ORLANDO – Response to checkpoint inhibitors was associated with pretreatment absolute lymphocyte count (pALC) and neutrophil-lymphocyte ratio (pNLR) in patients with kidney or bladder cancer treated in a real-world setting.

Sharon Worcester/MDedge News

In a retrospective study of 20 patients, those with lower pALCs and higher pNLRs were less likely to respond to checkpoint inhibitors.

Tonjeh Bah, MD, of Feist-Weiller Cancer Center at LSU Health Shreveport in Louisiana, and colleagues reported these results in a poster at the ASCO-SITC Clinical Immuno-Oncology Symposium.

Response rates were 75% in patients with pALC greater than 1,000 and 25% in patients with pALC less than 1,000. This difference was statistically significant (P = .027), Dr. Bah noted, adding that the groups were comparable with respect to age, sex, race, and type of checkpoint inhibitors used.

Similarly, response rates were 80% in patients with pNLR less than 3 (the established upper limit of normal) and 30% in patients with pNLR greater than 3 (P = .024).

Checkpoint inhibitors targeting cytotoxic T-lymphocyte-associated protein 4 and programmed death-1 and its ligand are essential components of therapy across multiple cancer types, Dr. Bah noted in an interview. She explained that prior studies – mostly in patients with lung cancer and head and neck cancers – have also shown pALC and pNLR to be independently associated with poor checkpoint inhibitor response and worse progression-free survival.

“But this is the first study to look at the connection in kidney and bladder cancer in a real-world setting,” she said.

Dr. Bah and colleagues conducted the study to test the hypothesis that “lymphopenia is a marker of immune exhaustion, which is characterized by dysfunctional T cells that have a limited antitumor effect even in the presence of [checkpoint inhibitors] and by the eventual depletion of antitumor lymphocytes,” they wrote in the poster.

Patients included in the study were all those with renal cell carcinoma (n = 13) or bladder-urothelial cancers (n = 7) who received checkpoint inhibitors at one of two medical centers in Louisiana during 2015-2019 and who had outcomes reported. Patients who attained stable disease or had partial or complete responses were categorized as responders. Patients who progressed on checkpoint inhibitors were considered nonresponders.

“Our findings were not a surprise, but they do document, for the first time and in a real-world setting, that pALC and pNLR may have prognostic utility in patients with kidney and bladder cancers who are treated with [checkpoint inhibitors],” Dr. Bah said.

She added that the findings could help determine which patients are candidates for checkpoint inhibitors, but the results require confirmation in a large, prospective study. Dr. Bah reported having no disclosures, and there was no sponsor for this study.

[email protected]

SOURCE: Bah T et al. ASCO-SITC 2020. Abstract 31.

ORLANDO – Response to checkpoint inhibitors was associated with pretreatment absolute lymphocyte count (pALC) and neutrophil-lymphocyte ratio (pNLR) in patients with kidney or bladder cancer treated in a real-world setting.

Sharon Worcester/MDedge News

In a retrospective study of 20 patients, those with lower pALCs and higher pNLRs were less likely to respond to checkpoint inhibitors.

Tonjeh Bah, MD, of Feist-Weiller Cancer Center at LSU Health Shreveport in Louisiana, and colleagues reported these results in a poster at the ASCO-SITC Clinical Immuno-Oncology Symposium.

Response rates were 75% in patients with pALC greater than 1,000 and 25% in patients with pALC less than 1,000. This difference was statistically significant (P = .027), Dr. Bah noted, adding that the groups were comparable with respect to age, sex, race, and type of checkpoint inhibitors used.

Similarly, response rates were 80% in patients with pNLR less than 3 (the established upper limit of normal) and 30% in patients with pNLR greater than 3 (P = .024).

Checkpoint inhibitors targeting cytotoxic T-lymphocyte-associated protein 4 and programmed death-1 and its ligand are essential components of therapy across multiple cancer types, Dr. Bah noted in an interview. She explained that prior studies – mostly in patients with lung cancer and head and neck cancers – have also shown pALC and pNLR to be independently associated with poor checkpoint inhibitor response and worse progression-free survival.

“But this is the first study to look at the connection in kidney and bladder cancer in a real-world setting,” she said.

Dr. Bah and colleagues conducted the study to test the hypothesis that “lymphopenia is a marker of immune exhaustion, which is characterized by dysfunctional T cells that have a limited antitumor effect even in the presence of [checkpoint inhibitors] and by the eventual depletion of antitumor lymphocytes,” they wrote in the poster.

Patients included in the study were all those with renal cell carcinoma (n = 13) or bladder-urothelial cancers (n = 7) who received checkpoint inhibitors at one of two medical centers in Louisiana during 2015-2019 and who had outcomes reported. Patients who attained stable disease or had partial or complete responses were categorized as responders. Patients who progressed on checkpoint inhibitors were considered nonresponders.

“Our findings were not a surprise, but they do document, for the first time and in a real-world setting, that pALC and pNLR may have prognostic utility in patients with kidney and bladder cancers who are treated with [checkpoint inhibitors],” Dr. Bah said.

She added that the findings could help determine which patients are candidates for checkpoint inhibitors, but the results require confirmation in a large, prospective study. Dr. Bah reported having no disclosures, and there was no sponsor for this study.

[email protected]

SOURCE: Bah T et al. ASCO-SITC 2020. Abstract 31.

ORLANDO – Response to checkpoint inhibitors was associated with pretreatment absolute lymphocyte count (pALC) and neutrophil-lymphocyte ratio (pNLR) in patients with kidney or bladder cancer treated in a real-world setting.

Sharon Worcester/MDedge News

In a retrospective study of 20 patients, those with lower pALCs and higher pNLRs were less likely to respond to checkpoint inhibitors.

Tonjeh Bah, MD, of Feist-Weiller Cancer Center at LSU Health Shreveport in Louisiana, and colleagues reported these results in a poster at the ASCO-SITC Clinical Immuno-Oncology Symposium.

Response rates were 75% in patients with pALC greater than 1,000 and 25% in patients with pALC less than 1,000. This difference was statistically significant (P = .027), Dr. Bah noted, adding that the groups were comparable with respect to age, sex, race, and type of checkpoint inhibitors used.

Similarly, response rates were 80% in patients with pNLR less than 3 (the established upper limit of normal) and 30% in patients with pNLR greater than 3 (P = .024).

Checkpoint inhibitors targeting cytotoxic T-lymphocyte-associated protein 4 and programmed death-1 and its ligand are essential components of therapy across multiple cancer types, Dr. Bah noted in an interview. She explained that prior studies – mostly in patients with lung cancer and head and neck cancers – have also shown pALC and pNLR to be independently associated with poor checkpoint inhibitor response and worse progression-free survival.

“But this is the first study to look at the connection in kidney and bladder cancer in a real-world setting,” she said.

Dr. Bah and colleagues conducted the study to test the hypothesis that “lymphopenia is a marker of immune exhaustion, which is characterized by dysfunctional T cells that have a limited antitumor effect even in the presence of [checkpoint inhibitors] and by the eventual depletion of antitumor lymphocytes,” they wrote in the poster.

Patients included in the study were all those with renal cell carcinoma (n = 13) or bladder-urothelial cancers (n = 7) who received checkpoint inhibitors at one of two medical centers in Louisiana during 2015-2019 and who had outcomes reported. Patients who attained stable disease or had partial or complete responses were categorized as responders. Patients who progressed on checkpoint inhibitors were considered nonresponders.

“Our findings were not a surprise, but they do document, for the first time and in a real-world setting, that pALC and pNLR may have prognostic utility in patients with kidney and bladder cancers who are treated with [checkpoint inhibitors],” Dr. Bah said.

She added that the findings could help determine which patients are candidates for checkpoint inhibitors, but the results require confirmation in a large, prospective study. Dr. Bah reported having no disclosures, and there was no sponsor for this study.

[email protected]

SOURCE: Bah T et al. ASCO-SITC 2020. Abstract 31.

The monoamine oxidase inhibitor phenelzine (Nardil) appeared safe and active in a phase 2 trial of patients with biochemically recurrent, nonmetastatic, castrate-sensitive prostate cancer.

“We sought to investigate if phenelzine would exert an anticancer effect demonstrated by decreasing PSA [prostate-specific antigen] values in biochemically recurrent prostate cancer patients,” study author Mitchell E. Gross, MD, PhD, of the University of Southern California, Los Angeles, and colleagues wrote. Their findings were published in Prostate Cancer and Prostatic Diseases.

The single-arm study included 20 patients with biochemically recurrent, nonmetastatic, castrate-sensitive prostate cancer who received primary treatment with either radical prostatectomy (n = 18) or radiotherapy (n = 2). Study subjects had normal levels of free testosterone (50 ng/dL or above) and showed no evidence of metastatic disease on bone and CT imaging.

With respect to dosing, 18 patients were successfully titrated to the target dose of 30 mg of oral phenelzine twice daily. Five of these patients subsequently had their dose increased to 45 mg twice daily. Each dosing cycle was 28 days, with escalations occurring during the first 2 weeks of therapy.

Therapy was continued until disease progression, patient preference, therapy interruption of more than 2 weeks from study-related toxicity, or physician decision.

The primary outcome measured was PSA reduction of at least 50% from baseline. Psychiatric outcomes were also evaluated using the Hospital Anxiety and Depression Scale.

The median treatment duration was 326 days (range, 40-954 days). Among 20 evaluable patients, 5 patients (25%) achieved a PSA reduction of at least 30% from baseline, and 2 patients (10%) achieved a reduction of at least 50% from baseline.

At 12 weeks, 17 patients were still on treatment. Four patients (24%) had PSA reductions of at least 30%, and one patient (6%) had a PSA reduction of at least 50%.

The most common grade 2 or higher phenelzine-related adverse effects were dizziness (35%), hypertension (30%), and edema (10%). Serious toxicities included one case of grade 4 hypertension and two cases of grade 3 syncope, which required treatment discontinuation.

With respect to mood outcomes, Hospital Anxiety and Depression Scale scores showed a significant decline in anxiety symptoms but no difference in depressive symptoms.

The researchers acknowledged that two key limitations of this study were the small sample size and the absence of a placebo arm. Hence, the results may not accurately reflect long-term clinically relevant outcomes, such as overall survival or disease progression.

“Further studies would be needed to determine if [monoamine oxidase inhibitors], used alone or in combination with other agents, may delay clinical progression and metastasis,” the researchers concluded.

This study was funded by the USC-Taiwan Center for Translational Research and the National Cancer Institute. Some of the authors disclosed financial affiliations with Amgen, Astellas, AstraZeneca, Bayer, and other companies.

SOURCE: Gross ME et al. Prostate Cancer Prostatic Dis. 2020 Mar 3. doi: 10.1038/s41391-020-0211-9.

The monoamine oxidase inhibitor phenelzine (Nardil) appeared safe and active in a phase 2 trial of patients with biochemically recurrent, nonmetastatic, castrate-sensitive prostate cancer.

“We sought to investigate if phenelzine would exert an anticancer effect demonstrated by decreasing PSA [prostate-specific antigen] values in biochemically recurrent prostate cancer patients,” study author Mitchell E. Gross, MD, PhD, of the University of Southern California, Los Angeles, and colleagues wrote. Their findings were published in Prostate Cancer and Prostatic Diseases.

The single-arm study included 20 patients with biochemically recurrent, nonmetastatic, castrate-sensitive prostate cancer who received primary treatment with either radical prostatectomy (n = 18) or radiotherapy (n = 2). Study subjects had normal levels of free testosterone (50 ng/dL or above) and showed no evidence of metastatic disease on bone and CT imaging.

With respect to dosing, 18 patients were successfully titrated to the target dose of 30 mg of oral phenelzine twice daily. Five of these patients subsequently had their dose increased to 45 mg twice daily. Each dosing cycle was 28 days, with escalations occurring during the first 2 weeks of therapy.

Therapy was continued until disease progression, patient preference, therapy interruption of more than 2 weeks from study-related toxicity, or physician decision.

The primary outcome measured was PSA reduction of at least 50% from baseline. Psychiatric outcomes were also evaluated using the Hospital Anxiety and Depression Scale.

The median treatment duration was 326 days (range, 40-954 days). Among 20 evaluable patients, 5 patients (25%) achieved a PSA reduction of at least 30% from baseline, and 2 patients (10%) achieved a reduction of at least 50% from baseline.

At 12 weeks, 17 patients were still on treatment. Four patients (24%) had PSA reductions of at least 30%, and one patient (6%) had a PSA reduction of at least 50%.

The most common grade 2 or higher phenelzine-related adverse effects were dizziness (35%), hypertension (30%), and edema (10%). Serious toxicities included one case of grade 4 hypertension and two cases of grade 3 syncope, which required treatment discontinuation.

With respect to mood outcomes, Hospital Anxiety and Depression Scale scores showed a significant decline in anxiety symptoms but no difference in depressive symptoms.

The researchers acknowledged that two key limitations of this study were the small sample size and the absence of a placebo arm. Hence, the results may not accurately reflect long-term clinically relevant outcomes, such as overall survival or disease progression.

“Further studies would be needed to determine if [monoamine oxidase inhibitors], used alone or in combination with other agents, may delay clinical progression and metastasis,” the researchers concluded.

This study was funded by the USC-Taiwan Center for Translational Research and the National Cancer Institute. Some of the authors disclosed financial affiliations with Amgen, Astellas, AstraZeneca, Bayer, and other companies.

SOURCE: Gross ME et al. Prostate Cancer Prostatic Dis. 2020 Mar 3. doi: 10.1038/s41391-020-0211-9.

The monoamine oxidase inhibitor phenelzine (Nardil) appeared safe and active in a phase 2 trial of patients with biochemically recurrent, nonmetastatic, castrate-sensitive prostate cancer.

“We sought to investigate if phenelzine would exert an anticancer effect demonstrated by decreasing PSA [prostate-specific antigen] values in biochemically recurrent prostate cancer patients,” study author Mitchell E. Gross, MD, PhD, of the University of Southern California, Los Angeles, and colleagues wrote. Their findings were published in Prostate Cancer and Prostatic Diseases.

The single-arm study included 20 patients with biochemically recurrent, nonmetastatic, castrate-sensitive prostate cancer who received primary treatment with either radical prostatectomy (n = 18) or radiotherapy (n = 2). Study subjects had normal levels of free testosterone (50 ng/dL or above) and showed no evidence of metastatic disease on bone and CT imaging.

With respect to dosing, 18 patients were successfully titrated to the target dose of 30 mg of oral phenelzine twice daily. Five of these patients subsequently had their dose increased to 45 mg twice daily. Each dosing cycle was 28 days, with escalations occurring during the first 2 weeks of therapy.

Therapy was continued until disease progression, patient preference, therapy interruption of more than 2 weeks from study-related toxicity, or physician decision.

The primary outcome measured was PSA reduction of at least 50% from baseline. Psychiatric outcomes were also evaluated using the Hospital Anxiety and Depression Scale.

The median treatment duration was 326 days (range, 40-954 days). Among 20 evaluable patients, 5 patients (25%) achieved a PSA reduction of at least 30% from baseline, and 2 patients (10%) achieved a reduction of at least 50% from baseline.

