A 79-year-old man presents for a routine skin check, in the context of his 40-year history of nonmelanoma skin cancer. He grew up on a farm and then became a farmer himself, spending almost every day in the sun (usually without a hat). His skin burned easily but would take on a “tan” by the start of summer.

In the succeeding years, he developed so many skin cancers (and had them removed) that he lost count. All were basal cell or squamous cell carcinomas, predominately manifesting on his face, arms, and ears. Several required Mohs surgery for removal.

EXAMINATION
Abundant evidence of excessive sun exposure is seen on the patient’s skin: actinic keratoses on the forehead, ears, and neck, and multiple solar lentigines on the face, neck, and arms. On his left neck, below the ear, is a large, oddly pigmented, dark macular patch. Dermatoscopic examination reveals focal pigmentary clumping and streaming, which prompts the decision to perform an incisional biopsy. The darkest and most irregular part of the lesion is taken as a sample. The pathology report shows lentigo maligna.

What is lentigo maligna?

DISCUSSION
Lentigo maligna (LM), also known as Hutchinson freckle, is a type of melanoma in situ that is typically seen on sun-exposed skin. It has indistinct margins with predominantly brown and black coloration. LM is usually seen on older, mostly fair-skinned patients who have a history of extensive sun exposure. Its preferred sites include the face, ears, neck, and upper extremities.

LM is, by definition, entirely superficial and therefore safe. Its main significance is that it can become focally invasive to the dermis, a phenomenon termed lentigo maligna melanoma (LMM). When that occurs, the clusters of spindle-shaped atypical cells can then progress to a vertical growth phase, resulting in intravascular invasion that eventuates in metastasis.

LMs grow so slowly that they often escape detection; they are sometimes mistaken for solar lentigines (SL). They can “collide” with SLs or other benign lesions (eg, seborrheic keratoses), which can effectively camouflage them. Suspicion is usually triggered by change (color, size) in a lesion.

Biopsy is the only method of detection. In this case, the central portion of this large, oddly pigmented and bordered, multicolored patch was excised and the darkest, most irregular part of the lesion collected. This is the gold standard for biopsy of a potential melanoma. A large deep shave biopsy (“saucerization”) would have accomplished the same thing; studies show that neither process will cause metastasis. The main mistake to avoid is performing a single punch biopsy, which risks a false-negative result.

The definitive surgical approach is to remove the lesion with a 1-cm margin around it and into the underlying adipose layer. The wound can either be left to heal by secondary intention or closed primarily. Either way, this patient’s prognosis is excellent, unless the final pathology report indicates focal invasion. With a patient of this age, the LM could have been left alone—although, once discovered, LM is irresistibly compelling to treat.

TAKE-HOME LEARNING POINTS
• Lentigo maligna (LM) is a type of melanoma in situ with the potential to progress to lentigo maligna melanoma, an invasive form of early melanoma.

• LM is common on sun-exposed skin of older patients with a history of excessive sun exposure.

• Faces, ears, arms, and necks are common areas for LM to manifest.

• Biopsy of suspected melanoma should incorporate a significant portion of the darkest, most irregular part of the lesion; it can be done by incisional technique or deep saucerization.

• LM is also known as Hutchinson freckle, since it often resembles a large, irregularly bordered and pigmented freckle.

A 79-year-old man presents for a routine skin check, in the context of his 40-year history of nonmelanoma skin cancer. He grew up on a farm and then became a farmer himself, spending almost every day in the sun (usually without a hat). His skin burned easily but would take on a “tan” by the start of summer.

In the succeeding years, he developed so many skin cancers (and had them removed) that he lost count. All were basal cell or squamous cell carcinomas, predominately manifesting on his face, arms, and ears. Several required Mohs surgery for removal.

EXAMINATION
Abundant evidence of excessive sun exposure is seen on the patient’s skin: actinic keratoses on the forehead, ears, and neck, and multiple solar lentigines on the face, neck, and arms. On his left neck, below the ear, is a large, oddly pigmented, dark macular patch. Dermatoscopic examination reveals focal pigmentary clumping and streaming, which prompts the decision to perform an incisional biopsy. The darkest and most irregular part of the lesion is taken as a sample. The pathology report shows lentigo maligna.

What is lentigo maligna?

DISCUSSION
Lentigo maligna (LM), also known as Hutchinson freckle, is a type of melanoma in situ that is typically seen on sun-exposed skin. It has indistinct margins with predominantly brown and black coloration. LM is usually seen on older, mostly fair-skinned patients who have a history of extensive sun exposure. Its preferred sites include the face, ears, neck, and upper extremities.

LM is, by definition, entirely superficial and therefore safe. Its main significance is that it can become focally invasive to the dermis, a phenomenon termed lentigo maligna melanoma (LMM). When that occurs, the clusters of spindle-shaped atypical cells can then progress to a vertical growth phase, resulting in intravascular invasion that eventuates in metastasis.

LMs grow so slowly that they often escape detection; they are sometimes mistaken for solar lentigines (SL). They can “collide” with SLs or other benign lesions (eg, seborrheic keratoses), which can effectively camouflage them. Suspicion is usually triggered by change (color, size) in a lesion.

Biopsy is the only method of detection. In this case, the central portion of this large, oddly pigmented and bordered, multicolored patch was excised and the darkest, most irregular part of the lesion collected. This is the gold standard for biopsy of a potential melanoma. A large deep shave biopsy (“saucerization”) would have accomplished the same thing; studies show that neither process will cause metastasis. The main mistake to avoid is performing a single punch biopsy, which risks a false-negative result.

The definitive surgical approach is to remove the lesion with a 1-cm margin around it and into the underlying adipose layer. The wound can either be left to heal by secondary intention or closed primarily. Either way, this patient’s prognosis is excellent, unless the final pathology report indicates focal invasion. With a patient of this age, the LM could have been left alone—although, once discovered, LM is irresistibly compelling to treat.

TAKE-HOME LEARNING POINTS
• Lentigo maligna (LM) is a type of melanoma in situ with the potential to progress to lentigo maligna melanoma, an invasive form of early melanoma.

• LM is common on sun-exposed skin of older patients with a history of excessive sun exposure.

• Faces, ears, arms, and necks are common areas for LM to manifest.

• Biopsy of suspected melanoma should incorporate a significant portion of the darkest, most irregular part of the lesion; it can be done by incisional technique or deep saucerization.

• LM is also known as Hutchinson freckle, since it often resembles a large, irregularly bordered and pigmented freckle.

A 79-year-old man presents for a routine skin check, in the context of his 40-year history of nonmelanoma skin cancer. He grew up on a farm and then became a farmer himself, spending almost every day in the sun (usually without a hat). His skin burned easily but would take on a “tan” by the start of summer.

In the succeeding years, he developed so many skin cancers (and had them removed) that he lost count. All were basal cell or squamous cell carcinomas, predominately manifesting on his face, arms, and ears. Several required Mohs surgery for removal.

EXAMINATION
Abundant evidence of excessive sun exposure is seen on the patient’s skin: actinic keratoses on the forehead, ears, and neck, and multiple solar lentigines on the face, neck, and arms. On his left neck, below the ear, is a large, oddly pigmented, dark macular patch. Dermatoscopic examination reveals focal pigmentary clumping and streaming, which prompts the decision to perform an incisional biopsy. The darkest and most irregular part of the lesion is taken as a sample. The pathology report shows lentigo maligna.

What is lentigo maligna?

DISCUSSION
Lentigo maligna (LM), also known as Hutchinson freckle, is a type of melanoma in situ that is typically seen on sun-exposed skin. It has indistinct margins with predominantly brown and black coloration. LM is usually seen on older, mostly fair-skinned patients who have a history of extensive sun exposure. Its preferred sites include the face, ears, neck, and upper extremities.

LM is, by definition, entirely superficial and therefore safe. Its main significance is that it can become focally invasive to the dermis, a phenomenon termed lentigo maligna melanoma (LMM). When that occurs, the clusters of spindle-shaped atypical cells can then progress to a vertical growth phase, resulting in intravascular invasion that eventuates in metastasis.

LMs grow so slowly that they often escape detection; they are sometimes mistaken for solar lentigines (SL). They can “collide” with SLs or other benign lesions (eg, seborrheic keratoses), which can effectively camouflage them. Suspicion is usually triggered by change (color, size) in a lesion.

Biopsy is the only method of detection. In this case, the central portion of this large, oddly pigmented and bordered, multicolored patch was excised and the darkest, most irregular part of the lesion collected. This is the gold standard for biopsy of a potential melanoma. A large deep shave biopsy (“saucerization”) would have accomplished the same thing; studies show that neither process will cause metastasis. The main mistake to avoid is performing a single punch biopsy, which risks a false-negative result.

The definitive surgical approach is to remove the lesion with a 1-cm margin around it and into the underlying adipose layer. The wound can either be left to heal by secondary intention or closed primarily. Either way, this patient’s prognosis is excellent, unless the final pathology report indicates focal invasion. With a patient of this age, the LM could have been left alone—although, once discovered, LM is irresistibly compelling to treat.

TAKE-HOME LEARNING POINTS
• Lentigo maligna (LM) is a type of melanoma in situ with the potential to progress to lentigo maligna melanoma, an invasive form of early melanoma.

• LM is common on sun-exposed skin of older patients with a history of excessive sun exposure.

• Faces, ears, arms, and necks are common areas for LM to manifest.

• Biopsy of suspected melanoma should incorporate a significant portion of the darkest, most irregular part of the lesion; it can be done by incisional technique or deep saucerization.

• LM is also known as Hutchinson freckle, since it often resembles a large, irregularly bordered and pigmented freckle.

DTI Reveals Changes in Brain Connections in Early Alzheimer’s Disease
Changes in brain connections visible on MRI could represent an imaging biomarker of Alzheimer’s disease, according to a study presented at the meeting.

As many as five million Americans have Alzheimer’s disease, and this number is expected to increase to 14 million by 2050, according to the Centers for Disease Control and Prevention. Preventive treatments may be most effective before Alzheimer’s disease is diagnosed, such as when a person is experiencing mild cognitive impairment.

Previous efforts at early detection have focused on beta amyloid. For the current study, researchers looked at the brain’s structural connectome, a map of white matter tracts that carry signals between various areas of the brain.

“The structural connectome provides us with a way to characterize and measure these connections and how they change through disease or age,” said Jeffrey W. Prescott, MD, PhD, a radiology resident at Duke University Medical Center in Durham, North Carolina, and a coauthor of the study.

Dr. Prescott and colleagues analyzed data for 102 patients enrolled in a national study called the Alzheimer’s Disease Neuroimaging Initiative 2. The patients had undergone diffusion tensor imaging (DTI), which assesses the integrity of white matter tracts in the brain by measuring how easy it is for water to move along them. “Water prefers moving along the defined physical connections between regions in the brain, which makes DTI a great tool for evaluating the structural connectome,” said Dr. Prescott.

The researchers compared changes in the structural connectome with results from florbetapir PET imaging, a technique that measures the amount of beta amyloid plaque in the brain. The results showed a strong association between florbetapir uptake and decreases in the strength of the structural connectome in each of the five areas of the brain studied.

“This study ties together two of the major changes in the Alzheimer’s brain—structural tissue changes and pathologic amyloid plaque deposition—and suggests a promising role for DTI as a possible diagnostic adjunct,” said Dr. Prescott.

Based on these findings, DTI may have a role in assessing brain damage in early Alzheimer’s disease and in monitoring the effect of new therapies.

“Traditionally, Alzheimer’s disease is believed to exert its effects on thinking via damage to the brain’s gray matter, where most of the nerve cells are concentrated,” said Jeffrey R. Petrella, MD, Professor of Radiology at Duke University and senior author of the research. “This study suggests that amyloid deposition in the gray matter affects the associated white matter connections, which are essential for conducting messages across the billions of nerve cells in the brain, allowing for all aspects of mental function.”

