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Nonopioids as effective as opioids in reducing acute pain in the ED
Clinical question: What is the most effective analgesic combination, opioid vs. nonopioid, for treating acute extremity pain in the emergency department?
Background: Patients often are prescribed opioids for acute pain in the ED while awaiting work-up. With the current opioid epidemic in the United States, it is important to examine the appropriate use of opioids and look for alternative medications for acute pain.
Setting: Two urban New York City emergency departments from July 2015 to August 2016.
Synopsis: 411 patients aged 21-65 years were randomized to four groups for treatment of acute extremity pain. Each received one oral analgesic combination: ibuprofen 400 mg and acetaminophen 1,000 mg; oxycodone 5 mg and acetaminophen 325 mg; hydrocodone 5 mg and acetaminophen 300 mg; or codeine 30 mg and acetaminophen 300 mg. Their pain was scored on presentation using a standard 0-10 numerical rating scale (NRS) and then at 2 hours after medication. The primary outcome was difference in NRS among groups. All patients had improvement in pain scores. Pain score improved by 4.4 in the oxycodone group, 4.3 in the ibuprofen group, 3.5 in the hydrocodone group, and 3.9 in the codeine group. There were no statistically significant differences among groups. Limitations to the study included short follow-up time, no reported data on adverse effects, and lack of uniform acetaminophen doses in each group.
Bottom line: There was no statistically significant difference in pain control among patients given a combination of acetaminophen and ibuprofen vs. three different opioids with acetaminophen when treating acute extremity pain in the ED.
Citation: Chang AK et al. Effect of a single dose of oral opioid and nonopioid analgesics on acute extremity pain in the emergency department: a randomized clinical trial. JAMA. 2017 Nov 7;318(17):1661-7.
Dr. Mathew is assistant professor of medicine, division of hospital medicine, University of Virginia.
Clinical question: What is the most effective analgesic combination, opioid vs. nonopioid, for treating acute extremity pain in the emergency department?
Background: Patients often are prescribed opioids for acute pain in the ED while awaiting work-up. With the current opioid epidemic in the United States, it is important to examine the appropriate use of opioids and look for alternative medications for acute pain.
Setting: Two urban New York City emergency departments from July 2015 to August 2016.
Synopsis: 411 patients aged 21-65 years were randomized to four groups for treatment of acute extremity pain. Each received one oral analgesic combination: ibuprofen 400 mg and acetaminophen 1,000 mg; oxycodone 5 mg and acetaminophen 325 mg; hydrocodone 5 mg and acetaminophen 300 mg; or codeine 30 mg and acetaminophen 300 mg. Their pain was scored on presentation using a standard 0-10 numerical rating scale (NRS) and then at 2 hours after medication. The primary outcome was difference in NRS among groups. All patients had improvement in pain scores. Pain score improved by 4.4 in the oxycodone group, 4.3 in the ibuprofen group, 3.5 in the hydrocodone group, and 3.9 in the codeine group. There were no statistically significant differences among groups. Limitations to the study included short follow-up time, no reported data on adverse effects, and lack of uniform acetaminophen doses in each group.
Bottom line: There was no statistically significant difference in pain control among patients given a combination of acetaminophen and ibuprofen vs. three different opioids with acetaminophen when treating acute extremity pain in the ED.
Citation: Chang AK et al. Effect of a single dose of oral opioid and nonopioid analgesics on acute extremity pain in the emergency department: a randomized clinical trial. JAMA. 2017 Nov 7;318(17):1661-7.
Dr. Mathew is assistant professor of medicine, division of hospital medicine, University of Virginia.
Clinical question: What is the most effective analgesic combination, opioid vs. nonopioid, for treating acute extremity pain in the emergency department?
Background: Patients often are prescribed opioids for acute pain in the ED while awaiting work-up. With the current opioid epidemic in the United States, it is important to examine the appropriate use of opioids and look for alternative medications for acute pain.
Setting: Two urban New York City emergency departments from July 2015 to August 2016.
Synopsis: 411 patients aged 21-65 years were randomized to four groups for treatment of acute extremity pain. Each received one oral analgesic combination: ibuprofen 400 mg and acetaminophen 1,000 mg; oxycodone 5 mg and acetaminophen 325 mg; hydrocodone 5 mg and acetaminophen 300 mg; or codeine 30 mg and acetaminophen 300 mg. Their pain was scored on presentation using a standard 0-10 numerical rating scale (NRS) and then at 2 hours after medication. The primary outcome was difference in NRS among groups. All patients had improvement in pain scores. Pain score improved by 4.4 in the oxycodone group, 4.3 in the ibuprofen group, 3.5 in the hydrocodone group, and 3.9 in the codeine group. There were no statistically significant differences among groups. Limitations to the study included short follow-up time, no reported data on adverse effects, and lack of uniform acetaminophen doses in each group.
Bottom line: There was no statistically significant difference in pain control among patients given a combination of acetaminophen and ibuprofen vs. three different opioids with acetaminophen when treating acute extremity pain in the ED.
Citation: Chang AK et al. Effect of a single dose of oral opioid and nonopioid analgesics on acute extremity pain in the emergency department: a randomized clinical trial. JAMA. 2017 Nov 7;318(17):1661-7.
Dr. Mathew is assistant professor of medicine, division of hospital medicine, University of Virginia.
Therapy targets ICU ‘teachable moment’ of suicide-attempt survivors
WASHINGTON – in a pair of controlled pilot studies with a total of 87 patients.
In the more recent study, the 32 patients who received this “teachable moment brief intervention” (TMBI) plus usual care tallied an overall satisfaction score of 3.88 on a 1-4 scale and showed a trend to higher motivation scores than patients managed with usual care alone, Stephen S. O’Connor, PhD, said at the annual conference of the American Association of Suicidology.
The TMBI was designed to help suicide-attempt survivors “wrap their head around what happened in a nonshaming way at a sensitive time. We try to help the patient understand what was the purpose of their attempt and what moving forward will look like,” Dr. O’Connor said in an interview.
The TMBI usually lasts about 30-45 minutes, and Dr. O’Connor described the general outline of the conversation: After the therapist establishes a rapport with the patient, the discussion moves to a functional analysis of what drove the patient to this action and why the suicide attempt seemed to make sense at the time. The therapist asks the patient what he or she sees as having been gained and lost by the event, and what the patient has gleaned from the experience. The goal is to help the patient understand what happened and its purpose, and also to discuss issues that need to be addressed going forward. “In a respectful, nonshaming way we get the patient to talk about what happened and how they got there,” he said.
The TMBI is a “drop in the ocean” of talk therapy that the patient will eventually receive, he said, but it is “all about the context.” In usual care, although the suicide attempter in the ICU may see a therapist, the conversation is generally about risk management and discharge planning.
In the initial test of the efficacy of this approach, Dr. O’Connor randomized 30 suicide survivors in the ICU to usual care or usual care plus the TMBI. The results showed a high level of patient satisfaction with the intervention and statistically significant improvements in readiness to change and in reasons for living, compared with controls (Gen Hosp Psychiatry. 2015 Sept-Oct;37[5]:427-33).
In a second pilot study that has not yet been published, Dr. O’Connor and his associates at Vanderbilt University in Nashville treated 32 patients with the TMBI and usual care and 25 with usual care only, with the study primarily designed to assess feasibility and acceptability to patients. Once again, patients who received the TMBI reported a high level of satisfaction with the encounter, including an average 3.96 rating (1-4 scale) of how likely they were to return to the service for future needs. Patients who received the extra intervention also showed trends toward a higher level of motivation after 3 months and less suicide ideation.
Further small-scale studies of the TMBI are now underway at two U.S. centers, and Dr. O’Connor said that a larger-scale test of the approach is now appropriate. One of the current limiting factors in dissemination is the training needed to perform a TMBI. One way to better leverage trained therapists might be to have the intervention occur remotely through telemedicine, with the patient encounter happening on a hand-held device.
The evidence collected so far on the TMBI has not yet proven its efficacy, Dr. O’Connor stressed. “We need to see to what degree this makes a difference. But there is clearly need for more engagement” with patients when they are in the ICU immediately after a suicide attempt. “Maybe it’s not the intervention, but just having someone being kind to the patient and sitting with them,” he suggested.
SOURCE: O’Connor S et al. American Association of Suicidology annual conference.
WASHINGTON – in a pair of controlled pilot studies with a total of 87 patients.
In the more recent study, the 32 patients who received this “teachable moment brief intervention” (TMBI) plus usual care tallied an overall satisfaction score of 3.88 on a 1-4 scale and showed a trend to higher motivation scores than patients managed with usual care alone, Stephen S. O’Connor, PhD, said at the annual conference of the American Association of Suicidology.
The TMBI was designed to help suicide-attempt survivors “wrap their head around what happened in a nonshaming way at a sensitive time. We try to help the patient understand what was the purpose of their attempt and what moving forward will look like,” Dr. O’Connor said in an interview.
The TMBI usually lasts about 30-45 minutes, and Dr. O’Connor described the general outline of the conversation: After the therapist establishes a rapport with the patient, the discussion moves to a functional analysis of what drove the patient to this action and why the suicide attempt seemed to make sense at the time. The therapist asks the patient what he or she sees as having been gained and lost by the event, and what the patient has gleaned from the experience. The goal is to help the patient understand what happened and its purpose, and also to discuss issues that need to be addressed going forward. “In a respectful, nonshaming way we get the patient to talk about what happened and how they got there,” he said.
The TMBI is a “drop in the ocean” of talk therapy that the patient will eventually receive, he said, but it is “all about the context.” In usual care, although the suicide attempter in the ICU may see a therapist, the conversation is generally about risk management and discharge planning.
In the initial test of the efficacy of this approach, Dr. O’Connor randomized 30 suicide survivors in the ICU to usual care or usual care plus the TMBI. The results showed a high level of patient satisfaction with the intervention and statistically significant improvements in readiness to change and in reasons for living, compared with controls (Gen Hosp Psychiatry. 2015 Sept-Oct;37[5]:427-33).
In a second pilot study that has not yet been published, Dr. O’Connor and his associates at Vanderbilt University in Nashville treated 32 patients with the TMBI and usual care and 25 with usual care only, with the study primarily designed to assess feasibility and acceptability to patients. Once again, patients who received the TMBI reported a high level of satisfaction with the encounter, including an average 3.96 rating (1-4 scale) of how likely they were to return to the service for future needs. Patients who received the extra intervention also showed trends toward a higher level of motivation after 3 months and less suicide ideation.
Further small-scale studies of the TMBI are now underway at two U.S. centers, and Dr. O’Connor said that a larger-scale test of the approach is now appropriate. One of the current limiting factors in dissemination is the training needed to perform a TMBI. One way to better leverage trained therapists might be to have the intervention occur remotely through telemedicine, with the patient encounter happening on a hand-held device.
The evidence collected so far on the TMBI has not yet proven its efficacy, Dr. O’Connor stressed. “We need to see to what degree this makes a difference. But there is clearly need for more engagement” with patients when they are in the ICU immediately after a suicide attempt. “Maybe it’s not the intervention, but just having someone being kind to the patient and sitting with them,” he suggested.
SOURCE: O’Connor S et al. American Association of Suicidology annual conference.
WASHINGTON – in a pair of controlled pilot studies with a total of 87 patients.
In the more recent study, the 32 patients who received this “teachable moment brief intervention” (TMBI) plus usual care tallied an overall satisfaction score of 3.88 on a 1-4 scale and showed a trend to higher motivation scores than patients managed with usual care alone, Stephen S. O’Connor, PhD, said at the annual conference of the American Association of Suicidology.
The TMBI was designed to help suicide-attempt survivors “wrap their head around what happened in a nonshaming way at a sensitive time. We try to help the patient understand what was the purpose of their attempt and what moving forward will look like,” Dr. O’Connor said in an interview.
The TMBI usually lasts about 30-45 minutes, and Dr. O’Connor described the general outline of the conversation: After the therapist establishes a rapport with the patient, the discussion moves to a functional analysis of what drove the patient to this action and why the suicide attempt seemed to make sense at the time. The therapist asks the patient what he or she sees as having been gained and lost by the event, and what the patient has gleaned from the experience. The goal is to help the patient understand what happened and its purpose, and also to discuss issues that need to be addressed going forward. “In a respectful, nonshaming way we get the patient to talk about what happened and how they got there,” he said.
The TMBI is a “drop in the ocean” of talk therapy that the patient will eventually receive, he said, but it is “all about the context.” In usual care, although the suicide attempter in the ICU may see a therapist, the conversation is generally about risk management and discharge planning.
