ATLANTA – Acute myocardial infarction is associated with a risk of stroke that extends beyond the 1-month time window currently considered the at-risk period, according to an analysis of Medicare data.

“The results of our study may allow clinicians to more accurately counsel patients regarding their stroke etiology and may allow refinement of stroke etiology classification systems and clinical trial selection criteria,” lead study author Alexander E. Merkler, MD, said in an interview in advance of the annual meeting of the American Neurological Association.

In an effort to better understand the duration of heightened stroke risk after acute myocardial infarction, Dr. Merkler, a neurologist at New York–based Weill Cornell Medicine, and his colleagues conducted a retrospective cohort study using inpatient and outpatient claims during 2008-2015 from a nationally representative 5% sample of Medicare beneficiaries who were at least 66 years old. They used previously validated ICD-9-CM diagnosis codes to ascertain the exposure variable of acute MI and the outcome of ischemic stroke but excluded strokes that occurred during an acute MI hospitalization.


Patients were censored at the time of ischemic stroke, death, end of Medicare coverage, or by Sept. 30, 2015. The researchers fit Cox regression models separately for the groups with and without acute MI to examine its association with ischemic stroke after adjusting for demographics, stroke risk factors, and Charlson comorbidities. Next, they used the corresponding survival probabilities to compute the hazard ratio (HR) in each 4-week interval after discharge, up to week 12. They also conducted a subgroup analysis to evaluate the duration of heightened ischemic stroke risk by MI type: ST-segment elevation MI (STEMI) versus non-STEMI (NSTEMI).

Dr. Merkler and his colleagues drew from data on 1.7 million eligible beneficiaries. Of these, 46,182 were hospitalized for acute MI and 80,466 for ischemic stroke. After they adjusted for demographics, stroke risk factors, and Charlson comorbidities, the researchers found that the risk of ischemic stroke was highest in the first 4 weeks after discharge from the MI hospitalization (HR, 2.7), yet remained elevated during weeks 5-8 (HR, 2.0) and weeks 9-12 (HR, 1.6). It was no longer significantly elevated afterward. The prolonged period of heightened ischemic stroke risk was evident in patients with both STEMI and NSTEMI.

“We were surprised by how long the risk of stroke lasts after MI,” Dr. Merkler said. He acknowledged certain limitations of the analysis, including the fact that patients were all over the age of 65 years. “In addition, we lack granular detail such as severity of MI [and] the extent of stroke work-up,” he said.

Dr. Merkler disclosed that he is supported by a grant from the National Institutes of Health and by the Leon Levy Foundation in Neuroscience. Most of his coauthors are also supported by NIH grants.

[email protected]

Source: Ann Neurol. 2018;84[S22]:S146-7, Abstract M122.

ATLANTA – Acute myocardial infarction is associated with a risk of stroke that extends beyond the 1-month time window currently considered the at-risk period, according to an analysis of Medicare data.

“The results of our study may allow clinicians to more accurately counsel patients regarding their stroke etiology and may allow refinement of stroke etiology classification systems and clinical trial selection criteria,” lead study author Alexander E. Merkler, MD, said in an interview in advance of the annual meeting of the American Neurological Association.

In an effort to better understand the duration of heightened stroke risk after acute myocardial infarction, Dr. Merkler, a neurologist at New York–based Weill Cornell Medicine, and his colleagues conducted a retrospective cohort study using inpatient and outpatient claims during 2008-2015 from a nationally representative 5% sample of Medicare beneficiaries who were at least 66 years old. They used previously validated ICD-9-CM diagnosis codes to ascertain the exposure variable of acute MI and the outcome of ischemic stroke but excluded strokes that occurred during an acute MI hospitalization.


Patients were censored at the time of ischemic stroke, death, end of Medicare coverage, or by Sept. 30, 2015. The researchers fit Cox regression models separately for the groups with and without acute MI to examine its association with ischemic stroke after adjusting for demographics, stroke risk factors, and Charlson comorbidities. Next, they used the corresponding survival probabilities to compute the hazard ratio (HR) in each 4-week interval after discharge, up to week 12. They also conducted a subgroup analysis to evaluate the duration of heightened ischemic stroke risk by MI type: ST-segment elevation MI (STEMI) versus non-STEMI (NSTEMI).

Dr. Merkler and his colleagues drew from data on 1.7 million eligible beneficiaries. Of these, 46,182 were hospitalized for acute MI and 80,466 for ischemic stroke. After they adjusted for demographics, stroke risk factors, and Charlson comorbidities, the researchers found that the risk of ischemic stroke was highest in the first 4 weeks after discharge from the MI hospitalization (HR, 2.7), yet remained elevated during weeks 5-8 (HR, 2.0) and weeks 9-12 (HR, 1.6). It was no longer significantly elevated afterward. The prolonged period of heightened ischemic stroke risk was evident in patients with both STEMI and NSTEMI.

“We were surprised by how long the risk of stroke lasts after MI,” Dr. Merkler said. He acknowledged certain limitations of the analysis, including the fact that patients were all over the age of 65 years. “In addition, we lack granular detail such as severity of MI [and] the extent of stroke work-up,” he said.

Dr. Merkler disclosed that he is supported by a grant from the National Institutes of Health and by the Leon Levy Foundation in Neuroscience. Most of his coauthors are also supported by NIH grants.

[email protected]

Source: Ann Neurol. 2018;84[S22]:S146-7, Abstract M122.

ATLANTA – Acute myocardial infarction is associated with a risk of stroke that extends beyond the 1-month time window currently considered the at-risk period, according to an analysis of Medicare data.

“The results of our study may allow clinicians to more accurately counsel patients regarding their stroke etiology and may allow refinement of stroke etiology classification systems and clinical trial selection criteria,” lead study author Alexander E. Merkler, MD, said in an interview in advance of the annual meeting of the American Neurological Association.

In an effort to better understand the duration of heightened stroke risk after acute myocardial infarction, Dr. Merkler, a neurologist at New York–based Weill Cornell Medicine, and his colleagues conducted a retrospective cohort study using inpatient and outpatient claims during 2008-2015 from a nationally representative 5% sample of Medicare beneficiaries who were at least 66 years old. They used previously validated ICD-9-CM diagnosis codes to ascertain the exposure variable of acute MI and the outcome of ischemic stroke but excluded strokes that occurred during an acute MI hospitalization.


Patients were censored at the time of ischemic stroke, death, end of Medicare coverage, or by Sept. 30, 2015. The researchers fit Cox regression models separately for the groups with and without acute MI to examine its association with ischemic stroke after adjusting for demographics, stroke risk factors, and Charlson comorbidities. Next, they used the corresponding survival probabilities to compute the hazard ratio (HR) in each 4-week interval after discharge, up to week 12. They also conducted a subgroup analysis to evaluate the duration of heightened ischemic stroke risk by MI type: ST-segment elevation MI (STEMI) versus non-STEMI (NSTEMI).

Dr. Merkler and his colleagues drew from data on 1.7 million eligible beneficiaries. Of these, 46,182 were hospitalized for acute MI and 80,466 for ischemic stroke. After they adjusted for demographics, stroke risk factors, and Charlson comorbidities, the researchers found that the risk of ischemic stroke was highest in the first 4 weeks after discharge from the MI hospitalization (HR, 2.7), yet remained elevated during weeks 5-8 (HR, 2.0) and weeks 9-12 (HR, 1.6). It was no longer significantly elevated afterward. The prolonged period of heightened ischemic stroke risk was evident in patients with both STEMI and NSTEMI.

“We were surprised by how long the risk of stroke lasts after MI,” Dr. Merkler said. He acknowledged certain limitations of the analysis, including the fact that patients were all over the age of 65 years. “In addition, we lack granular detail such as severity of MI [and] the extent of stroke work-up,” he said.

Dr. Merkler disclosed that he is supported by a grant from the National Institutes of Health and by the Leon Levy Foundation in Neuroscience. Most of his coauthors are also supported by NIH grants.

[email protected]

Source: Ann Neurol. 2018;84[S22]:S146-7, Abstract M122.

Researchers from general obstetrics and gynecology (ob.gyn.) practices in New York and Connecticut have shown that a 4-week intervention may improve genetic screening and testing rates for hereditary breast and ovarian cancers (HBOC).

Genetic screening and testing can reduce the morbidity and mortality from breast, ovarian, and endometrial cancers through prevention and early detection. Mark S. DeFrancesco, MD, of Westwood Women’s Health, Waterbury, Conn., and his colleagues reported that, in spite of the American College of Obstetricians and Gynecologists’ recommendation for ob.gyns. to regularly screen, counsel, and refer accordingly for HBOC (Obstet Gynecol. 2015;125:153843), the “incorporation of hereditary cancer risk assessment and testing remains underutilized in the [ob.gyn.] setting.” The authors have addressed this issue in their own practice with promising results and important caveats (Obstet Gynecol 2018;132:1121-9).

The intervention included a process evaluation, improvements to patient work flow, and training of providers by genetic counselors and engineering personnel from the testing laboratory (Myriad Genetics), which provided support for the study. Patients in the study completed a family history questionnaire and, those meeting National Comprehensive Cancer Center Network criteria for genetic testing, were given pretest counseling and offered testing on the same day or referral for testing within 2 weeks.

