Publications by authors named "Mark Schiffman"

440 Publications

STRIDES - STudying Risk to Improve DisparitiES in Cervical Cancer in Mississippi - Design and baseline results of a Statewide Cohort Study.

Prev Med 2021 Jul 19:106740. Epub 2021 Jul 19.

National Cancer Institute, Clinical Genetics Branch, Division of Cancer Epidemiology & Genetics, Rockville, MD, United States of America. Electronic address:

Cervical cancer rates in Mississippi are disproportionately high, particularly among Black individuals; yet, research in this population is lacking. We designed a statewide, racially diverse cohort of individuals undergoing cervical screening in Mississippi. Here, we report the baseline findings from this study. We included individuals aged 21 years and older undergoing cervical screening with cytology or cytology-human papillomavirus (HPV) co-testing at the Mississippi State Health Department (MSDH) and the University of Mississippi Medical Center (UMMC) (December 2017-May 2020). We collected discarded cytology specimens for future biomarker testing. Demographics and clinical results were abstracted from electronic medical records and evaluated using descriptive statistics and chi-square tests. A total of 24,796 individuals were included, with a median age of 34.8 years. The distribution of race in our cohort was 60.2% Black, 26.4% White, 7.5% other, and 5.9% missing. Approximately 15% had abnormal cytology and, among those who underwent co-testing at MSDH (n = 6377), HPV positivity was 17.4% and did not vary significantly by race. Among HPV positives, Black individuals were significantly less likely to be HPV16/18 positive and more likely to be positive for other high-risk 12 HPV types compared to White individuals (20.5% vs. 27.9%, and 79.5% and 72.1%, respectively, p = 0.011). Our statewide cohort represents one of the largest racially diverse studies of cervical screening in the U.S. We show a high burden of abnormal cytology and HPV positivity, with significant racial differences in HPV genotype prevalence. Future studies will evaluate cervical precancer risk, HPV genotyping, and novel biomarkers in this population.
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http://dx.doi.org/10.1016/j.ypmed.2021.106740DOI Listing
July 2021

Genetic and Epigenetic Variations of HPV52 in Cervical Precancer.

Int J Mol Sci 2021 Jun 16;22(12). Epub 2021 Jun 16.

Department of Pediatrics, Albert Einstein College of Medicine, Bronx, NY 10461, USA.

The goal of this study was to identify human papillomavirus (HPV) type 52 genetic and epigenetic changes associated with high-grade cervical precancer and cancer. Patients were selected from the HPV Persistence and Progression (PaP) cohort, a cervical cancer screening program at Kaiser Permanente Northern California (KPNC). We performed a nested case-control study of 89 HPV52-positive women, including 50 cases with predominantly cervical intraepithelial neoplasia grade 3 (CIN3) and 39 controls without evidence of abnormalities. We conducted methylation analyses using Illumina sequencing and viral whole genome Sanger sequencing. Of the 24 CpG sites examined, increased methylation at CpG site 5615 in HPV52 L1 region was the most significantly associated with CIN3, with a difference in median methylation of 17.9% (odds ratio (OR) = 4.8, 95% confidence interval (CI) = 1.9-11.8) and an area under the curve of 0.73 (AUC; 95% CI = 0.62-0.83). Complete genomic sequencing of HPV52 isolates revealed associations between SNPs present in sublineage C2 and a higher risk of CIN3, with ORs ranging from 2.8 to 3.3. This study identified genetic and epigenetic HPV52 variants associated with high risk for cervical precancer, improving the potential for early diagnosis of cervical neoplasia caused by HPV52.
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http://dx.doi.org/10.3390/ijms22126463DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8234014PMC
June 2021

Deep Metric Learning for Cervical Image Classification.

IEEE Access 2021 29;9:53266-53275. Epub 2021 Mar 29.

National Library of Medicine, National Institutes of Health, Bethesda, MD 20894, USA.

Cervical cancer is caused by the persistent infection of certain types of the Human Papillomavirus (HPV) and is a leading cause of female mortality particularly in low and middle-income countries (LMIC). Visual inspection of the cervix with acetic acid (VIA) is a commonly used technique in cervical screening. While this technique is inexpensive, clinical assessment is highly subjective, and relatively poor reproducibility has been reported. A deep learning-based algorithm for automatic visual evaluation (AVE) of aceto-whitened cervical images was shown to be effective in detecting confirmed precancer (i.e. direct precursor to invasive cervical cancer). The images were selected from a large longitudinal study conducted by the National Cancer Institute in the Guanacaste province of Costa Rica. The training of AVE used annotation for cervix boundary, and the data scarcity challenge was dealt with manually optimized data augmentation. In contrast, we present a novel approach for cervical precancer detection using a deep metric learning-based (DML) framework which does not incorporate any effort for cervix boundary marking. The DML is an advanced learning strategy that can deal with data scarcity and bias training due to class imbalance data in a better way. Three different widely-used state-of-the-art DML techniques are evaluated- (a) Contrastive loss minimization, (b) N-pair embedding loss minimization, and, (c) Batch-hard loss minimization. Three popular Deep Convolutional Neural Networks (ResNet-50, MobileNet, NasNet) are configured for training with DML to produce class-separated (i.e. linearly separable) image feature descriptors. Finally, a K-Nearest Neighbor (KNN) classifier is trained with the extracted deep features. Both the feature quality and classification performance are quantitatively evaluated on the same data set as used in AVE. It shows that, unlike AVE, without using any data augmentation, the best model produced from our research improves specificity in disease detection without compromising sensitivity. The present research thus paves the way for new research directions for the related field.
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http://dx.doi.org/10.1109/access.2021.3069346DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8224396PMC
March 2021

Network Visualization and Pyramidal Feature Comparison for Ablative Treatability Classification Using Digitized Cervix Images.

J Clin Med 2021 Mar 1;10(5). Epub 2021 Mar 1.

Communications Engineering Branch, Lister Hill National Center for Biomedical Communications, U.S. National Library of Medicine, National Institutes of Health, Bethesda, MD 20894, USA.

