Jun J. Yang, PhD

Photo by Peter Barta

New research has revealed inherited genetic variations associated with rapid hearing loss in young cancer patients who receive cisplatin.

The drug is used to treat a range of cancers and is known to pose a risk of severe hearing loss, but the risk factors involved are not completely understood.

Now, researchers have found that variations in the gene ACYP2 are associated with an increased risk of cisplatin-related hearing loss.

Jun J. Yang, PhD, of St Jude Children’s Research Hospital in Memphis, Tennessee, and his colleagues reported this discovery in Nature Genetics.

The researchers checked the DNA of 238 young patients with brain tumors for more than 1.7 million common genetic variations. The team found that variations in ACYP2 were associated with as much as a 4-fold greater risk of cisplatin-related hearing loss.

The screening is among the first to survey the genetic landscape for clues to help explain why the risk of cisplatin-related hearing loss varies so widely among patients.

“This is an important first step in being able to pinpoint patients who are at higher risk of developing cisplatin toxicity and to learn how to better manage that risk,” said study author Clinton Stewart, PharmD, also of St Jude.

The researchers confirmed the association between the high-risk ACYP2 variants and cisplatin-related hearing loss in a separate group of 68 brain tumor patients. The association was independent of other risk factors for cisplatin-related hearing loss, including patient age and receipt of radiation therapy.

Twenty-four of the 306 patients in this study had at least one copy of the high-risk ACYP2 variant. All 24 patients had measurable hearing loss that occurred as early as weeks after beginning cisplatin therapy.

Overall, however, the ACYP2 variant explained a relatively small proportion of hearing damage. Just 12.4% of the 194 patients in this study with cisplatin-related hearing loss carried the ACYP2 variant.

“This suggests that other genes also contribute to the risk of hearing loss and are yet to be identified,” Dr Yang said. “Further research is needed to understand how the ACYP2 variations modify the risk . . . of cisplatin toxicity.”

Such studies could potentially lead to new medications to protect high-risk patients from cisplatin-related toxicity or help identify candidates for intensive monitoring of their hearing, Dr Stewart said. Early intervention could then be offered if problems are identified.

This study included patients enrolled in 1 of 3 trials designed by St Jude investigators for newly diagnosed pediatric brain tumors. The protocols involved similar treatment, including surgery to remove as much of the tumor as possible, followed by radiation, which was modified based on patient age and other risk factors.

The patients were scheduled to receive 4 rounds of cisplatin therapy. Patients’ hearing was tested before treatment began, after radiation therapy, after each round of chemotherapy, and then at regular standardized intervals. Analysis of the resulting data led to identification of ACYP2 and other variants.

“Our primary goal is to cure children with brain tumors, but we also have a duty to help patients survive with a high quality of life,” said Giles Robinson, MD, also of St Jude.

“Hearing loss can have a significant impact on a child’s quality of life, language development, and academic performance. There is no easy fix, but the more we know about the risk factors, the better we will understand how to use cisplatin.”

Jun J. Yang, PhD

Photo by Peter Barta

New research has revealed inherited genetic variations associated with rapid hearing loss in young cancer patients who receive cisplatin.

The drug is used to treat a range of cancers and is known to pose a risk of severe hearing loss, but the risk factors involved are not completely understood.

Now, researchers have found that variations in the gene ACYP2 are associated with an increased risk of cisplatin-related hearing loss.

Jun J. Yang, PhD, of St Jude Children’s Research Hospital in Memphis, Tennessee, and his colleagues reported this discovery in Nature Genetics.

The researchers checked the DNA of 238 young patients with brain tumors for more than 1.7 million common genetic variations. The team found that variations in ACYP2 were associated with as much as a 4-fold greater risk of cisplatin-related hearing loss.

The screening is among the first to survey the genetic landscape for clues to help explain why the risk of cisplatin-related hearing loss varies so widely among patients.

“This is an important first step in being able to pinpoint patients who are at higher risk of developing cisplatin toxicity and to learn how to better manage that risk,” said study author Clinton Stewart, PharmD, also of St Jude.

The researchers confirmed the association between the high-risk ACYP2 variants and cisplatin-related hearing loss in a separate group of 68 brain tumor patients. The association was independent of other risk factors for cisplatin-related hearing loss, including patient age and receipt of radiation therapy.

Twenty-four of the 306 patients in this study had at least one copy of the high-risk ACYP2 variant. All 24 patients had measurable hearing loss that occurred as early as weeks after beginning cisplatin therapy.

Overall, however, the ACYP2 variant explained a relatively small proportion of hearing damage. Just 12.4% of the 194 patients in this study with cisplatin-related hearing loss carried the ACYP2 variant.

“This suggests that other genes also contribute to the risk of hearing loss and are yet to be identified,” Dr Yang said. “Further research is needed to understand how the ACYP2 variations modify the risk . . . of cisplatin toxicity.”

Such studies could potentially lead to new medications to protect high-risk patients from cisplatin-related toxicity or help identify candidates for intensive monitoring of their hearing, Dr Stewart said. Early intervention could then be offered if problems are identified.

This study included patients enrolled in 1 of 3 trials designed by St Jude investigators for newly diagnosed pediatric brain tumors. The protocols involved similar treatment, including surgery to remove as much of the tumor as possible, followed by radiation, which was modified based on patient age and other risk factors.

The patients were scheduled to receive 4 rounds of cisplatin therapy. Patients’ hearing was tested before treatment began, after radiation therapy, after each round of chemotherapy, and then at regular standardized intervals. Analysis of the resulting data led to identification of ACYP2 and other variants.

“Our primary goal is to cure children with brain tumors, but we also have a duty to help patients survive with a high quality of life,” said Giles Robinson, MD, also of St Jude.

“Hearing loss can have a significant impact on a child’s quality of life, language development, and academic performance. There is no easy fix, but the more we know about the risk factors, the better we will understand how to use cisplatin.”

Jun J. Yang, PhD

Photo by Peter Barta

New research has revealed inherited genetic variations associated with rapid hearing loss in young cancer patients who receive cisplatin.

The drug is used to treat a range of cancers and is known to pose a risk of severe hearing loss, but the risk factors involved are not completely understood.

Now, researchers have found that variations in the gene ACYP2 are associated with an increased risk of cisplatin-related hearing loss.

Jun J. Yang, PhD, of St Jude Children’s Research Hospital in Memphis, Tennessee, and his colleagues reported this discovery in Nature Genetics.

The researchers checked the DNA of 238 young patients with brain tumors for more than 1.7 million common genetic variations. The team found that variations in ACYP2 were associated with as much as a 4-fold greater risk of cisplatin-related hearing loss.

The screening is among the first to survey the genetic landscape for clues to help explain why the risk of cisplatin-related hearing loss varies so widely among patients.

“This is an important first step in being able to pinpoint patients who are at higher risk of developing cisplatin toxicity and to learn how to better manage that risk,” said study author Clinton Stewart, PharmD, also of St Jude.

The researchers confirmed the association between the high-risk ACYP2 variants and cisplatin-related hearing loss in a separate group of 68 brain tumor patients. The association was independent of other risk factors for cisplatin-related hearing loss, including patient age and receipt of radiation therapy.

Twenty-four of the 306 patients in this study had at least one copy of the high-risk ACYP2 variant. All 24 patients had measurable hearing loss that occurred as early as weeks after beginning cisplatin therapy.

Overall, however, the ACYP2 variant explained a relatively small proportion of hearing damage. Just 12.4% of the 194 patients in this study with cisplatin-related hearing loss carried the ACYP2 variant.

“This suggests that other genes also contribute to the risk of hearing loss and are yet to be identified,” Dr Yang said. “Further research is needed to understand how the ACYP2 variations modify the risk . . . of cisplatin toxicity.”

Such studies could potentially lead to new medications to protect high-risk patients from cisplatin-related toxicity or help identify candidates for intensive monitoring of their hearing, Dr Stewart said. Early intervention could then be offered if problems are identified.

This study included patients enrolled in 1 of 3 trials designed by St Jude investigators for newly diagnosed pediatric brain tumors. The protocols involved similar treatment, including surgery to remove as much of the tumor as possible, followed by radiation, which was modified based on patient age and other risk factors.

