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FDA approves Enhertu (trastuzumab deruxtecan) for HER2 lung cancer
Patients with lung cancer now have another treatment option: If their tumors are found to carry HER2 mutations, they can now be treated with trastuzumab deruxtecan (Enhertu), a drug that specifically targets that defect.
This product is already approved for used in HER2-positive breast cancer and gastric cancer. 
The FDA also approved companion diagnostic tests to detect HER2 mutations: Life Technologies Corporation’s Oncomine Dx Target Test for use in lung tissue and Guardant Health’s Guardant360 CDx for use on plasma samples. The agency notes that if no mutation is detected in a plasma specimen, the tumor tissue should be tested.
Specifically, the new indication is used in patients with unresectable or metastatic non–small cell lung cancer (NSCLC) whose tumors have activating HER2 (ERBB2) mutations, as detected by an FDA-approved test, and who have already received a prior systemic therapy.
About 3% of nonsquamous NSCLC tumors carry mutations in the HER2 gene, and they are associated with female sex, never-smokers, and a poor prognosis.
“HER2 mutant non–small cell lung cancer is an aggressive form of disease, which commonly affects young patients who have faced limited treatment options and a poor prognosis to date,” said Dave Fredrickson, executive vice-president of the oncology business unit at AstraZeneca.
The new approval “provides these patients with the opportunity to benefit from a targeted therapy and highlights the importance of testing for predictive markers, including HER2 in lung cancer, at the time of diagnosis to ensure patients receive the most appropriate treatment for their specific disease,” he commented in a company press release.
This is an accelerated approval, based on overall response rate data from the DESTINY-Lung02 phase 2 trial, the company noted. An interim efficacy analysis in a prespecified patient cohort showed that trastuzumab deruxtecan (at 5.4 mg/kg) demonstrated a confirmed overall response rate of 57.7% (n = 52; 95% confidence interval, 43.2%-71.3%) in patients with HER2-mutant unresectable or metastatic nonsquamous NSCLC who had received one prior systemic therapy as assessed by blinded independent central review. Complete responses were seen in 1.9% of patients (n = 1) and partial responses in 55.8% of patients (n = 29), with a median duration of response of 8.7 months (95% CI, 7.1-NE).
The FDA noted that for the 52 patients in the primary efficacy population of the DESTINY-Lung02 trial, the median age was 58 years (range, 30-78 years); 69% were female; and 79% were Asian, 12% were White, and 10% were of other races.
Clinical data welcomed by experts
Clinical data are already available from the DESTINY-Lung 01 trial, and the results were welcomed enthusiastically by experts when they were published in the New England Journal of Medicine earlier this year.
“These results establish the new standard of care for patients with NSCLC harboring HER2 mutations,” Antonio Passaro, MD, PhD, from the European Institute of Oncology IRCCS, Milan, and Solange Peters, MD, PhD, from Lausanne (Switzerland) University Hospital, wrote in an accompanying editorial.
This trial involved 91 patients, all treated with trastuzumab deruxtecan (at 6.4 mg/kg of body weight every 3 weeks). The median duration of treatment was 6.9 months, and the median follow-up was 13.1 months.
The results showed a 55% centrally confirmed objective response, and median duration of response was 9.3 months.
In addition, the investigators reported a median progression-free survival of 8.2 months and a median overall survival of almost 18 months, both of which they described as “encouraging” in this patient population.
However, the results also highlighted a problem with the drug in this patient population. Notably, 26% of patients experienced interstitial lung disease, which resulted in death in two patients. The drug was also withdrawn in 16 patients and interrupted in 8 patients because of this adverse event.
Editorialists Dr. Passaro and Dr. Peters described this finding as “a concern” and note that “the incidence of interstitial lung disease is significantly higher among patients with lung cancer than among those with breast or gastric cancers, which may indicate a role of smoking-related damage.”
They also highlighted the need for an “investigation of the clinical efficacy of a reduced dose of trastuzumab deruxtecan,” and so the dose was reduced for the DESTINY-Lung02 trial.
A version of this article first appeared on Medscape.com.
Patients with lung cancer now have another treatment option: If their tumors are found to carry HER2 mutations, they can now be treated with trastuzumab deruxtecan (Enhertu), a drug that specifically targets that defect.
This product is already approved for used in HER2-positive breast cancer and gastric cancer.
The FDA also approved companion diagnostic tests to detect HER2 mutations: Life Technologies Corporation’s Oncomine Dx Target Test for use in lung tissue and Guardant Health’s Guardant360 CDx for use on plasma samples. The agency notes that if no mutation is detected in a plasma specimen, the tumor tissue should be tested.
Specifically, the new indication is used in patients with unresectable or metastatic non–small cell lung cancer (NSCLC) whose tumors have activating HER2 (ERBB2) mutations, as detected by an FDA-approved test, and who have already received a prior systemic therapy.
About 3% of nonsquamous NSCLC tumors carry mutations in the HER2 gene, and they are associated with female sex, never-smokers, and a poor prognosis.
“HER2 mutant non–small cell lung cancer is an aggressive form of disease, which commonly affects young patients who have faced limited treatment options and a poor prognosis to date,” said Dave Fredrickson, executive vice-president of the oncology business unit at AstraZeneca.
The new approval “provides these patients with the opportunity to benefit from a targeted therapy and highlights the importance of testing for predictive markers, including HER2 in lung cancer, at the time of diagnosis to ensure patients receive the most appropriate treatment for their specific disease,” he commented in a company press release.
This is an accelerated approval, based on overall response rate data from the DESTINY-Lung02 phase 2 trial, the company noted. An interim efficacy analysis in a prespecified patient cohort showed that trastuzumab deruxtecan (at 5.4 mg/kg) demonstrated a confirmed overall response rate of 57.7% (n = 52; 95% confidence interval, 43.2%-71.3%) in patients with HER2-mutant unresectable or metastatic nonsquamous NSCLC who had received one prior systemic therapy as assessed by blinded independent central review. Complete responses were seen in 1.9% of patients (n = 1) and partial responses in 55.8% of patients (n = 29), with a median duration of response of 8.7 months (95% CI, 7.1-NE).
The FDA noted that for the 52 patients in the primary efficacy population of the DESTINY-Lung02 trial, the median age was 58 years (range, 30-78 years); 69% were female; and 79% were Asian, 12% were White, and 10% were of other races.
Clinical data welcomed by experts
Clinical data are already available from the DESTINY-Lung 01 trial, and the results were welcomed enthusiastically by experts when they were published in the New England Journal of Medicine earlier this year.
“These results establish the new standard of care for patients with NSCLC harboring HER2 mutations,” Antonio Passaro, MD, PhD, from the European Institute of Oncology IRCCS, Milan, and Solange Peters, MD, PhD, from Lausanne (Switzerland) University Hospital, wrote in an accompanying editorial.
This trial involved 91 patients, all treated with trastuzumab deruxtecan (at 6.4 mg/kg of body weight every 3 weeks). The median duration of treatment was 6.9 months, and the median follow-up was 13.1 months.
The results showed a 55% centrally confirmed objective response, and median duration of response was 9.3 months.
In addition, the investigators reported a median progression-free survival of 8.2 months and a median overall survival of almost 18 months, both of which they described as “encouraging” in this patient population.
However, the results also highlighted a problem with the drug in this patient population. Notably, 26% of patients experienced interstitial lung disease, which resulted in death in two patients. The drug was also withdrawn in 16 patients and interrupted in 8 patients because of this adverse event.
Editorialists Dr. Passaro and Dr. Peters described this finding as “a concern” and note that “the incidence of interstitial lung disease is significantly higher among patients with lung cancer than among those with breast or gastric cancers, which may indicate a role of smoking-related damage.”
They also highlighted the need for an “investigation of the clinical efficacy of a reduced dose of trastuzumab deruxtecan,” and so the dose was reduced for the DESTINY-Lung02 trial.
A version of this article first appeared on Medscape.com.
Patients with lung cancer now have another treatment option: If their tumors are found to carry HER2 mutations, they can now be treated with trastuzumab deruxtecan (Enhertu), a drug that specifically targets that defect.
This product is already approved for used in HER2-positive breast cancer and gastric cancer.
The FDA also approved companion diagnostic tests to detect HER2 mutations: Life Technologies Corporation’s Oncomine Dx Target Test for use in lung tissue and Guardant Health’s Guardant360 CDx for use on plasma samples. The agency notes that if no mutation is detected in a plasma specimen, the tumor tissue should be tested.
Specifically, the new indication is used in patients with unresectable or metastatic non–small cell lung cancer (NSCLC) whose tumors have activating HER2 (ERBB2) mutations, as detected by an FDA-approved test, and who have already received a prior systemic therapy.
About 3% of nonsquamous NSCLC tumors carry mutations in the HER2 gene, and they are associated with female sex, never-smokers, and a poor prognosis.
“HER2 mutant non–small cell lung cancer is an aggressive form of disease, which commonly affects young patients who have faced limited treatment options and a poor prognosis to date,” said Dave Fredrickson, executive vice-president of the oncology business unit at AstraZeneca.
The new approval “provides these patients with the opportunity to benefit from a targeted therapy and highlights the importance of testing for predictive markers, including HER2 in lung cancer, at the time of diagnosis to ensure patients receive the most appropriate treatment for their specific disease,” he commented in a company press release.
This is an accelerated approval, based on overall response rate data from the DESTINY-Lung02 phase 2 trial, the company noted. An interim efficacy analysis in a prespecified patient cohort showed that trastuzumab deruxtecan (at 5.4 mg/kg) demonstrated a confirmed overall response rate of 57.7% (n = 52; 95% confidence interval, 43.2%-71.3%) in patients with HER2-mutant unresectable or metastatic nonsquamous NSCLC who had received one prior systemic therapy as assessed by blinded independent central review. Complete responses were seen in 1.9% of patients (n = 1) and partial responses in 55.8% of patients (n = 29), with a median duration of response of 8.7 months (95% CI, 7.1-NE).
The FDA noted that for the 52 patients in the primary efficacy population of the DESTINY-Lung02 trial, the median age was 58 years (range, 30-78 years); 69% were female; and 79% were Asian, 12% were White, and 10% were of other races.
Clinical data welcomed by experts
Clinical data are already available from the DESTINY-Lung 01 trial, and the results were welcomed enthusiastically by experts when they were published in the New England Journal of Medicine earlier this year.
“These results establish the new standard of care for patients with NSCLC harboring HER2 mutations,” Antonio Passaro, MD, PhD, from the European Institute of Oncology IRCCS, Milan, and Solange Peters, MD, PhD, from Lausanne (Switzerland) University Hospital, wrote in an accompanying editorial.
This trial involved 91 patients, all treated with trastuzumab deruxtecan (at 6.4 mg/kg of body weight every 3 weeks). The median duration of treatment was 6.9 months, and the median follow-up was 13.1 months.
The results showed a 55% centrally confirmed objective response, and median duration of response was 9.3 months.
In addition, the investigators reported a median progression-free survival of 8.2 months and a median overall survival of almost 18 months, both of which they described as “encouraging” in this patient population.
However, the results also highlighted a problem with the drug in this patient population. Notably, 26% of patients experienced interstitial lung disease, which resulted in death in two patients. The drug was also withdrawn in 16 patients and interrupted in 8 patients because of this adverse event.
Editorialists Dr. Passaro and Dr. Peters described this finding as “a concern” and note that “the incidence of interstitial lung disease is significantly higher among patients with lung cancer than among those with breast or gastric cancers, which may indicate a role of smoking-related damage.”
They also highlighted the need for an “investigation of the clinical efficacy of a reduced dose of trastuzumab deruxtecan,” and so the dose was reduced for the DESTINY-Lung02 trial.
A version of this article first appeared on Medscape.com.
First weeks back to school: An uneasy transition
Parents are relieved when school starts up again in the fall. Kids also are eager to see their friends and go on to the next level of learning.
Or are they?
This year brings a greater mix of feelings than usual for many families.
Many parents and children have new worries: Are children going to be safe at school from COVID, bullies, and shooters? Are they going to be ready to learn at this next level after the intermittent schooling of the past 2+ pandemic years of Zoom school, home school, or no school? Are they going to be able to separate after months of closeness/entanglement? Are they going to be able to catch up academically and fit in socially?
Children may have additional worries about how they have changed over the pandemic. Will my former friends still accept me now that I am heavier, showing puberty, experiencing acne, or feeling depressed or anxious?
While most of these worries occurred in some form after other summer breaks, they may be exacerbated by the length and degree of uncertainty we have all been through.
Often, health supervision visits are happy reunions with our patients when we hear about their growth and goals. We hope that is true this year, too, but we need to be vigilant and open to discussing the worries just mentioned.
What can we do to help ease this magnified transition?
First, we need to be open to their worries. Echoing back their concerns and noting how they are understandable and common can be reassuring when families have been isolated and missing interactions that might have made this clear. Second, we can remind them of the steps that assist in any transition. Now more than ever they need to collect information by visiting the new classroom, meeting teachers, and attending open house meet-and-greets. Older students may do better by looking over textbooks or a syllabus to see what will be covered. Making an effort to meet kids and families new to the school is a kind gesture but also helps the experienced child take some initiative and feel more confident.
Setting up an organizational system for homework from the start is valuable as work gets harder and is especially important for kids with ADHD. Single-subject folders, an assignment book tracking short-term and long-term projects, a plan for a specific homework time and place, a bookbag checklist by the door, or even a homework buddy and duplicate textbooks may be needed. Any kind of active steps toward organization can reduce anxiety.
Third, adjusting to the new schedule can take time. The most important adjustment is resetting the child’s sleep-wake cycle. You can recommend a move of 1 hour per day closer to the required wake up time and a corresponding bedtime that affords at least 8 hours (for tweens and teens; 9-12 hours for younger children), then maintaining the sleep schedule within 1 hour 7 days per week. Keep phones and tablets out of the bedroom. If children over 4 (including teens) have been napping over the summer, this needs to stop. Shifting mealtimes to fit the new schedule helps. Ensuring that lights are dimmed in the evening and bright in the morning has been shown to help the brain adjust.
A “new school year” is a good time for families to set new goals. Summer is often a time of fun, freedom, and new things. Parents may need your encouragement to exert leadership after months of cutting slack for their kids during COVID. Setting new goals such as greater responsibilities, music lessons, or household rules can be balanced by higher allowance and new earned privileges. Planning things to look forward to in the new year can be a family activity with a pleasant tone rather than just evoking protest. Suggest involving everyone in brainstorming crazy, out-of-the-box ideas (large and small) without censorship at first – for instance, go on a Mars mission; have pizza for breakfast; get yoga lessons; borrow binoculars to see Saturn; have a dog party! Everyone should be heard and their creativity celebrated. The list can then be narrowed down and marked on a calendar, starting soon.
Wait, you are hearing, how do we get our child off media to achieve this? Changing the rules about media use is never easy, and more now than ever. It is not just that kids are addicted to media, but it has been their main connection to peers during the pandemic. The “information” about/from peers, cliques, bullies, and world news may also be contributing to anxiety about returning to school. They may feel that they “need to know” even though it is upsetting. You can help kids verbalize the pros and cons of media use and possible addiction for themselves. How important media is to them needs to be acknowledged but ownership of the device and the final rules about this life-altering exposure must belong to the parents.
Sharing the AAP Family Media Plan to set proportions of time for school, homework, exercise, media (less than 2 hours for nonhomework), fun, and sleep can set an objective structure for the conversation. Parents may need to change their own media habits too!
While we pediatricians may normalize worries to reassure patients and parents, we also need to be alert to children and families in need of help. Many children have developed significant anxiety, depression, or substance use during the pandemic while out of our oversight but may not bring it up. Bereavement, which affected so many families during the pandemic, may not resolve smoothly. Families may have lost support, jobs, housing, or health insurance and need help connecting with assistance. Use of screening tools can ensure these are not missed, while remembering that functional impairment (social, academic, daily living, distress) is what differentiates normal from abnormal. We may be able to counsel them ourselves or refer them.
All this may be happening for you and your family, too. It can be difficult to assist others when we are struggling ourselves. We have been called on to cope when everything has been uncertain and our patients are sad, angry, or distrustful, with no end to the stress in sight. Sharing with colleagues, taking a break, or getting help for yourself may need to be a new goal for the school year, too.
Dr. Howard is assistant professor of pediatrics at Johns Hopkins University, Baltimore, and creator of CHADIS. She had no other relevant disclosures. Dr. Howard’s contribution to this publication was as a paid expert to MDedge News. E-mail her at [email protected].
Parents are relieved when school starts up again in the fall. Kids also are eager to see their friends and go on to the next level of learning.
Or are they?
This year brings a greater mix of feelings than usual for many families.
Many parents and children have new worries: Are children going to be safe at school from COVID, bullies, and shooters? Are they going to be ready to learn at this next level after the intermittent schooling of the past 2+ pandemic years of Zoom school, home school, or no school? Are they going to be able to separate after months of closeness/entanglement? Are they going to be able to catch up academically and fit in socially?
Children may have additional worries about how they have changed over the pandemic. Will my former friends still accept me now that I am heavier, showing puberty, experiencing acne, or feeling depressed or anxious?
While most of these worries occurred in some form after other summer breaks, they may be exacerbated by the length and degree of uncertainty we have all been through.
Often, health supervision visits are happy reunions with our patients when we hear about their growth and goals. We hope that is true this year, too, but we need to be vigilant and open to discussing the worries just mentioned.