In the initial test of the efficacy of this approach, Dr. O’Connor randomized 30 suicide survivors in the ICU to usual care or usual care plus the TMBI. The results showed a high level of patient satisfaction with the intervention and statistically significant improvements in readiness to change and in reasons for living, compared with controls (Gen Hosp Psychiatry. 2015 Sept-Oct;37[5]:427-33).
In a second pilot study that has not yet been published, Dr. O’Connor and his associates at Vanderbilt University in Nashville treated 32 patients with the TMBI and usual care and 25 with usual care only, with the study primarily designed to assess feasibility and acceptability to patients. Once again, patients who received the TMBI reported a high level of satisfaction with the encounter, including an average 3.96 rating (1-4 scale) of how likely they were to return to the service for future needs. Patients who received the extra intervention also showed trends toward a higher level of motivation after 3 months and less suicide ideation.
Further small-scale studies of the TMBI are now underway at two U.S. centers, and Dr. O’Connor said that a larger-scale test of the approach is now appropriate. One of the current limiting factors in dissemination is the training needed to perform a TMBI. One way to better leverage trained therapists might be to have the intervention occur remotely through telemedicine, with the patient encounter happening on a hand-held device.
The evidence collected so far on the TMBI has not yet proven its efficacy, Dr. O’Connor stressed. “We need to see to what degree this makes a difference. But there is clearly need for more engagement” with patients when they are in the ICU immediately after a suicide attempt. “Maybe it’s not the intervention, but just having someone being kind to the patient and sitting with them,” he suggested.
SOURCE: O’Connor S et al. American Association of Suicidology annual conference.
REPORTING FROM THE AAS ANNUAL CONFERENCE
Key clinical point: A 30- to 45-minute conversation was feasible and acceptable to suicide-attempt survivors in the ICU.
Major finding: Overall patient satisfaction with the intervention was rated 3.88 on a 1-4 scale.
Study details: Single-center randomized study with 57 patients.
Disclosures: Dr. O’Connor had no disclosures.
Source: O’Connor S et al. American Association of Suicidology annual conference.
Don’t discount rare pityriasis rosea for kids with persistent itch
Persistent cases of small erythematous lesions could be the rare condition of relapsing pityriasis rosea, based on data from a case report of an 11-year-old girl.
Unlike standard pityriasis rosea (PR), relapsing cases tend to present with fewer, smaller lesions, Ilka Engelmann, MD, of the Centre P Boulanger Hôpital A Calmette in Lille, France, and colleagues wrote in Pediatrics.
“A viral etiology of PR is strongly suspected because human herpesvirus 7 (HHV-7) DNA is frequently detected in blood and saliva of patients with PR,” they said. Infection with the HHV-7 virus generally occurs in childhood and remains a lifelong latent condition with the potential for multiple recurrences, they added.
The authors described the case of an 11-year-old white girl who presented with pruritic, erythematous, oval-shaped lesions that began on the right side of her trunk and spread across the trunk over the next few days. The patient had no other symptoms or physical abnormalities on examination and was not taking any medications, although she reported some trouble sleeping.
The treating clinicians identified HHV-7 in a blood sample and diagnosed PR. The lesions resolved in approximately 2 months with no treatment, but, 2 years after the initial presentation, the patient developed similar lesions on her legs, which also resolved without treatment. Over the next 5 years, she presented with similar lesions in different locations approximately three times per year, and these episodes were usually associated with times of stress, such as school examinations. Some saliva specimens taken during the episodes tested positive for HHV-7. The lesions persisted for 4-8 weeks and resolved without treatment, but they were reduced in size and number after the third recurrence. The change in size and location are characteristic of relapsing PR, the authors said, but more than three relapses is rare. “To our knowledge, this is the first report of a case with frequently relapsing PR for 7 years, with several episodes per year,” they said.
The occurrence of the relapses during stressful periods “is consistent with the hypothesis of viral reactivation because stress has been described as a stimulus inducing the reactivation of Herpesviridae from latency,” they noted.
A differential diagnosis of PR includes other infectious diseases and medication-induced skin reactions, but a medication history and virologic tests can help make or rule out a relapsing PR diagnosis, the authors said.
The authors had no financial conflicts to disclose.
SOURCE: Engelmann I et al. Pediatrics. 2018 Apr 19; doi: 10.1542/peds.2017-3179.
Persistent cases of small erythematous lesions could be the rare condition of relapsing pityriasis rosea, based on data from a case report of an 11-year-old girl.
Unlike standard pityriasis rosea (PR), relapsing cases tend to present with fewer, smaller lesions, Ilka Engelmann, MD, of the Centre P Boulanger Hôpital A Calmette in Lille, France, and colleagues wrote in Pediatrics.
“A viral etiology of PR is strongly suspected because human herpesvirus 7 (HHV-7) DNA is frequently detected in blood and saliva of patients with PR,” they said. Infection with the HHV-7 virus generally occurs in childhood and remains a lifelong latent condition with the potential for multiple recurrences, they added.
The authors described the case of an 11-year-old white girl who presented with pruritic, erythematous, oval-shaped lesions that began on the right side of her trunk and spread across the trunk over the next few days. The patient had no other symptoms or physical abnormalities on examination and was not taking any medications, although she reported some trouble sleeping.
The treating clinicians identified HHV-7 in a blood sample and diagnosed PR. The lesions resolved in approximately 2 months with no treatment, but, 2 years after the initial presentation, the patient developed similar lesions on her legs, which also resolved without treatment. Over the next 5 years, she presented with similar lesions in different locations approximately three times per year, and these episodes were usually associated with times of stress, such as school examinations. Some saliva specimens taken during the episodes tested positive for HHV-7. The lesions persisted for 4-8 weeks and resolved without treatment, but they were reduced in size and number after the third recurrence. The change in size and location are characteristic of relapsing PR, the authors said, but more than three relapses is rare. “To our knowledge, this is the first report of a case with frequently relapsing PR for 7 years, with several episodes per year,” they said.
The occurrence of the relapses during stressful periods “is consistent with the hypothesis of viral reactivation because stress has been described as a stimulus inducing the reactivation of Herpesviridae from latency,” they noted.
A differential diagnosis of PR includes other infectious diseases and medication-induced skin reactions, but a medication history and virologic tests can help make or rule out a relapsing PR diagnosis, the authors said.
The authors had no financial conflicts to disclose.
SOURCE: Engelmann I et al. Pediatrics. 2018 Apr 19; doi: 10.1542/peds.2017-3179.
Persistent cases of small erythematous lesions could be the rare condition of relapsing pityriasis rosea, based on data from a case report of an 11-year-old girl.
Unlike standard pityriasis rosea (PR), relapsing cases tend to present with fewer, smaller lesions, Ilka Engelmann, MD, of the Centre P Boulanger Hôpital A Calmette in Lille, France, and colleagues wrote in Pediatrics.
“A viral etiology of PR is strongly suspected because human herpesvirus 7 (HHV-7) DNA is frequently detected in blood and saliva of patients with PR,” they said. Infection with the HHV-7 virus generally occurs in childhood and remains a lifelong latent condition with the potential for multiple recurrences, they added.
The authors described the case of an 11-year-old white girl who presented with pruritic, erythematous, oval-shaped lesions that began on the right side of her trunk and spread across the trunk over the next few days. The patient had no other symptoms or physical abnormalities on examination and was not taking any medications, although she reported some trouble sleeping.
The treating clinicians identified HHV-7 in a blood sample and diagnosed PR. The lesions resolved in approximately 2 months with no treatment, but, 2 years after the initial presentation, the patient developed similar lesions on her legs, which also resolved without treatment. Over the next 5 years, she presented with similar lesions in different locations approximately three times per year, and these episodes were usually associated with times of stress, such as school examinations. Some saliva specimens taken during the episodes tested positive for HHV-7. The lesions persisted for 4-8 weeks and resolved without treatment, but they were reduced in size and number after the third recurrence. The change in size and location are characteristic of relapsing PR, the authors said, but more than three relapses is rare. “To our knowledge, this is the first report of a case with frequently relapsing PR for 7 years, with several episodes per year,” they said.
The occurrence of the relapses during stressful periods “is consistent with the hypothesis of viral reactivation because stress has been described as a stimulus inducing the reactivation of Herpesviridae from latency,” they noted.
A differential diagnosis of PR includes other infectious diseases and medication-induced skin reactions, but a medication history and virologic tests can help make or rule out a relapsing PR diagnosis, the authors said.
The authors had no financial conflicts to disclose.
SOURCE: Engelmann I et al. Pediatrics. 2018 Apr 19; doi: 10.1542/peds.2017-3179.
FROM PEDIATRICS
Key clinical point: Check children with persistent erythematous lesions for human herpesvirus and possible pityriasis rosea.
Major finding: A presentation of erythematous lesions in an 11-year-old girl recurred over 7 years.
Study details: The data come from a case report of rare relapsing pityriasis rosea.
Disclosures: The authors presenting the case had no financial conflicts to disclose.
Source: Engelmann I et al. Pediatrics. 2018 Apr 19; doi: 10.1542/peds.2017-3179.
Artificial pancreas treatment improves glycemic control in T1DM: Meta-analysis
Use of artificial pancreas devices added nearly 2.5 hours of time in near normoglycemia over 24 hours in patients with type 1 diabetes, a meta-analysis of randomized clinical trials showed.
The improvement versus control subjects was primarily because of the favorable effect of the closed loop glucose control systems in the overnight period, authors of the meta-analysis reported in the BMJ.
Both single and dual hormone systems had robust results in the meta-anaysis, said lead researcher Eleni Bekiari, MD, PhD, of Aristotle University of Thessaloniki, Greece, and her coinvestigators.
Results were likewise robust for an analysis restricted to trials conducted under normal living conditions and no remote monitoring, supporting the convenience and ease of use of these systems, according to Dr. Bekiari and her colleagues.
“Overall, our results reflect the progress made over recent decades of extensive research and development in artificial pancreas use,” they wrote.
Despite the findings, more research needs to be done, they added, since the individual clinical trials supporting use of closed-loop systems in type 1 diabetes have included relatively few patients and have had short follow-up durations.
The systematic review and meta-analysis by Dr. Bekiari and her colleagues was based on 40 randomized controlled trials involving a total of 1,027 participants. The primary outcome of the analysis was proportion of time that sensor glucose level was in the normoglycemic range of 3.9-10 mmol/L.
Overall, use of the systems was associated with 140 additional minutes in near normoglycemia over 24 hours, with a 9.62% mean weighted difference (95% confidence interval, 7.54%-11.7%), reported data show.
The favorable effect was even more evident on overnight measures, the investigators said, with a weighted mean difference of 15.15% (95% CI, 12.21%-18.09%).
Results were similar even when the analysis was limited to studies that had a low risk of bias, and also when the analysis was limited to studies of unsupervised patients in normal living conditions, according to Dr. Bekiari and her associates.
Artificial pancreas use also had favorable impacts on time in hyperglycemia over the entire day. Compared with controls, time with glucose concentrations less than 10 mmol/L were shortened by about 2 hours, the investigators said.
Likewise, mean levels of sensor blood glucose over 24 hours fell by 0.48 mmol/L compared with control treatment (95% CI, 0.3-0.66 mmol/L), they reported.
Taken together, these findings suggest artificial pancreas systems are efficacious and safe for patients with type 1 diabetes, the investigators concluded.
“Further research with rigorous studies, cooperation of research groups in terms of outcome reporting, and cost-effectiveness data are required to verify these findings and support adoption of artificial pancreas systems in clinical practice,” they wrote.
Dr. Bekiari reported no disclosures. Her coauthors reported disclosures related to Medtronic, Novo Nordisk, Sanofi, AstraZeneca, Boehringer Ingelheim and others outside of the submitted work.
SOURCE: Bekiai E et al. BMJ 2018;361:k1310.
Closed-loop glucose control systems have much to offer patients, but better evidence will likely be needed to convince policy makers who have increasing demands and scarce resources, Dr. Norman Waugh and his coauthors said in an editorial.
Users of closed-loop systems did spend approximately 10% more time near normoglycemia when compared with control subjects in the present systematic review and meta-analysis of randomized clinical trials by Dr. Bekiari and colleagues.
The overall base of evidence is weak, however, and many studies in the review were low quality, according to Dr. Waugh and his coauthors. Moreover, the trials were short, with the majority lasting 7 days or less, they noted.
