Conference Coverage

Among older patients with acute myeloid leukemia (AML), survival is significantly better when they undergo reduced-intensity conditioning (RIC) before receiving an allogeneic hematopoietic cell transplant (HCT) at first remission. This improvement in survival is seen regardless of key factors such as genotype and the status of minimal residual disease (MRD) after initial chemotherapy, results from two large randomized trials show.

“Two consecutive trials of more than 1,500 older AML patients above 60 years of age demonstrate a consistent benefit for RIC transplant in first remission,” said first author Nigel Russell, MD, of Guy’s Hospital, London, and Nottingham University, England. “This benefit is seen independent of their post-course 1 MRD status,” he added.

Dr. Russell presented the new data at the European Hematology Association (EHA) 2021 Annual Meeting.

Commenting on the study, Charles Craddock, MD, said in an interview that the results “confirm the growing importance of RIC transplantation as a central treatment management strategy in high-risk AML and in this population high risk patients over 60.”

“[These findings] reinforce the evolving treatment paradigm that, in fit adults over 60 with AML, hematopoietic cell transplantation should be considered an essential component of their management plan,” said Dr. Craddock, academic director of the Center for Clinical Haematology, Queen Elizabeth Hospital, Birmingham, England.

Patients with AML who are older than 60 years can achieve complete remission with intensive chemotherapy alone; however, relapse is common, and only about 20% survive for 5 years, Dr. Russell explained.

HCT significantly improves survival outcomes, and the development of RIC has made transplantation accessible to high-risk patients by making the procedure more tolerable with lower toxicity in comparison with conventional conditioning regimens.

However, there is ongoing debate over the prognostic effect of key factors in pretransplant conditioning that may be predictive of the risk for post-transplant relapse – in particular, the presence of MRD after the first course of conditioning, he explained.

To more closely investigate those factors and the rate of survival of older patients with AML who undergo RIC transplant, Dr. Russell and his colleagues evaluated results from the National Cancer Research Institute’s (NCRI) AML16 trial, which was conducted from 2006 to 2012, and interim results from the NCRI AML18 trial, which started in 2015 and is ongoing.

Both trials employed double induction of daunorubicin and clofarabine or, in the AML16 trial, AraC ± gemtuzumab, and in the AML18 trial, daunorubicin and AraC (DA) + gemtuzumab.

In AML18, patients who were MRD positive after course 1 were randomly assigned to undergo either an intensification randomization after either FLAG-Ida or DA+cladribine or DA alone.

In AML16, of 983 patients in first complete response, 144 (15%) subsequently underwent RIC transplant. The median follow-up for survival from complete response was 45 months.

In the AML18 trial, of 847 patients, 648 patients achieved complete response. Among them, 201 (31%) underwent transplant. The median follow-up of survival was 45 months.

The results of both trials showed greater benefit with RIC transplant versus chemotherapy alone.

In the AML16 trial, among patients aged 60 to 70 who received RIC, survival at 5 years was significantly improved compared with chemotherapy alone (37% vs. 19%; hazard ratio, 0.65; 95% confidence interval, 0.52-0.82; P < .001).

In AML16, the higher survival benefit in comparison with chemotherapy alone was observed in the RIC group across subgroups of risk level, as stratified according to in the multivariate Wheatley risk group score. Subgroup stratification was based on age, cytogenics, and other factors (HR, 0.66; 95% CI, 0.53-0.83; P < .001).

Importantly, the survival benefits were significantly greater with RIC transplant regardless of MRD-negative or MRD-positive status after course 1 (HR, 0.68; 95% CI, 0.54-0.85; P < .001).

Allograft transplant was also more favorable regardless of FLT3 ITD or NPM1 mutation status (P for heterogeneity by genetic subgroups, 0.61).

In AML16, no groups were found to have benefited more with RIC. Consequently, the criteria for transplant in AML18 trial were based on patients’ health status and donor availability.

An interim analysis of the ongoing AML 18 trial further underscored an overall benefit of RIC transplant. Rates of 3-year survival from remission were 48% with RIC transplant, versus 37.4% with chemotherapy alone (P = .027). The benefit was independent of MRD status after conditioning course 1, similar to the AML16 results (HR, 0.71; 95% CI, 0.54-0.95; P = .02).

Although the rate of transplantation in the AML18 trial was higher among patients who were MRD positive in comparison with those who were MRD negative (36% vs. 24.8%), the rates of post-transplant survival were not significantly different between those who were MRD positive and those who were MRD negative after course 1 (51.1% vs. 46.6% at 3 years; P = .84).

The authors evaluated the effects of a second conditioning course on transplant outcomes among patients who did not initially achieve an MRD-negative complete remission.

They found that 60% of patients did convert from MRD-positive to MRD-negative status after course 2. Among those patients, the survival versus chemotherapy alone was substantially higher (HR, 0.32; 95% CI, 0.11-0.92) compared to those who remained MRD-negative (HR 0.74; 95% CI, 0.32-1.72).

However, the authors note that, owing to a lack of heterogeneity, the results don’t necessarily mean that the patients who remained MRD positive did not also benefit from transplant.

“There was a significant benefit for transplant in those who converted to MRD negativity,” Dr. Russell said.

“With a hazard ratio of .32, this was far superior to those who remained MRD-positive post course 2,” he said.

“These results show that MRD status after course 1 is important information in terms of response to therapy and can alter your treatment strategy if you’re considering a transplant as an option for these patients,” Dr. Russell told this news organization.

In further commenting, Dr. Craddock said the research highlights the importance of randomized trials with regard to whether patients who are MRD-positive before transplant will benefit from an additional course of therapy to reduce the MRD load.

“Most get two courses, but the question is, if they are still MRD positive, should they get a third course, and if so, what should that look like?” he said.

“There are currently no randomized controlled trials to address that ongoing question, and they need to be done,” he added.

Dr. Russell has relationships with Pfizer, Astellas, and Jazz Pharma. Dr. Craddock has a relationship with Bristol-Myers Squibb.

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

Among older patients with acute myeloid leukemia (AML), survival is significantly better when they undergo reduced-intensity conditioning (RIC) before receiving an allogeneic hematopoietic cell transplant (HCT) at first remission. This improvement in survival is seen regardless of key factors such as genotype and the status of minimal residual disease (MRD) after initial chemotherapy, results from two large randomized trials show.

“Two consecutive trials of more than 1,500 older AML patients above 60 years of age demonstrate a consistent benefit for RIC transplant in first remission,” said first author Nigel Russell, MD, of Guy’s Hospital, London, and Nottingham University, England. “This benefit is seen independent of their post-course 1 MRD status,” he added.

Dr. Russell presented the new data at the European Hematology Association (EHA) 2021 Annual Meeting.

Commenting on the study, Charles Craddock, MD, said in an interview that the results “confirm the growing importance of RIC transplantation as a central treatment management strategy in high-risk AML and in this population high risk patients over 60.”

“[These findings] reinforce the evolving treatment paradigm that, in fit adults over 60 with AML, hematopoietic cell transplantation should be considered an essential component of their management plan,” said Dr. Craddock, academic director of the Center for Clinical Haematology, Queen Elizabeth Hospital, Birmingham, England.

Patients with AML who are older than 60 years can achieve complete remission with intensive chemotherapy alone; however, relapse is common, and only about 20% survive for 5 years, Dr. Russell explained.

HCT significantly improves survival outcomes, and the development of RIC has made transplantation accessible to high-risk patients by making the procedure more tolerable with lower toxicity in comparison with conventional conditioning regimens.

However, there is ongoing debate over the prognostic effect of key factors in pretransplant conditioning that may be predictive of the risk for post-transplant relapse – in particular, the presence of MRD after the first course of conditioning, he explained.

To more closely investigate those factors and the rate of survival of older patients with AML who undergo RIC transplant, Dr. Russell and his colleagues evaluated results from the National Cancer Research Institute’s (NCRI) AML16 trial, which was conducted from 2006 to 2012, and interim results from the NCRI AML18 trial, which started in 2015 and is ongoing.

Both trials employed double induction of daunorubicin and clofarabine or, in the AML16 trial, AraC ± gemtuzumab, and in the AML18 trial, daunorubicin and AraC (DA) + gemtuzumab.

In AML18, patients who were MRD positive after course 1 were randomly assigned to undergo either an intensification randomization after either FLAG-Ida or DA+cladribine or DA alone.

In AML16, of 983 patients in first complete response, 144 (15%) subsequently underwent RIC transplant. The median follow-up for survival from complete response was 45 months.

In the AML18 trial, of 847 patients, 648 patients achieved complete response. Among them, 201 (31%) underwent transplant. The median follow-up of survival was 45 months.

The results of both trials showed greater benefit with RIC transplant versus chemotherapy alone.

In the AML16 trial, among patients aged 60 to 70 who received RIC, survival at 5 years was significantly improved compared with chemotherapy alone (37% vs. 19%; hazard ratio, 0.65; 95% confidence interval, 0.52-0.82; P < .001).

In AML16, the higher survival benefit in comparison with chemotherapy alone was observed in the RIC group across subgroups of risk level, as stratified according to in the multivariate Wheatley risk group score. Subgroup stratification was based on age, cytogenics, and other factors (HR, 0.66; 95% CI, 0.53-0.83; P < .001).

Importantly, the survival benefits were significantly greater with RIC transplant regardless of MRD-negative or MRD-positive status after course 1 (HR, 0.68; 95% CI, 0.54-0.85; P < .001).

Allograft transplant was also more favorable regardless of FLT3 ITD or NPM1 mutation status (P for heterogeneity by genetic subgroups, 0.61).

In AML16, no groups were found to have benefited more with RIC. Consequently, the criteria for transplant in AML18 trial were based on patients’ health status and donor availability.

An interim analysis of the ongoing AML 18 trial further underscored an overall benefit of RIC transplant. Rates of 3-year survival from remission were 48% with RIC transplant, versus 37.4% with chemotherapy alone (P = .027). The benefit was independent of MRD status after conditioning course 1, similar to the AML16 results (HR, 0.71; 95% CI, 0.54-0.95; P = .02).

Although the rate of transplantation in the AML18 trial was higher among patients who were MRD positive in comparison with those who were MRD negative (36% vs. 24.8%), the rates of post-transplant survival were not significantly different between those who were MRD positive and those who were MRD negative after course 1 (51.1% vs. 46.6% at 3 years; P = .84).

The authors evaluated the effects of a second conditioning course on transplant outcomes among patients who did not initially achieve an MRD-negative complete remission.

They found that 60% of patients did convert from MRD-positive to MRD-negative status after course 2. Among those patients, the survival versus chemotherapy alone was substantially higher (HR, 0.32; 95% CI, 0.11-0.92) compared to those who remained MRD-negative (HR 0.74; 95% CI, 0.32-1.72).

However, the authors note that, owing to a lack of heterogeneity, the results don’t necessarily mean that the patients who remained MRD positive did not also benefit from transplant.

“There was a significant benefit for transplant in those who converted to MRD negativity,” Dr. Russell said.

“With a hazard ratio of .32, this was far superior to those who remained MRD-positive post course 2,” he said.

“These results show that MRD status after course 1 is important information in terms of response to therapy and can alter your treatment strategy if you’re considering a transplant as an option for these patients,” Dr. Russell told this news organization.

In further commenting, Dr. Craddock said the research highlights the importance of randomized trials with regard to whether patients who are MRD-positive before transplant will benefit from an additional course of therapy to reduce the MRD load.

“Most get two courses, but the question is, if they are still MRD positive, should they get a third course, and if so, what should that look like?” he said.

“There are currently no randomized controlled trials to address that ongoing question, and they need to be done,” he added.

Dr. Russell has relationships with Pfizer, Astellas, and Jazz Pharma. Dr. Craddock has a relationship with Bristol-Myers Squibb.

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

Among older patients with acute myeloid leukemia (AML), survival is significantly better when they undergo reduced-intensity conditioning (RIC) before receiving an allogeneic hematopoietic cell transplant (HCT) at first remission. This improvement in survival is seen regardless of key factors such as genotype and the status of minimal residual disease (MRD) after initial chemotherapy, results from two large randomized trials show.

“Two consecutive trials of more than 1,500 older AML patients above 60 years of age demonstrate a consistent benefit for RIC transplant in first remission,” said first author Nigel Russell, MD, of Guy’s Hospital, London, and Nottingham University, England. “This benefit is seen independent of their post-course 1 MRD status,” he added.

Dr. Russell presented the new data at the European Hematology Association (EHA) 2021 Annual Meeting.

Commenting on the study, Charles Craddock, MD, said in an interview that the results “confirm the growing importance of RIC transplantation as a central treatment management strategy in high-risk AML and in this population high risk patients over 60.”

“[These findings] reinforce the evolving treatment paradigm that, in fit adults over 60 with AML, hematopoietic cell transplantation should be considered an essential component of their management plan,” said Dr. Craddock, academic director of the Center for Clinical Haematology, Queen Elizabeth Hospital, Birmingham, England.

Patients with AML who are older than 60 years can achieve complete remission with intensive chemotherapy alone; however, relapse is common, and only about 20% survive for 5 years, Dr. Russell explained.

HCT significantly improves survival outcomes, and the development of RIC has made transplantation accessible to high-risk patients by making the procedure more tolerable with lower toxicity in comparison with conventional conditioning regimens.

However, there is ongoing debate over the prognostic effect of key factors in pretransplant conditioning that may be predictive of the risk for post-transplant relapse – in particular, the presence of MRD after the first course of conditioning, he explained.

To more closely investigate those factors and the rate of survival of older patients with AML who undergo RIC transplant, Dr. Russell and his colleagues evaluated results from the National Cancer Research Institute’s (NCRI) AML16 trial, which was conducted from 2006 to 2012, and interim results from the NCRI AML18 trial, which started in 2015 and is ongoing.

Both trials employed double induction of daunorubicin and clofarabine or, in the AML16 trial, AraC ± gemtuzumab, and in the AML18 trial, daunorubicin and AraC (DA) + gemtuzumab.

In AML18, patients who were MRD positive after course 1 were randomly assigned to undergo either an intensification randomization after either FLAG-Ida or DA+cladribine or DA alone.

In AML16, of 983 patients in first complete response, 144 (15%) subsequently underwent RIC transplant. The median follow-up for survival from complete response was 45 months.

In the AML18 trial, of 847 patients, 648 patients achieved complete response. Among them, 201 (31%) underwent transplant. The median follow-up of survival was 45 months.

The results of both trials showed greater benefit with RIC transplant versus chemotherapy alone.

In the AML16 trial, among patients aged 60 to 70 who received RIC, survival at 5 years was significantly improved compared with chemotherapy alone (37% vs. 19%; hazard ratio, 0.65; 95% confidence interval, 0.52-0.82; P < .001).

In AML16, the higher survival benefit in comparison with chemotherapy alone was observed in the RIC group across subgroups of risk level, as stratified according to in the multivariate Wheatley risk group score. Subgroup stratification was based on age, cytogenics, and other factors (HR, 0.66; 95% CI, 0.53-0.83; P < .001).

Importantly, the survival benefits were significantly greater with RIC transplant regardless of MRD-negative or MRD-positive status after course 1 (HR, 0.68; 95% CI, 0.54-0.85; P < .001).

Allograft transplant was also more favorable regardless of FLT3 ITD or NPM1 mutation status (P for heterogeneity by genetic subgroups, 0.61).

In AML16, no groups were found to have benefited more with RIC. Consequently, the criteria for transplant in AML18 trial were based on patients’ health status and donor availability.

An interim analysis of the ongoing AML 18 trial further underscored an overall benefit of RIC transplant. Rates of 3-year survival from remission were 48% with RIC transplant, versus 37.4% with chemotherapy alone (P = .027). The benefit was independent of MRD status after conditioning course 1, similar to the AML16 results (HR, 0.71; 95% CI, 0.54-0.95; P = .02).

Although the rate of transplantation in the AML18 trial was higher among patients who were MRD positive in comparison with those who were MRD negative (36% vs. 24.8%), the rates of post-transplant survival were not significantly different between those who were MRD positive and those who were MRD negative after course 1 (51.1% vs. 46.6% at 3 years; P = .84).

The authors evaluated the effects of a second conditioning course on transplant outcomes among patients who did not initially achieve an MRD-negative complete remission.

They found that 60% of patients did convert from MRD-positive to MRD-negative status after course 2. Among those patients, the survival versus chemotherapy alone was substantially higher (HR, 0.32; 95% CI, 0.11-0.92) compared to those who remained MRD-negative (HR 0.74; 95% CI, 0.32-1.72).

