The Diagnosis: Bullous Henoch-Schönlein Purpura

Laboratory tests in this patient showed no abnormalities for complete blood cell count, immunoglobulins, anti–double-stranded DNA, antinuclear antibody, p–antineutrophil cytoplasmic antibodies, lupus anticoagulant, Sjögren antibodies, liver enzymes, and erythrocyte sedimentation rate. Urinalysis was normal. Punch biopsies were obtained and a histologic examination showed an intense inflammatory infiltrate of neutrophils around blood vessels within the dermis (Figure). These blood vessels showed swollen endothelium and narrowing of the vessel lumina with leukocytoclasia. Direct immunofluorescence revealed granular IgA, C3, fibrin, and weak IgM deposits in blood vessels in the papillary dermis consistent with Henoch-Schönlein purpura (HSP).

Henoch-Schönlein purpura is the most common vasculitis in children.^1-6 However, its bullous variant is rare, with few pediatric cases reported. Bullous HSP affects arterioles through an IgA-mediated pathway.^1-6 It is believed that the bullae are formed secondary to neutrophilic release of matrix metalloproteinase 9 (MMP-9), which degrades extracellular collagen.² Additionally, bullous fluid from HSP has been noted to have markedly elevated levels of soluble CD23, a form of the CD23 B-cell surface receptor used in antibody feedback regulation and B-cell recruitment, which also has been found to be elevated in the fluid of bullous pemphigoid, suggesting a similar pathogenesis of exaggerated humoral immunity.³

The most common sign of HSP is palpable purpura; however, other cutaneous findings can be present including targetoid plaques, macules, papules, petechiae, and bullae that may become hemorrhagic, ulcerated, necrotic, or scarred.^1-6 Bullae appear in the most dependent parts of the body, such as the feet and lower legs. Hydrostatic pressure may play a role in the pathogenesis of this phenomenon.¹ When other classic signs of HSP are absent, the presence of bullae clouds the diagnosis and creates controversy regarding treatment, as there is a dearth of literature on proper therapy for severe cutaneous manifestations of HSP.⁶

Our patient was treated with morphine for pain management along with topical mupirocin and nonadherent dressings for wound care. She also received pulse intravenous methylprednisolone 2 mg/kg daily for 3 days and then was transitioned to oral prednisone 1 mg/kg daily, which was tapered over 3 weeks after discharge. This regimen resulted in resolution of symptoms with rapid regression of bullae and subsequent postinflammatory hyperpigmentation. Prior reports have noted that the presence of bullae does not alter the prognosis or predict probability of renal involvement of this self-limited disease, leading to controversy in determining if treatment offers more favorable outcomes.^1,3 One study suggested that steroids only improve symptoms, arthralgia, and abdominal pain, but they do not aid in the resolution of cutaneous lesions or prevent the progression of renal disease.³ Contrarily, others have suggested that the presence of bullae and renal disease is an indication to start treatment.⁶ This claim is based on the mechanistic finding that immunosuppression with corticosteroids decreases inflammation by inhibiting activator protein 1, a transcription factor for MMP-9, thereby reducing MMP-9 activity and the formation of bullae.⁴ Clinical anecdotes, including our own, that demonstrate dramatic improvement of hemorrhagic bullae with the administration of corticosteroids substantiate this mechanism. Through the inhibition of neutrophil interactions and IgA production, other anti-inflammatory and immunosuppressive medications such as colchicine, dapsone, and azathioprine also have been reported to aid in resolution of the cutaneous lesions.^1,5,6 Although there is a clear drawback to the lack of controlled trials and prospective studies regarding the treatment of bullous HSP, it is nearly impossible to expect such studies to be carried out given the rare and unpredictable nature of the disease. For now, claims derived from case series and case reports guide our understanding of treatment efficacy.

Acknowledgment—Quiz photograph courtesy of Steve Taylor, BS, Phoenix, Arizona.

The Diagnosis: Bullous Henoch-Schönlein Purpura

Laboratory tests in this patient showed no abnormalities for complete blood cell count, immunoglobulins, anti–double-stranded DNA, antinuclear antibody, p–antineutrophil cytoplasmic antibodies, lupus anticoagulant, Sjögren antibodies, liver enzymes, and erythrocyte sedimentation rate. Urinalysis was normal. Punch biopsies were obtained and a histologic examination showed an intense inflammatory infiltrate of neutrophils around blood vessels within the dermis (Figure). These blood vessels showed swollen endothelium and narrowing of the vessel lumina with leukocytoclasia. Direct immunofluorescence revealed granular IgA, C3, fibrin, and weak IgM deposits in blood vessels in the papillary dermis consistent with Henoch-Schönlein purpura (HSP).

Henoch-Schönlein purpura is the most common vasculitis in children.^1-6 However, its bullous variant is rare, with few pediatric cases reported. Bullous HSP affects arterioles through an IgA-mediated pathway.^1-6 It is believed that the bullae are formed secondary to neutrophilic release of matrix metalloproteinase 9 (MMP-9), which degrades extracellular collagen.² Additionally, bullous fluid from HSP has been noted to have markedly elevated levels of soluble CD23, a form of the CD23 B-cell surface receptor used in antibody feedback regulation and B-cell recruitment, which also has been found to be elevated in the fluid of bullous pemphigoid, suggesting a similar pathogenesis of exaggerated humoral immunity.³

The most common sign of HSP is palpable purpura; however, other cutaneous findings can be present including targetoid plaques, macules, papules, petechiae, and bullae that may become hemorrhagic, ulcerated, necrotic, or scarred.^1-6 Bullae appear in the most dependent parts of the body, such as the feet and lower legs. Hydrostatic pressure may play a role in the pathogenesis of this phenomenon.¹ When other classic signs of HSP are absent, the presence of bullae clouds the diagnosis and creates controversy regarding treatment, as there is a dearth of literature on proper therapy for severe cutaneous manifestations of HSP.⁶

Our patient was treated with morphine for pain management along with topical mupirocin and nonadherent dressings for wound care. She also received pulse intravenous methylprednisolone 2 mg/kg daily for 3 days and then was transitioned to oral prednisone 1 mg/kg daily, which was tapered over 3 weeks after discharge. This regimen resulted in resolution of symptoms with rapid regression of bullae and subsequent postinflammatory hyperpigmentation. Prior reports have noted that the presence of bullae does not alter the prognosis or predict probability of renal involvement of this self-limited disease, leading to controversy in determining if treatment offers more favorable outcomes.^1,3 One study suggested that steroids only improve symptoms, arthralgia, and abdominal pain, but they do not aid in the resolution of cutaneous lesions or prevent the progression of renal disease.³ Contrarily, others have suggested that the presence of bullae and renal disease is an indication to start treatment.⁶ This claim is based on the mechanistic finding that immunosuppression with corticosteroids decreases inflammation by inhibiting activator protein 1, a transcription factor for MMP-9, thereby reducing MMP-9 activity and the formation of bullae.⁴ Clinical anecdotes, including our own, that demonstrate dramatic improvement of hemorrhagic bullae with the administration of corticosteroids substantiate this mechanism. Through the inhibition of neutrophil interactions and IgA production, other anti-inflammatory and immunosuppressive medications such as colchicine, dapsone, and azathioprine also have been reported to aid in resolution of the cutaneous lesions.^1,5,6 Although there is a clear drawback to the lack of controlled trials and prospective studies regarding the treatment of bullous HSP, it is nearly impossible to expect such studies to be carried out given the rare and unpredictable nature of the disease. For now, claims derived from case series and case reports guide our understanding of treatment efficacy.

Acknowledgment—Quiz photograph courtesy of Steve Taylor, BS, Phoenix, Arizona.

The Diagnosis: Bullous Henoch-Schönlein Purpura

Laboratory tests in this patient showed no abnormalities for complete blood cell count, immunoglobulins, anti–double-stranded DNA, antinuclear antibody, p–antineutrophil cytoplasmic antibodies, lupus anticoagulant, Sjögren antibodies, liver enzymes, and erythrocyte sedimentation rate. Urinalysis was normal. Punch biopsies were obtained and a histologic examination showed an intense inflammatory infiltrate of neutrophils around blood vessels within the dermis (Figure). These blood vessels showed swollen endothelium and narrowing of the vessel lumina with leukocytoclasia. Direct immunofluorescence revealed granular IgA, C3, fibrin, and weak IgM deposits in blood vessels in the papillary dermis consistent with Henoch-Schönlein purpura (HSP).

Henoch-Schönlein purpura is the most common vasculitis in children.^1-6 However, its bullous variant is rare, with few pediatric cases reported. Bullous HSP affects arterioles through an IgA-mediated pathway.^1-6 It is believed that the bullae are formed secondary to neutrophilic release of matrix metalloproteinase 9 (MMP-9), which degrades extracellular collagen.² Additionally, bullous fluid from HSP has been noted to have markedly elevated levels of soluble CD23, a form of the CD23 B-cell surface receptor used in antibody feedback regulation and B-cell recruitment, which also has been found to be elevated in the fluid of bullous pemphigoid, suggesting a similar pathogenesis of exaggerated humoral immunity.³

The most common sign of HSP is palpable purpura; however, other cutaneous findings can be present including targetoid plaques, macules, papules, petechiae, and bullae that may become hemorrhagic, ulcerated, necrotic, or scarred.^1-6 Bullae appear in the most dependent parts of the body, such as the feet and lower legs. Hydrostatic pressure may play a role in the pathogenesis of this phenomenon.¹ When other classic signs of HSP are absent, the presence of bullae clouds the diagnosis and creates controversy regarding treatment, as there is a dearth of literature on proper therapy for severe cutaneous manifestations of HSP.⁶

Our patient was treated with morphine for pain management along with topical mupirocin and nonadherent dressings for wound care. She also received pulse intravenous methylprednisolone 2 mg/kg daily for 3 days and then was transitioned to oral prednisone 1 mg/kg daily, which was tapered over 3 weeks after discharge. This regimen resulted in resolution of symptoms with rapid regression of bullae and subsequent postinflammatory hyperpigmentation. Prior reports have noted that the presence of bullae does not alter the prognosis or predict probability of renal involvement of this self-limited disease, leading to controversy in determining if treatment offers more favorable outcomes.^1,3 One study suggested that steroids only improve symptoms, arthralgia, and abdominal pain, but they do not aid in the resolution of cutaneous lesions or prevent the progression of renal disease.³ Contrarily, others have suggested that the presence of bullae and renal disease is an indication to start treatment.⁶ This claim is based on the mechanistic finding that immunosuppression with corticosteroids decreases inflammation by inhibiting activator protein 1, a transcription factor for MMP-9, thereby reducing MMP-9 activity and the formation of bullae.⁴ Clinical anecdotes, including our own, that demonstrate dramatic improvement of hemorrhagic bullae with the administration of corticosteroids substantiate this mechanism. Through the inhibition of neutrophil interactions and IgA production, other anti-inflammatory and immunosuppressive medications such as colchicine, dapsone, and azathioprine also have been reported to aid in resolution of the cutaneous lesions.^1,5,6 Although there is a clear drawback to the lack of controlled trials and prospective studies regarding the treatment of bullous HSP, it is nearly impossible to expect such studies to be carried out given the rare and unpredictable nature of the disease. For now, claims derived from case series and case reports guide our understanding of treatment efficacy.

Acknowledgment—Quiz photograph courtesy of Steve Taylor, BS, Phoenix, Arizona.

Clinical study of mitochondrial replacement techniques for human reproduction is ethically permissible, concluded a special panel formed by the Institute of Medicine and charged by the Food and Drug Administration to study the issue.

If the FDA accepts the recommendations, issued Feb. 3, the agency could proceed with approving investigational new drug (IND) applications from U.S. research groups to test mitochondrial replacement techniques (MRTs) with the goal of allowing couples to bear children who would not inherit mitochondrial DNA diseases affecting the mother.

Courtesy Wikimedia Commons/Archaeogenetics/Creative Commons License

MRT, also termed mitochondrial transfer, involves creating an embryo with nuclear DNA from the intended mother and mitochondrial DNA from a healthy donor through modification of either an oocyte or zygote. The mitochondrial transfer techniques currently being considered are maternal spindle transfer, which uses oocytes, and pronuclear transfer, which uses zygotes. Critics of the controversial techniques have labeled MRTs as “three parent” IVF and assert that allowing their use will create a slippery slope toward enabling modification of nuclear DNA and germ-line modification.

While the IOM report, which had been in the works since late 2014, helps clear the ethical pathway to clinical testing of these novel methods, lawmakers created a new roadblock with the passage of the fiscal 2016 omnibus budget legislation, which specifically barred the FDA from using budgeted funds to evaluate proposals for therapies that involve embryo modification.