Uterine cervical cancer is a leading cause of women's mortality worldwide. Cervical tissue ablation is an effective surgical excision of high grade lesions that are determined to be precancerous. Our prior work on the Automated Visual Examination (AVE) method demonstrated a highly effective technique to analyze digital images of the cervix for identifying precancer. Next step would be to determine if she is treatable using ablation. However, not all women are eligible for the therapy due to cervical characteristics. We present a machine learning algorithm that uses a deep learning object detection architecture to determine if a cervix is eligible for ablative treatment based on visual characteristics presented in the image. The algorithm builds on the well-known RetinaNet architecture to derive a simpler and novel architecture in which the last convolutional layer is constructed by upsampling and concatenating specific RetinaNet pretrained layers, followed by an output module consisting of a Global Average Pooling (GAP) layer and a fully connected layer. To explain the recommendation of the deep learning algorithm and determine if it is consistent with lesion presentation on the cervical anatomy, we visualize classification results using two techniques: our (i) Class-selective Relevance Map (CRM), which has been reported earlier, and (ii) Class Activation Map (CAM). The class prediction heatmaps are evaluated by a gynecologic oncologist with more than 20 years of experience. Based on our observation and the expert's opinion, the customized architecture not only outperforms the baseline RetinaNet network in treatability classification, but also provides insights about the features and regions considered significant by the network toward explaining reasons for treatment recommendation. Furthermore, by investigating the heatmaps on Gaussian-blurred images that serve as surrogates for out-of-focus cervical pictures we demonstrate the effect of image quality degradation on cervical treatability classification and underscoring the need for using images with good visual quality.
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http://dx.doi.org/10.3390/jcm10050953DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7957626PMC
March 2021

A proposed new generation of evidence-based microsimulation models to inform global control of cervical cancer.

Prev Med 2021 03 4;144:106438. Epub 2021 Mar 4.

Division of Cancer Epidemiology and Genetics, National Cancer Institute, 9609 Medical Center Drive, Rockville, MD, United States.

Health decision models are the only available tools designed to consider the lifetime natural history of human papillomavirus (HPV) infection and pathogenesis of cervical cancer, and the estimated long-term impact of preventive interventions. Yet health decision modeling results are often considered a lesser form of scientific evidence due to the inherent needs to rely on imperfect data and make numerous assumptions and extrapolations regarding complex processes. We propose a new health decision modeling framework that de-emphasizes cytologic-colposcopic-histologic diagnoses due to their subjectivity and lack of reproducibility, relying instead on HPV type and duration of infection as the major determinants of subsequent transition probabilities. We posit that the new model health states (normal, carcinogenic HPV infection, precancer, cancer) and corollary transitions are universal, but that the probabilities of transitioning between states may vary by population. Evidence for this variability in host response to HPV infections can be inferred from HPV prevalence patterns in different regions across the lifespan, and might be linked to different average population levels of immunologic control of HPV infections. By prioritizing direct estimation of model transition probabilities from longitudinal data (and limiting reliance on model-fitting techniques that may propagate error when applied to multiple transitions), we aim to reduce the number of assumptions for greater transparency and reliability. We propose this new microsimulation model for critique and discussion, hoping to contribute to models that maximally inform efficient strategies towards global cervical cancer elimination.
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http://dx.doi.org/10.1016/j.ypmed.2021.106438DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8041229PMC
March 2021

Summary of Current Guidelines for Cervical Cancer Screening and Management of Abnormal Test Results: 2016-2020.

J Womens Health (Larchmt) 2021 01;30(1):5-13

Department of Obstetrics/Gynecology, Brigham and Women's Hospital, Boston, Massachusetts, USA.

Cervical cancer can be prevented through routine screening and follow-up of abnormal results. Several guidelines have been published in the last 4 years from various medical societies and organizations. These guidelines aim to personalize screening and management, reducing unnecessary testing in low-risk patients and managing high-risk patients with more intensive follow-up. However, the resulting complexity can lead to confusion among providers. The CDC, NCI, and obstetrician-gynecologists involved in guideline development summarized current screening and management guidelines. For screening, guidelines for average-risk and high-risk populations are summarized and presented. For management, differences between the 2012 and 2019 consensus guidelines for managing abnormal cervical cancer screening tests and cancer precursors are summarized. Current screening guidelines for average-risk individuals have minor differences, but are evolving toward an HPV-based strategy. For management, HPV testing is preferred to cytology because it is a more sensitive test for cancer precursor detection and also allows for precise risk stratification. Current risk-based screening and management strategies can improve care by reducing unnecessary tests and procedures in low-risk patients and focusing resources on high-risk patients. Knowledge of screening and management guidelines is important to improve adherence and avoid both over- and under-use of screening and colposcopy.
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http://dx.doi.org/10.1089/jwh.2020.8918DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8020523PMC
January 2021

The relationship of human papillomavirus and cytology co-testing results with endometrial and ovarian cancer diagnoses.

Gynecol Oncol 2021 Apr 14;161(1):297-303. Epub 2021 Jan 14.

Regional Laboratory, Kaiser Permanente Northern California, Oakland, CA, USA.

Background: To investigate whether routine cervical screening using human papillomavirus (HPV) and cytology co-testing effectively identifies women with endometrial (EC) or ovarian (OvC) cancer.

Methods: In 2003, Kaiser Permanente Northern California implemented triennial co-testing in women aged ≥30 years. Index screening results (n = 2,385,729) were linked to subsequent EC (n = 3434) and OvC (n = 1113) diagnoses from January 1, 2003 to December 31, 2017. EC were categorized as type 1 or 2, and, selectively, EC and OvC diagnoses were stratified on whether symptoms were present at the time of the co-test. Fractions and absolute risks of EC or OvC of each co-testing result were calculated.

Results: Most EC (82.18%) and OvC (88.68%) were preceded by a negative HPV and negative cytology co-test. More EC were preceded by atypical squamous cells of undetermined significance (ASC-US) or more severe (ASC-US+) cytology and negative HPV test (n = 290) (8.44% of EC) compared to a negative cytology and a positive HPV test (n = 31) (0.89% of EC) (p < 0.001). The absolute risk of any EC diagnosis following ASC-US+ and negative HPV test was 0.48%. Atypical glandular cells (AGC) cytology and a negative HPV result preceded 6.92% of any EC diagnosis, with an absolute risk of 4.02%, but preceded only 1.13% of type 2 EC cases, with an absolute risk of 0.24%, in asymptomatic women. AGC cytology and a negative HPV result preceded 1.44% of OvC, with an absolute risk of 0.28%.

Conclusions: Abnormal cervical screening tests, even AGC cytology, rarely precedes and poorly predict women with EC or OvC.
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http://dx.doi.org/10.1016/j.ygyno.2021.01.005DOI Listing
April 2021

Cervical Screening Performance.

Am J Clin Pathol 2021 03;155(4):616-620

Division of Cancer Epidemiology and Genetics National Cancer Institute Bethesda, MD.

