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Triple threat: Novel agent shows potent T2D weight loss in phase 1
STOCKHOLM – First came the GLP-1 receptor agonists as treatments for patients with type 2 diabetes, then came tirzepatide (Mounjaro) which added a second incretin agonism for the receptor to the glucose-dependent insulinotropic polypeptide (GIP). Now coming onto the clinical scene is a molecule with triple agonism to the GLP-1 receptor, the GIP receptor, and to the glucagon receptor.
That molecule, LY3437943, showed reasonable safety and tolerability and an apparent incremental uptick in weight loss compared with the approved incretin-based agents for people with type 2 diabetes in a 12-week, dose-ranging study involving a 52 patients with type 2 diabetes who received the new agent.
The 12 people who uptitrated for a total of 12 weeks and reached the highest tested dose of LY3437943, 12 mg, injected once weekly during the final 4 weeks, showed an average weight loss of 8.65 kg, while the 11 patients who maxed out at a weekly dose of 6 mg of LY3437943 had an average 12-week weight loss of 7.52 kg, Zvonko Milicevic, MD, reported at the annual meeting of the European Association for the Study of Diabetes.
Fifteen more participants received placebo and five received a comparator GLP-1 receptor agonist. All 72 patients in the study were also already on treatment with metformin when they entered, and they were maintained on metformin throughout the study period.
The new agent showed “greater weight loss efficacy than currently approved medications,” said Dr. Milicevic, a staff researcher who works in Vienna for Eli Lilly, the company developing LY3437943.
‘Really impressive’ weight loss
Martin Haluzik, MD, who chaired the session where Dr. Milicevic spoke, agreed. “The data, especially for weight reduction, were really impressive,” Dr. Haluzik said in an interview. “It looks stronger than the best we have at the moment,” the dual incretin agonist tirzepatide, he added.
Cross-study comparisons are very unreliable, but to put the weight loss seen with LY3437943 in perspective, the 12-week weight reduction that occurred with the highest dose of tirzepatide tested (15 mg/weekly) in the pivotal SURPASS-2 trial with 1,879 randomized patients with type 2 diabetes was an average of roughly 5 kg, while the comparator of 1 mg weekly of semaglutide (Ozempic) tested in the same study produced an average weight loss of about 4 kg.
Other notable efficacy results for LY3437943 after 12 weeks on treatment included an average reduction in hemoglobin A1c from baseline of 1.90%, achieved in the group that received 6 mg weekly as their maximum dose for 8 weeks after a 4-week run-in at a lower dose; a reduction in systolic blood pressure of 7.99 mm Hg on the 6-mg maximum weekly dose and of 12.06 mm Hg on the maximum 12-mg weekly dose; and “robust” reductions in lipids including cuts from baseline of about 40% for both triglycerides and very-LDL cholesterol, Dr. Milicevic reported.
Adverse effects resemble approved incretin-based agents
The study, which ran at four U.S. sites, had a primary objective of safety assessment, and Dr. Milicevic said the results showed acceptable safety and tolerability consistent with the glucagon-like peptide-1 (GLP-1) receptor agonists and tirzepatide. Like those agents, LY3437943 caused primarily mild gastrointestinal adverse effects such as nausea and diarrhea. Of the 52 patients in the study who received the triple agonist, 4 discontinued treatment because of a treatment-emergent adverse effect, including 1 patient in the subgroup who received the maximum dose.
The only concerning adverse effect noted by Dr. Haluzik was the average increase in heart rate from baseline of 10.26 beats/min in the subgroup that received the maximum dose, roughly twice the increase seen with tirzepatide and semaglutide in SURPASS-2. The average heart rate increase was about half that, 5.30 beats/min compared with baseline, in the subgroup that received a maximum weekly dose of 6 mg.
Overall, the results showed “no major adverse effects that might hamper use,” said Dr. Haluzik, an endocrinologist and professor at Charles University in Prague.
Two phase 2 studies of LY3437943 are underway and are scheduled to finish before the end of 2022. They include a study of about 300 people with type 2 diabetes that’s running at 43 U.S. sites, and a second study of about 500 people with overweight or obesity running at 28 U.S. sites.
The study was sponsored by Eli Lilly, the company developing LY3437943. Dr. Milicevic is an employee of and stockholder of Eli Lilly. Dr. Haluzik has been an adviser to, consultant to, and received honoraria and research support from Eli Lilly. He has had similar relationships with Amgen, AstraZeneca, Boehringer Ingelheim, BristolMyersSquibb, Janssen, Johnson & Johnson, Mundipharma, Novo Nordisk, and Sanofi.
STOCKHOLM – First came the GLP-1 receptor agonists as treatments for patients with type 2 diabetes, then came tirzepatide (Mounjaro) which added a second incretin agonism for the receptor to the glucose-dependent insulinotropic polypeptide (GIP). Now coming onto the clinical scene is a molecule with triple agonism to the GLP-1 receptor, the GIP receptor, and to the glucagon receptor.
That molecule, LY3437943, showed reasonable safety and tolerability and an apparent incremental uptick in weight loss compared with the approved incretin-based agents for people with type 2 diabetes in a 12-week, dose-ranging study involving a 52 patients with type 2 diabetes who received the new agent.
The 12 people who uptitrated for a total of 12 weeks and reached the highest tested dose of LY3437943, 12 mg, injected once weekly during the final 4 weeks, showed an average weight loss of 8.65 kg, while the 11 patients who maxed out at a weekly dose of 6 mg of LY3437943 had an average 12-week weight loss of 7.52 kg, Zvonko Milicevic, MD, reported at the annual meeting of the European Association for the Study of Diabetes.
Fifteen more participants received placebo and five received a comparator GLP-1 receptor agonist. All 72 patients in the study were also already on treatment with metformin when they entered, and they were maintained on metformin throughout the study period.
The new agent showed “greater weight loss efficacy than currently approved medications,” said Dr. Milicevic, a staff researcher who works in Vienna for Eli Lilly, the company developing LY3437943.
‘Really impressive’ weight loss
Martin Haluzik, MD, who chaired the session where Dr. Milicevic spoke, agreed. “The data, especially for weight reduction, were really impressive,” Dr. Haluzik said in an interview. “It looks stronger than the best we have at the moment,” the dual incretin agonist tirzepatide, he added.
Cross-study comparisons are very unreliable, but to put the weight loss seen with LY3437943 in perspective, the 12-week weight reduction that occurred with the highest dose of tirzepatide tested (15 mg/weekly) in the pivotal SURPASS-2 trial with 1,879 randomized patients with type 2 diabetes was an average of roughly 5 kg, while the comparator of 1 mg weekly of semaglutide (Ozempic) tested in the same study produced an average weight loss of about 4 kg.
Other notable efficacy results for LY3437943 after 12 weeks on treatment included an average reduction in hemoglobin A1c from baseline of 1.90%, achieved in the group that received 6 mg weekly as their maximum dose for 8 weeks after a 4-week run-in at a lower dose; a reduction in systolic blood pressure of 7.99 mm Hg on the 6-mg maximum weekly dose and of 12.06 mm Hg on the maximum 12-mg weekly dose; and “robust” reductions in lipids including cuts from baseline of about 40% for both triglycerides and very-LDL cholesterol, Dr. Milicevic reported.
Adverse effects resemble approved incretin-based agents
The study, which ran at four U.S. sites, had a primary objective of safety assessment, and Dr. Milicevic said the results showed acceptable safety and tolerability consistent with the glucagon-like peptide-1 (GLP-1) receptor agonists and tirzepatide. Like those agents, LY3437943 caused primarily mild gastrointestinal adverse effects such as nausea and diarrhea. Of the 52 patients in the study who received the triple agonist, 4 discontinued treatment because of a treatment-emergent adverse effect, including 1 patient in the subgroup who received the maximum dose.
The only concerning adverse effect noted by Dr. Haluzik was the average increase in heart rate from baseline of 10.26 beats/min in the subgroup that received the maximum dose, roughly twice the increase seen with tirzepatide and semaglutide in SURPASS-2. The average heart rate increase was about half that, 5.30 beats/min compared with baseline, in the subgroup that received a maximum weekly dose of 6 mg.
Overall, the results showed “no major adverse effects that might hamper use,” said Dr. Haluzik, an endocrinologist and professor at Charles University in Prague.
Two phase 2 studies of LY3437943 are underway and are scheduled to finish before the end of 2022. They include a study of about 300 people with type 2 diabetes that’s running at 43 U.S. sites, and a second study of about 500 people with overweight or obesity running at 28 U.S. sites.
The study was sponsored by Eli Lilly, the company developing LY3437943. Dr. Milicevic is an employee of and stockholder of Eli Lilly. Dr. Haluzik has been an adviser to, consultant to, and received honoraria and research support from Eli Lilly. He has had similar relationships with Amgen, AstraZeneca, Boehringer Ingelheim, BristolMyersSquibb, Janssen, Johnson & Johnson, Mundipharma, Novo Nordisk, and Sanofi.
STOCKHOLM – First came the GLP-1 receptor agonists as treatments for patients with type 2 diabetes, then came tirzepatide (Mounjaro) which added a second incretin agonism for the receptor to the glucose-dependent insulinotropic polypeptide (GIP). Now coming onto the clinical scene is a molecule with triple agonism to the GLP-1 receptor, the GIP receptor, and to the glucagon receptor.
That molecule, LY3437943, showed reasonable safety and tolerability and an apparent incremental uptick in weight loss compared with the approved incretin-based agents for people with type 2 diabetes in a 12-week, dose-ranging study involving a 52 patients with type 2 diabetes who received the new agent.
The 12 people who uptitrated for a total of 12 weeks and reached the highest tested dose of LY3437943, 12 mg, injected once weekly during the final 4 weeks, showed an average weight loss of 8.65 kg, while the 11 patients who maxed out at a weekly dose of 6 mg of LY3437943 had an average 12-week weight loss of 7.52 kg, Zvonko Milicevic, MD, reported at the annual meeting of the European Association for the Study of Diabetes.
Fifteen more participants received placebo and five received a comparator GLP-1 receptor agonist. All 72 patients in the study were also already on treatment with metformin when they entered, and they were maintained on metformin throughout the study period.
The new agent showed “greater weight loss efficacy than currently approved medications,” said Dr. Milicevic, a staff researcher who works in Vienna for Eli Lilly, the company developing LY3437943.
‘Really impressive’ weight loss
Martin Haluzik, MD, who chaired the session where Dr. Milicevic spoke, agreed. “The data, especially for weight reduction, were really impressive,” Dr. Haluzik said in an interview. “It looks stronger than the best we have at the moment,” the dual incretin agonist tirzepatide, he added.
Cross-study comparisons are very unreliable, but to put the weight loss seen with LY3437943 in perspective, the 12-week weight reduction that occurred with the highest dose of tirzepatide tested (15 mg/weekly) in the pivotal SURPASS-2 trial with 1,879 randomized patients with type 2 diabetes was an average of roughly 5 kg, while the comparator of 1 mg weekly of semaglutide (Ozempic) tested in the same study produced an average weight loss of about 4 kg.
Other notable efficacy results for LY3437943 after 12 weeks on treatment included an average reduction in hemoglobin A1c from baseline of 1.90%, achieved in the group that received 6 mg weekly as their maximum dose for 8 weeks after a 4-week run-in at a lower dose; a reduction in systolic blood pressure of 7.99 mm Hg on the 6-mg maximum weekly dose and of 12.06 mm Hg on the maximum 12-mg weekly dose; and “robust” reductions in lipids including cuts from baseline of about 40% for both triglycerides and very-LDL cholesterol, Dr. Milicevic reported.
