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Background: Individuals with obesity have an increased risk of cervical cancer, in part related to challenges associated with cervical sampling and visualization that result in missed detection of cervical precancers. The influence of obesity on the effectiveness of excisional treatment of detected cervical precancers and posttreatment disease risk is unknown., Objective: The aim of this study was to evaluate posttreatment risks of cervical precancer and cancer by body mass index (BMI)., Study Design: This retrospective cohort study included individuals aged 25 years and older undergoing excisional treatment for cervical precancer, either cervical intraepithelial neoplasia (CIN) grade 2 or 3 or adenocarcinoma in situ as of January 2017 with follow-up through February 2023. Patients were excluded if they were missing BMI, had cancer upon excision or had hysterectomy in lieu of excision, or were missing a valid referral screening visit. We categorized BMI as follows: underweight/normal (<25 kg/m 2 ), overweight (25 to <30 kg/m 2 ), and obesity (≥30kg/m 2 ), as well as by class (I-III) of obesity. We calculated 2-year risks of CIN3 and cancer (combined as CIN3+) using Kaplan Meier methods and evaluated multivariable adjusted associations of BMI with CIN3+ using Cox Proportional Hazards regression analyses, accounting for age at treatment, race and ethnicity, and treatment type., Results: Among 10,614 patients, a total of 680 (6.4%) developed post-treatment CIN3+; most (91%) within 2 years of treatment. Two-year CIN3+ and cancer risks were highest in those with obesity (8.65%, 95% CI, 7.6%-9.9% and 0.79%, 95% CI, 0.5%-1.2%, respectively) and lowest in those with normal weight (5.57%, 95% CI, 4.9%-6.3% and 0.29%, 95% CI, 0.2%-0.5%, respectively). Hazard ratios measuring associations of BMI with risk of posttreatment CIN3+ ranged from 1.19 (95% CI, 1.0-1.4) among those with overweight to 1.89 (95% CI, 1.4-2.6) among those with class III obesity (P-trend<.0001). A similar trend was observed for cancer, from 1.62 (95% CI, 0.8-3.3) for overweight and 3.50 (95% CI, 1.3-9.3) for class III obesity (P-trend=.016)., Conclusion: Patients with obesity undergoing excisional treatment for cervical precancer have a higher risk of residual or recurrent disease, likely due to incomplete excision., (Published by Elsevier Inc.)

Objectives: The longer-term impact of introducing human papillomavirus (HPV) testing into routine cervical cancer screening on precancer and cancer rates by histologic type has not been well described. Calendar trends in diagnoses were examined using data from Kaiser Permanente Northern California, which introduced triennial HPV and cytology co-testing in 2003 for women aged ≥30 years., Methods: We examined trends in cervical precancer (cervical intraepithelial neoplasia grade 3 [CIN3] and adenocarcinoma in situ [AIS]) and cancer (squamous cell carcinoma [SCC] and adenocarcinoma [ADC]) diagnoses per 1000 screened during 2003-2018. We examined ratios of squamous vs. glandular diagnoses (SCC:ADC and CIN3:AIS)., Results: CIN3 and AIS diagnoses increased approximately 2% and 3% annually, respectively (p trend  < 0.001 for both). While SCC diagnoses decreased by 5% per annually (p trend  < 0.001), ADC diagnoses did not change. These patterns were generally observed within each age group (30-39, 40-49, and 50-64 years). ADC diagnoses per 1000 screened did not change even among those who underwent co-testing starting in 2003-2006. SCC:ADC decreased from approximately 2.5:1 in 2003-2006 to 1.3:1 in 2015-2018 while the CIN3:AIS remained relatively constant, ∼10:1., Conclusions: Since its introduction at KPNC, co-testing increased the detection of CIN3 over time, which likely caused a subsequent reduction of SCC. However, there has been no observed decrease in ADC. One possible explanation for lack of effectiveness against ADC is the underdiagnosis of AIS. Novel strategies to identify and treat women at high risk of ADC need to be developed and clinically validated., Competing Interests: Declaration of competing interest Dr. Castle has received HPV tests and assays for research at a reduced cost from Atila Biosystems in the last 3 years., (Published by Elsevier Inc.)