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http://dx.doi.org/10.1093/ajcp/aqaa198DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7962781PMC
March 2021

Risk Factors for NON-HPV16/18 Cervical Infections and Associated Lesions Among HPV-DNA-Negative Women Vaccinated Against HPV16/18 in the Costa Rica Vaccine Trial (CVT).

J Infect Dis 2020 Dec 16. Epub 2020 Dec 16.

Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, U.S.A.

Background: Factors that lead human papillomavirus (HPV) infections to persist and progress to cancer are not fully understood, especially among vaccinated women. We evaluated co-factors for acquisition, persistence and progression of non-HPV16/18 infections in a cohort of HPV-vaccinated women.

Methods: We analyzed 2,153 18-25-year-old women randomized to the HPV-vaccine arm of CVT. Women were HPV-DNA-negative for all types at baseline and followed for ~11 years. Acquisition was a type-specific cervical infection not present/detected at the previously scheduled visit. Persistence was a type-specific incident infection that persisted for ≥1-year with no intervening negatives. Progression of persistent incident infections to CIN2+ was based on histological findings by expert pathologists. GEE methods were used to account for correlated observations. Time-dependent factors evaluated were age, sexual behavior, marital status, hormonal-related factors, number of full-term pregnancies (FTP), smoking behavior, and baseline-BMI.

Results: 1,777 incident oncogenic non-HPV16/18 infections were detected in 12,292 visits (average 0.14 infections per visit). Age and sexual behavior-related variables were associated with oncogenic non-HPV16/18 acquisition. 26% of incident infections persisted for ≥1-year. None of the factors evaluated were statistically associated with persistence of oncogenic non-HPV16/18 infections. Risk of progression to CIN2+ increased with increasing age (p-trend=0.001), injectable contraceptives use [relative risk 2.61 (95%CI 1.19-5.73) ever vs. never] and increasing FTP (p-trend=0.034).

Conclusion: In a cohort of HPV16/18-vaccinated women, age and sexual behavior variables are associated with acquisition of oncogenic non-HPV16/18 infections, no notable factors are associated with persistence of acquired oncogenic non-HPV16/18 infections, and age, parity and hormonally-related exposures are associated with progression to CIN2+.
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http://dx.doi.org/10.1093/infdis/jiaa768DOI Listing
December 2020

Efficacy of the bivalent HPV vaccine against HPV 16/18-associated precancer: long-term follow-up results from the Costa Rica Vaccine Trial.

Lancet Oncol 2020 12;21(12):1643-1652

Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Rockville, MD, USA.

Background: Oncogenic human papillomavirus (HPV) infections cause most cases of cervical cancer. Here, we report long-term follow-up results for the Costa Rica Vaccine Trial (publicly funded and initiated before licensure of the HPV vaccines), with the aim of assessing the efficacy of the bivalent HPV vaccine for preventing HPV 16/18-associated cervical intraepithelial neoplasia grade 2 or worse (CIN2+).

Methods: Women aged 18-25 years were enrolled in a randomised, double-blind, controlled trial in Costa Rica, between June 28, 2004, and Dec 21, 2005, designed to assess the efficacy of a bivalent vaccine for the prevention of infection with HPV 16/18 and associated precancerous lesions at the cervix. Participants were randomly assigned (1:1) to receive an HPV 16/18 AS04-adjuvanted vaccine or control hepatitis A vaccine. Vaccines were administered intramuscularly in three 0·5 mL doses at 0, 1, and 6 months and participants were followed up annually for 4 years. After the blinded phase, women in the HPV vaccine group were invited to enrol in the long-term follow-up study, which extended follow-up for 7 additional years. The control group received HPV vaccine and was replaced with a new unvaccinated control group. Women were followed up every 2 years until year 11. Investigators and patients were aware of treatment allocation for the follow-up phase. At each visit, clinicians collected cervical cells from sexually active women for cytology and HPV testing. Women with abnormal cytology were referred to colposcopy, biopsy, and treatment as needed. Women with negative results at the last screening visit (year 11) exited the long-term follow-up study. The analytical cohort for vaccine efficacy included women who were HPV 16/18 DNA-negative at vaccination. The primary outcome of this analysis was defined as histopathologically confirmed CIN2+ or cervical intraepithelial neoplasia grade 3 or worse associated with HPV 16/18 cervical infection detected at colposcopy referral. We calculated vaccine efficacy by year and cumulatively. This long-term follow-up study is registered with ClinicalTrials.gov, NCT00867464.

Findings: 7466 women were enrolled in the Costa Rica Vaccine Trial; 3727 received the HPV vaccine and 3739 received the control vaccine. Between March 30, 2009, and July 5, 2012, 2635 women in the HPV vaccine group and 2836 women in the new unvaccinated control group were enrolled in the long-term follow-up study. 2635 women in the HPV vaccine group and 2677 women in the control group were included in the analysis cohort for years 0-4, and 2073 women from the HPV vaccine group and 2530 women from the new unvaccinated control group were included in the analysis cohort for years 7-11. Median follow-up time for the HPV group was 11·1 years (IQR 9·1-11·7), 4·6 years (4·3-5·3) for the original control group, and 6·2 years (5·5-6·9) for the new unvaccinated control group. At year 11, vaccine efficacy against incident HPV 16/18-associated CIN2+ was 100% (95% CI 89·2-100·0); 34 (1·5%) of 2233 unvaccinated women had a CIN2+ outcome compared with none of 1913 women in the HPV group. Cumulative vaccine efficacy against HPV 16/18-associated CIN2+ over the 11-year period was 97·4% (95% CI 88·0-99·6). Similar protection was observed against HPV 16/18-associated CIN3-specifically at year 11, vaccine efficacy was 100% (95% CI 78·8-100·0) and cumulative vaccine efficacy was 94·9% (73·7-99·4). During the long-term follow-up, no serious adverse events occurred that were deemed related to the HPV vaccine. The most common grade 3 or worse serious adverse events were pregnancy, puerperium, and perinatal conditions (in 255 [10%] of 2530 women in the unvaccinated control group and 201 [10%] of 2073 women in the HPV vaccine group). Four women in the unvaccinated control group and three in the HPV vaccine group died; no deaths were deemed to be related to the HPV vaccine.

Interpretation: The bivalent HPV vaccine has high efficacy against HPV 16/18-associated precancer for more than a decade after initial vaccination, supporting the notion that invasive cervical cancer is preventable.

