Publications by authors named "Cosette M Wheeler"

154 Publications

Adherence to National Guidelines on Cervical Screening: A Population-Based Evaluation from a Statewide Registry.

J Natl Cancer Inst 2021 Aug 31. Epub 2021 Aug 31.

University of New Mexico Comprehensive Cancer Center, Center for HPV Prevention, Albuquerque, USA.

In 2012, national recommendations for cervical-cancer screening of women aged 30-64 years were quinquennial human papillomavirus and cytology co-testing or triennial cytology. Data from a state-wide surveillance program in New Mexico demonstrated 65.2% (95% confidence interval [95%CI]= 64.6%% to 65.7%) of women screened in 2019 had negative co-test within the last 3 years. Percentages of women screened in 2013, 2016, and 2019 with a prior negative co-test more than 5 and up to 7 years ago were 2.6% (95% CI = 2.2% to 2.9%), 2.1% (95% CI = 1.9% to 2.2%), and 6.5% (95% CI = 6.2% to 6.8%), respectively (2-sided P trend<.001). Percentages of women screened in 2013, 2016, and 2019 with a prior negative cytology more than 5 and up to 7 years ago were 3.8% (95% CI = 3.7% to 3.9%), 9.0% (95% CI = 8.7% to 9.3%), and 14.9% (95% CI = 14.4% to 15.4%), respectively (2-sided P trend<.001). Thus, in 2019, only 12.7% (95% CI = 12.4% to 13.1%) of the 30,215 women aged 30-64 years underwent co-testing and 27.7% (95% CI = 27.1% to 28.3%) of the 18,733 underwent cytology at the recommended interval. The observed under- and over-screening could result in increases in cervical-cancer incidence and harms and costs, respectively.
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http://dx.doi.org/10.1093/jnci/djab173DOI Listing
August 2021

Clinical follow-up practices after cervical cancer screening by co-testing: A population-based study of adherence to U.S. guideline recommendations.

Prev Med 2021 Aug 18;153:106770. Epub 2021 Aug 18.

Center for HPV Prevention, New Mexico Comprehensive Cancer Center, Albuquerque, NM, USA.. Electronic address:

Failure to follow-up women after abnormal cervical screening could lead to cervical cancers, yet little is known about adherence to recommended follow-up after abnormal co-testing [cytology and high-risk human papillomavirus (hrHPV) testing]. We documented clinical management following cervical screening by co-testing in a diverse population-based setting. A statewide surveillance program for cervical screening, diagnosis, and treatment was used to investigate all cytology, hrHPV and biopsy reports in the state of New Mexico from January 2015 through August 2019. Guideline-adherent follow-up after co-testing required 1) biopsy within 6 months for low-grade cytology if positive for hrHPV, for high-grade cytology irrespective of hrHPV, and for HPV 16/18 positive results irrespective of cytology and; 2) repeat co-testing within 18 months if cytology was negative and hrHPV test was positive (excluding types 16/18). Screening co-tests (2015-2017) for 164,522 women were analyzed using descriptive statistics, Kaplan Meier curves, and pairwise comparisons between groups. Guideline adherence was highest when both cytology and hrHPV tests were abnormal, ranging from 61.7% to 80.3%. Guideline-adherent follow-up was lower for discordant results. Women with high-grade cytology were less likely to receive a timely biopsy when hrHPV-testing was negative (48.1%) versus positive (83.3%) (p < 0.001). Only 47.9% of women received biopsies following detection of HPV16/18 with normal cytology, and 30.8% received no follow-up within 18-months. Among women with hrHPV-positive normal cytology without evidence of HPV 16/18 infection, 51% received no follow-up within 18 months. Provider education and creation of robust recall systems may help ensure appropriate follow-up of abnormal screening results.
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http://dx.doi.org/10.1016/j.ypmed.2021.106770DOI Listing
August 2021

Performance of an affordable urine self-sampling method for human papillomavirus detection in Mexican women.

PLoS One 2021 21;16(7):e0254946. Epub 2021 Jul 21.

Facultad de Medicina, Centro de Investigación en Políticas, Población y Salud, Universidad Nacional Autónoma de México, Mexico City, Mexico.

Introduction: Urine self-sampling for human papillomavirus (HPV)-based cervical cancer screening is a non-invasive method that offers several logistical advantages and high acceptability, reducing barriers related to low screening coverage. This study developed and evaluated the performance of a low-cost urine self-sampling method for HPV-testing and explored the acceptability and feasibility of potential implementation of this alternative in routine screening.

Methods: A series of sequential laboratory assays examined the impact of several pre-analytical conditions for obtaining DNA from urine and subsequent HPV detection. Initially, we assessed the effect of ethylaminediaminetetraacetic acid (EDTA) as a DNA preservative examining several variables including EDTA concentration, specimen storage temperature, time between urine collection and DNA extraction, and first-morning micturition versus convenience sample collection. We further evaluated the agreement of HPV-testing between urine and clinician-collected cervical samples among 95 women. Finally, we explored the costs of self-sampling supplies as well as the acceptability and feasibility of urine self-sampling among women and healthcare workers.

Results: Our results revealed higher DNA concentrations were obtained when using a 40mM EDTA solution, storing specimens at 25°C and extracting DNA within 72 hrs. of urine collection, regardless of using first-morning micturition or a convenience sampling. We observed good agreement (Kappa = 0.72) between urine and clinician-collected cervical samples for HPV detection. Furthermore, urine self-sampling was an affordable method (USD 1.10), well accepted among cervical cancer screening users, healthcare workers, and decision-makers.

Conclusion: These results suggest urine self-sampling is feasible and appropriate alternative for HPV-testing in HPV-based screening programs in lower-resource contexts.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0254946PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8294492PMC
July 2021

Uptake of co-testing with HPV and cytology for cervical screening: A population-based evaluation in the United States.

Gynecol Oncol 2021 Sep 10;162(3):555-559. Epub 2021 Jul 10.

UNM Health Sciences Center (HSC), Department of Pathology, Albuquerque, NM, USA; UNM Comprehensive Cancer Center, Center for HPV Prevention, Albuquerque, NM, USA. Electronic address:

Objectives: Human papillomavirus (HPV) testing for cervical screening has been shown to increase the yield of precancerous disease and reduce the incidence of cervical cancer more than cytology alone. Here we document the state-wide uptake of co-testing with HPV and cytology in women aged 30-64 years as recommended by national and international bodies.

Methods: Registry-based study of all screening cytology and HPV tests in New Mexico from 2008 to 2019 among women aged 21-64 years, with a focus on cytology negative tests to distinguish co-testing from reflex HPV testing to triage equivocal or mildly abnormal cytology.

Results: A total of 1,704,055 cervical screening tests from 681,440 women aged 21-64 years in the state of New Mexico were identified. The proportion of screening tests which were co-tests rose from 5.6% in 2008 to 84.3% in 2019 among women aged 30-64 years with a marked change from the near exclusive use of the Hybrid Capture II HPV test, (a signal amplified test method) to the use of target amplified HPV tests. The largest increases were seen between 2013 and 2015, reflecting the introduction and adoption of new clinical guidelines. Increases in co-testing were also seen in younger women.