The IOM committee’s report noted that the FDA should consider approval of initial clinical investigations of MRTs “only if and when” several conditions are met, including establishment of safety and minimized risks, an adequate background of likely efficacy through preclinical research, limiting of research to women at risk for transmitting a mitochondrial DNA disease, and limiting of studies to investigators and centers with demonstrated expertise in relevant technologies.

Another key qualification the panel recommended is that initial studies be limited to male embryos so that when they become adults they would not pass their engineered mitochondrial genome to a next generation because mitochondrial inheritance occurs only via oocytes. The committee recommended that modification of mitochondrial DNA in oocytes or zygotes destined to become women be permitted in the future, but only after the procedure proved its safety in men.

The recommendations also stressed that the “health and well-being of any future children born as a result of clinical investigation protocols of MRT should have priority.”

“The main conclusion of the report is that it is ethically permissible to conduct investigations into MRT as long as significant conditions and parameters are met,” said Dr. Marni Falk, director of the mitochondrial-genetic disease clinic at the Children’s Hospital of Philadelphia and a member of the IOM committee.

Dr. Bruce H. Cohen, director of the neurodevelopmental science center and pediatric neurology at Akron (Ohio) Children’s Hospital, said he was pleased with the IOM report.

“There is nothing in the report that will stop this human research from going ahead in the United States. That’s the bottom line,” said Dr. Cohen, who has done clinical research in and drug development for children with mitochondrial disease. “They took everything into consideration, including the science and the pulse of the American public, and came up with a plan that will move this treatment forward.”

Dr. Cohen singled out the MRT research program at the Oregon Health & Science University (OHSU) as the U.S. effort closest to launching a clinical trial, and a senior research official at OHSU agreed that the panel’s recommendations represented a significant step forward.

“We feel the panel did a good job,” said Daniel Dorsa, Ph.D., senior vice president for research at OHSU in Portland. “They put in some restrictions, such as only using male embryos to start, but that is an understandable caution. We’re pleased the report is now out because we’ve been waiting for it. We’ve been in discussions with the FDA for an IND for mitochondrial transfer for quite a while, and the FDA said that we should wait for this report.”

The OHSU research team that works on MRT, led by Shoukhrat Mitalipov, Ph.D., already successfully used “maternal spindle transfer” to produce two macaque embryos that received donor mitochondrial DNA, said Dr. Dorsa. The two macaques remain in gestation with their delivery anticipated soon.

The next step for the OHSU group is to test the same technique with human oocytes, and they have identified several women with either Leigh syndrome or mitochondrial encephalomyopathy, lactic acidosis, and strokelike episodes (MELAS) who are interested in assisted reproduction using MRT.

“We’re anxiously waiting to see what the FDA will now do with the new recommendations in hand but with the congressional prohibition also in place,” Dr. Dorsa said. “With the recommendations now out, we anticipate that pressure will mount for Congress to change its position because for now U.S. women with mitochondrial DNA disease will be precluded from this cutting-edge technology that could ensure they give birth to healthy children.”

Dr. Dorsa said that OHSU holds several patents related to MRT, but these patents have not been licensed to any commercial entity.*

Dr. Falk cited results from a 2015 survey of 92 women with mitochondrial DNA disease or at-risk carriers of mutated mitochondrial DNA who expressed their interest in MRT. Among the 92 respondents, 21 said that they were interested in having children. Of that smaller group, 90% said they would be interested in MRT when becoming pregnant.

Dr. Falk also noted that roughly 30,000-60,000 Americans have a mitochondrial disease, although many others might be affected but have never been diagnosed or undergone confirmatory sequencing of their mitochondrial DNA.* Many affected patients have a mutation in 1 of the 200 nuclear genes that can produce mitochondrial dysfunction and not in 1 of the 37 genes contained in mitochondrial DNA. Only women with a mutation in their mitochondrial DNA can benefit from MRT.

*Correction, 2/5/2016: An earlier version of this story failed to correctly distinguish all forms of mitochondrial disease from mitochondrial DNA disease. 

*This story was updated 2/8/2016.

mzoler@frontlinemedcom.com

On Twitter@mitchelzoler

Clinical study of mitochondrial replacement techniques for human reproduction is ethically permissible, concluded a special panel formed by the Institute of Medicine and charged by the Food and Drug Administration to study the issue.

If the FDA accepts the recommendations, issued Feb. 3, the agency could proceed with approving investigational new drug (IND) applications from U.S. research groups to test mitochondrial replacement techniques (MRTs) with the goal of allowing couples to bear children who would not inherit mitochondrial DNA diseases affecting the mother.

Courtesy Wikimedia Commons/Archaeogenetics/Creative Commons License

MRT, also termed mitochondrial transfer, involves creating an embryo with nuclear DNA from the intended mother and mitochondrial DNA from a healthy donor through modification of either an oocyte or zygote. The mitochondrial transfer techniques currently being considered are maternal spindle transfer, which uses oocytes, and pronuclear transfer, which uses zygotes. Critics of the controversial techniques have labeled MRTs as “three parent” IVF and assert that allowing their use will create a slippery slope toward enabling modification of nuclear DNA and germ-line modification.

While the IOM report, which had been in the works since late 2014, helps clear the ethical pathway to clinical testing of these novel methods, lawmakers created a new roadblock with the passage of the fiscal 2016 omnibus budget legislation, which specifically barred the FDA from using budgeted funds to evaluate proposals for therapies that involve embryo modification.

The IOM committee’s report noted that the FDA should consider approval of initial clinical investigations of MRTs “only if and when” several conditions are met, including establishment of safety and minimized risks, an adequate background of likely efficacy through preclinical research, limiting of research to women at risk for transmitting a mitochondrial DNA disease, and limiting of studies to investigators and centers with demonstrated expertise in relevant technologies.

Another key qualification the panel recommended is that initial studies be limited to male embryos so that when they become adults they would not pass their engineered mitochondrial genome to a next generation because mitochondrial inheritance occurs only via oocytes. The committee recommended that modification of mitochondrial DNA in oocytes or zygotes destined to become women be permitted in the future, but only after the procedure proved its safety in men.

The recommendations also stressed that the “health and well-being of any future children born as a result of clinical investigation protocols of MRT should have priority.”

“The main conclusion of the report is that it is ethically permissible to conduct investigations into MRT as long as significant conditions and parameters are met,” said Dr. Marni Falk, director of the mitochondrial-genetic disease clinic at the Children’s Hospital of Philadelphia and a member of the IOM committee.

Dr. Bruce H. Cohen, director of the neurodevelopmental science center and pediatric neurology at Akron (Ohio) Children’s Hospital, said he was pleased with the IOM report.

“There is nothing in the report that will stop this human research from going ahead in the United States. That’s the bottom line,” said Dr. Cohen, who has done clinical research in and drug development for children with mitochondrial disease. “They took everything into consideration, including the science and the pulse of the American public, and came up with a plan that will move this treatment forward.”

Dr. Cohen singled out the MRT research program at the Oregon Health & Science University (OHSU) as the U.S. effort closest to launching a clinical trial, and a senior research official at OHSU agreed that the panel’s recommendations represented a significant step forward.

“We feel the panel did a good job,” said Daniel Dorsa, Ph.D., senior vice president for research at OHSU in Portland. “They put in some restrictions, such as only using male embryos to start, but that is an understandable caution. We’re pleased the report is now out because we’ve been waiting for it. We’ve been in discussions with the FDA for an IND for mitochondrial transfer for quite a while, and the FDA said that we should wait for this report.”

The OHSU research team that works on MRT, led by Shoukhrat Mitalipov, Ph.D., already successfully used “maternal spindle transfer” to produce two macaque embryos that received donor mitochondrial DNA, said Dr. Dorsa. The two macaques remain in gestation with their delivery anticipated soon.

The next step for the OHSU group is to test the same technique with human oocytes, and they have identified several women with either Leigh syndrome or mitochondrial encephalomyopathy, lactic acidosis, and strokelike episodes (MELAS) who are interested in assisted reproduction using MRT.

“We’re anxiously waiting to see what the FDA will now do with the new recommendations in hand but with the congressional prohibition also in place,” Dr. Dorsa said. “With the recommendations now out, we anticipate that pressure will mount for Congress to change its position because for now U.S. women with mitochondrial DNA disease will be precluded from this cutting-edge technology that could ensure they give birth to healthy children.”

Dr. Dorsa said that OHSU holds several patents related to MRT, but these patents have not been licensed to any commercial entity.*

Dr. Falk cited results from a 2015 survey of 92 women with mitochondrial DNA disease or at-risk carriers of mutated mitochondrial DNA who expressed their interest in MRT. Among the 92 respondents, 21 said that they were interested in having children. Of that smaller group, 90% said they would be interested in MRT when becoming pregnant.

Dr. Falk also noted that roughly 30,000-60,000 Americans have a mitochondrial disease, although many others might be affected but have never been diagnosed or undergone confirmatory sequencing of their mitochondrial DNA.* Many affected patients have a mutation in 1 of the 200 nuclear genes that can produce mitochondrial dysfunction and not in 1 of the 37 genes contained in mitochondrial DNA. Only women with a mutation in their mitochondrial DNA can benefit from MRT.

*Correction, 2/5/2016: An earlier version of this story failed to correctly distinguish all forms of mitochondrial disease from mitochondrial DNA disease. 

*This story was updated 2/8/2016.

mzoler@frontlinemedcom.com

On Twitter@mitchelzoler

Clinical study of mitochondrial replacement techniques for human reproduction is ethically permissible, concluded a special panel formed by the Institute of Medicine and charged by the Food and Drug Administration to study the issue.

If the FDA accepts the recommendations, issued Feb. 3, the agency could proceed with approving investigational new drug (IND) applications from U.S. research groups to test mitochondrial replacement techniques (MRTs) with the goal of allowing couples to bear children who would not inherit mitochondrial DNA diseases affecting the mother.

Courtesy Wikimedia Commons/Archaeogenetics/Creative Commons License

MRT, also termed mitochondrial transfer, involves creating an embryo with nuclear DNA from the intended mother and mitochondrial DNA from a healthy donor through modification of either an oocyte or zygote. The mitochondrial transfer techniques currently being considered are maternal spindle transfer, which uses oocytes, and pronuclear transfer, which uses zygotes. Critics of the controversial techniques have labeled MRTs as “three parent” IVF and assert that allowing their use will create a slippery slope toward enabling modification of nuclear DNA and germ-line modification.

While the IOM report, which had been in the works since late 2014, helps clear the ethical pathway to clinical testing of these novel methods, lawmakers created a new roadblock with the passage of the fiscal 2016 omnibus budget legislation, which specifically barred the FDA from using budgeted funds to evaluate proposals for therapies that involve embryo modification.

The IOM committee’s report noted that the FDA should consider approval of initial clinical investigations of MRTs “only if and when” several conditions are met, including establishment of safety and minimized risks, an adequate background of likely efficacy through preclinical research, limiting of research to women at risk for transmitting a mitochondrial DNA disease, and limiting of studies to investigators and centers with demonstrated expertise in relevant technologies.

Another key qualification the panel recommended is that initial studies be limited to male embryos so that when they become adults they would not pass their engineered mitochondrial genome to a next generation because mitochondrial inheritance occurs only via oocytes. The committee recommended that modification of mitochondrial DNA in oocytes or zygotes destined to become women be permitted in the future, but only after the procedure proved its safety in men.

The recommendations also stressed that the “health and well-being of any future children born as a result of clinical investigation protocols of MRT should have priority.”

“The main conclusion of the report is that it is ethically permissible to conduct investigations into MRT as long as significant conditions and parameters are met,” said Dr. Marni Falk, director of the mitochondrial-genetic disease clinic at the Children’s Hospital of Philadelphia and a member of the IOM committee.

Dr. Bruce H. Cohen, director of the neurodevelopmental science center and pediatric neurology at Akron (Ohio) Children’s Hospital, said he was pleased with the IOM report.

“There is nothing in the report that will stop this human research from going ahead in the United States. That’s the bottom line,” said Dr. Cohen, who has done clinical research in and drug development for children with mitochondrial disease. “They took everything into consideration, including the science and the pulse of the American public, and came up with a plan that will move this treatment forward.”

Dr. Cohen singled out the MRT research program at the Oregon Health & Science University (OHSU) as the U.S. effort closest to launching a clinical trial, and a senior research official at OHSU agreed that the panel’s recommendations represented a significant step forward.

