A new study sheds light on some of the risk factors for the development of psychosis, including the potentially causative role of sexual assault.

Investigators conducted an exposome-wide association analysis on more than 155,000 individuals. Of more than 140 correlates of psychotic experiences that they identified, they narrowed it down to 36 variables, which they further explored using Mendelian randomization analysis.

The analysis found that having been the victim of a sexual assault might be a potential causal risk factor for psychotic experiences. On the other hand, having experienced a physical violent crime, cannabis use, and prolonged worry after embarrassment showed a pleiotropic association and appeared to be an aftereffect of psychotic experience.

“From a public health perspective, we need more investment in comprehensive strategies to prevent traumatic experiences at the population level to decrease the burden of psychosis,” senior author Sinan Gülöksüz, MD, PhD, associate professor in the department of psychiatry and neuropsychiatry, Maastricht University Medical Center, the Netherlands, said in an interview.

“From a clinical perspective, clinicians should be aware of the harmful influence of traumatic experiences on mental health and address this through interventions such as trauma-informed care,” he said.

The study was published online in JAMA Psychiatry.

‘Disentangling’ cause and effect

“Previous research has shown associations between psychosis and a few environmental factors, such as substance use, urbanicity, pregnancy complications, and traumatic experiences, but research has so far investigated only a few specific environmental factors by singling them out in individual studies,” Dr. Gülöksüz said.

“Yet, environment is a much more complex and interactive network that includes many factors shaping our health – where we live, what we eat, our lifestyle preferences and habits such as exercise and smoking, and our social surrounding,” he continued. “Rarely has it been possible to understand whether these environmental factors have causal roles in developing psychosis.”

To investigate the question, the researchers turned to the UK Biobank, one of the largest population-based datasets in the world. The current study focused on individuals with completed data on mental questionnaires that assessed psychotic experiences (n = 155,247; mean [SD] age, 55.94 [7.74] years; 57% female).

They began by conducting an exposome-wide association study, using logistic regression analyses with psychotic experiences as the outcome and adjusting all analyses for age and sex.

“Initially, we identified many associations between environmental factors and psychotic experiences in this large cohort,” Dr. Gülöksüz reported.

In the final multivariable model, variables associated with psychotic experiences were further analyzed using “genetically informed approaches to probe potential associations.”

The researchers utilized Mendelian randomization (MR) methodology “to disentangle cause and effect in this observational study,” Dr. Gülöksüz said. “This method reduces confounding and reverse causation in observational studies by using genetic variants that have been passed on from generation to generation randomly as instruments.”

MR analysis “has allowed us to assess whether these associations reflect potentially causal influences of environmental factors on psychotic experiences,” he added.
 

Well-studied and unexplored risk factors

The researchers identified 162 variables associated with psychotic experiences in the discovery dataset and were able to replicate 148. When these 148 variables were subjected to multivariable analyses, 36 were found to be statistically significantly associated with psychotic experiences. Of these variables, 28 had “significant genetic overlap” with psychotic experiences.

When the researchers conducted one-sample MR analyses, they found forward associations with three variables and reverse associations with three variables.

Forward associations were found with ever having experienced sexual assault (odds ratio [OR], 1.32; 95% confidence interval [CI], 1.14-1.52; P = 2.67), and forward associations (with pleiotropy) were found with ever having experienced a physically violent crime and risk-taking behavior (OR, 1.25, 95% CI, 1.11-1.41; P = 3.28 and OR, 1.21, 95% CI, 1.08-1.35; P = 1.34, respectively).

“The allele scores for these 3 variables explained 0.03% to 0.23% variance of the corresponding variable” and the F statistics “ranged from 21.53 to 181.84, indicating that the results did not suffer from a weak-instrument bias,” the authors reported.

The researchers calculated an instrument based on increasing psychotic experiences risk allele scores and found that these scores explained 0.14% variance of psychotic experiences (F statistic, 19.26).

Using that calculation, they found a reverse association with having experienced a physically violent crime (OR, 1.08; 95% CI, 1.04-1.13; P = 3.92 × 10-4), cannabis use (OR, 1.11; 95% CI, 1.06-1.15; P = 2.64 × 10-6), and worrying too long after embarrassment (OR, 1.06; 95% CI, 1.03-1.10; P = 3.96 × 10-4). They then validated these associations.

The presence of all five correlates was associated with tenfold increased odds of psychotic experiences (OR, 10.63; 95% CI, 8.27-13.65, P = 1.2 × 10-114).

“Associations with psychotic experiences were found with both well-studied and unexplored multiple correlated variables,” the authors stated.
 

Era of ‘big data’

In a comment, Chirag Patel, PhD, associate professor of biomedical informatics at Harvard Medical School, Boston, who was not involved with the study, said he thought the study was “a nice example of a data-driven and comprehensive study of the environment coupled with attempts to triangulate evidence from genetics, made possible by biobank data.

“To guide public health policies and implementation of prevention strategies for psychosis, we need more systematic analyses and triangulate evidence with genetically informed methods to identify potentially modifiable risk factors in the era of ‘big data,’ ” he said.

“For instance, traumatic experiences contribute to poor mental and physical health, including psychosis,” Dr. Gülöksüz added.

The Kootstra Talent Fellowship, the Ophelia Research Project, and the Vidi Award from the Netherlands Scientific Organization provided funding to individual investigators. Dr. Gülöksüz and coauthors declared no relevant financial conflicts. Dr. Patel served as a reviewer on the study.

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

A new study sheds light on some of the risk factors for the development of psychosis, including the potentially causative role of sexual assault.

Investigators conducted an exposome-wide association analysis on more than 155,000 individuals. Of more than 140 correlates of psychotic experiences that they identified, they narrowed it down to 36 variables, which they further explored using Mendelian randomization analysis.

The analysis found that having been the victim of a sexual assault might be a potential causal risk factor for psychotic experiences. On the other hand, having experienced a physical violent crime, cannabis use, and prolonged worry after embarrassment showed a pleiotropic association and appeared to be an aftereffect of psychotic experience.

“From a public health perspective, we need more investment in comprehensive strategies to prevent traumatic experiences at the population level to decrease the burden of psychosis,” senior author Sinan Gülöksüz, MD, PhD, associate professor in the department of psychiatry and neuropsychiatry, Maastricht University Medical Center, the Netherlands, said in an interview.

“From a clinical perspective, clinicians should be aware of the harmful influence of traumatic experiences on mental health and address this through interventions such as trauma-informed care,” he said.

The study was published online in JAMA Psychiatry.

‘Disentangling’ cause and effect

“Previous research has shown associations between psychosis and a few environmental factors, such as substance use, urbanicity, pregnancy complications, and traumatic experiences, but research has so far investigated only a few specific environmental factors by singling them out in individual studies,” Dr. Gülöksüz said.

“Yet, environment is a much more complex and interactive network that includes many factors shaping our health – where we live, what we eat, our lifestyle preferences and habits such as exercise and smoking, and our social surrounding,” he continued. “Rarely has it been possible to understand whether these environmental factors have causal roles in developing psychosis.”

To investigate the question, the researchers turned to the UK Biobank, one of the largest population-based datasets in the world. The current study focused on individuals with completed data on mental questionnaires that assessed psychotic experiences (n = 155,247; mean [SD] age, 55.94 [7.74] years; 57% female).

They began by conducting an exposome-wide association study, using logistic regression analyses with psychotic experiences as the outcome and adjusting all analyses for age and sex.

“Initially, we identified many associations between environmental factors and psychotic experiences in this large cohort,” Dr. Gülöksüz reported.

In the final multivariable model, variables associated with psychotic experiences were further analyzed using “genetically informed approaches to probe potential associations.”

The researchers utilized Mendelian randomization (MR) methodology “to disentangle cause and effect in this observational study,” Dr. Gülöksüz said. “This method reduces confounding and reverse causation in observational studies by using genetic variants that have been passed on from generation to generation randomly as instruments.”

MR analysis “has allowed us to assess whether these associations reflect potentially causal influences of environmental factors on psychotic experiences,” he added.
 

Well-studied and unexplored risk factors

The researchers identified 162 variables associated with psychotic experiences in the discovery dataset and were able to replicate 148. When these 148 variables were subjected to multivariable analyses, 36 were found to be statistically significantly associated with psychotic experiences. Of these variables, 28 had “significant genetic overlap” with psychotic experiences.

When the researchers conducted one-sample MR analyses, they found forward associations with three variables and reverse associations with three variables.

Forward associations were found with ever having experienced sexual assault (odds ratio [OR], 1.32; 95% confidence interval [CI], 1.14-1.52; P = 2.67), and forward associations (with pleiotropy) were found with ever having experienced a physically violent crime and risk-taking behavior (OR, 1.25, 95% CI, 1.11-1.41; P = 3.28 and OR, 1.21, 95% CI, 1.08-1.35; P = 1.34, respectively).

“The allele scores for these 3 variables explained 0.03% to 0.23% variance of the corresponding variable” and the F statistics “ranged from 21.53 to 181.84, indicating that the results did not suffer from a weak-instrument bias,” the authors reported.

The researchers calculated an instrument based on increasing psychotic experiences risk allele scores and found that these scores explained 0.14% variance of psychotic experiences (F statistic, 19.26).

Using that calculation, they found a reverse association with having experienced a physically violent crime (OR, 1.08; 95% CI, 1.04-1.13; P = 3.92 × 10-4), cannabis use (OR, 1.11; 95% CI, 1.06-1.15; P = 2.64 × 10-6), and worrying too long after embarrassment (OR, 1.06; 95% CI, 1.03-1.10; P = 3.96 × 10-4). They then validated these associations.

The presence of all five correlates was associated with tenfold increased odds of psychotic experiences (OR, 10.63; 95% CI, 8.27-13.65, P = 1.2 × 10-114).

“Associations with psychotic experiences were found with both well-studied and unexplored multiple correlated variables,” the authors stated.
 

Era of ‘big data’

In a comment, Chirag Patel, PhD, associate professor of biomedical informatics at Harvard Medical School, Boston, who was not involved with the study, said he thought the study was “a nice example of a data-driven and comprehensive study of the environment coupled with attempts to triangulate evidence from genetics, made possible by biobank data.

“To guide public health policies and implementation of prevention strategies for psychosis, we need more systematic analyses and triangulate evidence with genetically informed methods to identify potentially modifiable risk factors in the era of ‘big data,’ ” he said.

“For instance, traumatic experiences contribute to poor mental and physical health, including psychosis,” Dr. Gülöksüz added.

The Kootstra Talent Fellowship, the Ophelia Research Project, and the Vidi Award from the Netherlands Scientific Organization provided funding to individual investigators. Dr. Gülöksüz and coauthors declared no relevant financial conflicts. Dr. Patel served as a reviewer on the study.

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

A new study sheds light on some of the risk factors for the development of psychosis, including the potentially causative role of sexual assault.

Investigators conducted an exposome-wide association analysis on more than 155,000 individuals. Of more than 140 correlates of psychotic experiences that they identified, they narrowed it down to 36 variables, which they further explored using Mendelian randomization analysis.

The analysis found that having been the victim of a sexual assault might be a potential causal risk factor for psychotic experiences. On the other hand, having experienced a physical violent crime, cannabis use, and prolonged worry after embarrassment showed a pleiotropic association and appeared to be an aftereffect of psychotic experience.

“From a public health perspective, we need more investment in comprehensive strategies to prevent traumatic experiences at the population level to decrease the burden of psychosis,” senior author Sinan Gülöksüz, MD, PhD, associate professor in the department of psychiatry and neuropsychiatry, Maastricht University Medical Center, the Netherlands, said in an interview.

“From a clinical perspective, clinicians should be aware of the harmful influence of traumatic experiences on mental health and address this through interventions such as trauma-informed care,” he said.

The study was published online in JAMA Psychiatry.

‘Disentangling’ cause and effect

“Previous research has shown associations between psychosis and a few environmental factors, such as substance use, urbanicity, pregnancy complications, and traumatic experiences, but research has so far investigated only a few specific environmental factors by singling them out in individual studies,” Dr. Gülöksüz said.

“Yet, environment is a much more complex and interactive network that includes many factors shaping our health – where we live, what we eat, our lifestyle preferences and habits such as exercise and smoking, and our social surrounding,” he continued. “Rarely has it been possible to understand whether these environmental factors have causal roles in developing psychosis.”

To investigate the question, the researchers turned to the UK Biobank, one of the largest population-based datasets in the world. The current study focused on individuals with completed data on mental questionnaires that assessed psychotic experiences (n = 155,247; mean [SD] age, 55.94 [7.74] years; 57% female).

They began by conducting an exposome-wide association study, using logistic regression analyses with psychotic experiences as the outcome and adjusting all analyses for age and sex.

“Initially, we identified many associations between environmental factors and psychotic experiences in this large cohort,” Dr. Gülöksüz reported.

In the final multivariable model, variables associated with psychotic experiences were further analyzed using “genetically informed approaches to probe potential associations.”

The researchers utilized Mendelian randomization (MR) methodology “to disentangle cause and effect in this observational study,” Dr. Gülöksüz said. “This method reduces confounding and reverse causation in observational studies by using genetic variants that have been passed on from generation to generation randomly as instruments.”

MR analysis “has allowed us to assess whether these associations reflect potentially causal influences of environmental factors on psychotic experiences,” he added.
 

Well-studied and unexplored risk factors

The researchers identified 162 variables associated with psychotic experiences in the discovery dataset and were able to replicate 148. When these 148 variables were subjected to multivariable analyses, 36 were found to be statistically significantly associated with psychotic experiences. Of these variables, 28 had “significant genetic overlap” with psychotic experiences.

When the researchers conducted one-sample MR analyses, they found forward associations with three variables and reverse associations with three variables.

Forward associations were found with ever having experienced sexual assault (odds ratio [OR], 1.32; 95% confidence interval [CI], 1.14-1.52; P = 2.67), and forward associations (with pleiotropy) were found with ever having experienced a physically violent crime and risk-taking behavior (OR, 1.25, 95% CI, 1.11-1.41; P = 3.28 and OR, 1.21, 95% CI, 1.08-1.35; P = 1.34, respectively).

“The allele scores for these 3 variables explained 0.03% to 0.23% variance of the corresponding variable” and the F statistics “ranged from 21.53 to 181.84, indicating that the results did not suffer from a weak-instrument bias,” the authors reported.

The researchers calculated an instrument based on increasing psychotic experiences risk allele scores and found that these scores explained 0.14% variance of psychotic experiences (F statistic, 19.26).

Using that calculation, they found a reverse association with having experienced a physically violent crime (OR, 1.08; 95% CI, 1.04-1.13; P = 3.92 × 10-4), cannabis use (OR, 1.11; 95% CI, 1.06-1.15; P = 2.64 × 10-6), and worrying too long after embarrassment (OR, 1.06; 95% CI, 1.03-1.10; P = 3.96 × 10-4). They then validated these associations.

The presence of all five correlates was associated with tenfold increased odds of psychotic experiences (OR, 10.63; 95% CI, 8.27-13.65, P = 1.2 × 10-114).

“Associations with psychotic experiences were found with both well-studied and unexplored multiple correlated variables,” the authors stated.
 

Era of ‘big data’

In a comment, Chirag Patel, PhD, associate professor of biomedical informatics at Harvard Medical School, Boston, who was not involved with the study, said he thought the study was “a nice example of a data-driven and comprehensive study of the environment coupled with attempts to triangulate evidence from genetics, made possible by biobank data.

“To guide public health policies and implementation of prevention strategies for psychosis, we need more systematic analyses and triangulate evidence with genetically informed methods to identify potentially modifiable risk factors in the era of ‘big data,’ ” he said.

“For instance, traumatic experiences contribute to poor mental and physical health, including psychosis,” Dr. Gülöksüz added.

The Kootstra Talent Fellowship, the Ophelia Research Project, and the Vidi Award from the Netherlands Scientific Organization provided funding to individual investigators. Dr. Gülöksüz and coauthors declared no relevant financial conflicts. Dr. Patel served as a reviewer on the study.

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

Some patients with blood cancers for whom all other therapeutic options have been exhausted have one final chance of getting rid of their disease: treatment with chimeric antigen-receptor (CAR) T cells.

Described as a “living drug,” the treatment involves genetically engineering the patient’s own blood cells and reinfusing them back into their system. These CAR T cells then hunt down and destroy cancer cells; in some cases, they manage to eradicate the disease completely.

About half of patients with leukemia or lymphoma and about a third of those with multiple myeloma who receive this treatment have a complete remission and achieve a functional “cure.”

But not all patients who could benefit from this therapy are able to get it. Some are spending months on waiting lists, often deteriorating while they wait. These patients have exhausted all other therapeutic options, and many are facing hospice and death.

The scope of this problem was illustrated by a recent survey of the centers that are certified to deliver this complex therapy.

The survey was led by Yi Lin, MD, PhD, associate professor of medicine at the Mayo Clinic, Rochester, Minn., and medical director for the cellular therapy program. It was published as an abstract at the annual meeting of the American Society of Clinical Oncology recently, although it was not presented there.

“We wanted to find out just how widespread this problem is,” Dr. Lin said, adding: “There had been nothing in the literature thus far about it.”

The team contacted 20 centers across the United States and received responses from 17. Results showed that the median time on the waiting list was 6 months and that only 25% of patients eventually received CAR T-cell therapy. An additional 25% were able to enter a CAR T clinical trial. The remaining 50% of patients either were enrolled in a different type of trial, entered hospice, or died.

For patient selection, all centers reported using a committee of experienced physicians to ensure consistency. They employed different ethical principles for selection. Some centers sought to maximize the total benefit, such as selecting the patients most likely to achieve leukapheresis or a clinical response, while others based their decisions on the time patients spent on waiting list or gave priority to the patients who were the “worst off” with the most limited therapeutic options.
 

Shortage affecting mostly myeloma patients

The shortages in CAR T-cell therapies primarily involve the products used for patients with multiple myeloma.

The problem has not, as yet, noticeably spilled over to lymphoma and leukemia treatments, which use a slightly different type of CAR T-cell therapy (it targets CD19, whereas the cell therapies used for myeloma target BCMA).

“We have backlog of myeloma patients who don’t have access,” said Nina Shah, MD, a hematologist and professor of medicine at the University of California, San Francisco. “We have only four slots for the two myeloma products but about 50-60 eligible patients.”

Long waiting times for CAR T cells for myeloma have been an issue ever since the first of these products appeared on the market: idecabtagene vicleucel (ide-cel; Abecma), developed by Bluebird Bio and Bristol-Myers Squibb. “As soon as it became available in March 2021, we had people waiting and limits on our access to it,” Dr. Shah said.

A second CAR T-cell therapy for myeloma, ciltacabtagene autoleucel (cilta-cel, Carvykti), developed by Janssen and Legend Biotech, received approval in February 2022. While that helped provide centers with a few more slots, it wasn’t sufficient to cut waiting times, and the demand for these myeloma therapies continues to outstrip the capacity to produce CAR-T products in a timely manner.

“For myeloma, the demand is very high, as most patients are not cured from any other existing myeloma therapies, and most patients will make it to fifth-line therapy where the two CAR T-cell products are approved right now,” said Krina K. Patel, MD, medical director of the department of lymphoma/myeloma in the division of cancer medicine at the University of Texas MD Anderson Cancer Center, Houston.

“We likely have 10 eligible CAR-T myeloma patients each month at our center,” she said, “but were getting two slots per month for the past 8 months, and now are getting four slots a month.”