Conclusions: Co-testing is now well established in women aged 30-64 years, but smaller increases have also been seen at younger ages, although this is not currently recommended. The impact of co-testing on cervical disease outcomes and number of colposcopies and biopsies in routine population settings remain important, especially in young women.
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http://dx.doi.org/10.1016/j.ygyno.2021.06.029DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8405560PMC
September 2021

Burden of Mycoplasma genitalium and bacterial co-infections in a population-based sample in New Mexico.

Sex Transm Dis 2021 May 14. Epub 2021 May 14.

Department of Obstetrics and Gynecology, Gødstrup Hospital, Gl. Landevej 61, 7400 Herning, Denmark Department of Clinical Medicine, Aarhus University, Palle Juul Jensens Boulevard 99, 8200 Aarhus N, Denmark Department of Obstetrics and Gynecology, Aarhus University Hospital, Denmark Department of Epidemiology and Public Health, University of Maryland School of Medicine, 660 W. Redwood St, Howard Hall 102-B, Baltimore, MD 21201, USA Wolfson Institute of Preventive Medicine, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, UK Department of Pathology, University of New Mexico Health Sciences Center, MSC02-1670 House of Prevention Epidemiology, Albuquerque, NM 87131, USA Department of Obstetrics and Gynecology, University of New Mexico Health Sciences Center, MSC02-1670 House of Prevention Epidemiology, Albuquerque, NM 87131, USA.

Abstract: In this population-based US study, the overall prevalence of Mycoplasma genitalium was 1.95% (95% CI 1.62-2.34), declining from 6.12% (95% CI 4.72 to 7.92) in women aged 21-24 to 0.48% (95% CI 0.25-0.94) in women aged 40-64. The prevalence of co-infections with Chlamydia trachomatis and Trichomonas vaginalis was low.
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http://dx.doi.org/10.1097/OLQ.0000000000001472DOI Listing
May 2021

Adjunctive testing by cytology, p16/Ki-67 dual-stained cytology or HPV16/18 E6 oncoprotein for the management of HPV16/18 screen-positive women.

Int J Cancer 2021 05 22;148(9):2264-2273. Epub 2020 Dec 22.

Faculty of Medine, Research Center on Policies, Population and Health, National Autonomous University of Mexico, Mexico City, Mexico.

High-risk human papillomavirus type 16/18 (HPV16/18) genotyping is unable to accurately discriminate nonprogressive infections from those that will progress to cervical cancer. Our study aimed to assesses if additional testing either with liquid-based cytology (LBC) or the putative progression markers p16/Ki-67 and HPV16/18 E6 oncoprotein (E6) can improve the efficiency of HPV16/18 genotyping for triaging high-risk HPV (hrHPV)-positive women through better cancer risk stratification. Women attending colposcopy after positive HPV16/18 genotyping results within the Forwarding Research for Improved Detection and Access for Cervical Cancer Screening and Triage (FRIDA) hrHPV-based screening study in Tlaxcala, Mexico, underwent further testing with LBC, p16/Ki-67 dual-stained (DS) cytology and E6. We calculated measures of test performance for detecting histologically confirmed cervical intraepithelial neoplasia grade 2 or higher (CIN2+) and grade 3 or higher (CIN3+). A number of 475 (64.3%) of 739 HPV16/18-positive women had complete results for all tests. Triage positivity rates were 14.1%, 18.5% and 24.4%, for LBC, E6 and DS, respectively. Compared with LBC, DS had higher sensitivity (24.4% vs 60.0%) although lower specificity (87.0% vs 79.3%) for CIN3+ (P < .001), whereas E6 had a sensitivity of 37.8% and a specificity of 83.5%. No invasive cancer was missed by DS or E6, but 75% were in normal cytology. DS test was associated with nearly 75% reduction of colposcopy referrals compared with the direct referral of all HPV16/18-positive women, giving the least number of colposcopies (n = 4.3) per CIN3+ detected. We show that adjunctive testing of HPV16/18-positive women with DS may greatly reduce unnecessary colposcopy referrals within HPV-based screening employing HPV16/18 genotyping while retaining acceptable sensitivity for CIN2+ and CIN3+.
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http://dx.doi.org/10.1002/ijc.33414DOI Listing
May 2021

A state-wide population-based evaluation of cervical cancers arising during opportunistic screening in the United States.

Gynecol Oncol 2020 11 22;159(2):344-353. Epub 2020 Sep 22.

Departments of Pathology and Obstetrics & Gynecology, University of New Mexico Health Sciences Center, Albuquerque, NM, USA.

Objective: Despite widespread cervical screening, an estimated 13,800 women will be diagnosed with cervical cancer in the United States in 2020. To inform improvements, the screening histories of women diagnosed with cervical cancer in New Mexico were assessed.

Methods: Data were collected on all cervical screening, diagnostic tests and treatment procedures for all women diagnosed with cervical cancer aged 25-64 yrs. in New Mexico from 2006 to 2016. Women were categorized by their screening attendance in the 5-40 months (screening interval) and 1-4 months (peri-diagnostic interval) prior to cancer diagnosis.

Results: Of the 504 women diagnosed between May 2009-December 2016, 64% were not screened or had only inadequate screening tests in the 5-40 months prior to diagnosis, and 90 of 182 screened women (49%) had only negative screens in this period. Only 32% (N = 162) of cervical cancers were screen-detected. Women with adenocarcinomas were more likely to have had a recent negative screen (41/57 = 722%) than women with squamous cancers (50/112 = 45%). Both older women (aged 45-64 years) and women with more advanced cancers were less likely to have been screened, and if screened, were more likely to have a false-negative outcome. Only 9% of cancers were diagnosed in women who did not attend biopsy or treatment after positive tests requiring clinical management. Screening currently prevents 35% of cancers, whereas full screening coverage could prevent 61% of cervical cancers.

Conclusion: Improved screening coverage has the largest potential for reducing cervical cancer incidence, though there is also a role for improved recall procedures and screening sensitivity.
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http://dx.doi.org/10.1016/j.ygyno.2020.08.033DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7594931PMC
November 2020

Antibodies to Variable Domain 4 Linear Epitopes of the Major Outer Membrane Protein Are Not Associated with Chlamydia Resolution or Reinfection in Women.

mSphere 2020 09 23;5(5). Epub 2020 Sep 23.

Department of Molecular Genetics and Microbiology, School of Medicine, University of New Mexico Health Sciences, Albuquerque, New Mexico, USA

is an obligate intracellular bacterium. infection is the most prevalent bacterial sexually transmitted infection and can lead to pelvic inflammatory disease and infertility in women. There is no licensed vaccine for prevention, in part due to gaps in our knowledge of -specific immune responses elicited during human infections. Previous investigations of the antibody response to have identified immunodominant antigens and antibodies that can neutralize infection in cell culture. However, epitope-specific responses to are not well characterized, and the impact of these antibodies on infection outcome is unknown. We recently developed a technology called deep sequence-coupled biopanning that uses bacteriophage virus-like particles to display peptides from antigens and affinity select against human serum IgG. Here, we used this technology to map -specific antibodies in groups of women with defined outcomes following infection: (i) negative upon presentation for treatment ("spontaneous resolvers"), (ii) negative at a 3-month follow-up visit after treatment ("nonreinfected"), and (iii) positive at a 3-month follow-up after treatment ("reinfected"). This analysis yielded immunodominant epitopes that had been previously described but also identified new epitopes targeted by human antibody responses to We focused on human antibody responses to the variable domain 4 serovar-conserved region of the major outer membrane protein (VD4-MOMP), a previously described immunodominant epitope. All three groups of women produced IgG to the VD4-MOMP, suggesting that detection of serum antibodies to VD4-MOMP in women with urogenital infection is not associated with protection against reinfection. infection is the most common bacterial sexually transmitted infection, and infection in women can lead to pelvic inflammatory disease and infertility. No licensed vaccine exists to prevent infection, and investigations of the natural immune response may inform the design of targeted vaccines for Our study fills a gap in knowledge regarding the epitope specificity of antibody responses that are elicited in response to infection in women. We identified several new B cell epitopes for antigens and confirmed B cell epitopes that have been identified by other methods. Our finding that women produce antibodies to the VD4-MOMP regardless of infection outcome provides insight into vaccine development, suggesting that vaccines targeting VD4-MOMP may need to elicit higher-titer antibody responses than natural infection imparts or that additional vaccine targets should be pursued in the future.
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http://dx.doi.org/10.1128/mSphere.00654-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7568647PMC
September 2020

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

Impact of screening on cervical cancer incidence: A population-based case-control study in the United States.