Of the 3,811 women who completed the questionnaire, 24% (906) met NCCN criteria, 90% of whom were offered testing. However, only 52% (165) of patients who agreed to testing underwent genetic evaluation. This included 70% of patients who were offered same-day testing and 35% of patients who were offered a referral appointment for testing.

Conversations about HBOC and genetic testing can be complicated and may not be a patient’s initial priority. The authors should be commended for identifying the vast majority of high-risk patients. However, only half of patients meeting criteria completed testing and 10% who should have been offered testing were not – numbers still well below target.

Incorporation of family history questionnaires should become commonplace in the generalist’s office and optimizing EHRs may be an opportunity for rapid risk interpretation. As the success of same-day genetic testing was striking, opportunities for partnerships with insurance companies and private laboratories are likely needed to make this a more feasible option. Lastly, assessing women’s knowledge and attitudes around genetic testing could help to more specifically address barriers to testing in future interventions.

Improving genetic screening and testing completion rates requires a coordinated effort. Using tools and applications to optimize convenience (same-day testing, telemedicine) and simplification (electronic screening platforms), we can strive to appropriately detect all women at high risk for hereditary breast and ovarian cancers.

Michelle Lightfoot is a gynecologic oncology fellow at the Ohio State University in Columbus. She has no relevant financial disclosures. Email her at [email protected].

Researchers from general obstetrics and gynecology (ob.gyn.) practices in New York and Connecticut have shown that a 4-week intervention may improve genetic screening and testing rates for hereditary breast and ovarian cancers (HBOC).

Genetic screening and testing can reduce the morbidity and mortality from breast, ovarian, and endometrial cancers through prevention and early detection. Mark S. DeFrancesco, MD, of Westwood Women’s Health, Waterbury, Conn., and his colleagues reported that, in spite of the American College of Obstetricians and Gynecologists’ recommendation for ob.gyns. to regularly screen, counsel, and refer accordingly for HBOC (Obstet Gynecol. 2015;125:153843), the “incorporation of hereditary cancer risk assessment and testing remains underutilized in the [ob.gyn.] setting.” The authors have addressed this issue in their own practice with promising results and important caveats (Obstet Gynecol 2018;132:1121-9).

The intervention included a process evaluation, improvements to patient work flow, and training of providers by genetic counselors and engineering personnel from the testing laboratory (Myriad Genetics), which provided support for the study. Patients in the study completed a family history questionnaire and, those meeting National Comprehensive Cancer Center Network criteria for genetic testing, were given pretest counseling and offered testing on the same day or referral for testing within 2 weeks.

Of the 3,811 women who completed the questionnaire, 24% (906) met NCCN criteria, 90% of whom were offered testing. However, only 52% (165) of patients who agreed to testing underwent genetic evaluation. This included 70% of patients who were offered same-day testing and 35% of patients who were offered a referral appointment for testing.

Conversations about HBOC and genetic testing can be complicated and may not be a patient’s initial priority. The authors should be commended for identifying the vast majority of high-risk patients. However, only half of patients meeting criteria completed testing and 10% who should have been offered testing were not – numbers still well below target.

Incorporation of family history questionnaires should become commonplace in the generalist’s office and optimizing EHRs may be an opportunity for rapid risk interpretation. As the success of same-day genetic testing was striking, opportunities for partnerships with insurance companies and private laboratories are likely needed to make this a more feasible option. Lastly, assessing women’s knowledge and attitudes around genetic testing could help to more specifically address barriers to testing in future interventions.

Improving genetic screening and testing completion rates requires a coordinated effort. Using tools and applications to optimize convenience (same-day testing, telemedicine) and simplification (electronic screening platforms), we can strive to appropriately detect all women at high risk for hereditary breast and ovarian cancers.

Michelle Lightfoot is a gynecologic oncology fellow at the Ohio State University in Columbus. She has no relevant financial disclosures. Email her at [email protected].

Researchers from general obstetrics and gynecology (ob.gyn.) practices in New York and Connecticut have shown that a 4-week intervention may improve genetic screening and testing rates for hereditary breast and ovarian cancers (HBOC).

Genetic screening and testing can reduce the morbidity and mortality from breast, ovarian, and endometrial cancers through prevention and early detection. Mark S. DeFrancesco, MD, of Westwood Women’s Health, Waterbury, Conn., and his colleagues reported that, in spite of the American College of Obstetricians and Gynecologists’ recommendation for ob.gyns. to regularly screen, counsel, and refer accordingly for HBOC (Obstet Gynecol. 2015;125:153843), the “incorporation of hereditary cancer risk assessment and testing remains underutilized in the [ob.gyn.] setting.” The authors have addressed this issue in their own practice with promising results and important caveats (Obstet Gynecol 2018;132:1121-9).

The intervention included a process evaluation, improvements to patient work flow, and training of providers by genetic counselors and engineering personnel from the testing laboratory (Myriad Genetics), which provided support for the study. Patients in the study completed a family history questionnaire and, those meeting National Comprehensive Cancer Center Network criteria for genetic testing, were given pretest counseling and offered testing on the same day or referral for testing within 2 weeks.

Of the 3,811 women who completed the questionnaire, 24% (906) met NCCN criteria, 90% of whom were offered testing. However, only 52% (165) of patients who agreed to testing underwent genetic evaluation. This included 70% of patients who were offered same-day testing and 35% of patients who were offered a referral appointment for testing.

Conversations about HBOC and genetic testing can be complicated and may not be a patient’s initial priority. The authors should be commended for identifying the vast majority of high-risk patients. However, only half of patients meeting criteria completed testing and 10% who should have been offered testing were not – numbers still well below target.

Incorporation of family history questionnaires should become commonplace in the generalist’s office and optimizing EHRs may be an opportunity for rapid risk interpretation. As the success of same-day genetic testing was striking, opportunities for partnerships with insurance companies and private laboratories are likely needed to make this a more feasible option. Lastly, assessing women’s knowledge and attitudes around genetic testing could help to more specifically address barriers to testing in future interventions.

Improving genetic screening and testing completion rates requires a coordinated effort. Using tools and applications to optimize convenience (same-day testing, telemedicine) and simplification (electronic screening platforms), we can strive to appropriately detect all women at high risk for hereditary breast and ovarian cancers.

Michelle Lightfoot is a gynecologic oncology fellow at the Ohio State University in Columbus. She has no relevant financial disclosures. Email her at [email protected].

PHILADELPHIA – Use of a device on the distal end of a colonoscope to expand the view of the colon lowered the mean inspection time during colonoscopy without significantly reducing adenoma or sessile serrated polyp detection rate, according to a presentation at the annual meeting of the American College of Gastroenterology.

“The finger projections on the tip of the Endocuff can engage the colonic folds, and that allows us to see the proximal sides of these folds,” Seth A. Gross, MD, chief of gastroenterology at NYU Langone Health Tisch Hospital in New York, said in his presentation. “It also changes topography and temporarily stretches different segments of the colon depending on where you are to help expose more surface area and ultimately identify more polyps.”

Dr. Gross and his colleagues analyzed the withdrawal time of colonoscopy with the Endocuff Vision (Olympus, Center Valley, Penn.) in 101 patients, compared with withdrawal time during a standard colonoscopy in 99 patients as measured by stopwatch. Other endpoints in the study included insertion time, adenoma detection rate (ADR), sessile serrated polyp detection (SSPD), and number of adenomas and sessile serrated polyps per colonoscopy. Patients were included if they were at least 40 years old with a screening, surveillance, or diagnostic indication for colonoscopy; they were excluded if they had inflammatory bowel disease, polyposis syndrome, prior colon resection, prior colorectal polyp or cancer, previous incomplete colonoscopy or severe diverticular disease.

Inspection time in the Endocuff group was 6.3 minutes, compared with 8.2 minutes in the standard colonoscopy group (P less than .001), and insertion time was 9.9 minutes in the Endocuff group, compared with 11.3 minutes in the standard colonoscopy group. A multivariate analysis showed the shorter inspection times in the Endocuff group remained significant (P less than .0001).

In the Endocuff group, ADR was 61.4% with 1.43 adenomas per colonoscopy, while the standard colonoscopy group had an ADR of 52.5% with an adenoma detection rate of 1.07 per colonoscopy. SSPD was 19.8% in the Endocuff group and 11.1% in the standard group with a SSPD per colonoscopy of 0.27 and 0.21, respectively.

The study was unblinded and there were two endoscopists performing the procedures, which raises the question of whether the results could be generalized to other gastroenterologists, Dr. Gross noted.

“We recommend that future studies that are meant to be powered for adenoma detection rate and sessile serrated lesions be done to sort of validate this, and probably have more endoscopists involved in a study like this,” Dr. Gross said. “But this is the start of an interesting conversation where one could be more efficient without sacrificing our detection rate for both adenomas and sessile serrated lesions.”

Dr. Gross reports a consultancy with Olympus.

SOURCE: Gross SA et al. ACG 2018, Presentation 37.

PHILADELPHIA – Use of a device on the distal end of a colonoscope to expand the view of the colon lowered the mean inspection time during colonoscopy without significantly reducing adenoma or sessile serrated polyp detection rate, according to a presentation at the annual meeting of the American College of Gastroenterology.

