Conference Coverage

Even within the first year of implementation, the Research to Accelerate Cures and Equity (RACE) for Children Act has made an impact.

“In the year prior to RACE implementation, there were no approvals of therapeutics that required pediatric studies,” said Brittany Avin McKelvey, PhD, science policy analyst with Friends of Cancer Research and a childhood cancer survivor. “Within the first year of implementation, almost half of approved therapeutics required pediatric study.”

The legislation was passed by Congress in 2017 and took effect in August 2020. It requires that therapeutics that are approved for adult cancers be tested in pediatric cancers if those drugs are directed at molecular targets relevant for pediatric cancers.

The RACE Act also requires testing of therapeutics that are given an orphan drug designation. Such drugs were previously exempt from pediatric trials.

Dr. McKelvey presented the new findings at the annual meeting of the American Association for Cancer Research.

To evaluate the impact of the RACE Act during the first year of its implementation, her team assessed all the new cancer drugs approved between August 2019 and August 2021.

Nineteen drugs were identified; 63.2% were approved in the year before the RACE Act took effect, and 36.8% were approved after its implementation. The team suspects that the coronavirus pandemic may have contributed to the lower number of post-RACE approvals.

The researchers found that prior to implementation of the RACE Act, none of the approved adult cancer therapeutics were required to be studied in pediatric populations. But more than 90% of those had molecular targets that would have required that they be studied in pediatric cancers had the RACE Act been in place. The majority of these drugs were exempt because of their designation as orphan drugs.

In the post-RACE group, however, 42.9% of approved drugs are required to be studied in pediatric cancers. One example is infigratinib (Truseltiq), a drug for adult cholangiocarcinoma that targets the protein fibroblast growth factor receptor 2 (FGFR2). Truseltiq is an orphan drug – and thus would have been exempt prior to the RACE Act – but it will now be studied in pediatric patients with advanced or metastatic tumors harboring alterations in FGFR2.

“I find these results encouraging, but it is still very early,” said John Maris, MD, an attending physician and professor of pediatrics at the Children’s Hospital of Philadelphia, who was not involved in the study. “This is only 1 year into implementation, and this legislation will be around for a long time.”

In an interview, Dr. McKelvey noted that although a handful of clinical trials for pediatric cancers have been launched since implementation of RACE, many drugs are still being waived for pediatric study even when a relevant mechanism of action is present – largely because the extremely low incidence of many childhood cancers makes it impractical or, in some cases, impossible to conduct such studies. “This highlights the need for additional opportunities to help facilitate and encourage robust pediatric studies,” she said.

The main limitation of the study is that it examined data 1 year after the implementation of the RACE Act; further analysis is needed to determine the full extent of its impact, Dr. McKelvey said. “The true measure of success will be determined by whether increased pediatric studies actually translate to label expansions for pediatric patient populations and access to these therapies.”

The study was supported by funding from Friends of Cancer Research.

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

Even within the first year of implementation, the Research to Accelerate Cures and Equity (RACE) for Children Act has made an impact.

“In the year prior to RACE implementation, there were no approvals of therapeutics that required pediatric studies,” said Brittany Avin McKelvey, PhD, science policy analyst with Friends of Cancer Research and a childhood cancer survivor. “Within the first year of implementation, almost half of approved therapeutics required pediatric study.”

The legislation was passed by Congress in 2017 and took effect in August 2020. It requires that therapeutics that are approved for adult cancers be tested in pediatric cancers if those drugs are directed at molecular targets relevant for pediatric cancers.

The RACE Act also requires testing of therapeutics that are given an orphan drug designation. Such drugs were previously exempt from pediatric trials.

Dr. McKelvey presented the new findings at the annual meeting of the American Association for Cancer Research.

To evaluate the impact of the RACE Act during the first year of its implementation, her team assessed all the new cancer drugs approved between August 2019 and August 2021.

Nineteen drugs were identified; 63.2% were approved in the year before the RACE Act took effect, and 36.8% were approved after its implementation. The team suspects that the coronavirus pandemic may have contributed to the lower number of post-RACE approvals.

The researchers found that prior to implementation of the RACE Act, none of the approved adult cancer therapeutics were required to be studied in pediatric populations. But more than 90% of those had molecular targets that would have required that they be studied in pediatric cancers had the RACE Act been in place. The majority of these drugs were exempt because of their designation as orphan drugs.

In the post-RACE group, however, 42.9% of approved drugs are required to be studied in pediatric cancers. One example is infigratinib (Truseltiq), a drug for adult cholangiocarcinoma that targets the protein fibroblast growth factor receptor 2 (FGFR2). Truseltiq is an orphan drug – and thus would have been exempt prior to the RACE Act – but it will now be studied in pediatric patients with advanced or metastatic tumors harboring alterations in FGFR2.

“I find these results encouraging, but it is still very early,” said John Maris, MD, an attending physician and professor of pediatrics at the Children’s Hospital of Philadelphia, who was not involved in the study. “This is only 1 year into implementation, and this legislation will be around for a long time.”

In an interview, Dr. McKelvey noted that although a handful of clinical trials for pediatric cancers have been launched since implementation of RACE, many drugs are still being waived for pediatric study even when a relevant mechanism of action is present – largely because the extremely low incidence of many childhood cancers makes it impractical or, in some cases, impossible to conduct such studies. “This highlights the need for additional opportunities to help facilitate and encourage robust pediatric studies,” she said.

The main limitation of the study is that it examined data 1 year after the implementation of the RACE Act; further analysis is needed to determine the full extent of its impact, Dr. McKelvey said. “The true measure of success will be determined by whether increased pediatric studies actually translate to label expansions for pediatric patient populations and access to these therapies.”

The study was supported by funding from Friends of Cancer Research.

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

Even within the first year of implementation, the Research to Accelerate Cures and Equity (RACE) for Children Act has made an impact.

“In the year prior to RACE implementation, there were no approvals of therapeutics that required pediatric studies,” said Brittany Avin McKelvey, PhD, science policy analyst with Friends of Cancer Research and a childhood cancer survivor. “Within the first year of implementation, almost half of approved therapeutics required pediatric study.”

The legislation was passed by Congress in 2017 and took effect in August 2020. It requires that therapeutics that are approved for adult cancers be tested in pediatric cancers if those drugs are directed at molecular targets relevant for pediatric cancers.

The RACE Act also requires testing of therapeutics that are given an orphan drug designation. Such drugs were previously exempt from pediatric trials.

Dr. McKelvey presented the new findings at the annual meeting of the American Association for Cancer Research.

To evaluate the impact of the RACE Act during the first year of its implementation, her team assessed all the new cancer drugs approved between August 2019 and August 2021.

Nineteen drugs were identified; 63.2% were approved in the year before the RACE Act took effect, and 36.8% were approved after its implementation. The team suspects that the coronavirus pandemic may have contributed to the lower number of post-RACE approvals.

The researchers found that prior to implementation of the RACE Act, none of the approved adult cancer therapeutics were required to be studied in pediatric populations. But more than 90% of those had molecular targets that would have required that they be studied in pediatric cancers had the RACE Act been in place. The majority of these drugs were exempt because of their designation as orphan drugs.

In the post-RACE group, however, 42.9% of approved drugs are required to be studied in pediatric cancers. One example is infigratinib (Truseltiq), a drug for adult cholangiocarcinoma that targets the protein fibroblast growth factor receptor 2 (FGFR2). Truseltiq is an orphan drug – and thus would have been exempt prior to the RACE Act – but it will now be studied in pediatric patients with advanced or metastatic tumors harboring alterations in FGFR2.

“I find these results encouraging, but it is still very early,” said John Maris, MD, an attending physician and professor of pediatrics at the Children’s Hospital of Philadelphia, who was not involved in the study. “This is only 1 year into implementation, and this legislation will be around for a long time.”

In an interview, Dr. McKelvey noted that although a handful of clinical trials for pediatric cancers have been launched since implementation of RACE, many drugs are still being waived for pediatric study even when a relevant mechanism of action is present – largely because the extremely low incidence of many childhood cancers makes it impractical or, in some cases, impossible to conduct such studies. “This highlights the need for additional opportunities to help facilitate and encourage robust pediatric studies,” she said.

The main limitation of the study is that it examined data 1 year after the implementation of the RACE Act; further analysis is needed to determine the full extent of its impact, Dr. McKelvey said. “The true measure of success will be determined by whether increased pediatric studies actually translate to label expansions for pediatric patient populations and access to these therapies.”

The study was supported by funding from Friends of Cancer Research.

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

In more than 10% of cases in which ductal carcinoma in situ (DCIS) recurs in the same breast, the new lesion is genetically distinct from the original lesion, according to a study presented at the annual meeting of the American Association for Cancer Research.

If these findings of de novo tumor recurrences hold true, “it should change how you should treat the patients in the clinic,” commented lead author Tanjina Kader, PhD, a postdoctoral researcher in the department of oncology at the Peter MacCallum Cancer Centre in the University of Melbourne.

Up to a quarter of cases of DCIS recur, and half of those cases emerge in the form of invasive breast cancer. Currently, all recurrent tumor patients are provided the same treatment on the assumption that all recurrences arise from the primary lesion, Dr. Kader commented.

But the new findings could change this practice. If a patient with DCIS returns to the clinic with a tumor independent of the primary lesion, physicians should consider preventive therapies, such as mastectomy or genetic counseling, she said in an interview.

For their study, Dr. Kader and colleagues gathered patient samples and extracted 67 pairs of primary DCIS and their recurrences from the same breast. They also collected 32 samples from nonrecurrent cases of DCIS.

They then used advanced DNA sequencing methods to conduct detailed molecular analyses in order to determine whether the recurrences were genetically distinct from the original lesion.

The team found that 82% of cases appeared to be clonal – derived from the same ancestral cell as the original tumor – and 18% were nonclonal – arose independently of the original DCIS.

The researchers also identified specific genetic changes, including a mutation in the TP53 gene, that were present in recurrences of DCIS but not in nonrecurrent or nonclonal cases.

“It was surprising to see that nonclonal tumors have a similar genetic profile as nonrecurrent tumors,” Dr. Kader said. This means that, if these genetic changes are used as biomarkers to predict the recurrence of DCIS, they could lead to the undertreatment of patients who could develop nonclonal tumors, since these individuals may be categorized as having a low risk of recurrence, she explained.

“For the last 10 years, everyone has been trying their best to find a biomarker without actually taking into account that independent tumors can actually arise on the same breast independently,” Dr. Kader said.

The main limitation of this study was the lack of DNA from matched healthy cells to compare to the patient samples, said Dr. Kader. Because of the lack of these samples, the study focused only on chromosomal changes.

This study is “highly relevant, as it adds to our knowledge to what extent DCIS can be considered a precursor lesion as well as a risk lesion,” said Jelle Wesseling, MD, PhD, a breast pathologist at the Netherlands Cancer Institute. He was not involved in this research, but his team has also found that primary DCIS lesions and their subsequent events can be clonally unrelated.

Dr. Wesseling said there are still many questions, such as whether inherited genetic variants or the tumor microenvironment contribute to DCIS recurrences. “There is a lot more work to be done here to tease this out in more detail.”

The study was funded by grants from the National Breast Cancer Foundation, the Cancer Council Victoria, and the Victorian Cancer Agency.

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

In more than 10% of cases in which ductal carcinoma in situ (DCIS) recurs in the same breast, the new lesion is genetically distinct from the original lesion, according to a study presented at the annual meeting of the American Association for Cancer Research.

If these findings of de novo tumor recurrences hold true, “it should change how you should treat the patients in the clinic,” commented lead author Tanjina Kader, PhD, a postdoctoral researcher in the department of oncology at the Peter MacCallum Cancer Centre in the University of Melbourne.

Up to a quarter of cases of DCIS recur, and half of those cases emerge in the form of invasive breast cancer. Currently, all recurrent tumor patients are provided the same treatment on the assumption that all recurrences arise from the primary lesion, Dr. Kader commented.

But the new findings could change this practice. If a patient with DCIS returns to the clinic with a tumor independent of the primary lesion, physicians should consider preventive therapies, such as mastectomy or genetic counseling, she said in an interview.

For their study, Dr. Kader and colleagues gathered patient samples and extracted 67 pairs of primary DCIS and their recurrences from the same breast. They also collected 32 samples from nonrecurrent cases of DCIS.

They then used advanced DNA sequencing methods to conduct detailed molecular analyses in order to determine whether the recurrences were genetically distinct from the original lesion.

The team found that 82% of cases appeared to be clonal – derived from the same ancestral cell as the original tumor – and 18% were nonclonal – arose independently of the original DCIS.

The researchers also identified specific genetic changes, including a mutation in the TP53 gene, that were present in recurrences of DCIS but not in nonrecurrent or nonclonal cases.

“It was surprising to see that nonclonal tumors have a similar genetic profile as nonrecurrent tumors,” Dr. Kader said. This means that, if these genetic changes are used as biomarkers to predict the recurrence of DCIS, they could lead to the undertreatment of patients who could develop nonclonal tumors, since these individuals may be categorized as having a low risk of recurrence, she explained.

“For the last 10 years, everyone has been trying their best to find a biomarker without actually taking into account that independent tumors can actually arise on the same breast independently,” Dr. Kader said.

The main limitation of this study was the lack of DNA from matched healthy cells to compare to the patient samples, said Dr. Kader. Because of the lack of these samples, the study focused only on chromosomal changes.

This study is “highly relevant, as it adds to our knowledge to what extent DCIS can be considered a precursor lesion as well as a risk lesion,” said Jelle Wesseling, MD, PhD, a breast pathologist at the Netherlands Cancer Institute. He was not involved in this research, but his team has also found that primary DCIS lesions and their subsequent events can be clonally unrelated.

Dr. Wesseling said there are still many questions, such as whether inherited genetic variants or the tumor microenvironment contribute to DCIS recurrences. “There is a lot more work to be done here to tease this out in more detail.”

The study was funded by grants from the National Breast Cancer Foundation, the Cancer Council Victoria, and the Victorian Cancer Agency.

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

In more than 10% of cases in which ductal carcinoma in situ (DCIS) recurs in the same breast, the new lesion is genetically distinct from the original lesion, according to a study presented at the annual meeting of the American Association for Cancer Research.

If these findings of de novo tumor recurrences hold true, “it should change how you should treat the patients in the clinic,” commented lead author Tanjina Kader, PhD, a postdoctoral researcher in the department of oncology at the Peter MacCallum Cancer Centre in the University of Melbourne.

