Despite the fact that hormonal contraceptives interact with certain antiepileptic drugs, a recent study has shown that only 35% of 397 female patients with epilepsy were given any clinician counseling about contraceptive choices during their first clinic visit. And these patients were unlikely to receive contraceptive counseling during subsequent visits. The implications of these findings are troubling:  Many antiepileptic agents decrease the efficacy of hormonal contraceptives by inducing hepatic enzymes, and estrogen-containing contraceptives are known to accelerate the metabolism of lamotrigine, an antiepileptic drug commonly prescribed in women of child-bearing age. Espinera et al also found that when women with epilepsy are given advice about the advantages of IUDs, they are far more likely to switch to IUDs, which are highly effective without AED drug interactions.

Espinera AR, Gavvala J, Bellinski I, et al. Counseling by epileptologists affects contraceptive choices of women with epilepsy. Epilepsy Behav. 2016;65:1-6.

Despite the fact that hormonal contraceptives interact with certain antiepileptic drugs, a recent study has shown that only 35% of 397 female patients with epilepsy were given any clinician counseling about contraceptive choices during their first clinic visit. And these patients were unlikely to receive contraceptive counseling during subsequent visits. The implications of these findings are troubling:  Many antiepileptic agents decrease the efficacy of hormonal contraceptives by inducing hepatic enzymes, and estrogen-containing contraceptives are known to accelerate the metabolism of lamotrigine, an antiepileptic drug commonly prescribed in women of child-bearing age. Espinera et al also found that when women with epilepsy are given advice about the advantages of IUDs, they are far more likely to switch to IUDs, which are highly effective without AED drug interactions.

Espinera AR, Gavvala J, Bellinski I, et al. Counseling by epileptologists affects contraceptive choices of women with epilepsy. Epilepsy Behav. 2016;65:1-6.

Despite the fact that hormonal contraceptives interact with certain antiepileptic drugs, a recent study has shown that only 35% of 397 female patients with epilepsy were given any clinician counseling about contraceptive choices during their first clinic visit. And these patients were unlikely to receive contraceptive counseling during subsequent visits. The implications of these findings are troubling:  Many antiepileptic agents decrease the efficacy of hormonal contraceptives by inducing hepatic enzymes, and estrogen-containing contraceptives are known to accelerate the metabolism of lamotrigine, an antiepileptic drug commonly prescribed in women of child-bearing age. Espinera et al also found that when women with epilepsy are given advice about the advantages of IUDs, they are far more likely to switch to IUDs, which are highly effective without AED drug interactions.

Espinera AR, Gavvala J, Bellinski I, et al. Counseling by epileptologists affects contraceptive choices of women with epilepsy. Epilepsy Behav. 2016;65:1-6.

Young adults with epilepsy are at greater risk for neurodevelopmental and behavioral disorders than some other patient populations, according to a recent case-control study that looked at hospital admissions, outpatients, and ED visits for adults with epilepsy, migraine, or leg fracture. The study cohort consisted of 5666 adult epilepsy patients  between 19 and 25 years of age who were seen in hospitals and EDs, 17,507 patients with migraine, and 5966 patients with leg fractures. The researchers found that 51.8% of patients with epilepsy had behavioral health issues versus 37.6% of those with migraine and 21.6% of patients with fractures. Similarly, patients with epilepsy were 297% more likely to have a neurodevelopmental disorder compared with those with migraine.

Wagner JL, Wilson DA, Kellermann T, el al. Behavioral health in young adults with epilepsy: Implications for transition of care. Epilepsy Behav. 2016;65:7-12.

Young adults with epilepsy are at greater risk for neurodevelopmental and behavioral disorders than some other patient populations, according to a recent case-control study that looked at hospital admissions, outpatients, and ED visits for adults with epilepsy, migraine, or leg fracture. The study cohort consisted of 5666 adult epilepsy patients  between 19 and 25 years of age who were seen in hospitals and EDs, 17,507 patients with migraine, and 5966 patients with leg fractures. The researchers found that 51.8% of patients with epilepsy had behavioral health issues versus 37.6% of those with migraine and 21.6% of patients with fractures. Similarly, patients with epilepsy were 297% more likely to have a neurodevelopmental disorder compared with those with migraine.

Wagner JL, Wilson DA, Kellermann T, el al. Behavioral health in young adults with epilepsy: Implications for transition of care. Epilepsy Behav. 2016;65:7-12.

Young adults with epilepsy are at greater risk for neurodevelopmental and behavioral disorders than some other patient populations, according to a recent case-control study that looked at hospital admissions, outpatients, and ED visits for adults with epilepsy, migraine, or leg fracture. The study cohort consisted of 5666 adult epilepsy patients  between 19 and 25 years of age who were seen in hospitals and EDs, 17,507 patients with migraine, and 5966 patients with leg fractures. The researchers found that 51.8% of patients with epilepsy had behavioral health issues versus 37.6% of those with migraine and 21.6% of patients with fractures. Similarly, patients with epilepsy were 297% more likely to have a neurodevelopmental disorder compared with those with migraine.

Wagner JL, Wilson DA, Kellermann T, el al. Behavioral health in young adults with epilepsy: Implications for transition of care. Epilepsy Behav. 2016;65:7-12.

To determine how well pregnant women with epilepsy adhere to their medication regimen, Ernst et al studied their intake of antiepileptic medication by providing them with an iPod Touch loaded with a mobile app specifically designed to track such data. Eighty-six women with epilepsy monitored their seizures and medication use. The study found that 75% of the women had tracked their medication usage for more than 80% of the days they were enrolled in the experiment. Among this subgroup, adherence to the anti-epilepsy drug regimen was 97.7%; 44% said they had missed taking their medication for at least one day. The investigators speculate that the high adherence rate may have been the result of using the mobile app itself.

Ernst L. Harden CL, Pennell PB, et al.  Medication adherence in women with epilepsy who are planning pregnancy. Epilepsia. 2016; 57(12):2039-2044.

To determine how well pregnant women with epilepsy adhere to their medication regimen, Ernst et al studied their intake of antiepileptic medication by providing them with an iPod Touch loaded with a mobile app specifically designed to track such data. Eighty-six women with epilepsy monitored their seizures and medication use. The study found that 75% of the women had tracked their medication usage for more than 80% of the days they were enrolled in the experiment. Among this subgroup, adherence to the anti-epilepsy drug regimen was 97.7%; 44% said they had missed taking their medication for at least one day. The investigators speculate that the high adherence rate may have been the result of using the mobile app itself.

Ernst L. Harden CL, Pennell PB, et al.  Medication adherence in women with epilepsy who are planning pregnancy. Epilepsia. 2016; 57(12):2039-2044.

To determine how well pregnant women with epilepsy adhere to their medication regimen, Ernst et al studied their intake of antiepileptic medication by providing them with an iPod Touch loaded with a mobile app specifically designed to track such data. Eighty-six women with epilepsy monitored their seizures and medication use. The study found that 75% of the women had tracked their medication usage for more than 80% of the days they were enrolled in the experiment. Among this subgroup, adherence to the anti-epilepsy drug regimen was 97.7%; 44% said they had missed taking their medication for at least one day. The investigators speculate that the high adherence rate may have been the result of using the mobile app itself.

Ernst L. Harden CL, Pennell PB, et al.  Medication adherence in women with epilepsy who are planning pregnancy. Epilepsia. 2016; 57(12):2039-2044.

Among patients who have experienced traumatic brain injury, those who have had immediate or late seizures during an acute hospital stay are at increased of developing later posttraumatic seizures. Researchers found that new onset posttraumatic seizures were mostly likely to occur between the time patients were discharged from inpatient rehabilitation and 1 year (9.2%). By year 5, the cumulative incidence of such seizures was 20.5%. A patient’s race, intracranial pathology, and neurosurgical procedures also factored into their relative risk of posttraumatic seizures.

Ritter AC, Wagner AK, Fabio A, et al.  Incidence and risk factors of posttraumatic seizures following traumatic brain injury: A Traumatic Brain Injury Model Systems Study. Epilepsia. 2016;57(12):1968-1977.

Among patients who have experienced traumatic brain injury, those who have had immediate or late seizures during an acute hospital stay are at increased of developing later posttraumatic seizures. Researchers found that new onset posttraumatic seizures were mostly likely to occur between the time patients were discharged from inpatient rehabilitation and 1 year (9.2%). By year 5, the cumulative incidence of such seizures was 20.5%. A patient’s race, intracranial pathology, and neurosurgical procedures also factored into their relative risk of posttraumatic seizures.

Ritter AC, Wagner AK, Fabio A, et al.  Incidence and risk factors of posttraumatic seizures following traumatic brain injury: A Traumatic Brain Injury Model Systems Study. Epilepsia. 2016;57(12):1968-1977.

Among patients who have experienced traumatic brain injury, those who have had immediate or late seizures during an acute hospital stay are at increased of developing later posttraumatic seizures. Researchers found that new onset posttraumatic seizures were mostly likely to occur between the time patients were discharged from inpatient rehabilitation and 1 year (9.2%). By year 5, the cumulative incidence of such seizures was 20.5%. A patient’s race, intracranial pathology, and neurosurgical procedures also factored into their relative risk of posttraumatic seizures.

