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The gut a new therapeutic target for major depression?
The gut microbiota differs significantly between patients with major depressive disorder (MDD) and healthy individuals and may be modifiable with a probiotic diet to improve stress and depression scores, two new studies suggest.
In one study, investigators compared stool samples between patients with MDD and healthy controls. They found significant differences in bacterial profiles between the two groups, as well as between patients who responded vs those who were resistant to treatment.
“This finding further supports the relevance of an altered composition of the gut microbiota in the etiopathogenesis of MDD and suggests a role in response to antidepressants,” coinvestigator Andrea Fontana, MSc, Fondazione IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy, said in an interview.
Results from the second study showed significant improvements in self-reported stress, anxiety, and depression scores in healthy individuals following a “psychobiotic” diet (using probiotics or prebiotics to manipulate the microbiota to improve mental health) that was rich in fruit, vegetables, and fermented foods vs. those who received dietary advice alone.
The investigators, led by Kirsten Berding, PhD, APC Microbiome Ireland, University College Cork, Ireland, now plan on testing their psychobiotic diet in patients with MDD and hope the findings could be helpful in “the development of adjuvant therapeutic opportunities” where pharmacologic treatment is not effective.
Both studies were presented at the virtual congress of the European College of Neuropsychopharmacology, held online this year because of the COVID-19 pandemic.
A “hallmark” of major depression
Mr. Fontana and colleagues note that the mostly suboptimal response to pharmacologic treatments among patients with MDD is one of the factors that “contributes to the large socioeconomic burden” of the disease.
Previous research shows patients with MDD have gut dysbiosis, or an imbalance in the natural flora; that antidepressants have antimicrobial properties; and that probiotics have an antibiotic effect. However, the correlation between the composition of the gut microbiota and antidepressant response is poorly understood.
The investigators recruited 34 patients with MDD (aged 18-70 years) who were in a euthymic phase and who did not have comorbid conditions that could affect the gut microbiota.
Eight patients were treatment resistant, defined as a poor response to at least two adequate trials of different antidepressant classes, while 19 were treatment responsive and seven were treatment naive.
The researchers also recruited 20 healthy individuals via word of mouth to act as the control group. There were no significant differences between patients and the control group in terms of baseline characteristics.
Genomic sequencing of bacteria obtained from stool samples showed that it was possible to distinguish between patients with MDD and the healthy individuals, especially at the family, genus, and species levels.
In particular, there were significant differences in the Paenibacillaceae and Flavobacteriaceaea families, for the genus Fenollaria, and the species Flintibacter butyricus, Christensenella timonensis, and Eisenbergiella massiliensis, among others.
Results also showed that the phyla Proteobacteria, Tenericutes, and the family Peptostreptococcaceae were more common in patients with treatment-resistant MDD, whereas the phylum Actinobacteria was more abundant in treatment responders.
Moreover, several bacteria were found only in the microbiota of patients with treatment-resistant MDD, while others were seen only in treatment-responsive patients. This made it possible to discriminate not only between treatment-resistant and -responsive patients but also between those two patient groups and healthy controls.
“The results of our study confirm that gut dysbiosis is a hallmark of MDD, and suggests that the gut microbiota of patients with treatment-resistant MDD significantly differs from responders to antidepressants,” Mr. Fontana said.
Psychobiotic diet
For the second study, Dr. Berding and colleagues note that “psychobiotics” has previously achieved “promising results.”
In addition, diet is both “one of the most influential modifying factors” for the gut microbiota and an easily accessible strategy, they wrote. However, there is also a paucity of studies in this area, they added.
The researchers randomly assigned healthy volunteers with relatively poor dietary habits to either a 4-week psychobiotic diet group (n = 21) or a control group (n = 19).
Individuals in the psychobiotic group were told to eat a diet rich in prebiotics, such as fruit and vegetables, fiber including whole grains and legumes, and fermented foods. The control group was educated on Irish healthy-eating guidelines.
Stool and saliva samples were collected and the participants completed several self-reported mental health questionnaires, as well as a 7-day food diary. They also took the socially evaluated cold-pressor test (SECPT) to measure acute stress responses.
Results showed that total daily energy intake decreased significantly in both the diet and control groups over the study period (P = .04 for both) but did not differ significantly between the groups.
In contrast, dietary fiber intake increased significantly in the diet group (P < .001) and was significantly higher than in the control group at the end of the intervention (P = .03).
Individuals in the diet group showed significant decreases in scores on the Perceived Stress Scale (P = .002) and the Beck Depression Inventory (P = .007) during the study, an effect that was not found in the control group.
Dietary intervention
There were no significant effects of diet on the acute stress response, but both groups showed improvements in self-concept, or perceived ability to cope, on the Primary Appraisal, Secondary Appraisal index (P = .03 for the diet group, P = .04 for the control group).
The results show that a dietary intervention targeted at the microbiota “can improve subjective feelings of stress and depression in a healthy population,” the investigators wrote.
However, elucidating the “contribution of the microbiota-gut-brain axis on the signaling response to dietary interventions” will require further studies on microbiota sequencing and biological measures of stress, they added.
This will “contribute to the understanding of the benefits of a psychobiotic diet on stress and anxiety,” wrote the researchers.
Dr. Berding said in an interview that while the consumption of dietary fiber changed the most in the diet group, “it would not be the only nutrient” that had an impact on the results, with fermented foods a likely candidate.
She said the next step is to test the dietary intervention in patients with MDD; however, “doing nutritional interventions in diseased populations is always difficult.”
Dr. Berding suggested that the best approach would be to study inpatients in a clinic, as “we would be able to provide every meal and only provide foods that are part of the dietary intervention.”
Although another option would be to conduct the study in outpatients, she noted that assessing inpatients “would give us the best control over compliance.”
“Brilliant ideas”
Commenting on the findings, Sergueï Fetissov, MD, PhD, professor of physiology at Rouen University, Mont-Saint-Aignan, France, said that although both studies bring attention to a possible role for the gut microbiota in MDD, neither “provide any experimental evidence of a causative nature.”
Dr. Fetissov, who was not involved in either study, noted that this topic has been the subject of clinical nutritional research for many years.
However, “we still need some strong evidence to prove that some bacteria can influence the regulation of mood and anxiety and stress,” he said.
In addition, researchers currently do not know what actually causes MDD. “How we can say the gut bacteria regulates something if we don’t know what really causes the altered mood?” said Dr. Fetissov.
He noted that over the last 50 years, there have been great advances in the development of drugs that alleviate depression and anxiety by regulating dopamine, serotonin, and other neurotransmitters. However, it is still unknown whether these reflect primary or secondary aspects of mood disorders.
Furthermore, it is not clear “how probiotics to bacteria can influence these neuronal pathways,” he said.
The research by Dr. Berding and colleagues is funded by a postdoctoral fellowship grant from the Irish Research Council. The study authors and Dr. Fetissov have disclosed no relevant financial relationships.
A version of this article originally appeared on Medscape.com.
The gut microbiota differs significantly between patients with major depressive disorder (MDD) and healthy individuals and may be modifiable with a probiotic diet to improve stress and depression scores, two new studies suggest.
In one study, investigators compared stool samples between patients with MDD and healthy controls. They found significant differences in bacterial profiles between the two groups, as well as between patients who responded vs those who were resistant to treatment.
“This finding further supports the relevance of an altered composition of the gut microbiota in the etiopathogenesis of MDD and suggests a role in response to antidepressants,” coinvestigator Andrea Fontana, MSc, Fondazione IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy, said in an interview.
Results from the second study showed significant improvements in self-reported stress, anxiety, and depression scores in healthy individuals following a “psychobiotic” diet (using probiotics or prebiotics to manipulate the microbiota to improve mental health) that was rich in fruit, vegetables, and fermented foods vs. those who received dietary advice alone.
The investigators, led by Kirsten Berding, PhD, APC Microbiome Ireland, University College Cork, Ireland, now plan on testing their psychobiotic diet in patients with MDD and hope the findings could be helpful in “the development of adjuvant therapeutic opportunities” where pharmacologic treatment is not effective.
Both studies were presented at the virtual congress of the European College of Neuropsychopharmacology, held online this year because of the COVID-19 pandemic.
A “hallmark” of major depression
Mr. Fontana and colleagues note that the mostly suboptimal response to pharmacologic treatments among patients with MDD is one of the factors that “contributes to the large socioeconomic burden” of the disease.
Previous research shows patients with MDD have gut dysbiosis, or an imbalance in the natural flora; that antidepressants have antimicrobial properties; and that probiotics have an antibiotic effect. However, the correlation between the composition of the gut microbiota and antidepressant response is poorly understood.
The investigators recruited 34 patients with MDD (aged 18-70 years) who were in a euthymic phase and who did not have comorbid conditions that could affect the gut microbiota.
Eight patients were treatment resistant, defined as a poor response to at least two adequate trials of different antidepressant classes, while 19 were treatment responsive and seven were treatment naive.
The researchers also recruited 20 healthy individuals via word of mouth to act as the control group. There were no significant differences between patients and the control group in terms of baseline characteristics.
Genomic sequencing of bacteria obtained from stool samples showed that it was possible to distinguish between patients with MDD and the healthy individuals, especially at the family, genus, and species levels.
In particular, there were significant differences in the Paenibacillaceae and Flavobacteriaceaea families, for the genus Fenollaria, and the species Flintibacter butyricus, Christensenella timonensis, and Eisenbergiella massiliensis, among others.
Results also showed that the phyla Proteobacteria, Tenericutes, and the family Peptostreptococcaceae were more common in patients with treatment-resistant MDD, whereas the phylum Actinobacteria was more abundant in treatment responders.
Moreover, several bacteria were found only in the microbiota of patients with treatment-resistant MDD, while others were seen only in treatment-responsive patients. This made it possible to discriminate not only between treatment-resistant and -responsive patients but also between those two patient groups and healthy controls.
“The results of our study confirm that gut dysbiosis is a hallmark of MDD, and suggests that the gut microbiota of patients with treatment-resistant MDD significantly differs from responders to antidepressants,” Mr. Fontana said.
Psychobiotic diet
For the second study, Dr. Berding and colleagues note that “psychobiotics” has previously achieved “promising results.”
In addition, diet is both “one of the most influential modifying factors” for the gut microbiota and an easily accessible strategy, they wrote. However, there is also a paucity of studies in this area, they added.
The researchers randomly assigned healthy volunteers with relatively poor dietary habits to either a 4-week psychobiotic diet group (n = 21) or a control group (n = 19).
Individuals in the psychobiotic group were told to eat a diet rich in prebiotics, such as fruit and vegetables, fiber including whole grains and legumes, and fermented foods. The control group was educated on Irish healthy-eating guidelines.
Stool and saliva samples were collected and the participants completed several self-reported mental health questionnaires, as well as a 7-day food diary. They also took the socially evaluated cold-pressor test (SECPT) to measure acute stress responses.
Results showed that total daily energy intake decreased significantly in both the diet and control groups over the study period (P = .04 for both) but did not differ significantly between the groups.
In contrast, dietary fiber intake increased significantly in the diet group (P < .001) and was significantly higher than in the control group at the end of the intervention (P = .03).
Individuals in the diet group showed significant decreases in scores on the Perceived Stress Scale (P = .002) and the Beck Depression Inventory (P = .007) during the study, an effect that was not found in the control group.
Dietary intervention
There were no significant effects of diet on the acute stress response, but both groups showed improvements in self-concept, or perceived ability to cope, on the Primary Appraisal, Secondary Appraisal index (P = .03 for the diet group, P = .04 for the control group).
The results show that a dietary intervention targeted at the microbiota “can improve subjective feelings of stress and depression in a healthy population,” the investigators wrote.
However, elucidating the “contribution of the microbiota-gut-brain axis on the signaling response to dietary interventions” will require further studies on microbiota sequencing and biological measures of stress, they added.
This will “contribute to the understanding of the benefits of a psychobiotic diet on stress and anxiety,” wrote the researchers.
Dr. Berding said in an interview that while the consumption of dietary fiber changed the most in the diet group, “it would not be the only nutrient” that had an impact on the results, with fermented foods a likely candidate.
She said the next step is to test the dietary intervention in patients with MDD; however, “doing nutritional interventions in diseased populations is always difficult.”
Dr. Berding suggested that the best approach would be to study inpatients in a clinic, as “we would be able to provide every meal and only provide foods that are part of the dietary intervention.”
Although another option would be to conduct the study in outpatients, she noted that assessing inpatients “would give us the best control over compliance.”
“Brilliant ideas”
Commenting on the findings, Sergueï Fetissov, MD, PhD, professor of physiology at Rouen University, Mont-Saint-Aignan, France, said that although both studies bring attention to a possible role for the gut microbiota in MDD, neither “provide any experimental evidence of a causative nature.”
Dr. Fetissov, who was not involved in either study, noted that this topic has been the subject of clinical nutritional research for many years.
However, “we still need some strong evidence to prove that some bacteria can influence the regulation of mood and anxiety and stress,” he said.
In addition, researchers currently do not know what actually causes MDD. “How we can say the gut bacteria regulates something if we don’t know what really causes the altered mood?” said Dr. Fetissov.
He noted that over the last 50 years, there have been great advances in the development of drugs that alleviate depression and anxiety by regulating dopamine, serotonin, and other neurotransmitters. However, it is still unknown whether these reflect primary or secondary aspects of mood disorders.
Furthermore, it is not clear “how probiotics to bacteria can influence these neuronal pathways,” he said.
The research by Dr. Berding and colleagues is funded by a postdoctoral fellowship grant from the Irish Research Council. The study authors and Dr. Fetissov have disclosed no relevant financial relationships.
A version of this article originally appeared on Medscape.com.
The gut microbiota differs significantly between patients with major depressive disorder (MDD) and healthy individuals and may be modifiable with a probiotic diet to improve stress and depression scores, two new studies suggest.
In one study, investigators compared stool samples between patients with MDD and healthy controls. They found significant differences in bacterial profiles between the two groups, as well as between patients who responded vs those who were resistant to treatment.
“This finding further supports the relevance of an altered composition of the gut microbiota in the etiopathogenesis of MDD and suggests a role in response to antidepressants,” coinvestigator Andrea Fontana, MSc, Fondazione IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy, said in an interview.
Results from the second study showed significant improvements in self-reported stress, anxiety, and depression scores in healthy individuals following a “psychobiotic” diet (using probiotics or prebiotics to manipulate the microbiota to improve mental health) that was rich in fruit, vegetables, and fermented foods vs. those who received dietary advice alone.
The investigators, led by Kirsten Berding, PhD, APC Microbiome Ireland, University College Cork, Ireland, now plan on testing their psychobiotic diet in patients with MDD and hope the findings could be helpful in “the development of adjuvant therapeutic opportunities” where pharmacologic treatment is not effective.
Both studies were presented at the virtual congress of the European College of Neuropsychopharmacology, held online this year because of the COVID-19 pandemic.
A “hallmark” of major depression
Mr. Fontana and colleagues note that the mostly suboptimal response to pharmacologic treatments among patients with MDD is one of the factors that “contributes to the large socioeconomic burden” of the disease.
Previous research shows patients with MDD have gut dysbiosis, or an imbalance in the natural flora; that antidepressants have antimicrobial properties; and that probiotics have an antibiotic effect. However, the correlation between the composition of the gut microbiota and antidepressant response is poorly understood.
The investigators recruited 34 patients with MDD (aged 18-70 years) who were in a euthymic phase and who did not have comorbid conditions that could affect the gut microbiota.
Eight patients were treatment resistant, defined as a poor response to at least two adequate trials of different antidepressant classes, while 19 were treatment responsive and seven were treatment naive.
The researchers also recruited 20 healthy individuals via word of mouth to act as the control group. There were no significant differences between patients and the control group in terms of baseline characteristics.
Genomic sequencing of bacteria obtained from stool samples showed that it was possible to distinguish between patients with MDD and the healthy individuals, especially at the family, genus, and species levels.
In particular, there were significant differences in the Paenibacillaceae and Flavobacteriaceaea families, for the genus Fenollaria, and the species Flintibacter butyricus, Christensenella timonensis, and Eisenbergiella massiliensis, among others.
Results also showed that the phyla Proteobacteria, Tenericutes, and the family Peptostreptococcaceae were more common in patients with treatment-resistant MDD, whereas the phylum Actinobacteria was more abundant in treatment responders.
Moreover, several bacteria were found only in the microbiota of patients with treatment-resistant MDD, while others were seen only in treatment-responsive patients. This made it possible to discriminate not only between treatment-resistant and -responsive patients but also between those two patient groups and healthy controls.
“The results of our study confirm that gut dysbiosis is a hallmark of MDD, and suggests that the gut microbiota of patients with treatment-resistant MDD significantly differs from responders to antidepressants,” Mr. Fontana said.
Psychobiotic diet
For the second study, Dr. Berding and colleagues note that “psychobiotics” has previously achieved “promising results.”
In addition, diet is both “one of the most influential modifying factors” for the gut microbiota and an easily accessible strategy, they wrote. However, there is also a paucity of studies in this area, they added.
The researchers randomly assigned healthy volunteers with relatively poor dietary habits to either a 4-week psychobiotic diet group (n = 21) or a control group (n = 19).
Individuals in the psychobiotic group were told to eat a diet rich in prebiotics, such as fruit and vegetables, fiber including whole grains and legumes, and fermented foods. The control group was educated on Irish healthy-eating guidelines.
