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Carefully Designing De-escalation Trials in Breast Cancer
Over the past few years, several new, highly effective treatment strategies have improved survival outcomes in patients with early breast cancer.
“We’ve been very fortunate” to see these advances, Sara M. Tolaney, MD, MPH, chief, Division of Breast Oncology, Dana-Farber Cancer Institute, Boston, told attendees at the European Society of Medical Oncology (ESMO) Breast Cancer annual congress.
However, Dr. Tolaney noted, these new treatment approaches can come with big limitations — namely, potential overtreatment of some patients as well as short- and long-term toxicities, some of which can be life-threatening.
These caveats have prompted trials exploring strategies to de-escalate therapy, which essentially means providing the right amount of treatment to the right patient at the right time, said Dr. Tolaney. The goal is to “right-size” or “optimize therapy” to maintain strong outcomes while mitigating side effects.
she explained.
But, she added, de-escalation trials are “not a very attractive strategy to pharmaceutical companies” and can be challenging for researchers to conduct. These trials may, for instance, lack adequate sample sizes and sufficient statistical power, which can interfere with achieving clinically meaningful findings that may affect practice.
That is why carefully designing de-escalation trials is crucial, Dr. Tolaney said.
In her talk at ESMO Breast, Dr. Tolaney highlighted several strategies for designing these trials.
One strategy is to shorten the duration of therapy, said Dr. Tolaney.
This approach was explored in the PHARE and PERSEPHONE trials, which looked at 6 vs 12 months of trastuzumab in nonmetastatic breast cancer. Other trials, such as GeparNuevo and KEYNOTE-522, explored whether adjuvant checkpoint inhibitor therapy was needed, or could be skipped, following neoadjuvant therapy. This approach requires establishing noninferiority, or similar efficacy, between the standard of care and the shorter duration of therapy.
A second strategy is to remove part of the chemotherapy regimen, typically the most toxic agent, Dr. Tolaney continued.
Conducting a prospective, randomized trial exploring this approach in human epidermal growth factor receptor 2–positive (HER2+) early breast cancer, for example, would be difficult for a range of reasons, such as the need to enroll thousands of patients.
Dr. Tolaney and colleagues, however, designed a nonrandomized prospective study — the APT trial — with just over 400 patients to assess adjuvant paclitaxel plus trastuzumab in patients with node-negative HER2+ disease. The open-label, single-arm, phase 2 APT trial found that adjuvant paclitaxel and trastuzumab led to a 10-year recurrence-free interval of 96.3%, 10-year overall survival of 94.3%, and 10-year breast cancer–specific survival of 98.8%.
Outcomes with this adjuvant regimen were comparable to previous findings in historical controls who received doxorubicin, cyclophosphamide, paclitaxel, and trastuzumab or docetaxel, carboplatin, and trastuzumab.
Dr. Tolaney concluded that given few events, “it’s unlikely we need to escalate therapy to do better for most patients,” and the APT regimen “can be considered a reasonable and appealing approach for the majority of patients” with node-negative HER2+ breast cancer.
“A single-arm design for a de-escalation study can be practice-changing but only if there are very few recurrences,” Dr. Tolaney said.
Substituting chemotherapy with a targeted, potentially less-toxic agent is a third de-escalation approach. The ATEMPT trial compared patients receiving trastuzumab emtansine (T-DM1) with those receiving paclitaxel plus trastuzumab followed by maintenance trastuzumab.
Investigators found that de-escalation with T-DM1 was associated with very few recurrences but similar rates of certain adverse events, including grade 2 or higher neurotoxicity, febrile neutropenia, and grade 4 or higher hematologic toxicity.
However, there are questions about how to define “less toxic,” Dr. Tolaney said. The trial found, for instance, that T-DM1 did have some advantages — patients reported better quality of life and experienced less alopecia and neurotoxicity, as well as a less severe impact on fertility.
Understanding the right endpoint to demonstrate less toxicity is critical, “as we start to think about how to replace standard chemotherapies with better targeted drugs,” she added.
The ATEMPT 2.0 trial, which is currently enrolling, will aim to answer some of these questions about defining and demonstrating less toxicity, she said.
Finally, some researchers are attempting to omit chemotherapy altogether with the help of biomarkers. The TAILORx trial, for instance, aimed to stratify patients with early-stage breast cancer by clinical risk factors combined with a 21-gene expression assay and found that adjuvant chemotherapy was not necessary in a large proportion of these women.
On the biomarker front, oncologists might be able to use ctDNA to guide decision-making and personalize therapy, Tolaney said. The presence of ctDNA is associated with an almost 100% likelihood of having a recurrence, whereas its absence suggests better outcomes, she explained.
Oncologists could use the presence or absence of ctDNA to guide next steps — assign patients to follow-up assessments when ctDNA is not present or to standard or experimental treatment when it is present. It may also be possible to leverage the presence of minimal residual disease to help direct treatment choices.
But ctDNA is currently not as perfect a predictor of outcome as it could be, she cautioned. “We need more sensitive assays [so] I’m not sure we’re quite ready to use lack of ctDNA to de-escalate treatment,” she said.
Dr. Tolaney declared relationships with Novartis, Pfizer, Merck, Lilly, AstraZeneca, Genentech/Roche, Eisai, Sanofi, Bristol Myers Squib, and other companies.
A version of this article appeared on Medscape.com .
Over the past few years, several new, highly effective treatment strategies have improved survival outcomes in patients with early breast cancer.
“We’ve been very fortunate” to see these advances, Sara M. Tolaney, MD, MPH, chief, Division of Breast Oncology, Dana-Farber Cancer Institute, Boston, told attendees at the European Society of Medical Oncology (ESMO) Breast Cancer annual congress.
However, Dr. Tolaney noted, these new treatment approaches can come with big limitations — namely, potential overtreatment of some patients as well as short- and long-term toxicities, some of which can be life-threatening.
These caveats have prompted trials exploring strategies to de-escalate therapy, which essentially means providing the right amount of treatment to the right patient at the right time, said Dr. Tolaney. The goal is to “right-size” or “optimize therapy” to maintain strong outcomes while mitigating side effects.
she explained.
But, she added, de-escalation trials are “not a very attractive strategy to pharmaceutical companies” and can be challenging for researchers to conduct. These trials may, for instance, lack adequate sample sizes and sufficient statistical power, which can interfere with achieving clinically meaningful findings that may affect practice.
That is why carefully designing de-escalation trials is crucial, Dr. Tolaney said.
In her talk at ESMO Breast, Dr. Tolaney highlighted several strategies for designing these trials.
One strategy is to shorten the duration of therapy, said Dr. Tolaney.
This approach was explored in the PHARE and PERSEPHONE trials, which looked at 6 vs 12 months of trastuzumab in nonmetastatic breast cancer. Other trials, such as GeparNuevo and KEYNOTE-522, explored whether adjuvant checkpoint inhibitor therapy was needed, or could be skipped, following neoadjuvant therapy. This approach requires establishing noninferiority, or similar efficacy, between the standard of care and the shorter duration of therapy.
A second strategy is to remove part of the chemotherapy regimen, typically the most toxic agent, Dr. Tolaney continued.
Conducting a prospective, randomized trial exploring this approach in human epidermal growth factor receptor 2–positive (HER2+) early breast cancer, for example, would be difficult for a range of reasons, such as the need to enroll thousands of patients.
Dr. Tolaney and colleagues, however, designed a nonrandomized prospective study — the APT trial — with just over 400 patients to assess adjuvant paclitaxel plus trastuzumab in patients with node-negative HER2+ disease. The open-label, single-arm, phase 2 APT trial found that adjuvant paclitaxel and trastuzumab led to a 10-year recurrence-free interval of 96.3%, 10-year overall survival of 94.3%, and 10-year breast cancer–specific survival of 98.8%.
Outcomes with this adjuvant regimen were comparable to previous findings in historical controls who received doxorubicin, cyclophosphamide, paclitaxel, and trastuzumab or docetaxel, carboplatin, and trastuzumab.
Dr. Tolaney concluded that given few events, “it’s unlikely we need to escalate therapy to do better for most patients,” and the APT regimen “can be considered a reasonable and appealing approach for the majority of patients” with node-negative HER2+ breast cancer.
“A single-arm design for a de-escalation study can be practice-changing but only if there are very few recurrences,” Dr. Tolaney said.
Substituting chemotherapy with a targeted, potentially less-toxic agent is a third de-escalation approach. The ATEMPT trial compared patients receiving trastuzumab emtansine (T-DM1) with those receiving paclitaxel plus trastuzumab followed by maintenance trastuzumab.
Investigators found that de-escalation with T-DM1 was associated with very few recurrences but similar rates of certain adverse events, including grade 2 or higher neurotoxicity, febrile neutropenia, and grade 4 or higher hematologic toxicity.
However, there are questions about how to define “less toxic,” Dr. Tolaney said. The trial found, for instance, that T-DM1 did have some advantages — patients reported better quality of life and experienced less alopecia and neurotoxicity, as well as a less severe impact on fertility.
Understanding the right endpoint to demonstrate less toxicity is critical, “as we start to think about how to replace standard chemotherapies with better targeted drugs,” she added.
The ATEMPT 2.0 trial, which is currently enrolling, will aim to answer some of these questions about defining and demonstrating less toxicity, she said.
Finally, some researchers are attempting to omit chemotherapy altogether with the help of biomarkers. The TAILORx trial, for instance, aimed to stratify patients with early-stage breast cancer by clinical risk factors combined with a 21-gene expression assay and found that adjuvant chemotherapy was not necessary in a large proportion of these women.
On the biomarker front, oncologists might be able to use ctDNA to guide decision-making and personalize therapy, Tolaney said. The presence of ctDNA is associated with an almost 100% likelihood of having a recurrence, whereas its absence suggests better outcomes, she explained.
Oncologists could use the presence or absence of ctDNA to guide next steps — assign patients to follow-up assessments when ctDNA is not present or to standard or experimental treatment when it is present. It may also be possible to leverage the presence of minimal residual disease to help direct treatment choices.
But ctDNA is currently not as perfect a predictor of outcome as it could be, she cautioned. “We need more sensitive assays [so] I’m not sure we’re quite ready to use lack of ctDNA to de-escalate treatment,” she said.
Dr. Tolaney declared relationships with Novartis, Pfizer, Merck, Lilly, AstraZeneca, Genentech/Roche, Eisai, Sanofi, Bristol Myers Squib, and other companies.
A version of this article appeared on Medscape.com .
Over the past few years, several new, highly effective treatment strategies have improved survival outcomes in patients with early breast cancer.
“We’ve been very fortunate” to see these advances, Sara M. Tolaney, MD, MPH, chief, Division of Breast Oncology, Dana-Farber Cancer Institute, Boston, told attendees at the European Society of Medical Oncology (ESMO) Breast Cancer annual congress.
However, Dr. Tolaney noted, these new treatment approaches can come with big limitations — namely, potential overtreatment of some patients as well as short- and long-term toxicities, some of which can be life-threatening.
These caveats have prompted trials exploring strategies to de-escalate therapy, which essentially means providing the right amount of treatment to the right patient at the right time, said Dr. Tolaney. The goal is to “right-size” or “optimize therapy” to maintain strong outcomes while mitigating side effects.
she explained.
But, she added, de-escalation trials are “not a very attractive strategy to pharmaceutical companies” and can be challenging for researchers to conduct. These trials may, for instance, lack adequate sample sizes and sufficient statistical power, which can interfere with achieving clinically meaningful findings that may affect practice.
That is why carefully designing de-escalation trials is crucial, Dr. Tolaney said.
In her talk at ESMO Breast, Dr. Tolaney highlighted several strategies for designing these trials.
One strategy is to shorten the duration of therapy, said Dr. Tolaney.
This approach was explored in the PHARE and PERSEPHONE trials, which looked at 6 vs 12 months of trastuzumab in nonmetastatic breast cancer. Other trials, such as GeparNuevo and KEYNOTE-522, explored whether adjuvant checkpoint inhibitor therapy was needed, or could be skipped, following neoadjuvant therapy. This approach requires establishing noninferiority, or similar efficacy, between the standard of care and the shorter duration of therapy.
A second strategy is to remove part of the chemotherapy regimen, typically the most toxic agent, Dr. Tolaney continued.
Conducting a prospective, randomized trial exploring this approach in human epidermal growth factor receptor 2–positive (HER2+) early breast cancer, for example, would be difficult for a range of reasons, such as the need to enroll thousands of patients.
Dr. Tolaney and colleagues, however, designed a nonrandomized prospective study — the APT trial — with just over 400 patients to assess adjuvant paclitaxel plus trastuzumab in patients with node-negative HER2+ disease. The open-label, single-arm, phase 2 APT trial found that adjuvant paclitaxel and trastuzumab led to a 10-year recurrence-free interval of 96.3%, 10-year overall survival of 94.3%, and 10-year breast cancer–specific survival of 98.8%.
Outcomes with this adjuvant regimen were comparable to previous findings in historical controls who received doxorubicin, cyclophosphamide, paclitaxel, and trastuzumab or docetaxel, carboplatin, and trastuzumab.
Dr. Tolaney concluded that given few events, “it’s unlikely we need to escalate therapy to do better for most patients,” and the APT regimen “can be considered a reasonable and appealing approach for the majority of patients” with node-negative HER2+ breast cancer.
“A single-arm design for a de-escalation study can be practice-changing but only if there are very few recurrences,” Dr. Tolaney said.
Substituting chemotherapy with a targeted, potentially less-toxic agent is a third de-escalation approach. The ATEMPT trial compared patients receiving trastuzumab emtansine (T-DM1) with those receiving paclitaxel plus trastuzumab followed by maintenance trastuzumab.
Investigators found that de-escalation with T-DM1 was associated with very few recurrences but similar rates of certain adverse events, including grade 2 or higher neurotoxicity, febrile neutropenia, and grade 4 or higher hematologic toxicity.
However, there are questions about how to define “less toxic,” Dr. Tolaney said. The trial found, for instance, that T-DM1 did have some advantages — patients reported better quality of life and experienced less alopecia and neurotoxicity, as well as a less severe impact on fertility.
Understanding the right endpoint to demonstrate less toxicity is critical, “as we start to think about how to replace standard chemotherapies with better targeted drugs,” she added.
The ATEMPT 2.0 trial, which is currently enrolling, will aim to answer some of these questions about defining and demonstrating less toxicity, she said.
Finally, some researchers are attempting to omit chemotherapy altogether with the help of biomarkers. The TAILORx trial, for instance, aimed to stratify patients with early-stage breast cancer by clinical risk factors combined with a 21-gene expression assay and found that adjuvant chemotherapy was not necessary in a large proportion of these women.
On the biomarker front, oncologists might be able to use ctDNA to guide decision-making and personalize therapy, Tolaney said. The presence of ctDNA is associated with an almost 100% likelihood of having a recurrence, whereas its absence suggests better outcomes, she explained.
Oncologists could use the presence or absence of ctDNA to guide next steps — assign patients to follow-up assessments when ctDNA is not present or to standard or experimental treatment when it is present. It may also be possible to leverage the presence of minimal residual disease to help direct treatment choices.
But ctDNA is currently not as perfect a predictor of outcome as it could be, she cautioned. “We need more sensitive assays [so] I’m not sure we’re quite ready to use lack of ctDNA to de-escalate treatment,” she said.
Dr. Tolaney declared relationships with Novartis, Pfizer, Merck, Lilly, AstraZeneca, Genentech/Roche, Eisai, Sanofi, Bristol Myers Squib, and other companies.
A version of this article appeared on Medscape.com .
FROM ESMO BREAST CANCER 2024
No Improvement in OS With Atezolizumab in Early Relapsing TNBC
Our results “highlight the importance of recognizing TNBC heterogeneity, especially in the first-line setting” said Rebecca A. Dent, MD, MSc, National Cancer Center Singapore and Duke-NUS Medical School, Singapore, who presented the study at the European Society for Medical Oncology (ESMO) Breast Cancer annual congress.
“These patients have a dismal prognosis and represent a high unmet need,” she added.
The current findings follow those from the IMpassion130 trial, which showed that the combination of atezolizumab with nab-paclitaxel chemotherapy offered no survival benefit in previously untreated locally advanced or metastatic TNBC despite a progression-free survival benefit on interim analysis.
Rapidly relapsing TNBC “represents one of most challenging clinical situations” because it is aggressive and “intrinsically resistant to standard therapies,” said Dr. Dent. It is also more common in younger patients with large primary tumors and no BRCA alterations.
“Most importantly, however, is that most trials actually exclude these patients,” she noted, “posing a real challenge for us in clinical practice.”
IMpassion132 enrolled 594 patients with unresectable locally advanced or metastatic TNBC who had experienced disease progression more than 12 months after their last treatment for early TNBC with curative intent.
Patients had received prior anthracycline and taxane therapy for but no prior chemotherapy for advanced disease.
Study participants were randomly assigned to chemotherapy with carboplatin-gemcitabine or capecitabine plus atezolizumab or placebo, with treatment continued until disease progression or unacceptable toxicity. The primary endpoint was overall survival.
Initially, all patients with TNBC who met the study criteria were enrolled in the randomized, phase 3, double-blinded trial; however, the trial was then amended to include only PD-L1–positive patients after the results of IMpassion130 “clearly showed us that the benefits of immune checkpoint inhibition were largely driven by those patients,” Dr. Dent explained.
The 354 patients with PD-L1–positive disease were “young,” she added, with a median age of 48 years. The youngest was 23 years old.
The majority (66%-69%) had a disease-free interval of less than 6 months after treatment with curative intent. Lung and/or liver metastases were present in 60%-62% of patients, and 18% had previously received platinum-based chemotherapy.
After a median follow-up of 9.8 months, overall survival was a median of 12.1 months in the atezolizumab group vs 11.2 months with placebo, at a hazard ratio of 0.93 (P = .59).
A similar result was seen when looking at the modified intention-to-treat population, and when stratifying the patients by prespecified subgroup.
Dr. Dent pointed out that in the placebo group, patients treated with capecitabine had a median overall survival of 12.6 months vs 9.9 months in those given carboplatin-gemcitabine , which she described as “hypothesis generating” because “prior therapy may trigger a variety of resistance mechanisms.”
The disease-free interval also seemed to play a role in the placebo group. Patients who had a disease-free interval of 6 or more months prior to study enrollment had a median overall survival of 12.8 months vs 9.4 months in those with an interval of less than 6 months.
