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Next-gen triple correctors look safe and effective for cystic fibrosis
Adding a next-generation corrector to dual corrector-potentiator therapy is safe and effective in cystic fibrosis patients with one or two Phe508del alleles, results of two randomized phase 2, proof-of-concept clinical trials suggest.
The were reported in the New England Journal of Medicine.
Both triple combinations improved lung function for patients heterozygous for the Phe508del cystic fibrosis transmembrane conductance regulator (CFTR) mutation and a minimal function mutation (Phe508del-MF) who had not previously received CFTR modulators, according to the investigators, who reported results simultaneously at the North American Cystic Fibrosis Conference in Denver.
These therapies also were effective in patients homozygous for Phe508del CFTR mutation (Phe508del-Phe508del) who had previously been treated with tezacaftor-ivacaftor, the results show.
No dose-limiting side effects or toxic effects were observed in the phase 2 studies, which included 4-week treatment periods.
“These trials provide proof of the concept that targeting the Phe508del CFTR protein with a triple-combination corrector–potentiator regimen can restore CFTR function and has the potential to represent a clinical advance for patients with cystic fibrosis who harbor either one or two Phe508del alleles, approximately 9 of every 10 patients with the disease,” Steven M. Rowe, MD, of the University of Alabama at Birmingham and his coauthors said in the report on VX-659 phase 2 study.
In that report, 63 patients with the Phe508del-MF genotype were randomized to one of three VX-659 doses in combination with tezacaftor and ivacaftor versus triple placebo for 4 weeks, while 29 Phe508del-Phe508del patients underwent a 4-week tezacaftor-ivacaftor run-in phase before starting 4 weeks of the triple combination.
The primary efficacy endpoint of the study was the absolute increase in percentage of predicted forced expiratory volume in 1 second (FEV1).
In the Phe508del-MF patients, adding VX-659 improved that endpoint by up to 13.3 points versus baseline (P less than .001), whereas the absolute change was just 0.4 in the placebo group, the report shows. In the Phe508del-phe508del group, there was a 9.7-point increase over baseline.
Similarly, the companion study on VX-445, reported by Jennifer L. Taylor‑Cousar, MD, of National Jewish Health, Denver, and her colleagues, showed an increase in percentage of predicted FEV1 of up to 13.8 points for Phe508del-MF patients (P less than .001), and an increase of 11.0 points in the Phe508del-Phe508del group (P less than .001).
Those results suggest that targeting the Phe508del CFTR mutation with a combination of two correctors and a potentiator can produce effective CFTR function in patients who have these forms of cystic fibrosis, according to Dr. Taylor-Cousar and her colleagues.
“Lung function was improved by a magnitude similar to that achieved with the CFTR modulator ivacaftor in patients with gating mutations, in whom treatment has been disease modifying,” the researchers wrote in their report.
Sweat chloride concentrations were reduced and respiratory domain scores were improved in patients receiving triple therapy, investigators reported.
Triple therapy improved Phe508del CFTR protein processing and trafficking, and chloride transport more so than any two agents in combination, according in vitro results, also described in the studies.
Phase 3 trials of these compounds are now underway, they said.
Both studies were supported by Vertex Pharmaceuticals, which received funding from the Cystic Fibrosis Foundation for the development of both VX-445 and VX-659. Dr. Rowe and Dr. Taylor-Cousar reported grants, personal fees, and nonfinancial support from Vertex while conducting the study. Study authors also reported disclosures related to AstraZeneca, Novartis, Bayer, Proteostasis, Gilead, Galapagos/AbbVie, and Celtaxsys, among other entities. Full disclosures for all authors were provided in the journal.
SOURCES: Keating D et al. N Engl J Med. 2018 Oct 18. doi: 10.1056/NEJMoa1807120; Davies JC et al. N Engl J Med. 2018 Oct 18. doi: 10.1056/NEJMoa1807119.
These recent investigations show that triple combination therapy improves lung function more than double combination therapy in patients with cystic fibrosis and Phe508del mutations, according to Fernando Holguin, MD, of the division of pulmonary sciences and critical care at the University of Colorado, Aurora.
“These reports represent a major breakthrough in cystic fibrosis therapeutics, with the potential for improving health and possibly survival in all patients who carry the most common cystic fibrosis transmembrane conductance regulator [CFTR] mutation,” Dr. Holguin said in an editorial.
Neither study reported dose-limiting side effects or toxicity, and only three patients in the VX-445 study stopped treatment due to adverse events, he remarked in his editorial.
However, it remains to be seen whether the lung function improvements will be maintained for longer treatment periods, he said. Patients in the phase 2 studies received a total of 4 weeks of the trial regimen, according to the reports. Also unknown is whether the new therapies will reduce exacerbation rates, or impact outcomes such as weight gain.
“These questions should soon be answered in the ongoing phase 3 trials of these regimens,” he added.
These comments are excerpted from an editorial by Dr. Holguin that accompanied the study (N Eng J Med. Oct 18; doi: 10.1056/NEJMe1811996). Dr. Holguin reported that he had no disclosures related to his editorial.
These recent investigations show that triple combination therapy improves lung function more than double combination therapy in patients with cystic fibrosis and Phe508del mutations, according to Fernando Holguin, MD, of the division of pulmonary sciences and critical care at the University of Colorado, Aurora.
“These reports represent a major breakthrough in cystic fibrosis therapeutics, with the potential for improving health and possibly survival in all patients who carry the most common cystic fibrosis transmembrane conductance regulator [CFTR] mutation,” Dr. Holguin said in an editorial.
Neither study reported dose-limiting side effects or toxicity, and only three patients in the VX-445 study stopped treatment due to adverse events, he remarked in his editorial.
However, it remains to be seen whether the lung function improvements will be maintained for longer treatment periods, he said. Patients in the phase 2 studies received a total of 4 weeks of the trial regimen, according to the reports. Also unknown is whether the new therapies will reduce exacerbation rates, or impact outcomes such as weight gain.
“These questions should soon be answered in the ongoing phase 3 trials of these regimens,” he added.
These comments are excerpted from an editorial by Dr. Holguin that accompanied the study (N Eng J Med. Oct 18; doi: 10.1056/NEJMe1811996). Dr. Holguin reported that he had no disclosures related to his editorial.
These recent investigations show that triple combination therapy improves lung function more than double combination therapy in patients with cystic fibrosis and Phe508del mutations, according to Fernando Holguin, MD, of the division of pulmonary sciences and critical care at the University of Colorado, Aurora.
“These reports represent a major breakthrough in cystic fibrosis therapeutics, with the potential for improving health and possibly survival in all patients who carry the most common cystic fibrosis transmembrane conductance regulator [CFTR] mutation,” Dr. Holguin said in an editorial.
Neither study reported dose-limiting side effects or toxicity, and only three patients in the VX-445 study stopped treatment due to adverse events, he remarked in his editorial.
However, it remains to be seen whether the lung function improvements will be maintained for longer treatment periods, he said. Patients in the phase 2 studies received a total of 4 weeks of the trial regimen, according to the reports. Also unknown is whether the new therapies will reduce exacerbation rates, or impact outcomes such as weight gain.
“These questions should soon be answered in the ongoing phase 3 trials of these regimens,” he added.
These comments are excerpted from an editorial by Dr. Holguin that accompanied the study (N Eng J Med. Oct 18; doi: 10.1056/NEJMe1811996). Dr. Holguin reported that he had no disclosures related to his editorial.
Adding a next-generation corrector to dual corrector-potentiator therapy is safe and effective in cystic fibrosis patients with one or two Phe508del alleles, results of two randomized phase 2, proof-of-concept clinical trials suggest.
The were reported in the New England Journal of Medicine.
Both triple combinations improved lung function for patients heterozygous for the Phe508del cystic fibrosis transmembrane conductance regulator (CFTR) mutation and a minimal function mutation (Phe508del-MF) who had not previously received CFTR modulators, according to the investigators, who reported results simultaneously at the North American Cystic Fibrosis Conference in Denver.
These therapies also were effective in patients homozygous for Phe508del CFTR mutation (Phe508del-Phe508del) who had previously been treated with tezacaftor-ivacaftor, the results show.
No dose-limiting side effects or toxic effects were observed in the phase 2 studies, which included 4-week treatment periods.
“These trials provide proof of the concept that targeting the Phe508del CFTR protein with a triple-combination corrector–potentiator regimen can restore CFTR function and has the potential to represent a clinical advance for patients with cystic fibrosis who harbor either one or two Phe508del alleles, approximately 9 of every 10 patients with the disease,” Steven M. Rowe, MD, of the University of Alabama at Birmingham and his coauthors said in the report on VX-659 phase 2 study.
In that report, 63 patients with the Phe508del-MF genotype were randomized to one of three VX-659 doses in combination with tezacaftor and ivacaftor versus triple placebo for 4 weeks, while 29 Phe508del-Phe508del patients underwent a 4-week tezacaftor-ivacaftor run-in phase before starting 4 weeks of the triple combination.
The primary efficacy endpoint of the study was the absolute increase in percentage of predicted forced expiratory volume in 1 second (FEV1).
In the Phe508del-MF patients, adding VX-659 improved that endpoint by up to 13.3 points versus baseline (P less than .001), whereas the absolute change was just 0.4 in the placebo group, the report shows. In the Phe508del-phe508del group, there was a 9.7-point increase over baseline.
Similarly, the companion study on VX-445, reported by Jennifer L. Taylor‑Cousar, MD, of National Jewish Health, Denver, and her colleagues, showed an increase in percentage of predicted FEV1 of up to 13.8 points for Phe508del-MF patients (P less than .001), and an increase of 11.0 points in the Phe508del-Phe508del group (P less than .001).
Those results suggest that targeting the Phe508del CFTR mutation with a combination of two correctors and a potentiator can produce effective CFTR function in patients who have these forms of cystic fibrosis, according to Dr. Taylor-Cousar and her colleagues.
“Lung function was improved by a magnitude similar to that achieved with the CFTR modulator ivacaftor in patients with gating mutations, in whom treatment has been disease modifying,” the researchers wrote in their report.
Sweat chloride concentrations were reduced and respiratory domain scores were improved in patients receiving triple therapy, investigators reported.
Triple therapy improved Phe508del CFTR protein processing and trafficking, and chloride transport more so than any two agents in combination, according in vitro results, also described in the studies.
Phase 3 trials of these compounds are now underway, they said.
Both studies were supported by Vertex Pharmaceuticals, which received funding from the Cystic Fibrosis Foundation for the development of both VX-445 and VX-659. Dr. Rowe and Dr. Taylor-Cousar reported grants, personal fees, and nonfinancial support from Vertex while conducting the study. Study authors also reported disclosures related to AstraZeneca, Novartis, Bayer, Proteostasis, Gilead, Galapagos/AbbVie, and Celtaxsys, among other entities. Full disclosures for all authors were provided in the journal.
SOURCES: Keating D et al. N Engl J Med. 2018 Oct 18. doi: 10.1056/NEJMoa1807120; Davies JC et al. N Engl J Med. 2018 Oct 18. doi: 10.1056/NEJMoa1807119.
Adding a next-generation corrector to dual corrector-potentiator therapy is safe and effective in cystic fibrosis patients with one or two Phe508del alleles, results of two randomized phase 2, proof-of-concept clinical trials suggest.
The were reported in the New England Journal of Medicine.
Both triple combinations improved lung function for patients heterozygous for the Phe508del cystic fibrosis transmembrane conductance regulator (CFTR) mutation and a minimal function mutation (Phe508del-MF) who had not previously received CFTR modulators, according to the investigators, who reported results simultaneously at the North American Cystic Fibrosis Conference in Denver.
These therapies also were effective in patients homozygous for Phe508del CFTR mutation (Phe508del-Phe508del) who had previously been treated with tezacaftor-ivacaftor, the results show.
No dose-limiting side effects or toxic effects were observed in the phase 2 studies, which included 4-week treatment periods.