The patients were scheduled to receive 4 rounds of cisplatin therapy. Patients’ hearing was tested before treatment began, after radiation therapy, after each round of chemotherapy, and then at regular standardized intervals. Analysis of the resulting data led to identification of ACYP2 and other variants.

“Our primary goal is to cure children with brain tumors, but we also have a duty to help patients survive with a high quality of life,” said Giles Robinson, MD, also of St Jude.

“Hearing loss can have a significant impact on a child’s quality of life, language development, and academic performance. There is no easy fix, but the more we know about the risk factors, the better we will understand how to use cisplatin.”

Doctor holding a clipboard

Researchers have identified 8 highly specific physical and cognitive signs that seem to be associated with imminent death in cancer patients.

The findings, published in Cancer, could offer clinicians the ability to better communicate with patients and their families.

The research might also help guide the medical team and caregivers when it comes to complex decision making, such as discontinuing tests and therapy, plans for hospital discharge, and hospice referral.

Previous studies in end-of-life care have focused on physicians prognosticating better. However, research on how to tell if a patient has entered the final days of life has been minimal, according to David Hui, MD, of the University of Texas MD Anderson Cancer Center in Houston.

“In the past, studies trying to understand the signs associated with impending death were conducted in people who were recognized as dying, so there’s a potential bias built into this model,” Dr Hui said.

“With our study, we observed a list of signs in patients from the time they were admitted to the palliative care unit. They were observed systematically, twice a day, without knowing if the patient would die or be discharged.”

Dr Hui and his colleagues observed 357 cancer patients, 57% of whom ultimately died. The researchers observed 52 physical and cognitive signs—identified by Dr Hui and his colleagues in previous research—twice a day from the patient’s admission to discharge or death.

Of those 52 signs, the 8 most highly associated with impending death within 3 days were:

• Nonreactive pupils
• Decreased response to verbal stimuli
• Decreased response to visual stimuli
• Inability to close eyelids
• Drooping of the nasolabial fold
• Neck hyperextension
• Grunting of vocal cords
• Upper gastrointestinal bleeding.

“When cancer patients reach the last days of life, this is an extremely emotional time for families; their stress levels cannot be understated,” Dr Hui said.

“Knowing when death is imminent would provide more information so caregivers can plan appropriately. For clinicians, having this information could help reassure families that we are providing the best care possible.”

Dr Hui stressed that this research is not yet practice-changing, but is an important step in understanding these 8 signs and their relation to impending death. In addition, the findings are only representative of imminent cancer death and should not be generalized to other causes of death.

Follow-up studies in different settings are planned. Dr Hui and his colleagues plan to look at the reliability of the identified signs, as well as evaluate this research in other countries and in the hospice setting.

Doctor holding a clipboard

Researchers have identified 8 highly specific physical and cognitive signs that seem to be associated with imminent death in cancer patients.

The findings, published in Cancer, could offer clinicians the ability to better communicate with patients and their families.

The research might also help guide the medical team and caregivers when it comes to complex decision making, such as discontinuing tests and therapy, plans for hospital discharge, and hospice referral.

Previous studies in end-of-life care have focused on physicians prognosticating better. However, research on how to tell if a patient has entered the final days of life has been minimal, according to David Hui, MD, of the University of Texas MD Anderson Cancer Center in Houston.

“In the past, studies trying to understand the signs associated with impending death were conducted in people who were recognized as dying, so there’s a potential bias built into this model,” Dr Hui said.

“With our study, we observed a list of signs in patients from the time they were admitted to the palliative care unit. They were observed systematically, twice a day, without knowing if the patient would die or be discharged.”

Dr Hui and his colleagues observed 357 cancer patients, 57% of whom ultimately died. The researchers observed 52 physical and cognitive signs—identified by Dr Hui and his colleagues in previous research—twice a day from the patient’s admission to discharge or death.

Of those 52 signs, the 8 most highly associated with impending death within 3 days were:

• Nonreactive pupils
• Decreased response to verbal stimuli
• Decreased response to visual stimuli
• Inability to close eyelids
• Drooping of the nasolabial fold
• Neck hyperextension
• Grunting of vocal cords
• Upper gastrointestinal bleeding.

“When cancer patients reach the last days of life, this is an extremely emotional time for families; their stress levels cannot be understated,” Dr Hui said.

“Knowing when death is imminent would provide more information so caregivers can plan appropriately. For clinicians, having this information could help reassure families that we are providing the best care possible.”

Dr Hui stressed that this research is not yet practice-changing, but is an important step in understanding these 8 signs and their relation to impending death. In addition, the findings are only representative of imminent cancer death and should not be generalized to other causes of death.

Follow-up studies in different settings are planned. Dr Hui and his colleagues plan to look at the reliability of the identified signs, as well as evaluate this research in other countries and in the hospice setting.

Doctor holding a clipboard

Researchers have identified 8 highly specific physical and cognitive signs that seem to be associated with imminent death in cancer patients.

The findings, published in Cancer, could offer clinicians the ability to better communicate with patients and their families.

The research might also help guide the medical team and caregivers when it comes to complex decision making, such as discontinuing tests and therapy, plans for hospital discharge, and hospice referral.

Previous studies in end-of-life care have focused on physicians prognosticating better. However, research on how to tell if a patient has entered the final days of life has been minimal, according to David Hui, MD, of the University of Texas MD Anderson Cancer Center in Houston.

“In the past, studies trying to understand the signs associated with impending death were conducted in people who were recognized as dying, so there’s a potential bias built into this model,” Dr Hui said.

“With our study, we observed a list of signs in patients from the time they were admitted to the palliative care unit. They were observed systematically, twice a day, without knowing if the patient would die or be discharged.”

Dr Hui and his colleagues observed 357 cancer patients, 57% of whom ultimately died. The researchers observed 52 physical and cognitive signs—identified by Dr Hui and his colleagues in previous research—twice a day from the patient’s admission to discharge or death.

Of those 52 signs, the 8 most highly associated with impending death within 3 days were:

• Nonreactive pupils
• Decreased response to verbal stimuli
• Decreased response to visual stimuli
• Inability to close eyelids
• Drooping of the nasolabial fold
• Neck hyperextension
• Grunting of vocal cords
• Upper gastrointestinal bleeding.

“When cancer patients reach the last days of life, this is an extremely emotional time for families; their stress levels cannot be understated,” Dr Hui said.

“Knowing when death is imminent would provide more information so caregivers can plan appropriately. For clinicians, having this information could help reassure families that we are providing the best care possible.”

Dr Hui stressed that this research is not yet practice-changing, but is an important step in understanding these 8 signs and their relation to impending death. In addition, the findings are only representative of imminent cancer death and should not be generalized to other causes of death.

Follow-up studies in different settings are planned. Dr Hui and his colleagues plan to look at the reliability of the identified signs, as well as evaluate this research in other countries and in the hospice setting.

NASHVILLE, TENN. – About 25% of patients with ischemic stroke who receive thrombolytic therapy get it in the field before hospital transfer with the “drip-and-ship” paradigm.

While there were only modest differences in clinical outcomes between these patients and those treated when admitted to an emergency department, drip-and-ship may actually increase the overall use of tissue plasminogen activator (TPA), Dr. Kevin N. Sheth said at the International Stroke Conference, sponsored by the American Heart Association.

The retrospective analysis, which was simultaneously published in Stroke (2015 Feb. 11 [doi:10.1161/STROKEAHA.114.007506]), plumbed the Get With the Guidelines registry for data to describe trends in the use of TPA and drip-and-ship administration across the United States over time. The study involved 1,440 hospitals and 44,667 patients who had an ischemic stroke during 2003-2010 and received TPA. Of these, 10,475 (23.5%) received it in the field before optional admission and within 3 hours of symptom onset.

Baseline characteristics were similar between the treatment groups. The patients’ mean age was 70 years, and the sex distribution was evenly split. More than 75% of each group was white.

The National Institutes of Health Stroke Scale (NIHSS) score was significantly higher among those who presented for hospital treatment (12.9 vs. 11). However, these patients were seen before TPA administration, while the drip-and-ship group had already been treated, a temporal difference that could have accounted for the score finding, cautioned Dr. Sheth, director of the neuroscience ICU and chief of clinical research at Yale University, New Haven, Conn.

In hospitals that employed drip-and-ship, there were significantly higher rates of stroke patients treated each year as well as more beds. Those hospitals also were more often teaching facilities and were designated as a primary stroke center.

