Patients with spastic arm paralysis who receive a contralateral C7 nerve graft from their nonparalyzed side to their paralyzed side may have greater improvement in arm function and reduction in spasticity after a year, compared with patients who undergo rehabilitation alone, according to research published January 4 in the New England Journal of Medicine.

The researchers randomly assigned 36 patients who had had unilateral arm paralysis for at least five years to either surgical C7 nerve transfer plus rehabilitation or rehabilitation alone. Participants in the surgery group had an average increase of 17.7 points on the Fugl-Meyer score, while those in the rehabilitation-only group had an average increase of 2.6 points.

To evaluate spasticity, the researchers used the Modified Ashworth Scale, which is scored from 0 to 5. A higher score indicates greater spasticity. Patients who received surgery had improvement from baseline in all five areas measured, and none worsened. The smallest difference between the two groups was in thumb extension. On this measure, 15 surgery patients had a one- or two-unit improvement and three had no change, while seven controls had a one- or two-unit improvement, seven had no improvement, and four had a one-unit worsening. At one year, 16 (89%) patients in the surgery group were able to accomplish three or more of the functional tasks that researchers gave them, whereas none of the controls could do so.

“The majority of clinical improvements coincided with physiologic evidence of connectivity between the hemisphere on the side of the donor nerve and the paralyzed arm,” said lead author Mou-Xiong Zheng, MD, PhD, a hand surgeon at Huashan Hospital at Fudan University in Shanghai, and colleagues.

A Modification to a Previous Surgical Method

Damage to the contralateral cerebral hemisphere after stroke arises from interruption of the inhibitory activity of upper motor neurons. This interruption causes spasticity, along with hand weakness and loss of fractionated fine motor control. In previous studies, researchers have observed activity in the cerebral hemisphere on the same side of paralysis during stroke recovery, but Dr. Zheng and coauthors asserted that connections between the hand and that part of the brain are “sparse,” thus limiting the body’s ability to compensate for spasticity and functional loss.

The latest findings are consistent with those of earlier studies, including one by Dr. Zheng’s coauthors that suggested that the paralyzed hand could be connected to the unaffected hemisphere by transferring a cervical spine nerve from the nonparalyzed side. Researchers previously found this treatment effective for injuries of the brachial plexus. Of the five nerves of the brachial plexus, Dr. Zheng and coauthors chose the C7 nerve because it accounts for about 20% of the nerve fibers in the brachial bundle. Severing the nerve typically results in transient weakness and numbness in the arm or leg on the same side. When they evaluated the hand on the side of the donor graft, the researchers found no significant changes in power, tactile threshold, or two-point discrimination as a result of surgery.

The authors’ surgical approach was a modification of the C7 nerve transfer method that Dr. Zheng and coauthors had previously reported. The operation involved making an incision at the superior aspect of the sternum, mobilizing the donor C7 nerve on the nonparalyzed side, and routing it between the spinal column and esophagus. Then, an anastomosis was performed directly with the C7 nerve on the paralyzed side.

Rehabilitation therapy for the surgery group and controls was identical. Rehabilitation sessions took place four times weekly for 12 months at a single facility, although surgery patients wore an immobilizing cast after their operations.

The nature of the study population (ie, men of various ages with various causes of the underlying cerebral lesions) makes it difficult to draw general conclusions from the findings, Dr. Zheng and coauthors noted. “A larger cohort, followed for a longer period, would be necessary to determine whether cervical nerve transfer results in safe, consistent, and long-term improvements in the function of an arm that is chronically paralyzed as a result of a cerebral lesion,” the authors concluded.

Results Need Clarification

The results that Dr. Zheng and coauthors reported “are exciting, but need clarification and confirmation,” said Robert J. Spinner, MD, Chair of the Department of Neurologic Surgery; Alexander Y. Shin, MD, Consultant in the Department of Orthopedic Surgery; and Allen T. Bishop, MD, Consultant in the Department of Orthopedic Surgery; all at the Mayo Clinic in Rochester, Minnesota, in an accompanying editorial.

Among the questions Dr. Spinner and coauthors raised about the study are whether distal muscles can functionally reinnervate in a year, and whether C7 neurotomy on the paralyzed side led to improvements in spasticity and function. “The C7 neurotomy itself, associated with an immediate reduction in spasticity, represents a major advance for some patients with brain injury who have poor function and spasticity,” they noted. Improvement of the damaged motor cortex, which ongoing physical therapy may enhance, may also contribute to a reduction in spasticity.

Dr. Spinner and coauthors also cited a previous trial by some of Dr. Zheng’s colleagues in which 49% of patients with brachial plexus injury had motor recovery within seven years. “The presence of physiological connectivity observed in the trials does not necessarily equate with functional recovery,” the authors stated.

Future studies of surgical C7 nerve transfer in patients with one-sided arm paralysis should include patients who have C7 neurotomy without nerve transfer, said Dr. Spinner and colleagues. They also noted that because Dr. Zheng and colleagues perform a relatively high volume of these operations, their results might not be easy to reproduce elsewhere.

“Factors other than technical ones, including differences in BMI and limb length across different populations, may lead to different surgical outcomes,” said Dr. Spinner and coauthors. Future research should focus on ways to enhance or speed up nerve regeneration, improve plasticity, and maximize rehabilitation, they added.

—Richard Mark Kirkner

Suggested Reading

Spinner RJ, Shin AY, Bishop AT. Rewiring to regain function in patients with spastic hemiplegia. N Engl J Med. 2018;378(1):83-84.

Zheng MX, Hua XY, Feng JT, et al. Trial of contralateral seventh cervical nerve transfer for spastic arm paralysis. N Engl J Med. 2018;378(1):22-34.

Patients with spastic arm paralysis who receive a contralateral C7 nerve graft from their nonparalyzed side to their paralyzed side may have greater improvement in arm function and reduction in spasticity after a year, compared with patients who undergo rehabilitation alone, according to research published January 4 in the New England Journal of Medicine.

The researchers randomly assigned 36 patients who had had unilateral arm paralysis for at least five years to either surgical C7 nerve transfer plus rehabilitation or rehabilitation alone. Participants in the surgery group had an average increase of 17.7 points on the Fugl-Meyer score, while those in the rehabilitation-only group had an average increase of 2.6 points.

To evaluate spasticity, the researchers used the Modified Ashworth Scale, which is scored from 0 to 5. A higher score indicates greater spasticity. Patients who received surgery had improvement from baseline in all five areas measured, and none worsened. The smallest difference between the two groups was in thumb extension. On this measure, 15 surgery patients had a one- or two-unit improvement and three had no change, while seven controls had a one- or two-unit improvement, seven had no improvement, and four had a one-unit worsening. At one year, 16 (89%) patients in the surgery group were able to accomplish three or more of the functional tasks that researchers gave them, whereas none of the controls could do so.

“The majority of clinical improvements coincided with physiologic evidence of connectivity between the hemisphere on the side of the donor nerve and the paralyzed arm,” said lead author Mou-Xiong Zheng, MD, PhD, a hand surgeon at Huashan Hospital at Fudan University in Shanghai, and colleagues.

A Modification to a Previous Surgical Method

Damage to the contralateral cerebral hemisphere after stroke arises from interruption of the inhibitory activity of upper motor neurons. This interruption causes spasticity, along with hand weakness and loss of fractionated fine motor control. In previous studies, researchers have observed activity in the cerebral hemisphere on the same side of paralysis during stroke recovery, but Dr. Zheng and coauthors asserted that connections between the hand and that part of the brain are “sparse,” thus limiting the body’s ability to compensate for spasticity and functional loss.

The latest findings are consistent with those of earlier studies, including one by Dr. Zheng’s coauthors that suggested that the paralyzed hand could be connected to the unaffected hemisphere by transferring a cervical spine nerve from the nonparalyzed side. Researchers previously found this treatment effective for injuries of the brachial plexus. Of the five nerves of the brachial plexus, Dr. Zheng and coauthors chose the C7 nerve because it accounts for about 20% of the nerve fibers in the brachial bundle. Severing the nerve typically results in transient weakness and numbness in the arm or leg on the same side. When they evaluated the hand on the side of the donor graft, the researchers found no significant changes in power, tactile threshold, or two-point discrimination as a result of surgery.

The authors’ surgical approach was a modification of the C7 nerve transfer method that Dr. Zheng and coauthors had previously reported. The operation involved making an incision at the superior aspect of the sternum, mobilizing the donor C7 nerve on the nonparalyzed side, and routing it between the spinal column and esophagus. Then, an anastomosis was performed directly with the C7 nerve on the paralyzed side.

Rehabilitation therapy for the surgery group and controls was identical. Rehabilitation sessions took place four times weekly for 12 months at a single facility, although surgery patients wore an immobilizing cast after their operations.

The nature of the study population (ie, men of various ages with various causes of the underlying cerebral lesions) makes it difficult to draw general conclusions from the findings, Dr. Zheng and coauthors noted. “A larger cohort, followed for a longer period, would be necessary to determine whether cervical nerve transfer results in safe, consistent, and long-term improvements in the function of an arm that is chronically paralyzed as a result of a cerebral lesion,” the authors concluded.

Results Need Clarification

The results that Dr. Zheng and coauthors reported “are exciting, but need clarification and confirmation,” said Robert J. Spinner, MD, Chair of the Department of Neurologic Surgery; Alexander Y. Shin, MD, Consultant in the Department of Orthopedic Surgery; and Allen T. Bishop, MD, Consultant in the Department of Orthopedic Surgery; all at the Mayo Clinic in Rochester, Minnesota, in an accompanying editorial.

Among the questions Dr. Spinner and coauthors raised about the study are whether distal muscles can functionally reinnervate in a year, and whether C7 neurotomy on the paralyzed side led to improvements in spasticity and function. “The C7 neurotomy itself, associated with an immediate reduction in spasticity, represents a major advance for some patients with brain injury who have poor function and spasticity,” they noted. Improvement of the damaged motor cortex, which ongoing physical therapy may enhance, may also contribute to a reduction in spasticity.

Dr. Spinner and coauthors also cited a previous trial by some of Dr. Zheng’s colleagues in which 49% of patients with brachial plexus injury had motor recovery within seven years. “The presence of physiological connectivity observed in the trials does not necessarily equate with functional recovery,” the authors stated.

Future studies of surgical C7 nerve transfer in patients with one-sided arm paralysis should include patients who have C7 neurotomy without nerve transfer, said Dr. Spinner and colleagues. They also noted that because Dr. Zheng and colleagues perform a relatively high volume of these operations, their results might not be easy to reproduce elsewhere.

“Factors other than technical ones, including differences in BMI and limb length across different populations, may lead to different surgical outcomes,” said Dr. Spinner and coauthors. Future research should focus on ways to enhance or speed up nerve regeneration, improve plasticity, and maximize rehabilitation, they added.

—Richard Mark Kirkner

Suggested Reading

Spinner RJ, Shin AY, Bishop AT. Rewiring to regain function in patients with spastic hemiplegia. N Engl J Med. 2018;378(1):83-84.

Zheng MX, Hua XY, Feng JT, et al. Trial of contralateral seventh cervical nerve transfer for spastic arm paralysis. N Engl J Med. 2018;378(1):22-34.

Patients with spastic arm paralysis who receive a contralateral C7 nerve graft from their nonparalyzed side to their paralyzed side may have greater improvement in arm function and reduction in spasticity after a year, compared with patients who undergo rehabilitation alone, according to research published January 4 in the New England Journal of Medicine.

