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CMS issues guidance on containing spread of coronavirus
The first guidance document, “Guidance for Infection Control and Prevention Concerning Coronavirus Disease (COVID-19): FAQs and Considerations for Patient Triage, Placement and Hospital Discharge,” issued March 4, provides some basic guidance, including identifying which patients are at risk, how facilities should screen for COVID-19, how facilities should monitor or restrict health care facility staff, and other recommendations for infection prevention and control.
“Hospitals should identify visitors and patients at risk for having COVID-19 infection before or immediately upon arrival to the healthcare facility,” the guidance document notes. “For patients, implement respiratory hygiene and cough etiquette (i.e., placing a face mask over the patient’s nose and mouth if that has not already been done) and isolate the patient in an examination room with the door closed. If the patient cannot be immediately moved to an examination room, ensure they are not allowed to wait among other patients seeking care.”
The document offers further information regarding the care of patients and provides numerous links to existing guidance from the Centers for Disease Control and Prevention.
The second document, “Guidance for Infection Control and Prevention of Coronavirus Disease 2019 (COVID-19) in Nursing Homes,” issued the same day, provides information on how to limit and monitor visitors as well as monitor and restrict health staff. It details when to transfer residents with suspected or confirmed coronavirus infection, and when a nursing home should accept a resident diagnosed with COVID-19.
Facilities “should contact their local health department if they have questions or suspect a resident of a nursing home has COVID-19,” the document states. “Per CDC, prompt detection, triage and isolation of potentially infectious patients are essential to prevent unnecessary exposure among patients, healthcare personnel, and visitors at the facility.”
The CMS also announced that it is suspending all nonemergency survey activity.
“CMS is suspending nonemergency inspections across the country, allowing inspectors to turn their focus on the most serious health and safety threats like infectious diseases and abuse,” the agency stated in a March 4 memo. “This shift in approach will also allow inspectors to focus on addressing the spread of ... COVID-19. CMS is issuing this memorandum to State Survey Agencies to provide important guidelines for the inspection process in situations in which a COVID-19 is suspected.”
In a statement, CMS Administrator Seema Verma said these actions “represent a call to action across the health care system. All health care providers must immediately review their procedures to ensure compliance with CMS’ infection control requirements, as well as the guidelines from the Centers for Disease Control and Prevention.”
The first guidance document, “Guidance for Infection Control and Prevention Concerning Coronavirus Disease (COVID-19): FAQs and Considerations for Patient Triage, Placement and Hospital Discharge,” issued March 4, provides some basic guidance, including identifying which patients are at risk, how facilities should screen for COVID-19, how facilities should monitor or restrict health care facility staff, and other recommendations for infection prevention and control.
“Hospitals should identify visitors and patients at risk for having COVID-19 infection before or immediately upon arrival to the healthcare facility,” the guidance document notes. “For patients, implement respiratory hygiene and cough etiquette (i.e., placing a face mask over the patient’s nose and mouth if that has not already been done) and isolate the patient in an examination room with the door closed. If the patient cannot be immediately moved to an examination room, ensure they are not allowed to wait among other patients seeking care.”
The document offers further information regarding the care of patients and provides numerous links to existing guidance from the Centers for Disease Control and Prevention.
The second document, “Guidance for Infection Control and Prevention of Coronavirus Disease 2019 (COVID-19) in Nursing Homes,” issued the same day, provides information on how to limit and monitor visitors as well as monitor and restrict health staff. It details when to transfer residents with suspected or confirmed coronavirus infection, and when a nursing home should accept a resident diagnosed with COVID-19.
Facilities “should contact their local health department if they have questions or suspect a resident of a nursing home has COVID-19,” the document states. “Per CDC, prompt detection, triage and isolation of potentially infectious patients are essential to prevent unnecessary exposure among patients, healthcare personnel, and visitors at the facility.”
The CMS also announced that it is suspending all nonemergency survey activity.
“CMS is suspending nonemergency inspections across the country, allowing inspectors to turn their focus on the most serious health and safety threats like infectious diseases and abuse,” the agency stated in a March 4 memo. “This shift in approach will also allow inspectors to focus on addressing the spread of ... COVID-19. CMS is issuing this memorandum to State Survey Agencies to provide important guidelines for the inspection process in situations in which a COVID-19 is suspected.”
In a statement, CMS Administrator Seema Verma said these actions “represent a call to action across the health care system. All health care providers must immediately review their procedures to ensure compliance with CMS’ infection control requirements, as well as the guidelines from the Centers for Disease Control and Prevention.”
The first guidance document, “Guidance for Infection Control and Prevention Concerning Coronavirus Disease (COVID-19): FAQs and Considerations for Patient Triage, Placement and Hospital Discharge,” issued March 4, provides some basic guidance, including identifying which patients are at risk, how facilities should screen for COVID-19, how facilities should monitor or restrict health care facility staff, and other recommendations for infection prevention and control.
“Hospitals should identify visitors and patients at risk for having COVID-19 infection before or immediately upon arrival to the healthcare facility,” the guidance document notes. “For patients, implement respiratory hygiene and cough etiquette (i.e., placing a face mask over the patient’s nose and mouth if that has not already been done) and isolate the patient in an examination room with the door closed. If the patient cannot be immediately moved to an examination room, ensure they are not allowed to wait among other patients seeking care.”
The document offers further information regarding the care of patients and provides numerous links to existing guidance from the Centers for Disease Control and Prevention.
The second document, “Guidance for Infection Control and Prevention of Coronavirus Disease 2019 (COVID-19) in Nursing Homes,” issued the same day, provides information on how to limit and monitor visitors as well as monitor and restrict health staff. It details when to transfer residents with suspected or confirmed coronavirus infection, and when a nursing home should accept a resident diagnosed with COVID-19.
Facilities “should contact their local health department if they have questions or suspect a resident of a nursing home has COVID-19,” the document states. “Per CDC, prompt detection, triage and isolation of potentially infectious patients are essential to prevent unnecessary exposure among patients, healthcare personnel, and visitors at the facility.”
The CMS also announced that it is suspending all nonemergency survey activity.
“CMS is suspending nonemergency inspections across the country, allowing inspectors to turn their focus on the most serious health and safety threats like infectious diseases and abuse,” the agency stated in a March 4 memo. “This shift in approach will also allow inspectors to focus on addressing the spread of ... COVID-19. CMS is issuing this memorandum to State Survey Agencies to provide important guidelines for the inspection process in situations in which a COVID-19 is suspected.”
In a statement, CMS Administrator Seema Verma said these actions “represent a call to action across the health care system. All health care providers must immediately review their procedures to ensure compliance with CMS’ infection control requirements, as well as the guidelines from the Centers for Disease Control and Prevention.”
Laparoscopic management of bladder fibroids: Surgical tips and tricks
Testing lab asks FDA to recall NDMA-tainted metformin
Valisure, an online pharmacy and analytical laboratory based in New Haven, Conn., has asked the U.S. Food and Drug Administration to request recalls of the diabetes drug metformin from 11 companies after its own testing found levels of the probable carcinogen N-nitrosodimethylamine (NDMA) exceeded those recognized by the agency as being safe, according to a petition filed with the FDA.
“The presence of this probable carcinogen in a medication that is taken daily by adults and adolescents for a chronic condition like diabetes, makes [these findings] particularly troubling,” the pharmacy said in the petition. It noted that NDMA is classified by the World Health Organization and the International Agency for Research on Cancer as a Group 2A compound, meaning that it is “probably carcinogenic to humans.”
The Valisure findings are in contrast to those from the FDA’s own testing of metformin from eight companies. In results released Feb. 2, the agency found no NDMA in metformin from seven of the companies, and elevations within the safe limit in metformin from the remaining company. Based on those results, the FDA did not issue a recall.
The FDA declined to comment on the petition, pending a formal written response, a spokesman said.
Valisure said in its petition that one reason it found NDMA at concerning levels, and the FDA did not, could be that the pharmacy’s testing was more thorough than the agency’s because it had used its proprietary analytical technologies in addition to FDA standard assays. The pharmacy said it also cast a wider net, testing samples from 22 companies instead of 8, as the FDA had.
“At least one company that consistently displayed high levels of NDMA in all Valisure-tested batches was a company whose metformin products, to Valisure’s knowledge, were not tested by FDA,” Valisure said in the petition.
The pharmacy tested 38 batches of metformin from 22 companies, and found 16 contaminated batches from 11 companies. Results from one company were confirmed by an independent laboratory in California.
In addition, “there was significant variability from batch to batch, even within a single company, underscoring the importance of batch-level chemical analysis and the necessity of overall increased quality surveillance of medications,” the pharmacy stated in the petition.
David Light, Valisure founder and CEO, said in a press release that the results “indicate that contaminated batches of drugs are scattered and intermixed with clean [batches] throughout the American pharmaceutical supply chain. This strongly suggests that neither the limited testing FDA is able to conduct nor the pharmaceutical companies’ self-reporting of analytical results is sufficient to protect American consumers.”
He explained in an interview that metformin contamination probably comes from poor manufacturing, as NDMA can form during the manufacturing process. Companies are supposed to have processes in place to limit its formation and to check for and remove it before products are shipped. The contaminated batches might have come from China, which makes the bulk of U.S. active pharmaceutical ingredients, he said.
Recently, Apotex and Ranbaxy Pharmaceuticals recalled specific metformin lots in Canada after Canadian health authorities requested NDMA testing. Metformin versions have also been recalled in Singapore. European health authorities are also looking into the issue, according to a Mar. 3 press release from the European Medicines Agency.
Over the past 2 years, NDMA contamination has led to recalls of angiotensin receptor blockers, such as valsartan and losartan, because of NDMA in excess of the daily limit, and ranitidine-containing products such as Zantac. Valisure said it hopes the FDA will avoid the “year-long rolling recalls” that have occurred for angiotensin receptor blockers.
Metformin, which is used to treat type 2 diabetes, is the fourth-most prescribed drug in the United States. About 80 million prescriptions were written for it during 2019, according to the press release.
Valisure launched its investigation after it found NDMA in metformin a client asked it to check.
Valisure, an online pharmacy and analytical laboratory based in New Haven, Conn., has asked the U.S. Food and Drug Administration to request recalls of the diabetes drug metformin from 11 companies after its own testing found levels of the probable carcinogen N-nitrosodimethylamine (NDMA) exceeded those recognized by the agency as being safe, according to a petition filed with the FDA.
“The presence of this probable carcinogen in a medication that is taken daily by adults and adolescents for a chronic condition like diabetes, makes [these findings] particularly troubling,” the pharmacy said in the petition. It noted that NDMA is classified by the World Health Organization and the International Agency for Research on Cancer as a Group 2A compound, meaning that it is “probably carcinogenic to humans.”
The Valisure findings are in contrast to those from the FDA’s own testing of metformin from eight companies. In results released Feb. 2, the agency found no NDMA in metformin from seven of the companies, and elevations within the safe limit in metformin from the remaining company. Based on those results, the FDA did not issue a recall.
The FDA declined to comment on the petition, pending a formal written response, a spokesman said.
Valisure said in its petition that one reason it found NDMA at concerning levels, and the FDA did not, could be that the pharmacy’s testing was more thorough than the agency’s because it had used its proprietary analytical technologies in addition to FDA standard assays. The pharmacy said it also cast a wider net, testing samples from 22 companies instead of 8, as the FDA had.
“At least one company that consistently displayed high levels of NDMA in all Valisure-tested batches was a company whose metformin products, to Valisure’s knowledge, were not tested by FDA,” Valisure said in the petition.
The pharmacy tested 38 batches of metformin from 22 companies, and found 16 contaminated batches from 11 companies. Results from one company were confirmed by an independent laboratory in California.
In addition, “there was significant variability from batch to batch, even within a single company, underscoring the importance of batch-level chemical analysis and the necessity of overall increased quality surveillance of medications,” the pharmacy stated in the petition.
David Light, Valisure founder and CEO, said in a press release that the results “indicate that contaminated batches of drugs are scattered and intermixed with clean [batches] throughout the American pharmaceutical supply chain. This strongly suggests that neither the limited testing FDA is able to conduct nor the pharmaceutical companies’ self-reporting of analytical results is sufficient to protect American consumers.”
He explained in an interview that metformin contamination probably comes from poor manufacturing, as NDMA can form during the manufacturing process. Companies are supposed to have processes in place to limit its formation and to check for and remove it before products are shipped. The contaminated batches might have come from China, which makes the bulk of U.S. active pharmaceutical ingredients, he said.
Recently, Apotex and Ranbaxy Pharmaceuticals recalled specific metformin lots in Canada after Canadian health authorities requested NDMA testing. Metformin versions have also been recalled in Singapore. European health authorities are also looking into the issue, according to a Mar. 3 press release from the European Medicines Agency.
