On the morning of Feb. 24, rheumatologist Olena Garmish woke at 5:50 a.m. from the blasts of rocket fire in Kiev, Ukraine, and saw the explosions through her window

She described that next week to this news organization: air sirens 20 hours a day, fearing death 24 hours a day, and growing food shortages.

Dr. Garmish, executive director of the Association of Rheumatologists of Ukraine, said she continued working at a Kiev hospital until March 4, but then had to leave the country with her children and has traveled to two other countries since. Now she is looking for employment abroad after 22 years as a clinical researcher and practitioner.

omersukrugoksu/Getty Images

“We lost our jobs and rheumatology practice,” she said. Now, she says, she provides online consultations to patients as much as she can.

As air strikes continued Tuesday in Ukraine’s capital city and elsewhere throughout the country, rheumatologists are among citizens forced to upend their personal and professional lives and make the best decisions they can to keep themselves and their families safe.

Roman Yatsyshyn, MD, professor at Ivano-Frankivsk National Medical University in Ivano-Frankivsk, Ukraine, and vice president of the Association of Rheumatologists of Ukraine, told this news organization that many rheumatologists, like Dr. Garmish, have been forced to close their practices and flee the country. The hope is that the moves are temporary, he said.

He said rheumatologists there are having very different experiences depending on their proximity to the shelling.

Dmytro Rekalov, MD, PhD, who has been a practicing rheumatologist for 20 years, said he has had to relocate – he hopes temporarily – to western Ukraine.

He told this news organization that the battles are about 40 km (25 miles) from him.

“I have a small private rheumatology clinic in Zaporizhzhia [in southeastern Ukraine], so if they invade our city, I’ll have to close my clinic and find another place to live and to practice in.” Zaporizhzhia is home to the largest nuclear plant in Europe, a facility that came under attack earlier this month.

Doctors from areas under siege have been forced to move to quieter locations and consult with patients remotely, Dr. Yatsyshyn said.  

“Moreover, all doctors are actively volunteering, helping refugees, and supporting our military at the front,” he said, adding that medications are in short supply.

“We express our sincere gratitude to the world and European medical communities for their help for Ukraine at this time. Medicines and medical devices come to Ukraine from many countries around the world every day,” he said.

Dr. Yatsyshyn said the Ministry of Health of Ukraine is coordinating delivery of medications.

“However, there is still a need for an uninterrupted supply of basic antirheumatic drugs, cytostatics, glucocorticosteroids, analgesics, and nonsteroidal anti-inflammatory drugs. We will be grateful if such help will continue to come from our colleagues,” Dr. Yatsyshyn said.

In most cases, he says, rheumatologists stay in touch with their patients via social media and apps, Skype, and Zoom.

“We have also created professional and patient groups in chat rooms,” he said. “There, we can respond quickly to current issues in different regions. If necessary, we send medicines in case of their absence or danger in certain regions of the country. Rheumatologists have set up a joint group for online counseling and exchange.”

Some rheumatologists have been retrained as emergency physicians, he said. In areas with less military activity, rheumatologists continue to treat patients at their practices. In places where it is relatively calm, rheumatologists consult not only local patients but also migrants from other regions affected by the war, Dr. Yatsyshyn explained.

The Association of Rheumatologists of Ukraine continues its activities, he said.

“We monitor the problems of our colleagues, their relocations, security, and the opportunity to work. In close cooperation with the Ministry of Health, we monitor the provision of necessary medicines to our patients. We are very grateful for the help of our colleagues from European associations, the United States, pharmaceutical companies, medical centers, universities, and volunteer organizations.”

“We have two other big requests to the entire medical and scientific community,” Dr. Yatsyshyn said. “To suspend the membership of all Russian medical communities in European and world associations (including EULAR, EUSTAR, Lupus Academy, ACR, British Society of Rheumatology, and others) with a ban on attending international forums just as almost all sports and art organizations in Europe and the civilized world have done.”

The second request, he said, is “to close the sky over Ukraine to stop killing children, civilians, destroying Ukrainian memories, and to destroy Ukrainians as a nation. We pray for this to all the conscious world.”

EULAR, the European Alliance of Associations for Rheumatology, said in a statement, “EULAR has stood for peace in Europe and globally, and for improving the lives of people with rheumatic and musculoskeletal diseases, for 75 years. We are committed to the tradition of humanity and peace and are deeply concerned about the general situation of the people in Ukraine. We will do our utmost to contribute to alleviate the suffering. To this end we are urgently exploring options together with other biomedical partners. Please also help to support the people in Ukraine, for example by donating to UNHCR (the UN refugee agency) or ICRC (International Committee of the Red Cross).

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

On the morning of Feb. 24, rheumatologist Olena Garmish woke at 5:50 a.m. from the blasts of rocket fire in Kiev, Ukraine, and saw the explosions through her window

She described that next week to this news organization: air sirens 20 hours a day, fearing death 24 hours a day, and growing food shortages.

Dr. Garmish, executive director of the Association of Rheumatologists of Ukraine, said she continued working at a Kiev hospital until March 4, but then had to leave the country with her children and has traveled to two other countries since. Now she is looking for employment abroad after 22 years as a clinical researcher and practitioner.

omersukrugoksu/Getty Images

“We lost our jobs and rheumatology practice,” she said. Now, she says, she provides online consultations to patients as much as she can.

As air strikes continued Tuesday in Ukraine’s capital city and elsewhere throughout the country, rheumatologists are among citizens forced to upend their personal and professional lives and make the best decisions they can to keep themselves and their families safe.

Roman Yatsyshyn, MD, professor at Ivano-Frankivsk National Medical University in Ivano-Frankivsk, Ukraine, and vice president of the Association of Rheumatologists of Ukraine, told this news organization that many rheumatologists, like Dr. Garmish, have been forced to close their practices and flee the country. The hope is that the moves are temporary, he said.

He said rheumatologists there are having very different experiences depending on their proximity to the shelling.

Dmytro Rekalov, MD, PhD, who has been a practicing rheumatologist for 20 years, said he has had to relocate – he hopes temporarily – to western Ukraine.

He told this news organization that the battles are about 40 km (25 miles) from him.

“I have a small private rheumatology clinic in Zaporizhzhia [in southeastern Ukraine], so if they invade our city, I’ll have to close my clinic and find another place to live and to practice in.” Zaporizhzhia is home to the largest nuclear plant in Europe, a facility that came under attack earlier this month.

Doctors from areas under siege have been forced to move to quieter locations and consult with patients remotely, Dr. Yatsyshyn said.  

“Moreover, all doctors are actively volunteering, helping refugees, and supporting our military at the front,” he said, adding that medications are in short supply.

“We express our sincere gratitude to the world and European medical communities for their help for Ukraine at this time. Medicines and medical devices come to Ukraine from many countries around the world every day,” he said.

Dr. Yatsyshyn said the Ministry of Health of Ukraine is coordinating delivery of medications.

“However, there is still a need for an uninterrupted supply of basic antirheumatic drugs, cytostatics, glucocorticosteroids, analgesics, and nonsteroidal anti-inflammatory drugs. We will be grateful if such help will continue to come from our colleagues,” Dr. Yatsyshyn said.

In most cases, he says, rheumatologists stay in touch with their patients via social media and apps, Skype, and Zoom.

“We have also created professional and patient groups in chat rooms,” he said. “There, we can respond quickly to current issues in different regions. If necessary, we send medicines in case of their absence or danger in certain regions of the country. Rheumatologists have set up a joint group for online counseling and exchange.”

Some rheumatologists have been retrained as emergency physicians, he said. In areas with less military activity, rheumatologists continue to treat patients at their practices. In places where it is relatively calm, rheumatologists consult not only local patients but also migrants from other regions affected by the war, Dr. Yatsyshyn explained.

The Association of Rheumatologists of Ukraine continues its activities, he said.

“We monitor the problems of our colleagues, their relocations, security, and the opportunity to work. In close cooperation with the Ministry of Health, we monitor the provision of necessary medicines to our patients. We are very grateful for the help of our colleagues from European associations, the United States, pharmaceutical companies, medical centers, universities, and volunteer organizations.”

“We have two other big requests to the entire medical and scientific community,” Dr. Yatsyshyn said. “To suspend the membership of all Russian medical communities in European and world associations (including EULAR, EUSTAR, Lupus Academy, ACR, British Society of Rheumatology, and others) with a ban on attending international forums just as almost all sports and art organizations in Europe and the civilized world have done.”

The second request, he said, is “to close the sky over Ukraine to stop killing children, civilians, destroying Ukrainian memories, and to destroy Ukrainians as a nation. We pray for this to all the conscious world.”

EULAR, the European Alliance of Associations for Rheumatology, said in a statement, “EULAR has stood for peace in Europe and globally, and for improving the lives of people with rheumatic and musculoskeletal diseases, for 75 years. We are committed to the tradition of humanity and peace and are deeply concerned about the general situation of the people in Ukraine. We will do our utmost to contribute to alleviate the suffering. To this end we are urgently exploring options together with other biomedical partners. Please also help to support the people in Ukraine, for example by donating to UNHCR (the UN refugee agency) or ICRC (International Committee of the Red Cross).

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

On the morning of Feb. 24, rheumatologist Olena Garmish woke at 5:50 a.m. from the blasts of rocket fire in Kiev, Ukraine, and saw the explosions through her window

She described that next week to this news organization: air sirens 20 hours a day, fearing death 24 hours a day, and growing food shortages.

Dr. Garmish, executive director of the Association of Rheumatologists of Ukraine, said she continued working at a Kiev hospital until March 4, but then had to leave the country with her children and has traveled to two other countries since. Now she is looking for employment abroad after 22 years as a clinical researcher and practitioner.

omersukrugoksu/Getty Images

“We lost our jobs and rheumatology practice,” she said. Now, she says, she provides online consultations to patients as much as she can.

As air strikes continued Tuesday in Ukraine’s capital city and elsewhere throughout the country, rheumatologists are among citizens forced to upend their personal and professional lives and make the best decisions they can to keep themselves and their families safe.

Roman Yatsyshyn, MD, professor at Ivano-Frankivsk National Medical University in Ivano-Frankivsk, Ukraine, and vice president of the Association of Rheumatologists of Ukraine, told this news organization that many rheumatologists, like Dr. Garmish, have been forced to close their practices and flee the country. The hope is that the moves are temporary, he said.

He said rheumatologists there are having very different experiences depending on their proximity to the shelling.

Dmytro Rekalov, MD, PhD, who has been a practicing rheumatologist for 20 years, said he has had to relocate – he hopes temporarily – to western Ukraine.

He told this news organization that the battles are about 40 km (25 miles) from him.

“I have a small private rheumatology clinic in Zaporizhzhia [in southeastern Ukraine], so if they invade our city, I’ll have to close my clinic and find another place to live and to practice in.” Zaporizhzhia is home to the largest nuclear plant in Europe, a facility that came under attack earlier this month.

Doctors from areas under siege have been forced to move to quieter locations and consult with patients remotely, Dr. Yatsyshyn said.  

“Moreover, all doctors are actively volunteering, helping refugees, and supporting our military at the front,” he said, adding that medications are in short supply.

“We express our sincere gratitude to the world and European medical communities for their help for Ukraine at this time. Medicines and medical devices come to Ukraine from many countries around the world every day,” he said.

Dr. Yatsyshyn said the Ministry of Health of Ukraine is coordinating delivery of medications.

“However, there is still a need for an uninterrupted supply of basic antirheumatic drugs, cytostatics, glucocorticosteroids, analgesics, and nonsteroidal anti-inflammatory drugs. We will be grateful if such help will continue to come from our colleagues,” Dr. Yatsyshyn said.

In most cases, he says, rheumatologists stay in touch with their patients via social media and apps, Skype, and Zoom.

“We have also created professional and patient groups in chat rooms,” he said. “There, we can respond quickly to current issues in different regions. If necessary, we send medicines in case of their absence or danger in certain regions of the country. Rheumatologists have set up a joint group for online counseling and exchange.”

Some rheumatologists have been retrained as emergency physicians, he said. In areas with less military activity, rheumatologists continue to treat patients at their practices. In places where it is relatively calm, rheumatologists consult not only local patients but also migrants from other regions affected by the war, Dr. Yatsyshyn explained.

The Association of Rheumatologists of Ukraine continues its activities, he said.

“We monitor the problems of our colleagues, their relocations, security, and the opportunity to work. In close cooperation with the Ministry of Health, we monitor the provision of necessary medicines to our patients. We are very grateful for the help of our colleagues from European associations, the United States, pharmaceutical companies, medical centers, universities, and volunteer organizations.”

“We have two other big requests to the entire medical and scientific community,” Dr. Yatsyshyn said. “To suspend the membership of all Russian medical communities in European and world associations (including EULAR, EUSTAR, Lupus Academy, ACR, British Society of Rheumatology, and others) with a ban on attending international forums just as almost all sports and art organizations in Europe and the civilized world have done.”

The second request, he said, is “to close the sky over Ukraine to stop killing children, civilians, destroying Ukrainian memories, and to destroy Ukrainians as a nation. We pray for this to all the conscious world.”

EULAR, the European Alliance of Associations for Rheumatology, said in a statement, “EULAR has stood for peace in Europe and globally, and for improving the lives of people with rheumatic and musculoskeletal diseases, for 75 years. We are committed to the tradition of humanity and peace and are deeply concerned about the general situation of the people in Ukraine. We will do our utmost to contribute to alleviate the suffering. To this end we are urgently exploring options together with other biomedical partners. Please also help to support the people in Ukraine, for example by donating to UNHCR (the UN refugee agency) or ICRC (International Committee of the Red Cross).

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

Most lung cancer patients with interstitial lung disease will not benefit from thoracic radiotherapy, based on data from a systematic review of 24 studies.

Thoracic radiotherapy remains a key part of lung cancer treatment for early and metastatic disease. However, patients with both small cell lung cancer (SCLC) and non–small cell lung cancer (NSCLC) associated with interstitial lung disease (ILD) fare worse than do those without ILD, often because of acute exacerbation of ILD and severe or fatal pneumonitis, wrote Animesh Saha, MD, of Apollo Multi-Specialty Hospitals, Kolkata, India, and colleagues. Consequently, clinicians may hesitate to offer radiotherapy to these patients.

In a review published in Clinical Oncology, the researchers identified 24 studies, including phase II and phase III randomized or nonrandomized trials, as well as prospective, observational studies and retrospective real-world studies. The goal of the review was to report the incidence and predictors of radiation pneumonitis associated with different types of thoracic radiotherapy for lung cancer patients with ILD, the researchers said. Treatment types included curative-intent fractionated radiotherapy or chemoradiotherapy or moderately hypofractionated (nonstereotactic ablative radiotherapy [SABR]) and hyperfractionated radiotherapy as well as particle beam therapies.

The studies included patients with SCLC or NSCLC and any form of ILD, including subclinical, radiologically diagnosed, or symptomatic, the researchers said.

Overall, the median incidence of grade 3 or higher radiation pneumonitis was 19.7%; the median incidence in patients treated with conventional radical radiotherapy, SABR, and particle beam therapy was 31.8%, 11.9%, and 20.25%, respectively.

Eighteen studies reported grade 5 radiation pneumonitis; the overall median incidence was 6%, but as high as 60% in some studies. When separated by treatment type, the median incidence was 2.7%, 6.25%, and 6.25%, respectively, in patients treated with radical radiotherapy (non-SABR), SABR, and particle beam therapy.

Independent predictors of severe radiation pneumonitis (grade 2 or higher and grade 3 or higher) included subclinical or radiological ILD, the researchers said. Among ILD subtypes, studies have shown increased risk for severe radiation pneumonitis among those with non-IPF or non-UIP pattern fibrosis.

In addition, patient-related factors of low forced vital capacity (FVC) and low forced expiratory volume in 1 second (FEV₁), have been associated with severe radiation pneumonitis, the researchers said. They also found increased risk for patients with lower lobe tumor location compared to other lobes.

As for treatment-related factors, a history of gemcitabine chemotherapy was associated with an increased risk of grade 3 or higher radiation pneumonitis.

“There is always concern about using thoracic radiotherapy in lung cancer patients with coexisting ILD in view of the risks involved,” the researchers wrote in their discussion of the findings. “Although thoracic radiotherapy is expected to produce similar local control, overall survival is worse in lung cancer patients with ILD than without, probably due to the poor prognosis associated with ILD and associated treatment-related mortality,” they said.

The findings were limited by several factors including the heterogeneity of the studies and study population and the retrospective design of most of the studies, the researchers noted.

However, the results highlight the increased risk of severe and fatal radiation pneumonitis in lung cancer patients with ILD and the need for careful patient selection and counseling if thoracic radiotherapy is to be considered, they concluded.

The study received no outside funding. The researchers had no financial conflicts to disclose.

Most lung cancer patients with interstitial lung disease will not benefit from thoracic radiotherapy, based on data from a systematic review of 24 studies.

Thoracic radiotherapy remains a key part of lung cancer treatment for early and metastatic disease. However, patients with both small cell lung cancer (SCLC) and non–small cell lung cancer (NSCLC) associated with interstitial lung disease (ILD) fare worse than do those without ILD, often because of acute exacerbation of ILD and severe or fatal pneumonitis, wrote Animesh Saha, MD, of Apollo Multi-Specialty Hospitals, Kolkata, India, and colleagues. Consequently, clinicians may hesitate to offer radiotherapy to these patients.

In a review published in Clinical Oncology, the researchers identified 24 studies, including phase II and phase III randomized or nonrandomized trials, as well as prospective, observational studies and retrospective real-world studies. The goal of the review was to report the incidence and predictors of radiation pneumonitis associated with different types of thoracic radiotherapy for lung cancer patients with ILD, the researchers said. Treatment types included curative-intent fractionated radiotherapy or chemoradiotherapy or moderately hypofractionated (nonstereotactic ablative radiotherapy [SABR]) and hyperfractionated radiotherapy as well as particle beam therapies.

The studies included patients with SCLC or NSCLC and any form of ILD, including subclinical, radiologically diagnosed, or symptomatic, the researchers said.

Overall, the median incidence of grade 3 or higher radiation pneumonitis was 19.7%; the median incidence in patients treated with conventional radical radiotherapy, SABR, and particle beam therapy was 31.8%, 11.9%, and 20.25%, respectively.

Eighteen studies reported grade 5 radiation pneumonitis; the overall median incidence was 6%, but as high as 60% in some studies. When separated by treatment type, the median incidence was 2.7%, 6.25%, and 6.25%, respectively, in patients treated with radical radiotherapy (non-SABR), SABR, and particle beam therapy.

Independent predictors of severe radiation pneumonitis (grade 2 or higher and grade 3 or higher) included subclinical or radiological ILD, the researchers said. Among ILD subtypes, studies have shown increased risk for severe radiation pneumonitis among those with non-IPF or non-UIP pattern fibrosis.

In addition, patient-related factors of low forced vital capacity (FVC) and low forced expiratory volume in 1 second (FEV₁), have been associated with severe radiation pneumonitis, the researchers said. They also found increased risk for patients with lower lobe tumor location compared to other lobes.

As for treatment-related factors, a history of gemcitabine chemotherapy was associated with an increased risk of grade 3 or higher radiation pneumonitis.

“There is always concern about using thoracic radiotherapy in lung cancer patients with coexisting ILD in view of the risks involved,” the researchers wrote in their discussion of the findings. “Although thoracic radiotherapy is expected to produce similar local control, overall survival is worse in lung cancer patients with ILD than without, probably due to the poor prognosis associated with ILD and associated treatment-related mortality,” they said.

The findings were limited by several factors including the heterogeneity of the studies and study population and the retrospective design of most of the studies, the researchers noted.

However, the results highlight the increased risk of severe and fatal radiation pneumonitis in lung cancer patients with ILD and the need for careful patient selection and counseling if thoracic radiotherapy is to be considered, they concluded.

The study received no outside funding. The researchers had no financial conflicts to disclose.

Most lung cancer patients with interstitial lung disease will not benefit from thoracic radiotherapy, based on data from a systematic review of 24 studies.

Thoracic radiotherapy remains a key part of lung cancer treatment for early and metastatic disease. However, patients with both small cell lung cancer (SCLC) and non–small cell lung cancer (NSCLC) associated with interstitial lung disease (ILD) fare worse than do those without ILD, often because of acute exacerbation of ILD and severe or fatal pneumonitis, wrote Animesh Saha, MD, of Apollo Multi-Specialty Hospitals, Kolkata, India, and colleagues. Consequently, clinicians may hesitate to offer radiotherapy to these patients.

In a review published in Clinical Oncology, the researchers identified 24 studies, including phase II and phase III randomized or nonrandomized trials, as well as prospective, observational studies and retrospective real-world studies. The goal of the review was to report the incidence and predictors of radiation pneumonitis associated with different types of thoracic radiotherapy for lung cancer patients with ILD, the researchers said. Treatment types included curative-intent fractionated radiotherapy or chemoradiotherapy or moderately hypofractionated (nonstereotactic ablative radiotherapy [SABR]) and hyperfractionated radiotherapy as well as particle beam therapies.

The studies included patients with SCLC or NSCLC and any form of ILD, including subclinical, radiologically diagnosed, or symptomatic, the researchers said.

Overall, the median incidence of grade 3 or higher radiation pneumonitis was 19.7%; the median incidence in patients treated with conventional radical radiotherapy, SABR, and particle beam therapy was 31.8%, 11.9%, and 20.25%, respectively.

Eighteen studies reported grade 5 radiation pneumonitis; the overall median incidence was 6%, but as high as 60% in some studies. When separated by treatment type, the median incidence was 2.7%, 6.25%, and 6.25%, respectively, in patients treated with radical radiotherapy (non-SABR), SABR, and particle beam therapy.

Independent predictors of severe radiation pneumonitis (grade 2 or higher and grade 3 or higher) included subclinical or radiological ILD, the researchers said. Among ILD subtypes, studies have shown increased risk for severe radiation pneumonitis among those with non-IPF or non-UIP pattern fibrosis.

In addition, patient-related factors of low forced vital capacity (FVC) and low forced expiratory volume in 1 second (FEV₁), have been associated with severe radiation pneumonitis, the researchers said. They also found increased risk for patients with lower lobe tumor location compared to other lobes.

As for treatment-related factors, a history of gemcitabine chemotherapy was associated with an increased risk of grade 3 or higher radiation pneumonitis.

“There is always concern about using thoracic radiotherapy in lung cancer patients with coexisting ILD in view of the risks involved,” the researchers wrote in their discussion of the findings. “Although thoracic radiotherapy is expected to produce similar local control, overall survival is worse in lung cancer patients with ILD than without, probably due to the poor prognosis associated with ILD and associated treatment-related mortality,” they said.

The findings were limited by several factors including the heterogeneity of the studies and study population and the retrospective design of most of the studies, the researchers noted.

However, the results highlight the increased risk of severe and fatal radiation pneumonitis in lung cancer patients with ILD and the need for careful patient selection and counseling if thoracic radiotherapy is to be considered, they concluded.

The study received no outside funding. The researchers had no financial conflicts to disclose.

WEST PALM BEACH, FL – Including serum neurofilament light chain (sNfL) and serum glial fibrillary acidic protein (sGFAP) at multiple sclerosis (MS) onset may lead to better prediction of long-term outcomes and relapse risk, new research suggests.

The research shows that once standard clinical models can be incorporated into practice, the early measurement of these biomarkers will provide useful information in predicting who may be at risk of poorer outcomes, researcher Gauruv Bose, MD, Brigham Multiple Sclerosis Center, Ann Romney Center for Neurologic Diseases, Brigham and Women’s Hospital, Harvard Medical School, Boston, told this news organization.

The findings were presented at annual meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS).
 

Better together?

Although higher baseline sNfL levels in MS have previously been linked to greater brain atrophy and other long-term outcomes, and sGFAP changes are also associated with inflammation and damage through the disease course, less is known about longer-term effects of the two biomarker measures combined, Dr. Bose said.

“The value of using both sNfL and sGFAP in predictive models is of interest, since one correlates with neuroaxonal damage, while the other has correlated with astrocytic glial damage/cell turnover – potentially, though differently, reflecting inflammatory damage and neurodegeneration,” he added.

To investigate the relationship, the researchers evaluated patients with MS enrolled at the Brigham Multiple Sclerosis Center. All underwent neurologic examinations every 6 months, and MRI scans and blood samples were collected every year. Some had more than 20 years of follow-up.

The first study involved 144 patients (mean age, 37.4 years) from whom two samples of sNfL and sGFAP were collected within 3 years of MS onset.

The median baseline sNfL level was 10.7 pg/mL, and 50 patients (34.7%) already showed increases in sNfL at the 1-year follow-up. Their median sGFAP level at onset was 96 pg/mL, and 59 patients (41%) showed increases in sGFAP at the 1-year follow-up.

Results showed that higher baseline sNfL levels were significantly associated with increased risk for MS relapse at 10 years (hazard ratio, 1.34; P = .04), as well as with the development of new MRI lesions (HR, 1.35; P = .022).

Of the study group, 25 (17.4%) developed secondary progressive MS (SPMS) by the 10-year follow-up. For those prognostic assessments, the investigators compared utilization of a model using well-established clinical predictors of SPMS with and without the inclusion of sNfL and sGFAP.