Drip-and-ship frequency remained fairly steady over the study period – about 25% of all eligible patients had it in both 2003 and 2010. Among those treated at the hospital, the frequency of TPA administration within 3 hours of stroke onset rose sharply over the study period, from about 11% in 2003 to 25% in 2010. In contrast, the percentage of timely thrombolysis in drip-and-ship patients moved very little, from about 5% to 9% over the same period.

Overall inpatient mortality was 10%, but was slightly higher among drip-and-ship patients (10.93% vs. 9.67). Symptomatic intracranial hemorrhage occurred in 5.79% of those treated via drip-and-ship and 5.22% of those treated in the hospital. Nearly the same percentage of patients were discharged walking independently (38.4% vs. 38.8%) and discharged home (40.3% vs. 40.6%).

Among the hospital-treated patients, fewer than 4% (1,200) underwent endovascular therapy; this occurred in 707 (7%) of drip-and-ship patients. Those who got endovascular treatment had higher median NIHSS scores at TPA administration than did those who did not (17 vs. 12, respectively). Endovascular treatment was significantly associated with higher mortality (20% vs. 10%) and intracranial hemorrhage (11% vs. 5%).

In a multivariate analysis that adjusted for NIHSS score, in-hospital mortality was significantly more likely in drip-and-ship patients (odds ratio, 1.23). Those patients also were significantly less likely to be independently walking at discharge (OR, 0.66) or discharge to home (OR, 0.66). Intracranial hemorrhage was significantly more likely in drip-and-ship patients (OR, 1.4), as was a hospital stay of longer than 4 days (OR, 1.20).

“These are very modest differences clinically,” Dr. Sheth said, adding that selection bias or unmeasured confounding could have influenced the findings.

Dr. Sheth is a member of the Get with the Guidelines (GWTG) Stroke Clinical Workgroup, and he is a coinvestigator and executive committee member for Glyburide Advantage in Malignant Edema and Stroke-Remedy Pharmaceuticals (GAMES-RP), a phase II trial to prevent swelling in patients with large stroke, funded by Remedy Pharmaceuticals.

[email protected]

On Twitter @alz_gal

NASHVILLE, TENN. – About 25% of patients with ischemic stroke who receive thrombolytic therapy get it in the field before hospital transfer with the “drip-and-ship” paradigm.

While there were only modest differences in clinical outcomes between these patients and those treated when admitted to an emergency department, drip-and-ship may actually increase the overall use of tissue plasminogen activator (TPA), Dr. Kevin N. Sheth said at the International Stroke Conference, sponsored by the American Heart Association.

The retrospective analysis, which was simultaneously published in Stroke (2015 Feb. 11 [doi:10.1161/STROKEAHA.114.007506]), plumbed the Get With the Guidelines registry for data to describe trends in the use of TPA and drip-and-ship administration across the United States over time. The study involved 1,440 hospitals and 44,667 patients who had an ischemic stroke during 2003-2010 and received TPA. Of these, 10,475 (23.5%) received it in the field before optional admission and within 3 hours of symptom onset.

Baseline characteristics were similar between the treatment groups. The patients’ mean age was 70 years, and the sex distribution was evenly split. More than 75% of each group was white.

The National Institutes of Health Stroke Scale (NIHSS) score was significantly higher among those who presented for hospital treatment (12.9 vs. 11). However, these patients were seen before TPA administration, while the drip-and-ship group had already been treated, a temporal difference that could have accounted for the score finding, cautioned Dr. Sheth, director of the neuroscience ICU and chief of clinical research at Yale University, New Haven, Conn.

In hospitals that employed drip-and-ship, there were significantly higher rates of stroke patients treated each year as well as more beds. Those hospitals also were more often teaching facilities and were designated as a primary stroke center.

Drip-and-ship frequency remained fairly steady over the study period – about 25% of all eligible patients had it in both 2003 and 2010. Among those treated at the hospital, the frequency of TPA administration within 3 hours of stroke onset rose sharply over the study period, from about 11% in 2003 to 25% in 2010. In contrast, the percentage of timely thrombolysis in drip-and-ship patients moved very little, from about 5% to 9% over the same period.

Overall inpatient mortality was 10%, but was slightly higher among drip-and-ship patients (10.93% vs. 9.67). Symptomatic intracranial hemorrhage occurred in 5.79% of those treated via drip-and-ship and 5.22% of those treated in the hospital. Nearly the same percentage of patients were discharged walking independently (38.4% vs. 38.8%) and discharged home (40.3% vs. 40.6%).

Among the hospital-treated patients, fewer than 4% (1,200) underwent endovascular therapy; this occurred in 707 (7%) of drip-and-ship patients. Those who got endovascular treatment had higher median NIHSS scores at TPA administration than did those who did not (17 vs. 12, respectively). Endovascular treatment was significantly associated with higher mortality (20% vs. 10%) and intracranial hemorrhage (11% vs. 5%).

In a multivariate analysis that adjusted for NIHSS score, in-hospital mortality was significantly more likely in drip-and-ship patients (odds ratio, 1.23). Those patients also were significantly less likely to be independently walking at discharge (OR, 0.66) or discharge to home (OR, 0.66). Intracranial hemorrhage was significantly more likely in drip-and-ship patients (OR, 1.4), as was a hospital stay of longer than 4 days (OR, 1.20).

“These are very modest differences clinically,” Dr. Sheth said, adding that selection bias or unmeasured confounding could have influenced the findings.

Dr. Sheth is a member of the Get with the Guidelines (GWTG) Stroke Clinical Workgroup, and he is a coinvestigator and executive committee member for Glyburide Advantage in Malignant Edema and Stroke-Remedy Pharmaceuticals (GAMES-RP), a phase II trial to prevent swelling in patients with large stroke, funded by Remedy Pharmaceuticals.

[email protected]

On Twitter @alz_gal

NASHVILLE, TENN. – About 25% of patients with ischemic stroke who receive thrombolytic therapy get it in the field before hospital transfer with the “drip-and-ship” paradigm.

While there were only modest differences in clinical outcomes between these patients and those treated when admitted to an emergency department, drip-and-ship may actually increase the overall use of tissue plasminogen activator (TPA), Dr. Kevin N. Sheth said at the International Stroke Conference, sponsored by the American Heart Association.

The retrospective analysis, which was simultaneously published in Stroke (2015 Feb. 11 [doi:10.1161/STROKEAHA.114.007506]), plumbed the Get With the Guidelines registry for data to describe trends in the use of TPA and drip-and-ship administration across the United States over time. The study involved 1,440 hospitals and 44,667 patients who had an ischemic stroke during 2003-2010 and received TPA. Of these, 10,475 (23.5%) received it in the field before optional admission and within 3 hours of symptom onset.

Baseline characteristics were similar between the treatment groups. The patients’ mean age was 70 years, and the sex distribution was evenly split. More than 75% of each group was white.

The National Institutes of Health Stroke Scale (NIHSS) score was significantly higher among those who presented for hospital treatment (12.9 vs. 11). However, these patients were seen before TPA administration, while the drip-and-ship group had already been treated, a temporal difference that could have accounted for the score finding, cautioned Dr. Sheth, director of the neuroscience ICU and chief of clinical research at Yale University, New Haven, Conn.

In hospitals that employed drip-and-ship, there were significantly higher rates of stroke patients treated each year as well as more beds. Those hospitals also were more often teaching facilities and were designated as a primary stroke center.

Drip-and-ship frequency remained fairly steady over the study period – about 25% of all eligible patients had it in both 2003 and 2010. Among those treated at the hospital, the frequency of TPA administration within 3 hours of stroke onset rose sharply over the study period, from about 11% in 2003 to 25% in 2010. In contrast, the percentage of timely thrombolysis in drip-and-ship patients moved very little, from about 5% to 9% over the same period.

Overall inpatient mortality was 10%, but was slightly higher among drip-and-ship patients (10.93% vs. 9.67). Symptomatic intracranial hemorrhage occurred in 5.79% of those treated via drip-and-ship and 5.22% of those treated in the hospital. Nearly the same percentage of patients were discharged walking independently (38.4% vs. 38.8%) and discharged home (40.3% vs. 40.6%).