Over the past 2 years, NDMA contamination has led to recalls of angiotensin receptor blockers, such as valsartan and losartan, because of NDMA in excess of the daily limit, and ranitidine-containing products such as Zantac. Valisure said it hopes the FDA will avoid the “year-long rolling recalls” that have occurred for angiotensin receptor blockers.
Metformin, which is used to treat type 2 diabetes, is the fourth-most prescribed drug in the United States. About 80 million prescriptions were written for it during 2019, according to the press release.
Valisure launched its investigation after it found NDMA in metformin a client asked it to check.
Valisure, an online pharmacy and analytical laboratory based in New Haven, Conn., has asked the U.S. Food and Drug Administration to request recalls of the diabetes drug metformin from 11 companies after its own testing found levels of the probable carcinogen N-nitrosodimethylamine (NDMA) exceeded those recognized by the agency as being safe, according to a petition filed with the FDA.
“The presence of this probable carcinogen in a medication that is taken daily by adults and adolescents for a chronic condition like diabetes, makes [these findings] particularly troubling,” the pharmacy said in the petition. It noted that NDMA is classified by the World Health Organization and the International Agency for Research on Cancer as a Group 2A compound, meaning that it is “probably carcinogenic to humans.”
The Valisure findings are in contrast to those from the FDA’s own testing of metformin from eight companies. In results released Feb. 2, the agency found no NDMA in metformin from seven of the companies, and elevations within the safe limit in metformin from the remaining company. Based on those results, the FDA did not issue a recall.
The FDA declined to comment on the petition, pending a formal written response, a spokesman said.
Valisure said in its petition that one reason it found NDMA at concerning levels, and the FDA did not, could be that the pharmacy’s testing was more thorough than the agency’s because it had used its proprietary analytical technologies in addition to FDA standard assays. The pharmacy said it also cast a wider net, testing samples from 22 companies instead of 8, as the FDA had.
“At least one company that consistently displayed high levels of NDMA in all Valisure-tested batches was a company whose metformin products, to Valisure’s knowledge, were not tested by FDA,” Valisure said in the petition.
The pharmacy tested 38 batches of metformin from 22 companies, and found 16 contaminated batches from 11 companies. Results from one company were confirmed by an independent laboratory in California.
In addition, “there was significant variability from batch to batch, even within a single company, underscoring the importance of batch-level chemical analysis and the necessity of overall increased quality surveillance of medications,” the pharmacy stated in the petition.
David Light, Valisure founder and CEO, said in a press release that the results “indicate that contaminated batches of drugs are scattered and intermixed with clean [batches] throughout the American pharmaceutical supply chain. This strongly suggests that neither the limited testing FDA is able to conduct nor the pharmaceutical companies’ self-reporting of analytical results is sufficient to protect American consumers.”
He explained in an interview that metformin contamination probably comes from poor manufacturing, as NDMA can form during the manufacturing process. Companies are supposed to have processes in place to limit its formation and to check for and remove it before products are shipped. The contaminated batches might have come from China, which makes the bulk of U.S. active pharmaceutical ingredients, he said.
Recently, Apotex and Ranbaxy Pharmaceuticals recalled specific metformin lots in Canada after Canadian health authorities requested NDMA testing. Metformin versions have also been recalled in Singapore. European health authorities are also looking into the issue, according to a Mar. 3 press release from the European Medicines Agency.
Over the past 2 years, NDMA contamination has led to recalls of angiotensin receptor blockers, such as valsartan and losartan, because of NDMA in excess of the daily limit, and ranitidine-containing products such as Zantac. Valisure said it hopes the FDA will avoid the “year-long rolling recalls” that have occurred for angiotensin receptor blockers.
Metformin, which is used to treat type 2 diabetes, is the fourth-most prescribed drug in the United States. About 80 million prescriptions were written for it during 2019, according to the press release.
Valisure launched its investigation after it found NDMA in metformin a client asked it to check.
Beginning estrogen soon after menopause slows atherosclerosis progression
PHOENIX – Oral estrogen therapy taken within 6 years after the onset of menopause significantly reduced progression of lipid deposition in the carotid arterial wall, compared with placebo. However, starting oral estrogen 10 years after menopause did not confer a similar benefit.
“The clinical practice of estradiol therapy has been nothing short of a roller coaster ride,” lead study author Roksana Karim, PhD, MBBS, said in an interview at the Epidemiology and Prevention/Lifestyle and Cardiometabolic Health meeting sponsored by the American Heart Association. “Clinicians have been sort of conservative in terms of prescribing estradiol therapy. But over the last 2 decades things have changed, and eventually the timing hypothesis evolved based on the final analysis of the Women’s Health Initiative results as well.”
The findings come from a secondary analysis of the Early Versus Late Intervention Trial With Estradiol (ELITE), which examined the effects of oral 17-beta-estradiol (estrogen) on the progression of early atherosclerosis and cognitive decline in healthy postmenopausal women.
In the original trial, 643 healthy postmenopausal women were randomized to receive 1 mg/day of estradiol or a placebo pill either within 6 years after the onset of menopause or more than a decade after menopause (N Engl J Med 2016;374[13]:1221-31). All study participants took estradiol or placebo daily for an average of 5 years. The study’s initial findings showed that the mean carotid intima-media thickness progression rate was decreased by 0.0034 mm per year with estradiol, compared with placebo, but only in women who initiated hormone therapy within 6 years of menopause onset.
For the current analysis, researchers led by Dr. Karim looked further into estradiol’s impact on heart health by using echogenicity to analyze lipids in the arterial wall among the ELITE participants. The main outcome of interest was gray-scale median (GSM, unitless), a qualitative measure of atherosclerosis based on echogenicity obtained by high-resolution ultrasonography of the common carotid arterial wall. Whereas higher GSM values result with plaques rich in calcium and fibrous tissue, lower GSM values indicate more lipid deposition.
Dr. Karim, an associate professor of clinical preventive medicine at the University of Southern California, Los Angeles, and colleagues assessed GSM and serum concentrations of estradiol every 6 months over a median 5-year trial period, and used linear mixed effects regression models to compare the rate of GSM progression between the randomized groups within time-since-menopause strata.
The researchers found that effect of estradiol on the annual rate of GSM progression significantly differed between women in the early and late postmenopause groups (P for interaction = .006). Specifically, the annual GSM progression rate among women in early postmenopause fell by 0.30 per year in women taking estradiol, compared with 1.41 per year in those in the placebo group (P less than .0001), indicating significantly more atherosclerosis in the placebo group. On the other hand, the annual GSM progression rate was not significantly different between the estradiol and placebo groups among the late postmenopausal women (P = .37).
“I think this should comfort clinicians in terms of prescribing estradiol therapy to women who don’t have any contraindications and who are within 6 years of menopause,” Dr. Karim said. “Accumulation of lipids is the key event for atherosclerosis progression.” She and her colleagues also observed that the positive association between mean on-trial serum estradiol levels and GSM progression rate was stronger and significant among early postmenopausal women (P = .008), compared with women in the late postmenopausal group (P = .003). However, this differential association between estradiol level and GSM progression rate was not statistically significant (P for interaction = .33).
“This study is important and raises a critical question: Is there a time period where getting hormone therapy would be most beneficial for the heart?” Nieca Goldberg, MD, medical director of the New York University women’s heart program and senior advisor for women’s health strategy at NYU Langone Health, said in an interview. “I think more studies and more analyses are needed, but we haven’t changed the indications for estradiol. We’re not giving estradiol to prevent progression of heart disease. We use estradiol hormone therapy as indicated for women who are having menopausal symptoms.”
Dr. Karim and colleagues plan to conduct a follow-up analysis from the same cohort of ELITE study participants to validate the findings by assessing lipid particles and markers of inflammation.
She reported having no financial disclosures. The study was funded by the National Institute on Aging.
SOURCE: Karim R et al. Epi/Lifestyle 2020, Abstract MP09.
PHOENIX – Oral estrogen therapy taken within 6 years after the onset of menopause significantly reduced progression of lipid deposition in the carotid arterial wall, compared with placebo. However, starting oral estrogen 10 years after menopause did not confer a similar benefit.
“The clinical practice of estradiol therapy has been nothing short of a roller coaster ride,” lead study author Roksana Karim, PhD, MBBS, said in an interview at the Epidemiology and Prevention/Lifestyle and Cardiometabolic Health meeting sponsored by the American Heart Association. “Clinicians have been sort of conservative in terms of prescribing estradiol therapy. But over the last 2 decades things have changed, and eventually the timing hypothesis evolved based on the final analysis of the Women’s Health Initiative results as well.”
The findings come from a secondary analysis of the Early Versus Late Intervention Trial With Estradiol (ELITE), which examined the effects of oral 17-beta-estradiol (estrogen) on the progression of early atherosclerosis and cognitive decline in healthy postmenopausal women.
In the original trial, 643 healthy postmenopausal women were randomized to receive 1 mg/day of estradiol or a placebo pill either within 6 years after the onset of menopause or more than a decade after menopause (N Engl J Med 2016;374[13]:1221-31). All study participants took estradiol or placebo daily for an average of 5 years. The study’s initial findings showed that the mean carotid intima-media thickness progression rate was decreased by 0.0034 mm per year with estradiol, compared with placebo, but only in women who initiated hormone therapy within 6 years of menopause onset.
For the current analysis, researchers led by Dr. Karim looked further into estradiol’s impact on heart health by using echogenicity to analyze lipids in the arterial wall among the ELITE participants. The main outcome of interest was gray-scale median (GSM, unitless), a qualitative measure of atherosclerosis based on echogenicity obtained by high-resolution ultrasonography of the common carotid arterial wall. Whereas higher GSM values result with plaques rich in calcium and fibrous tissue, lower GSM values indicate more lipid deposition.
Dr. Karim, an associate professor of clinical preventive medicine at the University of Southern California, Los Angeles, and colleagues assessed GSM and serum concentrations of estradiol every 6 months over a median 5-year trial period, and used linear mixed effects regression models to compare the rate of GSM progression between the randomized groups within time-since-menopause strata.
The researchers found that effect of estradiol on the annual rate of GSM progression significantly differed between women in the early and late postmenopause groups (P for interaction = .006). Specifically, the annual GSM progression rate among women in early postmenopause fell by 0.30 per year in women taking estradiol, compared with 1.41 per year in those in the placebo group (P less than .0001), indicating significantly more atherosclerosis in the placebo group. On the other hand, the annual GSM progression rate was not significantly different between the estradiol and placebo groups among the late postmenopausal women (P = .37).
“I think this should comfort clinicians in terms of prescribing estradiol therapy to women who don’t have any contraindications and who are within 6 years of menopause,” Dr. Karim said. “Accumulation of lipids is the key event for atherosclerosis progression.” She and her colleagues also observed that the positive association between mean on-trial serum estradiol levels and GSM progression rate was stronger and significant among early postmenopausal women (P = .008), compared with women in the late postmenopausal group (P = .003). However, this differential association between estradiol level and GSM progression rate was not statistically significant (P for interaction = .33).
“This study is important and raises a critical question: Is there a time period where getting hormone therapy would be most beneficial for the heart?” Nieca Goldberg, MD, medical director of the New York University women’s heart program and senior advisor for women’s health strategy at NYU Langone Health, said in an interview. “I think more studies and more analyses are needed, but we haven’t changed the indications for estradiol. We’re not giving estradiol to prevent progression of heart disease. We use estradiol hormone therapy as indicated for women who are having menopausal symptoms.”
Dr. Karim and colleagues plan to conduct a follow-up analysis from the same cohort of ELITE study participants to validate the findings by assessing lipid particles and markers of inflammation.
She reported having no financial disclosures. The study was funded by the National Institute on Aging.
SOURCE: Karim R et al. Epi/Lifestyle 2020, Abstract MP09.
PHOENIX – Oral estrogen therapy taken within 6 years after the onset of menopause significantly reduced progression of lipid deposition in the carotid arterial wall, compared with placebo. However, starting oral estrogen 10 years after menopause did not confer a similar benefit.
“The clinical practice of estradiol therapy has been nothing short of a roller coaster ride,” lead study author Roksana Karim, PhD, MBBS, said in an interview at the Epidemiology and Prevention/Lifestyle and Cardiometabolic Health meeting sponsored by the American Heart Association. “Clinicians have been sort of conservative in terms of prescribing estradiol therapy. But over the last 2 decades things have changed, and eventually the timing hypothesis evolved based on the final analysis of the Women’s Health Initiative results as well.”
The findings come from a secondary analysis of the Early Versus Late Intervention Trial With Estradiol (ELITE), which examined the effects of oral 17-beta-estradiol (estrogen) on the progression of early atherosclerosis and cognitive decline in healthy postmenopausal women.