What can we do to help ease this magnified transition?
First, we need to be open to their worries. Echoing back their concerns and noting how they are understandable and common can be reassuring when families have been isolated and missing interactions that might have made this clear. Second, we can remind them of the steps that assist in any transition. Now more than ever they need to collect information by visiting the new classroom, meeting teachers, and attending open house meet-and-greets. Older students may do better by looking over textbooks or a syllabus to see what will be covered. Making an effort to meet kids and families new to the school is a kind gesture but also helps the experienced child take some initiative and feel more confident.
Setting up an organizational system for homework from the start is valuable as work gets harder and is especially important for kids with ADHD. Single-subject folders, an assignment book tracking short-term and long-term projects, a plan for a specific homework time and place, a bookbag checklist by the door, or even a homework buddy and duplicate textbooks may be needed. Any kind of active steps toward organization can reduce anxiety.
Third, adjusting to the new schedule can take time. The most important adjustment is resetting the child’s sleep-wake cycle. You can recommend a move of 1 hour per day closer to the required wake up time and a corresponding bedtime that affords at least 8 hours (for tweens and teens; 9-12 hours for younger children), then maintaining the sleep schedule within 1 hour 7 days per week. Keep phones and tablets out of the bedroom. If children over 4 (including teens) have been napping over the summer, this needs to stop. Shifting mealtimes to fit the new schedule helps. Ensuring that lights are dimmed in the evening and bright in the morning has been shown to help the brain adjust.
A “new school year” is a good time for families to set new goals. Summer is often a time of fun, freedom, and new things. Parents may need your encouragement to exert leadership after months of cutting slack for their kids during COVID. Setting new goals such as greater responsibilities, music lessons, or household rules can be balanced by higher allowance and new earned privileges. Planning things to look forward to in the new year can be a family activity with a pleasant tone rather than just evoking protest. Suggest involving everyone in brainstorming crazy, out-of-the-box ideas (large and small) without censorship at first – for instance, go on a Mars mission; have pizza for breakfast; get yoga lessons; borrow binoculars to see Saturn; have a dog party! Everyone should be heard and their creativity celebrated. The list can then be narrowed down and marked on a calendar, starting soon.
Wait, you are hearing, how do we get our child off media to achieve this? Changing the rules about media use is never easy, and more now than ever. It is not just that kids are addicted to media, but it has been their main connection to peers during the pandemic. The “information” about/from peers, cliques, bullies, and world news may also be contributing to anxiety about returning to school. They may feel that they “need to know” even though it is upsetting. You can help kids verbalize the pros and cons of media use and possible addiction for themselves. How important media is to them needs to be acknowledged but ownership of the device and the final rules about this life-altering exposure must belong to the parents.
Sharing the AAP Family Media Plan to set proportions of time for school, homework, exercise, media (less than 2 hours for nonhomework), fun, and sleep can set an objective structure for the conversation. Parents may need to change their own media habits too!
While we pediatricians may normalize worries to reassure patients and parents, we also need to be alert to children and families in need of help. Many children have developed significant anxiety, depression, or substance use during the pandemic while out of our oversight but may not bring it up. Bereavement, which affected so many families during the pandemic, may not resolve smoothly. Families may have lost support, jobs, housing, or health insurance and need help connecting with assistance. Use of screening tools can ensure these are not missed, while remembering that functional impairment (social, academic, daily living, distress) is what differentiates normal from abnormal. We may be able to counsel them ourselves or refer them.
All this may be happening for you and your family, too. It can be difficult to assist others when we are struggling ourselves. We have been called on to cope when everything has been uncertain and our patients are sad, angry, or distrustful, with no end to the stress in sight. Sharing with colleagues, taking a break, or getting help for yourself may need to be a new goal for the school year, too.
Dr. Howard is assistant professor of pediatrics at Johns Hopkins University, Baltimore, and creator of CHADIS. She had no other relevant disclosures. Dr. Howard’s contribution to this publication was as a paid expert to MDedge News. E-mail her at [email protected].
Parents are relieved when school starts up again in the fall. Kids also are eager to see their friends and go on to the next level of learning.
Or are they?
This year brings a greater mix of feelings than usual for many families.
Many parents and children have new worries: Are children going to be safe at school from COVID, bullies, and shooters? Are they going to be ready to learn at this next level after the intermittent schooling of the past 2+ pandemic years of Zoom school, home school, or no school? Are they going to be able to separate after months of closeness/entanglement? Are they going to be able to catch up academically and fit in socially?
Children may have additional worries about how they have changed over the pandemic. Will my former friends still accept me now that I am heavier, showing puberty, experiencing acne, or feeling depressed or anxious?
While most of these worries occurred in some form after other summer breaks, they may be exacerbated by the length and degree of uncertainty we have all been through.
Often, health supervision visits are happy reunions with our patients when we hear about their growth and goals. We hope that is true this year, too, but we need to be vigilant and open to discussing the worries just mentioned.
What can we do to help ease this magnified transition?
First, we need to be open to their worries. Echoing back their concerns and noting how they are understandable and common can be reassuring when families have been isolated and missing interactions that might have made this clear. Second, we can remind them of the steps that assist in any transition. Now more than ever they need to collect information by visiting the new classroom, meeting teachers, and attending open house meet-and-greets. Older students may do better by looking over textbooks or a syllabus to see what will be covered. Making an effort to meet kids and families new to the school is a kind gesture but also helps the experienced child take some initiative and feel more confident.
Setting up an organizational system for homework from the start is valuable as work gets harder and is especially important for kids with ADHD. Single-subject folders, an assignment book tracking short-term and long-term projects, a plan for a specific homework time and place, a bookbag checklist by the door, or even a homework buddy and duplicate textbooks may be needed. Any kind of active steps toward organization can reduce anxiety.
Third, adjusting to the new schedule can take time. The most important adjustment is resetting the child’s sleep-wake cycle. You can recommend a move of 1 hour per day closer to the required wake up time and a corresponding bedtime that affords at least 8 hours (for tweens and teens; 9-12 hours for younger children), then maintaining the sleep schedule within 1 hour 7 days per week. Keep phones and tablets out of the bedroom. If children over 4 (including teens) have been napping over the summer, this needs to stop. Shifting mealtimes to fit the new schedule helps. Ensuring that lights are dimmed in the evening and bright in the morning has been shown to help the brain adjust.
A “new school year” is a good time for families to set new goals. Summer is often a time of fun, freedom, and new things. Parents may need your encouragement to exert leadership after months of cutting slack for their kids during COVID. Setting new goals such as greater responsibilities, music lessons, or household rules can be balanced by higher allowance and new earned privileges. Planning things to look forward to in the new year can be a family activity with a pleasant tone rather than just evoking protest. Suggest involving everyone in brainstorming crazy, out-of-the-box ideas (large and small) without censorship at first – for instance, go on a Mars mission; have pizza for breakfast; get yoga lessons; borrow binoculars to see Saturn; have a dog party! Everyone should be heard and their creativity celebrated. The list can then be narrowed down and marked on a calendar, starting soon.
Wait, you are hearing, how do we get our child off media to achieve this? Changing the rules about media use is never easy, and more now than ever. It is not just that kids are addicted to media, but it has been their main connection to peers during the pandemic. The “information” about/from peers, cliques, bullies, and world news may also be contributing to anxiety about returning to school. They may feel that they “need to know” even though it is upsetting. You can help kids verbalize the pros and cons of media use and possible addiction for themselves. How important media is to them needs to be acknowledged but ownership of the device and the final rules about this life-altering exposure must belong to the parents.
Sharing the AAP Family Media Plan to set proportions of time for school, homework, exercise, media (less than 2 hours for nonhomework), fun, and sleep can set an objective structure for the conversation. Parents may need to change their own media habits too!
While we pediatricians may normalize worries to reassure patients and parents, we also need to be alert to children and families in need of help. Many children have developed significant anxiety, depression, or substance use during the pandemic while out of our oversight but may not bring it up. Bereavement, which affected so many families during the pandemic, may not resolve smoothly. Families may have lost support, jobs, housing, or health insurance and need help connecting with assistance. Use of screening tools can ensure these are not missed, while remembering that functional impairment (social, academic, daily living, distress) is what differentiates normal from abnormal. We may be able to counsel them ourselves or refer them.
All this may be happening for you and your family, too. It can be difficult to assist others when we are struggling ourselves. We have been called on to cope when everything has been uncertain and our patients are sad, angry, or distrustful, with no end to the stress in sight. Sharing with colleagues, taking a break, or getting help for yourself may need to be a new goal for the school year, too.
Dr. Howard is assistant professor of pediatrics at Johns Hopkins University, Baltimore, and creator of CHADIS. She had no other relevant disclosures. Dr. Howard’s contribution to this publication was as a paid expert to MDedge News. E-mail her at [email protected].
Docs not talking about anal sex may put women at risk
Clinicians’ reluctance to discuss possible harms of anal sex may be letting down a generation of young women who are unaware of the risks, two researchers from the United Kingdom write in an opinion article published in The BMJ.
Failure to discuss the subject “exposes women to missed diagnoses, futile treatments, and further harm arising from a lack of medical advice,” write Tabitha Gana, MD, and Lesley Hunt, MD, with Sheffield Teaching Hospitals NHS Foundation Trust and Northern General Hospital, both in Sheffield, United Kingdom.
In their opinion, health care professionals, particularly those in general practice, gastroenterology, and colorectal surgery, “have a duty to acknowledge changes in society around anal sex in young women and to meet these changes with open, neutral, and non-judgmental conversations to ensure that all women have the information they need to make informed choices about sex.”
Asking about anal sex is standard practice in genitourinary medicine clinics, but it’s less common in general practice and colorectal clinics, they point out.
No longer taboo
Anal intercourse is becoming more common among young heterosexual couples. In the United Kingdom, participation in heterosexual anal intercourse among people aged 16-24 years rose from about 13% to 29% over the last few decades, according to national survey data.
The same thing is happening in the United States, where research suggests 30%-44% of men and women report having anal sex.
Individual motivation for anal sex varies. Young women cite pleasure, curiosity, pleasing the male partners, and coercion as factors. Up to 25% of women with experience of anal sex report they have been pressured into it at least once, Dr. Gana and Dr. Hunt say.
However, because of its association with alcohol, drug use, and multiple sex partners, anal intercourse is considered a risky sexual behavior.
It’s also associated with specific health concerns, Dr. Gana and Dr. Hunt point out. These include fecal incontinence and anal sphincter injury, which have been reported in women who engage in anal intercourse. When it comes to incontinence, women are at higher risk than men because of their different anatomy and the effects of hormones, pregnancy, and childbirth on the pelvic floor.
“Women have less robust anal sphincters and lower anal canal pressures than men, and damage caused by anal penetration is therefore more consequential,” Dr. Gana and Dr. Hunt point out.
“The pain and bleeding women report after anal sex is indicative of trauma, and risks may be increased if anal sex is coerced,” they add.
Knowledge of the underlying risk factors and taking a good history are key to effective management of anorectal disorders, they say.
Dr. Gana and Dr. Hunt worry that clinicians may shy away from talking about anal sex, influenced by society’s taboos.
Currently, NHS patient information on anal sex considers only sexually transmitted infections, making no mention of anal trauma, incontinence, or the psychological aftermath of being coerced into anal sex.
“It may not be just avoidance or stigma that prevents health professionals [from] talking to young women about the risks of anal sex. There is genuine concern that the message may be seen as judgmental or even misconstrued as homophobic,” Dr. Gana and Dr. Hunt write.
“However, by avoiding these discussions, we may be failing a generation of young women who are unaware of the risks,” they add.
“With better information, women who want anal sex would be able to protect themselves more effectively from possible harm, and those who agree to anal sex reluctantly to meet society’s expectations or please partners may feel better empowered to say no,” Dr. Gana and Dr. Hunt say.
This research had no specific funding. Dr. Gana and Dr. Hunt report no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Clinicians’ reluctance to discuss possible harms of anal sex may be letting down a generation of young women who are unaware of the risks, two researchers from the United Kingdom write in an opinion article published in The BMJ.
Failure to discuss the subject “exposes women to missed diagnoses, futile treatments, and further harm arising from a lack of medical advice,” write Tabitha Gana, MD, and Lesley Hunt, MD, with Sheffield Teaching Hospitals NHS Foundation Trust and Northern General Hospital, both in Sheffield, United Kingdom.
In their opinion, health care professionals, particularly those in general practice, gastroenterology, and colorectal surgery, “have a duty to acknowledge changes in society around anal sex in young women and to meet these changes with open, neutral, and non-judgmental conversations to ensure that all women have the information they need to make informed choices about sex.”
Asking about anal sex is standard practice in genitourinary medicine clinics, but it’s less common in general practice and colorectal clinics, they point out.
No longer taboo
Anal intercourse is becoming more common among young heterosexual couples. In the United Kingdom, participation in heterosexual anal intercourse among people aged 16-24 years rose from about 13% to 29% over the last few decades, according to national survey data.
The same thing is happening in the United States, where research suggests 30%-44% of men and women report having anal sex.
Individual motivation for anal sex varies. Young women cite pleasure, curiosity, pleasing the male partners, and coercion as factors. Up to 25% of women with experience of anal sex report they have been pressured into it at least once, Dr. Gana and Dr. Hunt say.
However, because of its association with alcohol, drug use, and multiple sex partners, anal intercourse is considered a risky sexual behavior.
It’s also associated with specific health concerns, Dr. Gana and Dr. Hunt point out. These include fecal incontinence and anal sphincter injury, which have been reported in women who engage in anal intercourse. When it comes to incontinence, women are at higher risk than men because of their different anatomy and the effects of hormones, pregnancy, and childbirth on the pelvic floor.
“Women have less robust anal sphincters and lower anal canal pressures than men, and damage caused by anal penetration is therefore more consequential,” Dr. Gana and Dr. Hunt point out.
“The pain and bleeding women report after anal sex is indicative of trauma, and risks may be increased if anal sex is coerced,” they add.
Knowledge of the underlying risk factors and taking a good history are key to effective management of anorectal disorders, they say.
Dr. Gana and Dr. Hunt worry that clinicians may shy away from talking about anal sex, influenced by society’s taboos.
Currently, NHS patient information on anal sex considers only sexually transmitted infections, making no mention of anal trauma, incontinence, or the psychological aftermath of being coerced into anal sex.
“It may not be just avoidance or stigma that prevents health professionals [from] talking to young women about the risks of anal sex. There is genuine concern that the message may be seen as judgmental or even misconstrued as homophobic,” Dr. Gana and Dr. Hunt write.
“However, by avoiding these discussions, we may be failing a generation of young women who are unaware of the risks,” they add.
“With better information, women who want anal sex would be able to protect themselves more effectively from possible harm, and those who agree to anal sex reluctantly to meet society’s expectations or please partners may feel better empowered to say no,” Dr. Gana and Dr. Hunt say.
This research had no specific funding. Dr. Gana and Dr. Hunt report no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Clinicians’ reluctance to discuss possible harms of anal sex may be letting down a generation of young women who are unaware of the risks, two researchers from the United Kingdom write in an opinion article published in The BMJ.
Failure to discuss the subject “exposes women to missed diagnoses, futile treatments, and further harm arising from a lack of medical advice,” write Tabitha Gana, MD, and Lesley Hunt, MD, with Sheffield Teaching Hospitals NHS Foundation Trust and Northern General Hospital, both in Sheffield, United Kingdom.
In their opinion, health care professionals, particularly those in general practice, gastroenterology, and colorectal surgery, “have a duty to acknowledge changes in society around anal sex in young women and to meet these changes with open, neutral, and non-judgmental conversations to ensure that all women have the information they need to make informed choices about sex.”
Asking about anal sex is standard practice in genitourinary medicine clinics, but it’s less common in general practice and colorectal clinics, they point out.
No longer taboo
Anal intercourse is becoming more common among young heterosexual couples. In the United Kingdom, participation in heterosexual anal intercourse among people aged 16-24 years rose from about 13% to 29% over the last few decades, according to national survey data.
The same thing is happening in the United States, where research suggests 30%-44% of men and women report having anal sex.
Individual motivation for anal sex varies. Young women cite pleasure, curiosity, pleasing the male partners, and coercion as factors. Up to 25% of women with experience of anal sex report they have been pressured into it at least once, Dr. Gana and Dr. Hunt say.
However, because of its association with alcohol, drug use, and multiple sex partners, anal intercourse is considered a risky sexual behavior.
It’s also associated with specific health concerns, Dr. Gana and Dr. Hunt point out. These include fecal incontinence and anal sphincter injury, which have been reported in women who engage in anal intercourse. When it comes to incontinence, women are at higher risk than men because of their different anatomy and the effects of hormones, pregnancy, and childbirth on the pelvic floor.
“Women have less robust anal sphincters and lower anal canal pressures than men, and damage caused by anal penetration is therefore more consequential,” Dr. Gana and Dr. Hunt point out.
“The pain and bleeding women report after anal sex is indicative of trauma, and risks may be increased if anal sex is coerced,” they add.
Knowledge of the underlying risk factors and taking a good history are key to effective management of anorectal disorders, they say.
Dr. Gana and Dr. Hunt worry that clinicians may shy away from talking about anal sex, influenced by society’s taboos.
Currently, NHS patient information on anal sex considers only sexually transmitted infections, making no mention of anal trauma, incontinence, or the psychological aftermath of being coerced into anal sex.