Ritter AC, Wagner AK, Fabio A, et al.  Incidence and risk factors of posttraumatic seizures following traumatic brain injury: A Traumatic Brain Injury Model Systems Study. Epilepsia. 2016;57(12):1968-1977.

Induced hypothermia does not improve clinical outcomes among patients with convulsive status epilepticus (CSE), according to a new multicenter study published in the New England Journal of Medicine. To reach that conclusion, investigators assigned 270 critically ill patients with CSE on mechanical ventilation to either standard care or standard care plus hypothermia, which lowered their body temperature to 32 to 34⁰C for 24 hours. To measure the impact of hypothermia, researchers used the Glasgow Outcome Scale (GOS) score and defined success as a GOS score of 5, which represents no or minimal neurologic deficit, at 90 days. Forty-nine percent of patients on hypothermia achieved a score of 5, compared to 43% of those on standard care, which was statistically insignificant (P=.43).

Legriel S, Lemiale V, Schenck, M, et al.  Hypothermia for Neuroprotection in Convulsive Status Epilepticus.  N Engl J Med. 2016;375(25):2457-2467.

Induced hypothermia does not improve clinical outcomes among patients with convulsive status epilepticus (CSE), according to a new multicenter study published in the New England Journal of Medicine. To reach that conclusion, investigators assigned 270 critically ill patients with CSE on mechanical ventilation to either standard care or standard care plus hypothermia, which lowered their body temperature to 32 to 34⁰C for 24 hours. To measure the impact of hypothermia, researchers used the Glasgow Outcome Scale (GOS) score and defined success as a GOS score of 5, which represents no or minimal neurologic deficit, at 90 days. Forty-nine percent of patients on hypothermia achieved a score of 5, compared to 43% of those on standard care, which was statistically insignificant (P=.43).

Legriel S, Lemiale V, Schenck, M, et al.  Hypothermia for Neuroprotection in Convulsive Status Epilepticus.  N Engl J Med. 2016;375(25):2457-2467.

Induced hypothermia does not improve clinical outcomes among patients with convulsive status epilepticus (CSE), according to a new multicenter study published in the New England Journal of Medicine. To reach that conclusion, investigators assigned 270 critically ill patients with CSE on mechanical ventilation to either standard care or standard care plus hypothermia, which lowered their body temperature to 32 to 34⁰C for 24 hours. To measure the impact of hypothermia, researchers used the Glasgow Outcome Scale (GOS) score and defined success as a GOS score of 5, which represents no or minimal neurologic deficit, at 90 days. Forty-nine percent of patients on hypothermia achieved a score of 5, compared to 43% of those on standard care, which was statistically insignificant (P=.43).

Legriel S, Lemiale V, Schenck, M, et al.  Hypothermia for Neuroprotection in Convulsive Status Epilepticus.  N Engl J Med. 2016;375(25):2457-2467.

This new phase III trial of solanezumab reveals that the drug is not effective for patients with mild Alzheimer’s disease, despite the hint that it was possibly effective based on post hoc analyses of earlier studies with this drug.

The findings expose the hazards of such post hoc analyses, typically done when the desired results are not observed, in the hope of squeezing lemonade from lemons. Although the subanalysis of patients with mild Alzheimer’s disease in the earlier studies suggested a 34% slowing of cognitive decline, as assessed by ADAS-Cog, an incremental slowing of 11% was seen in the new study that was not even statistically significant. While some secondary end points reached statistical significance, the slowing was so modest as to make no practical difference clinically.

I cannot emphasize enough that such equivocal results as seen in EXPEDITION3 do absolutely nothing to either confirm or deny the amyloid hypothesis. By now, there have been so many of these studies with antiamyloid agents, with little or no hint of efficacy, that we have long passed the definition of insanity: doing the same thing over and over in the hope of getting a different result.

The combination of all these clinical trial failures with the result of imaging studies that have shown amyloid deposition some 20 years before the expected onset of symptoms clearly tells us that antiamyloid agents should only be considered as potential prophylactics. By the time symptoms appear, disease progression is largely independent of amyloid and may be primarily tau-driven, spreading from neuron to neuron even when amyloid is effectively targeted by therapeutics. Even the A4 and DIAN studies are likely initiating treatment too late to make anything more than a modest effect with little practical value clinically. I am not suggesting that we drop amyloid as a target, only that we stop making these incremental changes in clinical trial design in the hope of getting a different result.

—Michael S. Wolfe, PhD
Mathias P. Mertes Professor of Medicinal Chemistry
University of Kansas, Lawrence

This new phase III trial of solanezumab reveals that the drug is not effective for patients with mild Alzheimer’s disease, despite the hint that it was possibly effective based on post hoc analyses of earlier studies with this drug.

The findings expose the hazards of such post hoc analyses, typically done when the desired results are not observed, in the hope of squeezing lemonade from lemons. Although the subanalysis of patients with mild Alzheimer’s disease in the earlier studies suggested a 34% slowing of cognitive decline, as assessed by ADAS-Cog, an incremental slowing of 11% was seen in the new study that was not even statistically significant. While some secondary end points reached statistical significance, the slowing was so modest as to make no practical difference clinically.

I cannot emphasize enough that such equivocal results as seen in EXPEDITION3 do absolutely nothing to either confirm or deny the amyloid hypothesis. By now, there have been so many of these studies with antiamyloid agents, with little or no hint of efficacy, that we have long passed the definition of insanity: doing the same thing over and over in the hope of getting a different result.

The combination of all these clinical trial failures with the result of imaging studies that have shown amyloid deposition some 20 years before the expected onset of symptoms clearly tells us that antiamyloid agents should only be considered as potential prophylactics. By the time symptoms appear, disease progression is largely independent of amyloid and may be primarily tau-driven, spreading from neuron to neuron even when amyloid is effectively targeted by therapeutics. Even the A4 and DIAN studies are likely initiating treatment too late to make anything more than a modest effect with little practical value clinically. I am not suggesting that we drop amyloid as a target, only that we stop making these incremental changes in clinical trial design in the hope of getting a different result.

—Michael S. Wolfe, PhD
Mathias P. Mertes Professor of Medicinal Chemistry
University of Kansas, Lawrence

This new phase III trial of solanezumab reveals that the drug is not effective for patients with mild Alzheimer’s disease, despite the hint that it was possibly effective based on post hoc analyses of earlier studies with this drug.

The findings expose the hazards of such post hoc analyses, typically done when the desired results are not observed, in the hope of squeezing lemonade from lemons. Although the subanalysis of patients with mild Alzheimer’s disease in the earlier studies suggested a 34% slowing of cognitive decline, as assessed by ADAS-Cog, an incremental slowing of 11% was seen in the new study that was not even statistically significant. While some secondary end points reached statistical significance, the slowing was so modest as to make no practical difference clinically.

I cannot emphasize enough that such equivocal results as seen in EXPEDITION3 do absolutely nothing to either confirm or deny the amyloid hypothesis. By now, there have been so many of these studies with antiamyloid agents, with little or no hint of efficacy, that we have long passed the definition of insanity: doing the same thing over and over in the hope of getting a different result.

The combination of all these clinical trial failures with the result of imaging studies that have shown amyloid deposition some 20 years before the expected onset of symptoms clearly tells us that antiamyloid agents should only be considered as potential prophylactics. By the time symptoms appear, disease progression is largely independent of amyloid and may be primarily tau-driven, spreading from neuron to neuron even when amyloid is effectively targeted by therapeutics. Even the A4 and DIAN studies are likely initiating treatment too late to make anything more than a modest effect with little practical value clinically. I am not suggesting that we drop amyloid as a target, only that we stop making these incremental changes in clinical trial design in the hope of getting a different result.

—Michael S. Wolfe, PhD
Mathias P. Mertes Professor of Medicinal Chemistry
University of Kansas, Lawrence

BOSTON – Lysosomal acid lipase deficiency (LAL-D), a rare genetic cause of marked dyslipidemia that causes early multisystem organ damage, was effectively treated by a human recombinant enzyme to replace deficient lysosomal acid lipase, and the replacement enzyme was well tolerated over a 76-week trial.

LAL-D, when it begins in infancy, is usually fatal within the first year.
 

When LAL-D occurs later in life, it’s believed to be an “underappreciated cause of fibrosis, cirrhosis, severe dyslipidemia, and early-onset atherosclerosis,” according to Katryn Furuya, MD, and the coauthors of a poster presentation given at the annual meeting of the American Association for the Study of Liver Diseases.

Supplying the human recombinant lysosomal acid lipase, termed sebelipase alfa (SA), to children and adults with LAL-D over a 76-week period resulted in a reduction in alanine aminotransferase (ALT) for 98% of participants, normalization of ALT for 51% of participants, and normalization of aspartate aminotransferase (AST) levels for 65% of patients. Patients on SA also experienced reductions in serum triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), and liver fat and total liver volume. “We’re basically replacing what they’re missing,” senior author Barbara Burton, MD, said in an interview.