In the original trial, 643 healthy postmenopausal women were randomized to receive 1 mg/day of estradiol or a placebo pill either within 6 years after the onset of menopause or more than a decade after menopause (N Engl J Med 2016;374[13]:1221-31). All study participants took estradiol or placebo daily for an average of 5 years. The study’s initial findings showed that the mean carotid intima-media thickness progression rate was decreased by 0.0034 mm per year with estradiol, compared with placebo, but only in women who initiated hormone therapy within 6 years of menopause onset.
For the current analysis, researchers led by Dr. Karim looked further into estradiol’s impact on heart health by using echogenicity to analyze lipids in the arterial wall among the ELITE participants. The main outcome of interest was gray-scale median (GSM, unitless), a qualitative measure of atherosclerosis based on echogenicity obtained by high-resolution ultrasonography of the common carotid arterial wall. Whereas higher GSM values result with plaques rich in calcium and fibrous tissue, lower GSM values indicate more lipid deposition.
Dr. Karim, an associate professor of clinical preventive medicine at the University of Southern California, Los Angeles, and colleagues assessed GSM and serum concentrations of estradiol every 6 months over a median 5-year trial period, and used linear mixed effects regression models to compare the rate of GSM progression between the randomized groups within time-since-menopause strata.
The researchers found that effect of estradiol on the annual rate of GSM progression significantly differed between women in the early and late postmenopause groups (P for interaction = .006). Specifically, the annual GSM progression rate among women in early postmenopause fell by 0.30 per year in women taking estradiol, compared with 1.41 per year in those in the placebo group (P less than .0001), indicating significantly more atherosclerosis in the placebo group. On the other hand, the annual GSM progression rate was not significantly different between the estradiol and placebo groups among the late postmenopausal women (P = .37).
“I think this should comfort clinicians in terms of prescribing estradiol therapy to women who don’t have any contraindications and who are within 6 years of menopause,” Dr. Karim said. “Accumulation of lipids is the key event for atherosclerosis progression.” She and her colleagues also observed that the positive association between mean on-trial serum estradiol levels and GSM progression rate was stronger and significant among early postmenopausal women (P = .008), compared with women in the late postmenopausal group (P = .003). However, this differential association between estradiol level and GSM progression rate was not statistically significant (P for interaction = .33).
“This study is important and raises a critical question: Is there a time period where getting hormone therapy would be most beneficial for the heart?” Nieca Goldberg, MD, medical director of the New York University women’s heart program and senior advisor for women’s health strategy at NYU Langone Health, said in an interview. “I think more studies and more analyses are needed, but we haven’t changed the indications for estradiol. We’re not giving estradiol to prevent progression of heart disease. We use estradiol hormone therapy as indicated for women who are having menopausal symptoms.”
Dr. Karim and colleagues plan to conduct a follow-up analysis from the same cohort of ELITE study participants to validate the findings by assessing lipid particles and markers of inflammation.
She reported having no financial disclosures. The study was funded by the National Institute on Aging.
SOURCE: Karim R et al. Epi/Lifestyle 2020, Abstract MP09.
REPORTING FROM EPI/LIFESTYLE 2020
Monthly injection therapy for HIV found noninferior to daily oral dosing
Two international phase 3 randomized trials of according to reports published in the New England Journal of Medicine.
The Long-Acting Cabotegravir and Rilpivirine after Oral Induction for HIV-1 Infection (FLAIR) study and the Long-Acting Cabotegravir and Rilpivirine for Maintenance of HIV-1 Suppression (ATLAS) study looked at a separate facet of the use of a monthly therapeutic injection as a replacement for daily oral HIV therapy.
The FLAIR trial (ClinicalTrials.gov number, NCT02938520) was a phase 3, randomized, open-label study in which adults with HIV-1 infection who had not previously received antiretroviral therapy were given 20 weeks of daily oral induction therapy with dolutegravir–abacavir–lamivudine. Those patients with an HIV-1 RNA level of less than 50 copies per milliliter after 16 weeks were then randomly assigned (1:1) to continue their current oral therapy or switch to oral cabotegravir plus rilpivirine for 1 month followed by monthly intramuscular injections of long-acting cabotegravir, an HIV-1 integrase strand-transfer inhibitor, and rilpivirine, a nonnucleoside reverse-transcriptase inhibitor.
At week 48, an HIV-1 RNA level of 50 copies per milliliter or higher was found in 6 of 283 patients (2.1%) who received the long-acting therapy and in 7 of 283 (2.5%) who received oral therapy, which met the criterion for noninferiority for the primary endpoint. An HIV-1 RNA level of less than 50 copies per milliliter at week 48 was found in 93.6% of patients who received long-acting therapy and in 93.3% who received oral therapy, which also met the criterion for noninferiority, according to the study published in the New England Journal of Medicine.
Injection site reactions were reported in 86% of the long-acting therapy patients, 4 of whom withdrew from the trial for injection-related reasons. Grade 3 or higher adverse events and events that met liver-related stopping criteria occurred in 11% and 2%, respectively, of those who received long-acting therapy and in 4% and 1% of those who received oral therapy.
An assessment of treatment satisfaction at 48 weeks showed that 91% of the patients who switched to long-acting therapy preferred it to their daily oral therapy.
The ATLAS trial (ClinicalTrials.gov number, NCT02951052) was a phase 3, open-label, multicenter, noninferiority trial involving patients who had plasma HIV-1 RNA levels of less than 50 copies per milliliter for at least 6 months while taking standard oral antiretroviral therapy. These patients were randomized (308 in each group) to the long-acting cabotegravir plus rilpivirine injection therapy or daily oral therapy.
At 48 weeks, HIV-1 RNA levels of 50 copies per milliliter or higher were found in five participants (1.6%) receiving long-acting therapy and in three (1.0%) receiving oral therapy, which met the criterion for noninferiority for the primary endpoint, according to a study reported in the New England Journal of Medicine.
HIV-1 RNA levels of less than 50 copies per milliliter at week 48 occurred in 92.5% of patients on long-acting therapy and in 95.5% of those receiving oral therapy, which also met the criterion for noninferiority for this endpoint. Three patients in the long-acting therapy group had virologic failure, compared with four participants who received oral therapy.
Adverse events were more common in the long-acting–therapy group and included injection-site pain, which occurred in 231 recipients (75%) of long-acting therapy. This was mild or moderate in most cases, according to the authors. However, 1% of the participants in this group withdrew because of it. Overall, serious adverse events were reported in no more than 5% of participants in each group.
Together, the ATLAS and the FLAIR trials show that long-acting intramuscular injection therapy is noninferior to oral therapy as both an early regimen for HIV treatment, as well as for later, maintenance dosing. The use of long-acting therapy may improve patient adherence to treatment, according to both sets of study authors.
The ATLAS and FLAIR trials were funded by ViiV Healthcare and Janssen. The authors of both studies reported ties to pharmaceutical associations, and some authors are employees of the two funding sources.
SOURCE: Orkin C et al. N Engl J Med. 2020 Mar 4. doi: 10.1056/NEJMoa1909512 and Swindells S et al. N Engl J Med. 2020 Mar 4. doi: 10.1056/NEJMoa1904398.
Two international phase 3 randomized trials of according to reports published in the New England Journal of Medicine.
The Long-Acting Cabotegravir and Rilpivirine after Oral Induction for HIV-1 Infection (FLAIR) study and the Long-Acting Cabotegravir and Rilpivirine for Maintenance of HIV-1 Suppression (ATLAS) study looked at a separate facet of the use of a monthly therapeutic injection as a replacement for daily oral HIV therapy.
The FLAIR trial (ClinicalTrials.gov number, NCT02938520) was a phase 3, randomized, open-label study in which adults with HIV-1 infection who had not previously received antiretroviral therapy were given 20 weeks of daily oral induction therapy with dolutegravir–abacavir–lamivudine. Those patients with an HIV-1 RNA level of less than 50 copies per milliliter after 16 weeks were then randomly assigned (1:1) to continue their current oral therapy or switch to oral cabotegravir plus rilpivirine for 1 month followed by monthly intramuscular injections of long-acting cabotegravir, an HIV-1 integrase strand-transfer inhibitor, and rilpivirine, a nonnucleoside reverse-transcriptase inhibitor.
At week 48, an HIV-1 RNA level of 50 copies per milliliter or higher was found in 6 of 283 patients (2.1%) who received the long-acting therapy and in 7 of 283 (2.5%) who received oral therapy, which met the criterion for noninferiority for the primary endpoint. An HIV-1 RNA level of less than 50 copies per milliliter at week 48 was found in 93.6% of patients who received long-acting therapy and in 93.3% who received oral therapy, which also met the criterion for noninferiority, according to the study published in the New England Journal of Medicine.
Injection site reactions were reported in 86% of the long-acting therapy patients, 4 of whom withdrew from the trial for injection-related reasons. Grade 3 or higher adverse events and events that met liver-related stopping criteria occurred in 11% and 2%, respectively, of those who received long-acting therapy and in 4% and 1% of those who received oral therapy.
An assessment of treatment satisfaction at 48 weeks showed that 91% of the patients who switched to long-acting therapy preferred it to their daily oral therapy.
The ATLAS trial (ClinicalTrials.gov number, NCT02951052) was a phase 3, open-label, multicenter, noninferiority trial involving patients who had plasma HIV-1 RNA levels of less than 50 copies per milliliter for at least 6 months while taking standard oral antiretroviral therapy. These patients were randomized (308 in each group) to the long-acting cabotegravir plus rilpivirine injection therapy or daily oral therapy.
At 48 weeks, HIV-1 RNA levels of 50 copies per milliliter or higher were found in five participants (1.6%) receiving long-acting therapy and in three (1.0%) receiving oral therapy, which met the criterion for noninferiority for the primary endpoint, according to a study reported in the New England Journal of Medicine.
HIV-1 RNA levels of less than 50 copies per milliliter at week 48 occurred in 92.5% of patients on long-acting therapy and in 95.5% of those receiving oral therapy, which also met the criterion for noninferiority for this endpoint. Three patients in the long-acting therapy group had virologic failure, compared with four participants who received oral therapy.
Adverse events were more common in the long-acting–therapy group and included injection-site pain, which occurred in 231 recipients (75%) of long-acting therapy. This was mild or moderate in most cases, according to the authors. However, 1% of the participants in this group withdrew because of it. Overall, serious adverse events were reported in no more than 5% of participants in each group.
Together, the ATLAS and the FLAIR trials show that long-acting intramuscular injection therapy is noninferior to oral therapy as both an early regimen for HIV treatment, as well as for later, maintenance dosing. The use of long-acting therapy may improve patient adherence to treatment, according to both sets of study authors.
The ATLAS and FLAIR trials were funded by ViiV Healthcare and Janssen. The authors of both studies reported ties to pharmaceutical associations, and some authors are employees of the two funding sources.
SOURCE: Orkin C et al. N Engl J Med. 2020 Mar 4. doi: 10.1056/NEJMoa1909512 and Swindells S et al. N Engl J Med. 2020 Mar 4. doi: 10.1056/NEJMoa1904398.
Two international phase 3 randomized trials of according to reports published in the New England Journal of Medicine.
The Long-Acting Cabotegravir and Rilpivirine after Oral Induction for HIV-1 Infection (FLAIR) study and the Long-Acting Cabotegravir and Rilpivirine for Maintenance of HIV-1 Suppression (ATLAS) study looked at a separate facet of the use of a monthly therapeutic injection as a replacement for daily oral HIV therapy.
The FLAIR trial (ClinicalTrials.gov number, NCT02938520) was a phase 3, randomized, open-label study in which adults with HIV-1 infection who had not previously received antiretroviral therapy were given 20 weeks of daily oral induction therapy with dolutegravir–abacavir–lamivudine. Those patients with an HIV-1 RNA level of less than 50 copies per milliliter after 16 weeks were then randomly assigned (1:1) to continue their current oral therapy or switch to oral cabotegravir plus rilpivirine for 1 month followed by monthly intramuscular injections of long-acting cabotegravir, an HIV-1 integrase strand-transfer inhibitor, and rilpivirine, a nonnucleoside reverse-transcriptase inhibitor.
At week 48, an HIV-1 RNA level of 50 copies per milliliter or higher was found in 6 of 283 patients (2.1%) who received the long-acting therapy and in 7 of 283 (2.5%) who received oral therapy, which met the criterion for noninferiority for the primary endpoint. An HIV-1 RNA level of less than 50 copies per milliliter at week 48 was found in 93.6% of patients who received long-acting therapy and in 93.3% who received oral therapy, which also met the criterion for noninferiority, according to the study published in the New England Journal of Medicine.
Injection site reactions were reported in 86% of the long-acting therapy patients, 4 of whom withdrew from the trial for injection-related reasons. Grade 3 or higher adverse events and events that met liver-related stopping criteria occurred in 11% and 2%, respectively, of those who received long-acting therapy and in 4% and 1% of those who received oral therapy.