Background: Human papillomavirus-related biomarkers such as p16/Ki-67 "dual-stain" (DS) cytology have shown promising clinical performance for anal cancer screening. Here, we assessed the performance of automated evaluation of DS cytology (automated DS) to detect anal precancer in men who have sex with men (MSM) and are living with human immunodeficiency virus (HIV)., Methods: We conducted a cross-sectional analysis of 320 MSM with HIV undergoing anal cancer screening and high-resolution anoscopy (HRA) in 2009-2010. We evaluated the performance of automated DS based on a deep-learning classifier compared to manual evaluation of DS cytology (manual DS) to detect anal intraepithelial neoplasia grade 2 or 3 (AIN2+) and grade 3 (AIN3). We evaluated different DS-positive cell thresholds quantified by the automated approach and modeled performance compared with other screening strategies in a hypothetical population of MSM with HIV., Results: Compared with manual DS, automated DS had significantly higher specificity (50.9% vs 42.2%; P < .001) and similar sensitivity (93.2% vs 92.1%) for detection of AIN2+. Human papillomavirus testing with automated DS triage was significantly more specific than automated DS alone (56.5% vs 50.9%; P < .001), with the same sensitivity (93.2%). In a modeled analysis assuming a 20% AIN2+ prevalence, automated DS detected more precancers than manual DS and anal cytology (186, 184, and 162, respectively) and had the lowest HRA referral rate per AIN2+ case detected (3.1, 3.5, and 3.3, respectively)., Conclusions: Compared with manual DS, automated DS detects the same number of precancers, with a lower HRA referral rate., Competing Interests: Potential conflicts of interest. B. L., L. B., A. Krauthoff, A. Keil, F. M., and N. G. report that Steinbeis Transfer Center for Medical Systems Biology (STCMED; their institution) has received grants or contracts from Roche Molecular Systems and that they have patents issued with STCMED. D. T. has a patent issued with STCMED (institution). P. E. C. has received human papillomavirus tests and assays for research at a reduced or no cost from Roche, Becton Dickinson, Cepheid, Atila Biosciences, and Arbor Vita. T. L. reports unpaid leadership roles as an associate editor for The Journal of Applied Laboratory Medicine and as a volunteer member of the board of directors, Project Santa Fe Foundation/Clinical Lab 2.0. T. M. D. is on the advisory boards for Roche and Boston Scientific and has been a consultant to Antiva and Boston Scientific. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (Published by Oxford University Press for the Infectious Diseases Society of America 2022.)

