Nancy A. Melville

Older men with chronic kidney disease (CKD) show higher resting muscle sympathetic nerve activity, but not vascular stiffness, compared with older women, offering clues to the underlying reasons why men with CKD have a higher cardiovascular risk than do women with the disease.

“Although it is well established that sympathetic nerve system activity is chronically elevated in patients with impaired kidney function, we show for the first time that males with CKD have higher resting muscle sympathetic nerve activity compared with females with CKD,” report the authors on research published in the American Journal of Physiology-Renal Physiology.

“For clinicians, the key takeaway is the importance of recognizing sex-specific differences in sympathetic activity and vascular function when assessing cardiovascular risk in CKD patients,” first author Matias G. Zanuzzi, MD, of the Division of Renal Medicine, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia, told this news organization.

In the general population, cardiovascular risk is lower in younger women vs men, but their risks converge in older age as women develop similar levels of sympathetic overactivity, vascular stiffness, and cardiovascular risk.

However, an exception to that pattern is seen in the CKD population, where men continue to have a higher cardiovascular mortality risk vs women even in older age.

Studies evaluating the reasons for that have been conflicting, with some reporting a tendency of higher muscle sympathetic nerve activity in older women compared with men and others suggest the opposite finding — lower activity vs men.

To further investigate, Dr. Zanuzzi and colleagues enrolled 129 participants, including 96 men and 33 women with stage III or IV CKD.

The mean age of the study participants was 64 years for men and65 years for women. Most had obesity, and importantly, more than 80% of participants in each group was Black. There were no significant differences between the groups in terms of body mass index or comorbidities, including smoking, diabetes, or hypertension.

At two separate study visits, vascular stiffness was assessed with carotid-femoral pulse wave velocity measurement, and resting muscle sympathetic nerve activity was measured using microneurography. 

The results showed that men with CKD had significantly higher resting muscle sympathetic nerve activity compared with women with CKD (68 vs 55 bursts per 100 heartbeats; P = .005), whereas no differences in vascular stiffness were observed between the genders (P = .248).

“The findings suggest that the higher cardiovascular disease risk observed in older males with CKD may be influenced by elevated sympathetic activity,” Dr. Zanuzzi explained.

“However, the lack of significant differences in vascular stiffness between genders implies that additional factors beyond vascular remodeling may contribute to the observed sex-specific differences in cardiovascular risk,” he said.

Of note, resting vascular stiffness was not associated with muscular sympathetic nerve activity in either men or women, which was surprising to the authors, Dr. Zanuzzi noted.

“This underscores the multifactorial nature of vascular pathophysiology in CKD and underscores the need for further research to unravel the underlying mechanisms.”

In other findings, although prior studies have shown a positive correlation between age and resting muscle sympathetic nerve activity in White, healthy women and men without obesity,, no similar relationship was observed in men or women with CKD.

“These findings suggest that the protective effect of younger age on sympathetic function may not be present in the setting of decreased kidney function in both males and females,” the authors note.

In addition, whereas previous research has shown a clear association between sympathetic overactivity and a wide variety of measures of obesity, in the current study, that association was only observed in men with CKD.

Important limitations of the study include the cross-sectional design and that the population was predominantly Black, Dr. Zanuzzi noted.

“Generalizability to other demographic groups may be limited, and future longitudinal studies are needed to validate these findings and explore potential causal relationships,” he said.

The findings underscore “the need for novel therapeutic approaches targeting sympathetic overactivity and vascular stiffness in CKD patients, especially considering the observed sex-specific differences,” Dr. Zanuzzi added. 

“Potential interventions may include pharmacological agents that modulate sympathetic tone or vascular remodeling pathways,” he said.

“Lifestyle modifications focusing on stress reduction and cardiovascular health promotion could also play a crucial role in mitigating cardiovascular risk.”

Dr. Zanuzzi concluded that “tailoring treatment strategies to address these differences may lead to more personalized and effective management approaches, ultimately improving clinical outcomes in this high-risk population.”

The authors had no disclosures to report.

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

Older men with chronic kidney disease (CKD) show higher resting muscle sympathetic nerve activity, but not vascular stiffness, compared with older women, offering clues to the underlying reasons why men with CKD have a higher cardiovascular risk than do women with the disease.

“Although it is well established that sympathetic nerve system activity is chronically elevated in patients with impaired kidney function, we show for the first time that males with CKD have higher resting muscle sympathetic nerve activity compared with females with CKD,” report the authors on research published in the American Journal of Physiology-Renal Physiology.

“For clinicians, the key takeaway is the importance of recognizing sex-specific differences in sympathetic activity and vascular function when assessing cardiovascular risk in CKD patients,” first author Matias G. Zanuzzi, MD, of the Division of Renal Medicine, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia, told this news organization.

In the general population, cardiovascular risk is lower in younger women vs men, but their risks converge in older age as women develop similar levels of sympathetic overactivity, vascular stiffness, and cardiovascular risk.

However, an exception to that pattern is seen in the CKD population, where men continue to have a higher cardiovascular mortality risk vs women even in older age.

Studies evaluating the reasons for that have been conflicting, with some reporting a tendency of higher muscle sympathetic nerve activity in older women compared with men and others suggest the opposite finding — lower activity vs men.

To further investigate, Dr. Zanuzzi and colleagues enrolled 129 participants, including 96 men and 33 women with stage III or IV CKD.

The mean age of the study participants was 64 years for men and65 years for women. Most had obesity, and importantly, more than 80% of participants in each group was Black. There were no significant differences between the groups in terms of body mass index or comorbidities, including smoking, diabetes, or hypertension.

At two separate study visits, vascular stiffness was assessed with carotid-femoral pulse wave velocity measurement, and resting muscle sympathetic nerve activity was measured using microneurography. 

The results showed that men with CKD had significantly higher resting muscle sympathetic nerve activity compared with women with CKD (68 vs 55 bursts per 100 heartbeats; P = .005), whereas no differences in vascular stiffness were observed between the genders (P = .248).

“The findings suggest that the higher cardiovascular disease risk observed in older males with CKD may be influenced by elevated sympathetic activity,” Dr. Zanuzzi explained.

“However, the lack of significant differences in vascular stiffness between genders implies that additional factors beyond vascular remodeling may contribute to the observed sex-specific differences in cardiovascular risk,” he said.

Of note, resting vascular stiffness was not associated with muscular sympathetic nerve activity in either men or women, which was surprising to the authors, Dr. Zanuzzi noted.

“This underscores the multifactorial nature of vascular pathophysiology in CKD and underscores the need for further research to unravel the underlying mechanisms.”

In other findings, although prior studies have shown a positive correlation between age and resting muscle sympathetic nerve activity in White, healthy women and men without obesity,, no similar relationship was observed in men or women with CKD.

“These findings suggest that the protective effect of younger age on sympathetic function may not be present in the setting of decreased kidney function in both males and females,” the authors note.

In addition, whereas previous research has shown a clear association between sympathetic overactivity and a wide variety of measures of obesity, in the current study, that association was only observed in men with CKD.

Important limitations of the study include the cross-sectional design and that the population was predominantly Black, Dr. Zanuzzi noted.

“Generalizability to other demographic groups may be limited, and future longitudinal studies are needed to validate these findings and explore potential causal relationships,” he said.

The findings underscore “the need for novel therapeutic approaches targeting sympathetic overactivity and vascular stiffness in CKD patients, especially considering the observed sex-specific differences,” Dr. Zanuzzi added. 

“Potential interventions may include pharmacological agents that modulate sympathetic tone or vascular remodeling pathways,” he said.

“Lifestyle modifications focusing on stress reduction and cardiovascular health promotion could also play a crucial role in mitigating cardiovascular risk.”

Dr. Zanuzzi concluded that “tailoring treatment strategies to address these differences may lead to more personalized and effective management approaches, ultimately improving clinical outcomes in this high-risk population.”

The authors had no disclosures to report.

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

Older men with chronic kidney disease (CKD) show higher resting muscle sympathetic nerve activity, but not vascular stiffness, compared with older women, offering clues to the underlying reasons why men with CKD have a higher cardiovascular risk than do women with the disease.

“Although it is well established that sympathetic nerve system activity is chronically elevated in patients with impaired kidney function, we show for the first time that males with CKD have higher resting muscle sympathetic nerve activity compared with females with CKD,” report the authors on research published in the American Journal of Physiology-Renal Physiology.

“For clinicians, the key takeaway is the importance of recognizing sex-specific differences in sympathetic activity and vascular function when assessing cardiovascular risk in CKD patients,” first author Matias G. Zanuzzi, MD, of the Division of Renal Medicine, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia, told this news organization.

In the general population, cardiovascular risk is lower in younger women vs men, but their risks converge in older age as women develop similar levels of sympathetic overactivity, vascular stiffness, and cardiovascular risk.

However, an exception to that pattern is seen in the CKD population, where men continue to have a higher cardiovascular mortality risk vs women even in older age.

Studies evaluating the reasons for that have been conflicting, with some reporting a tendency of higher muscle sympathetic nerve activity in older women compared with men and others suggest the opposite finding — lower activity vs men.

To further investigate, Dr. Zanuzzi and colleagues enrolled 129 participants, including 96 men and 33 women with stage III or IV CKD.

The mean age of the study participants was 64 years for men and65 years for women. Most had obesity, and importantly, more than 80% of participants in each group was Black. There were no significant differences between the groups in terms of body mass index or comorbidities, including smoking, diabetes, or hypertension.

At two separate study visits, vascular stiffness was assessed with carotid-femoral pulse wave velocity measurement, and resting muscle sympathetic nerve activity was measured using microneurography. 

The results showed that men with CKD had significantly higher resting muscle sympathetic nerve activity compared with women with CKD (68 vs 55 bursts per 100 heartbeats; P = .005), whereas no differences in vascular stiffness were observed between the genders (P = .248).

“The findings suggest that the higher cardiovascular disease risk observed in older males with CKD may be influenced by elevated sympathetic activity,” Dr. Zanuzzi explained.

“However, the lack of significant differences in vascular stiffness between genders implies that additional factors beyond vascular remodeling may contribute to the observed sex-specific differences in cardiovascular risk,” he said.

Of note, resting vascular stiffness was not associated with muscular sympathetic nerve activity in either men or women, which was surprising to the authors, Dr. Zanuzzi noted.

“This underscores the multifactorial nature of vascular pathophysiology in CKD and underscores the need for further research to unravel the underlying mechanisms.”

In other findings, although prior studies have shown a positive correlation between age and resting muscle sympathetic nerve activity in White, healthy women and men without obesity,, no similar relationship was observed in men or women with CKD.

“These findings suggest that the protective effect of younger age on sympathetic function may not be present in the setting of decreased kidney function in both males and females,” the authors note.

In addition, whereas previous research has shown a clear association between sympathetic overactivity and a wide variety of measures of obesity, in the current study, that association was only observed in men with CKD.

Important limitations of the study include the cross-sectional design and that the population was predominantly Black, Dr. Zanuzzi noted.

“Generalizability to other demographic groups may be limited, and future longitudinal studies are needed to validate these findings and explore potential causal relationships,” he said.

The findings underscore “the need for novel therapeutic approaches targeting sympathetic overactivity and vascular stiffness in CKD patients, especially considering the observed sex-specific differences,” Dr. Zanuzzi added. 

“Potential interventions may include pharmacological agents that modulate sympathetic tone or vascular remodeling pathways,” he said.

“Lifestyle modifications focusing on stress reduction and cardiovascular health promotion could also play a crucial role in mitigating cardiovascular risk.”

Dr. Zanuzzi concluded that “tailoring treatment strategies to address these differences may lead to more personalized and effective management approaches, ultimately improving clinical outcomes in this high-risk population.”

The authors had no disclosures to report.

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

Key novel genetic signatures in patients with relapsed/refractory large B-cell lymphoma (r/r LBCL) strongly correlate with improved survival outcomes in treatment with the anti-CD19 CAR T-cell therapy axicabtagene ciloleucel (axi-cel).

“Our transcriptomic analysis of ZUMA-7 dataset identified novel gene expression signatures predictive of outcome with axi-cel,” the authors reported in research presented at the annual meeting of the American Association for Cancer Research earlier in April. “These gene expression signatures could support risk-stratification of LBCL patients.”

The results are from a subanalysis of the phase 3 ZUMA-7 trial in which patients with early relapsed or primary refractory LBCL were treated with axi-cel, administered as a one-time dose in the second-line setting.

Long-term results from the trial showed a 4-year overall survival of 54.6% with axi-cel versus 46.0% with the standard of care (P = .03), with a median rate of progression-free survival of 14.7 months with axi-cel versus 3.7 months in the standard-second-line treatment.

In the study, the authors noted that, “although the use of axi-cel resulted in long-term survival in more than half of treated patients, it is important to continue to strive to improve patient outcomes.”

Following up on that, senior author Simone Filosto, of Kite, a Gilead Company, of Santa Monica, California, and colleagues launched their analysis of the genetic profiles of those who did and did not have favorable responses, using data from the ZUMA-7 trial.

Using gene expression profiling with the IO-360 Nanostring gene expression panel of 769 genes, they evaluated pretreated LBCL tumor samples from 134 of the patients treated with axi-cel.

After multivariate adjustment, the results showed that those with a distinctive 6-transcript genetic expression signature, consisting of CD19, CD45RA, CCL22, KLRK1, SOX11, and SIGLEC5, had a significantly higher rate of event-free survival (hazard ratio [HR], 0.27; P = 1.82 x 10^-8), as well as progression-free survival (HR, 0.27; P = 1.35 x 10^-7) after treatment with axi-cel, compared with those who did not have the signature.

The authors speculated that “the 6-gene expression signature may capture lymphomas with abundant adhesion molecules, a relatively low inflammation, and abundant expression of the targeted antigen (CD19).”

Conversely, the analysis showed that increased levels of an unfavorable 17-transcript gene expression signature had a strong negative correlation with event-free survival (HR, 6.19; P = 1.51 x 10^-13) and progression-free survival (HR, 7.58; P = 2.70 x 10^-14).

The 17-transcript signature included CD45RO, BCL2, IL-18R1, TNFSF4 [OX40L], KLRB1 [CD161], KIR3DL2, ITGB8, DUSP5, GPC4, PSMB5, RPS6KB1, SERPINA9, NBN, GLUD1, ESR1, ARID1A, and SLC16A1.

“The 17-gene expression signature is consistent with a high level of immune infiltration and inflammation paralleled by the activation of immune-escape mechanisms, such as the upregulation of anti-apoptotic genes,” the authors explain.

Of note, the 17-gene expression signature was elevated among 18 patients who progressed after axi-cel treatment.

Importantly, the gene expression signatures were not associated with outcomes observed among patients receiving second-line standard of care in the ZUMA-7 trial. And the signatures also did not correspond with outcomes following first-line R-CHOP chemotherapy reported in two online datasets, indicating their predictive rather than prognostic value.

Commenting on the findings, Marco Ruella, MD, noted that “stratifying the [CAR T-treated] patients is extremely important given that only a subset of them, 30%-40%, will experience long-term remission.”

“In an ideal scenario, we would want to treat only the patients who would benefit from such a complex and expensive therapy,” underscored Dr. Ruella, assistant professor in the Division of Hematology/Oncology and the Center for Cellular Immunotherapies and Scientific Director of the Lymphoma Program at the Hospital of the University of Pennsylvania in Philadelphia.

A key caveat is that the results need more validation before they true gain clinical value, he noted.

“We need more data before we can use such a score in the clinic as we would need to be absolutely confident on the predictive value of such a score in additional confirmatory cohorts.”

Furthermore, caution is warranted in avoiding excluding any patients unnecessarily, he added.

“Only if there are approximately zero chances of response would we be able to exclude a patient from a treatment,” Dr. Ruella noted. “If the chance of long-term cure are minimal but still present, it might still make sense for the patient.” 

Nevertheless, such findings advance the understanding of the therapy’s implication in a meaningful way, he said.

“I think this study [and similar others] are important studies that help us better understand the mechanisms of relapse,” he said.

“Translationally, we are getting closer to reaching a point where we can precisely predict outcomes and, perhaps in the future, select the patients that would benefit the most from these treatments.”

Dr. Filosto and other authors are employees of Kite, which manufactures axi-cel. Dr. Ruella treats patients with CAR T products that have been licensed to Novartis, Kite, and Vittoria Bio.

Key novel genetic signatures in patients with relapsed/refractory large B-cell lymphoma (r/r LBCL) strongly correlate with improved survival outcomes in treatment with the anti-CD19 CAR T-cell therapy axicabtagene ciloleucel (axi-cel).

“Our transcriptomic analysis of ZUMA-7 dataset identified novel gene expression signatures predictive of outcome with axi-cel,” the authors reported in research presented at the annual meeting of the American Association for Cancer Research earlier in April. “These gene expression signatures could support risk-stratification of LBCL patients.”

The results are from a subanalysis of the phase 3 ZUMA-7 trial in which patients with early relapsed or primary refractory LBCL were treated with axi-cel, administered as a one-time dose in the second-line setting.

Long-term results from the trial showed a 4-year overall survival of 54.6% with axi-cel versus 46.0% with the standard of care (P = .03), with a median rate of progression-free survival of 14.7 months with axi-cel versus 3.7 months in the standard-second-line treatment.

In the study, the authors noted that, “although the use of axi-cel resulted in long-term survival in more than half of treated patients, it is important to continue to strive to improve patient outcomes.”

Following up on that, senior author Simone Filosto, of Kite, a Gilead Company, of Santa Monica, California, and colleagues launched their analysis of the genetic profiles of those who did and did not have favorable responses, using data from the ZUMA-7 trial.

Using gene expression profiling with the IO-360 Nanostring gene expression panel of 769 genes, they evaluated pretreated LBCL tumor samples from 134 of the patients treated with axi-cel.

After multivariate adjustment, the results showed that those with a distinctive 6-transcript genetic expression signature, consisting of CD19, CD45RA, CCL22, KLRK1, SOX11, and SIGLEC5, had a significantly higher rate of event-free survival (hazard ratio [HR], 0.27; P = 1.82 x 10^-8), as well as progression-free survival (HR, 0.27; P = 1.35 x 10^-7) after treatment with axi-cel, compared with those who did not have the signature.

The authors speculated that “the 6-gene expression signature may capture lymphomas with abundant adhesion molecules, a relatively low inflammation, and abundant expression of the targeted antigen (CD19).”