At 12 weeks, 17 patients were still on treatment. Four patients (24%) had PSA reductions of at least 30%, and one patient (6%) had a PSA reduction of at least 50%.

The most common grade 2 or higher phenelzine-related adverse effects were dizziness (35%), hypertension (30%), and edema (10%). Serious toxicities included one case of grade 4 hypertension and two cases of grade 3 syncope, which required treatment discontinuation.

With respect to mood outcomes, Hospital Anxiety and Depression Scale scores showed a significant decline in anxiety symptoms but no difference in depressive symptoms.

The researchers acknowledged that two key limitations of this study were the small sample size and the absence of a placebo arm. Hence, the results may not accurately reflect long-term clinically relevant outcomes, such as overall survival or disease progression.

“Further studies would be needed to determine if [monoamine oxidase inhibitors], used alone or in combination with other agents, may delay clinical progression and metastasis,” the researchers concluded.

This study was funded by the USC-Taiwan Center for Translational Research and the National Cancer Institute. Some of the authors disclosed financial affiliations with Amgen, Astellas, AstraZeneca, Bayer, and other companies.

SOURCE: Gross ME et al. Prostate Cancer Prostatic Dis. 2020 Mar 3. doi: 10.1038/s41391-020-0211-9.

Martha Clare Morris, ScD, a pioneer in research linking nutrition to brain health and a creator of the breakthrough MIND diet, has died of cancer at the age of 64.

Morris was a professor in the Department of Internal Medicine, assistant provost of community research, and director of the Rush Institute for Healthy Aging at Rush University, in Chicago, Illinois. She was also a director of the internal medicine department’s Section of Community Epidemiology.

Long-time friend and colleague Julie A. Schneider, MD, the Deborah R. and Edgar D. Jannotta Presidential Professor of Pathology and Neurological Sciences, Rush University Medical Center, described Morris as creative, passionate, and adventurous.

Her death was “a shock” to the scientific community, Schneider told Medscape Medical News.

“It’s a tragic loss in so many ways,” said Schneider, who is also associate director of the Rush Alzheimer’s Disease Center. She was a very well-respected nutritional epidemiologist and was passionate about her work; she had just so much unwavering commitment to it.

Diet, said Schneider, is “notoriously a hard thing to study” because “it’s so intertwined with lifestyle” and other factors that create “barriers” to conducting such research.

But Morris had a unique and creative talent for filtering out what might be the individual contribution of a particular modifiable risk factor, said Heather Snyder, PhD, vice president of medical and scientific relations, Alzheimer’s Association, who also knew Morris both personally and professionally.

“Humble” trailblazer

Morris’s pioneering research examined the connection between nutrition and the prevention of cognitive decline. Taking results from this research, she developed the MIND diet – a hybrid of the Mediterranean diet and the Dietary Approaches to Stop Hypertension – along with colleagues at both Rush and Harvard Universities.

The MIND diet – an acronym for Mediterranean-DASH Intervention for Neurodegenerative Delay – emphasizes brain-healthy foods, including leafy green vegetables, nuts, berries, chicken, fish, whole grains, beans, olive oil, and moderate amounts of red wine. The diet limits consumption of red meat, butter, margarine, and processed foods.

In 2015, Morris published her initial findings on the MIND diet in Alzheimer’s and Dementia. Reported by Medscape Medical News at that time, the study showed that the diet protected cardiovascular health and slowed cognitive decline in older individuals.

The excitement around the findings inspired Morris to write “Diet for the Mind,” which was published in 2017. The book summarizes the benefits of the MIND diet and includes brain-healthy recipes created by her daughter Laura, who is a chef. Despite many accolades, Morris was “humble” about this project, said Schneider.

“This was not about publicity and trying to get a book out; she wanted to see if this diet really was going to change people’s lives. She wanted to bring it into the community,” she said.

Proud legacy

Since 2017, Morris had led a large clinical trial of the effectiveness of the MIND diet in preventing cognitive decline. The first study of its kind, the trial received a $14.5 million grant from the National Institutes of Health (NIH). Results of this study are expected in 2021.

The MIND diet was ranked among the top 10 diets for five consecutive years in US News and World Report.

Morris’s nutrition-related research went beyond diets and examined the impact of individual nutrients. One of her studies, published in 2018 and reported by Medscape Medical News, suggested that the presence of folate, phylloquinone, and lutein – nutrients found in relatively large amounts in green leafy vegetables – may account for why consuming a daily serving of these vegetables slows cognitive decline.

One of the most recent studies from Morris’ group, published in January 2020 and reported by Medscape Medical News at that time, provided the first evidence that dietary flavonols, which are found in many fruits and vegetables, are associated with a significantly reduced risk for dementia.

What Morris did so well was to “look at the big picture” and “think about commonalities that cross nutritional components” of diets such as MIND, DASH, the Mediterranean diet, and the Nordic diet, which is similar to the Mediterranean diet but highlights local foods such as fish from Nordic regions, Snyder told Medscape Medical News.

Morris was instrumental in getting the Alzheimer’s Association’s US POINTER (US Study to Protect Brain Health Through Lifestyle Intervention to Reduce Risk) study off the ground. The 2-year clinical trial is testing whether combining a healthy diet with exercise, cognitive and social stimulation, and the management of cardiovascular conditions protects cognitive function in older adults who are at increased risk for cognitive decline.

This study will be part of her legacy, said Snyder.

“She will be remembered for her perseverance to get us to a place where we can be looking at nutrition as a modifiable risk factor and now testing it in trials that she helped to set up,” she said.

Even before her involvement with US POINTER, Morris had long been an active volunteer for the Alzheimer’s Association, said Snyder.

“She contributed significant time and expertise as we looked at the state of the evidence around nutrition and other lifestyle and behavioral interventions.”

We’ll ‘always have Paris’

While Morris was “truly passionate” about diet and health “both professionally and personally,” she also had a fun side, said Schneider. She remembers she and Morris had a chance meeting in Paris, where they spent an entire day going to museums and restaurants and just talking about life and their travels. To the end, they joked they would “always have Paris,” said Schneider.

She was also a loyal friend. Morris threw a baby shower when Schneider was pregnant, organizing every detail, despite her extremely busy schedule.

Family was another of Morris’s passions. Snyder recalls Morris’s face lighting up when she talked about her children and grandchildren. She also remembers her friend’s zest for life. “She had an energy that was contagious.”

Morris also loved the outdoors and was a keen adventurer. She once trained for weeks before a long bike trip with her daughter and would take a helicopter to access remote backcountry on hiking excursions.

“She wanted to try everything,” said Schneider.

An author or contributor to more than 80 articles in peer-reviewed journals, Morris also served two terms (from 2011 to 2013) as chair of the NIH’s Neurological, Aging and Musculoskeletal Epidemiology Study Section.

She left behind multiple grants for various studies. One unique study, said Schneider, investigated the relationship between iron and other metals in the brain and the neuropathology of Alzheimer disease.

“She was really in the prime of her career,” noted Schneider. “She had so much left to give and to offer, so this is tremendously sad.”

According to news reports, Morris (nee Chinn) grew up in Homewood, Illinois, and earned bachelor’s and master’s degrees in sociology from the University of Iowa in Iowa City, where she met her husband, James Morris. The two married in 1978 and had three children.

Morris completed a doctorate in epidemiology at the Harvard School of Public Health. James died in 2012, also from cancer. Morris passed away peacefully at her home on February 15.

Martha Clare Morris, ScD, a pioneer in research linking nutrition to brain health and a creator of the breakthrough MIND diet, has died of cancer at the age of 64.

Morris was a professor in the Department of Internal Medicine, assistant provost of community research, and director of the Rush Institute for Healthy Aging at Rush University, in Chicago, Illinois. She was also a director of the internal medicine department’s Section of Community Epidemiology.

Long-time friend and colleague Julie A. Schneider, MD, the Deborah R. and Edgar D. Jannotta Presidential Professor of Pathology and Neurological Sciences, Rush University Medical Center, described Morris as creative, passionate, and adventurous.

Her death was “a shock” to the scientific community, Schneider told Medscape Medical News.

“It’s a tragic loss in so many ways,” said Schneider, who is also associate director of the Rush Alzheimer’s Disease Center. She was a very well-respected nutritional epidemiologist and was passionate about her work; she had just so much unwavering commitment to it.

Diet, said Schneider, is “notoriously a hard thing to study” because “it’s so intertwined with lifestyle” and other factors that create “barriers” to conducting such research.

But Morris had a unique and creative talent for filtering out what might be the individual contribution of a particular modifiable risk factor, said Heather Snyder, PhD, vice president of medical and scientific relations, Alzheimer’s Association, who also knew Morris both personally and professionally.

“Humble” trailblazer

Morris’s pioneering research examined the connection between nutrition and the prevention of cognitive decline. Taking results from this research, she developed the MIND diet – a hybrid of the Mediterranean diet and the Dietary Approaches to Stop Hypertension – along with colleagues at both Rush and Harvard Universities.

The MIND diet – an acronym for Mediterranean-DASH Intervention for Neurodegenerative Delay – emphasizes brain-healthy foods, including leafy green vegetables, nuts, berries, chicken, fish, whole grains, beans, olive oil, and moderate amounts of red wine. The diet limits consumption of red meat, butter, margarine, and processed foods.

In 2015, Morris published her initial findings on the MIND diet in Alzheimer’s and Dementia. Reported by Medscape Medical News at that time, the study showed that the diet protected cardiovascular health and slowed cognitive decline in older individuals.

The excitement around the findings inspired Morris to write “Diet for the Mind,” which was published in 2017. The book summarizes the benefits of the MIND diet and includes brain-healthy recipes created by her daughter Laura, who is a chef. Despite many accolades, Morris was “humble” about this project, said Schneider.

“This was not about publicity and trying to get a book out; she wanted to see if this diet really was going to change people’s lives. She wanted to bring it into the community,” she said.

Proud legacy

Since 2017, Morris had led a large clinical trial of the effectiveness of the MIND diet in preventing cognitive decline. The first study of its kind, the trial received a $14.5 million grant from the National Institutes of Health (NIH). Results of this study are expected in 2021.

The MIND diet was ranked among the top 10 diets for five consecutive years in US News and World Report.

Morris’s nutrition-related research went beyond diets and examined the impact of individual nutrients. One of her studies, published in 2018 and reported by Medscape Medical News, suggested that the presence of folate, phylloquinone, and lutein – nutrients found in relatively large amounts in green leafy vegetables – may account for why consuming a daily serving of these vegetables slows cognitive decline.

One of the most recent studies from Morris’ group, published in January 2020 and reported by Medscape Medical News at that time, provided the first evidence that dietary flavonols, which are found in many fruits and vegetables, are associated with a significantly reduced risk for dementia.

What Morris did so well was to “look at the big picture” and “think about commonalities that cross nutritional components” of diets such as MIND, DASH, the Mediterranean diet, and the Nordic diet, which is similar to the Mediterranean diet but highlights local foods such as fish from Nordic regions, Snyder told Medscape Medical News.

Morris was instrumental in getting the Alzheimer’s Association’s US POINTER (US Study to Protect Brain Health Through Lifestyle Intervention to Reduce Risk) study off the ground. The 2-year clinical trial is testing whether combining a healthy diet with exercise, cognitive and social stimulation, and the management of cardiovascular conditions protects cognitive function in older adults who are at increased risk for cognitive decline.

This study will be part of her legacy, said Snyder.

“She will be remembered for her perseverance to get us to a place where we can be looking at nutrition as a modifiable risk factor and now testing it in trials that she helped to set up,” she said.

Even before her involvement with US POINTER, Morris had long been an active volunteer for the Alzheimer’s Association, said Snyder.

“She contributed significant time and expertise as we looked at the state of the evidence around nutrition and other lifestyle and behavioral interventions.”

We’ll ‘always have Paris’

While Morris was “truly passionate” about diet and health “both professionally and personally,” she also had a fun side, said Schneider. She remembers she and Morris had a chance meeting in Paris, where they spent an entire day going to museums and restaurants and just talking about life and their travels. To the end, they joked they would “always have Paris,” said Schneider.

She was also a loyal friend. Morris threw a baby shower when Schneider was pregnant, organizing every detail, despite her extremely busy schedule.

Family was another of Morris’s passions. Snyder recalls Morris’s face lighting up when she talked about her children and grandchildren. She also remembers her friend’s zest for life. “She had an energy that was contagious.”

Morris also loved the outdoors and was a keen adventurer. She once trained for weeks before a long bike trip with her daughter and would take a helicopter to access remote backcountry on hiking excursions.

“She wanted to try everything,” said Schneider.

An author or contributor to more than 80 articles in peer-reviewed journals, Morris also served two terms (from 2011 to 2013) as chair of the NIH’s Neurological, Aging and Musculoskeletal Epidemiology Study Section.

She left behind multiple grants for various studies. One unique study, said Schneider, investigated the relationship between iron and other metals in the brain and the neuropathology of Alzheimer disease.

“She was really in the prime of her career,” noted Schneider. “She had so much left to give and to offer, so this is tremendously sad.”

According to news reports, Morris (nee Chinn) grew up in Homewood, Illinois, and earned bachelor’s and master’s degrees in sociology from the University of Iowa in Iowa City, where she met her husband, James Morris. The two married in 1978 and had three children.

Morris completed a doctorate in epidemiology at the Harvard School of Public Health. James died in 2012, also from cancer. Morris passed away peacefully at her home on February 15.

Martha Clare Morris, ScD, a pioneer in research linking nutrition to brain health and a creator of the breakthrough MIND diet, has died of cancer at the age of 64.

Morris was a professor in the Department of Internal Medicine, assistant provost of community research, and director of the Rush Institute for Healthy Aging at Rush University, in Chicago, Illinois. She was also a director of the internal medicine department’s Section of Community Epidemiology.

Long-time friend and colleague Julie A. Schneider, MD, the Deborah R. and Edgar D. Jannotta Presidential Professor of Pathology and Neurological Sciences, Rush University Medical Center, described Morris as creative, passionate, and adventurous.

Her death was “a shock” to the scientific community, Schneider told Medscape Medical News.

“It’s a tragic loss in so many ways,” said Schneider, who is also associate director of the Rush Alzheimer’s Disease Center. She was a very well-respected nutritional epidemiologist and was passionate about her work; she had just so much unwavering commitment to it.

Diet, said Schneider, is “notoriously a hard thing to study” because “it’s so intertwined with lifestyle” and other factors that create “barriers” to conducting such research.

But Morris had a unique and creative talent for filtering out what might be the individual contribution of a particular modifiable risk factor, said Heather Snyder, PhD, vice president of medical and scientific relations, Alzheimer’s Association, who also knew Morris both personally and professionally.

“Humble” trailblazer

Morris’s pioneering research examined the connection between nutrition and the prevention of cognitive decline. Taking results from this research, she developed the MIND diet – a hybrid of the Mediterranean diet and the Dietary Approaches to Stop Hypertension – along with colleagues at both Rush and Harvard Universities.