Stool and saliva samples were collected and the participants completed several self-reported mental health questionnaires, as well as a 7-day food diary. They also took the socially evaluated cold-pressor test (SECPT) to measure acute stress responses.
Results showed that total daily energy intake decreased significantly in both the diet and control groups over the study period (P = .04 for both) but did not differ significantly between the groups.
In contrast, dietary fiber intake increased significantly in the diet group (P < .001) and was significantly higher than in the control group at the end of the intervention (P = .03).
Individuals in the diet group showed significant decreases in scores on the Perceived Stress Scale (P = .002) and the Beck Depression Inventory (P = .007) during the study, an effect that was not found in the control group.
Dietary intervention
There were no significant effects of diet on the acute stress response, but both groups showed improvements in self-concept, or perceived ability to cope, on the Primary Appraisal, Secondary Appraisal index (P = .03 for the diet group, P = .04 for the control group).
The results show that a dietary intervention targeted at the microbiota “can improve subjective feelings of stress and depression in a healthy population,” the investigators wrote.
However, elucidating the “contribution of the microbiota-gut-brain axis on the signaling response to dietary interventions” will require further studies on microbiota sequencing and biological measures of stress, they added.
This will “contribute to the understanding of the benefits of a psychobiotic diet on stress and anxiety,” wrote the researchers.
Dr. Berding said in an interview that while the consumption of dietary fiber changed the most in the diet group, “it would not be the only nutrient” that had an impact on the results, with fermented foods a likely candidate.
She said the next step is to test the dietary intervention in patients with MDD; however, “doing nutritional interventions in diseased populations is always difficult.”
Dr. Berding suggested that the best approach would be to study inpatients in a clinic, as “we would be able to provide every meal and only provide foods that are part of the dietary intervention.”
Although another option would be to conduct the study in outpatients, she noted that assessing inpatients “would give us the best control over compliance.”
“Brilliant ideas”
Commenting on the findings, Sergueï Fetissov, MD, PhD, professor of physiology at Rouen University, Mont-Saint-Aignan, France, said that although both studies bring attention to a possible role for the gut microbiota in MDD, neither “provide any experimental evidence of a causative nature.”
Dr. Fetissov, who was not involved in either study, noted that this topic has been the subject of clinical nutritional research for many years.
However, “we still need some strong evidence to prove that some bacteria can influence the regulation of mood and anxiety and stress,” he said.
In addition, researchers currently do not know what actually causes MDD. “How we can say the gut bacteria regulates something if we don’t know what really causes the altered mood?” said Dr. Fetissov.
He noted that over the last 50 years, there have been great advances in the development of drugs that alleviate depression and anxiety by regulating dopamine, serotonin, and other neurotransmitters. However, it is still unknown whether these reflect primary or secondary aspects of mood disorders.
Furthermore, it is not clear “how probiotics to bacteria can influence these neuronal pathways,” he said.
The research by Dr. Berding and colleagues is funded by a postdoctoral fellowship grant from the Irish Research Council. The study authors and Dr. Fetissov have disclosed no relevant financial relationships.
A version of this article originally appeared on Medscape.com.
Dr. Fauci: ‘About 40%-45% of infections are asymptomatic’
Anthony Fauci, MD, highlighting the latest COVID-19 developments on Friday, said, “It is now clear that about 40%-45% of infections are asymptomatic.”
Asymptomatic carriers can account for a large proportion — up to 50% — of virus transmissions, Fauci, director of the National Institute of Allergy and Infectious Diseases, told a virtual crowd of critical care clinicians gathered by the Society of Critical Care Medicine.
Such transmissions have made response strategies, such as contact tracing, extremely difficult, he said.
Lew Kaplan, MD, president of SCCM, told Medscape Medical News after the presentation: “That really supports the universal wearing of masks and the capstone message from that – you should protect one another.
“That kind of social responsibility that sits within the public health domain to me is as important as the vaccine candidates and the science behind the receptors. It underpins the necessary relationship and the interdependence of the medical community with the public,” Kaplan added.
Fauci’s plenary led the SCCM’s conference, “COVID-19: What’s Next/Preparing for the Second Wave,” running today and Saturday.
Why U.S. response lags behind Spain and Italy
“This virus has literally exploded upon the planet in a pandemic manner which is unparalleled to anything we’ve seen in the last 102 years since the pandemic of 1918,” Fauci said.
“Unfortunately, the United States has been hit harder than any other country in the world, with 6 million reported cases.”
He explained that in the European Union countries the disease spiked early on and returned to a low baseline. “Unfortunately for them,” Fauci said, “as they’re trying to open up their economy, it’s coming back up.”
The United States, he explained, plateaued at about 20,000 cases a day, then a surge of cases in Florida, California, Texas, and Arizona brought the cases to 70,000 a day. Now cases have returned to 35,000-40,000 a day.
The difference in the trajectory of the response, he said, is that, compared with Spain and Italy for example, the United States has not shut down mobility in parks, outdoor spaces, and grocery stores nearly as much as some European countries did.
He pointed to numerous clusters of cases, spread from social or work gatherings, including the well-known Skagit County Washington state choir practice in March, in which a symptomatic choir member infected 87% of the 61 people rehearsing.
Vaccine by end of the year
As for a vaccine timeline, Fauci told SCCM members, “We project that by the end of this year, namely November/December, we will know if we have a safe and effective vaccine and we are cautiously optimistic that we will be successful, based on promising data in the animal model as well as good immunological data that we see from the phase 1 and phase 2 trials.”
However, also on Friday, Fauci told MSNBC’s Andrea Mitchell that a sense of normalcy is not likely before the middle of next year.
“By the time you mobilize the distribution of the vaccinations, and you get the majority, or more, of the population vaccinated and protected, that’s likely not going to happen [until] the mid- or end of 2021,” he said.
According to the Centers for Disease Control and Prevention (CDC) case tracker, as of Thursday, COVID-19 had resulted in more than 190,000 deaths overall and more than 256,000 new cases in the United States in the past 7 days.
Fauci has warned that the next few months will be critical in the virus’ trajectory, with the double onslaught of COVID-19 and the flu season.
On Thursday, Fauci said, “We need to hunker down and get through this fall and winter because it’s not going to be easy.”
Fauci remains a top trusted source in COVID-19 information, poll numbers show.
A Kaiser Family Foundation poll released Thursday found that 68% of US adults had a fair amount or a great deal of trust that Fauci would provide reliable information on COVID-19, just slightly more that the 67% who said they trust the CDC information. About half (53%) say they trust Deborah Birx, MD, the coordinator for the White House Coronavirus Task Force, as a reliable source of information.
The poll also found that 54% of Americans said they would not get a COVID-19 vaccine if one was approved by the US Food and Drug Administration before the November election and was made available and free to all who wanted it.
Kaplan and Fauci report no relevant financial relationships.
This article first appeared on Medscape.com.
Anthony Fauci, MD, highlighting the latest COVID-19 developments on Friday, said, “It is now clear that about 40%-45% of infections are asymptomatic.”
Asymptomatic carriers can account for a large proportion — up to 50% — of virus transmissions, Fauci, director of the National Institute of Allergy and Infectious Diseases, told a virtual crowd of critical care clinicians gathered by the Society of Critical Care Medicine.
Such transmissions have made response strategies, such as contact tracing, extremely difficult, he said.
Lew Kaplan, MD, president of SCCM, told Medscape Medical News after the presentation: “That really supports the universal wearing of masks and the capstone message from that – you should protect one another.
“That kind of social responsibility that sits within the public health domain to me is as important as the vaccine candidates and the science behind the receptors. It underpins the necessary relationship and the interdependence of the medical community with the public,” Kaplan added.
Fauci’s plenary led the SCCM’s conference, “COVID-19: What’s Next/Preparing for the Second Wave,” running today and Saturday.
Why U.S. response lags behind Spain and Italy
“This virus has literally exploded upon the planet in a pandemic manner which is unparalleled to anything we’ve seen in the last 102 years since the pandemic of 1918,” Fauci said.
“Unfortunately, the United States has been hit harder than any other country in the world, with 6 million reported cases.”
He explained that in the European Union countries the disease spiked early on and returned to a low baseline. “Unfortunately for them,” Fauci said, “as they’re trying to open up their economy, it’s coming back up.”
The United States, he explained, plateaued at about 20,000 cases a day, then a surge of cases in Florida, California, Texas, and Arizona brought the cases to 70,000 a day. Now cases have returned to 35,000-40,000 a day.
The difference in the trajectory of the response, he said, is that, compared with Spain and Italy for example, the United States has not shut down mobility in parks, outdoor spaces, and grocery stores nearly as much as some European countries did.
He pointed to numerous clusters of cases, spread from social or work gatherings, including the well-known Skagit County Washington state choir practice in March, in which a symptomatic choir member infected 87% of the 61 people rehearsing.
Vaccine by end of the year
As for a vaccine timeline, Fauci told SCCM members, “We project that by the end of this year, namely November/December, we will know if we have a safe and effective vaccine and we are cautiously optimistic that we will be successful, based on promising data in the animal model as well as good immunological data that we see from the phase 1 and phase 2 trials.”
However, also on Friday, Fauci told MSNBC’s Andrea Mitchell that a sense of normalcy is not likely before the middle of next year.
“By the time you mobilize the distribution of the vaccinations, and you get the majority, or more, of the population vaccinated and protected, that’s likely not going to happen [until] the mid- or end of 2021,” he said.
According to the Centers for Disease Control and Prevention (CDC) case tracker, as of Thursday, COVID-19 had resulted in more than 190,000 deaths overall and more than 256,000 new cases in the United States in the past 7 days.
Fauci has warned that the next few months will be critical in the virus’ trajectory, with the double onslaught of COVID-19 and the flu season.
On Thursday, Fauci said, “We need to hunker down and get through this fall and winter because it’s not going to be easy.”
Fauci remains a top trusted source in COVID-19 information, poll numbers show.
A Kaiser Family Foundation poll released Thursday found that 68% of US adults had a fair amount or a great deal of trust that Fauci would provide reliable information on COVID-19, just slightly more that the 67% who said they trust the CDC information. About half (53%) say they trust Deborah Birx, MD, the coordinator for the White House Coronavirus Task Force, as a reliable source of information.
The poll also found that 54% of Americans said they would not get a COVID-19 vaccine if one was approved by the US Food and Drug Administration before the November election and was made available and free to all who wanted it.
Kaplan and Fauci report no relevant financial relationships.
This article first appeared on Medscape.com.
Anthony Fauci, MD, highlighting the latest COVID-19 developments on Friday, said, “It is now clear that about 40%-45% of infections are asymptomatic.”
Asymptomatic carriers can account for a large proportion — up to 50% — of virus transmissions, Fauci, director of the National Institute of Allergy and Infectious Diseases, told a virtual crowd of critical care clinicians gathered by the Society of Critical Care Medicine.
Such transmissions have made response strategies, such as contact tracing, extremely difficult, he said.
Lew Kaplan, MD, president of SCCM, told Medscape Medical News after the presentation: “That really supports the universal wearing of masks and the capstone message from that – you should protect one another.
“That kind of social responsibility that sits within the public health domain to me is as important as the vaccine candidates and the science behind the receptors. It underpins the necessary relationship and the interdependence of the medical community with the public,” Kaplan added.
Fauci’s plenary led the SCCM’s conference, “COVID-19: What’s Next/Preparing for the Second Wave,” running today and Saturday.
Why U.S. response lags behind Spain and Italy
“This virus has literally exploded upon the planet in a pandemic manner which is unparalleled to anything we’ve seen in the last 102 years since the pandemic of 1918,” Fauci said.
“Unfortunately, the United States has been hit harder than any other country in the world, with 6 million reported cases.”
He explained that in the European Union countries the disease spiked early on and returned to a low baseline. “Unfortunately for them,” Fauci said, “as they’re trying to open up their economy, it’s coming back up.”
The United States, he explained, plateaued at about 20,000 cases a day, then a surge of cases in Florida, California, Texas, and Arizona brought the cases to 70,000 a day. Now cases have returned to 35,000-40,000 a day.
The difference in the trajectory of the response, he said, is that, compared with Spain and Italy for example, the United States has not shut down mobility in parks, outdoor spaces, and grocery stores nearly as much as some European countries did.
He pointed to numerous clusters of cases, spread from social or work gatherings, including the well-known Skagit County Washington state choir practice in March, in which a symptomatic choir member infected 87% of the 61 people rehearsing.
Vaccine by end of the year
As for a vaccine timeline, Fauci told SCCM members, “We project that by the end of this year, namely November/December, we will know if we have a safe and effective vaccine and we are cautiously optimistic that we will be successful, based on promising data in the animal model as well as good immunological data that we see from the phase 1 and phase 2 trials.”
However, also on Friday, Fauci told MSNBC’s Andrea Mitchell that a sense of normalcy is not likely before the middle of next year.
“By the time you mobilize the distribution of the vaccinations, and you get the majority, or more, of the population vaccinated and protected, that’s likely not going to happen [until] the mid- or end of 2021,” he said.
According to the Centers for Disease Control and Prevention (CDC) case tracker, as of Thursday, COVID-19 had resulted in more than 190,000 deaths overall and more than 256,000 new cases in the United States in the past 7 days.
Fauci has warned that the next few months will be critical in the virus’ trajectory, with the double onslaught of COVID-19 and the flu season.
On Thursday, Fauci said, “We need to hunker down and get through this fall and winter because it’s not going to be easy.”
Fauci remains a top trusted source in COVID-19 information, poll numbers show.
A Kaiser Family Foundation poll released Thursday found that 68% of US adults had a fair amount or a great deal of trust that Fauci would provide reliable information on COVID-19, just slightly more that the 67% who said they trust the CDC information. About half (53%) say they trust Deborah Birx, MD, the coordinator for the White House Coronavirus Task Force, as a reliable source of information.
The poll also found that 54% of Americans said they would not get a COVID-19 vaccine if one was approved by the US Food and Drug Administration before the November election and was made available and free to all who wanted it.
Kaplan and Fauci report no relevant financial relationships.
This article first appeared on Medscape.com.
Liberalized European sports cardiology guidelines break new ground
New guidelines on sports cardiology from the European Society of Cardiology break fresh ground by green-lighting participation in vigorous competitive sports by selected patients with stable coronary artery disease, heart failure, or mild arrhythmias.
These liberalized guidelines, released at the virtual annual congress of the European Society of Cardiology, thus move well beyond the standard exercise advice to engage in about 150 minutes per week of moderate physical activity, typically defined as brisk walking or its equivalent.
The guidelines reflect a conviction that exercise is powerful medicine for patients with cardiovascular disease and also affords a means to help curb the epidemics of diabetes and obesity that drive cardiovascular risk, according to Antonio Pelliccia, MD, who cochaired the 24-member task force of European and American experts that developed the guidelines.
In a session highlighting the new sports cardiology guidelines, Mats Borjesson, MD, head of the Center for Health and Performance at Gothenburg (Sweden) University, summarized the section devoted to patients with stable coronary artery disease: “If you have established CAD and a low risk of adverse events during exercise, you are eligible for high-intensity exercise and competitive sports. But if you have persistent ischemia despite medical treatment, or symptoms, then you’re only eligible for leisure-time subthreshold activity.”
Dr. Pelliccia put this new recommendation into context.
“We are not talking anymore in this particular disease just about cardiac rehabilitation or leisure-time activity, but we are also opening the border and talking about competitive sports activity in selected patients where you have the evidence for low risk of exercise-induced adverse events. This is a major achievement now for what is the major disease in our adult population,” said Dr. Pelliccia, chief of cardiology at the Institute of Sports Medicine and Science at the Italian National Olympic Committee and professor of sports cardiology at La Sapienza University of Rome.
The recommendation for individualized consideration of all types of exercise, even including vigorous competitive sports, in low-risk patients with CAD gets a class IIa, level of evidence (LOE) C recommendation in the new guidelines. That’s a big step down from a ringing class Ia endorsement, but since sports cardiology is a relatively young field with little evidence that’s based on randomized trials, the guidelines are rife with many other class IIa, LOE C recommendations as well.
“The level of evidence is rather low, so these guidelines are very much the personal perspective of the expert panel,” explained Martin Halle, MD, professor and head of the department of prevention, rehabilitation, and sports cardiology at Technical University of Munich.
The high-risk features for exercise-induced cardiac adverse events in patients with longstanding stable CAD, as cited in the guidelines, include a critical coronary stenosis, defined as a more than 70% lesion in a major coronary artery or a greater than 50% stenosis in the left main, and/or a fractional flow reserve score of less than 0.8; a left ventricular ejection fraction of 50% or less with wall-motion abnormalities; inducible myocardial ischemia on maximal exercise testing; nonsustained ventricular tachycardia; polymorphic or very frequent ventricular premature beats at rest and during maximum stress; and a recent acute coronary syndrome (ACS). These features call for an exercise prescription tailored to remain below the patient’s angina and ischemia thresholds.
“It’s important for cardiologists out there to understand that we definitely need a maximal exercise test. In somebody who is running and has an ACS and then wants to start running again, 200 watts on an ergometer is too low. We have to push them up to the end, and then if everything is okay – left ventricular function is okay, no ischemia, no arrhythmias under exercise testing – then it’s fine,” Dr. Halle said.