“We suspect that as amyloid plaque load in the gray matter increases, the brain’s white matter starts to break down or malfunction and lose its ability to move water and neurochemicals efficiently,” added Dr. Prescott.

The researchers plan to continue studying this cohort of patients over time to gain a better understanding of how the disease evolves in individual patients. They also intend to incorporate functional imaging into their research to learn about how the relationship between function and structure changes with increasing amyloid burden.

Asymptomatic Atherosclerosis May Be Associated With Cognitive Impairment
A buildup of plaque in the body’s major arteries is associated with mild cognitive impairment, according to a study of approximately 2,000 adults conducted at the University of Texas (UT) Southwestern Medical Center.

“It is well established that plaque buildup in the arteries is a predictor of heart disease, but the relationship between atherosclerosis and brain health is less clear,” said Christopher D. Maroules, MD, a radiology resident at UT Southwestern Medical Center in Dallas. “Our findings suggest that atherosclerosis not only affects the heart, but also brain health.”

Researchers analyzed the test results of 1,903 participants (mean age, 44) in the Dallas Heart Study, a multiethnic population-based study of adults from Dallas County, Texas. The participants included men and women who had no symptoms of cardiovascular disease.

Study participants completed the Montreal Cognitive Assessment (MoCA), a 30-point standardized test for detecting mild cognitive impairment, and underwent MRI of the brain to measure white matter hyperintensity volume. Bright white spots known as high signal intensity areas on a brain MRI indicate abnormal changes within the white matter.

“Increased white matter hyperintensity volume is part of the normal aging process,” explained Dr. Maroules. “But excessive white matter hyperintensity volume is a marker for cognitive impairment.”

Study participants also underwent imaging exams to measure the buildup of plaque in the arteries in three distinct vascular areas of the body. They underwent MRI to measure wall thickness in the carotid arteries and in the abdominal aorta, and received CT to measure coronary artery calcium.

Using the results, researchers performed a statistical regression to understand the relationship between the incidence of atherosclerosis and mild cognitive impairment. After adjusting for traditional risk factors for atherosclerosis, including age, ethnicity, male sex, diabetes, hypertension, smoking, and BMI, the investigators found independent relationships between atherosclerosis in all three vascular areas of the body and cognitive health, as measured by MoCA scores, and white matter hyperintensity volume on MRI.

Individuals in the highest quartile of internal carotid wall thickness were 21% more likely to have cognitive impairment, as indicated by a low MoCA score. An increasing coronary artery calcium score was predictive of large white matter intensity volume on MRI.

“These results underscore the importance of identifying atherosclerosis in its early stages, not just to help preserve heart function, but also to preserve cognition and brain health,” said Dr. Maroules. The MRI and CT imaging techniques provide valuable prognostic information about an individual’s downstream health risks, he added.

“Plaque buildup in blood vessels throughout the body offers us a window into brain health. Imaging with CT and MRI has an important role in identifying patients who are at a higher risk for cognitive impairment.”

A Season of High School Football Without Concussion May Cause Brain Changes
Some high school football players exhibit measurable brain changes after a single season of play, even in the absence of concussion, according to a study presented at the meeting.

“This study adds to the growing body of evidence that a season of play in a contact sport can affect the brain in the absence of clinical findings,” said Christopher T. Whitlow, MD, PhD, MHA, Associate Professor of Radiology at Wake Forest School of Medicine and radiologist at Wake Forest Baptist Medical Center in Winston-Salem, North Carolina.

In recent years, various reports have suggested the potential effects that participation in youth sports may have on the developing brain. Most of these studies have looked at brain changes as a result of concussion, however. Dr. Whitlow and colleagues set out to determine whether head impacts withstood in the course of a season of high school football produce white matter changes in the brain in the absence of clinically diagnosed concussion.

The researchers studied 24 high school football players between the ages of 16 and 18. For all games and practices, players were monitored with Head Impact Telemetry System (HITs) helmet-mounted accelerometers, which are used in youth and collegiate football to assess the frequency and severity of helmet impacts.

Risk-weighted cumulative exposure was computed from the HITs data and represented the risk of concussion over the course of the season. These data, along with the total number of impacts, were used to categorize the players as heavy hitters or light hitters. The researchers identified nine of the 24 participants as heavy hitters and 15 as light hitters. None of the players had concussion during the season.

All players underwent pre- and post-season evaluation with diffusion tensor imaging (DTI) of the brain. Diffusion tensor imaging measures fractional anisotropy, which indicates the movement of water molecules along axons. In healthy white matter, the direction of water movement is fairly uniform, and fractional anisotropy is high. When water movement is more random, fractional anisotropy values decrease, thus suggesting microstructural abnormalities.

The results showed that both groups demonstrated global increases of fractional anisotropy over time, likely reflecting the effects of brain development. However, the heavy-hitter group showed statistically significant areas of decreased fractional anisotropy post-season in specific areas of the brain, including the splenium of the corpus callosum and deep white matter tracts.

“Our study found that players experiencing greater levels of head impacts have more fractional anisotropy loss, compared with players with lower impact exposure,” said Dr. Whitlow. “Similar brain MRI changes have been previously associated with mild traumatic brain injury. However, it is unclear whether or not these effects will be associated with any negative long-term consequences.” These findings are preliminary, and more study needs to be performed, concluded Dr. Whitlow.

Mild Coronary Artery Disease Increases Risk of Cardiovascular Events
Patients with diabetes and mild coronary artery disease have the same relative risk for a heart attack or other major adverse heart event as patients with diabetes and serious single-vessel obstructive disease, according to a long-term study.

Researchers at the University of British Columbia and St. Paul’s Hospital in Vancouver analyzed data from the Coronary CT Angiography Evaluation For Clinical Outcomes: An International Multicenter (CONFIRM) Registry, which was developed to examine the prognostic value of cardiac computed tomography angiography (CCTA) for predicting adverse cardiac events related to coronary artery disease. The registry, which has CCTA data for 40,000 patients from 17 centers around the world, now has five-year follow-up data for 14,000 patients.

“The CONFIRM Registry is the largest long-term data set available and allowed us to evaluate the long-term prognostic value of CCTA in diabetic patients,” said Jonathan Leipsic, MD, vice chairman of the Department of Radiology at the University of British Columbia and study coauthor.

The researchers analyzed data for 1,823 patients with diabetes who underwent CCTA to detect and determine the extent of coronary artery disease. Men and women (median age, 61.7) in the study were categorized as having no coronary artery disease, mild disease (ie, coronary artery narrowed by less than 50%), or obstructive disease (ie, obstruction of more than 50% of the artery). Over a 5.2-year follow-up period, 246 deaths occurred, representing 13.5% of the total study group.

Major adverse cardiovascular event (MACE) data were available for 973 patients. During the follow-up period, 295 (30.3%) of the patients had a MACE, such as heart attack or a coronary revascularization.

The researchers found that both obstructive and mild, or nonobstructive, coronary artery disease, as determined by CCTA, were associated with patient deaths and MACE. Most importantly, the researchers found that the relative risk for death or MACE for a patient with mild coronary artery disease was comparable to that of patients with single vessel obstructive disease.

“Until now, two-year follow-up studies suggested that a diabetic patient with mild or nonobstructive coronary artery disease had a lower risk of major adverse cardiovascular events and death than patients with obstructive disease,” said Philipp Blanke, MD, a radiologist at the University of British Columbia and St. Paul’s Hospital and a coauthor of the study. “Our five-year follow-up data suggest that nonobstructive and obstructive coronary artery disease, as detected by cardiac CTA in diabetic patients, are both associated with higher rates of mortality.”

Researchers need a better understanding of the evolution of plaque in the arteries and of patient response to therapies, said Dr. Leipsic. “Cardiac CT angiography is helpful for identifying diabetic patients who are at higher risk for heart events and who may benefit from more aggressive therapy to help modify that risk,” he added.

Patients Prefer Direct Access to Imaging Records
Patients value direct, independent access to their medical exams, researchers reported.

Giampaolo Greco, PhD, MPH, Assistant Professor in the Department of Population Health Science and Policy at the Mount Sinai School of Medicine in New York City, and colleagues set out to evaluate patient and provider satisfaction with RSNA Image Share, an Internet-based interoperable image exchange system that gives patients ownership of their imaging exams and control over access to their imaging records. The network enables radiology sites to make results of imaging exams available for patients to incorporate in personal health record (PHR) accounts they can use to securely store, manage, and share their imaging records. Sites also can use the network to send patient imaging records to other participating sites to support better informed care.

For the study, patients undergoing radiologic exams at four academic centers were eligible to establish online PHR accounts using the RSNA Image Share network. Patients could then use their PHR accounts to maintain and share their images with selected providers, creating a detailed medical history accessible through any secure Internet connection.

Between July 2012 and August 2013, the study enrolled 2,562 patients, mean age 50.4, including a significant representation of older individuals. Older individuals have the highest healthcare utilization and often experience or perceive a significant barrier in using information technology.

The median number of exams uploaded per patient was six. Study participants were provided a brief survey to assess patient and physician experience with the exchange of images, and 502 patients completed and returned their surveys. Of these respondents, 448 patients identified the method used at the visit to share images: Internet, CDs, both Internet and CDs, or other, and 165 included a section completed by their physician.

Nearly all (96%) of the patients responded positively to having direct access to their medical images, and 78% viewed their images independently. There was no difference between Internet and CD users in satisfaction with privacy and security and timeliness of access to medical images. A greater percentage of Internet users reported being able to access their images without difficulty, compared with CD users (88.3% vs 77.5%).

DTI Reveals Changes in Brain Connections in Early Alzheimer’s Disease
Changes in brain connections visible on MRI could represent an imaging biomarker of Alzheimer’s disease, according to a study presented at the meeting.

As many as five million Americans have Alzheimer’s disease, and this number is expected to increase to 14 million by 2050, according to the Centers for Disease Control and Prevention. Preventive treatments may be most effective before Alzheimer’s disease is diagnosed, such as when a person is experiencing mild cognitive impairment.

Previous efforts at early detection have focused on beta amyloid. For the current study, researchers looked at the brain’s structural connectome, a map of white matter tracts that carry signals between various areas of the brain.

“The structural connectome provides us with a way to characterize and measure these connections and how they change through disease or age,” said Jeffrey W. Prescott, MD, PhD, a radiology resident at Duke University Medical Center in Durham, North Carolina, and a coauthor of the study.

Dr. Prescott and colleagues analyzed data for 102 patients enrolled in a national study called the Alzheimer’s Disease Neuroimaging Initiative 2. The patients had undergone diffusion tensor imaging (DTI), which assesses the integrity of white matter tracts in the brain by measuring how easy it is for water to move along them. “Water prefers moving along the defined physical connections between regions in the brain, which makes DTI a great tool for evaluating the structural connectome,” said Dr. Prescott.

The researchers compared changes in the structural connectome with results from florbetapir PET imaging, a technique that measures the amount of beta amyloid plaque in the brain. The results showed a strong association between florbetapir uptake and decreases in the strength of the structural connectome in each of the five areas of the brain studied.

“This study ties together two of the major changes in the Alzheimer’s brain—structural tissue changes and pathologic amyloid plaque deposition—and suggests a promising role for DTI as a possible diagnostic adjunct,” said Dr. Prescott.

Based on these findings, DTI may have a role in assessing brain damage in early Alzheimer’s disease and in monitoring the effect of new therapies.

“Traditionally, Alzheimer’s disease is believed to exert its effects on thinking via damage to the brain’s gray matter, where most of the nerve cells are concentrated,” said Jeffrey R. Petrella, MD, Professor of Radiology at Duke University and senior author of the research. “This study suggests that amyloid deposition in the gray matter affects the associated white matter connections, which are essential for conducting messages across the billions of nerve cells in the brain, allowing for all aspects of mental function.”

“We suspect that as amyloid plaque load in the gray matter increases, the brain’s white matter starts to break down or malfunction and lose its ability to move water and neurochemicals efficiently,” added Dr. Prescott.

