Children with Down syndrome often have sleep‐disordered breathing (SDB), and a new study suggests that long-term monitoring via sleep studies is warranted because the condition frequently persists and recurs.

©DenKuvaiev/Thinkstock

“Current screening recommendations to assess for SDB at a particular age may not be adequate in this population,” the authors of the study stated, adding that “persistence/recurrence of SDB is not easily predicted.”

The study, led by Joy Nehme, BSc, of Children’s Hospital of Eastern Ontario and the University of Ottawa, was published in Pediatric Pulmonology.

According to the study, research suggests that 43%-66% of children with Down syndrome have SDB, a category that encompasses sleep apnea (both obstructive and central) and hypoventilation. Those numbers are several times higher than the prevalence of SDB in children in the general population (1%-5%).

“Because SDB is associated with cardiometabolic and neurocognitive morbidity, its prompt and accurate diagnosis is important,” the researchers wrote. However, diagnosis requires a sleep study, which is not always performed although the American Academy of Pediatrics recommends children with Down syndrome undergo one by age 4.

Treatments include adenotonsillectomy (considered first-line), positive airway pressure, and lingual tonsillectomy.

The study aims to fill in gaps in knowledge about the condition over the long term since “there is little available literature on the trajectory of SDB in children and youth with Down syndrome over time.”

The researchers launched a retrospective study of 560 children with Down syndrome who were treated from 2004 to 2015 at Children’s Hospital of Eastern Ontario. Of those, 120 showed signs of SDB and underwent sleep studies (48% male, median age 6.6 years [range 4.5-10.5], median total apnea‐hypopnea index events per hour = 3.4 [1.6-10.8]).

Of the 120 children, 67 (56%) had obstructive-mixed SDB, 9 (8%) had central sleep apnea, and 5 (4%) had hypoventilation. The others (39, 32%) had no SDB.

Fifty-four children underwent at least two sleep studies during the period of the study, with at least one undergoing seven.

Researchers found weak, nonsignificant evidence that SDB persistence/occurrence varied by age (odds ratio per year = 1.15; 95% confidence interval, 0.96-1.41; P = .13).

As for treatment, adenotonsillectomy was most common, although “previous studies have ... shown that moderate to severe OSA in children with Down syndrome is likely to persist after a tonsillectomy.”

In regard to obstructive sleep apnea (OSA) specifically, the authors wrote, “our study ... showed that OSA‐SDB persisted or recurred in the vast majority of children. Further, persistence/recurrence could not be predicted by clinical features or SDB severity in our study. This, therefore, highlights the need for serial longitudinal screening for SDB in this population and for follow‐up PSG to ensure the success of treatment interventions.”

No study funding was reported. The study authors reported no disclosures.

SOURCE: Nehme J et al. Pediatr Pulmonol. 2019 Jun 6. doi: 10.1002/ppul.24380.

Children with Down syndrome often have sleep‐disordered breathing (SDB), and a new study suggests that long-term monitoring via sleep studies is warranted because the condition frequently persists and recurs.

©DenKuvaiev/Thinkstock

“Current screening recommendations to assess for SDB at a particular age may not be adequate in this population,” the authors of the study stated, adding that “persistence/recurrence of SDB is not easily predicted.”

The study, led by Joy Nehme, BSc, of Children’s Hospital of Eastern Ontario and the University of Ottawa, was published in Pediatric Pulmonology.

According to the study, research suggests that 43%-66% of children with Down syndrome have SDB, a category that encompasses sleep apnea (both obstructive and central) and hypoventilation. Those numbers are several times higher than the prevalence of SDB in children in the general population (1%-5%).

“Because SDB is associated with cardiometabolic and neurocognitive morbidity, its prompt and accurate diagnosis is important,” the researchers wrote. However, diagnosis requires a sleep study, which is not always performed although the American Academy of Pediatrics recommends children with Down syndrome undergo one by age 4.

Treatments include adenotonsillectomy (considered first-line), positive airway pressure, and lingual tonsillectomy.

The study aims to fill in gaps in knowledge about the condition over the long term since “there is little available literature on the trajectory of SDB in children and youth with Down syndrome over time.”

The researchers launched a retrospective study of 560 children with Down syndrome who were treated from 2004 to 2015 at Children’s Hospital of Eastern Ontario. Of those, 120 showed signs of SDB and underwent sleep studies (48% male, median age 6.6 years [range 4.5-10.5], median total apnea‐hypopnea index events per hour = 3.4 [1.6-10.8]).

Of the 120 children, 67 (56%) had obstructive-mixed SDB, 9 (8%) had central sleep apnea, and 5 (4%) had hypoventilation. The others (39, 32%) had no SDB.

Fifty-four children underwent at least two sleep studies during the period of the study, with at least one undergoing seven.

Researchers found weak, nonsignificant evidence that SDB persistence/occurrence varied by age (odds ratio per year = 1.15; 95% confidence interval, 0.96-1.41; P = .13).

As for treatment, adenotonsillectomy was most common, although “previous studies have ... shown that moderate to severe OSA in children with Down syndrome is likely to persist after a tonsillectomy.”

In regard to obstructive sleep apnea (OSA) specifically, the authors wrote, “our study ... showed that OSA‐SDB persisted or recurred in the vast majority of children. Further, persistence/recurrence could not be predicted by clinical features or SDB severity in our study. This, therefore, highlights the need for serial longitudinal screening for SDB in this population and for follow‐up PSG to ensure the success of treatment interventions.”

No study funding was reported. The study authors reported no disclosures.

SOURCE: Nehme J et al. Pediatr Pulmonol. 2019 Jun 6. doi: 10.1002/ppul.24380.

Children with Down syndrome often have sleep‐disordered breathing (SDB), and a new study suggests that long-term monitoring via sleep studies is warranted because the condition frequently persists and recurs.

©DenKuvaiev/Thinkstock

“Current screening recommendations to assess for SDB at a particular age may not be adequate in this population,” the authors of the study stated, adding that “persistence/recurrence of SDB is not easily predicted.”

The study, led by Joy Nehme, BSc, of Children’s Hospital of Eastern Ontario and the University of Ottawa, was published in Pediatric Pulmonology.

According to the study, research suggests that 43%-66% of children with Down syndrome have SDB, a category that encompasses sleep apnea (both obstructive and central) and hypoventilation. Those numbers are several times higher than the prevalence of SDB in children in the general population (1%-5%).

“Because SDB is associated with cardiometabolic and neurocognitive morbidity, its prompt and accurate diagnosis is important,” the researchers wrote. However, diagnosis requires a sleep study, which is not always performed although the American Academy of Pediatrics recommends children with Down syndrome undergo one by age 4.

Treatments include adenotonsillectomy (considered first-line), positive airway pressure, and lingual tonsillectomy.

The study aims to fill in gaps in knowledge about the condition over the long term since “there is little available literature on the trajectory of SDB in children and youth with Down syndrome over time.”

The researchers launched a retrospective study of 560 children with Down syndrome who were treated from 2004 to 2015 at Children’s Hospital of Eastern Ontario. Of those, 120 showed signs of SDB and underwent sleep studies (48% male, median age 6.6 years [range 4.5-10.5], median total apnea‐hypopnea index events per hour = 3.4 [1.6-10.8]).

Of the 120 children, 67 (56%) had obstructive-mixed SDB, 9 (8%) had central sleep apnea, and 5 (4%) had hypoventilation. The others (39, 32%) had no SDB.

Fifty-four children underwent at least two sleep studies during the period of the study, with at least one undergoing seven.

Researchers found weak, nonsignificant evidence that SDB persistence/occurrence varied by age (odds ratio per year = 1.15; 95% confidence interval, 0.96-1.41; P = .13).

As for treatment, adenotonsillectomy was most common, although “previous studies have ... shown that moderate to severe OSA in children with Down syndrome is likely to persist after a tonsillectomy.”

In regard to obstructive sleep apnea (OSA) specifically, the authors wrote, “our study ... showed that OSA‐SDB persisted or recurred in the vast majority of children. Further, persistence/recurrence could not be predicted by clinical features or SDB severity in our study. This, therefore, highlights the need for serial longitudinal screening for SDB in this population and for follow‐up PSG to ensure the success of treatment interventions.”

No study funding was reported. The study authors reported no disclosures.

SOURCE: Nehme J et al. Pediatr Pulmonol. 2019 Jun 6. doi: 10.1002/ppul.24380.

The Food and Drug Administration has approved bremelanotide (Vyleesi) to treat acquired, generalized hypoactive sexual desire disorder (HSDD) in premenopausal women.

“There are women who, for no known reason, have reduced sexual desire that causes marked distress, and who can benefit from safe and effective pharmacologic treatment,” Hylton V. Joffe, MD, director of the Center for Drug Evaluation and Research’s Division of Bone, Reproductive, and Urologic Products, stated in a press release. “Today’s approval provides women with another treatment option for this condition.”

