Patients with multiple sclerosis (MS) should follow local vaccine standards and receive the yearly influenza vaccine, unless there are specific contraindications, such as active treatment with immunosuppressive or immunomodulating agents, according to an American Academy of Neurology practice guideline.

itsmejust/Thinkstock

A summary of the guideline on vaccine-preventable infections and immunization in MS was published online Aug. 28 in Neurology. The new effort updates a 2002 guideline on this topic and incorporates new evidence, vaccines, and disease-modifying therapies (DMTs). The guideline was endorsed by the Consortium of Multiple Sclerosis Centers and by the Multiple Sclerosis Association of America.

To create the guideline, lead author Mauricio F. Farez, MD, of the Raúl Carrea Institute for Neurological Research (FLENI) in Buenos Aires and colleagues on the 17-member guideline panel performed a systematic review of the evidence and reached consensus on recommendations using a modified Delphi voting process. The review included randomized, controlled trials; cohort studies; and case-control studies published between 1990 and March 2018.

“Immunosuppressive or immunomodulating agents used to treat MS may suppress or modulate normal immune function. These drugs may increase susceptibility to infections and may reduce vaccine effectiveness because of a decreased ability to mount an immune response,” the authors said.

Based on its review of the evidence, principles of care, and inferences, the authors made the following eight recommendations:

• Clinicians should discuss with patients the evidence regarding immunization in MS (Level B). In addition, clinicians should examine patients’ opinions, preferences, and questions regarding immunizations (Level B).
• Clinicians should recommend that patients with MS follow all local vaccine standards in the absence of specific contraindications (Level B).
• Clinicians should consider local risks of vaccine-preventable diseases when counseling patients (Level B).
• Clinicians should recommend that patients with MS receive the influenza vaccination if there is no specific contraindication, such as a previous severe reaction (Level B).
• When treatment with an immunosuppressive or immunomodulating agent is considered, clinicians should counsel patients about infection risks associated with the specific medication and the treatment-specific vaccination guidance in the medication’s prescribing instructions (Level B). In addition, physicians should assess patients’ vaccination status before prescribing immunosuppressive or immunomodulating therapy and vaccinate patients according to local regulatory standards and treatment-specific infectious risks at least 4-6 weeks before initiating therapy, as advised by the prescribing information (Level B). Furthermore, clinicians may discuss the advantages of vaccination soon after MS diagnosis, regardless of initial therapeutic plans, to prevent delays should immunosuppressive or immunomodulating therapies be initiated in the future (Level C, based on variation in patient preferences).
• Clinicians must screen for certain infections (such as hepatitis, tuberculosis, and varicella zoster virus) according to a medication’s prescribing information before starting immunosuppressive or immunomodulating treatment (Level A) and should treat patients who have latent infections before MS treatment according to the medication prescribing information (Level B, based on feasibility and cost relative to benefit). Further, in high-risk populations or in countries with a high burden of infectious disease, clinicians must screen for latent infections before starting immunosuppressive or immunomodulating medications, even when such screening is not specifically mentioned in the prescribing information (Level A). Clinicians should consult infectious disease or other specialists about treating patients with latent infection before starting immunosuppressive or immunomodulating medications (Level B).
• Clinicians should recommend against live-attenuated vaccines in people with MS who receive immunosuppressive or immunomodulating therapies or have recently discontinued these therapies (Level B, based on importance of outcomes). When the risk of infection is high, clinicians may recommend live-attenuated vaccines if killed vaccines are unavailable (Level C, based on variation in patient preferences, benefit relative to harm, and importance of outcomes).
• If a patient with MS is experiencing a relapse, clinicians should delay vaccination until the relapse has clinically resolved or is no longer active, often many weeks after relapse onset (Level B).

Personal and population-level benefits

“There is no evidence that vaccination increases the risk of MS exacerbation, although the literature is sparse,” the authors said. “In addition to conferring personal benefits, vaccination of the MS patient population contributes to the well-established phenomenon of herd immunity for the communities in which patients with MS live,” the authors wrote.

Because influenza infection has known risks of exacerbation and morbidity, whereas influenza vaccine has no identified risks of exacerbation, “benefits of influenza vaccination outweigh the risks in most scenarios, although patients with MS receiving some [immunosuppressive or immunomodulating] treatments (fingolimod [Gilenya], glatiramer acetate [Copaxone], and mitoxantrone) may have a reduced response to influenza vaccination,” the authors said. Studies in patients with diseases other than MS suggest that rituximab (Rituxan) also may be associated with reduced influenza vaccine responsiveness.

Immunosuppressive or immunomodulatory medications including alemtuzumab (Lemtrada), dimethyl fumarate (Tecfidera), fingolimod, mitoxantrone, natalizumab (Tysabri), ocrelizumab (Ocrevus), rituximab, and teriflunomide (Aubagio) have been associated with severe occurrences or recurrences of vaccine-preventable infections, and many package inserts approved by the Food and Drug Administration provide guidance regarding immunization with live vaccines and treatment.

Prescribing information for alemtuzumab, fingolimod, ocrelizumab, and teriflunomide recommends against the use of live vaccines during and immediately preceding treatment. Furthermore, the prescribing information recommends waiting 2-6 months after treatment to immunize with live vaccines, depending on the half-life of the specific therapy.

“The guideline panel identified no evidence that vaccines increase the risk of relapse or worsen relapse severity, but studies are limited,” Dr. Farez and colleagues wrote. “Experts remain concerned that vaccines may worsen relapse severity if given to patients who are actively experiencing an MS relapse.” In addition, use of glucocorticoids may raise concerns about the safety of live-virus vaccines. “Immunization is not typically an urgent need and, in most cases, can be temporarily delayed without a marked increase in infection risk,” the guideline says.
 

Few high-quality studies

Data were lacking or insufficient to assess whether most vaccine-preventable diseases increase the risk of MS exacerbations. “It is probable that individuals with active MS exacerbations have higher odds of varicella zoster virus viral DNA present in peripheral blood mononuclear cells than individuals with MS in remission,” the guideline says.

Human papillomavirus, pertussis, and tetanus toxoid vaccinations probably are associated with a lower likelihood of a subsequent MS diagnosis, and smallpox vaccination is possibly associated with a lower likelihood of a subsequent MS diagnosis, the review found.

Studies included in the systematic review did not address whether live-attenuated vaccines are as effective in patients with MS as they are in the general population. With regard to the effectiveness of inactivated vaccines, patients with MS possibly are less likely to have a sufficient response to influenza vaccination, compared with controls.

The systematic review “found few high-quality studies to inform recommendations,” the authors said. “As more [immunosuppressive or immunomodulating] agents are developed to manage chronic diseases such as MS, long-term prospective cohort studies are required to evaluate both the safety and effectiveness of immunizations in MS.”

Dr. Farez has received funding for travel from Teva Argentina, Novartis Argentina, and Merck Serono Argentina and has received research support from Biogen. Coauthors’ disclosures included financial ties to pharmaceutical companies.

jremaly@mdedge.com

SOURCE: Farez M et al. Neurology. 2019 Aug 28. doi: 10.1212/WNL.0000000000008157.

Patients with multiple sclerosis (MS) should follow local vaccine standards and receive the yearly influenza vaccine, unless there are specific contraindications, such as active treatment with immunosuppressive or immunomodulating agents, according to an American Academy of Neurology practice guideline.

itsmejust/Thinkstock

A summary of the guideline on vaccine-preventable infections and immunization in MS was published online Aug. 28 in Neurology. The new effort updates a 2002 guideline on this topic and incorporates new evidence, vaccines, and disease-modifying therapies (DMTs). The guideline was endorsed by the Consortium of Multiple Sclerosis Centers and by the Multiple Sclerosis Association of America.

To create the guideline, lead author Mauricio F. Farez, MD, of the Raúl Carrea Institute for Neurological Research (FLENI) in Buenos Aires and colleagues on the 17-member guideline panel performed a systematic review of the evidence and reached consensus on recommendations using a modified Delphi voting process. The review included randomized, controlled trials; cohort studies; and case-control studies published between 1990 and March 2018.

“Immunosuppressive or immunomodulating agents used to treat MS may suppress or modulate normal immune function. These drugs may increase susceptibility to infections and may reduce vaccine effectiveness because of a decreased ability to mount an immune response,” the authors said.