The researchers plan to continue studying this cohort of patients over time to gain a better understanding of how the disease evolves in individual patients. They also intend to incorporate functional imaging into their research to learn about how the relationship between function and structure changes with increasing amyloid burden.

Asymptomatic Atherosclerosis May Be Associated With Cognitive Impairment
A buildup of plaque in the body’s major arteries is associated with mild cognitive impairment, according to a study of approximately 2,000 adults conducted at the University of Texas (UT) Southwestern Medical Center.

“It is well established that plaque buildup in the arteries is a predictor of heart disease, but the relationship between atherosclerosis and brain health is less clear,” said Christopher D. Maroules, MD, a radiology resident at UT Southwestern Medical Center in Dallas. “Our findings suggest that atherosclerosis not only affects the heart, but also brain health.”

Researchers analyzed the test results of 1,903 participants (mean age, 44) in the Dallas Heart Study, a multiethnic population-based study of adults from Dallas County, Texas. The participants included men and women who had no symptoms of cardiovascular disease.

Study participants completed the Montreal Cognitive Assessment (MoCA), a 30-point standardized test for detecting mild cognitive impairment, and underwent MRI of the brain to measure white matter hyperintensity volume. Bright white spots known as high signal intensity areas on a brain MRI indicate abnormal changes within the white matter.

“Increased white matter hyperintensity volume is part of the normal aging process,” explained Dr. Maroules. “But excessive white matter hyperintensity volume is a marker for cognitive impairment.”

Study participants also underwent imaging exams to measure the buildup of plaque in the arteries in three distinct vascular areas of the body. They underwent MRI to measure wall thickness in the carotid arteries and in the abdominal aorta, and received CT to measure coronary artery calcium.

Using the results, researchers performed a statistical regression to understand the relationship between the incidence of atherosclerosis and mild cognitive impairment. After adjusting for traditional risk factors for atherosclerosis, including age, ethnicity, male sex, diabetes, hypertension, smoking, and BMI, the investigators found independent relationships between atherosclerosis in all three vascular areas of the body and cognitive health, as measured by MoCA scores, and white matter hyperintensity volume on MRI.

Individuals in the highest quartile of internal carotid wall thickness were 21% more likely to have cognitive impairment, as indicated by a low MoCA score. An increasing coronary artery calcium score was predictive of large white matter intensity volume on MRI.

“These results underscore the importance of identifying atherosclerosis in its early stages, not just to help preserve heart function, but also to preserve cognition and brain health,” said Dr. Maroules. The MRI and CT imaging techniques provide valuable prognostic information about an individual’s downstream health risks, he added.

“Plaque buildup in blood vessels throughout the body offers us a window into brain health. Imaging with CT and MRI has an important role in identifying patients who are at a higher risk for cognitive impairment.”

A Season of High School Football Without Concussion May Cause Brain Changes
Some high school football players exhibit measurable brain changes after a single season of play, even in the absence of concussion, according to a study presented at the meeting.

“This study adds to the growing body of evidence that a season of play in a contact sport can affect the brain in the absence of clinical findings,” said Christopher T. Whitlow, MD, PhD, MHA, Associate Professor of Radiology at Wake Forest School of Medicine and radiologist at Wake Forest Baptist Medical Center in Winston-Salem, North Carolina.

In recent years, various reports have suggested the potential effects that participation in youth sports may have on the developing brain. Most of these studies have looked at brain changes as a result of concussion, however. Dr. Whitlow and colleagues set out to determine whether head impacts withstood in the course of a season of high school football produce white matter changes in the brain in the absence of clinically diagnosed concussion.

The researchers studied 24 high school football players between the ages of 16 and 18. For all games and practices, players were monitored with Head Impact Telemetry System (HITs) helmet-mounted accelerometers, which are used in youth and collegiate football to assess the frequency and severity of helmet impacts.

Risk-weighted cumulative exposure was computed from the HITs data and represented the risk of concussion over the course of the season. These data, along with the total number of impacts, were used to categorize the players as heavy hitters or light hitters. The researchers identified nine of the 24 participants as heavy hitters and 15 as light hitters. None of the players had concussion during the season.

All players underwent pre- and post-season evaluation with diffusion tensor imaging (DTI) of the brain. Diffusion tensor imaging measures fractional anisotropy, which indicates the movement of water molecules along axons. In healthy white matter, the direction of water movement is fairly uniform, and fractional anisotropy is high. When water movement is more random, fractional anisotropy values decrease, thus suggesting microstructural abnormalities.

The results showed that both groups demonstrated global increases of fractional anisotropy over time, likely reflecting the effects of brain development. However, the heavy-hitter group showed statistically significant areas of decreased fractional anisotropy post-season in specific areas of the brain, including the splenium of the corpus callosum and deep white matter tracts.

“Our study found that players experiencing greater levels of head impacts have more fractional anisotropy loss, compared with players with lower impact exposure,” said Dr. Whitlow. “Similar brain MRI changes have been previously associated with mild traumatic brain injury. However, it is unclear whether or not these effects will be associated with any negative long-term consequences.” These findings are preliminary, and more study needs to be performed, concluded Dr. Whitlow.

Mild Coronary Artery Disease Increases Risk of Cardiovascular Events
Patients with diabetes and mild coronary artery disease have the same relative risk for a heart attack or other major adverse heart event as patients with diabetes and serious single-vessel obstructive disease, according to a long-term study.

Researchers at the University of British Columbia and St. Paul’s Hospital in Vancouver analyzed data from the Coronary CT Angiography Evaluation For Clinical Outcomes: An International Multicenter (CONFIRM) Registry, which was developed to examine the prognostic value of cardiac computed tomography angiography (CCTA) for predicting adverse cardiac events related to coronary artery disease. The registry, which has CCTA data for 40,000 patients from 17 centers around the world, now has five-year follow-up data for 14,000 patients.

“The CONFIRM Registry is the largest long-term data set available and allowed us to evaluate the long-term prognostic value of CCTA in diabetic patients,” said Jonathan Leipsic, MD, vice chairman of the Department of Radiology at the University of British Columbia and study coauthor.

The researchers analyzed data for 1,823 patients with diabetes who underwent CCTA to detect and determine the extent of coronary artery disease. Men and women (median age, 61.7) in the study were categorized as having no coronary artery disease, mild disease (ie, coronary artery narrowed by less than 50%), or obstructive disease (ie, obstruction of more than 50% of the artery). Over a 5.2-year follow-up period, 246 deaths occurred, representing 13.5% of the total study group.

Major adverse cardiovascular event (MACE) data were available for 973 patients. During the follow-up period, 295 (30.3%) of the patients had a MACE, such as heart attack or a coronary revascularization.

The researchers found that both obstructive and mild, or nonobstructive, coronary artery disease, as determined by CCTA, were associated with patient deaths and MACE. Most importantly, the researchers found that the relative risk for death or MACE for a patient with mild coronary artery disease was comparable to that of patients with single vessel obstructive disease.

“Until now, two-year follow-up studies suggested that a diabetic patient with mild or nonobstructive coronary artery disease had a lower risk of major adverse cardiovascular events and death than patients with obstructive disease,” said Philipp Blanke, MD, a radiologist at the University of British Columbia and St. Paul’s Hospital and a coauthor of the study. “Our five-year follow-up data suggest that nonobstructive and obstructive coronary artery disease, as detected by cardiac CTA in diabetic patients, are both associated with higher rates of mortality.”

Researchers need a better understanding of the evolution of plaque in the arteries and of patient response to therapies, said Dr. Leipsic. “Cardiac CT angiography is helpful for identifying diabetic patients who are at higher risk for heart events and who may benefit from more aggressive therapy to help modify that risk,” he added.

Patients Prefer Direct Access to Imaging Records
Patients value direct, independent access to their medical exams, researchers reported.

Giampaolo Greco, PhD, MPH, Assistant Professor in the Department of Population Health Science and Policy at the Mount Sinai School of Medicine in New York City, and colleagues set out to evaluate patient and provider satisfaction with RSNA Image Share, an Internet-based interoperable image exchange system that gives patients ownership of their imaging exams and control over access to their imaging records. The network enables radiology sites to make results of imaging exams available for patients to incorporate in personal health record (PHR) accounts they can use to securely store, manage, and share their imaging records. Sites also can use the network to send patient imaging records to other participating sites to support better informed care.

For the study, patients undergoing radiologic exams at four academic centers were eligible to establish online PHR accounts using the RSNA Image Share network. Patients could then use their PHR accounts to maintain and share their images with selected providers, creating a detailed medical history accessible through any secure Internet connection.

Between July 2012 and August 2013, the study enrolled 2,562 patients, mean age 50.4, including a significant representation of older individuals. Older individuals have the highest healthcare utilization and often experience or perceive a significant barrier in using information technology.

The median number of exams uploaded per patient was six. Study participants were provided a brief survey to assess patient and physician experience with the exchange of images, and 502 patients completed and returned their surveys. Of these respondents, 448 patients identified the method used at the visit to share images: Internet, CDs, both Internet and CDs, or other, and 165 included a section completed by their physician.

Nearly all (96%) of the patients responded positively to having direct access to their medical images, and 78% viewed their images independently. There was no difference between Internet and CD users in satisfaction with privacy and security and timeliness of access to medical images. A greater percentage of Internet users reported being able to access their images without difficulty, compared with CD users (88.3% vs 77.5%).

DTI Reveals Changes in Brain Connections in Early Alzheimer’s Disease
Changes in brain connections visible on MRI could represent an imaging biomarker of Alzheimer’s disease, according to a study presented at the meeting.

As many as five million Americans have Alzheimer’s disease, and this number is expected to increase to 14 million by 2050, according to the Centers for Disease Control and Prevention. Preventive treatments may be most effective before Alzheimer’s disease is diagnosed, such as when a person is experiencing mild cognitive impairment.

Previous efforts at early detection have focused on beta amyloid. For the current study, researchers looked at the brain’s structural connectome, a map of white matter tracts that carry signals between various areas of the brain.

“The structural connectome provides us with a way to characterize and measure these connections and how they change through disease or age,” said Jeffrey W. Prescott, MD, PhD, a radiology resident at Duke University Medical Center in Durham, North Carolina, and a coauthor of the study.

Dr. Prescott and colleagues analyzed data for 102 patients enrolled in a national study called the Alzheimer’s Disease Neuroimaging Initiative 2. The patients had undergone diffusion tensor imaging (DTI), which assesses the integrity of white matter tracts in the brain by measuring how easy it is for water to move along them. “Water prefers moving along the defined physical connections between regions in the brain, which makes DTI a great tool for evaluating the structural connectome,” said Dr. Prescott.

The researchers compared changes in the structural connectome with results from florbetapir PET imaging, a technique that measures the amount of beta amyloid plaque in the brain. The results showed a strong association between florbetapir uptake and decreases in the strength of the structural connectome in each of the five areas of the brain studied.

“This study ties together two of the major changes in the Alzheimer’s brain—structural tissue changes and pathologic amyloid plaque deposition—and suggests a promising role for DTI as a possible diagnostic adjunct,” said Dr. Prescott.

Based on these findings, DTI may have a role in assessing brain damage in early Alzheimer’s disease and in monitoring the effect of new therapies.

“Traditionally, Alzheimer’s disease is believed to exert its effects on thinking via damage to the brain’s gray matter, where most of the nerve cells are concentrated,” said Jeffrey R. Petrella, MD, Professor of Radiology at Duke University and senior author of the research. “This study suggests that amyloid deposition in the gray matter affects the associated white matter connections, which are essential for conducting messages across the billions of nerve cells in the brain, allowing for all aspects of mental function.”

“We suspect that as amyloid plaque load in the gray matter increases, the brain’s white matter starts to break down or malfunction and lose its ability to move water and neurochemicals efficiently,” added Dr. Prescott.

The researchers plan to continue studying this cohort of patients over time to gain a better understanding of how the disease evolves in individual patients. They also intend to incorporate functional imaging into their research to learn about how the relationship between function and structure changes with increasing amyloid burden.