An assessment of treatment satisfaction at 48 weeks showed that 91% of the patients who switched to long-acting therapy preferred it to their daily oral therapy.
The ATLAS trial (ClinicalTrials.gov number, NCT02951052) was a phase 3, open-label, multicenter, noninferiority trial involving patients who had plasma HIV-1 RNA levels of less than 50 copies per milliliter for at least 6 months while taking standard oral antiretroviral therapy. These patients were randomized (308 in each group) to the long-acting cabotegravir plus rilpivirine injection therapy or daily oral therapy.
At 48 weeks, HIV-1 RNA levels of 50 copies per milliliter or higher were found in five participants (1.6%) receiving long-acting therapy and in three (1.0%) receiving oral therapy, which met the criterion for noninferiority for the primary endpoint, according to a study reported in the New England Journal of Medicine.
HIV-1 RNA levels of less than 50 copies per milliliter at week 48 occurred in 92.5% of patients on long-acting therapy and in 95.5% of those receiving oral therapy, which also met the criterion for noninferiority for this endpoint. Three patients in the long-acting therapy group had virologic failure, compared with four participants who received oral therapy.
Adverse events were more common in the long-acting–therapy group and included injection-site pain, which occurred in 231 recipients (75%) of long-acting therapy. This was mild or moderate in most cases, according to the authors. However, 1% of the participants in this group withdrew because of it. Overall, serious adverse events were reported in no more than 5% of participants in each group.
Together, the ATLAS and the FLAIR trials show that long-acting intramuscular injection therapy is noninferior to oral therapy as both an early regimen for HIV treatment, as well as for later, maintenance dosing. The use of long-acting therapy may improve patient adherence to treatment, according to both sets of study authors.
The ATLAS and FLAIR trials were funded by ViiV Healthcare and Janssen. The authors of both studies reported ties to pharmaceutical associations, and some authors are employees of the two funding sources.
SOURCE: Orkin C et al. N Engl J Med. 2020 Mar 4. doi: 10.1056/NEJMoa1909512 and Swindells S et al. N Engl J Med. 2020 Mar 4. doi: 10.1056/NEJMoa1904398.
FROM THE NEW ENGLAND JOURNAL OF MEDICINE
Genetic variants in nudix hydrolase linked to thiopurine myelosuppression
MAUI, HAWAII – There’s a new kid on the block to worry about when it comes to thiopurine pharmacogenetics: Genetic variants in the thiopurine-metabolizing enzyme nudix hydrolase 15 have been linked to a markedly increased risk of thiopurine myelosuppression among inflammatory bowel disease patients.
The Food and Drug Administration and others already recommend screening for genetic variants in thiopurine methyltransferase (TPMT), another enzyme that metabolizes thiopurine. Polymorphisms lead to TMPT dysfunction, accumulation of cytotoxic metabolites, and increased risk of thiopurine-induced myelosuppression (TIM). Carriers are advised to use reduced doses with careful drug monitoring, or to skip thiopurines altogether.
A similar picture is emerging for nudix hydrolase 15 (NUDT15). It’s been known for several years that genetic variants are not uncommon among East Asian people and lead to TIM, but their prevalence and impact among people of European decent wasn’t clearly understood until now.
Investigators led by Gareth Walker, MBBS, of the Royal Devon and Exeter Hospital in Exeter, England, compared rates of problematic TMPT and NUDT15 variants among European inflammatory bowel disease patients who had developed TIM and those who had not, about 1,000 patients in all. The majority were on azathioprine and had Crohn’s disease. Finnish people were excluded because “their unique genetic background ... has led to the enrichment of some disease-causing gene variants and losses of others,” according to the study, which was published in JAMA.
Carriage of any of three coding NUDT15 variants greatly increased the risk of TIM (odds ratio, 27.3; 95% confidence interval, 9.3-116.7), independent of TPMT genotype and thiopurine dose. A particular variant – an in-frame deletion in NUDT15 – increased the risk 38-fold (95% CI, 5.1-286.1), and was carried by 5.8% of TIM patients.
The analysis also confirmed the importance of TPMT variants, which were found in 30.5% of TIM patients (95/311) versus 16.4% (100/608) of patients who did not develop TIM.
“Patients with variants of either NUDT15 or TPMT, or among those with variants of both genes, had a faster onset of TIM, more severe TIM, and had a greater need for granulocyte colony–stimulating factor rescue therapy. ... Our data suggest that pretreatment sequencing of the NUDT15 gene ... may be considered prior to initiation of thiopurine therapy,” the team concluded.
The prevalence of problematic NUDT15 variants among non-Finnish Europeans is about 1.6%, 6.9% among people from Finland, and almost 30% among East Asians. The team estimated NUDT15 would have to be genotyped in 95 non-Finnish Europeans to prevent one case of TIM; the number is 123 for TPMT. “Given the widespread use of thiopurines” – primarily in rheumatology and transplant medicine, in addition to gastroenterology – “these findings may have ramifications beyond the management of IBD,” the investigators wrote.
“I do think it’s worthwhile” to screen for NUDT15, said Edward Loftus, MD, a professor and consultant in the division of gastroenterology and hepatology at the Mayo Clinic in Rochester, Minn., who reviewed the study at the Gastroenterology Updates, IBD, Liver Disease Conference. “If you are a homozygote for this, your chance of getting profound leukopenia is very high, so I would probably not use a thiopurine.”
“If you are going to start low dose on everyone” with careful blood monitoring, “I suppose you could just do that, but I would say if you can get” the test and “are reassured the patient is not” carrying problematic NUDT15 or TMPT variants, “then I think you just go ahead and do full dose,” he said.
Testing for the relevant variants is available through the Mayo Clinic and several commercial labs.
“Even though the thiopurine dose is adjusted based on genotype, patients still need to be monitored closely for the development of thiopurine-induced myelosuppression as” TMPT and NUDT15 variants “do not explain all cases of” TIM, Marieke Coenen, PhD, an associate professor of pharmacogenetics at Radboud University Medical Center in Nijmegen, the Netherlands, cautioned in an editorial (Transl Gastroenterol Hepatol. 2019 Dec 12;4:81).
The prevalence of problematic NUDT15 variants is 0.7% among African and 20.7% among Hispanic people.
The work was funded by the National Institutes of Health, Crohn’s & Colitis UK, the Wellcome Trust, and others. Dr. Walker and other investigators reported numerous industry ties. Dr. Loftus is a consultant and/or has research funding from Abbott, Pfizer, and other companies. Dr. Coenen had no disclosures.
SOURCE: Walker GJ et al. JAMA. 2019 Feb 26;321(8):773-85.
MAUI, HAWAII – There’s a new kid on the block to worry about when it comes to thiopurine pharmacogenetics: Genetic variants in the thiopurine-metabolizing enzyme nudix hydrolase 15 have been linked to a markedly increased risk of thiopurine myelosuppression among inflammatory bowel disease patients.
The Food and Drug Administration and others already recommend screening for genetic variants in thiopurine methyltransferase (TPMT), another enzyme that metabolizes thiopurine. Polymorphisms lead to TMPT dysfunction, accumulation of cytotoxic metabolites, and increased risk of thiopurine-induced myelosuppression (TIM). Carriers are advised to use reduced doses with careful drug monitoring, or to skip thiopurines altogether.
A similar picture is emerging for nudix hydrolase 15 (NUDT15). It’s been known for several years that genetic variants are not uncommon among East Asian people and lead to TIM, but their prevalence and impact among people of European decent wasn’t clearly understood until now.
Investigators led by Gareth Walker, MBBS, of the Royal Devon and Exeter Hospital in Exeter, England, compared rates of problematic TMPT and NUDT15 variants among European inflammatory bowel disease patients who had developed TIM and those who had not, about 1,000 patients in all. The majority were on azathioprine and had Crohn’s disease. Finnish people were excluded because “their unique genetic background ... has led to the enrichment of some disease-causing gene variants and losses of others,” according to the study, which was published in JAMA.
Carriage of any of three coding NUDT15 variants greatly increased the risk of TIM (odds ratio, 27.3; 95% confidence interval, 9.3-116.7), independent of TPMT genotype and thiopurine dose. A particular variant – an in-frame deletion in NUDT15 – increased the risk 38-fold (95% CI, 5.1-286.1), and was carried by 5.8% of TIM patients.
The analysis also confirmed the importance of TPMT variants, which were found in 30.5% of TIM patients (95/311) versus 16.4% (100/608) of patients who did not develop TIM.
“Patients with variants of either NUDT15 or TPMT, or among those with variants of both genes, had a faster onset of TIM, more severe TIM, and had a greater need for granulocyte colony–stimulating factor rescue therapy. ... Our data suggest that pretreatment sequencing of the NUDT15 gene ... may be considered prior to initiation of thiopurine therapy,” the team concluded.
The prevalence of problematic NUDT15 variants among non-Finnish Europeans is about 1.6%, 6.9% among people from Finland, and almost 30% among East Asians. The team estimated NUDT15 would have to be genotyped in 95 non-Finnish Europeans to prevent one case of TIM; the number is 123 for TPMT. “Given the widespread use of thiopurines” – primarily in rheumatology and transplant medicine, in addition to gastroenterology – “these findings may have ramifications beyond the management of IBD,” the investigators wrote.
“I do think it’s worthwhile” to screen for NUDT15, said Edward Loftus, MD, a professor and consultant in the division of gastroenterology and hepatology at the Mayo Clinic in Rochester, Minn., who reviewed the study at the Gastroenterology Updates, IBD, Liver Disease Conference. “If you are a homozygote for this, your chance of getting profound leukopenia is very high, so I would probably not use a thiopurine.”
“If you are going to start low dose on everyone” with careful blood monitoring, “I suppose you could just do that, but I would say if you can get” the test and “are reassured the patient is not” carrying problematic NUDT15 or TMPT variants, “then I think you just go ahead and do full dose,” he said.
Testing for the relevant variants is available through the Mayo Clinic and several commercial labs.
“Even though the thiopurine dose is adjusted based on genotype, patients still need to be monitored closely for the development of thiopurine-induced myelosuppression as” TMPT and NUDT15 variants “do not explain all cases of” TIM, Marieke Coenen, PhD, an associate professor of pharmacogenetics at Radboud University Medical Center in Nijmegen, the Netherlands, cautioned in an editorial (Transl Gastroenterol Hepatol. 2019 Dec 12;4:81).
The prevalence of problematic NUDT15 variants is 0.7% among African and 20.7% among Hispanic people.
The work was funded by the National Institutes of Health, Crohn’s & Colitis UK, the Wellcome Trust, and others. Dr. Walker and other investigators reported numerous industry ties. Dr. Loftus is a consultant and/or has research funding from Abbott, Pfizer, and other companies. Dr. Coenen had no disclosures.
SOURCE: Walker GJ et al. JAMA. 2019 Feb 26;321(8):773-85.
MAUI, HAWAII – There’s a new kid on the block to worry about when it comes to thiopurine pharmacogenetics: Genetic variants in the thiopurine-metabolizing enzyme nudix hydrolase 15 have been linked to a markedly increased risk of thiopurine myelosuppression among inflammatory bowel disease patients.
The Food and Drug Administration and others already recommend screening for genetic variants in thiopurine methyltransferase (TPMT), another enzyme that metabolizes thiopurine. Polymorphisms lead to TMPT dysfunction, accumulation of cytotoxic metabolites, and increased risk of thiopurine-induced myelosuppression (TIM). Carriers are advised to use reduced doses with careful drug monitoring, or to skip thiopurines altogether.
A similar picture is emerging for nudix hydrolase 15 (NUDT15). It’s been known for several years that genetic variants are not uncommon among East Asian people and lead to TIM, but their prevalence and impact among people of European decent wasn’t clearly understood until now.
Investigators led by Gareth Walker, MBBS, of the Royal Devon and Exeter Hospital in Exeter, England, compared rates of problematic TMPT and NUDT15 variants among European inflammatory bowel disease patients who had developed TIM and those who had not, about 1,000 patients in all. The majority were on azathioprine and had Crohn’s disease. Finnish people were excluded because “their unique genetic background ... has led to the enrichment of some disease-causing gene variants and losses of others,” according to the study, which was published in JAMA.
Carriage of any of three coding NUDT15 variants greatly increased the risk of TIM (odds ratio, 27.3; 95% confidence interval, 9.3-116.7), independent of TPMT genotype and thiopurine dose. A particular variant – an in-frame deletion in NUDT15 – increased the risk 38-fold (95% CI, 5.1-286.1), and was carried by 5.8% of TIM patients.
The analysis also confirmed the importance of TPMT variants, which were found in 30.5% of TIM patients (95/311) versus 16.4% (100/608) of patients who did not develop TIM.
“Patients with variants of either NUDT15 or TPMT, or among those with variants of both genes, had a faster onset of TIM, more severe TIM, and had a greater need for granulocyte colony–stimulating factor rescue therapy. ... Our data suggest that pretreatment sequencing of the NUDT15 gene ... may be considered prior to initiation of thiopurine therapy,” the team concluded.
