Patient-controlled epidural analgesia achieves pain control similar to that of patient-controlled intravenous analgesia after spinal fusion surgery, but is associated with a higher incidence of pruritus and paresthesia, a meta-analysis published in BMC Musculoskeletal Disorders has found.

The analysis of eight randomized controlled trials involving 482 patients found that patient-controlled epidural analgesia was associated with significantly better analgesic effects on day 1 and 2 after surgery (mean difference in visual analog scale scores of −0.47 and −0.66, respectively), but this difference was no longer statistically significant on day 3.

Thomas Northcut/ ©Thinkstock

The study, conducted by Dr. Peng Tian of Tianjin (China) Hospital and colleagues showed that patient-controlled epidural analgesia was associated with a significant 53% higher incidence of pruritus and a threefold increase in paresthesia, compared with patient-controlled intravenous analgesia, although there were no significant differences in the rates of nausea or vomiting (BMC Musculoskeletal Disorders 2015 Dec 15. doi: 10.1186/s12891-015-0849-y).

Researchers noted that patient-controlled epidural analgesia achieves a faster analgesic effect than does patient-controlled intravenous analgesia because it acts directly on the near-operative region, but the analgesic effect of the intravenous administration lasts longer.

“The most important findings of the present meta-analysis are that the application of PCEA [patient-controlled epidural analgesia] does not more effectively relieve” pain in 3 postoperative days compared with patient-controlled intravenous analgesia, “meanwhile increasing the incidence of some complications such as pruritus and paresthesia,” wrote the investigators.

The National Natural Science Foundation of China supported the study. No conflicts of interest were declared.

Patient-controlled epidural analgesia achieves pain control similar to that of patient-controlled intravenous analgesia after spinal fusion surgery, but is associated with a higher incidence of pruritus and paresthesia, a meta-analysis published in BMC Musculoskeletal Disorders has found.

The analysis of eight randomized controlled trials involving 482 patients found that patient-controlled epidural analgesia was associated with significantly better analgesic effects on day 1 and 2 after surgery (mean difference in visual analog scale scores of −0.47 and −0.66, respectively), but this difference was no longer statistically significant on day 3.

Thomas Northcut/ ©Thinkstock

The study, conducted by Dr. Peng Tian of Tianjin (China) Hospital and colleagues showed that patient-controlled epidural analgesia was associated with a significant 53% higher incidence of pruritus and a threefold increase in paresthesia, compared with patient-controlled intravenous analgesia, although there were no significant differences in the rates of nausea or vomiting (BMC Musculoskeletal Disorders 2015 Dec 15. doi: 10.1186/s12891-015-0849-y).

Researchers noted that patient-controlled epidural analgesia achieves a faster analgesic effect than does patient-controlled intravenous analgesia because it acts directly on the near-operative region, but the analgesic effect of the intravenous administration lasts longer.

“The most important findings of the present meta-analysis are that the application of PCEA [patient-controlled epidural analgesia] does not more effectively relieve” pain in 3 postoperative days compared with patient-controlled intravenous analgesia, “meanwhile increasing the incidence of some complications such as pruritus and paresthesia,” wrote the investigators.

The National Natural Science Foundation of China supported the study. No conflicts of interest were declared.

Patient-controlled epidural analgesia achieves pain control similar to that of patient-controlled intravenous analgesia after spinal fusion surgery, but is associated with a higher incidence of pruritus and paresthesia, a meta-analysis published in BMC Musculoskeletal Disorders has found.

The analysis of eight randomized controlled trials involving 482 patients found that patient-controlled epidural analgesia was associated with significantly better analgesic effects on day 1 and 2 after surgery (mean difference in visual analog scale scores of −0.47 and −0.66, respectively), but this difference was no longer statistically significant on day 3.

Thomas Northcut/ ©Thinkstock

The study, conducted by Dr. Peng Tian of Tianjin (China) Hospital and colleagues showed that patient-controlled epidural analgesia was associated with a significant 53% higher incidence of pruritus and a threefold increase in paresthesia, compared with patient-controlled intravenous analgesia, although there were no significant differences in the rates of nausea or vomiting (BMC Musculoskeletal Disorders 2015 Dec 15. doi: 10.1186/s12891-015-0849-y).

Researchers noted that patient-controlled epidural analgesia achieves a faster analgesic effect than does patient-controlled intravenous analgesia because it acts directly on the near-operative region, but the analgesic effect of the intravenous administration lasts longer.

“The most important findings of the present meta-analysis are that the application of PCEA [patient-controlled epidural analgesia] does not more effectively relieve” pain in 3 postoperative days compared with patient-controlled intravenous analgesia, “meanwhile increasing the incidence of some complications such as pruritus and paresthesia,” wrote the investigators.

The National Natural Science Foundation of China supported the study. No conflicts of interest were declared.

One of the things that Jennifer Feighner, MD, cheerfully came away with at HM16 was how to better complete a task that is distinctly uncheerful but also important to any high-performing hospital: how to collect the data of the dead.

The quality improvement session “Reducing Inpatient Mortality: A Standardized Approach to Identify Preventable Deaths” demonstrated still evolving but, so far, well-performing projects that have been rolled out at Brigham and Women’s Hospital and the Duke University Health System.

“I was struck by the methodology for getting input from multiple providers and the nursing staff,” said Dr. Feighner, director of hospital medicine at Marcus Daly Memorial Hospital in Hamilton, Mont.

As the role of the hospitalist as agent of change and improvement continues to grow, the topic of quality improvement (QI) maintained a high profile at the annual meeting, with talks on the latest literature, sustaining motivation to complete projects, and dealing with issues such as handoffs and frequent fliers.

In the mortality review session, presenters set out to give details that could be a model to be used elsewhere. At Brigham and Women’s, all of the frontline clinicians are asked by email to fill out a report when a death occurs in any case with which they’ve been involved, with the Web-based reports to be completed within 48 to 72 hours of the death.

The number of deaths, the report completion rate, death “preventability,” and issues that arose for the patient during hospitalization are some of the data that are tracked. So far, the system has identified such themes as “alarm fatigue,” high oxygen requirements on non-intensive-care floors, handoffs, and transfers from other hospitals, said Kiran Gupta, MD, MPH, who completed her residency at Brigham and is now assistant professor of clinical medicine at the University of California San Francisco.

At Duke, where the mortality review system improvements have been led by Jonathan Bae, MD, assistant professor of medicine, self-nicknamed “Dr. Death,” inpatient deaths undergo a similarly comprehensive review, with an enhanced end-of-life section to cover issues particular to those cases and flags for cases that need independent review.

Dr. Gupta and Dr. Bae emphasized the confidentiality of the reviews and that they are non-discoverable in the event of litigation, which they hope give clinicians the freedom to fully report their observations.

Dr. Feighner said that her 23-bed hospital is far smaller than either Brigham or Duke, of course, but that the overall ideas can translate.

“I am the medical director of our hospitalist program, and our chief of staff and I’ve created a peer-review medical staff quality improvement committee,” she said. “So this obviously has a lot of interest to me.”

With only 4.2 full-time equivalents (FTEs) in her department, she said changes would be even easier to put into place.

“I think that will be really helpful for our peer-review committee and our quality and safety committee. I could see how we could take this and kind of revise it a little bit,” she said. “When you’re in charge of that few people, it’s easy to get processes implemented. We are more limited in monetary resources, but we make up for that in manpower-to-problem ratio, I guess.”

In another session, Jordan Messler, MD, SFHM, a hospitalist and former medical director of the hospitalist group at Morton Plant Hospital in Clearwater, Fla., confronted the startling statistic that 80% of initiatives in hospitals never meet their objectives. Hurdles such as burnout and disengagement, he said, often stand in the way of successful QI projects.

He emphasized the importance of intrinsic motivation (a sense of ownership and passion for the work) over extrinsic motivation (a fear of reprisal if something isn’t done). A step as simple as assigning a title (e.g., “head of readmissions”) can be a motivator, he said. But he also emphasized that project ideas need to be timed correctly and the ideas should ideally come from the physicians leading them.

Robert Clothier, RN, a practice manager for the hospitalist group at ThedaCare in Wisconsin, said he was struck by the lessons gleaned in a workshop on the I-PASS system of handoffs—a standardized system with a handoff sheet, studied prospectively, in which medical errors decreased by 23% and preventable adverse events fell by 30%.1 The system was created in pediatric departments but was deliberately made to be translatable to other settings.

“Instead of focusing on the outcome of the quality of the handoff, they focus on the quality of the feedback sessions,” Clothier said. “So it’s not the person giving the handoff or receiving the handoff that actually assesses it. It’s just the person who’s sitting there watching.”

He said the workshop underscored the importance of standardization, a concept with which he was familiar but which now seemed particularly vital.

“If you do the process and everybody does it the same, then it’s not only the person that’s giving the information who can do it in a very standardized way but the person who’s listening already knows what they’re going to be listening for so they hear it more clearly because they don’t have to discern what’s coming next,” Clothier said. “They already know what’s coming next.” TH

Reference

1. Starmer AJ, Spector ND, Srivastava R, et al. Changes in medical errors after implementation of a handoff program. N Engl J Med. 2014;371:1803-1812.

One of the things that Jennifer Feighner, MD, cheerfully came away with at HM16 was how to better complete a task that is distinctly uncheerful but also important to any high-performing hospital: how to collect the data of the dead.

The quality improvement session “Reducing Inpatient Mortality: A Standardized Approach to Identify Preventable Deaths” demonstrated still evolving but, so far, well-performing projects that have been rolled out at Brigham and Women’s Hospital and the Duke University Health System.

“I was struck by the methodology for getting input from multiple providers and the nursing staff,” said Dr. Feighner, director of hospital medicine at Marcus Daly Memorial Hospital in Hamilton, Mont.

As the role of the hospitalist as agent of change and improvement continues to grow, the topic of quality improvement (QI) maintained a high profile at the annual meeting, with talks on the latest literature, sustaining motivation to complete projects, and dealing with issues such as handoffs and frequent fliers.

In the mortality review session, presenters set out to give details that could be a model to be used elsewhere. At Brigham and Women’s, all of the frontline clinicians are asked by email to fill out a report when a death occurs in any case with which they’ve been involved, with the Web-based reports to be completed within 48 to 72 hours of the death.

The number of deaths, the report completion rate, death “preventability,” and issues that arose for the patient during hospitalization are some of the data that are tracked. So far, the system has identified such themes as “alarm fatigue,” high oxygen requirements on non-intensive-care floors, handoffs, and transfers from other hospitals, said Kiran Gupta, MD, MPH, who completed her residency at Brigham and is now assistant professor of clinical medicine at the University of California San Francisco.