Dr. Pelliccia added that close follow-up is needed, because this is an evolving disease.”
Exercise and heart failure
Massimo F. Piepoli, MD, PhD, noted that the guidelines give a class IIb, LOE C recommendation for consideration of high-intensity recreational endurance and power sports in patients with heart failure with either midrange or preserved ejection fraction, provided they are stable, asymptomatic, on optimal guideline-directed medical therapy, and without abnormalities on a maximal exercise stress test.
However, such intense physical activity is not recommended in patients with heart failure with reduced ejection fraction, regardless of their symptom status, added Dr. Piepoli of Guglielmo da Saliceto Hospital in Placenza, Italy.
“We’re talking here, I think for the first time, about possible competitive sports participation in individuals with heart failure, depending on their clinical condition. We are really opening the barriers to sports participation, even in these patients in whom we never thought of it before,” Dr. Pelliccia observed.
Valvular heart disease and exercise
Guidelines panelist Sabiha Gati, MRCP, PhD, said asymptomatic individuals with mild valvular abnormalities can participate in all recreational and competitive sports; that’s a class I, LOE C recommendation.
“Moderate regurgitant lesions are better tolerated than stenotic lesions, and those with preserved systolic function, good functional capacity, without any exercise-induced arrhythmias or ischemia or abnormal hemodynamic response are considered to be low risk and can participate in all sports,” added Dr. Gati, a cardiologist at Royal Brompton Hospital, London.
The two most common valvular abnormalities encountered in clinical practice are bicuspid aortic valve and mitral valve prolapse. Dr. Gati noted that, while mitral valve prolapse has a benign prognosis in the great majority of affected individuals, the presence of specific features indicative of increased risk for sudden cardiac death precludes participation in strenuous exercise. These include T-wave inversion in the inferior leads on a 12-lead ECG, long QT, bileaflet mitral valve prolapse, basal inferolateral wall fibrosis, severe mitral regurgitation, or a family history of sudden cardiac death.
Bicuspid aortic valve has a prevalence of 1%-2% in the general population. It can be associated with aortic stenosis, aortic regurgitation, and increased risk of ascending aortic aneurysm and dissection. Since it remains unclear whether intensive exercise accelerates aortic dilatation, a cautious approach to sports participation is recommended in patients with an ascending aorta above the normal limit of 40 mm, she said.
The 80-page ESC sports cardiology guidelines, published online simultaneously with their presentation, cover a broad range of additional topics, including exercise recommendations for the general public, for the elderly, as well as for patients with cardiomyopathies, adult congenital heart disease, arrhythmias, and channelopathies. Gaps in evidence are also highlighted.
SOURCE: Pelliccia A. ESC 2020 and Eur Heart J. 2020 Aug 29. doi: 10.1093/eurheartj/ehaa605.
New guidelines on sports cardiology from the European Society of Cardiology break fresh ground by green-lighting participation in vigorous competitive sports by selected patients with stable coronary artery disease, heart failure, or mild arrhythmias.
These liberalized guidelines, released at the virtual annual congress of the European Society of Cardiology, thus move well beyond the standard exercise advice to engage in about 150 minutes per week of moderate physical activity, typically defined as brisk walking or its equivalent.
The guidelines reflect a conviction that exercise is powerful medicine for patients with cardiovascular disease and also affords a means to help curb the epidemics of diabetes and obesity that drive cardiovascular risk, according to Antonio Pelliccia, MD, who cochaired the 24-member task force of European and American experts that developed the guidelines.
In a session highlighting the new sports cardiology guidelines, Mats Borjesson, MD, head of the Center for Health and Performance at Gothenburg (Sweden) University, summarized the section devoted to patients with stable coronary artery disease: “If you have established CAD and a low risk of adverse events during exercise, you are eligible for high-intensity exercise and competitive sports. But if you have persistent ischemia despite medical treatment, or symptoms, then you’re only eligible for leisure-time subthreshold activity.”
Dr. Pelliccia put this new recommendation into context.
“We are not talking anymore in this particular disease just about cardiac rehabilitation or leisure-time activity, but we are also opening the border and talking about competitive sports activity in selected patients where you have the evidence for low risk of exercise-induced adverse events. This is a major achievement now for what is the major disease in our adult population,” said Dr. Pelliccia, chief of cardiology at the Institute of Sports Medicine and Science at the Italian National Olympic Committee and professor of sports cardiology at La Sapienza University of Rome.
The recommendation for individualized consideration of all types of exercise, even including vigorous competitive sports, in low-risk patients with CAD gets a class IIa, level of evidence (LOE) C recommendation in the new guidelines. That’s a big step down from a ringing class Ia endorsement, but since sports cardiology is a relatively young field with little evidence that’s based on randomized trials, the guidelines are rife with many other class IIa, LOE C recommendations as well.
“The level of evidence is rather low, so these guidelines are very much the personal perspective of the expert panel,” explained Martin Halle, MD, professor and head of the department of prevention, rehabilitation, and sports cardiology at Technical University of Munich.
The high-risk features for exercise-induced cardiac adverse events in patients with longstanding stable CAD, as cited in the guidelines, include a critical coronary stenosis, defined as a more than 70% lesion in a major coronary artery or a greater than 50% stenosis in the left main, and/or a fractional flow reserve score of less than 0.8; a left ventricular ejection fraction of 50% or less with wall-motion abnormalities; inducible myocardial ischemia on maximal exercise testing; nonsustained ventricular tachycardia; polymorphic or very frequent ventricular premature beats at rest and during maximum stress; and a recent acute coronary syndrome (ACS). These features call for an exercise prescription tailored to remain below the patient’s angina and ischemia thresholds.
“It’s important for cardiologists out there to understand that we definitely need a maximal exercise test. In somebody who is running and has an ACS and then wants to start running again, 200 watts on an ergometer is too low. We have to push them up to the end, and then if everything is okay – left ventricular function is okay, no ischemia, no arrhythmias under exercise testing – then it’s fine,” Dr. Halle said.
Dr. Pelliccia added that close follow-up is needed, because this is an evolving disease.”
Exercise and heart failure
Massimo F. Piepoli, MD, PhD, noted that the guidelines give a class IIb, LOE C recommendation for consideration of high-intensity recreational endurance and power sports in patients with heart failure with either midrange or preserved ejection fraction, provided they are stable, asymptomatic, on optimal guideline-directed medical therapy, and without abnormalities on a maximal exercise stress test.
However, such intense physical activity is not recommended in patients with heart failure with reduced ejection fraction, regardless of their symptom status, added Dr. Piepoli of Guglielmo da Saliceto Hospital in Placenza, Italy.
“We’re talking here, I think for the first time, about possible competitive sports participation in individuals with heart failure, depending on their clinical condition. We are really opening the barriers to sports participation, even in these patients in whom we never thought of it before,” Dr. Pelliccia observed.
Valvular heart disease and exercise
Guidelines panelist Sabiha Gati, MRCP, PhD, said asymptomatic individuals with mild valvular abnormalities can participate in all recreational and competitive sports; that’s a class I, LOE C recommendation.
“Moderate regurgitant lesions are better tolerated than stenotic lesions, and those with preserved systolic function, good functional capacity, without any exercise-induced arrhythmias or ischemia or abnormal hemodynamic response are considered to be low risk and can participate in all sports,” added Dr. Gati, a cardiologist at Royal Brompton Hospital, London.
The two most common valvular abnormalities encountered in clinical practice are bicuspid aortic valve and mitral valve prolapse. Dr. Gati noted that, while mitral valve prolapse has a benign prognosis in the great majority of affected individuals, the presence of specific features indicative of increased risk for sudden cardiac death precludes participation in strenuous exercise. These include T-wave inversion in the inferior leads on a 12-lead ECG, long QT, bileaflet mitral valve prolapse, basal inferolateral wall fibrosis, severe mitral regurgitation, or a family history of sudden cardiac death.
Bicuspid aortic valve has a prevalence of 1%-2% in the general population. It can be associated with aortic stenosis, aortic regurgitation, and increased risk of ascending aortic aneurysm and dissection. Since it remains unclear whether intensive exercise accelerates aortic dilatation, a cautious approach to sports participation is recommended in patients with an ascending aorta above the normal limit of 40 mm, she said.
The 80-page ESC sports cardiology guidelines, published online simultaneously with their presentation, cover a broad range of additional topics, including exercise recommendations for the general public, for the elderly, as well as for patients with cardiomyopathies, adult congenital heart disease, arrhythmias, and channelopathies. Gaps in evidence are also highlighted.
SOURCE: Pelliccia A. ESC 2020 and Eur Heart J. 2020 Aug 29. doi: 10.1093/eurheartj/ehaa605.
New guidelines on sports cardiology from the European Society of Cardiology break fresh ground by green-lighting participation in vigorous competitive sports by selected patients with stable coronary artery disease, heart failure, or mild arrhythmias.
These liberalized guidelines, released at the virtual annual congress of the European Society of Cardiology, thus move well beyond the standard exercise advice to engage in about 150 minutes per week of moderate physical activity, typically defined as brisk walking or its equivalent.
The guidelines reflect a conviction that exercise is powerful medicine for patients with cardiovascular disease and also affords a means to help curb the epidemics of diabetes and obesity that drive cardiovascular risk, according to Antonio Pelliccia, MD, who cochaired the 24-member task force of European and American experts that developed the guidelines.
In a session highlighting the new sports cardiology guidelines, Mats Borjesson, MD, head of the Center for Health and Performance at Gothenburg (Sweden) University, summarized the section devoted to patients with stable coronary artery disease: “If you have established CAD and a low risk of adverse events during exercise, you are eligible for high-intensity exercise and competitive sports. But if you have persistent ischemia despite medical treatment, or symptoms, then you’re only eligible for leisure-time subthreshold activity.”
Dr. Pelliccia put this new recommendation into context.
“We are not talking anymore in this particular disease just about cardiac rehabilitation or leisure-time activity, but we are also opening the border and talking about competitive sports activity in selected patients where you have the evidence for low risk of exercise-induced adverse events. This is a major achievement now for what is the major disease in our adult population,” said Dr. Pelliccia, chief of cardiology at the Institute of Sports Medicine and Science at the Italian National Olympic Committee and professor of sports cardiology at La Sapienza University of Rome.
The recommendation for individualized consideration of all types of exercise, even including vigorous competitive sports, in low-risk patients with CAD gets a class IIa, level of evidence (LOE) C recommendation in the new guidelines. That’s a big step down from a ringing class Ia endorsement, but since sports cardiology is a relatively young field with little evidence that’s based on randomized trials, the guidelines are rife with many other class IIa, LOE C recommendations as well.
“The level of evidence is rather low, so these guidelines are very much the personal perspective of the expert panel,” explained Martin Halle, MD, professor and head of the department of prevention, rehabilitation, and sports cardiology at Technical University of Munich.
The high-risk features for exercise-induced cardiac adverse events in patients with longstanding stable CAD, as cited in the guidelines, include a critical coronary stenosis, defined as a more than 70% lesion in a major coronary artery or a greater than 50% stenosis in the left main, and/or a fractional flow reserve score of less than 0.8; a left ventricular ejection fraction of 50% or less with wall-motion abnormalities; inducible myocardial ischemia on maximal exercise testing; nonsustained ventricular tachycardia; polymorphic or very frequent ventricular premature beats at rest and during maximum stress; and a recent acute coronary syndrome (ACS). These features call for an exercise prescription tailored to remain below the patient’s angina and ischemia thresholds.
“It’s important for cardiologists out there to understand that we definitely need a maximal exercise test. In somebody who is running and has an ACS and then wants to start running again, 200 watts on an ergometer is too low. We have to push them up to the end, and then if everything is okay – left ventricular function is okay, no ischemia, no arrhythmias under exercise testing – then it’s fine,” Dr. Halle said.
Dr. Pelliccia added that close follow-up is needed, because this is an evolving disease.”
Exercise and heart failure
Massimo F. Piepoli, MD, PhD, noted that the guidelines give a class IIb, LOE C recommendation for consideration of high-intensity recreational endurance and power sports in patients with heart failure with either midrange or preserved ejection fraction, provided they are stable, asymptomatic, on optimal guideline-directed medical therapy, and without abnormalities on a maximal exercise stress test.
However, such intense physical activity is not recommended in patients with heart failure with reduced ejection fraction, regardless of their symptom status, added Dr. Piepoli of Guglielmo da Saliceto Hospital in Placenza, Italy.
“We’re talking here, I think for the first time, about possible competitive sports participation in individuals with heart failure, depending on their clinical condition. We are really opening the barriers to sports participation, even in these patients in whom we never thought of it before,” Dr. Pelliccia observed.
Valvular heart disease and exercise
Guidelines panelist Sabiha Gati, MRCP, PhD, said asymptomatic individuals with mild valvular abnormalities can participate in all recreational and competitive sports; that’s a class I, LOE C recommendation.
“Moderate regurgitant lesions are better tolerated than stenotic lesions, and those with preserved systolic function, good functional capacity, without any exercise-induced arrhythmias or ischemia or abnormal hemodynamic response are considered to be low risk and can participate in all sports,” added Dr. Gati, a cardiologist at Royal Brompton Hospital, London.
The two most common valvular abnormalities encountered in clinical practice are bicuspid aortic valve and mitral valve prolapse. Dr. Gati noted that, while mitral valve prolapse has a benign prognosis in the great majority of affected individuals, the presence of specific features indicative of increased risk for sudden cardiac death precludes participation in strenuous exercise. These include T-wave inversion in the inferior leads on a 12-lead ECG, long QT, bileaflet mitral valve prolapse, basal inferolateral wall fibrosis, severe mitral regurgitation, or a family history of sudden cardiac death.
Bicuspid aortic valve has a prevalence of 1%-2% in the general population. It can be associated with aortic stenosis, aortic regurgitation, and increased risk of ascending aortic aneurysm and dissection. Since it remains unclear whether intensive exercise accelerates aortic dilatation, a cautious approach to sports participation is recommended in patients with an ascending aorta above the normal limit of 40 mm, she said.
The 80-page ESC sports cardiology guidelines, published online simultaneously with their presentation, cover a broad range of additional topics, including exercise recommendations for the general public, for the elderly, as well as for patients with cardiomyopathies, adult congenital heart disease, arrhythmias, and channelopathies. Gaps in evidence are also highlighted.
SOURCE: Pelliccia A. ESC 2020 and Eur Heart J. 2020 Aug 29. doi: 10.1093/eurheartj/ehaa605.
FROM ESC CONGRESS 2020
Many providers don’t follow hypertension guidelines
Many health care professionals are not following current, evidence-based guidelines to screen for and diagnose hypertension, and appear to have substantial gaps in knowledge, beliefs, and use of recommended practices, results from a large survey suggest.
“One surprising finding was that there was so much trust in the stethoscope, because the automated monitors are a better way to take blood pressure,” lead author Beverly Green, MD, of Kaiser Permanente Washington Health Research Institute, Seattle, said in an interview.
The results of the survey were presented Sept. 10 at the virtual joint scientific sessions of the American Heart Association Council on Hypertension, AHA Council on Kidney in Cardiovascular Disease, and American Society of Hypertension.
The U.S. Preventive Services Task Force (USPSTF) and the American Heart Association/American College of Cardiology recommend out-of-office blood pressure measurements – via ambulatory blood pressure monitoring (ABPM) or home BP monitoring – before making a new diagnosis of hypertension.
To gauge provider knowledge, beliefs, and practices related to BP diagnostic tests, the researchers surveyed 282 providers: 102 medical assistants (MA), 28 licensed practical nurses (LPNs), 33 registered nurses (RNs), 86 primary care physicians, and 33 advanced practitioners (APs).
More than three-quarters of providers (79%) felt that BP measured manually with a stethoscope and ABPM were “very or highly” accurate ways to measure BP when making a new diagnosis of hypertension.
Most did not think that automated clinic BPs, home BP, or kiosk BP measurements were very or highly accurate.
Nearly all providers surveyed (96%) reported that they “always or almost always” rely on clinic BP measurements when diagnosing hypertension, but the majority of physicians/APs would prefer using ABPM (61%) if available.
The problem with ABPM, said Dr. Green, is “it’s just not very available or convenient for patients, and a lot of providers think that patients won’t tolerate it.” Yet, without it, there is a risk for misclassification, she said.
Karen A. Griffin, MD, who chairs the AHA Council on Hypertension, said it became “customary to use clinic BP since ABPM was not previously reimbursed for the routine diagnosis of hypertension.
“Now that the payment for ABPM has been expanded, the number of machines at most institutions is not adequate for the need. Consequently, it will take some time to catch up with the current guidelines for diagnosing hypertension,” she said in an interview.
The provider survey by Dr. Green and colleagues also shows slow uptake of updated thresholds for high blood pressure.
Eighty-four percent of physicians/APs and 68% of MA/LPN/RNs said they used a clinic BP threshold of at least 140/90 mm Hg for making a new diagnosis of hypertension.
Only 3.5% and 9.0%, respectively, reported using the updated threshold of at least 130/80 mm Hg put forth in 2017.
Dr. Griffin said part of this stems from the fact that the survey began before the updated guidelines were released in 2017, “not to mention the fact that some societies have opposed the new threshold of 130/80 mm Hg.”
“I think, with time, the data on morbidity and mortality associated with the goal of 130/80 mm Hg will hopefully convince those who have not yet implemented these new guidelines that it is a safe and effective BP goal,” Dr. Griffin said.