Up to a quarter of cases of DCIS recur, and half of those cases emerge in the form of invasive breast cancer. Currently, all recurrent tumor patients are provided the same treatment on the assumption that all recurrences arise from the primary lesion, Dr. Kader commented.

But the new findings could change this practice. If a patient with DCIS returns to the clinic with a tumor independent of the primary lesion, physicians should consider preventive therapies, such as mastectomy or genetic counseling, she said in an interview.

For their study, Dr. Kader and colleagues gathered patient samples and extracted 67 pairs of primary DCIS and their recurrences from the same breast. They also collected 32 samples from nonrecurrent cases of DCIS.

They then used advanced DNA sequencing methods to conduct detailed molecular analyses in order to determine whether the recurrences were genetically distinct from the original lesion.

The team found that 82% of cases appeared to be clonal – derived from the same ancestral cell as the original tumor – and 18% were nonclonal – arose independently of the original DCIS.

The researchers also identified specific genetic changes, including a mutation in the TP53 gene, that were present in recurrences of DCIS but not in nonrecurrent or nonclonal cases.

“It was surprising to see that nonclonal tumors have a similar genetic profile as nonrecurrent tumors,” Dr. Kader said. This means that, if these genetic changes are used as biomarkers to predict the recurrence of DCIS, they could lead to the undertreatment of patients who could develop nonclonal tumors, since these individuals may be categorized as having a low risk of recurrence, she explained.

“For the last 10 years, everyone has been trying their best to find a biomarker without actually taking into account that independent tumors can actually arise on the same breast independently,” Dr. Kader said.

The main limitation of this study was the lack of DNA from matched healthy cells to compare to the patient samples, said Dr. Kader. Because of the lack of these samples, the study focused only on chromosomal changes.

This study is “highly relevant, as it adds to our knowledge to what extent DCIS can be considered a precursor lesion as well as a risk lesion,” said Jelle Wesseling, MD, PhD, a breast pathologist at the Netherlands Cancer Institute. He was not involved in this research, but his team has also found that primary DCIS lesions and their subsequent events can be clonally unrelated.

Dr. Wesseling said there are still many questions, such as whether inherited genetic variants or the tumor microenvironment contribute to DCIS recurrences. “There is a lot more work to be done here to tease this out in more detail.”

The study was funded by grants from the National Breast Cancer Foundation, the Cancer Council Victoria, and the Victorian Cancer Agency.

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

NEW ORLEANS – One third of patients with non–small cell lung cancers (NSCLC) bearing the KRASG12C mutation were alive 2 years after starting therapy with the first-in-class KRAS inhibitor sotorasib (Lumakras, Amgen).

The finding comes from an analysis of long-term follow-up data from the CodeBreaK100 trial, which showed a 2-year overall survival (OS) rate of 32.5% in pretreated patients with KRASG12C-mutant disease.

That rate compares favorably with historical data on NSCLC therapies, said Grace K. Dy, MD, from Roswell Park Comprehensive Cancer Center in Buffalo, N.Y.

“We expect about half of that [survival rate] in patients who are treated with docetaxel,” she said in a plenary session at the annual meeting of the American Association for Cancer Research.

Sotorasib was approved by the Food and Drug Administration in May 2021 as the first drug for patients with NSCLC and KRAS mutations and was described as a “historic milestone.” 

In this most recent analysis, which combined data from patients enrolled in phases 1 and 2 of the trial, the “objective response rate of 41% of patients was achieved with sotorasib, with a durable [disease] control rate of 84% and a median duration of response of 12.3 months, with no new safety signals emerging,” she said.

Nearly one-fourth of patients saw long-term benefit, as defined by progression-free survival of at least 12 months, and this long-term benefit was seen across variant allele frequencies of KRASG12C, programmed death–ligand 1 (PD-L1) tumor proportion score, and other comutations, she noted.

“KRASG12C inhibitors represent a major advance in the treatment of KRAS-mutant lung cancers and other types as well,” said invited discussant Mark M. Awad, MD, PhD, director of clinical research at the Lowe Center for Thoracic Oncology at Dana-Farber Cancer Center, Boston.

He cautioned, however, that “the therapeutic efficacy of these G12C inhibitors is currently limited by several things, including patient factors, intrinsic biology, and the emergence of complex resistance mechanisms.”

New approaches will be needed, he said, “to delay and overcome drug resistance to hopefully keep kicking cancer’s KRAS.”

At a media briefing where Dr. Dy presented the data prior to the oral abstract session, moderator Timothy A. Yap, MBBS, PhD, from the University of Texas MD Anderson Cancer Center, Houston, commented that the development of drug resistance is common in oncology.

“That is exactly why we’re now actively working on multiple different combinatorial approaches in the clinic. There have been pretty compelling data published from Mirati [Therapeutics] and from other companies, from Amgen, that really show the resistance mechanisms that actually come about upon monotherapy with KRASG12C inhibitors, including CDK4/6, including P13K-Akt pathways,” he said.

“The solution there really is, No. 1, we need to identify proactively the resistance mechanisms involved and driving each cancer’s resistance, and No. 2, then apply the combinatorial agent, to bring in a combination that’s a rational approach to match a patient’s molecular profile upon resistance,” he said.
 

Tarnished triumph

As previously reported, sotorasib was hailed as “a triumph of drug discovery” when early results of the trial were reported at the European Society of Medical Oncology annual meeting in 2020.

Sotorasib is a small-molecule, specific, and irreversible inhibitor of KRAS that interacts with a “pocket” on the gene’s surface that is present only in an inactive conformation of KRAS. The drug inhibits oncogenic signaling and tumorigenesis by preventing cycling of the oncogene into its active form.

But as Dr. Awad reported at the 2021 AACR annual meeting, the efficacy of sotorasib and other KRAS inhibitors in development has been threatened by the development of resistance caused by a wide range of genomic and histologic mechanisms.

Dr. Awad reported that among 30 patients with NSCLC or colorectal cancer bearing the KRASG12C mutation who had disease progression while being treated with the investigational inhibitor adagrasib in clinical trials, investigators found multiple on-target KRAS alterations and off-target bypass mechanisms of acquired resistance to the drug.

“Diverse mechanisms confer resistance to the KRASG12C inhibitors, including secondary KRAS mutations, MAP [mitogen-activated protein] kinase pathway alterations, acquired genomic rearrangements, and histologic transformation,” he said.
 

Long follow-up

The long-term data reported at the 2022 meeting by Dr. Dy and colleagues included data on 48 patients enrolled in phase 1 of the trial, which had a primary endpoint of safety and tolerability, and 126 patients enrolled in phase 2, with a primary endpoint of objective response rate by blinded independent review.

The trial was conducted in centers in the United States, Europe, Australia, Japan, and South Korea.

Nearly all patients were pretreated: 92.5% of patients had received prior platinum-based chemotherapy and 90.2% had received anti–PD-1/PD-L1 immunotherapy.

Patients received oral sotorasib 960 mg once daily and were followed with radiographic scans every 6 weeks for the first year and once every 12 weeks thereafter.

Of the 174 patients enrolled, two were not evaluable for response at 2 years because of a lack of measurable lesions at baseline.

At a median follow-up of 24.9 months, 5 patients (2.9%) had a complete response and 65 (37.8%) had a partial response, for an objective response rate of 40.7%. An additional 74 patients (43%) had stable disease, for a disease control rate of 83.7%. Of the remaining patients, 23 (13.4%) had disease progression, and 5 were either not evaluable or had missing scan data.

Median progression-free survival was 6.3 months. Median time to response was 6 weeks, and median duration of response was 12.3 months. Half of patients who had a response retained that response for at least 12 months.

Median OS was 12.5 months. The 1-year and 2-year OS rates were 50.8% and 32.5%, respectively.

Grade 3 or 4 treatment-related adverse events occurred in 21% of patients, and one patient had new-onset grade 3 hemolytic anemia 1 year after starting therapy. There were no treatment-related deaths and no treatment-related adverse events leading to discontinuation after the first year.

In exploratory analyses, the benefit of the drug was seen across tumors with varying levels of PD-L1 expression and the oncogenic STK11 comutation, and across KRASG12C variant allele frequency.

The investigators also reported that baseline circulating tumor DNA levels correlated with tumor burden, and that patients who had long-term benefits had lower baseline ctDNA. This finding is consistent with the documented role of ctDNA as a marker for poor prognosis regardless of therapy.

Dr. Dy reported receiving consulting fees from AstraZeneca, Eli Lilly, Mirati Therapeutics, and Takeda in the past 2 years. Dr. Yap disclosed receiving consulting fees from multiple companies. Dr. Awad disclosed consulting for multiple companies.

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

NEW ORLEANS – One third of patients with non–small cell lung cancers (NSCLC) bearing the KRASG12C mutation were alive 2 years after starting therapy with the first-in-class KRAS inhibitor sotorasib (Lumakras, Amgen).

The finding comes from an analysis of long-term follow-up data from the CodeBreaK100 trial, which showed a 2-year overall survival (OS) rate of 32.5% in pretreated patients with KRASG12C-mutant disease.

That rate compares favorably with historical data on NSCLC therapies, said Grace K. Dy, MD, from Roswell Park Comprehensive Cancer Center in Buffalo, N.Y.

“We expect about half of that [survival rate] in patients who are treated with docetaxel,” she said in a plenary session at the annual meeting of the American Association for Cancer Research.

Sotorasib was approved by the Food and Drug Administration in May 2021 as the first drug for patients with NSCLC and KRAS mutations and was described as a “historic milestone.” 

In this most recent analysis, which combined data from patients enrolled in phases 1 and 2 of the trial, the “objective response rate of 41% of patients was achieved with sotorasib, with a durable [disease] control rate of 84% and a median duration of response of 12.3 months, with no new safety signals emerging,” she said.

Nearly one-fourth of patients saw long-term benefit, as defined by progression-free survival of at least 12 months, and this long-term benefit was seen across variant allele frequencies of KRASG12C, programmed death–ligand 1 (PD-L1) tumor proportion score, and other comutations, she noted.

“KRASG12C inhibitors represent a major advance in the treatment of KRAS-mutant lung cancers and other types as well,” said invited discussant Mark M. Awad, MD, PhD, director of clinical research at the Lowe Center for Thoracic Oncology at Dana-Farber Cancer Center, Boston.

He cautioned, however, that “the therapeutic efficacy of these G12C inhibitors is currently limited by several things, including patient factors, intrinsic biology, and the emergence of complex resistance mechanisms.”

New approaches will be needed, he said, “to delay and overcome drug resistance to hopefully keep kicking cancer’s KRAS.”

At a media briefing where Dr. Dy presented the data prior to the oral abstract session, moderator Timothy A. Yap, MBBS, PhD, from the University of Texas MD Anderson Cancer Center, Houston, commented that the development of drug resistance is common in oncology.

“That is exactly why we’re now actively working on multiple different combinatorial approaches in the clinic. There have been pretty compelling data published from Mirati [Therapeutics] and from other companies, from Amgen, that really show the resistance mechanisms that actually come about upon monotherapy with KRASG12C inhibitors, including CDK4/6, including P13K-Akt pathways,” he said.

“The solution there really is, No. 1, we need to identify proactively the resistance mechanisms involved and driving each cancer’s resistance, and No. 2, then apply the combinatorial agent, to bring in a combination that’s a rational approach to match a patient’s molecular profile upon resistance,” he said.
 

Tarnished triumph

As previously reported, sotorasib was hailed as “a triumph of drug discovery” when early results of the trial were reported at the European Society of Medical Oncology annual meeting in 2020.

Sotorasib is a small-molecule, specific, and irreversible inhibitor of KRAS that interacts with a “pocket” on the gene’s surface that is present only in an inactive conformation of KRAS. The drug inhibits oncogenic signaling and tumorigenesis by preventing cycling of the oncogene into its active form.

But as Dr. Awad reported at the 2021 AACR annual meeting, the efficacy of sotorasib and other KRAS inhibitors in development has been threatened by the development of resistance caused by a wide range of genomic and histologic mechanisms.

Dr. Awad reported that among 30 patients with NSCLC or colorectal cancer bearing the KRASG12C mutation who had disease progression while being treated with the investigational inhibitor adagrasib in clinical trials, investigators found multiple on-target KRAS alterations and off-target bypass mechanisms of acquired resistance to the drug.

“Diverse mechanisms confer resistance to the KRASG12C inhibitors, including secondary KRAS mutations, MAP [mitogen-activated protein] kinase pathway alterations, acquired genomic rearrangements, and histologic transformation,” he said.
 

Long follow-up

The long-term data reported at the 2022 meeting by Dr. Dy and colleagues included data on 48 patients enrolled in phase 1 of the trial, which had a primary endpoint of safety and tolerability, and 126 patients enrolled in phase 2, with a primary endpoint of objective response rate by blinded independent review.

The trial was conducted in centers in the United States, Europe, Australia, Japan, and South Korea.

Nearly all patients were pretreated: 92.5% of patients had received prior platinum-based chemotherapy and 90.2% had received anti–PD-1/PD-L1 immunotherapy.

Patients received oral sotorasib 960 mg once daily and were followed with radiographic scans every 6 weeks for the first year and once every 12 weeks thereafter.

Of the 174 patients enrolled, two were not evaluable for response at 2 years because of a lack of measurable lesions at baseline.

At a median follow-up of 24.9 months, 5 patients (2.9%) had a complete response and 65 (37.8%) had a partial response, for an objective response rate of 40.7%. An additional 74 patients (43%) had stable disease, for a disease control rate of 83.7%. Of the remaining patients, 23 (13.4%) had disease progression, and 5 were either not evaluable or had missing scan data.

Median progression-free survival was 6.3 months. Median time to response was 6 weeks, and median duration of response was 12.3 months. Half of patients who had a response retained that response for at least 12 months.

Median OS was 12.5 months. The 1-year and 2-year OS rates were 50.8% and 32.5%, respectively.

Grade 3 or 4 treatment-related adverse events occurred in 21% of patients, and one patient had new-onset grade 3 hemolytic anemia 1 year after starting therapy. There were no treatment-related deaths and no treatment-related adverse events leading to discontinuation after the first year.

In exploratory analyses, the benefit of the drug was seen across tumors with varying levels of PD-L1 expression and the oncogenic STK11 comutation, and across KRASG12C variant allele frequency.

The investigators also reported that baseline circulating tumor DNA levels correlated with tumor burden, and that patients who had long-term benefits had lower baseline ctDNA. This finding is consistent with the documented role of ctDNA as a marker for poor prognosis regardless of therapy.