There were no significant differences in progression-free survival or duration of overall response between the atezolizumab and placebo groups.
“In terms of the safety data, clearly we’re getting better at identifying immune checkpoint inhibition toxicities and initiating therapies for these toxicities earlier,” Dr. Dent said, because there were “no new safety signals.”
The rate of treatment-related grade 3 or 4 adverse events was similar between patients given atezolizumab and those assigned to placebo, at 65% vs 62%. Rates of grade 5 events were identical, at 1%.
Commenting on the study, Sara M. Tolaney, MD, MPH, chief, Division of Breast Oncology, Susan F. Smith Center for Women’s Cancers, Dana-Farber Cancer Institute, Boston, questioned the role for immunotherapy in patients with TNBC who experience early relapse.
This is not the first trial to fail to show a benefit in this space, she said. Collectively, these results make “me think that these tumors are pretty immunologically cold, making them less likely to benefit from checkpoint inhibition.”
The patients that do relapse, “have highly treatment refractory disease,” and “we need to think about other novel therapeutic strategies for this population,” she told this news organization.
IMpassion132 nevertheless represents a “unique opportunity to better understand the biology of these rapidly relapsing tumors, and hopefully use this information to develop more novel treatment approaches for this population,” she said.
“That being said, I do think that this is going to become an even more challenging area,” Dr. Tolaney said. “In the modern era, these patients are receiving multi-agent chemotherapy with preoperative checkpoint inhibition, and many then go on to receive additional systemic treatment in the adjuvant setting.”
The study was sponsored by Hoffmann-La Roche.
Dr. Dent declares relationships with AstraZeneca, Roche, Eisai, Lilly, MSD, Novartis, and Pfizer. Dr. Tolaney declares relationships with Novartis, Pfizer, Merck, Lilly, AstraZeneca, Genentech/Roche, Eisai, Sanofi, Bristol Myers Squib, Seattle Genetics, CytomX Therapeutics, Daiichi Sankyo, Gilead, Ellipses Pharma, 4D Pharma, OncoSec Medical Inc, BeyondSpring Pharmaceuticals, OncXerna, Zymeworks, Zentalis, Blueprint Medicines, Reveal Genomics, ARC Therapeutics, Myovant, Zetagen, Umoja Biopharma, Menarini/Stemline, Aadi Biopharma, Bayer, Jazz Pharmaceuticals, Exelixis, Novartis, Nanonstring, and Cyclacel.
A version of this article appeared on Medscape.com .
Our results “highlight the importance of recognizing TNBC heterogeneity, especially in the first-line setting” said Rebecca A. Dent, MD, MSc, National Cancer Center Singapore and Duke-NUS Medical School, Singapore, who presented the study at the European Society for Medical Oncology (ESMO) Breast Cancer annual congress.
“These patients have a dismal prognosis and represent a high unmet need,” she added.
The current findings follow those from the IMpassion130 trial, which showed that the combination of atezolizumab with nab-paclitaxel chemotherapy offered no survival benefit in previously untreated locally advanced or metastatic TNBC despite a progression-free survival benefit on interim analysis.
Rapidly relapsing TNBC “represents one of most challenging clinical situations” because it is aggressive and “intrinsically resistant to standard therapies,” said Dr. Dent. It is also more common in younger patients with large primary tumors and no BRCA alterations.
“Most importantly, however, is that most trials actually exclude these patients,” she noted, “posing a real challenge for us in clinical practice.”
IMpassion132 enrolled 594 patients with unresectable locally advanced or metastatic TNBC who had experienced disease progression more than 12 months after their last treatment for early TNBC with curative intent.
Patients had received prior anthracycline and taxane therapy for but no prior chemotherapy for advanced disease.
Study participants were randomly assigned to chemotherapy with carboplatin-gemcitabine or capecitabine plus atezolizumab or placebo, with treatment continued until disease progression or unacceptable toxicity. The primary endpoint was overall survival.
Initially, all patients with TNBC who met the study criteria were enrolled in the randomized, phase 3, double-blinded trial; however, the trial was then amended to include only PD-L1–positive patients after the results of IMpassion130 “clearly showed us that the benefits of immune checkpoint inhibition were largely driven by those patients,” Dr. Dent explained.
The 354 patients with PD-L1–positive disease were “young,” she added, with a median age of 48 years. The youngest was 23 years old.
The majority (66%-69%) had a disease-free interval of less than 6 months after treatment with curative intent. Lung and/or liver metastases were present in 60%-62% of patients, and 18% had previously received platinum-based chemotherapy.
After a median follow-up of 9.8 months, overall survival was a median of 12.1 months in the atezolizumab group vs 11.2 months with placebo, at a hazard ratio of 0.93 (P = .59).
A similar result was seen when looking at the modified intention-to-treat population, and when stratifying the patients by prespecified subgroup.
Dr. Dent pointed out that in the placebo group, patients treated with capecitabine had a median overall survival of 12.6 months vs 9.9 months in those given carboplatin-gemcitabine , which she described as “hypothesis generating” because “prior therapy may trigger a variety of resistance mechanisms.”
The disease-free interval also seemed to play a role in the placebo group. Patients who had a disease-free interval of 6 or more months prior to study enrollment had a median overall survival of 12.8 months vs 9.4 months in those with an interval of less than 6 months.
There were no significant differences in progression-free survival or duration of overall response between the atezolizumab and placebo groups.
“In terms of the safety data, clearly we’re getting better at identifying immune checkpoint inhibition toxicities and initiating therapies for these toxicities earlier,” Dr. Dent said, because there were “no new safety signals.”
The rate of treatment-related grade 3 or 4 adverse events was similar between patients given atezolizumab and those assigned to placebo, at 65% vs 62%. Rates of grade 5 events were identical, at 1%.
Commenting on the study, Sara M. Tolaney, MD, MPH, chief, Division of Breast Oncology, Susan F. Smith Center for Women’s Cancers, Dana-Farber Cancer Institute, Boston, questioned the role for immunotherapy in patients with TNBC who experience early relapse.
This is not the first trial to fail to show a benefit in this space, she said. Collectively, these results make “me think that these tumors are pretty immunologically cold, making them less likely to benefit from checkpoint inhibition.”
The patients that do relapse, “have highly treatment refractory disease,” and “we need to think about other novel therapeutic strategies for this population,” she told this news organization.
IMpassion132 nevertheless represents a “unique opportunity to better understand the biology of these rapidly relapsing tumors, and hopefully use this information to develop more novel treatment approaches for this population,” she said.
“That being said, I do think that this is going to become an even more challenging area,” Dr. Tolaney said. “In the modern era, these patients are receiving multi-agent chemotherapy with preoperative checkpoint inhibition, and many then go on to receive additional systemic treatment in the adjuvant setting.”
The study was sponsored by Hoffmann-La Roche.
Dr. Dent declares relationships with AstraZeneca, Roche, Eisai, Lilly, MSD, Novartis, and Pfizer. Dr. Tolaney declares relationships with Novartis, Pfizer, Merck, Lilly, AstraZeneca, Genentech/Roche, Eisai, Sanofi, Bristol Myers Squib, Seattle Genetics, CytomX Therapeutics, Daiichi Sankyo, Gilead, Ellipses Pharma, 4D Pharma, OncoSec Medical Inc, BeyondSpring Pharmaceuticals, OncXerna, Zymeworks, Zentalis, Blueprint Medicines, Reveal Genomics, ARC Therapeutics, Myovant, Zetagen, Umoja Biopharma, Menarini/Stemline, Aadi Biopharma, Bayer, Jazz Pharmaceuticals, Exelixis, Novartis, Nanonstring, and Cyclacel.
A version of this article appeared on Medscape.com .
Our results “highlight the importance of recognizing TNBC heterogeneity, especially in the first-line setting” said Rebecca A. Dent, MD, MSc, National Cancer Center Singapore and Duke-NUS Medical School, Singapore, who presented the study at the European Society for Medical Oncology (ESMO) Breast Cancer annual congress.
“These patients have a dismal prognosis and represent a high unmet need,” she added.
The current findings follow those from the IMpassion130 trial, which showed that the combination of atezolizumab with nab-paclitaxel chemotherapy offered no survival benefit in previously untreated locally advanced or metastatic TNBC despite a progression-free survival benefit on interim analysis.
Rapidly relapsing TNBC “represents one of most challenging clinical situations” because it is aggressive and “intrinsically resistant to standard therapies,” said Dr. Dent. It is also more common in younger patients with large primary tumors and no BRCA alterations.
“Most importantly, however, is that most trials actually exclude these patients,” she noted, “posing a real challenge for us in clinical practice.”
IMpassion132 enrolled 594 patients with unresectable locally advanced or metastatic TNBC who had experienced disease progression more than 12 months after their last treatment for early TNBC with curative intent.
Patients had received prior anthracycline and taxane therapy for but no prior chemotherapy for advanced disease.
Study participants were randomly assigned to chemotherapy with carboplatin-gemcitabine or capecitabine plus atezolizumab or placebo, with treatment continued until disease progression or unacceptable toxicity. The primary endpoint was overall survival.
Initially, all patients with TNBC who met the study criteria were enrolled in the randomized, phase 3, double-blinded trial; however, the trial was then amended to include only PD-L1–positive patients after the results of IMpassion130 “clearly showed us that the benefits of immune checkpoint inhibition were largely driven by those patients,” Dr. Dent explained.
The 354 patients with PD-L1–positive disease were “young,” she added, with a median age of 48 years. The youngest was 23 years old.
The majority (66%-69%) had a disease-free interval of less than 6 months after treatment with curative intent. Lung and/or liver metastases were present in 60%-62% of patients, and 18% had previously received platinum-based chemotherapy.
After a median follow-up of 9.8 months, overall survival was a median of 12.1 months in the atezolizumab group vs 11.2 months with placebo, at a hazard ratio of 0.93 (P = .59).
A similar result was seen when looking at the modified intention-to-treat population, and when stratifying the patients by prespecified subgroup.
Dr. Dent pointed out that in the placebo group, patients treated with capecitabine had a median overall survival of 12.6 months vs 9.9 months in those given carboplatin-gemcitabine , which she described as “hypothesis generating” because “prior therapy may trigger a variety of resistance mechanisms.”
The disease-free interval also seemed to play a role in the placebo group. Patients who had a disease-free interval of 6 or more months prior to study enrollment had a median overall survival of 12.8 months vs 9.4 months in those with an interval of less than 6 months.
There were no significant differences in progression-free survival or duration of overall response between the atezolizumab and placebo groups.
“In terms of the safety data, clearly we’re getting better at identifying immune checkpoint inhibition toxicities and initiating therapies for these toxicities earlier,” Dr. Dent said, because there were “no new safety signals.”
The rate of treatment-related grade 3 or 4 adverse events was similar between patients given atezolizumab and those assigned to placebo, at 65% vs 62%. Rates of grade 5 events were identical, at 1%.
Commenting on the study, Sara M. Tolaney, MD, MPH, chief, Division of Breast Oncology, Susan F. Smith Center for Women’s Cancers, Dana-Farber Cancer Institute, Boston, questioned the role for immunotherapy in patients with TNBC who experience early relapse.
This is not the first trial to fail to show a benefit in this space, she said. Collectively, these results make “me think that these tumors are pretty immunologically cold, making them less likely to benefit from checkpoint inhibition.”
The patients that do relapse, “have highly treatment refractory disease,” and “we need to think about other novel therapeutic strategies for this population,” she told this news organization.
IMpassion132 nevertheless represents a “unique opportunity to better understand the biology of these rapidly relapsing tumors, and hopefully use this information to develop more novel treatment approaches for this population,” she said.
“That being said, I do think that this is going to become an even more challenging area,” Dr. Tolaney said. “In the modern era, these patients are receiving multi-agent chemotherapy with preoperative checkpoint inhibition, and many then go on to receive additional systemic treatment in the adjuvant setting.”
The study was sponsored by Hoffmann-La Roche.
Dr. Dent declares relationships with AstraZeneca, Roche, Eisai, Lilly, MSD, Novartis, and Pfizer. Dr. Tolaney declares relationships with Novartis, Pfizer, Merck, Lilly, AstraZeneca, Genentech/Roche, Eisai, Sanofi, Bristol Myers Squib, Seattle Genetics, CytomX Therapeutics, Daiichi Sankyo, Gilead, Ellipses Pharma, 4D Pharma, OncoSec Medical Inc, BeyondSpring Pharmaceuticals, OncXerna, Zymeworks, Zentalis, Blueprint Medicines, Reveal Genomics, ARC Therapeutics, Myovant, Zetagen, Umoja Biopharma, Menarini/Stemline, Aadi Biopharma, Bayer, Jazz Pharmaceuticals, Exelixis, Novartis, Nanonstring, and Cyclacel.
A version of this article appeared on Medscape.com .
FROM ESMO BREAST CANCER 2024
Hypofractionated Radiotherapy Limits Toxic Effects in Cervical Cancer
TOPLINE:
results from the phase 2 POHIM-CCRT trial suggested.
METHODOLOGY:
- To date, no studies have assessed the treatment outcomes and toxic effects of hypofractionated IMRT following radical hysterectomy in patients with cervical cancer undergoing curative radiotherapy.
- The team analyzed outcomes from 79 patients undergoing hypofractionated IMRT for cervical cancer after radical hysterectomy and pelvic lymph node dissection.
- Patients were a median age of 48; 29.5% had stage IB to IIA disease, another 29.5% had stage IIB disease, and 41% had stage III disease. Patients also had at least one of the following criteria following radical hysterectomy and pelvic lymph node dissection: lymph node metastasis (39.7%), parametrial invasion (54.4%), and positive resection margin (5.1%).
- The prescribed dose to the planning target volume was 40 Gy, delivered in 16 fractions to the whole pelvis, with any type of IMRT permitted. Overall, 71 patients also underwent concurrent weekly cisplatin (40 mg/m2 of body surface area for three cycles), and eight received fluorouracil (1000 mg/m2 on days 1-5) with cisplatin (60 mg/m2 for two cycles).
- The primary endpoint was the incidence of acute grade 3 or higher gastrointestinal tract, genitourinary, and hematologic toxic effects during radiotherapy or within 3 months of completing radiotherapy.
TAKEAWAY:
- After radiotherapy, only two patients (2.5%) experienced acute grade 3 or higher toxic effects. One was hospitalized for enterocolitis on the last day of radiotherapy and developed grade 3 anemia 3 months after completing radiotherapy; the other experienced hematologic toxic effects and also developed grade 3 anemia 3 months after completing radiotherapy.
- No patients experienced late grade 3 or higher toxic effects.
- When assessing toxic effects of any grade, acute and late gastrointestinal tract toxicities occurred in 76% and 31.6% of patients, respectively; acute and late genitourinary toxicities, all grade 1, occurred in 19% and 24.1% of patients, respectively; and hematologic toxicities occurred in 29.1% and 6.3% of patients, respectively.
- Overall, at 3 years, 79.3% of patients were disease-free and 98% were alive. After a median follow-up of 43 months, 16 patients (20.3%) experienced disease recurrence, four of whom were salvaged and three of whom died.
IN PRACTICE:
“This nonrandomized controlled trial is the first prospective trial, to our knowledge, to show acceptable acute toxic effects of hypofractionated IMRT for cervical cancer in a postoperative concurrent chemoradiotherapy setting,” the authors said, adding that the rate of grade 3 or higher acute toxic effects of 2.5% reported in this study was “substantially lower than our initial hypothesis of less than 15%.”
However , in an accompanying editorial, Mark E. Bernard, MD, of the University of Kentucky College of Medicine, Lexington, highlighted caveats to the study design and raised two core questions: “Should acute toxic effects be the primary endpoint of a single-group, phase 2 study using hypofractionation with fewer cycles of concurrent chemotherapy? Should the primary endpoint rather have been a cancer control endpoint, such as disease-free survival, overall survival, or local control?”
Still, Dr. Bernard wrote, “This trial does help lay the foundation for future pelvic hypofractionated trials with concurrent chemotherapy, especially for gynecological malignant tumors.”
SOURCE:
The research, led by Won Park, MD, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea, was published in JAMA Oncology.
LIMITATIONS:
The trial is a single-arm study, with a short follow-up time. In the editorial, Bernard listed several limitations, including the fact that patients received fewer cycles of concurrent chemotherapy than what’s typically given in this population.
DISCLOSURES:
No funding or relevant financial relationships were declared.
A version of this article appeared on Medscape.com.
TOPLINE:
results from the phase 2 POHIM-CCRT trial suggested.
METHODOLOGY:
- To date, no studies have assessed the treatment outcomes and toxic effects of hypofractionated IMRT following radical hysterectomy in patients with cervical cancer undergoing curative radiotherapy.
- The team analyzed outcomes from 79 patients undergoing hypofractionated IMRT for cervical cancer after radical hysterectomy and pelvic lymph node dissection.
- Patients were a median age of 48; 29.5% had stage IB to IIA disease, another 29.5% had stage IIB disease, and 41% had stage III disease. Patients also had at least one of the following criteria following radical hysterectomy and pelvic lymph node dissection: lymph node metastasis (39.7%), parametrial invasion (54.4%), and positive resection margin (5.1%).
- The prescribed dose to the planning target volume was 40 Gy, delivered in 16 fractions to the whole pelvis, with any type of IMRT permitted. Overall, 71 patients also underwent concurrent weekly cisplatin (40 mg/m2 of body surface area for three cycles), and eight received fluorouracil (1000 mg/m2 on days 1-5) with cisplatin (60 mg/m2 for two cycles).
- The primary endpoint was the incidence of acute grade 3 or higher gastrointestinal tract, genitourinary, and hematologic toxic effects during radiotherapy or within 3 months of completing radiotherapy.
TAKEAWAY:
- After radiotherapy, only two patients (2.5%) experienced acute grade 3 or higher toxic effects. One was hospitalized for enterocolitis on the last day of radiotherapy and developed grade 3 anemia 3 months after completing radiotherapy; the other experienced hematologic toxic effects and also developed grade 3 anemia 3 months after completing radiotherapy.
- No patients experienced late grade 3 or higher toxic effects.
- When assessing toxic effects of any grade, acute and late gastrointestinal tract toxicities occurred in 76% and 31.6% of patients, respectively; acute and late genitourinary toxicities, all grade 1, occurred in 19% and 24.1% of patients, respectively; and hematologic toxicities occurred in 29.1% and 6.3% of patients, respectively.
