Nancy A. Melville

With ever-expanding treatment options for the ablation of benign thyroid nodules, the American Thyroid Association has issued an expert consensus statement that addresses the safe implementation and utilization of the techniques.

“There are no documents to date in the United States focusing primarily on the safe adoption and implementation of ablation techniques, including learning curve considerations and necessary pre-procedural skillsets,” reports the ATA task force in the consensus statement, which was published in Thyroid.

“Although these emerging technologies hold great promise, they are not without risk and require development of a unique skill set and environment for optimal, safe performance and consistent outcomes,” task force co-author Catherine F. Sinclair, MD, an associate professor at the Icahn School of Medicine at Mount Sinai, New York, said in an interview.

Chemical ablation has long been utilized as a nonsurgical option for benign thyroid nodule ablation. However, the current array of treatment options has expanded with thermal ablation. Techniques such as radiofrequency ablation (RFA), laser ablation, microwave ablation, and high-intensity focused ultrasound have gained favor as minimally invasive alternatives to surgery.

Much has been published on indications and outcomes with the use of the techniques. The multidisciplinary global task force was convened to address key issues regarding safety and utilization. The report is directed toward specialists, including surgeons, endocrinologists, and interventional radiologists.

The recommendations cover three broad categories: safety considerations spanning preprocedural to postprocedural periods; necessary skill sets for optimal, safe performance with the approaches; and the expectations for success in the context of risks and benefits.
 

Ablation methods can depend on nodule type

Among key issues addressed are which ablation methods are most appropriate for which types of nodules. Recommendations include chemical ablation, typically involving the injection of dehydrated ethanol in a target nodule. In solid nodules, diffusion with chemical ablation can be unpredictable, which makes it more appropriate for cystic nodules.

Thermal ablation is considered best suited for patients with compressive and/or cosmetic complaints that clearly involve a single or dominant nodule, as well as for autonomously functioning thyroid nodules that cause subclinical or overt hyperthyroidism.

While ethanol ablation is recommended as a first-line treatment for benign cystic thyroid nodules, its efficacy decreases when there is an increase of more than 20% of the solid component. In such cases, RFA or a combination of ethanol ablation and RFA may be considered, the task force recommends.
 

Patient counseling – managing expectations

Another key consideration in treatment with thyroid nodule ablation is managing patients’ expectations.

Patients should be advised of benefits, such as the avoidance of surgery and general anesthesia and less recovery time. Risks can include thermal or chemical injury to the recurrent laryngeal nerve and other vital structures. The task force underscores discussion of alternative options with patients.

Alternative management options to ablation, including observation, radioactive iodine for functioning nodules, and surgery should also be discussed, and “their relative advantages and disadvantages should be presented without bias such that the patient can make an informed, individual treatment decision,” the task force recommends.

Patients should be informed that, in contrast to surgical management, the benefits of ablation are not immediate; rather, they accrue over the course of months. Reduction in nodule size within the first month is often limited.

Pain, soreness, and some swelling of the nodule and surrounding tissues are common in the first week. These symptoms usually peak in the first 3-5 days after the procedure. Importantly, patients rarely require opioid medications, and their use should be avoided, the task force recommends.

Patients should also be informed about the possibilities of nodule regrowth following ablation and the possible need for more than one ablation procedure.

“Although regrowth definitions in the literature vary, risk of regrowth after thermal ablation is 5%-40% and increases the larger the baseline nodule volume,” the task force notes.

Of note, most studies on ablation to date have shown that thermal ablation complication rates are low. Twelve months post procedure, volume reductions are typically greater than 50%.
 

Follow-up

For long-term monitoring following ablation, follow-up neck ultrasound is typically recommended at 1-3 months and at 6 and 12 months post ablation to assess volume reduction, nodule appearance, nodule vascularity, and areas at risk for regrowth, the authors note.

Prolonged serial biochemical evaluation of thyroid function is only recommended in cases of hyperfunctioning thyroid nodules.

Key considerations for additional ablative sessions for nodules greater than 20-30 mL in volume should include a failure to achieve adequate reduction in volume, nodule regrowth in previously untreated peripheral areas, and/or persistent or new compressive symptoms.
 

Learning curve

Dr. Sinclair underscored that successful thyroid nodule ablation requires skill – and experience.

“Probably the greatest concern shared by the writing group on this statement was the potential for clinicians to start ablation practices without having an appropriate prior skill set,” she said.

“Ablation is an advanced, ultrasound-guided procedure, and clinicians need to be experienced in performing neck ultrasounds and biopsies,” she added. “To consider performing ablations without this skill set is both unrealistic and dangerous.”

RFA, currently the most commonly used thermal ablation method for benign thyroid nodule ablation in the U.S., “has a good safety profile but can have a steep learning curve initially,” she said.

Among the most important recommendations is that for their first 20-60 ablation procedures, clinicians should consider limiting treatment to small- to medium-sized benign nodules rather than large-volume disease, Dr. Sinclair added.

“In addition, prior to starting thyroid ablation practices, clinicians should be proficient in ultrasound imaging and fine-needle biopsies and can gain valuable experience by practicing on phantoms and having expert proctoring for the first few cases,” she said.

For initial ablative cases, the task force recommends that clinicians select moderate-size (< 20-30 mL), nonvascular nodules with favorable characteristics and location. The final volume reduction should be based not only on baseline nodule characteristics, such as volume and vascularity, but also on the practitioner’s skill.

Clinicians furthermore should be board certified or eligible in an appropriate medical specialty, have extensive background knowledge, and “should have clinical experience in the clinical diagnosis and treatment of thyroid nodules; neck imaging anatomy; thyroid ultrasound imaging and fine needle aspiration biopsy procedures; and ultrasound risk stratification for benign and malignant thyroid tumors,” the group recommends.

Importantly, the statement is designed to reflect a consensus opinion of the panel of experts but is not meant to serve as a formal guideline or a standard of care for the clinical practice of thermal ablation, Dr. Sinclair added.

“It is not the intent of the statement to replace individual decision-making, the wishes of the patient or family, or clinical judgment.”

The authors’ disclosures are detailed in the published report.

A version of this article first appeared on Medscape.com.

With ever-expanding treatment options for the ablation of benign thyroid nodules, the American Thyroid Association has issued an expert consensus statement that addresses the safe implementation and utilization of the techniques.

“There are no documents to date in the United States focusing primarily on the safe adoption and implementation of ablation techniques, including learning curve considerations and necessary pre-procedural skillsets,” reports the ATA task force in the consensus statement, which was published in Thyroid.

“Although these emerging technologies hold great promise, they are not without risk and require development of a unique skill set and environment for optimal, safe performance and consistent outcomes,” task force co-author Catherine F. Sinclair, MD, an associate professor at the Icahn School of Medicine at Mount Sinai, New York, said in an interview.

Chemical ablation has long been utilized as a nonsurgical option for benign thyroid nodule ablation. However, the current array of treatment options has expanded with thermal ablation. Techniques such as radiofrequency ablation (RFA), laser ablation, microwave ablation, and high-intensity focused ultrasound have gained favor as minimally invasive alternatives to surgery.

Much has been published on indications and outcomes with the use of the techniques. The multidisciplinary global task force was convened to address key issues regarding safety and utilization. The report is directed toward specialists, including surgeons, endocrinologists, and interventional radiologists.

The recommendations cover three broad categories: safety considerations spanning preprocedural to postprocedural periods; necessary skill sets for optimal, safe performance with the approaches; and the expectations for success in the context of risks and benefits.
 

Ablation methods can depend on nodule type

Among key issues addressed are which ablation methods are most appropriate for which types of nodules. Recommendations include chemical ablation, typically involving the injection of dehydrated ethanol in a target nodule. In solid nodules, diffusion with chemical ablation can be unpredictable, which makes it more appropriate for cystic nodules.

Thermal ablation is considered best suited for patients with compressive and/or cosmetic complaints that clearly involve a single or dominant nodule, as well as for autonomously functioning thyroid nodules that cause subclinical or overt hyperthyroidism.

While ethanol ablation is recommended as a first-line treatment for benign cystic thyroid nodules, its efficacy decreases when there is an increase of more than 20% of the solid component. In such cases, RFA or a combination of ethanol ablation and RFA may be considered, the task force recommends.
 

Patient counseling – managing expectations

Another key consideration in treatment with thyroid nodule ablation is managing patients’ expectations.

Patients should be advised of benefits, such as the avoidance of surgery and general anesthesia and less recovery time. Risks can include thermal or chemical injury to the recurrent laryngeal nerve and other vital structures. The task force underscores discussion of alternative options with patients.

Alternative management options to ablation, including observation, radioactive iodine for functioning nodules, and surgery should also be discussed, and “their relative advantages and disadvantages should be presented without bias such that the patient can make an informed, individual treatment decision,” the task force recommends.

Patients should be informed that, in contrast to surgical management, the benefits of ablation are not immediate; rather, they accrue over the course of months. Reduction in nodule size within the first month is often limited.

Pain, soreness, and some swelling of the nodule and surrounding tissues are common in the first week. These symptoms usually peak in the first 3-5 days after the procedure. Importantly, patients rarely require opioid medications, and their use should be avoided, the task force recommends.

Patients should also be informed about the possibilities of nodule regrowth following ablation and the possible need for more than one ablation procedure.

“Although regrowth definitions in the literature vary, risk of regrowth after thermal ablation is 5%-40% and increases the larger the baseline nodule volume,” the task force notes.

Of note, most studies on ablation to date have shown that thermal ablation complication rates are low. Twelve months post procedure, volume reductions are typically greater than 50%.
 

Follow-up

For long-term monitoring following ablation, follow-up neck ultrasound is typically recommended at 1-3 months and at 6 and 12 months post ablation to assess volume reduction, nodule appearance, nodule vascularity, and areas at risk for regrowth, the authors note.

Prolonged serial biochemical evaluation of thyroid function is only recommended in cases of hyperfunctioning thyroid nodules.

Key considerations for additional ablative sessions for nodules greater than 20-30 mL in volume should include a failure to achieve adequate reduction in volume, nodule regrowth in previously untreated peripheral areas, and/or persistent or new compressive symptoms.
 

Learning curve

Dr. Sinclair underscored that successful thyroid nodule ablation requires skill – and experience.

“Probably the greatest concern shared by the writing group on this statement was the potential for clinicians to start ablation practices without having an appropriate prior skill set,” she said.

“Ablation is an advanced, ultrasound-guided procedure, and clinicians need to be experienced in performing neck ultrasounds and biopsies,” she added. “To consider performing ablations without this skill set is both unrealistic and dangerous.”

RFA, currently the most commonly used thermal ablation method for benign thyroid nodule ablation in the U.S., “has a good safety profile but can have a steep learning curve initially,” she said.

Among the most important recommendations is that for their first 20-60 ablation procedures, clinicians should consider limiting treatment to small- to medium-sized benign nodules rather than large-volume disease, Dr. Sinclair added.

“In addition, prior to starting thyroid ablation practices, clinicians should be proficient in ultrasound imaging and fine-needle biopsies and can gain valuable experience by practicing on phantoms and having expert proctoring for the first few cases,” she said.

For initial ablative cases, the task force recommends that clinicians select moderate-size (< 20-30 mL), nonvascular nodules with favorable characteristics and location. The final volume reduction should be based not only on baseline nodule characteristics, such as volume and vascularity, but also on the practitioner’s skill.

Clinicians furthermore should be board certified or eligible in an appropriate medical specialty, have extensive background knowledge, and “should have clinical experience in the clinical diagnosis and treatment of thyroid nodules; neck imaging anatomy; thyroid ultrasound imaging and fine needle aspiration biopsy procedures; and ultrasound risk stratification for benign and malignant thyroid tumors,” the group recommends.

Importantly, the statement is designed to reflect a consensus opinion of the panel of experts but is not meant to serve as a formal guideline or a standard of care for the clinical practice of thermal ablation, Dr. Sinclair added.

“It is not the intent of the statement to replace individual decision-making, the wishes of the patient or family, or clinical judgment.”

The authors’ disclosures are detailed in the published report.

A version of this article first appeared on Medscape.com.

With ever-expanding treatment options for the ablation of benign thyroid nodules, the American Thyroid Association has issued an expert consensus statement that addresses the safe implementation and utilization of the techniques.

“There are no documents to date in the United States focusing primarily on the safe adoption and implementation of ablation techniques, including learning curve considerations and necessary pre-procedural skillsets,” reports the ATA task force in the consensus statement, which was published in Thyroid.

“Although these emerging technologies hold great promise, they are not without risk and require development of a unique skill set and environment for optimal, safe performance and consistent outcomes,” task force co-author Catherine F. Sinclair, MD, an associate professor at the Icahn School of Medicine at Mount Sinai, New York, said in an interview.

Chemical ablation has long been utilized as a nonsurgical option for benign thyroid nodule ablation. However, the current array of treatment options has expanded with thermal ablation. Techniques such as radiofrequency ablation (RFA), laser ablation, microwave ablation, and high-intensity focused ultrasound have gained favor as minimally invasive alternatives to surgery.

Much has been published on indications and outcomes with the use of the techniques. The multidisciplinary global task force was convened to address key issues regarding safety and utilization. The report is directed toward specialists, including surgeons, endocrinologists, and interventional radiologists.

The recommendations cover three broad categories: safety considerations spanning preprocedural to postprocedural periods; necessary skill sets for optimal, safe performance with the approaches; and the expectations for success in the context of risks and benefits.
 

Ablation methods can depend on nodule type

Among key issues addressed are which ablation methods are most appropriate for which types of nodules. Recommendations include chemical ablation, typically involving the injection of dehydrated ethanol in a target nodule. In solid nodules, diffusion with chemical ablation can be unpredictable, which makes it more appropriate for cystic nodules.

Thermal ablation is considered best suited for patients with compressive and/or cosmetic complaints that clearly involve a single or dominant nodule, as well as for autonomously functioning thyroid nodules that cause subclinical or overt hyperthyroidism.

While ethanol ablation is recommended as a first-line treatment for benign cystic thyroid nodules, its efficacy decreases when there is an increase of more than 20% of the solid component. In such cases, RFA or a combination of ethanol ablation and RFA may be considered, the task force recommends.
 

Patient counseling – managing expectations

Another key consideration in treatment with thyroid nodule ablation is managing patients’ expectations.

Patients should be advised of benefits, such as the avoidance of surgery and general anesthesia and less recovery time. Risks can include thermal or chemical injury to the recurrent laryngeal nerve and other vital structures. The task force underscores discussion of alternative options with patients.

Alternative management options to ablation, including observation, radioactive iodine for functioning nodules, and surgery should also be discussed, and “their relative advantages and disadvantages should be presented without bias such that the patient can make an informed, individual treatment decision,” the task force recommends.

Patients should be informed that, in contrast to surgical management, the benefits of ablation are not immediate; rather, they accrue over the course of months. Reduction in nodule size within the first month is often limited.

Pain, soreness, and some swelling of the nodule and surrounding tissues are common in the first week. These symptoms usually peak in the first 3-5 days after the procedure. Importantly, patients rarely require opioid medications, and their use should be avoided, the task force recommends.

Patients should also be informed about the possibilities of nodule regrowth following ablation and the possible need for more than one ablation procedure.

“Although regrowth definitions in the literature vary, risk of regrowth after thermal ablation is 5%-40% and increases the larger the baseline nodule volume,” the task force notes.

Of note, most studies on ablation to date have shown that thermal ablation complication rates are low. Twelve months post procedure, volume reductions are typically greater than 50%.
 

Follow-up

For long-term monitoring following ablation, follow-up neck ultrasound is typically recommended at 1-3 months and at 6 and 12 months post ablation to assess volume reduction, nodule appearance, nodule vascularity, and areas at risk for regrowth, the authors note.

Prolonged serial biochemical evaluation of thyroid function is only recommended in cases of hyperfunctioning thyroid nodules.

Key considerations for additional ablative sessions for nodules greater than 20-30 mL in volume should include a failure to achieve adequate reduction in volume, nodule regrowth in previously untreated peripheral areas, and/or persistent or new compressive symptoms.
 

Learning curve

Dr. Sinclair underscored that successful thyroid nodule ablation requires skill – and experience.

“Probably the greatest concern shared by the writing group on this statement was the potential for clinicians to start ablation practices without having an appropriate prior skill set,” she said.

“Ablation is an advanced, ultrasound-guided procedure, and clinicians need to be experienced in performing neck ultrasounds and biopsies,” she added. “To consider performing ablations without this skill set is both unrealistic and dangerous.”

RFA, currently the most commonly used thermal ablation method for benign thyroid nodule ablation in the U.S., “has a good safety profile but can have a steep learning curve initially,” she said.

Among the most important recommendations is that for their first 20-60 ablation procedures, clinicians should consider limiting treatment to small- to medium-sized benign nodules rather than large-volume disease, Dr. Sinclair added.

“In addition, prior to starting thyroid ablation practices, clinicians should be proficient in ultrasound imaging and fine-needle biopsies and can gain valuable experience by practicing on phantoms and having expert proctoring for the first few cases,” she said.

For initial ablative cases, the task force recommends that clinicians select moderate-size (< 20-30 mL), nonvascular nodules with favorable characteristics and location. The final volume reduction should be based not only on baseline nodule characteristics, such as volume and vascularity, but also on the practitioner’s skill.

Clinicians furthermore should be board certified or eligible in an appropriate medical specialty, have extensive background knowledge, and “should have clinical experience in the clinical diagnosis and treatment of thyroid nodules; neck imaging anatomy; thyroid ultrasound imaging and fine needle aspiration biopsy procedures; and ultrasound risk stratification for benign and malignant thyroid tumors,” the group recommends.

Importantly, the statement is designed to reflect a consensus opinion of the panel of experts but is not meant to serve as a formal guideline or a standard of care for the clinical practice of thermal ablation, Dr. Sinclair added.

“It is not the intent of the statement to replace individual decision-making, the wishes of the patient or family, or clinical judgment.”

The authors’ disclosures are detailed in the published report.

A version of this article first appeared on Medscape.com.

TOPLINE

Biochemical recurrence (BCR) falls short as a reliable surrogate for overall survival in localized prostate cancer trials and may not be a suitable primary endpoint.