The MIND diet – an acronym for Mediterranean-DASH Intervention for Neurodegenerative Delay – emphasizes brain-healthy foods, including leafy green vegetables, nuts, berries, chicken, fish, whole grains, beans, olive oil, and moderate amounts of red wine. The diet limits consumption of red meat, butter, margarine, and processed foods.

In 2015, Morris published her initial findings on the MIND diet in Alzheimer’s and Dementia. Reported by Medscape Medical News at that time, the study showed that the diet protected cardiovascular health and slowed cognitive decline in older individuals.

The excitement around the findings inspired Morris to write “Diet for the Mind,” which was published in 2017. The book summarizes the benefits of the MIND diet and includes brain-healthy recipes created by her daughter Laura, who is a chef. Despite many accolades, Morris was “humble” about this project, said Schneider.

“This was not about publicity and trying to get a book out; she wanted to see if this diet really was going to change people’s lives. She wanted to bring it into the community,” she said.

Proud legacy

Since 2017, Morris had led a large clinical trial of the effectiveness of the MIND diet in preventing cognitive decline. The first study of its kind, the trial received a $14.5 million grant from the National Institutes of Health (NIH). Results of this study are expected in 2021.

The MIND diet was ranked among the top 10 diets for five consecutive years in US News and World Report.

Morris’s nutrition-related research went beyond diets and examined the impact of individual nutrients. One of her studies, published in 2018 and reported by Medscape Medical News, suggested that the presence of folate, phylloquinone, and lutein – nutrients found in relatively large amounts in green leafy vegetables – may account for why consuming a daily serving of these vegetables slows cognitive decline.

One of the most recent studies from Morris’ group, published in January 2020 and reported by Medscape Medical News at that time, provided the first evidence that dietary flavonols, which are found in many fruits and vegetables, are associated with a significantly reduced risk for dementia.

What Morris did so well was to “look at the big picture” and “think about commonalities that cross nutritional components” of diets such as MIND, DASH, the Mediterranean diet, and the Nordic diet, which is similar to the Mediterranean diet but highlights local foods such as fish from Nordic regions, Snyder told Medscape Medical News.

Morris was instrumental in getting the Alzheimer’s Association’s US POINTER (US Study to Protect Brain Health Through Lifestyle Intervention to Reduce Risk) study off the ground. The 2-year clinical trial is testing whether combining a healthy diet with exercise, cognitive and social stimulation, and the management of cardiovascular conditions protects cognitive function in older adults who are at increased risk for cognitive decline.

This study will be part of her legacy, said Snyder.

“She will be remembered for her perseverance to get us to a place where we can be looking at nutrition as a modifiable risk factor and now testing it in trials that she helped to set up,” she said.

Even before her involvement with US POINTER, Morris had long been an active volunteer for the Alzheimer’s Association, said Snyder.

“She contributed significant time and expertise as we looked at the state of the evidence around nutrition and other lifestyle and behavioral interventions.”

We’ll ‘always have Paris’

While Morris was “truly passionate” about diet and health “both professionally and personally,” she also had a fun side, said Schneider. She remembers she and Morris had a chance meeting in Paris, where they spent an entire day going to museums and restaurants and just talking about life and their travels. To the end, they joked they would “always have Paris,” said Schneider.

She was also a loyal friend. Morris threw a baby shower when Schneider was pregnant, organizing every detail, despite her extremely busy schedule.

Family was another of Morris’s passions. Snyder recalls Morris’s face lighting up when she talked about her children and grandchildren. She also remembers her friend’s zest for life. “She had an energy that was contagious.”

Morris also loved the outdoors and was a keen adventurer. She once trained for weeks before a long bike trip with her daughter and would take a helicopter to access remote backcountry on hiking excursions.

“She wanted to try everything,” said Schneider.

An author or contributor to more than 80 articles in peer-reviewed journals, Morris also served two terms (from 2011 to 2013) as chair of the NIH’s Neurological, Aging and Musculoskeletal Epidemiology Study Section.

She left behind multiple grants for various studies. One unique study, said Schneider, investigated the relationship between iron and other metals in the brain and the neuropathology of Alzheimer disease.

“She was really in the prime of her career,” noted Schneider. “She had so much left to give and to offer, so this is tremendously sad.”

According to news reports, Morris (nee Chinn) grew up in Homewood, Illinois, and earned bachelor’s and master’s degrees in sociology from the University of Iowa in Iowa City, where she met her husband, James Morris. The two married in 1978 and had three children.

Morris completed a doctorate in epidemiology at the Harvard School of Public Health. James died in 2012, also from cancer. Morris passed away peacefully at her home on February 15.

NATIONAL HARBOR, MD. – Anticoagulation reduces the risk of leaflet thrombosis at 30 days relative to antiplatelet therapy in low-risk patients undergoing transcatheter aortic valve replacement (TAVR), according to a randomized feasibility study presented at CRT 2020 sponsored by MedStar Heart & Vascular Institute..

Ted Bosworth/MDedge News

At 30 days, oral anticoagulation with warfarin did not appear to be associated with any increased risk of adverse outcomes, including bleeding events, relative to aspirin, according to Toby Rogers, MD, PhD, the scientific lead for the Structural Heart Disease Program at MedStar Heart & Vascular Institute, Washington.

The rationale for this feasibility study, called LRT 2.0, was to evaluate whether anticoagulation after low-risk TAVR reduces the risk of early subclinical leaflet thrombosis, a potential threat to long-term valve survival.

“In the first LRT trial, HALT [hypoattenuated leaflet thickening] was observed in 13.5% of patients on antiplatelet therapy but only 4.8% of those on oral anticoagulation,” Dr. Rogers said.

The two strategies have not been adequately compared, particularly in low-risk patients, according to Dr. Rogers. He noted that current guidelines recommend dual-antiplatelet therapy after TAVR but the oral anticoagulant warfarin after surgical valve replacement, a situation he characterized as a “discrepancy.”

In the multicenter, randomized LRT 2.0 trial, 94 patients undergoing TAVR and meeting prespecified low-risk criteria, such as a Society of Thoracic Surgeons score of 3 or lower, were randomized to warfarin or to aspirin. The study called for an enrollment of 200 patients but was closed early when the Food and Drug Administration approved TAVR for low-risk patients in 2019, causing “enrollment to dry up over night.”

However, an additional registry cohort was included in a separate analysis. This registry cohort consisted of 30 patients who were evaluated for trial inclusion but were found to be inappropriate for randomization because they already had an indication for anticoagulation or had an elevated risk of bleeding. These low-risk TAVR patients were assigned to anticoagulation or antiplatelet therapy as appropriate.

When the randomized groups were compared, the incidence of HALT at 30 days on CT scan was 4.7% among those on warfarin and 16.3% (P = .07) among those taking aspirin. Dr. Rogers believes the near miss for statistical significance was a problem of power, a position supported by the pooled analysis of randomized and registry patients. With the added patients, the difference in HALT did reach significance (3.1% vs. 16.4%; P = .01).

The numerical differences in reduced leaflet motion and hypoattenuated motion favoring anticoagulation trended for significance in the randomized cohort (P = .12) but reached the cusp of significance in the pooled cohort (1.5% vs. 9.4%; P = .052) for both reduced leaflet motion and hypoattenuated motion).

There were no deaths recorded in any treatment arm, whether restricted to the randomized trial or within the pooled cohort. For the pooled cohort, there were more strokes in the aspirin arm (5.4% vs. 1.5%) but Dr. Rogers said that no conclusions could be drawn about relative risk because of the study size and small number of events.

For anticoagulation relative to antiplatelet therapy, respectively, the incidence of new-onset atrial fibrillation (1.5% vs. 1.8%), pacemaker implantation (11.8% vs. 7.1%), major bleeding (1.5% vs. 5.4%), and median length of stay (2.2 vs. 2.4 days) were all similar. The improvements in hemodynamics 30 days after TAVR were substantial and similar in the two groups, according to Dr. Rogers.

Emphasizing that this is a feasibility study, Dr. Rogers cautioned that these data do not necessarily demonstrate that anticoagulation is a better strategy than antiplatelet therapy in low-risk patients after TAVR, but they do associate anticoagulation with a reduced risk of early leaflet thrombosis.

“We fear leaflet thrombosis for the potential that it will negatively impact valve durability, which is particularly important in younger lower-risk patients who might outlive their first valve prosthesis,” Dr. Rogers said.

Panelists at the late-breaking clinical trial session expressed interest in this concept but generally agreed that longer follow-up is needed. This additional follow-up is important for monitoring effect on leaflet thrombosis as well as on the overall impact of these strategies on adverse events.

“We need to see CT scans at later time points because we do not know where this complication comes from. The trigger for leaflet thrombosis might still be there after 30 days,” said Andreas Baumbach, MD, professor of interventional cardiology at the University of Bristol (England). However, he agreed that this is an important line of research, because the potential risk of leaflet thrombosis is “a very important question for us.”

Dr. Rogers reported financial relationships with Edwards Lifesciences and Medtronic.

NATIONAL HARBOR, MD. – Anticoagulation reduces the risk of leaflet thrombosis at 30 days relative to antiplatelet therapy in low-risk patients undergoing transcatheter aortic valve replacement (TAVR), according to a randomized feasibility study presented at CRT 2020 sponsored by MedStar Heart & Vascular Institute..

Ted Bosworth/MDedge News

At 30 days, oral anticoagulation with warfarin did not appear to be associated with any increased risk of adverse outcomes, including bleeding events, relative to aspirin, according to Toby Rogers, MD, PhD, the scientific lead for the Structural Heart Disease Program at MedStar Heart & Vascular Institute, Washington.

The rationale for this feasibility study, called LRT 2.0, was to evaluate whether anticoagulation after low-risk TAVR reduces the risk of early subclinical leaflet thrombosis, a potential threat to long-term valve survival.

“In the first LRT trial, HALT [hypoattenuated leaflet thickening] was observed in 13.5% of patients on antiplatelet therapy but only 4.8% of those on oral anticoagulation,” Dr. Rogers said.

The two strategies have not been adequately compared, particularly in low-risk patients, according to Dr. Rogers. He noted that current guidelines recommend dual-antiplatelet therapy after TAVR but the oral anticoagulant warfarin after surgical valve replacement, a situation he characterized as a “discrepancy.”

In the multicenter, randomized LRT 2.0 trial, 94 patients undergoing TAVR and meeting prespecified low-risk criteria, such as a Society of Thoracic Surgeons score of 3 or lower, were randomized to warfarin or to aspirin. The study called for an enrollment of 200 patients but was closed early when the Food and Drug Administration approved TAVR for low-risk patients in 2019, causing “enrollment to dry up over night.”

However, an additional registry cohort was included in a separate analysis. This registry cohort consisted of 30 patients who were evaluated for trial inclusion but were found to be inappropriate for randomization because they already had an indication for anticoagulation or had an elevated risk of bleeding. These low-risk TAVR patients were assigned to anticoagulation or antiplatelet therapy as appropriate.

When the randomized groups were compared, the incidence of HALT at 30 days on CT scan was 4.7% among those on warfarin and 16.3% (P = .07) among those taking aspirin. Dr. Rogers believes the near miss for statistical significance was a problem of power, a position supported by the pooled analysis of randomized and registry patients. With the added patients, the difference in HALT did reach significance (3.1% vs. 16.4%; P = .01).

The numerical differences in reduced leaflet motion and hypoattenuated motion favoring anticoagulation trended for significance in the randomized cohort (P = .12) but reached the cusp of significance in the pooled cohort (1.5% vs. 9.4%; P = .052) for both reduced leaflet motion and hypoattenuated motion).

There were no deaths recorded in any treatment arm, whether restricted to the randomized trial or within the pooled cohort. For the pooled cohort, there were more strokes in the aspirin arm (5.4% vs. 1.5%) but Dr. Rogers said that no conclusions could be drawn about relative risk because of the study size and small number of events.

For anticoagulation relative to antiplatelet therapy, respectively, the incidence of new-onset atrial fibrillation (1.5% vs. 1.8%), pacemaker implantation (11.8% vs. 7.1%), major bleeding (1.5% vs. 5.4%), and median length of stay (2.2 vs. 2.4 days) were all similar. The improvements in hemodynamics 30 days after TAVR were substantial and similar in the two groups, according to Dr. Rogers.

Emphasizing that this is a feasibility study, Dr. Rogers cautioned that these data do not necessarily demonstrate that anticoagulation is a better strategy than antiplatelet therapy in low-risk patients after TAVR, but they do associate anticoagulation with a reduced risk of early leaflet thrombosis.

“We fear leaflet thrombosis for the potential that it will negatively impact valve durability, which is particularly important in younger lower-risk patients who might outlive their first valve prosthesis,” Dr. Rogers said.

Panelists at the late-breaking clinical trial session expressed interest in this concept but generally agreed that longer follow-up is needed. This additional follow-up is important for monitoring effect on leaflet thrombosis as well as on the overall impact of these strategies on adverse events.

“We need to see CT scans at later time points because we do not know where this complication comes from. The trigger for leaflet thrombosis might still be there after 30 days,” said Andreas Baumbach, MD, professor of interventional cardiology at the University of Bristol (England). However, he agreed that this is an important line of research, because the potential risk of leaflet thrombosis is “a very important question for us.”

Dr. Rogers reported financial relationships with Edwards Lifesciences and Medtronic.

NATIONAL HARBOR, MD. – Anticoagulation reduces the risk of leaflet thrombosis at 30 days relative to antiplatelet therapy in low-risk patients undergoing transcatheter aortic valve replacement (TAVR), according to a randomized feasibility study presented at CRT 2020 sponsored by MedStar Heart & Vascular Institute..

Ted Bosworth/MDedge News

At 30 days, oral anticoagulation with warfarin did not appear to be associated with any increased risk of adverse outcomes, including bleeding events, relative to aspirin, according to Toby Rogers, MD, PhD, the scientific lead for the Structural Heart Disease Program at MedStar Heart & Vascular Institute, Washington.

The rationale for this feasibility study, called LRT 2.0, was to evaluate whether anticoagulation after low-risk TAVR reduces the risk of early subclinical leaflet thrombosis, a potential threat to long-term valve survival.

“In the first LRT trial, HALT [hypoattenuated leaflet thickening] was observed in 13.5% of patients on antiplatelet therapy but only 4.8% of those on oral anticoagulation,” Dr. Rogers said.

The two strategies have not been adequately compared, particularly in low-risk patients, according to Dr. Rogers. He noted that current guidelines recommend dual-antiplatelet therapy after TAVR but the oral anticoagulant warfarin after surgical valve replacement, a situation he characterized as a “discrepancy.”

In the multicenter, randomized LRT 2.0 trial, 94 patients undergoing TAVR and meeting prespecified low-risk criteria, such as a Society of Thoracic Surgeons score of 3 or lower, were randomized to warfarin or to aspirin. The study called for an enrollment of 200 patients but was closed early when the Food and Drug Administration approved TAVR for low-risk patients in 2019, causing “enrollment to dry up over night.”

