HYSTEROSCOPY TISSUE REMOVAL DEVICE

Hologic, Inc, has introduced the MyoSure^® MANUAL Tissue Removal Device for resecting and removing tissue during in-office hysteroscopic intrauterine procedures. When used with the MyoSure hysteroscope, the MyoSure MANUAL device has a fully integrated vacuum that does not require external suction and can be operated using a 1-L saline bag. The clear tissue trap allows for visual confirmation of removed tissue, holds up to 4 g of tissue, and detaches to send the specimen to pathology. Hologic says that the MyoSure MANUAL gives physicians multifunction control of the 360° blade for removal of tissue, including fibroids and polyps. The MyoSure Manual is a sterile, nonpowered, hand-actuated, single-use device.

This new Hologic product joins the MyoSure suite of gynecologic surgical products that includes the MyoSure, MyoSure REACH, MyoSure XL, and MyoSure LITE devices.

FOR MORE INFORMATION, VISIT: http://myosure.com/

SPINAL NAVIGATION TECHNOLOGY FOR EPIDURAL ANESTHESIA

The Accuro^® 3D image-guided spinal navigation technology by Rivanna Medical^® is a handheld, lightweight, untethered ultrasound-based system designed to help apply spinal and epidural anesthesia. Ultrasonography is the imaging modality of choice for epidurals in expectant mothers who must avoid the radiation involved in other imaging procedures, according to Rivanna Medical.

In a recent trial, Accuro identified the appropriate epidural injection sites along the lower spine and calculated the depth to the epidural space. Actual epidural depth was confirmed by measuring needle penetration during successful epidural delivery by anesthesia providers. Accuro predicted this depth within an average of 0.61 cm, reports Rivanna Medical. In addition, Accuro identified the appropriate spinal interspace for needle insertion in 94% of patients and enabled 87% success in first-attempt epidural administration.

FOR MORE INFORMATION, VISIT: https://rivannamedical.com/

SOFTWARE AND HUB HELP IDENTIFY CRITICALLY ILL L&D PATIENTS

PeriGen, Inc, a software-solutions company, has launched PeriWatch™ HUB™, new perinatal software and a dashboard for labor and delivery (L&D) units.

PeriGen says that its PeriWatch modules provide state-of-the-art L&D documentation and fetal surveillance coupled with analytics and an electronic critical-condition dashboard for hospital maternity units.

HUB is an intelligent perinatal dashboard designed to facilitate the timely recognition of maternity patients who develop critical illness. Using PeriGen’s proprietary algorithms, it prioritizes patients based on physician-chosen threshold settings for vital signs, labor progress, and fetal heart rate patterns, and consolidates that data into an easy-to-read interactive dashboard.  

FOR MORE INFORMATION, VISIT: http://perigen.com/

ORAL SPRAY VITAMINS: ALTERNATIVE TO PILLS

Instavit^® Spray Vitamins offer an alternative to patients who have difficulty swallowing pills. Instavit says that its oral vitamins, sprayed directly into the mouth, are sugar-free, tasty, gluten-free, and contain zero calories. The sprays are manufactured to the highest standard in cGMP, FDA approved facilities in the United States. Each Instavit spray provides an exact and measured amount of liquid, allowing for correct dosing and also permitting individualization of intake. A 14-oz spray bottle contains about 28 doses.

The Instavit line includes: “Prenatal Care,” “Vitamin B12,” “Instant Energy,” “Vitamin D,” “Daily Health,” “Sweet Dreams,” “Immune Strength,” “Clearer Thinking,” and “Instavit for Kids.” Instavit products are available in retail stores in North America.

FOR MORE INFORMATION, VISIT: http://www.instavit.com/

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

HYSTEROSCOPY TISSUE REMOVAL DEVICE

Hologic, Inc, has introduced the MyoSure^® MANUAL Tissue Removal Device for resecting and removing tissue during in-office hysteroscopic intrauterine procedures. When used with the MyoSure hysteroscope, the MyoSure MANUAL device has a fully integrated vacuum that does not require external suction and can be operated using a 1-L saline bag. The clear tissue trap allows for visual confirmation of removed tissue, holds up to 4 g of tissue, and detaches to send the specimen to pathology. Hologic says that the MyoSure MANUAL gives physicians multifunction control of the 360° blade for removal of tissue, including fibroids and polyps. The MyoSure Manual is a sterile, nonpowered, hand-actuated, single-use device.

This new Hologic product joins the MyoSure suite of gynecologic surgical products that includes the MyoSure, MyoSure REACH, MyoSure XL, and MyoSure LITE devices.

FOR MORE INFORMATION, VISIT: http://myosure.com/

SPINAL NAVIGATION TECHNOLOGY FOR EPIDURAL ANESTHESIA

The Accuro^® 3D image-guided spinal navigation technology by Rivanna Medical^® is a handheld, lightweight, untethered ultrasound-based system designed to help apply spinal and epidural anesthesia. Ultrasonography is the imaging modality of choice for epidurals in expectant mothers who must avoid the radiation involved in other imaging procedures, according to Rivanna Medical.

In a recent trial, Accuro identified the appropriate epidural injection sites along the lower spine and calculated the depth to the epidural space. Actual epidural depth was confirmed by measuring needle penetration during successful epidural delivery by anesthesia providers. Accuro predicted this depth within an average of 0.61 cm, reports Rivanna Medical. In addition, Accuro identified the appropriate spinal interspace for needle insertion in 94% of patients and enabled 87% success in first-attempt epidural administration.

FOR MORE INFORMATION, VISIT: https://rivannamedical.com/

SOFTWARE AND HUB HELP IDENTIFY CRITICALLY ILL L&D PATIENTS

PeriGen, Inc, a software-solutions company, has launched PeriWatch™ HUB™, new perinatal software and a dashboard for labor and delivery (L&D) units.

PeriGen says that its PeriWatch modules provide state-of-the-art L&D documentation and fetal surveillance coupled with analytics and an electronic critical-condition dashboard for hospital maternity units.

HUB is an intelligent perinatal dashboard designed to facilitate the timely recognition of maternity patients who develop critical illness. Using PeriGen’s proprietary algorithms, it prioritizes patients based on physician-chosen threshold settings for vital signs, labor progress, and fetal heart rate patterns, and consolidates that data into an easy-to-read interactive dashboard.  

FOR MORE INFORMATION, VISIT: http://perigen.com/

ORAL SPRAY VITAMINS: ALTERNATIVE TO PILLS

Instavit^® Spray Vitamins offer an alternative to patients who have difficulty swallowing pills. Instavit says that its oral vitamins, sprayed directly into the mouth, are sugar-free, tasty, gluten-free, and contain zero calories. The sprays are manufactured to the highest standard in cGMP, FDA approved facilities in the United States. Each Instavit spray provides an exact and measured amount of liquid, allowing for correct dosing and also permitting individualization of intake. A 14-oz spray bottle contains about 28 doses.

The Instavit line includes: “Prenatal Care,” “Vitamin B12,” “Instant Energy,” “Vitamin D,” “Daily Health,” “Sweet Dreams,” “Immune Strength,” “Clearer Thinking,” and “Instavit for Kids.” Instavit products are available in retail stores in North America.

FOR MORE INFORMATION, VISIT: http://www.instavit.com/

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

HYSTEROSCOPY TISSUE REMOVAL DEVICE

Hologic, Inc, has introduced the MyoSure^® MANUAL Tissue Removal Device for resecting and removing tissue during in-office hysteroscopic intrauterine procedures. When used with the MyoSure hysteroscope, the MyoSure MANUAL device has a fully integrated vacuum that does not require external suction and can be operated using a 1-L saline bag. The clear tissue trap allows for visual confirmation of removed tissue, holds up to 4 g of tissue, and detaches to send the specimen to pathology. Hologic says that the MyoSure MANUAL gives physicians multifunction control of the 360° blade for removal of tissue, including fibroids and polyps. The MyoSure Manual is a sterile, nonpowered, hand-actuated, single-use device.

This new Hologic product joins the MyoSure suite of gynecologic surgical products that includes the MyoSure, MyoSure REACH, MyoSure XL, and MyoSure LITE devices.

FOR MORE INFORMATION, VISIT: http://myosure.com/

SPINAL NAVIGATION TECHNOLOGY FOR EPIDURAL ANESTHESIA

The Accuro^® 3D image-guided spinal navigation technology by Rivanna Medical^® is a handheld, lightweight, untethered ultrasound-based system designed to help apply spinal and epidural anesthesia. Ultrasonography is the imaging modality of choice for epidurals in expectant mothers who must avoid the radiation involved in other imaging procedures, according to Rivanna Medical.

In a recent trial, Accuro identified the appropriate epidural injection sites along the lower spine and calculated the depth to the epidural space. Actual epidural depth was confirmed by measuring needle penetration during successful epidural delivery by anesthesia providers. Accuro predicted this depth within an average of 0.61 cm, reports Rivanna Medical. In addition, Accuro identified the appropriate spinal interspace for needle insertion in 94% of patients and enabled 87% success in first-attempt epidural administration.

FOR MORE INFORMATION, VISIT: https://rivannamedical.com/

SOFTWARE AND HUB HELP IDENTIFY CRITICALLY ILL L&D PATIENTS

PeriGen, Inc, a software-solutions company, has launched PeriWatch™ HUB™, new perinatal software and a dashboard for labor and delivery (L&D) units.

PeriGen says that its PeriWatch modules provide state-of-the-art L&D documentation and fetal surveillance coupled with analytics and an electronic critical-condition dashboard for hospital maternity units.

HUB is an intelligent perinatal dashboard designed to facilitate the timely recognition of maternity patients who develop critical illness. Using PeriGen’s proprietary algorithms, it prioritizes patients based on physician-chosen threshold settings for vital signs, labor progress, and fetal heart rate patterns, and consolidates that data into an easy-to-read interactive dashboard.  

FOR MORE INFORMATION, VISIT: http://perigen.com/

ORAL SPRAY VITAMINS: ALTERNATIVE TO PILLS

Instavit^® Spray Vitamins offer an alternative to patients who have difficulty swallowing pills. Instavit says that its oral vitamins, sprayed directly into the mouth, are sugar-free, tasty, gluten-free, and contain zero calories. The sprays are manufactured to the highest standard in cGMP, FDA approved facilities in the United States. Each Instavit spray provides an exact and measured amount of liquid, allowing for correct dosing and also permitting individualization of intake. A 14-oz spray bottle contains about 28 doses.

The Instavit line includes: “Prenatal Care,” “Vitamin B12,” “Instant Energy,” “Vitamin D,” “Daily Health,” “Sweet Dreams,” “Immune Strength,” “Clearer Thinking,” and “Instavit for Kids.” Instavit products are available in retail stores in North America.

FOR MORE INFORMATION, VISIT: http://www.instavit.com/

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

© Todd Buchanan 2017

ATLANTA—A population-based study indicates that, compared to other cancer survivors, patients who survive diffuse large B-cell lymphoma (DLBCL) have an increased risk of autoimmune and infectious diseases.

For example, investigators found the risk of being diagnosed with impaired humoral immunity was 16.2 times higher in female DLBCL survivors than in breast cancer survivors, 14.8 times higher in male DLBCL survivors than in prostate cancer survivors, and 12.5 times higher in all DLBCL survivors than in survivors of head and neck cancer.