As the US moves increasingly towards using human papillomavirus (HPV) testing with or without concurrent cytology for cervical cancer screening, it is unknown what the corresponding risks are following a screening result for women living with HIV (WLWH), which will dictate the optimal clinical follow-up. Therefore, using medical records data from Kaiser Permanente Northern California, which introduced triennial HPV and cytology co-testing in women aged 30-64 years in 2003, we compared risks of cervical intraepithelial neoplasia grade 2 (CIN2) or more severe diagnoses (CIN2+) in women not known to have HIV (HIV[-] women) (n = 67,488) frequency matched 111:1 on age and year of the first co-test to the 608 WLWH (n = 608). WLWH were more likely to test HPV positive (20.2% vs. 6.5%, p < 0.001) and have non-normal cytology (14.1% vs. 4.1%, p < 0.001) than HIV[-] women. Five-year CIN2+ risks for all WLWH and HIV[-] women were 3.5% (95%CI = 2.0-5.0%) and 1.6% (95%CI = 1.5-1.8%) (p = 0.01), respectively. Five-year CIN2+ risks for WLWH with positive HPV and non-normal cytology, positive HPV and normal cytology, negative HPV and non-normal cytology, and negative HPV and normal cytology were 24.9% (95%CI = 13.4-36.4%), 3.0% (95%CI = 0.0-7.4%), 3.6 (95%CI = 0.0-9.8%) and 0.3% (95%CI = 0.0-0.8%), respectively. Corresponding 5-year CIN2+ risks for HIV[-] women were 26.6% (95%CI = 24.6-28.7%), 8.5% (95%CI = 7.2-9.9%), 1.9% (95%CI = 1.0-2.8%), and 0.5% (95%CI = 0.4-0.6%), respectively. Thus, in this healthcare setting, the main cause in overall CIN2+ risk differences between WLWH and HIV[-] women was the former was more likely to screen positive and once the screening result is known, it may be reasonable to manage both populations similarly., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Objective: The US screening and management guidelines for cervical cancer are based on the absolute risk of precancer estimated from large clinical cohorts and trials. Given the widespread transition toward screening with human papillomavirus (HPV) testing, it is important to assess which additional factors to include in clinical risk assessment to optimize management of HPV-infected women., Materials and Methods: We analyzed data from HPV-infected women, ages 30-65 years, in the National Cancer Institute-Kaiser Permanente Northern California Persistence and Progression study. We estimated the influence of HPV risk group, cytology result, and selected cofactors on immediate risk of cervical intraepithelial neoplasia grade 3 or higher (CIN 3+) among 16,094 HPV-positive women. Cofactors considered included, age, race/ethnicity, income, smoking, and hormonal contraceptive use., Results: Human papillomavirus risk group and cytology test result were strongly correlated with CIN 3+ risk. After considering cytology and HPV risk group, other cofactors (age, race/ethnicity, income, smoking, and hormonal contraceptive use) had minimal impact on CIN 3+ risk and did not change recommended management based on accepted risk thresholds. We had insufficient data to assess the impact of long-duration heavy smoking, parity, history of sexually transmitted infection, or immunosuppression., Conclusions: In our study at the Kaiser Permanente Northern California, the risk of CIN 3+ was determined mainly by HPV risk group and cytology results, with other cofactors having limited impact in adjusted analyses. This supports the use of HPV and cytology results in risk-based management guidelines., Competing Interests: The National Cancer Institute (including all NCI-affiliated authors) receives cervical screening results at reduced or no cost from commercial research partners (Qiagen, Roche, BD, MobileODT, Arbor Vita) for independent evaluations of screening methods and strategies, A.-B.M. is a Merck and GSK, Advisory Board member. P.E.C. has received human papillomavirus tests and assays at a reduced or no cost from Roche, Becton Dickinson, Arbor Vita Corporation, and Cepheid for research. A.H. has received reagents for free from Roche, Denmark, for an unrelated study. The other authors have declared they have no conflicts of interest., (Copyright © 2022, ASCCP.)

Introduction: Biomarkers of Human Papillomavirus (HPV) cervical carcinogenesis are critical to address questions of how to triage and manage women who screen positive for high-risk HPV (HrHPV) and identify those at highest cancer risk., Methods: We describe the development of a large biorepository of cervical specimens for the Improving Risk Informed HPV Screening Study (IRIS) using residual specimens collected in the regional laboratory from women aged 25 and older who had cervical cancer screening or follow-up testing with high-risk human papillomavirus (HrHPV) testing and liquid-based cytology (co-testing) at Kaiser Permanente Northern California (KPNC) from January 2016 to August 2018. Specimen selection, processing for long-term storage, follow-up tracking, consent and demographic and clinical characteristics of the women in the IRIS cohort are described., Results: Selecting from 897,680 women who had at least one co-test during the study period, we collected 199,403 baseline and 216,390 follow-up HrHPV and cytology specimens from a stratified random sample of 81,348 women, of which 3,428 (4.2%) opted out of the study and were excluded. The majority (79.9%) of the baseline specimens were from HrHPV-positive women. The mean age was 36 years, and the cohort is racially/ethnically diverse with 56% of women being Hispanic or non-white. Over two-thirds of the cohort were members of KPNC for two or more years prior to inclusion. Of the 77,920 women included in the cohort, 57,414 (73.7%) had at least one follow-up co-test., Conclusion: Use of specimens from the biorepository will elucidate molecular mechanisms underlying HPV carcinogenesis and inform more effective screening and follow-up strategies., (Copyright © 2021. Published by Elsevier B.V.)

Competing Interests: Financial Disclosure Philip E. Castle has received HPV tests and assays for research at reduced or no cost from Roche, Cepheid, Becton Dickinson, and Arbor Vita Corporation. The other authors did not report any potential conflicts of interest.