HSDD is characterized by low sexual desire that causes marked distress or interpersonal difficulty and is not caused by a medical or psychiatric condition. Acquired HSDD develops in a patient who previously experienced no problems with sexual desire, and generalized HSDD is a lack of desire that occurs regardless of the type of sexual activity, situation, or partner.

Vyleesi was studied in two 24-week, randomized, double-blind, placebo-controlled trials in 1,247 premenopausal women with acquired, generalized HSDD. The women used Vyleesi two or three times per month and no more than once a week. About one-quarter of patients treated with Vyleesi had an increase of 1.2 or more in their sexual desire score (scored on a range of 1.2 to 6.0, with higher scores indicating greater sexual desire), compared with about 17% of those who took placebo. About 35% of the patients treated with Vyleesi had a decrease of one or more in their distress score (scored on a range of 0-4, with higher scores indicating greater distress from low sexual desire) compared with about 31% of those who took placebo.

The drug is injected under the skin of the abdomen or thigh at least 45 minutes before anticipated sexual activity. Patients may decide the optimal time to use Vyleesi based on the duration of benefit and any side effects, such as nausea. Patients should not take more than one dose of Vyleesi within 24 hours, or more than eight doses per month. Patients should discontinue treatment after 8 weeks if they do not report an improvement in sexual desire and associated distress.

Vyleesi works by activating melanocortin receptors but the exact mechanism for improving sexual desire is unknown. Some side effects were reported. “The most common side effects of Vyleesi are nausea and vomiting, flushing, injection site reactions, and headache. About 40% of patients in the clinical trials experienced nausea, most commonly with the first Vyleesi injection, and 13% needed medications for the treatment of nausea. About 1% of patients treated with Vyleesi in the clinical trials reported darkening of the gums and parts of the skin, including the face and breasts, which did not go away in about half the patients after stopping treatment. Patients with dark skin were more likely to develop this side effect,” according to the press release.

A temporary increase in blood pressure in patients after dosing with Vyleesi was observed during the clinical trials and therefore the drug is not recommended in patients at high risk for cardiovascular disease. In addition, patients who take a naltrexone-containing medication by mouth to treat alcohol or opioid dependence should not use Vyleesi because it may significantly decrease the levels of naltrexone in the blood and could lead to naltrexone treatment failure.

The full press release can be found on the FDA website.

[email protected]

The Food and Drug Administration has approved bremelanotide (Vyleesi) to treat acquired, generalized hypoactive sexual desire disorder (HSDD) in premenopausal women.

“There are women who, for no known reason, have reduced sexual desire that causes marked distress, and who can benefit from safe and effective pharmacologic treatment,” Hylton V. Joffe, MD, director of the Center for Drug Evaluation and Research’s Division of Bone, Reproductive, and Urologic Products, stated in a press release. “Today’s approval provides women with another treatment option for this condition.”

HSDD is characterized by low sexual desire that causes marked distress or interpersonal difficulty and is not caused by a medical or psychiatric condition. Acquired HSDD develops in a patient who previously experienced no problems with sexual desire, and generalized HSDD is a lack of desire that occurs regardless of the type of sexual activity, situation, or partner.

Vyleesi was studied in two 24-week, randomized, double-blind, placebo-controlled trials in 1,247 premenopausal women with acquired, generalized HSDD. The women used Vyleesi two or three times per month and no more than once a week. About one-quarter of patients treated with Vyleesi had an increase of 1.2 or more in their sexual desire score (scored on a range of 1.2 to 6.0, with higher scores indicating greater sexual desire), compared with about 17% of those who took placebo. About 35% of the patients treated with Vyleesi had a decrease of one or more in their distress score (scored on a range of 0-4, with higher scores indicating greater distress from low sexual desire) compared with about 31% of those who took placebo.

The drug is injected under the skin of the abdomen or thigh at least 45 minutes before anticipated sexual activity. Patients may decide the optimal time to use Vyleesi based on the duration of benefit and any side effects, such as nausea. Patients should not take more than one dose of Vyleesi within 24 hours, or more than eight doses per month. Patients should discontinue treatment after 8 weeks if they do not report an improvement in sexual desire and associated distress.

Vyleesi works by activating melanocortin receptors but the exact mechanism for improving sexual desire is unknown. Some side effects were reported. “The most common side effects of Vyleesi are nausea and vomiting, flushing, injection site reactions, and headache. About 40% of patients in the clinical trials experienced nausea, most commonly with the first Vyleesi injection, and 13% needed medications for the treatment of nausea. About 1% of patients treated with Vyleesi in the clinical trials reported darkening of the gums and parts of the skin, including the face and breasts, which did not go away in about half the patients after stopping treatment. Patients with dark skin were more likely to develop this side effect,” according to the press release.

A temporary increase in blood pressure in patients after dosing with Vyleesi was observed during the clinical trials and therefore the drug is not recommended in patients at high risk for cardiovascular disease. In addition, patients who take a naltrexone-containing medication by mouth to treat alcohol or opioid dependence should not use Vyleesi because it may significantly decrease the levels of naltrexone in the blood and could lead to naltrexone treatment failure.

The full press release can be found on the FDA website.

[email protected]

The Food and Drug Administration has approved bremelanotide (Vyleesi) to treat acquired, generalized hypoactive sexual desire disorder (HSDD) in premenopausal women.

“There are women who, for no known reason, have reduced sexual desire that causes marked distress, and who can benefit from safe and effective pharmacologic treatment,” Hylton V. Joffe, MD, director of the Center for Drug Evaluation and Research’s Division of Bone, Reproductive, and Urologic Products, stated in a press release. “Today’s approval provides women with another treatment option for this condition.”

HSDD is characterized by low sexual desire that causes marked distress or interpersonal difficulty and is not caused by a medical or psychiatric condition. Acquired HSDD develops in a patient who previously experienced no problems with sexual desire, and generalized HSDD is a lack of desire that occurs regardless of the type of sexual activity, situation, or partner.

Vyleesi was studied in two 24-week, randomized, double-blind, placebo-controlled trials in 1,247 premenopausal women with acquired, generalized HSDD. The women used Vyleesi two or three times per month and no more than once a week. About one-quarter of patients treated with Vyleesi had an increase of 1.2 or more in their sexual desire score (scored on a range of 1.2 to 6.0, with higher scores indicating greater sexual desire), compared with about 17% of those who took placebo. About 35% of the patients treated with Vyleesi had a decrease of one or more in their distress score (scored on a range of 0-4, with higher scores indicating greater distress from low sexual desire) compared with about 31% of those who took placebo.

The drug is injected under the skin of the abdomen or thigh at least 45 minutes before anticipated sexual activity. Patients may decide the optimal time to use Vyleesi based on the duration of benefit and any side effects, such as nausea. Patients should not take more than one dose of Vyleesi within 24 hours, or more than eight doses per month. Patients should discontinue treatment after 8 weeks if they do not report an improvement in sexual desire and associated distress.

Vyleesi works by activating melanocortin receptors but the exact mechanism for improving sexual desire is unknown. Some side effects were reported. “The most common side effects of Vyleesi are nausea and vomiting, flushing, injection site reactions, and headache. About 40% of patients in the clinical trials experienced nausea, most commonly with the first Vyleesi injection, and 13% needed medications for the treatment of nausea. About 1% of patients treated with Vyleesi in the clinical trials reported darkening of the gums and parts of the skin, including the face and breasts, which did not go away in about half the patients after stopping treatment. Patients with dark skin were more likely to develop this side effect,” according to the press release.

A temporary increase in blood pressure in patients after dosing with Vyleesi was observed during the clinical trials and therefore the drug is not recommended in patients at high risk for cardiovascular disease. In addition, patients who take a naltrexone-containing medication by mouth to treat alcohol or opioid dependence should not use Vyleesi because it may significantly decrease the levels of naltrexone in the blood and could lead to naltrexone treatment failure.

The full press release can be found on the FDA website.

[email protected]

CRYSTAL CITY, VA. – Borderline personality disorder has a genetic and neurobiological component, but researchers remain unable to discern exactly why specific genetic markers are attributed to the disease, Emil F. Coccaro, MD, said at Focus on Neuropsychiatry presented by Current Psychiatry and the American Academy of Clinical Psychiatrists.

“The neurobiology at this point gives us clues that what’s going on with borderline personality disorder isn’t simply developmental or environmental. That’s all that it tells us,” said Dr. Coccaro, director of the Clinical Neuroscience & Psychopharmacology Research Unit at the University of Chicago.

Similarly, studies in twins that show heritability of borderline personal disorder at rates between 31% and 49% “only show there’s something in the DNA,” he added. Dr. Coccaro called the evidence for the neurobiology of borderline personality disorder “hazy.” “The neurobiology of [borderline personality disorder] points to widespread brain network dysfunction affecting emotional processing and social cognition,” said Dr. Coccaro, also chairman of the university’s department of psychiatry and behavioral neuroscience.

That is true of a lot of disorders, he said, so only the details explain why patients with borderline personality disorder look different from those who might have “similar types of circuitry abnormalities,” he said.