“Most of the treatments that we give for lymphoma have profound effects on the immune system, either directly or indirectly, including many of the T-cell-directed therapies,” said Tanaya Shree, MD, PhD, of Stanford University Medical Center in California.

“There have been studies on many of the effects suffered by lymphoma survivors, but very little is known about their immune health.”

Dr Shree and her colleagues undertook this study to determine how the immune system fares in lymphoma survivors. The investigators limited their analysis to survivors of DLBCL.

Dr Shree presented the findings at the 2017 ASH Annual Meeting (abstract 198*).

Study design

Investigators pulled data from the California Cancer Registry for patients with DLBCL as their first primary cancer diagnosed between 1991 and 2012. Patients had to be 18 or older at diagnosis and have survived more than a year after diagnosis.

“Importantly, we counted only diagnoses [of autoimmune and infectious diseases] that first appeared between 1 and 10 years after cancer diagnosis,” Dr Shree explained. “So any diagnosis we saw that had also been seen prior to cancer diagnosis or even up to 1 year post-cancer diagnosis, we considered to be pre-existing and were excluded from the analysis in order to really focus on new incident cases during survivorship.”

Investigators used the same criteria for the comparator cohorts.

The survivor data was linked to statewide discharge databases, and investigators performed the incidence analysis based on ICD-9 codes.

Investigators used Poisson regression analysis to obtain incident ratios and adjusted the models for age, race, and year of diagnosis.

They graphed the incident rate ratios for all the diagnoses that were significantly different between the DLBCL cohort and the comparator cohorts.

“[W]e considered a P value of less than 0.0005 to be significant,” Dr Shree clarified.

Survivor characteristics

The cohorts comprised 802,255 survivors of DLBCL (n=21,690), breast cancer (n=337,591), prostate cancer (n=325,533), melanoma (n=73,196), and head and neck cancer (n=44,245).

“At least 75% of patients in each cohort were aged 40 to 79,” Dr Shree noted, “with a good representation of elderly patients.”

The median follow-up time was 6.1 years for DLBCL patients and ranged from 5.7 years for head and neck cancer survivors to 8.3 years for prostate cancer survivors.

About three-quarters of patients in each cohort had hospitalization data within 1 to 10 years from cancer diagnosis.

DLBCL vs breast cancer

“Interestingly, we found some familiar names amongst the top-scoring diagnoses,” Dr Shree said.

Deficiency of humoral immunity (16.2-fold), autoimmune hemolytic anemia (9.9-fold), Sicca syndrome (6.9-fold), and immune thrombocytopenia (3.1-fold) were higher in female DLBCL survivors than breast cancer survivors.

“All of these have known associations with lymphoma,” Dr Shree said. “But we also found, surprisingly, increased rates of fungal [6.0-fold] and viral pneumonia [3.3-fold], and many other codes associated with respiratory infections. We also found a 3-fold increased rate of meningitis.”

“The only diagnosis statistically more common amongst breast cancer patients was cervicitis and endocervicitis, and this likely relates to the fact that many of these patients are undergoing hormone therapy.”

DLBCL vs prostate cancer

“We saw some of the same diagnoses come up as top-scoring hits, including viral [4.5-fold] and fungal pneumonia [8.2-fold], and meningitis [3.9-fold], and, in this case, Staphylococcal meningitis [8.6-fold],” Dr Shree said.

Deficiency of humoral immunity (14.8-fold), autoimmune hemolytic anemia (8.9-fold), Sicca syndrome (8.6-fold), and immune thrombocytopenia (4.8-fold) were also higher in the male DLBCL survivors than in prostate cancer survivors.

“No diagnoses were statistically more common in the prostate cancer survivors [than in male DLBCL survivors],” Dr Shree noted.

DLBCL vs head and neck cancer

“Again, the top 4 hits were the same 4 diagnoses we have been seeing repeatedly,” Dr Shree said.

Deficiency of humoral immunity (12.5-fold), autoimmune hemolytic anemia (9.3-fold), Sicca syndrome (5.5-fold), and immune thrombocytopenia (4.5-fold) were increased for DLBCL survivors compared to survivors of head and neck cancer.

DLBCL survivors also had an increased risk of respiratory infections, especially viral (4.4-fold) and fungal pneumonias (4.0-fold), meningitis (3.0-fold), and chronic lymphocytic thyroiditis (2.8-fold), also known as Hashimoto’s thyroiditis.

On the other hand, bacterial pneumonias and skin infections were more common in the head and neck cancer survivors than in DLBCL survivors.

DLBCL vs melanoma

“Interestingly, we did not see an increased risk for immune thrombocytopenias [in DLBCL survivors] compared to melanoma survivors in this comparison, which we had in all the other comparisons,” Dr Shree noted.

“But we did see [an increased risk for] the other diagnoses that we had been tracking, including, again, fungal pneumonia [6.9-fold], viral pneumonia [4.7-fold], and miscellaneous viral infections [2.6-fold].”

The only diagnosis that was statistically more common among melanoma survivors than DLBCL survivors was vitiligo.

Risks persist over time

The investigators assessed whether the elevated risks were static over the 1- to 10-year analysis period.

They took the top diagnoses—humoral deficiency, autoimmune hemolytic anemia, Sicca syndrome, and immune thrombocytopenia—and reviewed them for all cohorts to determine the rate of new cases.

“[F]or 3 out of these 4 diagnoses [humoral deficiency, autoimmune hemolytic anemia, and Sicca syndrome], increased incident rates are highest in the first 1 to 3 years after diagnosis in the lymphoma patients,” Dr Shree said.

“But even at 5 to 10 years out, these patients continue to have increased incidence of these diagnoses compared to the other cohorts, suggesting that these risks really do remain elevated over some time.”

The investigators repeated the analysis using broader categories of diagnoses with each category encompassing many ICD-9 codes.

“[I]n 12 out of 18 broad categories that we looked at, we can still find statistically significant differences in the incident rates for these diagnoses, and they were all increased in the lymphoma patients compared to the other cohorts,” Dr Shree explained.

“[T]hese increases were seen across multiple comparisons, suggesting that this phenomenon seems to be really lymphoma-specific and not specific to any of the individual comparisons we had chosen to perform.”

The findings, she said, have a lot of implications.

“We are particularly interested in which features of patients’ treatment contribute most to these elevated risks,” Dr Shree said. “And, of course, we want to know what to be able to tell our patients and how to follow them during survivorship.”

The investigators are currently validating their findings with further analysis of the Stanford lymphoma survivors cohort of approximately 3500 patients.

*Data in the abstract differ from the presentation.

© Todd Buchanan 2017

ATLANTA—A population-based study indicates that, compared to other cancer survivors, patients who survive diffuse large B-cell lymphoma (DLBCL) have an increased risk of autoimmune and infectious diseases.

For example, investigators found the risk of being diagnosed with impaired humoral immunity was 16.2 times higher in female DLBCL survivors than in breast cancer survivors, 14.8 times higher in male DLBCL survivors than in prostate cancer survivors, and 12.5 times higher in all DLBCL survivors than in survivors of head and neck cancer.

“Most of the treatments that we give for lymphoma have profound effects on the immune system, either directly or indirectly, including many of the T-cell-directed therapies,” said Tanaya Shree, MD, PhD, of Stanford University Medical Center in California.

“There have been studies on many of the effects suffered by lymphoma survivors, but very little is known about their immune health.”

Dr Shree and her colleagues undertook this study to determine how the immune system fares in lymphoma survivors. The investigators limited their analysis to survivors of DLBCL.

Dr Shree presented the findings at the 2017 ASH Annual Meeting (abstract 198*).

Study design

Investigators pulled data from the California Cancer Registry for patients with DLBCL as their first primary cancer diagnosed between 1991 and 2012. Patients had to be 18 or older at diagnosis and have survived more than a year after diagnosis.

“Importantly, we counted only diagnoses [of autoimmune and infectious diseases] that first appeared between 1 and 10 years after cancer diagnosis,” Dr Shree explained. “So any diagnosis we saw that had also been seen prior to cancer diagnosis or even up to 1 year post-cancer diagnosis, we considered to be pre-existing and were excluded from the analysis in order to really focus on new incident cases during survivorship.”

Investigators used the same criteria for the comparator cohorts.

The survivor data was linked to statewide discharge databases, and investigators performed the incidence analysis based on ICD-9 codes.

Investigators used Poisson regression analysis to obtain incident ratios and adjusted the models for age, race, and year of diagnosis.

They graphed the incident rate ratios for all the diagnoses that were significantly different between the DLBCL cohort and the comparator cohorts.

“[W]e considered a P value of less than 0.0005 to be significant,” Dr Shree clarified.

Survivor characteristics

The cohorts comprised 802,255 survivors of DLBCL (n=21,690), breast cancer (n=337,591), prostate cancer (n=325,533), melanoma (n=73,196), and head and neck cancer (n=44,245).

“At least 75% of patients in each cohort were aged 40 to 79,” Dr Shree noted, “with a good representation of elderly patients.”

The median follow-up time was 6.1 years for DLBCL patients and ranged from 5.7 years for head and neck cancer survivors to 8.3 years for prostate cancer survivors.

About three-quarters of patients in each cohort had hospitalization data within 1 to 10 years from cancer diagnosis.

DLBCL vs breast cancer

“Interestingly, we found some familiar names amongst the top-scoring diagnoses,” Dr Shree said.

Deficiency of humoral immunity (16.2-fold), autoimmune hemolytic anemia (9.9-fold), Sicca syndrome (6.9-fold), and immune thrombocytopenia (3.1-fold) were higher in female DLBCL survivors than breast cancer survivors.

“All of these have known associations with lymphoma,” Dr Shree said. “But we also found, surprisingly, increased rates of fungal [6.0-fold] and viral pneumonia [3.3-fold], and many other codes associated with respiratory infections. We also found a 3-fold increased rate of meningitis.”

“The only diagnosis statistically more common amongst breast cancer patients was cervicitis and endocervicitis, and this likely relates to the fact that many of these patients are undergoing hormone therapy.”

DLBCL vs prostate cancer

“We saw some of the same diagnoses come up as top-scoring hits, including viral [4.5-fold] and fungal pneumonia [8.2-fold], and meningitis [3.9-fold], and, in this case, Staphylococcal meningitis [8.6-fold],” Dr Shree said.

Deficiency of humoral immunity (14.8-fold), autoimmune hemolytic anemia (8.9-fold), Sicca syndrome (8.6-fold), and immune thrombocytopenia (4.8-fold) were also higher in the male DLBCL survivors than in prostate cancer survivors.

“No diagnoses were statistically more common in the prostate cancer survivors [than in male DLBCL survivors],” Dr Shree noted.

DLBCL vs head and neck cancer

“Again, the top 4 hits were the same 4 diagnoses we have been seeing repeatedly,” Dr Shree said.

Deficiency of humoral immunity (12.5-fold), autoimmune hemolytic anemia (9.3-fold), Sicca syndrome (5.5-fold), and immune thrombocytopenia (4.5-fold) were increased for DLBCL survivors compared to survivors of head and neck cancer.

DLBCL survivors also had an increased risk of respiratory infections, especially viral (4.4-fold) and fungal pneumonias (4.0-fold), meningitis (3.0-fold), and chronic lymphocytic thyroiditis (2.8-fold), also known as Hashimoto’s thyroiditis.

On the other hand, bacterial pneumonias and skin infections were more common in the head and neck cancer survivors than in DLBCL survivors.

