In this interview, Dr. Lorenzo Norris, of Clinical Psychiatry News, and Dr. Henry A. Nasrallah, of Current Psychiatry, discuss the groundbreaking work of physicians that shows how early schizophrenia can begin manifesting in the brain. And they ask why psychiatry doesn’t seem to be taking the loss of brain tissue seen in schizophrenia and other forms of psychosis more seriously. When it comes to illnesses such as Alzheimer’s, physicians recognize the need to conserve brain tissue. Why is that not the case for schizophrenia?

“We can do much more for our patients than we’re doing right now,” Dr. Nasrallah said. “We’re delaying treatment, and that can lead to more brain damage. We also allow patients to relapse again and again ... it’s like benign neglect.”

Dr. Norris, editor in chief of MdEdge Psychiatry, has no disclosures. Dr. Nasrallah, editor in chief of Current Psychiatry, serves as a consultant and on the advisory boards of several companies, including Acadia, Alkermes, Allergan, Boehringer-Ingelheim, Janssen, Lundbeck, Neurocrine, Otsuka, Sunovion, and Teva. He also serves on speakers bureaus of several companies.

In this interview, Dr. Lorenzo Norris, of Clinical Psychiatry News, and Dr. Henry A. Nasrallah, of Current Psychiatry, discuss the groundbreaking work of physicians that shows how early schizophrenia can begin manifesting in the brain. And they ask why psychiatry doesn’t seem to be taking the loss of brain tissue seen in schizophrenia and other forms of psychosis more seriously. When it comes to illnesses such as Alzheimer’s, physicians recognize the need to conserve brain tissue. Why is that not the case for schizophrenia?

“We can do much more for our patients than we’re doing right now,” Dr. Nasrallah said. “We’re delaying treatment, and that can lead to more brain damage. We also allow patients to relapse again and again ... it’s like benign neglect.”

Dr. Norris, editor in chief of MdEdge Psychiatry, has no disclosures. Dr. Nasrallah, editor in chief of Current Psychiatry, serves as a consultant and on the advisory boards of several companies, including Acadia, Alkermes, Allergan, Boehringer-Ingelheim, Janssen, Lundbeck, Neurocrine, Otsuka, Sunovion, and Teva. He also serves on speakers bureaus of several companies.

In this interview, Dr. Lorenzo Norris, of Clinical Psychiatry News, and Dr. Henry A. Nasrallah, of Current Psychiatry, discuss the groundbreaking work of physicians that shows how early schizophrenia can begin manifesting in the brain. And they ask why psychiatry doesn’t seem to be taking the loss of brain tissue seen in schizophrenia and other forms of psychosis more seriously. When it comes to illnesses such as Alzheimer’s, physicians recognize the need to conserve brain tissue. Why is that not the case for schizophrenia?

“We can do much more for our patients than we’re doing right now,” Dr. Nasrallah said. “We’re delaying treatment, and that can lead to more brain damage. We also allow patients to relapse again and again ... it’s like benign neglect.”

Dr. Norris, editor in chief of MdEdge Psychiatry, has no disclosures. Dr. Nasrallah, editor in chief of Current Psychiatry, serves as a consultant and on the advisory boards of several companies, including Acadia, Alkermes, Allergan, Boehringer-Ingelheim, Janssen, Lundbeck, Neurocrine, Otsuka, Sunovion, and Teva. He also serves on speakers bureaus of several companies.

Fezakinumab, an interleukin-22 monoclonal antibody, “resulted in consistent improvements in clinical and molecular disease scores as compared with placebo” in a phase 2a study of adults with moderate to severe atopic dermatitis (AD), according to Emma Guttman-Yassky, MD, of Icahn School of Medicine at Mount Sinai, New York, and her associates.

In the double-blind, placebo-controlled trial, 60 patients were randomized to intravenous fezakinumab every 2 weeks for 10 weeks (40 patients) or placebo (20). Beginning at week 4, those who received fezakinumab “showed a consistently stronger and more significant mean SCORAD decline from baseline” compared with those on placebo. This became statistically significant at weeks 6-10 (P less than .05). “Differences between drug and placebo extended beyond the last dose” at week 10, they noted.*

The primary endpoint, the change in the SCORAD score from baseline at 12 weeks, was not statistically significant, however. 

In addition, progressive reductions were seen during weeks 14-20, with a significant difference between the drug and placebo arms (P = .049) observed at week 20.

[email protected]

SOURCE: Guttman-Yassky et al. J Am Acad Dermatol. 78(5);872-81.

Correction, 4/27/17: An earlier version of this article misstated the statistical significance of the primary endpoint.

Fezakinumab, an interleukin-22 monoclonal antibody, “resulted in consistent improvements in clinical and molecular disease scores as compared with placebo” in a phase 2a study of adults with moderate to severe atopic dermatitis (AD), according to Emma Guttman-Yassky, MD, of Icahn School of Medicine at Mount Sinai, New York, and her associates.

In the double-blind, placebo-controlled trial, 60 patients were randomized to intravenous fezakinumab every 2 weeks for 10 weeks (40 patients) or placebo (20). Beginning at week 4, those who received fezakinumab “showed a consistently stronger and more significant mean SCORAD decline from baseline” compared with those on placebo. This became statistically significant at weeks 6-10 (P less than .05). “Differences between drug and placebo extended beyond the last dose” at week 10, they noted.*

The primary endpoint, the change in the SCORAD score from baseline at 12 weeks, was not statistically significant, however. 

In addition, progressive reductions were seen during weeks 14-20, with a significant difference between the drug and placebo arms (P = .049) observed at week 20.

[email protected]

SOURCE: Guttman-Yassky et al. J Am Acad Dermatol. 78(5);872-81.

Correction, 4/27/17: An earlier version of this article misstated the statistical significance of the primary endpoint.

Fezakinumab, an interleukin-22 monoclonal antibody, “resulted in consistent improvements in clinical and molecular disease scores as compared with placebo” in a phase 2a study of adults with moderate to severe atopic dermatitis (AD), according to Emma Guttman-Yassky, MD, of Icahn School of Medicine at Mount Sinai, New York, and her associates.

In the double-blind, placebo-controlled trial, 60 patients were randomized to intravenous fezakinumab every 2 weeks for 10 weeks (40 patients) or placebo (20). Beginning at week 4, those who received fezakinumab “showed a consistently stronger and more significant mean SCORAD decline from baseline” compared with those on placebo. This became statistically significant at weeks 6-10 (P less than .05). “Differences between drug and placebo extended beyond the last dose” at week 10, they noted.*

The primary endpoint, the change in the SCORAD score from baseline at 12 weeks, was not statistically significant, however. 

In addition, progressive reductions were seen during weeks 14-20, with a significant difference between the drug and placebo arms (P = .049) observed at week 20.

[email protected]

SOURCE: Guttman-Yassky et al. J Am Acad Dermatol. 78(5);872-81.

Correction, 4/27/17: An earlier version of this article misstated the statistical significance of the primary endpoint.

The term climate refers to the average weather conditions of a specific geographic location measured over several decades.¹ While a certain degree of variation in the Earth’s climate is expected, a persistent warming or cooling trend is not. The factors driving the Earth’s warming remain difficult to prove.² We know the Earth previously has undergone dramatic climate changes and that natural factors driving these changes are varied (eg, the relationship between the Earth and the Sun, volcanic eruptions, solar irradiance).^1,3 These factors ideally change over protracted periods of time in a way that allows organisms to adapt to new environments.

Anthropogenic climate change refers to human-caused climate change. This is thought to be a major driving factor in the Earth’s recent warming trend, partly due to the rapidity of warming in recent years.³ According to climate scientists, the Earth’s temperature has risen 4°C to 7°C over the past 5000 years, but it has risen 0.7°C in just the past 100 years alone.⁴ Greenhouse gases such as carbon dioxide are emitted by various natural processes and human activities and play a central role in current warming because they trap solar heat and increase ambient temperature.³

In a recent edition of the commonly cited textbook Dermatology, Bolognia et al⁵ referenced climate change only once in a figure legend regarding the expansion of dengue fever in the Americas. However, climate change may have the potential to cause outright skin disease epidemics worldwide, and the Climate Change Committee of the International Society of Dermatology has called upon dermatologists across the globe to help raise awareness of this issue.⁶

Much of the literature regarding the effects of climate change on human health focuses on insect-borne diseases, but over the past decade other areas of impact also have been investigated, such as increases in airborne diseases, zoonoses, newly endemic saprophytic and dimorphic fungal infections, fecal-oral diseases, and severe allergic disease.^7,8 It is postulated that climate change leads to region-specific increases in human disease because it creates newly favorable habitats for infectious agents, their vectors. and their reservoirs, allowing expansion of their ranges and access to immunologically naïve populations.⁹ Furthermore, extreme weather events such as heat waves, hurricanes, and flooding, which are expected to increase in frequency as a result of climate change, have all been linked to infectious disease outbreaks.¹⁰

Lyme Disease

In the past 20 years, Lyme disease incidence has tripled in the United States.¹¹ It has been hypothesized that the increase may be occurring as a result of the expanding geographic distribution of the Ixodes tick and its mammalian hosts (eg, white-tailed deer) under the influence of climate change.¹² Lyme disease is a multisystem disease affecting the skin, joints, heart, and nervous system. Its most characteristic manifestation is cutaneous in the form of erythema migrans. Dermatologists may be called upon to play an increasingly important role in early detection and treatment of this potentially chronic and debilitating condition.

Arboviruses

Arboviruses are transmitted by arthropods and are an important category of climate change–related diseases due to the expansion of the mosquito habitat worldwide. The vectorial capacity for the transmission of dengue fever has increased worldwide by 9.4% via Aedes aegypti and 11.1% via Aedes albopictus since 1950.¹³ Dengue fever, also known as breakbone fever, presents with intense joint pain, fevers, headaches, and a transient morbilliform rash that desquamates with defervescence and in some cases will incite hemorrhagic skin lesions.¹⁴ Dengue fever previously was considered to be a tropical disease but locally acquired cases have been reported in the United States, including Texas, Hawaii, and Florida.^15,16

Reports of local transmission of chikungunya, another arbovirus transmitted by A albopictus and A aegypti mosquitoes in Florida, the US Virgin Islands, and Puerto Rico, began in 2014.¹⁷ A higher prevalence of these diseases within the United States also may be related to increased globalization, with US travelers returning from endemic regions with infections. Prior to 2014, transmission occurred in traditional endemic regions, primarily in Asia, Africa, or island nations in the Indian Ocean. Like dengue fever, chikungunya causes high fevers, cutaneous manifestations (eg, urticarial papules, morbilliform eruption, hypermelanosis, intertriginous lesions, lymphedema),¹⁷ and intense joint pain. Unlike dengue fever, however, joint involvement can be chronic, erosive, and debilitating.

Lastly, New World leishmaniasis, an arboviral disease characterized by mucocutaneous ulcers and transmitted by phlebotomine sand flies, has been acquired locally in Oklahoma and Texas when it was previously considered to be endemic to Mexico and Central and South America.^14,18 The habitats of New World Leishmania species are expected to expand northward, with an ecological niche model predicting that they reach southern Canada by the year 2080 due to the expanding habitats of sand fly and rodent vectors.¹⁹

Fungal Infections

In the Pacific Northwest, there have been reports of newly endemic Cryptococcus gattii and Coccidioides immitis, both of which previously had been confined to the southwestern United States.⁸ Endemic ranges of these mycotic pathogens may be expanding for a variety of reasons, with climate change creating new regions conducive to the colonization of these species.^8,20,21Coccidioides immitis is a soil-dwelling fungus that usually presents with primary pulmonary disease that can disseminate acutely or even months later. Prompt recognition of disseminated disease may allow life-saving therapy to be initiated. Cryptococcus gattii is a fungus with multiple niches, including oil, trees, and birds.²⁰ This fungus also is acquired via inhalation, with dissemination occurring most commonly in immunosuppressed patients to the central nervous system, bone, and skin. Primary or secondary infection with both of these fungi may present with cutaneous manifestations presenting as polymorphous lesions, including umbilicated or ulcerated papules, indurated nodules, and acneiform pustules.

Final Thoughts

Awareness of the shifting habitats of microorganisms and vectors locally is important in order for clinicians to make correct diagnoses in a timely fashion. Regional or endemic diseases are presenting outside their traditional boundaries due to changing habitats of microbes and vectors and may be easily overlooked, resulting in a delayed diagnosis. Being prepared to diagnose diseases with increasing incidence secondary to climate change and discussing this with patients is an important physician obligation, but it is not the only one. We cannot effectively advocate for the health of patients and the community while ignoring the destruction of the environment. Our additional responsibility is straightforward—being advocates for good stewardship of the Earth’s resources now on both a personal and a policy level.²²

The term climate refers to the average weather conditions of a specific geographic location measured over several decades.¹ While a certain degree of variation in the Earth’s climate is expected, a persistent warming or cooling trend is not. The factors driving the Earth’s warming remain difficult to prove.² We know the Earth previously has undergone dramatic climate changes and that natural factors driving these changes are varied (eg, the relationship between the Earth and the Sun, volcanic eruptions, solar irradiance).^1,3 These factors ideally change over protracted periods of time in a way that allows organisms to adapt to new environments.