However, the authors note that, owing to a lack of heterogeneity, the results don’t necessarily mean that the patients who remained MRD positive did not also benefit from transplant.

“There was a significant benefit for transplant in those who converted to MRD negativity,” Dr. Russell said.

“With a hazard ratio of .32, this was far superior to those who remained MRD-positive post course 2,” he said.

“These results show that MRD status after course 1 is important information in terms of response to therapy and can alter your treatment strategy if you’re considering a transplant as an option for these patients,” Dr. Russell told this news organization.

In further commenting, Dr. Craddock said the research highlights the importance of randomized trials with regard to whether patients who are MRD-positive before transplant will benefit from an additional course of therapy to reduce the MRD load.

“Most get two courses, but the question is, if they are still MRD positive, should they get a third course, and if so, what should that look like?” he said.

“There are currently no randomized controlled trials to address that ongoing question, and they need to be done,” he added.

Dr. Russell has relationships with Pfizer, Astellas, and Jazz Pharma. Dr. Craddock has a relationship with Bristol-Myers Squibb.

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

A biosignature tool helps women avoid unnecessary radiotherapy after undergoing lumpectomy for ductal carcinoma in situ (DCIS) – and also identifies women who need more intense treatment.

The DCISionRT test (PreludeDx) and its response subtype (Rst) biosignature provide personalized risk assessment, explains Frank Vicini, MD, a radiation oncologist at GenesisCare and a member of NRG Oncology, Pontiac, Mich.

He presented data on the test at a poster at the recent American Society of Clinical Oncology Annual Meeting.

This test and biosignature can identify women who are at low risk for recurrence risk and who could potentially forgo radiotherapy after surgery. They can also identify patients who would likely benefit from radiotherapy, Dr. Vicini reported.

The tool shows promise for identifying those whose cancer is likely to recur despite undergoing postlumpectomy radiotherapy – women who might benefit from intensified or alternate treatment approaches, he added.

The latter finding is particularly provocative because it suggests that the biosignatures “may appropriately identify patients with very radioresistant ductal carcinoma in situ,” Benjamin D. Smith, MD, commented during a poster discussion session at the meeting.

“I think these findings merit validation in translational research models,” said Dr. Smith, a radiation oncologist and professor of radiation oncology and health services research at the University of Texas MD Anderson Cancer Center, Houston.
 

DCISionRT, Rst, and risk

DCISionRT combines molecular biology innovations with risk-based scores to assess risk for recurrence, which is classified as either low or elevated, according to the test developer, PreludeDx.

Dr. Vicini and colleagues used the test to classify tissue samples from 485 women who were part of previous DCISionRT validation cohorts in Sweden, Australia, and the United States. The patients underwent breast cancer surgery (BCS) with or without radiotherapy between 1996 and 2011.

The Rst biosignature was used to further categorize those in the elevated-risk group as having a good response subtype (good Rst) or a poor response subtype (poor Rst) after BCS plus radiotherapy.

Radiotherapy was associated with significantly reduced recurrence rates among women with elevated risk and a good Rst (the hazard ratios for ipsilateral breast tumor recurrence [IBTR] and invasive breast cancer [IBC] were 0.18 and 0.15, respectively).

No radiotherapy benefit was seen among those with elevated risk and poor Rst.

The investigators also reported that, among patients with a poor Rst, 10-year IBTR and IBC rates were 25% and 16%, respectively, regardless of whether they received radiotherapy. These rates were much higher than the rates among women with good Rst (6.6% and 4.5%; hazard ratio, 3.6 and 4.4, respectively).

No significant difference was seen in 10-year IBTR and IBC rates among patients in the low-risk group, with or without radiotherapy.

Traditional clinicopathologic risk factors, including age younger than 50 years, grade 3 disease, and tumor size greater than 2.5 cm, did not identify poor versus good response subtypes in this cohort, and on multivariable analysis, neither of these factors nor endocrine therapy was significantly associated with IBTR or IBC.
 

Prospective validation needed

In his discussion, Dr. Smith said that the study provides “important data” that further validate the DCISionRT platform alone for assessing risk among women with DCIS who undergo BCS. But it is the Rst biosignature, which allows clinicians to “predict radioresistance of residual malignant chromogens following lumpectomy plus radiation therapy,” that really stands out, he added.

From the data presented, “it is reasonable to conclude that patients with a poor Rst score treated with lumpectomy and radiation had a much higher risk of in-breast tumor recurrence than one might predict or anticipate based on existing published randomized clinical trial data,” he said.

“In my opinion, it is very important to prospectively validate this finding with other cohorts,” he said. “Moving forward, I think there may come a time where there may be interest in studying radiosensitizing agents for poor-Rst ductal carcinoma in situ that are resistant to standard doses of radiation, and it may be that we consider the Rst as a factor moving forward in selecting patients for BCT versus mastectomy.”

However, because 75% of patients at elevated risk with poor Rst who undergo lumpectomy and radiotherapy do not experience recurrence in the decade following their treatment, it would be “inappropriate and misguided” to start recommending mastectomy for patients at DCISionRT elevated risk who have poor Rst, he said.

The study was funded by PreludeDx. Dr. Vicini reported employment with 21st Century Oncology and financial relationships with ImpediMed, Prelude Therapeutics, and Concure Oncology. Dr. Smith, through his employer, has an equity interest in Oncora Medical through a partnership agreement. He also has an uncompensated relationship with the American Society for Radiation Oncology.

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

A biosignature tool helps women avoid unnecessary radiotherapy after undergoing lumpectomy for ductal carcinoma in situ (DCIS) – and also identifies women who need more intense treatment.

The DCISionRT test (PreludeDx) and its response subtype (Rst) biosignature provide personalized risk assessment, explains Frank Vicini, MD, a radiation oncologist at GenesisCare and a member of NRG Oncology, Pontiac, Mich.

He presented data on the test at a poster at the recent American Society of Clinical Oncology Annual Meeting.

This test and biosignature can identify women who are at low risk for recurrence risk and who could potentially forgo radiotherapy after surgery. They can also identify patients who would likely benefit from radiotherapy, Dr. Vicini reported.

The tool shows promise for identifying those whose cancer is likely to recur despite undergoing postlumpectomy radiotherapy – women who might benefit from intensified or alternate treatment approaches, he added.

The latter finding is particularly provocative because it suggests that the biosignatures “may appropriately identify patients with very radioresistant ductal carcinoma in situ,” Benjamin D. Smith, MD, commented during a poster discussion session at the meeting.

“I think these findings merit validation in translational research models,” said Dr. Smith, a radiation oncologist and professor of radiation oncology and health services research at the University of Texas MD Anderson Cancer Center, Houston.
 

DCISionRT, Rst, and risk

DCISionRT combines molecular biology innovations with risk-based scores to assess risk for recurrence, which is classified as either low or elevated, according to the test developer, PreludeDx.

Dr. Vicini and colleagues used the test to classify tissue samples from 485 women who were part of previous DCISionRT validation cohorts in Sweden, Australia, and the United States. The patients underwent breast cancer surgery (BCS) with or without radiotherapy between 1996 and 2011.

The Rst biosignature was used to further categorize those in the elevated-risk group as having a good response subtype (good Rst) or a poor response subtype (poor Rst) after BCS plus radiotherapy.

Radiotherapy was associated with significantly reduced recurrence rates among women with elevated risk and a good Rst (the hazard ratios for ipsilateral breast tumor recurrence [IBTR] and invasive breast cancer [IBC] were 0.18 and 0.15, respectively).

No radiotherapy benefit was seen among those with elevated risk and poor Rst.

The investigators also reported that, among patients with a poor Rst, 10-year IBTR and IBC rates were 25% and 16%, respectively, regardless of whether they received radiotherapy. These rates were much higher than the rates among women with good Rst (6.6% and 4.5%; hazard ratio, 3.6 and 4.4, respectively).

No significant difference was seen in 10-year IBTR and IBC rates among patients in the low-risk group, with or without radiotherapy.

Traditional clinicopathologic risk factors, including age younger than 50 years, grade 3 disease, and tumor size greater than 2.5 cm, did not identify poor versus good response subtypes in this cohort, and on multivariable analysis, neither of these factors nor endocrine therapy was significantly associated with IBTR or IBC.
 

Prospective validation needed

In his discussion, Dr. Smith said that the study provides “important data” that further validate the DCISionRT platform alone for assessing risk among women with DCIS who undergo BCS. But it is the Rst biosignature, which allows clinicians to “predict radioresistance of residual malignant chromogens following lumpectomy plus radiation therapy,” that really stands out, he added.

From the data presented, “it is reasonable to conclude that patients with a poor Rst score treated with lumpectomy and radiation had a much higher risk of in-breast tumor recurrence than one might predict or anticipate based on existing published randomized clinical trial data,” he said.

“In my opinion, it is very important to prospectively validate this finding with other cohorts,” he said. “Moving forward, I think there may come a time where there may be interest in studying radiosensitizing agents for poor-Rst ductal carcinoma in situ that are resistant to standard doses of radiation, and it may be that we consider the Rst as a factor moving forward in selecting patients for BCT versus mastectomy.”

However, because 75% of patients at elevated risk with poor Rst who undergo lumpectomy and radiotherapy do not experience recurrence in the decade following their treatment, it would be “inappropriate and misguided” to start recommending mastectomy for patients at DCISionRT elevated risk who have poor Rst, he said.

The study was funded by PreludeDx. Dr. Vicini reported employment with 21st Century Oncology and financial relationships with ImpediMed, Prelude Therapeutics, and Concure Oncology. Dr. Smith, through his employer, has an equity interest in Oncora Medical through a partnership agreement. He also has an uncompensated relationship with the American Society for Radiation Oncology.

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

A biosignature tool helps women avoid unnecessary radiotherapy after undergoing lumpectomy for ductal carcinoma in situ (DCIS) – and also identifies women who need more intense treatment.

The DCISionRT test (PreludeDx) and its response subtype (Rst) biosignature provide personalized risk assessment, explains Frank Vicini, MD, a radiation oncologist at GenesisCare and a member of NRG Oncology, Pontiac, Mich.

He presented data on the test at a poster at the recent American Society of Clinical Oncology Annual Meeting.

This test and biosignature can identify women who are at low risk for recurrence risk and who could potentially forgo radiotherapy after surgery. They can also identify patients who would likely benefit from radiotherapy, Dr. Vicini reported.

The tool shows promise for identifying those whose cancer is likely to recur despite undergoing postlumpectomy radiotherapy – women who might benefit from intensified or alternate treatment approaches, he added.

The latter finding is particularly provocative because it suggests that the biosignatures “may appropriately identify patients with very radioresistant ductal carcinoma in situ,” Benjamin D. Smith, MD, commented during a poster discussion session at the meeting.

“I think these findings merit validation in translational research models,” said Dr. Smith, a radiation oncologist and professor of radiation oncology and health services research at the University of Texas MD Anderson Cancer Center, Houston.
 

DCISionRT, Rst, and risk

DCISionRT combines molecular biology innovations with risk-based scores to assess risk for recurrence, which is classified as either low or elevated, according to the test developer, PreludeDx.

Dr. Vicini and colleagues used the test to classify tissue samples from 485 women who were part of previous DCISionRT validation cohorts in Sweden, Australia, and the United States. The patients underwent breast cancer surgery (BCS) with or without radiotherapy between 1996 and 2011.

The Rst biosignature was used to further categorize those in the elevated-risk group as having a good response subtype (good Rst) or a poor response subtype (poor Rst) after BCS plus radiotherapy.

Radiotherapy was associated with significantly reduced recurrence rates among women with elevated risk and a good Rst (the hazard ratios for ipsilateral breast tumor recurrence [IBTR] and invasive breast cancer [IBC] were 0.18 and 0.15, respectively).

No radiotherapy benefit was seen among those with elevated risk and poor Rst.

The investigators also reported that, among patients with a poor Rst, 10-year IBTR and IBC rates were 25% and 16%, respectively, regardless of whether they received radiotherapy. These rates were much higher than the rates among women with good Rst (6.6% and 4.5%; hazard ratio, 3.6 and 4.4, respectively).

No significant difference was seen in 10-year IBTR and IBC rates among patients in the low-risk group, with or without radiotherapy.

Traditional clinicopathologic risk factors, including age younger than 50 years, grade 3 disease, and tumor size greater than 2.5 cm, did not identify poor versus good response subtypes in this cohort, and on multivariable analysis, neither of these factors nor endocrine therapy was significantly associated with IBTR or IBC.
 

Prospective validation needed

In his discussion, Dr. Smith said that the study provides “important data” that further validate the DCISionRT platform alone for assessing risk among women with DCIS who undergo BCS. But it is the Rst biosignature, which allows clinicians to “predict radioresistance of residual malignant chromogens following lumpectomy plus radiation therapy,” that really stands out, he added.

From the data presented, “it is reasonable to conclude that patients with a poor Rst score treated with lumpectomy and radiation had a much higher risk of in-breast tumor recurrence than one might predict or anticipate based on existing published randomized clinical trial data,” he said.

“In my opinion, it is very important to prospectively validate this finding with other cohorts,” he said. “Moving forward, I think there may come a time where there may be interest in studying radiosensitizing agents for poor-Rst ductal carcinoma in situ that are resistant to standard doses of radiation, and it may be that we consider the Rst as a factor moving forward in selecting patients for BCT versus mastectomy.”

However, because 75% of patients at elevated risk with poor Rst who undergo lumpectomy and radiotherapy do not experience recurrence in the decade following their treatment, it would be “inappropriate and misguided” to start recommending mastectomy for patients at DCISionRT elevated risk who have poor Rst, he said.

The study was funded by PreludeDx. Dr. Vicini reported employment with 21st Century Oncology and financial relationships with ImpediMed, Prelude Therapeutics, and Concure Oncology. Dr. Smith, through his employer, has an equity interest in Oncora Medical through a partnership agreement. He also has an uncompensated relationship with the American Society for Radiation Oncology.

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

Treating obstructive sleep apnea with continuous positive airway pressure therapy protects against myocardial infarction, stroke, and other cardiovascular (CV) events, particularly for patients with moderate to severe OSA and those who are more adherent to CPAP therapy, a new study suggests.

“Most clinical trials on the effect of CPAP on CV diseases to date have focused on secondary CV prevention. This study contributes another piece of evidence about the role of CPAP therapy to prevent CV diseases,” said Diego R. Mazzotti, PhD, an assistant professor at the University of Kansas Medical Center, Kansas City.

“Our study, while observational, suggests that clinical trials focused on understanding how to sustain long-term CPAP adherence in obstructive sleep apnea patients are necessary and could be critical for optimizing comorbidity risk reduction,” Dr. Mazzotti said.

The study was presented at the virtual annual meeting of the Associated Professional Sleep Societies.
 

Good adherence important

The researchers analyzed the electronic health records of adults referred for a sleep study through the Kaiser Permanente Southern California health system. The sample included 11,145 adults without OSA, 13,898 with OSA who used CPAP, and 20,884 adults with OSA who did not use CPAP. None of them had CV disease at baseline. Median follow-up was 262 days.

The primary outcome was first occurrence of myocardial infarction, stroke, unstable angina, heart failure, or death caused by CV disease.

In adjusted models, adults with moderate to severe OSA (apnea-hypopnea index ≥15) who did not use CPAP were 71% more likely than those without OSA to have a first CV event (hazard ratio, 1.71; 95% CI, 1.11-2.64). However, the risk for a CV event during follow-up was 32% lower among OSA patients with any CPAP use (HR, 0.68; 95% CI, 0.50-0.93; P = .016).

The effect was mostly driven by those who used CPAP for at least 4 hours per night (HR, 0.60; 95% CI, 0.39-0.95). This association was stronger for those with moderate to severe OSA (HR, 0.56; 95% CI, 0.39-0.81).

“This study highlights the importance of long-term management of CPAP therapy in patients with moderate-severe OSA,” Dr. Mazzotti said in an interview.

“It suggests that maintaining good CPAP adherence might be beneficial for cardiovascular health, besides the already established benefits on quality of life, sleepiness, and other cardiometabolic functions,” he said.

Dr. Mazzotti said several mechanisms might explain the association between CPAP use and lower risk for CV events. “CPAP treats OSA by preventing respiratory pauses that occur during sleep, therefore preventing arousals, sleep fragmentation, and decreases in blood oxygen. These improved cardiorespiratory functions can be beneficial to avoid certain molecular changes that are known to contribute to cardiovascular risk, such as oxidative stress and inflammation,” he explained.