The researchers randomly assigned 36 patients who had had unilateral arm paralysis for at least five years to either surgical C7 nerve transfer plus rehabilitation or rehabilitation alone. Participants in the surgery group had an average increase of 17.7 points on the Fugl-Meyer score, while those in the rehabilitation-only group had an average increase of 2.6 points.

To evaluate spasticity, the researchers used the Modified Ashworth Scale, which is scored from 0 to 5. A higher score indicates greater spasticity. Patients who received surgery had improvement from baseline in all five areas measured, and none worsened. The smallest difference between the two groups was in thumb extension. On this measure, 15 surgery patients had a one- or two-unit improvement and three had no change, while seven controls had a one- or two-unit improvement, seven had no improvement, and four had a one-unit worsening. At one year, 16 (89%) patients in the surgery group were able to accomplish three or more of the functional tasks that researchers gave them, whereas none of the controls could do so.

“The majority of clinical improvements coincided with physiologic evidence of connectivity between the hemisphere on the side of the donor nerve and the paralyzed arm,” said lead author Mou-Xiong Zheng, MD, PhD, a hand surgeon at Huashan Hospital at Fudan University in Shanghai, and colleagues.

A Modification to a Previous Surgical Method

Damage to the contralateral cerebral hemisphere after stroke arises from interruption of the inhibitory activity of upper motor neurons. This interruption causes spasticity, along with hand weakness and loss of fractionated fine motor control. In previous studies, researchers have observed activity in the cerebral hemisphere on the same side of paralysis during stroke recovery, but Dr. Zheng and coauthors asserted that connections between the hand and that part of the brain are “sparse,” thus limiting the body’s ability to compensate for spasticity and functional loss.

The latest findings are consistent with those of earlier studies, including one by Dr. Zheng’s coauthors that suggested that the paralyzed hand could be connected to the unaffected hemisphere by transferring a cervical spine nerve from the nonparalyzed side. Researchers previously found this treatment effective for injuries of the brachial plexus. Of the five nerves of the brachial plexus, Dr. Zheng and coauthors chose the C7 nerve because it accounts for about 20% of the nerve fibers in the brachial bundle. Severing the nerve typically results in transient weakness and numbness in the arm or leg on the same side. When they evaluated the hand on the side of the donor graft, the researchers found no significant changes in power, tactile threshold, or two-point discrimination as a result of surgery.

The authors’ surgical approach was a modification of the C7 nerve transfer method that Dr. Zheng and coauthors had previously reported. The operation involved making an incision at the superior aspect of the sternum, mobilizing the donor C7 nerve on the nonparalyzed side, and routing it between the spinal column and esophagus. Then, an anastomosis was performed directly with the C7 nerve on the paralyzed side.

Rehabilitation therapy for the surgery group and controls was identical. Rehabilitation sessions took place four times weekly for 12 months at a single facility, although surgery patients wore an immobilizing cast after their operations.

The nature of the study population (ie, men of various ages with various causes of the underlying cerebral lesions) makes it difficult to draw general conclusions from the findings, Dr. Zheng and coauthors noted. “A larger cohort, followed for a longer period, would be necessary to determine whether cervical nerve transfer results in safe, consistent, and long-term improvements in the function of an arm that is chronically paralyzed as a result of a cerebral lesion,” the authors concluded.

Results Need Clarification

The results that Dr. Zheng and coauthors reported “are exciting, but need clarification and confirmation,” said Robert J. Spinner, MD, Chair of the Department of Neurologic Surgery; Alexander Y. Shin, MD, Consultant in the Department of Orthopedic Surgery; and Allen T. Bishop, MD, Consultant in the Department of Orthopedic Surgery; all at the Mayo Clinic in Rochester, Minnesota, in an accompanying editorial.

Among the questions Dr. Spinner and coauthors raised about the study are whether distal muscles can functionally reinnervate in a year, and whether C7 neurotomy on the paralyzed side led to improvements in spasticity and function. “The C7 neurotomy itself, associated with an immediate reduction in spasticity, represents a major advance for some patients with brain injury who have poor function and spasticity,” they noted. Improvement of the damaged motor cortex, which ongoing physical therapy may enhance, may also contribute to a reduction in spasticity.

Dr. Spinner and coauthors also cited a previous trial by some of Dr. Zheng’s colleagues in which 49% of patients with brachial plexus injury had motor recovery within seven years. “The presence of physiological connectivity observed in the trials does not necessarily equate with functional recovery,” the authors stated.

Future studies of surgical C7 nerve transfer in patients with one-sided arm paralysis should include patients who have C7 neurotomy without nerve transfer, said Dr. Spinner and colleagues. They also noted that because Dr. Zheng and colleagues perform a relatively high volume of these operations, their results might not be easy to reproduce elsewhere.

“Factors other than technical ones, including differences in BMI and limb length across different populations, may lead to different surgical outcomes,” said Dr. Spinner and coauthors. Future research should focus on ways to enhance or speed up nerve regeneration, improve plasticity, and maximize rehabilitation, they added.

—Richard Mark Kirkner

Suggested Reading

Spinner RJ, Shin AY, Bishop AT. Rewiring to regain function in patients with spastic hemiplegia. N Engl J Med. 2018;378(1):83-84.

Zheng MX, Hua XY, Feng JT, et al. Trial of contralateral seventh cervical nerve transfer for spastic arm paralysis. N Engl J Med. 2018;378(1):22-34.

TORONTO – The Food and Drug Administration’s standards for demonstrating pharmacokinetic bioequivalence between two inhaled products, which allow for single batch comparisons of approved and generic candidate products, need to be revised to address batch to batch variability, suggested a presenter at the CHEST annual meeting.

Marketing approval of a new generic drug in the United States, including orally inhaled products, generally requires a demonstration of pharmacokinetic bioequivalence to a reference listed product. The standard criterion for statistical bioequivalence applied by the FDA requires the pharmacokinetics of the generic to be within about 10% of the branded product.

In early pharmacokinetic bioequivalence studies, Elise Burmeister Getz, PhD, and her colleagues compared single batches of their generic candidate OT329 Solis 100/50 to single batches of Advair Diskus 100/50 in five individual studies and single batches of Advair Diskus 100/50 to single batches of the same drug. The investigators found greater than 10% differences between some single batches of Advair Diskus 100/50 and some single batches of OT329 Solis 100/50. They also found Advair Diskus 100/50 batches that were more than 30% different from each other.

An FDA response?

Asked what the FDA makes of the batch-to-batch variability data, Dr. Burmeister Getz answered simply, “We don’t know.” Before she and her colleagues ran the 16 batch per product study, they submitted their protocol to the FDA for review, but 1 year later, they still hadn’t heard any response.

“Sponsors are apparently allowed to simply pick their batch in a careful and, dare I say manipulative way, to gain the result they want. With a single batch study the selection of batch will absolutely determine the outcome of the study.”

In vitro bioequivalence studies are already required to use multiple batches, she noted.

This research was funded by Oriel Therapeutics, an indirect wholly-owned subsidiary of Novartis AG.

imnews@frontlinemedcom.com

TORONTO – The Food and Drug Administration’s standards for demonstrating pharmacokinetic bioequivalence between two inhaled products, which allow for single batch comparisons of approved and generic candidate products, need to be revised to address batch to batch variability, suggested a presenter at the CHEST annual meeting.

Marketing approval of a new generic drug in the United States, including orally inhaled products, generally requires a demonstration of pharmacokinetic bioequivalence to a reference listed product. The standard criterion for statistical bioequivalence applied by the FDA requires the pharmacokinetics of the generic to be within about 10% of the branded product.

In early pharmacokinetic bioequivalence studies, Elise Burmeister Getz, PhD, and her colleagues compared single batches of their generic candidate OT329 Solis 100/50 to single batches of Advair Diskus 100/50 in five individual studies and single batches of Advair Diskus 100/50 to single batches of the same drug. The investigators found greater than 10% differences between some single batches of Advair Diskus 100/50 and some single batches of OT329 Solis 100/50. They also found Advair Diskus 100/50 batches that were more than 30% different from each other.

An FDA response?

Asked what the FDA makes of the batch-to-batch variability data, Dr. Burmeister Getz answered simply, “We don’t know.” Before she and her colleagues ran the 16 batch per product study, they submitted their protocol to the FDA for review, but 1 year later, they still hadn’t heard any response.

“Sponsors are apparently allowed to simply pick their batch in a careful and, dare I say manipulative way, to gain the result they want. With a single batch study the selection of batch will absolutely determine the outcome of the study.”

In vitro bioequivalence studies are already required to use multiple batches, she noted.

This research was funded by Oriel Therapeutics, an indirect wholly-owned subsidiary of Novartis AG.

imnews@frontlinemedcom.com

TORONTO – The Food and Drug Administration’s standards for demonstrating pharmacokinetic bioequivalence between two inhaled products, which allow for single batch comparisons of approved and generic candidate products, need to be revised to address batch to batch variability, suggested a presenter at the CHEST annual meeting.

Marketing approval of a new generic drug in the United States, including orally inhaled products, generally requires a demonstration of pharmacokinetic bioequivalence to a reference listed product. The standard criterion for statistical bioequivalence applied by the FDA requires the pharmacokinetics of the generic to be within about 10% of the branded product.

In early pharmacokinetic bioequivalence studies, Elise Burmeister Getz, PhD, and her colleagues compared single batches of their generic candidate OT329 Solis 100/50 to single batches of Advair Diskus 100/50 in five individual studies and single batches of Advair Diskus 100/50 to single batches of the same drug. The investigators found greater than 10% differences between some single batches of Advair Diskus 100/50 and some single batches of OT329 Solis 100/50. They also found Advair Diskus 100/50 batches that were more than 30% different from each other.

An FDA response?

Asked what the FDA makes of the batch-to-batch variability data, Dr. Burmeister Getz answered simply, “We don’t know.” Before she and her colleagues ran the 16 batch per product study, they submitted their protocol to the FDA for review, but 1 year later, they still hadn’t heard any response.

“Sponsors are apparently allowed to simply pick their batch in a careful and, dare I say manipulative way, to gain the result they want. With a single batch study the selection of batch will absolutely determine the outcome of the study.”

In vitro bioequivalence studies are already required to use multiple batches, she noted.

This research was funded by Oriel Therapeutics, an indirect wholly-owned subsidiary of Novartis AG.

imnews@frontlinemedcom.com

Two biomarkers were correlated with poor outcomes for patients with non–small cell lung cancer (NSCLC) who were treated with immune checkpoint inhibitors, according to the results of a multicenter retrospective study.

Furthermore, these two biomarkers – derived neutrophil to lymphocyte ratio (dNLR) and lactate dehydrogenase (LDH) – could make up a lung immune prognostic index (LIPI) to help predict response to immune checkpoint inhibitor therapy, Laura Mezquita, MD, of the Institut Gustave Roussy in Villejuif, France, and her associates reported in JAMA Oncology.

The median overall survival for the population evaluated was 10.1 months (95% CI, 9.0-11.7 months), and the population’s median progression-free survival was 4.0 months (95% confidence interval, 3.4-5.0 months).

Overall survival was independently associated with both a dNLR greater than three (HR, 2.22) and an LDH level greater than the upper limit of normal (HR, 2.51), they reported.

The researchers sought to examine dNLR and LDH after previously reported data had shown that those biomarkers predict immunotherapy response for other types of disease.

“We hypothesized that the combination of baseline dNLR and LDH could be correlated with resistance to ICI [immune checkpoint inhibitor] therapy ... and could be used to develop a long immune prognostic index,” Dr. Mezquita and her associates wrote.