Anthropogenic climate change refers to human-caused climate change. This is thought to be a major driving factor in the Earth’s recent warming trend, partly due to the rapidity of warming in recent years.³ According to climate scientists, the Earth’s temperature has risen 4°C to 7°C over the past 5000 years, but it has risen 0.7°C in just the past 100 years alone.⁴ Greenhouse gases such as carbon dioxide are emitted by various natural processes and human activities and play a central role in current warming because they trap solar heat and increase ambient temperature.³

In a recent edition of the commonly cited textbook Dermatology, Bolognia et al⁵ referenced climate change only once in a figure legend regarding the expansion of dengue fever in the Americas. However, climate change may have the potential to cause outright skin disease epidemics worldwide, and the Climate Change Committee of the International Society of Dermatology has called upon dermatologists across the globe to help raise awareness of this issue.⁶

Much of the literature regarding the effects of climate change on human health focuses on insect-borne diseases, but over the past decade other areas of impact also have been investigated, such as increases in airborne diseases, zoonoses, newly endemic saprophytic and dimorphic fungal infections, fecal-oral diseases, and severe allergic disease.^7,8 It is postulated that climate change leads to region-specific increases in human disease because it creates newly favorable habitats for infectious agents, their vectors. and their reservoirs, allowing expansion of their ranges and access to immunologically naïve populations.⁹ Furthermore, extreme weather events such as heat waves, hurricanes, and flooding, which are expected to increase in frequency as a result of climate change, have all been linked to infectious disease outbreaks.¹⁰

Lyme Disease

In the past 20 years, Lyme disease incidence has tripled in the United States.¹¹ It has been hypothesized that the increase may be occurring as a result of the expanding geographic distribution of the Ixodes tick and its mammalian hosts (eg, white-tailed deer) under the influence of climate change.¹² Lyme disease is a multisystem disease affecting the skin, joints, heart, and nervous system. Its most characteristic manifestation is cutaneous in the form of erythema migrans. Dermatologists may be called upon to play an increasingly important role in early detection and treatment of this potentially chronic and debilitating condition.

Arboviruses

Arboviruses are transmitted by arthropods and are an important category of climate change–related diseases due to the expansion of the mosquito habitat worldwide. The vectorial capacity for the transmission of dengue fever has increased worldwide by 9.4% via Aedes aegypti and 11.1% via Aedes albopictus since 1950.¹³ Dengue fever, also known as breakbone fever, presents with intense joint pain, fevers, headaches, and a transient morbilliform rash that desquamates with defervescence and in some cases will incite hemorrhagic skin lesions.¹⁴ Dengue fever previously was considered to be a tropical disease but locally acquired cases have been reported in the United States, including Texas, Hawaii, and Florida.^15,16

Reports of local transmission of chikungunya, another arbovirus transmitted by A albopictus and A aegypti mosquitoes in Florida, the US Virgin Islands, and Puerto Rico, began in 2014.¹⁷ A higher prevalence of these diseases within the United States also may be related to increased globalization, with US travelers returning from endemic regions with infections. Prior to 2014, transmission occurred in traditional endemic regions, primarily in Asia, Africa, or island nations in the Indian Ocean. Like dengue fever, chikungunya causes high fevers, cutaneous manifestations (eg, urticarial papules, morbilliform eruption, hypermelanosis, intertriginous lesions, lymphedema),¹⁷ and intense joint pain. Unlike dengue fever, however, joint involvement can be chronic, erosive, and debilitating.

Lastly, New World leishmaniasis, an arboviral disease characterized by mucocutaneous ulcers and transmitted by phlebotomine sand flies, has been acquired locally in Oklahoma and Texas when it was previously considered to be endemic to Mexico and Central and South America.^14,18 The habitats of New World Leishmania species are expected to expand northward, with an ecological niche model predicting that they reach southern Canada by the year 2080 due to the expanding habitats of sand fly and rodent vectors.¹⁹

Fungal Infections

In the Pacific Northwest, there have been reports of newly endemic Cryptococcus gattii and Coccidioides immitis, both of which previously had been confined to the southwestern United States.⁸ Endemic ranges of these mycotic pathogens may be expanding for a variety of reasons, with climate change creating new regions conducive to the colonization of these species.^8,20,21Coccidioides immitis is a soil-dwelling fungus that usually presents with primary pulmonary disease that can disseminate acutely or even months later. Prompt recognition of disseminated disease may allow life-saving therapy to be initiated. Cryptococcus gattii is a fungus with multiple niches, including oil, trees, and birds.²⁰ This fungus also is acquired via inhalation, with dissemination occurring most commonly in immunosuppressed patients to the central nervous system, bone, and skin. Primary or secondary infection with both of these fungi may present with cutaneous manifestations presenting as polymorphous lesions, including umbilicated or ulcerated papules, indurated nodules, and acneiform pustules.

Final Thoughts

Awareness of the shifting habitats of microorganisms and vectors locally is important in order for clinicians to make correct diagnoses in a timely fashion. Regional or endemic diseases are presenting outside their traditional boundaries due to changing habitats of microbes and vectors and may be easily overlooked, resulting in a delayed diagnosis. Being prepared to diagnose diseases with increasing incidence secondary to climate change and discussing this with patients is an important physician obligation, but it is not the only one. We cannot effectively advocate for the health of patients and the community while ignoring the destruction of the environment. Our additional responsibility is straightforward—being advocates for good stewardship of the Earth’s resources now on both a personal and a policy level.²²

The term climate refers to the average weather conditions of a specific geographic location measured over several decades.¹ While a certain degree of variation in the Earth’s climate is expected, a persistent warming or cooling trend is not. The factors driving the Earth’s warming remain difficult to prove.² We know the Earth previously has undergone dramatic climate changes and that natural factors driving these changes are varied (eg, the relationship between the Earth and the Sun, volcanic eruptions, solar irradiance).^1,3 These factors ideally change over protracted periods of time in a way that allows organisms to adapt to new environments.

Anthropogenic climate change refers to human-caused climate change. This is thought to be a major driving factor in the Earth’s recent warming trend, partly due to the rapidity of warming in recent years.³ According to climate scientists, the Earth’s temperature has risen 4°C to 7°C over the past 5000 years, but it has risen 0.7°C in just the past 100 years alone.⁴ Greenhouse gases such as carbon dioxide are emitted by various natural processes and human activities and play a central role in current warming because they trap solar heat and increase ambient temperature.³

In a recent edition of the commonly cited textbook Dermatology, Bolognia et al⁵ referenced climate change only once in a figure legend regarding the expansion of dengue fever in the Americas. However, climate change may have the potential to cause outright skin disease epidemics worldwide, and the Climate Change Committee of the International Society of Dermatology has called upon dermatologists across the globe to help raise awareness of this issue.⁶

Much of the literature regarding the effects of climate change on human health focuses on insect-borne diseases, but over the past decade other areas of impact also have been investigated, such as increases in airborne diseases, zoonoses, newly endemic saprophytic and dimorphic fungal infections, fecal-oral diseases, and severe allergic disease.^7,8 It is postulated that climate change leads to region-specific increases in human disease because it creates newly favorable habitats for infectious agents, their vectors. and their reservoirs, allowing expansion of their ranges and access to immunologically naïve populations.⁹ Furthermore, extreme weather events such as heat waves, hurricanes, and flooding, which are expected to increase in frequency as a result of climate change, have all been linked to infectious disease outbreaks.¹⁰

Lyme Disease

In the past 20 years, Lyme disease incidence has tripled in the United States.¹¹ It has been hypothesized that the increase may be occurring as a result of the expanding geographic distribution of the Ixodes tick and its mammalian hosts (eg, white-tailed deer) under the influence of climate change.¹² Lyme disease is a multisystem disease affecting the skin, joints, heart, and nervous system. Its most characteristic manifestation is cutaneous in the form of erythema migrans. Dermatologists may be called upon to play an increasingly important role in early detection and treatment of this potentially chronic and debilitating condition.

Arboviruses

Arboviruses are transmitted by arthropods and are an important category of climate change–related diseases due to the expansion of the mosquito habitat worldwide. The vectorial capacity for the transmission of dengue fever has increased worldwide by 9.4% via Aedes aegypti and 11.1% via Aedes albopictus since 1950.¹³ Dengue fever, also known as breakbone fever, presents with intense joint pain, fevers, headaches, and a transient morbilliform rash that desquamates with defervescence and in some cases will incite hemorrhagic skin lesions.¹⁴ Dengue fever previously was considered to be a tropical disease but locally acquired cases have been reported in the United States, including Texas, Hawaii, and Florida.^15,16

Reports of local transmission of chikungunya, another arbovirus transmitted by A albopictus and A aegypti mosquitoes in Florida, the US Virgin Islands, and Puerto Rico, began in 2014.¹⁷ A higher prevalence of these diseases within the United States also may be related to increased globalization, with US travelers returning from endemic regions with infections. Prior to 2014, transmission occurred in traditional endemic regions, primarily in Asia, Africa, or island nations in the Indian Ocean. Like dengue fever, chikungunya causes high fevers, cutaneous manifestations (eg, urticarial papules, morbilliform eruption, hypermelanosis, intertriginous lesions, lymphedema),¹⁷ and intense joint pain. Unlike dengue fever, however, joint involvement can be chronic, erosive, and debilitating.

Lastly, New World leishmaniasis, an arboviral disease characterized by mucocutaneous ulcers and transmitted by phlebotomine sand flies, has been acquired locally in Oklahoma and Texas when it was previously considered to be endemic to Mexico and Central and South America.^14,18 The habitats of New World Leishmania species are expected to expand northward, with an ecological niche model predicting that they reach southern Canada by the year 2080 due to the expanding habitats of sand fly and rodent vectors.¹⁹

Fungal Infections

In the Pacific Northwest, there have been reports of newly endemic Cryptococcus gattii and Coccidioides immitis, both of which previously had been confined to the southwestern United States.⁸ Endemic ranges of these mycotic pathogens may be expanding for a variety of reasons, with climate change creating new regions conducive to the colonization of these species.^8,20,21Coccidioides immitis is a soil-dwelling fungus that usually presents with primary pulmonary disease that can disseminate acutely or even months later. Prompt recognition of disseminated disease may allow life-saving therapy to be initiated. Cryptococcus gattii is a fungus with multiple niches, including oil, trees, and birds.²⁰ This fungus also is acquired via inhalation, with dissemination occurring most commonly in immunosuppressed patients to the central nervous system, bone, and skin. Primary or secondary infection with both of these fungi may present with cutaneous manifestations presenting as polymorphous lesions, including umbilicated or ulcerated papules, indurated nodules, and acneiform pustules.

Final Thoughts

Awareness of the shifting habitats of microorganisms and vectors locally is important in order for clinicians to make correct diagnoses in a timely fashion. Regional or endemic diseases are presenting outside their traditional boundaries due to changing habitats of microbes and vectors and may be easily overlooked, resulting in a delayed diagnosis. Being prepared to diagnose diseases with increasing incidence secondary to climate change and discussing this with patients is an important physician obligation, but it is not the only one. We cannot effectively advocate for the health of patients and the community while ignoring the destruction of the environment. Our additional responsibility is straightforward—being advocates for good stewardship of the Earth’s resources now on both a personal and a policy level.²²

LOS ANGELES—Once-daily treatment with valbenazine for 48 weeks provides substantial improvements on clinician- and patient-reported outcomes in adults with tardive dyskinesia, according to data described at the 70th Annual Meeting of the American Academy of Neurology. The results are consistent with those of previous trials, said the researchers. Valbenazine is well-tolerated and does not raise significant safety concerns.

Valbenazine was approved as a treatment for tardive dyskinesia on the basis of several short-term placebo-controlled trials, a blinded extension study, and the long-term KINECT 4 study. Stewart Factor, DO, Professor of Neurology at Emory University School of Medicine in Atlanta, and colleagues conducted a study to evaluate the long-term effects of once-daily valbenazine on tardive dyskinesia.

Eligible participants were adults with de novo tardive dyskinesia and those who had participated in prior trials of valbenazine. All participants received 48 weeks of open-label treatment with valbenazine. The initial dose was 40 mg. If an investigator judged that a patient had inadequate clinical response at week four, the dose was increased to 80 mg, based on tolerability. For patients who could not tolerate the 80-mg dose, the dose was decreased to 40 mg.

Dr. Factor and colleagues used the change from baseline in the Abnormal Involuntary Movement Scale (AIMS) total score to assess changes in tardive dyskinesia. Other efficacy assessments included the Patient Global Impression of Change (PGIC) and Clinical Global Impression of Change-Tardive Dyskinesia (CGI-TD) scales. The investigators applied standard safety methods, including treatment-emergent adverse event reporting.

The safety population included 163 participants. Of this group, 107 participants received and tolerated the 80-mg dose, 45 did not require escalation from the 40-mg dose, and 11 were escalated to 80-mg dose, but later required reduction to the 40-mg dose. The mean change from baseline to week 48 in AIMS total score indicated improvements in tardive dyskinesia in all dose groups. The 80-mg group had a decrease of 11.0 points, the 40-mg group had a decrease of 10.2 points, and the group whose dose was decreased from 80 mg to 40 mg had a decrease of 7.2 points.

At week 48, more than 75% of participants in each study arm had a PGIC score of 2 or lower (ie, much improved or very much improved). This outcome was achieved in 89.2% of the 80-mg group, 90.0% of the 40-mg group, and 77.8% of the group whose dose was decreased from 80 mg to 40 mg. Mean CGI-TD scores at week 48 were 1.6 for the 80-mg group, 1.7 for the 40-mg group, and 2.3 for the group whose dose was reduced from 80 mg to 40 mg. These scores indicated clinically meaningful long-term improvement for all dose groups.

Less than 15% of all participants had a serious treatment-emergent adverse event (12.9%) or treatment-emergent adverse event leading to discontinuation (14.7%).

The study was funded by Neurocrine Biosciences, the manufacturer of valbenazine.

LOS ANGELES—Once-daily treatment with valbenazine for 48 weeks provides substantial improvements on clinician- and patient-reported outcomes in adults with tardive dyskinesia, according to data described at the 70th Annual Meeting of the American Academy of Neurology. The results are consistent with those of previous trials, said the researchers. Valbenazine is well-tolerated and does not raise significant safety concerns.

Valbenazine was approved as a treatment for tardive dyskinesia on the basis of several short-term placebo-controlled trials, a blinded extension study, and the long-term KINECT 4 study. Stewart Factor, DO, Professor of Neurology at Emory University School of Medicine in Atlanta, and colleagues conducted a study to evaluate the long-term effects of once-daily valbenazine on tardive dyskinesia.