Asymptomatic Atherosclerosis May Be Associated With Cognitive Impairment
A buildup of plaque in the body’s major arteries is associated with mild cognitive impairment, according to a study of approximately 2,000 adults conducted at the University of Texas (UT) Southwestern Medical Center.

“It is well established that plaque buildup in the arteries is a predictor of heart disease, but the relationship between atherosclerosis and brain health is less clear,” said Christopher D. Maroules, MD, a radiology resident at UT Southwestern Medical Center in Dallas. “Our findings suggest that atherosclerosis not only affects the heart, but also brain health.”

Researchers analyzed the test results of 1,903 participants (mean age, 44) in the Dallas Heart Study, a multiethnic population-based study of adults from Dallas County, Texas. The participants included men and women who had no symptoms of cardiovascular disease.

Study participants completed the Montreal Cognitive Assessment (MoCA), a 30-point standardized test for detecting mild cognitive impairment, and underwent MRI of the brain to measure white matter hyperintensity volume. Bright white spots known as high signal intensity areas on a brain MRI indicate abnormal changes within the white matter.

“Increased white matter hyperintensity volume is part of the normal aging process,” explained Dr. Maroules. “But excessive white matter hyperintensity volume is a marker for cognitive impairment.”

Study participants also underwent imaging exams to measure the buildup of plaque in the arteries in three distinct vascular areas of the body. They underwent MRI to measure wall thickness in the carotid arteries and in the abdominal aorta, and received CT to measure coronary artery calcium.

Using the results, researchers performed a statistical regression to understand the relationship between the incidence of atherosclerosis and mild cognitive impairment. After adjusting for traditional risk factors for atherosclerosis, including age, ethnicity, male sex, diabetes, hypertension, smoking, and BMI, the investigators found independent relationships between atherosclerosis in all three vascular areas of the body and cognitive health, as measured by MoCA scores, and white matter hyperintensity volume on MRI.

Individuals in the highest quartile of internal carotid wall thickness were 21% more likely to have cognitive impairment, as indicated by a low MoCA score. An increasing coronary artery calcium score was predictive of large white matter intensity volume on MRI.

“These results underscore the importance of identifying atherosclerosis in its early stages, not just to help preserve heart function, but also to preserve cognition and brain health,” said Dr. Maroules. The MRI and CT imaging techniques provide valuable prognostic information about an individual’s downstream health risks, he added.

“Plaque buildup in blood vessels throughout the body offers us a window into brain health. Imaging with CT and MRI has an important role in identifying patients who are at a higher risk for cognitive impairment.”

A Season of High School Football Without Concussion May Cause Brain Changes
Some high school football players exhibit measurable brain changes after a single season of play, even in the absence of concussion, according to a study presented at the meeting.

“This study adds to the growing body of evidence that a season of play in a contact sport can affect the brain in the absence of clinical findings,” said Christopher T. Whitlow, MD, PhD, MHA, Associate Professor of Radiology at Wake Forest School of Medicine and radiologist at Wake Forest Baptist Medical Center in Winston-Salem, North Carolina.

In recent years, various reports have suggested the potential effects that participation in youth sports may have on the developing brain. Most of these studies have looked at brain changes as a result of concussion, however. Dr. Whitlow and colleagues set out to determine whether head impacts withstood in the course of a season of high school football produce white matter changes in the brain in the absence of clinically diagnosed concussion.

The researchers studied 24 high school football players between the ages of 16 and 18. For all games and practices, players were monitored with Head Impact Telemetry System (HITs) helmet-mounted accelerometers, which are used in youth and collegiate football to assess the frequency and severity of helmet impacts.

Risk-weighted cumulative exposure was computed from the HITs data and represented the risk of concussion over the course of the season. These data, along with the total number of impacts, were used to categorize the players as heavy hitters or light hitters. The researchers identified nine of the 24 participants as heavy hitters and 15 as light hitters. None of the players had concussion during the season.

All players underwent pre- and post-season evaluation with diffusion tensor imaging (DTI) of the brain. Diffusion tensor imaging measures fractional anisotropy, which indicates the movement of water molecules along axons. In healthy white matter, the direction of water movement is fairly uniform, and fractional anisotropy is high. When water movement is more random, fractional anisotropy values decrease, thus suggesting microstructural abnormalities.

The results showed that both groups demonstrated global increases of fractional anisotropy over time, likely reflecting the effects of brain development. However, the heavy-hitter group showed statistically significant areas of decreased fractional anisotropy post-season in specific areas of the brain, including the splenium of the corpus callosum and deep white matter tracts.

“Our study found that players experiencing greater levels of head impacts have more fractional anisotropy loss, compared with players with lower impact exposure,” said Dr. Whitlow. “Similar brain MRI changes have been previously associated with mild traumatic brain injury. However, it is unclear whether or not these effects will be associated with any negative long-term consequences.” These findings are preliminary, and more study needs to be performed, concluded Dr. Whitlow.

Mild Coronary Artery Disease Increases Risk of Cardiovascular Events
Patients with diabetes and mild coronary artery disease have the same relative risk for a heart attack or other major adverse heart event as patients with diabetes and serious single-vessel obstructive disease, according to a long-term study.

Researchers at the University of British Columbia and St. Paul’s Hospital in Vancouver analyzed data from the Coronary CT Angiography Evaluation For Clinical Outcomes: An International Multicenter (CONFIRM) Registry, which was developed to examine the prognostic value of cardiac computed tomography angiography (CCTA) for predicting adverse cardiac events related to coronary artery disease. The registry, which has CCTA data for 40,000 patients from 17 centers around the world, now has five-year follow-up data for 14,000 patients.

“The CONFIRM Registry is the largest long-term data set available and allowed us to evaluate the long-term prognostic value of CCTA in diabetic patients,” said Jonathan Leipsic, MD, vice chairman of the Department of Radiology at the University of British Columbia and study coauthor.

The researchers analyzed data for 1,823 patients with diabetes who underwent CCTA to detect and determine the extent of coronary artery disease. Men and women (median age, 61.7) in the study were categorized as having no coronary artery disease, mild disease (ie, coronary artery narrowed by less than 50%), or obstructive disease (ie, obstruction of more than 50% of the artery). Over a 5.2-year follow-up period, 246 deaths occurred, representing 13.5% of the total study group.

Major adverse cardiovascular event (MACE) data were available for 973 patients. During the follow-up period, 295 (30.3%) of the patients had a MACE, such as heart attack or a coronary revascularization.

The researchers found that both obstructive and mild, or nonobstructive, coronary artery disease, as determined by CCTA, were associated with patient deaths and MACE. Most importantly, the researchers found that the relative risk for death or MACE for a patient with mild coronary artery disease was comparable to that of patients with single vessel obstructive disease.

“Until now, two-year follow-up studies suggested that a diabetic patient with mild or nonobstructive coronary artery disease had a lower risk of major adverse cardiovascular events and death than patients with obstructive disease,” said Philipp Blanke, MD, a radiologist at the University of British Columbia and St. Paul’s Hospital and a coauthor of the study. “Our five-year follow-up data suggest that nonobstructive and obstructive coronary artery disease, as detected by cardiac CTA in diabetic patients, are both associated with higher rates of mortality.”

Researchers need a better understanding of the evolution of plaque in the arteries and of patient response to therapies, said Dr. Leipsic. “Cardiac CT angiography is helpful for identifying diabetic patients who are at higher risk for heart events and who may benefit from more aggressive therapy to help modify that risk,” he added.

Patients Prefer Direct Access to Imaging Records
Patients value direct, independent access to their medical exams, researchers reported.

Giampaolo Greco, PhD, MPH, Assistant Professor in the Department of Population Health Science and Policy at the Mount Sinai School of Medicine in New York City, and colleagues set out to evaluate patient and provider satisfaction with RSNA Image Share, an Internet-based interoperable image exchange system that gives patients ownership of their imaging exams and control over access to their imaging records. The network enables radiology sites to make results of imaging exams available for patients to incorporate in personal health record (PHR) accounts they can use to securely store, manage, and share their imaging records. Sites also can use the network to send patient imaging records to other participating sites to support better informed care.

For the study, patients undergoing radiologic exams at four academic centers were eligible to establish online PHR accounts using the RSNA Image Share network. Patients could then use their PHR accounts to maintain and share their images with selected providers, creating a detailed medical history accessible through any secure Internet connection.

Between July 2012 and August 2013, the study enrolled 2,562 patients, mean age 50.4, including a significant representation of older individuals. Older individuals have the highest healthcare utilization and often experience or perceive a significant barrier in using information technology.

The median number of exams uploaded per patient was six. Study participants were provided a brief survey to assess patient and physician experience with the exchange of images, and 502 patients completed and returned their surveys. Of these respondents, 448 patients identified the method used at the visit to share images: Internet, CDs, both Internet and CDs, or other, and 165 included a section completed by their physician.

Nearly all (96%) of the patients responded positively to having direct access to their medical images, and 78% viewed their images independently. There was no difference between Internet and CD users in satisfaction with privacy and security and timeliness of access to medical images. A greater percentage of Internet users reported being able to access their images without difficulty, compared with CD users (88.3% vs 77.5%).

Patients receiving targeted anticancer treatments are at a significant risk of developing xerosis, or abnormal dryness, according to Dr. Johannah Valentine and her associates.

In a systematic review and meta-analysis of clinical trials involving 58 targeted agents, nearly 18% of all patients developed xerosis, with 1% of patients developing high-grade xerosis. The incidence may be affected by age, concomitant medications, comorbidities, and underlying malignancies or skin conditions, and reporting may vary among physicians and institutions, the researchers said.

Patients should be counseled and treated early for this symptom to prevent suboptimal dosing and quality-of-life impairment, the investigators recommended.

Read the full article at the Journal of the American Academy of Dermatology (doi:10.1016/j.jaad.2014.12.010).

Patients receiving targeted anticancer treatments are at a significant risk of developing xerosis, or abnormal dryness, according to Dr. Johannah Valentine and her associates.

In a systematic review and meta-analysis of clinical trials involving 58 targeted agents, nearly 18% of all patients developed xerosis, with 1% of patients developing high-grade xerosis. The incidence may be affected by age, concomitant medications, comorbidities, and underlying malignancies or skin conditions, and reporting may vary among physicians and institutions, the researchers said.

Patients should be counseled and treated early for this symptom to prevent suboptimal dosing and quality-of-life impairment, the investigators recommended.

Read the full article at the Journal of the American Academy of Dermatology (doi:10.1016/j.jaad.2014.12.010).

Patients receiving targeted anticancer treatments are at a significant risk of developing xerosis, or abnormal dryness, according to Dr. Johannah Valentine and her associates.

In a systematic review and meta-analysis of clinical trials involving 58 targeted agents, nearly 18% of all patients developed xerosis, with 1% of patients developing high-grade xerosis. The incidence may be affected by age, concomitant medications, comorbidities, and underlying malignancies or skin conditions, and reporting may vary among physicians and institutions, the researchers said.

Patients should be counseled and treated early for this symptom to prevent suboptimal dosing and quality-of-life impairment, the investigators recommended.

Read the full article at the Journal of the American Academy of Dermatology (doi:10.1016/j.jaad.2014.12.010).

SHM Public Policy Committee Chair Ron Greeno, MD, MHM, talks about policy issues facing hospitalist, and how "Hill Day 2015" works as an advocacy tool.

SHM Public Policy Committee Chair Ron Greeno, MD, MHM, talks about policy issues facing hospitalist, and how "Hill Day 2015" works as an advocacy tool.

SHM Public Policy Committee Chair Ron Greeno, MD, MHM, talks about policy issues facing hospitalist, and how "Hill Day 2015" works as an advocacy tool.

After the school shooting in Newtown, Conn., in December 2012, we saw an unprecedented amount of proposed legislation at both the state and national levels. The legislation was aimed at fixing whatever it is that is broken in our country that either causes or allows a young man to kill more than two dozen innocent people. Some legislators focused on gun control, while others focused on changing the mental health system, with the idea that the shooter’s actions were caused by his untreated mental illness.