[email protected]

On Twitter @karioakes

BOSTON – Lysosomal acid lipase deficiency (LAL-D), a rare genetic cause of marked dyslipidemia that causes early multisystem organ damage, was effectively treated by a human recombinant enzyme to replace deficient lysosomal acid lipase, and the replacement enzyme was well tolerated over a 76-week trial.

LAL-D, when it begins in infancy, is usually fatal within the first year.
 

When LAL-D occurs later in life, it’s believed to be an “underappreciated cause of fibrosis, cirrhosis, severe dyslipidemia, and early-onset atherosclerosis,” according to Katryn Furuya, MD, and the coauthors of a poster presentation given at the annual meeting of the American Association for the Study of Liver Diseases.

Supplying the human recombinant lysosomal acid lipase, termed sebelipase alfa (SA), to children and adults with LAL-D over a 76-week period resulted in a reduction in alanine aminotransferase (ALT) for 98% of participants, normalization of ALT for 51% of participants, and normalization of aspartate aminotransferase (AST) levels for 65% of patients. Patients on SA also experienced reductions in serum triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), and liver fat and total liver volume. “We’re basically replacing what they’re missing,” senior author Barbara Burton, MD, said in an interview.

[email protected]

On Twitter @karioakes

BOSTON – Lysosomal acid lipase deficiency (LAL-D), a rare genetic cause of marked dyslipidemia that causes early multisystem organ damage, was effectively treated by a human recombinant enzyme to replace deficient lysosomal acid lipase, and the replacement enzyme was well tolerated over a 76-week trial.

LAL-D, when it begins in infancy, is usually fatal within the first year.
 

When LAL-D occurs later in life, it’s believed to be an “underappreciated cause of fibrosis, cirrhosis, severe dyslipidemia, and early-onset atherosclerosis,” according to Katryn Furuya, MD, and the coauthors of a poster presentation given at the annual meeting of the American Association for the Study of Liver Diseases.

Supplying the human recombinant lysosomal acid lipase, termed sebelipase alfa (SA), to children and adults with LAL-D over a 76-week period resulted in a reduction in alanine aminotransferase (ALT) for 98% of participants, normalization of ALT for 51% of participants, and normalization of aspartate aminotransferase (AST) levels for 65% of patients. Patients on SA also experienced reductions in serum triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), and liver fat and total liver volume. “We’re basically replacing what they’re missing,” senior author Barbara Burton, MD, said in an interview.

[email protected]

On Twitter @karioakes

SAN DIEGO—Solanezumab may not have slowed the clinical progression of Alzheimer’s disease, but it provided valuable evidence for the amyloid hypothesis, experts said during a wide-ranging discussion of Eli Lilly and Company’s recent EXPEDITION3 trial.

Lilly representatives and EXPEDITION investigators presented the study’s results at the Ninth Annual Clinical Trials for Alzheimer’s Disease meeting. While solanezumab failed to meet its primary end point, it did achieve significance on several secondary end points—findings that should be read as encouraging, rather than as a defeat, according to Paul Aisen, MD, Director of the Alzheimer’s Therapeutic Research Institute at the University of Southern California, Los Angeles.

“We have here a negative study that confirms a beneficial treatment,” said Dr. Aisen, an EXPEDITION3 investigator. “We have a treatment that engages its target, binds to soluble amyloid, and, by virtue of that mechanism, is slowing cognitive and functional decline,” not only in EXPEDITION3, but in its predecessors, EXPEDITION and EXPEDITION2.

“This is not a refutation of the amyloid hypothesis, but a confirmation of it.”

Nevertheless, the drug failed its trial, he said. There was no statistically significant separation between solanezumab and placebo on the 14-item Alzheimer’s Disease Assessment Scale-Cognitive subscale (ADAS-Cog14), an assessment of cognitive function that was the study’s primary end point. The active treatment group experienced 11% less decline than did the placebo group, but the result was not significant.

If the result had been significant, “it would still be a small effect size,” which would have thrown into question the drug’s clinical utility, Dr. Aisen said. “We thought we might see a 30% slowing of decline on the ADAS-Cog, and it was disappointing to only get 11%. But that is also what we saw on the key [secondary end points]. Overall, the effect size looks to be about 12% to 13%, and that’s just too small.”

Three Phase III Trials

EXPEDITION3 was the last of a triad of solanezumab studies, all of which posted signals of cognitive and functional benefit in patients with mild Alzheimer’s disease. It was based on subgroup analyses of EXPEDITION and EXPEDITION2, both of which failed to meet their primary end points and included patients with mild and moderate disease. When researchers pooled the patients with mild disease from the first two studies, they found that solanezumab was associated with a 34% slowing of cognitive decline on the ADAS-Cog14. Lilly conducted EXPEDITION3 in an attempt to confirm those findings.

Lawrence S. Honig, MD, PhD, Professor of Neurology at Columbia University Medical Center in New York and principal investigator of the EXPEDITION3 study, detailed the study’s results, including biomarker data.

The study included about 2,000 patients with imaging-confirmed amyloid brain plaques and mild dementia due to Alzheimer’s disease. They were randomized to receive placebo or monthly injections of 400 mg of solanezumab for 80 weeks. The study was conducted at 210 sites in 11 countries.

While solanezumab’s effect on the ADAS-Cog was not significant, its effect on the Mini-Mental State Examination score was significant, with a 13% slowing of decline, compared with placebo. There was also a significant 5% difference in the Clinical Dementia Rating scale-Sum of Boxes score.

Outcomes were mixed in measures of function. On the Alzheimer’s Disease Cooperative Study Activities of Daily Living (ADCS-ADL) and its related measure, the ADCS-ADL inventory instrumental items, patients who received solanezumab had significant 15% and 14% differences, respectively, relative to placebo.

But differences on the Functional Activities Questionnaire, an informant measure of more complex activities, were not significant.

Biomarkers trended the right way, Dr. Honig noted. Solanezumab resulted in a 500- to 800-fold increase in amyloid beta in plasma, relative to placebo. There were no changes in amyloid brain plaques, as measured by PET imaging. This finding was not surprising because the antibody does not recognize fibrillar amyloid, Dr. Aisen said.

“What we expect to see with biomarkers differs based on the epitope targeted,” he said. “Solanezumab ignores plaques. It targets the middle of the peptide, binding to soluble amyloid beta. Now, how that helps [treat Alzheimer’s disease] is something of a debate, but it is important to recognize that it does not attack plaques. Instead, by tying up monomeric amyloid beta, it may change the dynamic exchange of various species of amyloid around plaques; the toxicity of amyloid is thought to reside as much in oligomeric species as in the fibrillar deposits. I see this [plasma amyloid beta increase] as confirming that it’s tying up monomeric amyloid species and that the result is a slowing of disease progression. I believe it is supportive of the amyloid hypothesis.”

Solanezumab had no significant effect on tau in CSF or on imaging, nor did it change the progression of ventricular enlargement, a marker of whole brain atrophy.

The antibody was safe, with 17% of patients who received solanezumab reporting an adverse event, compared with 19% of patients who received placebo. There were nine deaths in the solanezumab arm and 16 in the placebo arm; about 4% of each group discontinued treatment because of an adverse event.

In late November 2016, Eric Siemers, MD, Senior Medical Director of the Alzheimer’s Disease Global Development Team at Lilly, said the company would not seek regulatory approval for solanezumab based on the trial results. “We didn’t expect this to be a cure for this disease, but we did hope it would be the first drug to slow its progress.... We are very disappointed,” Dr. Siemers said during the panel discussion.

Further Trials of Solanezumab

He and Dr. Aisen confirmed, however, that two other trials using solanezumab in different populations would go forward. The Anti-Amyloid Treatment in Asymptomatic Alzheimer’s study (A4 study) is investigating its effect in cognitively healthy elderly people with Alzheimer’s disease risk factors, and the Dominantly Inherited Alzheimer’s Network (DIAN) study is investigating its effects in patients with autosomal dominant mutations in Alzheimer’s disease genes.

Dr. Aisen is excited about solanezumab’s potential to target the disease before cognitive symptoms develop. “I expect all antiamyloid treatments would work better when neurodegeneration is not extensive,” he said. “Any of the antiamyloid antibodies would theoretically be more effective at a preclinical stage of Alzheimer’s disease than even in the mild dementia stage.”

Maria Carrillo, PhD, Chief Science Officer of the Alzheimer’s Association, said that EXPEDITION3 was far from a path to nowhere and urged the research community, patients, and families to double down on their commitment to tackling the disease.

“These results stress the urgency for pushing forward harder,” Dr. Carrillo said. “This is not a time to slow down. It’s a time to ramp up our efforts. This is not the time to sit back and say, ‘The amyloid hypothesis has been the wrong pathway, and we need to drop it.’ But we also need to pursue other pathways, to broaden our approach, and to broaden the armamentarium our clinicians will need to combat this disease.

“This is not a win, true. But it gets us a little closer to one.”

—Michele G. Sullivan

SAN DIEGO—Solanezumab may not have slowed the clinical progression of Alzheimer’s disease, but it provided valuable evidence for the amyloid hypothesis, experts said during a wide-ranging discussion of Eli Lilly and Company’s recent EXPEDITION3 trial.