“These trials provide proof of the concept that targeting the Phe508del CFTR protein with a triple-combination corrector–potentiator regimen can restore CFTR function and has the potential to represent a clinical advance for patients with cystic fibrosis who harbor either one or two Phe508del alleles, approximately 9 of every 10 patients with the disease,” Steven M. Rowe, MD, of the University of Alabama at Birmingham and his coauthors said in the report on VX-659 phase 2 study.
In that report, 63 patients with the Phe508del-MF genotype were randomized to one of three VX-659 doses in combination with tezacaftor and ivacaftor versus triple placebo for 4 weeks, while 29 Phe508del-Phe508del patients underwent a 4-week tezacaftor-ivacaftor run-in phase before starting 4 weeks of the triple combination.
The primary efficacy endpoint of the study was the absolute increase in percentage of predicted forced expiratory volume in 1 second (FEV1).
In the Phe508del-MF patients, adding VX-659 improved that endpoint by up to 13.3 points versus baseline (P less than .001), whereas the absolute change was just 0.4 in the placebo group, the report shows. In the Phe508del-phe508del group, there was a 9.7-point increase over baseline.
Similarly, the companion study on VX-445, reported by Jennifer L. Taylor‑Cousar, MD, of National Jewish Health, Denver, and her colleagues, showed an increase in percentage of predicted FEV1 of up to 13.8 points for Phe508del-MF patients (P less than .001), and an increase of 11.0 points in the Phe508del-Phe508del group (P less than .001).
Those results suggest that targeting the Phe508del CFTR mutation with a combination of two correctors and a potentiator can produce effective CFTR function in patients who have these forms of cystic fibrosis, according to Dr. Taylor-Cousar and her colleagues.
“Lung function was improved by a magnitude similar to that achieved with the CFTR modulator ivacaftor in patients with gating mutations, in whom treatment has been disease modifying,” the researchers wrote in their report.
Sweat chloride concentrations were reduced and respiratory domain scores were improved in patients receiving triple therapy, investigators reported.
Triple therapy improved Phe508del CFTR protein processing and trafficking, and chloride transport more so than any two agents in combination, according in vitro results, also described in the studies.
Phase 3 trials of these compounds are now underway, they said.
Both studies were supported by Vertex Pharmaceuticals, which received funding from the Cystic Fibrosis Foundation for the development of both VX-445 and VX-659. Dr. Rowe and Dr. Taylor-Cousar reported grants, personal fees, and nonfinancial support from Vertex while conducting the study. Study authors also reported disclosures related to AstraZeneca, Novartis, Bayer, Proteostasis, Gilead, Galapagos/AbbVie, and Celtaxsys, among other entities. Full disclosures for all authors were provided in the journal.
SOURCES: Keating D et al. N Engl J Med. 2018 Oct 18. doi: 10.1056/NEJMoa1807120; Davies JC et al. N Engl J Med. 2018 Oct 18. doi: 10.1056/NEJMoa1807119.
FROM THE NEW ENGLAND JOURNAL OF MEDICINE
Key clinical point: Adding the next-generation correctors VX-445 or VX-659 to tezacaftor-ivacaftor was safe and improved lung function in patients with one or two Phe508del alleles.
Major finding: Improvements of up to 13.8 points over baseline were noted in absolute increase in percentage of predicted FEV1, the primary efficacy endpoint of the investigations.
Study details: Companion phase 2, randomized proof-of-concept studies included a total of 117 and 123 patients with cystic fibrosis.
Disclosures: Both studies were supported by Vertex Pharmaceuticals. Lead investigators reported grants, personal fees, and nonfinancial support from Vertex during the study. Other disclosures reported were related to AstraZeneca, Novartis, Bayer, Gilead, and Galapagos/AbbVie, among others.
Sources: Keating D et al. N Engl J Med. 2018 Oct 18. doi: 10.1056/NEJMoa1807120; Davies JC et al. N Engl J Med. 2018 Oct 18. doi: 10.1056/NEJMoa1807119.
Flu vaccination lags among patients with psoriasis
Psoriasis patients are more vulnerable to systemic infections, including influenza-related pneumonia, but a new study shows that they are less likely to receive the influenza vaccine than patients with RA.
Vaccination rates were higher in psoriasis patients aged over 50 years, those who were female, and those with other chronic medical conditions, however.
Megan H. Noe, MD, of the department of dermatology at the University of Pennsylvania, Philadelphia, and her coauthors referred to recent evidence suggesting that psoriasis involves systemic inflammation that increase the risk of comorbidities and that hospitalization rates for serious infections, including lower respiratory tract infections and pneumonia, are higher among adults with psoriasis than those who do not have psoriasis.
drawing from administrative and commercial claims data from OptumInsight Clinformatics Data Mart. They examined all adult patients with psoriasis, RA, or chronic hypertension who required oral antihypertensive medication. The study population included individuals tracked during the 2010-2011 flu season and 24 months prior (September 2008 to March 2011). This year was chosen because it was labeled as a “typical” season by the Centers for Disease Control and Prevention.
The primary outcome was a claim for an influenza vaccine, and covariates included age, length of residency, gender, and a clinical history of a range of conditions known to be associated with greater risk of influenza complications.
The population included 17,078 patients with psoriasis, 21,832 with RA, and 496,972 with chronic hypertension. After controlling for sex and age, the probability of getting a flu vaccine was similar between psoriasis and hypertension patients, but RA patients were more likely to be vaccinated than patients with psoriasis (odds ratio, 1.08; 95% confidence interval, 1.03-1.13). But the likelihood varied with age: 30-year-old patients with RA were more likely than a 30-year-old psoriasis patient to get a flu shot (OR, 1.30; 95% CI, 1.18-1.45), while a 70-year-old patient with RA was about as likely to get the flu vaccine as a 70-year-old patient with psoriasis.
Female psoriasis patients were more likely to get a flu shot than males (OR, 1.29; 95% CI, 1.20-1.38). Among the psoriasis patients, having some medical comorbidities were linked to a greater likelihood of being vaccinated, including asthma (OR, 1.58; 95% CI, 1.40-1.77), chronic liver disease (OR, 1.23; 95%, 1.03-1.47), diabetes (OR, 1.48; 95% CI, 1.36-1.63), HIV (OR, 3.68; 95% CI, 2.06-6.57), history of malignancy (OR, 1.21; 95% CI, 1.09-1.34), and psoriatic arthritis (OR, 1.40; 95% CI, 1.25-1.58).
There was no association between the use of an oral systemic therapy or biologic treatment and vaccination rates.
The authors suggested that psoriasis patients, especially younger ones, may not get adequate counseling on the value of the flu vaccine from their physicians. Studies have shown that, among the American public, health care providers are the most influential source of information about the flu vaccine. Among younger patients, the dermatologist may be a psoriasis patient’s primary health care provider, so it is important for dermatologists to counsel patients about the recommended vaccines, the authors wrote.
“Further research understanding why adults with psoriasis do not receive recommended vaccinations will help to create targeted interventions to improve vaccination rates and decrease hospitalizations in adults with psoriasis,” they concluded.
The study relied on administrative claims, so the results may not be generalizable to patients with insurance types other than those in the database or who are uninsured, the authors noted.
This study was funded by the National Psoriasis Foundation, the Dermatology Foundation, and the National Institute of Arthritis and Musculoskeletal and Skin Diseases. Dr. Noe and three other authors did not report any disclosures, the fifth author reported multiple disclosures related to various pharmaceutical companies.
SOURCE: Noe MH et al. J Invest Dermatol. 2018 Oct 10. doi: 10.1016/j.jid.2018.09.012.
Psoriasis patients are more vulnerable to systemic infections, including influenza-related pneumonia, but a new study shows that they are less likely to receive the influenza vaccine than patients with RA.
Vaccination rates were higher in psoriasis patients aged over 50 years, those who were female, and those with other chronic medical conditions, however.
Megan H. Noe, MD, of the department of dermatology at the University of Pennsylvania, Philadelphia, and her coauthors referred to recent evidence suggesting that psoriasis involves systemic inflammation that increase the risk of comorbidities and that hospitalization rates for serious infections, including lower respiratory tract infections and pneumonia, are higher among adults with psoriasis than those who do not have psoriasis.
drawing from administrative and commercial claims data from OptumInsight Clinformatics Data Mart. They examined all adult patients with psoriasis, RA, or chronic hypertension who required oral antihypertensive medication. The study population included individuals tracked during the 2010-2011 flu season and 24 months prior (September 2008 to March 2011). This year was chosen because it was labeled as a “typical” season by the Centers for Disease Control and Prevention.
The primary outcome was a claim for an influenza vaccine, and covariates included age, length of residency, gender, and a clinical history of a range of conditions known to be associated with greater risk of influenza complications.
The population included 17,078 patients with psoriasis, 21,832 with RA, and 496,972 with chronic hypertension. After controlling for sex and age, the probability of getting a flu vaccine was similar between psoriasis and hypertension patients, but RA patients were more likely to be vaccinated than patients with psoriasis (odds ratio, 1.08; 95% confidence interval, 1.03-1.13). But the likelihood varied with age: 30-year-old patients with RA were more likely than a 30-year-old psoriasis patient to get a flu shot (OR, 1.30; 95% CI, 1.18-1.45), while a 70-year-old patient with RA was about as likely to get the flu vaccine as a 70-year-old patient with psoriasis.
Female psoriasis patients were more likely to get a flu shot than males (OR, 1.29; 95% CI, 1.20-1.38). Among the psoriasis patients, having some medical comorbidities were linked to a greater likelihood of being vaccinated, including asthma (OR, 1.58; 95% CI, 1.40-1.77), chronic liver disease (OR, 1.23; 95%, 1.03-1.47), diabetes (OR, 1.48; 95% CI, 1.36-1.63), HIV (OR, 3.68; 95% CI, 2.06-6.57), history of malignancy (OR, 1.21; 95% CI, 1.09-1.34), and psoriatic arthritis (OR, 1.40; 95% CI, 1.25-1.58).
There was no association between the use of an oral systemic therapy or biologic treatment and vaccination rates.
The authors suggested that psoriasis patients, especially younger ones, may not get adequate counseling on the value of the flu vaccine from their physicians. Studies have shown that, among the American public, health care providers are the most influential source of information about the flu vaccine. Among younger patients, the dermatologist may be a psoriasis patient’s primary health care provider, so it is important for dermatologists to counsel patients about the recommended vaccines, the authors wrote.
“Further research understanding why adults with psoriasis do not receive recommended vaccinations will help to create targeted interventions to improve vaccination rates and decrease hospitalizations in adults with psoriasis,” they concluded.
The study relied on administrative claims, so the results may not be generalizable to patients with insurance types other than those in the database or who are uninsured, the authors noted.
This study was funded by the National Psoriasis Foundation, the Dermatology Foundation, and the National Institute of Arthritis and Musculoskeletal and Skin Diseases. Dr. Noe and three other authors did not report any disclosures, the fifth author reported multiple disclosures related to various pharmaceutical companies.
SOURCE: Noe MH et al. J Invest Dermatol. 2018 Oct 10. doi: 10.1016/j.jid.2018.09.012.
Psoriasis patients are more vulnerable to systemic infections, including influenza-related pneumonia, but a new study shows that they are less likely to receive the influenza vaccine than patients with RA.
Vaccination rates were higher in psoriasis patients aged over 50 years, those who were female, and those with other chronic medical conditions, however.
Megan H. Noe, MD, of the department of dermatology at the University of Pennsylvania, Philadelphia, and her coauthors referred to recent evidence suggesting that psoriasis involves systemic inflammation that increase the risk of comorbidities and that hospitalization rates for serious infections, including lower respiratory tract infections and pneumonia, are higher among adults with psoriasis than those who do not have psoriasis.
drawing from administrative and commercial claims data from OptumInsight Clinformatics Data Mart. They examined all adult patients with psoriasis, RA, or chronic hypertension who required oral antihypertensive medication. The study population included individuals tracked during the 2010-2011 flu season and 24 months prior (September 2008 to March 2011). This year was chosen because it was labeled as a “typical” season by the Centers for Disease Control and Prevention.