Funding: US National Cancer Institute.
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http://dx.doi.org/10.1016/S1470-2045(20)30524-6DOI Listing
December 2020

A rapid, high-volume cervical screening project using self-sampling and isothermal PCR HPV testing.

Infect Agent Cancer 2020 22;15:64. Epub 2020 Oct 22.

United Family Hospitals, Beijing, China.

Objective: Rapid, high-volume screening programs are needed as part of cervical cancer prevention in China.

Methods: In a 5-day screening project in Inner Mongolia, 3345 women volunteered following a community awareness campaign, and self-swabbed to permit rapid HPV testing. Two AmpFire™ HPV detection systems (Atila Biosystems) were sufficient to provide pooled 15-HPV type data within an hour. HPV+ patients had same-day digital colposcopy (DC) performed by 1 of 6 physicians, using the EVA™ system (MobileODT). Digital images were obtained and, after biopsy of suspected lesions for later confirmatory diagnosis, women were treated immediately based on colposcopic impression. Suspected low- grade lesions were offered treatment with thermal ablation (Wisap), and suspected high-grade lesions were treated with LLETZ.

Results: Of 3345 women screened, 624 (18.7%) were HPV+. Of these, 88.5% HPV+ women underwent same-day colposcopy and 78 were treated. Later consensus histology results obtained on 197 women indicated 20 CIN2+, of whom 15 were detected and treated/referred at screening (10 by thermal ablation, 4 by LLETZ, 1 by referral).

Conclusions: Global control of cervical cancer will require both vaccination and screening of a huge number of women. This study illustrates a cervical screening strategy that can be used to screen-and-treat large numbers of women. HPV self-sampling facilitates high-volume screening. Specimens can be tested rapidly, promoting minimal loss-to-follow-up. Specifically, the AmpFire™ system used in this study is highly portable, simple, rapid (92 specimens per 65 min per unit), and economical. Visual triage can be performed on HPV+ women with a portable digital colposcope that provides magnification, lighting, and a recorded image. Diagnosis and appropriate treatment remain the most subjective elements. The digital image is under study for deep-learning based automated evaluation that could assist the management decision, either by itself or combined with HPV typing.
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http://dx.doi.org/10.1186/s13027-020-00329-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7579849PMC
October 2020

Designing low-cost, accurate cervical screening strategies that take into account COVID-19: a role for self-sampled HPV typing2.

Infect Agent Cancer 2020 14;15:61. Epub 2020 Oct 14.

Division of Cancer Epidemiology and Genetics, National Cancer Institute, Clinical Epidemiology Unit, Clinical Genetics Branch, 9609 Medical Center Drive Room 6E544, Rockville, MD 20850 USA.

Background: We propose an economical cervical screening research and implementation strategy designed to take into account the typically slow natural history of cervical cancer and the severe but hopefully temporary impact of COVID-19. The commentary introduces the practical validation of some critical components of the strategy, described in three manuscripts detailing recent project results in Asia and Africa.The main phases of a cervical screening program are 1) primary screening of women in the general population, 2) triage testing of the small minority of women that screen positive to determine need for treatment, and 3) treatment of triage-positive women thought to be at highest risk of precancer or even cancer. In each phase, attention must now be paid to safety in relation to SARS-CoV-2 transmission. The new imperatives of the COVID-19 pandemic support self-sampled HPV testing as the primary cervical screening method. Most women can be reassured for several years by a negative test performed on a self-sample collected at home, without need of clinic visit and speculum examination. The advent of relatively inexpensive, rapid and accurate HPV DNA testing makes it possible to return screening results from self-sampling very soon after specimen collection, minimizing loss to follow-up. Partial HPV typing provides important risk stratification useful for triage of HPV-positive women. A second "triage" test is often useful to guide management. In lower-resource settings, visual inspection with acetic acid (VIA) is still proposed but it is inaccurate and poorly reproducible, misclassifying the risk stratification gained by primary HPV testing. A deep-learning based approach to recognizing cervical precancer, adaptable to a smartphone camera, is being validated to improve VIA performance. The advent and approval of thermal ablation permits quick, affordable and safe, immediate treatment at the triage clinic of the majority of HPV-positive, triage-positive women.

Conclusions: Overall, only a small percentage of women in cervical screening programs need to attend the hospital clinic for a surgical procedure, particularly when screening is targeted to the optimal age range for detection of precancer rather than older ages with decreased visual screening performance and higher risks of hard-to-treat outcomes including invasive cancer.
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http://dx.doi.org/10.1186/s13027-020-00325-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7556607PMC
October 2020

Design and feasibility of a novel program of cervical screening in Nigeria: self-sampled HPV testing paired with visual triage.

Infect Agent Cancer 2020 14;15:60. Epub 2020 Oct 14.

Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Rockville, USA.

Background: Accelerated global control of cervical cancer would require primary prevention with human papillomavirus (HPV) vaccination in addition to novel screening program strategies that are simple, inexpensive, and effective. We present the feasibility and outcome of a community-based HPV self-sampled screening program.

Methods: In Ile Ife, Nigeria, 9406 women aged 30-49 years collected vaginal self-samples, which were tested for HPV in the local study laboratory using Hybrid Capture-2 (HC2) (Qiagen). HPV-positive women were referred to the colposcopy clinic. Gynecologist colposcopic impression dictated immediate management; biopsies were taken when definite acetowhitening was present to produce a histopathologic reference standard of precancer (and to determine final clinical management). Retrospective linkage to the medical records identified 442 of 9406 women living with HIV (WLWH).

Results: With self-sampling, it was possible to screen more than 100 women per day per clinic. Following an audio-visual presentation and in-person instructions, overall acceptability of self-sampling was very high (81.2% women preferring self-sampling over clinician collection). HPV positivity was found in 17.3% of women. Intensive follow-up contributed to 85.9% attendance at the colposcopy clinic. Of those referred, 8.2% were initially treated with thermal ablation and 5.6% with large loop excision of transformation zone (LLETZ). Full visibility of the squamocolumnar junction, necessary for optimal visual triage and ablation, declined from 68.5% at age 30 to 35.4% at age 49. CIN2+ and CIN3+ (CIN- Cervical intraepithelial neoplasia), including five cancers, were identified by histology in 5.9 and 3.2% of the HPV-positive women, respectively (0.9 and 0.5% of the total screening population), leading to additional treatment as indicated. The prevalences of HPV infection and CIN2+ were substantially higher (40.5 and 2.5%, respectively) among WLWH. Colposcopic impression led to over- and under-treatment compared to the histopathology reference standard.