Adverse effects resemble approved incretin-based agents
The study, which ran at four U.S. sites, had a primary objective of safety assessment, and Dr. Milicevic said the results showed acceptable safety and tolerability consistent with the glucagon-like peptide-1 (GLP-1) receptor agonists and tirzepatide. Like those agents, LY3437943 caused primarily mild gastrointestinal adverse effects such as nausea and diarrhea. Of the 52 patients in the study who received the triple agonist, 4 discontinued treatment because of a treatment-emergent adverse effect, including 1 patient in the subgroup who received the maximum dose.
The only concerning adverse effect noted by Dr. Haluzik was the average increase in heart rate from baseline of 10.26 beats/min in the subgroup that received the maximum dose, roughly twice the increase seen with tirzepatide and semaglutide in SURPASS-2. The average heart rate increase was about half that, 5.30 beats/min compared with baseline, in the subgroup that received a maximum weekly dose of 6 mg.
Overall, the results showed “no major adverse effects that might hamper use,” said Dr. Haluzik, an endocrinologist and professor at Charles University in Prague.
Two phase 2 studies of LY3437943 are underway and are scheduled to finish before the end of 2022. They include a study of about 300 people with type 2 diabetes that’s running at 43 U.S. sites, and a second study of about 500 people with overweight or obesity running at 28 U.S. sites.
The study was sponsored by Eli Lilly, the company developing LY3437943. Dr. Milicevic is an employee of and stockholder of Eli Lilly. Dr. Haluzik has been an adviser to, consultant to, and received honoraria and research support from Eli Lilly. He has had similar relationships with Amgen, AstraZeneca, Boehringer Ingelheim, BristolMyersSquibb, Janssen, Johnson & Johnson, Mundipharma, Novo Nordisk, and Sanofi.
AT EASD 2022
Hep C, HIV coinfection tied to higher MI risk with age
, a new analysis suggests.
By contrast, the risk increases by 30% every 10 years among PWH without HCV infection.
“There is other evidence that suggests people with HIV and HCV have a greater burden of negative health outcomes,” senior author Keri N. Althoff, PhD, MPH, of the Johns Hopkins Bloomberg School of Public Health in Baltimore, said in an interview. “But the magnitude of ‘greater’ was bigger than I expected.”
“Understanding the difference HCV can make in the risk of MI with increasing age among those with – compared to without – HCV is an important step for understanding additional potential benefits of HCV treatment (among PWH),” she said.
The amplified risk with age occurred even though, overall, the association between HCV coinfection and increased risk of type 1 myocardial infarction (T1MI) was not significant, the analysis showed.
The study was published online in the Journal of the American Heart Association.
How age counts
Dr. Althoff and colleagues analyzed data from 23,361 PWH aged 40-79 who had initiated antiretroviral therapy between 2000 and 2017. The primary outcome was T1MI.
A total of 4,677 participants (20%) had HCV. Eighty-nine T1MIs occurred among PWH with HCV (1.9%) vs. 314 among PWH without HCV (1.7%). In adjusted analyses, HCV was not associated with increased T1MI risk (adjusted hazard ratio, 0.98).
However, the risk of T1MI increased with age and was augmented in those with HCV (aHR per 10-year increase in age, 1.85) vs. those without HCV (aHR, 1.30).
Specifically, compared with those without HCV, the estimated T1MI risk was 17% higher among 50- to 59-year-olds with HCV and 77% higher among those 60 and older; neither association was statistically significant, although the authors suggest this probably was because of the smaller number of participants in the older age categories.
Even without HCV, the risk of T1MI increased in participants who had traditional risk factors. The risk was significantly higher among PWH aged 40-49 with diabetes, hypertension, chronic kidney disease, protease inhibitor (PI) use, and smoking, whereas among PWH aged 50-59, the T1MI risk was significantly greater among those with hypertension, PI use, and smoking.
Among those aged 60 or older, hypertension and low CD4 counts were associated with a significantly increased T1MI risk.
“Clinicians providing health care to people with HIV should know their patients’ HCV status,” Dr. Althoff said, “and provide support regarding HCV treatment and ways to reduce their cardiovascular risk, including smoking cessation, reaching and maintaining a healthy BMI, and substance use treatment.”
Truly additive?
American Heart Association expert volunteer Nieca Goldberg, MD, a clinical associate professor of medicine at New York University and medical director of Atria NY, said the increased T1MI risk with coinfection “makes sense” because both HIV and HCV are linked to inflammation.
However, she said in an interview, “the fact that the authors didn’t control for other, more traditional heart attack risk factors is a limitation. I would like to see a study that takes other risk factors into consideration to see if HCV is truly additive.”
Meanwhile, like Dr. Althoff, she said, “Clinicians should be taking a careful history that includes chronic infections as well as traditional heart risk factors.”
Additional studies are needed, Dr. Althoff agreed. “There are two paths we are keenly interested in pursuing. The first is understanding how metabolic risk factors for MI change after HCV treatment. We are working on this.”
“Ultimately,” she said, “we want to compare MI risk in people with HIV who had successful HCV treatment to those who have not had successful HCV treatment.”
In their current study, they had nearly 2 decades of follow-up, she noted. “Although we don’t need to wait that long, we would like to have close to a decade of potential follow-up time (since 2016, when sofosbuvir/velpatasvir became available) so that we have a large enough sample size to observe a sufficient number of MIs within the first 5 years after successful HCV treatment.”
No commercial funding or relevant disclosures were reported.
A version of this article first appeared on Medscape.com.
, a new analysis suggests.
By contrast, the risk increases by 30% every 10 years among PWH without HCV infection.
“There is other evidence that suggests people with HIV and HCV have a greater burden of negative health outcomes,” senior author Keri N. Althoff, PhD, MPH, of the Johns Hopkins Bloomberg School of Public Health in Baltimore, said in an interview. “But the magnitude of ‘greater’ was bigger than I expected.”
“Understanding the difference HCV can make in the risk of MI with increasing age among those with – compared to without – HCV is an important step for understanding additional potential benefits of HCV treatment (among PWH),” she said.
The amplified risk with age occurred even though, overall, the association between HCV coinfection and increased risk of type 1 myocardial infarction (T1MI) was not significant, the analysis showed.
The study was published online in the Journal of the American Heart Association.
How age counts
Dr. Althoff and colleagues analyzed data from 23,361 PWH aged 40-79 who had initiated antiretroviral therapy between 2000 and 2017. The primary outcome was T1MI.
A total of 4,677 participants (20%) had HCV. Eighty-nine T1MIs occurred among PWH with HCV (1.9%) vs. 314 among PWH without HCV (1.7%). In adjusted analyses, HCV was not associated with increased T1MI risk (adjusted hazard ratio, 0.98).
However, the risk of T1MI increased with age and was augmented in those with HCV (aHR per 10-year increase in age, 1.85) vs. those without HCV (aHR, 1.30).
Specifically, compared with those without HCV, the estimated T1MI risk was 17% higher among 50- to 59-year-olds with HCV and 77% higher among those 60 and older; neither association was statistically significant, although the authors suggest this probably was because of the smaller number of participants in the older age categories.
Even without HCV, the risk of T1MI increased in participants who had traditional risk factors. The risk was significantly higher among PWH aged 40-49 with diabetes, hypertension, chronic kidney disease, protease inhibitor (PI) use, and smoking, whereas among PWH aged 50-59, the T1MI risk was significantly greater among those with hypertension, PI use, and smoking.
Among those aged 60 or older, hypertension and low CD4 counts were associated with a significantly increased T1MI risk.
“Clinicians providing health care to people with HIV should know their patients’ HCV status,” Dr. Althoff said, “and provide support regarding HCV treatment and ways to reduce their cardiovascular risk, including smoking cessation, reaching and maintaining a healthy BMI, and substance use treatment.”
Truly additive?
American Heart Association expert volunteer Nieca Goldberg, MD, a clinical associate professor of medicine at New York University and medical director of Atria NY, said the increased T1MI risk with coinfection “makes sense” because both HIV and HCV are linked to inflammation.
However, she said in an interview, “the fact that the authors didn’t control for other, more traditional heart attack risk factors is a limitation. I would like to see a study that takes other risk factors into consideration to see if HCV is truly additive.”
Meanwhile, like Dr. Althoff, she said, “Clinicians should be taking a careful history that includes chronic infections as well as traditional heart risk factors.”
Additional studies are needed, Dr. Althoff agreed. “There are two paths we are keenly interested in pursuing. The first is understanding how metabolic risk factors for MI change after HCV treatment. We are working on this.”
“Ultimately,” she said, “we want to compare MI risk in people with HIV who had successful HCV treatment to those who have not had successful HCV treatment.”
In their current study, they had nearly 2 decades of follow-up, she noted. “Although we don’t need to wait that long, we would like to have close to a decade of potential follow-up time (since 2016, when sofosbuvir/velpatasvir became available) so that we have a large enough sample size to observe a sufficient number of MIs within the first 5 years after successful HCV treatment.”
No commercial funding or relevant disclosures were reported.
A version of this article first appeared on Medscape.com.
, a new analysis suggests.
By contrast, the risk increases by 30% every 10 years among PWH without HCV infection.
“There is other evidence that suggests people with HIV and HCV have a greater burden of negative health outcomes,” senior author Keri N. Althoff, PhD, MPH, of the Johns Hopkins Bloomberg School of Public Health in Baltimore, said in an interview. “But the magnitude of ‘greater’ was bigger than I expected.”
“Understanding the difference HCV can make in the risk of MI with increasing age among those with – compared to without – HCV is an important step for understanding additional potential benefits of HCV treatment (among PWH),” she said.
The amplified risk with age occurred even though, overall, the association between HCV coinfection and increased risk of type 1 myocardial infarction (T1MI) was not significant, the analysis showed.
The study was published online in the Journal of the American Heart Association.
How age counts
Dr. Althoff and colleagues analyzed data from 23,361 PWH aged 40-79 who had initiated antiretroviral therapy between 2000 and 2017. The primary outcome was T1MI.
A total of 4,677 participants (20%) had HCV. Eighty-nine T1MIs occurred among PWH with HCV (1.9%) vs. 314 among PWH without HCV (1.7%). In adjusted analyses, HCV was not associated with increased T1MI risk (adjusted hazard ratio, 0.98).
However, the risk of T1MI increased with age and was augmented in those with HCV (aHR per 10-year increase in age, 1.85) vs. those without HCV (aHR, 1.30).
Specifically, compared with those without HCV, the estimated T1MI risk was 17% higher among 50- to 59-year-olds with HCV and 77% higher among those 60 and older; neither association was statistically significant, although the authors suggest this probably was because of the smaller number of participants in the older age categories.
Even without HCV, the risk of T1MI increased in participants who had traditional risk factors. The risk was significantly higher among PWH aged 40-49 with diabetes, hypertension, chronic kidney disease, protease inhibitor (PI) use, and smoking, whereas among PWH aged 50-59, the T1MI risk was significantly greater among those with hypertension, PI use, and smoking.
Among those aged 60 or older, hypertension and low CD4 counts were associated with a significantly increased T1MI risk.
“Clinicians providing health care to people with HIV should know their patients’ HCV status,” Dr. Althoff said, “and provide support regarding HCV treatment and ways to reduce their cardiovascular risk, including smoking cessation, reaching and maintaining a healthy BMI, and substance use treatment.”
Truly additive?
American Heart Association expert volunteer Nieca Goldberg, MD, a clinical associate professor of medicine at New York University and medical director of Atria NY, said the increased T1MI risk with coinfection “makes sense” because both HIV and HCV are linked to inflammation.
However, she said in an interview, “the fact that the authors didn’t control for other, more traditional heart attack risk factors is a limitation. I would like to see a study that takes other risk factors into consideration to see if HCV is truly additive.”
Meanwhile, like Dr. Althoff, she said, “Clinicians should be taking a careful history that includes chronic infections as well as traditional heart risk factors.”