“However, specific studies fully understanding these mechanisms are necessary,” Dr. Mazzotti added.

In a comment, Nitun Verma, MD, a spokesperson for the American Academy of Sleep Medicine, said that “the frequent decreases in oxygen levels and fragmented sleep from apnea are associated with cardiovascular disorders. We know this from multiple studies. This, however, was a large study and strengthens the association between improving apnea and reduced serious cardiovascular events.”

Funding for the study was provided by the American Academy of Sleep Medicine Foundation and the American Heart Association. Dr. Mazzotti and Dr. Verma disclosed no relevant financial relationships.

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

Treating obstructive sleep apnea with continuous positive airway pressure therapy protects against myocardial infarction, stroke, and other cardiovascular (CV) events, particularly for patients with moderate to severe OSA and those who are more adherent to CPAP therapy, a new study suggests.

“Most clinical trials on the effect of CPAP on CV diseases to date have focused on secondary CV prevention. This study contributes another piece of evidence about the role of CPAP therapy to prevent CV diseases,” said Diego R. Mazzotti, PhD, an assistant professor at the University of Kansas Medical Center, Kansas City.

“Our study, while observational, suggests that clinical trials focused on understanding how to sustain long-term CPAP adherence in obstructive sleep apnea patients are necessary and could be critical for optimizing comorbidity risk reduction,” Dr. Mazzotti said.

The study was presented at the virtual annual meeting of the Associated Professional Sleep Societies.
 

Good adherence important

The researchers analyzed the electronic health records of adults referred for a sleep study through the Kaiser Permanente Southern California health system. The sample included 11,145 adults without OSA, 13,898 with OSA who used CPAP, and 20,884 adults with OSA who did not use CPAP. None of them had CV disease at baseline. Median follow-up was 262 days.

The primary outcome was first occurrence of myocardial infarction, stroke, unstable angina, heart failure, or death caused by CV disease.

In adjusted models, adults with moderate to severe OSA (apnea-hypopnea index ≥15) who did not use CPAP were 71% more likely than those without OSA to have a first CV event (hazard ratio, 1.71; 95% CI, 1.11-2.64). However, the risk for a CV event during follow-up was 32% lower among OSA patients with any CPAP use (HR, 0.68; 95% CI, 0.50-0.93; P = .016).

The effect was mostly driven by those who used CPAP for at least 4 hours per night (HR, 0.60; 95% CI, 0.39-0.95). This association was stronger for those with moderate to severe OSA (HR, 0.56; 95% CI, 0.39-0.81).

“This study highlights the importance of long-term management of CPAP therapy in patients with moderate-severe OSA,” Dr. Mazzotti said in an interview.

“It suggests that maintaining good CPAP adherence might be beneficial for cardiovascular health, besides the already established benefits on quality of life, sleepiness, and other cardiometabolic functions,” he said.

Dr. Mazzotti said several mechanisms might explain the association between CPAP use and lower risk for CV events. “CPAP treats OSA by preventing respiratory pauses that occur during sleep, therefore preventing arousals, sleep fragmentation, and decreases in blood oxygen. These improved cardiorespiratory functions can be beneficial to avoid certain molecular changes that are known to contribute to cardiovascular risk, such as oxidative stress and inflammation,” he explained.

“However, specific studies fully understanding these mechanisms are necessary,” Dr. Mazzotti added.

In a comment, Nitun Verma, MD, a spokesperson for the American Academy of Sleep Medicine, said that “the frequent decreases in oxygen levels and fragmented sleep from apnea are associated with cardiovascular disorders. We know this from multiple studies. This, however, was a large study and strengthens the association between improving apnea and reduced serious cardiovascular events.”

Funding for the study was provided by the American Academy of Sleep Medicine Foundation and the American Heart Association. Dr. Mazzotti and Dr. Verma disclosed no relevant financial relationships.

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

Treating obstructive sleep apnea with continuous positive airway pressure therapy protects against myocardial infarction, stroke, and other cardiovascular (CV) events, particularly for patients with moderate to severe OSA and those who are more adherent to CPAP therapy, a new study suggests.

“Most clinical trials on the effect of CPAP on CV diseases to date have focused on secondary CV prevention. This study contributes another piece of evidence about the role of CPAP therapy to prevent CV diseases,” said Diego R. Mazzotti, PhD, an assistant professor at the University of Kansas Medical Center, Kansas City.

“Our study, while observational, suggests that clinical trials focused on understanding how to sustain long-term CPAP adherence in obstructive sleep apnea patients are necessary and could be critical for optimizing comorbidity risk reduction,” Dr. Mazzotti said.

The study was presented at the virtual annual meeting of the Associated Professional Sleep Societies.
 

Good adherence important

The researchers analyzed the electronic health records of adults referred for a sleep study through the Kaiser Permanente Southern California health system. The sample included 11,145 adults without OSA, 13,898 with OSA who used CPAP, and 20,884 adults with OSA who did not use CPAP. None of them had CV disease at baseline. Median follow-up was 262 days.

The primary outcome was first occurrence of myocardial infarction, stroke, unstable angina, heart failure, or death caused by CV disease.

In adjusted models, adults with moderate to severe OSA (apnea-hypopnea index ≥15) who did not use CPAP were 71% more likely than those without OSA to have a first CV event (hazard ratio, 1.71; 95% CI, 1.11-2.64). However, the risk for a CV event during follow-up was 32% lower among OSA patients with any CPAP use (HR, 0.68; 95% CI, 0.50-0.93; P = .016).

The effect was mostly driven by those who used CPAP for at least 4 hours per night (HR, 0.60; 95% CI, 0.39-0.95). This association was stronger for those with moderate to severe OSA (HR, 0.56; 95% CI, 0.39-0.81).

“This study highlights the importance of long-term management of CPAP therapy in patients with moderate-severe OSA,” Dr. Mazzotti said in an interview.

“It suggests that maintaining good CPAP adherence might be beneficial for cardiovascular health, besides the already established benefits on quality of life, sleepiness, and other cardiometabolic functions,” he said.

Dr. Mazzotti said several mechanisms might explain the association between CPAP use and lower risk for CV events. “CPAP treats OSA by preventing respiratory pauses that occur during sleep, therefore preventing arousals, sleep fragmentation, and decreases in blood oxygen. These improved cardiorespiratory functions can be beneficial to avoid certain molecular changes that are known to contribute to cardiovascular risk, such as oxidative stress and inflammation,” he explained.

“However, specific studies fully understanding these mechanisms are necessary,” Dr. Mazzotti added.

In a comment, Nitun Verma, MD, a spokesperson for the American Academy of Sleep Medicine, said that “the frequent decreases in oxygen levels and fragmented sleep from apnea are associated with cardiovascular disorders. We know this from multiple studies. This, however, was a large study and strengthens the association between improving apnea and reduced serious cardiovascular events.”

Funding for the study was provided by the American Academy of Sleep Medicine Foundation and the American Heart Association. Dr. Mazzotti and Dr. Verma disclosed no relevant financial relationships.

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

What you experience in your dreams might feel random and disjointed, but that chaos during sleep might serve a function, according to Erin Wamsley, PhD, an associate professor of psychology and neuroscience at Furman University in Greenville, S.C. In fact, evidence uncovered by Dr. Wamsley and associates suggests that dreams can prepare the mind for future situations it will encounter.

Previous research and anecdotal evidence have shown that dreams use fragments of past experiences, Dr. Wamsley explained. While studying dreams, her team found that the mind is using select fragments of past experiences to prepare for a known upcoming event.

“This is new evidence that dreams reflect a memory-processing function,” said Dr. Wamsley, who presented the work at the virtual annual meeting of the Associated Professional Sleep Societies.

Some high performers already use past experiences to excel in future events. For instance, Michael Phelps, the most decorated Olympic swimmer, with 28 medals, would “mentally rehearse” his swims for up to 2 hours per day, according to his coach, Bob Bowman.

Using sleep to strengthen this process is an exciting prospect that scientists have been eager to figure out, said Allison Brager, PhD, director of human performance at the U.S. Army Warrior Fitness Training Center. Deep REM sleep can lead to improved learning and memory, she said. “So, hypothetically, better dreams mean better sleep, and that equals better performance.”

For their research, Dr. Wamsley’s team hooked 48 students up to a polysomnography machine to measure sleep cycles and how often they were in a deep REM sleep. The students who took part in the study spent the night in a sleep lab.

The students were woken up multiple times during the night and asked to report what they were dreaming about.

In the morning, they were given their reports and asked to identify familiar features or potential sources for particular dreams. More than half the dreams were tied to a memory the students recalled. One-quarter of the dreams were related to specific upcoming events the students reported. And about 40% of the dreams with a future event in them also included memories of past experiences. This was more common the longer the students dreamed, the scientists explained.

And this was also more common later in the night, possibly because the dreamer is closer to waking and the anticipated event is approaching, Dr. Wamsley said.

Studying dreams is a tricky, subjective business and not always taken as seriously as other aspects of sleep and neuroscience because it involves questions of human consciousness itself, said Erik Hoel, PhD, a research assistant professor of neuroscience at Tufts University in Medford, Mass.

In a recent report published in Patterns, he suggested that our weirdest dreams help our brains process our day-to-day experiences in a way that enables deeper learning.

“This type of research is challenged by the method,” Dr. Hoel said.

In the Wamsley study, “waking people up from a deep sleep and asking them to recollect their dream content will only get you part of the experience because it fades so quickly.” That said, the value of connecting what happens as a result could be meaningful, he noted. For example, study participants could be asked whether their future event went as planned and whether they think the outcome was related to how well they “prepared” in their dreams.

Even then, it would still be a subjective analysis. But going in those directions might lead to meaningful new training, Dr. Hoel said.

And training yourself to recall only specific memories right before sleep might prepare your mind in a focused way for certain events, from giving a presentation to having a difficult conversation with someone, or maybe even winning at the Olympics.

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

What you experience in your dreams might feel random and disjointed, but that chaos during sleep might serve a function, according to Erin Wamsley, PhD, an associate professor of psychology and neuroscience at Furman University in Greenville, S.C. In fact, evidence uncovered by Dr. Wamsley and associates suggests that dreams can prepare the mind for future situations it will encounter.

Previous research and anecdotal evidence have shown that dreams use fragments of past experiences, Dr. Wamsley explained. While studying dreams, her team found that the mind is using select fragments of past experiences to prepare for a known upcoming event.

“This is new evidence that dreams reflect a memory-processing function,” said Dr. Wamsley, who presented the work at the virtual annual meeting of the Associated Professional Sleep Societies.

Some high performers already use past experiences to excel in future events. For instance, Michael Phelps, the most decorated Olympic swimmer, with 28 medals, would “mentally rehearse” his swims for up to 2 hours per day, according to his coach, Bob Bowman.

Using sleep to strengthen this process is an exciting prospect that scientists have been eager to figure out, said Allison Brager, PhD, director of human performance at the U.S. Army Warrior Fitness Training Center. Deep REM sleep can lead to improved learning and memory, she said. “So, hypothetically, better dreams mean better sleep, and that equals better performance.”

For their research, Dr. Wamsley’s team hooked 48 students up to a polysomnography machine to measure sleep cycles and how often they were in a deep REM sleep. The students who took part in the study spent the night in a sleep lab.

The students were woken up multiple times during the night and asked to report what they were dreaming about.

In the morning, they were given their reports and asked to identify familiar features or potential sources for particular dreams. More than half the dreams were tied to a memory the students recalled. One-quarter of the dreams were related to specific upcoming events the students reported. And about 40% of the dreams with a future event in them also included memories of past experiences. This was more common the longer the students dreamed, the scientists explained.

And this was also more common later in the night, possibly because the dreamer is closer to waking and the anticipated event is approaching, Dr. Wamsley said.

Studying dreams is a tricky, subjective business and not always taken as seriously as other aspects of sleep and neuroscience because it involves questions of human consciousness itself, said Erik Hoel, PhD, a research assistant professor of neuroscience at Tufts University in Medford, Mass.

In a recent report published in Patterns, he suggested that our weirdest dreams help our brains process our day-to-day experiences in a way that enables deeper learning.

“This type of research is challenged by the method,” Dr. Hoel said.

In the Wamsley study, “waking people up from a deep sleep and asking them to recollect their dream content will only get you part of the experience because it fades so quickly.” That said, the value of connecting what happens as a result could be meaningful, he noted. For example, study participants could be asked whether their future event went as planned and whether they think the outcome was related to how well they “prepared” in their dreams.

Even then, it would still be a subjective analysis. But going in those directions might lead to meaningful new training, Dr. Hoel said.

And training yourself to recall only specific memories right before sleep might prepare your mind in a focused way for certain events, from giving a presentation to having a difficult conversation with someone, or maybe even winning at the Olympics.

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

What you experience in your dreams might feel random and disjointed, but that chaos during sleep might serve a function, according to Erin Wamsley, PhD, an associate professor of psychology and neuroscience at Furman University in Greenville, S.C. In fact, evidence uncovered by Dr. Wamsley and associates suggests that dreams can prepare the mind for future situations it will encounter.

Previous research and anecdotal evidence have shown that dreams use fragments of past experiences, Dr. Wamsley explained. While studying dreams, her team found that the mind is using select fragments of past experiences to prepare for a known upcoming event.

“This is new evidence that dreams reflect a memory-processing function,” said Dr. Wamsley, who presented the work at the virtual annual meeting of the Associated Professional Sleep Societies.

Some high performers already use past experiences to excel in future events. For instance, Michael Phelps, the most decorated Olympic swimmer, with 28 medals, would “mentally rehearse” his swims for up to 2 hours per day, according to his coach, Bob Bowman.

Using sleep to strengthen this process is an exciting prospect that scientists have been eager to figure out, said Allison Brager, PhD, director of human performance at the U.S. Army Warrior Fitness Training Center. Deep REM sleep can lead to improved learning and memory, she said. “So, hypothetically, better dreams mean better sleep, and that equals better performance.”

For their research, Dr. Wamsley’s team hooked 48 students up to a polysomnography machine to measure sleep cycles and how often they were in a deep REM sleep. The students who took part in the study spent the night in a sleep lab.

The students were woken up multiple times during the night and asked to report what they were dreaming about.

In the morning, they were given their reports and asked to identify familiar features or potential sources for particular dreams. More than half the dreams were tied to a memory the students recalled. One-quarter of the dreams were related to specific upcoming events the students reported. And about 40% of the dreams with a future event in them also included memories of past experiences. This was more common the longer the students dreamed, the scientists explained.

And this was also more common later in the night, possibly because the dreamer is closer to waking and the anticipated event is approaching, Dr. Wamsley said.

Studying dreams is a tricky, subjective business and not always taken as seriously as other aspects of sleep and neuroscience because it involves questions of human consciousness itself, said Erik Hoel, PhD, a research assistant professor of neuroscience at Tufts University in Medford, Mass.

In a recent report published in Patterns, he suggested that our weirdest dreams help our brains process our day-to-day experiences in a way that enables deeper learning.

“This type of research is challenged by the method,” Dr. Hoel said.

In the Wamsley study, “waking people up from a deep sleep and asking them to recollect their dream content will only get you part of the experience because it fades so quickly.” That said, the value of connecting what happens as a result could be meaningful, he noted. For example, study participants could be asked whether their future event went as planned and whether they think the outcome was related to how well they “prepared” in their dreams.

Even then, it would still be a subjective analysis. But going in those directions might lead to meaningful new training, Dr. Hoel said.

And training yourself to recall only specific memories right before sleep might prepare your mind in a focused way for certain events, from giving a presentation to having a difficult conversation with someone, or maybe even winning at the Olympics.

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

Difficulty falling asleep may be predictive of future cognitive impairment in older adults – and depressive symptoms and vascular disease may partially drive this association, new research suggests.

Trouble falling asleep “may be a modifiable risk factor for later-life cognitive impairment and dementia,” said lead author Afsara Zaheed, a PhD candidate in clinical science, department of psychology, University of Michigan, Ann Arbor.

“Patients should also be aware of the importance of insomnia on cognitive functioning so that they can bring up these concerns with their providers early,” she said.

The findings were presented at Virtual SLEEP 2021, the 35th Annual Meeting of the Associated Professional Sleep Societies.
 

Poor sleep common with age

As many as one-half of older adults report having poor sleep quality and insomnia, and growing evidence suggests that insomnia may be a unique risk factor for cognitive decline in later life, Ms. Zaheed explained.