Lilly representatives and EXPEDITION investigators presented the study’s results at the Ninth Annual Clinical Trials for Alzheimer’s Disease meeting. While solanezumab failed to meet its primary end point, it did achieve significance on several secondary end points—findings that should be read as encouraging, rather than as a defeat, according to Paul Aisen, MD, Director of the Alzheimer’s Therapeutic Research Institute at the University of Southern California, Los Angeles.

“We have here a negative study that confirms a beneficial treatment,” said Dr. Aisen, an EXPEDITION3 investigator. “We have a treatment that engages its target, binds to soluble amyloid, and, by virtue of that mechanism, is slowing cognitive and functional decline,” not only in EXPEDITION3, but in its predecessors, EXPEDITION and EXPEDITION2.

“This is not a refutation of the amyloid hypothesis, but a confirmation of it.”

Nevertheless, the drug failed its trial, he said. There was no statistically significant separation between solanezumab and placebo on the 14-item Alzheimer’s Disease Assessment Scale-Cognitive subscale (ADAS-Cog14), an assessment of cognitive function that was the study’s primary end point. The active treatment group experienced 11% less decline than did the placebo group, but the result was not significant.

If the result had been significant, “it would still be a small effect size,” which would have thrown into question the drug’s clinical utility, Dr. Aisen said. “We thought we might see a 30% slowing of decline on the ADAS-Cog, and it was disappointing to only get 11%. But that is also what we saw on the key [secondary end points]. Overall, the effect size looks to be about 12% to 13%, and that’s just too small.”

Three Phase III Trials

EXPEDITION3 was the last of a triad of solanezumab studies, all of which posted signals of cognitive and functional benefit in patients with mild Alzheimer’s disease. It was based on subgroup analyses of EXPEDITION and EXPEDITION2, both of which failed to meet their primary end points and included patients with mild and moderate disease. When researchers pooled the patients with mild disease from the first two studies, they found that solanezumab was associated with a 34% slowing of cognitive decline on the ADAS-Cog14. Lilly conducted EXPEDITION3 in an attempt to confirm those findings.

Lawrence S. Honig, MD, PhD, Professor of Neurology at Columbia University Medical Center in New York and principal investigator of the EXPEDITION3 study, detailed the study’s results, including biomarker data.

The study included about 2,000 patients with imaging-confirmed amyloid brain plaques and mild dementia due to Alzheimer’s disease. They were randomized to receive placebo or monthly injections of 400 mg of solanezumab for 80 weeks. The study was conducted at 210 sites in 11 countries.

While solanezumab’s effect on the ADAS-Cog was not significant, its effect on the Mini-Mental State Examination score was significant, with a 13% slowing of decline, compared with placebo. There was also a significant 5% difference in the Clinical Dementia Rating scale-Sum of Boxes score.

Outcomes were mixed in measures of function. On the Alzheimer’s Disease Cooperative Study Activities of Daily Living (ADCS-ADL) and its related measure, the ADCS-ADL inventory instrumental items, patients who received solanezumab had significant 15% and 14% differences, respectively, relative to placebo.

But differences on the Functional Activities Questionnaire, an informant measure of more complex activities, were not significant.

Biomarkers trended the right way, Dr. Honig noted. Solanezumab resulted in a 500- to 800-fold increase in amyloid beta in plasma, relative to placebo. There were no changes in amyloid brain plaques, as measured by PET imaging. This finding was not surprising because the antibody does not recognize fibrillar amyloid, Dr. Aisen said.

“What we expect to see with biomarkers differs based on the epitope targeted,” he said. “Solanezumab ignores plaques. It targets the middle of the peptide, binding to soluble amyloid beta. Now, how that helps [treat Alzheimer’s disease] is something of a debate, but it is important to recognize that it does not attack plaques. Instead, by tying up monomeric amyloid beta, it may change the dynamic exchange of various species of amyloid around plaques; the toxicity of amyloid is thought to reside as much in oligomeric species as in the fibrillar deposits. I see this [plasma amyloid beta increase] as confirming that it’s tying up monomeric amyloid species and that the result is a slowing of disease progression. I believe it is supportive of the amyloid hypothesis.”

Solanezumab had no significant effect on tau in CSF or on imaging, nor did it change the progression of ventricular enlargement, a marker of whole brain atrophy.

The antibody was safe, with 17% of patients who received solanezumab reporting an adverse event, compared with 19% of patients who received placebo. There were nine deaths in the solanezumab arm and 16 in the placebo arm; about 4% of each group discontinued treatment because of an adverse event.

In late November 2016, Eric Siemers, MD, Senior Medical Director of the Alzheimer’s Disease Global Development Team at Lilly, said the company would not seek regulatory approval for solanezumab based on the trial results. “We didn’t expect this to be a cure for this disease, but we did hope it would be the first drug to slow its progress.... We are very disappointed,” Dr. Siemers said during the panel discussion.

Further Trials of Solanezumab

He and Dr. Aisen confirmed, however, that two other trials using solanezumab in different populations would go forward. The Anti-Amyloid Treatment in Asymptomatic Alzheimer’s study (A4 study) is investigating its effect in cognitively healthy elderly people with Alzheimer’s disease risk factors, and the Dominantly Inherited Alzheimer’s Network (DIAN) study is investigating its effects in patients with autosomal dominant mutations in Alzheimer’s disease genes.

Dr. Aisen is excited about solanezumab’s potential to target the disease before cognitive symptoms develop. “I expect all antiamyloid treatments would work better when neurodegeneration is not extensive,” he said. “Any of the antiamyloid antibodies would theoretically be more effective at a preclinical stage of Alzheimer’s disease than even in the mild dementia stage.”

Maria Carrillo, PhD, Chief Science Officer of the Alzheimer’s Association, said that EXPEDITION3 was far from a path to nowhere and urged the research community, patients, and families to double down on their commitment to tackling the disease.

“These results stress the urgency for pushing forward harder,” Dr. Carrillo said. “This is not a time to slow down. It’s a time to ramp up our efforts. This is not the time to sit back and say, ‘The amyloid hypothesis has been the wrong pathway, and we need to drop it.’ But we also need to pursue other pathways, to broaden our approach, and to broaden the armamentarium our clinicians will need to combat this disease.

“This is not a win, true. But it gets us a little closer to one.”

—Michele G. Sullivan

SAN DIEGO—Solanezumab may not have slowed the clinical progression of Alzheimer’s disease, but it provided valuable evidence for the amyloid hypothesis, experts said during a wide-ranging discussion of Eli Lilly and Company’s recent EXPEDITION3 trial.

Lilly representatives and EXPEDITION investigators presented the study’s results at the Ninth Annual Clinical Trials for Alzheimer’s Disease meeting. While solanezumab failed to meet its primary end point, it did achieve significance on several secondary end points—findings that should be read as encouraging, rather than as a defeat, according to Paul Aisen, MD, Director of the Alzheimer’s Therapeutic Research Institute at the University of Southern California, Los Angeles.

“We have here a negative study that confirms a beneficial treatment,” said Dr. Aisen, an EXPEDITION3 investigator. “We have a treatment that engages its target, binds to soluble amyloid, and, by virtue of that mechanism, is slowing cognitive and functional decline,” not only in EXPEDITION3, but in its predecessors, EXPEDITION and EXPEDITION2.

“This is not a refutation of the amyloid hypothesis, but a confirmation of it.”

Nevertheless, the drug failed its trial, he said. There was no statistically significant separation between solanezumab and placebo on the 14-item Alzheimer’s Disease Assessment Scale-Cognitive subscale (ADAS-Cog14), an assessment of cognitive function that was the study’s primary end point. The active treatment group experienced 11% less decline than did the placebo group, but the result was not significant.

If the result had been significant, “it would still be a small effect size,” which would have thrown into question the drug’s clinical utility, Dr. Aisen said. “We thought we might see a 30% slowing of decline on the ADAS-Cog, and it was disappointing to only get 11%. But that is also what we saw on the key [secondary end points]. Overall, the effect size looks to be about 12% to 13%, and that’s just too small.”

Three Phase III Trials

EXPEDITION3 was the last of a triad of solanezumab studies, all of which posted signals of cognitive and functional benefit in patients with mild Alzheimer’s disease. It was based on subgroup analyses of EXPEDITION and EXPEDITION2, both of which failed to meet their primary end points and included patients with mild and moderate disease. When researchers pooled the patients with mild disease from the first two studies, they found that solanezumab was associated with a 34% slowing of cognitive decline on the ADAS-Cog14. Lilly conducted EXPEDITION3 in an attempt to confirm those findings.

Lawrence S. Honig, MD, PhD, Professor of Neurology at Columbia University Medical Center in New York and principal investigator of the EXPEDITION3 study, detailed the study’s results, including biomarker data.

The study included about 2,000 patients with imaging-confirmed amyloid brain plaques and mild dementia due to Alzheimer’s disease. They were randomized to receive placebo or monthly injections of 400 mg of solanezumab for 80 weeks. The study was conducted at 210 sites in 11 countries.

