BERLIN—Spinal cord volume deficits in patients with multiple sclerosis (MS) may explain clinical disability that appears out of proportion to lesion load on brain imaging, according to research presented at ECTRIMS 2018.

In a pool of 362 patients with mild to moderate MS-related disability and identical white matter lesion load identified by MRI, those with higher disability had significantly lower spinal cord volumes, compared with those with mild disability.

An Analysis of Patient Records

Some patients with MS have a relatively high level of disability, but a low burden of white matter intracerebral lesions on MRI. Little is known about spinal cord volume in patients with MS and a pronounced dissociation between intracerebral lesion load and disability, said Michaela Andelova, MD, of Charles University in Prague.

Dr. Andelova and her colleagues hypothesized that spinal cord volume would differ between patients with varying levels of disability despite identical white matter lesion load. To test this hypothesis, they looked at records for 1,245 patients with relapsing-remitting MS. They divided them into three groups by severity of clinical disability and extent of cerebral T2 hyperintense lesion load. The investigators identified 53 patients whose total volume of T2-weighted hyperintense lesions was less than 3 mL, but whose Expanded Disability Status Scale (EDSS) scores were at least 3.5. They called them the low lesion load–high disability (LLHD) group.

The researchers then identified another 71 patients with a volume of T2-weighted hyperintensities greater than 9 mL, but whose EDSS score was less than 1.5. They called them the high lesion load–low disability (HLLD) group.

The remaining 1,121 patients, who did not have these paradoxical associations, were analyzed separately.The investigators measured mean upper cervical cord area (MUCCA) for all patients. On the basis of images acquired by a 3-T MRI scanner, they used an in-house, semiautomated method to calculate MUCCA as the mean sum of spinal cord area in 21 slices centered at the C3–C4 intervertebral disk.

Mean Upper Cervical Cord Area Correlated With Disability

“Despite higher disability, LLHD patients demonstrated significantly higher normalized total brain volume, higher normalized volumes of the thalamus and callosum, and smaller lateral ventricles than the HLLD group,” said Dr. Andelova and her collaborators.

However, the LLHD patients had MUCCA values that were significantly lower than those of the other groups. The nonparadoxical group’s mean MUCCA was 84.02 mm2, while the HLLD group had a mean MUCCA of 85.75 mm2. The difference between these groups was not statistically significant. By contrast, the LLHD group’s mean MUCCA was significantly smaller than that of the other groups, at 80.40 mm2.

Next, Dr. Andelova and her colleagues compared 362 patients with moderate disability (ie, EDSS scores between 3.5 and 6.5) with matched patients who had mild MS-related disability (ie, EDSS score less than 3) and identical cerebral lesion loads. They found that MUCCA was significantly smaller in the group with moderate disability (78.86 mm2 vs 84.44 mm2).

In addition to having identical lesion loads, the mild and moderate disability groups had similar normalized total brain volume and regional brain volumes. The group with moderate disability had slightly less white matter volume, said Dr. Andelova. All differences between groups retained statistical significance after adjustment for potential confounders such as age, sex, and duration of disease.

“Reduced spinal cord volume may explain part of the clinical–radiologic paradox in patients who have high disability despite low intracranial lesion load,” said the researchers. “In line with this finding, relatively preserved spinal cord volume may be associated with functional reserve and less physical disability in patients with low disability despite high cerebral lesion load.”

Dr. Andelova and her collaborators plan to examine cerebral lesion distribution and perform quantitative MRI investigations of lesion distribution. They intend to seek potential associations between various distribution patterns and accelerated spinal atrophy.

—Kari Oakes 

BERLIN—Spinal cord volume deficits in patients with multiple sclerosis (MS) may explain clinical disability that appears out of proportion to lesion load on brain imaging, according to research presented at ECTRIMS 2018.

In a pool of 362 patients with mild to moderate MS-related disability and identical white matter lesion load identified by MRI, those with higher disability had significantly lower spinal cord volumes, compared with those with mild disability.

An Analysis of Patient Records

Some patients with MS have a relatively high level of disability, but a low burden of white matter intracerebral lesions on MRI. Little is known about spinal cord volume in patients with MS and a pronounced dissociation between intracerebral lesion load and disability, said Michaela Andelova, MD, of Charles University in Prague.

Dr. Andelova and her colleagues hypothesized that spinal cord volume would differ between patients with varying levels of disability despite identical white matter lesion load. To test this hypothesis, they looked at records for 1,245 patients with relapsing-remitting MS. They divided them into three groups by severity of clinical disability and extent of cerebral T2 hyperintense lesion load. The investigators identified 53 patients whose total volume of T2-weighted hyperintense lesions was less than 3 mL, but whose Expanded Disability Status Scale (EDSS) scores were at least 3.5. They called them the low lesion load–high disability (LLHD) group.

The researchers then identified another 71 patients with a volume of T2-weighted hyperintensities greater than 9 mL, but whose EDSS score was less than 1.5. They called them the high lesion load–low disability (HLLD) group.

The remaining 1,121 patients, who did not have these paradoxical associations, were analyzed separately.The investigators measured mean upper cervical cord area (MUCCA) for all patients. On the basis of images acquired by a 3-T MRI scanner, they used an in-house, semiautomated method to calculate MUCCA as the mean sum of spinal cord area in 21 slices centered at the C3–C4 intervertebral disk.

Mean Upper Cervical Cord Area Correlated With Disability

“Despite higher disability, LLHD patients demonstrated significantly higher normalized total brain volume, higher normalized volumes of the thalamus and callosum, and smaller lateral ventricles than the HLLD group,” said Dr. Andelova and her collaborators.

However, the LLHD patients had MUCCA values that were significantly lower than those of the other groups. The nonparadoxical group’s mean MUCCA was 84.02 mm2, while the HLLD group had a mean MUCCA of 85.75 mm2. The difference between these groups was not statistically significant. By contrast, the LLHD group’s mean MUCCA was significantly smaller than that of the other groups, at 80.40 mm2.

Next, Dr. Andelova and her colleagues compared 362 patients with moderate disability (ie, EDSS scores between 3.5 and 6.5) with matched patients who had mild MS-related disability (ie, EDSS score less than 3) and identical cerebral lesion loads. They found that MUCCA was significantly smaller in the group with moderate disability (78.86 mm2 vs 84.44 mm2).

In addition to having identical lesion loads, the mild and moderate disability groups had similar normalized total brain volume and regional brain volumes. The group with moderate disability had slightly less white matter volume, said Dr. Andelova. All differences between groups retained statistical significance after adjustment for potential confounders such as age, sex, and duration of disease.

“Reduced spinal cord volume may explain part of the clinical–radiologic paradox in patients who have high disability despite low intracranial lesion load,” said the researchers. “In line with this finding, relatively preserved spinal cord volume may be associated with functional reserve and less physical disability in patients with low disability despite high cerebral lesion load.”

Dr. Andelova and her collaborators plan to examine cerebral lesion distribution and perform quantitative MRI investigations of lesion distribution. They intend to seek potential associations between various distribution patterns and accelerated spinal atrophy.

—Kari Oakes 

BERLIN—Spinal cord volume deficits in patients with multiple sclerosis (MS) may explain clinical disability that appears out of proportion to lesion load on brain imaging, according to research presented at ECTRIMS 2018.

In a pool of 362 patients with mild to moderate MS-related disability and identical white matter lesion load identified by MRI, those with higher disability had significantly lower spinal cord volumes, compared with those with mild disability.

An Analysis of Patient Records

Some patients with MS have a relatively high level of disability, but a low burden of white matter intracerebral lesions on MRI. Little is known about spinal cord volume in patients with MS and a pronounced dissociation between intracerebral lesion load and disability, said Michaela Andelova, MD, of Charles University in Prague.

Dr. Andelova and her colleagues hypothesized that spinal cord volume would differ between patients with varying levels of disability despite identical white matter lesion load. To test this hypothesis, they looked at records for 1,245 patients with relapsing-remitting MS. They divided them into three groups by severity of clinical disability and extent of cerebral T2 hyperintense lesion load. The investigators identified 53 patients whose total volume of T2-weighted hyperintense lesions was less than 3 mL, but whose Expanded Disability Status Scale (EDSS) scores were at least 3.5. They called them the low lesion load–high disability (LLHD) group.

The researchers then identified another 71 patients with a volume of T2-weighted hyperintensities greater than 9 mL, but whose EDSS score was less than 1.5. They called them the high lesion load–low disability (HLLD) group.

The remaining 1,121 patients, who did not have these paradoxical associations, were analyzed separately.The investigators measured mean upper cervical cord area (MUCCA) for all patients. On the basis of images acquired by a 3-T MRI scanner, they used an in-house, semiautomated method to calculate MUCCA as the mean sum of spinal cord area in 21 slices centered at the C3–C4 intervertebral disk.

Mean Upper Cervical Cord Area Correlated With Disability

“Despite higher disability, LLHD patients demonstrated significantly higher normalized total brain volume, higher normalized volumes of the thalamus and callosum, and smaller lateral ventricles than the HLLD group,” said Dr. Andelova and her collaborators.

However, the LLHD patients had MUCCA values that were significantly lower than those of the other groups. The nonparadoxical group’s mean MUCCA was 84.02 mm2, while the HLLD group had a mean MUCCA of 85.75 mm2. The difference between these groups was not statistically significant. By contrast, the LLHD group’s mean MUCCA was significantly smaller than that of the other groups, at 80.40 mm2.

Next, Dr. Andelova and her colleagues compared 362 patients with moderate disability (ie, EDSS scores between 3.5 and 6.5) with matched patients who had mild MS-related disability (ie, EDSS score less than 3) and identical cerebral lesion loads. They found that MUCCA was significantly smaller in the group with moderate disability (78.86 mm2 vs 84.44 mm2).

In addition to having identical lesion loads, the mild and moderate disability groups had similar normalized total brain volume and regional brain volumes. The group with moderate disability had slightly less white matter volume, said Dr. Andelova. All differences between groups retained statistical significance after adjustment for potential confounders such as age, sex, and duration of disease.

“Reduced spinal cord volume may explain part of the clinical–radiologic paradox in patients who have high disability despite low intracranial lesion load,” said the researchers. “In line with this finding, relatively preserved spinal cord volume may be associated with functional reserve and less physical disability in patients with low disability despite high cerebral lesion load.”

Dr. Andelova and her collaborators plan to examine cerebral lesion distribution and perform quantitative MRI investigations of lesion distribution. They intend to seek potential associations between various distribution patterns and accelerated spinal atrophy.