Dr. Dy reported receiving consulting fees from AstraZeneca, Eli Lilly, Mirati Therapeutics, and Takeda in the past 2 years. Dr. Yap disclosed receiving consulting fees from multiple companies. Dr. Awad disclosed consulting for multiple companies.

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

NEW ORLEANS – One third of patients with non–small cell lung cancers (NSCLC) bearing the KRASG12C mutation were alive 2 years after starting therapy with the first-in-class KRAS inhibitor sotorasib (Lumakras, Amgen).

The finding comes from an analysis of long-term follow-up data from the CodeBreaK100 trial, which showed a 2-year overall survival (OS) rate of 32.5% in pretreated patients with KRASG12C-mutant disease.

That rate compares favorably with historical data on NSCLC therapies, said Grace K. Dy, MD, from Roswell Park Comprehensive Cancer Center in Buffalo, N.Y.

“We expect about half of that [survival rate] in patients who are treated with docetaxel,” she said in a plenary session at the annual meeting of the American Association for Cancer Research.

Sotorasib was approved by the Food and Drug Administration in May 2021 as the first drug for patients with NSCLC and KRAS mutations and was described as a “historic milestone.” 

In this most recent analysis, which combined data from patients enrolled in phases 1 and 2 of the trial, the “objective response rate of 41% of patients was achieved with sotorasib, with a durable [disease] control rate of 84% and a median duration of response of 12.3 months, with no new safety signals emerging,” she said.

Nearly one-fourth of patients saw long-term benefit, as defined by progression-free survival of at least 12 months, and this long-term benefit was seen across variant allele frequencies of KRASG12C, programmed death–ligand 1 (PD-L1) tumor proportion score, and other comutations, she noted.

“KRASG12C inhibitors represent a major advance in the treatment of KRAS-mutant lung cancers and other types as well,” said invited discussant Mark M. Awad, MD, PhD, director of clinical research at the Lowe Center for Thoracic Oncology at Dana-Farber Cancer Center, Boston.

He cautioned, however, that “the therapeutic efficacy of these G12C inhibitors is currently limited by several things, including patient factors, intrinsic biology, and the emergence of complex resistance mechanisms.”

New approaches will be needed, he said, “to delay and overcome drug resistance to hopefully keep kicking cancer’s KRAS.”

At a media briefing where Dr. Dy presented the data prior to the oral abstract session, moderator Timothy A. Yap, MBBS, PhD, from the University of Texas MD Anderson Cancer Center, Houston, commented that the development of drug resistance is common in oncology.

“That is exactly why we’re now actively working on multiple different combinatorial approaches in the clinic. There have been pretty compelling data published from Mirati [Therapeutics] and from other companies, from Amgen, that really show the resistance mechanisms that actually come about upon monotherapy with KRASG12C inhibitors, including CDK4/6, including P13K-Akt pathways,” he said.

“The solution there really is, No. 1, we need to identify proactively the resistance mechanisms involved and driving each cancer’s resistance, and No. 2, then apply the combinatorial agent, to bring in a combination that’s a rational approach to match a patient’s molecular profile upon resistance,” he said.
 

Tarnished triumph

As previously reported, sotorasib was hailed as “a triumph of drug discovery” when early results of the trial were reported at the European Society of Medical Oncology annual meeting in 2020.

Sotorasib is a small-molecule, specific, and irreversible inhibitor of KRAS that interacts with a “pocket” on the gene’s surface that is present only in an inactive conformation of KRAS. The drug inhibits oncogenic signaling and tumorigenesis by preventing cycling of the oncogene into its active form.

But as Dr. Awad reported at the 2021 AACR annual meeting, the efficacy of sotorasib and other KRAS inhibitors in development has been threatened by the development of resistance caused by a wide range of genomic and histologic mechanisms.

Dr. Awad reported that among 30 patients with NSCLC or colorectal cancer bearing the KRASG12C mutation who had disease progression while being treated with the investigational inhibitor adagrasib in clinical trials, investigators found multiple on-target KRAS alterations and off-target bypass mechanisms of acquired resistance to the drug.

“Diverse mechanisms confer resistance to the KRASG12C inhibitors, including secondary KRAS mutations, MAP [mitogen-activated protein] kinase pathway alterations, acquired genomic rearrangements, and histologic transformation,” he said.
 

Long follow-up

The long-term data reported at the 2022 meeting by Dr. Dy and colleagues included data on 48 patients enrolled in phase 1 of the trial, which had a primary endpoint of safety and tolerability, and 126 patients enrolled in phase 2, with a primary endpoint of objective response rate by blinded independent review.

The trial was conducted in centers in the United States, Europe, Australia, Japan, and South Korea.

Nearly all patients were pretreated: 92.5% of patients had received prior platinum-based chemotherapy and 90.2% had received anti–PD-1/PD-L1 immunotherapy.

Patients received oral sotorasib 960 mg once daily and were followed with radiographic scans every 6 weeks for the first year and once every 12 weeks thereafter.

Of the 174 patients enrolled, two were not evaluable for response at 2 years because of a lack of measurable lesions at baseline.

At a median follow-up of 24.9 months, 5 patients (2.9%) had a complete response and 65 (37.8%) had a partial response, for an objective response rate of 40.7%. An additional 74 patients (43%) had stable disease, for a disease control rate of 83.7%. Of the remaining patients, 23 (13.4%) had disease progression, and 5 were either not evaluable or had missing scan data.

Median progression-free survival was 6.3 months. Median time to response was 6 weeks, and median duration of response was 12.3 months. Half of patients who had a response retained that response for at least 12 months.

Median OS was 12.5 months. The 1-year and 2-year OS rates were 50.8% and 32.5%, respectively.

Grade 3 or 4 treatment-related adverse events occurred in 21% of patients, and one patient had new-onset grade 3 hemolytic anemia 1 year after starting therapy. There were no treatment-related deaths and no treatment-related adverse events leading to discontinuation after the first year.

In exploratory analyses, the benefit of the drug was seen across tumors with varying levels of PD-L1 expression and the oncogenic STK11 comutation, and across KRASG12C variant allele frequency.

The investigators also reported that baseline circulating tumor DNA levels correlated with tumor burden, and that patients who had long-term benefits had lower baseline ctDNA. This finding is consistent with the documented role of ctDNA as a marker for poor prognosis regardless of therapy.

Dr. Dy reported receiving consulting fees from AstraZeneca, Eli Lilly, Mirati Therapeutics, and Takeda in the past 2 years. Dr. Yap disclosed receiving consulting fees from multiple companies. Dr. Awad disclosed consulting for multiple companies.

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

Black and senior patients are more likely to be overprescribed antibiotics, according to a new study of 7 billion trips to health care centers – findings that doctors say warrant a further look into unequal prescription practices.

Researchers at the University of Texas Health Science Center found that 64% of antibiotic prescriptions to Black patients and 74% of antibiotic prescriptions to patients aged 65 years and older were deemed inappropriate. White patients, meanwhile, received prescriptions that were deemed inappropriate 56% of the time.

Most of those prescriptions were written for conditions like nonbacterial skin problems, viral respiratory tract infections, and bronchitis – none of which can be treated with antibiotics.

The study – which used data from visits to U.S. doctors’ offices, hospitals, and EDs – will be presented at the 2022 European Congress of Clinical Microbiology & Infectious Diseases in Lisbon.

Researchers also found that 58% of antibiotic prescriptions to patients with a Hispanic or Latin American background were also not appropriate for use.

“Our results suggest that Black and [Hispanic/Latino] patients may be not be properly treated and are receiving antibiotic prescriptions even when not indicated,” researcher Eric Young, PharmD, said in a news release.

Doctors typically will prescribe an antibiotic if they fear a patient’s symptoms may lead to an infection, Dr. Young said. This is particularly true if the doctor believes a patient is unlikely to return for a follow-up, which, he says, “more frequently happens in minority populations.”

The Centers for Disease Control and Prevention estimates that at least 30% of outpatient antibiotic prescriptions are not needed, and up to 50% of antibiotics prescribed are either unnecessary or the wrong type and/or dosage.

Overprescribing of antibiotics has long plagued the medical field. In 2015, the administration of then-President Barack Obama released a National Action Plan for Combating Antibiotic-Resistant Bacteria, with a goal to cut unneeded outpatient antibiotic use by at least half by 2020.

When antibiotics are overused, bacteria that infect us evolve to become stronger and defeat the drugs meant to save us.

Though the findings still need more study, at first glance they provide a concerning but unsurprising look at health inequities, said Rachel Villanueva, MD, president of the National Medical Association, the leading organization representing doctors and patients of African descent.

“We do know that these kind of inequities have existed for a long time in our society,” said Dr. Villanueva, a clinical assistant professor at the New York University. “They’re not new and have been well documented for many, many years. But this deserves further research and further evaluation.”

“This is just the first step – we need to do some more evaluation on how different communities are treated in the health care system. Why is this occurring?”

For patients 65 and older, it may be less about bias and more about having a hard time diagnosing certain conditions within that population, said Preeti Malani, MD, a professor of infectious diseases at the University of Michigan, Ann Arbor, and director of the National Poll on Healthy Aging.

For example, she said, some older patients may have a harder time describing their symptoms. In some cases, doctors may give these patients a prescription to fill in case the issue does not clear up, because it could be harder for them to get back into the office.

“Sometimes it’s hard to know exactly what’s going on,” Dr. Malani said. “Something I’ve done in my own practice in the past is say, ‘I’m giving you a prescription, but I don’t want you to fill it yet.’”

Dr. Malani said inappropriately prescribing antibiotics can be especially dangerous for people 65 and older because of drug interactions and complications like Achilles tendon rupture and a Clostridioides difficile infection, which can arise after antibiotic use.

“We need more information on what drives this in older adults,” she said.

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

Black and senior patients are more likely to be overprescribed antibiotics, according to a new study of 7 billion trips to health care centers – findings that doctors say warrant a further look into unequal prescription practices.

Researchers at the University of Texas Health Science Center found that 64% of antibiotic prescriptions to Black patients and 74% of antibiotic prescriptions to patients aged 65 years and older were deemed inappropriate. White patients, meanwhile, received prescriptions that were deemed inappropriate 56% of the time.

Most of those prescriptions were written for conditions like nonbacterial skin problems, viral respiratory tract infections, and bronchitis – none of which can be treated with antibiotics.

The study – which used data from visits to U.S. doctors’ offices, hospitals, and EDs – will be presented at the 2022 European Congress of Clinical Microbiology & Infectious Diseases in Lisbon.

Researchers also found that 58% of antibiotic prescriptions to patients with a Hispanic or Latin American background were also not appropriate for use.

“Our results suggest that Black and [Hispanic/Latino] patients may be not be properly treated and are receiving antibiotic prescriptions even when not indicated,” researcher Eric Young, PharmD, said in a news release.

Doctors typically will prescribe an antibiotic if they fear a patient’s symptoms may lead to an infection, Dr. Young said. This is particularly true if the doctor believes a patient is unlikely to return for a follow-up, which, he says, “more frequently happens in minority populations.”

The Centers for Disease Control and Prevention estimates that at least 30% of outpatient antibiotic prescriptions are not needed, and up to 50% of antibiotics prescribed are either unnecessary or the wrong type and/or dosage.

Overprescribing of antibiotics has long plagued the medical field. In 2015, the administration of then-President Barack Obama released a National Action Plan for Combating Antibiotic-Resistant Bacteria, with a goal to cut unneeded outpatient antibiotic use by at least half by 2020.

When antibiotics are overused, bacteria that infect us evolve to become stronger and defeat the drugs meant to save us.

Though the findings still need more study, at first glance they provide a concerning but unsurprising look at health inequities, said Rachel Villanueva, MD, president of the National Medical Association, the leading organization representing doctors and patients of African descent.

“We do know that these kind of inequities have existed for a long time in our society,” said Dr. Villanueva, a clinical assistant professor at the New York University. “They’re not new and have been well documented for many, many years. But this deserves further research and further evaluation.”

“This is just the first step – we need to do some more evaluation on how different communities are treated in the health care system. Why is this occurring?”

For patients 65 and older, it may be less about bias and more about having a hard time diagnosing certain conditions within that population, said Preeti Malani, MD, a professor of infectious diseases at the University of Michigan, Ann Arbor, and director of the National Poll on Healthy Aging.

For example, she said, some older patients may have a harder time describing their symptoms. In some cases, doctors may give these patients a prescription to fill in case the issue does not clear up, because it could be harder for them to get back into the office.

“Sometimes it’s hard to know exactly what’s going on,” Dr. Malani said. “Something I’ve done in my own practice in the past is say, ‘I’m giving you a prescription, but I don’t want you to fill it yet.’”

Dr. Malani said inappropriately prescribing antibiotics can be especially dangerous for people 65 and older because of drug interactions and complications like Achilles tendon rupture and a Clostridioides difficile infection, which can arise after antibiotic use.

“We need more information on what drives this in older adults,” she said.

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

Black and senior patients are more likely to be overprescribed antibiotics, according to a new study of 7 billion trips to health care centers – findings that doctors say warrant a further look into unequal prescription practices.

Researchers at the University of Texas Health Science Center found that 64% of antibiotic prescriptions to Black patients and 74% of antibiotic prescriptions to patients aged 65 years and older were deemed inappropriate. White patients, meanwhile, received prescriptions that were deemed inappropriate 56% of the time.

Most of those prescriptions were written for conditions like nonbacterial skin problems, viral respiratory tract infections, and bronchitis – none of which can be treated with antibiotics.

The study – which used data from visits to U.S. doctors’ offices, hospitals, and EDs – will be presented at the 2022 European Congress of Clinical Microbiology & Infectious Diseases in Lisbon.

Researchers also found that 58% of antibiotic prescriptions to patients with a Hispanic or Latin American background were also not appropriate for use.

“Our results suggest that Black and [Hispanic/Latino] patients may be not be properly treated and are receiving antibiotic prescriptions even when not indicated,” researcher Eric Young, PharmD, said in a news release.

Doctors typically will prescribe an antibiotic if they fear a patient’s symptoms may lead to an infection, Dr. Young said. This is particularly true if the doctor believes a patient is unlikely to return for a follow-up, which, he says, “more frequently happens in minority populations.”

The Centers for Disease Control and Prevention estimates that at least 30% of outpatient antibiotic prescriptions are not needed, and up to 50% of antibiotics prescribed are either unnecessary or the wrong type and/or dosage.