Rep. Tim Murphy, Ph.D., has the distinction of being the only clinical psychologist in Congress, so it’s certainly understandable that he would focus on making long-overdue changes to our troubled mental health system. In addition, Rep. Murphy, a Republican from Pennsylvania, has a strong history of voting against legislation that would curb gun rights, and he carries an “A” grade from the National Rifle Association. When Rep. Murphy publicly promised the families of the Newtown victims that he would enact change, it was clear that his passion was for changing the mental health system. In 2013, Rep. Murphy, with bipartisan support, proposed The Helping Families in Mental Health Crisis Act.

The Murphy bill proposed sweeping and complex changes, and the text was 135 pages long. A major component of the bill was to create a position for an assistant secretary for mental health and substance use disorders within the Department of Health & Human Services to coordinate federal programs and ensure that evidence-based treatments were being used.

The bill also called for shifting money from the Substance Abuse and Mental Health Services Administration (SAMHSA) to the National Institute of Mental Health in the wake of recent thought that SAMHSA has become insensitive to severe mental illness and too oriented toward a recovery model that carries a vague antipsychiatry sentiment.

From there, the issues of patients’ rights versus a doctor-knows-best sentiment have influenced the act, as though one can’t be in favor of both. Perhaps the most controversial requirements include a provision that mandates all states to have outpatient civil commitment programs and a provision that says that health care providers may release information to caretakers of patients with psychiatric disorders without the patient’s consent if the information is felt to be necessary for the patient’s safety or welfare.

This last point is likely to be interpreted as suggesting that psychiatric patients don’t have the same right to confidentiality that other patients have, which would be true. It has the potential to be stigmatizing and infantilizing, and there are people who will not seek care because of the perception this creates. In addition, it may create tension between family members who feel the law now entitles them to information and psychiatrists who don’t see this is as necessary or who fear that releasing information will damage the therapeutic relationship.

Many components of the Helping Families in Mental Health Crisis Act have been applauded universally, but the American Psychiatric Association did not formally support the bill, and an opposing bill was proposed in Congress by Rep. Ron Barber, a Democrat from Arizona who took Gabrielle Giffords’ seat after an assassination attempt by a mentally ill man left her unable to serve. Both bills died when the congressional session ended in December, and Mr. Barber lost a re-election bid and has not returned to Congress.

A new Congress has convened, and Rep. Murphy will be re-introducing the Helping Families in Mental Health Crisis Act with numerous changes. Although the APA did not endorse the previous legislation, the association last week announced, with unanimous backing by the Board of Trustees, its support for the Murphy bill.

“We are pleased that Chairman Murphy is refining and reintroducing his comprehensive mental health reform bill, the Helping Families in Mental Health Crisis Act,” APA President Paul Summergrad said in the last week of January. At an event in early February, he said that he intends to add reforms that align well with APA priorities, including boosting the psychiatric workforce and monitoring and enforcement of mental health parity.

“In December the APA Board of Trustees carefully reviewed its strategy, principles and options for reform and unanimously voted to fully support the efforts of Chairman Murphy and his lead Democratic cosponsor, Rep. Eddie Bernice Johnson. Their efforts are historic in scope, and we are hopeful that Congress will through the legislative process act to pass comprehensive mental health reform with the bipartisan support it deserves.”

Still, I heard the news and was terribly disappointed in the APA. The decision to support this sweeping legislation was made without a vote by the Assembly, with the knowledge that some of these issues are quite polarizing. In addition to the HIPAA disqualification, the issue of outpatient civil commitment, in particular, is controversial. Although proponents are quick to point to research that show its benefits – the research has been done specifically on Kendra’s Law in New York, where $125 million was placed into that state’s mental health system to shore up services – we don’t have the research to know if what helps is providing more services or strong-armed coercion. The text of the bill will be released in the coming weeks. At the very least, couldn’t the APA have waited to see exactly what it is we endorsed?

Dr. Miller is writing a book on involuntary psychiatric care.

After the school shooting in Newtown, Conn., in December 2012, we saw an unprecedented amount of proposed legislation at both the state and national levels. The legislation was aimed at fixing whatever it is that is broken in our country that either causes or allows a young man to kill more than two dozen innocent people. Some legislators focused on gun control, while others focused on changing the mental health system, with the idea that the shooter’s actions were caused by his untreated mental illness.

Rep. Tim Murphy, Ph.D., has the distinction of being the only clinical psychologist in Congress, so it’s certainly understandable that he would focus on making long-overdue changes to our troubled mental health system. In addition, Rep. Murphy, a Republican from Pennsylvania, has a strong history of voting against legislation that would curb gun rights, and he carries an “A” grade from the National Rifle Association. When Rep. Murphy publicly promised the families of the Newtown victims that he would enact change, it was clear that his passion was for changing the mental health system. In 2013, Rep. Murphy, with bipartisan support, proposed The Helping Families in Mental Health Crisis Act.

The Murphy bill proposed sweeping and complex changes, and the text was 135 pages long. A major component of the bill was to create a position for an assistant secretary for mental health and substance use disorders within the Department of Health & Human Services to coordinate federal programs and ensure that evidence-based treatments were being used.

The bill also called for shifting money from the Substance Abuse and Mental Health Services Administration (SAMHSA) to the National Institute of Mental Health in the wake of recent thought that SAMHSA has become insensitive to severe mental illness and too oriented toward a recovery model that carries a vague antipsychiatry sentiment.

From there, the issues of patients’ rights versus a doctor-knows-best sentiment have influenced the act, as though one can’t be in favor of both. Perhaps the most controversial requirements include a provision that mandates all states to have outpatient civil commitment programs and a provision that says that health care providers may release information to caretakers of patients with psychiatric disorders without the patient’s consent if the information is felt to be necessary for the patient’s safety or welfare.

This last point is likely to be interpreted as suggesting that psychiatric patients don’t have the same right to confidentiality that other patients have, which would be true. It has the potential to be stigmatizing and infantilizing, and there are people who will not seek care because of the perception this creates. In addition, it may create tension between family members who feel the law now entitles them to information and psychiatrists who don’t see this is as necessary or who fear that releasing information will damage the therapeutic relationship.

Many components of the Helping Families in Mental Health Crisis Act have been applauded universally, but the American Psychiatric Association did not formally support the bill, and an opposing bill was proposed in Congress by Rep. Ron Barber, a Democrat from Arizona who took Gabrielle Giffords’ seat after an assassination attempt by a mentally ill man left her unable to serve. Both bills died when the congressional session ended in December, and Mr. Barber lost a re-election bid and has not returned to Congress.

A new Congress has convened, and Rep. Murphy will be re-introducing the Helping Families in Mental Health Crisis Act with numerous changes. Although the APA did not endorse the previous legislation, the association last week announced, with unanimous backing by the Board of Trustees, its support for the Murphy bill.

“We are pleased that Chairman Murphy is refining and reintroducing his comprehensive mental health reform bill, the Helping Families in Mental Health Crisis Act,” APA President Paul Summergrad said in the last week of January. At an event in early February, he said that he intends to add reforms that align well with APA priorities, including boosting the psychiatric workforce and monitoring and enforcement of mental health parity.

“In December the APA Board of Trustees carefully reviewed its strategy, principles and options for reform and unanimously voted to fully support the efforts of Chairman Murphy and his lead Democratic cosponsor, Rep. Eddie Bernice Johnson. Their efforts are historic in scope, and we are hopeful that Congress will through the legislative process act to pass comprehensive mental health reform with the bipartisan support it deserves.”

Still, I heard the news and was terribly disappointed in the APA. The decision to support this sweeping legislation was made without a vote by the Assembly, with the knowledge that some of these issues are quite polarizing. In addition to the HIPAA disqualification, the issue of outpatient civil commitment, in particular, is controversial. Although proponents are quick to point to research that show its benefits – the research has been done specifically on Kendra’s Law in New York, where $125 million was placed into that state’s mental health system to shore up services – we don’t have the research to know if what helps is providing more services or strong-armed coercion. The text of the bill will be released in the coming weeks. At the very least, couldn’t the APA have waited to see exactly what it is we endorsed?

Dr. Miller is writing a book on involuntary psychiatric care.

After the school shooting in Newtown, Conn., in December 2012, we saw an unprecedented amount of proposed legislation at both the state and national levels. The legislation was aimed at fixing whatever it is that is broken in our country that either causes or allows a young man to kill more than two dozen innocent people. Some legislators focused on gun control, while others focused on changing the mental health system, with the idea that the shooter’s actions were caused by his untreated mental illness.

Rep. Tim Murphy, Ph.D., has the distinction of being the only clinical psychologist in Congress, so it’s certainly understandable that he would focus on making long-overdue changes to our troubled mental health system. In addition, Rep. Murphy, a Republican from Pennsylvania, has a strong history of voting against legislation that would curb gun rights, and he carries an “A” grade from the National Rifle Association. When Rep. Murphy publicly promised the families of the Newtown victims that he would enact change, it was clear that his passion was for changing the mental health system. In 2013, Rep. Murphy, with bipartisan support, proposed The Helping Families in Mental Health Crisis Act.

The Murphy bill proposed sweeping and complex changes, and the text was 135 pages long. A major component of the bill was to create a position for an assistant secretary for mental health and substance use disorders within the Department of Health & Human Services to coordinate federal programs and ensure that evidence-based treatments were being used.

The bill also called for shifting money from the Substance Abuse and Mental Health Services Administration (SAMHSA) to the National Institute of Mental Health in the wake of recent thought that SAMHSA has become insensitive to severe mental illness and too oriented toward a recovery model that carries a vague antipsychiatry sentiment.

From there, the issues of patients’ rights versus a doctor-knows-best sentiment have influenced the act, as though one can’t be in favor of both. Perhaps the most controversial requirements include a provision that mandates all states to have outpatient civil commitment programs and a provision that says that health care providers may release information to caretakers of patients with psychiatric disorders without the patient’s consent if the information is felt to be necessary for the patient’s safety or welfare.

This last point is likely to be interpreted as suggesting that psychiatric patients don’t have the same right to confidentiality that other patients have, which would be true. It has the potential to be stigmatizing and infantilizing, and there are people who will not seek care because of the perception this creates. In addition, it may create tension between family members who feel the law now entitles them to information and psychiatrists who don’t see this is as necessary or who fear that releasing information will damage the therapeutic relationship.

Many components of the Helping Families in Mental Health Crisis Act have been applauded universally, but the American Psychiatric Association did not formally support the bill, and an opposing bill was proposed in Congress by Rep. Ron Barber, a Democrat from Arizona who took Gabrielle Giffords’ seat after an assassination attempt by a mentally ill man left her unable to serve. Both bills died when the congressional session ended in December, and Mr. Barber lost a re-election bid and has not returned to Congress.

A new Congress has convened, and Rep. Murphy will be re-introducing the Helping Families in Mental Health Crisis Act with numerous changes. Although the APA did not endorse the previous legislation, the association last week announced, with unanimous backing by the Board of Trustees, its support for the Murphy bill.

“We are pleased that Chairman Murphy is refining and reintroducing his comprehensive mental health reform bill, the Helping Families in Mental Health Crisis Act,” APA President Paul Summergrad said in the last week of January. At an event in early February, he said that he intends to add reforms that align well with APA priorities, including boosting the psychiatric workforce and monitoring and enforcement of mental health parity.

“In December the APA Board of Trustees carefully reviewed its strategy, principles and options for reform and unanimously voted to fully support the efforts of Chairman Murphy and his lead Democratic cosponsor, Rep. Eddie Bernice Johnson. Their efforts are historic in scope, and we are hopeful that Congress will through the legislative process act to pass comprehensive mental health reform with the bipartisan support it deserves.”