- Overall, at 3 years, 79.3% of patients were disease-free and 98% were alive. After a median follow-up of 43 months, 16 patients (20.3%) experienced disease recurrence, four of whom were salvaged and three of whom died.
IN PRACTICE:
“This nonrandomized controlled trial is the first prospective trial, to our knowledge, to show acceptable acute toxic effects of hypofractionated IMRT for cervical cancer in a postoperative concurrent chemoradiotherapy setting,” the authors said, adding that the rate of grade 3 or higher acute toxic effects of 2.5% reported in this study was “substantially lower than our initial hypothesis of less than 15%.”
However , in an accompanying editorial, Mark E. Bernard, MD, of the University of Kentucky College of Medicine, Lexington, highlighted caveats to the study design and raised two core questions: “Should acute toxic effects be the primary endpoint of a single-group, phase 2 study using hypofractionation with fewer cycles of concurrent chemotherapy? Should the primary endpoint rather have been a cancer control endpoint, such as disease-free survival, overall survival, or local control?”
Still, Dr. Bernard wrote, “This trial does help lay the foundation for future pelvic hypofractionated trials with concurrent chemotherapy, especially for gynecological malignant tumors.”
SOURCE:
The research, led by Won Park, MD, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea, was published in JAMA Oncology.
LIMITATIONS:
The trial is a single-arm study, with a short follow-up time. In the editorial, Bernard listed several limitations, including the fact that patients received fewer cycles of concurrent chemotherapy than what’s typically given in this population.
DISCLOSURES:
No funding or relevant financial relationships were declared.
A version of this article appeared on Medscape.com.
TOPLINE:
results from the phase 2 POHIM-CCRT trial suggested.
METHODOLOGY:
- To date, no studies have assessed the treatment outcomes and toxic effects of hypofractionated IMRT following radical hysterectomy in patients with cervical cancer undergoing curative radiotherapy.
- The team analyzed outcomes from 79 patients undergoing hypofractionated IMRT for cervical cancer after radical hysterectomy and pelvic lymph node dissection.
- Patients were a median age of 48; 29.5% had stage IB to IIA disease, another 29.5% had stage IIB disease, and 41% had stage III disease. Patients also had at least one of the following criteria following radical hysterectomy and pelvic lymph node dissection: lymph node metastasis (39.7%), parametrial invasion (54.4%), and positive resection margin (5.1%).
- The prescribed dose to the planning target volume was 40 Gy, delivered in 16 fractions to the whole pelvis, with any type of IMRT permitted. Overall, 71 patients also underwent concurrent weekly cisplatin (40 mg/m2 of body surface area for three cycles), and eight received fluorouracil (1000 mg/m2 on days 1-5) with cisplatin (60 mg/m2 for two cycles).
- The primary endpoint was the incidence of acute grade 3 or higher gastrointestinal tract, genitourinary, and hematologic toxic effects during radiotherapy or within 3 months of completing radiotherapy.
TAKEAWAY:
- After radiotherapy, only two patients (2.5%) experienced acute grade 3 or higher toxic effects. One was hospitalized for enterocolitis on the last day of radiotherapy and developed grade 3 anemia 3 months after completing radiotherapy; the other experienced hematologic toxic effects and also developed grade 3 anemia 3 months after completing radiotherapy.
- No patients experienced late grade 3 or higher toxic effects.
- When assessing toxic effects of any grade, acute and late gastrointestinal tract toxicities occurred in 76% and 31.6% of patients, respectively; acute and late genitourinary toxicities, all grade 1, occurred in 19% and 24.1% of patients, respectively; and hematologic toxicities occurred in 29.1% and 6.3% of patients, respectively.
- Overall, at 3 years, 79.3% of patients were disease-free and 98% were alive. After a median follow-up of 43 months, 16 patients (20.3%) experienced disease recurrence, four of whom were salvaged and three of whom died.
IN PRACTICE:
“This nonrandomized controlled trial is the first prospective trial, to our knowledge, to show acceptable acute toxic effects of hypofractionated IMRT for cervical cancer in a postoperative concurrent chemoradiotherapy setting,” the authors said, adding that the rate of grade 3 or higher acute toxic effects of 2.5% reported in this study was “substantially lower than our initial hypothesis of less than 15%.”
However , in an accompanying editorial, Mark E. Bernard, MD, of the University of Kentucky College of Medicine, Lexington, highlighted caveats to the study design and raised two core questions: “Should acute toxic effects be the primary endpoint of a single-group, phase 2 study using hypofractionation with fewer cycles of concurrent chemotherapy? Should the primary endpoint rather have been a cancer control endpoint, such as disease-free survival, overall survival, or local control?”
Still, Dr. Bernard wrote, “This trial does help lay the foundation for future pelvic hypofractionated trials with concurrent chemotherapy, especially for gynecological malignant tumors.”
SOURCE:
The research, led by Won Park, MD, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea, was published in JAMA Oncology.
LIMITATIONS:
The trial is a single-arm study, with a short follow-up time. In the editorial, Bernard listed several limitations, including the fact that patients received fewer cycles of concurrent chemotherapy than what’s typically given in this population.
DISCLOSURES:
No funding or relevant financial relationships were declared.
A version of this article appeared on Medscape.com.
Microbiome Alterations Linked to Growth Hormone Deficiency
, said Chinese researchers.
The research, published recently in Pediatric Research, involved more than 80 children and showed that those with GHD had alterations in microbial populations that have been linked to longevity, as well as a microbial and metabolite signature that allowed accurate discrimination from ISS.
“These findings provide novel insights into potential early diagnosis and innovative treatment alternatives, such as fecal microbiota transplantation, for short stature with varying growth hormone levels,” the authors wrote.
Andrew Dauber, MD, MMSc, chief of endocrinology, Children’s National Hospital, Washington, who was not involved in the study, said that while this is “a really interesting area of research,” he expressed “hesitancy about getting too excited about this data yet.”
“One of the problems is how you define growth hormone deficiency,” as it is “not a black and white diagnosis,” and the etiology and child’s growth trajectory also need to be considered, Dr. Dauber told said.
He explained: “The problem is that, when you rely on the growth hormone stimulation test alone, there’s so many false positives and so much overlap between patients with true growth hormone deficiency and those without. And I think that this article fell prey to that.”
He added: “It would be really, really interesting and helpful to have a microbiome signature that allows you to distinguish between true growth hormone deficiency and patients with idiopathic short stature.”
“But you have to make sure that your groups are very well defined for this study to be really valid. And that’s one of my concerns here.”
Dr. Dauber continued: “Now, that being said, they did find some associations that correlated with growth hormone peak levels,” some which replicate previous findings, “so I do think that there are kernels of important findings here.”
‘Tease Out Influences’ to Isolate the Interaction
He pointed out that there are “many factors that influence the microbiome,” such as the use of antibiotics, diet, age, and geographic location. Therefore, a study that could truly tease out all these influences and isolate the interaction with growth hormone levels would need to be “very thoughtfully designed.”
A number of factors contribute to short stature, lead author Lan Li, MD, Department of Radiology, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, China, and colleagues.
These include genetic factors, environmental factors, and conditions such as being small for gestational age at birth, familial short stature, and chronic systemic diseases, as well as GHD and ISS.
Recent animal studies have suggested that there may be a bidirectional relationship between the gut microbiota and the growth hormone/insulin-like growth factor 1 axis, and it has been shown that individuals with GHD have significant alterations in their gut microbiota compared with healthy controls.
To investigate, they studied 36 children diagnosed with GHD, 32 with ISS, and 16 age- and sex-matched healthy controls, all of whom were recruited between February 2019 and June 2021 from the Pediatric Endocrinology Department of The Second Affiliated Hospital of Wenzhou Medical University.
Fecal samples obtained from the children underwent microbiome analysis using 16S ribosomal RNA gene sequencing, alongside nuclear MRI analysis of the metabolome, or the entire complement of small molecules in the samples.
Patients with GHD had a significantly higher body mass index than those with ISS (P < .05), and their peak growth hormone level was significantly lower (P < .001). Patients with GHD also had significantly higher total cholesterol and low-density lipoprotein cholesterol levels than patients with ISS (P < .05).
The team reports that the alpha diversity of the fecal microbiome, which measures the microbial diversity within a fecal sample, was similar between the three groups.
However, there was significant variation between the groups in the beta diversity, which quantifies the similarity or dissimilarity between two samples, and allows the overall taxonomic or functional diversity pattern to be linked to environmental features.
Compared with the healthy control group, the abundance of Pelomonas, Rodentibacter, and Rothia was significantly decreased in GHD and patients with ISS, while the abundance of Prevotellaceae_NK3B31_group was increased in the two patient groups, particularly in those with GHD.
In addition, the researchers found a decreased Firmicutes/Bacteroidota (F/B) ratio in participants with short stature, particularly in the GHD group. They noted that “emerging evidence suggests the F/B ratio may play a role in longevity.”
Nocardioides was substantially more common in the ISS group vs both patients with GHD and healthy controls, while Fusobacterium mortiferum was characteristic of GHD. The team suggests this “may serve as a critical intestinal factor contributing to the short stature observed in GHD.”
The metabolome analysis revealed that glucose, pyruvate, and pyrimidine metabolism may also play a significant role in distinguishing between patients with GHD and ISS and healthy control groups.
Finally, the team demonstrated that a panel combining 13 microbiome and metabolome markers was able to discriminate between GHD and ISS at an area under the receiver operating characteristic curve of 0.945, with a sensitivity of 87% and a specificity of 91%.
The study was supported by grants from the National Natural Science Foundation of China and Wenzhou Science and Technology Bureau in China. No relevant financial relationships were declared.
A version of this article appeared on Medscape.com.
, said Chinese researchers.
The research, published recently in Pediatric Research, involved more than 80 children and showed that those with GHD had alterations in microbial populations that have been linked to longevity, as well as a microbial and metabolite signature that allowed accurate discrimination from ISS.
“These findings provide novel insights into potential early diagnosis and innovative treatment alternatives, such as fecal microbiota transplantation, for short stature with varying growth hormone levels,” the authors wrote.
Andrew Dauber, MD, MMSc, chief of endocrinology, Children’s National Hospital, Washington, who was not involved in the study, said that while this is “a really interesting area of research,” he expressed “hesitancy about getting too excited about this data yet.”
“One of the problems is how you define growth hormone deficiency,” as it is “not a black and white diagnosis,” and the etiology and child’s growth trajectory also need to be considered, Dr. Dauber told said.
He explained: “The problem is that, when you rely on the growth hormone stimulation test alone, there’s so many false positives and so much overlap between patients with true growth hormone deficiency and those without. And I think that this article fell prey to that.”
He added: “It would be really, really interesting and helpful to have a microbiome signature that allows you to distinguish between true growth hormone deficiency and patients with idiopathic short stature.”
“But you have to make sure that your groups are very well defined for this study to be really valid. And that’s one of my concerns here.”
Dr. Dauber continued: “Now, that being said, they did find some associations that correlated with growth hormone peak levels,” some which replicate previous findings, “so I do think that there are kernels of important findings here.”
‘Tease Out Influences’ to Isolate the Interaction
He pointed out that there are “many factors that influence the microbiome,” such as the use of antibiotics, diet, age, and geographic location. Therefore, a study that could truly tease out all these influences and isolate the interaction with growth hormone levels would need to be “very thoughtfully designed.”
A number of factors contribute to short stature, lead author Lan Li, MD, Department of Radiology, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, China, and colleagues.
These include genetic factors, environmental factors, and conditions such as being small for gestational age at birth, familial short stature, and chronic systemic diseases, as well as GHD and ISS.
Recent animal studies have suggested that there may be a bidirectional relationship between the gut microbiota and the growth hormone/insulin-like growth factor 1 axis, and it has been shown that individuals with GHD have significant alterations in their gut microbiota compared with healthy controls.
To investigate, they studied 36 children diagnosed with GHD, 32 with ISS, and 16 age- and sex-matched healthy controls, all of whom were recruited between February 2019 and June 2021 from the Pediatric Endocrinology Department of The Second Affiliated Hospital of Wenzhou Medical University.
Fecal samples obtained from the children underwent microbiome analysis using 16S ribosomal RNA gene sequencing, alongside nuclear MRI analysis of the metabolome, or the entire complement of small molecules in the samples.
Patients with GHD had a significantly higher body mass index than those with ISS (P < .05), and their peak growth hormone level was significantly lower (P < .001). Patients with GHD also had significantly higher total cholesterol and low-density lipoprotein cholesterol levels than patients with ISS (P < .05).
The team reports that the alpha diversity of the fecal microbiome, which measures the microbial diversity within a fecal sample, was similar between the three groups.
However, there was significant variation between the groups in the beta diversity, which quantifies the similarity or dissimilarity between two samples, and allows the overall taxonomic or functional diversity pattern to be linked to environmental features.
Compared with the healthy control group, the abundance of Pelomonas, Rodentibacter, and Rothia was significantly decreased in GHD and patients with ISS, while the abundance of Prevotellaceae_NK3B31_group was increased in the two patient groups, particularly in those with GHD.
In addition, the researchers found a decreased Firmicutes/Bacteroidota (F/B) ratio in participants with short stature, particularly in the GHD group. They noted that “emerging evidence suggests the F/B ratio may play a role in longevity.”
Nocardioides was substantially more common in the ISS group vs both patients with GHD and healthy controls, while Fusobacterium mortiferum was characteristic of GHD. The team suggests this “may serve as a critical intestinal factor contributing to the short stature observed in GHD.”
The metabolome analysis revealed that glucose, pyruvate, and pyrimidine metabolism may also play a significant role in distinguishing between patients with GHD and ISS and healthy control groups.
Finally, the team demonstrated that a panel combining 13 microbiome and metabolome markers was able to discriminate between GHD and ISS at an area under the receiver operating characteristic curve of 0.945, with a sensitivity of 87% and a specificity of 91%.
The study was supported by grants from the National Natural Science Foundation of China and Wenzhou Science and Technology Bureau in China. No relevant financial relationships were declared.
A version of this article appeared on Medscape.com.
, said Chinese researchers.
The research, published recently in Pediatric Research, involved more than 80 children and showed that those with GHD had alterations in microbial populations that have been linked to longevity, as well as a microbial and metabolite signature that allowed accurate discrimination from ISS.
“These findings provide novel insights into potential early diagnosis and innovative treatment alternatives, such as fecal microbiota transplantation, for short stature with varying growth hormone levels,” the authors wrote.
Andrew Dauber, MD, MMSc, chief of endocrinology, Children’s National Hospital, Washington, who was not involved in the study, said that while this is “a really interesting area of research,” he expressed “hesitancy about getting too excited about this data yet.”
“One of the problems is how you define growth hormone deficiency,” as it is “not a black and white diagnosis,” and the etiology and child’s growth trajectory also need to be considered, Dr. Dauber told said.
He explained: “The problem is that, when you rely on the growth hormone stimulation test alone, there’s so many false positives and so much overlap between patients with true growth hormone deficiency and those without. And I think that this article fell prey to that.”
He added: “It would be really, really interesting and helpful to have a microbiome signature that allows you to distinguish between true growth hormone deficiency and patients with idiopathic short stature.”
“But you have to make sure that your groups are very well defined for this study to be really valid. And that’s one of my concerns here.”
Dr. Dauber continued: “Now, that being said, they did find some associations that correlated with growth hormone peak levels,” some which replicate previous findings, “so I do think that there are kernels of important findings here.”
‘Tease Out Influences’ to Isolate the Interaction
He pointed out that there are “many factors that influence the microbiome,” such as the use of antibiotics, diet, age, and geographic location. Therefore, a study that could truly tease out all these influences and isolate the interaction with growth hormone levels would need to be “very thoughtfully designed.”
A number of factors contribute to short stature, lead author Lan Li, MD, Department of Radiology, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, China, and colleagues.
These include genetic factors, environmental factors, and conditions such as being small for gestational age at birth, familial short stature, and chronic systemic diseases, as well as GHD and ISS.
Recent animal studies have suggested that there may be a bidirectional relationship between the gut microbiota and the growth hormone/insulin-like growth factor 1 axis, and it has been shown that individuals with GHD have significant alterations in their gut microbiota compared with healthy controls.
To investigate, they studied 36 children diagnosed with GHD, 32 with ISS, and 16 age- and sex-matched healthy controls, all of whom were recruited between February 2019 and June 2021 from the Pediatric Endocrinology Department of The Second Affiliated Hospital of Wenzhou Medical University.
Fecal samples obtained from the children underwent microbiome analysis using 16S ribosomal RNA gene sequencing, alongside nuclear MRI analysis of the metabolome, or the entire complement of small molecules in the samples.
Patients with GHD had a significantly higher body mass index than those with ISS (P < .05), and their peak growth hormone level was significantly lower (P < .001). Patients with GHD also had significantly higher total cholesterol and low-density lipoprotein cholesterol levels than patients with ISS (P < .05).
The team reports that the alpha diversity of the fecal microbiome, which measures the microbial diversity within a fecal sample, was similar between the three groups.
However, there was significant variation between the groups in the beta diversity, which quantifies the similarity or dissimilarity between two samples, and allows the overall taxonomic or functional diversity pattern to be linked to environmental features.
Compared with the healthy control group, the abundance of Pelomonas, Rodentibacter, and Rothia was significantly decreased in GHD and patients with ISS, while the abundance of Prevotellaceae_NK3B31_group was increased in the two patient groups, particularly in those with GHD.
In addition, the researchers found a decreased Firmicutes/Bacteroidota (F/B) ratio in participants with short stature, particularly in the GHD group. They noted that “emerging evidence suggests the F/B ratio may play a role in longevity.”
Nocardioides was substantially more common in the ISS group vs both patients with GHD and healthy controls, while Fusobacterium mortiferum was characteristic of GHD. The team suggests this “may serve as a critical intestinal factor contributing to the short stature observed in GHD.”
The metabolome analysis revealed that glucose, pyruvate, and pyrimidine metabolism may also play a significant role in distinguishing between patients with GHD and ISS and healthy control groups.
Finally, the team demonstrated that a panel combining 13 microbiome and metabolome markers was able to discriminate between GHD and ISS at an area under the receiver operating characteristic curve of 0.945, with a sensitivity of 87% and a specificity of 91%.