Overprescribing of antibiotics has long plagued the medical field. In 2015, the administration of then-President Barack Obama released a National Action Plan for Combating Antibiotic-Resistant Bacteria, with a goal to cut unneeded outpatient antibiotic use by at least half by 2020.

When antibiotics are overused, bacteria that infect us evolve to become stronger and defeat the drugs meant to save us.

Though the findings still need more study, at first glance they provide a concerning but unsurprising look at health inequities, said Rachel Villanueva, MD, president of the National Medical Association, the leading organization representing doctors and patients of African descent.

“We do know that these kind of inequities have existed for a long time in our society,” said Dr. Villanueva, a clinical assistant professor at the New York University. “They’re not new and have been well documented for many, many years. But this deserves further research and further evaluation.”

“This is just the first step – we need to do some more evaluation on how different communities are treated in the health care system. Why is this occurring?”

For patients 65 and older, it may be less about bias and more about having a hard time diagnosing certain conditions within that population, said Preeti Malani, MD, a professor of infectious diseases at the University of Michigan, Ann Arbor, and director of the National Poll on Healthy Aging.

For example, she said, some older patients may have a harder time describing their symptoms. In some cases, doctors may give these patients a prescription to fill in case the issue does not clear up, because it could be harder for them to get back into the office.

“Sometimes it’s hard to know exactly what’s going on,” Dr. Malani said. “Something I’ve done in my own practice in the past is say, ‘I’m giving you a prescription, but I don’t want you to fill it yet.’”

Dr. Malani said inappropriately prescribing antibiotics can be especially dangerous for people 65 and older because of drug interactions and complications like Achilles tendon rupture and a Clostridioides difficile infection, which can arise after antibiotic use.

“We need more information on what drives this in older adults,” she said.

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

Disulfiram, a U.S. Food and Drug Administration–approved medication for the treatment of chronic alcohol dependence, shows promise as a potential anxiolytic, early research suggests.

Japanese researchers, headed by Akiyoshi Saitoh, PhD, professor in the department of pharmacy, Tokyo University of Science, compared the reactions of mice that received a classic anxiolytic agent (diazepam) to those that received disulfiram while performing a maze task and found comparable reductions in anxiety in both groups of mice.

Moreover, unlike diazepam, disulfiram caused no sedation, amnesia, or impairments in coordination.

“These results indicate that disulfiram can be used safely by elderly patients suffering from anxiety and insomnia and has the potential to become a breakthrough psychotropic drug,” Dr. Saitoh said in a press release.

The study was published online in Frontiers in Pharmacology.
 

Inhibitory function

Disulfiram inhibits the enzyme aldehyde dehydrogenase (ALDH), which is responsible for alcohol metabolism. Recent research suggests that disulfiram may have broader inhibitory functions.

In particular, it inhibits the cytoplasmic protein FROUNT, preventing it from interacting with two chemokine receptors (CCR2 and CCRs) that are involved in cellular signaling pathways and are associated with regulating behaviors, including anxiety, in rodents, the authors write.

“Although the functions of FROUNT-chemokines signaling in the immune system are well documented, the potential role of CNS-expressed FROUNT chemokine–related molecules as neuromodulators remains largely unknown,” they write.

The researchers had been conducting preclinical research on the secondary pharmacologic properties of disulfiram and “coincidentally discovered” its “anxiolytic-like effects.” They investigated these effects further because currently used anxiolytics – i.e., benzodiazepines – have unwanted side effects.

The researchers utilized an elevated plus-maze (EPM) test to investigate the effects of disulfiram in mice. The EPM apparatus consists of four arms set in a cross pattern and are connected to a central square. Of these, two arms are protected by vertical boundaries, while the other two have unprotected edges. Typically, mice with anxiety prefer to spend time in the closed arms. The mice also underwent other tests of coordination and the ability to navigate a Y-maze.

Some mice received disulfiram, others received a benzodiazepine, and others received merely a “vehicle,” which served as a control.

Disulfiram “significantly and dose-dependently” increased the time spent in the open arms of the EPM, compared with the vehicle-treated group, at 30 minutes after administration (F [3, 30] = 16.64; P < .0001), suggesting less anxiety. The finding was confirmed by a Bonferroni analysis that showed a significant effect of disulfiram, compared with the vehicle-treated group, at all three doses (20 mg/kg: t = 0.9894; P > .05; 40 mg/kg: t = 3.863; P < .01; 80 mg/kg: t = 6.417; P < .001).

A Student’s t-test analysis showed that diazepam likewise had a significant effect, compared to the vehicle (t = 5.038; P < .001).

Disulfiram also “significantly and dose-dependently” increased the percentage of open-arm entries (F [3, 30] = 14.24; P < .0001). The Bonferroni analysis showed this effect at all three doses (20 mg/kg: t = 0.3999; P > .05; 40 mg/kg: t = 2.693; P > .05; 80 mg/kg: t = 5.864; P < .001).

Diazepam similarly showed a significant effect, compared to the vehicle condition (t = 3.733; P < .005).

In particular, the 40 mg/kg dose of disulfiram significantly increased the percentage of time spent in the open arms at 15, 30, and 60 minutes after administration, with the peak effect occurring at 30 minutes.

The researchers examined the effect of cyanamide, another ALDH inhibitor, on the anxiety behaviors of mice and found no effect on the number of open-arm entries or percentage of time the mice spent in the open arm, compared with the vehicle condition.

In contrast to diazepam, disulfiram had no effect on the amount of spontaneous locomotor activity, time spent on the rotarod, or activity on the Y-maze test displayed by the mice, “suggesting that there were no apparent sedative effects at the dosages used.” Moreover, unlike the mice treated with diazepam, there were no increases in the number of falls the mice experienced on the rotarod.

Glutamate levels in the prelimbic-prefrontal cortex (PL-PFC) “play an important role in the development of anxiety-like behavior in mice,” the authors state. Disulfiram “significantly and completely attenuated increased extracellular glutamate levels in the PL-PFC during stress exposure” on the EPM.

“We propose that DSF inhibits FROUNT protein and the chemokine signaling pathways under its influence, which may suppress presynaptic glutamatergic transmission in the brain,” said Dr. Saitoh. “This, in turn, attenuates the levels of glutamate in the brain, reducing overall anxiety.”
 

Humanity’s most common affliction

Commenting for this news organization, Roger McIntyre, MD, professor of psychiatry and pharmacology, University of Toronto, and head of the mood disorders psychopharmacology unit, noted that there is a “renewed interest in psychiatry in excitatory and inhibitory balance – for example, ketamine represents a treatment that facilitates excitatory activity, while neurosteroids are candidate medicines now for inhibitory activity.”

Dr. McIntyre, who is the chairman and executive director of the Brain and Cognitive Discover Foundation, Toronto, and was not involved with the study, said it is believed “that the excitatory-inhibitory balance may be relevant to brain health and disease.”

Dr. McIntyre also pointed out that the study “highlights not only the repurposing of a well-known medicine but also exploit[s] the potential brain therapeutic effects of immune targets that indirectly affect inhibitory systems, resulting in potentially a safer treatment for anxiety – the most common affliction of humanity.”

Also commenting for this article, Wilfrid Noel Raby, MD, PhD, a psychiatrist in private practice in Teaneck, N.J., called disulfiram “grossly underused for alcohol use disorders and even more so when people use alcohol and cocaine.”

Dr. Raby, who was not involved with the study, has found that patients withdrawing from cocaine, cannabis, or stimulants “can respond very well to disulfiram [not only] in terms of their cravings but also in terms of mood stabilization and anxiolysis.”

He has also found that for patients with bipolar disorder or attention-deficit/hyperactivity disorder with depression disulfiram and low-dose lithium “can provide anxiolysis and mood stabilization, especially if a rapid effect is required, usually within a week.”

However, Dr. Raby cautioned that “it is probably not advisable to maintain patients on disulfiram for periods long than 3 months consecutively because there is a risk of neuropathy and hepatopathology that are not common but are seen often enough.” He usually interrupts treatment for a month and then resumes if necessary.

The research was partially supported by the Tsukuba Clinical Research and Development Organization from the Japan Agency for Medical Research and Development. The authors and Dr. Raby have disclosed no relevant financial relationships. Dr. McIntyre reports receiving research grant support from CIHR/GACD/National Natural Science Foundation of China; speaker/consultation fees from Lundbeck, Janssen, Alkermes, Mitsubishi Tanabe, Purdue, Pfizer, Otsuka, Takeda, Neurocrine, Sunovion, Bausch Health, Axsome, Novo Nordisk, Kris, Sanofi, Eisai, Intra-Cellular, NewBridge Pharmaceuticals, AbbVie, and Atai Life Sciences. Dr. McIntyre is CEO of Braxia Scientific.

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

Disulfiram, a U.S. Food and Drug Administration–approved medication for the treatment of chronic alcohol dependence, shows promise as a potential anxiolytic, early research suggests.

Japanese researchers, headed by Akiyoshi Saitoh, PhD, professor in the department of pharmacy, Tokyo University of Science, compared the reactions of mice that received a classic anxiolytic agent (diazepam) to those that received disulfiram while performing a maze task and found comparable reductions in anxiety in both groups of mice.

Moreover, unlike diazepam, disulfiram caused no sedation, amnesia, or impairments in coordination.

“These results indicate that disulfiram can be used safely by elderly patients suffering from anxiety and insomnia and has the potential to become a breakthrough psychotropic drug,” Dr. Saitoh said in a press release.

The study was published online in Frontiers in Pharmacology.
 

Inhibitory function

Disulfiram inhibits the enzyme aldehyde dehydrogenase (ALDH), which is responsible for alcohol metabolism. Recent research suggests that disulfiram may have broader inhibitory functions.

In particular, it inhibits the cytoplasmic protein FROUNT, preventing it from interacting with two chemokine receptors (CCR2 and CCRs) that are involved in cellular signaling pathways and are associated with regulating behaviors, including anxiety, in rodents, the authors write.

“Although the functions of FROUNT-chemokines signaling in the immune system are well documented, the potential role of CNS-expressed FROUNT chemokine–related molecules as neuromodulators remains largely unknown,” they write.

The researchers had been conducting preclinical research on the secondary pharmacologic properties of disulfiram and “coincidentally discovered” its “anxiolytic-like effects.” They investigated these effects further because currently used anxiolytics – i.e., benzodiazepines – have unwanted side effects.

The researchers utilized an elevated plus-maze (EPM) test to investigate the effects of disulfiram in mice. The EPM apparatus consists of four arms set in a cross pattern and are connected to a central square. Of these, two arms are protected by vertical boundaries, while the other two have unprotected edges. Typically, mice with anxiety prefer to spend time in the closed arms. The mice also underwent other tests of coordination and the ability to navigate a Y-maze.

Some mice received disulfiram, others received a benzodiazepine, and others received merely a “vehicle,” which served as a control.

Disulfiram “significantly and dose-dependently” increased the time spent in the open arms of the EPM, compared with the vehicle-treated group, at 30 minutes after administration (F [3, 30] = 16.64; P < .0001), suggesting less anxiety. The finding was confirmed by a Bonferroni analysis that showed a significant effect of disulfiram, compared with the vehicle-treated group, at all three doses (20 mg/kg: t = 0.9894; P > .05; 40 mg/kg: t = 3.863; P < .01; 80 mg/kg: t = 6.417; P < .001).

A Student’s t-test analysis showed that diazepam likewise had a significant effect, compared to the vehicle (t = 5.038; P < .001).

Disulfiram also “significantly and dose-dependently” increased the percentage of open-arm entries (F [3, 30] = 14.24; P < .0001). The Bonferroni analysis showed this effect at all three doses (20 mg/kg: t = 0.3999; P > .05; 40 mg/kg: t = 2.693; P > .05; 80 mg/kg: t = 5.864; P < .001).

Diazepam similarly showed a significant effect, compared to the vehicle condition (t = 3.733; P < .005).

In particular, the 40 mg/kg dose of disulfiram significantly increased the percentage of time spent in the open arms at 15, 30, and 60 minutes after administration, with the peak effect occurring at 30 minutes.

The researchers examined the effect of cyanamide, another ALDH inhibitor, on the anxiety behaviors of mice and found no effect on the number of open-arm entries or percentage of time the mice spent in the open arm, compared with the vehicle condition.

In contrast to diazepam, disulfiram had no effect on the amount of spontaneous locomotor activity, time spent on the rotarod, or activity on the Y-maze test displayed by the mice, “suggesting that there were no apparent sedative effects at the dosages used.” Moreover, unlike the mice treated with diazepam, there were no increases in the number of falls the mice experienced on the rotarod.

Glutamate levels in the prelimbic-prefrontal cortex (PL-PFC) “play an important role in the development of anxiety-like behavior in mice,” the authors state. Disulfiram “significantly and completely attenuated increased extracellular glutamate levels in the PL-PFC during stress exposure” on the EPM.

“We propose that DSF inhibits FROUNT protein and the chemokine signaling pathways under its influence, which may suppress presynaptic glutamatergic transmission in the brain,” said Dr. Saitoh. “This, in turn, attenuates the levels of glutamate in the brain, reducing overall anxiety.”
 

Humanity’s most common affliction

Commenting for this news organization, Roger McIntyre, MD, professor of psychiatry and pharmacology, University of Toronto, and head of the mood disorders psychopharmacology unit, noted that there is a “renewed interest in psychiatry in excitatory and inhibitory balance – for example, ketamine represents a treatment that facilitates excitatory activity, while neurosteroids are candidate medicines now for inhibitory activity.”

Dr. McIntyre, who is the chairman and executive director of the Brain and Cognitive Discover Foundation, Toronto, and was not involved with the study, said it is believed “that the excitatory-inhibitory balance may be relevant to brain health and disease.”

Dr. McIntyre also pointed out that the study “highlights not only the repurposing of a well-known medicine but also exploit[s] the potential brain therapeutic effects of immune targets that indirectly affect inhibitory systems, resulting in potentially a safer treatment for anxiety – the most common affliction of humanity.”

Also commenting for this article, Wilfrid Noel Raby, MD, PhD, a psychiatrist in private practice in Teaneck, N.J., called disulfiram “grossly underused for alcohol use disorders and even more so when people use alcohol and cocaine.”

Dr. Raby, who was not involved with the study, has found that patients withdrawing from cocaine, cannabis, or stimulants “can respond very well to disulfiram [not only] in terms of their cravings but also in terms of mood stabilization and anxiolysis.”

He has also found that for patients with bipolar disorder or attention-deficit/hyperactivity disorder with depression disulfiram and low-dose lithium “can provide anxiolysis and mood stabilization, especially if a rapid effect is required, usually within a week.”