At Duke, where the mortality review system improvements have been led by Jonathan Bae, MD, assistant professor of medicine, self-nicknamed “Dr. Death,” inpatient deaths undergo a similarly comprehensive review, with an enhanced end-of-life section to cover issues particular to those cases and flags for cases that need independent review.

Dr. Gupta and Dr. Bae emphasized the confidentiality of the reviews and that they are non-discoverable in the event of litigation, which they hope give clinicians the freedom to fully report their observations.

Dr. Feighner said that her 23-bed hospital is far smaller than either Brigham or Duke, of course, but that the overall ideas can translate.

“I am the medical director of our hospitalist program, and our chief of staff and I’ve created a peer-review medical staff quality improvement committee,” she said. “So this obviously has a lot of interest to me.”

With only 4.2 full-time equivalents (FTEs) in her department, she said changes would be even easier to put into place.

“I think that will be really helpful for our peer-review committee and our quality and safety committee. I could see how we could take this and kind of revise it a little bit,” she said. “When you’re in charge of that few people, it’s easy to get processes implemented. We are more limited in monetary resources, but we make up for that in manpower-to-problem ratio, I guess.”

In another session, Jordan Messler, MD, SFHM, a hospitalist and former medical director of the hospitalist group at Morton Plant Hospital in Clearwater, Fla., confronted the startling statistic that 80% of initiatives in hospitals never meet their objectives. Hurdles such as burnout and disengagement, he said, often stand in the way of successful QI projects.

He emphasized the importance of intrinsic motivation (a sense of ownership and passion for the work) over extrinsic motivation (a fear of reprisal if something isn’t done). A step as simple as assigning a title (e.g., “head of readmissions”) can be a motivator, he said. But he also emphasized that project ideas need to be timed correctly and the ideas should ideally come from the physicians leading them.

Robert Clothier, RN, a practice manager for the hospitalist group at ThedaCare in Wisconsin, said he was struck by the lessons gleaned in a workshop on the I-PASS system of handoffs—a standardized system with a handoff sheet, studied prospectively, in which medical errors decreased by 23% and preventable adverse events fell by 30%.1 The system was created in pediatric departments but was deliberately made to be translatable to other settings.

“Instead of focusing on the outcome of the quality of the handoff, they focus on the quality of the feedback sessions,” Clothier said. “So it’s not the person giving the handoff or receiving the handoff that actually assesses it. It’s just the person who’s sitting there watching.”

He said the workshop underscored the importance of standardization, a concept with which he was familiar but which now seemed particularly vital.

“If you do the process and everybody does it the same, then it’s not only the person that’s giving the information who can do it in a very standardized way but the person who’s listening already knows what they’re going to be listening for so they hear it more clearly because they don’t have to discern what’s coming next,” Clothier said. “They already know what’s coming next.” TH

Reference

1. Starmer AJ, Spector ND, Srivastava R, et al. Changes in medical errors after implementation of a handoff program. N Engl J Med. 2014;371:1803-1812.

One of the things that Jennifer Feighner, MD, cheerfully came away with at HM16 was how to better complete a task that is distinctly uncheerful but also important to any high-performing hospital: how to collect the data of the dead.

The quality improvement session “Reducing Inpatient Mortality: A Standardized Approach to Identify Preventable Deaths” demonstrated still evolving but, so far, well-performing projects that have been rolled out at Brigham and Women’s Hospital and the Duke University Health System.

“I was struck by the methodology for getting input from multiple providers and the nursing staff,” said Dr. Feighner, director of hospital medicine at Marcus Daly Memorial Hospital in Hamilton, Mont.

As the role of the hospitalist as agent of change and improvement continues to grow, the topic of quality improvement (QI) maintained a high profile at the annual meeting, with talks on the latest literature, sustaining motivation to complete projects, and dealing with issues such as handoffs and frequent fliers.

In the mortality review session, presenters set out to give details that could be a model to be used elsewhere. At Brigham and Women’s, all of the frontline clinicians are asked by email to fill out a report when a death occurs in any case with which they’ve been involved, with the Web-based reports to be completed within 48 to 72 hours of the death.

The number of deaths, the report completion rate, death “preventability,” and issues that arose for the patient during hospitalization are some of the data that are tracked. So far, the system has identified such themes as “alarm fatigue,” high oxygen requirements on non-intensive-care floors, handoffs, and transfers from other hospitals, said Kiran Gupta, MD, MPH, who completed her residency at Brigham and is now assistant professor of clinical medicine at the University of California San Francisco.

At Duke, where the mortality review system improvements have been led by Jonathan Bae, MD, assistant professor of medicine, self-nicknamed “Dr. Death,” inpatient deaths undergo a similarly comprehensive review, with an enhanced end-of-life section to cover issues particular to those cases and flags for cases that need independent review.

Dr. Gupta and Dr. Bae emphasized the confidentiality of the reviews and that they are non-discoverable in the event of litigation, which they hope give clinicians the freedom to fully report their observations.

Dr. Feighner said that her 23-bed hospital is far smaller than either Brigham or Duke, of course, but that the overall ideas can translate.

“I am the medical director of our hospitalist program, and our chief of staff and I’ve created a peer-review medical staff quality improvement committee,” she said. “So this obviously has a lot of interest to me.”

With only 4.2 full-time equivalents (FTEs) in her department, she said changes would be even easier to put into place.

“I think that will be really helpful for our peer-review committee and our quality and safety committee. I could see how we could take this and kind of revise it a little bit,” she said. “When you’re in charge of that few people, it’s easy to get processes implemented. We are more limited in monetary resources, but we make up for that in manpower-to-problem ratio, I guess.”

In another session, Jordan Messler, MD, SFHM, a hospitalist and former medical director of the hospitalist group at Morton Plant Hospital in Clearwater, Fla., confronted the startling statistic that 80% of initiatives in hospitals never meet their objectives. Hurdles such as burnout and disengagement, he said, often stand in the way of successful QI projects.

He emphasized the importance of intrinsic motivation (a sense of ownership and passion for the work) over extrinsic motivation (a fear of reprisal if something isn’t done). A step as simple as assigning a title (e.g., “head of readmissions”) can be a motivator, he said. But he also emphasized that project ideas need to be timed correctly and the ideas should ideally come from the physicians leading them.

Robert Clothier, RN, a practice manager for the hospitalist group at ThedaCare in Wisconsin, said he was struck by the lessons gleaned in a workshop on the I-PASS system of handoffs—a standardized system with a handoff sheet, studied prospectively, in which medical errors decreased by 23% and preventable adverse events fell by 30%.1 The system was created in pediatric departments but was deliberately made to be translatable to other settings.

“Instead of focusing on the outcome of the quality of the handoff, they focus on the quality of the feedback sessions,” Clothier said. “So it’s not the person giving the handoff or receiving the handoff that actually assesses it. It’s just the person who’s sitting there watching.”

He said the workshop underscored the importance of standardization, a concept with which he was familiar but which now seemed particularly vital.

“If you do the process and everybody does it the same, then it’s not only the person that’s giving the information who can do it in a very standardized way but the person who’s listening already knows what they’re going to be listening for so they hear it more clearly because they don’t have to discern what’s coming next,” Clothier said. “They already know what’s coming next.” TH

Reference

1. Starmer AJ, Spector ND, Srivastava R, et al. Changes in medical errors after implementation of a handoff program. N Engl J Med. 2014;371:1803-1812.

(Reuters Health) - Elderly patients with hip fractures may get better care at smaller hospitals, a new study suggests. Seniors with hip fractures waited longer for surgery and were more likely to be rehospitalized if they were treated at a major trauma center than if they went to a smaller emergency room, researchers found.

Seniors in level 1 trauma centers were also more likely to develop blood clots in their legs, compared to their peers who were treated in settings designed for less serious injuries, the researchers reported March 11 in the journal Medical Care.

Level 1 trauma centers have the resources to treat very serious injuries, said lead author Dr. David Metcalfe of Brigham and Women's Hospital in Boston.

"However, because they care for the most complex patients, these hospitals are often very busy. There is therefore a risk that some groups of patients might be disadvantaged or 'lost' in the system," Metcalfe told Reuters Health by email.

For example, patients with multiple injuries or bones breaking through skin may be treated before seniors with hip fractures.

Each year in the U.S. alone, more than 250,000 people aged 65 and older are hospitalized for hip fractures, according to the Centers for Disease Control and Prevention.

The study team used statewide data from California on 91,401 seniors hospitalized between 2007 and 2011. All were over age 65 and had surgery for hip fractures.

Overall, 6% were treated at a level 1 trauma center, 18% at a level 2 trauma center and 70% in a non-trauma center.

On average, patients stayed in the hospital for five days and waited one day for surgery.

Patients in level 1 trauma centers stayed for one day longer than those in the other settings and waited nearly eight hours longer for surgery.

Seniors treated at level 1 centers were 62% more likely to be readmitted to the hospital within a month of their surgery than seniors treated in level 2 or non-trauma settings.Seniors were also 32% more likely to develop blood clots in their legs at level 1 centers.

Patients at level 2 trauma centers had the same outcomes as those at non-trauma centers, the authors found. There was no difference between any of the groups in risk of death, bed sores, or pneumonia, however.

"We now know that it is important to treat patients with hip fractures as quickly as possible," said Metcalfe, noting that older adults who wait too long for treatment may be at risk for bed sores, blood clots, and lung infections.

"The concern is that this delay will lead to increasing length of stay in hospital as well as increased complications for the patients because they spend longer in bed waiting for surgery," said Dr. Chris Gooding, a surgeon at Addenbrookes Hospital, a level 1 trauma center in Cambridge, UK. Gooding was not involved in the study.

"This is an important subject as in developed countries we have an aging population and as a result we are seeing increasing numbers of patients with hip fractures," Gooding told Reuters Health by email.

At the same time, Gooding noted, there are also a growing number of level 1 trauma centers.

"One of the best ways to help these patients is to get their operation done quickly so that they can start walking again and return to their own homes as soon as possible," Metcalfe advised.

(Reuters Health) - Elderly patients with hip fractures may get better care at smaller hospitals, a new study suggests. Seniors with hip fractures waited longer for surgery and were more likely to be rehospitalized if they were treated at a major trauma center than if they went to a smaller emergency room, researchers found.

Seniors in level 1 trauma centers were also more likely to develop blood clots in their legs, compared to their peers who were treated in settings designed for less serious injuries, the researchers reported March 11 in the journal Medical Care.

Level 1 trauma centers have the resources to treat very serious injuries, said lead author Dr. David Metcalfe of Brigham and Women's Hospital in Boston.