The clinical model included key factors such as age, sex, body mass index, Extended Disability Status Scale (EDSS), timed 25-foot walk, and other measures.

The researchers found the clinical model alone predicted 10-year outcomes with an area under the receiver operating characteristic curve (AUC) of 0.75. However, with the addition of baseline sNfL and sGFAP measures, the AUC was improved to 0.79 (P = .0008).

Furthermore, the inclusion of additional follow-up sNfL and sGFAP measurements taken after baseline further improved the model’s AUC (0.82; P = .046).

The addition of the sNfL and sGFAP measures to the clinical models also improved the prediction of disability in MS at 10 years on EDSS (P = .068), as well as prediction of 10-year brain T2 lesion volume (P = .009) and brain parenchymal fraction (P = .04).
 

Relapse predictor?

In the second study, Dr. Bose and colleagues evaluated the role of the two serum measures in predicting relapse after disease-modifying therapy (DMT) discontinuation. That study included 42 patients who discontinued DMT treatment after having been disease-activity free for 2 years while on the drugs. They were compared with 36 patients who had similar characteristics and had continued DMT treatment.

All patients (mean age, 44.5 years) had a mean of 7.4 years since prior disease activity.

Increases in sNfL following DMT discontinuation, but not before, were associated with a significantly greater risk for clinical disease worsening at a mean follow-up of 7.5 years (HR, 9.4; P = .007). Change in sGFAP was associated with new MRI lesions (HR, 8.3; P = .039), compared with no changes.

“The crux of this study” was that patients with increased biomarker levels after stopping DMTs “were at a significantly higher risk for disease activity in the future compared to those whose biomarker levels remained stable,” Dr. Bose noted.

“We think this finding, if replicated in another cohort, has the potential to be included in guidelines regarding stopping DMT in patients with MS,” he added.
 

Clinically useful?

Jeffrey Cohen, MD, current president of ACTRIMS, said the first study supports mounting evidence on how sNfL and sGFAP at onset can predict future disease and have the potential to improve current predictive models.

“Combining clinical, MRI, and serum biomarkers into a single model works better than any of the three factors individually,” said Dr. Cohen, who is director of the Mellen Center for MS Treatment and Research and professor of neurology at the Cleveland Clinic.

“For the clinician, this information may help with treatment selection,” he added.

Dr. Cohen noted that the suggestion that the biomarkers could also be helpful in predicting relapse after discontinuation is of importance.

“Increasingly, we are considering this issue in the clinical setting,” he said. However, he also noted some caveats.

“Interpretation of the results of the study is not straightforward, illustrating the complexity of the issue,” Dr. Cohen said. “One issue is that the patients in the study were relatively young, with an average age of 45, which is not a group in which we typically would consider stopping therapy.”

Dr. Bose has received a postdoctoral fellowship grant from the Multiple Sclerosis Society of Canada. Dr. Cohen reports having received personal compensation for consulting for Biogen, Bristol-Myers Squibb, Convelo, Genentech, Janssen, NervGen, Novartis, and PSI; speaking for H3 Communications; and serving as an editor of the Multiple Sclerosis Journal.

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

WEST PALM BEACH, FL – Including serum neurofilament light chain (sNfL) and serum glial fibrillary acidic protein (sGFAP) at multiple sclerosis (MS) onset may lead to better prediction of long-term outcomes and relapse risk, new research suggests.

The research shows that once standard clinical models can be incorporated into practice, the early measurement of these biomarkers will provide useful information in predicting who may be at risk of poorer outcomes, researcher Gauruv Bose, MD, Brigham Multiple Sclerosis Center, Ann Romney Center for Neurologic Diseases, Brigham and Women’s Hospital, Harvard Medical School, Boston, told this news organization.

The findings were presented at annual meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS).
 

Better together?

Although higher baseline sNfL levels in MS have previously been linked to greater brain atrophy and other long-term outcomes, and sGFAP changes are also associated with inflammation and damage through the disease course, less is known about longer-term effects of the two biomarker measures combined, Dr. Bose said.

“The value of using both sNfL and sGFAP in predictive models is of interest, since one correlates with neuroaxonal damage, while the other has correlated with astrocytic glial damage/cell turnover – potentially, though differently, reflecting inflammatory damage and neurodegeneration,” he added.

To investigate the relationship, the researchers evaluated patients with MS enrolled at the Brigham Multiple Sclerosis Center. All underwent neurologic examinations every 6 months, and MRI scans and blood samples were collected every year. Some had more than 20 years of follow-up.

The first study involved 144 patients (mean age, 37.4 years) from whom two samples of sNfL and sGFAP were collected within 3 years of MS onset.

The median baseline sNfL level was 10.7 pg/mL, and 50 patients (34.7%) already showed increases in sNfL at the 1-year follow-up. Their median sGFAP level at onset was 96 pg/mL, and 59 patients (41%) showed increases in sGFAP at the 1-year follow-up.

Results showed that higher baseline sNfL levels were significantly associated with increased risk for MS relapse at 10 years (hazard ratio, 1.34; P = .04), as well as with the development of new MRI lesions (HR, 1.35; P = .022).

Of the study group, 25 (17.4%) developed secondary progressive MS (SPMS) by the 10-year follow-up. For those prognostic assessments, the investigators compared utilization of a model using well-established clinical predictors of SPMS with and without the inclusion of sNfL and sGFAP.

The clinical model included key factors such as age, sex, body mass index, Extended Disability Status Scale (EDSS), timed 25-foot walk, and other measures.

The researchers found the clinical model alone predicted 10-year outcomes with an area under the receiver operating characteristic curve (AUC) of 0.75. However, with the addition of baseline sNfL and sGFAP measures, the AUC was improved to 0.79 (P = .0008).

Furthermore, the inclusion of additional follow-up sNfL and sGFAP measurements taken after baseline further improved the model’s AUC (0.82; P = .046).

The addition of the sNfL and sGFAP measures to the clinical models also improved the prediction of disability in MS at 10 years on EDSS (P = .068), as well as prediction of 10-year brain T2 lesion volume (P = .009) and brain parenchymal fraction (P = .04).
 

Relapse predictor?

In the second study, Dr. Bose and colleagues evaluated the role of the two serum measures in predicting relapse after disease-modifying therapy (DMT) discontinuation. That study included 42 patients who discontinued DMT treatment after having been disease-activity free for 2 years while on the drugs. They were compared with 36 patients who had similar characteristics and had continued DMT treatment.

All patients (mean age, 44.5 years) had a mean of 7.4 years since prior disease activity.

Increases in sNfL following DMT discontinuation, but not before, were associated with a significantly greater risk for clinical disease worsening at a mean follow-up of 7.5 years (HR, 9.4; P = .007). Change in sGFAP was associated with new MRI lesions (HR, 8.3; P = .039), compared with no changes.

“The crux of this study” was that patients with increased biomarker levels after stopping DMTs “were at a significantly higher risk for disease activity in the future compared to those whose biomarker levels remained stable,” Dr. Bose noted.

“We think this finding, if replicated in another cohort, has the potential to be included in guidelines regarding stopping DMT in patients with MS,” he added.
 

Clinically useful?

Jeffrey Cohen, MD, current president of ACTRIMS, said the first study supports mounting evidence on how sNfL and sGFAP at onset can predict future disease and have the potential to improve current predictive models.

“Combining clinical, MRI, and serum biomarkers into a single model works better than any of the three factors individually,” said Dr. Cohen, who is director of the Mellen Center for MS Treatment and Research and professor of neurology at the Cleveland Clinic.

“For the clinician, this information may help with treatment selection,” he added.

Dr. Cohen noted that the suggestion that the biomarkers could also be helpful in predicting relapse after discontinuation is of importance.

“Increasingly, we are considering this issue in the clinical setting,” he said. However, he also noted some caveats.

“Interpretation of the results of the study is not straightforward, illustrating the complexity of the issue,” Dr. Cohen said. “One issue is that the patients in the study were relatively young, with an average age of 45, which is not a group in which we typically would consider stopping therapy.”

Dr. Bose has received a postdoctoral fellowship grant from the Multiple Sclerosis Society of Canada. Dr. Cohen reports having received personal compensation for consulting for Biogen, Bristol-Myers Squibb, Convelo, Genentech, Janssen, NervGen, Novartis, and PSI; speaking for H3 Communications; and serving as an editor of the Multiple Sclerosis Journal.

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

WEST PALM BEACH, FL – Including serum neurofilament light chain (sNfL) and serum glial fibrillary acidic protein (sGFAP) at multiple sclerosis (MS) onset may lead to better prediction of long-term outcomes and relapse risk, new research suggests.

The research shows that once standard clinical models can be incorporated into practice, the early measurement of these biomarkers will provide useful information in predicting who may be at risk of poorer outcomes, researcher Gauruv Bose, MD, Brigham Multiple Sclerosis Center, Ann Romney Center for Neurologic Diseases, Brigham and Women’s Hospital, Harvard Medical School, Boston, told this news organization.

The findings were presented at annual meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS).
 

Better together?

Although higher baseline sNfL levels in MS have previously been linked to greater brain atrophy and other long-term outcomes, and sGFAP changes are also associated with inflammation and damage through the disease course, less is known about longer-term effects of the two biomarker measures combined, Dr. Bose said.

“The value of using both sNfL and sGFAP in predictive models is of interest, since one correlates with neuroaxonal damage, while the other has correlated with astrocytic glial damage/cell turnover – potentially, though differently, reflecting inflammatory damage and neurodegeneration,” he added.

To investigate the relationship, the researchers evaluated patients with MS enrolled at the Brigham Multiple Sclerosis Center. All underwent neurologic examinations every 6 months, and MRI scans and blood samples were collected every year. Some had more than 20 years of follow-up.

The first study involved 144 patients (mean age, 37.4 years) from whom two samples of sNfL and sGFAP were collected within 3 years of MS onset.

The median baseline sNfL level was 10.7 pg/mL, and 50 patients (34.7%) already showed increases in sNfL at the 1-year follow-up. Their median sGFAP level at onset was 96 pg/mL, and 59 patients (41%) showed increases in sGFAP at the 1-year follow-up.

Results showed that higher baseline sNfL levels were significantly associated with increased risk for MS relapse at 10 years (hazard ratio, 1.34; P = .04), as well as with the development of new MRI lesions (HR, 1.35; P = .022).

Of the study group, 25 (17.4%) developed secondary progressive MS (SPMS) by the 10-year follow-up. For those prognostic assessments, the investigators compared utilization of a model using well-established clinical predictors of SPMS with and without the inclusion of sNfL and sGFAP.

The clinical model included key factors such as age, sex, body mass index, Extended Disability Status Scale (EDSS), timed 25-foot walk, and other measures.

The researchers found the clinical model alone predicted 10-year outcomes with an area under the receiver operating characteristic curve (AUC) of 0.75. However, with the addition of baseline sNfL and sGFAP measures, the AUC was improved to 0.79 (P = .0008).

Furthermore, the inclusion of additional follow-up sNfL and sGFAP measurements taken after baseline further improved the model’s AUC (0.82; P = .046).

The addition of the sNfL and sGFAP measures to the clinical models also improved the prediction of disability in MS at 10 years on EDSS (P = .068), as well as prediction of 10-year brain T2 lesion volume (P = .009) and brain parenchymal fraction (P = .04).
 

Relapse predictor?

In the second study, Dr. Bose and colleagues evaluated the role of the two serum measures in predicting relapse after disease-modifying therapy (DMT) discontinuation. That study included 42 patients who discontinued DMT treatment after having been disease-activity free for 2 years while on the drugs. They were compared with 36 patients who had similar characteristics and had continued DMT treatment.

All patients (mean age, 44.5 years) had a mean of 7.4 years since prior disease activity.

Increases in sNfL following DMT discontinuation, but not before, were associated with a significantly greater risk for clinical disease worsening at a mean follow-up of 7.5 years (HR, 9.4; P = .007). Change in sGFAP was associated with new MRI lesions (HR, 8.3; P = .039), compared with no changes.

“The crux of this study” was that patients with increased biomarker levels after stopping DMTs “were at a significantly higher risk for disease activity in the future compared to those whose biomarker levels remained stable,” Dr. Bose noted.

“We think this finding, if replicated in another cohort, has the potential to be included in guidelines regarding stopping DMT in patients with MS,” he added.
 

Clinically useful?

Jeffrey Cohen, MD, current president of ACTRIMS, said the first study supports mounting evidence on how sNfL and sGFAP at onset can predict future disease and have the potential to improve current predictive models.

“Combining clinical, MRI, and serum biomarkers into a single model works better than any of the three factors individually,” said Dr. Cohen, who is director of the Mellen Center for MS Treatment and Research and professor of neurology at the Cleveland Clinic.

“For the clinician, this information may help with treatment selection,” he added.

Dr. Cohen noted that the suggestion that the biomarkers could also be helpful in predicting relapse after discontinuation is of importance.

“Increasingly, we are considering this issue in the clinical setting,” he said. However, he also noted some caveats.

“Interpretation of the results of the study is not straightforward, illustrating the complexity of the issue,” Dr. Cohen said. “One issue is that the patients in the study were relatively young, with an average age of 45, which is not a group in which we typically would consider stopping therapy.”

Dr. Bose has received a postdoctoral fellowship grant from the Multiple Sclerosis Society of Canada. Dr. Cohen reports having received personal compensation for consulting for Biogen, Bristol-Myers Squibb, Convelo, Genentech, Janssen, NervGen, Novartis, and PSI; speaking for H3 Communications; and serving as an editor of the Multiple Sclerosis Journal.

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

Small airway disease with air trapping appears to be a long-lasting sequela of SARS-CoV-2 infection, according to a prospective study that compared 100 COVID-19 survivors who had persistent symptoms and 106 healthy control persons.

“Something is going on in the distal airways related to either inflammation or fibrosis that is giving us a signal of air trapping,” noted senior author Alejandro P. Comellas, MD, in a press release. The study was stimulated by reports from University of Iowa clinicians noting that many patients with initial SARS-CoV-2 infection who were either hospitalized or were treated in the ambulatory setting later reported shortness of breath and other respiratory symptoms indicative of chronic lung disease.

Study results

Investigators classified patients (mean age, 48 years; 66 women) with post-acute sequelae of COVID-19 according to whether they were ambulatory (67%), hospitalized (17%), or required treatment in the intensive care unit (16%). They then compared CT findings of patients who had COVID-19 and persistent symptoms with those of a healthy control group.

COVID-19 severity did not affect the percentage of cases of lung with air trapping among these patients. Air trapping occurred at rates of 25.4% among ambulatory patients, 34.6% in hospitalized patients, and in 27.3% of those requiring intensive care (P = .10). The percentage of lungs affected by air trapping in ambulatory participants was sharply and significantly higher than in healthy controls (25.4% vs. 7.2%; P < .001). Also, air trapping persisted; it was still present in 8 of 9 participants who underwent imaging more than 200 days post diagnosis.

Qualitative analysis of chest CT images showed that the most common imaging abnormality was air trapping (58%); ground glass opacities (GGOs) were found in 51% (46/91), note Dr. Comellas and coauthors. This suggests ongoing lung inflammation, edema, or fibrosis. These symptoms are often observed during acute COVID-19, frequently in an organizing pneumonia pattern, and have been shown to persist for months after infection in survivors of severe disease. The mean percentage of total lung classified as having regional GGOs on chest CT scans was 13.2% and 28.7%, respectively, in the hospitalized and ICU groups, both very much higher than in the ambulatory group, at 3.7% (P < .001 for both). Among healthy controls, the GGO rate on chest CT was only 0.06% (P < .001).

In addition, air trapping correlated with the ratio of residual volume to total lung capacity (r = 0.6; P < .001) but not with spirometry results. In fact, the investigators did not observe airflow obstruction by spirometry in any group, suggesting that air trapping in these patients involves only small rather than large airways and that these small airways contribute little to total airway resistance. Only when a large percentage, perhaps 75% or more, of all small airways are obstructed will spirometry pick up small airways disease, the authors observe.

Continuing disease

The findings taken together suggest that functional small airways disease and air trapping are a consequence of SARS-CoV-2 infection, according to Dr. Comellas. “If a portion of patients continues to have small airways disease, then we need to think about the mechanisms behind it,” he said. “It could be something related to inflammation that’s reversible, or it may be something related to a scar that is irreversible, and then we need to look at ways to prevent further progression of the disease.” Furthermore, “studies aimed at determining the natural history of functional small airways disease in patients with post-acute sequelae of COVID-19 and the biological mechanisms that underlie these findings are urgently needed to identify therapeutic and preventative interventions,” Dr. Comellas, professor of internal medicine at Carver College of Medicine, University of Iowa, Iowa City, concluded.

The study limitations, the authors state, include the fact that theirs was a single-center study that enrolled participants infected early during the COVID-19 pandemic and did not include patients with Delta or Omicron variants, thus limiting the generalizability of the findings.

The study was published in Radiology.

The reported findings “indicate a long-term impact on bronchiolar obstruction,” states Brett M. Elicker, MD, professor of clinical radiology, University of California, San Francisco, in an accompanying editorial . Because collagen may be absorbed for months after an acute insult, it is not entirely clear whether the abnormalities seen in the current study will be permanent. He said further, “the presence of ground glass opacity and/or fibrosis on CT were most common in the patients admitted to the ICU and likely correspond to post-organizing pneumonia and/or post-diffuse alveolar damage fibrosis.”

Dr. Elicker also pointed out that organizing pneumonia is especially common among patients with COVID-19 and is usually highly steroid-responsive. The opacities improve or resolve with treatment, but sometimes residual fibrosis occurs. “Longer-term studies assessing the clinical and imaging manifestations 1-2 years after the initial infection are needed to fully ascertain the permanent manifestations of post-COVID fibrosis.”

The study was supported by grants from the National Institutes of Health. The authors and Dr. Elicker have disclosed no relevant financial relationships.

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

Small airway disease with air trapping appears to be a long-lasting sequela of SARS-CoV-2 infection, according to a prospective study that compared 100 COVID-19 survivors who had persistent symptoms and 106 healthy control persons.

“Something is going on in the distal airways related to either inflammation or fibrosis that is giving us a signal of air trapping,” noted senior author Alejandro P. Comellas, MD, in a press release. The study was stimulated by reports from University of Iowa clinicians noting that many patients with initial SARS-CoV-2 infection who were either hospitalized or were treated in the ambulatory setting later reported shortness of breath and other respiratory symptoms indicative of chronic lung disease.

Study results

Investigators classified patients (mean age, 48 years; 66 women) with post-acute sequelae of COVID-19 according to whether they were ambulatory (67%), hospitalized (17%), or required treatment in the intensive care unit (16%). They then compared CT findings of patients who had COVID-19 and persistent symptoms with those of a healthy control group.

COVID-19 severity did not affect the percentage of cases of lung with air trapping among these patients. Air trapping occurred at rates of 25.4% among ambulatory patients, 34.6% in hospitalized patients, and in 27.3% of those requiring intensive care (P = .10). The percentage of lungs affected by air trapping in ambulatory participants was sharply and significantly higher than in healthy controls (25.4% vs. 7.2%; P < .001). Also, air trapping persisted; it was still present in 8 of 9 participants who underwent imaging more than 200 days post diagnosis.

Qualitative analysis of chest CT images showed that the most common imaging abnormality was air trapping (58%); ground glass opacities (GGOs) were found in 51% (46/91), note Dr. Comellas and coauthors. This suggests ongoing lung inflammation, edema, or fibrosis. These symptoms are often observed during acute COVID-19, frequently in an organizing pneumonia pattern, and have been shown to persist for months after infection in survivors of severe disease. The mean percentage of total lung classified as having regional GGOs on chest CT scans was 13.2% and 28.7%, respectively, in the hospitalized and ICU groups, both very much higher than in the ambulatory group, at 3.7% (P < .001 for both). Among healthy controls, the GGO rate on chest CT was only 0.06% (P < .001).

In addition, air trapping correlated with the ratio of residual volume to total lung capacity (r = 0.6; P < .001) but not with spirometry results. In fact, the investigators did not observe airflow obstruction by spirometry in any group, suggesting that air trapping in these patients involves only small rather than large airways and that these small airways contribute little to total airway resistance. Only when a large percentage, perhaps 75% or more, of all small airways are obstructed will spirometry pick up small airways disease, the authors observe.

Continuing disease

The findings taken together suggest that functional small airways disease and air trapping are a consequence of SARS-CoV-2 infection, according to Dr. Comellas. “If a portion of patients continues to have small airways disease, then we need to think about the mechanisms behind it,” he said. “It could be something related to inflammation that’s reversible, or it may be something related to a scar that is irreversible, and then we need to look at ways to prevent further progression of the disease.” Furthermore, “studies aimed at determining the natural history of functional small airways disease in patients with post-acute sequelae of COVID-19 and the biological mechanisms that underlie these findings are urgently needed to identify therapeutic and preventative interventions,” Dr. Comellas, professor of internal medicine at Carver College of Medicine, University of Iowa, Iowa City, concluded.

The study limitations, the authors state, include the fact that theirs was a single-center study that enrolled participants infected early during the COVID-19 pandemic and did not include patients with Delta or Omicron variants, thus limiting the generalizability of the findings.

The study was published in Radiology.

The reported findings “indicate a long-term impact on bronchiolar obstruction,” states Brett M. Elicker, MD, professor of clinical radiology, University of California, San Francisco, in an accompanying editorial . Because collagen may be absorbed for months after an acute insult, it is not entirely clear whether the abnormalities seen in the current study will be permanent. He said further, “the presence of ground glass opacity and/or fibrosis on CT were most common in the patients admitted to the ICU and likely correspond to post-organizing pneumonia and/or post-diffuse alveolar damage fibrosis.”

Dr. Elicker also pointed out that organizing pneumonia is especially common among patients with COVID-19 and is usually highly steroid-responsive. The opacities improve or resolve with treatment, but sometimes residual fibrosis occurs. “Longer-term studies assessing the clinical and imaging manifestations 1-2 years after the initial infection are needed to fully ascertain the permanent manifestations of post-COVID fibrosis.”

The study was supported by grants from the National Institutes of Health. The authors and Dr. Elicker have disclosed no relevant financial relationships.

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

Small airway disease with air trapping appears to be a long-lasting sequela of SARS-CoV-2 infection, according to a prospective study that compared 100 COVID-19 survivors who had persistent symptoms and 106 healthy control persons.

“Something is going on in the distal airways related to either inflammation or fibrosis that is giving us a signal of air trapping,” noted senior author Alejandro P. Comellas, MD, in a press release. The study was stimulated by reports from University of Iowa clinicians noting that many patients with initial SARS-CoV-2 infection who were either hospitalized or were treated in the ambulatory setting later reported shortness of breath and other respiratory symptoms indicative of chronic lung disease.

Study results

Investigators classified patients (mean age, 48 years; 66 women) with post-acute sequelae of COVID-19 according to whether they were ambulatory (67%), hospitalized (17%), or required treatment in the intensive care unit (16%). They then compared CT findings of patients who had COVID-19 and persistent symptoms with those of a healthy control group.

COVID-19 severity did not affect the percentage of cases of lung with air trapping among these patients. Air trapping occurred at rates of 25.4% among ambulatory patients, 34.6% in hospitalized patients, and in 27.3% of those requiring intensive care (P = .10). The percentage of lungs affected by air trapping in ambulatory participants was sharply and significantly higher than in healthy controls (25.4% vs. 7.2%; P < .001). Also, air trapping persisted; it was still present in 8 of 9 participants who underwent imaging more than 200 days post diagnosis.

Qualitative analysis of chest CT images showed that the most common imaging abnormality was air trapping (58%); ground glass opacities (GGOs) were found in 51% (46/91), note Dr. Comellas and coauthors. This suggests ongoing lung inflammation, edema, or fibrosis. These symptoms are often observed during acute COVID-19, frequently in an organizing pneumonia pattern, and have been shown to persist for months after infection in survivors of severe disease. The mean percentage of total lung classified as having regional GGOs on chest CT scans was 13.2% and 28.7%, respectively, in the hospitalized and ICU groups, both very much higher than in the ambulatory group, at 3.7% (P < .001 for both). Among healthy controls, the GGO rate on chest CT was only 0.06% (P < .001).

In addition, air trapping correlated with the ratio of residual volume to total lung capacity (r = 0.6; P < .001) but not with spirometry results. In fact, the investigators did not observe airflow obstruction by spirometry in any group, suggesting that air trapping in these patients involves only small rather than large airways and that these small airways contribute little to total airway resistance. Only when a large percentage, perhaps 75% or more, of all small airways are obstructed will spirometry pick up small airways disease, the authors observe.

Continuing disease

The findings taken together suggest that functional small airways disease and air trapping are a consequence of SARS-CoV-2 infection, according to Dr. Comellas. “If a portion of patients continues to have small airways disease, then we need to think about the mechanisms behind it,” he said. “It could be something related to inflammation that’s reversible, or it may be something related to a scar that is irreversible, and then we need to look at ways to prevent further progression of the disease.” Furthermore, “studies aimed at determining the natural history of functional small airways disease in patients with post-acute sequelae of COVID-19 and the biological mechanisms that underlie these findings are urgently needed to identify therapeutic and preventative interventions,” Dr. Comellas, professor of internal medicine at Carver College of Medicine, University of Iowa, Iowa City, concluded.

