A new preprint server for the medical and health sciences – medRxiv – has launched, along with safeguards designed to mitigate the risk of non–peer-reviewed findings prematurely guiding clinical practice or misinforming the public.

The new repository of preprints is intended for researcher-to-researcher communication – and mainly to facilitate faster sharing of research findings before publication in peer-reviewed journals. Papers will not be scrutinized for study design or the strength of the science, but they will be screened by an external clinical scientist and – at least for now – by an editor funded by BMJ, the London-based publisher and one of the three cofounding organizations of medRxiv (pronounced “med archive”).

The server’s six-person leadership team – comprising leaders from BMJ and cofounders, Cold Spring Harbor Laboratory in New York, and Yale University in New Haven, Conn. – will make final decisions about whether to post papers that generate concerns.

“We’ve put in place more stringent screening procedures than existed for bioRxiv, [a biological preprint server launched in 2013 by Cold Spring Harbor Laboratory],”said Theodora Bloom, PhD, executive editor of BMJ. “We’ll specifically ask the question, is there a risk to public health or health-related behaviors if this preprint is posted and [turns out to be] wrong?”

Concerns that poor information will be disseminated to the public or that the public will misinterpret information published, were heard by the medRxiv founders as they “work-shopped the idea and talked with the community,” said Joseph Ross, MD, an associate professor of medicine and public health at Yale and codirector of the Yale Open Data Access (YODA) Project

“We’re taking a cautious approach, particularly in the early days as we learn from the process,” he said. “How a paper [could potentially influence clinical practice] will be a guiding question.”

The cofounders had several conversations, Dr. Ross said, with Howard Bauchner, MD, editor in chief of JAMA, who took a strong stance against preprints and shortcutting the peer review process in a 2017 editorial titled “The rush to publication: An editorial and scientific mistake.” (Dr. Ross is an associate editor at JAMA Internal Medicine. Dr. Bauchner was unavailable for comment on the safeguards built into medRvix.)

Aaron D. Viny, MD, a hematologist-oncologist at Memorial Sloan Kettering in New York, said he has mixed feelings about preprints and believes the stakes are higher with medRvix, given that it will house clinical content – including, he anticipates, single-institution, nonprospective outcome studies of off-label drug uses. “These aren’t bona fide clinical trials and may not have the best data,” he said.

Still, there are advantages for investigators – and for the progress of research – with earlier dissemination of findings, Dr. Viny said. He recently had a paper posted on bioRvix for the first time. The paper was undergoing revision for a peer-reviewed journal and was being presented at a national meeting at the time it was posted.

“We timed it [as such], so that not only were we presenting it at a national meeting, but it also got more Twitter buzz,” he said. “I thought it was a good body of work, and I was excited to discuss it online with the scientific community.”

Dr. Viny’s decision is common among preprint authors and reflects the values of the preprint server, Dr. Ross said. “When people are reading or hearing about [new findings] at a meeting, they can go to the papers to get more complete information.” And, he said, the investigators themselves can get more feedback than they otherwise would.

In addition to papers that are well on their way to publication in peer-reviewed journals, Dr. Ross anticipates that medRvix will house papers on qualitative studies and observational research that face more arduous publication paths. He said he expects to see research on medical education and hopes to see papers on “quality improvement work, which typically involve small interventions at a single institution, and have important insights but are hard to publish because of generalizability and controls.”

And while there has been a “positive shift” in the past 10 years in the publication of negative results in peer-reviewed literature, medRvix may well capture studies that have negative results “because they have challenges with recruitment or other [elements of study design],” Dr. Ross said. “There is still a lot that can be learned by the scientific community from these negative studies, but they’re very difficult to publish in a peer-reviewed journal.”
 

Road to preprints

BMJ has a history with preprints. The publisher established a preprint server for biomedical research in the late 1990s, but it never took off and was shut down in the early 2000s. “It just didn’t get the uptake,” said Dr. Bloom. “It’s hard to know exactly why.”

Photo by Gina Motisi, Cold Spring Harbor Laboratory

What is clear, she said, is what has changed in the past 20 years: Copious use of the Internet overall, a growing desire to stake out one’s research turf online, requests from funders to have preprints listed on grant applications, and disease outbreaks involving the Zika virus and Ebola that have highlighted the advantages of faster dissemination of research findings.

BMJ had begun discussions with John Inglis, PhD, of Cold Spring Harbor Laboratory about launching a preprint server for the medical sciences (building on the experience of bioRxiv) when they heard Harlan Krumholz, MD, professor of medicine at Yale and head of the YODA project, speak at the 2017 meeting of the International Congress on Peer Review & Scientific Publication. In his keynote address, Dr. Krumholz described Yale’s plans to launch a preprint server.

“We all felt it would be better working together than apart,” Dr. Bloom said.
 

Getting published

Each preprint on medRxiv will get a permanent DOI link and a disclaimer stating that preprints are not peer reviewed, should not be relied on to guide clinical practice, and should not be reported in the news media as established information.

Authors will be required to meet various standards and requirements common in the clinical and medical sciences, such as including details on ethics approvals, patient consent, funding sources and conflicts of interest, and trial registration numbers. They will have the option of adding a revision(s) of their preprint (each preprint will have a “history”), as well as the option of having their preprint marked as “withdrawn” if they can no longer stand by the findings or conclusions. Preprints will automatically be linked to final published papers.

Journals have wrestled with how to handle preprints. A look at several major peer-reviewed journals shows that they’ll consider articles that have appeared in early form as preprints (including the New England Journal of Medicine, according to media relations manager Jennifer Zeis), but there are caveats. JAMA, for instance, will look at whether submitted manuscripts add “meaningfully new” information above what the preprint disseminated.

Similarly, the American Society of Clinical Oncology (ASCO) will consider how preprints affect the “novelty” of the manuscript’s findings for its ASCO journal readers. Editors of the journal Blood will consider “public comments or coverage about [the] preprint” in its evaluation of the manuscript’s impact. Several of the major journals specify that preprints cannot be updated while manuscripts are under review.

A recent review of bioRxiv preprints shows that approximately two-thirds went on to peer-reviewed publication.

And according to the BMJ’s Dr. Bloom, “there is definitely evidence that preprints [overall] are getting cited [in the scientific literature] before peer-reviewed articles appear.”

The server medRvix began accepting manuscripts on June 6 and will go live on June 25. It will accept only research papers – not commentaries or case reports, Dr. Ross emphasized.

For now, Dr. Bloom said, the most immediate and “real question for us is, will clinical researchers embrace preprints? And if they do, can we continue to provide a light touch but rapid way to screen papers while ensuring the safety of what we’re posting?”

For his part, Dr. Viny is bracing for “public consumption” of medRxiv content, especially in the oncology community in which patients are often extraordinarily well educated about their disease and determined to learn about all possible treatment options. “My job as a clinician,” he said, “will be to contextualize the patient’s reference information.”

A new preprint server for the medical and health sciences – medRxiv – has launched, along with safeguards designed to mitigate the risk of non–peer-reviewed findings prematurely guiding clinical practice or misinforming the public.

The new repository of preprints is intended for researcher-to-researcher communication – and mainly to facilitate faster sharing of research findings before publication in peer-reviewed journals. Papers will not be scrutinized for study design or the strength of the science, but they will be screened by an external clinical scientist and – at least for now – by an editor funded by BMJ, the London-based publisher and one of the three cofounding organizations of medRxiv (pronounced “med archive”).

The server’s six-person leadership team – comprising leaders from BMJ and cofounders, Cold Spring Harbor Laboratory in New York, and Yale University in New Haven, Conn. – will make final decisions about whether to post papers that generate concerns.

“We’ve put in place more stringent screening procedures than existed for bioRxiv, [a biological preprint server launched in 2013 by Cold Spring Harbor Laboratory],”said Theodora Bloom, PhD, executive editor of BMJ. “We’ll specifically ask the question, is there a risk to public health or health-related behaviors if this preprint is posted and [turns out to be] wrong?”

Concerns that poor information will be disseminated to the public or that the public will misinterpret information published, were heard by the medRxiv founders as they “work-shopped the idea and talked with the community,” said Joseph Ross, MD, an associate professor of medicine and public health at Yale and codirector of the Yale Open Data Access (YODA) Project

“We’re taking a cautious approach, particularly in the early days as we learn from the process,” he said. “How a paper [could potentially influence clinical practice] will be a guiding question.”

The cofounders had several conversations, Dr. Ross said, with Howard Bauchner, MD, editor in chief of JAMA, who took a strong stance against preprints and shortcutting the peer review process in a 2017 editorial titled “The rush to publication: An editorial and scientific mistake.” (Dr. Ross is an associate editor at JAMA Internal Medicine. Dr. Bauchner was unavailable for comment on the safeguards built into medRvix.)

Aaron D. Viny, MD, a hematologist-oncologist at Memorial Sloan Kettering in New York, said he has mixed feelings about preprints and believes the stakes are higher with medRvix, given that it will house clinical content – including, he anticipates, single-institution, nonprospective outcome studies of off-label drug uses. “These aren’t bona fide clinical trials and may not have the best data,” he said.

Still, there are advantages for investigators – and for the progress of research – with earlier dissemination of findings, Dr. Viny said. He recently had a paper posted on bioRvix for the first time. The paper was undergoing revision for a peer-reviewed journal and was being presented at a national meeting at the time it was posted.

“We timed it [as such], so that not only were we presenting it at a national meeting, but it also got more Twitter buzz,” he said. “I thought it was a good body of work, and I was excited to discuss it online with the scientific community.”

Dr. Viny’s decision is common among preprint authors and reflects the values of the preprint server, Dr. Ross said. “When people are reading or hearing about [new findings] at a meeting, they can go to the papers to get more complete information.” And, he said, the investigators themselves can get more feedback than they otherwise would.

In addition to papers that are well on their way to publication in peer-reviewed journals, Dr. Ross anticipates that medRvix will house papers on qualitative studies and observational research that face more arduous publication paths. He said he expects to see research on medical education and hopes to see papers on “quality improvement work, which typically involve small interventions at a single institution, and have important insights but are hard to publish because of generalizability and controls.”

And while there has been a “positive shift” in the past 10 years in the publication of negative results in peer-reviewed literature, medRvix may well capture studies that have negative results “because they have challenges with recruitment or other [elements of study design],” Dr. Ross said. “There is still a lot that can be learned by the scientific community from these negative studies, but they’re very difficult to publish in a peer-reviewed journal.”
 

Road to preprints

BMJ has a history with preprints. The publisher established a preprint server for biomedical research in the late 1990s, but it never took off and was shut down in the early 2000s. “It just didn’t get the uptake,” said Dr. Bloom. “It’s hard to know exactly why.”

Photo by Gina Motisi, Cold Spring Harbor Laboratory

What is clear, she said, is what has changed in the past 20 years: Copious use of the Internet overall, a growing desire to stake out one’s research turf online, requests from funders to have preprints listed on grant applications, and disease outbreaks involving the Zika virus and Ebola that have highlighted the advantages of faster dissemination of research findings.

BMJ had begun discussions with John Inglis, PhD, of Cold Spring Harbor Laboratory about launching a preprint server for the medical sciences (building on the experience of bioRxiv) when they heard Harlan Krumholz, MD, professor of medicine at Yale and head of the YODA project, speak at the 2017 meeting of the International Congress on Peer Review & Scientific Publication. In his keynote address, Dr. Krumholz described Yale’s plans to launch a preprint server.

“We all felt it would be better working together than apart,” Dr. Bloom said.
 

Getting published

Each preprint on medRxiv will get a permanent DOI link and a disclaimer stating that preprints are not peer reviewed, should not be relied on to guide clinical practice, and should not be reported in the news media as established information.

Authors will be required to meet various standards and requirements common in the clinical and medical sciences, such as including details on ethics approvals, patient consent, funding sources and conflicts of interest, and trial registration numbers. They will have the option of adding a revision(s) of their preprint (each preprint will have a “history”), as well as the option of having their preprint marked as “withdrawn” if they can no longer stand by the findings or conclusions. Preprints will automatically be linked to final published papers.

Journals have wrestled with how to handle preprints. A look at several major peer-reviewed journals shows that they’ll consider articles that have appeared in early form as preprints (including the New England Journal of Medicine, according to media relations manager Jennifer Zeis), but there are caveats. JAMA, for instance, will look at whether submitted manuscripts add “meaningfully new” information above what the preprint disseminated.

Similarly, the American Society of Clinical Oncology (ASCO) will consider how preprints affect the “novelty” of the manuscript’s findings for its ASCO journal readers. Editors of the journal Blood will consider “public comments or coverage about [the] preprint” in its evaluation of the manuscript’s impact. Several of the major journals specify that preprints cannot be updated while manuscripts are under review.

A recent review of bioRxiv preprints shows that approximately two-thirds went on to peer-reviewed publication.

And according to the BMJ’s Dr. Bloom, “there is definitely evidence that preprints [overall] are getting cited [in the scientific literature] before peer-reviewed articles appear.”

The server medRvix began accepting manuscripts on June 6 and will go live on June 25. It will accept only research papers – not commentaries or case reports, Dr. Ross emphasized.

For now, Dr. Bloom said, the most immediate and “real question for us is, will clinical researchers embrace preprints? And if they do, can we continue to provide a light touch but rapid way to screen papers while ensuring the safety of what we’re posting?”

For his part, Dr. Viny is bracing for “public consumption” of medRxiv content, especially in the oncology community in which patients are often extraordinarily well educated about their disease and determined to learn about all possible treatment options. “My job as a clinician,” he said, “will be to contextualize the patient’s reference information.”

A new preprint server for the medical and health sciences – medRxiv – has launched, along with safeguards designed to mitigate the risk of non–peer-reviewed findings prematurely guiding clinical practice or misinforming the public.

The new repository of preprints is intended for researcher-to-researcher communication – and mainly to facilitate faster sharing of research findings before publication in peer-reviewed journals. Papers will not be scrutinized for study design or the strength of the science, but they will be screened by an external clinical scientist and – at least for now – by an editor funded by BMJ, the London-based publisher and one of the three cofounding organizations of medRxiv (pronounced “med archive”).

The server’s six-person leadership team – comprising leaders from BMJ and cofounders, Cold Spring Harbor Laboratory in New York, and Yale University in New Haven, Conn. – will make final decisions about whether to post papers that generate concerns.

“We’ve put in place more stringent screening procedures than existed for bioRxiv, [a biological preprint server launched in 2013 by Cold Spring Harbor Laboratory],”said Theodora Bloom, PhD, executive editor of BMJ. “We’ll specifically ask the question, is there a risk to public health or health-related behaviors if this preprint is posted and [turns out to be] wrong?”

Concerns that poor information will be disseminated to the public or that the public will misinterpret information published, were heard by the medRxiv founders as they “work-shopped the idea and talked with the community,” said Joseph Ross, MD, an associate professor of medicine and public health at Yale and codirector of the Yale Open Data Access (YODA) Project

“We’re taking a cautious approach, particularly in the early days as we learn from the process,” he said. “How a paper [could potentially influence clinical practice] will be a guiding question.”

The cofounders had several conversations, Dr. Ross said, with Howard Bauchner, MD, editor in chief of JAMA, who took a strong stance against preprints and shortcutting the peer review process in a 2017 editorial titled “The rush to publication: An editorial and scientific mistake.” (Dr. Ross is an associate editor at JAMA Internal Medicine. Dr. Bauchner was unavailable for comment on the safeguards built into medRvix.)

Aaron D. Viny, MD, a hematologist-oncologist at Memorial Sloan Kettering in New York, said he has mixed feelings about preprints and believes the stakes are higher with medRvix, given that it will house clinical content – including, he anticipates, single-institution, nonprospective outcome studies of off-label drug uses. “These aren’t bona fide clinical trials and may not have the best data,” he said.

Still, there are advantages for investigators – and for the progress of research – with earlier dissemination of findings, Dr. Viny said. He recently had a paper posted on bioRvix for the first time. The paper was undergoing revision for a peer-reviewed journal and was being presented at a national meeting at the time it was posted.

“We timed it [as such], so that not only were we presenting it at a national meeting, but it also got more Twitter buzz,” he said. “I thought it was a good body of work, and I was excited to discuss it online with the scientific community.”

Dr. Viny’s decision is common among preprint authors and reflects the values of the preprint server, Dr. Ross said. “When people are reading or hearing about [new findings] at a meeting, they can go to the papers to get more complete information.” And, he said, the investigators themselves can get more feedback than they otherwise would.

In addition to papers that are well on their way to publication in peer-reviewed journals, Dr. Ross anticipates that medRvix will house papers on qualitative studies and observational research that face more arduous publication paths. He said he expects to see research on medical education and hopes to see papers on “quality improvement work, which typically involve small interventions at a single institution, and have important insights but are hard to publish because of generalizability and controls.”