The primary outcome was a claim for an influenza vaccine, and covariates included age, length of residency, gender, and a clinical history of a range of conditions known to be associated with greater risk of influenza complications.
The population included 17,078 patients with psoriasis, 21,832 with RA, and 496,972 with chronic hypertension. After controlling for sex and age, the probability of getting a flu vaccine was similar between psoriasis and hypertension patients, but RA patients were more likely to be vaccinated than patients with psoriasis (odds ratio, 1.08; 95% confidence interval, 1.03-1.13). But the likelihood varied with age: 30-year-old patients with RA were more likely than a 30-year-old psoriasis patient to get a flu shot (OR, 1.30; 95% CI, 1.18-1.45), while a 70-year-old patient with RA was about as likely to get the flu vaccine as a 70-year-old patient with psoriasis.
Female psoriasis patients were more likely to get a flu shot than males (OR, 1.29; 95% CI, 1.20-1.38). Among the psoriasis patients, having some medical comorbidities were linked to a greater likelihood of being vaccinated, including asthma (OR, 1.58; 95% CI, 1.40-1.77), chronic liver disease (OR, 1.23; 95%, 1.03-1.47), diabetes (OR, 1.48; 95% CI, 1.36-1.63), HIV (OR, 3.68; 95% CI, 2.06-6.57), history of malignancy (OR, 1.21; 95% CI, 1.09-1.34), and psoriatic arthritis (OR, 1.40; 95% CI, 1.25-1.58).
There was no association between the use of an oral systemic therapy or biologic treatment and vaccination rates.
The authors suggested that psoriasis patients, especially younger ones, may not get adequate counseling on the value of the flu vaccine from their physicians. Studies have shown that, among the American public, health care providers are the most influential source of information about the flu vaccine. Among younger patients, the dermatologist may be a psoriasis patient’s primary health care provider, so it is important for dermatologists to counsel patients about the recommended vaccines, the authors wrote.
“Further research understanding why adults with psoriasis do not receive recommended vaccinations will help to create targeted interventions to improve vaccination rates and decrease hospitalizations in adults with psoriasis,” they concluded.
The study relied on administrative claims, so the results may not be generalizable to patients with insurance types other than those in the database or who are uninsured, the authors noted.
This study was funded by the National Psoriasis Foundation, the Dermatology Foundation, and the National Institute of Arthritis and Musculoskeletal and Skin Diseases. Dr. Noe and three other authors did not report any disclosures, the fifth author reported multiple disclosures related to various pharmaceutical companies.
SOURCE: Noe MH et al. J Invest Dermatol. 2018 Oct 10. doi: 10.1016/j.jid.2018.09.012.
FROM THE JOURNAL OF INVESTIGATIVE DERMATOLOGY
Key clinical point: Despite vulnerability to complications, fewer psoriasis patients received the vaccine, compared with RA patients.
Major finding: Patients with RA were 8% more likely to receive a flu vaccine than patients with psoriasis.
Study details: A retrospective cohort study of 535,882 subjects with psoriasis, RA, or hypertension.
Disclosures: This study was funded by the National Psoriasis Foundation, the Dermatology Foundation, and the National Institute of Arthritis and Musculoskeletal and Skin Diseases. Four authors did not report any disclosures; the fifth author reported multiple disclosures related to various pharmaceutical companies.
Source: Noe MH et al. J Invest Dermatol. 2018 Oct 10. doi: 10.1016/j.jid.2018.09.012.
November 2018
Desmoplastic trichilemmoma
that presents as a solitary, skin colored lesion on the midface. Lesions may appear smooth or verrucous. Lesions may occur alongside trichoepitheliomas. They may also occur on genital skin and resemble condyloma acuminata.
Histopathology reveals downward lobular growth of the epidermis. Keratinocytes are clear secondary to periodic acid-Schiff (PAS)–positive glycogen in the cells. In desmoplastic trichilemmoma, small clusters of cells are arranged in an infiltrative pattern that resembles invasive carcinoma. Often, the desmoplastic areas are surrounded by benign-appearing trichilemmomas, which helps to make the diagnosis. Desmoplastic trichilemmomas can also occur within nevus sebaceous. As trichilemmoma is a benign growth; no treatment is needed. However, if further removal is desired, electrodesiccation, cryotherapy, shave removal, or excision are treatment options. Rarely seen, the malignant counterpart to trichilemmomas is a trichilemmal carcinoma, which requires surgical excision or Mohs.
The appearance of multiple trichilemmomas is a marker for Cowden syndrome. Cowden syndrome is a rare autosomal dominant disorder in which there is a mutation in a tumor-suppressor gene called PTEN. Patients may have oral mucosal papillomas, sclerotic fibromas, acral keratotic papules, and are at risk for the development of adenocarcinoma of the breast, gastrointestinal tract, and thyroid.
Trichoepithelioma is a benign neoplasm derived from follicular germ cells that presents as a skin-colored papule on the midface, especially the nose. Multiple trichoepitheliomas are a marker for Brooke-Spiegler syndrome. A desmoplastic trichoepithelioma is a variant that has stromal sclerosis on pathology. It is a benign lesion, although may be difficult to differentiate from sclerosing basal cell or microcystic adnexal carcinoma.
Angiofibroma, or fibrous papule, is a commonly seen, benign, skin-colored papule also often occurring on the nose. They can be treated for cosmetic purposes. Multiple lesions are associated with tuberous sclerosis.
Dr. Bilu Martin is a board-certified dermatologist in private practice at Premier Dermatology, MD, in Aventura, Fla. More diagnostic cases are available at edermatologynews.com. To submit a case for possible publication, send an email to [email protected].
Desmoplastic trichilemmoma
that presents as a solitary, skin colored lesion on the midface. Lesions may appear smooth or verrucous. Lesions may occur alongside trichoepitheliomas. They may also occur on genital skin and resemble condyloma acuminata.
Histopathology reveals downward lobular growth of the epidermis. Keratinocytes are clear secondary to periodic acid-Schiff (PAS)–positive glycogen in the cells. In desmoplastic trichilemmoma, small clusters of cells are arranged in an infiltrative pattern that resembles invasive carcinoma. Often, the desmoplastic areas are surrounded by benign-appearing trichilemmomas, which helps to make the diagnosis. Desmoplastic trichilemmomas can also occur within nevus sebaceous. As trichilemmoma is a benign growth; no treatment is needed. However, if further removal is desired, electrodesiccation, cryotherapy, shave removal, or excision are treatment options. Rarely seen, the malignant counterpart to trichilemmomas is a trichilemmal carcinoma, which requires surgical excision or Mohs.
The appearance of multiple trichilemmomas is a marker for Cowden syndrome. Cowden syndrome is a rare autosomal dominant disorder in which there is a mutation in a tumor-suppressor gene called PTEN. Patients may have oral mucosal papillomas, sclerotic fibromas, acral keratotic papules, and are at risk for the development of adenocarcinoma of the breast, gastrointestinal tract, and thyroid.
Trichoepithelioma is a benign neoplasm derived from follicular germ cells that presents as a skin-colored papule on the midface, especially the nose. Multiple trichoepitheliomas are a marker for Brooke-Spiegler syndrome. A desmoplastic trichoepithelioma is a variant that has stromal sclerosis on pathology. It is a benign lesion, although may be difficult to differentiate from sclerosing basal cell or microcystic adnexal carcinoma.
Angiofibroma, or fibrous papule, is a commonly seen, benign, skin-colored papule also often occurring on the nose. They can be treated for cosmetic purposes. Multiple lesions are associated with tuberous sclerosis.
Dr. Bilu Martin is a board-certified dermatologist in private practice at Premier Dermatology, MD, in Aventura, Fla. More diagnostic cases are available at edermatologynews.com. To submit a case for possible publication, send an email to [email protected].
Desmoplastic trichilemmoma
that presents as a solitary, skin colored lesion on the midface. Lesions may appear smooth or verrucous. Lesions may occur alongside trichoepitheliomas. They may also occur on genital skin and resemble condyloma acuminata.
Histopathology reveals downward lobular growth of the epidermis. Keratinocytes are clear secondary to periodic acid-Schiff (PAS)–positive glycogen in the cells. In desmoplastic trichilemmoma, small clusters of cells are arranged in an infiltrative pattern that resembles invasive carcinoma. Often, the desmoplastic areas are surrounded by benign-appearing trichilemmomas, which helps to make the diagnosis. Desmoplastic trichilemmomas can also occur within nevus sebaceous. As trichilemmoma is a benign growth; no treatment is needed. However, if further removal is desired, electrodesiccation, cryotherapy, shave removal, or excision are treatment options. Rarely seen, the malignant counterpart to trichilemmomas is a trichilemmal carcinoma, which requires surgical excision or Mohs.
The appearance of multiple trichilemmomas is a marker for Cowden syndrome. Cowden syndrome is a rare autosomal dominant disorder in which there is a mutation in a tumor-suppressor gene called PTEN. Patients may have oral mucosal papillomas, sclerotic fibromas, acral keratotic papules, and are at risk for the development of adenocarcinoma of the breast, gastrointestinal tract, and thyroid.
Trichoepithelioma is a benign neoplasm derived from follicular germ cells that presents as a skin-colored papule on the midface, especially the nose. Multiple trichoepitheliomas are a marker for Brooke-Spiegler syndrome. A desmoplastic trichoepithelioma is a variant that has stromal sclerosis on pathology. It is a benign lesion, although may be difficult to differentiate from sclerosing basal cell or microcystic adnexal carcinoma.
Angiofibroma, or fibrous papule, is a commonly seen, benign, skin-colored papule also often occurring on the nose. They can be treated for cosmetic purposes. Multiple lesions are associated with tuberous sclerosis.
Dr. Bilu Martin is a board-certified dermatologist in private practice at Premier Dermatology, MD, in Aventura, Fla. More diagnostic cases are available at edermatologynews.com. To submit a case for possible publication, send an email to [email protected].
Macitentan brought down arterial pressure in PoPH trial
PARIS – In a multicenter, placebo-controlled including the primary endpoint of pulmonary vascular resistance, according to a late-breaking presentation at the annual congress of the European Respiratory Society.
“This is the first randomized, controlled trial that enrolled only patients with PoPH, and it demonstrates that a therapy used in pulmonary arterial hypertension improves hemodynamics in PoPH,” reported Olivier Sitbon, MD, of the Centre des Maladies Vasculaires Pulmonaires, Université de Paris–Sud, Clamart, France.
PoPH, defined by accompanying portal hypertension, is a variant on pulmonary arterial hypertension (PAH). Liver dysfunction is common but not required for a diagnosis. Although patients often receive therapies known to be effective in PAH, such as drugs in the endothelin receptor antagonist class, prostanoids, or phosphodiesterase-5 inhibitors, there “are very limited data” demonstrating efficacy of any drug specifically for patients with PoPH, according to Dr. Sitbon. One reason is that PoPH has been an exclusion criterion in large PAH treatment trials.
In PORTICO, a double-blind trial presented by Dr. Sitbon, 85 PoPH patients were randomized to 10 mg macitentan or placebo. Essentially, all were in World Health Organization functional class II or III with a median 6-minute walk distance (6MWD) of about 385 meters. During the trial, patients were permitted to remain on baseline therapies, including prostanoids and phosphodiesterase-5 inhibitors when doses had been stable for at least 3 months prior to randomization.
The primary endpoint was change in pulmonary vascular resistance (PVR) at 12 weeks. Other hemodynamic changes, such as change in cardiac index and total pulmonary resistance, were included in secondary endpoints along with change in WHO class and change in 6MWD.
When compared at 12 weeks with a model-adjusted ratio of geometric means, the ratio of PVR for the treatment to experimental arms was 0.65, which was a 35% relative improvement (P less than .0001) with macitentan.