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., Competing Interests: Declaration of Competing Interest None., (Copyright © 2021. Published by Elsevier Inc.)

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., (© The Author(s) 2020. Published by Oxford University Press.)

Many countries are transitioning to HPV testing for cervical cancer screening, despite a lack of long-term experience. To anticipate multi-round screening performance, we analyzed 15-year HPV testing results at Kaiser Permanente Northern California (KPNC). We evaluated HPV test result patterns among women aged 30-64 undergoing triennial HPV/cytology cotesting at KPNC during 2003-2018. We calculated incidence rates and proportion of CIN3+ diagnoses associated with the most frequent HPV testing patterns overall and stratified by age. From 2003 to 2018, a total of 1,361,581 women had a valid HPV test result, and 7,087 were diagnosed with CIN3+. Incidence rates of CIN3+ after HPV positivity were lowest when HPV detection was new and highest in women with prevalent infections (770 vs. 13,910/100,000 person-years). Repeat test negativity reduced subsequent incidence rates of CIN3+ to extremely low levels (18/100,000 person-years following four consecutive negative results). For mixed patterns of positivity/negativity, the recency and frequency of positive tests were associated with increased rates of CIN3+ diagnosis. Most CIN3+ cases (76%) were diagnosed in women who were positive at baseline (the first known positive HPV result); 16% were attributed to apparent newly detected infections and 3% to possible reappearing infections. These results corroborate previous findings that current HPV positivity, particularly when prevalent rather than new, is associated with the highest rates of CIN3+. In a screening program implementing HPV testing, most CIN3+ is detected at the first HPV positive test., (© 2020 UICC.)

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., Competing Interests: The following disclosure statements were reported: Dr. Demarco, Dr. Gage, Dr. Schiffman, and Dr. Wentzensen report that the NCI has received masked HPV and cytology test results at no cost from Roche Molecular Systems, BD Diagnostics, and Qiagen for independent evaluations of these technologies. Dr. Raine-Bennett reports other contracts from National Cancer Institute, during the conduct of the study. Dr. Campos reports other salary support from 10.13039/100000054National Cancer Institute, during the conduct of the study, and personal fees from Basic Health International, outside the submitted work. Dr. Coutlee reports grants from Réseau FRSQ SIDA-MI, during the conduct of the study. Dr. Burk reports grants from NIH, during the conduct of the study. Dr. Castle reports discounted or free HPV tests and assays for research from Roche, Becton Dickinson, Cepheid, and Arbor Vita Corporation. Dr. Hyun, Dr. Carter-Pokras, Dr. Cheung, Dr. Chen, Dr. Hammer, Dr. Kinney, Dr. Befano, Dr. Perkins, Dr. He, Dr. Dallal, Dr. Chen, Dr. Poitras, Dr. Lorey, and Dr. Mayrand have nothing to disclose., (© 2020 Published by Elsevier Ltd.)

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.

Importance: As cervical cancer screening transitions from Papanicolaou cytologic screening to primary human papillomavirus (HPV) testing worldwide, effective triage tests are needed to decide who among the HPV-positive women should receive further diagnostic evaluation to avoid unnecessary colposcopies and biopsies., Objective: To evaluate the performance of the p16/Ki-67 dual stain (DS) and HPV16/18 genotyping for the triage of HPV-positive women., Design, Setting, and Participants: A prospective observational study was conducted within the cervical cancer screening program at Kaiser Permanente Northern California of 3225 HPV-positive women undergoing HPV and Papanicolaou cytologic testing with a valid DS result from September 16 to October 31, 2015, with follow-up through December 31, 2018., Exposures: Human papillomavirus screening with partial genotyping and cytologic triage compared with DS triage., Main Outcomes and Measures: Cervical intraepithelial neoplasia grade 3 or more severe (CIN3+) and grade 2 or more severe (CIN2+), diagnosed within 3 years after sample collection., Results: A total of 3225 women (mean [SD] age, 37.9 [11.3] years) participated in the study. For triage of HPV-positive women with partial genotyping, DS showed better risk stratification for CIN3+ than did Papanicolaou cytologic testing, with women with positive DS results having a higher risk than women with positive Papanicolaou test results for CIN3+ (218 of 1818 [12.0%; 95% CI, 10.5%-13.5%] vs 219 of 2128 [10.3%; 95% CI, 9.0%-11.6%]; P = .005). Similarly, DS showed better risk stratification for CIN3+ compared with Papanicolaou cytologic testing in HPV-positive women, irrespective of genotyping. The greatest reassurance against CIN3+ was observed in HPV16/18-negative women with negative DS results, with a risk low enough to extend retesting intervals. Dual stain triage strategies required substantially fewer colposcopies per detection of CIN3+ compared with Papanicolaou cytologic testing, with a 32.1% (859 of 2677) reduction of colposcopies compared with the currently recommended triage strategy of HPV screening with Papanicolaou cytologic testing. Results for CIN2+ were very similar., Conclusions and Relevance: Triage of HPV-positive women with DS was superior to Papanicolaou cytologic testing in this study, demonstrating equal immediate detection of precancerous lesions and substantially reduced referral to colposcopy. These findings suggest that DS can safely replace Papanicolaou cytologic testing as a triage strategy for primary HPV screening, and that retesting intervals in HPV16/18-negative women with negative DS results can be safely extended to 3 years.