Conversely, the analysis showed that increased levels of an unfavorable 17-transcript gene expression signature had a strong negative correlation with event-free survival (HR, 6.19; P = 1.51 x 10^-13) and progression-free survival (HR, 7.58; P = 2.70 x 10^-14).

The 17-transcript signature included CD45RO, BCL2, IL-18R1, TNFSF4 [OX40L], KLRB1 [CD161], KIR3DL2, ITGB8, DUSP5, GPC4, PSMB5, RPS6KB1, SERPINA9, NBN, GLUD1, ESR1, ARID1A, and SLC16A1.

“The 17-gene expression signature is consistent with a high level of immune infiltration and inflammation paralleled by the activation of immune-escape mechanisms, such as the upregulation of anti-apoptotic genes,” the authors explain.

Of note, the 17-gene expression signature was elevated among 18 patients who progressed after axi-cel treatment.

Importantly, the gene expression signatures were not associated with outcomes observed among patients receiving second-line standard of care in the ZUMA-7 trial. And the signatures also did not correspond with outcomes following first-line R-CHOP chemotherapy reported in two online datasets, indicating their predictive rather than prognostic value.

Commenting on the findings, Marco Ruella, MD, noted that “stratifying the [CAR T-treated] patients is extremely important given that only a subset of them, 30%-40%, will experience long-term remission.”

“In an ideal scenario, we would want to treat only the patients who would benefit from such a complex and expensive therapy,” underscored Dr. Ruella, assistant professor in the Division of Hematology/Oncology and the Center for Cellular Immunotherapies and Scientific Director of the Lymphoma Program at the Hospital of the University of Pennsylvania in Philadelphia.

A key caveat is that the results need more validation before they true gain clinical value, he noted.

“We need more data before we can use such a score in the clinic as we would need to be absolutely confident on the predictive value of such a score in additional confirmatory cohorts.”

Furthermore, caution is warranted in avoiding excluding any patients unnecessarily, he added.

“Only if there are approximately zero chances of response would we be able to exclude a patient from a treatment,” Dr. Ruella noted. “If the chance of long-term cure are minimal but still present, it might still make sense for the patient.” 

Nevertheless, such findings advance the understanding of the therapy’s implication in a meaningful way, he said.

“I think this study [and similar others] are important studies that help us better understand the mechanisms of relapse,” he said.

“Translationally, we are getting closer to reaching a point where we can precisely predict outcomes and, perhaps in the future, select the patients that would benefit the most from these treatments.”

Dr. Filosto and other authors are employees of Kite, which manufactures axi-cel. Dr. Ruella treats patients with CAR T products that have been licensed to Novartis, Kite, and Vittoria Bio.

Key novel genetic signatures in patients with relapsed/refractory large B-cell lymphoma (r/r LBCL) strongly correlate with improved survival outcomes in treatment with the anti-CD19 CAR T-cell therapy axicabtagene ciloleucel (axi-cel).

“Our transcriptomic analysis of ZUMA-7 dataset identified novel gene expression signatures predictive of outcome with axi-cel,” the authors reported in research presented at the annual meeting of the American Association for Cancer Research earlier in April. “These gene expression signatures could support risk-stratification of LBCL patients.”

The results are from a subanalysis of the phase 3 ZUMA-7 trial in which patients with early relapsed or primary refractory LBCL were treated with axi-cel, administered as a one-time dose in the second-line setting.

Long-term results from the trial showed a 4-year overall survival of 54.6% with axi-cel versus 46.0% with the standard of care (P = .03), with a median rate of progression-free survival of 14.7 months with axi-cel versus 3.7 months in the standard-second-line treatment.

In the study, the authors noted that, “although the use of axi-cel resulted in long-term survival in more than half of treated patients, it is important to continue to strive to improve patient outcomes.”

Following up on that, senior author Simone Filosto, of Kite, a Gilead Company, of Santa Monica, California, and colleagues launched their analysis of the genetic profiles of those who did and did not have favorable responses, using data from the ZUMA-7 trial.

Using gene expression profiling with the IO-360 Nanostring gene expression panel of 769 genes, they evaluated pretreated LBCL tumor samples from 134 of the patients treated with axi-cel.

After multivariate adjustment, the results showed that those with a distinctive 6-transcript genetic expression signature, consisting of CD19, CD45RA, CCL22, KLRK1, SOX11, and SIGLEC5, had a significantly higher rate of event-free survival (hazard ratio [HR], 0.27; P = 1.82 x 10^-8), as well as progression-free survival (HR, 0.27; P = 1.35 x 10^-7) after treatment with axi-cel, compared with those who did not have the signature.

The authors speculated that “the 6-gene expression signature may capture lymphomas with abundant adhesion molecules, a relatively low inflammation, and abundant expression of the targeted antigen (CD19).”

Conversely, the analysis showed that increased levels of an unfavorable 17-transcript gene expression signature had a strong negative correlation with event-free survival (HR, 6.19; P = 1.51 x 10^-13) and progression-free survival (HR, 7.58; P = 2.70 x 10^-14).

The 17-transcript signature included CD45RO, BCL2, IL-18R1, TNFSF4 [OX40L], KLRB1 [CD161], KIR3DL2, ITGB8, DUSP5, GPC4, PSMB5, RPS6KB1, SERPINA9, NBN, GLUD1, ESR1, ARID1A, and SLC16A1.

“The 17-gene expression signature is consistent with a high level of immune infiltration and inflammation paralleled by the activation of immune-escape mechanisms, such as the upregulation of anti-apoptotic genes,” the authors explain.

Of note, the 17-gene expression signature was elevated among 18 patients who progressed after axi-cel treatment.

Importantly, the gene expression signatures were not associated with outcomes observed among patients receiving second-line standard of care in the ZUMA-7 trial. And the signatures also did not correspond with outcomes following first-line R-CHOP chemotherapy reported in two online datasets, indicating their predictive rather than prognostic value.

Commenting on the findings, Marco Ruella, MD, noted that “stratifying the [CAR T-treated] patients is extremely important given that only a subset of them, 30%-40%, will experience long-term remission.”

“In an ideal scenario, we would want to treat only the patients who would benefit from such a complex and expensive therapy,” underscored Dr. Ruella, assistant professor in the Division of Hematology/Oncology and the Center for Cellular Immunotherapies and Scientific Director of the Lymphoma Program at the Hospital of the University of Pennsylvania in Philadelphia.

A key caveat is that the results need more validation before they true gain clinical value, he noted.

“We need more data before we can use such a score in the clinic as we would need to be absolutely confident on the predictive value of such a score in additional confirmatory cohorts.”

Furthermore, caution is warranted in avoiding excluding any patients unnecessarily, he added.

“Only if there are approximately zero chances of response would we be able to exclude a patient from a treatment,” Dr. Ruella noted. “If the chance of long-term cure are minimal but still present, it might still make sense for the patient.” 

Nevertheless, such findings advance the understanding of the therapy’s implication in a meaningful way, he said.

“I think this study [and similar others] are important studies that help us better understand the mechanisms of relapse,” he said.

“Translationally, we are getting closer to reaching a point where we can precisely predict outcomes and, perhaps in the future, select the patients that would benefit the most from these treatments.”

Dr. Filosto and other authors are employees of Kite, which manufactures axi-cel. Dr. Ruella treats patients with CAR T products that have been licensed to Novartis, Kite, and Vittoria Bio.

A novel CD19 chimeric antigen responder (CAR) T-cell therapy administered in exceptionally low doses and designed to reinvigorate exhausted T-cells shows impressive early results in the treatment of patients with relapsed or refractory (r/r) diffuse large B-cell lymphoma (DLBCL) and B-cell acute lymphoblastic leukemia (B-ALL).

“Our study showed a manageable safety profile in r/r DLBCL/B-ALL, with promising breakthrough efficacy of a 100% complete remission in all dose groups,” said first author Jingjing Ren, MD, PhD, associate director of research and development with Leman Biotech in Shenzhen, China. Dr. Ren presented these findings at the American Association for Cancer Research annual meeting held in San Diego.

While CD19 CAR T-cell therapy has been transformative in the treatment of relapsed B -cell hematological malignancies in recent years, more than half of patients relapse within a year because of inadequate CAR T persistence.

To address the problem, Dr. Ren and her colleagues developed a metabolically armed, interleukin (IL)-10-expressing CAR T-cell product called Meta10-19 for the treatment patients with r/r DLBCL or r/r B-ALL.

According to the authors, the IL-10-expressing CAR T-cells trigger “stem-like memory responses” in various lymphoid organs, which prompt a “robust tumor eradication and durable protection,” and hence, better persistence.

Preclinical studies in mice showed the Meta10-19 CAR T-cells exhibited substantially higher expansion of approximately 100-fold compared with a control CD19 CAR-T product.

Therefore, “we dramatically reduced the dose to approximately 1% to 5% of commercial products for the IL-10-expressing CD19 CAR-T for patients,” coauthor Yugang Guo, PhD, cofounder and president of Leman Biotech said in an interview.

For the ongoing, open-label clinical trial, 12 adult patients with r/r DLBCL or r/r B-ALL and confirmed CD19 expression at a hospital center in China were enrolled between December 2022 and November 2023 and treated in three cohorts, receiving doses that corresponded to 1%, 2.5%, or 5% of the doses of other commercialized CAR-T infusion products.

All patients also underwent lympho-depleting chemotherapy with cyclophosphamide and fludarabine prior to the CAR T-cell infusion.

Six patients had r/r DLBCL and the other six had r/r B-ALL; their median age was 47 and their median time since diagnosis was 1 year.

In the single-arm, intent-to-treat analysis, the treatment induced a complete remission in all 12 patients, as evaluated by PET-CT scan, nuclear magnetic resonance (NMR) spectroscopy, or minimal residual disease assessment of bone marrow.

The median time to best response was 1 month (range 0.5 to 2.2 months).

There were no cases of severe cytokine storm syndrome or neurotoxicity, which are among key limitations with current commercial CAR-T products.

All of the patients continued to have a complete remission at 3 months. Two of the 12 patients, both with B-ALL, experienced relapses, one after 4.7 months and the other at 8 months.

The authors reported that the first treated patient had maintained continuous remission as of 9 months.

In comparison with the much higher full doses of commercial CD19 CAR-T products, only about 50% of patients with DLBCL and 70% of B-ALL patients have been shown to achieve CR at 3 months, the authors reported.

“Our IL-10 expressing CAR-T sustains CR at 3 months post infusion in the context of not following allogeneic hematopoietic stem cell transplant, which suggests IL-10 expressing CAR-T is more resistant to relapse,” Dr. Guo said.

In terms of safety, six patients with DLBCL and four with B-ALL experienced grade 1 cytokine release syndrome (CRS), and two patients with B-ALL developed grade 2 CRS. There were no grade 3 or 4 CRS cases.

One patient with B-ALL developed grade 3 ICANS.

Grade 3-4 cytopenias occurred in most patients, but all were limited to no later than 90 days.

“We observed reduced CRS, with no level 3 or 4, or ICANS,” Dr. Guo said. “There was increased cytopenia, but still manageable, compared with commercial products.”

Of note, the Meta10-19 cells showed efficacy in the extremely low infusion doses even among patients with bulky mass (≥ 7.5 cm) of DLBCL, which is associated with an increased risk of relapse.

One patient had primary central nervous system lymphoma (PCNSL), a rare form of DLBCL that is known to have the worst prognosis of all non-Hodgkin lymphomas.

Due to the unique nature of CNS primary tumors, the CAR T-cell infusion dose was further reduced to 1% of the standard dose for the patient.

The patient maintained complete remission for more than 8 months before relapsing in periphery blood, but not in the CNS, Dr. Guo noted.

“Luckily, this relapse has been easily controlled by chemotherapy, and the patient is maintaining complete remission again now,” Dr. Guo said.
 

Mechanisms?

Dr. Guo noted that the mechanism believed to explain the improvements despite such low doses is that “IL-10-expressing CAR-T exhibits enhanced proliferation, cytotoxicity, and stem-like antitumor memory due to enhanced metabolic activities of oxidative phosphorylation.”

The authors noted that a key major factor limiting accessibility to CAR-T therapies is the lengthy production cycle and high costs; however, the “extremely low doses of 1% to 5% can significantly reduce the production cycle and cost of CAR T-cell therapies, increasing accessibility,” they wrote in a press statement.

Currently, more than 20 patients have achieved a CR overall, and studies with a larger cohort and longer follow-up are ongoing, Dr. Guo reported.

The research team plans to launch further clinical investigation this year into patients with solid tumors.

Commenting on the study, Hongbo Chi, PhD, the Robert G. Webster Endowed Chair in Immunology at St. Jude Children’s Research Hospital in Memphis, Tennessee, noted that, based on the abstract, “the effects are quite remarkable, considering the therapeutic efficacy observed even at the low dose.

“Results from more patients are needed to fully validate these findings, but the results to date are very encouraging,” he said.

The study was sponsored by Leman Biotech. Dr. Chi had no disclosures to report.

A novel CD19 chimeric antigen responder (CAR) T-cell therapy administered in exceptionally low doses and designed to reinvigorate exhausted T-cells shows impressive early results in the treatment of patients with relapsed or refractory (r/r) diffuse large B-cell lymphoma (DLBCL) and B-cell acute lymphoblastic leukemia (B-ALL).

“Our study showed a manageable safety profile in r/r DLBCL/B-ALL, with promising breakthrough efficacy of a 100% complete remission in all dose groups,” said first author Jingjing Ren, MD, PhD, associate director of research and development with Leman Biotech in Shenzhen, China. Dr. Ren presented these findings at the American Association for Cancer Research annual meeting held in San Diego.

While CD19 CAR T-cell therapy has been transformative in the treatment of relapsed B -cell hematological malignancies in recent years, more than half of patients relapse within a year because of inadequate CAR T persistence.

To address the problem, Dr. Ren and her colleagues developed a metabolically armed, interleukin (IL)-10-expressing CAR T-cell product called Meta10-19 for the treatment patients with r/r DLBCL or r/r B-ALL.

According to the authors, the IL-10-expressing CAR T-cells trigger “stem-like memory responses” in various lymphoid organs, which prompt a “robust tumor eradication and durable protection,” and hence, better persistence.

Preclinical studies in mice showed the Meta10-19 CAR T-cells exhibited substantially higher expansion of approximately 100-fold compared with a control CD19 CAR-T product.

Therefore, “we dramatically reduced the dose to approximately 1% to 5% of commercial products for the IL-10-expressing CD19 CAR-T for patients,” coauthor Yugang Guo, PhD, cofounder and president of Leman Biotech said in an interview.

For the ongoing, open-label clinical trial, 12 adult patients with r/r DLBCL or r/r B-ALL and confirmed CD19 expression at a hospital center in China were enrolled between December 2022 and November 2023 and treated in three cohorts, receiving doses that corresponded to 1%, 2.5%, or 5% of the doses of other commercialized CAR-T infusion products.

All patients also underwent lympho-depleting chemotherapy with cyclophosphamide and fludarabine prior to the CAR T-cell infusion.

Six patients had r/r DLBCL and the other six had r/r B-ALL; their median age was 47 and their median time since diagnosis was 1 year.

In the single-arm, intent-to-treat analysis, the treatment induced a complete remission in all 12 patients, as evaluated by PET-CT scan, nuclear magnetic resonance (NMR) spectroscopy, or minimal residual disease assessment of bone marrow.

The median time to best response was 1 month (range 0.5 to 2.2 months).

There were no cases of severe cytokine storm syndrome or neurotoxicity, which are among key limitations with current commercial CAR-T products.

All of the patients continued to have a complete remission at 3 months. Two of the 12 patients, both with B-ALL, experienced relapses, one after 4.7 months and the other at 8 months.

The authors reported that the first treated patient had maintained continuous remission as of 9 months.

In comparison with the much higher full doses of commercial CD19 CAR-T products, only about 50% of patients with DLBCL and 70% of B-ALL patients have been shown to achieve CR at 3 months, the authors reported.

“Our IL-10 expressing CAR-T sustains CR at 3 months post infusion in the context of not following allogeneic hematopoietic stem cell transplant, which suggests IL-10 expressing CAR-T is more resistant to relapse,” Dr. Guo said.

In terms of safety, six patients with DLBCL and four with B-ALL experienced grade 1 cytokine release syndrome (CRS), and two patients with B-ALL developed grade 2 CRS. There were no grade 3 or 4 CRS cases.

One patient with B-ALL developed grade 3 ICANS.

Grade 3-4 cytopenias occurred in most patients, but all were limited to no later than 90 days.

“We observed reduced CRS, with no level 3 or 4, or ICANS,” Dr. Guo said. “There was increased cytopenia, but still manageable, compared with commercial products.”

Of note, the Meta10-19 cells showed efficacy in the extremely low infusion doses even among patients with bulky mass (≥ 7.5 cm) of DLBCL, which is associated with an increased risk of relapse.

One patient had primary central nervous system lymphoma (PCNSL), a rare form of DLBCL that is known to have the worst prognosis of all non-Hodgkin lymphomas.

Due to the unique nature of CNS primary tumors, the CAR T-cell infusion dose was further reduced to 1% of the standard dose for the patient.

The patient maintained complete remission for more than 8 months before relapsing in periphery blood, but not in the CNS, Dr. Guo noted.

“Luckily, this relapse has been easily controlled by chemotherapy, and the patient is maintaining complete remission again now,” Dr. Guo said.
 

Mechanisms?

Dr. Guo noted that the mechanism believed to explain the improvements despite such low doses is that “IL-10-expressing CAR-T exhibits enhanced proliferation, cytotoxicity, and stem-like antitumor memory due to enhanced metabolic activities of oxidative phosphorylation.”

The authors noted that a key major factor limiting accessibility to CAR-T therapies is the lengthy production cycle and high costs; however, the “extremely low doses of 1% to 5% can significantly reduce the production cycle and cost of CAR T-cell therapies, increasing accessibility,” they wrote in a press statement.

Currently, more than 20 patients have achieved a CR overall, and studies with a larger cohort and longer follow-up are ongoing, Dr. Guo reported.

The research team plans to launch further clinical investigation this year into patients with solid tumors.

Commenting on the study, Hongbo Chi, PhD, the Robert G. Webster Endowed Chair in Immunology at St. Jude Children’s Research Hospital in Memphis, Tennessee, noted that, based on the abstract, “the effects are quite remarkable, considering the therapeutic efficacy observed even at the low dose.

“Results from more patients are needed to fully validate these findings, but the results to date are very encouraging,” he said.