Based on its review of the evidence, principles of care, and inferences, the authors made the following eight recommendations:

• Clinicians should discuss with patients the evidence regarding immunization in MS (Level B). In addition, clinicians should examine patients’ opinions, preferences, and questions regarding immunizations (Level B).
• Clinicians should recommend that patients with MS follow all local vaccine standards in the absence of specific contraindications (Level B).
• Clinicians should consider local risks of vaccine-preventable diseases when counseling patients (Level B).
• Clinicians should recommend that patients with MS receive the influenza vaccination if there is no specific contraindication, such as a previous severe reaction (Level B).
• When treatment with an immunosuppressive or immunomodulating agent is considered, clinicians should counsel patients about infection risks associated with the specific medication and the treatment-specific vaccination guidance in the medication’s prescribing instructions (Level B). In addition, physicians should assess patients’ vaccination status before prescribing immunosuppressive or immunomodulating therapy and vaccinate patients according to local regulatory standards and treatment-specific infectious risks at least 4-6 weeks before initiating therapy, as advised by the prescribing information (Level B). Furthermore, clinicians may discuss the advantages of vaccination soon after MS diagnosis, regardless of initial therapeutic plans, to prevent delays should immunosuppressive or immunomodulating therapies be initiated in the future (Level C, based on variation in patient preferences).
• Clinicians must screen for certain infections (such as hepatitis, tuberculosis, and varicella zoster virus) according to a medication’s prescribing information before starting immunosuppressive or immunomodulating treatment (Level A) and should treat patients who have latent infections before MS treatment according to the medication prescribing information (Level B, based on feasibility and cost relative to benefit). Further, in high-risk populations or in countries with a high burden of infectious disease, clinicians must screen for latent infections before starting immunosuppressive or immunomodulating medications, even when such screening is not specifically mentioned in the prescribing information (Level A). Clinicians should consult infectious disease or other specialists about treating patients with latent infection before starting immunosuppressive or immunomodulating medications (Level B).
• Clinicians should recommend against live-attenuated vaccines in people with MS who receive immunosuppressive or immunomodulating therapies or have recently discontinued these therapies (Level B, based on importance of outcomes). When the risk of infection is high, clinicians may recommend live-attenuated vaccines if killed vaccines are unavailable (Level C, based on variation in patient preferences, benefit relative to harm, and importance of outcomes).
• If a patient with MS is experiencing a relapse, clinicians should delay vaccination until the relapse has clinically resolved or is no longer active, often many weeks after relapse onset (Level B).

Personal and population-level benefits

“There is no evidence that vaccination increases the risk of MS exacerbation, although the literature is sparse,” the authors said. “In addition to conferring personal benefits, vaccination of the MS patient population contributes to the well-established phenomenon of herd immunity for the communities in which patients with MS live,” the authors wrote.

Because influenza infection has known risks of exacerbation and morbidity, whereas influenza vaccine has no identified risks of exacerbation, “benefits of influenza vaccination outweigh the risks in most scenarios, although patients with MS receiving some [immunosuppressive or immunomodulating] treatments (fingolimod [Gilenya], glatiramer acetate [Copaxone], and mitoxantrone) may have a reduced response to influenza vaccination,” the authors said. Studies in patients with diseases other than MS suggest that rituximab (Rituxan) also may be associated with reduced influenza vaccine responsiveness.

Immunosuppressive or immunomodulatory medications including alemtuzumab (Lemtrada), dimethyl fumarate (Tecfidera), fingolimod, mitoxantrone, natalizumab (Tysabri), ocrelizumab (Ocrevus), rituximab, and teriflunomide (Aubagio) have been associated with severe occurrences or recurrences of vaccine-preventable infections, and many package inserts approved by the Food and Drug Administration provide guidance regarding immunization with live vaccines and treatment.

Prescribing information for alemtuzumab, fingolimod, ocrelizumab, and teriflunomide recommends against the use of live vaccines during and immediately preceding treatment. Furthermore, the prescribing information recommends waiting 2-6 months after treatment to immunize with live vaccines, depending on the half-life of the specific therapy.

“The guideline panel identified no evidence that vaccines increase the risk of relapse or worsen relapse severity, but studies are limited,” Dr. Farez and colleagues wrote. “Experts remain concerned that vaccines may worsen relapse severity if given to patients who are actively experiencing an MS relapse.” In addition, use of glucocorticoids may raise concerns about the safety of live-virus vaccines. “Immunization is not typically an urgent need and, in most cases, can be temporarily delayed without a marked increase in infection risk,” the guideline says.
 

Few high-quality studies

Data were lacking or insufficient to assess whether most vaccine-preventable diseases increase the risk of MS exacerbations. “It is probable that individuals with active MS exacerbations have higher odds of varicella zoster virus viral DNA present in peripheral blood mononuclear cells than individuals with MS in remission,” the guideline says.

Human papillomavirus, pertussis, and tetanus toxoid vaccinations probably are associated with a lower likelihood of a subsequent MS diagnosis, and smallpox vaccination is possibly associated with a lower likelihood of a subsequent MS diagnosis, the review found.

Studies included in the systematic review did not address whether live-attenuated vaccines are as effective in patients with MS as they are in the general population. With regard to the effectiveness of inactivated vaccines, patients with MS possibly are less likely to have a sufficient response to influenza vaccination, compared with controls.

The systematic review “found few high-quality studies to inform recommendations,” the authors said. “As more [immunosuppressive or immunomodulating] agents are developed to manage chronic diseases such as MS, long-term prospective cohort studies are required to evaluate both the safety and effectiveness of immunizations in MS.”

Dr. Farez has received funding for travel from Teva Argentina, Novartis Argentina, and Merck Serono Argentina and has received research support from Biogen. Coauthors’ disclosures included financial ties to pharmaceutical companies.

jremaly@mdedge.com

SOURCE: Farez M et al. Neurology. 2019 Aug 28. doi: 10.1212/WNL.0000000000008157.

Patients with multiple sclerosis (MS) should follow local vaccine standards and receive the yearly influenza vaccine, unless there are specific contraindications, such as active treatment with immunosuppressive or immunomodulating agents, according to an American Academy of Neurology practice guideline.

itsmejust/Thinkstock

A summary of the guideline on vaccine-preventable infections and immunization in MS was published online Aug. 28 in Neurology. The new effort updates a 2002 guideline on this topic and incorporates new evidence, vaccines, and disease-modifying therapies (DMTs). The guideline was endorsed by the Consortium of Multiple Sclerosis Centers and by the Multiple Sclerosis Association of America.

To create the guideline, lead author Mauricio F. Farez, MD, of the Raúl Carrea Institute for Neurological Research (FLENI) in Buenos Aires and colleagues on the 17-member guideline panel performed a systematic review of the evidence and reached consensus on recommendations using a modified Delphi voting process. The review included randomized, controlled trials; cohort studies; and case-control studies published between 1990 and March 2018.

“Immunosuppressive or immunomodulating agents used to treat MS may suppress or modulate normal immune function. These drugs may increase susceptibility to infections and may reduce vaccine effectiveness because of a decreased ability to mount an immune response,” the authors said.

Based on its review of the evidence, principles of care, and inferences, the authors made the following eight recommendations:

• Clinicians should discuss with patients the evidence regarding immunization in MS (Level B). In addition, clinicians should examine patients’ opinions, preferences, and questions regarding immunizations (Level B).
• Clinicians should recommend that patients with MS follow all local vaccine standards in the absence of specific contraindications (Level B).
• Clinicians should consider local risks of vaccine-preventable diseases when counseling patients (Level B).
• Clinicians should recommend that patients with MS receive the influenza vaccination if there is no specific contraindication, such as a previous severe reaction (Level B).
• When treatment with an immunosuppressive or immunomodulating agent is considered, clinicians should counsel patients about infection risks associated with the specific medication and the treatment-specific vaccination guidance in the medication’s prescribing instructions (Level B). In addition, physicians should assess patients’ vaccination status before prescribing immunosuppressive or immunomodulating therapy and vaccinate patients according to local regulatory standards and treatment-specific infectious risks at least 4-6 weeks before initiating therapy, as advised by the prescribing information (Level B). Furthermore, clinicians may discuss the advantages of vaccination soon after MS diagnosis, regardless of initial therapeutic plans, to prevent delays should immunosuppressive or immunomodulating therapies be initiated in the future (Level C, based on variation in patient preferences).
• Clinicians must screen for certain infections (such as hepatitis, tuberculosis, and varicella zoster virus) according to a medication’s prescribing information before starting immunosuppressive or immunomodulating treatment (Level A) and should treat patients who have latent infections before MS treatment according to the medication prescribing information (Level B, based on feasibility and cost relative to benefit). Further, in high-risk populations or in countries with a high burden of infectious disease, clinicians must screen for latent infections before starting immunosuppressive or immunomodulating medications, even when such screening is not specifically mentioned in the prescribing information (Level A). Clinicians should consult infectious disease or other specialists about treating patients with latent infection before starting immunosuppressive or immunomodulating medications (Level B).
• Clinicians should recommend against live-attenuated vaccines in people with MS who receive immunosuppressive or immunomodulating therapies or have recently discontinued these therapies (Level B, based on importance of outcomes). When the risk of infection is high, clinicians may recommend live-attenuated vaccines if killed vaccines are unavailable (Level C, based on variation in patient preferences, benefit relative to harm, and importance of outcomes).
• If a patient with MS is experiencing a relapse, clinicians should delay vaccination until the relapse has clinically resolved or is no longer active, often many weeks after relapse onset (Level B).

Personal and population-level benefits

“There is no evidence that vaccination increases the risk of MS exacerbation, although the literature is sparse,” the authors said. “In addition to conferring personal benefits, vaccination of the MS patient population contributes to the well-established phenomenon of herd immunity for the communities in which patients with MS live,” the authors wrote.

Because influenza infection has known risks of exacerbation and morbidity, whereas influenza vaccine has no identified risks of exacerbation, “benefits of influenza vaccination outweigh the risks in most scenarios, although patients with MS receiving some [immunosuppressive or immunomodulating] treatments (fingolimod [Gilenya], glatiramer acetate [Copaxone], and mitoxantrone) may have a reduced response to influenza vaccination,” the authors said. Studies in patients with diseases other than MS suggest that rituximab (Rituxan) also may be associated with reduced influenza vaccine responsiveness.