And while there has been a “positive shift” in the past 10 years in the publication of negative results in peer-reviewed literature, medRvix may well capture studies that have negative results “because they have challenges with recruitment or other [elements of study design],” Dr. Ross said. “There is still a lot that can be learned by the scientific community from these negative studies, but they’re very difficult to publish in a peer-reviewed journal.”
 

Road to preprints

BMJ has a history with preprints. The publisher established a preprint server for biomedical research in the late 1990s, but it never took off and was shut down in the early 2000s. “It just didn’t get the uptake,” said Dr. Bloom. “It’s hard to know exactly why.”

Photo by Gina Motisi, Cold Spring Harbor Laboratory

What is clear, she said, is what has changed in the past 20 years: Copious use of the Internet overall, a growing desire to stake out one’s research turf online, requests from funders to have preprints listed on grant applications, and disease outbreaks involving the Zika virus and Ebola that have highlighted the advantages of faster dissemination of research findings.

BMJ had begun discussions with John Inglis, PhD, of Cold Spring Harbor Laboratory about launching a preprint server for the medical sciences (building on the experience of bioRxiv) when they heard Harlan Krumholz, MD, professor of medicine at Yale and head of the YODA project, speak at the 2017 meeting of the International Congress on Peer Review & Scientific Publication. In his keynote address, Dr. Krumholz described Yale’s plans to launch a preprint server.

“We all felt it would be better working together than apart,” Dr. Bloom said.
 

Getting published

Each preprint on medRxiv will get a permanent DOI link and a disclaimer stating that preprints are not peer reviewed, should not be relied on to guide clinical practice, and should not be reported in the news media as established information.

Authors will be required to meet various standards and requirements common in the clinical and medical sciences, such as including details on ethics approvals, patient consent, funding sources and conflicts of interest, and trial registration numbers. They will have the option of adding a revision(s) of their preprint (each preprint will have a “history”), as well as the option of having their preprint marked as “withdrawn” if they can no longer stand by the findings or conclusions. Preprints will automatically be linked to final published papers.

Journals have wrestled with how to handle preprints. A look at several major peer-reviewed journals shows that they’ll consider articles that have appeared in early form as preprints (including the New England Journal of Medicine, according to media relations manager Jennifer Zeis), but there are caveats. JAMA, for instance, will look at whether submitted manuscripts add “meaningfully new” information above what the preprint disseminated.

Similarly, the American Society of Clinical Oncology (ASCO) will consider how preprints affect the “novelty” of the manuscript’s findings for its ASCO journal readers. Editors of the journal Blood will consider “public comments or coverage about [the] preprint” in its evaluation of the manuscript’s impact. Several of the major journals specify that preprints cannot be updated while manuscripts are under review.

A recent review of bioRxiv preprints shows that approximately two-thirds went on to peer-reviewed publication.

And according to the BMJ’s Dr. Bloom, “there is definitely evidence that preprints [overall] are getting cited [in the scientific literature] before peer-reviewed articles appear.”

The server medRvix began accepting manuscripts on June 6 and will go live on June 25. It will accept only research papers – not commentaries or case reports, Dr. Ross emphasized.

For now, Dr. Bloom said, the most immediate and “real question for us is, will clinical researchers embrace preprints? And if they do, can we continue to provide a light touch but rapid way to screen papers while ensuring the safety of what we’re posting?”

For his part, Dr. Viny is bracing for “public consumption” of medRxiv content, especially in the oncology community in which patients are often extraordinarily well educated about their disease and determined to learn about all possible treatment options. “My job as a clinician,” he said, “will be to contextualize the patient’s reference information.”

CHICAGO – Pregnancy after breast cancer is safe in BRCA-mutated patients, according to a retrospective study.

Pregnancy did not affect disease-free or overall survival in a cohort of BRCA-mutated breast cancer patients. Additionally, fetal and pregnancy complications in this cohort were similar to complications observed in the general population.

“We believe that our findings provide reassurance for counseling young BRCA-mutated breast cancer patients inquiring about the feasibility and safety of future conception,” said Matteo Lambertini, MD, PhD, of Policlinico San Martino Hospital in Genova, Italy.

Dr. Lambertini presented the findings at the annual meeting of the American Society of Clinical Oncology.

He and his colleagues conducted an international, multicenter, retrospective cohort study of 1,252 patients. The patients had been diagnosed with stage I-III breast cancer between January 2000 and December 2012 at age 40 years or younger. All patients had BRCA mutations – 811 with BRCA1 alone, 430 with BRCA2 alone, and 11 with both.
 

Pregnant versus nonpregnant patients

At a median of 4.5 years after diagnosis, 195 patients (16%) had experienced a pregnancy.

Compared with the nonpregnant women, pregnant patients were younger (P less than .001), more likely to have a BRCA1 mutation (P = .01), have smaller tumors (P = .04), have node-negative disease (P = .003), and have hormone receptor–negative tumors (P = .002). Roughly 95% of patients in both cohorts had received chemotherapy, and the most common regimens were anthracycline or taxane based.

Compared with patients in the nonpregnancy cohort, those in the pregnancy cohort were less likely to receive tamoxifen alone as endocrine therapy (P = .002), were more likely to have a shorter duration of endocrine therapy (P less than .001), and were less likely to undergo salpingo-oophorectomy (P less than .001).
 

Pregnancy outcomes

“In terms of pregnancy, fetal, and obstetrical outcomes, no alarming signals were observed,” Dr. Lambertini said.

Most pregnant patients had a spontaneous pregnancy (82.1%), completed the pregnancy (76.9%), delivered at term (90.8%), and had no complications (86.6%). However, 10.3% of patients had a spontaneous abortion, 9.2% of pregnancies were pre term, and 1.8% of babies had congenital abnormalities.

“All these rates were highly comparable to rates that are expected in the general healthy population,” Dr. Lambertini said.
 

Survival analyses

The researchers performed two survival analyses. The first was a case-control approach in which they matched each pregnant patient with three controls (patients without pregnancy) according to the following:

• Disease-free interval from breast cancer diagnosis (equal to or longer than that of pregnant patients).
• Year at diagnosis (plus or minus 2.5 years).
• Nodal status (negative vs. positive).
• Hormone receptor status (positive vs. negative).
• Type of BRCA mutation (BRCA1 vs. BRCA2).

The second survival analysis was an extended Cox model with pregnancy as a time-varying covariate.
 

Survival outcomes

At a median follow-up of 8.3 years, pregnant patients had better disease-free survival than nonpregnant patients in the case-control analysis, with a hazard ratio of 0.71 (P = .045). With the extended Cox model, the adjusted HR was 0.87 (P = .41). The analysis was adjusted for age, tumor size, nodal status, type of endocrine therapy, hormone receptor status, breast surgery, and BRCA mutation.

There was a significant interaction between type of BRCA mutation and pregnancy, with better disease-free survival observed in the BRCA1-mutated cohort. The HR was 0.53 in the BRCA1 cohort and 1.60 in the BRCA2 cohort (P less than .01). However, as Dr. Lambertini pointed out, only 44 pregnant patients had a BRCA1 mutation.

There was no significant interaction between hormone receptor status and pregnancy (P = .28).

Furthermore, there was no significant difference in overall survival between the pregnant and nonpregnant cohorts. In the case-control analysis, the HR was 0.86 (P = .65). In the extended Cox model, the adjusted HR was 0.88 (P = .66).

Dr. Lambertini disclosed a relationship with Teva.

jensmith@mdedge.com

SOURCE: Lambertini M et al. ASCO 2019, Abstract 11506.

CHICAGO – Pregnancy after breast cancer is safe in BRCA-mutated patients, according to a retrospective study.

Pregnancy did not affect disease-free or overall survival in a cohort of BRCA-mutated breast cancer patients. Additionally, fetal and pregnancy complications in this cohort were similar to complications observed in the general population.

“We believe that our findings provide reassurance for counseling young BRCA-mutated breast cancer patients inquiring about the feasibility and safety of future conception,” said Matteo Lambertini, MD, PhD, of Policlinico San Martino Hospital in Genova, Italy.

Dr. Lambertini presented the findings at the annual meeting of the American Society of Clinical Oncology.

He and his colleagues conducted an international, multicenter, retrospective cohort study of 1,252 patients. The patients had been diagnosed with stage I-III breast cancer between January 2000 and December 2012 at age 40 years or younger. All patients had BRCA mutations – 811 with BRCA1 alone, 430 with BRCA2 alone, and 11 with both.
 

Pregnant versus nonpregnant patients

At a median of 4.5 years after diagnosis, 195 patients (16%) had experienced a pregnancy.

Compared with the nonpregnant women, pregnant patients were younger (P less than .001), more likely to have a BRCA1 mutation (P = .01), have smaller tumors (P = .04), have node-negative disease (P = .003), and have hormone receptor–negative tumors (P = .002). Roughly 95% of patients in both cohorts had received chemotherapy, and the most common regimens were anthracycline or taxane based.

Compared with patients in the nonpregnancy cohort, those in the pregnancy cohort were less likely to receive tamoxifen alone as endocrine therapy (P = .002), were more likely to have a shorter duration of endocrine therapy (P less than .001), and were less likely to undergo salpingo-oophorectomy (P less than .001).
 

Pregnancy outcomes

“In terms of pregnancy, fetal, and obstetrical outcomes, no alarming signals were observed,” Dr. Lambertini said.

Most pregnant patients had a spontaneous pregnancy (82.1%), completed the pregnancy (76.9%), delivered at term (90.8%), and had no complications (86.6%). However, 10.3% of patients had a spontaneous abortion, 9.2% of pregnancies were pre term, and 1.8% of babies had congenital abnormalities.

“All these rates were highly comparable to rates that are expected in the general healthy population,” Dr. Lambertini said.
 

Survival analyses

The researchers performed two survival analyses. The first was a case-control approach in which they matched each pregnant patient with three controls (patients without pregnancy) according to the following:

• Disease-free interval from breast cancer diagnosis (equal to or longer than that of pregnant patients).
• Year at diagnosis (plus or minus 2.5 years).
• Nodal status (negative vs. positive).
• Hormone receptor status (positive vs. negative).
• Type of BRCA mutation (BRCA1 vs. BRCA2).

The second survival analysis was an extended Cox model with pregnancy as a time-varying covariate.
 

Survival outcomes

At a median follow-up of 8.3 years, pregnant patients had better disease-free survival than nonpregnant patients in the case-control analysis, with a hazard ratio of 0.71 (P = .045). With the extended Cox model, the adjusted HR was 0.87 (P = .41). The analysis was adjusted for age, tumor size, nodal status, type of endocrine therapy, hormone receptor status, breast surgery, and BRCA mutation.

There was a significant interaction between type of BRCA mutation and pregnancy, with better disease-free survival observed in the BRCA1-mutated cohort. The HR was 0.53 in the BRCA1 cohort and 1.60 in the BRCA2 cohort (P less than .01). However, as Dr. Lambertini pointed out, only 44 pregnant patients had a BRCA1 mutation.

There was no significant interaction between hormone receptor status and pregnancy (P = .28).

Furthermore, there was no significant difference in overall survival between the pregnant and nonpregnant cohorts. In the case-control analysis, the HR was 0.86 (P = .65). In the extended Cox model, the adjusted HR was 0.88 (P = .66).

Dr. Lambertini disclosed a relationship with Teva.

jensmith@mdedge.com

SOURCE: Lambertini M et al. ASCO 2019, Abstract 11506.

CHICAGO – Pregnancy after breast cancer is safe in BRCA-mutated patients, according to a retrospective study.

Pregnancy did not affect disease-free or overall survival in a cohort of BRCA-mutated breast cancer patients. Additionally, fetal and pregnancy complications in this cohort were similar to complications observed in the general population.

“We believe that our findings provide reassurance for counseling young BRCA-mutated breast cancer patients inquiring about the feasibility and safety of future conception,” said Matteo Lambertini, MD, PhD, of Policlinico San Martino Hospital in Genova, Italy.

Dr. Lambertini presented the findings at the annual meeting of the American Society of Clinical Oncology.

He and his colleagues conducted an international, multicenter, retrospective cohort study of 1,252 patients. The patients had been diagnosed with stage I-III breast cancer between January 2000 and December 2012 at age 40 years or younger. All patients had BRCA mutations – 811 with BRCA1 alone, 430 with BRCA2 alone, and 11 with both.
 

Pregnant versus nonpregnant patients

At a median of 4.5 years after diagnosis, 195 patients (16%) had experienced a pregnancy.

Compared with the nonpregnant women, pregnant patients were younger (P less than .001), more likely to have a BRCA1 mutation (P = .01), have smaller tumors (P = .04), have node-negative disease (P = .003), and have hormone receptor–negative tumors (P = .002). Roughly 95% of patients in both cohorts had received chemotherapy, and the most common regimens were anthracycline or taxane based.

Compared with patients in the nonpregnancy cohort, those in the pregnancy cohort were less likely to receive tamoxifen alone as endocrine therapy (P = .002), were more likely to have a shorter duration of endocrine therapy (P less than .001), and were less likely to undergo salpingo-oophorectomy (P less than .001).
 

Pregnancy outcomes

“In terms of pregnancy, fetal, and obstetrical outcomes, no alarming signals were observed,” Dr. Lambertini said.

Most pregnant patients had a spontaneous pregnancy (82.1%), completed the pregnancy (76.9%), delivered at term (90.8%), and had no complications (86.6%). However, 10.3% of patients had a spontaneous abortion, 9.2% of pregnancies were pre term, and 1.8% of babies had congenital abnormalities.

“All these rates were highly comparable to rates that are expected in the general healthy population,” Dr. Lambertini said.
 

Survival analyses

The researchers performed two survival analyses. The first was a case-control approach in which they matched each pregnant patient with three controls (patients without pregnancy) according to the following:

• Disease-free interval from breast cancer diagnosis (equal to or longer than that of pregnant patients).
• Year at diagnosis (plus or minus 2.5 years).
• Nodal status (negative vs. positive).
• Hormone receptor status (positive vs. negative).
• Type of BRCA mutation (BRCA1 vs. BRCA2).

The second survival analysis was an extended Cox model with pregnancy as a time-varying covariate.
 

Survival outcomes

At a median follow-up of 8.3 years, pregnant patients had better disease-free survival than nonpregnant patients in the case-control analysis, with a hazard ratio of 0.71 (P = .045). With the extended Cox model, the adjusted HR was 0.87 (P = .41). The analysis was adjusted for age, tumor size, nodal status, type of endocrine therapy, hormone receptor status, breast surgery, and BRCA mutation.

There was a significant interaction between type of BRCA mutation and pregnancy, with better disease-free survival observed in the BRCA1-mutated cohort. The HR was 0.53 in the BRCA1 cohort and 1.60 in the BRCA2 cohort (P less than .01). However, as Dr. Lambertini pointed out, only 44 pregnant patients had a BRCA1 mutation.

There was no significant interaction between hormone receptor status and pregnancy (P = .28).

Furthermore, there was no significant difference in overall survival between the pregnant and nonpregnant cohorts. In the case-control analysis, the HR was 0.86 (P = .65). In the extended Cox model, the adjusted HR was 0.88 (P = .66).

Dr. Lambertini disclosed a relationship with Teva.

jensmith@mdedge.com

SOURCE: Lambertini M et al. ASCO 2019, Abstract 11506.

CHICAGO – Neoadjuvant monotherapy with the immune checkpoint inhibitor atezolizumab is associated with “encouraging” responses with no new safety signals for patients with non–small cell lung cancer (NSCLC), an interim analysis of a multicenter phase 2 trial suggests.

Neil Osterweil/MDedge News

Among 77 of a planned 180 patients with resectable NSCLC enrolled in the LCMC3 (Lung Cancer Mutation Consortium 3) trial, the pathological complete response (pCR) rate following two cycles of neoadjuvant atezolizumab (Tecentriq) and surgery was 5%, and the major pathological response (MPR) rate was 19%, reported David J. Kwiatkowski, MD, PhD, of the Dana-Farber Cancer Institute in Boston.

“Pathological regression moderately correlated with target lesions’ measurements by RECIST [Response Evaluation Criteria in Solid Tumors] and MPR was observed irrespective of PD-L1 expression, although there was some correlation,” he said at the annual meeting of the American Society of Clinical Oncology.

The study was designed to test whether preoperative immunotherapy with an immune checkpoint inhibitor could have additional clinical benefits for patients with early-stage NSCLC.

Investigators are enrolling patients with stage IB, II, IIIA, or selected IIIB resectable, previously untreated NSCLC. Patients receive 1,200 mg atezolizumab on days 1 and 22 (two cycles), followed by surgery on or about day 40.

The primary endpoint, MPR, “means that at the time of surgical resection, all of the samples of the tumor that are cut into sections are reviewed by a pathologist, and an aggregate score of a percent of viable tumor cells is determined based on a comparison of viable tumor cells and necrotic tumor cells and stroma,” Dr. Kwiatkowski said.