“The finger projections on the tip of the Endocuff can engage the colonic folds, and that allows us to see the proximal sides of these folds,” Seth A. Gross, MD, chief of gastroenterology at NYU Langone Health Tisch Hospital in New York, said in his presentation. “It also changes topography and temporarily stretches different segments of the colon depending on where you are to help expose more surface area and ultimately identify more polyps.”

Dr. Gross and his colleagues analyzed the withdrawal time of colonoscopy with the Endocuff Vision (Olympus, Center Valley, Penn.) in 101 patients, compared with withdrawal time during a standard colonoscopy in 99 patients as measured by stopwatch. Other endpoints in the study included insertion time, adenoma detection rate (ADR), sessile serrated polyp detection (SSPD), and number of adenomas and sessile serrated polyps per colonoscopy. Patients were included if they were at least 40 years old with a screening, surveillance, or diagnostic indication for colonoscopy; they were excluded if they had inflammatory bowel disease, polyposis syndrome, prior colon resection, prior colorectal polyp or cancer, previous incomplete colonoscopy or severe diverticular disease.

Inspection time in the Endocuff group was 6.3 minutes, compared with 8.2 minutes in the standard colonoscopy group (P less than .001), and insertion time was 9.9 minutes in the Endocuff group, compared with 11.3 minutes in the standard colonoscopy group. A multivariate analysis showed the shorter inspection times in the Endocuff group remained significant (P less than .0001).

In the Endocuff group, ADR was 61.4% with 1.43 adenomas per colonoscopy, while the standard colonoscopy group had an ADR of 52.5% with an adenoma detection rate of 1.07 per colonoscopy. SSPD was 19.8% in the Endocuff group and 11.1% in the standard group with a SSPD per colonoscopy of 0.27 and 0.21, respectively.

The study was unblinded and there were two endoscopists performing the procedures, which raises the question of whether the results could be generalized to other gastroenterologists, Dr. Gross noted.

“We recommend that future studies that are meant to be powered for adenoma detection rate and sessile serrated lesions be done to sort of validate this, and probably have more endoscopists involved in a study like this,” Dr. Gross said. “But this is the start of an interesting conversation where one could be more efficient without sacrificing our detection rate for both adenomas and sessile serrated lesions.”

Dr. Gross reports a consultancy with Olympus.

SOURCE: Gross SA et al. ACG 2018, Presentation 37.

PHILADELPHIA – Use of a device on the distal end of a colonoscope to expand the view of the colon lowered the mean inspection time during colonoscopy without significantly reducing adenoma or sessile serrated polyp detection rate, according to a presentation at the annual meeting of the American College of Gastroenterology.

“The finger projections on the tip of the Endocuff can engage the colonic folds, and that allows us to see the proximal sides of these folds,” Seth A. Gross, MD, chief of gastroenterology at NYU Langone Health Tisch Hospital in New York, said in his presentation. “It also changes topography and temporarily stretches different segments of the colon depending on where you are to help expose more surface area and ultimately identify more polyps.”

Dr. Gross and his colleagues analyzed the withdrawal time of colonoscopy with the Endocuff Vision (Olympus, Center Valley, Penn.) in 101 patients, compared with withdrawal time during a standard colonoscopy in 99 patients as measured by stopwatch. Other endpoints in the study included insertion time, adenoma detection rate (ADR), sessile serrated polyp detection (SSPD), and number of adenomas and sessile serrated polyps per colonoscopy. Patients were included if they were at least 40 years old with a screening, surveillance, or diagnostic indication for colonoscopy; they were excluded if they had inflammatory bowel disease, polyposis syndrome, prior colon resection, prior colorectal polyp or cancer, previous incomplete colonoscopy or severe diverticular disease.

Inspection time in the Endocuff group was 6.3 minutes, compared with 8.2 minutes in the standard colonoscopy group (P less than .001), and insertion time was 9.9 minutes in the Endocuff group, compared with 11.3 minutes in the standard colonoscopy group. A multivariate analysis showed the shorter inspection times in the Endocuff group remained significant (P less than .0001).

In the Endocuff group, ADR was 61.4% with 1.43 adenomas per colonoscopy, while the standard colonoscopy group had an ADR of 52.5% with an adenoma detection rate of 1.07 per colonoscopy. SSPD was 19.8% in the Endocuff group and 11.1% in the standard group with a SSPD per colonoscopy of 0.27 and 0.21, respectively.

The study was unblinded and there were two endoscopists performing the procedures, which raises the question of whether the results could be generalized to other gastroenterologists, Dr. Gross noted.

“We recommend that future studies that are meant to be powered for adenoma detection rate and sessile serrated lesions be done to sort of validate this, and probably have more endoscopists involved in a study like this,” Dr. Gross said. “But this is the start of an interesting conversation where one could be more efficient without sacrificing our detection rate for both adenomas and sessile serrated lesions.”

Dr. Gross reports a consultancy with Olympus.

SOURCE: Gross SA et al. ACG 2018, Presentation 37.

In this edition, Carol A. Bernstein, MD, joins Lorenzo Norris, MD, to discuss physician burnout and mental health.

In this edition, Carol A. Bernstein, MD, joins Lorenzo Norris, MD, to discuss physician burnout and mental health.

In this edition, Carol A. Bernstein, MD, joins Lorenzo Norris, MD, to discuss physician burnout and mental health.

The CDC’s lifestyle change program (LCP), part of the National Diabetes Prevention Program, teaches people with prediabetes practical, real-life changes. Those changes can be enough to reduce the risk of type 2 diabetes by as much as 58%—or even 71% for people aged > 60 years. But are enough people getting the opportunity to participate?

CDC researchers assessed the availability of in-person LCP classes by diabetes incidence and socioeconomic status at the county level. They mapped 1,558 LCP class locations. They found classes in 711 (23%) US counties as of March 2017 (there may be more now, the researchers say).

But the classes were not necessarily located where they could do the most good, the researchers found. Only 17% of the counties with the highest diabetes incidence and 10% of counties with the most socioeconomic disadvantage had a publicly available class location. By contrast, 26.8% of counties in the lowest tertile of incidence had class locations.

The researchers say policy makers, program planners, and others engaged in expanding the availability of the classes can use the information to prioritize locations, especially for underrepresented populations.

The CDC’s lifestyle change program (LCP), part of the National Diabetes Prevention Program, teaches people with prediabetes practical, real-life changes. Those changes can be enough to reduce the risk of type 2 diabetes by as much as 58%—or even 71% for people aged > 60 years. But are enough people getting the opportunity to participate?

CDC researchers assessed the availability of in-person LCP classes by diabetes incidence and socioeconomic status at the county level. They mapped 1,558 LCP class locations. They found classes in 711 (23%) US counties as of March 2017 (there may be more now, the researchers say).

But the classes were not necessarily located where they could do the most good, the researchers found. Only 17% of the counties with the highest diabetes incidence and 10% of counties with the most socioeconomic disadvantage had a publicly available class location. By contrast, 26.8% of counties in the lowest tertile of incidence had class locations.

The researchers say policy makers, program planners, and others engaged in expanding the availability of the classes can use the information to prioritize locations, especially for underrepresented populations.

The CDC’s lifestyle change program (LCP), part of the National Diabetes Prevention Program, teaches people with prediabetes practical, real-life changes. Those changes can be enough to reduce the risk of type 2 diabetes by as much as 58%—or even 71% for people aged > 60 years. But are enough people getting the opportunity to participate?

CDC researchers assessed the availability of in-person LCP classes by diabetes incidence and socioeconomic status at the county level. They mapped 1,558 LCP class locations. They found classes in 711 (23%) US counties as of March 2017 (there may be more now, the researchers say).

But the classes were not necessarily located where they could do the most good, the researchers found. Only 17% of the counties with the highest diabetes incidence and 10% of counties with the most socioeconomic disadvantage had a publicly available class location. By contrast, 26.8% of counties in the lowest tertile of incidence had class locations.

The researchers say policy makers, program planners, and others engaged in expanding the availability of the classes can use the information to prioritize locations, especially for underrepresented populations.

The Ottawa Hospital

Preclinical research has revealed a potential treatment for chemotherapy-resistant acute myeloid leukemia (AML).

Researchers characterized a mechanism of chemotherapy resistance in AML and found that MDM2 is a key player in this dysregulated signaling pathway.

They tested MDM2 inhibitors and found these drugs could sensitize resistant AML to chemotherapy in vitro and in vivo.

In fact, mice with refractory AML responded to standard induction therapy when combined with an MDM2 inhibitor, showing no signs of disease and prolonged survival.

These results were published in Cancer Discovery.

“We were blown away when we saw the results,” said study author William Stanford, PhD, of Ottawa Hospital Research Institute in Ontario, Canada.

“If these findings hold up in clinical trials, we could have a new treatment for people who would almost certainly die of their disease today.”

Mechanism of resistance

Dr. Stanford’s research began with the protein MTF2. He and his colleagues previously found that MTF2 plays a role in erythropoiesis, and the team wanted to determine if MTF2 also plays a role in AML.

Using AML samples from patients treated at The Ottawa Hospital, the researchers found the mean survival was three times longer in patients with normal MTF2 activity than in patients with low MTF2 activity.