"However, because they care for the most complex patients, these hospitals are often very busy. There is therefore a risk that some groups of patients might be disadvantaged or 'lost' in the system," Metcalfe told Reuters Health by email.

For example, patients with multiple injuries or bones breaking through skin may be treated before seniors with hip fractures.

Each year in the U.S. alone, more than 250,000 people aged 65 and older are hospitalized for hip fractures, according to the Centers for Disease Control and Prevention.

The study team used statewide data from California on 91,401 seniors hospitalized between 2007 and 2011. All were over age 65 and had surgery for hip fractures.

Overall, 6% were treated at a level 1 trauma center, 18% at a level 2 trauma center and 70% in a non-trauma center.

On average, patients stayed in the hospital for five days and waited one day for surgery.

Patients in level 1 trauma centers stayed for one day longer than those in the other settings and waited nearly eight hours longer for surgery.

Seniors treated at level 1 centers were 62% more likely to be readmitted to the hospital within a month of their surgery than seniors treated in level 2 or non-trauma settings.Seniors were also 32% more likely to develop blood clots in their legs at level 1 centers.

Patients at level 2 trauma centers had the same outcomes as those at non-trauma centers, the authors found. There was no difference between any of the groups in risk of death, bed sores, or pneumonia, however.

"We now know that it is important to treat patients with hip fractures as quickly as possible," said Metcalfe, noting that older adults who wait too long for treatment may be at risk for bed sores, blood clots, and lung infections.

"The concern is that this delay will lead to increasing length of stay in hospital as well as increased complications for the patients because they spend longer in bed waiting for surgery," said Dr. Chris Gooding, a surgeon at Addenbrookes Hospital, a level 1 trauma center in Cambridge, UK. Gooding was not involved in the study.

"This is an important subject as in developed countries we have an aging population and as a result we are seeing increasing numbers of patients with hip fractures," Gooding told Reuters Health by email.

At the same time, Gooding noted, there are also a growing number of level 1 trauma centers.

"One of the best ways to help these patients is to get their operation done quickly so that they can start walking again and return to their own homes as soon as possible," Metcalfe advised.

(Reuters Health) - Elderly patients with hip fractures may get better care at smaller hospitals, a new study suggests. Seniors with hip fractures waited longer for surgery and were more likely to be rehospitalized if they were treated at a major trauma center than if they went to a smaller emergency room, researchers found.

Seniors in level 1 trauma centers were also more likely to develop blood clots in their legs, compared to their peers who were treated in settings designed for less serious injuries, the researchers reported March 11 in the journal Medical Care.

Level 1 trauma centers have the resources to treat very serious injuries, said lead author Dr. David Metcalfe of Brigham and Women's Hospital in Boston.

"However, because they care for the most complex patients, these hospitals are often very busy. There is therefore a risk that some groups of patients might be disadvantaged or 'lost' in the system," Metcalfe told Reuters Health by email.

For example, patients with multiple injuries or bones breaking through skin may be treated before seniors with hip fractures.

Each year in the U.S. alone, more than 250,000 people aged 65 and older are hospitalized for hip fractures, according to the Centers for Disease Control and Prevention.

The study team used statewide data from California on 91,401 seniors hospitalized between 2007 and 2011. All were over age 65 and had surgery for hip fractures.

Overall, 6% were treated at a level 1 trauma center, 18% at a level 2 trauma center and 70% in a non-trauma center.

On average, patients stayed in the hospital for five days and waited one day for surgery.

Patients in level 1 trauma centers stayed for one day longer than those in the other settings and waited nearly eight hours longer for surgery.

Seniors treated at level 1 centers were 62% more likely to be readmitted to the hospital within a month of their surgery than seniors treated in level 2 or non-trauma settings.Seniors were also 32% more likely to develop blood clots in their legs at level 1 centers.

Patients at level 2 trauma centers had the same outcomes as those at non-trauma centers, the authors found. There was no difference between any of the groups in risk of death, bed sores, or pneumonia, however.

"We now know that it is important to treat patients with hip fractures as quickly as possible," said Metcalfe, noting that older adults who wait too long for treatment may be at risk for bed sores, blood clots, and lung infections.

"The concern is that this delay will lead to increasing length of stay in hospital as well as increased complications for the patients because they spend longer in bed waiting for surgery," said Dr. Chris Gooding, a surgeon at Addenbrookes Hospital, a level 1 trauma center in Cambridge, UK. Gooding was not involved in the study.

"This is an important subject as in developed countries we have an aging population and as a result we are seeing increasing numbers of patients with hip fractures," Gooding told Reuters Health by email.

At the same time, Gooding noted, there are also a growing number of level 1 trauma centers.

"One of the best ways to help these patients is to get their operation done quickly so that they can start walking again and return to their own homes as soon as possible," Metcalfe advised.

Micrograph showing B-ALL

Combining a MEK inhibitor and a BCL-2/BCL-XL inhibitor may be a feasible treatment option for B-cell acute lymphoblastic leukemia (B-ALL), according to preclinical research published in Cell Death and Disease.

Researchers found that, when given alone, the MEK inhibitor trametinib did not block B-ALL cell growth.

And the BCL-2/BCL-XL inhibitors navitoclax (ABT-263) and venetoclax (ABT-199) did not prove particularly effective either.

However, combining trametinib with navitoclax or venetoclax successfully induced apoptosis in B-ALL cells.

“Cancer cells often outwit us by rewiring themselves, but this early research offers a promising idea to get ahead of them,” said study author Richard Marais, PhD, of the Cancer Research UK Manchester Institute.

“We’ll still need to do further research to prove that this is the case beyond cancer cells in the laboratory, and it may take many years before we see it in the clinic, but it’s the first step to finding a new, effective drug combination for B-cell acute lymphoblastic leukemia.”

Dr Marais and his colleagues found that, although the MEK/ERK pathway is activated in B-ALL cells driven by different oncogenes, MEK inhibition alone did not suppress B-ALL cell growth.

And although B-ALL cells were sensitive to treatment with navitoclax or venetoclax alone, the researchers did not see complete loss of cell viability at clinically achievable doses.

However, trametinib did synergize with either navitoclax or venetoclax to suppress proliferation and induce apoptosis in B-ALL cells.

Further investigation revealed that the resistance of B-ALL cells to BCL-2/BCL-XL inhibition is mediated by MCL-1. And the synergism between trametinib and navitoclax/venetoclax is mediated by the pro-apoptotic factor BIM.

BIM is dephosphorylated as a result of MEK inhibition, which allows it to bind to and neutralize MCL-1, thereby enhancing BCL-2/BCL-XL inhibitor-induced cell death.

The researchers said they observed this effect in B-ALL cells driven by a range of genetic abnormalities, so the combination of a MEK inhibitor and a BCL-2/BCL-XL inhibitor could have therapeutic potential in a range of B-ALL subtypes.

Micrograph showing B-ALL

Combining a MEK inhibitor and a BCL-2/BCL-XL inhibitor may be a feasible treatment option for B-cell acute lymphoblastic leukemia (B-ALL), according to preclinical research published in Cell Death and Disease.

Researchers found that, when given alone, the MEK inhibitor trametinib did not block B-ALL cell growth.

And the BCL-2/BCL-XL inhibitors navitoclax (ABT-263) and venetoclax (ABT-199) did not prove particularly effective either.

However, combining trametinib with navitoclax or venetoclax successfully induced apoptosis in B-ALL cells.

“Cancer cells often outwit us by rewiring themselves, but this early research offers a promising idea to get ahead of them,” said study author Richard Marais, PhD, of the Cancer Research UK Manchester Institute.

“We’ll still need to do further research to prove that this is the case beyond cancer cells in the laboratory, and it may take many years before we see it in the clinic, but it’s the first step to finding a new, effective drug combination for B-cell acute lymphoblastic leukemia.”

Dr Marais and his colleagues found that, although the MEK/ERK pathway is activated in B-ALL cells driven by different oncogenes, MEK inhibition alone did not suppress B-ALL cell growth.

And although B-ALL cells were sensitive to treatment with navitoclax or venetoclax alone, the researchers did not see complete loss of cell viability at clinically achievable doses.

However, trametinib did synergize with either navitoclax or venetoclax to suppress proliferation and induce apoptosis in B-ALL cells.

Further investigation revealed that the resistance of B-ALL cells to BCL-2/BCL-XL inhibition is mediated by MCL-1. And the synergism between trametinib and navitoclax/venetoclax is mediated by the pro-apoptotic factor BIM.

BIM is dephosphorylated as a result of MEK inhibition, which allows it to bind to and neutralize MCL-1, thereby enhancing BCL-2/BCL-XL inhibitor-induced cell death.

The researchers said they observed this effect in B-ALL cells driven by a range of genetic abnormalities, so the combination of a MEK inhibitor and a BCL-2/BCL-XL inhibitor could have therapeutic potential in a range of B-ALL subtypes.

Micrograph showing B-ALL

Combining a MEK inhibitor and a BCL-2/BCL-XL inhibitor may be a feasible treatment option for B-cell acute lymphoblastic leukemia (B-ALL), according to preclinical research published in Cell Death and Disease.

Researchers found that, when given alone, the MEK inhibitor trametinib did not block B-ALL cell growth.

And the BCL-2/BCL-XL inhibitors navitoclax (ABT-263) and venetoclax (ABT-199) did not prove particularly effective either.

However, combining trametinib with navitoclax or venetoclax successfully induced apoptosis in B-ALL cells.

“Cancer cells often outwit us by rewiring themselves, but this early research offers a promising idea to get ahead of them,” said study author Richard Marais, PhD, of the Cancer Research UK Manchester Institute.

“We’ll still need to do further research to prove that this is the case beyond cancer cells in the laboratory, and it may take many years before we see it in the clinic, but it’s the first step to finding a new, effective drug combination for B-cell acute lymphoblastic leukemia.”

Dr Marais and his colleagues found that, although the MEK/ERK pathway is activated in B-ALL cells driven by different oncogenes, MEK inhibition alone did not suppress B-ALL cell growth.

And although B-ALL cells were sensitive to treatment with navitoclax or venetoclax alone, the researchers did not see complete loss of cell viability at clinically achievable doses.

However, trametinib did synergize with either navitoclax or venetoclax to suppress proliferation and induce apoptosis in B-ALL cells.

Further investigation revealed that the resistance of B-ALL cells to BCL-2/BCL-XL inhibition is mediated by MCL-1. And the synergism between trametinib and navitoclax/venetoclax is mediated by the pro-apoptotic factor BIM.

BIM is dephosphorylated as a result of MEK inhibition, which allows it to bind to and neutralize MCL-1, thereby enhancing BCL-2/BCL-XL inhibitor-induced cell death.