“Our clinic has also experienced the impact of the low number of manufacturing slots offered to each cancer center for some CAR T-cell products,” said David Maloney, MD, PhD, medical director, Cellular Immunotherapy and Bezos Family Immunotherapy Clinic, Seattle Cancer Care Alliance.

He noted that, as with other cancer centers, for multiple myeloma they are provided a specific number of manufacturing slots for each treatment. “Our providers discuss which patients are most appropriate for available slots for that month,” said Dr. Maloney.

“Additionally, juggling patient schedules may be required to address the extended manufacturing time for some products. In some cases, clinical trials may be available in a more timely fashion for appropriate patients, and in some cases, switching to an alternative product is possible,” he commented.
 

Complex causes behind bottleneck

The cause of the current bottleneck for myeloma patients is complex. It stems from a shortage of raw materials and supply chain restraints, among other things.

While the biggest impact of shortages has been on patients with multiple myeloma, Dr. Patel pointed out that these constraints are also affecting patients with lymphoma at her institution, but to a lesser degree.

“This is multifactorial as to why, but most of the issues arise from manufacturing,” Dr. Patel said in an interview. “Initially, the FDA limited how many slots each new product could have per month, then there was a viral vector shortage, and then the quality-control process the FDA requires takes longer than the manufacturing of the cells actually do.”

On top of that, “we have about a 5% manufacturing fail rate so far,” she added. Such failures occur when the cells taken from a patient cannot be converted into CAR T cells for therapy.

Matthew J. Frigault, MD, from the Center for Cellular Therapies, Mass General Cancer Center, Boston, explained that the growing excitement about the potential for cellular therapy and recent approvals for these products for use in earlier lines of treatment have increased demand for them.

There are also problems regarding supply. Manufacture and delivery of CAR T is complicated and takes time to scale up, Dr. Frigault pointed out. “Therefore, we are seeing limited access, more so for the BCMA-directed therapies [which are used for myeloma].”

The shortages and delays likely involve two main factors. “For the newer indications, there is a significant backlog of patients who have been waiting for these therapies and have not been able to access them in the clinical trial setting, and manufacturing is extremely complicated and not easily scaled up,” he said.

“That being said, manufacturers are trying to increase the number of available manufacturing slots and decrease the time needed to manufacture cells,” Dr. Frigault commented.

Delays in access to myeloma CAR T-cell therapy are also affecting patient care at Fox Chase Cancer Center in Philadelphia. “We have had about one slot every 2 months for Abecma,” noted Henry Fung, MD, chair of the department of bone marrow transplant and cellular therapies at Fox Chase. “For Carvykti, there are only 32 certified centers in [the] U.S., and access is very limited.”

Dr. Fung explained that they have had to offer alternative treatments to many of their patients. “There are rumors that there’s shortage in obtaining raw materials, such as the virus used for transduction, although we have not encountered any problems in other CAR T products used for lymphomas.”
 

Pharma companies trying to meet the demand

This news organization reached out to the manufacturers of CAR T products. All have reported that they are doing what they feasibly can to ramp up production.

“The complexity of delivering CAR T-cell therapies is unlike any other traditional biologic or small-molecule medicine, using a patient’s own cells to start a highly sophisticated and personalized manufacturing process,” commented a spokesperson for BMS, which has two CAR T-cell products currently on the market.

“In this nascent field of cell therapy, we continue to evolve every day, addressing supply and manufacturing challenges head on by applying key learnings across our three state-of-the-art cell therapy facilities and two new facilities in progress.

“We have been encouraged by a steady increase in our manufacturing capacity, and we continue efforts to ramp up further to meet the demand for our cell therapies,” the BMS spokesperson commented. “We have already seen improvements in the stabilization of vector supply and expect additional improvements in capacity in the second half of 2022.”

Novartis said much the same thing. They have a “comprehensive, integrated global CAR-T manufacturing footprint that strengthens the flexibility, resilience, and sustainability of the Novartis manufacturing and supply chain. Together with an improved manufacturing process, we are confident in our ability to meet patient demand with timely delivery,” according to a Novartis spokesperson.

The spokesperson also pointed out that the company has continuously incorporated process improvements that have significantly increased manufacturing capacity and success rates for patients in need of CAR T cells.

“Data presented at [the] American Society of Hematology annual meeting in 2021 showed the Novartis Morris Plains facility, our flagship CAR T manufacturing site, had commercial manufacturing and shipping success rates of 96% and 99%, respectively, between January and August 2021,” according to the spokesperson.

Legend and Janssen, the companies behind Carvykti, one of the two approved cell products for myeloma, which launched earlier in 2022, said that they have continued to activate certified treatment centers in a phased approach that will enable them to expand availability throughout 2022 and beyond.

“This phased approach was designed to ensure the highest level of predictability and reliability for the patient and the certified treatment centers,” the spokesperson said. “We understand the urgency for patients in need of Carvyki and are committed to doing everything we can to accelerate our ability to deliver this important cell therapy in a reliable and timely manner.”

With regard to the industry-wide supply shortage of lentivirus, Legend and Janssen say they have put in place multiple processes to address the shortage, “including enhancing our own internal manufacturing capabilities of this essential drug substance, to ensure sufficient and sustained supply.”
 

Incredibly exciting potential

Given the immense potential of CAR T-cell therapy, the supply shortage that myeloma patients are experiencing is all the more poignant and distressing. While not everyone benefits, some patients for whom every other therapy failed and who were facing hospice have had dramatic results.

“Incredibly exciting with unbelievable potential” was how one expert described these new therapies when the first product was about to enter the marketplace. Since then, six CAR T-cell therapies have received regulatory approval for an ever-increasing range of hematologic malignancies.

But these CAR T-cell therapies have their own set of adverse events, which can be serious and even life-threatening. In addition, not all patients become cancer free, although long-term data are impressive.

A study that included one of the longest follow-ups to date was reported at the 2020 annual meeting of the American Society of Clinical Oncology. The researchers reported that remissions lasted over 9 years for patients with relapsed/refractory B-cell lymphoma or chronic lymphocytic leukemia who underwent treatment with Kite’s axicaptagene cilleucel (Yescarta). This review included 43 patients and showed an overall remission rate of 76%. Complete remission was achieved for 54% of patients, and partial remission was achieved for 22%.

The results with CAR T-cell therapy in multiple myeloma are not quite as impressive, but even so, the clinical data that supported the approval of Abecma showed that a third of patients, who had previously received a median of six prior therapies, achieved a complete response.

At the time of the Abecma approval, the lead investigator of the study, Nikhil Munshi, MD, of Dana-Farber Cancer Institute, Boston, commented: “The results of this trial represent a true turning point in the treatment of this disease. In my 30 years of treating myeloma, I have not seen any other therapy as effective in this group of patients.”

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

Some patients with blood cancers for whom all other therapeutic options have been exhausted have one final chance of getting rid of their disease: treatment with chimeric antigen-receptor (CAR) T cells.

Described as a “living drug,” the treatment involves genetically engineering the patient’s own blood cells and reinfusing them back into their system. These CAR T cells then hunt down and destroy cancer cells; in some cases, they manage to eradicate the disease completely.

About half of patients with leukemia or lymphoma and about a third of those with multiple myeloma who receive this treatment have a complete remission and achieve a functional “cure.”

But not all patients who could benefit from this therapy are able to get it. Some are spending months on waiting lists, often deteriorating while they wait. These patients have exhausted all other therapeutic options, and many are facing hospice and death.

The scope of this problem was illustrated by a recent survey of the centers that are certified to deliver this complex therapy.

The survey was led by Yi Lin, MD, PhD, associate professor of medicine at the Mayo Clinic, Rochester, Minn., and medical director for the cellular therapy program. It was published as an abstract at the annual meeting of the American Society of Clinical Oncology recently, although it was not presented there.

“We wanted to find out just how widespread this problem is,” Dr. Lin said, adding: “There had been nothing in the literature thus far about it.”

The team contacted 20 centers across the United States and received responses from 17. Results showed that the median time on the waiting list was 6 months and that only 25% of patients eventually received CAR T-cell therapy. An additional 25% were able to enter a CAR T clinical trial. The remaining 50% of patients either were enrolled in a different type of trial, entered hospice, or died.

For patient selection, all centers reported using a committee of experienced physicians to ensure consistency. They employed different ethical principles for selection. Some centers sought to maximize the total benefit, such as selecting the patients most likely to achieve leukapheresis or a clinical response, while others based their decisions on the time patients spent on waiting list or gave priority to the patients who were the “worst off” with the most limited therapeutic options.
 

Shortage affecting mostly myeloma patients

The shortages in CAR T-cell therapies primarily involve the products used for patients with multiple myeloma.

The problem has not, as yet, noticeably spilled over to lymphoma and leukemia treatments, which use a slightly different type of CAR T-cell therapy (it targets CD19, whereas the cell therapies used for myeloma target BCMA).

“We have backlog of myeloma patients who don’t have access,” said Nina Shah, MD, a hematologist and professor of medicine at the University of California, San Francisco. “We have only four slots for the two myeloma products but about 50-60 eligible patients.”

Long waiting times for CAR T cells for myeloma have been an issue ever since the first of these products appeared on the market: idecabtagene vicleucel (ide-cel; Abecma), developed by Bluebird Bio and Bristol-Myers Squibb. “As soon as it became available in March 2021, we had people waiting and limits on our access to it,” Dr. Shah said.

A second CAR T-cell therapy for myeloma, ciltacabtagene autoleucel (cilta-cel, Carvykti), developed by Janssen and Legend Biotech, received approval in February 2022. While that helped provide centers with a few more slots, it wasn’t sufficient to cut waiting times, and the demand for these myeloma therapies continues to outstrip the capacity to produce CAR-T products in a timely manner.

“For myeloma, the demand is very high, as most patients are not cured from any other existing myeloma therapies, and most patients will make it to fifth-line therapy where the two CAR T-cell products are approved right now,” said Krina K. Patel, MD, medical director of the department of lymphoma/myeloma in the division of cancer medicine at the University of Texas MD Anderson Cancer Center, Houston.

“We likely have 10 eligible CAR-T myeloma patients each month at our center,” she said, “but were getting two slots per month for the past 8 months, and now are getting four slots a month.”

“Our clinic has also experienced the impact of the low number of manufacturing slots offered to each cancer center for some CAR T-cell products,” said David Maloney, MD, PhD, medical director, Cellular Immunotherapy and Bezos Family Immunotherapy Clinic, Seattle Cancer Care Alliance.

He noted that, as with other cancer centers, for multiple myeloma they are provided a specific number of manufacturing slots for each treatment. “Our providers discuss which patients are most appropriate for available slots for that month,” said Dr. Maloney.

“Additionally, juggling patient schedules may be required to address the extended manufacturing time for some products. In some cases, clinical trials may be available in a more timely fashion for appropriate patients, and in some cases, switching to an alternative product is possible,” he commented.
 

Complex causes behind bottleneck

The cause of the current bottleneck for myeloma patients is complex. It stems from a shortage of raw materials and supply chain restraints, among other things.

While the biggest impact of shortages has been on patients with multiple myeloma, Dr. Patel pointed out that these constraints are also affecting patients with lymphoma at her institution, but to a lesser degree.

“This is multifactorial as to why, but most of the issues arise from manufacturing,” Dr. Patel said in an interview. “Initially, the FDA limited how many slots each new product could have per month, then there was a viral vector shortage, and then the quality-control process the FDA requires takes longer than the manufacturing of the cells actually do.”

On top of that, “we have about a 5% manufacturing fail rate so far,” she added. Such failures occur when the cells taken from a patient cannot be converted into CAR T cells for therapy.

Matthew J. Frigault, MD, from the Center for Cellular Therapies, Mass General Cancer Center, Boston, explained that the growing excitement about the potential for cellular therapy and recent approvals for these products for use in earlier lines of treatment have increased demand for them.

There are also problems regarding supply. Manufacture and delivery of CAR T is complicated and takes time to scale up, Dr. Frigault pointed out. “Therefore, we are seeing limited access, more so for the BCMA-directed therapies [which are used for myeloma].”

The shortages and delays likely involve two main factors. “For the newer indications, there is a significant backlog of patients who have been waiting for these therapies and have not been able to access them in the clinical trial setting, and manufacturing is extremely complicated and not easily scaled up,” he said.

“That being said, manufacturers are trying to increase the number of available manufacturing slots and decrease the time needed to manufacture cells,” Dr. Frigault commented.

Delays in access to myeloma CAR T-cell therapy are also affecting patient care at Fox Chase Cancer Center in Philadelphia. “We have had about one slot every 2 months for Abecma,” noted Henry Fung, MD, chair of the department of bone marrow transplant and cellular therapies at Fox Chase. “For Carvykti, there are only 32 certified centers in [the] U.S., and access is very limited.”

Dr. Fung explained that they have had to offer alternative treatments to many of their patients. “There are rumors that there’s shortage in obtaining raw materials, such as the virus used for transduction, although we have not encountered any problems in other CAR T products used for lymphomas.”
 

Pharma companies trying to meet the demand

This news organization reached out to the manufacturers of CAR T products. All have reported that they are doing what they feasibly can to ramp up production.

“The complexity of delivering CAR T-cell therapies is unlike any other traditional biologic or small-molecule medicine, using a patient’s own cells to start a highly sophisticated and personalized manufacturing process,” commented a spokesperson for BMS, which has two CAR T-cell products currently on the market.

“In this nascent field of cell therapy, we continue to evolve every day, addressing supply and manufacturing challenges head on by applying key learnings across our three state-of-the-art cell therapy facilities and two new facilities in progress.

“We have been encouraged by a steady increase in our manufacturing capacity, and we continue efforts to ramp up further to meet the demand for our cell therapies,” the BMS spokesperson commented. “We have already seen improvements in the stabilization of vector supply and expect additional improvements in capacity in the second half of 2022.”

Novartis said much the same thing. They have a “comprehensive, integrated global CAR-T manufacturing footprint that strengthens the flexibility, resilience, and sustainability of the Novartis manufacturing and supply chain. Together with an improved manufacturing process, we are confident in our ability to meet patient demand with timely delivery,” according to a Novartis spokesperson.

The spokesperson also pointed out that the company has continuously incorporated process improvements that have significantly increased manufacturing capacity and success rates for patients in need of CAR T cells.

“Data presented at [the] American Society of Hematology annual meeting in 2021 showed the Novartis Morris Plains facility, our flagship CAR T manufacturing site, had commercial manufacturing and shipping success rates of 96% and 99%, respectively, between January and August 2021,” according to the spokesperson.

Legend and Janssen, the companies behind Carvykti, one of the two approved cell products for myeloma, which launched earlier in 2022, said that they have continued to activate certified treatment centers in a phased approach that will enable them to expand availability throughout 2022 and beyond.

“This phased approach was designed to ensure the highest level of predictability and reliability for the patient and the certified treatment centers,” the spokesperson said. “We understand the urgency for patients in need of Carvyki and are committed to doing everything we can to accelerate our ability to deliver this important cell therapy in a reliable and timely manner.”

With regard to the industry-wide supply shortage of lentivirus, Legend and Janssen say they have put in place multiple processes to address the shortage, “including enhancing our own internal manufacturing capabilities of this essential drug substance, to ensure sufficient and sustained supply.”
 

Incredibly exciting potential

Given the immense potential of CAR T-cell therapy, the supply shortage that myeloma patients are experiencing is all the more poignant and distressing. While not everyone benefits, some patients for whom every other therapy failed and who were facing hospice have had dramatic results.

“Incredibly exciting with unbelievable potential” was how one expert described these new therapies when the first product was about to enter the marketplace. Since then, six CAR T-cell therapies have received regulatory approval for an ever-increasing range of hematologic malignancies.

But these CAR T-cell therapies have their own set of adverse events, which can be serious and even life-threatening. In addition, not all patients become cancer free, although long-term data are impressive.

A study that included one of the longest follow-ups to date was reported at the 2020 annual meeting of the American Society of Clinical Oncology. The researchers reported that remissions lasted over 9 years for patients with relapsed/refractory B-cell lymphoma or chronic lymphocytic leukemia who underwent treatment with Kite’s axicaptagene cilleucel (Yescarta). This review included 43 patients and showed an overall remission rate of 76%. Complete remission was achieved for 54% of patients, and partial remission was achieved for 22%.

The results with CAR T-cell therapy in multiple myeloma are not quite as impressive, but even so, the clinical data that supported the approval of Abecma showed that a third of patients, who had previously received a median of six prior therapies, achieved a complete response.

At the time of the Abecma approval, the lead investigator of the study, Nikhil Munshi, MD, of Dana-Farber Cancer Institute, Boston, commented: “The results of this trial represent a true turning point in the treatment of this disease. In my 30 years of treating myeloma, I have not seen any other therapy as effective in this group of patients.”

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

Some patients with blood cancers for whom all other therapeutic options have been exhausted have one final chance of getting rid of their disease: treatment with chimeric antigen-receptor (CAR) T cells.

Described as a “living drug,” the treatment involves genetically engineering the patient’s own blood cells and reinfusing them back into their system. These CAR T cells then hunt down and destroy cancer cells; in some cases, they manage to eradicate the disease completely.

About half of patients with leukemia or lymphoma and about a third of those with multiple myeloma who receive this treatment have a complete remission and achieve a functional “cure.”

But not all patients who could benefit from this therapy are able to get it. Some are spending months on waiting lists, often deteriorating while they wait. These patients have exhausted all other therapeutic options, and many are facing hospice and death.

The scope of this problem was illustrated by a recent survey of the centers that are certified to deliver this complex therapy.

The survey was led by Yi Lin, MD, PhD, associate professor of medicine at the Mayo Clinic, Rochester, Minn., and medical director for the cellular therapy program. It was published as an abstract at the annual meeting of the American Society of Clinical Oncology recently, although it was not presented there.

“We wanted to find out just how widespread this problem is,” Dr. Lin said, adding: “There had been nothing in the literature thus far about it.”

The team contacted 20 centers across the United States and received responses from 17. Results showed that the median time on the waiting list was 6 months and that only 25% of patients eventually received CAR T-cell therapy. An additional 25% were able to enter a CAR T clinical trial. The remaining 50% of patients either were enrolled in a different type of trial, entered hospice, or died.

For patient selection, all centers reported using a committee of experienced physicians to ensure consistency. They employed different ethical principles for selection. Some centers sought to maximize the total benefit, such as selecting the patients most likely to achieve leukapheresis or a clinical response, while others based their decisions on the time patients spent on waiting list or gave priority to the patients who were the “worst off” with the most limited therapeutic options.
 

Shortage affecting mostly myeloma patients

The shortages in CAR T-cell therapies primarily involve the products used for patients with multiple myeloma.

The problem has not, as yet, noticeably spilled over to lymphoma and leukemia treatments, which use a slightly different type of CAR T-cell therapy (it targets CD19, whereas the cell therapies used for myeloma target BCMA).

“We have backlog of myeloma patients who don’t have access,” said Nina Shah, MD, a hematologist and professor of medicine at the University of California, San Francisco. “We have only four slots for the two myeloma products but about 50-60 eligible patients.”

Long waiting times for CAR T cells for myeloma have been an issue ever since the first of these products appeared on the market: idecabtagene vicleucel (ide-cel; Abecma), developed by Bluebird Bio and Bristol-Myers Squibb. “As soon as it became available in March 2021, we had people waiting and limits on our access to it,” Dr. Shah said.

A second CAR T-cell therapy for myeloma, ciltacabtagene autoleucel (cilta-cel, Carvykti), developed by Janssen and Legend Biotech, received approval in February 2022. While that helped provide centers with a few more slots, it wasn’t sufficient to cut waiting times, and the demand for these myeloma therapies continues to outstrip the capacity to produce CAR-T products in a timely manner.