The study was sponsored by Leman Biotech. Dr. Chi had no disclosures to report.

A novel CD19 chimeric antigen responder (CAR) T-cell therapy administered in exceptionally low doses and designed to reinvigorate exhausted T-cells shows impressive early results in the treatment of patients with relapsed or refractory (r/r) diffuse large B-cell lymphoma (DLBCL) and B-cell acute lymphoblastic leukemia (B-ALL).

“Our study showed a manageable safety profile in r/r DLBCL/B-ALL, with promising breakthrough efficacy of a 100% complete remission in all dose groups,” said first author Jingjing Ren, MD, PhD, associate director of research and development with Leman Biotech in Shenzhen, China. Dr. Ren presented these findings at the American Association for Cancer Research annual meeting held in San Diego.

While CD19 CAR T-cell therapy has been transformative in the treatment of relapsed B -cell hematological malignancies in recent years, more than half of patients relapse within a year because of inadequate CAR T persistence.

To address the problem, Dr. Ren and her colleagues developed a metabolically armed, interleukin (IL)-10-expressing CAR T-cell product called Meta10-19 for the treatment patients with r/r DLBCL or r/r B-ALL.

According to the authors, the IL-10-expressing CAR T-cells trigger “stem-like memory responses” in various lymphoid organs, which prompt a “robust tumor eradication and durable protection,” and hence, better persistence.

Preclinical studies in mice showed the Meta10-19 CAR T-cells exhibited substantially higher expansion of approximately 100-fold compared with a control CD19 CAR-T product.

Therefore, “we dramatically reduced the dose to approximately 1% to 5% of commercial products for the IL-10-expressing CD19 CAR-T for patients,” coauthor Yugang Guo, PhD, cofounder and president of Leman Biotech said in an interview.

For the ongoing, open-label clinical trial, 12 adult patients with r/r DLBCL or r/r B-ALL and confirmed CD19 expression at a hospital center in China were enrolled between December 2022 and November 2023 and treated in three cohorts, receiving doses that corresponded to 1%, 2.5%, or 5% of the doses of other commercialized CAR-T infusion products.

All patients also underwent lympho-depleting chemotherapy with cyclophosphamide and fludarabine prior to the CAR T-cell infusion.

Six patients had r/r DLBCL and the other six had r/r B-ALL; their median age was 47 and their median time since diagnosis was 1 year.

In the single-arm, intent-to-treat analysis, the treatment induced a complete remission in all 12 patients, as evaluated by PET-CT scan, nuclear magnetic resonance (NMR) spectroscopy, or minimal residual disease assessment of bone marrow.

The median time to best response was 1 month (range 0.5 to 2.2 months).

There were no cases of severe cytokine storm syndrome or neurotoxicity, which are among key limitations with current commercial CAR-T products.

All of the patients continued to have a complete remission at 3 months. Two of the 12 patients, both with B-ALL, experienced relapses, one after 4.7 months and the other at 8 months.

The authors reported that the first treated patient had maintained continuous remission as of 9 months.

In comparison with the much higher full doses of commercial CD19 CAR-T products, only about 50% of patients with DLBCL and 70% of B-ALL patients have been shown to achieve CR at 3 months, the authors reported.

“Our IL-10 expressing CAR-T sustains CR at 3 months post infusion in the context of not following allogeneic hematopoietic stem cell transplant, which suggests IL-10 expressing CAR-T is more resistant to relapse,” Dr. Guo said.

In terms of safety, six patients with DLBCL and four with B-ALL experienced grade 1 cytokine release syndrome (CRS), and two patients with B-ALL developed grade 2 CRS. There were no grade 3 or 4 CRS cases.

One patient with B-ALL developed grade 3 ICANS.

Grade 3-4 cytopenias occurred in most patients, but all were limited to no later than 90 days.

“We observed reduced CRS, with no level 3 or 4, or ICANS,” Dr. Guo said. “There was increased cytopenia, but still manageable, compared with commercial products.”

Of note, the Meta10-19 cells showed efficacy in the extremely low infusion doses even among patients with bulky mass (≥ 7.5 cm) of DLBCL, which is associated with an increased risk of relapse.

One patient had primary central nervous system lymphoma (PCNSL), a rare form of DLBCL that is known to have the worst prognosis of all non-Hodgkin lymphomas.

Due to the unique nature of CNS primary tumors, the CAR T-cell infusion dose was further reduced to 1% of the standard dose for the patient.

The patient maintained complete remission for more than 8 months before relapsing in periphery blood, but not in the CNS, Dr. Guo noted.

“Luckily, this relapse has been easily controlled by chemotherapy, and the patient is maintaining complete remission again now,” Dr. Guo said.
 

Mechanisms?

Dr. Guo noted that the mechanism believed to explain the improvements despite such low doses is that “IL-10-expressing CAR-T exhibits enhanced proliferation, cytotoxicity, and stem-like antitumor memory due to enhanced metabolic activities of oxidative phosphorylation.”

The authors noted that a key major factor limiting accessibility to CAR-T therapies is the lengthy production cycle and high costs; however, the “extremely low doses of 1% to 5% can significantly reduce the production cycle and cost of CAR T-cell therapies, increasing accessibility,” they wrote in a press statement.

Currently, more than 20 patients have achieved a CR overall, and studies with a larger cohort and longer follow-up are ongoing, Dr. Guo reported.

The research team plans to launch further clinical investigation this year into patients with solid tumors.

Commenting on the study, Hongbo Chi, PhD, the Robert G. Webster Endowed Chair in Immunology at St. Jude Children’s Research Hospital in Memphis, Tennessee, noted that, based on the abstract, “the effects are quite remarkable, considering the therapeutic efficacy observed even at the low dose.

“Results from more patients are needed to fully validate these findings, but the results to date are very encouraging,” he said.

The study was sponsored by Leman Biotech. Dr. Chi had no disclosures to report.

Early data suggested that several new multicancer early detection (MCED) tests in development show promise for identifying cancers that lack routine screening options.

Analyses presented during a session at the American Association for Cancer Research annual meeting, revealed that three new MCED tests — CanScan, MERCURY, and OncoSeek — could detect a range of cancers and recognize the tissue of origin with high accuracy. One — OncoSeek — could also provide an affordable cancer screening option for individuals living in lower-income countries.

The need for these noninvasive liquid biopsy tests that can accurately identify multiple cancer types with a single blood draw, especially cancers without routine screening strategies, is pressing. “We know that the current cancer standard of care screening will identify less than 50% of all cancers, while more than 50% of all cancer deaths occur in types of cancer with no recommended screening,” said co-moderator Marie E. Wood, MD, of the University of Colorado Anschutz Medical Campus, in Aurora, Colorado.

That being said, “the clinical utility of multicancer detection tests has not been established and we’re concerned about issues of overdiagnosis and overtreatment,” she noted.

The Early Data 

One new MCED test called CanScan, developed by Geneseeq Technology, uses plasma cell-free DNA fragment patterns to detect cancer signals as well as identify the tissue of origin across 13 cancer types.

Overall, the CanScan test covers cancer types that contribute to two thirds of new cancer cases and 74% of morality globally, said presenter Shanshan Yang, of Geneseeq Research Institute, in Nanjing, China.

However, only five of these cancer types have screening recommendations issued by the US Preventive Services Task Force (USPSTF), Dr. Yang added.

The interim data comes from an ongoing large-scale prospective study evaluating the MCED test in a cohort of asymptomatic individuals between ages 45 and 75 years with an average risk for cancer and no cancer-related symptoms on enrollment.

Patients at baseline had their blood collected for the CanScan test and subsequently received annual routine physical exams once a year for 3 consecutive years, with an additional 2 years of follow-up. 

The analysis included 3724 participants with analyzable samples at the data cutoff in September 2023. Among the 3724 participants, 29 had confirmed cancer diagnoses. Among these cases, 14 patients had their cancer confirmed through USPSTF recommended screening and 15 were detected through outside of standard USPSTF screening, such as a thyroid ultrasound, Dr. Yang explained.

Almost 90% of the cancers (26 of 29) were detected in the stage I or II, and eight (27.5%) were not one of the test’s 13 targeted cancer types.

The CanScan test had a sensitivity of 55.2%, identifying 16 of 29 of the patients with cancer, including 10 of 21 individuals with stage I (47.6%), and two of three with stage II (66.7%). 

The test had a high specificity of 97.9%, meaning out of 100 people screened, only two had false negative findings.

Among the 15 patients who had their cancer detected outside of USPSTF screening recommendations, eight (53.3%) were found using a CanScan test, including patients with liver and endometrial cancers.

Compared with a positive predictive value of (PPV) of 1.6% with screening or physical exam methods alone, the CanScan test had a PPV of 17.4%, Dr. Yang reported. 

“The MCED test holds significant potential for early cancer screening in asymptomatic populations,” Dr. Yang and colleagues concluded.

Another new MCED test called MERCURY, also developed by Geneseeq Technology and presented during the session, used a similar method to detect cancer signals and predict the tissue of origin across 13 cancer types.

The researchers initially validated the test using 3076 patients with cancer and 3477 healthy controls with a target specificity of 99%. In this group, researchers reported a sensitivity of 0.865 and a specificity of 0.989.

The team then performed an independent validation analysis with 1465 participants, 732 with cancer and 733 with no cancer, and confirmed a high sensitivity and specificity of 0.874 and 0.978, respectively. The sensitivity increased incrementally by cancer stage — 0.768 for stage I, 0.840 for stage II, 0.923 for stage III, and 0.971 for stage IV.

The test identified the tissue of origin with high accuracy, the researchers noted, but cautioned that the test needs “to be further validated in a prospective cohort study.”

MCED in Low-Income Settings

The session also featured findings on a new affordable MCED test called OncoSeek, which could provide greater access to cancer testing in low- and middle-income countries.

The OncoSeek algorithm identifies the presence of cancer using seven protein tumor markers alongside clinical information, such as gender and age. Like other tests, the test also predicts the possible tissue of origin.

The test can be run on clinical protein assay instruments that are already widely available, such as Roche cobas analyzer, Mao Mao, MD, PhD, the founder and CEO of SeekIn, of Shenzhen, China, told this news organization.

This “feature makes the test accessible worldwide, even in low- and middle-income countries,” he said. “These instruments are fully-automated and part of today’s clinical practice. Therefore, the test does not require additional infrastructure building and lab personal training.”

Another notable advantage: the OncoSeek test only costs about $20, compared with other MCED tests, which can cost anywhere from $200 to $1000.

To validate the technology in a large, diverse cohort, Dr. Mao and colleagues enrolled approximately 10,000 participants, including 2003 cancer cases and 7888 non-cancer cases.

Peripheral blood was collected from each participant and analyzed using a panel of the seven protein tumor markers — AFP, CA125, CA15-3, CA19-9, CA72-4, CEA, and CYFRA 21-1.

To reduce the risk for false positive findings, the team designed the OncoSeek algorithm to achieve a specificity of 93%. Dr. Mao and colleagues found a sensitivity of 51.7%, resulting in an overall accuracy of 84.6%.

The performance was consistent in additional validation cohorts in Brazil, China, and the United States, with sensitivities ranging from 39.0% to 77.6% for detecting nine common cancer types, including breast, colorectal, liver, lung, lymphoma, esophagus, ovary, pancreas, and stomach. The sensitivity for pancreatic cancer was at the high end of 77.6%.

The test could predict the tissue of origin in about two thirds of cases. 

Given its low cost, OncoSeek represents an affordable and accessible option for cancer screening, the authors concluded. 

Overall, “I think MCEDs have the potential to enhance cancer screening,” Dr. Wood told this news organization.

Still, questions remain about the optimal use of these tests, such as whether they are best for average-risk or higher risk populations, and how to integrate them into standard screening, she said. 

Dr. Wood also cautioned that the studies presented in the session represent early data, and it is likely that the numbers, such as sensitivity and specificity, will change with further prospective analyses.

And ultimately, these tests should complement, not replace, standard screening. “A negative testing should not be taken as a sign to avoid standard screening,” Dr. Wood said.

Dr. Yang is an employee of Geneseeq Technology, Inc., and Dr. Mao is an employee of SeekIn. Dr. Wood had no disclosures to report.

A version of this article appeared on Medscape.com.

Early data suggested that several new multicancer early detection (MCED) tests in development show promise for identifying cancers that lack routine screening options.

Analyses presented during a session at the American Association for Cancer Research annual meeting, revealed that three new MCED tests — CanScan, MERCURY, and OncoSeek — could detect a range of cancers and recognize the tissue of origin with high accuracy. One — OncoSeek — could also provide an affordable cancer screening option for individuals living in lower-income countries.

The need for these noninvasive liquid biopsy tests that can accurately identify multiple cancer types with a single blood draw, especially cancers without routine screening strategies, is pressing. “We know that the current cancer standard of care screening will identify less than 50% of all cancers, while more than 50% of all cancer deaths occur in types of cancer with no recommended screening,” said co-moderator Marie E. Wood, MD, of the University of Colorado Anschutz Medical Campus, in Aurora, Colorado.

That being said, “the clinical utility of multicancer detection tests has not been established and we’re concerned about issues of overdiagnosis and overtreatment,” she noted.

The Early Data 

One new MCED test called CanScan, developed by Geneseeq Technology, uses plasma cell-free DNA fragment patterns to detect cancer signals as well as identify the tissue of origin across 13 cancer types.

Overall, the CanScan test covers cancer types that contribute to two thirds of new cancer cases and 74% of morality globally, said presenter Shanshan Yang, of Geneseeq Research Institute, in Nanjing, China.

However, only five of these cancer types have screening recommendations issued by the US Preventive Services Task Force (USPSTF), Dr. Yang added.

The interim data comes from an ongoing large-scale prospective study evaluating the MCED test in a cohort of asymptomatic individuals between ages 45 and 75 years with an average risk for cancer and no cancer-related symptoms on enrollment.

Patients at baseline had their blood collected for the CanScan test and subsequently received annual routine physical exams once a year for 3 consecutive years, with an additional 2 years of follow-up. 

The analysis included 3724 participants with analyzable samples at the data cutoff in September 2023. Among the 3724 participants, 29 had confirmed cancer diagnoses. Among these cases, 14 patients had their cancer confirmed through USPSTF recommended screening and 15 were detected through outside of standard USPSTF screening, such as a thyroid ultrasound, Dr. Yang explained.

Almost 90% of the cancers (26 of 29) were detected in the stage I or II, and eight (27.5%) were not one of the test’s 13 targeted cancer types.

The CanScan test had a sensitivity of 55.2%, identifying 16 of 29 of the patients with cancer, including 10 of 21 individuals with stage I (47.6%), and two of three with stage II (66.7%). 

The test had a high specificity of 97.9%, meaning out of 100 people screened, only two had false negative findings.

Among the 15 patients who had their cancer detected outside of USPSTF screening recommendations, eight (53.3%) were found using a CanScan test, including patients with liver and endometrial cancers.

Compared with a positive predictive value of (PPV) of 1.6% with screening or physical exam methods alone, the CanScan test had a PPV of 17.4%, Dr. Yang reported. 

“The MCED test holds significant potential for early cancer screening in asymptomatic populations,” Dr. Yang and colleagues concluded.

Another new MCED test called MERCURY, also developed by Geneseeq Technology and presented during the session, used a similar method to detect cancer signals and predict the tissue of origin across 13 cancer types.

The researchers initially validated the test using 3076 patients with cancer and 3477 healthy controls with a target specificity of 99%. In this group, researchers reported a sensitivity of 0.865 and a specificity of 0.989.

The team then performed an independent validation analysis with 1465 participants, 732 with cancer and 733 with no cancer, and confirmed a high sensitivity and specificity of 0.874 and 0.978, respectively. The sensitivity increased incrementally by cancer stage — 0.768 for stage I, 0.840 for stage II, 0.923 for stage III, and 0.971 for stage IV.

The test identified the tissue of origin with high accuracy, the researchers noted, but cautioned that the test needs “to be further validated in a prospective cohort study.”

MCED in Low-Income Settings

The session also featured findings on a new affordable MCED test called OncoSeek, which could provide greater access to cancer testing in low- and middle-income countries.

The OncoSeek algorithm identifies the presence of cancer using seven protein tumor markers alongside clinical information, such as gender and age. Like other tests, the test also predicts the possible tissue of origin.

The test can be run on clinical protein assay instruments that are already widely available, such as Roche cobas analyzer, Mao Mao, MD, PhD, the founder and CEO of SeekIn, of Shenzhen, China, told this news organization.

This “feature makes the test accessible worldwide, even in low- and middle-income countries,” he said. “These instruments are fully-automated and part of today’s clinical practice. Therefore, the test does not require additional infrastructure building and lab personal training.”

Another notable advantage: the OncoSeek test only costs about $20, compared with other MCED tests, which can cost anywhere from $200 to $1000.

To validate the technology in a large, diverse cohort, Dr. Mao and colleagues enrolled approximately 10,000 participants, including 2003 cancer cases and 7888 non-cancer cases.

Peripheral blood was collected from each participant and analyzed using a panel of the seven protein tumor markers — AFP, CA125, CA15-3, CA19-9, CA72-4, CEA, and CYFRA 21-1.

To reduce the risk for false positive findings, the team designed the OncoSeek algorithm to achieve a specificity of 93%. Dr. Mao and colleagues found a sensitivity of 51.7%, resulting in an overall accuracy of 84.6%.

The performance was consistent in additional validation cohorts in Brazil, China, and the United States, with sensitivities ranging from 39.0% to 77.6% for detecting nine common cancer types, including breast, colorectal, liver, lung, lymphoma, esophagus, ovary, pancreas, and stomach. The sensitivity for pancreatic cancer was at the high end of 77.6%.

The test could predict the tissue of origin in about two thirds of cases. 

Given its low cost, OncoSeek represents an affordable and accessible option for cancer screening, the authors concluded. 

Overall, “I think MCEDs have the potential to enhance cancer screening,” Dr. Wood told this news organization.

Still, questions remain about the optimal use of these tests, such as whether they are best for average-risk or higher risk populations, and how to integrate them into standard screening, she said. 

Dr. Wood also cautioned that the studies presented in the session represent early data, and it is likely that the numbers, such as sensitivity and specificity, will change with further prospective analyses.

And ultimately, these tests should complement, not replace, standard screening. “A negative testing should not be taken as a sign to avoid standard screening,” Dr. Wood said.

Dr. Yang is an employee of Geneseeq Technology, Inc., and Dr. Mao is an employee of SeekIn. Dr. Wood had no disclosures to report.