For example, genomewide association studies have found links between borderline personality disorder and the genes DPYD and PKP4, indicating problems with pyrimidine metabolism and myelin production. The study also found a strong association between borderline personality disorder, bipolar disorder, major depression, and schizophrenia (Transl Psychiatry. 2017 Jun. doi: 10.1038/tp.2017.115). DPYD has been associated with schizophrenia, but the relationship between DPYD and borderline personality disorder is unknown, Dr. Coccaro said.

“These [associations] are suggestive of what’s going on genetically, but it hardly makes a story that’s coherent enough to sink your teeth into,” he said.

CRYSTAL CITY, VA. – Borderline personality disorder has a genetic and neurobiological component, but researchers remain unable to discern exactly why specific genetic markers are attributed to the disease, Emil F. Coccaro, MD, said at Focus on Neuropsychiatry presented by Current Psychiatry and the American Academy of Clinical Psychiatrists.

“The neurobiology at this point gives us clues that what’s going on with borderline personality disorder isn’t simply developmental or environmental. That’s all that it tells us,” said Dr. Coccaro, director of the Clinical Neuroscience & Psychopharmacology Research Unit at the University of Chicago.

Similarly, studies in twins that show heritability of borderline personal disorder at rates between 31% and 49% “only show there’s something in the DNA,” he added. Dr. Coccaro called the evidence for the neurobiology of borderline personality disorder “hazy.” “The neurobiology of [borderline personality disorder] points to widespread brain network dysfunction affecting emotional processing and social cognition,” said Dr. Coccaro, also chairman of the university’s department of psychiatry and behavioral neuroscience.

That is true of a lot of disorders, he said, so only the details explain why patients with borderline personality disorder look different from those who might have “similar types of circuitry abnormalities,” he said.

For example, genomewide association studies have found links between borderline personality disorder and the genes DPYD and PKP4, indicating problems with pyrimidine metabolism and myelin production. The study also found a strong association between borderline personality disorder, bipolar disorder, major depression, and schizophrenia (Transl Psychiatry. 2017 Jun. doi: 10.1038/tp.2017.115). DPYD has been associated with schizophrenia, but the relationship between DPYD and borderline personality disorder is unknown, Dr. Coccaro said.

“These [associations] are suggestive of what’s going on genetically, but it hardly makes a story that’s coherent enough to sink your teeth into,” he said.

CRYSTAL CITY, VA. – Borderline personality disorder has a genetic and neurobiological component, but researchers remain unable to discern exactly why specific genetic markers are attributed to the disease, Emil F. Coccaro, MD, said at Focus on Neuropsychiatry presented by Current Psychiatry and the American Academy of Clinical Psychiatrists.

“The neurobiology at this point gives us clues that what’s going on with borderline personality disorder isn’t simply developmental or environmental. That’s all that it tells us,” said Dr. Coccaro, director of the Clinical Neuroscience & Psychopharmacology Research Unit at the University of Chicago.

Similarly, studies in twins that show heritability of borderline personal disorder at rates between 31% and 49% “only show there’s something in the DNA,” he added. Dr. Coccaro called the evidence for the neurobiology of borderline personality disorder “hazy.” “The neurobiology of [borderline personality disorder] points to widespread brain network dysfunction affecting emotional processing and social cognition,” said Dr. Coccaro, also chairman of the university’s department of psychiatry and behavioral neuroscience.

That is true of a lot of disorders, he said, so only the details explain why patients with borderline personality disorder look different from those who might have “similar types of circuitry abnormalities,” he said.

For example, genomewide association studies have found links between borderline personality disorder and the genes DPYD and PKP4, indicating problems with pyrimidine metabolism and myelin production. The study also found a strong association between borderline personality disorder, bipolar disorder, major depression, and schizophrenia (Transl Psychiatry. 2017 Jun. doi: 10.1038/tp.2017.115). DPYD has been associated with schizophrenia, but the relationship between DPYD and borderline personality disorder is unknown, Dr. Coccaro said.

“These [associations] are suggestive of what’s going on genetically, but it hardly makes a story that’s coherent enough to sink your teeth into,” he said.

AMSTERDAM – For patients with immune thrombocytopenia (ITP), platelet glycoprotein genotypes may predict effectiveness of specific therapies, according to investigators.

Will Pass/MDedge News

Significant relationships were detected between allelic polymorphisms of glycoprotein genes and durable responses to corticosteroids, thrombopoietin receptor agonists (aTPOr), and splenectomy, reported lead author Irina Zotova, MD, of the Russian Research Institute of Hematology and Transfusiology, Federal Biomedical Agency, in Saint Petersburg and colleagues.

These findings could guide clinical decision making in ITP, according to Dr. Zotova.

“Currently, the choice of therapeutic approach to ITP treatment, especially the second-line, is empirical, and often based on the experience of the clinician,” Dr. Zotova said during her presentation at the annual congress of the European Hematology Association. “Recent studies have shown that ... genes coding for glycoprotein are involved in platelet function and are associated with different responses to ITP treatment. This provides an opportunity for an individual approach and personalization of ITP therapy in accordance with the genetic status of the patient.”

In the present study, the investigators used PCR-RFLP (polymerase chain reaction–restriction fragment length polymorphism) to determine GPIa A1648G and GPIIb 2622TG gene status in 81 patients with primary ITP and compared these genotypes with clinical responses.

All patients received first-line corticosteroid therapy. If necessary, second-line treatment was delivered. In total, 37 patients (46%) received aTPOr, while 22 patients (27%) underwent splenectomy. Responses were classified as durable response, nondurable response, or no response.

Analysis showed that a significantly greater proportion of patients who had durable responses to corticosteroid therapy exhibited a heterozygous GPIIb 2622TG genotype, compared with patients who had nondurable responses (72.2% vs. 30.9%; odds ratio, 5.8; P = .005).

For second-line responses, patients who had durable response to aTPOr were much more likely to be homozygous for the GPIa A1648G than nonresponders (87.5% vs. 20.0%; OR, 28.0; P = .005). More strikingly, all patients who achieved durable responses to splenectomy had the GPIa A1648G genotype, compared with just 44% of nonresponders (OR, 33.0; P = .005).

“Gentoyping for the GPIIb T2622G and GPIa A1648G polymorphisms allows [clinicians] to predict the response to first-line and second-line treatment, giving the possibility to stratify patients to groups with favorable and unfavorable courses of the disease,” Dr. Zotova concluded.

Will Pass/MDedge News

Session moderator János Kappelmayer, MD, of the University of Debrecen (Hungary) highlighted a key opportunity presented by the study. “I think that one important aspect of these findings could be that splenectomy is an irreversible procedure, so one can exclude those patients who will not benefit from splenectomy,” he said. “I think this is a real advantage.”

The investigators reported no study funding or conflicts of interest.

SOURCE: Zotova I et al. EHA Congress, Abstract S848.

AMSTERDAM – For patients with immune thrombocytopenia (ITP), platelet glycoprotein genotypes may predict effectiveness of specific therapies, according to investigators.

Will Pass/MDedge News

Significant relationships were detected between allelic polymorphisms of glycoprotein genes and durable responses to corticosteroids, thrombopoietin receptor agonists (aTPOr), and splenectomy, reported lead author Irina Zotova, MD, of the Russian Research Institute of Hematology and Transfusiology, Federal Biomedical Agency, in Saint Petersburg and colleagues.

These findings could guide clinical decision making in ITP, according to Dr. Zotova.

“Currently, the choice of therapeutic approach to ITP treatment, especially the second-line, is empirical, and often based on the experience of the clinician,” Dr. Zotova said during her presentation at the annual congress of the European Hematology Association. “Recent studies have shown that ... genes coding for glycoprotein are involved in platelet function and are associated with different responses to ITP treatment. This provides an opportunity for an individual approach and personalization of ITP therapy in accordance with the genetic status of the patient.”

In the present study, the investigators used PCR-RFLP (polymerase chain reaction–restriction fragment length polymorphism) to determine GPIa A1648G and GPIIb 2622TG gene status in 81 patients with primary ITP and compared these genotypes with clinical responses.

All patients received first-line corticosteroid therapy. If necessary, second-line treatment was delivered. In total, 37 patients (46%) received aTPOr, while 22 patients (27%) underwent splenectomy. Responses were classified as durable response, nondurable response, or no response.

Analysis showed that a significantly greater proportion of patients who had durable responses to corticosteroid therapy exhibited a heterozygous GPIIb 2622TG genotype, compared with patients who had nondurable responses (72.2% vs. 30.9%; odds ratio, 5.8; P = .005).

For second-line responses, patients who had durable response to aTPOr were much more likely to be homozygous for the GPIa A1648G than nonresponders (87.5% vs. 20.0%; OR, 28.0; P = .005). More strikingly, all patients who achieved durable responses to splenectomy had the GPIa A1648G genotype, compared with just 44% of nonresponders (OR, 33.0; P = .005).