However, an additional registry cohort was included in a separate analysis. This registry cohort consisted of 30 patients who were evaluated for trial inclusion but were found to be inappropriate for randomization because they already had an indication for anticoagulation or had an elevated risk of bleeding. These low-risk TAVR patients were assigned to anticoagulation or antiplatelet therapy as appropriate.

When the randomized groups were compared, the incidence of HALT at 30 days on CT scan was 4.7% among those on warfarin and 16.3% (P = .07) among those taking aspirin. Dr. Rogers believes the near miss for statistical significance was a problem of power, a position supported by the pooled analysis of randomized and registry patients. With the added patients, the difference in HALT did reach significance (3.1% vs. 16.4%; P = .01).

The numerical differences in reduced leaflet motion and hypoattenuated motion favoring anticoagulation trended for significance in the randomized cohort (P = .12) but reached the cusp of significance in the pooled cohort (1.5% vs. 9.4%; P = .052) for both reduced leaflet motion and hypoattenuated motion).

There were no deaths recorded in any treatment arm, whether restricted to the randomized trial or within the pooled cohort. For the pooled cohort, there were more strokes in the aspirin arm (5.4% vs. 1.5%) but Dr. Rogers said that no conclusions could be drawn about relative risk because of the study size and small number of events.

For anticoagulation relative to antiplatelet therapy, respectively, the incidence of new-onset atrial fibrillation (1.5% vs. 1.8%), pacemaker implantation (11.8% vs. 7.1%), major bleeding (1.5% vs. 5.4%), and median length of stay (2.2 vs. 2.4 days) were all similar. The improvements in hemodynamics 30 days after TAVR were substantial and similar in the two groups, according to Dr. Rogers.

Emphasizing that this is a feasibility study, Dr. Rogers cautioned that these data do not necessarily demonstrate that anticoagulation is a better strategy than antiplatelet therapy in low-risk patients after TAVR, but they do associate anticoagulation with a reduced risk of early leaflet thrombosis.

“We fear leaflet thrombosis for the potential that it will negatively impact valve durability, which is particularly important in younger lower-risk patients who might outlive their first valve prosthesis,” Dr. Rogers said.

Panelists at the late-breaking clinical trial session expressed interest in this concept but generally agreed that longer follow-up is needed. This additional follow-up is important for monitoring effect on leaflet thrombosis as well as on the overall impact of these strategies on adverse events.

“We need to see CT scans at later time points because we do not know where this complication comes from. The trigger for leaflet thrombosis might still be there after 30 days,” said Andreas Baumbach, MD, professor of interventional cardiology at the University of Bristol (England). However, he agreed that this is an important line of research, because the potential risk of leaflet thrombosis is “a very important question for us.”

Dr. Rogers reported financial relationships with Edwards Lifesciences and Medtronic.

The novel coronavirus (2019-nCoV) is presenting a severe challenge to global health care, but its impact isn’t just felt in the emergency department. Specialists, including dermatologists, must also navigate the presence of the virus and its impact on patients and practices.

Courtesy CDC

A new report from dermatologists in China’s Wuhan province, where the 2019-nCoV outbreak began, outlines initial experiences and provides a blueprint for triaging potential cases before they reach the dermatology clinic. Despite its presence in the epicenter of the outbreak, the hospital has not detected any 2019-nCoV-infected patients in any of its departments.

The commentary appeared in the British Journal of Dermatology and was authored by a group led by Juan Tao of Huazhong University of Science and Technology (Br J Dermatol. 2020 Mar 5. doi: 10.1111/bjd.19011).

The hospital triages all patients at the hospital entrance. Those who are suspected of having 2019-nCoV infection are sent to a designated department. Those with a skin condition who are not suspected of being infected are allowed to go to a dermatology triage center, where they are examined again. If the second examination raises suspicion, they are sent to the designated 2019-nCoV department. If no infection is suspected, or a patient from the 2019-nCoV department is cleared, they are allowed access to the dermatology clinic.

The team also suggested that skin lesions associated with dermatological conditions could lead to increased risk of 2019-nCoV infection. Contacted by email, Dr. Tao outlined a theoretical risk that the virus could lead to infection through contact with subcutaneous tissues, mucosal surfaces, or blood vessels. He did not respond to a request for evidence that such a route of transmission had occurred.

However, Adam Friedman, MD, professor of dermatology at George Washington University, Washington, said he doubted any such transmission would occur since the virus does not infect keratinocytes, and expressed concern that the suggestion could add to the stigma experienced by dermatological patients, whose noticeable rashes can sometimes lead to social avoidance. “I don’t want to add to that,” said Dr. Friedman in an interview.

A critical aspect of dermatology is the immunosuppressive agents often used in dermatology patients. Such drugs could make them more susceptible to infections, or to worse outcomes in the event of disease. Dr. Friedman recounted sending a letter to one patient on an immunosuppressive medication, suggesting that she work remotely. “I think that’s something we have to think about in at-risk individuals. I know there’s such a focus on the elderly, but there’s a large population of individuals on medications that lower their immune system who are going to be at risk for more severe infections,” said Dr. Friedman.

To reduce patient exposure, the commentary recommended that dermatologists perform online consultation for mild and nonemergency cases.

The authors also covered hospitalized patients with primary or secondary skin conditions. A dermatologist is on site at the dermatology triage station to conduct in-depth assessments if needed. If a patient has a fever that is believed to be caused by a dermatologic condition, the on-site dermatologist assists in the consult.

Because some patients may only become symptomatic after admission to a ward, the authors recommend hospitals have a COVID-19 trained contingency group on hand to prevent and control outbreaks within the institution. The team should be in communication with respiratory intensive care and radiology departments to exclude 2019-nCoV when cases develop in-hospital, and to ensure proper care infected patients who require it.

When a hospitalized 2019-nCoV-infected patient has a skin condition requiring treatment, the authors recommend that pictures be sent to the dermatologist for evaluation, along with teleconferences to further assess the patient. If necessary, the dermatologist should go to the patient’s bedside, with as much information as possible related in advance in order to minimize bedside exposure.

There was no funding source. Dr. Tao and Dr. Friedman have no relevant financial conflicts.

The novel coronavirus (2019-nCoV) is presenting a severe challenge to global health care, but its impact isn’t just felt in the emergency department. Specialists, including dermatologists, must also navigate the presence of the virus and its impact on patients and practices.

Courtesy CDC

A new report from dermatologists in China’s Wuhan province, where the 2019-nCoV outbreak began, outlines initial experiences and provides a blueprint for triaging potential cases before they reach the dermatology clinic. Despite its presence in the epicenter of the outbreak, the hospital has not detected any 2019-nCoV-infected patients in any of its departments.

The commentary appeared in the British Journal of Dermatology and was authored by a group led by Juan Tao of Huazhong University of Science and Technology (Br J Dermatol. 2020 Mar 5. doi: 10.1111/bjd.19011).

The hospital triages all patients at the hospital entrance. Those who are suspected of having 2019-nCoV infection are sent to a designated department. Those with a skin condition who are not suspected of being infected are allowed to go to a dermatology triage center, where they are examined again. If the second examination raises suspicion, they are sent to the designated 2019-nCoV department. If no infection is suspected, or a patient from the 2019-nCoV department is cleared, they are allowed access to the dermatology clinic.

The team also suggested that skin lesions associated with dermatological conditions could lead to increased risk of 2019-nCoV infection. Contacted by email, Dr. Tao outlined a theoretical risk that the virus could lead to infection through contact with subcutaneous tissues, mucosal surfaces, or blood vessels. He did not respond to a request for evidence that such a route of transmission had occurred.

However, Adam Friedman, MD, professor of dermatology at George Washington University, Washington, said he doubted any such transmission would occur since the virus does not infect keratinocytes, and expressed concern that the suggestion could add to the stigma experienced by dermatological patients, whose noticeable rashes can sometimes lead to social avoidance. “I don’t want to add to that,” said Dr. Friedman in an interview.

A critical aspect of dermatology is the immunosuppressive agents often used in dermatology patients. Such drugs could make them more susceptible to infections, or to worse outcomes in the event of disease. Dr. Friedman recounted sending a letter to one patient on an immunosuppressive medication, suggesting that she work remotely. “I think that’s something we have to think about in at-risk individuals. I know there’s such a focus on the elderly, but there’s a large population of individuals on medications that lower their immune system who are going to be at risk for more severe infections,” said Dr. Friedman.

To reduce patient exposure, the commentary recommended that dermatologists perform online consultation for mild and nonemergency cases.

The authors also covered hospitalized patients with primary or secondary skin conditions. A dermatologist is on site at the dermatology triage station to conduct in-depth assessments if needed. If a patient has a fever that is believed to be caused by a dermatologic condition, the on-site dermatologist assists in the consult.

Because some patients may only become symptomatic after admission to a ward, the authors recommend hospitals have a COVID-19 trained contingency group on hand to prevent and control outbreaks within the institution. The team should be in communication with respiratory intensive care and radiology departments to exclude 2019-nCoV when cases develop in-hospital, and to ensure proper care infected patients who require it.

When a hospitalized 2019-nCoV-infected patient has a skin condition requiring treatment, the authors recommend that pictures be sent to the dermatologist for evaluation, along with teleconferences to further assess the patient. If necessary, the dermatologist should go to the patient’s bedside, with as much information as possible related in advance in order to minimize bedside exposure.

There was no funding source. Dr. Tao and Dr. Friedman have no relevant financial conflicts.

The novel coronavirus (2019-nCoV) is presenting a severe challenge to global health care, but its impact isn’t just felt in the emergency department. Specialists, including dermatologists, must also navigate the presence of the virus and its impact on patients and practices.

Courtesy CDC

A new report from dermatologists in China’s Wuhan province, where the 2019-nCoV outbreak began, outlines initial experiences and provides a blueprint for triaging potential cases before they reach the dermatology clinic. Despite its presence in the epicenter of the outbreak, the hospital has not detected any 2019-nCoV-infected patients in any of its departments.

The commentary appeared in the British Journal of Dermatology and was authored by a group led by Juan Tao of Huazhong University of Science and Technology (Br J Dermatol. 2020 Mar 5. doi: 10.1111/bjd.19011).

The hospital triages all patients at the hospital entrance. Those who are suspected of having 2019-nCoV infection are sent to a designated department. Those with a skin condition who are not suspected of being infected are allowed to go to a dermatology triage center, where they are examined again. If the second examination raises suspicion, they are sent to the designated 2019-nCoV department. If no infection is suspected, or a patient from the 2019-nCoV department is cleared, they are allowed access to the dermatology clinic.

The team also suggested that skin lesions associated with dermatological conditions could lead to increased risk of 2019-nCoV infection. Contacted by email, Dr. Tao outlined a theoretical risk that the virus could lead to infection through contact with subcutaneous tissues, mucosal surfaces, or blood vessels. He did not respond to a request for evidence that such a route of transmission had occurred.

However, Adam Friedman, MD, professor of dermatology at George Washington University, Washington, said he doubted any such transmission would occur since the virus does not infect keratinocytes, and expressed concern that the suggestion could add to the stigma experienced by dermatological patients, whose noticeable rashes can sometimes lead to social avoidance. “I don’t want to add to that,” said Dr. Friedman in an interview.

A critical aspect of dermatology is the immunosuppressive agents often used in dermatology patients. Such drugs could make them more susceptible to infections, or to worse outcomes in the event of disease. Dr. Friedman recounted sending a letter to one patient on an immunosuppressive medication, suggesting that she work remotely. “I think that’s something we have to think about in at-risk individuals. I know there’s such a focus on the elderly, but there’s a large population of individuals on medications that lower their immune system who are going to be at risk for more severe infections,” said Dr. Friedman.

To reduce patient exposure, the commentary recommended that dermatologists perform online consultation for mild and nonemergency cases.

The authors also covered hospitalized patients with primary or secondary skin conditions. A dermatologist is on site at the dermatology triage station to conduct in-depth assessments if needed. If a patient has a fever that is believed to be caused by a dermatologic condition, the on-site dermatologist assists in the consult.

Because some patients may only become symptomatic after admission to a ward, the authors recommend hospitals have a COVID-19 trained contingency group on hand to prevent and control outbreaks within the institution. The team should be in communication with respiratory intensive care and radiology departments to exclude 2019-nCoV when cases develop in-hospital, and to ensure proper care infected patients who require it.

When a hospitalized 2019-nCoV-infected patient has a skin condition requiring treatment, the authors recommend that pictures be sent to the dermatologist for evaluation, along with teleconferences to further assess the patient. If necessary, the dermatologist should go to the patient’s bedside, with as much information as possible related in advance in order to minimize bedside exposure.

There was no funding source. Dr. Tao and Dr. Friedman have no relevant financial conflicts.

Fecal-oral transmission may be part of the COVID-19 clinical picture, according to two reports published in Gastroenterology. The researchers find that RNA and proteins from SARS-CoV-2, the viral cause of COVID-19, are shed in feces early in infection and persist after respiratory symptoms abate.

But the discovery is preliminary. “There is evidence of the virus in stool, but not evidence of infectious virus,” David A. Johnson, MD, professor of medicine and chief of gastroenterology at the Eastern Virginia School of Medicine in Norfolk, told Medscape Medical News.

The findings are not entirely unexpected. Both of the coronaviruses behind SARS and MERS are shed in stool, Jinyang Gu, MD, from Shanghai Jiao Tong University School of Medicine in Shanghai, China, and colleagues, note in one of the newly published articles.

In addition, as COVID-19 spread beyond China, clinicians began noticing initial mild gastrointestinal (GI) symptoms in some patients, including diarrhea, nausea, vomiting, and abdominal pain, preceding the hallmark fever, dry cough, and dyspnea. The first patient diagnosed in the United States with COVID-19 reported having 2 days of nausea and vomiting, with viral RNA detected in fecal and respiratory specimens, according to an earlier report.

Gu and colleagues warn that initial investigations would likely have not considered cases that manifested initially only as mild gastrointestinal symptoms.

Although early reports indicated that only about 10% of people with COVID-19 have GI symptoms, it isn’t known whether some infected individuals have only GI symptoms, Johnson said.

The GI manifestations are consistent with the distribution of ACE2 receptors, which serve as entry points for SARS-CoV-2, as well as SARS-CoV-1, which causes SARS. The receptors are most abundant in the cell membranes of lung AT2 cells, as well as in enterocytes in the ileum and colon.

“Altogether, many efforts should be made to be alert on the initial digestive symptoms of COVID-19 for early detection, early diagnosis, early isolation and early intervention,” Gu and colleagues conclude.

But Johnson cautions, “gastroenterologists are not the ones managing diagnosis of COVID-19. It is diagnosed as a respiratory illness, but we are seeing concomitant gastrointestinal shedding in stool and saliva, and GI symptoms.”
 

Samples From 73 Patients Studied

In the second article published, Fei Xiao, MD, of Sun Yat-sen University in Guangdong Province, China, and colleagues report detecting viral RNA in samples from the mouths, noses, throats, urine, and feces of 73 patients hospitalized during the first 2 weeks of February.

Of the 73 hospitalized patients, 39 (53.24%; 25 males and 14 females) had viral RNA in their feces, present from 1 to 12 days. Seventeen (23.29%) of the patients continued to have viral RNA in their stool after respiratory symptoms had improved.

