The Food and Drug Administration has approved combination therapy of encorafenib (Braftovi) and binimetinib (Mektovi) for the treatment of unresectable or metastatic melanoma with BRAF V600E or BRAF V600K mutations; the FDA also has approved the THxID BRAF Kit as a companion diagnostic for this combination therapy.

The approval was based on results from the randomized, active-controlled, open-label, multicenter COLUMBUS trial, which included 517 patients. Progression-free survival, according to RECIST 1.1 criteria, was the major efficacy measure; the median progression-free survival was 14.9 months in the encorafenib/binimetinib combination arm versus 7.3 months in the vemurafenib (Zelboraf) monotherapy arm (hazard ratio, 0.54; 95% confidence interval, 0.41-0.71; P less than .0001).

Fatigue, nausea, diarrhea, vomiting, abdominal pain, and arthralgia were the most common adverse reactions. Discontinuation of therapy from adverse reactions occurred in 5% of patients receiving the combination, the FDA said in a press statement.

The full prescribing information for encorafenib and binimetinib can be found on the FDA website.






 

The Food and Drug Administration has approved combination therapy of encorafenib (Braftovi) and binimetinib (Mektovi) for the treatment of unresectable or metastatic melanoma with BRAF V600E or BRAF V600K mutations; the FDA also has approved the THxID BRAF Kit as a companion diagnostic for this combination therapy.

The approval was based on results from the randomized, active-controlled, open-label, multicenter COLUMBUS trial, which included 517 patients. Progression-free survival, according to RECIST 1.1 criteria, was the major efficacy measure; the median progression-free survival was 14.9 months in the encorafenib/binimetinib combination arm versus 7.3 months in the vemurafenib (Zelboraf) monotherapy arm (hazard ratio, 0.54; 95% confidence interval, 0.41-0.71; P less than .0001).

Fatigue, nausea, diarrhea, vomiting, abdominal pain, and arthralgia were the most common adverse reactions. Discontinuation of therapy from adverse reactions occurred in 5% of patients receiving the combination, the FDA said in a press statement.

The full prescribing information for encorafenib and binimetinib can be found on the FDA website.






 

The Food and Drug Administration has approved combination therapy of encorafenib (Braftovi) and binimetinib (Mektovi) for the treatment of unresectable or metastatic melanoma with BRAF V600E or BRAF V600K mutations; the FDA also has approved the THxID BRAF Kit as a companion diagnostic for this combination therapy.

The approval was based on results from the randomized, active-controlled, open-label, multicenter COLUMBUS trial, which included 517 patients. Progression-free survival, according to RECIST 1.1 criteria, was the major efficacy measure; the median progression-free survival was 14.9 months in the encorafenib/binimetinib combination arm versus 7.3 months in the vemurafenib (Zelboraf) monotherapy arm (hazard ratio, 0.54; 95% confidence interval, 0.41-0.71; P less than .0001).

Fatigue, nausea, diarrhea, vomiting, abdominal pain, and arthralgia were the most common adverse reactions. Discontinuation of therapy from adverse reactions occurred in 5% of patients receiving the combination, the FDA said in a press statement.

The full prescribing information for encorafenib and binimetinib can be found on the FDA website.






 

SAN DIEGO – Between 1999 and 2015, heroin use increased among high school students who live in Milwaukee, Chicago, and New York – trends that accompanied a rise in injection drug use in those cities.

“This implies that a subset of these students who are using heroin are probably injecting heroin as well; otherwise these trends wouldn’t be mirroring each other so well,” lead study author Sherri-Chanelle Brighthaupt said in an interview at the annual meeting of the College on Problems of Drug Dependence.

Doug Brunk/MDedge News

The finding comes from a trend analysis of heroin use and injection drug use in nine urban U.S. school districts drawn from Youth Risk Behavior Survey (YRBS) data from 1999-2015. The analysis was conducted using data from New York City, three Florida counties (Broward, Orange, and Miami-Dade), Dallas, Chicago, Milwaukee, and two California cities (San Diego and San Bernardino). “This is one of the first studies we know of that’s looking at adolescent heroin and injection drug use at the local level,” said Ms. Brighthaupt, a third-year doctoral student in the department of mental health at Johns Hopkins University, Baltimore. “National estimates may mask variation at the local level.”

The sample population studied included local-level YRBS responses from 260,952 students in grades 9-12. All responses were weighted by sex, grade, and race/ethnicity, and the researchers used logistic regression models to test for liner and quadratic trends in the pooled sample and in each city. Between 1999 and 2015, lifetime heroin use among this population increased significantly, from 2.8% to 7.4% in Milwaukee (P = .0001), from 3.1% to 4.1% in Chicago (P = .02), and from 1% to 2.5% in New York (P less than .0001). However, during the same time frame, heroin use decreased in San Bernardino from 4.6% to 1.6% (P = .0001).

The researchers also found that between 1999 and 2015, lifetime injection drug use in this age group increased significantly, from 0.8% to 2.2% in New York (P less than .0001) and from 2.5% to 2.7% in Chicago (P = .05). During the same time period, lifetime injection drug use decreased in San Bernardino, (from 2.5% to 1.9%; P = .05) and in Dallas after peaking in 2007 (from 3.6% to 1%; P = .02).

“The take-home message is to look locally,” Ms. Brighthaupt said. “Some cities may have a historically entrenched culture of heroin use, and prevention and intervention efforts should be tailored to the unique social and cultural context of the geographic region.”

The research was supported by grants from the National Institute on Drug Abuse. Ms. Brighthaupt reported having no financial disclosures.

[email protected]

SAN DIEGO – Between 1999 and 2015, heroin use increased among high school students who live in Milwaukee, Chicago, and New York – trends that accompanied a rise in injection drug use in those cities.

“This implies that a subset of these students who are using heroin are probably injecting heroin as well; otherwise these trends wouldn’t be mirroring each other so well,” lead study author Sherri-Chanelle Brighthaupt said in an interview at the annual meeting of the College on Problems of Drug Dependence.

Doug Brunk/MDedge News

The finding comes from a trend analysis of heroin use and injection drug use in nine urban U.S. school districts drawn from Youth Risk Behavior Survey (YRBS) data from 1999-2015. The analysis was conducted using data from New York City, three Florida counties (Broward, Orange, and Miami-Dade), Dallas, Chicago, Milwaukee, and two California cities (San Diego and San Bernardino). “This is one of the first studies we know of that’s looking at adolescent heroin and injection drug use at the local level,” said Ms. Brighthaupt, a third-year doctoral student in the department of mental health at Johns Hopkins University, Baltimore. “National estimates may mask variation at the local level.”

The sample population studied included local-level YRBS responses from 260,952 students in grades 9-12. All responses were weighted by sex, grade, and race/ethnicity, and the researchers used logistic regression models to test for liner and quadratic trends in the pooled sample and in each city. Between 1999 and 2015, lifetime heroin use among this population increased significantly, from 2.8% to 7.4% in Milwaukee (P = .0001), from 3.1% to 4.1% in Chicago (P = .02), and from 1% to 2.5% in New York (P less than .0001). However, during the same time frame, heroin use decreased in San Bernardino from 4.6% to 1.6% (P = .0001).

The researchers also found that between 1999 and 2015, lifetime injection drug use in this age group increased significantly, from 0.8% to 2.2% in New York (P less than .0001) and from 2.5% to 2.7% in Chicago (P = .05). During the same time period, lifetime injection drug use decreased in San Bernardino, (from 2.5% to 1.9%; P = .05) and in Dallas after peaking in 2007 (from 3.6% to 1%; P = .02).

“The take-home message is to look locally,” Ms. Brighthaupt said. “Some cities may have a historically entrenched culture of heroin use, and prevention and intervention efforts should be tailored to the unique social and cultural context of the geographic region.”

The research was supported by grants from the National Institute on Drug Abuse. Ms. Brighthaupt reported having no financial disclosures.

[email protected]

SAN DIEGO – Between 1999 and 2015, heroin use increased among high school students who live in Milwaukee, Chicago, and New York – trends that accompanied a rise in injection drug use in those cities.

“This implies that a subset of these students who are using heroin are probably injecting heroin as well; otherwise these trends wouldn’t be mirroring each other so well,” lead study author Sherri-Chanelle Brighthaupt said in an interview at the annual meeting of the College on Problems of Drug Dependence.

Doug Brunk/MDedge News

The finding comes from a trend analysis of heroin use and injection drug use in nine urban U.S. school districts drawn from Youth Risk Behavior Survey (YRBS) data from 1999-2015. The analysis was conducted using data from New York City, three Florida counties (Broward, Orange, and Miami-Dade), Dallas, Chicago, Milwaukee, and two California cities (San Diego and San Bernardino). “This is one of the first studies we know of that’s looking at adolescent heroin and injection drug use at the local level,” said Ms. Brighthaupt, a third-year doctoral student in the department of mental health at Johns Hopkins University, Baltimore. “National estimates may mask variation at the local level.”

The sample population studied included local-level YRBS responses from 260,952 students in grades 9-12. All responses were weighted by sex, grade, and race/ethnicity, and the researchers used logistic regression models to test for liner and quadratic trends in the pooled sample and in each city. Between 1999 and 2015, lifetime heroin use among this population increased significantly, from 2.8% to 7.4% in Milwaukee (P = .0001), from 3.1% to 4.1% in Chicago (P = .02), and from 1% to 2.5% in New York (P less than .0001). However, during the same time frame, heroin use decreased in San Bernardino from 4.6% to 1.6% (P = .0001).

The researchers also found that between 1999 and 2015, lifetime injection drug use in this age group increased significantly, from 0.8% to 2.2% in New York (P less than .0001) and from 2.5% to 2.7% in Chicago (P = .05). During the same time period, lifetime injection drug use decreased in San Bernardino, (from 2.5% to 1.9%; P = .05) and in Dallas after peaking in 2007 (from 3.6% to 1%; P = .02).

“The take-home message is to look locally,” Ms. Brighthaupt said. “Some cities may have a historically entrenched culture of heroin use, and prevention and intervention efforts should be tailored to the unique social and cultural context of the geographic region.”

The research was supported by grants from the National Institute on Drug Abuse. Ms. Brighthaupt reported having no financial disclosures.

[email protected]

EXPERT COMMENTARY

Prophylactic bilateral oophorectomy (BO) reduces the risk of future ovarian cancer in women who have BRCA1 gene mutations. Women in this high-risk population may be reluctant, however, to use menopausal hormone therapy (HT) to mitigate the symptoms of surgical menopause because of concerns that it might elevate their risk of breast cancer.

To determine the relationship between HT use and BRCA1-associated breast cancer, Kotsopoulos and colleagues conducted a multicenter international cohort study. They prospectively followed women with BRCA1 mutations who had undergone BO and had intact breasts and no history of breast cancer.

Details of the study

The study included women who had a BRCA1 mutation and considered HT use following BO. Women were excluded from the analysis if they had a prior diagnosis of breast cancer or had BO prior to study enrollment. Study participants completed a questionnaire at baseline and a follow-up questionnaire every 2 years thereafter. The primary end point was invasive breast cancer.

Among 872 participating BRCA1 carriers, 43% (n = 377) used HT following BO. Mean duration of HT use following BO was 3.9 years, with 69% of users taking estrogen therapy alone (ET) and 19% using estrogen plus progestogen therapy (EPT). Those who used HT were younger at the time of BO compared with women who never used HT (mean age, 43.0 vs 48.4 years).

During follow-up (mean, 7.6 years; range, 0.4–22.1), invasive breast cancer was diagnosed in similar proportions of HT users and nonusers—10.3% and 10.7%, respectively (P = .86). The hazard ratio was 0.97 (95% confidence interval, 0.62–1.52; P = .89) for ever use of any type of hormone therapy versus no use.