—Kari Oakes 

Symptoms alone are not typically sufficient for patients or for staff to determine if an ED visit is warranted. Also today, opioids have a negative effect on breathing during sleep, the American Academy of Pediatrics renews its public health approach regarding gun injury prevention, and fever and intestinal symptoms can delay diagnosis of Kawasaki disease in children.

Amazon Alexa

Apple Podcasts

Spotify

Symptoms alone are not typically sufficient for patients or for staff to determine if an ED visit is warranted. Also today, opioids have a negative effect on breathing during sleep, the American Academy of Pediatrics renews its public health approach regarding gun injury prevention, and fever and intestinal symptoms can delay diagnosis of Kawasaki disease in children.

Amazon Alexa

Apple Podcasts

Spotify

Symptoms alone are not typically sufficient for patients or for staff to determine if an ED visit is warranted. Also today, opioids have a negative effect on breathing during sleep, the American Academy of Pediatrics renews its public health approach regarding gun injury prevention, and fever and intestinal symptoms can delay diagnosis of Kawasaki disease in children.

Amazon Alexa

Apple Podcasts

Spotify

Bristol-Myers Squibb

The U.S. Food and Drug Administration (FDA) has approved elotuzumab (Empliciti®) in combination with pomalidomide and dexamethasone.

The combination is now approved for use in adults with multiple myeloma (MM) who have received at least two prior therapies, including lenalidomide and a proteasome inhibitor.

Elotuzumab is also FDA-approved in combination with lenalidomide and dexamethasone to treat adult MM patients who have received one to three prior therapies.

The FDA’s latest approval of elotuzumab is based on results from the phase 2 ELOQUENT-3 trial, which were presented at the 23rd Congress of the European Hematology Association in June.

ELOQUENT-3 enrolled MM patients who had refractory or relapsed and refractory MM and had received both lenalidomide and a proteasome inhibitor.

The patients were randomized to receive elotuzumab plus pomalidomide and dexamethasone (EPd, n=60) or pomalidomide and dexamethasone (Pd, n=57) in 28-day cycles until disease progression or unacceptable toxicity.

The overall response rate was 53.3% in the EPd arm and 26.3% in the Pd arm (P=0.0029). The rate of complete response or stringent complete response was 8.3% in the EPd arm and 1.8% in the Pd arm.

The median progression-free survival was 10.25 months with EPd and 4.67 months with Pd (hazard ratio=0.54, P=0.0078).

Serious adverse events (AEs) occurred in 22% of patients in the EPd arm and 15% in the Pd arm. The most frequent serious AEs (in the EPd and Pd arms, respectively) were pneumonia (13% and 11%) and respiratory tract infection (7% and 3.6%).

AEs occurring in at least 10% of patients in the EPd arm and at least 5% of those in the Pd arm (respectively) included:

• Constipation (22% and 11%)
• Hyperglycemia (20% and 15%)
• Pneumonia (18% and 13%)
• Diarrhea (18% and 9%)
• Respiratory tract infection (17% and 9%)
• Bone pain (15% and 9%)
• Dyspnea (15% and 7%)
• Muscle spasms (13% and 5%)
• Peripheral edema (13% and 7%)
• Lymphopenia (10% and 1.8%).

Additional results from ELOQUENT-3 can be found in the full prescribing information for elotuzumab, which is available at www.empliciti.com.

Bristol-Myers Squibb and AbbVie are co-developing elotuzumab, with Bristol-Myers Squibb solely responsible for commercial activities.

Bristol-Myers Squibb

The U.S. Food and Drug Administration (FDA) has approved elotuzumab (Empliciti®) in combination with pomalidomide and dexamethasone.

The combination is now approved for use in adults with multiple myeloma (MM) who have received at least two prior therapies, including lenalidomide and a proteasome inhibitor.

Elotuzumab is also FDA-approved in combination with lenalidomide and dexamethasone to treat adult MM patients who have received one to three prior therapies.

The FDA’s latest approval of elotuzumab is based on results from the phase 2 ELOQUENT-3 trial, which were presented at the 23rd Congress of the European Hematology Association in June.

ELOQUENT-3 enrolled MM patients who had refractory or relapsed and refractory MM and had received both lenalidomide and a proteasome inhibitor.

The patients were randomized to receive elotuzumab plus pomalidomide and dexamethasone (EPd, n=60) or pomalidomide and dexamethasone (Pd, n=57) in 28-day cycles until disease progression or unacceptable toxicity.

The overall response rate was 53.3% in the EPd arm and 26.3% in the Pd arm (P=0.0029). The rate of complete response or stringent complete response was 8.3% in the EPd arm and 1.8% in the Pd arm.

The median progression-free survival was 10.25 months with EPd and 4.67 months with Pd (hazard ratio=0.54, P=0.0078).

Serious adverse events (AEs) occurred in 22% of patients in the EPd arm and 15% in the Pd arm. The most frequent serious AEs (in the EPd and Pd arms, respectively) were pneumonia (13% and 11%) and respiratory tract infection (7% and 3.6%).

AEs occurring in at least 10% of patients in the EPd arm and at least 5% of those in the Pd arm (respectively) included:

• Constipation (22% and 11%)
• Hyperglycemia (20% and 15%)
• Pneumonia (18% and 13%)
• Diarrhea (18% and 9%)
• Respiratory tract infection (17% and 9%)
• Bone pain (15% and 9%)
• Dyspnea (15% and 7%)
• Muscle spasms (13% and 5%)
• Peripheral edema (13% and 7%)
• Lymphopenia (10% and 1.8%).

Additional results from ELOQUENT-3 can be found in the full prescribing information for elotuzumab, which is available at www.empliciti.com.

Bristol-Myers Squibb and AbbVie are co-developing elotuzumab, with Bristol-Myers Squibb solely responsible for commercial activities.

Bristol-Myers Squibb

The U.S. Food and Drug Administration (FDA) has approved elotuzumab (Empliciti®) in combination with pomalidomide and dexamethasone.

The combination is now approved for use in adults with multiple myeloma (MM) who have received at least two prior therapies, including lenalidomide and a proteasome inhibitor.

Elotuzumab is also FDA-approved in combination with lenalidomide and dexamethasone to treat adult MM patients who have received one to three prior therapies.

The FDA’s latest approval of elotuzumab is based on results from the phase 2 ELOQUENT-3 trial, which were presented at the 23rd Congress of the European Hematology Association in June.

ELOQUENT-3 enrolled MM patients who had refractory or relapsed and refractory MM and had received both lenalidomide and a proteasome inhibitor.

The patients were randomized to receive elotuzumab plus pomalidomide and dexamethasone (EPd, n=60) or pomalidomide and dexamethasone (Pd, n=57) in 28-day cycles until disease progression or unacceptable toxicity.

The overall response rate was 53.3% in the EPd arm and 26.3% in the Pd arm (P=0.0029). The rate of complete response or stringent complete response was 8.3% in the EPd arm and 1.8% in the Pd arm.

The median progression-free survival was 10.25 months with EPd and 4.67 months with Pd (hazard ratio=0.54, P=0.0078).

Serious adverse events (AEs) occurred in 22% of patients in the EPd arm and 15% in the Pd arm. The most frequent serious AEs (in the EPd and Pd arms, respectively) were pneumonia (13% and 11%) and respiratory tract infection (7% and 3.6%).

AEs occurring in at least 10% of patients in the EPd arm and at least 5% of those in the Pd arm (respectively) included:

• Constipation (22% and 11%)
• Hyperglycemia (20% and 15%)
• Pneumonia (18% and 13%)
• Diarrhea (18% and 9%)
• Respiratory tract infection (17% and 9%)
• Bone pain (15% and 9%)
• Dyspnea (15% and 7%)
• Muscle spasms (13% and 5%)
• Peripheral edema (13% and 7%)
• Lymphopenia (10% and 1.8%).

Additional results from ELOQUENT-3 can be found in the full prescribing information for elotuzumab, which is available at www.empliciti.com.

Bristol-Myers Squibb and AbbVie are co-developing elotuzumab, with Bristol-Myers Squibb solely responsible for commercial activities.

Photo from Yale Cancer Center

Researchers have found evidence to suggest that phlebotomy and hydroxyurea (HU) provide real-world benefits for older patients with polycythemia vera (PV), but both treatments are underused.

In a study of more than 800 PV patients, phlebotomy and HU treatment were both associated with lower risks of death and thrombosis.

However, 39% of patients didn’t receive HU, and 36% didn’t undergo phlebotomy.

“Our study highlights the value of adhering to PV treatment guidelines,” said study author Nikolai A. Podoltsev, MD, PhD, of Yale Cancer Center in New Haven, Connecticut.

“Use of the two recommended treatments saves lives.”

Dr. Podoltsev and his colleagues described this survival benefit in Blood Advances.

The researchers studied data from the linked Surveillance, Epidemiology, and End Results–Medicare database. They collected information on 820 older adults diagnosed with PV from 2007 to 2013.

The patients’ median age was 77 (range, 71-83), 57% were female, 91.2% were white, 12.7% had a disability, and 13.2% had a prior thrombotic event.

Patients received the following PV treatments:

• Both phlebotomy and HU concurrently or sequentially (41.1%)
• Phlebotomy only (23.0%)
• HU only (19.6%)
• Neither phlebotomy nor HU (16.3%).

Survival

The median follow-up was 2.83 years. During that time, 37.2% of patients (n=305) died.

The median survival was 6.29 years for phlebotomy recipients and 4.50 years for non-recipients (P<0.01). The median survival was 6.02 years for HU recipients and 5.25 years for non-recipients (P<0.01).

In a multivariable analysis, receipt of phlebotomy was associated with decreased mortality. The hazard ratio (HR) for death was 0.65 (P<0.01) for phlebotomy recipients.

Increasing phlebotomy intensity (the number of phlebotomies per year) was also associated with decreased mortality, with an HR of 0.71 (P<0.01).

A higher proportion of days covered (PDC) by HU treatment was associated with decreased mortality as well.

The researchers said every 10% increase of HU PDC was associated with an 8% to 9% lower risk of death. The HR was 0.92 in a model where phlebotomy was a binary variable and 0.91 in a model that included the frequency of phlebotomy (P<0.01 for both).

Thrombosis

In all, 36.1% of patients (n=296) had a thrombotic event, which includes venous and arterial thrombosis.