The study was supported by grants from the National Natural Science Foundation of China and Wenzhou Science and Technology Bureau in China. No relevant financial relationships were declared.
A version of this article appeared on Medscape.com.
FROM PEDIATRIC RESEARCH
Childhood Loneliness Predictive of Subsequent Psychosis?
BUDAPEST, HUNGARY — Self-perceived loneliness during childhood is linked to a more than twofold increased risk for subsequent first-episode psychosis (FEP) — new findings that may point to a novel marker for the disorder.
The association between loneliness and FEP “appears to extend beyond the effects of objective social isolation,” said study presenter Covadonga M. Díaz-Caneja, MD, PhD, Institute of Psychiatry and Mental Health, Hospital General Universitario Gregorio Marañón, Madrid, and “is particularly pronounced in females.”
“These findings suggest the potential of childhood loneliness as an early risk marker for psychosis that could help guide targeted interventions,” she added.
The results were presented at the European Psychiatric Association 2024 Congress.
Isolation a Major Risk Factor
There are two components to isolation, both of which are “major risk factors” for morbidity, mortality, and the onset of mental disorders, said Dr. Díaz-Caneja.
The first is “objective social isolation,” which consists of a demonstrable lack of social connections, including social interactions, contacts, and relationships, while the other is a perceived sense of isolation, or “loneliness,” defined as a “subjective feeling of distress associated with a lack of meaningful relationships,” regardless of the amount of actual social contact an individual experiences.
Childhood loneliness occurs before age 12 and is becoming increasingly prevalent, said Dr. Díaz-Caneja. A recent survey shows that approximately one third of children report they often feel lonely.
Genetic and observational research has shown there is a bidirectional relationship between loneliness and psychosis and that patients with schizophrenia are more likely to report loneliness than is the general population.
Dr. Díaz-Caneja noted that there is no previous research that has assessed the potential association between childhood loneliness and subsequent psychosis.
To investigate, the researchers conducted an observational, case-control study in seven university hospitals in Madrid. It included individuals aged 7-40 years, including FEP patients with a psychosis duration of less than 2 years, and healthy controls from the same geographic areas.
They assessed childhood objective social isolation using the Premorbid Adjustment Scale and examined childhood loneliness with the single item: “Have you ever felt lonely for more than 6 months before the age of 12?”
A range of measures and questionnaires were also administered to assess participants’ symptom scores, alongside the Global Assessment of Functioning (GAF).
Alone vs Lonely
Two hundred eighty-five patients with FEP participated in the study. They had a mean age of 24.5 years, and 32.6% were female. The study also included 261 healthy controls (average age, 25.9 years; 48.7% female).
After the researchers adjusted for age, gender, ethnicity, and socioeconomic status, loneliness during childhood was associated with a significantly increased risk for FEP (odds ratio [OR], 2.17; 95% CI, 1.40-3.51), which increased (OR, 2.70; 95% CI, 1.58-4.62) after further adjustment for objective social isolation.
Further analysis revealed that in those who did not have objective social isolation in childhood, loneliness was associated with a significantly increased risk for FEP (OR, 2.68; 95% CI, 1.56-4.60).
However, the relationship between loneliness and FEP was not significant in participants who were objectively socially isolated during childhood (OR, 0.33; 95% CI, 0.08-1.45).
Compared with males, females reporting loneliness had a markedly increased risk for FEP (OR, 4.74; 95% CI, 2.23-10.05 vs OR, 1.17; 95% CI, 0.63-2.19).
However, females had a reduced risk of receiving a diagnosis of schizophrenia spectrum disorder (OR, 0.155; 95% CI, 0.048-0.506), indicating that loneliness influenced the type of diagnosis, she noted.
There was a significant positive relationship between loneliness in childhood and symptom scores in men, and a negative association with GAF scores in men.
Dr. Díaz-Caneja noted that the study is preliminary and a “work in progress.” The investigators plan to increase the sample size and will conduct more complex analyses, she said.
“We also of course have to bear in mind that it is a cross-sectional study and that there may be some kind of recall biases [because] we are asking patients now about what happened in the past.”
She noted that it’s unclear whether the results can be extrapolated to individuals who are currently experiencing loneliness because “the determinants of loneliness 10 years ago or 15 years ago may be different.”
How, When to Intervene
Session chair Judit Lazáry, MD, PhD, Department of Clinical and Theoretical Mental Health, Kútvölgyi Clinical Center, Semmelweis University, Budapest, Hungary, told this news organization that the association between loneliness and FEP was “not surprising.”
She explained there are a lot of data indicating that premorbid symptoms in childhood are “predictive signs for the later onset of psychosis,” and loneliness may be “a part of that.”
Individuals experiencing loneliness are more anxious and have difficulties in cultivating and maintaining relationships. In addition, they tend to socially isolate, she said.
The key question, said Dr. Lazáry, is: “How can we intervene to prevent the onset of psychosis? What is the point at which we can support the young person?”
This is challenging, she added, because while “you can detect that a kid is always alone, you cannot detect the feeling of loneliness,” and children can’t always easily express themselves.
Another potential confounder is that in adults with current psychosis, the self-perception that they were lonely during childhood may be a consequence of the disorder.
In addition, she said, individuals with psychosis often experience cognitive impairment, which could affect memory reliability.
Nevertheless, said Dr. Lazáry, the study’s findings suggest that a young person reporting loneliness in childhood may be “another symptom that we have to investigate.”
No funding was declared.
Dr. Díaz-Caneja declared a relationship with Angelini, Janssen, and Viatris and grant support from Instituto de Salud Carlos III, the Spanish Ministry of Science and Innovation, and the European Commission.
A version of this article appeared on Medscape.com.
BUDAPEST, HUNGARY — Self-perceived loneliness during childhood is linked to a more than twofold increased risk for subsequent first-episode psychosis (FEP) — new findings that may point to a novel marker for the disorder.
The association between loneliness and FEP “appears to extend beyond the effects of objective social isolation,” said study presenter Covadonga M. Díaz-Caneja, MD, PhD, Institute of Psychiatry and Mental Health, Hospital General Universitario Gregorio Marañón, Madrid, and “is particularly pronounced in females.”
“These findings suggest the potential of childhood loneliness as an early risk marker for psychosis that could help guide targeted interventions,” she added.
The results were presented at the European Psychiatric Association 2024 Congress.
Isolation a Major Risk Factor
There are two components to isolation, both of which are “major risk factors” for morbidity, mortality, and the onset of mental disorders, said Dr. Díaz-Caneja.
The first is “objective social isolation,” which consists of a demonstrable lack of social connections, including social interactions, contacts, and relationships, while the other is a perceived sense of isolation, or “loneliness,” defined as a “subjective feeling of distress associated with a lack of meaningful relationships,” regardless of the amount of actual social contact an individual experiences.
Childhood loneliness occurs before age 12 and is becoming increasingly prevalent, said Dr. Díaz-Caneja. A recent survey shows that approximately one third of children report they often feel lonely.
Genetic and observational research has shown there is a bidirectional relationship between loneliness and psychosis and that patients with schizophrenia are more likely to report loneliness than is the general population.
Dr. Díaz-Caneja noted that there is no previous research that has assessed the potential association between childhood loneliness and subsequent psychosis.
To investigate, the researchers conducted an observational, case-control study in seven university hospitals in Madrid. It included individuals aged 7-40 years, including FEP patients with a psychosis duration of less than 2 years, and healthy controls from the same geographic areas.
They assessed childhood objective social isolation using the Premorbid Adjustment Scale and examined childhood loneliness with the single item: “Have you ever felt lonely for more than 6 months before the age of 12?”
A range of measures and questionnaires were also administered to assess participants’ symptom scores, alongside the Global Assessment of Functioning (GAF).
Alone vs Lonely
Two hundred eighty-five patients with FEP participated in the study. They had a mean age of 24.5 years, and 32.6% were female. The study also included 261 healthy controls (average age, 25.9 years; 48.7% female).
After the researchers adjusted for age, gender, ethnicity, and socioeconomic status, loneliness during childhood was associated with a significantly increased risk for FEP (odds ratio [OR], 2.17; 95% CI, 1.40-3.51), which increased (OR, 2.70; 95% CI, 1.58-4.62) after further adjustment for objective social isolation.
Further analysis revealed that in those who did not have objective social isolation in childhood, loneliness was associated with a significantly increased risk for FEP (OR, 2.68; 95% CI, 1.56-4.60).
However, the relationship between loneliness and FEP was not significant in participants who were objectively socially isolated during childhood (OR, 0.33; 95% CI, 0.08-1.45).
Compared with males, females reporting loneliness had a markedly increased risk for FEP (OR, 4.74; 95% CI, 2.23-10.05 vs OR, 1.17; 95% CI, 0.63-2.19).
However, females had a reduced risk of receiving a diagnosis of schizophrenia spectrum disorder (OR, 0.155; 95% CI, 0.048-0.506), indicating that loneliness influenced the type of diagnosis, she noted.
There was a significant positive relationship between loneliness in childhood and symptom scores in men, and a negative association with GAF scores in men.
Dr. Díaz-Caneja noted that the study is preliminary and a “work in progress.” The investigators plan to increase the sample size and will conduct more complex analyses, she said.
“We also of course have to bear in mind that it is a cross-sectional study and that there may be some kind of recall biases [because] we are asking patients now about what happened in the past.”
She noted that it’s unclear whether the results can be extrapolated to individuals who are currently experiencing loneliness because “the determinants of loneliness 10 years ago or 15 years ago may be different.”
How, When to Intervene
Session chair Judit Lazáry, MD, PhD, Department of Clinical and Theoretical Mental Health, Kútvölgyi Clinical Center, Semmelweis University, Budapest, Hungary, told this news organization that the association between loneliness and FEP was “not surprising.”
She explained there are a lot of data indicating that premorbid symptoms in childhood are “predictive signs for the later onset of psychosis,” and loneliness may be “a part of that.”
Individuals experiencing loneliness are more anxious and have difficulties in cultivating and maintaining relationships. In addition, they tend to socially isolate, she said.
The key question, said Dr. Lazáry, is: “How can we intervene to prevent the onset of psychosis? What is the point at which we can support the young person?”
This is challenging, she added, because while “you can detect that a kid is always alone, you cannot detect the feeling of loneliness,” and children can’t always easily express themselves.
Another potential confounder is that in adults with current psychosis, the self-perception that they were lonely during childhood may be a consequence of the disorder.
In addition, she said, individuals with psychosis often experience cognitive impairment, which could affect memory reliability.
Nevertheless, said Dr. Lazáry, the study’s findings suggest that a young person reporting loneliness in childhood may be “another symptom that we have to investigate.”
No funding was declared.
Dr. Díaz-Caneja declared a relationship with Angelini, Janssen, and Viatris and grant support from Instituto de Salud Carlos III, the Spanish Ministry of Science and Innovation, and the European Commission.
A version of this article appeared on Medscape.com.
BUDAPEST, HUNGARY — Self-perceived loneliness during childhood is linked to a more than twofold increased risk for subsequent first-episode psychosis (FEP) — new findings that may point to a novel marker for the disorder.
The association between loneliness and FEP “appears to extend beyond the effects of objective social isolation,” said study presenter Covadonga M. Díaz-Caneja, MD, PhD, Institute of Psychiatry and Mental Health, Hospital General Universitario Gregorio Marañón, Madrid, and “is particularly pronounced in females.”
“These findings suggest the potential of childhood loneliness as an early risk marker for psychosis that could help guide targeted interventions,” she added.
The results were presented at the European Psychiatric Association 2024 Congress.
Isolation a Major Risk Factor
There are two components to isolation, both of which are “major risk factors” for morbidity, mortality, and the onset of mental disorders, said Dr. Díaz-Caneja.
The first is “objective social isolation,” which consists of a demonstrable lack of social connections, including social interactions, contacts, and relationships, while the other is a perceived sense of isolation, or “loneliness,” defined as a “subjective feeling of distress associated with a lack of meaningful relationships,” regardless of the amount of actual social contact an individual experiences.
Childhood loneliness occurs before age 12 and is becoming increasingly prevalent, said Dr. Díaz-Caneja. A recent survey shows that approximately one third of children report they often feel lonely.
Genetic and observational research has shown there is a bidirectional relationship between loneliness and psychosis and that patients with schizophrenia are more likely to report loneliness than is the general population.
Dr. Díaz-Caneja noted that there is no previous research that has assessed the potential association between childhood loneliness and subsequent psychosis.
To investigate, the researchers conducted an observational, case-control study in seven university hospitals in Madrid. It included individuals aged 7-40 years, including FEP patients with a psychosis duration of less than 2 years, and healthy controls from the same geographic areas.
They assessed childhood objective social isolation using the Premorbid Adjustment Scale and examined childhood loneliness with the single item: “Have you ever felt lonely for more than 6 months before the age of 12?”
A range of measures and questionnaires were also administered to assess participants’ symptom scores, alongside the Global Assessment of Functioning (GAF).
Alone vs Lonely
Two hundred eighty-five patients with FEP participated in the study. They had a mean age of 24.5 years, and 32.6% were female. The study also included 261 healthy controls (average age, 25.9 years; 48.7% female).
After the researchers adjusted for age, gender, ethnicity, and socioeconomic status, loneliness during childhood was associated with a significantly increased risk for FEP (odds ratio [OR], 2.17; 95% CI, 1.40-3.51), which increased (OR, 2.70; 95% CI, 1.58-4.62) after further adjustment for objective social isolation.
Further analysis revealed that in those who did not have objective social isolation in childhood, loneliness was associated with a significantly increased risk for FEP (OR, 2.68; 95% CI, 1.56-4.60).
However, the relationship between loneliness and FEP was not significant in participants who were objectively socially isolated during childhood (OR, 0.33; 95% CI, 0.08-1.45).
Compared with males, females reporting loneliness had a markedly increased risk for FEP (OR, 4.74; 95% CI, 2.23-10.05 vs OR, 1.17; 95% CI, 0.63-2.19).
However, females had a reduced risk of receiving a diagnosis of schizophrenia spectrum disorder (OR, 0.155; 95% CI, 0.048-0.506), indicating that loneliness influenced the type of diagnosis, she noted.
There was a significant positive relationship between loneliness in childhood and symptom scores in men, and a negative association with GAF scores in men.
Dr. Díaz-Caneja noted that the study is preliminary and a “work in progress.” The investigators plan to increase the sample size and will conduct more complex analyses, she said.
“We also of course have to bear in mind that it is a cross-sectional study and that there may be some kind of recall biases [because] we are asking patients now about what happened in the past.”
She noted that it’s unclear whether the results can be extrapolated to individuals who are currently experiencing loneliness because “the determinants of loneliness 10 years ago or 15 years ago may be different.”
How, When to Intervene
Session chair Judit Lazáry, MD, PhD, Department of Clinical and Theoretical Mental Health, Kútvölgyi Clinical Center, Semmelweis University, Budapest, Hungary, told this news organization that the association between loneliness and FEP was “not surprising.”
She explained there are a lot of data indicating that premorbid symptoms in childhood are “predictive signs for the later onset of psychosis,” and loneliness may be “a part of that.”
Individuals experiencing loneliness are more anxious and have difficulties in cultivating and maintaining relationships. In addition, they tend to socially isolate, she said.
The key question, said Dr. Lazáry, is: “How can we intervene to prevent the onset of psychosis? What is the point at which we can support the young person?”
This is challenging, she added, because while “you can detect that a kid is always alone, you cannot detect the feeling of loneliness,” and children can’t always easily express themselves.
Another potential confounder is that in adults with current psychosis, the self-perception that they were lonely during childhood may be a consequence of the disorder.
In addition, she said, individuals with psychosis often experience cognitive impairment, which could affect memory reliability.
Nevertheless, said Dr. Lazáry, the study’s findings suggest that a young person reporting loneliness in childhood may be “another symptom that we have to investigate.”
No funding was declared.
Dr. Díaz-Caneja declared a relationship with Angelini, Janssen, and Viatris and grant support from Instituto de Salud Carlos III, the Spanish Ministry of Science and Innovation, and the European Commission.
A version of this article appeared on Medscape.com.
Positive Results for Intranasal Oxytocin in Adults With Autism
BUDAPEST, HUNGARY — Twice daily intranasal oxytocin has been associated with improved social functioning, quality of life, and overall symptoms in adults with autism spectrum disorder (ASD), results of a small randomized control trial showed.
“One of the challenges for adults with autism is experiencing poor social interactions and difficulties in making friends. Insufficient social support from peers, friends, and family members can contribute to loneliness in adolescents with ASD, which in turn leads to anxiety, sadness, and social isolation,” said study investigator Saba Faraji Niri, MD, assistant professor of psychiatry, Tehran University of Medical Sciences in Iran.
Recent US data show it is relatively common. In addition, previous research suggests intranasal oxytocin significantly increases activity in brain regions that play a role in establishing social interactions.
To evaluate the therapeutic effects and safety of intranasal oxytocin the researchers randomly assigned 39 adult patients with ASD to receive intranasal oxytocin or placebo with 24 units administered every 12 hours for 8 weeks.
Dr. Faraji Niri said study participants were required to stop all psychotropic medications for at least 8 weeks prior to study entry.
Participants were assessed at baseline and weeks 4 and 8 using the Autism Quotient, Ritvo Autism Asperger Diagnostic Scale — Revised (RAADS-R), Social Responsiveness Scale (SRS), Clinical Global Impression (CGI) scale, and the World Health Organization Quality of Life-BREF (WHOQL-BREF) questionnaire. Adverse events were also evaluated.
Dr. Faraji Niri said that those receiving intranasal oxytocin showed clinical improvement on RAADS-R scores (P = .010), as well as on the social communication subscale of the SRS (P = .002), the CGI scale (P = .000), and the physical (P = .004), psychological (P = .006), and social relationships (P = .046) domains of the WHOQL-BREF.
However, although the findings were positive, she said at this point it’s not possible to draw any definitive conclusions. She noted the study had several potential confounders. These included differences in baseline levels of endogenous oxytocin among study participants individuals, as well as difference in required treatment doses, which were adjusted by age and sex. The presence of comorbidities and interactions with other treatments could also affect the results.
Commenting on the findings for this news organization, session chair Szabolcs Kéri, PhD, Professor, Sztárai Institute, University of Tokaj, Sárospatak, Hungary, said the use of oxytocin for ASD is controversial. He said that, while the research contributes to the scientific debate, the clinical significance of the findings is unclear.