The current review does demonstrate that closed-loop systems improve control overnight and reduce the burden of self-management during the day, but it’s unknown if the systems can reduce long-term diabetes complications, according to the editorial authors, and evidence to date is insufficient for policy makers to perform cost-effectiveness analyses.
“We need longer and larger trials, in both adults and children, to compare closed-loop systems with self-management using continuous glucose monitoring,” Dr. Waugh and his colleagues wrote. “These trials should measure HbA1c for modeling the effects on complications, blood glucose variability, hypoglycemia, quality of life, and cost effectiveness.”
Norman Waugh is professor of public health medicine and health technology assessment at the University of Warwick, England. These comments are derived from an editorial by Dr. Waugh and his coauthors BMJ. 2018;361:k1613. doi: 10.1136/bmj.k1613 . They reported advising Roche and Novo Nordisk on matters not related to the topic of this editorial.
Closed-loop glucose control systems have much to offer patients, but better evidence will likely be needed to convince policy makers who have increasing demands and scarce resources, Dr. Norman Waugh and his coauthors said in an editorial.
Users of closed-loop systems did spend approximately 10% more time near normoglycemia when compared with control subjects in the present systematic review and meta-analysis of randomized clinical trials by Dr. Bekiari and colleagues.
The overall base of evidence is weak, however, and many studies in the review were low quality, according to Dr. Waugh and his coauthors. Moreover, the trials were short, with the majority lasting 7 days or less, they noted.
The current review does demonstrate that closed-loop systems improve control overnight and reduce the burden of self-management during the day, but it’s unknown if the systems can reduce long-term diabetes complications, according to the editorial authors, and evidence to date is insufficient for policy makers to perform cost-effectiveness analyses.
“We need longer and larger trials, in both adults and children, to compare closed-loop systems with self-management using continuous glucose monitoring,” Dr. Waugh and his colleagues wrote. “These trials should measure HbA1c for modeling the effects on complications, blood glucose variability, hypoglycemia, quality of life, and cost effectiveness.”
Norman Waugh is professor of public health medicine and health technology assessment at the University of Warwick, England. These comments are derived from an editorial by Dr. Waugh and his coauthors BMJ. 2018;361:k1613. doi: 10.1136/bmj.k1613 . They reported advising Roche and Novo Nordisk on matters not related to the topic of this editorial.
Closed-loop glucose control systems have much to offer patients, but better evidence will likely be needed to convince policy makers who have increasing demands and scarce resources, Dr. Norman Waugh and his coauthors said in an editorial.
Users of closed-loop systems did spend approximately 10% more time near normoglycemia when compared with control subjects in the present systematic review and meta-analysis of randomized clinical trials by Dr. Bekiari and colleagues.
The overall base of evidence is weak, however, and many studies in the review were low quality, according to Dr. Waugh and his coauthors. Moreover, the trials were short, with the majority lasting 7 days or less, they noted.
The current review does demonstrate that closed-loop systems improve control overnight and reduce the burden of self-management during the day, but it’s unknown if the systems can reduce long-term diabetes complications, according to the editorial authors, and evidence to date is insufficient for policy makers to perform cost-effectiveness analyses.
“We need longer and larger trials, in both adults and children, to compare closed-loop systems with self-management using continuous glucose monitoring,” Dr. Waugh and his colleagues wrote. “These trials should measure HbA1c for modeling the effects on complications, blood glucose variability, hypoglycemia, quality of life, and cost effectiveness.”
Norman Waugh is professor of public health medicine and health technology assessment at the University of Warwick, England. These comments are derived from an editorial by Dr. Waugh and his coauthors BMJ. 2018;361:k1613. doi: 10.1136/bmj.k1613 . They reported advising Roche and Novo Nordisk on matters not related to the topic of this editorial.
Use of artificial pancreas devices added nearly 2.5 hours of time in near normoglycemia over 24 hours in patients with type 1 diabetes, a meta-analysis of randomized clinical trials showed.
The improvement versus control subjects was primarily because of the favorable effect of the closed loop glucose control systems in the overnight period, authors of the meta-analysis reported in the BMJ.
Both single and dual hormone systems had robust results in the meta-anaysis, said lead researcher Eleni Bekiari, MD, PhD, of Aristotle University of Thessaloniki, Greece, and her coinvestigators.
Results were likewise robust for an analysis restricted to trials conducted under normal living conditions and no remote monitoring, supporting the convenience and ease of use of these systems, according to Dr. Bekiari and her colleagues.
“Overall, our results reflect the progress made over recent decades of extensive research and development in artificial pancreas use,” they wrote.
Despite the findings, more research needs to be done, they added, since the individual clinical trials supporting use of closed-loop systems in type 1 diabetes have included relatively few patients and have had short follow-up durations.
The systematic review and meta-analysis by Dr. Bekiari and her colleagues was based on 40 randomized controlled trials involving a total of 1,027 participants. The primary outcome of the analysis was proportion of time that sensor glucose level was in the normoglycemic range of 3.9-10 mmol/L.
Overall, use of the systems was associated with 140 additional minutes in near normoglycemia over 24 hours, with a 9.62% mean weighted difference (95% confidence interval, 7.54%-11.7%), reported data show.
The favorable effect was even more evident on overnight measures, the investigators said, with a weighted mean difference of 15.15% (95% CI, 12.21%-18.09%).
Results were similar even when the analysis was limited to studies that had a low risk of bias, and also when the analysis was limited to studies of unsupervised patients in normal living conditions, according to Dr. Bekiari and her associates.
Artificial pancreas use also had favorable impacts on time in hyperglycemia over the entire day. Compared with controls, time with glucose concentrations less than 10 mmol/L were shortened by about 2 hours, the investigators said.
Likewise, mean levels of sensor blood glucose over 24 hours fell by 0.48 mmol/L compared with control treatment (95% CI, 0.3-0.66 mmol/L), they reported.
Taken together, these findings suggest artificial pancreas systems are efficacious and safe for patients with type 1 diabetes, the investigators concluded.
“Further research with rigorous studies, cooperation of research groups in terms of outcome reporting, and cost-effectiveness data are required to verify these findings and support adoption of artificial pancreas systems in clinical practice,” they wrote.
Dr. Bekiari reported no disclosures. Her coauthors reported disclosures related to Medtronic, Novo Nordisk, Sanofi, AstraZeneca, Boehringer Ingelheim and others outside of the submitted work.
SOURCE: Bekiai E et al. BMJ 2018;361:k1310.
Use of artificial pancreas devices added nearly 2.5 hours of time in near normoglycemia over 24 hours in patients with type 1 diabetes, a meta-analysis of randomized clinical trials showed.
The improvement versus control subjects was primarily because of the favorable effect of the closed loop glucose control systems in the overnight period, authors of the meta-analysis reported in the BMJ.
Both single and dual hormone systems had robust results in the meta-anaysis, said lead researcher Eleni Bekiari, MD, PhD, of Aristotle University of Thessaloniki, Greece, and her coinvestigators.
Results were likewise robust for an analysis restricted to trials conducted under normal living conditions and no remote monitoring, supporting the convenience and ease of use of these systems, according to Dr. Bekiari and her colleagues.
“Overall, our results reflect the progress made over recent decades of extensive research and development in artificial pancreas use,” they wrote.
Despite the findings, more research needs to be done, they added, since the individual clinical trials supporting use of closed-loop systems in type 1 diabetes have included relatively few patients and have had short follow-up durations.
The systematic review and meta-analysis by Dr. Bekiari and her colleagues was based on 40 randomized controlled trials involving a total of 1,027 participants. The primary outcome of the analysis was proportion of time that sensor glucose level was in the normoglycemic range of 3.9-10 mmol/L.
Overall, use of the systems was associated with 140 additional minutes in near normoglycemia over 24 hours, with a 9.62% mean weighted difference (95% confidence interval, 7.54%-11.7%), reported data show.
The favorable effect was even more evident on overnight measures, the investigators said, with a weighted mean difference of 15.15% (95% CI, 12.21%-18.09%).
Results were similar even when the analysis was limited to studies that had a low risk of bias, and also when the analysis was limited to studies of unsupervised patients in normal living conditions, according to Dr. Bekiari and her associates.
Artificial pancreas use also had favorable impacts on time in hyperglycemia over the entire day. Compared with controls, time with glucose concentrations less than 10 mmol/L were shortened by about 2 hours, the investigators said.
Likewise, mean levels of sensor blood glucose over 24 hours fell by 0.48 mmol/L compared with control treatment (95% CI, 0.3-0.66 mmol/L), they reported.
Taken together, these findings suggest artificial pancreas systems are efficacious and safe for patients with type 1 diabetes, the investigators concluded.
“Further research with rigorous studies, cooperation of research groups in terms of outcome reporting, and cost-effectiveness data are required to verify these findings and support adoption of artificial pancreas systems in clinical practice,” they wrote.
Dr. Bekiari reported no disclosures. Her coauthors reported disclosures related to Medtronic, Novo Nordisk, Sanofi, AstraZeneca, Boehringer Ingelheim and others outside of the submitted work.
SOURCE: Bekiai E et al. BMJ 2018;361:k1310.
FROM THE BMJ
Key clinical point: In patients with type 1 diabetes, artificial pancreas systems were effective in increasing the amount of time patients spent in the near normoglycemic range.
Major finding: The proportion of time in the near-normoglycemic range was significantly higher both overnight (15.15% mean weighted difference) and over 24 hours (9.62% mean weighted difference) for artificial pancreas versus controls.
Study details: A systematic review and meta-analysis of 40 randomized controlled trials including 1,027 participants.
Disclosures: Authors reported disclosures related to Medtronic, Novo Nordisk, Sanofi, AstraZeneca, Boehringer Ingelheim, and others outside of the submitted work.
Source: Bekiari E et al. BMJ 2018;361:k1310.
VTE risk after bariatric surgery should be assessed
SEATTLE – Preop thromboelastometry can identify patients who need extra according to a prospective investigation of 40 patients at Conemaugh Memorial Medical Center in Johnstown, Pa.
Enoxaparin 40 mg twice daily just wasn’t enough for people who were hypercoagulable before surgery. The goal of the study was to find the best way to prevent venous thromboembolism (VTE) after weight loss surgery. At present, there’s no consensus on prophylaxis dosing, timing, duration, or even what agent to use for these patients. Conemaugh uses postop enoxaparin, a low-molecular-weight heparin. Among many other options, some hospitals opt for preop dosing with traditional heparin, which is less expensive.
The Conemaugh team turned to thromboelastometry (TEM) to look at the question of VTE risk in bariatric surgery patients. The test gauges coagulation status by measuring elasticity as a small blood sample clots over a few minutes. The investigators found that patients who were hypercoagulable before surgery were likely to be hypercoagulable afterwards. The finding argues for baseline TEM testing to guide postop anticoagulation.
The problem is that bariatric services don’t often have access to TEM equipment, and insurance doesn’t cover the $60 test. In this instance, the Lake Erie College of Osteopathic Medicine in Erie, Pa., had the equipment and covered the testing for the study.
The patients had TEM at baseline and then received 40 mg of enoxaparin about 4 hours after surgery – mostly laparoscopic gastric bypasses – and a second dose about 12 hours after the first. TEM was repeated about 2 hours after the second dose.
At baseline, 2 (5%) of the patients were hypocoagulable, 15 (37.5%) were normal, and 23 (57.5%) were hypercoagulable. On postop TEM, 17 patients (42.5%) were normal and 23 (57.5%) were hypercoagulable: “These 23 were inadequately anticoagulated,” said lead investigator Daniel Urias, MD, a general surgery resident at the medical center.
“There was an association between being normal at baseline and being normal postop, and being hypercoagulable at baseline and hypercoagulable postop. We didn’t anticipate finding such similarity between the numbers. Our suspicion that baseline status plays a major role is holding true,” Dr. Urias said at the World Congress of Endoscopic Surgery hosted by SAGES & CAGS.
When patients test hypercoagulable at baseline, “we are [now] leaning towards [enoxaparin] 60 mg twice daily,” he said.
Ultimately, anticoagulation TEM could be used to titrate patients into the normal range. For best outcomes, it’s likely that “obese patients require goal-directed therapy instead of weight-based or fixed dosing,” he said, but nothing is going to happen until insurance steps up.
The patients did not have underlying coagulopathies, and 33 (82.5%) were women; the average age was 44 years and average body mass index was 43.6 kg/m2. The mean preop Caprini score was 4, indicating moderate VTE risk. Surgery lasted about 200 minutes. Patients were out of bed and walking on postop day 0.
The investigators had no relevant disclosures.