To investigate further, the researchers analyzed data on 2,496 adults aged 51 years and older who were participants in the Health and Retirement Study, a longitudinal study of aging in a nationally representative population of older adults.

In 2002, participants were asked how often they had trouble falling asleep, woke up during the night, woke up too early, and were not able to fall asleep again and how often they felt really rested when they woke up in the morning.

In 2016, participants’ cognition was assessed using a battery of neuropsychological tests that gauged episodic memory, executive function, language, visuospatial/construction, and processing speed.

Analyses controlled for sociodemographics, baseline global cognitive performance, and the influence of depressive symptoms and vascular disease.

Compared with other insomnia symptoms, having difficulty falling asleep in 2002 was the main insomnia symptom that was predictive of cognitive impairment 14 years later, in 2016.

More frequent trouble falling asleep was predictive of poorer episodic memory, executive function, language, processing speed, and visuospatial performance.

The associations between sleep initiation and later cognitive impairment were partially explained by depressive symptoms and vascular disease burden for all domains except episodic memory, which was only partially explained by depressive symptoms.
 

Unclear mechanism

Ms. Zaheed said research is needed to uncover neurophysiologic mechanisms underlying the observed associations. “It may be that chronic difficulty with falling asleep is associated with inflammatory or metabolic processes that negatively affect brain structure and function over time,” she said.

“Insomnia has also been linked with higher accumulation of protein aggregates in the brain that disrupt cell communication and are characteristic of late-life disorders such as Alzheimer’s disease,” she added.

“While our project did not directly investigate these potential causal pathways between insomnia and cognition, our results suggest that investigating these potential mechanisms is an important area for future research,” Ms. Zaheed said.

“While additional intervention research is needed to determine whether targeting insomnia in older patients can have lasting cognitive benefits, results from this study suggest that discussing insomnia symptoms at the primary care level may be beneficial for both doctors and patients,” she added.

“By targeting insomnia – for example, through an evidence-based cognitive–behavioral therapy approach – individuals may improve various mental and physical health outcomes in addition to improving their sleep quality,” Ms. Zaheed said.

Reached for comment, Shaheen E. Lakhan, MD, PhD, neurologist in Newton, Massachusetts, said, “There is a strong link between chronic sleep disturbances and cognitive impairment, including dementia.”

“This study further supports this link and specifically calls out initiating sleep (as opposed to staying asleep) as the culprit. It also raises the hypothesis that the link is primarily mediated by depression and vascular disease; however, the verdict is still out,” said Dr. Lakhan.

The study was funded by the National Institute on Aging. Ms. Zaheed and Dr. Lakhan have disclosed no relevant financial relationships.

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

Difficulty falling asleep may be predictive of future cognitive impairment in older adults – and depressive symptoms and vascular disease may partially drive this association, new research suggests.

Trouble falling asleep “may be a modifiable risk factor for later-life cognitive impairment and dementia,” said lead author Afsara Zaheed, a PhD candidate in clinical science, department of psychology, University of Michigan, Ann Arbor.

“Patients should also be aware of the importance of insomnia on cognitive functioning so that they can bring up these concerns with their providers early,” she said.

The findings were presented at Virtual SLEEP 2021, the 35th Annual Meeting of the Associated Professional Sleep Societies.
 

Poor sleep common with age

As many as one-half of older adults report having poor sleep quality and insomnia, and growing evidence suggests that insomnia may be a unique risk factor for cognitive decline in later life, Ms. Zaheed explained.

To investigate further, the researchers analyzed data on 2,496 adults aged 51 years and older who were participants in the Health and Retirement Study, a longitudinal study of aging in a nationally representative population of older adults.

In 2002, participants were asked how often they had trouble falling asleep, woke up during the night, woke up too early, and were not able to fall asleep again and how often they felt really rested when they woke up in the morning.

In 2016, participants’ cognition was assessed using a battery of neuropsychological tests that gauged episodic memory, executive function, language, visuospatial/construction, and processing speed.

Analyses controlled for sociodemographics, baseline global cognitive performance, and the influence of depressive symptoms and vascular disease.

Compared with other insomnia symptoms, having difficulty falling asleep in 2002 was the main insomnia symptom that was predictive of cognitive impairment 14 years later, in 2016.

More frequent trouble falling asleep was predictive of poorer episodic memory, executive function, language, processing speed, and visuospatial performance.

The associations between sleep initiation and later cognitive impairment were partially explained by depressive symptoms and vascular disease burden for all domains except episodic memory, which was only partially explained by depressive symptoms.
 

Unclear mechanism

Ms. Zaheed said research is needed to uncover neurophysiologic mechanisms underlying the observed associations. “It may be that chronic difficulty with falling asleep is associated with inflammatory or metabolic processes that negatively affect brain structure and function over time,” she said.

“Insomnia has also been linked with higher accumulation of protein aggregates in the brain that disrupt cell communication and are characteristic of late-life disorders such as Alzheimer’s disease,” she added.

“While our project did not directly investigate these potential causal pathways between insomnia and cognition, our results suggest that investigating these potential mechanisms is an important area for future research,” Ms. Zaheed said.

“While additional intervention research is needed to determine whether targeting insomnia in older patients can have lasting cognitive benefits, results from this study suggest that discussing insomnia symptoms at the primary care level may be beneficial for both doctors and patients,” she added.

“By targeting insomnia – for example, through an evidence-based cognitive–behavioral therapy approach – individuals may improve various mental and physical health outcomes in addition to improving their sleep quality,” Ms. Zaheed said.

Reached for comment, Shaheen E. Lakhan, MD, PhD, neurologist in Newton, Massachusetts, said, “There is a strong link between chronic sleep disturbances and cognitive impairment, including dementia.”

“This study further supports this link and specifically calls out initiating sleep (as opposed to staying asleep) as the culprit. It also raises the hypothesis that the link is primarily mediated by depression and vascular disease; however, the verdict is still out,” said Dr. Lakhan.

The study was funded by the National Institute on Aging. Ms. Zaheed and Dr. Lakhan have disclosed no relevant financial relationships.

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

Difficulty falling asleep may be predictive of future cognitive impairment in older adults – and depressive symptoms and vascular disease may partially drive this association, new research suggests.

Trouble falling asleep “may be a modifiable risk factor for later-life cognitive impairment and dementia,” said lead author Afsara Zaheed, a PhD candidate in clinical science, department of psychology, University of Michigan, Ann Arbor.

“Patients should also be aware of the importance of insomnia on cognitive functioning so that they can bring up these concerns with their providers early,” she said.

The findings were presented at Virtual SLEEP 2021, the 35th Annual Meeting of the Associated Professional Sleep Societies.
 

Poor sleep common with age

As many as one-half of older adults report having poor sleep quality and insomnia, and growing evidence suggests that insomnia may be a unique risk factor for cognitive decline in later life, Ms. Zaheed explained.

To investigate further, the researchers analyzed data on 2,496 adults aged 51 years and older who were participants in the Health and Retirement Study, a longitudinal study of aging in a nationally representative population of older adults.

In 2002, participants were asked how often they had trouble falling asleep, woke up during the night, woke up too early, and were not able to fall asleep again and how often they felt really rested when they woke up in the morning.

In 2016, participants’ cognition was assessed using a battery of neuropsychological tests that gauged episodic memory, executive function, language, visuospatial/construction, and processing speed.

Analyses controlled for sociodemographics, baseline global cognitive performance, and the influence of depressive symptoms and vascular disease.

Compared with other insomnia symptoms, having difficulty falling asleep in 2002 was the main insomnia symptom that was predictive of cognitive impairment 14 years later, in 2016.

More frequent trouble falling asleep was predictive of poorer episodic memory, executive function, language, processing speed, and visuospatial performance.

The associations between sleep initiation and later cognitive impairment were partially explained by depressive symptoms and vascular disease burden for all domains except episodic memory, which was only partially explained by depressive symptoms.
 

Unclear mechanism

Ms. Zaheed said research is needed to uncover neurophysiologic mechanisms underlying the observed associations. “It may be that chronic difficulty with falling asleep is associated with inflammatory or metabolic processes that negatively affect brain structure and function over time,” she said.

“Insomnia has also been linked with higher accumulation of protein aggregates in the brain that disrupt cell communication and are characteristic of late-life disorders such as Alzheimer’s disease,” she added.

“While our project did not directly investigate these potential causal pathways between insomnia and cognition, our results suggest that investigating these potential mechanisms is an important area for future research,” Ms. Zaheed said.

“While additional intervention research is needed to determine whether targeting insomnia in older patients can have lasting cognitive benefits, results from this study suggest that discussing insomnia symptoms at the primary care level may be beneficial for both doctors and patients,” she added.

“By targeting insomnia – for example, through an evidence-based cognitive–behavioral therapy approach – individuals may improve various mental and physical health outcomes in addition to improving their sleep quality,” Ms. Zaheed said.

Reached for comment, Shaheen E. Lakhan, MD, PhD, neurologist in Newton, Massachusetts, said, “There is a strong link between chronic sleep disturbances and cognitive impairment, including dementia.”

“This study further supports this link and specifically calls out initiating sleep (as opposed to staying asleep) as the culprit. It also raises the hypothesis that the link is primarily mediated by depression and vascular disease; however, the verdict is still out,” said Dr. Lakhan.

The study was funded by the National Institute on Aging. Ms. Zaheed and Dr. Lakhan have disclosed no relevant financial relationships.

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

Insomnia in childhood persists into adulthood and may raise the risk for internalizing disorders in young adults, new research indicates. However, insomnia symptoms in childhood that remit in the transition to adolescence do not confer increased risk of mood or anxiety disorders later on, the study found.

“As insomnia symptoms may precipitate or maintain internalizing disorders, our findings further reinforce the need for early sleep interventions to prevent future mental health disorders,” said lead investigator Julio Fernandez-Mendoza, PhD, associate professor at Penn State University, Hershey.

He presented his research at Virtual SLEEP 2021, the 35th annual meeting of the Associated Professional Sleep Societies.
 

Results ‘very clear’

The findings are based on data from the Penn State Child Cohort, a longitudinal, population-based sample of 700 children with a median age of 9 years, including 421 who were followed up 8 years later as adolescents (median age, 16 years) and 502 who were followed up 15 years later as young adults (median age, 24 years).

The data are “very clear that the risk of having internalizing disorders in young adulthood associated with having persistent insomnia symptoms, since childhood through adolescence into young adulthood,” Dr. Fernandez-Mendoza said in his presentation.

A persistent developmental trajectory was associated with a threefold increased risk of adult internalizing disorder (hazard ratio, 3.19).

The risk of having an internalizing disorder in young adulthood associated with newly developing (incident) insomnia symptoms is about twofold higher (HR, 1.94), whereas the risk associated with the waxing and waning pattern of insomnia is 1.5-fold (HR, 1.53) higher and only marginally significant, he reported.

An equally important finding, said Dr. Fernandez-Mendoza, is that those who had remitted insomnia symptoms in the transition to adolescence and throughout young adulthood were not at increased risk of having an internalizing disorder in young adulthood.

“Insomnia symptoms in a persistent manner associated with long-term adverse mental health outcomes, but remission of those insomnia symptoms associated with a good prognosis,” he said.

It’s also important to note, he said, that about 40% of children do not outgrow their insomnia symptoms in the transition to adolescence and are at risk of developing mental health disorders later on during early adulthood.

Reached for comment, Nitun Verma, MD, a spokesperson for the American Academy of Sleep Medicine, said: “There is a connection with mood and anxiety disorders with sleep, especially insomnia. This is a good reminder that reviewing someone’s sleep habits should always be a part of assessing someone’s mental health.”

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

Insomnia in childhood persists into adulthood and may raise the risk for internalizing disorders in young adults, new research indicates. However, insomnia symptoms in childhood that remit in the transition to adolescence do not confer increased risk of mood or anxiety disorders later on, the study found.

“As insomnia symptoms may precipitate or maintain internalizing disorders, our findings further reinforce the need for early sleep interventions to prevent future mental health disorders,” said lead investigator Julio Fernandez-Mendoza, PhD, associate professor at Penn State University, Hershey.

He presented his research at Virtual SLEEP 2021, the 35th annual meeting of the Associated Professional Sleep Societies.
 

Results ‘very clear’

The findings are based on data from the Penn State Child Cohort, a longitudinal, population-based sample of 700 children with a median age of 9 years, including 421 who were followed up 8 years later as adolescents (median age, 16 years) and 502 who were followed up 15 years later as young adults (median age, 24 years).

The data are “very clear that the risk of having internalizing disorders in young adulthood associated with having persistent insomnia symptoms, since childhood through adolescence into young adulthood,” Dr. Fernandez-Mendoza said in his presentation.

A persistent developmental trajectory was associated with a threefold increased risk of adult internalizing disorder (hazard ratio, 3.19).

The risk of having an internalizing disorder in young adulthood associated with newly developing (incident) insomnia symptoms is about twofold higher (HR, 1.94), whereas the risk associated with the waxing and waning pattern of insomnia is 1.5-fold (HR, 1.53) higher and only marginally significant, he reported.

An equally important finding, said Dr. Fernandez-Mendoza, is that those who had remitted insomnia symptoms in the transition to adolescence and throughout young adulthood were not at increased risk of having an internalizing disorder in young adulthood.

“Insomnia symptoms in a persistent manner associated with long-term adverse mental health outcomes, but remission of those insomnia symptoms associated with a good prognosis,” he said.

It’s also important to note, he said, that about 40% of children do not outgrow their insomnia symptoms in the transition to adolescence and are at risk of developing mental health disorders later on during early adulthood.

Reached for comment, Nitun Verma, MD, a spokesperson for the American Academy of Sleep Medicine, said: “There is a connection with mood and anxiety disorders with sleep, especially insomnia. This is a good reminder that reviewing someone’s sleep habits should always be a part of assessing someone’s mental health.”

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

Insomnia in childhood persists into adulthood and may raise the risk for internalizing disorders in young adults, new research indicates. However, insomnia symptoms in childhood that remit in the transition to adolescence do not confer increased risk of mood or anxiety disorders later on, the study found.

“As insomnia symptoms may precipitate or maintain internalizing disorders, our findings further reinforce the need for early sleep interventions to prevent future mental health disorders,” said lead investigator Julio Fernandez-Mendoza, PhD, associate professor at Penn State University, Hershey.

He presented his research at Virtual SLEEP 2021, the 35th annual meeting of the Associated Professional Sleep Societies.
 

Results ‘very clear’

The findings are based on data from the Penn State Child Cohort, a longitudinal, population-based sample of 700 children with a median age of 9 years, including 421 who were followed up 8 years later as adolescents (median age, 16 years) and 502 who were followed up 15 years later as young adults (median age, 24 years).

The data are “very clear that the risk of having internalizing disorders in young adulthood associated with having persistent insomnia symptoms, since childhood through adolescence into young adulthood,” Dr. Fernandez-Mendoza said in his presentation.

A persistent developmental trajectory was associated with a threefold increased risk of adult internalizing disorder (hazard ratio, 3.19).

The risk of having an internalizing disorder in young adulthood associated with newly developing (incident) insomnia symptoms is about twofold higher (HR, 1.94), whereas the risk associated with the waxing and waning pattern of insomnia is 1.5-fold (HR, 1.53) higher and only marginally significant, he reported.

An equally important finding, said Dr. Fernandez-Mendoza, is that those who had remitted insomnia symptoms in the transition to adolescence and throughout young adulthood were not at increased risk of having an internalizing disorder in young adulthood.

“Insomnia symptoms in a persistent manner associated with long-term adverse mental health outcomes, but remission of those insomnia symptoms associated with a good prognosis,” he said.

It’s also important to note, he said, that about 40% of children do not outgrow their insomnia symptoms in the transition to adolescence and are at risk of developing mental health disorders later on during early adulthood.

Reached for comment, Nitun Verma, MD, a spokesperson for the American Academy of Sleep Medicine, said: “There is a connection with mood and anxiety disorders with sleep, especially insomnia. This is a good reminder that reviewing someone’s sleep habits should always be a part of assessing someone’s mental health.”

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

An in vitro study that used mouse endothelial cells to simulate the blood-brain barrier (BBB) suggests that specific proteins may be involved in destabilization of the protective barrier during a cortical spreading depression (CSD) event.

CSD has been linked to migraine aura, but a connection to pain symptoms is uncertain. “There’s just a lack of knowledge. We don’t understand migraine pathophysiology,” said Michael G. Harrington, MBChB, who was asked to comment on the study.