The threshold for MPR was 10% or fewer viable tumor cells at the time of resection.

Following surgery, patients received standard-of-care adjuvant chemotherapy and could receive optional continued atezolizumab for an additional 12 months.

At the time of this interim analysis, with a data cutoff of Sept. 5, 2018, 101 patients had been enrolled and were included in the interim safety analysis. Of this group, 11 did not undergo surgery, because of progressive disease, withdrawal of consent, failed echocardiogram (1 patient), or pulmonary artery involvement (1) patient.

Of the 10 patients with either progressive disease and no surgery or unresectable disease at surgery, 8 had stage IIIA tumors and 2 had stage IIIB tumors. All patients with stage I or II disease underwent resection.

Dr. Kwiatkowski presented interim data on 90 patients intended for surgery, of whom 84 had assessment of the primary endpoint, including 7 positive for EGFR and/or ALK, and 77 whose tumors were either EGFR/ALK negative or had unknown status. These 77 patients were the primary efficacy population.

As noted before, among the 77 in the primary efficacy population, 15 (19%) had a MPR, and 4 patients (5%) had a pCR. In addition, 38 patients (49%) had pathological regression of tumor of 50% or greater. Pathological regression correlated significantly with change in tumor lesion size (P less than .001).

Tumor mutational burden, however, was not significantly correlated with MPR or pathological regression.

Among the 101 patients in the safety population, there were two deaths deemed not related to study treatment: one cardiac death post surgical resection, and one from disease progression. Treatment-related adverse events occurred in 57% of patients, including 6% that were grade 3 or greater. Adverse events leading to treatment withdrawal occurred in 5% of patients.

The efficacy interim analysis passed the prespecified futility boundary, and investigators are continuing to enroll patients.

Neil Osterweil/MDedge News

Invited discussant Maximilian Diehn, MD, PhD, of Stanford (Calif.) University commented that neoadjuvant immunotherapy for NSCLC is promising, but added that the MPR endpoint still needs validation.

“Currently, it is not considered a validated surrogate endpoint for survival and therefore is not currently used for drug approvals. Secondly, the optimal cut point may differ by histology, such as being different for adenocarcinoma and squamous cell carcinoma. And this has potential implications for using this in trials that enroll patients of both histologies. And, third, there are some emerging data that MPR may need to measured somewhat differently after immunotherapy than after chemotherapy,” he said.

The study is supported by Genentech. Dr. Kwiatkowski disclosed research funding and a consulting or advisory role for the company. Dr. Diehn reported stock ownership, consulting, research funding, and travel expenses from various companies.

SOURCE: Kwiatkowski DJ et al. ASCO 2019, Abstract 8503.

CHICAGO – Neoadjuvant monotherapy with the immune checkpoint inhibitor atezolizumab is associated with “encouraging” responses with no new safety signals for patients with non–small cell lung cancer (NSCLC), an interim analysis of a multicenter phase 2 trial suggests.

Neil Osterweil/MDedge News

Among 77 of a planned 180 patients with resectable NSCLC enrolled in the LCMC3 (Lung Cancer Mutation Consortium 3) trial, the pathological complete response (pCR) rate following two cycles of neoadjuvant atezolizumab (Tecentriq) and surgery was 5%, and the major pathological response (MPR) rate was 19%, reported David J. Kwiatkowski, MD, PhD, of the Dana-Farber Cancer Institute in Boston.

“Pathological regression moderately correlated with target lesions’ measurements by RECIST [Response Evaluation Criteria in Solid Tumors] and MPR was observed irrespective of PD-L1 expression, although there was some correlation,” he said at the annual meeting of the American Society of Clinical Oncology.

The study was designed to test whether preoperative immunotherapy with an immune checkpoint inhibitor could have additional clinical benefits for patients with early-stage NSCLC.

Investigators are enrolling patients with stage IB, II, IIIA, or selected IIIB resectable, previously untreated NSCLC. Patients receive 1,200 mg atezolizumab on days 1 and 22 (two cycles), followed by surgery on or about day 40.

The primary endpoint, MPR, “means that at the time of surgical resection, all of the samples of the tumor that are cut into sections are reviewed by a pathologist, and an aggregate score of a percent of viable tumor cells is determined based on a comparison of viable tumor cells and necrotic tumor cells and stroma,” Dr. Kwiatkowski said.

The threshold for MPR was 10% or fewer viable tumor cells at the time of resection.

Following surgery, patients received standard-of-care adjuvant chemotherapy and could receive optional continued atezolizumab for an additional 12 months.

At the time of this interim analysis, with a data cutoff of Sept. 5, 2018, 101 patients had been enrolled and were included in the interim safety analysis. Of this group, 11 did not undergo surgery, because of progressive disease, withdrawal of consent, failed echocardiogram (1 patient), or pulmonary artery involvement (1) patient.

Of the 10 patients with either progressive disease and no surgery or unresectable disease at surgery, 8 had stage IIIA tumors and 2 had stage IIIB tumors. All patients with stage I or II disease underwent resection.

Dr. Kwiatkowski presented interim data on 90 patients intended for surgery, of whom 84 had assessment of the primary endpoint, including 7 positive for EGFR and/or ALK, and 77 whose tumors were either EGFR/ALK negative or had unknown status. These 77 patients were the primary efficacy population.

As noted before, among the 77 in the primary efficacy population, 15 (19%) had a MPR, and 4 patients (5%) had a pCR. In addition, 38 patients (49%) had pathological regression of tumor of 50% or greater. Pathological regression correlated significantly with change in tumor lesion size (P less than .001).

Tumor mutational burden, however, was not significantly correlated with MPR or pathological regression.

Among the 101 patients in the safety population, there were two deaths deemed not related to study treatment: one cardiac death post surgical resection, and one from disease progression. Treatment-related adverse events occurred in 57% of patients, including 6% that were grade 3 or greater. Adverse events leading to treatment withdrawal occurred in 5% of patients.

The efficacy interim analysis passed the prespecified futility boundary, and investigators are continuing to enroll patients.

Neil Osterweil/MDedge News

Invited discussant Maximilian Diehn, MD, PhD, of Stanford (Calif.) University commented that neoadjuvant immunotherapy for NSCLC is promising, but added that the MPR endpoint still needs validation.

“Currently, it is not considered a validated surrogate endpoint for survival and therefore is not currently used for drug approvals. Secondly, the optimal cut point may differ by histology, such as being different for adenocarcinoma and squamous cell carcinoma. And this has potential implications for using this in trials that enroll patients of both histologies. And, third, there are some emerging data that MPR may need to measured somewhat differently after immunotherapy than after chemotherapy,” he said.

The study is supported by Genentech. Dr. Kwiatkowski disclosed research funding and a consulting or advisory role for the company. Dr. Diehn reported stock ownership, consulting, research funding, and travel expenses from various companies.

SOURCE: Kwiatkowski DJ et al. ASCO 2019, Abstract 8503.

CHICAGO – Neoadjuvant monotherapy with the immune checkpoint inhibitor atezolizumab is associated with “encouraging” responses with no new safety signals for patients with non–small cell lung cancer (NSCLC), an interim analysis of a multicenter phase 2 trial suggests.

Neil Osterweil/MDedge News

Among 77 of a planned 180 patients with resectable NSCLC enrolled in the LCMC3 (Lung Cancer Mutation Consortium 3) trial, the pathological complete response (pCR) rate following two cycles of neoadjuvant atezolizumab (Tecentriq) and surgery was 5%, and the major pathological response (MPR) rate was 19%, reported David J. Kwiatkowski, MD, PhD, of the Dana-Farber Cancer Institute in Boston.

“Pathological regression moderately correlated with target lesions’ measurements by RECIST [Response Evaluation Criteria in Solid Tumors] and MPR was observed irrespective of PD-L1 expression, although there was some correlation,” he said at the annual meeting of the American Society of Clinical Oncology.

The study was designed to test whether preoperative immunotherapy with an immune checkpoint inhibitor could have additional clinical benefits for patients with early-stage NSCLC.

Investigators are enrolling patients with stage IB, II, IIIA, or selected IIIB resectable, previously untreated NSCLC. Patients receive 1,200 mg atezolizumab on days 1 and 22 (two cycles), followed by surgery on or about day 40.

The primary endpoint, MPR, “means that at the time of surgical resection, all of the samples of the tumor that are cut into sections are reviewed by a pathologist, and an aggregate score of a percent of viable tumor cells is determined based on a comparison of viable tumor cells and necrotic tumor cells and stroma,” Dr. Kwiatkowski said.

The threshold for MPR was 10% or fewer viable tumor cells at the time of resection.

Following surgery, patients received standard-of-care adjuvant chemotherapy and could receive optional continued atezolizumab for an additional 12 months.

At the time of this interim analysis, with a data cutoff of Sept. 5, 2018, 101 patients had been enrolled and were included in the interim safety analysis. Of this group, 11 did not undergo surgery, because of progressive disease, withdrawal of consent, failed echocardiogram (1 patient), or pulmonary artery involvement (1) patient.

Of the 10 patients with either progressive disease and no surgery or unresectable disease at surgery, 8 had stage IIIA tumors and 2 had stage IIIB tumors. All patients with stage I or II disease underwent resection.

Dr. Kwiatkowski presented interim data on 90 patients intended for surgery, of whom 84 had assessment of the primary endpoint, including 7 positive for EGFR and/or ALK, and 77 whose tumors were either EGFR/ALK negative or had unknown status. These 77 patients were the primary efficacy population.

As noted before, among the 77 in the primary efficacy population, 15 (19%) had a MPR, and 4 patients (5%) had a pCR. In addition, 38 patients (49%) had pathological regression of tumor of 50% or greater. Pathological regression correlated significantly with change in tumor lesion size (P less than .001).

Tumor mutational burden, however, was not significantly correlated with MPR or pathological regression.

Among the 101 patients in the safety population, there were two deaths deemed not related to study treatment: one cardiac death post surgical resection, and one from disease progression. Treatment-related adverse events occurred in 57% of patients, including 6% that were grade 3 or greater. Adverse events leading to treatment withdrawal occurred in 5% of patients.

The efficacy interim analysis passed the prespecified futility boundary, and investigators are continuing to enroll patients.

Neil Osterweil/MDedge News

Invited discussant Maximilian Diehn, MD, PhD, of Stanford (Calif.) University commented that neoadjuvant immunotherapy for NSCLC is promising, but added that the MPR endpoint still needs validation.

“Currently, it is not considered a validated surrogate endpoint for survival and therefore is not currently used for drug approvals. Secondly, the optimal cut point may differ by histology, such as being different for adenocarcinoma and squamous cell carcinoma. And this has potential implications for using this in trials that enroll patients of both histologies. And, third, there are some emerging data that MPR may need to measured somewhat differently after immunotherapy than after chemotherapy,” he said.

The study is supported by Genentech. Dr. Kwiatkowski disclosed research funding and a consulting or advisory role for the company. Dr. Diehn reported stock ownership, consulting, research funding, and travel expenses from various companies.

SOURCE: Kwiatkowski DJ et al. ASCO 2019, Abstract 8503.

Red blood cell (RBC) transfusions from either previously pregnant, sex-discordant, or female donors were not significantly associated with higher mortality among transfusion recipients, according to a retrospective analysis of more than 1 million donors.

“This study used data from 3 large cohorts in the United States and Scandinavia to investigate whether blood donor sex and pregnancy history were associated with mortality of transfusion recipients,” wrote Gustaf Edgren, MD, PhD, of Karolinska University Hospital, Stockholm, and colleagues. The findings were published in JAMA.

The researchers analyzed data from three separate cohorts that included a combined 1,047,382 red blood cell transfusion recipients. Data collected included donor-related information, such as sex and pregnancy history, as well as survival data of transfusion recipients. The primary outcome measured was in-hospital mortality, and the secondary outcome was long-term mortality. Data were collected until Dec. 31, 2016.

The researchers found no statistically significant associations between either sex-discordant donors (male donor to female recipient or female donor to male recipient), female donors, or previously pregnant donors and in-hospital mortality of transfusion recipients.

The hazard ratio estimates for each unit transfused from a previously pregnant donor ranged from 1.00-1.01 in the three cohorts. Similarly, the HR estimates ranged from 0.99-1.00 for female donors in the three cohorts and 0.99-1.02 for sex discordant donors.

The only significant association found was observed in the smallest cohort of 34,662 recipients. Researchers found an increased risk of death in patients who received one to two sex discordant transfusions (HR, 1.08; 95% confidence interval, 1.03-1.14) or five to six transfusions (HR, 1.14; 95%CI, 1.01-1.29), compared with recipients who received no sex-discordant transfusions.

“The results are reassuring in that the survival of patients who got transfused with red blood cells does not appear to be associated with whether the blood they received was donated by a man, by a woman who had been pregnant — or by one who had not. That’s important to know,” Simone Glynn, MD, chief of the Blood Epidemiology and Clinical Therapeutics Branch at the National Heart, Lung, and Blood Institute, as well as a study author, said in a statement.

The study was funded by the National Heart, Lung, and Blood Institute. The authors reported financial disclosures related to the National Institutes of Health, RTI International, Cerus, AABB, Creative Testing Solutions, and the Nordic Cancer Union.

SOURCE: Edgren G et al. JAMA. 2019 Jun 11. doi: 10.1001/jama.2019.7084.

Red blood cell (RBC) transfusions from either previously pregnant, sex-discordant, or female donors were not significantly associated with higher mortality among transfusion recipients, according to a retrospective analysis of more than 1 million donors.

“This study used data from 3 large cohorts in the United States and Scandinavia to investigate whether blood donor sex and pregnancy history were associated with mortality of transfusion recipients,” wrote Gustaf Edgren, MD, PhD, of Karolinska University Hospital, Stockholm, and colleagues. The findings were published in JAMA.

The researchers analyzed data from three separate cohorts that included a combined 1,047,382 red blood cell transfusion recipients. Data collected included donor-related information, such as sex and pregnancy history, as well as survival data of transfusion recipients. The primary outcome measured was in-hospital mortality, and the secondary outcome was long-term mortality. Data were collected until Dec. 31, 2016.

The researchers found no statistically significant associations between either sex-discordant donors (male donor to female recipient or female donor to male recipient), female donors, or previously pregnant donors and in-hospital mortality of transfusion recipients.

The hazard ratio estimates for each unit transfused from a previously pregnant donor ranged from 1.00-1.01 in the three cohorts. Similarly, the HR estimates ranged from 0.99-1.00 for female donors in the three cohorts and 0.99-1.02 for sex discordant donors.

The only significant association found was observed in the smallest cohort of 34,662 recipients. Researchers found an increased risk of death in patients who received one to two sex discordant transfusions (HR, 1.08; 95% confidence interval, 1.03-1.14) or five to six transfusions (HR, 1.14; 95%CI, 1.01-1.29), compared with recipients who received no sex-discordant transfusions.

“The results are reassuring in that the survival of patients who got transfused with red blood cells does not appear to be associated with whether the blood they received was donated by a man, by a woman who had been pregnant — or by one who had not. That’s important to know,” Simone Glynn, MD, chief of the Blood Epidemiology and Clinical Therapeutics Branch at the National Heart, Lung, and Blood Institute, as well as a study author, said in a statement.

The study was funded by the National Heart, Lung, and Blood Institute. The authors reported financial disclosures related to the National Institutes of Health, RTI International, Cerus, AABB, Creative Testing Solutions, and the Nordic Cancer Union.

SOURCE: Edgren G et al. JAMA. 2019 Jun 11. doi: 10.1001/jama.2019.7084.

Red blood cell (RBC) transfusions from either previously pregnant, sex-discordant, or female donors were not significantly associated with higher mortality among transfusion recipients, according to a retrospective analysis of more than 1 million donors.

“This study used data from 3 large cohorts in the United States and Scandinavia to investigate whether blood donor sex and pregnancy history were associated with mortality of transfusion recipients,” wrote Gustaf Edgren, MD, PhD, of Karolinska University Hospital, Stockholm, and colleagues. The findings were published in JAMA.

The researchers analyzed data from three separate cohorts that included a combined 1,047,382 red blood cell transfusion recipients. Data collected included donor-related information, such as sex and pregnancy history, as well as survival data of transfusion recipients. The primary outcome measured was in-hospital mortality, and the secondary outcome was long-term mortality. Data were collected until Dec. 31, 2016.

The researchers found no statistically significant associations between either sex-discordant donors (male donor to female recipient or female donor to male recipient), female donors, or previously pregnant donors and in-hospital mortality of transfusion recipients.

The hazard ratio estimates for each unit transfused from a previously pregnant donor ranged from 1.00-1.01 in the three cohorts. Similarly, the HR estimates ranged from 0.99-1.00 for female donors in the three cohorts and 0.99-1.02 for sex discordant donors.