The study limitations, the authors state, include the fact that theirs was a single-center study that enrolled participants infected early during the COVID-19 pandemic and did not include patients with Delta or Omicron variants, thus limiting the generalizability of the findings.

The study was published in Radiology.

The reported findings “indicate a long-term impact on bronchiolar obstruction,” states Brett M. Elicker, MD, professor of clinical radiology, University of California, San Francisco, in an accompanying editorial . Because collagen may be absorbed for months after an acute insult, it is not entirely clear whether the abnormalities seen in the current study will be permanent. He said further, “the presence of ground glass opacity and/or fibrosis on CT were most common in the patients admitted to the ICU and likely correspond to post-organizing pneumonia and/or post-diffuse alveolar damage fibrosis.”

Dr. Elicker also pointed out that organizing pneumonia is especially common among patients with COVID-19 and is usually highly steroid-responsive. The opacities improve or resolve with treatment, but sometimes residual fibrosis occurs. “Longer-term studies assessing the clinical and imaging manifestations 1-2 years after the initial infection are needed to fully ascertain the permanent manifestations of post-COVID fibrosis.”

The study was supported by grants from the National Institutes of Health. The authors and Dr. Elicker have disclosed no relevant financial relationships.

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

Despite the challenges of an ongoing COVID-19 pandemic, researchers in 2021 delivered practice-changing studies in gynecologic oncology. In this cancer Update, we highlight 4 studies that shed light on the surgical and systemic therapies that may improve outcomes for patients with cancers of the ovary, endometrium, and cervix. We review DESKTOP III, a trial that investigated the role of cytoreductive surgery in patients with recurrent ovarian cancer, and SENTOR, a study that evaluated the performance of sentinel lymph node biopsy in patients with high-grade endometrial cancers. Additionally, we examine 2 studies of systemic therapy that reveal the growing role of targeted therapies and immuno-oncology in the treatment of gynecologic malignancies.

A new era for patients with BRCA mutation–associated ovarian cancer

Banerjee S, Moore KN, Colombo N, et al. Maintenance olaparib for patients with newly diagnosed advanced ovarian cancer and a BRCA mutation (SOLO1/GOG 3004): 5-year follow-up of a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2021;22:1721-1731.

Ovarian cancer remains the most lethal gynecologic malignancy due to the frequency of advanced-stage diagnosis and frequent relapse after primary therapy. But for ovarian cancer patients with inherited mutations of the BRCA1 or BRCA2 genes, poly(ADP-ribose) polymerase (PARP) inhibitors, a class of oral anticancer medicines that target DNA repair, have ushered in a new era in which the possibility of long-term remission, and even cure, is more likely than at any other time.

Olaparib trial details

The SOLO1 study was a double-blind, placebo-controlled, phase 3 trial that investigated the role of PARP inhibitor maintenance therapy with olaparib in patients with pathologic BRCA1 or BRCA2 mutations who responded to platinum-based chemotherapy administered for a newly diagnosed, advanced-stage ovarian cancer.¹ The study enrolled 391 patients, with 260 randomly assigned to receive olaparib for 24 months and 131 patients randomly assigned to receive placebo tablets. Most patients in the study had a mutation in the BRCA1 gene (72%), 27% had a BRCA2 mutation, and 1% had mutations in both genes.

The primary analysis of SOLO1 was published in 2018 and was based on a median follow-up of 3.4 years.¹ That study showed that olaparib maintenance therapy resulted in a large progression-free survival benefit and led to its approval by the US Food and Drug Administration (FDA) as a maintenance therapy for patients with BRCA-mutated advanced ovarian cancer who responded to first-line platinum-based chemotherapy.

In 2021, Banerjee and colleagues updated the progression-free survival results for the SOLO1 trial after 5 years of follow-up.² In this study, the patients randomly assigned to olaparib maintenance therapy had a persistent and statistically significant progression-free survival benefit, with the median progression-free survival reaching 56 months among the olaparib group compared with 13.8 months in the placebo group (hazard ratio [HR], 0.33; 95% confidence interval [CI], 0.25–0.43).² Olaparib maintenance therapy resulted in more clinically significant adverse events, including anemia and neutropenia. Serious adverse events occurred in 55 (21%) of the olaparib-treated patients and 17 (13%) of the placebo-treated patients, but no treatment-related adverse events were fatal.

Continue to: Cytoreductive surgery for recurrent ovarian cancer improves survival in well-selected patients...

Cytoreductive surgery for recurrent ovarian cancer improves survival in well-selected patients

Harter P, Sehouli J, Vergote I, et al; DESKTOP III Investigators. Randomized trial of cytoreductive surgery for relapsed ovarian cancer. N Engl J Med. 2021;385:2123- 2131.

In the DESKTOP III trial, Harter and colleagues contribute results to the ongoing discourse surrounding treatment options for patients with recurrent, platinum-sensitive ovarian cancer.³ Systemic therapies continue to be the mainstay of treatment in this setting; however, several groups have attempted to evaluate the role of secondary cytoreductive surgery in this setting.^4,5

Specific inclusion criteria employed

The DESKTOP III investigators randomly assigned 407 patients with platinum-sensitive recurrent ovarian cancer to secondary cytoreductive surgery followed by platinum-based chemotherapy (n = 206) or platinum-based chemotherapy alone (n = 201).³ An essential aspect of the study’s design was the use of specific inclusion criteria known to identify patients with a high likelihood of complete resection at the time of secondary cytoreduction.^6,7 Patients were eligible only if they had at least a 6-month remission following platinum-based chemotherapy, had a complete resection at their previous surgery, had no restriction on physical activity, and had ascites of no more than 500 mL.

Surgery group had superior overall and progression-free survival

After a median follow-up of approximately 70 months, patients randomly assigned to surgery had superior overall survival (53.7 months) compared with those assigned to chemotherapy alone (46.0 months; HR, 0.75; 95% CI, 0.59–0.96).³ Progression-free survival also was improved among patients who underwent surgery (median 18.4 vs 12.7 months; HR, 0.66; 95% CI, 0.54–0.82). Subgroup analyses did not identify any subset of patients who did not benefit from surgery. Whether a complete resection was achieved at secondary cytoreduction was highly prognostic: Patients who had a complete resection had a median overall survival of 61.9 months compared with 27.7 months in patients with residual disease. There were no deaths within 90 days of surgery.

Continue to: Immunotherapy enters first-line treatment regimen for advanced cervical cancer...

Immunotherapy enters first-line treatment regimen for advanced cervical cancer

Colombo N, Dubot C, Lorusso D, et al; KEYNOTE-826 Investigators. Pembrolizumab for persistent, recurrent, or metastatic cervical cancer. N Engl J Med. 2021;385:1856-1867.

Persistent, recurrent, and metastatic cervical cancer carries a very poor prognosis: Most patients progress less than a year after starting treatment, and fewer than half survive for 2 years. First-line treatment in this setting has been platinum-based chemotherapy, often given with bevacizumab, a humanized monoclonal antibody that inhibits tumor growth by blocking angiogenesis.⁸ Pembrolizumab, an immune checkpoint inhibitor, targets cancer cells by blocking their ability to evade the immune system, and it is FDA approved and widely administered to patients with advanced cervical cancer who progress after first-line treatment.⁹

Addition of pembrolizumab extended survival

In the KEYNOTE-826 trial, Colombo and colleagues investigated the efficacy of incorporating an immune checkpoint inhibitor into the first-line treatment regimen for patients with persistent, recurrent, and metastatic cervical cancer.¹⁰ Researchers in this double-blinded, phase 3, randomized controlled trial assigned 617 patients to receive pembrolizumab or placebo concurrently with the investigator’s choice platinum-based chemotherapy. Bevacizumab was administered at the discretion of the treating oncologist.

The proportion of patients who survived at least 2 years following randomization was significantly higher among those assigned to pembrolizumab compared with placebo (53% vs 42%; HR, 0.67, 95% CI, 0.54–0.84).¹⁰ Similarly, median progression-free survival was superior among patients who received pembrolizumab compared with those who received placebo (10.4 months vs 8.2 months; HR, 0.65; 95% CI, 0.53–0.79). The role of bevacizumab in conjunction with pembrolizumab and platinum-based chemotherapy was not elucidated in this study because bevacizumab administration was not randomly assigned.

Anemia and neutropenia were the most common adverse events and were more frequent in the pembrolizumab group, but there were no new safety concerns related to concurrent use of pembrolizumab with cytotoxic chemotherapy and bevacizumab. Importantly, subgroup analysis results suggested that pembrolizumab was effective only in patients whose tumors expressed PD-L1 (programmed death ligand 1), a biomarker of pembrolizumab sensitivity in cervical cancer.

Continue to: Endometrial cancer surgical staging...

Endometrial cancer surgical staging: Is sentinel lymph node biopsy a viable option for high-risk histologies?

Cusimano MC, Vicus D, Pulman K, et al. Assessment of sentinel lymph node biopsy vs lymphadenectomy for intermediate- and high-grade endometrial cancer staging. JAMA Surg. 2021;156:157-164.

The use of intraoperative sentinel lymph node mapping and biopsy to identify lymph node metastases among patients undergoing surgical staging for endometrial cancer has become increasingly common. Lymph node status is an important prognostic factor, and it guides adjuvant treatment decisions in endometrial cancer. However, traditional pelvic and para-aortic lymphadenectomy is associated with increased risk of lower-extremity lymphedema, postoperative complications, and intraoperative injury.

Sentinel lymph node biopsy seeks to identify lymph node metastases while minimizing surgical morbidity by identifying and excising only lymph nodes that directly receive lymphatic drainage from the uterus. The combination of a fluorescent dye (indocyanine green) and near infrared cameras have led to the broad adoption of sentinel lymph node biopsy in endometrial cancer staging surgery. This practice is supported by prospective studies that demonstrate the high diagnostic accuracy of this approach.^11,12 However, because most patients included in prior studies had low-grade endometrial cancer, the utility of sentinel lymph node biopsy in cases of high-grade histology has been less clear.

Sentinel lymph node biopsy vs lymphadenectomy for staging

In the SENTOR trial, Cusimano and colleagues examined the diagnostic accuracy of sentinel lymph node mapping and biopsy, using indocyanine green, in patients with intermediate- or high-grade early-stage endometrial cancer.¹³

All eligible patients (N = 156) underwent traditional or robot-assisted laparoscopic hysterectomy with sentinel lymph node biopsy. Subsequently, patients with grade 2 endometrioid carcinoma underwent bilateral pelvic lymphadenectomy, and those with high-grade histology (grade 3 endometrioid, serous, carcinosarcoma, clear cell, undifferentiated or dedifferentiated, and mixed high grade) underwent bilateral pelvic and para-aortic lymphadenectomy. The investigators evaluated the diagnostic characteristics of sentinel lymph node biopsy, treating complete lymphadenectomy as the gold standard.

Of the 156 patients enrolled, the median age was 65.5 and median body mass index was 27.5; 126 patients (81%) had high-grade histology. The sentinel lymph node biopsy had a sensitivity of 96% (95% CI, 81%–100%), identifying 26 of the 27 patients with nodal metastases. The false-negative rate was 4% (95% CI, 0%–9%) and the negative predictive value was 99% (95% CI, 96%–100%). Intraoperative adverse events occurred in 5 patients (3%), but none occurred during the sentinel lymph node biopsy. ●

Despite the challenges of an ongoing COVID-19 pandemic, researchers in 2021 delivered practice-changing studies in gynecologic oncology. In this cancer Update, we highlight 4 studies that shed light on the surgical and systemic therapies that may improve outcomes for patients with cancers of the ovary, endometrium, and cervix. We review DESKTOP III, a trial that investigated the role of cytoreductive surgery in patients with recurrent ovarian cancer, and SENTOR, a study that evaluated the performance of sentinel lymph node biopsy in patients with high-grade endometrial cancers. Additionally, we examine 2 studies of systemic therapy that reveal the growing role of targeted therapies and immuno-oncology in the treatment of gynecologic malignancies.

A new era for patients with BRCA mutation–associated ovarian cancer

Banerjee S, Moore KN, Colombo N, et al. Maintenance olaparib for patients with newly diagnosed advanced ovarian cancer and a BRCA mutation (SOLO1/GOG 3004): 5-year follow-up of a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2021;22:1721-1731.

Ovarian cancer remains the most lethal gynecologic malignancy due to the frequency of advanced-stage diagnosis and frequent relapse after primary therapy. But for ovarian cancer patients with inherited mutations of the BRCA1 or BRCA2 genes, poly(ADP-ribose) polymerase (PARP) inhibitors, a class of oral anticancer medicines that target DNA repair, have ushered in a new era in which the possibility of long-term remission, and even cure, is more likely than at any other time.

Olaparib trial details

The SOLO1 study was a double-blind, placebo-controlled, phase 3 trial that investigated the role of PARP inhibitor maintenance therapy with olaparib in patients with pathologic BRCA1 or BRCA2 mutations who responded to platinum-based chemotherapy administered for a newly diagnosed, advanced-stage ovarian cancer.¹ The study enrolled 391 patients, with 260 randomly assigned to receive olaparib for 24 months and 131 patients randomly assigned to receive placebo tablets. Most patients in the study had a mutation in the BRCA1 gene (72%), 27% had a BRCA2 mutation, and 1% had mutations in both genes.

The primary analysis of SOLO1 was published in 2018 and was based on a median follow-up of 3.4 years.¹ That study showed that olaparib maintenance therapy resulted in a large progression-free survival benefit and led to its approval by the US Food and Drug Administration (FDA) as a maintenance therapy for patients with BRCA-mutated advanced ovarian cancer who responded to first-line platinum-based chemotherapy.

In 2021, Banerjee and colleagues updated the progression-free survival results for the SOLO1 trial after 5 years of follow-up.² In this study, the patients randomly assigned to olaparib maintenance therapy had a persistent and statistically significant progression-free survival benefit, with the median progression-free survival reaching 56 months among the olaparib group compared with 13.8 months in the placebo group (hazard ratio [HR], 0.33; 95% confidence interval [CI], 0.25–0.43).² Olaparib maintenance therapy resulted in more clinically significant adverse events, including anemia and neutropenia. Serious adverse events occurred in 55 (21%) of the olaparib-treated patients and 17 (13%) of the placebo-treated patients, but no treatment-related adverse events were fatal.

Continue to: Cytoreductive surgery for recurrent ovarian cancer improves survival in well-selected patients...

Cytoreductive surgery for recurrent ovarian cancer improves survival in well-selected patients

Harter P, Sehouli J, Vergote I, et al; DESKTOP III Investigators. Randomized trial of cytoreductive surgery for relapsed ovarian cancer. N Engl J Med. 2021;385:2123- 2131.

In the DESKTOP III trial, Harter and colleagues contribute results to the ongoing discourse surrounding treatment options for patients with recurrent, platinum-sensitive ovarian cancer.³ Systemic therapies continue to be the mainstay of treatment in this setting; however, several groups have attempted to evaluate the role of secondary cytoreductive surgery in this setting.^4,5

Specific inclusion criteria employed

The DESKTOP III investigators randomly assigned 407 patients with platinum-sensitive recurrent ovarian cancer to secondary cytoreductive surgery followed by platinum-based chemotherapy (n = 206) or platinum-based chemotherapy alone (n = 201).³ An essential aspect of the study’s design was the use of specific inclusion criteria known to identify patients with a high likelihood of complete resection at the time of secondary cytoreduction.^6,7 Patients were eligible only if they had at least a 6-month remission following platinum-based chemotherapy, had a complete resection at their previous surgery, had no restriction on physical activity, and had ascites of no more than 500 mL.

Surgery group had superior overall and progression-free survival

After a median follow-up of approximately 70 months, patients randomly assigned to surgery had superior overall survival (53.7 months) compared with those assigned to chemotherapy alone (46.0 months; HR, 0.75; 95% CI, 0.59–0.96).³ Progression-free survival also was improved among patients who underwent surgery (median 18.4 vs 12.7 months; HR, 0.66; 95% CI, 0.54–0.82). Subgroup analyses did not identify any subset of patients who did not benefit from surgery. Whether a complete resection was achieved at secondary cytoreduction was highly prognostic: Patients who had a complete resection had a median overall survival of 61.9 months compared with 27.7 months in patients with residual disease. There were no deaths within 90 days of surgery.

Continue to: Immunotherapy enters first-line treatment regimen for advanced cervical cancer...

Immunotherapy enters first-line treatment regimen for advanced cervical cancer

Colombo N, Dubot C, Lorusso D, et al; KEYNOTE-826 Investigators. Pembrolizumab for persistent, recurrent, or metastatic cervical cancer. N Engl J Med. 2021;385:1856-1867.

Persistent, recurrent, and metastatic cervical cancer carries a very poor prognosis: Most patients progress less than a year after starting treatment, and fewer than half survive for 2 years. First-line treatment in this setting has been platinum-based chemotherapy, often given with bevacizumab, a humanized monoclonal antibody that inhibits tumor growth by blocking angiogenesis.⁸ Pembrolizumab, an immune checkpoint inhibitor, targets cancer cells by blocking their ability to evade the immune system, and it is FDA approved and widely administered to patients with advanced cervical cancer who progress after first-line treatment.⁹

Addition of pembrolizumab extended survival

In the KEYNOTE-826 trial, Colombo and colleagues investigated the efficacy of incorporating an immune checkpoint inhibitor into the first-line treatment regimen for patients with persistent, recurrent, and metastatic cervical cancer.¹⁰ Researchers in this double-blinded, phase 3, randomized controlled trial assigned 617 patients to receive pembrolizumab or placebo concurrently with the investigator’s choice platinum-based chemotherapy. Bevacizumab was administered at the discretion of the treating oncologist.

The proportion of patients who survived at least 2 years following randomization was significantly higher among those assigned to pembrolizumab compared with placebo (53% vs 42%; HR, 0.67, 95% CI, 0.54–0.84).¹⁰ Similarly, median progression-free survival was superior among patients who received pembrolizumab compared with those who received placebo (10.4 months vs 8.2 months; HR, 0.65; 95% CI, 0.53–0.79). The role of bevacizumab in conjunction with pembrolizumab and platinum-based chemotherapy was not elucidated in this study because bevacizumab administration was not randomly assigned.

Anemia and neutropenia were the most common adverse events and were more frequent in the pembrolizumab group, but there were no new safety concerns related to concurrent use of pembrolizumab with cytotoxic chemotherapy and bevacizumab. Importantly, subgroup analysis results suggested that pembrolizumab was effective only in patients whose tumors expressed PD-L1 (programmed death ligand 1), a biomarker of pembrolizumab sensitivity in cervical cancer.

Continue to: Endometrial cancer surgical staging...

Endometrial cancer surgical staging: Is sentinel lymph node biopsy a viable option for high-risk histologies?

Cusimano MC, Vicus D, Pulman K, et al. Assessment of sentinel lymph node biopsy vs lymphadenectomy for intermediate- and high-grade endometrial cancer staging. JAMA Surg. 2021;156:157-164.

The use of intraoperative sentinel lymph node mapping and biopsy to identify lymph node metastases among patients undergoing surgical staging for endometrial cancer has become increasingly common. Lymph node status is an important prognostic factor, and it guides adjuvant treatment decisions in endometrial cancer. However, traditional pelvic and para-aortic lymphadenectomy is associated with increased risk of lower-extremity lymphedema, postoperative complications, and intraoperative injury.

Sentinel lymph node biopsy seeks to identify lymph node metastases while minimizing surgical morbidity by identifying and excising only lymph nodes that directly receive lymphatic drainage from the uterus. The combination of a fluorescent dye (indocyanine green) and near infrared cameras have led to the broad adoption of sentinel lymph node biopsy in endometrial cancer staging surgery. This practice is supported by prospective studies that demonstrate the high diagnostic accuracy of this approach.^11,12 However, because most patients included in prior studies had low-grade endometrial cancer, the utility of sentinel lymph node biopsy in cases of high-grade histology has been less clear.

Sentinel lymph node biopsy vs lymphadenectomy for staging

In the SENTOR trial, Cusimano and colleagues examined the diagnostic accuracy of sentinel lymph node mapping and biopsy, using indocyanine green, in patients with intermediate- or high-grade early-stage endometrial cancer.¹³

All eligible patients (N = 156) underwent traditional or robot-assisted laparoscopic hysterectomy with sentinel lymph node biopsy. Subsequently, patients with grade 2 endometrioid carcinoma underwent bilateral pelvic lymphadenectomy, and those with high-grade histology (grade 3 endometrioid, serous, carcinosarcoma, clear cell, undifferentiated or dedifferentiated, and mixed high grade) underwent bilateral pelvic and para-aortic lymphadenectomy. The investigators evaluated the diagnostic characteristics of sentinel lymph node biopsy, treating complete lymphadenectomy as the gold standard.

Of the 156 patients enrolled, the median age was 65.5 and median body mass index was 27.5; 126 patients (81%) had high-grade histology. The sentinel lymph node biopsy had a sensitivity of 96% (95% CI, 81%–100%), identifying 26 of the 27 patients with nodal metastases. The false-negative rate was 4% (95% CI, 0%–9%) and the negative predictive value was 99% (95% CI, 96%–100%). Intraoperative adverse events occurred in 5 patients (3%), but none occurred during the sentinel lymph node biopsy. ●

Despite the challenges of an ongoing COVID-19 pandemic, researchers in 2021 delivered practice-changing studies in gynecologic oncology. In this cancer Update, we highlight 4 studies that shed light on the surgical and systemic therapies that may improve outcomes for patients with cancers of the ovary, endometrium, and cervix. We review DESKTOP III, a trial that investigated the role of cytoreductive surgery in patients with recurrent ovarian cancer, and SENTOR, a study that evaluated the performance of sentinel lymph node biopsy in patients with high-grade endometrial cancers. Additionally, we examine 2 studies of systemic therapy that reveal the growing role of targeted therapies and immuno-oncology in the treatment of gynecologic malignancies.

A new era for patients with BRCA mutation–associated ovarian cancer

Banerjee S, Moore KN, Colombo N, et al. Maintenance olaparib for patients with newly diagnosed advanced ovarian cancer and a BRCA mutation (SOLO1/GOG 3004): 5-year follow-up of a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2021;22:1721-1731.

Ovarian cancer remains the most lethal gynecologic malignancy due to the frequency of advanced-stage diagnosis and frequent relapse after primary therapy. But for ovarian cancer patients with inherited mutations of the BRCA1 or BRCA2 genes, poly(ADP-ribose) polymerase (PARP) inhibitors, a class of oral anticancer medicines that target DNA repair, have ushered in a new era in which the possibility of long-term remission, and even cure, is more likely than at any other time.

Olaparib trial details

The SOLO1 study was a double-blind, placebo-controlled, phase 3 trial that investigated the role of PARP inhibitor maintenance therapy with olaparib in patients with pathologic BRCA1 or BRCA2 mutations who responded to platinum-based chemotherapy administered for a newly diagnosed, advanced-stage ovarian cancer.¹ The study enrolled 391 patients, with 260 randomly assigned to receive olaparib for 24 months and 131 patients randomly assigned to receive placebo tablets. Most patients in the study had a mutation in the BRCA1 gene (72%), 27% had a BRCA2 mutation, and 1% had mutations in both genes.

The primary analysis of SOLO1 was published in 2018 and was based on a median follow-up of 3.4 years.¹ That study showed that olaparib maintenance therapy resulted in a large progression-free survival benefit and led to its approval by the US Food and Drug Administration (FDA) as a maintenance therapy for patients with BRCA-mutated advanced ovarian cancer who responded to first-line platinum-based chemotherapy.

In 2021, Banerjee and colleagues updated the progression-free survival results for the SOLO1 trial after 5 years of follow-up.² In this study, the patients randomly assigned to olaparib maintenance therapy had a persistent and statistically significant progression-free survival benefit, with the median progression-free survival reaching 56 months among the olaparib group compared with 13.8 months in the placebo group (hazard ratio [HR], 0.33; 95% confidence interval [CI], 0.25–0.43).² Olaparib maintenance therapy resulted in more clinically significant adverse events, including anemia and neutropenia. Serious adverse events occurred in 55 (21%) of the olaparib-treated patients and 17 (13%) of the placebo-treated patients, but no treatment-related adverse events were fatal.

Continue to: Cytoreductive surgery for recurrent ovarian cancer improves survival in well-selected patients...

Cytoreductive surgery for recurrent ovarian cancer improves survival in well-selected patients

Harter P, Sehouli J, Vergote I, et al; DESKTOP III Investigators. Randomized trial of cytoreductive surgery for relapsed ovarian cancer. N Engl J Med. 2021;385:2123- 2131.