“The evidence for altered transport across the barrier in cortical spreading depression and the associated aura of migraine is pretty strong. The evidence for regular migraine, not so. In fact, there’s really no strong evidence for leakage in those people, and so it is still unresolved whether this initial cortical spreading depression that occurs in aura then triggers migraine afterwards, because it’s occurring during the aura. And in people who do not have the aura, is there a silent cortical spreading depression phenomenon with some leakage that triggers the migraine? That question is definitely not answered,” said Dr. Harrington, a research professor of neurology at the University of Southern California, Los Angeles.

Leakage of the BBB might allow passage of nociceptive compounds that could trigger migraine. Loss of BBB integrity has also been seen in other central nervous system pain disorders, suggesting that alterations to BBB functioning could have broader implications.

“In this model that we’re using, we’re seeing loss of overall barrier integrity, which lends itself to a whole cascade of further pathological possibilities,” Jared Wahl, a PhD candidate at the University of Arizona, Tucson, said in an interview. He presented the research at the American Headache Society’s 2021 annual meeting.

A leaky BBB could allow infiltration of a range of substances, but the potential for such a mechanism in migraine pathology is not well understood.

The researchers specifically investigated the potential role of claudin-5 in the tight junction (TJ) region of the BBB. The decision was made in part because the proteins involved in the BBB are difficult to study, and there is some familiarity with claudin-5, according to Mr. Wahl. ”Of all the proteins that are out there, for claudin-5 (there are) somewhat better techniques and products available to work with, and there’s been some previous research done to show that it’s implicated in blood brain barrier pathology. So it seemed like a good candidate to start with investigating this whole possible pathophysiological link between barrier disruption and migration of pronociceptive substances into the CNS during migraine attacks,” he said. The claudin proteins are also the major components of the tight junctions that seal off gaps between endothelial cells along the BBB.
 

Dynamic changes seen in the in vitro model

To simulate a CSD event, the researchers pulsed cultured cells for 5 minutes with astrocyte-conditioned media, artificial cerebrospinal fluid, KCl, glutamate, altered pH, or adenosine triphosphate (ATP). They used trans endothelial electrical resistance (TEER) to quickly and qualitatively screen for loss of barrier integrity, which is characterized by loss of electrical resistance. To quantify the magnitude of a breach, the researchers applied carbon-14 (C14)–labeled sucrose to one side of the barrier, and determined the amount of labeled sucrose transmitted to the other side of the barrier.

ATP and pH pulses that were outside normal physiological limits led to permeability. The team then used immunocytochemistry assays to visualize the condition of the model BBB, and found discontinuity of the tight junction membranes. Imaging of claudin-5 showed organizational changes within the tight junction, but there was no change in expression level, suggesting that the alterations were due to dynamic reorganization, according to Mr. Wahl.

Transient openings could allow passage of molecules such as bradykinin, calcitonin gene-related peptide (CGRP), and substance P, which could go on to affect the trigeminal nerve complex and trigger a migraine. “That’s sort of the crux of a lot of this migraine research, is gluing this physiological (mechanism) to how it is actually activating the CNS. And this is sort of where we’re going with it at the moment,” said Mr. Wahl.
 

Next steps

The researchers next plan to generate a cell line with claudin-5 linked to green fluorescent protein, then use confocal microscopy to image claudin-5 in real time as the BBB model responds to a simulated CSD.

Another important step will be to link physiological findings like those presented by Mr. Wahl to migraine-specific mechanisms. The results from this model will need to be expanded to include more than endothelial cells, especially astrocytes, pericytes, and neurons, as well as organoids, brain slices, or in vivo animal models, according to Dr. Harrington. “I think you could try and block the changes in occludin [another protein in the tight junction] or claudin-5 to see if, under the same provocation, that prevented the changes in a migraine model. That would be a direct way of connecting from CSD to migraine,” said Dr. Harrington.

If BBB disruption is confirmed to play an important role in migraine, and claudin-5 or other specific proteins are confirmed to be the cause, it could have clinical implications. A drug that could prevent those changes in the proteins and prevent a leak in the BBB could be a migraine preventative. “That could help prevent things like nociceptive substances migrating into the CNS, and could possibly be a well-tolerated drug target that doesn’t have the side effects or the overuse problems that a lot of stuff on the market has today,” said Mr. Wahl.

An in vitro study that used mouse endothelial cells to simulate the blood-brain barrier (BBB) suggests that specific proteins may be involved in destabilization of the protective barrier during a cortical spreading depression (CSD) event.

CSD has been linked to migraine aura, but a connection to pain symptoms is uncertain. “There’s just a lack of knowledge. We don’t understand migraine pathophysiology,” said Michael G. Harrington, MBChB, who was asked to comment on the study.

“The evidence for altered transport across the barrier in cortical spreading depression and the associated aura of migraine is pretty strong. The evidence for regular migraine, not so. In fact, there’s really no strong evidence for leakage in those people, and so it is still unresolved whether this initial cortical spreading depression that occurs in aura then triggers migraine afterwards, because it’s occurring during the aura. And in people who do not have the aura, is there a silent cortical spreading depression phenomenon with some leakage that triggers the migraine? That question is definitely not answered,” said Dr. Harrington, a research professor of neurology at the University of Southern California, Los Angeles.

Leakage of the BBB might allow passage of nociceptive compounds that could trigger migraine. Loss of BBB integrity has also been seen in other central nervous system pain disorders, suggesting that alterations to BBB functioning could have broader implications.

“In this model that we’re using, we’re seeing loss of overall barrier integrity, which lends itself to a whole cascade of further pathological possibilities,” Jared Wahl, a PhD candidate at the University of Arizona, Tucson, said in an interview. He presented the research at the American Headache Society’s 2021 annual meeting.

A leaky BBB could allow infiltration of a range of substances, but the potential for such a mechanism in migraine pathology is not well understood.

The researchers specifically investigated the potential role of claudin-5 in the tight junction (TJ) region of the BBB. The decision was made in part because the proteins involved in the BBB are difficult to study, and there is some familiarity with claudin-5, according to Mr. Wahl. ”Of all the proteins that are out there, for claudin-5 (there are) somewhat better techniques and products available to work with, and there’s been some previous research done to show that it’s implicated in blood brain barrier pathology. So it seemed like a good candidate to start with investigating this whole possible pathophysiological link between barrier disruption and migration of pronociceptive substances into the CNS during migraine attacks,” he said. The claudin proteins are also the major components of the tight junctions that seal off gaps between endothelial cells along the BBB.
 

Dynamic changes seen in the in vitro model

To simulate a CSD event, the researchers pulsed cultured cells for 5 minutes with astrocyte-conditioned media, artificial cerebrospinal fluid, KCl, glutamate, altered pH, or adenosine triphosphate (ATP). They used trans endothelial electrical resistance (TEER) to quickly and qualitatively screen for loss of barrier integrity, which is characterized by loss of electrical resistance. To quantify the magnitude of a breach, the researchers applied carbon-14 (C14)–labeled sucrose to one side of the barrier, and determined the amount of labeled sucrose transmitted to the other side of the barrier.

ATP and pH pulses that were outside normal physiological limits led to permeability. The team then used immunocytochemistry assays to visualize the condition of the model BBB, and found discontinuity of the tight junction membranes. Imaging of claudin-5 showed organizational changes within the tight junction, but there was no change in expression level, suggesting that the alterations were due to dynamic reorganization, according to Mr. Wahl.

Transient openings could allow passage of molecules such as bradykinin, calcitonin gene-related peptide (CGRP), and substance P, which could go on to affect the trigeminal nerve complex and trigger a migraine. “That’s sort of the crux of a lot of this migraine research, is gluing this physiological (mechanism) to how it is actually activating the CNS. And this is sort of where we’re going with it at the moment,” said Mr. Wahl.
 

Next steps

The researchers next plan to generate a cell line with claudin-5 linked to green fluorescent protein, then use confocal microscopy to image claudin-5 in real time as the BBB model responds to a simulated CSD.

Another important step will be to link physiological findings like those presented by Mr. Wahl to migraine-specific mechanisms. The results from this model will need to be expanded to include more than endothelial cells, especially astrocytes, pericytes, and neurons, as well as organoids, brain slices, or in vivo animal models, according to Dr. Harrington. “I think you could try and block the changes in occludin [another protein in the tight junction] or claudin-5 to see if, under the same provocation, that prevented the changes in a migraine model. That would be a direct way of connecting from CSD to migraine,” said Dr. Harrington.

If BBB disruption is confirmed to play an important role in migraine, and claudin-5 or other specific proteins are confirmed to be the cause, it could have clinical implications. A drug that could prevent those changes in the proteins and prevent a leak in the BBB could be a migraine preventative. “That could help prevent things like nociceptive substances migrating into the CNS, and could possibly be a well-tolerated drug target that doesn’t have the side effects or the overuse problems that a lot of stuff on the market has today,” said Mr. Wahl.

An in vitro study that used mouse endothelial cells to simulate the blood-brain barrier (BBB) suggests that specific proteins may be involved in destabilization of the protective barrier during a cortical spreading depression (CSD) event.

CSD has been linked to migraine aura, but a connection to pain symptoms is uncertain. “There’s just a lack of knowledge. We don’t understand migraine pathophysiology,” said Michael G. Harrington, MBChB, who was asked to comment on the study.

“The evidence for altered transport across the barrier in cortical spreading depression and the associated aura of migraine is pretty strong. The evidence for regular migraine, not so. In fact, there’s really no strong evidence for leakage in those people, and so it is still unresolved whether this initial cortical spreading depression that occurs in aura then triggers migraine afterwards, because it’s occurring during the aura. And in people who do not have the aura, is there a silent cortical spreading depression phenomenon with some leakage that triggers the migraine? That question is definitely not answered,” said Dr. Harrington, a research professor of neurology at the University of Southern California, Los Angeles.

Leakage of the BBB might allow passage of nociceptive compounds that could trigger migraine. Loss of BBB integrity has also been seen in other central nervous system pain disorders, suggesting that alterations to BBB functioning could have broader implications.

“In this model that we’re using, we’re seeing loss of overall barrier integrity, which lends itself to a whole cascade of further pathological possibilities,” Jared Wahl, a PhD candidate at the University of Arizona, Tucson, said in an interview. He presented the research at the American Headache Society’s 2021 annual meeting.

A leaky BBB could allow infiltration of a range of substances, but the potential for such a mechanism in migraine pathology is not well understood.

The researchers specifically investigated the potential role of claudin-5 in the tight junction (TJ) region of the BBB. The decision was made in part because the proteins involved in the BBB are difficult to study, and there is some familiarity with claudin-5, according to Mr. Wahl. ”Of all the proteins that are out there, for claudin-5 (there are) somewhat better techniques and products available to work with, and there’s been some previous research done to show that it’s implicated in blood brain barrier pathology. So it seemed like a good candidate to start with investigating this whole possible pathophysiological link between barrier disruption and migration of pronociceptive substances into the CNS during migraine attacks,” he said. The claudin proteins are also the major components of the tight junctions that seal off gaps between endothelial cells along the BBB.
 

Dynamic changes seen in the in vitro model

To simulate a CSD event, the researchers pulsed cultured cells for 5 minutes with astrocyte-conditioned media, artificial cerebrospinal fluid, KCl, glutamate, altered pH, or adenosine triphosphate (ATP). They used trans endothelial electrical resistance (TEER) to quickly and qualitatively screen for loss of barrier integrity, which is characterized by loss of electrical resistance. To quantify the magnitude of a breach, the researchers applied carbon-14 (C14)–labeled sucrose to one side of the barrier, and determined the amount of labeled sucrose transmitted to the other side of the barrier.

ATP and pH pulses that were outside normal physiological limits led to permeability. The team then used immunocytochemistry assays to visualize the condition of the model BBB, and found discontinuity of the tight junction membranes. Imaging of claudin-5 showed organizational changes within the tight junction, but there was no change in expression level, suggesting that the alterations were due to dynamic reorganization, according to Mr. Wahl.

Transient openings could allow passage of molecules such as bradykinin, calcitonin gene-related peptide (CGRP), and substance P, which could go on to affect the trigeminal nerve complex and trigger a migraine. “That’s sort of the crux of a lot of this migraine research, is gluing this physiological (mechanism) to how it is actually activating the CNS. And this is sort of where we’re going with it at the moment,” said Mr. Wahl.
 

Next steps

The researchers next plan to generate a cell line with claudin-5 linked to green fluorescent protein, then use confocal microscopy to image claudin-5 in real time as the BBB model responds to a simulated CSD.

Another important step will be to link physiological findings like those presented by Mr. Wahl to migraine-specific mechanisms. The results from this model will need to be expanded to include more than endothelial cells, especially astrocytes, pericytes, and neurons, as well as organoids, brain slices, or in vivo animal models, according to Dr. Harrington. “I think you could try and block the changes in occludin [another protein in the tight junction] or claudin-5 to see if, under the same provocation, that prevented the changes in a migraine model. That would be a direct way of connecting from CSD to migraine,” said Dr. Harrington.

If BBB disruption is confirmed to play an important role in migraine, and claudin-5 or other specific proteins are confirmed to be the cause, it could have clinical implications. A drug that could prevent those changes in the proteins and prevent a leak in the BBB could be a migraine preventative. “That could help prevent things like nociceptive substances migrating into the CNS, and could possibly be a well-tolerated drug target that doesn’t have the side effects or the overuse problems that a lot of stuff on the market has today,” said Mr. Wahl.

The migraine medication erenumab appears to pose no increased risk of hypertension, easing earlier concerns that this may be one of the drug’s adverse events, an analysis of postmarketing data shows. Nevertheless, investigators noted that more research is needed to confirm that this is the case.

While randomized clinical trials have shown no increased risk of hypertension related to the drug, it has been reported in postmarketing data. However, many of these events occurred in patients with previously documented hypertension or risk factors for the disorder, the investigators noted.

The rate of hypertension adverse events in postmarketing data was 0.144 per 100 person-years. Most such reports described only one instance of elevated blood pressure. In April 2020, the prescribing information for the drug was updated to include a mention of the risk of hypertension.

“Given the limitations of postmarketing reports, including incomplete information, lack of a control arm, and others, additional data are certainly needed to fully characterize the nature, the timing, and the extent to which hypertension is a risk associated with erenumab, and indeed other [calcitonin-gene-related peptide (CGRP)] pathway antagonists,” said study investigator David W. Dodick, MD, professor of neurology at the Mayo Clinic College of Medicine, Phoenix.

The findings were presented at the American Headache Society’s 2021 annual meeting.
 

No increased risk over time

A monoclonal antibody and CGRP antagonist, erenumab is approved in the United States for migraine prevention in adults. CGRP medications are vasodilators, and, therefore, migraine treatments that target this pathway could theoretically have hypertensive effects.

To assess the risk of hypertension in migraine patients treated with erenumab, investigators examined clinical trial and postmarketing data. The analysis included cases with limited information and patients with a different etiology for the development of hypertension.

Using Amgen Clinical Trial data, the researchers performed a pooled safety analysis of four placebo-controlled, double-blind phase 2 or 3 studies of the drug. Participants had episodic or chronic migraine and were between ages 18 and 60 years or age 65 years. The doses studied were 70 mg and 140 mg.

In these studies, blood pressure data for each patient were based on an average of at least two measurements taken after patients were in rested state for at least 5 minutes. The position used for blood pressure measurement for each patient was consistent throughout the study.

The investigators also analyzed postmarketing reports of hypertension from May 17, 2018, to Jan. 31, 2020, identified in Amgen Global Safety data.

The pooled studies included 1,043 participants receiving placebo, 893 receiving 70 mg of erenumab, and 507 receiving 140 mg of the drug. During the treatment phase, the incidence of hypertension was 0.9% among controls, 0.8% in the 70-mg group, and 0.2% in the 140-mg group. The proportion of patients who started a new antihypertensive medication was 1.2% in controls, 0.8% in the 70-mg group, and 0.2% in the 140-mg group.

In a long-term, open-label study, patients with episodic migraine received erenumab treatment for up to 5 years. The incidence of hypertension did not increase with time in this population.

The postmarketing data encompassed 245,682 person-years of erenumab exposure. The researchers identified 362 hypertension events (355 cases). The rate of these events was 0.144 per 100 person-years. The exposure-adjusted incidence of hypertension was 1.9 per 100 patient-years for erenumab.

Of the 362 hypertensive events, 158 (43.6%) were in patients with a medical history of hypertension or risk factors for hypertension. Information about the time to onset of hypertension was available for 121 (33.4%) adverse events.