DLBCL vs melanoma

“Interestingly, we did not see an increased risk for immune thrombocytopenias [in DLBCL survivors] compared to melanoma survivors in this comparison, which we had in all the other comparisons,” Dr Shree noted.

“But we did see [an increased risk for] the other diagnoses that we had been tracking, including, again, fungal pneumonia [6.9-fold], viral pneumonia [4.7-fold], and miscellaneous viral infections [2.6-fold].”

The only diagnosis that was statistically more common among melanoma survivors than DLBCL survivors was vitiligo.

Risks persist over time

The investigators assessed whether the elevated risks were static over the 1- to 10-year analysis period.

They took the top diagnoses—humoral deficiency, autoimmune hemolytic anemia, Sicca syndrome, and immune thrombocytopenia—and reviewed them for all cohorts to determine the rate of new cases.

“[F]or 3 out of these 4 diagnoses [humoral deficiency, autoimmune hemolytic anemia, and Sicca syndrome], increased incident rates are highest in the first 1 to 3 years after diagnosis in the lymphoma patients,” Dr Shree said.

“But even at 5 to 10 years out, these patients continue to have increased incidence of these diagnoses compared to the other cohorts, suggesting that these risks really do remain elevated over some time.”

The investigators repeated the analysis using broader categories of diagnoses with each category encompassing many ICD-9 codes.

“[I]n 12 out of 18 broad categories that we looked at, we can still find statistically significant differences in the incident rates for these diagnoses, and they were all increased in the lymphoma patients compared to the other cohorts,” Dr Shree explained.

“[T]hese increases were seen across multiple comparisons, suggesting that this phenomenon seems to be really lymphoma-specific and not specific to any of the individual comparisons we had chosen to perform.”

The findings, she said, have a lot of implications.

“We are particularly interested in which features of patients’ treatment contribute most to these elevated risks,” Dr Shree said. “And, of course, we want to know what to be able to tell our patients and how to follow them during survivorship.”

The investigators are currently validating their findings with further analysis of the Stanford lymphoma survivors cohort of approximately 3500 patients.

*Data in the abstract differ from the presentation.

© Todd Buchanan 2017

ATLANTA—A population-based study indicates that, compared to other cancer survivors, patients who survive diffuse large B-cell lymphoma (DLBCL) have an increased risk of autoimmune and infectious diseases.

For example, investigators found the risk of being diagnosed with impaired humoral immunity was 16.2 times higher in female DLBCL survivors than in breast cancer survivors, 14.8 times higher in male DLBCL survivors than in prostate cancer survivors, and 12.5 times higher in all DLBCL survivors than in survivors of head and neck cancer.

“Most of the treatments that we give for lymphoma have profound effects on the immune system, either directly or indirectly, including many of the T-cell-directed therapies,” said Tanaya Shree, MD, PhD, of Stanford University Medical Center in California.

“There have been studies on many of the effects suffered by lymphoma survivors, but very little is known about their immune health.”

Dr Shree and her colleagues undertook this study to determine how the immune system fares in lymphoma survivors. The investigators limited their analysis to survivors of DLBCL.

Dr Shree presented the findings at the 2017 ASH Annual Meeting (abstract 198*).

Study design

Investigators pulled data from the California Cancer Registry for patients with DLBCL as their first primary cancer diagnosed between 1991 and 2012. Patients had to be 18 or older at diagnosis and have survived more than a year after diagnosis.

“Importantly, we counted only diagnoses [of autoimmune and infectious diseases] that first appeared between 1 and 10 years after cancer diagnosis,” Dr Shree explained. “So any diagnosis we saw that had also been seen prior to cancer diagnosis or even up to 1 year post-cancer diagnosis, we considered to be pre-existing and were excluded from the analysis in order to really focus on new incident cases during survivorship.”

Investigators used the same criteria for the comparator cohorts.

The survivor data was linked to statewide discharge databases, and investigators performed the incidence analysis based on ICD-9 codes.

Investigators used Poisson regression analysis to obtain incident ratios and adjusted the models for age, race, and year of diagnosis.

They graphed the incident rate ratios for all the diagnoses that were significantly different between the DLBCL cohort and the comparator cohorts.

“[W]e considered a P value of less than 0.0005 to be significant,” Dr Shree clarified.

Survivor characteristics

The cohorts comprised 802,255 survivors of DLBCL (n=21,690), breast cancer (n=337,591), prostate cancer (n=325,533), melanoma (n=73,196), and head and neck cancer (n=44,245).

“At least 75% of patients in each cohort were aged 40 to 79,” Dr Shree noted, “with a good representation of elderly patients.”

The median follow-up time was 6.1 years for DLBCL patients and ranged from 5.7 years for head and neck cancer survivors to 8.3 years for prostate cancer survivors.

About three-quarters of patients in each cohort had hospitalization data within 1 to 10 years from cancer diagnosis.

DLBCL vs breast cancer

“Interestingly, we found some familiar names amongst the top-scoring diagnoses,” Dr Shree said.

Deficiency of humoral immunity (16.2-fold), autoimmune hemolytic anemia (9.9-fold), Sicca syndrome (6.9-fold), and immune thrombocytopenia (3.1-fold) were higher in female DLBCL survivors than breast cancer survivors.

“All of these have known associations with lymphoma,” Dr Shree said. “But we also found, surprisingly, increased rates of fungal [6.0-fold] and viral pneumonia [3.3-fold], and many other codes associated with respiratory infections. We also found a 3-fold increased rate of meningitis.”

“The only diagnosis statistically more common amongst breast cancer patients was cervicitis and endocervicitis, and this likely relates to the fact that many of these patients are undergoing hormone therapy.”

DLBCL vs prostate cancer

“We saw some of the same diagnoses come up as top-scoring hits, including viral [4.5-fold] and fungal pneumonia [8.2-fold], and meningitis [3.9-fold], and, in this case, Staphylococcal meningitis [8.6-fold],” Dr Shree said.

Deficiency of humoral immunity (14.8-fold), autoimmune hemolytic anemia (8.9-fold), Sicca syndrome (8.6-fold), and immune thrombocytopenia (4.8-fold) were also higher in the male DLBCL survivors than in prostate cancer survivors.

“No diagnoses were statistically more common in the prostate cancer survivors [than in male DLBCL survivors],” Dr Shree noted.

DLBCL vs head and neck cancer

“Again, the top 4 hits were the same 4 diagnoses we have been seeing repeatedly,” Dr Shree said.

Deficiency of humoral immunity (12.5-fold), autoimmune hemolytic anemia (9.3-fold), Sicca syndrome (5.5-fold), and immune thrombocytopenia (4.5-fold) were increased for DLBCL survivors compared to survivors of head and neck cancer.

DLBCL survivors also had an increased risk of respiratory infections, especially viral (4.4-fold) and fungal pneumonias (4.0-fold), meningitis (3.0-fold), and chronic lymphocytic thyroiditis (2.8-fold), also known as Hashimoto’s thyroiditis.

On the other hand, bacterial pneumonias and skin infections were more common in the head and neck cancer survivors than in DLBCL survivors.

DLBCL vs melanoma

“Interestingly, we did not see an increased risk for immune thrombocytopenias [in DLBCL survivors] compared to melanoma survivors in this comparison, which we had in all the other comparisons,” Dr Shree noted.

“But we did see [an increased risk for] the other diagnoses that we had been tracking, including, again, fungal pneumonia [6.9-fold], viral pneumonia [4.7-fold], and miscellaneous viral infections [2.6-fold].”

The only diagnosis that was statistically more common among melanoma survivors than DLBCL survivors was vitiligo.

Risks persist over time

The investigators assessed whether the elevated risks were static over the 1- to 10-year analysis period.

They took the top diagnoses—humoral deficiency, autoimmune hemolytic anemia, Sicca syndrome, and immune thrombocytopenia—and reviewed them for all cohorts to determine the rate of new cases.

“[F]or 3 out of these 4 diagnoses [humoral deficiency, autoimmune hemolytic anemia, and Sicca syndrome], increased incident rates are highest in the first 1 to 3 years after diagnosis in the lymphoma patients,” Dr Shree said.

“But even at 5 to 10 years out, these patients continue to have increased incidence of these diagnoses compared to the other cohorts, suggesting that these risks really do remain elevated over some time.”

The investigators repeated the analysis using broader categories of diagnoses with each category encompassing many ICD-9 codes.

“[I]n 12 out of 18 broad categories that we looked at, we can still find statistically significant differences in the incident rates for these diagnoses, and they were all increased in the lymphoma patients compared to the other cohorts,” Dr Shree explained.

“[T]hese increases were seen across multiple comparisons, suggesting that this phenomenon seems to be really lymphoma-specific and not specific to any of the individual comparisons we had chosen to perform.”

The findings, she said, have a lot of implications.

“We are particularly interested in which features of patients’ treatment contribute most to these elevated risks,” Dr Shree said. “And, of course, we want to know what to be able to tell our patients and how to follow them during survivorship.”

The investigators are currently validating their findings with further analysis of the Stanford lymphoma survivors cohort of approximately 3500 patients.

*Data in the abstract differ from the presentation.

Photo from Business Wire

The US Food and Drug Administration (FDA) has accepted for priority review a supplemental biologics license application (sBLA) for brentuximab vedotin (ADCETRIS).

With this sBLA, Seattle Genetics, Inc., is seeking approval for brentuximab vedotin in combination with chemotherapy for frontline treatment of patients with advanced classical Hodgkin lymphoma (HL).

The FDA expects to make a decision on the sBLA by May 1, 2018.

The agency’s goal is to take action on a priority review application within 6 months of receiving it, rather than the standard 10 months.

The FDA grants priority review to applications for products that may provide significant improvements in the treatment, diagnosis, or prevention of serious conditions.

The priority review for this sBLA is based on positive results from the phase 3 ECHELON-1 trial.

The FDA previously granted brentuximab vedotin breakthrough therapy designation based on ECHELON-1 results.

Breakthrough therapy designation is intended to expedite the development and review of promising drug candidates for serious or life-threatening conditions. It is based upon clinical evidence of substantial improvement over existing therapies in one or more clinically significant endpoints.

ECHELON-1

Result from ECHELON-1 were presented at the 2017 ASH Annual Meeting and simultaneously published in NEJM.

In this trial, researchers compared brentuximab vedotin, doxorubicin, vinblastine, and dacarbazine (A+AVD) to doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) as frontline treatment for 1334 patients with advanced HL.

The study’s primary endpoint was modified progression-free survival (PFS), which was defined as time to progression, death, or evidence of non-complete response after completion of frontline therapy followed by subsequent anticancer therapy.

According to an independent review facility, A+AVD provided a significant improvement in modified PFS compared to ABVD. The hazard ratio was 0.77 (P=0.035), which corresponds to a 23% reduction in the risk of progression, death, or the need for additional anticancer therapy.

The 2-year modified PFS rate was 82.1% in the A+AVD arm and 77.2% in the ABVD arm.

There was no significant difference between the treatment arms when it came to response rates or overall survival.

The objective response rate was 86% in the A+AVD arm and 83% in the ABVD arm (P=0.12). The complete response rate was 73% and 70%, respectively (P=0.22).

The interim 2-year overall survival rate was 97% in the A+AVD arm and 95% in the ABVD arm (hazard ratio=0.72; P=0.19).

