Gilteritinib, a tyrosine kinase inhibitor, had a generally favorable safety profile and inhibited FLT3 in a population enriched with relapsed/refractory acute myeloid leukemia (AML) patients who had the target mutations, based on results of a phase I/II trial.

The findings represent a step forward in treatment of AML with FLT3 inhibition, according to Alexander E. Perl, MD, of the University of Pennsylvania Abramson Comprehensive Cancer Center, Philadelphia, and his colleagues in the trial (NCT02014558), which is sponsored by Astellas Pharma Global Development.

Gilteritinib at 120 mg/day is being tested in phase III trials and in combination with chemotherapy regimens.

Initial entrants in the FLT3 inhibitor class had poor bioavailability, lacked potency and kinase specificity, and had low rates of response. While newer FLT3 inhibitors have had more potent effects, the proportions of patients who have responded have varied and their responses have often been transient, with resistance emerging within a few weeks of treatment.

Gilteritinib is attractive because it has in vitro activity against FLT3 internal tandem duplication mutations and tyrosine kinase domain mutations.

In the first-in-human, single-arm, open-label study — conducted at centers in the United States, Germany, France, and Italy — 252 patients were given one of seven gilteritinib doses, from 20 to 450 mg per day, either as part of a cohort to assess dose escalation or to expand a given dose.

FTL3 mutations were not required for study enrollment, but researchers did require 10 or more patients with confirmed FLT3 mutations to be enrolled in each of the dose expansion groups. Because they found that patients with the mutations were responding so much better than those with wild-type FLT3, they expanded the 120-mg and 200-mg dose cohorts to include only those with FLT3 mutations. In the end, 162 of 252 treated patients had internal tandem duplication mutations, 12 had codon D835 mutations, and 15 had both.

The most common grade 3 or 4 adverse events, regardless of relation to treatment, were neutropenia, seen in 39%, anemia (24%), thrombocytopenia (13%), sepsis (11%), and pneumonia (11%).

Commonly reported treatment-related adverse events were diarrhea (37%), anemia (34%), fatigue (33%), elevated aspartate aminotransferase (26%), and elevated alanine aminotransferase (19%).

Serious adverse events seen in at least 5% of patients included febrile neutropenia (39%; five cases of which were related to the treatment), progressive disease (17%), sepsis (14%; two of which were related to treatment), and pneumonia (11%), and acute renal failure (10%; five related to treatment), the researchers reported in The Lancet Oncology (doi: 10.1016/S1470-2045(17)30416-3).

Seven deaths were judged to be possibly or probably related to treatment, seen in the 20-mg, 80-mg, 120-mg, and 200-mg groups.

Of the 249 patients with data allowing a full analysis, 100 (40%) achieved a response, with 8% achieving a complete remission, 4% a complete remission with incomplete platelet recovery, 18% a complete remission with incomplete hematologic recovery, and 10% a partial remission.

At least 90% of the FLT3 inhibition was seen by the eighth day of treatment among those getting at least the 80-mg dose.

Median overall survival was 25 weeks, and leukemia-free survival will be reported in future data analyses, researchers said.

Only 19% of the patients with FLT3 mutations underwent a hematopoetic stem cell transplant after treatment, which was attributed in part to prior hematopioetic stem cell transplant and the advanced age of many of the patients. Among the patients who subsequently had transplants, the results did not have much effect. Median survival was 47 weeks for those with mutations who had an overall response to gilteritinib and had a transplant after treatment, compared to 42 weeks for those with mutations and an overall response but didn’t go on to transplant.

“Because gilteritinib as a single agent is likely to have limited curative capacity, even when used early in the disease course,” researchers wrote, “studies that integrate gilteritnib into frontline chemotherapy regimens are underway.”

Study authors reported receiving fees, grants, or nonfinancial support from Astellas, the sponsor of the trial, and other pharmaceutical companies.

Gilteritinib, a tyrosine kinase inhibitor, had a generally favorable safety profile and inhibited FLT3 in a population enriched with relapsed/refractory acute myeloid leukemia (AML) patients who had the target mutations, based on results of a phase I/II trial.

The findings represent a step forward in treatment of AML with FLT3 inhibition, according to Alexander E. Perl, MD, of the University of Pennsylvania Abramson Comprehensive Cancer Center, Philadelphia, and his colleagues in the trial (NCT02014558), which is sponsored by Astellas Pharma Global Development.

Gilteritinib at 120 mg/day is being tested in phase III trials and in combination with chemotherapy regimens.

Initial entrants in the FLT3 inhibitor class had poor bioavailability, lacked potency and kinase specificity, and had low rates of response. While newer FLT3 inhibitors have had more potent effects, the proportions of patients who have responded have varied and their responses have often been transient, with resistance emerging within a few weeks of treatment.

Gilteritinib is attractive because it has in vitro activity against FLT3 internal tandem duplication mutations and tyrosine kinase domain mutations.

In the first-in-human, single-arm, open-label study — conducted at centers in the United States, Germany, France, and Italy — 252 patients were given one of seven gilteritinib doses, from 20 to 450 mg per day, either as part of a cohort to assess dose escalation or to expand a given dose.

FTL3 mutations were not required for study enrollment, but researchers did require 10 or more patients with confirmed FLT3 mutations to be enrolled in each of the dose expansion groups. Because they found that patients with the mutations were responding so much better than those with wild-type FLT3, they expanded the 120-mg and 200-mg dose cohorts to include only those with FLT3 mutations. In the end, 162 of 252 treated patients had internal tandem duplication mutations, 12 had codon D835 mutations, and 15 had both.

The most common grade 3 or 4 adverse events, regardless of relation to treatment, were neutropenia, seen in 39%, anemia (24%), thrombocytopenia (13%), sepsis (11%), and pneumonia (11%).

Commonly reported treatment-related adverse events were diarrhea (37%), anemia (34%), fatigue (33%), elevated aspartate aminotransferase (26%), and elevated alanine aminotransferase (19%).

Serious adverse events seen in at least 5% of patients included febrile neutropenia (39%; five cases of which were related to the treatment), progressive disease (17%), sepsis (14%; two of which were related to treatment), and pneumonia (11%), and acute renal failure (10%; five related to treatment), the researchers reported in The Lancet Oncology (doi: 10.1016/S1470-2045(17)30416-3).

Seven deaths were judged to be possibly or probably related to treatment, seen in the 20-mg, 80-mg, 120-mg, and 200-mg groups.

Of the 249 patients with data allowing a full analysis, 100 (40%) achieved a response, with 8% achieving a complete remission, 4% a complete remission with incomplete platelet recovery, 18% a complete remission with incomplete hematologic recovery, and 10% a partial remission.

At least 90% of the FLT3 inhibition was seen by the eighth day of treatment among those getting at least the 80-mg dose.

Median overall survival was 25 weeks, and leukemia-free survival will be reported in future data analyses, researchers said.

Only 19% of the patients with FLT3 mutations underwent a hematopoetic stem cell transplant after treatment, which was attributed in part to prior hematopioetic stem cell transplant and the advanced age of many of the patients. Among the patients who subsequently had transplants, the results did not have much effect. Median survival was 47 weeks for those with mutations who had an overall response to gilteritinib and had a transplant after treatment, compared to 42 weeks for those with mutations and an overall response but didn’t go on to transplant.

“Because gilteritinib as a single agent is likely to have limited curative capacity, even when used early in the disease course,” researchers wrote, “studies that integrate gilteritnib into frontline chemotherapy regimens are underway.”

Study authors reported receiving fees, grants, or nonfinancial support from Astellas, the sponsor of the trial, and other pharmaceutical companies.

Gilteritinib, a tyrosine kinase inhibitor, had a generally favorable safety profile and inhibited FLT3 in a population enriched with relapsed/refractory acute myeloid leukemia (AML) patients who had the target mutations, based on results of a phase I/II trial.

The findings represent a step forward in treatment of AML with FLT3 inhibition, according to Alexander E. Perl, MD, of the University of Pennsylvania Abramson Comprehensive Cancer Center, Philadelphia, and his colleagues in the trial (NCT02014558), which is sponsored by Astellas Pharma Global Development.

Gilteritinib at 120 mg/day is being tested in phase III trials and in combination with chemotherapy regimens.

Initial entrants in the FLT3 inhibitor class had poor bioavailability, lacked potency and kinase specificity, and had low rates of response. While newer FLT3 inhibitors have had more potent effects, the proportions of patients who have responded have varied and their responses have often been transient, with resistance emerging within a few weeks of treatment.

Gilteritinib is attractive because it has in vitro activity against FLT3 internal tandem duplication mutations and tyrosine kinase domain mutations.

In the first-in-human, single-arm, open-label study — conducted at centers in the United States, Germany, France, and Italy — 252 patients were given one of seven gilteritinib doses, from 20 to 450 mg per day, either as part of a cohort to assess dose escalation or to expand a given dose.

FTL3 mutations were not required for study enrollment, but researchers did require 10 or more patients with confirmed FLT3 mutations to be enrolled in each of the dose expansion groups. Because they found that patients with the mutations were responding so much better than those with wild-type FLT3, they expanded the 120-mg and 200-mg dose cohorts to include only those with FLT3 mutations. In the end, 162 of 252 treated patients had internal tandem duplication mutations, 12 had codon D835 mutations, and 15 had both.

The most common grade 3 or 4 adverse events, regardless of relation to treatment, were neutropenia, seen in 39%, anemia (24%), thrombocytopenia (13%), sepsis (11%), and pneumonia (11%).

Commonly reported treatment-related adverse events were diarrhea (37%), anemia (34%), fatigue (33%), elevated aspartate aminotransferase (26%), and elevated alanine aminotransferase (19%).

Serious adverse events seen in at least 5% of patients included febrile neutropenia (39%; five cases of which were related to the treatment), progressive disease (17%), sepsis (14%; two of which were related to treatment), and pneumonia (11%), and acute renal failure (10%; five related to treatment), the researchers reported in The Lancet Oncology (doi: 10.1016/S1470-2045(17)30416-3).

Seven deaths were judged to be possibly or probably related to treatment, seen in the 20-mg, 80-mg, 120-mg, and 200-mg groups.

Of the 249 patients with data allowing a full analysis, 100 (40%) achieved a response, with 8% achieving a complete remission, 4% a complete remission with incomplete platelet recovery, 18% a complete remission with incomplete hematologic recovery, and 10% a partial remission.

At least 90% of the FLT3 inhibition was seen by the eighth day of treatment among those getting at least the 80-mg dose.

Median overall survival was 25 weeks, and leukemia-free survival will be reported in future data analyses, researchers said.

Only 19% of the patients with FLT3 mutations underwent a hematopoetic stem cell transplant after treatment, which was attributed in part to prior hematopioetic stem cell transplant and the advanced age of many of the patients. Among the patients who subsequently had transplants, the results did not have much effect. Median survival was 47 weeks for those with mutations who had an overall response to gilteritinib and had a transplant after treatment, compared to 42 weeks for those with mutations and an overall response but didn’t go on to transplant.

“Because gilteritinib as a single agent is likely to have limited curative capacity, even when used early in the disease course,” researchers wrote, “studies that integrate gilteritnib into frontline chemotherapy regimens are underway.”

Study authors reported receiving fees, grants, or nonfinancial support from Astellas, the sponsor of the trial, and other pharmaceutical companies.

Syringe

The US Food and Drug Administration (FDA) approved a new, subcutaneous (SC) formulation of rituximab with hyaluronidase human (Rituxan Hycela™).

The new formulation includes the same monoclonal antibody as intravenous rituximab, but is combined with an enzyme that helps to deliver rituximab under the skin.

The new treatment reduces administration time from 1.5 hours or more for intravenous rituximab to 5 to 7 minutes for the subcutaneous injection.

It is approved for use in adults with previously untreated and relapsed or refractory follicular lymphoma (FL), previously untreated diffuse large B-cell lymphoma (DLBCL), and previously untreated and previously treated chronic lymphocytic leukemia (CLL).

“[P]eople with 3 of the most common blood cancers now have a new treatment option which provides efficacy comparable with intravenous Rituxan and can be delivered under the skin in minutes instead of hours through IV infusion,” said Sandra Horning, MD, chief medical officer of Genentech.

Rituxan Hycela is manufactured by Genentech, Inc, a member of the Roche Group, and jointly marketed by Biogen and Genentech USA, Inc.

“People who benefit from Rituxan may receive years of repeated treatments for their blood cancer, so an option that reduces the administration time can be important,” she noted.

The FDA based its decision on results from 4 clinical studies:

• SABRINA (NCT01200758): Phase 3 combination study with chemotherapy and maintenance study in previously untreated FL
• SAWYER (NCT01292603): Phase 1b study in previously untreated CLL
• MabEase (NCT01649856): Phase 3 study in previously untreated DLBCL
• PrefMab (NCT01724021): Phase 3 patient preference study in previously untreated FL and DLBCL

This last study showed that 77% of patients preferred subcutaneous over intravenous administration, primarily because it reduced administration time.

Together, these trials represented nearly 2,000 people and demonstrated that subcutaneous administration of rituximab/hyaluronidase resulted in non-inferior levels of rituximab in the blood compared to intravenous rituximab.

And the subcutaneous formulation also demonstrated comparable clinical efficacy outcomes to the intravenous formulation.

Patients must have had at least 1 full dose of intravenous rituximab without severe adverse reactions before receiving the subcutaneous injection. There is a higher risk of certain severe adverse reactions during the first infusion.

The safety profile of rituximab/hyaluronidase is also comparable to intravenous rituximab, except for cutaneous reactions.

The most common (≥20%) adverse reactions observed with rituximab/hyaluronidase were:

• In FL, infections, neutropenia, nausea, constipation, cough, and fatigue.
• In DLBCL, infections, neutropenia, alopecia, nausea, and anemia.
• In CLL, infections, neutropenia, nausea, thrombocytopenia, pyrexia, vomiting, and erythema at the injection site.

Rituxan Hycela will be available in the US within 1 to 2 weeks, according to the manufacturer. Intravenous rituximab will continue to be available.

A subcutaneous formulation of rituximab (MabThera) had previously been approved for use in European markets by the European Commission.

For further information on the new US formulation, see the full prescribing information. 

Syringe

The US Food and Drug Administration (FDA) approved a new, subcutaneous (SC) formulation of rituximab with hyaluronidase human (Rituxan Hycela™).