METHODOLOGY

• In trials of localized prostate cancer, BCR remains a controversial surrogate endpoint for overall survival.
• The meta-analysis included 10,741 patients from 11 randomized clinical trials; the median follow-up was 9.2 years.
• Interventions included radiotherapy dose escalation, in which high-dose radiotherapy was compared with conventional radiotherapy (n = 3,639); short-term androgen deprivation therapy (ADT), in which radiotherapy plus short-term ADT was compared with radiotherapy alone (n = 3,930); and ADT prolongation, in which radiotherapy plus long-term ADT was compared with radiotherapy plus short-term ADT (n = 3,772).
• Prentice criteria and the two-stage meta-analytic approach were used to assess BCR as a surrogate endpoint for overall survival.
• The researchers assessed the treatment effect on BCR and on overall survival.

TAKEAWAY

• With regard to treatment effect on BCR, the three interventions significantly reduced BCR risk – dose escalation by 29%, short-term ADT by 47%, and ADT prolongation by 46%. With regard to survival, only short- and long-term ADT significantly improved overall survival, by 9% and 14%, respectively.
• At 48 months, BCR was associated with significantly increased mortality risk: 2.46-fold increased risk for dose escalation, 1.51-fold greater risk for short-term ADT, and 2.31-fold higher risk for ADT prolongation.
• However, after adjusting for BCR at 48 months, there was no significant treatment effect on overall survival (hazard ratio, 1.10; [95% confidence interval, 0.96-1.27]; HR, 0.96 [95% CI, 0.87-1.06]; HR, 1.00 [95% CI, 0.90-1.12], respectively).
• Patient-level correlation between time to BCR and overall survival was low after censoring for noncancer-related deaths. The correlation between BCR-free survival and overall survival ranged from low to moderate.

IN PRACTICE

Overall, “these results strongly suggest that BCR-based endpoints should not be the primary endpoint in randomized trials conducted for localized [prostate cancer],” the authors concluded. They added that metastasis-free survival represents a more appropriate measure.

SOURCE

The study was led by senior author Amar Kishan, MD, of the University of California, Los Angeles, and was published online in the Journal of Clinical Oncology.

LIMITATIONS

• The trials used different definitions of BCR – the older American Society of Therapeutic Radiation and Oncology definition, and the more current Phoenix criteria.
• Some trials were conducted more than 20 years ago, and a variety of factors, including patient selection, staging, diagnostic criteria, and therapeutic approaches, have evolved in that time.
• Quality of life was not captured.

DISCLOSURES

The study received support from Cancer Research UK, the UK National Health Service, the Prostate Cancer National Institutes of Health Specialized Programs of Research Excellence, the UK Department of Defense, the Prostate Cancer Foundation, and the American Society for Radiation Oncology. Authors’ relevant financial relationships are detailed in the published study.

A version of this article appeared on Medscape.com.

TOPLINE

Biochemical recurrence (BCR) falls short as a reliable surrogate for overall survival in localized prostate cancer trials and may not be a suitable primary endpoint.

METHODOLOGY

• In trials of localized prostate cancer, BCR remains a controversial surrogate endpoint for overall survival.
• The meta-analysis included 10,741 patients from 11 randomized clinical trials; the median follow-up was 9.2 years.
• Interventions included radiotherapy dose escalation, in which high-dose radiotherapy was compared with conventional radiotherapy (n = 3,639); short-term androgen deprivation therapy (ADT), in which radiotherapy plus short-term ADT was compared with radiotherapy alone (n = 3,930); and ADT prolongation, in which radiotherapy plus long-term ADT was compared with radiotherapy plus short-term ADT (n = 3,772).
• Prentice criteria and the two-stage meta-analytic approach were used to assess BCR as a surrogate endpoint for overall survival.
• The researchers assessed the treatment effect on BCR and on overall survival.

TAKEAWAY

• With regard to treatment effect on BCR, the three interventions significantly reduced BCR risk – dose escalation by 29%, short-term ADT by 47%, and ADT prolongation by 46%. With regard to survival, only short- and long-term ADT significantly improved overall survival, by 9% and 14%, respectively.
• At 48 months, BCR was associated with significantly increased mortality risk: 2.46-fold increased risk for dose escalation, 1.51-fold greater risk for short-term ADT, and 2.31-fold higher risk for ADT prolongation.
• However, after adjusting for BCR at 48 months, there was no significant treatment effect on overall survival (hazard ratio, 1.10; [95% confidence interval, 0.96-1.27]; HR, 0.96 [95% CI, 0.87-1.06]; HR, 1.00 [95% CI, 0.90-1.12], respectively).
• Patient-level correlation between time to BCR and overall survival was low after censoring for noncancer-related deaths. The correlation between BCR-free survival and overall survival ranged from low to moderate.

IN PRACTICE

Overall, “these results strongly suggest that BCR-based endpoints should not be the primary endpoint in randomized trials conducted for localized [prostate cancer],” the authors concluded. They added that metastasis-free survival represents a more appropriate measure.

SOURCE

The study was led by senior author Amar Kishan, MD, of the University of California, Los Angeles, and was published online in the Journal of Clinical Oncology.

LIMITATIONS

• The trials used different definitions of BCR – the older American Society of Therapeutic Radiation and Oncology definition, and the more current Phoenix criteria.
• Some trials were conducted more than 20 years ago, and a variety of factors, including patient selection, staging, diagnostic criteria, and therapeutic approaches, have evolved in that time.
• Quality of life was not captured.

DISCLOSURES

The study received support from Cancer Research UK, the UK National Health Service, the Prostate Cancer National Institutes of Health Specialized Programs of Research Excellence, the UK Department of Defense, the Prostate Cancer Foundation, and the American Society for Radiation Oncology. Authors’ relevant financial relationships are detailed in the published study.

A version of this article appeared on Medscape.com.

TOPLINE

Biochemical recurrence (BCR) falls short as a reliable surrogate for overall survival in localized prostate cancer trials and may not be a suitable primary endpoint.

METHODOLOGY

• In trials of localized prostate cancer, BCR remains a controversial surrogate endpoint for overall survival.
• The meta-analysis included 10,741 patients from 11 randomized clinical trials; the median follow-up was 9.2 years.
• Interventions included radiotherapy dose escalation, in which high-dose radiotherapy was compared with conventional radiotherapy (n = 3,639); short-term androgen deprivation therapy (ADT), in which radiotherapy plus short-term ADT was compared with radiotherapy alone (n = 3,930); and ADT prolongation, in which radiotherapy plus long-term ADT was compared with radiotherapy plus short-term ADT (n = 3,772).
• Prentice criteria and the two-stage meta-analytic approach were used to assess BCR as a surrogate endpoint for overall survival.
• The researchers assessed the treatment effect on BCR and on overall survival.

TAKEAWAY

• With regard to treatment effect on BCR, the three interventions significantly reduced BCR risk – dose escalation by 29%, short-term ADT by 47%, and ADT prolongation by 46%. With regard to survival, only short- and long-term ADT significantly improved overall survival, by 9% and 14%, respectively.
• At 48 months, BCR was associated with significantly increased mortality risk: 2.46-fold increased risk for dose escalation, 1.51-fold greater risk for short-term ADT, and 2.31-fold higher risk for ADT prolongation.
• However, after adjusting for BCR at 48 months, there was no significant treatment effect on overall survival (hazard ratio, 1.10; [95% confidence interval, 0.96-1.27]; HR, 0.96 [95% CI, 0.87-1.06]; HR, 1.00 [95% CI, 0.90-1.12], respectively).
• Patient-level correlation between time to BCR and overall survival was low after censoring for noncancer-related deaths. The correlation between BCR-free survival and overall survival ranged from low to moderate.

IN PRACTICE

Overall, “these results strongly suggest that BCR-based endpoints should not be the primary endpoint in randomized trials conducted for localized [prostate cancer],” the authors concluded. They added that metastasis-free survival represents a more appropriate measure.

SOURCE

The study was led by senior author Amar Kishan, MD, of the University of California, Los Angeles, and was published online in the Journal of Clinical Oncology.

LIMITATIONS

• The trials used different definitions of BCR – the older American Society of Therapeutic Radiation and Oncology definition, and the more current Phoenix criteria.
• Some trials were conducted more than 20 years ago, and a variety of factors, including patient selection, staging, diagnostic criteria, and therapeutic approaches, have evolved in that time.
• Quality of life was not captured.

DISCLOSURES

The study received support from Cancer Research UK, the UK National Health Service, the Prostate Cancer National Institutes of Health Specialized Programs of Research Excellence, the UK Department of Defense, the Prostate Cancer Foundation, and the American Society for Radiation Oncology. Authors’ relevant financial relationships are detailed in the published study.

A version of this article appeared on Medscape.com.

TOPLINE:

Patients undergoing systemic therapy for advanced cancer who received monthly screening for financial toxicity for up to 1 year were less likely to develop financial difficulties or have their financial issues get worse.

METHODOLOGY:

• About one in five cancer survivors report experiencing financial toxicity, but financial monitoring is not a routine part of clinical care.
• In the current analysis, researchers evaluated whether screening for financial toxicity during routine care could prevent patients with advanced cancer from developing financial difficulties.
• The study involved 1,191 patients undergoing systemic therapy for metastatic cancer at 52 community oncology practices in the United States. The practices were randomly assigned in a 1:1 ratio to use either digital symptom monitoring through patient-reported outcomes or usual care.
• With the digital monitoring, patients received online or automated telephone surveys between visits inquiring about symptoms, functioning, and financial toxicity for up to 1 year.
• The financial toxicity inquiry consisted of a single-item screening question, scored on a 0-5 scale, from the Functional Assessment of Chronic Illness Therapy COmprehensive Score for financial Toxicity (FACIT-COST): “In the last month, my illness has been a financial hardship to my family and me.” Scores higher than 2, indicating “quite a bit or very much,” triggered an automated alert to practice nurses.
• At different points, patients in both groups also received a question to assess a change in financial difficulties from baseline: “During the past week, has your physical condition or medical treatment caused you financial difficulties?”

TAKEAWAY:

• Among patients receiving financial toxicity screening, 30.2% developed or experienced worsening financial difficulties, compared with 39.0% of those treated at practices without the financial burden screening (P = .004).
• The results corresponded to a number needed to screen of 11.4, meaning that, on average, 11.4 patients would need to be screened for 1 additional patient to avoid developing financial difficulties or having their financial challenges get worse.
• Nurses and patients who were interviewed noted that financial screening helped them identify patients for financial counseling who otherwise may be reluctant to seek or were unaware of such assistance.
• The intervention had a similar positive impact among White patients, men, and women, compared with the overall study population, but appeared to have no effect among Black patients (38% for intervention vs. 39% for the control).

IN PRACTICE:

The findings suggest that “remote symptom monitoring, including [financial toxicity] screening, protected patients undergoing systemic therapy from experiencing worsening financial difficulties,” the authors concluded. Given the relatively low number needed to screen, “financial toxicity screening appears to be a high-yield intervention.”

SOURCE:

The analysis, by Victoria S. Binder, MD, of Memorial Sloan Kettering Cancer Center, New York, and colleagues was published online in the Journal of Clinical Oncology.

LIMITATIONS:

• The use of a single-item measure could call the replicability of the findings into question.
• Given that the financial toxicity monitoring did not appear to be effective among Black patients, the screening intervention may not adequately address all racial and ethnic groups.

DISCLOSURES:

The trial was sponsored by the Foundation of the Alliance for Clinical Trials in Oncology and was supported in part by a Patient-Centered Outcomes Research Institute Award IHS-1511-33, 392. The authors’ disclosures are detailed in the published study.

A version of this article first appeared on Medscape.com.

TOPLINE:

Patients undergoing systemic therapy for advanced cancer who received monthly screening for financial toxicity for up to 1 year were less likely to develop financial difficulties or have their financial issues get worse.

METHODOLOGY:

• About one in five cancer survivors report experiencing financial toxicity, but financial monitoring is not a routine part of clinical care.
• In the current analysis, researchers evaluated whether screening for financial toxicity during routine care could prevent patients with advanced cancer from developing financial difficulties.
• The study involved 1,191 patients undergoing systemic therapy for metastatic cancer at 52 community oncology practices in the United States. The practices were randomly assigned in a 1:1 ratio to use either digital symptom monitoring through patient-reported outcomes or usual care.
• With the digital monitoring, patients received online or automated telephone surveys between visits inquiring about symptoms, functioning, and financial toxicity for up to 1 year.
• The financial toxicity inquiry consisted of a single-item screening question, scored on a 0-5 scale, from the Functional Assessment of Chronic Illness Therapy COmprehensive Score for financial Toxicity (FACIT-COST): “In the last month, my illness has been a financial hardship to my family and me.” Scores higher than 2, indicating “quite a bit or very much,” triggered an automated alert to practice nurses.
• At different points, patients in both groups also received a question to assess a change in financial difficulties from baseline: “During the past week, has your physical condition or medical treatment caused you financial difficulties?”

TAKEAWAY:

• Among patients receiving financial toxicity screening, 30.2% developed or experienced worsening financial difficulties, compared with 39.0% of those treated at practices without the financial burden screening (P = .004).
• The results corresponded to a number needed to screen of 11.4, meaning that, on average, 11.4 patients would need to be screened for 1 additional patient to avoid developing financial difficulties or having their financial challenges get worse.
• Nurses and patients who were interviewed noted that financial screening helped them identify patients for financial counseling who otherwise may be reluctant to seek or were unaware of such assistance.
• The intervention had a similar positive impact among White patients, men, and women, compared with the overall study population, but appeared to have no effect among Black patients (38% for intervention vs. 39% for the control).

IN PRACTICE:

The findings suggest that “remote symptom monitoring, including [financial toxicity] screening, protected patients undergoing systemic therapy from experiencing worsening financial difficulties,” the authors concluded. Given the relatively low number needed to screen, “financial toxicity screening appears to be a high-yield intervention.”

SOURCE:

The analysis, by Victoria S. Binder, MD, of Memorial Sloan Kettering Cancer Center, New York, and colleagues was published online in the Journal of Clinical Oncology.

LIMITATIONS:

• The use of a single-item measure could call the replicability of the findings into question.
• Given that the financial toxicity monitoring did not appear to be effective among Black patients, the screening intervention may not adequately address all racial and ethnic groups.

DISCLOSURES:

The trial was sponsored by the Foundation of the Alliance for Clinical Trials in Oncology and was supported in part by a Patient-Centered Outcomes Research Institute Award IHS-1511-33, 392. The authors’ disclosures are detailed in the published study.

A version of this article first appeared on Medscape.com.

TOPLINE:

Patients undergoing systemic therapy for advanced cancer who received monthly screening for financial toxicity for up to 1 year were less likely to develop financial difficulties or have their financial issues get worse.

METHODOLOGY:

• About one in five cancer survivors report experiencing financial toxicity, but financial monitoring is not a routine part of clinical care.
• In the current analysis, researchers evaluated whether screening for financial toxicity during routine care could prevent patients with advanced cancer from developing financial difficulties.
• The study involved 1,191 patients undergoing systemic therapy for metastatic cancer at 52 community oncology practices in the United States. The practices were randomly assigned in a 1:1 ratio to use either digital symptom monitoring through patient-reported outcomes or usual care.
• With the digital monitoring, patients received online or automated telephone surveys between visits inquiring about symptoms, functioning, and financial toxicity for up to 1 year.
• The financial toxicity inquiry consisted of a single-item screening question, scored on a 0-5 scale, from the Functional Assessment of Chronic Illness Therapy COmprehensive Score for financial Toxicity (FACIT-COST): “In the last month, my illness has been a financial hardship to my family and me.” Scores higher than 2, indicating “quite a bit or very much,” triggered an automated alert to practice nurses.
• At different points, patients in both groups also received a question to assess a change in financial difficulties from baseline: “During the past week, has your physical condition or medical treatment caused you financial difficulties?”

TAKEAWAY:

• Among patients receiving financial toxicity screening, 30.2% developed or experienced worsening financial difficulties, compared with 39.0% of those treated at practices without the financial burden screening (P = .004).
• The results corresponded to a number needed to screen of 11.4, meaning that, on average, 11.4 patients would need to be screened for 1 additional patient to avoid developing financial difficulties or having their financial challenges get worse.
• Nurses and patients who were interviewed noted that financial screening helped them identify patients for financial counseling who otherwise may be reluctant to seek or were unaware of such assistance.
• The intervention had a similar positive impact among White patients, men, and women, compared with the overall study population, but appeared to have no effect among Black patients (38% for intervention vs. 39% for the control).

IN PRACTICE:

The findings suggest that “remote symptom monitoring, including [financial toxicity] screening, protected patients undergoing systemic therapy from experiencing worsening financial difficulties,” the authors concluded. Given the relatively low number needed to screen, “financial toxicity screening appears to be a high-yield intervention.”

SOURCE:

The analysis, by Victoria S. Binder, MD, of Memorial Sloan Kettering Cancer Center, New York, and colleagues was published online in the Journal of Clinical Oncology.

LIMITATIONS:

• The use of a single-item measure could call the replicability of the findings into question.
• Given that the financial toxicity monitoring did not appear to be effective among Black patients, the screening intervention may not adequately address all racial and ethnic groups.

DISCLOSURES:

The trial was sponsored by the Foundation of the Alliance for Clinical Trials in Oncology and was supported in part by a Patient-Centered Outcomes Research Institute Award IHS-1511-33, 392. The authors’ disclosures are detailed in the published study.

A version of this article first appeared on Medscape.com.

Concizumab (Novo Nordisk), a subcutaneous monoclonal antibody administered once daily, shows significant reductions in annualized bleeding rates in patients with hemophilia A or B with inhibitors, potentially representing the first subcutaneous treatment option for patients with hemophilia B with inhibitors.

“These results demonstrate the potential of concizumab as an efficacious treatment option for people living with hemophilia A or B with inhibitors – the latter a population with severely limited treatment options,” first author Tadashi Matsushita, MD, PhD, of the department of transfusion medicine, Nagoya (Japan) University Hospital, said in an interview regarding the study, published in the New England Journal of Medicine.