The investigators and Dr Keri reported no relevant financial disclosures.
A version of this article appeared on Medscape.com .
BUDAPEST, HUNGARY — Twice daily intranasal oxytocin has been associated with improved social functioning, quality of life, and overall symptoms in adults with autism spectrum disorder (ASD), results of a small randomized control trial showed.
“One of the challenges for adults with autism is experiencing poor social interactions and difficulties in making friends. Insufficient social support from peers, friends, and family members can contribute to loneliness in adolescents with ASD, which in turn leads to anxiety, sadness, and social isolation,” said study investigator Saba Faraji Niri, MD, assistant professor of psychiatry, Tehran University of Medical Sciences in Iran.
Recent US data show it is relatively common. In addition, previous research suggests intranasal oxytocin significantly increases activity in brain regions that play a role in establishing social interactions.
To evaluate the therapeutic effects and safety of intranasal oxytocin the researchers randomly assigned 39 adult patients with ASD to receive intranasal oxytocin or placebo with 24 units administered every 12 hours for 8 weeks.
Dr. Faraji Niri said study participants were required to stop all psychotropic medications for at least 8 weeks prior to study entry.
Participants were assessed at baseline and weeks 4 and 8 using the Autism Quotient, Ritvo Autism Asperger Diagnostic Scale — Revised (RAADS-R), Social Responsiveness Scale (SRS), Clinical Global Impression (CGI) scale, and the World Health Organization Quality of Life-BREF (WHOQL-BREF) questionnaire. Adverse events were also evaluated.
Dr. Faraji Niri said that those receiving intranasal oxytocin showed clinical improvement on RAADS-R scores (P = .010), as well as on the social communication subscale of the SRS (P = .002), the CGI scale (P = .000), and the physical (P = .004), psychological (P = .006), and social relationships (P = .046) domains of the WHOQL-BREF.
However, although the findings were positive, she said at this point it’s not possible to draw any definitive conclusions. She noted the study had several potential confounders. These included differences in baseline levels of endogenous oxytocin among study participants individuals, as well as difference in required treatment doses, which were adjusted by age and sex. The presence of comorbidities and interactions with other treatments could also affect the results.
Commenting on the findings for this news organization, session chair Szabolcs Kéri, PhD, Professor, Sztárai Institute, University of Tokaj, Sárospatak, Hungary, said the use of oxytocin for ASD is controversial. He said that, while the research contributes to the scientific debate, the clinical significance of the findings is unclear.
The investigators and Dr Keri reported no relevant financial disclosures.
A version of this article appeared on Medscape.com .
BUDAPEST, HUNGARY — Twice daily intranasal oxytocin has been associated with improved social functioning, quality of life, and overall symptoms in adults with autism spectrum disorder (ASD), results of a small randomized control trial showed.
“One of the challenges for adults with autism is experiencing poor social interactions and difficulties in making friends. Insufficient social support from peers, friends, and family members can contribute to loneliness in adolescents with ASD, which in turn leads to anxiety, sadness, and social isolation,” said study investigator Saba Faraji Niri, MD, assistant professor of psychiatry, Tehran University of Medical Sciences in Iran.
Recent US data show it is relatively common. In addition, previous research suggests intranasal oxytocin significantly increases activity in brain regions that play a role in establishing social interactions.
To evaluate the therapeutic effects and safety of intranasal oxytocin the researchers randomly assigned 39 adult patients with ASD to receive intranasal oxytocin or placebo with 24 units administered every 12 hours for 8 weeks.
Dr. Faraji Niri said study participants were required to stop all psychotropic medications for at least 8 weeks prior to study entry.
Participants were assessed at baseline and weeks 4 and 8 using the Autism Quotient, Ritvo Autism Asperger Diagnostic Scale — Revised (RAADS-R), Social Responsiveness Scale (SRS), Clinical Global Impression (CGI) scale, and the World Health Organization Quality of Life-BREF (WHOQL-BREF) questionnaire. Adverse events were also evaluated.
Dr. Faraji Niri said that those receiving intranasal oxytocin showed clinical improvement on RAADS-R scores (P = .010), as well as on the social communication subscale of the SRS (P = .002), the CGI scale (P = .000), and the physical (P = .004), psychological (P = .006), and social relationships (P = .046) domains of the WHOQL-BREF.
However, although the findings were positive, she said at this point it’s not possible to draw any definitive conclusions. She noted the study had several potential confounders. These included differences in baseline levels of endogenous oxytocin among study participants individuals, as well as difference in required treatment doses, which were adjusted by age and sex. The presence of comorbidities and interactions with other treatments could also affect the results.
Commenting on the findings for this news organization, session chair Szabolcs Kéri, PhD, Professor, Sztárai Institute, University of Tokaj, Sárospatak, Hungary, said the use of oxytocin for ASD is controversial. He said that, while the research contributes to the scientific debate, the clinical significance of the findings is unclear.
The investigators and Dr Keri reported no relevant financial disclosures.
A version of this article appeared on Medscape.com .
Esketamine Linked to Reduced Postpartum Depression Risk
BUDAPEST, Hungary — A single dose of intravenous esketamine during delivery or cesarean section appears to reduce the risk for postpartum depression (PPD) by more than 50% in the first 6 weeks, a new meta-analysis suggested. However, the long-term safety and efficacy of the drug are still unclear.
Study investigator Angelina Kozhokar, MD, Department of Medicine, Universitat Internacional de Catalunya, Barcelona, Sant Cugat del Valles, Spain, told this news organization she was “surprised” by the size of the PPD risk reduction associated with the drug.
However, she added, “it’s important to consider that preliminary studies on a lot of medications used for postpartum depression have also shown very big effect sizes.”
Dr. Kozhokar believes that as more studies examining esketamine for PPD are conducted, “we will see more definitive effect sizes, and the safety profile for this new treatment” will become clearer.
The findings were presented at the European Psychiatric Association (EPA) Congress.
Significant Reduction
As previously reported by this news organization, intranasal esketamine (Spravato, Janssen) was shown to be superior to extended-release quetiapine (Seroquel, AstraZeneca), an atypical antipsychotic, for treatment-resistant depression.
With up to 13% of women experiencing PPD in the perinatal period, the researchers sought to examine the impact of esketamine administered prophylactically during labor or cesarean section on the incidence of the disorder.
They searched the PubMed, Scopus, and Google Scholar databases for randomized controlled trials examining the efficacy of esketamine and screened for PPD using the Edinburgh Postpartum Depression Scale (EPDS).
While the intranasal spray is the only form of esketamine approved by the US Food and Drug Administration, an injectable solution is also available. The researchers identified seven eligible trials that included a total of 1287 women. Of these participants, 635 (49.3%) received esketamine. Esketamine was delivered as either patient-controlled intravenous analgesia or a single intravenous dose during delivery or cesarean section.
Across the seven trials, esketamine was associated with a significant reduction in PPD at 1 week after delivery at a risk ratio vs placebo of 0.459 (P < .05). At 6 weeks, the reduction in PPD incidence was maintained, at a risk ratio of 0.470 (P < .01).
However, Dr. Kozhokar pointed out that the EPDS is a subjective measure of PPD, and the studies used different cutoff scores for depression, ranging from 9 to 13 points.
Unanswered Questions
She also cautioned that the adverse effects of esketamine on maternal and neonatal health need to be assessed, as well as the long-term cost/benefit ratio of prophylactic treatment.
All seven studies included in the meta-analysis were conducted in China, which limits the generalizability of the findings.
“I suppose they were quicker to get to the topic than the rest of the world,” Dr. Kozhokar said, while also suggesting that, potentially, “we are more regulated here in Europe.”
She pointed out that there is “an important safety concern about the use of medications such as ketamine and esketamine” in terms of the potential for addiction and the effect on babies over the long term, which is currently unknown.
Session chair Linda Rubene, MD, a psychiatrist in the Department of Psychiatry and Narcology at Riga Stradinš University, Riga, Latvia, welcomed the study.
“If we had more options to treat postpartum depression and to treat depression during pregnancy, it would be a great improvement,” she said.
However, she noted, because there are no long-term outcome data for esketamine in PPD, more study is needed. It is possible, said Dr. Rubene, that esketamine may not work for all women.
The investigators and Dr. Rubene reported no relevant financial disclosures.
A version of this article first appeared on Medscape.com .
BUDAPEST, Hungary — A single dose of intravenous esketamine during delivery or cesarean section appears to reduce the risk for postpartum depression (PPD) by more than 50% in the first 6 weeks, a new meta-analysis suggested. However, the long-term safety and efficacy of the drug are still unclear.
Study investigator Angelina Kozhokar, MD, Department of Medicine, Universitat Internacional de Catalunya, Barcelona, Sant Cugat del Valles, Spain, told this news organization she was “surprised” by the size of the PPD risk reduction associated with the drug.
However, she added, “it’s important to consider that preliminary studies on a lot of medications used for postpartum depression have also shown very big effect sizes.”
Dr. Kozhokar believes that as more studies examining esketamine for PPD are conducted, “we will see more definitive effect sizes, and the safety profile for this new treatment” will become clearer.
The findings were presented at the European Psychiatric Association (EPA) Congress.
Significant Reduction
As previously reported by this news organization, intranasal esketamine (Spravato, Janssen) was shown to be superior to extended-release quetiapine (Seroquel, AstraZeneca), an atypical antipsychotic, for treatment-resistant depression.
With up to 13% of women experiencing PPD in the perinatal period, the researchers sought to examine the impact of esketamine administered prophylactically during labor or cesarean section on the incidence of the disorder.
They searched the PubMed, Scopus, and Google Scholar databases for randomized controlled trials examining the efficacy of esketamine and screened for PPD using the Edinburgh Postpartum Depression Scale (EPDS).
While the intranasal spray is the only form of esketamine approved by the US Food and Drug Administration, an injectable solution is also available. The researchers identified seven eligible trials that included a total of 1287 women. Of these participants, 635 (49.3%) received esketamine. Esketamine was delivered as either patient-controlled intravenous analgesia or a single intravenous dose during delivery or cesarean section.
Across the seven trials, esketamine was associated with a significant reduction in PPD at 1 week after delivery at a risk ratio vs placebo of 0.459 (P < .05). At 6 weeks, the reduction in PPD incidence was maintained, at a risk ratio of 0.470 (P < .01).
However, Dr. Kozhokar pointed out that the EPDS is a subjective measure of PPD, and the studies used different cutoff scores for depression, ranging from 9 to 13 points.
Unanswered Questions
She also cautioned that the adverse effects of esketamine on maternal and neonatal health need to be assessed, as well as the long-term cost/benefit ratio of prophylactic treatment.
All seven studies included in the meta-analysis were conducted in China, which limits the generalizability of the findings.
“I suppose they were quicker to get to the topic than the rest of the world,” Dr. Kozhokar said, while also suggesting that, potentially, “we are more regulated here in Europe.”
She pointed out that there is “an important safety concern about the use of medications such as ketamine and esketamine” in terms of the potential for addiction and the effect on babies over the long term, which is currently unknown.
Session chair Linda Rubene, MD, a psychiatrist in the Department of Psychiatry and Narcology at Riga Stradinš University, Riga, Latvia, welcomed the study.
“If we had more options to treat postpartum depression and to treat depression during pregnancy, it would be a great improvement,” she said.
However, she noted, because there are no long-term outcome data for esketamine in PPD, more study is needed. It is possible, said Dr. Rubene, that esketamine may not work for all women.
The investigators and Dr. Rubene reported no relevant financial disclosures.
A version of this article first appeared on Medscape.com .
BUDAPEST, Hungary — A single dose of intravenous esketamine during delivery or cesarean section appears to reduce the risk for postpartum depression (PPD) by more than 50% in the first 6 weeks, a new meta-analysis suggested. However, the long-term safety and efficacy of the drug are still unclear.
Study investigator Angelina Kozhokar, MD, Department of Medicine, Universitat Internacional de Catalunya, Barcelona, Sant Cugat del Valles, Spain, told this news organization she was “surprised” by the size of the PPD risk reduction associated with the drug.
However, she added, “it’s important to consider that preliminary studies on a lot of medications used for postpartum depression have also shown very big effect sizes.”
Dr. Kozhokar believes that as more studies examining esketamine for PPD are conducted, “we will see more definitive effect sizes, and the safety profile for this new treatment” will become clearer.
The findings were presented at the European Psychiatric Association (EPA) Congress.
Significant Reduction
As previously reported by this news organization, intranasal esketamine (Spravato, Janssen) was shown to be superior to extended-release quetiapine (Seroquel, AstraZeneca), an atypical antipsychotic, for treatment-resistant depression.
With up to 13% of women experiencing PPD in the perinatal period, the researchers sought to examine the impact of esketamine administered prophylactically during labor or cesarean section on the incidence of the disorder.
They searched the PubMed, Scopus, and Google Scholar databases for randomized controlled trials examining the efficacy of esketamine and screened for PPD using the Edinburgh Postpartum Depression Scale (EPDS).
While the intranasal spray is the only form of esketamine approved by the US Food and Drug Administration, an injectable solution is also available. The researchers identified seven eligible trials that included a total of 1287 women. Of these participants, 635 (49.3%) received esketamine. Esketamine was delivered as either patient-controlled intravenous analgesia or a single intravenous dose during delivery or cesarean section.
Across the seven trials, esketamine was associated with a significant reduction in PPD at 1 week after delivery at a risk ratio vs placebo of 0.459 (P < .05). At 6 weeks, the reduction in PPD incidence was maintained, at a risk ratio of 0.470 (P < .01).
However, Dr. Kozhokar pointed out that the EPDS is a subjective measure of PPD, and the studies used different cutoff scores for depression, ranging from 9 to 13 points.
Unanswered Questions
She also cautioned that the adverse effects of esketamine on maternal and neonatal health need to be assessed, as well as the long-term cost/benefit ratio of prophylactic treatment.
All seven studies included in the meta-analysis were conducted in China, which limits the generalizability of the findings.
“I suppose they were quicker to get to the topic than the rest of the world,” Dr. Kozhokar said, while also suggesting that, potentially, “we are more regulated here in Europe.”
She pointed out that there is “an important safety concern about the use of medications such as ketamine and esketamine” in terms of the potential for addiction and the effect on babies over the long term, which is currently unknown.
Session chair Linda Rubene, MD, a psychiatrist in the Department of Psychiatry and Narcology at Riga Stradinš University, Riga, Latvia, welcomed the study.
“If we had more options to treat postpartum depression and to treat depression during pregnancy, it would be a great improvement,” she said.
However, she noted, because there are no long-term outcome data for esketamine in PPD, more study is needed. It is possible, said Dr. Rubene, that esketamine may not work for all women.
The investigators and Dr. Rubene reported no relevant financial disclosures.
A version of this article first appeared on Medscape.com .
FROM EPA 2024
Tarlatamab Shows Promise in Tackling Previously Treated SCLC
The investigational bispecific T-cell engager tarlatamab achieved durable responses and clinically meaningful survival outcomes in patients with small-cell lung cancer (SCLC), particularly at lower doses, according to a follow-up analysis of the phase 1 DeLLphi-300 trial.
Most patients with central nervous system tumors also sustained tumor shrinkage long after receiving radiotherapy, providing “encouraging evidence” of the new agent’s intracranial activity, said study presenter Horst-Dieter Hummel, MD, Comprehensive Cancer Center Mainfranken, Würzburg, Germany.
The research was presented at the European Lung Cancer Congress 2024 on March 22.
Data from the phase 1 and phase 2 DeLLphi trials, published last year, showed the compound achieved “encouraging clinical activity” in pretreated patients, said Dr. Hummel.
The initial phase 1 DeLLphi study found that after a median follow-up of 8.7 months, the immunotherapy led to a disease control rate of 51.4%, a median progression-free survival of 3.7 months, and median overall survival of 13.2 months.
At the meeting, Dr. Hummel reported longer-term outcomes from the phase 1 study over a median of 12.1 months as well as intracranial activity in patients who received clinically relevant doses of tarlatamab, defined as ≥ 10 mg.
The 152 patients included in the analysis had a median of two prior lines of therapy; 76.3% had undergone radiotherapy, and 63.2% had received immunotherapy. Liver metastases were present in 42.1% of patients, and 25.0% had brain metastases.
Doses varied among participants, with 76 patients (50.0%) receiving 100 mg, 32 (21.0%) receiving 100 mg via extended intravenous infusion, 17 (11.2%) receiving 10 mg, and 8 (5.3%) receiving 30 mg.
The overall objective response rate was 25.0%, with a median duration of response of 11.2 months. Among patients given the 10-mg dose, the objective response rate was higher, at 35.3%, as was the median duration of response, at 14.9 months.
Tarlatamab was associated with a median overall survival of 17.5 months, with 57.9% of patients alive at 12 months. Patients receiving the 10 mg dose had a better median overall survival of 20.3 months.
Of the 16 patients with analyzable central nervous system tumors, 62.5% experienced tumor shrinkage by ≥ 30% and 87.5% experienced intracranial disease control, which lasted for a median of 7.4 months.
In this follow-up study, tarlatamab demonstrated “clinically meaningful survival outcomes in patients with previously treated SCLC, particularly with the 10 mg dose,” Dr. Hummel concluded in his presentation.
No new safety signals emerged, though almost all patients did experience tarlatamab-related adverse events (94.8% for doses > 10 mg and 100% of patients with 10 mg doses). Overall, 66.4% of the total cohort experienced cytokine release syndrome of any grade, and 11.8% developed immune effector cell-associated neurotoxicity syndrome.
Discontinuation due to treatment-related adverse events occurred in 9 patients overall, and adverse events that led to dose interruption or reduction occurred in 32 patients overall.
“After many efforts at DLL3 targeting, we finally have an agent that shows activity and efficacy, and with convincing data,” said Jessica Menis, MD, a medical oncologist at the oncology department of the University Hospital of Verona, Italy, who was not involved in the study. The intracranial activity of tarlatamab “needs to be further evaluated in untreated patients,” Dr. Menis noted, because the study included only patients with stable, treated brain metastases.
And given the high rates of adverse events, Dr. Menis cautioned that adverse event management “will be a challenge.”
On X (Twitter), Tom Newsom-Davis, MBBS, PhD, a consultant in medical oncology at Chelsea and Westminster Hospital, London, said that tarlatamab is “not a straightforward drug to use,” highlighting the occurrence of cytokine release syndrome.