Still, I heard the news and was terribly disappointed in the APA. The decision to support this sweeping legislation was made without a vote by the Assembly, with the knowledge that some of these issues are quite polarizing. In addition to the HIPAA disqualification, the issue of outpatient civil commitment, in particular, is controversial. Although proponents are quick to point to research that show its benefits – the research has been done specifically on Kendra’s Law in New York, where $125 million was placed into that state’s mental health system to shore up services – we don’t have the research to know if what helps is providing more services or strong-armed coercion. The text of the bill will be released in the coming weeks. At the very least, couldn’t the APA have waited to see exactly what it is we endorsed?

Dr. Miller is writing a book on involuntary psychiatric care.

Kaempferol (3,5,7,4’-tetrahydroxyflavone; C₁₅H₁₀O₆) is among the natural flavonols found in green tea, broccoli, cabbage, kale, endive, beans, leeks, tomatoes, grapes, apples, grapefruit, berries, and propolis, as well as myriad other plant sources, including Brassica and species (J. Agric. Food Chem. 2006;54:2951-6; Cancer Prev. Res. (Phila) 2014;7:958-67; Biochem. Pharmacol. 2010;80:2042-9; Chem. Pharm. Bull. (Tokyo) 2012;60:1171-5; J. Eur. Acad. Dermatol. Venereol. 2013 June 27 [doi:10.1111/jdv.12204]).

It is one of the most commonly found dietary flavonoids and is also present in beer, particularly hops (Carcinogenesis 2010;31:1338-43; J. Eur. Acad. Dermatol. Venereol. 2013 June 27 [doi:10.1111/jdv.12204]). Significantly, kaempferol is known to exhibit anticancer, anti-inflammatory, antioxidant, cytoprotective, and antiapoptotic activity (Cancer Prev. Res. (Phila) 2014;7:958-67; Biochem. Pharmacol. 2010;80:2042-9; Exp. Mol. Med. 2008;40:208-19), and is believed to play a role in protecting plants from ultraviolet (UV)-induced damage (J. Agric. Food Chem. 2012;60:6966-76).

Skin protection: antioxidant and anti-inflammatory activity

Among 35 flavonoids tested by Cos et al. in 2001 for lipid peroxidation-inhibiting activity, kaempferol was identified as having the highest antioxidant selectivity index (Planta Med. 2001;67:515-9).

Work by Kim et al. in 2002 revealed that four kaempferol glycosides are key active ingredients in the flowers of Prunus persica, which has long been used in traditional Chinese medicine to treat skin disorders (J. Cosmet. Sci. 2002;53:27-34). Kim and colleagues have also shown in animal studies that the topical application of P. persica may be effective at thwarting UVB-induced skin damage (J. Cosmet. Sci. 2002;53:27-34).

In addition, kaempferol is a key component in Punica granatum, which has been found to act as an effective protector against UVB-induced photodamage and aging in cultured skin fibroblasts (Int. J. Dermatol. 2010;49:276-82).

In various tests on the effects of natural flavonoids on matrix metalloproteinase (MMP)-1 activity and expression, Lim et al. reported in 2007 that kaempferol and quercetin potently inhibited recombinant human MMP-1, and both flavonols along with apigenin and wogonin were found to be strong inhibitors of MMP-1 induction in 12-O-tetradecanoylphorbol-13-acetate–treated human dermal fibroblasts. All four flavonoids also suppressed the activation of activator protein (AP)-1. Kaempferol also hindered p38 mitogen-activated protein kinase c-Jun N-terminal kinase (JNK) activation. The investigators concluded that kaempferol is among the flavonoids or plant extracts containing them that may be useful as an agent to protect against photoaging and to treat some cutaneous inflammatory conditions (Planta Med. 2007;73:1267-74).

In 2010, Park et al. demonstrated that kaempferol alleviated burn injuries in mice and that expression of tumor necrosis factor–alpha (TNF-alpha) induced by burn injuries was reduced by kaempferol. They concluded that their findings suggest the possible application of kaempferol to treat thermal burn–induced skin injuries (BMB Rep. 2010;43:46-51).

Anti-inflammatory as well as depigmenting activity was found by Rho et al. in 2011 to be associated with kaempferol and kaempferol rhamnosides isolated from Hibiscus cannabinus (Molecules 2011;16:3338-44).

In 2014, Kim et al. found that extracts of Aceriphyllum rossii (native to Korea and China) and its active constituents, quercetin and kaempferol, blocked secretion of beta-hexosaminidase and histamine; lowered the production and mRNA expression of interleukin-4 and TNF-alpha; and reduced prostaglandin E₂ and leukotriene B₄ synthesis as well as the expression of cyclooxygenase-2 (COX-2) and 5-lipoxygenase. These and other findings led the investigators to conclude that A. rossii and its active ingredients kaempferol and quercetin may be effective agents for the treatment of immediate-type hypersensitivity (J. Agric. Food Chem. 2014;62:3750-8).

Anticancer activity

Lee et al. reported in 2010 that the inhibition by kaempferol of phosphatidylinositol 3-kinase (PI3K) activity, a key factor in carcinogenesis, and its concomitant effects may account for the chemopreventive activity of the flavonol (Carcinogenesis 2010;31:1338-43).

At the end of that year, Lee et al. found that kaempferol inhibited UVB-induced COX-2 protein expression in mouse skin epidermal JB6 P+ cells, by blocking Src kinase activity and attenuated the UVB-induced transcriptional activities of COX-2 gene and the transcription factor AP-1. They concluded that kaempferol exerts robust chemopreventive activity against skin cancer by suppressing Src (Biochem. Pharmacol. 2010;80:2042-9).

In 2014, Yao et al. found that kaempferol acted as a safe and potent inhibitor of solar ultraviolet-induced mouse skin carcinogenesis that acted by targeting RSK2 and MSK1 (Cancer Prev. Res. (Phila) 2014;7:958-67).

Significantly, in terms of topical delivery, Chao et al. recently showed that submicron emulsions are effective carriers for the transdermal delivery of kaempferol (Chem. Pharm. Bull. (Tokyo) 2012;60:1171-5).

Conclusion

Kaempferol is one among the many natural flavonols found to exert significant salutary effects. Evidence suggests reasons for confidence that kaempferol can play a role in skin health. More research is necessary to determine the effectiveness of topical products intended to harness the benefits of this flavonoid as proper formulation is challenging.

Dr. Baumann is chief executive officer of the Baumann Cosmetic & Research Institute in the Design District in Miami. She founded the Cosmetic Dermatology Center at the University of Miami in 1997. Dr. Baumann wrote the textbook, “Cosmetic Dermatology: Principles and Practice” (New York: McGraw-Hill, 2002), and a book for consumers, “The Skin Type Solution” (New York: Bantam Dell, 2006). She has contributed to the Cosmeceutical Critique column in Dermatology News since January 2001. Her latest book, “Cosmeceuticals and Cosmetic Ingredients,” was published in November 2014. Dr. Baumann has received funding for clinical grants from Allergan, Aveeno, Avon Products, Evolus, Galderma, GlaxoSmithKline, Kythera, Mary Kay, Medicis Pharmaceuticals, Neutrogena, Philosophy, Topix Pharmaceuticals, and Unilever.

Kaempferol (3,5,7,4’-tetrahydroxyflavone; C₁₅H₁₀O₆) is among the natural flavonols found in green tea, broccoli, cabbage, kale, endive, beans, leeks, tomatoes, grapes, apples, grapefruit, berries, and propolis, as well as myriad other plant sources, including Brassica and species (J. Agric. Food Chem. 2006;54:2951-6; Cancer Prev. Res. (Phila) 2014;7:958-67; Biochem. Pharmacol. 2010;80:2042-9; Chem. Pharm. Bull. (Tokyo) 2012;60:1171-5; J. Eur. Acad. Dermatol. Venereol. 2013 June 27 [doi:10.1111/jdv.12204]).

It is one of the most commonly found dietary flavonoids and is also present in beer, particularly hops (Carcinogenesis 2010;31:1338-43; J. Eur. Acad. Dermatol. Venereol. 2013 June 27 [doi:10.1111/jdv.12204]). Significantly, kaempferol is known to exhibit anticancer, anti-inflammatory, antioxidant, cytoprotective, and antiapoptotic activity (Cancer Prev. Res. (Phila) 2014;7:958-67; Biochem. Pharmacol. 2010;80:2042-9; Exp. Mol. Med. 2008;40:208-19), and is believed to play a role in protecting plants from ultraviolet (UV)-induced damage (J. Agric. Food Chem. 2012;60:6966-76).

Skin protection: antioxidant and anti-inflammatory activity

Among 35 flavonoids tested by Cos et al. in 2001 for lipid peroxidation-inhibiting activity, kaempferol was identified as having the highest antioxidant selectivity index (Planta Med. 2001;67:515-9).

Work by Kim et al. in 2002 revealed that four kaempferol glycosides are key active ingredients in the flowers of Prunus persica, which has long been used in traditional Chinese medicine to treat skin disorders (J. Cosmet. Sci. 2002;53:27-34). Kim and colleagues have also shown in animal studies that the topical application of P. persica may be effective at thwarting UVB-induced skin damage (J. Cosmet. Sci. 2002;53:27-34).

In addition, kaempferol is a key component in Punica granatum, which has been found to act as an effective protector against UVB-induced photodamage and aging in cultured skin fibroblasts (Int. J. Dermatol. 2010;49:276-82).

In various tests on the effects of natural flavonoids on matrix metalloproteinase (MMP)-1 activity and expression, Lim et al. reported in 2007 that kaempferol and quercetin potently inhibited recombinant human MMP-1, and both flavonols along with apigenin and wogonin were found to be strong inhibitors of MMP-1 induction in 12-O-tetradecanoylphorbol-13-acetate–treated human dermal fibroblasts. All four flavonoids also suppressed the activation of activator protein (AP)-1. Kaempferol also hindered p38 mitogen-activated protein kinase c-Jun N-terminal kinase (JNK) activation. The investigators concluded that kaempferol is among the flavonoids or plant extracts containing them that may be useful as an agent to protect against photoaging and to treat some cutaneous inflammatory conditions (Planta Med. 2007;73:1267-74).

In 2010, Park et al. demonstrated that kaempferol alleviated burn injuries in mice and that expression of tumor necrosis factor–alpha (TNF-alpha) induced by burn injuries was reduced by kaempferol. They concluded that their findings suggest the possible application of kaempferol to treat thermal burn–induced skin injuries (BMB Rep. 2010;43:46-51).

Anti-inflammatory as well as depigmenting activity was found by Rho et al. in 2011 to be associated with kaempferol and kaempferol rhamnosides isolated from Hibiscus cannabinus (Molecules 2011;16:3338-44).

In 2014, Kim et al. found that extracts of Aceriphyllum rossii (native to Korea and China) and its active constituents, quercetin and kaempferol, blocked secretion of beta-hexosaminidase and histamine; lowered the production and mRNA expression of interleukin-4 and TNF-alpha; and reduced prostaglandin E₂ and leukotriene B₄ synthesis as well as the expression of cyclooxygenase-2 (COX-2) and 5-lipoxygenase. These and other findings led the investigators to conclude that A. rossii and its active ingredients kaempferol and quercetin may be effective agents for the treatment of immediate-type hypersensitivity (J. Agric. Food Chem. 2014;62:3750-8).

Anticancer activity

Lee et al. reported in 2010 that the inhibition by kaempferol of phosphatidylinositol 3-kinase (PI3K) activity, a key factor in carcinogenesis, and its concomitant effects may account for the chemopreventive activity of the flavonol (Carcinogenesis 2010;31:1338-43).

At the end of that year, Lee et al. found that kaempferol inhibited UVB-induced COX-2 protein expression in mouse skin epidermal JB6 P+ cells, by blocking Src kinase activity and attenuated the UVB-induced transcriptional activities of COX-2 gene and the transcription factor AP-1. They concluded that kaempferol exerts robust chemopreventive activity against skin cancer by suppressing Src (Biochem. Pharmacol. 2010;80:2042-9).

In 2014, Yao et al. found that kaempferol acted as a safe and potent inhibitor of solar ultraviolet-induced mouse skin carcinogenesis that acted by targeting RSK2 and MSK1 (Cancer Prev. Res. (Phila) 2014;7:958-67).