The researchers said they observed this effect in B-ALL cells driven by a range of genetic abnormalities, so the combination of a MEK inhibitor and a BCL-2/BCL-XL inhibitor could have therapeutic potential in a range of B-ALL subtypes.

Bride and groom

Photo by Alena Kratochvilova

Results from two new studies provide a possible explanation for the link between marital status and survival in cancer patients.

Previous studies have shown that married cancer patients are more likely to survive and tend to have longer survival times than unmarried cancer patients.

Now, a pair of studies published in Cancer suggest it is the social support a patient receives from a spouse that may improve the patient’s outcome.

In the first study, Scarlett Lin Gomez, PhD, of the Cancer Prevention Institute of California, and her colleagues assessed the impact of socioeconomic factors and marital status on survival in cancer patients.

The team found evidence to suggest that economic resources play a minimal role in explaining the inferior survival observed in unmarried cancer patients.

In the second study, María Elena Martínez, PhD, of UC San Diego Moores Cancer Center, and her colleagues assessed the roles that race/ethnicity, sex, and nativity play in the survival of married and unmarried cancer patients.

The group found that not being married was associated with higher mortality, but the association varied by race/ethnicity and sex. The researchers believe these differences can be explained by the differences in social support networks between racial/ethnic groups and between men and women.

Patient cohort

Both studies were conducted on the same cohort of patients from the California Cancer Registry.

The researchers studied 783,167 cancer patients—393,470 males and 389,697 females. They were diagnosed from 2000 through 2009 with a first primary, invasive cancer of the 10 most common sites of cancer-related death for each sex, which included leukemias and lymphomas.

The patients were followed through December 31, 2012. A total of 386,607 patients died from any cause—204,007 males and 182,600 females.

Economic factors

Dr Gomez and her colleagues evaluated health insurance status and neighborhood socioeconomic status for the nearly 800,000 patients.

The researchers found that unmarried cancer patients had a greater risk of death than married patients, and this risk was higher among males than females. The hazard ratio (HR) for males was 1.27 (95% CI, 1.26-1.29), and the HR for females was 1.19 (95% CI, 1.18-1.20, P-interaction <0.001).

When the researchers adjusted for insurance status and neighborhood socioeconomic status, the marital status HRs decreased to 1.22 (95% CI, 1.21–1.24) for males and 1.15 (95% CI, 1.14–1.16) for females.

Based on these results, the researchers concluded that the survival benefit of marriage operates independently of the economic resources evaluated in this study.

“While other studies have found similar protective effects associated with being married, ours is the first in a large, population-based setting to assess the extent to which economic resources explain these protective effects,” Dr Gomez said. “Our study provides evidence for social support as a key driver.”

Race/ethnicity, nativity, and sex

Dr Martínez and her colleagues found that all-cause mortality was higher in the unmarried patients than in the married patients, but this varied significantly according to race/ethnicity and sex.

Marriage conferred less of a survival benefit for women than for men. However, for both sexes, non-Hispanic whites benefitted the most from being married, and Hispanics and Asian Pacific Islanders benefitted less.

Among males, the adjusted HRs were 1.24 (95% CI, 1.23-1.26) in non-Hispanic whites, 1.20 (95% CI, 1.16-1.24) in blacks, 1.20 (95% CI, 1.17-1.23) in Hispanics, and 1.11 (95% CI, 1.07-1.15) in Asian Pacific Islanders.

In females, the adjusted HRs were 1.17 (95% CI, 1.15-1.18) in non-Hispanic whites, 1.09 (95% CI, 1.05-1.13) in blacks, 1.11 (95% CI, 1.08-1.14) in Hispanics, and 1.07 (95% CI, 1.04-1.11) in Asian Pacific Islanders.

The researchers also found that all-cause mortality associated with unmarried status was higher in US-born Asian Pacific Islander and Hispanic men and women relative to their foreign-born counterparts.

“The results suggest that the more acculturated you become to US culture, the more it impacts cancer survivorship,” Dr Martínez said. “Our hypothesis is that non-Hispanic whites don’t have the same social network as other cultures that have stronger bonds with family and friends outside of marriage.”

“As individuals acculturate, they tend to lose those bonds. It’s also been shown that women seek out help for health concerns more frequently than men, and women tend to remind spouses to see their physicians and live a healthy lifestyle.”

Bride and groom

Photo by Alena Kratochvilova

Results from two new studies provide a possible explanation for the link between marital status and survival in cancer patients.

Previous studies have shown that married cancer patients are more likely to survive and tend to have longer survival times than unmarried cancer patients.

Now, a pair of studies published in Cancer suggest it is the social support a patient receives from a spouse that may improve the patient’s outcome.

In the first study, Scarlett Lin Gomez, PhD, of the Cancer Prevention Institute of California, and her colleagues assessed the impact of socioeconomic factors and marital status on survival in cancer patients.

The team found evidence to suggest that economic resources play a minimal role in explaining the inferior survival observed in unmarried cancer patients.

In the second study, María Elena Martínez, PhD, of UC San Diego Moores Cancer Center, and her colleagues assessed the roles that race/ethnicity, sex, and nativity play in the survival of married and unmarried cancer patients.

The group found that not being married was associated with higher mortality, but the association varied by race/ethnicity and sex. The researchers believe these differences can be explained by the differences in social support networks between racial/ethnic groups and between men and women.

Patient cohort

Both studies were conducted on the same cohort of patients from the California Cancer Registry.

The researchers studied 783,167 cancer patients—393,470 males and 389,697 females. They were diagnosed from 2000 through 2009 with a first primary, invasive cancer of the 10 most common sites of cancer-related death for each sex, which included leukemias and lymphomas.

The patients were followed through December 31, 2012. A total of 386,607 patients died from any cause—204,007 males and 182,600 females.

Economic factors

Dr Gomez and her colleagues evaluated health insurance status and neighborhood socioeconomic status for the nearly 800,000 patients.

The researchers found that unmarried cancer patients had a greater risk of death than married patients, and this risk was higher among males than females. The hazard ratio (HR) for males was 1.27 (95% CI, 1.26-1.29), and the HR for females was 1.19 (95% CI, 1.18-1.20, P-interaction <0.001).

When the researchers adjusted for insurance status and neighborhood socioeconomic status, the marital status HRs decreased to 1.22 (95% CI, 1.21–1.24) for males and 1.15 (95% CI, 1.14–1.16) for females.

Based on these results, the researchers concluded that the survival benefit of marriage operates independently of the economic resources evaluated in this study.

“While other studies have found similar protective effects associated with being married, ours is the first in a large, population-based setting to assess the extent to which economic resources explain these protective effects,” Dr Gomez said. “Our study provides evidence for social support as a key driver.”

Race/ethnicity, nativity, and sex

Dr Martínez and her colleagues found that all-cause mortality was higher in the unmarried patients than in the married patients, but this varied significantly according to race/ethnicity and sex.

Marriage conferred less of a survival benefit for women than for men. However, for both sexes, non-Hispanic whites benefitted the most from being married, and Hispanics and Asian Pacific Islanders benefitted less.

Among males, the adjusted HRs were 1.24 (95% CI, 1.23-1.26) in non-Hispanic whites, 1.20 (95% CI, 1.16-1.24) in blacks, 1.20 (95% CI, 1.17-1.23) in Hispanics, and 1.11 (95% CI, 1.07-1.15) in Asian Pacific Islanders.

In females, the adjusted HRs were 1.17 (95% CI, 1.15-1.18) in non-Hispanic whites, 1.09 (95% CI, 1.05-1.13) in blacks, 1.11 (95% CI, 1.08-1.14) in Hispanics, and 1.07 (95% CI, 1.04-1.11) in Asian Pacific Islanders.

The researchers also found that all-cause mortality associated with unmarried status was higher in US-born Asian Pacific Islander and Hispanic men and women relative to their foreign-born counterparts.

“The results suggest that the more acculturated you become to US culture, the more it impacts cancer survivorship,” Dr Martínez said. “Our hypothesis is that non-Hispanic whites don’t have the same social network as other cultures that have stronger bonds with family and friends outside of marriage.”

“As individuals acculturate, they tend to lose those bonds. It’s also been shown that women seek out help for health concerns more frequently than men, and women tend to remind spouses to see their physicians and live a healthy lifestyle.”

Bride and groom

Photo by Alena Kratochvilova

Results from two new studies provide a possible explanation for the link between marital status and survival in cancer patients.

Previous studies have shown that married cancer patients are more likely to survive and tend to have longer survival times than unmarried cancer patients.

Now, a pair of studies published in Cancer suggest it is the social support a patient receives from a spouse that may improve the patient’s outcome.

In the first study, Scarlett Lin Gomez, PhD, of the Cancer Prevention Institute of California, and her colleagues assessed the impact of socioeconomic factors and marital status on survival in cancer patients.

The team found evidence to suggest that economic resources play a minimal role in explaining the inferior survival observed in unmarried cancer patients.

In the second study, María Elena Martínez, PhD, of UC San Diego Moores Cancer Center, and her colleagues assessed the roles that race/ethnicity, sex, and nativity play in the survival of married and unmarried cancer patients.

The group found that not being married was associated with higher mortality, but the association varied by race/ethnicity and sex. The researchers believe these differences can be explained by the differences in social support networks between racial/ethnic groups and between men and women.

Patient cohort

Both studies were conducted on the same cohort of patients from the California Cancer Registry.

The researchers studied 783,167 cancer patients—393,470 males and 389,697 females. They were diagnosed from 2000 through 2009 with a first primary, invasive cancer of the 10 most common sites of cancer-related death for each sex, which included leukemias and lymphomas.

The patients were followed through December 31, 2012. A total of 386,607 patients died from any cause—204,007 males and 182,600 females.

Economic factors

Dr Gomez and her colleagues evaluated health insurance status and neighborhood socioeconomic status for the nearly 800,000 patients.

The researchers found that unmarried cancer patients had a greater risk of death than married patients, and this risk was higher among males than females. The hazard ratio (HR) for males was 1.27 (95% CI, 1.26-1.29), and the HR for females was 1.19 (95% CI, 1.18-1.20, P-interaction <0.001).

When the researchers adjusted for insurance status and neighborhood socioeconomic status, the marital status HRs decreased to 1.22 (95% CI, 1.21–1.24) for males and 1.15 (95% CI, 1.14–1.16) for females.

Based on these results, the researchers concluded that the survival benefit of marriage operates independently of the economic resources evaluated in this study.

“While other studies have found similar protective effects associated with being married, ours is the first in a large, population-based setting to assess the extent to which economic resources explain these protective effects,” Dr Gomez said. “Our study provides evidence for social support as a key driver.”