“We feel the panel did a good job,” said Daniel Dorsa, Ph.D., senior vice president for research at OHSU in Portland. “They put in some restrictions, such as only using male embryos to start, but that is an understandable caution. We’re pleased the report is now out because we’ve been waiting for it. We’ve been in discussions with the FDA for an IND for mitochondrial transfer for quite a while, and the FDA said that we should wait for this report.”

The OHSU research team that works on MRT, led by Shoukhrat Mitalipov, Ph.D., already successfully used “maternal spindle transfer” to produce two macaque embryos that received donor mitochondrial DNA, said Dr. Dorsa. The two macaques remain in gestation with their delivery anticipated soon.

The next step for the OHSU group is to test the same technique with human oocytes, and they have identified several women with either Leigh syndrome or mitochondrial encephalomyopathy, lactic acidosis, and strokelike episodes (MELAS) who are interested in assisted reproduction using MRT.

“We’re anxiously waiting to see what the FDA will now do with the new recommendations in hand but with the congressional prohibition also in place,” Dr. Dorsa said. “With the recommendations now out, we anticipate that pressure will mount for Congress to change its position because for now U.S. women with mitochondrial DNA disease will be precluded from this cutting-edge technology that could ensure they give birth to healthy children.”

Dr. Dorsa said that OHSU holds several patents related to MRT, but these patents have not been licensed to any commercial entity.*

Dr. Falk cited results from a 2015 survey of 92 women with mitochondrial DNA disease or at-risk carriers of mutated mitochondrial DNA who expressed their interest in MRT. Among the 92 respondents, 21 said that they were interested in having children. Of that smaller group, 90% said they would be interested in MRT when becoming pregnant.

Dr. Falk also noted that roughly 30,000-60,000 Americans have a mitochondrial disease, although many others might be affected but have never been diagnosed or undergone confirmatory sequencing of their mitochondrial DNA.* Many affected patients have a mutation in 1 of the 200 nuclear genes that can produce mitochondrial dysfunction and not in 1 of the 37 genes contained in mitochondrial DNA. Only women with a mutation in their mitochondrial DNA can benefit from MRT.

*Correction, 2/5/2016: An earlier version of this story failed to correctly distinguish all forms of mitochondrial disease from mitochondrial DNA disease. 

*This story was updated 2/8/2016.

mzoler@frontlinemedcom.com

On Twitter@mitchelzoler

Daily oral treatment with venetoclax induced substantial responses with manageable adverse effects in patients with relapsed chronic lymphocytic leukemia or small lymphocytic lymphoma in a first-in-human phase I dose-escalation study.

The promising effects of the highly selective investigational inhibitor of BCL2 – a protein central to the survival of CLL cells – were noted even in patients with poor prognostic features, who comprised 89% of the cohort, reported Dr. Andrew W. Roberts of Royal Melbourne Hospital, Australia, and his colleagues. The study was published online Jan. 28 in The New England Journal of Medicine.

In the dose escalation phase of the study, 56 patients received active treatment at doses raging from 150 to 1,200 mg daily, and 60 additional patients received weekly stepwise ramp-up with doses beginning at 20 mg daily with weekly increases to 50 mg, 100 mg, and 200 mg daily up to the target dose of 400 mg daily. The patients had received a median of 3 previous therapies (range, 1-11).

Of 116 treated patients, 92 (79%) had a response, and 20% achieved complete remission, including 5% with no minimal residual disease on flow cytometry, the investigators said (N Engl J Med. 2016;374:311-22).

Venetoclax was active at all doses used in the study, and no maximum tolerated dose was identified.

Tumor lysis syndrome occurred in 10 patients, but clinically important sequelae occurred in only 3 of those patients, 2 of whom had severe sequelae. After adjustments were made to dosing schedule, no further cases occurred.

Other side effects included mild diarrhea, upper respiratory tract infection, nausea, and grade 3 or 4 neutropenia, which occurred in 41%-52% of patients. Serious adverse events included febrile neutropenia in 6% of patients, pneumonia in 4%, upper respiratory tract infection in 3%, and immune thrombocytopenia in 3%.

Among the patients with an adverse prognosis, treatment response rates ranged from 71% to 79%, depending on the subgroup. For example, the response rate was 79% in 70 patients with resistance to fludarabine, and 71% in 31 patients with chromosome 17p deletions.

New treatments, including ibrutinib monotherapy and idelalisib in combination with rituximab, have improved outcomes for patients with relapsed CLL, but despite these advances, complete remissions remain uncommon, the authors said.

“This first trial of venetoclax showed the potential of BCL2 antagonism as an additional therapeutic avenue for patients with relapsed CLL,” they wrote, adding that the 79% overall response rate in this study – including deep responses and complete responses without minimal residual disease in patients up to age 86 years and patients with poor prognostic factors – “provides support for further development of venetoclax as a treatment option for patients with heavily pretreated relapsed or refractory CLL or SLL.”

Of note, the Food and Drug Administration on Jan. 28 – the date this study was released – granted venetoclax Breakthrough Therapy Designation for use in combination with hypomethylating agents for the treatment of acute myeloid leukemia patients who aren’t eligible for standard induction chemotherapy. The designation – the third for the agent – is supported by data from a single study of untreated patients aged 65 years or older with AML. Prior venetoclax Breakthrough Therapy Designations were granted in April 2015 for its use as monotherapy in patients with refractory CLL who have the 17p deletion genetic mutation, and in January for its use with rituximab for the treatment of relapsed/refractory CLL.

AbbVie and Genentech supported the study. Dr. Roberts reported receiving grant support and study drugs form AbbVie, serving as an investigator in trials sponsored by Genentech, AbbVie, Janssen, and Beigene, and receiving institutional research funding from Genentech for the development of venetoclax. His coauthors reported ties to various pharmaceutical companies.

sworcester@frontlinemedcom.com

Daily oral treatment with venetoclax induced substantial responses with manageable adverse effects in patients with relapsed chronic lymphocytic leukemia or small lymphocytic lymphoma in a first-in-human phase I dose-escalation study.

The promising effects of the highly selective investigational inhibitor of BCL2 – a protein central to the survival of CLL cells – were noted even in patients with poor prognostic features, who comprised 89% of the cohort, reported Dr. Andrew W. Roberts of Royal Melbourne Hospital, Australia, and his colleagues. The study was published online Jan. 28 in The New England Journal of Medicine.

In the dose escalation phase of the study, 56 patients received active treatment at doses raging from 150 to 1,200 mg daily, and 60 additional patients received weekly stepwise ramp-up with doses beginning at 20 mg daily with weekly increases to 50 mg, 100 mg, and 200 mg daily up to the target dose of 400 mg daily. The patients had received a median of 3 previous therapies (range, 1-11).

Of 116 treated patients, 92 (79%) had a response, and 20% achieved complete remission, including 5% with no minimal residual disease on flow cytometry, the investigators said (N Engl J Med. 2016;374:311-22).

Venetoclax was active at all doses used in the study, and no maximum tolerated dose was identified.

Tumor lysis syndrome occurred in 10 patients, but clinically important sequelae occurred in only 3 of those patients, 2 of whom had severe sequelae. After adjustments were made to dosing schedule, no further cases occurred.

Other side effects included mild diarrhea, upper respiratory tract infection, nausea, and grade 3 or 4 neutropenia, which occurred in 41%-52% of patients. Serious adverse events included febrile neutropenia in 6% of patients, pneumonia in 4%, upper respiratory tract infection in 3%, and immune thrombocytopenia in 3%.

Among the patients with an adverse prognosis, treatment response rates ranged from 71% to 79%, depending on the subgroup. For example, the response rate was 79% in 70 patients with resistance to fludarabine, and 71% in 31 patients with chromosome 17p deletions.

New treatments, including ibrutinib monotherapy and idelalisib in combination with rituximab, have improved outcomes for patients with relapsed CLL, but despite these advances, complete remissions remain uncommon, the authors said.

“This first trial of venetoclax showed the potential of BCL2 antagonism as an additional therapeutic avenue for patients with relapsed CLL,” they wrote, adding that the 79% overall response rate in this study – including deep responses and complete responses without minimal residual disease in patients up to age 86 years and patients with poor prognostic factors – “provides support for further development of venetoclax as a treatment option for patients with heavily pretreated relapsed or refractory CLL or SLL.”

Of note, the Food and Drug Administration on Jan. 28 – the date this study was released – granted venetoclax Breakthrough Therapy Designation for use in combination with hypomethylating agents for the treatment of acute myeloid leukemia patients who aren’t eligible for standard induction chemotherapy. The designation – the third for the agent – is supported by data from a single study of untreated patients aged 65 years or older with AML. Prior venetoclax Breakthrough Therapy Designations were granted in April 2015 for its use as monotherapy in patients with refractory CLL who have the 17p deletion genetic mutation, and in January for its use with rituximab for the treatment of relapsed/refractory CLL.

AbbVie and Genentech supported the study. Dr. Roberts reported receiving grant support and study drugs form AbbVie, serving as an investigator in trials sponsored by Genentech, AbbVie, Janssen, and Beigene, and receiving institutional research funding from Genentech for the development of venetoclax. His coauthors reported ties to various pharmaceutical companies.

sworcester@frontlinemedcom.com

Daily oral treatment with venetoclax induced substantial responses with manageable adverse effects in patients with relapsed chronic lymphocytic leukemia or small lymphocytic lymphoma in a first-in-human phase I dose-escalation study.

The promising effects of the highly selective investigational inhibitor of BCL2 – a protein central to the survival of CLL cells – were noted even in patients with poor prognostic features, who comprised 89% of the cohort, reported Dr. Andrew W. Roberts of Royal Melbourne Hospital, Australia, and his colleagues. The study was published online Jan. 28 in The New England Journal of Medicine.

In the dose escalation phase of the study, 56 patients received active treatment at doses raging from 150 to 1,200 mg daily, and 60 additional patients received weekly stepwise ramp-up with doses beginning at 20 mg daily with weekly increases to 50 mg, 100 mg, and 200 mg daily up to the target dose of 400 mg daily. The patients had received a median of 3 previous therapies (range, 1-11).

Of 116 treated patients, 92 (79%) had a response, and 20% achieved complete remission, including 5% with no minimal residual disease on flow cytometry, the investigators said (N Engl J Med. 2016;374:311-22).

Venetoclax was active at all doses used in the study, and no maximum tolerated dose was identified.

Tumor lysis syndrome occurred in 10 patients, but clinically important sequelae occurred in only 3 of those patients, 2 of whom had severe sequelae. After adjustments were made to dosing schedule, no further cases occurred.

Other side effects included mild diarrhea, upper respiratory tract infection, nausea, and grade 3 or 4 neutropenia, which occurred in 41%-52% of patients. Serious adverse events included febrile neutropenia in 6% of patients, pneumonia in 4%, upper respiratory tract infection in 3%, and immune thrombocytopenia in 3%.

Among the patients with an adverse prognosis, treatment response rates ranged from 71% to 79%, depending on the subgroup. For example, the response rate was 79% in 70 patients with resistance to fludarabine, and 71% in 31 patients with chromosome 17p deletions.

New treatments, including ibrutinib monotherapy and idelalisib in combination with rituximab, have improved outcomes for patients with relapsed CLL, but despite these advances, complete remissions remain uncommon, the authors said.

“This first trial of venetoclax showed the potential of BCL2 antagonism as an additional therapeutic avenue for patients with relapsed CLL,” they wrote, adding that the 79% overall response rate in this study – including deep responses and complete responses without minimal residual disease in patients up to age 86 years and patients with poor prognostic factors – “provides support for further development of venetoclax as a treatment option for patients with heavily pretreated relapsed or refractory CLL or SLL.”

Of note, the Food and Drug Administration on Jan. 28 – the date this study was released – granted venetoclax Breakthrough Therapy Designation for use in combination with hypomethylating agents for the treatment of acute myeloid leukemia patients who aren’t eligible for standard induction chemotherapy. The designation – the third for the agent – is supported by data from a single study of untreated patients aged 65 years or older with AML. Prior venetoclax Breakthrough Therapy Designations were granted in April 2015 for its use as monotherapy in patients with refractory CLL who have the 17p deletion genetic mutation, and in January for its use with rituximab for the treatment of relapsed/refractory CLL.

AbbVie and Genentech supported the study. Dr. Roberts reported receiving grant support and study drugs form AbbVie, serving as an investigator in trials sponsored by Genentech, AbbVie, Janssen, and Beigene, and receiving institutional research funding from Genentech for the development of venetoclax. His coauthors reported ties to various pharmaceutical companies.

sworcester@frontlinemedcom.com

SAN ANTONIO – Tourniquets are being overemphasized in preparations for mass shootings in the United States, according to a review by the Committee for Tactical Emergency Casualty Care of wounding patterns in 12 mass shootings.