Immunosuppressive or immunomodulatory medications including alemtuzumab (Lemtrada), dimethyl fumarate (Tecfidera), fingolimod, mitoxantrone, natalizumab (Tysabri), ocrelizumab (Ocrevus), rituximab, and teriflunomide (Aubagio) have been associated with severe occurrences or recurrences of vaccine-preventable infections, and many package inserts approved by the Food and Drug Administration provide guidance regarding immunization with live vaccines and treatment.

Prescribing information for alemtuzumab, fingolimod, ocrelizumab, and teriflunomide recommends against the use of live vaccines during and immediately preceding treatment. Furthermore, the prescribing information recommends waiting 2-6 months after treatment to immunize with live vaccines, depending on the half-life of the specific therapy.

“The guideline panel identified no evidence that vaccines increase the risk of relapse or worsen relapse severity, but studies are limited,” Dr. Farez and colleagues wrote. “Experts remain concerned that vaccines may worsen relapse severity if given to patients who are actively experiencing an MS relapse.” In addition, use of glucocorticoids may raise concerns about the safety of live-virus vaccines. “Immunization is not typically an urgent need and, in most cases, can be temporarily delayed without a marked increase in infection risk,” the guideline says.
 

Few high-quality studies

Data were lacking or insufficient to assess whether most vaccine-preventable diseases increase the risk of MS exacerbations. “It is probable that individuals with active MS exacerbations have higher odds of varicella zoster virus viral DNA present in peripheral blood mononuclear cells than individuals with MS in remission,” the guideline says.

Human papillomavirus, pertussis, and tetanus toxoid vaccinations probably are associated with a lower likelihood of a subsequent MS diagnosis, and smallpox vaccination is possibly associated with a lower likelihood of a subsequent MS diagnosis, the review found.

Studies included in the systematic review did not address whether live-attenuated vaccines are as effective in patients with MS as they are in the general population. With regard to the effectiveness of inactivated vaccines, patients with MS possibly are less likely to have a sufficient response to influenza vaccination, compared with controls.

The systematic review “found few high-quality studies to inform recommendations,” the authors said. “As more [immunosuppressive or immunomodulating] agents are developed to manage chronic diseases such as MS, long-term prospective cohort studies are required to evaluate both the safety and effectiveness of immunizations in MS.”

Dr. Farez has received funding for travel from Teva Argentina, Novartis Argentina, and Merck Serono Argentina and has received research support from Biogen. Coauthors’ disclosures included financial ties to pharmaceutical companies.

jremaly@mdedge.com

SOURCE: Farez M et al. Neurology. 2019 Aug 28. doi: 10.1212/WNL.0000000000008157.

Nivolumab has “limited intracranial activity” in patients with clear cell renal cell carcinoma (ccRCC) and previously untreated brain metastases, according to researchers.

In a phase 2 trial, nivolumab produced an intracranial response rate of 12% in ccRCC patients with previously untreated brain metastases.

The median intracranial progression-free survival (PFS) was longer among patients who had received prior focal therapy than among those with previously untreated brain metastases.

These results suggest “brain imaging and focal therapy should be considered before immune checkpoint inhibitors in patients with metastatic ccRCC,” Ronan Flippot, MD, of Université Paris-Saclay in Villejuif, France, and colleagues wrote in the Journal of Clinical Oncology.

Dr. Flippot and colleagues conducted this analysis of patients from the phase 2 GETUG-AFU 26 NIVOREN trial (NCT03013335). The researchers looked at 73 ccRCC patients with asymptomatic brain metastases who had received at least one prior line of antiangiogenic treatment.

Patients were divided into two cohorts. Cohort A included patients with previously untreated brain metastases (n = 39), and cohort B included patients who had received focal therapy for brain metastases (n = 34).

Baseline characteristics were similar between the cohorts. The median ages were 61 years in cohort A (range, 39-77) and 58 years in cohort B (range, 33-78). Most patients had grade 3-4 tumors (64% in cohort A and 78% in cohort B), and most had one brain lesion (67% and 59%, respectively). The median sum of the diameters of target lesions was 11 mm in cohort A and 17 mm in cohort B.

All patients received intravenous nivolumab at 3 mg/kg every 2 weeks until they progressed, developed unacceptable toxicity, died, withdrew consent, or the investigator stopped treatment.

The median follow-up was 23.6 months in cohort A and 20.2 months in cohort B. The median duration of treatment was 4.9 months and 4.5 months, respectively. Five patients in cohort A and four in cohort B were still receiving nivolumab at the data cutoff.

Response

The primary endpoint was the intracranial response rate in cohort A, which was 12%. All four responders achieved a complete response. At baseline, all of them had grade 1-2 disease and a single brain lesion smaller than 1 cm.

Thirteen patients (38%) in cohort A had stable intracranial disease as their best response, and 17 (50%) had progressive intracranial disease. The remaining five patients could not be evaluated because they progressed and died before the first evaluation.

The extracranial response rate in cohort A was 21%, and all seven responders had partial responses. Ten patients had stable extracranial disease (30%), and 16 had extracranial progression (49%). The remaining six patients were not evaluable for extracranial response.

All four patients who achieved a complete intracranial response had a partial extracranial response. Six patients (18%) had discordant intracranial and extracranial responses.
 

Survival

The median intracranial PFS in cohort A was 2.7 months in cohort A versus 4.8 months in cohort B. When the researchers adjusted for baseline characteristics, they found that prior focal therapy decreased the risk of intracranial progression (hazard ratio, 0.49).

The median extracranial PFS was 2.8 months in cohort A versus 2.6 months in cohort B. The median global PFS was 2.4 months in cohort A versus 2.5 months in cohort B.

The overall survival rates at 12 months were 66.7% in cohort A and 58.8% in cohort B.

Safety

The most common treatment-related adverse events (in cohort A and B, respectively) were asthenia (21% and 24%) and rash (10% and 9%).

Grade 3/4 treatment-related adverse events occurred in four patients in cohort A and five in cohort B. In cohort A, these events were asthenia, elevated liver function tests, dyspnea, and atrioventricular block. In cohort B, the events were diarrhea, musculoskeletal pain, psoriasis, hypophosphatemia, and elevated creatinine (in two patients).

The patient who developed atrioventricular block permanently discontinued nivolumab. There were no other treatment-related adverse events that led to discontinuation.

This study was supported by Bristol-Myers Squibb. The researchers disclosed relationships with Bristol-Myers Squibb and many other companies.

SOURCE: Flippot R et al. J Clin Oncol. 2019 Aug 10;37(23):2008-16.

Nivolumab has “limited intracranial activity” in patients with clear cell renal cell carcinoma (ccRCC) and previously untreated brain metastases, according to researchers.

In a phase 2 trial, nivolumab produced an intracranial response rate of 12% in ccRCC patients with previously untreated brain metastases.

The median intracranial progression-free survival (PFS) was longer among patients who had received prior focal therapy than among those with previously untreated brain metastases.

These results suggest “brain imaging and focal therapy should be considered before immune checkpoint inhibitors in patients with metastatic ccRCC,” Ronan Flippot, MD, of Université Paris-Saclay in Villejuif, France, and colleagues wrote in the Journal of Clinical Oncology.

Dr. Flippot and colleagues conducted this analysis of patients from the phase 2 GETUG-AFU 26 NIVOREN trial (NCT03013335). The researchers looked at 73 ccRCC patients with asymptomatic brain metastases who had received at least one prior line of antiangiogenic treatment.

Patients were divided into two cohorts. Cohort A included patients with previously untreated brain metastases (n = 39), and cohort B included patients who had received focal therapy for brain metastases (n = 34).

Baseline characteristics were similar between the cohorts. The median ages were 61 years in cohort A (range, 39-77) and 58 years in cohort B (range, 33-78). Most patients had grade 3-4 tumors (64% in cohort A and 78% in cohort B), and most had one brain lesion (67% and 59%, respectively). The median sum of the diameters of target lesions was 11 mm in cohort A and 17 mm in cohort B.

All patients received intravenous nivolumab at 3 mg/kg every 2 weeks until they progressed, developed unacceptable toxicity, died, withdrew consent, or the investigator stopped treatment.

The median follow-up was 23.6 months in cohort A and 20.2 months in cohort B. The median duration of treatment was 4.9 months and 4.5 months, respectively. Five patients in cohort A and four in cohort B were still receiving nivolumab at the data cutoff.

Response

The primary endpoint was the intracranial response rate in cohort A, which was 12%. All four responders achieved a complete response. At baseline, all of them had grade 1-2 disease and a single brain lesion smaller than 1 cm.

Thirteen patients (38%) in cohort A had stable intracranial disease as their best response, and 17 (50%) had progressive intracranial disease. The remaining five patients could not be evaluated because they progressed and died before the first evaluation.

The extracranial response rate in cohort A was 21%, and all seven responders had partial responses. Ten patients had stable extracranial disease (30%), and 16 had extracranial progression (49%). The remaining six patients were not evaluable for extracranial response.

All four patients who achieved a complete intracranial response had a partial extracranial response. Six patients (18%) had discordant intracranial and extracranial responses.
 

Survival

The median intracranial PFS in cohort A was 2.7 months in cohort A versus 4.8 months in cohort B. When the researchers adjusted for baseline characteristics, they found that prior focal therapy decreased the risk of intracranial progression (hazard ratio, 0.49).

The median extracranial PFS was 2.8 months in cohort A versus 2.6 months in cohort B. The median global PFS was 2.4 months in cohort A versus 2.5 months in cohort B.

The overall survival rates at 12 months were 66.7% in cohort A and 58.8% in cohort B.