The only significant association found was observed in the smallest cohort of 34,662 recipients. Researchers found an increased risk of death in patients who received one to two sex discordant transfusions (HR, 1.08; 95% confidence interval, 1.03-1.14) or five to six transfusions (HR, 1.14; 95%CI, 1.01-1.29), compared with recipients who received no sex-discordant transfusions.

“The results are reassuring in that the survival of patients who got transfused with red blood cells does not appear to be associated with whether the blood they received was donated by a man, by a woman who had been pregnant — or by one who had not. That’s important to know,” Simone Glynn, MD, chief of the Blood Epidemiology and Clinical Therapeutics Branch at the National Heart, Lung, and Blood Institute, as well as a study author, said in a statement.

The study was funded by the National Heart, Lung, and Blood Institute. The authors reported financial disclosures related to the National Institutes of Health, RTI International, Cerus, AABB, Creative Testing Solutions, and the Nordic Cancer Union.

SOURCE: Edgren G et al. JAMA. 2019 Jun 11. doi: 10.1001/jama.2019.7084.

LJUBLJANA, SLOVENIA – Prevention or early effective treatment of respiratory syncytial virus (RSV) infection in infants and small children holds the promise of sharply reduced burdens of both acute otitis media (AOM) and pneumonia, Terho Heikkinen, MD, PhD, predicted in the Bill Marshall Award Lecture presented at the annual meeting of the European Society for Paediatric Infectious Diseases (ESPID).

RSV is by far the hottest virus in the world,” declared Dr. Heikkinen, professor of pediatrics at the University of Turku (Finland).

“A lot of progress is being made with respect to RSV. This increased understanding holds great promise for new interventions,” he explained. “Lots of different types of vaccines are being developed, monoclonal antibodies, antivirals. So there is a hope that within a number of years we will have interventions against RSV.”

Today influenza is the only respiratory viral infection that’s preventable via vaccine or effectively treatable using antiviral drugs. That situation has to change, as Dr. Heikkinen demonstrated early in his career; RSV is the respiratory virus that’s most likely to invade the middle ear during AOM. It’s much more ototropic than influenza, parainfluenza, enteroviruses, or adenoviruses (N Engl J Med. 1999 Jan 28;340[4]:260-4), he noted.

The Bill Marshall Award and Lecture, ESPID’s most prestigious award, is given annually to an individual recognized as having significantly advanced the field of pediatric infectious diseases. Dr. Heikkinen was singled out for his decades of work establishing that viruses, including RSV, play a key role in AOM, which had traditionally been regarded as a bacterial infection. He and his coinvestigators demonstrated that in about two-thirds of cases, AOM is actually caused by a combination of bacteria and viruses, which explains why patients’ clinical response to antibiotic therapy for AOM often is poor. They also described the chain of events whereby viral infection of the upper airway epithelium triggers an inflammatory response in the nasopharynx, with resultant Eustachian tube dysfunction and negative middle ear pressure, which in turn encourages microbial invasion of the middle ear. Moreover, they showed that the peak incidence of AOM isn’t on day 1 after onset of upper respiratory infection symptoms, but on day 3 or 4.

“What this tells us is that, once a child has a viral respiratory infection, there is a certain window of opportunity to try to prevent the development of the complication if we have the right tools in place,” Dr. Heikkinen said.

He and his colleagues put this lesson to good use nearly a decade ago in a randomized, double-blind trial in which they showed that giving oseltamivir (Tamiflu) within 12 hours after onset of influenza symptoms in children aged 1-3 years reduced the subsequent incidence of AOM by 85%, compared with placebo (Clin Infect Dis. 2010 Oct 15;51[8]:887-94).

These observations paved the way for the ongoing intensive research effort exploring ways of preventing AOM through interventions at two different levels: by developing viral vaccines to prevent a healthy child from contracting the viral upper respiratory infection that precedes AOM and by coming up with antiviral drugs or bacterial vaccines to prevent a upper respiratory infection from evolving into AOM.

The same applies to pneumonia. Other investigators showed years ago that both respiratory viruses and bacteria were present in two-thirds of sputum samples obtained from children with community-acquired pneumonia (Clin Microbiol Infect. 2012 Mar;18[3]:300-7).

RSV is the top cause of hospitalization for acute respiratory infection – pneumonia and bronchiolitis – in infants. Worldwide, it’s estimated that RSV accounts for more than 33 million episodes of pneumonia annually, with 3.2 million hospitalizations and 118,200 deaths.

Beyond the hospital, however, Dr. Heikkinen and colleagues conducted a prospective cohort study in Turku over the course of two consecutive respiratory infection seasons in which they captured the huge burden of RSV as an outpatient illness. It hit hardest in children younger than 3 years, in whom the average annual incidence of RSV infection was 275 cases per 1,000 children. In that youngest age population, RSV upper respiratory infection was followed by AOM 58% of the time, with antibiotics prescribed in 66% of the cases of this complication of RSV illness. The mean duration of RSV illness was greatest in this young age group, at 13 days, and it was associated with parental absenteeism from work at a rate of 136 days per 100 children with RSV illness.

Moreover, while AOM occurred less frequently in children aged 3-6 years, 46% of the cases were attributed to a preceding RSV infection, which led to antibiotic treatment nearly half of the time (J Infect Dis. 2017 Jan 1;215[1]:17-23). This documentation has spurred further efforts to develop RSV vaccines and antivirals.

bjancin@mdedge.com

LJUBLJANA, SLOVENIA – Prevention or early effective treatment of respiratory syncytial virus (RSV) infection in infants and small children holds the promise of sharply reduced burdens of both acute otitis media (AOM) and pneumonia, Terho Heikkinen, MD, PhD, predicted in the Bill Marshall Award Lecture presented at the annual meeting of the European Society for Paediatric Infectious Diseases (ESPID).

RSV is by far the hottest virus in the world,” declared Dr. Heikkinen, professor of pediatrics at the University of Turku (Finland).

“A lot of progress is being made with respect to RSV. This increased understanding holds great promise for new interventions,” he explained. “Lots of different types of vaccines are being developed, monoclonal antibodies, antivirals. So there is a hope that within a number of years we will have interventions against RSV.”

Today influenza is the only respiratory viral infection that’s preventable via vaccine or effectively treatable using antiviral drugs. That situation has to change, as Dr. Heikkinen demonstrated early in his career; RSV is the respiratory virus that’s most likely to invade the middle ear during AOM. It’s much more ototropic than influenza, parainfluenza, enteroviruses, or adenoviruses (N Engl J Med. 1999 Jan 28;340[4]:260-4), he noted.

The Bill Marshall Award and Lecture, ESPID’s most prestigious award, is given annually to an individual recognized as having significantly advanced the field of pediatric infectious diseases. Dr. Heikkinen was singled out for his decades of work establishing that viruses, including RSV, play a key role in AOM, which had traditionally been regarded as a bacterial infection. He and his coinvestigators demonstrated that in about two-thirds of cases, AOM is actually caused by a combination of bacteria and viruses, which explains why patients’ clinical response to antibiotic therapy for AOM often is poor. They also described the chain of events whereby viral infection of the upper airway epithelium triggers an inflammatory response in the nasopharynx, with resultant Eustachian tube dysfunction and negative middle ear pressure, which in turn encourages microbial invasion of the middle ear. Moreover, they showed that the peak incidence of AOM isn’t on day 1 after onset of upper respiratory infection symptoms, but on day 3 or 4.

“What this tells us is that, once a child has a viral respiratory infection, there is a certain window of opportunity to try to prevent the development of the complication if we have the right tools in place,” Dr. Heikkinen said.

He and his colleagues put this lesson to good use nearly a decade ago in a randomized, double-blind trial in which they showed that giving oseltamivir (Tamiflu) within 12 hours after onset of influenza symptoms in children aged 1-3 years reduced the subsequent incidence of AOM by 85%, compared with placebo (Clin Infect Dis. 2010 Oct 15;51[8]:887-94).

These observations paved the way for the ongoing intensive research effort exploring ways of preventing AOM through interventions at two different levels: by developing viral vaccines to prevent a healthy child from contracting the viral upper respiratory infection that precedes AOM and by coming up with antiviral drugs or bacterial vaccines to prevent a upper respiratory infection from evolving into AOM.

The same applies to pneumonia. Other investigators showed years ago that both respiratory viruses and bacteria were present in two-thirds of sputum samples obtained from children with community-acquired pneumonia (Clin Microbiol Infect. 2012 Mar;18[3]:300-7).

RSV is the top cause of hospitalization for acute respiratory infection – pneumonia and bronchiolitis – in infants. Worldwide, it’s estimated that RSV accounts for more than 33 million episodes of pneumonia annually, with 3.2 million hospitalizations and 118,200 deaths.

Beyond the hospital, however, Dr. Heikkinen and colleagues conducted a prospective cohort study in Turku over the course of two consecutive respiratory infection seasons in which they captured the huge burden of RSV as an outpatient illness. It hit hardest in children younger than 3 years, in whom the average annual incidence of RSV infection was 275 cases per 1,000 children. In that youngest age population, RSV upper respiratory infection was followed by AOM 58% of the time, with antibiotics prescribed in 66% of the cases of this complication of RSV illness. The mean duration of RSV illness was greatest in this young age group, at 13 days, and it was associated with parental absenteeism from work at a rate of 136 days per 100 children with RSV illness.

Moreover, while AOM occurred less frequently in children aged 3-6 years, 46% of the cases were attributed to a preceding RSV infection, which led to antibiotic treatment nearly half of the time (J Infect Dis. 2017 Jan 1;215[1]:17-23). This documentation has spurred further efforts to develop RSV vaccines and antivirals.

bjancin@mdedge.com

LJUBLJANA, SLOVENIA – Prevention or early effective treatment of respiratory syncytial virus (RSV) infection in infants and small children holds the promise of sharply reduced burdens of both acute otitis media (AOM) and pneumonia, Terho Heikkinen, MD, PhD, predicted in the Bill Marshall Award Lecture presented at the annual meeting of the European Society for Paediatric Infectious Diseases (ESPID).

RSV is by far the hottest virus in the world,” declared Dr. Heikkinen, professor of pediatrics at the University of Turku (Finland).

“A lot of progress is being made with respect to RSV. This increased understanding holds great promise for new interventions,” he explained. “Lots of different types of vaccines are being developed, monoclonal antibodies, antivirals. So there is a hope that within a number of years we will have interventions against RSV.”

Today influenza is the only respiratory viral infection that’s preventable via vaccine or effectively treatable using antiviral drugs. That situation has to change, as Dr. Heikkinen demonstrated early in his career; RSV is the respiratory virus that’s most likely to invade the middle ear during AOM. It’s much more ototropic than influenza, parainfluenza, enteroviruses, or adenoviruses (N Engl J Med. 1999 Jan 28;340[4]:260-4), he noted.

The Bill Marshall Award and Lecture, ESPID’s most prestigious award, is given annually to an individual recognized as having significantly advanced the field of pediatric infectious diseases. Dr. Heikkinen was singled out for his decades of work establishing that viruses, including RSV, play a key role in AOM, which had traditionally been regarded as a bacterial infection. He and his coinvestigators demonstrated that in about two-thirds of cases, AOM is actually caused by a combination of bacteria and viruses, which explains why patients’ clinical response to antibiotic therapy for AOM often is poor. They also described the chain of events whereby viral infection of the upper airway epithelium triggers an inflammatory response in the nasopharynx, with resultant Eustachian tube dysfunction and negative middle ear pressure, which in turn encourages microbial invasion of the middle ear. Moreover, they showed that the peak incidence of AOM isn’t on day 1 after onset of upper respiratory infection symptoms, but on day 3 or 4.

“What this tells us is that, once a child has a viral respiratory infection, there is a certain window of opportunity to try to prevent the development of the complication if we have the right tools in place,” Dr. Heikkinen said.

He and his colleagues put this lesson to good use nearly a decade ago in a randomized, double-blind trial in which they showed that giving oseltamivir (Tamiflu) within 12 hours after onset of influenza symptoms in children aged 1-3 years reduced the subsequent incidence of AOM by 85%, compared with placebo (Clin Infect Dis. 2010 Oct 15;51[8]:887-94).

These observations paved the way for the ongoing intensive research effort exploring ways of preventing AOM through interventions at two different levels: by developing viral vaccines to prevent a healthy child from contracting the viral upper respiratory infection that precedes AOM and by coming up with antiviral drugs or bacterial vaccines to prevent a upper respiratory infection from evolving into AOM.

The same applies to pneumonia. Other investigators showed years ago that both respiratory viruses and bacteria were present in two-thirds of sputum samples obtained from children with community-acquired pneumonia (Clin Microbiol Infect. 2012 Mar;18[3]:300-7).

RSV is the top cause of hospitalization for acute respiratory infection – pneumonia and bronchiolitis – in infants. Worldwide, it’s estimated that RSV accounts for more than 33 million episodes of pneumonia annually, with 3.2 million hospitalizations and 118,200 deaths.

Beyond the hospital, however, Dr. Heikkinen and colleagues conducted a prospective cohort study in Turku over the course of two consecutive respiratory infection seasons in which they captured the huge burden of RSV as an outpatient illness. It hit hardest in children younger than 3 years, in whom the average annual incidence of RSV infection was 275 cases per 1,000 children. In that youngest age population, RSV upper respiratory infection was followed by AOM 58% of the time, with antibiotics prescribed in 66% of the cases of this complication of RSV illness. The mean duration of RSV illness was greatest in this young age group, at 13 days, and it was associated with parental absenteeism from work at a rate of 136 days per 100 children with RSV illness.

Moreover, while AOM occurred less frequently in children aged 3-6 years, 46% of the cases were attributed to a preceding RSV infection, which led to antibiotic treatment nearly half of the time (J Infect Dis. 2017 Jan 1;215[1]:17-23). This documentation has spurred further efforts to develop RSV vaccines and antivirals.

bjancin@mdedge.com

About a quarter of all patients with ankylosing spondylitis, and more than half of those patients who were on Medicaid, received at least a 90-day supply of opioids in a year, based on an analysis of U.S. commercial claims data.

sdominick/iStock/Getty Images

The findings were noted in 2012-2017 data from a cohort of 11,945 patients in the Truven Health MarketScan Research database. Of those patients given the International Classification of Diseases (ICD) code 720.0, which is specific for ankylosing spondylitis, 23.5% of patients chronically used opioids. In the broader 720.x commercial claims cohort of 79,190 patients, the proportion who chronically used opioids was 27.3%.

More than 60% of the patients who chronically used opioids had a cumulative drug supply of 270 days or more.

“Patients with ankylosing spondylitis receive opioids with disturbing frequency,” said study author Victor S. Sloan, MD, and research colleagues in the June issue of the Journal of Rheumatology. Ankylosing spondylitis treatment guidelines “specify use of an NSAID as initial pharmacotherapy, with anti-TNF [tumor necrosis factor] therapy in cases of NSAID inefficacy or intolerance. However, for many patients, prescription opioids – while not addressing the underlying inflammation – may offer an inexpensive and rapid means of achieving symptomatic relief.”

Patients who chronically used opioids were more likely to have depression (25.4% vs. 12.5%) and anxiety (20.9% vs. 11.7%) during the baseline period of the study. Patients with chronic opioid use also were more likely to receive muscle relaxants (54.4% vs. 20.2%) and oral corticosteroids (18.4% vs. 9.6%), compared with patients without chronic opioid use, reported Dr. Sloan, vice president and immunology development strategy lead for UCB Pharma and of the Rutgers Robert Wood Johnson Medical School in New Brunswick, N.J., and colleagues.

Claims for anti-TNF therapies, disease-modifying antirheumatic drugs (DMARDs), and NSAIDs were similar for patients with and without chronic opioid use.

The patients in the study had claims with the specified diagnosis codes during Jan. 1, 2013–March 31, 2016 and were enrolled in medical and pharmacy benefits for 12 months before and after the first qualifying ICD code. The study excluded patients with a history of cancer other than nonmelanoma skin cancer. Opioid claims within 7 days of a hospitalization or 2 days of an emergency department or urgent care visit were not included.

The investigators assessed patients’ demographics, clinical characteristics, comorbidities, and prior treatments during a 12-month baseline period prior to the index date. They examined opioid use and exposure to other treatments during a 12-month follow-up period after the index date. They defined chronic opioid use as at least 90 cumulative days of opioid use based on the supply value on opioid pharmacy claims. They summed the days’ supply for all opioid claims during the follow-up period.

Chronic use of opioids was most pronounced in the 917 patients with Medicaid claims with 720.0 diagnosis codes; 57.1% chronically used opioids during follow-up. Among 14,041 patients with Medicaid claims with 720.x codes, 76.7% chronically used opioids.