A version of this article appeared on Medscape.com.

Early data suggested that several new multicancer early detection (MCED) tests in development show promise for identifying cancers that lack routine screening options.

Analyses presented during a session at the American Association for Cancer Research annual meeting, revealed that three new MCED tests — CanScan, MERCURY, and OncoSeek — could detect a range of cancers and recognize the tissue of origin with high accuracy. One — OncoSeek — could also provide an affordable cancer screening option for individuals living in lower-income countries.

The need for these noninvasive liquid biopsy tests that can accurately identify multiple cancer types with a single blood draw, especially cancers without routine screening strategies, is pressing. “We know that the current cancer standard of care screening will identify less than 50% of all cancers, while more than 50% of all cancer deaths occur in types of cancer with no recommended screening,” said co-moderator Marie E. Wood, MD, of the University of Colorado Anschutz Medical Campus, in Aurora, Colorado.

That being said, “the clinical utility of multicancer detection tests has not been established and we’re concerned about issues of overdiagnosis and overtreatment,” she noted.

The Early Data 

One new MCED test called CanScan, developed by Geneseeq Technology, uses plasma cell-free DNA fragment patterns to detect cancer signals as well as identify the tissue of origin across 13 cancer types.

Overall, the CanScan test covers cancer types that contribute to two thirds of new cancer cases and 74% of morality globally, said presenter Shanshan Yang, of Geneseeq Research Institute, in Nanjing, China.

However, only five of these cancer types have screening recommendations issued by the US Preventive Services Task Force (USPSTF), Dr. Yang added.

The interim data comes from an ongoing large-scale prospective study evaluating the MCED test in a cohort of asymptomatic individuals between ages 45 and 75 years with an average risk for cancer and no cancer-related symptoms on enrollment.

Patients at baseline had their blood collected for the CanScan test and subsequently received annual routine physical exams once a year for 3 consecutive years, with an additional 2 years of follow-up. 

The analysis included 3724 participants with analyzable samples at the data cutoff in September 2023. Among the 3724 participants, 29 had confirmed cancer diagnoses. Among these cases, 14 patients had their cancer confirmed through USPSTF recommended screening and 15 were detected through outside of standard USPSTF screening, such as a thyroid ultrasound, Dr. Yang explained.

Almost 90% of the cancers (26 of 29) were detected in the stage I or II, and eight (27.5%) were not one of the test’s 13 targeted cancer types.

The CanScan test had a sensitivity of 55.2%, identifying 16 of 29 of the patients with cancer, including 10 of 21 individuals with stage I (47.6%), and two of three with stage II (66.7%). 

The test had a high specificity of 97.9%, meaning out of 100 people screened, only two had false negative findings.

Among the 15 patients who had their cancer detected outside of USPSTF screening recommendations, eight (53.3%) were found using a CanScan test, including patients with liver and endometrial cancers.

Compared with a positive predictive value of (PPV) of 1.6% with screening or physical exam methods alone, the CanScan test had a PPV of 17.4%, Dr. Yang reported. 

“The MCED test holds significant potential for early cancer screening in asymptomatic populations,” Dr. Yang and colleagues concluded.

Another new MCED test called MERCURY, also developed by Geneseeq Technology and presented during the session, used a similar method to detect cancer signals and predict the tissue of origin across 13 cancer types.

The researchers initially validated the test using 3076 patients with cancer and 3477 healthy controls with a target specificity of 99%. In this group, researchers reported a sensitivity of 0.865 and a specificity of 0.989.

The team then performed an independent validation analysis with 1465 participants, 732 with cancer and 733 with no cancer, and confirmed a high sensitivity and specificity of 0.874 and 0.978, respectively. The sensitivity increased incrementally by cancer stage — 0.768 for stage I, 0.840 for stage II, 0.923 for stage III, and 0.971 for stage IV.

The test identified the tissue of origin with high accuracy, the researchers noted, but cautioned that the test needs “to be further validated in a prospective cohort study.”

MCED in Low-Income Settings

The session also featured findings on a new affordable MCED test called OncoSeek, which could provide greater access to cancer testing in low- and middle-income countries.

The OncoSeek algorithm identifies the presence of cancer using seven protein tumor markers alongside clinical information, such as gender and age. Like other tests, the test also predicts the possible tissue of origin.

The test can be run on clinical protein assay instruments that are already widely available, such as Roche cobas analyzer, Mao Mao, MD, PhD, the founder and CEO of SeekIn, of Shenzhen, China, told this news organization.

This “feature makes the test accessible worldwide, even in low- and middle-income countries,” he said. “These instruments are fully-automated and part of today’s clinical practice. Therefore, the test does not require additional infrastructure building and lab personal training.”

Another notable advantage: the OncoSeek test only costs about $20, compared with other MCED tests, which can cost anywhere from $200 to $1000.

To validate the technology in a large, diverse cohort, Dr. Mao and colleagues enrolled approximately 10,000 participants, including 2003 cancer cases and 7888 non-cancer cases.

Peripheral blood was collected from each participant and analyzed using a panel of the seven protein tumor markers — AFP, CA125, CA15-3, CA19-9, CA72-4, CEA, and CYFRA 21-1.

To reduce the risk for false positive findings, the team designed the OncoSeek algorithm to achieve a specificity of 93%. Dr. Mao and colleagues found a sensitivity of 51.7%, resulting in an overall accuracy of 84.6%.

The performance was consistent in additional validation cohorts in Brazil, China, and the United States, with sensitivities ranging from 39.0% to 77.6% for detecting nine common cancer types, including breast, colorectal, liver, lung, lymphoma, esophagus, ovary, pancreas, and stomach. The sensitivity for pancreatic cancer was at the high end of 77.6%.

The test could predict the tissue of origin in about two thirds of cases. 

Given its low cost, OncoSeek represents an affordable and accessible option for cancer screening, the authors concluded. 

Overall, “I think MCEDs have the potential to enhance cancer screening,” Dr. Wood told this news organization.

Still, questions remain about the optimal use of these tests, such as whether they are best for average-risk or higher risk populations, and how to integrate them into standard screening, she said. 

Dr. Wood also cautioned that the studies presented in the session represent early data, and it is likely that the numbers, such as sensitivity and specificity, will change with further prospective analyses.

And ultimately, these tests should complement, not replace, standard screening. “A negative testing should not be taken as a sign to avoid standard screening,” Dr. Wood said.

Dr. Yang is an employee of Geneseeq Technology, Inc., and Dr. Mao is an employee of SeekIn. Dr. Wood had no disclosures to report.

A version of this article appeared on Medscape.com.

TOPLINE:

The inclusion of sugar-substitute sweeteners and sweetness enhancers in a sugar-reduced maintenance diet following weight loss improves weight maintenance as well as well-being in adults, with no increases in type 2 diabetes or cardiovascular disease risk compared with a diet excluding the sweeteners, a randomized trial showed.

The study also showed that among overweight or obese children, greater reductions in uncontrolled eating were observed among those receiving the sweeteners.

The findings counter previous reports that raised concerns about the non-sugar sweeteners, including recent research from the World Health Organization suggesting no benefits in weight control and a possible increase in the risk for type 2 diabetes or cardiovascular disease with the sweeteners.

METHODOLOGY:

• The findings are from an exploratory analysis of the multicenter, randomized SWEET trial.
• The trial involved 341 adults with overweight or obesity (aged 18-65 years, 71% women, body mass index [BMI] ≥ 25) and 38 children with overweight (aged 6-12 years, 60% girls, BMI-for-age > 85th percentile), recruited in Denmark, Spain, Greece, and the Netherlands through webpages, social media, newspapers, and registries.
• For the first 2 months of the trial, adults were instructed to follow a low-energy diet (the Cambridge Weight Plan) with the goal of achieving at least 5% weight loss, while children received dietary advice to maintain body weight.
• In the subsequent 10 months, adults as well as children were randomized to healthy diets that either consisted of less than 10% of calories from added sugar but permitted foods and drinks with sweeteners and sweetness enhancers, or the same diet but not allowing the use of the sweeteners or sweetness enhancers.
• Participants had weight, BMI, anthropometry, and risk markers for type 2 diabetes and cardiovascular disease monitored at the trial’s baseline, as well as at 2, 6, and 12 months.
• In addition, participants completed food frequency questionnaires and provided urine samples to assess biomarkers of the sweeteners, fructose and sucrose, in order to measure compliance with the dietary instructions.

TAKEAWAY:

• While the sweetener and non-sweetener groups both had decreases in consumption of products high in sugar, the reduction was significantly higher in the group that allowed use of the sweeteners (P = .002).
• In the intention-to-treat analyses, adults (n = 277) permitted sweeteners showed a small but significantly greater weight loss maintenance after 1 year than the non-sweetener group (average weight loss, 7.2 kg vs 5.6 kg; P = .029).
• Among 203 participants who completed the trial, there were no differences between the groups in terms of markers for type 2 diabetes and cardiovascular disease.
• There were also no differences between the groups in terms of subjective appetite sensations and appetite hormones in a subgroup of 104 patients.
• In an analysis of 22 children who completed the study, there were no differences in BMI-for-age z scores between sweetener and non-sweetener groups.
• In terms of effects on eating behavior, adults in the sweetener group reported greater diet satisfaction when eating out (P = .03), increased positive mood (P = .013), and reduced craving for sweet food (P = .034) at 6 months than in the non-sweetener group.
• Conversely, those receiving no sweeteners had a greater liking bias for sweet vs savory foods at 6 months (P = .023) and 12 months (P = .005).
• There were no differences between the groups in reported physical activity or quality of life.
• However, among children with higher uncontrolled eating scores at baseline, the uncontrolled eating scores at 12 months were significantly lower among children who were allowed the sugar-substitute sweeteners vs the non-sweetener children (P = .021).

IN PRACTICE:

“Our findings suggest that the inclusion of low/no energy-sweetened products may benefit children who show high levels of uncontrolled eating,” said the study’s co-lead author, Clarissa Dakin, of the Appetite Control and Energy Balance Research Group at the University of Leeds, Leeds, England, in a press statement.

“Together, these findings provide important insights for the ongoing reevaluation of food additive sweeteners by the European Food Safety Authority and other health agencies worldwide,” she said.

Coauthor Jason Halford, head of the School of Psychology at the University of Leeds, added in the press statement that “the use of low-calorie sweeteners in weight management has been questioned, in part because of the link between their use and apparent weight gain in observational studies.”

“However, increasingly, it is becoming apparent that is not the case in long-term studies,” said a study co-author in a press statement.”

SOURCE:

The findings from the two abstracts will be presented in May at the European Association for the Study of Obesity. The study abstracts were issued in advance.

LIMITATIONS:

Some of the results, particularly in children’s subgroups, were limited by the relatively low number of children, underscoring the need for future studies on the issue, the authors noted.

DISCLOSURES:

Dr. Halford has received research funding from the American Beverage Association.

A version of this article appeared on Medscape.com.

TOPLINE:

The inclusion of sugar-substitute sweeteners and sweetness enhancers in a sugar-reduced maintenance diet following weight loss improves weight maintenance as well as well-being in adults, with no increases in type 2 diabetes or cardiovascular disease risk compared with a diet excluding the sweeteners, a randomized trial showed.

The study also showed that among overweight or obese children, greater reductions in uncontrolled eating were observed among those receiving the sweeteners.

The findings counter previous reports that raised concerns about the non-sugar sweeteners, including recent research from the World Health Organization suggesting no benefits in weight control and a possible increase in the risk for type 2 diabetes or cardiovascular disease with the sweeteners.

METHODOLOGY:

• The findings are from an exploratory analysis of the multicenter, randomized SWEET trial.
• The trial involved 341 adults with overweight or obesity (aged 18-65 years, 71% women, body mass index [BMI] ≥ 25) and 38 children with overweight (aged 6-12 years, 60% girls, BMI-for-age > 85th percentile), recruited in Denmark, Spain, Greece, and the Netherlands through webpages, social media, newspapers, and registries.
• For the first 2 months of the trial, adults were instructed to follow a low-energy diet (the Cambridge Weight Plan) with the goal of achieving at least 5% weight loss, while children received dietary advice to maintain body weight.
• In the subsequent 10 months, adults as well as children were randomized to healthy diets that either consisted of less than 10% of calories from added sugar but permitted foods and drinks with sweeteners and sweetness enhancers, or the same diet but not allowing the use of the sweeteners or sweetness enhancers.
• Participants had weight, BMI, anthropometry, and risk markers for type 2 diabetes and cardiovascular disease monitored at the trial’s baseline, as well as at 2, 6, and 12 months.
• In addition, participants completed food frequency questionnaires and provided urine samples to assess biomarkers of the sweeteners, fructose and sucrose, in order to measure compliance with the dietary instructions.

TAKEAWAY:

• While the sweetener and non-sweetener groups both had decreases in consumption of products high in sugar, the reduction was significantly higher in the group that allowed use of the sweeteners (P = .002).
• In the intention-to-treat analyses, adults (n = 277) permitted sweeteners showed a small but significantly greater weight loss maintenance after 1 year than the non-sweetener group (average weight loss, 7.2 kg vs 5.6 kg; P = .029).
• Among 203 participants who completed the trial, there were no differences between the groups in terms of markers for type 2 diabetes and cardiovascular disease.
• There were also no differences between the groups in terms of subjective appetite sensations and appetite hormones in a subgroup of 104 patients.
• In an analysis of 22 children who completed the study, there were no differences in BMI-for-age z scores between sweetener and non-sweetener groups.
• In terms of effects on eating behavior, adults in the sweetener group reported greater diet satisfaction when eating out (P = .03), increased positive mood (P = .013), and reduced craving for sweet food (P = .034) at 6 months than in the non-sweetener group.
• Conversely, those receiving no sweeteners had a greater liking bias for sweet vs savory foods at 6 months (P = .023) and 12 months (P = .005).
• There were no differences between the groups in reported physical activity or quality of life.
• However, among children with higher uncontrolled eating scores at baseline, the uncontrolled eating scores at 12 months were significantly lower among children who were allowed the sugar-substitute sweeteners vs the non-sweetener children (P = .021).

IN PRACTICE:

“Our findings suggest that the inclusion of low/no energy-sweetened products may benefit children who show high levels of uncontrolled eating,” said the study’s co-lead author, Clarissa Dakin, of the Appetite Control and Energy Balance Research Group at the University of Leeds, Leeds, England, in a press statement.

“Together, these findings provide important insights for the ongoing reevaluation of food additive sweeteners by the European Food Safety Authority and other health agencies worldwide,” she said.

Coauthor Jason Halford, head of the School of Psychology at the University of Leeds, added in the press statement that “the use of low-calorie sweeteners in weight management has been questioned, in part because of the link between their use and apparent weight gain in observational studies.”

“However, increasingly, it is becoming apparent that is not the case in long-term studies,” said a study co-author in a press statement.”

SOURCE:

The findings from the two abstracts will be presented in May at the European Association for the Study of Obesity. The study abstracts were issued in advance.

LIMITATIONS:

Some of the results, particularly in children’s subgroups, were limited by the relatively low number of children, underscoring the need for future studies on the issue, the authors noted.

DISCLOSURES:

Dr. Halford has received research funding from the American Beverage Association.

A version of this article appeared on Medscape.com.

TOPLINE:

The inclusion of sugar-substitute sweeteners and sweetness enhancers in a sugar-reduced maintenance diet following weight loss improves weight maintenance as well as well-being in adults, with no increases in type 2 diabetes or cardiovascular disease risk compared with a diet excluding the sweeteners, a randomized trial showed.

The study also showed that among overweight or obese children, greater reductions in uncontrolled eating were observed among those receiving the sweeteners.

The findings counter previous reports that raised concerns about the non-sugar sweeteners, including recent research from the World Health Organization suggesting no benefits in weight control and a possible increase in the risk for type 2 diabetes or cardiovascular disease with the sweeteners.

METHODOLOGY:

• The findings are from an exploratory analysis of the multicenter, randomized SWEET trial.
• The trial involved 341 adults with overweight or obesity (aged 18-65 years, 71% women, body mass index [BMI] ≥ 25) and 38 children with overweight (aged 6-12 years, 60% girls, BMI-for-age > 85th percentile), recruited in Denmark, Spain, Greece, and the Netherlands through webpages, social media, newspapers, and registries.
• For the first 2 months of the trial, adults were instructed to follow a low-energy diet (the Cambridge Weight Plan) with the goal of achieving at least 5% weight loss, while children received dietary advice to maintain body weight.
• In the subsequent 10 months, adults as well as children were randomized to healthy diets that either consisted of less than 10% of calories from added sugar but permitted foods and drinks with sweeteners and sweetness enhancers, or the same diet but not allowing the use of the sweeteners or sweetness enhancers.
• Participants had weight, BMI, anthropometry, and risk markers for type 2 diabetes and cardiovascular disease monitored at the trial’s baseline, as well as at 2, 6, and 12 months.
• In addition, participants completed food frequency questionnaires and provided urine samples to assess biomarkers of the sweeteners, fructose and sucrose, in order to measure compliance with the dietary instructions.

TAKEAWAY:

• While the sweetener and non-sweetener groups both had decreases in consumption of products high in sugar, the reduction was significantly higher in the group that allowed use of the sweeteners (P = .002).
• In the intention-to-treat analyses, adults (n = 277) permitted sweeteners showed a small but significantly greater weight loss maintenance after 1 year than the non-sweetener group (average weight loss, 7.2 kg vs 5.6 kg; P = .029).
• Among 203 participants who completed the trial, there were no differences between the groups in terms of markers for type 2 diabetes and cardiovascular disease.
• There were also no differences between the groups in terms of subjective appetite sensations and appetite hormones in a subgroup of 104 patients.
• In an analysis of 22 children who completed the study, there were no differences in BMI-for-age z scores between sweetener and non-sweetener groups.
• In terms of effects on eating behavior, adults in the sweetener group reported greater diet satisfaction when eating out (P = .03), increased positive mood (P = .013), and reduced craving for sweet food (P = .034) at 6 months than in the non-sweetener group.
• Conversely, those receiving no sweeteners had a greater liking bias for sweet vs savory foods at 6 months (P = .023) and 12 months (P = .005).
• There were no differences between the groups in reported physical activity or quality of life.
• However, among children with higher uncontrolled eating scores at baseline, the uncontrolled eating scores at 12 months were significantly lower among children who were allowed the sugar-substitute sweeteners vs the non-sweetener children (P = .021).

