Andrew D. Bowser

With careful review and some changes, cancer centers can provide effective care during the COVID-19 pandemic without sacrificing the safety of patients, caregivers, and health care workers, according to the authors of a special feature article in the Journal of the National Comprehensive Cancer Network.

Prescreening, telemedicine, and limiting procedures top the authors’ list of 10 recommendations for ensuring patient safety in U.S. oncology practices. Assuring appropriate personal proctective equipment (PPE), encouraging telecommuting, and providing wellness/stress management are a few of the ways to look out for health care worker safety during the crisis.

These recommendations were drafted to provide guidance during the rapidly evolving global pandemic that, in some cases, has deluged health care delivery systems and strained the ability of providers to assure safe and effective care, said lead author Pelin Cinar, MD, of the Hellen Diller Family Comprehensive Cancer Center at the University of California, San Francisco.

“I think we have been so overwhelmed that sometimes it’s difficult to get organized in our thought processes,” Dr. Cinar said in an interview. “So this [article] was really trying to provide some structure to each of the different steps that we should be addressing at minimum.”
 

Screening patients

Prescreening systems are a critical first step to ensure cancer centers are helping control community spread of the virus, according to the article. Whether done by phone or online, prescreening 1-2 days before a patient’s visit can help identify COVID-19 symptoms and exposure history, guiding whether patients need to be evaluated, monitored, or referred to an ED.

Next, screening clinics can help ensure cancer patients with COVID-19 symptoms are evaluated and tested in a unit with dedicated staff, according to the article.

“If symptomatic patients present to the cancer center for treatment after a negative prescreening assessment, they must be provided with a mask and directed to a screening clinic for evaluation and potential testing before moving forward with any cancer-directed therapy,” the article states.
 

Telemedicine and treatment

Telemedicine visits should be done whenever possible to avoid in-person visits, according to the article. Dr. Cinar said that her center, like other cancer centers, has seen a major uptick in these visits, which are typically done over video. In February, there were a total of 232 video visits at her center, which jumped to 1,702 in March, or an approximate 600% increase.

“Even though we had a relatively robust presence [before the pandemic], we still weren’t at a level where we are now,” Dr. Cinar said.

When it comes to cancer treatment, surgeries and procedures should be limited to essential or urgent cases, and, if possible, chemotherapy and systemic therapy regimens can be modified to allow for fewer visits to the cancer center or infusion center, according to the article.

Transitions to outpatient care can help further reduce the need for in-person visits, while intervals between scans can be increased, or biochemical markers can be used instead of scans.
 

Protecting providers

Health care workers providing cancer care should be assured appropriate PPE, and websites or other centralized resources should be in place to make sure workers are aware of current PPE guidelines and changes in workflow, according to the article.

The authors note that daily screening tools or temperature checks of symptomatic workers can help decrease the risk of exposure to others. The authors also recommend establishing clear rules for when health care workers with suspected or confirmed COVID-19 should be staying at home and returning to the job.

Telecommuting should be encouraged, with limited staff participating in onsite rotations to further reduce exposure risks, the article states.

Anxiety, insomnia, and distress have been reported among frontline health care workers managing patients with COVID-19, according to the article, which recommends wellness and stress management resources be available as an “invaluable resource” in cancer centers.

“We have to take care of ourselves to be able to take care of others,” Dr. Cinar said. “With PPE, you’re physically protecting yourself, while self-care, stress management, and wellness are also a big component of protecting ourselves.”

The report by Dr. Cinar and colleagues was an invited article from the NCCN Best Practices Committee. One coauthor reported relationships with Abbvie, Adaptive Biotechnologies, Aduro, and several other companies. Dr. Cinar and the remaining authors said they had no relevant conflicts of interest.

SOURCE: Cinar P et al. J Natl Compr Canc Netw. 2020 Apr 15. doi: 10.6004/jnccn.2020.7572.

With careful review and some changes, cancer centers can provide effective care during the COVID-19 pandemic without sacrificing the safety of patients, caregivers, and health care workers, according to the authors of a special feature article in the Journal of the National Comprehensive Cancer Network.

Prescreening, telemedicine, and limiting procedures top the authors’ list of 10 recommendations for ensuring patient safety in U.S. oncology practices. Assuring appropriate personal proctective equipment (PPE), encouraging telecommuting, and providing wellness/stress management are a few of the ways to look out for health care worker safety during the crisis.

These recommendations were drafted to provide guidance during the rapidly evolving global pandemic that, in some cases, has deluged health care delivery systems and strained the ability of providers to assure safe and effective care, said lead author Pelin Cinar, MD, of the Hellen Diller Family Comprehensive Cancer Center at the University of California, San Francisco.

“I think we have been so overwhelmed that sometimes it’s difficult to get organized in our thought processes,” Dr. Cinar said in an interview. “So this [article] was really trying to provide some structure to each of the different steps that we should be addressing at minimum.”
 

Screening patients

Prescreening systems are a critical first step to ensure cancer centers are helping control community spread of the virus, according to the article. Whether done by phone or online, prescreening 1-2 days before a patient’s visit can help identify COVID-19 symptoms and exposure history, guiding whether patients need to be evaluated, monitored, or referred to an ED.

Next, screening clinics can help ensure cancer patients with COVID-19 symptoms are evaluated and tested in a unit with dedicated staff, according to the article.

“If symptomatic patients present to the cancer center for treatment after a negative prescreening assessment, they must be provided with a mask and directed to a screening clinic for evaluation and potential testing before moving forward with any cancer-directed therapy,” the article states.
 

Telemedicine and treatment

Telemedicine visits should be done whenever possible to avoid in-person visits, according to the article. Dr. Cinar said that her center, like other cancer centers, has seen a major uptick in these visits, which are typically done over video. In February, there were a total of 232 video visits at her center, which jumped to 1,702 in March, or an approximate 600% increase.

“Even though we had a relatively robust presence [before the pandemic], we still weren’t at a level where we are now,” Dr. Cinar said.

When it comes to cancer treatment, surgeries and procedures should be limited to essential or urgent cases, and, if possible, chemotherapy and systemic therapy regimens can be modified to allow for fewer visits to the cancer center or infusion center, according to the article.

Transitions to outpatient care can help further reduce the need for in-person visits, while intervals between scans can be increased, or biochemical markers can be used instead of scans.
 

Protecting providers

Health care workers providing cancer care should be assured appropriate PPE, and websites or other centralized resources should be in place to make sure workers are aware of current PPE guidelines and changes in workflow, according to the article.

The authors note that daily screening tools or temperature checks of symptomatic workers can help decrease the risk of exposure to others. The authors also recommend establishing clear rules for when health care workers with suspected or confirmed COVID-19 should be staying at home and returning to the job.

Telecommuting should be encouraged, with limited staff participating in onsite rotations to further reduce exposure risks, the article states.

Anxiety, insomnia, and distress have been reported among frontline health care workers managing patients with COVID-19, according to the article, which recommends wellness and stress management resources be available as an “invaluable resource” in cancer centers.

“We have to take care of ourselves to be able to take care of others,” Dr. Cinar said. “With PPE, you’re physically protecting yourself, while self-care, stress management, and wellness are also a big component of protecting ourselves.”

The report by Dr. Cinar and colleagues was an invited article from the NCCN Best Practices Committee. One coauthor reported relationships with Abbvie, Adaptive Biotechnologies, Aduro, and several other companies. Dr. Cinar and the remaining authors said they had no relevant conflicts of interest.

SOURCE: Cinar P et al. J Natl Compr Canc Netw. 2020 Apr 15. doi: 10.6004/jnccn.2020.7572.

With careful review and some changes, cancer centers can provide effective care during the COVID-19 pandemic without sacrificing the safety of patients, caregivers, and health care workers, according to the authors of a special feature article in the Journal of the National Comprehensive Cancer Network.

Prescreening, telemedicine, and limiting procedures top the authors’ list of 10 recommendations for ensuring patient safety in U.S. oncology practices. Assuring appropriate personal proctective equipment (PPE), encouraging telecommuting, and providing wellness/stress management are a few of the ways to look out for health care worker safety during the crisis.

These recommendations were drafted to provide guidance during the rapidly evolving global pandemic that, in some cases, has deluged health care delivery systems and strained the ability of providers to assure safe and effective care, said lead author Pelin Cinar, MD, of the Hellen Diller Family Comprehensive Cancer Center at the University of California, San Francisco.

“I think we have been so overwhelmed that sometimes it’s difficult to get organized in our thought processes,” Dr. Cinar said in an interview. “So this [article] was really trying to provide some structure to each of the different steps that we should be addressing at minimum.”
 

Screening patients

Prescreening systems are a critical first step to ensure cancer centers are helping control community spread of the virus, according to the article. Whether done by phone or online, prescreening 1-2 days before a patient’s visit can help identify COVID-19 symptoms and exposure history, guiding whether patients need to be evaluated, monitored, or referred to an ED.

Next, screening clinics can help ensure cancer patients with COVID-19 symptoms are evaluated and tested in a unit with dedicated staff, according to the article.

“If symptomatic patients present to the cancer center for treatment after a negative prescreening assessment, they must be provided with a mask and directed to a screening clinic for evaluation and potential testing before moving forward with any cancer-directed therapy,” the article states.
 

Telemedicine and treatment

Telemedicine visits should be done whenever possible to avoid in-person visits, according to the article. Dr. Cinar said that her center, like other cancer centers, has seen a major uptick in these visits, which are typically done over video. In February, there were a total of 232 video visits at her center, which jumped to 1,702 in March, or an approximate 600% increase.

“Even though we had a relatively robust presence [before the pandemic], we still weren’t at a level where we are now,” Dr. Cinar said.

When it comes to cancer treatment, surgeries and procedures should be limited to essential or urgent cases, and, if possible, chemotherapy and systemic therapy regimens can be modified to allow for fewer visits to the cancer center or infusion center, according to the article.

Transitions to outpatient care can help further reduce the need for in-person visits, while intervals between scans can be increased, or biochemical markers can be used instead of scans.
 

Protecting providers

Health care workers providing cancer care should be assured appropriate PPE, and websites or other centralized resources should be in place to make sure workers are aware of current PPE guidelines and changes in workflow, according to the article.

The authors note that daily screening tools or temperature checks of symptomatic workers can help decrease the risk of exposure to others. The authors also recommend establishing clear rules for when health care workers with suspected or confirmed COVID-19 should be staying at home and returning to the job.

Telecommuting should be encouraged, with limited staff participating in onsite rotations to further reduce exposure risks, the article states.

Anxiety, insomnia, and distress have been reported among frontline health care workers managing patients with COVID-19, according to the article, which recommends wellness and stress management resources be available as an “invaluable resource” in cancer centers.

“We have to take care of ourselves to be able to take care of others,” Dr. Cinar said. “With PPE, you’re physically protecting yourself, while self-care, stress management, and wellness are also a big component of protecting ourselves.”

The report by Dr. Cinar and colleagues was an invited article from the NCCN Best Practices Committee. One coauthor reported relationships with Abbvie, Adaptive Biotechnologies, Aduro, and several other companies. Dr. Cinar and the remaining authors said they had no relevant conflicts of interest.

SOURCE: Cinar P et al. J Natl Compr Canc Netw. 2020 Apr 15. doi: 10.6004/jnccn.2020.7572.

It’s okay to consider breast-conserving therapy in breast cancer patients with high-risk hereditary genetic mutations, according to guidelines published in the Journal of Clinical Oncology.

The presence of a germline BRCA1 or BRCA2 mutation shouldn’t preclude breast-conserving therapy as long as the patient is otherwise eligible for the procedure, according to the guidelines, which were developed by an expert panel convened by the American Society of Clinical Oncology, American Society for Radiation Oncology, and Society for Surgical Oncology.

Nadine M. Tung, MD, of Beth Israel Deaconess Medical Center in Boston and the rest of the expert panel reviewed evidence from 58 published articles to create the guidelines.

In addition to supporting use of breast-conserving therapy, the guidelines suggest that radiation shouldn’t be withheld because of mutation status, except in patients with TP53 mutations. Furthermore, BRCA1/2 mutation carriers with metastatic HER2-negative disease can receive the poly (ADP-ribose) polymerase (PARP) inhibitors olaparib and talazoparib as an “alternative to chemotherapy” for first-, second-, or third-line therapy.

However, it’s the “license to consider breast-conserving therapy” for high-risk individuals that is one of the most noteworthy points in the guidelines, and the one that may surprise some readers, according to William J. Gradishar, MD, of Northwestern University in Chicago, who was not involved in developing the guidelines.

“We don’t have to be as dogmatic with these patients with respect to local therapies as we were in the past,” Dr. Gradishar said in an interview. “That’s a good thing for patients, but you also have to understand the nuances that go into recommending [breast-conserving surgery] to a patient. Other variables, like the age at which the patient develops breast cancer, family history, etc., all go into it.”

Weighing options for surgery

The guidelines emphasize that, for patients with germline BRCA1/2 mutations, health care providers need to discuss treatment options for the breast cancer at hand. However, patients should also be made aware of their increased risk of contralateral and new ipsilateral breast cancer as compared with noncarriers.

When weighing breast-conserving therapy versus mastectomy in light of contralateral breast cancer risk, the guidelines recommend considering not only age at diagnosis – the strongest predictor of a later contralateral breast cancer – but also family history, comorbidities, life expectancy, ability to undergo MRI, and prognosis from breast or other cancers, such as ovarian cancer.

If a bilateral mastectomy isn’t performed in a BRCA1/2 mutation carrier, an annual mammogram and MRI are warranted thereafter for screening of the remaining breast tissue, according to the guidelines.

The guidelines say breast-conserving therapy should be offered to patients with mutations in moderate-penetrance genes, including PALB2, CHEK2, and ATM. However, there’s not much data regarding the risk of ipsilateral breast cancer after breast-conserving therapy in these patients.

Likewise, there’s limited evidence on contralateral breast cancer risk for patients with mutations in moderate-penetrance genes aside from CHEK2. The guidelines say the risk should be discussed with patients “in the context of shared decision making.”

Nipple-sparing mastectomy is “reasonable” to consider in certain newly diagnosed patients with BRCA1/2 mutations, as well as in newly diagnosed patients with moderate-risk mutations, the guidelines state.

Women with breast cancer and a deleterious BRCA1/2 mutation who are undergoing unilateral mastectomy should be offered contralateral risk-reducing mastectomy. Likewise, women with moderate-risk mutations should be offered contralateral risk-reducing mastectomy, but not solely based on mutation status, according to the guidelines. Data are limited on contralateral breast cancer risk related to those mutations.

Considerations for radiation

Radiation therapy in the context of breast-conserving therapy or mastectomy should not be withheld because of hereditary mutations, except in the case of TP53 mutations, according to the guidelines.

There’s no evidence that radiotherapy increases toxicity or contralateral breast cancer risk for most BRCA1/2 or moderate-penetrance gene mutations. However, the intact breast shouldn’t be irradiated in germline TP53 mutation carriers, the guidelines say, because of the important role that TP53 plays in the ability to repair DNA damage after cellular stress.

“Carriers of a TP53 mutation would be expected to be unable to repair tissue damage from DNA damaging radiotherapy and be at risk for significant [radiotherapy]-associated sequelae,” the guidelines state.

Chemotherapy and PARP inhibitors

For women with metastatic breast cancer harboring germline BRCA1/2 mutations, the guidelines say platinum chemotherapy should be preferred over taxanes for platinum-naive patients.

Provided the breast cancer is HER2 negative, the PARP inhibitors olaparib or talazoparib “should be offered as an alternative to chemotherapy in the first- to third-line settings,” the guidelines state.