The results are from the prospective, multicenter, phase 3 explorer7 trial, involving 133 patients, including 80 with hemophilia A and 53 had hemophilia B, all with inhibitors, a complication of hemophilia therapy in which antibodies ‘inhibit’ clot formation and complicate standard treatment.

The patients, aged 12 or older and all receiving on-demand treatment with bypassing agents, were randomized to receive no prophylaxis for at least 24 weeks (n = 19) or concizumab prophylaxis for at least 32 weeks (n = 33), with the remaining patients nonrandomly assigned to two groups receiving concizumab prophylaxis for at least 24 weeks (n = 81).

For the primary endpoint of the estimated mean annualized bleeding rate, the rate in the no-prophylaxis group was 11.8 episodes versus just 1.7 episodes in the concizumab prophylaxis 32-week group (rate ratio, 0.14; P < .001).

The overall median annualized bleeding rate for patients in all three groups receiving concizumab was zero episodes.

Annualized rates of treated spontaneous, joint, and target joint bleeding episodes were also lower in the concizumab groups versus the no-prophylaxis group, with annualized rate ratios that were similar to the annualized rate ratio for the primary endpoint.

While similar annualized bleeding rates were observed in hemophilia subtypes, the study wasn’t powered to show superiority according the hemophilia A or B, the authors noted.

Plasma concentrations of concizumab remained stable over the course of the study.

There were no significant differences in terms of key secondary endpoints of change in bodily pain and physical functioning scores from the start of treatment to week 24.
 

Pause for safety

Treatment in the study was paused for 6 months from March 2020 to August 2020 following nonfatal thromboembolic events occurring in three patients receiving concizumab, including one in the explorer7 trial and two in the concurrent explorer8 trial, evaluating the drug in patients with hemophilia without inhibitors.

The authors wrote that the three patients had all received concomitant treatment for bleeding and had thrombotic risk factors including obesity and other comorbidities.

The trial resumed following mitigation measures that included revising the dosing regimen to include a 1–mg/kg concizumab loading dose, followed by a subcutaneous once-daily dose of 0.2 mg/kg concizumab. No further thromboembolic events were reported after the pause. Otherwise, adverse events were mainly low grade, with serious events being rare.
 

Option for hemophilia B important

Of the two disease types, hemophilia A is much more common, with an estimated prevalence in the United States of 12 cases per 100,000 males versus hemophilia B, which has a rate of only 3.7 cases per 100,000, according to the Centers for Disease Control and Prevention. Women make up only about 1% of cases with moderate to severe hemophilia.

A standard treatment of hemophilia A or B is prophylaxis with factor replacement therapies allow for improved clotting and reduced bleeding. However, one caveat is the need for intravenous injections, as often as once daily in some cases.

The development of inhibitors in response to replacement therapy may further necessitate the need for treatment with bypassing agents for breakthrough bleeding.

As an alternative, non–factor replacement therapies can promote coagulation, notably the factor VIII mimetic emicizumab, given by subcutaneous injection, and approved by the Food and Drug Administration in 2018 for patients with and without inhibitors.

Emicizumab is recommended by the World Federation on Hemophilia over bypassing agents as prophylaxis for patients with hemophilia A and persistent inhibitors.

Importantly, however, there are no effective prophylactic treatments or easily administered subcutaneous therapies available for hemophilia B with inhibitors, underscoring the potential importance of concizumab, which targets the tissue factor pathway inhibitor protein, linked to coagulation.

“Concizumab has the potential to become the first subcutaneous and first-in-class treatment for hemophilia B with inhibitors,” Dr. Matsushita said. “There are other therapies investigated for hemophilia B with and without inhibitors still in clinical development,” he noted.
 

FDA resubmission planned

In May, Novo Nordisk announced that the FDA had rejected its application for concizumab, requesting more information on the drug’s manufacturing process and its system for the monitoring and dosing of patients to ensure proper drug administration. In a statement, Novo Nordisk reported its plans to move ahead.

“Novo Nordisk has begun addressing the FDA’s feedback and is working closely with the FDA as plans for resubmission continue,” the company reported. “We are confident in the potential of concizumab to address a significant unmet need, particularly for people with hemophilia B with inhibitors who currently have limited prophylactic options and are committed to bringing this important treatment to people with hemophilia with inhibitors living in the U.S.A.”

Meanwhile in Canada, concizumab was approved in March 2023 for the treatment of adolescent and adult patients with hemophilia B with inhibitors and who require routine prophylaxis to prevent or reduce the frequency of bleeding episodes.

The authors wrote that concizumab continues to be investigated across all hemophilia subtypes, including in the explorer10 study, which is evaluating the drug in children living with hemophilia A or B, with and without inhibitors.

The study was supported by Novo Nordisk. Dr. Matsushita reported speaking for and participating on a scientific advisory board of Novo Nordisk.

Concizumab (Novo Nordisk), a subcutaneous monoclonal antibody administered once daily, shows significant reductions in annualized bleeding rates in patients with hemophilia A or B with inhibitors, potentially representing the first subcutaneous treatment option for patients with hemophilia B with inhibitors.

“These results demonstrate the potential of concizumab as an efficacious treatment option for people living with hemophilia A or B with inhibitors – the latter a population with severely limited treatment options,” first author Tadashi Matsushita, MD, PhD, of the department of transfusion medicine, Nagoya (Japan) University Hospital, said in an interview regarding the study, published in the New England Journal of Medicine.

The results are from the prospective, multicenter, phase 3 explorer7 trial, involving 133 patients, including 80 with hemophilia A and 53 had hemophilia B, all with inhibitors, a complication of hemophilia therapy in which antibodies ‘inhibit’ clot formation and complicate standard treatment.

The patients, aged 12 or older and all receiving on-demand treatment with bypassing agents, were randomized to receive no prophylaxis for at least 24 weeks (n = 19) or concizumab prophylaxis for at least 32 weeks (n = 33), with the remaining patients nonrandomly assigned to two groups receiving concizumab prophylaxis for at least 24 weeks (n = 81).

For the primary endpoint of the estimated mean annualized bleeding rate, the rate in the no-prophylaxis group was 11.8 episodes versus just 1.7 episodes in the concizumab prophylaxis 32-week group (rate ratio, 0.14; P < .001).

The overall median annualized bleeding rate for patients in all three groups receiving concizumab was zero episodes.

Annualized rates of treated spontaneous, joint, and target joint bleeding episodes were also lower in the concizumab groups versus the no-prophylaxis group, with annualized rate ratios that were similar to the annualized rate ratio for the primary endpoint.

While similar annualized bleeding rates were observed in hemophilia subtypes, the study wasn’t powered to show superiority according the hemophilia A or B, the authors noted.

Plasma concentrations of concizumab remained stable over the course of the study.

There were no significant differences in terms of key secondary endpoints of change in bodily pain and physical functioning scores from the start of treatment to week 24.
 

Pause for safety

Treatment in the study was paused for 6 months from March 2020 to August 2020 following nonfatal thromboembolic events occurring in three patients receiving concizumab, including one in the explorer7 trial and two in the concurrent explorer8 trial, evaluating the drug in patients with hemophilia without inhibitors.

The authors wrote that the three patients had all received concomitant treatment for bleeding and had thrombotic risk factors including obesity and other comorbidities.

The trial resumed following mitigation measures that included revising the dosing regimen to include a 1–mg/kg concizumab loading dose, followed by a subcutaneous once-daily dose of 0.2 mg/kg concizumab. No further thromboembolic events were reported after the pause. Otherwise, adverse events were mainly low grade, with serious events being rare.
 

Option for hemophilia B important

Of the two disease types, hemophilia A is much more common, with an estimated prevalence in the United States of 12 cases per 100,000 males versus hemophilia B, which has a rate of only 3.7 cases per 100,000, according to the Centers for Disease Control and Prevention. Women make up only about 1% of cases with moderate to severe hemophilia.

A standard treatment of hemophilia A or B is prophylaxis with factor replacement therapies allow for improved clotting and reduced bleeding. However, one caveat is the need for intravenous injections, as often as once daily in some cases.

The development of inhibitors in response to replacement therapy may further necessitate the need for treatment with bypassing agents for breakthrough bleeding.

As an alternative, non–factor replacement therapies can promote coagulation, notably the factor VIII mimetic emicizumab, given by subcutaneous injection, and approved by the Food and Drug Administration in 2018 for patients with and without inhibitors.

Emicizumab is recommended by the World Federation on Hemophilia over bypassing agents as prophylaxis for patients with hemophilia A and persistent inhibitors.

Importantly, however, there are no effective prophylactic treatments or easily administered subcutaneous therapies available for hemophilia B with inhibitors, underscoring the potential importance of concizumab, which targets the tissue factor pathway inhibitor protein, linked to coagulation.

“Concizumab has the potential to become the first subcutaneous and first-in-class treatment for hemophilia B with inhibitors,” Dr. Matsushita said. “There are other therapies investigated for hemophilia B with and without inhibitors still in clinical development,” he noted.
 

FDA resubmission planned

In May, Novo Nordisk announced that the FDA had rejected its application for concizumab, requesting more information on the drug’s manufacturing process and its system for the monitoring and dosing of patients to ensure proper drug administration. In a statement, Novo Nordisk reported its plans to move ahead.

“Novo Nordisk has begun addressing the FDA’s feedback and is working closely with the FDA as plans for resubmission continue,” the company reported. “We are confident in the potential of concizumab to address a significant unmet need, particularly for people with hemophilia B with inhibitors who currently have limited prophylactic options and are committed to bringing this important treatment to people with hemophilia with inhibitors living in the U.S.A.”

Meanwhile in Canada, concizumab was approved in March 2023 for the treatment of adolescent and adult patients with hemophilia B with inhibitors and who require routine prophylaxis to prevent or reduce the frequency of bleeding episodes.

The authors wrote that concizumab continues to be investigated across all hemophilia subtypes, including in the explorer10 study, which is evaluating the drug in children living with hemophilia A or B, with and without inhibitors.

The study was supported by Novo Nordisk. Dr. Matsushita reported speaking for and participating on a scientific advisory board of Novo Nordisk.

Concizumab (Novo Nordisk), a subcutaneous monoclonal antibody administered once daily, shows significant reductions in annualized bleeding rates in patients with hemophilia A or B with inhibitors, potentially representing the first subcutaneous treatment option for patients with hemophilia B with inhibitors.

“These results demonstrate the potential of concizumab as an efficacious treatment option for people living with hemophilia A or B with inhibitors – the latter a population with severely limited treatment options,” first author Tadashi Matsushita, MD, PhD, of the department of transfusion medicine, Nagoya (Japan) University Hospital, said in an interview regarding the study, published in the New England Journal of Medicine.

The results are from the prospective, multicenter, phase 3 explorer7 trial, involving 133 patients, including 80 with hemophilia A and 53 had hemophilia B, all with inhibitors, a complication of hemophilia therapy in which antibodies ‘inhibit’ clot formation and complicate standard treatment.

The patients, aged 12 or older and all receiving on-demand treatment with bypassing agents, were randomized to receive no prophylaxis for at least 24 weeks (n = 19) or concizumab prophylaxis for at least 32 weeks (n = 33), with the remaining patients nonrandomly assigned to two groups receiving concizumab prophylaxis for at least 24 weeks (n = 81).

For the primary endpoint of the estimated mean annualized bleeding rate, the rate in the no-prophylaxis group was 11.8 episodes versus just 1.7 episodes in the concizumab prophylaxis 32-week group (rate ratio, 0.14; P < .001).

The overall median annualized bleeding rate for patients in all three groups receiving concizumab was zero episodes.

Annualized rates of treated spontaneous, joint, and target joint bleeding episodes were also lower in the concizumab groups versus the no-prophylaxis group, with annualized rate ratios that were similar to the annualized rate ratio for the primary endpoint.

While similar annualized bleeding rates were observed in hemophilia subtypes, the study wasn’t powered to show superiority according the hemophilia A or B, the authors noted.

Plasma concentrations of concizumab remained stable over the course of the study.

There were no significant differences in terms of key secondary endpoints of change in bodily pain and physical functioning scores from the start of treatment to week 24.
 

Pause for safety

Treatment in the study was paused for 6 months from March 2020 to August 2020 following nonfatal thromboembolic events occurring in three patients receiving concizumab, including one in the explorer7 trial and two in the concurrent explorer8 trial, evaluating the drug in patients with hemophilia without inhibitors.

The authors wrote that the three patients had all received concomitant treatment for bleeding and had thrombotic risk factors including obesity and other comorbidities.

The trial resumed following mitigation measures that included revising the dosing regimen to include a 1–mg/kg concizumab loading dose, followed by a subcutaneous once-daily dose of 0.2 mg/kg concizumab. No further thromboembolic events were reported after the pause. Otherwise, adverse events were mainly low grade, with serious events being rare.
 

Option for hemophilia B important

Of the two disease types, hemophilia A is much more common, with an estimated prevalence in the United States of 12 cases per 100,000 males versus hemophilia B, which has a rate of only 3.7 cases per 100,000, according to the Centers for Disease Control and Prevention. Women make up only about 1% of cases with moderate to severe hemophilia.

A standard treatment of hemophilia A or B is prophylaxis with factor replacement therapies allow for improved clotting and reduced bleeding. However, one caveat is the need for intravenous injections, as often as once daily in some cases.

The development of inhibitors in response to replacement therapy may further necessitate the need for treatment with bypassing agents for breakthrough bleeding.

As an alternative, non–factor replacement therapies can promote coagulation, notably the factor VIII mimetic emicizumab, given by subcutaneous injection, and approved by the Food and Drug Administration in 2018 for patients with and without inhibitors.

Emicizumab is recommended by the World Federation on Hemophilia over bypassing agents as prophylaxis for patients with hemophilia A and persistent inhibitors.

Importantly, however, there are no effective prophylactic treatments or easily administered subcutaneous therapies available for hemophilia B with inhibitors, underscoring the potential importance of concizumab, which targets the tissue factor pathway inhibitor protein, linked to coagulation.

“Concizumab has the potential to become the first subcutaneous and first-in-class treatment for hemophilia B with inhibitors,” Dr. Matsushita said. “There are other therapies investigated for hemophilia B with and without inhibitors still in clinical development,” he noted.
 

FDA resubmission planned

In May, Novo Nordisk announced that the FDA had rejected its application for concizumab, requesting more information on the drug’s manufacturing process and its system for the monitoring and dosing of patients to ensure proper drug administration. In a statement, Novo Nordisk reported its plans to move ahead.

“Novo Nordisk has begun addressing the FDA’s feedback and is working closely with the FDA as plans for resubmission continue,” the company reported. “We are confident in the potential of concizumab to address a significant unmet need, particularly for people with hemophilia B with inhibitors who currently have limited prophylactic options and are committed to bringing this important treatment to people with hemophilia with inhibitors living in the U.S.A.”

Meanwhile in Canada, concizumab was approved in March 2023 for the treatment of adolescent and adult patients with hemophilia B with inhibitors and who require routine prophylaxis to prevent or reduce the frequency of bleeding episodes.

The authors wrote that concizumab continues to be investigated across all hemophilia subtypes, including in the explorer10 study, which is evaluating the drug in children living with hemophilia A or B, with and without inhibitors.

The study was supported by Novo Nordisk. Dr. Matsushita reported speaking for and participating on a scientific advisory board of Novo Nordisk.

Pediatric patients receiving donor stem cell transplantion with healthier pretransplant gut microbiota diversity show improved rates of survival and a lower risk of developing acute graft versus host disease (GvHD), similar to the patterns reported in adults.

“To the best of our knowledge, we present the first evidence of an association between pretransplantation lower gut microbiota diversity and poorer outcome in children undergoing allo-HSCT,” the authors report, in research published in the journal Blood. “Our findings underscore the importance of pre-transplant gut microbiota diversity and compositional structure in influencing allo-HSCT-related clinical outcomes in the pediatric setting.”

While allogeneic hematopoietic stem cell transplantation (allo-HSCT) can be potentially curative of hematologic malignancies, the stem cell transplantation process can wreak havoc on gut microbiota, because of factors including the conditioning regimen, antibiotic exposure, and dietary changes.

Specifically, the process can cause a substantial decrease in necessary alpha diversity and a potential expansion of possibly pathogenic bacteria.

While poor gut microbiota diversity has been linked to higher mortality in adult patients receiving allo-HSCT, research on the effects in pediatric patients is lacking.

“The gut microbiota of children differs from adults’ one, and this accounts for the need for specific pediatric studies on the gut microbiota-to–allo-HSCT relationship,” the authors write.

For the multicenter study, first author Riccardo Masetti, MD, PhD, of the department of pediatric oncology and hematology at the University of Bologna, Italy, and colleagues analyzed the gut microbiota diversity of 90 pediatric allo-HSCT recipients at four centers in Italy and one in Poland, stratifying the patients into groups of higher and lower diversity pretransplantation and again at the time of neutrophil engraftment.

Overall, gut microbiota diversity significantly declined from before allo-HSCT to afterward, at the time of neutrophil engraftment (P < .0001), with lower diversity observed in patients 3 years of age or younger.

With a median follow-up of 52 months, compared with the lower diversity group, those with higher diversity prior to transplantation had a significantly higher probability of overall survival (hazard ratio, 0.26; P = .011), after adjustment for age, graft source, donor type, intensity of conditioning regimen, center, and type of disease, with estimated overall survival at 52 months after allo-HSCT of 88.9% for the higher diversity group and 62.7% for the lower diversity group.

The cumulative incidence of grade II-IV acute GvHD was significantly lower for the higher diversity group versus lower diversity (20.0 versus 44.4, respectively; P = .017), as were the incidence rates of grade III-IV acute GvHD (2.2 versus 20.0; P = .007).

There were, however, no significant differences between the low and high diversity gut microbiota groups in relapse-free survival (P = .091).

The higher diversity group notably had higher relative abundances of potentially health-related bacterial families, including Ruminococcaceae and Oscillospiraceae, while the lower diversity group showed an overabundance of Enterococcaceae and Enterobacteriaceae.

Of note, the results differ from those observed in adults, among whom gut microbiota diversity before as well as after transplantation has been significantly associated with transplant outcomes, whereas with children, the association was limited to diversity prior to transplant.

In general, children have significantly lower diversity of gut microbiota than adults, with varying functional properties, and microbiota that is more easily modified by environmental factors, with larger changes occurring upon exposure to external stressors, the authors explain.