“It may not be just avoidance or stigma that prevents health professionals [from] talking to young women about the risks of anal sex. There is genuine concern that the message may be seen as judgmental or even misconstrued as homophobic,” Dr. Gana and Dr. Hunt write.
“However, by avoiding these discussions, we may be failing a generation of young women who are unaware of the risks,” they add.
“With better information, women who want anal sex would be able to protect themselves more effectively from possible harm, and those who agree to anal sex reluctantly to meet society’s expectations or please partners may feel better empowered to say no,” Dr. Gana and Dr. Hunt say.
This research had no specific funding. Dr. Gana and Dr. Hunt report no relevant financial relationships.
A version of this article first appeared on Medscape.com.
FROM THE BMJ
Alzheimer’s disease: Alternative mechanisms make clinical progress
SAN DIEGO – In 1906, a neuroanatomist and psychiatrist named Alois Alzheimer examined the brain of a 50-year-old woman whom he had treated for paranoia, sleep and memory problems, aggression, and confusion. His autopsy revealed plaques and tangles in her brain. The most common components of these tangles are beta-amyloid peptide (A-beta) and the microtubule binding protein tau. Over the past few decades, that finding has launched many clinical development programs and dozens of clinical trials.
To date, all but one program has failed. In 2021, amidst much controversy, FDA granted accelerated approval to Biogen’s Aduhelm, which effectively clears A-beta and tau deposits from patients’ brains. The problem is that the clinical benefit is small, and uptake has been so low that the company was forced to abandon a planned postmarketing observational trial.
Chasing the wrong target?
At a session at the 2022 Alzheimer’s Association International Conference, Raymond J. Tesi, MD, rather forcefully refuted that approach. “Amyloid and tau therapies have had 20 years to prove themselves. We have multiple cases where we’ve been able to decrease amyloid, maybe not so much tau, but certainly amyloid, and the benefits are mild at best. So I think that the Alzheimer’s drug development community, whether you look at the NIH, whether you look at academia, whether you look at biopharma, has focused on a target that has not proven itself, and it’s time to move on,” said Dr. Tesi, who is president, CEO, and chief medical officer at INmune Bio.
Later in the session,
One audience member defended the potential importance of A-beta and tau, especially in astrogliosis, which is a reaction to stress by astrocytes that attempts to limit tissue damage. The questioner suggested that it was still important to measure the effect of a novel drug on A-beta and tau. “What would be the cause of the reactive astrogliosis and microglia activation, if we are not giving a damn about amyloid and tau?” he asked.
After a bit of back and forth, Dr. Tesi replied: “We both have a religious belief here, and sooner or later we’ll get the answer.”
A diverse clinical pipeline
The session itself focused on four companies, including Dr. Tesi’s INmune Bio, which have drugs with alternative mechanisms entering the advanced stages of clinical development. That’s good news, according to Heather Snyder, PhD, who is vice president of Medical & Scientific Relations at the Alzheimer’s Association. “One of the things that I think is really important is the diversity of what’s in the clinical pipeline, and it’s not just in the very beginning anymore. We’re seeing [companies] now reporting phase 2 [studies] and planning their next stage. That’s something that as a field we should be excited about. As we understand more and more about the biology, we’re now seeing that translating into clinical trials and we’re seeing that translate through the clinical pipeline of development,” said Dr. Snyder in an interview.
Targeting neuroinflammation
Dr. Tesi kicked off the session describing INmune Bio’s focus on neuroinflammation. The company’s drug candidate targets soluble tumor necrosis factor (TNF), which the company believes is a direct cause of Alzheimer’s disease through promotion of inflammation. He noted that TNF is a primary mediator of inflammation in rheumatoid arthritis, and patients with RA have an eightfold increased risk of developing Alzheimer’s disease, compared with the general population, while patients with RA who are taking anti-TNF medication have a 60% lower risk than the general population.
The company’s TNF inhibitor XPro is also unique in that it induces remyelination in mice, while other TNF inhibitors potentially “abuse” the brain by causing demyelination. Earlier research showed that it reduces neuroinflammation, improves nerve cell survival, and improves synaptic function. The company is conducting two phase 2 clinical trials, one in patients with mild cognitive impairment (MCI) and one in mild Alzheimer’s disease. They also use the MCI Alzheimer’s Cognitive Composite (EMACC) tool for assessing outcomes rather than the more commonly used Alzheimer’s Disease Assessment Scale-Cognitive subscale (ADAS-Cog). “ADAS-Cog is like trying to make sushi with an axe. It is designed for moderate to severe disease, and trying to use it for mild (Alzheimer’s disease) or MCI is a mistake. EMACC is purpose built for mild [AD] and MCI patients,” said Dr. Tesi.
Maintaining homeostatis
Next, Hans Moebius, MD, PhD, chief medical officer of Athira Pharma, described his company’s focus on the hepatocyte growth factor (HGF) receptor, also known as tyrosine kinase MET (HGF/MET). It plays an important role in brain development and homeostasis, and it is expressed at lower levels in the frontal cortex and hippocampus of patients with Alzheimer’s disease. The company’s small-molecule drug candidate boosts the HGF/MET pathway, leading to downstream neuroprotection and neurotrophic effects. It also promotes formation of new synapses.
Dr. Moebius presented the results of a phase 2 trial showing that the drug, called fosgonimeton, led to significant cognitive improvement compared with placebo. The company is conducting a phase 3 clinical trial.
Type 3 diabetes?
In his talk, John Didsbury, PhD, founder and CEO of T3D Therapeutics, framed Alzheimer’s disease as a disease of metabolic dysfunction. He believes alterations to glucose and lipids in the brain cause structural changes that lead to symptoms. He pointed out that the strongest genetic Alzheimer’s disease risk factor is a mutant form of the lipid transport protein APOE4.
“What we have is dysregulated glucose energy metabolism and lipid metabolism that really cause, in our mind, the structural event changes and the stress event changes – plaques, tangles, inflammation, etc. – but these events perpetuate the dysregulated metabolism. It’s a massive positive feedback loop that many have called type 3 diabetes – a brain-specific form of diabetes,” said Dr. Didsbury.
The company’s approach is to use systems biology to identify a drug target that can bypass multiple aberrant insulin signaling pathways. Its drug candidate regulates the expression of multiple genes involved in glucose metabolism. Dr. Didsbury presented interim results from a phase 2 study showing improvement over placebo.
Focusing on neurotoxic proteins
The final presentation of the session was by Maria Maccecchini, PhD, founder, president, and CEO of Annovis Bio. The company’s drug, buntanetap, reduces expression of a range of neurotoxic proteins. The downstream effects include restoration of axonal transport, reduction of inflammation, and protection of nerve cells. The company believes that Alzheimer’s disease results from acute and chronic stress events that lead to high levels of neurotoxic proteins, which include A-beta, tau, alpha-synuclein, and TDP43. The proteins aren’t just players in Alzheimer’s disease – they are present in abnormal levels in Parkinson’s disease and a range of other brain pathologies.
“In the brain of an Alzheimer’s and of a Parkinson’s [patient], you’re going to find all four proteins. You’ll find them in different concentrations, at different time points, in different brain areas. If you just remove one, you still have the other three that cause impairment in axonal transport, and that leads to inflammation that leads to neurodegeneration,” said Dr. Maccecchini.
The company’s drug manages to reduce levels of all four proteins by binding to a segment of messenger RNA (mRNA) shared by all of them. mRNA serves as a template for protein synthesis. Under normal conditions, the neurotoxic protein concentrations are kept low because the mRNA segment remains bound to a regulatory protein that prevents synthesis from occurring. However, when stress leads to high levels of iron, this regulatory binding protein releases the mRNA segment (along with the rest of the mRNA). The freed mRNA becomes available to the cell’s protein synthesis machinery, which starts producing high levels of neurotoxic proteins. Annovis Bio’s drug improves the ability of the regulatory protein to bind to the mRNA segment, preventing protein expression even in high-iron conditions. It works on all four neurotoxic proteins because they all have the regulatory segment in their mRNA.
The drug led to improvements in phase 2 studies of Alzheimer’s disease and Parkinson’s disease, and the company is currently recruiting for a phase 3 study in Parkinson’s disease and a phase 2/3 dose-response study in Alzheimer’s disease.
Combination treatments for a complex disease
Taken together, the presentations provided a snapshot of the post–A-beta/tau Alzheimer’s development world, and the future could be messy. Alzheimer’s disease and other dementias are likely to require combination treatments, according to Dr. Snyder. “This is a complex disease, not just Alzheimer’s but other dementias. It’s not going to be a single drug, a single target. It’s going to require some type of combinatorial approach, whether that be with medication and lifestyle interventions, or risk reduction, and different medications,” she said.
The latest results are good news for that approach: “We’re seeing that maturation of the science in these trials,” said Dr. Snyder.
Cheng Fang, PhD, senior vice president of research and development at Annovis Bio, agreed with that sentiment. “I believe [Alzheimer’s disease and dementia] is a very complicated disease. I always call them diseases instead of a disease because it’s a spectrum. I don’t believe one drug can cure them all, as much as I am confident in our drug. I think it’s extremely important to encourage this kind of diverse thinking,” said Dr. Fang.
Dr. Snyder has no relevant financial disclosures. Dr. Tesi, Dr. Moebius, Dr. Didsbury, Dr. Maccecchini, and Dr. Fang are employees and in some cases stockholders of their respective companies.
SAN DIEGO – In 1906, a neuroanatomist and psychiatrist named Alois Alzheimer examined the brain of a 50-year-old woman whom he had treated for paranoia, sleep and memory problems, aggression, and confusion. His autopsy revealed plaques and tangles in her brain. The most common components of these tangles are beta-amyloid peptide (A-beta) and the microtubule binding protein tau. Over the past few decades, that finding has launched many clinical development programs and dozens of clinical trials.
To date, all but one program has failed. In 2021, amidst much controversy, FDA granted accelerated approval to Biogen’s Aduhelm, which effectively clears A-beta and tau deposits from patients’ brains. The problem is that the clinical benefit is small, and uptake has been so low that the company was forced to abandon a planned postmarketing observational trial.
Chasing the wrong target?
At a session at the 2022 Alzheimer’s Association International Conference, Raymond J. Tesi, MD, rather forcefully refuted that approach. “Amyloid and tau therapies have had 20 years to prove themselves. We have multiple cases where we’ve been able to decrease amyloid, maybe not so much tau, but certainly amyloid, and the benefits are mild at best. So I think that the Alzheimer’s drug development community, whether you look at the NIH, whether you look at academia, whether you look at biopharma, has focused on a target that has not proven itself, and it’s time to move on,” said Dr. Tesi, who is president, CEO, and chief medical officer at INmune Bio.
Later in the session,
One audience member defended the potential importance of A-beta and tau, especially in astrogliosis, which is a reaction to stress by astrocytes that attempts to limit tissue damage. The questioner suggested that it was still important to measure the effect of a novel drug on A-beta and tau. “What would be the cause of the reactive astrogliosis and microglia activation, if we are not giving a damn about amyloid and tau?” he asked.
After a bit of back and forth, Dr. Tesi replied: “We both have a religious belief here, and sooner or later we’ll get the answer.”
A diverse clinical pipeline
The session itself focused on four companies, including Dr. Tesi’s INmune Bio, which have drugs with alternative mechanisms entering the advanced stages of clinical development. That’s good news, according to Heather Snyder, PhD, who is vice president of Medical & Scientific Relations at the Alzheimer’s Association. “One of the things that I think is really important is the diversity of what’s in the clinical pipeline, and it’s not just in the very beginning anymore. We’re seeing [companies] now reporting phase 2 [studies] and planning their next stage. That’s something that as a field we should be excited about. As we understand more and more about the biology, we’re now seeing that translating into clinical trials and we’re seeing that translate through the clinical pipeline of development,” said Dr. Snyder in an interview.
Targeting neuroinflammation
Dr. Tesi kicked off the session describing INmune Bio’s focus on neuroinflammation. The company’s drug candidate targets soluble tumor necrosis factor (TNF), which the company believes is a direct cause of Alzheimer’s disease through promotion of inflammation. He noted that TNF is a primary mediator of inflammation in rheumatoid arthritis, and patients with RA have an eightfold increased risk of developing Alzheimer’s disease, compared with the general population, while patients with RA who are taking anti-TNF medication have a 60% lower risk than the general population.
The company’s TNF inhibitor XPro is also unique in that it induces remyelination in mice, while other TNF inhibitors potentially “abuse” the brain by causing demyelination. Earlier research showed that it reduces neuroinflammation, improves nerve cell survival, and improves synaptic function. The company is conducting two phase 2 clinical trials, one in patients with mild cognitive impairment (MCI) and one in mild Alzheimer’s disease. They also use the MCI Alzheimer’s Cognitive Composite (EMACC) tool for assessing outcomes rather than the more commonly used Alzheimer’s Disease Assessment Scale-Cognitive subscale (ADAS-Cog). “ADAS-Cog is like trying to make sushi with an axe. It is designed for moderate to severe disease, and trying to use it for mild (Alzheimer’s disease) or MCI is a mistake. EMACC is purpose built for mild [AD] and MCI patients,” said Dr. Tesi.
Maintaining homeostatis
Next, Hans Moebius, MD, PhD, chief medical officer of Athira Pharma, described his company’s focus on the hepatocyte growth factor (HGF) receptor, also known as tyrosine kinase MET (HGF/MET). It plays an important role in brain development and homeostasis, and it is expressed at lower levels in the frontal cortex and hippocampus of patients with Alzheimer’s disease. The company’s small-molecule drug candidate boosts the HGF/MET pathway, leading to downstream neuroprotection and neurotrophic effects. It also promotes formation of new synapses.
Dr. Moebius presented the results of a phase 2 trial showing that the drug, called fosgonimeton, led to significant cognitive improvement compared with placebo. The company is conducting a phase 3 clinical trial.
Type 3 diabetes?
In his talk, John Didsbury, PhD, founder and CEO of T3D Therapeutics, framed Alzheimer’s disease as a disease of metabolic dysfunction. He believes alterations to glucose and lipids in the brain cause structural changes that lead to symptoms. He pointed out that the strongest genetic Alzheimer’s disease risk factor is a mutant form of the lipid transport protein APOE4.
“What we have is dysregulated glucose energy metabolism and lipid metabolism that really cause, in our mind, the structural event changes and the stress event changes – plaques, tangles, inflammation, etc. – but these events perpetuate the dysregulated metabolism. It’s a massive positive feedback loop that many have called type 3 diabetes – a brain-specific form of diabetes,” said Dr. Didsbury.
The company’s approach is to use systems biology to identify a drug target that can bypass multiple aberrant insulin signaling pathways. Its drug candidate regulates the expression of multiple genes involved in glucose metabolism. Dr. Didsbury presented interim results from a phase 2 study showing improvement over placebo.
Focusing on neurotoxic proteins
The final presentation of the session was by Maria Maccecchini, PhD, founder, president, and CEO of Annovis Bio. The company’s drug, buntanetap, reduces expression of a range of neurotoxic proteins. The downstream effects include restoration of axonal transport, reduction of inflammation, and protection of nerve cells. The company believes that Alzheimer’s disease results from acute and chronic stress events that lead to high levels of neurotoxic proteins, which include A-beta, tau, alpha-synuclein, and TDP43. The proteins aren’t just players in Alzheimer’s disease – they are present in abnormal levels in Parkinson’s disease and a range of other brain pathologies.
“In the brain of an Alzheimer’s and of a Parkinson’s [patient], you’re going to find all four proteins. You’ll find them in different concentrations, at different time points, in different brain areas. If you just remove one, you still have the other three that cause impairment in axonal transport, and that leads to inflammation that leads to neurodegeneration,” said Dr. Maccecchini.
The company’s drug manages to reduce levels of all four proteins by binding to a segment of messenger RNA (mRNA) shared by all of them. mRNA serves as a template for protein synthesis. Under normal conditions, the neurotoxic protein concentrations are kept low because the mRNA segment remains bound to a regulatory protein that prevents synthesis from occurring. However, when stress leads to high levels of iron, this regulatory binding protein releases the mRNA segment (along with the rest of the mRNA). The freed mRNA becomes available to the cell’s protein synthesis machinery, which starts producing high levels of neurotoxic proteins. Annovis Bio’s drug improves the ability of the regulatory protein to bind to the mRNA segment, preventing protein expression even in high-iron conditions. It works on all four neurotoxic proteins because they all have the regulatory segment in their mRNA.
The drug led to improvements in phase 2 studies of Alzheimer’s disease and Parkinson’s disease, and the company is currently recruiting for a phase 3 study in Parkinson’s disease and a phase 2/3 dose-response study in Alzheimer’s disease.
Combination treatments for a complex disease
Taken together, the presentations provided a snapshot of the post–A-beta/tau Alzheimer’s development world, and the future could be messy. Alzheimer’s disease and other dementias are likely to require combination treatments, according to Dr. Snyder. “This is a complex disease, not just Alzheimer’s but other dementias. It’s not going to be a single drug, a single target. It’s going to require some type of combinatorial approach, whether that be with medication and lifestyle interventions, or risk reduction, and different medications,” she said.
The latest results are good news for that approach: “We’re seeing that maturation of the science in these trials,” said Dr. Snyder.
Cheng Fang, PhD, senior vice president of research and development at Annovis Bio, agreed with that sentiment. “I believe [Alzheimer’s disease and dementia] is a very complicated disease. I always call them diseases instead of a disease because it’s a spectrum. I don’t believe one drug can cure them all, as much as I am confident in our drug. I think it’s extremely important to encourage this kind of diverse thinking,” said Dr. Fang.