“Initially, we thought that MTF2 could be an important biomarker to identify patients who might benefit from experimental therapies,” Dr. Stanford said. “But then we started thinking that if we could understand what MTF2 was doing, maybe we could use this information to develop a new treatment.”

Dr. Stanford and his colleagues discovered that MTF2 represses MDM2, a protein that helps cells resist chemotherapy.

The team found that MTF2-deficient cells overexpress MDM2, which inhibits p53, and this leads to defects in cell-cycle regulation and apoptosis that enable resistance to chemotherapy.

Testing MDM2 inhibitors

Since MDM2 inhibitors are already being tested in clinical trials for other cancers, Dr. Stanford and his colleagues tested these inhibitors in vitro and in mouse models of chemotherapy-resistant AML.

The in vitro experiments included two MDM2 inhibitors—Nutlin3A and MI-773—combined with daunorubicin or cytarabine.

The researchers found that refractory, MTF2-deficient AML cells underwent apoptosis when treated with either daunorubicin or cytarabine in combination with Nutlin3A or MI-773. The effect was comparable to that observed in AML cells with normal MTF2.

The team found that Nutlin3A was more efficient at sensitizing refractory, MTF2-deficient AML cells to daunorubicin, so they used Nutlin3A in the in vivo experiments.

For these experiments, the researchers tested Nutlin3A in mice injected with either chemotherapy-responsive AML cells (with normal MTF2) or refractory, MTF2-deficient AML cells.

Once the mice had “a substantial leukemic burden” (≥ 20% CD45+CD33+ leukemic blasts in their peripheral blood), they were randomized to receive vehicle control, Nutlin3A, standard induction therapy, or induction plus Nutlin3A.

The mice engrafted with chemotherapy-responsive AML cells did not respond to vehicle control or Nutlin3A alone. However, they did respond to standard induction and induction plus Nutlin3A, surviving until the end of the experiment at 16 weeks.

Among the mice engrafted with refractory, MTF2-deficient AML cells, only those animals treated with induction plus Nutlin3A survived until the end of the experiment.

The researchers also noted a “dramatic loss” in the blast-containing CD45+CD33+ and CD34+CD38− populations in mice treated with induction plus Nutlin3A.

To assess residual disease, the researchers performed secondary transplants with cells from mice that had engrafted with refractory, MTF2-deficient AML cells but responded to induction plus Nutlin3A.

The recipient mice had no evidence of AML at 16 weeks after transplant when the experiment ended.

Dr. Stanford and his colleagues are now trying to obtain pharmaceutical-grade MDM2 inhibitors to conduct trials in AML patients at The Ottawa Hospital.

The researchers are also screening libraries of approved drugs to see if any of these can block MDM2, and they are working with a biotech company to develop a test to identify chemotherapy-resistant AML patients who would respond to MDM2 inhibitors.

The current research was supported by grants from the Canadian Cancer Society Research Institute, Canadian Institutes of Health Research, Cancer Research Society, National Institutes of Health, and a Tier 1 Canada Research Chair in Integrative Stem Cell Biology. One study author reported a relationship with Epicypher, Inc. No other conflicts of interest were reported.

The Ottawa Hospital

Preclinical research has revealed a potential treatment for chemotherapy-resistant acute myeloid leukemia (AML).

Researchers characterized a mechanism of chemotherapy resistance in AML and found that MDM2 is a key player in this dysregulated signaling pathway.

They tested MDM2 inhibitors and found these drugs could sensitize resistant AML to chemotherapy in vitro and in vivo.

In fact, mice with refractory AML responded to standard induction therapy when combined with an MDM2 inhibitor, showing no signs of disease and prolonged survival.

These results were published in Cancer Discovery.

“We were blown away when we saw the results,” said study author William Stanford, PhD, of Ottawa Hospital Research Institute in Ontario, Canada.

“If these findings hold up in clinical trials, we could have a new treatment for people who would almost certainly die of their disease today.”

Mechanism of resistance

Dr. Stanford’s research began with the protein MTF2. He and his colleagues previously found that MTF2 plays a role in erythropoiesis, and the team wanted to determine if MTF2 also plays a role in AML.

Using AML samples from patients treated at The Ottawa Hospital, the researchers found the mean survival was three times longer in patients with normal MTF2 activity than in patients with low MTF2 activity.

“Initially, we thought that MTF2 could be an important biomarker to identify patients who might benefit from experimental therapies,” Dr. Stanford said. “But then we started thinking that if we could understand what MTF2 was doing, maybe we could use this information to develop a new treatment.”

Dr. Stanford and his colleagues discovered that MTF2 represses MDM2, a protein that helps cells resist chemotherapy.

The team found that MTF2-deficient cells overexpress MDM2, which inhibits p53, and this leads to defects in cell-cycle regulation and apoptosis that enable resistance to chemotherapy.

Testing MDM2 inhibitors

Since MDM2 inhibitors are already being tested in clinical trials for other cancers, Dr. Stanford and his colleagues tested these inhibitors in vitro and in mouse models of chemotherapy-resistant AML.

The in vitro experiments included two MDM2 inhibitors—Nutlin3A and MI-773—combined with daunorubicin or cytarabine.

The researchers found that refractory, MTF2-deficient AML cells underwent apoptosis when treated with either daunorubicin or cytarabine in combination with Nutlin3A or MI-773. The effect was comparable to that observed in AML cells with normal MTF2.

The team found that Nutlin3A was more efficient at sensitizing refractory, MTF2-deficient AML cells to daunorubicin, so they used Nutlin3A in the in vivo experiments.

For these experiments, the researchers tested Nutlin3A in mice injected with either chemotherapy-responsive AML cells (with normal MTF2) or refractory, MTF2-deficient AML cells.

Once the mice had “a substantial leukemic burden” (≥ 20% CD45+CD33+ leukemic blasts in their peripheral blood), they were randomized to receive vehicle control, Nutlin3A, standard induction therapy, or induction plus Nutlin3A.

The mice engrafted with chemotherapy-responsive AML cells did not respond to vehicle control or Nutlin3A alone. However, they did respond to standard induction and induction plus Nutlin3A, surviving until the end of the experiment at 16 weeks.

Among the mice engrafted with refractory, MTF2-deficient AML cells, only those animals treated with induction plus Nutlin3A survived until the end of the experiment.

The researchers also noted a “dramatic loss” in the blast-containing CD45+CD33+ and CD34+CD38− populations in mice treated with induction plus Nutlin3A.

To assess residual disease, the researchers performed secondary transplants with cells from mice that had engrafted with refractory, MTF2-deficient AML cells but responded to induction plus Nutlin3A.

The recipient mice had no evidence of AML at 16 weeks after transplant when the experiment ended.

Dr. Stanford and his colleagues are now trying to obtain pharmaceutical-grade MDM2 inhibitors to conduct trials in AML patients at The Ottawa Hospital.

The researchers are also screening libraries of approved drugs to see if any of these can block MDM2, and they are working with a biotech company to develop a test to identify chemotherapy-resistant AML patients who would respond to MDM2 inhibitors.

The current research was supported by grants from the Canadian Cancer Society Research Institute, Canadian Institutes of Health Research, Cancer Research Society, National Institutes of Health, and a Tier 1 Canada Research Chair in Integrative Stem Cell Biology. One study author reported a relationship with Epicypher, Inc. No other conflicts of interest were reported.

The Ottawa Hospital

Preclinical research has revealed a potential treatment for chemotherapy-resistant acute myeloid leukemia (AML).

Researchers characterized a mechanism of chemotherapy resistance in AML and found that MDM2 is a key player in this dysregulated signaling pathway.

They tested MDM2 inhibitors and found these drugs could sensitize resistant AML to chemotherapy in vitro and in vivo.

In fact, mice with refractory AML responded to standard induction therapy when combined with an MDM2 inhibitor, showing no signs of disease and prolonged survival.

These results were published in Cancer Discovery.

“We were blown away when we saw the results,” said study author William Stanford, PhD, of Ottawa Hospital Research Institute in Ontario, Canada.

“If these findings hold up in clinical trials, we could have a new treatment for people who would almost certainly die of their disease today.”

Mechanism of resistance

Dr. Stanford’s research began with the protein MTF2. He and his colleagues previously found that MTF2 plays a role in erythropoiesis, and the team wanted to determine if MTF2 also plays a role in AML.

Using AML samples from patients treated at The Ottawa Hospital, the researchers found the mean survival was three times longer in patients with normal MTF2 activity than in patients with low MTF2 activity.

“Initially, we thought that MTF2 could be an important biomarker to identify patients who might benefit from experimental therapies,” Dr. Stanford said. “But then we started thinking that if we could understand what MTF2 was doing, maybe we could use this information to develop a new treatment.”

Dr. Stanford and his colleagues discovered that MTF2 represses MDM2, a protein that helps cells resist chemotherapy.

The team found that MTF2-deficient cells overexpress MDM2, which inhibits p53, and this leads to defects in cell-cycle regulation and apoptosis that enable resistance to chemotherapy.

Testing MDM2 inhibitors

Since MDM2 inhibitors are already being tested in clinical trials for other cancers, Dr. Stanford and his colleagues tested these inhibitors in vitro and in mouse models of chemotherapy-resistant AML.