Race/ethnicity, nativity, and sex

Dr Martínez and her colleagues found that all-cause mortality was higher in the unmarried patients than in the married patients, but this varied significantly according to race/ethnicity and sex.

Marriage conferred less of a survival benefit for women than for men. However, for both sexes, non-Hispanic whites benefitted the most from being married, and Hispanics and Asian Pacific Islanders benefitted less.

Among males, the adjusted HRs were 1.24 (95% CI, 1.23-1.26) in non-Hispanic whites, 1.20 (95% CI, 1.16-1.24) in blacks, 1.20 (95% CI, 1.17-1.23) in Hispanics, and 1.11 (95% CI, 1.07-1.15) in Asian Pacific Islanders.

In females, the adjusted HRs were 1.17 (95% CI, 1.15-1.18) in non-Hispanic whites, 1.09 (95% CI, 1.05-1.13) in blacks, 1.11 (95% CI, 1.08-1.14) in Hispanics, and 1.07 (95% CI, 1.04-1.11) in Asian Pacific Islanders.

The researchers also found that all-cause mortality associated with unmarried status was higher in US-born Asian Pacific Islander and Hispanic men and women relative to their foreign-born counterparts.

“The results suggest that the more acculturated you become to US culture, the more it impacts cancer survivorship,” Dr Martínez said. “Our hypothesis is that non-Hispanic whites don’t have the same social network as other cultures that have stronger bonds with family and friends outside of marriage.”

“As individuals acculturate, they tend to lose those bonds. It’s also been shown that women seek out help for health concerns more frequently than men, and women tend to remind spouses to see their physicians and live a healthy lifestyle.”

CHICAGO – CMX-2043, a novel agent intended for prevention of contrast-induced nephropathy, failed in the phase II, double-blind, placebo-controlled CARIN clinical trial presented at the annual meeting of the American College of Cardiology.

The drug had also shown promise in small preliminary studies for the prevention of periprocedural myocardial infarction in patients undergoing coronary stenting. There again, however, CMX-2043 – a derivative of alpha lipoic acid with antioxidant and cell membrane–stabilizing properties – proved ineffective in the 361-patient, 31-center phase II trial, reported Dr. Deepak L. Bhatt, professor of medicine at Harvard Medical School and executive director of interventional cardiovascular programs at Brigham and Women’s Hospital, both in Boston.

All participants in CARIN had baseline severe impairment of kidney function or mild to moderate renal impairment plus another risk factor, such as diabetes or age greater than 75 years. One hour prior to coronary angiography, they received various doses of CMX-2043 or placebo.

Unfortunately, no difference between the four treatment arms was present in terms of the primary study endpoint: the incidence of acute kidney injury as defined by at least a 0.3 mg/dL rise in serum creatinine from baseline on day 4. No dose response to CMX-2043 was evident, nor did the investigational agent have any impact on the risk of major adverse cardiovascular events.

Immediately prior to Dr. Bhatt’s presentation, Dr. Michelle L. O’Donoghue of Brigham and Women’s Hospital presented the equally negative results of the LATITUDE-TIMI 60 trial, a phase III trial of the investigational mitogen-activated protein kinase inhibitor losmapimod, a drug developed to improve outcomes in patients with an acute coronary syndrome.

“It’s a bit distressing” to witness back to back presentations of clinical trials that proved resoundingly negative despite very strong-looking preliminary data, commented discussant Dr. Anthony N. DeMaria, professor of medicine at the University of California, San Diego. What’s going on here? he asked.

“I think it’s a fundamental truth that a lot of things that look good in preclinical work, even when backed up by a lot of solid science, don’t pan out in human studies,” Dr. Bhatt replied. “That’s a challenge, and probably in no other arena more so than in tackling inflammation and antioxidant therapy.

“There’s a graveyard of compounds that have not worked, and now we’ve perhaps added another one,” Dr. Bhatt continued. “But it doesn’t mean that scientific inquiry isn’t important, because I think eventually we’ll have drugs for these problems, whether it’s reperfusion injury or contrast-induced nephropathy. It’ll probably just take a lot more time and effort.”

The one solace regarding the CARIN trial, in Dr. Bhatt’s view, is that it highlighted the advantages of what is known as an adaptive trial design. Instead of jumping from positive early-phase results straight to a definitive 10,000-patient phase III clinical trial, investigators were able to obtain answers regarding the drug’s ability to prevent two major problems in patients undergoing coronary angiography – contrast-induced nephropathy and major adverse cardiac events – by means of a single 361-patient trial that was comparatively inexpensive.

Acute kidney injury secondary to exposure to contrast agents remains a significant problem, with an incidence of 20%-25% in high-risk patients. Numerous proposed prophylactic agents have ultimately proved not useful, including sodium bicarbonate, N-acetylcysteine, and intravenous fenoldopam.

Indeed, the only preventive measures of proven effectiveness are hydration with saline for 12 hours preangioplasty, and limiting the volume of contrast agent used. In real-world clinical practice, however, it’s often impractical to administer the optimal 12 hours of saline because of hospital pressure to get patients out quickly, Dr. Bhatt observed.

“There remains an important unmet clinical need to find agents that reduce the occurrence of contrast nephropathy,” he stressed.

Ischemix funded the CARIN trial. Dr. Bhatt reported receiving a research grant from the company that was directed to Brigham and Women’s Hospital.

[email protected]

CHICAGO – CMX-2043, a novel agent intended for prevention of contrast-induced nephropathy, failed in the phase II, double-blind, placebo-controlled CARIN clinical trial presented at the annual meeting of the American College of Cardiology.

The drug had also shown promise in small preliminary studies for the prevention of periprocedural myocardial infarction in patients undergoing coronary stenting. There again, however, CMX-2043 – a derivative of alpha lipoic acid with antioxidant and cell membrane–stabilizing properties – proved ineffective in the 361-patient, 31-center phase II trial, reported Dr. Deepak L. Bhatt, professor of medicine at Harvard Medical School and executive director of interventional cardiovascular programs at Brigham and Women’s Hospital, both in Boston.

All participants in CARIN had baseline severe impairment of kidney function or mild to moderate renal impairment plus another risk factor, such as diabetes or age greater than 75 years. One hour prior to coronary angiography, they received various doses of CMX-2043 or placebo.

Unfortunately, no difference between the four treatment arms was present in terms of the primary study endpoint: the incidence of acute kidney injury as defined by at least a 0.3 mg/dL rise in serum creatinine from baseline on day 4. No dose response to CMX-2043 was evident, nor did the investigational agent have any impact on the risk of major adverse cardiovascular events.

Immediately prior to Dr. Bhatt’s presentation, Dr. Michelle L. O’Donoghue of Brigham and Women’s Hospital presented the equally negative results of the LATITUDE-TIMI 60 trial, a phase III trial of the investigational mitogen-activated protein kinase inhibitor losmapimod, a drug developed to improve outcomes in patients with an acute coronary syndrome.

“It’s a bit distressing” to witness back to back presentations of clinical trials that proved resoundingly negative despite very strong-looking preliminary data, commented discussant Dr. Anthony N. DeMaria, professor of medicine at the University of California, San Diego. What’s going on here? he asked.

“I think it’s a fundamental truth that a lot of things that look good in preclinical work, even when backed up by a lot of solid science, don’t pan out in human studies,” Dr. Bhatt replied. “That’s a challenge, and probably in no other arena more so than in tackling inflammation and antioxidant therapy.

“There’s a graveyard of compounds that have not worked, and now we’ve perhaps added another one,” Dr. Bhatt continued. “But it doesn’t mean that scientific inquiry isn’t important, because I think eventually we’ll have drugs for these problems, whether it’s reperfusion injury or contrast-induced nephropathy. It’ll probably just take a lot more time and effort.”

The one solace regarding the CARIN trial, in Dr. Bhatt’s view, is that it highlighted the advantages of what is known as an adaptive trial design. Instead of jumping from positive early-phase results straight to a definitive 10,000-patient phase III clinical trial, investigators were able to obtain answers regarding the drug’s ability to prevent two major problems in patients undergoing coronary angiography – contrast-induced nephropathy and major adverse cardiac events – by means of a single 361-patient trial that was comparatively inexpensive.

Acute kidney injury secondary to exposure to contrast agents remains a significant problem, with an incidence of 20%-25% in high-risk patients. Numerous proposed prophylactic agents have ultimately proved not useful, including sodium bicarbonate, N-acetylcysteine, and intravenous fenoldopam.

Indeed, the only preventive measures of proven effectiveness are hydration with saline for 12 hours preangioplasty, and limiting the volume of contrast agent used. In real-world clinical practice, however, it’s often impractical to administer the optimal 12 hours of saline because of hospital pressure to get patients out quickly, Dr. Bhatt observed.

“There remains an important unmet clinical need to find agents that reduce the occurrence of contrast nephropathy,” he stressed.

Ischemix funded the CARIN trial. Dr. Bhatt reported receiving a research grant from the company that was directed to Brigham and Women’s Hospital.

[email protected]

CHICAGO – CMX-2043, a novel agent intended for prevention of contrast-induced nephropathy, failed in the phase II, double-blind, placebo-controlled CARIN clinical trial presented at the annual meeting of the American College of Cardiology.

The drug had also shown promise in small preliminary studies for the prevention of periprocedural myocardial infarction in patients undergoing coronary stenting. There again, however, CMX-2043 – a derivative of alpha lipoic acid with antioxidant and cell membrane–stabilizing properties – proved ineffective in the 361-patient, 31-center phase II trial, reported Dr. Deepak L. Bhatt, professor of medicine at Harvard Medical School and executive director of interventional cardiovascular programs at Brigham and Women’s Hospital, both in Boston.

All participants in CARIN had baseline severe impairment of kidney function or mild to moderate renal impairment plus another risk factor, such as diabetes or age greater than 75 years. One hour prior to coronary angiography, they received various doses of CMX-2043 or placebo.

Unfortunately, no difference between the four treatment arms was present in terms of the primary study endpoint: the incidence of acute kidney injury as defined by at least a 0.3 mg/dL rise in serum creatinine from baseline on day 4. No dose response to CMX-2043 was evident, nor did the investigational agent have any impact on the risk of major adverse cardiovascular events.

Immediately prior to Dr. Bhatt’s presentation, Dr. Michelle L. O’Donoghue of Brigham and Women’s Hospital presented the equally negative results of the LATITUDE-TIMI 60 trial, a phase III trial of the investigational mitogen-activated protein kinase inhibitor losmapimod, a drug developed to improve outcomes in patients with an acute coronary syndrome.

“It’s a bit distressing” to witness back to back presentations of clinical trials that proved resoundingly negative despite very strong-looking preliminary data, commented discussant Dr. Anthony N. DeMaria, professor of medicine at the University of California, San Diego. What’s going on here? he asked.