One patient underwent endoscopy. There was no evidence of damage to the GI epithelium, but the clinicians detected slightly elevated levels of lymphocytes and plasma cells.

The researcher used laser scanning confocal microscopy to analyze samples taken during the endoscopy. They found evidence of both ACE2 receptors and viral nucleocapsid proteins in the gastric, duodenal, and rectal glandular epithelial cells.

Finding evidence of SARS-CoV-2 throughout the GI system, if not direct infectivity, suggests a fecal-oral route of transmission, the researchers conclude. “Our immunofluorescent data showed that ACE2 protein, a cell receptor for SARS-CoV-2, is abundantly expressed in the glandular cells of gastric, duodenal and rectal epithelia, supporting the entry of SARS-CoV-2 into the host cells.”

Detection of viral RNA at different time points in infection, they write, suggests that the virions are continually secreted and therefore likely infectious, which is under investigation. “Prevention of fecal-oral transmission should be taken into consideration to control the spread of the virus,” they write.

Current recommendations do not require that patients’ fecal samples be tested before being considered noninfectious. However, given their findings and evidence from other studies, Xiao and colleagues recommend that real-time reverse transcriptase-polymerase chain reaction (rRT-PCR) testing of fecal samples be added to current protocols.

Johnson offers practical suggestions based on the “potty hygiene” suggestions he gives to patients dealing with fecal shedding in Clostridioides difficile infection.

“To combat the microaerosolization of C. diff spores, I have patients do a complete bacteriocidal washing out of the toilet bowl, as well as clean surface areas and especially toothbrushes.” Keeping the bowl closed when not in use is important too in preventing “fecal-oral transmission of remnants” of toilet contents, he adds.

The new papers add to other reports suggesting that virus-bearing droplets may reach people in various ways, Johnson said. “Maybe the virus isn’t only spread by a cough or a sneeze.”

The researchers and commentator have disclosed no relevant financial relationships.

This article first appeared on Medscape.com.

Fecal-oral transmission may be part of the COVID-19 clinical picture, according to two reports published in Gastroenterology. The researchers find that RNA and proteins from SARS-CoV-2, the viral cause of COVID-19, are shed in feces early in infection and persist after respiratory symptoms abate.

But the discovery is preliminary. “There is evidence of the virus in stool, but not evidence of infectious virus,” David A. Johnson, MD, professor of medicine and chief of gastroenterology at the Eastern Virginia School of Medicine in Norfolk, told Medscape Medical News.

The findings are not entirely unexpected. Both of the coronaviruses behind SARS and MERS are shed in stool, Jinyang Gu, MD, from Shanghai Jiao Tong University School of Medicine in Shanghai, China, and colleagues, note in one of the newly published articles.

In addition, as COVID-19 spread beyond China, clinicians began noticing initial mild gastrointestinal (GI) symptoms in some patients, including diarrhea, nausea, vomiting, and abdominal pain, preceding the hallmark fever, dry cough, and dyspnea. The first patient diagnosed in the United States with COVID-19 reported having 2 days of nausea and vomiting, with viral RNA detected in fecal and respiratory specimens, according to an earlier report.

Gu and colleagues warn that initial investigations would likely have not considered cases that manifested initially only as mild gastrointestinal symptoms.

Although early reports indicated that only about 10% of people with COVID-19 have GI symptoms, it isn’t known whether some infected individuals have only GI symptoms, Johnson said.

The GI manifestations are consistent with the distribution of ACE2 receptors, which serve as entry points for SARS-CoV-2, as well as SARS-CoV-1, which causes SARS. The receptors are most abundant in the cell membranes of lung AT2 cells, as well as in enterocytes in the ileum and colon.

“Altogether, many efforts should be made to be alert on the initial digestive symptoms of COVID-19 for early detection, early diagnosis, early isolation and early intervention,” Gu and colleagues conclude.

But Johnson cautions, “gastroenterologists are not the ones managing diagnosis of COVID-19. It is diagnosed as a respiratory illness, but we are seeing concomitant gastrointestinal shedding in stool and saliva, and GI symptoms.”
 

Samples From 73 Patients Studied

In the second article published, Fei Xiao, MD, of Sun Yat-sen University in Guangdong Province, China, and colleagues report detecting viral RNA in samples from the mouths, noses, throats, urine, and feces of 73 patients hospitalized during the first 2 weeks of February.

Of the 73 hospitalized patients, 39 (53.24%; 25 males and 14 females) had viral RNA in their feces, present from 1 to 12 days. Seventeen (23.29%) of the patients continued to have viral RNA in their stool after respiratory symptoms had improved.

One patient underwent endoscopy. There was no evidence of damage to the GI epithelium, but the clinicians detected slightly elevated levels of lymphocytes and plasma cells.

The researcher used laser scanning confocal microscopy to analyze samples taken during the endoscopy. They found evidence of both ACE2 receptors and viral nucleocapsid proteins in the gastric, duodenal, and rectal glandular epithelial cells.

Finding evidence of SARS-CoV-2 throughout the GI system, if not direct infectivity, suggests a fecal-oral route of transmission, the researchers conclude. “Our immunofluorescent data showed that ACE2 protein, a cell receptor for SARS-CoV-2, is abundantly expressed in the glandular cells of gastric, duodenal and rectal epithelia, supporting the entry of SARS-CoV-2 into the host cells.”

Detection of viral RNA at different time points in infection, they write, suggests that the virions are continually secreted and therefore likely infectious, which is under investigation. “Prevention of fecal-oral transmission should be taken into consideration to control the spread of the virus,” they write.

Current recommendations do not require that patients’ fecal samples be tested before being considered noninfectious. However, given their findings and evidence from other studies, Xiao and colleagues recommend that real-time reverse transcriptase-polymerase chain reaction (rRT-PCR) testing of fecal samples be added to current protocols.

Johnson offers practical suggestions based on the “potty hygiene” suggestions he gives to patients dealing with fecal shedding in Clostridioides difficile infection.

“To combat the microaerosolization of C. diff spores, I have patients do a complete bacteriocidal washing out of the toilet bowl, as well as clean surface areas and especially toothbrushes.” Keeping the bowl closed when not in use is important too in preventing “fecal-oral transmission of remnants” of toilet contents, he adds.

The new papers add to other reports suggesting that virus-bearing droplets may reach people in various ways, Johnson said. “Maybe the virus isn’t only spread by a cough or a sneeze.”

The researchers and commentator have disclosed no relevant financial relationships.

This article first appeared on Medscape.com.

Fecal-oral transmission may be part of the COVID-19 clinical picture, according to two reports published in Gastroenterology. The researchers find that RNA and proteins from SARS-CoV-2, the viral cause of COVID-19, are shed in feces early in infection and persist after respiratory symptoms abate.

But the discovery is preliminary. “There is evidence of the virus in stool, but not evidence of infectious virus,” David A. Johnson, MD, professor of medicine and chief of gastroenterology at the Eastern Virginia School of Medicine in Norfolk, told Medscape Medical News.

The findings are not entirely unexpected. Both of the coronaviruses behind SARS and MERS are shed in stool, Jinyang Gu, MD, from Shanghai Jiao Tong University School of Medicine in Shanghai, China, and colleagues, note in one of the newly published articles.

In addition, as COVID-19 spread beyond China, clinicians began noticing initial mild gastrointestinal (GI) symptoms in some patients, including diarrhea, nausea, vomiting, and abdominal pain, preceding the hallmark fever, dry cough, and dyspnea. The first patient diagnosed in the United States with COVID-19 reported having 2 days of nausea and vomiting, with viral RNA detected in fecal and respiratory specimens, according to an earlier report.

Gu and colleagues warn that initial investigations would likely have not considered cases that manifested initially only as mild gastrointestinal symptoms.

Although early reports indicated that only about 10% of people with COVID-19 have GI symptoms, it isn’t known whether some infected individuals have only GI symptoms, Johnson said.

The GI manifestations are consistent with the distribution of ACE2 receptors, which serve as entry points for SARS-CoV-2, as well as SARS-CoV-1, which causes SARS. The receptors are most abundant in the cell membranes of lung AT2 cells, as well as in enterocytes in the ileum and colon.

“Altogether, many efforts should be made to be alert on the initial digestive symptoms of COVID-19 for early detection, early diagnosis, early isolation and early intervention,” Gu and colleagues conclude.

But Johnson cautions, “gastroenterologists are not the ones managing diagnosis of COVID-19. It is diagnosed as a respiratory illness, but we are seeing concomitant gastrointestinal shedding in stool and saliva, and GI symptoms.”
 

Samples From 73 Patients Studied

In the second article published, Fei Xiao, MD, of Sun Yat-sen University in Guangdong Province, China, and colleagues report detecting viral RNA in samples from the mouths, noses, throats, urine, and feces of 73 patients hospitalized during the first 2 weeks of February.

Of the 73 hospitalized patients, 39 (53.24%; 25 males and 14 females) had viral RNA in their feces, present from 1 to 12 days. Seventeen (23.29%) of the patients continued to have viral RNA in their stool after respiratory symptoms had improved.

One patient underwent endoscopy. There was no evidence of damage to the GI epithelium, but the clinicians detected slightly elevated levels of lymphocytes and plasma cells.

The researcher used laser scanning confocal microscopy to analyze samples taken during the endoscopy. They found evidence of both ACE2 receptors and viral nucleocapsid proteins in the gastric, duodenal, and rectal glandular epithelial cells.

Finding evidence of SARS-CoV-2 throughout the GI system, if not direct infectivity, suggests a fecal-oral route of transmission, the researchers conclude. “Our immunofluorescent data showed that ACE2 protein, a cell receptor for SARS-CoV-2, is abundantly expressed in the glandular cells of gastric, duodenal and rectal epithelia, supporting the entry of SARS-CoV-2 into the host cells.”

Detection of viral RNA at different time points in infection, they write, suggests that the virions are continually secreted and therefore likely infectious, which is under investigation. “Prevention of fecal-oral transmission should be taken into consideration to control the spread of the virus,” they write.

Current recommendations do not require that patients’ fecal samples be tested before being considered noninfectious. However, given their findings and evidence from other studies, Xiao and colleagues recommend that real-time reverse transcriptase-polymerase chain reaction (rRT-PCR) testing of fecal samples be added to current protocols.

Johnson offers practical suggestions based on the “potty hygiene” suggestions he gives to patients dealing with fecal shedding in Clostridioides difficile infection.

“To combat the microaerosolization of C. diff spores, I have patients do a complete bacteriocidal washing out of the toilet bowl, as well as clean surface areas and especially toothbrushes.” Keeping the bowl closed when not in use is important too in preventing “fecal-oral transmission of remnants” of toilet contents, he adds.

The new papers add to other reports suggesting that virus-bearing droplets may reach people in various ways, Johnson said. “Maybe the virus isn’t only spread by a cough or a sneeze.”

The researchers and commentator have disclosed no relevant financial relationships.

This article first appeared on Medscape.com.

For most patients, proton pump inhibitors do not control symptoms of gastroesophageal reflux disease, according to the findings of a large population-based survey study.

In all, 31% of respondents reported gastroesophageal reflux disease (GERD) symptoms within the past week, and 54% of those on proton pump inhibitors (PPIs) had breakthrough symptoms, said Sean D. Delshad, MD, MBA. In all, 54% of patients on PPIs for GERD reported having breakthrough symptoms of heartburn or regurgitation. Novel treatments are needed for patients with PPI-refractory symptoms of GERD, he and his associates wrote in Gastroenterology.

Prior population-based U.S. studies have reported a lower prevalence (16%-28%) of weekly or monthly GERD symptoms, noted Dr. Delshad of the Cedars-Sinai Center for Outcomes Research and Education in Los Angeles. However, the study cohorts do not reflect current U.S. demographics — two were 82%-90% white and the third was 43% African American. The most recent data also were collected approximately 15 years ago, the researchers noted.

For the study, they deployed a mobile app that guides users through an automated, online assessment of GI symptoms called AEGIS. Respondents were asked to select any GERD symptoms they had ever experienced and any symptoms they had experienced in the past week. Options included heartburn, acid reflux, gastroesophageal reflux, abdominal pain, bloating or gas, constipation, diarrhea, disrupted swallowing, fecal incontinence, nausea and vomiting, and “no symptoms.” All 71,812 respondents were recruited by a research firm and surveyed during a 3-week period in 2015.

In all, 44% of respondents reported having ever had heartburn, acid reflux, or gastroesophageal reflux, and 31% reported having GERD symptoms in the past week. In all, 55% of respondents who had ever experienced GERD symptoms were on PPIs, 24% were on histamine₂ receptor blockers, and 24% were on antacid agents.

Among more than 3,000 participants on daily PPIs, 54% had persistent symptoms of GERD, which compares with the results of prior community-based studies, the investigators wrote. Current GERD symptoms and PPI-refractory GERD were especially prevalent among women, non-Hispanic whites, and individuals with comorbidities such as irritable bowel syndrome, diabetes, Crohn’s disease, and endometriosis.

In an adjusted analysis, Latinos were 2.44 times more likely to have PPI-refractory GERD ,compared with non-Hispanic whites. “The reason behind this finding is unclear but may be secondary to physiologic or even cultural etiologies,” the researchers wrote.

The more independent and functional middle-aged and older adults are more likely to respond to online surveys. Furthermore, although incentives were used to reduce participation bias, calling the tool a “GI Survey” could have made those with GI symptoms more likely to respond. The survey also did not assess if respondents were taking PPIs correctly or if they had made behavioral changes to mitigate GERD.

This study was sponsored by Ironwood Pharmaceuticals, whose bile acid sequestrant IW-3718 is in late-phase development as an add-on to PPI therapy for patients with persistent GERD. Dr. Delshad reported having no relevant conflicts of interest, but two coinvestigators disclosed consulting relationships with Ironwood Pharmaceuticals.
 

SOURCE: Delshad SD et al. Gastroenterology. 2019 Dec 10. doi: 10.1053/j.gastro.2019.12.014.

For most patients, proton pump inhibitors do not control symptoms of gastroesophageal reflux disease, according to the findings of a large population-based survey study.

In all, 31% of respondents reported gastroesophageal reflux disease (GERD) symptoms within the past week, and 54% of those on proton pump inhibitors (PPIs) had breakthrough symptoms, said Sean D. Delshad, MD, MBA. In all, 54% of patients on PPIs for GERD reported having breakthrough symptoms of heartburn or regurgitation. Novel treatments are needed for patients with PPI-refractory symptoms of GERD, he and his associates wrote in Gastroenterology.

Prior population-based U.S. studies have reported a lower prevalence (16%-28%) of weekly or monthly GERD symptoms, noted Dr. Delshad of the Cedars-Sinai Center for Outcomes Research and Education in Los Angeles. However, the study cohorts do not reflect current U.S. demographics — two were 82%-90% white and the third was 43% African American. The most recent data also were collected approximately 15 years ago, the researchers noted.