This research had no specific funding. Dr. Green and Dr. Griffin have no relevant disclosures.
A version of this article originally appeared on Medscape.com.
Many health care professionals are not following current, evidence-based guidelines to screen for and diagnose hypertension, and appear to have substantial gaps in knowledge, beliefs, and use of recommended practices, results from a large survey suggest.
“One surprising finding was that there was so much trust in the stethoscope, because the automated monitors are a better way to take blood pressure,” lead author Beverly Green, MD, of Kaiser Permanente Washington Health Research Institute, Seattle, said in an interview.
The results of the survey were presented Sept. 10 at the virtual joint scientific sessions of the American Heart Association Council on Hypertension, AHA Council on Kidney in Cardiovascular Disease, and American Society of Hypertension.
The U.S. Preventive Services Task Force (USPSTF) and the American Heart Association/American College of Cardiology recommend out-of-office blood pressure measurements – via ambulatory blood pressure monitoring (ABPM) or home BP monitoring – before making a new diagnosis of hypertension.
To gauge provider knowledge, beliefs, and practices related to BP diagnostic tests, the researchers surveyed 282 providers: 102 medical assistants (MA), 28 licensed practical nurses (LPNs), 33 registered nurses (RNs), 86 primary care physicians, and 33 advanced practitioners (APs).
More than three-quarters of providers (79%) felt that BP measured manually with a stethoscope and ABPM were “very or highly” accurate ways to measure BP when making a new diagnosis of hypertension.
Most did not think that automated clinic BPs, home BP, or kiosk BP measurements were very or highly accurate.
Nearly all providers surveyed (96%) reported that they “always or almost always” rely on clinic BP measurements when diagnosing hypertension, but the majority of physicians/APs would prefer using ABPM (61%) if available.
The problem with ABPM, said Dr. Green, is “it’s just not very available or convenient for patients, and a lot of providers think that patients won’t tolerate it.” Yet, without it, there is a risk for misclassification, she said.
Karen A. Griffin, MD, who chairs the AHA Council on Hypertension, said it became “customary to use clinic BP since ABPM was not previously reimbursed for the routine diagnosis of hypertension.
“Now that the payment for ABPM has been expanded, the number of machines at most institutions is not adequate for the need. Consequently, it will take some time to catch up with the current guidelines for diagnosing hypertension,” she said in an interview.
The provider survey by Dr. Green and colleagues also shows slow uptake of updated thresholds for high blood pressure.
Eighty-four percent of physicians/APs and 68% of MA/LPN/RNs said they used a clinic BP threshold of at least 140/90 mm Hg for making a new diagnosis of hypertension.
Only 3.5% and 9.0%, respectively, reported using the updated threshold of at least 130/80 mm Hg put forth in 2017.
Dr. Griffin said part of this stems from the fact that the survey began before the updated guidelines were released in 2017, “not to mention the fact that some societies have opposed the new threshold of 130/80 mm Hg.”
“I think, with time, the data on morbidity and mortality associated with the goal of 130/80 mm Hg will hopefully convince those who have not yet implemented these new guidelines that it is a safe and effective BP goal,” Dr. Griffin said.
This research had no specific funding. Dr. Green and Dr. Griffin have no relevant disclosures.
A version of this article originally appeared on Medscape.com.
Many health care professionals are not following current, evidence-based guidelines to screen for and diagnose hypertension, and appear to have substantial gaps in knowledge, beliefs, and use of recommended practices, results from a large survey suggest.
“One surprising finding was that there was so much trust in the stethoscope, because the automated monitors are a better way to take blood pressure,” lead author Beverly Green, MD, of Kaiser Permanente Washington Health Research Institute, Seattle, said in an interview.
The results of the survey were presented Sept. 10 at the virtual joint scientific sessions of the American Heart Association Council on Hypertension, AHA Council on Kidney in Cardiovascular Disease, and American Society of Hypertension.
The U.S. Preventive Services Task Force (USPSTF) and the American Heart Association/American College of Cardiology recommend out-of-office blood pressure measurements – via ambulatory blood pressure monitoring (ABPM) or home BP monitoring – before making a new diagnosis of hypertension.
To gauge provider knowledge, beliefs, and practices related to BP diagnostic tests, the researchers surveyed 282 providers: 102 medical assistants (MA), 28 licensed practical nurses (LPNs), 33 registered nurses (RNs), 86 primary care physicians, and 33 advanced practitioners (APs).
More than three-quarters of providers (79%) felt that BP measured manually with a stethoscope and ABPM were “very or highly” accurate ways to measure BP when making a new diagnosis of hypertension.
Most did not think that automated clinic BPs, home BP, or kiosk BP measurements were very or highly accurate.
Nearly all providers surveyed (96%) reported that they “always or almost always” rely on clinic BP measurements when diagnosing hypertension, but the majority of physicians/APs would prefer using ABPM (61%) if available.
The problem with ABPM, said Dr. Green, is “it’s just not very available or convenient for patients, and a lot of providers think that patients won’t tolerate it.” Yet, without it, there is a risk for misclassification, she said.
Karen A. Griffin, MD, who chairs the AHA Council on Hypertension, said it became “customary to use clinic BP since ABPM was not previously reimbursed for the routine diagnosis of hypertension.
“Now that the payment for ABPM has been expanded, the number of machines at most institutions is not adequate for the need. Consequently, it will take some time to catch up with the current guidelines for diagnosing hypertension,” she said in an interview.
The provider survey by Dr. Green and colleagues also shows slow uptake of updated thresholds for high blood pressure.
Eighty-four percent of physicians/APs and 68% of MA/LPN/RNs said they used a clinic BP threshold of at least 140/90 mm Hg for making a new diagnosis of hypertension.
Only 3.5% and 9.0%, respectively, reported using the updated threshold of at least 130/80 mm Hg put forth in 2017.
Dr. Griffin said part of this stems from the fact that the survey began before the updated guidelines were released in 2017, “not to mention the fact that some societies have opposed the new threshold of 130/80 mm Hg.”
“I think, with time, the data on morbidity and mortality associated with the goal of 130/80 mm Hg will hopefully convince those who have not yet implemented these new guidelines that it is a safe and effective BP goal,” Dr. Griffin said.
This research had no specific funding. Dr. Green and Dr. Griffin have no relevant disclosures.
A version of this article originally appeared on Medscape.com.
COVID-19 prompts ‘democratization’ of cancer trials
The pandemic has taught researchers how to decentralize trials, which should not only improve patient satisfaction but increase trial accrual by providing access to typically underserved populations, Patricia M. LoRusso, DO, of Yale University, New Haven, Conn., said at the meeting.
Dr. LoRusso was one of six panelists who participated in a forum about changes to cancer trials that were prompted by the pandemic. The forum was moderated by Keith T. Flaherty, MD, of Massachusetts General Hospital in Boston.
Dr. Flaherty asked the panelists to explain adjustments their organizations have made in response to the pandemic, discuss accomplishments, and speculate on future challenges and priorities.
Trial, administrative, and patient-care modifications
COVID-19 put some cancer trials on hold. For others, the pandemic forced sponsors and study chairs to reduce trial complexity and identify nonessential aspects of the studies, according to panelist José Baselga, MD, PhD, of AstraZeneca.
Specifically, exploratory objectives were subjugated to patient safety and a focus on the primary endpoints of each trial.
Once the critical data were identified, study chairs were asked to determine whether data could be obtained through technologies that could substitute for face-to-face contact between patients and staff – for example, patient-reported outcome tools and at-home digital monitoring.
Modifications prompted by the pandemic include the following:
- On-site auditing was suspended.
- Oral investigational agents were shipped directly to patients.
- “Remote” informed consent (telephone or video consenting) was permitted.
- Local providers could perform study-related services, with oversight by the research site.
- Minor deviations from the written protocols were allowed, provided the deviations did not affect patient care or data integrity.
“Obviously, the pandemic has been horrible, but what it has allowed us to do, as investigators in the clinical research landscape, … is to change our focus somewhat and realize, first and foremost, the patient is at the center of this,” Dr. LoRusso said.
Operational accomplishments and benefits
The pandemic caused a 40% decline in accrual to studies supported by the National Cancer Institute’s (NCI) Clinical Trials Network (NCTN) from mid-March to early April, according to James H. Doroshow, MD, of NCI.
However, after modifications to administrative and regulatory procedures, accrual to NCTN trials recovered to approximately 80% of prepandemic levels, Dr. Doroshow said.
The pandemic prompted investigators to leverage tools and technology they had not previously used frequently or at all, the panelists pointed out.
Investigators discovered perforce that telehealth could be used for almost all trial-related assessments. In lieu of physical examination, patients could send pictures of rashes and use electronic devices to monitor blood sugar values and vital signs.
Digital radiographic studies were performed at sites that were most convenient for patients, downloaded, and reinterpreted at the study institution. Visiting nurses and neighborhood laboratories enabled less-frequent in-person visits for assessments.
These adjustments have been particularly important for geographically and/or socioeconomically disadvantaged patients, the panelists said.
Overall, there was agreement among the panelists that shared values and trust among regulatory authorities, sponsors, investigators, and clinicians were impressive in their urgency, sincerity, and patient centricity.
“This pandemic … has forced us to think differently and be nimble and creative to our approach to maintaining our overriding goals while at the same time bringing these innovative therapies forward for patients with cancer and other serious and life-threatening diseases as quickly as possible,” said panelist Kristen M. Hege, MD, of Bristol-Myers Squibb.
In fact, Dr. Hege noted, some cancer-related therapies (e.g., BTK inhibitors, JAK inhibitors, and immunomodulatory agents) were “repurposed” rapidly and tested against COVID-related complications.
Streamlining trial regulatory processes
In addition to changing ongoing trials, the pandemic has affected how new research projects are launched.
One new study that came together quickly in response to the pandemic is the NCI COVID-19 in Cancer Patients Study (NCCAPS). NCCAPS is a natural history study with biospecimens and an imaging library. It was approved in just 5 weeks and is active in 650 sites, with “gangbusters” accrual, Dr. Doroshow said.
The rapidness of NCCAPS’ design and implementation should prompt the revision of previously accepted timelines for trial activation and lead to streamlined future processes.
Another project that was launched quickly in response to the pandemic is the COVID-19 evidence accelerator, according to Paul G. Kluetz, MD, of the Food and Drug Administration.
The COVID-19 evidence accelerator integrates real-world evidence into a database to provide investigators and health systems with the ability to gather information, design rapid turnaround queries, and share results. The evidence accelerator can provide study chairs with information that may have relevance to the safety of participants in clinical trials.
Future directions and challenges
The panelists agreed that pandemic-related modifications in processes will not only accelerate trial approval and activation but should facilitate higher study accrual, increase the diversity of protocol participants, and decrease the costs associated with clinical trial conduct.
With that in mind, the NCI is planning randomized clinical trials in which “process A” is compared with “process B,” Dr. Doroshow said. The goal is to determine which modifications are most likely to make trials available to patients without compromising data integrity or patient safety.
“How much less data do you need to have an outcome that will be similar?” Dr. Doroshow asked. “How many fewer visits, how many fewer tests, how much can you save? Physicians, clinical trialists, all of us respond to data, and if you get the same outcome at a third of the cost, then everybody benefits.”
Nonetheless, we will need to be vigilant for unintended vulnerabilities from well-intended efforts, according to Dr. Kluetz. Study chairs, sponsors, and regulatory agencies will need to be attentive to whether there are important differences in scan quality or interpretation, missing data that influence trial outcomes, and so on.
Dr. Hege pointed out that differences among data sources may be less important when treatments generate large effects but may be vitally important when the relative differences among treatments are small.
On a practical level, decentralizing clinical research may negatively impact the finances of tertiary care centers, which could threaten the required infrastructure for clinical trials, a few panelists noted.
The relative balance of NCI-, industry-, and investigator-initiated trials may require adjustment so that research income is adequate to maintain the costs associated with cancer clinical trials.
Shared goals and democratization
The pandemic has required all stakeholders in clinical research to rely on relationships of trust and shared goals, said Caroline Robert, MD, PhD, of Institut Gustave Roussy in Villejuif, France.
Dr. Kluetz summarized those goals as improving trial efficiencies, decreasing patient burden, decentralizing trials, and maintaining trial integrity.
A decentralized clinical trials operational model could lead to better generalizability of study outcomes, normalization of life for patients on studies, and lower costs of trial conduct. As such, decentralization would promote democratization.
Coupled with ongoing efforts to reduce eligibility criteria in cancer trials, the pandemic has brought operational solutions that should be perpetuated and has reminded us of the interlocking and mutually supportive relationships on which clinical research success depends.
Dr. Doroshow and Dr. Kluetz disclosed no conflicts of interest. All other panelists disclosed financial relationships, including employment, with a range of companies.
Dr. Lyss was a community-based medical oncologist and clinical researcher for more than 35 years before his recent retirement. His clinical and research interests were focused on breast and lung cancers, as well as expanding clinical trial access to medically underserved populations. He is based in St. Louis. He has no conflicts of interest.
SOURCE: Flaherty KT et al. AACR: COVID-19 and Cancer, Regulatory and Operational Implications of Cancer Clinical Trial Changes During COVID-19.
The pandemic has taught researchers how to decentralize trials, which should not only improve patient satisfaction but increase trial accrual by providing access to typically underserved populations, Patricia M. LoRusso, DO, of Yale University, New Haven, Conn., said at the meeting.
Dr. LoRusso was one of six panelists who participated in a forum about changes to cancer trials that were prompted by the pandemic. The forum was moderated by Keith T. Flaherty, MD, of Massachusetts General Hospital in Boston.
Dr. Flaherty asked the panelists to explain adjustments their organizations have made in response to the pandemic, discuss accomplishments, and speculate on future challenges and priorities.
Trial, administrative, and patient-care modifications
COVID-19 put some cancer trials on hold. For others, the pandemic forced sponsors and study chairs to reduce trial complexity and identify nonessential aspects of the studies, according to panelist José Baselga, MD, PhD, of AstraZeneca.
Specifically, exploratory objectives were subjugated to patient safety and a focus on the primary endpoints of each trial.
Once the critical data were identified, study chairs were asked to determine whether data could be obtained through technologies that could substitute for face-to-face contact between patients and staff – for example, patient-reported outcome tools and at-home digital monitoring.
Modifications prompted by the pandemic include the following:
- On-site auditing was suspended.
- Oral investigational agents were shipped directly to patients.
- “Remote” informed consent (telephone or video consenting) was permitted.
- Local providers could perform study-related services, with oversight by the research site.
- Minor deviations from the written protocols were allowed, provided the deviations did not affect patient care or data integrity.
“Obviously, the pandemic has been horrible, but what it has allowed us to do, as investigators in the clinical research landscape, … is to change our focus somewhat and realize, first and foremost, the patient is at the center of this,” Dr. LoRusso said.
Operational accomplishments and benefits
The pandemic caused a 40% decline in accrual to studies supported by the National Cancer Institute’s (NCI) Clinical Trials Network (NCTN) from mid-March to early April, according to James H. Doroshow, MD, of NCI.
However, after modifications to administrative and regulatory procedures, accrual to NCTN trials recovered to approximately 80% of prepandemic levels, Dr. Doroshow said.
The pandemic prompted investigators to leverage tools and technology they had not previously used frequently or at all, the panelists pointed out.
Investigators discovered perforce that telehealth could be used for almost all trial-related assessments. In lieu of physical examination, patients could send pictures of rashes and use electronic devices to monitor blood sugar values and vital signs.
Digital radiographic studies were performed at sites that were most convenient for patients, downloaded, and reinterpreted at the study institution. Visiting nurses and neighborhood laboratories enabled less-frequent in-person visits for assessments.
These adjustments have been particularly important for geographically and/or socioeconomically disadvantaged patients, the panelists said.
Overall, there was agreement among the panelists that shared values and trust among regulatory authorities, sponsors, investigators, and clinicians were impressive in their urgency, sincerity, and patient centricity.
“This pandemic … has forced us to think differently and be nimble and creative to our approach to maintaining our overriding goals while at the same time bringing these innovative therapies forward for patients with cancer and other serious and life-threatening diseases as quickly as possible,” said panelist Kristen M. Hege, MD, of Bristol-Myers Squibb.
In fact, Dr. Hege noted, some cancer-related therapies (e.g., BTK inhibitors, JAK inhibitors, and immunomodulatory agents) were “repurposed” rapidly and tested against COVID-related complications.
Streamlining trial regulatory processes
In addition to changing ongoing trials, the pandemic has affected how new research projects are launched.
One new study that came together quickly in response to the pandemic is the NCI COVID-19 in Cancer Patients Study (NCCAPS). NCCAPS is a natural history study with biospecimens and an imaging library. It was approved in just 5 weeks and is active in 650 sites, with “gangbusters” accrual, Dr. Doroshow said.
The rapidness of NCCAPS’ design and implementation should prompt the revision of previously accepted timelines for trial activation and lead to streamlined future processes.
Another project that was launched quickly in response to the pandemic is the COVID-19 evidence accelerator, according to Paul G. Kluetz, MD, of the Food and Drug Administration.
The COVID-19 evidence accelerator integrates real-world evidence into a database to provide investigators and health systems with the ability to gather information, design rapid turnaround queries, and share results. The evidence accelerator can provide study chairs with information that may have relevance to the safety of participants in clinical trials.