Among the hospital-treated patients, fewer than 4% (1,200) underwent endovascular therapy; this occurred in 707 (7%) of drip-and-ship patients. Those who got endovascular treatment had higher median NIHSS scores at TPA administration than did those who did not (17 vs. 12, respectively). Endovascular treatment was significantly associated with higher mortality (20% vs. 10%) and intracranial hemorrhage (11% vs. 5%).

In a multivariate analysis that adjusted for NIHSS score, in-hospital mortality was significantly more likely in drip-and-ship patients (odds ratio, 1.23). Those patients also were significantly less likely to be independently walking at discharge (OR, 0.66) or discharge to home (OR, 0.66). Intracranial hemorrhage was significantly more likely in drip-and-ship patients (OR, 1.4), as was a hospital stay of longer than 4 days (OR, 1.20).

“These are very modest differences clinically,” Dr. Sheth said, adding that selection bias or unmeasured confounding could have influenced the findings.

Dr. Sheth is a member of the Get with the Guidelines (GWTG) Stroke Clinical Workgroup, and he is a coinvestigator and executive committee member for Glyburide Advantage in Malignant Edema and Stroke-Remedy Pharmaceuticals (GAMES-RP), a phase II trial to prevent swelling in patients with large stroke, funded by Remedy Pharmaceuticals.

[email protected]

On Twitter @alz_gal

CORONADO, CALIF. – Some patients with treatment-refractory obstructive sleep apnea may be candidates for upper airway stimulation, though those with complete concentric palatal collapse may not respond, according to Dr. Marion Boyd Gillespie.

“There’s been sound research showing that patients with obstructive sleep apnea have reduced neural tone, so it may not be due to fat in the tongue; some of it may have to do with reduced neural tone,” Dr. Gillespie, who directs the snoring clinics at the Medical University of South Carolina, Charleston, said at the Triological Society’s Combined Sections Meeting. “During these apneic events, there’s a reduction in the neural tone of the genioglossus muscle, which is the main dilator of the upper airway. With upper airway stimulation, we’re trying to account for that loss of neural tone by providing more neural impulse to these muscle groups that perform the dilator functions.”

In 2014 the Food and Drug Administration cleared an upper airway stimulation system manufactured by Inspire Medical Systems, a pacemakerlike device that’s implanted in the subclavicular space. The system features a stimulator lead that attaches to the right hypoglossal nerve and a sensing lead that goes between the external and internal intercostal muscles to detect breathing. “That allows the device to know when in the phase of respiration to fire,” said Dr. Gillespie, professor of otolaryngology–head and neck surgery at the university. “The sensing lead detects the respiratory wave, and the stimulatory lead starts stimulation at the end of expiration, because that’s when the airway is in its most collapsible state. It continues about two-thirds of the way through the inspiratory cycle to keep the airway open.”

Titration of the device is very similar to continuous positive airway pressure, he continued. Once implanted, the patient “will go back to the sleep lab where a tech who’s trained in the device will ramp up stimulation until observed apneas and hypopneas are adequately reduced. You would think that isolated stimulation of the hypoglossal nerve would only open up the airway at the level of the tongue. However, our initial investigation showed that there is dilation at the velopharynx as well,” Dr. Gillespie said. By moving the tongue out of the posterior airway, “you’re moving the dorsum of the tongue away from the velopharynx. You’re also getting active traction on the palatoglossal fold,” he added.

Results of the initial trial of the system in 126 patients with a mean body mass index of 28.4 kg/m² were published last year (N. Engl. J. Med. 2014;370:139-49). At 12 months of follow-up, patients experienced a 68% overall reduction in their apnea-hypopnea index (AHI) score, from a preoperative mean of 29 to a postoperative mean of 9. In addition, patients had a 70% overall reduction in their oxygen desaturation index (ODI). The researchers also observed normalization of patient-based outcomes, with improvement in the Functional Outcomes of Sleep Questionnaire score and reduction of the Epworth Sleepiness Scale score to a level of 10 on average. “We also saw a reduction of snoring,” said Dr. Gillespie, who was a member of the research team. “Snoring went from 72% of patients having severe, annoying snoring to the point where a bed partner leaves the room, to 15% postoperatively.” Even so, 96% of patients who had a previous history of uvulopalatopharyngoplasty (UPPP) or laser-assisted uvulopalatoplasty (LAUP) still had tongue-based collapse after 12 months of follow-up. “But we found that their response to this therapy was just as good as people who had never had a UPPP or LAUP,” Dr. Gillespie said at the meeting, jointly sponsored by the Triological Society and the American College of Surgeons. “So it seems like patients who have failed UPPP are still good candidates for upper airway stimulation therapy.”

Dr. Gillespie noted that selection criteria for the trial were limited to patients with a BMI of less than 32 kg/m² and to those who did not have complete circumferential collapse at the level of the soft palate on preoperative drug-induced endoscopy. These criteria were based on an earlier pilot study that showed that patients with complete circumferential collapse at the level of the soft palate did not respond to upper airway stimulation (J. Clin. Sleep Med. 2013;9:433-8).

Dr. Gillespie disclosed that he has received research support from Inspire Medical Systems, Olympus, and Surgical Specialties. He is also a consultant for those companies as well as for Medtronic.

[email protected]

On Twitter @dougbrunk

CORONADO, CALIF. – Some patients with treatment-refractory obstructive sleep apnea may be candidates for upper airway stimulation, though those with complete concentric palatal collapse may not respond, according to Dr. Marion Boyd Gillespie.

“There’s been sound research showing that patients with obstructive sleep apnea have reduced neural tone, so it may not be due to fat in the tongue; some of it may have to do with reduced neural tone,” Dr. Gillespie, who directs the snoring clinics at the Medical University of South Carolina, Charleston, said at the Triological Society’s Combined Sections Meeting. “During these apneic events, there’s a reduction in the neural tone of the genioglossus muscle, which is the main dilator of the upper airway. With upper airway stimulation, we’re trying to account for that loss of neural tone by providing more neural impulse to these muscle groups that perform the dilator functions.”

In 2014 the Food and Drug Administration cleared an upper airway stimulation system manufactured by Inspire Medical Systems, a pacemakerlike device that’s implanted in the subclavicular space. The system features a stimulator lead that attaches to the right hypoglossal nerve and a sensing lead that goes between the external and internal intercostal muscles to detect breathing. “That allows the device to know when in the phase of respiration to fire,” said Dr. Gillespie, professor of otolaryngology–head and neck surgery at the university. “The sensing lead detects the respiratory wave, and the stimulatory lead starts stimulation at the end of expiration, because that’s when the airway is in its most collapsible state. It continues about two-thirds of the way through the inspiratory cycle to keep the airway open.”

Titration of the device is very similar to continuous positive airway pressure, he continued. Once implanted, the patient “will go back to the sleep lab where a tech who’s trained in the device will ramp up stimulation until observed apneas and hypopneas are adequately reduced. You would think that isolated stimulation of the hypoglossal nerve would only open up the airway at the level of the tongue. However, our initial investigation showed that there is dilation at the velopharynx as well,” Dr. Gillespie said. By moving the tongue out of the posterior airway, “you’re moving the dorsum of the tongue away from the velopharynx. You’re also getting active traction on the palatoglossal fold,” he added.

Results of the initial trial of the system in 126 patients with a mean body mass index of 28.4 kg/m² were published last year (N. Engl. J. Med. 2014;370:139-49). At 12 months of follow-up, patients experienced a 68% overall reduction in their apnea-hypopnea index (AHI) score, from a preoperative mean of 29 to a postoperative mean of 9. In addition, patients had a 70% overall reduction in their oxygen desaturation index (ODI). The researchers also observed normalization of patient-based outcomes, with improvement in the Functional Outcomes of Sleep Questionnaire score and reduction of the Epworth Sleepiness Scale score to a level of 10 on average. “We also saw a reduction of snoring,” said Dr. Gillespie, who was a member of the research team. “Snoring went from 72% of patients having severe, annoying snoring to the point where a bed partner leaves the room, to 15% postoperatively.” Even so, 96% of patients who had a previous history of uvulopalatopharyngoplasty (UPPP) or laser-assisted uvulopalatoplasty (LAUP) still had tongue-based collapse after 12 months of follow-up. “But we found that their response to this therapy was just as good as people who had never had a UPPP or LAUP,” Dr. Gillespie said at the meeting, jointly sponsored by the Triological Society and the American College of Surgeons. “So it seems like patients who have failed UPPP are still good candidates for upper airway stimulation therapy.”