For the study, they deployed a mobile app that guides users through an automated, online assessment of GI symptoms called AEGIS. Respondents were asked to select any GERD symptoms they had ever experienced and any symptoms they had experienced in the past week. Options included heartburn, acid reflux, gastroesophageal reflux, abdominal pain, bloating or gas, constipation, diarrhea, disrupted swallowing, fecal incontinence, nausea and vomiting, and “no symptoms.” All 71,812 respondents were recruited by a research firm and surveyed during a 3-week period in 2015.

In all, 44% of respondents reported having ever had heartburn, acid reflux, or gastroesophageal reflux, and 31% reported having GERD symptoms in the past week. In all, 55% of respondents who had ever experienced GERD symptoms were on PPIs, 24% were on histamine₂ receptor blockers, and 24% were on antacid agents.

Among more than 3,000 participants on daily PPIs, 54% had persistent symptoms of GERD, which compares with the results of prior community-based studies, the investigators wrote. Current GERD symptoms and PPI-refractory GERD were especially prevalent among women, non-Hispanic whites, and individuals with comorbidities such as irritable bowel syndrome, diabetes, Crohn’s disease, and endometriosis.

In an adjusted analysis, Latinos were 2.44 times more likely to have PPI-refractory GERD ,compared with non-Hispanic whites. “The reason behind this finding is unclear but may be secondary to physiologic or even cultural etiologies,” the researchers wrote.

The more independent and functional middle-aged and older adults are more likely to respond to online surveys. Furthermore, although incentives were used to reduce participation bias, calling the tool a “GI Survey” could have made those with GI symptoms more likely to respond. The survey also did not assess if respondents were taking PPIs correctly or if they had made behavioral changes to mitigate GERD.

This study was sponsored by Ironwood Pharmaceuticals, whose bile acid sequestrant IW-3718 is in late-phase development as an add-on to PPI therapy for patients with persistent GERD. Dr. Delshad reported having no relevant conflicts of interest, but two coinvestigators disclosed consulting relationships with Ironwood Pharmaceuticals.
 

SOURCE: Delshad SD et al. Gastroenterology. 2019 Dec 10. doi: 10.1053/j.gastro.2019.12.014.

For most patients, proton pump inhibitors do not control symptoms of gastroesophageal reflux disease, according to the findings of a large population-based survey study.

In all, 31% of respondents reported gastroesophageal reflux disease (GERD) symptoms within the past week, and 54% of those on proton pump inhibitors (PPIs) had breakthrough symptoms, said Sean D. Delshad, MD, MBA. In all, 54% of patients on PPIs for GERD reported having breakthrough symptoms of heartburn or regurgitation. Novel treatments are needed for patients with PPI-refractory symptoms of GERD, he and his associates wrote in Gastroenterology.

Prior population-based U.S. studies have reported a lower prevalence (16%-28%) of weekly or monthly GERD symptoms, noted Dr. Delshad of the Cedars-Sinai Center for Outcomes Research and Education in Los Angeles. However, the study cohorts do not reflect current U.S. demographics — two were 82%-90% white and the third was 43% African American. The most recent data also were collected approximately 15 years ago, the researchers noted.

For the study, they deployed a mobile app that guides users through an automated, online assessment of GI symptoms called AEGIS. Respondents were asked to select any GERD symptoms they had ever experienced and any symptoms they had experienced in the past week. Options included heartburn, acid reflux, gastroesophageal reflux, abdominal pain, bloating or gas, constipation, diarrhea, disrupted swallowing, fecal incontinence, nausea and vomiting, and “no symptoms.” All 71,812 respondents were recruited by a research firm and surveyed during a 3-week period in 2015.

In all, 44% of respondents reported having ever had heartburn, acid reflux, or gastroesophageal reflux, and 31% reported having GERD symptoms in the past week. In all, 55% of respondents who had ever experienced GERD symptoms were on PPIs, 24% were on histamine₂ receptor blockers, and 24% were on antacid agents.

Among more than 3,000 participants on daily PPIs, 54% had persistent symptoms of GERD, which compares with the results of prior community-based studies, the investigators wrote. Current GERD symptoms and PPI-refractory GERD were especially prevalent among women, non-Hispanic whites, and individuals with comorbidities such as irritable bowel syndrome, diabetes, Crohn’s disease, and endometriosis.

In an adjusted analysis, Latinos were 2.44 times more likely to have PPI-refractory GERD ,compared with non-Hispanic whites. “The reason behind this finding is unclear but may be secondary to physiologic or even cultural etiologies,” the researchers wrote.

The more independent and functional middle-aged and older adults are more likely to respond to online surveys. Furthermore, although incentives were used to reduce participation bias, calling the tool a “GI Survey” could have made those with GI symptoms more likely to respond. The survey also did not assess if respondents were taking PPIs correctly or if they had made behavioral changes to mitigate GERD.

This study was sponsored by Ironwood Pharmaceuticals, whose bile acid sequestrant IW-3718 is in late-phase development as an add-on to PPI therapy for patients with persistent GERD. Dr. Delshad reported having no relevant conflicts of interest, but two coinvestigators disclosed consulting relationships with Ironwood Pharmaceuticals.
 

SOURCE: Delshad SD et al. Gastroenterology. 2019 Dec 10. doi: 10.1053/j.gastro.2019.12.014.

Individuals with Lynch syndrome were significantly more likely to have a personal history of gastric cancer if they were older, male, had an affected first-degree relative, or had pathogenic variants in the MLH1 or MSH2 mismatch repair genes, researchers reported.

“These findings suggest that personalized, risk-stratified approaches to gastric cancer surveillance may be appropriate for individuals with Lynch syndrome–associated mutations,” wrote Jaihwan Kim of Seoul National University Bundang Hospital, Seongnam, South Korea, and associates. Their report is in Clinical Gastroenterology and Hepatology.

Lynch syndrome, which involves autosomal dominant germline mutations in DNA mismatch repair (MMR) genes (MLH1, MSH2, MSH6, and PMS2) and EPCAM, significantly increases the risk for several types of cancer. Although Lynch syndrome increases gastric cancer risk almost tenfold, more than 90% of individuals with Lynch syndrome do not develop it, the researchers noted. Given the lethality of this cancer, they sought to better characterize risk factors.

To do so, they studied cancer histories and clinical and demographic data from 51,086 individuals who were tested for gene variants associated with Lynch syndrome at a commercial laboratory between 2006 and 2013. More than 3,800 individuals had pathogenic variants, including more than 1,300 with mutations of MLH1, more than 1,600 with mutations of MSH2, 670 with mutations of MSH6, 145 with mutations in PMS2, and 28 with mutations in EPCAM. In all, 41 (1%) individuals with pathogenic mutations had a personal history of gastric cancer, while 350 (9%) had an affected first or second-degree relative.

After the researchers controlled for potential confounders, males with Lynch syndrome–associated mutations had nearly triple the odds of a personal history of gastric cancer compared with females (odds ratio, 2.82; 95% CI, 1.48 to 5.38). The odds of gastric cancer also rose approximately twofold with each 10-year increase in age — and by 2.5-fold when individuals had an affected first-degree relative. Having a second-degree relative with gastric cancer was not an independent correlate. Compared with mutations in MSH6, PMS2, and EPCAM, gastric cancer was significantly more likely among individuals with mutations of MLH1 (OR, 6.53; 95% CI, 1.5 to 28.42) or MSH2 (OR = 5.23; 95% CI, 1.21 to 22.71).

Clinicians might use these factors to risk-stratify patients with Lynch syndrome to identify those who might benefit from enhanced surveillance with more frequent esophagogastroduodenoscopy, the researchers wrote. They noted that male sex, age, and first-degree family history increase the risk for sporadic gastric cancer unassociated with Lynch syndrome–associated mutations. Thus, these “traditional risk factors” might compound the inherited risk for gastric cancer observed in Lynch syndrome carriers.

The National Institutes of Health and the Pussycat Foundation Helen Gurley Brown Presidential Initiative provided funding. One coinvestigator disclosed a consulting relationship with Myriad Genetic Laboratories and having rights to an inventor portion of licensing revenues from PREMM5, a prediction model for Lynch syndrome mutations. The other researchers reported having no conflicts of interest.

SOURCE: Kim J et al. Clin Gastroenterol Hepatol. 2019 Jul 15. doi: 1016/j.cgh.2019.07.012.

Individuals with Lynch syndrome were significantly more likely to have a personal history of gastric cancer if they were older, male, had an affected first-degree relative, or had pathogenic variants in the MLH1 or MSH2 mismatch repair genes, researchers reported.

“These findings suggest that personalized, risk-stratified approaches to gastric cancer surveillance may be appropriate for individuals with Lynch syndrome–associated mutations,” wrote Jaihwan Kim of Seoul National University Bundang Hospital, Seongnam, South Korea, and associates. Their report is in Clinical Gastroenterology and Hepatology.

Lynch syndrome, which involves autosomal dominant germline mutations in DNA mismatch repair (MMR) genes (MLH1, MSH2, MSH6, and PMS2) and EPCAM, significantly increases the risk for several types of cancer. Although Lynch syndrome increases gastric cancer risk almost tenfold, more than 90% of individuals with Lynch syndrome do not develop it, the researchers noted. Given the lethality of this cancer, they sought to better characterize risk factors.

To do so, they studied cancer histories and clinical and demographic data from 51,086 individuals who were tested for gene variants associated with Lynch syndrome at a commercial laboratory between 2006 and 2013. More than 3,800 individuals had pathogenic variants, including more than 1,300 with mutations of MLH1, more than 1,600 with mutations of MSH2, 670 with mutations of MSH6, 145 with mutations in PMS2, and 28 with mutations in EPCAM. In all, 41 (1%) individuals with pathogenic mutations had a personal history of gastric cancer, while 350 (9%) had an affected first or second-degree relative.

After the researchers controlled for potential confounders, males with Lynch syndrome–associated mutations had nearly triple the odds of a personal history of gastric cancer compared with females (odds ratio, 2.82; 95% CI, 1.48 to 5.38). The odds of gastric cancer also rose approximately twofold with each 10-year increase in age — and by 2.5-fold when individuals had an affected first-degree relative. Having a second-degree relative with gastric cancer was not an independent correlate. Compared with mutations in MSH6, PMS2, and EPCAM, gastric cancer was significantly more likely among individuals with mutations of MLH1 (OR, 6.53; 95% CI, 1.5 to 28.42) or MSH2 (OR = 5.23; 95% CI, 1.21 to 22.71).

Clinicians might use these factors to risk-stratify patients with Lynch syndrome to identify those who might benefit from enhanced surveillance with more frequent esophagogastroduodenoscopy, the researchers wrote. They noted that male sex, age, and first-degree family history increase the risk for sporadic gastric cancer unassociated with Lynch syndrome–associated mutations. Thus, these “traditional risk factors” might compound the inherited risk for gastric cancer observed in Lynch syndrome carriers.

The National Institutes of Health and the Pussycat Foundation Helen Gurley Brown Presidential Initiative provided funding. One coinvestigator disclosed a consulting relationship with Myriad Genetic Laboratories and having rights to an inventor portion of licensing revenues from PREMM5, a prediction model for Lynch syndrome mutations. The other researchers reported having no conflicts of interest.

SOURCE: Kim J et al. Clin Gastroenterol Hepatol. 2019 Jul 15. doi: 1016/j.cgh.2019.07.012.

Individuals with Lynch syndrome were significantly more likely to have a personal history of gastric cancer if they were older, male, had an affected first-degree relative, or had pathogenic variants in the MLH1 or MSH2 mismatch repair genes, researchers reported.

“These findings suggest that personalized, risk-stratified approaches to gastric cancer surveillance may be appropriate for individuals with Lynch syndrome–associated mutations,” wrote Jaihwan Kim of Seoul National University Bundang Hospital, Seongnam, South Korea, and associates. Their report is in Clinical Gastroenterology and Hepatology.

Lynch syndrome, which involves autosomal dominant germline mutations in DNA mismatch repair (MMR) genes (MLH1, MSH2, MSH6, and PMS2) and EPCAM, significantly increases the risk for several types of cancer. Although Lynch syndrome increases gastric cancer risk almost tenfold, more than 90% of individuals with Lynch syndrome do not develop it, the researchers noted. Given the lethality of this cancer, they sought to better characterize risk factors.

To do so, they studied cancer histories and clinical and demographic data from 51,086 individuals who were tested for gene variants associated with Lynch syndrome at a commercial laboratory between 2006 and 2013. More than 3,800 individuals had pathogenic variants, including more than 1,300 with mutations of MLH1, more than 1,600 with mutations of MSH2, 670 with mutations of MSH6, 145 with mutations in PMS2, and 28 with mutations in EPCAM. In all, 41 (1%) individuals with pathogenic mutations had a personal history of gastric cancer, while 350 (9%) had an affected first or second-degree relative.

After the researchers controlled for potential confounders, males with Lynch syndrome–associated mutations had nearly triple the odds of a personal history of gastric cancer compared with females (odds ratio, 2.82; 95% CI, 1.48 to 5.38). The odds of gastric cancer also rose approximately twofold with each 10-year increase in age — and by 2.5-fold when individuals had an affected first-degree relative. Having a second-degree relative with gastric cancer was not an independent correlate. Compared with mutations in MSH6, PMS2, and EPCAM, gastric cancer was significantly more likely among individuals with mutations of MLH1 (OR, 6.53; 95% CI, 1.5 to 28.42) or MSH2 (OR = 5.23; 95% CI, 1.21 to 22.71).

Clinicians might use these factors to risk-stratify patients with Lynch syndrome to identify those who might benefit from enhanced surveillance with more frequent esophagogastroduodenoscopy, the researchers wrote. They noted that male sex, age, and first-degree family history increase the risk for sporadic gastric cancer unassociated with Lynch syndrome–associated mutations. Thus, these “traditional risk factors” might compound the inherited risk for gastric cancer observed in Lynch syndrome carriers.

The National Institutes of Health and the Pussycat Foundation Helen Gurley Brown Presidential Initiative provided funding. One coinvestigator disclosed a consulting relationship with Myriad Genetic Laboratories and having rights to an inventor portion of licensing revenues from PREMM5, a prediction model for Lynch syndrome mutations. The other researchers reported having no conflicts of interest.

SOURCE: Kim J et al. Clin Gastroenterol Hepatol. 2019 Jul 15. doi: 1016/j.cgh.2019.07.012.

It can be tough for doctors to find happiness in the office, but dermatologists are the best at it, according to Medscape’s 2020 Lifestyle, Happiness, and Burnout Report.

About 41% of dermatologists reported being very happy at work, making their specialty the only one to break the 40% barrier. While dermatologists weren’t the happiest outside of work – that honor went to rheumatologists – dermatology was only 4 percentage points behind (60% vs. 56%).

Perhaps unsurprisingly, the percentage of dermatologists who were burned out was lower than that of physicians overall (36% vs. 41%). The biggest factors leading to burnout in dermatologists were an overabundance of bureaucratic tasks (58%), increased time devoted to EHRs (38%), and compliance with government regulations (35%).