Future directions and challenges
The panelists agreed that pandemic-related modifications in processes will not only accelerate trial approval and activation but should facilitate higher study accrual, increase the diversity of protocol participants, and decrease the costs associated with clinical trial conduct.
With that in mind, the NCI is planning randomized clinical trials in which “process A” is compared with “process B,” Dr. Doroshow said. The goal is to determine which modifications are most likely to make trials available to patients without compromising data integrity or patient safety.
“How much less data do you need to have an outcome that will be similar?” Dr. Doroshow asked. “How many fewer visits, how many fewer tests, how much can you save? Physicians, clinical trialists, all of us respond to data, and if you get the same outcome at a third of the cost, then everybody benefits.”
Nonetheless, we will need to be vigilant for unintended vulnerabilities from well-intended efforts, according to Dr. Kluetz. Study chairs, sponsors, and regulatory agencies will need to be attentive to whether there are important differences in scan quality or interpretation, missing data that influence trial outcomes, and so on.
Dr. Hege pointed out that differences among data sources may be less important when treatments generate large effects but may be vitally important when the relative differences among treatments are small.
On a practical level, decentralizing clinical research may negatively impact the finances of tertiary care centers, which could threaten the required infrastructure for clinical trials, a few panelists noted.
The relative balance of NCI-, industry-, and investigator-initiated trials may require adjustment so that research income is adequate to maintain the costs associated with cancer clinical trials.
Shared goals and democratization
The pandemic has required all stakeholders in clinical research to rely on relationships of trust and shared goals, said Caroline Robert, MD, PhD, of Institut Gustave Roussy in Villejuif, France.
Dr. Kluetz summarized those goals as improving trial efficiencies, decreasing patient burden, decentralizing trials, and maintaining trial integrity.
A decentralized clinical trials operational model could lead to better generalizability of study outcomes, normalization of life for patients on studies, and lower costs of trial conduct. As such, decentralization would promote democratization.
Coupled with ongoing efforts to reduce eligibility criteria in cancer trials, the pandemic has brought operational solutions that should be perpetuated and has reminded us of the interlocking and mutually supportive relationships on which clinical research success depends.
Dr. Doroshow and Dr. Kluetz disclosed no conflicts of interest. All other panelists disclosed financial relationships, including employment, with a range of companies.
Dr. Lyss was a community-based medical oncologist and clinical researcher for more than 35 years before his recent retirement. His clinical and research interests were focused on breast and lung cancers, as well as expanding clinical trial access to medically underserved populations. He is based in St. Louis. He has no conflicts of interest.
SOURCE: Flaherty KT et al. AACR: COVID-19 and Cancer, Regulatory and Operational Implications of Cancer Clinical Trial Changes During COVID-19.
The pandemic has taught researchers how to decentralize trials, which should not only improve patient satisfaction but increase trial accrual by providing access to typically underserved populations, Patricia M. LoRusso, DO, of Yale University, New Haven, Conn., said at the meeting.
Dr. LoRusso was one of six panelists who participated in a forum about changes to cancer trials that were prompted by the pandemic. The forum was moderated by Keith T. Flaherty, MD, of Massachusetts General Hospital in Boston.
Dr. Flaherty asked the panelists to explain adjustments their organizations have made in response to the pandemic, discuss accomplishments, and speculate on future challenges and priorities.
Trial, administrative, and patient-care modifications
COVID-19 put some cancer trials on hold. For others, the pandemic forced sponsors and study chairs to reduce trial complexity and identify nonessential aspects of the studies, according to panelist José Baselga, MD, PhD, of AstraZeneca.
Specifically, exploratory objectives were subjugated to patient safety and a focus on the primary endpoints of each trial.
Once the critical data were identified, study chairs were asked to determine whether data could be obtained through technologies that could substitute for face-to-face contact between patients and staff – for example, patient-reported outcome tools and at-home digital monitoring.
Modifications prompted by the pandemic include the following:
- On-site auditing was suspended.
- Oral investigational agents were shipped directly to patients.
- “Remote” informed consent (telephone or video consenting) was permitted.
- Local providers could perform study-related services, with oversight by the research site.
- Minor deviations from the written protocols were allowed, provided the deviations did not affect patient care or data integrity.
“Obviously, the pandemic has been horrible, but what it has allowed us to do, as investigators in the clinical research landscape, … is to change our focus somewhat and realize, first and foremost, the patient is at the center of this,” Dr. LoRusso said.
Operational accomplishments and benefits
The pandemic caused a 40% decline in accrual to studies supported by the National Cancer Institute’s (NCI) Clinical Trials Network (NCTN) from mid-March to early April, according to James H. Doroshow, MD, of NCI.
However, after modifications to administrative and regulatory procedures, accrual to NCTN trials recovered to approximately 80% of prepandemic levels, Dr. Doroshow said.
The pandemic prompted investigators to leverage tools and technology they had not previously used frequently or at all, the panelists pointed out.
Investigators discovered perforce that telehealth could be used for almost all trial-related assessments. In lieu of physical examination, patients could send pictures of rashes and use electronic devices to monitor blood sugar values and vital signs.
Digital radiographic studies were performed at sites that were most convenient for patients, downloaded, and reinterpreted at the study institution. Visiting nurses and neighborhood laboratories enabled less-frequent in-person visits for assessments.
These adjustments have been particularly important for geographically and/or socioeconomically disadvantaged patients, the panelists said.
Overall, there was agreement among the panelists that shared values and trust among regulatory authorities, sponsors, investigators, and clinicians were impressive in their urgency, sincerity, and patient centricity.
“This pandemic … has forced us to think differently and be nimble and creative to our approach to maintaining our overriding goals while at the same time bringing these innovative therapies forward for patients with cancer and other serious and life-threatening diseases as quickly as possible,” said panelist Kristen M. Hege, MD, of Bristol-Myers Squibb.
In fact, Dr. Hege noted, some cancer-related therapies (e.g., BTK inhibitors, JAK inhibitors, and immunomodulatory agents) were “repurposed” rapidly and tested against COVID-related complications.
Streamlining trial regulatory processes
In addition to changing ongoing trials, the pandemic has affected how new research projects are launched.
One new study that came together quickly in response to the pandemic is the NCI COVID-19 in Cancer Patients Study (NCCAPS). NCCAPS is a natural history study with biospecimens and an imaging library. It was approved in just 5 weeks and is active in 650 sites, with “gangbusters” accrual, Dr. Doroshow said.
The rapidness of NCCAPS’ design and implementation should prompt the revision of previously accepted timelines for trial activation and lead to streamlined future processes.
Another project that was launched quickly in response to the pandemic is the COVID-19 evidence accelerator, according to Paul G. Kluetz, MD, of the Food and Drug Administration.
The COVID-19 evidence accelerator integrates real-world evidence into a database to provide investigators and health systems with the ability to gather information, design rapid turnaround queries, and share results. The evidence accelerator can provide study chairs with information that may have relevance to the safety of participants in clinical trials.
Future directions and challenges
The panelists agreed that pandemic-related modifications in processes will not only accelerate trial approval and activation but should facilitate higher study accrual, increase the diversity of protocol participants, and decrease the costs associated with clinical trial conduct.
With that in mind, the NCI is planning randomized clinical trials in which “process A” is compared with “process B,” Dr. Doroshow said. The goal is to determine which modifications are most likely to make trials available to patients without compromising data integrity or patient safety.
“How much less data do you need to have an outcome that will be similar?” Dr. Doroshow asked. “How many fewer visits, how many fewer tests, how much can you save? Physicians, clinical trialists, all of us respond to data, and if you get the same outcome at a third of the cost, then everybody benefits.”
Nonetheless, we will need to be vigilant for unintended vulnerabilities from well-intended efforts, according to Dr. Kluetz. Study chairs, sponsors, and regulatory agencies will need to be attentive to whether there are important differences in scan quality or interpretation, missing data that influence trial outcomes, and so on.
Dr. Hege pointed out that differences among data sources may be less important when treatments generate large effects but may be vitally important when the relative differences among treatments are small.
On a practical level, decentralizing clinical research may negatively impact the finances of tertiary care centers, which could threaten the required infrastructure for clinical trials, a few panelists noted.
The relative balance of NCI-, industry-, and investigator-initiated trials may require adjustment so that research income is adequate to maintain the costs associated with cancer clinical trials.
Shared goals and democratization
The pandemic has required all stakeholders in clinical research to rely on relationships of trust and shared goals, said Caroline Robert, MD, PhD, of Institut Gustave Roussy in Villejuif, France.
Dr. Kluetz summarized those goals as improving trial efficiencies, decreasing patient burden, decentralizing trials, and maintaining trial integrity.
A decentralized clinical trials operational model could lead to better generalizability of study outcomes, normalization of life for patients on studies, and lower costs of trial conduct. As such, decentralization would promote democratization.
Coupled with ongoing efforts to reduce eligibility criteria in cancer trials, the pandemic has brought operational solutions that should be perpetuated and has reminded us of the interlocking and mutually supportive relationships on which clinical research success depends.
Dr. Doroshow and Dr. Kluetz disclosed no conflicts of interest. All other panelists disclosed financial relationships, including employment, with a range of companies.
Dr. Lyss was a community-based medical oncologist and clinical researcher for more than 35 years before his recent retirement. His clinical and research interests were focused on breast and lung cancers, as well as expanding clinical trial access to medically underserved populations. He is based in St. Louis. He has no conflicts of interest.
SOURCE: Flaherty KT et al. AACR: COVID-19 and Cancer, Regulatory and Operational Implications of Cancer Clinical Trial Changes During COVID-19.
FROM AACR: COVID-19 and Cancer
Baseline gene expression predicts TKI response in CML
Baseline gene expression in patients with chronic myeloid leukemia (CML) who received tyrosine kinase inhibitor (TKI) therapy in the phase 3 ENESTnd trial differentiated those who achieved a good response from those with a poor response at 5 years in an exploratory analysis.
The investigators developed gene-expression models based on RNA sequencing of whole blood samples collected prior to treatment with nilotinib or imatinib in study participants who completed at least 5 years of therapy, including both good responders – those who achieved a major molecular response (MMR), defined as BCR-ABL1IS (a gene sequence found in an abnormal chromosome 22) less than 0.01% by 12 months and sustained deep molecular response (DMR) by 5 years, and poor responders – those without MMR by 12 months or with BCR-ABL1IS greater than 10% at 3 months.
A model based on the comparison of gene signatures from 47 patients who achieved a molecular response of 4.5 (MR4.5) on the International Scale (BCR-ABL1S less than 0.00032%), compared with 23 patients with a poor response, best predicted 5-year responder status (area under the receiver operating characteristic curve, 0.76), Jerald P. Radich, MD, reported during the Society of Hematologic Oncology virtual meeting.
“For this kind of work, that’s really quite good,” said Dr. Radich of the clinical research division at Fred Hutchinson Cancer Research Center, Seattle.
Notably, the differences in patient responses observed by 12 months in ENESTnd persisted for up to 10 years, he said.
The findings have potential implications for drug development and facilitation of DMR in patients on TKI therapy – a prerequisite for attempting treatment-free remission, he said.
Dr. Radich and colleagues assessed 24 clinical factors – such as Sokal risk score, TKI therapy type, age, and sex – according to responder status, and applied penalized regression to the clinical variables, to expression of 13,575 genes, and to a combination of the clinical variables and gene expression.
Clinical variables didn’t predict response in the trial, and including the clinical variables in the gene-expression model in the exploratory analysis did not improve it’s performance (AUC, 0.75). However, both the MR4.5 plus clinical variables model and the MR4.5-only model outperformed the clinical variables–only model (AUC, 0.59), he noted, adding: “So gene expression seems to be highly correlated with response.”
Of note, 458 genes were differentially expressed; those found in responders were most often associated with immune response, whereas those in poor responders were more likely to be associated with drug catabolism, WNT signaling, and cell cycle.
This suggests that good responders, compared with poor responders, have an activated immune system that is better able to engage after TKI therapy is administered to “cull through the heard, so to speak,” Dr. Radich said.
The findings were validated in an independent dataset of 19 good responders and 25 poor responders (AUC, 0.67 for the MR4.5 vs. poor-responder model).
A comparison of the expression of immune cell marker genes in good responders and poor responders further showed that T cells – particularly CD8 T cells, B cells, natural killer cells, and aggregate cytotoxic lymphocytes were expressed at significantly higher levels in good responders.
This was true in both the ENESTnd cohort and the validation dataset, he said.
The ENESTnd study is a randomized, open-label study comparing nilotinib and imatinib in adults with newly diagnosed Philadelphia chromosome–positive chronic-phase CML. A 5-year study update published in 2016 showed that 54% and 52% of patients in nilotinib 300- and 400-mg twice-daily arms, respectively, achieved MR4.5, compared with 31% of those in an imatinib 400-mg once-daily arm. In the current exploratory analysis, the gene expression model differentiated between good and poor responders regardless of the TKI used, Dr. Radich said.
The findings are of note because achieving sustained deep molecular response is necessary before CML patients can attempt treatment-free remission and because biomarkers for predicting DMR have been lacking, he explained.
“These findings could really be used, potentially, for a couple of things: One is to predict response, and that could drive patient goals, expectations, and maybe drug choice,” he said.
The findings could also be used to inform clinical trials to investigate how to best treat poor responders to improve their response, he added.
“I think there’s a lot of work to be done and a lot things to chew over, and we’re hoping that we’ll have more to talk to you about in the future,” he said.
The study was sponsored by Novartis. Dr. Radich is a paid consultant for Genentech, Cepheid, Bristol-Myers Squibb, Takeda, and Novartis.
SOURCE: Radich JP et al. SOHO 2020, Abstract CML-109.
Baseline gene expression in patients with chronic myeloid leukemia (CML) who received tyrosine kinase inhibitor (TKI) therapy in the phase 3 ENESTnd trial differentiated those who achieved a good response from those with a poor response at 5 years in an exploratory analysis.
The investigators developed gene-expression models based on RNA sequencing of whole blood samples collected prior to treatment with nilotinib or imatinib in study participants who completed at least 5 years of therapy, including both good responders – those who achieved a major molecular response (MMR), defined as BCR-ABL1IS (a gene sequence found in an abnormal chromosome 22) less than 0.01% by 12 months and sustained deep molecular response (DMR) by 5 years, and poor responders – those without MMR by 12 months or with BCR-ABL1IS greater than 10% at 3 months.
A model based on the comparison of gene signatures from 47 patients who achieved a molecular response of 4.5 (MR4.5) on the International Scale (BCR-ABL1S less than 0.00032%), compared with 23 patients with a poor response, best predicted 5-year responder status (area under the receiver operating characteristic curve, 0.76), Jerald P. Radich, MD, reported during the Society of Hematologic Oncology virtual meeting.
“For this kind of work, that’s really quite good,” said Dr. Radich of the clinical research division at Fred Hutchinson Cancer Research Center, Seattle.
Notably, the differences in patient responses observed by 12 months in ENESTnd persisted for up to 10 years, he said.
The findings have potential implications for drug development and facilitation of DMR in patients on TKI therapy – a prerequisite for attempting treatment-free remission, he said.
Dr. Radich and colleagues assessed 24 clinical factors – such as Sokal risk score, TKI therapy type, age, and sex – according to responder status, and applied penalized regression to the clinical variables, to expression of 13,575 genes, and to a combination of the clinical variables and gene expression.
Clinical variables didn’t predict response in the trial, and including the clinical variables in the gene-expression model in the exploratory analysis did not improve it’s performance (AUC, 0.75). However, both the MR4.5 plus clinical variables model and the MR4.5-only model outperformed the clinical variables–only model (AUC, 0.59), he noted, adding: “So gene expression seems to be highly correlated with response.”
Of note, 458 genes were differentially expressed; those found in responders were most often associated with immune response, whereas those in poor responders were more likely to be associated with drug catabolism, WNT signaling, and cell cycle.
This suggests that good responders, compared with poor responders, have an activated immune system that is better able to engage after TKI therapy is administered to “cull through the heard, so to speak,” Dr. Radich said.
The findings were validated in an independent dataset of 19 good responders and 25 poor responders (AUC, 0.67 for the MR4.5 vs. poor-responder model).
A comparison of the expression of immune cell marker genes in good responders and poor responders further showed that T cells – particularly CD8 T cells, B cells, natural killer cells, and aggregate cytotoxic lymphocytes were expressed at significantly higher levels in good responders.
This was true in both the ENESTnd cohort and the validation dataset, he said.
The ENESTnd study is a randomized, open-label study comparing nilotinib and imatinib in adults with newly diagnosed Philadelphia chromosome–positive chronic-phase CML. A 5-year study update published in 2016 showed that 54% and 52% of patients in nilotinib 300- and 400-mg twice-daily arms, respectively, achieved MR4.5, compared with 31% of those in an imatinib 400-mg once-daily arm. In the current exploratory analysis, the gene expression model differentiated between good and poor responders regardless of the TKI used, Dr. Radich said.
The findings are of note because achieving sustained deep molecular response is necessary before CML patients can attempt treatment-free remission and because biomarkers for predicting DMR have been lacking, he explained.
“These findings could really be used, potentially, for a couple of things: One is to predict response, and that could drive patient goals, expectations, and maybe drug choice,” he said.