The guidelines confirm that PARP inhibitors are a “valid starting point” for treatment of BCRA1/2–associated metastatic breast cancer, Dr. Gradishar said.

“When a patient progresses on a PARP inhibitor, assuming they’re not going on some other investigational drug or clinical trial, they’re going to get chemotherapy,” he said. “So the argument is that, if you have something that’s at least as good or maybe a little bit better and has fewer side effects, why not start with that and then move on to other things?”

By contrast, there’s not enough evidence to recommend PARP inhibitors for germline BRCA mutation carriers with nonmetastatic breast cancers, according to the guidelines, and there’s “no robust data” for using PARP inhibitors in patients with breast cancers with mutations in moderate-penetrance genes.

The guideline authors disclosed relationships with AstraZeneca, Myriad Genetics, Pfizer, Lilly, and other companies. Dr. Gradishar has relationships with AstraZeneca, Celltrion, Genentech, MacroGenics, Merck, Pfizer, and Seattle Genetics.

SOURCE: Tung NM et al. J Clin Oncol. 2020 Apr 3;JCO2000299. doi: 10.1200/JCO.20.00299.

It’s okay to consider breast-conserving therapy in breast cancer patients with high-risk hereditary genetic mutations, according to guidelines published in the Journal of Clinical Oncology.

The presence of a germline BRCA1 or BRCA2 mutation shouldn’t preclude breast-conserving therapy as long as the patient is otherwise eligible for the procedure, according to the guidelines, which were developed by an expert panel convened by the American Society of Clinical Oncology, American Society for Radiation Oncology, and Society for Surgical Oncology.

Nadine M. Tung, MD, of Beth Israel Deaconess Medical Center in Boston and the rest of the expert panel reviewed evidence from 58 published articles to create the guidelines.

In addition to supporting use of breast-conserving therapy, the guidelines suggest that radiation shouldn’t be withheld because of mutation status, except in patients with TP53 mutations. Furthermore, BRCA1/2 mutation carriers with metastatic HER2-negative disease can receive the poly (ADP-ribose) polymerase (PARP) inhibitors olaparib and talazoparib as an “alternative to chemotherapy” for first-, second-, or third-line therapy.

However, it’s the “license to consider breast-conserving therapy” for high-risk individuals that is one of the most noteworthy points in the guidelines, and the one that may surprise some readers, according to William J. Gradishar, MD, of Northwestern University in Chicago, who was not involved in developing the guidelines.

“We don’t have to be as dogmatic with these patients with respect to local therapies as we were in the past,” Dr. Gradishar said in an interview. “That’s a good thing for patients, but you also have to understand the nuances that go into recommending [breast-conserving surgery] to a patient. Other variables, like the age at which the patient develops breast cancer, family history, etc., all go into it.”

Weighing options for surgery

The guidelines emphasize that, for patients with germline BRCA1/2 mutations, health care providers need to discuss treatment options for the breast cancer at hand. However, patients should also be made aware of their increased risk of contralateral and new ipsilateral breast cancer as compared with noncarriers.

When weighing breast-conserving therapy versus mastectomy in light of contralateral breast cancer risk, the guidelines recommend considering not only age at diagnosis – the strongest predictor of a later contralateral breast cancer – but also family history, comorbidities, life expectancy, ability to undergo MRI, and prognosis from breast or other cancers, such as ovarian cancer.

If a bilateral mastectomy isn’t performed in a BRCA1/2 mutation carrier, an annual mammogram and MRI are warranted thereafter for screening of the remaining breast tissue, according to the guidelines.

The guidelines say breast-conserving therapy should be offered to patients with mutations in moderate-penetrance genes, including PALB2, CHEK2, and ATM. However, there’s not much data regarding the risk of ipsilateral breast cancer after breast-conserving therapy in these patients.

Likewise, there’s limited evidence on contralateral breast cancer risk for patients with mutations in moderate-penetrance genes aside from CHEK2. The guidelines say the risk should be discussed with patients “in the context of shared decision making.”

Nipple-sparing mastectomy is “reasonable” to consider in certain newly diagnosed patients with BRCA1/2 mutations, as well as in newly diagnosed patients with moderate-risk mutations, the guidelines state.

Women with breast cancer and a deleterious BRCA1/2 mutation who are undergoing unilateral mastectomy should be offered contralateral risk-reducing mastectomy. Likewise, women with moderate-risk mutations should be offered contralateral risk-reducing mastectomy, but not solely based on mutation status, according to the guidelines. Data are limited on contralateral breast cancer risk related to those mutations.

Considerations for radiation

Radiation therapy in the context of breast-conserving therapy or mastectomy should not be withheld because of hereditary mutations, except in the case of TP53 mutations, according to the guidelines.

There’s no evidence that radiotherapy increases toxicity or contralateral breast cancer risk for most BRCA1/2 or moderate-penetrance gene mutations. However, the intact breast shouldn’t be irradiated in germline TP53 mutation carriers, the guidelines say, because of the important role that TP53 plays in the ability to repair DNA damage after cellular stress.

“Carriers of a TP53 mutation would be expected to be unable to repair tissue damage from DNA damaging radiotherapy and be at risk for significant [radiotherapy]-associated sequelae,” the guidelines state.

Chemotherapy and PARP inhibitors

For women with metastatic breast cancer harboring germline BRCA1/2 mutations, the guidelines say platinum chemotherapy should be preferred over taxanes for platinum-naive patients.

Provided the breast cancer is HER2 negative, the PARP inhibitors olaparib or talazoparib “should be offered as an alternative to chemotherapy in the first- to third-line settings,” the guidelines state.

The guidelines confirm that PARP inhibitors are a “valid starting point” for treatment of BCRA1/2–associated metastatic breast cancer, Dr. Gradishar said.

“When a patient progresses on a PARP inhibitor, assuming they’re not going on some other investigational drug or clinical trial, they’re going to get chemotherapy,” he said. “So the argument is that, if you have something that’s at least as good or maybe a little bit better and has fewer side effects, why not start with that and then move on to other things?”

By contrast, there’s not enough evidence to recommend PARP inhibitors for germline BRCA mutation carriers with nonmetastatic breast cancers, according to the guidelines, and there’s “no robust data” for using PARP inhibitors in patients with breast cancers with mutations in moderate-penetrance genes.

The guideline authors disclosed relationships with AstraZeneca, Myriad Genetics, Pfizer, Lilly, and other companies. Dr. Gradishar has relationships with AstraZeneca, Celltrion, Genentech, MacroGenics, Merck, Pfizer, and Seattle Genetics.

SOURCE: Tung NM et al. J Clin Oncol. 2020 Apr 3;JCO2000299. doi: 10.1200/JCO.20.00299.

It’s okay to consider breast-conserving therapy in breast cancer patients with high-risk hereditary genetic mutations, according to guidelines published in the Journal of Clinical Oncology.

The presence of a germline BRCA1 or BRCA2 mutation shouldn’t preclude breast-conserving therapy as long as the patient is otherwise eligible for the procedure, according to the guidelines, which were developed by an expert panel convened by the American Society of Clinical Oncology, American Society for Radiation Oncology, and Society for Surgical Oncology.

Nadine M. Tung, MD, of Beth Israel Deaconess Medical Center in Boston and the rest of the expert panel reviewed evidence from 58 published articles to create the guidelines.

In addition to supporting use of breast-conserving therapy, the guidelines suggest that radiation shouldn’t be withheld because of mutation status, except in patients with TP53 mutations. Furthermore, BRCA1/2 mutation carriers with metastatic HER2-negative disease can receive the poly (ADP-ribose) polymerase (PARP) inhibitors olaparib and talazoparib as an “alternative to chemotherapy” for first-, second-, or third-line therapy.

However, it’s the “license to consider breast-conserving therapy” for high-risk individuals that is one of the most noteworthy points in the guidelines, and the one that may surprise some readers, according to William J. Gradishar, MD, of Northwestern University in Chicago, who was not involved in developing the guidelines.

“We don’t have to be as dogmatic with these patients with respect to local therapies as we were in the past,” Dr. Gradishar said in an interview. “That’s a good thing for patients, but you also have to understand the nuances that go into recommending [breast-conserving surgery] to a patient. Other variables, like the age at which the patient develops breast cancer, family history, etc., all go into it.”

Weighing options for surgery

The guidelines emphasize that, for patients with germline BRCA1/2 mutations, health care providers need to discuss treatment options for the breast cancer at hand. However, patients should also be made aware of their increased risk of contralateral and new ipsilateral breast cancer as compared with noncarriers.

When weighing breast-conserving therapy versus mastectomy in light of contralateral breast cancer risk, the guidelines recommend considering not only age at diagnosis – the strongest predictor of a later contralateral breast cancer – but also family history, comorbidities, life expectancy, ability to undergo MRI, and prognosis from breast or other cancers, such as ovarian cancer.

If a bilateral mastectomy isn’t performed in a BRCA1/2 mutation carrier, an annual mammogram and MRI are warranted thereafter for screening of the remaining breast tissue, according to the guidelines.

The guidelines say breast-conserving therapy should be offered to patients with mutations in moderate-penetrance genes, including PALB2, CHEK2, and ATM. However, there’s not much data regarding the risk of ipsilateral breast cancer after breast-conserving therapy in these patients.

Likewise, there’s limited evidence on contralateral breast cancer risk for patients with mutations in moderate-penetrance genes aside from CHEK2. The guidelines say the risk should be discussed with patients “in the context of shared decision making.”

Nipple-sparing mastectomy is “reasonable” to consider in certain newly diagnosed patients with BRCA1/2 mutations, as well as in newly diagnosed patients with moderate-risk mutations, the guidelines state.

Women with breast cancer and a deleterious BRCA1/2 mutation who are undergoing unilateral mastectomy should be offered contralateral risk-reducing mastectomy. Likewise, women with moderate-risk mutations should be offered contralateral risk-reducing mastectomy, but not solely based on mutation status, according to the guidelines. Data are limited on contralateral breast cancer risk related to those mutations.

Considerations for radiation

Radiation therapy in the context of breast-conserving therapy or mastectomy should not be withheld because of hereditary mutations, except in the case of TP53 mutations, according to the guidelines.

There’s no evidence that radiotherapy increases toxicity or contralateral breast cancer risk for most BRCA1/2 or moderate-penetrance gene mutations. However, the intact breast shouldn’t be irradiated in germline TP53 mutation carriers, the guidelines say, because of the important role that TP53 plays in the ability to repair DNA damage after cellular stress.

“Carriers of a TP53 mutation would be expected to be unable to repair tissue damage from DNA damaging radiotherapy and be at risk for significant [radiotherapy]-associated sequelae,” the guidelines state.

Chemotherapy and PARP inhibitors

For women with metastatic breast cancer harboring germline BRCA1/2 mutations, the guidelines say platinum chemotherapy should be preferred over taxanes for platinum-naive patients.

Provided the breast cancer is HER2 negative, the PARP inhibitors olaparib or talazoparib “should be offered as an alternative to chemotherapy in the first- to third-line settings,” the guidelines state.

The guidelines confirm that PARP inhibitors are a “valid starting point” for treatment of BCRA1/2–associated metastatic breast cancer, Dr. Gradishar said.

“When a patient progresses on a PARP inhibitor, assuming they’re not going on some other investigational drug or clinical trial, they’re going to get chemotherapy,” he said. “So the argument is that, if you have something that’s at least as good or maybe a little bit better and has fewer side effects, why not start with that and then move on to other things?”

By contrast, there’s not enough evidence to recommend PARP inhibitors for germline BRCA mutation carriers with nonmetastatic breast cancers, according to the guidelines, and there’s “no robust data” for using PARP inhibitors in patients with breast cancers with mutations in moderate-penetrance genes.

The guideline authors disclosed relationships with AstraZeneca, Myriad Genetics, Pfizer, Lilly, and other companies. Dr. Gradishar has relationships with AstraZeneca, Celltrion, Genentech, MacroGenics, Merck, Pfizer, and Seattle Genetics.

SOURCE: Tung NM et al. J Clin Oncol. 2020 Apr 3;JCO2000299. doi: 10.1200/JCO.20.00299.

While there are still no proven treatments for COVID-19, the antiviral medication remdesivir is currently the most promising therapy under investigation, according to authors of a recent review covering nearly 300 active clinical treatment trials underway for the disease.

Remdesivir, which has potent in vitro activity against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is not approved by the Food and Drug Administration and is currently being tested in randomized trials, according to the review authors, led by James M. Sanders, PhD, of the department of pharmacy at University of Texas Southwestern Medical Center in Dallas.

By contrast, oseltamivir has not demonstrated efficacy against the virus, corticosteroids are not recommended, and promising data from a small French hydroxychloroquine study are balanced by “several major limitations” including small sample size and exclusion of early dropouts from the analysis, among others, Dr. Sanders and coauthors said in their report.

“These limitations coupled with concerns of additive cardiotoxicity with combination therapy [i.e., hydroxychloroquine with azithromycin] do not support adoption of this regimen without additional studies,” the researchers wrote. Their report is in JAMA.

Dr. Sanders and colleagues identified 291 COVID-19–specific studies listed in ClinicalTrials.gov through April 2, including 29 placebo-controlled trials.

This might represent just a sliver of the treatments that could combat COVID-19, according to the researchers, who said more than 3,000 small-molecule drug candidates with potential activity against human coronaviruses have been identified.

“This large amount of potential agents will hopefully yield more candidate therapeutics in the race to find effective treatments or preventive strategies against COVID-19,” said Dr. Sanders and coauthors.
 

Remdesivir for COVID-19

Remdesivir, an investigational nucleotide analog, is one promising agent because of its broad-spectrum and potent activity against SARS-CoV-2 and other novel coronaviruses, they said, adding that phase 1 trials demonstrated the drug was well tolerated without observed liver or kidney toxicity.

There have been “successful” case reports of remdesivir use in COVID-19, and at least five ongoing clinical trials are evaluating the drug’s safety and antiviral activity in this disease. Among those studies is a National Institutes of Health–sponsored adaptive, randomized, placebo-controlled trial that will provide data on the use of remdesivir versus supportive care.

“As the results from randomized controlled trials are anticipated, inclusion of this agent for treatment of COVID-19 may be considered,” Dr. Sanders and colleagues wrote in their report. To date, remdesivir remains investigational and needs to be obtained via compassionate use, through expanded access, or by participating in a clinical trial, they added.

Hydroxychloroquine and chloroquine

Among the published hydroxychloroquine studies is a “promising” 36-patient open-label nonrandomized French study, in which the antimalarial agent given every 8 hours improved virologic clearance by day 6 versus controls (70% vs. 12.5%, respectively), the review authors said. Moreover, viral clearance was 100% for 6 patients who received hydroxychloroquine plus azithromycin, compared to 57% (8 of 14) for patients treated with hydroxychloroquine alone. However, that study had several important limitations, including the small sample size, variable viral loads at baseline between groups, and a lack of safety and clinical outcomes reporting, according to the investigators. Moreover, six patients in the hydroxychloroquine group were taken out of the analysis because of early treatment stoppage due to medical intolerance or critical illness, the authors noted.

One prospective study including 30 patients in China demonstrated no difference in virologic outcomes for patients randomized to hydroxychloroquine plus standard of care versus standard of care alone, they added. There is also a case series of more than 100 patients with COVID-19 that reportedly improved viral clearance and reduced disease progression, though they said results haven’t been published or presented beyond a news briefing in China.

Randomized, controlled trials of chloroquine and hydroxychloroquine for COVID-19 treatment are underway, and studies are planned or enrolling to look at chloroquine prophylaxis in health care personnel and hydroxychloroquine for postexposure prophylaxis, authors said.