However, Dr. Raby cautioned that “it is probably not advisable to maintain patients on disulfiram for periods long than 3 months consecutively because there is a risk of neuropathy and hepatopathology that are not common but are seen often enough.” He usually interrupts treatment for a month and then resumes if necessary.

The research was partially supported by the Tsukuba Clinical Research and Development Organization from the Japan Agency for Medical Research and Development. The authors and Dr. Raby have disclosed no relevant financial relationships. Dr. McIntyre reports receiving research grant support from CIHR/GACD/National Natural Science Foundation of China; speaker/consultation fees from Lundbeck, Janssen, Alkermes, Mitsubishi Tanabe, Purdue, Pfizer, Otsuka, Takeda, Neurocrine, Sunovion, Bausch Health, Axsome, Novo Nordisk, Kris, Sanofi, Eisai, Intra-Cellular, NewBridge Pharmaceuticals, AbbVie, and Atai Life Sciences. Dr. McIntyre is CEO of Braxia Scientific.

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

Disulfiram, a U.S. Food and Drug Administration–approved medication for the treatment of chronic alcohol dependence, shows promise as a potential anxiolytic, early research suggests.

Japanese researchers, headed by Akiyoshi Saitoh, PhD, professor in the department of pharmacy, Tokyo University of Science, compared the reactions of mice that received a classic anxiolytic agent (diazepam) to those that received disulfiram while performing a maze task and found comparable reductions in anxiety in both groups of mice.

Moreover, unlike diazepam, disulfiram caused no sedation, amnesia, or impairments in coordination.

“These results indicate that disulfiram can be used safely by elderly patients suffering from anxiety and insomnia and has the potential to become a breakthrough psychotropic drug,” Dr. Saitoh said in a press release.

The study was published online in Frontiers in Pharmacology.
 

Inhibitory function

Disulfiram inhibits the enzyme aldehyde dehydrogenase (ALDH), which is responsible for alcohol metabolism. Recent research suggests that disulfiram may have broader inhibitory functions.

In particular, it inhibits the cytoplasmic protein FROUNT, preventing it from interacting with two chemokine receptors (CCR2 and CCRs) that are involved in cellular signaling pathways and are associated with regulating behaviors, including anxiety, in rodents, the authors write.

“Although the functions of FROUNT-chemokines signaling in the immune system are well documented, the potential role of CNS-expressed FROUNT chemokine–related molecules as neuromodulators remains largely unknown,” they write.

The researchers had been conducting preclinical research on the secondary pharmacologic properties of disulfiram and “coincidentally discovered” its “anxiolytic-like effects.” They investigated these effects further because currently used anxiolytics – i.e., benzodiazepines – have unwanted side effects.

The researchers utilized an elevated plus-maze (EPM) test to investigate the effects of disulfiram in mice. The EPM apparatus consists of four arms set in a cross pattern and are connected to a central square. Of these, two arms are protected by vertical boundaries, while the other two have unprotected edges. Typically, mice with anxiety prefer to spend time in the closed arms. The mice also underwent other tests of coordination and the ability to navigate a Y-maze.

Some mice received disulfiram, others received a benzodiazepine, and others received merely a “vehicle,” which served as a control.

Disulfiram “significantly and dose-dependently” increased the time spent in the open arms of the EPM, compared with the vehicle-treated group, at 30 minutes after administration (F [3, 30] = 16.64; P < .0001), suggesting less anxiety. The finding was confirmed by a Bonferroni analysis that showed a significant effect of disulfiram, compared with the vehicle-treated group, at all three doses (20 mg/kg: t = 0.9894; P > .05; 40 mg/kg: t = 3.863; P < .01; 80 mg/kg: t = 6.417; P < .001).

A Student’s t-test analysis showed that diazepam likewise had a significant effect, compared to the vehicle (t = 5.038; P < .001).

Disulfiram also “significantly and dose-dependently” increased the percentage of open-arm entries (F [3, 30] = 14.24; P < .0001). The Bonferroni analysis showed this effect at all three doses (20 mg/kg: t = 0.3999; P > .05; 40 mg/kg: t = 2.693; P > .05; 80 mg/kg: t = 5.864; P < .001).

Diazepam similarly showed a significant effect, compared to the vehicle condition (t = 3.733; P < .005).

In particular, the 40 mg/kg dose of disulfiram significantly increased the percentage of time spent in the open arms at 15, 30, and 60 minutes after administration, with the peak effect occurring at 30 minutes.

The researchers examined the effect of cyanamide, another ALDH inhibitor, on the anxiety behaviors of mice and found no effect on the number of open-arm entries or percentage of time the mice spent in the open arm, compared with the vehicle condition.

In contrast to diazepam, disulfiram had no effect on the amount of spontaneous locomotor activity, time spent on the rotarod, or activity on the Y-maze test displayed by the mice, “suggesting that there were no apparent sedative effects at the dosages used.” Moreover, unlike the mice treated with diazepam, there were no increases in the number of falls the mice experienced on the rotarod.

Glutamate levels in the prelimbic-prefrontal cortex (PL-PFC) “play an important role in the development of anxiety-like behavior in mice,” the authors state. Disulfiram “significantly and completely attenuated increased extracellular glutamate levels in the PL-PFC during stress exposure” on the EPM.

“We propose that DSF inhibits FROUNT protein and the chemokine signaling pathways under its influence, which may suppress presynaptic glutamatergic transmission in the brain,” said Dr. Saitoh. “This, in turn, attenuates the levels of glutamate in the brain, reducing overall anxiety.”
 

Humanity’s most common affliction

Commenting for this news organization, Roger McIntyre, MD, professor of psychiatry and pharmacology, University of Toronto, and head of the mood disorders psychopharmacology unit, noted that there is a “renewed interest in psychiatry in excitatory and inhibitory balance – for example, ketamine represents a treatment that facilitates excitatory activity, while neurosteroids are candidate medicines now for inhibitory activity.”

Dr. McIntyre, who is the chairman and executive director of the Brain and Cognitive Discover Foundation, Toronto, and was not involved with the study, said it is believed “that the excitatory-inhibitory balance may be relevant to brain health and disease.”

Dr. McIntyre also pointed out that the study “highlights not only the repurposing of a well-known medicine but also exploit[s] the potential brain therapeutic effects of immune targets that indirectly affect inhibitory systems, resulting in potentially a safer treatment for anxiety – the most common affliction of humanity.”

Also commenting for this article, Wilfrid Noel Raby, MD, PhD, a psychiatrist in private practice in Teaneck, N.J., called disulfiram “grossly underused for alcohol use disorders and even more so when people use alcohol and cocaine.”

Dr. Raby, who was not involved with the study, has found that patients withdrawing from cocaine, cannabis, or stimulants “can respond very well to disulfiram [not only] in terms of their cravings but also in terms of mood stabilization and anxiolysis.”

He has also found that for patients with bipolar disorder or attention-deficit/hyperactivity disorder with depression disulfiram and low-dose lithium “can provide anxiolysis and mood stabilization, especially if a rapid effect is required, usually within a week.”

However, Dr. Raby cautioned that “it is probably not advisable to maintain patients on disulfiram for periods long than 3 months consecutively because there is a risk of neuropathy and hepatopathology that are not common but are seen often enough.” He usually interrupts treatment for a month and then resumes if necessary.

The research was partially supported by the Tsukuba Clinical Research and Development Organization from the Japan Agency for Medical Research and Development. The authors and Dr. Raby have disclosed no relevant financial relationships. Dr. McIntyre reports receiving research grant support from CIHR/GACD/National Natural Science Foundation of China; speaker/consultation fees from Lundbeck, Janssen, Alkermes, Mitsubishi Tanabe, Purdue, Pfizer, Otsuka, Takeda, Neurocrine, Sunovion, Bausch Health, Axsome, Novo Nordisk, Kris, Sanofi, Eisai, Intra-Cellular, NewBridge Pharmaceuticals, AbbVie, and Atai Life Sciences. Dr. McIntyre is CEO of Braxia Scientific.

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

Approximately one-third of critical care workers reported some degree of depression, anxiety, or somatic symptoms in the early phase of the COVID-19 pandemic, based on survey results from 939 health care professionals.

The emotional response of professionals in a critical care setting in the early phase of the COVID-19 pandemic has not been well studied, Robyn Branca, PhD, and Paul Branca, MD, of Carson Newman University and the University of Tennessee Medical Center, both in Knoxville, wrote in an abstract presented at the virtual Critical Care Congress sponsored by the Society of Critical Care Medicine.

The prevalence of depression, anxiety, and somatization is low in the general population overall, but the researchers predicted that these conditions increased among workers in critical care settings early in the pandemic.

To assess the prevalence of psychological problems during that time, they sent an email survey on April 7, 2020, to members of the Society of Critical Care Medicine. The survey collected data on demographics, perceived caseload, and potential course of the pandemic. The survey also collected responses to assessments for depression (using the Patient Health Questionnaire–9), anxiety (using the Generalized Anxiety Disorder [GAD] Scale–7), and symptom somatization (using the PHQ-15).

Of the 939 survey respondents, 37% were male, 61.4% were female, and 1.4% gave another or no response.

Overall, 32.3% reported encountering 0-50 COVID-19 cases, 31.1% had encountered 51-200 cases, 12.5% had encountered 201-500 cases, 9.4% had encountered 501-1000 cases, and 13.7% had encountered more than 1,000 cases.

Based on the PHQ-9 depression scale, 44.9% of the respondents had minimal symptoms, 31.1% mild symptoms, 14.3% moderate symptoms, and 9.7% met criteria for severe depressive symptoms. Based on the GAD-7 anxiety scale, 35.5% had minimal symptoms, 32.9% mild, 16.8% moderate, and 14.8% had severe symptoms. Based on the PHQ-15 somatization scale, 39.6% of respondents showed minimal symptoms, whereas 38.2% showed mild symptoms, 17.3% moderate symptoms, and 4.9% had a severe degree of somatic symptoms.

The study findings were limited by the reliance on self-reports; however, the results indicate that a high percentage of critical care workers experienced significant, diagnosable levels of depression, anxiety, and somatic symptoms, the researchers said.

The standard guidance is to pursue individual intervention for anyone with scores of moderate or severe on the scales used in the survey, the researchers said.

Therefore, the findings represent “an alarming degree of mental health impact,” they emphasized. “Immediate mitigation efforts are needed to preserve the health of our ICU workforce.”

The study is important at this time because clinician fatigue and occupational stress are at endemic levels, Bernard Chang, MD, of Columbia University Irving Medical Center, New York City, said in an interview. “It is vital that we take stock of how frontline workers in critical care settings are doing overall,” said Dr. Chang.  

Dr. Chang, who was not involved with the study but has conducted research on mental health in frontline health care workers during the pandemic, said he was not surprised by the findings. “This work builds on the growing body of literature in the pandemic noting high levels of stress, fatigue, and depression/anxiety symptoms across many frontline workers, from emergency department staff, first responders and others. These are all data points highlighting the urgent need for a broad safety net, not only for patients but the providers serving them.”

The takeaway message: “Clinicians are often so focused on providing care for their patients that they may overlook the need to care for their own well-being and mental health,” said Dr. Chang.

As for additional research, “we need to now take this important data and build on creating and identifying tangible solutions to improve the morale of the acute care/health care workforce to ensure career longevity, professional satisfaction, and overall well-being,” Dr. Chang emphasized. Mental health and morale affect not only health care workers, but also the patients they care for. Well–cared for health care providers can be at their best to provide the optimal care for their patients.

The study received no outside funding. The researchers and Dr. Chang disclosed no relevant financial relationships.

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

Approximately one-third of critical care workers reported some degree of depression, anxiety, or somatic symptoms in the early phase of the COVID-19 pandemic, based on survey results from 939 health care professionals.

The emotional response of professionals in a critical care setting in the early phase of the COVID-19 pandemic has not been well studied, Robyn Branca, PhD, and Paul Branca, MD, of Carson Newman University and the University of Tennessee Medical Center, both in Knoxville, wrote in an abstract presented at the virtual Critical Care Congress sponsored by the Society of Critical Care Medicine.

The prevalence of depression, anxiety, and somatization is low in the general population overall, but the researchers predicted that these conditions increased among workers in critical care settings early in the pandemic.

To assess the prevalence of psychological problems during that time, they sent an email survey on April 7, 2020, to members of the Society of Critical Care Medicine. The survey collected data on demographics, perceived caseload, and potential course of the pandemic. The survey also collected responses to assessments for depression (using the Patient Health Questionnaire–9), anxiety (using the Generalized Anxiety Disorder [GAD] Scale–7), and symptom somatization (using the PHQ-15).

Of the 939 survey respondents, 37% were male, 61.4% were female, and 1.4% gave another or no response.

Overall, 32.3% reported encountering 0-50 COVID-19 cases, 31.1% had encountered 51-200 cases, 12.5% had encountered 201-500 cases, 9.4% had encountered 501-1000 cases, and 13.7% had encountered more than 1,000 cases.

Based on the PHQ-9 depression scale, 44.9% of the respondents had minimal symptoms, 31.1% mild symptoms, 14.3% moderate symptoms, and 9.7% met criteria for severe depressive symptoms. Based on the GAD-7 anxiety scale, 35.5% had minimal symptoms, 32.9% mild, 16.8% moderate, and 14.8% had severe symptoms. Based on the PHQ-15 somatization scale, 39.6% of respondents showed minimal symptoms, whereas 38.2% showed mild symptoms, 17.3% moderate symptoms, and 4.9% had a severe degree of somatic symptoms.

The study findings were limited by the reliance on self-reports; however, the results indicate that a high percentage of critical care workers experienced significant, diagnosable levels of depression, anxiety, and somatic symptoms, the researchers said.

The standard guidance is to pursue individual intervention for anyone with scores of moderate or severe on the scales used in the survey, the researchers said.

Therefore, the findings represent “an alarming degree of mental health impact,” they emphasized. “Immediate mitigation efforts are needed to preserve the health of our ICU workforce.”

The study is important at this time because clinician fatigue and occupational stress are at endemic levels, Bernard Chang, MD, of Columbia University Irving Medical Center, New York City, said in an interview. “It is vital that we take stock of how frontline workers in critical care settings are doing overall,” said Dr. Chang.  