The relative reduction from baseline in total arterial pressure was also highly significant favoring macitentan (–199.8 vs. –18.3 dyne/sec per cm–5; P less than .0001). Mean pulmonary pressure was slightly increased at the end of 12 weeks relative to baseline in the placebo group (+0.4 mm Hg) but fell 6.4 mm Hg in the treatment group (P less than .0001). In addition, cardiac index improved substantially on macitentan but not on placebo (0.6 vs. 0.1 L/min per m2; P = .0009).
However, there were no significant differences at the end of 12 weeks between groups for change from baseline in WHO functional class or 6MWD. Change in hepatic venous pressure gradient was evaluated in patients with liver disease, but macitentan was not associated with any effect on this parameter.
Macitentan was well tolerated overall. Although one patient experienced a equal to or greater than three times the upper limit of normal elevation of liver enzymes, Dr. Sitbon reported that there were no other hepatic safety concerns. Overall, he characterized the safety of macitentan in PoPH as “consistent with that previously observed in PAH.”
Larger and longer-term trials are needed to evaluate the impact of treatment on clinical events, but Dr. Sitbon indicated that these results demonstrate acceptable safety and tolerability and a favorable effect on hemodynamics. He further suggested that this randomized study provides a first step toward establishing an evidence-based treatment in this disease.
Dr. Sitbon reported financial relationships with Bayer, GlaxoSmithKline, and Actelion, the sponsor of this trial.
PARIS – In a multicenter, placebo-controlled including the primary endpoint of pulmonary vascular resistance, according to a late-breaking presentation at the annual congress of the European Respiratory Society.
“This is the first randomized, controlled trial that enrolled only patients with PoPH, and it demonstrates that a therapy used in pulmonary arterial hypertension improves hemodynamics in PoPH,” reported Olivier Sitbon, MD, of the Centre des Maladies Vasculaires Pulmonaires, Université de Paris–Sud, Clamart, France.
PoPH, defined by accompanying portal hypertension, is a variant on pulmonary arterial hypertension (PAH). Liver dysfunction is common but not required for a diagnosis. Although patients often receive therapies known to be effective in PAH, such as drugs in the endothelin receptor antagonist class, prostanoids, or phosphodiesterase-5 inhibitors, there “are very limited data” demonstrating efficacy of any drug specifically for patients with PoPH, according to Dr. Sitbon. One reason is that PoPH has been an exclusion criterion in large PAH treatment trials.
In PORTICO, a double-blind trial presented by Dr. Sitbon, 85 PoPH patients were randomized to 10 mg macitentan or placebo. Essentially, all were in World Health Organization functional class II or III with a median 6-minute walk distance (6MWD) of about 385 meters. During the trial, patients were permitted to remain on baseline therapies, including prostanoids and phosphodiesterase-5 inhibitors when doses had been stable for at least 3 months prior to randomization.
The primary endpoint was change in pulmonary vascular resistance (PVR) at 12 weeks. Other hemodynamic changes, such as change in cardiac index and total pulmonary resistance, were included in secondary endpoints along with change in WHO class and change in 6MWD.
When compared at 12 weeks with a model-adjusted ratio of geometric means, the ratio of PVR for the treatment to experimental arms was 0.65, which was a 35% relative improvement (P less than .0001) with macitentan.
The relative reduction from baseline in total arterial pressure was also highly significant favoring macitentan (–199.8 vs. –18.3 dyne/sec per cm–5; P less than .0001). Mean pulmonary pressure was slightly increased at the end of 12 weeks relative to baseline in the placebo group (+0.4 mm Hg) but fell 6.4 mm Hg in the treatment group (P less than .0001). In addition, cardiac index improved substantially on macitentan but not on placebo (0.6 vs. 0.1 L/min per m2; P = .0009).
However, there were no significant differences at the end of 12 weeks between groups for change from baseline in WHO functional class or 6MWD. Change in hepatic venous pressure gradient was evaluated in patients with liver disease, but macitentan was not associated with any effect on this parameter.
Macitentan was well tolerated overall. Although one patient experienced a equal to or greater than three times the upper limit of normal elevation of liver enzymes, Dr. Sitbon reported that there were no other hepatic safety concerns. Overall, he characterized the safety of macitentan in PoPH as “consistent with that previously observed in PAH.”
Larger and longer-term trials are needed to evaluate the impact of treatment on clinical events, but Dr. Sitbon indicated that these results demonstrate acceptable safety and tolerability and a favorable effect on hemodynamics. He further suggested that this randomized study provides a first step toward establishing an evidence-based treatment in this disease.
Dr. Sitbon reported financial relationships with Bayer, GlaxoSmithKline, and Actelion, the sponsor of this trial.
PARIS – In a multicenter, placebo-controlled including the primary endpoint of pulmonary vascular resistance, according to a late-breaking presentation at the annual congress of the European Respiratory Society.
“This is the first randomized, controlled trial that enrolled only patients with PoPH, and it demonstrates that a therapy used in pulmonary arterial hypertension improves hemodynamics in PoPH,” reported Olivier Sitbon, MD, of the Centre des Maladies Vasculaires Pulmonaires, Université de Paris–Sud, Clamart, France.
PoPH, defined by accompanying portal hypertension, is a variant on pulmonary arterial hypertension (PAH). Liver dysfunction is common but not required for a diagnosis. Although patients often receive therapies known to be effective in PAH, such as drugs in the endothelin receptor antagonist class, prostanoids, or phosphodiesterase-5 inhibitors, there “are very limited data” demonstrating efficacy of any drug specifically for patients with PoPH, according to Dr. Sitbon. One reason is that PoPH has been an exclusion criterion in large PAH treatment trials.
In PORTICO, a double-blind trial presented by Dr. Sitbon, 85 PoPH patients were randomized to 10 mg macitentan or placebo. Essentially, all were in World Health Organization functional class II or III with a median 6-minute walk distance (6MWD) of about 385 meters. During the trial, patients were permitted to remain on baseline therapies, including prostanoids and phosphodiesterase-5 inhibitors when doses had been stable for at least 3 months prior to randomization.
The primary endpoint was change in pulmonary vascular resistance (PVR) at 12 weeks. Other hemodynamic changes, such as change in cardiac index and total pulmonary resistance, were included in secondary endpoints along with change in WHO class and change in 6MWD.
When compared at 12 weeks with a model-adjusted ratio of geometric means, the ratio of PVR for the treatment to experimental arms was 0.65, which was a 35% relative improvement (P less than .0001) with macitentan.
The relative reduction from baseline in total arterial pressure was also highly significant favoring macitentan (–199.8 vs. –18.3 dyne/sec per cm–5; P less than .0001). Mean pulmonary pressure was slightly increased at the end of 12 weeks relative to baseline in the placebo group (+0.4 mm Hg) but fell 6.4 mm Hg in the treatment group (P less than .0001). In addition, cardiac index improved substantially on macitentan but not on placebo (0.6 vs. 0.1 L/min per m2; P = .0009).
However, there were no significant differences at the end of 12 weeks between groups for change from baseline in WHO functional class or 6MWD. Change in hepatic venous pressure gradient was evaluated in patients with liver disease, but macitentan was not associated with any effect on this parameter.
Macitentan was well tolerated overall. Although one patient experienced a equal to or greater than three times the upper limit of normal elevation of liver enzymes, Dr. Sitbon reported that there were no other hepatic safety concerns. Overall, he characterized the safety of macitentan in PoPH as “consistent with that previously observed in PAH.”
Larger and longer-term trials are needed to evaluate the impact of treatment on clinical events, but Dr. Sitbon indicated that these results demonstrate acceptable safety and tolerability and a favorable effect on hemodynamics. He further suggested that this randomized study provides a first step toward establishing an evidence-based treatment in this disease.
Dr. Sitbon reported financial relationships with Bayer, GlaxoSmithKline, and Actelion, the sponsor of this trial.
Key clinical point: Compared with placebo, macitentan improves hemodynamic parameters in patients with portopulmonary hypertension.
Major finding: In a 12-week trial, macitentan reduced pulmonary vascular resistance by 35% (P less than 0.0001).
Study details: A double-blind, multicenter, placebo-controlled trial.
Disclosures: Dr. Sitbon reported financial relationships with Bayer, GlaxoSmithKline, and Actelion, the sponsor of this trial.
Overcoming social media’s false narratives; using fitness to fight addictions
For most people, life is a roller coaster of satisfaction and challenge. And in the midst of days filled with the latter, the social media chronicles of someone’s seemingly perfect life can set the teeth on edge. But should seeing those adventures from afar generate feelings of envy and self-loathing?
No, argues a piece written in The Guardian. Social media has created a world in which everyone seems ecstatic – apart from us.
Is there any way for people to curb their resentment? Yes, said Ethan Kross, PhD, professor of psychology at the University of Michigan, Ann Arbor, who studies Facebook’s impact on well-being. Interviewed for The Guardian article, Dr. Kross remarks that “envy is being taken to an extreme. We are constantly bombarded by ‘photoshopped lives’ and that exerts a toll on us the likes of which we have never experienced in the history of our species. And it is not particularly pleasant.”
Negotiating the era of envy requires a conscious effort to not compare one’s life with those of others, especially since their social presence may choose to gloss over their real-life troubles. Heavy lifting to boost personal self-esteem can be beneficial.
But these steps are far easier in theory than in practice. “ – we know that these images and narratives that are presented aren’t real, we can talk about it and rationalize it – but on an emotional level, it’s still pushing buttons,” clinical psychologist Rachel Andrew, ClinPsyD, said in the article. “If those images or narratives tap into what we aspire to, but what we don’t have, then it becomes very powerful.”
Gym seeks to help people stay in recovery
The world for those who are trying to rid themselves of substance use/addiction can be a fragile place. Having support can be the difference between a new clear-headed life and the slide back to darkness. For people with addictions in several U.S. cities, community gyms that operate under the moniker “The Phoenix” can be help.
The Phoenix was started by Scott Strode as a way to help people generate some sweat to stay sober. He has been sober for 21 years. There are no initiation fees to join and no monthly dues; funding comes from donations and grants. The absence of a financial burden comes with the requirements of 48 hours of sobriety, and the desire for that to continue.
The 14 Phoenix gyms in the United States have helped an estimated 26,000 people with their recovery.
“The hardest part about coming to Phoenix is opening the front door. But we’ve removed all those other barriers to access. Because it’s free, it doesn’t matter what insurance you have or how much money is in the bank account or what your addiction story is,” Mr. Strode said in an interview with “CBS This Morning: Saturday.”
Dana Smith has been sober for 9 years. Her introduction to The Phoenix was in prison, serving a sentence for a fatal traffic accident she caused while driving drunk. When asked by the interviewer how she lives with the reality that she took a life, Ms. Smith replies: “That’s another reason it was so important for me to come to Phoenix. I knew that I needed to be in a place where I felt comfortable talking about it. And I felt open and able to share ... I can help others ... and I have to listen the way that people listened for me and the way that people helped me to heal.”
Mr. Strode still burns with passion about the importance of The Phoenix. “For me, getting out of my addiction was like getting out of a burning building. And I just don’t feel like I can walk away if I know people are still in there,” he said.
Success vs. happiness: An illusion?
Harvard University academic Todd Rose, EdD, has taken on the idea that we can be happy or successful, but not both. In the book, “Dark Horse: Achieving Success Through the Pursuit of Fulfillment,” Dr. Rose and his coauthor Ogi Ogas, PhD, posit that striving for personal fulfillment can generate career success, and that this success does not come at the expense of happiness.
“For most of us, when we think about success, it’s pretty narrow, and we end up thinking about things like wealth, status, power. And we sort of think that you have to choose between that and being happy – and dark horses show us that you actually don’t have to choose,” Dr. Rose said in an interview on “CBS This Morning.”
There was a time when Dr. Rose was a young father on welfare with a bleak outlook. Following his father’s advice to find his motivation and pursue it changed his life.
“Think about the things that you enjoy doing and ask yourself why. ... The more you think about those things, the more you know what really moves you. And if you ask yourself that question often enough, it will reveal your broader motives and that will put you on a path to fulfillment,” Dr. Rose said.