In results from one of those randomized trials, just reported, a higher dose of chloroquine was associated with a cardiac adverse event and an increased mortality risk, leading to the closure of that study arm. In the parallel, double-blinded, phase IIb clinical trial, patients in Brazil with SARS-CoV-2 infection received low or high doses of chloroquine plus ceftriaxone and azithromycin. According to the preprint publication, a higher rate of heart rate–corrected QT interval (QTc) prolongation and a “trend toward higher lethality” was observed in the high-dose group, leading investigators to “strongly recommend” the higher dose be abandoned.

“No apparent benefit of chloroquine was seen regarding lethality in our patients so far, but we will still enroll patients in the low chloroquine dose group to complete the originally planned sample size,” said investigators of the study, which at the time of the report had enrolled 81 out of an anticipated 440 patients.
 

Other COVID-19 pharmacologic therapies under study

Treatments of note in the review included the following:

• Tocilizumab. This monoclonal antibody IL-6 receptor antagonist, approved by the FDA for treatment of rheumatoid arthritis and for cytokine release syndrome related to chimeric antigen receptor (CAR) T-cell therapy, has yielded success in small series of patients with severe cases of COVID-19, according to authors. In one 21-patient report, 91% had clinical improvement, usually after a single dose. In China, tocilizumab is included in COVID-19 treatment guidelines, and several randomized clinical trials are underway in China including patients with COVID-19 with severe pneumonia.
• Immunoglobulin therapy. Antibodies from recovered COVID-19 patients could help with free virus and infected cell immune clearance, the authors said, adding that further studies are warranted beyond a few small published case series that suggest promise. Furthermore, on March 24 the FDA released guidance for screening donors for COVID-19 convalescent plasma and on emergency investigational new drug applications based on this modality.

• Lopinavir/ritonavir. Despite demonstrated in vitro activity against other novel coronaviruses, there is no published in vitro data for lopinavir/ritonavir in SARS-CoV-2, and likely a “limited role” for this combination anticipated in treating COVID-19, according to the review authors. In an open-label randomized clinical trial published in the New England Journal of Medicine (2020 Mar 18. doi: 10.1056/NEJMoa2001282), there were no differences in clinical improvement, viral clearance, or mortality for antiviral treatment versus standard care. Delayed treatment initiation may explain the ineffectiveness, though a subgroup analysis didn’t show a shorter time to clinical improvement for those who got the treatment earlier.

• Ribavirin. Likewise, this antiviral medication has efficacy and safety data suggesting “limited value” for treatment of COVID-19. Treatment of SARS yielded “inconclusive results” for ribavirin, which was also associated with substantial toxicity that included hemolytic anemia in 60% of SARS patients.
• Oseltamivir. While it may treat influenza, it has no documented activity against SARS-CoV-2 in vitro: “This agent has no role in the management of COVID-19 once influenza has been excluded,” said Dr. Sanders and coauthors.
• Corticosteroids. They could decrease inflammatory responses in the lung, but they could also lead to delays in viral clearance and increases in secondary infection risk. Guidelines for COVID-19 say to avoid corticosteroids, and the authors of the review concur, saying that potential harms and lack of proven benefit mean they usually should not be used outside of a randomized clinical trial setting.
• Vaccines. Clearly, vaccines represent the “most effective long-term strategy” to prevent future COVID-19 outbreaks, though at least 12-18 months would be required until vaccines can be widely deployed, authors said.

Dr. Sanders reported no potential conflicts. Senior author James B. Cutrell, MD, also of the University of Texas Southwestern Medical Center, reported nonfinancial support from Gilead and Regeneron outside of the study. No other authors reported disclosures.

While there are still no proven treatments for COVID-19, the antiviral medication remdesivir is currently the most promising therapy under investigation, according to authors of a recent review covering nearly 300 active clinical treatment trials underway for the disease.

Remdesivir, which has potent in vitro activity against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is not approved by the Food and Drug Administration and is currently being tested in randomized trials, according to the review authors, led by James M. Sanders, PhD, of the department of pharmacy at University of Texas Southwestern Medical Center in Dallas.

By contrast, oseltamivir has not demonstrated efficacy against the virus, corticosteroids are not recommended, and promising data from a small French hydroxychloroquine study are balanced by “several major limitations” including small sample size and exclusion of early dropouts from the analysis, among others, Dr. Sanders and coauthors said in their report.

“These limitations coupled with concerns of additive cardiotoxicity with combination therapy [i.e., hydroxychloroquine with azithromycin] do not support adoption of this regimen without additional studies,” the researchers wrote. Their report is in JAMA.

Dr. Sanders and colleagues identified 291 COVID-19–specific studies listed in ClinicalTrials.gov through April 2, including 29 placebo-controlled trials.

This might represent just a sliver of the treatments that could combat COVID-19, according to the researchers, who said more than 3,000 small-molecule drug candidates with potential activity against human coronaviruses have been identified.

“This large amount of potential agents will hopefully yield more candidate therapeutics in the race to find effective treatments or preventive strategies against COVID-19,” said Dr. Sanders and coauthors.
 

Remdesivir for COVID-19

Remdesivir, an investigational nucleotide analog, is one promising agent because of its broad-spectrum and potent activity against SARS-CoV-2 and other novel coronaviruses, they said, adding that phase 1 trials demonstrated the drug was well tolerated without observed liver or kidney toxicity.

There have been “successful” case reports of remdesivir use in COVID-19, and at least five ongoing clinical trials are evaluating the drug’s safety and antiviral activity in this disease. Among those studies is a National Institutes of Health–sponsored adaptive, randomized, placebo-controlled trial that will provide data on the use of remdesivir versus supportive care.

“As the results from randomized controlled trials are anticipated, inclusion of this agent for treatment of COVID-19 may be considered,” Dr. Sanders and colleagues wrote in their report. To date, remdesivir remains investigational and needs to be obtained via compassionate use, through expanded access, or by participating in a clinical trial, they added.

Hydroxychloroquine and chloroquine

Among the published hydroxychloroquine studies is a “promising” 36-patient open-label nonrandomized French study, in which the antimalarial agent given every 8 hours improved virologic clearance by day 6 versus controls (70% vs. 12.5%, respectively), the review authors said. Moreover, viral clearance was 100% for 6 patients who received hydroxychloroquine plus azithromycin, compared to 57% (8 of 14) for patients treated with hydroxychloroquine alone. However, that study had several important limitations, including the small sample size, variable viral loads at baseline between groups, and a lack of safety and clinical outcomes reporting, according to the investigators. Moreover, six patients in the hydroxychloroquine group were taken out of the analysis because of early treatment stoppage due to medical intolerance or critical illness, the authors noted.

One prospective study including 30 patients in China demonstrated no difference in virologic outcomes for patients randomized to hydroxychloroquine plus standard of care versus standard of care alone, they added. There is also a case series of more than 100 patients with COVID-19 that reportedly improved viral clearance and reduced disease progression, though they said results haven’t been published or presented beyond a news briefing in China.

Randomized, controlled trials of chloroquine and hydroxychloroquine for COVID-19 treatment are underway, and studies are planned or enrolling to look at chloroquine prophylaxis in health care personnel and hydroxychloroquine for postexposure prophylaxis, authors said.

In results from one of those randomized trials, just reported, a higher dose of chloroquine was associated with a cardiac adverse event and an increased mortality risk, leading to the closure of that study arm. In the parallel, double-blinded, phase IIb clinical trial, patients in Brazil with SARS-CoV-2 infection received low or high doses of chloroquine plus ceftriaxone and azithromycin. According to the preprint publication, a higher rate of heart rate–corrected QT interval (QTc) prolongation and a “trend toward higher lethality” was observed in the high-dose group, leading investigators to “strongly recommend” the higher dose be abandoned.

“No apparent benefit of chloroquine was seen regarding lethality in our patients so far, but we will still enroll patients in the low chloroquine dose group to complete the originally planned sample size,” said investigators of the study, which at the time of the report had enrolled 81 out of an anticipated 440 patients.
 

Other COVID-19 pharmacologic therapies under study

Treatments of note in the review included the following:

• Tocilizumab. This monoclonal antibody IL-6 receptor antagonist, approved by the FDA for treatment of rheumatoid arthritis and for cytokine release syndrome related to chimeric antigen receptor (CAR) T-cell therapy, has yielded success in small series of patients with severe cases of COVID-19, according to authors. In one 21-patient report, 91% had clinical improvement, usually after a single dose. In China, tocilizumab is included in COVID-19 treatment guidelines, and several randomized clinical trials are underway in China including patients with COVID-19 with severe pneumonia.
• Immunoglobulin therapy. Antibodies from recovered COVID-19 patients could help with free virus and infected cell immune clearance, the authors said, adding that further studies are warranted beyond a few small published case series that suggest promise. Furthermore, on March 24 the FDA released guidance for screening donors for COVID-19 convalescent plasma and on emergency investigational new drug applications based on this modality.

• Lopinavir/ritonavir. Despite demonstrated in vitro activity against other novel coronaviruses, there is no published in vitro data for lopinavir/ritonavir in SARS-CoV-2, and likely a “limited role” for this combination anticipated in treating COVID-19, according to the review authors. In an open-label randomized clinical trial published in the New England Journal of Medicine (2020 Mar 18. doi: 10.1056/NEJMoa2001282), there were no differences in clinical improvement, viral clearance, or mortality for antiviral treatment versus standard care. Delayed treatment initiation may explain the ineffectiveness, though a subgroup analysis didn’t show a shorter time to clinical improvement for those who got the treatment earlier.

• Ribavirin. Likewise, this antiviral medication has efficacy and safety data suggesting “limited value” for treatment of COVID-19. Treatment of SARS yielded “inconclusive results” for ribavirin, which was also associated with substantial toxicity that included hemolytic anemia in 60% of SARS patients.
• Oseltamivir. While it may treat influenza, it has no documented activity against SARS-CoV-2 in vitro: “This agent has no role in the management of COVID-19 once influenza has been excluded,” said Dr. Sanders and coauthors.
• Corticosteroids. They could decrease inflammatory responses in the lung, but they could also lead to delays in viral clearance and increases in secondary infection risk. Guidelines for COVID-19 say to avoid corticosteroids, and the authors of the review concur, saying that potential harms and lack of proven benefit mean they usually should not be used outside of a randomized clinical trial setting.
• Vaccines. Clearly, vaccines represent the “most effective long-term strategy” to prevent future COVID-19 outbreaks, though at least 12-18 months would be required until vaccines can be widely deployed, authors said.

Dr. Sanders reported no potential conflicts. Senior author James B. Cutrell, MD, also of the University of Texas Southwestern Medical Center, reported nonfinancial support from Gilead and Regeneron outside of the study. No other authors reported disclosures.

While there are still no proven treatments for COVID-19, the antiviral medication remdesivir is currently the most promising therapy under investigation, according to authors of a recent review covering nearly 300 active clinical treatment trials underway for the disease.

Remdesivir, which has potent in vitro activity against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is not approved by the Food and Drug Administration and is currently being tested in randomized trials, according to the review authors, led by James M. Sanders, PhD, of the department of pharmacy at University of Texas Southwestern Medical Center in Dallas.

By contrast, oseltamivir has not demonstrated efficacy against the virus, corticosteroids are not recommended, and promising data from a small French hydroxychloroquine study are balanced by “several major limitations” including small sample size and exclusion of early dropouts from the analysis, among others, Dr. Sanders and coauthors said in their report.

“These limitations coupled with concerns of additive cardiotoxicity with combination therapy [i.e., hydroxychloroquine with azithromycin] do not support adoption of this regimen without additional studies,” the researchers wrote. Their report is in JAMA.

Dr. Sanders and colleagues identified 291 COVID-19–specific studies listed in ClinicalTrials.gov through April 2, including 29 placebo-controlled trials.

This might represent just a sliver of the treatments that could combat COVID-19, according to the researchers, who said more than 3,000 small-molecule drug candidates with potential activity against human coronaviruses have been identified.

“This large amount of potential agents will hopefully yield more candidate therapeutics in the race to find effective treatments or preventive strategies against COVID-19,” said Dr. Sanders and coauthors.
 

Remdesivir for COVID-19

Remdesivir, an investigational nucleotide analog, is one promising agent because of its broad-spectrum and potent activity against SARS-CoV-2 and other novel coronaviruses, they said, adding that phase 1 trials demonstrated the drug was well tolerated without observed liver or kidney toxicity.

There have been “successful” case reports of remdesivir use in COVID-19, and at least five ongoing clinical trials are evaluating the drug’s safety and antiviral activity in this disease. Among those studies is a National Institutes of Health–sponsored adaptive, randomized, placebo-controlled trial that will provide data on the use of remdesivir versus supportive care.

“As the results from randomized controlled trials are anticipated, inclusion of this agent for treatment of COVID-19 may be considered,” Dr. Sanders and colleagues wrote in their report. To date, remdesivir remains investigational and needs to be obtained via compassionate use, through expanded access, or by participating in a clinical trial, they added.

Hydroxychloroquine and chloroquine

Among the published hydroxychloroquine studies is a “promising” 36-patient open-label nonrandomized French study, in which the antimalarial agent given every 8 hours improved virologic clearance by day 6 versus controls (70% vs. 12.5%, respectively), the review authors said. Moreover, viral clearance was 100% for 6 patients who received hydroxychloroquine plus azithromycin, compared to 57% (8 of 14) for patients treated with hydroxychloroquine alone. However, that study had several important limitations, including the small sample size, variable viral loads at baseline between groups, and a lack of safety and clinical outcomes reporting, according to the investigators. Moreover, six patients in the hydroxychloroquine group were taken out of the analysis because of early treatment stoppage due to medical intolerance or critical illness, the authors noted.

One prospective study including 30 patients in China demonstrated no difference in virologic outcomes for patients randomized to hydroxychloroquine plus standard of care versus standard of care alone, they added. There is also a case series of more than 100 patients with COVID-19 that reportedly improved viral clearance and reduced disease progression, though they said results haven’t been published or presented beyond a news briefing in China.

Randomized, controlled trials of chloroquine and hydroxychloroquine for COVID-19 treatment are underway, and studies are planned or enrolling to look at chloroquine prophylaxis in health care personnel and hydroxychloroquine for postexposure prophylaxis, authors said.

In results from one of those randomized trials, just reported, a higher dose of chloroquine was associated with a cardiac adverse event and an increased mortality risk, leading to the closure of that study arm. In the parallel, double-blinded, phase IIb clinical trial, patients in Brazil with SARS-CoV-2 infection received low or high doses of chloroquine plus ceftriaxone and azithromycin. According to the preprint publication, a higher rate of heart rate–corrected QT interval (QTc) prolongation and a “trend toward higher lethality” was observed in the high-dose group, leading investigators to “strongly recommend” the higher dose be abandoned.

“No apparent benefit of chloroquine was seen regarding lethality in our patients so far, but we will still enroll patients in the low chloroquine dose group to complete the originally planned sample size,” said investigators of the study, which at the time of the report had enrolled 81 out of an anticipated 440 patients.
 

Other COVID-19 pharmacologic therapies under study

Treatments of note in the review included the following:

• Tocilizumab. This monoclonal antibody IL-6 receptor antagonist, approved by the FDA for treatment of rheumatoid arthritis and for cytokine release syndrome related to chimeric antigen receptor (CAR) T-cell therapy, has yielded success in small series of patients with severe cases of COVID-19, according to authors. In one 21-patient report, 91% had clinical improvement, usually after a single dose. In China, tocilizumab is included in COVID-19 treatment guidelines, and several randomized clinical trials are underway in China including patients with COVID-19 with severe pneumonia.
• Immunoglobulin therapy. Antibodies from recovered COVID-19 patients could help with free virus and infected cell immune clearance, the authors said, adding that further studies are warranted beyond a few small published case series that suggest promise. Furthermore, on March 24 the FDA released guidance for screening donors for COVID-19 convalescent plasma and on emergency investigational new drug applications based on this modality.