The new formulation includes the same monoclonal antibody as intravenous rituximab, but is combined with an enzyme that helps to deliver rituximab under the skin.

The new treatment reduces administration time from 1.5 hours or more for intravenous rituximab to 5 to 7 minutes for the subcutaneous injection.

It is approved for use in adults with previously untreated and relapsed or refractory follicular lymphoma (FL), previously untreated diffuse large B-cell lymphoma (DLBCL), and previously untreated and previously treated chronic lymphocytic leukemia (CLL).

“[P]eople with 3 of the most common blood cancers now have a new treatment option which provides efficacy comparable with intravenous Rituxan and can be delivered under the skin in minutes instead of hours through IV infusion,” said Sandra Horning, MD, chief medical officer of Genentech.

Rituxan Hycela is manufactured by Genentech, Inc, a member of the Roche Group, and jointly marketed by Biogen and Genentech USA, Inc.

“People who benefit from Rituxan may receive years of repeated treatments for their blood cancer, so an option that reduces the administration time can be important,” she noted.

The FDA based its decision on results from 4 clinical studies:

• SABRINA (NCT01200758): Phase 3 combination study with chemotherapy and maintenance study in previously untreated FL
• SAWYER (NCT01292603): Phase 1b study in previously untreated CLL
• MabEase (NCT01649856): Phase 3 study in previously untreated DLBCL
• PrefMab (NCT01724021): Phase 3 patient preference study in previously untreated FL and DLBCL

This last study showed that 77% of patients preferred subcutaneous over intravenous administration, primarily because it reduced administration time.

Together, these trials represented nearly 2,000 people and demonstrated that subcutaneous administration of rituximab/hyaluronidase resulted in non-inferior levels of rituximab in the blood compared to intravenous rituximab.

And the subcutaneous formulation also demonstrated comparable clinical efficacy outcomes to the intravenous formulation.

Patients must have had at least 1 full dose of intravenous rituximab without severe adverse reactions before receiving the subcutaneous injection. There is a higher risk of certain severe adverse reactions during the first infusion.

The safety profile of rituximab/hyaluronidase is also comparable to intravenous rituximab, except for cutaneous reactions.

The most common (≥20%) adverse reactions observed with rituximab/hyaluronidase were:

• In FL, infections, neutropenia, nausea, constipation, cough, and fatigue.
• In DLBCL, infections, neutropenia, alopecia, nausea, and anemia.
• In CLL, infections, neutropenia, nausea, thrombocytopenia, pyrexia, vomiting, and erythema at the injection site.

Rituxan Hycela will be available in the US within 1 to 2 weeks, according to the manufacturer. Intravenous rituximab will continue to be available.

A subcutaneous formulation of rituximab (MabThera) had previously been approved for use in European markets by the European Commission.

For further information on the new US formulation, see the full prescribing information. 

Syringe

The US Food and Drug Administration (FDA) approved a new, subcutaneous (SC) formulation of rituximab with hyaluronidase human (Rituxan Hycela™).

The new formulation includes the same monoclonal antibody as intravenous rituximab, but is combined with an enzyme that helps to deliver rituximab under the skin.

The new treatment reduces administration time from 1.5 hours or more for intravenous rituximab to 5 to 7 minutes for the subcutaneous injection.

It is approved for use in adults with previously untreated and relapsed or refractory follicular lymphoma (FL), previously untreated diffuse large B-cell lymphoma (DLBCL), and previously untreated and previously treated chronic lymphocytic leukemia (CLL).

“[P]eople with 3 of the most common blood cancers now have a new treatment option which provides efficacy comparable with intravenous Rituxan and can be delivered under the skin in minutes instead of hours through IV infusion,” said Sandra Horning, MD, chief medical officer of Genentech.

Rituxan Hycela is manufactured by Genentech, Inc, a member of the Roche Group, and jointly marketed by Biogen and Genentech USA, Inc.

“People who benefit from Rituxan may receive years of repeated treatments for their blood cancer, so an option that reduces the administration time can be important,” she noted.

The FDA based its decision on results from 4 clinical studies:

• SABRINA (NCT01200758): Phase 3 combination study with chemotherapy and maintenance study in previously untreated FL
• SAWYER (NCT01292603): Phase 1b study in previously untreated CLL
• MabEase (NCT01649856): Phase 3 study in previously untreated DLBCL
• PrefMab (NCT01724021): Phase 3 patient preference study in previously untreated FL and DLBCL

This last study showed that 77% of patients preferred subcutaneous over intravenous administration, primarily because it reduced administration time.

Together, these trials represented nearly 2,000 people and demonstrated that subcutaneous administration of rituximab/hyaluronidase resulted in non-inferior levels of rituximab in the blood compared to intravenous rituximab.

And the subcutaneous formulation also demonstrated comparable clinical efficacy outcomes to the intravenous formulation.

Patients must have had at least 1 full dose of intravenous rituximab without severe adverse reactions before receiving the subcutaneous injection. There is a higher risk of certain severe adverse reactions during the first infusion.

The safety profile of rituximab/hyaluronidase is also comparable to intravenous rituximab, except for cutaneous reactions.

The most common (≥20%) adverse reactions observed with rituximab/hyaluronidase were:

• In FL, infections, neutropenia, nausea, constipation, cough, and fatigue.
• In DLBCL, infections, neutropenia, alopecia, nausea, and anemia.
• In CLL, infections, neutropenia, nausea, thrombocytopenia, pyrexia, vomiting, and erythema at the injection site.

Rituxan Hycela will be available in the US within 1 to 2 weeks, according to the manufacturer. Intravenous rituximab will continue to be available.

A subcutaneous formulation of rituximab (MabThera) had previously been approved for use in European markets by the European Commission.

For further information on the new US formulation, see the full prescribing information. 

Photo by Rhoda Baer

A small study of 20 children aged 8 to 18 years with incurable or refractory cancers indicates children are reliable reporters of their symptoms and side effects.

The investigators collected reports from the children, who were enrolled on phase 1/2 clinical trials at 4 cancer centers and undergoing their first courses of chemotherapy.

The team assessed the feasibility and acceptability of collecting symptom, function, and quality of life (QOL) reports from the study participants.

The investigators also evaluated the measurement tool and interview questions at 2 time points.

They contend the youths’ self-reports potentially could be a new trial endpoint.

According to the investigators, only rarely do patient-reported outcomes (PROs) get incorporated into pediatric phase 1 or phase 2 trials.

And because these trials contribute to drug indications and labeling, the researchers decided to assess whether it was feasible to enroll young people and retain them in a PRO endeavor.

The researchers also assessed the reliability, validity, responsiveness, and range of the pediatric measures employed. They used the Patient-Reported Outcomes Measurement Information System (PROMIS) to capture statistically significant and clinically meaningful changes or minimally important differences (MIDs) in PROs.

Pamela S. Hinds, PhD, RN, of George Washington University in Washington, DC,  reported the findings on behalf of the Children's National Health System researchers in Cancer, the journal of the American Cancer Society.

"When experimental cancer drugs are studied, researchers collect details about how these promising therapies affect children's organs, but rarely do they ask the children themselves about symptoms they feel or the side effects they experience," Dr Hinds said.

"Without this crucial information, the full impact of the experimental treatment on the pediatric patient is likely underreported and clinicians are hobbled in their ability to effectively manage side effects," she added.

The team recruited children and adolescents enrolled in phase 1 safety or phase 2 efficacy trials at Children's National, Seattle Children's Hospital, Children's Hospital of Philadelphia, and Boston Children's Hospital.

Findings

Sixty percent of the participants were male and 70% were white.

Median age of the participants was 13.6 years: 7 (35%) were age 8 to 12, and 13 (65%) were 13 to 17.

Thirteen participants (65%) had solid tumors, 5 (25%) had brain tumors, and 2 (10%) had lymphoma.

A total of 29 patients were eligible to participate in the trial during 20 months of screening. Five parents and 2 patients declined to participate.

The remaining 22 patients who agreed to participate accounted for a 75.9% enrollment rate. Twenty of them (90.9%) participated at the first data time point, which was at the time of enrollment, and 77.3% participated 3 weeks later at time point 2.

The authors noted that refusals to enroll were more likely to come from parents (17.2%) than the eligible patients (8.3%).

And refusals only occurred when the self-report measures were not embedded in the clinical trial.

Of the 10 protocols represented, 7 patients were enrolled on the same protocol in which the PRO measures were embedded.

The researchers administered the 6-item short-form measures for the scales of Mobility, Pain, Fatigue, Depressive Symptoms, Anxiety, and Peer Relationships.

They asked the 4 open-ended questions—concerning QOL while receiving therapy and acceptability of the patient reporting—at time point 2.

At time point 1, 3 patients did not complete 3 PROMIS measures, for a person-missing rate of 15% and a measure-missing rate of 3.3%.

At the second time point, 2 patients did not complete 1 measure each, for a person-missing rate of 11.8% and a measure-missing rate of 2%.

All but one measure at time point 1 met the reliability criterion and all measures did so at time point 2.

The research team believes their findings support the feasibility and acceptability of completing quantitative and qualitative measures regarding symptom, function, and QOL experiences among children and adolescents with incurable cancer.

The researchers note the small study size and the number of parent refusals are limitations of the trial.

Nevertheless, they recommend embedding PROs in future pediatric oncology phase 1/2 trials. 

Photo by Rhoda Baer

A small study of 20 children aged 8 to 18 years with incurable or refractory cancers indicates children are reliable reporters of their symptoms and side effects.

The investigators collected reports from the children, who were enrolled on phase 1/2 clinical trials at 4 cancer centers and undergoing their first courses of chemotherapy.

The team assessed the feasibility and acceptability of collecting symptom, function, and quality of life (QOL) reports from the study participants.

The investigators also evaluated the measurement tool and interview questions at 2 time points.

They contend the youths’ self-reports potentially could be a new trial endpoint.

According to the investigators, only rarely do patient-reported outcomes (PROs) get incorporated into pediatric phase 1 or phase 2 trials.

And because these trials contribute to drug indications and labeling, the researchers decided to assess whether it was feasible to enroll young people and retain them in a PRO endeavor.

The researchers also assessed the reliability, validity, responsiveness, and range of the pediatric measures employed. They used the Patient-Reported Outcomes Measurement Information System (PROMIS) to capture statistically significant and clinically meaningful changes or minimally important differences (MIDs) in PROs.

Pamela S. Hinds, PhD, RN, of George Washington University in Washington, DC,  reported the findings on behalf of the Children's National Health System researchers in Cancer, the journal of the American Cancer Society.

"When experimental cancer drugs are studied, researchers collect details about how these promising therapies affect children's organs, but rarely do they ask the children themselves about symptoms they feel or the side effects they experience," Dr Hinds said.

"Without this crucial information, the full impact of the experimental treatment on the pediatric patient is likely underreported and clinicians are hobbled in their ability to effectively manage side effects," she added.

The team recruited children and adolescents enrolled in phase 1 safety or phase 2 efficacy trials at Children's National, Seattle Children's Hospital, Children's Hospital of Philadelphia, and Boston Children's Hospital.

Findings

Sixty percent of the participants were male and 70% were white.

Median age of the participants was 13.6 years: 7 (35%) were age 8 to 12, and 13 (65%) were 13 to 17.

Thirteen participants (65%) had solid tumors, 5 (25%) had brain tumors, and 2 (10%) had lymphoma.

A total of 29 patients were eligible to participate in the trial during 20 months of screening. Five parents and 2 patients declined to participate.

The remaining 22 patients who agreed to participate accounted for a 75.9% enrollment rate. Twenty of them (90.9%) participated at the first data time point, which was at the time of enrollment, and 77.3% participated 3 weeks later at time point 2.

The authors noted that refusals to enroll were more likely to come from parents (17.2%) than the eligible patients (8.3%).

And refusals only occurred when the self-report measures were not embedded in the clinical trial.

Of the 10 protocols represented, 7 patients were enrolled on the same protocol in which the PRO measures were embedded.

The researchers administered the 6-item short-form measures for the scales of Mobility, Pain, Fatigue, Depressive Symptoms, Anxiety, and Peer Relationships.

They asked the 4 open-ended questions—concerning QOL while receiving therapy and acceptability of the patient reporting—at time point 2.

At time point 1, 3 patients did not complete 3 PROMIS measures, for a person-missing rate of 15% and a measure-missing rate of 3.3%.

At the second time point, 2 patients did not complete 1 measure each, for a person-missing rate of 11.8% and a measure-missing rate of 2%.

All but one measure at time point 1 met the reliability criterion and all measures did so at time point 2.

The research team believes their findings support the feasibility and acceptability of completing quantitative and qualitative measures regarding symptom, function, and QOL experiences among children and adolescents with incurable cancer.

The researchers note the small study size and the number of parent refusals are limitations of the trial.

Nevertheless, they recommend embedding PROs in future pediatric oncology phase 1/2 trials. 

Photo by Rhoda Baer

A small study of 20 children aged 8 to 18 years with incurable or refractory cancers indicates children are reliable reporters of their symptoms and side effects.

The investigators collected reports from the children, who were enrolled on phase 1/2 clinical trials at 4 cancer centers and undergoing their first courses of chemotherapy.

The team assessed the feasibility and acceptability of collecting symptom, function, and quality of life (QOL) reports from the study participants.

The investigators also evaluated the measurement tool and interview questions at 2 time points.

They contend the youths’ self-reports potentially could be a new trial endpoint.

According to the investigators, only rarely do patient-reported outcomes (PROs) get incorporated into pediatric phase 1 or phase 2 trials.

And because these trials contribute to drug indications and labeling, the researchers decided to assess whether it was feasible to enroll young people and retain them in a PRO endeavor.

The researchers also assessed the reliability, validity, responsiveness, and range of the pediatric measures employed. They used the Patient-Reported Outcomes Measurement Information System (PROMIS) to capture statistically significant and clinically meaningful changes or minimally important differences (MIDs) in PROs.

Pamela S. Hinds, PhD, RN, of George Washington University in Washington, DC,  reported the findings on behalf of the Children's National Health System researchers in Cancer, the journal of the American Cancer Society.

"When experimental cancer drugs are studied, researchers collect details about how these promising therapies affect children's organs, but rarely do they ask the children themselves about symptoms they feel or the side effects they experience," Dr Hinds said.