“For myeloma, the demand is very high, as most patients are not cured from any other existing myeloma therapies, and most patients will make it to fifth-line therapy where the two CAR T-cell products are approved right now,” said Krina K. Patel, MD, medical director of the department of lymphoma/myeloma in the division of cancer medicine at the University of Texas MD Anderson Cancer Center, Houston.

“We likely have 10 eligible CAR-T myeloma patients each month at our center,” she said, “but were getting two slots per month for the past 8 months, and now are getting four slots a month.”

“Our clinic has also experienced the impact of the low number of manufacturing slots offered to each cancer center for some CAR T-cell products,” said David Maloney, MD, PhD, medical director, Cellular Immunotherapy and Bezos Family Immunotherapy Clinic, Seattle Cancer Care Alliance.

He noted that, as with other cancer centers, for multiple myeloma they are provided a specific number of manufacturing slots for each treatment. “Our providers discuss which patients are most appropriate for available slots for that month,” said Dr. Maloney.

“Additionally, juggling patient schedules may be required to address the extended manufacturing time for some products. In some cases, clinical trials may be available in a more timely fashion for appropriate patients, and in some cases, switching to an alternative product is possible,” he commented.
 

Complex causes behind bottleneck

The cause of the current bottleneck for myeloma patients is complex. It stems from a shortage of raw materials and supply chain restraints, among other things.

While the biggest impact of shortages has been on patients with multiple myeloma, Dr. Patel pointed out that these constraints are also affecting patients with lymphoma at her institution, but to a lesser degree.

“This is multifactorial as to why, but most of the issues arise from manufacturing,” Dr. Patel said in an interview. “Initially, the FDA limited how many slots each new product could have per month, then there was a viral vector shortage, and then the quality-control process the FDA requires takes longer than the manufacturing of the cells actually do.”

On top of that, “we have about a 5% manufacturing fail rate so far,” she added. Such failures occur when the cells taken from a patient cannot be converted into CAR T cells for therapy.

Matthew J. Frigault, MD, from the Center for Cellular Therapies, Mass General Cancer Center, Boston, explained that the growing excitement about the potential for cellular therapy and recent approvals for these products for use in earlier lines of treatment have increased demand for them.

There are also problems regarding supply. Manufacture and delivery of CAR T is complicated and takes time to scale up, Dr. Frigault pointed out. “Therefore, we are seeing limited access, more so for the BCMA-directed therapies [which are used for myeloma].”

The shortages and delays likely involve two main factors. “For the newer indications, there is a significant backlog of patients who have been waiting for these therapies and have not been able to access them in the clinical trial setting, and manufacturing is extremely complicated and not easily scaled up,” he said.

“That being said, manufacturers are trying to increase the number of available manufacturing slots and decrease the time needed to manufacture cells,” Dr. Frigault commented.

Delays in access to myeloma CAR T-cell therapy are also affecting patient care at Fox Chase Cancer Center in Philadelphia. “We have had about one slot every 2 months for Abecma,” noted Henry Fung, MD, chair of the department of bone marrow transplant and cellular therapies at Fox Chase. “For Carvykti, there are only 32 certified centers in [the] U.S., and access is very limited.”

Dr. Fung explained that they have had to offer alternative treatments to many of their patients. “There are rumors that there’s shortage in obtaining raw materials, such as the virus used for transduction, although we have not encountered any problems in other CAR T products used for lymphomas.”
 

Pharma companies trying to meet the demand

This news organization reached out to the manufacturers of CAR T products. All have reported that they are doing what they feasibly can to ramp up production.

“The complexity of delivering CAR T-cell therapies is unlike any other traditional biologic or small-molecule medicine, using a patient’s own cells to start a highly sophisticated and personalized manufacturing process,” commented a spokesperson for BMS, which has two CAR T-cell products currently on the market.

“In this nascent field of cell therapy, we continue to evolve every day, addressing supply and manufacturing challenges head on by applying key learnings across our three state-of-the-art cell therapy facilities and two new facilities in progress.

“We have been encouraged by a steady increase in our manufacturing capacity, and we continue efforts to ramp up further to meet the demand for our cell therapies,” the BMS spokesperson commented. “We have already seen improvements in the stabilization of vector supply and expect additional improvements in capacity in the second half of 2022.”

Novartis said much the same thing. They have a “comprehensive, integrated global CAR-T manufacturing footprint that strengthens the flexibility, resilience, and sustainability of the Novartis manufacturing and supply chain. Together with an improved manufacturing process, we are confident in our ability to meet patient demand with timely delivery,” according to a Novartis spokesperson.

The spokesperson also pointed out that the company has continuously incorporated process improvements that have significantly increased manufacturing capacity and success rates for patients in need of CAR T cells.

“Data presented at [the] American Society of Hematology annual meeting in 2021 showed the Novartis Morris Plains facility, our flagship CAR T manufacturing site, had commercial manufacturing and shipping success rates of 96% and 99%, respectively, between January and August 2021,” according to the spokesperson.

Legend and Janssen, the companies behind Carvykti, one of the two approved cell products for myeloma, which launched earlier in 2022, said that they have continued to activate certified treatment centers in a phased approach that will enable them to expand availability throughout 2022 and beyond.

“This phased approach was designed to ensure the highest level of predictability and reliability for the patient and the certified treatment centers,” the spokesperson said. “We understand the urgency for patients in need of Carvyki and are committed to doing everything we can to accelerate our ability to deliver this important cell therapy in a reliable and timely manner.”

With regard to the industry-wide supply shortage of lentivirus, Legend and Janssen say they have put in place multiple processes to address the shortage, “including enhancing our own internal manufacturing capabilities of this essential drug substance, to ensure sufficient and sustained supply.”
 

Incredibly exciting potential

Given the immense potential of CAR T-cell therapy, the supply shortage that myeloma patients are experiencing is all the more poignant and distressing. While not everyone benefits, some patients for whom every other therapy failed and who were facing hospice have had dramatic results.

“Incredibly exciting with unbelievable potential” was how one expert described these new therapies when the first product was about to enter the marketplace. Since then, six CAR T-cell therapies have received regulatory approval for an ever-increasing range of hematologic malignancies.

But these CAR T-cell therapies have their own set of adverse events, which can be serious and even life-threatening. In addition, not all patients become cancer free, although long-term data are impressive.

A study that included one of the longest follow-ups to date was reported at the 2020 annual meeting of the American Society of Clinical Oncology. The researchers reported that remissions lasted over 9 years for patients with relapsed/refractory B-cell lymphoma or chronic lymphocytic leukemia who underwent treatment with Kite’s axicaptagene cilleucel (Yescarta). This review included 43 patients and showed an overall remission rate of 76%. Complete remission was achieved for 54% of patients, and partial remission was achieved for 22%.

The results with CAR T-cell therapy in multiple myeloma are not quite as impressive, but even so, the clinical data that supported the approval of Abecma showed that a third of patients, who had previously received a median of six prior therapies, achieved a complete response.

At the time of the Abecma approval, the lead investigator of the study, Nikhil Munshi, MD, of Dana-Farber Cancer Institute, Boston, commented: “The results of this trial represent a true turning point in the treatment of this disease. In my 30 years of treating myeloma, I have not seen any other therapy as effective in this group of patients.”

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

There was no significant increase in the post-COVID pandemic monthly rate of incident diabetes in children and youth in Ontario, compared with the pre-pandemic rate, in new research.

This contrasts with findings from a U.S. study and a German study, but this is “not the final word” about this possible association, lead author Rayzel Shulman, MD, admits, since the study may have been underpowered.

The population-based, cross-sectional study was published recently as a research letter in JAMA Open.

The researchers found a nonsignificant increase in the monthly rate of new diabetes during the first 18 months of the COVID-19 pandemic, compared with the 3 prior years (relative risk 1.09, 95% confidence interval).
 

New study contrasts with previous reports

This differs from a Morbidity and Mortality Weekly Report from the U.S. Centers for Disease Control and Prevention, in which COVID-19 infection was associated with a significant increase in new onset of diabetes in children during March 2020 through June 2021, “although some experts have criticized the study methods and conclusion validity,” Dr. Shulman and colleagues write.

Another study, from Germany, reported a significant 1.15-fold increase in type 1 diabetes in children during the pandemic, they note.

The current study may have been underpowered and too small to show a significant association between COVID-19 and new diabetes, the researchers acknowledge. 

And the 1.30 upper limit of the confidence interval shows that it “cannot rule out a possible 1.3-fold increase” in relative risk of a diagnosis of diabetes related to COVID, Dr. Shulman explained to this news organization. 

It will be important to see how the rates have changed since September 2021 (the end of the current study), added Dr. Shulman, an adjunct scientist at the Institute for Clinical Evaluative Sciences (ICES) and a physician and scientist at the Hospital for Sick Children, Toronto.

The current study did find a decreased (delayed) rate of diagnosis of new diabetes during the first months of the pandemic when there were lockdowns, followed by a “catch-up” increase in rates later on, as has been reported earlier.

“Our study is definitely not the final word on this,” Dr. Shulman summarized in a statement from ICES. “However, our findings call into question whether a direct association between COVID-19 and new-onset diabetes in children exists.”
 

COVID-diabetes link?

The researchers analyzed health administrative data from January 2017 to September 2021.

They identified 2,700,178 children and youth in Ontario who were under age 18 in 2021, who had a mean age of 9.2, and about half were girls.

Between November 2020 and April 2021, an estimated 3.3% of children in Ontario had a SARS-COV-2 infection.

New diagnoses of diabetes in this age group are mostly type 1 diabetes, based on previous studies.

The rate of incident diabetes was 15%-32% lower during the first 3 months of the pandemic, March-May 2020 (1.67-2.34 cases per 100,000), compared with the pre-pandemic monthly rate during 2017, 2018, and 2019 (2.54-2.59 cases per 100,000).

The rate of incident diabetes was 33%-50% higher during February to July 2021 (3.48-4.18 cases per 100,000), compared with the pre-pandemic rate.

The pre-pandemic and pandemic monthly rates of incident diabetes were similar during the other months.

The group concludes: “The lack of both an observable increase in overall diabetes incidence among children during the 18-month pandemic restrictions [in this Ontario study] and a plausible biological mechanism call into question an association between COVID-19 and new-onset diabetes.”

More research is needed. “Given the variability in monthly [relative risks], additional population-based, longer-term data are needed to examine the direct and indirect effects of COVID-19 and diabetes risk among children,” the authors write.

This study was supported by ICES (which is funded by the Ontario Ministry of Health) and by a grant from the Canadian Institutes of Health Research. Dr. Shulman reported receiving fees from Dexcom outside the submitted work, and she and three other authors reported receiving grants from the Canadian Institutes of Health Research outside the submitted work.

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

There was no significant increase in the post-COVID pandemic monthly rate of incident diabetes in children and youth in Ontario, compared with the pre-pandemic rate, in new research.

This contrasts with findings from a U.S. study and a German study, but this is “not the final word” about this possible association, lead author Rayzel Shulman, MD, admits, since the study may have been underpowered.

The population-based, cross-sectional study was published recently as a research letter in JAMA Open.

The researchers found a nonsignificant increase in the monthly rate of new diabetes during the first 18 months of the COVID-19 pandemic, compared with the 3 prior years (relative risk 1.09, 95% confidence interval).
 

New study contrasts with previous reports

This differs from a Morbidity and Mortality Weekly Report from the U.S. Centers for Disease Control and Prevention, in which COVID-19 infection was associated with a significant increase in new onset of diabetes in children during March 2020 through June 2021, “although some experts have criticized the study methods and conclusion validity,” Dr. Shulman and colleagues write.

Another study, from Germany, reported a significant 1.15-fold increase in type 1 diabetes in children during the pandemic, they note.

The current study may have been underpowered and too small to show a significant association between COVID-19 and new diabetes, the researchers acknowledge. 

And the 1.30 upper limit of the confidence interval shows that it “cannot rule out a possible 1.3-fold increase” in relative risk of a diagnosis of diabetes related to COVID, Dr. Shulman explained to this news organization. 

It will be important to see how the rates have changed since September 2021 (the end of the current study), added Dr. Shulman, an adjunct scientist at the Institute for Clinical Evaluative Sciences (ICES) and a physician and scientist at the Hospital for Sick Children, Toronto.

The current study did find a decreased (delayed) rate of diagnosis of new diabetes during the first months of the pandemic when there were lockdowns, followed by a “catch-up” increase in rates later on, as has been reported earlier.

“Our study is definitely not the final word on this,” Dr. Shulman summarized in a statement from ICES. “However, our findings call into question whether a direct association between COVID-19 and new-onset diabetes in children exists.”
 

COVID-diabetes link?

The researchers analyzed health administrative data from January 2017 to September 2021.

They identified 2,700,178 children and youth in Ontario who were under age 18 in 2021, who had a mean age of 9.2, and about half were girls.

Between November 2020 and April 2021, an estimated 3.3% of children in Ontario had a SARS-COV-2 infection.

New diagnoses of diabetes in this age group are mostly type 1 diabetes, based on previous studies.

The rate of incident diabetes was 15%-32% lower during the first 3 months of the pandemic, March-May 2020 (1.67-2.34 cases per 100,000), compared with the pre-pandemic monthly rate during 2017, 2018, and 2019 (2.54-2.59 cases per 100,000).

The rate of incident diabetes was 33%-50% higher during February to July 2021 (3.48-4.18 cases per 100,000), compared with the pre-pandemic rate.

The pre-pandemic and pandemic monthly rates of incident diabetes were similar during the other months.

The group concludes: “The lack of both an observable increase in overall diabetes incidence among children during the 18-month pandemic restrictions [in this Ontario study] and a plausible biological mechanism call into question an association between COVID-19 and new-onset diabetes.”

More research is needed. “Given the variability in monthly [relative risks], additional population-based, longer-term data are needed to examine the direct and indirect effects of COVID-19 and diabetes risk among children,” the authors write.

This study was supported by ICES (which is funded by the Ontario Ministry of Health) and by a grant from the Canadian Institutes of Health Research. Dr. Shulman reported receiving fees from Dexcom outside the submitted work, and she and three other authors reported receiving grants from the Canadian Institutes of Health Research outside the submitted work.

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

There was no significant increase in the post-COVID pandemic monthly rate of incident diabetes in children and youth in Ontario, compared with the pre-pandemic rate, in new research.

This contrasts with findings from a U.S. study and a German study, but this is “not the final word” about this possible association, lead author Rayzel Shulman, MD, admits, since the study may have been underpowered.

The population-based, cross-sectional study was published recently as a research letter in JAMA Open.

The researchers found a nonsignificant increase in the monthly rate of new diabetes during the first 18 months of the COVID-19 pandemic, compared with the 3 prior years (relative risk 1.09, 95% confidence interval).
 

New study contrasts with previous reports

This differs from a Morbidity and Mortality Weekly Report from the U.S. Centers for Disease Control and Prevention, in which COVID-19 infection was associated with a significant increase in new onset of diabetes in children during March 2020 through June 2021, “although some experts have criticized the study methods and conclusion validity,” Dr. Shulman and colleagues write.

Another study, from Germany, reported a significant 1.15-fold increase in type 1 diabetes in children during the pandemic, they note.

The current study may have been underpowered and too small to show a significant association between COVID-19 and new diabetes, the researchers acknowledge. 

And the 1.30 upper limit of the confidence interval shows that it “cannot rule out a possible 1.3-fold increase” in relative risk of a diagnosis of diabetes related to COVID, Dr. Shulman explained to this news organization. 

It will be important to see how the rates have changed since September 2021 (the end of the current study), added Dr. Shulman, an adjunct scientist at the Institute for Clinical Evaluative Sciences (ICES) and a physician and scientist at the Hospital for Sick Children, Toronto.

The current study did find a decreased (delayed) rate of diagnosis of new diabetes during the first months of the pandemic when there were lockdowns, followed by a “catch-up” increase in rates later on, as has been reported earlier.

“Our study is definitely not the final word on this,” Dr. Shulman summarized in a statement from ICES. “However, our findings call into question whether a direct association between COVID-19 and new-onset diabetes in children exists.”
 

COVID-diabetes link?

The researchers analyzed health administrative data from January 2017 to September 2021.

They identified 2,700,178 children and youth in Ontario who were under age 18 in 2021, who had a mean age of 9.2, and about half were girls.

Between November 2020 and April 2021, an estimated 3.3% of children in Ontario had a SARS-COV-2 infection.

New diagnoses of diabetes in this age group are mostly type 1 diabetes, based on previous studies.

The rate of incident diabetes was 15%-32% lower during the first 3 months of the pandemic, March-May 2020 (1.67-2.34 cases per 100,000), compared with the pre-pandemic monthly rate during 2017, 2018, and 2019 (2.54-2.59 cases per 100,000).

The rate of incident diabetes was 33%-50% higher during February to July 2021 (3.48-4.18 cases per 100,000), compared with the pre-pandemic rate.

The pre-pandemic and pandemic monthly rates of incident diabetes were similar during the other months.

The group concludes: “The lack of both an observable increase in overall diabetes incidence among children during the 18-month pandemic restrictions [in this Ontario study] and a plausible biological mechanism call into question an association between COVID-19 and new-onset diabetes.”

More research is needed. “Given the variability in monthly [relative risks], additional population-based, longer-term data are needed to examine the direct and indirect effects of COVID-19 and diabetes risk among children,” the authors write.

This study was supported by ICES (which is funded by the Ontario Ministry of Health) and by a grant from the Canadian Institutes of Health Research. Dr. Shulman reported receiving fees from Dexcom outside the submitted work, and she and three other authors reported receiving grants from the Canadian Institutes of Health Research outside the submitted work.

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

A new blood test that analyzes DNA shed by metastatic cancers could reveal characteristics unique to each patient’s tumor and allow physicians to develop more personalized treatment plans, according to a new report.

The blood test focuses on circulating tumor DNA (ctDNA). By sequencing the complete genome of ctDNA, researchers can learn about the different metastases spread throughout the body.

“A key goal in cancer research is to better understand metastatic cancer in each affected person so we can select the best treatments and avoid giving toxic therapies to people who will not derive benefit,” senior author Alexander Wyatt, MD, DPhil, assistant professor of genitourinary cancer genomics at the University of British Columbia, Vancouver, and senior research scientist at the Vancouver Prostate Center, told this news organization.

“However, biopsies of metastatic cancer are rarely performed since they are invasive and have risks of complications,” he said. “In the past, this major barrier has prevented the widespread study of metastatic cancer and progress to better treatment of this lethal disease.”

The study was published in Nature.
 

Test methods

Blood-based biopsy technology, also known as “liquid biopsy,” has emerged as a tool for clinical cancer genotyping and longitudinal disease monitoring. Tests that use ctDNA have begun to influence the clinical management of people with cancer, the study authors wrote, though the full potential for understanding metastatic cancer biology hasn’t yet been unlocked.

Dr. Wyatt and colleagues analyzed serial plasma and synchronous metastases in patients with aggressive, treatment-resistant prostate cancer through deep whole-genome sequencing, which allows for a comprehensive assessment of every part of the genetic code within the cancer cells.

The researchers assessed all classes of genomic alterations and found that ctDNA contains multiple dominant populations, indicating that most people with metastatic cancer have different metastases spread around the body. They found that the whole-genome sequencing process provides a host of information about these different metastases.

The research team used newly developed computer programs to provide information about the genetic makeup of each cancer population, which can tell researchers about a person’s overall disease rather than about one metastatic tumor. In the future, this information could allow clinicians to make better decisions about managing a patient’s cancer.