Since the 2012 shootings in Newtown, Conn., efforts to improve survival have tended to emphasize tourniquets to stop bleeding from wounded limbs. The recently-launched federal “Stop the Bleed” campaign promotes public awareness of compression and tourniquets, and the American College of Surgeons and other groups recently called for public education and use of tourniquets as one of many responses to mass-casualty and active-shooter events, stating that “the most significant preventable cause of death in the prehospital environment is external hemorrhage.” There are thoughts of making tourniquets at least as common as automated external defibrillators in public settings.

The efforts are driven by combat experience in Afghanistan and Iraq, where about half of wounds were to arms and legs, and tourniquets saved many lives.

Wikimedia Creative Commons License/INDNAM

Tourniquets are important especially for civilian bombings, but fatalities in civilian mass shootings – shootings with at least four deaths in which killing is the primary aim – are from head and chest wounds, not extremity wounds. The emphasis on bleeding control overshadows public education about other simple interventions that could be more useful in shootings, according to emergency physician Dr. Reed Smith, medical director of the Arlington County (Va.) Fire Department and cofounder and cochairman of the Committee for Tactical Emergency Casualty Care (C-TECC).

“We need a civilian perspective on civilian incidents, not a military perspective,” he said at the Eastern Association for the Surgery of Trauma scientific assembly.

Dr. Smith and other C-TECC investigators reviewed autopsy reports from 12 U.S. civilian mass shootings from the period of 1996-2012. They tried to get data for more, but ran into significant resistance from authorities.

There were 371 bullet wounds and 139 deaths, an average of 2.7 wounds per victim but a range of 1-10. About 40% of deaths were from shots to the head; another 40% from shots to the chest or upper back; and the rest from shots to the face/neck, abdomen/lower back, or multiple regions.

“We looked at every one of these events, and with the exception of the Gabby Giffords Tucson shooting, no tourniquets were used. There were no cases of major peripheral vascular injury, and no fatalities from extremity exsanguination,” Dr. Smith said.

The investigators estimated that nine fatalities were potentially survivable, without injuries to the heart, brain, or major blood vessels, and definitive care available within 60 minutes. The victims died from face and torso wounds, not wounds to the limbs.

“Wounding in active-shooter events differs from combat and may require different therapeutic emphasis. Although tourniquets and external hemorrhage control techniques hold value, their role in active-shooter events may be overemphasized as a means to decrease fatality. The focus on external hemorrhage is important, but it’s not enough,” Dr. Smith said.

Additional interventions could be taught for every step in the chain of contact, from citizen to trauma surgeon, that could have greater benefit. Teachers, for instance, could be taught to roll victims on their sides and clear out their mouths to keep airways open, and to keep them warm to prevent hypothermia until help arrives. Police could learn to insert nasal airways, and occlude sucking chest wounds. Fire/EMS could start initial damage control. “Everything builds,” Dr. Smith said.

C-TECC made many recommendations for enhanced mass-causality response its 2015 Tactical Emergency Casualty Care Guidelines.

Dr. Smith had no disclosures.

aotto@frontlinemedcom.com

SAN ANTONIO – Tourniquets are being overemphasized in preparations for mass shootings in the United States, according to a review by the Committee for Tactical Emergency Casualty Care of wounding patterns in 12 mass shootings.

Since the 2012 shootings in Newtown, Conn., efforts to improve survival have tended to emphasize tourniquets to stop bleeding from wounded limbs. The recently-launched federal “Stop the Bleed” campaign promotes public awareness of compression and tourniquets, and the American College of Surgeons and other groups recently called for public education and use of tourniquets as one of many responses to mass-casualty and active-shooter events, stating that “the most significant preventable cause of death in the prehospital environment is external hemorrhage.” There are thoughts of making tourniquets at least as common as automated external defibrillators in public settings.

The efforts are driven by combat experience in Afghanistan and Iraq, where about half of wounds were to arms and legs, and tourniquets saved many lives.

Wikimedia Creative Commons License/INDNAM

Tourniquets are important especially for civilian bombings, but fatalities in civilian mass shootings – shootings with at least four deaths in which killing is the primary aim – are from head and chest wounds, not extremity wounds. The emphasis on bleeding control overshadows public education about other simple interventions that could be more useful in shootings, according to emergency physician Dr. Reed Smith, medical director of the Arlington County (Va.) Fire Department and cofounder and cochairman of the Committee for Tactical Emergency Casualty Care (C-TECC).

“We need a civilian perspective on civilian incidents, not a military perspective,” he said at the Eastern Association for the Surgery of Trauma scientific assembly.

Dr. Smith and other C-TECC investigators reviewed autopsy reports from 12 U.S. civilian mass shootings from the period of 1996-2012. They tried to get data for more, but ran into significant resistance from authorities.

There were 371 bullet wounds and 139 deaths, an average of 2.7 wounds per victim but a range of 1-10. About 40% of deaths were from shots to the head; another 40% from shots to the chest or upper back; and the rest from shots to the face/neck, abdomen/lower back, or multiple regions.

“We looked at every one of these events, and with the exception of the Gabby Giffords Tucson shooting, no tourniquets were used. There were no cases of major peripheral vascular injury, and no fatalities from extremity exsanguination,” Dr. Smith said.

The investigators estimated that nine fatalities were potentially survivable, without injuries to the heart, brain, or major blood vessels, and definitive care available within 60 minutes. The victims died from face and torso wounds, not wounds to the limbs.

“Wounding in active-shooter events differs from combat and may require different therapeutic emphasis. Although tourniquets and external hemorrhage control techniques hold value, their role in active-shooter events may be overemphasized as a means to decrease fatality. The focus on external hemorrhage is important, but it’s not enough,” Dr. Smith said.

Additional interventions could be taught for every step in the chain of contact, from citizen to trauma surgeon, that could have greater benefit. Teachers, for instance, could be taught to roll victims on their sides and clear out their mouths to keep airways open, and to keep them warm to prevent hypothermia until help arrives. Police could learn to insert nasal airways, and occlude sucking chest wounds. Fire/EMS could start initial damage control. “Everything builds,” Dr. Smith said.

C-TECC made many recommendations for enhanced mass-causality response its 2015 Tactical Emergency Casualty Care Guidelines.

Dr. Smith had no disclosures.

aotto@frontlinemedcom.com

SAN ANTONIO – Tourniquets are being overemphasized in preparations for mass shootings in the United States, according to a review by the Committee for Tactical Emergency Casualty Care of wounding patterns in 12 mass shootings.

Since the 2012 shootings in Newtown, Conn., efforts to improve survival have tended to emphasize tourniquets to stop bleeding from wounded limbs. The recently-launched federal “Stop the Bleed” campaign promotes public awareness of compression and tourniquets, and the American College of Surgeons and other groups recently called for public education and use of tourniquets as one of many responses to mass-casualty and active-shooter events, stating that “the most significant preventable cause of death in the prehospital environment is external hemorrhage.” There are thoughts of making tourniquets at least as common as automated external defibrillators in public settings.

The efforts are driven by combat experience in Afghanistan and Iraq, where about half of wounds were to arms and legs, and tourniquets saved many lives.

Wikimedia Creative Commons License/INDNAM

Tourniquets are important especially for civilian bombings, but fatalities in civilian mass shootings – shootings with at least four deaths in which killing is the primary aim – are from head and chest wounds, not extremity wounds. The emphasis on bleeding control overshadows public education about other simple interventions that could be more useful in shootings, according to emergency physician Dr. Reed Smith, medical director of the Arlington County (Va.) Fire Department and cofounder and cochairman of the Committee for Tactical Emergency Casualty Care (C-TECC).

“We need a civilian perspective on civilian incidents, not a military perspective,” he said at the Eastern Association for the Surgery of Trauma scientific assembly.

Dr. Smith and other C-TECC investigators reviewed autopsy reports from 12 U.S. civilian mass shootings from the period of 1996-2012. They tried to get data for more, but ran into significant resistance from authorities.

There were 371 bullet wounds and 139 deaths, an average of 2.7 wounds per victim but a range of 1-10. About 40% of deaths were from shots to the head; another 40% from shots to the chest or upper back; and the rest from shots to the face/neck, abdomen/lower back, or multiple regions.

“We looked at every one of these events, and with the exception of the Gabby Giffords Tucson shooting, no tourniquets were used. There were no cases of major peripheral vascular injury, and no fatalities from extremity exsanguination,” Dr. Smith said.

The investigators estimated that nine fatalities were potentially survivable, without injuries to the heart, brain, or major blood vessels, and definitive care available within 60 minutes. The victims died from face and torso wounds, not wounds to the limbs.

“Wounding in active-shooter events differs from combat and may require different therapeutic emphasis. Although tourniquets and external hemorrhage control techniques hold value, their role in active-shooter events may be overemphasized as a means to decrease fatality. The focus on external hemorrhage is important, but it’s not enough,” Dr. Smith said.

Additional interventions could be taught for every step in the chain of contact, from citizen to trauma surgeon, that could have greater benefit. Teachers, for instance, could be taught to roll victims on their sides and clear out their mouths to keep airways open, and to keep them warm to prevent hypothermia until help arrives. Police could learn to insert nasal airways, and occlude sucking chest wounds. Fire/EMS could start initial damage control. “Everything builds,” Dr. Smith said.

C-TECC made many recommendations for enhanced mass-causality response its 2015 Tactical Emergency Casualty Care Guidelines.

Dr. Smith had no disclosures.

aotto@frontlinemedcom.com

Less than half of children aged 6-23 months are vaccinated for influenza in the United States, according to an analysis of data obtained via the 2003-2013 National Immunization Survey.

The researchers analyzed providers’ reports of influenza vaccinations, received as one or two doses by children aged 6-23 months. The age group studied is at highest risk of influenza-related complications and was the first group of children for which the Advisory Committee on Immunization Practices recommended influenza vaccination, regardless of an individual’s medical condition.

© Sean Locke/iStockphoto.com

A child’s age was defined by his or her age on Nov. 1 of each influenza season under study. Two full calendar years of data files were combined to enable analysis of full influenza seasons, which cover parts of 2 consecutive calendar years. The percentages of children requiring two doses to be considered fully vaccinated were based on the dosage recommendations for each flu season.

Overall, flu vaccination coverage increased, reaching 45% in the 2011-2012 flu season, up from 5% during the 2002-2003 flu season. Within each racial/ethnic group examined, influenza vaccination coverage also grew; however, lower percentages of non-Hispanic black children and Hispanic children were vaccinated than of non-Hispanic white children during all 10 of the flu seasons studied. Coverage ranged from 24% in Mississippi to 72% in Massachusetts.

“Despite the increase, the majority of children 6-23 months in the United States were not fully vaccinated against influenza,” said Tammy A. Santibanez, Ph.D., of the Centers for Disease Control and Prevention, and her colleagues.

Among other findings consistent throughout each flu season examined was that full influenza vaccination coverage was higher among children requiring only one dose of a flu vaccine, compared with those requiring two doses of a flu vaccine.

“Prevention of influenza among infants and young children is a public health priority because of their high risk for influenza-related complications,” wrote Dr. Santibanez and her colleagues. “Appropriate implementation of evidence-based strategies is needed to increase the percentage of children who are fully vaccinated.”

Read the study in Pediatrics (doi: 10.1542/peds.2015.3280).

klennon@frontlinemedcom.com

Less than half of children aged 6-23 months are vaccinated for influenza in the United States, according to an analysis of data obtained via the 2003-2013 National Immunization Survey.

The researchers analyzed providers’ reports of influenza vaccinations, received as one or two doses by children aged 6-23 months. The age group studied is at highest risk of influenza-related complications and was the first group of children for which the Advisory Committee on Immunization Practices recommended influenza vaccination, regardless of an individual’s medical condition.

© Sean Locke/iStockphoto.com

A child’s age was defined by his or her age on Nov. 1 of each influenza season under study. Two full calendar years of data files were combined to enable analysis of full influenza seasons, which cover parts of 2 consecutive calendar years. The percentages of children requiring two doses to be considered fully vaccinated were based on the dosage recommendations for each flu season.

Overall, flu vaccination coverage increased, reaching 45% in the 2011-2012 flu season, up from 5% during the 2002-2003 flu season. Within each racial/ethnic group examined, influenza vaccination coverage also grew; however, lower percentages of non-Hispanic black children and Hispanic children were vaccinated than of non-Hispanic white children during all 10 of the flu seasons studied. Coverage ranged from 24% in Mississippi to 72% in Massachusetts.