When the type of HT used was examined, the 10-year actuarial risk of breast cancer was significantly lower with ET than with EPT (12% vs 22%, respectively; P = .04); this difference was more marked for women who underwent BO prior to age 45 (9% vs 24%; P = .009).

Study strengths and weaknesses

This investigation had several strengths, including the large number of BRCA1 mutation carriers studied, the relatively long follow-up, and the detailed exposure data obtained.

The use of self-administered questionnaires for collecting information on lifetime HT use and breast cancer diagnoses may be a limitation. In addition, the HT route, regimen, and dose were not considered in the analysis, and the effect of intrauterine devices as progestational endometrial protection was not evaluated. Finally, the relationship between HT and breast cancer risk in women with intact ovaries was not evaluated.

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

Prophylactic bilateral oophorectomy (BO) reduces the risk of future ovarian cancer in women who have BRCA1 gene mutations. Women in this high-risk population may be reluctant, however, to use menopausal hormone therapy (HT) to mitigate the symptoms of surgical menopause because of concerns that it might elevate their risk of breast cancer.

To determine the relationship between HT use and BRCA1-associated breast cancer, Kotsopoulos and colleagues conducted a multicenter international cohort study. They prospectively followed women with BRCA1 mutations who had undergone BO and had intact breasts and no history of breast cancer.

Details of the study

The study included women who had a BRCA1 mutation and considered HT use following BO. Women were excluded from the analysis if they had a prior diagnosis of breast cancer or had BO prior to study enrollment. Study participants completed a questionnaire at baseline and a follow-up questionnaire every 2 years thereafter. The primary end point was invasive breast cancer.

Among 872 participating BRCA1 carriers, 43% (n = 377) used HT following BO. Mean duration of HT use following BO was 3.9 years, with 69% of users taking estrogen therapy alone (ET) and 19% using estrogen plus progestogen therapy (EPT). Those who used HT were younger at the time of BO compared with women who never used HT (mean age, 43.0 vs 48.4 years).

During follow-up (mean, 7.6 years; range, 0.4–22.1), invasive breast cancer was diagnosed in similar proportions of HT users and nonusers—10.3% and 10.7%, respectively (P = .86). The hazard ratio was 0.97 (95% confidence interval, 0.62–1.52; P = .89) for ever use of any type of hormone therapy versus no use.

When the type of HT used was examined, the 10-year actuarial risk of breast cancer was significantly lower with ET than with EPT (12% vs 22%, respectively; P = .04); this difference was more marked for women who underwent BO prior to age 45 (9% vs 24%; P = .009).

Study strengths and weaknesses

This investigation had several strengths, including the large number of BRCA1 mutation carriers studied, the relatively long follow-up, and the detailed exposure data obtained.

The use of self-administered questionnaires for collecting information on lifetime HT use and breast cancer diagnoses may be a limitation. In addition, the HT route, regimen, and dose were not considered in the analysis, and the effect of intrauterine devices as progestational endometrial protection was not evaluated. Finally, the relationship between HT and breast cancer risk in women with intact ovaries was not evaluated.

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

Prophylactic bilateral oophorectomy (BO) reduces the risk of future ovarian cancer in women who have BRCA1 gene mutations. Women in this high-risk population may be reluctant, however, to use menopausal hormone therapy (HT) to mitigate the symptoms of surgical menopause because of concerns that it might elevate their risk of breast cancer.

To determine the relationship between HT use and BRCA1-associated breast cancer, Kotsopoulos and colleagues conducted a multicenter international cohort study. They prospectively followed women with BRCA1 mutations who had undergone BO and had intact breasts and no history of breast cancer.

Details of the study

The study included women who had a BRCA1 mutation and considered HT use following BO. Women were excluded from the analysis if they had a prior diagnosis of breast cancer or had BO prior to study enrollment. Study participants completed a questionnaire at baseline and a follow-up questionnaire every 2 years thereafter. The primary end point was invasive breast cancer.

Among 872 participating BRCA1 carriers, 43% (n = 377) used HT following BO. Mean duration of HT use following BO was 3.9 years, with 69% of users taking estrogen therapy alone (ET) and 19% using estrogen plus progestogen therapy (EPT). Those who used HT were younger at the time of BO compared with women who never used HT (mean age, 43.0 vs 48.4 years).

During follow-up (mean, 7.6 years; range, 0.4–22.1), invasive breast cancer was diagnosed in similar proportions of HT users and nonusers—10.3% and 10.7%, respectively (P = .86). The hazard ratio was 0.97 (95% confidence interval, 0.62–1.52; P = .89) for ever use of any type of hormone therapy versus no use.

When the type of HT used was examined, the 10-year actuarial risk of breast cancer was significantly lower with ET than with EPT (12% vs 22%, respectively; P = .04); this difference was more marked for women who underwent BO prior to age 45 (9% vs 24%; P = .009).

Study strengths and weaknesses

This investigation had several strengths, including the large number of BRCA1 mutation carriers studied, the relatively long follow-up, and the detailed exposure data obtained.

The use of self-administered questionnaires for collecting information on lifetime HT use and breast cancer diagnoses may be a limitation. In addition, the HT route, regimen, and dose were not considered in the analysis, and the effect of intrauterine devices as progestational endometrial protection was not evaluated. Finally, the relationship between HT and breast cancer risk in women with intact ovaries was not evaluated.

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.

Cervical cancer screening represents one of the great public health successes of the 20th Century. Two physician-scientists, George Papanicolaou, MD, PhD (1883–1962), and Harald zur Hausen, MD (1936–), made extraordinary contributions to the evolution of effective cervical cancer screening programs. Dr. Papanicolaou led development of the iconic Pap smear, creating techniques for collecting specimens and using cytologic techniques to identify cervical cancer and its precursors, and Dr. zur Hausen discovered the association of human papillomavirus (HPV) infection with cervical cancer.^1,2

Although it is but a distant memory, in the 1930s cervical and uterine cancer caused more deaths among women than breast, lung, or ovarian cancer. The successful deployment of Pap smear screening resulted in a decrease in cervical cancer rates in developed countries. Cervical cancer deaths remain common in many parts of the world, however. Cervical cancer screening programs can reduce cervical cancer incidence by greater than 80%.³ In the United States between 1973 and 2006, the invasive cervical cancer age-adjusted incidence rates dropped from 10.28 to 3.97 per 100,000 women.⁴

HPV causes cervical cancer

Dr. zur Hausen dedicated his career to identifying viral causes of human cancer. In his Nobel Laureate autobiography, he reported that during his 2-year rotating residency, he loved his obstetrics and gynecology experience, but found it “physically highly demanding” and decided to focus his career in microbiology and immunology.⁵ After proving that herpes simplex virus did not cause cervical cancer he began to explore the role of HPV in the disease process. He first identified HPV types 6 and 11 and showed that these agents caused genital warts. He then used low-stringency hybridization techniques to identify HPV types 16 and 18 in specimens of cervical cancer. Later, he and his colleagues proved that two HPV proteins, E6 and E7, interfere with the function of cell cycle control proteins p53 and retinoblastoma protein, resulting in dysregulated cell growth and cancer.² These findings permitted the development of both HPV vaccines and nucleic acid–based tests to identify high-risk oncogenic HPV (hrHPV) in cells and tissue specimens.

HPV vaccination

Dr. zur Hausen was an energetic and vocal advocate for the development and widescale deployment of HPV vaccines, including vaccination of males and females.⁶ Initially his ideas were rejected by the pharmaceutical industry, but eventually, with advances in virology and vaccine development, multiple companies pursued the development of HPV vaccines, the first cancer prevention vaccines. The best approach to cervical cancer prevention is intensive population-wide HPV vaccination of both boys and girls before exposure to the HPV virus. Beyond its beneficial effect on the incidence of cervical cancer, HPV vaccination also reduces the population incidence of anal, vulvar, and oropharyngeal cancer.⁷ Prevention of oropharyngeal cancer is especially important for men, supporting the recommendation for vaccination of all boys.⁸

Population-wide HPV vaccination will result in a lower prevalence of cervical cancer precursors and reduce the sensitivity of cytology, thereby making primary HPV screening more attractive.⁹ Based on one modelling study, universal HPV vaccination can reduce cervical cancer rates by greater than 50% over current levels, and introduction of primary HPV screening will reduce cervical cancer rates by an additional 20%.¹⁰ In an era of widespread vaccination for HPV, screening for cervical cancer should be intensified for nonvaccinated women.¹⁰

Read about Primary cervical cancer screening with cytology

Primary cervical cancer screening with cytology

Primary screening with cervical cytology alone remains an option supported by many authorities and professional society guidelines.¹¹ Most studies report that HPV testing has greater sensitivity than cervical cytology alone, especially for the detection of adenocarcinoma of the cervix.¹² In one Canadian study, 10,154 women were randomly assigned to HPV or cervical cytology testing. The sensitivity of HPV testing and cervical cytology for detecting cervical intraepithelial neoplasia grade 2 or 3 was 95% and 55%, respectively, with a specificity of 94% and 97%, respectively.¹³ When used together the sensitivity and specificity of cotesting was 100% and 93%, respectively, but resulted in an increased number of colposcopies, which may be costly and add stress for the patient. Many countries are beginning to move away from cervical cancer screening with cytology or cotesting to programs built upon a foundation of primary HPV testing.

Primary cervical cancer screening with HPV testing

The knowledge that hrHPV is a more sensitive test for cervical cancer and its precursors, as well as the relatively lower sensitivity of cytology, is the foundation for transitioning from primary screening with cervical cytology to primary screening with HPV testing. In the Netherlands¹⁴ and Australia^15,16 HPV testing with reflex cytology is the nationwide approach to cervical cancer screening. The basic components of the Dutch primary HPV screening program, as explained by Dr. Lai van Zulyan Mandres, are¹⁴:

1. Samples are collected by a general practitioner and sent to one of 5 central testing facilities for DNA testing for hrHPV.
2. If all previous samples tested negative, the screening occurs at ages 30, 35, 40, 50, and 60 years, a minimum of 5 screens per woman.
3. If there is a history of a previously positive hrHPV, the screening is intensified, with additional specimens collected at ages 45, 55, and 60 years.
4. If the sample is hrHPV negative, the patient continues screening at the standard intervals. No cytology testing is performed.
5. If the sample is hrHPV positive, reflex cytology is performed using the original collected sample. If the cytology shows no intraepithelial lesion or malignancy (NILM), another specimen is obtained for cytology within 6 months. If the second cytology specimen shows atypical squamous cells of undetermined significance (ASCUS) or a more worrisome cytology finding, the patient is sent for colposcopy. If two NILM cytology specimens have been obtained, the patient resumes primary hrHPV screening every 5 years.
6. If the specimen is hrHPV positive and cytology is ASCUS or more worrisome the patient is referred for colposcopy (FIGURE).¹⁴ The Dutch estimate that primary hrHPV screening will reduce the number of cervical cytology specimens by 90% annually.