The researchers studied multiple ctDNA samples collected over time to understand how a patient’s cancer evolved in response to treatment. They focused on inhibitors of the androgen receptor pathway. They found that current therapies for metastatic prostate cancer actively change the composition of cancer populations in the body and that treatment often selects for biologically aggressive cancer populations that underlie clinical resistance. This allowed them to pinpoint new genetic resistance mechanisms to the most common treatments for metastatic prostate cancer. The technique could be applied to other cancers as well.

The research team used nucleosome footprints in ctDNA to infer mRNA expression in metastases upon which biopsies were synchronously performed. They identified treatment-induced changes in androgen receptor transcription factor signaling activity. This means whole-genome sequencing of ctDNA can reveal the active processes occurring within cells, allowing clinicians to predict which treatments will be effective or ineffective in each patient.

“Our research significantly expands the breadth of cancer information that can be obtained from only a few drops of blood,” said Dr. Wyatt. “From a clinical perspective, this extra information can be used in new clinical trials that are testing strategies to direct cancer treatments only to those whose quality or whose length of life will be improved.”
 

Clinical trials

The study authors wrote that whole-genome ctDNA sequencing technology, which is minimally invasive, inexpensive, and scalable, is now being deployed in large clinical trials to help discover new treatment resistance mechanisms. These include precision oncology clinical trials that are being conducted with Canadian cancer patients at the Vancouver Prostate Centre and BC Cancer.

The technology can also be implemented in existing commercial ctDNA testing platforms, which means that patients could soon directly benefit from more comprehensive liquid biopsy testing. The research team has made the methods and computer code publicly and freely available so that the technology can be applied to other cancer types and clinical settings.

“Understanding how clonal evolution occurs and what drives it is one of the key questions that need to be addressed in almost all cancers, and this study provides that level of insight for advanced prostate cancer, as well as a model and tools for how to carry out this work,” Christopher Mueller, MD, PhD, a cancer biologist and geneticist at Queen’s Cancer Research Institute and a professor of biomedical and molecular sciences at Queen’s University, both in Kingston, Ont., said in an interview.

Dr. Mueller, who wasn’t involved with this study, has researched biomarkers and ctDNA as avenues for more precise management of advanced prostate cancer. He and his colleagues have developed blood tests for detecting and monitoring metastatic breast cancer, uveal melanoma, and prostate, pancreatic, and lung cancer.

“The expansion of treatment-resistant clones is how we lose almost all cancer patients, and they clearly demonstrate that in castrate-resistant prostate cancer, changes in the androgen receptor locus almost always drive this process,” Dr. Mueller said. “Understanding clonal evolution will allow us to design treatment strategies that overcome or limit their expansion, hopefully extending the lives of these patients.”

The study was funded by the Canadian Institutes of Health Research, the Canadian Cancer Society Research Institute, the Prostate Cancer Foundation, Prostate Cancer Canada, the Movember Foundation, the Jane and Aatos Erkko Foundation, the Academy of Finland Center of Excellence program, the Terry Fox New Frontiers Program, and the BC Cancer Foundation. Dr. Wyatt has served on advisory boards or has received honoraria from AstraZeneca, Astellas, Janssen, and Merck, and his research lab has a contract research agreement with ESSA Pharma. Dr. Mueller disclosed no relevant financial relationships.

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

A new blood test that analyzes DNA shed by metastatic cancers could reveal characteristics unique to each patient’s tumor and allow physicians to develop more personalized treatment plans, according to a new report.

The blood test focuses on circulating tumor DNA (ctDNA). By sequencing the complete genome of ctDNA, researchers can learn about the different metastases spread throughout the body.

“A key goal in cancer research is to better understand metastatic cancer in each affected person so we can select the best treatments and avoid giving toxic therapies to people who will not derive benefit,” senior author Alexander Wyatt, MD, DPhil, assistant professor of genitourinary cancer genomics at the University of British Columbia, Vancouver, and senior research scientist at the Vancouver Prostate Center, told this news organization.

“However, biopsies of metastatic cancer are rarely performed since they are invasive and have risks of complications,” he said. “In the past, this major barrier has prevented the widespread study of metastatic cancer and progress to better treatment of this lethal disease.”

The study was published in Nature.
 

Test methods

Blood-based biopsy technology, also known as “liquid biopsy,” has emerged as a tool for clinical cancer genotyping and longitudinal disease monitoring. Tests that use ctDNA have begun to influence the clinical management of people with cancer, the study authors wrote, though the full potential for understanding metastatic cancer biology hasn’t yet been unlocked.

Dr. Wyatt and colleagues analyzed serial plasma and synchronous metastases in patients with aggressive, treatment-resistant prostate cancer through deep whole-genome sequencing, which allows for a comprehensive assessment of every part of the genetic code within the cancer cells.

The researchers assessed all classes of genomic alterations and found that ctDNA contains multiple dominant populations, indicating that most people with metastatic cancer have different metastases spread around the body. They found that the whole-genome sequencing process provides a host of information about these different metastases.

The research team used newly developed computer programs to provide information about the genetic makeup of each cancer population, which can tell researchers about a person’s overall disease rather than about one metastatic tumor. In the future, this information could allow clinicians to make better decisions about managing a patient’s cancer.

The researchers studied multiple ctDNA samples collected over time to understand how a patient’s cancer evolved in response to treatment. They focused on inhibitors of the androgen receptor pathway. They found that current therapies for metastatic prostate cancer actively change the composition of cancer populations in the body and that treatment often selects for biologically aggressive cancer populations that underlie clinical resistance. This allowed them to pinpoint new genetic resistance mechanisms to the most common treatments for metastatic prostate cancer. The technique could be applied to other cancers as well.

The research team used nucleosome footprints in ctDNA to infer mRNA expression in metastases upon which biopsies were synchronously performed. They identified treatment-induced changes in androgen receptor transcription factor signaling activity. This means whole-genome sequencing of ctDNA can reveal the active processes occurring within cells, allowing clinicians to predict which treatments will be effective or ineffective in each patient.

“Our research significantly expands the breadth of cancer information that can be obtained from only a few drops of blood,” said Dr. Wyatt. “From a clinical perspective, this extra information can be used in new clinical trials that are testing strategies to direct cancer treatments only to those whose quality or whose length of life will be improved.”
 

Clinical trials

The study authors wrote that whole-genome ctDNA sequencing technology, which is minimally invasive, inexpensive, and scalable, is now being deployed in large clinical trials to help discover new treatment resistance mechanisms. These include precision oncology clinical trials that are being conducted with Canadian cancer patients at the Vancouver Prostate Centre and BC Cancer.

The technology can also be implemented in existing commercial ctDNA testing platforms, which means that patients could soon directly benefit from more comprehensive liquid biopsy testing. The research team has made the methods and computer code publicly and freely available so that the technology can be applied to other cancer types and clinical settings.

“Understanding how clonal evolution occurs and what drives it is one of the key questions that need to be addressed in almost all cancers, and this study provides that level of insight for advanced prostate cancer, as well as a model and tools for how to carry out this work,” Christopher Mueller, MD, PhD, a cancer biologist and geneticist at Queen’s Cancer Research Institute and a professor of biomedical and molecular sciences at Queen’s University, both in Kingston, Ont., said in an interview.

Dr. Mueller, who wasn’t involved with this study, has researched biomarkers and ctDNA as avenues for more precise management of advanced prostate cancer. He and his colleagues have developed blood tests for detecting and monitoring metastatic breast cancer, uveal melanoma, and prostate, pancreatic, and lung cancer.

“The expansion of treatment-resistant clones is how we lose almost all cancer patients, and they clearly demonstrate that in castrate-resistant prostate cancer, changes in the androgen receptor locus almost always drive this process,” Dr. Mueller said. “Understanding clonal evolution will allow us to design treatment strategies that overcome or limit their expansion, hopefully extending the lives of these patients.”

The study was funded by the Canadian Institutes of Health Research, the Canadian Cancer Society Research Institute, the Prostate Cancer Foundation, Prostate Cancer Canada, the Movember Foundation, the Jane and Aatos Erkko Foundation, the Academy of Finland Center of Excellence program, the Terry Fox New Frontiers Program, and the BC Cancer Foundation. Dr. Wyatt has served on advisory boards or has received honoraria from AstraZeneca, Astellas, Janssen, and Merck, and his research lab has a contract research agreement with ESSA Pharma. Dr. Mueller disclosed no relevant financial relationships.

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

A new blood test that analyzes DNA shed by metastatic cancers could reveal characteristics unique to each patient’s tumor and allow physicians to develop more personalized treatment plans, according to a new report.

The blood test focuses on circulating tumor DNA (ctDNA). By sequencing the complete genome of ctDNA, researchers can learn about the different metastases spread throughout the body.

“A key goal in cancer research is to better understand metastatic cancer in each affected person so we can select the best treatments and avoid giving toxic therapies to people who will not derive benefit,” senior author Alexander Wyatt, MD, DPhil, assistant professor of genitourinary cancer genomics at the University of British Columbia, Vancouver, and senior research scientist at the Vancouver Prostate Center, told this news organization.

“However, biopsies of metastatic cancer are rarely performed since they are invasive and have risks of complications,” he said. “In the past, this major barrier has prevented the widespread study of metastatic cancer and progress to better treatment of this lethal disease.”

The study was published in Nature.
 

Test methods

Blood-based biopsy technology, also known as “liquid biopsy,” has emerged as a tool for clinical cancer genotyping and longitudinal disease monitoring. Tests that use ctDNA have begun to influence the clinical management of people with cancer, the study authors wrote, though the full potential for understanding metastatic cancer biology hasn’t yet been unlocked.

Dr. Wyatt and colleagues analyzed serial plasma and synchronous metastases in patients with aggressive, treatment-resistant prostate cancer through deep whole-genome sequencing, which allows for a comprehensive assessment of every part of the genetic code within the cancer cells.

The researchers assessed all classes of genomic alterations and found that ctDNA contains multiple dominant populations, indicating that most people with metastatic cancer have different metastases spread around the body. They found that the whole-genome sequencing process provides a host of information about these different metastases.

The research team used newly developed computer programs to provide information about the genetic makeup of each cancer population, which can tell researchers about a person’s overall disease rather than about one metastatic tumor. In the future, this information could allow clinicians to make better decisions about managing a patient’s cancer.

The researchers studied multiple ctDNA samples collected over time to understand how a patient’s cancer evolved in response to treatment. They focused on inhibitors of the androgen receptor pathway. They found that current therapies for metastatic prostate cancer actively change the composition of cancer populations in the body and that treatment often selects for biologically aggressive cancer populations that underlie clinical resistance. This allowed them to pinpoint new genetic resistance mechanisms to the most common treatments for metastatic prostate cancer. The technique could be applied to other cancers as well.

The research team used nucleosome footprints in ctDNA to infer mRNA expression in metastases upon which biopsies were synchronously performed. They identified treatment-induced changes in androgen receptor transcription factor signaling activity. This means whole-genome sequencing of ctDNA can reveal the active processes occurring within cells, allowing clinicians to predict which treatments will be effective or ineffective in each patient.

“Our research significantly expands the breadth of cancer information that can be obtained from only a few drops of blood,” said Dr. Wyatt. “From a clinical perspective, this extra information can be used in new clinical trials that are testing strategies to direct cancer treatments only to those whose quality or whose length of life will be improved.”
 

Clinical trials

The study authors wrote that whole-genome ctDNA sequencing technology, which is minimally invasive, inexpensive, and scalable, is now being deployed in large clinical trials to help discover new treatment resistance mechanisms. These include precision oncology clinical trials that are being conducted with Canadian cancer patients at the Vancouver Prostate Centre and BC Cancer.

The technology can also be implemented in existing commercial ctDNA testing platforms, which means that patients could soon directly benefit from more comprehensive liquid biopsy testing. The research team has made the methods and computer code publicly and freely available so that the technology can be applied to other cancer types and clinical settings.

“Understanding how clonal evolution occurs and what drives it is one of the key questions that need to be addressed in almost all cancers, and this study provides that level of insight for advanced prostate cancer, as well as a model and tools for how to carry out this work,” Christopher Mueller, MD, PhD, a cancer biologist and geneticist at Queen’s Cancer Research Institute and a professor of biomedical and molecular sciences at Queen’s University, both in Kingston, Ont., said in an interview.

Dr. Mueller, who wasn’t involved with this study, has researched biomarkers and ctDNA as avenues for more precise management of advanced prostate cancer. He and his colleagues have developed blood tests for detecting and monitoring metastatic breast cancer, uveal melanoma, and prostate, pancreatic, and lung cancer.

“The expansion of treatment-resistant clones is how we lose almost all cancer patients, and they clearly demonstrate that in castrate-resistant prostate cancer, changes in the androgen receptor locus almost always drive this process,” Dr. Mueller said. “Understanding clonal evolution will allow us to design treatment strategies that overcome or limit their expansion, hopefully extending the lives of these patients.”

The study was funded by the Canadian Institutes of Health Research, the Canadian Cancer Society Research Institute, the Prostate Cancer Foundation, Prostate Cancer Canada, the Movember Foundation, the Jane and Aatos Erkko Foundation, the Academy of Finland Center of Excellence program, the Terry Fox New Frontiers Program, and the BC Cancer Foundation. Dr. Wyatt has served on advisory boards or has received honoraria from AstraZeneca, Astellas, Janssen, and Merck, and his research lab has a contract research agreement with ESSA Pharma. Dr. Mueller disclosed no relevant financial relationships.

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

After the US Supreme Court overturned Roe v Wade in June, Gilbert R. Cisneros Jr., Under Secretary of Defense for Personnel and Readiness, released a memo on “Ensuring Access to Essential Women’s Health Care Services for Service Members, Dependents, Beneficiaries, and Department of Defense Civilian Employees.” In the memo, Cisneros clarified the US Department of Defense (DoD) policies and emphasized, “There will be no interruption to this care.”

Covered abortions—instances where the life of the mother would be endangered if the fetus were carried to term, or when the pregnancy is the result of rape or incest—are still covered. Health care professionals will continue to follow this policy and military medical facilities leadership will implement measures to ensure continued access to care.

The implications of the Supreme Court decision are complicated, Cisneros said. “It is the Department of Justice’s longstanding position that States generally may not impose criminal or civil liability on federal employees who perform their duties in a manner authorized by federal law,” the memo continues. “We will work with the Department of Justice to ensure access to counsel for such civilian employees and Service members if needed and as appropriate.”

The decision also does not affect the DoD’s existing leave policies, which authorize active-duty service members to travel as necessary to receive abortion care. The travel may be government-funded official travel for a covered abortion, or for all other cases, may be undertaken as regular leave at the service member’s expense. DoD civilian employees may continue to use sick leave or other forms of leave to care for themselves or their family members. Sick leave may be used to cover travel to obtain any type of medical treatment.

The Court’s decision “will have significant implications,” Cisneros wrote, adding, “As Secretary Austin has made clear, nothing is more important than the health and well-being of our Service members, the civilian workforce, and DoD families, and we are committed to taking care of all our people and ensuring that the entire Force remains ready and resilient.”

After the US Supreme Court overturned Roe v Wade in June, Gilbert R. Cisneros Jr., Under Secretary of Defense for Personnel and Readiness, released a memo on “Ensuring Access to Essential Women’s Health Care Services for Service Members, Dependents, Beneficiaries, and Department of Defense Civilian Employees.” In the memo, Cisneros clarified the US Department of Defense (DoD) policies and emphasized, “There will be no interruption to this care.”

Covered abortions—instances where the life of the mother would be endangered if the fetus were carried to term, or when the pregnancy is the result of rape or incest—are still covered. Health care professionals will continue to follow this policy and military medical facilities leadership will implement measures to ensure continued access to care.

The implications of the Supreme Court decision are complicated, Cisneros said. “It is the Department of Justice’s longstanding position that States generally may not impose criminal or civil liability on federal employees who perform their duties in a manner authorized by federal law,” the memo continues. “We will work with the Department of Justice to ensure access to counsel for such civilian employees and Service members if needed and as appropriate.”

The decision also does not affect the DoD’s existing leave policies, which authorize active-duty service members to travel as necessary to receive abortion care. The travel may be government-funded official travel for a covered abortion, or for all other cases, may be undertaken as regular leave at the service member’s expense. DoD civilian employees may continue to use sick leave or other forms of leave to care for themselves or their family members. Sick leave may be used to cover travel to obtain any type of medical treatment.

The Court’s decision “will have significant implications,” Cisneros wrote, adding, “As Secretary Austin has made clear, nothing is more important than the health and well-being of our Service members, the civilian workforce, and DoD families, and we are committed to taking care of all our people and ensuring that the entire Force remains ready and resilient.”

After the US Supreme Court overturned Roe v Wade in June, Gilbert R. Cisneros Jr., Under Secretary of Defense for Personnel and Readiness, released a memo on “Ensuring Access to Essential Women’s Health Care Services for Service Members, Dependents, Beneficiaries, and Department of Defense Civilian Employees.” In the memo, Cisneros clarified the US Department of Defense (DoD) policies and emphasized, “There will be no interruption to this care.”

Covered abortions—instances where the life of the mother would be endangered if the fetus were carried to term, or when the pregnancy is the result of rape or incest—are still covered. Health care professionals will continue to follow this policy and military medical facilities leadership will implement measures to ensure continued access to care.

The implications of the Supreme Court decision are complicated, Cisneros said. “It is the Department of Justice’s longstanding position that States generally may not impose criminal or civil liability on federal employees who perform their duties in a manner authorized by federal law,” the memo continues. “We will work with the Department of Justice to ensure access to counsel for such civilian employees and Service members if needed and as appropriate.”

The decision also does not affect the DoD’s existing leave policies, which authorize active-duty service members to travel as necessary to receive abortion care. The travel may be government-funded official travel for a covered abortion, or for all other cases, may be undertaken as regular leave at the service member’s expense. DoD civilian employees may continue to use sick leave or other forms of leave to care for themselves or their family members. Sick leave may be used to cover travel to obtain any type of medical treatment.

The Court’s decision “will have significant implications,” Cisneros wrote, adding, “As Secretary Austin has made clear, nothing is more important than the health and well-being of our Service members, the civilian workforce, and DoD families, and we are committed to taking care of all our people and ensuring that the entire Force remains ready and resilient.”

INDIANAPOLIS – Despite the common prevalence of skin-picking disorder and trichotillomania (hair pulling), no Food and Drug Administration–approved treatments exist for either condition.

And while both body-focused repetitive behavior disorders affect a greater proportion of females than males, “we have no current information that is useful about what hormonal influences may or may not play in terms of picking and pulling behaviors,” Jon E. Grant, MD, JD, MPH, professor of psychiatry and behavioral neuroscience at the University of Chicago, said at the annual meeting of the Society for Pediatric Dermatology. “On a cognitive level, affected children and adolescents often have impaired inhibitory control but they are often 1-2 standard deviations above average IQ. They have Type A personalities [and are] very driven young kids. They also do not tolerate any down time or boredom. They need to be doing something all the time.”

According to the DSM-5, the diagnostic criteria for skin picking includes recurrent skin picking that results in skin lesions and is not attributable to another medical condition or substance. It also involves repeated attempts to decrease or stop the behavior and causes clinically significant distress or impairment.

“The other medical condition that we are interested in is the misuse of or dependence upon amphetamines or other prescription-based or illicit stimulants,” Dr. Grant said. “I saw a young man who was using about 600 mg of Ritalin a day, and he was picking all over the place. He did not have a primary skin disorder.”