IN PRACTICE:

“Our findings suggest that the inclusion of low/no energy-sweetened products may benefit children who show high levels of uncontrolled eating,” said the study’s co-lead author, Clarissa Dakin, of the Appetite Control and Energy Balance Research Group at the University of Leeds, Leeds, England, in a press statement.

“Together, these findings provide important insights for the ongoing reevaluation of food additive sweeteners by the European Food Safety Authority and other health agencies worldwide,” she said.

Coauthor Jason Halford, head of the School of Psychology at the University of Leeds, added in the press statement that “the use of low-calorie sweeteners in weight management has been questioned, in part because of the link between their use and apparent weight gain in observational studies.”

“However, increasingly, it is becoming apparent that is not the case in long-term studies,” said a study co-author in a press statement.”

SOURCE:

The findings from the two abstracts will be presented in May at the European Association for the Study of Obesity. The study abstracts were issued in advance.

LIMITATIONS:

Some of the results, particularly in children’s subgroups, were limited by the relatively low number of children, underscoring the need for future studies on the issue, the authors noted.

DISCLOSURES:

Dr. Halford has received research funding from the American Beverage Association.

A version of this article appeared on Medscape.com.

Among diagnostic interventions recommended to manage the common CAR-T cell therapy–associated side effect of immune effector cell–associated neurotoxicity syndrome (ICANS), only electroencephalogram (EEG) shows significant therapeutic benefit — while magnetic resonance imaging (MRI) and lumbar puncture appear to have limited value, new research shows.

“Our results emphasize for the first time the role of EEG in the current guidelines [for ICANS] but question the need for systematic MRI and lumbar puncture,” reported the authors of the study, published in Blood Advances.

The study underscores that “EEG does more that depict insignificant anomalies and plays a key role in patient management in daily practice,” first author Mattéo Mauget, said in an interview. He is a resident in the intensive care unit at the University Hospital of Rennes in France.

ICANS is among the most common of acute neurotoxicities occurring after CAR T-cell therapy, and international guidelines recommend MRI, lumbar puncture, and EEG in the management of the toxicity, which is typically treated with anti-cytokine therapy and steroids.

However, the guidelines widely vary. All recommend the use of MRI for ICANS grade 3 or higher, but fewer recommend the approach for grade 2. Meanwhile, only some recommend the use of lumbar puncture, and even fewer guidelines recommend the use of EEG.

While these measures are expensive — and in the case of lumbar puncture, invasive and burdensome for patients — the recommendations on these measures “rely on empirical practices and are only based on expert opinions with low scientific evidence,” the authors wrote.

To evaluate the interventions in a cohort of real-life patients treated with CAR T-cell therapy, the authors identified 190 consecutive patients receiving the therapy at the University Hospital of Rennes, France, between August 2018 and January 2023.

Of the patients, 62% were male and their median age was 64. Overall, 91 (48%) developed ICANS.

The majority of patients (73%) received CAR-T cell therapy for a refractory/relapsed (R/R) DLBCL (73%), and most (60%) had received the CAR-T product axicabtagene-ciloleucel (axi-cel) after two or more prior therapies.

While MRI was performed in 78% of patients with ICANS, the measure was determined to have had a therapeutic impact in just 4% of patients, despite common observations of abnormal findings.

Lumbar puncture was meanwhile performed in 47% of patients, resulting in preemptive antimicrobial agents in 7% of patients, with no infection detected.

While systematic EEG was performed in 56% of patients, the intervention led to therapeutic modifications among 16% of those patients.

“Our findings highlight some divergences between guidelines and daily practice regarding diagnostic investigations,” the authors noted.

The study “shows that EEG is the diagnostic investigation with the greatest therapeutic impact, while MRI and lumbar puncture appear to have a limited therapeutic impact,” they concluded.
 

EEG Findings

Of note, only 18% of EEGs in the cohort were normal, ranging from 50% of those with ICANS grade 1 to 6% among those with ICANS grade 4.

Encephalopathy was the most common EEG finding, observed in 45% of patients, while 6 EEGs (12%) showed seizures or status epilepticus.

Two patients with ICANS grade 2 and 3 (6% of EEG) developed seizure or status epilepticus on their EEGs, despite the absence of clinical symptoms of epilepsy, while the rate was 4 (33%) among patients with ICANS grade 4.

Among the eight (16%) patients who received therapeutic modification as the result of the EEG, seven were in the severe and life-threatening ICANS (grade 3+) group (24%).

In addition, all EEGs detecting seizure or status epilepticus resulted in an increase in antiepileptic prophylaxis with levetiracetam or the introduction of a new antiepileptics, mainly phenytoin.

Surprisingly, there were no cases of diffuse edema in the entire cohort, even among those with grade 4 ICANS, which is one of the key concerns of treating physicians managing severe ICANS, the authors noted.

A notable caveat is that EEG can be a time- and physician-consuming examination not easily accessed on a 24/7 daily practice level.

With such challenges, “[we] advocate for a close partnership between hematologists and electrophysiologists to make EEG access as easy as possible for this kind of patient, as EEG is a key game changer in patient course,” Mr. Mauget said.

Commenting on the findings, Marcela V. Maus, MD, PhD, director of the Cellular Immunotherapy Program at the Massachusetts General Hospital Cancer Center in Boston, agreed that the study adds importantly to a topic in need of more data.

“This is a very interesting study that starts to provide data behind the consensus recommendations that were initially made based purely on expert opinion and collective practices,” she said in an interview.

“I think [the EEG findings] are interesting, because EEG is often the most non-specific of these tests, and I would not have predicted this result. I also think that monitoring of cerebral spinal fluid [through lumbar puncture] could have potentially higher impact if there was a way to routinely quantify and detect the CAR-T cells,” Dr. Maus said.

“Although admittedly I think this may be of greater benefit when patients present with neurologic findings outside the typical window of ICANS, such as what can occur with delayed neurologic toxicities such as Parkinsonism after BCMA-directed CAR T cells,” she added.

Senior author Guillaume Manson, MD, a hematologist also with the University Hospital of Rennes, underscored that the results shouldn’t be construed to suggest that MRI or LP should not be used in such cases, but may often not be necessary.

“Every patient’s case is different, and these findings certainly do not say that certain tests should or should not be performed,” he said in a press statement.

“We did this research to generate clinical evidence to inform guidelines that support physicians in making clinical decisions when treating patients with these complex, and sometimes severe conditions,” he added.

Dr. Manson reported relationships with BMS-Celgene, Gilead-Kite, and Takeda. Dr. Maus disclosed ties with Century Therapeutics, TCR2, Kite/Gilead, Novartis, and several other companies in the field of cellular therapies.

Among diagnostic interventions recommended to manage the common CAR-T cell therapy–associated side effect of immune effector cell–associated neurotoxicity syndrome (ICANS), only electroencephalogram (EEG) shows significant therapeutic benefit — while magnetic resonance imaging (MRI) and lumbar puncture appear to have limited value, new research shows.

“Our results emphasize for the first time the role of EEG in the current guidelines [for ICANS] but question the need for systematic MRI and lumbar puncture,” reported the authors of the study, published in Blood Advances.

The study underscores that “EEG does more that depict insignificant anomalies and plays a key role in patient management in daily practice,” first author Mattéo Mauget, said in an interview. He is a resident in the intensive care unit at the University Hospital of Rennes in France.

ICANS is among the most common of acute neurotoxicities occurring after CAR T-cell therapy, and international guidelines recommend MRI, lumbar puncture, and EEG in the management of the toxicity, which is typically treated with anti-cytokine therapy and steroids.

However, the guidelines widely vary. All recommend the use of MRI for ICANS grade 3 or higher, but fewer recommend the approach for grade 2. Meanwhile, only some recommend the use of lumbar puncture, and even fewer guidelines recommend the use of EEG.

While these measures are expensive — and in the case of lumbar puncture, invasive and burdensome for patients — the recommendations on these measures “rely on empirical practices and are only based on expert opinions with low scientific evidence,” the authors wrote.

To evaluate the interventions in a cohort of real-life patients treated with CAR T-cell therapy, the authors identified 190 consecutive patients receiving the therapy at the University Hospital of Rennes, France, between August 2018 and January 2023.

Of the patients, 62% were male and their median age was 64. Overall, 91 (48%) developed ICANS.

The majority of patients (73%) received CAR-T cell therapy for a refractory/relapsed (R/R) DLBCL (73%), and most (60%) had received the CAR-T product axicabtagene-ciloleucel (axi-cel) after two or more prior therapies.

While MRI was performed in 78% of patients with ICANS, the measure was determined to have had a therapeutic impact in just 4% of patients, despite common observations of abnormal findings.

Lumbar puncture was meanwhile performed in 47% of patients, resulting in preemptive antimicrobial agents in 7% of patients, with no infection detected.

While systematic EEG was performed in 56% of patients, the intervention led to therapeutic modifications among 16% of those patients.

“Our findings highlight some divergences between guidelines and daily practice regarding diagnostic investigations,” the authors noted.

The study “shows that EEG is the diagnostic investigation with the greatest therapeutic impact, while MRI and lumbar puncture appear to have a limited therapeutic impact,” they concluded.
 

EEG Findings

Of note, only 18% of EEGs in the cohort were normal, ranging from 50% of those with ICANS grade 1 to 6% among those with ICANS grade 4.

Encephalopathy was the most common EEG finding, observed in 45% of patients, while 6 EEGs (12%) showed seizures or status epilepticus.

Two patients with ICANS grade 2 and 3 (6% of EEG) developed seizure or status epilepticus on their EEGs, despite the absence of clinical symptoms of epilepsy, while the rate was 4 (33%) among patients with ICANS grade 4.

Among the eight (16%) patients who received therapeutic modification as the result of the EEG, seven were in the severe and life-threatening ICANS (grade 3+) group (24%).

In addition, all EEGs detecting seizure or status epilepticus resulted in an increase in antiepileptic prophylaxis with levetiracetam or the introduction of a new antiepileptics, mainly phenytoin.

Surprisingly, there were no cases of diffuse edema in the entire cohort, even among those with grade 4 ICANS, which is one of the key concerns of treating physicians managing severe ICANS, the authors noted.

A notable caveat is that EEG can be a time- and physician-consuming examination not easily accessed on a 24/7 daily practice level.

With such challenges, “[we] advocate for a close partnership between hematologists and electrophysiologists to make EEG access as easy as possible for this kind of patient, as EEG is a key game changer in patient course,” Mr. Mauget said.

Commenting on the findings, Marcela V. Maus, MD, PhD, director of the Cellular Immunotherapy Program at the Massachusetts General Hospital Cancer Center in Boston, agreed that the study adds importantly to a topic in need of more data.

“This is a very interesting study that starts to provide data behind the consensus recommendations that were initially made based purely on expert opinion and collective practices,” she said in an interview.

“I think [the EEG findings] are interesting, because EEG is often the most non-specific of these tests, and I would not have predicted this result. I also think that monitoring of cerebral spinal fluid [through lumbar puncture] could have potentially higher impact if there was a way to routinely quantify and detect the CAR-T cells,” Dr. Maus said.

“Although admittedly I think this may be of greater benefit when patients present with neurologic findings outside the typical window of ICANS, such as what can occur with delayed neurologic toxicities such as Parkinsonism after BCMA-directed CAR T cells,” she added.

Senior author Guillaume Manson, MD, a hematologist also with the University Hospital of Rennes, underscored that the results shouldn’t be construed to suggest that MRI or LP should not be used in such cases, but may often not be necessary.

“Every patient’s case is different, and these findings certainly do not say that certain tests should or should not be performed,” he said in a press statement.

“We did this research to generate clinical evidence to inform guidelines that support physicians in making clinical decisions when treating patients with these complex, and sometimes severe conditions,” he added.

Dr. Manson reported relationships with BMS-Celgene, Gilead-Kite, and Takeda. Dr. Maus disclosed ties with Century Therapeutics, TCR2, Kite/Gilead, Novartis, and several other companies in the field of cellular therapies.

Among diagnostic interventions recommended to manage the common CAR-T cell therapy–associated side effect of immune effector cell–associated neurotoxicity syndrome (ICANS), only electroencephalogram (EEG) shows significant therapeutic benefit — while magnetic resonance imaging (MRI) and lumbar puncture appear to have limited value, new research shows.

“Our results emphasize for the first time the role of EEG in the current guidelines [for ICANS] but question the need for systematic MRI and lumbar puncture,” reported the authors of the study, published in Blood Advances.

The study underscores that “EEG does more that depict insignificant anomalies and plays a key role in patient management in daily practice,” first author Mattéo Mauget, said in an interview. He is a resident in the intensive care unit at the University Hospital of Rennes in France.

ICANS is among the most common of acute neurotoxicities occurring after CAR T-cell therapy, and international guidelines recommend MRI, lumbar puncture, and EEG in the management of the toxicity, which is typically treated with anti-cytokine therapy and steroids.

However, the guidelines widely vary. All recommend the use of MRI for ICANS grade 3 or higher, but fewer recommend the approach for grade 2. Meanwhile, only some recommend the use of lumbar puncture, and even fewer guidelines recommend the use of EEG.

While these measures are expensive — and in the case of lumbar puncture, invasive and burdensome for patients — the recommendations on these measures “rely on empirical practices and are only based on expert opinions with low scientific evidence,” the authors wrote.

To evaluate the interventions in a cohort of real-life patients treated with CAR T-cell therapy, the authors identified 190 consecutive patients receiving the therapy at the University Hospital of Rennes, France, between August 2018 and January 2023.

Of the patients, 62% were male and their median age was 64. Overall, 91 (48%) developed ICANS.

The majority of patients (73%) received CAR-T cell therapy for a refractory/relapsed (R/R) DLBCL (73%), and most (60%) had received the CAR-T product axicabtagene-ciloleucel (axi-cel) after two or more prior therapies.

While MRI was performed in 78% of patients with ICANS, the measure was determined to have had a therapeutic impact in just 4% of patients, despite common observations of abnormal findings.

Lumbar puncture was meanwhile performed in 47% of patients, resulting in preemptive antimicrobial agents in 7% of patients, with no infection detected.

While systematic EEG was performed in 56% of patients, the intervention led to therapeutic modifications among 16% of those patients.

“Our findings highlight some divergences between guidelines and daily practice regarding diagnostic investigations,” the authors noted.

The study “shows that EEG is the diagnostic investigation with the greatest therapeutic impact, while MRI and lumbar puncture appear to have a limited therapeutic impact,” they concluded.
 

EEG Findings

Of note, only 18% of EEGs in the cohort were normal, ranging from 50% of those with ICANS grade 1 to 6% among those with ICANS grade 4.

Encephalopathy was the most common EEG finding, observed in 45% of patients, while 6 EEGs (12%) showed seizures or status epilepticus.

Two patients with ICANS grade 2 and 3 (6% of EEG) developed seizure or status epilepticus on their EEGs, despite the absence of clinical symptoms of epilepsy, while the rate was 4 (33%) among patients with ICANS grade 4.

Among the eight (16%) patients who received therapeutic modification as the result of the EEG, seven were in the severe and life-threatening ICANS (grade 3+) group (24%).

In addition, all EEGs detecting seizure or status epilepticus resulted in an increase in antiepileptic prophylaxis with levetiracetam or the introduction of a new antiepileptics, mainly phenytoin.

Surprisingly, there were no cases of diffuse edema in the entire cohort, even among those with grade 4 ICANS, which is one of the key concerns of treating physicians managing severe ICANS, the authors noted.

A notable caveat is that EEG can be a time- and physician-consuming examination not easily accessed on a 24/7 daily practice level.

With such challenges, “[we] advocate for a close partnership between hematologists and electrophysiologists to make EEG access as easy as possible for this kind of patient, as EEG is a key game changer in patient course,” Mr. Mauget said.

Commenting on the findings, Marcela V. Maus, MD, PhD, director of the Cellular Immunotherapy Program at the Massachusetts General Hospital Cancer Center in Boston, agreed that the study adds importantly to a topic in need of more data.

“This is a very interesting study that starts to provide data behind the consensus recommendations that were initially made based purely on expert opinion and collective practices,” she said in an interview.

“I think [the EEG findings] are interesting, because EEG is often the most non-specific of these tests, and I would not have predicted this result. I also think that monitoring of cerebral spinal fluid [through lumbar puncture] could have potentially higher impact if there was a way to routinely quantify and detect the CAR-T cells,” Dr. Maus said.

“Although admittedly I think this may be of greater benefit when patients present with neurologic findings outside the typical window of ICANS, such as what can occur with delayed neurologic toxicities such as Parkinsonism after BCMA-directed CAR T cells,” she added.

Senior author Guillaume Manson, MD, a hematologist also with the University Hospital of Rennes, underscored that the results shouldn’t be construed to suggest that MRI or LP should not be used in such cases, but may often not be necessary.

“Every patient’s case is different, and these findings certainly do not say that certain tests should or should not be performed,” he said in a press statement.

“We did this research to generate clinical evidence to inform guidelines that support physicians in making clinical decisions when treating patients with these complex, and sometimes severe conditions,” he added.

Dr. Manson reported relationships with BMS-Celgene, Gilead-Kite, and Takeda. Dr. Maus disclosed ties with Century Therapeutics, TCR2, Kite/Gilead, Novartis, and several other companies in the field of cellular therapies.

Among adolescents with moderate to severe obesity, a nutritionally balanced, very low-calorie diet with the monitoring of a dietitian shows high adherence and safety, with significant weight loss over the course of a month and common, but mild side effects.

More research is needed to understand which patients are best suited for the diet; “however, given the associated rapid weight loss, the use of [very low-energy diets] should be emphasized in clinical practice guidelines for the treatment of severe obesity and obesity-related complications in adolescents, especially before pharmacological or surgical intervention,” first author Megan Gow, PhD, of Children’s Hospital Westmead Clinical School, The University of Sydney, Westmead, Australia, said in a press statement. 

The study will be presented in May at the upcoming European Congress on Obesity, in Venice, Italy.

While very low-calorie diets have been shown to promote rapid weight loss in adolescents, research is lacking on general side effects and acceptability of the regimens. Data is also lacking on important issues including the diet’s effect on growth, heart health, and psychological wellbeing. 

To investigate, Dr. Gow and colleagues conducted a subanalysis of the 52-week Fast Track to Health study evaluating the acceptability of different dietary plans for adolescents with obesity.