The prevalence of problematic NUDT15 variants among non-Finnish Europeans is about 1.6%, 6.9% among people from Finland, and almost 30% among East Asians. The team estimated NUDT15 would have to be genotyped in 95 non-Finnish Europeans to prevent one case of TIM; the number is 123 for TPMT. “Given the widespread use of thiopurines” – primarily in rheumatology and transplant medicine, in addition to gastroenterology – “these findings may have ramifications beyond the management of IBD,” the investigators wrote.
“I do think it’s worthwhile” to screen for NUDT15, said Edward Loftus, MD, a professor and consultant in the division of gastroenterology and hepatology at the Mayo Clinic in Rochester, Minn., who reviewed the study at the Gastroenterology Updates, IBD, Liver Disease Conference. “If you are a homozygote for this, your chance of getting profound leukopenia is very high, so I would probably not use a thiopurine.”
“If you are going to start low dose on everyone” with careful blood monitoring, “I suppose you could just do that, but I would say if you can get” the test and “are reassured the patient is not” carrying problematic NUDT15 or TMPT variants, “then I think you just go ahead and do full dose,” he said.
Testing for the relevant variants is available through the Mayo Clinic and several commercial labs.
“Even though the thiopurine dose is adjusted based on genotype, patients still need to be monitored closely for the development of thiopurine-induced myelosuppression as” TMPT and NUDT15 variants “do not explain all cases of” TIM, Marieke Coenen, PhD, an associate professor of pharmacogenetics at Radboud University Medical Center in Nijmegen, the Netherlands, cautioned in an editorial (Transl Gastroenterol Hepatol. 2019 Dec 12;4:81).
The prevalence of problematic NUDT15 variants is 0.7% among African and 20.7% among Hispanic people.
The work was funded by the National Institutes of Health, Crohn’s & Colitis UK, the Wellcome Trust, and others. Dr. Walker and other investigators reported numerous industry ties. Dr. Loftus is a consultant and/or has research funding from Abbott, Pfizer, and other companies. Dr. Coenen had no disclosures.
SOURCE: Walker GJ et al. JAMA. 2019 Feb 26;321(8):773-85.
REPORTING FROM GUILD 2020
Family history of MI may increase CVD mortality after bilateral salpingo-oophorectomy
Family history of premature MI (FHPMI) in women with bilateral salpingo-oophorectomy (BSO) modifies the increased mortality associated with heart disease and cardiovascular disease in those women, according to an analysis published in Menopause.
Duke Appiah, PhD, of the department of public health at Texas Tech University Health Sciences Center, Lubbock, and colleagues drew data for 4,066 postmenopausal women aged 40 years and older from the National Health and Nutrition Examination Survey III (1988-1994). Women were excluded if they had partial or unilateral oophorectomy; unknown or missing age at menopause; or prevalent MI, stroke, or heart failure, which left a sample of 2,763 women for the analysis.
Women with BSO were considered postmenopausal if they had not experienced a menstrual period within the previous 12 months. Women were asked whether any blood relatives, and especially any first-degree relatives, had a heart attack before age 50 years, which was considered premature MI. The average age at baseline was 62 years. Of those 2,763 women, 610 women had BSO, 338 had FHPMI, and 95 had both, which yields weighted proportions of 24%, 15%, and 5%, respectively.
When compared with having neither factor, presence of any FHPMI was modestly associated with increased risk of mortality from heart disease (HD), cardiovascular disease (CVD), and all causes in the multivariable adjusted analysis, and having undergone BSO was not significantly associated with any of those on its own. However, the combination of those two factors yielded much higher multivariable adjusted hazard ratios – HD mortality, 2.88; CVD mortality, 2.05; and all-cause mortality, 1.58.
These multivariable adjusted HRs were even more dramatic with first-degree FHPMI and BSO: 3.51 for HD mortality, 2.55 for CVD mortality, and 1.63 for all-cause mortality.
In the women who had the combination of FHPMI and BSO, the elevated risks of HD, CVD, and all-cause mortality “were stronger in women who underwent BSO before the age of 45 years than among those who had this procedure at or after the age of 45 years,” reported Dr. Appiah and colleagues. A significantly elevated risk of HD, CVD, or all-cause mortality was not evident in women with BSO alone “regardless of age at surgery.”
“This study provides additional evidence that removal of the ovaries before the natural age of menopause is associated with multiple adverse long-term health outcomes, including cardiovascular disease and early mortality and should be strongly discouraged in women who are not at increased genetic risk for ovarian cancer,” Stephanie Faubion, MD, medical director of North American of Menopause Science, commented in a press release. She was not involved in the study.
Limitations of the study include how FHPMI was self-reported; however, the investigators suggested that, given findings of other research regarding reporting family history (Genet Epidemiol. 1999;17:141-50), the true rate may actually have been underreported. The investigators cited the large, population-based sample size as one of the study’s strengths, suggesting it helps make the findings generalizable.
The investigators disclosed no external funding or conflicts of interest.
SOURCE: Appiah D et al. Menopause. 2020 Feb. doi: 10.1097/GME.0000000000001522.
Family history of premature MI (FHPMI) in women with bilateral salpingo-oophorectomy (BSO) modifies the increased mortality associated with heart disease and cardiovascular disease in those women, according to an analysis published in Menopause.
Duke Appiah, PhD, of the department of public health at Texas Tech University Health Sciences Center, Lubbock, and colleagues drew data for 4,066 postmenopausal women aged 40 years and older from the National Health and Nutrition Examination Survey III (1988-1994). Women were excluded if they had partial or unilateral oophorectomy; unknown or missing age at menopause; or prevalent MI, stroke, or heart failure, which left a sample of 2,763 women for the analysis.
Women with BSO were considered postmenopausal if they had not experienced a menstrual period within the previous 12 months. Women were asked whether any blood relatives, and especially any first-degree relatives, had a heart attack before age 50 years, which was considered premature MI. The average age at baseline was 62 years. Of those 2,763 women, 610 women had BSO, 338 had FHPMI, and 95 had both, which yields weighted proportions of 24%, 15%, and 5%, respectively.
When compared with having neither factor, presence of any FHPMI was modestly associated with increased risk of mortality from heart disease (HD), cardiovascular disease (CVD), and all causes in the multivariable adjusted analysis, and having undergone BSO was not significantly associated with any of those on its own. However, the combination of those two factors yielded much higher multivariable adjusted hazard ratios – HD mortality, 2.88; CVD mortality, 2.05; and all-cause mortality, 1.58.
These multivariable adjusted HRs were even more dramatic with first-degree FHPMI and BSO: 3.51 for HD mortality, 2.55 for CVD mortality, and 1.63 for all-cause mortality.
In the women who had the combination of FHPMI and BSO, the elevated risks of HD, CVD, and all-cause mortality “were stronger in women who underwent BSO before the age of 45 years than among those who had this procedure at or after the age of 45 years,” reported Dr. Appiah and colleagues. A significantly elevated risk of HD, CVD, or all-cause mortality was not evident in women with BSO alone “regardless of age at surgery.”
“This study provides additional evidence that removal of the ovaries before the natural age of menopause is associated with multiple adverse long-term health outcomes, including cardiovascular disease and early mortality and should be strongly discouraged in women who are not at increased genetic risk for ovarian cancer,” Stephanie Faubion, MD, medical director of North American of Menopause Science, commented in a press release. She was not involved in the study.
Limitations of the study include how FHPMI was self-reported; however, the investigators suggested that, given findings of other research regarding reporting family history (Genet Epidemiol. 1999;17:141-50), the true rate may actually have been underreported. The investigators cited the large, population-based sample size as one of the study’s strengths, suggesting it helps make the findings generalizable.
The investigators disclosed no external funding or conflicts of interest.
SOURCE: Appiah D et al. Menopause. 2020 Feb. doi: 10.1097/GME.0000000000001522.
Family history of premature MI (FHPMI) in women with bilateral salpingo-oophorectomy (BSO) modifies the increased mortality associated with heart disease and cardiovascular disease in those women, according to an analysis published in Menopause.
Duke Appiah, PhD, of the department of public health at Texas Tech University Health Sciences Center, Lubbock, and colleagues drew data for 4,066 postmenopausal women aged 40 years and older from the National Health and Nutrition Examination Survey III (1988-1994). Women were excluded if they had partial or unilateral oophorectomy; unknown or missing age at menopause; or prevalent MI, stroke, or heart failure, which left a sample of 2,763 women for the analysis.
Women with BSO were considered postmenopausal if they had not experienced a menstrual period within the previous 12 months. Women were asked whether any blood relatives, and especially any first-degree relatives, had a heart attack before age 50 years, which was considered premature MI. The average age at baseline was 62 years. Of those 2,763 women, 610 women had BSO, 338 had FHPMI, and 95 had both, which yields weighted proportions of 24%, 15%, and 5%, respectively.
When compared with having neither factor, presence of any FHPMI was modestly associated with increased risk of mortality from heart disease (HD), cardiovascular disease (CVD), and all causes in the multivariable adjusted analysis, and having undergone BSO was not significantly associated with any of those on its own. However, the combination of those two factors yielded much higher multivariable adjusted hazard ratios – HD mortality, 2.88; CVD mortality, 2.05; and all-cause mortality, 1.58.
These multivariable adjusted HRs were even more dramatic with first-degree FHPMI and BSO: 3.51 for HD mortality, 2.55 for CVD mortality, and 1.63 for all-cause mortality.
In the women who had the combination of FHPMI and BSO, the elevated risks of HD, CVD, and all-cause mortality “were stronger in women who underwent BSO before the age of 45 years than among those who had this procedure at or after the age of 45 years,” reported Dr. Appiah and colleagues. A significantly elevated risk of HD, CVD, or all-cause mortality was not evident in women with BSO alone “regardless of age at surgery.”
“This study provides additional evidence that removal of the ovaries before the natural age of menopause is associated with multiple adverse long-term health outcomes, including cardiovascular disease and early mortality and should be strongly discouraged in women who are not at increased genetic risk for ovarian cancer,” Stephanie Faubion, MD, medical director of North American of Menopause Science, commented in a press release. She was not involved in the study.
Limitations of the study include how FHPMI was self-reported; however, the investigators suggested that, given findings of other research regarding reporting family history (Genet Epidemiol. 1999;17:141-50), the true rate may actually have been underreported. The investigators cited the large, population-based sample size as one of the study’s strengths, suggesting it helps make the findings generalizable.
The investigators disclosed no external funding or conflicts of interest.
SOURCE: Appiah D et al. Menopause. 2020 Feb. doi: 10.1097/GME.0000000000001522.
FROM MENOPAUSE
FDA issues stronger warning on neuropsychiatric event risk linked to montelukast
The Food and Drug Administration has issued , a prescription drug for asthma and allergy.
The new boxed warning advises health care providers to avoid prescribing montelukast for patients with mild symptoms, particularly those with allergic rhinitis, the FDA said in a press release. The drug was first approved in 1998, and the product labeling was updated in 2008 to include information about neuropsychiatric adverse events reported with usage of montelukast.
While the Sentinel study, along with other observational studies, did not find an increased risk of mental health side effects with montelukast treatment, compared with inhaled corticosteroids, those studies had limitations that may have affected results, the FDA said in the Drug Safety Communication. However, the FDA has continued to receive reports of neuropsychiatric events – including agitation, depression, sleeping problems, and suicidal thoughts and actions – in patients receiving the medication.
“The incidence of neuropsychiatric events associated with montelukast is unknown, but some reports are serious, and many patients and health care professionals are not fully aware of these risks,” Sally Seymour, MD, director of the division of pulmonary, allergy and rheumatology products in the FDA’s Center for Drug Evaluation and Research, said in the press release. “There are many other safe and effective medications to treat allergies with extensive history of use and safety, such that many products are available over the counter without a prescription.”
In addition to the boxed warning, the FDA now requires a new medication guide to be given to patients with each montelukast prescription, the FDA said.
The Food and Drug Administration has issued , a prescription drug for asthma and allergy.
The new boxed warning advises health care providers to avoid prescribing montelukast for patients with mild symptoms, particularly those with allergic rhinitis, the FDA said in a press release. The drug was first approved in 1998, and the product labeling was updated in 2008 to include information about neuropsychiatric adverse events reported with usage of montelukast.
While the Sentinel study, along with other observational studies, did not find an increased risk of mental health side effects with montelukast treatment, compared with inhaled corticosteroids, those studies had limitations that may have affected results, the FDA said in the Drug Safety Communication. However, the FDA has continued to receive reports of neuropsychiatric events – including agitation, depression, sleeping problems, and suicidal thoughts and actions – in patients receiving the medication.