“Gentoyping for the GPIIb T2622G and GPIa A1648G polymorphisms allows [clinicians] to predict the response to first-line and second-line treatment, giving the possibility to stratify patients to groups with favorable and unfavorable courses of the disease,” Dr. Zotova concluded.

Will Pass/MDedge News

Session moderator János Kappelmayer, MD, of the University of Debrecen (Hungary) highlighted a key opportunity presented by the study. “I think that one important aspect of these findings could be that splenectomy is an irreversible procedure, so one can exclude those patients who will not benefit from splenectomy,” he said. “I think this is a real advantage.”

The investigators reported no study funding or conflicts of interest.

SOURCE: Zotova I et al. EHA Congress, Abstract S848.

AMSTERDAM – For patients with immune thrombocytopenia (ITP), platelet glycoprotein genotypes may predict effectiveness of specific therapies, according to investigators.

Will Pass/MDedge News

Significant relationships were detected between allelic polymorphisms of glycoprotein genes and durable responses to corticosteroids, thrombopoietin receptor agonists (aTPOr), and splenectomy, reported lead author Irina Zotova, MD, of the Russian Research Institute of Hematology and Transfusiology, Federal Biomedical Agency, in Saint Petersburg and colleagues.

These findings could guide clinical decision making in ITP, according to Dr. Zotova.

“Currently, the choice of therapeutic approach to ITP treatment, especially the second-line, is empirical, and often based on the experience of the clinician,” Dr. Zotova said during her presentation at the annual congress of the European Hematology Association. “Recent studies have shown that ... genes coding for glycoprotein are involved in platelet function and are associated with different responses to ITP treatment. This provides an opportunity for an individual approach and personalization of ITP therapy in accordance with the genetic status of the patient.”

In the present study, the investigators used PCR-RFLP (polymerase chain reaction–restriction fragment length polymorphism) to determine GPIa A1648G and GPIIb 2622TG gene status in 81 patients with primary ITP and compared these genotypes with clinical responses.

All patients received first-line corticosteroid therapy. If necessary, second-line treatment was delivered. In total, 37 patients (46%) received aTPOr, while 22 patients (27%) underwent splenectomy. Responses were classified as durable response, nondurable response, or no response.

Analysis showed that a significantly greater proportion of patients who had durable responses to corticosteroid therapy exhibited a heterozygous GPIIb 2622TG genotype, compared with patients who had nondurable responses (72.2% vs. 30.9%; odds ratio, 5.8; P = .005).

For second-line responses, patients who had durable response to aTPOr were much more likely to be homozygous for the GPIa A1648G than nonresponders (87.5% vs. 20.0%; OR, 28.0; P = .005). More strikingly, all patients who achieved durable responses to splenectomy had the GPIa A1648G genotype, compared with just 44% of nonresponders (OR, 33.0; P = .005).

“Gentoyping for the GPIIb T2622G and GPIa A1648G polymorphisms allows [clinicians] to predict the response to first-line and second-line treatment, giving the possibility to stratify patients to groups with favorable and unfavorable courses of the disease,” Dr. Zotova concluded.

Will Pass/MDedge News

Session moderator János Kappelmayer, MD, of the University of Debrecen (Hungary) highlighted a key opportunity presented by the study. “I think that one important aspect of these findings could be that splenectomy is an irreversible procedure, so one can exclude those patients who will not benefit from splenectomy,” he said. “I think this is a real advantage.”

The investigators reported no study funding or conflicts of interest.

SOURCE: Zotova I et al. EHA Congress, Abstract S848.

Myocardial perfusion cardiovascular MRI is as good as invasive angiography and measurement of fractional flow reserve to guide revascularization in patients with angina, research suggests.

In the New England Journal of Medicine, researchers present the outcomes of an unblinded, multicenter, clinical effectiveness trial comparing the two revascularization strategies in 918 patients who had typical angina and either two or more cardiovascular risk factors or a positive exercise treadmill test.

In the fractional flow reserve method, revascularization was recommended in all vessels with an FFR of 0.8 or less. In the MRI-guided method, all patients underwent myocardial perfusion cardiovascular MRI, and patients with clinically significant inducible ischemia then underwent invasive angiography, and revascularization if required.

Significantly fewer patients in the cardiovascular MRI group underwent index revascularization, compared with the fractional flow reserve group (36% vs. 45% respectively; P = .005), and only 48% in the cardiovascular MRI group underwent invasive angiography, compared with 97% of patients in the fractional flow reserve arm.

However, there was no significant difference between the two groups in the incidence of major cardiac adverse events after 1 year, signifying that the MRI approach met the criteria for noninferiority.

There was also no significant difference between the two groups in the percentage of patients who were free from angina after 12 months (49.2% in the MRI group and 43.8% in the FFR group).

“Current guidelines on the management of the care of patients with suspected coronary artery disease separate diagnostic strategies from therapeutic strategies owing to a lack of evidence comparing combined diagnostic and therapeutic pathways,” wrote Eike Nagel, MD, of the Goethe University Frankfurt Institute for Experimental and Translational Cardiovascular Imaging and coauthors. “The MR-INFORM trial closes this knowledge gap by comparing two frequently used, well-defined, standardized, and validated clinical management strategies.”

However, they pointed out that one limitation of their study was the lack of a third group of patients who received medical therapy without planned revascularization. They also noted that the incidence of the primary outcome of major adverse cardiac events was lower than expected at 1 year.

The study was supported by the Guy’s and St. Thomas’ Biomedical Research Centre of the National Institute for Health Research. Three authors declared support from study supporters related to the study, three declared grants, personal fees, and other support from the private sector unrelated to the study. No other conflicts of interest were declared.

SOURCE: Nagel E et al. New Engl J Med. 2019;380:2418-28. doi: 10.1056/NEJMoa1716734.

Myocardial perfusion cardiovascular MRI is as good as invasive angiography and measurement of fractional flow reserve to guide revascularization in patients with angina, research suggests.

In the New England Journal of Medicine, researchers present the outcomes of an unblinded, multicenter, clinical effectiveness trial comparing the two revascularization strategies in 918 patients who had typical angina and either two or more cardiovascular risk factors or a positive exercise treadmill test.

In the fractional flow reserve method, revascularization was recommended in all vessels with an FFR of 0.8 or less. In the MRI-guided method, all patients underwent myocardial perfusion cardiovascular MRI, and patients with clinically significant inducible ischemia then underwent invasive angiography, and revascularization if required.

Significantly fewer patients in the cardiovascular MRI group underwent index revascularization, compared with the fractional flow reserve group (36% vs. 45% respectively; P = .005), and only 48% in the cardiovascular MRI group underwent invasive angiography, compared with 97% of patients in the fractional flow reserve arm.

However, there was no significant difference between the two groups in the incidence of major cardiac adverse events after 1 year, signifying that the MRI approach met the criteria for noninferiority.

There was also no significant difference between the two groups in the percentage of patients who were free from angina after 12 months (49.2% in the MRI group and 43.8% in the FFR group).

“Current guidelines on the management of the care of patients with suspected coronary artery disease separate diagnostic strategies from therapeutic strategies owing to a lack of evidence comparing combined diagnostic and therapeutic pathways,” wrote Eike Nagel, MD, of the Goethe University Frankfurt Institute for Experimental and Translational Cardiovascular Imaging and coauthors. “The MR-INFORM trial closes this knowledge gap by comparing two frequently used, well-defined, standardized, and validated clinical management strategies.”

However, they pointed out that one limitation of their study was the lack of a third group of patients who received medical therapy without planned revascularization. They also noted that the incidence of the primary outcome of major adverse cardiac events was lower than expected at 1 year.

The study was supported by the Guy’s and St. Thomas’ Biomedical Research Centre of the National Institute for Health Research. Three authors declared support from study supporters related to the study, three declared grants, personal fees, and other support from the private sector unrelated to the study. No other conflicts of interest were declared.

SOURCE: Nagel E et al. New Engl J Med. 2019;380:2418-28. doi: 10.1056/NEJMoa1716734.

Myocardial perfusion cardiovascular MRI is as good as invasive angiography and measurement of fractional flow reserve to guide revascularization in patients with angina, research suggests.

In the New England Journal of Medicine, researchers present the outcomes of an unblinded, multicenter, clinical effectiveness trial comparing the two revascularization strategies in 918 patients who had typical angina and either two or more cardiovascular risk factors or a positive exercise treadmill test.

In the fractional flow reserve method, revascularization was recommended in all vessels with an FFR of 0.8 or less. In the MRI-guided method, all patients underwent myocardial perfusion cardiovascular MRI, and patients with clinically significant inducible ischemia then underwent invasive angiography, and revascularization if required.

Significantly fewer patients in the cardiovascular MRI group underwent index revascularization, compared with the fractional flow reserve group (36% vs. 45% respectively; P = .005), and only 48% in the cardiovascular MRI group underwent invasive angiography, compared with 97% of patients in the fractional flow reserve arm.

However, there was no significant difference between the two groups in the incidence of major cardiac adverse events after 1 year, signifying that the MRI approach met the criteria for noninferiority.