Safety

The most common treatment-related adverse events (in cohort A and B, respectively) were asthenia (21% and 24%) and rash (10% and 9%).

Grade 3/4 treatment-related adverse events occurred in four patients in cohort A and five in cohort B. In cohort A, these events were asthenia, elevated liver function tests, dyspnea, and atrioventricular block. In cohort B, the events were diarrhea, musculoskeletal pain, psoriasis, hypophosphatemia, and elevated creatinine (in two patients).

The patient who developed atrioventricular block permanently discontinued nivolumab. There were no other treatment-related adverse events that led to discontinuation.

This study was supported by Bristol-Myers Squibb. The researchers disclosed relationships with Bristol-Myers Squibb and many other companies.

SOURCE: Flippot R et al. J Clin Oncol. 2019 Aug 10;37(23):2008-16.

Nivolumab has “limited intracranial activity” in patients with clear cell renal cell carcinoma (ccRCC) and previously untreated brain metastases, according to researchers.

In a phase 2 trial, nivolumab produced an intracranial response rate of 12% in ccRCC patients with previously untreated brain metastases.

The median intracranial progression-free survival (PFS) was longer among patients who had received prior focal therapy than among those with previously untreated brain metastases.

These results suggest “brain imaging and focal therapy should be considered before immune checkpoint inhibitors in patients with metastatic ccRCC,” Ronan Flippot, MD, of Université Paris-Saclay in Villejuif, France, and colleagues wrote in the Journal of Clinical Oncology.

Dr. Flippot and colleagues conducted this analysis of patients from the phase 2 GETUG-AFU 26 NIVOREN trial (NCT03013335). The researchers looked at 73 ccRCC patients with asymptomatic brain metastases who had received at least one prior line of antiangiogenic treatment.

Patients were divided into two cohorts. Cohort A included patients with previously untreated brain metastases (n = 39), and cohort B included patients who had received focal therapy for brain metastases (n = 34).

Baseline characteristics were similar between the cohorts. The median ages were 61 years in cohort A (range, 39-77) and 58 years in cohort B (range, 33-78). Most patients had grade 3-4 tumors (64% in cohort A and 78% in cohort B), and most had one brain lesion (67% and 59%, respectively). The median sum of the diameters of target lesions was 11 mm in cohort A and 17 mm in cohort B.

All patients received intravenous nivolumab at 3 mg/kg every 2 weeks until they progressed, developed unacceptable toxicity, died, withdrew consent, or the investigator stopped treatment.

The median follow-up was 23.6 months in cohort A and 20.2 months in cohort B. The median duration of treatment was 4.9 months and 4.5 months, respectively. Five patients in cohort A and four in cohort B were still receiving nivolumab at the data cutoff.

Response

The primary endpoint was the intracranial response rate in cohort A, which was 12%. All four responders achieved a complete response. At baseline, all of them had grade 1-2 disease and a single brain lesion smaller than 1 cm.

Thirteen patients (38%) in cohort A had stable intracranial disease as their best response, and 17 (50%) had progressive intracranial disease. The remaining five patients could not be evaluated because they progressed and died before the first evaluation.

The extracranial response rate in cohort A was 21%, and all seven responders had partial responses. Ten patients had stable extracranial disease (30%), and 16 had extracranial progression (49%). The remaining six patients were not evaluable for extracranial response.

All four patients who achieved a complete intracranial response had a partial extracranial response. Six patients (18%) had discordant intracranial and extracranial responses.
 

Survival

The median intracranial PFS in cohort A was 2.7 months in cohort A versus 4.8 months in cohort B. When the researchers adjusted for baseline characteristics, they found that prior focal therapy decreased the risk of intracranial progression (hazard ratio, 0.49).

The median extracranial PFS was 2.8 months in cohort A versus 2.6 months in cohort B. The median global PFS was 2.4 months in cohort A versus 2.5 months in cohort B.

The overall survival rates at 12 months were 66.7% in cohort A and 58.8% in cohort B.

Safety

The most common treatment-related adverse events (in cohort A and B, respectively) were asthenia (21% and 24%) and rash (10% and 9%).

Grade 3/4 treatment-related adverse events occurred in four patients in cohort A and five in cohort B. In cohort A, these events were asthenia, elevated liver function tests, dyspnea, and atrioventricular block. In cohort B, the events were diarrhea, musculoskeletal pain, psoriasis, hypophosphatemia, and elevated creatinine (in two patients).

The patient who developed atrioventricular block permanently discontinued nivolumab. There were no other treatment-related adverse events that led to discontinuation.

This study was supported by Bristol-Myers Squibb. The researchers disclosed relationships with Bristol-Myers Squibb and many other companies.

SOURCE: Flippot R et al. J Clin Oncol. 2019 Aug 10;37(23):2008-16.

Novel extended half-life factor VIII (FVIII) and factor IX (FIX) products appear to decrease the number of infusions and maintain higher trough levels, especially for patients with hemophilia B, according to recent survey findings.

Crystal/Wikimedia Commons/Creative Commons Attribution 2.0

Preliminary data from a European multinational survey suggest these benefits may help overcome current limitations with standard clotting factor products.

“We administered a survey to determine the efficacy of [extended half-life] products after they became available in several European countries,” wrote Flora Peyvandi, MD, PhD, of Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico in Milan and colleagues. These results were published in Haemophilia.

The questionnaire, designed by the European Association for Haemophilia and Allied Disorders (EAHAD), was distributed to 48 hemophilia treatment centers in January 2018. In total, 33 centers completed the survey.

The survey explored the real-life clinical experiences of patients with hemophilia A and B using extended half-life FVIII and FIX products. At the time of the survey, pegylated factor products were not available for use. In particular, the survey collected general information related to the efficacy of prophylaxis after transitioning patients to novel extended half-life products.

After analysis, the researchers found that among responding centers, extended half-life FVIII products decreased the number of infusions by 30% or greater among hemophilia A patients and achieved trough levels of 3%-5% in 66%-67% of centers.

With respect to FIX products, all responding centers were able to reduce infusions by more than 30% among hemophilia B patients, with 67% maintaining a FIX trough level of no less than 5%-10%.

The researchers acknowledged that the findings are preliminary and should be confirmed by conducting a repeat survey.

“Evaluating the safety of these new drugs is of the utmost importance and should be monitored through careful, long‐term observation,” they concluded.

No funding sources were reported. The authors reported financial affiliations with Alnylam, Grifols, Kedrion, Pfizer, Roche, Sanofi, Bayer, Shire, and several other companies.

SOURCE: Peyvandi F et al. Haemophilia. 2019 Aug 16. doi: 10.1111/hae.13834.

Novel extended half-life factor VIII (FVIII) and factor IX (FIX) products appear to decrease the number of infusions and maintain higher trough levels, especially for patients with hemophilia B, according to recent survey findings.

Crystal/Wikimedia Commons/Creative Commons Attribution 2.0

Preliminary data from a European multinational survey suggest these benefits may help overcome current limitations with standard clotting factor products.

“We administered a survey to determine the efficacy of [extended half-life] products after they became available in several European countries,” wrote Flora Peyvandi, MD, PhD, of Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico in Milan and colleagues. These results were published in Haemophilia.

The questionnaire, designed by the European Association for Haemophilia and Allied Disorders (EAHAD), was distributed to 48 hemophilia treatment centers in January 2018. In total, 33 centers completed the survey.

The survey explored the real-life clinical experiences of patients with hemophilia A and B using extended half-life FVIII and FIX products. At the time of the survey, pegylated factor products were not available for use. In particular, the survey collected general information related to the efficacy of prophylaxis after transitioning patients to novel extended half-life products.

After analysis, the researchers found that among responding centers, extended half-life FVIII products decreased the number of infusions by 30% or greater among hemophilia A patients and achieved trough levels of 3%-5% in 66%-67% of centers.

With respect to FIX products, all responding centers were able to reduce infusions by more than 30% among hemophilia B patients, with 67% maintaining a FIX trough level of no less than 5%-10%.

The researchers acknowledged that the findings are preliminary and should be confirmed by conducting a repeat survey.

“Evaluating the safety of these new drugs is of the utmost importance and should be monitored through careful, long‐term observation,” they concluded.

No funding sources were reported. The authors reported financial affiliations with Alnylam, Grifols, Kedrion, Pfizer, Roche, Sanofi, Bayer, Shire, and several other companies.

SOURCE: Peyvandi F et al. Haemophilia. 2019 Aug 16. doi: 10.1111/hae.13834.

Novel extended half-life factor VIII (FVIII) and factor IX (FIX) products appear to decrease the number of infusions and maintain higher trough levels, especially for patients with hemophilia B, according to recent survey findings.

Crystal/Wikimedia Commons/Creative Commons Attribution 2.0

Preliminary data from a European multinational survey suggest these benefits may help overcome current limitations with standard clotting factor products.

“We administered a survey to determine the efficacy of [extended half-life] products after they became available in several European countries,” wrote Flora Peyvandi, MD, PhD, of Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico in Milan and colleagues. These results were published in Haemophilia.

The questionnaire, designed by the European Association for Haemophilia and Allied Disorders (EAHAD), was distributed to 48 hemophilia treatment centers in January 2018. In total, 33 centers completed the survey.

The survey explored the real-life clinical experiences of patients with hemophilia A and B using extended half-life FVIII and FIX products. At the time of the survey, pegylated factor products were not available for use. In particular, the survey collected general information related to the efficacy of prophylaxis after transitioning patients to novel extended half-life products.