In the DESKTOP III trial, Harter and colleagues contribute results to the ongoing discourse surrounding treatment options for patients with recurrent, platinum-sensitive ovarian cancer.³ Systemic therapies continue to be the mainstay of treatment in this setting; however, several groups have attempted to evaluate the role of secondary cytoreductive surgery in this setting.^4,5

Specific inclusion criteria employed

The DESKTOP III investigators randomly assigned 407 patients with platinum-sensitive recurrent ovarian cancer to secondary cytoreductive surgery followed by platinum-based chemotherapy (n = 206) or platinum-based chemotherapy alone (n = 201).³ An essential aspect of the study’s design was the use of specific inclusion criteria known to identify patients with a high likelihood of complete resection at the time of secondary cytoreduction.^6,7 Patients were eligible only if they had at least a 6-month remission following platinum-based chemotherapy, had a complete resection at their previous surgery, had no restriction on physical activity, and had ascites of no more than 500 mL.

Surgery group had superior overall and progression-free survival

After a median follow-up of approximately 70 months, patients randomly assigned to surgery had superior overall survival (53.7 months) compared with those assigned to chemotherapy alone (46.0 months; HR, 0.75; 95% CI, 0.59–0.96).³ Progression-free survival also was improved among patients who underwent surgery (median 18.4 vs 12.7 months; HR, 0.66; 95% CI, 0.54–0.82). Subgroup analyses did not identify any subset of patients who did not benefit from surgery. Whether a complete resection was achieved at secondary cytoreduction was highly prognostic: Patients who had a complete resection had a median overall survival of 61.9 months compared with 27.7 months in patients with residual disease. There were no deaths within 90 days of surgery.

Continue to: Immunotherapy enters first-line treatment regimen for advanced cervical cancer...

Immunotherapy enters first-line treatment regimen for advanced cervical cancer

Colombo N, Dubot C, Lorusso D, et al; KEYNOTE-826 Investigators. Pembrolizumab for persistent, recurrent, or metastatic cervical cancer. N Engl J Med. 2021;385:1856-1867.

Persistent, recurrent, and metastatic cervical cancer carries a very poor prognosis: Most patients progress less than a year after starting treatment, and fewer than half survive for 2 years. First-line treatment in this setting has been platinum-based chemotherapy, often given with bevacizumab, a humanized monoclonal antibody that inhibits tumor growth by blocking angiogenesis.⁸ Pembrolizumab, an immune checkpoint inhibitor, targets cancer cells by blocking their ability to evade the immune system, and it is FDA approved and widely administered to patients with advanced cervical cancer who progress after first-line treatment.⁹

Addition of pembrolizumab extended survival

In the KEYNOTE-826 trial, Colombo and colleagues investigated the efficacy of incorporating an immune checkpoint inhibitor into the first-line treatment regimen for patients with persistent, recurrent, and metastatic cervical cancer.¹⁰ Researchers in this double-blinded, phase 3, randomized controlled trial assigned 617 patients to receive pembrolizumab or placebo concurrently with the investigator’s choice platinum-based chemotherapy. Bevacizumab was administered at the discretion of the treating oncologist.

The proportion of patients who survived at least 2 years following randomization was significantly higher among those assigned to pembrolizumab compared with placebo (53% vs 42%; HR, 0.67, 95% CI, 0.54–0.84).¹⁰ Similarly, median progression-free survival was superior among patients who received pembrolizumab compared with those who received placebo (10.4 months vs 8.2 months; HR, 0.65; 95% CI, 0.53–0.79). The role of bevacizumab in conjunction with pembrolizumab and platinum-based chemotherapy was not elucidated in this study because bevacizumab administration was not randomly assigned.

Anemia and neutropenia were the most common adverse events and were more frequent in the pembrolizumab group, but there were no new safety concerns related to concurrent use of pembrolizumab with cytotoxic chemotherapy and bevacizumab. Importantly, subgroup analysis results suggested that pembrolizumab was effective only in patients whose tumors expressed PD-L1 (programmed death ligand 1), a biomarker of pembrolizumab sensitivity in cervical cancer.

Continue to: Endometrial cancer surgical staging...

Endometrial cancer surgical staging: Is sentinel lymph node biopsy a viable option for high-risk histologies?

Cusimano MC, Vicus D, Pulman K, et al. Assessment of sentinel lymph node biopsy vs lymphadenectomy for intermediate- and high-grade endometrial cancer staging. JAMA Surg. 2021;156:157-164.

The use of intraoperative sentinel lymph node mapping and biopsy to identify lymph node metastases among patients undergoing surgical staging for endometrial cancer has become increasingly common. Lymph node status is an important prognostic factor, and it guides adjuvant treatment decisions in endometrial cancer. However, traditional pelvic and para-aortic lymphadenectomy is associated with increased risk of lower-extremity lymphedema, postoperative complications, and intraoperative injury.

Sentinel lymph node biopsy seeks to identify lymph node metastases while minimizing surgical morbidity by identifying and excising only lymph nodes that directly receive lymphatic drainage from the uterus. The combination of a fluorescent dye (indocyanine green) and near infrared cameras have led to the broad adoption of sentinel lymph node biopsy in endometrial cancer staging surgery. This practice is supported by prospective studies that demonstrate the high diagnostic accuracy of this approach.^11,12 However, because most patients included in prior studies had low-grade endometrial cancer, the utility of sentinel lymph node biopsy in cases of high-grade histology has been less clear.

Sentinel lymph node biopsy vs lymphadenectomy for staging

In the SENTOR trial, Cusimano and colleagues examined the diagnostic accuracy of sentinel lymph node mapping and biopsy, using indocyanine green, in patients with intermediate- or high-grade early-stage endometrial cancer.¹³

All eligible patients (N = 156) underwent traditional or robot-assisted laparoscopic hysterectomy with sentinel lymph node biopsy. Subsequently, patients with grade 2 endometrioid carcinoma underwent bilateral pelvic lymphadenectomy, and those with high-grade histology (grade 3 endometrioid, serous, carcinosarcoma, clear cell, undifferentiated or dedifferentiated, and mixed high grade) underwent bilateral pelvic and para-aortic lymphadenectomy. The investigators evaluated the diagnostic characteristics of sentinel lymph node biopsy, treating complete lymphadenectomy as the gold standard.

Of the 156 patients enrolled, the median age was 65.5 and median body mass index was 27.5; 126 patients (81%) had high-grade histology. The sentinel lymph node biopsy had a sensitivity of 96% (95% CI, 81%–100%), identifying 26 of the 27 patients with nodal metastases. The false-negative rate was 4% (95% CI, 0%–9%) and the negative predictive value was 99% (95% CI, 96%–100%). Intraoperative adverse events occurred in 5 patients (3%), but none occurred during the sentinel lymph node biopsy. ●

CASE 1 Pregnant patient endures extensive wait and travel times to have antenatal testing

Pregnant at age 35 without comorbidities, Ms. H was instructed to schedule weekly biophysical profiles (BPP) after 36 weeks’ gestation for advanced maternal age. She receives care at a community office 25 miles from the hospital where she will deliver. Ms. H must complete her antenatal testing at the hospital where the sonographer performs BPPs. She sees her physician at the nearby clinic and then takes public transit to the hospital. She waits 2 hours to be seen then makes her way back home. Her prenatal care visit, which usually takes 30 minutes, turns into a 5-hour ordeal. Ms. H delivered a healthy baby at 39 weeks. Unfortunately, she was fired from her job for missing too many workdays.

Antenatal testing has become routine, and it is costly

For the prescriber, antenatal testing is simple: Order a weekly ultrasound exam to reduce the risk of stillbirth, decrease litigation, generate income, and maximize patient satisfaction (with the assumption that everyone likes to peek at their baby). Recommending antenatal testing has—with the best intentions—become a habit and therefore is difficult to break. However, the American College of Obstetricians and Gynecologists (ACOG) recognizes that “there is a paucity of evidenced-based recommendations on the timing and frequency of antenatal fetal surveillance because of the challenges of conducting prospective trials in pregnancies complicated by stillbirths and the varying conditions that place pregnancies at high risk for stillbirth. As a result, evidence for the efficacy of antenatal fetal surveillance, when available, is largely circumstantial.”¹

Antenatal testing without an evidence-based indication can be costly for the health care system, insurance companies, and patients. Many clinics, especially those in rural communities, do not have the equipment or personnel to complete antenatal testing on site. Asking a pregnant patient to travel repeatedly to another location for antenatal testing can increase her time off from work, complicate childcare, pose a financial burden, and lead to nonadherence. As clinicians, it is imperative that we work with our patients to create an individualized care plan to minimize these burdens and increase adherence.

Antenatal fetal surveillance can be considered for conditions in which stillbirth is reported more frequently than 0.8 per 1,000.

Advanced maternal age and stillbirth risk

One of the most common reasons for antenatal testing is advanced maternal age, that is, age older than 35. According to the Centers for Disease Control and Prevention and the National Vital Statistics System, from 2000 to 2012, 46 states and the District of Columbia (DC) reported an increase in first birth rates for women aged 35 to 39. Thirty-one states and DC saw a rise among women aged 40 to 44 in the same period (FIGURE).²

Advanced maternal age is an independent risk factor for stillbirth, with women aged 35 to 39 at 1.9-fold increased risk and women older than age 40 with a 2.4-fold higher risk compared with women younger than age 30.³ In a review of 44 studies including nearly 45,000,000 births, case-control studies, versus cohort studies, demonstrated a higher odds for stillbirth among women aged 35 and older (odds ratio [OR], 2.39; 95% confidence interval [CI], 1.57-3.66 vs OR, 1.73; 95% CI, 1.6-1.87).⁴ Now, many women older than age 35 may have a concomitant risk factor, such as diabetes or hypertension, that requires antenatal testing. However, for those without other risk factors, nearly 863 antenatal tests and 71 inductions would need to be completed to reduce the number of stillbirths by 1. Antenatal testing for women older than age 35 without other risk factors should be individualized through shared decision making.⁵ See the ACOG committee opinion for a table that outlines factors associated with an increased risk of stillbirth and suggested strategies for antenatal surveillance after viability.¹

Continue to: CASE 2 Patient with high BPP score and altered...

CASE 2 Patient with high BPP score and altered fetal movements delivered for nonreassuring fetal heart rate

Ms. Q was undergoing weekly BPPs for diet-controlled gestational diabetes and a prepregnancy body mass index (BMI) of 52. At 37 weeks’ gestation, she had a BPP score of 8/8. However, it took almost 30 minutes to see 2 discrete body or limb movements. Ms. Q mentioned to the nurse taking her vitals after the BPP that the baby’s movements had changed over the previous few days, especially after contractions. Ms. Q then completed a nonstress test (NST); she had 2 contractions and 2 fetal heart rate decelerations, each lasting approximately 60 seconds. Ms. Q was sent to labor and delivery for prolonged monitoring, and she was delivered that day for a nonreassuring fetal heart rate tracing. Meconium-stained amniotic fluid and a tight triple nuchal cord were noted at delivery.

BPP considerations

While considered an in-depth look at the fetal status, BPPs may not predict overall fetal well-being during acute changes, such as umbilical cord compression or placental abruption. BPPs take longer to complete, require a trained sonographer, and include components like fetal breathing that may be influenced by such factors as nicotine,^6-8 labor,⁹ rupture of membranes,¹⁰ magnesium sulfate,¹¹ and infection.¹²

If medically indicated, which antenatal surveillance technique is right for your patient?

Frequently used antepartum fetal surveillance techniques include maternal perception of fetal movement or “kick counting,” NST, BPP, modified BPP, contraction stress test (CST), and umbilical artery Doppler velocimetry.

Worldwide, the most common form of antenatal surveillance is fetal kick counting. It is noninvasive, can be completed frequently, may decrease maternal anxiety, may improve maternal-fetal bonding, and is free.¹³ According to the results of a 2020 meta-analysis of 468,601 fetuses, however, there was no difference in perinatal death among patients who assessed fetal movements (0.54%) and those who did not (0.59%).¹⁴ There was a statistically significant increase in induction of labor, cesarean delivery, and preterm delivery among patients who counted fetal movements. Women who perceive a decrease in fetal movement should seek medical attention from a health care provider.

An evaluation for decreased fetal movement typically includes taking a history that focuses on risk factors that may increase stillbirth, including hypertension, growth restriction, fetal anomalies, diabetes, and substance use, and auscultation with a fetal Doppler. In the absence of risk factors and the presence of a normal fetal heartbeat, pregnant women should be reassured of fetal well-being. In a pregnancy at greater than 28 weeks, a 20-minute NST can be completed as well; this has become part of the standard workup of decreased fetal movement in developed countries. A reactive NST indicates normal fetal autonomic function in real time and a low incidence of stillbirth (1.9/1,000) within 1 week.¹⁵

Additionally, by measuring the amniotic fluid volume using the largest maximal vertical pocket (MVP), clinicians can gain insight into overall uteroplacental function. The combination of the NST and the MVP—otherwise known as a modified BPP—provides both short-term acid-base status and long-term uteroplacental function. The incidence of stillbirth in the 1 week after a modified BPP has been reported to be 0.8/1,000, which is equivalent to stillbirth incidence using a full BPP (0.8/1,000).¹⁶ The negative predictive value for both the modified BPP and the BPP is 99.9%—equivalent.

The case for modified BPP use

The modified BPP requires less time, is less costly (cost savings of approximately 50%), does not require a specialized sonographer, and can be performed in local community clinics.

Perhaps the initial antepartum surveillance test of choice should be the modified BPP, with the BPP used in cases in which the results of a modified BPP are abnormal. ●

CASE 1 Pregnant patient endures extensive wait and travel times to have antenatal testing

Pregnant at age 35 without comorbidities, Ms. H was instructed to schedule weekly biophysical profiles (BPP) after 36 weeks’ gestation for advanced maternal age. She receives care at a community office 25 miles from the hospital where she will deliver. Ms. H must complete her antenatal testing at the hospital where the sonographer performs BPPs. She sees her physician at the nearby clinic and then takes public transit to the hospital. She waits 2 hours to be seen then makes her way back home. Her prenatal care visit, which usually takes 30 minutes, turns into a 5-hour ordeal. Ms. H delivered a healthy baby at 39 weeks. Unfortunately, she was fired from her job for missing too many workdays.

Antenatal testing has become routine, and it is costly

For the prescriber, antenatal testing is simple: Order a weekly ultrasound exam to reduce the risk of stillbirth, decrease litigation, generate income, and maximize patient satisfaction (with the assumption that everyone likes to peek at their baby). Recommending antenatal testing has—with the best intentions—become a habit and therefore is difficult to break. However, the American College of Obstetricians and Gynecologists (ACOG) recognizes that “there is a paucity of evidenced-based recommendations on the timing and frequency of antenatal fetal surveillance because of the challenges of conducting prospective trials in pregnancies complicated by stillbirths and the varying conditions that place pregnancies at high risk for stillbirth. As a result, evidence for the efficacy of antenatal fetal surveillance, when available, is largely circumstantial.”¹

Antenatal testing without an evidence-based indication can be costly for the health care system, insurance companies, and patients. Many clinics, especially those in rural communities, do not have the equipment or personnel to complete antenatal testing on site. Asking a pregnant patient to travel repeatedly to another location for antenatal testing can increase her time off from work, complicate childcare, pose a financial burden, and lead to nonadherence. As clinicians, it is imperative that we work with our patients to create an individualized care plan to minimize these burdens and increase adherence.

Antenatal fetal surveillance can be considered for conditions in which stillbirth is reported more frequently than 0.8 per 1,000.

Advanced maternal age and stillbirth risk

One of the most common reasons for antenatal testing is advanced maternal age, that is, age older than 35. According to the Centers for Disease Control and Prevention and the National Vital Statistics System, from 2000 to 2012, 46 states and the District of Columbia (DC) reported an increase in first birth rates for women aged 35 to 39. Thirty-one states and DC saw a rise among women aged 40 to 44 in the same period (FIGURE).²

Advanced maternal age is an independent risk factor for stillbirth, with women aged 35 to 39 at 1.9-fold increased risk and women older than age 40 with a 2.4-fold higher risk compared with women younger than age 30.³ In a review of 44 studies including nearly 45,000,000 births, case-control studies, versus cohort studies, demonstrated a higher odds for stillbirth among women aged 35 and older (odds ratio [OR], 2.39; 95% confidence interval [CI], 1.57-3.66 vs OR, 1.73; 95% CI, 1.6-1.87).⁴ Now, many women older than age 35 may have a concomitant risk factor, such as diabetes or hypertension, that requires antenatal testing. However, for those without other risk factors, nearly 863 antenatal tests and 71 inductions would need to be completed to reduce the number of stillbirths by 1. Antenatal testing for women older than age 35 without other risk factors should be individualized through shared decision making.⁵ See the ACOG committee opinion for a table that outlines factors associated with an increased risk of stillbirth and suggested strategies for antenatal surveillance after viability.¹

Continue to: CASE 2 Patient with high BPP score and altered...

CASE 2 Patient with high BPP score and altered fetal movements delivered for nonreassuring fetal heart rate

Ms. Q was undergoing weekly BPPs for diet-controlled gestational diabetes and a prepregnancy body mass index (BMI) of 52. At 37 weeks’ gestation, she had a BPP score of 8/8. However, it took almost 30 minutes to see 2 discrete body or limb movements. Ms. Q mentioned to the nurse taking her vitals after the BPP that the baby’s movements had changed over the previous few days, especially after contractions. Ms. Q then completed a nonstress test (NST); she had 2 contractions and 2 fetal heart rate decelerations, each lasting approximately 60 seconds. Ms. Q was sent to labor and delivery for prolonged monitoring, and she was delivered that day for a nonreassuring fetal heart rate tracing. Meconium-stained amniotic fluid and a tight triple nuchal cord were noted at delivery.

BPP considerations

While considered an in-depth look at the fetal status, BPPs may not predict overall fetal well-being during acute changes, such as umbilical cord compression or placental abruption. BPPs take longer to complete, require a trained sonographer, and include components like fetal breathing that may be influenced by such factors as nicotine,^6-8 labor,⁹ rupture of membranes,¹⁰ magnesium sulfate,¹¹ and infection.¹²

If medically indicated, which antenatal surveillance technique is right for your patient?

Frequently used antepartum fetal surveillance techniques include maternal perception of fetal movement or “kick counting,” NST, BPP, modified BPP, contraction stress test (CST), and umbilical artery Doppler velocimetry.

Worldwide, the most common form of antenatal surveillance is fetal kick counting. It is noninvasive, can be completed frequently, may decrease maternal anxiety, may improve maternal-fetal bonding, and is free.¹³ According to the results of a 2020 meta-analysis of 468,601 fetuses, however, there was no difference in perinatal death among patients who assessed fetal movements (0.54%) and those who did not (0.59%).¹⁴ There was a statistically significant increase in induction of labor, cesarean delivery, and preterm delivery among patients who counted fetal movements. Women who perceive a decrease in fetal movement should seek medical attention from a health care provider.

An evaluation for decreased fetal movement typically includes taking a history that focuses on risk factors that may increase stillbirth, including hypertension, growth restriction, fetal anomalies, diabetes, and substance use, and auscultation with a fetal Doppler. In the absence of risk factors and the presence of a normal fetal heartbeat, pregnant women should be reassured of fetal well-being. In a pregnancy at greater than 28 weeks, a 20-minute NST can be completed as well; this has become part of the standard workup of decreased fetal movement in developed countries. A reactive NST indicates normal fetal autonomic function in real time and a low incidence of stillbirth (1.9/1,000) within 1 week.¹⁵

Additionally, by measuring the amniotic fluid volume using the largest maximal vertical pocket (MVP), clinicians can gain insight into overall uteroplacental function. The combination of the NST and the MVP—otherwise known as a modified BPP—provides both short-term acid-base status and long-term uteroplacental function. The incidence of stillbirth in the 1 week after a modified BPP has been reported to be 0.8/1,000, which is equivalent to stillbirth incidence using a full BPP (0.8/1,000).¹⁶ The negative predictive value for both the modified BPP and the BPP is 99.9%—equivalent.

The case for modified BPP use

The modified BPP requires less time, is less costly (cost savings of approximately 50%), does not require a specialized sonographer, and can be performed in local community clinics.

Perhaps the initial antepartum surveillance test of choice should be the modified BPP, with the BPP used in cases in which the results of a modified BPP are abnormal. ●

CASE 1 Pregnant patient endures extensive wait and travel times to have antenatal testing

Pregnant at age 35 without comorbidities, Ms. H was instructed to schedule weekly biophysical profiles (BPP) after 36 weeks’ gestation for advanced maternal age. She receives care at a community office 25 miles from the hospital where she will deliver. Ms. H must complete her antenatal testing at the hospital where the sonographer performs BPPs. She sees her physician at the nearby clinic and then takes public transit to the hospital. She waits 2 hours to be seen then makes her way back home. Her prenatal care visit, which usually takes 30 minutes, turns into a 5-hour ordeal. Ms. H delivered a healthy baby at 39 weeks. Unfortunately, she was fired from her job for missing too many workdays.

Antenatal testing has become routine, and it is costly

For the prescriber, antenatal testing is simple: Order a weekly ultrasound exam to reduce the risk of stillbirth, decrease litigation, generate income, and maximize patient satisfaction (with the assumption that everyone likes to peek at their baby). Recommending antenatal testing has—with the best intentions—become a habit and therefore is difficult to break. However, the American College of Obstetricians and Gynecologists (ACOG) recognizes that “there is a paucity of evidenced-based recommendations on the timing and frequency of antenatal fetal surveillance because of the challenges of conducting prospective trials in pregnancies complicated by stillbirths and the varying conditions that place pregnancies at high risk for stillbirth. As a result, evidence for the efficacy of antenatal fetal surveillance, when available, is largely circumstantial.”¹

Antenatal testing without an evidence-based indication can be costly for the health care system, insurance companies, and patients. Many clinics, especially those in rural communities, do not have the equipment or personnel to complete antenatal testing on site. Asking a pregnant patient to travel repeatedly to another location for antenatal testing can increase her time off from work, complicate childcare, pose a financial burden, and lead to nonadherence. As clinicians, it is imperative that we work with our patients to create an individualized care plan to minimize these burdens and increase adherence.

Antenatal fetal surveillance can be considered for conditions in which stillbirth is reported more frequently than 0.8 per 1,000.

Advanced maternal age and stillbirth risk

One of the most common reasons for antenatal testing is advanced maternal age, that is, age older than 35. According to the Centers for Disease Control and Prevention and the National Vital Statistics System, from 2000 to 2012, 46 states and the District of Columbia (DC) reported an increase in first birth rates for women aged 35 to 39. Thirty-one states and DC saw a rise among women aged 40 to 44 in the same period (FIGURE).²

Advanced maternal age is an independent risk factor for stillbirth, with women aged 35 to 39 at 1.9-fold increased risk and women older than age 40 with a 2.4-fold higher risk compared with women younger than age 30.³ In a review of 44 studies including nearly 45,000,000 births, case-control studies, versus cohort studies, demonstrated a higher odds for stillbirth among women aged 35 and older (odds ratio [OR], 2.39; 95% confidence interval [CI], 1.57-3.66 vs OR, 1.73; 95% CI, 1.6-1.87).⁴ Now, many women older than age 35 may have a concomitant risk factor, such as diabetes or hypertension, that requires antenatal testing. However, for those without other risk factors, nearly 863 antenatal tests and 71 inductions would need to be completed to reduce the number of stillbirths by 1. Antenatal testing for women older than age 35 without other risk factors should be individualized through shared decision making.⁵ See the ACOG committee opinion for a table that outlines factors associated with an increased risk of stillbirth and suggested strategies for antenatal surveillance after viability.¹

Continue to: CASE 2 Patient with high BPP score and altered...

CASE 2 Patient with high BPP score and altered fetal movements delivered for nonreassuring fetal heart rate

Ms. Q was undergoing weekly BPPs for diet-controlled gestational diabetes and a prepregnancy body mass index (BMI) of 52. At 37 weeks’ gestation, she had a BPP score of 8/8. However, it took almost 30 minutes to see 2 discrete body or limb movements. Ms. Q mentioned to the nurse taking her vitals after the BPP that the baby’s movements had changed over the previous few days, especially after contractions. Ms. Q then completed a nonstress test (NST); she had 2 contractions and 2 fetal heart rate decelerations, each lasting approximately 60 seconds. Ms. Q was sent to labor and delivery for prolonged monitoring, and she was delivered that day for a nonreassuring fetal heart rate tracing. Meconium-stained amniotic fluid and a tight triple nuchal cord were noted at delivery.

BPP considerations

While considered an in-depth look at the fetal status, BPPs may not predict overall fetal well-being during acute changes, such as umbilical cord compression or placental abruption. BPPs take longer to complete, require a trained sonographer, and include components like fetal breathing that may be influenced by such factors as nicotine,^6-8 labor,⁹ rupture of membranes,¹⁰ magnesium sulfate,¹¹ and infection.¹²

If medically indicated, which antenatal surveillance technique is right for your patient?

Frequently used antepartum fetal surveillance techniques include maternal perception of fetal movement or “kick counting,” NST, BPP, modified BPP, contraction stress test (CST), and umbilical artery Doppler velocimetry.

Worldwide, the most common form of antenatal surveillance is fetal kick counting. It is noninvasive, can be completed frequently, may decrease maternal anxiety, may improve maternal-fetal bonding, and is free.¹³ According to the results of a 2020 meta-analysis of 468,601 fetuses, however, there was no difference in perinatal death among patients who assessed fetal movements (0.54%) and those who did not (0.59%).¹⁴ There was a statistically significant increase in induction of labor, cesarean delivery, and preterm delivery among patients who counted fetal movements. Women who perceive a decrease in fetal movement should seek medical attention from a health care provider.