Dr. Snyder has no relevant financial disclosures. Dr. Tesi, Dr. Moebius, Dr. Didsbury, Dr. Maccecchini, and Dr. Fang are employees and in some cases stockholders of their respective companies.
SAN DIEGO – In 1906, a neuroanatomist and psychiatrist named Alois Alzheimer examined the brain of a 50-year-old woman whom he had treated for paranoia, sleep and memory problems, aggression, and confusion. His autopsy revealed plaques and tangles in her brain. The most common components of these tangles are beta-amyloid peptide (A-beta) and the microtubule binding protein tau. Over the past few decades, that finding has launched many clinical development programs and dozens of clinical trials.
To date, all but one program has failed. In 2021, amidst much controversy, FDA granted accelerated approval to Biogen’s Aduhelm, which effectively clears A-beta and tau deposits from patients’ brains. The problem is that the clinical benefit is small, and uptake has been so low that the company was forced to abandon a planned postmarketing observational trial.
Chasing the wrong target?
At a session at the 2022 Alzheimer’s Association International Conference, Raymond J. Tesi, MD, rather forcefully refuted that approach. “Amyloid and tau therapies have had 20 years to prove themselves. We have multiple cases where we’ve been able to decrease amyloid, maybe not so much tau, but certainly amyloid, and the benefits are mild at best. So I think that the Alzheimer’s drug development community, whether you look at the NIH, whether you look at academia, whether you look at biopharma, has focused on a target that has not proven itself, and it’s time to move on,” said Dr. Tesi, who is president, CEO, and chief medical officer at INmune Bio.
Later in the session,
One audience member defended the potential importance of A-beta and tau, especially in astrogliosis, which is a reaction to stress by astrocytes that attempts to limit tissue damage. The questioner suggested that it was still important to measure the effect of a novel drug on A-beta and tau. “What would be the cause of the reactive astrogliosis and microglia activation, if we are not giving a damn about amyloid and tau?” he asked.
After a bit of back and forth, Dr. Tesi replied: “We both have a religious belief here, and sooner or later we’ll get the answer.”
A diverse clinical pipeline
The session itself focused on four companies, including Dr. Tesi’s INmune Bio, which have drugs with alternative mechanisms entering the advanced stages of clinical development. That’s good news, according to Heather Snyder, PhD, who is vice president of Medical & Scientific Relations at the Alzheimer’s Association. “One of the things that I think is really important is the diversity of what’s in the clinical pipeline, and it’s not just in the very beginning anymore. We’re seeing [companies] now reporting phase 2 [studies] and planning their next stage. That’s something that as a field we should be excited about. As we understand more and more about the biology, we’re now seeing that translating into clinical trials and we’re seeing that translate through the clinical pipeline of development,” said Dr. Snyder in an interview.
Targeting neuroinflammation
Dr. Tesi kicked off the session describing INmune Bio’s focus on neuroinflammation. The company’s drug candidate targets soluble tumor necrosis factor (TNF), which the company believes is a direct cause of Alzheimer’s disease through promotion of inflammation. He noted that TNF is a primary mediator of inflammation in rheumatoid arthritis, and patients with RA have an eightfold increased risk of developing Alzheimer’s disease, compared with the general population, while patients with RA who are taking anti-TNF medication have a 60% lower risk than the general population.
The company’s TNF inhibitor XPro is also unique in that it induces remyelination in mice, while other TNF inhibitors potentially “abuse” the brain by causing demyelination. Earlier research showed that it reduces neuroinflammation, improves nerve cell survival, and improves synaptic function. The company is conducting two phase 2 clinical trials, one in patients with mild cognitive impairment (MCI) and one in mild Alzheimer’s disease. They also use the MCI Alzheimer’s Cognitive Composite (EMACC) tool for assessing outcomes rather than the more commonly used Alzheimer’s Disease Assessment Scale-Cognitive subscale (ADAS-Cog). “ADAS-Cog is like trying to make sushi with an axe. It is designed for moderate to severe disease, and trying to use it for mild (Alzheimer’s disease) or MCI is a mistake. EMACC is purpose built for mild [AD] and MCI patients,” said Dr. Tesi.
Maintaining homeostatis
Next, Hans Moebius, MD, PhD, chief medical officer of Athira Pharma, described his company’s focus on the hepatocyte growth factor (HGF) receptor, also known as tyrosine kinase MET (HGF/MET). It plays an important role in brain development and homeostasis, and it is expressed at lower levels in the frontal cortex and hippocampus of patients with Alzheimer’s disease. The company’s small-molecule drug candidate boosts the HGF/MET pathway, leading to downstream neuroprotection and neurotrophic effects. It also promotes formation of new synapses.
Dr. Moebius presented the results of a phase 2 trial showing that the drug, called fosgonimeton, led to significant cognitive improvement compared with placebo. The company is conducting a phase 3 clinical trial.
Type 3 diabetes?
In his talk, John Didsbury, PhD, founder and CEO of T3D Therapeutics, framed Alzheimer’s disease as a disease of metabolic dysfunction. He believes alterations to glucose and lipids in the brain cause structural changes that lead to symptoms. He pointed out that the strongest genetic Alzheimer’s disease risk factor is a mutant form of the lipid transport protein APOE4.
“What we have is dysregulated glucose energy metabolism and lipid metabolism that really cause, in our mind, the structural event changes and the stress event changes – plaques, tangles, inflammation, etc. – but these events perpetuate the dysregulated metabolism. It’s a massive positive feedback loop that many have called type 3 diabetes – a brain-specific form of diabetes,” said Dr. Didsbury.
The company’s approach is to use systems biology to identify a drug target that can bypass multiple aberrant insulin signaling pathways. Its drug candidate regulates the expression of multiple genes involved in glucose metabolism. Dr. Didsbury presented interim results from a phase 2 study showing improvement over placebo.
Focusing on neurotoxic proteins
The final presentation of the session was by Maria Maccecchini, PhD, founder, president, and CEO of Annovis Bio. The company’s drug, buntanetap, reduces expression of a range of neurotoxic proteins. The downstream effects include restoration of axonal transport, reduction of inflammation, and protection of nerve cells. The company believes that Alzheimer’s disease results from acute and chronic stress events that lead to high levels of neurotoxic proteins, which include A-beta, tau, alpha-synuclein, and TDP43. The proteins aren’t just players in Alzheimer’s disease – they are present in abnormal levels in Parkinson’s disease and a range of other brain pathologies.
“In the brain of an Alzheimer’s and of a Parkinson’s [patient], you’re going to find all four proteins. You’ll find them in different concentrations, at different time points, in different brain areas. If you just remove one, you still have the other three that cause impairment in axonal transport, and that leads to inflammation that leads to neurodegeneration,” said Dr. Maccecchini.
The company’s drug manages to reduce levels of all four proteins by binding to a segment of messenger RNA (mRNA) shared by all of them. mRNA serves as a template for protein synthesis. Under normal conditions, the neurotoxic protein concentrations are kept low because the mRNA segment remains bound to a regulatory protein that prevents synthesis from occurring. However, when stress leads to high levels of iron, this regulatory binding protein releases the mRNA segment (along with the rest of the mRNA). The freed mRNA becomes available to the cell’s protein synthesis machinery, which starts producing high levels of neurotoxic proteins. Annovis Bio’s drug improves the ability of the regulatory protein to bind to the mRNA segment, preventing protein expression even in high-iron conditions. It works on all four neurotoxic proteins because they all have the regulatory segment in their mRNA.
The drug led to improvements in phase 2 studies of Alzheimer’s disease and Parkinson’s disease, and the company is currently recruiting for a phase 3 study in Parkinson’s disease and a phase 2/3 dose-response study in Alzheimer’s disease.
Combination treatments for a complex disease
Taken together, the presentations provided a snapshot of the post–A-beta/tau Alzheimer’s development world, and the future could be messy. Alzheimer’s disease and other dementias are likely to require combination treatments, according to Dr. Snyder. “This is a complex disease, not just Alzheimer’s but other dementias. It’s not going to be a single drug, a single target. It’s going to require some type of combinatorial approach, whether that be with medication and lifestyle interventions, or risk reduction, and different medications,” she said.
The latest results are good news for that approach: “We’re seeing that maturation of the science in these trials,” said Dr. Snyder.
Cheng Fang, PhD, senior vice president of research and development at Annovis Bio, agreed with that sentiment. “I believe [Alzheimer’s disease and dementia] is a very complicated disease. I always call them diseases instead of a disease because it’s a spectrum. I don’t believe one drug can cure them all, as much as I am confident in our drug. I think it’s extremely important to encourage this kind of diverse thinking,” said Dr. Fang.
Dr. Snyder has no relevant financial disclosures. Dr. Tesi, Dr. Moebius, Dr. Didsbury, Dr. Maccecchini, and Dr. Fang are employees and in some cases stockholders of their respective companies.
AT AAIC 2022
Tocolytic benefits for preterm birth outweigh risks
New research from the University of Birmingham, England, in collaboration with the World Health Organization, shows that tocolytic drugs used to delay preterm birth, and thus avert the ensuing associated mortality and morbidity, are all “probably effective in delaying preterm birth compared with placebo or no treatment.”
Expanded use of the drugs would be a safe means to reduce the global burden of neonatal death, the researchers suggest. Coauthor Victoria Hodgetts Morton, BMedSci, NIHR clinical lecturer in obstetrics at the University of Birmingham, said: “Preterm birth is the most common reason why a newborn baby may die, and the leading cause of death in children under 5 years of age.
“Tocolytics aim to delay preterm birth and allow time for the women to receive medicines that can help with baby’s breathing and feeding if born preterm, and medicines that lower the chance of cerebral palsy of the infant. Crucially, a short delay in preterm birth can enable women to reach specialist care.”
Network meta‐analysis drew on 122 trials
The new paper, published in Cochrane Reviews, aimed to find out which tocolytic was most effective in delaying preterm birth, safest, and with the fewest side effects. Researchers brought together data from 122 randomized clinical trials in a network meta‐analysis.
Unlike conventional Cochrane Reviews, this type of review simultaneously pools all direct and indirect evidence into one single coherent analysis. Indirect evidence is obtained by inferring the relative effectiveness of two competing drugs through a common comparator, even when these two drugs have not been directly compared. The method also enables researchers to calculate the probability for each competing drug to constitute the most effective drug with the least side effects. This thereby allowed the researchers to rank the available tocolytic drugs.
The trials, published between 1966 and 2021, involved 13,697 women across 39 countries and included high, middle and low-income states. The researchers looked for trials involving women with live fetus(es) who presented with signs and symptoms of preterm labor, defined as uterine activity with or without ruptured membranes; or ruptured membranes, with or without cervical dilatation or shortening or biomarkers consistent with a high risk of preterm birth.
Trials were eligible if they involved tocolytic drugs of any dosage, route, or regimen for delaying preterm birth, and compared them with other tocolytic drugs, placebo, or no treatment.
The team reported that overall, the evidence varied widely in quality, and their confidence in the effect estimates ranged from very low to high. Only 25 of the 122 studies (20%) were judged to be at “low risk of bias.” The effectiveness of different drugs was less clear in some of the studies considered.
Compared with the use of placebo or no tocolytic treatment, “all tocolytic drug classes assessed and their combinations were probably or possibly effective in delaying preterm birth for 48 hours, and 7 days,” the researchers found. “The most effective tocolytics for delaying preterm birth by 48 hours and 7 days were the nitric oxide donors, calcium channel blockers, oxytocin receptor antagonists, and combination tocolytics.”
Their figures showed:
- Betamimetics are possibly effective in delaying preterm birth by 48 hours (risk ratio [RR] 1.12), and 7 days (RR 1.14).
- Calcium channel blockers (for example, nifedipine) may be effective in delaying preterm birth by 48 hours (RR 1.16), and probably effective in delaying preterm birth by 7 days (RR 1.15), and prolong pregnancy by a mean of 5 days (0.1 to 9.2).
- Magnesium sulphate is probably effective in delaying preterm birth by 48 hours (RR 1.12).
- Oxytocin receptor antagonists (e.g., atosiban) are effective in delaying preterm birth by 7 days (RR 1.18), are probably effective in delaying preterm birth by 48 hours (RR 1.13), and possibly prolong pregnancy by an average of 10 days (95% confidence interval, 2.3 to 16.7).
- Nitric oxide donors (e.g., glyceryl trinitrate) are probably effective in delaying preterm birth by 48 hours (RR 1.17), and 7 days (RR 1.18).
- Cyclooxygenase-2 inhibitors (e.g., indomethacin) may be effective in delaying preterm birth by 48 hours (RR 1.11).
- Combination tocolytics – most common was magnesium sulphate with betamimetics - are probably effective effective in delaying preterm birth by 48 hours (RR 1.17), and 7 days (RR 1.19).
Uncertain mortality outcomes and a wide range of adverse effects
However, the effects of tocolytic use on neonatal and perinatal mortality, and on safety outcomes such as maternal and neonatal infection, were “uncertain,” the researchers said, and the drugs proved compatible with a wide range of effects compared with placebo or no tocolytic treatment for these outcomes.
“All tocolytics were compatible with a wide range of serious adverse effects (trials including 6,983 women) when compared with placebo or no treatment,” the researchers said. Betamimetics and combination tocolytics had the most side effects and were most likely to lead to cessation of treatment (results from 8,122 women).
Overall, “the findings show that the benefits of these drugs outweigh any risks associated with unwanted side effects,” said first author Amie Wilson, PhD, research fellow in global maternal health at the University of Birmingham. “These treatments are leading to a significant reduction in the number of deadly preterm births, and we now need to further understand the effectiveness of tocolytics for specific groups depending on pregnancy length,” she said.
“Our previous research has led to the improvement of guidelines for use of tocolysis drug use to delay preterm birth in the U.K. Knowing that this paper helped to inform the forthcoming recommendations of the World Health Organisation on the use of tocolytics, we hope that many more women around the globe will have access to these drugs, and have healthier births.”
A version of this article first appeared on Medscape UK.
New research from the University of Birmingham, England, in collaboration with the World Health Organization, shows that tocolytic drugs used to delay preterm birth, and thus avert the ensuing associated mortality and morbidity, are all “probably effective in delaying preterm birth compared with placebo or no treatment.”
Expanded use of the drugs would be a safe means to reduce the global burden of neonatal death, the researchers suggest. Coauthor Victoria Hodgetts Morton, BMedSci, NIHR clinical lecturer in obstetrics at the University of Birmingham, said: “Preterm birth is the most common reason why a newborn baby may die, and the leading cause of death in children under 5 years of age.
“Tocolytics aim to delay preterm birth and allow time for the women to receive medicines that can help with baby’s breathing and feeding if born preterm, and medicines that lower the chance of cerebral palsy of the infant. Crucially, a short delay in preterm birth can enable women to reach specialist care.”
Network meta‐analysis drew on 122 trials
The new paper, published in Cochrane Reviews, aimed to find out which tocolytic was most effective in delaying preterm birth, safest, and with the fewest side effects. Researchers brought together data from 122 randomized clinical trials in a network meta‐analysis.
Unlike conventional Cochrane Reviews, this type of review simultaneously pools all direct and indirect evidence into one single coherent analysis. Indirect evidence is obtained by inferring the relative effectiveness of two competing drugs through a common comparator, even when these two drugs have not been directly compared. The method also enables researchers to calculate the probability for each competing drug to constitute the most effective drug with the least side effects. This thereby allowed the researchers to rank the available tocolytic drugs.
The trials, published between 1966 and 2021, involved 13,697 women across 39 countries and included high, middle and low-income states. The researchers looked for trials involving women with live fetus(es) who presented with signs and symptoms of preterm labor, defined as uterine activity with or without ruptured membranes; or ruptured membranes, with or without cervical dilatation or shortening or biomarkers consistent with a high risk of preterm birth.
Trials were eligible if they involved tocolytic drugs of any dosage, route, or regimen for delaying preterm birth, and compared them with other tocolytic drugs, placebo, or no treatment.
The team reported that overall, the evidence varied widely in quality, and their confidence in the effect estimates ranged from very low to high. Only 25 of the 122 studies (20%) were judged to be at “low risk of bias.” The effectiveness of different drugs was less clear in some of the studies considered.
Compared with the use of placebo or no tocolytic treatment, “all tocolytic drug classes assessed and their combinations were probably or possibly effective in delaying preterm birth for 48 hours, and 7 days,” the researchers found. “The most effective tocolytics for delaying preterm birth by 48 hours and 7 days were the nitric oxide donors, calcium channel blockers, oxytocin receptor antagonists, and combination tocolytics.”
Their figures showed:
- Betamimetics are possibly effective in delaying preterm birth by 48 hours (risk ratio [RR] 1.12), and 7 days (RR 1.14).
- Calcium channel blockers (for example, nifedipine) may be effective in delaying preterm birth by 48 hours (RR 1.16), and probably effective in delaying preterm birth by 7 days (RR 1.15), and prolong pregnancy by a mean of 5 days (0.1 to 9.2).
- Magnesium sulphate is probably effective in delaying preterm birth by 48 hours (RR 1.12).
- Oxytocin receptor antagonists (e.g., atosiban) are effective in delaying preterm birth by 7 days (RR 1.18), are probably effective in delaying preterm birth by 48 hours (RR 1.13), and possibly prolong pregnancy by an average of 10 days (95% confidence interval, 2.3 to 16.7).