The lifetime prevalence of skin picking disorder ranges between 1.4% and 5.4% of the general population. However, about 63% of people in a community sample endorsed some form of skin picking, and in a study of 105 college students, almost 40% said they picked their skin and had noticeable tissue damage as a result.

“Skin picking is not the same as self-injury,” Dr. Grant said. “It is also not simply an anxiety disorder. Anxiety will make people who pick worse, so people will say that they pick when they’re under stress. I can give them benzodiazepines and they’re still going to pick.”

Animal and human studies demonstrate that skin picking and hair pulling primarily affect females. “You will encounter young boys that pick and pull, but it largely affects females, and it tends to start around puberty,” he said. “Picking can have an onset after the age of 30, which is quite uncommon.”

From a cognitive standpoint, pathological skin pickers demonstrate impaired inhibitory control, impaired stop signal reaction time, increased rates of negative urgency (a tendency to act impulsively in response to negative emotions), and increased rates of positive urgency (a tendency to act impulsively in response to exciting or pleasurable emotions).

Trichotillomania

The lifetime prevalence of trichotillomania ranges between 0.6% and 3.9%. The onset is typically from ages 10-13 years, and the mean duration of illness is 22 years.

The DSM-5 criteria for trichotillomania are similar to that of skin-picking disorder, “although we don’t really worry about the substance use issue with people who pull their hair,” Dr. Grant said. “It doesn’t seem to have a correlation.” In addition, sometimes, children “will worsen pulling or picking when they have co-occurring ADHD and they’ve been started on a stimulant, even at a typical dose. For kids who have those issues, we prefer to try nonstimulant options for their ADHD such as bupropion or atomoxetine.”

Individuals with trichotillomania also tend to have low self-esteem and increased social anxiety, he added, and about one-third report low or very low quality of life. “When you notice alopecia, particularly in young girls who often have longer hair, up to 20% will eat their hair,” Dr. Grant said. “We don’t know why. It’s not related to vitamin deficiencies; it’s not a pica type of iron deficiency. There seems to be a shame piece about eating one’s own hair, but it’s important to assess that. Ask about constipation or overflow incontinence because they can get a bezoar, which can rupture” and can be fatal.

Skin-picking disorder and trichotillomania co-occur in up to 20% of cases. “When they do it tends to be a more difficult problem,” he said. These patients often come for mental health care because of depression, and most, he added, say “I don’t think I would be depressed if I wasn’t covered with excoriations or missing most of my hair.”
 

Treatment for both conditions

According to Dr. Grant, the treatment of choice for skin-picking disorder and trichotillomania is a specific psychotherapy known as “habit reversal therapy,” which involves helping the patient gain better self-control. The drawback is that it’s difficult to find someone trained in habit reversal therapy, “who know anything about skin picking and hair pulling,” he said. “That has been a huge challenge in the field.”

In his experience, the medical treatment of choice for skin-picking disorder and trichotillomania is N-acetylcysteine, an over-the-counter amino acid and antioxidant, which has been shown to be helpful at a dose of 2,400 mg per day. “Patients report to me that some of the excoriations clear up a little quicker as they’re taking it,” Dr. Grant said.

There may also be a role for antipsychotic therapy, he said, “but because of the associated weight gain with most antipsychotics we prefer not to use them.”

The opioid antagonist naltrexone has been shown to be effective in the subset of patients with skin-picking or hair-pulling disorders whose parents have a substance use disorder, Dr. Grant said. “The thought is that there’s something addictive about this behavior in some kids. These kids will look forward to picking and find it rewarding and exciting.”

Dr. Grant reported having no relevant financial disclosures.

INDIANAPOLIS – Despite the common prevalence of skin-picking disorder and trichotillomania (hair pulling), no Food and Drug Administration–approved treatments exist for either condition.

And while both body-focused repetitive behavior disorders affect a greater proportion of females than males, “we have no current information that is useful about what hormonal influences may or may not play in terms of picking and pulling behaviors,” Jon E. Grant, MD, JD, MPH, professor of psychiatry and behavioral neuroscience at the University of Chicago, said at the annual meeting of the Society for Pediatric Dermatology. “On a cognitive level, affected children and adolescents often have impaired inhibitory control but they are often 1-2 standard deviations above average IQ. They have Type A personalities [and are] very driven young kids. They also do not tolerate any down time or boredom. They need to be doing something all the time.”

According to the DSM-5, the diagnostic criteria for skin picking includes recurrent skin picking that results in skin lesions and is not attributable to another medical condition or substance. It also involves repeated attempts to decrease or stop the behavior and causes clinically significant distress or impairment.

“The other medical condition that we are interested in is the misuse of or dependence upon amphetamines or other prescription-based or illicit stimulants,” Dr. Grant said. “I saw a young man who was using about 600 mg of Ritalin a day, and he was picking all over the place. He did not have a primary skin disorder.”

The lifetime prevalence of skin picking disorder ranges between 1.4% and 5.4% of the general population. However, about 63% of people in a community sample endorsed some form of skin picking, and in a study of 105 college students, almost 40% said they picked their skin and had noticeable tissue damage as a result.

“Skin picking is not the same as self-injury,” Dr. Grant said. “It is also not simply an anxiety disorder. Anxiety will make people who pick worse, so people will say that they pick when they’re under stress. I can give them benzodiazepines and they’re still going to pick.”

Animal and human studies demonstrate that skin picking and hair pulling primarily affect females. “You will encounter young boys that pick and pull, but it largely affects females, and it tends to start around puberty,” he said. “Picking can have an onset after the age of 30, which is quite uncommon.”

From a cognitive standpoint, pathological skin pickers demonstrate impaired inhibitory control, impaired stop signal reaction time, increased rates of negative urgency (a tendency to act impulsively in response to negative emotions), and increased rates of positive urgency (a tendency to act impulsively in response to exciting or pleasurable emotions).

Trichotillomania

The lifetime prevalence of trichotillomania ranges between 0.6% and 3.9%. The onset is typically from ages 10-13 years, and the mean duration of illness is 22 years.

The DSM-5 criteria for trichotillomania are similar to that of skin-picking disorder, “although we don’t really worry about the substance use issue with people who pull their hair,” Dr. Grant said. “It doesn’t seem to have a correlation.” In addition, sometimes, children “will worsen pulling or picking when they have co-occurring ADHD and they’ve been started on a stimulant, even at a typical dose. For kids who have those issues, we prefer to try nonstimulant options for their ADHD such as bupropion or atomoxetine.”

Individuals with trichotillomania also tend to have low self-esteem and increased social anxiety, he added, and about one-third report low or very low quality of life. “When you notice alopecia, particularly in young girls who often have longer hair, up to 20% will eat their hair,” Dr. Grant said. “We don’t know why. It’s not related to vitamin deficiencies; it’s not a pica type of iron deficiency. There seems to be a shame piece about eating one’s own hair, but it’s important to assess that. Ask about constipation or overflow incontinence because they can get a bezoar, which can rupture” and can be fatal.

Skin-picking disorder and trichotillomania co-occur in up to 20% of cases. “When they do it tends to be a more difficult problem,” he said. These patients often come for mental health care because of depression, and most, he added, say “I don’t think I would be depressed if I wasn’t covered with excoriations or missing most of my hair.”
 

Treatment for both conditions

According to Dr. Grant, the treatment of choice for skin-picking disorder and trichotillomania is a specific psychotherapy known as “habit reversal therapy,” which involves helping the patient gain better self-control. The drawback is that it’s difficult to find someone trained in habit reversal therapy, “who know anything about skin picking and hair pulling,” he said. “That has been a huge challenge in the field.”

In his experience, the medical treatment of choice for skin-picking disorder and trichotillomania is N-acetylcysteine, an over-the-counter amino acid and antioxidant, which has been shown to be helpful at a dose of 2,400 mg per day. “Patients report to me that some of the excoriations clear up a little quicker as they’re taking it,” Dr. Grant said.

There may also be a role for antipsychotic therapy, he said, “but because of the associated weight gain with most antipsychotics we prefer not to use them.”

The opioid antagonist naltrexone has been shown to be effective in the subset of patients with skin-picking or hair-pulling disorders whose parents have a substance use disorder, Dr. Grant said. “The thought is that there’s something addictive about this behavior in some kids. These kids will look forward to picking and find it rewarding and exciting.”

Dr. Grant reported having no relevant financial disclosures.

INDIANAPOLIS – Despite the common prevalence of skin-picking disorder and trichotillomania (hair pulling), no Food and Drug Administration–approved treatments exist for either condition.

And while both body-focused repetitive behavior disorders affect a greater proportion of females than males, “we have no current information that is useful about what hormonal influences may or may not play in terms of picking and pulling behaviors,” Jon E. Grant, MD, JD, MPH, professor of psychiatry and behavioral neuroscience at the University of Chicago, said at the annual meeting of the Society for Pediatric Dermatology. “On a cognitive level, affected children and adolescents often have impaired inhibitory control but they are often 1-2 standard deviations above average IQ. They have Type A personalities [and are] very driven young kids. They also do not tolerate any down time or boredom. They need to be doing something all the time.”

According to the DSM-5, the diagnostic criteria for skin picking includes recurrent skin picking that results in skin lesions and is not attributable to another medical condition or substance. It also involves repeated attempts to decrease or stop the behavior and causes clinically significant distress or impairment.

“The other medical condition that we are interested in is the misuse of or dependence upon amphetamines or other prescription-based or illicit stimulants,” Dr. Grant said. “I saw a young man who was using about 600 mg of Ritalin a day, and he was picking all over the place. He did not have a primary skin disorder.”

The lifetime prevalence of skin picking disorder ranges between 1.4% and 5.4% of the general population. However, about 63% of people in a community sample endorsed some form of skin picking, and in a study of 105 college students, almost 40% said they picked their skin and had noticeable tissue damage as a result.

“Skin picking is not the same as self-injury,” Dr. Grant said. “It is also not simply an anxiety disorder. Anxiety will make people who pick worse, so people will say that they pick when they’re under stress. I can give them benzodiazepines and they’re still going to pick.”

Animal and human studies demonstrate that skin picking and hair pulling primarily affect females. “You will encounter young boys that pick and pull, but it largely affects females, and it tends to start around puberty,” he said. “Picking can have an onset after the age of 30, which is quite uncommon.”

From a cognitive standpoint, pathological skin pickers demonstrate impaired inhibitory control, impaired stop signal reaction time, increased rates of negative urgency (a tendency to act impulsively in response to negative emotions), and increased rates of positive urgency (a tendency to act impulsively in response to exciting or pleasurable emotions).

Trichotillomania

The lifetime prevalence of trichotillomania ranges between 0.6% and 3.9%. The onset is typically from ages 10-13 years, and the mean duration of illness is 22 years.

The DSM-5 criteria for trichotillomania are similar to that of skin-picking disorder, “although we don’t really worry about the substance use issue with people who pull their hair,” Dr. Grant said. “It doesn’t seem to have a correlation.” In addition, sometimes, children “will worsen pulling or picking when they have co-occurring ADHD and they’ve been started on a stimulant, even at a typical dose. For kids who have those issues, we prefer to try nonstimulant options for their ADHD such as bupropion or atomoxetine.”

Individuals with trichotillomania also tend to have low self-esteem and increased social anxiety, he added, and about one-third report low or very low quality of life. “When you notice alopecia, particularly in young girls who often have longer hair, up to 20% will eat their hair,” Dr. Grant said. “We don’t know why. It’s not related to vitamin deficiencies; it’s not a pica type of iron deficiency. There seems to be a shame piece about eating one’s own hair, but it’s important to assess that. Ask about constipation or overflow incontinence because they can get a bezoar, which can rupture” and can be fatal.

Skin-picking disorder and trichotillomania co-occur in up to 20% of cases. “When they do it tends to be a more difficult problem,” he said. These patients often come for mental health care because of depression, and most, he added, say “I don’t think I would be depressed if I wasn’t covered with excoriations or missing most of my hair.”
 

Treatment for both conditions

According to Dr. Grant, the treatment of choice for skin-picking disorder and trichotillomania is a specific psychotherapy known as “habit reversal therapy,” which involves helping the patient gain better self-control. The drawback is that it’s difficult to find someone trained in habit reversal therapy, “who know anything about skin picking and hair pulling,” he said. “That has been a huge challenge in the field.”

In his experience, the medical treatment of choice for skin-picking disorder and trichotillomania is N-acetylcysteine, an over-the-counter amino acid and antioxidant, which has been shown to be helpful at a dose of 2,400 mg per day. “Patients report to me that some of the excoriations clear up a little quicker as they’re taking it,” Dr. Grant said.

There may also be a role for antipsychotic therapy, he said, “but because of the associated weight gain with most antipsychotics we prefer not to use them.”

The opioid antagonist naltrexone has been shown to be effective in the subset of patients with skin-picking or hair-pulling disorders whose parents have a substance use disorder, Dr. Grant said. “The thought is that there’s something addictive about this behavior in some kids. These kids will look forward to picking and find it rewarding and exciting.”

Dr. Grant reported having no relevant financial disclosures.

After a 5-year search, the US Senate in a 66-23 vote, confirmed a new US Department of Veterans Affairs (VA) Under Secretary for Health, filling a role that has been without permanent leadership since 2017. Shereef Elnahal, MD, takes over from Steve Lieberman, MD, who has been serving the role in an acting capacity since July 2021.

Elnahal’s nomination had been in limbo since May after Sen. Rick Scott (R-FL) blocked an attempt to fast-track his confirmation, which was led by Sen. John Tester (D-MT) who chairs the Senate Committee on Veterans’ Affairs. Scott, who had no specific objection to Elnahal, argued that President Joseph Biden’s nominees haven’t been qualified. The debate turned acrimonious, with Tester accusing Scott of “turning his back on America’s veterans.” He called Scott’s objection as “obstruction at the worst, because this stops our veterans from getting the health care that they need.”

Tester urged his colleagues to support Elnahal’s confirmation, stressing the importance of filling the position. “Dr. Shereef Elnahal has an impressive record of leading health care systems and agencies and has shown a strong commitment to serving millions of veterans and hardworking employees at VA. Now more than ever,” Tester said, “the Department needs permanent, qualified leadership to guide the nation’s largest integrated health care system in the right direction.”

In a statement, Rep. Mike Bost (R-IL), ranking member of the US House of Representatives Committee on Veterans’ Affairs, agreed, saying, “Dr. Elnahal’s position is a vitally important one, particularly as the VA health care system prepares to care for millions more toxic-exposed veterans under the PACT [Promise to Address Comprehensive Toxics] Act and the new electronic health record rollout continues to disappoint. Dr. Elnahal has his work cut out for him, and I look forward to working with him to ensure that veterans get the health care they have earned when they need it and where they want it, without having to wait too long or travel too far.”

Elnahal is in fact considered well qualified for the job. He was New Jersey’s 21st health commissioner, confirmed unanimously by the New Jersey Senate. During his nearly 2 years in that position, he led with what has become a signature move for him—increasing transparent access to information—by expanding the New Jersey Health Information Network, an interoperability platform that allows for electronic exchange of patient health information among health care providers.

Most recently, as president and CEO of University Hospital in Newark, New Jersey, he oversaw improvements in care quality and patient safety. He also established a partnership to provide supportive housing to patients experiencing homelessness, a hospital-based violence intervention program that has served as a national model, and a program that deploys trusted chaplains as community health workers. Notably, he led the hospital through the COVID-19 crisis; the hospital has served as a model for urban hospital and regional response efforts. Elnahal also set up one of the first COVID-19 vaccination sites in New Jersey.

Moreover, he’s not actually a newcomer to the VA. He served as Assistant Deputy Under Secretary for Health for Quality, Safety, and Value from 2016 through 2018, where he oversaw national policies around quality of care for the Veterans Health Administration (VHA).

During that earlier tenure, he was at the forefront of making VA care more transparent and responsive. Among other things, he cofounded the VHA Innovation Ecosystem, a program that fosters the spread of innovation and best practices. On his watch the VA also launched accesstocare.gov, which provides public access to performance, wait time, and other data. The rationale, Elnahal said in a 2018 interview with Federal Practitioner, was simple: “If we provide veterans with an easy-to-use tool that lets them see data on wait times and quality, they’ll be able to make informed decisions about where and when they receive their health care.” The site allows users to compare quality of care provided by VA medical centers with that of local private hospitals. For instance, they can see if a local VA facility’s wait time is better, worse, or the same as the regional average of private sector clinics.

In his drive to harness smart, sustainable ideas for improving veteran care, Elnahal also helmed the VA Diffusion of Excellence (VADOE) program, whose Shark Tank Competition gives a platform to employees “passionate about solving some of the toughest challenges across VHA.” The innovative winners have included VIONE, a medication deprescribing program, and the β-Lactam Allergy Assessment, an initiative to clarify which patients are truly allergic to BL antibiotics, reduce the incidence of multidrug-resistant infections, and reduce hospital length of stay. Both programs are being replicated across multiple facilities.

“We really empower and recognize the frontline employees who not only contribute the best practices but who replicate them,” Elnahal told Federal Practitioner in 2016. “Essentially, we give them a systemwide leadership role… This is part of many different initiatives that are trying to recognize and elevate the great work that physicians do and really improve their morale and reduce burnout.”

As Rep. Bost suggested, Elnahal now has even more work cut out for him. At this new starting gate, Elnahal says a top priority is improving recruiting and retention for clinical care positions. “The sacred healthcare mission of VA simply cannot be fulfilled without having people to do it, talented healthcare professionals who put the mission above all else.”

In a LinkedIn post, Elnahal thanked President Biden and VA Secretary McDonough for their confidence in him, and the US Senate for confirming him in a bipartisan vote. But “[m]ost of all,” he said, “my gratitude goes to Veterans, families, caregivers, and survivors…. Beyond thrilled and eager to get to work for them in a health system with more than 300,000 heroes. Onward to an incredible journey!”

After a 5-year search, the US Senate in a 66-23 vote, confirmed a new US Department of Veterans Affairs (VA) Under Secretary for Health, filling a role that has been without permanent leadership since 2017. Shereef Elnahal, MD, takes over from Steve Lieberman, MD, who has been serving the role in an acting capacity since July 2021.

Elnahal’s nomination had been in limbo since May after Sen. Rick Scott (R-FL) blocked an attempt to fast-track his confirmation, which was led by Sen. John Tester (D-MT) who chairs the Senate Committee on Veterans’ Affairs. Scott, who had no specific objection to Elnahal, argued that President Joseph Biden’s nominees haven’t been qualified. The debate turned acrimonious, with Tester accusing Scott of “turning his back on America’s veterans.” He called Scott’s objection as “obstruction at the worst, because this stops our veterans from getting the health care that they need.”

Tester urged his colleagues to support Elnahal’s confirmation, stressing the importance of filling the position. “Dr. Shereef Elnahal has an impressive record of leading health care systems and agencies and has shown a strong commitment to serving millions of veterans and hardworking employees at VA. Now more than ever,” Tester said, “the Department needs permanent, qualified leadership to guide the nation’s largest integrated health care system in the right direction.”

In a statement, Rep. Mike Bost (R-IL), ranking member of the US House of Representatives Committee on Veterans’ Affairs, agreed, saying, “Dr. Elnahal’s position is a vitally important one, particularly as the VA health care system prepares to care for millions more toxic-exposed veterans under the PACT [Promise to Address Comprehensive Toxics] Act and the new electronic health record rollout continues to disappoint. Dr. Elnahal has his work cut out for him, and I look forward to working with him to ensure that veterans get the health care they have earned when they need it and where they want it, without having to wait too long or travel too far.”