Significantly, in terms of topical delivery, Chao et al. recently showed that submicron emulsions are effective carriers for the transdermal delivery of kaempferol (Chem. Pharm. Bull. (Tokyo) 2012;60:1171-5).

Conclusion

Kaempferol is one among the many natural flavonols found to exert significant salutary effects. Evidence suggests reasons for confidence that kaempferol can play a role in skin health. More research is necessary to determine the effectiveness of topical products intended to harness the benefits of this flavonoid as proper formulation is challenging.

Dr. Baumann is chief executive officer of the Baumann Cosmetic & Research Institute in the Design District in Miami. She founded the Cosmetic Dermatology Center at the University of Miami in 1997. Dr. Baumann wrote the textbook, “Cosmetic Dermatology: Principles and Practice” (New York: McGraw-Hill, 2002), and a book for consumers, “The Skin Type Solution” (New York: Bantam Dell, 2006). She has contributed to the Cosmeceutical Critique column in Dermatology News since January 2001. Her latest book, “Cosmeceuticals and Cosmetic Ingredients,” was published in November 2014. Dr. Baumann has received funding for clinical grants from Allergan, Aveeno, Avon Products, Evolus, Galderma, GlaxoSmithKline, Kythera, Mary Kay, Medicis Pharmaceuticals, Neutrogena, Philosophy, Topix Pharmaceuticals, and Unilever.

Kaempferol (3,5,7,4’-tetrahydroxyflavone; C₁₅H₁₀O₆) is among the natural flavonols found in green tea, broccoli, cabbage, kale, endive, beans, leeks, tomatoes, grapes, apples, grapefruit, berries, and propolis, as well as myriad other plant sources, including Brassica and species (J. Agric. Food Chem. 2006;54:2951-6; Cancer Prev. Res. (Phila) 2014;7:958-67; Biochem. Pharmacol. 2010;80:2042-9; Chem. Pharm. Bull. (Tokyo) 2012;60:1171-5; J. Eur. Acad. Dermatol. Venereol. 2013 June 27 [doi:10.1111/jdv.12204]).

It is one of the most commonly found dietary flavonoids and is also present in beer, particularly hops (Carcinogenesis 2010;31:1338-43; J. Eur. Acad. Dermatol. Venereol. 2013 June 27 [doi:10.1111/jdv.12204]). Significantly, kaempferol is known to exhibit anticancer, anti-inflammatory, antioxidant, cytoprotective, and antiapoptotic activity (Cancer Prev. Res. (Phila) 2014;7:958-67; Biochem. Pharmacol. 2010;80:2042-9; Exp. Mol. Med. 2008;40:208-19), and is believed to play a role in protecting plants from ultraviolet (UV)-induced damage (J. Agric. Food Chem. 2012;60:6966-76).

Skin protection: antioxidant and anti-inflammatory activity

Among 35 flavonoids tested by Cos et al. in 2001 for lipid peroxidation-inhibiting activity, kaempferol was identified as having the highest antioxidant selectivity index (Planta Med. 2001;67:515-9).

Work by Kim et al. in 2002 revealed that four kaempferol glycosides are key active ingredients in the flowers of Prunus persica, which has long been used in traditional Chinese medicine to treat skin disorders (J. Cosmet. Sci. 2002;53:27-34). Kim and colleagues have also shown in animal studies that the topical application of P. persica may be effective at thwarting UVB-induced skin damage (J. Cosmet. Sci. 2002;53:27-34).

In addition, kaempferol is a key component in Punica granatum, which has been found to act as an effective protector against UVB-induced photodamage and aging in cultured skin fibroblasts (Int. J. Dermatol. 2010;49:276-82).

In various tests on the effects of natural flavonoids on matrix metalloproteinase (MMP)-1 activity and expression, Lim et al. reported in 2007 that kaempferol and quercetin potently inhibited recombinant human MMP-1, and both flavonols along with apigenin and wogonin were found to be strong inhibitors of MMP-1 induction in 12-O-tetradecanoylphorbol-13-acetate–treated human dermal fibroblasts. All four flavonoids also suppressed the activation of activator protein (AP)-1. Kaempferol also hindered p38 mitogen-activated protein kinase c-Jun N-terminal kinase (JNK) activation. The investigators concluded that kaempferol is among the flavonoids or plant extracts containing them that may be useful as an agent to protect against photoaging and to treat some cutaneous inflammatory conditions (Planta Med. 2007;73:1267-74).

In 2010, Park et al. demonstrated that kaempferol alleviated burn injuries in mice and that expression of tumor necrosis factor–alpha (TNF-alpha) induced by burn injuries was reduced by kaempferol. They concluded that their findings suggest the possible application of kaempferol to treat thermal burn–induced skin injuries (BMB Rep. 2010;43:46-51).

Anti-inflammatory as well as depigmenting activity was found by Rho et al. in 2011 to be associated with kaempferol and kaempferol rhamnosides isolated from Hibiscus cannabinus (Molecules 2011;16:3338-44).

In 2014, Kim et al. found that extracts of Aceriphyllum rossii (native to Korea and China) and its active constituents, quercetin and kaempferol, blocked secretion of beta-hexosaminidase and histamine; lowered the production and mRNA expression of interleukin-4 and TNF-alpha; and reduced prostaglandin E₂ and leukotriene B₄ synthesis as well as the expression of cyclooxygenase-2 (COX-2) and 5-lipoxygenase. These and other findings led the investigators to conclude that A. rossii and its active ingredients kaempferol and quercetin may be effective agents for the treatment of immediate-type hypersensitivity (J. Agric. Food Chem. 2014;62:3750-8).

Anticancer activity

Lee et al. reported in 2010 that the inhibition by kaempferol of phosphatidylinositol 3-kinase (PI3K) activity, a key factor in carcinogenesis, and its concomitant effects may account for the chemopreventive activity of the flavonol (Carcinogenesis 2010;31:1338-43).

At the end of that year, Lee et al. found that kaempferol inhibited UVB-induced COX-2 protein expression in mouse skin epidermal JB6 P+ cells, by blocking Src kinase activity and attenuated the UVB-induced transcriptional activities of COX-2 gene and the transcription factor AP-1. They concluded that kaempferol exerts robust chemopreventive activity against skin cancer by suppressing Src (Biochem. Pharmacol. 2010;80:2042-9).

In 2014, Yao et al. found that kaempferol acted as a safe and potent inhibitor of solar ultraviolet-induced mouse skin carcinogenesis that acted by targeting RSK2 and MSK1 (Cancer Prev. Res. (Phila) 2014;7:958-67).

Significantly, in terms of topical delivery, Chao et al. recently showed that submicron emulsions are effective carriers for the transdermal delivery of kaempferol (Chem. Pharm. Bull. (Tokyo) 2012;60:1171-5).

Conclusion

Kaempferol is one among the many natural flavonols found to exert significant salutary effects. Evidence suggests reasons for confidence that kaempferol can play a role in skin health. More research is necessary to determine the effectiveness of topical products intended to harness the benefits of this flavonoid as proper formulation is challenging.

Dr. Baumann is chief executive officer of the Baumann Cosmetic & Research Institute in the Design District in Miami. She founded the Cosmetic Dermatology Center at the University of Miami in 1997. Dr. Baumann wrote the textbook, “Cosmetic Dermatology: Principles and Practice” (New York: McGraw-Hill, 2002), and a book for consumers, “The Skin Type Solution” (New York: Bantam Dell, 2006). She has contributed to the Cosmeceutical Critique column in Dermatology News since January 2001. Her latest book, “Cosmeceuticals and Cosmetic Ingredients,” was published in November 2014. Dr. Baumann has received funding for clinical grants from Allergan, Aveeno, Avon Products, Evolus, Galderma, GlaxoSmithKline, Kythera, Mary Kay, Medicis Pharmaceuticals, Neutrogena, Philosophy, Topix Pharmaceuticals, and Unilever.

Michelle Fanale, MD

Photo by Larry Young

SAN FRANCISCO—Preclinical and early phase 1 results suggest the aurora A kinase inhibitor alisertib and the histone deacetylase (HDAC) inhibitor romidepsin have synergistic activity against T-cell lymphomas.

In the preclinical study, the drugs showed synergy in cutaneous T-cell lymphoma (CTCL) cell lines and a benefit over monotherapy in vivo.

In the phase 1 study, romidepsin and alisertib produced clinical benefits in patients with peripheral T-cell lymphoma (PTCL).

Unfortunately, there are currently no good markers for predicting which patients might benefit from this type of combination, potentially because the drugs have multivariate mechanisms of action, said Michelle Fanale, MD, of the University of Texas MD Anderson Cancer Center in Houston.

She presented data on romidepsin and alisertib in combination at the 7th Annual T-cell Lymphoma Forum.

Dr Fanale said she was inspired to test the combination (in a phase 1 trial) after researchers reported promising results with the aurora kinase inhibitors MK-0457 and MK-5108 in combination with the HDAC inhibitor vorinostat (Kretzner et al, Cancer Research 2011).

She noted that aurora kinase inhibitors work mainly through actions at the G2-M transition point, while HDAC inhibitors induce G1-S transition. HDAC inhibitors can also degrade aurora A and B kinases, and the drugs modify kinetochore assembly through hyperacetylation of pericentromeric histones.

“When you actually treat with an HDAC inhibitor by itself, you’re basically getting an increase of this sub-G1 population,” Dr Fanale said. “When you treat with your aurora kinase inhibitor by itself, you’re clearly getting an increase of cells that are arresting at G2/M.”

“When you treat with the combination, you’re actually getting a further increase in the sub-G1, denoting dead cells, and then you’re further getting some increase of cells spreading out now through the G2/M portion as well.”

Preclinical research

Dr Fanale presented preclinical results showing that alisertib is highly synergistic with romidepsin in T-cell, but not B-cell, lymphoma. She was not involved in the research, which was also presented at the recent ASH Annual Meeting (Zullo et al, ASH 2014, abst 4493).

The researchers administered romidepsin at IC_10-20 concentrations, with increasing concentrations of alisertib, and incubated cells for 72 hours. A synergy coefficient less than 1 denoted synergy.

The combination demonstrated synergy in the HH (CTCL) cell line when alisertib was given at 100 nM or 1000 nM (0.68 and 0.40, respectively) but not at 50 nM (1.05).

Likewise, the combination demonstrated synergy in the H9 (CTCL) cell line when alisertib was given at 100 nM or 1000 nM (0.66 and 0.46, respectively) but not at 50 nM (1.1).

Romidepsin was shown to cause a mild increase in the percent of cells in G1 compared with alisertib, which significantly increased the percent of cells in G2/M arrest. And live cell imaging showed marked cytokinesis failure following treatment.

“When looking at further markers for apoptosis, when giving the combination, there’s further increase in caspase 3 and PARP cleavage, as well as other pro-apoptotic proteins, including PUMA, and a decrease in the anti-apoptotic protein Bcl-xL,” Dr Fanale noted.

She also pointed out that, in an in vivo xenograft model, alisertib and romidepsin produced significantly better results than those observed with monotherapy or in controls.

Phase 1 trial

The phase 1 trial of romidepsin and alisertib in combination included patients with aggressive B- and T-cell lymphomas (NCT01897012; Fanale et al, ASH 2014, abst 1744).

Twelve patients have been enrolled to date. Ninety-two percent of patients had primary refractory disease, they had a median of 3.5 prior lines of therapy (range, 1 to 7), and none of the patients had received a stem cell transplant.

The patients received treatment as follows:

• Alisertib at 20 mg orally twice daily on days 1-7 and romidepsin at 6 mg/m² IV on days 1 and 8
• Alisertib at 20 mg orally twice daily on days 1-7 and romidepsin at 8 mg/m² IV on days 1 and 8
• Alisertib at 20 mg orally twice daily on days 1-7 and romidepsin at 10 mg/m² IV on days 1 and 8
• Alisertib at 40 mg orally twice daily on days 1-7 and romidepsin at 10 mg/m² IV on days 1 and 8
• Alisertib at 40 mg orally twice daily on days 1-7 and romidepsin at 12 mg/m² IV on days 1 and 8
• Alisertib at 40 mg orally twice daily on days 1-7 and romidepsin at 14 mg/m² IV on days 1 and 8.