Dr. Gillespie noted that selection criteria for the trial were limited to patients with a BMI of less than 32 kg/m² and to those who did not have complete circumferential collapse at the level of the soft palate on preoperative drug-induced endoscopy. These criteria were based on an earlier pilot study that showed that patients with complete circumferential collapse at the level of the soft palate did not respond to upper airway stimulation (J. Clin. Sleep Med. 2013;9:433-8).

Dr. Gillespie disclosed that he has received research support from Inspire Medical Systems, Olympus, and Surgical Specialties. He is also a consultant for those companies as well as for Medtronic.

[email protected]

On Twitter @dougbrunk

CORONADO, CALIF. – Some patients with treatment-refractory obstructive sleep apnea may be candidates for upper airway stimulation, though those with complete concentric palatal collapse may not respond, according to Dr. Marion Boyd Gillespie.

“There’s been sound research showing that patients with obstructive sleep apnea have reduced neural tone, so it may not be due to fat in the tongue; some of it may have to do with reduced neural tone,” Dr. Gillespie, who directs the snoring clinics at the Medical University of South Carolina, Charleston, said at the Triological Society’s Combined Sections Meeting. “During these apneic events, there’s a reduction in the neural tone of the genioglossus muscle, which is the main dilator of the upper airway. With upper airway stimulation, we’re trying to account for that loss of neural tone by providing more neural impulse to these muscle groups that perform the dilator functions.”

In 2014 the Food and Drug Administration cleared an upper airway stimulation system manufactured by Inspire Medical Systems, a pacemakerlike device that’s implanted in the subclavicular space. The system features a stimulator lead that attaches to the right hypoglossal nerve and a sensing lead that goes between the external and internal intercostal muscles to detect breathing. “That allows the device to know when in the phase of respiration to fire,” said Dr. Gillespie, professor of otolaryngology–head and neck surgery at the university. “The sensing lead detects the respiratory wave, and the stimulatory lead starts stimulation at the end of expiration, because that’s when the airway is in its most collapsible state. It continues about two-thirds of the way through the inspiratory cycle to keep the airway open.”

Titration of the device is very similar to continuous positive airway pressure, he continued. Once implanted, the patient “will go back to the sleep lab where a tech who’s trained in the device will ramp up stimulation until observed apneas and hypopneas are adequately reduced. You would think that isolated stimulation of the hypoglossal nerve would only open up the airway at the level of the tongue. However, our initial investigation showed that there is dilation at the velopharynx as well,” Dr. Gillespie said. By moving the tongue out of the posterior airway, “you’re moving the dorsum of the tongue away from the velopharynx. You’re also getting active traction on the palatoglossal fold,” he added.

Results of the initial trial of the system in 126 patients with a mean body mass index of 28.4 kg/m² were published last year (N. Engl. J. Med. 2014;370:139-49). At 12 months of follow-up, patients experienced a 68% overall reduction in their apnea-hypopnea index (AHI) score, from a preoperative mean of 29 to a postoperative mean of 9. In addition, patients had a 70% overall reduction in their oxygen desaturation index (ODI). The researchers also observed normalization of patient-based outcomes, with improvement in the Functional Outcomes of Sleep Questionnaire score and reduction of the Epworth Sleepiness Scale score to a level of 10 on average. “We also saw a reduction of snoring,” said Dr. Gillespie, who was a member of the research team. “Snoring went from 72% of patients having severe, annoying snoring to the point where a bed partner leaves the room, to 15% postoperatively.” Even so, 96% of patients who had a previous history of uvulopalatopharyngoplasty (UPPP) or laser-assisted uvulopalatoplasty (LAUP) still had tongue-based collapse after 12 months of follow-up. “But we found that their response to this therapy was just as good as people who had never had a UPPP or LAUP,” Dr. Gillespie said at the meeting, jointly sponsored by the Triological Society and the American College of Surgeons. “So it seems like patients who have failed UPPP are still good candidates for upper airway stimulation therapy.”

Dr. Gillespie noted that selection criteria for the trial were limited to patients with a BMI of less than 32 kg/m² and to those who did not have complete circumferential collapse at the level of the soft palate on preoperative drug-induced endoscopy. These criteria were based on an earlier pilot study that showed that patients with complete circumferential collapse at the level of the soft palate did not respond to upper airway stimulation (J. Clin. Sleep Med. 2013;9:433-8).

Dr. Gillespie disclosed that he has received research support from Inspire Medical Systems, Olympus, and Surgical Specialties. He is also a consultant for those companies as well as for Medtronic.

[email protected]

On Twitter @dougbrunk

HSCT preparation

Photo by Chad McNeeley

Leukocyte telomere length is associated with survival in patients who undergo hematopoietic stem cell transplant (HSCT) to treat severe aplastic anemia, according to research published in JAMA.

But it’s the donor’s telomere length—not the recipient’s—that makes the difference, the study showed.

Patients who received an HSCT from an unrelated donor had better overall survival at 5 years if that donor’s leukocytes had longer telomeres.

Shahinaz M. Gadalla, MD, PhD, of the National Cancer Institute in Rockville, Maryland, and colleagues conducted this research.

The group compared recipient and donor leukocyte telomere length prior to transplant with outcomes after unrelated HSCT for 330 patients with severe aplastic anemia.

The patients and their donors had pre-HSCT blood samples and other clinical results available at the Center for International Blood and Marrow Transplant Research. Patients underwent HSCT between 1989 and 2007 in 84 centers and were followed until March 2013.

The researchers categorized leukocyte telomere length for both recipients and donors based on the leukocyte telomere length tertiles in the donors: long (third tertile) and short (first and second tertiles combined).

The team found that longer donor leukocyte telomere length was associated with a higher overall survival. The 5-year overall survival was 56% in the longer telomere group and 40% in the shorter telomere group (P=0.009).

After adjusting for donor age and clinical factors associated with survival following HSCT in severe aplastic anemia, the risk of post-HSCT all-cause mortality remained approximately 40% lower in patients receiving HSCT from donors with long vs short leukocyte telomeres (hazard ratio [HR]=0.61).

There was no association between donor leukocyte telomere length and engraftment at 28 days (HR=0.94). Likewise, there was no association between telomere length and acute (HR=0.77) or chronic graft-vs-host disease (HR=0.81).

And recipient telomere length was not associated with overall survival (HR=0.91).

The researchers said these results suggest that donor leukocyte telomere length may have a role in long-term post-transplant survival. Authors of a related editorial explored what this discovery could mean for transplant centers.

HSCT preparation

Photo by Chad McNeeley

Leukocyte telomere length is associated with survival in patients who undergo hematopoietic stem cell transplant (HSCT) to treat severe aplastic anemia, according to research published in JAMA.

But it’s the donor’s telomere length—not the recipient’s—that makes the difference, the study showed.

Patients who received an HSCT from an unrelated donor had better overall survival at 5 years if that donor’s leukocytes had longer telomeres.

Shahinaz M. Gadalla, MD, PhD, of the National Cancer Institute in Rockville, Maryland, and colleagues conducted this research.

The group compared recipient and donor leukocyte telomere length prior to transplant with outcomes after unrelated HSCT for 330 patients with severe aplastic anemia.

The patients and their donors had pre-HSCT blood samples and other clinical results available at the Center for International Blood and Marrow Transplant Research. Patients underwent HSCT between 1989 and 2007 in 84 centers and were followed until March 2013.

The researchers categorized leukocyte telomere length for both recipients and donors based on the leukocyte telomere length tertiles in the donors: long (third tertile) and short (first and second tertiles combined).

The team found that longer donor leukocyte telomere length was associated with a higher overall survival. The 5-year overall survival was 56% in the longer telomere group and 40% in the shorter telomere group (P=0.009).

After adjusting for donor age and clinical factors associated with survival following HSCT in severe aplastic anemia, the risk of post-HSCT all-cause mortality remained approximately 40% lower in patients receiving HSCT from donors with long vs short leukocyte telomeres (hazard ratio [HR]=0.61).

There was no association between donor leukocyte telomere length and engraftment at 28 days (HR=0.94). Likewise, there was no association between telomere length and acute (HR=0.77) or chronic graft-vs-host disease (HR=0.81).

