients with high bone marrow tumor burden and in patients requiring treatment in an intensive care unit (ICU).
ICU care correlated with a higher percentage of bone marrow blasts before lymphodepletion chemotherapy, he added.
Elevations of serum C-reactive protein (CRP) and ferritin also correlated with bone marrow disease burden and with the occurrence of severe CRS requiring ICU care, he said, noting that ferritin and CRP levels declined after tocilizumab or corticosteroid therapy.
In addition, all patients in the study who developed neurotoxicity had evidence of CRS. Peak levels of IL-6, IFN-gamma, ferritin, and CRP were significantly higher in those who developed grade 3 or higher neurotoxicity. Further, serum IL-6 and IFN-gamma concentrations on day 1 after infusion were significantly higher in those who required ICU care and in those who subsequently developed grade 4 neurotoxicity than in patients who developed grade 3 neurotoxicity.
Multivariate analysis indicated that serum IL-6 concentration of more than 30 pg/mL on day 1 and the total number of CD19+ cells in bone marrow before therapy were independent predictors of subsequent development of grade 3 or higher neurotoxicity.
Notably, serum IL-6 of more than 30 pg/mL on day 1 identified all patients in the study who subsequently developed grade 4 or higher neurotoxicity, Dr. Turtle and his colleagues noted.
“The findings suggested that evaluation of serum IL-6 concentration early after CAR T-cell infusion might be useful for identifying patients at high risk of severe neurotoxicity and to evaluate early intervention approaches,” he said.
Neurotoxicity
In a 2017 study from Juliane Gust, MD, PhD, and her colleagues, bone marrow disease burden, lymphodepletion regimen, and CAR T-cell dose were found to be significantly associated with neurotoxicity during multivariate analysis (Cancer Discov. 2017 Dec;7[12]:1404-19).
Patients with severe neurotoxicity in that study demonstrated evidence of endothelial activation, including disseminated intravascular coagulation, capillary leak, and increased blood-brain barrier permeability – with the latter leading to a failure to protect the cerebrospinal fluid from high concentrations of systemic cytokines, including IFN-gamma. These high levels of cytokines may cause vascular pericyte activation and stress, Dr. Turtle explained.
Patients who subsequently developed grade 4 or higher neurotoxicity had higher pretreatment levels of endothelial activation biomarkers.
“Endothelial cells and pericytes contribute to the integrity of the blood-brain barrier; this suggests a potential role for IL-6 and vascular endothelial growth factor from pericytes to augment endothelial permeability,” Dr. Turtle said.
CRS
In another 2017 study, from Kevin A. Hay, MD, and his colleagues, similar factors were found to be associated with CRS (Blood. 2017 Nov 23;130[21]:2295-306).
Multivariable analysis identified high marrow tumor burden, lymphodepletion using cyclophosphamide and fludarabine, higher CAR T-cell dose, thrombocytopenia before lymphodepletion, and manufacturing of CAR T cells without selection of CD8+ central memory T cells as independent predictors of CRS.
Severe CRS was characterized by hemodynamic instability, capillary leak, and consumptive coagulopathy. As in the study by Dr. Gust and her colleagues, biomarkers of endothelial activation, including angiopoietin-2 and von Willebrand factor, were increased during severe CRS and before lymphodepletion in patients who subsequently developed CRS.
Potential modifications
The findings to date suggest that risk stratification, prophylaxis, early intervention and therapeutic intervention are among potential strategies for mitigating the risk of CD19-directed CAR T toxicity, Dr. Turtle said. Steroids, tocilizumab, siltuximab, anakinra, anti-GM-CSF, small molecules, plasma exchange, angiopoietin-1, and hypertransfusion are among candidates under consideration for such interventions, he noted.
Other approaches that have been tested in small studies, and which may reduce toxicity and improve the therapeutic index of CD19 CAR T-cell therapy for B-ALL, include split dosing and risk-adapted dosing.
“These approaches do appear to mitigate toxicity, but larger studies are needed to confirm that treatment efficacy is maintained,” Dr. Turtle said.
Toxicity prediction and early intervention to maintain the CAR T-cell dose while avoiding grade 4 or greater toxicities would be helpful and is within reach, he said, noting that the findings by Dr. Hay and his colleagues led to the development of “day-1 cytokine combination algorithms that predict grade 4-5 CRS and could direct preemptive intervention.”