There was also no significant difference between the two groups in the percentage of patients who were free from angina after 12 months (49.2% in the MRI group and 43.8% in the FFR group).

“Current guidelines on the management of the care of patients with suspected coronary artery disease separate diagnostic strategies from therapeutic strategies owing to a lack of evidence comparing combined diagnostic and therapeutic pathways,” wrote Eike Nagel, MD, of the Goethe University Frankfurt Institute for Experimental and Translational Cardiovascular Imaging and coauthors. “The MR-INFORM trial closes this knowledge gap by comparing two frequently used, well-defined, standardized, and validated clinical management strategies.”

However, they pointed out that one limitation of their study was the lack of a third group of patients who received medical therapy without planned revascularization. They also noted that the incidence of the primary outcome of major adverse cardiac events was lower than expected at 1 year.

The study was supported by the Guy’s and St. Thomas’ Biomedical Research Centre of the National Institute for Health Research. Three authors declared support from study supporters related to the study, three declared grants, personal fees, and other support from the private sector unrelated to the study. No other conflicts of interest were declared.

SOURCE: Nagel E et al. New Engl J Med. 2019;380:2418-28. doi: 10.1056/NEJMoa1716734.

The recombinant factor IX product nonacog alfa appears safe and effective for patients with hemophilia B, according to results from a recent postmarketing study in Japan.

While nonacog alfa was approved in the United States and Europe in 1997, the product wasn’t approved in Japan until 2009. Since it was the first recombinant factor IX product available there, and only a small number of patients were enrolled in domestic clinical trials, the Japanese government required additional real-world studies.

“In the last couple of years, several extended half‐life blood coagulation factor products gained regulatory approval for the treatment of hemophilia B. However, access to this most advanced treatment option remains limited to developed countries, and the need for standard half‐life recombinant or plasma‐derived FIX products is still high,” wrote Katsuyuki Fukutake, MD, PhD, of Tokyo Medical University, Japan, and colleagues.

The researchers conducted an observational postmarketing surveillance study of 312 patients with hemophilia B who received nonacog alfa therapy from 2010 to 2014. The team evaluated the real-world safety, including the incidence of inhibitors and adverse events, and effectiveness of the recombinant product in Japan.

The findings were published in Haemophilia.

The study included both previously treated and untreated participants who were followed for 1 and 2 years, respectively, after starting recombinant factor IX therapy.

The primary safety outcome was the incidence and number of adverse drug reactions. Effectiveness was measured using clinical effectiveness rates and annualized bleeding rates (ABR).

After analysis, the researchers found that the effectiveness rates were 95.5% and 93.7% for patients who received routine prophylaxis and on-demand treatment, respectively.

The median ABR was lower during routine prophylaxis – 2.0 – versus the rest of the observation period – 8.3. “This difference was prominent among patients with severe haemophilia B or haemophilic arthropathy,” the researchers wrote.

With respect to safety, 11 adverse drug reactions were seen in seven previously treated patients. New inhibitor development was not observed in any participants, but recurrence was seen in one patient.

“Our results are consistent with those of previous studies where the incidence of inhibitor antibody development in hemophilia B has been reported as 1%-5%,” Dr. Fukutake and colleagues wrote.

The researchers acknowledged that one key limitation of the study was the observational design.

“The results suggest that nonacog alfa was well tolerated and appropriately used under routine clinical practice,” the authors concluded.

The study was funded and conducted by Pfizer Japan. The authors reported financial relationships with Pfizer and several other companies. One coauthor is an employee of Pfizer Japan.

SOURCE: Fukutake K et al. Haemophilia. 2019 Jun 6. doi: 10.1111/hae.13783.
 

The recombinant factor IX product nonacog alfa appears safe and effective for patients with hemophilia B, according to results from a recent postmarketing study in Japan.

While nonacog alfa was approved in the United States and Europe in 1997, the product wasn’t approved in Japan until 2009. Since it was the first recombinant factor IX product available there, and only a small number of patients were enrolled in domestic clinical trials, the Japanese government required additional real-world studies.

“In the last couple of years, several extended half‐life blood coagulation factor products gained regulatory approval for the treatment of hemophilia B. However, access to this most advanced treatment option remains limited to developed countries, and the need for standard half‐life recombinant or plasma‐derived FIX products is still high,” wrote Katsuyuki Fukutake, MD, PhD, of Tokyo Medical University, Japan, and colleagues.

The researchers conducted an observational postmarketing surveillance study of 312 patients with hemophilia B who received nonacog alfa therapy from 2010 to 2014. The team evaluated the real-world safety, including the incidence of inhibitors and adverse events, and effectiveness of the recombinant product in Japan.

The findings were published in Haemophilia.

The study included both previously treated and untreated participants who were followed for 1 and 2 years, respectively, after starting recombinant factor IX therapy.

The primary safety outcome was the incidence and number of adverse drug reactions. Effectiveness was measured using clinical effectiveness rates and annualized bleeding rates (ABR).

After analysis, the researchers found that the effectiveness rates were 95.5% and 93.7% for patients who received routine prophylaxis and on-demand treatment, respectively.

The median ABR was lower during routine prophylaxis – 2.0 – versus the rest of the observation period – 8.3. “This difference was prominent among patients with severe haemophilia B or haemophilic arthropathy,” the researchers wrote.

With respect to safety, 11 adverse drug reactions were seen in seven previously treated patients. New inhibitor development was not observed in any participants, but recurrence was seen in one patient.

“Our results are consistent with those of previous studies where the incidence of inhibitor antibody development in hemophilia B has been reported as 1%-5%,” Dr. Fukutake and colleagues wrote.

The researchers acknowledged that one key limitation of the study was the observational design.

“The results suggest that nonacog alfa was well tolerated and appropriately used under routine clinical practice,” the authors concluded.

The study was funded and conducted by Pfizer Japan. The authors reported financial relationships with Pfizer and several other companies. One coauthor is an employee of Pfizer Japan.

SOURCE: Fukutake K et al. Haemophilia. 2019 Jun 6. doi: 10.1111/hae.13783.
 

The recombinant factor IX product nonacog alfa appears safe and effective for patients with hemophilia B, according to results from a recent postmarketing study in Japan.

While nonacog alfa was approved in the United States and Europe in 1997, the product wasn’t approved in Japan until 2009. Since it was the first recombinant factor IX product available there, and only a small number of patients were enrolled in domestic clinical trials, the Japanese government required additional real-world studies.

“In the last couple of years, several extended half‐life blood coagulation factor products gained regulatory approval for the treatment of hemophilia B. However, access to this most advanced treatment option remains limited to developed countries, and the need for standard half‐life recombinant or plasma‐derived FIX products is still high,” wrote Katsuyuki Fukutake, MD, PhD, of Tokyo Medical University, Japan, and colleagues.

The researchers conducted an observational postmarketing surveillance study of 312 patients with hemophilia B who received nonacog alfa therapy from 2010 to 2014. The team evaluated the real-world safety, including the incidence of inhibitors and adverse events, and effectiveness of the recombinant product in Japan.

The findings were published in Haemophilia.

The study included both previously treated and untreated participants who were followed for 1 and 2 years, respectively, after starting recombinant factor IX therapy.

The primary safety outcome was the incidence and number of adverse drug reactions. Effectiveness was measured using clinical effectiveness rates and annualized bleeding rates (ABR).

After analysis, the researchers found that the effectiveness rates were 95.5% and 93.7% for patients who received routine prophylaxis and on-demand treatment, respectively.

The median ABR was lower during routine prophylaxis – 2.0 – versus the rest of the observation period – 8.3. “This difference was prominent among patients with severe haemophilia B or haemophilic arthropathy,” the researchers wrote.

With respect to safety, 11 adverse drug reactions were seen in seven previously treated patients. New inhibitor development was not observed in any participants, but recurrence was seen in one patient.

“Our results are consistent with those of previous studies where the incidence of inhibitor antibody development in hemophilia B has been reported as 1%-5%,” Dr. Fukutake and colleagues wrote.

The researchers acknowledged that one key limitation of the study was the observational design.

“The results suggest that nonacog alfa was well tolerated and appropriately used under routine clinical practice,” the authors concluded.

The study was funded and conducted by Pfizer Japan. The authors reported financial relationships with Pfizer and several other companies. One coauthor is an employee of Pfizer Japan.

SOURCE: Fukutake K et al. Haemophilia. 2019 Jun 6. doi: 10.1111/hae.13783.
 

A preclinical study supports the use of BET inhibitors to treat activated B-cell–like diffuse large B-cell lymphoma (ABC-like DLBCL).

Courtesy Green Lab, UT MD Anderson

Researchers found the TCF4 (E2-2) transcription factor is an oncogene in ABC-like DLBCL, and TCF4 can be targeted via BET inhibition.

The BET protein degrader ARV771 reduced TCF4 expression and exhibited activity against ABC-like DLBCL in vitro and in vivo.

Neeraj Jain, PhD, of the University of Texas MD Anderson Cancer Center in Houston and colleagues reported these findings in Science Translational Medicine.