• Lopinavir/ritonavir. Despite demonstrated in vitro activity against other novel coronaviruses, there is no published in vitro data for lopinavir/ritonavir in SARS-CoV-2, and likely a “limited role” for this combination anticipated in treating COVID-19, according to the review authors. In an open-label randomized clinical trial published in the New England Journal of Medicine (2020 Mar 18. doi: 10.1056/NEJMoa2001282), there were no differences in clinical improvement, viral clearance, or mortality for antiviral treatment versus standard care. Delayed treatment initiation may explain the ineffectiveness, though a subgroup analysis didn’t show a shorter time to clinical improvement for those who got the treatment earlier.

• Ribavirin. Likewise, this antiviral medication has efficacy and safety data suggesting “limited value” for treatment of COVID-19. Treatment of SARS yielded “inconclusive results” for ribavirin, which was also associated with substantial toxicity that included hemolytic anemia in 60% of SARS patients.
• Oseltamivir. While it may treat influenza, it has no documented activity against SARS-CoV-2 in vitro: “This agent has no role in the management of COVID-19 once influenza has been excluded,” said Dr. Sanders and coauthors.
• Corticosteroids. They could decrease inflammatory responses in the lung, but they could also lead to delays in viral clearance and increases in secondary infection risk. Guidelines for COVID-19 say to avoid corticosteroids, and the authors of the review concur, saying that potential harms and lack of proven benefit mean they usually should not be used outside of a randomized clinical trial setting.
• Vaccines. Clearly, vaccines represent the “most effective long-term strategy” to prevent future COVID-19 outbreaks, though at least 12-18 months would be required until vaccines can be widely deployed, authors said.

Dr. Sanders reported no potential conflicts. Senior author James B. Cutrell, MD, also of the University of Texas Southwestern Medical Center, reported nonfinancial support from Gilead and Regeneron outside of the study. No other authors reported disclosures.

An early report pegged the prevalence of cancer among COVID-19 patients at 1%, but authors of a recent meta-analysis found an overall prevalence of 2% and up to 3% depending on the subset of data they reviewed.

However, those findings are limited by the retrospective nature of the studies published to date, according to the authors of the meta-analysis, led by Aakash Desai, MBBS, of the University of Connecticut, Farmington.

Nevertheless, the results do confirm that cancer patients and survivors are an important at-risk population for COVID-19, according to Dr. Desai and colleagues.

“We hope that additional data from China and Italy will provide information on the characteristics of patients with cancer at risk, types of cancer that confer higher risk, and systemic regimens that may increase COVID-19 infection complications,” the authors wrote in JCO Global Oncology.

More than 15 million individuals with cancer and many more cancer survivors are at increased risk of COVID-19 because of compromised immune systems, according to the authors.

Exactly how many individuals with cancer are among the COVID-19 cases remains unclear, though a previous report suggested the prevalence of cancer was 1% (95% confidence interval, 0.61%-1.65%) among COVID-19 patients in China (Lancet Oncol. 2020 Mar;21[3]:335-7). This “seems to be higher” than the 0.29% prevalence of cancer in the overall Chinese population, the investigators noted at the time.

That study revealed 18 cancer patients among 1,590 COVID-19 cases, though it was “hypothesis generating,” according to Dr. Desai and colleagues, who rolled that data into their meta-analysis of 11 reports including 3,661 COVID-19 cases.

Overall, Dr. Desai and colleagues found the pooled prevalence of cancer was 2.0% (95% CI, 2.0%-3.0%) in that population. In a subgroup analysis of five studies with sample sizes of less than 100 COVID-19 patients, the researchers found a “slightly higher” prevalence of 3.0% (95% CI, 1.0%-6.0%).

However, even that data wasn’t robust enough for Dr. Desai and colleagues to make any pronouncements on cancer prevalence. “Overall, current evidence on the association between cancer and COVID-19 remains inconclusive,” they wrote.

Though inconclusive, the findings raise questions about whether treatments or interventions might need to be postponed in certain patients, whether cancer patients and survivors need stronger personal protection, and how to deal with potential delays in cancer clinical trials, according to Dr. Desai and colleagues.

“As the evidence continues to rise, we must strive to answer the unanswered clinical questions,” the authors wrote.

Dr. Desai and colleagues reported no potential conflicts of interest related to the study.

SOURCE: Desai A et al. JCO Glob Oncol. 2020 Apr 6. doi: 10.1200/GO.20.00097.

An early report pegged the prevalence of cancer among COVID-19 patients at 1%, but authors of a recent meta-analysis found an overall prevalence of 2% and up to 3% depending on the subset of data they reviewed.

However, those findings are limited by the retrospective nature of the studies published to date, according to the authors of the meta-analysis, led by Aakash Desai, MBBS, of the University of Connecticut, Farmington.

Nevertheless, the results do confirm that cancer patients and survivors are an important at-risk population for COVID-19, according to Dr. Desai and colleagues.

“We hope that additional data from China and Italy will provide information on the characteristics of patients with cancer at risk, types of cancer that confer higher risk, and systemic regimens that may increase COVID-19 infection complications,” the authors wrote in JCO Global Oncology.

More than 15 million individuals with cancer and many more cancer survivors are at increased risk of COVID-19 because of compromised immune systems, according to the authors.

Exactly how many individuals with cancer are among the COVID-19 cases remains unclear, though a previous report suggested the prevalence of cancer was 1% (95% confidence interval, 0.61%-1.65%) among COVID-19 patients in China (Lancet Oncol. 2020 Mar;21[3]:335-7). This “seems to be higher” than the 0.29% prevalence of cancer in the overall Chinese population, the investigators noted at the time.

That study revealed 18 cancer patients among 1,590 COVID-19 cases, though it was “hypothesis generating,” according to Dr. Desai and colleagues, who rolled that data into their meta-analysis of 11 reports including 3,661 COVID-19 cases.

Overall, Dr. Desai and colleagues found the pooled prevalence of cancer was 2.0% (95% CI, 2.0%-3.0%) in that population. In a subgroup analysis of five studies with sample sizes of less than 100 COVID-19 patients, the researchers found a “slightly higher” prevalence of 3.0% (95% CI, 1.0%-6.0%).

However, even that data wasn’t robust enough for Dr. Desai and colleagues to make any pronouncements on cancer prevalence. “Overall, current evidence on the association between cancer and COVID-19 remains inconclusive,” they wrote.

Though inconclusive, the findings raise questions about whether treatments or interventions might need to be postponed in certain patients, whether cancer patients and survivors need stronger personal protection, and how to deal with potential delays in cancer clinical trials, according to Dr. Desai and colleagues.

“As the evidence continues to rise, we must strive to answer the unanswered clinical questions,” the authors wrote.

Dr. Desai and colleagues reported no potential conflicts of interest related to the study.

SOURCE: Desai A et al. JCO Glob Oncol. 2020 Apr 6. doi: 10.1200/GO.20.00097.

An early report pegged the prevalence of cancer among COVID-19 patients at 1%, but authors of a recent meta-analysis found an overall prevalence of 2% and up to 3% depending on the subset of data they reviewed.

However, those findings are limited by the retrospective nature of the studies published to date, according to the authors of the meta-analysis, led by Aakash Desai, MBBS, of the University of Connecticut, Farmington.

Nevertheless, the results do confirm that cancer patients and survivors are an important at-risk population for COVID-19, according to Dr. Desai and colleagues.

“We hope that additional data from China and Italy will provide information on the characteristics of patients with cancer at risk, types of cancer that confer higher risk, and systemic regimens that may increase COVID-19 infection complications,” the authors wrote in JCO Global Oncology.

More than 15 million individuals with cancer and many more cancer survivors are at increased risk of COVID-19 because of compromised immune systems, according to the authors.

Exactly how many individuals with cancer are among the COVID-19 cases remains unclear, though a previous report suggested the prevalence of cancer was 1% (95% confidence interval, 0.61%-1.65%) among COVID-19 patients in China (Lancet Oncol. 2020 Mar;21[3]:335-7). This “seems to be higher” than the 0.29% prevalence of cancer in the overall Chinese population, the investigators noted at the time.

That study revealed 18 cancer patients among 1,590 COVID-19 cases, though it was “hypothesis generating,” according to Dr. Desai and colleagues, who rolled that data into their meta-analysis of 11 reports including 3,661 COVID-19 cases.

Overall, Dr. Desai and colleagues found the pooled prevalence of cancer was 2.0% (95% CI, 2.0%-3.0%) in that population. In a subgroup analysis of five studies with sample sizes of less than 100 COVID-19 patients, the researchers found a “slightly higher” prevalence of 3.0% (95% CI, 1.0%-6.0%).

However, even that data wasn’t robust enough for Dr. Desai and colleagues to make any pronouncements on cancer prevalence. “Overall, current evidence on the association between cancer and COVID-19 remains inconclusive,” they wrote.

Though inconclusive, the findings raise questions about whether treatments or interventions might need to be postponed in certain patients, whether cancer patients and survivors need stronger personal protection, and how to deal with potential delays in cancer clinical trials, according to Dr. Desai and colleagues.

“As the evidence continues to rise, we must strive to answer the unanswered clinical questions,” the authors wrote.

Dr. Desai and colleagues reported no potential conflicts of interest related to the study.

SOURCE: Desai A et al. JCO Glob Oncol. 2020 Apr 6. doi: 10.1200/GO.20.00097.

While continuing trastuzumab after disease progression may provide clinical benefit in HER2-positive breast cancer, results of a phase 2 study failed to show the same in patients with HER2-positive gastric cancers.

Second-line treatment with paclitaxel plus trastuzumab didn’t improve progression-free survival, compared with paclitaxel alone, in the small, randomized study of patients with HER2-positive advanced gastric or gastroesophageal junction (GEJ) cancers who progressed on trastuzumab.

The failure of the paclitaxel/trastuzumab regimen in this study might be because of reduced HER2 positivity rather than acquired resistance to trastuzumab, according to the researchers, led by Akitaka Makiyama, MD, PhD, of Kyushu University Hospital in Fukuoka, Japan.

In any case, this approach of continuing trastuzumab beyond progression can’t be recommended as a standard of care, Dr. Makiyama and coauthors wrote in their report, which appears in the Journal of Clinical Oncology.

Drug development is meanwhile proceeding rapidly for several novel HER2-targeted treatments in this setting, the authors noted, including trastuzumab deruxtecan, an antibody-drug conjugate; ZW25, a bispecific antibody; and margetuximab, a chimeric monoclonal antibody with a modified Fc domain.

“We hope these new agents could confer survival benefit in HER2-positive gastric cancer by large-scale clinical trials comparing paclitaxel with ramucirumab as a standard arm,” the authors wrote, noting that paclitaxel with ramucirumab is considered a standard second-line regimen for advanced disease, regardless of HER2 status, based on analysis of the RAINBOW trial (Lancet Oncol. 2014 Oct;15[11]:1224-35).

The approval of novel therapies could be a significant advance for tumors in which HER2 is overexpressed or amplified, which represents about 10%-20% of gastric/GEJ cancers, according to Dr. Makiyama and coauthors.

In their phase 2 study, known as T-ACT (Trial to Assess the Concept of Using Trastuzumab Beyond Progression), Dr. Makiyama and colleagues included patients with HER2-positive advanced gastric or GEJ cancer that had progressed on a standard first-line chemotherapy regimen containing trastuzumab. Patients were enrolled at 52 centers in the West Japan Oncology Group.

A total of 91 patients were randomized to receive either paclitaxel at 80 mg/m² on days 1, 8, and 15 every 4 weeks or the same paclitaxel dose and schedule plus trastuzumab, given at an initial dose of 8 mg/kg and subsequently at 6 mg/kg every 3 weeks.

The median progression-free survival was 3.2 months in the paclitaxel arm and 3.7 months in the paclitaxel/trastuzumab arm (P = .33). The median overall survival was 10.0 months and 10.2 months, respectively (P = .20). Responses were seen in about a third of patients in each group, and adverse events were similar between arms.

In biomarker analyses of tumor tissue samples obtained after first-line treatment, only 5 of 16 patients (31%) maintained HER2 positivity. Of those five patients, two received paclitaxel plus trastuzumab, and one had long-term stable disease (9.4 months).

“Reevaluation of HER2 expression status would be essential, particularly for developing new generations of HER2-targeted therapeutic agents in patients treated with prior trastuzumab,” Dr. Makiyama and colleagues concluded.

Partial support for this study came from a Japan Society of Clinical Oncology grant program. The authors disclosed relationships with Chugai Pharma, Lilly, Takeda, and numerous other companies.

SOURCE: Makiyama A et al. J Clin Oncol. 2020 Mar 24. doi: 10.1200/JCO.19.03077.

While continuing trastuzumab after disease progression may provide clinical benefit in HER2-positive breast cancer, results of a phase 2 study failed to show the same in patients with HER2-positive gastric cancers.

Second-line treatment with paclitaxel plus trastuzumab didn’t improve progression-free survival, compared with paclitaxel alone, in the small, randomized study of patients with HER2-positive advanced gastric or gastroesophageal junction (GEJ) cancers who progressed on trastuzumab.

The failure of the paclitaxel/trastuzumab regimen in this study might be because of reduced HER2 positivity rather than acquired resistance to trastuzumab, according to the researchers, led by Akitaka Makiyama, MD, PhD, of Kyushu University Hospital in Fukuoka, Japan.

In any case, this approach of continuing trastuzumab beyond progression can’t be recommended as a standard of care, Dr. Makiyama and coauthors wrote in their report, which appears in the Journal of Clinical Oncology.

Drug development is meanwhile proceeding rapidly for several novel HER2-targeted treatments in this setting, the authors noted, including trastuzumab deruxtecan, an antibody-drug conjugate; ZW25, a bispecific antibody; and margetuximab, a chimeric monoclonal antibody with a modified Fc domain.

“We hope these new agents could confer survival benefit in HER2-positive gastric cancer by large-scale clinical trials comparing paclitaxel with ramucirumab as a standard arm,” the authors wrote, noting that paclitaxel with ramucirumab is considered a standard second-line regimen for advanced disease, regardless of HER2 status, based on analysis of the RAINBOW trial (Lancet Oncol. 2014 Oct;15[11]:1224-35).

The approval of novel therapies could be a significant advance for tumors in which HER2 is overexpressed or amplified, which represents about 10%-20% of gastric/GEJ cancers, according to Dr. Makiyama and coauthors.

In their phase 2 study, known as T-ACT (Trial to Assess the Concept of Using Trastuzumab Beyond Progression), Dr. Makiyama and colleagues included patients with HER2-positive advanced gastric or GEJ cancer that had progressed on a standard first-line chemotherapy regimen containing trastuzumab. Patients were enrolled at 52 centers in the West Japan Oncology Group.

A total of 91 patients were randomized to receive either paclitaxel at 80 mg/m² on days 1, 8, and 15 every 4 weeks or the same paclitaxel dose and schedule plus trastuzumab, given at an initial dose of 8 mg/kg and subsequently at 6 mg/kg every 3 weeks.

The median progression-free survival was 3.2 months in the paclitaxel arm and 3.7 months in the paclitaxel/trastuzumab arm (P = .33). The median overall survival was 10.0 months and 10.2 months, respectively (P = .20). Responses were seen in about a third of patients in each group, and adverse events were similar between arms.