The overall incidence of adverse events (AEs) was 99% in the A+AVD arm and 98% in the ABVD arm. The incidence of grade 3 or higher AEs was 83% and 66%, respectively, and the incidence of serious AEs was 43% and 27%, respectively.

Neutropenia, febrile neutropenia, and peripheral neuropathy were more common with A+AVD, while pulmonary toxicity was more common with ABVD.

About brentuximab vedotin

Brentuximab vedotin is already FDA-approved to treat adults with:

• Classical HL who have failed autologous hematopoietic stem cell transplant (auto-HSCT) or, in those who are not auto-HSCT candidates, have failed at least 2 prior multi-agent chemotherapy regimens.
• Classical HL at high risk of relapse or progression as post-auto-HSCT consolidation.
• Primary cutaneous anaplastic large-cell lymphoma (ALCL) or CD30-expressing mycosis fungoides who have received prior systemic therapy.
• Systemic ALCL who have failed at least 1 prior multi-agent chemotherapy regimen. (The drug has accelerated approval for this indication, based on overall response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.)
  

Photo from Business Wire

The US Food and Drug Administration (FDA) has accepted for priority review a supplemental biologics license application (sBLA) for brentuximab vedotin (ADCETRIS).

With this sBLA, Seattle Genetics, Inc., is seeking approval for brentuximab vedotin in combination with chemotherapy for frontline treatment of patients with advanced classical Hodgkin lymphoma (HL).

The FDA expects to make a decision on the sBLA by May 1, 2018.

The agency’s goal is to take action on a priority review application within 6 months of receiving it, rather than the standard 10 months.

The FDA grants priority review to applications for products that may provide significant improvements in the treatment, diagnosis, or prevention of serious conditions.

The priority review for this sBLA is based on positive results from the phase 3 ECHELON-1 trial.

The FDA previously granted brentuximab vedotin breakthrough therapy designation based on ECHELON-1 results.

Breakthrough therapy designation is intended to expedite the development and review of promising drug candidates for serious or life-threatening conditions. It is based upon clinical evidence of substantial improvement over existing therapies in one or more clinically significant endpoints.

ECHELON-1

Result from ECHELON-1 were presented at the 2017 ASH Annual Meeting and simultaneously published in NEJM.

In this trial, researchers compared brentuximab vedotin, doxorubicin, vinblastine, and dacarbazine (A+AVD) to doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) as frontline treatment for 1334 patients with advanced HL.

The study’s primary endpoint was modified progression-free survival (PFS), which was defined as time to progression, death, or evidence of non-complete response after completion of frontline therapy followed by subsequent anticancer therapy.

According to an independent review facility, A+AVD provided a significant improvement in modified PFS compared to ABVD. The hazard ratio was 0.77 (P=0.035), which corresponds to a 23% reduction in the risk of progression, death, or the need for additional anticancer therapy.

The 2-year modified PFS rate was 82.1% in the A+AVD arm and 77.2% in the ABVD arm.

There was no significant difference between the treatment arms when it came to response rates or overall survival.

The objective response rate was 86% in the A+AVD arm and 83% in the ABVD arm (P=0.12). The complete response rate was 73% and 70%, respectively (P=0.22).

The interim 2-year overall survival rate was 97% in the A+AVD arm and 95% in the ABVD arm (hazard ratio=0.72; P=0.19).

The overall incidence of adverse events (AEs) was 99% in the A+AVD arm and 98% in the ABVD arm. The incidence of grade 3 or higher AEs was 83% and 66%, respectively, and the incidence of serious AEs was 43% and 27%, respectively.

Neutropenia, febrile neutropenia, and peripheral neuropathy were more common with A+AVD, while pulmonary toxicity was more common with ABVD.

About brentuximab vedotin

Brentuximab vedotin is already FDA-approved to treat adults with:

• Classical HL who have failed autologous hematopoietic stem cell transplant (auto-HSCT) or, in those who are not auto-HSCT candidates, have failed at least 2 prior multi-agent chemotherapy regimens.
• Classical HL at high risk of relapse or progression as post-auto-HSCT consolidation.
• Primary cutaneous anaplastic large-cell lymphoma (ALCL) or CD30-expressing mycosis fungoides who have received prior systemic therapy.
• Systemic ALCL who have failed at least 1 prior multi-agent chemotherapy regimen. (The drug has accelerated approval for this indication, based on overall response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.)
  

Photo from Business Wire

The US Food and Drug Administration (FDA) has accepted for priority review a supplemental biologics license application (sBLA) for brentuximab vedotin (ADCETRIS).

With this sBLA, Seattle Genetics, Inc., is seeking approval for brentuximab vedotin in combination with chemotherapy for frontline treatment of patients with advanced classical Hodgkin lymphoma (HL).

The FDA expects to make a decision on the sBLA by May 1, 2018.

The agency’s goal is to take action on a priority review application within 6 months of receiving it, rather than the standard 10 months.

The FDA grants priority review to applications for products that may provide significant improvements in the treatment, diagnosis, or prevention of serious conditions.

The priority review for this sBLA is based on positive results from the phase 3 ECHELON-1 trial.

The FDA previously granted brentuximab vedotin breakthrough therapy designation based on ECHELON-1 results.

Breakthrough therapy designation is intended to expedite the development and review of promising drug candidates for serious or life-threatening conditions. It is based upon clinical evidence of substantial improvement over existing therapies in one or more clinically significant endpoints.

ECHELON-1

Result from ECHELON-1 were presented at the 2017 ASH Annual Meeting and simultaneously published in NEJM.

In this trial, researchers compared brentuximab vedotin, doxorubicin, vinblastine, and dacarbazine (A+AVD) to doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) as frontline treatment for 1334 patients with advanced HL.

The study’s primary endpoint was modified progression-free survival (PFS), which was defined as time to progression, death, or evidence of non-complete response after completion of frontline therapy followed by subsequent anticancer therapy.

According to an independent review facility, A+AVD provided a significant improvement in modified PFS compared to ABVD. The hazard ratio was 0.77 (P=0.035), which corresponds to a 23% reduction in the risk of progression, death, or the need for additional anticancer therapy.

The 2-year modified PFS rate was 82.1% in the A+AVD arm and 77.2% in the ABVD arm.

There was no significant difference between the treatment arms when it came to response rates or overall survival.

The objective response rate was 86% in the A+AVD arm and 83% in the ABVD arm (P=0.12). The complete response rate was 73% and 70%, respectively (P=0.22).

The interim 2-year overall survival rate was 97% in the A+AVD arm and 95% in the ABVD arm (hazard ratio=0.72; P=0.19).

The overall incidence of adverse events (AEs) was 99% in the A+AVD arm and 98% in the ABVD arm. The incidence of grade 3 or higher AEs was 83% and 66%, respectively, and the incidence of serious AEs was 43% and 27%, respectively.

Neutropenia, febrile neutropenia, and peripheral neuropathy were more common with A+AVD, while pulmonary toxicity was more common with ABVD.

About brentuximab vedotin

Brentuximab vedotin is already FDA-approved to treat adults with:

• Classical HL who have failed autologous hematopoietic stem cell transplant (auto-HSCT) or, in those who are not auto-HSCT candidates, have failed at least 2 prior multi-agent chemotherapy regimens.
• Classical HL at high risk of relapse or progression as post-auto-HSCT consolidation.
• Primary cutaneous anaplastic large-cell lymphoma (ALCL) or CD30-expressing mycosis fungoides who have received prior systemic therapy.
• Systemic ALCL who have failed at least 1 prior multi-agent chemotherapy regimen. (The drug has accelerated approval for this indication, based on overall response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.)
  

Photo by Esther Dyson

The US Food and Drug Administration (FDA) has lifted the clinical hold placed on a phase 1/2 trial of SEL24, a dual PIM/FLT3 kinase inhibitor, in patients with relapsed/refractory acute myeloid leukemia (AML).

Selvita and Menarini Group, the companies developing SEL24, agreed to continue the trial with additional provisions to its protocol.

The companies will be working with trial investigators and clinical sites to obtain institutional review board approval on the revised protocol and resume enrollment in the trial, according to Krzysztof Brzozka, PhD, chief scientific officer of Selvita.

The trial is a dose-escalation study of SEL24 in patients with relapsed and refractory AML. The study was designed to determine the maximum tolerated dose and recommended dose of SEL24.

The first patient was dosed in March 2017. The study began with a 25 mg daily dose, which was then escalated following cohort reviews.

In October, the trial was placed on full clinical hold, which meant no new patients could be enrolled on the trial, and enrolled patients could not receive SEL24 until the hold was lifted.

The hold was the result of a fatal cerebral adverse event that was considered possibly related to SEL24.

The event occurred in a patient who started treatment with a 150 mg dose of SEL24 as the third patient in this dose cohort.

The patient received 4 doses of the drug and developed a life-threatening, grade 4 venous thrombus in the brain with subsequent intracerebral hemorrhage, which required hospitalization.

The patient died in hospice 4 days later. The patient’s death was deemed possibly related to SEL24.

In response to the death, a safety report was submitted to the FDA, along with a review by the trial’s data monitoring committee.

The FDA then placed a hold on the trial and requested more safety data on patients who have received SEL24, as well as specific protocol changes and additional guidance to the study staff.

Selvita and Menarini Group complied with the FDA’s requests and agreed to revise the dose-finding scheme to a standard 3+3 design under an amended protocol.

Photo by Esther Dyson

The US Food and Drug Administration (FDA) has lifted the clinical hold placed on a phase 1/2 trial of SEL24, a dual PIM/FLT3 kinase inhibitor, in patients with relapsed/refractory acute myeloid leukemia (AML).

Selvita and Menarini Group, the companies developing SEL24, agreed to continue the trial with additional provisions to its protocol.

The companies will be working with trial investigators and clinical sites to obtain institutional review board approval on the revised protocol and resume enrollment in the trial, according to Krzysztof Brzozka, PhD, chief scientific officer of Selvita.

The trial is a dose-escalation study of SEL24 in patients with relapsed and refractory AML. The study was designed to determine the maximum tolerated dose and recommended dose of SEL24.

The first patient was dosed in March 2017. The study began with a 25 mg daily dose, which was then escalated following cohort reviews.

In October, the trial was placed on full clinical hold, which meant no new patients could be enrolled on the trial, and enrolled patients could not receive SEL24 until the hold was lifted.

The hold was the result of a fatal cerebral adverse event that was considered possibly related to SEL24.

The event occurred in a patient who started treatment with a 150 mg dose of SEL24 as the third patient in this dose cohort.

The patient received 4 doses of the drug and developed a life-threatening, grade 4 venous thrombus in the brain with subsequent intracerebral hemorrhage, which required hospitalization.

The patient died in hospice 4 days later. The patient’s death was deemed possibly related to SEL24.

In response to the death, a safety report was submitted to the FDA, along with a review by the trial’s data monitoring committee.

The FDA then placed a hold on the trial and requested more safety data on patients who have received SEL24, as well as specific protocol changes and additional guidance to the study staff.

Selvita and Menarini Group complied with the FDA’s requests and agreed to revise the dose-finding scheme to a standard 3+3 design under an amended protocol.

Photo by Esther Dyson

The US Food and Drug Administration (FDA) has lifted the clinical hold placed on a phase 1/2 trial of SEL24, a dual PIM/FLT3 kinase inhibitor, in patients with relapsed/refractory acute myeloid leukemia (AML).