“The incidence of neuropsychiatric events associated with montelukast is unknown, but some reports are serious, and many patients and health care professionals are not fully aware of these risks,” Sally Seymour, MD, director of the division of pulmonary, allergy and rheumatology products in the FDA’s Center for Drug Evaluation and Research, said in the press release. “There are many other safe and effective medications to treat allergies with extensive history of use and safety, such that many products are available over the counter without a prescription.”
In addition to the boxed warning, the FDA now requires a new medication guide to be given to patients with each montelukast prescription, the FDA said.
The Food and Drug Administration has issued , a prescription drug for asthma and allergy.
The new boxed warning advises health care providers to avoid prescribing montelukast for patients with mild symptoms, particularly those with allergic rhinitis, the FDA said in a press release. The drug was first approved in 1998, and the product labeling was updated in 2008 to include information about neuropsychiatric adverse events reported with usage of montelukast.
While the Sentinel study, along with other observational studies, did not find an increased risk of mental health side effects with montelukast treatment, compared with inhaled corticosteroids, those studies had limitations that may have affected results, the FDA said in the Drug Safety Communication. However, the FDA has continued to receive reports of neuropsychiatric events – including agitation, depression, sleeping problems, and suicidal thoughts and actions – in patients receiving the medication.
“The incidence of neuropsychiatric events associated with montelukast is unknown, but some reports are serious, and many patients and health care professionals are not fully aware of these risks,” Sally Seymour, MD, director of the division of pulmonary, allergy and rheumatology products in the FDA’s Center for Drug Evaluation and Research, said in the press release. “There are many other safe and effective medications to treat allergies with extensive history of use and safety, such that many products are available over the counter without a prescription.”
In addition to the boxed warning, the FDA now requires a new medication guide to be given to patients with each montelukast prescription, the FDA said.
RT plus checkpoint blockade active in head and neck cancer
The combination of a phase 2 trial suggests.
“There are convincing arguments that radiation sensitizes patients to immunotherapy and can enhance its effects,” Jared Weiss, MD, associate professor of medicine, UNC Lineberger Comprehensive Cancer, Chapel Hill, North Carolina, said in a statement.
“And the opposite direction also seems to be true – radiation therapy needs a functional immune system to work. Our hope was that pembrolizumab might be a radiation sensitizer for these patients,” he said.
The study was presented at the Multidisciplinary Head and Neck Cancer Symposium, sponsored by the American Society for Radiation Oncology.
Both modalities have had some outstanding results in the past, observed Weiss. “If you look back to the historic studies, radiation alone often cures patients with this disease, while some of the first patients treated with pembrolizumab for recurrent/metastatic cancer are still alive many years out, with no evidence of disease,” he said.
“Our concept was that, in addition to whatever synergy the immunotherapy might provide with radiation, we also conceived of it as a ‘second shot on goal’ towards a cure, because there is durable control with drug alone,” he added.
Single-arm trial
The single-arm trial included 29 patients with locally advanced HNSCC.
Only about 10% of patients were current smokers, but more than half of the study group had a history of smoking. Of those, more than 55% had a history of 10 pack-years or more.
In slightly more than one third of patients, the primary site of the cancer was the base of the tongue. The tonsils were the primary site in slightly more than one third.
Platinum ineligibility was defined by provider and standard measures.
More than two thirds of patients were ineligible to receive cisplatin because of preexisting otopathy, including hearing impairment and tinnitus.
The combination of cisplatin and definitive-dose radiotherapy is standard treatment for locally advanced head and neck cancer, but contraindications to cisplatin are common in everyday clinical practice. Weiss noted that contraindications are present in about one third of his patients.
“We replaced standard, every-3-week cisplatin with pembrolizumab every 3 weeks,” Weiss explained, “and we hypothesized that with the ongoing effects of radiation therapy after completion, that additional adjuvant cycles could further sensitize patients [to the effects of radiation] without impairing recovery, so we added three adjuvant cycles as well,” he added.
With six cycles of an every-3-week drug, patients received 18 weeks of pembrolizumab in total.
Echoing results from the previously reported KEYNOTE-48 trial, pembrolizumab given with radiotherapy instead of chemotherapy led to an overall progression-free survival (PFS) rate of 76% at 1 year and an estimated PFS of 71% at 2 years.
At 1 year, 86% of patients were still alive, and at 2 years, an estimated 75% of patients were still alive, Weiss added.
For patients with human papillomavirus 16–positive cancer, rates of PFS and overall survival were slightly better, at 88% and 94%, respectively.
With regard to toxicities, “For the most part, this [treatment regimen] looks like radiation alone with one very notable exception, which was lymphopenia,” Weiss observed. Grade 3-4 lymphopenia affected 59% of patients.
Lymphocyte count hit bottom at week 4, he added, with only partial recovery at week 20 and no further recovery at 40 weeks. Lymphocyte count alone or any change in it was not predictive of early progression.
However, in comparing patients who experienced early disease progression to patients who did not experience progression, levels of baseline naive B cells in peripheral blood were higher and levels of circulating marginal zone B cells were lower in patients with progressive disease, Weiss reported.
Patient-reported outcomes indicated that common symptoms of treatment peaked at week 10, and there was relative recovery by week 20.
As reflected by Functional Assessment of Cancer Therapy (FACT) scores, which include social, emotional, and functional well-being, as well as the head and neck cancer scale, “we again see a nadir at 10 weeks with relative recovery at 20 weeks,” Weiss noted.
“We found that concurrent pembrolizumab with radiotherapy is a safe and feasible option for locally advanced head and neck cancer patients with cisplatin ineligibility,” Weiss concluded.
More research is being conducted in this area, and multiple ongoing studies will further elucidate the value of PD-1 or PD-L1 checkpoint blockade with definitive radiation therapy, he added.
The study was funded by Merck & Co. Weiss’ institution has received research funding from Celgene, Pfizer, Merck, AZ/Medimmmune, Amgen, Carefusion, G1 Therapeutics, Immunicum, Loxo/Lilly, and the Jimmy V Foundation. Weiss has received honoraria for consulting from AstraZeneca, EMD Serono, Genentech, Inivata, Celgene, G1 Therapeutics, Jounce Therapeutics, Abbvie, Rakuten, Nanobiotix, Azitra, Loxo/Lilly, Pfizer, and Blueprint had has stock in Nektar and Vesselon.
This article first appeared on Medscape.com.
The combination of a phase 2 trial suggests.
“There are convincing arguments that radiation sensitizes patients to immunotherapy and can enhance its effects,” Jared Weiss, MD, associate professor of medicine, UNC Lineberger Comprehensive Cancer, Chapel Hill, North Carolina, said in a statement.
“And the opposite direction also seems to be true – radiation therapy needs a functional immune system to work. Our hope was that pembrolizumab might be a radiation sensitizer for these patients,” he said.
The study was presented at the Multidisciplinary Head and Neck Cancer Symposium, sponsored by the American Society for Radiation Oncology.
Both modalities have had some outstanding results in the past, observed Weiss. “If you look back to the historic studies, radiation alone often cures patients with this disease, while some of the first patients treated with pembrolizumab for recurrent/metastatic cancer are still alive many years out, with no evidence of disease,” he said.
“Our concept was that, in addition to whatever synergy the immunotherapy might provide with radiation, we also conceived of it as a ‘second shot on goal’ towards a cure, because there is durable control with drug alone,” he added.
Single-arm trial
The single-arm trial included 29 patients with locally advanced HNSCC.
Only about 10% of patients were current smokers, but more than half of the study group had a history of smoking. Of those, more than 55% had a history of 10 pack-years or more.
In slightly more than one third of patients, the primary site of the cancer was the base of the tongue. The tonsils were the primary site in slightly more than one third.
Platinum ineligibility was defined by provider and standard measures.
More than two thirds of patients were ineligible to receive cisplatin because of preexisting otopathy, including hearing impairment and tinnitus.
The combination of cisplatin and definitive-dose radiotherapy is standard treatment for locally advanced head and neck cancer, but contraindications to cisplatin are common in everyday clinical practice. Weiss noted that contraindications are present in about one third of his patients.
“We replaced standard, every-3-week cisplatin with pembrolizumab every 3 weeks,” Weiss explained, “and we hypothesized that with the ongoing effects of radiation therapy after completion, that additional adjuvant cycles could further sensitize patients [to the effects of radiation] without impairing recovery, so we added three adjuvant cycles as well,” he added.
With six cycles of an every-3-week drug, patients received 18 weeks of pembrolizumab in total.
Echoing results from the previously reported KEYNOTE-48 trial, pembrolizumab given with radiotherapy instead of chemotherapy led to an overall progression-free survival (PFS) rate of 76% at 1 year and an estimated PFS of 71% at 2 years.
At 1 year, 86% of patients were still alive, and at 2 years, an estimated 75% of patients were still alive, Weiss added.
For patients with human papillomavirus 16–positive cancer, rates of PFS and overall survival were slightly better, at 88% and 94%, respectively.
With regard to toxicities, “For the most part, this [treatment regimen] looks like radiation alone with one very notable exception, which was lymphopenia,” Weiss observed. Grade 3-4 lymphopenia affected 59% of patients.
Lymphocyte count hit bottom at week 4, he added, with only partial recovery at week 20 and no further recovery at 40 weeks. Lymphocyte count alone or any change in it was not predictive of early progression.
However, in comparing patients who experienced early disease progression to patients who did not experience progression, levels of baseline naive B cells in peripheral blood were higher and levels of circulating marginal zone B cells were lower in patients with progressive disease, Weiss reported.
Patient-reported outcomes indicated that common symptoms of treatment peaked at week 10, and there was relative recovery by week 20.
As reflected by Functional Assessment of Cancer Therapy (FACT) scores, which include social, emotional, and functional well-being, as well as the head and neck cancer scale, “we again see a nadir at 10 weeks with relative recovery at 20 weeks,” Weiss noted.
“We found that concurrent pembrolizumab with radiotherapy is a safe and feasible option for locally advanced head and neck cancer patients with cisplatin ineligibility,” Weiss concluded.
More research is being conducted in this area, and multiple ongoing studies will further elucidate the value of PD-1 or PD-L1 checkpoint blockade with definitive radiation therapy, he added.
The study was funded by Merck & Co. Weiss’ institution has received research funding from Celgene, Pfizer, Merck, AZ/Medimmmune, Amgen, Carefusion, G1 Therapeutics, Immunicum, Loxo/Lilly, and the Jimmy V Foundation. Weiss has received honoraria for consulting from AstraZeneca, EMD Serono, Genentech, Inivata, Celgene, G1 Therapeutics, Jounce Therapeutics, Abbvie, Rakuten, Nanobiotix, Azitra, Loxo/Lilly, Pfizer, and Blueprint had has stock in Nektar and Vesselon.
This article first appeared on Medscape.com.
The combination of a phase 2 trial suggests.
“There are convincing arguments that radiation sensitizes patients to immunotherapy and can enhance its effects,” Jared Weiss, MD, associate professor of medicine, UNC Lineberger Comprehensive Cancer, Chapel Hill, North Carolina, said in a statement.
“And the opposite direction also seems to be true – radiation therapy needs a functional immune system to work. Our hope was that pembrolizumab might be a radiation sensitizer for these patients,” he said.
The study was presented at the Multidisciplinary Head and Neck Cancer Symposium, sponsored by the American Society for Radiation Oncology.
Both modalities have had some outstanding results in the past, observed Weiss. “If you look back to the historic studies, radiation alone often cures patients with this disease, while some of the first patients treated with pembrolizumab for recurrent/metastatic cancer are still alive many years out, with no evidence of disease,” he said.
“Our concept was that, in addition to whatever synergy the immunotherapy might provide with radiation, we also conceived of it as a ‘second shot on goal’ towards a cure, because there is durable control with drug alone,” he added.
Single-arm trial
The single-arm trial included 29 patients with locally advanced HNSCC.
Only about 10% of patients were current smokers, but more than half of the study group had a history of smoking. Of those, more than 55% had a history of 10 pack-years or more.
In slightly more than one third of patients, the primary site of the cancer was the base of the tongue. The tonsils were the primary site in slightly more than one third.
Platinum ineligibility was defined by provider and standard measures.
More than two thirds of patients were ineligible to receive cisplatin because of preexisting otopathy, including hearing impairment and tinnitus.
The combination of cisplatin and definitive-dose radiotherapy is standard treatment for locally advanced head and neck cancer, but contraindications to cisplatin are common in everyday clinical practice. Weiss noted that contraindications are present in about one third of his patients.
“We replaced standard, every-3-week cisplatin with pembrolizumab every 3 weeks,” Weiss explained, “and we hypothesized that with the ongoing effects of radiation therapy after completion, that additional adjuvant cycles could further sensitize patients [to the effects of radiation] without impairing recovery, so we added three adjuvant cycles as well,” he added.
With six cycles of an every-3-week drug, patients received 18 weeks of pembrolizumab in total.