In biomarker analyses of tumor tissue samples obtained after first-line treatment, only 5 of 16 patients (31%) maintained HER2 positivity. Of those five patients, two received paclitaxel plus trastuzumab, and one had long-term stable disease (9.4 months).

“Reevaluation of HER2 expression status would be essential, particularly for developing new generations of HER2-targeted therapeutic agents in patients treated with prior trastuzumab,” Dr. Makiyama and colleagues concluded.

Partial support for this study came from a Japan Society of Clinical Oncology grant program. The authors disclosed relationships with Chugai Pharma, Lilly, Takeda, and numerous other companies.

SOURCE: Makiyama A et al. J Clin Oncol. 2020 Mar 24. doi: 10.1200/JCO.19.03077.

While continuing trastuzumab after disease progression may provide clinical benefit in HER2-positive breast cancer, results of a phase 2 study failed to show the same in patients with HER2-positive gastric cancers.

Second-line treatment with paclitaxel plus trastuzumab didn’t improve progression-free survival, compared with paclitaxel alone, in the small, randomized study of patients with HER2-positive advanced gastric or gastroesophageal junction (GEJ) cancers who progressed on trastuzumab.

The failure of the paclitaxel/trastuzumab regimen in this study might be because of reduced HER2 positivity rather than acquired resistance to trastuzumab, according to the researchers, led by Akitaka Makiyama, MD, PhD, of Kyushu University Hospital in Fukuoka, Japan.

In any case, this approach of continuing trastuzumab beyond progression can’t be recommended as a standard of care, Dr. Makiyama and coauthors wrote in their report, which appears in the Journal of Clinical Oncology.

Drug development is meanwhile proceeding rapidly for several novel HER2-targeted treatments in this setting, the authors noted, including trastuzumab deruxtecan, an antibody-drug conjugate; ZW25, a bispecific antibody; and margetuximab, a chimeric monoclonal antibody with a modified Fc domain.

“We hope these new agents could confer survival benefit in HER2-positive gastric cancer by large-scale clinical trials comparing paclitaxel with ramucirumab as a standard arm,” the authors wrote, noting that paclitaxel with ramucirumab is considered a standard second-line regimen for advanced disease, regardless of HER2 status, based on analysis of the RAINBOW trial (Lancet Oncol. 2014 Oct;15[11]:1224-35).

The approval of novel therapies could be a significant advance for tumors in which HER2 is overexpressed or amplified, which represents about 10%-20% of gastric/GEJ cancers, according to Dr. Makiyama and coauthors.

In their phase 2 study, known as T-ACT (Trial to Assess the Concept of Using Trastuzumab Beyond Progression), Dr. Makiyama and colleagues included patients with HER2-positive advanced gastric or GEJ cancer that had progressed on a standard first-line chemotherapy regimen containing trastuzumab. Patients were enrolled at 52 centers in the West Japan Oncology Group.

A total of 91 patients were randomized to receive either paclitaxel at 80 mg/m² on days 1, 8, and 15 every 4 weeks or the same paclitaxel dose and schedule plus trastuzumab, given at an initial dose of 8 mg/kg and subsequently at 6 mg/kg every 3 weeks.

The median progression-free survival was 3.2 months in the paclitaxel arm and 3.7 months in the paclitaxel/trastuzumab arm (P = .33). The median overall survival was 10.0 months and 10.2 months, respectively (P = .20). Responses were seen in about a third of patients in each group, and adverse events were similar between arms.

In biomarker analyses of tumor tissue samples obtained after first-line treatment, only 5 of 16 patients (31%) maintained HER2 positivity. Of those five patients, two received paclitaxel plus trastuzumab, and one had long-term stable disease (9.4 months).

“Reevaluation of HER2 expression status would be essential, particularly for developing new generations of HER2-targeted therapeutic agents in patients treated with prior trastuzumab,” Dr. Makiyama and colleagues concluded.

Partial support for this study came from a Japan Society of Clinical Oncology grant program. The authors disclosed relationships with Chugai Pharma, Lilly, Takeda, and numerous other companies.

SOURCE: Makiyama A et al. J Clin Oncol. 2020 Mar 24. doi: 10.1200/JCO.19.03077.

Asthma and chronic obstructive pulmonary disease were both linked to an increased risk of rheumatoid arthritis in a recent large, prospective cohort study, researchers have reported, which adds to a growing body of evidence that airway inflammation is implicated in the development of this disease.

RA risk was increased by about 50% among asthma patients, even when excluding those who had ever smoked, according to the study’s results, which were based on more than 200,000 women in the Nurses’ Health Study I and II.

Risk of RA nearly doubled among those with chronic obstructive pulmonary disease (COPD), with an even stronger association seen in older ever-smokers, according to authors of the study.

The findings not only strengthen the case for the potential role of obstructive lung diseases in RA development, according to the study’s authors, but also suggest that health care providers need to lower the bar for evaluation of patients with lung diseases and inflammatory joint symptoms.

“If these patients develop arthralgias, then the clinicians taking care of them should have a low threshold to consider RA, and perhaps refer, or check these patients with a diagnostic test for RA,” said researcher Jeffrey A. Sparks, MD, of Brigham and Women’s Hospital and Harvard Medical School in Boston.

What’s perhaps not as clear now is whether screening obstructive lung disease patients in the absence of early RA signs would be warranted: “I don’t know if we’re quite at the point where we would need to screen these patients if they’re not symptomatic,” Dr. Sparks said in an interview.

The study by Dr. Sparks and colleagues is, by far, not the first study to implicate asthma or other lung conditions in RA development. However, most previous studies are retrospective, and interpretation of the findings has been subject to limitations such as inadequate power to detect an increased risk or lack of adjustment for important confounding factors, such as smoking.

As such, the study by Dr. Sparks and colleagues is believed to be the first-ever prospective study to evaluate asthma and COPD as risk factors for RA, study authors reported in Arthritis & Rheumatology.

Researchers were able to identify 1,060 incident RA cases that developed in 15,148 women with asthma and 3,573 with COPD in the study with more than 4 million person-years of follow-up.

The association between asthma and increased RA risk was seen not only for the asthma population as a whole (hazard ratio, 1.53; 95% confidence interval, 1.24-1.88), but also for the subset of women who had never smoked, to a similar degree (HR, 1.53; 95% CI, 1.14-2.05), the report shows.

COPD’s association with RA risk was apparent overall (HR, 1.89; 95% CI, 1.31-2.75) and even more so in the subgroup of ever-smokers 55 years of age and older (HR, 2.20; 95% CI, 1.38-3.51), the data further show.

Findings of studies looking at the inflammation of airways and other mucosal sites are “critically important to understand” when it comes to trying to prevent RA, said Kevin Deane, MD, of the University of Colorado at Denver at Aurora.

“If we indeed are trying to prevent rheumatoid arthritis in terms of the joint disease, we may need to look at these mucosal sites in individuals who don’t yet have joint disease as potential sites to target for prevention, or at least areas to study to understand how prevention may work,” said Dr. Deane, principal investigator on the National Institutes of Health–funded Strategy for the Prevention of RA (StopRA) trial.

With that in mind, it’s conceivable targeting a lung process might prevent joint disease in a patient with asthma or airway inflammation and blood markers that indicate a risk of RA, Dr. Deane said in an interview.

Blood markers of RA have been evaluated in some recent studies, with findings that provide further evidence of a link between lung diseases and RA, and vice versa.

In particular, anti–citrullinated protein antibodies (ACPA) are clearly central to RA pathogenesis. And while asthma is increasingly linked to RA risk, there have been relatively little data on any potential links between ACPA and asthma.

That research gap led to a case-control study of the Nurses’ Health Study I and II (on which Dr. Sparks was senior author) showing that asthma was strongly linked to elevated ACPA in blood drawn from patients prior to a diagnosis of RA.

Results, published last year in Arthritis Research & Therapy, showed a significant association between asthma and pre-RA ACPA elevation (odds ratio, 3.57; 95% CI, 1.58-8.04), after adjustment for smoking and other potentially confounding factors. Investigators said the findings provided evidence that chronic mucosal airway inflammation is a factor in the development of ACPA and in the pathogenesis of RA.

In a follow-up study published more recently in Arthritis Care & Research, investigators showed that, among women in the Nurses Health Study I and II, pre-RA ACPA elevation was linked to increased risk of COPD, compared with controls (HR, 3.04; 95% CI, 1.33-7.00), while the risk for development of asthma was similar in women with or without elevated pre-RA ACPA.

That study was in part an attempt to establish a “timeline” related to antibodies, lung diseases, and RA onset, Dr. Sparks said in the interview.

“We think that probably the asthma is more important in developing the antibody, but that once you have the antibody, if you didn’t have asthma by then, you’re unlikely to develop it,” he said. “So asthma seems to be something that could happen before the antibody production, whereas COPD seems to happen after – but ACPA seems to be the common link in both of these obstructive lung diseases.”

The study in Arthritis & Rheumatology linking asthma and COPD to risk of incident RA was supported by the National Institutes of Health. Dr. Sparks reported grant support from Amgen and Bristol Myers Squibb and consulting fees from Inova and Optum. Coauthors provided disclosures related to GlaxoSmithKline, AstraZeneca, Merck, Neutrolis, and Genentech.

SOURCE: Ford JA et al. Arthritis Rheumatol. 2020 Mar 4. doi: 10.1002/art.41194.

Asthma and chronic obstructive pulmonary disease were both linked to an increased risk of rheumatoid arthritis in a recent large, prospective cohort study, researchers have reported, which adds to a growing body of evidence that airway inflammation is implicated in the development of this disease.

RA risk was increased by about 50% among asthma patients, even when excluding those who had ever smoked, according to the study’s results, which were based on more than 200,000 women in the Nurses’ Health Study I and II.

Risk of RA nearly doubled among those with chronic obstructive pulmonary disease (COPD), with an even stronger association seen in older ever-smokers, according to authors of the study.

The findings not only strengthen the case for the potential role of obstructive lung diseases in RA development, according to the study’s authors, but also suggest that health care providers need to lower the bar for evaluation of patients with lung diseases and inflammatory joint symptoms.

“If these patients develop arthralgias, then the clinicians taking care of them should have a low threshold to consider RA, and perhaps refer, or check these patients with a diagnostic test for RA,” said researcher Jeffrey A. Sparks, MD, of Brigham and Women’s Hospital and Harvard Medical School in Boston.

What’s perhaps not as clear now is whether screening obstructive lung disease patients in the absence of early RA signs would be warranted: “I don’t know if we’re quite at the point where we would need to screen these patients if they’re not symptomatic,” Dr. Sparks said in an interview.

The study by Dr. Sparks and colleagues is, by far, not the first study to implicate asthma or other lung conditions in RA development. However, most previous studies are retrospective, and interpretation of the findings has been subject to limitations such as inadequate power to detect an increased risk or lack of adjustment for important confounding factors, such as smoking.

As such, the study by Dr. Sparks and colleagues is believed to be the first-ever prospective study to evaluate asthma and COPD as risk factors for RA, study authors reported in Arthritis & Rheumatology.

Researchers were able to identify 1,060 incident RA cases that developed in 15,148 women with asthma and 3,573 with COPD in the study with more than 4 million person-years of follow-up.

The association between asthma and increased RA risk was seen not only for the asthma population as a whole (hazard ratio, 1.53; 95% confidence interval, 1.24-1.88), but also for the subset of women who had never smoked, to a similar degree (HR, 1.53; 95% CI, 1.14-2.05), the report shows.

COPD’s association with RA risk was apparent overall (HR, 1.89; 95% CI, 1.31-2.75) and even more so in the subgroup of ever-smokers 55 years of age and older (HR, 2.20; 95% CI, 1.38-3.51), the data further show.

Findings of studies looking at the inflammation of airways and other mucosal sites are “critically important to understand” when it comes to trying to prevent RA, said Kevin Deane, MD, of the University of Colorado at Denver at Aurora.

“If we indeed are trying to prevent rheumatoid arthritis in terms of the joint disease, we may need to look at these mucosal sites in individuals who don’t yet have joint disease as potential sites to target for prevention, or at least areas to study to understand how prevention may work,” said Dr. Deane, principal investigator on the National Institutes of Health–funded Strategy for the Prevention of RA (StopRA) trial.

With that in mind, it’s conceivable targeting a lung process might prevent joint disease in a patient with asthma or airway inflammation and blood markers that indicate a risk of RA, Dr. Deane said in an interview.

Blood markers of RA have been evaluated in some recent studies, with findings that provide further evidence of a link between lung diseases and RA, and vice versa.

In particular, anti–citrullinated protein antibodies (ACPA) are clearly central to RA pathogenesis. And while asthma is increasingly linked to RA risk, there have been relatively little data on any potential links between ACPA and asthma.

That research gap led to a case-control study of the Nurses’ Health Study I and II (on which Dr. Sparks was senior author) showing that asthma was strongly linked to elevated ACPA in blood drawn from patients prior to a diagnosis of RA.

Results, published last year in Arthritis Research & Therapy, showed a significant association between asthma and pre-RA ACPA elevation (odds ratio, 3.57; 95% CI, 1.58-8.04), after adjustment for smoking and other potentially confounding factors. Investigators said the findings provided evidence that chronic mucosal airway inflammation is a factor in the development of ACPA and in the pathogenesis of RA.

In a follow-up study published more recently in Arthritis Care & Research, investigators showed that, among women in the Nurses Health Study I and II, pre-RA ACPA elevation was linked to increased risk of COPD, compared with controls (HR, 3.04; 95% CI, 1.33-7.00), while the risk for development of asthma was similar in women with or without elevated pre-RA ACPA.

That study was in part an attempt to establish a “timeline” related to antibodies, lung diseases, and RA onset, Dr. Sparks said in the interview.

“We think that probably the asthma is more important in developing the antibody, but that once you have the antibody, if you didn’t have asthma by then, you’re unlikely to develop it,” he said. “So asthma seems to be something that could happen before the antibody production, whereas COPD seems to happen after – but ACPA seems to be the common link in both of these obstructive lung diseases.”

The study in Arthritis & Rheumatology linking asthma and COPD to risk of incident RA was supported by the National Institutes of Health. Dr. Sparks reported grant support from Amgen and Bristol Myers Squibb and consulting fees from Inova and Optum. Coauthors provided disclosures related to GlaxoSmithKline, AstraZeneca, Merck, Neutrolis, and Genentech.

SOURCE: Ford JA et al. Arthritis Rheumatol. 2020 Mar 4. doi: 10.1002/art.41194.

Asthma and chronic obstructive pulmonary disease were both linked to an increased risk of rheumatoid arthritis in a recent large, prospective cohort study, researchers have reported, which adds to a growing body of evidence that airway inflammation is implicated in the development of this disease.

RA risk was increased by about 50% among asthma patients, even when excluding those who had ever smoked, according to the study’s results, which were based on more than 200,000 women in the Nurses’ Health Study I and II.

Risk of RA nearly doubled among those with chronic obstructive pulmonary disease (COPD), with an even stronger association seen in older ever-smokers, according to authors of the study.

The findings not only strengthen the case for the potential role of obstructive lung diseases in RA development, according to the study’s authors, but also suggest that health care providers need to lower the bar for evaluation of patients with lung diseases and inflammatory joint symptoms.

“If these patients develop arthralgias, then the clinicians taking care of them should have a low threshold to consider RA, and perhaps refer, or check these patients with a diagnostic test for RA,” said researcher Jeffrey A. Sparks, MD, of Brigham and Women’s Hospital and Harvard Medical School in Boston.

What’s perhaps not as clear now is whether screening obstructive lung disease patients in the absence of early RA signs would be warranted: “I don’t know if we’re quite at the point where we would need to screen these patients if they’re not symptomatic,” Dr. Sparks said in an interview.