Importance: As cervical cancer screening transitions to primary human papillomavirus (HPV) testing, effective triage and management of HPV-positive women is critical to avoid unnecessary colposcopy referral and associated harms while maintaining high sensitivity for cervical precancer. Triage with p16/Ki-67 dual-stain (DS) testing has shown high sensitivity and specificity for detection of cervical precancers; however, longitudinal studies are needed to determine the long-term risk of precancer following a negative DS result., Objective: To evaluate the longitudinal performance of p16/Ki-67 DS triage for detection of cervical precancer in HPV-positive women over 5 years of follow-up in the context of clinical management thresholds., Design, Setting, and Participants: Prospective cohort study of HPV-positive women 30 years or older undergoing routine cervical cancer screening in 2012 with HPV and Papanicolaou (hereinafter "cytology") co-testing within the Kaiser Permanente Northern California health care system. Follow-up of medical records was conducted through 2017., Exposures: All p16/Ki-67 DS testing was performed on residual SurePath material, and slides were evaluated for p16/Ki-67 positivity., Main Outcomes and Measures: Histological end points were ascertained from the clinical database through 2017. We estimated 5-year cumulative risks of cervical intraepithelial neoplasia grades of 2 or worse (≥CIN2) or grades 3 or worse (≥CIN3) by baseline DS and cytology at yearly intervals using Logistic Weibull models. Risks were compared with clinical management thresholds for colposcopy referral and a 1-year return interval., Results: Among the 1549 HPV-positive women in this study, the mean age at enrollment was 42.2 years, and the median follow-up time was 3.7 years (range, 0.2-5.4 years). Positive DS results were associated with significantly higher cumulative 5-year risks of ≥CIN2 compared with abnormal cytology (31.0%; 95% CI, 27.2%-35.3% vs 25.0%; 95% CI, 21.7%-28.7%; P = .03). Women with DS-negative findings had significantly lower 5-year risks of ≥CIN2 compared with women with normal cytology (8.5%; 95% CI, 6.5%-11.1% vs 12.3%; 95% CI, 9.8%-15.4%; P = .04). In DS-negative women, the risks of both ≥CIN2 and ≥CIN3 remained below the colposcopy referral threshold for all 5 years, crossing the 1-year return threshold at 3 years., Conclusions and Relevance: Triage with p16/Ki-67 DS provides better long-term risk stratification than cytology over 5 years. The low risk of cervical precancer in p16/Ki-67 DS-negative women permits safe extension of follow-up intervals for 3 years.