- Nitric oxide donors (e.g., glyceryl trinitrate) are probably effective in delaying preterm birth by 48 hours (RR 1.17), and 7 days (RR 1.18).
- Cyclooxygenase-2 inhibitors (e.g., indomethacin) may be effective in delaying preterm birth by 48 hours (RR 1.11).
- Combination tocolytics – most common was magnesium sulphate with betamimetics - are probably effective effective in delaying preterm birth by 48 hours (RR 1.17), and 7 days (RR 1.19).
Uncertain mortality outcomes and a wide range of adverse effects
However, the effects of tocolytic use on neonatal and perinatal mortality, and on safety outcomes such as maternal and neonatal infection, were “uncertain,” the researchers said, and the drugs proved compatible with a wide range of effects compared with placebo or no tocolytic treatment for these outcomes.
“All tocolytics were compatible with a wide range of serious adverse effects (trials including 6,983 women) when compared with placebo or no treatment,” the researchers said. Betamimetics and combination tocolytics had the most side effects and were most likely to lead to cessation of treatment (results from 8,122 women).
Overall, “the findings show that the benefits of these drugs outweigh any risks associated with unwanted side effects,” said first author Amie Wilson, PhD, research fellow in global maternal health at the University of Birmingham. “These treatments are leading to a significant reduction in the number of deadly preterm births, and we now need to further understand the effectiveness of tocolytics for specific groups depending on pregnancy length,” she said.
“Our previous research has led to the improvement of guidelines for use of tocolysis drug use to delay preterm birth in the U.K. Knowing that this paper helped to inform the forthcoming recommendations of the World Health Organisation on the use of tocolytics, we hope that many more women around the globe will have access to these drugs, and have healthier births.”
A version of this article first appeared on Medscape UK.
New research from the University of Birmingham, England, in collaboration with the World Health Organization, shows that tocolytic drugs used to delay preterm birth, and thus avert the ensuing associated mortality and morbidity, are all “probably effective in delaying preterm birth compared with placebo or no treatment.”
Expanded use of the drugs would be a safe means to reduce the global burden of neonatal death, the researchers suggest. Coauthor Victoria Hodgetts Morton, BMedSci, NIHR clinical lecturer in obstetrics at the University of Birmingham, said: “Preterm birth is the most common reason why a newborn baby may die, and the leading cause of death in children under 5 years of age.
“Tocolytics aim to delay preterm birth and allow time for the women to receive medicines that can help with baby’s breathing and feeding if born preterm, and medicines that lower the chance of cerebral palsy of the infant. Crucially, a short delay in preterm birth can enable women to reach specialist care.”
Network meta‐analysis drew on 122 trials
The new paper, published in Cochrane Reviews, aimed to find out which tocolytic was most effective in delaying preterm birth, safest, and with the fewest side effects. Researchers brought together data from 122 randomized clinical trials in a network meta‐analysis.
Unlike conventional Cochrane Reviews, this type of review simultaneously pools all direct and indirect evidence into one single coherent analysis. Indirect evidence is obtained by inferring the relative effectiveness of two competing drugs through a common comparator, even when these two drugs have not been directly compared. The method also enables researchers to calculate the probability for each competing drug to constitute the most effective drug with the least side effects. This thereby allowed the researchers to rank the available tocolytic drugs.
The trials, published between 1966 and 2021, involved 13,697 women across 39 countries and included high, middle and low-income states. The researchers looked for trials involving women with live fetus(es) who presented with signs and symptoms of preterm labor, defined as uterine activity with or without ruptured membranes; or ruptured membranes, with or without cervical dilatation or shortening or biomarkers consistent with a high risk of preterm birth.
Trials were eligible if they involved tocolytic drugs of any dosage, route, or regimen for delaying preterm birth, and compared them with other tocolytic drugs, placebo, or no treatment.
The team reported that overall, the evidence varied widely in quality, and their confidence in the effect estimates ranged from very low to high. Only 25 of the 122 studies (20%) were judged to be at “low risk of bias.” The effectiveness of different drugs was less clear in some of the studies considered.
Compared with the use of placebo or no tocolytic treatment, “all tocolytic drug classes assessed and their combinations were probably or possibly effective in delaying preterm birth for 48 hours, and 7 days,” the researchers found. “The most effective tocolytics for delaying preterm birth by 48 hours and 7 days were the nitric oxide donors, calcium channel blockers, oxytocin receptor antagonists, and combination tocolytics.”
Their figures showed:
- Betamimetics are possibly effective in delaying preterm birth by 48 hours (risk ratio [RR] 1.12), and 7 days (RR 1.14).
- Calcium channel blockers (for example, nifedipine) may be effective in delaying preterm birth by 48 hours (RR 1.16), and probably effective in delaying preterm birth by 7 days (RR 1.15), and prolong pregnancy by a mean of 5 days (0.1 to 9.2).
- Magnesium sulphate is probably effective in delaying preterm birth by 48 hours (RR 1.12).
- Oxytocin receptor antagonists (e.g., atosiban) are effective in delaying preterm birth by 7 days (RR 1.18), are probably effective in delaying preterm birth by 48 hours (RR 1.13), and possibly prolong pregnancy by an average of 10 days (95% confidence interval, 2.3 to 16.7).
- Nitric oxide donors (e.g., glyceryl trinitrate) are probably effective in delaying preterm birth by 48 hours (RR 1.17), and 7 days (RR 1.18).
- Cyclooxygenase-2 inhibitors (e.g., indomethacin) may be effective in delaying preterm birth by 48 hours (RR 1.11).
- Combination tocolytics – most common was magnesium sulphate with betamimetics - are probably effective effective in delaying preterm birth by 48 hours (RR 1.17), and 7 days (RR 1.19).
Uncertain mortality outcomes and a wide range of adverse effects
However, the effects of tocolytic use on neonatal and perinatal mortality, and on safety outcomes such as maternal and neonatal infection, were “uncertain,” the researchers said, and the drugs proved compatible with a wide range of effects compared with placebo or no tocolytic treatment for these outcomes.
“All tocolytics were compatible with a wide range of serious adverse effects (trials including 6,983 women) when compared with placebo or no treatment,” the researchers said. Betamimetics and combination tocolytics had the most side effects and were most likely to lead to cessation of treatment (results from 8,122 women).
Overall, “the findings show that the benefits of these drugs outweigh any risks associated with unwanted side effects,” said first author Amie Wilson, PhD, research fellow in global maternal health at the University of Birmingham. “These treatments are leading to a significant reduction in the number of deadly preterm births, and we now need to further understand the effectiveness of tocolytics for specific groups depending on pregnancy length,” she said.
“Our previous research has led to the improvement of guidelines for use of tocolysis drug use to delay preterm birth in the U.K. Knowing that this paper helped to inform the forthcoming recommendations of the World Health Organisation on the use of tocolytics, we hope that many more women around the globe will have access to these drugs, and have healthier births.”
A version of this article first appeared on Medscape UK.
FROM COCHRANE REVIEWS
Low-level light therapy cap shows subtle effects on CCCA
though the treatment effects from a small prospective trial appear to be subtle.
Central centrifugal cicatricial alopecia (CCCA) is a form of scarring hair loss with unknown etiology and no known cure that affects mainly women of African descent.
“The low-level light therapy (LLLT) cap does indeed seem to help with symptoms and mild regrowth in CCCA,” senior study author Amy J. McMichael, MD, told this news organization. “The dual-wavelength cap we used appears to have anti-inflammatory properties, and that makes sense for a primarily inflammatory scarring from of alopecia.
“Quality of life improved with the treatment and there were no reported side effects,” added Dr. McMichael, professor of dermatology at Wake Forest University, Winston-Salem, N.C.
The results of the study were presented in a poster at the annual meeting of the Society for Investigative Dermatology.
The REVIAN RED cap (REVIAN Inc.) used in the study contains 119 light-emitting diodes (LEDs) arrayed on the cap’s interior surface that emit orange (620 nm) and red (660 nm) light.
The hypothesis for how the dual-wavelength lights work is that light is absorbed by the chromophore cytochrome c oxidase in the mitochondrial membrane. This induces the release of nitric oxide and the production of adenosine triphosphate (ATP), which leads to vasodilation, cytokine regulation, and increased transcription and release of growth factors.
LLLT is approved to treat androgenetic alopecia, the authors wrote, but has not been studied as a treatment for CCCA.
To assess the effects of LLLT on CCCA, Dr. McMichael and her colleagues at Wake Forest followed the condition’s progress in five Black women over their 6-month course of treatment. Four participants completed the study.
At baseline, all participants had been on individual stable CCCA treatment regimens for at least 3 months. They continued those treatments along with LLLT therapy throughout the study. The women ranged in age from 38 to 69 years, had had CCCA for an average of 12 years, and their disease severity ranged from stage IIB to IVA.
They were instructed to wear the REVIAN RED cap with the LEDs activated for 10 minutes each day.
At 2, 4, and 6 months, participants self-assessed their symptoms, a clinician evaluated the condition’s severity, and digital photographs were taken.
At 6 months:
- Three patients showed improved Dermatology Life Quality Index (DLQI).
- Three patients showed decreased loss of follicular openings and breakage.
- A dermoscopic image of the scalp of one patient revealed short, regrowing vellus hairs and minimal interfollicular and perifollicular scale.
- No patients reported side effects.
Small study raises big questions
“I hope this study will lead to a larger study that will look at the long-term outcomes of CCCA,” Dr. McMichael said. “This is a nice treatment that does not require application of something to the scalp that may affect hair styling, and it has no systemic side effects.”
Dr. McMichael acknowledges that the small sample size, participants continuing with their individual stable treatments while also undergoing light therapy, and the lack of patients with stage I disease, are weaknesses in the study.
“However, the strength is that none of the patients had side effects or stopped using the treatment due to difficulty with the system,” she added.
Dr. McMichael said she would like to investigate the effects of longer use of the cap and whether the cap can be used to prevent CCCA.
Chesahna Kindred, MD, assistant professor of dermatology at Howard University, Washington, D.C., and founder of Kindred Hair & Skin Center in Columbia, Md., told this news organization that she uses LLLT in her practice.
“I find that LLLT is mildly helpful, or at least does not worsen, androgenetic alopecia,” she said.
“Interestingly, while all four patients had stable disease upon initiating the study, it appears as though two of the four worsened after the use of LLLT, one improved, and one remained relatively stable,” noted Dr. Kindred, who was not involved in the study. “This is important because once there is complete destruction of the follicle, CCCA is difficult to improve.
“Given that there are several options to address inflammation and follicular damage in CCCA, more studies are needed before I would incorporate LLLT into my regular treatment algorithms,” she added.
“Studies like this are important and remind us to not lump all forms of hair loss together,” she said.
REVIAN Inc. provided the caps, but the study received no additional funding. Dr. McMichael and Dr. Kindred report relevant financial relationships with the pharmaceutical industry. Study coauthors have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
though the treatment effects from a small prospective trial appear to be subtle.
Central centrifugal cicatricial alopecia (CCCA) is a form of scarring hair loss with unknown etiology and no known cure that affects mainly women of African descent.
“The low-level light therapy (LLLT) cap does indeed seem to help with symptoms and mild regrowth in CCCA,” senior study author Amy J. McMichael, MD, told this news organization. “The dual-wavelength cap we used appears to have anti-inflammatory properties, and that makes sense for a primarily inflammatory scarring from of alopecia.
“Quality of life improved with the treatment and there were no reported side effects,” added Dr. McMichael, professor of dermatology at Wake Forest University, Winston-Salem, N.C.
The results of the study were presented in a poster at the annual meeting of the Society for Investigative Dermatology.
The REVIAN RED cap (REVIAN Inc.) used in the study contains 119 light-emitting diodes (LEDs) arrayed on the cap’s interior surface that emit orange (620 nm) and red (660 nm) light.
The hypothesis for how the dual-wavelength lights work is that light is absorbed by the chromophore cytochrome c oxidase in the mitochondrial membrane. This induces the release of nitric oxide and the production of adenosine triphosphate (ATP), which leads to vasodilation, cytokine regulation, and increased transcription and release of growth factors.
LLLT is approved to treat androgenetic alopecia, the authors wrote, but has not been studied as a treatment for CCCA.
To assess the effects of LLLT on CCCA, Dr. McMichael and her colleagues at Wake Forest followed the condition’s progress in five Black women over their 6-month course of treatment. Four participants completed the study.
At baseline, all participants had been on individual stable CCCA treatment regimens for at least 3 months. They continued those treatments along with LLLT therapy throughout the study. The women ranged in age from 38 to 69 years, had had CCCA for an average of 12 years, and their disease severity ranged from stage IIB to IVA.
They were instructed to wear the REVIAN RED cap with the LEDs activated for 10 minutes each day.
At 2, 4, and 6 months, participants self-assessed their symptoms, a clinician evaluated the condition’s severity, and digital photographs were taken.
At 6 months:
- Three patients showed improved Dermatology Life Quality Index (DLQI).
- Three patients showed decreased loss of follicular openings and breakage.
- A dermoscopic image of the scalp of one patient revealed short, regrowing vellus hairs and minimal interfollicular and perifollicular scale.
- No patients reported side effects.
Small study raises big questions
“I hope this study will lead to a larger study that will look at the long-term outcomes of CCCA,” Dr. McMichael said. “This is a nice treatment that does not require application of something to the scalp that may affect hair styling, and it has no systemic side effects.”
Dr. McMichael acknowledges that the small sample size, participants continuing with their individual stable treatments while also undergoing light therapy, and the lack of patients with stage I disease, are weaknesses in the study.
“However, the strength is that none of the patients had side effects or stopped using the treatment due to difficulty with the system,” she added.
Dr. McMichael said she would like to investigate the effects of longer use of the cap and whether the cap can be used to prevent CCCA.
Chesahna Kindred, MD, assistant professor of dermatology at Howard University, Washington, D.C., and founder of Kindred Hair & Skin Center in Columbia, Md., told this news organization that she uses LLLT in her practice.
“I find that LLLT is mildly helpful, or at least does not worsen, androgenetic alopecia,” she said.
“Interestingly, while all four patients had stable disease upon initiating the study, it appears as though two of the four worsened after the use of LLLT, one improved, and one remained relatively stable,” noted Dr. Kindred, who was not involved in the study. “This is important because once there is complete destruction of the follicle, CCCA is difficult to improve.
“Given that there are several options to address inflammation and follicular damage in CCCA, more studies are needed before I would incorporate LLLT into my regular treatment algorithms,” she added.
“Studies like this are important and remind us to not lump all forms of hair loss together,” she said.
REVIAN Inc. provided the caps, but the study received no additional funding. Dr. McMichael and Dr. Kindred report relevant financial relationships with the pharmaceutical industry. Study coauthors have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
though the treatment effects from a small prospective trial appear to be subtle.
Central centrifugal cicatricial alopecia (CCCA) is a form of scarring hair loss with unknown etiology and no known cure that affects mainly women of African descent.
“The low-level light therapy (LLLT) cap does indeed seem to help with symptoms and mild regrowth in CCCA,” senior study author Amy J. McMichael, MD, told this news organization. “The dual-wavelength cap we used appears to have anti-inflammatory properties, and that makes sense for a primarily inflammatory scarring from of alopecia.
“Quality of life improved with the treatment and there were no reported side effects,” added Dr. McMichael, professor of dermatology at Wake Forest University, Winston-Salem, N.C.
The results of the study were presented in a poster at the annual meeting of the Society for Investigative Dermatology.
The REVIAN RED cap (REVIAN Inc.) used in the study contains 119 light-emitting diodes (LEDs) arrayed on the cap’s interior surface that emit orange (620 nm) and red (660 nm) light.
The hypothesis for how the dual-wavelength lights work is that light is absorbed by the chromophore cytochrome c oxidase in the mitochondrial membrane. This induces the release of nitric oxide and the production of adenosine triphosphate (ATP), which leads to vasodilation, cytokine regulation, and increased transcription and release of growth factors.
LLLT is approved to treat androgenetic alopecia, the authors wrote, but has not been studied as a treatment for CCCA.
To assess the effects of LLLT on CCCA, Dr. McMichael and her colleagues at Wake Forest followed the condition’s progress in five Black women over their 6-month course of treatment. Four participants completed the study.
At baseline, all participants had been on individual stable CCCA treatment regimens for at least 3 months. They continued those treatments along with LLLT therapy throughout the study. The women ranged in age from 38 to 69 years, had had CCCA for an average of 12 years, and their disease severity ranged from stage IIB to IVA.
They were instructed to wear the REVIAN RED cap with the LEDs activated for 10 minutes each day.
At 2, 4, and 6 months, participants self-assessed their symptoms, a clinician evaluated the condition’s severity, and digital photographs were taken.
At 6 months:
- Three patients showed improved Dermatology Life Quality Index (DLQI).
- Three patients showed decreased loss of follicular openings and breakage.
- A dermoscopic image of the scalp of one patient revealed short, regrowing vellus hairs and minimal interfollicular and perifollicular scale.
- No patients reported side effects.
Small study raises big questions
“I hope this study will lead to a larger study that will look at the long-term outcomes of CCCA,” Dr. McMichael said. “This is a nice treatment that does not require application of something to the scalp that may affect hair styling, and it has no systemic side effects.”
Dr. McMichael acknowledges that the small sample size, participants continuing with their individual stable treatments while also undergoing light therapy, and the lack of patients with stage I disease, are weaknesses in the study.