The maximum-tolerated dose has not yet been reached. The main side effect was reversible myelosuppression. In the 24 cycles administered, patients experienced grade 3/4 neutropenia (62.5%), anemia (29%), and thrombocytopenia (48%).

Dr Fanale noted that 3 of the 4 patients with T-cell lymphomas had some level of clinical benefit after therapy.

One patient, a heavily pretreated patient with PTCL who was treated at the lowest dose, had a complete response lasting 10 months. The patient had received 7 prior lines of therapy, including romidepsin alone.

Two other patients had stable disease, one with PTCL and one with an overlap diagnosis of B-cell and T-cell lymphoma. The PTCL patient went on to receive a matched, unrelated-donor transplant and is doing well, Dr Fanale said.

“We’ve taken a pause from this clinical trial,” she added. “We plan to reopen it toward T-cell lymphoma patients, potentially exclusively, . . . and also potentially to change a bit of the dosing schema with both romidepsin and alisertib.”

Michelle Fanale, MD

Photo by Larry Young

SAN FRANCISCO—Preclinical and early phase 1 results suggest the aurora A kinase inhibitor alisertib and the histone deacetylase (HDAC) inhibitor romidepsin have synergistic activity against T-cell lymphomas.

In the preclinical study, the drugs showed synergy in cutaneous T-cell lymphoma (CTCL) cell lines and a benefit over monotherapy in vivo.

In the phase 1 study, romidepsin and alisertib produced clinical benefits in patients with peripheral T-cell lymphoma (PTCL).

Unfortunately, there are currently no good markers for predicting which patients might benefit from this type of combination, potentially because the drugs have multivariate mechanisms of action, said Michelle Fanale, MD, of the University of Texas MD Anderson Cancer Center in Houston.

She presented data on romidepsin and alisertib in combination at the 7th Annual T-cell Lymphoma Forum.

Dr Fanale said she was inspired to test the combination (in a phase 1 trial) after researchers reported promising results with the aurora kinase inhibitors MK-0457 and MK-5108 in combination with the HDAC inhibitor vorinostat (Kretzner et al, Cancer Research 2011).

She noted that aurora kinase inhibitors work mainly through actions at the G2-M transition point, while HDAC inhibitors induce G1-S transition. HDAC inhibitors can also degrade aurora A and B kinases, and the drugs modify kinetochore assembly through hyperacetylation of pericentromeric histones.

“When you actually treat with an HDAC inhibitor by itself, you’re basically getting an increase of this sub-G1 population,” Dr Fanale said. “When you treat with your aurora kinase inhibitor by itself, you’re clearly getting an increase of cells that are arresting at G2/M.”

“When you treat with the combination, you’re actually getting a further increase in the sub-G1, denoting dead cells, and then you’re further getting some increase of cells spreading out now through the G2/M portion as well.”

Preclinical research

Dr Fanale presented preclinical results showing that alisertib is highly synergistic with romidepsin in T-cell, but not B-cell, lymphoma. She was not involved in the research, which was also presented at the recent ASH Annual Meeting (Zullo et al, ASH 2014, abst 4493).

The researchers administered romidepsin at IC_10-20 concentrations, with increasing concentrations of alisertib, and incubated cells for 72 hours. A synergy coefficient less than 1 denoted synergy.

The combination demonstrated synergy in the HH (CTCL) cell line when alisertib was given at 100 nM or 1000 nM (0.68 and 0.40, respectively) but not at 50 nM (1.05).

Likewise, the combination demonstrated synergy in the H9 (CTCL) cell line when alisertib was given at 100 nM or 1000 nM (0.66 and 0.46, respectively) but not at 50 nM (1.1).

Romidepsin was shown to cause a mild increase in the percent of cells in G1 compared with alisertib, which significantly increased the percent of cells in G2/M arrest. And live cell imaging showed marked cytokinesis failure following treatment.

“When looking at further markers for apoptosis, when giving the combination, there’s further increase in caspase 3 and PARP cleavage, as well as other pro-apoptotic proteins, including PUMA, and a decrease in the anti-apoptotic protein Bcl-xL,” Dr Fanale noted.

She also pointed out that, in an in vivo xenograft model, alisertib and romidepsin produced significantly better results than those observed with monotherapy or in controls.

Phase 1 trial

The phase 1 trial of romidepsin and alisertib in combination included patients with aggressive B- and T-cell lymphomas (NCT01897012; Fanale et al, ASH 2014, abst 1744).

Twelve patients have been enrolled to date. Ninety-two percent of patients had primary refractory disease, they had a median of 3.5 prior lines of therapy (range, 1 to 7), and none of the patients had received a stem cell transplant.

The patients received treatment as follows:

• Alisertib at 20 mg orally twice daily on days 1-7 and romidepsin at 6 mg/m² IV on days 1 and 8
• Alisertib at 20 mg orally twice daily on days 1-7 and romidepsin at 8 mg/m² IV on days 1 and 8
• Alisertib at 20 mg orally twice daily on days 1-7 and romidepsin at 10 mg/m² IV on days 1 and 8
• Alisertib at 40 mg orally twice daily on days 1-7 and romidepsin at 10 mg/m² IV on days 1 and 8
• Alisertib at 40 mg orally twice daily on days 1-7 and romidepsin at 12 mg/m² IV on days 1 and 8
• Alisertib at 40 mg orally twice daily on days 1-7 and romidepsin at 14 mg/m² IV on days 1 and 8.

The maximum-tolerated dose has not yet been reached. The main side effect was reversible myelosuppression. In the 24 cycles administered, patients experienced grade 3/4 neutropenia (62.5%), anemia (29%), and thrombocytopenia (48%).

Dr Fanale noted that 3 of the 4 patients with T-cell lymphomas had some level of clinical benefit after therapy.

One patient, a heavily pretreated patient with PTCL who was treated at the lowest dose, had a complete response lasting 10 months. The patient had received 7 prior lines of therapy, including romidepsin alone.

Two other patients had stable disease, one with PTCL and one with an overlap diagnosis of B-cell and T-cell lymphoma. The PTCL patient went on to receive a matched, unrelated-donor transplant and is doing well, Dr Fanale said.

“We’ve taken a pause from this clinical trial,” she added. “We plan to reopen it toward T-cell lymphoma patients, potentially exclusively, . . . and also potentially to change a bit of the dosing schema with both romidepsin and alisertib.”

Michelle Fanale, MD

Photo by Larry Young

SAN FRANCISCO—Preclinical and early phase 1 results suggest the aurora A kinase inhibitor alisertib and the histone deacetylase (HDAC) inhibitor romidepsin have synergistic activity against T-cell lymphomas.

In the preclinical study, the drugs showed synergy in cutaneous T-cell lymphoma (CTCL) cell lines and a benefit over monotherapy in vivo.

In the phase 1 study, romidepsin and alisertib produced clinical benefits in patients with peripheral T-cell lymphoma (PTCL).

Unfortunately, there are currently no good markers for predicting which patients might benefit from this type of combination, potentially because the drugs have multivariate mechanisms of action, said Michelle Fanale, MD, of the University of Texas MD Anderson Cancer Center in Houston.

She presented data on romidepsin and alisertib in combination at the 7th Annual T-cell Lymphoma Forum.

Dr Fanale said she was inspired to test the combination (in a phase 1 trial) after researchers reported promising results with the aurora kinase inhibitors MK-0457 and MK-5108 in combination with the HDAC inhibitor vorinostat (Kretzner et al, Cancer Research 2011).

She noted that aurora kinase inhibitors work mainly through actions at the G2-M transition point, while HDAC inhibitors induce G1-S transition. HDAC inhibitors can also degrade aurora A and B kinases, and the drugs modify kinetochore assembly through hyperacetylation of pericentromeric histones.

“When you actually treat with an HDAC inhibitor by itself, you’re basically getting an increase of this sub-G1 population,” Dr Fanale said. “When you treat with your aurora kinase inhibitor by itself, you’re clearly getting an increase of cells that are arresting at G2/M.”

“When you treat with the combination, you’re actually getting a further increase in the sub-G1, denoting dead cells, and then you’re further getting some increase of cells spreading out now through the G2/M portion as well.”

Preclinical research

Dr Fanale presented preclinical results showing that alisertib is highly synergistic with romidepsin in T-cell, but not B-cell, lymphoma. She was not involved in the research, which was also presented at the recent ASH Annual Meeting (Zullo et al, ASH 2014, abst 4493).

The researchers administered romidepsin at IC_10-20 concentrations, with increasing concentrations of alisertib, and incubated cells for 72 hours. A synergy coefficient less than 1 denoted synergy.

The combination demonstrated synergy in the HH (CTCL) cell line when alisertib was given at 100 nM or 1000 nM (0.68 and 0.40, respectively) but not at 50 nM (1.05).

Likewise, the combination demonstrated synergy in the H9 (CTCL) cell line when alisertib was given at 100 nM or 1000 nM (0.66 and 0.46, respectively) but not at 50 nM (1.1).

Romidepsin was shown to cause a mild increase in the percent of cells in G1 compared with alisertib, which significantly increased the percent of cells in G2/M arrest. And live cell imaging showed marked cytokinesis failure following treatment.

“When looking at further markers for apoptosis, when giving the combination, there’s further increase in caspase 3 and PARP cleavage, as well as other pro-apoptotic proteins, including PUMA, and a decrease in the anti-apoptotic protein Bcl-xL,” Dr Fanale noted.

She also pointed out that, in an in vivo xenograft model, alisertib and romidepsin produced significantly better results than those observed with monotherapy or in controls.

Phase 1 trial

The phase 1 trial of romidepsin and alisertib in combination included patients with aggressive B- and T-cell lymphomas (NCT01897012; Fanale et al, ASH 2014, abst 1744).

Twelve patients have been enrolled to date. Ninety-two percent of patients had primary refractory disease, they had a median of 3.5 prior lines of therapy (range, 1 to 7), and none of the patients had received a stem cell transplant.

The patients received treatment as follows:

• Alisertib at 20 mg orally twice daily on days 1-7 and romidepsin at 6 mg/m² IV on days 1 and 8
• Alisertib at 20 mg orally twice daily on days 1-7 and romidepsin at 8 mg/m² IV on days 1 and 8
• Alisertib at 20 mg orally twice daily on days 1-7 and romidepsin at 10 mg/m² IV on days 1 and 8
• Alisertib at 40 mg orally twice daily on days 1-7 and romidepsin at 10 mg/m² IV on days 1 and 8
• Alisertib at 40 mg orally twice daily on days 1-7 and romidepsin at 12 mg/m² IV on days 1 and 8
• Alisertib at 40 mg orally twice daily on days 1-7 and romidepsin at 14 mg/m² IV on days 1 and 8.

The maximum-tolerated dose has not yet been reached. The main side effect was reversible myelosuppression. In the 24 cycles administered, patients experienced grade 3/4 neutropenia (62.5%), anemia (29%), and thrombocytopenia (48%).

Dr Fanale noted that 3 of the 4 patients with T-cell lymphomas had some level of clinical benefit after therapy.

One patient, a heavily pretreated patient with PTCL who was treated at the lowest dose, had a complete response lasting 10 months. The patient had received 7 prior lines of therapy, including romidepsin alone.

Two other patients had stable disease, one with PTCL and one with an overlap diagnosis of B-cell and T-cell lymphoma. The PTCL patient went on to receive a matched, unrelated-donor transplant and is doing well, Dr Fanale said.

“We’ve taken a pause from this clinical trial,” she added. “We plan to reopen it toward T-cell lymphoma patients, potentially exclusively, . . . and also potentially to change a bit of the dosing schema with both romidepsin and alisertib.”