Dr. Chang, who was not involved with the study but has conducted research on mental health in frontline health care workers during the pandemic, said he was not surprised by the findings. “This work builds on the growing body of literature in the pandemic noting high levels of stress, fatigue, and depression/anxiety symptoms across many frontline workers, from emergency department staff, first responders and others. These are all data points highlighting the urgent need for a broad safety net, not only for patients but the providers serving them.”

The takeaway message: “Clinicians are often so focused on providing care for their patients that they may overlook the need to care for their own well-being and mental health,” said Dr. Chang.

As for additional research, “we need to now take this important data and build on creating and identifying tangible solutions to improve the morale of the acute care/health care workforce to ensure career longevity, professional satisfaction, and overall well-being,” Dr. Chang emphasized. Mental health and morale affect not only health care workers, but also the patients they care for. Well–cared for health care providers can be at their best to provide the optimal care for their patients.

The study received no outside funding. The researchers and Dr. Chang disclosed no relevant financial relationships.

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

Approximately one-third of critical care workers reported some degree of depression, anxiety, or somatic symptoms in the early phase of the COVID-19 pandemic, based on survey results from 939 health care professionals.

The emotional response of professionals in a critical care setting in the early phase of the COVID-19 pandemic has not been well studied, Robyn Branca, PhD, and Paul Branca, MD, of Carson Newman University and the University of Tennessee Medical Center, both in Knoxville, wrote in an abstract presented at the virtual Critical Care Congress sponsored by the Society of Critical Care Medicine.

The prevalence of depression, anxiety, and somatization is low in the general population overall, but the researchers predicted that these conditions increased among workers in critical care settings early in the pandemic.

To assess the prevalence of psychological problems during that time, they sent an email survey on April 7, 2020, to members of the Society of Critical Care Medicine. The survey collected data on demographics, perceived caseload, and potential course of the pandemic. The survey also collected responses to assessments for depression (using the Patient Health Questionnaire–9), anxiety (using the Generalized Anxiety Disorder [GAD] Scale–7), and symptom somatization (using the PHQ-15).

Of the 939 survey respondents, 37% were male, 61.4% were female, and 1.4% gave another or no response.

Overall, 32.3% reported encountering 0-50 COVID-19 cases, 31.1% had encountered 51-200 cases, 12.5% had encountered 201-500 cases, 9.4% had encountered 501-1000 cases, and 13.7% had encountered more than 1,000 cases.

Based on the PHQ-9 depression scale, 44.9% of the respondents had minimal symptoms, 31.1% mild symptoms, 14.3% moderate symptoms, and 9.7% met criteria for severe depressive symptoms. Based on the GAD-7 anxiety scale, 35.5% had minimal symptoms, 32.9% mild, 16.8% moderate, and 14.8% had severe symptoms. Based on the PHQ-15 somatization scale, 39.6% of respondents showed minimal symptoms, whereas 38.2% showed mild symptoms, 17.3% moderate symptoms, and 4.9% had a severe degree of somatic symptoms.

The study findings were limited by the reliance on self-reports; however, the results indicate that a high percentage of critical care workers experienced significant, diagnosable levels of depression, anxiety, and somatic symptoms, the researchers said.

The standard guidance is to pursue individual intervention for anyone with scores of moderate or severe on the scales used in the survey, the researchers said.

Therefore, the findings represent “an alarming degree of mental health impact,” they emphasized. “Immediate mitigation efforts are needed to preserve the health of our ICU workforce.”

The study is important at this time because clinician fatigue and occupational stress are at endemic levels, Bernard Chang, MD, of Columbia University Irving Medical Center, New York City, said in an interview. “It is vital that we take stock of how frontline workers in critical care settings are doing overall,” said Dr. Chang.  

Dr. Chang, who was not involved with the study but has conducted research on mental health in frontline health care workers during the pandemic, said he was not surprised by the findings. “This work builds on the growing body of literature in the pandemic noting high levels of stress, fatigue, and depression/anxiety symptoms across many frontline workers, from emergency department staff, first responders and others. These are all data points highlighting the urgent need for a broad safety net, not only for patients but the providers serving them.”

The takeaway message: “Clinicians are often so focused on providing care for their patients that they may overlook the need to care for their own well-being and mental health,” said Dr. Chang.

As for additional research, “we need to now take this important data and build on creating and identifying tangible solutions to improve the morale of the acute care/health care workforce to ensure career longevity, professional satisfaction, and overall well-being,” Dr. Chang emphasized. Mental health and morale affect not only health care workers, but also the patients they care for. Well–cared for health care providers can be at their best to provide the optimal care for their patients.

The study received no outside funding. The researchers and Dr. Chang disclosed no relevant financial relationships.

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

The International Cancer Benchmarking Partnership, a collaboration of physicians, clinicians, researchers, policy makers, and data experts, has reached a consensus on key actions designed to standardize and homogenize lung cancer care that includes early diagnosis and access to care for all patients.

This consensus, reported at the 2022 European Lung Cancer Congress, is an effort to address disparities in care recognized by the group’s in-house research team. The team identified significantly different survival rates in early stage lung cancer patients from a group of countries with similar health care metrics, such as health care expenditure and universal access to health care.

“This group of countries is very comparable, but we saw a 20% difference in survival in localized, stage I and II cancers. When you consider that lung cancer is a bigger killer than any other cancer –more than breast, prostate, and colon cancer combined – that’s thousands of people,” said the project’s lead clinician, Christian Finley, MD, a thoracic surgeon with St. Joseph’s Healthcare Hamilton (Ont.).

Founded in 2009, the ICBP includes about 500 experts in its core countries of Sweden, Norway, Denmark, Australia, the United Kingdom, and Canada; New Zealand and Ireland have also participated. The goal of the partnership is to benchmark survival and other outcomes in cancer and to research why disparities between countries exist.

“That’s why we keep the membership fairly small, so that we can actually make more meaningful research projects to get into depth in factors beyond benchmarking survival and mortality,” said study author Charlotte Lynch, MSc, a senior researcher with Cancer Research UK in London.

To help narrow the disparity gap, Ms. Lynch, Dr. Finley and colleagues brought together nine key informants from ICBP countries to discuss local clinical insights and best practices, and ultimately came up a list of five recommendations considered most crucial: implementing cost-effective, equitable, and effective screening; ensuring diagnoses of lung cancer within 30 days of referral; developing thoracic centers of excellence; launching an international audit of lung cancer care; and prioritizing the recognition of improvements in lung cancer care and outcomes.

They identified 13 best practice points to support the development and implementation of the calls to action.

“For example, points supporting the screening call to action focus on timely access to cross-sectional imaging and availability and development of patient and health care practitioner lung cancer awareness materials,” Ms. Lynch said.

Another example would be the point that describes the need for a minimum data set to evaluate lung cancer patients’ diagnosis, treatment, and aftercare.

“I think we all work in a very disrupted system right now. Screening programs really took a hit during the pandemic, and I think people coming out of those disruptions are trying to imagine a more effective system using tools like information technologies, mobile clinics and having a better understanding of equity,” Dr. Finley said.

Ms. Lynch said the ICBP intends to use the consensus to generate concrete actions. “We’re thinking about how we can get everyone in the room to share lessons learned and best practices to push things forward rather than saying, ‘this is what should be done,’ making sure we do the next steps, collaborative thinking, and moving forward.”

In a press release, Antonio Passaro, MD, a lung cancer expert from the European Institute of Oncology in Milan, said there is a need to prioritize primary and secondary prevention of lung cancer.

“Although a much-debated topic in recent years, a strong body of research has now shown that lung cancer screening through annual computed tomography scans in individuals with a history of smoking can improve detection rates. Targeting the right populations with these interventions will be crucial to implementing screening approaches that are both efficacious and cost effective,” he stated.

The authors declared no conflicts of interest and this study was not funded.

The International Cancer Benchmarking Partnership, a collaboration of physicians, clinicians, researchers, policy makers, and data experts, has reached a consensus on key actions designed to standardize and homogenize lung cancer care that includes early diagnosis and access to care for all patients.

This consensus, reported at the 2022 European Lung Cancer Congress, is an effort to address disparities in care recognized by the group’s in-house research team. The team identified significantly different survival rates in early stage lung cancer patients from a group of countries with similar health care metrics, such as health care expenditure and universal access to health care.

“This group of countries is very comparable, but we saw a 20% difference in survival in localized, stage I and II cancers. When you consider that lung cancer is a bigger killer than any other cancer –more than breast, prostate, and colon cancer combined – that’s thousands of people,” said the project’s lead clinician, Christian Finley, MD, a thoracic surgeon with St. Joseph’s Healthcare Hamilton (Ont.).

Founded in 2009, the ICBP includes about 500 experts in its core countries of Sweden, Norway, Denmark, Australia, the United Kingdom, and Canada; New Zealand and Ireland have also participated. The goal of the partnership is to benchmark survival and other outcomes in cancer and to research why disparities between countries exist.

“That’s why we keep the membership fairly small, so that we can actually make more meaningful research projects to get into depth in factors beyond benchmarking survival and mortality,” said study author Charlotte Lynch, MSc, a senior researcher with Cancer Research UK in London.

To help narrow the disparity gap, Ms. Lynch, Dr. Finley and colleagues brought together nine key informants from ICBP countries to discuss local clinical insights and best practices, and ultimately came up a list of five recommendations considered most crucial: implementing cost-effective, equitable, and effective screening; ensuring diagnoses of lung cancer within 30 days of referral; developing thoracic centers of excellence; launching an international audit of lung cancer care; and prioritizing the recognition of improvements in lung cancer care and outcomes.

They identified 13 best practice points to support the development and implementation of the calls to action.

“For example, points supporting the screening call to action focus on timely access to cross-sectional imaging and availability and development of patient and health care practitioner lung cancer awareness materials,” Ms. Lynch said.

Another example would be the point that describes the need for a minimum data set to evaluate lung cancer patients’ diagnosis, treatment, and aftercare.

“I think we all work in a very disrupted system right now. Screening programs really took a hit during the pandemic, and I think people coming out of those disruptions are trying to imagine a more effective system using tools like information technologies, mobile clinics and having a better understanding of equity,” Dr. Finley said.

Ms. Lynch said the ICBP intends to use the consensus to generate concrete actions. “We’re thinking about how we can get everyone in the room to share lessons learned and best practices to push things forward rather than saying, ‘this is what should be done,’ making sure we do the next steps, collaborative thinking, and moving forward.”

In a press release, Antonio Passaro, MD, a lung cancer expert from the European Institute of Oncology in Milan, said there is a need to prioritize primary and secondary prevention of lung cancer.

“Although a much-debated topic in recent years, a strong body of research has now shown that lung cancer screening through annual computed tomography scans in individuals with a history of smoking can improve detection rates. Targeting the right populations with these interventions will be crucial to implementing screening approaches that are both efficacious and cost effective,” he stated.

The authors declared no conflicts of interest and this study was not funded.

The International Cancer Benchmarking Partnership, a collaboration of physicians, clinicians, researchers, policy makers, and data experts, has reached a consensus on key actions designed to standardize and homogenize lung cancer care that includes early diagnosis and access to care for all patients.

This consensus, reported at the 2022 European Lung Cancer Congress, is an effort to address disparities in care recognized by the group’s in-house research team. The team identified significantly different survival rates in early stage lung cancer patients from a group of countries with similar health care metrics, such as health care expenditure and universal access to health care.

“This group of countries is very comparable, but we saw a 20% difference in survival in localized, stage I and II cancers. When you consider that lung cancer is a bigger killer than any other cancer –more than breast, prostate, and colon cancer combined – that’s thousands of people,” said the project’s lead clinician, Christian Finley, MD, a thoracic surgeon with St. Joseph’s Healthcare Hamilton (Ont.).

Founded in 2009, the ICBP includes about 500 experts in its core countries of Sweden, Norway, Denmark, Australia, the United Kingdom, and Canada; New Zealand and Ireland have also participated. The goal of the partnership is to benchmark survival and other outcomes in cancer and to research why disparities between countries exist.

“That’s why we keep the membership fairly small, so that we can actually make more meaningful research projects to get into depth in factors beyond benchmarking survival and mortality,” said study author Charlotte Lynch, MSc, a senior researcher with Cancer Research UK in London.

To help narrow the disparity gap, Ms. Lynch, Dr. Finley and colleagues brought together nine key informants from ICBP countries to discuss local clinical insights and best practices, and ultimately came up a list of five recommendations considered most crucial: implementing cost-effective, equitable, and effective screening; ensuring diagnoses of lung cancer within 30 days of referral; developing thoracic centers of excellence; launching an international audit of lung cancer care; and prioritizing the recognition of improvements in lung cancer care and outcomes.

They identified 13 best practice points to support the development and implementation of the calls to action.

“For example, points supporting the screening call to action focus on timely access to cross-sectional imaging and availability and development of patient and health care practitioner lung cancer awareness materials,” Ms. Lynch said.

Another example would be the point that describes the need for a minimum data set to evaluate lung cancer patients’ diagnosis, treatment, and aftercare.

“I think we all work in a very disrupted system right now. Screening programs really took a hit during the pandemic, and I think people coming out of those disruptions are trying to imagine a more effective system using tools like information technologies, mobile clinics and having a better understanding of equity,” Dr. Finley said.

Ms. Lynch said the ICBP intends to use the consensus to generate concrete actions. “We’re thinking about how we can get everyone in the room to share lessons learned and best practices to push things forward rather than saying, ‘this is what should be done,’ making sure we do the next steps, collaborative thinking, and moving forward.”

In a press release, Antonio Passaro, MD, a lung cancer expert from the European Institute of Oncology in Milan, said there is a need to prioritize primary and secondary prevention of lung cancer.

“Although a much-debated topic in recent years, a strong body of research has now shown that lung cancer screening through annual computed tomography scans in individuals with a history of smoking can improve detection rates. Targeting the right populations with these interventions will be crucial to implementing screening approaches that are both efficacious and cost effective,” he stated.

The authors declared no conflicts of interest and this study was not funded.

Despite Spain’s lack of a national project or standard protocol for biomarker testing, more than half of patients diagnosed with stage 4 non–small cell lung cancer (NSCLC) are tested for biomarkers, according to a Spanish national registry study reported at the 2022 European Lung Cancer Congress.

“In recent years we’ve developed drugs that target biomarkers, so it’s important to identify those biomarkers to guide treatment and have an impact on the survival of our patients,” said lead author Virginia Calvo, MD, a medical oncologist with the Puerta de Hierro Majadahonda University Hospital, Madrid.

“If we don’t know our patients’ biomarkers, we can’t treat them with targeted therapies,” she added, noting that the overall survival of lung cancer patients has increased by 15% in the last 10 years, largely because of better therapies such as targeted drugs for advanced stage disease and immunotherapies.