The data suggest that some patients may receive opioids before they receive recommended therapies. “If this is the case, there may be an opportunity to prevent chronic opioid use by intervening with recommended therapies earlier in the patient’s treatment course,” the authors wrote.

Dr. Sloan and colleagues noted that they had limited information about the timing of opioid use relative to ankylosing spondylitis diagnosis, opioid potency and dose, and the indication for which opioids were prescribed.

UCB Pharma funded the study. The authors are employees of UCB Pharma.

jremaly@mdedge.com

SOURCE: Sloan VS et al. J Rheumatol. 2019 Jan 15. doi: 10.3899/jrheum.180972.

About a quarter of all patients with ankylosing spondylitis, and more than half of those patients who were on Medicaid, received at least a 90-day supply of opioids in a year, based on an analysis of U.S. commercial claims data.

sdominick/iStock/Getty Images

The findings were noted in 2012-2017 data from a cohort of 11,945 patients in the Truven Health MarketScan Research database. Of those patients given the International Classification of Diseases (ICD) code 720.0, which is specific for ankylosing spondylitis, 23.5% of patients chronically used opioids. In the broader 720.x commercial claims cohort of 79,190 patients, the proportion who chronically used opioids was 27.3%.

More than 60% of the patients who chronically used opioids had a cumulative drug supply of 270 days or more.

“Patients with ankylosing spondylitis receive opioids with disturbing frequency,” said study author Victor S. Sloan, MD, and research colleagues in the June issue of the Journal of Rheumatology. Ankylosing spondylitis treatment guidelines “specify use of an NSAID as initial pharmacotherapy, with anti-TNF [tumor necrosis factor] therapy in cases of NSAID inefficacy or intolerance. However, for many patients, prescription opioids – while not addressing the underlying inflammation – may offer an inexpensive and rapid means of achieving symptomatic relief.”

Patients who chronically used opioids were more likely to have depression (25.4% vs. 12.5%) and anxiety (20.9% vs. 11.7%) during the baseline period of the study. Patients with chronic opioid use also were more likely to receive muscle relaxants (54.4% vs. 20.2%) and oral corticosteroids (18.4% vs. 9.6%), compared with patients without chronic opioid use, reported Dr. Sloan, vice president and immunology development strategy lead for UCB Pharma and of the Rutgers Robert Wood Johnson Medical School in New Brunswick, N.J., and colleagues.

Claims for anti-TNF therapies, disease-modifying antirheumatic drugs (DMARDs), and NSAIDs were similar for patients with and without chronic opioid use.

The patients in the study had claims with the specified diagnosis codes during Jan. 1, 2013–March 31, 2016 and were enrolled in medical and pharmacy benefits for 12 months before and after the first qualifying ICD code. The study excluded patients with a history of cancer other than nonmelanoma skin cancer. Opioid claims within 7 days of a hospitalization or 2 days of an emergency department or urgent care visit were not included.

The investigators assessed patients’ demographics, clinical characteristics, comorbidities, and prior treatments during a 12-month baseline period prior to the index date. They examined opioid use and exposure to other treatments during a 12-month follow-up period after the index date. They defined chronic opioid use as at least 90 cumulative days of opioid use based on the supply value on opioid pharmacy claims. They summed the days’ supply for all opioid claims during the follow-up period.

Chronic use of opioids was most pronounced in the 917 patients with Medicaid claims with 720.0 diagnosis codes; 57.1% chronically used opioids during follow-up. Among 14,041 patients with Medicaid claims with 720.x codes, 76.7% chronically used opioids.

The data suggest that some patients may receive opioids before they receive recommended therapies. “If this is the case, there may be an opportunity to prevent chronic opioid use by intervening with recommended therapies earlier in the patient’s treatment course,” the authors wrote.

Dr. Sloan and colleagues noted that they had limited information about the timing of opioid use relative to ankylosing spondylitis diagnosis, opioid potency and dose, and the indication for which opioids were prescribed.

UCB Pharma funded the study. The authors are employees of UCB Pharma.

jremaly@mdedge.com

SOURCE: Sloan VS et al. J Rheumatol. 2019 Jan 15. doi: 10.3899/jrheum.180972.

About a quarter of all patients with ankylosing spondylitis, and more than half of those patients who were on Medicaid, received at least a 90-day supply of opioids in a year, based on an analysis of U.S. commercial claims data.

sdominick/iStock/Getty Images

The findings were noted in 2012-2017 data from a cohort of 11,945 patients in the Truven Health MarketScan Research database. Of those patients given the International Classification of Diseases (ICD) code 720.0, which is specific for ankylosing spondylitis, 23.5% of patients chronically used opioids. In the broader 720.x commercial claims cohort of 79,190 patients, the proportion who chronically used opioids was 27.3%.

More than 60% of the patients who chronically used opioids had a cumulative drug supply of 270 days or more.

“Patients with ankylosing spondylitis receive opioids with disturbing frequency,” said study author Victor S. Sloan, MD, and research colleagues in the June issue of the Journal of Rheumatology. Ankylosing spondylitis treatment guidelines “specify use of an NSAID as initial pharmacotherapy, with anti-TNF [tumor necrosis factor] therapy in cases of NSAID inefficacy or intolerance. However, for many patients, prescription opioids – while not addressing the underlying inflammation – may offer an inexpensive and rapid means of achieving symptomatic relief.”

Patients who chronically used opioids were more likely to have depression (25.4% vs. 12.5%) and anxiety (20.9% vs. 11.7%) during the baseline period of the study. Patients with chronic opioid use also were more likely to receive muscle relaxants (54.4% vs. 20.2%) and oral corticosteroids (18.4% vs. 9.6%), compared with patients without chronic opioid use, reported Dr. Sloan, vice president and immunology development strategy lead for UCB Pharma and of the Rutgers Robert Wood Johnson Medical School in New Brunswick, N.J., and colleagues.

Claims for anti-TNF therapies, disease-modifying antirheumatic drugs (DMARDs), and NSAIDs were similar for patients with and without chronic opioid use.

The patients in the study had claims with the specified diagnosis codes during Jan. 1, 2013–March 31, 2016 and were enrolled in medical and pharmacy benefits for 12 months before and after the first qualifying ICD code. The study excluded patients with a history of cancer other than nonmelanoma skin cancer. Opioid claims within 7 days of a hospitalization or 2 days of an emergency department or urgent care visit were not included.

The investigators assessed patients’ demographics, clinical characteristics, comorbidities, and prior treatments during a 12-month baseline period prior to the index date. They examined opioid use and exposure to other treatments during a 12-month follow-up period after the index date. They defined chronic opioid use as at least 90 cumulative days of opioid use based on the supply value on opioid pharmacy claims. They summed the days’ supply for all opioid claims during the follow-up period.

Chronic use of opioids was most pronounced in the 917 patients with Medicaid claims with 720.0 diagnosis codes; 57.1% chronically used opioids during follow-up. Among 14,041 patients with Medicaid claims with 720.x codes, 76.7% chronically used opioids.

The data suggest that some patients may receive opioids before they receive recommended therapies. “If this is the case, there may be an opportunity to prevent chronic opioid use by intervening with recommended therapies earlier in the patient’s treatment course,” the authors wrote.

Dr. Sloan and colleagues noted that they had limited information about the timing of opioid use relative to ankylosing spondylitis diagnosis, opioid potency and dose, and the indication for which opioids were prescribed.

UCB Pharma funded the study. The authors are employees of UCB Pharma.

jremaly@mdedge.com

SOURCE: Sloan VS et al. J Rheumatol. 2019 Jan 15. doi: 10.3899/jrheum.180972.

CHICAGO – Two immune checkpoint inhibitors were better than one as neoadjuvant therapy for patients with resectable early-stage non–small cell lung cancer (NSCLC) in the phase 2 NEOSTAR trial.

Among 44 patients with stage I-IIIA NSCLC who were randomized to either a combination of nivolumab (Opdivo) and ipilimumab (Yervoy) or to nivolumab alone, the combination was associated with higher rates of the primary endpoint of major pathological response (MPR), defined as a reduction in viable tumors cells to 10% or less, reported Tina Cascone, MD, PhD, from the University of Texas MD Anderson Cancer Center in Houston.

“Nivolumab/ipilimumab induced a 44% MPR rate in resected patients, met the trial prespecified boundary with seven MPRs in the intention-to-treat population, and induced pathologic complete responses in 38% of resected patients,” she said at the annual meeting of the American Society of Clinical Oncology.

To test whether neoadjuvant monotherapy or combination therapy could improve outcomes of standard induction chemotherapy, NEOSTAR investigators enrolled patients with NSCLC stage I-IIIA, including patients with a single involved mediastinal node (N2 single station) who were eligible for surgical resection.

The patients were randomized on a 1:1 basis to receive nivolumab 3 mg/kg on days 1, 15 and 29 alone or in combination with ipilimumab delivered 1 mg/kg on day 1, followed by surgery 3-6 weeks after the last study dose and then postoperative standard-of-care chemotherapy.

Of 53 patients screened, 44 were eligible, with 23 randomized to nivolumab monotherapy and 21 randomized to nivolumab/ipilimumab. Of this group, five did not proceed to surgery (one in the monotherapy arm, four in the combination arm) because of either high surgical risk, lack of respectability, or refusal of surgery. The mean age at randomization was 65.6 years. In all, 18% were never smokers, and the remaining 82% were former or current smokers.

The MPR rate in the intention-to-treat population – the primary endpoint – was reached in four patients (17%) in the monotherapy arm and in seven patients (33%) in the combination arm. As noted, the combination arm reached the prespecified boundary of six or more patients with an MPR. All patients in each arm who had an MPR also had a pathologic complete responses.

Of the 39 patients who went on to resection, 37 were evaluable, and in these patients the respective MPR rates were 19% and 44%. Two patients on nivolumab alone and six on nivolumab plus ipilimumab had 0% viable tumor detectable at the time of surgery. Radiographic responses included one complete response in the combination arm and eight total partial responses, in five and three patients, respectively. The objective response rated was 20%. The responses, assessed by Response Evaluation Criteria in Solid Tumors (RECIST) were positively associated with MPR, Dr. Cascone said.

In 11% of patients, the investigators observed apparent radiographic progression after neoadjuvant immune checkpoint inhibitors in mediastinal and or in nonregional nodes. However, pathological assessment and evaluation of the flaring nodes did not reveal evidence of disease, but instead showed noncaseating granulomas that were not present at baseline.

“Awareness of this phenomenon, which we named the ‘nodal immune flare,’ is of critical importance, as if the clinician fails to distinguish the nodal immune flare from disease progression, potential curative surgery for these patients could be avoided,” she said.

Grade 1 or 2 treatment-related adverse events included rash, itching, fatigue, anemia, cough, and diarrhea. Grade 3 or greater treatment-related adverse events included hypoxia, pneumonia, and pneumonitis in the nivolumab monotherapy arm and diarrhea and hyponatremia in the combination group. One patient treated with nivolumab monotherapy, who had achieved 0% viable tumor, had grade 3 pneumonia and pneumonitis, which was treated with steroids that impeded the healing of a bronchopleural fistula and subsequent empyema. Other surgical complications included air leaks, which occurred in five patients in the nivolumab group and three in the nivolumab plus ipilimumab arm.

Two patients died, one in the monotherapy arm from steroid-treated pneumonitis 4.1 months after randomization and one in the combination arm who had progressive disease 2 months after randomization, and died from the disease 15 months later.

Invited discussant Maximilian Diehn, MD, PhD, from Stanford (California) University School of Medicine, commented that the choice of neoadjuvant immunotherapy was not based on molecular markers, “and I think we have a major unmet need for developing biomarkers for personalized treatment in this area.

“Ideally, the biomarkers that we would have in this setting would, A, allow us to identify which patients have micrometastatic disease and therefore are likely to benefit from the upfront systemic therapy and, secondly, also could tell us which neoadjuvant therapy they would respond to, be it immunotherapy, chemotherapy, or the combination,” he added.

The study was supported by Bristol-Myers Squibb. Dr. Cascone disclosed honoraria from the company. Dr. Diehn reported stock ownership, consulting, research funding and travel expenses from various companies.



SOURCE: Cascone T. et al. ASCO 2019, Abstract 8504.

CHICAGO – Two immune checkpoint inhibitors were better than one as neoadjuvant therapy for patients with resectable early-stage non–small cell lung cancer (NSCLC) in the phase 2 NEOSTAR trial.

Among 44 patients with stage I-IIIA NSCLC who were randomized to either a combination of nivolumab (Opdivo) and ipilimumab (Yervoy) or to nivolumab alone, the combination was associated with higher rates of the primary endpoint of major pathological response (MPR), defined as a reduction in viable tumors cells to 10% or less, reported Tina Cascone, MD, PhD, from the University of Texas MD Anderson Cancer Center in Houston.

“Nivolumab/ipilimumab induced a 44% MPR rate in resected patients, met the trial prespecified boundary with seven MPRs in the intention-to-treat population, and induced pathologic complete responses in 38% of resected patients,” she said at the annual meeting of the American Society of Clinical Oncology.

To test whether neoadjuvant monotherapy or combination therapy could improve outcomes of standard induction chemotherapy, NEOSTAR investigators enrolled patients with NSCLC stage I-IIIA, including patients with a single involved mediastinal node (N2 single station) who were eligible for surgical resection.

The patients were randomized on a 1:1 basis to receive nivolumab 3 mg/kg on days 1, 15 and 29 alone or in combination with ipilimumab delivered 1 mg/kg on day 1, followed by surgery 3-6 weeks after the last study dose and then postoperative standard-of-care chemotherapy.

Of 53 patients screened, 44 were eligible, with 23 randomized to nivolumab monotherapy and 21 randomized to nivolumab/ipilimumab. Of this group, five did not proceed to surgery (one in the monotherapy arm, four in the combination arm) because of either high surgical risk, lack of respectability, or refusal of surgery. The mean age at randomization was 65.6 years. In all, 18% were never smokers, and the remaining 82% were former or current smokers.

The MPR rate in the intention-to-treat population – the primary endpoint – was reached in four patients (17%) in the monotherapy arm and in seven patients (33%) in the combination arm. As noted, the combination arm reached the prespecified boundary of six or more patients with an MPR. All patients in each arm who had an MPR also had a pathologic complete responses.

Of the 39 patients who went on to resection, 37 were evaluable, and in these patients the respective MPR rates were 19% and 44%. Two patients on nivolumab alone and six on nivolumab plus ipilimumab had 0% viable tumor detectable at the time of surgery. Radiographic responses included one complete response in the combination arm and eight total partial responses, in five and three patients, respectively. The objective response rated was 20%. The responses, assessed by Response Evaluation Criteria in Solid Tumors (RECIST) were positively associated with MPR, Dr. Cascone said.

In 11% of patients, the investigators observed apparent radiographic progression after neoadjuvant immune checkpoint inhibitors in mediastinal and or in nonregional nodes. However, pathological assessment and evaluation of the flaring nodes did not reveal evidence of disease, but instead showed noncaseating granulomas that were not present at baseline.

“Awareness of this phenomenon, which we named the ‘nodal immune flare,’ is of critical importance, as if the clinician fails to distinguish the nodal immune flare from disease progression, potential curative surgery for these patients could be avoided,” she said.

Grade 1 or 2 treatment-related adverse events included rash, itching, fatigue, anemia, cough, and diarrhea. Grade 3 or greater treatment-related adverse events included hypoxia, pneumonia, and pneumonitis in the nivolumab monotherapy arm and diarrhea and hyponatremia in the combination group. One patient treated with nivolumab monotherapy, who had achieved 0% viable tumor, had grade 3 pneumonia and pneumonitis, which was treated with steroids that impeded the healing of a bronchopleural fistula and subsequent empyema. Other surgical complications included air leaks, which occurred in five patients in the nivolumab group and three in the nivolumab plus ipilimumab arm.

Two patients died, one in the monotherapy arm from steroid-treated pneumonitis 4.1 months after randomization and one in the combination arm who had progressive disease 2 months after randomization, and died from the disease 15 months later.

Invited discussant Maximilian Diehn, MD, PhD, from Stanford (California) University School of Medicine, commented that the choice of neoadjuvant immunotherapy was not based on molecular markers, “and I think we have a major unmet need for developing biomarkers for personalized treatment in this area.

“Ideally, the biomarkers that we would have in this setting would, A, allow us to identify which patients have micrometastatic disease and therefore are likely to benefit from the upfront systemic therapy and, secondly, also could tell us which neoadjuvant therapy they would respond to, be it immunotherapy, chemotherapy, or the combination,” he added.

The study was supported by Bristol-Myers Squibb. Dr. Cascone disclosed honoraria from the company. Dr. Diehn reported stock ownership, consulting, research funding and travel expenses from various companies.



SOURCE: Cascone T. et al. ASCO 2019, Abstract 8504.