SOURCE: Urias D et al. World Congress of Endoscopic Surgery hosted by SAGES & CAGS abstract S023.
SEATTLE – Preop thromboelastometry can identify patients who need extra according to a prospective investigation of 40 patients at Conemaugh Memorial Medical Center in Johnstown, Pa.
Enoxaparin 40 mg twice daily just wasn’t enough for people who were hypercoagulable before surgery. The goal of the study was to find the best way to prevent venous thromboembolism (VTE) after weight loss surgery. At present, there’s no consensus on prophylaxis dosing, timing, duration, or even what agent to use for these patients. Conemaugh uses postop enoxaparin, a low-molecular-weight heparin. Among many other options, some hospitals opt for preop dosing with traditional heparin, which is less expensive.
The Conemaugh team turned to thromboelastometry (TEM) to look at the question of VTE risk in bariatric surgery patients. The test gauges coagulation status by measuring elasticity as a small blood sample clots over a few minutes. The investigators found that patients who were hypercoagulable before surgery were likely to be hypercoagulable afterwards. The finding argues for baseline TEM testing to guide postop anticoagulation.
The problem is that bariatric services don’t often have access to TEM equipment, and insurance doesn’t cover the $60 test. In this instance, the Lake Erie College of Osteopathic Medicine in Erie, Pa., had the equipment and covered the testing for the study.
The patients had TEM at baseline and then received 40 mg of enoxaparin about 4 hours after surgery – mostly laparoscopic gastric bypasses – and a second dose about 12 hours after the first. TEM was repeated about 2 hours after the second dose.
At baseline, 2 (5%) of the patients were hypocoagulable, 15 (37.5%) were normal, and 23 (57.5%) were hypercoagulable. On postop TEM, 17 patients (42.5%) were normal and 23 (57.5%) were hypercoagulable: “These 23 were inadequately anticoagulated,” said lead investigator Daniel Urias, MD, a general surgery resident at the medical center.
“There was an association between being normal at baseline and being normal postop, and being hypercoagulable at baseline and hypercoagulable postop. We didn’t anticipate finding such similarity between the numbers. Our suspicion that baseline status plays a major role is holding true,” Dr. Urias said at the World Congress of Endoscopic Surgery hosted by SAGES & CAGS.
When patients test hypercoagulable at baseline, “we are [now] leaning towards [enoxaparin] 60 mg twice daily,” he said.
Ultimately, anticoagulation TEM could be used to titrate patients into the normal range. For best outcomes, it’s likely that “obese patients require goal-directed therapy instead of weight-based or fixed dosing,” he said, but nothing is going to happen until insurance steps up.
The patients did not have underlying coagulopathies, and 33 (82.5%) were women; the average age was 44 years and average body mass index was 43.6 kg/m2. The mean preop Caprini score was 4, indicating moderate VTE risk. Surgery lasted about 200 minutes. Patients were out of bed and walking on postop day 0.
The investigators had no relevant disclosures.
SOURCE: Urias D et al. World Congress of Endoscopic Surgery hosted by SAGES & CAGS abstract S023.
SEATTLE – Preop thromboelastometry can identify patients who need extra according to a prospective investigation of 40 patients at Conemaugh Memorial Medical Center in Johnstown, Pa.
Enoxaparin 40 mg twice daily just wasn’t enough for people who were hypercoagulable before surgery. The goal of the study was to find the best way to prevent venous thromboembolism (VTE) after weight loss surgery. At present, there’s no consensus on prophylaxis dosing, timing, duration, or even what agent to use for these patients. Conemaugh uses postop enoxaparin, a low-molecular-weight heparin. Among many other options, some hospitals opt for preop dosing with traditional heparin, which is less expensive.
The Conemaugh team turned to thromboelastometry (TEM) to look at the question of VTE risk in bariatric surgery patients. The test gauges coagulation status by measuring elasticity as a small blood sample clots over a few minutes. The investigators found that patients who were hypercoagulable before surgery were likely to be hypercoagulable afterwards. The finding argues for baseline TEM testing to guide postop anticoagulation.
The problem is that bariatric services don’t often have access to TEM equipment, and insurance doesn’t cover the $60 test. In this instance, the Lake Erie College of Osteopathic Medicine in Erie, Pa., had the equipment and covered the testing for the study.
The patients had TEM at baseline and then received 40 mg of enoxaparin about 4 hours after surgery – mostly laparoscopic gastric bypasses – and a second dose about 12 hours after the first. TEM was repeated about 2 hours after the second dose.
At baseline, 2 (5%) of the patients were hypocoagulable, 15 (37.5%) were normal, and 23 (57.5%) were hypercoagulable. On postop TEM, 17 patients (42.5%) were normal and 23 (57.5%) were hypercoagulable: “These 23 were inadequately anticoagulated,” said lead investigator Daniel Urias, MD, a general surgery resident at the medical center.
“There was an association between being normal at baseline and being normal postop, and being hypercoagulable at baseline and hypercoagulable postop. We didn’t anticipate finding such similarity between the numbers. Our suspicion that baseline status plays a major role is holding true,” Dr. Urias said at the World Congress of Endoscopic Surgery hosted by SAGES & CAGS.
When patients test hypercoagulable at baseline, “we are [now] leaning towards [enoxaparin] 60 mg twice daily,” he said.
Ultimately, anticoagulation TEM could be used to titrate patients into the normal range. For best outcomes, it’s likely that “obese patients require goal-directed therapy instead of weight-based or fixed dosing,” he said, but nothing is going to happen until insurance steps up.
The patients did not have underlying coagulopathies, and 33 (82.5%) were women; the average age was 44 years and average body mass index was 43.6 kg/m2. The mean preop Caprini score was 4, indicating moderate VTE risk. Surgery lasted about 200 minutes. Patients were out of bed and walking on postop day 0.
The investigators had no relevant disclosures.
SOURCE: Urias D et al. World Congress of Endoscopic Surgery hosted by SAGES & CAGS abstract S023.
REPORTING FROM SAGES 2018
Key clinical point: Preoperative thromboelastometry identifies patients who need extra anticoagulation against venous thromboembolism following bariatric surgery.
Major finding: Baseline and postop coagulation were similar: 37.5% vs. 42.5% were normal and 57.5% vs 57.5% were hypercoagulable.
Study details: Prospective study of 40 bariatric surgery patients.
Disclosures: The investigators did not have any relevant disclosures. The Lake Erie College of Osteopathic Medicine paid for the testing.
Source: Urias D et al. World Congress of Endoscopic Surgery hosted by SAGES & CAGS abstract S023.
Therapy shows early promise in phase 1 MM trial
CHICAGO—Early phase 1 results suggest a chimeric antigen receptor (CAR) T-cell therapy can induce tumor regression in heavily pretreated patients with multiple myeloma (MM).
The therapy, P-BCMA-101, has only been tested in 3 patients in the lowest dose cohort.
However, signs of efficacy have been seen in all 3 patients, including a lasting partial response in 1 patient.
There have been no dose-limiting toxicities, and none of the patients have developed cytokine release syndrome (CRS).
“The results from the first cohort of the phase 1 P-BCMA-101 study have surpassed historical benchmarks of safety and efficacy in multiple myeloma at this dose level and give us confidence to move ahead into additional dose cohorts,” said Eric Ostertag, MD, PhD, chief executive officer of Poseida Therapeutics, Inc.
Dr Ostertag and his colleagues presented these results at the AACR Annual Meeting 2018 (abstract CT130). The trial is sponsored by Poseida Therapeutics, Inc.
The trial is enrolling patients with relapsed/refractory MM who have received a proteasome inhibitor and immunomodulatory agent.
Conditioning consists of standard cyclophosphamide (300 mg/m2) and fludarabine (30 mg/m2) on days -5 to -3. Patients then receive a single dose of P-BCMA-101 on day 0.
The trial has a 3+3 dose-escalation design, with up to 6 dose levels. The first dose level is 0.75 x 106 P-BCMA-101 cells/kg.
The 3 patients who have received this dose had 6 to 9 prior therapies.
Patient 1
The first patient was a 54-year-old female with lambda light chain MM. She had t(11;14), del13q14, and 11q23(x3).
Before she received P-BCMA-101, the patient had an increase in free light chains (FLCs) to 3290 mg/L, which caused renal failure. She was treated with cyclophosphamide/prednisone and plasmapheresis bridging therapy before proceeding to P-BCMA-101.
The patient achieved a partial response 2 weeks after receiving P-BCMA-101, and this has persisted through week 12. She had a maximal reduction in urine M-protein of 92% and a reduction in plasma FLCs of 79%.
The patient did not experience any adverse events (AEs) considered related to P-BCMA-101.
Patient 2
The second patient was a 50-year-old female with oligosecretory kappa light chain MM and plasmacytomas. She had del17p (TP53) and 11q13(x3).
Due to enlarging plasmacytomas, the patient was treated with DT-PACE (dexamethasone plus thalidomide with cisplatin, doxorubicin, cyclophosphamide, and etoposide) before receiving P-BCMA-101.
Her bone plasmacytomas resolved to below background within 4 to 8 weeks of P-BCMA-101 administration, but 1 new non-bone lesion appeared months later.
AEs considered at least possibly related to treatment in this patient included grade 2-4 neutropenia as well as grade 3-4 thrombocytopenia.
Patient 3
The third patient was a 65-year-old female with lambda light chain MM and del13q14.
Her urine M-protein and FLCs briefly dipped and rose after she received bridging therapy with lenalidomide and dexamethasone, but they decreased at 4 weeks after P-BCMA-101 administration, which corresponded with P-BCMA-101 expansion in the peripheral blood.
AEs considered at least possibly related to treatment included easy bruising (grade 1), fatigue (grade 2), febrile neutropenia (grade 3), hypogammaglobinemia (grade 2), neutropenia (grade 2-3), and thrombocytopenia (grade 3-4).
“The lack of cytokine release syndrome in any of the 3 patients, in spite of marked efficacy, is unprecedented at this dose, which we believe is attributable to multiple differentiated aspects of our technology, resulting in a highly purified CAR T product with a high percentage of cells with a T stem cell memory phenotype,” Dr Ostertag said.
In addition to a lack of CRS, there were no dose-limiting toxicities. Therefore, the dose has been escalated to 2 x 106 P-BCMA-101+ CAR T cells/kg for the next patient cohort. The first patient has been treated at this dose level, with no CRS yet reported.
About P-BCMA-101
P-BCMA-101 employs a B-cell maturation antigen-specific Centyrin™ fused to a second-generation CAR scaffold (a CARTyrin) rather than a single-chain variable fragment (scFv).
Centyrins have similar binding affinities as scFvs but are said to be potentially less immunogenic than scFvs, more stable at the cell surface, and resistant to antigen/ligand-independent tonic signaling.
P-BCMA-101 is engineered using PiggyBac™, a transposon-based system requiring only mRNA and plasmid DNA (no virus).
The increased cargo capacity of PiggyBac allows for the incorporation of a safety switch and a selectable gene. The safety switch can be activated to enable depletion in case AEs occur. And the selectable gene allows for enrichment of CAR+ cells.
CHICAGO—Early phase 1 results suggest a chimeric antigen receptor (CAR) T-cell therapy can induce tumor regression in heavily pretreated patients with multiple myeloma (MM).
The therapy, P-BCMA-101, has only been tested in 3 patients in the lowest dose cohort.
However, signs of efficacy have been seen in all 3 patients, including a lasting partial response in 1 patient.
There have been no dose-limiting toxicities, and none of the patients have developed cytokine release syndrome (CRS).
“The results from the first cohort of the phase 1 P-BCMA-101 study have surpassed historical benchmarks of safety and efficacy in multiple myeloma at this dose level and give us confidence to move ahead into additional dose cohorts,” said Eric Ostertag, MD, PhD, chief executive officer of Poseida Therapeutics, Inc.
Dr Ostertag and his colleagues presented these results at the AACR Annual Meeting 2018 (abstract CT130). The trial is sponsored by Poseida Therapeutics, Inc.
The trial is enrolling patients with relapsed/refractory MM who have received a proteasome inhibitor and immunomodulatory agent.
Conditioning consists of standard cyclophosphamide (300 mg/m2) and fludarabine (30 mg/m2) on days -5 to -3. Patients then receive a single dose of P-BCMA-101 on day 0.
The trial has a 3+3 dose-escalation design, with up to 6 dose levels. The first dose level is 0.75 x 106 P-BCMA-101 cells/kg.
The 3 patients who have received this dose had 6 to 9 prior therapies.