The researchers examined whether, at baseline, patients had a dNLR greater than three or an LDH level greater than the upper limit of normal. They then derived the LIPI by categorizing patients based on whether they met both biomarker criteria (“poor”), only one (“intermediate”), or neither (“good”), and analyzed the results accordingly.

Researchers evaluated 431 patients using the LIPI: 15% of these patients were in the poor group, 48% were in the intermediate group, and 38% were in the good group.

Patients in the poor group experienced worse median overall survival (4.8 months) and progression-free survival (2 months) than did those who had an LIPI considered intermediate (OS, 10 months; PFS, 3.7 months) or good (OS, 16.5 months; PFS, 6.3 months), according to Dr. Mezquita and her associates.

The investigators noted that the retrospective nature of the study and unknown clinical and pathological data may have limited these findings, but they concluded that LIPI with PD-L1 expression ought to be explored in future prospective trials and that LIPI could be used for patient stratification in future randomized trials.

The researchers reported no disclosures.

SOURCE: Mezquita L et al. Jama Oncol. 2018 Jan 11. doi: 10.1001/jamaoncol.2017.4771.

Two biomarkers were correlated with poor outcomes for patients with non–small cell lung cancer (NSCLC) who were treated with immune checkpoint inhibitors, according to the results of a multicenter retrospective study.

Furthermore, these two biomarkers – derived neutrophil to lymphocyte ratio (dNLR) and lactate dehydrogenase (LDH) – could make up a lung immune prognostic index (LIPI) to help predict response to immune checkpoint inhibitor therapy, Laura Mezquita, MD, of the Institut Gustave Roussy in Villejuif, France, and her associates reported in JAMA Oncology.

The median overall survival for the population evaluated was 10.1 months (95% CI, 9.0-11.7 months), and the population’s median progression-free survival was 4.0 months (95% confidence interval, 3.4-5.0 months).

Overall survival was independently associated with both a dNLR greater than three (HR, 2.22) and an LDH level greater than the upper limit of normal (HR, 2.51), they reported.

The researchers sought to examine dNLR and LDH after previously reported data had shown that those biomarkers predict immunotherapy response for other types of disease.

“We hypothesized that the combination of baseline dNLR and LDH could be correlated with resistance to ICI [immune checkpoint inhibitor] therapy ... and could be used to develop a long immune prognostic index,” Dr. Mezquita and her associates wrote.

The researchers examined whether, at baseline, patients had a dNLR greater than three or an LDH level greater than the upper limit of normal. They then derived the LIPI by categorizing patients based on whether they met both biomarker criteria (“poor”), only one (“intermediate”), or neither (“good”), and analyzed the results accordingly.

Researchers evaluated 431 patients using the LIPI: 15% of these patients were in the poor group, 48% were in the intermediate group, and 38% were in the good group.

Patients in the poor group experienced worse median overall survival (4.8 months) and progression-free survival (2 months) than did those who had an LIPI considered intermediate (OS, 10 months; PFS, 3.7 months) or good (OS, 16.5 months; PFS, 6.3 months), according to Dr. Mezquita and her associates.

The investigators noted that the retrospective nature of the study and unknown clinical and pathological data may have limited these findings, but they concluded that LIPI with PD-L1 expression ought to be explored in future prospective trials and that LIPI could be used for patient stratification in future randomized trials.

The researchers reported no disclosures.

SOURCE: Mezquita L et al. Jama Oncol. 2018 Jan 11. doi: 10.1001/jamaoncol.2017.4771.

Two biomarkers were correlated with poor outcomes for patients with non–small cell lung cancer (NSCLC) who were treated with immune checkpoint inhibitors, according to the results of a multicenter retrospective study.

Furthermore, these two biomarkers – derived neutrophil to lymphocyte ratio (dNLR) and lactate dehydrogenase (LDH) – could make up a lung immune prognostic index (LIPI) to help predict response to immune checkpoint inhibitor therapy, Laura Mezquita, MD, of the Institut Gustave Roussy in Villejuif, France, and her associates reported in JAMA Oncology.

The median overall survival for the population evaluated was 10.1 months (95% CI, 9.0-11.7 months), and the population’s median progression-free survival was 4.0 months (95% confidence interval, 3.4-5.0 months).

Overall survival was independently associated with both a dNLR greater than three (HR, 2.22) and an LDH level greater than the upper limit of normal (HR, 2.51), they reported.

The researchers sought to examine dNLR and LDH after previously reported data had shown that those biomarkers predict immunotherapy response for other types of disease.

“We hypothesized that the combination of baseline dNLR and LDH could be correlated with resistance to ICI [immune checkpoint inhibitor] therapy ... and could be used to develop a long immune prognostic index,” Dr. Mezquita and her associates wrote.

The researchers examined whether, at baseline, patients had a dNLR greater than three or an LDH level greater than the upper limit of normal. They then derived the LIPI by categorizing patients based on whether they met both biomarker criteria (“poor”), only one (“intermediate”), or neither (“good”), and analyzed the results accordingly.

Researchers evaluated 431 patients using the LIPI: 15% of these patients were in the poor group, 48% were in the intermediate group, and 38% were in the good group.

Patients in the poor group experienced worse median overall survival (4.8 months) and progression-free survival (2 months) than did those who had an LIPI considered intermediate (OS, 10 months; PFS, 3.7 months) or good (OS, 16.5 months; PFS, 6.3 months), according to Dr. Mezquita and her associates.

The investigators noted that the retrospective nature of the study and unknown clinical and pathological data may have limited these findings, but they concluded that LIPI with PD-L1 expression ought to be explored in future prospective trials and that LIPI could be used for patient stratification in future randomized trials.

The researchers reported no disclosures.

SOURCE: Mezquita L et al. Jama Oncol. 2018 Jan 11. doi: 10.1001/jamaoncol.2017.4771.

The U.S. Preventive Services Task Force issued a draft recommendation that all pregnant women be screened for syphilis infection.

The recommendation, released Feb. 6, follows an evidence review of studies conducted since the task force’s most recent recommendation in 2009, which also called for universal screening of pregnant women.

“Despite consistent recommendations and legal mandates, screening for syphilis in pregnancy continues to be suboptimal in certain populations,” the evidence review noted. The rate of congenital syphilis in the United States nearly doubled from 2012 to 2016.

jarun011/Thinkstock

The U.S. Preventive Services Task Force issued a draft recommendation that all pregnant women be screened for syphilis infection.

The recommendation, released Feb. 6, follows an evidence review of studies conducted since the task force’s most recent recommendation in 2009, which also called for universal screening of pregnant women.

“Despite consistent recommendations and legal mandates, screening for syphilis in pregnancy continues to be suboptimal in certain populations,” the evidence review noted. The rate of congenital syphilis in the United States nearly doubled from 2012 to 2016.

jarun011/Thinkstock

The U.S. Preventive Services Task Force issued a draft recommendation that all pregnant women be screened for syphilis infection.

The recommendation, released Feb. 6, follows an evidence review of studies conducted since the task force’s most recent recommendation in 2009, which also called for universal screening of pregnant women.

“Despite consistent recommendations and legal mandates, screening for syphilis in pregnancy continues to be suboptimal in certain populations,” the evidence review noted. The rate of congenital syphilis in the United States nearly doubled from 2012 to 2016.

jarun011/Thinkstock

LAS VEGAS—Compared with conventional medical management, intrathecal baclofen significantly improves poststroke spasticity, according to research presented at the 21st Annual Meeting of the North American Neuromodulation Society. Intrathecal baclofen also appears to improve functional independence and reduce pain, compared with standard treatment.

“This was the first randomized, controlled trial comparing intrathecal baclofen and conventional medical management in a poststroke patient population,” said Michael J. Creamer, DO, a pain medicine specialist at Central Florida Pain Relief Centers in Orlando. The results may “provide additional options to stroke survivors and their families,” he added.

The SISTERS Trial

The prevalence of poststroke spasticity is estimated to be as high as 43%. Approximately 70% of stroke survivors with spasticity and their caregivers rank spasticity as one of the top three symptoms that affect their lives. Treatments for managing poststroke spasticity include physical therapy, occupational therapy, oral antispasmodic agents, intrathecal baclofen, and botulinum toxin.

Dr. Creamer and colleagues conducted the Spasticity in Stroke Randomized Study (SISTERS) to compare the effect of an intrathecal baclofen pump on poststroke spasticity with that of conventional medical management. The study used the Medtronic SynchroMed II Infusion System to deliver Lioresal Intrathecal (baclofen). The investigators also sought to analyze the pump’s effects on function and pain. They conducted the open-label, phase IV study at 11 centers in Europe and seven in the United States.

Eligible participants had a prior cerebrovascular accident, had substantial upper- and lower-limb spasticity (ie, an Ashworth Scale score of 3 or higher in at least two muscle groups of the lower extremity), had failed prior treatment, and had significant functional limitations. Patients were randomized to an intrathecal baclofen trial or a continuation of oral antispasmodic agents. Patients who successfully completed the baclofen trial underwent pump implantation. Both study groups received physical therapy. At regular visits, investigators measured participants’ spasticity and pain and monitored participants for functional improvements and adverse effects.

The primary outcome was change in Ashworth Scale in the lower extremities from baseline to six months. Secondary outcomes included change in upper-limb spasticity, functional independence, and pain.

Implanted Patients Had More Adverse Events

Dr. Creamer and colleagues randomized 60 patients, and 25 patients underwent intrathecal baclofen pump implantation. A total of 48 patients completed the study, 24 in each treatment arm. Demographic characteristics were similar between groups. The population was predominantly young (mean age, 56) and male (70%). Mean poststroke spasticity duration was approximately four years at enrollment.

Mean reduction in Ashworth Scale score was 0.99 points for patients who received intrathecal baclofen, compared with 0.43 points for those who received conventional medical management. The researchers saw no correlation between catheter tip placement and successful reduction of upper-limb spasticity.

The researchers observed a trend toward improvement in Functional Independence Measure score for patients who underwent pump implantation, but the data did not reach statistical significance.The rate of satisfaction with the pump was high among implanted patients.

In addition, Dr. Creamer and colleagues recorded statistically significant reductions in Numeric Pain Rating Scale scores for actual pain and least pain. Scores for worst pain also improved, but the result was not statistically significant.

The rate of adverse events was higher in the intrathecal baclofen group (96%) than in the conventional medical management group (63%). Adverse events in the former group generally were consistent with the known safety profile of intrathecal baclofen therapy. All serious adverse events related to the drug or device were resolved by the conclusion of the study.

The study’s strengths include its randomized, controlled design and objective spasticity measurements. One limitation, however, is that the sample size was lower than anticipated because of recruitment difficulties. Furthermore, the study was not powered to detect treatment differences for secondary outcomes. Finally, the six-month follow-up period was relatively short, said Dr. Creamer.

—Erik Greb

Suggested Reading

Creamer M, Cloud G, Kossmehl P, et al. Intrathecal baclofen therapy versus conventional medical management for severe poststroke spasticity: results from a multicentre, randomised, controlled, open-label trial (SISTERS). J Neurol Neurosurg Psychiatry. 2018 Jan 11 [Epub ahead of print].

LAS VEGAS—Compared with conventional medical management, intrathecal baclofen significantly improves poststroke spasticity, according to research presented at the 21st Annual Meeting of the North American Neuromodulation Society. Intrathecal baclofen also appears to improve functional independence and reduce pain, compared with standard treatment.