Int J Cancer 2020 08 31;147(3):887-896. Epub 2019 Dec 31.

Department of Pathology and Obstetrics & Gynecology, University of New Mexico Health Sciences Center, Albuquerque, NM.

Cervical cancer is widely preventable through screening, but little is known about the duration of protection offered by a negative screen in North America. A case-control study was conducted with records from population-based registries in New Mexico. Cases were women diagnosed with cervical cancer in 2006-2016, obtained from the Tumor Registry. Five controls per case from the New Mexico HPV Pap Registry were matched to cases by sex, age and place of residence. Dates and results of all cervical screening and diagnostic tests since 2006 were identified from the pap registry. We estimated the odds ratio of nonlocalized (Stage II+) and localized (Stage I) cervical cancer associated with attending screening in the 3 years prior to case-diagnosis compared to women not screened in 5 years. Of 876 cases, 527 were aged 25-64 years with ≥3 years of potential screening data. Only 38% of cases and 61% of controls attended screening in a 3-year period. Women screened in the 3 years prior to diagnosis had 83% lower risk of nonlocalized cancer (odds ratio [OR] = 0.17, 95% CI: 0.12-0.24) and 48% lower odds of localized cancer (OR = 0.52, 95% CI: 0.38-0.72), compared to women not screened in the 5 years prior to diagnosis. Women remained at low risk of nonlocalized cancer for 3.5-5 years after a negative screen compared to women with no negative screens in the 5 years prior to diagnosis. Routine cervical screening is effective at preventing localized and nonlocalized cervical cancers; 3 yearly screening prevents 83% of nonlocalized cancers, with no additional benefit of more frequent screening. Increasing screening coverage remains essential to further reduce cervical cancer incidence.
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http://dx.doi.org/10.1002/ijc.32826DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7282928PMC
August 2020

Comparison of HPV-16 and HPV-18 Genotyping and Cytological Testing as Triage Testing Within Human Papillomavirus-Based Screening in Mexico.

JAMA Netw Open 2019 11 1;2(11):e1915781. Epub 2019 Nov 1.

Research Center on Policies, Population, and Health, Faculty of Medicine, National Autonomous University of Mexico, Mexico City, Mexico.

Importance: Triage tests enhance the efficiency cervical cancer screening based on human papillomavirus (HPV), but the best approach for maximizing programmatic effectiveness is still uncertain, particularly in a real-world scenario.

Objective: To compare the clinical performance of 6 triage strategies based on liquid-based cytology (LBC) and HPV-16 and HPV-18 genotyping individually or in combination as sequential triage tests to detect cervical intraepithelial neoplasia (CIN) grade 2 or higher among women with high-risk HPV.

Design, Setting, And Participants: This diagnostic study of routine cervical cancer screening was conducted at 100 primary health centers in Tlaxcala, Mexico. Women aged 30 to 64 years were recruited from August 1, 2013, to February 24, 2016, as part of the Forwarding Research for Improved Detection and Access for Cervical Cancer Screening and Triage study. Six triage scenarios for referral to colposcopy were examined: (1) LBC testing that found atypical squamous cells of undetermined significance (ASC-US) or worse, (2) positive results in HPV-16 genotyping, (3) positive results in HPV-18 genotyping, (4) positive results in HPV-16/HPV-18 genotyping, (5) positive results in HPV-16 genotyping or, if genotyping results were negative, reflex LBC testing that found ASC-US or worse, and (6) positive results in HPV-16/HPV-18 genotyping or, if genotyping results were negative, reflex LBC testing that found ASC-US or worse. Data were analyzed from October 2017 to August 2018.

Exposures: Liquid-based cytological testing with simultaneous HPV-16 and HPV-18 genotyping. Women whose HPV genotyping results were positive for HPV-16 or HPV-18 or whose LBC results found ASC-US or worse and a random set of negative and normal results were referred to colposcopy with histologic analysis used for disease confirmation.

Main Outcomes And Measures: Clinical performance of each test strategy for detection of CIN grade 2 or higher. Secondary outcomes included resource utilization of each triage scenario, measured by the number of tests performed, the referral rate for colposcopy, and the numbers of colposcopies per CIN grade 2 or higher detected.

Results: A total of 36 212 women (median [interquartile range] age, 40 [35-47] years) were screened, and 4051 women (11.2%) had high-risk HPV. Of these women, 1109 (24.6%) were found to have HPV-16, HPV-18, or ASC-US or worse. Further histologic testing detected CIN grade 2 or higher in 110 of 788 women (14.0%) who underwent follow-up colposcopy. Sensitivity and specificity for 3 main triage strategies were 42.9% and 74.0% for LBC; 58.3% and 54.4% for HPV-16/HPV-18 genotyping; and 86.6% and 34.0% for HPV-16/HPV-18 genotyping with reflex LBC. The referral rate to colposcopy was 29% for HPV-16/HPV-18 with reflex LBC, which was 2-fold higher than the referral rate of 12% for LBC.

Conclusions And Relevance: Triage of women with high-risk HPV with HPV-16/HPV-18 genotyping with reflex LBC was significantly associated with improvement in detection of CIN grade 2 or higher compared with LBC alone. The benefit of disease prevented may outweigh the cost of increasing requirements for colposcopy services in settings with limited adherence to follow-up after a positive screening result.
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http://dx.doi.org/10.1001/jamanetworkopen.2019.15781DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6902808PMC
November 2019

Relationships of p16 Immunohistochemistry and Other Biomarkers With Diagnoses of Cervical Abnormalities: Implications for LAST Terminology.

Arch Pathol Lab Med 2020 06 13;144(6):725-734. Epub 2019 Nov 13.

From Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, New York (Dr Castle); Wolfson Institute of Preventive Medicine, Queen Mary University of London, London, United Kingdom (Ms Adcock and Dr Cuzick); Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Rockville, Maryland (Drs Wentzensen and Schiffman); the Department of Pathology, University of New Mexico Cancer Center, Albuquerque (Ms Torrez-Martinez, Dr Torres, Dr Joste, Dr Gravitt, Mr Hunt, and Dr Wheeler); the Department of Pathology, University of Virginia Health System, Charlottesville (Dr Stoler); the Department of Pathology, Johns Hopkins University, Baltimore, Maryland (Dr Ronnett); the Department of Pathology, University of California, San Francisco (Dr Darragh); and Sacramento, California (Dr Kinney).