Eligible participants were adults with de novo tardive dyskinesia and those who had participated in prior trials of valbenazine. All participants received 48 weeks of open-label treatment with valbenazine. The initial dose was 40 mg. If an investigator judged that a patient had inadequate clinical response at week four, the dose was increased to 80 mg, based on tolerability. For patients who could not tolerate the 80-mg dose, the dose was decreased to 40 mg.

Dr. Factor and colleagues used the change from baseline in the Abnormal Involuntary Movement Scale (AIMS) total score to assess changes in tardive dyskinesia. Other efficacy assessments included the Patient Global Impression of Change (PGIC) and Clinical Global Impression of Change-Tardive Dyskinesia (CGI-TD) scales. The investigators applied standard safety methods, including treatment-emergent adverse event reporting.

The safety population included 163 participants. Of this group, 107 participants received and tolerated the 80-mg dose, 45 did not require escalation from the 40-mg dose, and 11 were escalated to 80-mg dose, but later required reduction to the 40-mg dose. The mean change from baseline to week 48 in AIMS total score indicated improvements in tardive dyskinesia in all dose groups. The 80-mg group had a decrease of 11.0 points, the 40-mg group had a decrease of 10.2 points, and the group whose dose was decreased from 80 mg to 40 mg had a decrease of 7.2 points.

At week 48, more than 75% of participants in each study arm had a PGIC score of 2 or lower (ie, much improved or very much improved). This outcome was achieved in 89.2% of the 80-mg group, 90.0% of the 40-mg group, and 77.8% of the group whose dose was decreased from 80 mg to 40 mg. Mean CGI-TD scores at week 48 were 1.6 for the 80-mg group, 1.7 for the 40-mg group, and 2.3 for the group whose dose was reduced from 80 mg to 40 mg. These scores indicated clinically meaningful long-term improvement for all dose groups.

Less than 15% of all participants had a serious treatment-emergent adverse event (12.9%) or treatment-emergent adverse event leading to discontinuation (14.7%).

The study was funded by Neurocrine Biosciences, the manufacturer of valbenazine.

LOS ANGELES—Once-daily treatment with valbenazine for 48 weeks provides substantial improvements on clinician- and patient-reported outcomes in adults with tardive dyskinesia, according to data described at the 70th Annual Meeting of the American Academy of Neurology. The results are consistent with those of previous trials, said the researchers. Valbenazine is well-tolerated and does not raise significant safety concerns.

Valbenazine was approved as a treatment for tardive dyskinesia on the basis of several short-term placebo-controlled trials, a blinded extension study, and the long-term KINECT 4 study. Stewart Factor, DO, Professor of Neurology at Emory University School of Medicine in Atlanta, and colleagues conducted a study to evaluate the long-term effects of once-daily valbenazine on tardive dyskinesia.

Eligible participants were adults with de novo tardive dyskinesia and those who had participated in prior trials of valbenazine. All participants received 48 weeks of open-label treatment with valbenazine. The initial dose was 40 mg. If an investigator judged that a patient had inadequate clinical response at week four, the dose was increased to 80 mg, based on tolerability. For patients who could not tolerate the 80-mg dose, the dose was decreased to 40 mg.

Dr. Factor and colleagues used the change from baseline in the Abnormal Involuntary Movement Scale (AIMS) total score to assess changes in tardive dyskinesia. Other efficacy assessments included the Patient Global Impression of Change (PGIC) and Clinical Global Impression of Change-Tardive Dyskinesia (CGI-TD) scales. The investigators applied standard safety methods, including treatment-emergent adverse event reporting.

The safety population included 163 participants. Of this group, 107 participants received and tolerated the 80-mg dose, 45 did not require escalation from the 40-mg dose, and 11 were escalated to 80-mg dose, but later required reduction to the 40-mg dose. The mean change from baseline to week 48 in AIMS total score indicated improvements in tardive dyskinesia in all dose groups. The 80-mg group had a decrease of 11.0 points, the 40-mg group had a decrease of 10.2 points, and the group whose dose was decreased from 80 mg to 40 mg had a decrease of 7.2 points.

At week 48, more than 75% of participants in each study arm had a PGIC score of 2 or lower (ie, much improved or very much improved). This outcome was achieved in 89.2% of the 80-mg group, 90.0% of the 40-mg group, and 77.8% of the group whose dose was decreased from 80 mg to 40 mg. Mean CGI-TD scores at week 48 were 1.6 for the 80-mg group, 1.7 for the 40-mg group, and 2.3 for the group whose dose was reduced from 80 mg to 40 mg. These scores indicated clinically meaningful long-term improvement for all dose groups.

Less than 15% of all participants had a serious treatment-emergent adverse event (12.9%) or treatment-emergent adverse event leading to discontinuation (14.7%).

The study was funded by Neurocrine Biosciences, the manufacturer of valbenazine.

In this Update, I outline important findings from several studies published in the past year. First and foremost, what are best practices for performing colposcopy in the United States? The American Society for Colposcopy and Cervical Pathology (ASCCP) released guidelines addressing such practices. Second, what are the implications of repeated negative screening and patients’ acceptance of extended screening intervals? A recent observational cohort study and a large study of Kaiser Permanente’s practices since 2003 shed light on these questions. Last, where do we stand with HPV vaccination? Two studies shed light on the efficacy of vaccination against human papillomavirus (HPV), and subsequent cervical intraepithelial neoplasia (CIN) and cervical cancer.

ASCCP releases updated quality guidelines for performing colposcopy

Khan MJ, Werner CL, Darragh TM, et al. ASCCP colposcopy standards: Role of colposcopy, benefits, potential harms, and terminology for colposcopic practice. J Low Genit Tract Dis. 2017;21(4):223-229.

Waxman AG, Conageski C, Silver MI, et al. ASCCP colposcopy standards: How do we perform colposcopy? Implications for establishing standards. J Low Genit Tract Dis. 2017;21(4):235-241.

Wentzensen N, Schiffman M, Silver MI, et al. ASCCP colposcopy standards: Risk-based colposcopy practice. J Low Genit Tract Dis. 2017;21(4):230-234.

In October 2017, the ASCCP released a set of standards on the role and performance of colposcopy that represents best practices in women's health care in the United States. The work of these groups comprised a literature search, a national survey of ASCCP members, public comment, and expert consensus, and addressed:

• establishment of a common understanding of 1) the benefits of colposcopy in health maintenance and risk prevention, 2) risks presented by the procedure, and 3) terminology and criteria for reporting results that reduce subjectivity in reporting  
• the rationale for, approach to, and recommendations regarding assessment of cervical precancer at colposcopy
• both minimum and comprehensive guidelines for the colposcopic examination, from preprocedure evaluation to follow-up.

Each Working Group performed the analysis and produced its own report and recommendations, published sequentially in a 2017 issue of the Journal of Lower Urinary Tract Disease. The findings and standards that they produced 1) offer essential insight for high- and low-volume coloposcopists and 2) are intended to improve the quality of colposcopy, reduce subjectivity in reporting findings, and improve the sensitivity of the procedure. Aware of the concerns and objectives of payers and hospital credentialing committees, the ASCCP found it important to establish what would be considered US-based minimum quality standards and to present goals that providers and systems could strive to achieve.

Selected details of the 3 guideline reports

The past 6 years have brought us through a great deal of transition in the prevention of cervical precancer, with regard to screening intervals and types of screening (for example, see "HPV−cytology co-testing every 3 years lowers population rates of cervical precancer and cancer," in the 2017 "Cervical Disease Update," OBG Management, May 2017). The most significant change was in 2012, when American Cancer Society/ASCCP guidelines were revised to abandon screening with annual Pap testing on most patients--an effort to strike a balance between the lifesaving value of identifying precancer and the potential harm of excessive colposcopy.

If, as the US Preventive Services Task Force (USPSTF) has declared, excessive colposcopy is a harm of screening, then we should be adapting our practices, especially in terms of the frequency of screening, to 1) reduce the risk of unnecessarily screening and potentially triaging patients to colposcopy and 2) bring the highest standards of performance and reporting to colposcopic practice (see "Why aren't you doing a Pap on me?"). In other words, "This is the way I've always done it" shouldn't characterize efforts to detect disease, when the data are clear that doing less might be more beneficial for our patients. Adherence to extended screening intervals is not yet good enough to balance benefit and risk of harm, as Rendle and colleagues showed in an article this year in Preventive Medicine (discussed in the next section of this "Update"). We need to do better.

Here is a limited encapsulation of the 3 wide-ranging reports on the ASCCP colposcopy recommendations:

Role of colposcopy; benefits, potential harms, terminology (Khan et al; Working Group 1). The authors provide reinforcement: The strategic benefit of colposcopy is clear--a "drastic" reduction in excisional procedures by limiting them to patients in whom cervical cancer precursors have been confirmed or who present a high risk of occult invasive cervical cancer. Furthermore, the rate of adverse events for colposcopy−including significant bleeding and infection−is low.

Nevertheless, the potential for harm exists when an unskilled provider performs colposcopy; the Working Group emphasizes that proficiency comes with training and experience. Even in skilled hands, however, anxiety and the discomfort of a speculum examination and from acetic acid, as well as cramping and pain, might dissuade some women from receiving regular cervical screening subsequently. The authors cite research showing that educational interventions can help soothe anxiety about colposcopy and potential findings,^1,2 although consensus is lacking on the value of such interventions.

The Working Group 1) developed recommended terminology for reporting findings in colposcopy practice in the United States and 2) defined the comprehensive documentation of the procedure as comprising cervix and squamocolumnar junction visibility; acetowhitening; presence of a lesion; lesion visibility, size and location of lesion(s); vascular changes; other features; and colposcopic impression (TABLE 1).³ Minimum criteria for reporting colposcopy results were also proposed, extracted from the comprehensive standards.

Risk-based colposcopy practice (Wentzensen et al). Women referred to colposcopy present with a range of underlying risk of precancer. Assessing that risk at the colposcopy visit allows the provider to modify and individualize the procedure. Risk can be estimated by referral screening tests (eg, cytology, HPV testing) performed in conjunction with the colposcopic impression. As opposed to a lack of standards for a minimum number of biopsies, the Working Group recommends that, as a standard, multiple targeted biopsies (≥2, as many as 4) are needed to improve detection of prevalent precancers. Colposcopic impression alone is not enough to diagnose precancerous cells. Let's face it: Our eyes with a colposcopic magnification of 15X do not make a microscope.

Implementing the Working Group's recommendations is expected to lead to improved detection of cervical precancers at colposcopy and to provide stronger reassurance of negative colposcopy results. Regarding biopsy of lesions, ASCCP did not find added benefit to taking random (nondirected) biopsies for women at low risk for precancer. The sensitivity of biopsy is increased by taking multiple biopsies of suspicious lesions, based on a risk-based approach detailed in the ASCCP guidelines. So, depending on underlying risk (estimated from screening and triage tests), colposcopy practice can be adapted in a useful manner to account for differences in risk:

• When risk of precancer is very high, for example, immediate treatment might reduce cost and prevent the patient from being lost to follow-up. When risk is very low, consider expectant management (serial cytology and HPV testing) with limited need for biopsy. In a setting of intermediate risk, the Working Group proposes, "multiple biopsies of acetowhite lesions lead to increased detection of precancer."
• Perform multiple biopsies that target all areas characterized by 1) acetowhitening, 2) metaplasia, and 3) higher abnormalities.
• Do not perform nontargeted biopsies on patients at the lowest end of risk who have been referred to colposcopy−ie, those with cytology that is less than HSIL; no evidence of HPV types 16/18; and a normal colposcopic impression (ie, no acetowhitening or metaplasia, or other visible abnormality).  
• Immediate excision without biopsy confirmation or colposcopy with multiple targeted biopsies is acceptable in nonpregnant women 25 years and older whose risk of precancer is very high (≥2 of the following: HSIL cytology, HPV 16- or HPV 18-positive(or both), and high-grade colposcopy impression). Endocervical sampling should be conducted according to ASCCP's 2012 management guidelines. If biopsies do not show precancer, manage the patient using ASCCP's 2012 management guidelines, the Working Group recommends.

How do we perform colposcopy? Implications for establishing standards (Waxman et al; Working Group 3). To serve as a guide to standardizing colposcopy across the United States, the authors defined and delineated 6 major components (and their constituent parts) of a comprehensive colposcopy:

• precolposcopy evaluation
• the examination
• use of colposcopy adjuncts
• documentation
• biopsy sampling
• postcolposcopy procedures.

The constituent parts of these components are laid out in TABLE 2.⁴ A set of components for a minimum colposcopy procedure is drawn mostly from the comprehensive protocol.

The Working Group acknowledges that, in the United States, "the accuracy and reproducibility of colposcopy with biopsy as a diagnostic tool are limited." Why? Three contributing factors, the authors write, might be the absence of practice recommendations for colposcopy-biopsy procedures; of measures of quality assurance; and of standardized terminology.

Standards arrive for practice

Minimum quality standards are becoming part of almost everything US health care providers do−whether it is documentation, billing practices, or good care. Our work in gynecology, including colposcopy, is now being assessed as it is in much of the world, where minimum standards are already in place and guidelines must be followed. (In some countries standards require performing a minimum number of colposcopies per year to be identified as a "certified" colposcopist.)

What should be considered "minimum standards" for colposcopy in the United States? These ASCCP reports ask, and deliver answers to that question, bringing a broad range of concerns about high-quality practice into focus. Physicians and advanced-practice clinicians in this country who perform colposcopies have been trained to do so, but they have never had minimum standards by which to model and assess their performance. A procedure that has the potential to lead to additional testing for either cervical cancer, or to surveillance, should have minimum standards by which it is performed and documented in the United States as it is for much of the world that has widespread cervical cancer screening.

Read about adherence to cervical cancer screening.

Cervical screening adherence is relatively low, but safe. Extended intervals are very safe.