Patient 1
The first patient was a 54-year-old female with lambda light chain MM. She had t(11;14), del13q14, and 11q23(x3).
Before she received P-BCMA-101, the patient had an increase in free light chains (FLCs) to 3290 mg/L, which caused renal failure. She was treated with cyclophosphamide/prednisone and plasmapheresis bridging therapy before proceeding to P-BCMA-101.
The patient achieved a partial response 2 weeks after receiving P-BCMA-101, and this has persisted through week 12. She had a maximal reduction in urine M-protein of 92% and a reduction in plasma FLCs of 79%.
The patient did not experience any adverse events (AEs) considered related to P-BCMA-101.
Patient 2
The second patient was a 50-year-old female with oligosecretory kappa light chain MM and plasmacytomas. She had del17p (TP53) and 11q13(x3).
Due to enlarging plasmacytomas, the patient was treated with DT-PACE (dexamethasone plus thalidomide with cisplatin, doxorubicin, cyclophosphamide, and etoposide) before receiving P-BCMA-101.
Her bone plasmacytomas resolved to below background within 4 to 8 weeks of P-BCMA-101 administration, but 1 new non-bone lesion appeared months later.
AEs considered at least possibly related to treatment in this patient included grade 2-4 neutropenia as well as grade 3-4 thrombocytopenia.
Patient 3
The third patient was a 65-year-old female with lambda light chain MM and del13q14.
Her urine M-protein and FLCs briefly dipped and rose after she received bridging therapy with lenalidomide and dexamethasone, but they decreased at 4 weeks after P-BCMA-101 administration, which corresponded with P-BCMA-101 expansion in the peripheral blood.
AEs considered at least possibly related to treatment included easy bruising (grade 1), fatigue (grade 2), febrile neutropenia (grade 3), hypogammaglobinemia (grade 2), neutropenia (grade 2-3), and thrombocytopenia (grade 3-4).
“The lack of cytokine release syndrome in any of the 3 patients, in spite of marked efficacy, is unprecedented at this dose, which we believe is attributable to multiple differentiated aspects of our technology, resulting in a highly purified CAR T product with a high percentage of cells with a T stem cell memory phenotype,” Dr Ostertag said.
In addition to a lack of CRS, there were no dose-limiting toxicities. Therefore, the dose has been escalated to 2 x 106 P-BCMA-101+ CAR T cells/kg for the next patient cohort. The first patient has been treated at this dose level, with no CRS yet reported.
About P-BCMA-101
P-BCMA-101 employs a B-cell maturation antigen-specific Centyrin™ fused to a second-generation CAR scaffold (a CARTyrin) rather than a single-chain variable fragment (scFv).
Centyrins have similar binding affinities as scFvs but are said to be potentially less immunogenic than scFvs, more stable at the cell surface, and resistant to antigen/ligand-independent tonic signaling.
P-BCMA-101 is engineered using PiggyBac™, a transposon-based system requiring only mRNA and plasmid DNA (no virus).
The increased cargo capacity of PiggyBac allows for the incorporation of a safety switch and a selectable gene. The safety switch can be activated to enable depletion in case AEs occur. And the selectable gene allows for enrichment of CAR+ cells.
CHICAGO—Early phase 1 results suggest a chimeric antigen receptor (CAR) T-cell therapy can induce tumor regression in heavily pretreated patients with multiple myeloma (MM).
The therapy, P-BCMA-101, has only been tested in 3 patients in the lowest dose cohort.
However, signs of efficacy have been seen in all 3 patients, including a lasting partial response in 1 patient.
There have been no dose-limiting toxicities, and none of the patients have developed cytokine release syndrome (CRS).
“The results from the first cohort of the phase 1 P-BCMA-101 study have surpassed historical benchmarks of safety and efficacy in multiple myeloma at this dose level and give us confidence to move ahead into additional dose cohorts,” said Eric Ostertag, MD, PhD, chief executive officer of Poseida Therapeutics, Inc.
Dr Ostertag and his colleagues presented these results at the AACR Annual Meeting 2018 (abstract CT130). The trial is sponsored by Poseida Therapeutics, Inc.
The trial is enrolling patients with relapsed/refractory MM who have received a proteasome inhibitor and immunomodulatory agent.
Conditioning consists of standard cyclophosphamide (300 mg/m2) and fludarabine (30 mg/m2) on days -5 to -3. Patients then receive a single dose of P-BCMA-101 on day 0.
The trial has a 3+3 dose-escalation design, with up to 6 dose levels. The first dose level is 0.75 x 106 P-BCMA-101 cells/kg.
The 3 patients who have received this dose had 6 to 9 prior therapies.
Patient 1
The first patient was a 54-year-old female with lambda light chain MM. She had t(11;14), del13q14, and 11q23(x3).
Before she received P-BCMA-101, the patient had an increase in free light chains (FLCs) to 3290 mg/L, which caused renal failure. She was treated with cyclophosphamide/prednisone and plasmapheresis bridging therapy before proceeding to P-BCMA-101.
The patient achieved a partial response 2 weeks after receiving P-BCMA-101, and this has persisted through week 12. She had a maximal reduction in urine M-protein of 92% and a reduction in plasma FLCs of 79%.
The patient did not experience any adverse events (AEs) considered related to P-BCMA-101.
Patient 2
The second patient was a 50-year-old female with oligosecretory kappa light chain MM and plasmacytomas. She had del17p (TP53) and 11q13(x3).
Due to enlarging plasmacytomas, the patient was treated with DT-PACE (dexamethasone plus thalidomide with cisplatin, doxorubicin, cyclophosphamide, and etoposide) before receiving P-BCMA-101.
Her bone plasmacytomas resolved to below background within 4 to 8 weeks of P-BCMA-101 administration, but 1 new non-bone lesion appeared months later.
AEs considered at least possibly related to treatment in this patient included grade 2-4 neutropenia as well as grade 3-4 thrombocytopenia.
Patient 3
The third patient was a 65-year-old female with lambda light chain MM and del13q14.
Her urine M-protein and FLCs briefly dipped and rose after she received bridging therapy with lenalidomide and dexamethasone, but they decreased at 4 weeks after P-BCMA-101 administration, which corresponded with P-BCMA-101 expansion in the peripheral blood.
AEs considered at least possibly related to treatment included easy bruising (grade 1), fatigue (grade 2), febrile neutropenia (grade 3), hypogammaglobinemia (grade 2), neutropenia (grade 2-3), and thrombocytopenia (grade 3-4).
“The lack of cytokine release syndrome in any of the 3 patients, in spite of marked efficacy, is unprecedented at this dose, which we believe is attributable to multiple differentiated aspects of our technology, resulting in a highly purified CAR T product with a high percentage of cells with a T stem cell memory phenotype,” Dr Ostertag said.
In addition to a lack of CRS, there were no dose-limiting toxicities. Therefore, the dose has been escalated to 2 x 106 P-BCMA-101+ CAR T cells/kg for the next patient cohort. The first patient has been treated at this dose level, with no CRS yet reported.
About P-BCMA-101
P-BCMA-101 employs a B-cell maturation antigen-specific Centyrin™ fused to a second-generation CAR scaffold (a CARTyrin) rather than a single-chain variable fragment (scFv).
Centyrins have similar binding affinities as scFvs but are said to be potentially less immunogenic than scFvs, more stable at the cell surface, and resistant to antigen/ligand-independent tonic signaling.
P-BCMA-101 is engineered using PiggyBac™, a transposon-based system requiring only mRNA and plasmid DNA (no virus).
The increased cargo capacity of PiggyBac allows for the incorporation of a safety switch and a selectable gene. The safety switch can be activated to enable depletion in case AEs occur. And the selectable gene allows for enrichment of CAR+ cells.
Comorbidity occurs earlier and more commonly with HIV infection
The research was conducted as a cross-sectional analysis using medical chart data from a total of 416 patients treated at the Hospital de Clínicas de Porto Alegre, a tertiary referral hospital in south Brazil, Rafael Aguilar Maciel, MD of the Universidade Federal do Rio Grande do Sul, Porto Alegre, and his associates reported in the International Journal of Infectious Diseases.
The randomly selected participants were 208 well-controlled persons living with HIV (PLWH) – outpatients identified from the South Brazilian HIV Cohort unit – who were individually matched by age, sex, and ethnicity to HIV-negative control counterparts from the primary practice unit of the same hospital. The study group (median age, 57 years) consisted primarily of individuals who were white in origin (79%); 44.2% were women. Nearly all (98.1%) PLWH participants were on highly active antiretroviral therapy (HAART), with 88% having an undetectable viral load. A higher tendency for alcohol use (16% vs. 6%) and a lower mean body mass index (26 kg/m2 vs. 26-30 kg/m2) also were noted for the PLWH group, compared with the HIV-negative control group.
Individuals with multimorbidity had at least two chronic comorbid diseases including hypertension, diabetes mellitus, chronic kidney disease, bone disease, hepatic disease, or cardiovascular disease at the time of the study. Neoplastic disease also was included if reported previously or as a current condition. Results from the Poisson regression analysis used to identify multimorbidity-associated factors and potential confounders were stratified by age category (50-55, 56-60, 61-65, and older than 65).
Individuals with HIV had a significantly higher prevalence of multimorbidity than did HIV-negative controls (63% vs. 43%; P less than .001). Renal, hepatic, and bone diseases were the main sources of this difference. The overall median number of comorbidities of the PLWH individuals was two, which was double the median number observed in the HIV-negative controls. Furthermore, examination of the age-stratified data showed that the PLWH patients in the 50-60 age group had almost twice the burden of disease as the corresponding HIV-negative individuals. Similarity in prevalence of comorbidities was apparent when comparing the youngest PLWH age group (50-55) with their HIV-negative counterparts who were at least 10 years older, the investigators said.
Regression analysis failed to reveal a specific covariate risk factor associated with a higher prevalence of multimorbidity between the HIV and control groups. However, univariate analysis showed significant associations with age (15% per 5 years over 50 years old; P less than .001) and being HIV positive (prevalence ratio, 1.47; P less than .001). Further investigation found that duration of HIV infection and cART exposure time were significantly associated with multimorbidity, resulting in an adjusted model of age (P = .015), duration of HIV infection (P = .027), and time on cART (P = .015), they said.
Of the considered comorbidities, it was noted that between groups there was no significant difference in cardiovascular disease, which may be due to better awareness and care of this risk in HIV-positive patients. In contrast, there was an increased prevalence of HIV-associated bone and kidney disease consistent with the proposed mechanisms of long-term chronic HIV-induced inflammation and antiretroviral toxicities that have previously been implicated as risk factors for excess multimorbidity in aging HIV populations.
This study was designed to investigate the burden of noninfectious comorbidities associated with HIV and, by conducting it in southern Brazil, explore “the risk factors for the occurrence of multimorbidity in HIV-positive individuals in the developing world,” Dr. Maciel and his associates wrote.
The 63% prevalence of multimorbidity associated with HIV was high compared with other reports that ranged from 7% to 29%. This may in part be associated with the Brazilian socioeconomic status in comparison with high-income countries. The researchers also showed that PLWH individuals would develop similar age-related comorbidities as HIV-negative controls but 10 years earlier. Based on this and the high multimorbidity occurrence they had reported in this study, the investigators said that health care providers “must be ready to face the emerging epidemic of multimorbidity affecting people living with HIV in the developing world.”
The authors reported that they had no conflicts of interest.
SOURCE: Maciel RA et al. Int J Infect Dis. 2018 May;70:30-5. doi: 10.1016/j.ijid.2018.02.009.
The research was conducted as a cross-sectional analysis using medical chart data from a total of 416 patients treated at the Hospital de Clínicas de Porto Alegre, a tertiary referral hospital in south Brazil, Rafael Aguilar Maciel, MD of the Universidade Federal do Rio Grande do Sul, Porto Alegre, and his associates reported in the International Journal of Infectious Diseases.
The randomly selected participants were 208 well-controlled persons living with HIV (PLWH) – outpatients identified from the South Brazilian HIV Cohort unit – who were individually matched by age, sex, and ethnicity to HIV-negative control counterparts from the primary practice unit of the same hospital. The study group (median age, 57 years) consisted primarily of individuals who were white in origin (79%); 44.2% were women. Nearly all (98.1%) PLWH participants were on highly active antiretroviral therapy (HAART), with 88% having an undetectable viral load. A higher tendency for alcohol use (16% vs. 6%) and a lower mean body mass index (26 kg/m2 vs. 26-30 kg/m2) also were noted for the PLWH group, compared with the HIV-negative control group.