Conclusion: A cervical cancer screening program using self-sampled HPV testing, with colposcopic immediate management of women positive for HPV, proved feasible in Nigeria. Based on the collected specimens and images, we are now evaluating the use of a combination of partial HPV typing and automated visual evaluation (AVE) of cervical images to improve the accuracy of the screening program.
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http://dx.doi.org/10.1186/s13027-020-00324-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7556552PMC
October 2020

Risk of cervical precancer and cancer among uninsured and underserved women from 2009 to 2017.

Am J Obstet Gynecol 2021 04 6;224(4):366.e1-366.e32. Epub 2020 Oct 6.

Centers for Disease Control and Prevention, Division of Cancer Prevention and Control, Atlanta, GA.

Background: New guidelines for managing cervical precancer among women in the United States use risk directly to guide clinical actions for individuals who are being screened. These risk-based management guidelines have previously only been based on risks from a large integrated healthcare system. We present here data representative of women of low income without continuous insurance coverage to inform the 2019 guidelines and ensure applicability.

Objective: We examined the risks of high-grade precancer after human papillomavirus and cytology tests in underserved women and assessed the applicability of the 2019 guidelines to this population.

Study Design: We examined cervical cancer screening and follow-up data among 363,546 women enrolled in the Centers for Disease Control and Prevention's National Breast and Cervical Cancer Early Detection Program from 2009 to 2017. We estimated the immediate (prevalent) risks of cervical intraepithelial lesion grade 3 or cancer by using prevalence-incidence mixture models. Risks were estimated for each combination of human papillomavirus and cytology result and were stratified by screening history. We compared these risks with published estimates used in new risk-based management guidelines.

Results: Women who were up-to-date with their screening, defined as being screened with cytology within the past 5 years, had immediate risks of cervical intraepithelial neoplasia grade 3 or higher similar to that of women at Kaiser Permanente Northern California, whose data were used to develop the management guidelines. However, women in the Centers for Disease Control and Prevention's National Breast and Cervical Cancer Early Detection Program had greater immediate risks if they were never screened or not up-to-date with their screening.

Conclusion: New cervical risk-based management guidelines are applicable for underinsured and uninsured women with a low income in the United States who are up-to-date with their screening. The increased risk observed here among women who received human papillomavirus-positive, high-grade cytology results, who were never screened, or who were not up-to-date with their cervical cancer screening, led to a recommendation in the management guidelines for immediate treatment among these women.
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http://dx.doi.org/10.1016/j.ajog.2020.10.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8009811PMC
April 2021

Efficacy of AS04-Adjuvanted Vaccine Against Human Papillomavirus (HPV) Types 16 and 18 in Clearing Incident HPV Infections: Pooled Analysis of Data From the Costa Rica Vaccine Trial and the PATRICIA Study.

J Infect Dis 2021 May;223(9):1576-1581

Divison of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland, USA.

Clinical trial data and real-world evidence suggest that the AS04-adjuvanted vaccine targeting human papillomavirus types 16 and 18 (AS04-HPV-16/18) vaccine provides nearly 90% protection against cervical intraepithelial neoplasia grade 3 or higher irrespective of type, among women vaccinated before sexual debut. This high efficacy is not fully explained by cross-protection. Although AS04-HPV-16/18 vaccination does not affect clearance of prevalent infections, it may accelerate clearance of newly acquired infections. We pooled data from 2 large-scale randomized controlled trials to evaluate efficacy of the AS04-HPV-16/18 vaccine against clearance of nontargeted incident infections. Results of our analysis do not suggest an effect in expediting clearance of incident infections.
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http://dx.doi.org/10.1093/infdis/jiaa561DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8248553PMC
May 2021

The Orderly Incorporation of Continuing Technologic Advances Into Cervical Cancer Screening.

J Natl Cancer Inst 2021 Mar;113(3):231-233

Clinical Epidemiology Unit, Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA.

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http://dx.doi.org/10.1093/jnci/djaa106DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7936058PMC
March 2021

A Pooled Analysis to Compare the Clinical Characteristics of Human Papillomavirus-positive and -Negative Cervical Precancers.

Cancer Prev Res (Phila) 2020 10 12;13(10):829-840. Epub 2020 Jul 12.

HPV Research Group, University of Washington, Seattle, Washington.

Given that high-risk human papillomavirus (HPV) is the necessary cause of virtually all cervical cancer, the clinical meaning of HPV-negative cervical precancer is unknown. We, therefore, conducted a literature search in Ovid MEDLINE, PubMed Central, and Google Scholar to identify English-language studies in which (i) HPV-negative and -positive, histologically confirmed cervical intraepithelial neoplasia grade 2 or more severe diagnoses (CIN2+) were detected and (ii) summarized statistics or deidentified individual data were available to summarize proportions of biomarkers indicating risk of cancer. Nineteen studies including 3,089 (91.0%) HPV-positive and 307 (9.0%) HPV-negative CIN2+ were analyzed. HPV-positive CIN2+ (vs. HPV-negative CIN2+) was more likely to test positive for biomarkers linked to cancer risk: a study diagnosis of CIN3+ (vs. CIN2; 18 studies; 0.56 vs. 0.24; < 0.001) preceding high-grade squamous intraepithelial lesion cytology (15 studies; 0.54 vs. 0.10; < 0.001); and high-grade colposcopic impression (13 studies; 0.30 vs. 0.18; = 0.03). HPV-negative CIN2+ was more likely to test positive for low-risk HPV genotypes than HPV-positive CIN2+ ( < 0.001). HPV-negative CIN2+ appears to have lower cancer risk than HPV-positive CIN2+. Clinical studies of human high-risk HPV testing for screening to prevent cervical cancer may refer samples of HPV test-negative women for disease ascertainment to correct verification bias in the estimates of clinical performance. However, verification bias adjustment of the clinical performance of HPV testing may overcorrect/underestimate its clinical performance to detect truly precancerous abnormalities.
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http://dx.doi.org/10.1158/1940-6207.CAPR-20-0182DOI Listing
October 2020

Ensemble Deep Learning for Cervix Image Selection toward Improving Reliability in Automated Cervical Precancer Screening.

Diagnostics (Basel) 2020 Jul 3;10(7). Epub 2020 Jul 3.

Communications Engineering Branch, Lister Hill National Center for Biomedical Communications, U.S. National Library of Medicine, National Institutes of Health, Bethesda, MD 20894, USA.