Castle PE, Kinney WK, Xue X, et al. Effect of several negative rounds of human papillomavirus and cytology co-testing on safety against cervical cancer: an observational cohort study. Ann Intern Med. 2018;168(1):20-29.

Rendle KA, Schiffman M, Cheung LC, et al. Adherence patterns to extended cervical screening intervals in women undergoing human papillomavirus (HPV) and cytology cotesting. Prev Med. 2018;109:44-50.

Patients who have been screened for cervical cancer for a long time--decades, even--have a diminishing likelihood that cancer will ever be detected. Furthermore, highest-risk patients already have been triaged into further testing or procedures, such as a loop excision electrosurgical procedure or hysterectomy. Two recent studies examined the implications of repeated negative screening and patients' acceptance of extended screening intervals.

Details of the studies

Several negative rounds of cotesting (HPV and cytology) might justify changes to the screening interval. To determine the rate of detection of CIN3, adenocarcinoma in situ, and cervical cancer (≥CIN3) in routine practice after successive negative screening at 3-year intervals, Castle and colleagues looked at records of more than 990,000 women in an integrated health care system who underwent cotesting (HPV and cytology) between 2003 and 2014. They determined that the risk of invasive cervical cancer and ≥CIN3 declined with each round of cotesting; the absolute risk fell more between first and second rounds than between second and third rounds.

At any given round of cotesting, Castle found that the ability to reassure a patient about cancer and cancer risk was similar when looking at an HPV result alone, whatever the cytology or HPV-cytology cotest result was. The investigators concluded that similar patterns of risk would have been seen had stand-alone HPV testing been used, instead of co-testing, (HPV testing alone might have missed a few cases of CIN3 and adenocarcinoma in situ leading to cancer). A single negative cotest was so effective at ruling out ≥CIN3 and cervical cancer that, after a second round of cotesting, they found that no interval cancer cases were detected among women who had a negative HPV result.

Women aged 50 years or older had a 5- to 6-fold lower risk after their third consecutive negative cotest than women aged 30 to 39 years had after their first negative cotest. These data support the ideas, Castle noted, that 1) assigning screening intervals based on both age and number of previous negative screens and 2) extending the screening interval even further than 3 years after 2--perhaps even after 1--negative cotests or HPV tests are worth entertaining. Screening women of this age becomes inefficient and cost-ineffective, even at 5-year intervals.

Is patients' adherence to an extended interval of cotesting reliable enough to change practice? Rendle and colleagues examined the records of more than 491,000 women (in the same integrated health care system that Castle studied) who had undergone routine cervical cancer screening between 2003 and 2015. Their goal was to determine how high adherence had become to the system's recommendation of an every-3-year screening interval--an interval that mirrors long-standing guidelines elsewhere.

In short, researchers observed increasing and relatively rapid clinical adoption of every-3-year cotesting for routine cervical screening over time; between 2003 and 2009, the cohort grew significantly less likely overall to come in early for screening. In this setting, adoption of an extended screeninginterval appears to run counter to earlier understanding that patients are likely to resist such extension.

Women aged 60 to 64 were most likely to screen early across 2 consecutive intervals. What Rendle termed a "modest" decrease in the percentage of late screeners (but still within a 5-year interval) was also noted during adoption of the 3-year interval.

What next?

Molecular-based testing. Research, mostly outside of the United States, is taking us in the direction of molecular-based technologies as at least a component of cervical cancer screening. Today, we rely mostly on Pap tests and colposcopy, but these are subjective screens, with a human operator. With molecular testing (mostly of components of HPV), results are objective--a "Yes" or "No" finding based on clinically validated thresholds. Methods such as genotyping, P16^INK4a/Ki-67 gene product dual-stain cytology, and testing for E6 and E7 HPV mRNA transcripts are in development, and hold promise to allow us to screen safely using almost completely molecular testing, thus eliminating human error and subjectivity and enriching the population that needs further management with very sensitive and potentially specific testing.

We are being presented with the possibility that almost all aspects of screening can be done without a provider, until the patient needs treatment.

Access to screening. Research is also looking at improving access, such as self-sampling for primary screening. That includes home cervical and vaginal sampling, with specimens mailed to the laboratory, from where results and follow-up instructions as communicated to patients. The Netherlands and the United Kingdom are moving to self-sampling primary screens; the United States is not--yet. But that is the direction research is taking us.

Modified guidelines. Eyes are on the work of the USPSTF. Last year, the Task Force issued draft recommendations (https://www.uspre ventiveservicestaskforce.org/Page/Document/draft-recommendation-statement/cervical-cancer-screening2#clinical), followed by a comment period (now closed), for updating 2012 cervical cancer screening guidelines in a way that would trigger a major change in clinical practice. Those draft recommendations and public comments are under review; final recommendations are possible within this calendar year.  

Read about the safety and efficacy of HPV vaccination.

Primary prevention of cervical cancer with vaccination is critical in any cancer prevention program

Benard VB, Castle PE, Jenison SA, et al; New Mexico HPV Pap Registry Steering Committee. Population-based incidence rates of cervical intraepithelial neoplasia in the human papillomavirus vaccine era. JAMA Oncol. 2017;3(6):833-837.

Luostarinen T, Apter D, Dillner J, et al. Vaccination protects against invasive HPV-associated cancers. Int J Cancer. 2018;142(10):2186-2187.

The success story of HPV vaccination, after more than a decade of use, continued to unfold in important ways over the past year.

Safety. With tens of millions of doses delivered, we know that the vaccine is safe, and we have retreated on some of the precautions that we once took: For example, we no longer perform a routine pregnancy test before vaccination on reproductive-age women.

Efficacy. We have learned, based on what we see in Australia and Western Europe, that vaccination is highly effective. We are also starting to see evidence of efficacy in areas of the United States, even though the vaccine is voluntary and there are no school-based recommendations. And we know that herd vaccination is very effective. The 2 studies described here add to our understanding of how vaccination is having an impact on endpoints.

Findings of the 2 studies

HPV vaccination has a direct impact on the precursor of cancer, CIN. Benard and colleagues examined data from the New Mexico HPV Pap Registry, a mandatory statewide surveillance system of cervical cancer screening that captured estimates of both screening prevalence and CIN since the time HPV vaccination was introduced in 2007 to 2014. The investigators examined registry data to gauge trends in the rate of CIN and to estimate the effect of HPV vaccination on that rate when adjusted for changes in screening for cervical cancer.

The incidence of CIN declined significantly across all grades in 2 groups between 2007 and 2015: females aged 15 to 19 years and females aged 20 to 24 years (but not in females 25 to 29 years of age). During those years, mean uptake of HPV vaccination among females 13 to 17 years of age reached as high as 40% (in 2014).

Although a reduction in CIN2 and CIN3 precancers "are early benchmarks for achieving this aim [of reducing the rate of cancer]," the investigators note, a reduction in CIN1 is "a direct measure of reductions in HPV infections requisite to the development of almost all invasive cervical cancer."

Benard moves on to conclude that a reduction in clinical outcomes of CIN among groups who are partially vaccinated for HPV is going to change clinical practice and reduce the cost-effectiveness of clinical care that supports prevention of cervical cancer. Of greatest importance, modalities and strategies for screening, and management algorithms, are going to need to evolve as HPV vaccination and cervical screening are integrated in a rational manner. Furthermore, it might be feasible to factor in population-level decreases in CIN among cohorts who are partially vaccinated for HPV when reassessing clinical practice guidelines for cervical cancer screening.

What does this mean? As we start to eliminate HPV from the population, any positive screening result will be that much more meaningful because the outcome--cervical cancer--will be much rarer. The onus will be on providers and public health officials to re-strategize how to screen what is going to be a widely-vaccinated population; more and more, we will be looking for needles in a haystack.

How are we going to someday screen women in their 20s who were vaccinated at 11 or 12 years of age? Likely, screening will start at a later age, and screening will be conducted at longer intervals. Any finding of HPV or disease is going to be highly significant, and likely, far less frequent.

HPV vaccination protects against invasive HPV-associated cancer. Luostarinen and colleagues report proof of highly efficacious protection offered by a population-based HPV vaccination program in Finland, in the form of a decrease in the key endpoint: cases of invasive HPV-associated cancer. Examining vaccinated (3,331 females) and unvaccinated (15,665 females) cohorts in the nationwide Finnish Cancer Registry, the investigators identified 10 cases of HPV-caused cancer (8 cervical, 1 oropharyngeal, 1 vulvar) in the unvaccinated females and 0 cases in vaccinated females--a statistically significant difference.

From the evidence gathered in this first intention-to-treat trial, the investigators conclude that vaccination protects against invasive HPV-associated cancer--what they call "an awaited, pivotal corollary" to high vaccine efficacy against HPV infection.

Summing up

This success story continues to unfold, despite well-organized, antivaccine campaigns. The HPV vaccine has been an easy target: It is novel, it involves a sexually transmitted infection, and the endpoint of protecting against invasive HPV-associated cancer is years--decades--away. But antivaccine groups can no longer argue the point that studies have not been designed to yield evidence of the impact of the vaccine on decisive endpoints, including cervical cancer.

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

In this Update, I outline important findings from several studies published in the past year. First and foremost, what are best practices for performing colposcopy in the United States? The American Society for Colposcopy and Cervical Pathology (ASCCP) released guidelines addressing such practices. Second, what are the implications of repeated negative screening and patients’ acceptance of extended screening intervals? A recent observational cohort study and a large study of Kaiser Permanente’s practices since 2003 shed light on these questions. Last, where do we stand with HPV vaccination? Two studies shed light on the efficacy of vaccination against human papillomavirus (HPV), and subsequent cervical intraepithelial neoplasia (CIN) and cervical cancer.

ASCCP releases updated quality guidelines for performing colposcopy

Khan MJ, Werner CL, Darragh TM, et al. ASCCP colposcopy standards: Role of colposcopy, benefits, potential harms, and terminology for colposcopic practice. J Low Genit Tract Dis. 2017;21(4):223-229.

Waxman AG, Conageski C, Silver MI, et al. ASCCP colposcopy standards: How do we perform colposcopy? Implications for establishing standards. J Low Genit Tract Dis. 2017;21(4):235-241.

Wentzensen N, Schiffman M, Silver MI, et al. ASCCP colposcopy standards: Risk-based colposcopy practice. J Low Genit Tract Dis. 2017;21(4):230-234.

In October 2017, the ASCCP released a set of standards on the role and performance of colposcopy that represents best practices in women's health care in the United States. The work of these groups comprised a literature search, a national survey of ASCCP members, public comment, and expert consensus, and addressed:

• establishment of a common understanding of 1) the benefits of colposcopy in health maintenance and risk prevention, 2) risks presented by the procedure, and 3) terminology and criteria for reporting results that reduce subjectivity in reporting  
• the rationale for, approach to, and recommendations regarding assessment of cervical precancer at colposcopy
• both minimum and comprehensive guidelines for the colposcopic examination, from preprocedure evaluation to follow-up.

Each Working Group performed the analysis and produced its own report and recommendations, published sequentially in a 2017 issue of the Journal of Lower Urinary Tract Disease. The findings and standards that they produced 1) offer essential insight for high- and low-volume coloposcopists and 2) are intended to improve the quality of colposcopy, reduce subjectivity in reporting findings, and improve the sensitivity of the procedure. Aware of the concerns and objectives of payers and hospital credentialing committees, the ASCCP found it important to establish what would be considered US-based minimum quality standards and to present goals that providers and systems could strive to achieve.

Selected details of the 3 guideline reports

The past 6 years have brought us through a great deal of transition in the prevention of cervical precancer, with regard to screening intervals and types of screening (for example, see "HPV−cytology co-testing every 3 years lowers population rates of cervical precancer and cancer," in the 2017 "Cervical Disease Update," OBG Management, May 2017). The most significant change was in 2012, when American Cancer Society/ASCCP guidelines were revised to abandon screening with annual Pap testing on most patients--an effort to strike a balance between the lifesaving value of identifying precancer and the potential harm of excessive colposcopy.

If, as the US Preventive Services Task Force (USPSTF) has declared, excessive colposcopy is a harm of screening, then we should be adapting our practices, especially in terms of the frequency of screening, to 1) reduce the risk of unnecessarily screening and potentially triaging patients to colposcopy and 2) bring the highest standards of performance and reporting to colposcopic practice (see "Why aren't you doing a Pap on me?"). In other words, "This is the way I've always done it" shouldn't characterize efforts to detect disease, when the data are clear that doing less might be more beneficial for our patients. Adherence to extended screening intervals is not yet good enough to balance benefit and risk of harm, as Rendle and colleagues showed in an article this year in Preventive Medicine (discussed in the next section of this "Update"). We need to do better.

Here is a limited encapsulation of the 3 wide-ranging reports on the ASCCP colposcopy recommendations:

Role of colposcopy; benefits, potential harms, terminology (Khan et al; Working Group 1). The authors provide reinforcement: The strategic benefit of colposcopy is clear--a "drastic" reduction in excisional procedures by limiting them to patients in whom cervical cancer precursors have been confirmed or who present a high risk of occult invasive cervical cancer. Furthermore, the rate of adverse events for colposcopy−including significant bleeding and infection−is low.

Nevertheless, the potential for harm exists when an unskilled provider performs colposcopy; the Working Group emphasizes that proficiency comes with training and experience. Even in skilled hands, however, anxiety and the discomfort of a speculum examination and from acetic acid, as well as cramping and pain, might dissuade some women from receiving regular cervical screening subsequently. The authors cite research showing that educational interventions can help soothe anxiety about colposcopy and potential findings,^1,2 although consensus is lacking on the value of such interventions.

The Working Group 1) developed recommended terminology for reporting findings in colposcopy practice in the United States and 2) defined the comprehensive documentation of the procedure as comprising cervix and squamocolumnar junction visibility; acetowhitening; presence of a lesion; lesion visibility, size and location of lesion(s); vascular changes; other features; and colposcopic impression (TABLE 1).³ Minimum criteria for reporting colposcopy results were also proposed, extracted from the comprehensive standards.