Individuals with multimorbidity had at least two chronic comorbid diseases including hypertension, diabetes mellitus, chronic kidney disease, bone disease, hepatic disease, or cardiovascular disease at the time of the study. Neoplastic disease also was included if reported previously or as a current condition. Results from the Poisson regression analysis used to identify multimorbidity-associated factors and potential confounders were stratified by age category (50-55, 56-60, 61-65, and older than 65).
Individuals with HIV had a significantly higher prevalence of multimorbidity than did HIV-negative controls (63% vs. 43%; P less than .001). Renal, hepatic, and bone diseases were the main sources of this difference. The overall median number of comorbidities of the PLWH individuals was two, which was double the median number observed in the HIV-negative controls. Furthermore, examination of the age-stratified data showed that the PLWH patients in the 50-60 age group had almost twice the burden of disease as the corresponding HIV-negative individuals. Similarity in prevalence of comorbidities was apparent when comparing the youngest PLWH age group (50-55) with their HIV-negative counterparts who were at least 10 years older, the investigators said.
Regression analysis failed to reveal a specific covariate risk factor associated with a higher prevalence of multimorbidity between the HIV and control groups. However, univariate analysis showed significant associations with age (15% per 5 years over 50 years old; P less than .001) and being HIV positive (prevalence ratio, 1.47; P less than .001). Further investigation found that duration of HIV infection and cART exposure time were significantly associated with multimorbidity, resulting in an adjusted model of age (P = .015), duration of HIV infection (P = .027), and time on cART (P = .015), they said.
Of the considered comorbidities, it was noted that between groups there was no significant difference in cardiovascular disease, which may be due to better awareness and care of this risk in HIV-positive patients. In contrast, there was an increased prevalence of HIV-associated bone and kidney disease consistent with the proposed mechanisms of long-term chronic HIV-induced inflammation and antiretroviral toxicities that have previously been implicated as risk factors for excess multimorbidity in aging HIV populations.
This study was designed to investigate the burden of noninfectious comorbidities associated with HIV and, by conducting it in southern Brazil, explore “the risk factors for the occurrence of multimorbidity in HIV-positive individuals in the developing world,” Dr. Maciel and his associates wrote.
The 63% prevalence of multimorbidity associated with HIV was high compared with other reports that ranged from 7% to 29%. This may in part be associated with the Brazilian socioeconomic status in comparison with high-income countries. The researchers also showed that PLWH individuals would develop similar age-related comorbidities as HIV-negative controls but 10 years earlier. Based on this and the high multimorbidity occurrence they had reported in this study, the investigators said that health care providers “must be ready to face the emerging epidemic of multimorbidity affecting people living with HIV in the developing world.”
The authors reported that they had no conflicts of interest.
SOURCE: Maciel RA et al. Int J Infect Dis. 2018 May;70:30-5. doi: 10.1016/j.ijid.2018.02.009.
The research was conducted as a cross-sectional analysis using medical chart data from a total of 416 patients treated at the Hospital de Clínicas de Porto Alegre, a tertiary referral hospital in south Brazil, Rafael Aguilar Maciel, MD of the Universidade Federal do Rio Grande do Sul, Porto Alegre, and his associates reported in the International Journal of Infectious Diseases.
The randomly selected participants were 208 well-controlled persons living with HIV (PLWH) – outpatients identified from the South Brazilian HIV Cohort unit – who were individually matched by age, sex, and ethnicity to HIV-negative control counterparts from the primary practice unit of the same hospital. The study group (median age, 57 years) consisted primarily of individuals who were white in origin (79%); 44.2% were women. Nearly all (98.1%) PLWH participants were on highly active antiretroviral therapy (HAART), with 88% having an undetectable viral load. A higher tendency for alcohol use (16% vs. 6%) and a lower mean body mass index (26 kg/m2 vs. 26-30 kg/m2) also were noted for the PLWH group, compared with the HIV-negative control group.
Individuals with multimorbidity had at least two chronic comorbid diseases including hypertension, diabetes mellitus, chronic kidney disease, bone disease, hepatic disease, or cardiovascular disease at the time of the study. Neoplastic disease also was included if reported previously or as a current condition. Results from the Poisson regression analysis used to identify multimorbidity-associated factors and potential confounders were stratified by age category (50-55, 56-60, 61-65, and older than 65).
Individuals with HIV had a significantly higher prevalence of multimorbidity than did HIV-negative controls (63% vs. 43%; P less than .001). Renal, hepatic, and bone diseases were the main sources of this difference. The overall median number of comorbidities of the PLWH individuals was two, which was double the median number observed in the HIV-negative controls. Furthermore, examination of the age-stratified data showed that the PLWH patients in the 50-60 age group had almost twice the burden of disease as the corresponding HIV-negative individuals. Similarity in prevalence of comorbidities was apparent when comparing the youngest PLWH age group (50-55) with their HIV-negative counterparts who were at least 10 years older, the investigators said.
Regression analysis failed to reveal a specific covariate risk factor associated with a higher prevalence of multimorbidity between the HIV and control groups. However, univariate analysis showed significant associations with age (15% per 5 years over 50 years old; P less than .001) and being HIV positive (prevalence ratio, 1.47; P less than .001). Further investigation found that duration of HIV infection and cART exposure time were significantly associated with multimorbidity, resulting in an adjusted model of age (P = .015), duration of HIV infection (P = .027), and time on cART (P = .015), they said.
Of the considered comorbidities, it was noted that between groups there was no significant difference in cardiovascular disease, which may be due to better awareness and care of this risk in HIV-positive patients. In contrast, there was an increased prevalence of HIV-associated bone and kidney disease consistent with the proposed mechanisms of long-term chronic HIV-induced inflammation and antiretroviral toxicities that have previously been implicated as risk factors for excess multimorbidity in aging HIV populations.
This study was designed to investigate the burden of noninfectious comorbidities associated with HIV and, by conducting it in southern Brazil, explore “the risk factors for the occurrence of multimorbidity in HIV-positive individuals in the developing world,” Dr. Maciel and his associates wrote.
The 63% prevalence of multimorbidity associated with HIV was high compared with other reports that ranged from 7% to 29%. This may in part be associated with the Brazilian socioeconomic status in comparison with high-income countries. The researchers also showed that PLWH individuals would develop similar age-related comorbidities as HIV-negative controls but 10 years earlier. Based on this and the high multimorbidity occurrence they had reported in this study, the investigators said that health care providers “must be ready to face the emerging epidemic of multimorbidity affecting people living with HIV in the developing world.”
The authors reported that they had no conflicts of interest.
SOURCE: Maciel RA et al. Int J Infect Dis. 2018 May;70:30-5. doi: 10.1016/j.ijid.2018.02.009.
FROM INTERNATIONAL JOURNAL OF INFECTIOUS DISEASES
Key clinical point: Toxicity of, and time on, combined antiretroviral therapy (cART) are implicated in contributing to higher comorbidity occurring in an aging HIV population.
Major finding: Compared with HIV-negative controls, individuals at least 50 years old with well-managed HIV infection had a higher frequency (63% vs. 43%) of multimorbidity and a median of two comorbidities to one for controls.
Study details: A cross-sectional study conducted in Brazil from Jan. 1 to June 30, 2016, with 208 HIV-positive and 208 HIV-negative patients matched by age, sex, and ethnicity.
Disclosures: The authors reported that they had no conflicts of interest.
Source: Maciel RA et al. Int J Infect Dis. 2018 May;70:30-5.
Measles exacts high toll among Europe’s youngest citizens
MADRID – Children younger than 2 years who contracted measles were significantly more likely to die of the disease than were older children, according to new data from the European Center for Disease Control and Prevention.
Infants younger than 12 months faced the worst mortality outcomes, with a sevenfold increased risk of death, compared with children aged 2 years or older, Emmanuel Robesyn, MD said at the European Society of Clinical Microbiology and Infectious Diseases annual congress. Infants and children younger than 2 years also were much more likely to develop severe complications of the disease, including pneumonia and encephalitis.
The statistics should drive home the point that measles can be a life-threatening disease, especially for small children, said Dr. Robesyn, an expert in outbreak response at the European Center for Disease Prevention and Control, Stockholm.
“We want the population to understand that measles is much more than a nuisance illness of childhood,” he said. “Already this year we have recorded 13 deaths from measles,” which were not included in the data he presented.
“As you know, measles has been set for elimination” as a communicable disease, he said. “We need high immune coverage to achieve that, meaning 95% of the population covered with two doses. That is a challenge.”
Infants are especially vulnerable, and they fully reliant on the immunity of others to avoid measles.
“Vaccination recommendations begin at age 1, so before that, infants are dependent on their mothers’ antibodies, and on herd immunity. It’s very important that we have high vaccine coverage to protect them.”
Dr. Robesyn described measles outcomes in children 24 months and younger in 30 member states of the European Union and the European Economic Area from 2013 to 2017. Data were extracted from the European Surveillance System, which collects and analyzes infectious disease data across Europe.
During that period, there were 37,365 measles cases in people of all ages. Most were in Italy, Romania, Germany, the Netherlands, and the United Kingdom, with each reporting more than 5% of the cases. These countries also had the most cases that had not been connected with importation of the disease.
Overall, the patients were a mean of 12 years old. Less than 2% had been fully vaccinated against the disease. Complications (diarrhea, otitis media, pneumonia, or encephalitis) occurred in 13.6%, and about 33% of patients had to be hospitalized. Most cases (81%) occurred in people aged 2 years and older, 9% occurred in children who were 12-24 months old, and 10% occurred in children younger than 12 months. These younger children, however, accounted for 61% of the deaths in the cohort, Dr. Robesyn said.
Most of the cases occurred in unvaccinated or incompletely vaccinated patients. Forty-six died from measles, a mortality rate of about 1 per 1,000 who contracted the disease. Of these deaths, 16 were among children younger than 12 months, 12 among children aged 12-24 months, and the remainder among those older than 2 years.
These younger patients were also more susceptible to complications of measles, both mild (diarrhea and otitis media) and severe (pneumonia and encephalitis). Most of the uncomplicated cases (75%) occurred in children older than 24 months, with just 25% of uncomplicated cases occurring in the younger groups.
“When we looked at age as a continuous variable, we saw that the chance of having no complications or just mild complications increased with age, and the chance of having severe complications decreased with age,” Dr. Robesyn said.
“We definitely saw that these two groups are at increased risk. The consequences however, are different. For the children who are 1 year of age or older, the message is that it’s really important to strictly follow national recommendations and get timely and complete vaccination. For those younger than 1 year, we have to rely on the population to be vaccinated. It is very important that we reach this 95% coverage rate to protect these youngest children. We need adolescents and young adults who have missed vaccinations to get them completed,” he said.
Dr. Robesyn had no financial disclosures.
SOURCE: Robesyn E et al. ECCMID 2018, abstract O0060
MADRID – Children younger than 2 years who contracted measles were significantly more likely to die of the disease than were older children, according to new data from the European Center for Disease Control and Prevention.
Infants younger than 12 months faced the worst mortality outcomes, with a sevenfold increased risk of death, compared with children aged 2 years or older, Emmanuel Robesyn, MD said at the European Society of Clinical Microbiology and Infectious Diseases annual congress. Infants and children younger than 2 years also were much more likely to develop severe complications of the disease, including pneumonia and encephalitis.
The statistics should drive home the point that measles can be a life-threatening disease, especially for small children, said Dr. Robesyn, an expert in outbreak response at the European Center for Disease Prevention and Control, Stockholm.
“We want the population to understand that measles is much more than a nuisance illness of childhood,” he said. “Already this year we have recorded 13 deaths from measles,” which were not included in the data he presented.
“As you know, measles has been set for elimination” as a communicable disease, he said. “We need high immune coverage to achieve that, meaning 95% of the population covered with two doses. That is a challenge.”
Infants are especially vulnerable, and they fully reliant on the immunity of others to avoid measles.
“Vaccination recommendations begin at age 1, so before that, infants are dependent on their mothers’ antibodies, and on herd immunity. It’s very important that we have high vaccine coverage to protect them.”
Dr. Robesyn described measles outcomes in children 24 months and younger in 30 member states of the European Union and the European Economic Area from 2013 to 2017. Data were extracted from the European Surveillance System, which collects and analyzes infectious disease data across Europe.
During that period, there were 37,365 measles cases in people of all ages. Most were in Italy, Romania, Germany, the Netherlands, and the United Kingdom, with each reporting more than 5% of the cases. These countries also had the most cases that had not been connected with importation of the disease.