While solanezumab’s effect on the ADAS-Cog was not significant, its effect on the Mini-Mental State Examination score was significant, with a 13% slowing of decline, compared with placebo. There was also a significant 5% difference in the Clinical Dementia Rating scale-Sum of Boxes score.

Outcomes were mixed in measures of function. On the Alzheimer’s Disease Cooperative Study Activities of Daily Living (ADCS-ADL) and its related measure, the ADCS-ADL inventory instrumental items, patients who received solanezumab had significant 15% and 14% differences, respectively, relative to placebo.

But differences on the Functional Activities Questionnaire, an informant measure of more complex activities, were not significant.

Biomarkers trended the right way, Dr. Honig noted. Solanezumab resulted in a 500- to 800-fold increase in amyloid beta in plasma, relative to placebo. There were no changes in amyloid brain plaques, as measured by PET imaging. This finding was not surprising because the antibody does not recognize fibrillar amyloid, Dr. Aisen said.

“What we expect to see with biomarkers differs based on the epitope targeted,” he said. “Solanezumab ignores plaques. It targets the middle of the peptide, binding to soluble amyloid beta. Now, how that helps [treat Alzheimer’s disease] is something of a debate, but it is important to recognize that it does not attack plaques. Instead, by tying up monomeric amyloid beta, it may change the dynamic exchange of various species of amyloid around plaques; the toxicity of amyloid is thought to reside as much in oligomeric species as in the fibrillar deposits. I see this [plasma amyloid beta increase] as confirming that it’s tying up monomeric amyloid species and that the result is a slowing of disease progression. I believe it is supportive of the amyloid hypothesis.”

Solanezumab had no significant effect on tau in CSF or on imaging, nor did it change the progression of ventricular enlargement, a marker of whole brain atrophy.

The antibody was safe, with 17% of patients who received solanezumab reporting an adverse event, compared with 19% of patients who received placebo. There were nine deaths in the solanezumab arm and 16 in the placebo arm; about 4% of each group discontinued treatment because of an adverse event.

In late November 2016, Eric Siemers, MD, Senior Medical Director of the Alzheimer’s Disease Global Development Team at Lilly, said the company would not seek regulatory approval for solanezumab based on the trial results. “We didn’t expect this to be a cure for this disease, but we did hope it would be the first drug to slow its progress.... We are very disappointed,” Dr. Siemers said during the panel discussion.

Further Trials of Solanezumab

He and Dr. Aisen confirmed, however, that two other trials using solanezumab in different populations would go forward. The Anti-Amyloid Treatment in Asymptomatic Alzheimer’s study (A4 study) is investigating its effect in cognitively healthy elderly people with Alzheimer’s disease risk factors, and the Dominantly Inherited Alzheimer’s Network (DIAN) study is investigating its effects in patients with autosomal dominant mutations in Alzheimer’s disease genes.

Dr. Aisen is excited about solanezumab’s potential to target the disease before cognitive symptoms develop. “I expect all antiamyloid treatments would work better when neurodegeneration is not extensive,” he said. “Any of the antiamyloid antibodies would theoretically be more effective at a preclinical stage of Alzheimer’s disease than even in the mild dementia stage.”

Maria Carrillo, PhD, Chief Science Officer of the Alzheimer’s Association, said that EXPEDITION3 was far from a path to nowhere and urged the research community, patients, and families to double down on their commitment to tackling the disease.

“These results stress the urgency for pushing forward harder,” Dr. Carrillo said. “This is not a time to slow down. It’s a time to ramp up our efforts. This is not the time to sit back and say, ‘The amyloid hypothesis has been the wrong pathway, and we need to drop it.’ But we also need to pursue other pathways, to broaden our approach, and to broaden the armamentarium our clinicians will need to combat this disease.

“This is not a win, true. But it gets us a little closer to one.”

—Michele G. Sullivan

Metastatic Clear Cell Renal Cell Carcinoma

The differential diagnosis of cutaneous neoplasms with clear cells is broad. Clear cell features can be seen in primary tumors arising from the epidermis and cutaneous adnexa as well as in mesenchymal and melanocytic neoplasms. Furthermore, metastatic disease should be considered in the histologic differential diagnosis, as many visceral malignancies have clear cell features. This patient was subsequently found to have a large renal mass with metastasis to the lungs, spleen, and bone. The histologic findings support the diagnosis of metastatic clear cell renal cell carcinoma (RCC) to the skin.

Approximately 30% of patients with clear cell RCC present with metastatic disease with approximately 8% of those involving the skin.^1,2 Cutaneous RCC metastases show a predilection for the head, especially the scalp. The clinical presentation is variable, but there often is a history of a rapidly growing brown, black, or purple nodule or plaque. A thorough review of the patient's history should be conducted if metastatic RCC is in the differential diagnosis, as it has been reported to occur up to 20 years after initial diagnosis.³

Histologically, clear cell RCC (quiz image) is composed of nests of tumor cells with clear cytoplasm and centrally located nuclei with prominent nucleoli. The clear cell features result from abundant cytoplasmic glycogen and lipid but may not be present in every case. One of the most important histologic features is the presence of delicate branching blood vessels (Figure 1). Numerous extravasated red blood cells also may be present. Positive immunohistochemical staining for PAX8, CD10, and RCC antigens support the diagnosis.⁴

Balloon cell nevi (Figure 2) most commonly occur on the head and neck in adolescents and young adults but clinically are indistinguishable from other banal nevi. The nevus cells are large with foamy to finely vacuolated cytoplasm and lack atypia. The clear cell change is the result of melanosome degeneration and may be extensive. The presence of melanin pigment, nests of typical nevus cells, and positive staining with MART-1 can help distinguish the tumor from xanthomas and RCC.⁵

Clear cell hidradenoma (Figure 3) is a well-circumscribed tumor of sweat gland origin that arises in the dermis. The architecture usually is solid, cystic, or a combination of both. The cytology is classically bland with poroid, squamoid, or clear cell morphology. Clear cells that are positive on periodic acid-Schiff staining predominate in up to one-third of cases. Carcinoembryonic antigen and epithelial membrane antigen can be used to highlight the eosinophilic cuticles of ducts within solid areas.⁶

Sebaceous carcinoma (Figure 4) most frequently arises in a periorbital distribution, although extraocular lesions are known to occur. Histologically, there is a proliferation of both mature sebocytes and basaloid cells in the dermis, occasionally involving the epidermis. The mature sebocytes demonstrate clear cell features with foamy to vacuolated cytoplasm and large nuclei with scalloped borders. The clear cells may vary greatly in number and often are sparse in poorly differentiated tumors in which pleomorphic basaloid cells may predominate. The basaloid cells may resemble those of squamous or basal cell carcinoma, leading to a diagnostic dilemma in some cases. Special staining with Sudan black B and oil red O highlights the cytoplasmic lipid but must be performed on frozen section specimens. Although not entirely specific, immunohistochemical expression of epithelial membrane antigen, androgen receptor, and membranous vesicular adipophilin staining in sebaceous carcinoma can assist in the diagnosis.⁷

Cutaneous xanthomas (Figure 5) may arise in patients of any age and represent deposition of lipid-laden macrophages. Classification often is dependent on the clinical presentation; however, some subtypes demonstrate unique morphologic features (eg, verruciform xanthomas). Xanthomas classically arise in association with elevated serum lipids, but they also may occur in normolipemic patients. Individuals with Erdheim-Chester disease have an increased propensity to develop xanthelasma. Similarly, plane xanthomas have been associated with monoclonal gammopathy. Histologically, xanthomas are characterized by sheets of foamy macrophages within the dermis and subcutis. Positive immunohistochemical staining for CD68 highlighting the histiocytic nature of the cells and the absence of a delicate vascular network aid in the differentiation from RCC.

Metastatic Clear Cell Renal Cell Carcinoma

The differential diagnosis of cutaneous neoplasms with clear cells is broad. Clear cell features can be seen in primary tumors arising from the epidermis and cutaneous adnexa as well as in mesenchymal and melanocytic neoplasms. Furthermore, metastatic disease should be considered in the histologic differential diagnosis, as many visceral malignancies have clear cell features. This patient was subsequently found to have a large renal mass with metastasis to the lungs, spleen, and bone. The histologic findings support the diagnosis of metastatic clear cell renal cell carcinoma (RCC) to the skin.