The findings could also be used to inform clinical trials to investigate how to best treat poor responders to improve their response, he added.
“I think there’s a lot of work to be done and a lot things to chew over, and we’re hoping that we’ll have more to talk to you about in the future,” he said.
The study was sponsored by Novartis. Dr. Radich is a paid consultant for Genentech, Cepheid, Bristol-Myers Squibb, Takeda, and Novartis.
SOURCE: Radich JP et al. SOHO 2020, Abstract CML-109.
Baseline gene expression in patients with chronic myeloid leukemia (CML) who received tyrosine kinase inhibitor (TKI) therapy in the phase 3 ENESTnd trial differentiated those who achieved a good response from those with a poor response at 5 years in an exploratory analysis.
The investigators developed gene-expression models based on RNA sequencing of whole blood samples collected prior to treatment with nilotinib or imatinib in study participants who completed at least 5 years of therapy, including both good responders – those who achieved a major molecular response (MMR), defined as BCR-ABL1IS (a gene sequence found in an abnormal chromosome 22) less than 0.01% by 12 months and sustained deep molecular response (DMR) by 5 years, and poor responders – those without MMR by 12 months or with BCR-ABL1IS greater than 10% at 3 months.
A model based on the comparison of gene signatures from 47 patients who achieved a molecular response of 4.5 (MR4.5) on the International Scale (BCR-ABL1S less than 0.00032%), compared with 23 patients with a poor response, best predicted 5-year responder status (area under the receiver operating characteristic curve, 0.76), Jerald P. Radich, MD, reported during the Society of Hematologic Oncology virtual meeting.
“For this kind of work, that’s really quite good,” said Dr. Radich of the clinical research division at Fred Hutchinson Cancer Research Center, Seattle.
Notably, the differences in patient responses observed by 12 months in ENESTnd persisted for up to 10 years, he said.
The findings have potential implications for drug development and facilitation of DMR in patients on TKI therapy – a prerequisite for attempting treatment-free remission, he said.
Dr. Radich and colleagues assessed 24 clinical factors – such as Sokal risk score, TKI therapy type, age, and sex – according to responder status, and applied penalized regression to the clinical variables, to expression of 13,575 genes, and to a combination of the clinical variables and gene expression.
Clinical variables didn’t predict response in the trial, and including the clinical variables in the gene-expression model in the exploratory analysis did not improve it’s performance (AUC, 0.75). However, both the MR4.5 plus clinical variables model and the MR4.5-only model outperformed the clinical variables–only model (AUC, 0.59), he noted, adding: “So gene expression seems to be highly correlated with response.”
Of note, 458 genes were differentially expressed; those found in responders were most often associated with immune response, whereas those in poor responders were more likely to be associated with drug catabolism, WNT signaling, and cell cycle.
This suggests that good responders, compared with poor responders, have an activated immune system that is better able to engage after TKI therapy is administered to “cull through the heard, so to speak,” Dr. Radich said.
The findings were validated in an independent dataset of 19 good responders and 25 poor responders (AUC, 0.67 for the MR4.5 vs. poor-responder model).
A comparison of the expression of immune cell marker genes in good responders and poor responders further showed that T cells – particularly CD8 T cells, B cells, natural killer cells, and aggregate cytotoxic lymphocytes were expressed at significantly higher levels in good responders.
This was true in both the ENESTnd cohort and the validation dataset, he said.
The ENESTnd study is a randomized, open-label study comparing nilotinib and imatinib in adults with newly diagnosed Philadelphia chromosome–positive chronic-phase CML. A 5-year study update published in 2016 showed that 54% and 52% of patients in nilotinib 300- and 400-mg twice-daily arms, respectively, achieved MR4.5, compared with 31% of those in an imatinib 400-mg once-daily arm. In the current exploratory analysis, the gene expression model differentiated between good and poor responders regardless of the TKI used, Dr. Radich said.
The findings are of note because achieving sustained deep molecular response is necessary before CML patients can attempt treatment-free remission and because biomarkers for predicting DMR have been lacking, he explained.
“These findings could really be used, potentially, for a couple of things: One is to predict response, and that could drive patient goals, expectations, and maybe drug choice,” he said.
The findings could also be used to inform clinical trials to investigate how to best treat poor responders to improve their response, he added.
“I think there’s a lot of work to be done and a lot things to chew over, and we’re hoping that we’ll have more to talk to you about in the future,” he said.
The study was sponsored by Novartis. Dr. Radich is a paid consultant for Genentech, Cepheid, Bristol-Myers Squibb, Takeda, and Novartis.
SOURCE: Radich JP et al. SOHO 2020, Abstract CML-109.
FROM SOHO 2020
RAP device being investigated as a way to improve appearance of cellulite
.
“The procedure is relatively painless, without anesthesia and can easily be delegated with physician oversight,” Mathew M. Avram, MD, JD, said during the virtual annual Masters of Aesthetics Symposium. “Side effects have been minimal and transient to date. There is no down time.”
According to Dr. Avram, director of laser, cosmetics, and dermatologic surgery at Massachusetts General Hospital, Boston, the RAP device emits rapid acoustic pulses (shock waves) that are transmitted through the skin to rupture or “shear” the fibrotic septa. This causes the release of septa, which results in a smoothening of skin dimples.
“Basically, what you have is a repetition rate and very short rise time that provide microscopic mechanical disruption to the targeted cellular level structures and vacuoles,” Dr. Avram explained. “There’s a high leak pressure and fast repetition rate that exploits the viscoelastic nature of the tissue. You get compressed pulses from electronic filtering and the reflector shape eliminates cavitation, heat, and pain.”
The procedure takes 20-30 minutes to perform and it generates minimal heat and pain, “which is an advantage of the treatment,” he said. “It is completely noninvasive, with no incision whatsoever. No anesthetic is required. There can be physician oversight of delivery, so it is delegable, and there is no recovery time. More study is needed, and we need to stay tuned.”
Dr. Avram disclosed that he has received consulting fees from Allergan, Merz, Sciton, and Soliton. He also reported having ownership and/or shareholder interest in Cytrellis.
.
“The procedure is relatively painless, without anesthesia and can easily be delegated with physician oversight,” Mathew M. Avram, MD, JD, said during the virtual annual Masters of Aesthetics Symposium. “Side effects have been minimal and transient to date. There is no down time.”
According to Dr. Avram, director of laser, cosmetics, and dermatologic surgery at Massachusetts General Hospital, Boston, the RAP device emits rapid acoustic pulses (shock waves) that are transmitted through the skin to rupture or “shear” the fibrotic septa. This causes the release of septa, which results in a smoothening of skin dimples.
“Basically, what you have is a repetition rate and very short rise time that provide microscopic mechanical disruption to the targeted cellular level structures and vacuoles,” Dr. Avram explained. “There’s a high leak pressure and fast repetition rate that exploits the viscoelastic nature of the tissue. You get compressed pulses from electronic filtering and the reflector shape eliminates cavitation, heat, and pain.”
The procedure takes 20-30 minutes to perform and it generates minimal heat and pain, “which is an advantage of the treatment,” he said. “It is completely noninvasive, with no incision whatsoever. No anesthetic is required. There can be physician oversight of delivery, so it is delegable, and there is no recovery time. More study is needed, and we need to stay tuned.”
Dr. Avram disclosed that he has received consulting fees from Allergan, Merz, Sciton, and Soliton. He also reported having ownership and/or shareholder interest in Cytrellis.
.
“The procedure is relatively painless, without anesthesia and can easily be delegated with physician oversight,” Mathew M. Avram, MD, JD, said during the virtual annual Masters of Aesthetics Symposium. “Side effects have been minimal and transient to date. There is no down time.”
According to Dr. Avram, director of laser, cosmetics, and dermatologic surgery at Massachusetts General Hospital, Boston, the RAP device emits rapid acoustic pulses (shock waves) that are transmitted through the skin to rupture or “shear” the fibrotic septa. This causes the release of septa, which results in a smoothening of skin dimples.
“Basically, what you have is a repetition rate and very short rise time that provide microscopic mechanical disruption to the targeted cellular level structures and vacuoles,” Dr. Avram explained. “There’s a high leak pressure and fast repetition rate that exploits the viscoelastic nature of the tissue. You get compressed pulses from electronic filtering and the reflector shape eliminates cavitation, heat, and pain.”
The procedure takes 20-30 minutes to perform and it generates minimal heat and pain, “which is an advantage of the treatment,” he said. “It is completely noninvasive, with no incision whatsoever. No anesthetic is required. There can be physician oversight of delivery, so it is delegable, and there is no recovery time. More study is needed, and we need to stay tuned.”
Dr. Avram disclosed that he has received consulting fees from Allergan, Merz, Sciton, and Soliton. He also reported having ownership and/or shareholder interest in Cytrellis.
FROM MOA 2020
HMAs plus novel agents may improve outcomes in higher-risk MDS
Several recently approved and late-phase investigational agents may improve care for patients with higher risk myelodysplastic syndrome (MDS) by augmenting hypomethylating agents (HMAs), which are the current standard of care.
“HMA failure remains a challenge, and new approaches, such as ex vivo drug screening, are needed to improve outcomes,” said Brian A. Jonas, MD, PhD, from the University of California, Davis, in an online presentation during the virtual American Society of Hematology (ASH) Meeting on Hematologic Malignancies.
The goal of treatment for patients with higher-risk MDS – defined as a Revised International Prognostic Scoring System (R-IPSS) intermediate, high-risk, or very high–risk category – is to alter as much as possible the natural history of the disease.
Treatment options include monotherapy with HMAs, HMAs in combination with other agents, high-intensity chemotherapy, allogeneic hematopoietic stem cell transplant (allo-HSCT), or a clinical trial, Dr. Jonas said.
Improving bioavailability
Although HMAs, either azacitidine or decitabine, remain the standard of care for patients with higher-risk MDS, the oral bioavailability of these agents is limited by the rapid clearance of cytidine deaminase in the gut and liver.
But as Savona and colleagues reported in The Lancet Haematology, the combination of oral decitabine with cedazuridine, a novel cytidine deaminase inhibitor, significantly improved the bioavailability of the HMA, with an efficacy comparable to that of intravenous decitabine. The findings were confirmed by results from the phase 2 ASCERTAIN trial.
The combination (Inqovi) was approved by the US Food and Drug Administration in July 2020 for the treatment of MDS and chronic myelomonocytic leukemia in IPSS intermediate-1 or higher risk categories. The approved dose is 35 mg decitabine and 100 mg cedazuridine in a single oral tablet once daily on days 1 through 5 of each 28-day cycle.
New drugs, potential new targets
Another promising approach to improving HMA therapy is the combination of azacitidine and the BCL-2 inhibitor venetoclax (Venclexta).
Results of a phase 1b study of the combination as first-line therapy for patients with higher-risk MDS showed a combined complete response and marrow complete response rate of 77.2%, with estimated 6-month and 12-month survival rates of 100% and 93.8%, respectively, for patients who had a complete response and 85.9% at both 6 and 12 months for patients with a marrow complete response.
“The question is does this challenge the standard of care for higher-risk MDS? I would argue that many are using the regimen since the abstract came out, and I myself consider this regimen for use in select patients with high–blast count MDS who are maybe going to transplant or need to have their disease controlled rapidly,” Dr. Jonas said.
A randomized trial of the combination (NCT04401748) is currently recruiting.
Novel checkpoint inhibitor
Another promising combination pairs azacitidine with magrolimab, an experimental immune checkpoint inhibitor that targets CD47, the “don’t eat me” signal that inhibits macrophages from carrying out their crucial phagocytosis role.
As previously reported, magrolimab in combination with rituximab showed good efficacy in patients with relapsed or refractory indolent or aggressive non-Hodgkin lymphomas, and more recently showed promise in combination with azacitidine in a phase 1b study for the treatment of MDS and acute myeloid leukemia (AML).
Among patients with MDS in the trial, the overall response rate was 91% (30 of 33 patients). In all, 14 patients had complete responses, one had a partial response, eight had marrow complete responses, and seven had hematologic improvement.
The tolerability profile was similar to that seen with azacitidine monotherapy, with no significant worsening of cytopenias or infections or autoimmune adverse events. There were no deaths in the first 60 days on therapy, and no treatment discontinuation for drug-related adverse events.
Azacitidine was paired with a different novel agent, APR-246 in a clinical trial testing the combination in patients with TP53 mutant MDS and AML. APR-246 is a novel, first-in-class small molecule that binds covalently to p53, and selectively induces apoptosis in metastatic TP53 cells via thermodynamically stabilizing the p53 protein and shifting equilibrium toward the wild-type conformation.
Among 33 evaluable patients with higher-risk MDS, the combination was associated with an overall response in 29 (81%) including 20 patients (61%) with a complete response. After a median follow-up of 10.8 months, the median duration of response was 7.3 months, and 17 patients went on to allo-HSCT.
The combination of magrolimab and azacitidine has also shown preliminary activity in TP53-mutated MDS, Dr. Jonas noted.
HMA-refractory disease
Patients who experience disease progression to AML or to higher-risk MDS; have stable disease but no complete, partial, or marrow responses; or have hematologic improvement after four to six cycles of HMA may have primary resistance to this class of agents. Patients can also have disease that develops resistance to HMAs after an initial response.
“Unfortunately, the prognosis is very dismal for these patients,” with a median overall survival of 5.6 months and 2-year overall survival of just 15%, Dr. Jonas said.
As reported at the 2019 ASH annual meeting, in patients with relapsed/refractory MDS, venetoclax plus azacitidine was associated with a median progression-free survival of 9.1 months versus 3.3 months for venetoclax alone, and a median overall survival for the combination that was not reached, with a 12-month overall survival estimate of 65%. The median overall survival with venetoclax monotherapy was 5.5 months.
Adverse events included cytopenias, gastrointestinal events, and infections in both arms (ASH 2019 Abstract 565).
There are also data to suggest benefits of the isocitrate dehydrogenase inhibitors ivosidenib in patients with HMA-refractory MDS with IDH1 mutations and enasidenib in patients with HMA-refractory MDS with IDH2 mutations, Dr. Jonas said.
Finally, he described a pilot and feasibility study of ex vivo screening of myeloid neoplasms for drug sensitivity conducted at Stanford (Calif.) University. In 21 patients with HMA-refractory MDS, the ex vivo screening system provided results in a clinically actionable time frame comparable to that of a 596-gene panel. The positive predictive value of the screen was 92%, the negative predictive value was 82%, and the accuracy was 85%.
“This looks like a potentially promising approach to offer personalized therapy in patients with MDS,” he said.
No funding source for the presentation was reported. Dr. Jonas disclosed consulting activities for AbbVie, Celgen, GlycoMimetics, Jazz, Takeda, Tolero, and Treadwell; institutional research funding from multiple companies; and discussion of off-label use of various drugs not specifically approved for MDS.
Several recently approved and late-phase investigational agents may improve care for patients with higher risk myelodysplastic syndrome (MDS) by augmenting hypomethylating agents (HMAs), which are the current standard of care.
“HMA failure remains a challenge, and new approaches, such as ex vivo drug screening, are needed to improve outcomes,” said Brian A. Jonas, MD, PhD, from the University of California, Davis, in an online presentation during the virtual American Society of Hematology (ASH) Meeting on Hematologic Malignancies.
The goal of treatment for patients with higher-risk MDS – defined as a Revised International Prognostic Scoring System (R-IPSS) intermediate, high-risk, or very high–risk category – is to alter as much as possible the natural history of the disease.
Treatment options include monotherapy with HMAs, HMAs in combination with other agents, high-intensity chemotherapy, allogeneic hematopoietic stem cell transplant (allo-HSCT), or a clinical trial, Dr. Jonas said.
Improving bioavailability
Although HMAs, either azacitidine or decitabine, remain the standard of care for patients with higher-risk MDS, the oral bioavailability of these agents is limited by the rapid clearance of cytidine deaminase in the gut and liver.
But as Savona and colleagues reported in The Lancet Haematology, the combination of oral decitabine with cedazuridine, a novel cytidine deaminase inhibitor, significantly improved the bioavailability of the HMA, with an efficacy comparable to that of intravenous decitabine. The findings were confirmed by results from the phase 2 ASCERTAIN trial.
The combination (Inqovi) was approved by the US Food and Drug Administration in July 2020 for the treatment of MDS and chronic myelomonocytic leukemia in IPSS intermediate-1 or higher risk categories. The approved dose is 35 mg decitabine and 100 mg cedazuridine in a single oral tablet once daily on days 1 through 5 of each 28-day cycle.
New drugs, potential new targets
Another promising approach to improving HMA therapy is the combination of azacitidine and the BCL-2 inhibitor venetoclax (Venclexta).
Results of a phase 1b study of the combination as first-line therapy for patients with higher-risk MDS showed a combined complete response and marrow complete response rate of 77.2%, with estimated 6-month and 12-month survival rates of 100% and 93.8%, respectively, for patients who had a complete response and 85.9% at both 6 and 12 months for patients with a marrow complete response.
“The question is does this challenge the standard of care for higher-risk MDS? I would argue that many are using the regimen since the abstract came out, and I myself consider this regimen for use in select patients with high–blast count MDS who are maybe going to transplant or need to have their disease controlled rapidly,” Dr. Jonas said.
A randomized trial of the combination (NCT04401748) is currently recruiting.