Automated Visual Examination (AVE) is a deep learning algorithm that aims to improve the effectiveness of cervical precancer screening, particularly in low- and medium-resource regions. It was trained on data from a large longitudinal study conducted by the National Cancer Institute (NCI) and has been shown to accurately identify cervices with early stages of cervical neoplasia for clinical evaluation and treatment. The algorithm processes images of the uterine cervix taken with a digital camera and alerts the user if the woman is a candidate for further evaluation. This requires that the algorithm be presented with images of the cervix, which is the object of interest, of acceptable quality, i.e., in sharp focus, with good illumination, without shadows or other occlusions, and showing the entire squamo-columnar transformation zone. Our prior work has addressed some of these constraints to help discard images that do not meet these criteria. In this work, we present a novel algorithm that determines that the image contains the cervix to a sufficient extent. Non-cervix or other inadequate images could lead to suboptimal or wrong results. Manual removal of such images is labor intensive and time-consuming, particularly in working with large retrospective collections acquired with inadequate quality control. In this work, we present a novel ensemble deep learning method to identify cervix images and non-cervix images in a smartphone-acquired cervical image dataset. The ensemble method combined the assessment of three deep learning architectures, RetinaNet, Deep SVDD, and a customized CNN (Convolutional Neural Network), each using a different strategy to arrive at its decision, i.e., object detection, one-class classification, and binary classification. We examined the performance of each individual architecture and an ensemble of all three architectures. An average accuracy and F-1 score of 91.6% and 0.890, respectively, were achieved on a separate test dataset consisting of more than 30,000 smartphone-captured images.
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http://dx.doi.org/10.3390/diagnostics10070451DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7400120PMC
July 2020

The D2 and D3 Sublineages of Human Papilloma Virus 16-Positive Cervical Cancer in Guatemala Differ in Integration Rate and Age of Diagnosis.

Cancer Res 2020 09 6;80(18):3803-3809. Epub 2020 Jul 6.

Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, NCI, Gaithersburg, Maryland.

Human papillomavirus (HPV) 16 displays substantial sequence variation; four HPV16 lineages (A, B, C, and D) have been described as well as multiple sublineages. To identify molecular events associated with HPV16 carcinogenesis, we evaluated viral variation, the integration of HPV16, and somatic mutation in 96 cervical cancer samples from Guatemala. A total of 65% (62/96) of the samples had integrated HPV16 sequences and integration was associated with an earlier age of diagnosis and premenopausal disease. HPV16 integration sites were broadly distributed in the genome, but in one tumor, HPV16 integrated into the promoter of the IFN regulatory factor 4 () gene, which plays an important role in the regulation of the IFN response to viral infection. The HPV16 D2 and D3 sublineages were found in 23% and 30% of the tumors, respectively, and were significantly associated with adenocarcinoma. D2-positive tumors had a higher rate of integration, earlier age of diagnosis, and a lower rate of somatic mutation, whereas D3-positive tumors were less likely to integrate, had later age of diagnosis, and exhibited a higher rate of somatic mutation. In conclusion, Guatemalan cervical tumors have a high frequency of very high-risk HPV16 D2 and D3 sublineages harboring distinct histology, which may help guide future therapeutic strategies to target the tumor and reduce recurrence. SIGNIFICANCE: This study details the biological and molecular properties of the most pathogenic forms of HPV16, the cause of the majority of cervical cancers.
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http://dx.doi.org/10.1158/0008-5472.CAN-20-0029DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7501218PMC
September 2020

Accuracy and Efficiency of Deep-Learning-Based Automation of Dual Stain Cytology in Cervical Cancer Screening.

J Natl Cancer Inst 2021 01;113(1):72-79

Steinbeis Transfer Center for Medical Systems Biology, Heidelberg, Germany.

Background: With the advent of primary human papillomavirus testing followed by cytology for cervical cancer screening, visual interpretation of cytology slides remains the last subjective analysis step and suffers from low sensitivity and reproducibility.

Methods: We developed a cloud-based whole-slide imaging platform with a deep-learning classifier for p16/Ki-67 dual-stained (DS) slides trained on biopsy-based gold standards. We compared it with conventional Pap and manual DS in 3 epidemiological studies of cervical and anal precancers from Kaiser Permanente Northern California and the University of Oklahoma comprising 4253 patients. All statistical tests were 2-sided.

Results: In independent validation at Kaiser Permanente Northern California, artificial intelligence (AI)-based DS had lower positivity than cytology (P < .001) and manual DS (P < .001) with equal sensitivity and substantially higher specificity compared with both Pap (P < .001) and manual DS (P < .001), respectively. Compared with Pap, AI-based DS reduced referral to colposcopy by one-third (41.9% vs 60.1%, P < .001). At a higher cutoff, AI-based DS had similar performance to high-grade squamous intraepithelial lesions cytology, indicating a risk high enough to allow for immediate treatment. The classifier was robust, showing comparable performance in 2 cytology systems and in anal cytology.

Conclusions: Automated DS evaluation removes the remaining subjective component from cervical cancer screening and delivers consistent quality for providers and patients. Moving from Pap to automated DS substantially reduces the number of colposcopies and also achieves excellent performance in a simulated fully vaccinated population. Through cloud-based implementation, this approach is globally accessible. Our results demonstrate that AI not only provides automation and objectivity but also delivers a substantial benefit for women by reduction of unnecessary colposcopies.
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http://dx.doi.org/10.1093/jnci/djaa066DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7781458PMC
January 2021

A study of type-specific HPV natural history and implications for contemporary cervical cancer screening programs.

EClinicalMedicine 2020 May 25;22:100293. Epub 2020 Apr 25.

Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, United States.

Background: HPV testing is replacing cytology for cervical cancer screening because of greater sensitivity and superior reassurance following negative tests for the dozen HPV genotypes that cause cervical cancer. Management of women testing positive is unresolved. The need for identification of individual HPV genotypes for clinical use is debated. Also, it is unclear how long to observe persistent infections when precancer is not initially found.

Methods: In the longitudinal NCI-Kaiser Permanente Northern California Persistence and Progression (PaP) Study, we observed the clinical outcomes (clearance, progression to CIN3+, or persistence without progression) of 11,573 HPV-positive women aged 30-65 yielding 14,158 type-specific infections.