“Considering these different ecological properties compared to adults, we hypothesize that allo-HSCT–induced dysbiosis in the pediatric setting may imply loss of age-related gut microbiota signatures, including alpha diversity, with high interpatient variability,” they say.

Characteristics that were associated with higher or lower gut microbiota diversity prior to allo-HSCT included the treating center, suggesting that the geographical region may affect the diversity and the type of antibiotic exposure prior to the transplant.

Limitations included that “we didn’t assess other pretransplant characteristics such as the type of chemotherapy received, or the lifestyle, and this should be addressed in future studies on larger cohorts,” Dr. Masetti said in an interview.

While lengthy delays in screening of samples are barriers in the use of the gut microbiome as a tool in clinical practice, he noted that clinicians can take key measures to improve the microbiota.

“[Preventive measures] include the avoidance of unnecessary antibiotic treatment, which has a detrimental effect on the microbiota,” he said. “Moreover, some dietary changes may promote microbiota health.”

In addition, key measures can be taken during the allo-HSCT to preserve the microbiota, he added.

“In our center, we use enteral nutrition with a nasogastric tube rather than parenteral nutrition, which helps the microbiota to recover faster,” Dr. Masetti explained. “Moreover, other interventional measures such as fecal microbiota transplantation or the use of probiotics are under testing.”

“In particular, our data emphasize the importance of an overall healthy network, rather than the abundance of specific families or genera, in preventing complications and unfavorable outcomes.”

Commenting on the study, Robert Jenq, MD, an assistant professor in the departments of genomic medicine and stem cell transplantation and cellular therapy at the University of Texas M.D. Anderson Cancer Center, Houston, noted that with the growing evidence of the effects of poor gut microbiota diversity on clinical outcomes, multiple early-phase clinical trials are being conducted to test various strategies to prevent or treat gut injury.

“I’m not aware of any one approach that has shown enough promise to warrant being tested in multicenter studies yet, but it’s still a bit early,” Dr. Jenq said.“In the meantime, discontinuing or de-escalating antibiotics when medically safe, and encouraging patients to eat as much as they’re able to is a reasonable recommendation.”

Dr. Jenq added that, with most of the data on the issue being retrospective, a causative role has not been established, and “the finding of an association between the gut microbiota composition and survival, while interesting and provocative, does not provide evidence that intervening on the gut microbiota will lead to a clinical benefit.”

“I’m hopeful that randomized clinical trials will eventually demonstrate that we can protect or restore the gut microbiota, and this will lead to substantial clinical benefits, but this remains to be seen,” he said.

The authors had no disclosures to report. Dr. Jenq is an advisor for Seres Therapeutics, Prolacta Biosciences, and MaaT Pharma.

Pediatric patients receiving donor stem cell transplantion with healthier pretransplant gut microbiota diversity show improved rates of survival and a lower risk of developing acute graft versus host disease (GvHD), similar to the patterns reported in adults.

“To the best of our knowledge, we present the first evidence of an association between pretransplantation lower gut microbiota diversity and poorer outcome in children undergoing allo-HSCT,” the authors report, in research published in the journal Blood. “Our findings underscore the importance of pre-transplant gut microbiota diversity and compositional structure in influencing allo-HSCT-related clinical outcomes in the pediatric setting.”

While allogeneic hematopoietic stem cell transplantation (allo-HSCT) can be potentially curative of hematologic malignancies, the stem cell transplantation process can wreak havoc on gut microbiota, because of factors including the conditioning regimen, antibiotic exposure, and dietary changes.

Specifically, the process can cause a substantial decrease in necessary alpha diversity and a potential expansion of possibly pathogenic bacteria.

While poor gut microbiota diversity has been linked to higher mortality in adult patients receiving allo-HSCT, research on the effects in pediatric patients is lacking.

“The gut microbiota of children differs from adults’ one, and this accounts for the need for specific pediatric studies on the gut microbiota-to–allo-HSCT relationship,” the authors write.

For the multicenter study, first author Riccardo Masetti, MD, PhD, of the department of pediatric oncology and hematology at the University of Bologna, Italy, and colleagues analyzed the gut microbiota diversity of 90 pediatric allo-HSCT recipients at four centers in Italy and one in Poland, stratifying the patients into groups of higher and lower diversity pretransplantation and again at the time of neutrophil engraftment.

Overall, gut microbiota diversity significantly declined from before allo-HSCT to afterward, at the time of neutrophil engraftment (P < .0001), with lower diversity observed in patients 3 years of age or younger.

With a median follow-up of 52 months, compared with the lower diversity group, those with higher diversity prior to transplantation had a significantly higher probability of overall survival (hazard ratio, 0.26; P = .011), after adjustment for age, graft source, donor type, intensity of conditioning regimen, center, and type of disease, with estimated overall survival at 52 months after allo-HSCT of 88.9% for the higher diversity group and 62.7% for the lower diversity group.

The cumulative incidence of grade II-IV acute GvHD was significantly lower for the higher diversity group versus lower diversity (20.0 versus 44.4, respectively; P = .017), as were the incidence rates of grade III-IV acute GvHD (2.2 versus 20.0; P = .007).

There were, however, no significant differences between the low and high diversity gut microbiota groups in relapse-free survival (P = .091).

The higher diversity group notably had higher relative abundances of potentially health-related bacterial families, including Ruminococcaceae and Oscillospiraceae, while the lower diversity group showed an overabundance of Enterococcaceae and Enterobacteriaceae.

Of note, the results differ from those observed in adults, among whom gut microbiota diversity before as well as after transplantation has been significantly associated with transplant outcomes, whereas with children, the association was limited to diversity prior to transplant.

In general, children have significantly lower diversity of gut microbiota than adults, with varying functional properties, and microbiota that is more easily modified by environmental factors, with larger changes occurring upon exposure to external stressors, the authors explain.

“Considering these different ecological properties compared to adults, we hypothesize that allo-HSCT–induced dysbiosis in the pediatric setting may imply loss of age-related gut microbiota signatures, including alpha diversity, with high interpatient variability,” they say.

Characteristics that were associated with higher or lower gut microbiota diversity prior to allo-HSCT included the treating center, suggesting that the geographical region may affect the diversity and the type of antibiotic exposure prior to the transplant.

Limitations included that “we didn’t assess other pretransplant characteristics such as the type of chemotherapy received, or the lifestyle, and this should be addressed in future studies on larger cohorts,” Dr. Masetti said in an interview.

While lengthy delays in screening of samples are barriers in the use of the gut microbiome as a tool in clinical practice, he noted that clinicians can take key measures to improve the microbiota.

“[Preventive measures] include the avoidance of unnecessary antibiotic treatment, which has a detrimental effect on the microbiota,” he said. “Moreover, some dietary changes may promote microbiota health.”

In addition, key measures can be taken during the allo-HSCT to preserve the microbiota, he added.

“In our center, we use enteral nutrition with a nasogastric tube rather than parenteral nutrition, which helps the microbiota to recover faster,” Dr. Masetti explained. “Moreover, other interventional measures such as fecal microbiota transplantation or the use of probiotics are under testing.”

“In particular, our data emphasize the importance of an overall healthy network, rather than the abundance of specific families or genera, in preventing complications and unfavorable outcomes.”

Commenting on the study, Robert Jenq, MD, an assistant professor in the departments of genomic medicine and stem cell transplantation and cellular therapy at the University of Texas M.D. Anderson Cancer Center, Houston, noted that with the growing evidence of the effects of poor gut microbiota diversity on clinical outcomes, multiple early-phase clinical trials are being conducted to test various strategies to prevent or treat gut injury.

“I’m not aware of any one approach that has shown enough promise to warrant being tested in multicenter studies yet, but it’s still a bit early,” Dr. Jenq said.“In the meantime, discontinuing or de-escalating antibiotics when medically safe, and encouraging patients to eat as much as they’re able to is a reasonable recommendation.”

Dr. Jenq added that, with most of the data on the issue being retrospective, a causative role has not been established, and “the finding of an association between the gut microbiota composition and survival, while interesting and provocative, does not provide evidence that intervening on the gut microbiota will lead to a clinical benefit.”

“I’m hopeful that randomized clinical trials will eventually demonstrate that we can protect or restore the gut microbiota, and this will lead to substantial clinical benefits, but this remains to be seen,” he said.

The authors had no disclosures to report. Dr. Jenq is an advisor for Seres Therapeutics, Prolacta Biosciences, and MaaT Pharma.

Pediatric patients receiving donor stem cell transplantion with healthier pretransplant gut microbiota diversity show improved rates of survival and a lower risk of developing acute graft versus host disease (GvHD), similar to the patterns reported in adults.

“To the best of our knowledge, we present the first evidence of an association between pretransplantation lower gut microbiota diversity and poorer outcome in children undergoing allo-HSCT,” the authors report, in research published in the journal Blood. “Our findings underscore the importance of pre-transplant gut microbiota diversity and compositional structure in influencing allo-HSCT-related clinical outcomes in the pediatric setting.”

While allogeneic hematopoietic stem cell transplantation (allo-HSCT) can be potentially curative of hematologic malignancies, the stem cell transplantation process can wreak havoc on gut microbiota, because of factors including the conditioning regimen, antibiotic exposure, and dietary changes.

Specifically, the process can cause a substantial decrease in necessary alpha diversity and a potential expansion of possibly pathogenic bacteria.

While poor gut microbiota diversity has been linked to higher mortality in adult patients receiving allo-HSCT, research on the effects in pediatric patients is lacking.

“The gut microbiota of children differs from adults’ one, and this accounts for the need for specific pediatric studies on the gut microbiota-to–allo-HSCT relationship,” the authors write.

For the multicenter study, first author Riccardo Masetti, MD, PhD, of the department of pediatric oncology and hematology at the University of Bologna, Italy, and colleagues analyzed the gut microbiota diversity of 90 pediatric allo-HSCT recipients at four centers in Italy and one in Poland, stratifying the patients into groups of higher and lower diversity pretransplantation and again at the time of neutrophil engraftment.

Overall, gut microbiota diversity significantly declined from before allo-HSCT to afterward, at the time of neutrophil engraftment (P < .0001), with lower diversity observed in patients 3 years of age or younger.

With a median follow-up of 52 months, compared with the lower diversity group, those with higher diversity prior to transplantation had a significantly higher probability of overall survival (hazard ratio, 0.26; P = .011), after adjustment for age, graft source, donor type, intensity of conditioning regimen, center, and type of disease, with estimated overall survival at 52 months after allo-HSCT of 88.9% for the higher diversity group and 62.7% for the lower diversity group.

The cumulative incidence of grade II-IV acute GvHD was significantly lower for the higher diversity group versus lower diversity (20.0 versus 44.4, respectively; P = .017), as were the incidence rates of grade III-IV acute GvHD (2.2 versus 20.0; P = .007).

There were, however, no significant differences between the low and high diversity gut microbiota groups in relapse-free survival (P = .091).

The higher diversity group notably had higher relative abundances of potentially health-related bacterial families, including Ruminococcaceae and Oscillospiraceae, while the lower diversity group showed an overabundance of Enterococcaceae and Enterobacteriaceae.

Of note, the results differ from those observed in adults, among whom gut microbiota diversity before as well as after transplantation has been significantly associated with transplant outcomes, whereas with children, the association was limited to diversity prior to transplant.

In general, children have significantly lower diversity of gut microbiota than adults, with varying functional properties, and microbiota that is more easily modified by environmental factors, with larger changes occurring upon exposure to external stressors, the authors explain.

“Considering these different ecological properties compared to adults, we hypothesize that allo-HSCT–induced dysbiosis in the pediatric setting may imply loss of age-related gut microbiota signatures, including alpha diversity, with high interpatient variability,” they say.

Characteristics that were associated with higher or lower gut microbiota diversity prior to allo-HSCT included the treating center, suggesting that the geographical region may affect the diversity and the type of antibiotic exposure prior to the transplant.

Limitations included that “we didn’t assess other pretransplant characteristics such as the type of chemotherapy received, or the lifestyle, and this should be addressed in future studies on larger cohorts,” Dr. Masetti said in an interview.

While lengthy delays in screening of samples are barriers in the use of the gut microbiome as a tool in clinical practice, he noted that clinicians can take key measures to improve the microbiota.

“[Preventive measures] include the avoidance of unnecessary antibiotic treatment, which has a detrimental effect on the microbiota,” he said. “Moreover, some dietary changes may promote microbiota health.”

In addition, key measures can be taken during the allo-HSCT to preserve the microbiota, he added.

“In our center, we use enteral nutrition with a nasogastric tube rather than parenteral nutrition, which helps the microbiota to recover faster,” Dr. Masetti explained. “Moreover, other interventional measures such as fecal microbiota transplantation or the use of probiotics are under testing.”

“In particular, our data emphasize the importance of an overall healthy network, rather than the abundance of specific families or genera, in preventing complications and unfavorable outcomes.”

Commenting on the study, Robert Jenq, MD, an assistant professor in the departments of genomic medicine and stem cell transplantation and cellular therapy at the University of Texas M.D. Anderson Cancer Center, Houston, noted that with the growing evidence of the effects of poor gut microbiota diversity on clinical outcomes, multiple early-phase clinical trials are being conducted to test various strategies to prevent or treat gut injury.

“I’m not aware of any one approach that has shown enough promise to warrant being tested in multicenter studies yet, but it’s still a bit early,” Dr. Jenq said.“In the meantime, discontinuing or de-escalating antibiotics when medically safe, and encouraging patients to eat as much as they’re able to is a reasonable recommendation.”

Dr. Jenq added that, with most of the data on the issue being retrospective, a causative role has not been established, and “the finding of an association between the gut microbiota composition and survival, while interesting and provocative, does not provide evidence that intervening on the gut microbiota will lead to a clinical benefit.”

“I’m hopeful that randomized clinical trials will eventually demonstrate that we can protect or restore the gut microbiota, and this will lead to substantial clinical benefits, but this remains to be seen,” he said.

The authors had no disclosures to report. Dr. Jenq is an advisor for Seres Therapeutics, Prolacta Biosciences, and MaaT Pharma.

Caffeine consumption may improve thyroid function for people with metabolic disorders, new research shows.

“Although the causal relationship between caffeine intake and thyroid function requires further verification, as an easily obtainable and widely consumed dietary ingredient, caffeine is a potential candidate for improving thyroid health in people with metabolic disorders,” reported the authors in the study, published in Nutritional Journal.

Caffeine intake, within established healthy ranges, showed a nonlinear association with thyroid levels.

Moderate caffeine intake has been associated with reducing the risk of metabolic disorders in addition to showing some mental health benefits. However, research on its effects on thyroid hormone, which importantly plays a key role in systemic metabolism and neurologic development, is lacking.

To investigate the effects, Yu Zhou, of the Department of Rehabilitation Medicine, School of Health, Fujian Medical University, Fuzhou, China, and colleagues evaluated data from the National Health and Nutrition Examination Survey (NHANES) III 2007-2012 study involving 2,582 participants for whom data were available regarding medical conditions, dietary intake, thyroid function, and demographic background.

The participants were divided into three subgroups based on sex, age, body mass index, hyperglycemia, hypertension, and cardio-cerebral vascular disease (CVD).

Group 1 (n = 208) was the most metabolically unhealthy. Patients in that group had the highest BMI and were of oldest age. In addition, that group had higher rates of hypertension, hyperglycemia, and CVD, but, notably, it had the lowest level of caffeine consumption.

In group 2 (n = 543), all participants were current smokers, and 90.4% had a habit of drinking alcohol. That group also had the highest percentage of men.

Group 3 (n = 1,183) was the most metabolically healthy, with more women, younger age, and lowest BMI. No participants in that group had hyperglycemia, hypertension, or CVD.

Group 1, the most metabolically unhealthy, had the highest serum thyroid-stimulating hormone (TSH) levels. Of note, while participants with thyroid diseases were initially excluded from the analysis, higher TSH levels are predictive of subclinical hypothyroidism or progression to overt hypothyroidism.

Overall, there was no association between caffeine and TSH levels.

However, a subgroup analysis of the groups showed that in group 1, caffeine intake correlated with TSH nonlinearly (P = .0019), with minimal average consumption of caffeine (< 9.97 mg/d). There was an association with slightly higher TSH levels (P = .035) after adjustment for age, sex, race, drink, disease state, micronutrients, and macronutrients.

However, in higher, moderate amounts of caffeine consumption (9.97 – 264.97 mg/d), there was an inverse association, with lower TSH (P = .001).

There was no association between daily caffeine consumption of more than 264.97 mg and TSH levels.

For context, a typical 8-ounce cup of coffee generally contains 80-100 mg of caffeine, and the Food and Drug Administration indicates that 400 mg/d of caffeine is safe for healthy adults.

Group 2 consumed the highest amount of caffeine. Notably, that group had the lowest serum TSH levels of the three groups. There were no significant associations between caffeine consumption and TSH levels in group 2 or group 3.

There were no significant associations between caffeine consumption and levels of serum FT4 or FT3, also linked to thyroid dysfunction, in any of the groups.

The findings show that “caffeine consumption was correlated with serum TSH nonlinearly, and when taken in moderate amounts (9.97-264.97 mg/d), caffeine demonstrated a positive correlation with serum TSH levels in patients with metabolic disorders,” the authors concluded.
 

Mechanisms?

Caffeine is believed to modulate pituitary hormone secretion, which has been shown to influence the hypothalamic-pituitary-adrenal axis. The authors speculated that caffeine could potentially affect thyroid activity by affecting pituitary function.

“However, the effects of transient and chronic caffeine administration on human thyroid function need to be verified further, and the related mechanisms remain unclear,” they noted.

Commenting on the study, Maik Pietzner, PhD, of the Berlin Institute of Health, noted that an important limitation of the study is that various patient groups were excluded, including those with abnormal TSH levels.

“What makes me wonder is the high number of exclusions and the focus on very specific groups of people. This almost certainly introduces bias, e.g., what is specific to people not reporting coffee consumption,” Dr. Pietzner said.

Furthermore, “we already know that patients with poor metabolic health do also have slight variations in thyroid hormone levels and also have different dietary patterns,” he explained.