Novel checkpoint inhibitor
Another promising combination pairs azacitidine with magrolimab, an experimental immune checkpoint inhibitor that targets CD47, the “don’t eat me” signal that inhibits macrophages from carrying out their crucial phagocytosis role.
As previously reported, magrolimab in combination with rituximab showed good efficacy in patients with relapsed or refractory indolent or aggressive non-Hodgkin lymphomas, and more recently showed promise in combination with azacitidine in a phase 1b study for the treatment of MDS and acute myeloid leukemia (AML).
Among patients with MDS in the trial, the overall response rate was 91% (30 of 33 patients). In all, 14 patients had complete responses, one had a partial response, eight had marrow complete responses, and seven had hematologic improvement.
The tolerability profile was similar to that seen with azacitidine monotherapy, with no significant worsening of cytopenias or infections or autoimmune adverse events. There were no deaths in the first 60 days on therapy, and no treatment discontinuation for drug-related adverse events.
Azacitidine was paired with a different novel agent, APR-246 in a clinical trial testing the combination in patients with TP53 mutant MDS and AML. APR-246 is a novel, first-in-class small molecule that binds covalently to p53, and selectively induces apoptosis in metastatic TP53 cells via thermodynamically stabilizing the p53 protein and shifting equilibrium toward the wild-type conformation.
Among 33 evaluable patients with higher-risk MDS, the combination was associated with an overall response in 29 (81%) including 20 patients (61%) with a complete response. After a median follow-up of 10.8 months, the median duration of response was 7.3 months, and 17 patients went on to allo-HSCT.
The combination of magrolimab and azacitidine has also shown preliminary activity in TP53-mutated MDS, Dr. Jonas noted.
HMA-refractory disease
Patients who experience disease progression to AML or to higher-risk MDS; have stable disease but no complete, partial, or marrow responses; or have hematologic improvement after four to six cycles of HMA may have primary resistance to this class of agents. Patients can also have disease that develops resistance to HMAs after an initial response.
“Unfortunately, the prognosis is very dismal for these patients,” with a median overall survival of 5.6 months and 2-year overall survival of just 15%, Dr. Jonas said.
As reported at the 2019 ASH annual meeting, in patients with relapsed/refractory MDS, venetoclax plus azacitidine was associated with a median progression-free survival of 9.1 months versus 3.3 months for venetoclax alone, and a median overall survival for the combination that was not reached, with a 12-month overall survival estimate of 65%. The median overall survival with venetoclax monotherapy was 5.5 months.
Adverse events included cytopenias, gastrointestinal events, and infections in both arms (ASH 2019 Abstract 565).
There are also data to suggest benefits of the isocitrate dehydrogenase inhibitors ivosidenib in patients with HMA-refractory MDS with IDH1 mutations and enasidenib in patients with HMA-refractory MDS with IDH2 mutations, Dr. Jonas said.
Finally, he described a pilot and feasibility study of ex vivo screening of myeloid neoplasms for drug sensitivity conducted at Stanford (Calif.) University. In 21 patients with HMA-refractory MDS, the ex vivo screening system provided results in a clinically actionable time frame comparable to that of a 596-gene panel. The positive predictive value of the screen was 92%, the negative predictive value was 82%, and the accuracy was 85%.
“This looks like a potentially promising approach to offer personalized therapy in patients with MDS,” he said.
No funding source for the presentation was reported. Dr. Jonas disclosed consulting activities for AbbVie, Celgen, GlycoMimetics, Jazz, Takeda, Tolero, and Treadwell; institutional research funding from multiple companies; and discussion of off-label use of various drugs not specifically approved for MDS.
Several recently approved and late-phase investigational agents may improve care for patients with higher risk myelodysplastic syndrome (MDS) by augmenting hypomethylating agents (HMAs), which are the current standard of care.
“HMA failure remains a challenge, and new approaches, such as ex vivo drug screening, are needed to improve outcomes,” said Brian A. Jonas, MD, PhD, from the University of California, Davis, in an online presentation during the virtual American Society of Hematology (ASH) Meeting on Hematologic Malignancies.
The goal of treatment for patients with higher-risk MDS – defined as a Revised International Prognostic Scoring System (R-IPSS) intermediate, high-risk, or very high–risk category – is to alter as much as possible the natural history of the disease.
Treatment options include monotherapy with HMAs, HMAs in combination with other agents, high-intensity chemotherapy, allogeneic hematopoietic stem cell transplant (allo-HSCT), or a clinical trial, Dr. Jonas said.
Improving bioavailability
Although HMAs, either azacitidine or decitabine, remain the standard of care for patients with higher-risk MDS, the oral bioavailability of these agents is limited by the rapid clearance of cytidine deaminase in the gut and liver.
But as Savona and colleagues reported in The Lancet Haematology, the combination of oral decitabine with cedazuridine, a novel cytidine deaminase inhibitor, significantly improved the bioavailability of the HMA, with an efficacy comparable to that of intravenous decitabine. The findings were confirmed by results from the phase 2 ASCERTAIN trial.
The combination (Inqovi) was approved by the US Food and Drug Administration in July 2020 for the treatment of MDS and chronic myelomonocytic leukemia in IPSS intermediate-1 or higher risk categories. The approved dose is 35 mg decitabine and 100 mg cedazuridine in a single oral tablet once daily on days 1 through 5 of each 28-day cycle.
New drugs, potential new targets
Another promising approach to improving HMA therapy is the combination of azacitidine and the BCL-2 inhibitor venetoclax (Venclexta).
Results of a phase 1b study of the combination as first-line therapy for patients with higher-risk MDS showed a combined complete response and marrow complete response rate of 77.2%, with estimated 6-month and 12-month survival rates of 100% and 93.8%, respectively, for patients who had a complete response and 85.9% at both 6 and 12 months for patients with a marrow complete response.
“The question is does this challenge the standard of care for higher-risk MDS? I would argue that many are using the regimen since the abstract came out, and I myself consider this regimen for use in select patients with high–blast count MDS who are maybe going to transplant or need to have their disease controlled rapidly,” Dr. Jonas said.
A randomized trial of the combination (NCT04401748) is currently recruiting.
Novel checkpoint inhibitor
Another promising combination pairs azacitidine with magrolimab, an experimental immune checkpoint inhibitor that targets CD47, the “don’t eat me” signal that inhibits macrophages from carrying out their crucial phagocytosis role.
As previously reported, magrolimab in combination with rituximab showed good efficacy in patients with relapsed or refractory indolent or aggressive non-Hodgkin lymphomas, and more recently showed promise in combination with azacitidine in a phase 1b study for the treatment of MDS and acute myeloid leukemia (AML).
Among patients with MDS in the trial, the overall response rate was 91% (30 of 33 patients). In all, 14 patients had complete responses, one had a partial response, eight had marrow complete responses, and seven had hematologic improvement.
The tolerability profile was similar to that seen with azacitidine monotherapy, with no significant worsening of cytopenias or infections or autoimmune adverse events. There were no deaths in the first 60 days on therapy, and no treatment discontinuation for drug-related adverse events.
Azacitidine was paired with a different novel agent, APR-246 in a clinical trial testing the combination in patients with TP53 mutant MDS and AML. APR-246 is a novel, first-in-class small molecule that binds covalently to p53, and selectively induces apoptosis in metastatic TP53 cells via thermodynamically stabilizing the p53 protein and shifting equilibrium toward the wild-type conformation.
Among 33 evaluable patients with higher-risk MDS, the combination was associated with an overall response in 29 (81%) including 20 patients (61%) with a complete response. After a median follow-up of 10.8 months, the median duration of response was 7.3 months, and 17 patients went on to allo-HSCT.
The combination of magrolimab and azacitidine has also shown preliminary activity in TP53-mutated MDS, Dr. Jonas noted.
HMA-refractory disease
Patients who experience disease progression to AML or to higher-risk MDS; have stable disease but no complete, partial, or marrow responses; or have hematologic improvement after four to six cycles of HMA may have primary resistance to this class of agents. Patients can also have disease that develops resistance to HMAs after an initial response.
“Unfortunately, the prognosis is very dismal for these patients,” with a median overall survival of 5.6 months and 2-year overall survival of just 15%, Dr. Jonas said.
As reported at the 2019 ASH annual meeting, in patients with relapsed/refractory MDS, venetoclax plus azacitidine was associated with a median progression-free survival of 9.1 months versus 3.3 months for venetoclax alone, and a median overall survival for the combination that was not reached, with a 12-month overall survival estimate of 65%. The median overall survival with venetoclax monotherapy was 5.5 months.
Adverse events included cytopenias, gastrointestinal events, and infections in both arms (ASH 2019 Abstract 565).
There are also data to suggest benefits of the isocitrate dehydrogenase inhibitors ivosidenib in patients with HMA-refractory MDS with IDH1 mutations and enasidenib in patients with HMA-refractory MDS with IDH2 mutations, Dr. Jonas said.
Finally, he described a pilot and feasibility study of ex vivo screening of myeloid neoplasms for drug sensitivity conducted at Stanford (Calif.) University. In 21 patients with HMA-refractory MDS, the ex vivo screening system provided results in a clinically actionable time frame comparable to that of a 596-gene panel. The positive predictive value of the screen was 92%, the negative predictive value was 82%, and the accuracy was 85%.
“This looks like a potentially promising approach to offer personalized therapy in patients with MDS,” he said.
No funding source for the presentation was reported. Dr. Jonas disclosed consulting activities for AbbVie, Celgen, GlycoMimetics, Jazz, Takeda, Tolero, and Treadwell; institutional research funding from multiple companies; and discussion of off-label use of various drugs not specifically approved for MDS.
FROM ASH HEMATOLOGIC MALIGNANCIES
Large waistline linked to higher risk of prostate cancer death
Men with prostate cancer may be wise to watch their waistlines, according to the findings of a large observational study in which patients with the highest waist measurements had a higher chance of dying from prostate cancer.
Researchers found that, over a 10.8-year period, men with the largest waist circumferences appeared 35% more likely to die from prostate cancer, when compared to men with the smallest waist circumferences (hazard ratio = 1.35, 95% confidence interval [CI], 1.05–1.73).
Men in the highest quartile for waist-to-hip ratio measurements also had a 34% higher risk of dying from prostate cancer, when compared to men in the lowest quartile (HR = 1.34, 95% CI, 1.04–1.72).
There was no association between the total body fat percentage (HR = 1.00, 95% CI, 0.79–1.28) or body mass index (HR = 1.00, 95% CI, 0.78–1.28) and the risk for prostate cancer death.
The findings – reported in a late-breaking poster at the European and International Conference on Obesity (ECOICO) – provide further insight into how fat and its distribution may be associated with prostate cancer death.
A ‘complex’ relationship
“Obesity is a known risk factor for many cancer sites, but its association with prostate cancer is less clear. It’s very complex,” said study investigator Aurora Pérez-Cornago, PhD, a nutritional epidemiologist in the Nuffield Department of Population Health at University of Oxford, England.
Three years ago, Dr. Pérez-Cornago and collaborators looked for risk factors for prostate cancer among men who had volunteered to participate in the prospective UK Biobank cohort study.
One of the group’s findings was that excess adiposity and body fat were not associated with an increase in the development of prostate cancer (Br J Cancer. 2017 Nov 7;117[10]:1562-71). In fact, these factors were associated with a lower risk. This inverse association likely had more to do with prostate-specific antigen screening than a true effect of body weight, as men with obesity were potentially less likely to be screened or have lower prostate-specific antigen levels, Dr. Pérez-Cornago said.
For the present study, attention was turned to men with aggressive prostate tumors as “these are the kind of tumors we are more interested in because they are the ones that can kill these men,” Dr. Pérez-Cornago said.
There was also previous evidence suggesting that adiposity may be associated with a higher risk of aggressive disease.
Data on 218,225 men with no previous cancer when they enrolled in the UK Biobank cohort study were linked to health care administrative databases that provided information on prostate cancer deaths. This showed that 571 men died from prostate cancer over a 10.8-year follow-up period.
“When we looked at the association of adiposity measurements – we looked at [body mass index] and body fat percentage as markers of total adiposity, and waist circumference and waist-to-hip ratio as markers of central adiposity – we found that the association seems to be more specific for fat located around the waist,” Dr. Pérez-Cornago said.
“Excessive fat accumulation around your belly is likely to be visceral fat, which may induce metabolic and hormonal dysfunction that, in turn, may help prostate cancer cells to develop and to progress,” she added.
Study strengths and next steps
As this was an observational study, the researchers could not confirm a causal association between central adiposity and prostate cancer death. That is why Dr. Perez-Cornago and collaborators plan to do further work that will include biomarker studies. The team also will look at stage and grade data when available in the UK Biobank.
“There is strong evidence that men with greater body fat are at a higher risk of advanced and fatal prostate cancer. It is time to build on this,” said Barbra Dickerman, PhD, who has looked at the relationship between obesity and prostate cancer progression (Cancer. 2019 Aug 15;125[16]:2877-85).
“First, predictive analyses of directly measured body fat distribution may sharpen our view of who is at the highest risk,” observed Dr. Dickerman, a research fellow in the department of epidemiology at Harvard T.H. Chan School of Public Health in Boston.
“Second, causal analyses of precisely defined energy balance strategies may help to identify targeted prevention strategies that minimize that risk,” she added.
One of the strengths of Dr. Pérez-Cornago’s work was that it used data from a large, prospective study to examine the link between adiposity and the risk of fatal prostate cancer, observed Ying Wang, PhD, a senior principal scientist of epidemiology research at The American Cancer Society.
“In addition to the large sample size, anthropometric measurements were obtained by trained research clinic staff rather than self-reported by participants, which is a strength compared with many other studies,” Dr. Wang noted.
Furthermore, Dr. Wang said, “The study was also able to control for multiple confounders, including lifestyle factors such as smoking and physical activity. Future studies need to confirm their findings.”
The study was supported by a fellowship from Cancer Research UK. The investigators, Dr. Dickerman, and Dr. Wang had no conflicts of interest to disclose.
SOURCE: Pérez-Cornago A et al. ECOICO 2020. LBP-075.
Men with prostate cancer may be wise to watch their waistlines, according to the findings of a large observational study in which patients with the highest waist measurements had a higher chance of dying from prostate cancer.
Researchers found that, over a 10.8-year period, men with the largest waist circumferences appeared 35% more likely to die from prostate cancer, when compared to men with the smallest waist circumferences (hazard ratio = 1.35, 95% confidence interval [CI], 1.05–1.73).
Men in the highest quartile for waist-to-hip ratio measurements also had a 34% higher risk of dying from prostate cancer, when compared to men in the lowest quartile (HR = 1.34, 95% CI, 1.04–1.72).
There was no association between the total body fat percentage (HR = 1.00, 95% CI, 0.79–1.28) or body mass index (HR = 1.00, 95% CI, 0.78–1.28) and the risk for prostate cancer death.
The findings – reported in a late-breaking poster at the European and International Conference on Obesity (ECOICO) – provide further insight into how fat and its distribution may be associated with prostate cancer death.
A ‘complex’ relationship
“Obesity is a known risk factor for many cancer sites, but its association with prostate cancer is less clear. It’s very complex,” said study investigator Aurora Pérez-Cornago, PhD, a nutritional epidemiologist in the Nuffield Department of Population Health at University of Oxford, England.
Three years ago, Dr. Pérez-Cornago and collaborators looked for risk factors for prostate cancer among men who had volunteered to participate in the prospective UK Biobank cohort study.
One of the group’s findings was that excess adiposity and body fat were not associated with an increase in the development of prostate cancer (Br J Cancer. 2017 Nov 7;117[10]:1562-71). In fact, these factors were associated with a lower risk. This inverse association likely had more to do with prostate-specific antigen screening than a true effect of body weight, as men with obesity were potentially less likely to be screened or have lower prostate-specific antigen levels, Dr. Pérez-Cornago said.
For the present study, attention was turned to men with aggressive prostate tumors as “these are the kind of tumors we are more interested in because they are the ones that can kill these men,” Dr. Pérez-Cornago said.
There was also previous evidence suggesting that adiposity may be associated with a higher risk of aggressive disease.
Data on 218,225 men with no previous cancer when they enrolled in the UK Biobank cohort study were linked to health care administrative databases that provided information on prostate cancer deaths. This showed that 571 men died from prostate cancer over a 10.8-year follow-up period.
“When we looked at the association of adiposity measurements – we looked at [body mass index] and body fat percentage as markers of total adiposity, and waist circumference and waist-to-hip ratio as markers of central adiposity – we found that the association seems to be more specific for fat located around the waist,” Dr. Pérez-Cornago said.
“Excessive fat accumulation around your belly is likely to be visceral fat, which may induce metabolic and hormonal dysfunction that, in turn, may help prostate cancer cells to develop and to progress,” she added.
Study strengths and next steps
As this was an observational study, the researchers could not confirm a causal association between central adiposity and prostate cancer death. That is why Dr. Perez-Cornago and collaborators plan to do further work that will include biomarker studies. The team also will look at stage and grade data when available in the UK Biobank.
“There is strong evidence that men with greater body fat are at a higher risk of advanced and fatal prostate cancer. It is time to build on this,” said Barbra Dickerman, PhD, who has looked at the relationship between obesity and prostate cancer progression (Cancer. 2019 Aug 15;125[16]:2877-85).