"Without this crucial information, the full impact of the experimental treatment on the pediatric patient is likely underreported and clinicians are hobbled in their ability to effectively manage side effects," she added.

The team recruited children and adolescents enrolled in phase 1 safety or phase 2 efficacy trials at Children's National, Seattle Children's Hospital, Children's Hospital of Philadelphia, and Boston Children's Hospital.

Findings

Sixty percent of the participants were male and 70% were white.

Median age of the participants was 13.6 years: 7 (35%) were age 8 to 12, and 13 (65%) were 13 to 17.

Thirteen participants (65%) had solid tumors, 5 (25%) had brain tumors, and 2 (10%) had lymphoma.

A total of 29 patients were eligible to participate in the trial during 20 months of screening. Five parents and 2 patients declined to participate.

The remaining 22 patients who agreed to participate accounted for a 75.9% enrollment rate. Twenty of them (90.9%) participated at the first data time point, which was at the time of enrollment, and 77.3% participated 3 weeks later at time point 2.

The authors noted that refusals to enroll were more likely to come from parents (17.2%) than the eligible patients (8.3%).

And refusals only occurred when the self-report measures were not embedded in the clinical trial.

Of the 10 protocols represented, 7 patients were enrolled on the same protocol in which the PRO measures were embedded.

The researchers administered the 6-item short-form measures for the scales of Mobility, Pain, Fatigue, Depressive Symptoms, Anxiety, and Peer Relationships.

They asked the 4 open-ended questions—concerning QOL while receiving therapy and acceptability of the patient reporting—at time point 2.

At time point 1, 3 patients did not complete 3 PROMIS measures, for a person-missing rate of 15% and a measure-missing rate of 3.3%.

At the second time point, 2 patients did not complete 1 measure each, for a person-missing rate of 11.8% and a measure-missing rate of 2%.

All but one measure at time point 1 met the reliability criterion and all measures did so at time point 2.

The research team believes their findings support the feasibility and acceptability of completing quantitative and qualitative measures regarding symptom, function, and QOL experiences among children and adolescents with incurable cancer.

The researchers note the small study size and the number of parent refusals are limitations of the trial.

Nevertheless, they recommend embedding PROs in future pediatric oncology phase 1/2 trials. 

What I thought would be a typical morning at the major county hospital – if that were ever possible on a psychiatric emergency unit (EU) – quickly turned atypical when I encountered a patient whom I will call Olivia.

Olivia is a 51-year-old male-to-female transgender woman who has not yet undergone gender reassignment surgery. She was brought to the EU by police, after expressing suicidal ideation during a phone call with a tax accountant. This was Olivia’s third visit to the psychiatric emergency unit because of suicide threats within 2 months. Though she was chronically suicidal, her current visit was triggered by a tax audit, which led her to view herself as an unwanted burden on society.

Historical perspective

Societal views of transgendered people vary. On one end of the spectrum is acceptance; in the middle is perhaps tolerance or mild discomfort at perceived abnormality; and at the other extreme are virulent hatred, discrimination, and invalidation of these individuals’ gender-affirming efforts.

Awareness of these hostile attitudes creates a vicious cycle of marginalization and mental illness among many transgender individuals.

Controversies surrounding sexual minorities are rooted in societal perceptions of gender delineations, and prevailing societal norms surrounding ethical and moral conduct. Most societies have a narrow perspective on gender, and seek to maintain a strict delineation of male and female identities, which contributes to the rejection of those with gender identity issues.^1,2 This often results in the invalidation of or active opposition to transgender individuals’ transition efforts. The reasons behind the rejection of transgender men and women are multifactorial, and can include a lack of awareness, homophobia, religious dogma, social stigmatization, and perceived non-employability – all often stemming largely from the lack of awareness that sexual identity and orientation are not a choice, but rather are predetermined by biological mechanisms. The intensifying familial, societal, political, and financial pressures all contribute to increased mental health issues, including increased incidence of suicide among sexual minorities.

Globally, sexual minorities continue to be subjected to gross human rights violations. Against the backdrop of prevalent social discrimination, transgender people experience a roughly threefold increase in the risk of developing anxiety disorders, which impair self-esteem and interpersonal functioning.³ The lifetime risk of attempted suicide is four times higher among transgender men, and two times higher among transgender women, than it is among cisgender men and women, respectively. Institutional discrimination in the public and private sectors results from laws and policies that impose inequities, or fail to protect sexual minorities. Examples are current policies denying medical coverage for sex reassignment surgery, denying health care by a provider because of transgender identity and numerous obstacles to obtain health insurance coverage.⁴

Impact of low acceptance

Recall Olivia’s need to delay the vocal cord surgery that arguably would have had a positive impact on her self-esteem. The transgender population faces increased health risks and barriers to appropriate mental health evaluation and inclusive care, particularly individuals with low acceptance from family, friends, and partners.⁵

A century ago, changing one’s gender was considered both highly disreputable and an impossible feat.⁶ Today, sex reassignment is the focus of political debate, with activists seeking equal rights for transgender individuals, despite the high rate of mental disorders in the community. While there is some positive public perception of transgender people, most still hold religious or moral objections to sex reassignment. Olivia’s family, for example, is typical in their rejection of her gender-affirming efforts. One example of this rejection is forbidding her to wear women’s clothing, stating that it makes them feel ashamed and subjects them to social ridicule.

As a result, Olivia lacks the social support that could work to remedy, to some extent, her suicidal ideation. Efforts to alleviate financial burdens that result from workplace discrimination, impediments to the pursuit of health, security, and happiness and the bureaucratic hurdles to gender affirmation are needed.^7,8 According to research by Kristen Clements-Nolle, PhD, MPH, and her associates, suicidality may be largely a reaction to the absence of legally secure equal rights for transgender men and women.⁹ In Olivia’s case, financial struggles with her mortgage, medical expenses for her autistic son, and anxiety about potentially losing the disability benefits on which she depends have added to her insecurity.

Financial insecurity resulting from her unemployment likely has exacerbated her feelings of inadequacy and depression. For example, because of her lack of financial resources, she had to delay the vocal cord surgery she desired. What would her prognosis be if her legal rights, including employment protection, were firmly in place? Likewise, the demands of parenting an autistic son posed another significant stressor that likely contributes to reciprocal stress for the child, resulting in the worsening of his autism symptoms.

In summary, transgender individuals face bias and discrimination in response to their gender-affirming efforts, which creates a vicious cycle of mental illness, suicidality, and societal marginalization. Addressing these endemic issues requires a multifaceted approach. Preventive strategies, including identification of mental health issues, and integration of mental health service with primary health care, are needed. Case registration, as a research measure to help understand the prevalence and severity of suicide among the LGBT population, would be beneficial.

Monitoring and follow-up of identified cases for supportive care (for example, gatekeeper training similar to the World Health Organization’s Suicide Prevention Initiative) also are needed to identify protective factors, in order to foster resilience in LGBT individuals facing negative reactions to disclosure of their sexual minority status. Legislation aimed at better facilitating a seamless integration of transgender men and women into mainstream society also is necessary. Supportive measures, particularly social supports promoting better mental health in trans individuals, could help reduce suicide rates. Finally, governmental initiatives to protect the human and constitutional rights of transgender people are key to minimizing the incidence of mental health issues and suicides among this vulnerable sexual minority group.

The path to addressing the issues faced by transgender individuals begins with education, which then leads to understanding. From understanding comes acceptance. Acceptance leads to equality – social, legal, and thereby, economic. Ensuring acceptance of all sexes as equal could mitigate the marginalization – in all its forms – experienced by gender-affirming individuals, with the end result being less mental illness and reduced rates of suicidality in this vulnerable population.⁷

Dr. Ahmed is a second-year resident in the department of psychiatry at the Nassau University Medical Center, East Meadow, New York. His interests include public social psychiatry, health care policy, health disparities, mental health stigma, and addiction psychiatry. Dr. Ahmed is a member of the American Psychiatric Association, the American Society of Clinical Psychopharmacology, and the American Association for Social Psychiatry.

References

1. LGBT Health. 2014 Jun;1(2):98-106.

2. Signs: Journal of Women in Culture and Society. 2006;32(1):83-111.

3. Int J Transgenderism. 2016:18(1):16-26.

4. Am J Public Health. 2014 Mar;104(3):e31-8.

5. Int J Transgenderism. 2017;18(1):104-18.

6. “Suicide attempts among transgender and gender non-conforming adults,” American Foundation for Suicide Prevention, 2014.

7. “Injustice at every turn: A report of the national transgender discrimination survey,” National Center for Transgender Equality, 2011.

8. J Gay Lesbian Soc Serv. 2014;26(2):186-206.

9. J Homosex. 2006;51(3):53-69.

What I thought would be a typical morning at the major county hospital – if that were ever possible on a psychiatric emergency unit (EU) – quickly turned atypical when I encountered a patient whom I will call Olivia.

Olivia is a 51-year-old male-to-female transgender woman who has not yet undergone gender reassignment surgery. She was brought to the EU by police, after expressing suicidal ideation during a phone call with a tax accountant. This was Olivia’s third visit to the psychiatric emergency unit because of suicide threats within 2 months. Though she was chronically suicidal, her current visit was triggered by a tax audit, which led her to view herself as an unwanted burden on society.

Historical perspective

Societal views of transgendered people vary. On one end of the spectrum is acceptance; in the middle is perhaps tolerance or mild discomfort at perceived abnormality; and at the other extreme are virulent hatred, discrimination, and invalidation of these individuals’ gender-affirming efforts.

Awareness of these hostile attitudes creates a vicious cycle of marginalization and mental illness among many transgender individuals.

Controversies surrounding sexual minorities are rooted in societal perceptions of gender delineations, and prevailing societal norms surrounding ethical and moral conduct. Most societies have a narrow perspective on gender, and seek to maintain a strict delineation of male and female identities, which contributes to the rejection of those with gender identity issues.^1,2 This often results in the invalidation of or active opposition to transgender individuals’ transition efforts. The reasons behind the rejection of transgender men and women are multifactorial, and can include a lack of awareness, homophobia, religious dogma, social stigmatization, and perceived non-employability – all often stemming largely from the lack of awareness that sexual identity and orientation are not a choice, but rather are predetermined by biological mechanisms. The intensifying familial, societal, political, and financial pressures all contribute to increased mental health issues, including increased incidence of suicide among sexual minorities.

Globally, sexual minorities continue to be subjected to gross human rights violations. Against the backdrop of prevalent social discrimination, transgender people experience a roughly threefold increase in the risk of developing anxiety disorders, which impair self-esteem and interpersonal functioning.³ The lifetime risk of attempted suicide is four times higher among transgender men, and two times higher among transgender women, than it is among cisgender men and women, respectively. Institutional discrimination in the public and private sectors results from laws and policies that impose inequities, or fail to protect sexual minorities. Examples are current policies denying medical coverage for sex reassignment surgery, denying health care by a provider because of transgender identity and numerous obstacles to obtain health insurance coverage.⁴

Impact of low acceptance

Recall Olivia’s need to delay the vocal cord surgery that arguably would have had a positive impact on her self-esteem. The transgender population faces increased health risks and barriers to appropriate mental health evaluation and inclusive care, particularly individuals with low acceptance from family, friends, and partners.⁵

A century ago, changing one’s gender was considered both highly disreputable and an impossible feat.⁶ Today, sex reassignment is the focus of political debate, with activists seeking equal rights for transgender individuals, despite the high rate of mental disorders in the community. While there is some positive public perception of transgender people, most still hold religious or moral objections to sex reassignment. Olivia’s family, for example, is typical in their rejection of her gender-affirming efforts. One example of this rejection is forbidding her to wear women’s clothing, stating that it makes them feel ashamed and subjects them to social ridicule.

As a result, Olivia lacks the social support that could work to remedy, to some extent, her suicidal ideation. Efforts to alleviate financial burdens that result from workplace discrimination, impediments to the pursuit of health, security, and happiness and the bureaucratic hurdles to gender affirmation are needed.^7,8 According to research by Kristen Clements-Nolle, PhD, MPH, and her associates, suicidality may be largely a reaction to the absence of legally secure equal rights for transgender men and women.⁹ In Olivia’s case, financial struggles with her mortgage, medical expenses for her autistic son, and anxiety about potentially losing the disability benefits on which she depends have added to her insecurity.

Financial insecurity resulting from her unemployment likely has exacerbated her feelings of inadequacy and depression. For example, because of her lack of financial resources, she had to delay the vocal cord surgery she desired. What would her prognosis be if her legal rights, including employment protection, were firmly in place? Likewise, the demands of parenting an autistic son posed another significant stressor that likely contributes to reciprocal stress for the child, resulting in the worsening of his autism symptoms.

In summary, transgender individuals face bias and discrimination in response to their gender-affirming efforts, which creates a vicious cycle of mental illness, suicidality, and societal marginalization. Addressing these endemic issues requires a multifaceted approach. Preventive strategies, including identification of mental health issues, and integration of mental health service with primary health care, are needed. Case registration, as a research measure to help understand the prevalence and severity of suicide among the LGBT population, would be beneficial.

Monitoring and follow-up of identified cases for supportive care (for example, gatekeeper training similar to the World Health Organization’s Suicide Prevention Initiative) also are needed to identify protective factors, in order to foster resilience in LGBT individuals facing negative reactions to disclosure of their sexual minority status. Legislation aimed at better facilitating a seamless integration of transgender men and women into mainstream society also is necessary. Supportive measures, particularly social supports promoting better mental health in trans individuals, could help reduce suicide rates. Finally, governmental initiatives to protect the human and constitutional rights of transgender people are key to minimizing the incidence of mental health issues and suicides among this vulnerable sexual minority group.

The path to addressing the issues faced by transgender individuals begins with education, which then leads to understanding. From understanding comes acceptance. Acceptance leads to equality – social, legal, and thereby, economic. Ensuring acceptance of all sexes as equal could mitigate the marginalization – in all its forms – experienced by gender-affirming individuals, with the end result being less mental illness and reduced rates of suicidality in this vulnerable population.⁷

Dr. Ahmed is a second-year resident in the department of psychiatry at the Nassau University Medical Center, East Meadow, New York. His interests include public social psychiatry, health care policy, health disparities, mental health stigma, and addiction psychiatry. Dr. Ahmed is a member of the American Psychiatric Association, the American Society of Clinical Psychopharmacology, and the American Association for Social Psychiatry.