“I think it’s a fundamental truth that a lot of things that look good in preclinical work, even when backed up by a lot of solid science, don’t pan out in human studies,” Dr. Bhatt replied. “That’s a challenge, and probably in no other arena more so than in tackling inflammation and antioxidant therapy.

“There’s a graveyard of compounds that have not worked, and now we’ve perhaps added another one,” Dr. Bhatt continued. “But it doesn’t mean that scientific inquiry isn’t important, because I think eventually we’ll have drugs for these problems, whether it’s reperfusion injury or contrast-induced nephropathy. It’ll probably just take a lot more time and effort.”

The one solace regarding the CARIN trial, in Dr. Bhatt’s view, is that it highlighted the advantages of what is known as an adaptive trial design. Instead of jumping from positive early-phase results straight to a definitive 10,000-patient phase III clinical trial, investigators were able to obtain answers regarding the drug’s ability to prevent two major problems in patients undergoing coronary angiography – contrast-induced nephropathy and major adverse cardiac events – by means of a single 361-patient trial that was comparatively inexpensive.

Acute kidney injury secondary to exposure to contrast agents remains a significant problem, with an incidence of 20%-25% in high-risk patients. Numerous proposed prophylactic agents have ultimately proved not useful, including sodium bicarbonate, N-acetylcysteine, and intravenous fenoldopam.

Indeed, the only preventive measures of proven effectiveness are hydration with saline for 12 hours preangioplasty, and limiting the volume of contrast agent used. In real-world clinical practice, however, it’s often impractical to administer the optimal 12 hours of saline because of hospital pressure to get patients out quickly, Dr. Bhatt observed.

“There remains an important unmet clinical need to find agents that reduce the occurrence of contrast nephropathy,” he stressed.

Ischemix funded the CARIN trial. Dr. Bhatt reported receiving a research grant from the company that was directed to Brigham and Women’s Hospital.

[email protected]

LOS ANGELES – Children who pass oral food challenges to baked egg and milk with wheat flour are at risk for reacting to baked goods made with nonwheat flours, according to a review of more than 200 pediatric food challenges at National Jewish Health in Denver.

The children were already known to be sensitive to egg and milk, and some were being challenged to see if exposure therapy was helping. Unbeknown to the pediatric food allergy team, a kitchen worker at National Jewish had started making muffins with rice flour, thinking it would be safer.

During the month of muffins with rice flour, the failure rate for baked egg challenge muffins rose from 28% (33/120) to 58% (11/19) with rice flour. Failure to baked milk muffins rose from 14% (9/66) to 36% (5/14) (J Allergy Clin Immunol. 2016 Feb. doi: 10.1016/j.jaci.2015.12.579).

Adjusting for age, gender, and atopic dermatitis, children were more than five times more likely to fail baked eggs without wheat (odds ratio, 5.4; P = .002), and more than four times more likely to fail baked milk (OR, 4.06; P = .05).

Given that the phenomenon hasn’t been reported before, “This was very surprising to us,” said study investigator Dr. Bruce Lanser, director of the pediatric food allergy program at National Jewish. “You have to warn parents that if children pass a baked challenge with wheat, they have to continue to eat their baked milk and egg with wheat. Gluten-free products are not going to have the same effect.

“If somebody is avoiding wheat because it causes a bit of redness and itchiness, you have to clear that wheat allergy” before moving to baked egg and milk, Dr. Lanser added.

There’s also concern that “kids will go home after passing a wheat muffin challenge, eat something that’s gluten-free, and have a reaction,” he noted. Wheat-free baked goods might also not build tolerance as well, although that’s not clear from the study, Dr. Lanser said at the annual meeting of the American Academy of Allergy, Asthma, and Immunology.

Wheat seems to have something unique that alters the allergic properties of egg and milk proteins to help children outgrow their sensitivities. “Rice doesn’t have the same effect,” he observed, and it’s not known if any other grains do. Dr. Lanser said he is interested in looking into rye, barley, oats, and other alternatives.

The mean age of the children in the study was 6 years, and most children had multiple food allergies. Sensitization was confirmed by skin tests and specific IgE.

Meanwhile, there’s a new rule in the National Jewish kitchen: Unless a child has true celiac disease, “always make [challenge] muffins with wheat,” Dr. Lanser said.

There was no industry funding for the work, and the investigators had no disclosures.

[email protected]

LOS ANGELES – Children who pass oral food challenges to baked egg and milk with wheat flour are at risk for reacting to baked goods made with nonwheat flours, according to a review of more than 200 pediatric food challenges at National Jewish Health in Denver.

The children were already known to be sensitive to egg and milk, and some were being challenged to see if exposure therapy was helping. Unbeknown to the pediatric food allergy team, a kitchen worker at National Jewish had started making muffins with rice flour, thinking it would be safer.

During the month of muffins with rice flour, the failure rate for baked egg challenge muffins rose from 28% (33/120) to 58% (11/19) with rice flour. Failure to baked milk muffins rose from 14% (9/66) to 36% (5/14) (J Allergy Clin Immunol. 2016 Feb. doi: 10.1016/j.jaci.2015.12.579).

Adjusting for age, gender, and atopic dermatitis, children were more than five times more likely to fail baked eggs without wheat (odds ratio, 5.4; P = .002), and more than four times more likely to fail baked milk (OR, 4.06; P = .05).

Given that the phenomenon hasn’t been reported before, “This was very surprising to us,” said study investigator Dr. Bruce Lanser, director of the pediatric food allergy program at National Jewish. “You have to warn parents that if children pass a baked challenge with wheat, they have to continue to eat their baked milk and egg with wheat. Gluten-free products are not going to have the same effect.

“If somebody is avoiding wheat because it causes a bit of redness and itchiness, you have to clear that wheat allergy” before moving to baked egg and milk, Dr. Lanser added.

There’s also concern that “kids will go home after passing a wheat muffin challenge, eat something that’s gluten-free, and have a reaction,” he noted. Wheat-free baked goods might also not build tolerance as well, although that’s not clear from the study, Dr. Lanser said at the annual meeting of the American Academy of Allergy, Asthma, and Immunology.

Wheat seems to have something unique that alters the allergic properties of egg and milk proteins to help children outgrow their sensitivities. “Rice doesn’t have the same effect,” he observed, and it’s not known if any other grains do. Dr. Lanser said he is interested in looking into rye, barley, oats, and other alternatives.

The mean age of the children in the study was 6 years, and most children had multiple food allergies. Sensitization was confirmed by skin tests and specific IgE.

Meanwhile, there’s a new rule in the National Jewish kitchen: Unless a child has true celiac disease, “always make [challenge] muffins with wheat,” Dr. Lanser said.

There was no industry funding for the work, and the investigators had no disclosures.

[email protected]

LOS ANGELES – Children who pass oral food challenges to baked egg and milk with wheat flour are at risk for reacting to baked goods made with nonwheat flours, according to a review of more than 200 pediatric food challenges at National Jewish Health in Denver.

The children were already known to be sensitive to egg and milk, and some were being challenged to see if exposure therapy was helping. Unbeknown to the pediatric food allergy team, a kitchen worker at National Jewish had started making muffins with rice flour, thinking it would be safer.

During the month of muffins with rice flour, the failure rate for baked egg challenge muffins rose from 28% (33/120) to 58% (11/19) with rice flour. Failure to baked milk muffins rose from 14% (9/66) to 36% (5/14) (J Allergy Clin Immunol. 2016 Feb. doi: 10.1016/j.jaci.2015.12.579).

Adjusting for age, gender, and atopic dermatitis, children were more than five times more likely to fail baked eggs without wheat (odds ratio, 5.4; P = .002), and more than four times more likely to fail baked milk (OR, 4.06; P = .05).

Given that the phenomenon hasn’t been reported before, “This was very surprising to us,” said study investigator Dr. Bruce Lanser, director of the pediatric food allergy program at National Jewish. “You have to warn parents that if children pass a baked challenge with wheat, they have to continue to eat their baked milk and egg with wheat. Gluten-free products are not going to have the same effect.

“If somebody is avoiding wheat because it causes a bit of redness and itchiness, you have to clear that wheat allergy” before moving to baked egg and milk, Dr. Lanser added.

There’s also concern that “kids will go home after passing a wheat muffin challenge, eat something that’s gluten-free, and have a reaction,” he noted. Wheat-free baked goods might also not build tolerance as well, although that’s not clear from the study, Dr. Lanser said at the annual meeting of the American Academy of Allergy, Asthma, and Immunology.

Wheat seems to have something unique that alters the allergic properties of egg and milk proteins to help children outgrow their sensitivities. “Rice doesn’t have the same effect,” he observed, and it’s not known if any other grains do. Dr. Lanser said he is interested in looking into rye, barley, oats, and other alternatives.

The mean age of the children in the study was 6 years, and most children had multiple food allergies. Sensitization was confirmed by skin tests and specific IgE.

Meanwhile, there’s a new rule in the National Jewish kitchen: Unless a child has true celiac disease, “always make [challenge] muffins with wheat,” Dr. Lanser said.

There was no industry funding for the work, and the investigators had no disclosures.

[email protected]

Neonates with the highest transepidermal water loss at birth, likely mediated through an impaired epidermal barrier, show significantly elevated chymotrypsinlike protease activity and reduced levels of filaggrin-derived natural moisturizing factors, which may predispose them to the development of atopic dermatitis, according to a report published online in the British Journal of Dermatology.

John Chittock of the University of Sheffield, England, and his colleagues assessed the biophysical, biologic, and functional properties of the developing neonatal stratum corneum (SC) from birth to 4 weeks of age in 115 healthy, full-term (at least 37 weeks’ gestation) neonates from the OBSERVE (Oil in Baby Skincare) randomized study birth cohort recruited at Saint Mary’s Hospital, Central Manchester NHS Foundation Trust, between September 2013 and June 2014.

For comparative purposes, an unrelated cohort of 20 adults with healthy skin was recruited from the local community between January and April 2015 (Br J Dermatol. 2016 Mar 19. doi: 10.1111/bjd.14568).

The researchers found that the biophysical properties of the neonatal SC are transitional from birth. For example, overall transepidermal water loss (TEWL) increased significantly during the first 4 weeks of infant life. Compared with adult skin, the newborn infant SC was found to be drier and more alkaline. In addition, levels of superficial chymotrypsinlike protease activity at birth did not differ between newborns and adults, while levels of filaggrin-derived natural moisturizing factors (NMF) were significantly lower at birth than in adulthood.

The increased chymotrypsinlike protease activity and NMF at 4 weeks of age exceeded levels found in healthy adults, rather than reaching their mature state. Compared with adult skin, the skin of infants is functionally immature, with undeveloped mechanisms of desquamation and differentiation, the investigators noted.