An evaluation for decreased fetal movement typically includes taking a history that focuses on risk factors that may increase stillbirth, including hypertension, growth restriction, fetal anomalies, diabetes, and substance use, and auscultation with a fetal Doppler. In the absence of risk factors and the presence of a normal fetal heartbeat, pregnant women should be reassured of fetal well-being. In a pregnancy at greater than 28 weeks, a 20-minute NST can be completed as well; this has become part of the standard workup of decreased fetal movement in developed countries. A reactive NST indicates normal fetal autonomic function in real time and a low incidence of stillbirth (1.9/1,000) within 1 week.¹⁵

Additionally, by measuring the amniotic fluid volume using the largest maximal vertical pocket (MVP), clinicians can gain insight into overall uteroplacental function. The combination of the NST and the MVP—otherwise known as a modified BPP—provides both short-term acid-base status and long-term uteroplacental function. The incidence of stillbirth in the 1 week after a modified BPP has been reported to be 0.8/1,000, which is equivalent to stillbirth incidence using a full BPP (0.8/1,000).¹⁶ The negative predictive value for both the modified BPP and the BPP is 99.9%—equivalent.

The case for modified BPP use

The modified BPP requires less time, is less costly (cost savings of approximately 50%), does not require a specialized sonographer, and can be performed in local community clinics.

Perhaps the initial antepartum surveillance test of choice should be the modified BPP, with the BPP used in cases in which the results of a modified BPP are abnormal. ●

Copyright: Digital illustrations by John J. DeNapoli/Cristian Storto Fotografia/IStock/Getty Images Plus/Prostock-Studio/IStock/Getty Images Plus/ClaudioVentrella/IStock Getty Images Plus

COVID-19 vaccination is recommended for all reproductive-aged women, regardless of pregnancy status.¹ Yet, national vaccination rates in pregnancy remain woefully low—lower than vaccine coverage rates for other recommended vaccines during pregnancy.^2,3 COVID-19 infection has clearly documented risks for maternal and fetal health, and data continue to accumulate on the maternal and neonatal benefits of COVID-19 vaccination in pregnancy, as well as the safety of vaccination during pregnancy.

Maternal and neonatal benefits of COVID-19 vaccination

Does vaccination in pregnancy result in decreased rates of severe COVID-19 infection? Results from a study from a Louisiana health system comparing maternal outcomes between fully vaccinated (defined as 2 weeks after the final vaccine dose) and unvaccinated or partially vaccinated pregnant women during the delta variant—predominant COVID-19 surge clearly answer this question. Vaccination in pregnancy resulted in a 90% risk reduction in severe or critical COVID-19 infection and a 70% risk reduction in COVID-19 infection of any severity among fully vaccinated women. The study also provides some useful absolute numbers for patient counseling: Although none of the 1,332 vaccinated pregnant women in the study required supplemental oxygen or intensive care unit (ICU) admission, there was 1 maternal death, 5 ICU admissions, and 6 stillbirths among the 8,760 unvaccinated pregnant women.⁴

A larger population-based data set from Scotland and Israel demonstrated similar findings.⁵ Most importantly, the Scotland data, with most patients having had an mRNA-based vaccine, showed that, while 77% of all COVID-19 infections occurred in unvaccinated pregnant women, 91% of all hospital admissions occurred in unvaccinated women, and 98% of all critical care admissions occurred in unvaccinated women. Furthermore, although 13% of all COVID-19 hospitalizations in pregnancy occurred among vaccinated women, only 2% of critical care admissions occurred among vaccinated women. The Israeli experience (which identified nearly 30,000 eligible pregnancies from 1 of 4 state-mandated health funds in the country), demonstrated that the efficacy of the Pfizer/BioNTech vaccine to prevent a SARS-CoV-2 infection of any severity once fully vaccinated is more than 80%.⁶

Breakthrough infections, which were more prevalent during the omicron surge, have caused some patients to question the utility of COVID-19 vaccination. Recent data from South Africa, where the omicron variant was first identified, noted that efficacy of the Pfizer/ BioNTech vaccine to prevent hospitalization with COVID-19 infection during an omicron-predominant period was 70%—versus 93% efficacy in a delta-predominant period.⁷ These data, however, were in the absence of a booster dose, and in vitro studies suggest increased vaccine efficacy with a booster dose.⁸

Continue to: Counseling women on vaccination benefits and risks...

Counseling women on vaccination benefits and risks. No matter the specific numeric rate of efficacy against a COVID-19 infection, it is important to counsel women that the goal of vaccination is to prevent severe or critical COVID-19 infections, and these data all demonstrate that COVID-19 vaccination meets this goal. However, women may have additional questions regarding both fetal/neonatal benefits and safety with immunization in pregnancy.

Let us address the question of benefit first. In a large cohort of more than 1,300 women vaccinated during pregnancy and delivering at >34 weeks’ gestation, a few observations are worth noting.⁹ The first is that women who were fully vaccinated by the time of delivery had detectable antibodies at birth, even with first trimester vaccination, and these antibodies did cross the placenta to the neonate. Although higher maternal and neonatal antibody levels are achieved with early third trimester vaccination, it is key that women interpret this finding in light of 2 important points:

1. women cannot know what gestational age they will deliver, thus waiting until the early third trimester for vaccination to optimize neonatal antibody levels could result in delivery prior to planned vaccination, with benefit for neither the woman nor the baby
2. partial vaccination in the early third trimester resulted in lower maternal and neonatal antibody levels than full vaccination in the first trimester.

In addition, while the data were limited, a booster dose in the third trimester results in the highest antibody levels at delivery. Given the recommendation to initiate a booster dose 5 months after the completion of the primary vaccine series,¹⁰ many women will be eligible for a booster prior to delivery and thus can achieve the goals of high maternal and neonatal antibody levels simultaneously. One caveat to these data is that, while higher antibody levels seem comforting and may be better, we do not yet know the level of neonatal antibody necessary to decrease risks of COVID-19 infection in early newborn life.⁹ Recent data from the Centers for Disease Control and Prevention provide real-world evidence that maternal vaccination decreases the risk of hospitalization from COVID-19 for infants aged <6 months, with vaccine efficacy estimated to be 61% during a period of both Delta and Omicron predominance.¹¹

The evidence is clear—the time for COVID-19 vaccination is now. There is no “optimal” time of vaccination in pregnancy for neonatal benefit that would be worth risking any amount of time a woman is susceptible to COVID-19, especially given the promising data regarding maternal and neonatal antibody levels achieved after a booster dose.

Safety of COVID-19 vaccination: Current data

Risks for pregnancy loss, birth defects, and preterm delivery often are concerns of pregnant women considering a COVID-19 vaccination. Data from more than 2,400 women who submitted their information to the v-SAFE registry demonstrated a 14% risk for pregnancy loss between 6 and 20 weeks’ gestation—well within the expected rate of pregnancy loss in this gestational age range.¹²

Data from more than 46,000 pregnancies included in the Vaccine Safety Datalink, which includes data from health care organizations in 6 states, demonstrated a preterm birth rate of 6.6% and a small-for-gestational-age rate of 8.2% among fully vaccinated women, rates that were no different among unvaccinated women. There were no differences in the outcomes by trimester of vaccination, and these rates are comparable to the expected rates of these outcomes.¹³

Women also worry about the risks of vaccine side effects, such as fever or rare adverse events. Although all adverse events (ie, Guillain-Barre syndrome, pericarditis/myocarditis, thrombosis with thrombocytopenia syndrome [TTS]) are very rare, the American College of Obstetricians and Gynecologists does recommend that women get an mRNA COVID-19 vaccine, as the Johnson & Johnson/Janssen vaccine is associated with TTS, which occurred more commonly (although still rare) in women of reproductive age.¹⁴

Two large studies of typical side effects experienced after COVID-19 vaccination in pregnancy are incredibly reassuring. In the first, authors of a large study of more than 12,000 pregnant women enrolled in the v-SAFE registry reported that the most common side effect after each mRNA dose was injection site pain (88% after dose 1, 92% after dose 2).¹⁵ Self-reported fever occurred in 4% of women after dose 1 and 35% after dose 2. Although this frequency may seem high, a fever of 38.0°C (100.4°F) or higher only occurred among 8% of all participants.

In another study of almost 8,000 women self-reporting side effects (some of whom also may have contributed data to the v-SAFE study), fever occurred in approximately 5% after dose 1 and in about 20% after dose 2.¹⁶ In this study, the highest mean temperature was 38.1°C (100.6°F) after dose 1 and 38.2°C (100.7°F) after dose 2. Although it is a reasonable expectation for fever to follow COVID-19 vaccination, particularly after the second dose, the typical fever is a low-grade temperature that will not harm a developing fetus and will be responsive to acetaminophen administration. Moreover, if the fever were the harbinger of harm, then it might stand to reason that an increased signal of preterm delivery may be observed, but data from nearly 10,000 pregnant women vaccinated during the second or third trimesters showed no association with preterm birth (adjusted hazard ratio, 0.91; 95% confidence interval, 0.82–1.01).¹³

The bottom line

The data are clear. COVID-19 vaccination decreases the risks of severe infection in pregnancy, confers antibodies to neonates with at least some level of protection, and has no demonstrated harmful side effects in pregnancy. ●

Copyright: Digital illustrations by John J. DeNapoli/Cristian Storto Fotografia/IStock/Getty Images Plus/Prostock-Studio/IStock/Getty Images Plus/ClaudioVentrella/IStock Getty Images Plus

COVID-19 vaccination is recommended for all reproductive-aged women, regardless of pregnancy status.¹ Yet, national vaccination rates in pregnancy remain woefully low—lower than vaccine coverage rates for other recommended vaccines during pregnancy.^2,3 COVID-19 infection has clearly documented risks for maternal and fetal health, and data continue to accumulate on the maternal and neonatal benefits of COVID-19 vaccination in pregnancy, as well as the safety of vaccination during pregnancy.

Maternal and neonatal benefits of COVID-19 vaccination

Does vaccination in pregnancy result in decreased rates of severe COVID-19 infection? Results from a study from a Louisiana health system comparing maternal outcomes between fully vaccinated (defined as 2 weeks after the final vaccine dose) and unvaccinated or partially vaccinated pregnant women during the delta variant—predominant COVID-19 surge clearly answer this question. Vaccination in pregnancy resulted in a 90% risk reduction in severe or critical COVID-19 infection and a 70% risk reduction in COVID-19 infection of any severity among fully vaccinated women. The study also provides some useful absolute numbers for patient counseling: Although none of the 1,332 vaccinated pregnant women in the study required supplemental oxygen or intensive care unit (ICU) admission, there was 1 maternal death, 5 ICU admissions, and 6 stillbirths among the 8,760 unvaccinated pregnant women.⁴

A larger population-based data set from Scotland and Israel demonstrated similar findings.⁵ Most importantly, the Scotland data, with most patients having had an mRNA-based vaccine, showed that, while 77% of all COVID-19 infections occurred in unvaccinated pregnant women, 91% of all hospital admissions occurred in unvaccinated women, and 98% of all critical care admissions occurred in unvaccinated women. Furthermore, although 13% of all COVID-19 hospitalizations in pregnancy occurred among vaccinated women, only 2% of critical care admissions occurred among vaccinated women. The Israeli experience (which identified nearly 30,000 eligible pregnancies from 1 of 4 state-mandated health funds in the country), demonstrated that the efficacy of the Pfizer/BioNTech vaccine to prevent a SARS-CoV-2 infection of any severity once fully vaccinated is more than 80%.⁶

Breakthrough infections, which were more prevalent during the omicron surge, have caused some patients to question the utility of COVID-19 vaccination. Recent data from South Africa, where the omicron variant was first identified, noted that efficacy of the Pfizer/ BioNTech vaccine to prevent hospitalization with COVID-19 infection during an omicron-predominant period was 70%—versus 93% efficacy in a delta-predominant period.⁷ These data, however, were in the absence of a booster dose, and in vitro studies suggest increased vaccine efficacy with a booster dose.⁸

Continue to: Counseling women on vaccination benefits and risks...

Counseling women on vaccination benefits and risks. No matter the specific numeric rate of efficacy against a COVID-19 infection, it is important to counsel women that the goal of vaccination is to prevent severe or critical COVID-19 infections, and these data all demonstrate that COVID-19 vaccination meets this goal. However, women may have additional questions regarding both fetal/neonatal benefits and safety with immunization in pregnancy.

Let us address the question of benefit first. In a large cohort of more than 1,300 women vaccinated during pregnancy and delivering at >34 weeks’ gestation, a few observations are worth noting.⁹ The first is that women who were fully vaccinated by the time of delivery had detectable antibodies at birth, even with first trimester vaccination, and these antibodies did cross the placenta to the neonate. Although higher maternal and neonatal antibody levels are achieved with early third trimester vaccination, it is key that women interpret this finding in light of 2 important points:

1. women cannot know what gestational age they will deliver, thus waiting until the early third trimester for vaccination to optimize neonatal antibody levels could result in delivery prior to planned vaccination, with benefit for neither the woman nor the baby
2. partial vaccination in the early third trimester resulted in lower maternal and neonatal antibody levels than full vaccination in the first trimester.

In addition, while the data were limited, a booster dose in the third trimester results in the highest antibody levels at delivery. Given the recommendation to initiate a booster dose 5 months after the completion of the primary vaccine series,¹⁰ many women will be eligible for a booster prior to delivery and thus can achieve the goals of high maternal and neonatal antibody levels simultaneously. One caveat to these data is that, while higher antibody levels seem comforting and may be better, we do not yet know the level of neonatal antibody necessary to decrease risks of COVID-19 infection in early newborn life.⁹ Recent data from the Centers for Disease Control and Prevention provide real-world evidence that maternal vaccination decreases the risk of hospitalization from COVID-19 for infants aged <6 months, with vaccine efficacy estimated to be 61% during a period of both Delta and Omicron predominance.¹¹

The evidence is clear—the time for COVID-19 vaccination is now. There is no “optimal” time of vaccination in pregnancy for neonatal benefit that would be worth risking any amount of time a woman is susceptible to COVID-19, especially given the promising data regarding maternal and neonatal antibody levels achieved after a booster dose.

Safety of COVID-19 vaccination: Current data

Risks for pregnancy loss, birth defects, and preterm delivery often are concerns of pregnant women considering a COVID-19 vaccination. Data from more than 2,400 women who submitted their information to the v-SAFE registry demonstrated a 14% risk for pregnancy loss between 6 and 20 weeks’ gestation—well within the expected rate of pregnancy loss in this gestational age range.¹²

Data from more than 46,000 pregnancies included in the Vaccine Safety Datalink, which includes data from health care organizations in 6 states, demonstrated a preterm birth rate of 6.6% and a small-for-gestational-age rate of 8.2% among fully vaccinated women, rates that were no different among unvaccinated women. There were no differences in the outcomes by trimester of vaccination, and these rates are comparable to the expected rates of these outcomes.¹³

Women also worry about the risks of vaccine side effects, such as fever or rare adverse events. Although all adverse events (ie, Guillain-Barre syndrome, pericarditis/myocarditis, thrombosis with thrombocytopenia syndrome [TTS]) are very rare, the American College of Obstetricians and Gynecologists does recommend that women get an mRNA COVID-19 vaccine, as the Johnson & Johnson/Janssen vaccine is associated with TTS, which occurred more commonly (although still rare) in women of reproductive age.¹⁴

Two large studies of typical side effects experienced after COVID-19 vaccination in pregnancy are incredibly reassuring. In the first, authors of a large study of more than 12,000 pregnant women enrolled in the v-SAFE registry reported that the most common side effect after each mRNA dose was injection site pain (88% after dose 1, 92% after dose 2).¹⁵ Self-reported fever occurred in 4% of women after dose 1 and 35% after dose 2. Although this frequency may seem high, a fever of 38.0°C (100.4°F) or higher only occurred among 8% of all participants.

In another study of almost 8,000 women self-reporting side effects (some of whom also may have contributed data to the v-SAFE study), fever occurred in approximately 5% after dose 1 and in about 20% after dose 2.¹⁶ In this study, the highest mean temperature was 38.1°C (100.6°F) after dose 1 and 38.2°C (100.7°F) after dose 2. Although it is a reasonable expectation for fever to follow COVID-19 vaccination, particularly after the second dose, the typical fever is a low-grade temperature that will not harm a developing fetus and will be responsive to acetaminophen administration. Moreover, if the fever were the harbinger of harm, then it might stand to reason that an increased signal of preterm delivery may be observed, but data from nearly 10,000 pregnant women vaccinated during the second or third trimesters showed no association with preterm birth (adjusted hazard ratio, 0.91; 95% confidence interval, 0.82–1.01).¹³

The bottom line

The data are clear. COVID-19 vaccination decreases the risks of severe infection in pregnancy, confers antibodies to neonates with at least some level of protection, and has no demonstrated harmful side effects in pregnancy. ●

Copyright: Digital illustrations by John J. DeNapoli/Cristian Storto Fotografia/IStock/Getty Images Plus/Prostock-Studio/IStock/Getty Images Plus/ClaudioVentrella/IStock Getty Images Plus

COVID-19 vaccination is recommended for all reproductive-aged women, regardless of pregnancy status.¹ Yet, national vaccination rates in pregnancy remain woefully low—lower than vaccine coverage rates for other recommended vaccines during pregnancy.^2,3 COVID-19 infection has clearly documented risks for maternal and fetal health, and data continue to accumulate on the maternal and neonatal benefits of COVID-19 vaccination in pregnancy, as well as the safety of vaccination during pregnancy.

Maternal and neonatal benefits of COVID-19 vaccination

Does vaccination in pregnancy result in decreased rates of severe COVID-19 infection? Results from a study from a Louisiana health system comparing maternal outcomes between fully vaccinated (defined as 2 weeks after the final vaccine dose) and unvaccinated or partially vaccinated pregnant women during the delta variant—predominant COVID-19 surge clearly answer this question. Vaccination in pregnancy resulted in a 90% risk reduction in severe or critical COVID-19 infection and a 70% risk reduction in COVID-19 infection of any severity among fully vaccinated women. The study also provides some useful absolute numbers for patient counseling: Although none of the 1,332 vaccinated pregnant women in the study required supplemental oxygen or intensive care unit (ICU) admission, there was 1 maternal death, 5 ICU admissions, and 6 stillbirths among the 8,760 unvaccinated pregnant women.⁴

A larger population-based data set from Scotland and Israel demonstrated similar findings.⁵ Most importantly, the Scotland data, with most patients having had an mRNA-based vaccine, showed that, while 77% of all COVID-19 infections occurred in unvaccinated pregnant women, 91% of all hospital admissions occurred in unvaccinated women, and 98% of all critical care admissions occurred in unvaccinated women. Furthermore, although 13% of all COVID-19 hospitalizations in pregnancy occurred among vaccinated women, only 2% of critical care admissions occurred among vaccinated women. The Israeli experience (which identified nearly 30,000 eligible pregnancies from 1 of 4 state-mandated health funds in the country), demonstrated that the efficacy of the Pfizer/BioNTech vaccine to prevent a SARS-CoV-2 infection of any severity once fully vaccinated is more than 80%.⁶

Breakthrough infections, which were more prevalent during the omicron surge, have caused some patients to question the utility of COVID-19 vaccination. Recent data from South Africa, where the omicron variant was first identified, noted that efficacy of the Pfizer/ BioNTech vaccine to prevent hospitalization with COVID-19 infection during an omicron-predominant period was 70%—versus 93% efficacy in a delta-predominant period.⁷ These data, however, were in the absence of a booster dose, and in vitro studies suggest increased vaccine efficacy with a booster dose.⁸

Continue to: Counseling women on vaccination benefits and risks...

Counseling women on vaccination benefits and risks. No matter the specific numeric rate of efficacy against a COVID-19 infection, it is important to counsel women that the goal of vaccination is to prevent severe or critical COVID-19 infections, and these data all demonstrate that COVID-19 vaccination meets this goal. However, women may have additional questions regarding both fetal/neonatal benefits and safety with immunization in pregnancy.

Let us address the question of benefit first. In a large cohort of more than 1,300 women vaccinated during pregnancy and delivering at >34 weeks’ gestation, a few observations are worth noting.⁹ The first is that women who were fully vaccinated by the time of delivery had detectable antibodies at birth, even with first trimester vaccination, and these antibodies did cross the placenta to the neonate. Although higher maternal and neonatal antibody levels are achieved with early third trimester vaccination, it is key that women interpret this finding in light of 2 important points:

1. women cannot know what gestational age they will deliver, thus waiting until the early third trimester for vaccination to optimize neonatal antibody levels could result in delivery prior to planned vaccination, with benefit for neither the woman nor the baby
2. partial vaccination in the early third trimester resulted in lower maternal and neonatal antibody levels than full vaccination in the first trimester.

In addition, while the data were limited, a booster dose in the third trimester results in the highest antibody levels at delivery. Given the recommendation to initiate a booster dose 5 months after the completion of the primary vaccine series,¹⁰ many women will be eligible for a booster prior to delivery and thus can achieve the goals of high maternal and neonatal antibody levels simultaneously. One caveat to these data is that, while higher antibody levels seem comforting and may be better, we do not yet know the level of neonatal antibody necessary to decrease risks of COVID-19 infection in early newborn life.⁹ Recent data from the Centers for Disease Control and Prevention provide real-world evidence that maternal vaccination decreases the risk of hospitalization from COVID-19 for infants aged <6 months, with vaccine efficacy estimated to be 61% during a period of both Delta and Omicron predominance.¹¹

The evidence is clear—the time for COVID-19 vaccination is now. There is no “optimal” time of vaccination in pregnancy for neonatal benefit that would be worth risking any amount of time a woman is susceptible to COVID-19, especially given the promising data regarding maternal and neonatal antibody levels achieved after a booster dose.

Safety of COVID-19 vaccination: Current data

Risks for pregnancy loss, birth defects, and preterm delivery often are concerns of pregnant women considering a COVID-19 vaccination. Data from more than 2,400 women who submitted their information to the v-SAFE registry demonstrated a 14% risk for pregnancy loss between 6 and 20 weeks’ gestation—well within the expected rate of pregnancy loss in this gestational age range.¹²

Data from more than 46,000 pregnancies included in the Vaccine Safety Datalink, which includes data from health care organizations in 6 states, demonstrated a preterm birth rate of 6.6% and a small-for-gestational-age rate of 8.2% among fully vaccinated women, rates that were no different among unvaccinated women. There were no differences in the outcomes by trimester of vaccination, and these rates are comparable to the expected rates of these outcomes.¹³

Women also worry about the risks of vaccine side effects, such as fever or rare adverse events. Although all adverse events (ie, Guillain-Barre syndrome, pericarditis/myocarditis, thrombosis with thrombocytopenia syndrome [TTS]) are very rare, the American College of Obstetricians and Gynecologists does recommend that women get an mRNA COVID-19 vaccine, as the Johnson & Johnson/Janssen vaccine is associated with TTS, which occurred more commonly (although still rare) in women of reproductive age.¹⁴

Two large studies of typical side effects experienced after COVID-19 vaccination in pregnancy are incredibly reassuring. In the first, authors of a large study of more than 12,000 pregnant women enrolled in the v-SAFE registry reported that the most common side effect after each mRNA dose was injection site pain (88% after dose 1, 92% after dose 2).¹⁵ Self-reported fever occurred in 4% of women after dose 1 and 35% after dose 2. Although this frequency may seem high, a fever of 38.0°C (100.4°F) or higher only occurred among 8% of all participants.

In another study of almost 8,000 women self-reporting side effects (some of whom also may have contributed data to the v-SAFE study), fever occurred in approximately 5% after dose 1 and in about 20% after dose 2.¹⁶ In this study, the highest mean temperature was 38.1°C (100.6°F) after dose 1 and 38.2°C (100.7°F) after dose 2. Although it is a reasonable expectation for fever to follow COVID-19 vaccination, particularly after the second dose, the typical fever is a low-grade temperature that will not harm a developing fetus and will be responsive to acetaminophen administration. Moreover, if the fever were the harbinger of harm, then it might stand to reason that an increased signal of preterm delivery may be observed, but data from nearly 10,000 pregnant women vaccinated during the second or third trimesters showed no association with preterm birth (adjusted hazard ratio, 0.91; 95% confidence interval, 0.82–1.01).¹³

The bottom line

The data are clear. COVID-19 vaccination decreases the risks of severe infection in pregnancy, confers antibodies to neonates with at least some level of protection, and has no demonstrated harmful side effects in pregnancy. ●

Ananth CV, Brandt JS, Hill J, et al. Historical and recent changes in maternal mortality due to hypertensive disorders in the United States, 1979 to 2018. Hypertension. 2021;78:1414–1422. doi: 10.1161/HYPERTENSIONAHA.121.17661.