Findings: Risks of CIN3+ progression differed substantially by type, with HPV16 conveying uniquely elevated risk (26% of infections with seven-year CIN3+ risk of 22%). The other carcinogenic HPV types fell into 3 distinct seven-year CIN3+ risk groups: HPV18, 45 (13% of infections, risks >5%, with known elevated cancer risk); HPV31, 33, 35, 52, 58 (39%, risks >5%); and HPV39, 51, 56, 59, 68 (23%, risks <5%). In the absence of progression, HPV clearance rates were similar by type, with 80% of infections no longer detected within three years; persistence to seven years without progression was uncommon. The predictive value of abnormal cytology was most evident for prevalent CIN3+, but less evident in follow-up. A woman's age did not modify risk; rather it was the duration of persistence that was important.

Interpretation: HPV type and persistence are the major predictors of progression to CIN3+; at a minimum, distinguishing HPV16 is clinically important. Dividing the other HPV types into three risk-groups is worth considering.
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http://dx.doi.org/10.1016/j.eclinm.2020.100293DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7264956PMC
May 2020

Association of HPV35 with cervical carcinogenesis among women of African ancestry: Evidence of viral-host interaction with implications for disease intervention.

Int J Cancer 2020 11 16;147(10):2677-2686. Epub 2020 May 16.

Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Rockville, Maryland, USA.

HPV35 has been found in only ∼2% of invasive cervical cancers (ICC) worldwide but up to 10% in Sub-Saharan Africa, warranting further investigation and consideration of impact on preventive strategies. We studied HPV35 and ethnicity, in relation to the known steps in cervical carcinogenesis, using multiple large epidemiologic studies in the U.S. and internationally. Combining five U.S. studies, we measured HPV35 positivity and, in Northern California, observed HPV35 type-specific population prevalence and estimated 5-year risk of developing precancer when HPV35-positive. HPV35 genetic variation was examined for differences in carcinogenicity in 1053 HPV35+ cervical specimens from a U.S. cohort and an international collection. African-American women had more HPV35 (12.1% vs 5.1%, P < .001) and more HPV35-associated precancers (7.4% vs 2.1%, P < .001) compared to other ethnicities. Precancer risks after HPV35 infection did not vary by ethnicity (global P = .52). The HPV35 A2 sublineage showed an increased association with precancer/cancer in African-Americans (OR = 5.6 vs A1, 95% CI = 1.3-24.8) and A2 was more prevalent among ICC in Africa than other world regions (41.9% vs 10.4%, P < .01). Our analyses support a strong link between HPV35 and cervical carcinogenesis in women of African ancestry. Current HPV vaccines cover the majority of cervical precancer/cancer across all ethnic groups; additional analyses are required to determine whether the addition of HPV35 to the already highly effective nine-valent HPV vaccine would provide better protection for women in Africa or of African ancestry.
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http://dx.doi.org/10.1002/ijc.33033DOI Listing
November 2020

A demonstration of automated visual evaluation of cervical images taken with a smartphone camera.

Int J Cancer 2020 11 19;147(9):2416-2423. Epub 2020 May 19.

Lister Hill National Center for Biomedical Communications, National Library of Medicine, National Institutes of Health, Bethesda, Maryland, USA.

We examined whether automated visual evaluation (AVE), a deep learning computer application for cervical cancer screening, can be used on cervix images taken by a contemporary smartphone camera. A large number of cervix images acquired by the commercial MobileODT EVA system were filtered for acceptable visual quality and then 7587 filtered images from 3221 women were annotated by a group of gynecologic oncologists (so the gold standard is an expert impression, not histopathology). We tested and analyzed on multiple random splits of the images using two deep learning, object detection networks. For all the receiver operating characteristics curves, the area under the curve values for the discrimination of the most likely precancer cases from least likely cases (most likely controls) were above 0.90. These results showed that AVE can classify cervix images with confidence scores that are strongly associated with expert evaluations of severity for the same images. The results on a small subset of images that have histopathologic diagnoses further supported the capability of AVE for predicting cervical precancer. We examined the associations of AVE severity score with gynecologic oncologist impression at all regions where we had a sufficient number of cases and controls, and the influence of a woman's age. The method was found generally resilient to regional variation in the appearance of the cervix. This work suggests that using AVE on smartphones could be a useful adjunct to health-worker visual assessment with acetic acid, a cervical cancer screening method commonly used in low- and middle-resource settings.
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http://dx.doi.org/10.1002/ijc.33029DOI Listing
November 2020

Racial differences in HPV type 16 prevalence in women with ASCUS of the uterine cervix.

Cancer Cytopathol 2020 08 3;128(8):528-534. Epub 2020 Apr 3.

National Cancer Institute, Rockville, Maryland.

Background: Understanding racial influences on human papillomavirus (HPV) distribution in women with atypical squamous cells of undetermined significance (ASCUS) cytology via partial genotyping in a statewide population can inform HPV-based prevention efforts.

Methods: Women aged 21 to 65 years with any cytology result and partial HPV genotyping for ASCUS triage between January 1, 2014, and December 31, 2017, were included. All women attended a Mississippi State Department of Health clinic. Age, race, cytopathologic, and HPV data were extracted from the electronic health record and analyzed. Cytologic specimens were processed with ThinPrep and HPV testing with the Cobas 4800 assay. HPV genotypes were evaluated in hierarchical categories. Chi-square tests and multinomial logistic regression models evaluated associations between race and type prevalence.

Results: There were 43,106 women who underwent cervical cancer screening with cytology and ASCUS triage. Of these, 34,363 (80.2%) had normal cytology, 4672 (10.9%) had ASCUS, 2683 (6.3%) had a low-grade squamous intraepithelial lesion, and 633 (1.5%) had a high-grade squamous intraepithelial lesion. Blacks represented 69.3% of the sample and had a higher proportion of HPV-positive ASCUS (6.5%) in comparison with whites (5.6%). Blacks had significantly decreased odds of HPV-16 (odds ratio [OR], 0.66; 95% confidence interval [CI], 0.6-0.9; P = .002) and significantly increased odds for 12 other types (OR, 1.37; 95% CI, 1.2-1.5; P < .0001) in comparison with whites.

Conclusions: In a diverse population, significant differences in HPV genotypes are shown by race. Importantly, blacks with ASCUS are less likely to be positive for HPV-16 in comparison with whites. Ongoing work is evaluating the individual genotype prevalence and genotype-specific risk of precancer by race.
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http://dx.doi.org/10.1002/cncy.22267DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7728239PMC
August 2020

Challenges Associated With Cervical Cancer Screening and Management in Obese Women: A Provider Perspective.

J Low Genit Tract Dis 2020 Apr;24(2):184-191

Division of Cancer Epidemiology & Genetics, National Cancer Institute, National Institutes of Health, Rockville, MD.