After analysis, the researchers found that among responding centers, extended half-life FVIII products decreased the number of infusions by 30% or greater among hemophilia A patients and achieved trough levels of 3%-5% in 66%-67% of centers.

With respect to FIX products, all responding centers were able to reduce infusions by more than 30% among hemophilia B patients, with 67% maintaining a FIX trough level of no less than 5%-10%.

The researchers acknowledged that the findings are preliminary and should be confirmed by conducting a repeat survey.

“Evaluating the safety of these new drugs is of the utmost importance and should be monitored through careful, long‐term observation,” they concluded.

No funding sources were reported. The authors reported financial affiliations with Alnylam, Grifols, Kedrion, Pfizer, Roche, Sanofi, Bayer, Shire, and several other companies.

SOURCE: Peyvandi F et al. Haemophilia. 2019 Aug 16. doi: 10.1111/hae.13834.

BANGKOK – Investigators at University College London have identified what appears to be an important mechanism underlying the efficacy of ketogenic diet therapy for seizure reduction in patients with drug-refractory epilepsy, then used that insight to develop a medium-chain triglyceride–based drink designed to address the well-known shortcomings of standard ketogenic diets.

Chief among those shortcomings is the notoriously poor compliance with these highly restrictive diets, which, as defining features, emphasize high fat intake and scrupulous restriction of carbohydrates in an effort to mimic the metabolic effects of starvation, J. Helen Cross, MD, explained at the International Epilepsy Congress.

She was a coauthor of a study led by Natasha E. Schoeler, PhD, a research dietician at the University College London Great Ormond Street Institute of Child Health, which demonstrated that children and adults with epilepsy who experience a significant antiseizure effect in response to ketogenic diet therapies have higher baseline blood levels of acetyl carnitine (Epilepsia. 2017 May;58(5):893-900).

The importance of this novel observation is twofold: It indicates a potential role for baseline acetyl carnitine level as a predictor of differential response to ketogenic diet therapies, a predictor for which there is an unmet need, and it is consistent with the hypothesis that an important potential mechanism of ketogenic diet effectiveness in epilepsy involves altered mitochondrial energy metabolism. That is because acetyl carnitine plays an essential role in mitochondrial uptake of long-chain fatty acids, noted Dr. Cross, professor of pediatric neurology and head of the developmental neurosciences program at the University College London Great Ormond Street Institute of Child Health.

At the congress sponsored by the International League Against Epilepsy, Dr. Cross and Dr. Schoeler presented the results of the initial 12-week tolerability study of Betashot, a ready-to-use, palatable blend of specific medium-chain triglycerides designed to be consumed three to four times daily with normal meals, limiting only intake of foods high in refined sugar. The Betashot beverage was developed in conjunction with Vitaflo International, a nutritional products company.

“It actually tastes good. It tastes like a strawberry shake,” according to Dr. Schoeler.

The 12-week study included 35 children with genetically caused forms of epilepsy and 26 adults with drug-resistant epilepsy. This was primarily a tolerability and compliance study, and the main finding was that two-thirds of the children and 69% of adults who started the study were still using Betashot at the 12-week mark. Moreover, 91% of the children and 56% of adults who completed the study elected to stay on Betashot afterwards. By week 12, after titrating their daily dose of Betashot upward as tolerated, the pediatric patients averaged 18% of their total daily energy intake from Betashot, the adults 24%.

The most common reasons for discontinuation among both children and adults were gastrointestinal side effects: abdominal discomfort, diarrhea, and/or vomiting.

“What’s exciting is that, even though the study is not powered to look at seizure response – it’s a tolerability study – we can report that there was a statistically significant reduction in the number of seizures in the group overall after 3 months of treatment,” Dr. Cross said.

She declined to provide specific data on seizure frequency because the study was underpowered for that endpoint. However, she added that further larger studies looking at a possible antiseizure effect of Betashot are ongoing.

The Betashot study was funded by Vitaflo International.

bjancin@mdedge.com

BANGKOK – Investigators at University College London have identified what appears to be an important mechanism underlying the efficacy of ketogenic diet therapy for seizure reduction in patients with drug-refractory epilepsy, then used that insight to develop a medium-chain triglyceride–based drink designed to address the well-known shortcomings of standard ketogenic diets.

Chief among those shortcomings is the notoriously poor compliance with these highly restrictive diets, which, as defining features, emphasize high fat intake and scrupulous restriction of carbohydrates in an effort to mimic the metabolic effects of starvation, J. Helen Cross, MD, explained at the International Epilepsy Congress.

She was a coauthor of a study led by Natasha E. Schoeler, PhD, a research dietician at the University College London Great Ormond Street Institute of Child Health, which demonstrated that children and adults with epilepsy who experience a significant antiseizure effect in response to ketogenic diet therapies have higher baseline blood levels of acetyl carnitine (Epilepsia. 2017 May;58(5):893-900).

The importance of this novel observation is twofold: It indicates a potential role for baseline acetyl carnitine level as a predictor of differential response to ketogenic diet therapies, a predictor for which there is an unmet need, and it is consistent with the hypothesis that an important potential mechanism of ketogenic diet effectiveness in epilepsy involves altered mitochondrial energy metabolism. That is because acetyl carnitine plays an essential role in mitochondrial uptake of long-chain fatty acids, noted Dr. Cross, professor of pediatric neurology and head of the developmental neurosciences program at the University College London Great Ormond Street Institute of Child Health.

At the congress sponsored by the International League Against Epilepsy, Dr. Cross and Dr. Schoeler presented the results of the initial 12-week tolerability study of Betashot, a ready-to-use, palatable blend of specific medium-chain triglycerides designed to be consumed three to four times daily with normal meals, limiting only intake of foods high in refined sugar. The Betashot beverage was developed in conjunction with Vitaflo International, a nutritional products company.

“It actually tastes good. It tastes like a strawberry shake,” according to Dr. Schoeler.

The 12-week study included 35 children with genetically caused forms of epilepsy and 26 adults with drug-resistant epilepsy. This was primarily a tolerability and compliance study, and the main finding was that two-thirds of the children and 69% of adults who started the study were still using Betashot at the 12-week mark. Moreover, 91% of the children and 56% of adults who completed the study elected to stay on Betashot afterwards. By week 12, after titrating their daily dose of Betashot upward as tolerated, the pediatric patients averaged 18% of their total daily energy intake from Betashot, the adults 24%.

The most common reasons for discontinuation among both children and adults were gastrointestinal side effects: abdominal discomfort, diarrhea, and/or vomiting.

“What’s exciting is that, even though the study is not powered to look at seizure response – it’s a tolerability study – we can report that there was a statistically significant reduction in the number of seizures in the group overall after 3 months of treatment,” Dr. Cross said.

She declined to provide specific data on seizure frequency because the study was underpowered for that endpoint. However, she added that further larger studies looking at a possible antiseizure effect of Betashot are ongoing.

The Betashot study was funded by Vitaflo International.

bjancin@mdedge.com

BANGKOK – Investigators at University College London have identified what appears to be an important mechanism underlying the efficacy of ketogenic diet therapy for seizure reduction in patients with drug-refractory epilepsy, then used that insight to develop a medium-chain triglyceride–based drink designed to address the well-known shortcomings of standard ketogenic diets.

Chief among those shortcomings is the notoriously poor compliance with these highly restrictive diets, which, as defining features, emphasize high fat intake and scrupulous restriction of carbohydrates in an effort to mimic the metabolic effects of starvation, J. Helen Cross, MD, explained at the International Epilepsy Congress.

She was a coauthor of a study led by Natasha E. Schoeler, PhD, a research dietician at the University College London Great Ormond Street Institute of Child Health, which demonstrated that children and adults with epilepsy who experience a significant antiseizure effect in response to ketogenic diet therapies have higher baseline blood levels of acetyl carnitine (Epilepsia. 2017 May;58(5):893-900).

The importance of this novel observation is twofold: It indicates a potential role for baseline acetyl carnitine level as a predictor of differential response to ketogenic diet therapies, a predictor for which there is an unmet need, and it is consistent with the hypothesis that an important potential mechanism of ketogenic diet effectiveness in epilepsy involves altered mitochondrial energy metabolism. That is because acetyl carnitine plays an essential role in mitochondrial uptake of long-chain fatty acids, noted Dr. Cross, professor of pediatric neurology and head of the developmental neurosciences program at the University College London Great Ormond Street Institute of Child Health.

At the congress sponsored by the International League Against Epilepsy, Dr. Cross and Dr. Schoeler presented the results of the initial 12-week tolerability study of Betashot, a ready-to-use, palatable blend of specific medium-chain triglycerides designed to be consumed three to four times daily with normal meals, limiting only intake of foods high in refined sugar. The Betashot beverage was developed in conjunction with Vitaflo International, a nutritional products company.

“It actually tastes good. It tastes like a strawberry shake,” according to Dr. Schoeler.

The 12-week study included 35 children with genetically caused forms of epilepsy and 26 adults with drug-resistant epilepsy. This was primarily a tolerability and compliance study, and the main finding was that two-thirds of the children and 69% of adults who started the study were still using Betashot at the 12-week mark. Moreover, 91% of the children and 56% of adults who completed the study elected to stay on Betashot afterwards. By week 12, after titrating their daily dose of Betashot upward as tolerated, the pediatric patients averaged 18% of their total daily energy intake from Betashot, the adults 24%.