EXPERT COMMENTARY

Maternal mortality is a pressing public health issue and is largely preventable. Up to 10% of all US pregnancies are complicated by a hypertensive disorder, and rates of chronic hypertension and severe preeclampsia have steadily increased over the last 4 decades. However, maternal mortality is an outcome in a population with advancing maternal age, increasing obesity, and undermanaged chronic disease. The MMR due to hypertension is substantially higher among Black women compared with White women. Countless studies attribute systemic racism to these disparities.

Details of the study

Spanning 40 years, a recent study by Ananth and colleagues included live births across all 50 United States and Washington, DC. Of the 1.5 million live births examined, there were 3,287 hypertension-related maternal deaths.

Data were deidentified and available in the public domain. The researchers compiled mortality data and live births among women aged 15 to 49. The MMR was considered the death of a woman during pregnancy or within the 42 days following a live birth.

Key points of the study included:

• An estimated two-thirds of maternal deaths are preventable.
• The hypertension-related MMR was 2.1 per 100,000 live births.
• Preeclampsia-related MMR decreased, while hypertension-related MMR increased.
• The MMR from chronic hypertension has increased annually by 9.2%.
• Pregnancies among women with advanced maternal age have grown, especially among those over age 40.
• The MMR due to hypertension increases with age and is highest among women age 45 to 49.

Study strengths and limitations

A major strength of this study is the sheer size of the sample. This is one of the largest studies that examined changes in the MMR in the United States.

As with any study that spans a long period, a primary limitation is inconsistencies in the data collected. In 2003, the US death certificate was revised to include a set of “pregnancy checkboxes” indicating pregnancy at the time of death.

There also have been shifts in diagnostic coding and criteria for preeclampsia.

Classification of race and ethnicity has improved and broadened over time. Despite these limitations, the overarching trends are compelling. ●

Ananth CV, Brandt JS, Hill J, et al. Historical and recent changes in maternal mortality due to hypertensive disorders in the United States, 1979 to 2018. Hypertension. 2021;78:1414–1422. doi: 10.1161/HYPERTENSIONAHA.121.17661.

EXPERT COMMENTARY

Maternal mortality is a pressing public health issue and is largely preventable. Up to 10% of all US pregnancies are complicated by a hypertensive disorder, and rates of chronic hypertension and severe preeclampsia have steadily increased over the last 4 decades. However, maternal mortality is an outcome in a population with advancing maternal age, increasing obesity, and undermanaged chronic disease. The MMR due to hypertension is substantially higher among Black women compared with White women. Countless studies attribute systemic racism to these disparities.

Details of the study

Spanning 40 years, a recent study by Ananth and colleagues included live births across all 50 United States and Washington, DC. Of the 1.5 million live births examined, there were 3,287 hypertension-related maternal deaths.

Data were deidentified and available in the public domain. The researchers compiled mortality data and live births among women aged 15 to 49. The MMR was considered the death of a woman during pregnancy or within the 42 days following a live birth.

Key points of the study included:

• An estimated two-thirds of maternal deaths are preventable.
• The hypertension-related MMR was 2.1 per 100,000 live births.
• Preeclampsia-related MMR decreased, while hypertension-related MMR increased.
• The MMR from chronic hypertension has increased annually by 9.2%.
• Pregnancies among women with advanced maternal age have grown, especially among those over age 40.
• The MMR due to hypertension increases with age and is highest among women age 45 to 49.

Study strengths and limitations

A major strength of this study is the sheer size of the sample. This is one of the largest studies that examined changes in the MMR in the United States.

As with any study that spans a long period, a primary limitation is inconsistencies in the data collected. In 2003, the US death certificate was revised to include a set of “pregnancy checkboxes” indicating pregnancy at the time of death.

There also have been shifts in diagnostic coding and criteria for preeclampsia.

Classification of race and ethnicity has improved and broadened over time. Despite these limitations, the overarching trends are compelling. ●

Ananth CV, Brandt JS, Hill J, et al. Historical and recent changes in maternal mortality due to hypertensive disorders in the United States, 1979 to 2018. Hypertension. 2021;78:1414–1422. doi: 10.1161/HYPERTENSIONAHA.121.17661.

EXPERT COMMENTARY

Maternal mortality is a pressing public health issue and is largely preventable. Up to 10% of all US pregnancies are complicated by a hypertensive disorder, and rates of chronic hypertension and severe preeclampsia have steadily increased over the last 4 decades. However, maternal mortality is an outcome in a population with advancing maternal age, increasing obesity, and undermanaged chronic disease. The MMR due to hypertension is substantially higher among Black women compared with White women. Countless studies attribute systemic racism to these disparities.

Details of the study

Spanning 40 years, a recent study by Ananth and colleagues included live births across all 50 United States and Washington, DC. Of the 1.5 million live births examined, there were 3,287 hypertension-related maternal deaths.

Data were deidentified and available in the public domain. The researchers compiled mortality data and live births among women aged 15 to 49. The MMR was considered the death of a woman during pregnancy or within the 42 days following a live birth.

Key points of the study included:

• An estimated two-thirds of maternal deaths are preventable.
• The hypertension-related MMR was 2.1 per 100,000 live births.
• Preeclampsia-related MMR decreased, while hypertension-related MMR increased.
• The MMR from chronic hypertension has increased annually by 9.2%.
• Pregnancies among women with advanced maternal age have grown, especially among those over age 40.
• The MMR due to hypertension increases with age and is highest among women age 45 to 49.

Study strengths and limitations

A major strength of this study is the sheer size of the sample. This is one of the largest studies that examined changes in the MMR in the United States.

As with any study that spans a long period, a primary limitation is inconsistencies in the data collected. In 2003, the US death certificate was revised to include a set of “pregnancy checkboxes” indicating pregnancy at the time of death.

There also have been shifts in diagnostic coding and criteria for preeclampsia.

Classification of race and ethnicity has improved and broadened over time. Despite these limitations, the overarching trends are compelling. ●

Over the past 200 years, identification of the specific organism causing an infection has evolved from a reliance on patient history and physical examination to the use of microscopic examination of relevant biological samples to the rise of microbial culture and immunological testing as the gold standards for diagnosis. More recently, advances in nucleic acid testing have made nucleic acid amplification testing (NAAT) a primary method for identifying the specific organism causing an infection.

The evolution of the diagnosis of gonorrhea in clinical practice is a good example of the inexorable evolution of diagnostic techniques from physical examination to microscopic analysis to culture and finally to NAAT. Neiseer discovered Neisseria gonorrhea in 1879.¹ In 19th century general medical practice gonorrhea was often diagnosed based on history and physical examination and sometimes microscopy was also utilized.² In the mid-20th century, it was realized that culture was a superior approach to diagnosis of gonorrhea, and it became the gold standard for diagnosis in general practice.³ NAAT has now replaced culture as the gold standard for the diagnosis of gonorrhea because of its superior performance in clinical practice.⁴ It may now be time to consider using NAAT rather than microscopy and culture in general practice for the identification of specific microorganisms causing vaginitis.

Trichomoniasis

Vaginitis caused by Trichomonas vaginalis is characterized by a discharge that is foamy and green-yellow in color, with a vaginal pH that is >4.5. Microscopy of a vaginal specimen has low sensitivity, in the range of 50%, for detecting T vaginalis.^5-7 There are many factors that make microscopy a poor approach to the diagnosis of T vaginalis, including the rapid decrease in protozoan motility once a vaginal specimen is placed on a glass slide and the similar size of non-motile T vaginalis and other cells in the vagina.

Given the low sensitivity of microscopy for the diagnosis of trichomoniasis, the American College of Obstetricians and Gynecologists (ACOG) recommends NAAT as a primary approach to test for T vaginalis, with culture or NAAT testing as alternative approaches.⁸ The Centers for Disease Control and Prevention (CDC) recommends that if a wet mount is negative for T vaginalis that NAAT should be utilized.⁹

In this 2-step testing process, the first step is to test the vaginal pH and perform a microscopic examination of a vaginal specimen for T vaginalis. If T vaginalis organisms are detected, the diagnosis of trichomoniasis is confirmed. If organisms are not detected the second step would be to send a vaginal or urine specimen for NAAT for T vaginalis or for culture. An advantage of NAAT over culture is that urine specimens can be used for diagnosis of T vaginalis while urine specimens are not suitable for culture because of low sensitivity. For patients diagnosed with trichomoniasis, the CDC recommends that testing be repeated in 3 months because of high rates of reinfection. NAAT would be an optimal test to use in this situation.

Continue to: Bacterial vaginosis and candidiasis...

Bacterial vaginosis and candidiasis

ACOG recommends using Amsel criteria or Nugent scoring of a specimen colorized with a Gram stain for the diagnosis of bacterial vaginosis and microscopy or culture for the diagnosis of candidiasis.⁸ Recent research reports that NAAT testing for bacterial vaginosis and candidiasis may be more sensitive than standard office-based approaches for detecting these two causes of vaginitis. In a study of approximately 1,740 patients with symptoms of vaginitis, vaginal specimens were analyzed using NAAT or standard office approaches to diagnosis.¹⁰ In this study the diagnostic gold standards were Nugent scoring with Amsel criteria to resolve intermediate Nugent scores for bacterial vaginosis and culture for Candida. The study demonstrated the superiority of NAAT testing over standard office approaches for the identification of the cause of the vaginitis. NAAT testing was reported to have superior sensitivity for diagnosing bacterial vaginosis compared with the original Amsel criteria (93% vs 76%, respectively (P <.0001), with similar respective specificities of 92% and 94% .¹⁰ NAAT testing also had superior sensitivity for diagnosing Candidiasis compared with microscopy after potassium hydroxide treatment of a vaginal specimen (91% vs 58%, respectively (P <.0001).¹⁰ NAAT testing also had superior specificity compared with microscopy after potassium hydroxide treatment of a vaginal specimen (94% vs 89%, respectively (P < .0005).¹⁰

In another study comparing NAAT with clinical diagnosis for 466 patients with symptoms of vaginitis, standard office approaches to the diagnosis of vaginitis resulted in the failure to identify the correct infection in a large number of cases. For the diagnosis of bacterial vaginosis, clinicians missed 42% of the cases identified by NAAT. For the diagnosis of Candida, clinicians missed 46% of the cases identified by NAAT. For T vaginalis diagnosis, clinicians missed 72% of the cases identified by NAAT. Clearly, this resulted in clinicians not treating many infections detected by NAAT.¹¹

Continue to: One in 5 patients with symptoms of vaginitis have 2 causes of vaginitis...

In a recent study, 1,471 patients with a symptom of vaginitis (abnormal vaginal discharge, itching or irritation, or odor) self-collected a vaginal swab and had a vaginal swab collected by a clinician.¹² The swabs were placed in buffer and the samples were tested by NAAT using the BD Max system (Franklin Lakes, New Jersey) for the presence of nucleic acid sequences of the microorganisms responsible for the most common causes of vaginitis. In this cohort, using the clinician collected vaginal swabs for NAAT, the investigators reported the following pattern of detection of nucleic acid sequences: 36.1%, bacterial vaginosis pattern; 16.2%, Candida spp.; 1.6%, T vaginalis; 0.7%, Candida glabrata; and 0.1%, Candida krusei. Nucleic acid sequences of multiple organisms were detected in 21.7% of patients, including 13.9% with bacterial vaginosis pattern plus Candida spp., 4.9% with bacterial vaginosis pattern plus T vaginalis, 0.3% with Candida spp. plus T vaginalis, 0.2% with Candida spp. plus Candida glabrata, 0.2% with bacterial vaginosis pattern plus Candida glabrata, and 2.2% with all 3 organisms. A total of 23.8% of the women had no detectable nucleic acid sequences associated with organisms known to cause vaginitis.

In another study of 1,491 patients with a symptom of vaginitis, clinician-collected vaginal swabs were tested by NAAT using the Aptima BV and Aptima Candida/Trichomonas systems (Hologic, Marlborough, Massachusetts) for the presence of nucleic acid sequences of microorganisms responsible for most cases of vaginitis.¹³ The investigators reported the following pattern of detection of nucleic acid sequences: 28.6%, bacterial vaginosis pattern; 14.2%, Candida spp.; 3%, T vaginalis; 1.9%, Candida glabrata.¹³ Nucleic acid sequences from multiple organisms were detected in 23.3% of patients. Nucleic acid sequences suggesting the presence of two different causes of vaginitis were detected among 20.8% of patients, including bacterial vaginosis plus Candida spp., 11.1%; bacterial vaginosis plus T vaginalis, 7.2%; Candida spp. plus T vaginalis, 1.0%; Candida spp. plus Candida glabrata, 0.9%; bacterial vaginosis plus Candida spp., 0.5%; Candida glabrata plus T vaginalis, 0.1%. Nucleic acid sequences suggesting the presence of 3 different causes of vaginitis were detected in 2.4% of patients, the most common being the combination of bacterial vaginosis plus Candida spp. plus T vaginalis, 1.7% and bacterial vaginosis plus Candida spp. plus Candida glabrata, 0.5%. Nucleic acid sequences suggesting the presence of 4 different causes of vaginitis were detected in 0.1% of patients. A total of 28.8% of the women had no detectable nucleic acid sequences associated with organisms known to cause vaginitis.¹³

In clinical practice it is uncommon to see the diagnosis of multiple causes of vaginitis recorded in the medical record of a patient. This suggests that we are not effectively identifying the 20% of patients with multiple causes of vaginitis.

When multiple organisms that cause vaginitis are present, NAAT is superior to clinical evaluation for diagnosis

In a study of 1,264 patients with symptoms of vaginitis who had an identified microbial cause, more than 20% had multiple organisms detected by NAAT.¹⁰ The reference methods for diagnosis in this study were Nugent scoring with Amsel criteria to resolve intermediate Nugent scores for bacterial vaginosis, culture for Candida, and culture for T vaginalis. Compared with the reference method for diagnosis, the sensitivities for NAAT and clinician detection of cases of bacterial vaginosis plus Candida were 74% and 18%, respectively (P <.0001). Compared with the reference method for diagnosis, the sensitivities for NAAT and clinician detection of cases of bacterial vaginosis plus T vaginalis were 72% and 21%, respectively (P <.0001). Compared with the reference method for diagnosis, the sensitivities for NAAT and clinician detection of cases of bacterial vaginosis plus Candida plus T vaginalis were 80% and 10%, respectively (P <.0005).¹⁰ Based on this one study, it appears that clinicians are not very effective at diagnosing a case of vaginitis caused by multiple different microorganisms.

Patient collection of a vaginal swab for NAAT

Multiple studies have reported that collection of a vaginal swab for NAAT by the patient or a clinician results in similar excellent test performance.^4,12,13 This observation might catalyze the development of clinical protocols where patients with vaginitis could collect the swab for NAAT analysis, without needing to have a speculum examination by a clinician.

When collecting a vaginal specimen for NAAT it is important that no vaginal lubricants or creams contaminate the collection swab. Vaginal lubricants and creams may inhibit the polymerase chain reaction enzymes resulting in a false negative. The swab may be directly inserted into the vagina to collect the specimen or a speculum without a lubricant, except water can be used to facilitate specimen collection. To collect a specimen without a speculum the swab is inserted 2 inches into the vagina and rotated for 10 to 15 seconds.

What should clinicians do while waiting for a NAAT result?

A major problem with NAAT testing for vaginitis is that the results are not available at the initial patient visit, impacting the ability to make an immediate diagnosis and provide targeted antibiotic treatment. Given that bacterial vaginosis and Candida species are the most common causes of infectious vaginitis in many populations of gynecology patients, one approach is to initiate treatment with one dose of an oral antifungal agent and a multiday course of vaginal metronidazole. Once the NAAT test results are available, the treatment can be refined to specific infectious agents identified by the test, or the antibiotics can be discontinued if no relevant microorganisms are detected. Another approach would be to wait until the NAAT test is completed and then prescribe the appropriate antibiotic. My sense is that most patients would not favor this wait and see approach.

Barriers to the use of NAAT for vaginitis

A barrier to the use of NAAT for the diagnosis of vaginitis is that leading organizations do not currently recommend NAAT as a primary approach to diagnosis, favoring microscopy and measurement of vaginal pH.⁹ In addition, clinicians and patients may be rightfully concerned about the cost of NAAT, which can be substantial.

Vaginitis, especially when it is recurrent, can be stressful¹⁴ and have an impact on a patient’s quality of life^15,16 and sexual health.¹⁷ Arguably, our current practice algorithms for diagnosing the cause of vaginitis are not optimized.¹⁸ Our failure to accurately diagnose the cause of vaginitis contributes to inappropriate antibiotic treatment and return visits because of inadequate initial treatment.¹⁸ We can improve and simplify our approach to the diagnosis of vaginitis by prioritizing the use of NAAT.¹⁹ In turn, reliably making the right diagnosis will result in the optimization of treatment. ●

Over the past 200 years, identification of the specific organism causing an infection has evolved from a reliance on patient history and physical examination to the use of microscopic examination of relevant biological samples to the rise of microbial culture and immunological testing as the gold standards for diagnosis. More recently, advances in nucleic acid testing have made nucleic acid amplification testing (NAAT) a primary method for identifying the specific organism causing an infection.

The evolution of the diagnosis of gonorrhea in clinical practice is a good example of the inexorable evolution of diagnostic techniques from physical examination to microscopic analysis to culture and finally to NAAT. Neiseer discovered Neisseria gonorrhea in 1879.¹ In 19th century general medical practice gonorrhea was often diagnosed based on history and physical examination and sometimes microscopy was also utilized.² In the mid-20th century, it was realized that culture was a superior approach to diagnosis of gonorrhea, and it became the gold standard for diagnosis in general practice.³ NAAT has now replaced culture as the gold standard for the diagnosis of gonorrhea because of its superior performance in clinical practice.⁴ It may now be time to consider using NAAT rather than microscopy and culture in general practice for the identification of specific microorganisms causing vaginitis.

Trichomoniasis

Vaginitis caused by Trichomonas vaginalis is characterized by a discharge that is foamy and green-yellow in color, with a vaginal pH that is >4.5. Microscopy of a vaginal specimen has low sensitivity, in the range of 50%, for detecting T vaginalis.^5-7 There are many factors that make microscopy a poor approach to the diagnosis of T vaginalis, including the rapid decrease in protozoan motility once a vaginal specimen is placed on a glass slide and the similar size of non-motile T vaginalis and other cells in the vagina.

Given the low sensitivity of microscopy for the diagnosis of trichomoniasis, the American College of Obstetricians and Gynecologists (ACOG) recommends NAAT as a primary approach to test for T vaginalis, with culture or NAAT testing as alternative approaches.⁸ The Centers for Disease Control and Prevention (CDC) recommends that if a wet mount is negative for T vaginalis that NAAT should be utilized.⁹

In this 2-step testing process, the first step is to test the vaginal pH and perform a microscopic examination of a vaginal specimen for T vaginalis. If T vaginalis organisms are detected, the diagnosis of trichomoniasis is confirmed. If organisms are not detected the second step would be to send a vaginal or urine specimen for NAAT for T vaginalis or for culture. An advantage of NAAT over culture is that urine specimens can be used for diagnosis of T vaginalis while urine specimens are not suitable for culture because of low sensitivity. For patients diagnosed with trichomoniasis, the CDC recommends that testing be repeated in 3 months because of high rates of reinfection. NAAT would be an optimal test to use in this situation.

Continue to: Bacterial vaginosis and candidiasis...

Bacterial vaginosis and candidiasis

ACOG recommends using Amsel criteria or Nugent scoring of a specimen colorized with a Gram stain for the diagnosis of bacterial vaginosis and microscopy or culture for the diagnosis of candidiasis.⁸ Recent research reports that NAAT testing for bacterial vaginosis and candidiasis may be more sensitive than standard office-based approaches for detecting these two causes of vaginitis. In a study of approximately 1,740 patients with symptoms of vaginitis, vaginal specimens were analyzed using NAAT or standard office approaches to diagnosis.¹⁰ In this study the diagnostic gold standards were Nugent scoring with Amsel criteria to resolve intermediate Nugent scores for bacterial vaginosis and culture for Candida. The study demonstrated the superiority of NAAT testing over standard office approaches for the identification of the cause of the vaginitis. NAAT testing was reported to have superior sensitivity for diagnosing bacterial vaginosis compared with the original Amsel criteria (93% vs 76%, respectively (P <.0001), with similar respective specificities of 92% and 94% .¹⁰ NAAT testing also had superior sensitivity for diagnosing Candidiasis compared with microscopy after potassium hydroxide treatment of a vaginal specimen (91% vs 58%, respectively (P <.0001).¹⁰ NAAT testing also had superior specificity compared with microscopy after potassium hydroxide treatment of a vaginal specimen (94% vs 89%, respectively (P < .0005).¹⁰

In another study comparing NAAT with clinical diagnosis for 466 patients with symptoms of vaginitis, standard office approaches to the diagnosis of vaginitis resulted in the failure to identify the correct infection in a large number of cases. For the diagnosis of bacterial vaginosis, clinicians missed 42% of the cases identified by NAAT. For the diagnosis of Candida, clinicians missed 46% of the cases identified by NAAT. For T vaginalis diagnosis, clinicians missed 72% of the cases identified by NAAT. Clearly, this resulted in clinicians not treating many infections detected by NAAT.¹¹

Continue to: One in 5 patients with symptoms of vaginitis have 2 causes of vaginitis...

In a recent study, 1,471 patients with a symptom of vaginitis (abnormal vaginal discharge, itching or irritation, or odor) self-collected a vaginal swab and had a vaginal swab collected by a clinician.¹² The swabs were placed in buffer and the samples were tested by NAAT using the BD Max system (Franklin Lakes, New Jersey) for the presence of nucleic acid sequences of the microorganisms responsible for the most common causes of vaginitis. In this cohort, using the clinician collected vaginal swabs for NAAT, the investigators reported the following pattern of detection of nucleic acid sequences: 36.1%, bacterial vaginosis pattern; 16.2%, Candida spp.; 1.6%, T vaginalis; 0.7%, Candida glabrata; and 0.1%, Candida krusei. Nucleic acid sequences of multiple organisms were detected in 21.7% of patients, including 13.9% with bacterial vaginosis pattern plus Candida spp., 4.9% with bacterial vaginosis pattern plus T vaginalis, 0.3% with Candida spp. plus T vaginalis, 0.2% with Candida spp. plus Candida glabrata, 0.2% with bacterial vaginosis pattern plus Candida glabrata, and 2.2% with all 3 organisms. A total of 23.8% of the women had no detectable nucleic acid sequences associated with organisms known to cause vaginitis.

In another study of 1,491 patients with a symptom of vaginitis, clinician-collected vaginal swabs were tested by NAAT using the Aptima BV and Aptima Candida/Trichomonas systems (Hologic, Marlborough, Massachusetts) for the presence of nucleic acid sequences of microorganisms responsible for most cases of vaginitis.¹³ The investigators reported the following pattern of detection of nucleic acid sequences: 28.6%, bacterial vaginosis pattern; 14.2%, Candida spp.; 3%, T vaginalis; 1.9%, Candida glabrata.¹³ Nucleic acid sequences from multiple organisms were detected in 23.3% of patients. Nucleic acid sequences suggesting the presence of two different causes of vaginitis were detected among 20.8% of patients, including bacterial vaginosis plus Candida spp., 11.1%; bacterial vaginosis plus T vaginalis, 7.2%; Candida spp. plus T vaginalis, 1.0%; Candida spp. plus Candida glabrata, 0.9%; bacterial vaginosis plus Candida spp., 0.5%; Candida glabrata plus T vaginalis, 0.1%. Nucleic acid sequences suggesting the presence of 3 different causes of vaginitis were detected in 2.4% of patients, the most common being the combination of bacterial vaginosis plus Candida spp. plus T vaginalis, 1.7% and bacterial vaginosis plus Candida spp. plus Candida glabrata, 0.5%. Nucleic acid sequences suggesting the presence of 4 different causes of vaginitis were detected in 0.1% of patients. A total of 28.8% of the women had no detectable nucleic acid sequences associated with organisms known to cause vaginitis.¹³

In clinical practice it is uncommon to see the diagnosis of multiple causes of vaginitis recorded in the medical record of a patient. This suggests that we are not effectively identifying the 20% of patients with multiple causes of vaginitis.

When multiple organisms that cause vaginitis are present, NAAT is superior to clinical evaluation for diagnosis

In a study of 1,264 patients with symptoms of vaginitis who had an identified microbial cause, more than 20% had multiple organisms detected by NAAT.¹⁰ The reference methods for diagnosis in this study were Nugent scoring with Amsel criteria to resolve intermediate Nugent scores for bacterial vaginosis, culture for Candida, and culture for T vaginalis. Compared with the reference method for diagnosis, the sensitivities for NAAT and clinician detection of cases of bacterial vaginosis plus Candida were 74% and 18%, respectively (P <.0001). Compared with the reference method for diagnosis, the sensitivities for NAAT and clinician detection of cases of bacterial vaginosis plus T vaginalis were 72% and 21%, respectively (P <.0001). Compared with the reference method for diagnosis, the sensitivities for NAAT and clinician detection of cases of bacterial vaginosis plus Candida plus T vaginalis were 80% and 10%, respectively (P <.0005).¹⁰ Based on this one study, it appears that clinicians are not very effective at diagnosing a case of vaginitis caused by multiple different microorganisms.