CHICAGO – Two immune checkpoint inhibitors were better than one as neoadjuvant therapy for patients with resectable early-stage non–small cell lung cancer (NSCLC) in the phase 2 NEOSTAR trial.

Among 44 patients with stage I-IIIA NSCLC who were randomized to either a combination of nivolumab (Opdivo) and ipilimumab (Yervoy) or to nivolumab alone, the combination was associated with higher rates of the primary endpoint of major pathological response (MPR), defined as a reduction in viable tumors cells to 10% or less, reported Tina Cascone, MD, PhD, from the University of Texas MD Anderson Cancer Center in Houston.

“Nivolumab/ipilimumab induced a 44% MPR rate in resected patients, met the trial prespecified boundary with seven MPRs in the intention-to-treat population, and induced pathologic complete responses in 38% of resected patients,” she said at the annual meeting of the American Society of Clinical Oncology.

To test whether neoadjuvant monotherapy or combination therapy could improve outcomes of standard induction chemotherapy, NEOSTAR investigators enrolled patients with NSCLC stage I-IIIA, including patients with a single involved mediastinal node (N2 single station) who were eligible for surgical resection.

The patients were randomized on a 1:1 basis to receive nivolumab 3 mg/kg on days 1, 15 and 29 alone or in combination with ipilimumab delivered 1 mg/kg on day 1, followed by surgery 3-6 weeks after the last study dose and then postoperative standard-of-care chemotherapy.

Of 53 patients screened, 44 were eligible, with 23 randomized to nivolumab monotherapy and 21 randomized to nivolumab/ipilimumab. Of this group, five did not proceed to surgery (one in the monotherapy arm, four in the combination arm) because of either high surgical risk, lack of respectability, or refusal of surgery. The mean age at randomization was 65.6 years. In all, 18% were never smokers, and the remaining 82% were former or current smokers.

The MPR rate in the intention-to-treat population – the primary endpoint – was reached in four patients (17%) in the monotherapy arm and in seven patients (33%) in the combination arm. As noted, the combination arm reached the prespecified boundary of six or more patients with an MPR. All patients in each arm who had an MPR also had a pathologic complete responses.

Of the 39 patients who went on to resection, 37 were evaluable, and in these patients the respective MPR rates were 19% and 44%. Two patients on nivolumab alone and six on nivolumab plus ipilimumab had 0% viable tumor detectable at the time of surgery. Radiographic responses included one complete response in the combination arm and eight total partial responses, in five and three patients, respectively. The objective response rated was 20%. The responses, assessed by Response Evaluation Criteria in Solid Tumors (RECIST) were positively associated with MPR, Dr. Cascone said.

In 11% of patients, the investigators observed apparent radiographic progression after neoadjuvant immune checkpoint inhibitors in mediastinal and or in nonregional nodes. However, pathological assessment and evaluation of the flaring nodes did not reveal evidence of disease, but instead showed noncaseating granulomas that were not present at baseline.

“Awareness of this phenomenon, which we named the ‘nodal immune flare,’ is of critical importance, as if the clinician fails to distinguish the nodal immune flare from disease progression, potential curative surgery for these patients could be avoided,” she said.

Grade 1 or 2 treatment-related adverse events included rash, itching, fatigue, anemia, cough, and diarrhea. Grade 3 or greater treatment-related adverse events included hypoxia, pneumonia, and pneumonitis in the nivolumab monotherapy arm and diarrhea and hyponatremia in the combination group. One patient treated with nivolumab monotherapy, who had achieved 0% viable tumor, had grade 3 pneumonia and pneumonitis, which was treated with steroids that impeded the healing of a bronchopleural fistula and subsequent empyema. Other surgical complications included air leaks, which occurred in five patients in the nivolumab group and three in the nivolumab plus ipilimumab arm.

Two patients died, one in the monotherapy arm from steroid-treated pneumonitis 4.1 months after randomization and one in the combination arm who had progressive disease 2 months after randomization, and died from the disease 15 months later.

Invited discussant Maximilian Diehn, MD, PhD, from Stanford (California) University School of Medicine, commented that the choice of neoadjuvant immunotherapy was not based on molecular markers, “and I think we have a major unmet need for developing biomarkers for personalized treatment in this area.

“Ideally, the biomarkers that we would have in this setting would, A, allow us to identify which patients have micrometastatic disease and therefore are likely to benefit from the upfront systemic therapy and, secondly, also could tell us which neoadjuvant therapy they would respond to, be it immunotherapy, chemotherapy, or the combination,” he added.

The study was supported by Bristol-Myers Squibb. Dr. Cascone disclosed honoraria from the company. Dr. Diehn reported stock ownership, consulting, research funding and travel expenses from various companies.



SOURCE: Cascone T. et al. ASCO 2019, Abstract 8504.

The U.S. Preventive Services Task Force reaffirmed its recommendations for screening patients for HIV infection.

According to the task force, screening is recommended for all patients aged 15-65 years. Screening also is recommended for adolescents and older adults at increased risk for acquiring HIV infection and for all pregnant patients, including those in labor whose HIV status is unknown (JAMA. 2019. doi: 10.1001/jama.2019.6587).

Patients who are considered at increased risk for acquiring HIV include the following: Men who have sex with men, those who inject drugs, those who have receptive sex without a condom, those with at least one partner whose HIV status is positive or unknown, those who have transactional sex, and those who request testing for sexually transmitted infection, including HIV. All recommendations are A-level, meaning the task force recommends the service,with high certainty that the net benefit is substantial.

In a systematic review created for the task force, Roger Chou, MD, of Oregon Health & Science University, Portland, and colleagues found there continued to be no studies that examined the benefits and harms of HIV screening for HIV infections, compared with no screening, but new evidence found beginning antiretroviral therapy (ART) for patients with CD4 cell counts greater than 500/mm³ who are otherwise asymptomatic was associated with a reduced risk of mortality, compared with waiting for ART in cases of CD4 cell counts less than 350/mm³ (JAMA. 2019. doi: 10.1001/jama.2019.2592).

A second systematic review of pregnant patients by Shelley S. Selph, MD, also of Oregon Health & Science University, Portland, and colleagues found no studies examining the effectiveness of prenatal screening on mother-to-child HIV transmission, but combination ART was significantly effective at reducing transmission between mother and child, while ART that includes a boosted protease inhibitor may result in preterm delivery (JAMA. 2019. doi: 10.1001/jama.2019.2593).

Although no studies have been conducted that compare the benefits of screening with not screening for HIV, the task force concluded with “high certainty” that early HIV detection and treatment has “substantial benefits.”

“Clinicians can make a real difference toward reducing the burden of HIV in the United States,” Douglas K. Owens, MD, task force chairman, said in a statement. “HIV screening and HIV prevention work to reduce new HIV infections and ultimately save lives.”

The USPSTF is a voluntary, independent body, with operations supported by the U.S. Agency for Healthcare Research and Quality. Task force members received travel reimbursement and an honorarium for attending meetings. Dr. Owens reports financial disclosures with relation to HIV infection screening, preexposure prophylaxis for HIV prevention, and hepatitis C screening. Other task force members reported no relevant conflicts of interest.

SOURCE: JAMA. 2019. doi: 10.1001/jama.2019.6587.

The U.S. Preventive Services Task Force reaffirmed its recommendations for screening patients for HIV infection.

According to the task force, screening is recommended for all patients aged 15-65 years. Screening also is recommended for adolescents and older adults at increased risk for acquiring HIV infection and for all pregnant patients, including those in labor whose HIV status is unknown (JAMA. 2019. doi: 10.1001/jama.2019.6587).

Patients who are considered at increased risk for acquiring HIV include the following: Men who have sex with men, those who inject drugs, those who have receptive sex without a condom, those with at least one partner whose HIV status is positive or unknown, those who have transactional sex, and those who request testing for sexually transmitted infection, including HIV. All recommendations are A-level, meaning the task force recommends the service,with high certainty that the net benefit is substantial.

In a systematic review created for the task force, Roger Chou, MD, of Oregon Health & Science University, Portland, and colleagues found there continued to be no studies that examined the benefits and harms of HIV screening for HIV infections, compared with no screening, but new evidence found beginning antiretroviral therapy (ART) for patients with CD4 cell counts greater than 500/mm³ who are otherwise asymptomatic was associated with a reduced risk of mortality, compared with waiting for ART in cases of CD4 cell counts less than 350/mm³ (JAMA. 2019. doi: 10.1001/jama.2019.2592).

A second systematic review of pregnant patients by Shelley S. Selph, MD, also of Oregon Health & Science University, Portland, and colleagues found no studies examining the effectiveness of prenatal screening on mother-to-child HIV transmission, but combination ART was significantly effective at reducing transmission between mother and child, while ART that includes a boosted protease inhibitor may result in preterm delivery (JAMA. 2019. doi: 10.1001/jama.2019.2593).

Although no studies have been conducted that compare the benefits of screening with not screening for HIV, the task force concluded with “high certainty” that early HIV detection and treatment has “substantial benefits.”

“Clinicians can make a real difference toward reducing the burden of HIV in the United States,” Douglas K. Owens, MD, task force chairman, said in a statement. “HIV screening and HIV prevention work to reduce new HIV infections and ultimately save lives.”

The USPSTF is a voluntary, independent body, with operations supported by the U.S. Agency for Healthcare Research and Quality. Task force members received travel reimbursement and an honorarium for attending meetings. Dr. Owens reports financial disclosures with relation to HIV infection screening, preexposure prophylaxis for HIV prevention, and hepatitis C screening. Other task force members reported no relevant conflicts of interest.

SOURCE: JAMA. 2019. doi: 10.1001/jama.2019.6587.

The U.S. Preventive Services Task Force reaffirmed its recommendations for screening patients for HIV infection.

According to the task force, screening is recommended for all patients aged 15-65 years. Screening also is recommended for adolescents and older adults at increased risk for acquiring HIV infection and for all pregnant patients, including those in labor whose HIV status is unknown (JAMA. 2019. doi: 10.1001/jama.2019.6587).

Patients who are considered at increased risk for acquiring HIV include the following: Men who have sex with men, those who inject drugs, those who have receptive sex without a condom, those with at least one partner whose HIV status is positive or unknown, those who have transactional sex, and those who request testing for sexually transmitted infection, including HIV. All recommendations are A-level, meaning the task force recommends the service,with high certainty that the net benefit is substantial.

In a systematic review created for the task force, Roger Chou, MD, of Oregon Health & Science University, Portland, and colleagues found there continued to be no studies that examined the benefits and harms of HIV screening for HIV infections, compared with no screening, but new evidence found beginning antiretroviral therapy (ART) for patients with CD4 cell counts greater than 500/mm³ who are otherwise asymptomatic was associated with a reduced risk of mortality, compared with waiting for ART in cases of CD4 cell counts less than 350/mm³ (JAMA. 2019. doi: 10.1001/jama.2019.2592).

A second systematic review of pregnant patients by Shelley S. Selph, MD, also of Oregon Health & Science University, Portland, and colleagues found no studies examining the effectiveness of prenatal screening on mother-to-child HIV transmission, but combination ART was significantly effective at reducing transmission between mother and child, while ART that includes a boosted protease inhibitor may result in preterm delivery (JAMA. 2019. doi: 10.1001/jama.2019.2593).

Although no studies have been conducted that compare the benefits of screening with not screening for HIV, the task force concluded with “high certainty” that early HIV detection and treatment has “substantial benefits.”

“Clinicians can make a real difference toward reducing the burden of HIV in the United States,” Douglas K. Owens, MD, task force chairman, said in a statement. “HIV screening and HIV prevention work to reduce new HIV infections and ultimately save lives.”

The USPSTF is a voluntary, independent body, with operations supported by the U.S. Agency for Healthcare Research and Quality. Task force members received travel reimbursement and an honorarium for attending meetings. Dr. Owens reports financial disclosures with relation to HIV infection screening, preexposure prophylaxis for HIV prevention, and hepatitis C screening. Other task force members reported no relevant conflicts of interest.

SOURCE: JAMA. 2019. doi: 10.1001/jama.2019.6587.

Hypertension is one of the most common reasons for patient visits.¹ According to the US Preventive Services Task Force, more than 70 million individuals older than 20 have hypertension, which is defined as a blood pressure (BP) of ≥ 130/85 mm Hg.² Essential hypertension is the most common form of this condition; most affected patients will show improvement with evidence-based pharmacologic treatment, lifestyle modifications, and risk factor reductions.

For patients with refractory hypertension, however, identifying what steps to take in screening and diagnosis can be daunting for clinicians. It is important to identify cases of secondary hypertension, because if it is left undiagnosed and untreated, serious complications—such as cardiovascular and renal disease—are likely to occur.^3,4

Secondary hypertension can be caused by myriad disease states and disorders, including endocrine ­disorders, renal disease, neurologic disorders, acute stress, and drug-induced hypertension.⁵ Endocrine hypertension is most commonly caused by adrenal gland disorders, including primary aldosteronism, Cushing syndrome, and pheochromocytoma. (Of note, Cushing syndrome is caused by glucocorticoid-secreting adrenal tumors, while Cushing disease is a condition in which there is glucocorticoid excess caused by oversecretion of pituitary adrenocorticotropic hormone.⁶ Cushing disease is more common than Cushing syndrome, which is rare.⁷) While nonadrenal endocrine disorders are not as common, they pose significant health issues, including growth hormone excess or deficiency, thyroid disorders, testosterone deficiency, obesity, insulin resistance, and metabolic syndrome.⁸

Understanding the endocrine causes of hypertension is a valuable resource for clinicians to have in their toolbox. Although the negative consequences of endocrine disorders are significant, these conditions are often recognizable, and pharmacologic treatment and/or surgical interventions can potentially resolve or improve hypertension and reduce risk for other comorbidities. This article summarizes screening and diagnosis guidelines for several possible causes of endocrine hypertension: primary aldosteronism, Cushing syndrome, and pheochromocytoma.

PRIMARY ALDOSTERONISM

Primary aldosteronism occurs in 5% to 10% of all hypertensive patients and is a common cause of secondary and endocrine hypertension (although in younger—particularly female—patients, it most commonly causes renal artery stenosis).^9,10 Historically, primary aldosteronism was considered rare and not generally included in a differential diagnosis for patients presenting with resistant hypertension. However, clinical investigations have indicated that primary aldosteronism is more prevalent than previously thought.¹¹

Patients develop this condition when there is increased aldosterone production independent of the renin-angiotensin system. The resulting sodium retention can lead to hypertension, hypokalemia, and high plasma aldosterone/renin ratio (ARR).¹² Clinical findings and symptoms can be vague, increasing the difficulty in identifying primary aldosteronism as the diagnosis. Patients may be asymptomatic, with the only abnormal lab finding being hypokalemia (an infrequent finding, affecting < 25% of patients).¹³ If hypokalemia is present, symptoms can include nocturia, polyuria, muscle weakness, cramps, paresthesias, and palpitations.¹¹

The Endocrine Society has identified 8 characteristics that increase the likelihood of primary aldosteronism. Patients require further screening if they

1. Have a sustained elevated BP (≥ 150 mm Hg [systolic] and/or 100 mm Hg [diastolic])
2. Have hypertension (BP > 140/90 mm Hg) that is resistant to 3 conventional antihypertensive drugs, including a diuretic
3. Have controlled BP (BP < 140/90 mm Hg) with ≥ 4 antihypertensive drugs
4. Have hypertension and spontaneous or diuretic-induced hypokalemia
5. Have hypertension and adrenal incidentaloma
6. Have hypertension and obstructive sleep apnea
7. Have hypertension and a family history of early-onset hypertension or a cerebrovascular accident at a young age (< 40 years)
8. Are hypertensive and a first-degree relative of a patient with primary aldosteronism.¹⁴

Continue to: The most reliable screening test...

The most reliable screening test for primary aldosterone is the ARR, although false-negative and false-positive results are possible.¹¹ False-negative results can be caused by dietary salt restriction, hypokalemia, and use of medications including diuretics, calcium channel blockers, ACE inhibitors, and angiotensin receptor antagonists. Use of ß-adrenergic blockers, α-methyldopa, or NSAIDs can cause false-positive results.¹⁵ Patients should be encouraged to follow a liberal sodium diet before ARR testing, and efforts to correct hypokalemia should be implemented. Before ARR is measured, diuretics (specifically spironolactone) should be stopped for at least 4 weeks; other possible interfering medications should be stopped for at least 2 weeks.¹⁶

The ARR should be obtained multiple times to confirm elevated readings.¹⁶ Reference ranges vary, but generally plasma aldosterone concentrations > 20 ng/dL and plasma renin activity < 1 ng/mL/h indicate whether confirmatory testing should be completed.¹⁴ Further confirmatory testing can be achieved with efforts to suppress plasma aldosterone to < 10 ng/dL after an IV infusion of 2 L isotonic saline over 4 hours.¹² Oral sodium load is used as well and usually before IV infusion.