Additional studies are needed, Dr. Althoff agreed. “There are two paths we are keenly interested in pursuing. The first is understanding how metabolic risk factors for MI change after HCV treatment. We are working on this.”
“Ultimately,” she said, “we want to compare MI risk in people with HIV who had successful HCV treatment to those who have not had successful HCV treatment.”
In their current study, they had nearly 2 decades of follow-up, she noted. “Although we don’t need to wait that long, we would like to have close to a decade of potential follow-up time (since 2016, when sofosbuvir/velpatasvir became available) so that we have a large enough sample size to observe a sufficient number of MIs within the first 5 years after successful HCV treatment.”
No commercial funding or relevant disclosures were reported.
A version of this article first appeared on Medscape.com.
FROM JOURNAL OF THE AMERICAN HEART ASSOCIATION
High BMI linked to better survival for cancer patients treated with ICI, but for men only
That is the conclusion of a new retrospective analysis presented during a poster session given at the annual meeting of the European Society for Medical Oncology. The study sought to better understand ICI outcomes. “These are complex new treatments and, because they harness the immune system, no two patients are likely to respond in the same way. BMI has previously been associated with improved survival in patients with advanced lung cancer treated with immunotherapy. However, the reasons behind this observation, and the implications for treatment are unknown, as is whether this observation is specific for patients with only certain types of cancers,” study author Dwight Owen, MD, said in an email.
He pointed out that the retrospective nature of the findings means that they have no immediate clinical implications. “The reason for the discrepancy in males remains unclear. Although our study included a relatively large number of patients, it is a heterogenous cohort and there may be confounding factors that we haven’t recognized, so these findings need to be replicated in larger cohorts,” said Dr. Owen, a medical oncologist with The Ohio State University Comprehensive Cancer Center, Columbus.
Asked if there is a potential biological explanation for a difference between males and females, Dr. Owen said that this is an area of intense research. One recent study examined whether androgen could help explain why men are more likely than women to both develop and have more aggressive nonreproductive cancers. They concluded that androgen receptor signaling may be leading to loss of effector and proliferative potential of CD8+ T cells in the tumor microenvironment. Once exhausted, these cells do not respond well to stimulation that can occur after ICI treatment.
On the opposite end of the spectrum, cancer cachexia is also a key subject of study. It is characterized by weight loss and is associated with worse clinical outcomes. A cachexia mouse model found that weight loss can lead to more clearance of immune checkpoint antibodies.
Still, much more work needs to be done. “For now, how BMI, obesity, and cachexia relate to other factors, for instance the microbiome and tumor immunogenicity, are still not fully understood,” Dr. Owen said.
The study data
The researchers analyzed data from 688 patients with metastatic cancer treated at their center between 2011 and 2017. 94% were White and 5% were Black. 41% were female and the mean age was 61.9 years. The mean BMI was 28.8 kg/m2; 40% of patients had melanoma, 23% had non–small cell lung cancer, 10% had renal cancer, and 27% had another form of cancer.
For every unit decrease in BMI, the researchers observed a 1.8% decrease in mortality (hazard ratio, 0.982; P = .007). Patients with a BMI of 40 or above had better survival than all other patients grouped by 5 BMI increments (that is, 35-40, 30-35, etc.). When separated by sex, males had a significant decrease in mortality for every increase in BMI unit (HR, 0.964; P = .004), but there was no significant difference among women (HR, 1.003; P = .706). The relationship in men held up after adjustment for Eastern Cooperative Oncology Group score, line of therapy, and cancer type (HR, 0.979; P = .0308). The researchers also looked at a separate cohort of 185 normal weight and 15 obese (BMI ≥ 40) NSCLC patients. Median survival was 27.5 months in the obese group and 9.1 months in the normal weight group (HR, 0.474; 95% CI, 0.232-0.969).
Dr. Owen has received research funding through his institution from Bristol-Myers Squibb, Genentech, Pfizer, Palobiofarma, and Onc.AI.
That is the conclusion of a new retrospective analysis presented during a poster session given at the annual meeting of the European Society for Medical Oncology. The study sought to better understand ICI outcomes. “These are complex new treatments and, because they harness the immune system, no two patients are likely to respond in the same way. BMI has previously been associated with improved survival in patients with advanced lung cancer treated with immunotherapy. However, the reasons behind this observation, and the implications for treatment are unknown, as is whether this observation is specific for patients with only certain types of cancers,” study author Dwight Owen, MD, said in an email.
He pointed out that the retrospective nature of the findings means that they have no immediate clinical implications. “The reason for the discrepancy in males remains unclear. Although our study included a relatively large number of patients, it is a heterogenous cohort and there may be confounding factors that we haven’t recognized, so these findings need to be replicated in larger cohorts,” said Dr. Owen, a medical oncologist with The Ohio State University Comprehensive Cancer Center, Columbus.
Asked if there is a potential biological explanation for a difference between males and females, Dr. Owen said that this is an area of intense research. One recent study examined whether androgen could help explain why men are more likely than women to both develop and have more aggressive nonreproductive cancers. They concluded that androgen receptor signaling may be leading to loss of effector and proliferative potential of CD8+ T cells in the tumor microenvironment. Once exhausted, these cells do not respond well to stimulation that can occur after ICI treatment.
On the opposite end of the spectrum, cancer cachexia is also a key subject of study. It is characterized by weight loss and is associated with worse clinical outcomes. A cachexia mouse model found that weight loss can lead to more clearance of immune checkpoint antibodies.
Still, much more work needs to be done. “For now, how BMI, obesity, and cachexia relate to other factors, for instance the microbiome and tumor immunogenicity, are still not fully understood,” Dr. Owen said.
The study data
The researchers analyzed data from 688 patients with metastatic cancer treated at their center between 2011 and 2017. 94% were White and 5% were Black. 41% were female and the mean age was 61.9 years. The mean BMI was 28.8 kg/m2; 40% of patients had melanoma, 23% had non–small cell lung cancer, 10% had renal cancer, and 27% had another form of cancer.
For every unit decrease in BMI, the researchers observed a 1.8% decrease in mortality (hazard ratio, 0.982; P = .007). Patients with a BMI of 40 or above had better survival than all other patients grouped by 5 BMI increments (that is, 35-40, 30-35, etc.). When separated by sex, males had a significant decrease in mortality for every increase in BMI unit (HR, 0.964; P = .004), but there was no significant difference among women (HR, 1.003; P = .706). The relationship in men held up after adjustment for Eastern Cooperative Oncology Group score, line of therapy, and cancer type (HR, 0.979; P = .0308). The researchers also looked at a separate cohort of 185 normal weight and 15 obese (BMI ≥ 40) NSCLC patients. Median survival was 27.5 months in the obese group and 9.1 months in the normal weight group (HR, 0.474; 95% CI, 0.232-0.969).
Dr. Owen has received research funding through his institution from Bristol-Myers Squibb, Genentech, Pfizer, Palobiofarma, and Onc.AI.
That is the conclusion of a new retrospective analysis presented during a poster session given at the annual meeting of the European Society for Medical Oncology. The study sought to better understand ICI outcomes. “These are complex new treatments and, because they harness the immune system, no two patients are likely to respond in the same way. BMI has previously been associated with improved survival in patients with advanced lung cancer treated with immunotherapy. However, the reasons behind this observation, and the implications for treatment are unknown, as is whether this observation is specific for patients with only certain types of cancers,” study author Dwight Owen, MD, said in an email.
He pointed out that the retrospective nature of the findings means that they have no immediate clinical implications. “The reason for the discrepancy in males remains unclear. Although our study included a relatively large number of patients, it is a heterogenous cohort and there may be confounding factors that we haven’t recognized, so these findings need to be replicated in larger cohorts,” said Dr. Owen, a medical oncologist with The Ohio State University Comprehensive Cancer Center, Columbus.
Asked if there is a potential biological explanation for a difference between males and females, Dr. Owen said that this is an area of intense research. One recent study examined whether androgen could help explain why men are more likely than women to both develop and have more aggressive nonreproductive cancers. They concluded that androgen receptor signaling may be leading to loss of effector and proliferative potential of CD8+ T cells in the tumor microenvironment. Once exhausted, these cells do not respond well to stimulation that can occur after ICI treatment.
On the opposite end of the spectrum, cancer cachexia is also a key subject of study. It is characterized by weight loss and is associated with worse clinical outcomes. A cachexia mouse model found that weight loss can lead to more clearance of immune checkpoint antibodies.
Still, much more work needs to be done. “For now, how BMI, obesity, and cachexia relate to other factors, for instance the microbiome and tumor immunogenicity, are still not fully understood,” Dr. Owen said.
The study data
The researchers analyzed data from 688 patients with metastatic cancer treated at their center between 2011 and 2017. 94% were White and 5% were Black. 41% were female and the mean age was 61.9 years. The mean BMI was 28.8 kg/m2; 40% of patients had melanoma, 23% had non–small cell lung cancer, 10% had renal cancer, and 27% had another form of cancer.
For every unit decrease in BMI, the researchers observed a 1.8% decrease in mortality (hazard ratio, 0.982; P = .007). Patients with a BMI of 40 or above had better survival than all other patients grouped by 5 BMI increments (that is, 35-40, 30-35, etc.). When separated by sex, males had a significant decrease in mortality for every increase in BMI unit (HR, 0.964; P = .004), but there was no significant difference among women (HR, 1.003; P = .706). The relationship in men held up after adjustment for Eastern Cooperative Oncology Group score, line of therapy, and cancer type (HR, 0.979; P = .0308). The researchers also looked at a separate cohort of 185 normal weight and 15 obese (BMI ≥ 40) NSCLC patients. Median survival was 27.5 months in the obese group and 9.1 months in the normal weight group (HR, 0.474; 95% CI, 0.232-0.969).
Dr. Owen has received research funding through his institution from Bristol-Myers Squibb, Genentech, Pfizer, Palobiofarma, and Onc.AI.
FROM ESMO CONGRESS 2022
Scalp plaque
A punch biopsy was performed, and the results were consistent with pityriasis amiantacea arising from psoriasis. In an older patient, a keratinaceous horn would be worrisome for a squamous cell carcinoma. In a younger patient, like this one, it is more likely an atypical manifestation of a more common dermatosis.
Pityriasis amiantacea is an unusual disorder in which thick adherent scales form on the scalp; it is most common in children, adolescents, and young adults. There is no racial predilection. With this condition, patients complain of a fixed plaque that may shed scale but not as quickly as it accumulates. It can be an isolated finding, but more often it is a secondary manifestation of an underlying case of psoriasis, seborrheic dermatitis, tinea capitis, or atopic dermatitis.1
A punch biopsy performed on the scalp should include the skin underlying the compact keratin scale. However, to avoid excessive bleeding, use lidocaine with epinephrine. Allow 15 minutes for the anesthesia to take effect before beginning the procedure.
Treatment depends on the underlying cause but includes debridement of the aggregated scale with a topical keratolytic (such as salicylic acid or topical fluocinolone oil 0.01% applied) at night and washed out 7 to 10 hours later.
The patient was advised to use over-the-counter 2% salicylic acid shampoo daily and to apply topical clobetasol 0.05% solution nightly for 4 weeks and once weekly after clearance for another 3 months. At the 3-month follow-up, the patient’s scalp was clear.
Photos and text for Photo Rounds Friday courtesy of Jonathan Karnes, MD (copyright retained). Dr. Karnes is the medical director of MDFMR Dermatology Services, Augusta, ME.