“So reverse confounding might occur in which the poor metabolic health is associated with both poor thyroid hormone levels and coffee consumption,” Dr. Pietzner said.

He also noted the “somewhat odd” finding that the group with the highest metabolic disorders had the lowest coffee consumption, yet the highest TSH levels.

“My guess would be that this might also be a chance finding, given that the distribution of TSH values is very skewed, which can have a strong effect in linear regression models,” Dr. Pietzner said.

In general, “the evidence generated by the study is rather weak, but there is good evidence that higher coffee consumption is linked to better metabolic health, although the exact mechanisms is not known, if indeed causal,” Dr. Pietzner added. “Prospective studies are needed to evaluate whether higher coffee consumption indeed lowers the risk for thyroid disease.”

A version of this article first appeared on Medscape.com.

Caffeine consumption may improve thyroid function for people with metabolic disorders, new research shows.

“Although the causal relationship between caffeine intake and thyroid function requires further verification, as an easily obtainable and widely consumed dietary ingredient, caffeine is a potential candidate for improving thyroid health in people with metabolic disorders,” reported the authors in the study, published in Nutritional Journal.

Caffeine intake, within established healthy ranges, showed a nonlinear association with thyroid levels.

Moderate caffeine intake has been associated with reducing the risk of metabolic disorders in addition to showing some mental health benefits. However, research on its effects on thyroid hormone, which importantly plays a key role in systemic metabolism and neurologic development, is lacking.

To investigate the effects, Yu Zhou, of the Department of Rehabilitation Medicine, School of Health, Fujian Medical University, Fuzhou, China, and colleagues evaluated data from the National Health and Nutrition Examination Survey (NHANES) III 2007-2012 study involving 2,582 participants for whom data were available regarding medical conditions, dietary intake, thyroid function, and demographic background.

The participants were divided into three subgroups based on sex, age, body mass index, hyperglycemia, hypertension, and cardio-cerebral vascular disease (CVD).

Group 1 (n = 208) was the most metabolically unhealthy. Patients in that group had the highest BMI and were of oldest age. In addition, that group had higher rates of hypertension, hyperglycemia, and CVD, but, notably, it had the lowest level of caffeine consumption.

In group 2 (n = 543), all participants were current smokers, and 90.4% had a habit of drinking alcohol. That group also had the highest percentage of men.

Group 3 (n = 1,183) was the most metabolically healthy, with more women, younger age, and lowest BMI. No participants in that group had hyperglycemia, hypertension, or CVD.

Group 1, the most metabolically unhealthy, had the highest serum thyroid-stimulating hormone (TSH) levels. Of note, while participants with thyroid diseases were initially excluded from the analysis, higher TSH levels are predictive of subclinical hypothyroidism or progression to overt hypothyroidism.

Overall, there was no association between caffeine and TSH levels.

However, a subgroup analysis of the groups showed that in group 1, caffeine intake correlated with TSH nonlinearly (P = .0019), with minimal average consumption of caffeine (< 9.97 mg/d). There was an association with slightly higher TSH levels (P = .035) after adjustment for age, sex, race, drink, disease state, micronutrients, and macronutrients.

However, in higher, moderate amounts of caffeine consumption (9.97 – 264.97 mg/d), there was an inverse association, with lower TSH (P = .001).

There was no association between daily caffeine consumption of more than 264.97 mg and TSH levels.

For context, a typical 8-ounce cup of coffee generally contains 80-100 mg of caffeine, and the Food and Drug Administration indicates that 400 mg/d of caffeine is safe for healthy adults.

Group 2 consumed the highest amount of caffeine. Notably, that group had the lowest serum TSH levels of the three groups. There were no significant associations between caffeine consumption and TSH levels in group 2 or group 3.

There were no significant associations between caffeine consumption and levels of serum FT4 or FT3, also linked to thyroid dysfunction, in any of the groups.

The findings show that “caffeine consumption was correlated with serum TSH nonlinearly, and when taken in moderate amounts (9.97-264.97 mg/d), caffeine demonstrated a positive correlation with serum TSH levels in patients with metabolic disorders,” the authors concluded.
 

Mechanisms?

Caffeine is believed to modulate pituitary hormone secretion, which has been shown to influence the hypothalamic-pituitary-adrenal axis. The authors speculated that caffeine could potentially affect thyroid activity by affecting pituitary function.

“However, the effects of transient and chronic caffeine administration on human thyroid function need to be verified further, and the related mechanisms remain unclear,” they noted.

Commenting on the study, Maik Pietzner, PhD, of the Berlin Institute of Health, noted that an important limitation of the study is that various patient groups were excluded, including those with abnormal TSH levels.

“What makes me wonder is the high number of exclusions and the focus on very specific groups of people. This almost certainly introduces bias, e.g., what is specific to people not reporting coffee consumption,” Dr. Pietzner said.

Furthermore, “we already know that patients with poor metabolic health do also have slight variations in thyroid hormone levels and also have different dietary patterns,” he explained.

“So reverse confounding might occur in which the poor metabolic health is associated with both poor thyroid hormone levels and coffee consumption,” Dr. Pietzner said.

He also noted the “somewhat odd” finding that the group with the highest metabolic disorders had the lowest coffee consumption, yet the highest TSH levels.

“My guess would be that this might also be a chance finding, given that the distribution of TSH values is very skewed, which can have a strong effect in linear regression models,” Dr. Pietzner said.

In general, “the evidence generated by the study is rather weak, but there is good evidence that higher coffee consumption is linked to better metabolic health, although the exact mechanisms is not known, if indeed causal,” Dr. Pietzner added. “Prospective studies are needed to evaluate whether higher coffee consumption indeed lowers the risk for thyroid disease.”

A version of this article first appeared on Medscape.com.

Caffeine consumption may improve thyroid function for people with metabolic disorders, new research shows.

“Although the causal relationship between caffeine intake and thyroid function requires further verification, as an easily obtainable and widely consumed dietary ingredient, caffeine is a potential candidate for improving thyroid health in people with metabolic disorders,” reported the authors in the study, published in Nutritional Journal.

Caffeine intake, within established healthy ranges, showed a nonlinear association with thyroid levels.

Moderate caffeine intake has been associated with reducing the risk of metabolic disorders in addition to showing some mental health benefits. However, research on its effects on thyroid hormone, which importantly plays a key role in systemic metabolism and neurologic development, is lacking.

To investigate the effects, Yu Zhou, of the Department of Rehabilitation Medicine, School of Health, Fujian Medical University, Fuzhou, China, and colleagues evaluated data from the National Health and Nutrition Examination Survey (NHANES) III 2007-2012 study involving 2,582 participants for whom data were available regarding medical conditions, dietary intake, thyroid function, and demographic background.

The participants were divided into three subgroups based on sex, age, body mass index, hyperglycemia, hypertension, and cardio-cerebral vascular disease (CVD).

Group 1 (n = 208) was the most metabolically unhealthy. Patients in that group had the highest BMI and were of oldest age. In addition, that group had higher rates of hypertension, hyperglycemia, and CVD, but, notably, it had the lowest level of caffeine consumption.

In group 2 (n = 543), all participants were current smokers, and 90.4% had a habit of drinking alcohol. That group also had the highest percentage of men.

Group 3 (n = 1,183) was the most metabolically healthy, with more women, younger age, and lowest BMI. No participants in that group had hyperglycemia, hypertension, or CVD.

Group 1, the most metabolically unhealthy, had the highest serum thyroid-stimulating hormone (TSH) levels. Of note, while participants with thyroid diseases were initially excluded from the analysis, higher TSH levels are predictive of subclinical hypothyroidism or progression to overt hypothyroidism.

Overall, there was no association between caffeine and TSH levels.

However, a subgroup analysis of the groups showed that in group 1, caffeine intake correlated with TSH nonlinearly (P = .0019), with minimal average consumption of caffeine (< 9.97 mg/d). There was an association with slightly higher TSH levels (P = .035) after adjustment for age, sex, race, drink, disease state, micronutrients, and macronutrients.

However, in higher, moderate amounts of caffeine consumption (9.97 – 264.97 mg/d), there was an inverse association, with lower TSH (P = .001).

There was no association between daily caffeine consumption of more than 264.97 mg and TSH levels.

For context, a typical 8-ounce cup of coffee generally contains 80-100 mg of caffeine, and the Food and Drug Administration indicates that 400 mg/d of caffeine is safe for healthy adults.

Group 2 consumed the highest amount of caffeine. Notably, that group had the lowest serum TSH levels of the three groups. There were no significant associations between caffeine consumption and TSH levels in group 2 or group 3.

There were no significant associations between caffeine consumption and levels of serum FT4 or FT3, also linked to thyroid dysfunction, in any of the groups.

The findings show that “caffeine consumption was correlated with serum TSH nonlinearly, and when taken in moderate amounts (9.97-264.97 mg/d), caffeine demonstrated a positive correlation with serum TSH levels in patients with metabolic disorders,” the authors concluded.
 

Mechanisms?

Caffeine is believed to modulate pituitary hormone secretion, which has been shown to influence the hypothalamic-pituitary-adrenal axis. The authors speculated that caffeine could potentially affect thyroid activity by affecting pituitary function.

“However, the effects of transient and chronic caffeine administration on human thyroid function need to be verified further, and the related mechanisms remain unclear,” they noted.

Commenting on the study, Maik Pietzner, PhD, of the Berlin Institute of Health, noted that an important limitation of the study is that various patient groups were excluded, including those with abnormal TSH levels.

“What makes me wonder is the high number of exclusions and the focus on very specific groups of people. This almost certainly introduces bias, e.g., what is specific to people not reporting coffee consumption,” Dr. Pietzner said.

Furthermore, “we already know that patients with poor metabolic health do also have slight variations in thyroid hormone levels and also have different dietary patterns,” he explained.

“So reverse confounding might occur in which the poor metabolic health is associated with both poor thyroid hormone levels and coffee consumption,” Dr. Pietzner said.

He also noted the “somewhat odd” finding that the group with the highest metabolic disorders had the lowest coffee consumption, yet the highest TSH levels.

“My guess would be that this might also be a chance finding, given that the distribution of TSH values is very skewed, which can have a strong effect in linear regression models,” Dr. Pietzner said.

In general, “the evidence generated by the study is rather weak, but there is good evidence that higher coffee consumption is linked to better metabolic health, although the exact mechanisms is not known, if indeed causal,” Dr. Pietzner added. “Prospective studies are needed to evaluate whether higher coffee consumption indeed lowers the risk for thyroid disease.”

A version of this article first appeared on Medscape.com.

Despite improvements in life expectancy among children with sickle cell disease (SCD), adult patients continue to show significantly shorter life expectancy than those without the disease, new research shows, and the data indicate significant disparities based on types of insurance coverage.

“To the best of our knowledge, this is the first United States nationwide investigation into lifetime survival for individuals with sickle cell disease covered by Medicare and Medicaid and disparities in survival by public insurance type, using comprehensive claims data collected from all 50 states,” the authors report in the study, published in Blood Advances.

“Our study underscores the persistent life expectancy shortfall for patients with sickle cell disease, the burden of premature mortality during adulthood, and survival disparities by insurance status,” they write.

SCD, which disproportionately affects people of African descent, significantly increases the risk of various acute and chronic life-threatening complications, including acute pain crisis, stroke, acute chest syndrome, chronic pain, symptomatic anemia, infections, and organ damage.

In recent years, advances ranging from newborn screening to prophylactic antibiotics have significantly improved the survival rates of children with SCD in the United States. However, premature mortality in adulthood has remained well above that of the general public.

A recent study of a U.S. birth cohort predicted life expectancy with SCD to be approximately 2 decades shorter than in those without the disease. However, those projections were based on a simulation model, and other life expectancy estimates have had sample sizes with state or regional limitations.

With no population-level individual data–based periodic life tables existing for individuals with SCD, the authors turned to nationwide data on Medicare and Medicaid beneficiaries to get a better idea of survival predictions.

For the study, they identified 94,616 individuals diagnosed with SCD who had not undergone transplant and were receiving common care, based on nationwide Medicare and Medicaid claim data from 2008 to 2016 on beneficiaries in all 50 states.

Of the patients, 74% were Black and 53% resided in the South at the index date. The patients had a mean entry age overall of 26.6 years across insurance types.

The results showed projected life expectancy at birth with SCD to be 52.6 years, with the life expectancy at birth for females significantly longer, compared with that of males (55.0 versus 49.3 years). For the general population, U.S. life expectancy estimates have been reported to be about 76 years.

Specifically, life expectancy in the cohort into adulthood was 35.4 years at 18 years of age; 24.1 years at 35 years of age; 19.6 years at 45 years old; 13.2 years at 65 years of age; and 5.4 years at 85 years old.

Likewise, survival probability rates were high during childhood, with survival probability at 18 years being 0.98, declining to 0.804 at age 30; 0.628 at age 45; 0.267 at age 65 and 0.70 at age 85.

Black individuals had a significantly shorter life expectancy at birth than non-Black individuals (52.2 vs. 55.1 years), with the survival expectancy for Black individuals significantly shorter than the 75-year life expectancy estimated by the 2016 U.S. Centers for Disease Control and Prevention life table for the Black population in general.

Of the patients, only 5% had Medicare old age and survivor’s insurance, and 4% had Medicare disability insurance benefits or end-stage renal disease (ESRD), while 48% had Medicaid, and 43% were dually eligible for Medicare and Medicaid. The racial and regional distributions were similar across insurance types.

Adults covered by Medicare had a life expectancy of 39.8 years at 18 years of age, an improvement over life expectancy for those with Medicare for disabilities or ESRD and those dually insured by Medicare and Medicaid.

And the shorter life expectancy with Medicare and Medicaid was also observed among beneficiaries aged 65 or older, compared with those enrolled in Medicare old age and survivor’s insurance.

“Evidently, the life expectancy gap persists among patients with sickle cell disease, even though they are protected by public insurance,” the authors report.

The shorter life expectancy among those with dual eligibility for Medicare and Medicaid is consistent with that of the general population, the authors add.

“It is well-recognized that the dual-eligible individuals are a vulnerable population with some of the most complex and expensive health care needs,” they write. “They are more likely to have fewer socioeconomic resources, more chronic conditions, and poorer survival outcomes than single eligible.”

First author Boshen Jiao, PhD, MPH, of the Harvard T.H. Chan School of Public Health, in Boston, noted that socioeconomic factors, on a broader level, have an important impact on SCD.

“Even the first and most established FDA-approved medication for sickle cell disease, hydroxyurea, suffers from underutilization,” he told MDedge. “This issue can be associated with disparities along racial lines, particularly concerning access to treatments.”

Such factors can also play a role in the lack of a well-coordinated transition program needed to prevent gaps in care between youth and adulthood, as well as a lack of access to specialized care needed to potentially initiate new therapies.

Ultimately, the decline in survival seen from childhood to adulthood in SCD “emphasizes the pivotal role of health care during the critical transition phase from childhood to adulthood for individuals with sickle cell disease,” Dr. Jiao said. “Moreover, the prospect of a curative therapy that can intervene in the early stages of life, prior to adulthood, stands as a desirable goal.”

The authors urge that “future studies should uncover factors influencing survival outcomes and explore policy options to address the unmet needs of the disabled or dually eligible population with SCD.” They had no disclosures to report.

A version of this article first appeared on Medscape.com.

Despite improvements in life expectancy among children with sickle cell disease (SCD), adult patients continue to show significantly shorter life expectancy than those without the disease, new research shows, and the data indicate significant disparities based on types of insurance coverage.

“To the best of our knowledge, this is the first United States nationwide investigation into lifetime survival for individuals with sickle cell disease covered by Medicare and Medicaid and disparities in survival by public insurance type, using comprehensive claims data collected from all 50 states,” the authors report in the study, published in Blood Advances.

“Our study underscores the persistent life expectancy shortfall for patients with sickle cell disease, the burden of premature mortality during adulthood, and survival disparities by insurance status,” they write.

SCD, which disproportionately affects people of African descent, significantly increases the risk of various acute and chronic life-threatening complications, including acute pain crisis, stroke, acute chest syndrome, chronic pain, symptomatic anemia, infections, and organ damage.

In recent years, advances ranging from newborn screening to prophylactic antibiotics have significantly improved the survival rates of children with SCD in the United States. However, premature mortality in adulthood has remained well above that of the general public.

A recent study of a U.S. birth cohort predicted life expectancy with SCD to be approximately 2 decades shorter than in those without the disease. However, those projections were based on a simulation model, and other life expectancy estimates have had sample sizes with state or regional limitations.

With no population-level individual data–based periodic life tables existing for individuals with SCD, the authors turned to nationwide data on Medicare and Medicaid beneficiaries to get a better idea of survival predictions.

For the study, they identified 94,616 individuals diagnosed with SCD who had not undergone transplant and were receiving common care, based on nationwide Medicare and Medicaid claim data from 2008 to 2016 on beneficiaries in all 50 states.

Of the patients, 74% were Black and 53% resided in the South at the index date. The patients had a mean entry age overall of 26.6 years across insurance types.

The results showed projected life expectancy at birth with SCD to be 52.6 years, with the life expectancy at birth for females significantly longer, compared with that of males (55.0 versus 49.3 years). For the general population, U.S. life expectancy estimates have been reported to be about 76 years.

Specifically, life expectancy in the cohort into adulthood was 35.4 years at 18 years of age; 24.1 years at 35 years of age; 19.6 years at 45 years old; 13.2 years at 65 years of age; and 5.4 years at 85 years old.

Likewise, survival probability rates were high during childhood, with survival probability at 18 years being 0.98, declining to 0.804 at age 30; 0.628 at age 45; 0.267 at age 65 and 0.70 at age 85.

Black individuals had a significantly shorter life expectancy at birth than non-Black individuals (52.2 vs. 55.1 years), with the survival expectancy for Black individuals significantly shorter than the 75-year life expectancy estimated by the 2016 U.S. Centers for Disease Control and Prevention life table for the Black population in general.

Of the patients, only 5% had Medicare old age and survivor’s insurance, and 4% had Medicare disability insurance benefits or end-stage renal disease (ESRD), while 48% had Medicaid, and 43% were dually eligible for Medicare and Medicaid. The racial and regional distributions were similar across insurance types.