Of this group, 56 (46.2%) occurred within 1 week of erenumab initiation, including 43 (35.5%) that occurred within 1 day. This rapid time to hypertension onset “is inconsistent with the pharmacokinetic profile of once-monthly erenumab 70 mg or 140 mg, which has a peak serum concentration in approximately 6 days,” said Dr. Dodick.
 

Hypertension ‘not a barrier’ to treatment

Commenting on the findings, Richard B. Lipton, MD, Edwin S. Lowe professor and vice chair of neurology at Albert Einstein College of Medicine, New York, noted that in theory blocking CGRP could increase blood pressure. However, he noted that the data and clinical experience do not suggest erenumab poses a serious risk.

“I have rarely seen new-onset hypertension with erenumab in the patients treated at our medical center. The few cases I have seen were in older adults with pre-existing hypertension,” he said.

The investigators’ review of clinical trial data together with global safety databases was a strength of their study, said Dr. Lipton. In clinical trials, patients are monitored carefully, and a placebo control group aids in the determination of background rates.

“In the trials, the incidence of new-onset hypertension or hypertension exacerbation was 0.9%, while the placebo rate was 0.2%,” said Dr. Lipton. “The absolute increase in the risk of hypertension was 0.6% or six cases per thousand: A low rate.” But clinical trials enroll carefully selected patients who do not represent the broad group of people treated with erenumab in clinical practice, he added.

The global safety data are more representative of patients who receive erenumab in real-world settings. The weaknesses of these data, though, are the lack of a control group and the incomplete ascertainment of data associated with spontaneous reporting.

Yet both types of studies, with their complementary strengths and weaknesses, indicated low rates of hypertension.

“The low incidence of hypertension, in my view, is not a barrier to the use of erenumab, though checking blood pressure after starting any new migraine therapy is prudent,” Dr. Lipton concluded.

The study was funded by Amgen. Dr. Dodick had no relevant disclosures. Dr. Lipton has consulted for and conducted studies funded by Amgen and by other companies that manufacture CGRP drugs. He has stock options in Biohaven.

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

The migraine medication erenumab appears to pose no increased risk of hypertension, easing earlier concerns that this may be one of the drug’s adverse events, an analysis of postmarketing data shows. Nevertheless, investigators noted that more research is needed to confirm that this is the case.

While randomized clinical trials have shown no increased risk of hypertension related to the drug, it has been reported in postmarketing data. However, many of these events occurred in patients with previously documented hypertension or risk factors for the disorder, the investigators noted.

The rate of hypertension adverse events in postmarketing data was 0.144 per 100 person-years. Most such reports described only one instance of elevated blood pressure. In April 2020, the prescribing information for the drug was updated to include a mention of the risk of hypertension.

“Given the limitations of postmarketing reports, including incomplete information, lack of a control arm, and others, additional data are certainly needed to fully characterize the nature, the timing, and the extent to which hypertension is a risk associated with erenumab, and indeed other [calcitonin-gene-related peptide (CGRP)] pathway antagonists,” said study investigator David W. Dodick, MD, professor of neurology at the Mayo Clinic College of Medicine, Phoenix.

The findings were presented at the American Headache Society’s 2021 annual meeting.
 

No increased risk over time

A monoclonal antibody and CGRP antagonist, erenumab is approved in the United States for migraine prevention in adults. CGRP medications are vasodilators, and, therefore, migraine treatments that target this pathway could theoretically have hypertensive effects.

To assess the risk of hypertension in migraine patients treated with erenumab, investigators examined clinical trial and postmarketing data. The analysis included cases with limited information and patients with a different etiology for the development of hypertension.

Using Amgen Clinical Trial data, the researchers performed a pooled safety analysis of four placebo-controlled, double-blind phase 2 or 3 studies of the drug. Participants had episodic or chronic migraine and were between ages 18 and 60 years or age 65 years. The doses studied were 70 mg and 140 mg.

In these studies, blood pressure data for each patient were based on an average of at least two measurements taken after patients were in rested state for at least 5 minutes. The position used for blood pressure measurement for each patient was consistent throughout the study.

The investigators also analyzed postmarketing reports of hypertension from May 17, 2018, to Jan. 31, 2020, identified in Amgen Global Safety data.

The pooled studies included 1,043 participants receiving placebo, 893 receiving 70 mg of erenumab, and 507 receiving 140 mg of the drug. During the treatment phase, the incidence of hypertension was 0.9% among controls, 0.8% in the 70-mg group, and 0.2% in the 140-mg group. The proportion of patients who started a new antihypertensive medication was 1.2% in controls, 0.8% in the 70-mg group, and 0.2% in the 140-mg group.

In a long-term, open-label study, patients with episodic migraine received erenumab treatment for up to 5 years. The incidence of hypertension did not increase with time in this population.

The postmarketing data encompassed 245,682 person-years of erenumab exposure. The researchers identified 362 hypertension events (355 cases). The rate of these events was 0.144 per 100 person-years. The exposure-adjusted incidence of hypertension was 1.9 per 100 patient-years for erenumab.

Of the 362 hypertensive events, 158 (43.6%) were in patients with a medical history of hypertension or risk factors for hypertension. Information about the time to onset of hypertension was available for 121 (33.4%) adverse events.

Of this group, 56 (46.2%) occurred within 1 week of erenumab initiation, including 43 (35.5%) that occurred within 1 day. This rapid time to hypertension onset “is inconsistent with the pharmacokinetic profile of once-monthly erenumab 70 mg or 140 mg, which has a peak serum concentration in approximately 6 days,” said Dr. Dodick.
 

Hypertension ‘not a barrier’ to treatment

Commenting on the findings, Richard B. Lipton, MD, Edwin S. Lowe professor and vice chair of neurology at Albert Einstein College of Medicine, New York, noted that in theory blocking CGRP could increase blood pressure. However, he noted that the data and clinical experience do not suggest erenumab poses a serious risk.

“I have rarely seen new-onset hypertension with erenumab in the patients treated at our medical center. The few cases I have seen were in older adults with pre-existing hypertension,” he said.

The investigators’ review of clinical trial data together with global safety databases was a strength of their study, said Dr. Lipton. In clinical trials, patients are monitored carefully, and a placebo control group aids in the determination of background rates.

“In the trials, the incidence of new-onset hypertension or hypertension exacerbation was 0.9%, while the placebo rate was 0.2%,” said Dr. Lipton. “The absolute increase in the risk of hypertension was 0.6% or six cases per thousand: A low rate.” But clinical trials enroll carefully selected patients who do not represent the broad group of people treated with erenumab in clinical practice, he added.

The global safety data are more representative of patients who receive erenumab in real-world settings. The weaknesses of these data, though, are the lack of a control group and the incomplete ascertainment of data associated with spontaneous reporting.

Yet both types of studies, with their complementary strengths and weaknesses, indicated low rates of hypertension.

“The low incidence of hypertension, in my view, is not a barrier to the use of erenumab, though checking blood pressure after starting any new migraine therapy is prudent,” Dr. Lipton concluded.

The study was funded by Amgen. Dr. Dodick had no relevant disclosures. Dr. Lipton has consulted for and conducted studies funded by Amgen and by other companies that manufacture CGRP drugs. He has stock options in Biohaven.

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

The migraine medication erenumab appears to pose no increased risk of hypertension, easing earlier concerns that this may be one of the drug’s adverse events, an analysis of postmarketing data shows. Nevertheless, investigators noted that more research is needed to confirm that this is the case.

While randomized clinical trials have shown no increased risk of hypertension related to the drug, it has been reported in postmarketing data. However, many of these events occurred in patients with previously documented hypertension or risk factors for the disorder, the investigators noted.

The rate of hypertension adverse events in postmarketing data was 0.144 per 100 person-years. Most such reports described only one instance of elevated blood pressure. In April 2020, the prescribing information for the drug was updated to include a mention of the risk of hypertension.

“Given the limitations of postmarketing reports, including incomplete information, lack of a control arm, and others, additional data are certainly needed to fully characterize the nature, the timing, and the extent to which hypertension is a risk associated with erenumab, and indeed other [calcitonin-gene-related peptide (CGRP)] pathway antagonists,” said study investigator David W. Dodick, MD, professor of neurology at the Mayo Clinic College of Medicine, Phoenix.

The findings were presented at the American Headache Society’s 2021 annual meeting.
 

No increased risk over time

A monoclonal antibody and CGRP antagonist, erenumab is approved in the United States for migraine prevention in adults. CGRP medications are vasodilators, and, therefore, migraine treatments that target this pathway could theoretically have hypertensive effects.

To assess the risk of hypertension in migraine patients treated with erenumab, investigators examined clinical trial and postmarketing data. The analysis included cases with limited information and patients with a different etiology for the development of hypertension.

Using Amgen Clinical Trial data, the researchers performed a pooled safety analysis of four placebo-controlled, double-blind phase 2 or 3 studies of the drug. Participants had episodic or chronic migraine and were between ages 18 and 60 years or age 65 years. The doses studied were 70 mg and 140 mg.

In these studies, blood pressure data for each patient were based on an average of at least two measurements taken after patients were in rested state for at least 5 minutes. The position used for blood pressure measurement for each patient was consistent throughout the study.

The investigators also analyzed postmarketing reports of hypertension from May 17, 2018, to Jan. 31, 2020, identified in Amgen Global Safety data.

The pooled studies included 1,043 participants receiving placebo, 893 receiving 70 mg of erenumab, and 507 receiving 140 mg of the drug. During the treatment phase, the incidence of hypertension was 0.9% among controls, 0.8% in the 70-mg group, and 0.2% in the 140-mg group. The proportion of patients who started a new antihypertensive medication was 1.2% in controls, 0.8% in the 70-mg group, and 0.2% in the 140-mg group.

In a long-term, open-label study, patients with episodic migraine received erenumab treatment for up to 5 years. The incidence of hypertension did not increase with time in this population.

The postmarketing data encompassed 245,682 person-years of erenumab exposure. The researchers identified 362 hypertension events (355 cases). The rate of these events was 0.144 per 100 person-years. The exposure-adjusted incidence of hypertension was 1.9 per 100 patient-years for erenumab.

Of the 362 hypertensive events, 158 (43.6%) were in patients with a medical history of hypertension or risk factors for hypertension. Information about the time to onset of hypertension was available for 121 (33.4%) adverse events.

Of this group, 56 (46.2%) occurred within 1 week of erenumab initiation, including 43 (35.5%) that occurred within 1 day. This rapid time to hypertension onset “is inconsistent with the pharmacokinetic profile of once-monthly erenumab 70 mg or 140 mg, which has a peak serum concentration in approximately 6 days,” said Dr. Dodick.
 

Hypertension ‘not a barrier’ to treatment

Commenting on the findings, Richard B. Lipton, MD, Edwin S. Lowe professor and vice chair of neurology at Albert Einstein College of Medicine, New York, noted that in theory blocking CGRP could increase blood pressure. However, he noted that the data and clinical experience do not suggest erenumab poses a serious risk.

“I have rarely seen new-onset hypertension with erenumab in the patients treated at our medical center. The few cases I have seen were in older adults with pre-existing hypertension,” he said.

The investigators’ review of clinical trial data together with global safety databases was a strength of their study, said Dr. Lipton. In clinical trials, patients are monitored carefully, and a placebo control group aids in the determination of background rates.

“In the trials, the incidence of new-onset hypertension or hypertension exacerbation was 0.9%, while the placebo rate was 0.2%,” said Dr. Lipton. “The absolute increase in the risk of hypertension was 0.6% or six cases per thousand: A low rate.” But clinical trials enroll carefully selected patients who do not represent the broad group of people treated with erenumab in clinical practice, he added.

The global safety data are more representative of patients who receive erenumab in real-world settings. The weaknesses of these data, though, are the lack of a control group and the incomplete ascertainment of data associated with spontaneous reporting.

Yet both types of studies, with their complementary strengths and weaknesses, indicated low rates of hypertension.

“The low incidence of hypertension, in my view, is not a barrier to the use of erenumab, though checking blood pressure after starting any new migraine therapy is prudent,” Dr. Lipton concluded.

The study was funded by Amgen. Dr. Dodick had no relevant disclosures. Dr. Lipton has consulted for and conducted studies funded by Amgen and by other companies that manufacture CGRP drugs. He has stock options in Biohaven.

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

Long-acting injectable (LAI) antipsychotic therapies continue to be largely reserved for patients who already have adherence issues. But most patients, including first-episode patients, should be considering drugs with this mode of delivery for their broad array of advantages, according to an overview presented by Current Psychiatry and the American Academy of Clinical Psychiatrists.

“Due to the perception that long-acting injectables are for coercive applications, patients are not hearing about the many reasons this option might be preferable,” reported Diana Perkins, MD, MPH, professor, department of psychiatry, University of North Carolina, Chapel Hill.

According to Dr. Perkins, patients starting treatment for first-episode schizophrenia are particularly unlikely to even hear about injectable therapies even though “these might be the best candidates.”

The advantage of LAI in first-episode patients is that it takes adherence off the table as a risk for treatment failure. Ultimately, many patients educated about LAI in the context of other options, prefer LAI, according to Dr. Perkins, and she provided data to support these assertions.

Of several published articles reporting that patients fail to discuss LAI with patients, one was published last year (J Clin Psychopharmacol. 2020 Jul/Aug;40:346-9). For evidence that patients prefer LAI over pills for antipsychotic treatment, Dr. Perkins cited a study with data from more than 1,400 patients (Patient Prefer Adherence. 2020;14:1093-102).

In this latter analysis, 77% of patients preferred LAI over pills, Dr. Perkins reported at the virtual meeting, presented by MedscapeLive. Moreover, 50% of patients preferred every-3-month injections over monthly injections. For those who preferred LAI, the reasons included the convenience of avoiding daily therapy but also the empowerment derived from feeling healthier from not having to depend on a daily schedule of treatment.
 

LAI has benefits independent of adherence

“Some patients prefer injectables because the daily pills remind them of their illness even when they are feeling well,” Dr. Perkins said.

By eliminating pills and pill bottles, injections also provide a certain degree of confidentiality, said Dr. Perkins. She said that LAI, which avoids the peaks and troughs inherent in pill taking, provides more consistent drug levels even to the degree that doses can sometimes be lowered and adverse events reduced.

Yet, of all the reasons that patients might want to consider LAI, the most compelling is a lower risk of failure from inadequate adherence to daily pills. The evidence that patients do not take daily pills for chronic diseases, whether schizophrenia or any other illness that requires maintenance regimens for persistent disease control, is extensive and overwhelming, according to Dr. Perkins, who cited multiple studies.

For schizophrenia, with a relapsing and remitting pattern of symptoms, poor adherence is a particular risk. When symptoms abate, the cue and motivation for adherence dissipates.

“Most patients with schizophrenia already have some ambivalence about taking their medication. Symptoms are a powerful reminder, but people just forget when the treatment is for prevention,” Dr. Perkins said.

When patients forget their daily pills or when the they decide to skip doses when they feel well, they do not necessarily tell their physicians.
 

Poor adherence often goes unrecognized

“Clinicians are not very good at estimating adherence in their patients,” Dr. Perkins said. While she listed several strategies to help patients adhere to daily pills, she also said that LAI should not be discounted as a means to circumvent this problem altogether.

Importantly, suboptimal adherence by itself places the patient at a high risk for relapse. In one study of partial adherence, delayed doses were associated with increased risk of hospitalization overall, but each increment in further delay led to still more risk (Psychiatr Serv. 2004;55:886-91).

Imperfect adherence to daily pills is very common. In one study evaluating 34,000 veterans with schizophrenia, the proportion with consistently good adherence over the 12 months of study was not quite 40% (J Clin Psychiatry. 2006 Oct;67[10]:1542-50). While most of the remaining were intermittently adherent, more than 15% of the populations was consistently poorly adherent.
 

Simple regimens and adherence closely linked

In general, the simpler the regimen, the greater the adherence, according to Dr. Perkins. For oral therapies, one pill per day is associated with greater adherence than is more than one. LAI, which is even simpler, is consistently associated with a large relative advantage. In one comparative study, 77% were adherent to LAI versus about 30% (P < .001) over a period of 12 months (Ment Health Clin. 2018 Mar 26;8[2]:56-62).

In a large recently published meta-analysis, LAI was associated with objective advantages over oral therapy (Lancet Psychiatry. 2021 May 1;8:[5]387-404). This included a statistically significant lower risk of hospitalizations or relapses for LAI over oral therapy whether the two modes of delivery were compared in randomized controls studies (RR 0.88; P = .033) or cohort studies (RR 0.92; P = .0044).