One algorithm based on three cytokines had high sensitivity and specificity, but would require screening of all patients.
Early intervention in patients in whom toxicity is predicted has not been extensively evaluated in clinical studies, he said.
Dr. Hay and his colleagues did, however, develop a “classification tree model of early intervention strategies” using their findings.
A complicating factor in predicting risk and intervening is that each CAR T-cell product is associated with differing levels of toxicity risk. The varying rates of toxicity suggest that promising approaches for addressing CAR T toxicity require validation for each product with respect to cutpoints, efficacy, and maintenance of response, Dr. Turtle said.
“The findings to date are encouraging and show that potentially targetable factors for mitigating the toxicity of CAR T-cell therapy can be identified,” he said. “But clinical studies have yet to convincingly establish the best approach.”
Dr. Turtle has served on advisory boards for Juno/Celgene, Kite/Gilead, Novartis, Precision Biosciences, Eureka Therapeutics, Caribou Biosciences, Nektar Therapeutics, Humanigen, and Aptevo; has intellectual property rights licensed to Juno; has stock options with Precision Biosciences, Eureka Therapeutics, and Caribou Biosciences; and has received research funding from Juno and Nektar Therapeutics.
REPORTING FROM TCT 2019
Pulmonologist: In COPD, try dual therapy before adding corticosteroid
PHILADELPHIA – While triple therapy is effective for patients with chronic obstructive pulmonary disease (COPD), not all patients actually need the inhaled corticosteroid component to reduce exacerbations, a Mayo Clinic pulmonologist said at the annual meeting of the American College of Physicians.
“When you’re increasing therapy, we can go to a dual-bronchodilator combination before adding corticosteroids,” Megan Dulohery Scrodin, MD, of Mayo Clinic, Rochester, Minn., noted in a well-attended session.
That approach came as news to many internists, at least going by results of an audience poll in which 76% of attendees picked triple therapy for a 65-year-old male with COPD and frequent exacerbations despite having used a long-acting muscarinic antagonist (LAMA). Only 10% picked what Dr. Dulohery Scrodin said was optimal: to keep the patient on the LAMA, and add a long-acting beta-agonist (LABA).
“I would encourage you to do this as a stepwise process,” Dr. Dulohery Scrodin told attendees after seeing those poll results.
For a patient with minimal symptoms and few exacerbations, the best approach is a short-acting bronchodilator plus smoking cessation, avoidance of environmental triggers, and keeping up to date with vaccinations, she said.
For patients with more severe symptoms or frequent exacerbations, adding a LAMA or LABA would be warranted, along with considering pulmonary rehabilitation.
“There’s been studies comparing long-acting muscarinic antagonists to long-acting beta agonists, and the long-acting muscarinic antagonists like tiotropium seem to be superior,” she said. “So I always do a LAMA inhaler first.”
For patients still having exacerbations despite one long-acting bronchodilator, the best approach would be to add the second bronchodilator, and if that still doesn’t work, she said, add an inhaled corticosteroid and consider a pulmonary consultation for advanced therapy.
“If the patient doesn’t need an inhaled corticosteroid, we try to avoid it and use dual bronchodilator therapy,” said Dr. Dulohery Scrodin, noting that inhaled corticosteroids are associated with increased risk of pneumonia, along with other complications such as dysphonia and oral candidiasis.
In studies, single-inhaler triple therapy with fluticasone furoate, umeclidinium, and vilanterol does seem to reduce exacerbations more than LABA/LAMA combination therapy or LABA/inhaled corticosteroid treatment, but that doesn’t necessarily mean it should be automatically chosen over dual therapy, the presenter noted.
“Similar to asthma, I would do the least amount of therapy that your patient gets under control,” she told the audience.
Dr. Dulohery Scrodin reported that she had no relevant disclosures.
PHILADELPHIA – While triple therapy is effective for patients with chronic obstructive pulmonary disease (COPD), not all patients actually need the inhaled corticosteroid component to reduce exacerbations, a Mayo Clinic pulmonologist said at the annual meeting of the American College of Physicians.
“When you’re increasing therapy, we can go to a dual-bronchodilator combination before adding corticosteroids,” Megan Dulohery Scrodin, MD, of Mayo Clinic, Rochester, Minn., noted in a well-attended session.