The researchers performed a genomic analysis of 1,000 DLBCL tumors and discovered that gains of 18q21.2 were the most frequent genetic alteration in ABC-like DLBCL. In analyzing another 249 tumors, the researchers found that TCF4 was the target of the 18q21.2 gains.

Additional experiments with primary DLBCL tumors and DLBCL cell lines indicated that TCF4 regulates IGHM and MYC expression. The researchers also found that the TCF4 gene was “one of the most highly BRD4-loaded genes in DLBCL,” and knocking down BRD4 in DLBCL cell lines reduced TCF4 expression.

These findings prompted the team to test small-molecule BET inhibitors – JQ1 and OTX015 – and a BET protein degrader – ARV771 – in ABC-like DLBCL cell lines with a high TCF4 copy number.

Treatment with JQ1 and OTX015 resulted in upregulation of BRD4, but ARV771 treatment did not. As a result, subsequent experiments were performed with ARV771.

The researchers found that ARV771 induced apoptosis in the cell lines and reduced the expression of TCF4, IgM, and MYC. However, enforced TCF4 expression during ARV771 treatment rescued IgM and MYC expression. This suggests that “reduction of TCF4 is one of the mechanisms by which BET inhibition reduces IgM and MYC expression and induces apoptosis,” according to the researchers.

The team also tested ARV771 in mouse models of ABC-like DLBCL with high TCF4 expression. ARV771 significantly reduced tumor growth and prolonged survival (P less than .05 for both), and there were no signs of toxicity in ARV771-treated mice.

“Our data provide a clear functional rationale for BET inhibition in ABC-like DLBCL,” the researchers wrote. They did note, however, that BCL2 overexpression is associated with resistance to BET inhibitors, and most of the 18q DNA copy number gains the researchers observed in DLBCL encompass TCF4 and BCL2. The team therefore theorized that combining a BET inhibitor with a BCL2 inhibitor could be a promising treatment approach in ABC-like DLBCL and is worthy of further investigation.

This research was supported by the Nebraska Department of Health & Human Services, the Schweitzer Family Fund, the Fred & Pamela Buffet Cancer Center Support Grant, and the MD Anderson Cancer Center NCI CORE Grant. The authors reported having no conflicts of interest related to the study.

[email protected]

SOURCE: Jain N et al. Sci. Transl. Med. 2019 Jun 19. doi: 10.1126/scitranslmed.aav5599.

A preclinical study supports the use of BET inhibitors to treat activated B-cell–like diffuse large B-cell lymphoma (ABC-like DLBCL).

Courtesy Green Lab, UT MD Anderson

Researchers found the TCF4 (E2-2) transcription factor is an oncogene in ABC-like DLBCL, and TCF4 can be targeted via BET inhibition.

The BET protein degrader ARV771 reduced TCF4 expression and exhibited activity against ABC-like DLBCL in vitro and in vivo.

Neeraj Jain, PhD, of the University of Texas MD Anderson Cancer Center in Houston and colleagues reported these findings in Science Translational Medicine.

The researchers performed a genomic analysis of 1,000 DLBCL tumors and discovered that gains of 18q21.2 were the most frequent genetic alteration in ABC-like DLBCL. In analyzing another 249 tumors, the researchers found that TCF4 was the target of the 18q21.2 gains.

Additional experiments with primary DLBCL tumors and DLBCL cell lines indicated that TCF4 regulates IGHM and MYC expression. The researchers also found that the TCF4 gene was “one of the most highly BRD4-loaded genes in DLBCL,” and knocking down BRD4 in DLBCL cell lines reduced TCF4 expression.

These findings prompted the team to test small-molecule BET inhibitors – JQ1 and OTX015 – and a BET protein degrader – ARV771 – in ABC-like DLBCL cell lines with a high TCF4 copy number.

Treatment with JQ1 and OTX015 resulted in upregulation of BRD4, but ARV771 treatment did not. As a result, subsequent experiments were performed with ARV771.

The researchers found that ARV771 induced apoptosis in the cell lines and reduced the expression of TCF4, IgM, and MYC. However, enforced TCF4 expression during ARV771 treatment rescued IgM and MYC expression. This suggests that “reduction of TCF4 is one of the mechanisms by which BET inhibition reduces IgM and MYC expression and induces apoptosis,” according to the researchers.

The team also tested ARV771 in mouse models of ABC-like DLBCL with high TCF4 expression. ARV771 significantly reduced tumor growth and prolonged survival (P less than .05 for both), and there were no signs of toxicity in ARV771-treated mice.

“Our data provide a clear functional rationale for BET inhibition in ABC-like DLBCL,” the researchers wrote. They did note, however, that BCL2 overexpression is associated with resistance to BET inhibitors, and most of the 18q DNA copy number gains the researchers observed in DLBCL encompass TCF4 and BCL2. The team therefore theorized that combining a BET inhibitor with a BCL2 inhibitor could be a promising treatment approach in ABC-like DLBCL and is worthy of further investigation.

This research was supported by the Nebraska Department of Health & Human Services, the Schweitzer Family Fund, the Fred & Pamela Buffet Cancer Center Support Grant, and the MD Anderson Cancer Center NCI CORE Grant. The authors reported having no conflicts of interest related to the study.

[email protected]

SOURCE: Jain N et al. Sci. Transl. Med. 2019 Jun 19. doi: 10.1126/scitranslmed.aav5599.

A preclinical study supports the use of BET inhibitors to treat activated B-cell–like diffuse large B-cell lymphoma (ABC-like DLBCL).

Courtesy Green Lab, UT MD Anderson

Researchers found the TCF4 (E2-2) transcription factor is an oncogene in ABC-like DLBCL, and TCF4 can be targeted via BET inhibition.

The BET protein degrader ARV771 reduced TCF4 expression and exhibited activity against ABC-like DLBCL in vitro and in vivo.

Neeraj Jain, PhD, of the University of Texas MD Anderson Cancer Center in Houston and colleagues reported these findings in Science Translational Medicine.

The researchers performed a genomic analysis of 1,000 DLBCL tumors and discovered that gains of 18q21.2 were the most frequent genetic alteration in ABC-like DLBCL. In analyzing another 249 tumors, the researchers found that TCF4 was the target of the 18q21.2 gains.

Additional experiments with primary DLBCL tumors and DLBCL cell lines indicated that TCF4 regulates IGHM and MYC expression. The researchers also found that the TCF4 gene was “one of the most highly BRD4-loaded genes in DLBCL,” and knocking down BRD4 in DLBCL cell lines reduced TCF4 expression.

These findings prompted the team to test small-molecule BET inhibitors – JQ1 and OTX015 – and a BET protein degrader – ARV771 – in ABC-like DLBCL cell lines with a high TCF4 copy number.

Treatment with JQ1 and OTX015 resulted in upregulation of BRD4, but ARV771 treatment did not. As a result, subsequent experiments were performed with ARV771.

The researchers found that ARV771 induced apoptosis in the cell lines and reduced the expression of TCF4, IgM, and MYC. However, enforced TCF4 expression during ARV771 treatment rescued IgM and MYC expression. This suggests that “reduction of TCF4 is one of the mechanisms by which BET inhibition reduces IgM and MYC expression and induces apoptosis,” according to the researchers.

The team also tested ARV771 in mouse models of ABC-like DLBCL with high TCF4 expression. ARV771 significantly reduced tumor growth and prolonged survival (P less than .05 for both), and there were no signs of toxicity in ARV771-treated mice.

“Our data provide a clear functional rationale for BET inhibition in ABC-like DLBCL,” the researchers wrote. They did note, however, that BCL2 overexpression is associated with resistance to BET inhibitors, and most of the 18q DNA copy number gains the researchers observed in DLBCL encompass TCF4 and BCL2. The team therefore theorized that combining a BET inhibitor with a BCL2 inhibitor could be a promising treatment approach in ABC-like DLBCL and is worthy of further investigation.

This research was supported by the Nebraska Department of Health & Human Services, the Schweitzer Family Fund, the Fred & Pamela Buffet Cancer Center Support Grant, and the MD Anderson Cancer Center NCI CORE Grant. The authors reported having no conflicts of interest related to the study.

[email protected]

SOURCE: Jain N et al. Sci. Transl. Med. 2019 Jun 19. doi: 10.1126/scitranslmed.aav5599.

The federal government may go forward with its plan to restrict Title X funding from clinics that provide abortion counseling or that refer patients for abortion services under a June 20 decision by the 9th U.S. Circuit Court of Appeals.

The panel ruled that the Trump administration’s funding restrictions were a reasonable interpretation of the federal Title X statute and that the administration is likely to prevail in its argument that lower courts erroneously halted the rules from taking effect. The ruling means the restrictions can take effect in every state except for Maryland, which passed a 2019 measure approving the use of state funds to replace federal Title X money if the new rule is enacted.

Alex Azar, secretary of the Department of Health & Human Services, said agency officials were pleased the 9th Circuit recognized there was no need to hold up the new family planning rules that simply enforce laws already on the books.