The same advice goes for parents trying to counsel their children about career choices. “But if you think about us as parents, we actually don’t ask our kids (what motivates them) very often. We spend a lot of time telling them what should matter and very little time helping them figure it out for themselves,” Dr. Rose said. “They need to figure out what really matters to them and what motivates them, and we can help them by asking.”
Healthy elders break stereotypes
Medical care is focused on helping patients get better. Another aspect of medical care – keeping healthy people healthy – is not always high on the learning agenda. But at more than 20 medical schools in the United States, second-year students are getting another perspective on health care from healthy seniors.
Eighty two-year-old Elizabeth Shepherd is a participant in the program being offered to medical students at Cornell University in New York City. Ms. Shepherd acquaints the students with her everyday life, which includes the occasional fall, dealing with macular degeneration, and the desire for more sexual activity. “It’s important that they don’t think life stops as you get older,” Ms. Shepherd said in an interview with The New York Times. “So I decided I would be frank with them.”
The program can help re-jig the sometimes distorted view that med students have of older adults. “Unfortunately, most education takes place within the hospital,” said Ronald D. Adelman, MD, who developed the program at Cornell. “If you’re only seeing the hospitalized elderly, you’re seeing the debilitated, the physically deteriorating, the demented. It’s easy to pick up ageist stereotypes.”
A powerful take-home message for the students is that all people are worth treating, regardless of age.
Family separations worse than thought
The trauma of the separation of children from family members seeking to enter the United States from Mexico and countries farther south is undeniable. Now, as reported in Mother Jones, Amnesty International indicates far more families than officially tallied have been separated.
“The Trump administration is waging a deliberate campaign of widespread human rights violations in order to punish and deter people seeking safety at the U.S.-Mexico border,” Erika Guevara-Rosas, the Americas director at Amnesty International, said in a statement.
The American Psychiatric Association has called for an end to the policy on mental health grounds. “Children depend on their parents for safety and support. Any forced separation is highly stressful for children and can cause lifelong trauma, as well as an increased risk of other mental illnesses, such as depression, anxiety, and posttraumatic stress disorder. The evidence is clear that this level of trauma also results in serious medical and health consequences for these children and their caregivers,” according to the APA statement.
Compounding the trauma, if a child’s parents are deported while the child is in detention, the child could be put up for adoption without notification of the parents. Reports of abuse of children at some detention centers have heightened criticism of the policy.
For most people, life is a roller coaster of satisfaction and challenge. And in the midst of days filled with the latter, the social media chronicles of someone’s seemingly perfect life can set the teeth on edge. But should seeing those adventures from afar generate feelings of envy and self-loathing?
No, argues a piece written in The Guardian. Social media has created a world in which everyone seems ecstatic – apart from us.
Is there any way for people to curb their resentment? Yes, said Ethan Kross, PhD, professor of psychology at the University of Michigan, Ann Arbor, who studies Facebook’s impact on well-being. Interviewed for The Guardian article, Dr. Kross remarks that “envy is being taken to an extreme. We are constantly bombarded by ‘photoshopped lives’ and that exerts a toll on us the likes of which we have never experienced in the history of our species. And it is not particularly pleasant.”
Negotiating the era of envy requires a conscious effort to not compare one’s life with those of others, especially since their social presence may choose to gloss over their real-life troubles. Heavy lifting to boost personal self-esteem can be beneficial.
But these steps are far easier in theory than in practice. “ – we know that these images and narratives that are presented aren’t real, we can talk about it and rationalize it – but on an emotional level, it’s still pushing buttons,” clinical psychologist Rachel Andrew, ClinPsyD, said in the article. “If those images or narratives tap into what we aspire to, but what we don’t have, then it becomes very powerful.”
Gym seeks to help people stay in recovery
The world for those who are trying to rid themselves of substance use/addiction can be a fragile place. Having support can be the difference between a new clear-headed life and the slide back to darkness. For people with addictions in several U.S. cities, community gyms that operate under the moniker “The Phoenix” can be help.
The Phoenix was started by Scott Strode as a way to help people generate some sweat to stay sober. He has been sober for 21 years. There are no initiation fees to join and no monthly dues; funding comes from donations and grants. The absence of a financial burden comes with the requirements of 48 hours of sobriety, and the desire for that to continue.
The 14 Phoenix gyms in the United States have helped an estimated 26,000 people with their recovery.
“The hardest part about coming to Phoenix is opening the front door. But we’ve removed all those other barriers to access. Because it’s free, it doesn’t matter what insurance you have or how much money is in the bank account or what your addiction story is,” Mr. Strode said in an interview with “CBS This Morning: Saturday.”
Dana Smith has been sober for 9 years. Her introduction to The Phoenix was in prison, serving a sentence for a fatal traffic accident she caused while driving drunk. When asked by the interviewer how she lives with the reality that she took a life, Ms. Smith replies: “That’s another reason it was so important for me to come to Phoenix. I knew that I needed to be in a place where I felt comfortable talking about it. And I felt open and able to share ... I can help others ... and I have to listen the way that people listened for me and the way that people helped me to heal.”
Mr. Strode still burns with passion about the importance of The Phoenix. “For me, getting out of my addiction was like getting out of a burning building. And I just don’t feel like I can walk away if I know people are still in there,” he said.
Success vs. happiness: An illusion?
Harvard University academic Todd Rose, EdD, has taken on the idea that we can be happy or successful, but not both. In the book, “Dark Horse: Achieving Success Through the Pursuit of Fulfillment,” Dr. Rose and his coauthor Ogi Ogas, PhD, posit that striving for personal fulfillment can generate career success, and that this success does not come at the expense of happiness.
“For most of us, when we think about success, it’s pretty narrow, and we end up thinking about things like wealth, status, power. And we sort of think that you have to choose between that and being happy – and dark horses show us that you actually don’t have to choose,” Dr. Rose said in an interview on “CBS This Morning.”
There was a time when Dr. Rose was a young father on welfare with a bleak outlook. Following his father’s advice to find his motivation and pursue it changed his life.
“Think about the things that you enjoy doing and ask yourself why. ... The more you think about those things, the more you know what really moves you. And if you ask yourself that question often enough, it will reveal your broader motives and that will put you on a path to fulfillment,” Dr. Rose said.
The same advice goes for parents trying to counsel their children about career choices. “But if you think about us as parents, we actually don’t ask our kids (what motivates them) very often. We spend a lot of time telling them what should matter and very little time helping them figure it out for themselves,” Dr. Rose said. “They need to figure out what really matters to them and what motivates them, and we can help them by asking.”
Healthy elders break stereotypes
Medical care is focused on helping patients get better. Another aspect of medical care – keeping healthy people healthy – is not always high on the learning agenda. But at more than 20 medical schools in the United States, second-year students are getting another perspective on health care from healthy seniors.
Eighty two-year-old Elizabeth Shepherd is a participant in the program being offered to medical students at Cornell University in New York City. Ms. Shepherd acquaints the students with her everyday life, which includes the occasional fall, dealing with macular degeneration, and the desire for more sexual activity. “It’s important that they don’t think life stops as you get older,” Ms. Shepherd said in an interview with The New York Times. “So I decided I would be frank with them.”
The program can help re-jig the sometimes distorted view that med students have of older adults. “Unfortunately, most education takes place within the hospital,” said Ronald D. Adelman, MD, who developed the program at Cornell. “If you’re only seeing the hospitalized elderly, you’re seeing the debilitated, the physically deteriorating, the demented. It’s easy to pick up ageist stereotypes.”
A powerful take-home message for the students is that all people are worth treating, regardless of age.
Family separations worse than thought
The trauma of the separation of children from family members seeking to enter the United States from Mexico and countries farther south is undeniable. Now, as reported in Mother Jones, Amnesty International indicates far more families than officially tallied have been separated.
“The Trump administration is waging a deliberate campaign of widespread human rights violations in order to punish and deter people seeking safety at the U.S.-Mexico border,” Erika Guevara-Rosas, the Americas director at Amnesty International, said in a statement.
The American Psychiatric Association has called for an end to the policy on mental health grounds. “Children depend on their parents for safety and support. Any forced separation is highly stressful for children and can cause lifelong trauma, as well as an increased risk of other mental illnesses, such as depression, anxiety, and posttraumatic stress disorder. The evidence is clear that this level of trauma also results in serious medical and health consequences for these children and their caregivers,” according to the APA statement.
Compounding the trauma, if a child’s parents are deported while the child is in detention, the child could be put up for adoption without notification of the parents. Reports of abuse of children at some detention centers have heightened criticism of the policy.
For most people, life is a roller coaster of satisfaction and challenge. And in the midst of days filled with the latter, the social media chronicles of someone’s seemingly perfect life can set the teeth on edge. But should seeing those adventures from afar generate feelings of envy and self-loathing?
No, argues a piece written in The Guardian. Social media has created a world in which everyone seems ecstatic – apart from us.
Is there any way for people to curb their resentment? Yes, said Ethan Kross, PhD, professor of psychology at the University of Michigan, Ann Arbor, who studies Facebook’s impact on well-being. Interviewed for The Guardian article, Dr. Kross remarks that “envy is being taken to an extreme. We are constantly bombarded by ‘photoshopped lives’ and that exerts a toll on us the likes of which we have never experienced in the history of our species. And it is not particularly pleasant.”
Negotiating the era of envy requires a conscious effort to not compare one’s life with those of others, especially since their social presence may choose to gloss over their real-life troubles. Heavy lifting to boost personal self-esteem can be beneficial.
But these steps are far easier in theory than in practice. “ – we know that these images and narratives that are presented aren’t real, we can talk about it and rationalize it – but on an emotional level, it’s still pushing buttons,” clinical psychologist Rachel Andrew, ClinPsyD, said in the article. “If those images or narratives tap into what we aspire to, but what we don’t have, then it becomes very powerful.”
Gym seeks to help people stay in recovery
The world for those who are trying to rid themselves of substance use/addiction can be a fragile place. Having support can be the difference between a new clear-headed life and the slide back to darkness. For people with addictions in several U.S. cities, community gyms that operate under the moniker “The Phoenix” can be help.
The Phoenix was started by Scott Strode as a way to help people generate some sweat to stay sober. He has been sober for 21 years. There are no initiation fees to join and no monthly dues; funding comes from donations and grants. The absence of a financial burden comes with the requirements of 48 hours of sobriety, and the desire for that to continue.
The 14 Phoenix gyms in the United States have helped an estimated 26,000 people with their recovery.
“The hardest part about coming to Phoenix is opening the front door. But we’ve removed all those other barriers to access. Because it’s free, it doesn’t matter what insurance you have or how much money is in the bank account or what your addiction story is,” Mr. Strode said in an interview with “CBS This Morning: Saturday.”
Dana Smith has been sober for 9 years. Her introduction to The Phoenix was in prison, serving a sentence for a fatal traffic accident she caused while driving drunk. When asked by the interviewer how she lives with the reality that she took a life, Ms. Smith replies: “That’s another reason it was so important for me to come to Phoenix. I knew that I needed to be in a place where I felt comfortable talking about it. And I felt open and able to share ... I can help others ... and I have to listen the way that people listened for me and the way that people helped me to heal.”
Mr. Strode still burns with passion about the importance of The Phoenix. “For me, getting out of my addiction was like getting out of a burning building. And I just don’t feel like I can walk away if I know people are still in there,” he said.
Success vs. happiness: An illusion?
Harvard University academic Todd Rose, EdD, has taken on the idea that we can be happy or successful, but not both. In the book, “Dark Horse: Achieving Success Through the Pursuit of Fulfillment,” Dr. Rose and his coauthor Ogi Ogas, PhD, posit that striving for personal fulfillment can generate career success, and that this success does not come at the expense of happiness.
“For most of us, when we think about success, it’s pretty narrow, and we end up thinking about things like wealth, status, power. And we sort of think that you have to choose between that and being happy – and dark horses show us that you actually don’t have to choose,” Dr. Rose said in an interview on “CBS This Morning.”
There was a time when Dr. Rose was a young father on welfare with a bleak outlook. Following his father’s advice to find his motivation and pursue it changed his life.