And recipient telomere length was not associated with overall survival (HR=0.91).

The researchers said these results suggest that donor leukocyte telomere length may have a role in long-term post-transplant survival. Authors of a related editorial explored what this discovery could mean for transplant centers.

HSCT preparation

Photo by Chad McNeeley

Leukocyte telomere length is associated with survival in patients who undergo hematopoietic stem cell transplant (HSCT) to treat severe aplastic anemia, according to research published in JAMA.

But it’s the donor’s telomere length—not the recipient’s—that makes the difference, the study showed.

Patients who received an HSCT from an unrelated donor had better overall survival at 5 years if that donor’s leukocytes had longer telomeres.

Shahinaz M. Gadalla, MD, PhD, of the National Cancer Institute in Rockville, Maryland, and colleagues conducted this research.

The group compared recipient and donor leukocyte telomere length prior to transplant with outcomes after unrelated HSCT for 330 patients with severe aplastic anemia.

The patients and their donors had pre-HSCT blood samples and other clinical results available at the Center for International Blood and Marrow Transplant Research. Patients underwent HSCT between 1989 and 2007 in 84 centers and were followed until March 2013.

The researchers categorized leukocyte telomere length for both recipients and donors based on the leukocyte telomere length tertiles in the donors: long (third tertile) and short (first and second tertiles combined).

The team found that longer donor leukocyte telomere length was associated with a higher overall survival. The 5-year overall survival was 56% in the longer telomere group and 40% in the shorter telomere group (P=0.009).

After adjusting for donor age and clinical factors associated with survival following HSCT in severe aplastic anemia, the risk of post-HSCT all-cause mortality remained approximately 40% lower in patients receiving HSCT from donors with long vs short leukocyte telomeres (hazard ratio [HR]=0.61).

There was no association between donor leukocyte telomere length and engraftment at 28 days (HR=0.94). Likewise, there was no association between telomere length and acute (HR=0.77) or chronic graft-vs-host disease (HR=0.81).

And recipient telomere length was not associated with overall survival (HR=0.91).

The researchers said these results suggest that donor leukocyte telomere length may have a role in long-term post-transplant survival. Authors of a related editorial explored what this discovery could mean for transplant centers.

Prescription medications

Photo courtesy of CDC

New research indicates that a tyrosine kinase inhibitor (TKI) approved to treat advanced renal cell carcinoma could prove useful in treating patients with drug-resistant chronic myeloid leukemia (CML) or acute lymphoblastic leukemia (ALL).

The study showed that the TKI, axitinib, can inhibit BCR-ABL1 (T315I), a mutation known to confer drug resistance in CML and ALL.

“Since axitinib is already used to treat cancer, its safety is known,” said Kimmo Porkka, MD, PhD, of the University of Helsinki in Finland.

“[A] formal exploration of its clinical utility in drug-resistant leukemia can now be done in a fast-track mode. Thus, the normally very long path from lab bench to bedside is now significantly shortened.”

Dr Porkka and his colleagues described the newfound activity of axitinib in Nature.

The researchers used a drug sensitivity and resistance testing method developed at the University of Helsinki’s Institute for Molecular Medicine Finland (FIMM) to examine how patient-derived leukemia cells responded to a large panel of drugs.

In this way, the group identified axitinib as a promising drug candidate for CML and ALL. Axitinib effectively eliminated drug-resistant leukemia cells.

The TKI inhibited BCR-ABL1 (T315I) at biochemical and cellular levels by binding to the active form of ABL1 (T315I) in a mutation-selective binding mode.

The researchers said this suggests the T315I mutation shifts the conformational equilibrium of the kinase in favor of an active (DFG-in) A-loop conformation, which has more optimal binding interactions with axitinib.

“If you think of the targeted protein as a lock into which the cancer drug fits in as a key, the resistant protein changes in such a way that we need a different key,” said study author Brion Murray, PhD, of Pfizer Worldwide Research & Development in San Diego, California.

“In the case of axitinib, it acts as two distinct keys—one for renal cell carcinoma and one for leukemia.”

The researchers also treated a CML patient with axitinib and observed a “rapid reduction” of T315I-positive cells in the patient’s bone marrow.

“Further research will determine whether these findings have the potential to significantly improve the standard of care for this select group of CML patients and patients with other related leukemias,” Dr Murray concluded.

Prescription medications

Photo courtesy of CDC

New research indicates that a tyrosine kinase inhibitor (TKI) approved to treat advanced renal cell carcinoma could prove useful in treating patients with drug-resistant chronic myeloid leukemia (CML) or acute lymphoblastic leukemia (ALL).

The study showed that the TKI, axitinib, can inhibit BCR-ABL1 (T315I), a mutation known to confer drug resistance in CML and ALL.

“Since axitinib is already used to treat cancer, its safety is known,” said Kimmo Porkka, MD, PhD, of the University of Helsinki in Finland.

“[A] formal exploration of its clinical utility in drug-resistant leukemia can now be done in a fast-track mode. Thus, the normally very long path from lab bench to bedside is now significantly shortened.”

Dr Porkka and his colleagues described the newfound activity of axitinib in Nature.

The researchers used a drug sensitivity and resistance testing method developed at the University of Helsinki’s Institute for Molecular Medicine Finland (FIMM) to examine how patient-derived leukemia cells responded to a large panel of drugs.

In this way, the group identified axitinib as a promising drug candidate for CML and ALL. Axitinib effectively eliminated drug-resistant leukemia cells.

The TKI inhibited BCR-ABL1 (T315I) at biochemical and cellular levels by binding to the active form of ABL1 (T315I) in a mutation-selective binding mode.

The researchers said this suggests the T315I mutation shifts the conformational equilibrium of the kinase in favor of an active (DFG-in) A-loop conformation, which has more optimal binding interactions with axitinib.

“If you think of the targeted protein as a lock into which the cancer drug fits in as a key, the resistant protein changes in such a way that we need a different key,” said study author Brion Murray, PhD, of Pfizer Worldwide Research & Development in San Diego, California.

“In the case of axitinib, it acts as two distinct keys—one for renal cell carcinoma and one for leukemia.”

The researchers also treated a CML patient with axitinib and observed a “rapid reduction” of T315I-positive cells in the patient’s bone marrow.

“Further research will determine whether these findings have the potential to significantly improve the standard of care for this select group of CML patients and patients with other related leukemias,” Dr Murray concluded.

Prescription medications

Photo courtesy of CDC

New research indicates that a tyrosine kinase inhibitor (TKI) approved to treat advanced renal cell carcinoma could prove useful in treating patients with drug-resistant chronic myeloid leukemia (CML) or acute lymphoblastic leukemia (ALL).

The study showed that the TKI, axitinib, can inhibit BCR-ABL1 (T315I), a mutation known to confer drug resistance in CML and ALL.

“Since axitinib is already used to treat cancer, its safety is known,” said Kimmo Porkka, MD, PhD, of the University of Helsinki in Finland.

“[A] formal exploration of its clinical utility in drug-resistant leukemia can now be done in a fast-track mode. Thus, the normally very long path from lab bench to bedside is now significantly shortened.”

Dr Porkka and his colleagues described the newfound activity of axitinib in Nature.

The researchers used a drug sensitivity and resistance testing method developed at the University of Helsinki’s Institute for Molecular Medicine Finland (FIMM) to examine how patient-derived leukemia cells responded to a large panel of drugs.

In this way, the group identified axitinib as a promising drug candidate for CML and ALL. Axitinib effectively eliminated drug-resistant leukemia cells.

The TKI inhibited BCR-ABL1 (T315I) at biochemical and cellular levels by binding to the active form of ABL1 (T315I) in a mutation-selective binding mode.

The researchers said this suggests the T315I mutation shifts the conformational equilibrium of the kinase in favor of an active (DFG-in) A-loop conformation, which has more optimal binding interactions with axitinib.

“If you think of the targeted protein as a lock into which the cancer drug fits in as a key, the resistant protein changes in such a way that we need a different key,” said study author Brion Murray, PhD, of Pfizer Worldwide Research & Development in San Diego, California.

“In the case of axitinib, it acts as two distinct keys—one for renal cell carcinoma and one for leukemia.”

The researchers also treated a CML patient with axitinib and observed a “rapid reduction” of T315I-positive cells in the patient’s bone marrow.