“We are also pleased that the [9th] Circuit agreed that the three preliminary injunctions against the new rules, including two nationwide injunctions, were inappropriate,” Mr. Azar said in the statement. “This decision is a major step toward the Trump administration being able to ensure that all Title X projects comply with the Title X statute and do not support abortion as a method of family planning.”

Leana Wen, MD, president for the Planned Parenthood Federation of America called the court ruling “devastating” for the millions of patients who rely on Title X health centers for cancer screenings, HIV tests, affordable birth control, and other critical primary and preventive care.

“We will be immediately seeking emergency relief from the [U.S.] Court of Appeals,” Dr. Wen said in a statement. “Planned Parenthood will not let the government censor our doctors and nurses from informing patients where and how they can access health care. We will continue to fight the Trump administration in the courts and alongside champions in Congress to protect everyone’s fundamental right to health care.”

The changes to the Title X program – originally scheduled to take effect May 3 – make health clinics ineligible for Title X funding if they offer, promote, or support abortion as a method of family planning. Title X grants generally go to health centers that provide reproductive health care – such as STD testing, cancer screenings, and contraception – to low-income families. Under the rule, the government would withdraw financial assistance to clinics if they allow counseling or referrals associated with abortion, regardless of whether the money is used for other health care services.

More than 20 states and several abortion rights organizations sued over the rules in four separate states. District judges in Oregon, Washington, and California temporarily blocked the rules from taking effect. The 9th Circuit ruling overturns these injunctions.

The American College of Physicians, the American Academy of Family Physicians, the American College of Obstetricians and Gynecologists, the American Academy of Pediatrics, and other groups have voiced their opposition to the Title X restrictions.

In a joint court brief, the medical societies wrote that the Trump administration’s limitations to the Title X program will create cultural, geographic, and financial barriers to care; erode the physician-patient relationship; and cause extreme, immediate, and irreparable harm to millions of patients.

[email protected]

The federal government may go forward with its plan to restrict Title X funding from clinics that provide abortion counseling or that refer patients for abortion services under a June 20 decision by the 9th U.S. Circuit Court of Appeals.

The panel ruled that the Trump administration’s funding restrictions were a reasonable interpretation of the federal Title X statute and that the administration is likely to prevail in its argument that lower courts erroneously halted the rules from taking effect. The ruling means the restrictions can take effect in every state except for Maryland, which passed a 2019 measure approving the use of state funds to replace federal Title X money if the new rule is enacted.

Alex Azar, secretary of the Department of Health & Human Services, said agency officials were pleased the 9th Circuit recognized there was no need to hold up the new family planning rules that simply enforce laws already on the books.

“We are also pleased that the [9th] Circuit agreed that the three preliminary injunctions against the new rules, including two nationwide injunctions, were inappropriate,” Mr. Azar said in the statement. “This decision is a major step toward the Trump administration being able to ensure that all Title X projects comply with the Title X statute and do not support abortion as a method of family planning.”

Leana Wen, MD, president for the Planned Parenthood Federation of America called the court ruling “devastating” for the millions of patients who rely on Title X health centers for cancer screenings, HIV tests, affordable birth control, and other critical primary and preventive care.

“We will be immediately seeking emergency relief from the [U.S.] Court of Appeals,” Dr. Wen said in a statement. “Planned Parenthood will not let the government censor our doctors and nurses from informing patients where and how they can access health care. We will continue to fight the Trump administration in the courts and alongside champions in Congress to protect everyone’s fundamental right to health care.”

The changes to the Title X program – originally scheduled to take effect May 3 – make health clinics ineligible for Title X funding if they offer, promote, or support abortion as a method of family planning. Title X grants generally go to health centers that provide reproductive health care – such as STD testing, cancer screenings, and contraception – to low-income families. Under the rule, the government would withdraw financial assistance to clinics if they allow counseling or referrals associated with abortion, regardless of whether the money is used for other health care services.

More than 20 states and several abortion rights organizations sued over the rules in four separate states. District judges in Oregon, Washington, and California temporarily blocked the rules from taking effect. The 9th Circuit ruling overturns these injunctions.

The American College of Physicians, the American Academy of Family Physicians, the American College of Obstetricians and Gynecologists, the American Academy of Pediatrics, and other groups have voiced their opposition to the Title X restrictions.

In a joint court brief, the medical societies wrote that the Trump administration’s limitations to the Title X program will create cultural, geographic, and financial barriers to care; erode the physician-patient relationship; and cause extreme, immediate, and irreparable harm to millions of patients.

[email protected]

The federal government may go forward with its plan to restrict Title X funding from clinics that provide abortion counseling or that refer patients for abortion services under a June 20 decision by the 9th U.S. Circuit Court of Appeals.

The panel ruled that the Trump administration’s funding restrictions were a reasonable interpretation of the federal Title X statute and that the administration is likely to prevail in its argument that lower courts erroneously halted the rules from taking effect. The ruling means the restrictions can take effect in every state except for Maryland, which passed a 2019 measure approving the use of state funds to replace federal Title X money if the new rule is enacted.

Alex Azar, secretary of the Department of Health & Human Services, said agency officials were pleased the 9th Circuit recognized there was no need to hold up the new family planning rules that simply enforce laws already on the books.

“We are also pleased that the [9th] Circuit agreed that the three preliminary injunctions against the new rules, including two nationwide injunctions, were inappropriate,” Mr. Azar said in the statement. “This decision is a major step toward the Trump administration being able to ensure that all Title X projects comply with the Title X statute and do not support abortion as a method of family planning.”

Leana Wen, MD, president for the Planned Parenthood Federation of America called the court ruling “devastating” for the millions of patients who rely on Title X health centers for cancer screenings, HIV tests, affordable birth control, and other critical primary and preventive care.

“We will be immediately seeking emergency relief from the [U.S.] Court of Appeals,” Dr. Wen said in a statement. “Planned Parenthood will not let the government censor our doctors and nurses from informing patients where and how they can access health care. We will continue to fight the Trump administration in the courts and alongside champions in Congress to protect everyone’s fundamental right to health care.”

The changes to the Title X program – originally scheduled to take effect May 3 – make health clinics ineligible for Title X funding if they offer, promote, or support abortion as a method of family planning. Title X grants generally go to health centers that provide reproductive health care – such as STD testing, cancer screenings, and contraception – to low-income families. Under the rule, the government would withdraw financial assistance to clinics if they allow counseling or referrals associated with abortion, regardless of whether the money is used for other health care services.

More than 20 states and several abortion rights organizations sued over the rules in four separate states. District judges in Oregon, Washington, and California temporarily blocked the rules from taking effect. The 9th Circuit ruling overturns these injunctions.

The American College of Physicians, the American Academy of Family Physicians, the American College of Obstetricians and Gynecologists, the American Academy of Pediatrics, and other groups have voiced their opposition to the Title X restrictions.

In a joint court brief, the medical societies wrote that the Trump administration’s limitations to the Title X program will create cultural, geographic, and financial barriers to care; erode the physician-patient relationship; and cause extreme, immediate, and irreparable harm to millions of patients.

[email protected]

Does Medicare-for-all mean that everyone gets health insurance coverage?

The public is not convinced that this would be the case, and Republicans are even more skeptical, according to a new survey from the Kaiser Family Foundation.

Less than two-thirds of American adults believe that all U.S. residents would have health insurance under a national health plan, and there is a sizable split between Republicans and Democrats on the issue. Republicans, in fact, were more likely to say that all residents would not have coverage, with less than 49% of people identifying as Republican having answered “no” to the question and 45% having answered “yes”, Kaiser reported in its latest Health Tracking Poll.

Democrats were much more optimistic but not all were certain that all U.S. residents would have health insurance coverage. While 76% of Democrats responded yes when queried about whether all residents would get coverage, 21% answered no to the question. Responses to the question from independents – 61% said yes and 35% said no – very closely reflected the overall vote of 62% yes and 34% no, Kaiser said.

The partisan divide appeared again when respondents were asked if physicians and hospitals would be paid less under a national health plan: 64% of Republicans said payments would be reduced versus 42% of Democrats. Similarly, more than half of Republicans (53%) said that people who buy their own insurance would not be able to keep their current plans, compared with 24% of Democrats, the poll data show.

Those looking for common ground can point to responses regarding a couple of other potential effects of a national health plan. Republicans (57%) and Democrats (52%) largely agreed that private health insurance companies would not be the primary way Americans get health coverage, and they agreed that people would continue to pay deductibles and copays when they used health care services (68% for Republicans, 71% for Democrats), Kaiser said.

The poll was conducted from May 30 to June 4, 2019, and involved responses from 1,206 adults. The margin of sampling error was plus or minus 3 percentage points.

[email protected]

Does Medicare-for-all mean that everyone gets health insurance coverage?

The public is not convinced that this would be the case, and Republicans are even more skeptical, according to a new survey from the Kaiser Family Foundation.