“First, predictive analyses of directly measured body fat distribution may sharpen our view of who is at the highest risk,” observed Dr. Dickerman, a research fellow in the department of epidemiology at Harvard T.H. Chan School of Public Health in Boston.
“Second, causal analyses of precisely defined energy balance strategies may help to identify targeted prevention strategies that minimize that risk,” she added.
One of the strengths of Dr. Pérez-Cornago’s work was that it used data from a large, prospective study to examine the link between adiposity and the risk of fatal prostate cancer, observed Ying Wang, PhD, a senior principal scientist of epidemiology research at The American Cancer Society.
“In addition to the large sample size, anthropometric measurements were obtained by trained research clinic staff rather than self-reported by participants, which is a strength compared with many other studies,” Dr. Wang noted.
Furthermore, Dr. Wang said, “The study was also able to control for multiple confounders, including lifestyle factors such as smoking and physical activity. Future studies need to confirm their findings.”
The study was supported by a fellowship from Cancer Research UK. The investigators, Dr. Dickerman, and Dr. Wang had no conflicts of interest to disclose.
SOURCE: Pérez-Cornago A et al. ECOICO 2020. LBP-075.
Men with prostate cancer may be wise to watch their waistlines, according to the findings of a large observational study in which patients with the highest waist measurements had a higher chance of dying from prostate cancer.
Researchers found that, over a 10.8-year period, men with the largest waist circumferences appeared 35% more likely to die from prostate cancer, when compared to men with the smallest waist circumferences (hazard ratio = 1.35, 95% confidence interval [CI], 1.05–1.73).
Men in the highest quartile for waist-to-hip ratio measurements also had a 34% higher risk of dying from prostate cancer, when compared to men in the lowest quartile (HR = 1.34, 95% CI, 1.04–1.72).
There was no association between the total body fat percentage (HR = 1.00, 95% CI, 0.79–1.28) or body mass index (HR = 1.00, 95% CI, 0.78–1.28) and the risk for prostate cancer death.
The findings – reported in a late-breaking poster at the European and International Conference on Obesity (ECOICO) – provide further insight into how fat and its distribution may be associated with prostate cancer death.
A ‘complex’ relationship
“Obesity is a known risk factor for many cancer sites, but its association with prostate cancer is less clear. It’s very complex,” said study investigator Aurora Pérez-Cornago, PhD, a nutritional epidemiologist in the Nuffield Department of Population Health at University of Oxford, England.
Three years ago, Dr. Pérez-Cornago and collaborators looked for risk factors for prostate cancer among men who had volunteered to participate in the prospective UK Biobank cohort study.
One of the group’s findings was that excess adiposity and body fat were not associated with an increase in the development of prostate cancer (Br J Cancer. 2017 Nov 7;117[10]:1562-71). In fact, these factors were associated with a lower risk. This inverse association likely had more to do with prostate-specific antigen screening than a true effect of body weight, as men with obesity were potentially less likely to be screened or have lower prostate-specific antigen levels, Dr. Pérez-Cornago said.
For the present study, attention was turned to men with aggressive prostate tumors as “these are the kind of tumors we are more interested in because they are the ones that can kill these men,” Dr. Pérez-Cornago said.
There was also previous evidence suggesting that adiposity may be associated with a higher risk of aggressive disease.
Data on 218,225 men with no previous cancer when they enrolled in the UK Biobank cohort study were linked to health care administrative databases that provided information on prostate cancer deaths. This showed that 571 men died from prostate cancer over a 10.8-year follow-up period.
“When we looked at the association of adiposity measurements – we looked at [body mass index] and body fat percentage as markers of total adiposity, and waist circumference and waist-to-hip ratio as markers of central adiposity – we found that the association seems to be more specific for fat located around the waist,” Dr. Pérez-Cornago said.
“Excessive fat accumulation around your belly is likely to be visceral fat, which may induce metabolic and hormonal dysfunction that, in turn, may help prostate cancer cells to develop and to progress,” she added.
Study strengths and next steps
As this was an observational study, the researchers could not confirm a causal association between central adiposity and prostate cancer death. That is why Dr. Perez-Cornago and collaborators plan to do further work that will include biomarker studies. The team also will look at stage and grade data when available in the UK Biobank.
“There is strong evidence that men with greater body fat are at a higher risk of advanced and fatal prostate cancer. It is time to build on this,” said Barbra Dickerman, PhD, who has looked at the relationship between obesity and prostate cancer progression (Cancer. 2019 Aug 15;125[16]:2877-85).
“First, predictive analyses of directly measured body fat distribution may sharpen our view of who is at the highest risk,” observed Dr. Dickerman, a research fellow in the department of epidemiology at Harvard T.H. Chan School of Public Health in Boston.
“Second, causal analyses of precisely defined energy balance strategies may help to identify targeted prevention strategies that minimize that risk,” she added.
One of the strengths of Dr. Pérez-Cornago’s work was that it used data from a large, prospective study to examine the link between adiposity and the risk of fatal prostate cancer, observed Ying Wang, PhD, a senior principal scientist of epidemiology research at The American Cancer Society.
“In addition to the large sample size, anthropometric measurements were obtained by trained research clinic staff rather than self-reported by participants, which is a strength compared with many other studies,” Dr. Wang noted.
Furthermore, Dr. Wang said, “The study was also able to control for multiple confounders, including lifestyle factors such as smoking and physical activity. Future studies need to confirm their findings.”
The study was supported by a fellowship from Cancer Research UK. The investigators, Dr. Dickerman, and Dr. Wang had no conflicts of interest to disclose.
SOURCE: Pérez-Cornago A et al. ECOICO 2020. LBP-075.
FROM ECOICO 2020
COVID-19 and Blood Clots: Inside the Battle to Save Patients
Abnormal coagulation is a hallmark of COVID-19. Now, as we’re learning more about the high risk of thrombosis, physicians need to prescribe prophylaxis routinely in the hospital, stay alert, and act immediately when signs of trouble appear. “We must have a low suspicion for diagnosis and treatment of thrombosis,” said hematologist-oncologist Thomas DeLoughery, MD, professor of medicine at Oregon Health & Science University in Portland in a presentation at the virtual 2020 annual meeting of the Association of VA Hematology/Oncology (AVAHO).
Still, research is sparse, and there are disagreements about the best strategies to protect patients, said DeLoughery. Physicians recognized coagulation problems early on during the course of the COVID-19 pandemic, he said, and they’re very common. According to DeLoughery, most patients have abnormal coagulation, very high D-dimer test results, and very high fibrinogen levels—even to the extraordinary level of 1,500 mg/dL, he said. And unlike in typical patients with septic shock, patients with thrombosis have a higher risk than bleeding.
A high D-dimer level is a major prognostic indicator of thrombosis and bad outcomes. “It’s representative of widespread coagulation activation, and it can be a sign of pulmonary thrombosis and local thrombosis happening at the site of the COVID infection,” he said.
DeLoughery highlighted an April 2020 study that found that “patients with D‐dimer levels ≥ 2.0 µg/mL had a higher incidence of mortality when compared with those who with D‐dimer levels < 2.0 µg/mL (12/67 vs 1/267; P < .001; hazard ratio, 51.5; 95% CI, 12.9‐206.7).”
Research also suggests that “there's something about getting COVID and going to the intensive care unit (ICU) that dramatically raises the risk of thrombosis,” he said, and the risk goes up over time in the ICU. Venous thrombosis isn’t the only risk. Relatively young patients with COVID have suffered from arterial thrombosis, even though they have minimal to no respiratory symptoms and no cardiovascular risk factors.
As for treatments, DeLoughery noted that thrombosis can occur despite standard prophylaxis, and patients may show resistance to heparin and, therefore, need massive doses. Still, there’s consensus that every patient with COVID-19 in the hospital should get thromboprophylaxis with low-molecular-weight heparin (LMWH), he said, and unfractionated heparin is appropriate for those with renal failure.
“The problem is everything else is controversial,” he said. For example, hematologists are split evenly on whether heparin dosing should be increased beyond standard protocol for patients in the ICU with 1.5 to 3 times normal D-dimers levels. He agreed with this approach but notes that some centers set their D-dimer triggers higher—at 3 to 6 times the normal level.
“The problem is that there’s limited data,” he said. “We have lots of observational studies suggesting benefits from higher doses, but we have no randomized trial data, and the observational studies are not uniform in their recommendations.”
What about outpatient prophylaxis? It appears that risk of thrombosis is < 1% percent when patients are out of the hospital, he said. “This is very reassuring that once the patient gets better, their prothrombotic drive goes away.”
Dr. DeLoughery highlighted the protocol at Oregon Health & Science University:
- Prophylaxis. Everyone with COVID-19 admitted to the hospital receives enoxaparin 40 mg daily. If the patient’s body mass index > 40, it should be increased to twice daily. For patients with renal failure, use unfractionated heparin 5000 u twice daily or enoxaparin 30 mg daily.
- In the ICU. Screen for deep vein thrombosis at admission and every 4 to 5 days thereafter. Increase enoxaparin to 40 mg twice daily, and to 1 mg/kg twice daily if signs of thrombosis develop, such as sudden deterioration, respiratory failure, the patient is too unstable to get a computed tomography, or with D-dimer > 3.0 µg/mL. “People’s thresholds for initiating empiric therapy differ, but this is an option,” he said.
For outpatient patients who are likely to be immobile for a month, 40 mg enoxaparin or 10 mg rivaroxaban are appropriate. “We’re not as aggressive as we used to be about outpatient prophylaxis,” he said.
Moving forward, he said, “this is an area where we really need clinical trials. There's just so much uncertainty.”
DeLoughery reported no disclosures.
Abnormal coagulation is a hallmark of COVID-19. Now, as we’re learning more about the high risk of thrombosis, physicians need to prescribe prophylaxis routinely in the hospital, stay alert, and act immediately when signs of trouble appear. “We must have a low suspicion for diagnosis and treatment of thrombosis,” said hematologist-oncologist Thomas DeLoughery, MD, professor of medicine at Oregon Health & Science University in Portland in a presentation at the virtual 2020 annual meeting of the Association of VA Hematology/Oncology (AVAHO).
Still, research is sparse, and there are disagreements about the best strategies to protect patients, said DeLoughery. Physicians recognized coagulation problems early on during the course of the COVID-19 pandemic, he said, and they’re very common. According to DeLoughery, most patients have abnormal coagulation, very high D-dimer test results, and very high fibrinogen levels—even to the extraordinary level of 1,500 mg/dL, he said. And unlike in typical patients with septic shock, patients with thrombosis have a higher risk than bleeding.
A high D-dimer level is a major prognostic indicator of thrombosis and bad outcomes. “It’s representative of widespread coagulation activation, and it can be a sign of pulmonary thrombosis and local thrombosis happening at the site of the COVID infection,” he said.
DeLoughery highlighted an April 2020 study that found that “patients with D‐dimer levels ≥ 2.0 µg/mL had a higher incidence of mortality when compared with those who with D‐dimer levels < 2.0 µg/mL (12/67 vs 1/267; P < .001; hazard ratio, 51.5; 95% CI, 12.9‐206.7).”
Research also suggests that “there's something about getting COVID and going to the intensive care unit (ICU) that dramatically raises the risk of thrombosis,” he said, and the risk goes up over time in the ICU. Venous thrombosis isn’t the only risk. Relatively young patients with COVID have suffered from arterial thrombosis, even though they have minimal to no respiratory symptoms and no cardiovascular risk factors.
As for treatments, DeLoughery noted that thrombosis can occur despite standard prophylaxis, and patients may show resistance to heparin and, therefore, need massive doses. Still, there’s consensus that every patient with COVID-19 in the hospital should get thromboprophylaxis with low-molecular-weight heparin (LMWH), he said, and unfractionated heparin is appropriate for those with renal failure.
“The problem is everything else is controversial,” he said. For example, hematologists are split evenly on whether heparin dosing should be increased beyond standard protocol for patients in the ICU with 1.5 to 3 times normal D-dimers levels. He agreed with this approach but notes that some centers set their D-dimer triggers higher—at 3 to 6 times the normal level.
“The problem is that there’s limited data,” he said. “We have lots of observational studies suggesting benefits from higher doses, but we have no randomized trial data, and the observational studies are not uniform in their recommendations.”
What about outpatient prophylaxis? It appears that risk of thrombosis is < 1% percent when patients are out of the hospital, he said. “This is very reassuring that once the patient gets better, their prothrombotic drive goes away.”
Dr. DeLoughery highlighted the protocol at Oregon Health & Science University:
- Prophylaxis. Everyone with COVID-19 admitted to the hospital receives enoxaparin 40 mg daily. If the patient’s body mass index > 40, it should be increased to twice daily. For patients with renal failure, use unfractionated heparin 5000 u twice daily or enoxaparin 30 mg daily.
- In the ICU. Screen for deep vein thrombosis at admission and every 4 to 5 days thereafter. Increase enoxaparin to 40 mg twice daily, and to 1 mg/kg twice daily if signs of thrombosis develop, such as sudden deterioration, respiratory failure, the patient is too unstable to get a computed tomography, or with D-dimer > 3.0 µg/mL. “People’s thresholds for initiating empiric therapy differ, but this is an option,” he said.
For outpatient patients who are likely to be immobile for a month, 40 mg enoxaparin or 10 mg rivaroxaban are appropriate. “We’re not as aggressive as we used to be about outpatient prophylaxis,” he said.
Moving forward, he said, “this is an area where we really need clinical trials. There's just so much uncertainty.”
DeLoughery reported no disclosures.
Abnormal coagulation is a hallmark of COVID-19. Now, as we’re learning more about the high risk of thrombosis, physicians need to prescribe prophylaxis routinely in the hospital, stay alert, and act immediately when signs of trouble appear. “We must have a low suspicion for diagnosis and treatment of thrombosis,” said hematologist-oncologist Thomas DeLoughery, MD, professor of medicine at Oregon Health & Science University in Portland in a presentation at the virtual 2020 annual meeting of the Association of VA Hematology/Oncology (AVAHO).
Still, research is sparse, and there are disagreements about the best strategies to protect patients, said DeLoughery. Physicians recognized coagulation problems early on during the course of the COVID-19 pandemic, he said, and they’re very common. According to DeLoughery, most patients have abnormal coagulation, very high D-dimer test results, and very high fibrinogen levels—even to the extraordinary level of 1,500 mg/dL, he said. And unlike in typical patients with septic shock, patients with thrombosis have a higher risk than bleeding.
A high D-dimer level is a major prognostic indicator of thrombosis and bad outcomes. “It’s representative of widespread coagulation activation, and it can be a sign of pulmonary thrombosis and local thrombosis happening at the site of the COVID infection,” he said.
DeLoughery highlighted an April 2020 study that found that “patients with D‐dimer levels ≥ 2.0 µg/mL had a higher incidence of mortality when compared with those who with D‐dimer levels < 2.0 µg/mL (12/67 vs 1/267; P < .001; hazard ratio, 51.5; 95% CI, 12.9‐206.7).”
Research also suggests that “there's something about getting COVID and going to the intensive care unit (ICU) that dramatically raises the risk of thrombosis,” he said, and the risk goes up over time in the ICU. Venous thrombosis isn’t the only risk. Relatively young patients with COVID have suffered from arterial thrombosis, even though they have minimal to no respiratory symptoms and no cardiovascular risk factors.
As for treatments, DeLoughery noted that thrombosis can occur despite standard prophylaxis, and patients may show resistance to heparin and, therefore, need massive doses. Still, there’s consensus that every patient with COVID-19 in the hospital should get thromboprophylaxis with low-molecular-weight heparin (LMWH), he said, and unfractionated heparin is appropriate for those with renal failure.
“The problem is everything else is controversial,” he said. For example, hematologists are split evenly on whether heparin dosing should be increased beyond standard protocol for patients in the ICU with 1.5 to 3 times normal D-dimers levels. He agreed with this approach but notes that some centers set their D-dimer triggers higher—at 3 to 6 times the normal level.
“The problem is that there’s limited data,” he said. “We have lots of observational studies suggesting benefits from higher doses, but we have no randomized trial data, and the observational studies are not uniform in their recommendations.”
What about outpatient prophylaxis? It appears that risk of thrombosis is < 1% percent when patients are out of the hospital, he said. “This is very reassuring that once the patient gets better, their prothrombotic drive goes away.”
Dr. DeLoughery highlighted the protocol at Oregon Health & Science University:
- Prophylaxis. Everyone with COVID-19 admitted to the hospital receives enoxaparin 40 mg daily. If the patient’s body mass index > 40, it should be increased to twice daily. For patients with renal failure, use unfractionated heparin 5000 u twice daily or enoxaparin 30 mg daily.
- In the ICU. Screen for deep vein thrombosis at admission and every 4 to 5 days thereafter. Increase enoxaparin to 40 mg twice daily, and to 1 mg/kg twice daily if signs of thrombosis develop, such as sudden deterioration, respiratory failure, the patient is too unstable to get a computed tomography, or with D-dimer > 3.0 µg/mL. “People’s thresholds for initiating empiric therapy differ, but this is an option,” he said.
For outpatient patients who are likely to be immobile for a month, 40 mg enoxaparin or 10 mg rivaroxaban are appropriate. “We’re not as aggressive as we used to be about outpatient prophylaxis,” he said.
Moving forward, he said, “this is an area where we really need clinical trials. There's just so much uncertainty.”
DeLoughery reported no disclosures.