Purpose: Human papillomavirus (HPV) DNA methylation testing is a promising triage option for women testing HPV positive during cervical cancer screening. However, the extent to which methylation indicates precancer for all 12 carcinogenic HPV types has not been evaluated. Experimental Design: In this nested case-control study, we tested up to 30 cases of precancer [cervical intraepithelial neoplasia grade 3 (CIN3)/adenocarcinoma in situ (AIS)] and 30 normal controls for each carcinogenic type (single infections with 16/18/31/33/35/39/45/51/52/56/58/59). Next-generation bisulfite sequencing was performed on CpG sites within the L1 and L2 genes. We calculated differences in methylation, ORs, and AUC. Using a fixed sensitivity of 80%, we evaluated the specificity and the risk of CIN3/AIS for best performing CpG sites, and compared the performance of an explorative multi-type methylation assay with current triage strategies. Results: Methylation was positively associated with CIN3/AIS across all 12 types. AUCs for the top sites ranged from 0.71 (HPV51 and HPV56) to 0.86 (HPV18). A combined 12-type methylation assay had the highest Youden index (0.46), compared with cytology (0.31) and a 5-type methylation assay, including only previously described types (0.26). The 12-type methylation assay had higher sensitivity (80% vs. 76.6%) and lower test positivity compared with cytology (38.5% vs. 48.7%). The risk of CIN3/AIS was highest for methylation positives and lowest for cytology or HPV16/18 positives. Conclusions: HPV DNA methylation is a general phenomenon marking the transition from HPV infection to precancer for all 12 carcinogenic types. Development of a combined multitype methylation assay may serve as a triage test for HPV-positive women. Clin Cancer Res; 24(9); 2194-202. ©2018 AACR ., (©2018 American Association for Cancer Research.)

As cervical cancer screening shifts from cytology to human papillomavirus (HPV) testing, a major question is the clinical value of identifying individual HPV types. We aimed to validate Onclarity (Becton Dickinson Diagnostics, Sparks, MD), a nine-channel HPV test recently approved by the FDA, by assessing (i) the association of Onclarity types/channels with precancer/cancer; (ii) HPV type/channel agreement between the results of Onclarity and cobas (Roche Molecular Systems, Pleasanton, CA), another FDA-approved test; and (iii) Onclarity typing for all types/channels compared to typing results from a research assay (linear array [LA]; Roche). We compared Onclarity to histopathology, cobas, and LA. We tested a stratified random sample ( n = 9,701) of discarded routine clinical specimens that had tested positive by Hybrid Capture 2 (HC2; Qiagen, Germantown, MD). A subset had already been tested by cobas and LA ( n = 1,965). Cervical histopathology was ascertained from electronic health records. Hierarchical Onclarity channels showed a significant linear association with histological severity. Onclarity and cobas had excellent agreement on partial typing of HPV16, HPV18, and the other 12 types as a pool (sample-weighted kappa value of 0.83); cobas was slightly more sensitive for HPV18 and slightly less sensitive for the pooled high-risk types. Typing by Onclarity showed excellent agreement with types and groups of types identified by LA (kappa values from 0.80 for HPV39/68/35 to 0.97 for HPV16). Onclarity typing results corresponded well to histopathology and to an already validated HPV DNA test and could provide additional clinical typing if such discrimination is determined to be clinically desirable., (This is a work of the U.S. Government and is not subject to copyright protection in the United States. Foreign copyrights may apply.)

HPV testing is more sensitive than cytology for cervical screening. However, to incorporate HPV tests into screening, risk-stratification ("triage") of HPV-positive women is needed to avoid excessive colposcopy and overtreatment. We prospectively evaluated combinations of partial HPV typing (Onclarity, BD) and cytology triage, and explored whether management could be simplified, based on grouping combinations yielding similar 3-year or 18-month CIN3+ risks. We typed ∼9,000 archived specimens, taken at enrollment (2007-2011) into the NCI-Kaiser Permanente Northern California (KPNC) HPV Persistence and Progression (PaP) cohort. Stratified sampling, with reweighting in the statistical analysis, permitted risk estimation of HPV/cytology combinations for the 700,000+-woman KPNC screening population. Based on 3-year CIN3+ risks, Onclarity results could be combined into five groups (HPV16, else HPV18/45, else HPV31/33/58/52, else HPV51/35/39/68/56/66/68, else HPV negative); cytology results fell into three risk groups ("high-grade," ASC-US/LSIL, NILM). For the resultant 15 HPV group-cytology combinations, 3-year CIN3+ risks ranged 1,000-fold from 60.6% to 0.06%. To guide management, we compared the risks to established "benchmark" risk/management thresholds in this same population (e.g., LSIL predicted 3-year CIN3+ risk of 5.8% in the screening population, providing the benchmark for colposcopic referral). By benchmarking to 3-year risk thresholds (supplemented by 18-month estimates), the widely varying risk strata could be condensed into four action bands (very high risk of CIN3+ mandating consideration of cone biopsy if colposcopy did not find precancer; moderate risk justifying colposcopy; low risk managed by intensified follow-up to permit HPV "clearance"; and very low risk permitting routine screening.) Overall, the results support primary HPV testing, with management of HPV-positive women using partial HPV typing and cytology., (© 2016 UICC.)