References

1. LGBT Health. 2014 Jun;1(2):98-106.

2. Signs: Journal of Women in Culture and Society. 2006;32(1):83-111.

3. Int J Transgenderism. 2016:18(1):16-26.

4. Am J Public Health. 2014 Mar;104(3):e31-8.

5. Int J Transgenderism. 2017;18(1):104-18.

6. “Suicide attempts among transgender and gender non-conforming adults,” American Foundation for Suicide Prevention, 2014.

7. “Injustice at every turn: A report of the national transgender discrimination survey,” National Center for Transgender Equality, 2011.

8. J Gay Lesbian Soc Serv. 2014;26(2):186-206.

9. J Homosex. 2006;51(3):53-69.

What I thought would be a typical morning at the major county hospital – if that were ever possible on a psychiatric emergency unit (EU) – quickly turned atypical when I encountered a patient whom I will call Olivia.

Olivia is a 51-year-old male-to-female transgender woman who has not yet undergone gender reassignment surgery. She was brought to the EU by police, after expressing suicidal ideation during a phone call with a tax accountant. This was Olivia’s third visit to the psychiatric emergency unit because of suicide threats within 2 months. Though she was chronically suicidal, her current visit was triggered by a tax audit, which led her to view herself as an unwanted burden on society.

Historical perspective

Societal views of transgendered people vary. On one end of the spectrum is acceptance; in the middle is perhaps tolerance or mild discomfort at perceived abnormality; and at the other extreme are virulent hatred, discrimination, and invalidation of these individuals’ gender-affirming efforts.

Awareness of these hostile attitudes creates a vicious cycle of marginalization and mental illness among many transgender individuals.

Controversies surrounding sexual minorities are rooted in societal perceptions of gender delineations, and prevailing societal norms surrounding ethical and moral conduct. Most societies have a narrow perspective on gender, and seek to maintain a strict delineation of male and female identities, which contributes to the rejection of those with gender identity issues.^1,2 This often results in the invalidation of or active opposition to transgender individuals’ transition efforts. The reasons behind the rejection of transgender men and women are multifactorial, and can include a lack of awareness, homophobia, religious dogma, social stigmatization, and perceived non-employability – all often stemming largely from the lack of awareness that sexual identity and orientation are not a choice, but rather are predetermined by biological mechanisms. The intensifying familial, societal, political, and financial pressures all contribute to increased mental health issues, including increased incidence of suicide among sexual minorities.

Globally, sexual minorities continue to be subjected to gross human rights violations. Against the backdrop of prevalent social discrimination, transgender people experience a roughly threefold increase in the risk of developing anxiety disorders, which impair self-esteem and interpersonal functioning.³ The lifetime risk of attempted suicide is four times higher among transgender men, and two times higher among transgender women, than it is among cisgender men and women, respectively. Institutional discrimination in the public and private sectors results from laws and policies that impose inequities, or fail to protect sexual minorities. Examples are current policies denying medical coverage for sex reassignment surgery, denying health care by a provider because of transgender identity and numerous obstacles to obtain health insurance coverage.⁴

Impact of low acceptance

Recall Olivia’s need to delay the vocal cord surgery that arguably would have had a positive impact on her self-esteem. The transgender population faces increased health risks and barriers to appropriate mental health evaluation and inclusive care, particularly individuals with low acceptance from family, friends, and partners.⁵

A century ago, changing one’s gender was considered both highly disreputable and an impossible feat.⁶ Today, sex reassignment is the focus of political debate, with activists seeking equal rights for transgender individuals, despite the high rate of mental disorders in the community. While there is some positive public perception of transgender people, most still hold religious or moral objections to sex reassignment. Olivia’s family, for example, is typical in their rejection of her gender-affirming efforts. One example of this rejection is forbidding her to wear women’s clothing, stating that it makes them feel ashamed and subjects them to social ridicule.

As a result, Olivia lacks the social support that could work to remedy, to some extent, her suicidal ideation. Efforts to alleviate financial burdens that result from workplace discrimination, impediments to the pursuit of health, security, and happiness and the bureaucratic hurdles to gender affirmation are needed.^7,8 According to research by Kristen Clements-Nolle, PhD, MPH, and her associates, suicidality may be largely a reaction to the absence of legally secure equal rights for transgender men and women.⁹ In Olivia’s case, financial struggles with her mortgage, medical expenses for her autistic son, and anxiety about potentially losing the disability benefits on which she depends have added to her insecurity.

Financial insecurity resulting from her unemployment likely has exacerbated her feelings of inadequacy and depression. For example, because of her lack of financial resources, she had to delay the vocal cord surgery she desired. What would her prognosis be if her legal rights, including employment protection, were firmly in place? Likewise, the demands of parenting an autistic son posed another significant stressor that likely contributes to reciprocal stress for the child, resulting in the worsening of his autism symptoms.

In summary, transgender individuals face bias and discrimination in response to their gender-affirming efforts, which creates a vicious cycle of mental illness, suicidality, and societal marginalization. Addressing these endemic issues requires a multifaceted approach. Preventive strategies, including identification of mental health issues, and integration of mental health service with primary health care, are needed. Case registration, as a research measure to help understand the prevalence and severity of suicide among the LGBT population, would be beneficial.

Monitoring and follow-up of identified cases for supportive care (for example, gatekeeper training similar to the World Health Organization’s Suicide Prevention Initiative) also are needed to identify protective factors, in order to foster resilience in LGBT individuals facing negative reactions to disclosure of their sexual minority status. Legislation aimed at better facilitating a seamless integration of transgender men and women into mainstream society also is necessary. Supportive measures, particularly social supports promoting better mental health in trans individuals, could help reduce suicide rates. Finally, governmental initiatives to protect the human and constitutional rights of transgender people are key to minimizing the incidence of mental health issues and suicides among this vulnerable sexual minority group.

The path to addressing the issues faced by transgender individuals begins with education, which then leads to understanding. From understanding comes acceptance. Acceptance leads to equality – social, legal, and thereby, economic. Ensuring acceptance of all sexes as equal could mitigate the marginalization – in all its forms – experienced by gender-affirming individuals, with the end result being less mental illness and reduced rates of suicidality in this vulnerable population.⁷

Dr. Ahmed is a second-year resident in the department of psychiatry at the Nassau University Medical Center, East Meadow, New York. His interests include public social psychiatry, health care policy, health disparities, mental health stigma, and addiction psychiatry. Dr. Ahmed is a member of the American Psychiatric Association, the American Society of Clinical Psychopharmacology, and the American Association for Social Psychiatry.

References

1. LGBT Health. 2014 Jun;1(2):98-106.

2. Signs: Journal of Women in Culture and Society. 2006;32(1):83-111.

3. Int J Transgenderism. 2016:18(1):16-26.

4. Am J Public Health. 2014 Mar;104(3):e31-8.

5. Int J Transgenderism. 2017;18(1):104-18.

6. “Suicide attempts among transgender and gender non-conforming adults,” American Foundation for Suicide Prevention, 2014.

7. “Injustice at every turn: A report of the national transgender discrimination survey,” National Center for Transgender Equality, 2011.

8. J Gay Lesbian Soc Serv. 2014;26(2):186-206.

9. J Homosex. 2006;51(3):53-69.

MADRID – The evidence thus far comes only from animal models, but commonly encountered childhood infections may be able to trigger the development of leukemia in those children with certain genetic predispositions to B-cell precursor acute lymphoblastic leukemia (BCP-ALL).

Mice genetically modified to mimic BCP-ALL susceptibility and its most common subtype (ETV6-RUNX1 BCP-ALL) developed leukemia only after exposure to a common infectious environment.

[email protected]

MADRID – The evidence thus far comes only from animal models, but commonly encountered childhood infections may be able to trigger the development of leukemia in those children with certain genetic predispositions to B-cell precursor acute lymphoblastic leukemia (BCP-ALL).

Mice genetically modified to mimic BCP-ALL susceptibility and its most common subtype (ETV6-RUNX1 BCP-ALL) developed leukemia only after exposure to a common infectious environment.

[email protected]

MADRID – The evidence thus far comes only from animal models, but commonly encountered childhood infections may be able to trigger the development of leukemia in those children with certain genetic predispositions to B-cell precursor acute lymphoblastic leukemia (BCP-ALL).

Mice genetically modified to mimic BCP-ALL susceptibility and its most common subtype (ETV6-RUNX1 BCP-ALL) developed leukemia only after exposure to a common infectious environment.

[email protected]

Past and Current Psychiatric Symptoms

“One in three people with epilepsy will at some point in their lives have [a] psychiatric disorder,” said Dr. Kanner, citing a population-based study of 36,984 subjects that compared people with and without epilepsy in Canada. The data showed that one in four people have experienced suicidal ideation or a suicide attempt, one in five had a major depressive episode, and one in five had an anxiety disorder. Epilepsy is associated with premature mortality, and patients with epilepsy and a mood or anxiety disorder have a 12- to 32-fold higher risk of committing suicide than the general population does.

Psychiatric disorders often precede the onset of epilepsy, Dr. Kanner noted, and a family psychiatric history increases the likelihood of psychiatric disorders in patients with epilepsy. He pointed out that people with epilepsy have a five- to 20-fold higher risk of depression than does the general population, and that patients with depression have a two- to threefold higher risk of epilepsy. Patients with a history of suicidality may have a fivefold higher risk of epilepsy. “Therefore, there is a bidirectional relationship between these conditions.”

Patients who had psychiatric illness before the onset of epilepsy, as well as those with recurring mood and anxiety disorders, have an increased risk that AEDs will cause negative psychiatric symptoms. Phenobarbital, levetiracetam, topiramate, zonisamide, and perampanel are some of the AEDs associated with negative psychotropic properties, said Dr. Kanner. Carbamazepine, oxcarbazepine, valproic acid, lamotrigine, gabapentin, and pregabalin have positive psychotropic properties, which can often yield a therapeutic effect in patients with these conditions.

“Mood and anxiety disorders are more frequently seen in people with temporal and frontal lobe epilepsies, although we now recognize that people with generalized epilepsy are also at increased risk,” Dr. Kanner said. A large percentage of patients with a history of mood and anxiety disorders experience a recurrence of these symptoms within three to six months after temporal lobectomies, he added.

Clinical tools that neurologists can use to identify patients with psychiatric symptoms include the Neurological Disorders Depression Inventory for Epilepsy and Generalized Anxiety Disorder-7 scales.

Timing Is Important

Many physicians recognize when a patient’s depressive or anxiety episode is an interictal phenomenon, meaning that it occurs independently of the seizure. However, they often overlook peri-ictal psychiatric symptoms, Dr. Kanner said. Peri-ictal symptoms include preictal symptoms, which precede the onset of the seizure by two to three days, with the intensity of the symptoms increasing as the seizure gets closer; ictal symptoms, in which the psychiatric symptom is the clinical manifestation of the seizure; and postictal symptoms, which typically follow the seizure within 12 hours to five days.

Interictal psychiatric symptoms respond to pharmacotherapy or cognitive behavioral therapy, Dr. Kanner explained. Ictal phenomena abate with the treatment of the seizure. Preictal and postictal psychiatric symptoms typically do not respond to psychotropic medication.

“People with interictal psychiatric phenomena often have peri-ictal psychiatric symptoms as well,” Dr. Kanner noted. “It is not simply one or the other. It can be one and the other.” He added that iatrogenic psychiatric symptoms that result from psychopharmacologic treatment or surgical treatment are often overlooked.

Quality of Life

“Multiple studies in the last two decades have shown that depression and anxiety are associated with poor quality of life,” said Dr. Kanner. “In fact, in patients with intractable focal epilepsy and comorbid mood and anxiety disorders, the frequency and severity of seizures stop driving the quality of life, and the strongest predictors of poor quality of life end up being the presence of AED toxicity and comorbid mood and anxiety disorders.”

Postictal psychiatric symptoms are also an unrecognized cause of poor quality of life. For example, the median duration of postictal psychiatric symptoms is 24 hours, Dr. Kanner pointed out. “What is worse, a seizure that lasts one to two minutes or 24 hours of thinking, ‘How am I going to kill myself?’” Cognitive behavioral therapy is a good option for postictal symptoms that do not respond to pharmacotherapy. “We teach patients that they are dealing with short-duration, time-sensitive symptoms and show them strategies to overcome them, particularly suicidal ideation.”

Panic Attack or Ictal Fear?

Symptoms of fear that patients experience as part of their epileptic seizure are often misdiagnosed as a panic disorder, Dr. Kanner said. “However, by taking a careful history, physicians can identify red flags to help distinguish between the two.”

With panic disorder, for example, consciousness is usually preserved, whereas patients with ictal fear can report confusion, difficulty focusing, or the need to take a nap after the panic episode. Also, the duration of a panic attack is at least five minutes and can last up to 20 minutes with anxiety symptoms persisting for hours, while ictal fear typically lasts less than one minute. Patients with ictal panic may salivate excessively, but people with a panic attack have a dry mouth. Patients with ictal panic rarely experience agoraphobia, but those with panic attacks do. “Furthermore, the intensity of the fear is not as strong [in ictal fear] as that of the patient with a panic attack,” Dr. Kanner noted. “The panic attack patient has a feeling of impending doom. They think they are going to die.” The two conditions are not mutually exclusive, however. Patients with ictal fear have an increased risk of panic disorder, compared with the general population.

—Adriene Marshall

Suggested Reading

Alper K, Schwartz KA, Kolts RL, Khan A. Seizure incidence in psychopharmacological clinical trials: an analysis of Food and Drug Administration (FDA) summary basis of approval reports. Biol Psychiatry. 2007;62(4):345-354.

Kanner AM, Barry JJ, Gilliam F, et al. Depressive and anxiety disorders in epilepsy: do they differ in their potential to worsen common antiepileptic drug-related adverse events? Epilepsia. 2012;53(6):1104-1108.

Perucca P, Jacoby A, Marson AG, et al. Adverse antiepileptic drug effects in new-onset seizures: a case-control study. Neurology. 2011;76(3):273-279.

Tellez-Zenteno JF, Patten SB, Jetté N, et al. Psychiatric comorbidity in epilepsy: a population-based analysis. Epilepsia. 2007;48(12):2336-2344.