Risk-based colposcopy practice (Wentzensen et al). Women referred to colposcopy present with a range of underlying risk of precancer. Assessing that risk at the colposcopy visit allows the provider to modify and individualize the procedure. Risk can be estimated by referral screening tests (eg, cytology, HPV testing) performed in conjunction with the colposcopic impression. As opposed to a lack of standards for a minimum number of biopsies, the Working Group recommends that, as a standard, multiple targeted biopsies (≥2, as many as 4) are needed to improve detection of prevalent precancers. Colposcopic impression alone is not enough to diagnose precancerous cells. Let's face it: Our eyes with a colposcopic magnification of 15X do not make a microscope.

Implementing the Working Group's recommendations is expected to lead to improved detection of cervical precancers at colposcopy and to provide stronger reassurance of negative colposcopy results. Regarding biopsy of lesions, ASCCP did not find added benefit to taking random (nondirected) biopsies for women at low risk for precancer. The sensitivity of biopsy is increased by taking multiple biopsies of suspicious lesions, based on a risk-based approach detailed in the ASCCP guidelines. So, depending on underlying risk (estimated from screening and triage tests), colposcopy practice can be adapted in a useful manner to account for differences in risk:

• When risk of precancer is very high, for example, immediate treatment might reduce cost and prevent the patient from being lost to follow-up. When risk is very low, consider expectant management (serial cytology and HPV testing) with limited need for biopsy. In a setting of intermediate risk, the Working Group proposes, "multiple biopsies of acetowhite lesions lead to increased detection of precancer."
• Perform multiple biopsies that target all areas characterized by 1) acetowhitening, 2) metaplasia, and 3) higher abnormalities.
• Do not perform nontargeted biopsies on patients at the lowest end of risk who have been referred to colposcopy−ie, those with cytology that is less than HSIL; no evidence of HPV types 16/18; and a normal colposcopic impression (ie, no acetowhitening or metaplasia, or other visible abnormality).  
• Immediate excision without biopsy confirmation or colposcopy with multiple targeted biopsies is acceptable in nonpregnant women 25 years and older whose risk of precancer is very high (≥2 of the following: HSIL cytology, HPV 16- or HPV 18-positive(or both), and high-grade colposcopy impression). Endocervical sampling should be conducted according to ASCCP's 2012 management guidelines. If biopsies do not show precancer, manage the patient using ASCCP's 2012 management guidelines, the Working Group recommends.

How do we perform colposcopy? Implications for establishing standards (Waxman et al; Working Group 3). To serve as a guide to standardizing colposcopy across the United States, the authors defined and delineated 6 major components (and their constituent parts) of a comprehensive colposcopy:

• precolposcopy evaluation
• the examination
• use of colposcopy adjuncts
• documentation
• biopsy sampling
• postcolposcopy procedures.

The constituent parts of these components are laid out in TABLE 2.⁴ A set of components for a minimum colposcopy procedure is drawn mostly from the comprehensive protocol.

The Working Group acknowledges that, in the United States, "the accuracy and reproducibility of colposcopy with biopsy as a diagnostic tool are limited." Why? Three contributing factors, the authors write, might be the absence of practice recommendations for colposcopy-biopsy procedures; of measures of quality assurance; and of standardized terminology.

Standards arrive for practice

Minimum quality standards are becoming part of almost everything US health care providers do−whether it is documentation, billing practices, or good care. Our work in gynecology, including colposcopy, is now being assessed as it is in much of the world, where minimum standards are already in place and guidelines must be followed. (In some countries standards require performing a minimum number of colposcopies per year to be identified as a "certified" colposcopist.)

What should be considered "minimum standards" for colposcopy in the United States? These ASCCP reports ask, and deliver answers to that question, bringing a broad range of concerns about high-quality practice into focus. Physicians and advanced-practice clinicians in this country who perform colposcopies have been trained to do so, but they have never had minimum standards by which to model and assess their performance. A procedure that has the potential to lead to additional testing for either cervical cancer, or to surveillance, should have minimum standards by which it is performed and documented in the United States as it is for much of the world that has widespread cervical cancer screening.

Read about adherence to cervical cancer screening.

Cervical screening adherence is relatively low, but safe. Extended intervals are very safe.

Castle PE, Kinney WK, Xue X, et al. Effect of several negative rounds of human papillomavirus and cytology co-testing on safety against cervical cancer: an observational cohort study. Ann Intern Med. 2018;168(1):20-29.

Rendle KA, Schiffman M, Cheung LC, et al. Adherence patterns to extended cervical screening intervals in women undergoing human papillomavirus (HPV) and cytology cotesting. Prev Med. 2018;109:44-50.

Patients who have been screened for cervical cancer for a long time--decades, even--have a diminishing likelihood that cancer will ever be detected. Furthermore, highest-risk patients already have been triaged into further testing or procedures, such as a loop excision electrosurgical procedure or hysterectomy. Two recent studies examined the implications of repeated negative screening and patients' acceptance of extended screening intervals.

Details of the studies

Several negative rounds of cotesting (HPV and cytology) might justify changes to the screening interval. To determine the rate of detection of CIN3, adenocarcinoma in situ, and cervical cancer (≥CIN3) in routine practice after successive negative screening at 3-year intervals, Castle and colleagues looked at records of more than 990,000 women in an integrated health care system who underwent cotesting (HPV and cytology) between 2003 and 2014. They determined that the risk of invasive cervical cancer and ≥CIN3 declined with each round of cotesting; the absolute risk fell more between first and second rounds than between second and third rounds.

At any given round of cotesting, Castle found that the ability to reassure a patient about cancer and cancer risk was similar when looking at an HPV result alone, whatever the cytology or HPV-cytology cotest result was. The investigators concluded that similar patterns of risk would have been seen had stand-alone HPV testing been used, instead of co-testing, (HPV testing alone might have missed a few cases of CIN3 and adenocarcinoma in situ leading to cancer). A single negative cotest was so effective at ruling out ≥CIN3 and cervical cancer that, after a second round of cotesting, they found that no interval cancer cases were detected among women who had a negative HPV result.

Women aged 50 years or older had a 5- to 6-fold lower risk after their third consecutive negative cotest than women aged 30 to 39 years had after their first negative cotest. These data support the ideas, Castle noted, that 1) assigning screening intervals based on both age and number of previous negative screens and 2) extending the screening interval even further than 3 years after 2--perhaps even after 1--negative cotests or HPV tests are worth entertaining. Screening women of this age becomes inefficient and cost-ineffective, even at 5-year intervals.

Is patients' adherence to an extended interval of cotesting reliable enough to change practice? Rendle and colleagues examined the records of more than 491,000 women (in the same integrated health care system that Castle studied) who had undergone routine cervical cancer screening between 2003 and 2015. Their goal was to determine how high adherence had become to the system's recommendation of an every-3-year screening interval--an interval that mirrors long-standing guidelines elsewhere.

In short, researchers observed increasing and relatively rapid clinical adoption of every-3-year cotesting for routine cervical screening over time; between 2003 and 2009, the cohort grew significantly less likely overall to come in early for screening. In this setting, adoption of an extended screeninginterval appears to run counter to earlier understanding that patients are likely to resist such extension.

Women aged 60 to 64 were most likely to screen early across 2 consecutive intervals. What Rendle termed a "modest" decrease in the percentage of late screeners (but still within a 5-year interval) was also noted during adoption of the 3-year interval.

What next?

Molecular-based testing. Research, mostly outside of the United States, is taking us in the direction of molecular-based technologies as at least a component of cervical cancer screening. Today, we rely mostly on Pap tests and colposcopy, but these are subjective screens, with a human operator. With molecular testing (mostly of components of HPV), results are objective--a "Yes" or "No" finding based on clinically validated thresholds. Methods such as genotyping, P16^INK4a/Ki-67 gene product dual-stain cytology, and testing for E6 and E7 HPV mRNA transcripts are in development, and hold promise to allow us to screen safely using almost completely molecular testing, thus eliminating human error and subjectivity and enriching the population that needs further management with very sensitive and potentially specific testing.

We are being presented with the possibility that almost all aspects of screening can be done without a provider, until the patient needs treatment.

Access to screening. Research is also looking at improving access, such as self-sampling for primary screening. That includes home cervical and vaginal sampling, with specimens mailed to the laboratory, from where results and follow-up instructions as communicated to patients. The Netherlands and the United Kingdom are moving to self-sampling primary screens; the United States is not--yet. But that is the direction research is taking us.

Modified guidelines. Eyes are on the work of the USPSTF. Last year, the Task Force issued draft recommendations (https://www.uspre ventiveservicestaskforce.org/Page/Document/draft-recommendation-statement/cervical-cancer-screening2#clinical), followed by a comment period (now closed), for updating 2012 cervical cancer screening guidelines in a way that would trigger a major change in clinical practice. Those draft recommendations and public comments are under review; final recommendations are possible within this calendar year.  

Read about the safety and efficacy of HPV vaccination.

Primary prevention of cervical cancer with vaccination is critical in any cancer prevention program

Benard VB, Castle PE, Jenison SA, et al; New Mexico HPV Pap Registry Steering Committee. Population-based incidence rates of cervical intraepithelial neoplasia in the human papillomavirus vaccine era. JAMA Oncol. 2017;3(6):833-837.

Luostarinen T, Apter D, Dillner J, et al. Vaccination protects against invasive HPV-associated cancers. Int J Cancer. 2018;142(10):2186-2187.

The success story of HPV vaccination, after more than a decade of use, continued to unfold in important ways over the past year.

Safety. With tens of millions of doses delivered, we know that the vaccine is safe, and we have retreated on some of the precautions that we once took: For example, we no longer perform a routine pregnancy test before vaccination on reproductive-age women.

Efficacy. We have learned, based on what we see in Australia and Western Europe, that vaccination is highly effective. We are also starting to see evidence of efficacy in areas of the United States, even though the vaccine is voluntary and there are no school-based recommendations. And we know that herd vaccination is very effective. The 2 studies described here add to our understanding of how vaccination is having an impact on endpoints.

Findings of the 2 studies

HPV vaccination has a direct impact on the precursor of cancer, CIN. Benard and colleagues examined data from the New Mexico HPV Pap Registry, a mandatory statewide surveillance system of cervical cancer screening that captured estimates of both screening prevalence and CIN since the time HPV vaccination was introduced in 2007 to 2014. The investigators examined registry data to gauge trends in the rate of CIN and to estimate the effect of HPV vaccination on that rate when adjusted for changes in screening for cervical cancer.

The incidence of CIN declined significantly across all grades in 2 groups between 2007 and 2015: females aged 15 to 19 years and females aged 20 to 24 years (but not in females 25 to 29 years of age). During those years, mean uptake of HPV vaccination among females 13 to 17 years of age reached as high as 40% (in 2014).

Although a reduction in CIN2 and CIN3 precancers "are early benchmarks for achieving this aim [of reducing the rate of cancer]," the investigators note, a reduction in CIN1 is "a direct measure of reductions in HPV infections requisite to the development of almost all invasive cervical cancer."

Benard moves on to conclude that a reduction in clinical outcomes of CIN among groups who are partially vaccinated for HPV is going to change clinical practice and reduce the cost-effectiveness of clinical care that supports prevention of cervical cancer. Of greatest importance, modalities and strategies for screening, and management algorithms, are going to need to evolve as HPV vaccination and cervical screening are integrated in a rational manner. Furthermore, it might be feasible to factor in population-level decreases in CIN among cohorts who are partially vaccinated for HPV when reassessing clinical practice guidelines for cervical cancer screening.

What does this mean? As we start to eliminate HPV from the population, any positive screening result will be that much more meaningful because the outcome--cervical cancer--will be much rarer. The onus will be on providers and public health officials to re-strategize how to screen what is going to be a widely-vaccinated population; more and more, we will be looking for needles in a haystack.

How are we going to someday screen women in their 20s who were vaccinated at 11 or 12 years of age? Likely, screening will start at a later age, and screening will be conducted at longer intervals. Any finding of HPV or disease is going to be highly significant, and likely, far less frequent.

HPV vaccination protects against invasive HPV-associated cancer. Luostarinen and colleagues report proof of highly efficacious protection offered by a population-based HPV vaccination program in Finland, in the form of a decrease in the key endpoint: cases of invasive HPV-associated cancer. Examining vaccinated (3,331 females) and unvaccinated (15,665 females) cohorts in the nationwide Finnish Cancer Registry, the investigators identified 10 cases of HPV-caused cancer (8 cervical, 1 oropharyngeal, 1 vulvar) in the unvaccinated females and 0 cases in vaccinated females--a statistically significant difference.

From the evidence gathered in this first intention-to-treat trial, the investigators conclude that vaccination protects against invasive HPV-associated cancer--what they call "an awaited, pivotal corollary" to high vaccine efficacy against HPV infection.

Summing up

This success story continues to unfold, despite well-organized, antivaccine campaigns. The HPV vaccine has been an easy target: It is novel, it involves a sexually transmitted infection, and the endpoint of protecting against invasive HPV-associated cancer is years--decades--away. But antivaccine groups can no longer argue the point that studies have not been designed to yield evidence of the impact of the vaccine on decisive endpoints, including cervical cancer.

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

In this Update, I outline important findings from several studies published in the past year. First and foremost, what are best practices for performing colposcopy in the United States? The American Society for Colposcopy and Cervical Pathology (ASCCP) released guidelines addressing such practices. Second, what are the implications of repeated negative screening and patients’ acceptance of extended screening intervals? A recent observational cohort study and a large study of Kaiser Permanente’s practices since 2003 shed light on these questions. Last, where do we stand with HPV vaccination? Two studies shed light on the efficacy of vaccination against human papillomavirus (HPV), and subsequent cervical intraepithelial neoplasia (CIN) and cervical cancer.