The most common reasons for discontinuation among both children and adults were gastrointestinal side effects: abdominal discomfort, diarrhea, and/or vomiting.

“What’s exciting is that, even though the study is not powered to look at seizure response – it’s a tolerability study – we can report that there was a statistically significant reduction in the number of seizures in the group overall after 3 months of treatment,” Dr. Cross said.

She declined to provide specific data on seizure frequency because the study was underpowered for that endpoint. However, she added that further larger studies looking at a possible antiseizure effect of Betashot are ongoing.

The Betashot study was funded by Vitaflo International.

bjancin@mdedge.com

Combination quercetin and desferrioxamine could decrease iron overload in patients with transfusion-dependent beta-thalassemia major, according to a randomized clinical study.

Over the course of treatment, quercetin was well tolerated and no major complications were reported. The findings highlight the potential of quercetin to lower ferritin levels in patients with thalassemia major.

“Quercetin is a member of flavone family that mainly exists in apples, onions, tea, red wines, and berries,” wrote Zohreh Sajadi Hezaveh of Iran University of Medical Sciences in Tehran and colleagues. The findings of the study were published in Complementary Therapies in Medicine.

The researchers conducted a randomized, double-blind trial of 84 patients with thalassemia major. Of those enrolled, 71 patients were included in the final analysis.

Study patients were randomly assigned to receive either oral quercetin 500 mg daily or placebo for a total of 12 weeks. At baseline, all patients received desferrioxamine monotherapy. All participants were enrolled in the single-center study from April 2017 to March 2018. The team measured several inflammatory and iron-related markers during the study.

In comparison with placebo, combined therapy significantly improved high sensitivity C-reactive protein (P = .046), ferritin (P = .043), serum iron (P = .036), transferrin (P = .045), and transferrin saturation (P = .008), but not tumor necrosis factor–alpha (P = .310) or total iron-binding capacity (P = .734).

With respect to ferritin levels, a significant decrease was observed in the quercetin group, while patients in the placebo group had a marginal increase in levels.

“Insignificant results for [tumor necrosis factor–alpha] prevents us from making definitive comments [about inflammation],” the researchers wrote.

One key limitation of the study was the significant loss to follow-up seen in the placebo group. As a result, the generalizability of the findings may be limited.

“These results need to be confirmed by studies with larger sample size, longer follow-up period, and different doses of quercetin,” the researchers concluded.

The study was funded by the Iran University of Medical Sciences. The authors reported having no conflicts of interest.

SOURCE: Sajadi Hezaveh Z et al. Complement Ther Med. 2019;46:24-8.

Combination quercetin and desferrioxamine could decrease iron overload in patients with transfusion-dependent beta-thalassemia major, according to a randomized clinical study.

Over the course of treatment, quercetin was well tolerated and no major complications were reported. The findings highlight the potential of quercetin to lower ferritin levels in patients with thalassemia major.

“Quercetin is a member of flavone family that mainly exists in apples, onions, tea, red wines, and berries,” wrote Zohreh Sajadi Hezaveh of Iran University of Medical Sciences in Tehran and colleagues. The findings of the study were published in Complementary Therapies in Medicine.

The researchers conducted a randomized, double-blind trial of 84 patients with thalassemia major. Of those enrolled, 71 patients were included in the final analysis.

Study patients were randomly assigned to receive either oral quercetin 500 mg daily or placebo for a total of 12 weeks. At baseline, all patients received desferrioxamine monotherapy. All participants were enrolled in the single-center study from April 2017 to March 2018. The team measured several inflammatory and iron-related markers during the study.

In comparison with placebo, combined therapy significantly improved high sensitivity C-reactive protein (P = .046), ferritin (P = .043), serum iron (P = .036), transferrin (P = .045), and transferrin saturation (P = .008), but not tumor necrosis factor–alpha (P = .310) or total iron-binding capacity (P = .734).

With respect to ferritin levels, a significant decrease was observed in the quercetin group, while patients in the placebo group had a marginal increase in levels.

“Insignificant results for [tumor necrosis factor–alpha] prevents us from making definitive comments [about inflammation],” the researchers wrote.

One key limitation of the study was the significant loss to follow-up seen in the placebo group. As a result, the generalizability of the findings may be limited.

“These results need to be confirmed by studies with larger sample size, longer follow-up period, and different doses of quercetin,” the researchers concluded.

The study was funded by the Iran University of Medical Sciences. The authors reported having no conflicts of interest.

SOURCE: Sajadi Hezaveh Z et al. Complement Ther Med. 2019;46:24-8.

Combination quercetin and desferrioxamine could decrease iron overload in patients with transfusion-dependent beta-thalassemia major, according to a randomized clinical study.

Over the course of treatment, quercetin was well tolerated and no major complications were reported. The findings highlight the potential of quercetin to lower ferritin levels in patients with thalassemia major.

“Quercetin is a member of flavone family that mainly exists in apples, onions, tea, red wines, and berries,” wrote Zohreh Sajadi Hezaveh of Iran University of Medical Sciences in Tehran and colleagues. The findings of the study were published in Complementary Therapies in Medicine.

The researchers conducted a randomized, double-blind trial of 84 patients with thalassemia major. Of those enrolled, 71 patients were included in the final analysis.

Study patients were randomly assigned to receive either oral quercetin 500 mg daily or placebo for a total of 12 weeks. At baseline, all patients received desferrioxamine monotherapy. All participants were enrolled in the single-center study from April 2017 to March 2018. The team measured several inflammatory and iron-related markers during the study.

In comparison with placebo, combined therapy significantly improved high sensitivity C-reactive protein (P = .046), ferritin (P = .043), serum iron (P = .036), transferrin (P = .045), and transferrin saturation (P = .008), but not tumor necrosis factor–alpha (P = .310) or total iron-binding capacity (P = .734).

With respect to ferritin levels, a significant decrease was observed in the quercetin group, while patients in the placebo group had a marginal increase in levels.

“Insignificant results for [tumor necrosis factor–alpha] prevents us from making definitive comments [about inflammation],” the researchers wrote.

One key limitation of the study was the significant loss to follow-up seen in the placebo group. As a result, the generalizability of the findings may be limited.

“These results need to be confirmed by studies with larger sample size, longer follow-up period, and different doses of quercetin,” the researchers concluded.

The study was funded by the Iran University of Medical Sciences. The authors reported having no conflicts of interest.

SOURCE: Sajadi Hezaveh Z et al. Complement Ther Med. 2019;46:24-8.

SEATTLE – If your hospital’s methicillin-resistant Staphylococcus aureus rate is less than 10%, cefazolin is a reasonable empiric choice for pediatric acute hematogenous osteomyelitis (AHO). It covers the usual suspects: methicillin-susceptible Staphylococcus aureus, group A Streptococcus, and Kingella.

Above the 10% mark, coverage should include considerations of MRSA; clindamycin is good option so long as 85% of isolates are susceptible. Above that, it’s time for vancomycin, according to Nivedita Srinivas, MD, a pediatric infectious disease specialist at Stanford (Calif.) University.

There are no practice guidelines in the United States for the diagnosis and management of AHO in children; Dr. Srinivas and colleagues sought to plug the gaps in a talk at Pediatric Hospitalist Medicine.

Pediatric AHO is more common in children under 5 years old and in boys. Lower extremities are the usual targets. Staphylococcus aureus, group B Streptococcus, and gram negatives are the most common causes in newborns; Staphylococcus aureus, group A Streptococcus, and Kingella in older infants and preschoolers; and Staphylococcus aureus and group A Streptococcus in older children.

About half the time, treatment remains empiric because nothing grows out on culture, and there are a few clinical pearls to keep in mind in those cases. A family history of boils or spider bites is suspicious for MRSA, and coverage should include Salmonella in children with abnormal hemoglobins and Streptococcus pneumoniae in children without a spleen or with functional asplenia. Pseudomonas has to be kept in mind with puncture wounds, and Brucella in children who drink unpasteurized milk, Dr. Srinivas said.

A switch from IV to oral therapy is appropriate when C-reactive protein (CRP) drops 50% from its peak or below 3 mg/dL, positive cultures – if any – turn negative, fever has been absent for 24 hours, there’s no sign of metastatic disease, and patients have markedly reduced pain and can bear weight on the infected limb, said copresenter Marie Wang, MD, also a pediatric infectious disease specialist at Stanford.

The oral switch, of course, must have similar coverage as the IV antibiotic: high-dose cephalexin for cefazolin, for instance. Children can be sent home on a PICC line to continue IV treatment, but they won’t do any better than children switched to an oral treatment, and the indwelling catheter can cause problems, she said.

Pleuritic or other sudden pain at a distant site suggests septic emboli. “[Staphylococcus aureus] is notorious for going places you don’t” expect it to go “and forming microabscesses, which become larger abscesses” and need to be drained, said the third presenter, Russell McCulloh, MD, a pediatric infectious disease specialist at the University of Nebraska Medical Center, Omaha.

Four weeks of antibiotics are usually enough, so long as there aren’t complications such as septic thrombophlebitis, endocarditis, sickle cell disease, skull involvement, or immunodeficiencies. Source control and good, postdischarge care – including regular CRP and antibiotic toxicity labs – are critical. Monitoring is recommended for a year.

“X-rays are good at looking for longer-term complications, but bony abnormalities are not going to show up for the first 2 weeks,” Dr. McCulloh said.