Dermatologists dealt with burnout through a variety of ways, with the most common being exercise (44%), talk with family/friends (44%), and isolation from others (40%). In addition, dermatologists took slightly more vacation time than did physicians overall, with 51% of dermatologists taking 3-4 weeks of vacation, compared with 44% for physicians overall.

About 16% of dermatologists have contemplated suicide; however, none reported attempting suicide, and 72% of dermatologists have never felt suicidal. Most dermatologists also plan to deal with burnout or depression on their own, with only 31% reporting that they are currently seeking professional help, planning to seek help, or are not currently looking but have been treated in the past.

The Medscape survey was conducted from June 25 to Sept. 19, 2019, and involved 15,181 physicians.

[email protected]

It can be tough for doctors to find happiness in the office, but dermatologists are the best at it, according to Medscape’s 2020 Lifestyle, Happiness, and Burnout Report.

About 41% of dermatologists reported being very happy at work, making their specialty the only one to break the 40% barrier. While dermatologists weren’t the happiest outside of work – that honor went to rheumatologists – dermatology was only 4 percentage points behind (60% vs. 56%).

Perhaps unsurprisingly, the percentage of dermatologists who were burned out was lower than that of physicians overall (36% vs. 41%). The biggest factors leading to burnout in dermatologists were an overabundance of bureaucratic tasks (58%), increased time devoted to EHRs (38%), and compliance with government regulations (35%).

Dermatologists dealt with burnout through a variety of ways, with the most common being exercise (44%), talk with family/friends (44%), and isolation from others (40%). In addition, dermatologists took slightly more vacation time than did physicians overall, with 51% of dermatologists taking 3-4 weeks of vacation, compared with 44% for physicians overall.

About 16% of dermatologists have contemplated suicide; however, none reported attempting suicide, and 72% of dermatologists have never felt suicidal. Most dermatologists also plan to deal with burnout or depression on their own, with only 31% reporting that they are currently seeking professional help, planning to seek help, or are not currently looking but have been treated in the past.

The Medscape survey was conducted from June 25 to Sept. 19, 2019, and involved 15,181 physicians.

[email protected]

It can be tough for doctors to find happiness in the office, but dermatologists are the best at it, according to Medscape’s 2020 Lifestyle, Happiness, and Burnout Report.

About 41% of dermatologists reported being very happy at work, making their specialty the only one to break the 40% barrier. While dermatologists weren’t the happiest outside of work – that honor went to rheumatologists – dermatology was only 4 percentage points behind (60% vs. 56%).

Perhaps unsurprisingly, the percentage of dermatologists who were burned out was lower than that of physicians overall (36% vs. 41%). The biggest factors leading to burnout in dermatologists were an overabundance of bureaucratic tasks (58%), increased time devoted to EHRs (38%), and compliance with government regulations (35%).

Dermatologists dealt with burnout through a variety of ways, with the most common being exercise (44%), talk with family/friends (44%), and isolation from others (40%). In addition, dermatologists took slightly more vacation time than did physicians overall, with 51% of dermatologists taking 3-4 weeks of vacation, compared with 44% for physicians overall.

About 16% of dermatologists have contemplated suicide; however, none reported attempting suicide, and 72% of dermatologists have never felt suicidal. Most dermatologists also plan to deal with burnout or depression on their own, with only 31% reporting that they are currently seeking professional help, planning to seek help, or are not currently looking but have been treated in the past.

The Medscape survey was conducted from June 25 to Sept. 19, 2019, and involved 15,181 physicians.

[email protected]

LONDON – Despite a number of recent trials testing various topical therapies for epidermolysis bullosa, none so far has been able to provide the data needed to gain regulatory approval.

Results from trials such as ESSENCE, with allantoin, and DELIVERS, with diacerein, were “disappointing,” Dédée Murrell, BMBCh, MD, pointed out at the EB World Congress, organized by the Dystrophic Epidermolysis Bullosa Association (DEBRA).

Those two topical agents were most likely let down by the trials’ design, said Dr. Murrell, of St. George Hospital, University of New South Wales, Sydney, but she noted that there were still some promising trials that were either ongoing, such as EASE, with Oleogel-S10, or that were about to be unblinded, such as SISTERS, with sirolimus.

Epidermolysis bullosa (EB) is a group of rare genetic diseases that can cause the skin to blister and peel away to varying degrees, causing itchy and painful skin, as well as recurrent wounds, some of which may seem never to heal and that increase the risk for squamous cell carcinoma. Although finding a cure for the disease is high on the research agenda, finding a reliable therapy that can soothe and protect the skin is of equal importance.
 

Trials and tribulations

Conducting trials in rare diseases can be difficult because the studies are often small and poorly controlled, Dr. Murrell said during an oral presentation at the meeting. To gain regulatory approval, trials need to have an active and a placebo arm, because “even though we’re dealing with a rare disease, we still have to show statistical significance between the two arms.”

However, it is not just about finding enough participants who meet the inclusion criteria and adequately controlling the study, as finding funding can also be a significant hurdle. That is the case particularly when an existing drug with no patent protection is proposed to be repurposed. As an example, Dr. Murrell said that many patients with EB may use gentian violet to treat their condition, but it has been around for so long and is so widely used, that funding a trial to formally prove its merit is unlikely. ­In addition, “there are special caveats that occur in dermatology clinical trials with topical drugs that don’t exist [in trials] with systemic treatments, one of which is that it is very important to keep other variables the same,” Dr. Murrell said. “So, for example, the dressings need to stay the same throughout a trial with a topical therapy, because if you improve the dressings [during the course of the trial], you could mask the effect of the treatment.” Similarly, the bathing and cleansing routines of the participants need to remain the same throughout the trial.

“We also need to have validated instruments to prove whether these treatments are working, and the instruments need to be objective as well as subjective,” Dr. Murrell advised. For example, inflammation and blistering need to be scored separately from scarring and skin damage. “You have to conduct a clinical trial to be able to verify that there is diminished scarring or damage, because those are the longer-term complications.” Inflammation and blistering are valid endpoints to use in shorter-term studies.

Dr. Murrell also cautioned on getting too enthused about the results of case reports. “We do get excited when we see a patient using something new and they seem to be getting much better,” but such reports do not have a placebo arm, or, if there is one, then there is no vehicle control, she said. It’s important to include a run-in period in a trial to establish a new baseline and to ensure that any effects seen with a topical agent are independent of the carrier substance or any altered bathing behavior or dressing habits, which could skew the results.
 

ESSENCE and allantoin

So what went wrong in the phase 3 ESSENCE trial with allantoin, which was halted early in September 2017? The trial had included 169 patients with any type of EB – simplex, recessive dystrophic, and junctional non-Herlitz – who were randomized to treatment with the allantoin-containing cream SD-101 or a placebo cream containing only the vehicle. The creams were applied daily to the entire body for 3 months, with the primary endpoint being total wound closure at the end of the treatment period. Total wound closure was a requirement of the Food and Drug Administration, Dr. Murrell said, but it is now known that 100% closure is not always likely, which the agency itself now concedes.

“Most disappointingly, no significant difference was found [between the study drug and placebo], therefore it didn’t meet the primary endpoint, and you’re not even allowed to consider secondary endpoints – those are the rules of the game,” she said. As a result, the trial was stopped in 2017.

For inclusion in the study, patients had to have at least one target wound that had been present for at least 3 weeks, but there was no stratification on the duration of wounds in the randomization process. That meant that some individuals with wounds of shorter duration had unintentionally ended up in the placebo arm – favoring healing – and those with more chronic wounds had been in the allantoin arm. So, because the study arms might not have been equally balanced at baseline, it would have been harder for the actual treatment to demonstrate a benefit, Dr. Murrell suggested.

Another problem with the trial was that the vehicle cream contained elements, such as lanolin, already associated with wound healing. That would have given patients in the placebo arm an advantage because anyone applying the cream every day would probably get better or improve to some degree.

The patients were also required to have daily dressing changes and baths and, “if you give any patient that advice and they comply with it for a period of time, they are going to improve,” whether or not they are applying the study drug. Dr. Murrell said that the researchers likely should have done a run-in period first and then established a new baseline to randomize the patients.

“Lastly, no one had ever done a study of what we essentially tell eczema patients to do every day … to moisturize, because that will provide extra protection and barrier to their skin. So, if anything, the ESSENCE study shows that moisturizing has a protective effect of the vehicle for patients with EB,” she said.
 

DELIVERS and diacerein

Another trial that was stopped prematurely was the phase 2 DELIVERS study, which was set up to assess the benefits of topical diacerein in people with EB simplex. Diacerein, an extract of rhubarb root, was tested in 54 patients, who were randomized to apply either diacerein or vehicle ointment for 8 weeks.

Initially, the results “looked very promising,” Dr. Murrell said, because there was a trend toward improved EB simplex lesions, with the primary endpoint of at least a 60% reduction in lesions met by 57.1% of diacerein-treated and 53.8% of vehicle-treated patients.

However, the trial included use of the Investigator’s Global Assessment Scale at the FDA’s behest, but the tool had not been validated in previous EB trials, and which didn’t seem to show any benefit of the active over the placebo ointment. (The Investigator’s Global Assessment is a 5-point scale used for overall clinical assessment of severity of disease, ranging from 0 to 4, where a higher score denotes worse outcome.)In a poster presented separately at the meeting, the DELIVERS researchers noted that “the lack of statistical significance in the primary endpoint could be explained in part by milder disease in the diacerein group.” The mean body surface area of EB simplex lesions within the assessment area at baseline was 5.76% in the diacerein group and 7.13% in the vehicle group. The researchers proposed that perhaps a higher concentration of diacerein than the 1% used in the trial might have been needed.


 

Sirolimus and EB simplex

Dr. Murrell noted that a pilot study, known as the SISTERS trial, had been conducted with a 2% sirolimus topical ointment at her institution and at Stanford (Calif.) University. This prospective, double-blind study had involved 16 patients with EB simplex, in which blisters tend to be confined to the palms of the hands and soles of the feet. The patients were assigned to treat both feet with either topical sirolimus or a placebo cream for 12 weeks. After a 4-week wash-out period, the patients switched to using the opposite cream for an additional 12 weeks.

Sirolimus is an inhibitor of the mTOR pathway, and, according to a description of the study on ClinicalTrials.gov, the researchers’ aim was to inhibit “the mTOR pathway to down-regulate the translation of defective keratin proteins.” That would allow a transition from supportive care, which is the current practice for EB simplex, to using a targeted molecular therapy to improve patient mobility and quality of life, they note on the site.

“We look forward to having that study unblinded,” Dr. Murrell said, adding that “data should be ready in a few months.”
 

EASE and Oleogel-S10

Oleogel-S10 is a gel that contains a birch bark extract dissolved in sunflower oil. It is already approved in Europe (Episalvan) for the treatment of partial-thickness skin wounds, but its use in EB remains investigational.

In a poster presentation at the meeting, Stella Gewert, MD, of the University of Freiburg (Germany) and colleagues discussed their experience using Oleogel-S10 in the treatment of four patients – each with a different type of EB – who applied the gel for between 6 days and 3 months.

Promising effects were seen, including reduced pruritus and pain, wounds healing more quickly, and reductions in lesion size. “During treatment, dressing requirements were reduced, and patient quality of life improved,” the researchers observed.

Mark Sumeray, MD, the chief medical officer of Amryt Pharmaceuticals, which is developing Oleogel-S10, said it was important to emphasize that Oleogel-S10 is a gel and not a cream. Gels are mixed with oil and are easier to apply – an important consideration for those with EB, he explained, whereas creams tend to be mixed with water and are stickier.

The phase 3 EASE trial is looking at the efficacy and safety of the gel in patients with junctional and dystrophic EB, and recruitment is ongoing, Dr. Murrell said. The primary endpoint is the proportion of patients with the first complete closure of a target wound within 45 days of treatment initiation. The estimated primary completion date for the trial is June 2020, and it is projected to end by 2022.

Scioderm, in collaboration with Amicus, funded the ESSENCE trial; Castle Creek financed the DELIVERS study; Amryt is supporting the EASE study; and Stanford University is sponsor of the SISTERS study. Dr. Murrell has been the principal investigator for trials run by Amicus, Amryt, Castle Creek, and Shire, and she acknowledged receipt of honoraria or consultation fees from those companies and others. Dr. Gewert did not report any financial disclosures. Dr. Sumeray is an employee and shareholder of Amryt.

LONDON – Despite a number of recent trials testing various topical therapies for epidermolysis bullosa, none so far has been able to provide the data needed to gain regulatory approval.

Results from trials such as ESSENCE, with allantoin, and DELIVERS, with diacerein, were “disappointing,” Dédée Murrell, BMBCh, MD, pointed out at the EB World Congress, organized by the Dystrophic Epidermolysis Bullosa Association (DEBRA).

Those two topical agents were most likely let down by the trials’ design, said Dr. Murrell, of St. George Hospital, University of New South Wales, Sydney, but she noted that there were still some promising trials that were either ongoing, such as EASE, with Oleogel-S10, or that were about to be unblinded, such as SISTERS, with sirolimus.

Epidermolysis bullosa (EB) is a group of rare genetic diseases that can cause the skin to blister and peel away to varying degrees, causing itchy and painful skin, as well as recurrent wounds, some of which may seem never to heal and that increase the risk for squamous cell carcinoma. Although finding a cure for the disease is high on the research agenda, finding a reliable therapy that can soothe and protect the skin is of equal importance.
 

Trials and tribulations

Conducting trials in rare diseases can be difficult because the studies are often small and poorly controlled, Dr. Murrell said during an oral presentation at the meeting. To gain regulatory approval, trials need to have an active and a placebo arm, because “even though we’re dealing with a rare disease, we still have to show statistical significance between the two arms.”

However, it is not just about finding enough participants who meet the inclusion criteria and adequately controlling the study, as finding funding can also be a significant hurdle. That is the case particularly when an existing drug with no patent protection is proposed to be repurposed. As an example, Dr. Murrell said that many patients with EB may use gentian violet to treat their condition, but it has been around for so long and is so widely used, that funding a trial to formally prove its merit is unlikely. ­In addition, “there are special caveats that occur in dermatology clinical trials with topical drugs that don’t exist [in trials] with systemic treatments, one of which is that it is very important to keep other variables the same,” Dr. Murrell said. “So, for example, the dressings need to stay the same throughout a trial with a topical therapy, because if you improve the dressings [during the course of the trial], you could mask the effect of the treatment.” Similarly, the bathing and cleansing routines of the participants need to remain the same throughout the trial.

“We also need to have validated instruments to prove whether these treatments are working, and the instruments need to be objective as well as subjective,” Dr. Murrell advised. For example, inflammation and blistering need to be scored separately from scarring and skin damage. “You have to conduct a clinical trial to be able to verify that there is diminished scarring or damage, because those are the longer-term complications.” Inflammation and blistering are valid endpoints to use in shorter-term studies.

Dr. Murrell also cautioned on getting too enthused about the results of case reports. “We do get excited when we see a patient using something new and they seem to be getting much better,” but such reports do not have a placebo arm, or, if there is one, then there is no vehicle control, she said. It’s important to include a run-in period in a trial to establish a new baseline and to ensure that any effects seen with a topical agent are independent of the carrier substance or any altered bathing behavior or dressing habits, which could skew the results.
 