ASCCP releases updated quality guidelines for performing colposcopy

Khan MJ, Werner CL, Darragh TM, et al. ASCCP colposcopy standards: Role of colposcopy, benefits, potential harms, and terminology for colposcopic practice. J Low Genit Tract Dis. 2017;21(4):223-229.

Waxman AG, Conageski C, Silver MI, et al. ASCCP colposcopy standards: How do we perform colposcopy? Implications for establishing standards. J Low Genit Tract Dis. 2017;21(4):235-241.

Wentzensen N, Schiffman M, Silver MI, et al. ASCCP colposcopy standards: Risk-based colposcopy practice. J Low Genit Tract Dis. 2017;21(4):230-234.

In October 2017, the ASCCP released a set of standards on the role and performance of colposcopy that represents best practices in women's health care in the United States. The work of these groups comprised a literature search, a national survey of ASCCP members, public comment, and expert consensus, and addressed:

• establishment of a common understanding of 1) the benefits of colposcopy in health maintenance and risk prevention, 2) risks presented by the procedure, and 3) terminology and criteria for reporting results that reduce subjectivity in reporting  
• the rationale for, approach to, and recommendations regarding assessment of cervical precancer at colposcopy
• both minimum and comprehensive guidelines for the colposcopic examination, from preprocedure evaluation to follow-up.

Each Working Group performed the analysis and produced its own report and recommendations, published sequentially in a 2017 issue of the Journal of Lower Urinary Tract Disease. The findings and standards that they produced 1) offer essential insight for high- and low-volume coloposcopists and 2) are intended to improve the quality of colposcopy, reduce subjectivity in reporting findings, and improve the sensitivity of the procedure. Aware of the concerns and objectives of payers and hospital credentialing committees, the ASCCP found it important to establish what would be considered US-based minimum quality standards and to present goals that providers and systems could strive to achieve.

Selected details of the 3 guideline reports

The past 6 years have brought us through a great deal of transition in the prevention of cervical precancer, with regard to screening intervals and types of screening (for example, see "HPV−cytology co-testing every 3 years lowers population rates of cervical precancer and cancer," in the 2017 "Cervical Disease Update," OBG Management, May 2017). The most significant change was in 2012, when American Cancer Society/ASCCP guidelines were revised to abandon screening with annual Pap testing on most patients--an effort to strike a balance between the lifesaving value of identifying precancer and the potential harm of excessive colposcopy.

If, as the US Preventive Services Task Force (USPSTF) has declared, excessive colposcopy is a harm of screening, then we should be adapting our practices, especially in terms of the frequency of screening, to 1) reduce the risk of unnecessarily screening and potentially triaging patients to colposcopy and 2) bring the highest standards of performance and reporting to colposcopic practice (see "Why aren't you doing a Pap on me?"). In other words, "This is the way I've always done it" shouldn't characterize efforts to detect disease, when the data are clear that doing less might be more beneficial for our patients. Adherence to extended screening intervals is not yet good enough to balance benefit and risk of harm, as Rendle and colleagues showed in an article this year in Preventive Medicine (discussed in the next section of this "Update"). We need to do better.

Here is a limited encapsulation of the 3 wide-ranging reports on the ASCCP colposcopy recommendations:

Role of colposcopy; benefits, potential harms, terminology (Khan et al; Working Group 1). The authors provide reinforcement: The strategic benefit of colposcopy is clear--a "drastic" reduction in excisional procedures by limiting them to patients in whom cervical cancer precursors have been confirmed or who present a high risk of occult invasive cervical cancer. Furthermore, the rate of adverse events for colposcopy−including significant bleeding and infection−is low.

Nevertheless, the potential for harm exists when an unskilled provider performs colposcopy; the Working Group emphasizes that proficiency comes with training and experience. Even in skilled hands, however, anxiety and the discomfort of a speculum examination and from acetic acid, as well as cramping and pain, might dissuade some women from receiving regular cervical screening subsequently. The authors cite research showing that educational interventions can help soothe anxiety about colposcopy and potential findings,^1,2 although consensus is lacking on the value of such interventions.

The Working Group 1) developed recommended terminology for reporting findings in colposcopy practice in the United States and 2) defined the comprehensive documentation of the procedure as comprising cervix and squamocolumnar junction visibility; acetowhitening; presence of a lesion; lesion visibility, size and location of lesion(s); vascular changes; other features; and colposcopic impression (TABLE 1).³ Minimum criteria for reporting colposcopy results were also proposed, extracted from the comprehensive standards.

Risk-based colposcopy practice (Wentzensen et al). Women referred to colposcopy present with a range of underlying risk of precancer. Assessing that risk at the colposcopy visit allows the provider to modify and individualize the procedure. Risk can be estimated by referral screening tests (eg, cytology, HPV testing) performed in conjunction with the colposcopic impression. As opposed to a lack of standards for a minimum number of biopsies, the Working Group recommends that, as a standard, multiple targeted biopsies (≥2, as many as 4) are needed to improve detection of prevalent precancers. Colposcopic impression alone is not enough to diagnose precancerous cells. Let's face it: Our eyes with a colposcopic magnification of 15X do not make a microscope.

Implementing the Working Group's recommendations is expected to lead to improved detection of cervical precancers at colposcopy and to provide stronger reassurance of negative colposcopy results. Regarding biopsy of lesions, ASCCP did not find added benefit to taking random (nondirected) biopsies for women at low risk for precancer. The sensitivity of biopsy is increased by taking multiple biopsies of suspicious lesions, based on a risk-based approach detailed in the ASCCP guidelines. So, depending on underlying risk (estimated from screening and triage tests), colposcopy practice can be adapted in a useful manner to account for differences in risk:

• When risk of precancer is very high, for example, immediate treatment might reduce cost and prevent the patient from being lost to follow-up. When risk is very low, consider expectant management (serial cytology and HPV testing) with limited need for biopsy. In a setting of intermediate risk, the Working Group proposes, "multiple biopsies of acetowhite lesions lead to increased detection of precancer."
• Perform multiple biopsies that target all areas characterized by 1) acetowhitening, 2) metaplasia, and 3) higher abnormalities.
• Do not perform nontargeted biopsies on patients at the lowest end of risk who have been referred to colposcopy−ie, those with cytology that is less than HSIL; no evidence of HPV types 16/18; and a normal colposcopic impression (ie, no acetowhitening or metaplasia, or other visible abnormality).  
• Immediate excision without biopsy confirmation or colposcopy with multiple targeted biopsies is acceptable in nonpregnant women 25 years and older whose risk of precancer is very high (≥2 of the following: HSIL cytology, HPV 16- or HPV 18-positive(or both), and high-grade colposcopy impression). Endocervical sampling should be conducted according to ASCCP's 2012 management guidelines. If biopsies do not show precancer, manage the patient using ASCCP's 2012 management guidelines, the Working Group recommends.

How do we perform colposcopy? Implications for establishing standards (Waxman et al; Working Group 3). To serve as a guide to standardizing colposcopy across the United States, the authors defined and delineated 6 major components (and their constituent parts) of a comprehensive colposcopy:

• precolposcopy evaluation
• the examination
• use of colposcopy adjuncts
• documentation
• biopsy sampling
• postcolposcopy procedures.

The constituent parts of these components are laid out in TABLE 2.⁴ A set of components for a minimum colposcopy procedure is drawn mostly from the comprehensive protocol.

The Working Group acknowledges that, in the United States, "the accuracy and reproducibility of colposcopy with biopsy as a diagnostic tool are limited." Why? Three contributing factors, the authors write, might be the absence of practice recommendations for colposcopy-biopsy procedures; of measures of quality assurance; and of standardized terminology.

Standards arrive for practice

Minimum quality standards are becoming part of almost everything US health care providers do−whether it is documentation, billing practices, or good care. Our work in gynecology, including colposcopy, is now being assessed as it is in much of the world, where minimum standards are already in place and guidelines must be followed. (In some countries standards require performing a minimum number of colposcopies per year to be identified as a "certified" colposcopist.)

What should be considered "minimum standards" for colposcopy in the United States? These ASCCP reports ask, and deliver answers to that question, bringing a broad range of concerns about high-quality practice into focus. Physicians and advanced-practice clinicians in this country who perform colposcopies have been trained to do so, but they have never had minimum standards by which to model and assess their performance. A procedure that has the potential to lead to additional testing for either cervical cancer, or to surveillance, should have minimum standards by which it is performed and documented in the United States as it is for much of the world that has widespread cervical cancer screening.

Read about adherence to cervical cancer screening.

Cervical screening adherence is relatively low, but safe. Extended intervals are very safe.

Castle PE, Kinney WK, Xue X, et al. Effect of several negative rounds of human papillomavirus and cytology co-testing on safety against cervical cancer: an observational cohort study. Ann Intern Med. 2018;168(1):20-29.

Rendle KA, Schiffman M, Cheung LC, et al. Adherence patterns to extended cervical screening intervals in women undergoing human papillomavirus (HPV) and cytology cotesting. Prev Med. 2018;109:44-50.

Patients who have been screened for cervical cancer for a long time--decades, even--have a diminishing likelihood that cancer will ever be detected. Furthermore, highest-risk patients already have been triaged into further testing or procedures, such as a loop excision electrosurgical procedure or hysterectomy. Two recent studies examined the implications of repeated negative screening and patients' acceptance of extended screening intervals.

Details of the studies

Several negative rounds of cotesting (HPV and cytology) might justify changes to the screening interval. To determine the rate of detection of CIN3, adenocarcinoma in situ, and cervical cancer (≥CIN3) in routine practice after successive negative screening at 3-year intervals, Castle and colleagues looked at records of more than 990,000 women in an integrated health care system who underwent cotesting (HPV and cytology) between 2003 and 2014. They determined that the risk of invasive cervical cancer and ≥CIN3 declined with each round of cotesting; the absolute risk fell more between first and second rounds than between second and third rounds.

At any given round of cotesting, Castle found that the ability to reassure a patient about cancer and cancer risk was similar when looking at an HPV result alone, whatever the cytology or HPV-cytology cotest result was. The investigators concluded that similar patterns of risk would have been seen had stand-alone HPV testing been used, instead of co-testing, (HPV testing alone might have missed a few cases of CIN3 and adenocarcinoma in situ leading to cancer). A single negative cotest was so effective at ruling out ≥CIN3 and cervical cancer that, after a second round of cotesting, they found that no interval cancer cases were detected among women who had a negative HPV result.

Women aged 50 years or older had a 5- to 6-fold lower risk after their third consecutive negative cotest than women aged 30 to 39 years had after their first negative cotest. These data support the ideas, Castle noted, that 1) assigning screening intervals based on both age and number of previous negative screens and 2) extending the screening interval even further than 3 years after 2--perhaps even after 1--negative cotests or HPV tests are worth entertaining. Screening women of this age becomes inefficient and cost-ineffective, even at 5-year intervals.

Is patients' adherence to an extended interval of cotesting reliable enough to change practice? Rendle and colleagues examined the records of more than 491,000 women (in the same integrated health care system that Castle studied) who had undergone routine cervical cancer screening between 2003 and 2015. Their goal was to determine how high adherence had become to the system's recommendation of an every-3-year screening interval--an interval that mirrors long-standing guidelines elsewhere.

In short, researchers observed increasing and relatively rapid clinical adoption of every-3-year cotesting for routine cervical screening over time; between 2003 and 2009, the cohort grew significantly less likely overall to come in early for screening. In this setting, adoption of an extended screeninginterval appears to run counter to earlier understanding that patients are likely to resist such extension.

Women aged 60 to 64 were most likely to screen early across 2 consecutive intervals. What Rendle termed a "modest" decrease in the percentage of late screeners (but still within a 5-year interval) was also noted during adoption of the 3-year interval.

What next?

Molecular-based testing. Research, mostly outside of the United States, is taking us in the direction of molecular-based technologies as at least a component of cervical cancer screening. Today, we rely mostly on Pap tests and colposcopy, but these are subjective screens, with a human operator. With molecular testing (mostly of components of HPV), results are objective--a "Yes" or "No" finding based on clinically validated thresholds. Methods such as genotyping, P16^INK4a/Ki-67 gene product dual-stain cytology, and testing for E6 and E7 HPV mRNA transcripts are in development, and hold promise to allow us to screen safely using almost completely molecular testing, thus eliminating human error and subjectivity and enriching the population that needs further management with very sensitive and potentially specific testing.

We are being presented with the possibility that almost all aspects of screening can be done without a provider, until the patient needs treatment.

Access to screening. Research is also looking at improving access, such as self-sampling for primary screening. That includes home cervical and vaginal sampling, with specimens mailed to the laboratory, from where results and follow-up instructions as communicated to patients. The Netherlands and the United Kingdom are moving to self-sampling primary screens; the United States is not--yet. But that is the direction research is taking us.

Modified guidelines. Eyes are on the work of the USPSTF. Last year, the Task Force issued draft recommendations (https://www.uspre ventiveservicestaskforce.org/Page/Document/draft-recommendation-statement/cervical-cancer-screening2#clinical), followed by a comment period (now closed), for updating 2012 cervical cancer screening guidelines in a way that would trigger a major change in clinical practice. Those draft recommendations and public comments are under review; final recommendations are possible within this calendar year.  

Read about the safety and efficacy of HPV vaccination.

Primary prevention of cervical cancer with vaccination is critical in any cancer prevention program

Benard VB, Castle PE, Jenison SA, et al; New Mexico HPV Pap Registry Steering Committee. Population-based incidence rates of cervical intraepithelial neoplasia in the human papillomavirus vaccine era. JAMA Oncol. 2017;3(6):833-837.

Luostarinen T, Apter D, Dillner J, et al. Vaccination protects against invasive HPV-associated cancers. Int J Cancer. 2018;142(10):2186-2187.

The success story of HPV vaccination, after more than a decade of use, continued to unfold in important ways over the past year.