Context.—: Lower Anogenital Squamous Terminology (LAST) standardization recommended p16 immunohistochemistry (p16 IHC) for biopsies diagnosed morphologically as cervical intraepithelial neoplasia (CIN) grade 2 (CIN2) to classify them as low-grade or high-grade squamous intraepithelial lesions (HSILs).

Objective.—: To describe the relationships of p16 IHC and other biomarkers associated with cervical cancer risk with biopsy diagnoses.

Design.—: A statewide, stratified sample of cervical biopsies diagnosed by community pathologists (CPs), including 1512 CIN2, underwent a consensus, expert pathologist panel (EP) review (without p16 IHC results), p16 IHC interpretation by a third pathology group, and human papillomavirus (HPV) genotyping, results of which were grouped hierarchically according to cancer risk. Antecedent cytologic interpretations were also available.

Results.—: Biopsies were more likely to test p16 IHC positive with increasing severity of CP diagnoses, overall ( ≤ .001) and within each HPV risk group ( ≤ .001 except for low-risk HPV [ < .010]). All abnormal grades of CP-diagnosed biopsies were more likely to test p16 IHC positive with a higher HPV risk group ( < .001), and testing p16 IHC positive was associated with higher HPV risk group than testing p16 IHC negative for each grade of CP-diagnosed biopsies ( < .001). p16 IHC-positive, CP-diagnosed CIN2 biopsies were less likely than CP-diagnosed CIN3 biopsies to test HPV16 positive, have an antecedent HSIL cytology, or to be diagnosed as CIN3 by the EP ( .001 for all). p16 IHC-positive, CP-diagnosed CIN1 biopsies had lower HPV risk groups than p16 IHC-negative, CP-diagnosed CIN2 biopsies ( < .001).

Conclusions.—: p16 IHC-positive, CP-diagnosed CIN2 appears to be lower cancer risk than CP-diagnosed CIN3. LAST classification of "HSIL" diagnosis, which includes p16 IHC-positive CIN2, should annotate the morphologic diagnosis (CIN2 or CIN3) to inform all management decisions, which is especially important for young (<30 years) women diagnosed with CIN2 for whom surveillance rather than treatment is recommended.
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http://dx.doi.org/10.5858/arpa.2019-0241-OADOI Listing
June 2020

Efficacy of the AS04-Adjuvanted HPV16/18 Vaccine: Pooled Analysis of the Costa Rica Vaccine and PATRICIA Randomized Controlled Trials.

J Natl Cancer Inst 2020 08;112(8):818-828

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

Background: The AS04-adjuvanted HPV16/18 (AS04-HPV16/18) vaccine provides excellent protection against targeted human papillomavirus (HPV) types and a variable degree of cross-protection against others, including types 6/11/31/33/45. High efficacy against any cervical intraepithelial neoplasia grade 3 or greater (CIN3+; >90%) suggests that lower levels of protection may exist for a wide range of oncogenic HPV types, which is difficult to quantify in individual trials. Pooling individual-level data from two randomized controlled trials, we aimed to evaluate AS04-HPV16/18 vaccine efficacy against incident HPV infections and cervical abnormalities .

Methods: Data were available from the Costa Rica Vaccine Trial (NCT00128661) and Papilloma Trial Against Cancer in Young Adults trial (NCT00122681), two large-scale, double-blind randomized controlled trials of the AS04-HPV16/18 vaccine. Primary analyses focused on disease-free women with no detectable cervicovaginal HPV at baseline.

Results: A total of 12 550 women were included in our primary analyses (HPV arm = 6271, control arm = 6279). Incidence of 6-month persistent oncogenic and nononcogenic infections, excluding known and accepted protected types 6/11/16/18/31/33/45 (focusing on 34/35/39/40/42/43/44/51/52/53/54/56/58/59/66/68/73/70/74), was statistically significantly lower in the HPV arm than in the control arm (efficacy = 9.9%, 95% confidence interval [CI] = 1.7% to 17.4%). Statistically significant efficacy (P < .05) was observed for individual oncogenic types 16/18/31/33/45/52 and nononcogenic types 6/11/53/74. Efficacy against cervical abnormalities (all types) increased with severity, ranging from 27.7% (95% CI = 21.7% to 33.3%) to 58.7% (95% CI = 34.1% to 74.7%) for cytologic outcomes (low-grade squamous intraepithelial neoplasia lesion or greater, and high-grade squamous intraepithelial neoplasia lesion or greater, respectively) and 66.0% (95% CI = 54.4% to 74.9%) to 87.8% (95% CI = 71.1% to 95.7%) for histologic outcomes (CIN2+ and CIN3+, respectively). Comparing Costa Rica Vaccine Trial and Papilloma Trial Against Cancer in Young Adults results, there was no evidence of heterogeneity, except for type 51 (efficacy = -28.6% and 20.7%, respectively; two-sided P = .03).

Conclusions: The AS04-HPV16/18 vaccine provides some additional cross-protection beyond established protected types, which partially explains the high efficacy against CIN3+.
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http://dx.doi.org/10.1093/jnci/djz222DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7825474PMC
August 2020

Role of HPV Genotype, Multiple Infections, and Viral Load on the Risk of High-Grade Cervical Neoplasia.

Cancer Epidemiol Biomarkers Prev 2019 11 5;28(11):1816-1824. Epub 2019 Sep 5.

Center for HPV Prevention, University of New Mexico Health Sciences Center, Albuquerque, New Mexico.

Background: Human papillomavirus (HPV) testing provides a much more sensitive method of detection for high-grade lesions than cytology, but specificity is low. Here, we explore the extent to which full HPV genotyping, viral load, and multiplicity of types can be used to improve specificity.

Methods: A population-based sample of 47,120 women undergoing cervical screening was tested for 13 high-risk HPV genotypes. Positive predictive values (PPV) for cervical intraepithelial neoplasia (CIN) grade 2 or worse (CIN2+; = 3,449) and CIN3 or worse (CIN3+; = 1,475) over 3 years of follow-up were estimated for HPV genotype and viral load. Weighted multivariate logistic regression models were used to estimate the odds of CIN2+ or CIN3+ according to genotype, multiplicity of types, and viral load.

Results: High-risk HPV was detected in 15.4% of women. A hierarchy of HPV genotypes based on sequentially maximizing PPVs for CIN3+ found HPV16>33>31 to be the most predictive, followed sequentially by HPV18>35>58>45>52>59>51>39>56>68. After adjusting for higher ranked genotypes, the inclusion of multiple HPV infections added little to risk prediction. High viral loads for HPV18, 35, 52, and 58 carried more risk than low viral loads for HPV16, 31, and 33. High viral load for HPV16 was significantly more associated with CIN3+ than low viral load.

Conclusions: HPV genotype and viral load, but not multiplicity of HPV infections, are important predictors of CIN2+ and CIN3+.

Impact: The ability to identify women at higher risk of CIN2+ and CIN3+ based on both HPV genotype and viral load could be important for individualizing triage plans, particularly as HPV becomes the primary screening test.
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http://dx.doi.org/10.1158/1055-9965.EPI-19-0239DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8394698PMC
November 2019

Evaluating Screening Participation, Follow-up, and Outcomes for Breast, Cervical, and Colorectal Cancer in the PROSPR Consortium.

J Natl Cancer Inst 2020 03;112(3):238-246

Simmons Comprehensive Cancer Center, Dallas, TX.