ESSENCE and allantoin

So what went wrong in the phase 3 ESSENCE trial with allantoin, which was halted early in September 2017? The trial had included 169 patients with any type of EB – simplex, recessive dystrophic, and junctional non-Herlitz – who were randomized to treatment with the allantoin-containing cream SD-101 or a placebo cream containing only the vehicle. The creams were applied daily to the entire body for 3 months, with the primary endpoint being total wound closure at the end of the treatment period. Total wound closure was a requirement of the Food and Drug Administration, Dr. Murrell said, but it is now known that 100% closure is not always likely, which the agency itself now concedes.

“Most disappointingly, no significant difference was found [between the study drug and placebo], therefore it didn’t meet the primary endpoint, and you’re not even allowed to consider secondary endpoints – those are the rules of the game,” she said. As a result, the trial was stopped in 2017.

For inclusion in the study, patients had to have at least one target wound that had been present for at least 3 weeks, but there was no stratification on the duration of wounds in the randomization process. That meant that some individuals with wounds of shorter duration had unintentionally ended up in the placebo arm – favoring healing – and those with more chronic wounds had been in the allantoin arm. So, because the study arms might not have been equally balanced at baseline, it would have been harder for the actual treatment to demonstrate a benefit, Dr. Murrell suggested.

Another problem with the trial was that the vehicle cream contained elements, such as lanolin, already associated with wound healing. That would have given patients in the placebo arm an advantage because anyone applying the cream every day would probably get better or improve to some degree.

The patients were also required to have daily dressing changes and baths and, “if you give any patient that advice and they comply with it for a period of time, they are going to improve,” whether or not they are applying the study drug. Dr. Murrell said that the researchers likely should have done a run-in period first and then established a new baseline to randomize the patients.

“Lastly, no one had ever done a study of what we essentially tell eczema patients to do every day … to moisturize, because that will provide extra protection and barrier to their skin. So, if anything, the ESSENCE study shows that moisturizing has a protective effect of the vehicle for patients with EB,” she said.
 

DELIVERS and diacerein

Another trial that was stopped prematurely was the phase 2 DELIVERS study, which was set up to assess the benefits of topical diacerein in people with EB simplex. Diacerein, an extract of rhubarb root, was tested in 54 patients, who were randomized to apply either diacerein or vehicle ointment for 8 weeks.

Initially, the results “looked very promising,” Dr. Murrell said, because there was a trend toward improved EB simplex lesions, with the primary endpoint of at least a 60% reduction in lesions met by 57.1% of diacerein-treated and 53.8% of vehicle-treated patients.

However, the trial included use of the Investigator’s Global Assessment Scale at the FDA’s behest, but the tool had not been validated in previous EB trials, and which didn’t seem to show any benefit of the active over the placebo ointment. (The Investigator’s Global Assessment is a 5-point scale used for overall clinical assessment of severity of disease, ranging from 0 to 4, where a higher score denotes worse outcome.)In a poster presented separately at the meeting, the DELIVERS researchers noted that “the lack of statistical significance in the primary endpoint could be explained in part by milder disease in the diacerein group.” The mean body surface area of EB simplex lesions within the assessment area at baseline was 5.76% in the diacerein group and 7.13% in the vehicle group. The researchers proposed that perhaps a higher concentration of diacerein than the 1% used in the trial might have been needed.


 

Sirolimus and EB simplex

Dr. Murrell noted that a pilot study, known as the SISTERS trial, had been conducted with a 2% sirolimus topical ointment at her institution and at Stanford (Calif.) University. This prospective, double-blind study had involved 16 patients with EB simplex, in which blisters tend to be confined to the palms of the hands and soles of the feet. The patients were assigned to treat both feet with either topical sirolimus or a placebo cream for 12 weeks. After a 4-week wash-out period, the patients switched to using the opposite cream for an additional 12 weeks.

Sirolimus is an inhibitor of the mTOR pathway, and, according to a description of the study on ClinicalTrials.gov, the researchers’ aim was to inhibit “the mTOR pathway to down-regulate the translation of defective keratin proteins.” That would allow a transition from supportive care, which is the current practice for EB simplex, to using a targeted molecular therapy to improve patient mobility and quality of life, they note on the site.

“We look forward to having that study unblinded,” Dr. Murrell said, adding that “data should be ready in a few months.”
 

EASE and Oleogel-S10

Oleogel-S10 is a gel that contains a birch bark extract dissolved in sunflower oil. It is already approved in Europe (Episalvan) for the treatment of partial-thickness skin wounds, but its use in EB remains investigational.

In a poster presentation at the meeting, Stella Gewert, MD, of the University of Freiburg (Germany) and colleagues discussed their experience using Oleogel-S10 in the treatment of four patients – each with a different type of EB – who applied the gel for between 6 days and 3 months.

Promising effects were seen, including reduced pruritus and pain, wounds healing more quickly, and reductions in lesion size. “During treatment, dressing requirements were reduced, and patient quality of life improved,” the researchers observed.

Mark Sumeray, MD, the chief medical officer of Amryt Pharmaceuticals, which is developing Oleogel-S10, said it was important to emphasize that Oleogel-S10 is a gel and not a cream. Gels are mixed with oil and are easier to apply – an important consideration for those with EB, he explained, whereas creams tend to be mixed with water and are stickier.

The phase 3 EASE trial is looking at the efficacy and safety of the gel in patients with junctional and dystrophic EB, and recruitment is ongoing, Dr. Murrell said. The primary endpoint is the proportion of patients with the first complete closure of a target wound within 45 days of treatment initiation. The estimated primary completion date for the trial is June 2020, and it is projected to end by 2022.

Scioderm, in collaboration with Amicus, funded the ESSENCE trial; Castle Creek financed the DELIVERS study; Amryt is supporting the EASE study; and Stanford University is sponsor of the SISTERS study. Dr. Murrell has been the principal investigator for trials run by Amicus, Amryt, Castle Creek, and Shire, and she acknowledged receipt of honoraria or consultation fees from those companies and others. Dr. Gewert did not report any financial disclosures. Dr. Sumeray is an employee and shareholder of Amryt.

LONDON – Despite a number of recent trials testing various topical therapies for epidermolysis bullosa, none so far has been able to provide the data needed to gain regulatory approval.

Results from trials such as ESSENCE, with allantoin, and DELIVERS, with diacerein, were “disappointing,” Dédée Murrell, BMBCh, MD, pointed out at the EB World Congress, organized by the Dystrophic Epidermolysis Bullosa Association (DEBRA).

Those two topical agents were most likely let down by the trials’ design, said Dr. Murrell, of St. George Hospital, University of New South Wales, Sydney, but she noted that there were still some promising trials that were either ongoing, such as EASE, with Oleogel-S10, or that were about to be unblinded, such as SISTERS, with sirolimus.

Epidermolysis bullosa (EB) is a group of rare genetic diseases that can cause the skin to blister and peel away to varying degrees, causing itchy and painful skin, as well as recurrent wounds, some of which may seem never to heal and that increase the risk for squamous cell carcinoma. Although finding a cure for the disease is high on the research agenda, finding a reliable therapy that can soothe and protect the skin is of equal importance.
 

Trials and tribulations

Conducting trials in rare diseases can be difficult because the studies are often small and poorly controlled, Dr. Murrell said during an oral presentation at the meeting. To gain regulatory approval, trials need to have an active and a placebo arm, because “even though we’re dealing with a rare disease, we still have to show statistical significance between the two arms.”

However, it is not just about finding enough participants who meet the inclusion criteria and adequately controlling the study, as finding funding can also be a significant hurdle. That is the case particularly when an existing drug with no patent protection is proposed to be repurposed. As an example, Dr. Murrell said that many patients with EB may use gentian violet to treat their condition, but it has been around for so long and is so widely used, that funding a trial to formally prove its merit is unlikely. ­In addition, “there are special caveats that occur in dermatology clinical trials with topical drugs that don’t exist [in trials] with systemic treatments, one of which is that it is very important to keep other variables the same,” Dr. Murrell said. “So, for example, the dressings need to stay the same throughout a trial with a topical therapy, because if you improve the dressings [during the course of the trial], you could mask the effect of the treatment.” Similarly, the bathing and cleansing routines of the participants need to remain the same throughout the trial.

“We also need to have validated instruments to prove whether these treatments are working, and the instruments need to be objective as well as subjective,” Dr. Murrell advised. For example, inflammation and blistering need to be scored separately from scarring and skin damage. “You have to conduct a clinical trial to be able to verify that there is diminished scarring or damage, because those are the longer-term complications.” Inflammation and blistering are valid endpoints to use in shorter-term studies.

Dr. Murrell also cautioned on getting too enthused about the results of case reports. “We do get excited when we see a patient using something new and they seem to be getting much better,” but such reports do not have a placebo arm, or, if there is one, then there is no vehicle control, she said. It’s important to include a run-in period in a trial to establish a new baseline and to ensure that any effects seen with a topical agent are independent of the carrier substance or any altered bathing behavior or dressing habits, which could skew the results.
 

ESSENCE and allantoin

So what went wrong in the phase 3 ESSENCE trial with allantoin, which was halted early in September 2017? The trial had included 169 patients with any type of EB – simplex, recessive dystrophic, and junctional non-Herlitz – who were randomized to treatment with the allantoin-containing cream SD-101 or a placebo cream containing only the vehicle. The creams were applied daily to the entire body for 3 months, with the primary endpoint being total wound closure at the end of the treatment period. Total wound closure was a requirement of the Food and Drug Administration, Dr. Murrell said, but it is now known that 100% closure is not always likely, which the agency itself now concedes.

“Most disappointingly, no significant difference was found [between the study drug and placebo], therefore it didn’t meet the primary endpoint, and you’re not even allowed to consider secondary endpoints – those are the rules of the game,” she said. As a result, the trial was stopped in 2017.

For inclusion in the study, patients had to have at least one target wound that had been present for at least 3 weeks, but there was no stratification on the duration of wounds in the randomization process. That meant that some individuals with wounds of shorter duration had unintentionally ended up in the placebo arm – favoring healing – and those with more chronic wounds had been in the allantoin arm. So, because the study arms might not have been equally balanced at baseline, it would have been harder for the actual treatment to demonstrate a benefit, Dr. Murrell suggested.

Another problem with the trial was that the vehicle cream contained elements, such as lanolin, already associated with wound healing. That would have given patients in the placebo arm an advantage because anyone applying the cream every day would probably get better or improve to some degree.

The patients were also required to have daily dressing changes and baths and, “if you give any patient that advice and they comply with it for a period of time, they are going to improve,” whether or not they are applying the study drug. Dr. Murrell said that the researchers likely should have done a run-in period first and then established a new baseline to randomize the patients.

“Lastly, no one had ever done a study of what we essentially tell eczema patients to do every day … to moisturize, because that will provide extra protection and barrier to their skin. So, if anything, the ESSENCE study shows that moisturizing has a protective effect of the vehicle for patients with EB,” she said.
 

DELIVERS and diacerein

Another trial that was stopped prematurely was the phase 2 DELIVERS study, which was set up to assess the benefits of topical diacerein in people with EB simplex. Diacerein, an extract of rhubarb root, was tested in 54 patients, who were randomized to apply either diacerein or vehicle ointment for 8 weeks.

Initially, the results “looked very promising,” Dr. Murrell said, because there was a trend toward improved EB simplex lesions, with the primary endpoint of at least a 60% reduction in lesions met by 57.1% of diacerein-treated and 53.8% of vehicle-treated patients.

However, the trial included use of the Investigator’s Global Assessment Scale at the FDA’s behest, but the tool had not been validated in previous EB trials, and which didn’t seem to show any benefit of the active over the placebo ointment. (The Investigator’s Global Assessment is a 5-point scale used for overall clinical assessment of severity of disease, ranging from 0 to 4, where a higher score denotes worse outcome.)In a poster presented separately at the meeting, the DELIVERS researchers noted that “the lack of statistical significance in the primary endpoint could be explained in part by milder disease in the diacerein group.” The mean body surface area of EB simplex lesions within the assessment area at baseline was 5.76% in the diacerein group and 7.13% in the vehicle group. The researchers proposed that perhaps a higher concentration of diacerein than the 1% used in the trial might have been needed.


 

Sirolimus and EB simplex

Dr. Murrell noted that a pilot study, known as the SISTERS trial, had been conducted with a 2% sirolimus topical ointment at her institution and at Stanford (Calif.) University. This prospective, double-blind study had involved 16 patients with EB simplex, in which blisters tend to be confined to the palms of the hands and soles of the feet. The patients were assigned to treat both feet with either topical sirolimus or a placebo cream for 12 weeks. After a 4-week wash-out period, the patients switched to using the opposite cream for an additional 12 weeks.

Sirolimus is an inhibitor of the mTOR pathway, and, according to a description of the study on ClinicalTrials.gov, the researchers’ aim was to inhibit “the mTOR pathway to down-regulate the translation of defective keratin proteins.” That would allow a transition from supportive care, which is the current practice for EB simplex, to using a targeted molecular therapy to improve patient mobility and quality of life, they note on the site.

“We look forward to having that study unblinded,” Dr. Murrell said, adding that “data should be ready in a few months.”
 

EASE and Oleogel-S10

Oleogel-S10 is a gel that contains a birch bark extract dissolved in sunflower oil. It is already approved in Europe (Episalvan) for the treatment of partial-thickness skin wounds, but its use in EB remains investigational.

In a poster presentation at the meeting, Stella Gewert, MD, of the University of Freiburg (Germany) and colleagues discussed their experience using Oleogel-S10 in the treatment of four patients – each with a different type of EB – who applied the gel for between 6 days and 3 months.

Promising effects were seen, including reduced pruritus and pain, wounds healing more quickly, and reductions in lesion size. “During treatment, dressing requirements were reduced, and patient quality of life improved,” the researchers observed.

Mark Sumeray, MD, the chief medical officer of Amryt Pharmaceuticals, which is developing Oleogel-S10, said it was important to emphasize that Oleogel-S10 is a gel and not a cream. Gels are mixed with oil and are easier to apply – an important consideration for those with EB, he explained, whereas creams tend to be mixed with water and are stickier.

The phase 3 EASE trial is looking at the efficacy and safety of the gel in patients with junctional and dystrophic EB, and recruitment is ongoing, Dr. Murrell said. The primary endpoint is the proportion of patients with the first complete closure of a target wound within 45 days of treatment initiation. The estimated primary completion date for the trial is June 2020, and it is projected to end by 2022.

Scioderm, in collaboration with Amicus, funded the ESSENCE trial; Castle Creek financed the DELIVERS study; Amryt is supporting the EASE study; and Stanford University is sponsor of the SISTERS study. Dr. Murrell has been the principal investigator for trials run by Amicus, Amryt, Castle Creek, and Shire, and she acknowledged receipt of honoraria or consultation fees from those companies and others. Dr. Gewert did not report any financial disclosures. Dr. Sumeray is an employee and shareholder of Amryt.