“This was the first randomized, controlled trial comparing intrathecal baclofen and conventional medical management in a poststroke patient population,” said Michael J. Creamer, DO, a pain medicine specialist at Central Florida Pain Relief Centers in Orlando. The results may “provide additional options to stroke survivors and their families,” he added.

The SISTERS Trial

The prevalence of poststroke spasticity is estimated to be as high as 43%. Approximately 70% of stroke survivors with spasticity and their caregivers rank spasticity as one of the top three symptoms that affect their lives. Treatments for managing poststroke spasticity include physical therapy, occupational therapy, oral antispasmodic agents, intrathecal baclofen, and botulinum toxin.

Dr. Creamer and colleagues conducted the Spasticity in Stroke Randomized Study (SISTERS) to compare the effect of an intrathecal baclofen pump on poststroke spasticity with that of conventional medical management. The study used the Medtronic SynchroMed II Infusion System to deliver Lioresal Intrathecal (baclofen). The investigators also sought to analyze the pump’s effects on function and pain. They conducted the open-label, phase IV study at 11 centers in Europe and seven in the United States.

Eligible participants had a prior cerebrovascular accident, had substantial upper- and lower-limb spasticity (ie, an Ashworth Scale score of 3 or higher in at least two muscle groups of the lower extremity), had failed prior treatment, and had significant functional limitations. Patients were randomized to an intrathecal baclofen trial or a continuation of oral antispasmodic agents. Patients who successfully completed the baclofen trial underwent pump implantation. Both study groups received physical therapy. At regular visits, investigators measured participants’ spasticity and pain and monitored participants for functional improvements and adverse effects.

The primary outcome was change in Ashworth Scale in the lower extremities from baseline to six months. Secondary outcomes included change in upper-limb spasticity, functional independence, and pain.

Implanted Patients Had More Adverse Events

Dr. Creamer and colleagues randomized 60 patients, and 25 patients underwent intrathecal baclofen pump implantation. A total of 48 patients completed the study, 24 in each treatment arm. Demographic characteristics were similar between groups. The population was predominantly young (mean age, 56) and male (70%). Mean poststroke spasticity duration was approximately four years at enrollment.

Mean reduction in Ashworth Scale score was 0.99 points for patients who received intrathecal baclofen, compared with 0.43 points for those who received conventional medical management. The researchers saw no correlation between catheter tip placement and successful reduction of upper-limb spasticity.

The researchers observed a trend toward improvement in Functional Independence Measure score for patients who underwent pump implantation, but the data did not reach statistical significance.The rate of satisfaction with the pump was high among implanted patients.

In addition, Dr. Creamer and colleagues recorded statistically significant reductions in Numeric Pain Rating Scale scores for actual pain and least pain. Scores for worst pain also improved, but the result was not statistically significant.

The rate of adverse events was higher in the intrathecal baclofen group (96%) than in the conventional medical management group (63%). Adverse events in the former group generally were consistent with the known safety profile of intrathecal baclofen therapy. All serious adverse events related to the drug or device were resolved by the conclusion of the study.

The study’s strengths include its randomized, controlled design and objective spasticity measurements. One limitation, however, is that the sample size was lower than anticipated because of recruitment difficulties. Furthermore, the study was not powered to detect treatment differences for secondary outcomes. Finally, the six-month follow-up period was relatively short, said Dr. Creamer.

—Erik Greb

Suggested Reading

Creamer M, Cloud G, Kossmehl P, et al. Intrathecal baclofen therapy versus conventional medical management for severe poststroke spasticity: results from a multicentre, randomised, controlled, open-label trial (SISTERS). J Neurol Neurosurg Psychiatry. 2018 Jan 11 [Epub ahead of print].

LAS VEGAS—Compared with conventional medical management, intrathecal baclofen significantly improves poststroke spasticity, according to research presented at the 21st Annual Meeting of the North American Neuromodulation Society. Intrathecal baclofen also appears to improve functional independence and reduce pain, compared with standard treatment.

“This was the first randomized, controlled trial comparing intrathecal baclofen and conventional medical management in a poststroke patient population,” said Michael J. Creamer, DO, a pain medicine specialist at Central Florida Pain Relief Centers in Orlando. The results may “provide additional options to stroke survivors and their families,” he added.

The SISTERS Trial

The prevalence of poststroke spasticity is estimated to be as high as 43%. Approximately 70% of stroke survivors with spasticity and their caregivers rank spasticity as one of the top three symptoms that affect their lives. Treatments for managing poststroke spasticity include physical therapy, occupational therapy, oral antispasmodic agents, intrathecal baclofen, and botulinum toxin.

Dr. Creamer and colleagues conducted the Spasticity in Stroke Randomized Study (SISTERS) to compare the effect of an intrathecal baclofen pump on poststroke spasticity with that of conventional medical management. The study used the Medtronic SynchroMed II Infusion System to deliver Lioresal Intrathecal (baclofen). The investigators also sought to analyze the pump’s effects on function and pain. They conducted the open-label, phase IV study at 11 centers in Europe and seven in the United States.

Eligible participants had a prior cerebrovascular accident, had substantial upper- and lower-limb spasticity (ie, an Ashworth Scale score of 3 or higher in at least two muscle groups of the lower extremity), had failed prior treatment, and had significant functional limitations. Patients were randomized to an intrathecal baclofen trial or a continuation of oral antispasmodic agents. Patients who successfully completed the baclofen trial underwent pump implantation. Both study groups received physical therapy. At regular visits, investigators measured participants’ spasticity and pain and monitored participants for functional improvements and adverse effects.

The primary outcome was change in Ashworth Scale in the lower extremities from baseline to six months. Secondary outcomes included change in upper-limb spasticity, functional independence, and pain.

Implanted Patients Had More Adverse Events

Dr. Creamer and colleagues randomized 60 patients, and 25 patients underwent intrathecal baclofen pump implantation. A total of 48 patients completed the study, 24 in each treatment arm. Demographic characteristics were similar between groups. The population was predominantly young (mean age, 56) and male (70%). Mean poststroke spasticity duration was approximately four years at enrollment.

Mean reduction in Ashworth Scale score was 0.99 points for patients who received intrathecal baclofen, compared with 0.43 points for those who received conventional medical management. The researchers saw no correlation between catheter tip placement and successful reduction of upper-limb spasticity.

The researchers observed a trend toward improvement in Functional Independence Measure score for patients who underwent pump implantation, but the data did not reach statistical significance.The rate of satisfaction with the pump was high among implanted patients.

In addition, Dr. Creamer and colleagues recorded statistically significant reductions in Numeric Pain Rating Scale scores for actual pain and least pain. Scores for worst pain also improved, but the result was not statistically significant.

The rate of adverse events was higher in the intrathecal baclofen group (96%) than in the conventional medical management group (63%). Adverse events in the former group generally were consistent with the known safety profile of intrathecal baclofen therapy. All serious adverse events related to the drug or device were resolved by the conclusion of the study.

The study’s strengths include its randomized, controlled design and objective spasticity measurements. One limitation, however, is that the sample size was lower than anticipated because of recruitment difficulties. Furthermore, the study was not powered to detect treatment differences for secondary outcomes. Finally, the six-month follow-up period was relatively short, said Dr. Creamer.

—Erik Greb

Suggested Reading

Creamer M, Cloud G, Kossmehl P, et al. Intrathecal baclofen therapy versus conventional medical management for severe poststroke spasticity: results from a multicentre, randomised, controlled, open-label trial (SISTERS). J Neurol Neurosurg Psychiatry. 2018 Jan 11 [Epub ahead of print].

High fasting triglyceride levels in midlife are associated with increased risk of amyloid β and tau pathology in the brain 20 years later, according to research published in the January 2 issue of Neurology. Increased levels of medium and large low-density lipoprotein (LDL) subfractions also may be risk factors for amyloid β pathology, said the researchers.

“Even though our results were not robust regarding all amyloid β measures, our findings, together with previous studies, may indicate that triglycerides are associated with early amyloid β accumulation and [that] cholesterol is associated with later stages of the predementia phase of Alzheimer’s disease,” said Katarina Nägga, MD, PhD, Associate Professor of Clinical Memory Research at Lund University in Sweden, and colleagues.

Patients Were Recruited From a Longitudinal Study

In 2016, researchers conducting a cross-sectional study in healthy elderly participants found an association between higher triglyceride levels and amyloid β PET. The following year, two longitudinal studies suggested that an increased number of midlife vascular risk factors and midlife dyslipidemia were associated with brain amyloid deposition, as measured with PET.

Dr. Nägga and colleagues sought to examine the association between midlife lipid levels and brain amyloid 20 years later in people who were asymptomatic at baseline and cognitively normal at follow-up. They also aimed to determine whether lipoprotein subfractions are associated with Alzheimer’s disease pathology.

In 2009, the investigators recruited participants from the longitudinal, population-based Malmö Diet and Cancer Study (MDCS) cardiovascular cohort. In that study, baseline examinations, including fasted triglyceride, cholesterol, and high-density lipoprotein (HDL) measurements, occurred between 1991 and 1994. LDL was calculated using the Friedewald formula. Follow-up took place between 2007 and 2012.

Participants who were eligible for Dr. Nägga’s study were older than 60, had a Mini-Mental State Examination score of 27 points or greater, and were without subjective cognitive impairment. People with a history of transient ischemic attack or stroke, severe neurologic or psychiatric disease, dementia, or mild cognitive impairment were excluded.

The investigators enrolled 361 patients into their study. Participants underwent cognitive testing, brain MRI, and lumbar puncture between 2010 and 2015. Dr. Nägga and colleagues measured brain amyloid β using [¹⁸F] flutemetamol PET in 134 patients. They also examined308 participants for white matter lesions using 3T MRI.

Large HDL Had a Protective Effect

In all, 318 participants were included in the analysis. Mean age was 54 at baseline and 73 at entry into Dr. Nägga’s study. Approximately 60% of participants were women. At follow-up, 23% of the population had an abnormal CSF amyloid β level, and 16% had amyloid and tau pathology.

After adjustments for age, sex, APOE ε4, education, and vascular risk factors, the odds ratio (OR) of abnormal CSF amyloid β was 1.34 among participants with high triglyceride levels at midlife. The OR of an abnormal ratio of amyloid β to phosphorylated tau was 1.46 among participants with high triglyceride levels at midlife.

Furthermore, triglycerides were associated with abnormal amyloid β PET measurements in multivariable regression models, but the association was attenuated in the fully adjusted model. Lipid levels were not associated with white matter lesion volume.

Medium and large LDL were associated with an approximately doubled risk of abnormal amyloid β PET in multivariable regression models. Large HDL decreased the risk of amyloid β pathology by about 75%. Small HDL and very small LDL were not associated with increased risk in the fully adjusted model.

A Possible Basis for Intervention Trials

One potential limitation of the current study is that its participants were healthier than the majority of participants who presented for reexamination in MDCS, said the authors. This difference introduced possible selection bias and might have caused an underestimation of the associations identified. Nevertheless, the sample size of the present study was larger than those of previous studies examining lipids and brain amyloid β.

“If our finding that increased triglyceride levels in midlife lead to an increase in abnormal amyloid β accumulation can be reproduced in larger cohorts, it would be of great interest to initiate intervention trials with triglyceride-lowering therapies in midlife and study potential long-term reductions in amyloid β as the main outcome,” said Dr. Nägga and colleagues. “If such treatments can decrease the risk of developing Alzheimer’s disease pathology, this could lead to significant health improvements for millions of people.”

—Erik Greb

Suggested Reading

Nägga K, Gustavsson AM, Stomrud E, et al. Increased midlife triglycerides predict brain β-amyloid and tau pathology 20 years later. Neurology. 2018;90(1):e73-e81.