1. Ettler J, Wetter DA, Pittelkow MR. Pityriasis amiantacea: a distinctive presentation of psoriasis associated with tumour necrosis factor-α inhibitor therapy. Clin Exp Dermatol. 2012;37:639-641. doi: 10.1111/j.1365-2230.2011.04286.x
A punch biopsy was performed, and the results were consistent with pityriasis amiantacea arising from psoriasis. In an older patient, a keratinaceous horn would be worrisome for a squamous cell carcinoma. In a younger patient, like this one, it is more likely an atypical manifestation of a more common dermatosis.
Pityriasis amiantacea is an unusual disorder in which thick adherent scales form on the scalp; it is most common in children, adolescents, and young adults. There is no racial predilection. With this condition, patients complain of a fixed plaque that may shed scale but not as quickly as it accumulates. It can be an isolated finding, but more often it is a secondary manifestation of an underlying case of psoriasis, seborrheic dermatitis, tinea capitis, or atopic dermatitis.1
A punch biopsy performed on the scalp should include the skin underlying the compact keratin scale. However, to avoid excessive bleeding, use lidocaine with epinephrine. Allow 15 minutes for the anesthesia to take effect before beginning the procedure.
Treatment depends on the underlying cause but includes debridement of the aggregated scale with a topical keratolytic (such as salicylic acid or topical fluocinolone oil 0.01% applied) at night and washed out 7 to 10 hours later.
The patient was advised to use over-the-counter 2% salicylic acid shampoo daily and to apply topical clobetasol 0.05% solution nightly for 4 weeks and once weekly after clearance for another 3 months. At the 3-month follow-up, the patient’s scalp was clear.
Photos and text for Photo Rounds Friday courtesy of Jonathan Karnes, MD (copyright retained). Dr. Karnes is the medical director of MDFMR Dermatology Services, Augusta, ME.
A punch biopsy was performed, and the results were consistent with pityriasis amiantacea arising from psoriasis. In an older patient, a keratinaceous horn would be worrisome for a squamous cell carcinoma. In a younger patient, like this one, it is more likely an atypical manifestation of a more common dermatosis.
Pityriasis amiantacea is an unusual disorder in which thick adherent scales form on the scalp; it is most common in children, adolescents, and young adults. There is no racial predilection. With this condition, patients complain of a fixed plaque that may shed scale but not as quickly as it accumulates. It can be an isolated finding, but more often it is a secondary manifestation of an underlying case of psoriasis, seborrheic dermatitis, tinea capitis, or atopic dermatitis.1
A punch biopsy performed on the scalp should include the skin underlying the compact keratin scale. However, to avoid excessive bleeding, use lidocaine with epinephrine. Allow 15 minutes for the anesthesia to take effect before beginning the procedure.
Treatment depends on the underlying cause but includes debridement of the aggregated scale with a topical keratolytic (such as salicylic acid or topical fluocinolone oil 0.01% applied) at night and washed out 7 to 10 hours later.
The patient was advised to use over-the-counter 2% salicylic acid shampoo daily and to apply topical clobetasol 0.05% solution nightly for 4 weeks and once weekly after clearance for another 3 months. At the 3-month follow-up, the patient’s scalp was clear.
Photos and text for Photo Rounds Friday courtesy of Jonathan Karnes, MD (copyright retained). Dr. Karnes is the medical director of MDFMR Dermatology Services, Augusta, ME.
1. Ettler J, Wetter DA, Pittelkow MR. Pityriasis amiantacea: a distinctive presentation of psoriasis associated with tumour necrosis factor-α inhibitor therapy. Clin Exp Dermatol. 2012;37:639-641. doi: 10.1111/j.1365-2230.2011.04286.x
1. Ettler J, Wetter DA, Pittelkow MR. Pityriasis amiantacea: a distinctive presentation of psoriasis associated with tumour necrosis factor-α inhibitor therapy. Clin Exp Dermatol. 2012;37:639-641. doi: 10.1111/j.1365-2230.2011.04286.x
New liver stiffness thresholds refine NASH risk stratification
New liver stiffness (LS) thresholds offer accurate prediction of disease progression and clinical outcomes in patients with nonalcoholic steatohepatitis (NASH) and advanced fibrosis, according to investigators.
These new LS thresholds are more reliable because they are based on high-quality prospective data drawn from four randomized controlled trials, reported lead author Rohit Loomba, MD, of the University of California, San Diego, and colleagues.
“Retrospective studies report that increasing baseline LS by VCTE [vibration-controlled transient elastography] is associated with the risk of disease progression in patients with NAFLD [non-alcoholic fatty liver disease], but prospective data in well-characterized NASH cohorts with biopsy-confirmed advanced fibrosis are limited,” the investigators wrote in Gut. “The optimal LS thresholds for prognostication of fibrosis progression and decompensation are unknown.”
Seeking clarity, Dr. Loomba and colleagues leveraged data from two phase 3 placebo-controlled trials for selonsertib and two phase 2b placebo-controlled trials for simtuzumab.
“While the studies were discontinued prematurely due to lack of efficacy, the prospectively collected data in these well-characterized participants with serial liver biopsies provides a unique opportunity to study the association between baseline LS by VCTE and disease progression,” the investigators wrote.
Across all four studies, bridging fibrosis (F3) was present in 664 participants, while 734 individuals had cirrhosis (F4). In the selonsertib studies, fibrosis was staged at baseline and week 48. The simtuzumab studies measured liver fibrosis at baseline and week 96. Out of the 664 participants with bridging fibrosis, 103 (16%) progressed to cirrhosis. Among the 734 patients with cirrhosis, 27 (4%) experienced liver-related events. Comparing these outcomes with LS data at baseline and throughout the study revealed optimal LS thresholds.
The best threshold for predicting progression from bridging fibrosis to cirrhosis was 16.6 kPa. According to the authors, the sensitivity, specificity, positive predictive value, and negative predictive value of this threshold for progression to cirrhosis were 58%, 76%, 31%, and 91%, respectively. Among patients at or above 16.6 kPa, 31% progressed to cirrhosis, compared with 9.1% of those under that threshold. Furthermore, individuals with a baseline LS at or above 16.6 kPa had nearly four times greater risk of developing cirrhosis (adjusted hazard ratio, 3.99; 95% CI, 2.66-5.98; P < .0001).
For patients with cirrhosis at baseline, the optimal threshold for predicting liver-related events, such as ascites, hepatic encephalopathy, and portal hypertension–related GI bleeding, liver transplantation, or mortality, was 30.7 kPa. The sensitivity, specificity, PPV, and NPV of this threshold for liver-related events were 62%, 87%, 10%, and 99%, respectively, according to the authors. Patients with an LS above this mark were 10 times as likely to experience liver-related events (aHR, 10.13; 95% CI, 4.38-23.41; P < .0001).
Scott L. Friedman, MD, chief of the division of liver diseases and dean for Therapeutic Discovery at the Icahn School of Medicine at Mount Sinai, New York, called the study “an important effort” that offers valuable insights for both researchers and practitioners.
“For clinical trials, [these thresholds] really allow for greater refinement or enrichment of patients who are suitable for enrollment in the trial because they’re at a higher risk of clinical problems that might be mitigated if the drug is effective,” Dr. Friedman said in an interview. “For clinical practice, it might indicate that the patient should either be fast tracked for a clinical trial or, more importantly, maybe needs to be referred for evaluation for a liver transplant. It may also indicate – although they didn’t look at it in this study – that there’s a need to begin or accelerate screening for liver cancer, which becomes an encroaching risk as the fibrosis advances to later stages.”
The study was funded by Gilead Sciences. The investigators disclosed additional relationships with Amgen, Eli Lilly, CohBar, and others. Dr. Friedman reported no relevant conflicts of interest.
New liver stiffness (LS) thresholds offer accurate prediction of disease progression and clinical outcomes in patients with nonalcoholic steatohepatitis (NASH) and advanced fibrosis, according to investigators.
These new LS thresholds are more reliable because they are based on high-quality prospective data drawn from four randomized controlled trials, reported lead author Rohit Loomba, MD, of the University of California, San Diego, and colleagues.
“Retrospective studies report that increasing baseline LS by VCTE [vibration-controlled transient elastography] is associated with the risk of disease progression in patients with NAFLD [non-alcoholic fatty liver disease], but prospective data in well-characterized NASH cohorts with biopsy-confirmed advanced fibrosis are limited,” the investigators wrote in Gut. “The optimal LS thresholds for prognostication of fibrosis progression and decompensation are unknown.”
Seeking clarity, Dr. Loomba and colleagues leveraged data from two phase 3 placebo-controlled trials for selonsertib and two phase 2b placebo-controlled trials for simtuzumab.
“While the studies were discontinued prematurely due to lack of efficacy, the prospectively collected data in these well-characterized participants with serial liver biopsies provides a unique opportunity to study the association between baseline LS by VCTE and disease progression,” the investigators wrote.
Across all four studies, bridging fibrosis (F3) was present in 664 participants, while 734 individuals had cirrhosis (F4). In the selonsertib studies, fibrosis was staged at baseline and week 48. The simtuzumab studies measured liver fibrosis at baseline and week 96. Out of the 664 participants with bridging fibrosis, 103 (16%) progressed to cirrhosis. Among the 734 patients with cirrhosis, 27 (4%) experienced liver-related events. Comparing these outcomes with LS data at baseline and throughout the study revealed optimal LS thresholds.
The best threshold for predicting progression from bridging fibrosis to cirrhosis was 16.6 kPa. According to the authors, the sensitivity, specificity, positive predictive value, and negative predictive value of this threshold for progression to cirrhosis were 58%, 76%, 31%, and 91%, respectively. Among patients at or above 16.6 kPa, 31% progressed to cirrhosis, compared with 9.1% of those under that threshold. Furthermore, individuals with a baseline LS at or above 16.6 kPa had nearly four times greater risk of developing cirrhosis (adjusted hazard ratio, 3.99; 95% CI, 2.66-5.98; P < .0001).
For patients with cirrhosis at baseline, the optimal threshold for predicting liver-related events, such as ascites, hepatic encephalopathy, and portal hypertension–related GI bleeding, liver transplantation, or mortality, was 30.7 kPa. The sensitivity, specificity, PPV, and NPV of this threshold for liver-related events were 62%, 87%, 10%, and 99%, respectively, according to the authors. Patients with an LS above this mark were 10 times as likely to experience liver-related events (aHR, 10.13; 95% CI, 4.38-23.41; P < .0001).
Scott L. Friedman, MD, chief of the division of liver diseases and dean for Therapeutic Discovery at the Icahn School of Medicine at Mount Sinai, New York, called the study “an important effort” that offers valuable insights for both researchers and practitioners.
“For clinical trials, [these thresholds] really allow for greater refinement or enrichment of patients who are suitable for enrollment in the trial because they’re at a higher risk of clinical problems that might be mitigated if the drug is effective,” Dr. Friedman said in an interview. “For clinical practice, it might indicate that the patient should either be fast tracked for a clinical trial or, more importantly, maybe needs to be referred for evaluation for a liver transplant. It may also indicate – although they didn’t look at it in this study – that there’s a need to begin or accelerate screening for liver cancer, which becomes an encroaching risk as the fibrosis advances to later stages.”
The study was funded by Gilead Sciences. The investigators disclosed additional relationships with Amgen, Eli Lilly, CohBar, and others. Dr. Friedman reported no relevant conflicts of interest.
New liver stiffness (LS) thresholds offer accurate prediction of disease progression and clinical outcomes in patients with nonalcoholic steatohepatitis (NASH) and advanced fibrosis, according to investigators.
These new LS thresholds are more reliable because they are based on high-quality prospective data drawn from four randomized controlled trials, reported lead author Rohit Loomba, MD, of the University of California, San Diego, and colleagues.