Australia also has implemented nationwide primary HPV testing for cervical cancer screening. This change was implemented following a 10-year program of universal school-based vaccination of girls and boys, and biennial cytology screening for all women. The Australian screening program initiates hrHPV testing at age 25 years and thereafter every 5 years until age 74. If the hrHPV test is positive, reflex testing for HPV types 16 and 18 are performed on the original specimen along with cervical cytology. Women who test positive for HPV 16 or 18 are immediately referred for colposcopy. If the hrHPV test is positive and reflex testing for HPV 16 and 18 is negative, cervical cytology demonstrating ASCUS, low- or high-grade squamous intraepithelial lesions, or more worrisome results trigger a referral for colposcopy. The Australian program supports testing of self-collected vaginal samples for women who are underscreened or have never been screened.^15,16

Read about Pros and cons of switching approaches

Pros and cons of switching approaches

Deployment of new technology often yields benefits and challenges. A putative benefit of primary HPV screening is a reduction in health care costs without an increase in cervical cancer deaths. Another benefit of primary HPV screening is that it may enable self-collection of specimens for analysis, thereby increasing access to cervical cancer screening for underserved and marginalized populations of women who are not currently participating in cervical cancer screening programs.¹⁷ One challenge is that many women are unaware that hrHPV is the cause of most invasive cervical cancers. The detection of hrHPV in a woman in a long-term relationship who was previously negative for hrHPV may cause the emotions of surprise, fear, anxiety, and anger, thereby stressing the relationship.¹⁸

Another concern is that many women are worried about no longer receiving the familiar “Pap smear” cancer screening test in which they have tremendous faith. When Australia transitioned to primary HPV screening, more than 70,000 women signed a petition to “save women’s lives” by permitting continued access to the cervical cytology testing.¹⁹ Primary HPV testing may result in a transient increase in the number of women referred for colposcopy, potentially overwhelming the capacity of the health care system to deliver this vital service.^20,21 The HPV types that most often cause cervical cancer may vary among countries. For example, in Thailand, HPV 52 and 58 are frequently detected in women with high-grade squamous lesions, and including these subtypes in reflex genotyping may be of regional benefit.²²

Primary cervical cancer screening with HPV testing: When will it be used widely in the United States?

In contrast to the United States, the Netherlands is a small, densely populated country that has a highly integrated health system with centralized laboratory centers, a nationwide electronic health record, and clinicians organized to perform as an integrated team. These features ensure that all lifetime tests results are available in one record, that HPV testing is highly standardized, and that clinicians will follow a prescribed care pathway. The Netherlands’ health system is organized to support the successful transition, in a single step, to primary HPV testing. The United States is the third most populous country in the world, following China and India, with a diverse approach to health care, a highly mobile population, no single interoperable electronic health record, and minimal central control of clinical practice. The United States is not organized to make a “big bang” transition to primary HPV cervical cancer screening. It is likely that the introduction of primary HPV screening will occur first in highly integrated health systems that control the clinical, laboratory, and electronic records of a large population.

The results of the ATHENA study provide a clear clinical algorithm for implementing a primary HPV screening program for cervical cancer in the United States.^23–25 Samples are collected for hrHPV testing at a specified interval, 3 or 5 years, beginning at age 25 years. Women younger than age 25 years should be screened with cytology alone. Detection of hrHPV results in reflex viral typing for HPV 16 and 18. Women with samples positive for HPV 16 and 18 are immediately referred for colposcopy. Samples positive for hrHPV and negative for HPV 16 and 18 have reflex cytology testing performed on the original HPV specimen. If cytology testing reports NILM, repeat cotesting is performed in one year. If cytology testing reports ASCUS or a more concerning result, the woman is referred for colposcopy.

Malcolm Gladwell, in his book The Tipping Point, identified 3 processes that help push an innovative new approach from obscurity into widespread use.²⁶ First, authoritative voices that can catalyze change need to consistently communicate their shared vision for the future. Second, there must be a clear message that galvanizes the many to change their approach. Third, the historical context must be supportive of the change. Over the next decade we are likely to hit a tipping point and transition from cervical cancer screening that relies on cervical cytology to an approach that prioritizes hrHPV testing. When that change will occur in the United States is unclear. But our colleagues in other countries already have transitioned to primary hrHPV testing for cervical cancer screening.

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.

Cervical cancer screening represents one of the great public health successes of the 20th Century. Two physician-scientists, George Papanicolaou, MD, PhD (1883–1962), and Harald zur Hausen, MD (1936–), made extraordinary contributions to the evolution of effective cervical cancer screening programs. Dr. Papanicolaou led development of the iconic Pap smear, creating techniques for collecting specimens and using cytologic techniques to identify cervical cancer and its precursors, and Dr. zur Hausen discovered the association of human papillomavirus (HPV) infection with cervical cancer.^1,2

Although it is but a distant memory, in the 1930s cervical and uterine cancer caused more deaths among women than breast, lung, or ovarian cancer. The successful deployment of Pap smear screening resulted in a decrease in cervical cancer rates in developed countries. Cervical cancer deaths remain common in many parts of the world, however. Cervical cancer screening programs can reduce cervical cancer incidence by greater than 80%.³ In the United States between 1973 and 2006, the invasive cervical cancer age-adjusted incidence rates dropped from 10.28 to 3.97 per 100,000 women.⁴

HPV causes cervical cancer

Dr. zur Hausen dedicated his career to identifying viral causes of human cancer. In his Nobel Laureate autobiography, he reported that during his 2-year rotating residency, he loved his obstetrics and gynecology experience, but found it “physically highly demanding” and decided to focus his career in microbiology and immunology.⁵ After proving that herpes simplex virus did not cause cervical cancer he began to explore the role of HPV in the disease process. He first identified HPV types 6 and 11 and showed that these agents caused genital warts. He then used low-stringency hybridization techniques to identify HPV types 16 and 18 in specimens of cervical cancer. Later, he and his colleagues proved that two HPV proteins, E6 and E7, interfere with the function of cell cycle control proteins p53 and retinoblastoma protein, resulting in dysregulated cell growth and cancer.² These findings permitted the development of both HPV vaccines and nucleic acid–based tests to identify high-risk oncogenic HPV (hrHPV) in cells and tissue specimens.

HPV vaccination

Dr. zur Hausen was an energetic and vocal advocate for the development and widescale deployment of HPV vaccines, including vaccination of males and females.⁶ Initially his ideas were rejected by the pharmaceutical industry, but eventually, with advances in virology and vaccine development, multiple companies pursued the development of HPV vaccines, the first cancer prevention vaccines. The best approach to cervical cancer prevention is intensive population-wide HPV vaccination of both boys and girls before exposure to the HPV virus. Beyond its beneficial effect on the incidence of cervical cancer, HPV vaccination also reduces the population incidence of anal, vulvar, and oropharyngeal cancer.⁷ Prevention of oropharyngeal cancer is especially important for men, supporting the recommendation for vaccination of all boys.⁸

Population-wide HPV vaccination will result in a lower prevalence of cervical cancer precursors and reduce the sensitivity of cytology, thereby making primary HPV screening more attractive.⁹ Based on one modelling study, universal HPV vaccination can reduce cervical cancer rates by greater than 50% over current levels, and introduction of primary HPV screening will reduce cervical cancer rates by an additional 20%.¹⁰ In an era of widespread vaccination for HPV, screening for cervical cancer should be intensified for nonvaccinated women.¹⁰

Read about Primary cervical cancer screening with cytology

Primary cervical cancer screening with cytology

Primary screening with cervical cytology alone remains an option supported by many authorities and professional society guidelines.¹¹ Most studies report that HPV testing has greater sensitivity than cervical cytology alone, especially for the detection of adenocarcinoma of the cervix.¹² In one Canadian study, 10,154 women were randomly assigned to HPV or cervical cytology testing. The sensitivity of HPV testing and cervical cytology for detecting cervical intraepithelial neoplasia grade 2 or 3 was 95% and 55%, respectively, with a specificity of 94% and 97%, respectively.¹³ When used together the sensitivity and specificity of cotesting was 100% and 93%, respectively, but resulted in an increased number of colposcopies, which may be costly and add stress for the patient. Many countries are beginning to move away from cervical cancer screening with cytology or cotesting to programs built upon a foundation of primary HPV testing.

Primary cervical cancer screening with HPV testing

The knowledge that hrHPV is a more sensitive test for cervical cancer and its precursors, as well as the relatively lower sensitivity of cytology, is the foundation for transitioning from primary screening with cervical cytology to primary screening with HPV testing. In the Netherlands¹⁴ and Australia^15,16 HPV testing with reflex cytology is the nationwide approach to cervical cancer screening. The basic components of the Dutch primary HPV screening program, as explained by Dr. Lai van Zulyan Mandres, are¹⁴:

1. Samples are collected by a general practitioner and sent to one of 5 central testing facilities for DNA testing for hrHPV.
2. If all previous samples tested negative, the screening occurs at ages 30, 35, 40, 50, and 60 years, a minimum of 5 screens per woman.
3. If there is a history of a previously positive hrHPV, the screening is intensified, with additional specimens collected at ages 45, 55, and 60 years.
4. If the sample is hrHPV negative, the patient continues screening at the standard intervals. No cytology testing is performed.
5. If the sample is hrHPV positive, reflex cytology is performed using the original collected sample. If the cytology shows no intraepithelial lesion or malignancy (NILM), another specimen is obtained for cytology within 6 months. If the second cytology specimen shows atypical squamous cells of undetermined significance (ASCUS) or a more worrisome cytology finding, the patient is sent for colposcopy. If two NILM cytology specimens have been obtained, the patient resumes primary hrHPV screening every 5 years.
6. If the specimen is hrHPV positive and cytology is ASCUS or more worrisome the patient is referred for colposcopy (FIGURE).¹⁴ The Dutch estimate that primary hrHPV screening will reduce the number of cervical cytology specimens by 90% annually.

Australia also has implemented nationwide primary HPV testing for cervical cancer screening. This change was implemented following a 10-year program of universal school-based vaccination of girls and boys, and biennial cytology screening for all women. The Australian screening program initiates hrHPV testing at age 25 years and thereafter every 5 years until age 74. If the hrHPV test is positive, reflex testing for HPV types 16 and 18 are performed on the original specimen along with cervical cytology. Women who test positive for HPV 16 or 18 are immediately referred for colposcopy. If the hrHPV test is positive and reflex testing for HPV 16 and 18 is negative, cervical cytology demonstrating ASCUS, low- or high-grade squamous intraepithelial lesions, or more worrisome results trigger a referral for colposcopy. The Australian program supports testing of self-collected vaginal samples for women who are underscreened or have never been screened.^15,16

Read about Pros and cons of switching approaches

Pros and cons of switching approaches

Deployment of new technology often yields benefits and challenges. A putative benefit of primary HPV screening is a reduction in health care costs without an increase in cervical cancer deaths. Another benefit of primary HPV screening is that it may enable self-collection of specimens for analysis, thereby increasing access to cervical cancer screening for underserved and marginalized populations of women who are not currently participating in cervical cancer screening programs.¹⁷ One challenge is that many women are unaware that hrHPV is the cause of most invasive cervical cancers. The detection of hrHPV in a woman in a long-term relationship who was previously negative for hrHPV may cause the emotions of surprise, fear, anxiety, and anger, thereby stressing the relationship.¹⁸

Another concern is that many women are worried about no longer receiving the familiar “Pap smear” cancer screening test in which they have tremendous faith. When Australia transitioned to primary HPV screening, more than 70,000 women signed a petition to “save women’s lives” by permitting continued access to the cervical cytology testing.¹⁹ Primary HPV testing may result in a transient increase in the number of women referred for colposcopy, potentially overwhelming the capacity of the health care system to deliver this vital service.^20,21 The HPV types that most often cause cervical cancer may vary among countries. For example, in Thailand, HPV 52 and 58 are frequently detected in women with high-grade squamous lesions, and including these subtypes in reflex genotyping may be of regional benefit.²²

Primary cervical cancer screening with HPV testing: When will it be used widely in the United States?