“But in this significantly pretreated population and in this hard-to-treat tumor type,” the rate and duration of responses seen with the extended follow-up are ‘impressive’,” he added.
DeLLphi-300, 301, and 304 were funded by Amgen Inc. Dr. Hummel declared relationships with several companies, including Amgen, Bristol Myers Squibb, AstraZeneca, Celgene, Merck, Novartis, Daiichi Sankyo, and Roche. Dr. Menis declared relationships with AstraZeneca, BMS, MSD, Roche, and Novartis.
A version of this article appeared on Medscape.com.
The investigational bispecific T-cell engager tarlatamab achieved durable responses and clinically meaningful survival outcomes in patients with small-cell lung cancer (SCLC), particularly at lower doses, according to a follow-up analysis of the phase 1 DeLLphi-300 trial.
Most patients with central nervous system tumors also sustained tumor shrinkage long after receiving radiotherapy, providing “encouraging evidence” of the new agent’s intracranial activity, said study presenter Horst-Dieter Hummel, MD, Comprehensive Cancer Center Mainfranken, Würzburg, Germany.
The research was presented at the European Lung Cancer Congress 2024 on March 22.
Data from the phase 1 and phase 2 DeLLphi trials, published last year, showed the compound achieved “encouraging clinical activity” in pretreated patients, said Dr. Hummel.
The initial phase 1 DeLLphi study found that after a median follow-up of 8.7 months, the immunotherapy led to a disease control rate of 51.4%, a median progression-free survival of 3.7 months, and median overall survival of 13.2 months.
At the meeting, Dr. Hummel reported longer-term outcomes from the phase 1 study over a median of 12.1 months as well as intracranial activity in patients who received clinically relevant doses of tarlatamab, defined as ≥ 10 mg.
The 152 patients included in the analysis had a median of two prior lines of therapy; 76.3% had undergone radiotherapy, and 63.2% had received immunotherapy. Liver metastases were present in 42.1% of patients, and 25.0% had brain metastases.
Doses varied among participants, with 76 patients (50.0%) receiving 100 mg, 32 (21.0%) receiving 100 mg via extended intravenous infusion, 17 (11.2%) receiving 10 mg, and 8 (5.3%) receiving 30 mg.
The overall objective response rate was 25.0%, with a median duration of response of 11.2 months. Among patients given the 10-mg dose, the objective response rate was higher, at 35.3%, as was the median duration of response, at 14.9 months.
Tarlatamab was associated with a median overall survival of 17.5 months, with 57.9% of patients alive at 12 months. Patients receiving the 10 mg dose had a better median overall survival of 20.3 months.
Of the 16 patients with analyzable central nervous system tumors, 62.5% experienced tumor shrinkage by ≥ 30% and 87.5% experienced intracranial disease control, which lasted for a median of 7.4 months.
In this follow-up study, tarlatamab demonstrated “clinically meaningful survival outcomes in patients with previously treated SCLC, particularly with the 10 mg dose,” Dr. Hummel concluded in his presentation.
No new safety signals emerged, though almost all patients did experience tarlatamab-related adverse events (94.8% for doses > 10 mg and 100% of patients with 10 mg doses). Overall, 66.4% of the total cohort experienced cytokine release syndrome of any grade, and 11.8% developed immune effector cell-associated neurotoxicity syndrome.
Discontinuation due to treatment-related adverse events occurred in 9 patients overall, and adverse events that led to dose interruption or reduction occurred in 32 patients overall.
“After many efforts at DLL3 targeting, we finally have an agent that shows activity and efficacy, and with convincing data,” said Jessica Menis, MD, a medical oncologist at the oncology department of the University Hospital of Verona, Italy, who was not involved in the study. The intracranial activity of tarlatamab “needs to be further evaluated in untreated patients,” Dr. Menis noted, because the study included only patients with stable, treated brain metastases.
And given the high rates of adverse events, Dr. Menis cautioned that adverse event management “will be a challenge.”
On X (Twitter), Tom Newsom-Davis, MBBS, PhD, a consultant in medical oncology at Chelsea and Westminster Hospital, London, said that tarlatamab is “not a straightforward drug to use,” highlighting the occurrence of cytokine release syndrome.
“But in this significantly pretreated population and in this hard-to-treat tumor type,” the rate and duration of responses seen with the extended follow-up are ‘impressive’,” he added.
DeLLphi-300, 301, and 304 were funded by Amgen Inc. Dr. Hummel declared relationships with several companies, including Amgen, Bristol Myers Squibb, AstraZeneca, Celgene, Merck, Novartis, Daiichi Sankyo, and Roche. Dr. Menis declared relationships with AstraZeneca, BMS, MSD, Roche, and Novartis.
A version of this article appeared on Medscape.com.
The investigational bispecific T-cell engager tarlatamab achieved durable responses and clinically meaningful survival outcomes in patients with small-cell lung cancer (SCLC), particularly at lower doses, according to a follow-up analysis of the phase 1 DeLLphi-300 trial.
Most patients with central nervous system tumors also sustained tumor shrinkage long after receiving radiotherapy, providing “encouraging evidence” of the new agent’s intracranial activity, said study presenter Horst-Dieter Hummel, MD, Comprehensive Cancer Center Mainfranken, Würzburg, Germany.
The research was presented at the European Lung Cancer Congress 2024 on March 22.
Data from the phase 1 and phase 2 DeLLphi trials, published last year, showed the compound achieved “encouraging clinical activity” in pretreated patients, said Dr. Hummel.
The initial phase 1 DeLLphi study found that after a median follow-up of 8.7 months, the immunotherapy led to a disease control rate of 51.4%, a median progression-free survival of 3.7 months, and median overall survival of 13.2 months.
At the meeting, Dr. Hummel reported longer-term outcomes from the phase 1 study over a median of 12.1 months as well as intracranial activity in patients who received clinically relevant doses of tarlatamab, defined as ≥ 10 mg.
The 152 patients included in the analysis had a median of two prior lines of therapy; 76.3% had undergone radiotherapy, and 63.2% had received immunotherapy. Liver metastases were present in 42.1% of patients, and 25.0% had brain metastases.
Doses varied among participants, with 76 patients (50.0%) receiving 100 mg, 32 (21.0%) receiving 100 mg via extended intravenous infusion, 17 (11.2%) receiving 10 mg, and 8 (5.3%) receiving 30 mg.
The overall objective response rate was 25.0%, with a median duration of response of 11.2 months. Among patients given the 10-mg dose, the objective response rate was higher, at 35.3%, as was the median duration of response, at 14.9 months.
Tarlatamab was associated with a median overall survival of 17.5 months, with 57.9% of patients alive at 12 months. Patients receiving the 10 mg dose had a better median overall survival of 20.3 months.
Of the 16 patients with analyzable central nervous system tumors, 62.5% experienced tumor shrinkage by ≥ 30% and 87.5% experienced intracranial disease control, which lasted for a median of 7.4 months.
In this follow-up study, tarlatamab demonstrated “clinically meaningful survival outcomes in patients with previously treated SCLC, particularly with the 10 mg dose,” Dr. Hummel concluded in his presentation.
No new safety signals emerged, though almost all patients did experience tarlatamab-related adverse events (94.8% for doses > 10 mg and 100% of patients with 10 mg doses). Overall, 66.4% of the total cohort experienced cytokine release syndrome of any grade, and 11.8% developed immune effector cell-associated neurotoxicity syndrome.
Discontinuation due to treatment-related adverse events occurred in 9 patients overall, and adverse events that led to dose interruption or reduction occurred in 32 patients overall.
“After many efforts at DLL3 targeting, we finally have an agent that shows activity and efficacy, and with convincing data,” said Jessica Menis, MD, a medical oncologist at the oncology department of the University Hospital of Verona, Italy, who was not involved in the study. The intracranial activity of tarlatamab “needs to be further evaluated in untreated patients,” Dr. Menis noted, because the study included only patients with stable, treated brain metastases.
And given the high rates of adverse events, Dr. Menis cautioned that adverse event management “will be a challenge.”
On X (Twitter), Tom Newsom-Davis, MBBS, PhD, a consultant in medical oncology at Chelsea and Westminster Hospital, London, said that tarlatamab is “not a straightforward drug to use,” highlighting the occurrence of cytokine release syndrome.
“But in this significantly pretreated population and in this hard-to-treat tumor type,” the rate and duration of responses seen with the extended follow-up are ‘impressive’,” he added.
DeLLphi-300, 301, and 304 were funded by Amgen Inc. Dr. Hummel declared relationships with several companies, including Amgen, Bristol Myers Squibb, AstraZeneca, Celgene, Merck, Novartis, Daiichi Sankyo, and Roche. Dr. Menis declared relationships with AstraZeneca, BMS, MSD, Roche, and Novartis.
A version of this article appeared on Medscape.com.
FROM ELCC 2024
CHIP: The Silent Threat Steps Into the Limelight
While it is increasingly apparent that , it has not been clear what to do about it.
Now, researchers at the cutting edge of both oncologic and cardiovascular research are not only defining the prognosis of CHIP with greater granularity but are also finding clues to mitigate the risks.
“It’s a very, very rapidly moving area,” said Christie M. Ballantyne, MD, Director, Center for Cardiometabolic Disease Prevention, Baylor College of Medicine, Houston, adding that, in many respects, “it’s a totally new area.”
CHIP Defined
CHIP was first recognized in the 1990s, when Martin F. Fey, MD, and colleagues from University and Inselspital, Bern, Switzerland, found X-linked inactivation in older women and suggested it was the result of acquired clonality later referred to as being of “indeterminate potential,” although that added syntax is currently a matter of debate.
Further work showed that, while somatic gene mutations occur spontaneously and are an unavoidable consequence of aging, their impact can vary widely.
The majority are “functionally silent,” while others may affect genes crucial to tissue self-renewal and differentiation, Lukasz Gondek, MD, PhD, assistant professor, Johns Hopkins Cellular and Molecular Medicine Program, Baltimore, and colleagues, noted in a recent review.
This results in the outgrowth of affected cells, known as clonal expansion, further dubbed clonal hematopoiesis when it occurs in hematopoietic tissue.
“Even though there’s clonal expansion, there’s no one CHIP,” Dr. Gondek said. “There are different flavors, and it depends on the genes that are mutated in the hematopoietic cells.”
He continued: “The older we get, the more mutations we acquire, and the probability that this mutation will hit the gene that’s responsible for expansion of the clone is higher.”
“That’s why CHIP is very uncommon in people under the age of 40, but it becomes more common in the fifth, sixth, and seventh decade of life and beyond.”
Indeed, it occurs in 10% to 15% of people aged 65 years or older, and in at least 30% of individuals by 80 years of age. In contrast, just 1% of those aged less than 50 years have the condition.
The most commonly affected genes, in around 80% of patients with CHIP, are the epigenetic regulators DNMT3A, TET2, and ASXL1; the DNA damage repair genes PPM1D and TP53; the regulatory tyrosine kinase JAK2; and the messenger RNA spliceosome components SF3B1 and SRSF2.
These mutations can have “two potential consequences,” explained Lachelle D. Weeks, MD, PhD, a hematologist at the Dana-Farber Cancer Institute, Boston.
“One is that there’s a risk of blood cancer development,” as several of the mutations are known drivers of leukemia or myelodysplastic syndromes (MDS).
Although the majority of individuals who acquire clonal hematopoiesis with age will never develop MDS, it nevertheless confers an 11- to 13-fold increased risk or an absolute risk of approximately 0.5%-1.0% per year.
Dr. Weeks continued that “the other side of it, though, is that those cells that have these mutations can also accelerate the risk of developing nonmalignant diseases like cardiovascular disease.”
This, Dr. Gondek explained, is because the mutations will be retained when the stem cells become monocytes or macrophages and, by either silencing or activating individual genes, they can make the cells more pro-inflammatory.
The result is that CHIP is associated with a marked increased risk for arteriosclerotic events such as stroke, myocardial infarction, decompensated heart failure, and cardiogenic shock, and worse outcomes after these events.
Researchers have shown that CHIP-related somatic mutations are associated with a twofold increased risk for coronary heart disease, a more than 2.5-fold increased risk for ischemic stroke, and a fourfold greater risk for myocardial infarction. A study from earlier this year found that CHIP also increases the risk for heart failure with preserved ejection fraction more than twofold.
There is even evidence to suggest that CHIP is associated with more severe acute kidney injury (AKI) and greater post-AKI kidney fibrosis.
The consequence is that individuals with CHIP face a 40% increased risk for all-cause mortality over 8 years.
No CHIP Test Yet
All of which has led for some to call for CHIP testing.
However, there are currently no screening programs for CHIP and no plans to introduce any. “So most CHIP is actually being diagnosed incidentally, when patients get genetic testing for some other indication,” said Dr. Weeks.
“The patients that we see in our CHIP clinic at Dana-Farber have genetic testing because they have low blood counts,” she continued, “and somebody’s trying to figure out: Do you have MDS?”
Other patients have genetic testing due to a family history of other cancers, “and so they’re getting hereditary cancer panels to determine if they have Lynch syndrome, or other hereditary syndromes,” which are picking up gene mutations associated with CHIP.
In other cases, study protocols are identifying CHIP “in various research contexts, and then as a follow-up, some of those patients end up with our clinic,” added Dr. Weeks.
Due to the associated risks for CHIP, “obviously everyone wants to know whether they are at risk for hematologic malignancy, or not,” said Dr. Gondek. To those ends, Dr. Weeks and colleagues developed the clonal hematopoiesis risk score (CHRS).
Published by NEJM Evidence in 2023, the score takes a range of predictive variables, such as age, number of mutations and their degree of associated risk, the variant allele fraction, and a series of blood indices to define patients as low-, intermediate-, or high-risk.
“A little over half” of high-risk individuals “will develop a blood cancer” such as MDS or acute myeloid leukemia (AML)” over the next 10 years, Weeks explained, while “for your intermediate risk folks, in that same time period, 7%-8% of them will develop a blood cancer.”
In low-risk individuals, the 10-year risk for MDS or AML is just 1%.
Dr. Weeks noted the “caveat that there are environmental factors or patient-specific issues that might increase your risk that are not considered in the calculator,” such the presence of hereditary cancer syndromes, “or if you’re getting chemotherapy for other cancers.”
From a cardiology point of view, Dr. Ballantyne said that, above all, “cardiologists need to be aware that some of these people are at increased risk for cardiovascular events.” This prompted a team including Dr. Weeks and Dr. Ballantyne to study whether the CHRS can also predict cardiovascular risk.
They found that people designated low-risk on the score faced an 8% increased risk for all-cause mortality vs individuals without CHIP during a median follow-up of 7 years. This rose to a 12% increase in intermediate-risk individuals.
And those deemed high-risk had a 2.5-fold increased risk for early mortality and a threefold higher risk for cardiovascular death.
Dr. Weeks noted: “We have not done a dedicated study to define a cardiovascular disease-specific calculator for CHIP,” but in the meantime, the CHRS is a “very reasonable way to estimate what someone’s risk of progression or adverse events is for cardiovascular disease.”
For clinicians, however, the key question becomes: What can be done to mitigate the risks, particularly in high-risk individuals?
For malignant conditions, the approach is to monitor patients, although “we and other centers are in the process of developing various interventional clinical trials to test various agents on their ability to improve blood counts, as well as to mitigate the risk of progression to overt blood cancer,” said Dr. Weeks.
Treat CHIP Like Lipoprotein(a)?
As for cardiovascular risk, Dr. Ballantyne believes that, because CHIP is an unmodifiable risk factor, an example to follow could be lipoprotein(a) (LP[a]).
“We don’t have a therapy specifically to target LP(a) yet, but we do know that the things that benefit in general,” he said, such as “taking a statin, lowering blood pressure into the optimal zone, diet ,and exercise.”
“What we do in our clinic, and what others have been doing,” Dr. Weeks added, “is for every patient who comes in and is diagnosed with CHIP, we are referring them to preventative cardiology for very aggressive preventative management.”
Finally, both Dr. Ballantyne and Dr. Weeks agree that there are many potential innovations on the horizon.
“It’s pretty exciting in terms of beginning to understand some of the links between aging, cardiovascular disease, and cancer that we had not been thinking about,” Dr. Ballantyne said.
On the malignant side, Dr. Weeks is already working on a prospective study to determine how the risks associated with CHIP evolve when patients undergo chemotherapy and radiation for other cancers.
“That will be really exciting and will help us to develop a specific calculator in that context,” she said, adding that a cardiovascular-specific calculator “is also coming down the line.”
Dr. Weeks declared relationships with Abbvie, Vertex, and Sobi. Dr. Ballantyne declared a relationship with Ten Sixteen Bio, and funding from the National Heart, Lung, and Blood Institute. No other relevant financial relationships were declared.
A version of this article appeared on Medscape.com.
While it is increasingly apparent that , it has not been clear what to do about it.
Now, researchers at the cutting edge of both oncologic and cardiovascular research are not only defining the prognosis of CHIP with greater granularity but are also finding clues to mitigate the risks.
“It’s a very, very rapidly moving area,” said Christie M. Ballantyne, MD, Director, Center for Cardiometabolic Disease Prevention, Baylor College of Medicine, Houston, adding that, in many respects, “it’s a totally new area.”
CHIP Defined
CHIP was first recognized in the 1990s, when Martin F. Fey, MD, and colleagues from University and Inselspital, Bern, Switzerland, found X-linked inactivation in older women and suggested it was the result of acquired clonality later referred to as being of “indeterminate potential,” although that added syntax is currently a matter of debate.
Further work showed that, while somatic gene mutations occur spontaneously and are an unavoidable consequence of aging, their impact can vary widely.
The majority are “functionally silent,” while others may affect genes crucial to tissue self-renewal and differentiation, Lukasz Gondek, MD, PhD, assistant professor, Johns Hopkins Cellular and Molecular Medicine Program, Baltimore, and colleagues, noted in a recent review.
This results in the outgrowth of affected cells, known as clonal expansion, further dubbed clonal hematopoiesis when it occurs in hematopoietic tissue.
“Even though there’s clonal expansion, there’s no one CHIP,” Dr. Gondek said. “There are different flavors, and it depends on the genes that are mutated in the hematopoietic cells.”