Selvita and Menarini Group, the companies developing SEL24, agreed to continue the trial with additional provisions to its protocol.

The companies will be working with trial investigators and clinical sites to obtain institutional review board approval on the revised protocol and resume enrollment in the trial, according to Krzysztof Brzozka, PhD, chief scientific officer of Selvita.

The trial is a dose-escalation study of SEL24 in patients with relapsed and refractory AML. The study was designed to determine the maximum tolerated dose and recommended dose of SEL24.

The first patient was dosed in March 2017. The study began with a 25 mg daily dose, which was then escalated following cohort reviews.

In October, the trial was placed on full clinical hold, which meant no new patients could be enrolled on the trial, and enrolled patients could not receive SEL24 until the hold was lifted.

The hold was the result of a fatal cerebral adverse event that was considered possibly related to SEL24.

The event occurred in a patient who started treatment with a 150 mg dose of SEL24 as the third patient in this dose cohort.

The patient received 4 doses of the drug and developed a life-threatening, grade 4 venous thrombus in the brain with subsequent intracerebral hemorrhage, which required hospitalization.

The patient died in hospice 4 days later. The patient’s death was deemed possibly related to SEL24.

In response to the death, a safety report was submitted to the FDA, along with a review by the trial’s data monitoring committee.

The FDA then placed a hold on the trial and requested more safety data on patients who have received SEL24, as well as specific protocol changes and additional guidance to the study staff.

Selvita and Menarini Group complied with the FDA’s requests and agreed to revise the dose-finding scheme to a standard 3+3 design under an amended protocol.

ANSWER

The correct interpretation includes marked sinus bradycardia with a second-degree atrioventricular (AV) block (Mobitz I) and occasional junctional escape, left-axis deviation, and evidence of an inferior MI. Poor R-wave progression is also noted in the precordial leads.

Marked sinus bradycardia is seen in the first three and the last four P waves of the rhythm strip. The P-P intervals have a rate of 50 beats/min—different than the overall rate of the QRS complex (remember, “sinus” is synonymous with “P wave”!). The rate of the QRS complex (38 beats/min) is slower than the atrial rate, signifying a block of some sort.

Second-degree AV block is evident from the lengthening PR interval in the first two P-QRS complexes, followed by a P wave with no associated QRS complex. Although the fourth QRS complex in the rhythm strip is narrow and similar in appearance to the others, it’s too far from the previous P wave to have been conducted from the atrium—indicating a junctional escape beat arising from the AV node. (The rhythm returns to second-degree AV block for the remainder of the beats seen on the ECG.)

Left-axis deviation is signified by the R axis of –78° (lower than the normal limit of –30°). The Q waves in leads II, III, and aVF indicate a prior inferior MI. Finally, poor R-wave progression is seen in the precordial leads, with no significant transition between leads V₁ and V₆.

Although second-degree AV block is not an indication for permanent pacing, symptomatic bradycardia that persists despite medical management is. Because this patient was symptomatic while taking an AV nodal blocking agent (metoprolol), a permanent pacemaker was recommended.

ANSWER

The correct interpretation includes marked sinus bradycardia with a second-degree atrioventricular (AV) block (Mobitz I) and occasional junctional escape, left-axis deviation, and evidence of an inferior MI. Poor R-wave progression is also noted in the precordial leads.

Marked sinus bradycardia is seen in the first three and the last four P waves of the rhythm strip. The P-P intervals have a rate of 50 beats/min—different than the overall rate of the QRS complex (remember, “sinus” is synonymous with “P wave”!). The rate of the QRS complex (38 beats/min) is slower than the atrial rate, signifying a block of some sort.

Second-degree AV block is evident from the lengthening PR interval in the first two P-QRS complexes, followed by a P wave with no associated QRS complex. Although the fourth QRS complex in the rhythm strip is narrow and similar in appearance to the others, it’s too far from the previous P wave to have been conducted from the atrium—indicating a junctional escape beat arising from the AV node. (The rhythm returns to second-degree AV block for the remainder of the beats seen on the ECG.)

Left-axis deviation is signified by the R axis of –78° (lower than the normal limit of –30°). The Q waves in leads II, III, and aVF indicate a prior inferior MI. Finally, poor R-wave progression is seen in the precordial leads, with no significant transition between leads V₁ and V₆.

Although second-degree AV block is not an indication for permanent pacing, symptomatic bradycardia that persists despite medical management is. Because this patient was symptomatic while taking an AV nodal blocking agent (metoprolol), a permanent pacemaker was recommended.

ANSWER

The correct interpretation includes marked sinus bradycardia with a second-degree atrioventricular (AV) block (Mobitz I) and occasional junctional escape, left-axis deviation, and evidence of an inferior MI. Poor R-wave progression is also noted in the precordial leads.

Marked sinus bradycardia is seen in the first three and the last four P waves of the rhythm strip. The P-P intervals have a rate of 50 beats/min—different than the overall rate of the QRS complex (remember, “sinus” is synonymous with “P wave”!). The rate of the QRS complex (38 beats/min) is slower than the atrial rate, signifying a block of some sort.

Second-degree AV block is evident from the lengthening PR interval in the first two P-QRS complexes, followed by a P wave with no associated QRS complex. Although the fourth QRS complex in the rhythm strip is narrow and similar in appearance to the others, it’s too far from the previous P wave to have been conducted from the atrium—indicating a junctional escape beat arising from the AV node. (The rhythm returns to second-degree AV block for the remainder of the beats seen on the ECG.)

Left-axis deviation is signified by the R axis of –78° (lower than the normal limit of –30°). The Q waves in leads II, III, and aVF indicate a prior inferior MI. Finally, poor R-wave progression is seen in the precordial leads, with no significant transition between leads V₁ and V₆.

Although second-degree AV block is not an indication for permanent pacing, symptomatic bradycardia that persists despite medical management is. Because this patient was symptomatic while taking an AV nodal blocking agent (metoprolol), a permanent pacemaker was recommended.

According to researchers from William Paterson University, Emory University, and the CDC, screening for CCHD could save at least 120 babies a year.

Congenital heart disease accounted for 6% of U.S. infant deaths from 1999 to 2006. Almost 1 in every 4 babies born with a congenital heart defect has critical congenital heart disease (CCHD) and will need surgery or other procedures in the first year. About 7,200 babies born in the U.S .each year have 1 of 7 CCHDs. But some babies can seem healthy and be sent home before the heart defect is detected.

In 2011, CCHD was added to the U.S. Recommended Uniform Screening Panel for newborns. As of June 2013, 8 states had implemented mandatory screening policies, 5 had voluntary screening policies, and 9 had adopted but not yet implemented mandates.

The study was conducted in 2013 and involved data for nearly 27 million births. Between 2007 and 2013, 2,734 infants died due to CCHD; 3,967 died of other or unspecified causes.

The study, which is the first look at the impact of state policies to require or recommend screening for CCHD at birth, found that states with screening requirements saw the most significant drop in numbers of infant deaths. Voluntary policies or mandated policies not yet implemented were not associated with reductions. However, 47 states and DC now have mandatory screening policies in place.

According to researchers from William Paterson University, Emory University, and the CDC, screening for CCHD could save at least 120 babies a year.

Congenital heart disease accounted for 6% of U.S. infant deaths from 1999 to 2006. Almost 1 in every 4 babies born with a congenital heart defect has critical congenital heart disease (CCHD) and will need surgery or other procedures in the first year. About 7,200 babies born in the U.S .each year have 1 of 7 CCHDs. But some babies can seem healthy and be sent home before the heart defect is detected.

In 2011, CCHD was added to the U.S. Recommended Uniform Screening Panel for newborns. As of June 2013, 8 states had implemented mandatory screening policies, 5 had voluntary screening policies, and 9 had adopted but not yet implemented mandates.

The study was conducted in 2013 and involved data for nearly 27 million births. Between 2007 and 2013, 2,734 infants died due to CCHD; 3,967 died of other or unspecified causes.

The study, which is the first look at the impact of state policies to require or recommend screening for CCHD at birth, found that states with screening requirements saw the most significant drop in numbers of infant deaths. Voluntary policies or mandated policies not yet implemented were not associated with reductions. However, 47 states and DC now have mandatory screening policies in place.

According to researchers from William Paterson University, Emory University, and the CDC, screening for CCHD could save at least 120 babies a year.

Congenital heart disease accounted for 6% of U.S. infant deaths from 1999 to 2006. Almost 1 in every 4 babies born with a congenital heart defect has critical congenital heart disease (CCHD) and will need surgery or other procedures in the first year. About 7,200 babies born in the U.S .each year have 1 of 7 CCHDs. But some babies can seem healthy and be sent home before the heart defect is detected.

In 2011, CCHD was added to the U.S. Recommended Uniform Screening Panel for newborns. As of June 2013, 8 states had implemented mandatory screening policies, 5 had voluntary screening policies, and 9 had adopted but not yet implemented mandates.

The study was conducted in 2013 and involved data for nearly 27 million births. Between 2007 and 2013, 2,734 infants died due to CCHD; 3,967 died of other or unspecified causes.

The study, which is the first look at the impact of state policies to require or recommend screening for CCHD at birth, found that states with screening requirements saw the most significant drop in numbers of infant deaths. Voluntary policies or mandated policies not yet implemented were not associated with reductions. However, 47 states and DC now have mandatory screening policies in place.

New use of inhaled long-acting beta-2 agonists (LABAs) or long-acting antimuscarinic antagonists (LAMAs) was associated with a 1.5-fold increased cardiovascular risk within 30 days of initiation in patients with chronic obstructive pulmonary disease, irrespective of prior cardiovascular disease status and history of exacerbations, according to a review of more than 280,000 COPD patients in Taiwan.

The relationship between cardiovascular disease (CVD) and LABAs and LAMAs in chronic obstructive pulmonary disease (COPD) has long been debated. The new study addressed some limitations of previous studies, which had found conflicting results ranging from no increased risk to up to a 4.5-fold increased risk of cardiovascular events when the medications were used for COPD.

Previous randomized trials haven’t raised much concern, but they included prior users who may have developed tolerance to the heart effects and excluded patients with baseline CVD. “We caution physicians to closely monitor new users of LABAs or LAMAs for cardiovascular symptoms.” Health care professionals should be vigilant for any cardiovascular symptoms during the first 30 days of inhalation therapy, said investigators led by Meng-Ting Wang, PhD, of the National Defense Medical Center, Taipei.

“We suspect that there may exist a subgroup of patients with COPD who are particularly at risk of CVD with initial exposure to LABAs or LAMAs ... we suggest that the use of inhaled long-acting bronchodilators in COPD needs to be carefully assessed, and a thorough cardiovascular physical examination, especially heart rate measurement and electrocardiograms, needs to be performed” before prescribing LABAs and LAMAs, they wrote in an article in JAMA Internal Medicine.

The team identified 284,220 COPD patients in the Taiwan National Health Insurance Research Database during 2007-2011 who were new to the medications. During a mean follow-up of 2 years, 37,719 developed severe CVD requiring hospitalization or emergency care, including coronary artery disease, heart failure, ischemic stroke, and arrhythmia.

The team compared their CVD subjects with controls who did not have a heart event and found that new LABA and LAMA use in COPD was associated with a 1.50-fold (95% confidence interval, 1.35-1.67; P less than .001) and a 1.52-fold (95% CI, 1.28-1.80; P less than .001) increased cardiovascular risk within 30 days of initiation, respectively.