In contrast to the United States, the Netherlands is a small, densely populated country that has a highly integrated health system with centralized laboratory centers, a nationwide electronic health record, and clinicians organized to perform as an integrated team. These features ensure that all lifetime tests results are available in one record, that HPV testing is highly standardized, and that clinicians will follow a prescribed care pathway. The Netherlands’ health system is organized to support the successful transition, in a single step, to primary HPV testing. The United States is the third most populous country in the world, following China and India, with a diverse approach to health care, a highly mobile population, no single interoperable electronic health record, and minimal central control of clinical practice. The United States is not organized to make a “big bang” transition to primary HPV cervical cancer screening. It is likely that the introduction of primary HPV screening will occur first in highly integrated health systems that control the clinical, laboratory, and electronic records of a large population.

The results of the ATHENA study provide a clear clinical algorithm for implementing a primary HPV screening program for cervical cancer in the United States.^23–25 Samples are collected for hrHPV testing at a specified interval, 3 or 5 years, beginning at age 25 years. Women younger than age 25 years should be screened with cytology alone. Detection of hrHPV results in reflex viral typing for HPV 16 and 18. Women with samples positive for HPV 16 and 18 are immediately referred for colposcopy. Samples positive for hrHPV and negative for HPV 16 and 18 have reflex cytology testing performed on the original HPV specimen. If cytology testing reports NILM, repeat cotesting is performed in one year. If cytology testing reports ASCUS or a more concerning result, the woman is referred for colposcopy.

Malcolm Gladwell, in his book The Tipping Point, identified 3 processes that help push an innovative new approach from obscurity into widespread use.²⁶ First, authoritative voices that can catalyze change need to consistently communicate their shared vision for the future. Second, there must be a clear message that galvanizes the many to change their approach. Third, the historical context must be supportive of the change. Over the next decade we are likely to hit a tipping point and transition from cervical cancer screening that relies on cervical cytology to an approach that prioritizes hrHPV testing. When that change will occur in the United States is unclear. But our colleagues in other countries already have transitioned to primary hrHPV testing for cervical cancer screening.

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.

Cervical cancer screening represents one of the great public health successes of the 20th Century. Two physician-scientists, George Papanicolaou, MD, PhD (1883–1962), and Harald zur Hausen, MD (1936–), made extraordinary contributions to the evolution of effective cervical cancer screening programs. Dr. Papanicolaou led development of the iconic Pap smear, creating techniques for collecting specimens and using cytologic techniques to identify cervical cancer and its precursors, and Dr. zur Hausen discovered the association of human papillomavirus (HPV) infection with cervical cancer.^1,2

Although it is but a distant memory, in the 1930s cervical and uterine cancer caused more deaths among women than breast, lung, or ovarian cancer. The successful deployment of Pap smear screening resulted in a decrease in cervical cancer rates in developed countries. Cervical cancer deaths remain common in many parts of the world, however. Cervical cancer screening programs can reduce cervical cancer incidence by greater than 80%.³ In the United States between 1973 and 2006, the invasive cervical cancer age-adjusted incidence rates dropped from 10.28 to 3.97 per 100,000 women.⁴

HPV causes cervical cancer

Dr. zur Hausen dedicated his career to identifying viral causes of human cancer. In his Nobel Laureate autobiography, he reported that during his 2-year rotating residency, he loved his obstetrics and gynecology experience, but found it “physically highly demanding” and decided to focus his career in microbiology and immunology.⁵ After proving that herpes simplex virus did not cause cervical cancer he began to explore the role of HPV in the disease process. He first identified HPV types 6 and 11 and showed that these agents caused genital warts. He then used low-stringency hybridization techniques to identify HPV types 16 and 18 in specimens of cervical cancer. Later, he and his colleagues proved that two HPV proteins, E6 and E7, interfere with the function of cell cycle control proteins p53 and retinoblastoma protein, resulting in dysregulated cell growth and cancer.² These findings permitted the development of both HPV vaccines and nucleic acid–based tests to identify high-risk oncogenic HPV (hrHPV) in cells and tissue specimens.

HPV vaccination

Dr. zur Hausen was an energetic and vocal advocate for the development and widescale deployment of HPV vaccines, including vaccination of males and females.⁶ Initially his ideas were rejected by the pharmaceutical industry, but eventually, with advances in virology and vaccine development, multiple companies pursued the development of HPV vaccines, the first cancer prevention vaccines. The best approach to cervical cancer prevention is intensive population-wide HPV vaccination of both boys and girls before exposure to the HPV virus. Beyond its beneficial effect on the incidence of cervical cancer, HPV vaccination also reduces the population incidence of anal, vulvar, and oropharyngeal cancer.⁷ Prevention of oropharyngeal cancer is especially important for men, supporting the recommendation for vaccination of all boys.⁸

Population-wide HPV vaccination will result in a lower prevalence of cervical cancer precursors and reduce the sensitivity of cytology, thereby making primary HPV screening more attractive.⁹ Based on one modelling study, universal HPV vaccination can reduce cervical cancer rates by greater than 50% over current levels, and introduction of primary HPV screening will reduce cervical cancer rates by an additional 20%.¹⁰ In an era of widespread vaccination for HPV, screening for cervical cancer should be intensified for nonvaccinated women.¹⁰

Read about Primary cervical cancer screening with cytology

Primary cervical cancer screening with cytology

Primary screening with cervical cytology alone remains an option supported by many authorities and professional society guidelines.¹¹ Most studies report that HPV testing has greater sensitivity than cervical cytology alone, especially for the detection of adenocarcinoma of the cervix.¹² In one Canadian study, 10,154 women were randomly assigned to HPV or cervical cytology testing. The sensitivity of HPV testing and cervical cytology for detecting cervical intraepithelial neoplasia grade 2 or 3 was 95% and 55%, respectively, with a specificity of 94% and 97%, respectively.¹³ When used together the sensitivity and specificity of cotesting was 100% and 93%, respectively, but resulted in an increased number of colposcopies, which may be costly and add stress for the patient. Many countries are beginning to move away from cervical cancer screening with cytology or cotesting to programs built upon a foundation of primary HPV testing.

Primary cervical cancer screening with HPV testing

The knowledge that hrHPV is a more sensitive test for cervical cancer and its precursors, as well as the relatively lower sensitivity of cytology, is the foundation for transitioning from primary screening with cervical cytology to primary screening with HPV testing. In the Netherlands¹⁴ and Australia^15,16 HPV testing with reflex cytology is the nationwide approach to cervical cancer screening. The basic components of the Dutch primary HPV screening program, as explained by Dr. Lai van Zulyan Mandres, are¹⁴:

1. Samples are collected by a general practitioner and sent to one of 5 central testing facilities for DNA testing for hrHPV.
2. If all previous samples tested negative, the screening occurs at ages 30, 35, 40, 50, and 60 years, a minimum of 5 screens per woman.
3. If there is a history of a previously positive hrHPV, the screening is intensified, with additional specimens collected at ages 45, 55, and 60 years.
4. If the sample is hrHPV negative, the patient continues screening at the standard intervals. No cytology testing is performed.
5. If the sample is hrHPV positive, reflex cytology is performed using the original collected sample. If the cytology shows no intraepithelial lesion or malignancy (NILM), another specimen is obtained for cytology within 6 months. If the second cytology specimen shows atypical squamous cells of undetermined significance (ASCUS) or a more worrisome cytology finding, the patient is sent for colposcopy. If two NILM cytology specimens have been obtained, the patient resumes primary hrHPV screening every 5 years.
6. If the specimen is hrHPV positive and cytology is ASCUS or more worrisome the patient is referred for colposcopy (FIGURE).¹⁴ The Dutch estimate that primary hrHPV screening will reduce the number of cervical cytology specimens by 90% annually.

Australia also has implemented nationwide primary HPV testing for cervical cancer screening. This change was implemented following a 10-year program of universal school-based vaccination of girls and boys, and biennial cytology screening for all women. The Australian screening program initiates hrHPV testing at age 25 years and thereafter every 5 years until age 74. If the hrHPV test is positive, reflex testing for HPV types 16 and 18 are performed on the original specimen along with cervical cytology. Women who test positive for HPV 16 or 18 are immediately referred for colposcopy. If the hrHPV test is positive and reflex testing for HPV 16 and 18 is negative, cervical cytology demonstrating ASCUS, low- or high-grade squamous intraepithelial lesions, or more worrisome results trigger a referral for colposcopy. The Australian program supports testing of self-collected vaginal samples for women who are underscreened or have never been screened.^15,16

Read about Pros and cons of switching approaches

Pros and cons of switching approaches

Deployment of new technology often yields benefits and challenges. A putative benefit of primary HPV screening is a reduction in health care costs without an increase in cervical cancer deaths. Another benefit of primary HPV screening is that it may enable self-collection of specimens for analysis, thereby increasing access to cervical cancer screening for underserved and marginalized populations of women who are not currently participating in cervical cancer screening programs.¹⁷ One challenge is that many women are unaware that hrHPV is the cause of most invasive cervical cancers. The detection of hrHPV in a woman in a long-term relationship who was previously negative for hrHPV may cause the emotions of surprise, fear, anxiety, and anger, thereby stressing the relationship.¹⁸

Another concern is that many women are worried about no longer receiving the familiar “Pap smear” cancer screening test in which they have tremendous faith. When Australia transitioned to primary HPV screening, more than 70,000 women signed a petition to “save women’s lives” by permitting continued access to the cervical cytology testing.¹⁹ Primary HPV testing may result in a transient increase in the number of women referred for colposcopy, potentially overwhelming the capacity of the health care system to deliver this vital service.^20,21 The HPV types that most often cause cervical cancer may vary among countries. For example, in Thailand, HPV 52 and 58 are frequently detected in women with high-grade squamous lesions, and including these subtypes in reflex genotyping may be of regional benefit.²²

Primary cervical cancer screening with HPV testing: When will it be used widely in the United States?

In contrast to the United States, the Netherlands is a small, densely populated country that has a highly integrated health system with centralized laboratory centers, a nationwide electronic health record, and clinicians organized to perform as an integrated team. These features ensure that all lifetime tests results are available in one record, that HPV testing is highly standardized, and that clinicians will follow a prescribed care pathway. The Netherlands’ health system is organized to support the successful transition, in a single step, to primary HPV testing. The United States is the third most populous country in the world, following China and India, with a diverse approach to health care, a highly mobile population, no single interoperable electronic health record, and minimal central control of clinical practice. The United States is not organized to make a “big bang” transition to primary HPV cervical cancer screening. It is likely that the introduction of primary HPV screening will occur first in highly integrated health systems that control the clinical, laboratory, and electronic records of a large population.

The results of the ATHENA study provide a clear clinical algorithm for implementing a primary HPV screening program for cervical cancer in the United States.^23–25 Samples are collected for hrHPV testing at a specified interval, 3 or 5 years, beginning at age 25 years. Women younger than age 25 years should be screened with cytology alone. Detection of hrHPV results in reflex viral typing for HPV 16 and 18. Women with samples positive for HPV 16 and 18 are immediately referred for colposcopy. Samples positive for hrHPV and negative for HPV 16 and 18 have reflex cytology testing performed on the original HPV specimen. If cytology testing reports NILM, repeat cotesting is performed in one year. If cytology testing reports ASCUS or a more concerning result, the woman is referred for colposcopy.

Malcolm Gladwell, in his book The Tipping Point, identified 3 processes that help push an innovative new approach from obscurity into widespread use.²⁶ First, authoritative voices that can catalyze change need to consistently communicate their shared vision for the future. Second, there must be a clear message that galvanizes the many to change their approach. Third, the historical context must be supportive of the change. Over the next decade we are likely to hit a tipping point and transition from cervical cancer screening that relies on cervical cytology to an approach that prioritizes hrHPV testing. When that change will occur in the United States is unclear. But our colleagues in other countries already have transitioned to primary hrHPV testing for cervical cancer screening.