“However, the strength is that none of the patients had side effects or stopped using the treatment due to difficulty with the system,” she added.
Dr. McMichael said she would like to investigate the effects of longer use of the cap and whether the cap can be used to prevent CCCA.
Chesahna Kindred, MD, assistant professor of dermatology at Howard University, Washington, D.C., and founder of Kindred Hair & Skin Center in Columbia, Md., told this news organization that she uses LLLT in her practice.
“I find that LLLT is mildly helpful, or at least does not worsen, androgenetic alopecia,” she said.
“Interestingly, while all four patients had stable disease upon initiating the study, it appears as though two of the four worsened after the use of LLLT, one improved, and one remained relatively stable,” noted Dr. Kindred, who was not involved in the study. “This is important because once there is complete destruction of the follicle, CCCA is difficult to improve.
“Given that there are several options to address inflammation and follicular damage in CCCA, more studies are needed before I would incorporate LLLT into my regular treatment algorithms,” she added.
“Studies like this are important and remind us to not lump all forms of hair loss together,” she said.
REVIAN Inc. provided the caps, but the study received no additional funding. Dr. McMichael and Dr. Kindred report relevant financial relationships with the pharmaceutical industry. Study coauthors have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
FROM SID 2022
More than 64% of younger adults with lung cancer diagnosed at later stages
Advances have been made in earlier diagnosis and better overall survival among older patients with lung cancer, but younger adults have not experienced the same benefit, according to a new study.
The improvements in patients aged 55-80 are likely associated with the introduction in 2013 of low dose computed tomography lung cancer screening.
“It was unknown whether young adults diagnosed with lung cancer, who are ineligible for screening, have experienced a similar shift to earlier stages of lung cancer. While previous studies have shown that young adults diagnosed with lung cancer have distinct tumor characteristics and survival compared to older adults diagnosed with lung cancer, no study has examined whether recent improvements in early diagnosis and survival among older adults with lung cancer extend to younger adults diagnosed with lung cancer,” study coauthor Alexandra Potter told this news organization.
The study was presented by Chi-Fu Jeffrey Yang, MD, at a press conference held at the World Conference on Lung Cancer. Dr. Yang is a thoracic surgeon at Massachusetts General Hospital, Boston.
The difference might be explained by difference in tumor biology, as younger adults are often diagnosed with more aggressive cancers. Other factors include delayed diagnosis and a lack of early detection strategies for this population. Older patients likely benefited from the onset of lung cancer screening, as well as an increase in non-screening chest CT use in hospital settings, which may lead to more incidental diagnoses, according to Ms. Potter, a research assistant Massachusetts General Hospital and president of the American Lung Cancer Screening Initiative.
Investigators found that about three in four lung cancer diagnoses among adults aged 20-29 were stage IV disease, and only 8% in that group were stage I. “I was surprised” by the high frequency of stage IV cancer, said Ms. Potter. “I would also highlight that there has been no improvement in early diagnosis among patients aged 20-49 during the study period,” she added.
And : Five-year survival was 10%-15% among patients diagnosed at age 20-49 with stage IV cancer. “More research is needed to better understand the risk factors, diagnosis, treatment, and survival of lung cancer in young adults,” Ms. Potter said.
There are strategies in development, including biomarkers, machine learning analysis of CT scans, and risk prediction models, but none have yet borne fruit. “Once we are able to [identify high-risk young adults], this will allow us to offer lung cancer screening to these young adults who are at high risk for developing lung cancer,” Ms. Potter said.
Study methodology
The researchers analyzed data from the United States Cancer Statistics (USCS) database and the National Cancer Database (NCDB). They included patients aged 20-79 diagnosed with non–small cell lung cancer (NSCLC) between 2010 and 2018. The study included 1,328 individuals aged 20-29, 5,682 men and women aged 30-39, 39,323 individuals aged 40-49, 202,709 aged 50-59, 410,482 aged 60-69, and 447,366 aged 70-79.
Stage IV diagnoses were most common in the youngest group (76% versus 8% stage I), and steadily declined with age 30-39 (70% versus 10%), age 40-49 (60% versus 14%), 50-59 (52%versus 19%), 60-69 (45% versus 25%), and 70-79 (40% versus 25%; P < .001). The trend reversed among patients aged 80-89, with 45% of patients diagnosed with stage IV cancer, though the rising trend of stage I diagnoses continued at 29%. Between 2010 and 2018, there was a statistically significant increase in stage IV diagnoses among those aged 40-49, and a decrease among those aged 50-59, 60-69, and 70-79.
Five-year overall survival was lowest among patients aged 20-29 at 20%. It was 27%-28% among each 10-year age group up to age 69, then dropped to 24% among those aged 70-79 (P < .001).
The study was limited by a lack of data on disease-free or recurrence-free survival, as well as use of biomarkers or targeted therapy. Ms. Potter has no relevant financial disclosures. The conference was sponsored by the International Association for the Study of Lung Cancer.
Advances have been made in earlier diagnosis and better overall survival among older patients with lung cancer, but younger adults have not experienced the same benefit, according to a new study.
The improvements in patients aged 55-80 are likely associated with the introduction in 2013 of low dose computed tomography lung cancer screening.
“It was unknown whether young adults diagnosed with lung cancer, who are ineligible for screening, have experienced a similar shift to earlier stages of lung cancer. While previous studies have shown that young adults diagnosed with lung cancer have distinct tumor characteristics and survival compared to older adults diagnosed with lung cancer, no study has examined whether recent improvements in early diagnosis and survival among older adults with lung cancer extend to younger adults diagnosed with lung cancer,” study coauthor Alexandra Potter told this news organization.
The study was presented by Chi-Fu Jeffrey Yang, MD, at a press conference held at the World Conference on Lung Cancer. Dr. Yang is a thoracic surgeon at Massachusetts General Hospital, Boston.
The difference might be explained by difference in tumor biology, as younger adults are often diagnosed with more aggressive cancers. Other factors include delayed diagnosis and a lack of early detection strategies for this population. Older patients likely benefited from the onset of lung cancer screening, as well as an increase in non-screening chest CT use in hospital settings, which may lead to more incidental diagnoses, according to Ms. Potter, a research assistant Massachusetts General Hospital and president of the American Lung Cancer Screening Initiative.
Investigators found that about three in four lung cancer diagnoses among adults aged 20-29 were stage IV disease, and only 8% in that group were stage I. “I was surprised” by the high frequency of stage IV cancer, said Ms. Potter. “I would also highlight that there has been no improvement in early diagnosis among patients aged 20-49 during the study period,” she added.
And : Five-year survival was 10%-15% among patients diagnosed at age 20-49 with stage IV cancer. “More research is needed to better understand the risk factors, diagnosis, treatment, and survival of lung cancer in young adults,” Ms. Potter said.
There are strategies in development, including biomarkers, machine learning analysis of CT scans, and risk prediction models, but none have yet borne fruit. “Once we are able to [identify high-risk young adults], this will allow us to offer lung cancer screening to these young adults who are at high risk for developing lung cancer,” Ms. Potter said.
Study methodology
The researchers analyzed data from the United States Cancer Statistics (USCS) database and the National Cancer Database (NCDB). They included patients aged 20-79 diagnosed with non–small cell lung cancer (NSCLC) between 2010 and 2018. The study included 1,328 individuals aged 20-29, 5,682 men and women aged 30-39, 39,323 individuals aged 40-49, 202,709 aged 50-59, 410,482 aged 60-69, and 447,366 aged 70-79.
Stage IV diagnoses were most common in the youngest group (76% versus 8% stage I), and steadily declined with age 30-39 (70% versus 10%), age 40-49 (60% versus 14%), 50-59 (52%versus 19%), 60-69 (45% versus 25%), and 70-79 (40% versus 25%; P < .001). The trend reversed among patients aged 80-89, with 45% of patients diagnosed with stage IV cancer, though the rising trend of stage I diagnoses continued at 29%. Between 2010 and 2018, there was a statistically significant increase in stage IV diagnoses among those aged 40-49, and a decrease among those aged 50-59, 60-69, and 70-79.
Five-year overall survival was lowest among patients aged 20-29 at 20%. It was 27%-28% among each 10-year age group up to age 69, then dropped to 24% among those aged 70-79 (P < .001).
The study was limited by a lack of data on disease-free or recurrence-free survival, as well as use of biomarkers or targeted therapy. Ms. Potter has no relevant financial disclosures. The conference was sponsored by the International Association for the Study of Lung Cancer.
Advances have been made in earlier diagnosis and better overall survival among older patients with lung cancer, but younger adults have not experienced the same benefit, according to a new study.
The improvements in patients aged 55-80 are likely associated with the introduction in 2013 of low dose computed tomography lung cancer screening.
“It was unknown whether young adults diagnosed with lung cancer, who are ineligible for screening, have experienced a similar shift to earlier stages of lung cancer. While previous studies have shown that young adults diagnosed with lung cancer have distinct tumor characteristics and survival compared to older adults diagnosed with lung cancer, no study has examined whether recent improvements in early diagnosis and survival among older adults with lung cancer extend to younger adults diagnosed with lung cancer,” study coauthor Alexandra Potter told this news organization.
The study was presented by Chi-Fu Jeffrey Yang, MD, at a press conference held at the World Conference on Lung Cancer. Dr. Yang is a thoracic surgeon at Massachusetts General Hospital, Boston.
The difference might be explained by difference in tumor biology, as younger adults are often diagnosed with more aggressive cancers. Other factors include delayed diagnosis and a lack of early detection strategies for this population. Older patients likely benefited from the onset of lung cancer screening, as well as an increase in non-screening chest CT use in hospital settings, which may lead to more incidental diagnoses, according to Ms. Potter, a research assistant Massachusetts General Hospital and president of the American Lung Cancer Screening Initiative.
Investigators found that about three in four lung cancer diagnoses among adults aged 20-29 were stage IV disease, and only 8% in that group were stage I. “I was surprised” by the high frequency of stage IV cancer, said Ms. Potter. “I would also highlight that there has been no improvement in early diagnosis among patients aged 20-49 during the study period,” she added.
And : Five-year survival was 10%-15% among patients diagnosed at age 20-49 with stage IV cancer. “More research is needed to better understand the risk factors, diagnosis, treatment, and survival of lung cancer in young adults,” Ms. Potter said.
There are strategies in development, including biomarkers, machine learning analysis of CT scans, and risk prediction models, but none have yet borne fruit. “Once we are able to [identify high-risk young adults], this will allow us to offer lung cancer screening to these young adults who are at high risk for developing lung cancer,” Ms. Potter said.
Study methodology
The researchers analyzed data from the United States Cancer Statistics (USCS) database and the National Cancer Database (NCDB). They included patients aged 20-79 diagnosed with non–small cell lung cancer (NSCLC) between 2010 and 2018. The study included 1,328 individuals aged 20-29, 5,682 men and women aged 30-39, 39,323 individuals aged 40-49, 202,709 aged 50-59, 410,482 aged 60-69, and 447,366 aged 70-79.
Stage IV diagnoses were most common in the youngest group (76% versus 8% stage I), and steadily declined with age 30-39 (70% versus 10%), age 40-49 (60% versus 14%), 50-59 (52%versus 19%), 60-69 (45% versus 25%), and 70-79 (40% versus 25%; P < .001). The trend reversed among patients aged 80-89, with 45% of patients diagnosed with stage IV cancer, though the rising trend of stage I diagnoses continued at 29%. Between 2010 and 2018, there was a statistically significant increase in stage IV diagnoses among those aged 40-49, and a decrease among those aged 50-59, 60-69, and 70-79.
Five-year overall survival was lowest among patients aged 20-29 at 20%. It was 27%-28% among each 10-year age group up to age 69, then dropped to 24% among those aged 70-79 (P < .001).
The study was limited by a lack of data on disease-free or recurrence-free survival, as well as use of biomarkers or targeted therapy. Ms. Potter has no relevant financial disclosures. The conference was sponsored by the International Association for the Study of Lung Cancer.
FROM WCLC 2022
Early PT for lower back pain sends fewer patients to specialists
The study found that patients who were referred to physical therapists within 2 weeks of seeing their physicians for LBP were significantly less likely to make visits to a chiropractor, pain specialist, or orthopedist.
Patients also filed fewer claims for advanced imaging or epidural steroid injections and were half as likely to visit an emergency department (ED) within 30 days compared with those who did not start early physical therapy (PT), according to the study, published in BMC Health Services Research.
“Some lower back pain resolves itself, but often, that recovery is incomplete, leading to increased health care and opioid use,” said Richard L. Skolasky Jr., ScD, director of the Spine Outcomes Research Center at Johns Hopkins Medicine, Baltimore, and a coauthor of the study. “Our hope is this study helps more primary care physicians embrace nonpharmacologic, first-line treatments.”
LBP accounts for an estimated $1.8 billion annually in health care costs among the patients who do not receive surgery for the condition, according to a 2019 JAMA analysis of commercial insurance and Medicare claims. In addition, LBP accounts for approximately 2.7 million ED visits annually, a 2010 study published in Spine showed.
Dr. Skolasky and his colleagues assessed 980,000 outpatient claims over a period of almost 4 years that ended in 2014. The researchers used Truven MarketScan, a group of U.S.-based administrative commercial health care insurance claims databases. Patients who had a history of conditions that cause LBP, such as endometriosis and spinal fracture, were excluded from the analysis. Approximately 11% of patients in the total sample received early PT, defined as PT received within 2 weeks of their initial visit to a primary care clinician.
After adjustment for sex, age, and Charlson Morbidity Index, patients who received PT were about half as likely as were those who didn’t to see chiropractor or a pain specialist or have an ED visit within 30 days of their initial appointment. They were about one-third as likely to receive an epidural steroid injection, and they were 43% less likely to have claims for advanced imaging, according to the researchers (P < .001 for all).
In addition, the cost of claims was lower for patients who received early PT ($747 vs. $799), the researchers found.
The effects diminished somewhat over time but remained statistically significant.
At 1 year, patients who received early PT had slightly higher health care costs than did those who did not undergo PT ($2,588 vs. $2,510). Dr. Skolasky hypothesized that the increase was attributable to therapy visits and not having as many specialist visits. He said additional research could investigate whether early PT reduces the health care costs associated with LBP over a longer period.
“Physical therapy addresses a patient’s current pain and physical limitations and arms them with resources, exercises, and nonpharmacologic ways to deal with recurrences,” Dr. Skolasky said in an interview. “If we can follow patients even longer than a year, we may see a longer-term reduction in cost.”
Michael Knight, MD, associate chief quality and population health officer at George Washington University Medical Faculty Associates, Washington, said he refers patients to physical therapists if their pain has not resolved within 2 weeks of stretching at home and taking over-the-counter analgesics.
Dr. Knight recalled one patient who had strained her back doing yard work. When home exercises did not help, Dr. Knight referred her to a physical therapist, who created a customized treatment plan. Within 4 weeks, her condition had improved.
“She was then able to take what she learned and continue those exercises at home,” Dr. Knight said. “She got better, and we avoided MRI costs for her and the health care system.”
Dr. Skolasky and his fellow researchers found significant regional differences in the number of patients referred for early PT. The odds of PT utilization within 90 days after the onset of LBP were 1.6 times higher in the Northeast and 0.82 times lower in the South.
“There are health care deserts,” Dr. Skolasky said. “This study should spark a conversation about the inadequacy of distribution of physical resources to meet the needs of patients with LBP.”
Dr. Skolasky said telehealth could be one option for serving patients in these health care deserts – including those with LBP. He has conducted several studies that concluded that patients benefit from and are happy with telehealth PT.
Dr. Knight said Dr. Skolasky’s study will help patients better understand their options.
“Sometimes patients have an expectation – they want an MRI or pain medication when it’s not necessary,” he said. “This kind of evidence helps strengthen our recommendation for early intervention that really can help.”
The study was supported by a grant from the National Institutes of Health’s National Institute on Aging. Dr. Skolasky reports no relevant financial relationships.
A version of this article first appeared on Medscape.com.
The study found that patients who were referred to physical therapists within 2 weeks of seeing their physicians for LBP were significantly less likely to make visits to a chiropractor, pain specialist, or orthopedist.
Patients also filed fewer claims for advanced imaging or epidural steroid injections and were half as likely to visit an emergency department (ED) within 30 days compared with those who did not start early physical therapy (PT), according to the study, published in BMC Health Services Research.
“Some lower back pain resolves itself, but often, that recovery is incomplete, leading to increased health care and opioid use,” said Richard L. Skolasky Jr., ScD, director of the Spine Outcomes Research Center at Johns Hopkins Medicine, Baltimore, and a coauthor of the study. “Our hope is this study helps more primary care physicians embrace nonpharmacologic, first-line treatments.”
LBP accounts for an estimated $1.8 billion annually in health care costs among the patients who do not receive surgery for the condition, according to a 2019 JAMA analysis of commercial insurance and Medicare claims. In addition, LBP accounts for approximately 2.7 million ED visits annually, a 2010 study published in Spine showed.
Dr. Skolasky and his colleagues assessed 980,000 outpatient claims over a period of almost 4 years that ended in 2014. The researchers used Truven MarketScan, a group of U.S.-based administrative commercial health care insurance claims databases. Patients who had a history of conditions that cause LBP, such as endometriosis and spinal fracture, were excluded from the analysis. Approximately 11% of patients in the total sample received early PT, defined as PT received within 2 weeks of their initial visit to a primary care clinician.