Adults covered by Medicare had a life expectancy of 39.8 years at 18 years of age, an improvement over life expectancy for those with Medicare for disabilities or ESRD and those dually insured by Medicare and Medicaid.

And the shorter life expectancy with Medicare and Medicaid was also observed among beneficiaries aged 65 or older, compared with those enrolled in Medicare old age and survivor’s insurance.

“Evidently, the life expectancy gap persists among patients with sickle cell disease, even though they are protected by public insurance,” the authors report.

The shorter life expectancy among those with dual eligibility for Medicare and Medicaid is consistent with that of the general population, the authors add.

“It is well-recognized that the dual-eligible individuals are a vulnerable population with some of the most complex and expensive health care needs,” they write. “They are more likely to have fewer socioeconomic resources, more chronic conditions, and poorer survival outcomes than single eligible.”

First author Boshen Jiao, PhD, MPH, of the Harvard T.H. Chan School of Public Health, in Boston, noted that socioeconomic factors, on a broader level, have an important impact on SCD.

“Even the first and most established FDA-approved medication for sickle cell disease, hydroxyurea, suffers from underutilization,” he told MDedge. “This issue can be associated with disparities along racial lines, particularly concerning access to treatments.”

Such factors can also play a role in the lack of a well-coordinated transition program needed to prevent gaps in care between youth and adulthood, as well as a lack of access to specialized care needed to potentially initiate new therapies.

Ultimately, the decline in survival seen from childhood to adulthood in SCD “emphasizes the pivotal role of health care during the critical transition phase from childhood to adulthood for individuals with sickle cell disease,” Dr. Jiao said. “Moreover, the prospect of a curative therapy that can intervene in the early stages of life, prior to adulthood, stands as a desirable goal.”

The authors urge that “future studies should uncover factors influencing survival outcomes and explore policy options to address the unmet needs of the disabled or dually eligible population with SCD.” They had no disclosures to report.

A version of this article first appeared on Medscape.com.

Despite improvements in life expectancy among children with sickle cell disease (SCD), adult patients continue to show significantly shorter life expectancy than those without the disease, new research shows, and the data indicate significant disparities based on types of insurance coverage.

“To the best of our knowledge, this is the first United States nationwide investigation into lifetime survival for individuals with sickle cell disease covered by Medicare and Medicaid and disparities in survival by public insurance type, using comprehensive claims data collected from all 50 states,” the authors report in the study, published in Blood Advances.

“Our study underscores the persistent life expectancy shortfall for patients with sickle cell disease, the burden of premature mortality during adulthood, and survival disparities by insurance status,” they write.

SCD, which disproportionately affects people of African descent, significantly increases the risk of various acute and chronic life-threatening complications, including acute pain crisis, stroke, acute chest syndrome, chronic pain, symptomatic anemia, infections, and organ damage.

In recent years, advances ranging from newborn screening to prophylactic antibiotics have significantly improved the survival rates of children with SCD in the United States. However, premature mortality in adulthood has remained well above that of the general public.

A recent study of a U.S. birth cohort predicted life expectancy with SCD to be approximately 2 decades shorter than in those without the disease. However, those projections were based on a simulation model, and other life expectancy estimates have had sample sizes with state or regional limitations.

With no population-level individual data–based periodic life tables existing for individuals with SCD, the authors turned to nationwide data on Medicare and Medicaid beneficiaries to get a better idea of survival predictions.

For the study, they identified 94,616 individuals diagnosed with SCD who had not undergone transplant and were receiving common care, based on nationwide Medicare and Medicaid claim data from 2008 to 2016 on beneficiaries in all 50 states.

Of the patients, 74% were Black and 53% resided in the South at the index date. The patients had a mean entry age overall of 26.6 years across insurance types.

The results showed projected life expectancy at birth with SCD to be 52.6 years, with the life expectancy at birth for females significantly longer, compared with that of males (55.0 versus 49.3 years). For the general population, U.S. life expectancy estimates have been reported to be about 76 years.

Specifically, life expectancy in the cohort into adulthood was 35.4 years at 18 years of age; 24.1 years at 35 years of age; 19.6 years at 45 years old; 13.2 years at 65 years of age; and 5.4 years at 85 years old.

Likewise, survival probability rates were high during childhood, with survival probability at 18 years being 0.98, declining to 0.804 at age 30; 0.628 at age 45; 0.267 at age 65 and 0.70 at age 85.

Black individuals had a significantly shorter life expectancy at birth than non-Black individuals (52.2 vs. 55.1 years), with the survival expectancy for Black individuals significantly shorter than the 75-year life expectancy estimated by the 2016 U.S. Centers for Disease Control and Prevention life table for the Black population in general.

Of the patients, only 5% had Medicare old age and survivor’s insurance, and 4% had Medicare disability insurance benefits or end-stage renal disease (ESRD), while 48% had Medicaid, and 43% were dually eligible for Medicare and Medicaid. The racial and regional distributions were similar across insurance types.

Adults covered by Medicare had a life expectancy of 39.8 years at 18 years of age, an improvement over life expectancy for those with Medicare for disabilities or ESRD and those dually insured by Medicare and Medicaid.

And the shorter life expectancy with Medicare and Medicaid was also observed among beneficiaries aged 65 or older, compared with those enrolled in Medicare old age and survivor’s insurance.

“Evidently, the life expectancy gap persists among patients with sickle cell disease, even though they are protected by public insurance,” the authors report.

The shorter life expectancy among those with dual eligibility for Medicare and Medicaid is consistent with that of the general population, the authors add.

“It is well-recognized that the dual-eligible individuals are a vulnerable population with some of the most complex and expensive health care needs,” they write. “They are more likely to have fewer socioeconomic resources, more chronic conditions, and poorer survival outcomes than single eligible.”

First author Boshen Jiao, PhD, MPH, of the Harvard T.H. Chan School of Public Health, in Boston, noted that socioeconomic factors, on a broader level, have an important impact on SCD.

“Even the first and most established FDA-approved medication for sickle cell disease, hydroxyurea, suffers from underutilization,” he told MDedge. “This issue can be associated with disparities along racial lines, particularly concerning access to treatments.”

Such factors can also play a role in the lack of a well-coordinated transition program needed to prevent gaps in care between youth and adulthood, as well as a lack of access to specialized care needed to potentially initiate new therapies.

Ultimately, the decline in survival seen from childhood to adulthood in SCD “emphasizes the pivotal role of health care during the critical transition phase from childhood to adulthood for individuals with sickle cell disease,” Dr. Jiao said. “Moreover, the prospect of a curative therapy that can intervene in the early stages of life, prior to adulthood, stands as a desirable goal.”

The authors urge that “future studies should uncover factors influencing survival outcomes and explore policy options to address the unmet needs of the disabled or dually eligible population with SCD.” They had no disclosures to report.

A version of this article first appeared on Medscape.com.

Cisgender women who identify as sexual minorities may have an increased risk of postpartum depression compared with heterosexual women, new research shows. However, with sexual orientation highly underdocumented among women giving birth, understanding of the prevalence is lacking.

“To our knowledge, this cohort study was the first to examine perinatal depression screening and symptom endorsement among sexual minority women in a major medical center in the U.S.,” reported the authors of the study published in JAMA Psychiatry.

The results “highlight the need for investigations that include strategies for measuring sexual orientation because reliance on medical record review has substantial limitations with regard to the research questions and the validity of the data,” they noted.

Clinical guidelines recommend universal perinatal depression screening at obstetric and pediatric well-infant visits; however, there are significant gaps in data on the issue when it comes to sexual minority women.

To assess the prevalence of sexual minority people giving birth and compare perinatal depression screening rates and scores with those of heterosexual cisgender women, the authors conducted a review of medical records of 18,243 female patients who gave birth at a large, diverse, university-based medical center in Chicago between January and December of 2019.

Of the patients, 57.3% of whom were non-Hispanic White, 1.5% (280) had documentation of their sexual orientation, or sexual minority status.

The results show that those identified as being in sexual minorities, including lesbian, bisexual, queer, pansexual or asexual, were more likely than were heterosexual women to be more engaged in their care – they were more likely to have attended at least one prenatal visit (20.0% vs. 13.7%; P = .002) and at least one postpartum care visit (18.6% vs. 12.8%; P = .004), and more likely to be screened for depression during postpartum care (odds ratio, 1.77; P = .002).

Sexual minority women were also significantly more likely to screen positive for depression during the postpartum period than were heterosexual women (odds ratio, 2.38; P = .03); however, all other comparisons were not significantly different.

The finding regarding postpartum depression was consistent with recent literature, including a systematic review indicating that the stress of being in a sexual minority may be heightened during the postpartum period, the authors noted.

Reasons for the heightened stress may include “being perceived as inadequate parents, heteronormativity in perinatal care, such as intake forms asking for information about the child’s father, and lack of familial social support due to nonacceptance of the parents’ sexual orientation,” the researchers explained.

The rate of only 1.5% of people giving birth who identified as a sexual minority was significantly lower than expected, and much lower that the 17% reported in a recent nationally representative sample of women, first author Leiszle Lapping-Carr, PhD, director of the sexual and relationship health program, department of psychiatry and behavioral sciences, Northwestern University, Chicago, said in an interview.

“I did not expect a rate as low at 1.5%,” she said. “I anticipated it would not be as high as the 17%, but this was quite low. I think one primary reason is that women are not interested in disclosing their sexual orientation to their ob.gyns. if they don’t have to.”

Furthermore, Dr. Lapping-Carr said, “most medical systems do not have an easy way to document sexual orientation or gender identity, and even if it exists many physicians are unaware of the process.”

On a broader level, the lower rates may be indicative of a lack of acknowledgment of sexual minorities in the ob.gyn. setting, Dr. Lapping-Carr added.

Dr. Lapping-Carr

Develop more supportive systems

To address postpartum depression among sexual minority women, Dr. Lapping-Carr suggested that clinicians generally start by avoiding language and behaviors that could suggest the potential bias that sexual minority patients can face.

“The main change [in treatment] that would likely be helpful for postpartum depression treatment is removing heteronormative language, e.g., not referring to partners as ‘fathers,’ ” she said.

Also, patients may benefit from “discussion of issues of relevance to people with sexual minority identities, such as the process of adoption for female non-birthing partners,” Dr. Lapping-Carr added.

“Starting to create spaces that are inclusive and welcoming for people of all identities will go a long way in increasing your patient’s trust in you,” she said.

While there is a lack of published data regarding increases in rates of sexual minority patients who are giving birth, societal trends suggest the rates may likely be on the rise, Dr. Lapping-Carr said.

“We do know that among adolescents, endorsement of sexual and gender minority identities is much higher than in previous generations, so it would follow that the proportion of birthing people with sexual and gender minority identities would also increase,” she said.

Commenting on the study, K. Ashley Brandt, DO, obstetrics section chief and medical director of Gender Affirming Surgery at Reading Hospital, in West Reading, Pa., noted that limitations include a lack of information about the bigger picture of patients’ risk factors.

“There is no documentation of other risks factors, including rates of depression in the antenatal period, which is higher in LGBTQ individuals and also a risk factor for postpartum depression,” Dr. Brandt told this news organization.

She agreed, however, that patients may be reluctant to report their sexual minority status on the record – but such issues are often addressed.

“I believe that obstetricians do ask this question far more than other providers, but it may not be easily captured in medical records, and patients may also hesitate to disclose sexual practices and sexual orientation due to fear of medical discrimination, which is still extremely prevalent,” Dr. Brandt said. 

The study underscores, however, that “same-sex parents are a reality that providers will face,” she said. “They have unique social determinants for health that often go undocumented and unaddressed, which could contribute to higher rates of depression in the postpartum period.”

Factors that may be ignored or undocumented, such as sexual minorities’ religious beliefs or social and familial support, can play significant roles in health care outcomes, Dr. Brandt added.

“Providers need to find ways to better educate themselves about LGBTQ individuals and develop more supportive systems to ensure patients feel safe in disclosing their identities.”  

The authors and Dr. Brandt had no disclosures to report.

Cisgender women who identify as sexual minorities may have an increased risk of postpartum depression compared with heterosexual women, new research shows. However, with sexual orientation highly underdocumented among women giving birth, understanding of the prevalence is lacking.

“To our knowledge, this cohort study was the first to examine perinatal depression screening and symptom endorsement among sexual minority women in a major medical center in the U.S.,” reported the authors of the study published in JAMA Psychiatry.

The results “highlight the need for investigations that include strategies for measuring sexual orientation because reliance on medical record review has substantial limitations with regard to the research questions and the validity of the data,” they noted.

Clinical guidelines recommend universal perinatal depression screening at obstetric and pediatric well-infant visits; however, there are significant gaps in data on the issue when it comes to sexual minority women.

To assess the prevalence of sexual minority people giving birth and compare perinatal depression screening rates and scores with those of heterosexual cisgender women, the authors conducted a review of medical records of 18,243 female patients who gave birth at a large, diverse, university-based medical center in Chicago between January and December of 2019.

Of the patients, 57.3% of whom were non-Hispanic White, 1.5% (280) had documentation of their sexual orientation, or sexual minority status.

The results show that those identified as being in sexual minorities, including lesbian, bisexual, queer, pansexual or asexual, were more likely than were heterosexual women to be more engaged in their care – they were more likely to have attended at least one prenatal visit (20.0% vs. 13.7%; P = .002) and at least one postpartum care visit (18.6% vs. 12.8%; P = .004), and more likely to be screened for depression during postpartum care (odds ratio, 1.77; P = .002).

Sexual minority women were also significantly more likely to screen positive for depression during the postpartum period than were heterosexual women (odds ratio, 2.38; P = .03); however, all other comparisons were not significantly different.

The finding regarding postpartum depression was consistent with recent literature, including a systematic review indicating that the stress of being in a sexual minority may be heightened during the postpartum period, the authors noted.

Reasons for the heightened stress may include “being perceived as inadequate parents, heteronormativity in perinatal care, such as intake forms asking for information about the child’s father, and lack of familial social support due to nonacceptance of the parents’ sexual orientation,” the researchers explained.

The rate of only 1.5% of people giving birth who identified as a sexual minority was significantly lower than expected, and much lower that the 17% reported in a recent nationally representative sample of women, first author Leiszle Lapping-Carr, PhD, director of the sexual and relationship health program, department of psychiatry and behavioral sciences, Northwestern University, Chicago, said in an interview.

“I did not expect a rate as low at 1.5%,” she said. “I anticipated it would not be as high as the 17%, but this was quite low. I think one primary reason is that women are not interested in disclosing their sexual orientation to their ob.gyns. if they don’t have to.”

Furthermore, Dr. Lapping-Carr said, “most medical systems do not have an easy way to document sexual orientation or gender identity, and even if it exists many physicians are unaware of the process.”

On a broader level, the lower rates may be indicative of a lack of acknowledgment of sexual minorities in the ob.gyn. setting, Dr. Lapping-Carr added.

Dr. Lapping-Carr

Develop more supportive systems

To address postpartum depression among sexual minority women, Dr. Lapping-Carr suggested that clinicians generally start by avoiding language and behaviors that could suggest the potential bias that sexual minority patients can face.

“The main change [in treatment] that would likely be helpful for postpartum depression treatment is removing heteronormative language, e.g., not referring to partners as ‘fathers,’ ” she said.

Also, patients may benefit from “discussion of issues of relevance to people with sexual minority identities, such as the process of adoption for female non-birthing partners,” Dr. Lapping-Carr added.

“Starting to create spaces that are inclusive and welcoming for people of all identities will go a long way in increasing your patient’s trust in you,” she said.

While there is a lack of published data regarding increases in rates of sexual minority patients who are giving birth, societal trends suggest the rates may likely be on the rise, Dr. Lapping-Carr said.

“We do know that among adolescents, endorsement of sexual and gender minority identities is much higher than in previous generations, so it would follow that the proportion of birthing people with sexual and gender minority identities would also increase,” she said.

Commenting on the study, K. Ashley Brandt, DO, obstetrics section chief and medical director of Gender Affirming Surgery at Reading Hospital, in West Reading, Pa., noted that limitations include a lack of information about the bigger picture of patients’ risk factors.

“There is no documentation of other risks factors, including rates of depression in the antenatal period, which is higher in LGBTQ individuals and also a risk factor for postpartum depression,” Dr. Brandt told this news organization.

She agreed, however, that patients may be reluctant to report their sexual minority status on the record – but such issues are often addressed.

“I believe that obstetricians do ask this question far more than other providers, but it may not be easily captured in medical records, and patients may also hesitate to disclose sexual practices and sexual orientation due to fear of medical discrimination, which is still extremely prevalent,” Dr. Brandt said. 

The study underscores, however, that “same-sex parents are a reality that providers will face,” she said. “They have unique social determinants for health that often go undocumented and unaddressed, which could contribute to higher rates of depression in the postpartum period.”

Factors that may be ignored or undocumented, such as sexual minorities’ religious beliefs or social and familial support, can play significant roles in health care outcomes, Dr. Brandt added.

“Providers need to find ways to better educate themselves about LGBTQ individuals and develop more supportive systems to ensure patients feel safe in disclosing their identities.”  

The authors and Dr. Brandt had no disclosures to report.

Cisgender women who identify as sexual minorities may have an increased risk of postpartum depression compared with heterosexual women, new research shows. However, with sexual orientation highly underdocumented among women giving birth, understanding of the prevalence is lacking.

“To our knowledge, this cohort study was the first to examine perinatal depression screening and symptom endorsement among sexual minority women in a major medical center in the U.S.,” reported the authors of the study published in JAMA Psychiatry.

The results “highlight the need for investigations that include strategies for measuring sexual orientation because reliance on medical record review has substantial limitations with regard to the research questions and the validity of the data,” they noted.

Clinical guidelines recommend universal perinatal depression screening at obstetric and pediatric well-infant visits; however, there are significant gaps in data on the issue when it comes to sexual minority women.

To assess the prevalence of sexual minority people giving birth and compare perinatal depression screening rates and scores with those of heterosexual cisgender women, the authors conducted a review of medical records of 18,243 female patients who gave birth at a large, diverse, university-based medical center in Chicago between January and December of 2019.