CUSHING SYNDROME

Cushing syndrome is caused by excess circulating levels of glucocorticoids and affects < 0.1% of the world population.¹⁷ Signs and symptoms include centripetal obesity, moon facies, facial plethora, easy bruising, buffalo hump (or posterior cervical fat pad), hirsutism, and wide-purple striae.¹⁸ Up to 80% of these patients also have hypertension.¹⁹ If these patients have chronic exposure to high levels of glucocorticoid (the most common source being therapeutic administration of exogenous glucocorticoids), multiple complications can occur.^6,20

The Endocrine Society Clinical Practice Guideline recommends the following patient groups be tested for Cushing syndrome:

1. Young patients with unusual medical conditions, such as osteoporosis and resistant hypertension
2. Patients with classic signs and symptoms, such as easy bruising, weight gain, facial plethora, and purple striae
3. Children with decreasing height percentile and increasing weight
4. Patients with adrenal incidentaloma compatible with adenoma.¹⁸

If Cushing syndrome is suspected, 1 of the following 3 initial tests can be completed: 24-hour, urine-free cortisol and creatinine; late-night salivary cortisol; or 1-mg overnight dexamethasone suppression test. Two of these tests must have abnormal results for confirmation before appropriate pituitary or adrenal imaging. If a patient has clinical features indicating Cushing syndrome but test results are normal, he or she should be referred to an endocrinologist. If a patient has ≥ 2 normal tests and probability of Cushing syndrome is unlikely, patients should be recommended for follow-up in 6 months to evaluate for any worsening of symptoms.¹⁸

Continue to: PHEOCHROMOCYTOMA

 

 

PHEOCHROMOCYTOMA

Pheochromocytoma is a condition in which there is secretion of excess catecholamines, epinephrine, norepinephrine, and dopamine due to a tumor of the adrenal medulla.²¹ This is a rare disease and accounts for only 0.2% to 0.6% of all causes of hypertension.²² Hypertension (persistent or paroxysmal) is the most common finding for patients with pheochromocy­toma, with 80% to 90% presenting with this finding.²³ It is important to note that approximately 10% of these patients will be normotensive. Three of the condition’s classic symptoms are headache, sweating, and palpitations.²⁴ Additional symptoms include anxiety, sense of impending doom, fever, nausea, or vomiting.²¹

If left untreated, there is risk for hypertensive retinopathy, nephropathy, myocardial infarction, stroke from cerebral infarction, intracranial hemorrhage, or embolism.²⁵ Due to the high rate of morbidity and mortality with untreated pheochromocytoma, laboratory testing should be initiated immediately upon suspicion of this diagnosis or if the patient has relevant family history.¹¹

Patients should be screened for pheochromocytoma if they have ≥ 1 of the following factors:

1. Resistant hypertension and hyperadrenergic symptoms (palpitations, perspiration, pallor, or headache)
2. Family history of pheochromocytoma
3. Any genetic syndrome with a known association to pheochromocytoma
4. An adrenal mass that is > 4 cm, is cystic, or has hemorrhagic changes.¹⁹

Pheochromocytoma is diagnosed by identifying high concentrations of plasma-free metanephrines or 24-hour fractionated metanephrines and catecholamines. Some medications can interfere with the accuracy of lab results and therefore may need to be temporarily stopped; it is important to check the specific lab guidelines and review the patient’s medication lists before tests are ordered and conducted.²⁵

ALWAYS SCREEN THE PATIENT

Although the causes of endocrine-related hypertension are very rare, screening for endocrine hypertension in patients who present with signs and symptoms of these conditions can greatly improve their lives. The endocrine disorders discussed in this article can be treated or controlled with appropriate diagnosis and treatment. In addition, resolving uncontrolled hypertension by addressing endocrine disorders can reduce the risk for long-term sequelae. It is important for clinicians to consider referral to an endocrine specialist if a patient has endocrine-related hypertension. In particular, patients with pheochromocytoma require quick referral due to a risk for high morbidity and mortality if left untreated.¹¹

Hypertension is one of the most common reasons for patient visits.¹ According to the US Preventive Services Task Force, more than 70 million individuals older than 20 have hypertension, which is defined as a blood pressure (BP) of ≥ 130/85 mm Hg.² Essential hypertension is the most common form of this condition; most affected patients will show improvement with evidence-based pharmacologic treatment, lifestyle modifications, and risk factor reductions.

For patients with refractory hypertension, however, identifying what steps to take in screening and diagnosis can be daunting for clinicians. It is important to identify cases of secondary hypertension, because if it is left undiagnosed and untreated, serious complications—such as cardiovascular and renal disease—are likely to occur.^3,4

Secondary hypertension can be caused by myriad disease states and disorders, including endocrine ­disorders, renal disease, neurologic disorders, acute stress, and drug-induced hypertension.⁵ Endocrine hypertension is most commonly caused by adrenal gland disorders, including primary aldosteronism, Cushing syndrome, and pheochromocytoma. (Of note, Cushing syndrome is caused by glucocorticoid-secreting adrenal tumors, while Cushing disease is a condition in which there is glucocorticoid excess caused by oversecretion of pituitary adrenocorticotropic hormone.⁶ Cushing disease is more common than Cushing syndrome, which is rare.⁷) While nonadrenal endocrine disorders are not as common, they pose significant health issues, including growth hormone excess or deficiency, thyroid disorders, testosterone deficiency, obesity, insulin resistance, and metabolic syndrome.⁸

Understanding the endocrine causes of hypertension is a valuable resource for clinicians to have in their toolbox. Although the negative consequences of endocrine disorders are significant, these conditions are often recognizable, and pharmacologic treatment and/or surgical interventions can potentially resolve or improve hypertension and reduce risk for other comorbidities. This article summarizes screening and diagnosis guidelines for several possible causes of endocrine hypertension: primary aldosteronism, Cushing syndrome, and pheochromocytoma.

PRIMARY ALDOSTERONISM

Primary aldosteronism occurs in 5% to 10% of all hypertensive patients and is a common cause of secondary and endocrine hypertension (although in younger—particularly female—patients, it most commonly causes renal artery stenosis).^9,10 Historically, primary aldosteronism was considered rare and not generally included in a differential diagnosis for patients presenting with resistant hypertension. However, clinical investigations have indicated that primary aldosteronism is more prevalent than previously thought.¹¹

Patients develop this condition when there is increased aldosterone production independent of the renin-angiotensin system. The resulting sodium retention can lead to hypertension, hypokalemia, and high plasma aldosterone/renin ratio (ARR).¹² Clinical findings and symptoms can be vague, increasing the difficulty in identifying primary aldosteronism as the diagnosis. Patients may be asymptomatic, with the only abnormal lab finding being hypokalemia (an infrequent finding, affecting < 25% of patients).¹³ If hypokalemia is present, symptoms can include nocturia, polyuria, muscle weakness, cramps, paresthesias, and palpitations.¹¹

The Endocrine Society has identified 8 characteristics that increase the likelihood of primary aldosteronism. Patients require further screening if they

1. Have a sustained elevated BP (≥ 150 mm Hg [systolic] and/or 100 mm Hg [diastolic])
2. Have hypertension (BP > 140/90 mm Hg) that is resistant to 3 conventional antihypertensive drugs, including a diuretic
3. Have controlled BP (BP < 140/90 mm Hg) with ≥ 4 antihypertensive drugs
4. Have hypertension and spontaneous or diuretic-induced hypokalemia
5. Have hypertension and adrenal incidentaloma
6. Have hypertension and obstructive sleep apnea
7. Have hypertension and a family history of early-onset hypertension or a cerebrovascular accident at a young age (< 40 years)
8. Are hypertensive and a first-degree relative of a patient with primary aldosteronism.¹⁴

Continue to: The most reliable screening test...

The most reliable screening test for primary aldosterone is the ARR, although false-negative and false-positive results are possible.¹¹ False-negative results can be caused by dietary salt restriction, hypokalemia, and use of medications including diuretics, calcium channel blockers, ACE inhibitors, and angiotensin receptor antagonists. Use of ß-adrenergic blockers, α-methyldopa, or NSAIDs can cause false-positive results.¹⁵ Patients should be encouraged to follow a liberal sodium diet before ARR testing, and efforts to correct hypokalemia should be implemented. Before ARR is measured, diuretics (specifically spironolactone) should be stopped for at least 4 weeks; other possible interfering medications should be stopped for at least 2 weeks.¹⁶

The ARR should be obtained multiple times to confirm elevated readings.¹⁶ Reference ranges vary, but generally plasma aldosterone concentrations > 20 ng/dL and plasma renin activity < 1 ng/mL/h indicate whether confirmatory testing should be completed.¹⁴ Further confirmatory testing can be achieved with efforts to suppress plasma aldosterone to < 10 ng/dL after an IV infusion of 2 L isotonic saline over 4 hours.¹² Oral sodium load is used as well and usually before IV infusion.

CUSHING SYNDROME

Cushing syndrome is caused by excess circulating levels of glucocorticoids and affects < 0.1% of the world population.¹⁷ Signs and symptoms include centripetal obesity, moon facies, facial plethora, easy bruising, buffalo hump (or posterior cervical fat pad), hirsutism, and wide-purple striae.¹⁸ Up to 80% of these patients also have hypertension.¹⁹ If these patients have chronic exposure to high levels of glucocorticoid (the most common source being therapeutic administration of exogenous glucocorticoids), multiple complications can occur.^6,20

The Endocrine Society Clinical Practice Guideline recommends the following patient groups be tested for Cushing syndrome:

1. Young patients with unusual medical conditions, such as osteoporosis and resistant hypertension
2. Patients with classic signs and symptoms, such as easy bruising, weight gain, facial plethora, and purple striae
3. Children with decreasing height percentile and increasing weight
4. Patients with adrenal incidentaloma compatible with adenoma.¹⁸

If Cushing syndrome is suspected, 1 of the following 3 initial tests can be completed: 24-hour, urine-free cortisol and creatinine; late-night salivary cortisol; or 1-mg overnight dexamethasone suppression test. Two of these tests must have abnormal results for confirmation before appropriate pituitary or adrenal imaging. If a patient has clinical features indicating Cushing syndrome but test results are normal, he or she should be referred to an endocrinologist. If a patient has ≥ 2 normal tests and probability of Cushing syndrome is unlikely, patients should be recommended for follow-up in 6 months to evaluate for any worsening of symptoms.¹⁸

Continue to: PHEOCHROMOCYTOMA

 

 

PHEOCHROMOCYTOMA

Pheochromocytoma is a condition in which there is secretion of excess catecholamines, epinephrine, norepinephrine, and dopamine due to a tumor of the adrenal medulla.²¹ This is a rare disease and accounts for only 0.2% to 0.6% of all causes of hypertension.²² Hypertension (persistent or paroxysmal) is the most common finding for patients with pheochromocy­toma, with 80% to 90% presenting with this finding.²³ It is important to note that approximately 10% of these patients will be normotensive. Three of the condition’s classic symptoms are headache, sweating, and palpitations.²⁴ Additional symptoms include anxiety, sense of impending doom, fever, nausea, or vomiting.²¹

If left untreated, there is risk for hypertensive retinopathy, nephropathy, myocardial infarction, stroke from cerebral infarction, intracranial hemorrhage, or embolism.²⁵ Due to the high rate of morbidity and mortality with untreated pheochromocytoma, laboratory testing should be initiated immediately upon suspicion of this diagnosis or if the patient has relevant family history.¹¹

Patients should be screened for pheochromocytoma if they have ≥ 1 of the following factors:

1. Resistant hypertension and hyperadrenergic symptoms (palpitations, perspiration, pallor, or headache)
2. Family history of pheochromocytoma
3. Any genetic syndrome with a known association to pheochromocytoma
4. An adrenal mass that is > 4 cm, is cystic, or has hemorrhagic changes.¹⁹

Pheochromocytoma is diagnosed by identifying high concentrations of plasma-free metanephrines or 24-hour fractionated metanephrines and catecholamines. Some medications can interfere with the accuracy of lab results and therefore may need to be temporarily stopped; it is important to check the specific lab guidelines and review the patient’s medication lists before tests are ordered and conducted.²⁵

ALWAYS SCREEN THE PATIENT

Although the causes of endocrine-related hypertension are very rare, screening for endocrine hypertension in patients who present with signs and symptoms of these conditions can greatly improve their lives. The endocrine disorders discussed in this article can be treated or controlled with appropriate diagnosis and treatment. In addition, resolving uncontrolled hypertension by addressing endocrine disorders can reduce the risk for long-term sequelae. It is important for clinicians to consider referral to an endocrine specialist if a patient has endocrine-related hypertension. In particular, patients with pheochromocytoma require quick referral due to a risk for high morbidity and mortality if left untreated.¹¹

Hypertension is one of the most common reasons for patient visits.¹ According to the US Preventive Services Task Force, more than 70 million individuals older than 20 have hypertension, which is defined as a blood pressure (BP) of ≥ 130/85 mm Hg.² Essential hypertension is the most common form of this condition; most affected patients will show improvement with evidence-based pharmacologic treatment, lifestyle modifications, and risk factor reductions.

For patients with refractory hypertension, however, identifying what steps to take in screening and diagnosis can be daunting for clinicians. It is important to identify cases of secondary hypertension, because if it is left undiagnosed and untreated, serious complications—such as cardiovascular and renal disease—are likely to occur.^3,4

Secondary hypertension can be caused by myriad disease states and disorders, including endocrine ­disorders, renal disease, neurologic disorders, acute stress, and drug-induced hypertension.⁵ Endocrine hypertension is most commonly caused by adrenal gland disorders, including primary aldosteronism, Cushing syndrome, and pheochromocytoma. (Of note, Cushing syndrome is caused by glucocorticoid-secreting adrenal tumors, while Cushing disease is a condition in which there is glucocorticoid excess caused by oversecretion of pituitary adrenocorticotropic hormone.⁶ Cushing disease is more common than Cushing syndrome, which is rare.⁷) While nonadrenal endocrine disorders are not as common, they pose significant health issues, including growth hormone excess or deficiency, thyroid disorders, testosterone deficiency, obesity, insulin resistance, and metabolic syndrome.⁸

Understanding the endocrine causes of hypertension is a valuable resource for clinicians to have in their toolbox. Although the negative consequences of endocrine disorders are significant, these conditions are often recognizable, and pharmacologic treatment and/or surgical interventions can potentially resolve or improve hypertension and reduce risk for other comorbidities. This article summarizes screening and diagnosis guidelines for several possible causes of endocrine hypertension: primary aldosteronism, Cushing syndrome, and pheochromocytoma.

PRIMARY ALDOSTERONISM

Primary aldosteronism occurs in 5% to 10% of all hypertensive patients and is a common cause of secondary and endocrine hypertension (although in younger—particularly female—patients, it most commonly causes renal artery stenosis).^9,10 Historically, primary aldosteronism was considered rare and not generally included in a differential diagnosis for patients presenting with resistant hypertension. However, clinical investigations have indicated that primary aldosteronism is more prevalent than previously thought.¹¹

Patients develop this condition when there is increased aldosterone production independent of the renin-angiotensin system. The resulting sodium retention can lead to hypertension, hypokalemia, and high plasma aldosterone/renin ratio (ARR).¹² Clinical findings and symptoms can be vague, increasing the difficulty in identifying primary aldosteronism as the diagnosis. Patients may be asymptomatic, with the only abnormal lab finding being hypokalemia (an infrequent finding, affecting < 25% of patients).¹³ If hypokalemia is present, symptoms can include nocturia, polyuria, muscle weakness, cramps, paresthesias, and palpitations.¹¹

The Endocrine Society has identified 8 characteristics that increase the likelihood of primary aldosteronism. Patients require further screening if they

1. Have a sustained elevated BP (≥ 150 mm Hg [systolic] and/or 100 mm Hg [diastolic])
2. Have hypertension (BP > 140/90 mm Hg) that is resistant to 3 conventional antihypertensive drugs, including a diuretic
3. Have controlled BP (BP < 140/90 mm Hg) with ≥ 4 antihypertensive drugs
4. Have hypertension and spontaneous or diuretic-induced hypokalemia
5. Have hypertension and adrenal incidentaloma
6. Have hypertension and obstructive sleep apnea
7. Have hypertension and a family history of early-onset hypertension or a cerebrovascular accident at a young age (< 40 years)
8. Are hypertensive and a first-degree relative of a patient with primary aldosteronism.¹⁴

Continue to: The most reliable screening test...