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.

Human parvovirus B19 can sometimes cause the appearance of multiple bullae alone, a pattern not typically seen with parvovirus B19 infections, reported Shoko Yoshii, MD, and his associates at the National Center for Child Health and Development in Tokyo.

In a case study, a 2-year-old boy was admitted to an ED with swelling of both lower limbs. In the 2 weeks previous, he had had a fever that lasted 3 days followed by erythema on the cheeks and limbs. A physical examination reveled edematous erythema on his lower limbs with a predominance of them on the left leg. Doctors analyzed his laboratory results and found that the boy’s white blood cell count was in the normal range, with C-reactive protein level of 3.2 mg/L. The boy was treated with cefazolin for suspected bacterial cellulitis, but this did little; erythema and edema progressed on the left leg and multiple bullae developed 2 days after admission. Within a week, the bullae spontaneously ruptured and resolved.

Parvovirus B19 infection was suspected, and parvovirus B19 IgM was positive on the first day of admission. The boy ultimately recovered and has had no further episodes within 1 year of follow-up.Bullae or vesicles are considered rare manifestations of parvovirus B19 infection, which more typically presents with a “slapped-cheek” appearance and lacy exanthema, sometimes called erythema infectiosum. In adults with parvovirus infection, bullae or vesicles develop at the same time as papular purpuric gloves-and-socks syndrome.

This case did not follow this pattern, with lesions appearing on the lower legs with no involvement of the hands or feet. The few cases of parvovirus infection that have been reported with bulbous skin lesions in children generally were not associated with papular purpuric gloves-and-socks syndrome, which is widely considered a textbook manifestation of parvovirus infection, the authors wrote.

This case study was supported by a grant from National Center for Child Health and Development. No disclosures were reported.

[email protected]

SOURCE: Yoshii S et al. J Pediatr. 2018. doi: 10.1016/j.jpeds.2018.05.038.

Human parvovirus B19 can sometimes cause the appearance of multiple bullae alone, a pattern not typically seen with parvovirus B19 infections, reported Shoko Yoshii, MD, and his associates at the National Center for Child Health and Development in Tokyo.

In a case study, a 2-year-old boy was admitted to an ED with swelling of both lower limbs. In the 2 weeks previous, he had had a fever that lasted 3 days followed by erythema on the cheeks and limbs. A physical examination reveled edematous erythema on his lower limbs with a predominance of them on the left leg. Doctors analyzed his laboratory results and found that the boy’s white blood cell count was in the normal range, with C-reactive protein level of 3.2 mg/L. The boy was treated with cefazolin for suspected bacterial cellulitis, but this did little; erythema and edema progressed on the left leg and multiple bullae developed 2 days after admission. Within a week, the bullae spontaneously ruptured and resolved.

Parvovirus B19 infection was suspected, and parvovirus B19 IgM was positive on the first day of admission. The boy ultimately recovered and has had no further episodes within 1 year of follow-up.Bullae or vesicles are considered rare manifestations of parvovirus B19 infection, which more typically presents with a “slapped-cheek” appearance and lacy exanthema, sometimes called erythema infectiosum. In adults with parvovirus infection, bullae or vesicles develop at the same time as papular purpuric gloves-and-socks syndrome.

This case did not follow this pattern, with lesions appearing on the lower legs with no involvement of the hands or feet. The few cases of parvovirus infection that have been reported with bulbous skin lesions in children generally were not associated with papular purpuric gloves-and-socks syndrome, which is widely considered a textbook manifestation of parvovirus infection, the authors wrote.

This case study was supported by a grant from National Center for Child Health and Development. No disclosures were reported.

[email protected]

SOURCE: Yoshii S et al. J Pediatr. 2018. doi: 10.1016/j.jpeds.2018.05.038.

Human parvovirus B19 can sometimes cause the appearance of multiple bullae alone, a pattern not typically seen with parvovirus B19 infections, reported Shoko Yoshii, MD, and his associates at the National Center for Child Health and Development in Tokyo.

In a case study, a 2-year-old boy was admitted to an ED with swelling of both lower limbs. In the 2 weeks previous, he had had a fever that lasted 3 days followed by erythema on the cheeks and limbs. A physical examination reveled edematous erythema on his lower limbs with a predominance of them on the left leg. Doctors analyzed his laboratory results and found that the boy’s white blood cell count was in the normal range, with C-reactive protein level of 3.2 mg/L. The boy was treated with cefazolin for suspected bacterial cellulitis, but this did little; erythema and edema progressed on the left leg and multiple bullae developed 2 days after admission. Within a week, the bullae spontaneously ruptured and resolved.

Parvovirus B19 infection was suspected, and parvovirus B19 IgM was positive on the first day of admission. The boy ultimately recovered and has had no further episodes within 1 year of follow-up.Bullae or vesicles are considered rare manifestations of parvovirus B19 infection, which more typically presents with a “slapped-cheek” appearance and lacy exanthema, sometimes called erythema infectiosum. In adults with parvovirus infection, bullae or vesicles develop at the same time as papular purpuric gloves-and-socks syndrome.

This case did not follow this pattern, with lesions appearing on the lower legs with no involvement of the hands or feet. The few cases of parvovirus infection that have been reported with bulbous skin lesions in children generally were not associated with papular purpuric gloves-and-socks syndrome, which is widely considered a textbook manifestation of parvovirus infection, the authors wrote.

This case study was supported by a grant from National Center for Child Health and Development. No disclosures were reported.

[email protected]

SOURCE: Yoshii S et al. J Pediatr. 2018. doi: 10.1016/j.jpeds.2018.05.038.

ORLANDO – Adalimumab (Humira) did not reduce aortic inflammation in a year-long, randomized trial that pitted the tumor necrosis factor (TNF) blocker against phototherapy and placebo in 97 psoriasis patients.

M. Alexander Otto/MDedge News

“Now we have two trials that are definitively negative for TNF inhibitors” reducing aortic inflammation, a risk factor for cardiovascular events, said senior investigator Joel M. Gelfand, MD, a dermatology professor at the University of Pennsylvania, Philadelphia.

The other trial, from Canada, also found no effect in the ascending aorta after 52 weeks of treatment, but it did find a modest increase in carotid inflammation (J Invest Dermatol. 2017 Aug;137[8]:1638-45).

Both studies used positron emission tomography/computed tomography to assess vascular inflammation.

“We know patients with psoriasis are at increased risk for cardiovascular disease. We think the same kind of inflammation that occurs in atherosclerosis occurs in psoriasis, but we are still teasing out the impact of therapy and which one is most likely to lower the risk of heart attacks, strokes, and things of that nature,” Dr. Gelfand said at the International Investigative Dermatology meeting. The study was published when he gave his presentation (Circ Cardiovasc Imaging. 2018 Jun. doi: 10.1161/CIRCIMAGING.117.007394).

Although it didn’t reduce aortic inflammation, adalimumab had a positive effect on glycoprotein acetylation, a marker of inflammation and subclinical cardiovascular disease in psoriasis. Observational studies have also reported a drop in cardiovascular events with adalimumab. Taken together, the mixed findings “give us pause for thought,” Dr. Gelfand said.

In a previous trial, he and his colleagues had found that the interleukin blocker ustekinumab (Stelara) reduced aortic inflammation in psoriasis by about 19%, but Dr. Gelfand said at the meeting that it’s too early to opt for ustekinumab over adalimumab for cardiovascular protection: “I don’t think we are quite there yet; we are still not certain.”

Following washout of psoriasis treatments, the 97 subjects were randomized to either adalimumab for 12 months or ultraviolet B phototherapy or placebo for 12 weeks, followed by adalimumab for 12 months.

Aortic inflammation was used as a proxy for cardiovascular events because trials to assess actual event rates would require thousands of patients treated for several years. “They’re not likely to be done in psoriasis any time soon,” Dr. Gelfand said.

At both 12 and 52 weeks, adalimumab patients had no change in aortic inflammation, compared with placebo and baseline. Phototherapy patients had a 4% drop from baseline at 12 weeks, but it was not statistically significant when compared with placebo.

Both adalimumab and phototherapy decreased systemic inflammation as gauged by serum C-reactive protein and interleukin-6 levels, but only adalimumab reduced TNF levels and glycoprotein acetylation at 12 and 52 weeks. Neither treatment affected insulin, adiponectin, or leptin levels. Adalimumab dropped HDL cholesterol a bit, a known side effect, while phototherapy increased it.

About half of the patients in both treatment arms had a 75% reduction in the Psoriasis Area and Severity Index at 12 weeks, compared with 7% of those on placebo. Subjects were aged 43 years, on average, and more than two-thirds were men. They had a mean psoriasis duration of 17 years and a baseline PASI score of 19.

[email protected]

SOURCE: Gelfand JM et al. IID 2018, Abstract 393.

ORLANDO – Adalimumab (Humira) did not reduce aortic inflammation in a year-long, randomized trial that pitted the tumor necrosis factor (TNF) blocker against phototherapy and placebo in 97 psoriasis patients.

M. Alexander Otto/MDedge News

“Now we have two trials that are definitively negative for TNF inhibitors” reducing aortic inflammation, a risk factor for cardiovascular events, said senior investigator Joel M. Gelfand, MD, a dermatology professor at the University of Pennsylvania, Philadelphia.

The other trial, from Canada, also found no effect in the ascending aorta after 52 weeks of treatment, but it did find a modest increase in carotid inflammation (J Invest Dermatol. 2017 Aug;137[8]:1638-45).

Both studies used positron emission tomography/computed tomography to assess vascular inflammation.

“We know patients with psoriasis are at increased risk for cardiovascular disease. We think the same kind of inflammation that occurs in atherosclerosis occurs in psoriasis, but we are still teasing out the impact of therapy and which one is most likely to lower the risk of heart attacks, strokes, and things of that nature,” Dr. Gelfand said at the International Investigative Dermatology meeting. The study was published when he gave his presentation (Circ Cardiovasc Imaging. 2018 Jun. doi: 10.1161/CIRCIMAGING.117.007394).

Although it didn’t reduce aortic inflammation, adalimumab had a positive effect on glycoprotein acetylation, a marker of inflammation and subclinical cardiovascular disease in psoriasis. Observational studies have also reported a drop in cardiovascular events with adalimumab. Taken together, the mixed findings “give us pause for thought,” Dr. Gelfand said.

In a previous trial, he and his colleagues had found that the interleukin blocker ustekinumab (Stelara) reduced aortic inflammation in psoriasis by about 19%, but Dr. Gelfand said at the meeting that it’s too early to opt for ustekinumab over adalimumab for cardiovascular protection: “I don’t think we are quite there yet; we are still not certain.”

Following washout of psoriasis treatments, the 97 subjects were randomized to either adalimumab for 12 months or ultraviolet B phototherapy or placebo for 12 weeks, followed by adalimumab for 12 months.

Aortic inflammation was used as a proxy for cardiovascular events because trials to assess actual event rates would require thousands of patients treated for several years. “They’re not likely to be done in psoriasis any time soon,” Dr. Gelfand said.

At both 12 and 52 weeks, adalimumab patients had no change in aortic inflammation, compared with placebo and baseline. Phototherapy patients had a 4% drop from baseline at 12 weeks, but it was not statistically significant when compared with placebo.