Patient collection of a vaginal swab for NAAT

Multiple studies have reported that collection of a vaginal swab for NAAT by the patient or a clinician results in similar excellent test performance.^4,12,13 This observation might catalyze the development of clinical protocols where patients with vaginitis could collect the swab for NAAT analysis, without needing to have a speculum examination by a clinician.

When collecting a vaginal specimen for NAAT it is important that no vaginal lubricants or creams contaminate the collection swab. Vaginal lubricants and creams may inhibit the polymerase chain reaction enzymes resulting in a false negative. The swab may be directly inserted into the vagina to collect the specimen or a speculum without a lubricant, except water can be used to facilitate specimen collection. To collect a specimen without a speculum the swab is inserted 2 inches into the vagina and rotated for 10 to 15 seconds.

What should clinicians do while waiting for a NAAT result?

A major problem with NAAT testing for vaginitis is that the results are not available at the initial patient visit, impacting the ability to make an immediate diagnosis and provide targeted antibiotic treatment. Given that bacterial vaginosis and Candida species are the most common causes of infectious vaginitis in many populations of gynecology patients, one approach is to initiate treatment with one dose of an oral antifungal agent and a multiday course of vaginal metronidazole. Once the NAAT test results are available, the treatment can be refined to specific infectious agents identified by the test, or the antibiotics can be discontinued if no relevant microorganisms are detected. Another approach would be to wait until the NAAT test is completed and then prescribe the appropriate antibiotic. My sense is that most patients would not favor this wait and see approach.

Barriers to the use of NAAT for vaginitis

A barrier to the use of NAAT for the diagnosis of vaginitis is that leading organizations do not currently recommend NAAT as a primary approach to diagnosis, favoring microscopy and measurement of vaginal pH.⁹ In addition, clinicians and patients may be rightfully concerned about the cost of NAAT, which can be substantial.

Vaginitis, especially when it is recurrent, can be stressful¹⁴ and have an impact on a patient’s quality of life^15,16 and sexual health.¹⁷ Arguably, our current practice algorithms for diagnosing the cause of vaginitis are not optimized.¹⁸ Our failure to accurately diagnose the cause of vaginitis contributes to inappropriate antibiotic treatment and return visits because of inadequate initial treatment.¹⁸ We can improve and simplify our approach to the diagnosis of vaginitis by prioritizing the use of NAAT.¹⁹ In turn, reliably making the right diagnosis will result in the optimization of treatment. ●

Over the past 200 years, identification of the specific organism causing an infection has evolved from a reliance on patient history and physical examination to the use of microscopic examination of relevant biological samples to the rise of microbial culture and immunological testing as the gold standards for diagnosis. More recently, advances in nucleic acid testing have made nucleic acid amplification testing (NAAT) a primary method for identifying the specific organism causing an infection.

The evolution of the diagnosis of gonorrhea in clinical practice is a good example of the inexorable evolution of diagnostic techniques from physical examination to microscopic analysis to culture and finally to NAAT. Neiseer discovered Neisseria gonorrhea in 1879.¹ In 19th century general medical practice gonorrhea was often diagnosed based on history and physical examination and sometimes microscopy was also utilized.² In the mid-20th century, it was realized that culture was a superior approach to diagnosis of gonorrhea, and it became the gold standard for diagnosis in general practice.³ NAAT has now replaced culture as the gold standard for the diagnosis of gonorrhea because of its superior performance in clinical practice.⁴ It may now be time to consider using NAAT rather than microscopy and culture in general practice for the identification of specific microorganisms causing vaginitis.

Trichomoniasis

Vaginitis caused by Trichomonas vaginalis is characterized by a discharge that is foamy and green-yellow in color, with a vaginal pH that is >4.5. Microscopy of a vaginal specimen has low sensitivity, in the range of 50%, for detecting T vaginalis.^5-7 There are many factors that make microscopy a poor approach to the diagnosis of T vaginalis, including the rapid decrease in protozoan motility once a vaginal specimen is placed on a glass slide and the similar size of non-motile T vaginalis and other cells in the vagina.

Given the low sensitivity of microscopy for the diagnosis of trichomoniasis, the American College of Obstetricians and Gynecologists (ACOG) recommends NAAT as a primary approach to test for T vaginalis, with culture or NAAT testing as alternative approaches.⁸ The Centers for Disease Control and Prevention (CDC) recommends that if a wet mount is negative for T vaginalis that NAAT should be utilized.⁹

In this 2-step testing process, the first step is to test the vaginal pH and perform a microscopic examination of a vaginal specimen for T vaginalis. If T vaginalis organisms are detected, the diagnosis of trichomoniasis is confirmed. If organisms are not detected the second step would be to send a vaginal or urine specimen for NAAT for T vaginalis or for culture. An advantage of NAAT over culture is that urine specimens can be used for diagnosis of T vaginalis while urine specimens are not suitable for culture because of low sensitivity. For patients diagnosed with trichomoniasis, the CDC recommends that testing be repeated in 3 months because of high rates of reinfection. NAAT would be an optimal test to use in this situation.

Continue to: Bacterial vaginosis and candidiasis...

Bacterial vaginosis and candidiasis

ACOG recommends using Amsel criteria or Nugent scoring of a specimen colorized with a Gram stain for the diagnosis of bacterial vaginosis and microscopy or culture for the diagnosis of candidiasis.⁸ Recent research reports that NAAT testing for bacterial vaginosis and candidiasis may be more sensitive than standard office-based approaches for detecting these two causes of vaginitis. In a study of approximately 1,740 patients with symptoms of vaginitis, vaginal specimens were analyzed using NAAT or standard office approaches to diagnosis.¹⁰ In this study the diagnostic gold standards were Nugent scoring with Amsel criteria to resolve intermediate Nugent scores for bacterial vaginosis and culture for Candida. The study demonstrated the superiority of NAAT testing over standard office approaches for the identification of the cause of the vaginitis. NAAT testing was reported to have superior sensitivity for diagnosing bacterial vaginosis compared with the original Amsel criteria (93% vs 76%, respectively (P <.0001), with similar respective specificities of 92% and 94% .¹⁰ NAAT testing also had superior sensitivity for diagnosing Candidiasis compared with microscopy after potassium hydroxide treatment of a vaginal specimen (91% vs 58%, respectively (P <.0001).¹⁰ NAAT testing also had superior specificity compared with microscopy after potassium hydroxide treatment of a vaginal specimen (94% vs 89%, respectively (P < .0005).¹⁰

In another study comparing NAAT with clinical diagnosis for 466 patients with symptoms of vaginitis, standard office approaches to the diagnosis of vaginitis resulted in the failure to identify the correct infection in a large number of cases. For the diagnosis of bacterial vaginosis, clinicians missed 42% of the cases identified by NAAT. For the diagnosis of Candida, clinicians missed 46% of the cases identified by NAAT. For T vaginalis diagnosis, clinicians missed 72% of the cases identified by NAAT. Clearly, this resulted in clinicians not treating many infections detected by NAAT.¹¹

Continue to: One in 5 patients with symptoms of vaginitis have 2 causes of vaginitis...

In a recent study, 1,471 patients with a symptom of vaginitis (abnormal vaginal discharge, itching or irritation, or odor) self-collected a vaginal swab and had a vaginal swab collected by a clinician.¹² The swabs were placed in buffer and the samples were tested by NAAT using the BD Max system (Franklin Lakes, New Jersey) for the presence of nucleic acid sequences of the microorganisms responsible for the most common causes of vaginitis. In this cohort, using the clinician collected vaginal swabs for NAAT, the investigators reported the following pattern of detection of nucleic acid sequences: 36.1%, bacterial vaginosis pattern; 16.2%, Candida spp.; 1.6%, T vaginalis; 0.7%, Candida glabrata; and 0.1%, Candida krusei. Nucleic acid sequences of multiple organisms were detected in 21.7% of patients, including 13.9% with bacterial vaginosis pattern plus Candida spp., 4.9% with bacterial vaginosis pattern plus T vaginalis, 0.3% with Candida spp. plus T vaginalis, 0.2% with Candida spp. plus Candida glabrata, 0.2% with bacterial vaginosis pattern plus Candida glabrata, and 2.2% with all 3 organisms. A total of 23.8% of the women had no detectable nucleic acid sequences associated with organisms known to cause vaginitis.

In another study of 1,491 patients with a symptom of vaginitis, clinician-collected vaginal swabs were tested by NAAT using the Aptima BV and Aptima Candida/Trichomonas systems (Hologic, Marlborough, Massachusetts) for the presence of nucleic acid sequences of microorganisms responsible for most cases of vaginitis.¹³ The investigators reported the following pattern of detection of nucleic acid sequences: 28.6%, bacterial vaginosis pattern; 14.2%, Candida spp.; 3%, T vaginalis; 1.9%, Candida glabrata.¹³ Nucleic acid sequences from multiple organisms were detected in 23.3% of patients. Nucleic acid sequences suggesting the presence of two different causes of vaginitis were detected among 20.8% of patients, including bacterial vaginosis plus Candida spp., 11.1%; bacterial vaginosis plus T vaginalis, 7.2%; Candida spp. plus T vaginalis, 1.0%; Candida spp. plus Candida glabrata, 0.9%; bacterial vaginosis plus Candida spp., 0.5%; Candida glabrata plus T vaginalis, 0.1%. Nucleic acid sequences suggesting the presence of 3 different causes of vaginitis were detected in 2.4% of patients, the most common being the combination of bacterial vaginosis plus Candida spp. plus T vaginalis, 1.7% and bacterial vaginosis plus Candida spp. plus Candida glabrata, 0.5%. Nucleic acid sequences suggesting the presence of 4 different causes of vaginitis were detected in 0.1% of patients. A total of 28.8% of the women had no detectable nucleic acid sequences associated with organisms known to cause vaginitis.¹³

In clinical practice it is uncommon to see the diagnosis of multiple causes of vaginitis recorded in the medical record of a patient. This suggests that we are not effectively identifying the 20% of patients with multiple causes of vaginitis.

When multiple organisms that cause vaginitis are present, NAAT is superior to clinical evaluation for diagnosis

In a study of 1,264 patients with symptoms of vaginitis who had an identified microbial cause, more than 20% had multiple organisms detected by NAAT.¹⁰ The reference methods for diagnosis in this study were Nugent scoring with Amsel criteria to resolve intermediate Nugent scores for bacterial vaginosis, culture for Candida, and culture for T vaginalis. Compared with the reference method for diagnosis, the sensitivities for NAAT and clinician detection of cases of bacterial vaginosis plus Candida were 74% and 18%, respectively (P <.0001). Compared with the reference method for diagnosis, the sensitivities for NAAT and clinician detection of cases of bacterial vaginosis plus T vaginalis were 72% and 21%, respectively (P <.0001). Compared with the reference method for diagnosis, the sensitivities for NAAT and clinician detection of cases of bacterial vaginosis plus Candida plus T vaginalis were 80% and 10%, respectively (P <.0005).¹⁰ Based on this one study, it appears that clinicians are not very effective at diagnosing a case of vaginitis caused by multiple different microorganisms.

Patient collection of a vaginal swab for NAAT

Multiple studies have reported that collection of a vaginal swab for NAAT by the patient or a clinician results in similar excellent test performance.^4,12,13 This observation might catalyze the development of clinical protocols where patients with vaginitis could collect the swab for NAAT analysis, without needing to have a speculum examination by a clinician.

When collecting a vaginal specimen for NAAT it is important that no vaginal lubricants or creams contaminate the collection swab. Vaginal lubricants and creams may inhibit the polymerase chain reaction enzymes resulting in a false negative. The swab may be directly inserted into the vagina to collect the specimen or a speculum without a lubricant, except water can be used to facilitate specimen collection. To collect a specimen without a speculum the swab is inserted 2 inches into the vagina and rotated for 10 to 15 seconds.

What should clinicians do while waiting for a NAAT result?

A major problem with NAAT testing for vaginitis is that the results are not available at the initial patient visit, impacting the ability to make an immediate diagnosis and provide targeted antibiotic treatment. Given that bacterial vaginosis and Candida species are the most common causes of infectious vaginitis in many populations of gynecology patients, one approach is to initiate treatment with one dose of an oral antifungal agent and a multiday course of vaginal metronidazole. Once the NAAT test results are available, the treatment can be refined to specific infectious agents identified by the test, or the antibiotics can be discontinued if no relevant microorganisms are detected. Another approach would be to wait until the NAAT test is completed and then prescribe the appropriate antibiotic. My sense is that most patients would not favor this wait and see approach.

Barriers to the use of NAAT for vaginitis

A barrier to the use of NAAT for the diagnosis of vaginitis is that leading organizations do not currently recommend NAAT as a primary approach to diagnosis, favoring microscopy and measurement of vaginal pH.⁹ In addition, clinicians and patients may be rightfully concerned about the cost of NAAT, which can be substantial.

Vaginitis, especially when it is recurrent, can be stressful¹⁴ and have an impact on a patient’s quality of life^15,16 and sexual health.¹⁷ Arguably, our current practice algorithms for diagnosing the cause of vaginitis are not optimized.¹⁸ Our failure to accurately diagnose the cause of vaginitis contributes to inappropriate antibiotic treatment and return visits because of inadequate initial treatment.¹⁸ We can improve and simplify our approach to the diagnosis of vaginitis by prioritizing the use of NAAT.¹⁹ In turn, reliably making the right diagnosis will result in the optimization of treatment. ●

We have been interested in the quiz series focused on breast cancer screening for women with dense breasts presented in OBG Management by DenseBreast-Info.org. However, we have concerns with the answer as presented in the December 2021 issue, “Average-risk women with dense breasts—What breast screening is appropriate?” (OBG Manag. 2021;33(12):18-19. doi: 10.12788/obgm.0155.) The main question asks about appropriate imaging beyond mammography/tomosynthesis for women with extremely dense breasts and no other risk factors for breast cancer. The authors recommend magnetic resonance imaging (MRI), ultrasonography, or contrast-enhanced mammography (if MRI is not an option). This advice, however, does not follow current guidelines from the American College of Obstetricians and Gynecologists (ACOG) and other professional organizations. We can certainly understand that an advocacy group would want ObGyns to be proactive about adjunctive imaging in average-risk women with heterogeneously dense or extremely dense breasts. However, at this point in time, there are no clear data to support a recommendation for adding universal MRI in this population, for many reasons that we will discuss herein.

The concerns with breast cancer in particular

Breast cancer is not cervical cancer. It isn’t one disease. It is a multitude of diseases that happen to show up in the breast. Some are relatively slow-growing—the kinds of cancers that lend themselves to screening and to early intervention. But other cancers are rapidly-growing; they show up no matter how often or what modality we use for screening. Our goal should be to find an approach to screening that can diagnose breast cancer at a stage where we can intervene and positively impact breast cancer specific and overall mortality.

Screening guidelines vary

The variety of screening guidelines published by different professional organizations reflect differing assumptions and sets of values related to the early diagnosis and treatment of breast cancer. (For a comprehensive table of current screening guidelines, see https://www.cdc.gov/cancer/breast/pdf/breast-cancer-screening-guidelines-508.pdf.)

ACOG’s approach—to offer screening at age 40 but to begin by at least age 50 and, through shared decision making with the patient, screen every 1 or 2 years—is focused on capturing as many cases as we can identify, while minimizing the harms of false-positives.¹ The perspective of the US Preventive Services Task Force (USPSTF) recommendations (to screen every 2 years beginning at age 50) is at the population level, a cost-effective approach that will have the greatest benefit while minimizing harms in the population at large.² The American Society of Breast Surgeons recommends screening to begin by age 40.³ Like the breast surgeons, radiologists dedicated to breast imaging are focused on an individual rather than a population level. They strive to identify each and every instance of possible cancer, and therefore recommend annual screening beginning at age 40.⁴ However, with more aggressive screening in average-risk women many cases of ductal carcinoma in situ (DCIS) are identified—a lesion that, if not detected, may not impact the woman’s health during her lifetime—representing what some might call “overdiagnosis.” Yet there may be some instances in which the DCIS might affect an individual woman’s health. Unfortunately, we can’t prospectively distinguish between the first and the second types of cases.

Continue to: Research on breast cancer screening varies by design...

Research on breast cancer screening varies by design

There has not been a randomized clinical trial conducted on screening mammography since the days of the analog mammogram. The research that has been conducted is difficult to compare due to variations in screening ages and intervals, technology sensitivity, and patient adherence with recommended screening. Treatments for breast cancer also have changed dramatically over time, so the findings of older studies may no longer be relevant to current breast cancer screening. The kind of analysis that needs to be done is an interrupted time series, where you can look at the trajectory of breast cancer survival and whether screening mammography shifts that survival in any way.

One specific study from Australia measured the impact of newer available breast cancer treatments, including tamoxifen for women with receptor-positive tumors and newer chemotherapy strategies.⁵ The authors analyzed screening mammography trends in one large province where women aged 50 to 69 were offered biennial screening. Trends from the 1990s showed that more women were being screened over time. Simultaneously, however, advances in therapy were entering clinical practice. The researchers pointed to a substantial decline in mortality from breast cancer from the early 1980s until 2013. But their conclusion was that none of the decline in mortality for breast cancer could be attributed to screening mammography when they looked at time trends; from their perspective all of the important decline in breast cancer mortality resulted from better treatment. They concluded that government programs should not support screening mammography.⁵

That is a recommendation that we do not support. However, we do recognize the conundrum that mammography is less sensitive among those who have dense breasts. In order to have congruent professional guidelines, we support research funding to determine which types, starting ages, and intervals of screening would be best in various patient populations. The USPSTF cites data from studies performed in the 1980s based on outdated technology; more recent (and relevant) randomized clinical trials have not been performed, and yet this information is critical to provide sufficient evidence to develop appropriate guidelines.

Our recommendations for gathering new data

The kind of data we would find most valuable would assess how different screening strategies impact overall mortality and breast cancer-specific mortality. It would require decades of follow-up—which of course means that screening technology will change over that time. A surrogate for evaluating overall survival is to look at interval cancers, which are all breast cancers diagnosed following negative mammograms and prior to the next screening. These cancers may or may not be biologically active, again focusing us on the need to look at overall survival of the patient. In addition, reducing breast cancer mortality may not reduce overall mortality, because the treatment for breast cancer may cause heart disease, or osteoporosis, or something else that impacts overall survival. These are important considerations for women and physicians who are making choices on treatment. What matters to a patient are 2 overlapping questions:

• Do I have a life-threatening condition or do I not?
• Has screening identified a condition that might lead to treatment that’s unnecessary?

The problem is that with breast cancer we can’t tell the difference. We do not understand the biological potential of a lesion when we evaluate an image on MRI, or computed tomography (CT), or mammography.

A re-look at presented data

A trial conducted by Bakker and colleagues⁶ was discussed by the authors of the DenseBreast-info.org quiz in which they recommended breast MRI for all women with extremely dense breasts (but no other risk factors for breast cancer) detected on screening mammograms.⁷ The Bakker study was large and conducted in the Netherlands. The primary outcome of the trial was to compare the incidence of interval breast cancers of women aged 50 to 75 randomly assigned to MRI versus those assigned to continued screening mammography every 2 years. Importantly, among the more than 8,000 women who were assigned to MRI, 59%, or fewer than two-thirds, chose to actually undergo MRI.

Among women randomized to MRI, 20 interval cancers were found—4 were diagnosed in those who actually had MRIs, and 16 were diagnosed among women who were randomized to MRI but didn’t undergo the study. Among women assigned to screening mammography only, 161 interval cancers were diagnosed among more than 32,000 women screened. The primary outcome findings were 2.5 interval cancers per 1,000 screenings among women randomly assigned to MRI, and 5 interval cancers per 1,000 screenings among those randomly assigned to mammography only.⁶

Because the trial included women aged 50 and older, we can’t apply these results to younger women, who often undergo screening mammography in the United States. In addition, the majority of the population in the Netherlands are of Western European ethnicity, a less-diverse population of women than in the United States. Furthermore, among the tumors that were detected in the MRI group, a larger proportion were DCIS, early-stage tumors, well differentiated, and hormone receptor-positive. This observation supports that many of the MRI-detected tumors were cases of overdiagnosis, or the detection of tumors destined not to cause clinical problems for the patient during her lifetime, or for which earlier diagnosis would impact survival.

We also know that treatment of these small ER-positive tumors carries risks for patients, as we may treat them by depriving a patient of estrogen for the rest of her life, with potential consequences of sexual dysfunction, osteoporosis, and perhaps cardiovascular disease depending on her age at the time of that diagnosis. Weighing the risks and benefits of not only treatment but also use of more sensitive screening techniques such as MRI is extremely important. Although Bakker and colleagues’ study results are interesting, we do not feel they support routinely recommending MRI for women found to have extremely dense breasts with mammography.

Overdiagnosis: A difficult concept

One reason overdiagnosis is so challenging to understand is that it can’t be directly measured, which makes comprehending it that much more problematic for clinicians and our patients.

One way to help grasp the overall issue is to compare screening mammography with cervical and colon cancer screening.

We are well aware that cervical cancer screening has reduced the incidence of mortality from invasive cervical cancer.⁸ We can argue very validly that the biggest success in any cancer screening program in history and globally has been cervical cancer screening. Our specialty, in particular, should feel proud about this. Screening colonoscopy also has repeatedly been found to reduce colon cancer mortality.⁹ For breast cancer, decades of media messaging have emphasized the benefits of screening mammograms; however, in contrast with cervical cancer screening and colonoscopy, screening mammography has not reduced the incidence of breast cancer presenting with metastatic or advanced disease. Danish authors pointed out in 2017 that screening mammography has not achieved the hoped for or the promised reduction in breast cancer mortality.¹⁰

A report published in the March 2022, issue of Annals of Internal Medicine used modeling techniques to estimate the incidence of overdiagnosis and concluded that, among women aged 50-74 years receiving biennial screening mammograms (consistent with USPSTF recommendations), more than 15% of screen-detected breast cancers would represent cases of overdiagnosis. Of note, the study authors found that, among screen-detected cancers, the proportion representing overdiagnosis among women in their 60s (16.7%) and early 70s (23.6%) was higher than among women in their 50s-60s (11.5%-11.6%).¹¹

The former Chief Medical and Scientific Officer for the American Cancer Society Otis Brawley, MD, has stated that, at the same time that breast cancer screening should not be abandoned, “We must acknowledge that overdiagnosis is common. The benefits of screening have been overstated, and some patients considered as ‘cured’ from breast cancer have, in fact, been harmed by unneeded treatment.”¹²

“Everybody loves early detection,” said Donald Berry, PhD, from MD Anderson Cancer Center, “but it comes with harms.” He points out that mortality rates have improved for breast cancer, but he attributes it to improved treatment. “The harms [of screening] we know, but the benefits of screening are very uncertain.”¹³

Continue to: Limitations of breast MRI...

Limitations of breast MRI

Overall, MRI is a diagnostic and monitoring test. It is costlier than mammography, and because it is not recommended in guidelines as a screening modality for most women, it is not typically covered by insurance. Abbreviated (rapid) MRI is a non-standardized imaging strategy being used at a few health centers. It has a shorter protocol overall than MRI, so it takes less time than current MRI and is less expensive, but there are few data on sensitivity and specificity. It is yet to be determined which populations could benefit from this newer technology.

As mentioned, 41% of women in the Bakker et al trial who were randomly assigned to breast MRI chose not to proceed with that exam even though it would have been at no cost to them.⁶ Anecdotally, some patients who have undergone MRI say they would forgo it a second time as a screening modality because it was a very unpleasant, stressful experience. It’s not a perfect test, although it is more sensitive than mammography.

Other options for following up dense-breast screening. Besides MRI and abbreviated MRI, the following modalities can be used to evaluate women found to have dense breasts with screening mammograms: CT mammography with contrast, molecular breast imaging, and ultrasonography.

Screening and treatment advances

3D mammography. In the US, the great majority of screening mammography now is performed with tomosynthesis, or what our patients sometimes call 3D mammography. In fact, it is approaching standard of care. Women whose screening mammography includes tomosynthesis are less likely to experience a so-called callback for additional imaging with diagnostic mammography or breast ultrasonography.¹⁴

Liquid biopsy. A potential major advancement for making decisions about when to treat cancers in general involves determining the biological behavior of a tumor, based on analysis of either circulating tumor DNA or proteins in the blood. As more experience with this new technology accumulates, the role of liquid biopsies for breast cancer will expand.¹⁵ Liquid biopsies for screening remain investigational for now, but they hold tremendous potential.

Noninvasive proteomics. With the development of noninvasive proteomic biomarkers obtained from blood, saliva, or nipple aspiration fluid, there exists the possibility of not just evaluating an image of a tumor seen on a mammogram, but actually studying the biological characteristics of that lesion.¹⁶ The cost of this technology is far less in terms of resources than MRI or molecular-based imaging, and actually reveals the flaws with using image-based screening. With proteomics, we can tell whether or not a lump is generating proteins that are going to make that disease biologically meaningful, and treatment decisions can be based on that information. This idea has the potential to disrupt our current breast cancer screening paradigm.