“Further research will determine whether these findings have the potential to significantly improve the standard of care for this select group of CML patients and patients with other related leukemias,” Dr Murray concluded.

Preparing capsules for a trial

Photo by Esther Dyson

A new study suggests that, when the US Food and Drug Administration (FDA) identifies problems at clinical trial sites, those findings are seldom reported in peer-reviewed articles later written about the research.

Only 4% of the articles analyzed in this study disclosed that an FDA inspection revealed significant problems at a trial site.

Charles Seife, of the Carter Institute of Journalism at New York University in New York, New York, reported this finding in JAMA Internal Medicine.

Seife noted that the FDA classifies its inspections based on the severity of the violations, and the most severe is “official action indicated (OAI),” which means objectionable conditions or practices that warrant regulatory action.

During the 2013 fiscal year, about 2% of the 644 inspections the FDA conducted at trial sites were classified as OAI.

With this in mind, Seife and his students set out to identify published trials in which an FDA inspection revealed significant problems and determine whether there was mention of it in the medical literature.

The group identified 57 trials in which an FDA inspection uncovered the following problems:

• Falsification or submission of false information (22 trials, 39%)
• Problems with adverse events reporting (14 trials, 25%)
• Protocol violations (42 trials, 74%)
• Inadequate or inaccurate recordkeeping (35 trials, 61%)
• Failure to protect the safety of patients and/or issues with oversight or informed consent (30 trials, 53%)
• Violations that were not otherwise characterized (20 trials, 35%).

Only 3 of the 78 publications (4%) that resulted from these trials mentioned the objectionable conditions or practices.

“The FDA does not typically notify journals when a site participating in a published clinical trial receives an OAI inspection, nor does it generally make any announcement intended to alert the public about the research misconduct that it finds,” Seife wrote.

“The documents the agency discloses tend to be heavily redacted. As a result, it is usually very difficult, or even impossible, to determine which published clinical trials are implicated by the FDA’s allegations of research misconduct.”

In a related editorial, Robert Steinbrook, MD, of the Yale School of Medicine in New Haven, Connecticut, and Rita F. Redberg, MD, of the University of California, San Francisco, wrote that Seife’s study highlights an important area for improved reporting of clinical trials and enhanced transparency at the FDA.

“A central responsibility of medical journals is maintaining and improving trust in the medical literature,” they wrote. “Journals should expect that investigators and sponsors of clinical trials would promptly notify them of substantial findings from FDA and other regulatory agency inspections and modify their reports of clinical trials as needed, either before or after publication.”

Preparing capsules for a trial

Photo by Esther Dyson

A new study suggests that, when the US Food and Drug Administration (FDA) identifies problems at clinical trial sites, those findings are seldom reported in peer-reviewed articles later written about the research.

Only 4% of the articles analyzed in this study disclosed that an FDA inspection revealed significant problems at a trial site.

Charles Seife, of the Carter Institute of Journalism at New York University in New York, New York, reported this finding in JAMA Internal Medicine.

Seife noted that the FDA classifies its inspections based on the severity of the violations, and the most severe is “official action indicated (OAI),” which means objectionable conditions or practices that warrant regulatory action.

During the 2013 fiscal year, about 2% of the 644 inspections the FDA conducted at trial sites were classified as OAI.

With this in mind, Seife and his students set out to identify published trials in which an FDA inspection revealed significant problems and determine whether there was mention of it in the medical literature.

The group identified 57 trials in which an FDA inspection uncovered the following problems:

• Falsification or submission of false information (22 trials, 39%)
• Problems with adverse events reporting (14 trials, 25%)
• Protocol violations (42 trials, 74%)
• Inadequate or inaccurate recordkeeping (35 trials, 61%)
• Failure to protect the safety of patients and/or issues with oversight or informed consent (30 trials, 53%)
• Violations that were not otherwise characterized (20 trials, 35%).

Only 3 of the 78 publications (4%) that resulted from these trials mentioned the objectionable conditions or practices.

“The FDA does not typically notify journals when a site participating in a published clinical trial receives an OAI inspection, nor does it generally make any announcement intended to alert the public about the research misconduct that it finds,” Seife wrote.

“The documents the agency discloses tend to be heavily redacted. As a result, it is usually very difficult, or even impossible, to determine which published clinical trials are implicated by the FDA’s allegations of research misconduct.”

In a related editorial, Robert Steinbrook, MD, of the Yale School of Medicine in New Haven, Connecticut, and Rita F. Redberg, MD, of the University of California, San Francisco, wrote that Seife’s study highlights an important area for improved reporting of clinical trials and enhanced transparency at the FDA.

“A central responsibility of medical journals is maintaining and improving trust in the medical literature,” they wrote. “Journals should expect that investigators and sponsors of clinical trials would promptly notify them of substantial findings from FDA and other regulatory agency inspections and modify their reports of clinical trials as needed, either before or after publication.”

Preparing capsules for a trial

Photo by Esther Dyson

A new study suggests that, when the US Food and Drug Administration (FDA) identifies problems at clinical trial sites, those findings are seldom reported in peer-reviewed articles later written about the research.

Only 4% of the articles analyzed in this study disclosed that an FDA inspection revealed significant problems at a trial site.

Charles Seife, of the Carter Institute of Journalism at New York University in New York, New York, reported this finding in JAMA Internal Medicine.

Seife noted that the FDA classifies its inspections based on the severity of the violations, and the most severe is “official action indicated (OAI),” which means objectionable conditions or practices that warrant regulatory action.

During the 2013 fiscal year, about 2% of the 644 inspections the FDA conducted at trial sites were classified as OAI.

With this in mind, Seife and his students set out to identify published trials in which an FDA inspection revealed significant problems and determine whether there was mention of it in the medical literature.

The group identified 57 trials in which an FDA inspection uncovered the following problems:

• Falsification or submission of false information (22 trials, 39%)
• Problems with adverse events reporting (14 trials, 25%)
• Protocol violations (42 trials, 74%)
• Inadequate or inaccurate recordkeeping (35 trials, 61%)
• Failure to protect the safety of patients and/or issues with oversight or informed consent (30 trials, 53%)
• Violations that were not otherwise characterized (20 trials, 35%).

Only 3 of the 78 publications (4%) that resulted from these trials mentioned the objectionable conditions or practices.

“The FDA does not typically notify journals when a site participating in a published clinical trial receives an OAI inspection, nor does it generally make any announcement intended to alert the public about the research misconduct that it finds,” Seife wrote.

“The documents the agency discloses tend to be heavily redacted. As a result, it is usually very difficult, or even impossible, to determine which published clinical trials are implicated by the FDA’s allegations of research misconduct.”

In a related editorial, Robert Steinbrook, MD, of the Yale School of Medicine in New Haven, Connecticut, and Rita F. Redberg, MD, of the University of California, San Francisco, wrote that Seife’s study highlights an important area for improved reporting of clinical trials and enhanced transparency at the FDA.

“A central responsibility of medical journals is maintaining and improving trust in the medical literature,” they wrote. “Journals should expect that investigators and sponsors of clinical trials would promptly notify them of substantial findings from FDA and other regulatory agency inspections and modify their reports of clinical trials as needed, either before or after publication.”

Blood donation

Photo by Charles Haymond

Low-dose oral iron supplementation can reduce the time to hemoglobin recovery after blood donation, according to a study published in JAMA.

Researchers found that a daily dose of ferrous gluconate (37.5 mg of elemental iron) reduced blood donors’ time to 80% hemoglobin recovery, whether the donors were iron-depleted (with ferritin levels of 26 ng/mL or lower) or iron-replete (with ferritin levels higher than 26 ng/mL).

Joseph E. Kiss, MD, of the Institute for Transfusion Medicine in Pittsburgh, Pennsylvania, and his colleagues conducted this study at 4 regional blood centers in the US.

The researchers randomized 215 subjects (who had not donated whole blood or red blood cells within 4 months) to receive one tablet of ferrous gluconate daily or no iron for 24 weeks after donating a unit of whole blood (500 mL).

The study’s primary outcomes were time to recovery of 80% of the post-donation decrease in hemoglobin and recovery of baseline ferritin levels.

The researchers found that subjects who received iron supplementation achieved 80% hemoglobin recovery more quickly than subjects who did not receive iron, regardless of ferritin levels.