He continued: “The older we get, the more mutations we acquire, and the probability that this mutation will hit the gene that’s responsible for expansion of the clone is higher.”
“That’s why CHIP is very uncommon in people under the age of 40, but it becomes more common in the fifth, sixth, and seventh decade of life and beyond.”
Indeed, it occurs in 10% to 15% of people aged 65 years or older, and in at least 30% of individuals by 80 years of age. In contrast, just 1% of those aged less than 50 years have the condition.
The most commonly affected genes, in around 80% of patients with CHIP, are the epigenetic regulators DNMT3A, TET2, and ASXL1; the DNA damage repair genes PPM1D and TP53; the regulatory tyrosine kinase JAK2; and the messenger RNA spliceosome components SF3B1 and SRSF2.
These mutations can have “two potential consequences,” explained Lachelle D. Weeks, MD, PhD, a hematologist at the Dana-Farber Cancer Institute, Boston.
“One is that there’s a risk of blood cancer development,” as several of the mutations are known drivers of leukemia or myelodysplastic syndromes (MDS).
Although the majority of individuals who acquire clonal hematopoiesis with age will never develop MDS, it nevertheless confers an 11- to 13-fold increased risk or an absolute risk of approximately 0.5%-1.0% per year.
Dr. Weeks continued that “the other side of it, though, is that those cells that have these mutations can also accelerate the risk of developing nonmalignant diseases like cardiovascular disease.”
This, Dr. Gondek explained, is because the mutations will be retained when the stem cells become monocytes or macrophages and, by either silencing or activating individual genes, they can make the cells more pro-inflammatory.
The result is that CHIP is associated with a marked increased risk for arteriosclerotic events such as stroke, myocardial infarction, decompensated heart failure, and cardiogenic shock, and worse outcomes after these events.
Researchers have shown that CHIP-related somatic mutations are associated with a twofold increased risk for coronary heart disease, a more than 2.5-fold increased risk for ischemic stroke, and a fourfold greater risk for myocardial infarction. A study from earlier this year found that CHIP also increases the risk for heart failure with preserved ejection fraction more than twofold.
There is even evidence to suggest that CHIP is associated with more severe acute kidney injury (AKI) and greater post-AKI kidney fibrosis.
The consequence is that individuals with CHIP face a 40% increased risk for all-cause mortality over 8 years.
No CHIP Test Yet
All of which has led for some to call for CHIP testing.
However, there are currently no screening programs for CHIP and no plans to introduce any. “So most CHIP is actually being diagnosed incidentally, when patients get genetic testing for some other indication,” said Dr. Weeks.
“The patients that we see in our CHIP clinic at Dana-Farber have genetic testing because they have low blood counts,” she continued, “and somebody’s trying to figure out: Do you have MDS?”
Other patients have genetic testing due to a family history of other cancers, “and so they’re getting hereditary cancer panels to determine if they have Lynch syndrome, or other hereditary syndromes,” which are picking up gene mutations associated with CHIP.
In other cases, study protocols are identifying CHIP “in various research contexts, and then as a follow-up, some of those patients end up with our clinic,” added Dr. Weeks.
Due to the associated risks for CHIP, “obviously everyone wants to know whether they are at risk for hematologic malignancy, or not,” said Dr. Gondek. To those ends, Dr. Weeks and colleagues developed the clonal hematopoiesis risk score (CHRS).
Published by NEJM Evidence in 2023, the score takes a range of predictive variables, such as age, number of mutations and their degree of associated risk, the variant allele fraction, and a series of blood indices to define patients as low-, intermediate-, or high-risk.
“A little over half” of high-risk individuals “will develop a blood cancer” such as MDS or acute myeloid leukemia (AML)” over the next 10 years, Weeks explained, while “for your intermediate risk folks, in that same time period, 7%-8% of them will develop a blood cancer.”
In low-risk individuals, the 10-year risk for MDS or AML is just 1%.
Dr. Weeks noted the “caveat that there are environmental factors or patient-specific issues that might increase your risk that are not considered in the calculator,” such the presence of hereditary cancer syndromes, “or if you’re getting chemotherapy for other cancers.”
From a cardiology point of view, Dr. Ballantyne said that, above all, “cardiologists need to be aware that some of these people are at increased risk for cardiovascular events.” This prompted a team including Dr. Weeks and Dr. Ballantyne to study whether the CHRS can also predict cardiovascular risk.
They found that people designated low-risk on the score faced an 8% increased risk for all-cause mortality vs individuals without CHIP during a median follow-up of 7 years. This rose to a 12% increase in intermediate-risk individuals.
And those deemed high-risk had a 2.5-fold increased risk for early mortality and a threefold higher risk for cardiovascular death.
Dr. Weeks noted: “We have not done a dedicated study to define a cardiovascular disease-specific calculator for CHIP,” but in the meantime, the CHRS is a “very reasonable way to estimate what someone’s risk of progression or adverse events is for cardiovascular disease.”
For clinicians, however, the key question becomes: What can be done to mitigate the risks, particularly in high-risk individuals?
For malignant conditions, the approach is to monitor patients, although “we and other centers are in the process of developing various interventional clinical trials to test various agents on their ability to improve blood counts, as well as to mitigate the risk of progression to overt blood cancer,” said Dr. Weeks.
Treat CHIP Like Lipoprotein(a)?
As for cardiovascular risk, Dr. Ballantyne believes that, because CHIP is an unmodifiable risk factor, an example to follow could be lipoprotein(a) (LP[a]).
“We don’t have a therapy specifically to target LP(a) yet, but we do know that the things that benefit in general,” he said, such as “taking a statin, lowering blood pressure into the optimal zone, diet ,and exercise.”
“What we do in our clinic, and what others have been doing,” Dr. Weeks added, “is for every patient who comes in and is diagnosed with CHIP, we are referring them to preventative cardiology for very aggressive preventative management.”
Finally, both Dr. Ballantyne and Dr. Weeks agree that there are many potential innovations on the horizon.
“It’s pretty exciting in terms of beginning to understand some of the links between aging, cardiovascular disease, and cancer that we had not been thinking about,” Dr. Ballantyne said.
On the malignant side, Dr. Weeks is already working on a prospective study to determine how the risks associated with CHIP evolve when patients undergo chemotherapy and radiation for other cancers.
“That will be really exciting and will help us to develop a specific calculator in that context,” she said, adding that a cardiovascular-specific calculator “is also coming down the line.”
Dr. Weeks declared relationships with Abbvie, Vertex, and Sobi. Dr. Ballantyne declared a relationship with Ten Sixteen Bio, and funding from the National Heart, Lung, and Blood Institute. No other relevant financial relationships were declared.
A version of this article appeared on Medscape.com.
While it is increasingly apparent that , it has not been clear what to do about it.
Now, researchers at the cutting edge of both oncologic and cardiovascular research are not only defining the prognosis of CHIP with greater granularity but are also finding clues to mitigate the risks.
“It’s a very, very rapidly moving area,” said Christie M. Ballantyne, MD, Director, Center for Cardiometabolic Disease Prevention, Baylor College of Medicine, Houston, adding that, in many respects, “it’s a totally new area.”
CHIP Defined
CHIP was first recognized in the 1990s, when Martin F. Fey, MD, and colleagues from University and Inselspital, Bern, Switzerland, found X-linked inactivation in older women and suggested it was the result of acquired clonality later referred to as being of “indeterminate potential,” although that added syntax is currently a matter of debate.
Further work showed that, while somatic gene mutations occur spontaneously and are an unavoidable consequence of aging, their impact can vary widely.
The majority are “functionally silent,” while others may affect genes crucial to tissue self-renewal and differentiation, Lukasz Gondek, MD, PhD, assistant professor, Johns Hopkins Cellular and Molecular Medicine Program, Baltimore, and colleagues, noted in a recent review.
This results in the outgrowth of affected cells, known as clonal expansion, further dubbed clonal hematopoiesis when it occurs in hematopoietic tissue.
“Even though there’s clonal expansion, there’s no one CHIP,” Dr. Gondek said. “There are different flavors, and it depends on the genes that are mutated in the hematopoietic cells.”
He continued: “The older we get, the more mutations we acquire, and the probability that this mutation will hit the gene that’s responsible for expansion of the clone is higher.”
“That’s why CHIP is very uncommon in people under the age of 40, but it becomes more common in the fifth, sixth, and seventh decade of life and beyond.”
Indeed, it occurs in 10% to 15% of people aged 65 years or older, and in at least 30% of individuals by 80 years of age. In contrast, just 1% of those aged less than 50 years have the condition.
The most commonly affected genes, in around 80% of patients with CHIP, are the epigenetic regulators DNMT3A, TET2, and ASXL1; the DNA damage repair genes PPM1D and TP53; the regulatory tyrosine kinase JAK2; and the messenger RNA spliceosome components SF3B1 and SRSF2.
These mutations can have “two potential consequences,” explained Lachelle D. Weeks, MD, PhD, a hematologist at the Dana-Farber Cancer Institute, Boston.
“One is that there’s a risk of blood cancer development,” as several of the mutations are known drivers of leukemia or myelodysplastic syndromes (MDS).
Although the majority of individuals who acquire clonal hematopoiesis with age will never develop MDS, it nevertheless confers an 11- to 13-fold increased risk or an absolute risk of approximately 0.5%-1.0% per year.
Dr. Weeks continued that “the other side of it, though, is that those cells that have these mutations can also accelerate the risk of developing nonmalignant diseases like cardiovascular disease.”
This, Dr. Gondek explained, is because the mutations will be retained when the stem cells become monocytes or macrophages and, by either silencing or activating individual genes, they can make the cells more pro-inflammatory.
The result is that CHIP is associated with a marked increased risk for arteriosclerotic events such as stroke, myocardial infarction, decompensated heart failure, and cardiogenic shock, and worse outcomes after these events.
Researchers have shown that CHIP-related somatic mutations are associated with a twofold increased risk for coronary heart disease, a more than 2.5-fold increased risk for ischemic stroke, and a fourfold greater risk for myocardial infarction. A study from earlier this year found that CHIP also increases the risk for heart failure with preserved ejection fraction more than twofold.
There is even evidence to suggest that CHIP is associated with more severe acute kidney injury (AKI) and greater post-AKI kidney fibrosis.
The consequence is that individuals with CHIP face a 40% increased risk for all-cause mortality over 8 years.
No CHIP Test Yet
All of which has led for some to call for CHIP testing.
However, there are currently no screening programs for CHIP and no plans to introduce any. “So most CHIP is actually being diagnosed incidentally, when patients get genetic testing for some other indication,” said Dr. Weeks.
“The patients that we see in our CHIP clinic at Dana-Farber have genetic testing because they have low blood counts,” she continued, “and somebody’s trying to figure out: Do you have MDS?”
Other patients have genetic testing due to a family history of other cancers, “and so they’re getting hereditary cancer panels to determine if they have Lynch syndrome, or other hereditary syndromes,” which are picking up gene mutations associated with CHIP.
In other cases, study protocols are identifying CHIP “in various research contexts, and then as a follow-up, some of those patients end up with our clinic,” added Dr. Weeks.
Due to the associated risks for CHIP, “obviously everyone wants to know whether they are at risk for hematologic malignancy, or not,” said Dr. Gondek. To those ends, Dr. Weeks and colleagues developed the clonal hematopoiesis risk score (CHRS).
Published by NEJM Evidence in 2023, the score takes a range of predictive variables, such as age, number of mutations and their degree of associated risk, the variant allele fraction, and a series of blood indices to define patients as low-, intermediate-, or high-risk.
“A little over half” of high-risk individuals “will develop a blood cancer” such as MDS or acute myeloid leukemia (AML)” over the next 10 years, Weeks explained, while “for your intermediate risk folks, in that same time period, 7%-8% of them will develop a blood cancer.”
In low-risk individuals, the 10-year risk for MDS or AML is just 1%.
Dr. Weeks noted the “caveat that there are environmental factors or patient-specific issues that might increase your risk that are not considered in the calculator,” such the presence of hereditary cancer syndromes, “or if you’re getting chemotherapy for other cancers.”
From a cardiology point of view, Dr. Ballantyne said that, above all, “cardiologists need to be aware that some of these people are at increased risk for cardiovascular events.” This prompted a team including Dr. Weeks and Dr. Ballantyne to study whether the CHRS can also predict cardiovascular risk.
They found that people designated low-risk on the score faced an 8% increased risk for all-cause mortality vs individuals without CHIP during a median follow-up of 7 years. This rose to a 12% increase in intermediate-risk individuals.
And those deemed high-risk had a 2.5-fold increased risk for early mortality and a threefold higher risk for cardiovascular death.
Dr. Weeks noted: “We have not done a dedicated study to define a cardiovascular disease-specific calculator for CHIP,” but in the meantime, the CHRS is a “very reasonable way to estimate what someone’s risk of progression or adverse events is for cardiovascular disease.”
For clinicians, however, the key question becomes: What can be done to mitigate the risks, particularly in high-risk individuals?
For malignant conditions, the approach is to monitor patients, although “we and other centers are in the process of developing various interventional clinical trials to test various agents on their ability to improve blood counts, as well as to mitigate the risk of progression to overt blood cancer,” said Dr. Weeks.
Treat CHIP Like Lipoprotein(a)?
As for cardiovascular risk, Dr. Ballantyne believes that, because CHIP is an unmodifiable risk factor, an example to follow could be lipoprotein(a) (LP[a]).
“We don’t have a therapy specifically to target LP(a) yet, but we do know that the things that benefit in general,” he said, such as “taking a statin, lowering blood pressure into the optimal zone, diet ,and exercise.”
“What we do in our clinic, and what others have been doing,” Dr. Weeks added, “is for every patient who comes in and is diagnosed with CHIP, we are referring them to preventative cardiology for very aggressive preventative management.”
Finally, both Dr. Ballantyne and Dr. Weeks agree that there are many potential innovations on the horizon.
“It’s pretty exciting in terms of beginning to understand some of the links between aging, cardiovascular disease, and cancer that we had not been thinking about,” Dr. Ballantyne said.
On the malignant side, Dr. Weeks is already working on a prospective study to determine how the risks associated with CHIP evolve when patients undergo chemotherapy and radiation for other cancers.
“That will be really exciting and will help us to develop a specific calculator in that context,” she said, adding that a cardiovascular-specific calculator “is also coming down the line.”
Dr. Weeks declared relationships with Abbvie, Vertex, and Sobi. Dr. Ballantyne declared a relationship with Ten Sixteen Bio, and funding from the National Heart, Lung, and Blood Institute. No other relevant financial relationships were declared.
A version of this article appeared on Medscape.com.
Can an Ingestible Vibrating Capsule Tackle Obesity?
A novel vibrating capsule that signals a postprandial feeling of fullness reduced both food and energy intake and lowered weight gain in animal studies, said researchers who are developing it as a more affordable treatment for obesity.
The capsule, called the Vibrating Ingestible BioElectronic Stimulator (VIBES), is the size of a large adult multivitamin pill and is meant to be swallowed before a meal. The VIBES capsule works by stimulating gastric stretch receptors that signal the brain through the vagal nerve and stimulate a sense of satiety.
“Application of mechanoreceptor biology could transform our capacity to help patients suffering from nutritional disorders,” wrote Shriya S. Srinivasan, PhD, at Harvard University, Boston, and her coauthors. Srinivasan, founder and director of the Biohybrid Organs and Neuroprosthetics (BIONIC) Lab, led the team that designed and prototyped the VIBES capsule.
In a pig model, the VIBES activated mechanoreceptors and triggered gastric mucosal receptors, the researchers reported. Across 108 meals, swine treated with VIBES had nearly 40% reduced food intake compared to controls given a sham pill, with no apparent neural adaptation observed.
The research was published online in Science Advances.
Satiety Signaling in Obesity Treatment
Caroline M. Apovian, MD, codirector, Center for Weight Management and Wellness, Brigham and Women’s Hospital, Boston, who was not involved in the study, said the concept of creating the illusion of satiety is not a new one.
She was part of team that showed medically meaningful weight loss at 2 years with a surgically implanted device that intermittently blocked the vagus nerves near the junction of the stomach and esophagus. “So we’ve been aware of the potential of things like this to produce a sense of satiety and weight loss,” she said.
However, Dr. Apovian believed that a capsule such as VIBES faces a number of hurdles before it is widely used in the clinic, even if it is successfully tested on humans.
She pointed to a superabsorbent hydrogel device, Plenity (Gelesis), delivered as three oral capsules that expand with water in the stomach to create a feeling of satiety. While approved by the US Food and Drug Administration (FDA), it is not widely used, she said, as there are “hurdles” for patients to overcome, particularly in obtaining it from the pharmacy.
The VIBES capsule would in theory be acceptable to patients, Apovian said, but they are “overwhelmed by the media attention” on medications such as glucagon-like peptide 1 (GLP-1) receptor agonists, which promise dramatic weight loss, far higher than the sorts of figures VIBES could achieve.
Nevertheless, the capsule could form a part of the obesity treatment armamentarium, with the idea that it could be combined with “an agent that would act more centrally to change the body weight setpoint,” she said.
Allan Geliebter, PhD, professor, department of psychiatry, Icahn School of Medicine at Mount Sinai, New York City, said that the thinking behind the capsule is a “clever, original approach,” but he is personally skeptical that people will take them.
“It’s the largest possible capsule that’s on the market today that is approved by the FDA for swallowing,” he said, and people “have to assume it’s going to come out the other end.”
“I think it will,” Dr. Geliebter added, “but if you’re taking at least two of these a day, what’s the guarantee one won’t get stuck along the ride?”
And when it does come out, “maybe it will be visible, maybe not,” but either way, “I can see people being anxious.”
He agreed with Dr. Apovian that the arrival of GLP-1 agonists has made obesity “a tough market to compete in right now,” although he noted that the drugs “do have side effects, and not everybody tolerates them.”
The VIBES Approach
The authors noted that another approved satiety device, intragastic balloons, also were designed to induce early satiety through distension of the stomach, but they do not lead to sustained changes in hunger or eating behavior due to neural adaptation to the continuing distension.
Moreover, some balloons have been withdrawn due to safety concerns, including several deaths.
The team reasoned a mechanism or device “capable of selective mechanoreceptor activation would pose great clinical value.”
Dr. Srinivasan explained: “While vibration has been known to create proprioceptive illusions in muscles, to our knowledge, no one has tried this in the stomach.”