That approach came as news to many internists, at least going by results of an audience poll in which 76% of attendees picked triple therapy for a 65-year-old male with COPD and frequent exacerbations despite having used a long-acting muscarinic antagonist (LAMA). Only 10% picked what Dr. Dulohery Scrodin said was optimal: to keep the patient on the LAMA, and add a long-acting beta-agonist (LABA).
“I would encourage you to do this as a stepwise process,” Dr. Dulohery Scrodin told attendees after seeing those poll results.
For a patient with minimal symptoms and few exacerbations, the best approach is a short-acting bronchodilator plus smoking cessation, avoidance of environmental triggers, and keeping up to date with vaccinations, she said.
For patients with more severe symptoms or frequent exacerbations, adding a LAMA or LABA would be warranted, along with considering pulmonary rehabilitation.
“There’s been studies comparing long-acting muscarinic antagonists to long-acting beta agonists, and the long-acting muscarinic antagonists like tiotropium seem to be superior,” she said. “So I always do a LAMA inhaler first.”
For patients still having exacerbations despite one long-acting bronchodilator, the best approach would be to add the second bronchodilator, and if that still doesn’t work, she said, add an inhaled corticosteroid and consider a pulmonary consultation for advanced therapy.
“If the patient doesn’t need an inhaled corticosteroid, we try to avoid it and use dual bronchodilator therapy,” said Dr. Dulohery Scrodin, noting that inhaled corticosteroids are associated with increased risk of pneumonia, along with other complications such as dysphonia and oral candidiasis.
In studies, single-inhaler triple therapy with fluticasone furoate, umeclidinium, and vilanterol does seem to reduce exacerbations more than LABA/LAMA combination therapy or LABA/inhaled corticosteroid treatment, but that doesn’t necessarily mean it should be automatically chosen over dual therapy, the presenter noted.
“Similar to asthma, I would do the least amount of therapy that your patient gets under control,” she told the audience.
Dr. Dulohery Scrodin reported that she had no relevant disclosures.
PHILADELPHIA – While triple therapy is effective for patients with chronic obstructive pulmonary disease (COPD), not all patients actually need the inhaled corticosteroid component to reduce exacerbations, a Mayo Clinic pulmonologist said at the annual meeting of the American College of Physicians.
“When you’re increasing therapy, we can go to a dual-bronchodilator combination before adding corticosteroids,” Megan Dulohery Scrodin, MD, of Mayo Clinic, Rochester, Minn., noted in a well-attended session.
That approach came as news to many internists, at least going by results of an audience poll in which 76% of attendees picked triple therapy for a 65-year-old male with COPD and frequent exacerbations despite having used a long-acting muscarinic antagonist (LAMA). Only 10% picked what Dr. Dulohery Scrodin said was optimal: to keep the patient on the LAMA, and add a long-acting beta-agonist (LABA).
“I would encourage you to do this as a stepwise process,” Dr. Dulohery Scrodin told attendees after seeing those poll results.
For a patient with minimal symptoms and few exacerbations, the best approach is a short-acting bronchodilator plus smoking cessation, avoidance of environmental triggers, and keeping up to date with vaccinations, she said.
For patients with more severe symptoms or frequent exacerbations, adding a LAMA or LABA would be warranted, along with considering pulmonary rehabilitation.
“There’s been studies comparing long-acting muscarinic antagonists to long-acting beta agonists, and the long-acting muscarinic antagonists like tiotropium seem to be superior,” she said. “So I always do a LAMA inhaler first.”
For patients still having exacerbations despite one long-acting bronchodilator, the best approach would be to add the second bronchodilator, and if that still doesn’t work, she said, add an inhaled corticosteroid and consider a pulmonary consultation for advanced therapy.
“If the patient doesn’t need an inhaled corticosteroid, we try to avoid it and use dual bronchodilator therapy,” said Dr. Dulohery Scrodin, noting that inhaled corticosteroids are associated with increased risk of pneumonia, along with other complications such as dysphonia and oral candidiasis.
In studies, single-inhaler triple therapy with fluticasone furoate, umeclidinium, and vilanterol does seem to reduce exacerbations more than LABA/LAMA combination therapy or LABA/inhaled corticosteroid treatment, but that doesn’t necessarily mean it should be automatically chosen over dual therapy, the presenter noted.
“Similar to asthma, I would do the least amount of therapy that your patient gets under control,” she told the audience.
Dr. Dulohery Scrodin reported that she had no relevant disclosures.
REPORTING FROM INTERNAL MEDICINE 2019