In the low-ferritin group, the mean time to 80% hemoglobin recovery was 32 days in subjects who received iron and 158 days in those who did not (P<0.001). In the higher-ferritin group, the mean time to 80% hemoglobin recovery was 31 days in subjects who received iron and 78 days in those who did not (P=0.02).

In the low-ferritin group, the median time to recovery of baseline ferritin levels was 21 days in subjects who received iron and more than 168 days in subjects who did not. In the higher-ferritin group, the median time to recovery of baseline ferritin levels was 107 days in subjects who received iron and more than 168 days in those who did not.

The median time to recovery of iron stores was 76 days in all subjects who received iron supplements and more than 168 days in those who did not (P<0.001). Sixty-seven percent of subjects who did not receive iron had failed to recover their iron stores by 168 days.

The researchers said these findings raise important considerations regarding the 8-week minimum waiting period between blood donations that is required in the US and Canada. This is a shorter period than those allowed in many other countries.

The study suggests that hemoglobin recovery differs according to a donor’s pre-donation ferritin level, but, even in iron-replete donors, the mean recovery was only 70% at 8 weeks.

Prolonging the minimum wait time between blood donations would allow for more thorough recovery, the researchers noted, but it could also compromise the blood supply. Furthermore, increasing the waiting period might not be adequate for donors who do not take iron supplements.

Blood donation

Photo by Charles Haymond

Low-dose oral iron supplementation can reduce the time to hemoglobin recovery after blood donation, according to a study published in JAMA.

Researchers found that a daily dose of ferrous gluconate (37.5 mg of elemental iron) reduced blood donors’ time to 80% hemoglobin recovery, whether the donors were iron-depleted (with ferritin levels of 26 ng/mL or lower) or iron-replete (with ferritin levels higher than 26 ng/mL).

Joseph E. Kiss, MD, of the Institute for Transfusion Medicine in Pittsburgh, Pennsylvania, and his colleagues conducted this study at 4 regional blood centers in the US.

The researchers randomized 215 subjects (who had not donated whole blood or red blood cells within 4 months) to receive one tablet of ferrous gluconate daily or no iron for 24 weeks after donating a unit of whole blood (500 mL).

The study’s primary outcomes were time to recovery of 80% of the post-donation decrease in hemoglobin and recovery of baseline ferritin levels.

The researchers found that subjects who received iron supplementation achieved 80% hemoglobin recovery more quickly than subjects who did not receive iron, regardless of ferritin levels.

In the low-ferritin group, the mean time to 80% hemoglobin recovery was 32 days in subjects who received iron and 158 days in those who did not (P<0.001). In the higher-ferritin group, the mean time to 80% hemoglobin recovery was 31 days in subjects who received iron and 78 days in those who did not (P=0.02).

In the low-ferritin group, the median time to recovery of baseline ferritin levels was 21 days in subjects who received iron and more than 168 days in subjects who did not. In the higher-ferritin group, the median time to recovery of baseline ferritin levels was 107 days in subjects who received iron and more than 168 days in those who did not.

The median time to recovery of iron stores was 76 days in all subjects who received iron supplements and more than 168 days in those who did not (P<0.001). Sixty-seven percent of subjects who did not receive iron had failed to recover their iron stores by 168 days.

The researchers said these findings raise important considerations regarding the 8-week minimum waiting period between blood donations that is required in the US and Canada. This is a shorter period than those allowed in many other countries.

The study suggests that hemoglobin recovery differs according to a donor’s pre-donation ferritin level, but, even in iron-replete donors, the mean recovery was only 70% at 8 weeks.

Prolonging the minimum wait time between blood donations would allow for more thorough recovery, the researchers noted, but it could also compromise the blood supply. Furthermore, increasing the waiting period might not be adequate for donors who do not take iron supplements.

Blood donation

Photo by Charles Haymond

Low-dose oral iron supplementation can reduce the time to hemoglobin recovery after blood donation, according to a study published in JAMA.

Researchers found that a daily dose of ferrous gluconate (37.5 mg of elemental iron) reduced blood donors’ time to 80% hemoglobin recovery, whether the donors were iron-depleted (with ferritin levels of 26 ng/mL or lower) or iron-replete (with ferritin levels higher than 26 ng/mL).

Joseph E. Kiss, MD, of the Institute for Transfusion Medicine in Pittsburgh, Pennsylvania, and his colleagues conducted this study at 4 regional blood centers in the US.

The researchers randomized 215 subjects (who had not donated whole blood or red blood cells within 4 months) to receive one tablet of ferrous gluconate daily or no iron for 24 weeks after donating a unit of whole blood (500 mL).

The study’s primary outcomes were time to recovery of 80% of the post-donation decrease in hemoglobin and recovery of baseline ferritin levels.

The researchers found that subjects who received iron supplementation achieved 80% hemoglobin recovery more quickly than subjects who did not receive iron, regardless of ferritin levels.

In the low-ferritin group, the mean time to 80% hemoglobin recovery was 32 days in subjects who received iron and 158 days in those who did not (P<0.001). In the higher-ferritin group, the mean time to 80% hemoglobin recovery was 31 days in subjects who received iron and 78 days in those who did not (P=0.02).

In the low-ferritin group, the median time to recovery of baseline ferritin levels was 21 days in subjects who received iron and more than 168 days in subjects who did not. In the higher-ferritin group, the median time to recovery of baseline ferritin levels was 107 days in subjects who received iron and more than 168 days in those who did not.

The median time to recovery of iron stores was 76 days in all subjects who received iron supplements and more than 168 days in those who did not (P<0.001). Sixty-seven percent of subjects who did not receive iron had failed to recover their iron stores by 168 days.

The researchers said these findings raise important considerations regarding the 8-week minimum waiting period between blood donations that is required in the US and Canada. This is a shorter period than those allowed in many other countries.

The study suggests that hemoglobin recovery differs according to a donor’s pre-donation ferritin level, but, even in iron-replete donors, the mean recovery was only 70% at 8 weeks.

Prolonging the minimum wait time between blood donations would allow for more thorough recovery, the researchers noted, but it could also compromise the blood supply. Furthermore, increasing the waiting period might not be adequate for donors who do not take iron supplements.

Follow a case and the associated discussion, to learn the latest evidence on fetal heart rate monitoring and the appropriate approaches to monitoring in labor and delivery units via an exercise sponsored by the Agency for Healthcare Research and Quality.

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Follow a case and the associated discussion, to learn the latest evidence on fetal heart rate monitoring and the appropriate approaches to monitoring in labor and delivery units via an exercise sponsored by the Agency for Healthcare Research and Quality.

Click here to learn more at the AHRQ Web M&M site.

Follow a case and the associated discussion, to learn the latest evidence on fetal heart rate monitoring and the appropriate approaches to monitoring in labor and delivery units via an exercise sponsored by the Agency for Healthcare Research and Quality.

Click here to learn more at the AHRQ Web M&M site.

During transitions in care, unintentional medication discrepancies commonly occur and can threaten patient safety. To improve medication reconciliation, and in response to Joint Commission requirements, most hospitals have developed medication reconciliation processes.

The successes of such programs have been varied, but there is now collective experience about effective approaches to medication reconciliation.

MARQUIS identifies best practices and offers a framework for assembling a team and adaptable implementation strategy.

To download a copy of the implementation strategy developed by the Society of Hospital Medicine, click here.

During transitions in care, unintentional medication discrepancies commonly occur and can threaten patient safety. To improve medication reconciliation, and in response to Joint Commission requirements, most hospitals have developed medication reconciliation processes.

The successes of such programs have been varied, but there is now collective experience about effective approaches to medication reconciliation.

MARQUIS identifies best practices and offers a framework for assembling a team and adaptable implementation strategy.

To download a copy of the implementation strategy developed by the Society of Hospital Medicine, click here.

During transitions in care, unintentional medication discrepancies commonly occur and can threaten patient safety. To improve medication reconciliation, and in response to Joint Commission requirements, most hospitals have developed medication reconciliation processes.

The successes of such programs have been varied, but there is now collective experience about effective approaches to medication reconciliation.

MARQUIS identifies best practices and offers a framework for assembling a team and adaptable implementation strategy.

To download a copy of the implementation strategy developed by the Society of Hospital Medicine, click here.