The in vitro experiments included two MDM2 inhibitors—Nutlin3A and MI-773—combined with daunorubicin or cytarabine.

The researchers found that refractory, MTF2-deficient AML cells underwent apoptosis when treated with either daunorubicin or cytarabine in combination with Nutlin3A or MI-773. The effect was comparable to that observed in AML cells with normal MTF2.

The team found that Nutlin3A was more efficient at sensitizing refractory, MTF2-deficient AML cells to daunorubicin, so they used Nutlin3A in the in vivo experiments.

For these experiments, the researchers tested Nutlin3A in mice injected with either chemotherapy-responsive AML cells (with normal MTF2) or refractory, MTF2-deficient AML cells.

Once the mice had “a substantial leukemic burden” (≥ 20% CD45+CD33+ leukemic blasts in their peripheral blood), they were randomized to receive vehicle control, Nutlin3A, standard induction therapy, or induction plus Nutlin3A.

The mice engrafted with chemotherapy-responsive AML cells did not respond to vehicle control or Nutlin3A alone. However, they did respond to standard induction and induction plus Nutlin3A, surviving until the end of the experiment at 16 weeks.

Among the mice engrafted with refractory, MTF2-deficient AML cells, only those animals treated with induction plus Nutlin3A survived until the end of the experiment.

The researchers also noted a “dramatic loss” in the blast-containing CD45+CD33+ and CD34+CD38− populations in mice treated with induction plus Nutlin3A.

To assess residual disease, the researchers performed secondary transplants with cells from mice that had engrafted with refractory, MTF2-deficient AML cells but responded to induction plus Nutlin3A.

The recipient mice had no evidence of AML at 16 weeks after transplant when the experiment ended.

Dr. Stanford and his colleagues are now trying to obtain pharmaceutical-grade MDM2 inhibitors to conduct trials in AML patients at The Ottawa Hospital.

The researchers are also screening libraries of approved drugs to see if any of these can block MDM2, and they are working with a biotech company to develop a test to identify chemotherapy-resistant AML patients who would respond to MDM2 inhibitors.

The current research was supported by grants from the Canadian Cancer Society Research Institute, Canadian Institutes of Health Research, Cancer Research Society, National Institutes of Health, and a Tier 1 Canada Research Chair in Integrative Stem Cell Biology. One study author reported a relationship with Epicypher, Inc. No other conflicts of interest were reported.

Warfarin tablets

Researchers say they have identified single-nucleotide polymorphisms (SNPs) that are associated with increased bleeding risk in African-American patients on warfarin.

A retrospective study revealed four SNPs associated with increased bleeding risk in African Americans with an international normalized ratio (INR) of less than 4.

One of these SNPs was seen in more than a third of bleeding cases and less than 5% of controls.

These preliminary findings could have implications for patients of African descent, but independent validation of the study results are needed, according to Minoli A. Perera, PharmD, PhD, of Northwestern University in Chicago, and her coauthors.

The researchers reported their findings in JAMA.

The report covered findings in a discovery cohort of African-American patients from a genome-wide study conducted at the University of Chicago and a replication cohort of patients who self-identified as African American and had routinely received care at University of Chicago hospitals.

The discovery cohort included 31 patients with major bleeding that occurred at an INR less than 4 and 184 controls with no documented history of bleeding related to warfarin.

In that cohort, Dr. Perera and her colleagues found four SNPs in linkage disequilibrium on chromosome 6 associated with warfarin-related bleeding:

• rs115112393
• rs16871327
• rs78132896
• rs114504854.

In particular, rs78132896 was found in 35.5% of cases (11/31) and 4.9% of controls (9/184), with an odds ratio of 8.31 (95% confidence interval [CI], 3.2-21.5).

The replication cohort, including 40 cases and 148 warfarin-treated controls, was genotyped specifically for rs78132896. The SNP was similarly found in 35.0% of cases (14/40) and 4.8% of controls (7/148), with an odds ratio of 8.24 (95% CI, 3.1-25.3).

“Genome-wide significance of this cohort was achieved when the cohorts were combined via meta-analysis,” the researchers wrote. They reported an odds ratio of 8.27 for that analysis (95% CI, 4.18-16.38).

Further analysis showed that, compared with wild-type alleles, the rs16871327 and rs78132896 risk alleles increased EPHA7 gene transcription.

Expression of the EPHA7 gene on vascular endothelial cells and peripheral lymphocytes is increased during inflammation, according to Dr. Perera and her coauthors. Increased EPHA7 expression might lead to bleeding in patients who are taking warfarin.

“This haplotype might also have potential implications for bleeding risk with direct oral anticoagulants,” the researchers wrote.

Dr. Perera and her coauthors reported no conflicts of interest related to their work on this study, which was funded by grants from the National Heart, Lung, and Blood Institute; the National Institute of General Medicine; the National Institutes of Health; and the American Heart Association Midwest Affiliate; as well as a research award from the University of Illinois at Chicago College of Pharmacy.

Warfarin tablets

Researchers say they have identified single-nucleotide polymorphisms (SNPs) that are associated with increased bleeding risk in African-American patients on warfarin.

A retrospective study revealed four SNPs associated with increased bleeding risk in African Americans with an international normalized ratio (INR) of less than 4.

One of these SNPs was seen in more than a third of bleeding cases and less than 5% of controls.

These preliminary findings could have implications for patients of African descent, but independent validation of the study results are needed, according to Minoli A. Perera, PharmD, PhD, of Northwestern University in Chicago, and her coauthors.

The researchers reported their findings in JAMA.

The report covered findings in a discovery cohort of African-American patients from a genome-wide study conducted at the University of Chicago and a replication cohort of patients who self-identified as African American and had routinely received care at University of Chicago hospitals.

The discovery cohort included 31 patients with major bleeding that occurred at an INR less than 4 and 184 controls with no documented history of bleeding related to warfarin.

In that cohort, Dr. Perera and her colleagues found four SNPs in linkage disequilibrium on chromosome 6 associated with warfarin-related bleeding:

• rs115112393
• rs16871327
• rs78132896
• rs114504854.

In particular, rs78132896 was found in 35.5% of cases (11/31) and 4.9% of controls (9/184), with an odds ratio of 8.31 (95% confidence interval [CI], 3.2-21.5).

The replication cohort, including 40 cases and 148 warfarin-treated controls, was genotyped specifically for rs78132896. The SNP was similarly found in 35.0% of cases (14/40) and 4.8% of controls (7/148), with an odds ratio of 8.24 (95% CI, 3.1-25.3).

“Genome-wide significance of this cohort was achieved when the cohorts were combined via meta-analysis,” the researchers wrote. They reported an odds ratio of 8.27 for that analysis (95% CI, 4.18-16.38).

Further analysis showed that, compared with wild-type alleles, the rs16871327 and rs78132896 risk alleles increased EPHA7 gene transcription.

Expression of the EPHA7 gene on vascular endothelial cells and peripheral lymphocytes is increased during inflammation, according to Dr. Perera and her coauthors. Increased EPHA7 expression might lead to bleeding in patients who are taking warfarin.

“This haplotype might also have potential implications for bleeding risk with direct oral anticoagulants,” the researchers wrote.

Dr. Perera and her coauthors reported no conflicts of interest related to their work on this study, which was funded by grants from the National Heart, Lung, and Blood Institute; the National Institute of General Medicine; the National Institutes of Health; and the American Heart Association Midwest Affiliate; as well as a research award from the University of Illinois at Chicago College of Pharmacy.

Warfarin tablets

Researchers say they have identified single-nucleotide polymorphisms (SNPs) that are associated with increased bleeding risk in African-American patients on warfarin.

A retrospective study revealed four SNPs associated with increased bleeding risk in African Americans with an international normalized ratio (INR) of less than 4.

One of these SNPs was seen in more than a third of bleeding cases and less than 5% of controls.

These preliminary findings could have implications for patients of African descent, but independent validation of the study results are needed, according to Minoli A. Perera, PharmD, PhD, of Northwestern University in Chicago, and her coauthors.

The researchers reported their findings in JAMA.

The report covered findings in a discovery cohort of African-American patients from a genome-wide study conducted at the University of Chicago and a replication cohort of patients who self-identified as African American and had routinely received care at University of Chicago hospitals.

The discovery cohort included 31 patients with major bleeding that occurred at an INR less than 4 and 184 controls with no documented history of bleeding related to warfarin.

In that cohort, Dr. Perera and her colleagues found four SNPs in linkage disequilibrium on chromosome 6 associated with warfarin-related bleeding:

• rs115112393
• rs16871327
• rs78132896
• rs114504854.

In particular, rs78132896 was found in 35.5% of cases (11/31) and 4.9% of controls (9/184), with an odds ratio of 8.31 (95% confidence interval [CI], 3.2-21.5).

The replication cohort, including 40 cases and 148 warfarin-treated controls, was genotyped specifically for rs78132896. The SNP was similarly found in 35.0% of cases (14/40) and 4.8% of controls (7/148), with an odds ratio of 8.24 (95% CI, 3.1-25.3).

“Genome-wide significance of this cohort was achieved when the cohorts were combined via meta-analysis,” the researchers wrote. They reported an odds ratio of 8.27 for that analysis (95% CI, 4.18-16.38).