High fasting triglyceride levels in midlife are associated with increased risk of amyloid β and tau pathology in the brain 20 years later, according to research published in the January 2 issue of Neurology. Increased levels of medium and large low-density lipoprotein (LDL) subfractions also may be risk factors for amyloid β pathology, said the researchers.

“Even though our results were not robust regarding all amyloid β measures, our findings, together with previous studies, may indicate that triglycerides are associated with early amyloid β accumulation and [that] cholesterol is associated with later stages of the predementia phase of Alzheimer’s disease,” said Katarina Nägga, MD, PhD, Associate Professor of Clinical Memory Research at Lund University in Sweden, and colleagues.

Patients Were Recruited From a Longitudinal Study

In 2016, researchers conducting a cross-sectional study in healthy elderly participants found an association between higher triglyceride levels and amyloid β PET. The following year, two longitudinal studies suggested that an increased number of midlife vascular risk factors and midlife dyslipidemia were associated with brain amyloid deposition, as measured with PET.

Dr. Nägga and colleagues sought to examine the association between midlife lipid levels and brain amyloid 20 years later in people who were asymptomatic at baseline and cognitively normal at follow-up. They also aimed to determine whether lipoprotein subfractions are associated with Alzheimer’s disease pathology.

In 2009, the investigators recruited participants from the longitudinal, population-based Malmö Diet and Cancer Study (MDCS) cardiovascular cohort. In that study, baseline examinations, including fasted triglyceride, cholesterol, and high-density lipoprotein (HDL) measurements, occurred between 1991 and 1994. LDL was calculated using the Friedewald formula. Follow-up took place between 2007 and 2012.

Participants who were eligible for Dr. Nägga’s study were older than 60, had a Mini-Mental State Examination score of 27 points or greater, and were without subjective cognitive impairment. People with a history of transient ischemic attack or stroke, severe neurologic or psychiatric disease, dementia, or mild cognitive impairment were excluded.

The investigators enrolled 361 patients into their study. Participants underwent cognitive testing, brain MRI, and lumbar puncture between 2010 and 2015. Dr. Nägga and colleagues measured brain amyloid β using [¹⁸F] flutemetamol PET in 134 patients. They also examined308 participants for white matter lesions using 3T MRI.

Large HDL Had a Protective Effect

In all, 318 participants were included in the analysis. Mean age was 54 at baseline and 73 at entry into Dr. Nägga’s study. Approximately 60% of participants were women. At follow-up, 23% of the population had an abnormal CSF amyloid β level, and 16% had amyloid and tau pathology.

After adjustments for age, sex, APOE ε4, education, and vascular risk factors, the odds ratio (OR) of abnormal CSF amyloid β was 1.34 among participants with high triglyceride levels at midlife. The OR of an abnormal ratio of amyloid β to phosphorylated tau was 1.46 among participants with high triglyceride levels at midlife.

Furthermore, triglycerides were associated with abnormal amyloid β PET measurements in multivariable regression models, but the association was attenuated in the fully adjusted model. Lipid levels were not associated with white matter lesion volume.

Medium and large LDL were associated with an approximately doubled risk of abnormal amyloid β PET in multivariable regression models. Large HDL decreased the risk of amyloid β pathology by about 75%. Small HDL and very small LDL were not associated with increased risk in the fully adjusted model.

A Possible Basis for Intervention Trials

One potential limitation of the current study is that its participants were healthier than the majority of participants who presented for reexamination in MDCS, said the authors. This difference introduced possible selection bias and might have caused an underestimation of the associations identified. Nevertheless, the sample size of the present study was larger than those of previous studies examining lipids and brain amyloid β.

“If our finding that increased triglyceride levels in midlife lead to an increase in abnormal amyloid β accumulation can be reproduced in larger cohorts, it would be of great interest to initiate intervention trials with triglyceride-lowering therapies in midlife and study potential long-term reductions in amyloid β as the main outcome,” said Dr. Nägga and colleagues. “If such treatments can decrease the risk of developing Alzheimer’s disease pathology, this could lead to significant health improvements for millions of people.”

—Erik Greb

Suggested Reading

Nägga K, Gustavsson AM, Stomrud E, et al. Increased midlife triglycerides predict brain β-amyloid and tau pathology 20 years later. Neurology. 2018;90(1):e73-e81.

High fasting triglyceride levels in midlife are associated with increased risk of amyloid β and tau pathology in the brain 20 years later, according to research published in the January 2 issue of Neurology. Increased levels of medium and large low-density lipoprotein (LDL) subfractions also may be risk factors for amyloid β pathology, said the researchers.

“Even though our results were not robust regarding all amyloid β measures, our findings, together with previous studies, may indicate that triglycerides are associated with early amyloid β accumulation and [that] cholesterol is associated with later stages of the predementia phase of Alzheimer’s disease,” said Katarina Nägga, MD, PhD, Associate Professor of Clinical Memory Research at Lund University in Sweden, and colleagues.

Patients Were Recruited From a Longitudinal Study

In 2016, researchers conducting a cross-sectional study in healthy elderly participants found an association between higher triglyceride levels and amyloid β PET. The following year, two longitudinal studies suggested that an increased number of midlife vascular risk factors and midlife dyslipidemia were associated with brain amyloid deposition, as measured with PET.

Dr. Nägga and colleagues sought to examine the association between midlife lipid levels and brain amyloid 20 years later in people who were asymptomatic at baseline and cognitively normal at follow-up. They also aimed to determine whether lipoprotein subfractions are associated with Alzheimer’s disease pathology.

In 2009, the investigators recruited participants from the longitudinal, population-based Malmö Diet and Cancer Study (MDCS) cardiovascular cohort. In that study, baseline examinations, including fasted triglyceride, cholesterol, and high-density lipoprotein (HDL) measurements, occurred between 1991 and 1994. LDL was calculated using the Friedewald formula. Follow-up took place between 2007 and 2012.

Participants who were eligible for Dr. Nägga’s study were older than 60, had a Mini-Mental State Examination score of 27 points or greater, and were without subjective cognitive impairment. People with a history of transient ischemic attack or stroke, severe neurologic or psychiatric disease, dementia, or mild cognitive impairment were excluded.

The investigators enrolled 361 patients into their study. Participants underwent cognitive testing, brain MRI, and lumbar puncture between 2010 and 2015. Dr. Nägga and colleagues measured brain amyloid β using [¹⁸F] flutemetamol PET in 134 patients. They also examined308 participants for white matter lesions using 3T MRI.

Large HDL Had a Protective Effect

In all, 318 participants were included in the analysis. Mean age was 54 at baseline and 73 at entry into Dr. Nägga’s study. Approximately 60% of participants were women. At follow-up, 23% of the population had an abnormal CSF amyloid β level, and 16% had amyloid and tau pathology.

After adjustments for age, sex, APOE ε4, education, and vascular risk factors, the odds ratio (OR) of abnormal CSF amyloid β was 1.34 among participants with high triglyceride levels at midlife. The OR of an abnormal ratio of amyloid β to phosphorylated tau was 1.46 among participants with high triglyceride levels at midlife.

Furthermore, triglycerides were associated with abnormal amyloid β PET measurements in multivariable regression models, but the association was attenuated in the fully adjusted model. Lipid levels were not associated with white matter lesion volume.

Medium and large LDL were associated with an approximately doubled risk of abnormal amyloid β PET in multivariable regression models. Large HDL decreased the risk of amyloid β pathology by about 75%. Small HDL and very small LDL were not associated with increased risk in the fully adjusted model.

A Possible Basis for Intervention Trials

One potential limitation of the current study is that its participants were healthier than the majority of participants who presented for reexamination in MDCS, said the authors. This difference introduced possible selection bias and might have caused an underestimation of the associations identified. Nevertheless, the sample size of the present study was larger than those of previous studies examining lipids and brain amyloid β.

“If our finding that increased triglyceride levels in midlife lead to an increase in abnormal amyloid β accumulation can be reproduced in larger cohorts, it would be of great interest to initiate intervention trials with triglyceride-lowering therapies in midlife and study potential long-term reductions in amyloid β as the main outcome,” said Dr. Nägga and colleagues. “If such treatments can decrease the risk of developing Alzheimer’s disease pathology, this could lead to significant health improvements for millions of people.”

—Erik Greb

Suggested Reading

Nägga K, Gustavsson AM, Stomrud E, et al. Increased midlife triglycerides predict brain β-amyloid and tau pathology 20 years later. Neurology. 2018;90(1):e73-e81.

The American College of Surgeons (ACS) Clinical Congress is designed to offer a broad range of substantive opportunities for surgeons to interact with colleagues, participate in discussions, and learn about the latest innovations in our profession. The 2017 ACS Clinical Congress met all of these expectations.

The ACS Clinical Congress Report is a collection of news articles and videos from the meeting. This sampling of reportage by ACS Surgery News is meant to convey the essence of the meeting: new ideas, intense debate, and a profound commitment to professional development. We are especially proud to highlight the many substantive presentations by surgical trainees.

We hope this collection of articles will serve as a reminder of what the Clinical Congress is all about. The 2018 ACS Clinical Congress will be held in Boston, Oct. 21-25. Surgeons will be offered another great opportunity hear important presentations and updates, meet with colleagues, and witness firsthand the breaking news and unveiling of discoveries in our field. We hope you are inspired to attend.

Click on the PDF Download link above to read the report!

Karen E. Deveney, MD, FACS
Tyler G. Hughes, MD, FACS
Co-Editors, ACS Surgery News


Therese Borden
Managing Editor, ACS Surgery News

The American College of Surgeons (ACS) Clinical Congress is designed to offer a broad range of substantive opportunities for surgeons to interact with colleagues, participate in discussions, and learn about the latest innovations in our profession. The 2017 ACS Clinical Congress met all of these expectations.

The ACS Clinical Congress Report is a collection of news articles and videos from the meeting. This sampling of reportage by ACS Surgery News is meant to convey the essence of the meeting: new ideas, intense debate, and a profound commitment to professional development. We are especially proud to highlight the many substantive presentations by surgical trainees.

We hope this collection of articles will serve as a reminder of what the Clinical Congress is all about. The 2018 ACS Clinical Congress will be held in Boston, Oct. 21-25. Surgeons will be offered another great opportunity hear important presentations and updates, meet with colleagues, and witness firsthand the breaking news and unveiling of discoveries in our field. We hope you are inspired to attend.

Click on the PDF Download link above to read the report!

Karen E. Deveney, MD, FACS
Tyler G. Hughes, MD, FACS
Co-Editors, ACS Surgery News


Therese Borden
Managing Editor, ACS Surgery News

The American College of Surgeons (ACS) Clinical Congress is designed to offer a broad range of substantive opportunities for surgeons to interact with colleagues, participate in discussions, and learn about the latest innovations in our profession. The 2017 ACS Clinical Congress met all of these expectations.

The ACS Clinical Congress Report is a collection of news articles and videos from the meeting. This sampling of reportage by ACS Surgery News is meant to convey the essence of the meeting: new ideas, intense debate, and a profound commitment to professional development. We are especially proud to highlight the many substantive presentations by surgical trainees.

We hope this collection of articles will serve as a reminder of what the Clinical Congress is all about. The 2018 ACS Clinical Congress will be held in Boston, Oct. 21-25. Surgeons will be offered another great opportunity hear important presentations and updates, meet with colleagues, and witness firsthand the breaking news and unveiling of discoveries in our field. We hope you are inspired to attend.

Click on the PDF Download link above to read the report!