The analysis included 141 adolescents between the ages of 13 and 17 years with moderate to severe obesity (average body mass index, 35 kg/m²) and at least one obesity-related complication, such as high blood pressure or insulin resistance.

The participants were placed on a nutritionally balanced very low-energy diet consisting of 800 calories per day. 

The diet involved one of two regimens — either four Optifast-formulated meal replacement products per day, including shakes, soups, bars, and/or dessert, along with low carbohydrate vegetables, such as broccoli, celery, capsicum, mushrooms, and tomatoes, with one teaspoon of vegetable oil, or a regimen of three Optifast-formulated meal replacements and one meal consisting of 100-150 g lean cooked meat, low-carbohydrate vegetables, and one teaspoon of vegetable oil.

Participants, about half of whom were women, also received dietitian support at least weekly. 

After 4 weeks, most of the adolescents, ie, 134 of the 141, with an average age of 14.9 years, completed the diet, with an average weight loss of 5.5 kg or 12 pounds (P < .001).

Most patients (95%) experienced at least one side effect, and 70% reported at least 3 of the side effects, with the most common side effects including hunger, fatigue, headache, irritability, loose stools, constipation, nausea, and a lack of concentration.

Viral infections occurred in seven participants.

While most side effects occurred at the end of week 1, the development of side effects earlier, at day 3-4, was associated with higher levels of weight loss at the 4-week cut-off, which the authors noted could suggest a greater adherence to the diet at that stage.

One adverse event occurred, consisting of a single fainting episode determined to be potentially related to the dietary intervention.

In surveys, the adolescents gave the intervention an acceptability rating of 61 on a scale of 100, the score was 53 of 100 in terms of being “enjoyable to follow.”

The most-liked aspects of the intervention were losing weight (described by 34% of participants) and the prescriptive structure (listed by 28% of participants).

The least-liked aspects included the diet’s restrictive nature, described by 45% of participants, and the taste of meal replacement products, listed by 20% of participants.
 

Alternative to Weight Loss Drugs?

While weight loss drugs are transforming the obesity treatment and semaglutide is now approved for adolescents as young as age 12 years, “access to these medications is limited, and not all families want to commence on medication for their child›s obesity,” Dr. Gow said.

As an alternative, a very low-energy diet, with the interaction of a dietitian, can enable adolescents “to develop a healthier relationship with food, including encouraging the consumption of more fruits and vegetables in their diet, not only to assist in weight loss but for good health,” she said.
 

Very Low-Calorie Diet Concerns for Adolescents Addressed

Early studies suggested concerns of health effects from very low-calorie diets in adolescents, including potential cardiac effects; however, subsequent studies, including a systematic review published by Dr. Gow and her team, have shown that such results were likely the result of nutritional deficiencies in the diets, which can be overcome with careful food selection and dietary counseling.

Another key concern has been a potential effect on growth, but Dr. Gow noted that “in our short-term study we saw small increase in height (0.1 cm), and other more recent studies suggest that a short-term very low-energy diet does not impact growth.”

And in an earlier pilot study, the authors also found an association between the very low-calorie diet and an improvement in the quality of life for youth with type 2 diabetes.

A key caveat with the findings is that participants in the study all received supervision and monitoring from a trained dietitian, and Gow noted that that element is essential.

“We therefore do not recommend adolescents in the community undertake this type of diet without appropriate support,” she said.

“Close monitoring of adolescents by a health professional following a very low-energy diet is essential to ensure that the very low-energy diet is leading to holistic health benefits for the individual.”

Following the 4-week regimen, participants were randomized to transition to interventions of either continuous energy restriction or intermittent energy restriction over the 52 weeks, and further findings from the study will be presented at the obesity meeting in May.

The authors had no disclosures to report.

A version of this article appeared on Medscape.com.

Among adolescents with moderate to severe obesity, a nutritionally balanced, very low-calorie diet with the monitoring of a dietitian shows high adherence and safety, with significant weight loss over the course of a month and common, but mild side effects.

More research is needed to understand which patients are best suited for the diet; “however, given the associated rapid weight loss, the use of [very low-energy diets] should be emphasized in clinical practice guidelines for the treatment of severe obesity and obesity-related complications in adolescents, especially before pharmacological or surgical intervention,” first author Megan Gow, PhD, of Children’s Hospital Westmead Clinical School, The University of Sydney, Westmead, Australia, said in a press statement. 

The study will be presented in May at the upcoming European Congress on Obesity, in Venice, Italy.

While very low-calorie diets have been shown to promote rapid weight loss in adolescents, research is lacking on general side effects and acceptability of the regimens. Data is also lacking on important issues including the diet’s effect on growth, heart health, and psychological wellbeing. 

To investigate, Dr. Gow and colleagues conducted a subanalysis of the 52-week Fast Track to Health study evaluating the acceptability of different dietary plans for adolescents with obesity.

The analysis included 141 adolescents between the ages of 13 and 17 years with moderate to severe obesity (average body mass index, 35 kg/m²) and at least one obesity-related complication, such as high blood pressure or insulin resistance.

The participants were placed on a nutritionally balanced very low-energy diet consisting of 800 calories per day. 

The diet involved one of two regimens — either four Optifast-formulated meal replacement products per day, including shakes, soups, bars, and/or dessert, along with low carbohydrate vegetables, such as broccoli, celery, capsicum, mushrooms, and tomatoes, with one teaspoon of vegetable oil, or a regimen of three Optifast-formulated meal replacements and one meal consisting of 100-150 g lean cooked meat, low-carbohydrate vegetables, and one teaspoon of vegetable oil.

Participants, about half of whom were women, also received dietitian support at least weekly. 

After 4 weeks, most of the adolescents, ie, 134 of the 141, with an average age of 14.9 years, completed the diet, with an average weight loss of 5.5 kg or 12 pounds (P < .001).

Most patients (95%) experienced at least one side effect, and 70% reported at least 3 of the side effects, with the most common side effects including hunger, fatigue, headache, irritability, loose stools, constipation, nausea, and a lack of concentration.

Viral infections occurred in seven participants.

While most side effects occurred at the end of week 1, the development of side effects earlier, at day 3-4, was associated with higher levels of weight loss at the 4-week cut-off, which the authors noted could suggest a greater adherence to the diet at that stage.

One adverse event occurred, consisting of a single fainting episode determined to be potentially related to the dietary intervention.

In surveys, the adolescents gave the intervention an acceptability rating of 61 on a scale of 100, the score was 53 of 100 in terms of being “enjoyable to follow.”

The most-liked aspects of the intervention were losing weight (described by 34% of participants) and the prescriptive structure (listed by 28% of participants).

The least-liked aspects included the diet’s restrictive nature, described by 45% of participants, and the taste of meal replacement products, listed by 20% of participants.
 

Alternative to Weight Loss Drugs?

While weight loss drugs are transforming the obesity treatment and semaglutide is now approved for adolescents as young as age 12 years, “access to these medications is limited, and not all families want to commence on medication for their child›s obesity,” Dr. Gow said.

As an alternative, a very low-energy diet, with the interaction of a dietitian, can enable adolescents “to develop a healthier relationship with food, including encouraging the consumption of more fruits and vegetables in their diet, not only to assist in weight loss but for good health,” she said.
 

Very Low-Calorie Diet Concerns for Adolescents Addressed

Early studies suggested concerns of health effects from very low-calorie diets in adolescents, including potential cardiac effects; however, subsequent studies, including a systematic review published by Dr. Gow and her team, have shown that such results were likely the result of nutritional deficiencies in the diets, which can be overcome with careful food selection and dietary counseling.

Another key concern has been a potential effect on growth, but Dr. Gow noted that “in our short-term study we saw small increase in height (0.1 cm), and other more recent studies suggest that a short-term very low-energy diet does not impact growth.”

And in an earlier pilot study, the authors also found an association between the very low-calorie diet and an improvement in the quality of life for youth with type 2 diabetes.

A key caveat with the findings is that participants in the study all received supervision and monitoring from a trained dietitian, and Gow noted that that element is essential.

“We therefore do not recommend adolescents in the community undertake this type of diet without appropriate support,” she said.

“Close monitoring of adolescents by a health professional following a very low-energy diet is essential to ensure that the very low-energy diet is leading to holistic health benefits for the individual.”

Following the 4-week regimen, participants were randomized to transition to interventions of either continuous energy restriction or intermittent energy restriction over the 52 weeks, and further findings from the study will be presented at the obesity meeting in May.

The authors had no disclosures to report.

A version of this article appeared on Medscape.com.

Among adolescents with moderate to severe obesity, a nutritionally balanced, very low-calorie diet with the monitoring of a dietitian shows high adherence and safety, with significant weight loss over the course of a month and common, but mild side effects.

More research is needed to understand which patients are best suited for the diet; “however, given the associated rapid weight loss, the use of [very low-energy diets] should be emphasized in clinical practice guidelines for the treatment of severe obesity and obesity-related complications in adolescents, especially before pharmacological or surgical intervention,” first author Megan Gow, PhD, of Children’s Hospital Westmead Clinical School, The University of Sydney, Westmead, Australia, said in a press statement. 

The study will be presented in May at the upcoming European Congress on Obesity, in Venice, Italy.

While very low-calorie diets have been shown to promote rapid weight loss in adolescents, research is lacking on general side effects and acceptability of the regimens. Data is also lacking on important issues including the diet’s effect on growth, heart health, and psychological wellbeing. 

To investigate, Dr. Gow and colleagues conducted a subanalysis of the 52-week Fast Track to Health study evaluating the acceptability of different dietary plans for adolescents with obesity.

The analysis included 141 adolescents between the ages of 13 and 17 years with moderate to severe obesity (average body mass index, 35 kg/m²) and at least one obesity-related complication, such as high blood pressure or insulin resistance.

The participants were placed on a nutritionally balanced very low-energy diet consisting of 800 calories per day. 

The diet involved one of two regimens — either four Optifast-formulated meal replacement products per day, including shakes, soups, bars, and/or dessert, along with low carbohydrate vegetables, such as broccoli, celery, capsicum, mushrooms, and tomatoes, with one teaspoon of vegetable oil, or a regimen of three Optifast-formulated meal replacements and one meal consisting of 100-150 g lean cooked meat, low-carbohydrate vegetables, and one teaspoon of vegetable oil.

Participants, about half of whom were women, also received dietitian support at least weekly. 

After 4 weeks, most of the adolescents, ie, 134 of the 141, with an average age of 14.9 years, completed the diet, with an average weight loss of 5.5 kg or 12 pounds (P < .001).

Most patients (95%) experienced at least one side effect, and 70% reported at least 3 of the side effects, with the most common side effects including hunger, fatigue, headache, irritability, loose stools, constipation, nausea, and a lack of concentration.

Viral infections occurred in seven participants.

While most side effects occurred at the end of week 1, the development of side effects earlier, at day 3-4, was associated with higher levels of weight loss at the 4-week cut-off, which the authors noted could suggest a greater adherence to the diet at that stage.

One adverse event occurred, consisting of a single fainting episode determined to be potentially related to the dietary intervention.

In surveys, the adolescents gave the intervention an acceptability rating of 61 on a scale of 100, the score was 53 of 100 in terms of being “enjoyable to follow.”

The most-liked aspects of the intervention were losing weight (described by 34% of participants) and the prescriptive structure (listed by 28% of participants).

The least-liked aspects included the diet’s restrictive nature, described by 45% of participants, and the taste of meal replacement products, listed by 20% of participants.
 

Alternative to Weight Loss Drugs?

While weight loss drugs are transforming the obesity treatment and semaglutide is now approved for adolescents as young as age 12 years, “access to these medications is limited, and not all families want to commence on medication for their child›s obesity,” Dr. Gow said.

As an alternative, a very low-energy diet, with the interaction of a dietitian, can enable adolescents “to develop a healthier relationship with food, including encouraging the consumption of more fruits and vegetables in their diet, not only to assist in weight loss but for good health,” she said.
 

Very Low-Calorie Diet Concerns for Adolescents Addressed

Early studies suggested concerns of health effects from very low-calorie diets in adolescents, including potential cardiac effects; however, subsequent studies, including a systematic review published by Dr. Gow and her team, have shown that such results were likely the result of nutritional deficiencies in the diets, which can be overcome with careful food selection and dietary counseling.

Another key concern has been a potential effect on growth, but Dr. Gow noted that “in our short-term study we saw small increase in height (0.1 cm), and other more recent studies suggest that a short-term very low-energy diet does not impact growth.”

And in an earlier pilot study, the authors also found an association between the very low-calorie diet and an improvement in the quality of life for youth with type 2 diabetes.

A key caveat with the findings is that participants in the study all received supervision and monitoring from a trained dietitian, and Gow noted that that element is essential.

“We therefore do not recommend adolescents in the community undertake this type of diet without appropriate support,” she said.

“Close monitoring of adolescents by a health professional following a very low-energy diet is essential to ensure that the very low-energy diet is leading to holistic health benefits for the individual.”

Following the 4-week regimen, participants were randomized to transition to interventions of either continuous energy restriction or intermittent energy restriction over the 52 weeks, and further findings from the study will be presented at the obesity meeting in May.

The authors had no disclosures to report.

A version of this article appeared on Medscape.com.

TOPLINE: 

The spices and aromatic herbs of the Mediterranean diet with significant benefits in improving glycemic health in type 2 diabetes are limited to ginger, cinnamon, black cumin, turmeric, and saffron, with ginger, black cumin, and cinnamon having the strongest effects on fasting glucose, according to a systematic review and meta-analysis of research.

The meta-analysis also evaluated clove, thyme, turmeric, and various other spices and herbs common in the diet but showed no other correlations with glycemic benefits. 

METHODOLOGY:

• In the analysis of 77 studies, 45, involving 3050 participants, were included in the meta-analysis and 32 studies in the systematic review.
• The studies’ inclusion criteria included adult patients with type 2 diabetes, with data on fasting glucose and/or A1c and/or , and involving any supplementation with black cumin, clove, , saffron, thyme, ginger, black pepper, , curcumin, cinnamon, basil, and/or oregano.
• The number of studies involving clove, parsley, thyme, black pepper, rosemary, basil, or oregano and their association with glycemic factors in people with type 2 diabetes was insufficient, hence the analysis primarily focused on the remaining five ingredients of cinnamon, curcumin, ginger, black cumin, saffron, and rosemary.

TAKEAWAY: 

• Improvements in fasting glucose of subjects with type 2 diabetes were observed with all five ingredients of cinnamon, turmeric, ginger, black cumin, and saffron.
• However, the most significant decreases in fasting glucose, between 17 mg/dL and 27 mg/dL, occurred after supplementation with black cumin, followed by cinnamon and ginger.
• Notably, only ginger and black cumin were associated with a significant improvement in A1c.
• Only cinnamon and ginger were associated with a significant decrease in insulin values.
• Of the 11 studies including cinnamon in the meta-analysis, 6 reported significant differences in fasting glucose, while 4 had differences in A1c after the supplementation.
• However, ginger was the only component associated with a significant decrease in each of the 3 outcomes examined of fasting glucose, A1c, and insulin.

IN PRACTICE:

“The Mediterranean Diet is the dietary pattern par excellence for managing and preventing metabolic diseases, such as type 2 diabetes,” the authors reported.

“As far as we are aware, this is the first systematic review and meta-analysis aiming to evaluate the effect of aromatic herbs and spices included in the Mediterranean Diet, such as black cumin, clove [and others], on the glycemic profile of individuals with type 2 diabetes,” they added.

“When focusing on HbA1c, only ginger and black cumin demonstrated therapeutic effects,” the authors noted. “However, our meta-analysis highlights ginger as an herb with substantial translational potential for diabetes treatment, impacting all three glycemic parameters.”

“Regarding clove, parsley, thyme, black pepper, rosemary, basil, and oregano, more studies are needed to analyze the effect of these herbs on the glycemic profile in type 2 diabetes subjects,” the authors concluded.

SOURCE:

The study was published on March 7, 2024, in Nutrients. The first author was Maria Carmen Garza, PhD, of the Department of Human Anatomy and Histology, School Medicine, University of Zaragoza, Zaragoza, Spain.

LIMITATIONS:

Despite the results, a variety of other factors can affect fasting glucose levels, including changes in body weight or body mass index, as well as the combination of spice or aromatic herb supplementation with physical activity or lifestyle changes, the authors noted.

Due to the studies’ differences, the determination of effective dosages of the herbs and spices was not possible.

Furthermore, the studies had wide variations in quality, with few studies including adequate statistical analysis.

DISCLOSURES:

The authors had no disclosures to report.

A version of this article appeared on Medscape.com.

TOPLINE: 

The spices and aromatic herbs of the Mediterranean diet with significant benefits in improving glycemic health in type 2 diabetes are limited to ginger, cinnamon, black cumin, turmeric, and saffron, with ginger, black cumin, and cinnamon having the strongest effects on fasting glucose, according to a systematic review and meta-analysis of research.

The meta-analysis also evaluated clove, thyme, turmeric, and various other spices and herbs common in the diet but showed no other correlations with glycemic benefits. 

METHODOLOGY:

• In the analysis of 77 studies, 45, involving 3050 participants, were included in the meta-analysis and 32 studies in the systematic review.
• The studies’ inclusion criteria included adult patients with type 2 diabetes, with data on fasting glucose and/or A1c and/or , and involving any supplementation with black cumin, clove, , saffron, thyme, ginger, black pepper, , curcumin, cinnamon, basil, and/or oregano.
• The number of studies involving clove, parsley, thyme, black pepper, rosemary, basil, or oregano and their association with glycemic factors in people with type 2 diabetes was insufficient, hence the analysis primarily focused on the remaining five ingredients of cinnamon, curcumin, ginger, black cumin, saffron, and rosemary.

TAKEAWAY: 

• Improvements in fasting glucose of subjects with type 2 diabetes were observed with all five ingredients of cinnamon, turmeric, ginger, black cumin, and saffron.
• However, the most significant decreases in fasting glucose, between 17 mg/dL and 27 mg/dL, occurred after supplementation with black cumin, followed by cinnamon and ginger.
• Notably, only ginger and black cumin were associated with a significant improvement in A1c.
• Only cinnamon and ginger were associated with a significant decrease in insulin values.
• Of the 11 studies including cinnamon in the meta-analysis, 6 reported significant differences in fasting glucose, while 4 had differences in A1c after the supplementation.
• However, ginger was the only component associated with a significant decrease in each of the 3 outcomes examined of fasting glucose, A1c, and insulin.