Both adalimumab and phototherapy decreased systemic inflammation as gauged by serum C-reactive protein and interleukin-6 levels, but only adalimumab reduced TNF levels and glycoprotein acetylation at 12 and 52 weeks. Neither treatment affected insulin, adiponectin, or leptin levels. Adalimumab dropped HDL cholesterol a bit, a known side effect, while phototherapy increased it.

About half of the patients in both treatment arms had a 75% reduction in the Psoriasis Area and Severity Index at 12 weeks, compared with 7% of those on placebo. Subjects were aged 43 years, on average, and more than two-thirds were men. They had a mean psoriasis duration of 17 years and a baseline PASI score of 19.

[email protected]

SOURCE: Gelfand JM et al. IID 2018, Abstract 393.

ORLANDO – Adalimumab (Humira) did not reduce aortic inflammation in a year-long, randomized trial that pitted the tumor necrosis factor (TNF) blocker against phototherapy and placebo in 97 psoriasis patients.

M. Alexander Otto/MDedge News

“Now we have two trials that are definitively negative for TNF inhibitors” reducing aortic inflammation, a risk factor for cardiovascular events, said senior investigator Joel M. Gelfand, MD, a dermatology professor at the University of Pennsylvania, Philadelphia.

The other trial, from Canada, also found no effect in the ascending aorta after 52 weeks of treatment, but it did find a modest increase in carotid inflammation (J Invest Dermatol. 2017 Aug;137[8]:1638-45).

Both studies used positron emission tomography/computed tomography to assess vascular inflammation.

“We know patients with psoriasis are at increased risk for cardiovascular disease. We think the same kind of inflammation that occurs in atherosclerosis occurs in psoriasis, but we are still teasing out the impact of therapy and which one is most likely to lower the risk of heart attacks, strokes, and things of that nature,” Dr. Gelfand said at the International Investigative Dermatology meeting. The study was published when he gave his presentation (Circ Cardiovasc Imaging. 2018 Jun. doi: 10.1161/CIRCIMAGING.117.007394).

Although it didn’t reduce aortic inflammation, adalimumab had a positive effect on glycoprotein acetylation, a marker of inflammation and subclinical cardiovascular disease in psoriasis. Observational studies have also reported a drop in cardiovascular events with adalimumab. Taken together, the mixed findings “give us pause for thought,” Dr. Gelfand said.

In a previous trial, he and his colleagues had found that the interleukin blocker ustekinumab (Stelara) reduced aortic inflammation in psoriasis by about 19%, but Dr. Gelfand said at the meeting that it’s too early to opt for ustekinumab over adalimumab for cardiovascular protection: “I don’t think we are quite there yet; we are still not certain.”

Following washout of psoriasis treatments, the 97 subjects were randomized to either adalimumab for 12 months or ultraviolet B phototherapy or placebo for 12 weeks, followed by adalimumab for 12 months.

Aortic inflammation was used as a proxy for cardiovascular events because trials to assess actual event rates would require thousands of patients treated for several years. “They’re not likely to be done in psoriasis any time soon,” Dr. Gelfand said.

At both 12 and 52 weeks, adalimumab patients had no change in aortic inflammation, compared with placebo and baseline. Phototherapy patients had a 4% drop from baseline at 12 weeks, but it was not statistically significant when compared with placebo.

Both adalimumab and phototherapy decreased systemic inflammation as gauged by serum C-reactive protein and interleukin-6 levels, but only adalimumab reduced TNF levels and glycoprotein acetylation at 12 and 52 weeks. Neither treatment affected insulin, adiponectin, or leptin levels. Adalimumab dropped HDL cholesterol a bit, a known side effect, while phototherapy increased it.

About half of the patients in both treatment arms had a 75% reduction in the Psoriasis Area and Severity Index at 12 weeks, compared with 7% of those on placebo. Subjects were aged 43 years, on average, and more than two-thirds were men. They had a mean psoriasis duration of 17 years and a baseline PASI score of 19.

[email protected]

SOURCE: Gelfand JM et al. IID 2018, Abstract 393.

Potty-training seats may be to blame in toddlers presenting with pruritic rash on their buttocks and upper thighs. In such cases, be on the alert for contact dermatitis, reported Claire O. Dorfman, DO, of Lehigh Valley Health Network, Allentown, Pa., and her associates at Hershey (Pa.) Medical Center.

A 3-year-old white boy with a 6-month history of a pruritic rash on his buttocks and bilateral posterior thighs was treated without improvement at the pediatric dermatology clinic with low-potency topical corticosteroids, as well as topical antibiotic and antifungal agents.

Reptile8488/iStock/Getty Images

SOURCE: Dorfman CO et al. Pediatr Dermatol. 2018 May 29. doi: 10.1111/pde.13534.

Potty-training seats may be to blame in toddlers presenting with pruritic rash on their buttocks and upper thighs. In such cases, be on the alert for contact dermatitis, reported Claire O. Dorfman, DO, of Lehigh Valley Health Network, Allentown, Pa., and her associates at Hershey (Pa.) Medical Center.

A 3-year-old white boy with a 6-month history of a pruritic rash on his buttocks and bilateral posterior thighs was treated without improvement at the pediatric dermatology clinic with low-potency topical corticosteroids, as well as topical antibiotic and antifungal agents.

Reptile8488/iStock/Getty Images

SOURCE: Dorfman CO et al. Pediatr Dermatol. 2018 May 29. doi: 10.1111/pde.13534.

Potty-training seats may be to blame in toddlers presenting with pruritic rash on their buttocks and upper thighs. In such cases, be on the alert for contact dermatitis, reported Claire O. Dorfman, DO, of Lehigh Valley Health Network, Allentown, Pa., and her associates at Hershey (Pa.) Medical Center.

A 3-year-old white boy with a 6-month history of a pruritic rash on his buttocks and bilateral posterior thighs was treated without improvement at the pediatric dermatology clinic with low-potency topical corticosteroids, as well as topical antibiotic and antifungal agents.

Reptile8488/iStock/Getty Images

SOURCE: Dorfman CO et al. Pediatr Dermatol. 2018 May 29. doi: 10.1111/pde.13534.

Pazopanib can be considered as a first line alternative treatment to doxorubicin in patients over age 60 with advanced, inoperable soft tissue sarcomas, based on the results of the phase 2 EPAZ study presented at the annual meeting of the American Society of Clinical Oncology.

Pazopanib outcomes compared to those with doxorubicin in the study; but unlike doxorubicin, pazopanib was not associated with neutropenia, reported Viktor Grünwald, MD, of the Medical School Hanover, Germany. “The distinct AE (adverse event) profile may be used to council patients and tailor therapy to individual needs.”

In the randomized study with a median 12-month follow up of previously untreated patients with a median age of 71 years, the incidence of grade 4 neutropenia and neutropenic fever were 56% and 10% for 39 patients given doxorubicin and 0% and 0% for 81 patients given pazopanib, respectively. Overall survival was 14.3 months and 12.3 months, a nonsignificant difference. The most frequent adverse events for doxorubicin were fatigue (64.9%), alopecia (56.8%) and nausea (48.6%), and for pazopanib they were fatigue (58%), nausea (43.2%) and diarrhea (43.2%). Similar outcomes were reported for global EORTC QLQ-C30 measures.

EPAZ included patients aged 60 years and older (median 71 years) with no prior systemic treatment for soft tissue sarcoma, progressive disease, ECOG 0-2, and adequate organ function. After 1:2 randomization, patients received either doxorubicin 75 mg/m² every 3 weeks for a total of 6 cycles or oral pazopanib 800 mg/day given continuously. ECOG 2 and liposarcoma histology were used for stratification.

Dr. Grunwald and several of his co-authors disclosed financial relationships with various drug companies including Novartis, the maker of pazopanib (Votrient). Clinical trial information: NCT01861951
 

SOURCE: Grunwald V et al. ASCO 2018 (annual meeting of the American Society of Clinical Oncology), Abstract 11506.

Pazopanib can be considered as a first line alternative treatment to doxorubicin in patients over age 60 with advanced, inoperable soft tissue sarcomas, based on the results of the phase 2 EPAZ study presented at the annual meeting of the American Society of Clinical Oncology.

Pazopanib outcomes compared to those with doxorubicin in the study; but unlike doxorubicin, pazopanib was not associated with neutropenia, reported Viktor Grünwald, MD, of the Medical School Hanover, Germany. “The distinct AE (adverse event) profile may be used to council patients and tailor therapy to individual needs.”

In the randomized study with a median 12-month follow up of previously untreated patients with a median age of 71 years, the incidence of grade 4 neutropenia and neutropenic fever were 56% and 10% for 39 patients given doxorubicin and 0% and 0% for 81 patients given pazopanib, respectively. Overall survival was 14.3 months and 12.3 months, a nonsignificant difference. The most frequent adverse events for doxorubicin were fatigue (64.9%), alopecia (56.8%) and nausea (48.6%), and for pazopanib they were fatigue (58%), nausea (43.2%) and diarrhea (43.2%). Similar outcomes were reported for global EORTC QLQ-C30 measures.

EPAZ included patients aged 60 years and older (median 71 years) with no prior systemic treatment for soft tissue sarcoma, progressive disease, ECOG 0-2, and adequate organ function. After 1:2 randomization, patients received either doxorubicin 75 mg/m² every 3 weeks for a total of 6 cycles or oral pazopanib 800 mg/day given continuously. ECOG 2 and liposarcoma histology were used for stratification.

Dr. Grunwald and several of his co-authors disclosed financial relationships with various drug companies including Novartis, the maker of pazopanib (Votrient). Clinical trial information: NCT01861951
 

SOURCE: Grunwald V et al. ASCO 2018 (annual meeting of the American Society of Clinical Oncology), Abstract 11506.

Pazopanib can be considered as a first line alternative treatment to doxorubicin in patients over age 60 with advanced, inoperable soft tissue sarcomas, based on the results of the phase 2 EPAZ study presented at the annual meeting of the American Society of Clinical Oncology.

Pazopanib outcomes compared to those with doxorubicin in the study; but unlike doxorubicin, pazopanib was not associated with neutropenia, reported Viktor Grünwald, MD, of the Medical School Hanover, Germany. “The distinct AE (adverse event) profile may be used to council patients and tailor therapy to individual needs.”

In the randomized study with a median 12-month follow up of previously untreated patients with a median age of 71 years, the incidence of grade 4 neutropenia and neutropenic fever were 56% and 10% for 39 patients given doxorubicin and 0% and 0% for 81 patients given pazopanib, respectively. Overall survival was 14.3 months and 12.3 months, a nonsignificant difference. The most frequent adverse events for doxorubicin were fatigue (64.9%), alopecia (56.8%) and nausea (48.6%), and for pazopanib they were fatigue (58%), nausea (43.2%) and diarrhea (43.2%). Similar outcomes were reported for global EORTC QLQ-C30 measures.

EPAZ included patients aged 60 years and older (median 71 years) with no prior systemic treatment for soft tissue sarcoma, progressive disease, ECOG 0-2, and adequate organ function. After 1:2 randomization, patients received either doxorubicin 75 mg/m² every 3 weeks for a total of 6 cycles or oral pazopanib 800 mg/day given continuously. ECOG 2 and liposarcoma histology were used for stratification.

Dr. Grunwald and several of his co-authors disclosed financial relationships with various drug companies including Novartis, the maker of pazopanib (Votrient). Clinical trial information: NCT01861951
 

SOURCE: Grunwald V et al. ASCO 2018 (annual meeting of the American Society of Clinical Oncology), Abstract 11506.

Pexidartinib significantly improved overall response rates and functioning in patients with advanced tenosynovial giant cell tumors (TGCT), based on the final results of the ENLIVEN study, presented at the annual meeting of the American Society of Clinical Oncology in Chicago.