Elnahal is in fact considered well qualified for the job. He was New Jersey’s 21st health commissioner, confirmed unanimously by the New Jersey Senate. During his nearly 2 years in that position, he led with what has become a signature move for him—increasing transparent access to information—by expanding the New Jersey Health Information Network, an interoperability platform that allows for electronic exchange of patient health information among health care providers.

Most recently, as president and CEO of University Hospital in Newark, New Jersey, he oversaw improvements in care quality and patient safety. He also established a partnership to provide supportive housing to patients experiencing homelessness, a hospital-based violence intervention program that has served as a national model, and a program that deploys trusted chaplains as community health workers. Notably, he led the hospital through the COVID-19 crisis; the hospital has served as a model for urban hospital and regional response efforts. Elnahal also set up one of the first COVID-19 vaccination sites in New Jersey.

Moreover, he’s not actually a newcomer to the VA. He served as Assistant Deputy Under Secretary for Health for Quality, Safety, and Value from 2016 through 2018, where he oversaw national policies around quality of care for the Veterans Health Administration (VHA).

During that earlier tenure, he was at the forefront of making VA care more transparent and responsive. Among other things, he cofounded the VHA Innovation Ecosystem, a program that fosters the spread of innovation and best practices. On his watch the VA also launched accesstocare.gov, which provides public access to performance, wait time, and other data. The rationale, Elnahal said in a 2018 interview with Federal Practitioner, was simple: “If we provide veterans with an easy-to-use tool that lets them see data on wait times and quality, they’ll be able to make informed decisions about where and when they receive their health care.” The site allows users to compare quality of care provided by VA medical centers with that of local private hospitals. For instance, they can see if a local VA facility’s wait time is better, worse, or the same as the regional average of private sector clinics.

In his drive to harness smart, sustainable ideas for improving veteran care, Elnahal also helmed the VA Diffusion of Excellence (VADOE) program, whose Shark Tank Competition gives a platform to employees “passionate about solving some of the toughest challenges across VHA.” The innovative winners have included VIONE, a medication deprescribing program, and the β-Lactam Allergy Assessment, an initiative to clarify which patients are truly allergic to BL antibiotics, reduce the incidence of multidrug-resistant infections, and reduce hospital length of stay. Both programs are being replicated across multiple facilities.

“We really empower and recognize the frontline employees who not only contribute the best practices but who replicate them,” Elnahal told Federal Practitioner in 2016. “Essentially, we give them a systemwide leadership role… This is part of many different initiatives that are trying to recognize and elevate the great work that physicians do and really improve their morale and reduce burnout.”

As Rep. Bost suggested, Elnahal now has even more work cut out for him. At this new starting gate, Elnahal says a top priority is improving recruiting and retention for clinical care positions. “The sacred healthcare mission of VA simply cannot be fulfilled without having people to do it, talented healthcare professionals who put the mission above all else.”

In a LinkedIn post, Elnahal thanked President Biden and VA Secretary McDonough for their confidence in him, and the US Senate for confirming him in a bipartisan vote. But “[m]ost of all,” he said, “my gratitude goes to Veterans, families, caregivers, and survivors…. Beyond thrilled and eager to get to work for them in a health system with more than 300,000 heroes. Onward to an incredible journey!”

After a 5-year search, the US Senate in a 66-23 vote, confirmed a new US Department of Veterans Affairs (VA) Under Secretary for Health, filling a role that has been without permanent leadership since 2017. Shereef Elnahal, MD, takes over from Steve Lieberman, MD, who has been serving the role in an acting capacity since July 2021.

Elnahal’s nomination had been in limbo since May after Sen. Rick Scott (R-FL) blocked an attempt to fast-track his confirmation, which was led by Sen. John Tester (D-MT) who chairs the Senate Committee on Veterans’ Affairs. Scott, who had no specific objection to Elnahal, argued that President Joseph Biden’s nominees haven’t been qualified. The debate turned acrimonious, with Tester accusing Scott of “turning his back on America’s veterans.” He called Scott’s objection as “obstruction at the worst, because this stops our veterans from getting the health care that they need.”

Tester urged his colleagues to support Elnahal’s confirmation, stressing the importance of filling the position. “Dr. Shereef Elnahal has an impressive record of leading health care systems and agencies and has shown a strong commitment to serving millions of veterans and hardworking employees at VA. Now more than ever,” Tester said, “the Department needs permanent, qualified leadership to guide the nation’s largest integrated health care system in the right direction.”

In a statement, Rep. Mike Bost (R-IL), ranking member of the US House of Representatives Committee on Veterans’ Affairs, agreed, saying, “Dr. Elnahal’s position is a vitally important one, particularly as the VA health care system prepares to care for millions more toxic-exposed veterans under the PACT [Promise to Address Comprehensive Toxics] Act and the new electronic health record rollout continues to disappoint. Dr. Elnahal has his work cut out for him, and I look forward to working with him to ensure that veterans get the health care they have earned when they need it and where they want it, without having to wait too long or travel too far.”

Elnahal is in fact considered well qualified for the job. He was New Jersey’s 21st health commissioner, confirmed unanimously by the New Jersey Senate. During his nearly 2 years in that position, he led with what has become a signature move for him—increasing transparent access to information—by expanding the New Jersey Health Information Network, an interoperability platform that allows for electronic exchange of patient health information among health care providers.

Most recently, as president and CEO of University Hospital in Newark, New Jersey, he oversaw improvements in care quality and patient safety. He also established a partnership to provide supportive housing to patients experiencing homelessness, a hospital-based violence intervention program that has served as a national model, and a program that deploys trusted chaplains as community health workers. Notably, he led the hospital through the COVID-19 crisis; the hospital has served as a model for urban hospital and regional response efforts. Elnahal also set up one of the first COVID-19 vaccination sites in New Jersey.

Moreover, he’s not actually a newcomer to the VA. He served as Assistant Deputy Under Secretary for Health for Quality, Safety, and Value from 2016 through 2018, where he oversaw national policies around quality of care for the Veterans Health Administration (VHA).

During that earlier tenure, he was at the forefront of making VA care more transparent and responsive. Among other things, he cofounded the VHA Innovation Ecosystem, a program that fosters the spread of innovation and best practices. On his watch the VA also launched accesstocare.gov, which provides public access to performance, wait time, and other data. The rationale, Elnahal said in a 2018 interview with Federal Practitioner, was simple: “If we provide veterans with an easy-to-use tool that lets them see data on wait times and quality, they’ll be able to make informed decisions about where and when they receive their health care.” The site allows users to compare quality of care provided by VA medical centers with that of local private hospitals. For instance, they can see if a local VA facility’s wait time is better, worse, or the same as the regional average of private sector clinics.

In his drive to harness smart, sustainable ideas for improving veteran care, Elnahal also helmed the VA Diffusion of Excellence (VADOE) program, whose Shark Tank Competition gives a platform to employees “passionate about solving some of the toughest challenges across VHA.” The innovative winners have included VIONE, a medication deprescribing program, and the β-Lactam Allergy Assessment, an initiative to clarify which patients are truly allergic to BL antibiotics, reduce the incidence of multidrug-resistant infections, and reduce hospital length of stay. Both programs are being replicated across multiple facilities.

“We really empower and recognize the frontline employees who not only contribute the best practices but who replicate them,” Elnahal told Federal Practitioner in 2016. “Essentially, we give them a systemwide leadership role… This is part of many different initiatives that are trying to recognize and elevate the great work that physicians do and really improve their morale and reduce burnout.”

As Rep. Bost suggested, Elnahal now has even more work cut out for him. At this new starting gate, Elnahal says a top priority is improving recruiting and retention for clinical care positions. “The sacred healthcare mission of VA simply cannot be fulfilled without having people to do it, talented healthcare professionals who put the mission above all else.”

In a LinkedIn post, Elnahal thanked President Biden and VA Secretary McDonough for their confidence in him, and the US Senate for confirming him in a bipartisan vote. But “[m]ost of all,” he said, “my gratitude goes to Veterans, families, caregivers, and survivors…. Beyond thrilled and eager to get to work for them in a health system with more than 300,000 heroes. Onward to an incredible journey!”

High-dose vitamin B6 supplements may reduce feelings of anxiety and depression, new research suggests.

Investigators compared supplementation with a 1-month course of vitamin B6 or B12 to supplementation with placebo in almost 500 adults. Results showed that vitamin B6 supplementation was associated with reductions in self-reported anxiety and a trend toward decreased depressive symptoms.

In addition, the vitamin B6 group showed increased levels of gamma-aminobutyric acid (GABA), as indicated by results on a visual test that was administered at the end of the trial. The test results demonstrated subtle changes in participants’ visual performance. The researchers considered this to be consistent with controlled levels of GABA-related brain activity.

However, “before practicing clinicians would recommend taking high doses of vitamin B6, a full-scale clinical trial would have to be carried out to verify the findings, assess any side effects, and find out which types of patients do or don’t benefit,” study investigator David Field, PhD, associate professor, School of Psychological and Clinical Language Sciences, University of Reading (England), told this news organization.

“My relatively small study can only be considered as an initial proof of concept,” Dr. Field said.

The findings were published online in the Journal of Human Psychopharmacology: Clinical and Experimental.
 

Eat Marmite?

“Recent research has connected mood disorders and some other neuropsychiatric conditions with disturbance in this balance, often in the direction of raised levels of brain activity,” Dr. Field noted.

Vitamin B6 is a coenzyme in the synthesis of GABA, an inhibitory neurotransmitter, from glutamate. Some previous research has suggested that vitamins B6 and B12 have a role in improving mood-related outcomes.

Dr. Field had reviewed a 2017 study of the effects on visual processing of eating Marmite, a type of food spread rich in vitamin B, every day for a few weeks.

“Remarkably, the results of that study suggested that eating Marmite had increased the level of the inhibitory neurotransmitter GABA in the visual part of the brain, damping down the level of neural activity slightly,” he said.

However, Marmite contains other B vitamins and other ingredients that might potentially account for this result, “plus, a lot of people don’t like the taste of Marmite,” Dr. Field noted.

Therefore, he wanted to “find out which individual ingredients were driving the effect, and B6 and B12 were the most plausible candidates.”

He decided to test these vitamins individually and to compare them to placebo. “I added the measures of anxiety and depression that were not in the Marmite study because I reasoned that if GABA levels were altered, this could improve those disorders, because we know that decreased levels of GABA in the brain occur in both of those conditions,” Dr. Field added.

Over the course of 5 years, investigators recruited 478 participants aged 18-58 years (mean age, 23 years; 381 women). Of these, 265 reported having anxiety, and 146 reported having depression.

The study participants were randomly assigned to receive either vitamin B6 (100 mg pyroxidine hydrochloride), vitamin B12 (1,000 mg methylcobalmin), or placebo tablets once daily for a month.

They also completed the Screen for Adult Anxiety Related Disorders (SCAARED) and the Mood and Feelings Questionnaire (MFQ) long version at baseline and following supplementation (“post test”), and they underwent three sensory tests that acted as assays of inhibitory function at post test.

In addition, 307 participants completed the Visual Contrast Sensitivity and Surround Suppression, which “measures the minimum percentage contrast between the lighter and darker regions of a striped pattern that can be detected (called the contrast threshold),” the investigators note.

The contrast threshold was measured with and without a suppressive surround mask that increases the threshold – an effect mediated by GABAergic connections in the visual cortex.

Participants (n = 172) also completed the Binocular Rivalry test and the Tactile Test Battery (n = 180). Both tests are designed to measure responses requiring GABAergic inhibitory activity.
 

‘Subtle changes’

ANOVA analyses revealed a “highly significant” reduction in anxiety at post test (F[1,173] = 10.03; P = .002; np 2 = .055), driven primarily by reduced anxiety in the B6 group (t[88] = 3.51; P < .001; d = .37). The placebo group also showed some reduction in anxiety, but it was not deemed significant, and the overall interaction itself did not reach significance.

A comparison of the B12 group with the group that received placebo revealed a significant reduction in anxiety at post test (F[1,175] = 4.08; P = .045; np 2 = .023), similarly driven by reduced anxiety in the B12 group (t[89] = 1.84; P = .069; d = .19) – but the interaction was not significant.

Among the B6 group, there was a highly significant reduction in scores on the generalized anxiety disorder and social anxiety subscales of the SCAARED, and there was a trend toward reductions on the other subscales. Among the B12 group, there was a significant reduction only on scores on the separation anxiety subscale. No significant changes were found in the placebo group.

The ANOVA test analysis of the B6 and placebo group data showed “no uniform direction of change” in depression at post test. The researchers found a “tendency” for depression scores to decrease between baseline and post test in the B6 group but to increase in the placebo group – an interaction that “approached” significance (F[1,96] = 3.08; P = .083; np 2 = .031), they report.

The ANOVA analysis of the B12 and placebo group data revealed no significant or trending effects, and the t-test comparing baseline and post-test scores in the B12 group was similarly nonsignificant.

B6 supplementation did change visual contrast thresholds, but only when a suppressive surround was present. There were “no clear effects” of B6 supplementation on other outcome measures, including binocular rivalry reversal rate and the tactile test battery, the investigators note.

“We found that supplementation with B6 produced subtle changes in tests of visual processing in a way that suggested an increase in the level of the inhibitory neurotransmitter GABA,” Dr. Field reported.

Vitamin B6 is a “cofactor for a metabolic pathway in the brain that converts the excitatory neurotransmitter glutamate into the inhibitory/calming GABA,” he said.

“By increasing the quantity of the cofactor, we slightly speed up the rate of this metabolic process, and so you end up with a bit more of the GABA neurotransmitter and a bit less glutamate. The net effect of this is to slightly reduce the amount of activity in the brain,” Dr. Field added.
 

Most common nutrient deficiency

Carol Johnston, PhD, professor and associate dean for faculty success, College of Health Solutions, Arizona State University, Phoenix, said vitamin B6 is “the most common nutrient deficiency in the United States;” 16% of men and 32% of women are reportedly B6 deficient.

“Young women on birth control are at higher risk for B6 deficiency due to effects of oral contraceptives on B6 metabolism,” whereas vitamin B12 deficiency is more common in older adults, said Dr. Johnston, who was not involved with the study.

The current study’s population mainly consisted of young women, and the interpretation of the data is “limited” because the researchers did not measure blood status for B6 and B12, Dr. Johnston noted. It is possible the sample was low in B6 and that the supplements “improved cognitive measures.”

Because the population was young – no one was older than 60 years – B12 status was likely “adequate in the sample, and supplementation did not have an impact,” she said.

Overall, Dr. Johnston cautioned that it is important to “alert clinicians and the general public about the concerns of overdosing B6.” For example, supplementation at high amounts can cause potentially irreversible sensory neuropathy, she noted.

“The safe upper limit defined by experts is 100 mg per day – the dosage used in this trial. Daily supplementation should not exceed this level,” Dr. Johnston said.

The vitamin tablets used in the study were supplied by Innopure. The investigators and Dr. Johnston have reported no relevant financial relationships.

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

High-dose vitamin B6 supplements may reduce feelings of anxiety and depression, new research suggests.

Investigators compared supplementation with a 1-month course of vitamin B6 or B12 to supplementation with placebo in almost 500 adults. Results showed that vitamin B6 supplementation was associated with reductions in self-reported anxiety and a trend toward decreased depressive symptoms.

In addition, the vitamin B6 group showed increased levels of gamma-aminobutyric acid (GABA), as indicated by results on a visual test that was administered at the end of the trial. The test results demonstrated subtle changes in participants’ visual performance. The researchers considered this to be consistent with controlled levels of GABA-related brain activity.

However, “before practicing clinicians would recommend taking high doses of vitamin B6, a full-scale clinical trial would have to be carried out to verify the findings, assess any side effects, and find out which types of patients do or don’t benefit,” study investigator David Field, PhD, associate professor, School of Psychological and Clinical Language Sciences, University of Reading (England), told this news organization.

“My relatively small study can only be considered as an initial proof of concept,” Dr. Field said.

The findings were published online in the Journal of Human Psychopharmacology: Clinical and Experimental.
 

Eat Marmite?

“Recent research has connected mood disorders and some other neuropsychiatric conditions with disturbance in this balance, often in the direction of raised levels of brain activity,” Dr. Field noted.

Vitamin B6 is a coenzyme in the synthesis of GABA, an inhibitory neurotransmitter, from glutamate. Some previous research has suggested that vitamins B6 and B12 have a role in improving mood-related outcomes.

Dr. Field had reviewed a 2017 study of the effects on visual processing of eating Marmite, a type of food spread rich in vitamin B, every day for a few weeks.

“Remarkably, the results of that study suggested that eating Marmite had increased the level of the inhibitory neurotransmitter GABA in the visual part of the brain, damping down the level of neural activity slightly,” he said.

However, Marmite contains other B vitamins and other ingredients that might potentially account for this result, “plus, a lot of people don’t like the taste of Marmite,” Dr. Field noted.

Therefore, he wanted to “find out which individual ingredients were driving the effect, and B6 and B12 were the most plausible candidates.”

He decided to test these vitamins individually and to compare them to placebo. “I added the measures of anxiety and depression that were not in the Marmite study because I reasoned that if GABA levels were altered, this could improve those disorders, because we know that decreased levels of GABA in the brain occur in both of those conditions,” Dr. Field added.

Over the course of 5 years, investigators recruited 478 participants aged 18-58 years (mean age, 23 years; 381 women). Of these, 265 reported having anxiety, and 146 reported having depression.

The study participants were randomly assigned to receive either vitamin B6 (100 mg pyroxidine hydrochloride), vitamin B12 (1,000 mg methylcobalmin), or placebo tablets once daily for a month.

They also completed the Screen for Adult Anxiety Related Disorders (SCAARED) and the Mood and Feelings Questionnaire (MFQ) long version at baseline and following supplementation (“post test”), and they underwent three sensory tests that acted as assays of inhibitory function at post test.

In addition, 307 participants completed the Visual Contrast Sensitivity and Surround Suppression, which “measures the minimum percentage contrast between the lighter and darker regions of a striped pattern that can be detected (called the contrast threshold),” the investigators note.

The contrast threshold was measured with and without a suppressive surround mask that increases the threshold – an effect mediated by GABAergic connections in the visual cortex.

Participants (n = 172) also completed the Binocular Rivalry test and the Tactile Test Battery (n = 180). Both tests are designed to measure responses requiring GABAergic inhibitory activity.
 

‘Subtle changes’

ANOVA analyses revealed a “highly significant” reduction in anxiety at post test (F[1,173] = 10.03; P = .002; np 2 = .055), driven primarily by reduced anxiety in the B6 group (t[88] = 3.51; P < .001; d = .37). The placebo group also showed some reduction in anxiety, but it was not deemed significant, and the overall interaction itself did not reach significance.

A comparison of the B12 group with the group that received placebo revealed a significant reduction in anxiety at post test (F[1,175] = 4.08; P = .045; np 2 = .023), similarly driven by reduced anxiety in the B12 group (t[89] = 1.84; P = .069; d = .19) – but the interaction was not significant.

Among the B6 group, there was a highly significant reduction in scores on the generalized anxiety disorder and social anxiety subscales of the SCAARED, and there was a trend toward reductions on the other subscales. Among the B12 group, there was a significant reduction only on scores on the separation anxiety subscale. No significant changes were found in the placebo group.

The ANOVA test analysis of the B6 and placebo group data showed “no uniform direction of change” in depression at post test. The researchers found a “tendency” for depression scores to decrease between baseline and post test in the B6 group but to increase in the placebo group – an interaction that “approached” significance (F[1,96] = 3.08; P = .083; np 2 = .031), they report.