Background: Cancer screening is a complex process encompassing risk assessment, the initial screening examination, diagnostic evaluation, and treatment of cancer precursors or early cancers. Metrics that enable comparisons across different screening targets are needed. We present population-based screening metrics for breast, cervical, and colorectal cancers for nine sites participating in the Population-based Research Optimizing Screening through Personalized Regimens consortium.

Methods: We describe how selected metrics map to a trans-organ conceptual model of the screening process. For each cancer type, we calculated calendar year 2013 metrics for the screen-eligible target population (breast: ages 40-74 years; cervical: ages 21-64 years; colorectal: ages 50-75 years). Metrics for screening participation, timely diagnostic evaluation, and diagnosed cancers in the screened and total populations are presented for the total eligible population and stratified by age group and cancer type.

Results: The overall screening-eligible populations in 2013 were 305 568 participants for breast, 3 160 128 for cervical, and 2 363 922 for colorectal cancer screening. Being up-to-date for testing was common for all three cancer types: breast (63.5%), cervical (84.6%), and colorectal (77.5%). The percentage of abnormal screens ranged from 10.7% for breast, 4.4% for cervical, and 4.5% for colorectal cancer screening. Abnormal breast screens were followed up diagnostically in almost all (96.8%) cases, and cervical and colorectal were similar (76.2% and 76.3%, respectively). Cancer rates per 1000 screens were 5.66, 0.17, and 1.46 for breast, cervical, and colorectal cancer, respectively.

Conclusions: Comprehensive assessment of metrics by the Population-based Research Optimizing Screening through Personalized Regimens consortium enabled systematic identification of screening process steps in need of improvement. We encourage widespread use of common metrics to allow interventions to be tested across cancer types and health-care settings.
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http://dx.doi.org/10.1093/jnci/djz137DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7073922PMC
March 2020

Cervical cancer screening research in the PROSPR I consortium: Rationale, methods and baseline findings from a US cohort.

Int J Cancer 2019 03 20;144(6):1460-1473. Epub 2018 Dec 20.

Division of Cancer Control and Population Sciences, National Cancer Institute, Bethesda, MD.

Little is known about the effect of evolving risk-based cervical cancer screening and management guidelines on United States (US) clinical practice and patient outcomes. We describe the National Cancer Institute's Population-based Research Optimizing Screening through Personalized Regimens (PROSPR I) consortium, methods and baseline findings from its cervical sites: Kaiser Permanente Washington, Kaiser Permanente Northern California, Kaiser Permanente Southern California, Parkland Health & Hospital System/University of Texas Southwestern (Parkland-UTSW) and New Mexico HPV Pap Registry housed by University of New Mexico (UNM-NMHPVPR). Across these diverse healthcare settings, we collected data on human papillomavirus (HPV) vaccinations, screening tests/results, diagnostic and treatment procedures/results and cancer diagnoses on nearly 4.7 million women aged 18-89 years from 2010 to 2014. We calculated baseline (2012 for UNM-NMHPVPR; 2010 for other sites) frequencies for sociodemographics, cervical cancer risk factors and key screening process measures for each site's cohort. Healthcare delivery settings, cervical cancer screening strategy, race/ethnicity and insurance status varied among sites. The proportion of women receiving a Pap test during the baseline year was similar across sites (26.1-36.1%). Most high-risk HPV tests were performed either reflexively or as cotests, and utilization pattern varied by site. Prevalence of colposcopy or biopsy was higher at Parkland-UTSW (3.6%) than other sites (1.3-1.4%). Incident cervical cancer was rare. HPV vaccination among age-eligible women not already immunized was modest across sites (0.1-7.2%). Cervical PROSPR I makes available high-quality, multilevel, longitudinal screening process data from a large and diverse cohort of women to evaluate and improve the effectiveness of US cervical cancer screening delivery.
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http://dx.doi.org/10.1002/ijc.31940DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6941787PMC
March 2019

Human Papillomavirus Genotypes From Vaginal and Vulvar Intraepithelial Neoplasia in Females 15-26 Years of Age.

Obstet Gynecol 2018 08;132(2):261-270

Department of Microbiology Infectious Diseases, the Royal Women's Hospital, Department of Microbiology, the Royal Children's Hospital, Infection and Immunity, Murdoch Children's Research Institute, Department of Obstetrics and Gynaecology, University of Melbourne, Melbourne, Australia; the Department of Gynecology and Obstetrics, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria; the Department of Obstetrics and Gynecology, University of Kansas Medical Center, Kansas City, Kansas; Institut Catala d'Oncologia, IDIBELL, CIBER-ESP, RTICC, L'Hospitalet de Llobregat, Barcelona, Spain; the Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana; the Department of Pathology, SMBD Jewish General Hospital and McGill University, Montréal, Québec, Canada; the Department of Obstetrics and Gynecology, Augusta University, Augusta, Georgia; the Center for Infection Research in Cancer, Moffitt Cancer Center, Tampa, Florida; the National Institute of Public Health, Cuernavaca, Morelos, Mexico; the Division of Gynecologic Oncology, University of Alabama, Birmingham, Alabama; the Department of Clinical Science, University of Bergen/Haukeland University Hospital, Bergen, Norway; the Danish Cancer Society Research Center, Copenhagen, Denmark and Department of Gynecology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark; Johns Hopkins University School of Medicine, Baltimore, Maryland; the Department of Obstetrics and Gynecology, Clinica Colsanitas, Fundacion Universitaria Sanitas, Bogota, Colombia; Institut du col, Paris, France; the National Institute of Cancer, Bogotá, Colombia; the Department of Obstetrics and Gynecology, University Central Hospital, Helsinki, Finland; the Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand; Direction des Risques Biologiques et de la Santé au Travail, Institut National de Santé Publique du Québec, Montréal, Québec, Canada; Robert E. Fechner Laboratory of Surgical Pathology, University of Virginia Health System, Charlottesville, Virginia; the Departments of Pathology and Obstetrics and Gynecology, University of New Mexico Health Sciences Center, Albuquerque, New Mexico; UCLA School of Nursing, Los Angeles, California; Merck & Co, Inc., Kenilworth, New Jersey; Universidad del Rosario, Bogota, Colombia; and Analytica LASÉR, Montréal, Québec, Canada.

Objective: To estimate the proportion of vulvar and vaginal low-grade and high-grade squamous intraepithelial lesions (LSILs and HSILs) in females 15-26 years of age attributable to 14 human papillomavirus (HPV) genotypes (6, 11, 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59).

Methods: A post hoc analysis of prospectively diagnosed vulvar and vaginal LSILs and HSILs among females 15-26 years of age enrolled in the placebo arms of two phase 3, randomized HPV vaccine trials assessed 14 prespecified HPV genotypes associated with cervical cancers or anogenital warts using a type-specific multiplex polymerase chain reaction assay. The frequency of lesions associated with specific HPV genotypes was estimated by proportional and other attribution methods.