The incidence of thrombosis was 29.3% (n=142) in phlebotomy recipients and 46.0% (n=154) in non-recipients (P<0.01). The incidence was 27.6% (n=118) in HU recipients and 45.4% (n=178) in non-recipients (P<0.01).

In a multivariable analysis, receipt of phlebotomy was associated with a decreased risk of thrombosis, with an HR of 0.52 (P<0.01).

Increasing phlebotomy intensity was associated with a decreased risk of thrombosis as well, with an HR of 0.46 (P<0.01).

And every 10% increase of HU PDC was associated with an 8% lower risk of thrombosis. The HR was 0.92 in both models (P<0.01 for both).

“All of the patients we studied were high-risk for clot development, and we now know from our findings that guideline-recommended treatments reduce the risk of both thrombosis and death,” Dr. Podoltsev said.

“We hope that our research will raise clinicians’ awareness of and adherence to the guidelines and improve the outcomes of PV patients in the future.”

This research was supported by the Frederick A. DeLuca Foundation. Study authors reported relationships with 24 pharmaceutical companies.

Photo from Yale Cancer Center

Researchers have found evidence to suggest that phlebotomy and hydroxyurea (HU) provide real-world benefits for older patients with polycythemia vera (PV), but both treatments are underused.

In a study of more than 800 PV patients, phlebotomy and HU treatment were both associated with lower risks of death and thrombosis.

However, 39% of patients didn’t receive HU, and 36% didn’t undergo phlebotomy.

“Our study highlights the value of adhering to PV treatment guidelines,” said study author Nikolai A. Podoltsev, MD, PhD, of Yale Cancer Center in New Haven, Connecticut.

“Use of the two recommended treatments saves lives.”

Dr. Podoltsev and his colleagues described this survival benefit in Blood Advances.

The researchers studied data from the linked Surveillance, Epidemiology, and End Results–Medicare database. They collected information on 820 older adults diagnosed with PV from 2007 to 2013.

The patients’ median age was 77 (range, 71-83), 57% were female, 91.2% were white, 12.7% had a disability, and 13.2% had a prior thrombotic event.

Patients received the following PV treatments:

• Both phlebotomy and HU concurrently or sequentially (41.1%)
• Phlebotomy only (23.0%)
• HU only (19.6%)
• Neither phlebotomy nor HU (16.3%).

Survival

The median follow-up was 2.83 years. During that time, 37.2% of patients (n=305) died.

The median survival was 6.29 years for phlebotomy recipients and 4.50 years for non-recipients (P<0.01). The median survival was 6.02 years for HU recipients and 5.25 years for non-recipients (P<0.01).

In a multivariable analysis, receipt of phlebotomy was associated with decreased mortality. The hazard ratio (HR) for death was 0.65 (P<0.01) for phlebotomy recipients.

Increasing phlebotomy intensity (the number of phlebotomies per year) was also associated with decreased mortality, with an HR of 0.71 (P<0.01).

A higher proportion of days covered (PDC) by HU treatment was associated with decreased mortality as well.

The researchers said every 10% increase of HU PDC was associated with an 8% to 9% lower risk of death. The HR was 0.92 in a model where phlebotomy was a binary variable and 0.91 in a model that included the frequency of phlebotomy (P<0.01 for both).

Thrombosis

In all, 36.1% of patients (n=296) had a thrombotic event, which includes venous and arterial thrombosis.

The incidence of thrombosis was 29.3% (n=142) in phlebotomy recipients and 46.0% (n=154) in non-recipients (P<0.01). The incidence was 27.6% (n=118) in HU recipients and 45.4% (n=178) in non-recipients (P<0.01).

In a multivariable analysis, receipt of phlebotomy was associated with a decreased risk of thrombosis, with an HR of 0.52 (P<0.01).

Increasing phlebotomy intensity was associated with a decreased risk of thrombosis as well, with an HR of 0.46 (P<0.01).

And every 10% increase of HU PDC was associated with an 8% lower risk of thrombosis. The HR was 0.92 in both models (P<0.01 for both).

“All of the patients we studied were high-risk for clot development, and we now know from our findings that guideline-recommended treatments reduce the risk of both thrombosis and death,” Dr. Podoltsev said.

“We hope that our research will raise clinicians’ awareness of and adherence to the guidelines and improve the outcomes of PV patients in the future.”

This research was supported by the Frederick A. DeLuca Foundation. Study authors reported relationships with 24 pharmaceutical companies.

Photo from Yale Cancer Center

Researchers have found evidence to suggest that phlebotomy and hydroxyurea (HU) provide real-world benefits for older patients with polycythemia vera (PV), but both treatments are underused.

In a study of more than 800 PV patients, phlebotomy and HU treatment were both associated with lower risks of death and thrombosis.

However, 39% of patients didn’t receive HU, and 36% didn’t undergo phlebotomy.

“Our study highlights the value of adhering to PV treatment guidelines,” said study author Nikolai A. Podoltsev, MD, PhD, of Yale Cancer Center in New Haven, Connecticut.

“Use of the two recommended treatments saves lives.”

Dr. Podoltsev and his colleagues described this survival benefit in Blood Advances.

The researchers studied data from the linked Surveillance, Epidemiology, and End Results–Medicare database. They collected information on 820 older adults diagnosed with PV from 2007 to 2013.

The patients’ median age was 77 (range, 71-83), 57% were female, 91.2% were white, 12.7% had a disability, and 13.2% had a prior thrombotic event.

Patients received the following PV treatments:

• Both phlebotomy and HU concurrently or sequentially (41.1%)
• Phlebotomy only (23.0%)
• HU only (19.6%)
• Neither phlebotomy nor HU (16.3%).

Survival

The median follow-up was 2.83 years. During that time, 37.2% of patients (n=305) died.

The median survival was 6.29 years for phlebotomy recipients and 4.50 years for non-recipients (P<0.01). The median survival was 6.02 years for HU recipients and 5.25 years for non-recipients (P<0.01).

In a multivariable analysis, receipt of phlebotomy was associated with decreased mortality. The hazard ratio (HR) for death was 0.65 (P<0.01) for phlebotomy recipients.

Increasing phlebotomy intensity (the number of phlebotomies per year) was also associated with decreased mortality, with an HR of 0.71 (P<0.01).

A higher proportion of days covered (PDC) by HU treatment was associated with decreased mortality as well.

The researchers said every 10% increase of HU PDC was associated with an 8% to 9% lower risk of death. The HR was 0.92 in a model where phlebotomy was a binary variable and 0.91 in a model that included the frequency of phlebotomy (P<0.01 for both).

Thrombosis

In all, 36.1% of patients (n=296) had a thrombotic event, which includes venous and arterial thrombosis.

The incidence of thrombosis was 29.3% (n=142) in phlebotomy recipients and 46.0% (n=154) in non-recipients (P<0.01). The incidence was 27.6% (n=118) in HU recipients and 45.4% (n=178) in non-recipients (P<0.01).

In a multivariable analysis, receipt of phlebotomy was associated with a decreased risk of thrombosis, with an HR of 0.52 (P<0.01).

Increasing phlebotomy intensity was associated with a decreased risk of thrombosis as well, with an HR of 0.46 (P<0.01).

And every 10% increase of HU PDC was associated with an 8% lower risk of thrombosis. The HR was 0.92 in both models (P<0.01 for both).

“All of the patients we studied were high-risk for clot development, and we now know from our findings that guideline-recommended treatments reduce the risk of both thrombosis and death,” Dr. Podoltsev said.

“We hope that our research will raise clinicians’ awareness of and adherence to the guidelines and improve the outcomes of PV patients in the future.”

This research was supported by the Frederick A. DeLuca Foundation. Study authors reported relationships with 24 pharmaceutical companies.

Henrique Orlandi Mourao

The European Medicines Agency has granted accelerated assessment to the marketing authorization application (MAA) for the FLT3 inhibitor quizartinib.

With this MAA, Daiichi Sankyo Company, Ltd., is seeking authorization for quizartinib to treat adults with FLT3-ITD-positive, relapsed or refractory acute myeloid leukemia (AML).

Accelerated assessment is given to products expected to be of major interest for public health and therapeutic innovation, and it can reduce the review timeline from 210 days to 150 days.

Quizartinib also has orphan drug designation from the European Commission.

The MAA for quizartinib is based on the phase 3 QuANTUM-R study. Results from this trial were presented at the 23rd Congress of the European Hematology Association in June.

QuANTUM-R enrolled adults with FLT3-ITD AML (at least 3% FLT3-ITD allelic ratio) who had refractory disease or had relapsed within 6 months of their first complete response (CR).

Patients were randomized to receive once-daily treatment with quizartinib (n=245) or a salvage chemotherapy regimen (n=122)—low-dose cytarabine (LoDAC, n=29); combination mitoxantrone, etoposide, and cytarabine (MEC, n=40); or combination fludarabine, cytarabine, and idarubicin (FLAG-IDA, n=53).

Patients who responded to treatment could proceed to hematopoietic stem cell transplant (HSCT), and those in the quizartinib arm could resume quizartinib after HSCT.

In all, 241 patients received quizartinib, and 94 received salvage chemotherapy—LoDAC (n=22), MEC (n=25), and FLAG-IDA (n=47). Of the 28 patients in the chemotherapy group who were not treated, most withdrew consent.

Thirty-two percent of quizartinib-treated patients and 12% of the chemotherapy group went on to HSCT.

Efficacy

The median follow-up was 23.5 months. The efficacy results include all randomized patients.

The overall response rate was 69% in the quizartinib arm and 30% in the chemotherapy arm.

The composite CR rate was 48% in the quizartinib arm and 27% in the chemotherapy arm. This includes:

• The CR rate (4% and 1%, respectively)
• The rate of CR with incomplete platelet recovery (4% and 0%, respectively)
• The rate of CR with incomplete hematologic recovery (40% and 26%, respectively).

The median event-free survival was 6.0 weeks in the quizartinib arm and 3.7 weeks in the chemotherapy arm (hazard ratio=0.90, P=0.1071).

The median overall survival was 6.2 months in the quizartinib arm and 4.7 months in the chemotherapy arm (hazard ratio=0.76, P=0.0177). The 1-year overall survival rate was 27% and 20%, respectively.

Safety

The safety results include only patients who received their assigned treatment.

Grade 3 or higher hematologic treatment-emergent adverse events occurring in at least 5% of patients (in the quizartinib and chemotherapy groups, respectively) included:

• Thrombocytopenia (35% and 34%)
• Anemia (30% and 29%)
• Neutropenia (32% and 25%)
• Febrile neutropenia (31% and 21%)
• Leukopenia (17% and 16%).