“Despite the increase, the majority of children 6-23 months in the United States were not fully vaccinated against influenza,” said Tammy A. Santibanez, Ph.D., of the Centers for Disease Control and Prevention, and her colleagues.

Among other findings consistent throughout each flu season examined was that full influenza vaccination coverage was higher among children requiring only one dose of a flu vaccine, compared with those requiring two doses of a flu vaccine.

“Prevention of influenza among infants and young children is a public health priority because of their high risk for influenza-related complications,” wrote Dr. Santibanez and her colleagues. “Appropriate implementation of evidence-based strategies is needed to increase the percentage of children who are fully vaccinated.”

Read the study in Pediatrics (doi: 10.1542/peds.2015.3280).

klennon@frontlinemedcom.com

Less than half of children aged 6-23 months are vaccinated for influenza in the United States, according to an analysis of data obtained via the 2003-2013 National Immunization Survey.

The researchers analyzed providers’ reports of influenza vaccinations, received as one or two doses by children aged 6-23 months. The age group studied is at highest risk of influenza-related complications and was the first group of children for which the Advisory Committee on Immunization Practices recommended influenza vaccination, regardless of an individual’s medical condition.

© Sean Locke/iStockphoto.com

A child’s age was defined by his or her age on Nov. 1 of each influenza season under study. Two full calendar years of data files were combined to enable analysis of full influenza seasons, which cover parts of 2 consecutive calendar years. The percentages of children requiring two doses to be considered fully vaccinated were based on the dosage recommendations for each flu season.

Overall, flu vaccination coverage increased, reaching 45% in the 2011-2012 flu season, up from 5% during the 2002-2003 flu season. Within each racial/ethnic group examined, influenza vaccination coverage also grew; however, lower percentages of non-Hispanic black children and Hispanic children were vaccinated than of non-Hispanic white children during all 10 of the flu seasons studied. Coverage ranged from 24% in Mississippi to 72% in Massachusetts.

“Despite the increase, the majority of children 6-23 months in the United States were not fully vaccinated against influenza,” said Tammy A. Santibanez, Ph.D., of the Centers for Disease Control and Prevention, and her colleagues.

Among other findings consistent throughout each flu season examined was that full influenza vaccination coverage was higher among children requiring only one dose of a flu vaccine, compared with those requiring two doses of a flu vaccine.

“Prevention of influenza among infants and young children is a public health priority because of their high risk for influenza-related complications,” wrote Dr. Santibanez and her colleagues. “Appropriate implementation of evidence-based strategies is needed to increase the percentage of children who are fully vaccinated.”

Read the study in Pediatrics (doi: 10.1542/peds.2015.3280).

klennon@frontlinemedcom.com

As the practice of medicine continues to transition to performance-based payment systems, the number of mergers of hospitalists and specialists has surged. Payment models that focus on clinical outcomes and best practices link payment to the ability of physicians to provide efficient, quality healthcare and improve patient outcomes. These payment systems are changing the way healthcare services are delivered by demanding better patient care at a lower cost. The result is increasing pressure on physicians to meet operational and quality goals, or receive less reimbursement for their services.

Studies have shown that the effective use of hospitalists can improve standardized patient care for surgical patients. Hospitalists also provide value to specialists by freeing up time so they can focus on their area of expertise. As a result, co-management arrangements between hospitalists and specialists have become a popular tool to define working relationships and improve the quality of care patients receive.

Hospitalist Evolution

When hospitalists first debuted, they were seen as a threat to primary care physicians and specialists. Over time, they were criticized for performing routine work for specialized physicians. To overcome these negative connotations and prove their worth, hospitalists began co-managing patients for surgical specialists, who soon realized the significant value hospitalist services provided. Not only do they share in the responsibility of care provided to patients, but they also reduce readmissions and costs associated with providing healthcare.

Now there are even specialty hospitalists who specialize in a particular field, such as orthopedics or obstetrics.

Why Co-Management?

Hospitalists add value by helping to alleviate the burden on specialists—providing ED coverage, assisting in the operating room, and rounding on patients. They evaluate surgical patients for medical issues, reconcile medications across the spectrum of a patient’s care, and standardize the patient discharge and communication processes.

Providing these services frees specialists from rounding and allows them to concentrate on their specialty. Hospitalists do not have office-based practices, which allows them to spend their time in the hospital caring for admitted, pre-operative, and post-operative patients.

It is in the pre-operative and post-operative environments where hospitalists have established their extreme value to specialists. Under co-management arrangements, hospitalists are able to ensure that all pre-operative tests are conducted, reports are dictated, and the patient’s medical history is available. Pre-operative evaluations allow the hospitalist to develop a post-operative plan of care and proactively address many medical concerns. Also, the hospitalist is available to see patients immediately after surgery, allowing immediate evaluation and treatment for high blood pressure, diabetic issues, or other medical issues.

In sum, the hospitalist is responsible for the medical care of the specialist’s patients, and the specialist is able to focus on the specialty services he or she provides. Providing these services gives hospitalists the opportunity to anticipate problems and overcome issues, which results in more efficient care, shorter lengths of stay in the hospital, and improved patient satisfaction. Such results make hospitalists critical to success in performance-based payment systems.

Successful Co-Management Arrangements

A key to success in establishing a co-management arrangement between a hospitalist and a specialist is setting forth the parameters of the relationship in a written agreement. It is particularly important that the relationship foster equality among the parties, regardless of who is the attending physician of record. The parties should be jointly responsible for patient care, with the hospitalist treating the patient’s general medical concerns and the specialist focusing on techniques within his specialty to improve the patient’s issues.

The agreement should clearly state the responsibilities of each party, including delineating the party responsible for decisions such as admission and discharge. It should address resources and set forth the standardized processes and protocols to be used when treating patients.

Specialists can vary in their treatment of patients, so it is best to document their expectations at the onset of the relationship. Also, successful co-management is contingent upon regular communication between the hospitalist and the specialist. It is important to establish those boundaries in advance to prevent miscommunication down the road.

In particular, the agreement should explicitly describe the lines of authority and how conflicts will be addressed.

Final Thoughts

Co-management is a growing trend that can provide an opportunity for hospitalists to expand their practice and reinforce their value to both specialists and the hospital. The improved quality of care and patient satisfaction that is associated with hospitalist services can be crucial to maximizing reimbursement under a value-based reimbursement system. TH

As the practice of medicine continues to transition to performance-based payment systems, the number of mergers of hospitalists and specialists has surged. Payment models that focus on clinical outcomes and best practices link payment to the ability of physicians to provide efficient, quality healthcare and improve patient outcomes. These payment systems are changing the way healthcare services are delivered by demanding better patient care at a lower cost. The result is increasing pressure on physicians to meet operational and quality goals, or receive less reimbursement for their services.

Studies have shown that the effective use of hospitalists can improve standardized patient care for surgical patients. Hospitalists also provide value to specialists by freeing up time so they can focus on their area of expertise. As a result, co-management arrangements between hospitalists and specialists have become a popular tool to define working relationships and improve the quality of care patients receive.

Hospitalist Evolution

When hospitalists first debuted, they were seen as a threat to primary care physicians and specialists. Over time, they were criticized for performing routine work for specialized physicians. To overcome these negative connotations and prove their worth, hospitalists began co-managing patients for surgical specialists, who soon realized the significant value hospitalist services provided. Not only do they share in the responsibility of care provided to patients, but they also reduce readmissions and costs associated with providing healthcare.

Now there are even specialty hospitalists who specialize in a particular field, such as orthopedics or obstetrics.

Why Co-Management?

Hospitalists add value by helping to alleviate the burden on specialists—providing ED coverage, assisting in the operating room, and rounding on patients. They evaluate surgical patients for medical issues, reconcile medications across the spectrum of a patient’s care, and standardize the patient discharge and communication processes.

Providing these services frees specialists from rounding and allows them to concentrate on their specialty. Hospitalists do not have office-based practices, which allows them to spend their time in the hospital caring for admitted, pre-operative, and post-operative patients.

It is in the pre-operative and post-operative environments where hospitalists have established their extreme value to specialists. Under co-management arrangements, hospitalists are able to ensure that all pre-operative tests are conducted, reports are dictated, and the patient’s medical history is available. Pre-operative evaluations allow the hospitalist to develop a post-operative plan of care and proactively address many medical concerns. Also, the hospitalist is available to see patients immediately after surgery, allowing immediate evaluation and treatment for high blood pressure, diabetic issues, or other medical issues.

In sum, the hospitalist is responsible for the medical care of the specialist’s patients, and the specialist is able to focus on the specialty services he or she provides. Providing these services gives hospitalists the opportunity to anticipate problems and overcome issues, which results in more efficient care, shorter lengths of stay in the hospital, and improved patient satisfaction. Such results make hospitalists critical to success in performance-based payment systems.

Successful Co-Management Arrangements

A key to success in establishing a co-management arrangement between a hospitalist and a specialist is setting forth the parameters of the relationship in a written agreement. It is particularly important that the relationship foster equality among the parties, regardless of who is the attending physician of record. The parties should be jointly responsible for patient care, with the hospitalist treating the patient’s general medical concerns and the specialist focusing on techniques within his specialty to improve the patient’s issues.

The agreement should clearly state the responsibilities of each party, including delineating the party responsible for decisions such as admission and discharge. It should address resources and set forth the standardized processes and protocols to be used when treating patients.

Specialists can vary in their treatment of patients, so it is best to document their expectations at the onset of the relationship. Also, successful co-management is contingent upon regular communication between the hospitalist and the specialist. It is important to establish those boundaries in advance to prevent miscommunication down the road.

In particular, the agreement should explicitly describe the lines of authority and how conflicts will be addressed.

Final Thoughts

Co-management is a growing trend that can provide an opportunity for hospitalists to expand their practice and reinforce their value to both specialists and the hospital. The improved quality of care and patient satisfaction that is associated with hospitalist services can be crucial to maximizing reimbursement under a value-based reimbursement system. TH

As the practice of medicine continues to transition to performance-based payment systems, the number of mergers of hospitalists and specialists has surged. Payment models that focus on clinical outcomes and best practices link payment to the ability of physicians to provide efficient, quality healthcare and improve patient outcomes. These payment systems are changing the way healthcare services are delivered by demanding better patient care at a lower cost. The result is increasing pressure on physicians to meet operational and quality goals, or receive less reimbursement for their services.

Studies have shown that the effective use of hospitalists can improve standardized patient care for surgical patients. Hospitalists also provide value to specialists by freeing up time so they can focus on their area of expertise. As a result, co-management arrangements between hospitalists and specialists have become a popular tool to define working relationships and improve the quality of care patients receive.

Hospitalist Evolution

When hospitalists first debuted, they were seen as a threat to primary care physicians and specialists. Over time, they were criticized for performing routine work for specialized physicians. To overcome these negative connotations and prove their worth, hospitalists began co-managing patients for surgical specialists, who soon realized the significant value hospitalist services provided. Not only do they share in the responsibility of care provided to patients, but they also reduce readmissions and costs associated with providing healthcare.

Now there are even specialty hospitalists who specialize in a particular field, such as orthopedics or obstetrics.

Why Co-Management?

Hospitalists add value by helping to alleviate the burden on specialists—providing ED coverage, assisting in the operating room, and rounding on patients. They evaluate surgical patients for medical issues, reconcile medications across the spectrum of a patient’s care, and standardize the patient discharge and communication processes.

Providing these services frees specialists from rounding and allows them to concentrate on their specialty. Hospitalists do not have office-based practices, which allows them to spend their time in the hospital caring for admitted, pre-operative, and post-operative patients.

It is in the pre-operative and post-operative environments where hospitalists have established their extreme value to specialists. Under co-management arrangements, hospitalists are able to ensure that all pre-operative tests are conducted, reports are dictated, and the patient’s medical history is available. Pre-operative evaluations allow the hospitalist to develop a post-operative plan of care and proactively address many medical concerns. Also, the hospitalist is available to see patients immediately after surgery, allowing immediate evaluation and treatment for high blood pressure, diabetic issues, or other medical issues.

In sum, the hospitalist is responsible for the medical care of the specialist’s patients, and the specialist is able to focus on the specialty services he or she provides. Providing these services gives hospitalists the opportunity to anticipate problems and overcome issues, which results in more efficient care, shorter lengths of stay in the hospital, and improved patient satisfaction. Such results make hospitalists critical to success in performance-based payment systems.

Successful Co-Management Arrangements

A key to success in establishing a co-management arrangement between a hospitalist and a specialist is setting forth the parameters of the relationship in a written agreement. It is particularly important that the relationship foster equality among the parties, regardless of who is the attending physician of record. The parties should be jointly responsible for patient care, with the hospitalist treating the patient’s general medical concerns and the specialist focusing on techniques within his specialty to improve the patient’s issues.