Further analysis showed that, compared with wild-type alleles, the rs16871327 and rs78132896 risk alleles increased EPHA7 gene transcription.

Expression of the EPHA7 gene on vascular endothelial cells and peripheral lymphocytes is increased during inflammation, according to Dr. Perera and her coauthors. Increased EPHA7 expression might lead to bleeding in patients who are taking warfarin.

“This haplotype might also have potential implications for bleeding risk with direct oral anticoagulants,” the researchers wrote.

Dr. Perera and her coauthors reported no conflicts of interest related to their work on this study, which was funded by grants from the National Heart, Lung, and Blood Institute; the National Institute of General Medicine; the National Institutes of Health; and the American Heart Association Midwest Affiliate; as well as a research award from the University of Illinois at Chicago College of Pharmacy.

Image by Megan Farrell

LAUSANNE, SWITZERLAND—A mesenchymal stem cell (MSC) product could treat acute graft-versus-host disease (GVHD), according to preclinical research.

The product, apceth-201, improved symptoms of GVHD and prolonged survival in two mouse models.

Researchers described results with apceth-201 in a poster presentation at the Annual Congress of the European Society of Gene and Cell Therapy.

Most of the researchers involved in this study work for apceth Biopharma, the company developing apceth-201.

Apceth-201 consists of allogeneic human MSCs that have been genetically modified to express alpha-1 antitrypsin, a protease inhibitor exerting anti-inflammatory and tissue-protective functions.

In vitro assays showed that apceth-201 suppresses T-cell proliferation, polarizes macrophages to an anti-inflammatory M2 type, converts dendritic cells to a tolerogenic phenotype, and increases induction of regulatory T cells.

Apeceth-201 also demonstrated activity in vivo.

In a humanized GVHD model, treatment with apceth-201 improved bone marrow cellularity and reduced levels of inflammatory markers.

Additionally, mice treated with apceth-201 had double the median survival of mice treated with native MSCs.

Researchers also tested the effects of apceth-201 against GVHD in a model of haploidentical hematopoietic stem cell transplant.

All control mice succumbed to GVHD within 22 days, but more than half of mice treated with apceth-201 survived until the end of the experiment, which was 100 days.

All of the survivors had complete resolution of GVHD symptoms.

The researchers also said apceth-201 was safe. It did not impair T-cell-dependent antibody responses, and host resistance was similar in treated mice and controls.

“We are very excited with these results that clearly show the transformative therapeutic potential of apceth-201 in an immune-mediated disease with high unmet medical need and few treatment options,” said Christine Guenther, CEO of apceth Biopharma.

“Based on these promising and impressive data, we are currently preparing to initiate a phase 1/2 clinical study assessing the safety and efficacy of apceth-201 in adult steroid-refractory GVHD patients.”

Image by Megan Farrell

LAUSANNE, SWITZERLAND—A mesenchymal stem cell (MSC) product could treat acute graft-versus-host disease (GVHD), according to preclinical research.

The product, apceth-201, improved symptoms of GVHD and prolonged survival in two mouse models.

Researchers described results with apceth-201 in a poster presentation at the Annual Congress of the European Society of Gene and Cell Therapy.

Most of the researchers involved in this study work for apceth Biopharma, the company developing apceth-201.

Apceth-201 consists of allogeneic human MSCs that have been genetically modified to express alpha-1 antitrypsin, a protease inhibitor exerting anti-inflammatory and tissue-protective functions.

In vitro assays showed that apceth-201 suppresses T-cell proliferation, polarizes macrophages to an anti-inflammatory M2 type, converts dendritic cells to a tolerogenic phenotype, and increases induction of regulatory T cells.

Apeceth-201 also demonstrated activity in vivo.

In a humanized GVHD model, treatment with apceth-201 improved bone marrow cellularity and reduced levels of inflammatory markers.

Additionally, mice treated with apceth-201 had double the median survival of mice treated with native MSCs.

Researchers also tested the effects of apceth-201 against GVHD in a model of haploidentical hematopoietic stem cell transplant.

All control mice succumbed to GVHD within 22 days, but more than half of mice treated with apceth-201 survived until the end of the experiment, which was 100 days.

All of the survivors had complete resolution of GVHD symptoms.

The researchers also said apceth-201 was safe. It did not impair T-cell-dependent antibody responses, and host resistance was similar in treated mice and controls.

“We are very excited with these results that clearly show the transformative therapeutic potential of apceth-201 in an immune-mediated disease with high unmet medical need and few treatment options,” said Christine Guenther, CEO of apceth Biopharma.

“Based on these promising and impressive data, we are currently preparing to initiate a phase 1/2 clinical study assessing the safety and efficacy of apceth-201 in adult steroid-refractory GVHD patients.”

Image by Megan Farrell

LAUSANNE, SWITZERLAND—A mesenchymal stem cell (MSC) product could treat acute graft-versus-host disease (GVHD), according to preclinical research.

The product, apceth-201, improved symptoms of GVHD and prolonged survival in two mouse models.

Researchers described results with apceth-201 in a poster presentation at the Annual Congress of the European Society of Gene and Cell Therapy.

Most of the researchers involved in this study work for apceth Biopharma, the company developing apceth-201.

Apceth-201 consists of allogeneic human MSCs that have been genetically modified to express alpha-1 antitrypsin, a protease inhibitor exerting anti-inflammatory and tissue-protective functions.

In vitro assays showed that apceth-201 suppresses T-cell proliferation, polarizes macrophages to an anti-inflammatory M2 type, converts dendritic cells to a tolerogenic phenotype, and increases induction of regulatory T cells.

Apeceth-201 also demonstrated activity in vivo.

In a humanized GVHD model, treatment with apceth-201 improved bone marrow cellularity and reduced levels of inflammatory markers.

Additionally, mice treated with apceth-201 had double the median survival of mice treated with native MSCs.

Researchers also tested the effects of apceth-201 against GVHD in a model of haploidentical hematopoietic stem cell transplant.

All control mice succumbed to GVHD within 22 days, but more than half of mice treated with apceth-201 survived until the end of the experiment, which was 100 days.

All of the survivors had complete resolution of GVHD symptoms.

The researchers also said apceth-201 was safe. It did not impair T-cell-dependent antibody responses, and host resistance was similar in treated mice and controls.

“We are very excited with these results that clearly show the transformative therapeutic potential of apceth-201 in an immune-mediated disease with high unmet medical need and few treatment options,” said Christine Guenther, CEO of apceth Biopharma.

“Based on these promising and impressive data, we are currently preparing to initiate a phase 1/2 clinical study assessing the safety and efficacy of apceth-201 in adult steroid-refractory GVHD patients.”

WASHINGTON – Ataxia is the most common symptom at disease onset in patients with opsoclonus-myoclonus syndrome (OMS), a rare disease affecting only 1 in 5,000,000 individuals, mostly aged 1-5 years, based on data from a new patient registry.

In partnership with the National Organization of Rare Disorders (NORD) the nonprofit OMSLife Foundation has created a patient registry to better understand the disease experience in patients, wrote Mike Michaelis, chairman of OMSLife, and his colleagues. Early data from 275 enrolled patients were presented in a poster at the NORD Rare Summit, held by the National Organization for Rare Disorders.

The registry patients were mainly born in the United States (86%) and white (74%); approximately half were female. Of 150 patients who indicated symptoms at onset, 87% reported ataxia. Additional symptoms at onset were myoclonus (61%), opsoclonus (59%), tremors (46%), sleep disturbances (45%), temper tantrums (38%), vomiting (27%), fever (13%), headache (9%) and other symptoms (13%).

The researchers reviewed associations of symptoms at onset to determine the frequency of other symptoms for each individual symptom. Ataxia was present with 89% or higher instances of the other reported symptoms. Of note, some symptoms occurred more frequently than expected, such as temper tantrums and tremors in approximately 70% of patients with sleep disturbances. Myoclonus and opsoclonus, as well as fever and vomiting, also were significantly associated with the presence of other symptoms.

Two-thirds of the registry patients (69%) were diagnosed within 3 months of symptom onset, and 83% of these were diagnosed by a neurologist. Based on the Mitchell-Pike OMS severity scale, 59% of the patients met criteria for severe disease, 34% were classified as moderate, and 7% were mild. The registry is ongoing, but the current data provide insight on the clinical picture and common symptoms of OMS, the researchers said.

OMS Life was established in 2012 to support patients, caregivers, and researchers in raising awareness of opsoclonus-myoclonus syndrome as well as funds for research.

The study was supported by the OMSLife Foundation, NORD, and Trio Health Analytics. The researchers are employed by these organizations.

WASHINGTON – Ataxia is the most common symptom at disease onset in patients with opsoclonus-myoclonus syndrome (OMS), a rare disease affecting only 1 in 5,000,000 individuals, mostly aged 1-5 years, based on data from a new patient registry.

In partnership with the National Organization of Rare Disorders (NORD) the nonprofit OMSLife Foundation has created a patient registry to better understand the disease experience in patients, wrote Mike Michaelis, chairman of OMSLife, and his colleagues. Early data from 275 enrolled patients were presented in a poster at the NORD Rare Summit, held by the National Organization for Rare Disorders.