Past and Current Psychiatric Symptoms

“One in three people with epilepsy will at some point in their lives have [a] psychiatric disorder,” said Dr. Kanner, citing a population-based study of 36,984 subjects that compared people with and without epilepsy in Canada. The data showed that one in four people have experienced suicidal ideation or a suicide attempt, one in five had a major depressive episode, and one in five had an anxiety disorder. Epilepsy is associated with premature mortality, and patients with epilepsy and a mood or anxiety disorder have a 12- to 32-fold higher risk of committing suicide than the general population does.

Psychiatric disorders often precede the onset of epilepsy, Dr. Kanner noted, and a family psychiatric history increases the likelihood of psychiatric disorders in patients with epilepsy. He pointed out that people with epilepsy have a five- to 20-fold higher risk of depression than does the general population, and that patients with depression have a two- to threefold higher risk of epilepsy. Patients with a history of suicidality may have a fivefold higher risk of epilepsy. “Therefore, there is a bidirectional relationship between these conditions.”

Patients who had psychiatric illness before the onset of epilepsy, as well as those with recurring mood and anxiety disorders, have an increased risk that AEDs will cause negative psychiatric symptoms. Phenobarbital, levetiracetam, topiramate, zonisamide, and perampanel are some of the AEDs associated with negative psychotropic properties, said Dr. Kanner. Carbamazepine, oxcarbazepine, valproic acid, lamotrigine, gabapentin, and pregabalin have positive psychotropic properties, which can often yield a therapeutic effect in patients with these conditions.

“Mood and anxiety disorders are more frequently seen in people with temporal and frontal lobe epilepsies, although we now recognize that people with generalized epilepsy are also at increased risk,” Dr. Kanner said. A large percentage of patients with a history of mood and anxiety disorders experience a recurrence of these symptoms within three to six months after temporal lobectomies, he added.

Clinical tools that neurologists can use to identify patients with psychiatric symptoms include the Neurological Disorders Depression Inventory for Epilepsy and Generalized Anxiety Disorder-7 scales.

Timing Is Important

Many physicians recognize when a patient’s depressive or anxiety episode is an interictal phenomenon, meaning that it occurs independently of the seizure. However, they often overlook peri-ictal psychiatric symptoms, Dr. Kanner said. Peri-ictal symptoms include preictal symptoms, which precede the onset of the seizure by two to three days, with the intensity of the symptoms increasing as the seizure gets closer; ictal symptoms, in which the psychiatric symptom is the clinical manifestation of the seizure; and postictal symptoms, which typically follow the seizure within 12 hours to five days.

Interictal psychiatric symptoms respond to pharmacotherapy or cognitive behavioral therapy, Dr. Kanner explained. Ictal phenomena abate with the treatment of the seizure. Preictal and postictal psychiatric symptoms typically do not respond to psychotropic medication.

“People with interictal psychiatric phenomena often have peri-ictal psychiatric symptoms as well,” Dr. Kanner noted. “It is not simply one or the other. It can be one and the other.” He added that iatrogenic psychiatric symptoms that result from psychopharmacologic treatment or surgical treatment are often overlooked.

Quality of Life

“Multiple studies in the last two decades have shown that depression and anxiety are associated with poor quality of life,” said Dr. Kanner. “In fact, in patients with intractable focal epilepsy and comorbid mood and anxiety disorders, the frequency and severity of seizures stop driving the quality of life, and the strongest predictors of poor quality of life end up being the presence of AED toxicity and comorbid mood and anxiety disorders.”

Postictal psychiatric symptoms are also an unrecognized cause of poor quality of life. For example, the median duration of postictal psychiatric symptoms is 24 hours, Dr. Kanner pointed out. “What is worse, a seizure that lasts one to two minutes or 24 hours of thinking, ‘How am I going to kill myself?’” Cognitive behavioral therapy is a good option for postictal symptoms that do not respond to pharmacotherapy. “We teach patients that they are dealing with short-duration, time-sensitive symptoms and show them strategies to overcome them, particularly suicidal ideation.”

Panic Attack or Ictal Fear?

Symptoms of fear that patients experience as part of their epileptic seizure are often misdiagnosed as a panic disorder, Dr. Kanner said. “However, by taking a careful history, physicians can identify red flags to help distinguish between the two.”

With panic disorder, for example, consciousness is usually preserved, whereas patients with ictal fear can report confusion, difficulty focusing, or the need to take a nap after the panic episode. Also, the duration of a panic attack is at least five minutes and can last up to 20 minutes with anxiety symptoms persisting for hours, while ictal fear typically lasts less than one minute. Patients with ictal panic may salivate excessively, but people with a panic attack have a dry mouth. Patients with ictal panic rarely experience agoraphobia, but those with panic attacks do. “Furthermore, the intensity of the fear is not as strong [in ictal fear] as that of the patient with a panic attack,” Dr. Kanner noted. “The panic attack patient has a feeling of impending doom. They think they are going to die.” The two conditions are not mutually exclusive, however. Patients with ictal fear have an increased risk of panic disorder, compared with the general population.

—Adriene Marshall

Suggested Reading

Alper K, Schwartz KA, Kolts RL, Khan A. Seizure incidence in psychopharmacological clinical trials: an analysis of Food and Drug Administration (FDA) summary basis of approval reports. Biol Psychiatry. 2007;62(4):345-354.

Kanner AM, Barry JJ, Gilliam F, et al. Depressive and anxiety disorders in epilepsy: do they differ in their potential to worsen common antiepileptic drug-related adverse events? Epilepsia. 2012;53(6):1104-1108.

Perucca P, Jacoby A, Marson AG, et al. Adverse antiepileptic drug effects in new-onset seizures: a case-control study. Neurology. 2011;76(3):273-279.

Tellez-Zenteno JF, Patten SB, Jetté N, et al. Psychiatric comorbidity in epilepsy: a population-based analysis. Epilepsia. 2007;48(12):2336-2344.

Past and Current Psychiatric Symptoms

“One in three people with epilepsy will at some point in their lives have [a] psychiatric disorder,” said Dr. Kanner, citing a population-based study of 36,984 subjects that compared people with and without epilepsy in Canada. The data showed that one in four people have experienced suicidal ideation or a suicide attempt, one in five had a major depressive episode, and one in five had an anxiety disorder. Epilepsy is associated with premature mortality, and patients with epilepsy and a mood or anxiety disorder have a 12- to 32-fold higher risk of committing suicide than the general population does.

Psychiatric disorders often precede the onset of epilepsy, Dr. Kanner noted, and a family psychiatric history increases the likelihood of psychiatric disorders in patients with epilepsy. He pointed out that people with epilepsy have a five- to 20-fold higher risk of depression than does the general population, and that patients with depression have a two- to threefold higher risk of epilepsy. Patients with a history of suicidality may have a fivefold higher risk of epilepsy. “Therefore, there is a bidirectional relationship between these conditions.”

Patients who had psychiatric illness before the onset of epilepsy, as well as those with recurring mood and anxiety disorders, have an increased risk that AEDs will cause negative psychiatric symptoms. Phenobarbital, levetiracetam, topiramate, zonisamide, and perampanel are some of the AEDs associated with negative psychotropic properties, said Dr. Kanner. Carbamazepine, oxcarbazepine, valproic acid, lamotrigine, gabapentin, and pregabalin have positive psychotropic properties, which can often yield a therapeutic effect in patients with these conditions.

“Mood and anxiety disorders are more frequently seen in people with temporal and frontal lobe epilepsies, although we now recognize that people with generalized epilepsy are also at increased risk,” Dr. Kanner said. A large percentage of patients with a history of mood and anxiety disorders experience a recurrence of these symptoms within three to six months after temporal lobectomies, he added.

Clinical tools that neurologists can use to identify patients with psychiatric symptoms include the Neurological Disorders Depression Inventory for Epilepsy and Generalized Anxiety Disorder-7 scales.

Timing Is Important

Many physicians recognize when a patient’s depressive or anxiety episode is an interictal phenomenon, meaning that it occurs independently of the seizure. However, they often overlook peri-ictal psychiatric symptoms, Dr. Kanner said. Peri-ictal symptoms include preictal symptoms, which precede the onset of the seizure by two to three days, with the intensity of the symptoms increasing as the seizure gets closer; ictal symptoms, in which the psychiatric symptom is the clinical manifestation of the seizure; and postictal symptoms, which typically follow the seizure within 12 hours to five days.

Interictal psychiatric symptoms respond to pharmacotherapy or cognitive behavioral therapy, Dr. Kanner explained. Ictal phenomena abate with the treatment of the seizure. Preictal and postictal psychiatric symptoms typically do not respond to psychotropic medication.

“People with interictal psychiatric phenomena often have peri-ictal psychiatric symptoms as well,” Dr. Kanner noted. “It is not simply one or the other. It can be one and the other.” He added that iatrogenic psychiatric symptoms that result from psychopharmacologic treatment or surgical treatment are often overlooked.

Quality of Life

“Multiple studies in the last two decades have shown that depression and anxiety are associated with poor quality of life,” said Dr. Kanner. “In fact, in patients with intractable focal epilepsy and comorbid mood and anxiety disorders, the frequency and severity of seizures stop driving the quality of life, and the strongest predictors of poor quality of life end up being the presence of AED toxicity and comorbid mood and anxiety disorders.”

Postictal psychiatric symptoms are also an unrecognized cause of poor quality of life. For example, the median duration of postictal psychiatric symptoms is 24 hours, Dr. Kanner pointed out. “What is worse, a seizure that lasts one to two minutes or 24 hours of thinking, ‘How am I going to kill myself?’” Cognitive behavioral therapy is a good option for postictal symptoms that do not respond to pharmacotherapy. “We teach patients that they are dealing with short-duration, time-sensitive symptoms and show them strategies to overcome them, particularly suicidal ideation.”

Panic Attack or Ictal Fear?

Symptoms of fear that patients experience as part of their epileptic seizure are often misdiagnosed as a panic disorder, Dr. Kanner said. “However, by taking a careful history, physicians can identify red flags to help distinguish between the two.”

With panic disorder, for example, consciousness is usually preserved, whereas patients with ictal fear can report confusion, difficulty focusing, or the need to take a nap after the panic episode. Also, the duration of a panic attack is at least five minutes and can last up to 20 minutes with anxiety symptoms persisting for hours, while ictal fear typically lasts less than one minute. Patients with ictal panic may salivate excessively, but people with a panic attack have a dry mouth. Patients with ictal panic rarely experience agoraphobia, but those with panic attacks do. “Furthermore, the intensity of the fear is not as strong [in ictal fear] as that of the patient with a panic attack,” Dr. Kanner noted. “The panic attack patient has a feeling of impending doom. They think they are going to die.” The two conditions are not mutually exclusive, however. Patients with ictal fear have an increased risk of panic disorder, compared with the general population.

—Adriene Marshall

Suggested Reading

Alper K, Schwartz KA, Kolts RL, Khan A. Seizure incidence in psychopharmacological clinical trials: an analysis of Food and Drug Administration (FDA) summary basis of approval reports. Biol Psychiatry. 2007;62(4):345-354.

Kanner AM, Barry JJ, Gilliam F, et al. Depressive and anxiety disorders in epilepsy: do they differ in their potential to worsen common antiepileptic drug-related adverse events? Epilepsia. 2012;53(6):1104-1108.

Perucca P, Jacoby A, Marson AG, et al. Adverse antiepileptic drug effects in new-onset seizures: a case-control study. Neurology. 2011;76(3):273-279.

Tellez-Zenteno JF, Patten SB, Jetté N, et al. Psychiatric comorbidity in epilepsy: a population-based analysis. Epilepsia. 2007;48(12):2336-2344.

Betrixaban, a factor Xa inhibitor, has been approved for the prophylaxis of venous thromboembolism (VTE) in at-risk adult patients hospitalized with an acute illness, according to an announcement from the Food and Drug Administration.

Approval was based on results from a randomized, double-blind clinical trial in which over 7,000 hospitalized patients at risk for VTE received either extended-duration betrixaban (35-42 days) or short duration enoxaparin (6-14 days), a low molecular weight heparin administered subcutaneously. The rate of deep vein thrombosis, nonfatal pulmonary embolism, or VTE-related death was 4.4% among patients receiving betrixaban and 6% among patients receiving enoxaparin (relative risk, 0.75; 95% confidence interval: 0.61, 0.91).

Courtesy Wikimedia Commons/FitzColinGerald/Creative Commons License

[email protected]

Betrixaban, a factor Xa inhibitor, has been approved for the prophylaxis of venous thromboembolism (VTE) in at-risk adult patients hospitalized with an acute illness, according to an announcement from the Food and Drug Administration.

Approval was based on results from a randomized, double-blind clinical trial in which over 7,000 hospitalized patients at risk for VTE received either extended-duration betrixaban (35-42 days) or short duration enoxaparin (6-14 days), a low molecular weight heparin administered subcutaneously. The rate of deep vein thrombosis, nonfatal pulmonary embolism, or VTE-related death was 4.4% among patients receiving betrixaban and 6% among patients receiving enoxaparin (relative risk, 0.75; 95% confidence interval: 0.61, 0.91).

Courtesy Wikimedia Commons/FitzColinGerald/Creative Commons License

[email protected]

Betrixaban, a factor Xa inhibitor, has been approved for the prophylaxis of venous thromboembolism (VTE) in at-risk adult patients hospitalized with an acute illness, according to an announcement from the Food and Drug Administration.

Approval was based on results from a randomized, double-blind clinical trial in which over 7,000 hospitalized patients at risk for VTE received either extended-duration betrixaban (35-42 days) or short duration enoxaparin (6-14 days), a low molecular weight heparin administered subcutaneously. The rate of deep vein thrombosis, nonfatal pulmonary embolism, or VTE-related death was 4.4% among patients receiving betrixaban and 6% among patients receiving enoxaparin (relative risk, 0.75; 95% confidence interval: 0.61, 0.91).

Courtesy Wikimedia Commons/FitzColinGerald/Creative Commons License

[email protected]

WASHINGTON – Hospitals with a higher volume of transcatheter aortic valve replacements (TAVRs) have significantly lower 30-day readmission rates, according to an observational study.