“Retrospective studies report that increasing baseline LS by VCTE [vibration-controlled transient elastography] is associated with the risk of disease progression in patients with NAFLD [non-alcoholic fatty liver disease], but prospective data in well-characterized NASH cohorts with biopsy-confirmed advanced fibrosis are limited,” the investigators wrote in Gut. “The optimal LS thresholds for prognostication of fibrosis progression and decompensation are unknown.”
Seeking clarity, Dr. Loomba and colleagues leveraged data from two phase 3 placebo-controlled trials for selonsertib and two phase 2b placebo-controlled trials for simtuzumab.
“While the studies were discontinued prematurely due to lack of efficacy, the prospectively collected data in these well-characterized participants with serial liver biopsies provides a unique opportunity to study the association between baseline LS by VCTE and disease progression,” the investigators wrote.
Across all four studies, bridging fibrosis (F3) was present in 664 participants, while 734 individuals had cirrhosis (F4). In the selonsertib studies, fibrosis was staged at baseline and week 48. The simtuzumab studies measured liver fibrosis at baseline and week 96. Out of the 664 participants with bridging fibrosis, 103 (16%) progressed to cirrhosis. Among the 734 patients with cirrhosis, 27 (4%) experienced liver-related events. Comparing these outcomes with LS data at baseline and throughout the study revealed optimal LS thresholds.
The best threshold for predicting progression from bridging fibrosis to cirrhosis was 16.6 kPa. According to the authors, the sensitivity, specificity, positive predictive value, and negative predictive value of this threshold for progression to cirrhosis were 58%, 76%, 31%, and 91%, respectively. Among patients at or above 16.6 kPa, 31% progressed to cirrhosis, compared with 9.1% of those under that threshold. Furthermore, individuals with a baseline LS at or above 16.6 kPa had nearly four times greater risk of developing cirrhosis (adjusted hazard ratio, 3.99; 95% CI, 2.66-5.98; P < .0001).
For patients with cirrhosis at baseline, the optimal threshold for predicting liver-related events, such as ascites, hepatic encephalopathy, and portal hypertension–related GI bleeding, liver transplantation, or mortality, was 30.7 kPa. The sensitivity, specificity, PPV, and NPV of this threshold for liver-related events were 62%, 87%, 10%, and 99%, respectively, according to the authors. Patients with an LS above this mark were 10 times as likely to experience liver-related events (aHR, 10.13; 95% CI, 4.38-23.41; P < .0001).
Scott L. Friedman, MD, chief of the division of liver diseases and dean for Therapeutic Discovery at the Icahn School of Medicine at Mount Sinai, New York, called the study “an important effort” that offers valuable insights for both researchers and practitioners.
“For clinical trials, [these thresholds] really allow for greater refinement or enrichment of patients who are suitable for enrollment in the trial because they’re at a higher risk of clinical problems that might be mitigated if the drug is effective,” Dr. Friedman said in an interview. “For clinical practice, it might indicate that the patient should either be fast tracked for a clinical trial or, more importantly, maybe needs to be referred for evaluation for a liver transplant. It may also indicate – although they didn’t look at it in this study – that there’s a need to begin or accelerate screening for liver cancer, which becomes an encroaching risk as the fibrosis advances to later stages.”
The study was funded by Gilead Sciences. The investigators disclosed additional relationships with Amgen, Eli Lilly, CohBar, and others. Dr. Friedman reported no relevant conflicts of interest.
FROM GUT
Sotorasib superior to docetaxel in KRAS G12C–mutated NSCLC
PARIS – For patients with non–small cell lung cancers (NSCLC) bearing the KRAS G12C mutation that have progressed on prior therapies, the first-in-class KRAS G12C inhibitor sotorasib (Lumykras) was associated with better progression-free survival (PFS) and objective response rates than docetaxel in the randomized, phase 3 CodeBreaK 200 trial.
Among 345 patients who had experienced disease progression after prior platinum-based chemotherapy and an immune checkpoint inhibitor, 1-year PFS rates at a median follow-up of 17.7 months were 24.8% for patients randomized to receive sotorasib versus 10.1% for patients assigned to docetaxel, reported Melissa L, Johnson, MD, from the Sarah Cannon Research Institute at Tennessee Oncology in Nashville.
“In my opinion, this supports sotorasib as a new second-line standard for patients with KRAS G12C non–small cell lung cancer,” she said in a media briefing prior to her presentation of the data in an oral abstract session at the annual meeting of the European Society for Medical Oncology.
First phase 3, randomized, controlled trial
The trial is the first head-to-head, randomized comparison pitting a KRAS G12C inhibitor against the standard of care in patients with NSCLC.
Approximately 30% of patients with NSCLC have KRAS driver mutations, and KRAS G12C–mutant NSCLC comprises an estimated 13% of all NSCLC cases, Dr. Johnson said.
Sotorasib was hailed as “a triumph of drug discovery” when early results of the trial were reported at the 2020 ESMO annual meeting. It is a small-molecule, specific, and irreversible inhibitor of KRAS that interacts with a “pocket” on the gene’s surface that is present only in an inactive conformation of KRAS. The drug inhibits oncogenic signaling and tumorigenesis by preventing cycling of the oncogene into its active form.
CodeBreaK 200 details
A total of 345 patients from sites in the United States, Europe, Asia and Australia were enrolled and randomly assigned to receive either oral sotorasib 960 mg daily, or intravenous docetaxel 75 mg/m2 every 3 weeks.
As noted before, the trial met its primary endpoint of a statistically significant improvement in PFS with sotorasib as measured by independent central reviewers blinded to study assignment, with a hazard ratio of 0.66 (P = .002). Median PFS with sotorasib was 5.6 months, compared with 4.5 months for docetaxel.
The objective response rate was significantly improved for sotorasib versus docetaxel (28.1% vs. 13.2%, P < .001), as was the disease control rate at 82.5% for sotorasib versus 60.3% for docetaxel. Overall survival was not significantly different between treatment arms, though the study was not powered for this endpoint.
Sotorasib was also superior to docetaxel at forestalling deterioration of patients’ global health status, physical functioning, and cancer-related symptoms such as dyspnea and cough. There was no significant difference between the study arms in reported chest pain, however.
Grade 3 or greater treatment-related adverse events occurred in 33.1% of patients with sotorasib, compared with 40.4% of patients on docetaxel.
‘Tremendous advance’
“I think the conduct of this study is impressive, it’s well designed, it was well run, any imbalances really favored the control arm, and I think that this advance is relevant not just for performance status 0 and 1 KRAS G12C–mutant patients, but even beyond, to performance status 2 and perhaps even performance status 3,” commented Natasha Leighl, MD, MMSc, from the Princess Margaret Cancer Center, Toronto, the invited discussant.
Comparing the drug performance of the respective arms, Dr. Leighl said that “I don’t think I’ve ever seen such good outcomes in a randomized trial with the chemotherapy, but unfortunately sotorasib performed a little bit less well than we had hoped.”
Nonetheless, “I think CodeBreaK 200 is a tremendous advance for patients. It is a confirmatory positive trial, and I think sotorasib is the new standard of care in patients who have received chemo and immunotherapy for KRAS G12C–mutant lung cancer,” she said.
CodeBreaK 200 was supported by Amgen. Dr. Johnson disclosed a consulting and advisory role with payments to her institution from Amgen and others. Dr. Leighl disclosed institutional grant funding and personal honoraria from Amgen and others.
PARIS – For patients with non–small cell lung cancers (NSCLC) bearing the KRAS G12C mutation that have progressed on prior therapies, the first-in-class KRAS G12C inhibitor sotorasib (Lumykras) was associated with better progression-free survival (PFS) and objective response rates than docetaxel in the randomized, phase 3 CodeBreaK 200 trial.
Among 345 patients who had experienced disease progression after prior platinum-based chemotherapy and an immune checkpoint inhibitor, 1-year PFS rates at a median follow-up of 17.7 months were 24.8% for patients randomized to receive sotorasib versus 10.1% for patients assigned to docetaxel, reported Melissa L, Johnson, MD, from the Sarah Cannon Research Institute at Tennessee Oncology in Nashville.
“In my opinion, this supports sotorasib as a new second-line standard for patients with KRAS G12C non–small cell lung cancer,” she said in a media briefing prior to her presentation of the data in an oral abstract session at the annual meeting of the European Society for Medical Oncology.
First phase 3, randomized, controlled trial
The trial is the first head-to-head, randomized comparison pitting a KRAS G12C inhibitor against the standard of care in patients with NSCLC.
Approximately 30% of patients with NSCLC have KRAS driver mutations, and KRAS G12C–mutant NSCLC comprises an estimated 13% of all NSCLC cases, Dr. Johnson said.
Sotorasib was hailed as “a triumph of drug discovery” when early results of the trial were reported at the 2020 ESMO annual meeting. It is a small-molecule, specific, and irreversible inhibitor of KRAS that interacts with a “pocket” on the gene’s surface that is present only in an inactive conformation of KRAS. The drug inhibits oncogenic signaling and tumorigenesis by preventing cycling of the oncogene into its active form.
CodeBreaK 200 details
A total of 345 patients from sites in the United States, Europe, Asia and Australia were enrolled and randomly assigned to receive either oral sotorasib 960 mg daily, or intravenous docetaxel 75 mg/m2 every 3 weeks.
As noted before, the trial met its primary endpoint of a statistically significant improvement in PFS with sotorasib as measured by independent central reviewers blinded to study assignment, with a hazard ratio of 0.66 (P = .002). Median PFS with sotorasib was 5.6 months, compared with 4.5 months for docetaxel.
The objective response rate was significantly improved for sotorasib versus docetaxel (28.1% vs. 13.2%, P < .001), as was the disease control rate at 82.5% for sotorasib versus 60.3% for docetaxel. Overall survival was not significantly different between treatment arms, though the study was not powered for this endpoint.
Sotorasib was also superior to docetaxel at forestalling deterioration of patients’ global health status, physical functioning, and cancer-related symptoms such as dyspnea and cough. There was no significant difference between the study arms in reported chest pain, however.
Grade 3 or greater treatment-related adverse events occurred in 33.1% of patients with sotorasib, compared with 40.4% of patients on docetaxel.
‘Tremendous advance’
“I think the conduct of this study is impressive, it’s well designed, it was well run, any imbalances really favored the control arm, and I think that this advance is relevant not just for performance status 0 and 1 KRAS G12C–mutant patients, but even beyond, to performance status 2 and perhaps even performance status 3,” commented Natasha Leighl, MD, MMSc, from the Princess Margaret Cancer Center, Toronto, the invited discussant.
Comparing the drug performance of the respective arms, Dr. Leighl said that “I don’t think I’ve ever seen such good outcomes in a randomized trial with the chemotherapy, but unfortunately sotorasib performed a little bit less well than we had hoped.”
Nonetheless, “I think CodeBreaK 200 is a tremendous advance for patients. It is a confirmatory positive trial, and I think sotorasib is the new standard of care in patients who have received chemo and immunotherapy for KRAS G12C–mutant lung cancer,” she said.
CodeBreaK 200 was supported by Amgen. Dr. Johnson disclosed a consulting and advisory role with payments to her institution from Amgen and others. Dr. Leighl disclosed institutional grant funding and personal honoraria from Amgen and others.
PARIS – For patients with non–small cell lung cancers (NSCLC) bearing the KRAS G12C mutation that have progressed on prior therapies, the first-in-class KRAS G12C inhibitor sotorasib (Lumykras) was associated with better progression-free survival (PFS) and objective response rates than docetaxel in the randomized, phase 3 CodeBreaK 200 trial.
Among 345 patients who had experienced disease progression after prior platinum-based chemotherapy and an immune checkpoint inhibitor, 1-year PFS rates at a median follow-up of 17.7 months were 24.8% for patients randomized to receive sotorasib versus 10.1% for patients assigned to docetaxel, reported Melissa L, Johnson, MD, from the Sarah Cannon Research Institute at Tennessee Oncology in Nashville.