“Think about the things that you enjoy doing and ask yourself why. ... The more you think about those things, the more you know what really moves you. And if you ask yourself that question often enough, it will reveal your broader motives and that will put you on a path to fulfillment,” Dr. Rose said.
The same advice goes for parents trying to counsel their children about career choices. “But if you think about us as parents, we actually don’t ask our kids (what motivates them) very often. We spend a lot of time telling them what should matter and very little time helping them figure it out for themselves,” Dr. Rose said. “They need to figure out what really matters to them and what motivates them, and we can help them by asking.”
Healthy elders break stereotypes
Medical care is focused on helping patients get better. Another aspect of medical care – keeping healthy people healthy – is not always high on the learning agenda. But at more than 20 medical schools in the United States, second-year students are getting another perspective on health care from healthy seniors.
Eighty two-year-old Elizabeth Shepherd is a participant in the program being offered to medical students at Cornell University in New York City. Ms. Shepherd acquaints the students with her everyday life, which includes the occasional fall, dealing with macular degeneration, and the desire for more sexual activity. “It’s important that they don’t think life stops as you get older,” Ms. Shepherd said in an interview with The New York Times. “So I decided I would be frank with them.”
The program can help re-jig the sometimes distorted view that med students have of older adults. “Unfortunately, most education takes place within the hospital,” said Ronald D. Adelman, MD, who developed the program at Cornell. “If you’re only seeing the hospitalized elderly, you’re seeing the debilitated, the physically deteriorating, the demented. It’s easy to pick up ageist stereotypes.”
A powerful take-home message for the students is that all people are worth treating, regardless of age.
Family separations worse than thought
The trauma of the separation of children from family members seeking to enter the United States from Mexico and countries farther south is undeniable. Now, as reported in Mother Jones, Amnesty International indicates far more families than officially tallied have been separated.
“The Trump administration is waging a deliberate campaign of widespread human rights violations in order to punish and deter people seeking safety at the U.S.-Mexico border,” Erika Guevara-Rosas, the Americas director at Amnesty International, said in a statement.
The American Psychiatric Association has called for an end to the policy on mental health grounds. “Children depend on their parents for safety and support. Any forced separation is highly stressful for children and can cause lifelong trauma, as well as an increased risk of other mental illnesses, such as depression, anxiety, and posttraumatic stress disorder. The evidence is clear that this level of trauma also results in serious medical and health consequences for these children and their caregivers,” according to the APA statement.
Compounding the trauma, if a child’s parents are deported while the child is in detention, the child could be put up for adoption without notification of the parents. Reports of abuse of children at some detention centers have heightened criticism of the policy.
With site-neutral payments, the devil is in the details
Physician groups are pushing back against a proposal to implement site-neutral payments, despite the fact that they generally support the concept of it.
In the proposed update to the Hospital Outpatient Prospective Payment System (OPPS) for 2019, the Centers for Medicare & Medicaid Services introduced a physician fee schedule–equivalent payment for clinic visit services when provided at an off-campus, provider-based department that is paid under the OPPS.
The American Medical Association said in a letter to the CMS that, while it “generally supports site-neutral payments, we do not believe that it is possible to sustain a high-quality health care system if site neutrality is defined as shrinking all payments to the lowest amount paid in any setting.” The AMA said that the current proposed rule is “complex, confusing, and is not truly site neutral because the policies do not apply equally to all hospital outpatient clinics,” adding that a contributor to the differential between private practice and hospital outpatient departments stems from physicians being underpaid in the physician fee schedule.
The American Academy of Family Physicians stated in a letter to Seema Verma, current administrator of the CMS, that while it supports the idea of site-neutral payments, “we note that the payment methodology for 2019 will not assure equal payments for the same service, regardless of site of service.” The AAFP noted that the goal of curbing hospital acquisition of independent physician practices may not come to fruition and that “hospitals may still be incentivized to buy physician practices based on the mix of services they provide and bill them as PBDs [provider-based departments] at Medicare rates higher than would have been paid had the practice not been bought by the hospital.”
The American College of Cardiology offered support for site-neutral payments and, while it did not come out against the CMS’ proposal, it did offer a series of recommendations to consider, including determining that payments reflect “the resources required to provide patient care in each setting” and that “payment differences across sites should be related to documented differences in the resources needed to ensure patient access and high-quality care.”
The American Academy of Dermatology Association voiced its support for the proposal to the agency.
In a letter signed by the American College of Gastroenterology, the American Gastroenterological Association, and the American Society for Gastrointestinal Endoscopy, they wrote that reimbursement for services provided in ambulatory surgical centers and hospital outpatient departments “should be the same. Our societies support payment rates appropriate for each site of service and using appropriate policy and payment levers that result in patients receiving care in the most cost-efficient site of service.”
Physician groups are pushing back against a proposal to implement site-neutral payments, despite the fact that they generally support the concept of it.
In the proposed update to the Hospital Outpatient Prospective Payment System (OPPS) for 2019, the Centers for Medicare & Medicaid Services introduced a physician fee schedule–equivalent payment for clinic visit services when provided at an off-campus, provider-based department that is paid under the OPPS.
The American Medical Association said in a letter to the CMS that, while it “generally supports site-neutral payments, we do not believe that it is possible to sustain a high-quality health care system if site neutrality is defined as shrinking all payments to the lowest amount paid in any setting.” The AMA said that the current proposed rule is “complex, confusing, and is not truly site neutral because the policies do not apply equally to all hospital outpatient clinics,” adding that a contributor to the differential between private practice and hospital outpatient departments stems from physicians being underpaid in the physician fee schedule.
The American Academy of Family Physicians stated in a letter to Seema Verma, current administrator of the CMS, that while it supports the idea of site-neutral payments, “we note that the payment methodology for 2019 will not assure equal payments for the same service, regardless of site of service.” The AAFP noted that the goal of curbing hospital acquisition of independent physician practices may not come to fruition and that “hospitals may still be incentivized to buy physician practices based on the mix of services they provide and bill them as PBDs [provider-based departments] at Medicare rates higher than would have been paid had the practice not been bought by the hospital.”
The American College of Cardiology offered support for site-neutral payments and, while it did not come out against the CMS’ proposal, it did offer a series of recommendations to consider, including determining that payments reflect “the resources required to provide patient care in each setting” and that “payment differences across sites should be related to documented differences in the resources needed to ensure patient access and high-quality care.”
The American Academy of Dermatology Association voiced its support for the proposal to the agency.
In a letter signed by the American College of Gastroenterology, the American Gastroenterological Association, and the American Society for Gastrointestinal Endoscopy, they wrote that reimbursement for services provided in ambulatory surgical centers and hospital outpatient departments “should be the same. Our societies support payment rates appropriate for each site of service and using appropriate policy and payment levers that result in patients receiving care in the most cost-efficient site of service.”
Physician groups are pushing back against a proposal to implement site-neutral payments, despite the fact that they generally support the concept of it.
In the proposed update to the Hospital Outpatient Prospective Payment System (OPPS) for 2019, the Centers for Medicare & Medicaid Services introduced a physician fee schedule–equivalent payment for clinic visit services when provided at an off-campus, provider-based department that is paid under the OPPS.
The American Medical Association said in a letter to the CMS that, while it “generally supports site-neutral payments, we do not believe that it is possible to sustain a high-quality health care system if site neutrality is defined as shrinking all payments to the lowest amount paid in any setting.” The AMA said that the current proposed rule is “complex, confusing, and is not truly site neutral because the policies do not apply equally to all hospital outpatient clinics,” adding that a contributor to the differential between private practice and hospital outpatient departments stems from physicians being underpaid in the physician fee schedule.
The American Academy of Family Physicians stated in a letter to Seema Verma, current administrator of the CMS, that while it supports the idea of site-neutral payments, “we note that the payment methodology for 2019 will not assure equal payments for the same service, regardless of site of service.” The AAFP noted that the goal of curbing hospital acquisition of independent physician practices may not come to fruition and that “hospitals may still be incentivized to buy physician practices based on the mix of services they provide and bill them as PBDs [provider-based departments] at Medicare rates higher than would have been paid had the practice not been bought by the hospital.”
The American College of Cardiology offered support for site-neutral payments and, while it did not come out against the CMS’ proposal, it did offer a series of recommendations to consider, including determining that payments reflect “the resources required to provide patient care in each setting” and that “payment differences across sites should be related to documented differences in the resources needed to ensure patient access and high-quality care.”
The American Academy of Dermatology Association voiced its support for the proposal to the agency.
In a letter signed by the American College of Gastroenterology, the American Gastroenterological Association, and the American Society for Gastrointestinal Endoscopy, they wrote that reimbursement for services provided in ambulatory surgical centers and hospital outpatient departments “should be the same. Our societies support payment rates appropriate for each site of service and using appropriate policy and payment levers that result in patients receiving care in the most cost-efficient site of service.”
Genes more important than food in hyperuricemia
Also today, time reveals a benefit of CABG over PCI for left main artery disease, lower-limb atherosclerosis predicts long-term mortality in patients with PAD, and TV ads could be required to display drug prices.
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Also today, time reveals a benefit of CABG over PCI for left main artery disease, lower-limb atherosclerosis predicts long-term mortality in patients with PAD, and TV ads could be required to display drug prices.
Subscribe here:
Amazon Alexa
Apple Podcasts
Google Podcasts
Spotify
Also today, time reveals a benefit of CABG over PCI for left main artery disease, lower-limb atherosclerosis predicts long-term mortality in patients with PAD, and TV ads could be required to display drug prices.
Subscribe here:
Amazon Alexa
Apple Podcasts
Google Podcasts
Spotify
Anti-inflammatory Drug Could Help Prevent MS Brain Tissue Loss
Findings from a recent study of ibudilast, an anti-inflammatory drug, “provide a glimmer of hope” for people with progressive multiple sclerosis, according to the National Institute of Neurological Disorders and Stroke researchers.
Ibudilast is a phosphodiesterase inhibitor with bronchodilator, vasodilator, and neuroprotective effects, mainly used in the treatment of asthma and stroke.
In the placebo-controlled study, 255 participants were assigned to take up to 10 capsules of ibudilast or placebo per day for 96 weeks. Every 6 months, they had magnetic resonance imaging (MRI) brain scans. The researchers observed a difference in brain shrinkage of about 2.5 mL of brain tissue per year between the 2 groups. (The human brain has a volume of about 1,350 mL.) It is unknown whether the difference had an effect on symptoms or loss of function.
Reported adverse events were similar in both groups. The most common with ibudilast were gastrointestinal, headaches, and depression.
Findings from a recent study of ibudilast, an anti-inflammatory drug, “provide a glimmer of hope” for people with progressive multiple sclerosis, according to the National Institute of Neurological Disorders and Stroke researchers.
Ibudilast is a phosphodiesterase inhibitor with bronchodilator, vasodilator, and neuroprotective effects, mainly used in the treatment of asthma and stroke.
In the placebo-controlled study, 255 participants were assigned to take up to 10 capsules of ibudilast or placebo per day for 96 weeks. Every 6 months, they had magnetic resonance imaging (MRI) brain scans. The researchers observed a difference in brain shrinkage of about 2.5 mL of brain tissue per year between the 2 groups. (The human brain has a volume of about 1,350 mL.) It is unknown whether the difference had an effect on symptoms or loss of function.
Reported adverse events were similar in both groups. The most common with ibudilast were gastrointestinal, headaches, and depression.
Findings from a recent study of ibudilast, an anti-inflammatory drug, “provide a glimmer of hope” for people with progressive multiple sclerosis, according to the National Institute of Neurological Disorders and Stroke researchers.
Ibudilast is a phosphodiesterase inhibitor with bronchodilator, vasodilator, and neuroprotective effects, mainly used in the treatment of asthma and stroke.