Further analysis revealed a correlation between TEWL and both superficial chymotrypsinlike protease activity and filaggrin-derived NMF at birth.

To explore that link, the researchers stratified the neonatal cohort according to TEWL percentile. The neonates in the 76th-100th percentile, the highest TEWL at birth, showed significantly elevated chymotrypsinlike protease activity and reduced levels of filaggrin-derived NMF, compared with neonates in lower percentiles. Therefore, those neonates are at highest risk for developing atopic dermatitis, the study authors said.

The findings indicate a need for infant skin care regimens that protect and support normal barrier development from birth, the researchers noted. They also suggested that clinical strategies targeting the early mechanisms of barrier breakdown could act as preventive measures in neonates at increased risk of developing atopic dermatitis.

The research was funded jointly by the University of Sheffield and a doctoral research fellowship supported by the National Institute for Health Research. The authors declared no conflicts of interest.

Neonates with the highest transepidermal water loss at birth, likely mediated through an impaired epidermal barrier, show significantly elevated chymotrypsinlike protease activity and reduced levels of filaggrin-derived natural moisturizing factors, which may predispose them to the development of atopic dermatitis, according to a report published online in the British Journal of Dermatology.

John Chittock of the University of Sheffield, England, and his colleagues assessed the biophysical, biologic, and functional properties of the developing neonatal stratum corneum (SC) from birth to 4 weeks of age in 115 healthy, full-term (at least 37 weeks’ gestation) neonates from the OBSERVE (Oil in Baby Skincare) randomized study birth cohort recruited at Saint Mary’s Hospital, Central Manchester NHS Foundation Trust, between September 2013 and June 2014.

For comparative purposes, an unrelated cohort of 20 adults with healthy skin was recruited from the local community between January and April 2015 (Br J Dermatol. 2016 Mar 19. doi: 10.1111/bjd.14568).

The researchers found that the biophysical properties of the neonatal SC are transitional from birth. For example, overall transepidermal water loss (TEWL) increased significantly during the first 4 weeks of infant life. Compared with adult skin, the newborn infant SC was found to be drier and more alkaline. In addition, levels of superficial chymotrypsinlike protease activity at birth did not differ between newborns and adults, while levels of filaggrin-derived natural moisturizing factors (NMF) were significantly lower at birth than in adulthood.

The increased chymotrypsinlike protease activity and NMF at 4 weeks of age exceeded levels found in healthy adults, rather than reaching their mature state. Compared with adult skin, the skin of infants is functionally immature, with undeveloped mechanisms of desquamation and differentiation, the investigators noted.

Further analysis revealed a correlation between TEWL and both superficial chymotrypsinlike protease activity and filaggrin-derived NMF at birth.

To explore that link, the researchers stratified the neonatal cohort according to TEWL percentile. The neonates in the 76th-100th percentile, the highest TEWL at birth, showed significantly elevated chymotrypsinlike protease activity and reduced levels of filaggrin-derived NMF, compared with neonates in lower percentiles. Therefore, those neonates are at highest risk for developing atopic dermatitis, the study authors said.

The findings indicate a need for infant skin care regimens that protect and support normal barrier development from birth, the researchers noted. They also suggested that clinical strategies targeting the early mechanisms of barrier breakdown could act as preventive measures in neonates at increased risk of developing atopic dermatitis.

The research was funded jointly by the University of Sheffield and a doctoral research fellowship supported by the National Institute for Health Research. The authors declared no conflicts of interest.

Neonates with the highest transepidermal water loss at birth, likely mediated through an impaired epidermal barrier, show significantly elevated chymotrypsinlike protease activity and reduced levels of filaggrin-derived natural moisturizing factors, which may predispose them to the development of atopic dermatitis, according to a report published online in the British Journal of Dermatology.

John Chittock of the University of Sheffield, England, and his colleagues assessed the biophysical, biologic, and functional properties of the developing neonatal stratum corneum (SC) from birth to 4 weeks of age in 115 healthy, full-term (at least 37 weeks’ gestation) neonates from the OBSERVE (Oil in Baby Skincare) randomized study birth cohort recruited at Saint Mary’s Hospital, Central Manchester NHS Foundation Trust, between September 2013 and June 2014.

For comparative purposes, an unrelated cohort of 20 adults with healthy skin was recruited from the local community between January and April 2015 (Br J Dermatol. 2016 Mar 19. doi: 10.1111/bjd.14568).

The researchers found that the biophysical properties of the neonatal SC are transitional from birth. For example, overall transepidermal water loss (TEWL) increased significantly during the first 4 weeks of infant life. Compared with adult skin, the newborn infant SC was found to be drier and more alkaline. In addition, levels of superficial chymotrypsinlike protease activity at birth did not differ between newborns and adults, while levels of filaggrin-derived natural moisturizing factors (NMF) were significantly lower at birth than in adulthood.

The increased chymotrypsinlike protease activity and NMF at 4 weeks of age exceeded levels found in healthy adults, rather than reaching their mature state. Compared with adult skin, the skin of infants is functionally immature, with undeveloped mechanisms of desquamation and differentiation, the investigators noted.

Further analysis revealed a correlation between TEWL and both superficial chymotrypsinlike protease activity and filaggrin-derived NMF at birth.

To explore that link, the researchers stratified the neonatal cohort according to TEWL percentile. The neonates in the 76th-100th percentile, the highest TEWL at birth, showed significantly elevated chymotrypsinlike protease activity and reduced levels of filaggrin-derived NMF, compared with neonates in lower percentiles. Therefore, those neonates are at highest risk for developing atopic dermatitis, the study authors said.

The findings indicate a need for infant skin care regimens that protect and support normal barrier development from birth, the researchers noted. They also suggested that clinical strategies targeting the early mechanisms of barrier breakdown could act as preventive measures in neonates at increased risk of developing atopic dermatitis.

The research was funded jointly by the University of Sheffield and a doctoral research fellowship supported by the National Institute for Health Research. The authors declared no conflicts of interest.

As a single agent for use in patients with lymphoma, an acceptable once-daily dose of OTX015 appears to be 80 mg on a 14 days on, 7 days off schedule, the results of a phase 1 study indicate.

The small-molecule inhibitor, which inhibits binding of bromodomain and exterminal proteins to acetylated histones, was associated with acceptable toxicity and efficacy in this regimen. The investigational drug is now being tested in expansion cohorts on a schedule of 14 days every 3 weeks, a regimen projected to allow for recovery from the drug’s toxic effects, Dr. Sandy Amorin of Hôpital Saint Louis, Paris, and associates reported.

The drug also is being evaluated in patients with acute leukemias.

Adults with nonleukemia hematologic malignancies that progressed on standard therapies participated in the open-label study, which was conducted at seven university hospital centers in Europe. Oral OTX015 was given once a day at one of five doses (10 mg, 20 mg, 40 mg, 80 mg, and 120 mg). The 3 + 3 study design permitted evaluation of alternative administration schedules. The primary endpoint was dose-limiting toxicity in the first treatment cycle (21 days). Secondary objectives were to evaluate safety, pharmacokinetics, and preliminary clinical activity of OTX015. The study is ongoing and is registered with ClinicalTrials.gov, number NCT01713582.

The study included 33 patients with lymphoma and 12 with myeloma; patients’ median age was 66 years, and they had received a median of four lines of prior therapy. No dose-limiting toxicities were seen in three patients given doses as high as 80 mg once a day. However, grade 4 thrombocytopenia occurred in five of six patients on a 21-day schedule of 40 mg twice a day. No patient tolerated various schedules of 120 mg once a day (Lancet Haematol. 2016;3[4]:e196-204).

The researchers then examined the 80 mg once a day dose on a continuous basis in four patients, two of whom developed grade 4 thrombocytopenia. In light of these and other toxicities, a regimen was proposed of 80 mg once a day on a schedule of 14 days on, 7 days off.

Thrombocytopenia affected 43 of 45 patients, and 26 of them had grade 3-4 events. Other grade 3-4 events were infrequent. Anemia was seen in 41, and neutropenia in 23.

Of three patients with diffuse large B-cell lymphoma, two had complete responses at 120 mg once a day, and one had a partial response at 80 mg once a day. Six additional patients, two with diffuse large B-cell lymphoma and four with indolent lymphomas, had evidence of clinical activity, but did not meet the criteria for an objective response.

The study was funded by the developers of OTX015, Oncoethix GmbH, a wholly owned subsidiary of Merck Sharp & Dohme.

[email protected]

On Twitter @maryjodales

As a single agent for use in patients with lymphoma, an acceptable once-daily dose of OTX015 appears to be 80 mg on a 14 days on, 7 days off schedule, the results of a phase 1 study indicate.

The small-molecule inhibitor, which inhibits binding of bromodomain and exterminal proteins to acetylated histones, was associated with acceptable toxicity and efficacy in this regimen. The investigational drug is now being tested in expansion cohorts on a schedule of 14 days every 3 weeks, a regimen projected to allow for recovery from the drug’s toxic effects, Dr. Sandy Amorin of Hôpital Saint Louis, Paris, and associates reported.

The drug also is being evaluated in patients with acute leukemias.

Adults with nonleukemia hematologic malignancies that progressed on standard therapies participated in the open-label study, which was conducted at seven university hospital centers in Europe. Oral OTX015 was given once a day at one of five doses (10 mg, 20 mg, 40 mg, 80 mg, and 120 mg). The 3 + 3 study design permitted evaluation of alternative administration schedules. The primary endpoint was dose-limiting toxicity in the first treatment cycle (21 days). Secondary objectives were to evaluate safety, pharmacokinetics, and preliminary clinical activity of OTX015. The study is ongoing and is registered with ClinicalTrials.gov, number NCT01713582.

The study included 33 patients with lymphoma and 12 with myeloma; patients’ median age was 66 years, and they had received a median of four lines of prior therapy. No dose-limiting toxicities were seen in three patients given doses as high as 80 mg once a day. However, grade 4 thrombocytopenia occurred in five of six patients on a 21-day schedule of 40 mg twice a day. No patient tolerated various schedules of 120 mg once a day (Lancet Haematol. 2016;3[4]:e196-204).

The researchers then examined the 80 mg once a day dose on a continuous basis in four patients, two of whom developed grade 4 thrombocytopenia. In light of these and other toxicities, a regimen was proposed of 80 mg once a day on a schedule of 14 days on, 7 days off.

Thrombocytopenia affected 43 of 45 patients, and 26 of them had grade 3-4 events. Other grade 3-4 events were infrequent. Anemia was seen in 41, and neutropenia in 23.