The registry patients were mainly born in the United States (86%) and white (74%); approximately half were female. Of 150 patients who indicated symptoms at onset, 87% reported ataxia. Additional symptoms at onset were myoclonus (61%), opsoclonus (59%), tremors (46%), sleep disturbances (45%), temper tantrums (38%), vomiting (27%), fever (13%), headache (9%) and other symptoms (13%).

The researchers reviewed associations of symptoms at onset to determine the frequency of other symptoms for each individual symptom. Ataxia was present with 89% or higher instances of the other reported symptoms. Of note, some symptoms occurred more frequently than expected, such as temper tantrums and tremors in approximately 70% of patients with sleep disturbances. Myoclonus and opsoclonus, as well as fever and vomiting, also were significantly associated with the presence of other symptoms.

Two-thirds of the registry patients (69%) were diagnosed within 3 months of symptom onset, and 83% of these were diagnosed by a neurologist. Based on the Mitchell-Pike OMS severity scale, 59% of the patients met criteria for severe disease, 34% were classified as moderate, and 7% were mild. The registry is ongoing, but the current data provide insight on the clinical picture and common symptoms of OMS, the researchers said.

OMS Life was established in 2012 to support patients, caregivers, and researchers in raising awareness of opsoclonus-myoclonus syndrome as well as funds for research.

The study was supported by the OMSLife Foundation, NORD, and Trio Health Analytics. The researchers are employed by these organizations.

WASHINGTON – Ataxia is the most common symptom at disease onset in patients with opsoclonus-myoclonus syndrome (OMS), a rare disease affecting only 1 in 5,000,000 individuals, mostly aged 1-5 years, based on data from a new patient registry.

In partnership with the National Organization of Rare Disorders (NORD) the nonprofit OMSLife Foundation has created a patient registry to better understand the disease experience in patients, wrote Mike Michaelis, chairman of OMSLife, and his colleagues. Early data from 275 enrolled patients were presented in a poster at the NORD Rare Summit, held by the National Organization for Rare Disorders.

The registry patients were mainly born in the United States (86%) and white (74%); approximately half were female. Of 150 patients who indicated symptoms at onset, 87% reported ataxia. Additional symptoms at onset were myoclonus (61%), opsoclonus (59%), tremors (46%), sleep disturbances (45%), temper tantrums (38%), vomiting (27%), fever (13%), headache (9%) and other symptoms (13%).

The researchers reviewed associations of symptoms at onset to determine the frequency of other symptoms for each individual symptom. Ataxia was present with 89% or higher instances of the other reported symptoms. Of note, some symptoms occurred more frequently than expected, such as temper tantrums and tremors in approximately 70% of patients with sleep disturbances. Myoclonus and opsoclonus, as well as fever and vomiting, also were significantly associated with the presence of other symptoms.

Two-thirds of the registry patients (69%) were diagnosed within 3 months of symptom onset, and 83% of these were diagnosed by a neurologist. Based on the Mitchell-Pike OMS severity scale, 59% of the patients met criteria for severe disease, 34% were classified as moderate, and 7% were mild. The registry is ongoing, but the current data provide insight on the clinical picture and common symptoms of OMS, the researchers said.

OMS Life was established in 2012 to support patients, caregivers, and researchers in raising awareness of opsoclonus-myoclonus syndrome as well as funds for research.

The study was supported by the OMSLife Foundation, NORD, and Trio Health Analytics. The researchers are employed by these organizations.

In July 2018, The BMJ published a study examining the cardiovascular risks of diclofenac initiation compared with initiation of other traditional non-steroidal anti-inflammatory drugs, initiation of paracetamol, and no initiation. The results showed a 50% increase in adverse events among diclofenac initiators compared with non-initiators (as well as a 20% increase over paracetamol/ibuprofen initiators, and 30% increase over naproxen initiators). (Read the full study here). Here, I asked several of my colleagues to weigh in on the results of this study and its implications for our practices, and then I share my own thoughts on these findings:

Marcelo Bigal, MD, PhD
Chief Medical Officer, Purdue Pharma

It is well established that NSAIDs are associated with increased risk of poor cardiovascular outcomes. This study offers powerful evidence that the risk after frequent diclofenac use is disproportionally increased relative to other commonly used NSAIDs, such as ibuprofen or naproxen. It is relevant to discuss the implications of the findings for the treatment of migraine.

The acute treatment of migraine associated with attack-related disability should favor triptans as first line therapy, not NSAIDs. Because triptans are vasoconstrictive medications, unmet needs exist in patients at cardiovascular risk. Anti-CGRP acute migraine therapies, as well as “ditans” (5HT-1f antagonist) are under regulatory review and may address the needs of these patients. In the context of acute migraine therapy, diclofenac and NSAIDs are typically used instead of triptans, or with triptans when additional efficacy is needed. We certainly find that the use of diclofenac in these situations should be judicious, and reserved to those who clearly need it, have infrequent migraine attacks, and are otherwise healthy.

Diclofenac is also often used in the emergency department in many countries as a rescue therapy. In a series of clinical trials where we tested most commonly used drugs in this setting in Brazil, we found that efficacies were 83.6% for intravenous dipyrone, 66.7% for intramuscular diclofenac and 81.8% for intravenous chlorpromazine. We continue to believe that diclofenac is an important, non-sedative and non-opioid option for the management of headaches in the emergency department, assuming that at discharge, patients would receive proper guidance on the management of migraine without relying on frequent use of NSAIDs.

Jack Schim, MD
Co-Director, The Headache Center of Southern California

This article supports findings of prior epidemiologic studies correlating exposure to NSAIDs with increased cerebrovascular and cardiovascular risk. Prior studies have shown a dose-related response in risk associated with NSAID therapy, supporting a causal association. However, while relative risk is significantly higher in individuals with NSAID exposure, the absolute risk remains very low. The greater risk from NSAIDs continues to be to the kidneys, and to the stomach.  

As with all therapies, we need to weigh the advantages and disadvantages of NSAID therapy with our headache patients. All medications carry their own risks. For acute treatment of migraines, our primary tool, triptans, are contraindicated in a significant subset of individuals, including patients with ischemic coronary artery as well as those with history of stroke or transient ischemic attack (TIA). The alternatives, NSAIDs, dopamine blocking agents, have utility and risks.

Diclofenac powder to be dissolved in water is an effective abortive for migraine for many individuals. In general, our patients have intermittent exposure, preferably not more than 2 days per week. For the appropriate individual, NSAIDS, including diclofenac, remain an important tool in the acute care armamentarium.

Rob Cowan, MD, FAAN, FAHS
Higgins Professor of Neurology and Neurosciences
Chief, Division of Headache Medicine, Dept. of Neurology and Neurosciences
Director, Stanford University School of Medicine

These kinds of large, population-based studies must be interpreted with caution. While they may emulate the protocol of prospective studies, they lack proper inclusion/exclusion criteria, particularly with respect to indication. It may be reasonable to assume that the population of diclofenac users is "sicker" than the general population and the population that is using cheaper, more accessible NSAIDs or paracetamol. Without knowing the access and economic issues in Denmark, it is difficult to weigh these variables in the study. Thus, while it is certainly an important issue to explore (the relative risks and benefits of a given medication within a class), the absence of a well-designed, prospective study precludes any definitive conclusion regarding relative safety and risk profile for Diclofenac.

+++

These are great comments by my colleagues. My impression after seeing the data and reading my colleague’s comments, is that diclofenac may be riskier than other NSAIDs in this study; but when used properly in generally healthy migraineurs, it is probably more effective than dangerous when evaluating the risk/benefit ratio. When diclofenac is used as an oral solution (Cambia), 2 days per week or less, in a patient without serious gastrointestinal, renal, cardiac or hypertensive issues, it appears to pose little risk to the patient. When given to the wrong patient, or when taken too frequently, is could be dangerous. What I really like about this preparation is that it causes fewer adverse events compared to triptans and works very quickly. It can be used when triptans have been used enough that week or if they tend to cause significant adverse events when taken. We can use diclofenac for our headache patients, but we should remain vigilant to give it cautiously and only to patients who have no contraindication to its use.

Please write to us at Neurology Reviews Migraine Resource Center ([email protected]) with your opinions.

Alan M. Rapoport, M.D.
Editor-in-Chief
Migraine Resource Center

Clinical Professor of Neurology
The David Geffen School of Medicine at UCLA
Los Angeles, California

In July 2018, The BMJ published a study examining the cardiovascular risks of diclofenac initiation compared with initiation of other traditional non-steroidal anti-inflammatory drugs, initiation of paracetamol, and no initiation. The results showed a 50% increase in adverse events among diclofenac initiators compared with non-initiators (as well as a 20% increase over paracetamol/ibuprofen initiators, and 30% increase over naproxen initiators). (Read the full study here). Here, I asked several of my colleagues to weigh in on the results of this study and its implications for our practices, and then I share my own thoughts on these findings:

Marcelo Bigal, MD, PhD
Chief Medical Officer, Purdue Pharma

It is well established that NSAIDs are associated with increased risk of poor cardiovascular outcomes. This study offers powerful evidence that the risk after frequent diclofenac use is disproportionally increased relative to other commonly used NSAIDs, such as ibuprofen or naproxen. It is relevant to discuss the implications of the findings for the treatment of migraine.