In a study of 129 hospitals, those that performed more than 100 TAVR procedures had a 24% and 25% lower readmission rate compared with hospitals that performed 50 to100 TAVRs (P less than .001) and hospitals that performed fewer that 50 TAVRs (P = .007) respectively (JAMA Cardiol. 2017 May 11. doi: 10.1001/jamacardio.2017.1630).

This finding could have serious financial and medical implications for hospitals that are deciding whether or not to focus on this minimally invasive procedure, according to Sahil Khera, MD, MPH, chief resident and cardiology fellow at New York Medical College, Valhalla, and his colleagues.

“Lower readmission rates at high-volume hospitals substantially reduce health care expenditure,” said Dr. Khera and colleagues. “As new TAVR programs open across the country, these data will guide policymakers to identify targets for optimizing and standardizing TAVR outcomes across hospitals.”

To study the correlation between TAVR procedures and readmission rates, the investigators gathered records on hospitals that performed at least five TAVRs in 2014, which were then categorized into high-, medium-, or low-volume categories, and cross-referenced with the 2014 Nationwide Readmissions Database.

Of the 16,252 TAVR procedures conducted in 2014, 663 (4%), 3,067 (19%), and 12,522 (77%) were performed at low-, medium-, and high-volume hospitals, respectively, according to the investigators.

Patients undergoing these procedures were on average 81 years of age, with an average of four Elixhauser comorbidities, most commonly dyslipidemia (64%), hypertension (80%), heart failure (75%), and known coronary artery disease (69%), with a majority having undergone an endovascular procedure (83%).

However, the researchers found the population of TAVR patients of high volume hospitals were slightly younger, had fewer women, were more likely to be in a higher income household, and were less likely to undergo a transapical procedure than in low volume hospitals, which Dr. Khera and fellow researchers believe may have some impact on their findings.

“Low-volume hospitals were more likely to operate on patients with a higher number of comorbidities compared with high-volume hospitals and were more likely to use the TA approach,” according to investigators, “Transapical TAVR is associated with poorer short- and intermediate-term mortality, increased use of skilled nursing care facilities, longer hospital stays, and readmissions when compared with transfemoral TAVR.”

Overall, there were 2,667 readmissions reported, among which high volume hospitals reported a 30-day readmission rate of 15.6%, while low- and medium-volume hospitals reported similarly higher rates of 19.5% and 19%.

When looking into the causes for these readmissions, the investigators found that 1,619 (61%) were due to noncardiac causes, which appeared in all three hospitals, despite a larger proportion present in low-volume hospitals as opposed to medium and high-volume hospitals (65.6% vs. 60.1% and 60.6%, respectively).

“Infection, respiratory, endocrine/metabolic, renal, and trauma problems were more common in low-volume hospitals,” according to the researchers. “Whereas gastrointestinal and TIA/stroke issues were more common in medium and high volume hospitals.”

While price and length of stay did not differ among the volume categories, the investigators estimate the lower rate of readmissions saved high-volume hospitals approximately $6.5 million.

They found that while the difference of readmissions between hospital classifications narrowed when controlling for experience, the margin was still significant. They admitted, however, that the possibility of greater access to more technologically advanced TAVR in high-volume hospitals may affect the findings.

This study was limited by administrative nature of the database used, which does not make available information such as valve type, patient risk scores, or medications.

One investigator has received personal fees from Edwards Lifesciences and Medtronic; another has received grants and personal fees from various pharmaceutical companies, educational institutions, and publications; and a third has consulted for Medtronic.

[email protected]

On Twitter @eaztweets

WASHINGTON – Hospitals with a higher volume of transcatheter aortic valve replacements (TAVRs) have significantly lower 30-day readmission rates, according to an observational study.

In a study of 129 hospitals, those that performed more than 100 TAVR procedures had a 24% and 25% lower readmission rate compared with hospitals that performed 50 to100 TAVRs (P less than .001) and hospitals that performed fewer that 50 TAVRs (P = .007) respectively (JAMA Cardiol. 2017 May 11. doi: 10.1001/jamacardio.2017.1630).

This finding could have serious financial and medical implications for hospitals that are deciding whether or not to focus on this minimally invasive procedure, according to Sahil Khera, MD, MPH, chief resident and cardiology fellow at New York Medical College, Valhalla, and his colleagues.

“Lower readmission rates at high-volume hospitals substantially reduce health care expenditure,” said Dr. Khera and colleagues. “As new TAVR programs open across the country, these data will guide policymakers to identify targets for optimizing and standardizing TAVR outcomes across hospitals.”

To study the correlation between TAVR procedures and readmission rates, the investigators gathered records on hospitals that performed at least five TAVRs in 2014, which were then categorized into high-, medium-, or low-volume categories, and cross-referenced with the 2014 Nationwide Readmissions Database.

Of the 16,252 TAVR procedures conducted in 2014, 663 (4%), 3,067 (19%), and 12,522 (77%) were performed at low-, medium-, and high-volume hospitals, respectively, according to the investigators.

Patients undergoing these procedures were on average 81 years of age, with an average of four Elixhauser comorbidities, most commonly dyslipidemia (64%), hypertension (80%), heart failure (75%), and known coronary artery disease (69%), with a majority having undergone an endovascular procedure (83%).

However, the researchers found the population of TAVR patients of high volume hospitals were slightly younger, had fewer women, were more likely to be in a higher income household, and were less likely to undergo a transapical procedure than in low volume hospitals, which Dr. Khera and fellow researchers believe may have some impact on their findings.

“Low-volume hospitals were more likely to operate on patients with a higher number of comorbidities compared with high-volume hospitals and were more likely to use the TA approach,” according to investigators, “Transapical TAVR is associated with poorer short- and intermediate-term mortality, increased use of skilled nursing care facilities, longer hospital stays, and readmissions when compared with transfemoral TAVR.”

Overall, there were 2,667 readmissions reported, among which high volume hospitals reported a 30-day readmission rate of 15.6%, while low- and medium-volume hospitals reported similarly higher rates of 19.5% and 19%.

When looking into the causes for these readmissions, the investigators found that 1,619 (61%) were due to noncardiac causes, which appeared in all three hospitals, despite a larger proportion present in low-volume hospitals as opposed to medium and high-volume hospitals (65.6% vs. 60.1% and 60.6%, respectively).

“Infection, respiratory, endocrine/metabolic, renal, and trauma problems were more common in low-volume hospitals,” according to the researchers. “Whereas gastrointestinal and TIA/stroke issues were more common in medium and high volume hospitals.”

While price and length of stay did not differ among the volume categories, the investigators estimate the lower rate of readmissions saved high-volume hospitals approximately $6.5 million.

They found that while the difference of readmissions between hospital classifications narrowed when controlling for experience, the margin was still significant. They admitted, however, that the possibility of greater access to more technologically advanced TAVR in high-volume hospitals may affect the findings.

This study was limited by administrative nature of the database used, which does not make available information such as valve type, patient risk scores, or medications.

One investigator has received personal fees from Edwards Lifesciences and Medtronic; another has received grants and personal fees from various pharmaceutical companies, educational institutions, and publications; and a third has consulted for Medtronic.

[email protected]

On Twitter @eaztweets

WASHINGTON – Hospitals with a higher volume of transcatheter aortic valve replacements (TAVRs) have significantly lower 30-day readmission rates, according to an observational study.

In a study of 129 hospitals, those that performed more than 100 TAVR procedures had a 24% and 25% lower readmission rate compared with hospitals that performed 50 to100 TAVRs (P less than .001) and hospitals that performed fewer that 50 TAVRs (P = .007) respectively (JAMA Cardiol. 2017 May 11. doi: 10.1001/jamacardio.2017.1630).

This finding could have serious financial and medical implications for hospitals that are deciding whether or not to focus on this minimally invasive procedure, according to Sahil Khera, MD, MPH, chief resident and cardiology fellow at New York Medical College, Valhalla, and his colleagues.

“Lower readmission rates at high-volume hospitals substantially reduce health care expenditure,” said Dr. Khera and colleagues. “As new TAVR programs open across the country, these data will guide policymakers to identify targets for optimizing and standardizing TAVR outcomes across hospitals.”

To study the correlation between TAVR procedures and readmission rates, the investigators gathered records on hospitals that performed at least five TAVRs in 2014, which were then categorized into high-, medium-, or low-volume categories, and cross-referenced with the 2014 Nationwide Readmissions Database.

Of the 16,252 TAVR procedures conducted in 2014, 663 (4%), 3,067 (19%), and 12,522 (77%) were performed at low-, medium-, and high-volume hospitals, respectively, according to the investigators.

Patients undergoing these procedures were on average 81 years of age, with an average of four Elixhauser comorbidities, most commonly dyslipidemia (64%), hypertension (80%), heart failure (75%), and known coronary artery disease (69%), with a majority having undergone an endovascular procedure (83%).

However, the researchers found the population of TAVR patients of high volume hospitals were slightly younger, had fewer women, were more likely to be in a higher income household, and were less likely to undergo a transapical procedure than in low volume hospitals, which Dr. Khera and fellow researchers believe may have some impact on their findings.

“Low-volume hospitals were more likely to operate on patients with a higher number of comorbidities compared with high-volume hospitals and were more likely to use the TA approach,” according to investigators, “Transapical TAVR is associated with poorer short- and intermediate-term mortality, increased use of skilled nursing care facilities, longer hospital stays, and readmissions when compared with transfemoral TAVR.”

Overall, there were 2,667 readmissions reported, among which high volume hospitals reported a 30-day readmission rate of 15.6%, while low- and medium-volume hospitals reported similarly higher rates of 19.5% and 19%.

When looking into the causes for these readmissions, the investigators found that 1,619 (61%) were due to noncardiac causes, which appeared in all three hospitals, despite a larger proportion present in low-volume hospitals as opposed to medium and high-volume hospitals (65.6% vs. 60.1% and 60.6%, respectively).

“Infection, respiratory, endocrine/metabolic, renal, and trauma problems were more common in low-volume hospitals,” according to the researchers. “Whereas gastrointestinal and TIA/stroke issues were more common in medium and high volume hospitals.”

While price and length of stay did not differ among the volume categories, the investigators estimate the lower rate of readmissions saved high-volume hospitals approximately $6.5 million.

They found that while the difference of readmissions between hospital classifications narrowed when controlling for experience, the margin was still significant. They admitted, however, that the possibility of greater access to more technologically advanced TAVR in high-volume hospitals may affect the findings.

This study was limited by administrative nature of the database used, which does not make available information such as valve type, patient risk scores, or medications.

One investigator has received personal fees from Edwards Lifesciences and Medtronic; another has received grants and personal fees from various pharmaceutical companies, educational institutions, and publications; and a third has consulted for Medtronic.

[email protected]

On Twitter @eaztweets

CHICAGO – The efficacy of ibrutinib is durable for patients with relapsed chronic lymphocytic leukemia (CLL), and combination strategies are showing the potential to improve on this benefit, based on results from three studies reported in a poster discussion session at the annual meeting of the American Society of Clinical Oncology.

Ibrutinib monotherapy

In the phase III randomized RESONATE trial, funded by Pharmacyclics, investigators compared ibrutinib with ofatumumab (Arzerra), an anti-CD20 antibody, among 391 patients with CLL or small lymphocytic lymphoma (SLL), with cross-over allowed. Initial results favored ibrutinib.

Investigators led by John C. Byrd, MD, director of the division of hematology at the Ohio State University Comprehensive Cancer Center in Columbus, reported updated data in a poster session at the meeting, now with a median 44 months of follow-up in the ibrutinib arm.

Median progression-free survival was not reached with ibrutinib, compared with 8.1 months with ofatumumab (hazard ratio, 0.133). The 3-year rate of progression-free survival was 59% and 3%, respectively.

The pattern was generally similar across patients stratified by cytogenetics (deletion of 17p, deletion of 11q, or neither), IGHV and TP53 mutation status, and prior lines of therapy, reported Dr. Byrd, who disclosed that he receives research funding from Pharmacyclics, among other companies.

The 3-year overall survival rate for ibrutinib was 74%. In analyses adjusted for cross-over, patients given the inhibitor had a markedly lower risk of death than did peers given the antibody (HR, 0.37).

The overall response rate with ibrutinib was 91%. Although the rate of complete response increased with follow-up, it was still just 9%.

The most common grade 3 or worse adverse events were neutropenia (23%), pneumonia (17%), and anemia, thrombocytopenia, and hypertension (8% each). Of patients, 6% each had a major hemorrhage and grade 3 or worse atrial fibrillation.

“These long-term results from the international phase III RESONATE study show that extended treatment with ibrutinib is tolerable and continues to show sustained PFS in previously treated patients with CLL regardless of high-risk cytogenetics,” the investigators conclude. “Traditional poor prognostic factors for survival with chemoimmunotherapy, including del(17p) and del(11q), were not significant factors predictive of [progression-free survival] outcomes with ibrutinib therapy.”

Ibrutinib plus ublituximab and umbralisib

In a phase 1/1b trial funded by TG Therapeutics, investigators led by Loretta J. Nastoupil, MD, of the department of lymphoma/myeloma at the University of Texas MD Anderson Cancer Center, Houston, tested a triplet consisting of ibrutinib with ublituximab – another anti-CD20 antibody – and umbralisib (TGR-1202) – an oral PI3 kinase–delta inhibitor.

A total of 38 patients with generally heavily pretreated leukemias and lymphomas were studied, including 20 with CLL or SLL. Notably, eight patients (50%) with CLL had a 17p or 11q deletion.

The median time on study was 11.1 months, reported Dr. Nastoupil, who disclosed that she receives honoraria and research funding from TG Therapeutics and that she has relationships with other companies. The overall response rate for the 19 evaluable patients with CLL or SLL was 100% (complete response in 32%, partial response in 68%).

The main grade 3 or 4 adverse events in the entire trial population were neutropenia (18%) and pyrexia (8%). Only two patients discontinued treatment because of adverse events.

“An expansion cohort is ongoing at the highest dose, and we will clearly need more patients treated and longer follow-up to really know the efficacy,” commented Dr. Brown, the discussant for the poster session. “But overall, I think the safety looks encouraging with this combination.”

“Novel agent combinations are feasible and hold promise for deeper remission and/or time-limited therapy. Most of the excitement is focused around BTK and BCL-2 inhibitors, but there is clearly a role for kinase-kinase combinations because we see here that it was safe to combine ibrutinib with a PI3 kinase inhibitor,” she noted. “So, we should continue to pursue other kinase-kinase combinations, as well as BCL-2–kinase combinations.”
 