To assess the status of biomarker testing in Spain, Dr. Calvo and colleagues analyzed data from the country’s Thoracic Tumor Registry on 9,239 patients diagnosed with metastatic NSCLC from 2016 to the present, 7,467 (81%) with nonsquamous tumors and 1,772 (19%) with squamous tumors.

They found that 85% of patients with nonsquamous NSCLC and about 53% of those with squamous cancers had undergone biomarker testing. They discovered that 4,115 (44%) of patients tested positive for EGFR, ALK, KRAS, BRAF, ROS1, or PD-L1.

Dr. Calvo attributes the widespread use of biomarker testing and its significant increase in the last 5 years to the growing knowledge and understanding of the disease.

“We are learning more about NSCLC, and I think in the next few years the number of biomarkers are going to grow,” she said.

The study’s findings also highlight the importance of establishing and maintaining cancer registries, Dr. Calvo said, noting that 182 hospitals across Spain and more than 550 experts participate in the Thoracic Tumors Registry, which includes data on patients from every Spanish territory.

“It’s important to collect information on real-life cancer care so that we know what our real situation is and take steps to improve it,” she said.

She anticipates that treatment for NSCLC patients will become increasingly complex in the future with the growing number of different biomarkers and the proportion of patients who test positive for them. “We may need to establish national strategies to implement next generation sequencing so that we can identify different biomarkers and improve the survival of our patients.”

In a press release, Rolf Stahel, MD, president of the European Thoracic Oncology Platform, said that it would be helpful to look at how frequently molecular testing led to patients receiving appropriate targeted treatment.

In the United States, the National Comprehensive Cancer Network recommends biomarker testing for eligible patients with newly diagnosed stage 4 NSCLC, and it can be considered for patients with squamous histology because 5%-10% of these tumors have targetable mutations. “This is because numerous lines of evidence show that patients with stage 4 NSCLC and a targetable mutation, typically have improved overall survival when treated with a targeted therapy,” wrote the authors of the NCCN recommendations.

“For newly diagnosed stage 4 NSCLC, there is always a tension between the need to start therapy versus waiting for molecular results. This is because if a recommended targeted option is identified, it is the optimal first-line therapy. Targeted therapy cannot be given to everyone. Different biomarkers predict response to different agents. This has been well illustrated and it makes testing critically important for patients with NSCLC,” Dara Aisner, MD, PhD, associate professor of pathology with the University of Colorado at Denver, Aurora, wrote in the NCCN guideline.

The study presented at ELCC was funded by a grant from the European Union’s Horizon 2020 Research and Innovation Program. Dr. Calvo has received fees from Roche, Bristol-Myers Squibb, MSD and AstraZeneca.

Despite Spain’s lack of a national project or standard protocol for biomarker testing, more than half of patients diagnosed with stage 4 non–small cell lung cancer (NSCLC) are tested for biomarkers, according to a Spanish national registry study reported at the 2022 European Lung Cancer Congress.

“In recent years we’ve developed drugs that target biomarkers, so it’s important to identify those biomarkers to guide treatment and have an impact on the survival of our patients,” said lead author Virginia Calvo, MD, a medical oncologist with the Puerta de Hierro Majadahonda University Hospital, Madrid.

“If we don’t know our patients’ biomarkers, we can’t treat them with targeted therapies,” she added, noting that the overall survival of lung cancer patients has increased by 15% in the last 10 years, largely because of better therapies such as targeted drugs for advanced stage disease and immunotherapies.

To assess the status of biomarker testing in Spain, Dr. Calvo and colleagues analyzed data from the country’s Thoracic Tumor Registry on 9,239 patients diagnosed with metastatic NSCLC from 2016 to the present, 7,467 (81%) with nonsquamous tumors and 1,772 (19%) with squamous tumors.

They found that 85% of patients with nonsquamous NSCLC and about 53% of those with squamous cancers had undergone biomarker testing. They discovered that 4,115 (44%) of patients tested positive for EGFR, ALK, KRAS, BRAF, ROS1, or PD-L1.

Dr. Calvo attributes the widespread use of biomarker testing and its significant increase in the last 5 years to the growing knowledge and understanding of the disease.

“We are learning more about NSCLC, and I think in the next few years the number of biomarkers are going to grow,” she said.

The study’s findings also highlight the importance of establishing and maintaining cancer registries, Dr. Calvo said, noting that 182 hospitals across Spain and more than 550 experts participate in the Thoracic Tumors Registry, which includes data on patients from every Spanish territory.

“It’s important to collect information on real-life cancer care so that we know what our real situation is and take steps to improve it,” she said.

She anticipates that treatment for NSCLC patients will become increasingly complex in the future with the growing number of different biomarkers and the proportion of patients who test positive for them. “We may need to establish national strategies to implement next generation sequencing so that we can identify different biomarkers and improve the survival of our patients.”

In a press release, Rolf Stahel, MD, president of the European Thoracic Oncology Platform, said that it would be helpful to look at how frequently molecular testing led to patients receiving appropriate targeted treatment.

In the United States, the National Comprehensive Cancer Network recommends biomarker testing for eligible patients with newly diagnosed stage 4 NSCLC, and it can be considered for patients with squamous histology because 5%-10% of these tumors have targetable mutations. “This is because numerous lines of evidence show that patients with stage 4 NSCLC and a targetable mutation, typically have improved overall survival when treated with a targeted therapy,” wrote the authors of the NCCN recommendations.

“For newly diagnosed stage 4 NSCLC, there is always a tension between the need to start therapy versus waiting for molecular results. This is because if a recommended targeted option is identified, it is the optimal first-line therapy. Targeted therapy cannot be given to everyone. Different biomarkers predict response to different agents. This has been well illustrated and it makes testing critically important for patients with NSCLC,” Dara Aisner, MD, PhD, associate professor of pathology with the University of Colorado at Denver, Aurora, wrote in the NCCN guideline.

The study presented at ELCC was funded by a grant from the European Union’s Horizon 2020 Research and Innovation Program. Dr. Calvo has received fees from Roche, Bristol-Myers Squibb, MSD and AstraZeneca.

Despite Spain’s lack of a national project or standard protocol for biomarker testing, more than half of patients diagnosed with stage 4 non–small cell lung cancer (NSCLC) are tested for biomarkers, according to a Spanish national registry study reported at the 2022 European Lung Cancer Congress.

“In recent years we’ve developed drugs that target biomarkers, so it’s important to identify those biomarkers to guide treatment and have an impact on the survival of our patients,” said lead author Virginia Calvo, MD, a medical oncologist with the Puerta de Hierro Majadahonda University Hospital, Madrid.

“If we don’t know our patients’ biomarkers, we can’t treat them with targeted therapies,” she added, noting that the overall survival of lung cancer patients has increased by 15% in the last 10 years, largely because of better therapies such as targeted drugs for advanced stage disease and immunotherapies.

To assess the status of biomarker testing in Spain, Dr. Calvo and colleagues analyzed data from the country’s Thoracic Tumor Registry on 9,239 patients diagnosed with metastatic NSCLC from 2016 to the present, 7,467 (81%) with nonsquamous tumors and 1,772 (19%) with squamous tumors.

They found that 85% of patients with nonsquamous NSCLC and about 53% of those with squamous cancers had undergone biomarker testing. They discovered that 4,115 (44%) of patients tested positive for EGFR, ALK, KRAS, BRAF, ROS1, or PD-L1.

Dr. Calvo attributes the widespread use of biomarker testing and its significant increase in the last 5 years to the growing knowledge and understanding of the disease.

“We are learning more about NSCLC, and I think in the next few years the number of biomarkers are going to grow,” she said.

The study’s findings also highlight the importance of establishing and maintaining cancer registries, Dr. Calvo said, noting that 182 hospitals across Spain and more than 550 experts participate in the Thoracic Tumors Registry, which includes data on patients from every Spanish territory.

“It’s important to collect information on real-life cancer care so that we know what our real situation is and take steps to improve it,” she said.

She anticipates that treatment for NSCLC patients will become increasingly complex in the future with the growing number of different biomarkers and the proportion of patients who test positive for them. “We may need to establish national strategies to implement next generation sequencing so that we can identify different biomarkers and improve the survival of our patients.”

In a press release, Rolf Stahel, MD, president of the European Thoracic Oncology Platform, said that it would be helpful to look at how frequently molecular testing led to patients receiving appropriate targeted treatment.

In the United States, the National Comprehensive Cancer Network recommends biomarker testing for eligible patients with newly diagnosed stage 4 NSCLC, and it can be considered for patients with squamous histology because 5%-10% of these tumors have targetable mutations. “This is because numerous lines of evidence show that patients with stage 4 NSCLC and a targetable mutation, typically have improved overall survival when treated with a targeted therapy,” wrote the authors of the NCCN recommendations.

“For newly diagnosed stage 4 NSCLC, there is always a tension between the need to start therapy versus waiting for molecular results. This is because if a recommended targeted option is identified, it is the optimal first-line therapy. Targeted therapy cannot be given to everyone. Different biomarkers predict response to different agents. This has been well illustrated and it makes testing critically important for patients with NSCLC,” Dara Aisner, MD, PhD, associate professor of pathology with the University of Colorado at Denver, Aurora, wrote in the NCCN guideline.

The study presented at ELCC was funded by a grant from the European Union’s Horizon 2020 Research and Innovation Program. Dr. Calvo has received fees from Roche, Bristol-Myers Squibb, MSD and AstraZeneca.

The prevalence of exercise-induced arrhythmias in young athletes with fragmented QRS (fQRS) patterns in lead V1 was 27%, similar to that seen in adult athletes, based on data from nearly 700 individuals.

Recent data suggest that fQRS complex in lead V1 (fQRS_V1) in healthy athletes may promote arrhythmias in the context of training-induced right ventricular remodeling, but the prevalence and significance in young athletes has not been well studied, Guilia Quinto, MD, of the University of Padova (Italy) said in a presentation at the annual congress of the European Association of Preventive Cardiology.

KatarzynaBialasiewicz/Thinkstock

Dr. Quinto and colleagues assessed data from of young athletes on ventricular arrhythmias during exercise tests.

The study population included 684 young athletes with a mean age of 15 years; 64% were male. Baseline data collection included medical history, physical exam, resting ECG, standardized maximum exercise tolerance, and echocardiography evaluation.

The overall prevalence of fQRS_V1 was 27%. Individuals with fQRS_V1 were significantly less likely than those without fQRS_V1 to be female (22% vs. 43%), and to present with a lower resting heart rate (66.98 beats per minute vs. 70.08 beats per minute).

Echocardiographic data showed that individuals with fQRS_V1 had significantly different morphological and functional right ventricular characteristics.

Notably, right ventricular end-diastolic diameter was 20.42 mm/m2 among individuals with fQRS_V1 and 19.81 mm/m2 in those without, a significant difference (P = .019), Dr. Quinto said. Tricuspid annulus plain systolic excursion also differed significantly; 24.33 mm and 23.75 mm for individuals with and without fQRS_V1, respectively (P = .013).

However, the individuals with fQRS_V1 showed no increased occurrence of any type of exercise-induced arrhythmias regardless of morphology or complexity, said Dr. Quinto.

The prevalence of common and uncommon arrhythmias among individuals with and without fQRS_V1 was 31% versus 34% and 13% versus 11%, respectively; these differences were not significant.

The study findings were limited by the relatively small size, but were strengthened by the review of echocardiographic data by two independent physicians, she said.

The results show that the overall prevalence of fQRS_V1 in young athletes is comparable with patterns seen in studies of adult athletes, and no differences in exercise-induced arrhythmias occurred despite differences in right ventricular characteristics, she concluded.

Expanded insight into evaluation

The ECG pattern identified in the current study is often encountered in the evaluation of athletes, but its importance was unknown, Matthew Martinez, MD, a sports cardiologist at the Atlantic Health System in Morristown, N.J., said in an interview.

“Studies of ECG findings in athletes continues to inform us about which findings are important to evaluate. This study furthers our understanding of how to proceed,” and will serve as a guide for additional testing to reduce athlete risk, he said.

Looking ahead, “this study should guide clinicians about additional testing and evaluation when fQRS is present in adolescent athletes compared to adults,” Dr. Martinez noted. However, additional research is needed to determine which is the next best test, and whether the patient requires ongoing surveillance, or whether a single evaluation is sufficient, he said. “Further study should focus on best practices after fQRS is identified and whether outcomes can be linked to this finding.”

The study received no outside funding. Dr. Quinto and Dr. Martinez had no financial conflicts to disclose.

The prevalence of exercise-induced arrhythmias in young athletes with fragmented QRS (fQRS) patterns in lead V1 was 27%, similar to that seen in adult athletes, based on data from nearly 700 individuals.

Recent data suggest that fQRS complex in lead V1 (fQRS_V1) in healthy athletes may promote arrhythmias in the context of training-induced right ventricular remodeling, but the prevalence and significance in young athletes has not been well studied, Guilia Quinto, MD, of the University of Padova (Italy) said in a presentation at the annual congress of the European Association of Preventive Cardiology.

KatarzynaBialasiewicz/Thinkstock

Dr. Quinto and colleagues assessed data from of young athletes on ventricular arrhythmias during exercise tests.

The study population included 684 young athletes with a mean age of 15 years; 64% were male. Baseline data collection included medical history, physical exam, resting ECG, standardized maximum exercise tolerance, and echocardiography evaluation.

The overall prevalence of fQRS_V1 was 27%. Individuals with fQRS_V1 were significantly less likely than those without fQRS_V1 to be female (22% vs. 43%), and to present with a lower resting heart rate (66.98 beats per minute vs. 70.08 beats per minute).

Echocardiographic data showed that individuals with fQRS_V1 had significantly different morphological and functional right ventricular characteristics.

Notably, right ventricular end-diastolic diameter was 20.42 mm/m2 among individuals with fQRS_V1 and 19.81 mm/m2 in those without, a significant difference (P = .019), Dr. Quinto said. Tricuspid annulus plain systolic excursion also differed significantly; 24.33 mm and 23.75 mm for individuals with and without fQRS_V1, respectively (P = .013).

However, the individuals with fQRS_V1 showed no increased occurrence of any type of exercise-induced arrhythmias regardless of morphology or complexity, said Dr. Quinto.

The prevalence of common and uncommon arrhythmias among individuals with and without fQRS_V1 was 31% versus 34% and 13% versus 11%, respectively; these differences were not significant.