Results: During approximately 4 years of follow-up in 8,798 females, 40 vulvar LSILs and 46 vulvar HSILs were diagnosed in 68 females, and 118 vaginal LSILs and 33 vaginal HSILs were diagnosed in 107 females. Females developing vulvar (41.2%) or vaginal (49.5%) lesions also had cervical lesions, whereas 6.5% of females with cervical lesions had vaginal or vulvar lesions. At least 1 of the 14 HPV genotypes was detected in females with vulvar LSIL (72.5%), vulvar HSIL (91.3%), vaginal LSIL (61.9%), and vaginal HSIL (72.7%). Considering only HPV-positive lesions, the nine most common genotypes causing cervical cancer and anogenital warts (6, 11, 16, 18, 31, 33, 45, 52, and 58) were found in 89.4% of vulvar LSILs, 100% of vulvar HSILs, 56.0% of vaginal LSILs, and 78.3% of vaginal HSILs.

Conclusion: Most vulvar and vaginal lesions were attributable to at least 1 of the 14 HPV genotypes analyzed. Effective immunization programs could potentially prevent substantial numbers of HPV-related vulvar and vaginal LSILs and HSILs.

Clinical Trial Registration: CLINICALTRIALS.GOV,: NCT00092521 and NCT00092534.
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http://dx.doi.org/10.1097/AOG.0000000000002736DOI Listing
August 2018

Timely follow-up of positive cancer screening results: A systematic review and recommendations from the PROSPR Consortium.

CA Cancer J Clin 2018 05 30;68(3):199-216. Epub 2018 Mar 30.

Physician in Chief, General Medicine Division, MA General Hospital, Harvard Medical School, Boston, MA.

Timely follow-up for positive cancer screening results remains suboptimal, and the evidence base to inform decisions on optimizing the timeliness of diagnostic testing is unclear. This systematic review evaluated published studies regarding time to follow-up after a positive screening for breast, cervical, colorectal, and lung cancers. The quality of available evidence was very low or low across cancers, with potential attenuated or reversed associations from confounding by indication in most studies. Overall, evidence suggested that the risk for poorer cancer outcomes rises with longer wait times that vary within and across cancer types, which supports performing diagnostic testing as soon as feasible after the positive result, but evidence for specific time targets is limited. Within these limitations, we provide our opinion on cancer-specific recommendations for times to follow-up and how existing guidelines relate to the current evidence. Thresholds set should consider patient worry, potential for loss to follow-up with prolonged wait times, and available resources. Research is needed to better guide the timeliness of diagnostic follow-up, including considerations for patient preferences and existing barriers, while addressing methodological weaknesses. Research is also needed to identify effective interventions for reducing wait times for diagnostic testing, particularly in underserved or low-resource settings. CA Cancer J Clin 2018;68:199-216. © 2018 American Cancer Society.
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http://dx.doi.org/10.3322/caac.21452DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5980732PMC
May 2018

Inefficiencies of over-screening and under-screening for cervical cancer prevention in the U.S.

Prev Med 2018 06 14;111:177-179. Epub 2018 Mar 14.

Department of Health Policy and Management, Harvard University, Boston, MA, USA.

There is limited information on the cost-inefficiencies of non-adherence to recommended cervical cancer screening or the potential value for improving non-adherence. We estimated the incremental value of adhering to recommended screening every three years with cytology, using a disease simulation model that integrated real-world screening practice data from New Mexico. The amount that can be spent to improve adherence was estimated by calculating the incremental net monetary benefit (INMB) under scenarios of Current Practice (assuming a population of mixed adherence) and Uniformly Non-Adherent populations with imperfect or perfect adherence to follow-up of screen-positive women. Getting unscreened women screened every three years by cytology was a better value than increasing screening in the under-screened or reducing screening in the over-screened. For example, INMBs were $3998 for screening previously unscreened women versus $136 for eliminating annual screening at a willingness-to-pay threshold of $100,000 per quality-adjusted life-year gained. Strategies to reach unscreened women are potentially high-value investments.
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http://dx.doi.org/10.1016/j.ypmed.2018.03.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5930058PMC
June 2018

Primary Prevention of Cervical Cancer: American Society of Clinical Oncology Resource-Stratified Guideline.

J Glob Oncol 2017 Oct 17;3(5):611-634. Epub 2017 Mar 17.

, Instituto Nacional del Cancer, Buenos Aires, Argentina; , American Society of Clinical Oncology, Alexandria, VA; , University of Melbourne, Melbourne, Victoria, Australia; , University of Washington; , PATH, Seattle, WA; , All India Institute of Medical Sciences, New Delhi, India; and , Institut Català d'Oncologia, L'Hospitalet de Llobregat, Barcelona, Spain; , Universiti Kebangsaan Malaysia Medical Centre, Kuala Lumpur, Malaysia; , Cervivor, Upper Marlboro, MD; , Institut National de Santé Publique, Algiers, Algeria; , Jichi Medical University, Saitama Medical Center, Saitama, Japan; , Sylvester Comprehensive Cancer Center, Miami, FL; , PATH, Kampala, Uganda; , International Agency for Research on Cancer, Lyon, France; , University of Alabama at Birmingham Comprehensive Cancer Center, Birmingham, AL; , University of Cambridge, Cambridge, United Kingdom; , University of New Mexico, Albuquerque, NM; and , Ministry of Health, Abuja, Nigeria.

Purpose: To provide resource-stratified (four tiers), evidence-based recommendations on the primary prevention of cervical cancer globally.

Methods: The American Society of Clinical Oncology convened a multidisciplinary, multinational panel of oncology, obstetrics/gynecology, public health, cancer control, epidemiology/biostatistics, health economics, behavioral/implementation science, and patient advocacy experts. The Expert Panel reviewed existing guidelines and conducted a modified ADAPTE process and a formal consensus-based process with additional experts (consensus ratings group) for one round of formal ratings.

Results: Existing sets of guidelines from five guideline developers were identified and reviewed; adapted recommendations formed the evidence base. Five systematic reviews, along with cost-effectiveness analyses, provided evidence to inform the formal consensus process, which resulted in agreement of ≥ 75%.

Recommendations: In all resource settings, two doses of human papillomavirus vaccine are recommended for girls age 9 to 14 years, with an interval of at least 6 months and possibly up to 12 to 15 months. Individuals with HIV positivity should receive three doses. Maximal and enhanced settings: if girls are age ≥ 15 years and received their first dose before age 15 years, they may complete the series; if no doses were received before age 15 years, three doses should be administered; in both scenarios, vaccination may be through age 26 years. Limited and basic settings: if sufficient resources remain after vaccinating girls age 9 to 14 years, girls who received one dose may receive additional doses between age 15 and 26 years. Maximal, enhanced, and limited settings: if ≥ 50% coverage in the priority female target population, sufficient resources, and cost effectiveness, boys may be vaccinated to prevent other noncervical human papillomavirus-related cancers and diseases. Basic settings: vaccinating boys is not recommended.

It is the view of the American Society of Clinical Oncology that health care providers and health care system decision makers should be guided by the recommendations for the highest stratum of resources available. The guideline is intended to complement but not replace local guidelines.
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http://dx.doi.org/10.1200/JGO.2016.008151DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5646902PMC
October 2017

Human papillomavirus detection in cervical neoplasia attributed to 12 high-risk human papillomavirus genotypes by region.

Papillomavirus Res 2016 12 14;2:61-69. Epub 2016 Mar 14.

Merck & Co., Inc., Kenilworth, NJ, USA.

Background: We estimated the proportion of cervical intraepithelial neoplasia (CIN) cases attributed to 14 HPV types, including quadrivalent (qHPV) (6/11/16/18) and 9-valent (9vHPV) (6/11/16/18/31/33/45/52/58) vaccine types, by region METHODS: Women ages 15-26 and 24-45 years from 5 regions were enrolled in qHPV vaccine clinical trials. Among 10,706 women (placebo arms), 1539 CIN1, 945 CIN2/3, and 24 adenocarcinoma in situ (AIS) cases were diagnosed by pathology panel consensus.