One severe CVD event requiring hospitalization or ED care occurred for every 406 (95% CI, 303-580) new LABA users and 391 (95% CI, 254-725) new LAMA users during the first 30 days of therapy.

The LABA- and LAMA-associated CVD risk remained significant, regardless of patients’ CVD history and COPD exacerbations. Analyses of individual CVD outcomes revealed increased risks of coronary artery disease and heart failure with LABA and LAMA treatment, and an increased risk for cardiac arrhythmias with LAMA therapy.

The cardiovascular risks peaked at around the 30th day of treatment, waned from 31-60 days of treatment, and reduced to a level lower than the baseline risk from 71-240 days.

“Given that CVD is highly prevalent among patients with COPD, clinicians should also pay attention to the management of CVD risk factors throughout the duration of LABA or LAMA therapy ... if needed, a preventive therapy for CVD should be considered during the initial treatment of inhaled long-acting bronchodilators,” the investigators said.

LABAs and LAMAs are believed to cause sympathetic overactivation by activating sympathetic beta-2 adrenergic receptors and suppressing parasympathetic muscarinic-3 receptors, which could contribute to the CVD risk. Also, LABA and LAMA use in COPD has been observed to increase inflammatory cytokine levels, which might also play a role.

The subjects were 40 years or older; the mean age was 71.4 years and 68.9% of the participants were men.

The work was supported by Taiwan’s Ministry of Science and Technology. The investigators had no disclosures.

Eli Zimmerman contributed to this report.

[email protected]

SOURCE: Wang MT et al. JAMA Intern Med. 2018 Jan 2. doi: 10.1001/jamainternmed.2017.7720.

New use of inhaled long-acting beta-2 agonists (LABAs) or long-acting antimuscarinic antagonists (LAMAs) was associated with a 1.5-fold increased cardiovascular risk within 30 days of initiation in patients with chronic obstructive pulmonary disease, irrespective of prior cardiovascular disease status and history of exacerbations, according to a review of more than 280,000 COPD patients in Taiwan.

The relationship between cardiovascular disease (CVD) and LABAs and LAMAs in chronic obstructive pulmonary disease (COPD) has long been debated. The new study addressed some limitations of previous studies, which had found conflicting results ranging from no increased risk to up to a 4.5-fold increased risk of cardiovascular events when the medications were used for COPD.

Previous randomized trials haven’t raised much concern, but they included prior users who may have developed tolerance to the heart effects and excluded patients with baseline CVD. “We caution physicians to closely monitor new users of LABAs or LAMAs for cardiovascular symptoms.” Health care professionals should be vigilant for any cardiovascular symptoms during the first 30 days of inhalation therapy, said investigators led by Meng-Ting Wang, PhD, of the National Defense Medical Center, Taipei.

“We suspect that there may exist a subgroup of patients with COPD who are particularly at risk of CVD with initial exposure to LABAs or LAMAs ... we suggest that the use of inhaled long-acting bronchodilators in COPD needs to be carefully assessed, and a thorough cardiovascular physical examination, especially heart rate measurement and electrocardiograms, needs to be performed” before prescribing LABAs and LAMAs, they wrote in an article in JAMA Internal Medicine.

The team identified 284,220 COPD patients in the Taiwan National Health Insurance Research Database during 2007-2011 who were new to the medications. During a mean follow-up of 2 years, 37,719 developed severe CVD requiring hospitalization or emergency care, including coronary artery disease, heart failure, ischemic stroke, and arrhythmia.

The team compared their CVD subjects with controls who did not have a heart event and found that new LABA and LAMA use in COPD was associated with a 1.50-fold (95% confidence interval, 1.35-1.67; P less than .001) and a 1.52-fold (95% CI, 1.28-1.80; P less than .001) increased cardiovascular risk within 30 days of initiation, respectively.

One severe CVD event requiring hospitalization or ED care occurred for every 406 (95% CI, 303-580) new LABA users and 391 (95% CI, 254-725) new LAMA users during the first 30 days of therapy.

The LABA- and LAMA-associated CVD risk remained significant, regardless of patients’ CVD history and COPD exacerbations. Analyses of individual CVD outcomes revealed increased risks of coronary artery disease and heart failure with LABA and LAMA treatment, and an increased risk for cardiac arrhythmias with LAMA therapy.

The cardiovascular risks peaked at around the 30th day of treatment, waned from 31-60 days of treatment, and reduced to a level lower than the baseline risk from 71-240 days.

“Given that CVD is highly prevalent among patients with COPD, clinicians should also pay attention to the management of CVD risk factors throughout the duration of LABA or LAMA therapy ... if needed, a preventive therapy for CVD should be considered during the initial treatment of inhaled long-acting bronchodilators,” the investigators said.

LABAs and LAMAs are believed to cause sympathetic overactivation by activating sympathetic beta-2 adrenergic receptors and suppressing parasympathetic muscarinic-3 receptors, which could contribute to the CVD risk. Also, LABA and LAMA use in COPD has been observed to increase inflammatory cytokine levels, which might also play a role.

The subjects were 40 years or older; the mean age was 71.4 years and 68.9% of the participants were men.

The work was supported by Taiwan’s Ministry of Science and Technology. The investigators had no disclosures.

Eli Zimmerman contributed to this report.

[email protected]

SOURCE: Wang MT et al. JAMA Intern Med. 2018 Jan 2. doi: 10.1001/jamainternmed.2017.7720.

New use of inhaled long-acting beta-2 agonists (LABAs) or long-acting antimuscarinic antagonists (LAMAs) was associated with a 1.5-fold increased cardiovascular risk within 30 days of initiation in patients with chronic obstructive pulmonary disease, irrespective of prior cardiovascular disease status and history of exacerbations, according to a review of more than 280,000 COPD patients in Taiwan.

The relationship between cardiovascular disease (CVD) and LABAs and LAMAs in chronic obstructive pulmonary disease (COPD) has long been debated. The new study addressed some limitations of previous studies, which had found conflicting results ranging from no increased risk to up to a 4.5-fold increased risk of cardiovascular events when the medications were used for COPD.

Previous randomized trials haven’t raised much concern, but they included prior users who may have developed tolerance to the heart effects and excluded patients with baseline CVD. “We caution physicians to closely monitor new users of LABAs or LAMAs for cardiovascular symptoms.” Health care professionals should be vigilant for any cardiovascular symptoms during the first 30 days of inhalation therapy, said investigators led by Meng-Ting Wang, PhD, of the National Defense Medical Center, Taipei.

“We suspect that there may exist a subgroup of patients with COPD who are particularly at risk of CVD with initial exposure to LABAs or LAMAs ... we suggest that the use of inhaled long-acting bronchodilators in COPD needs to be carefully assessed, and a thorough cardiovascular physical examination, especially heart rate measurement and electrocardiograms, needs to be performed” before prescribing LABAs and LAMAs, they wrote in an article in JAMA Internal Medicine.

The team identified 284,220 COPD patients in the Taiwan National Health Insurance Research Database during 2007-2011 who were new to the medications. During a mean follow-up of 2 years, 37,719 developed severe CVD requiring hospitalization or emergency care, including coronary artery disease, heart failure, ischemic stroke, and arrhythmia.

The team compared their CVD subjects with controls who did not have a heart event and found that new LABA and LAMA use in COPD was associated with a 1.50-fold (95% confidence interval, 1.35-1.67; P less than .001) and a 1.52-fold (95% CI, 1.28-1.80; P less than .001) increased cardiovascular risk within 30 days of initiation, respectively.

One severe CVD event requiring hospitalization or ED care occurred for every 406 (95% CI, 303-580) new LABA users and 391 (95% CI, 254-725) new LAMA users during the first 30 days of therapy.

The LABA- and LAMA-associated CVD risk remained significant, regardless of patients’ CVD history and COPD exacerbations. Analyses of individual CVD outcomes revealed increased risks of coronary artery disease and heart failure with LABA and LAMA treatment, and an increased risk for cardiac arrhythmias with LAMA therapy.

The cardiovascular risks peaked at around the 30th day of treatment, waned from 31-60 days of treatment, and reduced to a level lower than the baseline risk from 71-240 days.

“Given that CVD is highly prevalent among patients with COPD, clinicians should also pay attention to the management of CVD risk factors throughout the duration of LABA or LAMA therapy ... if needed, a preventive therapy for CVD should be considered during the initial treatment of inhaled long-acting bronchodilators,” the investigators said.

LABAs and LAMAs are believed to cause sympathetic overactivation by activating sympathetic beta-2 adrenergic receptors and suppressing parasympathetic muscarinic-3 receptors, which could contribute to the CVD risk. Also, LABA and LAMA use in COPD has been observed to increase inflammatory cytokine levels, which might also play a role.

The subjects were 40 years or older; the mean age was 71.4 years and 68.9% of the participants were men.

The work was supported by Taiwan’s Ministry of Science and Technology. The investigators had no disclosures.

Eli Zimmerman contributed to this report.

[email protected]

SOURCE: Wang MT et al. JAMA Intern Med. 2018 Jan 2. doi: 10.1001/jamainternmed.2017.7720.

WASHINGTON, DC—Age of seizure onset is significantly associated with age of menarche, according to research presented at the 71st Annual Meeting of the American Epilepsy Society. Seizure onset, however, is also common in the years before and after menarche, suggesting an impact of increased production of neuroactive steroids.

“The levels of some hormones in the blood increase tenfold during this time of life, including neuroactive steroids that affect the brain and make a seizure more likely,” said Andrew G. Herzog, MD, Professor of Neurology at Harvard Medical School and Director of the Harvard Neuroendocrine Unit of Beth Israel Deaconess Medical Center in Boston. “Clearly more seizures develop in girls during that period of time, so we need to begin looking at risk factors as well as potential treatments.”

—Erica Tricarico

WASHINGTON, DC—Age of seizure onset is significantly associated with age of menarche, according to research presented at the 71st Annual Meeting of the American Epilepsy Society. Seizure onset, however, is also common in the years before and after menarche, suggesting an impact of increased production of neuroactive steroids.

“The levels of some hormones in the blood increase tenfold during this time of life, including neuroactive steroids that affect the brain and make a seizure more likely,” said Andrew G. Herzog, MD, Professor of Neurology at Harvard Medical School and Director of the Harvard Neuroendocrine Unit of Beth Israel Deaconess Medical Center in Boston. “Clearly more seizures develop in girls during that period of time, so we need to begin looking at risk factors as well as potential treatments.”

—Erica Tricarico

WASHINGTON, DC—Age of seizure onset is significantly associated with age of menarche, according to research presented at the 71st Annual Meeting of the American Epilepsy Society. Seizure onset, however, is also common in the years before and after menarche, suggesting an impact of increased production of neuroactive steroids.

“The levels of some hormones in the blood increase tenfold during this time of life, including neuroactive steroids that affect the brain and make a seizure more likely,” said Andrew G. Herzog, MD, Professor of Neurology at Harvard Medical School and Director of the Harvard Neuroendocrine Unit of Beth Israel Deaconess Medical Center in Boston. “Clearly more seizures develop in girls during that period of time, so we need to begin looking at risk factors as well as potential treatments.”