Approximately 30% of patients with clear cell RCC present with metastatic disease with approximately 8% of those involving the skin.^1,2 Cutaneous RCC metastases show a predilection for the head, especially the scalp. The clinical presentation is variable, but there often is a history of a rapidly growing brown, black, or purple nodule or plaque. A thorough review of the patient's history should be conducted if metastatic RCC is in the differential diagnosis, as it has been reported to occur up to 20 years after initial diagnosis.³

Histologically, clear cell RCC (quiz image) is composed of nests of tumor cells with clear cytoplasm and centrally located nuclei with prominent nucleoli. The clear cell features result from abundant cytoplasmic glycogen and lipid but may not be present in every case. One of the most important histologic features is the presence of delicate branching blood vessels (Figure 1). Numerous extravasated red blood cells also may be present. Positive immunohistochemical staining for PAX8, CD10, and RCC antigens support the diagnosis.⁴

Balloon cell nevi (Figure 2) most commonly occur on the head and neck in adolescents and young adults but clinically are indistinguishable from other banal nevi. The nevus cells are large with foamy to finely vacuolated cytoplasm and lack atypia. The clear cell change is the result of melanosome degeneration and may be extensive. The presence of melanin pigment, nests of typical nevus cells, and positive staining with MART-1 can help distinguish the tumor from xanthomas and RCC.⁵

Clear cell hidradenoma (Figure 3) is a well-circumscribed tumor of sweat gland origin that arises in the dermis. The architecture usually is solid, cystic, or a combination of both. The cytology is classically bland with poroid, squamoid, or clear cell morphology. Clear cells that are positive on periodic acid-Schiff staining predominate in up to one-third of cases. Carcinoembryonic antigen and epithelial membrane antigen can be used to highlight the eosinophilic cuticles of ducts within solid areas.⁶

Sebaceous carcinoma (Figure 4) most frequently arises in a periorbital distribution, although extraocular lesions are known to occur. Histologically, there is a proliferation of both mature sebocytes and basaloid cells in the dermis, occasionally involving the epidermis. The mature sebocytes demonstrate clear cell features with foamy to vacuolated cytoplasm and large nuclei with scalloped borders. The clear cells may vary greatly in number and often are sparse in poorly differentiated tumors in which pleomorphic basaloid cells may predominate. The basaloid cells may resemble those of squamous or basal cell carcinoma, leading to a diagnostic dilemma in some cases. Special staining with Sudan black B and oil red O highlights the cytoplasmic lipid but must be performed on frozen section specimens. Although not entirely specific, immunohistochemical expression of epithelial membrane antigen, androgen receptor, and membranous vesicular adipophilin staining in sebaceous carcinoma can assist in the diagnosis.⁷

Cutaneous xanthomas (Figure 5) may arise in patients of any age and represent deposition of lipid-laden macrophages. Classification often is dependent on the clinical presentation; however, some subtypes demonstrate unique morphologic features (eg, verruciform xanthomas). Xanthomas classically arise in association with elevated serum lipids, but they also may occur in normolipemic patients. Individuals with Erdheim-Chester disease have an increased propensity to develop xanthelasma. Similarly, plane xanthomas have been associated with monoclonal gammopathy. Histologically, xanthomas are characterized by sheets of foamy macrophages within the dermis and subcutis. Positive immunohistochemical staining for CD68 highlighting the histiocytic nature of the cells and the absence of a delicate vascular network aid in the differentiation from RCC.

Metastatic Clear Cell Renal Cell Carcinoma

The differential diagnosis of cutaneous neoplasms with clear cells is broad. Clear cell features can be seen in primary tumors arising from the epidermis and cutaneous adnexa as well as in mesenchymal and melanocytic neoplasms. Furthermore, metastatic disease should be considered in the histologic differential diagnosis, as many visceral malignancies have clear cell features. This patient was subsequently found to have a large renal mass with metastasis to the lungs, spleen, and bone. The histologic findings support the diagnosis of metastatic clear cell renal cell carcinoma (RCC) to the skin.

Approximately 30% of patients with clear cell RCC present with metastatic disease with approximately 8% of those involving the skin.^1,2 Cutaneous RCC metastases show a predilection for the head, especially the scalp. The clinical presentation is variable, but there often is a history of a rapidly growing brown, black, or purple nodule or plaque. A thorough review of the patient's history should be conducted if metastatic RCC is in the differential diagnosis, as it has been reported to occur up to 20 years after initial diagnosis.³

Histologically, clear cell RCC (quiz image) is composed of nests of tumor cells with clear cytoplasm and centrally located nuclei with prominent nucleoli. The clear cell features result from abundant cytoplasmic glycogen and lipid but may not be present in every case. One of the most important histologic features is the presence of delicate branching blood vessels (Figure 1). Numerous extravasated red blood cells also may be present. Positive immunohistochemical staining for PAX8, CD10, and RCC antigens support the diagnosis.⁴

Balloon cell nevi (Figure 2) most commonly occur on the head and neck in adolescents and young adults but clinically are indistinguishable from other banal nevi. The nevus cells are large with foamy to finely vacuolated cytoplasm and lack atypia. The clear cell change is the result of melanosome degeneration and may be extensive. The presence of melanin pigment, nests of typical nevus cells, and positive staining with MART-1 can help distinguish the tumor from xanthomas and RCC.⁵

Clear cell hidradenoma (Figure 3) is a well-circumscribed tumor of sweat gland origin that arises in the dermis. The architecture usually is solid, cystic, or a combination of both. The cytology is classically bland with poroid, squamoid, or clear cell morphology. Clear cells that are positive on periodic acid-Schiff staining predominate in up to one-third of cases. Carcinoembryonic antigen and epithelial membrane antigen can be used to highlight the eosinophilic cuticles of ducts within solid areas.⁶

Sebaceous carcinoma (Figure 4) most frequently arises in a periorbital distribution, although extraocular lesions are known to occur. Histologically, there is a proliferation of both mature sebocytes and basaloid cells in the dermis, occasionally involving the epidermis. The mature sebocytes demonstrate clear cell features with foamy to vacuolated cytoplasm and large nuclei with scalloped borders. The clear cells may vary greatly in number and often are sparse in poorly differentiated tumors in which pleomorphic basaloid cells may predominate. The basaloid cells may resemble those of squamous or basal cell carcinoma, leading to a diagnostic dilemma in some cases. Special staining with Sudan black B and oil red O highlights the cytoplasmic lipid but must be performed on frozen section specimens. Although not entirely specific, immunohistochemical expression of epithelial membrane antigen, androgen receptor, and membranous vesicular adipophilin staining in sebaceous carcinoma can assist in the diagnosis.⁷

Cutaneous xanthomas (Figure 5) may arise in patients of any age and represent deposition of lipid-laden macrophages. Classification often is dependent on the clinical presentation; however, some subtypes demonstrate unique morphologic features (eg, verruciform xanthomas). Xanthomas classically arise in association with elevated serum lipids, but they also may occur in normolipemic patients. Individuals with Erdheim-Chester disease have an increased propensity to develop xanthelasma. Similarly, plane xanthomas have been associated with monoclonal gammopathy. Histologically, xanthomas are characterized by sheets of foamy macrophages within the dermis and subcutis. Positive immunohistochemical staining for CD68 highlighting the histiocytic nature of the cells and the absence of a delicate vascular network aid in the differentiation from RCC.

As estrogen levels decline, postmenopausal women commonly experience uncomfortable and distressing symptoms of genital atrophy, or genitourinary syndrome of menopause (GSM). Moreover, aromatase inhibitors (AIs), increasingly used as adjuvant therapy by menopausal breast cancer survivors, contribute to vaginal dryness and sexual pain. This discussion focuses on studies of several local vaginal treatments (including a recently approved agent) that ameliorate GSM symptoms but do not appreciably raise serum sex steroid levels—reassuring data for certain patient populations.

EXPERT COMMENTARY

Andrew M. Kaunitz, MD, is University of Florida Research Foundation Professor and Associate Chairman, Department of Obstetrics and Gynecology, University of Florida College of Medicine–Jacksonville. He is the  Medical  Director  and  Director  of  Menopause  and  Gynecologic  Ultrasound  Services,  UF  Women’s  Health Specialists–Emerson. Dr. Kaunitz serves on the OBG Management Board of Editors.

Dr. Kaunitz reports that in 2015 he served on a contraception advisory board for Pfizer, which markets the low-dose estradiol vaginal ring.

Read expert commentary from Dr. Kaunitz

For women with early-stage breast cancer receiving an AI, is a vaginal estradiol ring or testosterone cream safe for genital atrophy?

Yes, according to results of a randomized, noncomparative short-term trial that found both agents improved vaginal dryness and sexual dysfunction and had little tendency to persistently elevate serum estradiol levels

Melisko ME, Goldman ME, Hwang J, et al. Vaginal testosterone cream vs estradiol vaginal ring for vaginal dryness or decreased libido in women receiving aromatase inhibitors for early-stage breast cancer: a randomized clinical trial [published online ahead of print November 10, 2016]. JAMA Oncol. doi: 10.1001/jamaoncol.2016.3904.

Long-term adjuvant AI therapy, which often causes vaginal dryness and sexual dysfunction, is recommended for postmenopausal women with hormone receptor-positive breast cancer. Although use of a vaginally administered low-dose 3-month estradiol ring as well as compounded testosterone cream is known to improve menopausal genital atrophy and sexual symptoms, little data address these agents' impact on serum estradiol levels in women using AIs.

In a safety evaluation study of these treatments performed at an academic US cancer center, Melisko and colleagues randomly assigned postmenopausal women with hormone receptor-positive breast cancer who reported vaginal dryness, sexual pain, or reduced sexual desire to 12 weeks of off-label treatment with an estradiol vaginal ring or intravaginal testosterone cream.