Results: Predominant HPV types were 16/51/52/56 (anogenital infection), 16/39/51/52/56 (CIN1), and 16/31/52/58 (CIN2/3). In regions with largest sample sizes, minimal regional variation was observed in 9vHPV type prevalence in CIN1 (~50%) and CIN2/3 (81-85%). Types 31/33/45/52/58 accounted for 25-30% of CIN1 in Latin America and Europe, but 14-18% in North America and Asia. Types 31/33/45/52/58 accounted for 33-38% of CIN2/3 in Latin America (younger women), Europe, and Asia, but 17-18% of CIN2/3 in Latin America (older women) and North America. Non-vaccine HPV types 35/39/51/56/59 had similar or higher prevalence than qHPV types in CIN1 and were attributed to 2-11% of CIN2/3.

Conclusions: The 9vHPV vaccine could potentially prevent the majority of CIN1-3, irrespective of geographic region. Notwithstanding, non-vaccine types 35/39/51/56/59 may still be responsible for some CIN1, and to a lesser extent CIN2/3.
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http://dx.doi.org/10.1016/j.pvr.2016.03.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5886863PMC
December 2016

Outcomes in Women With Cytology Showing Atypical Squamous Cells of Undetermined Significance With vs Without Human Papillomavirus Testing.

JAMA Oncol 2017 Oct;3(10):1327-1334

Department of Pathology, University of New Mexico Health Sciences Center, Albuquerque.

Importance: Little is known about the long-term yield of high-grade cervical intraepithelial neoplasia (CIN) and the influence on biopsy and treatment rates of human papillomavirus (HPV) triage of cytology showing atypical squamous cells of undetermined significance (hereafter ASC-US cytology).

Objective: To examine 5-year outcomes after ASC-US cytology with vs without HPV testing.

Design, Setting, And Participants: In this observational study, all cervical cytology and HPV testing reports from January 1, 2007, to December 31, 2012, were obtained for women throughout New Mexico and linked to pathology reports. The dates of the analysis were May 4, 2015, to January 13, 2017.

Main Outcomes And Measures: Influence of HPV testing on disease yield, time to histologically confirmed disease, and biopsy or loop electrosurgical excision procedure rates.

Results: A total of 457 317 women (mean [SD] age, 39.8 [12.5] years) with a screening test were recorded between 2008 and 2012, and 20 677 (4.5%) of the first cytology results per woman were reported as ASC-US. CIN grade 3 or more severe (CIN3+) lesions were detected in 2.49% of women with HPV testing vs 2.15% of women without HPV testing (P = .23). Time to CIN3+ detection was much shorter in those with HPV testing vs those without testing (median, 103 vs 393 days; P < .001). CIN grade 1 was detected in 11.6% of women with HPV testing vs 6.6% without testing (relative risk, 1.76; 95% CI, 1.56-2.00; P < .001). Loop electrosurgical excision procedure rates within 5 years were 20.0% higher in those who underwent HPV testing, resulting in more CIN2+ and CIN3+ detection.

Conclusions And Relevance: Human papillomavirus testing led to faster and more complete diagnosis of cervical disease, but 55.8% more biopsies and 20.0% more loop electrosurgical excision procedures were performed. In those tested, virtually all high-grade disease occurred in the 43.1% of women who were HPV positive, allowing clinical resources to be focused on women who need them most. These data provide essential information for cervical screening guidelines and public health policy.
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http://dx.doi.org/10.1001/jamaoncol.2017.1040DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5710525PMC
October 2017

An analysis of the process and results of manual geocode correction.

Geospat Health 2017 05 11;12(1):526. Epub 2017 May 11.

Department of Geography, College of Geosciences, Texas A&M University, College Station, TX.

Geocoding is the science and process of assigning geographical coordinates (i.e. latitude, longitude) to a postal address. The quality of the geocode can vary dramatically depending on several variables, including incorrect input address data, missing address components, and spelling mistakes. A dataset with a considerable number of geocoding inaccuracies can potentially result in an imprecise analysis and invalid conclusions. There has been little quantitative analysis of the amount of effort (i.e. time) to perform geocoding correction, and how such correction could improve geocode quality type. This study used a low-cost and easy to implement method to improve geocode quality type of an input database (i.e. addresses to be matched) through the processes of manual geocode intervention, and it assessed the amount of effort to manually correct inaccurate geocodes, reported the resulting match rate improvement between the original and the corrected geocodes, and documented the corresponding spatial shift by geocode quality type resulting from the corrections. Findings demonstrated that manual intervention of geocoding resulted in a 90% improvement of geocode quality type, took 42 hours to process, and the spatial shift ranged from 0.02 to 151,368 m. This study provides evidence to inform research teams considering the application of manual geocoding intervention that it is a low-cost and relatively easy process to execute.
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http://dx.doi.org/10.4081/gh.2017.526DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5978681PMC
May 2017

Evaluation of Type Replacement Following HPV16/18 Vaccination: Pooled Analysis of Two Randomized Trials.

J Natl Cancer Inst 2017 01 28;109(7). Epub 2017 Jan 28.

Affiliations of authors: Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD (JET, ARK, MS, AH); GSK Vaccines, Wavre, Belgium (FS, DB); National Institute for Health and Welfare, Oulu, Finland (MM); Proyecto Epidemiológico Guanacaste, Fundación INCIENSA, San José, Costa Rica (PG); Cancer Epidemiology Research Program, Catalan Institute of Oncology (ICO)-IDIBELL, CIBER-ESP, L'Hospitalet de Llobregat, Spain (XC); Department of Gynecology and Obstetrics, Federal University of Paraná, Infectious Diseases in Gynecology and Obstetrics Sector/Clinics Hospital, Curitiba, Brazil (NSdC); Department of Microbiology and Infectious Diseases, Royal Women's Hospital, Parkville, Victoria, Australia (SMG); Murdoch Childrens Research Institute, Parkville, Victoria, Australia (SMG); Department of Obstetrics and Gynaecology, University of Melbourne, Victoria, Parkville, Australia (SMG); Geisel School of Medicine at Dartmouth, Hanover, NH (DMH); GSK Vaccines, Bangalore, India (NK); Berner Heerweg 157, Hamburg, Germany (KP); Department of Gynaecology, University Hospital KU Leuven Gasthuisberg, Leuven, Belgium (WAJP); Proyecto Epidemiológico Guanacaste, Fundación INCIENSA, San José, Costa Rica (CP, ACR, RH); DDL Diagnostic Laboratory, Rijswijk, the Netherlands (WQ); Information Management Systems, Rockville, MD (JS); Vaccines Trials Group, Telethon Institute for Child Health Research, Perth, WA, and Sydney University Discipline of Paediatrics and Child Health, Children's Hospital Westmead, Sydney, NSW, Australia (SRS); Department of Gynecology, Oncology Division-CAISM, State University of Campinas, Campinas, Brazil (JCT); University of Tampere, School of Public Health, Tampere, Finland (ML).