“Pexidartinib, a novel CSF1 receptor inhibitor, may offer a relevant treatment option for patients with TGCT, which is associated with severe morbidity or functional limitations, and for which surgery is not recommended,” said William Tap, MD, of Memorial Sloan Kettering Cancer Center, New York.

Compared with placebo in patients with advanced, symptomatic TGCT, pexidartinib significantly improved overall response rates; RECIST was 39% with pexidartinib and 0% with placebo. Tumor volume score improvement was 56% with pexidartinib and 0% with placebo. Both results were significant at P less than 0.0001.

“Importantly, these responses correlated with improved patient symptoms and function,” Dr. Tap said. “Pexidartinib was generally well tolerated with serious, nonfatal liver toxicity with increased bilirubin in 4% of patients.” The majority of other adverse events with pexidartinib (hair color changes, vomiting, fatigue, dysgeusia, and periorbital edema) were less than grade 3.

The primary treatment for these patients is surgery; there are currently no approved systemic therapies for advanced tenosynovial giant cell tumor. In previous studies by others, imatinib, evaluated in 27 patients, was associated with a 19% overall response rate (ORR). Nilotinib, evaluated in 51 patients, was associated with a 0% ORR at week 12.

ENLIVEN is a double-blind, randomized, placebo-controlled international, phase 3 study whose participants had histologically confirmed, advanced, symptomatic TGCT of greater than 2 cm. Several had previous surgeries, but further surgical resection would have been associated with the potential for worsening functional limitations or severe morbidity.

In ENLIVEN, 61 patients were randomized to pexidartinib and 59 to placebo. All had recurrent or inoperable TGCT. Patients received placebo or pexidartinib 1000 mg/day (split, BID for 2 weeks) then 800 mg/day (split BID for 22 weeks).

Nine patients in the active treatment group and 11 in the placebo group discontinued therapy. Eight patients discontinued pexidartinib due to hepatic adverse events; all serious hepatic events appeared in the first 2 months of treatment.

At 25 weeks, blinded reviews of MRI scans were performed. A partial response was seen in 12 (52%) patients and stable disease was seen in 7 (30%), based on RECIST 1.1.

Also at week 25, pexidartinib-treated patients did better on scores of functional endpoints related to range of motion, PROMIS physical function, stiffness, and BPI worst pain response. Based on functional endpoints, 9 of 61 (15%) had a complete response and 15 (25%) had a partial response, for an overall response rate of 24 (39%); P less than 0.0001.

None of the 59 patients in the placebo group had a response.

Tumor volume scores at week 25 were complete in 3 (5%) and partial in 31 (51%); overall response rate was 34 (56%); P less than 0.0001. Disease was stable in 14 (23%), progressive in 1 (2%), and not evaluable in 12 (20%). There were no complete or partial responses in the placebo group; disease was stable in 45 (76%), progressive in 2 (3%), and not evaluable in 12 (20%).

Dr. Tap disclosed consulting or advisory roles with Daiichi Sankyo, the maker of pexidartinib; as well as Adaptimmune; Blueprint Medicines; Eisai; EMD Serono; Immune Design; Janssen; Lilly; Loxo; Novartis; Plexxikon; TRACON Pharma. Clinical trial information: NCT02371369.

SOURCE: Tap W et al. ASCO 2018 (annual meeting of the American Society of Clinical Oncology), Abstract 11502.

Pexidartinib significantly improved overall response rates and functioning in patients with advanced tenosynovial giant cell tumors (TGCT), based on the final results of the ENLIVEN study, presented at the annual meeting of the American Society of Clinical Oncology in Chicago.

“Pexidartinib, a novel CSF1 receptor inhibitor, may offer a relevant treatment option for patients with TGCT, which is associated with severe morbidity or functional limitations, and for which surgery is not recommended,” said William Tap, MD, of Memorial Sloan Kettering Cancer Center, New York.

Compared with placebo in patients with advanced, symptomatic TGCT, pexidartinib significantly improved overall response rates; RECIST was 39% with pexidartinib and 0% with placebo. Tumor volume score improvement was 56% with pexidartinib and 0% with placebo. Both results were significant at P less than 0.0001.

“Importantly, these responses correlated with improved patient symptoms and function,” Dr. Tap said. “Pexidartinib was generally well tolerated with serious, nonfatal liver toxicity with increased bilirubin in 4% of patients.” The majority of other adverse events with pexidartinib (hair color changes, vomiting, fatigue, dysgeusia, and periorbital edema) were less than grade 3.

The primary treatment for these patients is surgery; there are currently no approved systemic therapies for advanced tenosynovial giant cell tumor. In previous studies by others, imatinib, evaluated in 27 patients, was associated with a 19% overall response rate (ORR). Nilotinib, evaluated in 51 patients, was associated with a 0% ORR at week 12.

ENLIVEN is a double-blind, randomized, placebo-controlled international, phase 3 study whose participants had histologically confirmed, advanced, symptomatic TGCT of greater than 2 cm. Several had previous surgeries, but further surgical resection would have been associated with the potential for worsening functional limitations or severe morbidity.

In ENLIVEN, 61 patients were randomized to pexidartinib and 59 to placebo. All had recurrent or inoperable TGCT. Patients received placebo or pexidartinib 1000 mg/day (split, BID for 2 weeks) then 800 mg/day (split BID for 22 weeks).

Nine patients in the active treatment group and 11 in the placebo group discontinued therapy. Eight patients discontinued pexidartinib due to hepatic adverse events; all serious hepatic events appeared in the first 2 months of treatment.

At 25 weeks, blinded reviews of MRI scans were performed. A partial response was seen in 12 (52%) patients and stable disease was seen in 7 (30%), based on RECIST 1.1.

Also at week 25, pexidartinib-treated patients did better on scores of functional endpoints related to range of motion, PROMIS physical function, stiffness, and BPI worst pain response. Based on functional endpoints, 9 of 61 (15%) had a complete response and 15 (25%) had a partial response, for an overall response rate of 24 (39%); P less than 0.0001.

None of the 59 patients in the placebo group had a response.

Tumor volume scores at week 25 were complete in 3 (5%) and partial in 31 (51%); overall response rate was 34 (56%); P less than 0.0001. Disease was stable in 14 (23%), progressive in 1 (2%), and not evaluable in 12 (20%). There were no complete or partial responses in the placebo group; disease was stable in 45 (76%), progressive in 2 (3%), and not evaluable in 12 (20%).

Dr. Tap disclosed consulting or advisory roles with Daiichi Sankyo, the maker of pexidartinib; as well as Adaptimmune; Blueprint Medicines; Eisai; EMD Serono; Immune Design; Janssen; Lilly; Loxo; Novartis; Plexxikon; TRACON Pharma. Clinical trial information: NCT02371369.

SOURCE: Tap W et al. ASCO 2018 (annual meeting of the American Society of Clinical Oncology), Abstract 11502.

Pexidartinib significantly improved overall response rates and functioning in patients with advanced tenosynovial giant cell tumors (TGCT), based on the final results of the ENLIVEN study, presented at the annual meeting of the American Society of Clinical Oncology in Chicago.

“Pexidartinib, a novel CSF1 receptor inhibitor, may offer a relevant treatment option for patients with TGCT, which is associated with severe morbidity or functional limitations, and for which surgery is not recommended,” said William Tap, MD, of Memorial Sloan Kettering Cancer Center, New York.

Compared with placebo in patients with advanced, symptomatic TGCT, pexidartinib significantly improved overall response rates; RECIST was 39% with pexidartinib and 0% with placebo. Tumor volume score improvement was 56% with pexidartinib and 0% with placebo. Both results were significant at P less than 0.0001.

“Importantly, these responses correlated with improved patient symptoms and function,” Dr. Tap said. “Pexidartinib was generally well tolerated with serious, nonfatal liver toxicity with increased bilirubin in 4% of patients.” The majority of other adverse events with pexidartinib (hair color changes, vomiting, fatigue, dysgeusia, and periorbital edema) were less than grade 3.

The primary treatment for these patients is surgery; there are currently no approved systemic therapies for advanced tenosynovial giant cell tumor. In previous studies by others, imatinib, evaluated in 27 patients, was associated with a 19% overall response rate (ORR). Nilotinib, evaluated in 51 patients, was associated with a 0% ORR at week 12.

ENLIVEN is a double-blind, randomized, placebo-controlled international, phase 3 study whose participants had histologically confirmed, advanced, symptomatic TGCT of greater than 2 cm. Several had previous surgeries, but further surgical resection would have been associated with the potential for worsening functional limitations or severe morbidity.

In ENLIVEN, 61 patients were randomized to pexidartinib and 59 to placebo. All had recurrent or inoperable TGCT. Patients received placebo or pexidartinib 1000 mg/day (split, BID for 2 weeks) then 800 mg/day (split BID for 22 weeks).

Nine patients in the active treatment group and 11 in the placebo group discontinued therapy. Eight patients discontinued pexidartinib due to hepatic adverse events; all serious hepatic events appeared in the first 2 months of treatment.

At 25 weeks, blinded reviews of MRI scans were performed. A partial response was seen in 12 (52%) patients and stable disease was seen in 7 (30%), based on RECIST 1.1.

Also at week 25, pexidartinib-treated patients did better on scores of functional endpoints related to range of motion, PROMIS physical function, stiffness, and BPI worst pain response. Based on functional endpoints, 9 of 61 (15%) had a complete response and 15 (25%) had a partial response, for an overall response rate of 24 (39%); P less than 0.0001.

None of the 59 patients in the placebo group had a response.

Tumor volume scores at week 25 were complete in 3 (5%) and partial in 31 (51%); overall response rate was 34 (56%); P less than 0.0001. Disease was stable in 14 (23%), progressive in 1 (2%), and not evaluable in 12 (20%). There were no complete or partial responses in the placebo group; disease was stable in 45 (76%), progressive in 2 (3%), and not evaluable in 12 (20%).

Dr. Tap disclosed consulting or advisory roles with Daiichi Sankyo, the maker of pexidartinib; as well as Adaptimmune; Blueprint Medicines; Eisai; EMD Serono; Immune Design; Janssen; Lilly; Loxo; Novartis; Plexxikon; TRACON Pharma. Clinical trial information: NCT02371369.

SOURCE: Tap W et al. ASCO 2018 (annual meeting of the American Society of Clinical Oncology), Abstract 11502.

PARIS – The Amplatzer Amulet left atrial appendage occlusion device reduced stroke risk by nearly 60% at 1 year in a large, real-world registry of patients with atrial fibrillation at dual high risk for stroke and bleeding, Ulf Landmesser, MD, reported at the annual meeting of the European Association of Percutaneous Cardiovascular Interventions.

One of the most impressive findings was that this feat was accomplished by and large without background oral anticoagulation. Indeed, 83% of the 1,088 patients in this 61-center, 17-country study had contraindications to oral anticoagulation. Only 11% of subjects were discharged on oral anticoagulation after device implantation, while 22.5% were discharged on aspirin or clopidogrel monotherapy. By 1-3 months post implantation, 60% of patients were either on a single antiplatelet agent or no antithrombotic medication at all.

Bruce Jancin/MDedge News

“Antithrombotic therapy was individualized by the patient’s physician. There didn’t seem to be an increased risk of device-related thrombus in these patients on single antiplatelet therapy. Our data suggest that, given the high bleeding risk, single antiplatelet therapy seems to be a good option for these patients,” said Dr. Landmesser, a professor in and the chair of the department of cardiology at Charité Medical School in Berlin.