Safety. With tens of millions of doses delivered, we know that the vaccine is safe, and we have retreated on some of the precautions that we once took: For example, we no longer perform a routine pregnancy test before vaccination on reproductive-age women.

Efficacy. We have learned, based on what we see in Australia and Western Europe, that vaccination is highly effective. We are also starting to see evidence of efficacy in areas of the United States, even though the vaccine is voluntary and there are no school-based recommendations. And we know that herd vaccination is very effective. The 2 studies described here add to our understanding of how vaccination is having an impact on endpoints.

Findings of the 2 studies

HPV vaccination has a direct impact on the precursor of cancer, CIN. Benard and colleagues examined data from the New Mexico HPV Pap Registry, a mandatory statewide surveillance system of cervical cancer screening that captured estimates of both screening prevalence and CIN since the time HPV vaccination was introduced in 2007 to 2014. The investigators examined registry data to gauge trends in the rate of CIN and to estimate the effect of HPV vaccination on that rate when adjusted for changes in screening for cervical cancer.

The incidence of CIN declined significantly across all grades in 2 groups between 2007 and 2015: females aged 15 to 19 years and females aged 20 to 24 years (but not in females 25 to 29 years of age). During those years, mean uptake of HPV vaccination among females 13 to 17 years of age reached as high as 40% (in 2014).

Although a reduction in CIN2 and CIN3 precancers "are early benchmarks for achieving this aim [of reducing the rate of cancer]," the investigators note, a reduction in CIN1 is "a direct measure of reductions in HPV infections requisite to the development of almost all invasive cervical cancer."

Benard moves on to conclude that a reduction in clinical outcomes of CIN among groups who are partially vaccinated for HPV is going to change clinical practice and reduce the cost-effectiveness of clinical care that supports prevention of cervical cancer. Of greatest importance, modalities and strategies for screening, and management algorithms, are going to need to evolve as HPV vaccination and cervical screening are integrated in a rational manner. Furthermore, it might be feasible to factor in population-level decreases in CIN among cohorts who are partially vaccinated for HPV when reassessing clinical practice guidelines for cervical cancer screening.

What does this mean? As we start to eliminate HPV from the population, any positive screening result will be that much more meaningful because the outcome--cervical cancer--will be much rarer. The onus will be on providers and public health officials to re-strategize how to screen what is going to be a widely-vaccinated population; more and more, we will be looking for needles in a haystack.

How are we going to someday screen women in their 20s who were vaccinated at 11 or 12 years of age? Likely, screening will start at a later age, and screening will be conducted at longer intervals. Any finding of HPV or disease is going to be highly significant, and likely, far less frequent.

HPV vaccination protects against invasive HPV-associated cancer. Luostarinen and colleagues report proof of highly efficacious protection offered by a population-based HPV vaccination program in Finland, in the form of a decrease in the key endpoint: cases of invasive HPV-associated cancer. Examining vaccinated (3,331 females) and unvaccinated (15,665 females) cohorts in the nationwide Finnish Cancer Registry, the investigators identified 10 cases of HPV-caused cancer (8 cervical, 1 oropharyngeal, 1 vulvar) in the unvaccinated females and 0 cases in vaccinated females--a statistically significant difference.

From the evidence gathered in this first intention-to-treat trial, the investigators conclude that vaccination protects against invasive HPV-associated cancer--what they call "an awaited, pivotal corollary" to high vaccine efficacy against HPV infection.

Summing up

This success story continues to unfold, despite well-organized, antivaccine campaigns. The HPV vaccine has been an easy target: It is novel, it involves a sexually transmitted infection, and the endpoint of protecting against invasive HPV-associated cancer is years--decades--away. But antivaccine groups can no longer argue the point that studies have not been designed to yield evidence of the impact of the vaccine on decisive endpoints, including cervical cancer.

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

Clinical question: Is dabigatran superior to warfarin with regards to the risk of intracranial hemorrhage and myocardial infarction in patients with atrial fibrillation?

Background: Several studies – including the RELY trial – have revealed a lower rate of intracranial hemorrhage with dabigatran, compared with warfarin, in patients with atrial fibrillation; however, few of these have been on populations generalizable to clinical practice. Furthermore, there are conflicting data on the association of dabigatran with higher rates of myocardial infarction in patients with atrial fibrillation versus warfarin.

Study design: Retrospective cohort study.

Dr. Mehta is assistant professor, division of hospital medicine, University of Virginia.

Clinical question: Is dabigatran superior to warfarin with regards to the risk of intracranial hemorrhage and myocardial infarction in patients with atrial fibrillation?

Background: Several studies – including the RELY trial – have revealed a lower rate of intracranial hemorrhage with dabigatran, compared with warfarin, in patients with atrial fibrillation; however, few of these have been on populations generalizable to clinical practice. Furthermore, there are conflicting data on the association of dabigatran with higher rates of myocardial infarction in patients with atrial fibrillation versus warfarin.

Study design: Retrospective cohort study.

Dr. Mehta is assistant professor, division of hospital medicine, University of Virginia.

Clinical question: Is dabigatran superior to warfarin with regards to the risk of intracranial hemorrhage and myocardial infarction in patients with atrial fibrillation?

Background: Several studies – including the RELY trial – have revealed a lower rate of intracranial hemorrhage with dabigatran, compared with warfarin, in patients with atrial fibrillation; however, few of these have been on populations generalizable to clinical practice. Furthermore, there are conflicting data on the association of dabigatran with higher rates of myocardial infarction in patients with atrial fibrillation versus warfarin.

Study design: Retrospective cohort study.

Dr. Mehta is assistant professor, division of hospital medicine, University of Virginia.

LOS ANGELES – A reorganization of stroke systems of care is needed to meet the rising demand for screening, triaging, and treating acute ischemic stroke patients who may benefit from mechanical thrombectomy, according to Lawrence Wechsler, MD.

In a video interview at the annual meeting of the American Academy of Neurology, Dr. Wechsler described steps being taken at the University of Pittsburgh Medical Center’s comprehensive stroke center to handle the additional workload.

UPMC conducts telemedicine acute stroke evaluations of patients at community hospitals’ primary stroke centers in the greater Pittsburgh area to make sure that only the cases that require mechanical thrombectomy are transferred to them for specialized care, while also continuing to see nontransferred patients via telemedicine for follow-up, said Dr. Wechsler, chair of the department of neurology at UPMC and founder of its Stroke Institute and telestroke network.

This sort of solution may be more feasible and practical for comprehensive stroke centers to implement in order to manage the number of cases, instead of expanding neurology residencies, capping stroke services, adding a nonteaching service, adding advanced practice providers, or increasing the case loads of vascular neurology fellows and attending neurologists, he said.

[email protected]

LOS ANGELES – A reorganization of stroke systems of care is needed to meet the rising demand for screening, triaging, and treating acute ischemic stroke patients who may benefit from mechanical thrombectomy, according to Lawrence Wechsler, MD.

In a video interview at the annual meeting of the American Academy of Neurology, Dr. Wechsler described steps being taken at the University of Pittsburgh Medical Center’s comprehensive stroke center to handle the additional workload.

UPMC conducts telemedicine acute stroke evaluations of patients at community hospitals’ primary stroke centers in the greater Pittsburgh area to make sure that only the cases that require mechanical thrombectomy are transferred to them for specialized care, while also continuing to see nontransferred patients via telemedicine for follow-up, said Dr. Wechsler, chair of the department of neurology at UPMC and founder of its Stroke Institute and telestroke network.

This sort of solution may be more feasible and practical for comprehensive stroke centers to implement in order to manage the number of cases, instead of expanding neurology residencies, capping stroke services, adding a nonteaching service, adding advanced practice providers, or increasing the case loads of vascular neurology fellows and attending neurologists, he said.

[email protected]

LOS ANGELES – A reorganization of stroke systems of care is needed to meet the rising demand for screening, triaging, and treating acute ischemic stroke patients who may benefit from mechanical thrombectomy, according to Lawrence Wechsler, MD.

In a video interview at the annual meeting of the American Academy of Neurology, Dr. Wechsler described steps being taken at the University of Pittsburgh Medical Center’s comprehensive stroke center to handle the additional workload.

UPMC conducts telemedicine acute stroke evaluations of patients at community hospitals’ primary stroke centers in the greater Pittsburgh area to make sure that only the cases that require mechanical thrombectomy are transferred to them for specialized care, while also continuing to see nontransferred patients via telemedicine for follow-up, said Dr. Wechsler, chair of the department of neurology at UPMC and founder of its Stroke Institute and telestroke network.

This sort of solution may be more feasible and practical for comprehensive stroke centers to implement in order to manage the number of cases, instead of expanding neurology residencies, capping stroke services, adding a nonteaching service, adding advanced practice providers, or increasing the case loads of vascular neurology fellows and attending neurologists, he said.

[email protected]

EXPERT COMMENTARY

Hormonal contraception (HC), including OC, is a central component of women’s health care worldwide. In addition to its many potential health benefits (pregnancy prevention, menstrual symptom management), HC use modifies the risk of various cancers. As we discussed in the February 2018 issue of OBG Management, a recent large population-based study in Denmark showed a small but statistically significant increase in breast cancer risk in HC users.^1,2 Conversely, HC use has a long recognized protective effect against ovarian and endometrial cancers. These risk relationships may be altered by other modifiable lifestyle characteristics, such as smoking, alcohol use, obesity, and physical activity.

Details of the study

Michels and colleagues evaluated the association between OC use and multiple cancers, stratifying these risks by duration of use and various modifiable lifestyle characteristics.³ The authors used a prospective survey-based cohort (the NIH-AARP Diet and Health Study) linked with state cancer registries to evaluate this relationship in a diverse population of 196,536 women across 6 US states and 2 metropolitan areas. Women were enrolled in 1995–1996 and followed until 2011. Cancer risks were presented as hazard ratios (HR), which indicate the risk of developing a specific cancer type in OC users compared with nonusers. HRs differ from relative risks (RR) and odds ratios because they compare the instantaneous risk difference between the 2 groups, rather than the cumulative risk difference over the entire study period.⁴

Duration of OC use and risk reduction

In this study population, OC use was associated with a significantly decreased risk of ovarian cancer, and this risk increased with longer duration of use (TABLE). Similarly, long-term OC use was associated with a decreased risk for endometrial cancer. These effects were true across various lifestyle characteristics, including smoking status, alcohol use, body mass index (BMI), and physical activity level.

There was a nonsignificant trend toward increased risk of breast cancer among OC users. The most significant elevation in breast cancer risk was found in long-term users who were current smokers (HR, 1.21 [95% confidence interval (CI), 1.01–1.44]). OC use had a minimal effect on colorectal cancer risk.

The bottom line. US women using OCs were significantly less likely to develop ovarian and endometrial cancers compared with nonusers. This risk reduction increased with longer duration of OC use and was true regardless of lifestyle. Conversely, there was a trend toward a slightly increased risk of developing breast cancer in OC users.

Study strengths and weaknesses

The effect on breast cancer risk is less pronounced than that reported in a recent large, prospective cohort study in Denmark, which reported an RR of developing breast cancer of 1.20 (95% CI, 1.14–1.26) among all current or recent HC users.¹ These differing results may be due to the US study population’s increased heterogeneity compared with the Danish cohort; potential recall bias in the US study (not present in the Danish study because pharmacy records were used); the larger size of the Danish study (that is, ability to detect very small effect sizes); and lack of information on OC formulation, recency of use, and parity in the US study.

Nevertheless, the significant protective effect against ovarian and endometrial cancers (reported previously in numerous studies) should be a part of totality of cancer risk when counseling patients on any potential increased risk of breast cancer with OC use.

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

EXPERT COMMENTARY

Hormonal contraception (HC), including OC, is a central component of women’s health care worldwide. In addition to its many potential health benefits (pregnancy prevention, menstrual symptom management), HC use modifies the risk of various cancers. As we discussed in the February 2018 issue of OBG Management, a recent large population-based study in Denmark showed a small but statistically significant increase in breast cancer risk in HC users.^1,2 Conversely, HC use has a long recognized protective effect against ovarian and endometrial cancers. These risk relationships may be altered by other modifiable lifestyle characteristics, such as smoking, alcohol use, obesity, and physical activity.

Details of the study

Michels and colleagues evaluated the association between OC use and multiple cancers, stratifying these risks by duration of use and various modifiable lifestyle characteristics.³ The authors used a prospective survey-based cohort (the NIH-AARP Diet and Health Study) linked with state cancer registries to evaluate this relationship in a diverse population of 196,536 women across 6 US states and 2 metropolitan areas. Women were enrolled in 1995–1996 and followed until 2011. Cancer risks were presented as hazard ratios (HR), which indicate the risk of developing a specific cancer type in OC users compared with nonusers. HRs differ from relative risks (RR) and odds ratios because they compare the instantaneous risk difference between the 2 groups, rather than the cumulative risk difference over the entire study period.⁴

Duration of OC use and risk reduction

In this study population, OC use was associated with a significantly decreased risk of ovarian cancer, and this risk increased with longer duration of use (TABLE). Similarly, long-term OC use was associated with a decreased risk for endometrial cancer. These effects were true across various lifestyle characteristics, including smoking status, alcohol use, body mass index (BMI), and physical activity level.

There was a nonsignificant trend toward increased risk of breast cancer among OC users. The most significant elevation in breast cancer risk was found in long-term users who were current smokers (HR, 1.21 [95% confidence interval (CI), 1.01–1.44]). OC use had a minimal effect on colorectal cancer risk.

The bottom line. US women using OCs were significantly less likely to develop ovarian and endometrial cancers compared with nonusers. This risk reduction increased with longer duration of OC use and was true regardless of lifestyle. Conversely, there was a trend toward a slightly increased risk of developing breast cancer in OC users.