The study by Dr. Sparks and colleagues is, by far, not the first study to implicate asthma or other lung conditions in RA development. However, most previous studies are retrospective, and interpretation of the findings has been subject to limitations such as inadequate power to detect an increased risk or lack of adjustment for important confounding factors, such as smoking.

As such, the study by Dr. Sparks and colleagues is believed to be the first-ever prospective study to evaluate asthma and COPD as risk factors for RA, study authors reported in Arthritis & Rheumatology.

Researchers were able to identify 1,060 incident RA cases that developed in 15,148 women with asthma and 3,573 with COPD in the study with more than 4 million person-years of follow-up.

The association between asthma and increased RA risk was seen not only for the asthma population as a whole (hazard ratio, 1.53; 95% confidence interval, 1.24-1.88), but also for the subset of women who had never smoked, to a similar degree (HR, 1.53; 95% CI, 1.14-2.05), the report shows.

COPD’s association with RA risk was apparent overall (HR, 1.89; 95% CI, 1.31-2.75) and even more so in the subgroup of ever-smokers 55 years of age and older (HR, 2.20; 95% CI, 1.38-3.51), the data further show.

Findings of studies looking at the inflammation of airways and other mucosal sites are “critically important to understand” when it comes to trying to prevent RA, said Kevin Deane, MD, of the University of Colorado at Denver at Aurora.

“If we indeed are trying to prevent rheumatoid arthritis in terms of the joint disease, we may need to look at these mucosal sites in individuals who don’t yet have joint disease as potential sites to target for prevention, or at least areas to study to understand how prevention may work,” said Dr. Deane, principal investigator on the National Institutes of Health–funded Strategy for the Prevention of RA (StopRA) trial.

With that in mind, it’s conceivable targeting a lung process might prevent joint disease in a patient with asthma or airway inflammation and blood markers that indicate a risk of RA, Dr. Deane said in an interview.

Blood markers of RA have been evaluated in some recent studies, with findings that provide further evidence of a link between lung diseases and RA, and vice versa.

In particular, anti–citrullinated protein antibodies (ACPA) are clearly central to RA pathogenesis. And while asthma is increasingly linked to RA risk, there have been relatively little data on any potential links between ACPA and asthma.

That research gap led to a case-control study of the Nurses’ Health Study I and II (on which Dr. Sparks was senior author) showing that asthma was strongly linked to elevated ACPA in blood drawn from patients prior to a diagnosis of RA.

Results, published last year in Arthritis Research & Therapy, showed a significant association between asthma and pre-RA ACPA elevation (odds ratio, 3.57; 95% CI, 1.58-8.04), after adjustment for smoking and other potentially confounding factors. Investigators said the findings provided evidence that chronic mucosal airway inflammation is a factor in the development of ACPA and in the pathogenesis of RA.

In a follow-up study published more recently in Arthritis Care & Research, investigators showed that, among women in the Nurses Health Study I and II, pre-RA ACPA elevation was linked to increased risk of COPD, compared with controls (HR, 3.04; 95% CI, 1.33-7.00), while the risk for development of asthma was similar in women with or without elevated pre-RA ACPA.

That study was in part an attempt to establish a “timeline” related to antibodies, lung diseases, and RA onset, Dr. Sparks said in the interview.

“We think that probably the asthma is more important in developing the antibody, but that once you have the antibody, if you didn’t have asthma by then, you’re unlikely to develop it,” he said. “So asthma seems to be something that could happen before the antibody production, whereas COPD seems to happen after – but ACPA seems to be the common link in both of these obstructive lung diseases.”

The study in Arthritis & Rheumatology linking asthma and COPD to risk of incident RA was supported by the National Institutes of Health. Dr. Sparks reported grant support from Amgen and Bristol Myers Squibb and consulting fees from Inova and Optum. Coauthors provided disclosures related to GlaxoSmithKline, AstraZeneca, Merck, Neutrolis, and Genentech.

SOURCE: Ford JA et al. Arthritis Rheumatol. 2020 Mar 4. doi: 10.1002/art.41194.

Newly updated guidance on treating patients with the novel coronavirus (COVID-19) has been published by the World Health Organization.

While it can’t replace clinical judgment or specialist consultation, the new guidance may help strengthen the clinical management of patients when COVID-19 is suspected, according to its authors.

The guidance, adapted from an earlier edition focused on the management of suspected Middle East respiratory syndrome coronavirus (MERS-CoV), covers best practices for triage, infection prevention and control, and optimized supportive care for mild, severe, or critical coronavirus disease 2019 (COVID-19).

“This guidance should serve as a foundation for optimized supportive care to ensure the best possible chance for survival,” the authors wrote in the guidance.

Newly updated guidance on treating patients with the novel coronavirus (COVID-19) has been published by the World Health Organization.

While it can’t replace clinical judgment or specialist consultation, the new guidance may help strengthen the clinical management of patients when COVID-19 is suspected, according to its authors.

The guidance, adapted from an earlier edition focused on the management of suspected Middle East respiratory syndrome coronavirus (MERS-CoV), covers best practices for triage, infection prevention and control, and optimized supportive care for mild, severe, or critical coronavirus disease 2019 (COVID-19).

“This guidance should serve as a foundation for optimized supportive care to ensure the best possible chance for survival,” the authors wrote in the guidance.

Newly updated guidance on treating patients with the novel coronavirus (COVID-19) has been published by the World Health Organization.

While it can’t replace clinical judgment or specialist consultation, the new guidance may help strengthen the clinical management of patients when COVID-19 is suspected, according to its authors.

The guidance, adapted from an earlier edition focused on the management of suspected Middle East respiratory syndrome coronavirus (MERS-CoV), covers best practices for triage, infection prevention and control, and optimized supportive care for mild, severe, or critical coronavirus disease 2019 (COVID-19).

“This guidance should serve as a foundation for optimized supportive care to ensure the best possible chance for survival,” the authors wrote in the guidance.

For patients undergoing transcatheter aortic valve replacement, using a specific orientation at deployment may optimize valve alignment and potentially preserve coronary access, at least for some devices, results of a pilot imaging study suggest.

In particular, positioning the Evolut THV (Medtronic) at a certain way at deployment led to an improvement in commissural alignment and a significant reduction in coronary artery overlap, according to authors of the study, led by Gilbert H. L. Tang, MD, MSc, MBA, surgical director of the structural heart program at Mount Sinai Health System, and associate professor of cardiovascular surgery, Mount Sinai Medical Center, New York.

Likewise, a specific positioning of the commissural post at deployment appeared to improve alignment and reduce coronary overlap when using the ACURATE-neo (Boston Scientific), though results with this transcatheter heart valve need to be considered preliminary because of the smaller number of cases, Dr. Tang said in an interview.

By contrast, initial deployment orientation of the SAPIEN 3 (Edwards Lifesciences) did not seem to have an impact on final orientation or neocommissural overlap with arteries in this study by Dr. Tang and colleagues, which was published in JACC: Cardiovascular Interventions and had been planned for presentation at the joint scientific sessions of the American College of Cardiology and the World Heart Federation. ACC organizers chose to present parts of the meeting virtually after COVID-19 concerns caused them to cancel the meeting.

Improved positioning may have important future implications for patients undergoing transcatheter aortic valve replacement (TAVR), particularly if they are younger and therefore perhaps more likely than older patients to undergo a procedure requiring coronary access at some point in the future, according to Dr. Tang.

“Right now, device design does not permit us to have consistent commissural alignment,” said Dr. Tang in the interview. “What this study shows is that, with modification of delivery catheter insertion technique, at least for the EVOLUT valve, we can improve commissural alignment and hypothetically speaking, improve the likelihood of coronary access.”

While the technique modifications described by Dr. Tang and colleagues are commendable, the overall impact on commissural alignment and coronary overlap are “modest” and do not solve the problem, according to Hasan Jilaihawi, MD, associate professor of medicine and cardiothoracic surgery at NYU Langone Health, New York.

Instead, the onus should be on the device manufacturers to develop solutions that allow for better alignment between their devices and patients’ commissures, said Dr. Jilaihawi.

“We need really industry to focus wholeheartedly on this,” Dr. Jilaihawi said in an interview. “I think they will, and there will be some discussions about focusing on [commissural alignment], but I think it’s coming really very late.”

Dr. Tang agreed on the need for increased focus on achieving commissural alignment. Of note, he said, there are newer transcatheter heart valves under study that may be more likely to achieve alignment and reduce the possibility of severe coronary overlap, including the JenaValve (JenaValve Technology) and the J-Valve (JC Medical).

“We hope that manufacturers can design valves that would improve commissural alignment for these patients, so that in 10 or even 20 years’ time, when these patients require reintervention, we won’t have to do surgery because the valves are not aligned,” said Dr. Tang. “Ideally, we might have to do one surgical intervention in their lifetime, but really what we are talking about now is the lifetime management of these patients as the coronary artery disease progresses, and also the aortic valve disease returns with the prosthetic valve.”

The pilot imaging study by Dr. Tang and colleagues included a total of 828 patients undergoing TAVR, including 483 treated with SAPIEN 3, 245 with Evolut, and 100 with ACURATE-neo.

To track deployment orientation, the SAPIEN 3 cases had a commissure crimped at 3, 6, 9, or 12 o’clock orientation relative to the delivery catheter. However, crimping orientation at initial deployment did not appear to have an impact on the final orientation, with overall incidence of severe coronary overlap of 36.6% for the left main coronary artery (LMCA), 23.6% for the right coronary artery (RCA), and 51.3% for one or both, according to the report.

For 107 cases treated with Evolut, the investigators sought to have a marker on the device (known as the “hat” marker) oriented to the outer curve of the descending aorta; to do that, they inserted the delivery catheter with the flush port at the 3 o’clock position. Those cases with the hat marker at the outer curve or the center front had improved commissural alignment as compared to those with the hat at the inner curve or center back, according to investigators. The incidence of coronary overlap with the LMCA was 15.7% for those with the hat at the outer curve or center front, compared to 66.0% for those with the hat at the inner curve or center back (P < .001), and the differences in coronary overlap were likewise significantly different in favor of the outer curve/center front for the RCA or both coronaries.

Finally, the incidence of coronary overlap with the ACURATE-neo was much lower when the commissural post at initial deployment was at the center back or inner curve, and in a few cases where the operators tried to torque the delivery catheter to position the commissural post to the inner curve, commissural alignment was achieved in about three-quarters of the patients (five of seven cases).

This is believed to be the first study to systematically characterize how the initial orientation of different transcatheter heart valves impact commissural alignment and coronary overlap, according to Dr. Tang and coinvestigators.

Dr. Jilaihawi, who was not involved in the study, said the investigators studied this phenomenon in a “very detailed, methodical fashion,” but emphasized the need for new device innovations to improve alignment and overlap.

“Their efforts weren’t completely in vain, but they really made a small difference in something that is too important to be [addressed] in a kind of ‘MacGyver’ approach to this problem,” he said in the interview.

Disclosures reported by Dr. Tang were related to Edwards Lifesciences (physician proctor) and Medtronic (physician proctor, consultant). Coauthors reported disclosures related to Edwards, Medtronic, and Boston Scientific, among others.

SOURCE: ACC 20. Tang GHL et al. JACC Cardiovasc Interv. 2020 Mar 16. doi: 10.1016/j.jcin.2020.02.005.

For patients undergoing transcatheter aortic valve replacement, using a specific orientation at deployment may optimize valve alignment and potentially preserve coronary access, at least for some devices, results of a pilot imaging study suggest.

In particular, positioning the Evolut THV (Medtronic) at a certain way at deployment led to an improvement in commissural alignment and a significant reduction in coronary artery overlap, according to authors of the study, led by Gilbert H. L. Tang, MD, MSc, MBA, surgical director of the structural heart program at Mount Sinai Health System, and associate professor of cardiovascular surgery, Mount Sinai Medical Center, New York.

Likewise, a specific positioning of the commissural post at deployment appeared to improve alignment and reduce coronary overlap when using the ACURATE-neo (Boston Scientific), though results with this transcatheter heart valve need to be considered preliminary because of the smaller number of cases, Dr. Tang said in an interview.

By contrast, initial deployment orientation of the SAPIEN 3 (Edwards Lifesciences) did not seem to have an impact on final orientation or neocommissural overlap with arteries in this study by Dr. Tang and colleagues, which was published in JACC: Cardiovascular Interventions and had been planned for presentation at the joint scientific sessions of the American College of Cardiology and the World Heart Federation. ACC organizers chose to present parts of the meeting virtually after COVID-19 concerns caused them to cancel the meeting.

Improved positioning may have important future implications for patients undergoing transcatheter aortic valve replacement (TAVR), particularly if they are younger and therefore perhaps more likely than older patients to undergo a procedure requiring coronary access at some point in the future, according to Dr. Tang.

“Right now, device design does not permit us to have consistent commissural alignment,” said Dr. Tang in the interview. “What this study shows is that, with modification of delivery catheter insertion technique, at least for the EVOLUT valve, we can improve commissural alignment and hypothetically speaking, improve the likelihood of coronary access.”

While the technique modifications described by Dr. Tang and colleagues are commendable, the overall impact on commissural alignment and coronary overlap are “modest” and do not solve the problem, according to Hasan Jilaihawi, MD, associate professor of medicine and cardiothoracic surgery at NYU Langone Health, New York.

Instead, the onus should be on the device manufacturers to develop solutions that allow for better alignment between their devices and patients’ commissures, said Dr. Jilaihawi.

“We need really industry to focus wholeheartedly on this,” Dr. Jilaihawi said in an interview. “I think they will, and there will be some discussions about focusing on [commissural alignment], but I think it’s coming really very late.”

Dr. Tang agreed on the need for increased focus on achieving commissural alignment. Of note, he said, there are newer transcatheter heart valves under study that may be more likely to achieve alignment and reduce the possibility of severe coronary overlap, including the JenaValve (JenaValve Technology) and the J-Valve (JC Medical).

“We hope that manufacturers can design valves that would improve commissural alignment for these patients, so that in 10 or even 20 years’ time, when these patients require reintervention, we won’t have to do surgery because the valves are not aligned,” said Dr. Tang. “Ideally, we might have to do one surgical intervention in their lifetime, but really what we are talking about now is the lifetime management of these patients as the coronary artery disease progresses, and also the aortic valve disease returns with the prosthetic valve.”

The pilot imaging study by Dr. Tang and colleagues included a total of 828 patients undergoing TAVR, including 483 treated with SAPIEN 3, 245 with Evolut, and 100 with ACURATE-neo.

To track deployment orientation, the SAPIEN 3 cases had a commissure crimped at 3, 6, 9, or 12 o’clock orientation relative to the delivery catheter. However, crimping orientation at initial deployment did not appear to have an impact on the final orientation, with overall incidence of severe coronary overlap of 36.6% for the left main coronary artery (LMCA), 23.6% for the right coronary artery (RCA), and 51.3% for one or both, according to the report.

For 107 cases treated with Evolut, the investigators sought to have a marker on the device (known as the “hat” marker) oriented to the outer curve of the descending aorta; to do that, they inserted the delivery catheter with the flush port at the 3 o’clock position. Those cases with the hat marker at the outer curve or the center front had improved commissural alignment as compared to those with the hat at the inner curve or center back, according to investigators. The incidence of coronary overlap with the LMCA was 15.7% for those with the hat at the outer curve or center front, compared to 66.0% for those with the hat at the inner curve or center back (P < .001), and the differences in coronary overlap were likewise significantly different in favor of the outer curve/center front for the RCA or both coronaries.