The agreement should clearly state the responsibilities of each party, including delineating the party responsible for decisions such as admission and discharge. It should address resources and set forth the standardized processes and protocols to be used when treating patients.

Specialists can vary in their treatment of patients, so it is best to document their expectations at the onset of the relationship. Also, successful co-management is contingent upon regular communication between the hospitalist and the specialist. It is important to establish those boundaries in advance to prevent miscommunication down the road.

In particular, the agreement should explicitly describe the lines of authority and how conflicts will be addressed.

Final Thoughts

Co-management is a growing trend that can provide an opportunity for hospitalists to expand their practice and reinforce their value to both specialists and the hospital. The improved quality of care and patient satisfaction that is associated with hospitalist services can be crucial to maximizing reimbursement under a value-based reimbursement system. TH

NEW YORK (Reuters Health)—Women with heart failure (HF) derive as much benefit from implantable cardiac defibrillators (ICDs) for primary prevention as men, according to a comparative effectiveness study.

"Randomized clinical trials demonstrated that the ICD confers survival benefit to many patients with heart failure; however, data on ICDs in women were inadequate due to the relatively small number of women enrolled in those trials," study investigator Dr. Sana Al-Khatib, heart rhythm specialist from Duke Clinical Research Institute in Durham, North Carolina, told Reuters Health by email.

This analysis, online January 12 in Circulation: Heart Failure, showed that women with heart failure and an ICD had "significantly better survival than women with no ICD," Dr. Al-Khatib said.

"Our findings support the gender-neutral guideline recommendations regarding the use of primary prevention ICDs in eligible patients. As a result, women with heart failure should be equally considered for a primary prevention ICD as men," she added.

For the analysis, researchers linked data from 264 hospitals participating in the Get With The Guidelines Heart Failure registry with data from the Centers for Medicare and Medicaid

Services.

Using propensity score matching, they created a cohort of 430 women with heart failure and a preventive ICD and 430 similar women with heart failure but no ICD. For comparison, they propensity score matched 859 men with heart failure and an ICD to 859 men without an ICD.

After three years, 40.2% of women with an ICD had died, compared with 48.7% of women without an ICD. The corresponding mortality rates in men were 42.9% and 52.9%.

In the matched cohorts, an ICD was associated with "similarly better survival" in women and men (hazard ratios, 0.78 and 0.76, respectively). There was no interaction between sex and presence of an ICD with regard to survival (p=0.79).

"Despite the survival benefits of primary prevention ICDs in patients with HF demonstrated in randomized clinical trials, benefit in the subgroup of women from these trials has not been

definitively proved. This uncertainty on survival benefit may be one of several contributing factors to the lower rates of ICD referral and implantation in eligible women," the investigators note in their article.

The current data, they conclude, "support current guideline recommendations" for the implantation of a primary prevention ICD in eligible women and men with HF and reduced left ventricular ejection fraction.

The Agency for Healthcare Research and Quality funded the study. One author reported consulting for Medtronic.

NEW YORK (Reuters Health)—Women with heart failure (HF) derive as much benefit from implantable cardiac defibrillators (ICDs) for primary prevention as men, according to a comparative effectiveness study.

"Randomized clinical trials demonstrated that the ICD confers survival benefit to many patients with heart failure; however, data on ICDs in women were inadequate due to the relatively small number of women enrolled in those trials," study investigator Dr. Sana Al-Khatib, heart rhythm specialist from Duke Clinical Research Institute in Durham, North Carolina, told Reuters Health by email.

This analysis, online January 12 in Circulation: Heart Failure, showed that women with heart failure and an ICD had "significantly better survival than women with no ICD," Dr. Al-Khatib said.

"Our findings support the gender-neutral guideline recommendations regarding the use of primary prevention ICDs in eligible patients. As a result, women with heart failure should be equally considered for a primary prevention ICD as men," she added.

For the analysis, researchers linked data from 264 hospitals participating in the Get With The Guidelines Heart Failure registry with data from the Centers for Medicare and Medicaid

Services.

Using propensity score matching, they created a cohort of 430 women with heart failure and a preventive ICD and 430 similar women with heart failure but no ICD. For comparison, they propensity score matched 859 men with heart failure and an ICD to 859 men without an ICD.

After three years, 40.2% of women with an ICD had died, compared with 48.7% of women without an ICD. The corresponding mortality rates in men were 42.9% and 52.9%.

In the matched cohorts, an ICD was associated with "similarly better survival" in women and men (hazard ratios, 0.78 and 0.76, respectively). There was no interaction between sex and presence of an ICD with regard to survival (p=0.79).

"Despite the survival benefits of primary prevention ICDs in patients with HF demonstrated in randomized clinical trials, benefit in the subgroup of women from these trials has not been

definitively proved. This uncertainty on survival benefit may be one of several contributing factors to the lower rates of ICD referral and implantation in eligible women," the investigators note in their article.

The current data, they conclude, "support current guideline recommendations" for the implantation of a primary prevention ICD in eligible women and men with HF and reduced left ventricular ejection fraction.

The Agency for Healthcare Research and Quality funded the study. One author reported consulting for Medtronic.

NEW YORK (Reuters Health)—Women with heart failure (HF) derive as much benefit from implantable cardiac defibrillators (ICDs) for primary prevention as men, according to a comparative effectiveness study.

"Randomized clinical trials demonstrated that the ICD confers survival benefit to many patients with heart failure; however, data on ICDs in women were inadequate due to the relatively small number of women enrolled in those trials," study investigator Dr. Sana Al-Khatib, heart rhythm specialist from Duke Clinical Research Institute in Durham, North Carolina, told Reuters Health by email.

This analysis, online January 12 in Circulation: Heart Failure, showed that women with heart failure and an ICD had "significantly better survival than women with no ICD," Dr. Al-Khatib said.

"Our findings support the gender-neutral guideline recommendations regarding the use of primary prevention ICDs in eligible patients. As a result, women with heart failure should be equally considered for a primary prevention ICD as men," she added.

For the analysis, researchers linked data from 264 hospitals participating in the Get With The Guidelines Heart Failure registry with data from the Centers for Medicare and Medicaid

Services.

Using propensity score matching, they created a cohort of 430 women with heart failure and a preventive ICD and 430 similar women with heart failure but no ICD. For comparison, they propensity score matched 859 men with heart failure and an ICD to 859 men without an ICD.

After three years, 40.2% of women with an ICD had died, compared with 48.7% of women without an ICD. The corresponding mortality rates in men were 42.9% and 52.9%.

In the matched cohorts, an ICD was associated with "similarly better survival" in women and men (hazard ratios, 0.78 and 0.76, respectively). There was no interaction between sex and presence of an ICD with regard to survival (p=0.79).

"Despite the survival benefits of primary prevention ICDs in patients with HF demonstrated in randomized clinical trials, benefit in the subgroup of women from these trials has not been

definitively proved. This uncertainty on survival benefit may be one of several contributing factors to the lower rates of ICD referral and implantation in eligible women," the investigators note in their article.

The current data, they conclude, "support current guideline recommendations" for the implantation of a primary prevention ICD in eligible women and men with HF and reduced left ventricular ejection fraction.

The Agency for Healthcare Research and Quality funded the study. One author reported consulting for Medtronic.

Meng-Meng Ji, MD, PhD

Photo by Larry Young

SAN FRANCISCO—Preclinical research has revealed mutations that may affect the performance of histone deacetylase inhibitors (HDACis) in patients with peripheral T-cell lymphoma-not otherwise specified (PTCL-NOS).

The researchers identified histone-modifying gene mutations in patients with PTCL-NOS and found evidence to suggest these mutations confer shorter survival.

The team also conducted experiments in Jurkat cells showing that certain HDACis could counteract loss-of-function mutations, while others could not.

Meng-Meng Ji, MD, PhD, of the Shanghai Institute of Hematology in China, presented this research at the 8th Annual T-cell Lymphoma Forum.

Dr Ji and her colleagues first performed targeted sequencing in tumor samples from 105 patients newly diagnosed with PTCL-NOS.

The team discovered 62 mutations of “important” lymphoma-associated histone-modifying genes in 31 patients. They found mutations in MLL2 (n=21), TET2 (n=17), EP300 (n=8), CREBBP (n=8), and SETD2 (n=6).

Clinical data revealed a significant difference in overall survival between patients who had these mutations and those who did not (P=0.0038).

Because most of the mutations they identified are loss-of-function mutations, Dr Ji and her colleagues wanted to determine whether HDACis could restore the expression of the mutated genes. So they tested 4 HDACis—valproic acid, vorinostat, romidepsin, and chidamide—in Jurkat cells.

All 4 HDACis upregulated expression of EP300 and CREBBP. However, only romidepsin and chidamide upregulated MLL2, and only valproic acid and vorinostat upregulated SETD2. Dr Ji said there was no obvious change in TET2 expression with any of the HDACis.

The researchers then took a closer look at the EP300, MLL2, and SETD2 mutations. They found that most EP300 mutations were located on the HAT domain. MLL2 mutations could be found in a variety of locations, but some were located on the SET domain. And most SETD2 mutations were located on the SET domain.

Based on the crystal structure of each gene, the team found that EP300 mutations on the HAT domain and both MLL2 mutations and SETD2 mutations located on the SET domain induce loss of function.

So the researchers constructed a mutant for EP300 (p.H1377R), MLL2 (p.V5389M), and SETD2 (p.R1598_) and transfected Jurkat cells with each mutant.

The mutants reduced gene expression significantly when compared to wild-type cells.

Like in the previous experiments, all 4 HDACis could restore the expression of EP300. But only romidepsin and chidamide could restore MLL2 expression, and only valproic acid and vorinostat could restore SETD2 expression.

In addition, all 4 HDACis restored H3K18 hypoacetylation, which was inhibited in Jurkat cells transfected with the EP300 mutant.

Romidepsin and chidamide restored H3K4me3 expression, which was inhibited by the MLL2 mutant. And valproic acid and vorinostat restored H3K36me3 expression, which was inhibited by the SETD2 mutant.

“HDACis targeted differently histone H3 acetylation or methylation modulated by the mutations, suggesting their distinct therapeutic efficiency in PTCL-NOS,” Dr Ji noted.

She said she and her colleagues are continuing this research in samples from patients with PTCL-NOS.

Meng-Meng Ji, MD, PhD

Photo by Larry Young

SAN FRANCISCO—Preclinical research has revealed mutations that may affect the performance of histone deacetylase inhibitors (HDACis) in patients with peripheral T-cell lymphoma-not otherwise specified (PTCL-NOS).

The researchers identified histone-modifying gene mutations in patients with PTCL-NOS and found evidence to suggest these mutations confer shorter survival.

The team also conducted experiments in Jurkat cells showing that certain HDACis could counteract loss-of-function mutations, while others could not.

Meng-Meng Ji, MD, PhD, of the Shanghai Institute of Hematology in China, presented this research at the 8th Annual T-cell Lymphoma Forum.

Dr Ji and her colleagues first performed targeted sequencing in tumor samples from 105 patients newly diagnosed with PTCL-NOS.

The team discovered 62 mutations of “important” lymphoma-associated histone-modifying genes in 31 patients. They found mutations in MLL2 (n=21), TET2 (n=17), EP300 (n=8), CREBBP (n=8), and SETD2 (n=6).

Clinical data revealed a significant difference in overall survival between patients who had these mutations and those who did not (P=0.0038).

Because most of the mutations they identified are loss-of-function mutations, Dr Ji and her colleagues wanted to determine whether HDACis could restore the expression of the mutated genes. So they tested 4 HDACis—valproic acid, vorinostat, romidepsin, and chidamide—in Jurkat cells.

All 4 HDACis upregulated expression of EP300 and CREBBP. However, only romidepsin and chidamide upregulated MLL2, and only valproic acid and vorinostat upregulated SETD2. Dr Ji said there was no obvious change in TET2 expression with any of the HDACis.

The researchers then took a closer look at the EP300, MLL2, and SETD2 mutations. They found that most EP300 mutations were located on the HAT domain. MLL2 mutations could be found in a variety of locations, but some were located on the SET domain. And most SETD2 mutations were located on the SET domain.

Based on the crystal structure of each gene, the team found that EP300 mutations on the HAT domain and both MLL2 mutations and SETD2 mutations located on the SET domain induce loss of function.

So the researchers constructed a mutant for EP300 (p.H1377R), MLL2 (p.V5389M), and SETD2 (p.R1598_) and transfected Jurkat cells with each mutant.