Background: Current HPV vaccines do not protect against all oncogenic HPV types. Following vaccination, type replacement may occur, especially if different HPV types competitively interact during natural infection. Because of their common route of transmission, it is difficult to assess type interactions in observational studies. Our aim was to evaluate type replacement in the setting of HPV vaccine randomized controlled trials (RCTs).

Methods: Data were pooled from the Costa Rica Vaccine Trial (CVT; NCT00128661) and PATRICIA trial (NCT001226810)-two large-scale, double-blind RCTs of the HPV-16/18 AS04-adjuvanted vaccine-to compare cumulative incidence of nonprotected HPV infections across trial arms after four years. Negative rate difference estimates (rate in control minus vaccine arm) were interpreted as evidence of replacement if the associated 95% confidence interval excluded zero. All statistical tests were two-sided.

Results: After applying relevant exclusion criteria, 21 596 women were included in our analysis (HPV arm = 10 750; control arm = 10 846). Incidence rates (per 1000 infection-years) were lower in the HPV arm than in the control arm for grouped nonprotected oncogenic types (rate difference = 1.6, 95% confidence interval [CI] = 0.9 to 2.3) and oncogenic/nononcogenic types (rate difference = 0.2, 95% CI = -0.3 to 0.7). Focusing on individual HPV types separately, no deleterious effect was observed. In contrast, a statistically significant protective effect (positive rate difference and 95% CI excluded zero) was observed against oncogenic HPV types 35, 52, 58, and 68/73, as well as nononcogenic types 6 and 70.

Conclusion: HPV type replacement does not occur among vaccinated individuals within four years and is unlikely to occur in vaccinated populations.
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http://dx.doi.org/10.1093/jnci/djw300DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5967353PMC
January 2017

The safety of Cervarix? - Authors' reply.

Lancet Infect Dis 2017 01;17(1):20-21

GSK Vaccines, Wavre, Belgium.

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http://dx.doi.org/10.1016/S1473-3099(16)30540-0DOI Listing
January 2017

Similar Risk Patterns After Cervical Screening in Two Large U.S. Populations: Implications for Clinical Guidelines.

Obstet Gynecol 2016 12;128(6):1248-1257

Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health & Human Services, Bethesda, Maryland; the Departments of Pathology, Internal Medicine, and Obstetrics and Gynecology, University of New Mexico Health Sciences Center, Albuquerque, New Mexico; Information Management Services Inc., Calverton, Maryland; the Centre for Cancer Prevention, Wolfson Institute of Preventive Medicine, Queen Mary University of London, Charterhouse Square, London, United Kingdom; the Division of Gynecologic Oncology, Kaiser Permanente Medical Care Program, Oakland, California; and the Albert Einstein College of Medicine, New York, New York.

Objective: To compare the risks of histologic high-grade cervical intraepithelial neoplasia (CIN) or worse after different cervical cancer screening test results between two of the largest U.S. clinical practice research data sets.

Methods: The New Mexico Human Papillomavirus (HPV) Pap Registry is a statewide registry representing a diverse population experiencing varied clinical practice delivery. Kaiser Permanente Northern California is a large integrated health care delivery system practicing routine HPV cotesting since 2003. In this retrospective cohort study, a logistic-Weibull survival model was used to estimate and compare the cumulative 3- and 5-year risks of histologic CIN 3 or worse among women aged 21-64 years screened in 2007-2011 in the New Mexico HPV Pap Registry and 2003-2013 in Kaiser Permanente Northern California. Results were stratified by age and baseline screening result: negative cytology, atypical squamous cells of undetermined significance (ASC-US) (with or without HPV triage), low-grade squamous intraepithelial lesion, and high-grade squamous intraepithelial lesion.

Results: There were 453,618 women in the New Mexico HPV Pap Registry and 1,307,528 women at Kaiser Permanente Northern California. The 5-year CIN 3 or worse risks were similar within screening results across populations: cytology negative (0.52% and 0.30%, respectively, P<.001), HPV-negative and ASC-US (0.72% and 0.49%, respectively, P=.5), ASC-US (3.4% and 3.4%, respectively, P=.8), HPV-positive and ASC-US (7.7% and 7.1%, respectively, P=.3), low-grade squamous intraepithelial lesion (6.5% and 5.4%, respectively, P=.009), and high-grade squamous intraepithelial lesion (53.1% and 50.4%, respectively, P=.2). Cervical intraepithelial neoplasia grade 2 or worse risks and 3-year risks had similar trends across populations. Age-stratified analyses showed more variability, especially among women aged younger than 30 years, but patterns of risk stratification were comparable.

Conclusion: Current U.S. cervical screening and management recommendations are based on comparative risks of histologic high-grade CIN after screening test results. The similar results from these two large cohorts from different real-life clinical practice settings support risk-based management thresholds across U.S. clinical populations and practice settings.
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http://dx.doi.org/10.1097/AOG.0000000000001721DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5247269PMC
December 2016

Population-Based Incidence Rates of Cervical Intraepithelial Neoplasia in the Human Papillomavirus Vaccine Era.

JAMA Oncol 2017 Jun;3(6):833-837

House of Prevention Epidemiology (HOPE), Department of Pathology, University of New Mexico Health Sciences Center, Albuquerque.

Importance: A substantial effect of human papillomavirus (HPV) vaccines on reducing HPV-related cervical disease is essential before modifying clinical practice guidelines in partially vaccinated populations.

Objective: To determine the population-based cervical intraepithelial neoplasia (CIN) trends when adjusting for changes in cervical screening practices that overlapped with HPV vaccination implementation.

Design, Setting, And Participants: The New Mexico HPV Pap Registry, which captures population-based estimates of both cervical screening prevalence and CIN, was used to compute CIN trends from January 1, 2007, to December 31, 2014. Under New Mexico Administrative Code, the New Mexico HPV Pap Registry, a statewide public health surveillance program, receives mandatory reporting of all cervical screening (cytologic and HPV testing) and any cervical, vulvar, and vaginal histopathological findings for all women residing in New Mexico irrespective of outcome.

Main Outcome Measures: Prespecified outcome measures included low-grade CIN (grade 1 [CIN1]) and high-grade CIN (grade 2 [CIN2] and grade 3 [CIN3]).

Results: From 2007 to 2014, a total of 13 520 CIN1, 4296 CIN2, and 2823 CIN3 lesions were diagnosed among female individuals 15 to 29 years old. After adjustment for changes in cervical screening across the period, reductions in the CIN incidence per 100 000 women screened were significant for all grades of CIN among female individuals 15 to 19 years old, dropping from 3468.3 to 1590.6 for CIN1 (annual percentage change [APC], -9.0; 95% CI, -12.0 to -5.8; P < .001), from 896.4 to 414.9 for CIN2 (APC, -10.5; 95% CI, -18.8 to -1.2; P = .03), and from 240.2 to 0 for CIN3 (APC, -41.3; 95% CI, -65.7 to 0.3; P = .05). Reductions in the CIN2 incidence were also significant for women 20 to 24 years old, dropping from 1027.7 to 627.1 (APC, -6.3; 95% CI, -10.9 to -1.4; P = .02).

Conclusions And Relevance: Population-level decreases in CIN among cohorts partially vaccinated for HPV may be considered when clinical practice guidelines for cervical cancer screening are reassessed. Evidence is rapidly growing to suggest that further increases in raising the age to start screening are imminent, one step toward integrating screening and vaccination.
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http://dx.doi.org/10.1001/jamaoncol.2016.3609DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5765871PMC
June 2017
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