The study findings were limited by the relatively small size, but were strengthened by the review of echocardiographic data by two independent physicians, she said.

The results show that the overall prevalence of fQRS_V1 in young athletes is comparable with patterns seen in studies of adult athletes, and no differences in exercise-induced arrhythmias occurred despite differences in right ventricular characteristics, she concluded.

Expanded insight into evaluation

The ECG pattern identified in the current study is often encountered in the evaluation of athletes, but its importance was unknown, Matthew Martinez, MD, a sports cardiologist at the Atlantic Health System in Morristown, N.J., said in an interview.

“Studies of ECG findings in athletes continues to inform us about which findings are important to evaluate. This study furthers our understanding of how to proceed,” and will serve as a guide for additional testing to reduce athlete risk, he said.

Looking ahead, “this study should guide clinicians about additional testing and evaluation when fQRS is present in adolescent athletes compared to adults,” Dr. Martinez noted. However, additional research is needed to determine which is the next best test, and whether the patient requires ongoing surveillance, or whether a single evaluation is sufficient, he said. “Further study should focus on best practices after fQRS is identified and whether outcomes can be linked to this finding.”

The study received no outside funding. Dr. Quinto and Dr. Martinez had no financial conflicts to disclose.

The prevalence of exercise-induced arrhythmias in young athletes with fragmented QRS (fQRS) patterns in lead V1 was 27%, similar to that seen in adult athletes, based on data from nearly 700 individuals.

Recent data suggest that fQRS complex in lead V1 (fQRS_V1) in healthy athletes may promote arrhythmias in the context of training-induced right ventricular remodeling, but the prevalence and significance in young athletes has not been well studied, Guilia Quinto, MD, of the University of Padova (Italy) said in a presentation at the annual congress of the European Association of Preventive Cardiology.

KatarzynaBialasiewicz/Thinkstock

Dr. Quinto and colleagues assessed data from of young athletes on ventricular arrhythmias during exercise tests.

The study population included 684 young athletes with a mean age of 15 years; 64% were male. Baseline data collection included medical history, physical exam, resting ECG, standardized maximum exercise tolerance, and echocardiography evaluation.

The overall prevalence of fQRS_V1 was 27%. Individuals with fQRS_V1 were significantly less likely than those without fQRS_V1 to be female (22% vs. 43%), and to present with a lower resting heart rate (66.98 beats per minute vs. 70.08 beats per minute).

Echocardiographic data showed that individuals with fQRS_V1 had significantly different morphological and functional right ventricular characteristics.

Notably, right ventricular end-diastolic diameter was 20.42 mm/m2 among individuals with fQRS_V1 and 19.81 mm/m2 in those without, a significant difference (P = .019), Dr. Quinto said. Tricuspid annulus plain systolic excursion also differed significantly; 24.33 mm and 23.75 mm for individuals with and without fQRS_V1, respectively (P = .013).

However, the individuals with fQRS_V1 showed no increased occurrence of any type of exercise-induced arrhythmias regardless of morphology or complexity, said Dr. Quinto.

The prevalence of common and uncommon arrhythmias among individuals with and without fQRS_V1 was 31% versus 34% and 13% versus 11%, respectively; these differences were not significant.

The study findings were limited by the relatively small size, but were strengthened by the review of echocardiographic data by two independent physicians, she said.

The results show that the overall prevalence of fQRS_V1 in young athletes is comparable with patterns seen in studies of adult athletes, and no differences in exercise-induced arrhythmias occurred despite differences in right ventricular characteristics, she concluded.

Expanded insight into evaluation

The ECG pattern identified in the current study is often encountered in the evaluation of athletes, but its importance was unknown, Matthew Martinez, MD, a sports cardiologist at the Atlantic Health System in Morristown, N.J., said in an interview.

“Studies of ECG findings in athletes continues to inform us about which findings are important to evaluate. This study furthers our understanding of how to proceed,” and will serve as a guide for additional testing to reduce athlete risk, he said.

Looking ahead, “this study should guide clinicians about additional testing and evaluation when fQRS is present in adolescent athletes compared to adults,” Dr. Martinez noted. However, additional research is needed to determine which is the next best test, and whether the patient requires ongoing surveillance, or whether a single evaluation is sufficient, he said. “Further study should focus on best practices after fQRS is identified and whether outcomes can be linked to this finding.”

The study received no outside funding. Dr. Quinto and Dr. Martinez had no financial conflicts to disclose.

Peripheral muscle fatigue was the most common cause of exercise limitation in patients recovered from COVID-19 regardless of disease severity, in a study of nearly 300 individuals.

The source and magnitude of exercise intolerance in post–COVID-19 patients has not been well studied, said Mauricio Milani, MD, of Fitcordis Exercise Medicine Clinic, Brasilia, Brazil, in a presentation at the annual congress of the European Association of Preventive Cardiology.

Midas Anim/Shutterstock

To assess exercise intolerance, the researchers performed cardiopulmonary exercise testing (CPET) on 144 adults who had recovered from COVID-19 and 144 matched controls who had not had COVID-19. The average age of the participants was 43 years, and 57% were male. COVID-19 was defined as mild, moderate, or severe in 60%, 21%, and 19% of the cases, respectively.

Residual symptoms were present in 41% of cases. CPET was performed at roughly 14 weeks after disease onset.

Among the COVID-19 patients, most of the CPET limitations (92%) were caused by muscle fatigue; cardiovascular limitations were noted in 2%, and pulmonary limitations were noted in 6%.

Data from the post-COVID CPET showed differences in peak oxygen consumption, as well as the first and second ventilatory thresholds (VT1 and VT2) between COVID-19 patients and controls, and with lower values related to higher illness severities, Dr. Milani said. Heart rate also varied according to illness severity, with lower values significantly related to higher illness severities and significant differences between COVID patients and controls.

A total of 42 individuals with COVID-19 had previous CPET data for comparison (27 with mild disease and 15 with moderate or severe disease), Dr. Milani said. In the subgroup with mild disease, the only significant difference in CPET results before and after COVID-19 was peak speed. In the moderate/severe group, the researchers observed higher reductions in peak speed and also reductions in oxygen consumption at peak and thresholds.

However, peak oxygen flows were not different before and after COVID-19 in either the mild or moderate/severe subgroups, Dr. Milani said.

The study findings were limited in part by the relatively small study population; however, the results indicate that peripheral muscle fatigue is the primary etiology in exercise limitation in post–COVID-19 patients.

“Our data suggest that treatment should emphasize comprehensive rehabilitation programs, including aerobic and muscle strengthening components,” Dr. Milani concluded.

COVID challenges remain unclear

“After COVID, patients often display a postviral syndrome with a wide range of symptoms,” Matthew Martinez, MD, a sports cardiologist at the Atlantic Health System in Morristown, N.J., in an interview said. “These conditions frequently lead to a sense of tiredness and weakness, pain, difficulty concentrating, and headaches that linger after the viral infection has cleared,” and these symptoms may continue for weeks.

However, this scenario is not unique to COVID-19: “This study confirms the importance of muscle fatigue in recovery,” said Dr. Martinez. “Recovery from viral illness requires hydration, sleep and slow progression return to exercise.” Consequently, Dr. Martinez said he was not surprised by the current study findings.

The take-home message for clinicians is to be aware that COVID-19 can have postviral syndrome, as is common after other infections, Dr. Martinez noted. The findings provide a starting point for discussing concerns with patients and explaining that a slow return to normal with usual care is expected. “Time to recovery will vary by individual,” he said. “Additional research is needed to identify which specific therapies are most important to help reduce time to recovery, and what new therapies could be developed to help facilitate muscle fatigue recovery and reduce time needed to recover.”

The study was supported by CAPES and CNPq. Dr. Milani had no financial conflicts to disclose. Dr. Martinez had no financial conflicts to disclose.

Peripheral muscle fatigue was the most common cause of exercise limitation in patients recovered from COVID-19 regardless of disease severity, in a study of nearly 300 individuals.

The source and magnitude of exercise intolerance in post–COVID-19 patients has not been well studied, said Mauricio Milani, MD, of Fitcordis Exercise Medicine Clinic, Brasilia, Brazil, in a presentation at the annual congress of the European Association of Preventive Cardiology.

Midas Anim/Shutterstock

To assess exercise intolerance, the researchers performed cardiopulmonary exercise testing (CPET) on 144 adults who had recovered from COVID-19 and 144 matched controls who had not had COVID-19. The average age of the participants was 43 years, and 57% were male. COVID-19 was defined as mild, moderate, or severe in 60%, 21%, and 19% of the cases, respectively.

Residual symptoms were present in 41% of cases. CPET was performed at roughly 14 weeks after disease onset.

Among the COVID-19 patients, most of the CPET limitations (92%) were caused by muscle fatigue; cardiovascular limitations were noted in 2%, and pulmonary limitations were noted in 6%.

Data from the post-COVID CPET showed differences in peak oxygen consumption, as well as the first and second ventilatory thresholds (VT1 and VT2) between COVID-19 patients and controls, and with lower values related to higher illness severities, Dr. Milani said. Heart rate also varied according to illness severity, with lower values significantly related to higher illness severities and significant differences between COVID patients and controls.

A total of 42 individuals with COVID-19 had previous CPET data for comparison (27 with mild disease and 15 with moderate or severe disease), Dr. Milani said. In the subgroup with mild disease, the only significant difference in CPET results before and after COVID-19 was peak speed. In the moderate/severe group, the researchers observed higher reductions in peak speed and also reductions in oxygen consumption at peak and thresholds.

However, peak oxygen flows were not different before and after COVID-19 in either the mild or moderate/severe subgroups, Dr. Milani said.

The study findings were limited in part by the relatively small study population; however, the results indicate that peripheral muscle fatigue is the primary etiology in exercise limitation in post–COVID-19 patients.

“Our data suggest that treatment should emphasize comprehensive rehabilitation programs, including aerobic and muscle strengthening components,” Dr. Milani concluded.

COVID challenges remain unclear

“After COVID, patients often display a postviral syndrome with a wide range of symptoms,” Matthew Martinez, MD, a sports cardiologist at the Atlantic Health System in Morristown, N.J., in an interview said. “These conditions frequently lead to a sense of tiredness and weakness, pain, difficulty concentrating, and headaches that linger after the viral infection has cleared,” and these symptoms may continue for weeks.

However, this scenario is not unique to COVID-19: “This study confirms the importance of muscle fatigue in recovery,” said Dr. Martinez. “Recovery from viral illness requires hydration, sleep and slow progression return to exercise.” Consequently, Dr. Martinez said he was not surprised by the current study findings.

The take-home message for clinicians is to be aware that COVID-19 can have postviral syndrome, as is common after other infections, Dr. Martinez noted. The findings provide a starting point for discussing concerns with patients and explaining that a slow return to normal with usual care is expected. “Time to recovery will vary by individual,” he said. “Additional research is needed to identify which specific therapies are most important to help reduce time to recovery, and what new therapies could be developed to help facilitate muscle fatigue recovery and reduce time needed to recover.”

The study was supported by CAPES and CNPq. Dr. Milani had no financial conflicts to disclose. Dr. Martinez had no financial conflicts to disclose.

Peripheral muscle fatigue was the most common cause of exercise limitation in patients recovered from COVID-19 regardless of disease severity, in a study of nearly 300 individuals.

The source and magnitude of exercise intolerance in post–COVID-19 patients has not been well studied, said Mauricio Milani, MD, of Fitcordis Exercise Medicine Clinic, Brasilia, Brazil, in a presentation at the annual congress of the European Association of Preventive Cardiology.

Midas Anim/Shutterstock

To assess exercise intolerance, the researchers performed cardiopulmonary exercise testing (CPET) on 144 adults who had recovered from COVID-19 and 144 matched controls who had not had COVID-19. The average age of the participants was 43 years, and 57% were male. COVID-19 was defined as mild, moderate, or severe in 60%, 21%, and 19% of the cases, respectively.

Residual symptoms were present in 41% of cases. CPET was performed at roughly 14 weeks after disease onset.

Among the COVID-19 patients, most of the CPET limitations (92%) were caused by muscle fatigue; cardiovascular limitations were noted in 2%, and pulmonary limitations were noted in 6%.

Data from the post-COVID CPET showed differences in peak oxygen consumption, as well as the first and second ventilatory thresholds (VT1 and VT2) between COVID-19 patients and controls, and with lower values related to higher illness severities, Dr. Milani said. Heart rate also varied according to illness severity, with lower values significantly related to higher illness severities and significant differences between COVID patients and controls.

A total of 42 individuals with COVID-19 had previous CPET data for comparison (27 with mild disease and 15 with moderate or severe disease), Dr. Milani said. In the subgroup with mild disease, the only significant difference in CPET results before and after COVID-19 was peak speed. In the moderate/severe group, the researchers observed higher reductions in peak speed and also reductions in oxygen consumption at peak and thresholds.

However, peak oxygen flows were not different before and after COVID-19 in either the mild or moderate/severe subgroups, Dr. Milani said.

The study findings were limited in part by the relatively small study population; however, the results indicate that peripheral muscle fatigue is the primary etiology in exercise limitation in post–COVID-19 patients.

“Our data suggest that treatment should emphasize comprehensive rehabilitation programs, including aerobic and muscle strengthening components,” Dr. Milani concluded.

COVID challenges remain unclear

“After COVID, patients often display a postviral syndrome with a wide range of symptoms,” Matthew Martinez, MD, a sports cardiologist at the Atlantic Health System in Morristown, N.J., in an interview said. “These conditions frequently lead to a sense of tiredness and weakness, pain, difficulty concentrating, and headaches that linger after the viral infection has cleared,” and these symptoms may continue for weeks.

However, this scenario is not unique to COVID-19: “This study confirms the importance of muscle fatigue in recovery,” said Dr. Martinez. “Recovery from viral illness requires hydration, sleep and slow progression return to exercise.” Consequently, Dr. Martinez said he was not surprised by the current study findings.

The take-home message for clinicians is to be aware that COVID-19 can have postviral syndrome, as is common after other infections, Dr. Martinez noted. The findings provide a starting point for discussing concerns with patients and explaining that a slow return to normal with usual care is expected. “Time to recovery will vary by individual,” he said. “Additional research is needed to identify which specific therapies are most important to help reduce time to recovery, and what new therapies could be developed to help facilitate muscle fatigue recovery and reduce time needed to recover.”

The study was supported by CAPES and CNPq. Dr. Milani had no financial conflicts to disclose. Dr. Martinez had no financial conflicts to disclose.