Related article:
Does extending aromatase-inhibitor use from 5 to 10 years benefit menopausal women with hormone-positive breast cancer?

Details of the study

Among 68 evaluable women (mean age, 56 years), mean baseline estradiol levels were 20 pg/mL (range, <2 to 127 pg/mL); estradiol levels were above the postmenopausal range (>10 pg/mL) in 37% of participants. During the 12-week trial, transient and persistent estradiol levels above this threshold were noted, respectively, in 4 and 0 women treated with the vaginal ring and in 4 and 4 women treated with testosterone cream. Estradiol levels assessed using commercially available (liquid chromatography and mass spectrometry) and research laboratory (radioimmune assay) methodology yielded similar results. In the testosterone cream group, persistent elevations above the normal postmenopausal range were common.

Atrophic vaginal changes, sexual desire, and sexual dysfunction improved in both treatment groups based on gynecologic examinations and sexual quality-of-life questionnaires completed at baseline and week 12.

Read on for Dr. Kaunitz’s comments on a new dyspareunia treatment

What's new for the treatment of dyspareunia associated with GSM?

Intrarosa, a once-daily vaginal insert containing prasterone as the active ingredient, was recently approved for the treatment of moderate to severe dyspareunia, a symptom of vulvar and vaginal atrophy due to menopause

FDA approves Intrarosa for postmenopausal women experiencing pain during sex [news release]. Silver Spring, MD: US Food and Drug Administration; November 17, 2016. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm529641.htm. Accessed December 19, 2017.

Intrarosa [package insert]. Quebec City, Canada: Endoceutics Inc; 2016.

On November 17, 2016, the US Food and Drug Administration (FDA) approved Intrarosa, vaginal dehydroepiandrosterone (DHEA)--also known as prasterone--for women experiencing moderate to severe pain during sexual intercourse due to menopause-related genital atrophy, or GSM. In clinical trials, daily treatment with a 6.5-mg vaginal ovule of DHEA was found effective in reducing symptoms of atrophy. Vaginal discharge was the most common adverse effect.

After menopause, DHEA, which is produced largely by the adrenal glands, represents the dominant source of all sex steroids. DHEA is enzymatically transformed at the intracellular level into estrogens. Because estradiol is inactivated at the site of its synthesis, use of vaginal DHEA causes little if any rise in serum estradiol levels.^1,2

Related article:
2014 Update on Fertility

Details of 2 studies

A pivotal randomized, double-blind, placebo-controlled phase 3 trial of intravaginal DHEA (6.5 mg daily) for treating postmenopausal dyspareunia in women with vulvovaginal atrophy was conducted over 12 weeks.1 The trial included 325 women treated with DHEA and 157 who received placebo.

All 4 coprimary objectives measured improved with treatment compared with mean baseline levels: percentage of parabasal cells in treated participants decreased by 27.7% over placebo (P<.0001); percentage of superficial cells increased by 8.44% over placebo (P<.0001); vaginal pH decreased by 0.66 pH unit over placebo (P<.0001); and pain with sexual activity decreased by 1.42 severity score unit from baseline or 0.36 unit over placebo (P = .0002). In addition, participant-reported moderate to severe vaginal dryness (present in 84% of women at baseline) improved considerably at 12 weeks, and gynecologic evaluation revealed improvements in vaginal secretions, epithelial integrity and surface thickness, and color.1

About 6% of participants reported vaginal discharge as an adverse effect. Levels of serum steroids remained within the normal range for postmenopausal women.¹

Another study, in which authors integrated data from four phase 3 clinical trials of postmenopausal women with vulvovaginal atrophy treated with vaginal DHEA (n = 723)  or placebo (n = 266) for 12 weeks, analyzed serum steroid levels measured at Day 1 and Week 12 by liquid chromatography-tandem mass spectrometry.²

At 12 weeks' treatment, mean levels of the most relevant sex steroid, serum estradiol, was noted to be 3.36 pg/mL, 19% below the normal postmenopausal value of 4.17 pg/mL.The mean level of estrone sulfate was noted to be 209 pg/mL, lower than the normal 220 pg/mL level in postmenopausal women. Further, androsterone glucuronide, the primary metabolite of androgens, also remained well within normal postmenopausal values.²

The authors concluded that the study data demonstrate that a daily 6.5-mg dose of intravaginal DHEA in postmenopausal women achieves the desired local efficacy (ie, amelioration of vulvovaginal atrophy symptoms) without systemic sex steroid exposure.²

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

As estrogen levels decline, postmenopausal women commonly experience uncomfortable and distressing symptoms of genital atrophy, or genitourinary syndrome of menopause (GSM). Moreover, aromatase inhibitors (AIs), increasingly used as adjuvant therapy by menopausal breast cancer survivors, contribute to vaginal dryness and sexual pain. This discussion focuses on studies of several local vaginal treatments (including a recently approved agent) that ameliorate GSM symptoms but do not appreciably raise serum sex steroid levels—reassuring data for certain patient populations.

EXPERT COMMENTARY

Andrew M. Kaunitz, MD, is University of Florida Research Foundation Professor and Associate Chairman, Department of Obstetrics and Gynecology, University of Florida College of Medicine–Jacksonville. He is the  Medical  Director  and  Director  of  Menopause  and  Gynecologic  Ultrasound  Services,  UF  Women’s  Health Specialists–Emerson. Dr. Kaunitz serves on the OBG Management Board of Editors.

Dr. Kaunitz reports that in 2015 he served on a contraception advisory board for Pfizer, which markets the low-dose estradiol vaginal ring.

Read expert commentary from Dr. Kaunitz

For women with early-stage breast cancer receiving an AI, is a vaginal estradiol ring or testosterone cream safe for genital atrophy?

Yes, according to results of a randomized, noncomparative short-term trial that found both agents improved vaginal dryness and sexual dysfunction and had little tendency to persistently elevate serum estradiol levels

Melisko ME, Goldman ME, Hwang J, et al. Vaginal testosterone cream vs estradiol vaginal ring for vaginal dryness or decreased libido in women receiving aromatase inhibitors for early-stage breast cancer: a randomized clinical trial [published online ahead of print November 10, 2016]. JAMA Oncol. doi: 10.1001/jamaoncol.2016.3904.

Long-term adjuvant AI therapy, which often causes vaginal dryness and sexual dysfunction, is recommended for postmenopausal women with hormone receptor-positive breast cancer. Although use of a vaginally administered low-dose 3-month estradiol ring as well as compounded testosterone cream is known to improve menopausal genital atrophy and sexual symptoms, little data address these agents' impact on serum estradiol levels in women using AIs.

In a safety evaluation study of these treatments performed at an academic US cancer center, Melisko and colleagues randomly assigned postmenopausal women with hormone receptor-positive breast cancer who reported vaginal dryness, sexual pain, or reduced sexual desire to 12 weeks of off-label treatment with an estradiol vaginal ring or intravaginal testosterone cream.

Related article:
Does extending aromatase-inhibitor use from 5 to 10 years benefit menopausal women with hormone-positive breast cancer?

Details of the study

Among 68 evaluable women (mean age, 56 years), mean baseline estradiol levels were 20 pg/mL (range, <2 to 127 pg/mL); estradiol levels were above the postmenopausal range (>10 pg/mL) in 37% of participants. During the 12-week trial, transient and persistent estradiol levels above this threshold were noted, respectively, in 4 and 0 women treated with the vaginal ring and in 4 and 4 women treated with testosterone cream. Estradiol levels assessed using commercially available (liquid chromatography and mass spectrometry) and research laboratory (radioimmune assay) methodology yielded similar results. In the testosterone cream group, persistent elevations above the normal postmenopausal range were common.

Atrophic vaginal changes, sexual desire, and sexual dysfunction improved in both treatment groups based on gynecologic examinations and sexual quality-of-life questionnaires completed at baseline and week 12.

Read on for Dr. Kaunitz’s comments on a new dyspareunia treatment

What's new for the treatment of dyspareunia associated with GSM?

Intrarosa, a once-daily vaginal insert containing prasterone as the active ingredient, was recently approved for the treatment of moderate to severe dyspareunia, a symptom of vulvar and vaginal atrophy due to menopause

FDA approves Intrarosa for postmenopausal women experiencing pain during sex [news release]. Silver Spring, MD: US Food and Drug Administration; November 17, 2016. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm529641.htm. Accessed December 19, 2017.

Intrarosa [package insert]. Quebec City, Canada: Endoceutics Inc; 2016.

On November 17, 2016, the US Food and Drug Administration (FDA) approved Intrarosa, vaginal dehydroepiandrosterone (DHEA)--also known as prasterone--for women experiencing moderate to severe pain during sexual intercourse due to menopause-related genital atrophy, or GSM. In clinical trials, daily treatment with a 6.5-mg vaginal ovule of DHEA was found effective in reducing symptoms of atrophy. Vaginal discharge was the most common adverse effect.