Karen E. Deveney, MD, FACS
Tyler G. Hughes, MD, FACS
Co-Editors, ACS Surgery News


Therese Borden
Managing Editor, ACS Surgery News

Most cognitively normal adults with elevated brain amyloid in an Alzheimer’s disease prevention trial “understood that elevated amyloid conferred an increased but uncertain risk of developing Alzheimer’s disease,” according to research published in the January issue of JAMA Neurology. Some participants, however, “desired clarification of the term ‘elevated’ beyond its being a categorical result enabling trial entry eligibility.”

“Clinicians should be prepared to explain how and why a dimensional biomarker, in this case amyloid-β as measured using PET, is converted to a categorical state … and what the result means in terms of a person’s risk for developing Alzheimer disease dementia,” the researchers said.

Trials in Asymptomatic Populations

Advances in understanding the pathophysiology of Alzheimer’s disease have led to clinical trials in cognitively normal adults with evidence of Alzheimer’s disease biomarkers, but data are limited regarding how cognitively normal adults, comprehend biomarker results. A person’s knowledge of his or her amyloid status “may generate clinical and ethical problems, including the potential for misunderstanding, discrimination, stigma, depression, anxiety, and, in the most extreme cases, suicide in the face of a debilitating disease with no treatment,” the researchers said. “There is no consensus … about whether and how to return Alzheimer’s disease biomarker results to cognitively normal adults, given the prognostic uncertainty and absence of available treatments.”

To determine participants’ comprehension of an elevated amyloid PET biomarker result, Jessica Mozersky, PhD, of the Department of Medical Ethics and Health Policy at Perelman School of Medicine, University of Pennsylvania in Philadelphia, and colleagues conducted the Study of Knowledge and Reactions to Amyloid Testing (SOKRATES).

The A4 Study and SOKRATES

SOKRATES is a substudy of the Anti-Amyloid Treatment in Asymptomatic Alzheimer (A4) study, which is testing whether solanezumab, compared with placebo, affects the rate of cognitive decline in cognitively normal adults with elevated amyloid.

Clinicians informed all A4 study participants of their amyloid PET scan result through a disclosure process that was designed to maximize safety and effectiveness. The process included a depression and anxiety prescreen, an educational session, a teach-back exercise to check comprehension, an in-person disclosure by a trained clinician, and a telephone follow-up to assess mood. In addition, a study guide provided information about the amyloid PET scan, its purpose, possible results, and limitations. “The study guide describes ‘preclinical’ or ‘asymptomatic’ Alzheimer’s disease as a new concept in development and explains that elevated amyloid ‘does not necessarily mean you will develop Alzheimer’s disease-related memory loss’ but can be associated with an increased risk, and individual risk estimates are not possible. It further explains that ‘not elevated’ does not mean you will never develop Alzheimer’s disease or ‘elevated amyloid’ in the future,” the researchers said.

A4 trial sites provided participants with materials describing the SOKRATES substudy, and interested participants contacted the SOKRATES researchers at the University of Pennsylvania.

The researchers examined comprehension of an elevated amyloid PET scan result by analyzing participants’ responses to the following questions: “What was the result of your amyloid PET scan?” (followed by “Can you tell me in your own words what that means?” or “How would you explain it to a friend?”), “Was it the result you expected?” and “Did the result teach you anything or clarify anything for you?”

Understanding Risk

When asked, “What was your result,” 64% used the word “amyloid” or “amyloids,” and the remaining participants primarily referred to the presence of “plaques” or to the result being “positive.” Two answers suggested misunderstanding. Six participants used the word “elevated” to describe their amyloid result, while most participants used other words (eg, “increased,” “higher levels,” or “excessive”). Nineteen participants described the result in terms of qualifying for the A4 study (eg, “enough amyloid buildup to qualify for the study”).

More than half of the participants (54%) expected their elevated result due to a family history of Alzheimer’s disease or subjective memory problems. Fifteen participants (30%) were unsure what result they had expected or were prepared for either result. Eight participants (16%) expected not to have elevated amyloid because they had led a healthy lifestyle, had no family history of Alzheimer’s disease, and had no subjective memory concerns.

When asked about the meaning of the result, 94% responded with their understanding of the risk of developing Alzheimer’s disease conferred by elevated amyloid. Thirty-one participants (62%) interpreted the result as signaling an increased risk of developing Alzheimer’s disease, while 10 participants (20%) perceived the risk conferred by elevated amyloid to be equivocal. Six participants (12%) perceived elevated amyloid to mean that Alzheimer’s disease was imminent or that it was diagnostic of Alzheimer’s disease.

Twenty participants (40%) were dissatisfied “with the lack of specificity regarding the meaning of ‘elevated,’” the researchers said. Some wanted “a granular result describing the degree of amyloid elevation … and how close they were to the threshold for study entry,” and some participants expressed frustration at the lack of detail.

Implications

The results suggest that some people who are cognitively normal but have subjective memory concerns “will use an Alzheimer’s disease biomarker test to explain their memory concerns, potentially pathologizing normal and nondisease-related cognitive aging,” the researchers said. In addition, people without a family history of Alzheimer’s disease or subjective memory concerns “may be unprepared to receive their biomarker results.”

A desire for more specific and detailed information about the results may be especially relevant to cognitively normal adults. “Such specific information is likely less relevant for symptomatic individuals who receive a binary result that either confirms or rules out a diagnosis that explains their history of cognitive decline,” the researchers said.

Because most participants were highly educated and had a family history of Alzheimer’s disease, the applicability of the results to other populations is limited. In future studies, the researchers plan to assess how elevated versus not-elevated brain amyloid results influenced SOKRATES participants’ sense of self, social relationships, and behaviors.

Potential Interventions and Ethical Concerns

The long prodromal period of Alzheimer’s disease “represents our greatest hope for effective therapeutic intervention as well as a domain of serious ethical concern,” said Winston Chiong, MD, PhD, of the Memory and Aging Center, Weill Institute for Neurosciences, University of California, San Francisco, in an accompanying editorial. “Prevailing appropriate use criteria advise against clinical use of amyloid imaging in asymptomatic individuals, citing ‘a significant potential for patients and families to make inaccurate assumptions about risk and future outcomes on the basis of amyloid PET results.’” The A4 trial, however, “not only requires that amyloid imaging be performed but also effectively requires that the results of such imaging be disclosed to participants.”

Qualitative research may elicit unanticipated beliefs or concerns, and in SOKRATES, “a sizable proportion of participants … expressed dissatisfaction with the categorical characterization of results.”

“Overall, the findings of Mozersky and colleagues are broadly reassuring regarding research participants’ ability to understand the prognostic uncertainty of amyloid imaging. But as the authors note, caution is needed in generalizing their results,” Dr. Chiong said. “These participants represent a selected subpopulation of an already rarified group: prospective participants in the A4 study were provided with study materials for this substudy, and interested participants themselves contacted the study investigators. These participants were thus likely to be particularly supportive of the Alzheimer’s disease research enterprise, and given their family histories and high educational attainment may have been better positioned to interpret information about the limitations and ambiguities of testing than other groups.”

Suggested Reading

Chiong W. Challenges in communicating and understanding predictive biomarker imaging for Alzheimer disease. JAMA Neurol. 2018;75(1):18-19.

Mozersky J, Sankar P, Harkins K, et al. Comprehension of an elevated amyloid positron emission tomography biomarker result by cognitively normal older adults. JAMA Neurol. 2018;75(1):44-50.

Most cognitively normal adults with elevated brain amyloid in an Alzheimer’s disease prevention trial “understood that elevated amyloid conferred an increased but uncertain risk of developing Alzheimer’s disease,” according to research published in the January issue of JAMA Neurology. Some participants, however, “desired clarification of the term ‘elevated’ beyond its being a categorical result enabling trial entry eligibility.”

“Clinicians should be prepared to explain how and why a dimensional biomarker, in this case amyloid-β as measured using PET, is converted to a categorical state … and what the result means in terms of a person’s risk for developing Alzheimer disease dementia,” the researchers said.

Trials in Asymptomatic Populations

Advances in understanding the pathophysiology of Alzheimer’s disease have led to clinical trials in cognitively normal adults with evidence of Alzheimer’s disease biomarkers, but data are limited regarding how cognitively normal adults, comprehend biomarker results. A person’s knowledge of his or her amyloid status “may generate clinical and ethical problems, including the potential for misunderstanding, discrimination, stigma, depression, anxiety, and, in the most extreme cases, suicide in the face of a debilitating disease with no treatment,” the researchers said. “There is no consensus … about whether and how to return Alzheimer’s disease biomarker results to cognitively normal adults, given the prognostic uncertainty and absence of available treatments.”

To determine participants’ comprehension of an elevated amyloid PET biomarker result, Jessica Mozersky, PhD, of the Department of Medical Ethics and Health Policy at Perelman School of Medicine, University of Pennsylvania in Philadelphia, and colleagues conducted the Study of Knowledge and Reactions to Amyloid Testing (SOKRATES).

The A4 Study and SOKRATES

SOKRATES is a substudy of the Anti-Amyloid Treatment in Asymptomatic Alzheimer (A4) study, which is testing whether solanezumab, compared with placebo, affects the rate of cognitive decline in cognitively normal adults with elevated amyloid.

Clinicians informed all A4 study participants of their amyloid PET scan result through a disclosure process that was designed to maximize safety and effectiveness. The process included a depression and anxiety prescreen, an educational session, a teach-back exercise to check comprehension, an in-person disclosure by a trained clinician, and a telephone follow-up to assess mood. In addition, a study guide provided information about the amyloid PET scan, its purpose, possible results, and limitations. “The study guide describes ‘preclinical’ or ‘asymptomatic’ Alzheimer’s disease as a new concept in development and explains that elevated amyloid ‘does not necessarily mean you will develop Alzheimer’s disease-related memory loss’ but can be associated with an increased risk, and individual risk estimates are not possible. It further explains that ‘not elevated’ does not mean you will never develop Alzheimer’s disease or ‘elevated amyloid’ in the future,” the researchers said.

A4 trial sites provided participants with materials describing the SOKRATES substudy, and interested participants contacted the SOKRATES researchers at the University of Pennsylvania.

The researchers examined comprehension of an elevated amyloid PET scan result by analyzing participants’ responses to the following questions: “What was the result of your amyloid PET scan?” (followed by “Can you tell me in your own words what that means?” or “How would you explain it to a friend?”), “Was it the result you expected?” and “Did the result teach you anything or clarify anything for you?”

Understanding Risk

When asked, “What was your result,” 64% used the word “amyloid” or “amyloids,” and the remaining participants primarily referred to the presence of “plaques” or to the result being “positive.” Two answers suggested misunderstanding. Six participants used the word “elevated” to describe their amyloid result, while most participants used other words (eg, “increased,” “higher levels,” or “excessive”). Nineteen participants described the result in terms of qualifying for the A4 study (eg, “enough amyloid buildup to qualify for the study”).

More than half of the participants (54%) expected their elevated result due to a family history of Alzheimer’s disease or subjective memory problems. Fifteen participants (30%) were unsure what result they had expected or were prepared for either result. Eight participants (16%) expected not to have elevated amyloid because they had led a healthy lifestyle, had no family history of Alzheimer’s disease, and had no subjective memory concerns.

When asked about the meaning of the result, 94% responded with their understanding of the risk of developing Alzheimer’s disease conferred by elevated amyloid. Thirty-one participants (62%) interpreted the result as signaling an increased risk of developing Alzheimer’s disease, while 10 participants (20%) perceived the risk conferred by elevated amyloid to be equivocal. Six participants (12%) perceived elevated amyloid to mean that Alzheimer’s disease was imminent or that it was diagnostic of Alzheimer’s disease.