Advocacy’s role in mandating legislation

Many advocacy groups lobby on Capitol Hill for legislation related to health care, but we don’t feel that is the best way to make scientific decisions, and it’s not the way to do medicine. Passionate people, who truly believe that their outcome would have been different had something else been done, have every right to advocate, and should. However, without longer-term data focusing on breast cancer and overall mortality, rather than surrogate outcomes like interval cancers, it is not clear that routinely recommending supplemental MRI will improve survival for women with extremely dense breasts. Unfortunately, overall, earlier diagnosis of highly aggressive breast cancer tumors does not result in better outcomes for patients. ●

We have been interested in the quiz series focused on breast cancer screening for women with dense breasts presented in OBG Management by DenseBreast-Info.org. However, we have concerns with the answer as presented in the December 2021 issue, “Average-risk women with dense breasts—What breast screening is appropriate?” (OBG Manag. 2021;33(12):18-19. doi: 10.12788/obgm.0155.) The main question asks about appropriate imaging beyond mammography/tomosynthesis for women with extremely dense breasts and no other risk factors for breast cancer. The authors recommend magnetic resonance imaging (MRI), ultrasonography, or contrast-enhanced mammography (if MRI is not an option). This advice, however, does not follow current guidelines from the American College of Obstetricians and Gynecologists (ACOG) and other professional organizations. We can certainly understand that an advocacy group would want ObGyns to be proactive about adjunctive imaging in average-risk women with heterogeneously dense or extremely dense breasts. However, at this point in time, there are no clear data to support a recommendation for adding universal MRI in this population, for many reasons that we will discuss herein.

The concerns with breast cancer in particular

Breast cancer is not cervical cancer. It isn’t one disease. It is a multitude of diseases that happen to show up in the breast. Some are relatively slow-growing—the kinds of cancers that lend themselves to screening and to early intervention. But other cancers are rapidly-growing; they show up no matter how often or what modality we use for screening. Our goal should be to find an approach to screening that can diagnose breast cancer at a stage where we can intervene and positively impact breast cancer specific and overall mortality.

Screening guidelines vary

The variety of screening guidelines published by different professional organizations reflect differing assumptions and sets of values related to the early diagnosis and treatment of breast cancer. (For a comprehensive table of current screening guidelines, see https://www.cdc.gov/cancer/breast/pdf/breast-cancer-screening-guidelines-508.pdf.)

ACOG’s approach—to offer screening at age 40 but to begin by at least age 50 and, through shared decision making with the patient, screen every 1 or 2 years—is focused on capturing as many cases as we can identify, while minimizing the harms of false-positives.¹ The perspective of the US Preventive Services Task Force (USPSTF) recommendations (to screen every 2 years beginning at age 50) is at the population level, a cost-effective approach that will have the greatest benefit while minimizing harms in the population at large.² The American Society of Breast Surgeons recommends screening to begin by age 40.³ Like the breast surgeons, radiologists dedicated to breast imaging are focused on an individual rather than a population level. They strive to identify each and every instance of possible cancer, and therefore recommend annual screening beginning at age 40.⁴ However, with more aggressive screening in average-risk women many cases of ductal carcinoma in situ (DCIS) are identified—a lesion that, if not detected, may not impact the woman’s health during her lifetime—representing what some might call “overdiagnosis.” Yet there may be some instances in which the DCIS might affect an individual woman’s health. Unfortunately, we can’t prospectively distinguish between the first and the second types of cases.

Continue to: Research on breast cancer screening varies by design...

Research on breast cancer screening varies by design

There has not been a randomized clinical trial conducted on screening mammography since the days of the analog mammogram. The research that has been conducted is difficult to compare due to variations in screening ages and intervals, technology sensitivity, and patient adherence with recommended screening. Treatments for breast cancer also have changed dramatically over time, so the findings of older studies may no longer be relevant to current breast cancer screening. The kind of analysis that needs to be done is an interrupted time series, where you can look at the trajectory of breast cancer survival and whether screening mammography shifts that survival in any way.

One specific study from Australia measured the impact of newer available breast cancer treatments, including tamoxifen for women with receptor-positive tumors and newer chemotherapy strategies.⁵ The authors analyzed screening mammography trends in one large province where women aged 50 to 69 were offered biennial screening. Trends from the 1990s showed that more women were being screened over time. Simultaneously, however, advances in therapy were entering clinical practice. The researchers pointed to a substantial decline in mortality from breast cancer from the early 1980s until 2013. But their conclusion was that none of the decline in mortality for breast cancer could be attributed to screening mammography when they looked at time trends; from their perspective all of the important decline in breast cancer mortality resulted from better treatment. They concluded that government programs should not support screening mammography.⁵

That is a recommendation that we do not support. However, we do recognize the conundrum that mammography is less sensitive among those who have dense breasts. In order to have congruent professional guidelines, we support research funding to determine which types, starting ages, and intervals of screening would be best in various patient populations. The USPSTF cites data from studies performed in the 1980s based on outdated technology; more recent (and relevant) randomized clinical trials have not been performed, and yet this information is critical to provide sufficient evidence to develop appropriate guidelines.

Our recommendations for gathering new data

The kind of data we would find most valuable would assess how different screening strategies impact overall mortality and breast cancer-specific mortality. It would require decades of follow-up—which of course means that screening technology will change over that time. A surrogate for evaluating overall survival is to look at interval cancers, which are all breast cancers diagnosed following negative mammograms and prior to the next screening. These cancers may or may not be biologically active, again focusing us on the need to look at overall survival of the patient. In addition, reducing breast cancer mortality may not reduce overall mortality, because the treatment for breast cancer may cause heart disease, or osteoporosis, or something else that impacts overall survival. These are important considerations for women and physicians who are making choices on treatment. What matters to a patient are 2 overlapping questions:

• Do I have a life-threatening condition or do I not?
• Has screening identified a condition that might lead to treatment that’s unnecessary?

The problem is that with breast cancer we can’t tell the difference. We do not understand the biological potential of a lesion when we evaluate an image on MRI, or computed tomography (CT), or mammography.

A re-look at presented data

A trial conducted by Bakker and colleagues⁶ was discussed by the authors of the DenseBreast-info.org quiz in which they recommended breast MRI for all women with extremely dense breasts (but no other risk factors for breast cancer) detected on screening mammograms.⁷ The Bakker study was large and conducted in the Netherlands. The primary outcome of the trial was to compare the incidence of interval breast cancers of women aged 50 to 75 randomly assigned to MRI versus those assigned to continued screening mammography every 2 years. Importantly, among the more than 8,000 women who were assigned to MRI, 59%, or fewer than two-thirds, chose to actually undergo MRI.

Among women randomized to MRI, 20 interval cancers were found—4 were diagnosed in those who actually had MRIs, and 16 were diagnosed among women who were randomized to MRI but didn’t undergo the study. Among women assigned to screening mammography only, 161 interval cancers were diagnosed among more than 32,000 women screened. The primary outcome findings were 2.5 interval cancers per 1,000 screenings among women randomly assigned to MRI, and 5 interval cancers per 1,000 screenings among those randomly assigned to mammography only.⁶

Because the trial included women aged 50 and older, we can’t apply these results to younger women, who often undergo screening mammography in the United States. In addition, the majority of the population in the Netherlands are of Western European ethnicity, a less-diverse population of women than in the United States. Furthermore, among the tumors that were detected in the MRI group, a larger proportion were DCIS, early-stage tumors, well differentiated, and hormone receptor-positive. This observation supports that many of the MRI-detected tumors were cases of overdiagnosis, or the detection of tumors destined not to cause clinical problems for the patient during her lifetime, or for which earlier diagnosis would impact survival.

We also know that treatment of these small ER-positive tumors carries risks for patients, as we may treat them by depriving a patient of estrogen for the rest of her life, with potential consequences of sexual dysfunction, osteoporosis, and perhaps cardiovascular disease depending on her age at the time of that diagnosis. Weighing the risks and benefits of not only treatment but also use of more sensitive screening techniques such as MRI is extremely important. Although Bakker and colleagues’ study results are interesting, we do not feel they support routinely recommending MRI for women found to have extremely dense breasts with mammography.

Overdiagnosis: A difficult concept

One reason overdiagnosis is so challenging to understand is that it can’t be directly measured, which makes comprehending it that much more problematic for clinicians and our patients.

One way to help grasp the overall issue is to compare screening mammography with cervical and colon cancer screening.

We are well aware that cervical cancer screening has reduced the incidence of mortality from invasive cervical cancer.⁸ We can argue very validly that the biggest success in any cancer screening program in history and globally has been cervical cancer screening. Our specialty, in particular, should feel proud about this. Screening colonoscopy also has repeatedly been found to reduce colon cancer mortality.⁹ For breast cancer, decades of media messaging have emphasized the benefits of screening mammograms; however, in contrast with cervical cancer screening and colonoscopy, screening mammography has not reduced the incidence of breast cancer presenting with metastatic or advanced disease. Danish authors pointed out in 2017 that screening mammography has not achieved the hoped for or the promised reduction in breast cancer mortality.¹⁰

A report published in the March 2022, issue of Annals of Internal Medicine used modeling techniques to estimate the incidence of overdiagnosis and concluded that, among women aged 50-74 years receiving biennial screening mammograms (consistent with USPSTF recommendations), more than 15% of screen-detected breast cancers would represent cases of overdiagnosis. Of note, the study authors found that, among screen-detected cancers, the proportion representing overdiagnosis among women in their 60s (16.7%) and early 70s (23.6%) was higher than among women in their 50s-60s (11.5%-11.6%).¹¹

The former Chief Medical and Scientific Officer for the American Cancer Society Otis Brawley, MD, has stated that, at the same time that breast cancer screening should not be abandoned, “We must acknowledge that overdiagnosis is common. The benefits of screening have been overstated, and some patients considered as ‘cured’ from breast cancer have, in fact, been harmed by unneeded treatment.”¹²

“Everybody loves early detection,” said Donald Berry, PhD, from MD Anderson Cancer Center, “but it comes with harms.” He points out that mortality rates have improved for breast cancer, but he attributes it to improved treatment. “The harms [of screening] we know, but the benefits of screening are very uncertain.”¹³

Continue to: Limitations of breast MRI...

Limitations of breast MRI

Overall, MRI is a diagnostic and monitoring test. It is costlier than mammography, and because it is not recommended in guidelines as a screening modality for most women, it is not typically covered by insurance. Abbreviated (rapid) MRI is a non-standardized imaging strategy being used at a few health centers. It has a shorter protocol overall than MRI, so it takes less time than current MRI and is less expensive, but there are few data on sensitivity and specificity. It is yet to be determined which populations could benefit from this newer technology.

As mentioned, 41% of women in the Bakker et al trial who were randomly assigned to breast MRI chose not to proceed with that exam even though it would have been at no cost to them.⁶ Anecdotally, some patients who have undergone MRI say they would forgo it a second time as a screening modality because it was a very unpleasant, stressful experience. It’s not a perfect test, although it is more sensitive than mammography.

Other options for following up dense-breast screening. Besides MRI and abbreviated MRI, the following modalities can be used to evaluate women found to have dense breasts with screening mammograms: CT mammography with contrast, molecular breast imaging, and ultrasonography.

Screening and treatment advances

3D mammography. In the US, the great majority of screening mammography now is performed with tomosynthesis, or what our patients sometimes call 3D mammography. In fact, it is approaching standard of care. Women whose screening mammography includes tomosynthesis are less likely to experience a so-called callback for additional imaging with diagnostic mammography or breast ultrasonography.¹⁴

Liquid biopsy. A potential major advancement for making decisions about when to treat cancers in general involves determining the biological behavior of a tumor, based on analysis of either circulating tumor DNA or proteins in the blood. As more experience with this new technology accumulates, the role of liquid biopsies for breast cancer will expand.¹⁵ Liquid biopsies for screening remain investigational for now, but they hold tremendous potential.

Noninvasive proteomics. With the development of noninvasive proteomic biomarkers obtained from blood, saliva, or nipple aspiration fluid, there exists the possibility of not just evaluating an image of a tumor seen on a mammogram, but actually studying the biological characteristics of that lesion.¹⁶ The cost of this technology is far less in terms of resources than MRI or molecular-based imaging, and actually reveals the flaws with using image-based screening. With proteomics, we can tell whether or not a lump is generating proteins that are going to make that disease biologically meaningful, and treatment decisions can be based on that information. This idea has the potential to disrupt our current breast cancer screening paradigm.

Advocacy’s role in mandating legislation

Many advocacy groups lobby on Capitol Hill for legislation related to health care, but we don’t feel that is the best way to make scientific decisions, and it’s not the way to do medicine. Passionate people, who truly believe that their outcome would have been different had something else been done, have every right to advocate, and should. However, without longer-term data focusing on breast cancer and overall mortality, rather than surrogate outcomes like interval cancers, it is not clear that routinely recommending supplemental MRI will improve survival for women with extremely dense breasts. Unfortunately, overall, earlier diagnosis of highly aggressive breast cancer tumors does not result in better outcomes for patients. ●

We have been interested in the quiz series focused on breast cancer screening for women with dense breasts presented in OBG Management by DenseBreast-Info.org. However, we have concerns with the answer as presented in the December 2021 issue, “Average-risk women with dense breasts—What breast screening is appropriate?” (OBG Manag. 2021;33(12):18-19. doi: 10.12788/obgm.0155.) The main question asks about appropriate imaging beyond mammography/tomosynthesis for women with extremely dense breasts and no other risk factors for breast cancer. The authors recommend magnetic resonance imaging (MRI), ultrasonography, or contrast-enhanced mammography (if MRI is not an option). This advice, however, does not follow current guidelines from the American College of Obstetricians and Gynecologists (ACOG) and other professional organizations. We can certainly understand that an advocacy group would want ObGyns to be proactive about adjunctive imaging in average-risk women with heterogeneously dense or extremely dense breasts. However, at this point in time, there are no clear data to support a recommendation for adding universal MRI in this population, for many reasons that we will discuss herein.

The concerns with breast cancer in particular

Breast cancer is not cervical cancer. It isn’t one disease. It is a multitude of diseases that happen to show up in the breast. Some are relatively slow-growing—the kinds of cancers that lend themselves to screening and to early intervention. But other cancers are rapidly-growing; they show up no matter how often or what modality we use for screening. Our goal should be to find an approach to screening that can diagnose breast cancer at a stage where we can intervene and positively impact breast cancer specific and overall mortality.

Screening guidelines vary

The variety of screening guidelines published by different professional organizations reflect differing assumptions and sets of values related to the early diagnosis and treatment of breast cancer. (For a comprehensive table of current screening guidelines, see https://www.cdc.gov/cancer/breast/pdf/breast-cancer-screening-guidelines-508.pdf.)

ACOG’s approach—to offer screening at age 40 but to begin by at least age 50 and, through shared decision making with the patient, screen every 1 or 2 years—is focused on capturing as many cases as we can identify, while minimizing the harms of false-positives.¹ The perspective of the US Preventive Services Task Force (USPSTF) recommendations (to screen every 2 years beginning at age 50) is at the population level, a cost-effective approach that will have the greatest benefit while minimizing harms in the population at large.² The American Society of Breast Surgeons recommends screening to begin by age 40.³ Like the breast surgeons, radiologists dedicated to breast imaging are focused on an individual rather than a population level. They strive to identify each and every instance of possible cancer, and therefore recommend annual screening beginning at age 40.⁴ However, with more aggressive screening in average-risk women many cases of ductal carcinoma in situ (DCIS) are identified—a lesion that, if not detected, may not impact the woman’s health during her lifetime—representing what some might call “overdiagnosis.” Yet there may be some instances in which the DCIS might affect an individual woman’s health. Unfortunately, we can’t prospectively distinguish between the first and the second types of cases.

Continue to: Research on breast cancer screening varies by design...

Research on breast cancer screening varies by design

There has not been a randomized clinical trial conducted on screening mammography since the days of the analog mammogram. The research that has been conducted is difficult to compare due to variations in screening ages and intervals, technology sensitivity, and patient adherence with recommended screening. Treatments for breast cancer also have changed dramatically over time, so the findings of older studies may no longer be relevant to current breast cancer screening. The kind of analysis that needs to be done is an interrupted time series, where you can look at the trajectory of breast cancer survival and whether screening mammography shifts that survival in any way.

One specific study from Australia measured the impact of newer available breast cancer treatments, including tamoxifen for women with receptor-positive tumors and newer chemotherapy strategies.⁵ The authors analyzed screening mammography trends in one large province where women aged 50 to 69 were offered biennial screening. Trends from the 1990s showed that more women were being screened over time. Simultaneously, however, advances in therapy were entering clinical practice. The researchers pointed to a substantial decline in mortality from breast cancer from the early 1980s until 2013. But their conclusion was that none of the decline in mortality for breast cancer could be attributed to screening mammography when they looked at time trends; from their perspective all of the important decline in breast cancer mortality resulted from better treatment. They concluded that government programs should not support screening mammography.⁵

That is a recommendation that we do not support. However, we do recognize the conundrum that mammography is less sensitive among those who have dense breasts. In order to have congruent professional guidelines, we support research funding to determine which types, starting ages, and intervals of screening would be best in various patient populations. The USPSTF cites data from studies performed in the 1980s based on outdated technology; more recent (and relevant) randomized clinical trials have not been performed, and yet this information is critical to provide sufficient evidence to develop appropriate guidelines.

Our recommendations for gathering new data

The kind of data we would find most valuable would assess how different screening strategies impact overall mortality and breast cancer-specific mortality. It would require decades of follow-up—which of course means that screening technology will change over that time. A surrogate for evaluating overall survival is to look at interval cancers, which are all breast cancers diagnosed following negative mammograms and prior to the next screening. These cancers may or may not be biologically active, again focusing us on the need to look at overall survival of the patient. In addition, reducing breast cancer mortality may not reduce overall mortality, because the treatment for breast cancer may cause heart disease, or osteoporosis, or something else that impacts overall survival. These are important considerations for women and physicians who are making choices on treatment. What matters to a patient are 2 overlapping questions:

• Do I have a life-threatening condition or do I not?
• Has screening identified a condition that might lead to treatment that’s unnecessary?

The problem is that with breast cancer we can’t tell the difference. We do not understand the biological potential of a lesion when we evaluate an image on MRI, or computed tomography (CT), or mammography.

A re-look at presented data

A trial conducted by Bakker and colleagues⁶ was discussed by the authors of the DenseBreast-info.org quiz in which they recommended breast MRI for all women with extremely dense breasts (but no other risk factors for breast cancer) detected on screening mammograms.⁷ The Bakker study was large and conducted in the Netherlands. The primary outcome of the trial was to compare the incidence of interval breast cancers of women aged 50 to 75 randomly assigned to MRI versus those assigned to continued screening mammography every 2 years. Importantly, among the more than 8,000 women who were assigned to MRI, 59%, or fewer than two-thirds, chose to actually undergo MRI.

Among women randomized to MRI, 20 interval cancers were found—4 were diagnosed in those who actually had MRIs, and 16 were diagnosed among women who were randomized to MRI but didn’t undergo the study. Among women assigned to screening mammography only, 161 interval cancers were diagnosed among more than 32,000 women screened. The primary outcome findings were 2.5 interval cancers per 1,000 screenings among women randomly assigned to MRI, and 5 interval cancers per 1,000 screenings among those randomly assigned to mammography only.⁶

Because the trial included women aged 50 and older, we can’t apply these results to younger women, who often undergo screening mammography in the United States. In addition, the majority of the population in the Netherlands are of Western European ethnicity, a less-diverse population of women than in the United States. Furthermore, among the tumors that were detected in the MRI group, a larger proportion were DCIS, early-stage tumors, well differentiated, and hormone receptor-positive. This observation supports that many of the MRI-detected tumors were cases of overdiagnosis, or the detection of tumors destined not to cause clinical problems for the patient during her lifetime, or for which earlier diagnosis would impact survival.

We also know that treatment of these small ER-positive tumors carries risks for patients, as we may treat them by depriving a patient of estrogen for the rest of her life, with potential consequences of sexual dysfunction, osteoporosis, and perhaps cardiovascular disease depending on her age at the time of that diagnosis. Weighing the risks and benefits of not only treatment but also use of more sensitive screening techniques such as MRI is extremely important. Although Bakker and colleagues’ study results are interesting, we do not feel they support routinely recommending MRI for women found to have extremely dense breasts with mammography.

Overdiagnosis: A difficult concept

One reason overdiagnosis is so challenging to understand is that it can’t be directly measured, which makes comprehending it that much more problematic for clinicians and our patients.

One way to help grasp the overall issue is to compare screening mammography with cervical and colon cancer screening.

We are well aware that cervical cancer screening has reduced the incidence of mortality from invasive cervical cancer.⁸ We can argue very validly that the biggest success in any cancer screening program in history and globally has been cervical cancer screening. Our specialty, in particular, should feel proud about this. Screening colonoscopy also has repeatedly been found to reduce colon cancer mortality.⁹ For breast cancer, decades of media messaging have emphasized the benefits of screening mammograms; however, in contrast with cervical cancer screening and colonoscopy, screening mammography has not reduced the incidence of breast cancer presenting with metastatic or advanced disease. Danish authors pointed out in 2017 that screening mammography has not achieved the hoped for or the promised reduction in breast cancer mortality.¹⁰

A report published in the March 2022, issue of Annals of Internal Medicine used modeling techniques to estimate the incidence of overdiagnosis and concluded that, among women aged 50-74 years receiving biennial screening mammograms (consistent with USPSTF recommendations), more than 15% of screen-detected breast cancers would represent cases of overdiagnosis. Of note, the study authors found that, among screen-detected cancers, the proportion representing overdiagnosis among women in their 60s (16.7%) and early 70s (23.6%) was higher than among women in their 50s-60s (11.5%-11.6%).¹¹

The former Chief Medical and Scientific Officer for the American Cancer Society Otis Brawley, MD, has stated that, at the same time that breast cancer screening should not be abandoned, “We must acknowledge that overdiagnosis is common. The benefits of screening have been overstated, and some patients considered as ‘cured’ from breast cancer have, in fact, been harmed by unneeded treatment.”¹²

“Everybody loves early detection,” said Donald Berry, PhD, from MD Anderson Cancer Center, “but it comes with harms.” He points out that mortality rates have improved for breast cancer, but he attributes it to improved treatment. “The harms [of screening] we know, but the benefits of screening are very uncertain.”¹³

Continue to: Limitations of breast MRI...

Limitations of breast MRI

Overall, MRI is a diagnostic and monitoring test. It is costlier than mammography, and because it is not recommended in guidelines as a screening modality for most women, it is not typically covered by insurance. Abbreviated (rapid) MRI is a non-standardized imaging strategy being used at a few health centers. It has a shorter protocol overall than MRI, so it takes less time than current MRI and is less expensive, but there are few data on sensitivity and specificity. It is yet to be determined which populations could benefit from this newer technology.

As mentioned, 41% of women in the Bakker et al trial who were randomly assigned to breast MRI chose not to proceed with that exam even though it would have been at no cost to them.⁶ Anecdotally, some patients who have undergone MRI say they would forgo it a second time as a screening modality because it was a very unpleasant, stressful experience. It’s not a perfect test, although it is more sensitive than mammography.

Other options for following up dense-breast screening. Besides MRI and abbreviated MRI, the following modalities can be used to evaluate women found to have dense breasts with screening mammograms: CT mammography with contrast, molecular breast imaging, and ultrasonography.

Screening and treatment advances

3D mammography. In the US, the great majority of screening mammography now is performed with tomosynthesis, or what our patients sometimes call 3D mammography. In fact, it is approaching standard of care. Women whose screening mammography includes tomosynthesis are less likely to experience a so-called callback for additional imaging with diagnostic mammography or breast ultrasonography.¹⁴

Liquid biopsy. A potential major advancement for making decisions about when to treat cancers in general involves determining the biological behavior of a tumor, based on analysis of either circulating tumor DNA or proteins in the blood. As more experience with this new technology accumulates, the role of liquid biopsies for breast cancer will expand.¹⁵ Liquid biopsies for screening remain investigational for now, but they hold tremendous potential.

Noninvasive proteomics. With the development of noninvasive proteomic biomarkers obtained from blood, saliva, or nipple aspiration fluid, there exists the possibility of not just evaluating an image of a tumor seen on a mammogram, but actually studying the biological characteristics of that lesion.¹⁶ The cost of this technology is far less in terms of resources than MRI or molecular-based imaging, and actually reveals the flaws with using image-based screening. With proteomics, we can tell whether or not a lump is generating proteins that are going to make that disease biologically meaningful, and treatment decisions can be based on that information. This idea has the potential to disrupt our current breast cancer screening paradigm.

Advocacy’s role in mandating legislation

Many advocacy groups lobby on Capitol Hill for legislation related to health care, but we don’t feel that is the best way to make scientific decisions, and it’s not the way to do medicine. Passionate people, who truly believe that their outcome would have been different had something else been done, have every right to advocate, and should. However, without longer-term data focusing on breast cancer and overall mortality, rather than surrogate outcomes like interval cancers, it is not clear that routinely recommending supplemental MRI will improve survival for women with extremely dense breasts. Unfortunately, overall, earlier diagnosis of highly aggressive breast cancer tumors does not result in better outcomes for patients. ●