Objectives: Obese women are at increased risk of cervical cancer, partly due to missed detection of cervical precancers during routine cervical cancer screening. We administered a clinician survey to better understand specific challenges and identify potential solutions to performing cervical cancer screening and management in obese women.

Materials And Methods: We administered a web-based survey to 2,319 members of the American Society of Colposcopy and Cervical Pathology including questions related to challenges associated with cervical sampling and visualization in obese compared with normal weight women and potential strategies for improvement. We summarized providers' responses using descriptive statistics and used Fisher exact tests to evaluate associations between provider characteristics and challenges with cervical sampling, visualization, and biopsy.

Results: Of the 240 providers that completed the survey, 89% and 93% reported that cervical sampling and visualization are more challenging in obese women, respectively, whereas 80% reported that taking a biopsy was more challenging. Commonly reported barriers included vaginal prolapse, difficulty visualizing and accessing the cervix, and lack of long enough sampling devices and large enough speculums. Frequently used techniques to improve sampling and visualization included use of a condom or examination glove finger to sheath a speculum and using a tenaculum. Most providers identified training for cervical sampling and colposcopy in obese women as a learning gap, and only 8% reported receiving such training.

Conclusions: Cervical cancer screening and management are more challenging in obese compared with normal weight women. Major barriers to cervical sampling and visualization included lack of adequately sized equipment and lack of education and training.
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http://dx.doi.org/10.1097/LGT.0000000000000506DOI Listing
April 2020

A Study of Partial Human Papillomavirus Genotyping in Support of the 2019 ASCCP Risk-Based Management Consensus Guidelines.

J Low Genit Tract Dis 2020 Apr;24(2):144-147

Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD.

Introduction: The 2019 ASCCP Risk-Based Management Consensus Guidelines include recommendations for partial human papillomavirus (HPV) genotyping in management of abnormal cervical cancer screening results. The guidelines are based on matching estimates of cervical intraepithelial neoplasia (CIN) 3+ risk to consensus clinical action thresholds. In support of the guidelines, this analysis addresses the risks predicted by individual identification of HPV 16 and HPV 18.

Methods: Risk estimates were drawn from a subset of women in the Kaiser Permanente Northern California screening program, whose residual cervical specimens were HPV typed as part of the HPV Persistence and Progression study. We calculated risk of CIN 3+ to assess how identification of HPV 16, HPV 18, or 12 other "high-risk" HPV types would influence recommended clinical management of new abnormal screening results, taking into account current cytologic results and recent screening history. Immediate and/or 5-year risks of CIN 3+ were matched to clinical actions identified in the guidelines.

Results: Identification of HPV 16 at the first visit including HPV testing elevated immediate risk of diagnosing CIN 3+ sufficiently to mandate colposcopic referral even when cytology was Negative for Intraepithelial Lesions or Malignancy and to support a preference for treatment of cytologic high-grade squamous intraepithelial lesion. HPV 18 less clearly elevated CIN 3+ risk.

Conclusions: Identification of HPV 16 clearly mandated consideration in clinical management of new abnormal screening results. HPV 18 positivity must be considered as a special situation because of established disproportionate risk of invasive cancer. More detailed genotyping and use beyond initial management will be considered in guideline updates.
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http://dx.doi.org/10.1097/LGT.0000000000000530DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7141756PMC
April 2020

Risk Estimates Supporting the 2019 ASCCP Risk-Based Management Consensus Guidelines.

J Low Genit Tract Dis 2020 Apr;24(2):132-143

Division of Gynecologic Oncology, Kaiser Permanente Medical Care Program, Oakland, CA (contributed before retirement).

The 2019 American Society for Colposcopy and Cervical Pathology Risk-Based Management Consensus Guidelines for the management of cervical cancer screening abnormalities recommend 1 of 6 clinical actions (treatment, optional treatment or colposcopy/biopsy, colposcopy/biopsy, 1-year surveillance, 3-year surveillance, 5-year return to regular screening) based on the risk of cervical intraepithelial neoplasia grade 3, adenocarcinoma in situ, or cancer (CIN 3+) for the many different combinations of current and recent past screening results. This article supports the main guidelines presentation by presenting and explaining the risk estimates that supported the guidelines.

Methods: From 2003 to 2017 at Kaiser Permanente Northern California (KPNC), 1.5 million individuals aged 25 to 65 years were screened with human papillomavirus (HPV) and cytology cotesting scheduled every 3 years. We estimated immediate and 5-year risks of CIN 3+ for combinations of current test results paired with history of screening test and colposcopy/biopsy results.

Results: Risk tables are presented for different clinical scenarios. Examples of important results are highlighted; for example, the risk posed by most current abnormalities is greatly reduced if the prior screening round was HPV-negative. The immediate and 5-year risks of CIN 3+ used to decide clinical management are shown.

Conclusions: The new risk-based guidelines present recommendations for the management of abnormal screening test and histology results; the key risk estimates supporting guidelines are presented in this article. Comprehensive risk estimates are freely available online at https://CervixCa.nlm.nih.gov/RiskTables.
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http://dx.doi.org/10.1097/LGT.0000000000000529DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7147417PMC
April 2020

2019 ASCCP Risk-Based Management Consensus Guidelines: Methods for Risk Estimation, Recommended Management, and Validation.

J Low Genit Tract Dis 2020 Apr;24(2):90-101

Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Rockville, MD.

Objective: To manage cervical screening abnormalities, the 2019 ASCCP management consensus guidelines will recommend clinical action on the basis of risk of cervical precancer and cancer. This article details the methods used to estimate risk, to determine the risk-based management, and to validate that the risk-based recommendations are of general use in different settings.

Methods: Based on 1.5 million patients undergoing triennial cervical screening by cotesting at the Kaiser Permanente Northern California from 2003 to 2017, we estimated risk profiles for different clinical scenarios and combinations of past and current human papillomavirus and cytology test results. We validated the recommended management by comparing with the estimated risks in several external data sources.

Results: Risk and management tables are presented separately by Egemen et al. and Demarco et al. Risk-based management derived from the Kaiser Permanente Northern California largely agreed with the management implied from the estimated risks of the other data sources.

Conclusions: The new risk-based guidelines present management of abnormal cervical screening results. By describing the steps used to develop these guidelines, the methods presented in this article can provide a basis for future extensions of the risk-based guidelines.
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http://dx.doi.org/10.1097/LGT.0000000000000528DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7147416PMC
April 2020
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