IN PRACTICE:

“The Mediterranean Diet is the dietary pattern par excellence for managing and preventing metabolic diseases, such as type 2 diabetes,” the authors reported.

“As far as we are aware, this is the first systematic review and meta-analysis aiming to evaluate the effect of aromatic herbs and spices included in the Mediterranean Diet, such as black cumin, clove [and others], on the glycemic profile of individuals with type 2 diabetes,” they added.

“When focusing on HbA1c, only ginger and black cumin demonstrated therapeutic effects,” the authors noted. “However, our meta-analysis highlights ginger as an herb with substantial translational potential for diabetes treatment, impacting all three glycemic parameters.”

“Regarding clove, parsley, thyme, black pepper, rosemary, basil, and oregano, more studies are needed to analyze the effect of these herbs on the glycemic profile in type 2 diabetes subjects,” the authors concluded.

SOURCE:

The study was published on March 7, 2024, in Nutrients. The first author was Maria Carmen Garza, PhD, of the Department of Human Anatomy and Histology, School Medicine, University of Zaragoza, Zaragoza, Spain.

LIMITATIONS:

Despite the results, a variety of other factors can affect fasting glucose levels, including changes in body weight or body mass index, as well as the combination of spice or aromatic herb supplementation with physical activity or lifestyle changes, the authors noted.

Due to the studies’ differences, the determination of effective dosages of the herbs and spices was not possible.

Furthermore, the studies had wide variations in quality, with few studies including adequate statistical analysis.

DISCLOSURES:

The authors had no disclosures to report.

A version of this article appeared on Medscape.com.

TOPLINE: 

The spices and aromatic herbs of the Mediterranean diet with significant benefits in improving glycemic health in type 2 diabetes are limited to ginger, cinnamon, black cumin, turmeric, and saffron, with ginger, black cumin, and cinnamon having the strongest effects on fasting glucose, according to a systematic review and meta-analysis of research.

The meta-analysis also evaluated clove, thyme, turmeric, and various other spices and herbs common in the diet but showed no other correlations with glycemic benefits. 

METHODOLOGY:

• In the analysis of 77 studies, 45, involving 3050 participants, were included in the meta-analysis and 32 studies in the systematic review.
• The studies’ inclusion criteria included adult patients with type 2 diabetes, with data on fasting glucose and/or A1c and/or , and involving any supplementation with black cumin, clove, , saffron, thyme, ginger, black pepper, , curcumin, cinnamon, basil, and/or oregano.
• The number of studies involving clove, parsley, thyme, black pepper, rosemary, basil, or oregano and their association with glycemic factors in people with type 2 diabetes was insufficient, hence the analysis primarily focused on the remaining five ingredients of cinnamon, curcumin, ginger, black cumin, saffron, and rosemary.

TAKEAWAY: 

• Improvements in fasting glucose of subjects with type 2 diabetes were observed with all five ingredients of cinnamon, turmeric, ginger, black cumin, and saffron.
• However, the most significant decreases in fasting glucose, between 17 mg/dL and 27 mg/dL, occurred after supplementation with black cumin, followed by cinnamon and ginger.
• Notably, only ginger and black cumin were associated with a significant improvement in A1c.
• Only cinnamon and ginger were associated with a significant decrease in insulin values.
• Of the 11 studies including cinnamon in the meta-analysis, 6 reported significant differences in fasting glucose, while 4 had differences in A1c after the supplementation.
• However, ginger was the only component associated with a significant decrease in each of the 3 outcomes examined of fasting glucose, A1c, and insulin.

IN PRACTICE:

“The Mediterranean Diet is the dietary pattern par excellence for managing and preventing metabolic diseases, such as type 2 diabetes,” the authors reported.

“As far as we are aware, this is the first systematic review and meta-analysis aiming to evaluate the effect of aromatic herbs and spices included in the Mediterranean Diet, such as black cumin, clove [and others], on the glycemic profile of individuals with type 2 diabetes,” they added.

“When focusing on HbA1c, only ginger and black cumin demonstrated therapeutic effects,” the authors noted. “However, our meta-analysis highlights ginger as an herb with substantial translational potential for diabetes treatment, impacting all three glycemic parameters.”

“Regarding clove, parsley, thyme, black pepper, rosemary, basil, and oregano, more studies are needed to analyze the effect of these herbs on the glycemic profile in type 2 diabetes subjects,” the authors concluded.

SOURCE:

The study was published on March 7, 2024, in Nutrients. The first author was Maria Carmen Garza, PhD, of the Department of Human Anatomy and Histology, School Medicine, University of Zaragoza, Zaragoza, Spain.

LIMITATIONS:

Despite the results, a variety of other factors can affect fasting glucose levels, including changes in body weight or body mass index, as well as the combination of spice or aromatic herb supplementation with physical activity or lifestyle changes, the authors noted.

Due to the studies’ differences, the determination of effective dosages of the herbs and spices was not possible.

Furthermore, the studies had wide variations in quality, with few studies including adequate statistical analysis.

DISCLOSURES:

The authors had no disclosures to report.

A version of this article appeared on Medscape.com.

Bone-modifying agents — most notably denosumab — are often prescribed to prevent skeletal-related complications in patients with metastatic castration-sensitive prostate cancer, but the drugs are not recommended for this indication and can lead to severe toxicities.

How much does Medicare spend each year on non-recommended bone therapy?

The answer, according to a new analysis in JCO Oncology Practice, is more than $44 million, with about $43 million coming from denosumab alone.

Overall, this study found that “the Medicare program pays tens of millions of dollars each year” for bone-modifying agents in patients with metastatic castration-sensitive prostate cancer, “which is not effective and may cause side effects,” lead author Aaron Mitchell, MD, MPH, a medical oncologist at Memorial Sloan Kettering Cancer Center, New York City, and colleagues concluded.

“These findings suggest reducing bone agent overuse could be a rare healthcare ‘win-win.’ Lower costs AND improved patient outcomes,” tweeted Dr. Mitchell. “If I were a payer, I’d be paying attention!”
 

In Prostate Cancer, Bone-Modifying Drug Indications Vary

Bone-modifying drugs are indicated for some patients with prostate cancer.

The American Society of Clinical Oncology has endorsed guidelines that recommend the use of denosumab in men with nonmetastatic prostate cancer at high risk for fracture while taking androgen deprivation therapy.

Among men with metastatic castration-resistant prostate cancer, guidelines also recommend zoledronic acid or denosumab for preventing or delaying skeletal-related events, such as pathologic fractures and spinal cord compression.

For patients with metastatic castration-sensitive disease, however, the bone-modifying agents show no benefit in preventing skeletal-related events and are not recommended for that indication.

In this population, “treatment with bone agents results only in avoidable toxicity and financial cost,” Dr. Mitchell tweeted. In its higher-dose formulation, denosumab comes with a price tag of approximately $40,000 per year in the United States.

An earlier study from Dr. Mitchell and colleagues revealed that the use of bone-modifying drugs to prevent skeletal events in metastatic castration-sensitive prostate cancer is common.

To better understand the costs associated with this inappropriate use, the researchers reviewed Surveillance, Epidemiology, and End Results Program Medicare data from 2011 to 2015. The team identified the frequency and number of doses of zoledronic acid and denosumab prescribed against recommendations in the metastatic castration-sensitive setting, making sure to distinguish between the use of denosumab to prevent osteoporotic fractures (appropriate use) and to prevent skeletal-related events (non-recommended use).

The team found that, among 2627 patients with metastatic castration-sensitive prostate cancer, 42% received at least one dose of denosumab and 18% received at least one dose of zoledronic acid.

The authors also found that unnecessary use of these drugs increased over time — with a little over 17% of patients receiving zoledronic acid between 2007 and 2009 and just over 28% receiving either denosumab (20.3%) or zoledronic acid (8.4%) from 2012 to 2015.

The annual costs to Medicare from non-recommended prescribing came to $44,105,041 for both agents, with the costs associated with denosumab representing the lion’s share at $43,303,078.

Non-recommended use of these agents also came with adverse events, such as femur fracture and hypocalcemia, which cost an estimated $758,450 to treat annually — $682,865 for denosumab and $75,585 for zoledronic acid.

The study focused on the Medicare-age population, which means the estimates are conservative. “Denosumab overuse for younger patients with castration-sensitive prostate cancer would add substantially to this total,” the authors wrote.

“This study contributes new evidence of overuse in the metastatic castrate-sensitive prostate cancer setting, which I must admit reflects my clinical experience in seeing patients for second opinions who are treated in the community,” said Samuel U. Takvorian, MD, of the Division of Hematology and Oncology, Perelman School of Medicine, Philadelphia, who wasn’t involved in the research. “While there are some circumstances in which one would consider using a bone-modifying agent in the metastatic castrate-sensitive prostate cancer setting, most [of these] men don’t need them upfront.”
 

Why Is the Overuse Happening?

One reason for the inappropriate use of bone-modifying drugs could be confusion surrounding the recommendations because the drugs are recommended for some patients with prostate cancer.

Michael R. Laurent, MD, PhD, of Imelda Hospital, Bonheiden, Belgium, explained that the use of bone-modifying drugs is, paradoxically, often overlooked in settings where they are recommended — when patients have an elevated risk for osteoporosis or fracture.

“Guidelines are quite unequivocal in their recommendations to prevent osteoporosis in mostly older men who receive androgen deprivation therapy,” but “I think there is significant undertreatment” in these patients, Dr. Laurent told this news organization.

However, the recommendation for patients at risk for osteoporosis or bone fracture calls for less intense regimens, which may include lower-dose denosumab, administered once every 6 months, zoledronic acid, given yearly, or another lower potency agent, such as oral alendronate weekly, explained Philip J. Saylor, MD, an attending physician at Massachusetts General Hospital and assistant professor at Harvard Medical School, Boston.

Meanwhile, “monthly high-intensity therapy to prevent skeletal events should be reserved specifically for bone metastatic castration-resistant prostate cancer for more than just cost reasons,” Dr. Saylor said.

When it comes to the higher dose, monthly therapy in castration-sensitive prostate cancer, “we have no evidence that it is beneficial,” he said, adding that “when the prostate cancer itself is well controlled by hormonal therapy, there just aren’t very many pathologic fractures or other bone complications.”

Alongside possible confusion over the recommendations, many physicians also likely don’t know how much denosumab costs.

“In our recent physician interview study, we did find that most physicians were very much unaware of the cost of this drug, or the cost difference between denosumab and zoledronic acid, so I do think that lack of cost awareness is a factor,” Dr. Mitchell said.

Part of the reason may be how Medicare covers these agents. Typically, Medicare would not cover non-recommended indications, but “in this case, Medicare coverage is broader and includes both the guideline-recommended and non-recommended uses,” Dr. Mitchell explained.

However, the authors also identified a more cynical reason for non-recommended prescribing — promotional payments from drug makers to physicians.

In another recent paper, Dr. Mitchell said he found about “30% of doctors treating prostate cancer had received payments from Amgen for Xgeva [denosumab] promotion during the last year.”

These payments appeared to influence non-recommended prescribing: Among patients whose doctor had not received payments, 31.4% received non-recommended denosumab, which increased to nearly 50% of patients among doctors who had received payments.

Dr. Mitchell suggested a few ways to help curb inappropriate prescribing.

Medicare could, for instance, change its coverage policy to include only the recommended uses of these agents, Dr. Mitchell said.

More physician education would be another solution. “I think that physician education would be one ‘bottom-up’ approach that could work,” Dr. Mitchell added.

Dr. Mitchell, Dr. Takvorian, and Dr. Saylor had no disclosures to report. Dr. Laurent has received lecture and consultancy fees from Alexion, AM Pharma, Amgen, Galapagos, Kyowa Kirin, Menarini, Orifarm, Pharmanovia, Takeda, UCB, and Will Pharma.
 

A version of this article appeared on Medscape.com.

Bone-modifying agents — most notably denosumab — are often prescribed to prevent skeletal-related complications in patients with metastatic castration-sensitive prostate cancer, but the drugs are not recommended for this indication and can lead to severe toxicities.

How much does Medicare spend each year on non-recommended bone therapy?

The answer, according to a new analysis in JCO Oncology Practice, is more than $44 million, with about $43 million coming from denosumab alone.

Overall, this study found that “the Medicare program pays tens of millions of dollars each year” for bone-modifying agents in patients with metastatic castration-sensitive prostate cancer, “which is not effective and may cause side effects,” lead author Aaron Mitchell, MD, MPH, a medical oncologist at Memorial Sloan Kettering Cancer Center, New York City, and colleagues concluded.

“These findings suggest reducing bone agent overuse could be a rare healthcare ‘win-win.’ Lower costs AND improved patient outcomes,” tweeted Dr. Mitchell. “If I were a payer, I’d be paying attention!”
 

In Prostate Cancer, Bone-Modifying Drug Indications Vary

Bone-modifying drugs are indicated for some patients with prostate cancer.

The American Society of Clinical Oncology has endorsed guidelines that recommend the use of denosumab in men with nonmetastatic prostate cancer at high risk for fracture while taking androgen deprivation therapy.

Among men with metastatic castration-resistant prostate cancer, guidelines also recommend zoledronic acid or denosumab for preventing or delaying skeletal-related events, such as pathologic fractures and spinal cord compression.

For patients with metastatic castration-sensitive disease, however, the bone-modifying agents show no benefit in preventing skeletal-related events and are not recommended for that indication.

In this population, “treatment with bone agents results only in avoidable toxicity and financial cost,” Dr. Mitchell tweeted. In its higher-dose formulation, denosumab comes with a price tag of approximately $40,000 per year in the United States.

An earlier study from Dr. Mitchell and colleagues revealed that the use of bone-modifying drugs to prevent skeletal events in metastatic castration-sensitive prostate cancer is common.

To better understand the costs associated with this inappropriate use, the researchers reviewed Surveillance, Epidemiology, and End Results Program Medicare data from 2011 to 2015. The team identified the frequency and number of doses of zoledronic acid and denosumab prescribed against recommendations in the metastatic castration-sensitive setting, making sure to distinguish between the use of denosumab to prevent osteoporotic fractures (appropriate use) and to prevent skeletal-related events (non-recommended use).

The team found that, among 2627 patients with metastatic castration-sensitive prostate cancer, 42% received at least one dose of denosumab and 18% received at least one dose of zoledronic acid.

The authors also found that unnecessary use of these drugs increased over time — with a little over 17% of patients receiving zoledronic acid between 2007 and 2009 and just over 28% receiving either denosumab (20.3%) or zoledronic acid (8.4%) from 2012 to 2015.

The annual costs to Medicare from non-recommended prescribing came to $44,105,041 for both agents, with the costs associated with denosumab representing the lion’s share at $43,303,078.

Non-recommended use of these agents also came with adverse events, such as femur fracture and hypocalcemia, which cost an estimated $758,450 to treat annually — $682,865 for denosumab and $75,585 for zoledronic acid.

The study focused on the Medicare-age population, which means the estimates are conservative. “Denosumab overuse for younger patients with castration-sensitive prostate cancer would add substantially to this total,” the authors wrote.

“This study contributes new evidence of overuse in the metastatic castrate-sensitive prostate cancer setting, which I must admit reflects my clinical experience in seeing patients for second opinions who are treated in the community,” said Samuel U. Takvorian, MD, of the Division of Hematology and Oncology, Perelman School of Medicine, Philadelphia, who wasn’t involved in the research. “While there are some circumstances in which one would consider using a bone-modifying agent in the metastatic castrate-sensitive prostate cancer setting, most [of these] men don’t need them upfront.”
 

Why Is the Overuse Happening?

One reason for the inappropriate use of bone-modifying drugs could be confusion surrounding the recommendations because the drugs are recommended for some patients with prostate cancer.

Michael R. Laurent, MD, PhD, of Imelda Hospital, Bonheiden, Belgium, explained that the use of bone-modifying drugs is, paradoxically, often overlooked in settings where they are recommended — when patients have an elevated risk for osteoporosis or fracture.

“Guidelines are quite unequivocal in their recommendations to prevent osteoporosis in mostly older men who receive androgen deprivation therapy,” but “I think there is significant undertreatment” in these patients, Dr. Laurent told this news organization.

However, the recommendation for patients at risk for osteoporosis or bone fracture calls for less intense regimens, which may include lower-dose denosumab, administered once every 6 months, zoledronic acid, given yearly, or another lower potency agent, such as oral alendronate weekly, explained Philip J. Saylor, MD, an attending physician at Massachusetts General Hospital and assistant professor at Harvard Medical School, Boston.

Meanwhile, “monthly high-intensity therapy to prevent skeletal events should be reserved specifically for bone metastatic castration-resistant prostate cancer for more than just cost reasons,” Dr. Saylor said.

When it comes to the higher dose, monthly therapy in castration-sensitive prostate cancer, “we have no evidence that it is beneficial,” he said, adding that “when the prostate cancer itself is well controlled by hormonal therapy, there just aren’t very many pathologic fractures or other bone complications.”

Alongside possible confusion over the recommendations, many physicians also likely don’t know how much denosumab costs.

“In our recent physician interview study, we did find that most physicians were very much unaware of the cost of this drug, or the cost difference between denosumab and zoledronic acid, so I do think that lack of cost awareness is a factor,” Dr. Mitchell said.

Part of the reason may be how Medicare covers these agents. Typically, Medicare would not cover non-recommended indications, but “in this case, Medicare coverage is broader and includes both the guideline-recommended and non-recommended uses,” Dr. Mitchell explained.

However, the authors also identified a more cynical reason for non-recommended prescribing — promotional payments from drug makers to physicians.

In another recent paper, Dr. Mitchell said he found about “30% of doctors treating prostate cancer had received payments from Amgen for Xgeva [denosumab] promotion during the last year.”

These payments appeared to influence non-recommended prescribing: Among patients whose doctor had not received payments, 31.4% received non-recommended denosumab, which increased to nearly 50% of patients among doctors who had received payments.

Dr. Mitchell suggested a few ways to help curb inappropriate prescribing.

Medicare could, for instance, change its coverage policy to include only the recommended uses of these agents, Dr. Mitchell said.

More physician education would be another solution. “I think that physician education would be one ‘bottom-up’ approach that could work,” Dr. Mitchell added.

Dr. Mitchell, Dr. Takvorian, and Dr. Saylor had no disclosures to report. Dr. Laurent has received lecture and consultancy fees from Alexion, AM Pharma, Amgen, Galapagos, Kyowa Kirin, Menarini, Orifarm, Pharmanovia, Takeda, UCB, and Will Pharma.
 