The mutants reduced gene expression significantly when compared to wild-type cells.

Like in the previous experiments, all 4 HDACis could restore the expression of EP300. But only romidepsin and chidamide could restore MLL2 expression, and only valproic acid and vorinostat could restore SETD2 expression.

In addition, all 4 HDACis restored H3K18 hypoacetylation, which was inhibited in Jurkat cells transfected with the EP300 mutant.

Romidepsin and chidamide restored H3K4me3 expression, which was inhibited by the MLL2 mutant. And valproic acid and vorinostat restored H3K36me3 expression, which was inhibited by the SETD2 mutant.

“HDACis targeted differently histone H3 acetylation or methylation modulated by the mutations, suggesting their distinct therapeutic efficiency in PTCL-NOS,” Dr Ji noted.

She said she and her colleagues are continuing this research in samples from patients with PTCL-NOS.

Meng-Meng Ji, MD, PhD

Photo by Larry Young

SAN FRANCISCO—Preclinical research has revealed mutations that may affect the performance of histone deacetylase inhibitors (HDACis) in patients with peripheral T-cell lymphoma-not otherwise specified (PTCL-NOS).

The researchers identified histone-modifying gene mutations in patients with PTCL-NOS and found evidence to suggest these mutations confer shorter survival.

The team also conducted experiments in Jurkat cells showing that certain HDACis could counteract loss-of-function mutations, while others could not.

Meng-Meng Ji, MD, PhD, of the Shanghai Institute of Hematology in China, presented this research at the 8th Annual T-cell Lymphoma Forum.

Dr Ji and her colleagues first performed targeted sequencing in tumor samples from 105 patients newly diagnosed with PTCL-NOS.

The team discovered 62 mutations of “important” lymphoma-associated histone-modifying genes in 31 patients. They found mutations in MLL2 (n=21), TET2 (n=17), EP300 (n=8), CREBBP (n=8), and SETD2 (n=6).

Clinical data revealed a significant difference in overall survival between patients who had these mutations and those who did not (P=0.0038).

Because most of the mutations they identified are loss-of-function mutations, Dr Ji and her colleagues wanted to determine whether HDACis could restore the expression of the mutated genes. So they tested 4 HDACis—valproic acid, vorinostat, romidepsin, and chidamide—in Jurkat cells.

All 4 HDACis upregulated expression of EP300 and CREBBP. However, only romidepsin and chidamide upregulated MLL2, and only valproic acid and vorinostat upregulated SETD2. Dr Ji said there was no obvious change in TET2 expression with any of the HDACis.

The researchers then took a closer look at the EP300, MLL2, and SETD2 mutations. They found that most EP300 mutations were located on the HAT domain. MLL2 mutations could be found in a variety of locations, but some were located on the SET domain. And most SETD2 mutations were located on the SET domain.

Based on the crystal structure of each gene, the team found that EP300 mutations on the HAT domain and both MLL2 mutations and SETD2 mutations located on the SET domain induce loss of function.

So the researchers constructed a mutant for EP300 (p.H1377R), MLL2 (p.V5389M), and SETD2 (p.R1598_) and transfected Jurkat cells with each mutant.

The mutants reduced gene expression significantly when compared to wild-type cells.

Like in the previous experiments, all 4 HDACis could restore the expression of EP300. But only romidepsin and chidamide could restore MLL2 expression, and only valproic acid and vorinostat could restore SETD2 expression.

In addition, all 4 HDACis restored H3K18 hypoacetylation, which was inhibited in Jurkat cells transfected with the EP300 mutant.

Romidepsin and chidamide restored H3K4me3 expression, which was inhibited by the MLL2 mutant. And valproic acid and vorinostat restored H3K36me3 expression, which was inhibited by the SETD2 mutant.

“HDACis targeted differently histone H3 acetylation or methylation modulated by the mutations, suggesting their distinct therapeutic efficiency in PTCL-NOS,” Dr Ji noted.

She said she and her colleagues are continuing this research in samples from patients with PTCL-NOS.

Patient consults pharmacist

Photo by Rhoda Baer

Sun Pharma has announced the US launch of imatinib mesylate tablets, which are a generic version of Novartis’s Gleevec, for indications approved by the US Food and Drug Administration (FDA).

As part of this launch, Sun Pharma has rolled out a savings card program. The goal is to provide greater access to imatinib mesylate tablets for patients who have commercial insurance, but their out-of-pocket cost may exceed an affordable amount.

Sun Pharma’s Imatinib Mesylate Savings Card will reduce patient’s co-payment to $10. The card will also offer patients an additional savings benefit of up to $700 for a 30-day fill to offset any additional out-of-pocket cost should they be required to meet their deductible or co-insurance.

Participating pharmacies across the US can use the patient’s card as part of this program.

Eligible patients can participate in Sun Pharma’s Imatinib Mesylate Savings Card program by registering at www.imatinibrx.com or by requesting a savings card from their oncologist. Sun Pharma will be supplying its Imatinib Mesylate Savings Cards to more than 4500 oncologists.

Sun Pharma has established a Hub service so patients can call and speak with a trained healthcare professional about imatinib mesylate. The number is 1-844-502-5950.

In addition, qualifying patients can receive Sun Pharma’s imatinib mesylate at no cost. Based on qualifications for applying and including a doctor’s prescription, the Hub service will determine if a patient is qualified to receive imatinib mesylate for free. Upon acceptance, the prescription will be processed and delivered to the qualifying patient at no cost.

Sun Pharma’s imatinib mesylate was approved by the FDA in December 2015 and was granted 180 days of marketing exclusivity from the time of its launch. The drug is available in 100 mg and 400 mg tablets.

It is approved to treat:

• Newly diagnosed adult and pediatric patients with Philadelphia-chromosome-positive chronic myeloid leukemia (Ph+ CML) in chronic phase
• Patients with Ph+ CML in blast crisis, accelerated phase, or in chronic phase after failure of interferon-alpha therapy
• Adults with relapsed or refractory Ph+ acute lymphoblastic leukemia
• Adults with myelodysplastic/myeloproliferative diseases associated with PDGFR gene re-arrangements
• Adults with aggressive systemic mastocytosis without the D816V c-Kit mutation or with c-Kit mutational status unknown
• Adults with hypereosinophilic syndrome and/or chronic eosinophilic leukemia, including those who have the FIP1L1-PDGFRα fusion kinase
• Adult patients with unresectable, recurrent, and/or metastatic dermatofibrosarcoma protuberans.

Sun Pharma’s imatinib mesylate is not approved to treat patients with KIT (CD117)-positive unresectable and/or metastatic malignant gastrointestinal stromal tumors.

Patient consults pharmacist

Photo by Rhoda Baer

Sun Pharma has announced the US launch of imatinib mesylate tablets, which are a generic version of Novartis’s Gleevec, for indications approved by the US Food and Drug Administration (FDA).

As part of this launch, Sun Pharma has rolled out a savings card program. The goal is to provide greater access to imatinib mesylate tablets for patients who have commercial insurance, but their out-of-pocket cost may exceed an affordable amount.

Sun Pharma’s Imatinib Mesylate Savings Card will reduce patient’s co-payment to $10. The card will also offer patients an additional savings benefit of up to $700 for a 30-day fill to offset any additional out-of-pocket cost should they be required to meet their deductible or co-insurance.

Participating pharmacies across the US can use the patient’s card as part of this program.

Eligible patients can participate in Sun Pharma’s Imatinib Mesylate Savings Card program by registering at www.imatinibrx.com or by requesting a savings card from their oncologist. Sun Pharma will be supplying its Imatinib Mesylate Savings Cards to more than 4500 oncologists.

Sun Pharma has established a Hub service so patients can call and speak with a trained healthcare professional about imatinib mesylate. The number is 1-844-502-5950.

In addition, qualifying patients can receive Sun Pharma’s imatinib mesylate at no cost. Based on qualifications for applying and including a doctor’s prescription, the Hub service will determine if a patient is qualified to receive imatinib mesylate for free. Upon acceptance, the prescription will be processed and delivered to the qualifying patient at no cost.

Sun Pharma’s imatinib mesylate was approved by the FDA in December 2015 and was granted 180 days of marketing exclusivity from the time of its launch. The drug is available in 100 mg and 400 mg tablets.

It is approved to treat:

• Newly diagnosed adult and pediatric patients with Philadelphia-chromosome-positive chronic myeloid leukemia (Ph+ CML) in chronic phase
• Patients with Ph+ CML in blast crisis, accelerated phase, or in chronic phase after failure of interferon-alpha therapy
• Adults with relapsed or refractory Ph+ acute lymphoblastic leukemia
• Adults with myelodysplastic/myeloproliferative diseases associated with PDGFR gene re-arrangements
• Adults with aggressive systemic mastocytosis without the D816V c-Kit mutation or with c-Kit mutational status unknown
• Adults with hypereosinophilic syndrome and/or chronic eosinophilic leukemia, including those who have the FIP1L1-PDGFRα fusion kinase
• Adult patients with unresectable, recurrent, and/or metastatic dermatofibrosarcoma protuberans.

Sun Pharma’s imatinib mesylate is not approved to treat patients with KIT (CD117)-positive unresectable and/or metastatic malignant gastrointestinal stromal tumors.

Patient consults pharmacist

Photo by Rhoda Baer

Sun Pharma has announced the US launch of imatinib mesylate tablets, which are a generic version of Novartis’s Gleevec, for indications approved by the US Food and Drug Administration (FDA).

As part of this launch, Sun Pharma has rolled out a savings card program. The goal is to provide greater access to imatinib mesylate tablets for patients who have commercial insurance, but their out-of-pocket cost may exceed an affordable amount.

Sun Pharma’s Imatinib Mesylate Savings Card will reduce patient’s co-payment to $10. The card will also offer patients an additional savings benefit of up to $700 for a 30-day fill to offset any additional out-of-pocket cost should they be required to meet their deductible or co-insurance.

Participating pharmacies across the US can use the patient’s card as part of this program.

Eligible patients can participate in Sun Pharma’s Imatinib Mesylate Savings Card program by registering at www.imatinibrx.com or by requesting a savings card from their oncologist. Sun Pharma will be supplying its Imatinib Mesylate Savings Cards to more than 4500 oncologists.

Sun Pharma has established a Hub service so patients can call and speak with a trained healthcare professional about imatinib mesylate. The number is 1-844-502-5950.

In addition, qualifying patients can receive Sun Pharma’s imatinib mesylate at no cost. Based on qualifications for applying and including a doctor’s prescription, the Hub service will determine if a patient is qualified to receive imatinib mesylate for free. Upon acceptance, the prescription will be processed and delivered to the qualifying patient at no cost.

Sun Pharma’s imatinib mesylate was approved by the FDA in December 2015 and was granted 180 days of marketing exclusivity from the time of its launch. The drug is available in 100 mg and 400 mg tablets.

It is approved to treat:

• Newly diagnosed adult and pediatric patients with Philadelphia-chromosome-positive chronic myeloid leukemia (Ph+ CML) in chronic phase
• Patients with Ph+ CML in blast crisis, accelerated phase, or in chronic phase after failure of interferon-alpha therapy
• Adults with relapsed or refractory Ph+ acute lymphoblastic leukemia
• Adults with myelodysplastic/myeloproliferative diseases associated with PDGFR gene re-arrangements
• Adults with aggressive systemic mastocytosis without the D816V c-Kit mutation or with c-Kit mutational status unknown
• Adults with hypereosinophilic syndrome and/or chronic eosinophilic leukemia, including those who have the FIP1L1-PDGFRα fusion kinase
• Adult patients with unresectable, recurrent, and/or metastatic dermatofibrosarcoma protuberans.

Sun Pharma’s imatinib mesylate is not approved to treat patients with KIT (CD117)-positive unresectable and/or metastatic malignant gastrointestinal stromal tumors.

HSCT preparation

Photo by Chad McNeeley

Results of a phase 3 trial suggest defibrotide may improve survival in patients who develop hepatic veno-occlusive disease (VOD) and multi-organ failure (MOF) after hematopoietic stem cell transplant (HSCT).

The patients in this trial had a significant improvement in complete response (CR) rate and survival at day 100 after HSCT, when compared with historical controls.

The researchers said defibrotide was generally well-tolerated, and toxicity was manageable.

However, nearly all defibrotide-treated patients had at least 1 adverse event (AE), as did all historical controls. And a majority of patients in both groups had a fatal AE.

Paul G. Richardson, MD, of the Dana-Farber Cancer Institute in Boston, Massachusetts, and his colleagues reported these results in Blood. The trial was sponsored by Jazz Pharmaceuticals, makers of defibrotide.