Less than two-thirds of American adults believe that all U.S. residents would have health insurance under a national health plan, and there is a sizable split between Republicans and Democrats on the issue. Republicans, in fact, were more likely to say that all residents would not have coverage, with less than 49% of people identifying as Republican having answered “no” to the question and 45% having answered “yes”, Kaiser reported in its latest Health Tracking Poll.

Democrats were much more optimistic but not all were certain that all U.S. residents would have health insurance coverage. While 76% of Democrats responded yes when queried about whether all residents would get coverage, 21% answered no to the question. Responses to the question from independents – 61% said yes and 35% said no – very closely reflected the overall vote of 62% yes and 34% no, Kaiser said.

The partisan divide appeared again when respondents were asked if physicians and hospitals would be paid less under a national health plan: 64% of Republicans said payments would be reduced versus 42% of Democrats. Similarly, more than half of Republicans (53%) said that people who buy their own insurance would not be able to keep their current plans, compared with 24% of Democrats, the poll data show.

Those looking for common ground can point to responses regarding a couple of other potential effects of a national health plan. Republicans (57%) and Democrats (52%) largely agreed that private health insurance companies would not be the primary way Americans get health coverage, and they agreed that people would continue to pay deductibles and copays when they used health care services (68% for Republicans, 71% for Democrats), Kaiser said.

The poll was conducted from May 30 to June 4, 2019, and involved responses from 1,206 adults. The margin of sampling error was plus or minus 3 percentage points.

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Does Medicare-for-all mean that everyone gets health insurance coverage?

The public is not convinced that this would be the case, and Republicans are even more skeptical, according to a new survey from the Kaiser Family Foundation.

Less than two-thirds of American adults believe that all U.S. residents would have health insurance under a national health plan, and there is a sizable split between Republicans and Democrats on the issue. Republicans, in fact, were more likely to say that all residents would not have coverage, with less than 49% of people identifying as Republican having answered “no” to the question and 45% having answered “yes”, Kaiser reported in its latest Health Tracking Poll.

Democrats were much more optimistic but not all were certain that all U.S. residents would have health insurance coverage. While 76% of Democrats responded yes when queried about whether all residents would get coverage, 21% answered no to the question. Responses to the question from independents – 61% said yes and 35% said no – very closely reflected the overall vote of 62% yes and 34% no, Kaiser said.

The partisan divide appeared again when respondents were asked if physicians and hospitals would be paid less under a national health plan: 64% of Republicans said payments would be reduced versus 42% of Democrats. Similarly, more than half of Republicans (53%) said that people who buy their own insurance would not be able to keep their current plans, compared with 24% of Democrats, the poll data show.

Those looking for common ground can point to responses regarding a couple of other potential effects of a national health plan. Republicans (57%) and Democrats (52%) largely agreed that private health insurance companies would not be the primary way Americans get health coverage, and they agreed that people would continue to pay deductibles and copays when they used health care services (68% for Republicans, 71% for Democrats), Kaiser said.

The poll was conducted from May 30 to June 4, 2019, and involved responses from 1,206 adults. The margin of sampling error was plus or minus 3 percentage points.

[email protected]

SAN FRANCISCO – Under an accountable care contract with airplane maker Boeing, the University of Washington, Seattle, increased the rate of depression remission from about 10% to 35%, and the number of people in remission improved, based on Patient Health Questionnaire (PHQ-9) scores, from 20% to 70% – both in less than a year.

M. Alexander Otto/MDedge News

Boeing was particularly concerned about depression among its roughly 27,000 Puget Sound–area employees when it entered a contract with the University of Washington (UW) a few years ago for health services. Workers with depression are less likely to show up to work, and when they do, they are more likely to make mistakes and cause safety problems. To ensure that the university addressed the problem, Boeing tied payments to improved depression scores.

It didn’t take UW long to meet the PHQ-9 targets for improvement and remission, meaning a score below 5 points. Boeing also wanted its employees to be screened annually for depression and repeated testing of patients with depression to track how well they were doing. The university increased the number of patients rescreened within 8 weeks of their first PHQ-9 from about 45% to 75% – also in less than a year.

UW was able to come up to speed quickly because it had been developing a collaborative care model for depression management in primary care for years. It simply scaled up the approach to meet Boeing’s targets.

“This has been an interesting journey,” said Jürgen Unützer, MD, MPH, who has been key to the efforts. “It’s required quite a bit of work, but it can be done. We’ve made a lot of progress,” he said at the American Psychiatric Association annual meeting.

Key components, besides the primary care provider, include evidence-based treatment, a mental health case manager, a system to track outcomes, and a psychiatrist to consult when patients do not improve. It’s a team approach.

Dr. Unützer and his colleagues have proved that it can work among older adults with depression and, in the end, save money (Am J Manag Care. 2008 Feb;14[2]:95-100). They’ve even published a how-to book, “Integrated Care: Creating Effective Mental and Primary Health Care Teams” (John Wiley & Sons, 2016).

A key challenge with Boeing was making sure that depressed patients returned for follow-up care and repeat PHQ-9s, and that they did not languish on ineffective treatments.

[email protected]

SAN FRANCISCO – Under an accountable care contract with airplane maker Boeing, the University of Washington, Seattle, increased the rate of depression remission from about 10% to 35%, and the number of people in remission improved, based on Patient Health Questionnaire (PHQ-9) scores, from 20% to 70% – both in less than a year.

M. Alexander Otto/MDedge News

Boeing was particularly concerned about depression among its roughly 27,000 Puget Sound–area employees when it entered a contract with the University of Washington (UW) a few years ago for health services. Workers with depression are less likely to show up to work, and when they do, they are more likely to make mistakes and cause safety problems. To ensure that the university addressed the problem, Boeing tied payments to improved depression scores.

It didn’t take UW long to meet the PHQ-9 targets for improvement and remission, meaning a score below 5 points. Boeing also wanted its employees to be screened annually for depression and repeated testing of patients with depression to track how well they were doing. The university increased the number of patients rescreened within 8 weeks of their first PHQ-9 from about 45% to 75% – also in less than a year.

UW was able to come up to speed quickly because it had been developing a collaborative care model for depression management in primary care for years. It simply scaled up the approach to meet Boeing’s targets.

“This has been an interesting journey,” said Jürgen Unützer, MD, MPH, who has been key to the efforts. “It’s required quite a bit of work, but it can be done. We’ve made a lot of progress,” he said at the American Psychiatric Association annual meeting.

Key components, besides the primary care provider, include evidence-based treatment, a mental health case manager, a system to track outcomes, and a psychiatrist to consult when patients do not improve. It’s a team approach.

Dr. Unützer and his colleagues have proved that it can work among older adults with depression and, in the end, save money (Am J Manag Care. 2008 Feb;14[2]:95-100). They’ve even published a how-to book, “Integrated Care: Creating Effective Mental and Primary Health Care Teams” (John Wiley & Sons, 2016).

A key challenge with Boeing was making sure that depressed patients returned for follow-up care and repeat PHQ-9s, and that they did not languish on ineffective treatments.

[email protected]

SAN FRANCISCO – Under an accountable care contract with airplane maker Boeing, the University of Washington, Seattle, increased the rate of depression remission from about 10% to 35%, and the number of people in remission improved, based on Patient Health Questionnaire (PHQ-9) scores, from 20% to 70% – both in less than a year.

M. Alexander Otto/MDedge News

Boeing was particularly concerned about depression among its roughly 27,000 Puget Sound–area employees when it entered a contract with the University of Washington (UW) a few years ago for health services. Workers with depression are less likely to show up to work, and when they do, they are more likely to make mistakes and cause safety problems. To ensure that the university addressed the problem, Boeing tied payments to improved depression scores.

It didn’t take UW long to meet the PHQ-9 targets for improvement and remission, meaning a score below 5 points. Boeing also wanted its employees to be screened annually for depression and repeated testing of patients with depression to track how well they were doing. The university increased the number of patients rescreened within 8 weeks of their first PHQ-9 from about 45% to 75% – also in less than a year.

UW was able to come up to speed quickly because it had been developing a collaborative care model for depression management in primary care for years. It simply scaled up the approach to meet Boeing’s targets.

“This has been an interesting journey,” said Jürgen Unützer, MD, MPH, who has been key to the efforts. “It’s required quite a bit of work, but it can be done. We’ve made a lot of progress,” he said at the American Psychiatric Association annual meeting.

Key components, besides the primary care provider, include evidence-based treatment, a mental health case manager, a system to track outcomes, and a psychiatrist to consult when patients do not improve. It’s a team approach.

Dr. Unützer and his colleagues have proved that it can work among older adults with depression and, in the end, save money (Am J Manag Care. 2008 Feb;14[2]:95-100). They’ve even published a how-to book, “Integrated Care: Creating Effective Mental and Primary Health Care Teams” (John Wiley & Sons, 2016).

A key challenge with Boeing was making sure that depressed patients returned for follow-up care and repeat PHQ-9s, and that they did not languish on ineffective treatments.

[email protected]