The presenters didn’t have any relevant disclosures. The meeting was sponsored by the Society of Hospital Medicine, the American Academy of Pediatrics, and the Academic Pediatric Association.

aotto@mdedge.com

SEATTLE – If your hospital’s methicillin-resistant Staphylococcus aureus rate is less than 10%, cefazolin is a reasonable empiric choice for pediatric acute hematogenous osteomyelitis (AHO). It covers the usual suspects: methicillin-susceptible Staphylococcus aureus, group A Streptococcus, and Kingella.

Above the 10% mark, coverage should include considerations of MRSA; clindamycin is good option so long as 85% of isolates are susceptible. Above that, it’s time for vancomycin, according to Nivedita Srinivas, MD, a pediatric infectious disease specialist at Stanford (Calif.) University.

There are no practice guidelines in the United States for the diagnosis and management of AHO in children; Dr. Srinivas and colleagues sought to plug the gaps in a talk at Pediatric Hospitalist Medicine.

Pediatric AHO is more common in children under 5 years old and in boys. Lower extremities are the usual targets. Staphylococcus aureus, group B Streptococcus, and gram negatives are the most common causes in newborns; Staphylococcus aureus, group A Streptococcus, and Kingella in older infants and preschoolers; and Staphylococcus aureus and group A Streptococcus in older children.

About half the time, treatment remains empiric because nothing grows out on culture, and there are a few clinical pearls to keep in mind in those cases. A family history of boils or spider bites is suspicious for MRSA, and coverage should include Salmonella in children with abnormal hemoglobins and Streptococcus pneumoniae in children without a spleen or with functional asplenia. Pseudomonas has to be kept in mind with puncture wounds, and Brucella in children who drink unpasteurized milk, Dr. Srinivas said.

A switch from IV to oral therapy is appropriate when C-reactive protein (CRP) drops 50% from its peak or below 3 mg/dL, positive cultures – if any – turn negative, fever has been absent for 24 hours, there’s no sign of metastatic disease, and patients have markedly reduced pain and can bear weight on the infected limb, said copresenter Marie Wang, MD, also a pediatric infectious disease specialist at Stanford.

The oral switch, of course, must have similar coverage as the IV antibiotic: high-dose cephalexin for cefazolin, for instance. Children can be sent home on a PICC line to continue IV treatment, but they won’t do any better than children switched to an oral treatment, and the indwelling catheter can cause problems, she said.

Pleuritic or other sudden pain at a distant site suggests septic emboli. “[Staphylococcus aureus] is notorious for going places you don’t” expect it to go “and forming microabscesses, which become larger abscesses” and need to be drained, said the third presenter, Russell McCulloh, MD, a pediatric infectious disease specialist at the University of Nebraska Medical Center, Omaha.

Four weeks of antibiotics are usually enough, so long as there aren’t complications such as septic thrombophlebitis, endocarditis, sickle cell disease, skull involvement, or immunodeficiencies. Source control and good, postdischarge care – including regular CRP and antibiotic toxicity labs – are critical. Monitoring is recommended for a year.

“X-rays are good at looking for longer-term complications, but bony abnormalities are not going to show up for the first 2 weeks,” Dr. McCulloh said.

The presenters didn’t have any relevant disclosures. The meeting was sponsored by the Society of Hospital Medicine, the American Academy of Pediatrics, and the Academic Pediatric Association.

aotto@mdedge.com

SEATTLE – If your hospital’s methicillin-resistant Staphylococcus aureus rate is less than 10%, cefazolin is a reasonable empiric choice for pediatric acute hematogenous osteomyelitis (AHO). It covers the usual suspects: methicillin-susceptible Staphylococcus aureus, group A Streptococcus, and Kingella.

Above the 10% mark, coverage should include considerations of MRSA; clindamycin is good option so long as 85% of isolates are susceptible. Above that, it’s time for vancomycin, according to Nivedita Srinivas, MD, a pediatric infectious disease specialist at Stanford (Calif.) University.

There are no practice guidelines in the United States for the diagnosis and management of AHO in children; Dr. Srinivas and colleagues sought to plug the gaps in a talk at Pediatric Hospitalist Medicine.

Pediatric AHO is more common in children under 5 years old and in boys. Lower extremities are the usual targets. Staphylococcus aureus, group B Streptococcus, and gram negatives are the most common causes in newborns; Staphylococcus aureus, group A Streptococcus, and Kingella in older infants and preschoolers; and Staphylococcus aureus and group A Streptococcus in older children.

About half the time, treatment remains empiric because nothing grows out on culture, and there are a few clinical pearls to keep in mind in those cases. A family history of boils or spider bites is suspicious for MRSA, and coverage should include Salmonella in children with abnormal hemoglobins and Streptococcus pneumoniae in children without a spleen or with functional asplenia. Pseudomonas has to be kept in mind with puncture wounds, and Brucella in children who drink unpasteurized milk, Dr. Srinivas said.

A switch from IV to oral therapy is appropriate when C-reactive protein (CRP) drops 50% from its peak or below 3 mg/dL, positive cultures – if any – turn negative, fever has been absent for 24 hours, there’s no sign of metastatic disease, and patients have markedly reduced pain and can bear weight on the infected limb, said copresenter Marie Wang, MD, also a pediatric infectious disease specialist at Stanford.

The oral switch, of course, must have similar coverage as the IV antibiotic: high-dose cephalexin for cefazolin, for instance. Children can be sent home on a PICC line to continue IV treatment, but they won’t do any better than children switched to an oral treatment, and the indwelling catheter can cause problems, she said.

Pleuritic or other sudden pain at a distant site suggests septic emboli. “[Staphylococcus aureus] is notorious for going places you don’t” expect it to go “and forming microabscesses, which become larger abscesses” and need to be drained, said the third presenter, Russell McCulloh, MD, a pediatric infectious disease specialist at the University of Nebraska Medical Center, Omaha.

Four weeks of antibiotics are usually enough, so long as there aren’t complications such as septic thrombophlebitis, endocarditis, sickle cell disease, skull involvement, or immunodeficiencies. Source control and good, postdischarge care – including regular CRP and antibiotic toxicity labs – are critical. Monitoring is recommended for a year.

“X-rays are good at looking for longer-term complications, but bony abnormalities are not going to show up for the first 2 weeks,” Dr. McCulloh said.

The presenters didn’t have any relevant disclosures. The meeting was sponsored by the Society of Hospital Medicine, the American Academy of Pediatrics, and the Academic Pediatric Association.

aotto@mdedge.com

Key clinical point: Clinical and imaging outcomes improve among patients with MS who switch from interferon beta-1a to alemtuzumab.

Major finding: The rate of freedom from relapse ranged from 83% to 90%, and disability scores were stable for 51% of patients.

Study details: An examination of data for 117 patients with MS who participated in extensions of the CARE-MS II trial.

Disclosures: Sanofi and Bayer HealthCare Pharmaceuticals supported this study. Dr. Ionete received research support from Biogen, Roche, and Sanofi. She reported receiving compensation for advisory board participation from Sanofi.

Citation: REPORTING FROM CMSC 2019

Key clinical point: Clinical and imaging outcomes improve among patients with MS who switch from interferon beta-1a to alemtuzumab.

Major finding: The rate of freedom from relapse ranged from 83% to 90%, and disability scores were stable for 51% of patients.

Study details: An examination of data for 117 patients with MS who participated in extensions of the CARE-MS II trial.

Disclosures: Sanofi and Bayer HealthCare Pharmaceuticals supported this study. Dr. Ionete received research support from Biogen, Roche, and Sanofi. She reported receiving compensation for advisory board participation from Sanofi.

Citation: REPORTING FROM CMSC 2019

Key clinical point: Clinical and imaging outcomes improve among patients with MS who switch from interferon beta-1a to alemtuzumab.

Major finding: The rate of freedom from relapse ranged from 83% to 90%, and disability scores were stable for 51% of patients.

Study details: An examination of data for 117 patients with MS who participated in extensions of the CARE-MS II trial.

Disclosures: Sanofi and Bayer HealthCare Pharmaceuticals supported this study. Dr. Ionete received research support from Biogen, Roche, and Sanofi. She reported receiving compensation for advisory board participation from Sanofi.

Citation: REPORTING FROM CMSC 2019

Key clinical point: Patients with multiple sclerosis who consider marijuana use are more likely to smoke and drink alcohol.

Major finding: Among multiple sclerosis patients who responded to a survey, 25.4% had used marijuana for their multiple sclerosis, 20.0% had discussed it with their doctors, and 16.1% were currently using some form of marijuana.

Study details: Questionnaire responses about health behaviors from 5,481 active participants in the North American Research Committee on Multiple Sclerosis.

Disclosures: The North American Research Committee on Multiple Sclerosis is funded in part by the Consortium of Multiple Sclerosis Centers and the Foundation of the CMSC. The present study had no funding support. Dr. Cofield reported receiving a consulting fee from the U.S. Department of Defense.

Citation: REPORTING FROM CMSC 2019

Key clinical point: Patients with multiple sclerosis who consider marijuana use are more likely to smoke and drink alcohol.

Major finding: Among multiple sclerosis patients who responded to a survey, 25.4% had used marijuana for their multiple sclerosis, 20.0% had discussed it with their doctors, and 16.1% were currently using some form of marijuana.