In the placebo-controlled study, 255 participants were assigned to take up to 10 capsules of ibudilast or placebo per day for 96 weeks. Every 6 months, they had magnetic resonance imaging (MRI) brain scans. The researchers observed a difference in brain shrinkage of about 2.5 mL of brain tissue per year between the 2 groups. (The human brain has a volume of about 1,350 mL.) It is unknown whether the difference had an effect on symptoms or loss of function.
Reported adverse events were similar in both groups. The most common with ibudilast were gastrointestinal, headaches, and depression.
Dataset could reveal better therapies for AML
Researchers have released a dataset detailing the molecular makeup of tumor cells from more than 500 patients with acute myeloid leukemia (AML).
The team discovered mutations not previously observed in AML and found associations between mutations and responses to certain therapies.
For instance, AML cases with FLT3, NPM1, and DNMT3A mutations proved sensitive to the BTK inhibitor ibrutinib.
The researchers described their findings in Nature.
The team also made their dataset available via Vizome, an online data viewer. Other researchers can use Vizome to find out which targeted therapies might be most effective against specific subsets of AML cells.
“People can get online, search our database, and very quickly get answers to ‘Is this a good drug?’ or ‘Is there a patient population my drug can work in?’” said study author Brian Druker, MD, of Oregon Health & Science University (OHSU) in Portland, Oregon.
Newly identified mutations
For this study, part of the Beat AML initiative, Dr. Druker and his colleagues performed whole-exome and RNA sequencing on 672 samples from 562 AML patients.
The team identified mutations in 11 genes that were called in 1% or more of patients in this dataset but had not been observed in previous AML sequencing studies. The genes were:
- CUB and Sushi multiple domains 2 (CSMD2)
- NAC alpha domain containing (NACAD)
- Teneurin transmembrane protein 2 (TENM2)
- Aggrecan (ACAN)
- ADAM metallopeptidase with thrombospondin type 1 motif 7 (ADAMTS7)
- Immunoglobulin-like and fibronectin type III domain containing 1 (IGFN1)
- Neurobeachin-like 2 (NBEAL2)
- Poly(U) binding splicing factor 60 (PUF60)
- Zinc-finger protein 687 (ZNF687)
- Cadherin EGF LAG sevenpass G-type receptor 2 (CELSR2)
- Glutamate ionotropic receptor NMDA type subunit 2B (GRIN2B).
Testing therapies
The researchers also assessed how AML cells from 409 of the patient samples responded to each of 122 targeted therapies.
The team found that mutations in TP53, ASXL1, NRAS, and KRAS caused “a broad pattern of drug resistance.”
However, cases with TP53 mutations were sensitive to elesclomol (a drug that targets cancer cell metabolism), cases with ASXL1 mutations were sensitive to the HDAC inhibitor panobinostat, and cases with KRAS/NRAS mutations were sensitive to MAPK inhibitors (with NRAS-mutated cases demonstrating greater sensitivity).
The researchers also found that IDH2 mutations “conferred sensitivity to a broad spectrum of drugs,” but IDH1 mutations were associated with resistance to most drugs.
As previously mentioned, the researchers found a significant association between mutations in FLT3, NPM1, and DNMT3A and sensitivity to ibrutinib. However, the team found that cases with DNMT3A mutations alone or mutations in DNMT3A and FLT3 were not significantly different from cases with wild-type genes.
On the other hand, cases with FLT3-ITD alone or any combination with a mutation in NPM1 (including mutations in all three genes) were significantly more sensitive to ibrutinib than cases with wild-type genes.
Cases with FLT3-ITD and mutations in NPM1 were sensitive to another kinase inhibitor, entospletinib, as well.
The researchers also found that mutations in both BCOR and RUNX1 correlated with increased sensitivity to four JAK inhibitors—momelotinib, ruxolitinib, tofacitinib, and JAK inhibitor I.
However, cases with BCOR mutations alone or mutations in BCOR and DNMT3A or SRSF2 showed no difference in sensitivity to the JAK inhibitors from cases with wild-type genes.
Next steps
“We’re just starting to scratch the surface of what we can do when we analyze the data,” Dr. Druker said. “The real power comes when you start to integrate all that data. You can analyze what drug worked and why it worked.”
In fact, the researchers are already developing and initiating clinical trials to test hypotheses generated by this study.
“You can start to sense some momentum building with new, better therapeutics for AML patients, and, hopefully, this dataset will help fuel that momentum even further,” said study author Jeff Tyner, PhD, of the OHSU School of Medicine.
“We want to parlay this information into clinical trials as much as we can, and we also want the broader community to use this dataset to accelerate their own work.”
Funding for the current study was provided by grants from The Leukemia & Lymphoma Society, the National Cancer Institute, the National Library of Medicine, and other groups.
Researchers have released a dataset detailing the molecular makeup of tumor cells from more than 500 patients with acute myeloid leukemia (AML).
The team discovered mutations not previously observed in AML and found associations between mutations and responses to certain therapies.
For instance, AML cases with FLT3, NPM1, and DNMT3A mutations proved sensitive to the BTK inhibitor ibrutinib.
The researchers described their findings in Nature.
The team also made their dataset available via Vizome, an online data viewer. Other researchers can use Vizome to find out which targeted therapies might be most effective against specific subsets of AML cells.
“People can get online, search our database, and very quickly get answers to ‘Is this a good drug?’ or ‘Is there a patient population my drug can work in?’” said study author Brian Druker, MD, of Oregon Health & Science University (OHSU) in Portland, Oregon.
Newly identified mutations
For this study, part of the Beat AML initiative, Dr. Druker and his colleagues performed whole-exome and RNA sequencing on 672 samples from 562 AML patients.
The team identified mutations in 11 genes that were called in 1% or more of patients in this dataset but had not been observed in previous AML sequencing studies. The genes were:
- CUB and Sushi multiple domains 2 (CSMD2)
- NAC alpha domain containing (NACAD)
- Teneurin transmembrane protein 2 (TENM2)
- Aggrecan (ACAN)
- ADAM metallopeptidase with thrombospondin type 1 motif 7 (ADAMTS7)
- Immunoglobulin-like and fibronectin type III domain containing 1 (IGFN1)
- Neurobeachin-like 2 (NBEAL2)
- Poly(U) binding splicing factor 60 (PUF60)
- Zinc-finger protein 687 (ZNF687)
- Cadherin EGF LAG sevenpass G-type receptor 2 (CELSR2)
- Glutamate ionotropic receptor NMDA type subunit 2B (GRIN2B).
Testing therapies
The researchers also assessed how AML cells from 409 of the patient samples responded to each of 122 targeted therapies.
The team found that mutations in TP53, ASXL1, NRAS, and KRAS caused “a broad pattern of drug resistance.”
However, cases with TP53 mutations were sensitive to elesclomol (a drug that targets cancer cell metabolism), cases with ASXL1 mutations were sensitive to the HDAC inhibitor panobinostat, and cases with KRAS/NRAS mutations were sensitive to MAPK inhibitors (with NRAS-mutated cases demonstrating greater sensitivity).
The researchers also found that IDH2 mutations “conferred sensitivity to a broad spectrum of drugs,” but IDH1 mutations were associated with resistance to most drugs.
As previously mentioned, the researchers found a significant association between mutations in FLT3, NPM1, and DNMT3A and sensitivity to ibrutinib. However, the team found that cases with DNMT3A mutations alone or mutations in DNMT3A and FLT3 were not significantly different from cases with wild-type genes.
On the other hand, cases with FLT3-ITD alone or any combination with a mutation in NPM1 (including mutations in all three genes) were significantly more sensitive to ibrutinib than cases with wild-type genes.
Cases with FLT3-ITD and mutations in NPM1 were sensitive to another kinase inhibitor, entospletinib, as well.
The researchers also found that mutations in both BCOR and RUNX1 correlated with increased sensitivity to four JAK inhibitors—momelotinib, ruxolitinib, tofacitinib, and JAK inhibitor I.
However, cases with BCOR mutations alone or mutations in BCOR and DNMT3A or SRSF2 showed no difference in sensitivity to the JAK inhibitors from cases with wild-type genes.
Next steps
“We’re just starting to scratch the surface of what we can do when we analyze the data,” Dr. Druker said. “The real power comes when you start to integrate all that data. You can analyze what drug worked and why it worked.”
In fact, the researchers are already developing and initiating clinical trials to test hypotheses generated by this study.
“You can start to sense some momentum building with new, better therapeutics for AML patients, and, hopefully, this dataset will help fuel that momentum even further,” said study author Jeff Tyner, PhD, of the OHSU School of Medicine.
“We want to parlay this information into clinical trials as much as we can, and we also want the broader community to use this dataset to accelerate their own work.”
Funding for the current study was provided by grants from The Leukemia & Lymphoma Society, the National Cancer Institute, the National Library of Medicine, and other groups.
Researchers have released a dataset detailing the molecular makeup of tumor cells from more than 500 patients with acute myeloid leukemia (AML).
The team discovered mutations not previously observed in AML and found associations between mutations and responses to certain therapies.
For instance, AML cases with FLT3, NPM1, and DNMT3A mutations proved sensitive to the BTK inhibitor ibrutinib.
The researchers described their findings in Nature.
The team also made their dataset available via Vizome, an online data viewer. Other researchers can use Vizome to find out which targeted therapies might be most effective against specific subsets of AML cells.
“People can get online, search our database, and very quickly get answers to ‘Is this a good drug?’ or ‘Is there a patient population my drug can work in?’” said study author Brian Druker, MD, of Oregon Health & Science University (OHSU) in Portland, Oregon.
Newly identified mutations
For this study, part of the Beat AML initiative, Dr. Druker and his colleagues performed whole-exome and RNA sequencing on 672 samples from 562 AML patients.
The team identified mutations in 11 genes that were called in 1% or more of patients in this dataset but had not been observed in previous AML sequencing studies. The genes were:
- CUB and Sushi multiple domains 2 (CSMD2)
- NAC alpha domain containing (NACAD)
- Teneurin transmembrane protein 2 (TENM2)
- Aggrecan (ACAN)
- ADAM metallopeptidase with thrombospondin type 1 motif 7 (ADAMTS7)
- Immunoglobulin-like and fibronectin type III domain containing 1 (IGFN1)
- Neurobeachin-like 2 (NBEAL2)
- Poly(U) binding splicing factor 60 (PUF60)
- Zinc-finger protein 687 (ZNF687)
- Cadherin EGF LAG sevenpass G-type receptor 2 (CELSR2)
- Glutamate ionotropic receptor NMDA type subunit 2B (GRIN2B).
Testing therapies
The researchers also assessed how AML cells from 409 of the patient samples responded to each of 122 targeted therapies.
The team found that mutations in TP53, ASXL1, NRAS, and KRAS caused “a broad pattern of drug resistance.”
However, cases with TP53 mutations were sensitive to elesclomol (a drug that targets cancer cell metabolism), cases with ASXL1 mutations were sensitive to the HDAC inhibitor panobinostat, and cases with KRAS/NRAS mutations were sensitive to MAPK inhibitors (with NRAS-mutated cases demonstrating greater sensitivity).
The researchers also found that IDH2 mutations “conferred sensitivity to a broad spectrum of drugs,” but IDH1 mutations were associated with resistance to most drugs.
As previously mentioned, the researchers found a significant association between mutations in FLT3, NPM1, and DNMT3A and sensitivity to ibrutinib. However, the team found that cases with DNMT3A mutations alone or mutations in DNMT3A and FLT3 were not significantly different from cases with wild-type genes.
On the other hand, cases with FLT3-ITD alone or any combination with a mutation in NPM1 (including mutations in all three genes) were significantly more sensitive to ibrutinib than cases with wild-type genes.
Cases with FLT3-ITD and mutations in NPM1 were sensitive to another kinase inhibitor, entospletinib, as well.
The researchers also found that mutations in both BCOR and RUNX1 correlated with increased sensitivity to four JAK inhibitors—momelotinib, ruxolitinib, tofacitinib, and JAK inhibitor I.
However, cases with BCOR mutations alone or mutations in BCOR and DNMT3A or SRSF2 showed no difference in sensitivity to the JAK inhibitors from cases with wild-type genes.