Twenty participants (40%) were dissatisfied “with the lack of specificity regarding the meaning of ‘elevated,’” the researchers said. Some wanted “a granular result describing the degree of amyloid elevation … and how close they were to the threshold for study entry,” and some participants expressed frustration at the lack of detail.

Implications

The results suggest that some people who are cognitively normal but have subjective memory concerns “will use an Alzheimer’s disease biomarker test to explain their memory concerns, potentially pathologizing normal and nondisease-related cognitive aging,” the researchers said. In addition, people without a family history of Alzheimer’s disease or subjective memory concerns “may be unprepared to receive their biomarker results.”

A desire for more specific and detailed information about the results may be especially relevant to cognitively normal adults. “Such specific information is likely less relevant for symptomatic individuals who receive a binary result that either confirms or rules out a diagnosis that explains their history of cognitive decline,” the researchers said.

Because most participants were highly educated and had a family history of Alzheimer’s disease, the applicability of the results to other populations is limited. In future studies, the researchers plan to assess how elevated versus not-elevated brain amyloid results influenced SOKRATES participants’ sense of self, social relationships, and behaviors.

Potential Interventions and Ethical Concerns

The long prodromal period of Alzheimer’s disease “represents our greatest hope for effective therapeutic intervention as well as a domain of serious ethical concern,” said Winston Chiong, MD, PhD, of the Memory and Aging Center, Weill Institute for Neurosciences, University of California, San Francisco, in an accompanying editorial. “Prevailing appropriate use criteria advise against clinical use of amyloid imaging in asymptomatic individuals, citing ‘a significant potential for patients and families to make inaccurate assumptions about risk and future outcomes on the basis of amyloid PET results.’” The A4 trial, however, “not only requires that amyloid imaging be performed but also effectively requires that the results of such imaging be disclosed to participants.”

Qualitative research may elicit unanticipated beliefs or concerns, and in SOKRATES, “a sizable proportion of participants … expressed dissatisfaction with the categorical characterization of results.”

“Overall, the findings of Mozersky and colleagues are broadly reassuring regarding research participants’ ability to understand the prognostic uncertainty of amyloid imaging. But as the authors note, caution is needed in generalizing their results,” Dr. Chiong said. “These participants represent a selected subpopulation of an already rarified group: prospective participants in the A4 study were provided with study materials for this substudy, and interested participants themselves contacted the study investigators. These participants were thus likely to be particularly supportive of the Alzheimer’s disease research enterprise, and given their family histories and high educational attainment may have been better positioned to interpret information about the limitations and ambiguities of testing than other groups.”

Suggested Reading

Chiong W. Challenges in communicating and understanding predictive biomarker imaging for Alzheimer disease. JAMA Neurol. 2018;75(1):18-19.

Mozersky J, Sankar P, Harkins K, et al. Comprehension of an elevated amyloid positron emission tomography biomarker result by cognitively normal older adults. JAMA Neurol. 2018;75(1):44-50.

Most cognitively normal adults with elevated brain amyloid in an Alzheimer’s disease prevention trial “understood that elevated amyloid conferred an increased but uncertain risk of developing Alzheimer’s disease,” according to research published in the January issue of JAMA Neurology. Some participants, however, “desired clarification of the term ‘elevated’ beyond its being a categorical result enabling trial entry eligibility.”

“Clinicians should be prepared to explain how and why a dimensional biomarker, in this case amyloid-β as measured using PET, is converted to a categorical state … and what the result means in terms of a person’s risk for developing Alzheimer disease dementia,” the researchers said.

Trials in Asymptomatic Populations

Advances in understanding the pathophysiology of Alzheimer’s disease have led to clinical trials in cognitively normal adults with evidence of Alzheimer’s disease biomarkers, but data are limited regarding how cognitively normal adults, comprehend biomarker results. A person’s knowledge of his or her amyloid status “may generate clinical and ethical problems, including the potential for misunderstanding, discrimination, stigma, depression, anxiety, and, in the most extreme cases, suicide in the face of a debilitating disease with no treatment,” the researchers said. “There is no consensus … about whether and how to return Alzheimer’s disease biomarker results to cognitively normal adults, given the prognostic uncertainty and absence of available treatments.”

To determine participants’ comprehension of an elevated amyloid PET biomarker result, Jessica Mozersky, PhD, of the Department of Medical Ethics and Health Policy at Perelman School of Medicine, University of Pennsylvania in Philadelphia, and colleagues conducted the Study of Knowledge and Reactions to Amyloid Testing (SOKRATES).

The A4 Study and SOKRATES

SOKRATES is a substudy of the Anti-Amyloid Treatment in Asymptomatic Alzheimer (A4) study, which is testing whether solanezumab, compared with placebo, affects the rate of cognitive decline in cognitively normal adults with elevated amyloid.

Clinicians informed all A4 study participants of their amyloid PET scan result through a disclosure process that was designed to maximize safety and effectiveness. The process included a depression and anxiety prescreen, an educational session, a teach-back exercise to check comprehension, an in-person disclosure by a trained clinician, and a telephone follow-up to assess mood. In addition, a study guide provided information about the amyloid PET scan, its purpose, possible results, and limitations. “The study guide describes ‘preclinical’ or ‘asymptomatic’ Alzheimer’s disease as a new concept in development and explains that elevated amyloid ‘does not necessarily mean you will develop Alzheimer’s disease-related memory loss’ but can be associated with an increased risk, and individual risk estimates are not possible. It further explains that ‘not elevated’ does not mean you will never develop Alzheimer’s disease or ‘elevated amyloid’ in the future,” the researchers said.

A4 trial sites provided participants with materials describing the SOKRATES substudy, and interested participants contacted the SOKRATES researchers at the University of Pennsylvania.

The researchers examined comprehension of an elevated amyloid PET scan result by analyzing participants’ responses to the following questions: “What was the result of your amyloid PET scan?” (followed by “Can you tell me in your own words what that means?” or “How would you explain it to a friend?”), “Was it the result you expected?” and “Did the result teach you anything or clarify anything for you?”

Understanding Risk

When asked, “What was your result,” 64% used the word “amyloid” or “amyloids,” and the remaining participants primarily referred to the presence of “plaques” or to the result being “positive.” Two answers suggested misunderstanding. Six participants used the word “elevated” to describe their amyloid result, while most participants used other words (eg, “increased,” “higher levels,” or “excessive”). Nineteen participants described the result in terms of qualifying for the A4 study (eg, “enough amyloid buildup to qualify for the study”).

More than half of the participants (54%) expected their elevated result due to a family history of Alzheimer’s disease or subjective memory problems. Fifteen participants (30%) were unsure what result they had expected or were prepared for either result. Eight participants (16%) expected not to have elevated amyloid because they had led a healthy lifestyle, had no family history of Alzheimer’s disease, and had no subjective memory concerns.

When asked about the meaning of the result, 94% responded with their understanding of the risk of developing Alzheimer’s disease conferred by elevated amyloid. Thirty-one participants (62%) interpreted the result as signaling an increased risk of developing Alzheimer’s disease, while 10 participants (20%) perceived the risk conferred by elevated amyloid to be equivocal. Six participants (12%) perceived elevated amyloid to mean that Alzheimer’s disease was imminent or that it was diagnostic of Alzheimer’s disease.

Twenty participants (40%) were dissatisfied “with the lack of specificity regarding the meaning of ‘elevated,’” the researchers said. Some wanted “a granular result describing the degree of amyloid elevation … and how close they were to the threshold for study entry,” and some participants expressed frustration at the lack of detail.

Implications

The results suggest that some people who are cognitively normal but have subjective memory concerns “will use an Alzheimer’s disease biomarker test to explain their memory concerns, potentially pathologizing normal and nondisease-related cognitive aging,” the researchers said. In addition, people without a family history of Alzheimer’s disease or subjective memory concerns “may be unprepared to receive their biomarker results.”

A desire for more specific and detailed information about the results may be especially relevant to cognitively normal adults. “Such specific information is likely less relevant for symptomatic individuals who receive a binary result that either confirms or rules out a diagnosis that explains their history of cognitive decline,” the researchers said.

Because most participants were highly educated and had a family history of Alzheimer’s disease, the applicability of the results to other populations is limited. In future studies, the researchers plan to assess how elevated versus not-elevated brain amyloid results influenced SOKRATES participants’ sense of self, social relationships, and behaviors.

Potential Interventions and Ethical Concerns

The long prodromal period of Alzheimer’s disease “represents our greatest hope for effective therapeutic intervention as well as a domain of serious ethical concern,” said Winston Chiong, MD, PhD, of the Memory and Aging Center, Weill Institute for Neurosciences, University of California, San Francisco, in an accompanying editorial. “Prevailing appropriate use criteria advise against clinical use of amyloid imaging in asymptomatic individuals, citing ‘a significant potential for patients and families to make inaccurate assumptions about risk and future outcomes on the basis of amyloid PET results.’” The A4 trial, however, “not only requires that amyloid imaging be performed but also effectively requires that the results of such imaging be disclosed to participants.”

Qualitative research may elicit unanticipated beliefs or concerns, and in SOKRATES, “a sizable proportion of participants … expressed dissatisfaction with the categorical characterization of results.”

“Overall, the findings of Mozersky and colleagues are broadly reassuring regarding research participants’ ability to understand the prognostic uncertainty of amyloid imaging. But as the authors note, caution is needed in generalizing their results,” Dr. Chiong said. “These participants represent a selected subpopulation of an already rarified group: prospective participants in the A4 study were provided with study materials for this substudy, and interested participants themselves contacted the study investigators. These participants were thus likely to be particularly supportive of the Alzheimer’s disease research enterprise, and given their family histories and high educational attainment may have been better positioned to interpret information about the limitations and ambiguities of testing than other groups.”

Suggested Reading

Chiong W. Challenges in communicating and understanding predictive biomarker imaging for Alzheimer disease. JAMA Neurol. 2018;75(1):18-19.

Mozersky J, Sankar P, Harkins K, et al. Comprehension of an elevated amyloid positron emission tomography biomarker result by cognitively normal older adults. JAMA Neurol. 2018;75(1):44-50.

The Diagnosis: Metastatic Renal Cell Carcinoma

Histopathologic examination of the punch biopsy demonstrated epithelioid cells with abundant clear cytoplasm and numerous chicken wire-like vascular channels consistent with a diagnosis of cutaneous metastasis of renal cell carcinoma (RCC)(Figure). Collateral history revealed that 8 years prior, the patient had been diagnosed with clear cell RCC, stage III (T3aN0M0). At that time, he was treated with radical nephrectomy, which was considered curative. He remained disease free until several months prior to the development of the cutaneous lesion when he was found to have pulmonary and cerebral metastases with biopsies showing metastatic RCC. He was treated with lobectomy and Gamma Knife radiation for the lung and cerebral metastases, respectively. His oncologist planned to initiate therapy with the multikinase inhibitor sunitinib, which inhibits vascular endothelial growth factor (VEGF) signaling. Unfortunately, the patient died prior to treatment due to overwhelming tumor burden.