“Based on the results of this pivotal phase 3 study, we believe defibrotide provides a promising treatment option for patients with this urgent unmet need,” Dr Richardson said.

“Although HSCT has improved substantially over the last decade, hepatic [VOD] with MOF remains a very real and life-threatening complication post-HSCT, and for which there are no currently approved therapies."

Dr Richardson and his colleagues investigated the safety and efficacy of defibrotide in 102 adult and pediatric HSCT patients with established hepatic VOD with MOF.

The patients received defibrotide intravenously at 25 mg/kg/day for a minimum of 21 days. Treatment was scheduled to continue beyond 21 days until the resolution of VOD or the patient’s discharge from the hospital.

The researchers compared the 102 patients who received defibrotide with 32 historical controls who were treated at the same institutions. The controls were identified via a review of medical charts of HSCT patients by an independent medical review committee, which was blinded to outcomes.

Baseline characteristics

Baseline characteristics between the groups were largely well balanced. This includes underlying disease, graft source, conditioning regimen, myeloablative regimen, and VOD and MOF parameters.

However, 15% of defibrotide-treated patients received tacrolimus plus sirolimus as graft-versus-host disease prophylaxis, compared with none of the historical controls. Most patients discontinued this regimen upon diagnosis of VOD.

All patients had hyperbilirubinemia. Ascites, weight gain, and hepatomegaly were present in 72% of patients in the defibrotide group and 59% of historical controls.

Renal dysfunction was present in 78% of patients in the defibrotide group (20% dialysis-dependent) and 75% of historical controls (6% dialysis-dependent). Pulmonary dysfunction was present in 85% (26% ventilator-dependent) and 97% (19% ventilator-dependent), respectively.

Sixty-four percent of patients in the defibrotide group and 72% of historical controls had both renal and pulmonary dysfunction.

Response and survival

The primary endpoint was survival at day 100 post-HSCT, which was 38.2% in the defibrotide group and 25% in the historical control group. The estimated between-group difference, using a propensity-adjusted analysis, was 23% (P=0.0109).

The CR rate was 25.5% in the defibrotide group and 12.5% in the historical control group. The estimated difference, adjusted for propensity score, was 19% (P=0.0160).

The median time to CR was 34.5 days in the defibrotide group and 39.5 days in the control group. CR was durable for 22 of 26 patients in the defibrotide group, who still had a CR at last observation. Four patients in the defibrotide group had CR end dates before day 180. All 4 patients died of sepsis or leukemia.

In the historical control group, 1 patient had a durable CR (162 days), 2 patients had a limited CR duration (9 and 10 days, respectively), and 1 patient could not be assessed.

Safety

The median duration of defibrotide treatment was 21.5 days. Eleven patients discontinued treatment prematurely due to possible drug-related toxicity (10.7%).

All but 1 of the defibrotide-treated patients and all historical controls had at least 1 AE. Hypotension was the most common AE in both groups—39.2% with defibrotide and 50.0% for historical controls. Diarrhea was also common—23.5% and 37.5%, respectively.

Sixty-four percent of patients in the defibrotide group (n=65) and 69% of historical controls (n=22) had a fatal AE.

Fifteen patients (14.7%) in the defibrotide group and 2 (6.3%) in the historical control group had 1 or more hemorrhagic AEs leading to death.

For the defibrotide group, these were gastrointestinal hemorrhage (n=1), cerebral hemorrhage (n=2), intracranial hemorrhage (n=1), subarachnoid hemorrhage (n=1), pulmonary alveolar hemorrhage (n=7), pulmonary hemorrhage (n=2), and vascular disorders hemorrhage (n=1).

Both hemorrhagic AEs leading to death in historical controls were pulmonary alveolar hemorrhage.

HSCT preparation

Photo by Chad McNeeley

Results of a phase 3 trial suggest defibrotide may improve survival in patients who develop hepatic veno-occlusive disease (VOD) and multi-organ failure (MOF) after hematopoietic stem cell transplant (HSCT).

The patients in this trial had a significant improvement in complete response (CR) rate and survival at day 100 after HSCT, when compared with historical controls.

The researchers said defibrotide was generally well-tolerated, and toxicity was manageable.

However, nearly all defibrotide-treated patients had at least 1 adverse event (AE), as did all historical controls. And a majority of patients in both groups had a fatal AE.

Paul G. Richardson, MD, of the Dana-Farber Cancer Institute in Boston, Massachusetts, and his colleagues reported these results in Blood. The trial was sponsored by Jazz Pharmaceuticals, makers of defibrotide.

“Based on the results of this pivotal phase 3 study, we believe defibrotide provides a promising treatment option for patients with this urgent unmet need,” Dr Richardson said.

“Although HSCT has improved substantially over the last decade, hepatic [VOD] with MOF remains a very real and life-threatening complication post-HSCT, and for which there are no currently approved therapies."

Dr Richardson and his colleagues investigated the safety and efficacy of defibrotide in 102 adult and pediatric HSCT patients with established hepatic VOD with MOF.

The patients received defibrotide intravenously at 25 mg/kg/day for a minimum of 21 days. Treatment was scheduled to continue beyond 21 days until the resolution of VOD or the patient’s discharge from the hospital.

The researchers compared the 102 patients who received defibrotide with 32 historical controls who were treated at the same institutions. The controls were identified via a review of medical charts of HSCT patients by an independent medical review committee, which was blinded to outcomes.

Baseline characteristics

Baseline characteristics between the groups were largely well balanced. This includes underlying disease, graft source, conditioning regimen, myeloablative regimen, and VOD and MOF parameters.

However, 15% of defibrotide-treated patients received tacrolimus plus sirolimus as graft-versus-host disease prophylaxis, compared with none of the historical controls. Most patients discontinued this regimen upon diagnosis of VOD.

All patients had hyperbilirubinemia. Ascites, weight gain, and hepatomegaly were present in 72% of patients in the defibrotide group and 59% of historical controls.

Renal dysfunction was present in 78% of patients in the defibrotide group (20% dialysis-dependent) and 75% of historical controls (6% dialysis-dependent). Pulmonary dysfunction was present in 85% (26% ventilator-dependent) and 97% (19% ventilator-dependent), respectively.

Sixty-four percent of patients in the defibrotide group and 72% of historical controls had both renal and pulmonary dysfunction.

Response and survival

The primary endpoint was survival at day 100 post-HSCT, which was 38.2% in the defibrotide group and 25% in the historical control group. The estimated between-group difference, using a propensity-adjusted analysis, was 23% (P=0.0109).

The CR rate was 25.5% in the defibrotide group and 12.5% in the historical control group. The estimated difference, adjusted for propensity score, was 19% (P=0.0160).

The median time to CR was 34.5 days in the defibrotide group and 39.5 days in the control group. CR was durable for 22 of 26 patients in the defibrotide group, who still had a CR at last observation. Four patients in the defibrotide group had CR end dates before day 180. All 4 patients died of sepsis or leukemia.

In the historical control group, 1 patient had a durable CR (162 days), 2 patients had a limited CR duration (9 and 10 days, respectively), and 1 patient could not be assessed.

Safety

The median duration of defibrotide treatment was 21.5 days. Eleven patients discontinued treatment prematurely due to possible drug-related toxicity (10.7%).

All but 1 of the defibrotide-treated patients and all historical controls had at least 1 AE. Hypotension was the most common AE in both groups—39.2% with defibrotide and 50.0% for historical controls. Diarrhea was also common—23.5% and 37.5%, respectively.

Sixty-four percent of patients in the defibrotide group (n=65) and 69% of historical controls (n=22) had a fatal AE.

Fifteen patients (14.7%) in the defibrotide group and 2 (6.3%) in the historical control group had 1 or more hemorrhagic AEs leading to death.

For the defibrotide group, these were gastrointestinal hemorrhage (n=1), cerebral hemorrhage (n=2), intracranial hemorrhage (n=1), subarachnoid hemorrhage (n=1), pulmonary alveolar hemorrhage (n=7), pulmonary hemorrhage (n=2), and vascular disorders hemorrhage (n=1).

Both hemorrhagic AEs leading to death in historical controls were pulmonary alveolar hemorrhage.

HSCT preparation

Photo by Chad McNeeley

Results of a phase 3 trial suggest defibrotide may improve survival in patients who develop hepatic veno-occlusive disease (VOD) and multi-organ failure (MOF) after hematopoietic stem cell transplant (HSCT).

The patients in this trial had a significant improvement in complete response (CR) rate and survival at day 100 after HSCT, when compared with historical controls.

The researchers said defibrotide was generally well-tolerated, and toxicity was manageable.

However, nearly all defibrotide-treated patients had at least 1 adverse event (AE), as did all historical controls. And a majority of patients in both groups had a fatal AE.

Paul G. Richardson, MD, of the Dana-Farber Cancer Institute in Boston, Massachusetts, and his colleagues reported these results in Blood. The trial was sponsored by Jazz Pharmaceuticals, makers of defibrotide.

“Based on the results of this pivotal phase 3 study, we believe defibrotide provides a promising treatment option for patients with this urgent unmet need,” Dr Richardson said.

“Although HSCT has improved substantially over the last decade, hepatic [VOD] with MOF remains a very real and life-threatening complication post-HSCT, and for which there are no currently approved therapies."

Dr Richardson and his colleagues investigated the safety and efficacy of defibrotide in 102 adult and pediatric HSCT patients with established hepatic VOD with MOF.

The patients received defibrotide intravenously at 25 mg/kg/day for a minimum of 21 days. Treatment was scheduled to continue beyond 21 days until the resolution of VOD or the patient’s discharge from the hospital.

The researchers compared the 102 patients who received defibrotide with 32 historical controls who were treated at the same institutions. The controls were identified via a review of medical charts of HSCT patients by an independent medical review committee, which was blinded to outcomes.

Baseline characteristics

Baseline characteristics between the groups were largely well balanced. This includes underlying disease, graft source, conditioning regimen, myeloablative regimen, and VOD and MOF parameters.

However, 15% of defibrotide-treated patients received tacrolimus plus sirolimus as graft-versus-host disease prophylaxis, compared with none of the historical controls. Most patients discontinued this regimen upon diagnosis of VOD.

All patients had hyperbilirubinemia. Ascites, weight gain, and hepatomegaly were present in 72% of patients in the defibrotide group and 59% of historical controls.

Renal dysfunction was present in 78% of patients in the defibrotide group (20% dialysis-dependent) and 75% of historical controls (6% dialysis-dependent). Pulmonary dysfunction was present in 85% (26% ventilator-dependent) and 97% (19% ventilator-dependent), respectively.

Sixty-four percent of patients in the defibrotide group and 72% of historical controls had both renal and pulmonary dysfunction.

Response and survival

The primary endpoint was survival at day 100 post-HSCT, which was 38.2% in the defibrotide group and 25% in the historical control group. The estimated between-group difference, using a propensity-adjusted analysis, was 23% (P=0.0109).

The CR rate was 25.5% in the defibrotide group and 12.5% in the historical control group. The estimated difference, adjusted for propensity score, was 19% (P=0.0160).

The median time to CR was 34.5 days in the defibrotide group and 39.5 days in the control group. CR was durable for 22 of 26 patients in the defibrotide group, who still had a CR at last observation. Four patients in the defibrotide group had CR end dates before day 180. All 4 patients died of sepsis or leukemia.

In the historical control group, 1 patient had a durable CR (162 days), 2 patients had a limited CR duration (9 and 10 days, respectively), and 1 patient could not be assessed.

Safety

The median duration of defibrotide treatment was 21.5 days. Eleven patients discontinued treatment prematurely due to possible drug-related toxicity (10.7%).

All but 1 of the defibrotide-treated patients and all historical controls had at least 1 AE. Hypotension was the most common AE in both groups—39.2% with defibrotide and 50.0% for historical controls. Diarrhea was also common—23.5% and 37.5%, respectively.

Sixty-four percent of patients in the defibrotide group (n=65) and 69% of historical controls (n=22) had a fatal AE.

Fifteen patients (14.7%) in the defibrotide group and 2 (6.3%) in the historical control group had 1 or more hemorrhagic AEs leading to death.

For the defibrotide group, these were gastrointestinal hemorrhage (n=1), cerebral hemorrhage (n=2), intracranial hemorrhage (n=1), subarachnoid hemorrhage (n=1), pulmonary alveolar hemorrhage (n=7), pulmonary hemorrhage (n=2), and vascular disorders hemorrhage (n=1).

Both hemorrhagic AEs leading to death in historical controls were pulmonary alveolar hemorrhage.