“In my opinion, this supports sotorasib as a new second-line standard for patients with KRAS G12C non–small cell lung cancer,” she said in a media briefing prior to her presentation of the data in an oral abstract session at the annual meeting of the European Society for Medical Oncology.
First phase 3, randomized, controlled trial
The trial is the first head-to-head, randomized comparison pitting a KRAS G12C inhibitor against the standard of care in patients with NSCLC.
Approximately 30% of patients with NSCLC have KRAS driver mutations, and KRAS G12C–mutant NSCLC comprises an estimated 13% of all NSCLC cases, Dr. Johnson said.
Sotorasib was hailed as “a triumph of drug discovery” when early results of the trial were reported at the 2020 ESMO annual meeting. It is a small-molecule, specific, and irreversible inhibitor of KRAS that interacts with a “pocket” on the gene’s surface that is present only in an inactive conformation of KRAS. The drug inhibits oncogenic signaling and tumorigenesis by preventing cycling of the oncogene into its active form.
CodeBreaK 200 details
A total of 345 patients from sites in the United States, Europe, Asia and Australia were enrolled and randomly assigned to receive either oral sotorasib 960 mg daily, or intravenous docetaxel 75 mg/m2 every 3 weeks.
As noted before, the trial met its primary endpoint of a statistically significant improvement in PFS with sotorasib as measured by independent central reviewers blinded to study assignment, with a hazard ratio of 0.66 (P = .002). Median PFS with sotorasib was 5.6 months, compared with 4.5 months for docetaxel.
The objective response rate was significantly improved for sotorasib versus docetaxel (28.1% vs. 13.2%, P < .001), as was the disease control rate at 82.5% for sotorasib versus 60.3% for docetaxel. Overall survival was not significantly different between treatment arms, though the study was not powered for this endpoint.
Sotorasib was also superior to docetaxel at forestalling deterioration of patients’ global health status, physical functioning, and cancer-related symptoms such as dyspnea and cough. There was no significant difference between the study arms in reported chest pain, however.
Grade 3 or greater treatment-related adverse events occurred in 33.1% of patients with sotorasib, compared with 40.4% of patients on docetaxel.
‘Tremendous advance’
“I think the conduct of this study is impressive, it’s well designed, it was well run, any imbalances really favored the control arm, and I think that this advance is relevant not just for performance status 0 and 1 KRAS G12C–mutant patients, but even beyond, to performance status 2 and perhaps even performance status 3,” commented Natasha Leighl, MD, MMSc, from the Princess Margaret Cancer Center, Toronto, the invited discussant.
Comparing the drug performance of the respective arms, Dr. Leighl said that “I don’t think I’ve ever seen such good outcomes in a randomized trial with the chemotherapy, but unfortunately sotorasib performed a little bit less well than we had hoped.”
Nonetheless, “I think CodeBreaK 200 is a tremendous advance for patients. It is a confirmatory positive trial, and I think sotorasib is the new standard of care in patients who have received chemo and immunotherapy for KRAS G12C–mutant lung cancer,” she said.
CodeBreaK 200 was supported by Amgen. Dr. Johnson disclosed a consulting and advisory role with payments to her institution from Amgen and others. Dr. Leighl disclosed institutional grant funding and personal honoraria from Amgen and others.
AT ESMO CONGRESS 2022
A 10-year-old with a red bump on her lower lip
The patient’s history and examination are consistent with a diagnosis of pyogenic granuloma. Specifically, the history of rapid growth, friable nature, associated bleeding, and hemorrhagic crusting point to pyogenic granuloma as the most likely diagnosis.
Pyogenic granuloma is an acquired benign vascular growth of the skin or mucous membranes.1 It most frequently occurs in children and young adults and most commonly affects the skin of the head, trunk, and extremities.2 Common mucosal sites include the gingiva, lips, and tongue.2 The etiology of pyogenic granuloma is unknown, though it is thought to be a process akin to the overgrowth of granulation tissue.3,4 Expression of angiogenic factors and subsequent vascular hyperplasia are also implicated as key players in the pathogenesis of pyogenic granuloma.1,4 In addition, several associated factors and inciting triggers have been proposed including trauma, infections, and hormonal fluctuations.3-5 However, the majority of patients do not report predisposing factors or a history of prior trauma at the site.3,6
Clinically, pyogenic granuloma usually presents as a painless, erythematous, dome-shaped friable papule or nodule that easily bleeds and may ulcerate. It typically undergoes a period of growth over weeks to months followed by stabilization. Occasionally, pyogenic granulomas will spontaneously involute, though most do not.7 Pyogenic granuloma may occur within an existing capillary malformation, such as a port wine stain, spontaneously or as a sequela of laser treatment.8,9 Diagnosis of pyogenic granuloma can typically be made clinically on the basis of history and exam. Dermoscopic evaluation of pyogenic granuloma will reveal a homogeneous papule with a surrounding white-brown collarette, and potentially white intersecting lines.10 Histopathologic evaluation may be necessary to differentiate lesions from conditions that may mimic pyogenic granuloma.
What’s on the differential?
The differential diagnosis for pyogenic granuloma consists of Spitz nevus, cherry hemangioma, amelanotic melanoma, and glomus tumor.
Spitz nevus
Spitz nevus (spindle and epithelial cell nevus) is a benign melanocytic lesion that classically appears as a sharply circumscribed, smooth, dome-shaped, pink-red, or brown papule or plaque. There is typically a history of rapid growth over several months followed by stabilization. It usually presents in childhood or adolescence and is most commonly located on the face and extremities. While there are similarities in the appearance of Spitz nevi and pyogenic granuloma, Spitz nevi are not usually friable nor associated with bleeding as in our patient. Furthermore, on dermoscopy, Spitz nevus typically exhibits a starburst pattern with regularly distributed dotted vessels, or a peripheral globular pattern with reticular depigmentation. The definitive diagnosis of Spitz nevi relies on histopathologic evaluation, which is critical for discriminating Spitz nevi from melanoma.
Cherry hemangioma
Cherry angiomas are the most common type of acquired benign vascular proliferation. They present as small, bright red or violaceous macules or papules. However, they typically appear in early to midadulthood and increase in number with age. The age of our patient and solitary presentation of the lesion make this diagnosis unlikely. In addition, cherry angiomas are not usually associated with bleeding. It is important to note that, depending on the age of the patient, pyogenic granuloma may also be confused with infantile hemangioma. Infantile hemangiomas may become bright red papules, nodules, or plaques that appear in early infancy. They characteristically involute, which does not typically happen with pyogenic granuloma.
Amelanotic melanoma
Amelanotic melanoma is an uncommon variant of melanoma with little to no pigmentation. It may appear as a skin-colored to light-brown, pink, or red macule, papule, or nodule. The lesion may be asymmetric with irregular and well-defined borders. The variable and uncharacteristic appearance of this melanoma variant makes it diagnostically challenging and it is often confused with benign lesions including pyogenic granuloma. Dermoscopy can help distinguish amelanotic melanoma from other benign conditions, and will reveal areas of pink to white, polymorphous vessels and crystalline structures. However, ultimately biopsy and histopathological evaluation is necessary for accurate diagnosis.
Glomus tumor
Glomus tumors are rare, benign neoplasms originating from cells of the glomus body that presents as a red-purple, vascular papule or nodule. They are usually found in areas rich in glomus bodies, such as the subungual regions, fingertips, palms, wrists, and forearms. Glomus tumors are typically associated with tenderness, paroxysmal pain, and cold sensitivity. They do not bleed or ulcerate. While pyogenic granuloma may be confused for glomus tumor when present on the fingers or extremities, the location of the lesion in our patient is not consistent with a diagnosis of glomus tumor.
Management and disease course
Management with procedural or topical interventions is usually pursued for pyogenic granuloma because of frequent bleeding and ulceration of lesions. The most common approach is simple excision by a scoop or shave technique, with or without curettage and most commonly with electrocautery of the base. Other options include full-thickness excision, destruction with laser therapy, cryotherapy, or topical treatments (for example, timolol).11 Lesion recurrence can occur with both surgical and nonsurgical management.11 Regardless of management technique, it is useful to obtain histopathologic evaluation of tissue for accurate diagnosis.
Our patient underwent surgical destruction of her lower-lip lesion with shave excision followed by electrocautery. The surgical specimen was sent for pathology, which confirmed the diagnosis of pyogenic granuloma. The patient experienced no complications from the procedure and did not have recurrence of the lesion.
Ms. Sui is a research associate in the department of dermatology, division of pediatric and adolescent dermatology, University of California, San Diego, and Rady Children’s Hospital, San Diego. Dr. Eichenfield is vice chair of the department of dermatology and professor of dermatology and pediatrics at the University of California, San Diego, and Rady Children’s Hospital, San Diego. Neither Ms. Sui nor Dr. Eichenfield have any relevant financial disclosures.
References
1. Lin RL and Janniger CK. Cutis. 2004 Oct;74(4):229-33.
2. Harris MN et al. J Am Acad Dermatol. 2000 Jun;42(6):1012-6.
3. Pagliai KA and Cohen BA. Pediatr Dermatol. 2004 Jan-Feb;21(1):10-3.
4. Kamal R et al. J Oral Maxillofac Pathol. 2012 Jan;16(1):79-82.
5. Requena L and Sangueza OP. J Am Acad Dermatol. 1997 Dec;37(6):887-919.
6. Patrice SJ et al. Pediatr Dermatol. 1991 Dec;8(4):267-76.
7. Luba MC et al. Am Fam Physician. 2003 Feb 15;67(4):729-38.
8. Swerlick RA and Cooper PH. J Am Acad Dermatol. 1983 May;8(5):627-30.
9. Sheehan DJ and Lesher JL Jr. Cutis. 2004 Mar;73(3):175-80.
10. Zaballos P et al. Br J Dermatol. 2006 Jun;154(6):1108-11.
11. Lee J et al. J Plast Reconstr Aesthet Surg. 2011 Sep;64(9):1216-20. .
The patient’s history and examination are consistent with a diagnosis of pyogenic granuloma. Specifically, the history of rapid growth, friable nature, associated bleeding, and hemorrhagic crusting point to pyogenic granuloma as the most likely diagnosis.
Pyogenic granuloma is an acquired benign vascular growth of the skin or mucous membranes.1 It most frequently occurs in children and young adults and most commonly affects the skin of the head, trunk, and extremities.2 Common mucosal sites include the gingiva, lips, and tongue.2 The etiology of pyogenic granuloma is unknown, though it is thought to be a process akin to the overgrowth of granulation tissue.3,4 Expression of angiogenic factors and subsequent vascular hyperplasia are also implicated as key players in the pathogenesis of pyogenic granuloma.1,4 In addition, several associated factors and inciting triggers have been proposed including trauma, infections, and hormonal fluctuations.3-5 However, the majority of patients do not report predisposing factors or a history of prior trauma at the site.3,6
Clinically, pyogenic granuloma usually presents as a painless, erythematous, dome-shaped friable papule or nodule that easily bleeds and may ulcerate. It typically undergoes a period of growth over weeks to months followed by stabilization. Occasionally, pyogenic granulomas will spontaneously involute, though most do not.7 Pyogenic granuloma may occur within an existing capillary malformation, such as a port wine stain, spontaneously or as a sequela of laser treatment.8,9 Diagnosis of pyogenic granuloma can typically be made clinically on the basis of history and exam. Dermoscopic evaluation of pyogenic granuloma will reveal a homogeneous papule with a surrounding white-brown collarette, and potentially white intersecting lines.10 Histopathologic evaluation may be necessary to differentiate lesions from conditions that may mimic pyogenic granuloma.
What’s on the differential?