Overall, clinicians should discard several false assumptions about LAI, including the fact they are not appropriate in first-episode disease and that patients will not elect to take LAI if informed of the choices, according to Dr. Perkins. Rather than just listing LAI among options, Dr. Perkins suggested that clinicians should specifically explain the many advantages.

“When people say I do not like shots, this is not necessarily a no,” she said. If patients understand the potential for a reduced risk of relapse without having to take a daily pill, injections might be preferable whether or not they like shots in particular.

This is not an isolated view among experienced physicians. John M. Kane, MD, chairman of psychiatry, Zucker Hillside Hospital, Northwell Health, Glen Oaks, N.Y., also sees LAI as method of drug delivery that should be considered widely in schizophrenia.

“I am in complete agreement with Dr. Perkins that long-acting injectable formulations of antipsychotic medications should be presented routinely to patients and families as an option for illness management and relapse prevention,” said Dr. Kane, who was a coauthor of the meta-analysis published in Lancet Psychiatry.

“This would include patients early in the course of illness who currently have an unnecessarily high risk of relapse and hospitalization,” he added.

MedscapeLive and this news organization are owned by the same parent company. Dr. Perkins has a financial relationship with Alkermes. Dr. Kane has financial relationships with Abbott, AstraZeneca, Bristol-Myers Squibb, Janssen, Lilly, Otsuka, Pfizer, and Wyeth.

Long-acting injectable (LAI) antipsychotic therapies continue to be largely reserved for patients who already have adherence issues. But most patients, including first-episode patients, should be considering drugs with this mode of delivery for their broad array of advantages, according to an overview presented by Current Psychiatry and the American Academy of Clinical Psychiatrists.

“Due to the perception that long-acting injectables are for coercive applications, patients are not hearing about the many reasons this option might be preferable,” reported Diana Perkins, MD, MPH, professor, department of psychiatry, University of North Carolina, Chapel Hill.

According to Dr. Perkins, patients starting treatment for first-episode schizophrenia are particularly unlikely to even hear about injectable therapies even though “these might be the best candidates.”

The advantage of LAI in first-episode patients is that it takes adherence off the table as a risk for treatment failure. Ultimately, many patients educated about LAI in the context of other options, prefer LAI, according to Dr. Perkins, and she provided data to support these assertions.

Of several published articles reporting that patients fail to discuss LAI with patients, one was published last year (J Clin Psychopharmacol. 2020 Jul/Aug;40:346-9). For evidence that patients prefer LAI over pills for antipsychotic treatment, Dr. Perkins cited a study with data from more than 1,400 patients (Patient Prefer Adherence. 2020;14:1093-102).

In this latter analysis, 77% of patients preferred LAI over pills, Dr. Perkins reported at the virtual meeting, presented by MedscapeLive. Moreover, 50% of patients preferred every-3-month injections over monthly injections. For those who preferred LAI, the reasons included the convenience of avoiding daily therapy but also the empowerment derived from feeling healthier from not having to depend on a daily schedule of treatment.
 

LAI has benefits independent of adherence

“Some patients prefer injectables because the daily pills remind them of their illness even when they are feeling well,” Dr. Perkins said.

By eliminating pills and pill bottles, injections also provide a certain degree of confidentiality, said Dr. Perkins. She said that LAI, which avoids the peaks and troughs inherent in pill taking, provides more consistent drug levels even to the degree that doses can sometimes be lowered and adverse events reduced.

Yet, of all the reasons that patients might want to consider LAI, the most compelling is a lower risk of failure from inadequate adherence to daily pills. The evidence that patients do not take daily pills for chronic diseases, whether schizophrenia or any other illness that requires maintenance regimens for persistent disease control, is extensive and overwhelming, according to Dr. Perkins, who cited multiple studies.

For schizophrenia, with a relapsing and remitting pattern of symptoms, poor adherence is a particular risk. When symptoms abate, the cue and motivation for adherence dissipates.

“Most patients with schizophrenia already have some ambivalence about taking their medication. Symptoms are a powerful reminder, but people just forget when the treatment is for prevention,” Dr. Perkins said.

When patients forget their daily pills or when the they decide to skip doses when they feel well, they do not necessarily tell their physicians.
 

Poor adherence often goes unrecognized

“Clinicians are not very good at estimating adherence in their patients,” Dr. Perkins said. While she listed several strategies to help patients adhere to daily pills, she also said that LAI should not be discounted as a means to circumvent this problem altogether.

Importantly, suboptimal adherence by itself places the patient at a high risk for relapse. In one study of partial adherence, delayed doses were associated with increased risk of hospitalization overall, but each increment in further delay led to still more risk (Psychiatr Serv. 2004;55:886-91).

Imperfect adherence to daily pills is very common. In one study evaluating 34,000 veterans with schizophrenia, the proportion with consistently good adherence over the 12 months of study was not quite 40% (J Clin Psychiatry. 2006 Oct;67[10]:1542-50). While most of the remaining were intermittently adherent, more than 15% of the populations was consistently poorly adherent.
 

Simple regimens and adherence closely linked

In general, the simpler the regimen, the greater the adherence, according to Dr. Perkins. For oral therapies, one pill per day is associated with greater adherence than is more than one. LAI, which is even simpler, is consistently associated with a large relative advantage. In one comparative study, 77% were adherent to LAI versus about 30% (P < .001) over a period of 12 months (Ment Health Clin. 2018 Mar 26;8[2]:56-62).

In a large recently published meta-analysis, LAI was associated with objective advantages over oral therapy (Lancet Psychiatry. 2021 May 1;8:[5]387-404). This included a statistically significant lower risk of hospitalizations or relapses for LAI over oral therapy whether the two modes of delivery were compared in randomized controls studies (RR 0.88; P = .033) or cohort studies (RR 0.92; P = .0044).

Overall, clinicians should discard several false assumptions about LAI, including the fact they are not appropriate in first-episode disease and that patients will not elect to take LAI if informed of the choices, according to Dr. Perkins. Rather than just listing LAI among options, Dr. Perkins suggested that clinicians should specifically explain the many advantages.

“When people say I do not like shots, this is not necessarily a no,” she said. If patients understand the potential for a reduced risk of relapse without having to take a daily pill, injections might be preferable whether or not they like shots in particular.

This is not an isolated view among experienced physicians. John M. Kane, MD, chairman of psychiatry, Zucker Hillside Hospital, Northwell Health, Glen Oaks, N.Y., also sees LAI as method of drug delivery that should be considered widely in schizophrenia.

“I am in complete agreement with Dr. Perkins that long-acting injectable formulations of antipsychotic medications should be presented routinely to patients and families as an option for illness management and relapse prevention,” said Dr. Kane, who was a coauthor of the meta-analysis published in Lancet Psychiatry.

“This would include patients early in the course of illness who currently have an unnecessarily high risk of relapse and hospitalization,” he added.

MedscapeLive and this news organization are owned by the same parent company. Dr. Perkins has a financial relationship with Alkermes. Dr. Kane has financial relationships with Abbott, AstraZeneca, Bristol-Myers Squibb, Janssen, Lilly, Otsuka, Pfizer, and Wyeth.

Long-acting injectable (LAI) antipsychotic therapies continue to be largely reserved for patients who already have adherence issues. But most patients, including first-episode patients, should be considering drugs with this mode of delivery for their broad array of advantages, according to an overview presented by Current Psychiatry and the American Academy of Clinical Psychiatrists.

“Due to the perception that long-acting injectables are for coercive applications, patients are not hearing about the many reasons this option might be preferable,” reported Diana Perkins, MD, MPH, professor, department of psychiatry, University of North Carolina, Chapel Hill.

According to Dr. Perkins, patients starting treatment for first-episode schizophrenia are particularly unlikely to even hear about injectable therapies even though “these might be the best candidates.”

The advantage of LAI in first-episode patients is that it takes adherence off the table as a risk for treatment failure. Ultimately, many patients educated about LAI in the context of other options, prefer LAI, according to Dr. Perkins, and she provided data to support these assertions.

Of several published articles reporting that patients fail to discuss LAI with patients, one was published last year (J Clin Psychopharmacol. 2020 Jul/Aug;40:346-9). For evidence that patients prefer LAI over pills for antipsychotic treatment, Dr. Perkins cited a study with data from more than 1,400 patients (Patient Prefer Adherence. 2020;14:1093-102).

In this latter analysis, 77% of patients preferred LAI over pills, Dr. Perkins reported at the virtual meeting, presented by MedscapeLive. Moreover, 50% of patients preferred every-3-month injections over monthly injections. For those who preferred LAI, the reasons included the convenience of avoiding daily therapy but also the empowerment derived from feeling healthier from not having to depend on a daily schedule of treatment.
 

LAI has benefits independent of adherence

“Some patients prefer injectables because the daily pills remind them of their illness even when they are feeling well,” Dr. Perkins said.

By eliminating pills and pill bottles, injections also provide a certain degree of confidentiality, said Dr. Perkins. She said that LAI, which avoids the peaks and troughs inherent in pill taking, provides more consistent drug levels even to the degree that doses can sometimes be lowered and adverse events reduced.

Yet, of all the reasons that patients might want to consider LAI, the most compelling is a lower risk of failure from inadequate adherence to daily pills. The evidence that patients do not take daily pills for chronic diseases, whether schizophrenia or any other illness that requires maintenance regimens for persistent disease control, is extensive and overwhelming, according to Dr. Perkins, who cited multiple studies.

For schizophrenia, with a relapsing and remitting pattern of symptoms, poor adherence is a particular risk. When symptoms abate, the cue and motivation for adherence dissipates.

“Most patients with schizophrenia already have some ambivalence about taking their medication. Symptoms are a powerful reminder, but people just forget when the treatment is for prevention,” Dr. Perkins said.

When patients forget their daily pills or when the they decide to skip doses when they feel well, they do not necessarily tell their physicians.
 

Poor adherence often goes unrecognized

“Clinicians are not very good at estimating adherence in their patients,” Dr. Perkins said. While she listed several strategies to help patients adhere to daily pills, she also said that LAI should not be discounted as a means to circumvent this problem altogether.

Importantly, suboptimal adherence by itself places the patient at a high risk for relapse. In one study of partial adherence, delayed doses were associated with increased risk of hospitalization overall, but each increment in further delay led to still more risk (Psychiatr Serv. 2004;55:886-91).

Imperfect adherence to daily pills is very common. In one study evaluating 34,000 veterans with schizophrenia, the proportion with consistently good adherence over the 12 months of study was not quite 40% (J Clin Psychiatry. 2006 Oct;67[10]:1542-50). While most of the remaining were intermittently adherent, more than 15% of the populations was consistently poorly adherent.
 

Simple regimens and adherence closely linked

In general, the simpler the regimen, the greater the adherence, according to Dr. Perkins. For oral therapies, one pill per day is associated with greater adherence than is more than one. LAI, which is even simpler, is consistently associated with a large relative advantage. In one comparative study, 77% were adherent to LAI versus about 30% (P < .001) over a period of 12 months (Ment Health Clin. 2018 Mar 26;8[2]:56-62).

In a large recently published meta-analysis, LAI was associated with objective advantages over oral therapy (Lancet Psychiatry. 2021 May 1;8:[5]387-404). This included a statistically significant lower risk of hospitalizations or relapses for LAI over oral therapy whether the two modes of delivery were compared in randomized controls studies (RR 0.88; P = .033) or cohort studies (RR 0.92; P = .0044).

Overall, clinicians should discard several false assumptions about LAI, including the fact they are not appropriate in first-episode disease and that patients will not elect to take LAI if informed of the choices, according to Dr. Perkins. Rather than just listing LAI among options, Dr. Perkins suggested that clinicians should specifically explain the many advantages.

“When people say I do not like shots, this is not necessarily a no,” she said. If patients understand the potential for a reduced risk of relapse without having to take a daily pill, injections might be preferable whether or not they like shots in particular.

This is not an isolated view among experienced physicians. John M. Kane, MD, chairman of psychiatry, Zucker Hillside Hospital, Northwell Health, Glen Oaks, N.Y., also sees LAI as method of drug delivery that should be considered widely in schizophrenia.

“I am in complete agreement with Dr. Perkins that long-acting injectable formulations of antipsychotic medications should be presented routinely to patients and families as an option for illness management and relapse prevention,” said Dr. Kane, who was a coauthor of the meta-analysis published in Lancet Psychiatry.

“This would include patients early in the course of illness who currently have an unnecessarily high risk of relapse and hospitalization,” he added.

MedscapeLive and this news organization are owned by the same parent company. Dr. Perkins has a financial relationship with Alkermes. Dr. Kane has financial relationships with Abbott, AstraZeneca, Bristol-Myers Squibb, Janssen, Lilly, Otsuka, Pfizer, and Wyeth.

Diaphragmatic endometriosis is often diagnosed several years after the start of symptoms – mainly moderate to severe pain – and this is potentially because of general lack of awareness of diaphragmatic endometriosis among the general population and medical professionals.

Findings of the international survey that explored the diagnosis and treatment of diaphragmatic endometriosis were presented at this year’s Royal College of Obstetricians and Gynecologists 2021 Virtual World Congress by medical student Rachel Piccus, MSc, based at the University of Birmingham (England). Robert Sutcliffe, MD, consultant in hepatobiliary and pancreatic surgery, at Queen Elizabeth Hospital Birmingham was senior author. Results were also published in the May 2021 issue of the European Journal of Obstetrics and Gynaecology and Reproductive Biology.

The study found that it took an average of five visits to a primary physician before referral to a gynecologist.

“Late diagnosis could also be due to the idea that diaphragmatic endometriosis symptoms often present before pelvic symptoms and therefore the site of pain is considered atypical for pelvic endometriosis,” Ms. Piccus said, adding that “clinicians are screening for cyclical pain, which is typical of endometriosis, but our study has shown that pain can in fact be more frequent – daily and weekly.”

These significant diagnostic delays, seen from the time of the initial primary care and gynecology consultation has the potential to significantly affect quality of life as seen in pelvic endometriosis, said Ms. Piccus. “These delays are partly due to a lack of awareness among gynecologists, but could also be due to pelvic laparoscopy being insufficient to examine the diaphragm behind the liver.”

Justin Clark, MD, consultant gynaecologist, Birmingham (England) Women’s and Children Hospital, moderated the session and agreed that the study highlights the need for greater awareness of this variant of endometriosis. “Whilst endometriosis affecting the diaphragm, subdiaphragm, and thorax is rare, the condition causes substantial morbidity.”

“Greater knowledge of thoracic endometriosis amongst clinicians in both primary and secondary care is needed to ensure accurate and timely diagnosis,” he added.

Diaphragmatic endometriosis is estimated to affect 1%-1.5% of all endometriosis patients and presents as cyclical pain in the chest, abdomen, and shoulder tip, as well as other respiratory symptoms such as catamenial pneumothorax and difficulty breathing.

“Cross-sectional imaging has shown low sensitivity so upper abdominal laparoscopy is the gold standard; however, this has implications for diagnostic delay because a strong clinical suspicion is required to refer for this invasive procedure,” explained Ms. Piccus referring to one of the reasons underpinning the need for the study.

When successfully diagnosed, treatment requires excision or ablation surgery and studies show symptomatic relief in 75%-100% of cases.

To gauge the extent of delayed diagnosis as well as treatment outcomes from a patient perspective, Ms. Piccus circulated an anonymous online survey among women with a previous history of surgery for diaphragmatic endometriosis.
 

Diaphragmatic endometriosis pain – daily and weekly as well as cyclical

A total of 137 participants responded to the survey, with a median age of 34 years (range, 19-53). Median age of diaphragmatic endometriosis onset was 27 years (range, 11-50), and importantly, diaphragmatic endometriosis symptoms started before pelvic symptoms in 90 respondents (66%).

The dominant symptom was pain. A total of 38% reported cyclical pain (related to endometrial shedding during menstruation), 15% weekly pain, and 47% daily pain, both of which were worse during the menstrual cycle. Furthermore, 14% reported other symptoms including catamenial pneumothorax, difficulty breathing, and hemoptysis.

“Whilst this cyclical pain is typical of endometriosis, we see that diagnostic delays may be due to misdiagnosis because clinicians are screening for this cyclical pain whilst our study has shown that pain can in fact be more frequent, being daily and weekly,” noted Ms. Piccus. Moderate to severe pain was reported in 67% of respondents and moderate in 31%, only 2% reported pain as mild.