The most reliable screening test for primary aldosterone is the ARR, although false-negative and false-positive results are possible.¹¹ False-negative results can be caused by dietary salt restriction, hypokalemia, and use of medications including diuretics, calcium channel blockers, ACE inhibitors, and angiotensin receptor antagonists. Use of ß-adrenergic blockers, α-methyldopa, or NSAIDs can cause false-positive results.¹⁵ Patients should be encouraged to follow a liberal sodium diet before ARR testing, and efforts to correct hypokalemia should be implemented. Before ARR is measured, diuretics (specifically spironolactone) should be stopped for at least 4 weeks; other possible interfering medications should be stopped for at least 2 weeks.¹⁶

The ARR should be obtained multiple times to confirm elevated readings.¹⁶ Reference ranges vary, but generally plasma aldosterone concentrations > 20 ng/dL and plasma renin activity < 1 ng/mL/h indicate whether confirmatory testing should be completed.¹⁴ Further confirmatory testing can be achieved with efforts to suppress plasma aldosterone to < 10 ng/dL after an IV infusion of 2 L isotonic saline over 4 hours.¹² Oral sodium load is used as well and usually before IV infusion.

CUSHING SYNDROME

Cushing syndrome is caused by excess circulating levels of glucocorticoids and affects < 0.1% of the world population.¹⁷ Signs and symptoms include centripetal obesity, moon facies, facial plethora, easy bruising, buffalo hump (or posterior cervical fat pad), hirsutism, and wide-purple striae.¹⁸ Up to 80% of these patients also have hypertension.¹⁹ If these patients have chronic exposure to high levels of glucocorticoid (the most common source being therapeutic administration of exogenous glucocorticoids), multiple complications can occur.^6,20

The Endocrine Society Clinical Practice Guideline recommends the following patient groups be tested for Cushing syndrome:

1. Young patients with unusual medical conditions, such as osteoporosis and resistant hypertension
2. Patients with classic signs and symptoms, such as easy bruising, weight gain, facial plethora, and purple striae
3. Children with decreasing height percentile and increasing weight
4. Patients with adrenal incidentaloma compatible with adenoma.¹⁸

If Cushing syndrome is suspected, 1 of the following 3 initial tests can be completed: 24-hour, urine-free cortisol and creatinine; late-night salivary cortisol; or 1-mg overnight dexamethasone suppression test. Two of these tests must have abnormal results for confirmation before appropriate pituitary or adrenal imaging. If a patient has clinical features indicating Cushing syndrome but test results are normal, he or she should be referred to an endocrinologist. If a patient has ≥ 2 normal tests and probability of Cushing syndrome is unlikely, patients should be recommended for follow-up in 6 months to evaluate for any worsening of symptoms.¹⁸

Continue to: PHEOCHROMOCYTOMA

 

 

PHEOCHROMOCYTOMA

Pheochromocytoma is a condition in which there is secretion of excess catecholamines, epinephrine, norepinephrine, and dopamine due to a tumor of the adrenal medulla.²¹ This is a rare disease and accounts for only 0.2% to 0.6% of all causes of hypertension.²² Hypertension (persistent or paroxysmal) is the most common finding for patients with pheochromocy­toma, with 80% to 90% presenting with this finding.²³ It is important to note that approximately 10% of these patients will be normotensive. Three of the condition’s classic symptoms are headache, sweating, and palpitations.²⁴ Additional symptoms include anxiety, sense of impending doom, fever, nausea, or vomiting.²¹

If left untreated, there is risk for hypertensive retinopathy, nephropathy, myocardial infarction, stroke from cerebral infarction, intracranial hemorrhage, or embolism.²⁵ Due to the high rate of morbidity and mortality with untreated pheochromocytoma, laboratory testing should be initiated immediately upon suspicion of this diagnosis or if the patient has relevant family history.¹¹

Patients should be screened for pheochromocytoma if they have ≥ 1 of the following factors:

1. Resistant hypertension and hyperadrenergic symptoms (palpitations, perspiration, pallor, or headache)
2. Family history of pheochromocytoma
3. Any genetic syndrome with a known association to pheochromocytoma
4. An adrenal mass that is > 4 cm, is cystic, or has hemorrhagic changes.¹⁹

Pheochromocytoma is diagnosed by identifying high concentrations of plasma-free metanephrines or 24-hour fractionated metanephrines and catecholamines. Some medications can interfere with the accuracy of lab results and therefore may need to be temporarily stopped; it is important to check the specific lab guidelines and review the patient’s medication lists before tests are ordered and conducted.²⁵

ALWAYS SCREEN THE PATIENT

Although the causes of endocrine-related hypertension are very rare, screening for endocrine hypertension in patients who present with signs and symptoms of these conditions can greatly improve their lives. The endocrine disorders discussed in this article can be treated or controlled with appropriate diagnosis and treatment. In addition, resolving uncontrolled hypertension by addressing endocrine disorders can reduce the risk for long-term sequelae. It is important for clinicians to consider referral to an endocrine specialist if a patient has endocrine-related hypertension. In particular, patients with pheochromocytoma require quick referral due to a risk for high morbidity and mortality if left untreated.¹¹

PHILADELPHIA – Mutant huntingtin and neurofilament light are valid potential biomarkers in Huntington’s disease and could be used in future clinical trials, according to an investigation presented at the annual meeting of the American Academy of Neurology. These biomarkers appear to reflect the earliest detectable changes in the natural history of Huntington’s disease, but the longitudinal prognostic value of changes in these biomarkers requires further investigation, the researchers said.

Huntington’s disease has a long prodromal phase and is associated with long survival. Investigators still need well-validated biomarkers of disease progression, prognosis, and pharmacodynamics to aid drug development, said Filipe B. Rodrigues, MD, clinical research fellow at University College London. After several years of study, Dr. Rodrigues and colleagues found mutant huntingtin and neurofilament light (NfL) to be the most promising potential biomarkers in Huntington’s disease. They sought to understand how these two biomarkers compare with each other, what their predictive ability is, and how they change longitudinally.

To this end, Dr. Rodrigues and colleagues designed the HD-CSF study, a prospective, observational, longitudinal cohort study with a 2-year follow-up. They recruited 20 healthy controls, 20 patients with premanifest Huntington’s disease, and 40 patients with manifest Huntington’s disease. All participants underwent regular clinical assessments and standardized collections of cerebrospinal fluid (CSF) and blood. They also had the option of undergoing brain MRI scans.

The investigators analyzed their data using multiple linear regression models, Pearson’s correlations, receiver operating characteristic curves, and sample size calculations. They used an event-based model to evaluate the temporal sequence of changes in Huntington’s disease-related biomarkers.

Dr. Rodrigues and colleagues first observed that all three biomarkers successfully distinguished between healthy controls, patients with premanifest Huntington’s disease, and patients with Huntington’s disease. Mutant huntingtin, the pathogenic agent in Huntington’s disease, discriminated perfectly between healthy controls and mutation carriers, as the researchers had expected. CSF and plasma levels of NfL also discriminated well between healthy controls and mutation carriers. These biomarkers had areas under the ROC curve greater than 0.9. NfL in plasma and CSF also distinguished well between patients with premanifest Huntington’s disease and those with manifest Huntington’s disease, with areas under the curve greater than 0.9. Their discriminative ability in this regard was significantly better than that of mutant huntingtin.

When the researchers examined the relationship between the three biomarkers, they found that CSF levels of NfL were strongly correlated in a linear fashion with plasma levels of NfL. CSF levels of mutant huntingtin were moderately associated with CSF levels of NfL.

Levels of all three biomarkers increased significantly as the disease progressed and were associated with all clinical scales and imaging measures. CSF and plasma levels of NfL had superior predictive ability for clinical and imaging measures, compared with mutant huntingtin. CSF and plasma NfL were associated with brain volume, but mutant huntingtin was not.

All three biomarkers were stable during a 6-week period. Dr. Rodrigues and colleagues calculated sample sizes for a two-arm interventional trial involving various hypothetical therapeutic effects. They found that the required sample sizes were small enough to be incorporated easily into ongoing and future clinical trials.

In silico modeling suggested among the markers measured in the HD-CSF study, the three biofluid biomarkers were the first factors to be altered in the course of Huntington’s disease. Alterations in the biomarkers were followed by changes in imaging markers, and then by changes in clinical markers (for example, motor and cognitive function).

Finally, Dr. Rodrigues and colleagues found preliminary evidence that levels of NfL in CSF and plasma increase over time at different rates in patients with Huntington’s disease, compared with healthy controls. NfL appears to be more useful than mutant huntingtin for evaluating the rate of disease progression than for gauging response to treatment, said Dr. Rodrigues. “If [we] can prove that we can assess response to treatment by measuring NfL, I think that would be great.”

The investigators are currently analyzing the longitudinal predictive value of changes in these biomarkers. They also have begun analyzing other markers such as tau and brain-derived neurotrophic factor.

This study was funded by the Medical Research Council UK, the CHDI Foundation, and F. Hoffmann-La Roche.
 

This article was updated 6/18/19.

egreb@mdedge.com

SOURCE: Rodrigues FB et al. AAN 2019, Abstract S16.003.

PHILADELPHIA – Mutant huntingtin and neurofilament light are valid potential biomarkers in Huntington’s disease and could be used in future clinical trials, according to an investigation presented at the annual meeting of the American Academy of Neurology. These biomarkers appear to reflect the earliest detectable changes in the natural history of Huntington’s disease, but the longitudinal prognostic value of changes in these biomarkers requires further investigation, the researchers said.

Huntington’s disease has a long prodromal phase and is associated with long survival. Investigators still need well-validated biomarkers of disease progression, prognosis, and pharmacodynamics to aid drug development, said Filipe B. Rodrigues, MD, clinical research fellow at University College London. After several years of study, Dr. Rodrigues and colleagues found mutant huntingtin and neurofilament light (NfL) to be the most promising potential biomarkers in Huntington’s disease. They sought to understand how these two biomarkers compare with each other, what their predictive ability is, and how they change longitudinally.

To this end, Dr. Rodrigues and colleagues designed the HD-CSF study, a prospective, observational, longitudinal cohort study with a 2-year follow-up. They recruited 20 healthy controls, 20 patients with premanifest Huntington’s disease, and 40 patients with manifest Huntington’s disease. All participants underwent regular clinical assessments and standardized collections of cerebrospinal fluid (CSF) and blood. They also had the option of undergoing brain MRI scans.

The investigators analyzed their data using multiple linear regression models, Pearson’s correlations, receiver operating characteristic curves, and sample size calculations. They used an event-based model to evaluate the temporal sequence of changes in Huntington’s disease-related biomarkers.

Dr. Rodrigues and colleagues first observed that all three biomarkers successfully distinguished between healthy controls, patients with premanifest Huntington’s disease, and patients with Huntington’s disease. Mutant huntingtin, the pathogenic agent in Huntington’s disease, discriminated perfectly between healthy controls and mutation carriers, as the researchers had expected. CSF and plasma levels of NfL also discriminated well between healthy controls and mutation carriers. These biomarkers had areas under the ROC curve greater than 0.9. NfL in plasma and CSF also distinguished well between patients with premanifest Huntington’s disease and those with manifest Huntington’s disease, with areas under the curve greater than 0.9. Their discriminative ability in this regard was significantly better than that of mutant huntingtin.

When the researchers examined the relationship between the three biomarkers, they found that CSF levels of NfL were strongly correlated in a linear fashion with plasma levels of NfL. CSF levels of mutant huntingtin were moderately associated with CSF levels of NfL.

Levels of all three biomarkers increased significantly as the disease progressed and were associated with all clinical scales and imaging measures. CSF and plasma levels of NfL had superior predictive ability for clinical and imaging measures, compared with mutant huntingtin. CSF and plasma NfL were associated with brain volume, but mutant huntingtin was not.

All three biomarkers were stable during a 6-week period. Dr. Rodrigues and colleagues calculated sample sizes for a two-arm interventional trial involving various hypothetical therapeutic effects. They found that the required sample sizes were small enough to be incorporated easily into ongoing and future clinical trials.

In silico modeling suggested among the markers measured in the HD-CSF study, the three biofluid biomarkers were the first factors to be altered in the course of Huntington’s disease. Alterations in the biomarkers were followed by changes in imaging markers, and then by changes in clinical markers (for example, motor and cognitive function).

Finally, Dr. Rodrigues and colleagues found preliminary evidence that levels of NfL in CSF and plasma increase over time at different rates in patients with Huntington’s disease, compared with healthy controls. NfL appears to be more useful than mutant huntingtin for evaluating the rate of disease progression than for gauging response to treatment, said Dr. Rodrigues. “If [we] can prove that we can assess response to treatment by measuring NfL, I think that would be great.”

The investigators are currently analyzing the longitudinal predictive value of changes in these biomarkers. They also have begun analyzing other markers such as tau and brain-derived neurotrophic factor.

This study was funded by the Medical Research Council UK, the CHDI Foundation, and F. Hoffmann-La Roche.
 

This article was updated 6/18/19.

egreb@mdedge.com

SOURCE: Rodrigues FB et al. AAN 2019, Abstract S16.003.

PHILADELPHIA – Mutant huntingtin and neurofilament light are valid potential biomarkers in Huntington’s disease and could be used in future clinical trials, according to an investigation presented at the annual meeting of the American Academy of Neurology. These biomarkers appear to reflect the earliest detectable changes in the natural history of Huntington’s disease, but the longitudinal prognostic value of changes in these biomarkers requires further investigation, the researchers said.

Huntington’s disease has a long prodromal phase and is associated with long survival. Investigators still need well-validated biomarkers of disease progression, prognosis, and pharmacodynamics to aid drug development, said Filipe B. Rodrigues, MD, clinical research fellow at University College London. After several years of study, Dr. Rodrigues and colleagues found mutant huntingtin and neurofilament light (NfL) to be the most promising potential biomarkers in Huntington’s disease. They sought to understand how these two biomarkers compare with each other, what their predictive ability is, and how they change longitudinally.

To this end, Dr. Rodrigues and colleagues designed the HD-CSF study, a prospective, observational, longitudinal cohort study with a 2-year follow-up. They recruited 20 healthy controls, 20 patients with premanifest Huntington’s disease, and 40 patients with manifest Huntington’s disease. All participants underwent regular clinical assessments and standardized collections of cerebrospinal fluid (CSF) and blood. They also had the option of undergoing brain MRI scans.

The investigators analyzed their data using multiple linear regression models, Pearson’s correlations, receiver operating characteristic curves, and sample size calculations. They used an event-based model to evaluate the temporal sequence of changes in Huntington’s disease-related biomarkers.

Dr. Rodrigues and colleagues first observed that all three biomarkers successfully distinguished between healthy controls, patients with premanifest Huntington’s disease, and patients with Huntington’s disease. Mutant huntingtin, the pathogenic agent in Huntington’s disease, discriminated perfectly between healthy controls and mutation carriers, as the researchers had expected. CSF and plasma levels of NfL also discriminated well between healthy controls and mutation carriers. These biomarkers had areas under the ROC curve greater than 0.9. NfL in plasma and CSF also distinguished well between patients with premanifest Huntington’s disease and those with manifest Huntington’s disease, with areas under the curve greater than 0.9. Their discriminative ability in this regard was significantly better than that of mutant huntingtin.

When the researchers examined the relationship between the three biomarkers, they found that CSF levels of NfL were strongly correlated in a linear fashion with plasma levels of NfL. CSF levels of mutant huntingtin were moderately associated with CSF levels of NfL.

Levels of all three biomarkers increased significantly as the disease progressed and were associated with all clinical scales and imaging measures. CSF and plasma levels of NfL had superior predictive ability for clinical and imaging measures, compared with mutant huntingtin. CSF and plasma NfL were associated with brain volume, but mutant huntingtin was not.

All three biomarkers were stable during a 6-week period. Dr. Rodrigues and colleagues calculated sample sizes for a two-arm interventional trial involving various hypothetical therapeutic effects. They found that the required sample sizes were small enough to be incorporated easily into ongoing and future clinical trials.

In silico modeling suggested among the markers measured in the HD-CSF study, the three biofluid biomarkers were the first factors to be altered in the course of Huntington’s disease. Alterations in the biomarkers were followed by changes in imaging markers, and then by changes in clinical markers (for example, motor and cognitive function).

Finally, Dr. Rodrigues and colleagues found preliminary evidence that levels of NfL in CSF and plasma increase over time at different rates in patients with Huntington’s disease, compared with healthy controls. NfL appears to be more useful than mutant huntingtin for evaluating the rate of disease progression than for gauging response to treatment, said Dr. Rodrigues. “If [we] can prove that we can assess response to treatment by measuring NfL, I think that would be great.”

The investigators are currently analyzing the longitudinal predictive value of changes in these biomarkers. They also have begun analyzing other markers such as tau and brain-derived neurotrophic factor.

This study was funded by the Medical Research Council UK, the CHDI Foundation, and F. Hoffmann-La Roche.
 

This article was updated 6/18/19.

egreb@mdedge.com

SOURCE: Rodrigues FB et al. AAN 2019, Abstract S16.003.