Next steps
“We’re just starting to scratch the surface of what we can do when we analyze the data,” Dr. Druker said. “The real power comes when you start to integrate all that data. You can analyze what drug worked and why it worked.”
In fact, the researchers are already developing and initiating clinical trials to test hypotheses generated by this study.
“You can start to sense some momentum building with new, better therapeutics for AML patients, and, hopefully, this dataset will help fuel that momentum even further,” said study author Jeff Tyner, PhD, of the OHSU School of Medicine.
“We want to parlay this information into clinical trials as much as we can, and we also want the broader community to use this dataset to accelerate their own work.”
Funding for the current study was provided by grants from The Leukemia & Lymphoma Society, the National Cancer Institute, the National Library of Medicine, and other groups.
BTK inhibitor shows early promise for WM
NEW YORK—The BTK inhibitor zanubrutinib has demonstrated “robust activity” and “good tolerability” in patients with Waldenström’s macroglobulinemia (WM), according to an investigator.
In a phase 1 trial, zanubrutinib produced an overall response rate (ORR) of 92%, and the estimated 12-month progression-free survival (PFS) rate was 89%.
Most adverse events (AEs) in this trial were grade 1 or 2 in severity, although the incidence of serious AEs was 42%.
Constantine Tam, MD, of the Peter MacCallum Cancer Center in Victoria, Australia, presented these results at the 10th International Workshop on Waldenström’s Macroglobulinemia.
The trial is sponsored by BeiGene, Ltd., the company developing zanubrutinib.
The trial (NCT02343120) includes patients with WM and other B-cell malignancies. As of July 24, 2018, 77 patients with treatment-naïve or relapsed/refractory WM had been enrolled.
Seventy-three patients were evaluable for efficacy in this analysis, and the median follow-up time was 22.5 months (range, 4.1-43.9).
At the time of the data cutoff, 62 patients remained on study treatment. Four patients (3%) discontinued treatment due to disease progression, and one patient remains on treatment post-progression.
Efficacy
The median time to response was 85 days (range, 55-749).
The ORR was 92% (67/73), and the major response rate (MRR) was 82%. Forty-one percent of patients achieved a very good partial response (VGPR), defined as a greater than 90% reduction in baseline immunoglobulin M (IgM) levels and improvement of extramedullary disease by computed tomography.
The median IgM decreased from 32.7 g/L (range, 5.3-91.9) at baseline to 8.2 g/L (range, 0.3-57.8). The median hemoglobin increased from 8.85 g/dL (range, 6.3-9.8) to 13.4 g/dL (range, 7.7-17.0) among 32 patients with hemoglobin less than 10 g/dL at baseline.
MYD88 genotype was known in 63 patients. In the subset known to have the MYD88L265P mutation (n=54), the ORR was 94%, the MRR was 89%, and the VGPR rate was 46%.
In the nine patients known to have wild-type MYD88 (a genotype that, historically, has had sub-optimal response to BTK inhibition), the ORR was 89%, the MRR was 67%, and the VGPR rate was 22%.
The 12-month PFS was estimated to be 89%, and the median PFS had not been reached.
Safety
The most frequent AEs of any attribution were petechiae/purpura/contusion (43%), upper respiratory tract infection (42%), cough (17%), diarrhea (17%), constipation (16%), back pain (16%), and headache (16%).
Grade 3-4 AEs of any attribution reported in three or more patients included neutropenia (9%), anemia (7%), hypertension (5%), basal cell carcinoma (5%), renal and urinary disorders (4%), and pneumonia (4%).
Serious AEs were seen in 32 patients (42%). Events in five patients (7%) were considered possibly related to zanubrutinib treatment—febrile neutropenia, colitis, atrial fibrillation, hemothorax, and pneumonia.
Nine patients (12%) discontinued study treatment due to AEs, but all of these events were considered unrelated to treatment. The AEs (n=1 for each) included abdominal sepsis (fatal), gastric adenocarcinoma (fatal), septic shoulder, worsening bronchiectasis, scedosporium infection, prostate adenocarcinoma, metastatic neuroendocrine carcinoma, acute myeloid leukemia, and breast cancer.
Atrial fibrillation/flutter occurred in four patients (5%), and major hemorrhage was observed in two patients (3%).
“We are encouraged that additional data on zanubrutinib in patients with WM confirms the initially reported experience, with consistent demonstration of robust activity and good tolerability,” Dr. Tam said.
“We are hopeful that zanubrutinib, if approved, could potentially provide an important new treatment option to patients with WM and other hematologic malignancies.”
Dr. Tam reported financial relationships with BeiGene and other companies.
NEW YORK—The BTK inhibitor zanubrutinib has demonstrated “robust activity” and “good tolerability” in patients with Waldenström’s macroglobulinemia (WM), according to an investigator.
In a phase 1 trial, zanubrutinib produced an overall response rate (ORR) of 92%, and the estimated 12-month progression-free survival (PFS) rate was 89%.
Most adverse events (AEs) in this trial were grade 1 or 2 in severity, although the incidence of serious AEs was 42%.
Constantine Tam, MD, of the Peter MacCallum Cancer Center in Victoria, Australia, presented these results at the 10th International Workshop on Waldenström’s Macroglobulinemia.
The trial is sponsored by BeiGene, Ltd., the company developing zanubrutinib.
The trial (NCT02343120) includes patients with WM and other B-cell malignancies. As of July 24, 2018, 77 patients with treatment-naïve or relapsed/refractory WM had been enrolled.
Seventy-three patients were evaluable for efficacy in this analysis, and the median follow-up time was 22.5 months (range, 4.1-43.9).
At the time of the data cutoff, 62 patients remained on study treatment. Four patients (3%) discontinued treatment due to disease progression, and one patient remains on treatment post-progression.
Efficacy
The median time to response was 85 days (range, 55-749).
The ORR was 92% (67/73), and the major response rate (MRR) was 82%. Forty-one percent of patients achieved a very good partial response (VGPR), defined as a greater than 90% reduction in baseline immunoglobulin M (IgM) levels and improvement of extramedullary disease by computed tomography.
The median IgM decreased from 32.7 g/L (range, 5.3-91.9) at baseline to 8.2 g/L (range, 0.3-57.8). The median hemoglobin increased from 8.85 g/dL (range, 6.3-9.8) to 13.4 g/dL (range, 7.7-17.0) among 32 patients with hemoglobin less than 10 g/dL at baseline.
MYD88 genotype was known in 63 patients. In the subset known to have the MYD88L265P mutation (n=54), the ORR was 94%, the MRR was 89%, and the VGPR rate was 46%.
In the nine patients known to have wild-type MYD88 (a genotype that, historically, has had sub-optimal response to BTK inhibition), the ORR was 89%, the MRR was 67%, and the VGPR rate was 22%.
The 12-month PFS was estimated to be 89%, and the median PFS had not been reached.
Safety
The most frequent AEs of any attribution were petechiae/purpura/contusion (43%), upper respiratory tract infection (42%), cough (17%), diarrhea (17%), constipation (16%), back pain (16%), and headache (16%).
Grade 3-4 AEs of any attribution reported in three or more patients included neutropenia (9%), anemia (7%), hypertension (5%), basal cell carcinoma (5%), renal and urinary disorders (4%), and pneumonia (4%).
Serious AEs were seen in 32 patients (42%). Events in five patients (7%) were considered possibly related to zanubrutinib treatment—febrile neutropenia, colitis, atrial fibrillation, hemothorax, and pneumonia.
Nine patients (12%) discontinued study treatment due to AEs, but all of these events were considered unrelated to treatment. The AEs (n=1 for each) included abdominal sepsis (fatal), gastric adenocarcinoma (fatal), septic shoulder, worsening bronchiectasis, scedosporium infection, prostate adenocarcinoma, metastatic neuroendocrine carcinoma, acute myeloid leukemia, and breast cancer.
Atrial fibrillation/flutter occurred in four patients (5%), and major hemorrhage was observed in two patients (3%).
“We are encouraged that additional data on zanubrutinib in patients with WM confirms the initially reported experience, with consistent demonstration of robust activity and good tolerability,” Dr. Tam said.
“We are hopeful that zanubrutinib, if approved, could potentially provide an important new treatment option to patients with WM and other hematologic malignancies.”
Dr. Tam reported financial relationships with BeiGene and other companies.
NEW YORK—The BTK inhibitor zanubrutinib has demonstrated “robust activity” and “good tolerability” in patients with Waldenström’s macroglobulinemia (WM), according to an investigator.
In a phase 1 trial, zanubrutinib produced an overall response rate (ORR) of 92%, and the estimated 12-month progression-free survival (PFS) rate was 89%.
Most adverse events (AEs) in this trial were grade 1 or 2 in severity, although the incidence of serious AEs was 42%.
Constantine Tam, MD, of the Peter MacCallum Cancer Center in Victoria, Australia, presented these results at the 10th International Workshop on Waldenström’s Macroglobulinemia.
The trial is sponsored by BeiGene, Ltd., the company developing zanubrutinib.
The trial (NCT02343120) includes patients with WM and other B-cell malignancies. As of July 24, 2018, 77 patients with treatment-naïve or relapsed/refractory WM had been enrolled.
Seventy-three patients were evaluable for efficacy in this analysis, and the median follow-up time was 22.5 months (range, 4.1-43.9).
At the time of the data cutoff, 62 patients remained on study treatment. Four patients (3%) discontinued treatment due to disease progression, and one patient remains on treatment post-progression.
Efficacy
The median time to response was 85 days (range, 55-749).
The ORR was 92% (67/73), and the major response rate (MRR) was 82%. Forty-one percent of patients achieved a very good partial response (VGPR), defined as a greater than 90% reduction in baseline immunoglobulin M (IgM) levels and improvement of extramedullary disease by computed tomography.
The median IgM decreased from 32.7 g/L (range, 5.3-91.9) at baseline to 8.2 g/L (range, 0.3-57.8). The median hemoglobin increased from 8.85 g/dL (range, 6.3-9.8) to 13.4 g/dL (range, 7.7-17.0) among 32 patients with hemoglobin less than 10 g/dL at baseline.
MYD88 genotype was known in 63 patients. In the subset known to have the MYD88L265P mutation (n=54), the ORR was 94%, the MRR was 89%, and the VGPR rate was 46%.
In the nine patients known to have wild-type MYD88 (a genotype that, historically, has had sub-optimal response to BTK inhibition), the ORR was 89%, the MRR was 67%, and the VGPR rate was 22%.
The 12-month PFS was estimated to be 89%, and the median PFS had not been reached.
Safety
The most frequent AEs of any attribution were petechiae/purpura/contusion (43%), upper respiratory tract infection (42%), cough (17%), diarrhea (17%), constipation (16%), back pain (16%), and headache (16%).
Grade 3-4 AEs of any attribution reported in three or more patients included neutropenia (9%), anemia (7%), hypertension (5%), basal cell carcinoma (5%), renal and urinary disorders (4%), and pneumonia (4%).
Serious AEs were seen in 32 patients (42%). Events in five patients (7%) were considered possibly related to zanubrutinib treatment—febrile neutropenia, colitis, atrial fibrillation, hemothorax, and pneumonia.
Nine patients (12%) discontinued study treatment due to AEs, but all of these events were considered unrelated to treatment. The AEs (n=1 for each) included abdominal sepsis (fatal), gastric adenocarcinoma (fatal), septic shoulder, worsening bronchiectasis, scedosporium infection, prostate adenocarcinoma, metastatic neuroendocrine carcinoma, acute myeloid leukemia, and breast cancer.
Atrial fibrillation/flutter occurred in four patients (5%), and major hemorrhage was observed in two patients (3%).
“We are encouraged that additional data on zanubrutinib in patients with WM confirms the initially reported experience, with consistent demonstration of robust activity and good tolerability,” Dr. Tam said.
“We are hopeful that zanubrutinib, if approved, could potentially provide an important new treatment option to patients with WM and other hematologic malignancies.”
Dr. Tam reported financial relationships with BeiGene and other companies.