Overall, the patients were a mean of 12 years old. Less than 2% had been fully vaccinated against the disease. Complications (diarrhea, otitis media, pneumonia, or encephalitis) occurred in 13.6%, and about 33% of patients had to be hospitalized. Most cases (81%) occurred in people aged 2 years and older, 9% occurred in children who were 12-24 months old, and 10% occurred in children younger than 12 months. These younger children, however, accounted for 61% of the deaths in the cohort, Dr. Robesyn said.
Most of the cases occurred in unvaccinated or incompletely vaccinated patients. Forty-six died from measles, a mortality rate of about 1 per 1,000 who contracted the disease. Of these deaths, 16 were among children younger than 12 months, 12 among children aged 12-24 months, and the remainder among those older than 2 years.
These younger patients were also more susceptible to complications of measles, both mild (diarrhea and otitis media) and severe (pneumonia and encephalitis). Most of the uncomplicated cases (75%) occurred in children older than 24 months, with just 25% of uncomplicated cases occurring in the younger groups.
“When we looked at age as a continuous variable, we saw that the chance of having no complications or just mild complications increased with age, and the chance of having severe complications decreased with age,” Dr. Robesyn said.
“We definitely saw that these two groups are at increased risk. The consequences however, are different. For the children who are 1 year of age or older, the message is that it’s really important to strictly follow national recommendations and get timely and complete vaccination. For those younger than 1 year, we have to rely on the population to be vaccinated. It is very important that we reach this 95% coverage rate to protect these youngest children. We need adolescents and young adults who have missed vaccinations to get them completed,” he said.
Dr. Robesyn had no financial disclosures.
SOURCE: Robesyn E et al. ECCMID 2018, abstract O0060
MADRID – Children younger than 2 years who contracted measles were significantly more likely to die of the disease than were older children, according to new data from the European Center for Disease Control and Prevention.
Infants younger than 12 months faced the worst mortality outcomes, with a sevenfold increased risk of death, compared with children aged 2 years or older, Emmanuel Robesyn, MD said at the European Society of Clinical Microbiology and Infectious Diseases annual congress. Infants and children younger than 2 years also were much more likely to develop severe complications of the disease, including pneumonia and encephalitis.
The statistics should drive home the point that measles can be a life-threatening disease, especially for small children, said Dr. Robesyn, an expert in outbreak response at the European Center for Disease Prevention and Control, Stockholm.
“We want the population to understand that measles is much more than a nuisance illness of childhood,” he said. “Already this year we have recorded 13 deaths from measles,” which were not included in the data he presented.
“As you know, measles has been set for elimination” as a communicable disease, he said. “We need high immune coverage to achieve that, meaning 95% of the population covered with two doses. That is a challenge.”
Infants are especially vulnerable, and they fully reliant on the immunity of others to avoid measles.
“Vaccination recommendations begin at age 1, so before that, infants are dependent on their mothers’ antibodies, and on herd immunity. It’s very important that we have high vaccine coverage to protect them.”
Dr. Robesyn described measles outcomes in children 24 months and younger in 30 member states of the European Union and the European Economic Area from 2013 to 2017. Data were extracted from the European Surveillance System, which collects and analyzes infectious disease data across Europe.
During that period, there were 37,365 measles cases in people of all ages. Most were in Italy, Romania, Germany, the Netherlands, and the United Kingdom, with each reporting more than 5% of the cases. These countries also had the most cases that had not been connected with importation of the disease.
Overall, the patients were a mean of 12 years old. Less than 2% had been fully vaccinated against the disease. Complications (diarrhea, otitis media, pneumonia, or encephalitis) occurred in 13.6%, and about 33% of patients had to be hospitalized. Most cases (81%) occurred in people aged 2 years and older, 9% occurred in children who were 12-24 months old, and 10% occurred in children younger than 12 months. These younger children, however, accounted for 61% of the deaths in the cohort, Dr. Robesyn said.
Most of the cases occurred in unvaccinated or incompletely vaccinated patients. Forty-six died from measles, a mortality rate of about 1 per 1,000 who contracted the disease. Of these deaths, 16 were among children younger than 12 months, 12 among children aged 12-24 months, and the remainder among those older than 2 years.
These younger patients were also more susceptible to complications of measles, both mild (diarrhea and otitis media) and severe (pneumonia and encephalitis). Most of the uncomplicated cases (75%) occurred in children older than 24 months, with just 25% of uncomplicated cases occurring in the younger groups.
“When we looked at age as a continuous variable, we saw that the chance of having no complications or just mild complications increased with age, and the chance of having severe complications decreased with age,” Dr. Robesyn said.
“We definitely saw that these two groups are at increased risk. The consequences however, are different. For the children who are 1 year of age or older, the message is that it’s really important to strictly follow national recommendations and get timely and complete vaccination. For those younger than 1 year, we have to rely on the population to be vaccinated. It is very important that we reach this 95% coverage rate to protect these youngest children. We need adolescents and young adults who have missed vaccinations to get them completed,” he said.
Dr. Robesyn had no financial disclosures.
SOURCE: Robesyn E et al. ECCMID 2018, abstract O0060
REPORTING FROM ECCMID 2018
Key clinical point: Measles is most dangerous to children younger than 2 years.
Major finding: Children younger than 12 months who contracted measles were seven times more likely to die of the disease than were children 2 years and older.
Study details: The analysis involved 37,365 measles cases that occurred in the European Union from 2013 to 2017.
Disclosures: The analysis was conducted by the European Center for Disease Prevention and Control.
Source: Robesyn E et al. ECCMID 2018, abstract O0060.
Suicide prevention, NRA team up for safer gun storage
WASHINGTON – A suicide prevention organization based at the University of Washington partnered with the National Rifle Association and other gun-user organizations to launch a state-wide program in Washington aimed at safe firearm storage to cut suicide rates.
with plans to expand these activities, Jennifer P. Stuber, Ph.D., said at the annual conference of the American Association of Suicidology.
The idea behind SAFER Homes came from recognition that a majority of suicides are caused by firearms, a majority of deaths from firearms are suicides, and that a potentially effective way to cut suicide numbers is by restricting unauthorized or unintended firearm access, especially to middle-aged men, said Dr. Stuber, a health policy researcher at the University of Washington, Seattle, and founder and policy director of Forefront Suicide Prevention, a social impact organization operated by the university’s school of social work. SAFER Homes also came into being as Dr. Stuber realized that she had a receptive audience on the issue of safe gun storage to prevent suicides among gun owners, gun retailers, and gun-rights proponents.
“There is remarkably little push back. These are folks who care about suicide. Seventy percent of gun-shop owners have experienced a personal suicide loss, and shop owners don’t want to be the one who sells someone a gun who then uses it to end their life,” Dr. Stuber said in an interview.
The Second Amendment Foundation gun-rights organization has been the main partner with Forefront Suicide Prevention in launching SAFER Homes Suicide Aware, but the campaign also received endorsement from the National Rifle Association. Dr. Stuber also worked with the Second Amendment Foundation and the National Rifle Association to get legislation passed in Washington to expand education on suicide prevention through improved gun safety. Dr. Stuber became an advocate for suicide prevention and safer gun storage following the firearm suicide of her husband in 2011, an experience she wrote about in a 2016 essay.
Preventing suicide through safer storage of firearms makes sense because the U.S. demographic subgroup with the highest number of suicides is men 35-64 years old. In this subgroup, the majority of those killed by suicide were never identified as depressed or having a mental health problem, and more than 80% never had a prior suicide attempt, said Jeffrey C. Sung, MD, a psychiatrist at the University of Washington who has worked with Dr. Stuber on the SAFER Homes campaign. He cited a study of 310 suicides among patients in the Veterans Health Administration system (93% men, 76% aged 50 years or older) that showed 72% reported having no suicide ideation on the most recent health questionnaire prior to their suicide (Psych Services. 2016 May;67[5]:517-22).
Because men like these do not come to clinical attention prior to their suicide, the best preventive strategy is to focus on improved safety measures to control potential means of lethality, said Dr. Sung, who is also immediate past president of the Washington State Psychiatric Society.
SAFER Homes “goes to community-based settings, like gun shows, where men in their middle years can be reached,” Dr. Stuber noted. By talking about taking steps to reduce the risk of firearm suicide with attendees at gun shows and with gun retailers, “you’re pushing on an open door,” Dr. Sung added.
Dr. Stuber and Dr. Sung had no disclosures.
SOURCE: Stuber J et al. Annual conference of the American Association of Suicidology.
WASHINGTON – A suicide prevention organization based at the University of Washington partnered with the National Rifle Association and other gun-user organizations to launch a state-wide program in Washington aimed at safe firearm storage to cut suicide rates.
with plans to expand these activities, Jennifer P. Stuber, Ph.D., said at the annual conference of the American Association of Suicidology.
The idea behind SAFER Homes came from recognition that a majority of suicides are caused by firearms, a majority of deaths from firearms are suicides, and that a potentially effective way to cut suicide numbers is by restricting unauthorized or unintended firearm access, especially to middle-aged men, said Dr. Stuber, a health policy researcher at the University of Washington, Seattle, and founder and policy director of Forefront Suicide Prevention, a social impact organization operated by the university’s school of social work. SAFER Homes also came into being as Dr. Stuber realized that she had a receptive audience on the issue of safe gun storage to prevent suicides among gun owners, gun retailers, and gun-rights proponents.
“There is remarkably little push back. These are folks who care about suicide. Seventy percent of gun-shop owners have experienced a personal suicide loss, and shop owners don’t want to be the one who sells someone a gun who then uses it to end their life,” Dr. Stuber said in an interview.
The Second Amendment Foundation gun-rights organization has been the main partner with Forefront Suicide Prevention in launching SAFER Homes Suicide Aware, but the campaign also received endorsement from the National Rifle Association. Dr. Stuber also worked with the Second Amendment Foundation and the National Rifle Association to get legislation passed in Washington to expand education on suicide prevention through improved gun safety. Dr. Stuber became an advocate for suicide prevention and safer gun storage following the firearm suicide of her husband in 2011, an experience she wrote about in a 2016 essay.
Preventing suicide through safer storage of firearms makes sense because the U.S. demographic subgroup with the highest number of suicides is men 35-64 years old. In this subgroup, the majority of those killed by suicide were never identified as depressed or having a mental health problem, and more than 80% never had a prior suicide attempt, said Jeffrey C. Sung, MD, a psychiatrist at the University of Washington who has worked with Dr. Stuber on the SAFER Homes campaign. He cited a study of 310 suicides among patients in the Veterans Health Administration system (93% men, 76% aged 50 years or older) that showed 72% reported having no suicide ideation on the most recent health questionnaire prior to their suicide (Psych Services. 2016 May;67[5]:517-22).
Because men like these do not come to clinical attention prior to their suicide, the best preventive strategy is to focus on improved safety measures to control potential means of lethality, said Dr. Sung, who is also immediate past president of the Washington State Psychiatric Society.
SAFER Homes “goes to community-based settings, like gun shows, where men in their middle years can be reached,” Dr. Stuber noted. By talking about taking steps to reduce the risk of firearm suicide with attendees at gun shows and with gun retailers, “you’re pushing on an open door,” Dr. Sung added.
Dr. Stuber and Dr. Sung had no disclosures.
SOURCE: Stuber J et al. Annual conference of the American Association of Suicidology.
WASHINGTON – A suicide prevention organization based at the University of Washington partnered with the National Rifle Association and other gun-user organizations to launch a state-wide program in Washington aimed at safe firearm storage to cut suicide rates.
with plans to expand these activities, Jennifer P. Stuber, Ph.D., said at the annual conference of the American Association of Suicidology.
The idea behind SAFER Homes came from recognition that a majority of suicides are caused by firearms, a majority of deaths from firearms are suicides, and that a potentially effective way to cut suicide numbers is by restricting unauthorized or unintended firearm access, especially to middle-aged men, said Dr. Stuber, a health policy researcher at the University of Washington, Seattle, and founder and policy director of Forefront Suicide Prevention, a social impact organization operated by the university’s school of social work. SAFER Homes also came into being as Dr. Stuber realized that she had a receptive audience on the issue of safe gun storage to prevent suicides among gun owners, gun retailers, and gun-rights proponents.
“There is remarkably little push back. These are folks who care about suicide. Seventy percent of gun-shop owners have experienced a personal suicide loss, and shop owners don’t want to be the one who sells someone a gun who then uses it to end their life,” Dr. Stuber said in an interview.