Study strengths and weaknesses

The effect on breast cancer risk is less pronounced than that reported in a recent large, prospective cohort study in Denmark, which reported an RR of developing breast cancer of 1.20 (95% CI, 1.14–1.26) among all current or recent HC users.¹ These differing results may be due to the US study population’s increased heterogeneity compared with the Danish cohort; potential recall bias in the US study (not present in the Danish study because pharmacy records were used); the larger size of the Danish study (that is, ability to detect very small effect sizes); and lack of information on OC formulation, recency of use, and parity in the US study.

Nevertheless, the significant protective effect against ovarian and endometrial cancers (reported previously in numerous studies) should be a part of totality of cancer risk when counseling patients on any potential increased risk of breast cancer with OC use.

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

EXPERT COMMENTARY

Hormonal contraception (HC), including OC, is a central component of women’s health care worldwide. In addition to its many potential health benefits (pregnancy prevention, menstrual symptom management), HC use modifies the risk of various cancers. As we discussed in the February 2018 issue of OBG Management, a recent large population-based study in Denmark showed a small but statistically significant increase in breast cancer risk in HC users.^1,2 Conversely, HC use has a long recognized protective effect against ovarian and endometrial cancers. These risk relationships may be altered by other modifiable lifestyle characteristics, such as smoking, alcohol use, obesity, and physical activity.

Details of the study

Michels and colleagues evaluated the association between OC use and multiple cancers, stratifying these risks by duration of use and various modifiable lifestyle characteristics.³ The authors used a prospective survey-based cohort (the NIH-AARP Diet and Health Study) linked with state cancer registries to evaluate this relationship in a diverse population of 196,536 women across 6 US states and 2 metropolitan areas. Women were enrolled in 1995–1996 and followed until 2011. Cancer risks were presented as hazard ratios (HR), which indicate the risk of developing a specific cancer type in OC users compared with nonusers. HRs differ from relative risks (RR) and odds ratios because they compare the instantaneous risk difference between the 2 groups, rather than the cumulative risk difference over the entire study period.⁴

Duration of OC use and risk reduction

In this study population, OC use was associated with a significantly decreased risk of ovarian cancer, and this risk increased with longer duration of use (TABLE). Similarly, long-term OC use was associated with a decreased risk for endometrial cancer. These effects were true across various lifestyle characteristics, including smoking status, alcohol use, body mass index (BMI), and physical activity level.

There was a nonsignificant trend toward increased risk of breast cancer among OC users. The most significant elevation in breast cancer risk was found in long-term users who were current smokers (HR, 1.21 [95% confidence interval (CI), 1.01–1.44]). OC use had a minimal effect on colorectal cancer risk.

The bottom line. US women using OCs were significantly less likely to develop ovarian and endometrial cancers compared with nonusers. This risk reduction increased with longer duration of OC use and was true regardless of lifestyle. Conversely, there was a trend toward a slightly increased risk of developing breast cancer in OC users.

Study strengths and weaknesses

The effect on breast cancer risk is less pronounced than that reported in a recent large, prospective cohort study in Denmark, which reported an RR of developing breast cancer of 1.20 (95% CI, 1.14–1.26) among all current or recent HC users.¹ These differing results may be due to the US study population’s increased heterogeneity compared with the Danish cohort; potential recall bias in the US study (not present in the Danish study because pharmacy records were used); the larger size of the Danish study (that is, ability to detect very small effect sizes); and lack of information on OC formulation, recency of use, and parity in the US study.

Nevertheless, the significant protective effect against ovarian and endometrial cancers (reported previously in numerous studies) should be a part of totality of cancer risk when counseling patients on any potential increased risk of breast cancer with OC use.

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

LOS ANGELES – New results from phase 3 randomized trials of the prophylactic migraine treatment eptinezumab show significant reductions in the number of monthly migraine headache days experienced by patients with chronic or frequent episodic migraines.

Eptinezumab, an experimental monoclonal antibody delivered by intravenous infusion, is one of several antimigraine agents in development that targets calcitonin gene-related peptide (CGRP), a key mediator of migraine.

At the annual meeting of the American Academy of Neurology, Richard Lipton, MD, of Albert Einstein College of Medicine in New York, presented results from PROMISE 2, a phase 3 randomized, placebo-controlled trial of eptinezumab in patients with chronic migraine, or 15 or more days with migraine per month.

The investigators randomized 1,072 patients to quarterly IV infusions of eptinezumab 100 or 300 mg or placebo.

The vast majority of patients in the study were women, (86%-90% across groups) with a mean age of about 40 years. Patients reported 11-12 years of chronic migraine and about 16 migraine days per month at baseline, Dr. Lipton told the conference, reflecting a high level of disability in the cohort.

The primary endpoint of the study was mean change in monthly migraine days from baseline through week 12. Dr. Lipton reported that the placebo group saw a 5.6-day reduction in migraine, while the 100-mg group saw a 7.7-day reduction, and patients receiving the 300-mg dose saw an 8.2-day reduction during the first 12 weeks after injection (P less than .0001 for both).

One-third of patients receiving the highest dose saw a 75% or greater reduction in monthly migraine days by week 12, “a relatively high bar” to meet, Dr. Lipton said. Some 61% of patients on the high dose saw a reduction of 50% or more in the same time period.

SOURCE: Saper J et al. AAN 2018, Abstract S20.001 and Lipton R et al. AAN 2018, Clinical Trials Plenary Session Abstract.

LOS ANGELES – New results from phase 3 randomized trials of the prophylactic migraine treatment eptinezumab show significant reductions in the number of monthly migraine headache days experienced by patients with chronic or frequent episodic migraines.

Eptinezumab, an experimental monoclonal antibody delivered by intravenous infusion, is one of several antimigraine agents in development that targets calcitonin gene-related peptide (CGRP), a key mediator of migraine.

At the annual meeting of the American Academy of Neurology, Richard Lipton, MD, of Albert Einstein College of Medicine in New York, presented results from PROMISE 2, a phase 3 randomized, placebo-controlled trial of eptinezumab in patients with chronic migraine, or 15 or more days with migraine per month.

The investigators randomized 1,072 patients to quarterly IV infusions of eptinezumab 100 or 300 mg or placebo.

The vast majority of patients in the study were women, (86%-90% across groups) with a mean age of about 40 years. Patients reported 11-12 years of chronic migraine and about 16 migraine days per month at baseline, Dr. Lipton told the conference, reflecting a high level of disability in the cohort.

The primary endpoint of the study was mean change in monthly migraine days from baseline through week 12. Dr. Lipton reported that the placebo group saw a 5.6-day reduction in migraine, while the 100-mg group saw a 7.7-day reduction, and patients receiving the 300-mg dose saw an 8.2-day reduction during the first 12 weeks after injection (P less than .0001 for both).

One-third of patients receiving the highest dose saw a 75% or greater reduction in monthly migraine days by week 12, “a relatively high bar” to meet, Dr. Lipton said. Some 61% of patients on the high dose saw a reduction of 50% or more in the same time period.

SOURCE: Saper J et al. AAN 2018, Abstract S20.001 and Lipton R et al. AAN 2018, Clinical Trials Plenary Session Abstract.

LOS ANGELES – New results from phase 3 randomized trials of the prophylactic migraine treatment eptinezumab show significant reductions in the number of monthly migraine headache days experienced by patients with chronic or frequent episodic migraines.

Eptinezumab, an experimental monoclonal antibody delivered by intravenous infusion, is one of several antimigraine agents in development that targets calcitonin gene-related peptide (CGRP), a key mediator of migraine.

At the annual meeting of the American Academy of Neurology, Richard Lipton, MD, of Albert Einstein College of Medicine in New York, presented results from PROMISE 2, a phase 3 randomized, placebo-controlled trial of eptinezumab in patients with chronic migraine, or 15 or more days with migraine per month.

The investigators randomized 1,072 patients to quarterly IV infusions of eptinezumab 100 or 300 mg or placebo.

The vast majority of patients in the study were women, (86%-90% across groups) with a mean age of about 40 years. Patients reported 11-12 years of chronic migraine and about 16 migraine days per month at baseline, Dr. Lipton told the conference, reflecting a high level of disability in the cohort.

The primary endpoint of the study was mean change in monthly migraine days from baseline through week 12. Dr. Lipton reported that the placebo group saw a 5.6-day reduction in migraine, while the 100-mg group saw a 7.7-day reduction, and patients receiving the 300-mg dose saw an 8.2-day reduction during the first 12 weeks after injection (P less than .0001 for both).

One-third of patients receiving the highest dose saw a 75% or greater reduction in monthly migraine days by week 12, “a relatively high bar” to meet, Dr. Lipton said. Some 61% of patients on the high dose saw a reduction of 50% or more in the same time period.

SOURCE: Saper J et al. AAN 2018, Abstract S20.001 and Lipton R et al. AAN 2018, Clinical Trials Plenary Session Abstract.

SAN DIEGO – Emicizumab is a safe and effective new therapy for individuals with hemophilia A and inhibitor antibodies that will likely provide a paradigm shift for managing this patient population, according to Michael U. Callaghan, MD.

“It’s a safe drug, but you do have to be cautious about treating breakthrough bleeds with activated prothrombin complex concentrate (aPCC) resistance in particular,” Dr. Callaghan, a pediatric hematologist/oncologist at Children’s Hospital of Michigan, Detroit, said in an interview at the biennial summit of the Thrombosis & Hemostasis Societies of North America. “Patients require laboratory monitoring, and you need to educate anyone who’s going to see the patient about how the drug affects laboratory tests.”

Approved in November 2017, emicizumab (Hemlibra) is a recombinant, humanized bispecific immunoglobulin G4 monoclonal antibody that mimics the cofactor function of activated factor VIII (FVIIIa) by bridging activated factor IX and factor X. After 4 weeks of a loading dose of 3 mg/kg, subcutaneous once weekly dosing at 1.5 mg/kg demonstrated significant reduction in annualized bleeding rates in patients of all ages with congenital hemophilia A and inhibitors. But treatment-related adverse events occurred during the pivotal trials.

In an effort to provide recommendations on use of emicizumab beyond information contained in the agent’s package insert, Dr. Callaghan and his associates reviewed published literature, meeting abstracts, and expert experience with emicizumab on clinical trials.

Doug Brunk/MDedge News

To prevent, monitor, and treat TMA and TE, prior to starting emicizumab, patients should be informed that baseline hemostasis is increased with the agent and that there is an increased risk of pathologic thrombosis with bypassing agents.

*Correction, 4/26/2018: An earlier version of this story misstated the number of cases of thrombotic microangiopathy.

[email protected]

SAN DIEGO – Emicizumab is a safe and effective new therapy for individuals with hemophilia A and inhibitor antibodies that will likely provide a paradigm shift for managing this patient population, according to Michael U. Callaghan, MD.

“It’s a safe drug, but you do have to be cautious about treating breakthrough bleeds with activated prothrombin complex concentrate (aPCC) resistance in particular,” Dr. Callaghan, a pediatric hematologist/oncologist at Children’s Hospital of Michigan, Detroit, said in an interview at the biennial summit of the Thrombosis & Hemostasis Societies of North America. “Patients require laboratory monitoring, and you need to educate anyone who’s going to see the patient about how the drug affects laboratory tests.”

Approved in November 2017, emicizumab (Hemlibra) is a recombinant, humanized bispecific immunoglobulin G4 monoclonal antibody that mimics the cofactor function of activated factor VIII (FVIIIa) by bridging activated factor IX and factor X. After 4 weeks of a loading dose of 3 mg/kg, subcutaneous once weekly dosing at 1.5 mg/kg demonstrated significant reduction in annualized bleeding rates in patients of all ages with congenital hemophilia A and inhibitors. But treatment-related adverse events occurred during the pivotal trials.

In an effort to provide recommendations on use of emicizumab beyond information contained in the agent’s package insert, Dr. Callaghan and his associates reviewed published literature, meeting abstracts, and expert experience with emicizumab on clinical trials.

Doug Brunk/MDedge News

To prevent, monitor, and treat TMA and TE, prior to starting emicizumab, patients should be informed that baseline hemostasis is increased with the agent and that there is an increased risk of pathologic thrombosis with bypassing agents.

*Correction, 4/26/2018: An earlier version of this story misstated the number of cases of thrombotic microangiopathy.

[email protected]

SAN DIEGO – Emicizumab is a safe and effective new therapy for individuals with hemophilia A and inhibitor antibodies that will likely provide a paradigm shift for managing this patient population, according to Michael U. Callaghan, MD.

“It’s a safe drug, but you do have to be cautious about treating breakthrough bleeds with activated prothrombin complex concentrate (aPCC) resistance in particular,” Dr. Callaghan, a pediatric hematologist/oncologist at Children’s Hospital of Michigan, Detroit, said in an interview at the biennial summit of the Thrombosis & Hemostasis Societies of North America. “Patients require laboratory monitoring, and you need to educate anyone who’s going to see the patient about how the drug affects laboratory tests.”

Approved in November 2017, emicizumab (Hemlibra) is a recombinant, humanized bispecific immunoglobulin G4 monoclonal antibody that mimics the cofactor function of activated factor VIII (FVIIIa) by bridging activated factor IX and factor X. After 4 weeks of a loading dose of 3 mg/kg, subcutaneous once weekly dosing at 1.5 mg/kg demonstrated significant reduction in annualized bleeding rates in patients of all ages with congenital hemophilia A and inhibitors. But treatment-related adverse events occurred during the pivotal trials.

In an effort to provide recommendations on use of emicizumab beyond information contained in the agent’s package insert, Dr. Callaghan and his associates reviewed published literature, meeting abstracts, and expert experience with emicizumab on clinical trials.

Doug Brunk/MDedge News

To prevent, monitor, and treat TMA and TE, prior to starting emicizumab, patients should be informed that baseline hemostasis is increased with the agent and that there is an increased risk of pathologic thrombosis with bypassing agents.

*Correction, 4/26/2018: An earlier version of this story misstated the number of cases of thrombotic microangiopathy.

[email protected]