Echoing results from the previously reported KEYNOTE-48 trial, pembrolizumab given with radiotherapy instead of chemotherapy led to an overall progression-free survival (PFS) rate of 76% at 1 year and an estimated PFS of 71% at 2 years.
At 1 year, 86% of patients were still alive, and at 2 years, an estimated 75% of patients were still alive, Weiss added.
For patients with human papillomavirus 16–positive cancer, rates of PFS and overall survival were slightly better, at 88% and 94%, respectively.
With regard to toxicities, “For the most part, this [treatment regimen] looks like radiation alone with one very notable exception, which was lymphopenia,” Weiss observed. Grade 3-4 lymphopenia affected 59% of patients.
Lymphocyte count hit bottom at week 4, he added, with only partial recovery at week 20 and no further recovery at 40 weeks. Lymphocyte count alone or any change in it was not predictive of early progression.
However, in comparing patients who experienced early disease progression to patients who did not experience progression, levels of baseline naive B cells in peripheral blood were higher and levels of circulating marginal zone B cells were lower in patients with progressive disease, Weiss reported.
Patient-reported outcomes indicated that common symptoms of treatment peaked at week 10, and there was relative recovery by week 20.
As reflected by Functional Assessment of Cancer Therapy (FACT) scores, which include social, emotional, and functional well-being, as well as the head and neck cancer scale, “we again see a nadir at 10 weeks with relative recovery at 20 weeks,” Weiss noted.
“We found that concurrent pembrolizumab with radiotherapy is a safe and feasible option for locally advanced head and neck cancer patients with cisplatin ineligibility,” Weiss concluded.
More research is being conducted in this area, and multiple ongoing studies will further elucidate the value of PD-1 or PD-L1 checkpoint blockade with definitive radiation therapy, he added.
The study was funded by Merck & Co. Weiss’ institution has received research funding from Celgene, Pfizer, Merck, AZ/Medimmmune, Amgen, Carefusion, G1 Therapeutics, Immunicum, Loxo/Lilly, and the Jimmy V Foundation. Weiss has received honoraria for consulting from AstraZeneca, EMD Serono, Genentech, Inivata, Celgene, G1 Therapeutics, Jounce Therapeutics, Abbvie, Rakuten, Nanobiotix, Azitra, Loxo/Lilly, Pfizer, and Blueprint had has stock in Nektar and Vesselon.
This article first appeared on Medscape.com.
REPORTING FROM HEAD AND NECK CANCERS SYMPOSIUM 2020
Residency Training During the #MeToo Movement
The #MeToo movement that took hold in the wake of the Harvey Weinstein allegations in 2017 likely will be considered one of the major cultural touchpoints of the 2010s. Although activism within the entertainment industry initially drew attention to this movement, it is understood that virtually no workplace is immune to sexual misconduct. Many medical professionals acknowledge #MeToo as a catchy hashtag summarizing a problem that has long been recognized in the field of medicine but often has been inadequately addressed.1 As dermatology residency program directors (PDs) at the University of Southern California (USC) Keck School of Medicine (Los Angeles, California), we have seen the considerable impact that recent high-profile allegations of sexual assault have had at our institution, leading us to take part in institutional and departmental initiatives and reflections that we believe have strengthened the culture within our residency program and positioned us to be proactive in addressing this critical issue.
Before we discuss the efforts to combat sexual misconduct and gender inequality at USC and within our dermatology department, it is worth reflecting on where we stand as a specialty with regard to gender representation. A recent JAMA Dermatology article reported that in 1970 only 10.8% of dermatology academic faculty were women but by 2018 that number had skyrocketed to 51.2%; however, in contrast to this overall increase, only 19.4% of dermatology department chairs in 2018 were women.2 Although we have made large strides as a field, this discrepancy indicates that we still have a long way to go to achieve gender equality.
Although dermatology as a specialty is working toward gender equality, we believe it is crucial to consider this issue in the context of the entire field of medicine, particularly because academic physicians and trainees often interface with a myriad of specialties. It is well known that women in medicine are more likely to be victims of sexual harassment or assault in the workplace and that subsequent issues with imposter syndrome and/or depression are more prevalent in female physicians.3,4 Gender inequality and sexism, among other factors, can make it difficult for women to obtain and maintain leadership positions and can negatively impact the culture of an academic institution in numerous downstream ways.
We also know that academic environments in medicine have a higher prevalence of gender equality issues than in private practice or in settings where medicine is practiced without trainees due to the hierarchical nature of training and the necessary differences in experience between trainees and faculty.3 Furthermore, because trainees form and solidify their professional identities during graduate medical education (GME) training, it is a prime time to emphasize the importance of gender equality and establish zero tolerance policies for workplace abuse and transgressions.5
The data and our personal experiences delineate a clear need for continued vigilance regarding gender equality issues both in dermatology as a specialty and in medicine in general. As PDs, we feel fortunate to have worked in conjunction with our GME committee and our dermatology department to solidify and create policies that work to promote a culture of gender equality. Herein, we will outline some of these efforts with the hope that other academic institutions may consider implementing these programs to protect members of their community from harassment, sexual violence, and gender discrimination.
Create a SAFE Committee
At the institutional level, our GME committee has created the SAFE (Safety, Fairness & Equity) committee under the leadership of Lawrence Opas, MD. The SAFE committee is headed by a female faculty physician and includes members of the medical community who have the influence to affect change and a commitment to protect vulnerable populations. Members include the Chief Medical Officer, the Designated Institutional Officer, the Director of Resident Wellness, and the Dean of the Keck School of Medicine at USC. The SAFE committee serves as a 24/7 reporting resource whereby trainees can report any issues relating to harassment in the workplace via a telephone hotline or online platform. Issues brought to this committee are immediately dealt with and reviewed at monthly GME meetings to keep institutional PDs up-to-date on issues pertaining to sexual harassment and assault within our workplace. The SAFE committee also has departmental resident liaisons who bring information to residents and help guide them to appropriate resources.
Emphasize Resident Wellness
Along with the development of robust reporting resources, our institution has continued to build upon a culture that places a strong emphasis on resident wellness. One of the most meaningful efforts over the last 5 years has included recruitment of a clinical psychologist, Tobi Fishel, PhD, to serve as our institution’s Director of Wellness. She is available to meet confidentially with our residents and helps to serve as a link between trainees and the GME committee.
Our dermatology department takes a tremendous amount of pride in its culture. We are fortunate to have David Peng, MD, MPH, Chair, and Stefani Takahashi, MD, Vice Chair of Education, working daily to create an environment that values teamwork, selflessness, and wellness. We have been continuously grateful for their leadership and guidance in addressing the allegations of sexual assault and harassment that arose at USC over the past several years. Our department has a zero tolerance policy for sexual harassment or harassment of any kind, and we have taken important steps to ensure and promote a safe environment for our trainees, many of which are focused on communication. We try to avoid assumptions and encourage both residents and faculty to explicitly state their experiences and opinions in general but also in relation to instances of potential misconduct.
Encourage Communication
When allegations of sexual misconduct in the workplace were made at our institution, we prioritized immediate in-person communication with our residents to reinforce our zero tolerance policy and to remind them that we are available should any similar issues arise in our department. It was of equal value to remind our trainees of potential resources, such as the SAFE committee, to whom they could bring their concerns if they were not comfortable communicating directly with us. Although we hoped that our trainees understood that we would not be tolerant of any form of harassment based on our past actions and communications, we felt that it was helpful to explicitly delineate this by laying out other avenues of support on a regular basis with them. By ensuring there is a space for a dialogue with others, if needed, our institution and department have provided an extra layer of security for our trainees. Multiple channels of support are crucial to ensure trainee safety.
Dr. Peng also created a workplace safety committee that includes several female faculty members. The committee regularly shares and highlights institutional and departmental resources as they pertain to gender equality and safety within the workplace and also has considerable faculty overlap with our departmental diversity committee. Together, these committees work toward the common goal of fostering an environment in which all members of our department feel comfortable voicing concerns, and we are best able to recruit and retain a diverse faculty.
As PDs, we work to reinforce departmental and institutional messages in our daily communication with residents. We have found that ensuring frequent and varied interactions—quarterly meetings, biannual evaluations, faculty-led didactics 2 half-days per week, and weekly clinical interactions—with our trainees can help to create a culture where they feel comfortable bringing up issues, be they routine clinical operations questions or issues relating to their professional identity. We hope it also has created the space for them to approach us with any issues pertaining to harassment should they ever arise, and we are grateful to know that even if this comfort does not exist, our institution and department have other resources for them.
Final Thoughts
Although some of the measures discussed here were reactionary, many predated the recent institutional concerns and allegations at USC. We hope and believe that the culture we foster within our department has helped our trainees feel safe and cared for during a time of institutional turbulence. We also believe that taking similar proactive measures may benefit the overall culture and foster the development of diverse physicians and leadership at other institutions. In conjunction with reworking legislation and implementing institutional safeguards, the long-term goals of taking these proactive measures are to promote gender equality and workplace safety and to cultivate and retain effective female leadership in medical institutions and training programs.
We feel incredibly fortunate to be part of a specialty in which gender equality has long been considered and sought after. We also are proud to be members of the Association of Professors of Dermatology, which has addressed issues such as diversity and gender equality in a transparent and head-on manner and continues to do so. As a specialty, we hope we can support our trainees in their professional growth and help to cultivate sensitive physicians who will care for an increasingly diverse population and better support each other in their own career development.
- Ladika S. Sexual harassment: health care, it is #youtoo. Manag Care. 2018;27:14-17.
- Xierali IM, Nivet MA, Pandya AG. US dermatology department faculty diversity trends by sex and underrepresented-in-medicine status, 1970 to 2018 [published online January 8, 2020]. JAMA Dermatol. doi:10.1001/jamadermatol.2019.4297.
- Minkina N. Can #MeToo abolish sexual harassment and discrimination in medicine? Lancet. 2019;394:383-384.
- Dzau VJ, Johnson PA. Ending sexual harassment in academic medicine. N Engl J Med. 2018;379:1589-1591.
- Nothnagle M, Reis S, Goldman RE, et al. Fostering professional formation in residency: development and evaluation of the “forum” seminar series. Teach Learn Med. 2014;26:230-238.
The #MeToo movement that took hold in the wake of the Harvey Weinstein allegations in 2017 likely will be considered one of the major cultural touchpoints of the 2010s. Although activism within the entertainment industry initially drew attention to this movement, it is understood that virtually no workplace is immune to sexual misconduct. Many medical professionals acknowledge #MeToo as a catchy hashtag summarizing a problem that has long been recognized in the field of medicine but often has been inadequately addressed.1 As dermatology residency program directors (PDs) at the University of Southern California (USC) Keck School of Medicine (Los Angeles, California), we have seen the considerable impact that recent high-profile allegations of sexual assault have had at our institution, leading us to take part in institutional and departmental initiatives and reflections that we believe have strengthened the culture within our residency program and positioned us to be proactive in addressing this critical issue.
Before we discuss the efforts to combat sexual misconduct and gender inequality at USC and within our dermatology department, it is worth reflecting on where we stand as a specialty with regard to gender representation. A recent JAMA Dermatology article reported that in 1970 only 10.8% of dermatology academic faculty were women but by 2018 that number had skyrocketed to 51.2%; however, in contrast to this overall increase, only 19.4% of dermatology department chairs in 2018 were women.2 Although we have made large strides as a field, this discrepancy indicates that we still have a long way to go to achieve gender equality.
Although dermatology as a specialty is working toward gender equality, we believe it is crucial to consider this issue in the context of the entire field of medicine, particularly because academic physicians and trainees often interface with a myriad of specialties. It is well known that women in medicine are more likely to be victims of sexual harassment or assault in the workplace and that subsequent issues with imposter syndrome and/or depression are more prevalent in female physicians.3,4 Gender inequality and sexism, among other factors, can make it difficult for women to obtain and maintain leadership positions and can negatively impact the culture of an academic institution in numerous downstream ways.
We also know that academic environments in medicine have a higher prevalence of gender equality issues than in private practice or in settings where medicine is practiced without trainees due to the hierarchical nature of training and the necessary differences in experience between trainees and faculty.3 Furthermore, because trainees form and solidify their professional identities during graduate medical education (GME) training, it is a prime time to emphasize the importance of gender equality and establish zero tolerance policies for workplace abuse and transgressions.5
The data and our personal experiences delineate a clear need for continued vigilance regarding gender equality issues both in dermatology as a specialty and in medicine in general. As PDs, we feel fortunate to have worked in conjunction with our GME committee and our dermatology department to solidify and create policies that work to promote a culture of gender equality. Herein, we will outline some of these efforts with the hope that other academic institutions may consider implementing these programs to protect members of their community from harassment, sexual violence, and gender discrimination.