After adjustment for sex, age, and Charlson Morbidity Index, patients who received PT were about half as likely as were those who didn’t to see chiropractor or a pain specialist or have an ED visit within 30 days of their initial appointment. They were about one-third as likely to receive an epidural steroid injection, and they were 43% less likely to have claims for advanced imaging, according to the researchers (P < .001 for all).
In addition, the cost of claims was lower for patients who received early PT ($747 vs. $799), the researchers found.
The effects diminished somewhat over time but remained statistically significant.
At 1 year, patients who received early PT had slightly higher health care costs than did those who did not undergo PT ($2,588 vs. $2,510). Dr. Skolasky hypothesized that the increase was attributable to therapy visits and not having as many specialist visits. He said additional research could investigate whether early PT reduces the health care costs associated with LBP over a longer period.
“Physical therapy addresses a patient’s current pain and physical limitations and arms them with resources, exercises, and nonpharmacologic ways to deal with recurrences,” Dr. Skolasky said in an interview. “If we can follow patients even longer than a year, we may see a longer-term reduction in cost.”
Michael Knight, MD, associate chief quality and population health officer at George Washington University Medical Faculty Associates, Washington, said he refers patients to physical therapists if their pain has not resolved within 2 weeks of stretching at home and taking over-the-counter analgesics.
Dr. Knight recalled one patient who had strained her back doing yard work. When home exercises did not help, Dr. Knight referred her to a physical therapist, who created a customized treatment plan. Within 4 weeks, her condition had improved.
“She was then able to take what she learned and continue those exercises at home,” Dr. Knight said. “She got better, and we avoided MRI costs for her and the health care system.”
Dr. Skolasky and his fellow researchers found significant regional differences in the number of patients referred for early PT. The odds of PT utilization within 90 days after the onset of LBP were 1.6 times higher in the Northeast and 0.82 times lower in the South.
“There are health care deserts,” Dr. Skolasky said. “This study should spark a conversation about the inadequacy of distribution of physical resources to meet the needs of patients with LBP.”
Dr. Skolasky said telehealth could be one option for serving patients in these health care deserts – including those with LBP. He has conducted several studies that concluded that patients benefit from and are happy with telehealth PT.
Dr. Knight said Dr. Skolasky’s study will help patients better understand their options.
“Sometimes patients have an expectation – they want an MRI or pain medication when it’s not necessary,” he said. “This kind of evidence helps strengthen our recommendation for early intervention that really can help.”
The study was supported by a grant from the National Institutes of Health’s National Institute on Aging. Dr. Skolasky reports no relevant financial relationships.
A version of this article first appeared on Medscape.com.
The study found that patients who were referred to physical therapists within 2 weeks of seeing their physicians for LBP were significantly less likely to make visits to a chiropractor, pain specialist, or orthopedist.
Patients also filed fewer claims for advanced imaging or epidural steroid injections and were half as likely to visit an emergency department (ED) within 30 days compared with those who did not start early physical therapy (PT), according to the study, published in BMC Health Services Research.
“Some lower back pain resolves itself, but often, that recovery is incomplete, leading to increased health care and opioid use,” said Richard L. Skolasky Jr., ScD, director of the Spine Outcomes Research Center at Johns Hopkins Medicine, Baltimore, and a coauthor of the study. “Our hope is this study helps more primary care physicians embrace nonpharmacologic, first-line treatments.”
LBP accounts for an estimated $1.8 billion annually in health care costs among the patients who do not receive surgery for the condition, according to a 2019 JAMA analysis of commercial insurance and Medicare claims. In addition, LBP accounts for approximately 2.7 million ED visits annually, a 2010 study published in Spine showed.
Dr. Skolasky and his colleagues assessed 980,000 outpatient claims over a period of almost 4 years that ended in 2014. The researchers used Truven MarketScan, a group of U.S.-based administrative commercial health care insurance claims databases. Patients who had a history of conditions that cause LBP, such as endometriosis and spinal fracture, were excluded from the analysis. Approximately 11% of patients in the total sample received early PT, defined as PT received within 2 weeks of their initial visit to a primary care clinician.
After adjustment for sex, age, and Charlson Morbidity Index, patients who received PT were about half as likely as were those who didn’t to see chiropractor or a pain specialist or have an ED visit within 30 days of their initial appointment. They were about one-third as likely to receive an epidural steroid injection, and they were 43% less likely to have claims for advanced imaging, according to the researchers (P < .001 for all).
In addition, the cost of claims was lower for patients who received early PT ($747 vs. $799), the researchers found.
The effects diminished somewhat over time but remained statistically significant.
At 1 year, patients who received early PT had slightly higher health care costs than did those who did not undergo PT ($2,588 vs. $2,510). Dr. Skolasky hypothesized that the increase was attributable to therapy visits and not having as many specialist visits. He said additional research could investigate whether early PT reduces the health care costs associated with LBP over a longer period.
“Physical therapy addresses a patient’s current pain and physical limitations and arms them with resources, exercises, and nonpharmacologic ways to deal with recurrences,” Dr. Skolasky said in an interview. “If we can follow patients even longer than a year, we may see a longer-term reduction in cost.”
Michael Knight, MD, associate chief quality and population health officer at George Washington University Medical Faculty Associates, Washington, said he refers patients to physical therapists if their pain has not resolved within 2 weeks of stretching at home and taking over-the-counter analgesics.
Dr. Knight recalled one patient who had strained her back doing yard work. When home exercises did not help, Dr. Knight referred her to a physical therapist, who created a customized treatment plan. Within 4 weeks, her condition had improved.
“She was then able to take what she learned and continue those exercises at home,” Dr. Knight said. “She got better, and we avoided MRI costs for her and the health care system.”
Dr. Skolasky and his fellow researchers found significant regional differences in the number of patients referred for early PT. The odds of PT utilization within 90 days after the onset of LBP were 1.6 times higher in the Northeast and 0.82 times lower in the South.
“There are health care deserts,” Dr. Skolasky said. “This study should spark a conversation about the inadequacy of distribution of physical resources to meet the needs of patients with LBP.”
Dr. Skolasky said telehealth could be one option for serving patients in these health care deserts – including those with LBP. He has conducted several studies that concluded that patients benefit from and are happy with telehealth PT.
Dr. Knight said Dr. Skolasky’s study will help patients better understand their options.
“Sometimes patients have an expectation – they want an MRI or pain medication when it’s not necessary,” he said. “This kind of evidence helps strengthen our recommendation for early intervention that really can help.”
The study was supported by a grant from the National Institutes of Health’s National Institute on Aging. Dr. Skolasky reports no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Commentary: Comparing Migraine Treatments, August 2022
Migraine is a unique neurologic condition, in that a person can't prove they have it and there are few objective tools neurologists have to guide their diagnostic process. The recognition of the role of the vasoactive peptide calcitonin gene-related peptide (CGRP) in the 1990s changed the way many researchers and clinicians conceptualized migraine. Subsequent studies have used CGRP as a human model for migraine, and most recently pituitary adenylate cyclase–activating polypeptide 38 (PACAP-38) has also been recognized for its important role in migraine propagation. All of the existing data have been in adults, and no studies until now have specifically investigated the presence of these peptides in children with migraine.
Pediatric migraine is unique in a number of ways. Children with migraine present less unilaterally, the duration of their attacks is typically shorter, and the associated symptoms can often be more prominent than the headache pain during an attack. There are unique pediatric migraine subtypes that are exceptionally rare in adults, such as periodic paralysis attacks and abdominal migraine. For this reason, it is not entirely clear whether the same biomarkers of disease in adults would also be present in the pediatric population.
In the study by Liu and colleagues, the investigators enrolled 76 pediatric patients with migraine (the diagnosis was confirmed by at least two neurologists). Patients were excluded if there was any analgesic medication use over the past 2 months; if there was concern for secondary headache; or any underlying mood disorders, congenital disease, or other major medical conditions. An additional 77 controls were matched for age and sex. Blood was collected from all participants after an 8-hour fast to avoid collecting after potentially ingesting a food trigger. Blood samples were obtained during an ictal period (within 8 hours of a migraine attack) as well as interictally (not taken if the participant had a migraine attack within the past 24 hours).
The plasma CGRP and PACAP-38 levels were significantly higher in pediatric patients with migraine than in those without a migraine history, in both the ictal state and the interictal state. Among patients with migraine, there was a nonsignificant trend toward a higher CGRP level in the ictal phase, and no difference in these phases with PACAP-38. There was no difference in the CGRP or PACAP-38 levels between participants with and those without aura. When different aura groups were compared (with the participants separated on the basis of a history of motor vs vision vs sensory aura), no difference was seen among the different aura groups. Binary logistic regression testing and analysis of variance also showed that CGRP and PACAP-38 are independent risk factors for pediatric migraine, and specific levels of each were associated with an 11 and a 13 times increased risk, respectively.
Biomarker testing is still not clinically performed for migraine either in adults or children. This is primarily due to cost and the fact that most commercially available laboratories do not currently offer these tests. The results above do shed additional light on migraine pathogenesis and indicate that the phenotypic differences seen in pediatric migraine are less likely related to differences in brain function in children.
Levetiracetam is a commonly used antiepileptic medication. Prior studies have investigated the use of this medication for migraine, both acutely and preventively. Other antiepileptic medications have been shown to be very effective for both of these indications. Topiramate and valproic acid are both commonly used for migraine: topiramate primarily preventively and valproic acid both for prevention and, commonly in its intravenous form, for acute treatment. Levetiracetam is currently not commonly used for migraine, although some institutions will use the intravenous formulation for severe refractory status migrainosus.
Evers and colleagues investigated the open label use of levetiracetam for migraine prevention at a dose of 1000 mg twice daily in a small population of 50 persons. The study participants were started at a dose of 500 mg twice daily for 4 weeks, then increased to 1000 mg twice daily for a total of 12 weeks. The primary endpoint was migraine attack frequency during the last 4 weeks of treatment.
A 50% reduction in headache frequency was seen in 46% of the enrolled participants. The most common reported side effects were sedation, nausea, and weight gain, as well as cognitive change (five patients dropped out of the study owing to intolerance of the treatment). A post hoc comparison between the patients with and without response to levetiracetam revealed that those who responded were those with a less refractory history — they had tried fewer medications and were using fewer acute medications as well.
The antiepileptic class of preventive migraine medications is notorious for issues with tolerance. Among the antiepileptic medications, levetiracetam is commonly used but also commonly stopped owing to mood and cognitive complaints. Although the researchers here do show early evidence for a moderate amount of efficacy for treating migraine, the fact that there are now more migraine-specific preventive medications that are better tolerated and overall more efficacious make choosing levetiracetam for prevention less necessary.
Now that there are multiple classes of migraine-specific acute medications, the outstanding question remains: What are the potential benefits and drawbacks for the use of triptans compared with the oral CGRP receptor antagonists (gepants)? Most obviously, triptan medications are contraindicated in patients with significant vascular risk factors; however, what is not known is whether some of the other adverse events associated with triptans are more or less prominent with gepant use. Lee and colleagues conducted a meta-analysis of 15 studies to review this data.
A previous meta-analysis demonstrated that oral CGRP receptor antagonists are more effective than placebo, but less effective than triptans against acute migraine. The most common intolerances for gepants are nausea, somnolence, and dry mouth, but the safety and tolerability of gepants have not been compared with that of triptans. These authors pooled the data on five gepant medications (BI44370TA, MK-3207, rimegepant, telcagepant, and ubrogepant). The primary outcome was incidence of treatment-related adverse events and the secondary outcome was the incidence of the specific intolerances of diarrhea, dizziness, dry mouth, fatigue, nausea, paresthesia, somnolence, upper abdominal pain, and vomiting.
Compared with placebo, the relative risk for any adverse event was found to be low, at 1.15, and the relative risk for treatment-related adverse events was only slightly higher, at 1.18. Gepants were found to be significantly more associated with an increased risk for fatigue, nausea, and somnolence vs placebo. Compared with triptans, the CGRP antagonists were associated with significantly less treatment-related adverse events as well as any adverse event. There was no significant difference in the incidence of diarrhea, nausea, and vomiting between the two groups.
This study helps elucidate some of the differences between the two classes of migraine-specific acute medications. As noted above, a prior meta-analysis did reveal some benefits with the triptan class, specifically better effectiveness. When choosing a better-tolerated medication for your patients, you may want to consider a gepant; when considering a stronger or more potent option, you might stick with a triptan.
Migraine is a unique neurologic condition, in that a person can't prove they have it and there are few objective tools neurologists have to guide their diagnostic process. The recognition of the role of the vasoactive peptide calcitonin gene-related peptide (CGRP) in the 1990s changed the way many researchers and clinicians conceptualized migraine. Subsequent studies have used CGRP as a human model for migraine, and most recently pituitary adenylate cyclase–activating polypeptide 38 (PACAP-38) has also been recognized for its important role in migraine propagation. All of the existing data have been in adults, and no studies until now have specifically investigated the presence of these peptides in children with migraine.
Pediatric migraine is unique in a number of ways. Children with migraine present less unilaterally, the duration of their attacks is typically shorter, and the associated symptoms can often be more prominent than the headache pain during an attack. There are unique pediatric migraine subtypes that are exceptionally rare in adults, such as periodic paralysis attacks and abdominal migraine. For this reason, it is not entirely clear whether the same biomarkers of disease in adults would also be present in the pediatric population.
In the study by Liu and colleagues, the investigators enrolled 76 pediatric patients with migraine (the diagnosis was confirmed by at least two neurologists). Patients were excluded if there was any analgesic medication use over the past 2 months; if there was concern for secondary headache; or any underlying mood disorders, congenital disease, or other major medical conditions. An additional 77 controls were matched for age and sex. Blood was collected from all participants after an 8-hour fast to avoid collecting after potentially ingesting a food trigger. Blood samples were obtained during an ictal period (within 8 hours of a migraine attack) as well as interictally (not taken if the participant had a migraine attack within the past 24 hours).
The plasma CGRP and PACAP-38 levels were significantly higher in pediatric patients with migraine than in those without a migraine history, in both the ictal state and the interictal state. Among patients with migraine, there was a nonsignificant trend toward a higher CGRP level in the ictal phase, and no difference in these phases with PACAP-38. There was no difference in the CGRP or PACAP-38 levels between participants with and those without aura. When different aura groups were compared (with the participants separated on the basis of a history of motor vs vision vs sensory aura), no difference was seen among the different aura groups. Binary logistic regression testing and analysis of variance also showed that CGRP and PACAP-38 are independent risk factors for pediatric migraine, and specific levels of each were associated with an 11 and a 13 times increased risk, respectively.
Biomarker testing is still not clinically performed for migraine either in adults or children. This is primarily due to cost and the fact that most commercially available laboratories do not currently offer these tests. The results above do shed additional light on migraine pathogenesis and indicate that the phenotypic differences seen in pediatric migraine are less likely related to differences in brain function in children.
Levetiracetam is a commonly used antiepileptic medication. Prior studies have investigated the use of this medication for migraine, both acutely and preventively. Other antiepileptic medications have been shown to be very effective for both of these indications. Topiramate and valproic acid are both commonly used for migraine: topiramate primarily preventively and valproic acid both for prevention and, commonly in its intravenous form, for acute treatment. Levetiracetam is currently not commonly used for migraine, although some institutions will use the intravenous formulation for severe refractory status migrainosus.
Evers and colleagues investigated the open label use of levetiracetam for migraine prevention at a dose of 1000 mg twice daily in a small population of 50 persons. The study participants were started at a dose of 500 mg twice daily for 4 weeks, then increased to 1000 mg twice daily for a total of 12 weeks. The primary endpoint was migraine attack frequency during the last 4 weeks of treatment.
A 50% reduction in headache frequency was seen in 46% of the enrolled participants. The most common reported side effects were sedation, nausea, and weight gain, as well as cognitive change (five patients dropped out of the study owing to intolerance of the treatment). A post hoc comparison between the patients with and without response to levetiracetam revealed that those who responded were those with a less refractory history — they had tried fewer medications and were using fewer acute medications as well.
The antiepileptic class of preventive migraine medications is notorious for issues with tolerance. Among the antiepileptic medications, levetiracetam is commonly used but also commonly stopped owing to mood and cognitive complaints. Although the researchers here do show early evidence for a moderate amount of efficacy for treating migraine, the fact that there are now more migraine-specific preventive medications that are better tolerated and overall more efficacious make choosing levetiracetam for prevention less necessary.
Now that there are multiple classes of migraine-specific acute medications, the outstanding question remains: What are the potential benefits and drawbacks for the use of triptans compared with the oral CGRP receptor antagonists (gepants)? Most obviously, triptan medications are contraindicated in patients with significant vascular risk factors; however, what is not known is whether some of the other adverse events associated with triptans are more or less prominent with gepant use. Lee and colleagues conducted a meta-analysis of 15 studies to review this data.
A previous meta-analysis demonstrated that oral CGRP receptor antagonists are more effective than placebo, but less effective than triptans against acute migraine. The most common intolerances for gepants are nausea, somnolence, and dry mouth, but the safety and tolerability of gepants have not been compared with that of triptans. These authors pooled the data on five gepant medications (BI44370TA, MK-3207, rimegepant, telcagepant, and ubrogepant). The primary outcome was incidence of treatment-related adverse events and the secondary outcome was the incidence of the specific intolerances of diarrhea, dizziness, dry mouth, fatigue, nausea, paresthesia, somnolence, upper abdominal pain, and vomiting.