After menopause, DHEA, which is produced largely by the adrenal glands, represents the dominant source of all sex steroids. DHEA is enzymatically transformed at the intracellular level into estrogens. Because estradiol is inactivated at the site of its synthesis, use of vaginal DHEA causes little if any rise in serum estradiol levels.^1,2

Related article:
2014 Update on Fertility

Details of 2 studies

A pivotal randomized, double-blind, placebo-controlled phase 3 trial of intravaginal DHEA (6.5 mg daily) for treating postmenopausal dyspareunia in women with vulvovaginal atrophy was conducted over 12 weeks.1 The trial included 325 women treated with DHEA and 157 who received placebo.

All 4 coprimary objectives measured improved with treatment compared with mean baseline levels: percentage of parabasal cells in treated participants decreased by 27.7% over placebo (P<.0001); percentage of superficial cells increased by 8.44% over placebo (P<.0001); vaginal pH decreased by 0.66 pH unit over placebo (P<.0001); and pain with sexual activity decreased by 1.42 severity score unit from baseline or 0.36 unit over placebo (P = .0002). In addition, participant-reported moderate to severe vaginal dryness (present in 84% of women at baseline) improved considerably at 12 weeks, and gynecologic evaluation revealed improvements in vaginal secretions, epithelial integrity and surface thickness, and color.1

About 6% of participants reported vaginal discharge as an adverse effect. Levels of serum steroids remained within the normal range for postmenopausal women.¹

Another study, in which authors integrated data from four phase 3 clinical trials of postmenopausal women with vulvovaginal atrophy treated with vaginal DHEA (n = 723)  or placebo (n = 266) for 12 weeks, analyzed serum steroid levels measured at Day 1 and Week 12 by liquid chromatography-tandem mass spectrometry.²

At 12 weeks' treatment, mean levels of the most relevant sex steroid, serum estradiol, was noted to be 3.36 pg/mL, 19% below the normal postmenopausal value of 4.17 pg/mL.The mean level of estrone sulfate was noted to be 209 pg/mL, lower than the normal 220 pg/mL level in postmenopausal women. Further, androsterone glucuronide, the primary metabolite of androgens, also remained well within normal postmenopausal values.²

The authors concluded that the study data demonstrate that a daily 6.5-mg dose of intravaginal DHEA in postmenopausal women achieves the desired local efficacy (ie, amelioration of vulvovaginal atrophy symptoms) without systemic sex steroid exposure.²

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

As estrogen levels decline, postmenopausal women commonly experience uncomfortable and distressing symptoms of genital atrophy, or genitourinary syndrome of menopause (GSM). Moreover, aromatase inhibitors (AIs), increasingly used as adjuvant therapy by menopausal breast cancer survivors, contribute to vaginal dryness and sexual pain. This discussion focuses on studies of several local vaginal treatments (including a recently approved agent) that ameliorate GSM symptoms but do not appreciably raise serum sex steroid levels—reassuring data for certain patient populations.

EXPERT COMMENTARY

Andrew M. Kaunitz, MD, is University of Florida Research Foundation Professor and Associate Chairman, Department of Obstetrics and Gynecology, University of Florida College of Medicine–Jacksonville. He is the  Medical  Director  and  Director  of  Menopause  and  Gynecologic  Ultrasound  Services,  UF  Women’s  Health Specialists–Emerson. Dr. Kaunitz serves on the OBG Management Board of Editors.

Dr. Kaunitz reports that in 2015 he served on a contraception advisory board for Pfizer, which markets the low-dose estradiol vaginal ring.

Read expert commentary from Dr. Kaunitz

For women with early-stage breast cancer receiving an AI, is a vaginal estradiol ring or testosterone cream safe for genital atrophy?

Yes, according to results of a randomized, noncomparative short-term trial that found both agents improved vaginal dryness and sexual dysfunction and had little tendency to persistently elevate serum estradiol levels

Melisko ME, Goldman ME, Hwang J, et al. Vaginal testosterone cream vs estradiol vaginal ring for vaginal dryness or decreased libido in women receiving aromatase inhibitors for early-stage breast cancer: a randomized clinical trial [published online ahead of print November 10, 2016]. JAMA Oncol. doi: 10.1001/jamaoncol.2016.3904.

Long-term adjuvant AI therapy, which often causes vaginal dryness and sexual dysfunction, is recommended for postmenopausal women with hormone receptor-positive breast cancer. Although use of a vaginally administered low-dose 3-month estradiol ring as well as compounded testosterone cream is known to improve menopausal genital atrophy and sexual symptoms, little data address these agents' impact on serum estradiol levels in women using AIs.

In a safety evaluation study of these treatments performed at an academic US cancer center, Melisko and colleagues randomly assigned postmenopausal women with hormone receptor-positive breast cancer who reported vaginal dryness, sexual pain, or reduced sexual desire to 12 weeks of off-label treatment with an estradiol vaginal ring or intravaginal testosterone cream.

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Does extending aromatase-inhibitor use from 5 to 10 years benefit menopausal women with hormone-positive breast cancer?

Details of the study

Among 68 evaluable women (mean age, 56 years), mean baseline estradiol levels were 20 pg/mL (range, <2 to 127 pg/mL); estradiol levels were above the postmenopausal range (>10 pg/mL) in 37% of participants. During the 12-week trial, transient and persistent estradiol levels above this threshold were noted, respectively, in 4 and 0 women treated with the vaginal ring and in 4 and 4 women treated with testosterone cream. Estradiol levels assessed using commercially available (liquid chromatography and mass spectrometry) and research laboratory (radioimmune assay) methodology yielded similar results. In the testosterone cream group, persistent elevations above the normal postmenopausal range were common.

Atrophic vaginal changes, sexual desire, and sexual dysfunction improved in both treatment groups based on gynecologic examinations and sexual quality-of-life questionnaires completed at baseline and week 12.

Read on for Dr. Kaunitz’s comments on a new dyspareunia treatment

What's new for the treatment of dyspareunia associated with GSM?

Intrarosa, a once-daily vaginal insert containing prasterone as the active ingredient, was recently approved for the treatment of moderate to severe dyspareunia, a symptom of vulvar and vaginal atrophy due to menopause

FDA approves Intrarosa for postmenopausal women experiencing pain during sex [news release]. Silver Spring, MD: US Food and Drug Administration; November 17, 2016. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm529641.htm. Accessed December 19, 2017.

Intrarosa [package insert]. Quebec City, Canada: Endoceutics Inc; 2016.

On November 17, 2016, the US Food and Drug Administration (FDA) approved Intrarosa, vaginal dehydroepiandrosterone (DHEA)--also known as prasterone--for women experiencing moderate to severe pain during sexual intercourse due to menopause-related genital atrophy, or GSM. In clinical trials, daily treatment with a 6.5-mg vaginal ovule of DHEA was found effective in reducing symptoms of atrophy. Vaginal discharge was the most common adverse effect.

After menopause, DHEA, which is produced largely by the adrenal glands, represents the dominant source of all sex steroids. DHEA is enzymatically transformed at the intracellular level into estrogens. Because estradiol is inactivated at the site of its synthesis, use of vaginal DHEA causes little if any rise in serum estradiol levels.^1,2

Related article:
2014 Update on Fertility

Details of 2 studies

A pivotal randomized, double-blind, placebo-controlled phase 3 trial of intravaginal DHEA (6.5 mg daily) for treating postmenopausal dyspareunia in women with vulvovaginal atrophy was conducted over 12 weeks.1 The trial included 325 women treated with DHEA and 157 who received placebo.

All 4 coprimary objectives measured improved with treatment compared with mean baseline levels: percentage of parabasal cells in treated participants decreased by 27.7% over placebo (P<.0001); percentage of superficial cells increased by 8.44% over placebo (P<.0001); vaginal pH decreased by 0.66 pH unit over placebo (P<.0001); and pain with sexual activity decreased by 1.42 severity score unit from baseline or 0.36 unit over placebo (P = .0002). In addition, participant-reported moderate to severe vaginal dryness (present in 84% of women at baseline) improved considerably at 12 weeks, and gynecologic evaluation revealed improvements in vaginal secretions, epithelial integrity and surface thickness, and color.1

About 6% of participants reported vaginal discharge as an adverse effect. Levels of serum steroids remained within the normal range for postmenopausal women.¹

Another study, in which authors integrated data from four phase 3 clinical trials of postmenopausal women with vulvovaginal atrophy treated with vaginal DHEA (n = 723)  or placebo (n = 266) for 12 weeks, analyzed serum steroid levels measured at Day 1 and Week 12 by liquid chromatography-tandem mass spectrometry.²

At 12 weeks' treatment, mean levels of the most relevant sex steroid, serum estradiol, was noted to be 3.36 pg/mL, 19% below the normal postmenopausal value of 4.17 pg/mL.The mean level of estrone sulfate was noted to be 209 pg/mL, lower than the normal 220 pg/mL level in postmenopausal women. Further, androsterone glucuronide, the primary metabolite of androgens, also remained well within normal postmenopausal values.²

The authors concluded that the study data demonstrate that a daily 6.5-mg dose of intravaginal DHEA in postmenopausal women achieves the desired local efficacy (ie, amelioration of vulvovaginal atrophy symptoms) without systemic sex steroid exposure.²

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