Of the patients, 57.3% of whom were non-Hispanic White, 1.5% (280) had documentation of their sexual orientation, or sexual minority status.

The results show that those identified as being in sexual minorities, including lesbian, bisexual, queer, pansexual or asexual, were more likely than were heterosexual women to be more engaged in their care – they were more likely to have attended at least one prenatal visit (20.0% vs. 13.7%; P = .002) and at least one postpartum care visit (18.6% vs. 12.8%; P = .004), and more likely to be screened for depression during postpartum care (odds ratio, 1.77; P = .002).

Sexual minority women were also significantly more likely to screen positive for depression during the postpartum period than were heterosexual women (odds ratio, 2.38; P = .03); however, all other comparisons were not significantly different.

The finding regarding postpartum depression was consistent with recent literature, including a systematic review indicating that the stress of being in a sexual minority may be heightened during the postpartum period, the authors noted.

Reasons for the heightened stress may include “being perceived as inadequate parents, heteronormativity in perinatal care, such as intake forms asking for information about the child’s father, and lack of familial social support due to nonacceptance of the parents’ sexual orientation,” the researchers explained.

The rate of only 1.5% of people giving birth who identified as a sexual minority was significantly lower than expected, and much lower that the 17% reported in a recent nationally representative sample of women, first author Leiszle Lapping-Carr, PhD, director of the sexual and relationship health program, department of psychiatry and behavioral sciences, Northwestern University, Chicago, said in an interview.

“I did not expect a rate as low at 1.5%,” she said. “I anticipated it would not be as high as the 17%, but this was quite low. I think one primary reason is that women are not interested in disclosing their sexual orientation to their ob.gyns. if they don’t have to.”

Furthermore, Dr. Lapping-Carr said, “most medical systems do not have an easy way to document sexual orientation or gender identity, and even if it exists many physicians are unaware of the process.”

On a broader level, the lower rates may be indicative of a lack of acknowledgment of sexual minorities in the ob.gyn. setting, Dr. Lapping-Carr added.

Dr. Lapping-Carr

Develop more supportive systems

To address postpartum depression among sexual minority women, Dr. Lapping-Carr suggested that clinicians generally start by avoiding language and behaviors that could suggest the potential bias that sexual minority patients can face.

“The main change [in treatment] that would likely be helpful for postpartum depression treatment is removing heteronormative language, e.g., not referring to partners as ‘fathers,’ ” she said.

Also, patients may benefit from “discussion of issues of relevance to people with sexual minority identities, such as the process of adoption for female non-birthing partners,” Dr. Lapping-Carr added.

“Starting to create spaces that are inclusive and welcoming for people of all identities will go a long way in increasing your patient’s trust in you,” she said.

While there is a lack of published data regarding increases in rates of sexual minority patients who are giving birth, societal trends suggest the rates may likely be on the rise, Dr. Lapping-Carr said.

“We do know that among adolescents, endorsement of sexual and gender minority identities is much higher than in previous generations, so it would follow that the proportion of birthing people with sexual and gender minority identities would also increase,” she said.

Commenting on the study, K. Ashley Brandt, DO, obstetrics section chief and medical director of Gender Affirming Surgery at Reading Hospital, in West Reading, Pa., noted that limitations include a lack of information about the bigger picture of patients’ risk factors.

“There is no documentation of other risks factors, including rates of depression in the antenatal period, which is higher in LGBTQ individuals and also a risk factor for postpartum depression,” Dr. Brandt told this news organization.

She agreed, however, that patients may be reluctant to report their sexual minority status on the record – but such issues are often addressed.

“I believe that obstetricians do ask this question far more than other providers, but it may not be easily captured in medical records, and patients may also hesitate to disclose sexual practices and sexual orientation due to fear of medical discrimination, which is still extremely prevalent,” Dr. Brandt said. 

The study underscores, however, that “same-sex parents are a reality that providers will face,” she said. “They have unique social determinants for health that often go undocumented and unaddressed, which could contribute to higher rates of depression in the postpartum period.”

Factors that may be ignored or undocumented, such as sexual minorities’ religious beliefs or social and familial support, can play significant roles in health care outcomes, Dr. Brandt added.

“Providers need to find ways to better educate themselves about LGBTQ individuals and develop more supportive systems to ensure patients feel safe in disclosing their identities.”  

The authors and Dr. Brandt had no disclosures to report.

Early, intriguing research suggests that preventing acute graft-versus-host disease (GVHD) in the gut – a potentially life-threatening complication of allogeneic hematopoietic cell transplantation (allo-HCT) – could be accomplished by the administration of a single antibody that targets the anti-DLL4 Notch signaling pathway, without compromising the stem cell transplant.

“The major surprise was that none of the anti–DLL4-treated animals developed acute gastrointestinal GVHD for the entire duration of the study. This was a remarkable finding, given that intestinal GVHD is otherwise seen in the vast majority of nonhuman primate transplant recipients that receive either no prophylaxis, or prophylaxis with agents other than anti-DLL4 antibodies,” co–senior author Ivan Maillard, MD, PhD, a professor of medicine and vice chief for research in hematology-oncology at the University of Pennsylvania, Philadelphia, said in an interview.

“The timing was critical,” the authors noted in the study, recently published in Science Translational Medicine. “Intervening before any symptoms of GvHD appear made the long-term protection possible.”

While GVHD may be mild to moderate in chronic forms, acute cases can be serious, if not fatal, and nearly all severe acute GVHD prominently involves the gastrointestinal tract, which can drive activation of pathogenic T cells and potentially lead to tissue damage following allo-HCT.

Systemic corticosteroids are standard first-line treatment for acute GVHD. However, response rates generally range only from 40% to 60%, and there are concerns of side effects. Meanwhile, second-line treatments are of inconsistent benefit.

With previous studies on mice showing benefits of targeting Notch pathway inhibition, particularly DLL4, Dr. Maillard and colleagues further investigated the effects in nonhuman primates that were allo-HCT recipients, using the anti-DLL4 antibody REGN421, which has pharmacokinetic and toxicity information available from previous studies.

The nonhuman primates were treated with one of two dosing regimens: a single dose of REGN421 3 mg/kg at baseline, post HCT, (n = 7) or three weekly doses at days 0, 7 and 14, post transplant (n = 4). Those primates were compared with 11 primates receiving allo-HCT transplants that received supportive care only.

Primates receiving three weekly doses of REGN421 showed antibody concentrations of greater than 2 mcg/mL for more than 30 days post HCT. A single dose of REGN421 was associated with protection from acute GVHD at day 0, while three weekly doses showed protection at day 0, 7, and 14, consistent with an impact of REGN421 during the early phases of T-cell activation.

Compared with animals receiving only supportive care, prophylaxis with REGN421 was associated with delayed acute GVHD onset and lengthened survival.

Of the 11 primates treated with REGN421, none developed clinical signs of gastrointestinal acute GVHD, whereas the majority of those receiving standard care or other preventive interventions did.

“Detailed analysis of acute GVHD clinical presentations in REGN421-treated animals in comparison to no treatment controls revealed near complete protection from GI-acute GvHD with REGN421,” the authors reported.

Furthermore, pathology scores in the gastrointestinal tract were lower with REGN421 treatment, compared with the no-treatment cohort, and the scores matched those of healthy nontransplanted nonhuman primates.

The primates treated with REGN421 did ultimately develop other clinical and pathologic signs of skin, hepatic or pulmonary acute GVHD, but without gastrointestinal disease.

The treatment was not associated with any adverse effects on the allo-HCT, with primates receiving either a single dose or three weekly doses of REGN421 showing rapid donor engraftment after allo-HCT, including high bone marrow, whole blood, and T-cell donor chimerism.

“Reassuringly, short-term systemic DLL4 blockade with REGN421 did not trigger unexpected side effects in our nonhuman primate model, while preserving rapid engraftment as well hematopoietic and immune reconstitution.”

The mechanism preserving the engraftment, described as a “major surprise,” specifically involved DLL4 inhibition blocking the homing of pathogenic T cells to the gut while preserving homing of regulatory T cells that dampen the immune response, Dr. Maillard explained.

“This effect turned out to be at least in part through a posttranslational effect of DLL4/Notch blockade on integrin pairing at the T-cell surface,” he explained. “This was a novel and quite unexpected mechanism of action conserved from mice to nonhuman primates.”

The results are encouraging in terms of translating to humans because of their closer similarities in various physiological factors, Dr. Maillard said.

“The nonhuman primate model of transplantation [offers] a transplantation model very close to what is being performed in humans, as well as the opportunity to study an immune system very similar to that of humans in nonhuman primates,” he said.

Dr. Maillard noted that, while trials in humans are not underway yet, “we are in active discussions about it,” and the team is indeed interested in testing REGN421 itself, with the effects likely to be as a prophylactic strategy.

There are currently no approved anti-DLL4 antibody drugs for use in humans.

“Our approach is mostly promising as a preventive treatment, rather than as a secondary treatment for GVHD, because DLL4/Notch blockade seems most active when applied early after transplantation during the time of initial seeding of the gut by T cells (in mice, we had observed the critical time window for a successful intervention to be within 48 hours of transplantation),” Dr. Maillard said.“There remain questions about which other prophylactic treatments we should ideally combine anti-DLL4 antibodies with.”

Dr. Maillard has received research funding from Regeneron and Genentech and is a member of Garuda Therapeutics’s scientific advisory board.

Early, intriguing research suggests that preventing acute graft-versus-host disease (GVHD) in the gut – a potentially life-threatening complication of allogeneic hematopoietic cell transplantation (allo-HCT) – could be accomplished by the administration of a single antibody that targets the anti-DLL4 Notch signaling pathway, without compromising the stem cell transplant.

“The major surprise was that none of the anti–DLL4-treated animals developed acute gastrointestinal GVHD for the entire duration of the study. This was a remarkable finding, given that intestinal GVHD is otherwise seen in the vast majority of nonhuman primate transplant recipients that receive either no prophylaxis, or prophylaxis with agents other than anti-DLL4 antibodies,” co–senior author Ivan Maillard, MD, PhD, a professor of medicine and vice chief for research in hematology-oncology at the University of Pennsylvania, Philadelphia, said in an interview.

“The timing was critical,” the authors noted in the study, recently published in Science Translational Medicine. “Intervening before any symptoms of GvHD appear made the long-term protection possible.”

While GVHD may be mild to moderate in chronic forms, acute cases can be serious, if not fatal, and nearly all severe acute GVHD prominently involves the gastrointestinal tract, which can drive activation of pathogenic T cells and potentially lead to tissue damage following allo-HCT.

Systemic corticosteroids are standard first-line treatment for acute GVHD. However, response rates generally range only from 40% to 60%, and there are concerns of side effects. Meanwhile, second-line treatments are of inconsistent benefit.

With previous studies on mice showing benefits of targeting Notch pathway inhibition, particularly DLL4, Dr. Maillard and colleagues further investigated the effects in nonhuman primates that were allo-HCT recipients, using the anti-DLL4 antibody REGN421, which has pharmacokinetic and toxicity information available from previous studies.

The nonhuman primates were treated with one of two dosing regimens: a single dose of REGN421 3 mg/kg at baseline, post HCT, (n = 7) or three weekly doses at days 0, 7 and 14, post transplant (n = 4). Those primates were compared with 11 primates receiving allo-HCT transplants that received supportive care only.

Primates receiving three weekly doses of REGN421 showed antibody concentrations of greater than 2 mcg/mL for more than 30 days post HCT. A single dose of REGN421 was associated with protection from acute GVHD at day 0, while three weekly doses showed protection at day 0, 7, and 14, consistent with an impact of REGN421 during the early phases of T-cell activation.

Compared with animals receiving only supportive care, prophylaxis with REGN421 was associated with delayed acute GVHD onset and lengthened survival.

Of the 11 primates treated with REGN421, none developed clinical signs of gastrointestinal acute GVHD, whereas the majority of those receiving standard care or other preventive interventions did.

“Detailed analysis of acute GVHD clinical presentations in REGN421-treated animals in comparison to no treatment controls revealed near complete protection from GI-acute GvHD with REGN421,” the authors reported.

Furthermore, pathology scores in the gastrointestinal tract were lower with REGN421 treatment, compared with the no-treatment cohort, and the scores matched those of healthy nontransplanted nonhuman primates.

The primates treated with REGN421 did ultimately develop other clinical and pathologic signs of skin, hepatic or pulmonary acute GVHD, but without gastrointestinal disease.

The treatment was not associated with any adverse effects on the allo-HCT, with primates receiving either a single dose or three weekly doses of REGN421 showing rapid donor engraftment after allo-HCT, including high bone marrow, whole blood, and T-cell donor chimerism.

“Reassuringly, short-term systemic DLL4 blockade with REGN421 did not trigger unexpected side effects in our nonhuman primate model, while preserving rapid engraftment as well hematopoietic and immune reconstitution.”

The mechanism preserving the engraftment, described as a “major surprise,” specifically involved DLL4 inhibition blocking the homing of pathogenic T cells to the gut while preserving homing of regulatory T cells that dampen the immune response, Dr. Maillard explained.

“This effect turned out to be at least in part through a posttranslational effect of DLL4/Notch blockade on integrin pairing at the T-cell surface,” he explained. “This was a novel and quite unexpected mechanism of action conserved from mice to nonhuman primates.”

The results are encouraging in terms of translating to humans because of their closer similarities in various physiological factors, Dr. Maillard said.

“The nonhuman primate model of transplantation [offers] a transplantation model very close to what is being performed in humans, as well as the opportunity to study an immune system very similar to that of humans in nonhuman primates,” he said.

Dr. Maillard noted that, while trials in humans are not underway yet, “we are in active discussions about it,” and the team is indeed interested in testing REGN421 itself, with the effects likely to be as a prophylactic strategy.

There are currently no approved anti-DLL4 antibody drugs for use in humans.

“Our approach is mostly promising as a preventive treatment, rather than as a secondary treatment for GVHD, because DLL4/Notch blockade seems most active when applied early after transplantation during the time of initial seeding of the gut by T cells (in mice, we had observed the critical time window for a successful intervention to be within 48 hours of transplantation),” Dr. Maillard said.“There remain questions about which other prophylactic treatments we should ideally combine anti-DLL4 antibodies with.”

Dr. Maillard has received research funding from Regeneron and Genentech and is a member of Garuda Therapeutics’s scientific advisory board.

Early, intriguing research suggests that preventing acute graft-versus-host disease (GVHD) in the gut – a potentially life-threatening complication of allogeneic hematopoietic cell transplantation (allo-HCT) – could be accomplished by the administration of a single antibody that targets the anti-DLL4 Notch signaling pathway, without compromising the stem cell transplant.

“The major surprise was that none of the anti–DLL4-treated animals developed acute gastrointestinal GVHD for the entire duration of the study. This was a remarkable finding, given that intestinal GVHD is otherwise seen in the vast majority of nonhuman primate transplant recipients that receive either no prophylaxis, or prophylaxis with agents other than anti-DLL4 antibodies,” co–senior author Ivan Maillard, MD, PhD, a professor of medicine and vice chief for research in hematology-oncology at the University of Pennsylvania, Philadelphia, said in an interview.

“The timing was critical,” the authors noted in the study, recently published in Science Translational Medicine. “Intervening before any symptoms of GvHD appear made the long-term protection possible.”

While GVHD may be mild to moderate in chronic forms, acute cases can be serious, if not fatal, and nearly all severe acute GVHD prominently involves the gastrointestinal tract, which can drive activation of pathogenic T cells and potentially lead to tissue damage following allo-HCT.

Systemic corticosteroids are standard first-line treatment for acute GVHD. However, response rates generally range only from 40% to 60%, and there are concerns of side effects. Meanwhile, second-line treatments are of inconsistent benefit.

With previous studies on mice showing benefits of targeting Notch pathway inhibition, particularly DLL4, Dr. Maillard and colleagues further investigated the effects in nonhuman primates that were allo-HCT recipients, using the anti-DLL4 antibody REGN421, which has pharmacokinetic and toxicity information available from previous studies.

The nonhuman primates were treated with one of two dosing regimens: a single dose of REGN421 3 mg/kg at baseline, post HCT, (n = 7) or three weekly doses at days 0, 7 and 14, post transplant (n = 4). Those primates were compared with 11 primates receiving allo-HCT transplants that received supportive care only.

Primates receiving three weekly doses of REGN421 showed antibody concentrations of greater than 2 mcg/mL for more than 30 days post HCT. A single dose of REGN421 was associated with protection from acute GVHD at day 0, while three weekly doses showed protection at day 0, 7, and 14, consistent with an impact of REGN421 during the early phases of T-cell activation.

Compared with animals receiving only supportive care, prophylaxis with REGN421 was associated with delayed acute GVHD onset and lengthened survival.

Of the 11 primates treated with REGN421, none developed clinical signs of gastrointestinal acute GVHD, whereas the majority of those receiving standard care or other preventive interventions did.

“Detailed analysis of acute GVHD clinical presentations in REGN421-treated animals in comparison to no treatment controls revealed near complete protection from GI-acute GvHD with REGN421,” the authors reported.

Furthermore, pathology scores in the gastrointestinal tract were lower with REGN421 treatment, compared with the no-treatment cohort, and the scores matched those of healthy nontransplanted nonhuman primates.

The primates treated with REGN421 did ultimately develop other clinical and pathologic signs of skin, hepatic or pulmonary acute GVHD, but without gastrointestinal disease.

The treatment was not associated with any adverse effects on the allo-HCT, with primates receiving either a single dose or three weekly doses of REGN421 showing rapid donor engraftment after allo-HCT, including high bone marrow, whole blood, and T-cell donor chimerism.

“Reassuringly, short-term systemic DLL4 blockade with REGN421 did not trigger unexpected side effects in our nonhuman primate model, while preserving rapid engraftment as well hematopoietic and immune reconstitution.”

The mechanism preserving the engraftment, described as a “major surprise,” specifically involved DLL4 inhibition blocking the homing of pathogenic T cells to the gut while preserving homing of regulatory T cells that dampen the immune response, Dr. Maillard explained.

“This effect turned out to be at least in part through a posttranslational effect of DLL4/Notch blockade on integrin pairing at the T-cell surface,” he explained. “This was a novel and quite unexpected mechanism of action conserved from mice to nonhuman primates.”