—Erica Tricarico

WASHINGTON, DC—Among patients with Dravet syndrome, adjunctive treatment with fenfluramine hydrochloride oral solution significantly reduces convulsive seizure frequency, compared with placebo, according to data presented at the 71st Annual Meeting of the American Epilepsy Society. The treatment is generally well tolerated at doses of 30 mg/day or less, and no clinical or echocardiographic signs of cardiac valvulopathy or pulmonary hypertension were observed in a phase III trial, investigators said.

Fenfluramine has been used at higher doses for weight loss, but the drug was withdrawn from US and European markets because it was associated with cardiac valvulopathy and pulmonary hypertension. Investigators in Belgium, however, continued exploratory studies of low-dose fenfluramine for refractory pediatric epilepsy. The studies suggested that fenfluramine reduced seizure frequency. Zogenix, based in Emeryville, California, is developing the drug, known as ZX008.

No FDA-approved treatments for seizures associated with Dravet syndrome exist, and 45% of patients with Dravet syndrome have four or more tonic-clonic seizures per month despite polytherapy with antiepileptic drugs (AEDs), said the investigators.

A Placebo-Controlled Trial

Lieven Lagae, MD, PhD, Professor at the University of Leuven in Belgium and Head of the Pediatric Neurology Department and Director of the Childhood Epilepsy Program at the University of Leuven Hospitals, and colleagues conducted a phase III, randomized, placebo-controlled, double-blind, 14-week, fixed-dose clinical trial at sites in the United States, Canada, Europe, and Australia.

The researchers included patients with Dravet syndrome ages 2 to 18 whose seizures were not completely controlled by their current AED regimen and whose medications and interventions (eg, ketogenic diet and vagal nerve stimulation) had been stable for at least four weeks before screening. The researchers excluded patients with a history of cardiovascular or cerebrovascular disease, concomitant serotonergic or cannabinoid treatment, treatment with stiripentol in the 21 days before screening, or any diagnosis that might alter the risk–benefit ratio or impede participation in the trial.

Patients underwent six weeks of baseline observation before they were randomized 1:1:1 to receive ZX008 (0.8 mg/kg/day), ZX008 (0.2 mg/kg/day), or placebo. The treatment period included a two-week titration period followed by a 12-week maintenance period. The maximum daily dose was 30 mg. The primary efficacy end point was change in mean convulsive seizure frequency from the baseline period to the 14-week treatment period between ZX008 (0.8 mg/kg/day) and placebo.

Frequency of Seizures

The study included 119 patients. Patients had a mean age of 9, and about 54% were male. Average baseline convulsive seizure frequency was about 42 seizures per 28 days.

Patients who received ZX008 (0.8 mg/kg/day) had a 63.9% reduction in mean monthly convulsive seizures, compared with placebo. The median percent reduction in monthly convulsive seizure frequency was 72.4% among patients who received ZX008 (0.8 mg/kg/day), compared with 17.4% among patients who received placebo.

Significantly more patients who received either dose of ZX008 had at least a 25%, 50%, or 75% reduction in convulsive seizures during treatment, compared with patients who received placebo. The median longest seizure-free interval was significantly longer in patients treated with ZX008 (0.8 mg/kg/day) or ZX008 (0.2 mg/kg/day), compared with patients who received placebo (20.5 days, 14 days, and nine days, respectively).

Noncardiovascular treatment-emergent adverse events included diarrhea, fatigue, lethargy, and decreased weight and appetite. “No cases of FDA-defined cardiac valvulopathy were observed during the trial,” the researchers said. “No echocardiographic findings or clinical symptoms suggesting pulmonary hypertension were noted.”

Caregivers and clinicians rated a greater proportion of patients who received ZX008 to be very much or much improved following treatment, compared with patients who received placebo. Results from another phase III trial are expected in 2018.

“Patients treated with ZX008 achieved a clinically meaningful reduction in seizure frequency,” said Dr. Lagae. “If approved, ZX008 could play an important role in changing the treatment paradigm for patients and their families whose lives have been greatly impacted by the lack of effective seizure control provided by current treatment options.”

—Jake Remaly

WASHINGTON, DC—Among patients with Dravet syndrome, adjunctive treatment with fenfluramine hydrochloride oral solution significantly reduces convulsive seizure frequency, compared with placebo, according to data presented at the 71st Annual Meeting of the American Epilepsy Society. The treatment is generally well tolerated at doses of 30 mg/day or less, and no clinical or echocardiographic signs of cardiac valvulopathy or pulmonary hypertension were observed in a phase III trial, investigators said.

Fenfluramine has been used at higher doses for weight loss, but the drug was withdrawn from US and European markets because it was associated with cardiac valvulopathy and pulmonary hypertension. Investigators in Belgium, however, continued exploratory studies of low-dose fenfluramine for refractory pediatric epilepsy. The studies suggested that fenfluramine reduced seizure frequency. Zogenix, based in Emeryville, California, is developing the drug, known as ZX008.

No FDA-approved treatments for seizures associated with Dravet syndrome exist, and 45% of patients with Dravet syndrome have four or more tonic-clonic seizures per month despite polytherapy with antiepileptic drugs (AEDs), said the investigators.

A Placebo-Controlled Trial

Lieven Lagae, MD, PhD, Professor at the University of Leuven in Belgium and Head of the Pediatric Neurology Department and Director of the Childhood Epilepsy Program at the University of Leuven Hospitals, and colleagues conducted a phase III, randomized, placebo-controlled, double-blind, 14-week, fixed-dose clinical trial at sites in the United States, Canada, Europe, and Australia.

The researchers included patients with Dravet syndrome ages 2 to 18 whose seizures were not completely controlled by their current AED regimen and whose medications and interventions (eg, ketogenic diet and vagal nerve stimulation) had been stable for at least four weeks before screening. The researchers excluded patients with a history of cardiovascular or cerebrovascular disease, concomitant serotonergic or cannabinoid treatment, treatment with stiripentol in the 21 days before screening, or any diagnosis that might alter the risk–benefit ratio or impede participation in the trial.

Patients underwent six weeks of baseline observation before they were randomized 1:1:1 to receive ZX008 (0.8 mg/kg/day), ZX008 (0.2 mg/kg/day), or placebo. The treatment period included a two-week titration period followed by a 12-week maintenance period. The maximum daily dose was 30 mg. The primary efficacy end point was change in mean convulsive seizure frequency from the baseline period to the 14-week treatment period between ZX008 (0.8 mg/kg/day) and placebo.

Frequency of Seizures

The study included 119 patients. Patients had a mean age of 9, and about 54% were male. Average baseline convulsive seizure frequency was about 42 seizures per 28 days.

Patients who received ZX008 (0.8 mg/kg/day) had a 63.9% reduction in mean monthly convulsive seizures, compared with placebo. The median percent reduction in monthly convulsive seizure frequency was 72.4% among patients who received ZX008 (0.8 mg/kg/day), compared with 17.4% among patients who received placebo.

Significantly more patients who received either dose of ZX008 had at least a 25%, 50%, or 75% reduction in convulsive seizures during treatment, compared with patients who received placebo. The median longest seizure-free interval was significantly longer in patients treated with ZX008 (0.8 mg/kg/day) or ZX008 (0.2 mg/kg/day), compared with patients who received placebo (20.5 days, 14 days, and nine days, respectively).

Noncardiovascular treatment-emergent adverse events included diarrhea, fatigue, lethargy, and decreased weight and appetite. “No cases of FDA-defined cardiac valvulopathy were observed during the trial,” the researchers said. “No echocardiographic findings or clinical symptoms suggesting pulmonary hypertension were noted.”

Caregivers and clinicians rated a greater proportion of patients who received ZX008 to be very much or much improved following treatment, compared with patients who received placebo. Results from another phase III trial are expected in 2018.

“Patients treated with ZX008 achieved a clinically meaningful reduction in seizure frequency,” said Dr. Lagae. “If approved, ZX008 could play an important role in changing the treatment paradigm for patients and their families whose lives have been greatly impacted by the lack of effective seizure control provided by current treatment options.”

—Jake Remaly

WASHINGTON, DC—Among patients with Dravet syndrome, adjunctive treatment with fenfluramine hydrochloride oral solution significantly reduces convulsive seizure frequency, compared with placebo, according to data presented at the 71st Annual Meeting of the American Epilepsy Society. The treatment is generally well tolerated at doses of 30 mg/day or less, and no clinical or echocardiographic signs of cardiac valvulopathy or pulmonary hypertension were observed in a phase III trial, investigators said.

Fenfluramine has been used at higher doses for weight loss, but the drug was withdrawn from US and European markets because it was associated with cardiac valvulopathy and pulmonary hypertension. Investigators in Belgium, however, continued exploratory studies of low-dose fenfluramine for refractory pediatric epilepsy. The studies suggested that fenfluramine reduced seizure frequency. Zogenix, based in Emeryville, California, is developing the drug, known as ZX008.

No FDA-approved treatments for seizures associated with Dravet syndrome exist, and 45% of patients with Dravet syndrome have four or more tonic-clonic seizures per month despite polytherapy with antiepileptic drugs (AEDs), said the investigators.

A Placebo-Controlled Trial

Lieven Lagae, MD, PhD, Professor at the University of Leuven in Belgium and Head of the Pediatric Neurology Department and Director of the Childhood Epilepsy Program at the University of Leuven Hospitals, and colleagues conducted a phase III, randomized, placebo-controlled, double-blind, 14-week, fixed-dose clinical trial at sites in the United States, Canada, Europe, and Australia.

The researchers included patients with Dravet syndrome ages 2 to 18 whose seizures were not completely controlled by their current AED regimen and whose medications and interventions (eg, ketogenic diet and vagal nerve stimulation) had been stable for at least four weeks before screening. The researchers excluded patients with a history of cardiovascular or cerebrovascular disease, concomitant serotonergic or cannabinoid treatment, treatment with stiripentol in the 21 days before screening, or any diagnosis that might alter the risk–benefit ratio or impede participation in the trial.

Patients underwent six weeks of baseline observation before they were randomized 1:1:1 to receive ZX008 (0.8 mg/kg/day), ZX008 (0.2 mg/kg/day), or placebo. The treatment period included a two-week titration period followed by a 12-week maintenance period. The maximum daily dose was 30 mg. The primary efficacy end point was change in mean convulsive seizure frequency from the baseline period to the 14-week treatment period between ZX008 (0.8 mg/kg/day) and placebo.

Frequency of Seizures

The study included 119 patients. Patients had a mean age of 9, and about 54% were male. Average baseline convulsive seizure frequency was about 42 seizures per 28 days.

Patients who received ZX008 (0.8 mg/kg/day) had a 63.9% reduction in mean monthly convulsive seizures, compared with placebo. The median percent reduction in monthly convulsive seizure frequency was 72.4% among patients who received ZX008 (0.8 mg/kg/day), compared with 17.4% among patients who received placebo.

Significantly more patients who received either dose of ZX008 had at least a 25%, 50%, or 75% reduction in convulsive seizures during treatment, compared with patients who received placebo. The median longest seizure-free interval was significantly longer in patients treated with ZX008 (0.8 mg/kg/day) or ZX008 (0.2 mg/kg/day), compared with patients who received placebo (20.5 days, 14 days, and nine days, respectively).

Noncardiovascular treatment-emergent adverse events included diarrhea, fatigue, lethargy, and decreased weight and appetite. “No cases of FDA-defined cardiac valvulopathy were observed during the trial,” the researchers said. “No echocardiographic findings or clinical symptoms suggesting pulmonary hypertension were noted.”