Finally, the incidence of coronary overlap with the ACURATE-neo was much lower when the commissural post at initial deployment was at the center back or inner curve, and in a few cases where the operators tried to torque the delivery catheter to position the commissural post to the inner curve, commissural alignment was achieved in about three-quarters of the patients (five of seven cases).

This is believed to be the first study to systematically characterize how the initial orientation of different transcatheter heart valves impact commissural alignment and coronary overlap, according to Dr. Tang and coinvestigators.

Dr. Jilaihawi, who was not involved in the study, said the investigators studied this phenomenon in a “very detailed, methodical fashion,” but emphasized the need for new device innovations to improve alignment and overlap.

“Their efforts weren’t completely in vain, but they really made a small difference in something that is too important to be [addressed] in a kind of ‘MacGyver’ approach to this problem,” he said in the interview.

Disclosures reported by Dr. Tang were related to Edwards Lifesciences (physician proctor) and Medtronic (physician proctor, consultant). Coauthors reported disclosures related to Edwards, Medtronic, and Boston Scientific, among others.

SOURCE: ACC 20. Tang GHL et al. JACC Cardiovasc Interv. 2020 Mar 16. doi: 10.1016/j.jcin.2020.02.005.

For patients undergoing transcatheter aortic valve replacement, using a specific orientation at deployment may optimize valve alignment and potentially preserve coronary access, at least for some devices, results of a pilot imaging study suggest.

In particular, positioning the Evolut THV (Medtronic) at a certain way at deployment led to an improvement in commissural alignment and a significant reduction in coronary artery overlap, according to authors of the study, led by Gilbert H. L. Tang, MD, MSc, MBA, surgical director of the structural heart program at Mount Sinai Health System, and associate professor of cardiovascular surgery, Mount Sinai Medical Center, New York.

Likewise, a specific positioning of the commissural post at deployment appeared to improve alignment and reduce coronary overlap when using the ACURATE-neo (Boston Scientific), though results with this transcatheter heart valve need to be considered preliminary because of the smaller number of cases, Dr. Tang said in an interview.

By contrast, initial deployment orientation of the SAPIEN 3 (Edwards Lifesciences) did not seem to have an impact on final orientation or neocommissural overlap with arteries in this study by Dr. Tang and colleagues, which was published in JACC: Cardiovascular Interventions and had been planned for presentation at the joint scientific sessions of the American College of Cardiology and the World Heart Federation. ACC organizers chose to present parts of the meeting virtually after COVID-19 concerns caused them to cancel the meeting.

Improved positioning may have important future implications for patients undergoing transcatheter aortic valve replacement (TAVR), particularly if they are younger and therefore perhaps more likely than older patients to undergo a procedure requiring coronary access at some point in the future, according to Dr. Tang.

“Right now, device design does not permit us to have consistent commissural alignment,” said Dr. Tang in the interview. “What this study shows is that, with modification of delivery catheter insertion technique, at least for the EVOLUT valve, we can improve commissural alignment and hypothetically speaking, improve the likelihood of coronary access.”

While the technique modifications described by Dr. Tang and colleagues are commendable, the overall impact on commissural alignment and coronary overlap are “modest” and do not solve the problem, according to Hasan Jilaihawi, MD, associate professor of medicine and cardiothoracic surgery at NYU Langone Health, New York.

Instead, the onus should be on the device manufacturers to develop solutions that allow for better alignment between their devices and patients’ commissures, said Dr. Jilaihawi.

“We need really industry to focus wholeheartedly on this,” Dr. Jilaihawi said in an interview. “I think they will, and there will be some discussions about focusing on [commissural alignment], but I think it’s coming really very late.”

Dr. Tang agreed on the need for increased focus on achieving commissural alignment. Of note, he said, there are newer transcatheter heart valves under study that may be more likely to achieve alignment and reduce the possibility of severe coronary overlap, including the JenaValve (JenaValve Technology) and the J-Valve (JC Medical).

“We hope that manufacturers can design valves that would improve commissural alignment for these patients, so that in 10 or even 20 years’ time, when these patients require reintervention, we won’t have to do surgery because the valves are not aligned,” said Dr. Tang. “Ideally, we might have to do one surgical intervention in their lifetime, but really what we are talking about now is the lifetime management of these patients as the coronary artery disease progresses, and also the aortic valve disease returns with the prosthetic valve.”

The pilot imaging study by Dr. Tang and colleagues included a total of 828 patients undergoing TAVR, including 483 treated with SAPIEN 3, 245 with Evolut, and 100 with ACURATE-neo.

To track deployment orientation, the SAPIEN 3 cases had a commissure crimped at 3, 6, 9, or 12 o’clock orientation relative to the delivery catheter. However, crimping orientation at initial deployment did not appear to have an impact on the final orientation, with overall incidence of severe coronary overlap of 36.6% for the left main coronary artery (LMCA), 23.6% for the right coronary artery (RCA), and 51.3% for one or both, according to the report.

For 107 cases treated with Evolut, the investigators sought to have a marker on the device (known as the “hat” marker) oriented to the outer curve of the descending aorta; to do that, they inserted the delivery catheter with the flush port at the 3 o’clock position. Those cases with the hat marker at the outer curve or the center front had improved commissural alignment as compared to those with the hat at the inner curve or center back, according to investigators. The incidence of coronary overlap with the LMCA was 15.7% for those with the hat at the outer curve or center front, compared to 66.0% for those with the hat at the inner curve or center back (P < .001), and the differences in coronary overlap were likewise significantly different in favor of the outer curve/center front for the RCA or both coronaries.

Finally, the incidence of coronary overlap with the ACURATE-neo was much lower when the commissural post at initial deployment was at the center back or inner curve, and in a few cases where the operators tried to torque the delivery catheter to position the commissural post to the inner curve, commissural alignment was achieved in about three-quarters of the patients (five of seven cases).

This is believed to be the first study to systematically characterize how the initial orientation of different transcatheter heart valves impact commissural alignment and coronary overlap, according to Dr. Tang and coinvestigators.

Dr. Jilaihawi, who was not involved in the study, said the investigators studied this phenomenon in a “very detailed, methodical fashion,” but emphasized the need for new device innovations to improve alignment and overlap.

“Their efforts weren’t completely in vain, but they really made a small difference in something that is too important to be [addressed] in a kind of ‘MacGyver’ approach to this problem,” he said in the interview.

Disclosures reported by Dr. Tang were related to Edwards Lifesciences (physician proctor) and Medtronic (physician proctor, consultant). Coauthors reported disclosures related to Edwards, Medtronic, and Boston Scientific, among others.

SOURCE: ACC 20. Tang GHL et al. JACC Cardiovasc Interv. 2020 Mar 16. doi: 10.1016/j.jcin.2020.02.005.

Patients with lupus who have sustained high blood pressure may be at significantly increased risk of cardiovascular events, compared with those patients whose blood pressure is in the range now considered to be normal, results of a retrospective, single-center investigation suggest.

FatCamera/E+/Getty Images

Risk of atherosclerotic vascular events was increased by 73% for patients with systemic lupus erythematosus (SLE) who sustained a mean blood pressure of 130/80 to 139/89 mm Hg over 2 years in the study, which included 1,532 patients treated at a clinic in Toronto.

Management of hypertension in SLE patients should start early, and should aim to achieve levels below 130/80 mm Hg, according to the investigators, led by Konstantinos Tselios, MD, PhD, of the Centre for Prognosis Studies in the Rheumatic Diseases at the University of Toronto.

“The findings of the present study support that the target BP should be less than 130/80 mm Hg in all patients with lupus in order to minimize their cardiovascular risk,” Dr. Tselios and coauthors said in their study, which appears in Annals of the Rheumatic Diseases.

Despite the limitations inherent in a retrospective, observational study, this work by Dr. Tselios and colleagues may help inform the care of patients with SLE, according to C. Michael Stein, MBChB, professor of medicine at Vanderbilt University in Nashville, Tenn.

“It’s really interesting data that’s important and helps us think in terms of figuring out what may be reasonable to do for a particular patient,” Dr. Stein said in an interview.

Starting antihypertensive management early and aiming at levels below 130/80 mm Hg is a strategy that should be “reasonable” for most patients with SLE, said Dr. Stein, adding that the approach specified in the 2017 American College of Cardiology/American Heart Association (ACC/AHA) hypertension guidelines are appropriate to follow. In those guidelines, the threshold for diagnosis of hypertension was lowered to 130/80 mm Hg.

“You can start with risk factor modification, in terms of losing weight, exercising, stopping alcohol, and decreasing salt in the diet to see if you can get the blood pressure down, though it may come down to drug therapy for many patients, I believe,” Dr. Stein said.

Authors of those 2017 ACC/AHA guidelines made no recommendations for patients with SLE or other connective tissue diseases, despite including a section devoted to specific patient subgroups and comorbidities of interest, Dr. Tselios and coauthors noted in their report.

Management of hypertension in patients with lupus may be “delayed” in patients with blood pressures reaching the current hypertension threshold, according to Dr. Tselios and colleagues, due in part to difficulties in cardiovascular risk calculation in SLE patients, as well as current risk considerations outlined in the guidelines.

“On the basis of the recent guidelines, the patient with typical lupus (young female with no traditional atherosclerotic risk factors) would be considered as a low-risk individual and not offered treatment for a BP of 130-139/80-89 mm Hg,” they said in their report.

Accordingly, Dr. Tselios and colleagues sought to determine whether the new hypertension definition predicted atherosclerotic vascular events, including new-onset angina, acute myocardial infarction, cerebrovascular events, revascularization procedures, heart failure, or peripheral vascular disease requiring angioplasty, in patients with SLE treated at a Canadian clinic.

Their analysis comprised 1,532 patients with SLE who had at least 2 years of follow-up and had no prior atherosclerotic events on record. Over a mean follow-up of nearly 11 years, there were 124 such events documented in those patients.

With a mean follow-up of nearly 11 years, the incidence of atherosclerotic events was 18.9 per 1,000 patient-years for patients with blood pressure ≥ 140/90 mm Hg, 11.5 per 1,000 patient-years for the 130-139/80-89 mm Hg group, and 4.5 per 1,000 patient-years for those with blood pressures of 130/80 mm Hg or lower, with differences that were statistically significant between groups, according to the report.

An adjusted blood pressure of 130-139/80-89 mm Hg over the first 2 years since enrollment in the clinic was independently associated with the occurrence of an atherosclerotic event, with a hazard ratio of 1.73 (95% confidence interval, 1.13-2.69, P = 0.011), according to results of a multivariable analysis.

Those findings support targeting a blood pressure below 130/80 mm Hg in all patients with lupus, according to Dr. Tselios and coauthors.

“It seems reasonable that clinicians should not rely on CV risk calculators in SLE and commence treatment as soon as possible in cases of sustained BP elevation above the threshold of 130/80 mm Hg,” they wrote in their report.

How low to go remains unclear, however, as targeting lower levels of blood pressure might be unsafe in certain groups, such as those SLE patients with prior heart disease or heart failure; nevertheless, recent observational data from non-SLE populations suggest that effective treatment to levels lower than 130/80 mm Hg would “further reduce the incidence of atherosclerotic events in SLE,” the authors said in a discussion of their results.

Dr. Tselios and coauthors said they had no competing interests relative to the study. They reported funding for the University of Toronto Lupus Clinic from the University Health Network, Lou & Marissa Rocca, Mark & Diana Bozzo, and the Lupus Foundation of Ontario.

SOURCE: Tselios K et al. Ann Rheum Dis. 2020 Mar 10. doi: 10.1136/annrheumdis-2019-216764

Patients with lupus who have sustained high blood pressure may be at significantly increased risk of cardiovascular events, compared with those patients whose blood pressure is in the range now considered to be normal, results of a retrospective, single-center investigation suggest.

FatCamera/E+/Getty Images

Risk of atherosclerotic vascular events was increased by 73% for patients with systemic lupus erythematosus (SLE) who sustained a mean blood pressure of 130/80 to 139/89 mm Hg over 2 years in the study, which included 1,532 patients treated at a clinic in Toronto.

Management of hypertension in SLE patients should start early, and should aim to achieve levels below 130/80 mm Hg, according to the investigators, led by Konstantinos Tselios, MD, PhD, of the Centre for Prognosis Studies in the Rheumatic Diseases at the University of Toronto.

“The findings of the present study support that the target BP should be less than 130/80 mm Hg in all patients with lupus in order to minimize their cardiovascular risk,” Dr. Tselios and coauthors said in their study, which appears in Annals of the Rheumatic Diseases.

Despite the limitations inherent in a retrospective, observational study, this work by Dr. Tselios and colleagues may help inform the care of patients with SLE, according to C. Michael Stein, MBChB, professor of medicine at Vanderbilt University in Nashville, Tenn.

“It’s really interesting data that’s important and helps us think in terms of figuring out what may be reasonable to do for a particular patient,” Dr. Stein said in an interview.

Starting antihypertensive management early and aiming at levels below 130/80 mm Hg is a strategy that should be “reasonable” for most patients with SLE, said Dr. Stein, adding that the approach specified in the 2017 American College of Cardiology/American Heart Association (ACC/AHA) hypertension guidelines are appropriate to follow. In those guidelines, the threshold for diagnosis of hypertension was lowered to 130/80 mm Hg.

“You can start with risk factor modification, in terms of losing weight, exercising, stopping alcohol, and decreasing salt in the diet to see if you can get the blood pressure down, though it may come down to drug therapy for many patients, I believe,” Dr. Stein said.

Authors of those 2017 ACC/AHA guidelines made no recommendations for patients with SLE or other connective tissue diseases, despite including a section devoted to specific patient subgroups and comorbidities of interest, Dr. Tselios and coauthors noted in their report.

Management of hypertension in patients with lupus may be “delayed” in patients with blood pressures reaching the current hypertension threshold, according to Dr. Tselios and colleagues, due in part to difficulties in cardiovascular risk calculation in SLE patients, as well as current risk considerations outlined in the guidelines.

“On the basis of the recent guidelines, the patient with typical lupus (young female with no traditional atherosclerotic risk factors) would be considered as a low-risk individual and not offered treatment for a BP of 130-139/80-89 mm Hg,” they said in their report.

Accordingly, Dr. Tselios and colleagues sought to determine whether the new hypertension definition predicted atherosclerotic vascular events, including new-onset angina, acute myocardial infarction, cerebrovascular events, revascularization procedures, heart failure, or peripheral vascular disease requiring angioplasty, in patients with SLE treated at a Canadian clinic.

Their analysis comprised 1,532 patients with SLE who had at least 2 years of follow-up and had no prior atherosclerotic events on record. Over a mean follow-up of nearly 11 years, there were 124 such events documented in those patients.

With a mean follow-up of nearly 11 years, the incidence of atherosclerotic events was 18.9 per 1,000 patient-years for patients with blood pressure ≥ 140/90 mm Hg, 11.5 per 1,000 patient-years for the 130-139/80-89 mm Hg group, and 4.5 per 1,000 patient-years for those with blood pressures of 130/80 mm Hg or lower, with differences that were statistically significant between groups, according to the report.

An adjusted blood pressure of 130-139/80-89 mm Hg over the first 2 years since enrollment in the clinic was independently associated with the occurrence of an atherosclerotic event, with a hazard ratio of 1.73 (95% confidence interval, 1.13-2.69, P = 0.011), according to results of a multivariable analysis.

Those findings support targeting a blood pressure below 130/80 mm Hg in all patients with lupus, according to Dr. Tselios and coauthors.

“It seems reasonable that clinicians should not rely on CV risk calculators in SLE and commence treatment as soon as possible in cases of sustained BP elevation above the threshold of 130/80 mm Hg,” they wrote in their report.