Background: Two sets of diagnostic criteria of paediatric multiple organ dysfunction syndrome (MODS) were published by Proulx in 1996 and by Goldstein in 2005. We hypothesized that this changes the epidemiology of MODS. Thus, we determined the epidemiology of MODS, according to these two sets of diagnostic criteria, we studied the intra- and inter-observer reproducibility of each set of diagnostic criteria, and we compared the association between cases of MODS at paediatric intensive care unit (PICU) entry, as diagnosed by each set of diagnostic criteria, and 90-day all-cause mortality., Methods: All consecutive patients admitted to the tertiary care PICU of Sainte-Justine Hospital, from April 21, 2009 to April 20, 2010, were considered eligible for enrolment into this prospective observational cohort study. The exclusion criteria were gestational age < 40 weeks, age < 3 days or > 18 years at PICU entry, pregnancy, admission immediately after delivery. No patients were censored. Daily monitoring using medical chart ended when the patient died or was discharged from PICU. Mortality was monitored up to death, hospital discharge, or 90 days post PICU entry, whatever happened first. Concordance rate and kappa score were calculated to assess reproducibility. The number of MODS identified with Proulx and Goldstein definitions was compared using 2-by-2 contingency tables. Student's t test or Wilcoxon signed-ranked test was used to compare continuous variables with normal or abnormal distribution, respectively. We performed a Kaplan-Meier survival analysis to assess the association between MODS at PICU entry and 90-day mortality., Results: The occurrence of MODS was monitored daily and prospectively in 842 consecutive patients admitted to the PICU of Sainte-Justine Hospital over 1 year. According to Proulx and Goldstein diagnostic criteria, 180 (21.4 %) and 314 patients (37.3 %) had MODS over PICU stay, respectively. Concordance of MODS diagnosis over PICU stay was 81.3 % (95 % CI 78.6-83.9 %), and kappa score was 0.56 (95 % CI 0.50-0.61). Discordance was mainly attributable to cardiovascular or neurological dysfunction criteria. The proportion of patients with MODS at PICU entry who died within 90 days was higher with MODS diagnosed with Proulx criteria (17.8 vs. 11.5 %, p = 0.038), as well as the likelihood ratio of death (4.84 vs. 2.37). On the other hand, 90-day survival rate of patients without MODS at PICU entry was similar (98.6 vs. 98.9 % (p = 0.73)., Conclusions: Proulx and Goldstein diagnostic criteria of paediatric MODS are not equivalent. The epidemiology of paediatric MODS varies depending on which set of diagnostic criteria is applied.

Background: Human papillomavirus (HPV)-based cervical cancer screening requires triage markers to decide who should be referred to colposcopy. p16/Ki-67 dual stain cytology has been proposed as a biomarker for cervical precancers. We evaluated the dual stain in a large population of HPV-positive women., Methods: One thousand five hundred and nine HPV-positive women screened with HPV/cytology cotesting at Kaiser Permanente California were enrolled into a prospective observational study in 2012. Dual stain cytology was performed on residual Surepath material, and slides were evaluated for dual stain-positive cells. Disease endpoints were ascertained from the clinical database at KPNC. We evaluated the clinical performance of the assay among all HPV-positive women and among HPV-positive, cytology-negative women. We used internal benchmarks for clinical management to evaluate the clinical relevance of the dual stain assay. We evaluated sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of the dual stain compared with Pap cytology. All statistical tests were two-sided., Results: The dual stain had lower positivity (45.9%) compared with cytology at an ASC-US threshold (53.4%). For detection of CIN2+, the dual stain had similar sensitivity (83.4% vs 76.6%, P = .1), and statistically higher specificity (58.9% vs 49.6%, P < .001), PPV (21.0% vs 16.6%, P < .001), and NPV (96.4% vs 94.2%, P = .01) compared with cytology. Similar patterns were observed for CIN3+. Women with a positive test had high enough risk for referral to colposcopy, while the risk for women with negative tests was below a one-year return threshold based on current US management guidelines., Conclusion: Dual stain cytology showed good risk stratification for all HPV-positive women and for HPV-positive women with normal cytology. Additional follow-up is needed to determine how long dual stain negative women remain at low risk of precancer., (Published by Oxford University Press 2015. This work is written by (a) US Government employee(s) and is in the public domain in the US.)