Caregivers and clinicians rated a greater proportion of patients who received ZX008 to be very much or much improved following treatment, compared with patients who received placebo. Results from another phase III trial are expected in 2018.

“Patients treated with ZX008 achieved a clinically meaningful reduction in seizure frequency,” said Dr. Lagae. “If approved, ZX008 could play an important role in changing the treatment paradigm for patients and their families whose lives have been greatly impacted by the lack of effective seizure control provided by current treatment options.”

—Jake Remaly

PARIS—Ibudilast decreases the rate of brain atrophy, compared with placebo, in patients with progressive multiple sclerosis (MS), according to top-line results presented at the Seventh Joint ECTRIMS–ACTRIMS Meeting. The drug appears to be safe and tolerable.

Ibudilast is an orally bioavailable small-molecule drug that is available in Japan for treating asthma and post stroke dizziness. In a phase II trial that included patients with relapsing-remitting MS, ibudilast slowed brain atrophy progression in a dose-dependent manner. In addition, animal models suggest that the drug may promote neuroprotection.

Examining Ibudilast in a Phase II Trial

Robert Fox, MD, a neurologist at the Cleveland Clinic, and colleagues conducted a phase II clinical trial at 28 sites to analyze ibudilast’s effects in patients with primary or secondary progressive MS. Eligible patients were between ages 18 and 65, had a maximum Expanded Disability Status Scale (EDSS) score of 6.5, had disability progression in the previous two years, and were allowed to receive concurrent treatment with interferon beta or glatiramer acetate.

Patients were randomized in equal groups to placebo or ibudilast. The intervention group received 60 mg/day, 80 mg/day, or 100 mg/day of ibudilast as tolerated. Randomization was stratified by primary or secondary progressive MS and by whether the subjects received injectable disease-modifying therapies. For the first three months of treatment, patients presented for monthly safety evaluations. From the third month onward, patients returned quarterly for safety assessments and every six months for efficacy assessments, which included clinical disability and 3-T MRI measures. The treatment period was two years.

The trial’s primary end points were brain atrophy, as measured by brain parenchymal fraction; safety; and tolerability. Secondary outcomes included magnetization transfer ratio (MTR), diffusion tensor imaging (DTI), optical coherence tomography of the retinal nerve fiber layer, and cortical atrophy.

Researchers Observed Gastrointestinal Side Effects

The investigators enrolled 255 patients into the study. The population’s mean age was approximately 56, and mean EDSS was about 5. The study sample had approximately equal numbers of patients with primary progressive MS and secondary progressive MS. Eleven participants withdrew from the study before the first efficacy assessment, and another 24 participants discontinued the trial before week 96. The trial’s retention rate was 86%.

In the primary analysis, ibudilast was associated with a 48% reduction in the progression of brain atrophy over two years, compared with placebo. A per-protocol sensitivity analysis confirmed that ibudilast reduced the progression of brain atrophy by half, compared with placebo.

Treatment-related adverse events included gastrointestinal side effects such as nausea, vomiting, diarrhea, and abdominal pain. Patients treated with ibudilast also had higher rates of rash, depression, and fatigue than did controls. The rate of serious adverse events was similar in both groups. There were no related and unanticipated serious adverse events.

There was no significant difference in the rates of treatment discontinuation, early study termination, and early drug withdrawal between the two study arms. Approximately 25% of controls discontinued treatment during the study, compared with 30% of the ibudilast group.

Compared with placebo, ibudilast was associated with a significant slowing of the progression of MTR in normal-appearing brain tissue and normal-appearing gray matter. The researchers did not find a significant difference between treatment groups on DTI. Additional analyses of the secondary and tertiary outcomes are forthcoming, said Dr. Fox.

—Erik Greb

Suggested Reading

Barkhof F, Hulst HE, Drulovic J, et al. Ibudilast in relapsing-remitting multiple sclerosis: a neuroprotectant? Neurology. 2010;74(13):1033-1040.

Fox RJ, Coffey CS, Cudkowicz ME, et al. Design, rationale, and baseline characteristics of the randomized double-blind phase II clinical trial of ibudilast in progressive multiple sclerosis. Contemp Clin Trials. 2016;50:166-177.

PARIS—Ibudilast decreases the rate of brain atrophy, compared with placebo, in patients with progressive multiple sclerosis (MS), according to top-line results presented at the Seventh Joint ECTRIMS–ACTRIMS Meeting. The drug appears to be safe and tolerable.

Ibudilast is an orally bioavailable small-molecule drug that is available in Japan for treating asthma and post stroke dizziness. In a phase II trial that included patients with relapsing-remitting MS, ibudilast slowed brain atrophy progression in a dose-dependent manner. In addition, animal models suggest that the drug may promote neuroprotection.

Examining Ibudilast in a Phase II Trial

Robert Fox, MD, a neurologist at the Cleveland Clinic, and colleagues conducted a phase II clinical trial at 28 sites to analyze ibudilast’s effects in patients with primary or secondary progressive MS. Eligible patients were between ages 18 and 65, had a maximum Expanded Disability Status Scale (EDSS) score of 6.5, had disability progression in the previous two years, and were allowed to receive concurrent treatment with interferon beta or glatiramer acetate.

Patients were randomized in equal groups to placebo or ibudilast. The intervention group received 60 mg/day, 80 mg/day, or 100 mg/day of ibudilast as tolerated. Randomization was stratified by primary or secondary progressive MS and by whether the subjects received injectable disease-modifying therapies. For the first three months of treatment, patients presented for monthly safety evaluations. From the third month onward, patients returned quarterly for safety assessments and every six months for efficacy assessments, which included clinical disability and 3-T MRI measures. The treatment period was two years.

The trial’s primary end points were brain atrophy, as measured by brain parenchymal fraction; safety; and tolerability. Secondary outcomes included magnetization transfer ratio (MTR), diffusion tensor imaging (DTI), optical coherence tomography of the retinal nerve fiber layer, and cortical atrophy.

Researchers Observed Gastrointestinal Side Effects

The investigators enrolled 255 patients into the study. The population’s mean age was approximately 56, and mean EDSS was about 5. The study sample had approximately equal numbers of patients with primary progressive MS and secondary progressive MS. Eleven participants withdrew from the study before the first efficacy assessment, and another 24 participants discontinued the trial before week 96. The trial’s retention rate was 86%.

In the primary analysis, ibudilast was associated with a 48% reduction in the progression of brain atrophy over two years, compared with placebo. A per-protocol sensitivity analysis confirmed that ibudilast reduced the progression of brain atrophy by half, compared with placebo.

Treatment-related adverse events included gastrointestinal side effects such as nausea, vomiting, diarrhea, and abdominal pain. Patients treated with ibudilast also had higher rates of rash, depression, and fatigue than did controls. The rate of serious adverse events was similar in both groups. There were no related and unanticipated serious adverse events.

There was no significant difference in the rates of treatment discontinuation, early study termination, and early drug withdrawal between the two study arms. Approximately 25% of controls discontinued treatment during the study, compared with 30% of the ibudilast group.

Compared with placebo, ibudilast was associated with a significant slowing of the progression of MTR in normal-appearing brain tissue and normal-appearing gray matter. The researchers did not find a significant difference between treatment groups on DTI. Additional analyses of the secondary and tertiary outcomes are forthcoming, said Dr. Fox.

—Erik Greb

Suggested Reading

Barkhof F, Hulst HE, Drulovic J, et al. Ibudilast in relapsing-remitting multiple sclerosis: a neuroprotectant? Neurology. 2010;74(13):1033-1040.

Fox RJ, Coffey CS, Cudkowicz ME, et al. Design, rationale, and baseline characteristics of the randomized double-blind phase II clinical trial of ibudilast in progressive multiple sclerosis. Contemp Clin Trials. 2016;50:166-177.

PARIS—Ibudilast decreases the rate of brain atrophy, compared with placebo, in patients with progressive multiple sclerosis (MS), according to top-line results presented at the Seventh Joint ECTRIMS–ACTRIMS Meeting. The drug appears to be safe and tolerable.

Ibudilast is an orally bioavailable small-molecule drug that is available in Japan for treating asthma and post stroke dizziness. In a phase II trial that included patients with relapsing-remitting MS, ibudilast slowed brain atrophy progression in a dose-dependent manner. In addition, animal models suggest that the drug may promote neuroprotection.

Examining Ibudilast in a Phase II Trial

Robert Fox, MD, a neurologist at the Cleveland Clinic, and colleagues conducted a phase II clinical trial at 28 sites to analyze ibudilast’s effects in patients with primary or secondary progressive MS. Eligible patients were between ages 18 and 65, had a maximum Expanded Disability Status Scale (EDSS) score of 6.5, had disability progression in the previous two years, and were allowed to receive concurrent treatment with interferon beta or glatiramer acetate.

Patients were randomized in equal groups to placebo or ibudilast. The intervention group received 60 mg/day, 80 mg/day, or 100 mg/day of ibudilast as tolerated. Randomization was stratified by primary or secondary progressive MS and by whether the subjects received injectable disease-modifying therapies. For the first three months of treatment, patients presented for monthly safety evaluations. From the third month onward, patients returned quarterly for safety assessments and every six months for efficacy assessments, which included clinical disability and 3-T MRI measures. The treatment period was two years.

The trial’s primary end points were brain atrophy, as measured by brain parenchymal fraction; safety; and tolerability. Secondary outcomes included magnetization transfer ratio (MTR), diffusion tensor imaging (DTI), optical coherence tomography of the retinal nerve fiber layer, and cortical atrophy.

Researchers Observed Gastrointestinal Side Effects

The investigators enrolled 255 patients into the study. The population’s mean age was approximately 56, and mean EDSS was about 5. The study sample had approximately equal numbers of patients with primary progressive MS and secondary progressive MS. Eleven participants withdrew from the study before the first efficacy assessment, and another 24 participants discontinued the trial before week 96. The trial’s retention rate was 86%.

In the primary analysis, ibudilast was associated with a 48% reduction in the progression of brain atrophy over two years, compared with placebo. A per-protocol sensitivity analysis confirmed that ibudilast reduced the progression of brain atrophy by half, compared with placebo.

Treatment-related adverse events included gastrointestinal side effects such as nausea, vomiting, diarrhea, and abdominal pain. Patients treated with ibudilast also had higher rates of rash, depression, and fatigue than did controls. The rate of serious adverse events was similar in both groups. There were no related and unanticipated serious adverse events.

There was no significant difference in the rates of treatment discontinuation, early study termination, and early drug withdrawal between the two study arms. Approximately 25% of controls discontinued treatment during the study, compared with 30% of the ibudilast group.

Compared with placebo, ibudilast was associated with a significant slowing of the progression of MTR in normal-appearing brain tissue and normal-appearing gray matter. The researchers did not find a significant difference between treatment groups on DTI. Additional analyses of the secondary and tertiary outcomes are forthcoming, said Dr. Fox.

—Erik Greb

Suggested Reading

Barkhof F, Hulst HE, Drulovic J, et al. Ibudilast in relapsing-remitting multiple sclerosis: a neuroprotectant? Neurology. 2010;74(13):1033-1040.

Fox RJ, Coffey CS, Cudkowicz ME, et al. Design, rationale, and baseline characteristics of the randomized double-blind phase II clinical trial of ibudilast in progressive multiple sclerosis. Contemp Clin Trials. 2016;50:166-177.