Location of pain comprised moderate to severe pain in the upper abdomen (68%), chest (64%) and shoulder (54%). Pain was right-sided in 54%, left-sided in 11% and bilateral in 35%. Upper back and neck were also reported as sites of pain.

Indirectly providing a measure of the lack of awareness of diaphragmatic endometriosis on behalf of primary care, 122 participants reported initially visiting their primary care physician for help and 65 were given a diagnosis – in only 14 cases was that diaphragmatic endometriosis. There were a range of other gynecologic (e.g. ovarian cyst, two), respiratory (spontaneous pneumothorax, seven), gastrointestinal (gastritis/reflux, eight), musculoskeletal (six), and psychological (anxiety/stress, four) diagnoses.

A median of 5 primary care consultations (range, 1-100) were required before referral to a gynecologist, with 30% seeing a primary care physician over 10 times. A further 14 patients self-referred to gynecologist.

“These findings have implications for diagnostic delay, added Ms. Piccus. “While the majority of respondents were diagnosed less than a year from the first GP visit, the median delay was 2 years, with 31% diagnosed after 5 or more years. One took 23 years for an initial diagnosis.”

Most cases were diagnosed at the time of surgery – 93%, with 52% at pelvic laparoscopy, 35% upper abdominal laparoscopy, with 30% requiring two or more laparoscopies before they were diagnosed with diaphragmatic endometriosis. A total of 7% were diagnosed via cross-sectional imaging prior to surgery.
 

Treatment outcomes for diaphragmatic endometriosis

Reflecting the literature, surgery to remove the endometriosis lesions was mainly laparoscopic with 47% abdominal excisions, and 29% abdominal ablations; 6% received open abdominal procedures, and 18% received open thoracotomy or video-assisted thoracoscopic surgery.

The survey asked about postoperative symptoms 6 months after surgery and at the time of survey. Symptoms at 6 months post surgery had completely resolved in 18%, shown significant improvement in 48%, and no improvement in 20%. Worsening of symptoms was seen in 14%. Long-term pain was reported by 21% as severe, 27% as moderate, 35% as mild, and 17% had no symptoms.

Further findings included that 23% underwent additional procedures to treat their diaphragmatic endometriosis, and that there was no significant difference between excision and ablation, nor between age of onset of symptoms or length of diagnostic delay.

“Surgical treatment to remove these extra pelvic deposits of endometriosis will depend upon the type and distribution of thoracic endometriosis and a variety of surgical specialties may need to be involved including gynecologists, cardiothoracic, and upper gastrointestinal/liver surgeons,” Dr. Clark said.

He added that familiar hormonal medical treatments for more typical pelvic endometriosis should also be considered for primary and maintenance treatment. “These data suggest a high symptomatic recurrence rate after surgical treatment and so medical treatments should be considered to try and minimize the risks of endometriosis symptoms returning.”

Dr. Clark also pointed out that multidisciplinary clinical teams should be established in specialized centers to plan surgical and medical management to enhance clinical outcomes and collect data to better understand this enigmatic condition.

Ms. Piccus and Dr. Clark have no relevant conflicts of interest.

Diaphragmatic endometriosis is often diagnosed several years after the start of symptoms – mainly moderate to severe pain – and this is potentially because of general lack of awareness of diaphragmatic endometriosis among the general population and medical professionals.

Findings of the international survey that explored the diagnosis and treatment of diaphragmatic endometriosis were presented at this year’s Royal College of Obstetricians and Gynecologists 2021 Virtual World Congress by medical student Rachel Piccus, MSc, based at the University of Birmingham (England). Robert Sutcliffe, MD, consultant in hepatobiliary and pancreatic surgery, at Queen Elizabeth Hospital Birmingham was senior author. Results were also published in the May 2021 issue of the European Journal of Obstetrics and Gynaecology and Reproductive Biology.

The study found that it took an average of five visits to a primary physician before referral to a gynecologist.

“Late diagnosis could also be due to the idea that diaphragmatic endometriosis symptoms often present before pelvic symptoms and therefore the site of pain is considered atypical for pelvic endometriosis,” Ms. Piccus said, adding that “clinicians are screening for cyclical pain, which is typical of endometriosis, but our study has shown that pain can in fact be more frequent – daily and weekly.”

These significant diagnostic delays, seen from the time of the initial primary care and gynecology consultation has the potential to significantly affect quality of life as seen in pelvic endometriosis, said Ms. Piccus. “These delays are partly due to a lack of awareness among gynecologists, but could also be due to pelvic laparoscopy being insufficient to examine the diaphragm behind the liver.”

Justin Clark, MD, consultant gynaecologist, Birmingham (England) Women’s and Children Hospital, moderated the session and agreed that the study highlights the need for greater awareness of this variant of endometriosis. “Whilst endometriosis affecting the diaphragm, subdiaphragm, and thorax is rare, the condition causes substantial morbidity.”

“Greater knowledge of thoracic endometriosis amongst clinicians in both primary and secondary care is needed to ensure accurate and timely diagnosis,” he added.

Diaphragmatic endometriosis is estimated to affect 1%-1.5% of all endometriosis patients and presents as cyclical pain in the chest, abdomen, and shoulder tip, as well as other respiratory symptoms such as catamenial pneumothorax and difficulty breathing.

“Cross-sectional imaging has shown low sensitivity so upper abdominal laparoscopy is the gold standard; however, this has implications for diagnostic delay because a strong clinical suspicion is required to refer for this invasive procedure,” explained Ms. Piccus referring to one of the reasons underpinning the need for the study.

When successfully diagnosed, treatment requires excision or ablation surgery and studies show symptomatic relief in 75%-100% of cases.

To gauge the extent of delayed diagnosis as well as treatment outcomes from a patient perspective, Ms. Piccus circulated an anonymous online survey among women with a previous history of surgery for diaphragmatic endometriosis.
 

Diaphragmatic endometriosis pain – daily and weekly as well as cyclical

A total of 137 participants responded to the survey, with a median age of 34 years (range, 19-53). Median age of diaphragmatic endometriosis onset was 27 years (range, 11-50), and importantly, diaphragmatic endometriosis symptoms started before pelvic symptoms in 90 respondents (66%).

The dominant symptom was pain. A total of 38% reported cyclical pain (related to endometrial shedding during menstruation), 15% weekly pain, and 47% daily pain, both of which were worse during the menstrual cycle. Furthermore, 14% reported other symptoms including catamenial pneumothorax, difficulty breathing, and hemoptysis.

“Whilst this cyclical pain is typical of endometriosis, we see that diagnostic delays may be due to misdiagnosis because clinicians are screening for this cyclical pain whilst our study has shown that pain can in fact be more frequent, being daily and weekly,” noted Ms. Piccus. Moderate to severe pain was reported in 67% of respondents and moderate in 31%, only 2% reported pain as mild.

Location of pain comprised moderate to severe pain in the upper abdomen (68%), chest (64%) and shoulder (54%). Pain was right-sided in 54%, left-sided in 11% and bilateral in 35%. Upper back and neck were also reported as sites of pain.

Indirectly providing a measure of the lack of awareness of diaphragmatic endometriosis on behalf of primary care, 122 participants reported initially visiting their primary care physician for help and 65 were given a diagnosis – in only 14 cases was that diaphragmatic endometriosis. There were a range of other gynecologic (e.g. ovarian cyst, two), respiratory (spontaneous pneumothorax, seven), gastrointestinal (gastritis/reflux, eight), musculoskeletal (six), and psychological (anxiety/stress, four) diagnoses.

A median of 5 primary care consultations (range, 1-100) were required before referral to a gynecologist, with 30% seeing a primary care physician over 10 times. A further 14 patients self-referred to gynecologist.

“These findings have implications for diagnostic delay, added Ms. Piccus. “While the majority of respondents were diagnosed less than a year from the first GP visit, the median delay was 2 years, with 31% diagnosed after 5 or more years. One took 23 years for an initial diagnosis.”

Most cases were diagnosed at the time of surgery – 93%, with 52% at pelvic laparoscopy, 35% upper abdominal laparoscopy, with 30% requiring two or more laparoscopies before they were diagnosed with diaphragmatic endometriosis. A total of 7% were diagnosed via cross-sectional imaging prior to surgery.
 

Treatment outcomes for diaphragmatic endometriosis

Reflecting the literature, surgery to remove the endometriosis lesions was mainly laparoscopic with 47% abdominal excisions, and 29% abdominal ablations; 6% received open abdominal procedures, and 18% received open thoracotomy or video-assisted thoracoscopic surgery.

The survey asked about postoperative symptoms 6 months after surgery and at the time of survey. Symptoms at 6 months post surgery had completely resolved in 18%, shown significant improvement in 48%, and no improvement in 20%. Worsening of symptoms was seen in 14%. Long-term pain was reported by 21% as severe, 27% as moderate, 35% as mild, and 17% had no symptoms.

Further findings included that 23% underwent additional procedures to treat their diaphragmatic endometriosis, and that there was no significant difference between excision and ablation, nor between age of onset of symptoms or length of diagnostic delay.

“Surgical treatment to remove these extra pelvic deposits of endometriosis will depend upon the type and distribution of thoracic endometriosis and a variety of surgical specialties may need to be involved including gynecologists, cardiothoracic, and upper gastrointestinal/liver surgeons,” Dr. Clark said.

He added that familiar hormonal medical treatments for more typical pelvic endometriosis should also be considered for primary and maintenance treatment. “These data suggest a high symptomatic recurrence rate after surgical treatment and so medical treatments should be considered to try and minimize the risks of endometriosis symptoms returning.”

Dr. Clark also pointed out that multidisciplinary clinical teams should be established in specialized centers to plan surgical and medical management to enhance clinical outcomes and collect data to better understand this enigmatic condition.

Ms. Piccus and Dr. Clark have no relevant conflicts of interest.

Diaphragmatic endometriosis is often diagnosed several years after the start of symptoms – mainly moderate to severe pain – and this is potentially because of general lack of awareness of diaphragmatic endometriosis among the general population and medical professionals.

Findings of the international survey that explored the diagnosis and treatment of diaphragmatic endometriosis were presented at this year’s Royal College of Obstetricians and Gynecologists 2021 Virtual World Congress by medical student Rachel Piccus, MSc, based at the University of Birmingham (England). Robert Sutcliffe, MD, consultant in hepatobiliary and pancreatic surgery, at Queen Elizabeth Hospital Birmingham was senior author. Results were also published in the May 2021 issue of the European Journal of Obstetrics and Gynaecology and Reproductive Biology.

The study found that it took an average of five visits to a primary physician before referral to a gynecologist.

“Late diagnosis could also be due to the idea that diaphragmatic endometriosis symptoms often present before pelvic symptoms and therefore the site of pain is considered atypical for pelvic endometriosis,” Ms. Piccus said, adding that “clinicians are screening for cyclical pain, which is typical of endometriosis, but our study has shown that pain can in fact be more frequent – daily and weekly.”

These significant diagnostic delays, seen from the time of the initial primary care and gynecology consultation has the potential to significantly affect quality of life as seen in pelvic endometriosis, said Ms. Piccus. “These delays are partly due to a lack of awareness among gynecologists, but could also be due to pelvic laparoscopy being insufficient to examine the diaphragm behind the liver.”

Justin Clark, MD, consultant gynaecologist, Birmingham (England) Women’s and Children Hospital, moderated the session and agreed that the study highlights the need for greater awareness of this variant of endometriosis. “Whilst endometriosis affecting the diaphragm, subdiaphragm, and thorax is rare, the condition causes substantial morbidity.”

“Greater knowledge of thoracic endometriosis amongst clinicians in both primary and secondary care is needed to ensure accurate and timely diagnosis,” he added.

Diaphragmatic endometriosis is estimated to affect 1%-1.5% of all endometriosis patients and presents as cyclical pain in the chest, abdomen, and shoulder tip, as well as other respiratory symptoms such as catamenial pneumothorax and difficulty breathing.

“Cross-sectional imaging has shown low sensitivity so upper abdominal laparoscopy is the gold standard; however, this has implications for diagnostic delay because a strong clinical suspicion is required to refer for this invasive procedure,” explained Ms. Piccus referring to one of the reasons underpinning the need for the study.

When successfully diagnosed, treatment requires excision or ablation surgery and studies show symptomatic relief in 75%-100% of cases.

To gauge the extent of delayed diagnosis as well as treatment outcomes from a patient perspective, Ms. Piccus circulated an anonymous online survey among women with a previous history of surgery for diaphragmatic endometriosis.
 

Diaphragmatic endometriosis pain – daily and weekly as well as cyclical

A total of 137 participants responded to the survey, with a median age of 34 years (range, 19-53). Median age of diaphragmatic endometriosis onset was 27 years (range, 11-50), and importantly, diaphragmatic endometriosis symptoms started before pelvic symptoms in 90 respondents (66%).

The dominant symptom was pain. A total of 38% reported cyclical pain (related to endometrial shedding during menstruation), 15% weekly pain, and 47% daily pain, both of which were worse during the menstrual cycle. Furthermore, 14% reported other symptoms including catamenial pneumothorax, difficulty breathing, and hemoptysis.

“Whilst this cyclical pain is typical of endometriosis, we see that diagnostic delays may be due to misdiagnosis because clinicians are screening for this cyclical pain whilst our study has shown that pain can in fact be more frequent, being daily and weekly,” noted Ms. Piccus. Moderate to severe pain was reported in 67% of respondents and moderate in 31%, only 2% reported pain as mild.

Location of pain comprised moderate to severe pain in the upper abdomen (68%), chest (64%) and shoulder (54%). Pain was right-sided in 54%, left-sided in 11% and bilateral in 35%. Upper back and neck were also reported as sites of pain.

Indirectly providing a measure of the lack of awareness of diaphragmatic endometriosis on behalf of primary care, 122 participants reported initially visiting their primary care physician for help and 65 were given a diagnosis – in only 14 cases was that diaphragmatic endometriosis. There were a range of other gynecologic (e.g. ovarian cyst, two), respiratory (spontaneous pneumothorax, seven), gastrointestinal (gastritis/reflux, eight), musculoskeletal (six), and psychological (anxiety/stress, four) diagnoses.

A median of 5 primary care consultations (range, 1-100) were required before referral to a gynecologist, with 30% seeing a primary care physician over 10 times. A further 14 patients self-referred to gynecologist.

“These findings have implications for diagnostic delay, added Ms. Piccus. “While the majority of respondents were diagnosed less than a year from the first GP visit, the median delay was 2 years, with 31% diagnosed after 5 or more years. One took 23 years for an initial diagnosis.”

Most cases were diagnosed at the time of surgery – 93%, with 52% at pelvic laparoscopy, 35% upper abdominal laparoscopy, with 30% requiring two or more laparoscopies before they were diagnosed with diaphragmatic endometriosis. A total of 7% were diagnosed via cross-sectional imaging prior to surgery.
 

Treatment outcomes for diaphragmatic endometriosis

Reflecting the literature, surgery to remove the endometriosis lesions was mainly laparoscopic with 47% abdominal excisions, and 29% abdominal ablations; 6% received open abdominal procedures, and 18% received open thoracotomy or video-assisted thoracoscopic surgery.

The survey asked about postoperative symptoms 6 months after surgery and at the time of survey. Symptoms at 6 months post surgery had completely resolved in 18%, shown significant improvement in 48%, and no improvement in 20%. Worsening of symptoms was seen in 14%. Long-term pain was reported by 21% as severe, 27% as moderate, 35% as mild, and 17% had no symptoms.

Further findings included that 23% underwent additional procedures to treat their diaphragmatic endometriosis, and that there was no significant difference between excision and ablation, nor between age of onset of symptoms or length of diagnostic delay.

“Surgical treatment to remove these extra pelvic deposits of endometriosis will depend upon the type and distribution of thoracic endometriosis and a variety of surgical specialties may need to be involved including gynecologists, cardiothoracic, and upper gastrointestinal/liver surgeons,” Dr. Clark said.

He added that familiar hormonal medical treatments for more typical pelvic endometriosis should also be considered for primary and maintenance treatment. “These data suggest a high symptomatic recurrence rate after surgical treatment and so medical treatments should be considered to try and minimize the risks of endometriosis symptoms returning.”

Dr. Clark also pointed out that multidisciplinary clinical teams should be established in specialized centers to plan surgical and medical management to enhance clinical outcomes and collect data to better understand this enigmatic condition.

Ms. Piccus and Dr. Clark have no relevant conflicts of interest.