How low to go remains unclear, however, as targeting lower levels of blood pressure might be unsafe in certain groups, such as those SLE patients with prior heart disease or heart failure; nevertheless, recent observational data from non-SLE populations suggest that effective treatment to levels lower than 130/80 mm Hg would “further reduce the incidence of atherosclerotic events in SLE,” the authors said in a discussion of their results.

Dr. Tselios and coauthors said they had no competing interests relative to the study. They reported funding for the University of Toronto Lupus Clinic from the University Health Network, Lou & Marissa Rocca, Mark & Diana Bozzo, and the Lupus Foundation of Ontario.

SOURCE: Tselios K et al. Ann Rheum Dis. 2020 Mar 10. doi: 10.1136/annrheumdis-2019-216764

Patients with lupus who have sustained high blood pressure may be at significantly increased risk of cardiovascular events, compared with those patients whose blood pressure is in the range now considered to be normal, results of a retrospective, single-center investigation suggest.

FatCamera/E+/Getty Images

Risk of atherosclerotic vascular events was increased by 73% for patients with systemic lupus erythematosus (SLE) who sustained a mean blood pressure of 130/80 to 139/89 mm Hg over 2 years in the study, which included 1,532 patients treated at a clinic in Toronto.

Management of hypertension in SLE patients should start early, and should aim to achieve levels below 130/80 mm Hg, according to the investigators, led by Konstantinos Tselios, MD, PhD, of the Centre for Prognosis Studies in the Rheumatic Diseases at the University of Toronto.

“The findings of the present study support that the target BP should be less than 130/80 mm Hg in all patients with lupus in order to minimize their cardiovascular risk,” Dr. Tselios and coauthors said in their study, which appears in Annals of the Rheumatic Diseases.

Despite the limitations inherent in a retrospective, observational study, this work by Dr. Tselios and colleagues may help inform the care of patients with SLE, according to C. Michael Stein, MBChB, professor of medicine at Vanderbilt University in Nashville, Tenn.

“It’s really interesting data that’s important and helps us think in terms of figuring out what may be reasonable to do for a particular patient,” Dr. Stein said in an interview.

Starting antihypertensive management early and aiming at levels below 130/80 mm Hg is a strategy that should be “reasonable” for most patients with SLE, said Dr. Stein, adding that the approach specified in the 2017 American College of Cardiology/American Heart Association (ACC/AHA) hypertension guidelines are appropriate to follow. In those guidelines, the threshold for diagnosis of hypertension was lowered to 130/80 mm Hg.

“You can start with risk factor modification, in terms of losing weight, exercising, stopping alcohol, and decreasing salt in the diet to see if you can get the blood pressure down, though it may come down to drug therapy for many patients, I believe,” Dr. Stein said.

Authors of those 2017 ACC/AHA guidelines made no recommendations for patients with SLE or other connective tissue diseases, despite including a section devoted to specific patient subgroups and comorbidities of interest, Dr. Tselios and coauthors noted in their report.

Management of hypertension in patients with lupus may be “delayed” in patients with blood pressures reaching the current hypertension threshold, according to Dr. Tselios and colleagues, due in part to difficulties in cardiovascular risk calculation in SLE patients, as well as current risk considerations outlined in the guidelines.

“On the basis of the recent guidelines, the patient with typical lupus (young female with no traditional atherosclerotic risk factors) would be considered as a low-risk individual and not offered treatment for a BP of 130-139/80-89 mm Hg,” they said in their report.

Accordingly, Dr. Tselios and colleagues sought to determine whether the new hypertension definition predicted atherosclerotic vascular events, including new-onset angina, acute myocardial infarction, cerebrovascular events, revascularization procedures, heart failure, or peripheral vascular disease requiring angioplasty, in patients with SLE treated at a Canadian clinic.

Their analysis comprised 1,532 patients with SLE who had at least 2 years of follow-up and had no prior atherosclerotic events on record. Over a mean follow-up of nearly 11 years, there were 124 such events documented in those patients.

With a mean follow-up of nearly 11 years, the incidence of atherosclerotic events was 18.9 per 1,000 patient-years for patients with blood pressure ≥ 140/90 mm Hg, 11.5 per 1,000 patient-years for the 130-139/80-89 mm Hg group, and 4.5 per 1,000 patient-years for those with blood pressures of 130/80 mm Hg or lower, with differences that were statistically significant between groups, according to the report.

An adjusted blood pressure of 130-139/80-89 mm Hg over the first 2 years since enrollment in the clinic was independently associated with the occurrence of an atherosclerotic event, with a hazard ratio of 1.73 (95% confidence interval, 1.13-2.69, P = 0.011), according to results of a multivariable analysis.

Those findings support targeting a blood pressure below 130/80 mm Hg in all patients with lupus, according to Dr. Tselios and coauthors.

“It seems reasonable that clinicians should not rely on CV risk calculators in SLE and commence treatment as soon as possible in cases of sustained BP elevation above the threshold of 130/80 mm Hg,” they wrote in their report.

How low to go remains unclear, however, as targeting lower levels of blood pressure might be unsafe in certain groups, such as those SLE patients with prior heart disease or heart failure; nevertheless, recent observational data from non-SLE populations suggest that effective treatment to levels lower than 130/80 mm Hg would “further reduce the incidence of atherosclerotic events in SLE,” the authors said in a discussion of their results.

Dr. Tselios and coauthors said they had no competing interests relative to the study. They reported funding for the University of Toronto Lupus Clinic from the University Health Network, Lou & Marissa Rocca, Mark & Diana Bozzo, and the Lupus Foundation of Ontario.

SOURCE: Tselios K et al. Ann Rheum Dis. 2020 Mar 10. doi: 10.1136/annrheumdis-2019-216764

Although a 14-day quarantine after exposure to novel coronavirus is “well supported” by evidence, some infected individuals will not become symptomatic until after that period, according to authors of a recent analysis published in Annals of Internal Medicine.

Most individuals infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) will develop symptoms by day 12 of the infection, which is within the 14-day period of active monitoring currently recommended by the Centers for Disease Control and Prevention, the authors wrote.

However, an estimated 101 out of 10,000 cases could become symptomatic after the end of that 14-day monitoring period, they cautioned.

“Our analyses do not preclude that estimate from being higher,” said the investigators, led by Stephen A. Lauer, PhD, MD, of Johns Hopkins Bloomberg School of Public Health, Baltimore.

The analysis, based on 181 confirmed cases of coronavirus disease 2019 (COVID-19) that were documented outside of the outbreak epicenter, Wuhan, China, makes “more conservative assumptions” about the window of symptom onset and potential for continued exposure, compared with analyses in previous studies, the researchers wrote.

The estimated incubation period for SARS-CoV-2 in the 181-patient study was a median of 5.1 days, which is comparable with previous estimates based on COVID-19 cases outside of Wuhan and consistent with other known human coronavirus diseases, such as SARS, which had a reported mean incubation period of 5 days, Dr. Lauer and colleagues noted.

Symptoms developed within 11.5 days for 97.5% of patients in the study.

Whether it’s acceptable to have 101 out of 10,000 cases becoming symptomatic beyond the recommended quarantine window depends on two factors, according to the authors. The first is the expected infection risk in the population that is being monitored, and the second is “judgment about the cost of missing cases,” wrote the authors.

In an interview, Aaron Eli Glatt, MD, chair of medicine at Mount Sinai South Nassau, Oceanside, N.Y., said that in practical terms, the results suggest that the majority of patients with COVID-19 will be identified within 14 days, with an “outside chance” of an infected individual leaving quarantine and transmitting virus for a short period of time before becoming symptomatic.

“I think the proper message to give those patients [who are asymptomatic upon leaving quarantine] is, ‘after 14 days, we’re pretty sure you’re out of the woods, but should you get any symptoms, immediately requarantine yourself and seek medical care,” he said.

Study coauthor Kyra H. Grantz, a doctoral graduate student at the Johns Hopkins Bloomberg School of Public Health, said that extending a quarantine beyond 14 days might be considered in the highest-risk scenarios, though the benefits of doing so would have to be weighed against the costs to public health and to the individuals under quarantine.

“Our estimate of the incubation period definitely supports the 14-day recommendation that the CDC has been using,” she said in an interview.

Dr. Grantz emphasized that the estimate of 101 out of 10,000 cases developing symptoms after day 14 of active monitoring – representing the 99th percentile of cases – assumes the “most conservative, worst-case scenario” in a population that is fully infected.

“If you’re looking at a following a cohort of 1,000 people whom you think may have been exposed, only a certain percentage will be infected, and only a certain percentage of those will even develop symptoms – before we get to this idea of how many people would we miss,” she said.

The study was supported by the Centers for Disease Control and Prevention, the National Institute of Allergy and Infectious Diseases, the National Institute of General Medical Sciences, and the Alexander von Humboldt Foundation. Four authors reported disclosures related to those entities, and the remaining five reported no conflicts of interest.
 

SOURCE: Lauer SA et al. Ann Intern Med. 2020 Mar 9. doi:10.1101/2020.02.02.20020016.

Although a 14-day quarantine after exposure to novel coronavirus is “well supported” by evidence, some infected individuals will not become symptomatic until after that period, according to authors of a recent analysis published in Annals of Internal Medicine.

Most individuals infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) will develop symptoms by day 12 of the infection, which is within the 14-day period of active monitoring currently recommended by the Centers for Disease Control and Prevention, the authors wrote.

However, an estimated 101 out of 10,000 cases could become symptomatic after the end of that 14-day monitoring period, they cautioned.

“Our analyses do not preclude that estimate from being higher,” said the investigators, led by Stephen A. Lauer, PhD, MD, of Johns Hopkins Bloomberg School of Public Health, Baltimore.

The analysis, based on 181 confirmed cases of coronavirus disease 2019 (COVID-19) that were documented outside of the outbreak epicenter, Wuhan, China, makes “more conservative assumptions” about the window of symptom onset and potential for continued exposure, compared with analyses in previous studies, the researchers wrote.

The estimated incubation period for SARS-CoV-2 in the 181-patient study was a median of 5.1 days, which is comparable with previous estimates based on COVID-19 cases outside of Wuhan and consistent with other known human coronavirus diseases, such as SARS, which had a reported mean incubation period of 5 days, Dr. Lauer and colleagues noted.

Symptoms developed within 11.5 days for 97.5% of patients in the study.

Whether it’s acceptable to have 101 out of 10,000 cases becoming symptomatic beyond the recommended quarantine window depends on two factors, according to the authors. The first is the expected infection risk in the population that is being monitored, and the second is “judgment about the cost of missing cases,” wrote the authors.

In an interview, Aaron Eli Glatt, MD, chair of medicine at Mount Sinai South Nassau, Oceanside, N.Y., said that in practical terms, the results suggest that the majority of patients with COVID-19 will be identified within 14 days, with an “outside chance” of an infected individual leaving quarantine and transmitting virus for a short period of time before becoming symptomatic.

“I think the proper message to give those patients [who are asymptomatic upon leaving quarantine] is, ‘after 14 days, we’re pretty sure you’re out of the woods, but should you get any symptoms, immediately requarantine yourself and seek medical care,” he said.

Study coauthor Kyra H. Grantz, a doctoral graduate student at the Johns Hopkins Bloomberg School of Public Health, said that extending a quarantine beyond 14 days might be considered in the highest-risk scenarios, though the benefits of doing so would have to be weighed against the costs to public health and to the individuals under quarantine.

“Our estimate of the incubation period definitely supports the 14-day recommendation that the CDC has been using,” she said in an interview.

Dr. Grantz emphasized that the estimate of 101 out of 10,000 cases developing symptoms after day 14 of active monitoring – representing the 99th percentile of cases – assumes the “most conservative, worst-case scenario” in a population that is fully infected.

“If you’re looking at a following a cohort of 1,000 people whom you think may have been exposed, only a certain percentage will be infected, and only a certain percentage of those will even develop symptoms – before we get to this idea of how many people would we miss,” she said.

The study was supported by the Centers for Disease Control and Prevention, the National Institute of Allergy and Infectious Diseases, the National Institute of General Medical Sciences, and the Alexander von Humboldt Foundation. Four authors reported disclosures related to those entities, and the remaining five reported no conflicts of interest.
 

SOURCE: Lauer SA et al. Ann Intern Med. 2020 Mar 9. doi:10.1101/2020.02.02.20020016.

Although a 14-day quarantine after exposure to novel coronavirus is “well supported” by evidence, some infected individuals will not become symptomatic until after that period, according to authors of a recent analysis published in Annals of Internal Medicine.

Most individuals infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) will develop symptoms by day 12 of the infection, which is within the 14-day period of active monitoring currently recommended by the Centers for Disease Control and Prevention, the authors wrote.

However, an estimated 101 out of 10,000 cases could become symptomatic after the end of that 14-day monitoring period, they cautioned.

“Our analyses do not preclude that estimate from being higher,” said the investigators, led by Stephen A. Lauer, PhD, MD, of Johns Hopkins Bloomberg School of Public Health, Baltimore.

The analysis, based on 181 confirmed cases of coronavirus disease 2019 (COVID-19) that were documented outside of the outbreak epicenter, Wuhan, China, makes “more conservative assumptions” about the window of symptom onset and potential for continued exposure, compared with analyses in previous studies, the researchers wrote.

The estimated incubation period for SARS-CoV-2 in the 181-patient study was a median of 5.1 days, which is comparable with previous estimates based on COVID-19 cases outside of Wuhan and consistent with other known human coronavirus diseases, such as SARS, which had a reported mean incubation period of 5 days, Dr. Lauer and colleagues noted.

Symptoms developed within 11.5 days for 97.5% of patients in the study.

Whether it’s acceptable to have 101 out of 10,000 cases becoming symptomatic beyond the recommended quarantine window depends on two factors, according to the authors. The first is the expected infection risk in the population that is being monitored, and the second is “judgment about the cost of missing cases,” wrote the authors.

In an interview, Aaron Eli Glatt, MD, chair of medicine at Mount Sinai South Nassau, Oceanside, N.Y., said that in practical terms, the results suggest that the majority of patients with COVID-19 will be identified within 14 days, with an “outside chance” of an infected individual leaving quarantine and transmitting virus for a short period of time before becoming symptomatic.

“I think the proper message to give those patients [who are asymptomatic upon leaving quarantine] is, ‘after 14 days, we’re pretty sure you’re out of the woods, but should you get any symptoms, immediately requarantine yourself and seek medical care,” he said.

Study coauthor Kyra H. Grantz, a doctoral graduate student at the Johns Hopkins Bloomberg School of Public Health, said that extending a quarantine beyond 14 days might be considered in the highest-risk scenarios, though the benefits of doing so would have to be weighed against the costs to public health and to the individuals under quarantine.

“Our estimate of the incubation period definitely supports the 14-day recommendation that the CDC has been using,” she said in an interview.

Dr. Grantz emphasized that the estimate of 101 out of 10,000 cases developing symptoms after day 14 of active monitoring – representing the 99th percentile of cases – assumes the “most conservative, worst-case scenario” in a population that is fully infected.

“If you’re looking at a following a cohort of 1,000 people whom you think may have been exposed, only a certain percentage will be infected, and only a certain percentage of those will even develop symptoms – before we get to this idea of how many people would we miss,” she said.

The study was supported by the Centers for Disease Control and Prevention, the National Institute of Allergy and Infectious Diseases, the National Institute of General Medical Sciences, and the Alexander von Humboldt Foundation. Four authors reported disclosures related to those entities, and the remaining five reported no conflicts of interest.
 

SOURCE: Lauer SA et al. Ann Intern Med. 2020 Mar 9. doi:10.1101/2020.02.02.20020016.