The acute treatment of migraine associated with attack-related disability should favor triptans as first line therapy, not NSAIDs. Because triptans are vasoconstrictive medications, unmet needs exist in patients at cardiovascular risk. Anti-CGRP acute migraine therapies, as well as “ditans” (5HT-1f antagonist) are under regulatory review and may address the needs of these patients. In the context of acute migraine therapy, diclofenac and NSAIDs are typically used instead of triptans, or with triptans when additional efficacy is needed. We certainly find that the use of diclofenac in these situations should be judicious, and reserved to those who clearly need it, have infrequent migraine attacks, and are otherwise healthy.

Diclofenac is also often used in the emergency department in many countries as a rescue therapy. In a series of clinical trials where we tested most commonly used drugs in this setting in Brazil, we found that efficacies were 83.6% for intravenous dipyrone, 66.7% for intramuscular diclofenac and 81.8% for intravenous chlorpromazine. We continue to believe that diclofenac is an important, non-sedative and non-opioid option for the management of headaches in the emergency department, assuming that at discharge, patients would receive proper guidance on the management of migraine without relying on frequent use of NSAIDs.

Jack Schim, MD
Co-Director, The Headache Center of Southern California

This article supports findings of prior epidemiologic studies correlating exposure to NSAIDs with increased cerebrovascular and cardiovascular risk. Prior studies have shown a dose-related response in risk associated with NSAID therapy, supporting a causal association. However, while relative risk is significantly higher in individuals with NSAID exposure, the absolute risk remains very low. The greater risk from NSAIDs continues to be to the kidneys, and to the stomach.  

As with all therapies, we need to weigh the advantages and disadvantages of NSAID therapy with our headache patients. All medications carry their own risks. For acute treatment of migraines, our primary tool, triptans, are contraindicated in a significant subset of individuals, including patients with ischemic coronary artery as well as those with history of stroke or transient ischemic attack (TIA). The alternatives, NSAIDs, dopamine blocking agents, have utility and risks.

Diclofenac powder to be dissolved in water is an effective abortive for migraine for many individuals. In general, our patients have intermittent exposure, preferably not more than 2 days per week. For the appropriate individual, NSAIDS, including diclofenac, remain an important tool in the acute care armamentarium.

Rob Cowan, MD, FAAN, FAHS
Higgins Professor of Neurology and Neurosciences
Chief, Division of Headache Medicine, Dept. of Neurology and Neurosciences
Director, Stanford University School of Medicine

These kinds of large, population-based studies must be interpreted with caution. While they may emulate the protocol of prospective studies, they lack proper inclusion/exclusion criteria, particularly with respect to indication. It may be reasonable to assume that the population of diclofenac users is "sicker" than the general population and the population that is using cheaper, more accessible NSAIDs or paracetamol. Without knowing the access and economic issues in Denmark, it is difficult to weigh these variables in the study. Thus, while it is certainly an important issue to explore (the relative risks and benefits of a given medication within a class), the absence of a well-designed, prospective study precludes any definitive conclusion regarding relative safety and risk profile for Diclofenac.

+++

These are great comments by my colleagues. My impression after seeing the data and reading my colleague’s comments, is that diclofenac may be riskier than other NSAIDs in this study; but when used properly in generally healthy migraineurs, it is probably more effective than dangerous when evaluating the risk/benefit ratio. When diclofenac is used as an oral solution (Cambia), 2 days per week or less, in a patient without serious gastrointestinal, renal, cardiac or hypertensive issues, it appears to pose little risk to the patient. When given to the wrong patient, or when taken too frequently, is could be dangerous. What I really like about this preparation is that it causes fewer adverse events compared to triptans and works very quickly. It can be used when triptans have been used enough that week or if they tend to cause significant adverse events when taken. We can use diclofenac for our headache patients, but we should remain vigilant to give it cautiously and only to patients who have no contraindication to its use.

Please write to us at Neurology Reviews Migraine Resource Center ([email protected]) with your opinions.

Alan M. Rapoport, M.D.
Editor-in-Chief
Migraine Resource Center

Clinical Professor of Neurology
The David Geffen School of Medicine at UCLA
Los Angeles, California

In July 2018, The BMJ published a study examining the cardiovascular risks of diclofenac initiation compared with initiation of other traditional non-steroidal anti-inflammatory drugs, initiation of paracetamol, and no initiation. The results showed a 50% increase in adverse events among diclofenac initiators compared with non-initiators (as well as a 20% increase over paracetamol/ibuprofen initiators, and 30% increase over naproxen initiators). (Read the full study here). Here, I asked several of my colleagues to weigh in on the results of this study and its implications for our practices, and then I share my own thoughts on these findings:

Marcelo Bigal, MD, PhD
Chief Medical Officer, Purdue Pharma

It is well established that NSAIDs are associated with increased risk of poor cardiovascular outcomes. This study offers powerful evidence that the risk after frequent diclofenac use is disproportionally increased relative to other commonly used NSAIDs, such as ibuprofen or naproxen. It is relevant to discuss the implications of the findings for the treatment of migraine.

The acute treatment of migraine associated with attack-related disability should favor triptans as first line therapy, not NSAIDs. Because triptans are vasoconstrictive medications, unmet needs exist in patients at cardiovascular risk. Anti-CGRP acute migraine therapies, as well as “ditans” (5HT-1f antagonist) are under regulatory review and may address the needs of these patients. In the context of acute migraine therapy, diclofenac and NSAIDs are typically used instead of triptans, or with triptans when additional efficacy is needed. We certainly find that the use of diclofenac in these situations should be judicious, and reserved to those who clearly need it, have infrequent migraine attacks, and are otherwise healthy.

Diclofenac is also often used in the emergency department in many countries as a rescue therapy. In a series of clinical trials where we tested most commonly used drugs in this setting in Brazil, we found that efficacies were 83.6% for intravenous dipyrone, 66.7% for intramuscular diclofenac and 81.8% for intravenous chlorpromazine. We continue to believe that diclofenac is an important, non-sedative and non-opioid option for the management of headaches in the emergency department, assuming that at discharge, patients would receive proper guidance on the management of migraine without relying on frequent use of NSAIDs.

Jack Schim, MD
Co-Director, The Headache Center of Southern California

This article supports findings of prior epidemiologic studies correlating exposure to NSAIDs with increased cerebrovascular and cardiovascular risk. Prior studies have shown a dose-related response in risk associated with NSAID therapy, supporting a causal association. However, while relative risk is significantly higher in individuals with NSAID exposure, the absolute risk remains very low. The greater risk from NSAIDs continues to be to the kidneys, and to the stomach.  

As with all therapies, we need to weigh the advantages and disadvantages of NSAID therapy with our headache patients. All medications carry their own risks. For acute treatment of migraines, our primary tool, triptans, are contraindicated in a significant subset of individuals, including patients with ischemic coronary artery as well as those with history of stroke or transient ischemic attack (TIA). The alternatives, NSAIDs, dopamine blocking agents, have utility and risks.

Diclofenac powder to be dissolved in water is an effective abortive for migraine for many individuals. In general, our patients have intermittent exposure, preferably not more than 2 days per week. For the appropriate individual, NSAIDS, including diclofenac, remain an important tool in the acute care armamentarium.

Rob Cowan, MD, FAAN, FAHS
Higgins Professor of Neurology and Neurosciences
Chief, Division of Headache Medicine, Dept. of Neurology and Neurosciences
Director, Stanford University School of Medicine

These kinds of large, population-based studies must be interpreted with caution. While they may emulate the protocol of prospective studies, they lack proper inclusion/exclusion criteria, particularly with respect to indication. It may be reasonable to assume that the population of diclofenac users is "sicker" than the general population and the population that is using cheaper, more accessible NSAIDs or paracetamol. Without knowing the access and economic issues in Denmark, it is difficult to weigh these variables in the study. Thus, while it is certainly an important issue to explore (the relative risks and benefits of a given medication within a class), the absence of a well-designed, prospective study precludes any definitive conclusion regarding relative safety and risk profile for Diclofenac.

+++

These are great comments by my colleagues. My impression after seeing the data and reading my colleague’s comments, is that diclofenac may be riskier than other NSAIDs in this study; but when used properly in generally healthy migraineurs, it is probably more effective than dangerous when evaluating the risk/benefit ratio. When diclofenac is used as an oral solution (Cambia), 2 days per week or less, in a patient without serious gastrointestinal, renal, cardiac or hypertensive issues, it appears to pose little risk to the patient. When given to the wrong patient, or when taken too frequently, is could be dangerous. What I really like about this preparation is that it causes fewer adverse events compared to triptans and works very quickly. It can be used when triptans have been used enough that week or if they tend to cause significant adverse events when taken. We can use diclofenac for our headache patients, but we should remain vigilant to give it cautiously and only to patients who have no contraindication to its use.

Please write to us at Neurology Reviews Migraine Resource Center ([email protected]) with your opinions.

Alan M. Rapoport, M.D.
Editor-in-Chief
Migraine Resource Center

Clinical Professor of Neurology
The David Geffen School of Medicine at UCLA
Los Angeles, California