The Second Amendment Foundation gun-rights organization has been the main partner with Forefront Suicide Prevention in launching SAFER Homes Suicide Aware, but the campaign also received endorsement from the National Rifle Association. Dr. Stuber also worked with the Second Amendment Foundation and the National Rifle Association to get legislation passed in Washington to expand education on suicide prevention through improved gun safety. Dr. Stuber became an advocate for suicide prevention and safer gun storage following the firearm suicide of her husband in 2011, an experience she wrote about in a 2016 essay.
Preventing suicide through safer storage of firearms makes sense because the U.S. demographic subgroup with the highest number of suicides is men 35-64 years old. In this subgroup, the majority of those killed by suicide were never identified as depressed or having a mental health problem, and more than 80% never had a prior suicide attempt, said Jeffrey C. Sung, MD, a psychiatrist at the University of Washington who has worked with Dr. Stuber on the SAFER Homes campaign. He cited a study of 310 suicides among patients in the Veterans Health Administration system (93% men, 76% aged 50 years or older) that showed 72% reported having no suicide ideation on the most recent health questionnaire prior to their suicide (Psych Services. 2016 May;67[5]:517-22).
Because men like these do not come to clinical attention prior to their suicide, the best preventive strategy is to focus on improved safety measures to control potential means of lethality, said Dr. Sung, who is also immediate past president of the Washington State Psychiatric Society.
SAFER Homes “goes to community-based settings, like gun shows, where men in their middle years can be reached,” Dr. Stuber noted. By talking about taking steps to reduce the risk of firearm suicide with attendees at gun shows and with gun retailers, “you’re pushing on an open door,” Dr. Sung added.
Dr. Stuber and Dr. Sung had no disclosures.
SOURCE: Stuber J et al. Annual conference of the American Association of Suicidology.
EXPERT ANALYSIS FROM THE AAS ANNUAL CONFERENCE
BET inhibitor has lasting effects in AML, MM
CHICAGO—A BET inhibitor can have potent and long-lasting effects against leukemia and multiple myeloma (MM), according to researchers.
The inhibitor, TG-1601 (or CK-103), exhibited cytotoxicity in MM and leukemia cell lines but did not affect the growth of normal cell lines.
TG-1601 also reduced tumor volume in mouse models of MM and acute myeloid leukemia (AML), and drug holidays had little impact on this activity.
Furthermore, researchers observed enduring MYC inhibition in mice treated with TG-1601.
This research was presented at the AACR Annual Meeting 2018 (abstract 5790).
The work was conducted by researchers from TG Therapeutics and Checkpoint Therapeutics—the companies developing TG-1601—as well as Jubilant Biosys.
In vitro activity
Researchers assessed the cytotoxic activity of TG-1601 in leukemia, MM, and normal cell lines by incubating the cells with increasing concentrations of the drug for 72 hours.
The results suggested TG-1601 inhibits MM and leukemia cell growth, as all EC50 values were below 100 nM.
In the leukemia cell lines, EC50 values were 35 nM (Jurkat), 31 nM (HEL92.1.7), 24 nM (CCRF-CEM and MV4-11), and 18 nM (OCI-AML3).
In the MM cell lines, EC50 values were 85 nM (RPMI8226), 32 nM (KMS28PE), 24 nM (KMS28BM), 21 nM (MOLP8), and 15 nM (MM1s).
In the normal cell lines (Beas2B and WT9-12), cell growth wasn’t inhibited more than 50% with TG-1601 at 10 μM.
In vivo activity
For their MM model, researchers used mice inoculated with MM1 cells. The mice received TG-1601 at 10 mg/kg twice a day.
At day 17 after treatment initiation, there was a 70% reduction in tumor volume. During a week-long drug holiday, tumors did not grow back as fast in TG-1601-treated mice as they did in vehicle control mice.
For their AML model, researchers used mice inoculated with MV4-11 cells. The mice received TG-1601 as a single dose of 20 mg/kg/day—continuously or with 2, 3, or 4 days off per week—or at 10 mg/kg twice a day.
At day 15, 100% of mice that received the drug at 10 mg/kg twice a day were tumor-free. Mice that received the single 20 mg/kg dose had a 94% reduction in tumor volume.
The reduction in tumor volume was 91% in mice with the 2-day drug holiday, 78% in those with the 3-day holiday, and 82% in those with the 4-day holiday.
The researchers also found that TG-1601 had synergistic antitumor activity with an anti-PD-1 antibody in a mouse model of melanoma.
Pharmacodynamic activity
In the MV4-11 cell line, TG-1601 induced “rapid” downregulation of MYC and BCL2 and an increase of p21 mRNA, according to the researchers.
The team also assessed MYC expression in mice with MV4-11 tumors. They said MYC levels rapidly decreased in the tumors and were undetectable at 3 hours after a single dose of TG-1601.
The researchers noted that, at 24 hours after dosing, TG-1601 was cleared from the tumor. However, MYC levels remained below 40% their initial level.
The team said this suggests a long-lasting effect of TG-1601 that may be attributed to its enhanced binding affinity.
“These data demonstrate [TG-1601’s] potential to be a novel BET inhibitor that potently inhibits MYC expression,” said James F. Oliviero, president and chief executive officer of Checkpoint Therapeutics.
“We believe the preclinical data presented today provides encouraging evidence to support the development of [TG-1601] as an anticancer agent, alone and in combination with our anti-PD-L1 antibody, and look forward to the advancement of [TG-1601] into a first-in-human phase 1 trial expected to commence later this year.”
CHICAGO—A BET inhibitor can have potent and long-lasting effects against leukemia and multiple myeloma (MM), according to researchers.
The inhibitor, TG-1601 (or CK-103), exhibited cytotoxicity in MM and leukemia cell lines but did not affect the growth of normal cell lines.
TG-1601 also reduced tumor volume in mouse models of MM and acute myeloid leukemia (AML), and drug holidays had little impact on this activity.
Furthermore, researchers observed enduring MYC inhibition in mice treated with TG-1601.
This research was presented at the AACR Annual Meeting 2018 (abstract 5790).
The work was conducted by researchers from TG Therapeutics and Checkpoint Therapeutics—the companies developing TG-1601—as well as Jubilant Biosys.
In vitro activity
Researchers assessed the cytotoxic activity of TG-1601 in leukemia, MM, and normal cell lines by incubating the cells with increasing concentrations of the drug for 72 hours.
The results suggested TG-1601 inhibits MM and leukemia cell growth, as all EC50 values were below 100 nM.
In the leukemia cell lines, EC50 values were 35 nM (Jurkat), 31 nM (HEL92.1.7), 24 nM (CCRF-CEM and MV4-11), and 18 nM (OCI-AML3).
In the MM cell lines, EC50 values were 85 nM (RPMI8226), 32 nM (KMS28PE), 24 nM (KMS28BM), 21 nM (MOLP8), and 15 nM (MM1s).
In the normal cell lines (Beas2B and WT9-12), cell growth wasn’t inhibited more than 50% with TG-1601 at 10 μM.
In vivo activity
For their MM model, researchers used mice inoculated with MM1 cells. The mice received TG-1601 at 10 mg/kg twice a day.
At day 17 after treatment initiation, there was a 70% reduction in tumor volume. During a week-long drug holiday, tumors did not grow back as fast in TG-1601-treated mice as they did in vehicle control mice.
For their AML model, researchers used mice inoculated with MV4-11 cells. The mice received TG-1601 as a single dose of 20 mg/kg/day—continuously or with 2, 3, or 4 days off per week—or at 10 mg/kg twice a day.
At day 15, 100% of mice that received the drug at 10 mg/kg twice a day were tumor-free. Mice that received the single 20 mg/kg dose had a 94% reduction in tumor volume.
The reduction in tumor volume was 91% in mice with the 2-day drug holiday, 78% in those with the 3-day holiday, and 82% in those with the 4-day holiday.
The researchers also found that TG-1601 had synergistic antitumor activity with an anti-PD-1 antibody in a mouse model of melanoma.
Pharmacodynamic activity
In the MV4-11 cell line, TG-1601 induced “rapid” downregulation of MYC and BCL2 and an increase of p21 mRNA, according to the researchers.
The team also assessed MYC expression in mice with MV4-11 tumors. They said MYC levels rapidly decreased in the tumors and were undetectable at 3 hours after a single dose of TG-1601.
The researchers noted that, at 24 hours after dosing, TG-1601 was cleared from the tumor. However, MYC levels remained below 40% their initial level.
The team said this suggests a long-lasting effect of TG-1601 that may be attributed to its enhanced binding affinity.
“These data demonstrate [TG-1601’s] potential to be a novel BET inhibitor that potently inhibits MYC expression,” said James F. Oliviero, president and chief executive officer of Checkpoint Therapeutics.
“We believe the preclinical data presented today provides encouraging evidence to support the development of [TG-1601] as an anticancer agent, alone and in combination with our anti-PD-L1 antibody, and look forward to the advancement of [TG-1601] into a first-in-human phase 1 trial expected to commence later this year.”
CHICAGO—A BET inhibitor can have potent and long-lasting effects against leukemia and multiple myeloma (MM), according to researchers.
The inhibitor, TG-1601 (or CK-103), exhibited cytotoxicity in MM and leukemia cell lines but did not affect the growth of normal cell lines.
TG-1601 also reduced tumor volume in mouse models of MM and acute myeloid leukemia (AML), and drug holidays had little impact on this activity.
Furthermore, researchers observed enduring MYC inhibition in mice treated with TG-1601.
This research was presented at the AACR Annual Meeting 2018 (abstract 5790).
The work was conducted by researchers from TG Therapeutics and Checkpoint Therapeutics—the companies developing TG-1601—as well as Jubilant Biosys.
In vitro activity
Researchers assessed the cytotoxic activity of TG-1601 in leukemia, MM, and normal cell lines by incubating the cells with increasing concentrations of the drug for 72 hours.
The results suggested TG-1601 inhibits MM and leukemia cell growth, as all EC50 values were below 100 nM.
In the leukemia cell lines, EC50 values were 35 nM (Jurkat), 31 nM (HEL92.1.7), 24 nM (CCRF-CEM and MV4-11), and 18 nM (OCI-AML3).
In the MM cell lines, EC50 values were 85 nM (RPMI8226), 32 nM (KMS28PE), 24 nM (KMS28BM), 21 nM (MOLP8), and 15 nM (MM1s).
In the normal cell lines (Beas2B and WT9-12), cell growth wasn’t inhibited more than 50% with TG-1601 at 10 μM.
In vivo activity
For their MM model, researchers used mice inoculated with MM1 cells. The mice received TG-1601 at 10 mg/kg twice a day.
At day 17 after treatment initiation, there was a 70% reduction in tumor volume. During a week-long drug holiday, tumors did not grow back as fast in TG-1601-treated mice as they did in vehicle control mice.
For their AML model, researchers used mice inoculated with MV4-11 cells. The mice received TG-1601 as a single dose of 20 mg/kg/day—continuously or with 2, 3, or 4 days off per week—or at 10 mg/kg twice a day.
At day 15, 100% of mice that received the drug at 10 mg/kg twice a day were tumor-free. Mice that received the single 20 mg/kg dose had a 94% reduction in tumor volume.
The reduction in tumor volume was 91% in mice with the 2-day drug holiday, 78% in those with the 3-day holiday, and 82% in those with the 4-day holiday.
The researchers also found that TG-1601 had synergistic antitumor activity with an anti-PD-1 antibody in a mouse model of melanoma.
Pharmacodynamic activity
In the MV4-11 cell line, TG-1601 induced “rapid” downregulation of MYC and BCL2 and an increase of p21 mRNA, according to the researchers.
The team also assessed MYC expression in mice with MV4-11 tumors. They said MYC levels rapidly decreased in the tumors and were undetectable at 3 hours after a single dose of TG-1601.
The researchers noted that, at 24 hours after dosing, TG-1601 was cleared from the tumor. However, MYC levels remained below 40% their initial level.
The team said this suggests a long-lasting effect of TG-1601 that may be attributed to its enhanced binding affinity.
“These data demonstrate [TG-1601’s] potential to be a novel BET inhibitor that potently inhibits MYC expression,” said James F. Oliviero, president and chief executive officer of Checkpoint Therapeutics.
“We believe the preclinical data presented today provides encouraging evidence to support the development of [TG-1601] as an anticancer agent, alone and in combination with our anti-PD-L1 antibody, and look forward to the advancement of [TG-1601] into a first-in-human phase 1 trial expected to commence later this year.”