The ANOVA analysis of the B12 and placebo group data revealed no significant or trending effects, and the t-test comparing baseline and post-test scores in the B12 group was similarly nonsignificant.

B6 supplementation did change visual contrast thresholds, but only when a suppressive surround was present. There were “no clear effects” of B6 supplementation on other outcome measures, including binocular rivalry reversal rate and the tactile test battery, the investigators note.

“We found that supplementation with B6 produced subtle changes in tests of visual processing in a way that suggested an increase in the level of the inhibitory neurotransmitter GABA,” Dr. Field reported.

Vitamin B6 is a “cofactor for a metabolic pathway in the brain that converts the excitatory neurotransmitter glutamate into the inhibitory/calming GABA,” he said.

“By increasing the quantity of the cofactor, we slightly speed up the rate of this metabolic process, and so you end up with a bit more of the GABA neurotransmitter and a bit less glutamate. The net effect of this is to slightly reduce the amount of activity in the brain,” Dr. Field added.
 

Most common nutrient deficiency

Carol Johnston, PhD, professor and associate dean for faculty success, College of Health Solutions, Arizona State University, Phoenix, said vitamin B6 is “the most common nutrient deficiency in the United States;” 16% of men and 32% of women are reportedly B6 deficient.

“Young women on birth control are at higher risk for B6 deficiency due to effects of oral contraceptives on B6 metabolism,” whereas vitamin B12 deficiency is more common in older adults, said Dr. Johnston, who was not involved with the study.

The current study’s population mainly consisted of young women, and the interpretation of the data is “limited” because the researchers did not measure blood status for B6 and B12, Dr. Johnston noted. It is possible the sample was low in B6 and that the supplements “improved cognitive measures.”

Because the population was young – no one was older than 60 years – B12 status was likely “adequate in the sample, and supplementation did not have an impact,” she said.

Overall, Dr. Johnston cautioned that it is important to “alert clinicians and the general public about the concerns of overdosing B6.” For example, supplementation at high amounts can cause potentially irreversible sensory neuropathy, she noted.

“The safe upper limit defined by experts is 100 mg per day – the dosage used in this trial. Daily supplementation should not exceed this level,” Dr. Johnston said.

The vitamin tablets used in the study were supplied by Innopure. The investigators and Dr. Johnston have reported no relevant financial relationships.

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

High-dose vitamin B6 supplements may reduce feelings of anxiety and depression, new research suggests.

Investigators compared supplementation with a 1-month course of vitamin B6 or B12 to supplementation with placebo in almost 500 adults. Results showed that vitamin B6 supplementation was associated with reductions in self-reported anxiety and a trend toward decreased depressive symptoms.

In addition, the vitamin B6 group showed increased levels of gamma-aminobutyric acid (GABA), as indicated by results on a visual test that was administered at the end of the trial. The test results demonstrated subtle changes in participants’ visual performance. The researchers considered this to be consistent with controlled levels of GABA-related brain activity.

However, “before practicing clinicians would recommend taking high doses of vitamin B6, a full-scale clinical trial would have to be carried out to verify the findings, assess any side effects, and find out which types of patients do or don’t benefit,” study investigator David Field, PhD, associate professor, School of Psychological and Clinical Language Sciences, University of Reading (England), told this news organization.

“My relatively small study can only be considered as an initial proof of concept,” Dr. Field said.

The findings were published online in the Journal of Human Psychopharmacology: Clinical and Experimental.
 

Eat Marmite?

“Recent research has connected mood disorders and some other neuropsychiatric conditions with disturbance in this balance, often in the direction of raised levels of brain activity,” Dr. Field noted.

Vitamin B6 is a coenzyme in the synthesis of GABA, an inhibitory neurotransmitter, from glutamate. Some previous research has suggested that vitamins B6 and B12 have a role in improving mood-related outcomes.

Dr. Field had reviewed a 2017 study of the effects on visual processing of eating Marmite, a type of food spread rich in vitamin B, every day for a few weeks.

“Remarkably, the results of that study suggested that eating Marmite had increased the level of the inhibitory neurotransmitter GABA in the visual part of the brain, damping down the level of neural activity slightly,” he said.

However, Marmite contains other B vitamins and other ingredients that might potentially account for this result, “plus, a lot of people don’t like the taste of Marmite,” Dr. Field noted.

Therefore, he wanted to “find out which individual ingredients were driving the effect, and B6 and B12 were the most plausible candidates.”

He decided to test these vitamins individually and to compare them to placebo. “I added the measures of anxiety and depression that were not in the Marmite study because I reasoned that if GABA levels were altered, this could improve those disorders, because we know that decreased levels of GABA in the brain occur in both of those conditions,” Dr. Field added.

Over the course of 5 years, investigators recruited 478 participants aged 18-58 years (mean age, 23 years; 381 women). Of these, 265 reported having anxiety, and 146 reported having depression.

The study participants were randomly assigned to receive either vitamin B6 (100 mg pyroxidine hydrochloride), vitamin B12 (1,000 mg methylcobalmin), or placebo tablets once daily for a month.

They also completed the Screen for Adult Anxiety Related Disorders (SCAARED) and the Mood and Feelings Questionnaire (MFQ) long version at baseline and following supplementation (“post test”), and they underwent three sensory tests that acted as assays of inhibitory function at post test.

In addition, 307 participants completed the Visual Contrast Sensitivity and Surround Suppression, which “measures the minimum percentage contrast between the lighter and darker regions of a striped pattern that can be detected (called the contrast threshold),” the investigators note.

The contrast threshold was measured with and without a suppressive surround mask that increases the threshold – an effect mediated by GABAergic connections in the visual cortex.

Participants (n = 172) also completed the Binocular Rivalry test and the Tactile Test Battery (n = 180). Both tests are designed to measure responses requiring GABAergic inhibitory activity.
 

‘Subtle changes’

ANOVA analyses revealed a “highly significant” reduction in anxiety at post test (F[1,173] = 10.03; P = .002; np 2 = .055), driven primarily by reduced anxiety in the B6 group (t[88] = 3.51; P < .001; d = .37). The placebo group also showed some reduction in anxiety, but it was not deemed significant, and the overall interaction itself did not reach significance.

A comparison of the B12 group with the group that received placebo revealed a significant reduction in anxiety at post test (F[1,175] = 4.08; P = .045; np 2 = .023), similarly driven by reduced anxiety in the B12 group (t[89] = 1.84; P = .069; d = .19) – but the interaction was not significant.

Among the B6 group, there was a highly significant reduction in scores on the generalized anxiety disorder and social anxiety subscales of the SCAARED, and there was a trend toward reductions on the other subscales. Among the B12 group, there was a significant reduction only on scores on the separation anxiety subscale. No significant changes were found in the placebo group.

The ANOVA test analysis of the B6 and placebo group data showed “no uniform direction of change” in depression at post test. The researchers found a “tendency” for depression scores to decrease between baseline and post test in the B6 group but to increase in the placebo group – an interaction that “approached” significance (F[1,96] = 3.08; P = .083; np 2 = .031), they report.

The ANOVA analysis of the B12 and placebo group data revealed no significant or trending effects, and the t-test comparing baseline and post-test scores in the B12 group was similarly nonsignificant.

B6 supplementation did change visual contrast thresholds, but only when a suppressive surround was present. There were “no clear effects” of B6 supplementation on other outcome measures, including binocular rivalry reversal rate and the tactile test battery, the investigators note.

“We found that supplementation with B6 produced subtle changes in tests of visual processing in a way that suggested an increase in the level of the inhibitory neurotransmitter GABA,” Dr. Field reported.

Vitamin B6 is a “cofactor for a metabolic pathway in the brain that converts the excitatory neurotransmitter glutamate into the inhibitory/calming GABA,” he said.

“By increasing the quantity of the cofactor, we slightly speed up the rate of this metabolic process, and so you end up with a bit more of the GABA neurotransmitter and a bit less glutamate. The net effect of this is to slightly reduce the amount of activity in the brain,” Dr. Field added.
 

Most common nutrient deficiency

Carol Johnston, PhD, professor and associate dean for faculty success, College of Health Solutions, Arizona State University, Phoenix, said vitamin B6 is “the most common nutrient deficiency in the United States;” 16% of men and 32% of women are reportedly B6 deficient.

“Young women on birth control are at higher risk for B6 deficiency due to effects of oral contraceptives on B6 metabolism,” whereas vitamin B12 deficiency is more common in older adults, said Dr. Johnston, who was not involved with the study.

The current study’s population mainly consisted of young women, and the interpretation of the data is “limited” because the researchers did not measure blood status for B6 and B12, Dr. Johnston noted. It is possible the sample was low in B6 and that the supplements “improved cognitive measures.”

Because the population was young – no one was older than 60 years – B12 status was likely “adequate in the sample, and supplementation did not have an impact,” she said.

Overall, Dr. Johnston cautioned that it is important to “alert clinicians and the general public about the concerns of overdosing B6.” For example, supplementation at high amounts can cause potentially irreversible sensory neuropathy, she noted.

“The safe upper limit defined by experts is 100 mg per day – the dosage used in this trial. Daily supplementation should not exceed this level,” Dr. Johnston said.

The vitamin tablets used in the study were supplied by Innopure. The investigators and Dr. Johnston have reported no relevant financial relationships.

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

Pharmacogenetic testing, which is used to classify how patients with major depressive disorder (MDD) metabolize medications, reduces adverse drug-gene interactions, new research shows.

In a randomized clinical trial that included almost 2,000 adults with MDD, patients in the pharmacogenomics-guided group were more likely to receive an antidepressant that had no potential drug-gene interaction than the patients who received usual care.

In addition, among the intervention group, the rate of remission over 24 weeks was significantly greater.

“These tests can be helpful in rethinking choices of antidepressants, but clinicians should not expect them to be helpful for every patient,” study investigator David W. Oslin, MD, Corporal Michael J. Crescenz VA Medical Center and professor of psychiatry at Perelman School of Medicine, University of Pennsylvania, Philadelphia, said in an interview.

The findings were published online  in JAMA.

Less trial and error

Pharmacogenomic testing can provide information to inform drug selection or dosing for patients with a genetic variation that alters pharmacokinetics or pharmacodynamics. Such testing may be particularly useful for patients with MDD, as fewer than 40% of these patients achieve clinical remission after an initial treatment with an antidepressant, the investigators note.

“To get to a treatment that works for an individual, it’s not unusual to have to try two or three or four antidepressants,” said Dr. Oslin. “If we could reduce that variance a little bit with a test like this, that would be huge from a public health perspective.”

The study included 676 physicians and 1,944 adults with MDD (mean age, 48 years; 24% women) who were receiving care at 22 Department of Veterans Affairs medical centers. Eligible patients were set to start a new antidepressant monotherapy, and all underwent a pharmacogenomic test using a cheek swab.

Investigators randomly assigned patients to receive test results when available (pharmacogenomic-guided group) or 24 weeks later (usual-care group). For the former group, clinicians were asked to initiate treatment when test results were available, typically within 2-3 days. For the latter group, they were asked to initiate treatment on a day of randomization.

Assessments included the 9-item Patient Health questionnaire (PHQ-9), scores for which range from 0-27 points, with higher scores indicating worse symptoms.

Of the total patient population, 79% completed the 24-week assessment.

Researchers characterized antidepressant medications on the basis of drug-gene interaction categories: no known interactions, moderate interactions, and substantial interactions.

The co-primary outcomes were treatment initiation within 30 days, determined on the basis of drug-gene interaction categories, and remission from depression symptoms, defined as a PHQ-9 score of less than or equal to 5.

Raters who were blinded to clinical care and study randomization assessed outcomes at 4, 8, 12, 18, and 24 weeks.
 

Significant impact?

Results showed that the pharmacogenomic-guided group was more likely to receive an antidepressant that had no potential drug-gene interaction, as opposed to one with a moderate/substantial interaction (odds ratio, 4.32; 95% confidence interval, 3.47-5.39; P < .001).

The usual-care group was more likely to receive a drug with mild potential drug-gene interaction (no/moderate interaction vs. substantial interaction: OR, 2.08; 95% CI, 1.52-2.84; P = .005).

For the intervention group, the estimated rates of receiving an antidepressant with no, moderate, and substantial drug-gene interactions were 59.3%, 30.0%, and 10.7%, respectively. For the usual-care group, the estimates were 25.7%, 54.6%, and 19.7%.

The finding that 1 in 5 patients who received usual care were initially given a medication for which there were significant drug-gene interactions means it is “not a rare event,” said Dr. Oslin. “If we can make an impact on 20% of the people we prescribe to, that’s actually pretty big.”

Rates of remission were greater in the pharmacogenomic-guided group over 24 weeks (OR, 1.28; 95% CI, 1.05-1.57; P = .02; absolute risk difference, 2.8%; 95% CI, 0.6%-5.1%).

The secondary outcomes of response to treatment, defined as at least a 50% decrease in PHQ-9 score, also favored the pharmacogenomic-guided group. This was also the case for the secondary outcome of reduction in symptom severity on the PHQ-9 score.

Some physicians have expressed skepticism about pharmacogenomic testing, but the study provides additional evidence of its usefulness, Dr. Oslin noted.

“While I don’t think testing should be standard of practice, I also don’t think we should put barriers into the testing until we can better understand how to target the testing” to those who will benefit the most, he added.

The tests are available at a commercial cost of about $1,000 – which may not be that expensive if testing has a significant impact on a patient’s life, said Dr. Oslin.
 

Important research, but with several limitations

In an accompanying editorial, Dan V. Iosifescu, MD, associate professor of psychiatry at New York University School of Medicine and director of clinical research at the Nathan Kline Institute for Psychiatric Research, called the study an important addition to the literature on pharmacogenomic testing for patients with MDD.

The study was significantly larger and had broader inclusion criteria and longer follow-up than previous clinical trials and is one of the few investigations not funded by a manufacturer of pharmacogenomic tests, writes Dr. Iosifescu, who was not involved with the research.

However, he notes that an antidepressant was not initiated for 30 days after randomization in 25% of the intervention group and in 31% of the usual-care group, which was “puzzling.” “Because these rates were comparable in the 2 groups, it cannot be explained primarily by the delay of the pharmacogenomic test results in the intervention group,” he writes.

In addition, in the co-primary outcome of symptom remission rate, the difference in clinical improvement in favor of the pharmacogenomic-guided treatment was only “modest” – the gain was of less than 2% in the proportion of patients achieving remission, Dr. Iosifescu adds.

He adds this is “likely not very meaningful clinically despite this difference achieving statistical significance in this large study sample.”

Other potential study limitations he cites include the lack of patient blinding to treatment assignment and the absence of clarity about why rates of MDD response and remission over time were relatively low in both treatment groups.

A possible approach to optimize antidepressant choices could involve integration of pharmacogenomic data into larger predictive models that include clinical and demographic variables, Dr. Iosifescu notes.

“The development of such complex models is challenging, but it is now possible given the recent substantial advances in the proficiency of computational tools,” he writes.

The study was funded by the U.S. Department of Veterans Affairs (VA), Health Services Research and Development Service, and the Mental Illness Research, Education, and Clinical Center at the Corporal Michael J. Crescenz VA Medical Center. Dr. Oslin reports having received grants from the VA Office of Research and Development and Janssen Pharmaceuticals and nonfinancial support from Myriad Genetics during the conduct of the study. Dr. Iosifescu report having received personal fees from Alkermes, Allergan, Axsome, Biogen, the Centers for Psychiatric Excellence, Jazz, Lundbeck, Precision Neuroscience, Sage, and Sunovion and grants from Alkermes, AstraZeneca, Brainsway, Litecure, Neosync, Otsuka, Roche, and Shire.

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

Pharmacogenetic testing, which is used to classify how patients with major depressive disorder (MDD) metabolize medications, reduces adverse drug-gene interactions, new research shows.

In a randomized clinical trial that included almost 2,000 adults with MDD, patients in the pharmacogenomics-guided group were more likely to receive an antidepressant that had no potential drug-gene interaction than the patients who received usual care.

In addition, among the intervention group, the rate of remission over 24 weeks was significantly greater.

“These tests can be helpful in rethinking choices of antidepressants, but clinicians should not expect them to be helpful for every patient,” study investigator David W. Oslin, MD, Corporal Michael J. Crescenz VA Medical Center and professor of psychiatry at Perelman School of Medicine, University of Pennsylvania, Philadelphia, said in an interview.

The findings were published online  in JAMA.

Less trial and error

Pharmacogenomic testing can provide information to inform drug selection or dosing for patients with a genetic variation that alters pharmacokinetics or pharmacodynamics. Such testing may be particularly useful for patients with MDD, as fewer than 40% of these patients achieve clinical remission after an initial treatment with an antidepressant, the investigators note.

“To get to a treatment that works for an individual, it’s not unusual to have to try two or three or four antidepressants,” said Dr. Oslin. “If we could reduce that variance a little bit with a test like this, that would be huge from a public health perspective.”

The study included 676 physicians and 1,944 adults with MDD (mean age, 48 years; 24% women) who were receiving care at 22 Department of Veterans Affairs medical centers. Eligible patients were set to start a new antidepressant monotherapy, and all underwent a pharmacogenomic test using a cheek swab.

Investigators randomly assigned patients to receive test results when available (pharmacogenomic-guided group) or 24 weeks later (usual-care group). For the former group, clinicians were asked to initiate treatment when test results were available, typically within 2-3 days. For the latter group, they were asked to initiate treatment on a day of randomization.

Assessments included the 9-item Patient Health questionnaire (PHQ-9), scores for which range from 0-27 points, with higher scores indicating worse symptoms.

Of the total patient population, 79% completed the 24-week assessment.

Researchers characterized antidepressant medications on the basis of drug-gene interaction categories: no known interactions, moderate interactions, and substantial interactions.

The co-primary outcomes were treatment initiation within 30 days, determined on the basis of drug-gene interaction categories, and remission from depression symptoms, defined as a PHQ-9 score of less than or equal to 5.

Raters who were blinded to clinical care and study randomization assessed outcomes at 4, 8, 12, 18, and 24 weeks.
 

Significant impact?

Results showed that the pharmacogenomic-guided group was more likely to receive an antidepressant that had no potential drug-gene interaction, as opposed to one with a moderate/substantial interaction (odds ratio, 4.32; 95% confidence interval, 3.47-5.39; P < .001).

The usual-care group was more likely to receive a drug with mild potential drug-gene interaction (no/moderate interaction vs. substantial interaction: OR, 2.08; 95% CI, 1.52-2.84; P = .005).

For the intervention group, the estimated rates of receiving an antidepressant with no, moderate, and substantial drug-gene interactions were 59.3%, 30.0%, and 10.7%, respectively. For the usual-care group, the estimates were 25.7%, 54.6%, and 19.7%.

The finding that 1 in 5 patients who received usual care were initially given a medication for which there were significant drug-gene interactions means it is “not a rare event,” said Dr. Oslin. “If we can make an impact on 20% of the people we prescribe to, that’s actually pretty big.”

Rates of remission were greater in the pharmacogenomic-guided group over 24 weeks (OR, 1.28; 95% CI, 1.05-1.57; P = .02; absolute risk difference, 2.8%; 95% CI, 0.6%-5.1%).

The secondary outcomes of response to treatment, defined as at least a 50% decrease in PHQ-9 score, also favored the pharmacogenomic-guided group. This was also the case for the secondary outcome of reduction in symptom severity on the PHQ-9 score.

Some physicians have expressed skepticism about pharmacogenomic testing, but the study provides additional evidence of its usefulness, Dr. Oslin noted.