Clear cell RCC, the most common renal malignancy, presents with metastatic disease at the time of diagnosis in 21% of patients.¹ An additional 20% of patients with localized disease develop metastases within several years of receiving a nephrectomy without adjuvant therapy, which is standard treatment for stage I to stage III disease.^1,2 Metastatic RCC most frequently targets the lungs, bone, liver, and brain, though virtually any organ can be involved. Cutaneous involvement is estimated to occur in 3.3% of RCC cases,³ accounting for only 1.4% of cutaneous metastases overall.⁴ The risk for developing cutaneous metastases is greatest within 3 years following nephrectomy.³ However, our patient demonstrates that metastasis of RCC to skin can be long delayed (>5 years) despite an initial diagnosis of localized disease.

Cutaneous RCC classically presents as a painless firm papulonodule with a deep red or purple color due to its high vascularity.⁴ Several retrospective studies have identified the scalp as the most frequent site of cutaneous involvement, followed by the chest, abdomen, and nephrectomy scar.^3,4 The differential diagnosis includes other vascular lesions such as pyogenic granuloma, hemangioma, angiosarcoma, bacillary angiomatosis, and Kaposi sarcoma. Diagnosis usually is easily confirmed histologically. Proliferative nests of epithelioid cells with clear cell morphology are surrounded by delicately branching vessels referred to as chicken wire-like vasculature. Immunohistochemical studies demonstrate positivity for pan-cytokeratin, vimentin, and CD-10, and negativity for p63 and cytokeratins 5 and 6, helping to confirm the diagnosis in more challenging cases, especially when there is no known history of primary RCC.⁵

If cutaneous metastasis of RCC is diagnosed, a chest and abdominal computed tomography scan as well as serum alkaline phosphatase test are warranted, as up to 90% of patients with RCC in the skin have additional lesions in at least 1 other site such as the lungs, bones, or liver.³ Management of metastatic RCC includes surgical excision if a single metastasis is found and either immunotherapy with high-dose IL-2 or an anti-programmed cell death inhibitor. Patients with progressive disease also may receive targeted anti-VEGF inhibitors (eg, axitinib, pazopanib, sunitinib), which have been shown to increase progression-free survival in metastatic RCC.^6-8 Interestingly, some evidence suggests severely delayed recurrence of RCC (>5 years following nephrectomy) may predict better response to systemic therapy.⁹

This case of severely delayed metastasis of RCC 8 years after nephrectomy raises the question of whether routine surveillance for RCC recurrence should continue beyond 5 years. It also underscores the need for further studies to determine the utility of postsurgical adjuvant therapy for localized disease (stages I-III). A randomized clinical trial showed no significant difference in disease-free survival when the multikinase inhibitors sunitinib and sorafenib were used as adjuvant therapy.¹⁰ The randomized, placebo-controlled PROTECT trial showed no significant difference in disease-free survival between the VEGF inhibitor pazopanib and placebo when used as adjuvant therapy.¹¹ However, trials are ongoing to investigate a potential survival advantage of adjuvant therapy with the VEGF receptor inhibitor axitinib and the mammalian target of rapamycin inhibitor everolimus.

The Diagnosis: Metastatic Renal Cell Carcinoma

Histopathologic examination of the punch biopsy demonstrated epithelioid cells with abundant clear cytoplasm and numerous chicken wire-like vascular channels consistent with a diagnosis of cutaneous metastasis of renal cell carcinoma (RCC)(Figure). Collateral history revealed that 8 years prior, the patient had been diagnosed with clear cell RCC, stage III (T3aN0M0). At that time, he was treated with radical nephrectomy, which was considered curative. He remained disease free until several months prior to the development of the cutaneous lesion when he was found to have pulmonary and cerebral metastases with biopsies showing metastatic RCC. He was treated with lobectomy and Gamma Knife radiation for the lung and cerebral metastases, respectively. His oncologist planned to initiate therapy with the multikinase inhibitor sunitinib, which inhibits vascular endothelial growth factor (VEGF) signaling. Unfortunately, the patient died prior to treatment due to overwhelming tumor burden.

Clear cell RCC, the most common renal malignancy, presents with metastatic disease at the time of diagnosis in 21% of patients.¹ An additional 20% of patients with localized disease develop metastases within several years of receiving a nephrectomy without adjuvant therapy, which is standard treatment for stage I to stage III disease.^1,2 Metastatic RCC most frequently targets the lungs, bone, liver, and brain, though virtually any organ can be involved. Cutaneous involvement is estimated to occur in 3.3% of RCC cases,³ accounting for only 1.4% of cutaneous metastases overall.⁴ The risk for developing cutaneous metastases is greatest within 3 years following nephrectomy.³ However, our patient demonstrates that metastasis of RCC to skin can be long delayed (>5 years) despite an initial diagnosis of localized disease.

Cutaneous RCC classically presents as a painless firm papulonodule with a deep red or purple color due to its high vascularity.⁴ Several retrospective studies have identified the scalp as the most frequent site of cutaneous involvement, followed by the chest, abdomen, and nephrectomy scar.^3,4 The differential diagnosis includes other vascular lesions such as pyogenic granuloma, hemangioma, angiosarcoma, bacillary angiomatosis, and Kaposi sarcoma. Diagnosis usually is easily confirmed histologically. Proliferative nests of epithelioid cells with clear cell morphology are surrounded by delicately branching vessels referred to as chicken wire-like vasculature. Immunohistochemical studies demonstrate positivity for pan-cytokeratin, vimentin, and CD-10, and negativity for p63 and cytokeratins 5 and 6, helping to confirm the diagnosis in more challenging cases, especially when there is no known history of primary RCC.⁵

If cutaneous metastasis of RCC is diagnosed, a chest and abdominal computed tomography scan as well as serum alkaline phosphatase test are warranted, as up to 90% of patients with RCC in the skin have additional lesions in at least 1 other site such as the lungs, bones, or liver.³ Management of metastatic RCC includes surgical excision if a single metastasis is found and either immunotherapy with high-dose IL-2 or an anti-programmed cell death inhibitor. Patients with progressive disease also may receive targeted anti-VEGF inhibitors (eg, axitinib, pazopanib, sunitinib), which have been shown to increase progression-free survival in metastatic RCC.^6-8 Interestingly, some evidence suggests severely delayed recurrence of RCC (>5 years following nephrectomy) may predict better response to systemic therapy.⁹

This case of severely delayed metastasis of RCC 8 years after nephrectomy raises the question of whether routine surveillance for RCC recurrence should continue beyond 5 years. It also underscores the need for further studies to determine the utility of postsurgical adjuvant therapy for localized disease (stages I-III). A randomized clinical trial showed no significant difference in disease-free survival when the multikinase inhibitors sunitinib and sorafenib were used as adjuvant therapy.¹⁰ The randomized, placebo-controlled PROTECT trial showed no significant difference in disease-free survival between the VEGF inhibitor pazopanib and placebo when used as adjuvant therapy.¹¹ However, trials are ongoing to investigate a potential survival advantage of adjuvant therapy with the VEGF receptor inhibitor axitinib and the mammalian target of rapamycin inhibitor everolimus.

The Diagnosis: Metastatic Renal Cell Carcinoma

Histopathologic examination of the punch biopsy demonstrated epithelioid cells with abundant clear cytoplasm and numerous chicken wire-like vascular channels consistent with a diagnosis of cutaneous metastasis of renal cell carcinoma (RCC)(Figure). Collateral history revealed that 8 years prior, the patient had been diagnosed with clear cell RCC, stage III (T3aN0M0). At that time, he was treated with radical nephrectomy, which was considered curative. He remained disease free until several months prior to the development of the cutaneous lesion when he was found to have pulmonary and cerebral metastases with biopsies showing metastatic RCC. He was treated with lobectomy and Gamma Knife radiation for the lung and cerebral metastases, respectively. His oncologist planned to initiate therapy with the multikinase inhibitor sunitinib, which inhibits vascular endothelial growth factor (VEGF) signaling. Unfortunately, the patient died prior to treatment due to overwhelming tumor burden.

Clear cell RCC, the most common renal malignancy, presents with metastatic disease at the time of diagnosis in 21% of patients.¹ An additional 20% of patients with localized disease develop metastases within several years of receiving a nephrectomy without adjuvant therapy, which is standard treatment for stage I to stage III disease.^1,2 Metastatic RCC most frequently targets the lungs, bone, liver, and brain, though virtually any organ can be involved. Cutaneous involvement is estimated to occur in 3.3% of RCC cases,³ accounting for only 1.4% of cutaneous metastases overall.⁴ The risk for developing cutaneous metastases is greatest within 3 years following nephrectomy.³ However, our patient demonstrates that metastasis of RCC to skin can be long delayed (>5 years) despite an initial diagnosis of localized disease.

Cutaneous RCC classically presents as a painless firm papulonodule with a deep red or purple color due to its high vascularity.⁴ Several retrospective studies have identified the scalp as the most frequent site of cutaneous involvement, followed by the chest, abdomen, and nephrectomy scar.^3,4 The differential diagnosis includes other vascular lesions such as pyogenic granuloma, hemangioma, angiosarcoma, bacillary angiomatosis, and Kaposi sarcoma. Diagnosis usually is easily confirmed histologically. Proliferative nests of epithelioid cells with clear cell morphology are surrounded by delicately branching vessels referred to as chicken wire-like vasculature. Immunohistochemical studies demonstrate positivity for pan-cytokeratin, vimentin, and CD-10, and negativity for p63 and cytokeratins 5 and 6, helping to confirm the diagnosis in more challenging cases, especially when there is no known history of primary RCC.⁵

If cutaneous metastasis of RCC is diagnosed, a chest and abdominal computed tomography scan as well as serum alkaline phosphatase test are warranted, as up to 90% of patients with RCC in the skin have additional lesions in at least 1 other site such as the lungs, bones, or liver.³ Management of metastatic RCC includes surgical excision if a single metastasis is found and either immunotherapy with high-dose IL-2 or an anti-programmed cell death inhibitor. Patients with progressive disease also may receive targeted anti-VEGF inhibitors (eg, axitinib, pazopanib, sunitinib), which have been shown to increase progression-free survival in metastatic RCC.^6-8 Interestingly, some evidence suggests severely delayed recurrence of RCC (>5 years following nephrectomy) may predict better response to systemic therapy.⁹

This case of severely delayed metastasis of RCC 8 years after nephrectomy raises the question of whether routine surveillance for RCC recurrence should continue beyond 5 years. It also underscores the need for further studies to determine the utility of postsurgical adjuvant therapy for localized disease (stages I-III). A randomized clinical trial showed no significant difference in disease-free survival when the multikinase inhibitors sunitinib and sorafenib were used as adjuvant therapy.¹⁰ The randomized, placebo-controlled PROTECT trial showed no significant difference in disease-free survival between the VEGF inhibitor pazopanib and placebo when used as adjuvant therapy.¹¹ However, trials are ongoing to investigate a potential survival advantage of adjuvant therapy with the VEGF receptor inhibitor axitinib and the mammalian target of rapamycin inhibitor everolimus.

The eyes may be windows into a coming stroke, E&M visits may soon mean more money, many doctors still reach for the wrong atopic dermatitis tool, and misfolded proteins may plant the seed for multiple sclerosis.

Listen to the MDedge Daily News podcast for all the details on today’s top news.

The eyes may be windows into a coming stroke, E&M visits may soon mean more money, many doctors still reach for the wrong atopic dermatitis tool, and misfolded proteins may plant the seed for multiple sclerosis.

Listen to the MDedge Daily News podcast for all the details on today’s top news.

The eyes may be windows into a coming stroke, E&M visits may soon mean more money, many doctors still reach for the wrong atopic dermatitis tool, and misfolded proteins may plant the seed for multiple sclerosis.

Listen to the MDedge Daily News podcast for all the details on today’s top news.