“Given my penchant for mechanoreceptor physiology, I was curious to see if stretch receptors in the smooth muscle could be manipulated by mechanostimulation.”
The team designed an orally ingestible 3D-printed capsule in three sections, one of which allows entry of gastric fluid to dissolve a glucose layer. This causes the release of a spring-loaded pogo pin that completes a circuit to activate the vibrating motor.
Initial testing demonstrated that the capsule, which is the size of a triple zero pill, vibrated for an average of 38.3 minutes, which was deemed acceptable as “meals are generally consumed in a 20- to 30-min window and gastric contents undergo primary mixing in approximately an hour,” the authors wrote.
Immersing the capsule in simulated gastric fluid for 24 hours and simulated intestinal fluid for 10 days at 37 °C didn’t lead to changes in the capsule; thus, it “would not damage the gastrointestinal tract even if it were to reside in the stomach for a full day or in the intestines for over a week,” the authors wrote.
Testing VIBES Satiety in Swine
To test the capsule’s performance as a potential obesity treatment, the researchers turned to a model of Yorkshire pigs ages 4-6 months. Their “gastric anatomy is similar to that of humans,” the authors wrote, and they have been widely used to evaluate biomedical devices.
The researchers found that the vibration from the capsule not only induced the afferent neural activation of gastric mechanoreceptors sensitive to stomach distention but also triggered gastric secretory activity via by what the authors call “stroking” of the gastric mucosa.
To examine the impact of the capsule on hunger and feeding behavior, they monitored the food intake of four pigs in each of three conditions:
- No treatment (control)
- Treated with a sham capsule tethered via a percutaneous endoscopic gastrostomy (PEG) tube (PEG-control)
- Treated with a VIBES capsule tethered via a PEG tube
After 2 weeks, VIBES-treated pigs consumed an average of 58.1% of their meals (n = 108 meals), PEG-control pigs consumed 84.1% (n = 100 meals), and the control group consumed 78.4% (n = 96) meals among PEG-only swine.
Per animal on average, the capsule reduced intake by 31% (P < .001), and the energy consumed per meal for each treated animal was significantly lower than that in the control period (P < .001), with no significant difference between the control and PEG-only groups (P < .1).
In a cross-over experiment, treating the swine for three meals, leaving them untreated for three meals, then treating them for another three revealed that intake increased by 38% during the untreated window.
The crossover results suggest the capsule “functions through temporal vagal activation, with little neural adaptation or long-term effect,” the team wrote.
Weight gain in VIBES-treated pigs was also significantly lower than that in the control and in the PEG-control groups (P < .05).
“Together, these data suggest that the VIBES pill significantly decreases food intake and slows the rate of weight gain in a large animal model,” the team wrote.
The VIBES capsule passed out of the treated pigs after an average of 4.4 days vs 8.3 days for a sham pill. As the “pigs generally take 7-9 days to excrete a given meal,” Dr. Srinivasan noted, “4 days is actually quite fast.”
“In humans, we expect this to pass on the same timescale as a regular meal,” she said, or approximately 24 hours. With no safety concerns identified in the study, Dr. Srinivasan did not expect there to be any significant concern over having multiple devices in the intestines from ingesting one with every meal.
The study was supported in part by grants from the National Institutes of Health, Novo Nordisk, and MIT Department of Mechanical Engineering, alongside support to individual authors via a Schmidt Science Fellowship and a National Science Foundation grant to the Computing Research Association for the CIFellows Project.
Dr. Srinivasan and two coauthors were coinventors on a patent application (application filed by the Massachusetts Institute of Technology describing the developments discussed here). Another author declared a consulting relationship with Novo Nordisk.
No other relevant financial relationships were declared.
A version of this article appeared on Medscape.com.
A novel vibrating capsule that signals a postprandial feeling of fullness reduced both food and energy intake and lowered weight gain in animal studies, said researchers who are developing it as a more affordable treatment for obesity.
The capsule, called the Vibrating Ingestible BioElectronic Stimulator (VIBES), is the size of a large adult multivitamin pill and is meant to be swallowed before a meal. The VIBES capsule works by stimulating gastric stretch receptors that signal the brain through the vagal nerve and stimulate a sense of satiety.
“Application of mechanoreceptor biology could transform our capacity to help patients suffering from nutritional disorders,” wrote Shriya S. Srinivasan, PhD, at Harvard University, Boston, and her coauthors. Srinivasan, founder and director of the Biohybrid Organs and Neuroprosthetics (BIONIC) Lab, led the team that designed and prototyped the VIBES capsule.
In a pig model, the VIBES activated mechanoreceptors and triggered gastric mucosal receptors, the researchers reported. Across 108 meals, swine treated with VIBES had nearly 40% reduced food intake compared to controls given a sham pill, with no apparent neural adaptation observed.
The research was published online in Science Advances.
Satiety Signaling in Obesity Treatment
Caroline M. Apovian, MD, codirector, Center for Weight Management and Wellness, Brigham and Women’s Hospital, Boston, who was not involved in the study, said the concept of creating the illusion of satiety is not a new one.
She was part of team that showed medically meaningful weight loss at 2 years with a surgically implanted device that intermittently blocked the vagus nerves near the junction of the stomach and esophagus. “So we’ve been aware of the potential of things like this to produce a sense of satiety and weight loss,” she said.
However, Dr. Apovian believed that a capsule such as VIBES faces a number of hurdles before it is widely used in the clinic, even if it is successfully tested on humans.
She pointed to a superabsorbent hydrogel device, Plenity (Gelesis), delivered as three oral capsules that expand with water in the stomach to create a feeling of satiety. While approved by the US Food and Drug Administration (FDA), it is not widely used, she said, as there are “hurdles” for patients to overcome, particularly in obtaining it from the pharmacy.
The VIBES capsule would in theory be acceptable to patients, Apovian said, but they are “overwhelmed by the media attention” on medications such as glucagon-like peptide 1 (GLP-1) receptor agonists, which promise dramatic weight loss, far higher than the sorts of figures VIBES could achieve.
Nevertheless, the capsule could form a part of the obesity treatment armamentarium, with the idea that it could be combined with “an agent that would act more centrally to change the body weight setpoint,” she said.
Allan Geliebter, PhD, professor, department of psychiatry, Icahn School of Medicine at Mount Sinai, New York City, said that the thinking behind the capsule is a “clever, original approach,” but he is personally skeptical that people will take them.
“It’s the largest possible capsule that’s on the market today that is approved by the FDA for swallowing,” he said, and people “have to assume it’s going to come out the other end.”
“I think it will,” Dr. Geliebter added, “but if you’re taking at least two of these a day, what’s the guarantee one won’t get stuck along the ride?”
And when it does come out, “maybe it will be visible, maybe not,” but either way, “I can see people being anxious.”
He agreed with Dr. Apovian that the arrival of GLP-1 agonists has made obesity “a tough market to compete in right now,” although he noted that the drugs “do have side effects, and not everybody tolerates them.”
The VIBES Approach
The authors noted that another approved satiety device, intragastic balloons, also were designed to induce early satiety through distension of the stomach, but they do not lead to sustained changes in hunger or eating behavior due to neural adaptation to the continuing distension.
Moreover, some balloons have been withdrawn due to safety concerns, including several deaths.
The team reasoned a mechanism or device “capable of selective mechanoreceptor activation would pose great clinical value.”
Dr. Srinivasan explained: “While vibration has been known to create proprioceptive illusions in muscles, to our knowledge, no one has tried this in the stomach.”
“Given my penchant for mechanoreceptor physiology, I was curious to see if stretch receptors in the smooth muscle could be manipulated by mechanostimulation.”
The team designed an orally ingestible 3D-printed capsule in three sections, one of which allows entry of gastric fluid to dissolve a glucose layer. This causes the release of a spring-loaded pogo pin that completes a circuit to activate the vibrating motor.
Initial testing demonstrated that the capsule, which is the size of a triple zero pill, vibrated for an average of 38.3 minutes, which was deemed acceptable as “meals are generally consumed in a 20- to 30-min window and gastric contents undergo primary mixing in approximately an hour,” the authors wrote.
Immersing the capsule in simulated gastric fluid for 24 hours and simulated intestinal fluid for 10 days at 37 °C didn’t lead to changes in the capsule; thus, it “would not damage the gastrointestinal tract even if it were to reside in the stomach for a full day or in the intestines for over a week,” the authors wrote.
Testing VIBES Satiety in Swine
To test the capsule’s performance as a potential obesity treatment, the researchers turned to a model of Yorkshire pigs ages 4-6 months. Their “gastric anatomy is similar to that of humans,” the authors wrote, and they have been widely used to evaluate biomedical devices.
The researchers found that the vibration from the capsule not only induced the afferent neural activation of gastric mechanoreceptors sensitive to stomach distention but also triggered gastric secretory activity via by what the authors call “stroking” of the gastric mucosa.
To examine the impact of the capsule on hunger and feeding behavior, they monitored the food intake of four pigs in each of three conditions:
- No treatment (control)
- Treated with a sham capsule tethered via a percutaneous endoscopic gastrostomy (PEG) tube (PEG-control)
- Treated with a VIBES capsule tethered via a PEG tube
After 2 weeks, VIBES-treated pigs consumed an average of 58.1% of their meals (n = 108 meals), PEG-control pigs consumed 84.1% (n = 100 meals), and the control group consumed 78.4% (n = 96) meals among PEG-only swine.
Per animal on average, the capsule reduced intake by 31% (P < .001), and the energy consumed per meal for each treated animal was significantly lower than that in the control period (P < .001), with no significant difference between the control and PEG-only groups (P < .1).
In a cross-over experiment, treating the swine for three meals, leaving them untreated for three meals, then treating them for another three revealed that intake increased by 38% during the untreated window.
The crossover results suggest the capsule “functions through temporal vagal activation, with little neural adaptation or long-term effect,” the team wrote.
Weight gain in VIBES-treated pigs was also significantly lower than that in the control and in the PEG-control groups (P < .05).
“Together, these data suggest that the VIBES pill significantly decreases food intake and slows the rate of weight gain in a large animal model,” the team wrote.
The VIBES capsule passed out of the treated pigs after an average of 4.4 days vs 8.3 days for a sham pill. As the “pigs generally take 7-9 days to excrete a given meal,” Dr. Srinivasan noted, “4 days is actually quite fast.”
“In humans, we expect this to pass on the same timescale as a regular meal,” she said, or approximately 24 hours. With no safety concerns identified in the study, Dr. Srinivasan did not expect there to be any significant concern over having multiple devices in the intestines from ingesting one with every meal.
The study was supported in part by grants from the National Institutes of Health, Novo Nordisk, and MIT Department of Mechanical Engineering, alongside support to individual authors via a Schmidt Science Fellowship and a National Science Foundation grant to the Computing Research Association for the CIFellows Project.
Dr. Srinivasan and two coauthors were coinventors on a patent application (application filed by the Massachusetts Institute of Technology describing the developments discussed here). Another author declared a consulting relationship with Novo Nordisk.
No other relevant financial relationships were declared.
A version of this article appeared on Medscape.com.
A novel vibrating capsule that signals a postprandial feeling of fullness reduced both food and energy intake and lowered weight gain in animal studies, said researchers who are developing it as a more affordable treatment for obesity.
The capsule, called the Vibrating Ingestible BioElectronic Stimulator (VIBES), is the size of a large adult multivitamin pill and is meant to be swallowed before a meal. The VIBES capsule works by stimulating gastric stretch receptors that signal the brain through the vagal nerve and stimulate a sense of satiety.
“Application of mechanoreceptor biology could transform our capacity to help patients suffering from nutritional disorders,” wrote Shriya S. Srinivasan, PhD, at Harvard University, Boston, and her coauthors. Srinivasan, founder and director of the Biohybrid Organs and Neuroprosthetics (BIONIC) Lab, led the team that designed and prototyped the VIBES capsule.
In a pig model, the VIBES activated mechanoreceptors and triggered gastric mucosal receptors, the researchers reported. Across 108 meals, swine treated with VIBES had nearly 40% reduced food intake compared to controls given a sham pill, with no apparent neural adaptation observed.
The research was published online in Science Advances.
Satiety Signaling in Obesity Treatment
Caroline M. Apovian, MD, codirector, Center for Weight Management and Wellness, Brigham and Women’s Hospital, Boston, who was not involved in the study, said the concept of creating the illusion of satiety is not a new one.
She was part of team that showed medically meaningful weight loss at 2 years with a surgically implanted device that intermittently blocked the vagus nerves near the junction of the stomach and esophagus. “So we’ve been aware of the potential of things like this to produce a sense of satiety and weight loss,” she said.
However, Dr. Apovian believed that a capsule such as VIBES faces a number of hurdles before it is widely used in the clinic, even if it is successfully tested on humans.
She pointed to a superabsorbent hydrogel device, Plenity (Gelesis), delivered as three oral capsules that expand with water in the stomach to create a feeling of satiety. While approved by the US Food and Drug Administration (FDA), it is not widely used, she said, as there are “hurdles” for patients to overcome, particularly in obtaining it from the pharmacy.
The VIBES capsule would in theory be acceptable to patients, Apovian said, but they are “overwhelmed by the media attention” on medications such as glucagon-like peptide 1 (GLP-1) receptor agonists, which promise dramatic weight loss, far higher than the sorts of figures VIBES could achieve.
Nevertheless, the capsule could form a part of the obesity treatment armamentarium, with the idea that it could be combined with “an agent that would act more centrally to change the body weight setpoint,” she said.
Allan Geliebter, PhD, professor, department of psychiatry, Icahn School of Medicine at Mount Sinai, New York City, said that the thinking behind the capsule is a “clever, original approach,” but he is personally skeptical that people will take them.
“It’s the largest possible capsule that’s on the market today that is approved by the FDA for swallowing,” he said, and people “have to assume it’s going to come out the other end.”
“I think it will,” Dr. Geliebter added, “but if you’re taking at least two of these a day, what’s the guarantee one won’t get stuck along the ride?”
And when it does come out, “maybe it will be visible, maybe not,” but either way, “I can see people being anxious.”
He agreed with Dr. Apovian that the arrival of GLP-1 agonists has made obesity “a tough market to compete in right now,” although he noted that the drugs “do have side effects, and not everybody tolerates them.”
The VIBES Approach
The authors noted that another approved satiety device, intragastic balloons, also were designed to induce early satiety through distension of the stomach, but they do not lead to sustained changes in hunger or eating behavior due to neural adaptation to the continuing distension.
Moreover, some balloons have been withdrawn due to safety concerns, including several deaths.
The team reasoned a mechanism or device “capable of selective mechanoreceptor activation would pose great clinical value.”
Dr. Srinivasan explained: “While vibration has been known to create proprioceptive illusions in muscles, to our knowledge, no one has tried this in the stomach.”
“Given my penchant for mechanoreceptor physiology, I was curious to see if stretch receptors in the smooth muscle could be manipulated by mechanostimulation.”
The team designed an orally ingestible 3D-printed capsule in three sections, one of which allows entry of gastric fluid to dissolve a glucose layer. This causes the release of a spring-loaded pogo pin that completes a circuit to activate the vibrating motor.
Initial testing demonstrated that the capsule, which is the size of a triple zero pill, vibrated for an average of 38.3 minutes, which was deemed acceptable as “meals are generally consumed in a 20- to 30-min window and gastric contents undergo primary mixing in approximately an hour,” the authors wrote.
Immersing the capsule in simulated gastric fluid for 24 hours and simulated intestinal fluid for 10 days at 37 °C didn’t lead to changes in the capsule; thus, it “would not damage the gastrointestinal tract even if it were to reside in the stomach for a full day or in the intestines for over a week,” the authors wrote.
Testing VIBES Satiety in Swine
To test the capsule’s performance as a potential obesity treatment, the researchers turned to a model of Yorkshire pigs ages 4-6 months. Their “gastric anatomy is similar to that of humans,” the authors wrote, and they have been widely used to evaluate biomedical devices.
The researchers found that the vibration from the capsule not only induced the afferent neural activation of gastric mechanoreceptors sensitive to stomach distention but also triggered gastric secretory activity via by what the authors call “stroking” of the gastric mucosa.
To examine the impact of the capsule on hunger and feeding behavior, they monitored the food intake of four pigs in each of three conditions:
- No treatment (control)
- Treated with a sham capsule tethered via a percutaneous endoscopic gastrostomy (PEG) tube (PEG-control)
- Treated with a VIBES capsule tethered via a PEG tube
After 2 weeks, VIBES-treated pigs consumed an average of 58.1% of their meals (n = 108 meals), PEG-control pigs consumed 84.1% (n = 100 meals), and the control group consumed 78.4% (n = 96) meals among PEG-only swine.
Per animal on average, the capsule reduced intake by 31% (P < .001), and the energy consumed per meal for each treated animal was significantly lower than that in the control period (P < .001), with no significant difference between the control and PEG-only groups (P < .1).
In a cross-over experiment, treating the swine for three meals, leaving them untreated for three meals, then treating them for another three revealed that intake increased by 38% during the untreated window.
The crossover results suggest the capsule “functions through temporal vagal activation, with little neural adaptation or long-term effect,” the team wrote.
Weight gain in VIBES-treated pigs was also significantly lower than that in the control and in the PEG-control groups (P < .05).
“Together, these data suggest that the VIBES pill significantly decreases food intake and slows the rate of weight gain in a large animal model,” the team wrote.
The VIBES capsule passed out of the treated pigs after an average of 4.4 days vs 8.3 days for a sham pill. As the “pigs generally take 7-9 days to excrete a given meal,” Dr. Srinivasan noted, “4 days is actually quite fast.”
“In humans, we expect this to pass on the same timescale as a regular meal,” she said, or approximately 24 hours. With no safety concerns identified in the study, Dr. Srinivasan did not expect there to be any significant concern over having multiple devices in the intestines from ingesting one with every meal.
The study was supported in part by grants from the National Institutes of Health, Novo Nordisk, and MIT Department of Mechanical Engineering, alongside support to individual authors via a Schmidt Science Fellowship and a National Science Foundation grant to the Computing Research Association for the CIFellows Project.
Dr. Srinivasan and two coauthors were coinventors on a patent application (application filed by the Massachusetts Institute of Technology describing the developments discussed here). Another author declared a consulting relationship with Novo Nordisk.
No other relevant financial relationships were declared.
A version of this article appeared on Medscape.com.