Of three patients with diffuse large B-cell lymphoma, two had complete responses at 120 mg once a day, and one had a partial response at 80 mg once a day. Six additional patients, two with diffuse large B-cell lymphoma and four with indolent lymphomas, had evidence of clinical activity, but did not meet the criteria for an objective response.

The study was funded by the developers of OTX015, Oncoethix GmbH, a wholly owned subsidiary of Merck Sharp & Dohme.

[email protected]

On Twitter @maryjodales

As a single agent for use in patients with lymphoma, an acceptable once-daily dose of OTX015 appears to be 80 mg on a 14 days on, 7 days off schedule, the results of a phase 1 study indicate.

The small-molecule inhibitor, which inhibits binding of bromodomain and exterminal proteins to acetylated histones, was associated with acceptable toxicity and efficacy in this regimen. The investigational drug is now being tested in expansion cohorts on a schedule of 14 days every 3 weeks, a regimen projected to allow for recovery from the drug’s toxic effects, Dr. Sandy Amorin of Hôpital Saint Louis, Paris, and associates reported.

The drug also is being evaluated in patients with acute leukemias.

Adults with nonleukemia hematologic malignancies that progressed on standard therapies participated in the open-label study, which was conducted at seven university hospital centers in Europe. Oral OTX015 was given once a day at one of five doses (10 mg, 20 mg, 40 mg, 80 mg, and 120 mg). The 3 + 3 study design permitted evaluation of alternative administration schedules. The primary endpoint was dose-limiting toxicity in the first treatment cycle (21 days). Secondary objectives were to evaluate safety, pharmacokinetics, and preliminary clinical activity of OTX015. The study is ongoing and is registered with ClinicalTrials.gov, number NCT01713582.

The study included 33 patients with lymphoma and 12 with myeloma; patients’ median age was 66 years, and they had received a median of four lines of prior therapy. No dose-limiting toxicities were seen in three patients given doses as high as 80 mg once a day. However, grade 4 thrombocytopenia occurred in five of six patients on a 21-day schedule of 40 mg twice a day. No patient tolerated various schedules of 120 mg once a day (Lancet Haematol. 2016;3[4]:e196-204).

The researchers then examined the 80 mg once a day dose on a continuous basis in four patients, two of whom developed grade 4 thrombocytopenia. In light of these and other toxicities, a regimen was proposed of 80 mg once a day on a schedule of 14 days on, 7 days off.

Thrombocytopenia affected 43 of 45 patients, and 26 of them had grade 3-4 events. Other grade 3-4 events were infrequent. Anemia was seen in 41, and neutropenia in 23.

Of three patients with diffuse large B-cell lymphoma, two had complete responses at 120 mg once a day, and one had a partial response at 80 mg once a day. Six additional patients, two with diffuse large B-cell lymphoma and four with indolent lymphomas, had evidence of clinical activity, but did not meet the criteria for an objective response.

The study was funded by the developers of OTX015, Oncoethix GmbH, a wholly owned subsidiary of Merck Sharp & Dohme.

[email protected]

On Twitter @maryjodales

BOSTON – A prospective cohort study of women with polycystic ovarian syndrome who developed gestational diabetes mellitus during pregnancy has implicated fasting blood glucose, non–high density lipoprotein, and sex hormone–binding globulin as significant predictive factors for the development of GDM.

“Polycystic ovarian syndrome [PCOS] is the most common reproductive disorder in women of reproductive age and is commonly associated with metabolic disorders including diabetes and obesity. In women with GDM, a history of PCOS is associated with higher incidence of complications and postpregnancy glucose intolerance. Risk factors during early pregnancy in women with PCOS for development of GDM have not been well characterized,” said Dr. Wenyu Huang of Northwestern University, Chicago.

To provide some clarity, Dr. Huang and his colleagues conducted a prospective cohort study. Inclusion criteria were age 18-45 years, diagnosis of PCOS prior to conception, singlet pregnancy, and enrollment during the first trimester. Preexisting chronic disease including diabetes, hypertension, and thyroid, kidney, or cardiovascular disease was grounds for exclusion. The findings were presented at the annual meeting of the Endocrine Society.

The 248 women with PCOS enrolled from 2011 to 2013 from a screened population of 25,000 pregnant women were followed from their first prenatal visit (before week 18) to delivery. Blood was collected at the first visit for analysis of metabolic hormones. A 75-g oral glucose tolerance test (OGTT) was carried out at week 24-28 and diagnosis of GDM was according to 2013 American Diabetes Association OGTT criteria.

Of the 248 women, 75 (30.2%) developed GDM, and 173 (69.8%) women had normal OGTT results. Examination over the same time period early in pregnancy revealed a higher incidence of GDM in women with PCOS.

In a univariate analysis, PCOS patients who developed GDM had higher fasting blood glucose (FBG), Homeostasis Model Assessment-Insulin resistance (HOMA-IR) score, total cholesterol, low-density lipoprotein cholesterol, non-HDL cholesterol, systolic and diastolic blood pressures, and free testosterone index. These patients also had lower levels of sex hormone–binding globulin (SHBG) and higher likelihood of family history of diabetes and earlier delivery.

Multiple logistic regression revealed associations between increased incidence of GDM and FBG greater than or equal to 4.86 mmol/L, non-HDL cholesterol greater than or equal to 2.84 mmol/L, and SHBG greater than or equal to 222 nmol/L. The predictive power of the three factors for the development of GDM in PCOS was relatively strong.

Future studies could aim to validate the prediction model and clarify the pathogenic basis of GDM in PCOS women, according to the researchers .

The study was funded by the Beijing Science Committee. Dr. Huang had no disclosures.

BOSTON – A prospective cohort study of women with polycystic ovarian syndrome who developed gestational diabetes mellitus during pregnancy has implicated fasting blood glucose, non–high density lipoprotein, and sex hormone–binding globulin as significant predictive factors for the development of GDM.

“Polycystic ovarian syndrome [PCOS] is the most common reproductive disorder in women of reproductive age and is commonly associated with metabolic disorders including diabetes and obesity. In women with GDM, a history of PCOS is associated with higher incidence of complications and postpregnancy glucose intolerance. Risk factors during early pregnancy in women with PCOS for development of GDM have not been well characterized,” said Dr. Wenyu Huang of Northwestern University, Chicago.

To provide some clarity, Dr. Huang and his colleagues conducted a prospective cohort study. Inclusion criteria were age 18-45 years, diagnosis of PCOS prior to conception, singlet pregnancy, and enrollment during the first trimester. Preexisting chronic disease including diabetes, hypertension, and thyroid, kidney, or cardiovascular disease was grounds for exclusion. The findings were presented at the annual meeting of the Endocrine Society.

The 248 women with PCOS enrolled from 2011 to 2013 from a screened population of 25,000 pregnant women were followed from their first prenatal visit (before week 18) to delivery. Blood was collected at the first visit for analysis of metabolic hormones. A 75-g oral glucose tolerance test (OGTT) was carried out at week 24-28 and diagnosis of GDM was according to 2013 American Diabetes Association OGTT criteria.

Of the 248 women, 75 (30.2%) developed GDM, and 173 (69.8%) women had normal OGTT results. Examination over the same time period early in pregnancy revealed a higher incidence of GDM in women with PCOS.

In a univariate analysis, PCOS patients who developed GDM had higher fasting blood glucose (FBG), Homeostasis Model Assessment-Insulin resistance (HOMA-IR) score, total cholesterol, low-density lipoprotein cholesterol, non-HDL cholesterol, systolic and diastolic blood pressures, and free testosterone index. These patients also had lower levels of sex hormone–binding globulin (SHBG) and higher likelihood of family history of diabetes and earlier delivery.

Multiple logistic regression revealed associations between increased incidence of GDM and FBG greater than or equal to 4.86 mmol/L, non-HDL cholesterol greater than or equal to 2.84 mmol/L, and SHBG greater than or equal to 222 nmol/L. The predictive power of the three factors for the development of GDM in PCOS was relatively strong.

Future studies could aim to validate the prediction model and clarify the pathogenic basis of GDM in PCOS women, according to the researchers .

The study was funded by the Beijing Science Committee. Dr. Huang had no disclosures.

BOSTON – A prospective cohort study of women with polycystic ovarian syndrome who developed gestational diabetes mellitus during pregnancy has implicated fasting blood glucose, non–high density lipoprotein, and sex hormone–binding globulin as significant predictive factors for the development of GDM.

“Polycystic ovarian syndrome [PCOS] is the most common reproductive disorder in women of reproductive age and is commonly associated with metabolic disorders including diabetes and obesity. In women with GDM, a history of PCOS is associated with higher incidence of complications and postpregnancy glucose intolerance. Risk factors during early pregnancy in women with PCOS for development of GDM have not been well characterized,” said Dr. Wenyu Huang of Northwestern University, Chicago.

To provide some clarity, Dr. Huang and his colleagues conducted a prospective cohort study. Inclusion criteria were age 18-45 years, diagnosis of PCOS prior to conception, singlet pregnancy, and enrollment during the first trimester. Preexisting chronic disease including diabetes, hypertension, and thyroid, kidney, or cardiovascular disease was grounds for exclusion. The findings were presented at the annual meeting of the Endocrine Society.

The 248 women with PCOS enrolled from 2011 to 2013 from a screened population of 25,000 pregnant women were followed from their first prenatal visit (before week 18) to delivery. Blood was collected at the first visit for analysis of metabolic hormones. A 75-g oral glucose tolerance test (OGTT) was carried out at week 24-28 and diagnosis of GDM was according to 2013 American Diabetes Association OGTT criteria.

Of the 248 women, 75 (30.2%) developed GDM, and 173 (69.8%) women had normal OGTT results. Examination over the same time period early in pregnancy revealed a higher incidence of GDM in women with PCOS.

In a univariate analysis, PCOS patients who developed GDM had higher fasting blood glucose (FBG), Homeostasis Model Assessment-Insulin resistance (HOMA-IR) score, total cholesterol, low-density lipoprotein cholesterol, non-HDL cholesterol, systolic and diastolic blood pressures, and free testosterone index. These patients also had lower levels of sex hormone–binding globulin (SHBG) and higher likelihood of family history of diabetes and earlier delivery.

Multiple logistic regression revealed associations between increased incidence of GDM and FBG greater than or equal to 4.86 mmol/L, non-HDL cholesterol greater than or equal to 2.84 mmol/L, and SHBG greater than or equal to 222 nmol/L. The predictive power of the three factors for the development of GDM in PCOS was relatively strong.

Future studies could aim to validate the prediction model and clarify the pathogenic basis of GDM in PCOS women, according to the researchers .

The study was funded by the Beijing Science Committee. Dr. Huang had no disclosures.