Create a SAFE Committee
At the institutional level, our GME committee has created the SAFE (Safety, Fairness & Equity) committee under the leadership of Lawrence Opas, MD. The SAFE committee is headed by a female faculty physician and includes members of the medical community who have the influence to affect change and a commitment to protect vulnerable populations. Members include the Chief Medical Officer, the Designated Institutional Officer, the Director of Resident Wellness, and the Dean of the Keck School of Medicine at USC. The SAFE committee serves as a 24/7 reporting resource whereby trainees can report any issues relating to harassment in the workplace via a telephone hotline or online platform. Issues brought to this committee are immediately dealt with and reviewed at monthly GME meetings to keep institutional PDs up-to-date on issues pertaining to sexual harassment and assault within our workplace. The SAFE committee also has departmental resident liaisons who bring information to residents and help guide them to appropriate resources.
Emphasize Resident Wellness
Along with the development of robust reporting resources, our institution has continued to build upon a culture that places a strong emphasis on resident wellness. One of the most meaningful efforts over the last 5 years has included recruitment of a clinical psychologist, Tobi Fishel, PhD, to serve as our institution’s Director of Wellness. She is available to meet confidentially with our residents and helps to serve as a link between trainees and the GME committee.
Our dermatology department takes a tremendous amount of pride in its culture. We are fortunate to have David Peng, MD, MPH, Chair, and Stefani Takahashi, MD, Vice Chair of Education, working daily to create an environment that values teamwork, selflessness, and wellness. We have been continuously grateful for their leadership and guidance in addressing the allegations of sexual assault and harassment that arose at USC over the past several years. Our department has a zero tolerance policy for sexual harassment or harassment of any kind, and we have taken important steps to ensure and promote a safe environment for our trainees, many of which are focused on communication. We try to avoid assumptions and encourage both residents and faculty to explicitly state their experiences and opinions in general but also in relation to instances of potential misconduct.
Encourage Communication
When allegations of sexual misconduct in the workplace were made at our institution, we prioritized immediate in-person communication with our residents to reinforce our zero tolerance policy and to remind them that we are available should any similar issues arise in our department. It was of equal value to remind our trainees of potential resources, such as the SAFE committee, to whom they could bring their concerns if they were not comfortable communicating directly with us. Although we hoped that our trainees understood that we would not be tolerant of any form of harassment based on our past actions and communications, we felt that it was helpful to explicitly delineate this by laying out other avenues of support on a regular basis with them. By ensuring there is a space for a dialogue with others, if needed, our institution and department have provided an extra layer of security for our trainees. Multiple channels of support are crucial to ensure trainee safety.
Dr. Peng also created a workplace safety committee that includes several female faculty members. The committee regularly shares and highlights institutional and departmental resources as they pertain to gender equality and safety within the workplace and also has considerable faculty overlap with our departmental diversity committee. Together, these committees work toward the common goal of fostering an environment in which all members of our department feel comfortable voicing concerns, and we are best able to recruit and retain a diverse faculty.
As PDs, we work to reinforce departmental and institutional messages in our daily communication with residents. We have found that ensuring frequent and varied interactions—quarterly meetings, biannual evaluations, faculty-led didactics 2 half-days per week, and weekly clinical interactions—with our trainees can help to create a culture where they feel comfortable bringing up issues, be they routine clinical operations questions or issues relating to their professional identity. We hope it also has created the space for them to approach us with any issues pertaining to harassment should they ever arise, and we are grateful to know that even if this comfort does not exist, our institution and department have other resources for them.
Final Thoughts
Although some of the measures discussed here were reactionary, many predated the recent institutional concerns and allegations at USC. We hope and believe that the culture we foster within our department has helped our trainees feel safe and cared for during a time of institutional turbulence. We also believe that taking similar proactive measures may benefit the overall culture and foster the development of diverse physicians and leadership at other institutions. In conjunction with reworking legislation and implementing institutional safeguards, the long-term goals of taking these proactive measures are to promote gender equality and workplace safety and to cultivate and retain effective female leadership in medical institutions and training programs.
We feel incredibly fortunate to be part of a specialty in which gender equality has long been considered and sought after. We also are proud to be members of the Association of Professors of Dermatology, which has addressed issues such as diversity and gender equality in a transparent and head-on manner and continues to do so. As a specialty, we hope we can support our trainees in their professional growth and help to cultivate sensitive physicians who will care for an increasingly diverse population and better support each other in their own career development.
The #MeToo movement that took hold in the wake of the Harvey Weinstein allegations in 2017 likely will be considered one of the major cultural touchpoints of the 2010s. Although activism within the entertainment industry initially drew attention to this movement, it is understood that virtually no workplace is immune to sexual misconduct. Many medical professionals acknowledge #MeToo as a catchy hashtag summarizing a problem that has long been recognized in the field of medicine but often has been inadequately addressed.1 As dermatology residency program directors (PDs) at the University of Southern California (USC) Keck School of Medicine (Los Angeles, California), we have seen the considerable impact that recent high-profile allegations of sexual assault have had at our institution, leading us to take part in institutional and departmental initiatives and reflections that we believe have strengthened the culture within our residency program and positioned us to be proactive in addressing this critical issue.
Before we discuss the efforts to combat sexual misconduct and gender inequality at USC and within our dermatology department, it is worth reflecting on where we stand as a specialty with regard to gender representation. A recent JAMA Dermatology article reported that in 1970 only 10.8% of dermatology academic faculty were women but by 2018 that number had skyrocketed to 51.2%; however, in contrast to this overall increase, only 19.4% of dermatology department chairs in 2018 were women.2 Although we have made large strides as a field, this discrepancy indicates that we still have a long way to go to achieve gender equality.
Although dermatology as a specialty is working toward gender equality, we believe it is crucial to consider this issue in the context of the entire field of medicine, particularly because academic physicians and trainees often interface with a myriad of specialties. It is well known that women in medicine are more likely to be victims of sexual harassment or assault in the workplace and that subsequent issues with imposter syndrome and/or depression are more prevalent in female physicians.3,4 Gender inequality and sexism, among other factors, can make it difficult for women to obtain and maintain leadership positions and can negatively impact the culture of an academic institution in numerous downstream ways.
We also know that academic environments in medicine have a higher prevalence of gender equality issues than in private practice or in settings where medicine is practiced without trainees due to the hierarchical nature of training and the necessary differences in experience between trainees and faculty.3 Furthermore, because trainees form and solidify their professional identities during graduate medical education (GME) training, it is a prime time to emphasize the importance of gender equality and establish zero tolerance policies for workplace abuse and transgressions.5
The data and our personal experiences delineate a clear need for continued vigilance regarding gender equality issues both in dermatology as a specialty and in medicine in general. As PDs, we feel fortunate to have worked in conjunction with our GME committee and our dermatology department to solidify and create policies that work to promote a culture of gender equality. Herein, we will outline some of these efforts with the hope that other academic institutions may consider implementing these programs to protect members of their community from harassment, sexual violence, and gender discrimination.
Create a SAFE Committee
At the institutional level, our GME committee has created the SAFE (Safety, Fairness & Equity) committee under the leadership of Lawrence Opas, MD. The SAFE committee is headed by a female faculty physician and includes members of the medical community who have the influence to affect change and a commitment to protect vulnerable populations. Members include the Chief Medical Officer, the Designated Institutional Officer, the Director of Resident Wellness, and the Dean of the Keck School of Medicine at USC. The SAFE committee serves as a 24/7 reporting resource whereby trainees can report any issues relating to harassment in the workplace via a telephone hotline or online platform. Issues brought to this committee are immediately dealt with and reviewed at monthly GME meetings to keep institutional PDs up-to-date on issues pertaining to sexual harassment and assault within our workplace. The SAFE committee also has departmental resident liaisons who bring information to residents and help guide them to appropriate resources.
Emphasize Resident Wellness
Along with the development of robust reporting resources, our institution has continued to build upon a culture that places a strong emphasis on resident wellness. One of the most meaningful efforts over the last 5 years has included recruitment of a clinical psychologist, Tobi Fishel, PhD, to serve as our institution’s Director of Wellness. She is available to meet confidentially with our residents and helps to serve as a link between trainees and the GME committee.
Our dermatology department takes a tremendous amount of pride in its culture. We are fortunate to have David Peng, MD, MPH, Chair, and Stefani Takahashi, MD, Vice Chair of Education, working daily to create an environment that values teamwork, selflessness, and wellness. We have been continuously grateful for their leadership and guidance in addressing the allegations of sexual assault and harassment that arose at USC over the past several years. Our department has a zero tolerance policy for sexual harassment or harassment of any kind, and we have taken important steps to ensure and promote a safe environment for our trainees, many of which are focused on communication. We try to avoid assumptions and encourage both residents and faculty to explicitly state their experiences and opinions in general but also in relation to instances of potential misconduct.
Encourage Communication
When allegations of sexual misconduct in the workplace were made at our institution, we prioritized immediate in-person communication with our residents to reinforce our zero tolerance policy and to remind them that we are available should any similar issues arise in our department. It was of equal value to remind our trainees of potential resources, such as the SAFE committee, to whom they could bring their concerns if they were not comfortable communicating directly with us. Although we hoped that our trainees understood that we would not be tolerant of any form of harassment based on our past actions and communications, we felt that it was helpful to explicitly delineate this by laying out other avenues of support on a regular basis with them. By ensuring there is a space for a dialogue with others, if needed, our institution and department have provided an extra layer of security for our trainees. Multiple channels of support are crucial to ensure trainee safety.
Dr. Peng also created a workplace safety committee that includes several female faculty members. The committee regularly shares and highlights institutional and departmental resources as they pertain to gender equality and safety within the workplace and also has considerable faculty overlap with our departmental diversity committee. Together, these committees work toward the common goal of fostering an environment in which all members of our department feel comfortable voicing concerns, and we are best able to recruit and retain a diverse faculty.
As PDs, we work to reinforce departmental and institutional messages in our daily communication with residents. We have found that ensuring frequent and varied interactions—quarterly meetings, biannual evaluations, faculty-led didactics 2 half-days per week, and weekly clinical interactions—with our trainees can help to create a culture where they feel comfortable bringing up issues, be they routine clinical operations questions or issues relating to their professional identity. We hope it also has created the space for them to approach us with any issues pertaining to harassment should they ever arise, and we are grateful to know that even if this comfort does not exist, our institution and department have other resources for them.
Final Thoughts
Although some of the measures discussed here were reactionary, many predated the recent institutional concerns and allegations at USC. We hope and believe that the culture we foster within our department has helped our trainees feel safe and cared for during a time of institutional turbulence. We also believe that taking similar proactive measures may benefit the overall culture and foster the development of diverse physicians and leadership at other institutions. In conjunction with reworking legislation and implementing institutional safeguards, the long-term goals of taking these proactive measures are to promote gender equality and workplace safety and to cultivate and retain effective female leadership in medical institutions and training programs.
We feel incredibly fortunate to be part of a specialty in which gender equality has long been considered and sought after. We also are proud to be members of the Association of Professors of Dermatology, which has addressed issues such as diversity and gender equality in a transparent and head-on manner and continues to do so. As a specialty, we hope we can support our trainees in their professional growth and help to cultivate sensitive physicians who will care for an increasingly diverse population and better support each other in their own career development.
- Ladika S. Sexual harassment: health care, it is #youtoo. Manag Care. 2018;27:14-17.
- Xierali IM, Nivet MA, Pandya AG. US dermatology department faculty diversity trends by sex and underrepresented-in-medicine status, 1970 to 2018 [published online January 8, 2020]. JAMA Dermatol. doi:10.1001/jamadermatol.2019.4297.
- Minkina N. Can #MeToo abolish sexual harassment and discrimination in medicine? Lancet. 2019;394:383-384.
- Dzau VJ, Johnson PA. Ending sexual harassment in academic medicine. N Engl J Med. 2018;379:1589-1591.
- Nothnagle M, Reis S, Goldman RE, et al. Fostering professional formation in residency: development and evaluation of the “forum” seminar series. Teach Learn Med. 2014;26:230-238.
- Ladika S. Sexual harassment: health care, it is #youtoo. Manag Care. 2018;27:14-17.
- Xierali IM, Nivet MA, Pandya AG. US dermatology department faculty diversity trends by sex and underrepresented-in-medicine status, 1970 to 2018 [published online January 8, 2020]. JAMA Dermatol. doi:10.1001/jamadermatol.2019.4297.
- Minkina N. Can #MeToo abolish sexual harassment and discrimination in medicine? Lancet. 2019;394:383-384.
- Dzau VJ, Johnson PA. Ending sexual harassment in academic medicine. N Engl J Med. 2018;379:1589-1591.
- Nothnagle M, Reis S, Goldman RE, et al. Fostering professional formation in residency: development and evaluation of the “forum” seminar series. Teach Learn Med. 2014;26:230-238.