Study details: Questionnaire responses about health behaviors from 5,481 active participants in the North American Research Committee on Multiple Sclerosis.

Disclosures: The North American Research Committee on Multiple Sclerosis is funded in part by the Consortium of Multiple Sclerosis Centers and the Foundation of the CMSC. The present study had no funding support. Dr. Cofield reported receiving a consulting fee from the U.S. Department of Defense.

Citation: REPORTING FROM CMSC 2019

Key clinical point: Patients with multiple sclerosis who consider marijuana use are more likely to smoke and drink alcohol.

Major finding: Among multiple sclerosis patients who responded to a survey, 25.4% had used marijuana for their multiple sclerosis, 20.0% had discussed it with their doctors, and 16.1% were currently using some form of marijuana.

Study details: Questionnaire responses about health behaviors from 5,481 active participants in the North American Research Committee on Multiple Sclerosis.

Disclosures: The North American Research Committee on Multiple Sclerosis is funded in part by the Consortium of Multiple Sclerosis Centers and the Foundation of the CMSC. The present study had no funding support. Dr. Cofield reported receiving a consulting fee from the U.S. Department of Defense.

Citation: REPORTING FROM CMSC 2019

Key clinical point: Patients with pediatric-onset multiple sclerosis (MS) are more likely than those with adult-onset MS to have cognitive impairment in adulthood.

Major finding: At age 35 years, the mean Symbol Digit Modalities Test score for patients with adult-onset MS was 61, whereas for patients with pediatric-onset MS it was 51. By age 40 years, the mean score was 58 for adult-onset MS versus 46 for pediatric-onset MS.

Study details: A Swedish population-based, longitudinal cohort study of 5,704 patients with MS, 300 of whom had pediatric-onset MS (5%).

Disclosures: The study was supported by the Swedish Research Council, the Swedish Brain Foundation, and by postdoctoral awards from the Canadian Institutes of Health Research and European Committee for Treatment and Research in Multiple Sclerosis, both to Dr. McKay. Coauthors reported receiving honoraria for speaking and serving on advisory boards for various pharmaceutical companies, as well as receiving research funding from agencies, foundations, and pharmaceutical companies.

Citation: McKay KA et al. JAMA Neurol. 2019 Jun 17. doi: 10.1001/jamaneurol.2019.1546.

Key clinical point: Patients with pediatric-onset multiple sclerosis (MS) are more likely than those with adult-onset MS to have cognitive impairment in adulthood.

Major finding: At age 35 years, the mean Symbol Digit Modalities Test score for patients with adult-onset MS was 61, whereas for patients with pediatric-onset MS it was 51. By age 40 years, the mean score was 58 for adult-onset MS versus 46 for pediatric-onset MS.

Study details: A Swedish population-based, longitudinal cohort study of 5,704 patients with MS, 300 of whom had pediatric-onset MS (5%).

Disclosures: The study was supported by the Swedish Research Council, the Swedish Brain Foundation, and by postdoctoral awards from the Canadian Institutes of Health Research and European Committee for Treatment and Research in Multiple Sclerosis, both to Dr. McKay. Coauthors reported receiving honoraria for speaking and serving on advisory boards for various pharmaceutical companies, as well as receiving research funding from agencies, foundations, and pharmaceutical companies.

Citation: McKay KA et al. JAMA Neurol. 2019 Jun 17. doi: 10.1001/jamaneurol.2019.1546.

Key clinical point: Patients with pediatric-onset multiple sclerosis (MS) are more likely than those with adult-onset MS to have cognitive impairment in adulthood.

Major finding: At age 35 years, the mean Symbol Digit Modalities Test score for patients with adult-onset MS was 61, whereas for patients with pediatric-onset MS it was 51. By age 40 years, the mean score was 58 for adult-onset MS versus 46 for pediatric-onset MS.

Study details: A Swedish population-based, longitudinal cohort study of 5,704 patients with MS, 300 of whom had pediatric-onset MS (5%).

Disclosures: The study was supported by the Swedish Research Council, the Swedish Brain Foundation, and by postdoctoral awards from the Canadian Institutes of Health Research and European Committee for Treatment and Research in Multiple Sclerosis, both to Dr. McKay. Coauthors reported receiving honoraria for speaking and serving on advisory boards for various pharmaceutical companies, as well as receiving research funding from agencies, foundations, and pharmaceutical companies.

Citation: McKay KA et al. JAMA Neurol. 2019 Jun 17. doi: 10.1001/jamaneurol.2019.1546.

Zoledronic acid was effective at preventing symptomatic periodontal disease in patients with osteoporosis and good oral hygiene, according to Akira Taguchi, DDS, PhD, of the department of oral and maxillofacial radiology at Matsumoto Dental University, Nagano, Japan, and associates.

bernardbodo/iStock/Getty Images Plus

In a study published in Menopause, the investigators retrospectively analyzed 542 men and women with osteoporosis who participated in the randomized ZONE (Zoledronate Treatment in Efficacy to Osteoporosis) trial. Patients received either zoledronic acid (n = 258) or placebo (n = 284) once yearly for 2 years by IV infusion; mean age was 74 years in both groups. Patients were instructed to maintain good oral health at baseline and every 3 months afterward. Participants with signs or symptoms involving the oral cavity at the follow-up approximately every 3 months were referred to dentists for examination of oral disease.

Oral adverse events were significantly more common in the placebo group, compared with the zoledronic acid group (20% vs. 14%; P = .04); incidence of symptomatic periodontal disease also was significantly more common in those receiving placebo (12% vs. 5%; P = .002). While loss of teeth was more common in the control group than in those receiving zoledronic acid (11% vs. 7%), the difference was not significant.

“Because zoledronic acid can prevent symptomatic periodontal disease when combined with good oral hygiene management, it is possible that the procedures performed in this study could eventually suppress the development of [osteonecrosis of the jaw],” the investigators concluded.

The study was funded by Asahi-Kasei Pharma. The investigators reported employment or receiving consulting fees from numerous pharmaceutical companies.

lfranki@mdedge.com

SOURCE: Taguchi A et al. Menopause. 2019 Aug 19. doi: 10.1097/GME.0000000000001393.

Zoledronic acid was effective at preventing symptomatic periodontal disease in patients with osteoporosis and good oral hygiene, according to Akira Taguchi, DDS, PhD, of the department of oral and maxillofacial radiology at Matsumoto Dental University, Nagano, Japan, and associates.

bernardbodo/iStock/Getty Images Plus

In a study published in Menopause, the investigators retrospectively analyzed 542 men and women with osteoporosis who participated in the randomized ZONE (Zoledronate Treatment in Efficacy to Osteoporosis) trial. Patients received either zoledronic acid (n = 258) or placebo (n = 284) once yearly for 2 years by IV infusion; mean age was 74 years in both groups. Patients were instructed to maintain good oral health at baseline and every 3 months afterward. Participants with signs or symptoms involving the oral cavity at the follow-up approximately every 3 months were referred to dentists for examination of oral disease.

Oral adverse events were significantly more common in the placebo group, compared with the zoledronic acid group (20% vs. 14%; P = .04); incidence of symptomatic periodontal disease also was significantly more common in those receiving placebo (12% vs. 5%; P = .002). While loss of teeth was more common in the control group than in those receiving zoledronic acid (11% vs. 7%), the difference was not significant.

“Because zoledronic acid can prevent symptomatic periodontal disease when combined with good oral hygiene management, it is possible that the procedures performed in this study could eventually suppress the development of [osteonecrosis of the jaw],” the investigators concluded.

The study was funded by Asahi-Kasei Pharma. The investigators reported employment or receiving consulting fees from numerous pharmaceutical companies.

lfranki@mdedge.com

SOURCE: Taguchi A et al. Menopause. 2019 Aug 19. doi: 10.1097/GME.0000000000001393.

Zoledronic acid was effective at preventing symptomatic periodontal disease in patients with osteoporosis and good oral hygiene, according to Akira Taguchi, DDS, PhD, of the department of oral and maxillofacial radiology at Matsumoto Dental University, Nagano, Japan, and associates.

bernardbodo/iStock/Getty Images Plus

In a study published in Menopause, the investigators retrospectively analyzed 542 men and women with osteoporosis who participated in the randomized ZONE (Zoledronate Treatment in Efficacy to Osteoporosis) trial. Patients received either zoledronic acid (n = 258) or placebo (n = 284) once yearly for 2 years by IV infusion; mean age was 74 years in both groups. Patients were instructed to maintain good oral health at baseline and every 3 months afterward. Participants with signs or symptoms involving the oral cavity at the follow-up approximately every 3 months were referred to dentists for examination of oral disease.

Oral adverse events were significantly more common in the placebo group, compared with the zoledronic acid group (20% vs. 14%; P = .04); incidence of symptomatic periodontal disease also was significantly more common in those receiving placebo (12% vs. 5%; P = .002). While loss of teeth was more common in the control group than in those receiving zoledronic acid (11% vs. 7%), the difference was not significant.

“Because zoledronic acid can prevent symptomatic periodontal disease when combined with good oral hygiene management, it is possible that the procedures performed in this study could eventually suppress the development of [osteonecrosis of the jaw],” the investigators concluded.

The study was funded by Asahi-Kasei Pharma. The investigators reported employment or receiving consulting fees from numerous pharmaceutical companies.

lfranki@mdedge.com

SOURCE: Taguchi A et al. Menopause. 2019 Aug 19. doi: 10.1097/GME.0000000000001393.