The differential diagnosis for pyogenic granuloma consists of Spitz nevus, cherry hemangioma, amelanotic melanoma, and glomus tumor.
Spitz nevus
Spitz nevus (spindle and epithelial cell nevus) is a benign melanocytic lesion that classically appears as a sharply circumscribed, smooth, dome-shaped, pink-red, or brown papule or plaque. There is typically a history of rapid growth over several months followed by stabilization. It usually presents in childhood or adolescence and is most commonly located on the face and extremities. While there are similarities in the appearance of Spitz nevi and pyogenic granuloma, Spitz nevi are not usually friable nor associated with bleeding as in our patient. Furthermore, on dermoscopy, Spitz nevus typically exhibits a starburst pattern with regularly distributed dotted vessels, or a peripheral globular pattern with reticular depigmentation. The definitive diagnosis of Spitz nevi relies on histopathologic evaluation, which is critical for discriminating Spitz nevi from melanoma.
Cherry hemangioma
Cherry angiomas are the most common type of acquired benign vascular proliferation. They present as small, bright red or violaceous macules or papules. However, they typically appear in early to midadulthood and increase in number with age. The age of our patient and solitary presentation of the lesion make this diagnosis unlikely. In addition, cherry angiomas are not usually associated with bleeding. It is important to note that, depending on the age of the patient, pyogenic granuloma may also be confused with infantile hemangioma. Infantile hemangiomas may become bright red papules, nodules, or plaques that appear in early infancy. They characteristically involute, which does not typically happen with pyogenic granuloma.
Amelanotic melanoma
Amelanotic melanoma is an uncommon variant of melanoma with little to no pigmentation. It may appear as a skin-colored to light-brown, pink, or red macule, papule, or nodule. The lesion may be asymmetric with irregular and well-defined borders. The variable and uncharacteristic appearance of this melanoma variant makes it diagnostically challenging and it is often confused with benign lesions including pyogenic granuloma. Dermoscopy can help distinguish amelanotic melanoma from other benign conditions, and will reveal areas of pink to white, polymorphous vessels and crystalline structures. However, ultimately biopsy and histopathological evaluation is necessary for accurate diagnosis.
Glomus tumor
Glomus tumors are rare, benign neoplasms originating from cells of the glomus body that presents as a red-purple, vascular papule or nodule. They are usually found in areas rich in glomus bodies, such as the subungual regions, fingertips, palms, wrists, and forearms. Glomus tumors are typically associated with tenderness, paroxysmal pain, and cold sensitivity. They do not bleed or ulcerate. While pyogenic granuloma may be confused for glomus tumor when present on the fingers or extremities, the location of the lesion in our patient is not consistent with a diagnosis of glomus tumor.
Management and disease course
Management with procedural or topical interventions is usually pursued for pyogenic granuloma because of frequent bleeding and ulceration of lesions. The most common approach is simple excision by a scoop or shave technique, with or without curettage and most commonly with electrocautery of the base. Other options include full-thickness excision, destruction with laser therapy, cryotherapy, or topical treatments (for example, timolol).11 Lesion recurrence can occur with both surgical and nonsurgical management.11 Regardless of management technique, it is useful to obtain histopathologic evaluation of tissue for accurate diagnosis.
Our patient underwent surgical destruction of her lower-lip lesion with shave excision followed by electrocautery. The surgical specimen was sent for pathology, which confirmed the diagnosis of pyogenic granuloma. The patient experienced no complications from the procedure and did not have recurrence of the lesion.
Ms. Sui is a research associate in the department of dermatology, division of pediatric and adolescent dermatology, University of California, San Diego, and Rady Children’s Hospital, San Diego. Dr. Eichenfield is vice chair of the department of dermatology and professor of dermatology and pediatrics at the University of California, San Diego, and Rady Children’s Hospital, San Diego. Neither Ms. Sui nor Dr. Eichenfield have any relevant financial disclosures.
References
1. Lin RL and Janniger CK. Cutis. 2004 Oct;74(4):229-33.
2. Harris MN et al. J Am Acad Dermatol. 2000 Jun;42(6):1012-6.
3. Pagliai KA and Cohen BA. Pediatr Dermatol. 2004 Jan-Feb;21(1):10-3.
4. Kamal R et al. J Oral Maxillofac Pathol. 2012 Jan;16(1):79-82.
5. Requena L and Sangueza OP. J Am Acad Dermatol. 1997 Dec;37(6):887-919.
6. Patrice SJ et al. Pediatr Dermatol. 1991 Dec;8(4):267-76.
7. Luba MC et al. Am Fam Physician. 2003 Feb 15;67(4):729-38.
8. Swerlick RA and Cooper PH. J Am Acad Dermatol. 1983 May;8(5):627-30.
9. Sheehan DJ and Lesher JL Jr. Cutis. 2004 Mar;73(3):175-80.
10. Zaballos P et al. Br J Dermatol. 2006 Jun;154(6):1108-11.
11. Lee J et al. J Plast Reconstr Aesthet Surg. 2011 Sep;64(9):1216-20. .
The patient’s history and examination are consistent with a diagnosis of pyogenic granuloma. Specifically, the history of rapid growth, friable nature, associated bleeding, and hemorrhagic crusting point to pyogenic granuloma as the most likely diagnosis.
Pyogenic granuloma is an acquired benign vascular growth of the skin or mucous membranes.1 It most frequently occurs in children and young adults and most commonly affects the skin of the head, trunk, and extremities.2 Common mucosal sites include the gingiva, lips, and tongue.2 The etiology of pyogenic granuloma is unknown, though it is thought to be a process akin to the overgrowth of granulation tissue.3,4 Expression of angiogenic factors and subsequent vascular hyperplasia are also implicated as key players in the pathogenesis of pyogenic granuloma.1,4 In addition, several associated factors and inciting triggers have been proposed including trauma, infections, and hormonal fluctuations.3-5 However, the majority of patients do not report predisposing factors or a history of prior trauma at the site.3,6
Clinically, pyogenic granuloma usually presents as a painless, erythematous, dome-shaped friable papule or nodule that easily bleeds and may ulcerate. It typically undergoes a period of growth over weeks to months followed by stabilization. Occasionally, pyogenic granulomas will spontaneously involute, though most do not.7 Pyogenic granuloma may occur within an existing capillary malformation, such as a port wine stain, spontaneously or as a sequela of laser treatment.8,9 Diagnosis of pyogenic granuloma can typically be made clinically on the basis of history and exam. Dermoscopic evaluation of pyogenic granuloma will reveal a homogeneous papule with a surrounding white-brown collarette, and potentially white intersecting lines.10 Histopathologic evaluation may be necessary to differentiate lesions from conditions that may mimic pyogenic granuloma.
What’s on the differential?
The differential diagnosis for pyogenic granuloma consists of Spitz nevus, cherry hemangioma, amelanotic melanoma, and glomus tumor.
Spitz nevus
Spitz nevus (spindle and epithelial cell nevus) is a benign melanocytic lesion that classically appears as a sharply circumscribed, smooth, dome-shaped, pink-red, or brown papule or plaque. There is typically a history of rapid growth over several months followed by stabilization. It usually presents in childhood or adolescence and is most commonly located on the face and extremities. While there are similarities in the appearance of Spitz nevi and pyogenic granuloma, Spitz nevi are not usually friable nor associated with bleeding as in our patient. Furthermore, on dermoscopy, Spitz nevus typically exhibits a starburst pattern with regularly distributed dotted vessels, or a peripheral globular pattern with reticular depigmentation. The definitive diagnosis of Spitz nevi relies on histopathologic evaluation, which is critical for discriminating Spitz nevi from melanoma.
Cherry hemangioma
Cherry angiomas are the most common type of acquired benign vascular proliferation. They present as small, bright red or violaceous macules or papules. However, they typically appear in early to midadulthood and increase in number with age. The age of our patient and solitary presentation of the lesion make this diagnosis unlikely. In addition, cherry angiomas are not usually associated with bleeding. It is important to note that, depending on the age of the patient, pyogenic granuloma may also be confused with infantile hemangioma. Infantile hemangiomas may become bright red papules, nodules, or plaques that appear in early infancy. They characteristically involute, which does not typically happen with pyogenic granuloma.
Amelanotic melanoma
Amelanotic melanoma is an uncommon variant of melanoma with little to no pigmentation. It may appear as a skin-colored to light-brown, pink, or red macule, papule, or nodule. The lesion may be asymmetric with irregular and well-defined borders. The variable and uncharacteristic appearance of this melanoma variant makes it diagnostically challenging and it is often confused with benign lesions including pyogenic granuloma. Dermoscopy can help distinguish amelanotic melanoma from other benign conditions, and will reveal areas of pink to white, polymorphous vessels and crystalline structures. However, ultimately biopsy and histopathological evaluation is necessary for accurate diagnosis.
Glomus tumor
Glomus tumors are rare, benign neoplasms originating from cells of the glomus body that presents as a red-purple, vascular papule or nodule. They are usually found in areas rich in glomus bodies, such as the subungual regions, fingertips, palms, wrists, and forearms. Glomus tumors are typically associated with tenderness, paroxysmal pain, and cold sensitivity. They do not bleed or ulcerate. While pyogenic granuloma may be confused for glomus tumor when present on the fingers or extremities, the location of the lesion in our patient is not consistent with a diagnosis of glomus tumor.
Management and disease course
Management with procedural or topical interventions is usually pursued for pyogenic granuloma because of frequent bleeding and ulceration of lesions. The most common approach is simple excision by a scoop or shave technique, with or without curettage and most commonly with electrocautery of the base. Other options include full-thickness excision, destruction with laser therapy, cryotherapy, or topical treatments (for example, timolol).11 Lesion recurrence can occur with both surgical and nonsurgical management.11 Regardless of management technique, it is useful to obtain histopathologic evaluation of tissue for accurate diagnosis.
Our patient underwent surgical destruction of her lower-lip lesion with shave excision followed by electrocautery. The surgical specimen was sent for pathology, which confirmed the diagnosis of pyogenic granuloma. The patient experienced no complications from the procedure and did not have recurrence of the lesion.
Ms. Sui is a research associate in the department of dermatology, division of pediatric and adolescent dermatology, University of California, San Diego, and Rady Children’s Hospital, San Diego. Dr. Eichenfield is vice chair of the department of dermatology and professor of dermatology and pediatrics at the University of California, San Diego, and Rady Children’s Hospital, San Diego. Neither Ms. Sui nor Dr. Eichenfield have any relevant financial disclosures.
References
1. Lin RL and Janniger CK. Cutis. 2004 Oct;74(4):229-33.
2. Harris MN et al. J Am Acad Dermatol. 2000 Jun;42(6):1012-6.
3. Pagliai KA and Cohen BA. Pediatr Dermatol. 2004 Jan-Feb;21(1):10-3.
4. Kamal R et al. J Oral Maxillofac Pathol. 2012 Jan;16(1):79-82.
5. Requena L and Sangueza OP. J Am Acad Dermatol. 1997 Dec;37(6):887-919.
6. Patrice SJ et al. Pediatr Dermatol. 1991 Dec;8(4):267-76.
7. Luba MC et al. Am Fam Physician. 2003 Feb 15;67(4):729-38.
8. Swerlick RA and Cooper PH. J Am Acad Dermatol. 1983 May;8(5):627-30.
9. Sheehan DJ and Lesher JL Jr. Cutis. 2004 Mar;73(3):175-80.
10. Zaballos P et al. Br J Dermatol. 2006 Jun;154(6):1108-11.
11. Lee J et al. J Plast Reconstr Aesthet Surg. 2011 Sep;64(9):1216-20. .
Night owls may have greater risks of T2D and CVD
In the study involving 51 people, night owls metabolized fat less efficiently, showed less insulin sensitivity, and demonstrated lower physical fitness than early birds, lead author Steven K. Malin, PhD, of Rutgers University, New Brunswick, N.J., and colleagues reported.