A version of this article appeared on Medscape.com.

Bone-modifying agents — most notably denosumab — are often prescribed to prevent skeletal-related complications in patients with metastatic castration-sensitive prostate cancer, but the drugs are not recommended for this indication and can lead to severe toxicities.

How much does Medicare spend each year on non-recommended bone therapy?

The answer, according to a new analysis in JCO Oncology Practice, is more than $44 million, with about $43 million coming from denosumab alone.

Overall, this study found that “the Medicare program pays tens of millions of dollars each year” for bone-modifying agents in patients with metastatic castration-sensitive prostate cancer, “which is not effective and may cause side effects,” lead author Aaron Mitchell, MD, MPH, a medical oncologist at Memorial Sloan Kettering Cancer Center, New York City, and colleagues concluded.

“These findings suggest reducing bone agent overuse could be a rare healthcare ‘win-win.’ Lower costs AND improved patient outcomes,” tweeted Dr. Mitchell. “If I were a payer, I’d be paying attention!”
 

In Prostate Cancer, Bone-Modifying Drug Indications Vary

Bone-modifying drugs are indicated for some patients with prostate cancer.

The American Society of Clinical Oncology has endorsed guidelines that recommend the use of denosumab in men with nonmetastatic prostate cancer at high risk for fracture while taking androgen deprivation therapy.

Among men with metastatic castration-resistant prostate cancer, guidelines also recommend zoledronic acid or denosumab for preventing or delaying skeletal-related events, such as pathologic fractures and spinal cord compression.

For patients with metastatic castration-sensitive disease, however, the bone-modifying agents show no benefit in preventing skeletal-related events and are not recommended for that indication.

In this population, “treatment with bone agents results only in avoidable toxicity and financial cost,” Dr. Mitchell tweeted. In its higher-dose formulation, denosumab comes with a price tag of approximately $40,000 per year in the United States.

An earlier study from Dr. Mitchell and colleagues revealed that the use of bone-modifying drugs to prevent skeletal events in metastatic castration-sensitive prostate cancer is common.

To better understand the costs associated with this inappropriate use, the researchers reviewed Surveillance, Epidemiology, and End Results Program Medicare data from 2011 to 2015. The team identified the frequency and number of doses of zoledronic acid and denosumab prescribed against recommendations in the metastatic castration-sensitive setting, making sure to distinguish between the use of denosumab to prevent osteoporotic fractures (appropriate use) and to prevent skeletal-related events (non-recommended use).

The team found that, among 2627 patients with metastatic castration-sensitive prostate cancer, 42% received at least one dose of denosumab and 18% received at least one dose of zoledronic acid.

The authors also found that unnecessary use of these drugs increased over time — with a little over 17% of patients receiving zoledronic acid between 2007 and 2009 and just over 28% receiving either denosumab (20.3%) or zoledronic acid (8.4%) from 2012 to 2015.

The annual costs to Medicare from non-recommended prescribing came to $44,105,041 for both agents, with the costs associated with denosumab representing the lion’s share at $43,303,078.

Non-recommended use of these agents also came with adverse events, such as femur fracture and hypocalcemia, which cost an estimated $758,450 to treat annually — $682,865 for denosumab and $75,585 for zoledronic acid.

The study focused on the Medicare-age population, which means the estimates are conservative. “Denosumab overuse for younger patients with castration-sensitive prostate cancer would add substantially to this total,” the authors wrote.

“This study contributes new evidence of overuse in the metastatic castrate-sensitive prostate cancer setting, which I must admit reflects my clinical experience in seeing patients for second opinions who are treated in the community,” said Samuel U. Takvorian, MD, of the Division of Hematology and Oncology, Perelman School of Medicine, Philadelphia, who wasn’t involved in the research. “While there are some circumstances in which one would consider using a bone-modifying agent in the metastatic castrate-sensitive prostate cancer setting, most [of these] men don’t need them upfront.”
 

Why Is the Overuse Happening?

One reason for the inappropriate use of bone-modifying drugs could be confusion surrounding the recommendations because the drugs are recommended for some patients with prostate cancer.

Michael R. Laurent, MD, PhD, of Imelda Hospital, Bonheiden, Belgium, explained that the use of bone-modifying drugs is, paradoxically, often overlooked in settings where they are recommended — when patients have an elevated risk for osteoporosis or fracture.

“Guidelines are quite unequivocal in their recommendations to prevent osteoporosis in mostly older men who receive androgen deprivation therapy,” but “I think there is significant undertreatment” in these patients, Dr. Laurent told this news organization.

However, the recommendation for patients at risk for osteoporosis or bone fracture calls for less intense regimens, which may include lower-dose denosumab, administered once every 6 months, zoledronic acid, given yearly, or another lower potency agent, such as oral alendronate weekly, explained Philip J. Saylor, MD, an attending physician at Massachusetts General Hospital and assistant professor at Harvard Medical School, Boston.

Meanwhile, “monthly high-intensity therapy to prevent skeletal events should be reserved specifically for bone metastatic castration-resistant prostate cancer for more than just cost reasons,” Dr. Saylor said.

When it comes to the higher dose, monthly therapy in castration-sensitive prostate cancer, “we have no evidence that it is beneficial,” he said, adding that “when the prostate cancer itself is well controlled by hormonal therapy, there just aren’t very many pathologic fractures or other bone complications.”

Alongside possible confusion over the recommendations, many physicians also likely don’t know how much denosumab costs.

“In our recent physician interview study, we did find that most physicians were very much unaware of the cost of this drug, or the cost difference between denosumab and zoledronic acid, so I do think that lack of cost awareness is a factor,” Dr. Mitchell said.

Part of the reason may be how Medicare covers these agents. Typically, Medicare would not cover non-recommended indications, but “in this case, Medicare coverage is broader and includes both the guideline-recommended and non-recommended uses,” Dr. Mitchell explained.

However, the authors also identified a more cynical reason for non-recommended prescribing — promotional payments from drug makers to physicians.

In another recent paper, Dr. Mitchell said he found about “30% of doctors treating prostate cancer had received payments from Amgen for Xgeva [denosumab] promotion during the last year.”

These payments appeared to influence non-recommended prescribing: Among patients whose doctor had not received payments, 31.4% received non-recommended denosumab, which increased to nearly 50% of patients among doctors who had received payments.

Dr. Mitchell suggested a few ways to help curb inappropriate prescribing.

Medicare could, for instance, change its coverage policy to include only the recommended uses of these agents, Dr. Mitchell said.

More physician education would be another solution. “I think that physician education would be one ‘bottom-up’ approach that could work,” Dr. Mitchell added.

Dr. Mitchell, Dr. Takvorian, and Dr. Saylor had no disclosures to report. Dr. Laurent has received lecture and consultancy fees from Alexion, AM Pharma, Amgen, Galapagos, Kyowa Kirin, Menarini, Orifarm, Pharmanovia, Takeda, UCB, and Will Pharma.
 

A version of this article appeared on Medscape.com.

TOPLINE:

More than a billion children, adolescents, and adults are living with obesity, globally, with rates of obesity among children and adolescents quadrupling between 1990 and 2022.

Obesity rates nearly tripled among adult men and more than doubled among women during the time period, according to results from a collaboration between the NCD Risk Factor Collaboration and the World Health Organization (WHO).

The rates of being underweight have meanwhile declined, making obesity now the most common form of malnutrition in most regions.

METHODOLOGY:

In this global analysis, the authors evaluated 3663 population-based studies conducted in 200 countries and territories, with data on 222 million participants in the general population, including height and weight.

Trends were established according to categories of body mass index (BMI) in groups of adults aged 20 years or older, representing 150 million individuals, and 63 million school-aged children and adolescents aged 5-19 years, spanning from 1990 to 2022.

Assessments of adults focus on the individual and combined prevalence of underweight (BMI < 18.5 kg/m²) and obesity (BMI ≥ 30 kg/m²).

For school-aged children and adolescents, assessments were for thinness (BMI < 2 standard deviation [SD] below the median of the WHO growth reference) and obesity (BMI > 2 SD above the median).

TAKEAWAY:

The combined prevalence of obesity as well as underweight increased over the study period in most countries for women (162 countries, 81%) and men (140 countries, 70%), with increases driven by increases in obesity in nearly all countries, while underweight or thinness rates decreased.

In 2022, obesity rates were higher than underweight in 177 countries (89%) for women and 145 countries (73%) for men.

Likewise, among school-aged children and adolescents, obesity in 2022 was more prevalent than thinness among girls in 130 countries (67%) and boys in 125 countries (63%), while thinness was more prevalent in only 18% and 21% of the countries, respectively.

In 2022, the combined prevalence of underweight and obesity was highest in island nations in the Caribbean and Polynesia and Micronesia, as well as in countries in the Middle East and North Africa.

Among school-aged children, the countries with the highest combined prevalence of underweight and obesity were Polynesia and Micronesia and the Caribbean for both sexes and Chile and Qatar for boys.

The prevalence of obesity surpassed 60% among women in eight countries (4%) and men in six countries (3%), all in Polynesia and Micronesia.

In the United States, the obesity rate increased from 21.2% in 1990 to 43.8% in 2022 for women and from 16.9% to 41.6% in 2022 for men.

As of 2022, the prevalence of obesity in the United States ranked 36th highest in the world for women and 10th highest in the world for men.

IN PRACTICE:

“It is very concerning that the epidemic of obesity that was evident among adults in much of the world in 1990 is now mirrored in school-aged children and adolescents,” senior author Majid Ezzati, PhD, of Imperial College of London, said in a press statement.

“At the same time, hundreds of millions are still affected by undernutrition, particularly in some of the poorest parts of the world,” he said. “To successfully tackle both forms of malnutrition, it is vital we significantly improve the availability and affordability of healthy, nutritious foods.”

Tedros Adhanom Ghebreyesus, PhD, WHO Director-General, added in the press statement that “this new study highlights the importance of preventing and managing obesity from early life to adulthood, through diet, physical activity, and adequate care, as needed.

“Getting back on track to meet the global targets for curbing obesity will take the work of governments and communities, supported by evidence-based policies from WHO and national public health agencies,” he said.

“Importantly, it requires the cooperation of the private sector, which must be accountable for the health impacts of their products.”

SOURCE:

The study was published on February 29, 2024, in The Lancet. The study was conducted by the NCD Risk Factor Collaboration and the WHO.

LIMITATIONS:

Data differences in countries included that some had limited data and three had none, requiring some estimates to be formed using data from other countries. Data availability was also lower among the youngest and oldest patients, increasing uncertainty of data in those age groups. In addition, data from health surveys can be subject to error, and BMI can be an imperfect measure of the extent or distribution of body fat.

DISCLOSURES:

The study was funded by UK Medical Research Council, UK Research and Innovation, and the European Commission.
 

A version of this article appeared on Medscape.com.

TOPLINE:

More than a billion children, adolescents, and adults are living with obesity, globally, with rates of obesity among children and adolescents quadrupling between 1990 and 2022.

Obesity rates nearly tripled among adult men and more than doubled among women during the time period, according to results from a collaboration between the NCD Risk Factor Collaboration and the World Health Organization (WHO).

The rates of being underweight have meanwhile declined, making obesity now the most common form of malnutrition in most regions.

METHODOLOGY:

In this global analysis, the authors evaluated 3663 population-based studies conducted in 200 countries and territories, with data on 222 million participants in the general population, including height and weight.

Trends were established according to categories of body mass index (BMI) in groups of adults aged 20 years or older, representing 150 million individuals, and 63 million school-aged children and adolescents aged 5-19 years, spanning from 1990 to 2022.

Assessments of adults focus on the individual and combined prevalence of underweight (BMI < 18.5 kg/m²) and obesity (BMI ≥ 30 kg/m²).

For school-aged children and adolescents, assessments were for thinness (BMI < 2 standard deviation [SD] below the median of the WHO growth reference) and obesity (BMI > 2 SD above the median).

TAKEAWAY:

The combined prevalence of obesity as well as underweight increased over the study period in most countries for women (162 countries, 81%) and men (140 countries, 70%), with increases driven by increases in obesity in nearly all countries, while underweight or thinness rates decreased.

In 2022, obesity rates were higher than underweight in 177 countries (89%) for women and 145 countries (73%) for men.

Likewise, among school-aged children and adolescents, obesity in 2022 was more prevalent than thinness among girls in 130 countries (67%) and boys in 125 countries (63%), while thinness was more prevalent in only 18% and 21% of the countries, respectively.

In 2022, the combined prevalence of underweight and obesity was highest in island nations in the Caribbean and Polynesia and Micronesia, as well as in countries in the Middle East and North Africa.

Among school-aged children, the countries with the highest combined prevalence of underweight and obesity were Polynesia and Micronesia and the Caribbean for both sexes and Chile and Qatar for boys.

The prevalence of obesity surpassed 60% among women in eight countries (4%) and men in six countries (3%), all in Polynesia and Micronesia.

In the United States, the obesity rate increased from 21.2% in 1990 to 43.8% in 2022 for women and from 16.9% to 41.6% in 2022 for men.

As of 2022, the prevalence of obesity in the United States ranked 36th highest in the world for women and 10th highest in the world for men.

IN PRACTICE:

“It is very concerning that the epidemic of obesity that was evident among adults in much of the world in 1990 is now mirrored in school-aged children and adolescents,” senior author Majid Ezzati, PhD, of Imperial College of London, said in a press statement.

“At the same time, hundreds of millions are still affected by undernutrition, particularly in some of the poorest parts of the world,” he said. “To successfully tackle both forms of malnutrition, it is vital we significantly improve the availability and affordability of healthy, nutritious foods.”

Tedros Adhanom Ghebreyesus, PhD, WHO Director-General, added in the press statement that “this new study highlights the importance of preventing and managing obesity from early life to adulthood, through diet, physical activity, and adequate care, as needed.

“Getting back on track to meet the global targets for curbing obesity will take the work of governments and communities, supported by evidence-based policies from WHO and national public health agencies,” he said.

“Importantly, it requires the cooperation of the private sector, which must be accountable for the health impacts of their products.”

SOURCE:

The study was published on February 29, 2024, in The Lancet. The study was conducted by the NCD Risk Factor Collaboration and the WHO.

LIMITATIONS:

Data differences in countries included that some had limited data and three had none, requiring some estimates to be formed using data from other countries. Data availability was also lower among the youngest and oldest patients, increasing uncertainty of data in those age groups. In addition, data from health surveys can be subject to error, and BMI can be an imperfect measure of the extent or distribution of body fat.

DISCLOSURES:

The study was funded by UK Medical Research Council, UK Research and Innovation, and the European Commission.
 

A version of this article appeared on Medscape.com.

TOPLINE:

More than a billion children, adolescents, and adults are living with obesity, globally, with rates of obesity among children and adolescents quadrupling between 1990 and 2022.

Obesity rates nearly tripled among adult men and more than doubled among women during the time period, according to results from a collaboration between the NCD Risk Factor Collaboration and the World Health Organization (WHO).

The rates of being underweight have meanwhile declined, making obesity now the most common form of malnutrition in most regions.

METHODOLOGY:

In this global analysis, the authors evaluated 3663 population-based studies conducted in 200 countries and territories, with data on 222 million participants in the general population, including height and weight.

Trends were established according to categories of body mass index (BMI) in groups of adults aged 20 years or older, representing 150 million individuals, and 63 million school-aged children and adolescents aged 5-19 years, spanning from 1990 to 2022.

Assessments of adults focus on the individual and combined prevalence of underweight (BMI < 18.5 kg/m²) and obesity (BMI ≥ 30 kg/m²).

For school-aged children and adolescents, assessments were for thinness (BMI < 2 standard deviation [SD] below the median of the WHO growth reference) and obesity (BMI > 2 SD above the median).

TAKEAWAY:

The combined prevalence of obesity as well as underweight increased over the study period in most countries for women (162 countries, 81%) and men (140 countries, 70%), with increases driven by increases in obesity in nearly all countries, while underweight or thinness rates decreased.

In 2022, obesity rates were higher than underweight in 177 countries (89%) for women and 145 countries (73%) for men.

Likewise, among school-aged children and adolescents, obesity in 2022 was more prevalent than thinness among girls in 130 countries (67%) and boys in 125 countries (63%), while thinness was more prevalent in only 18% and 21% of the countries, respectively.

In 2022, the combined prevalence of underweight and obesity was highest in island nations in the Caribbean and Polynesia and Micronesia, as well as in countries in the Middle East and North Africa.

Among school-aged children, the countries with the highest combined prevalence of underweight and obesity were Polynesia and Micronesia and the Caribbean for both sexes and Chile and Qatar for boys.

The prevalence of obesity surpassed 60% among women in eight countries (4%) and men in six countries (3%), all in Polynesia and Micronesia.

In the United States, the obesity rate increased from 21.2% in 1990 to 43.8% in 2022 for women and from 16.9% to 41.6% in 2022 for men.

As of 2022, the prevalence of obesity in the United States ranked 36th highest in the world for women and 10th highest in the world for men.

IN PRACTICE:

“It is very concerning that the epidemic of obesity that was evident among adults in much of the world in 1990 is now mirrored in school-aged children and adolescents,” senior author Majid Ezzati, PhD, of Imperial College of London, said in a press statement.

“At the same time, hundreds of millions are still affected by undernutrition, particularly in some of the poorest parts of the world,” he said. “To successfully tackle both forms of malnutrition, it is vital we significantly improve the availability and affordability of healthy, nutritious foods.”

Tedros Adhanom Ghebreyesus, PhD, WHO Director-General, added in the press statement that “this new study highlights the importance of preventing and managing obesity from early life to adulthood, through diet, physical activity, and adequate care, as needed.

“Getting back on track to meet the global targets for curbing obesity will take the work of governments and communities, supported by evidence-based policies from WHO and national public health agencies,” he said.

“Importantly, it requires the cooperation of the private sector, which must be accountable for the health impacts of their products.”

SOURCE:

The study was published on February 29, 2024, in The Lancet. The study was conducted by the NCD Risk Factor Collaboration and the WHO.

LIMITATIONS:

Data differences in countries included that some had limited data and three had none, requiring some estimates to be formed using data from other countries. Data availability was also lower among the youngest and oldest patients, increasing uncertainty of data in those age groups. In addition, data from health surveys can be subject to error, and BMI can be an imperfect measure of the extent or distribution of body fat.

DISCLOSURES:

The study was funded by UK Medical Research Council, UK Research and Innovation, and the European Commission.
 

A version of this article appeared on Medscape.com.