Compared with placebo, the relative risk for any adverse event was found to be low, at 1.15, and the relative risk for treatment-related adverse events was only slightly higher, at 1.18. Gepants were found to be significantly more associated with an increased risk for fatigue, nausea, and somnolence vs placebo. Compared with triptans, the CGRP antagonists were associated with significantly less treatment-related adverse events as well as any adverse event. There was no significant difference in the incidence of diarrhea, nausea, and vomiting between the two groups.
This study helps elucidate some of the differences between the two classes of migraine-specific acute medications. As noted above, a prior meta-analysis did reveal some benefits with the triptan class, specifically better effectiveness. When choosing a better-tolerated medication for your patients, you may want to consider a gepant; when considering a stronger or more potent option, you might stick with a triptan.
Migraine is a unique neurologic condition, in that a person can't prove they have it and there are few objective tools neurologists have to guide their diagnostic process. The recognition of the role of the vasoactive peptide calcitonin gene-related peptide (CGRP) in the 1990s changed the way many researchers and clinicians conceptualized migraine. Subsequent studies have used CGRP as a human model for migraine, and most recently pituitary adenylate cyclase–activating polypeptide 38 (PACAP-38) has also been recognized for its important role in migraine propagation. All of the existing data have been in adults, and no studies until now have specifically investigated the presence of these peptides in children with migraine.
Pediatric migraine is unique in a number of ways. Children with migraine present less unilaterally, the duration of their attacks is typically shorter, and the associated symptoms can often be more prominent than the headache pain during an attack. There are unique pediatric migraine subtypes that are exceptionally rare in adults, such as periodic paralysis attacks and abdominal migraine. For this reason, it is not entirely clear whether the same biomarkers of disease in adults would also be present in the pediatric population.
In the study by Liu and colleagues, the investigators enrolled 76 pediatric patients with migraine (the diagnosis was confirmed by at least two neurologists). Patients were excluded if there was any analgesic medication use over the past 2 months; if there was concern for secondary headache; or any underlying mood disorders, congenital disease, or other major medical conditions. An additional 77 controls were matched for age and sex. Blood was collected from all participants after an 8-hour fast to avoid collecting after potentially ingesting a food trigger. Blood samples were obtained during an ictal period (within 8 hours of a migraine attack) as well as interictally (not taken if the participant had a migraine attack within the past 24 hours).
The plasma CGRP and PACAP-38 levels were significantly higher in pediatric patients with migraine than in those without a migraine history, in both the ictal state and the interictal state. Among patients with migraine, there was a nonsignificant trend toward a higher CGRP level in the ictal phase, and no difference in these phases with PACAP-38. There was no difference in the CGRP or PACAP-38 levels between participants with and those without aura. When different aura groups were compared (with the participants separated on the basis of a history of motor vs vision vs sensory aura), no difference was seen among the different aura groups. Binary logistic regression testing and analysis of variance also showed that CGRP and PACAP-38 are independent risk factors for pediatric migraine, and specific levels of each were associated with an 11 and a 13 times increased risk, respectively.
Biomarker testing is still not clinically performed for migraine either in adults or children. This is primarily due to cost and the fact that most commercially available laboratories do not currently offer these tests. The results above do shed additional light on migraine pathogenesis and indicate that the phenotypic differences seen in pediatric migraine are less likely related to differences in brain function in children.
Levetiracetam is a commonly used antiepileptic medication. Prior studies have investigated the use of this medication for migraine, both acutely and preventively. Other antiepileptic medications have been shown to be very effective for both of these indications. Topiramate and valproic acid are both commonly used for migraine: topiramate primarily preventively and valproic acid both for prevention and, commonly in its intravenous form, for acute treatment. Levetiracetam is currently not commonly used for migraine, although some institutions will use the intravenous formulation for severe refractory status migrainosus.
Evers and colleagues investigated the open label use of levetiracetam for migraine prevention at a dose of 1000 mg twice daily in a small population of 50 persons. The study participants were started at a dose of 500 mg twice daily for 4 weeks, then increased to 1000 mg twice daily for a total of 12 weeks. The primary endpoint was migraine attack frequency during the last 4 weeks of treatment.
A 50% reduction in headache frequency was seen in 46% of the enrolled participants. The most common reported side effects were sedation, nausea, and weight gain, as well as cognitive change (five patients dropped out of the study owing to intolerance of the treatment). A post hoc comparison between the patients with and without response to levetiracetam revealed that those who responded were those with a less refractory history — they had tried fewer medications and were using fewer acute medications as well.
The antiepileptic class of preventive migraine medications is notorious for issues with tolerance. Among the antiepileptic medications, levetiracetam is commonly used but also commonly stopped owing to mood and cognitive complaints. Although the researchers here do show early evidence for a moderate amount of efficacy for treating migraine, the fact that there are now more migraine-specific preventive medications that are better tolerated and overall more efficacious make choosing levetiracetam for prevention less necessary.
Now that there are multiple classes of migraine-specific acute medications, the outstanding question remains: What are the potential benefits and drawbacks for the use of triptans compared with the oral CGRP receptor antagonists (gepants)? Most obviously, triptan medications are contraindicated in patients with significant vascular risk factors; however, what is not known is whether some of the other adverse events associated with triptans are more or less prominent with gepant use. Lee and colleagues conducted a meta-analysis of 15 studies to review this data.
A previous meta-analysis demonstrated that oral CGRP receptor antagonists are more effective than placebo, but less effective than triptans against acute migraine. The most common intolerances for gepants are nausea, somnolence, and dry mouth, but the safety and tolerability of gepants have not been compared with that of triptans. These authors pooled the data on five gepant medications (BI44370TA, MK-3207, rimegepant, telcagepant, and ubrogepant). The primary outcome was incidence of treatment-related adverse events and the secondary outcome was the incidence of the specific intolerances of diarrhea, dizziness, dry mouth, fatigue, nausea, paresthesia, somnolence, upper abdominal pain, and vomiting.
Compared with placebo, the relative risk for any adverse event was found to be low, at 1.15, and the relative risk for treatment-related adverse events was only slightly higher, at 1.18. Gepants were found to be significantly more associated with an increased risk for fatigue, nausea, and somnolence vs placebo. Compared with triptans, the CGRP antagonists were associated with significantly less treatment-related adverse events as well as any adverse event. There was no significant difference in the incidence of diarrhea, nausea, and vomiting between the two groups.
This study helps elucidate some of the differences between the two classes of migraine-specific acute medications. As noted above, a prior meta-analysis did reveal some benefits with the triptan class, specifically better effectiveness. When choosing a better-tolerated medication for your patients, you may want to consider a gepant; when considering a stronger or more potent option, you might stick with a triptan.
Commentary: Concomitant Therapies May Affect NSCLC Survival, August 2022
A Danish population-based cohort study by Ehrenstein and colleagues involved 21,282 patients with non–small-cell lung cancer (NSCLC), 8758 of whom received a diagnosis at stage I-IIIA. Of those, 4071 (46%) were tested for epidermal growth factor receptor (EGFR) mutations at diagnosis. Median overall survival (OS) was 5.7 years among patients with EGFR mutation–positive status (n = 361) and 4.4 years among patients with EGFR mutation–negative status (n = 3710). EGFR mutation–positive status was associated with lower all-cause mortality in all subgroups. This is not surprising, because EGFR-mutated lung cancers are associated with never or light smoking history and the patients tend to be younger and have fewer medical comorbidities. Nevertheless, the lower risk for all-cause mortality was consistent across all subgroups (stage at diagnosis, age, sex, comorbidity, and surgery receipt), with hazard ratios (HR) ranging from 0.48 to 0.83. In addition, targeted therapies, such as osimertinib, improved OS and progression-free survival (PFS) in the metastatic setting as first-line treatment. Now that the ADAURA study has demonstrated a substantial disease-free survival benefit with osimertinib in the adjuvant setting in early-stage EGFR-mutated NSCLC (with final OS results still to come) it will be interesting to see whether this magnitude of difference in OS grows over time.
Wang and colleagues conducted a large meta-analysis of 10 retrospective studies and one prospective study including a total of 5892 patients with NSCLC who were receiving programmed cell death protein 1 (PD-1)/ programmed death-ligand 1 (PD-L1) inhibitors with the concomitant use of gastric acid suppressants (GAS). Use of PD-1/PD-L1 inhibitors with vs without GAS worsened PFS by 32% (HR 1.32; P < .001) and OS by 36% (HR 1.36; P < .001). The GAS in these studies were predominantly proton-pump inhibitors (PPI). There is still much to learn about medications that may influence outcomes to immune checkpoint blockade, such as steroids, antibiotics, GAS, and others. We are also learning that the microbiome probably plays an important role in contributing to activity of PD-1/PDL-1 antibodies and PPI may modify the microbiome. More research is needed, but it is reasonable to try and switch patients receiving PD-1/PDL-1 inhibitors from PPI to other GAS, if clinically appropriate.
Nazha and colleagues performed a SEER-Medicare database analysis evaluating 367,750 patients with lung cancer. A total of 11,061 patients had an initial prostate cancer diagnosis and subsequent lung cancer diagnosis, 3017 had an initial lung cancer diagnosis and subsequent prostate cancer diagnosis, and the remaining patients had an isolated lung cancer diagnosis. Patients who received androgen deprivation therapy (ADT) for a previously diagnosed prostate cancer showed improved survival after lung cancer diagnosis (adjusted HR for death 0.88; P = .02) and a shorter latency period to the diagnosis of lung cancer (40 vs 47 months; P < .001) compared with those who did not receive ADT. This finding applied mainly to White patients and may not apply to Black patients because there was an underrepresentation of Black patients in the study. The association of ADT for prostate cancer improving clinical outcomes in patients subsequently diagnosed with lung cancer is intriguing. There is known crosstalk between receptor kinase signaling and androgen receptor signaling that may biologically explain the findings in this study. This theoretically could apply more to certain molecular subtypes of lung cancer, such as EGFR-mutated lung cancer. However, further studies are needed to confirm this because confounding factors and immortal time bias (where patients receiving ADT may be more likely to have more frequent interactions in the healthcare system and thus receive an earlier lung cancer diagnosis) may in part explain the findings in this retrospective analysis. More research is needed to determine whether patients with prostate cancer receiving ADT had improved survival compared with those who did not receive ADT.
A Danish population-based cohort study by Ehrenstein and colleagues involved 21,282 patients with non–small-cell lung cancer (NSCLC), 8758 of whom received a diagnosis at stage I-IIIA. Of those, 4071 (46%) were tested for epidermal growth factor receptor (EGFR) mutations at diagnosis. Median overall survival (OS) was 5.7 years among patients with EGFR mutation–positive status (n = 361) and 4.4 years among patients with EGFR mutation–negative status (n = 3710). EGFR mutation–positive status was associated with lower all-cause mortality in all subgroups. This is not surprising, because EGFR-mutated lung cancers are associated with never or light smoking history and the patients tend to be younger and have fewer medical comorbidities. Nevertheless, the lower risk for all-cause mortality was consistent across all subgroups (stage at diagnosis, age, sex, comorbidity, and surgery receipt), with hazard ratios (HR) ranging from 0.48 to 0.83. In addition, targeted therapies, such as osimertinib, improved OS and progression-free survival (PFS) in the metastatic setting as first-line treatment. Now that the ADAURA study has demonstrated a substantial disease-free survival benefit with osimertinib in the adjuvant setting in early-stage EGFR-mutated NSCLC (with final OS results still to come) it will be interesting to see whether this magnitude of difference in OS grows over time.
Wang and colleagues conducted a large meta-analysis of 10 retrospective studies and one prospective study including a total of 5892 patients with NSCLC who were receiving programmed cell death protein 1 (PD-1)/ programmed death-ligand 1 (PD-L1) inhibitors with the concomitant use of gastric acid suppressants (GAS). Use of PD-1/PD-L1 inhibitors with vs without GAS worsened PFS by 32% (HR 1.32; P < .001) and OS by 36% (HR 1.36; P < .001). The GAS in these studies were predominantly proton-pump inhibitors (PPI). There is still much to learn about medications that may influence outcomes to immune checkpoint blockade, such as steroids, antibiotics, GAS, and others. We are also learning that the microbiome probably plays an important role in contributing to activity of PD-1/PDL-1 antibodies and PPI may modify the microbiome. More research is needed, but it is reasonable to try and switch patients receiving PD-1/PDL-1 inhibitors from PPI to other GAS, if clinically appropriate.
Nazha and colleagues performed a SEER-Medicare database analysis evaluating 367,750 patients with lung cancer. A total of 11,061 patients had an initial prostate cancer diagnosis and subsequent lung cancer diagnosis, 3017 had an initial lung cancer diagnosis and subsequent prostate cancer diagnosis, and the remaining patients had an isolated lung cancer diagnosis. Patients who received androgen deprivation therapy (ADT) for a previously diagnosed prostate cancer showed improved survival after lung cancer diagnosis (adjusted HR for death 0.88; P = .02) and a shorter latency period to the diagnosis of lung cancer (40 vs 47 months; P < .001) compared with those who did not receive ADT. This finding applied mainly to White patients and may not apply to Black patients because there was an underrepresentation of Black patients in the study. The association of ADT for prostate cancer improving clinical outcomes in patients subsequently diagnosed with lung cancer is intriguing. There is known crosstalk between receptor kinase signaling and androgen receptor signaling that may biologically explain the findings in this study. This theoretically could apply more to certain molecular subtypes of lung cancer, such as EGFR-mutated lung cancer. However, further studies are needed to confirm this because confounding factors and immortal time bias (where patients receiving ADT may be more likely to have more frequent interactions in the healthcare system and thus receive an earlier lung cancer diagnosis) may in part explain the findings in this retrospective analysis. More research is needed to determine whether patients with prostate cancer receiving ADT had improved survival compared with those who did not receive ADT.
A Danish population-based cohort study by Ehrenstein and colleagues involved 21,282 patients with non–small-cell lung cancer (NSCLC), 8758 of whom received a diagnosis at stage I-IIIA. Of those, 4071 (46%) were tested for epidermal growth factor receptor (EGFR) mutations at diagnosis. Median overall survival (OS) was 5.7 years among patients with EGFR mutation–positive status (n = 361) and 4.4 years among patients with EGFR mutation–negative status (n = 3710). EGFR mutation–positive status was associated with lower all-cause mortality in all subgroups. This is not surprising, because EGFR-mutated lung cancers are associated with never or light smoking history and the patients tend to be younger and have fewer medical comorbidities. Nevertheless, the lower risk for all-cause mortality was consistent across all subgroups (stage at diagnosis, age, sex, comorbidity, and surgery receipt), with hazard ratios (HR) ranging from 0.48 to 0.83. In addition, targeted therapies, such as osimertinib, improved OS and progression-free survival (PFS) in the metastatic setting as first-line treatment. Now that the ADAURA study has demonstrated a substantial disease-free survival benefit with osimertinib in the adjuvant setting in early-stage EGFR-mutated NSCLC (with final OS results still to come) it will be interesting to see whether this magnitude of difference in OS grows over time.
Wang and colleagues conducted a large meta-analysis of 10 retrospective studies and one prospective study including a total of 5892 patients with NSCLC who were receiving programmed cell death protein 1 (PD-1)/ programmed death-ligand 1 (PD-L1) inhibitors with the concomitant use of gastric acid suppressants (GAS). Use of PD-1/PD-L1 inhibitors with vs without GAS worsened PFS by 32% (HR 1.32; P < .001) and OS by 36% (HR 1.36; P < .001). The GAS in these studies were predominantly proton-pump inhibitors (PPI). There is still much to learn about medications that may influence outcomes to immune checkpoint blockade, such as steroids, antibiotics, GAS, and others. We are also learning that the microbiome probably plays an important role in contributing to activity of PD-1/PDL-1 antibodies and PPI may modify the microbiome. More research is needed, but it is reasonable to try and switch patients receiving PD-1/PDL-1 inhibitors from PPI to other GAS, if clinically appropriate.
Nazha and colleagues performed a SEER-Medicare database analysis evaluating 367,750 patients with lung cancer. A total of 11,061 patients had an initial prostate cancer diagnosis and subsequent lung cancer diagnosis, 3017 had an initial lung cancer diagnosis and subsequent prostate cancer diagnosis, and the remaining patients had an isolated lung cancer diagnosis. Patients who received androgen deprivation therapy (ADT) for a previously diagnosed prostate cancer showed improved survival after lung cancer diagnosis (adjusted HR for death 0.88; P = .02) and a shorter latency period to the diagnosis of lung cancer (40 vs 47 months; P < .001) compared with those who did not receive ADT. This finding applied mainly to White patients and may not apply to Black patients because there was an underrepresentation of Black patients in the study. The association of ADT for prostate cancer improving clinical outcomes in patients subsequently diagnosed with lung cancer is intriguing. There is known crosstalk between receptor kinase signaling and androgen receptor signaling that may biologically explain the findings in this study. This theoretically could apply more to certain molecular subtypes of lung cancer, such as EGFR-mutated lung cancer. However, further studies are needed to confirm this because confounding factors and immortal time bias (where patients receiving ADT may be more likely to have more frequent interactions in the healthcare system and thus receive an earlier lung cancer diagnosis) may in part explain the findings in this retrospective analysis. More research is needed to determine whether patients with prostate cancer receiving ADT had improved survival compared with those who did not receive ADT.