Prior publications have suggested that night owls, formally known as “late chronotypes,” have an increased risk of obesity, type 2 diabetes, and cardiovascular disease, Dr. Malin said in an interview. But no previous research involved the gold-standard measurement tools used in this study, including euglycemic clamp and indirect calorimetry to quantify fat metabolism.
Dr. Malin also noted that this is the first study of its kind to characterize metabolism during both rest and exercise.
The study, published in Experimental Physiology, involved 24 early birds and 27 night owls classified by the Morning-Eveningness Questionnaire. All participants were sedentary, reporting less than one hour of structured exercise per week, and had metabolic syndrome according to Adult Treatment Panel III report criteria. Groups were otherwise demographically similar, with average ages in each group of approximately 54-55 years.
Compared with night owls, early birds were more physically active during the morning into midday. During exercise, they metabolized more fat and demonstrated greater physical fitness based on VO2max readings. At rest, early birds also came out ahead – they had higher fat oxidation and non–oxidative glucose disposal, suggesting more sensitivity to insulin.
“Collectively, this work highlights and supports chronotype as a potential risk factor related to type 2 diabetes and cardiovascular disease risk,” the investigators concluded.
Night owls have less metabolic control
Jed Friedman, PhD, director of OU Health Harold Hamm Diabetes Center at the University of Oklahoma Health Sciences Center, Oklahoma City, praised the study for the size of the groups the researchers compared with each other and how well matched those groups were, as well as the “state-of-the-art” measurement tools employed.
The findings show that night owls have “less metabolic control,” Dr. Friedman said in an interview.
“That’s a term that’s frequently invoked in [regard to] prediabetes,” he said. “Blood sugar goes up, because when you’re eating a high carbohydrate diet, your cells aren’t metabolizing sugar properly. That tends to raise your risk for a lot of diseases.”
Dr. Friedman added that the findings align with those of previous studies that have linked less sleep with changes in brain biology, and therefore behavior, especially in dietary choices.
“When you’re tired, the mechanisms for appetite control go haywire,” Dr. Friedman explained. “The evidence suggests that sugar is the primary driver for what people eat when they’re tired. That obviously has implications for diabetes and metabolic syndrome. So sleeping more really can help you control cravings.”
Dr. Friedman also noted that people who are tired tend to engage in less physical activity, further increasing their risk of metabolic issues. To control this risk, he advised people to return to their circadian rhythms, which could mean forgetting the midnight snack.
“Having a daily pattern that’s in sync with chronicity, or these daily rhythms, is associated with greater health,” Dr. Friedman said. “We’re not really made to eat at night. I think this [study] kind of reinforces that.”
Can a night owl become an early bird?
When asked if a person’s natural circadian rhythm can be later, Dr. Malin responded that chronotypes may be dictated by genetics and age, as well as external drivers like work schedule. For these reasons, it’s “tricky” to answer whether night owls can turn into early birds and reap the potential health benefits of making that shift.
“Given that so many life factors can influence what our routine entails, it’s hard to know if we [can] truly change our chronotype or if rather we [can] learn to manage,” Dr. Malin said. “In either case, there is some work that suggests people can adopt earlier bedtimes and waketimes through practical recommendations.”
Specifically, he suggested increasing physical activity during the day, and adjusting bedtimes gradually by 15-minute increments.
“Go to bed 15 minutes earlier then wake up 15 minutes earlier,” Dr. Malin said. “In time, and depending on how things are going, this can expand to another 15-minute window. Then, during the earlier time waking up, a person can engage in light physical activity to help with promoting general fitness. If they can get outside with sunlight, that would be great too, as the natural sunlight would provide cues to the circadian system to adjust.”
The study was supported by the National Institutes of Health. The investigators and Dr. Friedman disclosed no conflicts of interest.
In the study involving 51 people, night owls metabolized fat less efficiently, showed less insulin sensitivity, and demonstrated lower physical fitness than early birds, lead author Steven K. Malin, PhD, of Rutgers University, New Brunswick, N.J., and colleagues reported.
Prior publications have suggested that night owls, formally known as “late chronotypes,” have an increased risk of obesity, type 2 diabetes, and cardiovascular disease, Dr. Malin said in an interview. But no previous research involved the gold-standard measurement tools used in this study, including euglycemic clamp and indirect calorimetry to quantify fat metabolism.
Dr. Malin also noted that this is the first study of its kind to characterize metabolism during both rest and exercise.
The study, published in Experimental Physiology, involved 24 early birds and 27 night owls classified by the Morning-Eveningness Questionnaire. All participants were sedentary, reporting less than one hour of structured exercise per week, and had metabolic syndrome according to Adult Treatment Panel III report criteria. Groups were otherwise demographically similar, with average ages in each group of approximately 54-55 years.
Compared with night owls, early birds were more physically active during the morning into midday. During exercise, they metabolized more fat and demonstrated greater physical fitness based on VO2max readings. At rest, early birds also came out ahead – they had higher fat oxidation and non–oxidative glucose disposal, suggesting more sensitivity to insulin.
“Collectively, this work highlights and supports chronotype as a potential risk factor related to type 2 diabetes and cardiovascular disease risk,” the investigators concluded.
Night owls have less metabolic control
Jed Friedman, PhD, director of OU Health Harold Hamm Diabetes Center at the University of Oklahoma Health Sciences Center, Oklahoma City, praised the study for the size of the groups the researchers compared with each other and how well matched those groups were, as well as the “state-of-the-art” measurement tools employed.
The findings show that night owls have “less metabolic control,” Dr. Friedman said in an interview.
“That’s a term that’s frequently invoked in [regard to] prediabetes,” he said. “Blood sugar goes up, because when you’re eating a high carbohydrate diet, your cells aren’t metabolizing sugar properly. That tends to raise your risk for a lot of diseases.”
Dr. Friedman added that the findings align with those of previous studies that have linked less sleep with changes in brain biology, and therefore behavior, especially in dietary choices.
“When you’re tired, the mechanisms for appetite control go haywire,” Dr. Friedman explained. “The evidence suggests that sugar is the primary driver for what people eat when they’re tired. That obviously has implications for diabetes and metabolic syndrome. So sleeping more really can help you control cravings.”
Dr. Friedman also noted that people who are tired tend to engage in less physical activity, further increasing their risk of metabolic issues. To control this risk, he advised people to return to their circadian rhythms, which could mean forgetting the midnight snack.
“Having a daily pattern that’s in sync with chronicity, or these daily rhythms, is associated with greater health,” Dr. Friedman said. “We’re not really made to eat at night. I think this [study] kind of reinforces that.”
Can a night owl become an early bird?
When asked if a person’s natural circadian rhythm can be later, Dr. Malin responded that chronotypes may be dictated by genetics and age, as well as external drivers like work schedule. For these reasons, it’s “tricky” to answer whether night owls can turn into early birds and reap the potential health benefits of making that shift.
“Given that so many life factors can influence what our routine entails, it’s hard to know if we [can] truly change our chronotype or if rather we [can] learn to manage,” Dr. Malin said. “In either case, there is some work that suggests people can adopt earlier bedtimes and waketimes through practical recommendations.”
Specifically, he suggested increasing physical activity during the day, and adjusting bedtimes gradually by 15-minute increments.
“Go to bed 15 minutes earlier then wake up 15 minutes earlier,” Dr. Malin said. “In time, and depending on how things are going, this can expand to another 15-minute window. Then, during the earlier time waking up, a person can engage in light physical activity to help with promoting general fitness. If they can get outside with sunlight, that would be great too, as the natural sunlight would provide cues to the circadian system to adjust.”
The study was supported by the National Institutes of Health. The investigators and Dr. Friedman disclosed no conflicts of interest.
In the study involving 51 people, night owls metabolized fat less efficiently, showed less insulin sensitivity, and demonstrated lower physical fitness than early birds, lead author Steven K. Malin, PhD, of Rutgers University, New Brunswick, N.J., and colleagues reported.
Prior publications have suggested that night owls, formally known as “late chronotypes,” have an increased risk of obesity, type 2 diabetes, and cardiovascular disease, Dr. Malin said in an interview. But no previous research involved the gold-standard measurement tools used in this study, including euglycemic clamp and indirect calorimetry to quantify fat metabolism.
Dr. Malin also noted that this is the first study of its kind to characterize metabolism during both rest and exercise.
The study, published in Experimental Physiology, involved 24 early birds and 27 night owls classified by the Morning-Eveningness Questionnaire. All participants were sedentary, reporting less than one hour of structured exercise per week, and had metabolic syndrome according to Adult Treatment Panel III report criteria. Groups were otherwise demographically similar, with average ages in each group of approximately 54-55 years.
Compared with night owls, early birds were more physically active during the morning into midday. During exercise, they metabolized more fat and demonstrated greater physical fitness based on VO2max readings. At rest, early birds also came out ahead – they had higher fat oxidation and non–oxidative glucose disposal, suggesting more sensitivity to insulin.
“Collectively, this work highlights and supports chronotype as a potential risk factor related to type 2 diabetes and cardiovascular disease risk,” the investigators concluded.
Night owls have less metabolic control
Jed Friedman, PhD, director of OU Health Harold Hamm Diabetes Center at the University of Oklahoma Health Sciences Center, Oklahoma City, praised the study for the size of the groups the researchers compared with each other and how well matched those groups were, as well as the “state-of-the-art” measurement tools employed.
The findings show that night owls have “less metabolic control,” Dr. Friedman said in an interview.
“That’s a term that’s frequently invoked in [regard to] prediabetes,” he said. “Blood sugar goes up, because when you’re eating a high carbohydrate diet, your cells aren’t metabolizing sugar properly. That tends to raise your risk for a lot of diseases.”
Dr. Friedman added that the findings align with those of previous studies that have linked less sleep with changes in brain biology, and therefore behavior, especially in dietary choices.
“When you’re tired, the mechanisms for appetite control go haywire,” Dr. Friedman explained. “The evidence suggests that sugar is the primary driver for what people eat when they’re tired. That obviously has implications for diabetes and metabolic syndrome. So sleeping more really can help you control cravings.”
Dr. Friedman also noted that people who are tired tend to engage in less physical activity, further increasing their risk of metabolic issues. To control this risk, he advised people to return to their circadian rhythms, which could mean forgetting the midnight snack.
“Having a daily pattern that’s in sync with chronicity, or these daily rhythms, is associated with greater health,” Dr. Friedman said. “We’re not really made to eat at night. I think this [study] kind of reinforces that.”
Can a night owl become an early bird?
When asked if a person’s natural circadian rhythm can be later, Dr. Malin responded that chronotypes may be dictated by genetics and age, as well as external drivers like work schedule. For these reasons, it’s “tricky” to answer whether night owls can turn into early birds and reap the potential health benefits of making that shift.
“Given that so many life factors can influence what our routine entails, it’s hard to know if we [can] truly change our chronotype or if rather we [can] learn to manage,” Dr. Malin said. “In either case, there is some work that suggests people can adopt earlier bedtimes and waketimes through practical recommendations.”
Specifically, he suggested increasing physical activity during the day, and adjusting bedtimes gradually by 15-minute increments.
“Go to bed 15 minutes earlier then wake up 15 minutes earlier,” Dr. Malin said. “In time, and depending on how things are going, this can expand to another 15-minute window. Then, during the earlier time waking up, a person can engage in light physical activity to help with promoting general fitness. If they can get outside with sunlight, that would be great too, as the natural sunlight would provide cues to the circadian system to adjust.”
The study was supported by the National Institutes of Health. The investigators and Dr. Friedman disclosed no conflicts of interest.
FROM EXPERIMENTAL PHYSIOLOGY