The results are encouraging in terms of translating to humans because of their closer similarities in various physiological factors, Dr. Maillard said.

“The nonhuman primate model of transplantation [offers] a transplantation model very close to what is being performed in humans, as well as the opportunity to study an immune system very similar to that of humans in nonhuman primates,” he said.

Dr. Maillard noted that, while trials in humans are not underway yet, “we are in active discussions about it,” and the team is indeed interested in testing REGN421 itself, with the effects likely to be as a prophylactic strategy.

There are currently no approved anti-DLL4 antibody drugs for use in humans.

“Our approach is mostly promising as a preventive treatment, rather than as a secondary treatment for GVHD, because DLL4/Notch blockade seems most active when applied early after transplantation during the time of initial seeding of the gut by T cells (in mice, we had observed the critical time window for a successful intervention to be within 48 hours of transplantation),” Dr. Maillard said.“There remain questions about which other prophylactic treatments we should ideally combine anti-DLL4 antibodies with.”

Dr. Maillard has received research funding from Regeneron and Genentech and is a member of Garuda Therapeutics’s scientific advisory board.

People with or at a high risk of cardiovascular disease who maintain a vegetarian diet for 6 months or longer show significant improvements in key risk factors, including cholesterol, glycemic control, and body weight, a meta-analysis of randomized controlled trials shows.

©KaterynaSednieva/Thinkstock

“To the best of our knowledge, this meta-analysis is the first that generates evidence from randomized controlled trials to assess the association of vegetarian diets with outcomes in people affected by cardiovascular diseases,” report the authors. The study was published online in JAMA Network Open.

“The greatest improvements in hemoglobin A1c and low-density lipoprotein cholesterol (LDL-C) were observed in individuals with type 2 diabetes and people at high risk of cardiovascular disease, highlighting the potential protective and synergistic effects of vegetarian diets for the primary prevention of cardiovascular disease,” they say.

Poor diet is well-established as increasing the morbidity and mortality associated with cardiovascular disease; however, although data has linked vegetarian diets to cardiovascular disease prevention in the general population, research on the effectiveness of such diets in people at high risk of cardiovascular disease is lacking.

“To the best of our knowledge, no meta-analysis of randomized controlled trials has been conducted to investigate the association of vegetarian diets with outcomes among people with CVD – indeed, research here has primarily focused on observational studies,” writes Tian Wang, RD, and colleagues at the University of Sydney.
 

Greater decreases in LDL-C, A1c, and body weight with vegetarian diets

For the meta-analysis, researchers identified 20 randomized controlled trials involving vegetarian diets that included 1,878 adults with or at a high risk of cardiovascular disease and included measurements of LDL-C, A1c, or systolic blood pressure.

The studies were conducted in the United States, Asia, Europe, and New Zealand between 1990 and 2021. Sample sizes ranged from 12 to 291 participants.

The mean range age of participants was 28-64 years. Studies included patients with cardiovascular disease (four studies), diabetes (seven studies), and those with at least two cardiovascular risk factors (nine studies).

The mean duration of the dietary intervention was 25.4 weeks (range 2-24 months). The most commonly prescribed diets were vegan (plant-based foods only), lacto-ovo-vegetarian (excluded meat, poultry, seafood, and dairy products, but allowed eggs), and lacto-vegetarian (same as previous but allowed dairy products).

Overall, those who consumed a vegetarian diet for an average of 6 months, versus comparison diets, had significantly greater decreases in LDL-C (6.6 mg/dL beyond the reduction achieved with standard therapy); A1c (0.24%); and body weight (3.4 kg), but the reduction in systolic blood pressure (0.1 mmHg) was not significantly greater.

Assessment of the overall certainty of evidence evaluated using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) tool showed a moderate level of evidence for reductions in LDL-C and A1c with the vegetarian diet.

Lacto-ovo vegetarian diets were associated with the greatest reduction in LDL-C (14.1 mg/dL); however, four out of the five trials restricted energy intake.

Of note, vegetarian diets were most effective for achieving glycemic control among people with type 2 diabetes and leading to improvements in weight among those at high risk of cardiovascular disease as well as those with type 2 diabetes.

The effects “suggest that vegetarian diets might have a synergistic [or at least nonantagonistic] use in potentiating the effects of optimal drug therapy in the prevention and treatment of a range of cardiometabolic diseases,” the authors write.

Although previous studies have shown similar improvements associated with a vegetarian diet, most studies did not stratify populations based on disease status, type of vegetarian diet, or comparison diet, the authors note.

The lack of improvement in systolic blood pressure is consistent with previous meta-analyses of vegetarian diets in general and suggests that salt intake may be the more important factor for those measures.

“[The meta-analysis] suggests that diet quality plays a major role in lowering blood pressure independent of animal food consumption, as the DASH [Dietary Approaches to Stop Hypertension] ... trial demonstrated,” the authors note.
 

Decreases in medication dose with vegetarian diet

Although most patients were taking medications to manage hypertension, hyperglycemia, and/or dyslipidemia at trial enrollment in as many as eight of the studies, the vegetarian diet intervention resulted in a decrease in medication dose.

In fact, medication use could obscure the favorable effects of vegetarian diets, which could have a larger effect size, the authors speculate.

“This hypothesis is supported by two randomized controlled trials in our meta-analysis that required patients not to take medication that could influence cardiometabolic outcomes, [and] these studies significantly improved systolic blood pressure and LDL-C,” they write.
 

Not all vegetarian diets are healthy

Although there are numerous variations in vegetarian diets, ranging from vegan diets that eliminate all animal food to pesco-vegetarian diets that allow fish or seafood, most that are well-balanced can provide health benefits including lower saturated fat, L-carnitine, and choline (precursors of the atherogenic TMAO), and other benefits that might explain the improvements seen in the meta-analysis.  

The diets may also be high in dietary fiber, mono- and polyunsaturated fatty acids, potassium, magnesium, and phytochemical, and have lower glycemic index scores.

Of note, 12 studies in the meta-analysis emphasized low-fat content, which the authors speculate may have contributed to the improvements observed in LDC-C.

Specifically, lacto-ovo vegetarian diets were associated with the greatest reduction in LDL-C (–14.1 mg/dL); however, four out of five of the trials restricted energy intake, which could have also played a role in improvements.

Importantly, not all vegetarian diets are healthy, and the authors caution about some that allow, for instance, deep-fried foods rich in trans-fatty acids and salt, such as tempura vegetables, potentially increasing the risk of type 2 diabetes and coronary heart disease.

They note that “more than one-third of the studies included in our meta-analysis did not emphasize the importance of consuming minimally processed plant-based whole foods.”

Overall, however, the fact that the greatest improvements in A1c and LDL-C were seen in patients with type 2 diabetes and those at high risk of CVD “highlight[s] the potential protective and synergistic effects of vegetarian diets for the primary prevention of CVD.”

A version of this article first appeared on Medscape.com.

People with or at a high risk of cardiovascular disease who maintain a vegetarian diet for 6 months or longer show significant improvements in key risk factors, including cholesterol, glycemic control, and body weight, a meta-analysis of randomized controlled trials shows.

©KaterynaSednieva/Thinkstock

“To the best of our knowledge, this meta-analysis is the first that generates evidence from randomized controlled trials to assess the association of vegetarian diets with outcomes in people affected by cardiovascular diseases,” report the authors. The study was published online in JAMA Network Open.

“The greatest improvements in hemoglobin A1c and low-density lipoprotein cholesterol (LDL-C) were observed in individuals with type 2 diabetes and people at high risk of cardiovascular disease, highlighting the potential protective and synergistic effects of vegetarian diets for the primary prevention of cardiovascular disease,” they say.

Poor diet is well-established as increasing the morbidity and mortality associated with cardiovascular disease; however, although data has linked vegetarian diets to cardiovascular disease prevention in the general population, research on the effectiveness of such diets in people at high risk of cardiovascular disease is lacking.

“To the best of our knowledge, no meta-analysis of randomized controlled trials has been conducted to investigate the association of vegetarian diets with outcomes among people with CVD – indeed, research here has primarily focused on observational studies,” writes Tian Wang, RD, and colleagues at the University of Sydney.
 

Greater decreases in LDL-C, A1c, and body weight with vegetarian diets

For the meta-analysis, researchers identified 20 randomized controlled trials involving vegetarian diets that included 1,878 adults with or at a high risk of cardiovascular disease and included measurements of LDL-C, A1c, or systolic blood pressure.

The studies were conducted in the United States, Asia, Europe, and New Zealand between 1990 and 2021. Sample sizes ranged from 12 to 291 participants.

The mean range age of participants was 28-64 years. Studies included patients with cardiovascular disease (four studies), diabetes (seven studies), and those with at least two cardiovascular risk factors (nine studies).

The mean duration of the dietary intervention was 25.4 weeks (range 2-24 months). The most commonly prescribed diets were vegan (plant-based foods only), lacto-ovo-vegetarian (excluded meat, poultry, seafood, and dairy products, but allowed eggs), and lacto-vegetarian (same as previous but allowed dairy products).

Overall, those who consumed a vegetarian diet for an average of 6 months, versus comparison diets, had significantly greater decreases in LDL-C (6.6 mg/dL beyond the reduction achieved with standard therapy); A1c (0.24%); and body weight (3.4 kg), but the reduction in systolic blood pressure (0.1 mmHg) was not significantly greater.

Assessment of the overall certainty of evidence evaluated using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) tool showed a moderate level of evidence for reductions in LDL-C and A1c with the vegetarian diet.

Lacto-ovo vegetarian diets were associated with the greatest reduction in LDL-C (14.1 mg/dL); however, four out of the five trials restricted energy intake.

Of note, vegetarian diets were most effective for achieving glycemic control among people with type 2 diabetes and leading to improvements in weight among those at high risk of cardiovascular disease as well as those with type 2 diabetes.

The effects “suggest that vegetarian diets might have a synergistic [or at least nonantagonistic] use in potentiating the effects of optimal drug therapy in the prevention and treatment of a range of cardiometabolic diseases,” the authors write.

Although previous studies have shown similar improvements associated with a vegetarian diet, most studies did not stratify populations based on disease status, type of vegetarian diet, or comparison diet, the authors note.

The lack of improvement in systolic blood pressure is consistent with previous meta-analyses of vegetarian diets in general and suggests that salt intake may be the more important factor for those measures.

“[The meta-analysis] suggests that diet quality plays a major role in lowering blood pressure independent of animal food consumption, as the DASH [Dietary Approaches to Stop Hypertension] ... trial demonstrated,” the authors note.
 

Decreases in medication dose with vegetarian diet

Although most patients were taking medications to manage hypertension, hyperglycemia, and/or dyslipidemia at trial enrollment in as many as eight of the studies, the vegetarian diet intervention resulted in a decrease in medication dose.

In fact, medication use could obscure the favorable effects of vegetarian diets, which could have a larger effect size, the authors speculate.

“This hypothesis is supported by two randomized controlled trials in our meta-analysis that required patients not to take medication that could influence cardiometabolic outcomes, [and] these studies significantly improved systolic blood pressure and LDL-C,” they write.
 

Not all vegetarian diets are healthy

Although there are numerous variations in vegetarian diets, ranging from vegan diets that eliminate all animal food to pesco-vegetarian diets that allow fish or seafood, most that are well-balanced can provide health benefits including lower saturated fat, L-carnitine, and choline (precursors of the atherogenic TMAO), and other benefits that might explain the improvements seen in the meta-analysis.  

The diets may also be high in dietary fiber, mono- and polyunsaturated fatty acids, potassium, magnesium, and phytochemical, and have lower glycemic index scores.

Of note, 12 studies in the meta-analysis emphasized low-fat content, which the authors speculate may have contributed to the improvements observed in LDC-C.

Specifically, lacto-ovo vegetarian diets were associated with the greatest reduction in LDL-C (–14.1 mg/dL); however, four out of five of the trials restricted energy intake, which could have also played a role in improvements.

Importantly, not all vegetarian diets are healthy, and the authors caution about some that allow, for instance, deep-fried foods rich in trans-fatty acids and salt, such as tempura vegetables, potentially increasing the risk of type 2 diabetes and coronary heart disease.

They note that “more than one-third of the studies included in our meta-analysis did not emphasize the importance of consuming minimally processed plant-based whole foods.”

Overall, however, the fact that the greatest improvements in A1c and LDL-C were seen in patients with type 2 diabetes and those at high risk of CVD “highlight[s] the potential protective and synergistic effects of vegetarian diets for the primary prevention of CVD.”

A version of this article first appeared on Medscape.com.

People with or at a high risk of cardiovascular disease who maintain a vegetarian diet for 6 months or longer show significant improvements in key risk factors, including cholesterol, glycemic control, and body weight, a meta-analysis of randomized controlled trials shows.

©KaterynaSednieva/Thinkstock

“To the best of our knowledge, this meta-analysis is the first that generates evidence from randomized controlled trials to assess the association of vegetarian diets with outcomes in people affected by cardiovascular diseases,” report the authors. The study was published online in JAMA Network Open.

“The greatest improvements in hemoglobin A1c and low-density lipoprotein cholesterol (LDL-C) were observed in individuals with type 2 diabetes and people at high risk of cardiovascular disease, highlighting the potential protective and synergistic effects of vegetarian diets for the primary prevention of cardiovascular disease,” they say.

Poor diet is well-established as increasing the morbidity and mortality associated with cardiovascular disease; however, although data has linked vegetarian diets to cardiovascular disease prevention in the general population, research on the effectiveness of such diets in people at high risk of cardiovascular disease is lacking.

“To the best of our knowledge, no meta-analysis of randomized controlled trials has been conducted to investigate the association of vegetarian diets with outcomes among people with CVD – indeed, research here has primarily focused on observational studies,” writes Tian Wang, RD, and colleagues at the University of Sydney.
 

Greater decreases in LDL-C, A1c, and body weight with vegetarian diets

For the meta-analysis, researchers identified 20 randomized controlled trials involving vegetarian diets that included 1,878 adults with or at a high risk of cardiovascular disease and included measurements of LDL-C, A1c, or systolic blood pressure.

The studies were conducted in the United States, Asia, Europe, and New Zealand between 1990 and 2021. Sample sizes ranged from 12 to 291 participants.

The mean range age of participants was 28-64 years. Studies included patients with cardiovascular disease (four studies), diabetes (seven studies), and those with at least two cardiovascular risk factors (nine studies).

The mean duration of the dietary intervention was 25.4 weeks (range 2-24 months). The most commonly prescribed diets were vegan (plant-based foods only), lacto-ovo-vegetarian (excluded meat, poultry, seafood, and dairy products, but allowed eggs), and lacto-vegetarian (same as previous but allowed dairy products).

Overall, those who consumed a vegetarian diet for an average of 6 months, versus comparison diets, had significantly greater decreases in LDL-C (6.6 mg/dL beyond the reduction achieved with standard therapy); A1c (0.24%); and body weight (3.4 kg), but the reduction in systolic blood pressure (0.1 mmHg) was not significantly greater.

Assessment of the overall certainty of evidence evaluated using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) tool showed a moderate level of evidence for reductions in LDL-C and A1c with the vegetarian diet.

Lacto-ovo vegetarian diets were associated with the greatest reduction in LDL-C (14.1 mg/dL); however, four out of the five trials restricted energy intake.

Of note, vegetarian diets were most effective for achieving glycemic control among people with type 2 diabetes and leading to improvements in weight among those at high risk of cardiovascular disease as well as those with type 2 diabetes.

The effects “suggest that vegetarian diets might have a synergistic [or at least nonantagonistic] use in potentiating the effects of optimal drug therapy in the prevention and treatment of a range of cardiometabolic diseases,” the authors write.

Although previous studies have shown similar improvements associated with a vegetarian diet, most studies did not stratify populations based on disease status, type of vegetarian diet, or comparison diet, the authors note.

The lack of improvement in systolic blood pressure is consistent with previous meta-analyses of vegetarian diets in general and suggests that salt intake may be the more important factor for those measures.

“[The meta-analysis] suggests that diet quality plays a major role in lowering blood pressure independent of animal food consumption, as the DASH [Dietary Approaches to Stop Hypertension] ... trial demonstrated,” the authors note.
 

Decreases in medication dose with vegetarian diet

Although most patients were taking medications to manage hypertension, hyperglycemia, and/or dyslipidemia at trial enrollment in as many as eight of the studies, the vegetarian diet intervention resulted in a decrease in medication dose.

In fact, medication use could obscure the favorable effects of vegetarian diets, which could have a larger effect size, the authors speculate.

“This hypothesis is supported by two randomized controlled trials in our meta-analysis that required patients not to take medication that could influence cardiometabolic outcomes, [and] these studies significantly improved systolic blood pressure and LDL-C,” they write.
 

Not all vegetarian diets are healthy

Although there are numerous variations in vegetarian diets, ranging from vegan diets that eliminate all animal food to pesco-vegetarian diets that allow fish or seafood, most that are well-balanced can provide health benefits including lower saturated fat, L-carnitine, and choline (precursors of the atherogenic TMAO), and other benefits that might explain the improvements seen in the meta-analysis.  

The diets may also be high in dietary fiber, mono- and polyunsaturated fatty acids, potassium, magnesium, and phytochemical, and have lower glycemic index scores.

Of note, 12 studies in the meta-analysis emphasized low-fat content, which the authors speculate may have contributed to the improvements observed in LDC-C.

Specifically, lacto-ovo vegetarian diets were associated with the greatest reduction in LDL-C (–14.1 mg/dL); however, four out of five of the trials restricted energy intake, which could have also played a role in improvements.

Importantly, not all vegetarian diets are healthy, and the authors caution about some that allow, for instance, deep-fried foods rich in trans-fatty acids and salt, such as tempura vegetables, potentially increasing the risk of type 2 diabetes and coronary heart disease.

They note that “more than one-third of the studies included in our meta-analysis did not emphasize the importance of consuming minimally processed plant-based whole foods.”

Overall, however, the fact that the greatest improvements in A1c and LDL-C were seen in patients with type 2 diabetes and those at high risk of CVD “highlight[s] the potential protective and synergistic effects of vegetarian diets for the primary prevention of CVD.”

A version of this article first appeared on Medscape.com.