Grade 3 or higher non-hematologic treatment-emergent adverse events occurring in at least 5% of patients (in the quizartinib and chemotherapy groups, respectively) included:

• Sepsis/septic shock (16% and 18%)
• Hypokalemia (12% and 9%)
• Pneumonia (12% and 9%)
• Fatigue (8% and 1%)
• Dyspnea (5% for both)
• Hypophosphatemia (5% for both).

Henrique Orlandi Mourao

The European Medicines Agency has granted accelerated assessment to the marketing authorization application (MAA) for the FLT3 inhibitor quizartinib.

With this MAA, Daiichi Sankyo Company, Ltd., is seeking authorization for quizartinib to treat adults with FLT3-ITD-positive, relapsed or refractory acute myeloid leukemia (AML).

Accelerated assessment is given to products expected to be of major interest for public health and therapeutic innovation, and it can reduce the review timeline from 210 days to 150 days.

Quizartinib also has orphan drug designation from the European Commission.

The MAA for quizartinib is based on the phase 3 QuANTUM-R study. Results from this trial were presented at the 23rd Congress of the European Hematology Association in June.

QuANTUM-R enrolled adults with FLT3-ITD AML (at least 3% FLT3-ITD allelic ratio) who had refractory disease or had relapsed within 6 months of their first complete response (CR).

Patients were randomized to receive once-daily treatment with quizartinib (n=245) or a salvage chemotherapy regimen (n=122)—low-dose cytarabine (LoDAC, n=29); combination mitoxantrone, etoposide, and cytarabine (MEC, n=40); or combination fludarabine, cytarabine, and idarubicin (FLAG-IDA, n=53).

Patients who responded to treatment could proceed to hematopoietic stem cell transplant (HSCT), and those in the quizartinib arm could resume quizartinib after HSCT.

In all, 241 patients received quizartinib, and 94 received salvage chemotherapy—LoDAC (n=22), MEC (n=25), and FLAG-IDA (n=47). Of the 28 patients in the chemotherapy group who were not treated, most withdrew consent.

Thirty-two percent of quizartinib-treated patients and 12% of the chemotherapy group went on to HSCT.

Efficacy

The median follow-up was 23.5 months. The efficacy results include all randomized patients.

The overall response rate was 69% in the quizartinib arm and 30% in the chemotherapy arm.

The composite CR rate was 48% in the quizartinib arm and 27% in the chemotherapy arm. This includes:

• The CR rate (4% and 1%, respectively)
• The rate of CR with incomplete platelet recovery (4% and 0%, respectively)
• The rate of CR with incomplete hematologic recovery (40% and 26%, respectively).

The median event-free survival was 6.0 weeks in the quizartinib arm and 3.7 weeks in the chemotherapy arm (hazard ratio=0.90, P=0.1071).

The median overall survival was 6.2 months in the quizartinib arm and 4.7 months in the chemotherapy arm (hazard ratio=0.76, P=0.0177). The 1-year overall survival rate was 27% and 20%, respectively.

Safety

The safety results include only patients who received their assigned treatment.

Grade 3 or higher hematologic treatment-emergent adverse events occurring in at least 5% of patients (in the quizartinib and chemotherapy groups, respectively) included:

• Thrombocytopenia (35% and 34%)
• Anemia (30% and 29%)
• Neutropenia (32% and 25%)
• Febrile neutropenia (31% and 21%)
• Leukopenia (17% and 16%).

Grade 3 or higher non-hematologic treatment-emergent adverse events occurring in at least 5% of patients (in the quizartinib and chemotherapy groups, respectively) included:

• Sepsis/septic shock (16% and 18%)
• Hypokalemia (12% and 9%)
• Pneumonia (12% and 9%)
• Fatigue (8% and 1%)
• Dyspnea (5% for both)
• Hypophosphatemia (5% for both).

Henrique Orlandi Mourao

The European Medicines Agency has granted accelerated assessment to the marketing authorization application (MAA) for the FLT3 inhibitor quizartinib.

With this MAA, Daiichi Sankyo Company, Ltd., is seeking authorization for quizartinib to treat adults with FLT3-ITD-positive, relapsed or refractory acute myeloid leukemia (AML).

Accelerated assessment is given to products expected to be of major interest for public health and therapeutic innovation, and it can reduce the review timeline from 210 days to 150 days.

Quizartinib also has orphan drug designation from the European Commission.

The MAA for quizartinib is based on the phase 3 QuANTUM-R study. Results from this trial were presented at the 23rd Congress of the European Hematology Association in June.

QuANTUM-R enrolled adults with FLT3-ITD AML (at least 3% FLT3-ITD allelic ratio) who had refractory disease or had relapsed within 6 months of their first complete response (CR).

Patients were randomized to receive once-daily treatment with quizartinib (n=245) or a salvage chemotherapy regimen (n=122)—low-dose cytarabine (LoDAC, n=29); combination mitoxantrone, etoposide, and cytarabine (MEC, n=40); or combination fludarabine, cytarabine, and idarubicin (FLAG-IDA, n=53).

Patients who responded to treatment could proceed to hematopoietic stem cell transplant (HSCT), and those in the quizartinib arm could resume quizartinib after HSCT.

In all, 241 patients received quizartinib, and 94 received salvage chemotherapy—LoDAC (n=22), MEC (n=25), and FLAG-IDA (n=47). Of the 28 patients in the chemotherapy group who were not treated, most withdrew consent.

Thirty-two percent of quizartinib-treated patients and 12% of the chemotherapy group went on to HSCT.

Efficacy

The median follow-up was 23.5 months. The efficacy results include all randomized patients.

The overall response rate was 69% in the quizartinib arm and 30% in the chemotherapy arm.

The composite CR rate was 48% in the quizartinib arm and 27% in the chemotherapy arm. This includes:

• The CR rate (4% and 1%, respectively)
• The rate of CR with incomplete platelet recovery (4% and 0%, respectively)
• The rate of CR with incomplete hematologic recovery (40% and 26%, respectively).

The median event-free survival was 6.0 weeks in the quizartinib arm and 3.7 weeks in the chemotherapy arm (hazard ratio=0.90, P=0.1071).

The median overall survival was 6.2 months in the quizartinib arm and 4.7 months in the chemotherapy arm (hazard ratio=0.76, P=0.0177). The 1-year overall survival rate was 27% and 20%, respectively.

Safety

The safety results include only patients who received their assigned treatment.

Grade 3 or higher hematologic treatment-emergent adverse events occurring in at least 5% of patients (in the quizartinib and chemotherapy groups, respectively) included:

• Thrombocytopenia (35% and 34%)
• Anemia (30% and 29%)
• Neutropenia (32% and 25%)
• Febrile neutropenia (31% and 21%)
• Leukopenia (17% and 16%).

Grade 3 or higher non-hematologic treatment-emergent adverse events occurring in at least 5% of patients (in the quizartinib and chemotherapy groups, respectively) included:

• Sepsis/septic shock (16% and 18%)
• Hypokalemia (12% and 9%)
• Pneumonia (12% and 9%)
• Fatigue (8% and 1%)
• Dyspnea (5% for both)
• Hypophosphatemia (5% for both).

By the time you receive this issue, we will know election results. The effects on medical care, medical coverage, Medicare, and Medicaid will be profound. American medicine is integrally linked to Congress and the Supreme Court because on July 30, 1965, Lyndon Johnson signed Title 18 of the Social Security Act and created Medicare – a move that took medical care out of personal law and into public law.

In November, CMS will publish its “final rule” about documentation and reimbursement changes, site of service reimbursement, and several other impactful policy changes. We have an extended article from the AGA Partners in Value conference about these potential changes.

This month we highlight the medical home concept for IBD – an idea that is gaining traction. More intense colon cancer screening may be needed for families with nonhereditary colon cancer. An interesting article from JAMA suggests that obesity may play a role in colon cancer rates in young women.

Antibiotic resistance in H. pylori infections is reaching alarming levels and this information may alter our practice. We feature an “In Focus” section on endosopic treatment for obese patients. We also continue highlighting some popular and interesting discussion chains emanating from the AGA Community.

Please stay involved as leaders in health care economics, delivery, and politics. We need thoughtful discussions and we need to bring patient stories to our politicians. It often seems that our advocacy does little to alter the national debate but who better to speak for the people that entrust us with their care?

John I. Allen, MD, MBA, AGAF
Editor in Chief

By the time you receive this issue, we will know election results. The effects on medical care, medical coverage, Medicare, and Medicaid will be profound. American medicine is integrally linked to Congress and the Supreme Court because on July 30, 1965, Lyndon Johnson signed Title 18 of the Social Security Act and created Medicare – a move that took medical care out of personal law and into public law.

In November, CMS will publish its “final rule” about documentation and reimbursement changes, site of service reimbursement, and several other impactful policy changes. We have an extended article from the AGA Partners in Value conference about these potential changes.

This month we highlight the medical home concept for IBD – an idea that is gaining traction. More intense colon cancer screening may be needed for families with nonhereditary colon cancer. An interesting article from JAMA suggests that obesity may play a role in colon cancer rates in young women.

Antibiotic resistance in H. pylori infections is reaching alarming levels and this information may alter our practice. We feature an “In Focus” section on endosopic treatment for obese patients. We also continue highlighting some popular and interesting discussion chains emanating from the AGA Community.

Please stay involved as leaders in health care economics, delivery, and politics. We need thoughtful discussions and we need to bring patient stories to our politicians. It often seems that our advocacy does little to alter the national debate but who better to speak for the people that entrust us with their care?

John I. Allen, MD, MBA, AGAF
Editor in Chief

By the time you receive this issue, we will know election results. The effects on medical care, medical coverage, Medicare, and Medicaid will be profound. American medicine is integrally linked to Congress and the Supreme Court because on July 30, 1965, Lyndon Johnson signed Title 18 of the Social Security Act and created Medicare – a move that took medical care out of personal law and into public law.

In November, CMS will publish its “final rule” about documentation and reimbursement changes, site of service reimbursement, and several other impactful policy changes. We have an extended article from the AGA Partners in Value conference about these potential changes.

This month we highlight the medical home concept for IBD – an idea that is gaining traction. More intense colon cancer screening may be needed for families with nonhereditary colon cancer. An interesting article from JAMA suggests that obesity may play a role in colon cancer rates in young women.