Participants in the Global Prospective Amulet Study averaged 75 years of age, and 72% had a history of major bleeding. The average CHA2DS2-VASc score was 4.2, with a HAS-BLED score of 3.3, which emphasizes the high-risk nature of study participants.

On the basis of the CHA2DS2-VASc score, the predicted 1-year ischemic stroke rate without oral anticoagulation was 6.7%, so the actual 2.9% rate represented a 57% reduction in risk. Similarly, for the composite endpoint of ischemic stroke, transient ischemic attack, or systemic embolism, the predicted rate was 9.4%, but the achieved rate was 3.8%, which represented a 60% reduction in risk.

The annualized major bleeding rate was 10.3% despite the low usage of oral anticoagulation or dual-antiplatelet therapy. However, the rate of procedure- or device-related major bleeding was only 3.2%; the other 7.1% was unrelated to Amulet and reflected the underlying high risk of the study population.

The 1-year mortality rate was 8.4%. Thirty-five deaths had cardiovascular causes, 35 were noncardiovascular, and in 18 patients, cause of death couldn’t be determined.

The device-related thrombus rate through 1 year was 1.7%; 10 of 18 cases occurred within the first 90 days.

Dr. Landmesser emphasized that this was a particularly rigorously conducted registry. A unique feature was its use of an independent echocardiography core lab to assess procedural success, as well as an independent clinical events committee to adjudicate serious adverse events. Prior studies of other left atrial appendage (LAA) occlusion devices didn’t use these measures.

The Amplatzer Amulet is a second-generation occlusion device designed for easier placement and more complete sealing than its predecessor and comes in eight sizes to address anatomic variations. At implantation, adequate LAA occlusion as defined by the echocardiography core laboratory was achieved in 99.3% of patients; at that time, 89.4% of patients had no residual flow, and another 9.9% had a residual flow of less than 3 mm. At 1-3 months of follow-up, echocardiography showed 98.4% of patients had adequate occlusion.

Session cochair Alberto Cremonesi, MD, pronounced this to be “really important data.”

“I want to stress that these device implantations were transesophageal echocardiography–guided. In my mind this is absolutely essential to your excellent long-term results,” observed Dr. Cremonesi of Maria Cecilia Hospital in Cotignola, Italy.

Asked to speculate on what outcomes might have looked like had patients been treated with an oral anticoagulant rather than the Amulet occlusion device, Dr. Landmesser predicted the major bleeding rate would have been substantially higher than 10.3%. Most of the bleeding events in the study were gastrointestinal, and the novel oral anticoagulants are known to boost the risk of GI bleeding.

But that’s speculation. He noted that two ongoing randomized trials – one in Germany, the other in Scandinavia – are randomizing high-risk patients to a LAA occlusion device or best medical care, including a novel oral anticoagulant when not contraindicated. The Scandinavian study uses the Amulet, while the German trial uses both the Amulet and the Watchman device. The primary endpoint is the ischemic stroke rate.

The Amulet registry, which will continue for a second year of follow-up, was sponsored by Abbott Laboratories, which developed the Amulet device. Dr. Landmesser reported serving as a consultant to Abbott, as well as Biotronik, Rewa, and Bayer.

[email protected]

PARIS – The Amplatzer Amulet left atrial appendage occlusion device reduced stroke risk by nearly 60% at 1 year in a large, real-world registry of patients with atrial fibrillation at dual high risk for stroke and bleeding, Ulf Landmesser, MD, reported at the annual meeting of the European Association of Percutaneous Cardiovascular Interventions.

One of the most impressive findings was that this feat was accomplished by and large without background oral anticoagulation. Indeed, 83% of the 1,088 patients in this 61-center, 17-country study had contraindications to oral anticoagulation. Only 11% of subjects were discharged on oral anticoagulation after device implantation, while 22.5% were discharged on aspirin or clopidogrel monotherapy. By 1-3 months post implantation, 60% of patients were either on a single antiplatelet agent or no antithrombotic medication at all.

Bruce Jancin/MDedge News

“Antithrombotic therapy was individualized by the patient’s physician. There didn’t seem to be an increased risk of device-related thrombus in these patients on single antiplatelet therapy. Our data suggest that, given the high bleeding risk, single antiplatelet therapy seems to be a good option for these patients,” said Dr. Landmesser, a professor in and the chair of the department of cardiology at Charité Medical School in Berlin.

Participants in the Global Prospective Amulet Study averaged 75 years of age, and 72% had a history of major bleeding. The average CHA2DS2-VASc score was 4.2, with a HAS-BLED score of 3.3, which emphasizes the high-risk nature of study participants.

On the basis of the CHA2DS2-VASc score, the predicted 1-year ischemic stroke rate without oral anticoagulation was 6.7%, so the actual 2.9% rate represented a 57% reduction in risk. Similarly, for the composite endpoint of ischemic stroke, transient ischemic attack, or systemic embolism, the predicted rate was 9.4%, but the achieved rate was 3.8%, which represented a 60% reduction in risk.

The annualized major bleeding rate was 10.3% despite the low usage of oral anticoagulation or dual-antiplatelet therapy. However, the rate of procedure- or device-related major bleeding was only 3.2%; the other 7.1% was unrelated to Amulet and reflected the underlying high risk of the study population.

The 1-year mortality rate was 8.4%. Thirty-five deaths had cardiovascular causes, 35 were noncardiovascular, and in 18 patients, cause of death couldn’t be determined.

The device-related thrombus rate through 1 year was 1.7%; 10 of 18 cases occurred within the first 90 days.

Dr. Landmesser emphasized that this was a particularly rigorously conducted registry. A unique feature was its use of an independent echocardiography core lab to assess procedural success, as well as an independent clinical events committee to adjudicate serious adverse events. Prior studies of other left atrial appendage (LAA) occlusion devices didn’t use these measures.

The Amplatzer Amulet is a second-generation occlusion device designed for easier placement and more complete sealing than its predecessor and comes in eight sizes to address anatomic variations. At implantation, adequate LAA occlusion as defined by the echocardiography core laboratory was achieved in 99.3% of patients; at that time, 89.4% of patients had no residual flow, and another 9.9% had a residual flow of less than 3 mm. At 1-3 months of follow-up, echocardiography showed 98.4% of patients had adequate occlusion.

Session cochair Alberto Cremonesi, MD, pronounced this to be “really important data.”

“I want to stress that these device implantations were transesophageal echocardiography–guided. In my mind this is absolutely essential to your excellent long-term results,” observed Dr. Cremonesi of Maria Cecilia Hospital in Cotignola, Italy.

Asked to speculate on what outcomes might have looked like had patients been treated with an oral anticoagulant rather than the Amulet occlusion device, Dr. Landmesser predicted the major bleeding rate would have been substantially higher than 10.3%. Most of the bleeding events in the study were gastrointestinal, and the novel oral anticoagulants are known to boost the risk of GI bleeding.

But that’s speculation. He noted that two ongoing randomized trials – one in Germany, the other in Scandinavia – are randomizing high-risk patients to a LAA occlusion device or best medical care, including a novel oral anticoagulant when not contraindicated. The Scandinavian study uses the Amulet, while the German trial uses both the Amulet and the Watchman device. The primary endpoint is the ischemic stroke rate.

The Amulet registry, which will continue for a second year of follow-up, was sponsored by Abbott Laboratories, which developed the Amulet device. Dr. Landmesser reported serving as a consultant to Abbott, as well as Biotronik, Rewa, and Bayer.

[email protected]

PARIS – The Amplatzer Amulet left atrial appendage occlusion device reduced stroke risk by nearly 60% at 1 year in a large, real-world registry of patients with atrial fibrillation at dual high risk for stroke and bleeding, Ulf Landmesser, MD, reported at the annual meeting of the European Association of Percutaneous Cardiovascular Interventions.

One of the most impressive findings was that this feat was accomplished by and large without background oral anticoagulation. Indeed, 83% of the 1,088 patients in this 61-center, 17-country study had contraindications to oral anticoagulation. Only 11% of subjects were discharged on oral anticoagulation after device implantation, while 22.5% were discharged on aspirin or clopidogrel monotherapy. By 1-3 months post implantation, 60% of patients were either on a single antiplatelet agent or no antithrombotic medication at all.

Bruce Jancin/MDedge News

“Antithrombotic therapy was individualized by the patient’s physician. There didn’t seem to be an increased risk of device-related thrombus in these patients on single antiplatelet therapy. Our data suggest that, given the high bleeding risk, single antiplatelet therapy seems to be a good option for these patients,” said Dr. Landmesser, a professor in and the chair of the department of cardiology at Charité Medical School in Berlin.

Participants in the Global Prospective Amulet Study averaged 75 years of age, and 72% had a history of major bleeding. The average CHA2DS2-VASc score was 4.2, with a HAS-BLED score of 3.3, which emphasizes the high-risk nature of study participants.

On the basis of the CHA2DS2-VASc score, the predicted 1-year ischemic stroke rate without oral anticoagulation was 6.7%, so the actual 2.9% rate represented a 57% reduction in risk. Similarly, for the composite endpoint of ischemic stroke, transient ischemic attack, or systemic embolism, the predicted rate was 9.4%, but the achieved rate was 3.8%, which represented a 60% reduction in risk.

The annualized major bleeding rate was 10.3% despite the low usage of oral anticoagulation or dual-antiplatelet therapy. However, the rate of procedure- or device-related major bleeding was only 3.2%; the other 7.1% was unrelated to Amulet and reflected the underlying high risk of the study population.

The 1-year mortality rate was 8.4%. Thirty-five deaths had cardiovascular causes, 35 were noncardiovascular, and in 18 patients, cause of death couldn’t be determined.

The device-related thrombus rate through 1 year was 1.7%; 10 of 18 cases occurred within the first 90 days.

Dr. Landmesser emphasized that this was a particularly rigorously conducted registry. A unique feature was its use of an independent echocardiography core lab to assess procedural success, as well as an independent clinical events committee to adjudicate serious adverse events. Prior studies of other left atrial appendage (LAA) occlusion devices didn’t use these measures.

The Amplatzer Amulet is a second-generation occlusion device designed for easier placement and more complete sealing than its predecessor and comes in eight sizes to address anatomic variations. At implantation, adequate LAA occlusion as defined by the echocardiography core laboratory was achieved in 99.3% of patients; at that time, 89.4% of patients had no residual flow, and another 9.9% had a residual flow of less than 3 mm. At 1-3 months of follow-up, echocardiography showed 98.4% of patients had adequate occlusion.

Session cochair Alberto Cremonesi, MD, pronounced this to be “really important data.”

“I want to stress that these device implantations were transesophageal echocardiography–guided. In my mind this is absolutely essential to your excellent long-term results,” observed Dr. Cremonesi of Maria Cecilia Hospital in Cotignola, Italy.

Asked to speculate on what outcomes might have looked like had patients been treated with an oral anticoagulant rather than the Amulet occlusion device, Dr. Landmesser predicted the major bleeding rate would have been substantially higher than 10.3%. Most of the bleeding events in the study were gastrointestinal, and the novel oral anticoagulants are known to boost the risk of GI bleeding.

But that’s speculation. He noted that two ongoing randomized trials – one in Germany, the other in Scandinavia – are randomizing high-risk patients to a LAA occlusion device or best medical care, including a novel oral anticoagulant when not contraindicated. The Scandinavian study uses the Amulet, while the German trial uses both the Amulet and the Watchman device. The primary endpoint is the ischemic stroke rate.

The Amulet registry, which will continue for a second year of follow-up, was sponsored by Abbott Laboratories, which developed the Amulet device. Dr. Landmesser reported serving as a consultant to Abbott, as well as Biotronik, Rewa, and Bayer.

[email protected]