“While I don’t think testing should be standard of practice, I also don’t think we should put barriers into the testing until we can better understand how to target the testing” to those who will benefit the most, he added.

The tests are available at a commercial cost of about $1,000 – which may not be that expensive if testing has a significant impact on a patient’s life, said Dr. Oslin.
 

Important research, but with several limitations

In an accompanying editorial, Dan V. Iosifescu, MD, associate professor of psychiatry at New York University School of Medicine and director of clinical research at the Nathan Kline Institute for Psychiatric Research, called the study an important addition to the literature on pharmacogenomic testing for patients with MDD.

The study was significantly larger and had broader inclusion criteria and longer follow-up than previous clinical trials and is one of the few investigations not funded by a manufacturer of pharmacogenomic tests, writes Dr. Iosifescu, who was not involved with the research.

However, he notes that an antidepressant was not initiated for 30 days after randomization in 25% of the intervention group and in 31% of the usual-care group, which was “puzzling.” “Because these rates were comparable in the 2 groups, it cannot be explained primarily by the delay of the pharmacogenomic test results in the intervention group,” he writes.

In addition, in the co-primary outcome of symptom remission rate, the difference in clinical improvement in favor of the pharmacogenomic-guided treatment was only “modest” – the gain was of less than 2% in the proportion of patients achieving remission, Dr. Iosifescu adds.

He adds this is “likely not very meaningful clinically despite this difference achieving statistical significance in this large study sample.”

Other potential study limitations he cites include the lack of patient blinding to treatment assignment and the absence of clarity about why rates of MDD response and remission over time were relatively low in both treatment groups.

A possible approach to optimize antidepressant choices could involve integration of pharmacogenomic data into larger predictive models that include clinical and demographic variables, Dr. Iosifescu notes.

“The development of such complex models is challenging, but it is now possible given the recent substantial advances in the proficiency of computational tools,” he writes.

The study was funded by the U.S. Department of Veterans Affairs (VA), Health Services Research and Development Service, and the Mental Illness Research, Education, and Clinical Center at the Corporal Michael J. Crescenz VA Medical Center. Dr. Oslin reports having received grants from the VA Office of Research and Development and Janssen Pharmaceuticals and nonfinancial support from Myriad Genetics during the conduct of the study. Dr. Iosifescu report having received personal fees from Alkermes, Allergan, Axsome, Biogen, the Centers for Psychiatric Excellence, Jazz, Lundbeck, Precision Neuroscience, Sage, and Sunovion and grants from Alkermes, AstraZeneca, Brainsway, Litecure, Neosync, Otsuka, Roche, and Shire.

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

Pharmacogenetic testing, which is used to classify how patients with major depressive disorder (MDD) metabolize medications, reduces adverse drug-gene interactions, new research shows.

In a randomized clinical trial that included almost 2,000 adults with MDD, patients in the pharmacogenomics-guided group were more likely to receive an antidepressant that had no potential drug-gene interaction than the patients who received usual care.

In addition, among the intervention group, the rate of remission over 24 weeks was significantly greater.

“These tests can be helpful in rethinking choices of antidepressants, but clinicians should not expect them to be helpful for every patient,” study investigator David W. Oslin, MD, Corporal Michael J. Crescenz VA Medical Center and professor of psychiatry at Perelman School of Medicine, University of Pennsylvania, Philadelphia, said in an interview.

The findings were published online  in JAMA.

Less trial and error

Pharmacogenomic testing can provide information to inform drug selection or dosing for patients with a genetic variation that alters pharmacokinetics or pharmacodynamics. Such testing may be particularly useful for patients with MDD, as fewer than 40% of these patients achieve clinical remission after an initial treatment with an antidepressant, the investigators note.

“To get to a treatment that works for an individual, it’s not unusual to have to try two or three or four antidepressants,” said Dr. Oslin. “If we could reduce that variance a little bit with a test like this, that would be huge from a public health perspective.”

The study included 676 physicians and 1,944 adults with MDD (mean age, 48 years; 24% women) who were receiving care at 22 Department of Veterans Affairs medical centers. Eligible patients were set to start a new antidepressant monotherapy, and all underwent a pharmacogenomic test using a cheek swab.

Investigators randomly assigned patients to receive test results when available (pharmacogenomic-guided group) or 24 weeks later (usual-care group). For the former group, clinicians were asked to initiate treatment when test results were available, typically within 2-3 days. For the latter group, they were asked to initiate treatment on a day of randomization.

Assessments included the 9-item Patient Health questionnaire (PHQ-9), scores for which range from 0-27 points, with higher scores indicating worse symptoms.

Of the total patient population, 79% completed the 24-week assessment.

Researchers characterized antidepressant medications on the basis of drug-gene interaction categories: no known interactions, moderate interactions, and substantial interactions.

The co-primary outcomes were treatment initiation within 30 days, determined on the basis of drug-gene interaction categories, and remission from depression symptoms, defined as a PHQ-9 score of less than or equal to 5.

Raters who were blinded to clinical care and study randomization assessed outcomes at 4, 8, 12, 18, and 24 weeks.
 

Significant impact?

Results showed that the pharmacogenomic-guided group was more likely to receive an antidepressant that had no potential drug-gene interaction, as opposed to one with a moderate/substantial interaction (odds ratio, 4.32; 95% confidence interval, 3.47-5.39; P < .001).

The usual-care group was more likely to receive a drug with mild potential drug-gene interaction (no/moderate interaction vs. substantial interaction: OR, 2.08; 95% CI, 1.52-2.84; P = .005).

For the intervention group, the estimated rates of receiving an antidepressant with no, moderate, and substantial drug-gene interactions were 59.3%, 30.0%, and 10.7%, respectively. For the usual-care group, the estimates were 25.7%, 54.6%, and 19.7%.

The finding that 1 in 5 patients who received usual care were initially given a medication for which there were significant drug-gene interactions means it is “not a rare event,” said Dr. Oslin. “If we can make an impact on 20% of the people we prescribe to, that’s actually pretty big.”

Rates of remission were greater in the pharmacogenomic-guided group over 24 weeks (OR, 1.28; 95% CI, 1.05-1.57; P = .02; absolute risk difference, 2.8%; 95% CI, 0.6%-5.1%).

The secondary outcomes of response to treatment, defined as at least a 50% decrease in PHQ-9 score, also favored the pharmacogenomic-guided group. This was also the case for the secondary outcome of reduction in symptom severity on the PHQ-9 score.

Some physicians have expressed skepticism about pharmacogenomic testing, but the study provides additional evidence of its usefulness, Dr. Oslin noted.

“While I don’t think testing should be standard of practice, I also don’t think we should put barriers into the testing until we can better understand how to target the testing” to those who will benefit the most, he added.

The tests are available at a commercial cost of about $1,000 – which may not be that expensive if testing has a significant impact on a patient’s life, said Dr. Oslin.
 

Important research, but with several limitations

In an accompanying editorial, Dan V. Iosifescu, MD, associate professor of psychiatry at New York University School of Medicine and director of clinical research at the Nathan Kline Institute for Psychiatric Research, called the study an important addition to the literature on pharmacogenomic testing for patients with MDD.

The study was significantly larger and had broader inclusion criteria and longer follow-up than previous clinical trials and is one of the few investigations not funded by a manufacturer of pharmacogenomic tests, writes Dr. Iosifescu, who was not involved with the research.

However, he notes that an antidepressant was not initiated for 30 days after randomization in 25% of the intervention group and in 31% of the usual-care group, which was “puzzling.” “Because these rates were comparable in the 2 groups, it cannot be explained primarily by the delay of the pharmacogenomic test results in the intervention group,” he writes.

In addition, in the co-primary outcome of symptom remission rate, the difference in clinical improvement in favor of the pharmacogenomic-guided treatment was only “modest” – the gain was of less than 2% in the proportion of patients achieving remission, Dr. Iosifescu adds.

He adds this is “likely not very meaningful clinically despite this difference achieving statistical significance in this large study sample.”

Other potential study limitations he cites include the lack of patient blinding to treatment assignment and the absence of clarity about why rates of MDD response and remission over time were relatively low in both treatment groups.

A possible approach to optimize antidepressant choices could involve integration of pharmacogenomic data into larger predictive models that include clinical and demographic variables, Dr. Iosifescu notes.

“The development of such complex models is challenging, but it is now possible given the recent substantial advances in the proficiency of computational tools,” he writes.

The study was funded by the U.S. Department of Veterans Affairs (VA), Health Services Research and Development Service, and the Mental Illness Research, Education, and Clinical Center at the Corporal Michael J. Crescenz VA Medical Center. Dr. Oslin reports having received grants from the VA Office of Research and Development and Janssen Pharmaceuticals and nonfinancial support from Myriad Genetics during the conduct of the study. Dr. Iosifescu report having received personal fees from Alkermes, Allergan, Axsome, Biogen, the Centers for Psychiatric Excellence, Jazz, Lundbeck, Precision Neuroscience, Sage, and Sunovion and grants from Alkermes, AstraZeneca, Brainsway, Litecure, Neosync, Otsuka, Roche, and Shire.

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

Young women with a new diagnosis of node-negative triple-negative breast cancer (TNBC) who have high levels of stromal tumor-infiltrating lymphocytes (sTILs) have a very good long-term prognosis, and may be suitable candidates for reduced intensity pre- or postoperative chemotherapy, according to a team of European investigators.

Among 441 women in a Dutch cancer registry who were younger than 40 when they were diagnosed with node-negative TNBC and had not undergone systemic therapy, those who had 75% or more TILs in the intratumoral stromal area had a 15-year cumulative incidence of distant metastases or death of just 2.1%, and every 10% increase in sTILs was associated with a 19% decrease in the risk of death.

In contrast, the 15-year cumulative incidence of distant metastases was 38.4% for women with stromal TIL scores of less than 30%, according to researchers writing in the Journal of Clinical Oncology.

“These data could be used as a starting point for designing a randomized controlled chemotherapy de-escalation trial. The current study confirms the importance of sTILs as a valuable addition to the set of standard prognostic factors in patients with TNBC,” wrote the researchers, who were led by Sabine C. Linn, MD, of the Netherlands Cancer Institute, Amsterdam.
 

Markers for immune response

Stromal TILs, a mixture of mononuclear immune cells, have been shown in previous studies to be prognostic for outcomes in patients with early-stage TNBC treated either with or without neoadjuvant or adjuvant chemotherapy.

For example, investigators cited a study published in JCO in 2014, that showed among women with TNBC enrolled in the phase 3 ECOG 2197 clinical trial and the related ECOG 119 clinical trial, after a nearly 11-year follow-up, higher sTIL scores were associated with significantly better prognosis with every 10% increase translating into a 14% reduction in the risk of recurrence or death (P = .02).

“The prognostic importance of sTILs is, however, unexplored in patients diagnosed under age 40 years, let alone in the subgroup of systemic therapy–naive patients,” Dr. Linn and colleagues wrote.
 

Retrospective study

To see whether the prognostic value of sTILs was as strong among young, systemic therapy–naive women, the investigators conducted a retrospective study of women enrolled in the Netherlands Cancer Registry who were diagnosed with node-negative TNBC from 1989 to 2000. The patients selected had undergone only locoregional treatment, including axillary node dissection, but had not received any systemic therapy.

Pathologists reviewed samples, with TILs reported for the stromal compartment. The samples were grouped by sTIL score categories of high (75% or greater), intermediate (30% to less than 75%), or low (less than 30%). The investigators looked at overall survival (OS) and distant metastasis-free survival (DMFS) stratified by sTIL scores,

During a median follow-up of 15 years, 107 women died or developed distant metastases, and 78 experienced a second primary cancer.

The results were as noted, with patients in the highest category of sTILs having very low rates of either death or distant metastases during follow-up.

“We confirm the prognostic value of sTILs in young patients with early-stage N0 TNBC who are systemic therapy naive by taking advantage of a prospectively collected population-based cohort. Increasing sTILs are significantly associated with improved OS and DMFS. Patients with high sTILs (> 75%) had an excellent 10-year overall survival and a very low 10-year incidence of distant metastasis or death.

The study was supported by grants from The Netherlands Organization for Health Research and Development, A Sister’s Hope, De Vrienden van UMC Utrecht, Agilent Technologies, the Dutch Cancer Society, and Breast Cancer Research Foundation. Dr. Linn reported consulting with and receiving compensation from Daiichi Sankyo, as well as receiving research funding from Genentech/Roche, AstraZeneca, Bristol-Myers Squibb, Tesaro, Merck, Immunomedics, Eurocept Pharmaceuticals, Agendia, and Novartis.

Young women with a new diagnosis of node-negative triple-negative breast cancer (TNBC) who have high levels of stromal tumor-infiltrating lymphocytes (sTILs) have a very good long-term prognosis, and may be suitable candidates for reduced intensity pre- or postoperative chemotherapy, according to a team of European investigators.

Among 441 women in a Dutch cancer registry who were younger than 40 when they were diagnosed with node-negative TNBC and had not undergone systemic therapy, those who had 75% or more TILs in the intratumoral stromal area had a 15-year cumulative incidence of distant metastases or death of just 2.1%, and every 10% increase in sTILs was associated with a 19% decrease in the risk of death.

In contrast, the 15-year cumulative incidence of distant metastases was 38.4% for women with stromal TIL scores of less than 30%, according to researchers writing in the Journal of Clinical Oncology.

“These data could be used as a starting point for designing a randomized controlled chemotherapy de-escalation trial. The current study confirms the importance of sTILs as a valuable addition to the set of standard prognostic factors in patients with TNBC,” wrote the researchers, who were led by Sabine C. Linn, MD, of the Netherlands Cancer Institute, Amsterdam.
 

Markers for immune response

Stromal TILs, a mixture of mononuclear immune cells, have been shown in previous studies to be prognostic for outcomes in patients with early-stage TNBC treated either with or without neoadjuvant or adjuvant chemotherapy.

For example, investigators cited a study published in JCO in 2014, that showed among women with TNBC enrolled in the phase 3 ECOG 2197 clinical trial and the related ECOG 119 clinical trial, after a nearly 11-year follow-up, higher sTIL scores were associated with significantly better prognosis with every 10% increase translating into a 14% reduction in the risk of recurrence or death (P = .02).

“The prognostic importance of sTILs is, however, unexplored in patients diagnosed under age 40 years, let alone in the subgroup of systemic therapy–naive patients,” Dr. Linn and colleagues wrote.
 

Retrospective study

To see whether the prognostic value of sTILs was as strong among young, systemic therapy–naive women, the investigators conducted a retrospective study of women enrolled in the Netherlands Cancer Registry who were diagnosed with node-negative TNBC from 1989 to 2000. The patients selected had undergone only locoregional treatment, including axillary node dissection, but had not received any systemic therapy.

Pathologists reviewed samples, with TILs reported for the stromal compartment. The samples were grouped by sTIL score categories of high (75% or greater), intermediate (30% to less than 75%), or low (less than 30%). The investigators looked at overall survival (OS) and distant metastasis-free survival (DMFS) stratified by sTIL scores,

During a median follow-up of 15 years, 107 women died or developed distant metastases, and 78 experienced a second primary cancer.

The results were as noted, with patients in the highest category of sTILs having very low rates of either death or distant metastases during follow-up.

“We confirm the prognostic value of sTILs in young patients with early-stage N0 TNBC who are systemic therapy naive by taking advantage of a prospectively collected population-based cohort. Increasing sTILs are significantly associated with improved OS and DMFS. Patients with high sTILs (> 75%) had an excellent 10-year overall survival and a very low 10-year incidence of distant metastasis or death.

The study was supported by grants from The Netherlands Organization for Health Research and Development, A Sister’s Hope, De Vrienden van UMC Utrecht, Agilent Technologies, the Dutch Cancer Society, and Breast Cancer Research Foundation. Dr. Linn reported consulting with and receiving compensation from Daiichi Sankyo, as well as receiving research funding from Genentech/Roche, AstraZeneca, Bristol-Myers Squibb, Tesaro, Merck, Immunomedics, Eurocept Pharmaceuticals, Agendia, and Novartis.

Young women with a new diagnosis of node-negative triple-negative breast cancer (TNBC) who have high levels of stromal tumor-infiltrating lymphocytes (sTILs) have a very good long-term prognosis, and may be suitable candidates for reduced intensity pre- or postoperative chemotherapy, according to a team of European investigators.

Among 441 women in a Dutch cancer registry who were younger than 40 when they were diagnosed with node-negative TNBC and had not undergone systemic therapy, those who had 75% or more TILs in the intratumoral stromal area had a 15-year cumulative incidence of distant metastases or death of just 2.1%, and every 10% increase in sTILs was associated with a 19% decrease in the risk of death.

In contrast, the 15-year cumulative incidence of distant metastases was 38.4% for women with stromal TIL scores of less than 30%, according to researchers writing in the Journal of Clinical Oncology.

“These data could be used as a starting point for designing a randomized controlled chemotherapy de-escalation trial. The current study confirms the importance of sTILs as a valuable addition to the set of standard prognostic factors in patients with TNBC,” wrote the researchers, who were led by Sabine C. Linn, MD, of the Netherlands Cancer Institute, Amsterdam.
 

Markers for immune response

Stromal TILs, a mixture of mononuclear immune cells, have been shown in previous studies to be prognostic for outcomes in patients with early-stage TNBC treated either with or without neoadjuvant or adjuvant chemotherapy.

For example, investigators cited a study published in JCO in 2014, that showed among women with TNBC enrolled in the phase 3 ECOG 2197 clinical trial and the related ECOG 119 clinical trial, after a nearly 11-year follow-up, higher sTIL scores were associated with significantly better prognosis with every 10% increase translating into a 14% reduction in the risk of recurrence or death (P = .02).

“The prognostic importance of sTILs is, however, unexplored in patients diagnosed under age 40 years, let alone in the subgroup of systemic therapy–naive patients,” Dr. Linn and colleagues wrote.
 

Retrospective study

To see whether the prognostic value of sTILs was as strong among young, systemic therapy–naive women, the investigators conducted a retrospective study of women enrolled in the Netherlands Cancer Registry who were diagnosed with node-negative TNBC from 1989 to 2000. The patients selected had undergone only locoregional treatment, including axillary node dissection, but had not received any systemic therapy.

Pathologists reviewed samples, with TILs reported for the stromal compartment. The samples were grouped by sTIL score categories of high (75% or greater), intermediate (30% to less than 75%), or low (less than 30%). The investigators looked at overall survival (OS) and distant metastasis-free survival (DMFS) stratified by sTIL scores,

During a median follow-up of 15 years, 107 women died or developed distant metastases, and 78 experienced a second primary cancer.

The results were as noted, with patients in the highest category of sTILs having very low rates of either death or distant metastases during follow-up.

“We confirm the prognostic value of sTILs in young patients with early-stage N0 TNBC who are systemic therapy naive by taking advantage of a prospectively collected population-based cohort. Increasing sTILs are significantly associated with improved OS and DMFS. Patients with high sTILs (> 75%) had an excellent 10-year overall survival and a very low 10-year incidence of distant metastasis or death.

The study was supported by grants from The Netherlands Organization for Health Research and Development, A Sister’s Hope, De Vrienden van UMC Utrecht, Agilent Technologies, the Dutch Cancer Society, and Breast Cancer Research Foundation. Dr. Linn reported consulting with and receiving compensation from Daiichi Sankyo, as well as receiving research funding from Genentech/Roche, AstraZeneca, Bristol-Myers Squibb, Tesaro, Merck, Immunomedics, Eurocept Pharmaceuticals, Agendia, and Novartis.