Antibiotic resistance in H. pylori infections is reaching alarming levels and this information may alter our practice. We feature an “In Focus” section on endosopic treatment for obese patients. We also continue highlighting some popular and interesting discussion chains emanating from the AGA Community.

Please stay involved as leaders in health care economics, delivery, and politics. We need thoughtful discussions and we need to bring patient stories to our politicians. It often seems that our advocacy does little to alter the national debate but who better to speak for the people that entrust us with their care?

John I. Allen, MD, MBA, AGAF
Editor in Chief

CHICAGO – Subgroup categorization of patients with severe scleroderma by their gene-expression profile correlated with responses to a newly proven treatment for the disease that involves myeloablation and autologous hematopoietic stem cell transplantation (HSCT).

Patients who fell into the “fibroproliferative” scleroderma subgroup, roughly one-third of patients enrolled in the treatment study, showed a high level of benefit from myeloablation and autologous HSCT, Michael L. Whitfield, PhD, said at the annual meeting of the American College of Rheumatology.

In contrast, the roughly one-third of patients in the study with a gene-expression profile that placed them into the “normal-like” subgroup had outcomes that closely matched the normal-like patients in the control group, who were treated with cyclophosphamide, which suggests that the normal-like patients are probably not good candidates for HSCT, said Dr. Whitfield, a professor of molecular and systems biology at the Geisel School of Medicine at Dartmouth in Hanover, N.H.

This study starts to get at the question of “How do you do personalized medicine in a disease like scleroderma?” he explained. “HSCT may be a game changer for patients with the fibroproliferative type of scleroderma,” who did relatively poorly in the control group of the trial when they received cyclophosphamide. Categorization of patients by their gene-expression profiles is a way to find order among scleroderma patients in what is otherwise “a very heterogeneous disease, where some patients improve on a treatment and others do not,” Dr Whitfield said.

The study used data collected in the SCOT (Scleroderma: Cyclophosphamide or Transplantation) trial, which enrolled 75 patients with severe scleroderma at any of 26 sites in the United States and Canada. SCOT compared the safety and efficacy of myeloablation followed by autologous HSCT with that of treatment with cyclophosphamide, and it followed patients for a median of 54 months. The results showed that overall HSCT was superior for the primary endpoint and several secondary endpoints, including event-free survival, which was 79% after HSCT and 50% in control patients by the end of follow-up (N Engl J Med. 2018 Jan 4;378[1]:35-47).

Dr. Whitfield’s group took peripheral blood cells from 30 of the patients treated by HSCT and from 33 of the patients treated with cyclophosphamide per protocol and analyzed the gene-expression profiles of the cells to categorize patients into the gene-expression subtypes of scleroderma that had been previously defined by Dr. Whitfield and his associates: fibroproliferative, inflammatory, limited, or normal-like (PLOS One. 2008 Jul 18;3[7]:e2696). The gene-expression analysis, which now looks at the activity of about 1,300 genes, showed that the 33 cyclophosphamide-treated patients included 12 with an inflammatory profile, 12 with a normal-like profile, and 9 with a fibroproliferative profile. Among the 30 patients treated with HSCT, 11 were in the fibroproliferative group, 11 were normal-like, and 8 had an inflammatory pattern.

Analysis of event-free survival out to 6 years following enrollment showed that, in the fibroproliferative subgroup, roughly 90% of patients treated with HSCT remained alive and event free, compared with about 35% of the cyclophosphamide patients, a highly statistically significant difference. In the inflammatory subgroup, event-free survival persisted in about 90% in the HSCT recipients, compared with about 50% of those in the control arm, a difference that did not reach statistical significance. Among patients with normal-like gene expression, the event-free survival rate was about the same regardless of treatment, about 60% in each treatment arm. The results suggest that patients with normal-like disease “are probably not good candidates for a treatment as intensive as HSCT,” Dr. Whitfield said in an interview.

Although the HSCT and cyclophosphamide treatment groups included relatively small numbers of patients, when the researchers subdivided the trial cohort into three different scleroderma types, the analysis remained “powered well enough to see a difference; the difference was very clearly statistically significant,” Dr. Whitfield declared.

“Now that we have a treatment [HSCT] to tie to the [gene-expression analysis], we can think about using this in routine practice,” he concluded.

Dr. Whitfield is a cofounder of Celdara, and he has been a consultant to Bristol-Myers Squibb, Corbus, UCB, and Third Rock Ventures.

[email protected]

SOURCE: Franks J et al. Arthritis Rheumatol. 2018;70(suppl 10): Abstract 1876.

CHICAGO – Subgroup categorization of patients with severe scleroderma by their gene-expression profile correlated with responses to a newly proven treatment for the disease that involves myeloablation and autologous hematopoietic stem cell transplantation (HSCT).

Patients who fell into the “fibroproliferative” scleroderma subgroup, roughly one-third of patients enrolled in the treatment study, showed a high level of benefit from myeloablation and autologous HSCT, Michael L. Whitfield, PhD, said at the annual meeting of the American College of Rheumatology.

In contrast, the roughly one-third of patients in the study with a gene-expression profile that placed them into the “normal-like” subgroup had outcomes that closely matched the normal-like patients in the control group, who were treated with cyclophosphamide, which suggests that the normal-like patients are probably not good candidates for HSCT, said Dr. Whitfield, a professor of molecular and systems biology at the Geisel School of Medicine at Dartmouth in Hanover, N.H.

This study starts to get at the question of “How do you do personalized medicine in a disease like scleroderma?” he explained. “HSCT may be a game changer for patients with the fibroproliferative type of scleroderma,” who did relatively poorly in the control group of the trial when they received cyclophosphamide. Categorization of patients by their gene-expression profiles is a way to find order among scleroderma patients in what is otherwise “a very heterogeneous disease, where some patients improve on a treatment and others do not,” Dr Whitfield said.

The study used data collected in the SCOT (Scleroderma: Cyclophosphamide or Transplantation) trial, which enrolled 75 patients with severe scleroderma at any of 26 sites in the United States and Canada. SCOT compared the safety and efficacy of myeloablation followed by autologous HSCT with that of treatment with cyclophosphamide, and it followed patients for a median of 54 months. The results showed that overall HSCT was superior for the primary endpoint and several secondary endpoints, including event-free survival, which was 79% after HSCT and 50% in control patients by the end of follow-up (N Engl J Med. 2018 Jan 4;378[1]:35-47).

Dr. Whitfield’s group took peripheral blood cells from 30 of the patients treated by HSCT and from 33 of the patients treated with cyclophosphamide per protocol and analyzed the gene-expression profiles of the cells to categorize patients into the gene-expression subtypes of scleroderma that had been previously defined by Dr. Whitfield and his associates: fibroproliferative, inflammatory, limited, or normal-like (PLOS One. 2008 Jul 18;3[7]:e2696). The gene-expression analysis, which now looks at the activity of about 1,300 genes, showed that the 33 cyclophosphamide-treated patients included 12 with an inflammatory profile, 12 with a normal-like profile, and 9 with a fibroproliferative profile. Among the 30 patients treated with HSCT, 11 were in the fibroproliferative group, 11 were normal-like, and 8 had an inflammatory pattern.

Analysis of event-free survival out to 6 years following enrollment showed that, in the fibroproliferative subgroup, roughly 90% of patients treated with HSCT remained alive and event free, compared with about 35% of the cyclophosphamide patients, a highly statistically significant difference. In the inflammatory subgroup, event-free survival persisted in about 90% in the HSCT recipients, compared with about 50% of those in the control arm, a difference that did not reach statistical significance. Among patients with normal-like gene expression, the event-free survival rate was about the same regardless of treatment, about 60% in each treatment arm. The results suggest that patients with normal-like disease “are probably not good candidates for a treatment as intensive as HSCT,” Dr. Whitfield said in an interview.

Although the HSCT and cyclophosphamide treatment groups included relatively small numbers of patients, when the researchers subdivided the trial cohort into three different scleroderma types, the analysis remained “powered well enough to see a difference; the difference was very clearly statistically significant,” Dr. Whitfield declared.

“Now that we have a treatment [HSCT] to tie to the [gene-expression analysis], we can think about using this in routine practice,” he concluded.

Dr. Whitfield is a cofounder of Celdara, and he has been a consultant to Bristol-Myers Squibb, Corbus, UCB, and Third Rock Ventures.

[email protected]

SOURCE: Franks J et al. Arthritis Rheumatol. 2018;70(suppl 10): Abstract 1876.

CHICAGO – Subgroup categorization of patients with severe scleroderma by their gene-expression profile correlated with responses to a newly proven treatment for the disease that involves myeloablation and autologous hematopoietic stem cell transplantation (HSCT).

Patients who fell into the “fibroproliferative” scleroderma subgroup, roughly one-third of patients enrolled in the treatment study, showed a high level of benefit from myeloablation and autologous HSCT, Michael L. Whitfield, PhD, said at the annual meeting of the American College of Rheumatology.

In contrast, the roughly one-third of patients in the study with a gene-expression profile that placed them into the “normal-like” subgroup had outcomes that closely matched the normal-like patients in the control group, who were treated with cyclophosphamide, which suggests that the normal-like patients are probably not good candidates for HSCT, said Dr. Whitfield, a professor of molecular and systems biology at the Geisel School of Medicine at Dartmouth in Hanover, N.H.

This study starts to get at the question of “How do you do personalized medicine in a disease like scleroderma?” he explained. “HSCT may be a game changer for patients with the fibroproliferative type of scleroderma,” who did relatively poorly in the control group of the trial when they received cyclophosphamide. Categorization of patients by their gene-expression profiles is a way to find order among scleroderma patients in what is otherwise “a very heterogeneous disease, where some patients improve on a treatment and others do not,” Dr Whitfield said.

The study used data collected in the SCOT (Scleroderma: Cyclophosphamide or Transplantation) trial, which enrolled 75 patients with severe scleroderma at any of 26 sites in the United States and Canada. SCOT compared the safety and efficacy of myeloablation followed by autologous HSCT with that of treatment with cyclophosphamide, and it followed patients for a median of 54 months. The results showed that overall HSCT was superior for the primary endpoint and several secondary endpoints, including event-free survival, which was 79% after HSCT and 50% in control patients by the end of follow-up (N Engl J Med. 2018 Jan 4;378[1]:35-47).