Ibrutinib plus CAR-T cells

In a pilot trial funded by Novartis, investigators led by Saar Gill, MD, PhD, of the hospital of the University of Pennsylvania in Philadelphia, tested the combination of ibrutinib with chimeric antigen receptor–T cells (CAR-T cells) against CD19, on the basis of preclinical evidence of synergy.

Trial participants were 10 patients with CLL or SLL who had not achieved complete response with ibrutinib. All had a 17p deletion or a p53 mutation, or a complex karyotype, and some had a known ibrutinib resistance mutation.

At 3 months, eight (89%) of nine evaluable patients had no evidence of disease in bone marrow, reported Dr. Gill, who disclosed that he receives research funding from Novartis (institutional) and has patents for CAR-T cells for acute myeloid leukemia, among other disclosures. Seven patients (78%) achieved a complete or partial radiographic response in the spleen and lymph nodes.

Overall, the treatment was well tolerated. One patient developed grade 4 tumor lysis syndrome, and two developed grade 3 cytokine release syndrome. But, none required anticytokine therapy.

Most patients remain on ibrutinib and are being monitored. In addition, the researchers plan to treat 25 more patients with the same combination.

“We don’t know what will happen if the patients stop ibrutinib at some point, which is a question for the future,” commented Dr. Brown, the discussant.

“CAR-T cell therapy in CLL has historically had lower response rates than in ALL, but preclinical and early clinical data support ongoing investigation of combination therapy with ibrutinib as it appears that ibrutinib may enhance the production and engraftment of the T cells,” she noted. “Ultimately, of course, the role of CAR-T cell therapy in CLL will require a very clear, well-defined safety [protocol] if it is being used in comparison to some of the oral drugs that we can maintain many of the patients on for a long time.”

CHICAGO – The efficacy of ibrutinib is durable for patients with relapsed chronic lymphocytic leukemia (CLL), and combination strategies are showing the potential to improve on this benefit, based on results from three studies reported in a poster discussion session at the annual meeting of the American Society of Clinical Oncology.

Ibrutinib monotherapy

In the phase III randomized RESONATE trial, funded by Pharmacyclics, investigators compared ibrutinib with ofatumumab (Arzerra), an anti-CD20 antibody, among 391 patients with CLL or small lymphocytic lymphoma (SLL), with cross-over allowed. Initial results favored ibrutinib.

Investigators led by John C. Byrd, MD, director of the division of hematology at the Ohio State University Comprehensive Cancer Center in Columbus, reported updated data in a poster session at the meeting, now with a median 44 months of follow-up in the ibrutinib arm.

Median progression-free survival was not reached with ibrutinib, compared with 8.1 months with ofatumumab (hazard ratio, 0.133). The 3-year rate of progression-free survival was 59% and 3%, respectively.

The pattern was generally similar across patients stratified by cytogenetics (deletion of 17p, deletion of 11q, or neither), IGHV and TP53 mutation status, and prior lines of therapy, reported Dr. Byrd, who disclosed that he receives research funding from Pharmacyclics, among other companies.

The 3-year overall survival rate for ibrutinib was 74%. In analyses adjusted for cross-over, patients given the inhibitor had a markedly lower risk of death than did peers given the antibody (HR, 0.37).

The overall response rate with ibrutinib was 91%. Although the rate of complete response increased with follow-up, it was still just 9%.

The most common grade 3 or worse adverse events were neutropenia (23%), pneumonia (17%), and anemia, thrombocytopenia, and hypertension (8% each). Of patients, 6% each had a major hemorrhage and grade 3 or worse atrial fibrillation.

“These long-term results from the international phase III RESONATE study show that extended treatment with ibrutinib is tolerable and continues to show sustained PFS in previously treated patients with CLL regardless of high-risk cytogenetics,” the investigators conclude. “Traditional poor prognostic factors for survival with chemoimmunotherapy, including del(17p) and del(11q), were not significant factors predictive of [progression-free survival] outcomes with ibrutinib therapy.”

Ibrutinib plus ublituximab and umbralisib

In a phase 1/1b trial funded by TG Therapeutics, investigators led by Loretta J. Nastoupil, MD, of the department of lymphoma/myeloma at the University of Texas MD Anderson Cancer Center, Houston, tested a triplet consisting of ibrutinib with ublituximab – another anti-CD20 antibody – and umbralisib (TGR-1202) – an oral PI3 kinase–delta inhibitor.

A total of 38 patients with generally heavily pretreated leukemias and lymphomas were studied, including 20 with CLL or SLL. Notably, eight patients (50%) with CLL had a 17p or 11q deletion.

The median time on study was 11.1 months, reported Dr. Nastoupil, who disclosed that she receives honoraria and research funding from TG Therapeutics and that she has relationships with other companies. The overall response rate for the 19 evaluable patients with CLL or SLL was 100% (complete response in 32%, partial response in 68%).

The main grade 3 or 4 adverse events in the entire trial population were neutropenia (18%) and pyrexia (8%). Only two patients discontinued treatment because of adverse events.

“An expansion cohort is ongoing at the highest dose, and we will clearly need more patients treated and longer follow-up to really know the efficacy,” commented Dr. Brown, the discussant for the poster session. “But overall, I think the safety looks encouraging with this combination.”

“Novel agent combinations are feasible and hold promise for deeper remission and/or time-limited therapy. Most of the excitement is focused around BTK and BCL-2 inhibitors, but there is clearly a role for kinase-kinase combinations because we see here that it was safe to combine ibrutinib with a PI3 kinase inhibitor,” she noted. “So, we should continue to pursue other kinase-kinase combinations, as well as BCL-2–kinase combinations.”
 

Ibrutinib plus CAR-T cells

In a pilot trial funded by Novartis, investigators led by Saar Gill, MD, PhD, of the hospital of the University of Pennsylvania in Philadelphia, tested the combination of ibrutinib with chimeric antigen receptor–T cells (CAR-T cells) against CD19, on the basis of preclinical evidence of synergy.

Trial participants were 10 patients with CLL or SLL who had not achieved complete response with ibrutinib. All had a 17p deletion or a p53 mutation, or a complex karyotype, and some had a known ibrutinib resistance mutation.

At 3 months, eight (89%) of nine evaluable patients had no evidence of disease in bone marrow, reported Dr. Gill, who disclosed that he receives research funding from Novartis (institutional) and has patents for CAR-T cells for acute myeloid leukemia, among other disclosures. Seven patients (78%) achieved a complete or partial radiographic response in the spleen and lymph nodes.

Overall, the treatment was well tolerated. One patient developed grade 4 tumor lysis syndrome, and two developed grade 3 cytokine release syndrome. But, none required anticytokine therapy.

Most patients remain on ibrutinib and are being monitored. In addition, the researchers plan to treat 25 more patients with the same combination.

“We don’t know what will happen if the patients stop ibrutinib at some point, which is a question for the future,” commented Dr. Brown, the discussant.

“CAR-T cell therapy in CLL has historically had lower response rates than in ALL, but preclinical and early clinical data support ongoing investigation of combination therapy with ibrutinib as it appears that ibrutinib may enhance the production and engraftment of the T cells,” she noted. “Ultimately, of course, the role of CAR-T cell therapy in CLL will require a very clear, well-defined safety [protocol] if it is being used in comparison to some of the oral drugs that we can maintain many of the patients on for a long time.”

CHICAGO – The efficacy of ibrutinib is durable for patients with relapsed chronic lymphocytic leukemia (CLL), and combination strategies are showing the potential to improve on this benefit, based on results from three studies reported in a poster discussion session at the annual meeting of the American Society of Clinical Oncology.

Ibrutinib monotherapy

In the phase III randomized RESONATE trial, funded by Pharmacyclics, investigators compared ibrutinib with ofatumumab (Arzerra), an anti-CD20 antibody, among 391 patients with CLL or small lymphocytic lymphoma (SLL), with cross-over allowed. Initial results favored ibrutinib.

Investigators led by John C. Byrd, MD, director of the division of hematology at the Ohio State University Comprehensive Cancer Center in Columbus, reported updated data in a poster session at the meeting, now with a median 44 months of follow-up in the ibrutinib arm.

Median progression-free survival was not reached with ibrutinib, compared with 8.1 months with ofatumumab (hazard ratio, 0.133). The 3-year rate of progression-free survival was 59% and 3%, respectively.

The pattern was generally similar across patients stratified by cytogenetics (deletion of 17p, deletion of 11q, or neither), IGHV and TP53 mutation status, and prior lines of therapy, reported Dr. Byrd, who disclosed that he receives research funding from Pharmacyclics, among other companies.

The 3-year overall survival rate for ibrutinib was 74%. In analyses adjusted for cross-over, patients given the inhibitor had a markedly lower risk of death than did peers given the antibody (HR, 0.37).

The overall response rate with ibrutinib was 91%. Although the rate of complete response increased with follow-up, it was still just 9%.

The most common grade 3 or worse adverse events were neutropenia (23%), pneumonia (17%), and anemia, thrombocytopenia, and hypertension (8% each). Of patients, 6% each had a major hemorrhage and grade 3 or worse atrial fibrillation.

“These long-term results from the international phase III RESONATE study show that extended treatment with ibrutinib is tolerable and continues to show sustained PFS in previously treated patients with CLL regardless of high-risk cytogenetics,” the investigators conclude. “Traditional poor prognostic factors for survival with chemoimmunotherapy, including del(17p) and del(11q), were not significant factors predictive of [progression-free survival] outcomes with ibrutinib therapy.”

Ibrutinib plus ublituximab and umbralisib

In a phase 1/1b trial funded by TG Therapeutics, investigators led by Loretta J. Nastoupil, MD, of the department of lymphoma/myeloma at the University of Texas MD Anderson Cancer Center, Houston, tested a triplet consisting of ibrutinib with ublituximab – another anti-CD20 antibody – and umbralisib (TGR-1202) – an oral PI3 kinase–delta inhibitor.

A total of 38 patients with generally heavily pretreated leukemias and lymphomas were studied, including 20 with CLL or SLL. Notably, eight patients (50%) with CLL had a 17p or 11q deletion.

The median time on study was 11.1 months, reported Dr. Nastoupil, who disclosed that she receives honoraria and research funding from TG Therapeutics and that she has relationships with other companies. The overall response rate for the 19 evaluable patients with CLL or SLL was 100% (complete response in 32%, partial response in 68%).

The main grade 3 or 4 adverse events in the entire trial population were neutropenia (18%) and pyrexia (8%). Only two patients discontinued treatment because of adverse events.

“An expansion cohort is ongoing at the highest dose, and we will clearly need more patients treated and longer follow-up to really know the efficacy,” commented Dr. Brown, the discussant for the poster session. “But overall, I think the safety looks encouraging with this combination.”

“Novel agent combinations are feasible and hold promise for deeper remission and/or time-limited therapy. Most of the excitement is focused around BTK and BCL-2 inhibitors, but there is clearly a role for kinase-kinase combinations because we see here that it was safe to combine ibrutinib with a PI3 kinase inhibitor,” she noted. “So, we should continue to pursue other kinase-kinase combinations, as well as BCL-2–kinase combinations.”
 

Ibrutinib plus CAR-T cells

In a pilot trial funded by Novartis, investigators led by Saar Gill, MD, PhD, of the hospital of the University of Pennsylvania in Philadelphia, tested the combination of ibrutinib with chimeric antigen receptor–T cells (CAR-T cells) against CD19, on the basis of preclinical evidence of synergy.

Trial participants were 10 patients with CLL or SLL who had not achieved complete response with ibrutinib. All had a 17p deletion or a p53 mutation, or a complex karyotype, and some had a known ibrutinib resistance mutation.

At 3 months, eight (89%) of nine evaluable patients had no evidence of disease in bone marrow, reported Dr. Gill, who disclosed that he receives research funding from Novartis (institutional) and has patents for CAR-T cells for acute myeloid leukemia, among other disclosures. Seven patients (78%) achieved a complete or partial radiographic response in the spleen and lymph nodes.

Overall, the treatment was well tolerated. One patient developed grade 4 tumor lysis syndrome, and two developed grade 3 cytokine release syndrome. But, none required anticytokine therapy.

Most patients remain on ibrutinib and are being monitored. In addition, the researchers plan to treat 25 more patients with the same combination.

“We don’t know what will happen if the patients stop ibrutinib at some point, which is a question for the future,” commented Dr. Brown, the discussant.

“CAR-T cell therapy in CLL has historically had lower response rates than in ALL, but preclinical and early clinical data support ongoing investigation of combination therapy with ibrutinib as it appears that ibrutinib may enhance the production and engraftment of the T cells,” she noted. “Ultimately, of course, the role of CAR-T cell therapy in CLL will require a very clear, well-defined safety [protocol] if it is being used in comparison to some of the oral drugs that we can maintain many of the patients on for a long time.”

Migraine is the most common disabling neurologic disease, with an estimated 1 billion sufferers worldwide.¹ In children aged 5-15 years, migraine prevalence is 10%, and these children miss more school than their peers.^2,3 Research specific to the child and adolescent migraine population is imperative, as the findings in adult studies do not always correlate or translate to pediatrics. The American Headache Society (AHS) held its 59th annual scientific meeting in Boston in June 2017, a meeting designed to showcase the latest advances in the field of headache medicine. Several interesting pediatric headache studies were presented.

Pediatric patient, parent goals and preferences for preventive treatment

There is a general consensus among headache specialists that migraine preventive treatment should be instituted when a migraineur has at least four headache days per month. Clinically, and in most research trials, migraine preventive treatment is considered effective when a 50% reduction in headache days or the headache frequency is reduced to no more than four headache days per month.