Dr. Whitfield’s group took peripheral blood cells from 30 of the patients treated by HSCT and from 33 of the patients treated with cyclophosphamide per protocol and analyzed the gene-expression profiles of the cells to categorize patients into the gene-expression subtypes of scleroderma that had been previously defined by Dr. Whitfield and his associates: fibroproliferative, inflammatory, limited, or normal-like (PLOS One. 2008 Jul 18;3[7]:e2696). The gene-expression analysis, which now looks at the activity of about 1,300 genes, showed that the 33 cyclophosphamide-treated patients included 12 with an inflammatory profile, 12 with a normal-like profile, and 9 with a fibroproliferative profile. Among the 30 patients treated with HSCT, 11 were in the fibroproliferative group, 11 were normal-like, and 8 had an inflammatory pattern.

Analysis of event-free survival out to 6 years following enrollment showed that, in the fibroproliferative subgroup, roughly 90% of patients treated with HSCT remained alive and event free, compared with about 35% of the cyclophosphamide patients, a highly statistically significant difference. In the inflammatory subgroup, event-free survival persisted in about 90% in the HSCT recipients, compared with about 50% of those in the control arm, a difference that did not reach statistical significance. Among patients with normal-like gene expression, the event-free survival rate was about the same regardless of treatment, about 60% in each treatment arm. The results suggest that patients with normal-like disease “are probably not good candidates for a treatment as intensive as HSCT,” Dr. Whitfield said in an interview.

Although the HSCT and cyclophosphamide treatment groups included relatively small numbers of patients, when the researchers subdivided the trial cohort into three different scleroderma types, the analysis remained “powered well enough to see a difference; the difference was very clearly statistically significant,” Dr. Whitfield declared.

“Now that we have a treatment [HSCT] to tie to the [gene-expression analysis], we can think about using this in routine practice,” he concluded.

Dr. Whitfield is a cofounder of Celdara, and he has been a consultant to Bristol-Myers Squibb, Corbus, UCB, and Third Rock Ventures.

[email protected]

SOURCE: Franks J et al. Arthritis Rheumatol. 2018;70(suppl 10): Abstract 1876.

Of the trials chosen for the six Late-Breaking Clinical Trial sessions, all being presented in the first 2 days of the American Heart Association scientific sessions in Chicago Nov. 10-12. Here are some of the most potentially practice-changing studies to look out for.

Courtesy of the Chicago Architecture Foundation.

Saturday

• REDUCE-IT: Relative to placebo, the fish oil derivative AMR101 (icosapent-ethyl) evaluated in the REDUCE-IT trial was associated with a 25% reduction in a primary composite endpoint of major adverse cardiovascular events (MACE), according top-line data released in September. A highly purified ethyl ester of eicosapentaenoic acid (EPA), AMR101 (Vascepa, Amarin) was studied on top of statin therapy in both primary and secondary prevention cohorts among the 8,000 patients randomized. Relative efficacy for primary and secondary prevention was not described in the initial release of data and will be of particular when the full results are released on Saturday, Nov. 10 at 2:00 p.m.

• DECLARE TIMI58: In top line results from DECLARE TIMI58, which randomized more than 17,000 participants with type 2 diabetes an experimental arm or placebo, the SGLT2 inhibitor dapagliflozin (Farxiga, AstraZeneca) was linked to a reduction in the composite endpoint of hospitalization for heart failure or cardiovascular death. In the early release of results, no mention was made of the effect of this agent on a composite of cardiovascular death, MI, or ischemic stroke, which was a secondary co-primary endpoint. This and the impact of dapagliflozin on an array of secondary endpoints will be revealed when the full results are made available in the Saturday late-breaker session at 2:00 p.m.

• VITAL: The relative effect of vitamin D, fish oil, or both on body composition was compared in the VITAL study, which randomized more than 20,000 patients. Fish oil plus vitamin D, fish oil plus placebo, vitamin D plus placebo, and two placebos were compared in a 2 x 2 factorial design. The primary outcome includes total body fat and lean mass as well as these components in the abdomen and other anatomic sites. Body mass index, waist circumference, and waist-to-hip ratio are among secondary outcomes. In addition, the relative effects of these treatments on lipids, blood glucose, and other aspects of metabolism were followed over the 2 years of the study, to presented at 2 p.m. on Saturday.

• CIRT: Responding to the evidence that inflammation is a crucial contributor to atherothrombosis, the CIRT trial tested whether the anti-inflammatory agent methotrexate reduces rates of MI, stroke, and cardiovascular death relative to placebo in patients with stable coronary artery disease and either type 2 diabetes or metabolic syndrome. The study enrolled about 7,000 patients and will have follow-up of nearly 6 years. Secondary endpoints, such as the impact of methotrexate on rates of coronary revascularization, peripheral artery disease, venous thromboembolism, and aortic stenosis, may provide insight about the ways in which control of inflammation affects vascular pathology. The presentation is at 2 p.m. on Saturday.

• Also on Saturday, diverse trial hypotheses are being tested. For example, the cost effectiveness of a PCSK9 inhibitor will be the focus of the ODYSSEY OUTCOMES economics study, presented at the 2:00 session. The results of YOGA-CaRe, a multicenter trial of a yoga-based cardiac rehabilitation program, will be presented in a subsequent Saturday late-breaking session. Of highlights of the third Saturday late-breaking session, ALERT-AF will determine whether a computerized decision protocol affected anticoagulation management in hospitalized patients with atrial fibrillation.

Sunday

• PIONEER-HF: It has been previously shown that sacubitril/valsartan improves outcome in stable heart failure patients with a reduced ejection fraction (HRrEF), but PIONEER-HF will test the tolerability of this strategy when this treatment is initiated prior to hospital discharge. Patients with a left ventricular ejection fraction of 40% or less and elevated N-terminal pro hormone BNP (NT-proBNP) will be randomized to sacubitril/valsartan (Entresto, Novartis) or the ACE inhibitor enalapril. The primary outcome of the trial, which enrolled more than 700 patients, is the time-averaged percentage change in NT-proBNP from baseline. Secondary outcome measures included the proportion of patients with symptomatic hypotension, hyperkalemia, and angioedema. Presentation will be at the Sunday 10:45 a.m. session.

• TICAB: The hypothesis that ticagrelor is superior to aspirin for preventing a composite MACE endpoint of CV death, myocardial infarction, target vessel revascularization, and stroke in patients undergoing coronary artery bypass grafting is the basis for the TICAB trial. The nearly 1,900 patients were randomized to 90 mg of ticagrelor twice daily or 100 mg of aspirin twice daily. Major bleeding events, CV death, and all cause death are key secondary outcomes. Relative benefit in context of safety, particularly bleeding risk, will be of interest when the final results are revealed at 5:30 p.m. on Sunday.

All-in-all, the Sunday late-breaking sessions are no less crowded with potentially practice-changing studies, including T-TIME, an evaluation of low-dose alteplase during primary percutaneous intervention at 9:00 a.m., TRED-HF, a study of withdrawal of heart failure therapy in patients who have recovered from dilated cardiomyopathy at 10:45 a.m., and ISAR TEST 4, which will provide 10-year outcomes after coronary stents with biodegradable versus permanent polymer coated devices, at 5:30 p.m.
 

Of the trials chosen for the six Late-Breaking Clinical Trial sessions, all being presented in the first 2 days of the American Heart Association scientific sessions in Chicago Nov. 10-12. Here are some of the most potentially practice-changing studies to look out for.

Courtesy of the Chicago Architecture Foundation.

Saturday

• REDUCE-IT: Relative to placebo, the fish oil derivative AMR101 (icosapent-ethyl) evaluated in the REDUCE-IT trial was associated with a 25% reduction in a primary composite endpoint of major adverse cardiovascular events (MACE), according top-line data released in September. A highly purified ethyl ester of eicosapentaenoic acid (EPA), AMR101 (Vascepa, Amarin) was studied on top of statin therapy in both primary and secondary prevention cohorts among the 8,000 patients randomized. Relative efficacy for primary and secondary prevention was not described in the initial release of data and will be of particular when the full results are released on Saturday, Nov. 10 at 2:00 p.m.

• DECLARE TIMI58: In top line results from DECLARE TIMI58, which randomized more than 17,000 participants with type 2 diabetes an experimental arm or placebo, the SGLT2 inhibitor dapagliflozin (Farxiga, AstraZeneca) was linked to a reduction in the composite endpoint of hospitalization for heart failure or cardiovascular death. In the early release of results, no mention was made of the effect of this agent on a composite of cardiovascular death, MI, or ischemic stroke, which was a secondary co-primary endpoint. This and the impact of dapagliflozin on an array of secondary endpoints will be revealed when the full results are made available in the Saturday late-breaker session at 2:00 p.m.

• VITAL: The relative effect of vitamin D, fish oil, or both on body composition was compared in the VITAL study, which randomized more than 20,000 patients. Fish oil plus vitamin D, fish oil plus placebo, vitamin D plus placebo, and two placebos were compared in a 2 x 2 factorial design. The primary outcome includes total body fat and lean mass as well as these components in the abdomen and other anatomic sites. Body mass index, waist circumference, and waist-to-hip ratio are among secondary outcomes. In addition, the relative effects of these treatments on lipids, blood glucose, and other aspects of metabolism were followed over the 2 years of the study, to presented at 2 p.m. on Saturday.

• CIRT: Responding to the evidence that inflammation is a crucial contributor to atherothrombosis, the CIRT trial tested whether the anti-inflammatory agent methotrexate reduces rates of MI, stroke, and cardiovascular death relative to placebo in patients with stable coronary artery disease and either type 2 diabetes or metabolic syndrome. The study enrolled about 7,000 patients and will have follow-up of nearly 6 years. Secondary endpoints, such as the impact of methotrexate on rates of coronary revascularization, peripheral artery disease, venous thromboembolism, and aortic stenosis, may provide insight about the ways in which control of inflammation affects vascular pathology. The presentation is at 2 p.m. on Saturday.

• Also on Saturday, diverse trial hypotheses are being tested. For example, the cost effectiveness of a PCSK9 inhibitor will be the focus of the ODYSSEY OUTCOMES economics study, presented at the 2:00 session. The results of YOGA-CaRe, a multicenter trial of a yoga-based cardiac rehabilitation program, will be presented in a subsequent Saturday late-breaking session. Of highlights of the third Saturday late-breaking session, ALERT-AF will determine whether a computerized decision protocol affected anticoagulation management in hospitalized patients with atrial fibrillation.

Sunday

• PIONEER-HF: It has been previously shown that sacubitril/valsartan improves outcome in stable heart failure patients with a reduced ejection fraction (HRrEF), but PIONEER-HF will test the tolerability of this strategy when this treatment is initiated prior to hospital discharge. Patients with a left ventricular ejection fraction of 40% or less and elevated N-terminal pro hormone BNP (NT-proBNP) will be randomized to sacubitril/valsartan (Entresto, Novartis) or the ACE inhibitor enalapril. The primary outcome of the trial, which enrolled more than 700 patients, is the time-averaged percentage change in NT-proBNP from baseline. Secondary outcome measures included the proportion of patients with symptomatic hypotension, hyperkalemia, and angioedema. Presentation will be at the Sunday 10:45 a.m. session.

• TICAB: The hypothesis that ticagrelor is superior to aspirin for preventing a composite MACE endpoint of CV death, myocardial infarction, target vessel revascularization, and stroke in patients undergoing coronary artery bypass grafting is the basis for the TICAB trial. The nearly 1,900 patients were randomized to 90 mg of ticagrelor twice daily or 100 mg of aspirin twice daily. Major bleeding events, CV death, and all cause death are key secondary outcomes. Relative benefit in context of safety, particularly bleeding risk, will be of interest when the final results are revealed at 5:30 p.m. on Sunday.

All-in-all, the Sunday late-breaking sessions are no less crowded with potentially practice-changing studies, including T-TIME, an evaluation of low-dose alteplase during primary percutaneous intervention at 9:00 a.m., TRED-HF, a study of withdrawal of heart failure therapy in patients who have recovered from dilated cardiomyopathy at 10:45 a.m., and ISAR TEST 4, which will provide 10-year outcomes after coronary stents with biodegradable versus permanent polymer coated devices, at 5:30 p.m.
 

Of the trials chosen for the six Late-Breaking Clinical Trial sessions, all being presented in the first 2 days of the American Heart Association scientific sessions in Chicago Nov. 10-12. Here are some of the most potentially practice-changing studies to look out for.

Courtesy of the Chicago Architecture Foundation.

Saturday

• REDUCE-IT: Relative to placebo, the fish oil derivative AMR101 (icosapent-ethyl) evaluated in the REDUCE-IT trial was associated with a 25% reduction in a primary composite endpoint of major adverse cardiovascular events (MACE), according top-line data released in September. A highly purified ethyl ester of eicosapentaenoic acid (EPA), AMR101 (Vascepa, Amarin) was studied on top of statin therapy in both primary and secondary prevention cohorts among the 8,000 patients randomized. Relative efficacy for primary and secondary prevention was not described in the initial release of data and will be of particular when the full results are released on Saturday, Nov. 10 at 2:00 p.m.

• DECLARE TIMI58: In top line results from DECLARE TIMI58, which randomized more than 17,000 participants with type 2 diabetes an experimental arm or placebo, the SGLT2 inhibitor dapagliflozin (Farxiga, AstraZeneca) was linked to a reduction in the composite endpoint of hospitalization for heart failure or cardiovascular death. In the early release of results, no mention was made of the effect of this agent on a composite of cardiovascular death, MI, or ischemic stroke, which was a secondary co-primary endpoint. This and the impact of dapagliflozin on an array of secondary endpoints will be revealed when the full results are made available in the Saturday late-breaker session at 2:00 p.m.

• VITAL: The relative effect of vitamin D, fish oil, or both on body composition was compared in the VITAL study, which randomized more than 20,000 patients. Fish oil plus vitamin D, fish oil plus placebo, vitamin D plus placebo, and two placebos were compared in a 2 x 2 factorial design. The primary outcome includes total body fat and lean mass as well as these components in the abdomen and other anatomic sites. Body mass index, waist circumference, and waist-to-hip ratio are among secondary outcomes. In addition, the relative effects of these treatments on lipids, blood glucose, and other aspects of metabolism were followed over the 2 years of the study, to presented at 2 p.m. on Saturday.

• CIRT: Responding to the evidence that inflammation is a crucial contributor to atherothrombosis, the CIRT trial tested whether the anti-inflammatory agent methotrexate reduces rates of MI, stroke, and cardiovascular death relative to placebo in patients with stable coronary artery disease and either type 2 diabetes or metabolic syndrome. The study enrolled about 7,000 patients and will have follow-up of nearly 6 years. Secondary endpoints, such as the impact of methotrexate on rates of coronary revascularization, peripheral artery disease, venous thromboembolism, and aortic stenosis, may provide insight about the ways in which control of inflammation affects vascular pathology. The presentation is at 2 p.m. on Saturday.

• Also on Saturday, diverse trial hypotheses are being tested. For example, the cost effectiveness of a PCSK9 inhibitor will be the focus of the ODYSSEY OUTCOMES economics study, presented at the 2:00 session. The results of YOGA-CaRe, a multicenter trial of a yoga-based cardiac rehabilitation program, will be presented in a subsequent Saturday late-breaking session. Of highlights of the third Saturday late-breaking session, ALERT-AF will determine whether a computerized decision protocol affected anticoagulation management in hospitalized patients with atrial fibrillation.

Sunday

• PIONEER-HF: It has been previously shown that sacubitril/valsartan improves outcome in stable heart failure patients with a reduced ejection fraction (HRrEF), but PIONEER-HF will test the tolerability of this strategy when this treatment is initiated prior to hospital discharge. Patients with a left ventricular ejection fraction of 40% or less and elevated N-terminal pro hormone BNP (NT-proBNP) will be randomized to sacubitril/valsartan (Entresto, Novartis) or the ACE inhibitor enalapril. The primary outcome of the trial, which enrolled more than 700 patients, is the time-averaged percentage change in NT-proBNP from baseline. Secondary outcome measures included the proportion of patients with symptomatic hypotension, hyperkalemia, and angioedema. Presentation will be at the Sunday 10:45 a.m. session.

• TICAB: The hypothesis that ticagrelor is superior to aspirin for preventing a composite MACE endpoint of CV death, myocardial infarction, target vessel revascularization, and stroke in patients undergoing coronary artery bypass grafting is the basis for the TICAB trial. The nearly 1,900 patients were randomized to 90 mg of ticagrelor twice daily or 100 mg of aspirin twice daily. Major bleeding events, CV death, and all cause death are key secondary outcomes. Relative benefit in context of safety, particularly bleeding risk, will be of interest when the final results are revealed at 5:30 p.m. on Sunday.

All-in-all, the Sunday late-breaking sessions are no less crowded with potentially practice-changing studies, including T-TIME, an evaluation of low-dose alteplase during primary percutaneous intervention at 9:00 a.m., TRED-HF, a study of withdrawal of heart failure therapy in patients who have recovered from dilated cardiomyopathy at 10:45 a.m., and ISAR TEST 4, which will provide 10-year outcomes after coronary stents with biodegradable versus permanent polymer coated devices, at 5:30 p.m.
 

ATLANTA – In the fall of 2013, world-famous actor and comedian Robin Williams began to suffer symptoms from a disease he would never know the name of: Lewy body dementia.

Doug Brunk/MDedge News

“With our medical team’s care, for the next 10 months we chased symptoms, but they were so elusive,” Mr. Williams’ widow, Susan Schneider Williams, said during a keynote address at the annual meeting of the American Neurological Association. “One hallmark of LBD is that symptoms appear and disappear randomly. The game whack-a-mole comes to mind. As soon as you think you are about to figure out a symptom, it disappears, and another one pops up.”

Mr. Williams’ medical team included one general physician, one neurologist, one motor specialist, two psychiatrists, one hypnotherapist, one physical trainer, and assorted alternative specialists. “We had been celebrating our second wedding anniversary when Robin started having gut discomfort,” Ms. Williams recalled. “He was tested for diverticulitis [but] the results came back negative. The pain eventually subsided but what was alarming was Robin’s reaction to it. He had a sudden and sustained spike in fear and anxiety unlike anything I’d seen before. By that point, we’d been by each other’s side long enough that I knew his normal baseline moods, fears, and anxieties. This was totally out of character, and I wondered privately: ‘Is my husband a hypochondriac?’ What I know now is that he was exhibiting a notable hallmark of LBD: new onset anxiety, sustained.” Lewy body disease is characterized by more than 40 symptoms, she continued, “and Robin experienced nearly all of them. He was particularly debilitated by fear, anxiety, delusions, paranoia, and as I came to find out later, hallucinations.”

The medical team continued running all sorts of tests, but everything kept came back negative, except for a very high cortisol count. By the late spring of 2014, however, Mr. Williams was diagnosed with Parkinson’s disease. “I was relieved to find out we finally had an answer, but I could tell, Robin was not buying it,” said Ms. Williams, who is a California-based fine artist, author, and brain health advocate. “The motor specialist said it was early and mild and that he’d be feeling better once he adjusted to the medications, [that] he had another 10 good years.”

In an attempt to treat the Parkinson’s and what was assumed to be depression, his care plan involved adjusting Parkinson’s medications, combined with an antidepressant. His physician also recommended a visit to the Dan Anderson Renewal Center in Minnesota, “for enhanced 12-step work to augment his sobriety,” Ms. Williams said. “The hope was this might help with fear and anxiety. Robin was clean and sober for 8 continuous years when he passed. I watched how he gained spiritually in so many ways from all the work he’d been doing, but his brain biology was going in the exact opposite direction. He tried desperately to join the parts of his heart, mind, and spirit, but his brain was pulling him apart. I felt like I was watching my husband disintegrate before my eyes, and there was nothing anyone could do about it. There came a day when we were getting ready to go to one of our dear friend’s birthday party. I came and saw Robin as he lay on our bed, imprisoned by fear and anxiety. Through tears, he pleaded, ‘I just want to reboot my brain!’ I promised him, ‘I know, honey. I swear we’re going to get to the bottom of this.’ ”

The couple was about a week away from choosing which neurocognitive testing facility to go to for further evaluation when Mr. Williams took his own life in his Paradise Cay, Calif., home on Aug. 11, 2014. “Robin was exhausted from the terror coming from his brain,” Ms. Williams said. “He took [his own life] before it could take any more of him.”

[email protected]

ATLANTA – In the fall of 2013, world-famous actor and comedian Robin Williams began to suffer symptoms from a disease he would never know the name of: Lewy body dementia.

Doug Brunk/MDedge News

“With our medical team’s care, for the next 10 months we chased symptoms, but they were so elusive,” Mr. Williams’ widow, Susan Schneider Williams, said during a keynote address at the annual meeting of the American Neurological Association. “One hallmark of LBD is that symptoms appear and disappear randomly. The game whack-a-mole comes to mind. As soon as you think you are about to figure out a symptom, it disappears, and another one pops up.”