© Monkey Business Images Ltd./Thinkstockphotos.com

Premonitory symptoms

Migraine is disabling not simply because of the headache but because of the range of symptoms that occur around the headache. Migraine may involve four phases: premonitory, aura, headache, and postdrome. The premonitory phase involves symptoms that may occur hours to days prior to the headache. Functional imaging studies reveal hypothalamic activation during this phase.⁴ In a large retrospective study, premonitory symptoms occurred in approximately three-quarters of pediatric and adult migraineurs.⁵ In a prior pediatric chart review, the most common premonitory symptoms in order of decreasing frequency were fatigue, mood change, neck stiffness, and yawning.⁶

wckiw/ThinkStock

Mapping pain in pediatric migraine

Diagnosis of migraine is based on the International Classification of Headache Disorders 3rd edition beta (ICHD-3b). For adults with migraine, part of the diagnostic criteria requires at least two of a number of features: unilateral location, pulsating quality, moderate or severe pain intensity, or aggravation by or avoidance of routine physical activity. The comments section of the ICHD-3b mentions that, in children under 18 years, the pain may be bilateral.

This study sought to characterize the location and quality of headache pain in the pediatric and young adult population. Sixty migraineurs were enrolled and divided into three age groups: children (7-11 years), adolescents (12-18), and young adults (19-26). The patients were guided to use a diagram to draw pain location and quality. The pain was bilateral for the majority of patients in all age groups. Of the young adult group, 85% had bilateral headache. This is of interest, as adults with migraine are conventionally thought to have unilateral headache. The main descriptors among all three groups were throbbing, pounding, and pressing. In children, tightening was more common than throbbing.

When diagnosing migraine, it is helpful to take these differences into consideration. Overall, this study provides a better understanding of the quality and location of migraine in the pediatric and young adult population.
 

Efficacy of zolmitriptan nasal spray in adolescents

Zolmitriptan nasal spray (NS) was approved by the Food and Drug Administration in 2015 for acute migraine treatment in adolescents ages 12-17 years. This was the first triptan NS approved for use in pediatric migraine. The NS route benefits migraineurs who need a rapidly absorbed triptan or those who do not tolerate oral triptans because of significant nausea or emesis with their migraine. The efficacy of zolmitriptan NS in adolescents was established in a multicenter, double-blind, randomized placebo controlled study with 798 participants.⁷ The primary endpoint of pain freedom at 2 hours after treatment for the 5-mg dose was superior to placebo, 30% vs. 17%, respectively (P less than .001; odds ratio, 2.18; 95% confidence interval, 1.40, 3.39). Patients with migraine going from moderate or severe to mild or no headache at 2 hours post treatment were 51% vs. 39%, respectively (P = .010).

The follow-up study presented at AHS was a subgroup analysis of the above data in younger (12-14 years) and older (15-17 years) adolescents. The primary efficacy endpoint of being pain free at 2 hours post treatment was similarly better for zolmitriptan 5 mg, compared with placebo, in both the younger and older adolescent migraineurs.

This study reinforces that zolmitriptan 5-mg NS is an effective abortive migraine treatment in adolescents and is generally well tolerated.
 

New migraine treatments

Although not pediatric studies, several presentations addressed exciting new preventive treatments that target one of the main neuropeptides implicated in migraine pathophysiology, calcitonin gene related peptide. Four drug companies have completed phase II and phase III adult trials in which they have developed humanized monoclonal antibodies that bind to CGRP or its receptor. These medications have shown great promise and appear to be very well tolerated. These are the first medications developed specifically for migraine prevention, as opposed to current medications which we borrow from other fields of medicine. It is anticipated they will be available for use in adult migraineurs later this year.

Dr. Qubty is a pediatric headache specialist and an assistant professor of neurology at the University of California, San Francisco, and he is a member of the American Headache Society. He said he had no relevant financial disclosures.

*Correction, 8/10/2017: An earlier version of this article misstated the percentage of pediatric migraine patients who had premonitory signs, and  how common premonitory signs were among episodic migraineurs with and without aura.  

References

1. Lancet. 2016 Oct 8;388(10053):1545-1602.

2. Dev Med Child Neurol. 2010 Dec;52(12):1088-97.

3. Neurology. 2012 Oct 30;79(18):1881-8.

4. Brain. 2014 Jan;137(Pt 1):232-41.

5. Cephalalgia 2016;36:951-959.

6. J Headache Pain. 2016 Dec;17(1):94.

7. Headache. 2016 Jul;56(7):1107-19.

Migraine is the most common disabling neurologic disease, with an estimated 1 billion sufferers worldwide.¹ In children aged 5-15 years, migraine prevalence is 10%, and these children miss more school than their peers.^2,3 Research specific to the child and adolescent migraine population is imperative, as the findings in adult studies do not always correlate or translate to pediatrics. The American Headache Society (AHS) held its 59th annual scientific meeting in Boston in June 2017, a meeting designed to showcase the latest advances in the field of headache medicine. Several interesting pediatric headache studies were presented.

Pediatric patient, parent goals and preferences for preventive treatment

There is a general consensus among headache specialists that migraine preventive treatment should be instituted when a migraineur has at least four headache days per month. Clinically, and in most research trials, migraine preventive treatment is considered effective when a 50% reduction in headache days or the headache frequency is reduced to no more than four headache days per month.

© Monkey Business Images Ltd./Thinkstockphotos.com

Premonitory symptoms

Migraine is disabling not simply because of the headache but because of the range of symptoms that occur around the headache. Migraine may involve four phases: premonitory, aura, headache, and postdrome. The premonitory phase involves symptoms that may occur hours to days prior to the headache. Functional imaging studies reveal hypothalamic activation during this phase.⁴ In a large retrospective study, premonitory symptoms occurred in approximately three-quarters of pediatric and adult migraineurs.⁵ In a prior pediatric chart review, the most common premonitory symptoms in order of decreasing frequency were fatigue, mood change, neck stiffness, and yawning.⁶

wckiw/ThinkStock

Mapping pain in pediatric migraine

Diagnosis of migraine is based on the International Classification of Headache Disorders 3rd edition beta (ICHD-3b). For adults with migraine, part of the diagnostic criteria requires at least two of a number of features: unilateral location, pulsating quality, moderate or severe pain intensity, or aggravation by or avoidance of routine physical activity. The comments section of the ICHD-3b mentions that, in children under 18 years, the pain may be bilateral.

This study sought to characterize the location and quality of headache pain in the pediatric and young adult population. Sixty migraineurs were enrolled and divided into three age groups: children (7-11 years), adolescents (12-18), and young adults (19-26). The patients were guided to use a diagram to draw pain location and quality. The pain was bilateral for the majority of patients in all age groups. Of the young adult group, 85% had bilateral headache. This is of interest, as adults with migraine are conventionally thought to have unilateral headache. The main descriptors among all three groups were throbbing, pounding, and pressing. In children, tightening was more common than throbbing.

When diagnosing migraine, it is helpful to take these differences into consideration. Overall, this study provides a better understanding of the quality and location of migraine in the pediatric and young adult population.
 

Efficacy of zolmitriptan nasal spray in adolescents

Zolmitriptan nasal spray (NS) was approved by the Food and Drug Administration in 2015 for acute migraine treatment in adolescents ages 12-17 years. This was the first triptan NS approved for use in pediatric migraine. The NS route benefits migraineurs who need a rapidly absorbed triptan or those who do not tolerate oral triptans because of significant nausea or emesis with their migraine. The efficacy of zolmitriptan NS in adolescents was established in a multicenter, double-blind, randomized placebo controlled study with 798 participants.⁷ The primary endpoint of pain freedom at 2 hours after treatment for the 5-mg dose was superior to placebo, 30% vs. 17%, respectively (P less than .001; odds ratio, 2.18; 95% confidence interval, 1.40, 3.39). Patients with migraine going from moderate or severe to mild or no headache at 2 hours post treatment were 51% vs. 39%, respectively (P = .010).

The follow-up study presented at AHS was a subgroup analysis of the above data in younger (12-14 years) and older (15-17 years) adolescents. The primary efficacy endpoint of being pain free at 2 hours post treatment was similarly better for zolmitriptan 5 mg, compared with placebo, in both the younger and older adolescent migraineurs.

This study reinforces that zolmitriptan 5-mg NS is an effective abortive migraine treatment in adolescents and is generally well tolerated.
 

New migraine treatments

Although not pediatric studies, several presentations addressed exciting new preventive treatments that target one of the main neuropeptides implicated in migraine pathophysiology, calcitonin gene related peptide. Four drug companies have completed phase II and phase III adult trials in which they have developed humanized monoclonal antibodies that bind to CGRP or its receptor. These medications have shown great promise and appear to be very well tolerated. These are the first medications developed specifically for migraine prevention, as opposed to current medications which we borrow from other fields of medicine. It is anticipated they will be available for use in adult migraineurs later this year.

Dr. Qubty is a pediatric headache specialist and an assistant professor of neurology at the University of California, San Francisco, and he is a member of the American Headache Society. He said he had no relevant financial disclosures.

*Correction, 8/10/2017: An earlier version of this article misstated the percentage of pediatric migraine patients who had premonitory signs, and  how common premonitory signs were among episodic migraineurs with and without aura.  

References

1. Lancet. 2016 Oct 8;388(10053):1545-1602.

2. Dev Med Child Neurol. 2010 Dec;52(12):1088-97.

3. Neurology. 2012 Oct 30;79(18):1881-8.

4. Brain. 2014 Jan;137(Pt 1):232-41.

5. Cephalalgia 2016;36:951-959.

6. J Headache Pain. 2016 Dec;17(1):94.

7. Headache. 2016 Jul;56(7):1107-19.

Migraine is the most common disabling neurologic disease, with an estimated 1 billion sufferers worldwide.¹ In children aged 5-15 years, migraine prevalence is 10%, and these children miss more school than their peers.^2,3 Research specific to the child and adolescent migraine population is imperative, as the findings in adult studies do not always correlate or translate to pediatrics. The American Headache Society (AHS) held its 59th annual scientific meeting in Boston in June 2017, a meeting designed to showcase the latest advances in the field of headache medicine. Several interesting pediatric headache studies were presented.

Pediatric patient, parent goals and preferences for preventive treatment

There is a general consensus among headache specialists that migraine preventive treatment should be instituted when a migraineur has at least four headache days per month. Clinically, and in most research trials, migraine preventive treatment is considered effective when a 50% reduction in headache days or the headache frequency is reduced to no more than four headache days per month.

© Monkey Business Images Ltd./Thinkstockphotos.com

Premonitory symptoms

Migraine is disabling not simply because of the headache but because of the range of symptoms that occur around the headache. Migraine may involve four phases: premonitory, aura, headache, and postdrome. The premonitory phase involves symptoms that may occur hours to days prior to the headache. Functional imaging studies reveal hypothalamic activation during this phase.⁴ In a large retrospective study, premonitory symptoms occurred in approximately three-quarters of pediatric and adult migraineurs.⁵ In a prior pediatric chart review, the most common premonitory symptoms in order of decreasing frequency were fatigue, mood change, neck stiffness, and yawning.⁶

wckiw/ThinkStock

Mapping pain in pediatric migraine

Diagnosis of migraine is based on the International Classification of Headache Disorders 3rd edition beta (ICHD-3b). For adults with migraine, part of the diagnostic criteria requires at least two of a number of features: unilateral location, pulsating quality, moderate or severe pain intensity, or aggravation by or avoidance of routine physical activity. The comments section of the ICHD-3b mentions that, in children under 18 years, the pain may be bilateral.

This study sought to characterize the location and quality of headache pain in the pediatric and young adult population. Sixty migraineurs were enrolled and divided into three age groups: children (7-11 years), adolescents (12-18), and young adults (19-26). The patients were guided to use a diagram to draw pain location and quality. The pain was bilateral for the majority of patients in all age groups. Of the young adult group, 85% had bilateral headache. This is of interest, as adults with migraine are conventionally thought to have unilateral headache. The main descriptors among all three groups were throbbing, pounding, and pressing. In children, tightening was more common than throbbing.

When diagnosing migraine, it is helpful to take these differences into consideration. Overall, this study provides a better understanding of the quality and location of migraine in the pediatric and young adult population.
 

Efficacy of zolmitriptan nasal spray in adolescents

Zolmitriptan nasal spray (NS) was approved by the Food and Drug Administration in 2015 for acute migraine treatment in adolescents ages 12-17 years. This was the first triptan NS approved for use in pediatric migraine. The NS route benefits migraineurs who need a rapidly absorbed triptan or those who do not tolerate oral triptans because of significant nausea or emesis with their migraine. The efficacy of zolmitriptan NS in adolescents was established in a multicenter, double-blind, randomized placebo controlled study with 798 participants.⁷ The primary endpoint of pain freedom at 2 hours after treatment for the 5-mg dose was superior to placebo, 30% vs. 17%, respectively (P less than .001; odds ratio, 2.18; 95% confidence interval, 1.40, 3.39). Patients with migraine going from moderate or severe to mild or no headache at 2 hours post treatment were 51% vs. 39%, respectively (P = .010).

The follow-up study presented at AHS was a subgroup analysis of the above data in younger (12-14 years) and older (15-17 years) adolescents. The primary efficacy endpoint of being pain free at 2 hours post treatment was similarly better for zolmitriptan 5 mg, compared with placebo, in both the younger and older adolescent migraineurs.

This study reinforces that zolmitriptan 5-mg NS is an effective abortive migraine treatment in adolescents and is generally well tolerated.
 

New migraine treatments

Although not pediatric studies, several presentations addressed exciting new preventive treatments that target one of the main neuropeptides implicated in migraine pathophysiology, calcitonin gene related peptide. Four drug companies have completed phase II and phase III adult trials in which they have developed humanized monoclonal antibodies that bind to CGRP or its receptor. These medications have shown great promise and appear to be very well tolerated. These are the first medications developed specifically for migraine prevention, as opposed to current medications which we borrow from other fields of medicine. It is anticipated they will be available for use in adult migraineurs later this year.

Dr. Qubty is a pediatric headache specialist and an assistant professor of neurology at the University of California, San Francisco, and he is a member of the American Headache Society. He said he had no relevant financial disclosures.

*Correction, 8/10/2017: An earlier version of this article misstated the percentage of pediatric migraine patients who had premonitory signs, and  how common premonitory signs were among episodic migraineurs with and without aura.  

References

1. Lancet. 2016 Oct 8;388(10053):1545-1602.

2. Dev Med Child Neurol. 2010 Dec;52(12):1088-97.

3. Neurology. 2012 Oct 30;79(18):1881-8.

4. Brain. 2014 Jan;137(Pt 1):232-41.

5. Cephalalgia 2016;36:951-959.

6. J Headache Pain. 2016 Dec;17(1):94.

7. Headache. 2016 Jul;56(7):1107-19.