Mr. Williams’ medical team included one general physician, one neurologist, one motor specialist, two psychiatrists, one hypnotherapist, one physical trainer, and assorted alternative specialists. “We had been celebrating our second wedding anniversary when Robin started having gut discomfort,” Ms. Williams recalled. “He was tested for diverticulitis [but] the results came back negative. The pain eventually subsided but what was alarming was Robin’s reaction to it. He had a sudden and sustained spike in fear and anxiety unlike anything I’d seen before. By that point, we’d been by each other’s side long enough that I knew his normal baseline moods, fears, and anxieties. This was totally out of character, and I wondered privately: ‘Is my husband a hypochondriac?’ What I know now is that he was exhibiting a notable hallmark of LBD: new onset anxiety, sustained.” Lewy body disease is characterized by more than 40 symptoms, she continued, “and Robin experienced nearly all of them. He was particularly debilitated by fear, anxiety, delusions, paranoia, and as I came to find out later, hallucinations.”

The medical team continued running all sorts of tests, but everything kept came back negative, except for a very high cortisol count. By the late spring of 2014, however, Mr. Williams was diagnosed with Parkinson’s disease. “I was relieved to find out we finally had an answer, but I could tell, Robin was not buying it,” said Ms. Williams, who is a California-based fine artist, author, and brain health advocate. “The motor specialist said it was early and mild and that he’d be feeling better once he adjusted to the medications, [that] he had another 10 good years.”

In an attempt to treat the Parkinson’s and what was assumed to be depression, his care plan involved adjusting Parkinson’s medications, combined with an antidepressant. His physician also recommended a visit to the Dan Anderson Renewal Center in Minnesota, “for enhanced 12-step work to augment his sobriety,” Ms. Williams said. “The hope was this might help with fear and anxiety. Robin was clean and sober for 8 continuous years when he passed. I watched how he gained spiritually in so many ways from all the work he’d been doing, but his brain biology was going in the exact opposite direction. He tried desperately to join the parts of his heart, mind, and spirit, but his brain was pulling him apart. I felt like I was watching my husband disintegrate before my eyes, and there was nothing anyone could do about it. There came a day when we were getting ready to go to one of our dear friend’s birthday party. I came and saw Robin as he lay on our bed, imprisoned by fear and anxiety. Through tears, he pleaded, ‘I just want to reboot my brain!’ I promised him, ‘I know, honey. I swear we’re going to get to the bottom of this.’ ”

The couple was about a week away from choosing which neurocognitive testing facility to go to for further evaluation when Mr. Williams took his own life in his Paradise Cay, Calif., home on Aug. 11, 2014. “Robin was exhausted from the terror coming from his brain,” Ms. Williams said. “He took [his own life] before it could take any more of him.”

[email protected]

ATLANTA – In the fall of 2013, world-famous actor and comedian Robin Williams began to suffer symptoms from a disease he would never know the name of: Lewy body dementia.

Doug Brunk/MDedge News

“With our medical team’s care, for the next 10 months we chased symptoms, but they were so elusive,” Mr. Williams’ widow, Susan Schneider Williams, said during a keynote address at the annual meeting of the American Neurological Association. “One hallmark of LBD is that symptoms appear and disappear randomly. The game whack-a-mole comes to mind. As soon as you think you are about to figure out a symptom, it disappears, and another one pops up.”

Mr. Williams’ medical team included one general physician, one neurologist, one motor specialist, two psychiatrists, one hypnotherapist, one physical trainer, and assorted alternative specialists. “We had been celebrating our second wedding anniversary when Robin started having gut discomfort,” Ms. Williams recalled. “He was tested for diverticulitis [but] the results came back negative. The pain eventually subsided but what was alarming was Robin’s reaction to it. He had a sudden and sustained spike in fear and anxiety unlike anything I’d seen before. By that point, we’d been by each other’s side long enough that I knew his normal baseline moods, fears, and anxieties. This was totally out of character, and I wondered privately: ‘Is my husband a hypochondriac?’ What I know now is that he was exhibiting a notable hallmark of LBD: new onset anxiety, sustained.” Lewy body disease is characterized by more than 40 symptoms, she continued, “and Robin experienced nearly all of them. He was particularly debilitated by fear, anxiety, delusions, paranoia, and as I came to find out later, hallucinations.”

The medical team continued running all sorts of tests, but everything kept came back negative, except for a very high cortisol count. By the late spring of 2014, however, Mr. Williams was diagnosed with Parkinson’s disease. “I was relieved to find out we finally had an answer, but I could tell, Robin was not buying it,” said Ms. Williams, who is a California-based fine artist, author, and brain health advocate. “The motor specialist said it was early and mild and that he’d be feeling better once he adjusted to the medications, [that] he had another 10 good years.”

In an attempt to treat the Parkinson’s and what was assumed to be depression, his care plan involved adjusting Parkinson’s medications, combined with an antidepressant. His physician also recommended a visit to the Dan Anderson Renewal Center in Minnesota, “for enhanced 12-step work to augment his sobriety,” Ms. Williams said. “The hope was this might help with fear and anxiety. Robin was clean and sober for 8 continuous years when he passed. I watched how he gained spiritually in so many ways from all the work he’d been doing, but his brain biology was going in the exact opposite direction. He tried desperately to join the parts of his heart, mind, and spirit, but his brain was pulling him apart. I felt like I was watching my husband disintegrate before my eyes, and there was nothing anyone could do about it. There came a day when we were getting ready to go to one of our dear friend’s birthday party. I came and saw Robin as he lay on our bed, imprisoned by fear and anxiety. Through tears, he pleaded, ‘I just want to reboot my brain!’ I promised him, ‘I know, honey. I swear we’re going to get to the bottom of this.’ ”

The couple was about a week away from choosing which neurocognitive testing facility to go to for further evaluation when Mr. Williams took his own life in his Paradise Cay, Calif., home on Aug. 11, 2014. “Robin was exhausted from the terror coming from his brain,” Ms. Williams said. “He took [his own life] before it could take any more of him.”

[email protected]

Currently, there is no effective hepatitis C virus (HCV) vaccine available despite numerous ongoing studies, according to the results of a review published in Gastroenterology.

copyright itsmejust/Thinkstock

In their article, Justin R. Bailey, MD, of Johns Hopkins University, Baltimore, and his colleagues reviewed the limited feasibility of applying traditional vaccine design to HCV and the problem of genetic diversity in the virus, as well as trials of vaccines designed to elicit T-cell responses.

One profound difficulty in the development and testing of an HCV vaccine is that the cohort most predictably at risk for high infection levels, people who inject drugs, are notoriously difficult to recruit, maintain consistent treatment, and follow up on – all necessary aspects of an appropriate vaccine trial.

Thus, at present, adjuvant envelope or core protein and virus-vectored nonstructural antigen vaccines have been tested only in healthy volunteers who are not at risk for HCV infection; viral vectors encoding nonstructural proteins remain the only vaccine strategy tested in truly at-risk individuals, according to Dr. Bailey and his colleagues.

“Although pharmaceutical companies invest in drug development, vaccine development requires investment from sources beyond government and charitable foundations. A prophylactic HCV vaccine is an important part of a successful strategy for global control. Although development is not easy, the quest is a worthy challenge,” Dr. Bailey and his colleagues concluded.

The authors reported having no conflicts.

[email protected]

SOURCE: Bailey JR et al. Gastroenterology. 2018 Sep 27. doi: 10.1053/j.gastro.2018.08.060.

Currently, there is no effective hepatitis C virus (HCV) vaccine available despite numerous ongoing studies, according to the results of a review published in Gastroenterology.

copyright itsmejust/Thinkstock

In their article, Justin R. Bailey, MD, of Johns Hopkins University, Baltimore, and his colleagues reviewed the limited feasibility of applying traditional vaccine design to HCV and the problem of genetic diversity in the virus, as well as trials of vaccines designed to elicit T-cell responses.

One profound difficulty in the development and testing of an HCV vaccine is that the cohort most predictably at risk for high infection levels, people who inject drugs, are notoriously difficult to recruit, maintain consistent treatment, and follow up on – all necessary aspects of an appropriate vaccine trial.

Thus, at present, adjuvant envelope or core protein and virus-vectored nonstructural antigen vaccines have been tested only in healthy volunteers who are not at risk for HCV infection; viral vectors encoding nonstructural proteins remain the only vaccine strategy tested in truly at-risk individuals, according to Dr. Bailey and his colleagues.

“Although pharmaceutical companies invest in drug development, vaccine development requires investment from sources beyond government and charitable foundations. A prophylactic HCV vaccine is an important part of a successful strategy for global control. Although development is not easy, the quest is a worthy challenge,” Dr. Bailey and his colleagues concluded.

The authors reported having no conflicts.

[email protected]

SOURCE: Bailey JR et al. Gastroenterology. 2018 Sep 27. doi: 10.1053/j.gastro.2018.08.060.

Currently, there is no effective hepatitis C virus (HCV) vaccine available despite numerous ongoing studies, according to the results of a review published in Gastroenterology.

copyright itsmejust/Thinkstock

In their article, Justin R. Bailey, MD, of Johns Hopkins University, Baltimore, and his colleagues reviewed the limited feasibility of applying traditional vaccine design to HCV and the problem of genetic diversity in the virus, as well as trials of vaccines designed to elicit T-cell responses.

One profound difficulty in the development and testing of an HCV vaccine is that the cohort most predictably at risk for high infection levels, people who inject drugs, are notoriously difficult to recruit, maintain consistent treatment, and follow up on – all necessary aspects of an appropriate vaccine trial.

Thus, at present, adjuvant envelope or core protein and virus-vectored nonstructural antigen vaccines have been tested only in healthy volunteers who are not at risk for HCV infection; viral vectors encoding nonstructural proteins remain the only vaccine strategy tested in truly at-risk individuals, according to Dr. Bailey and his colleagues.

“Although pharmaceutical companies invest in drug development, vaccine development requires investment from sources beyond government and charitable foundations. A prophylactic HCV vaccine is an important part of a successful strategy for global control. Although development is not easy, the quest is a worthy challenge,” Dr. Bailey and his colleagues concluded.

The authors reported having no conflicts.

[email protected]

SOURCE: Bailey JR et al. Gastroenterology. 2018 Sep 27. doi: 10.1053/j.gastro.2018.08.060.