Objective: Respiratory complications associated with RBC transfusions may be underestimated in PICUs because current definitions exclude patients with preexisting respiratory dysfunction. This study aims to determine the prevalence and characterize the risk factors and outcomes of new or progressive respiratory dysfunction observed after RBC transfusion in critically ill children., Design: Prospective cohort study of all children admitted over a 1-year period., Setting: A multidisciplinary PICU in a tertiary pediatric university hospital., Patients: Patients who received a RBC transfusion while in PICU., Interventions: None., Measurements and Main Results: Two independent adjudicators established the diagnosis of respiratory dysfunction. A respiratory dysfunction associated with transfusion was considered new if it appeared after the first RBC transfusion in PICU. A progressive respiratory dysfunction associated with transfusion was diagnosed if the respiratory dysfunction was present before the transfusion and the PaO2/FIO2 or the SpO2/FIO2 ratio dropped by at least 20% thereafter. Among 842 children admitted into the PICU, 136 received at least one RBC transfusion and were analyzed. Fifty-eight cases of respiratory dysfunction associated with transfusion (43% of transfused patients) were detected, including nine new respiratory dysfunction associated with transfusion (7%) and 49 progressive respiratory dysfunction associated with transfusion (36%). Higher severity of illness, multiple organ dysfunction syndrome prior to transfusion, and volume (mL/kg) of RBC transfusion were independently associated with respiratory dysfunction associated with transfusion. A dose-response relationship was observed between transfusion volume (mL/kg) and the prevalence of respiratory dysfunction associated with transfusion. Patients with respiratory dysfunction associated with transfusion had more progressive multiple organ dysfunction and less ventilation-free and PICU-free days at day 28., Conclusions: Development of respiratory dysfunction associated with transfusion is frequent in PICU and occurs mainly in patients with prior respiratory dysfunction, who would not be identified using current definitions for transfusion-associated complications. A cause-effect relationship cannot be confirmed. However, the high prevalence and the serious adverse outcomes associated with respiratory dysfunction associated with transfusion suggest that this complication should be further studied.

Background: Dual-stain cytology for p16 and Ki-67 has been proposed as a biomarker in cervical cancer screening. The authors evaluated the reproducibility and accuracy of dual-stain cytology among 10 newly trained evaluators., Methods: In total, 480 p16/Ki-67-stained slides from human papillomavirus-positive women were evaluated in masked fashion by 10 evaluators. None of the evaluators had previous experience with p16 or p16/Ki-67 cytology. All participants underwent p16/Ki-67 training and subsequent proficiency testing. Reproducibility of dual-stain cytology was measured using the percentage agreement, individual and aggregate κ values, as well as McNemar statistics. Clinical performance for the detection of cervical intraepithelial neoplasia grade 2 or greater (CIN2+) was evaluated for each individual evaluator and for all evaluators combined compared with the reference evaluation by a cytotechnologist who had extensive experience with dual-stain cytology., Results: The percentage agreement of individual evaluators with the reference evaluation ranged from 83% to 91%, and the κ values ranged from 0.65 to 0.81. The combined κ value was 0.71 for all evaluators and 0.73 for cytotechnologists. The average sensitivity and specificity for the detection of CIN2+ among novice evaluators was 82% and 64%, respectively; whereas the reference evaluation had 84% sensitivity and 63% specificity, respectively. Agreement on dual-stain positivity increased with greater numbers of p16/Ki-67-positive cells on the slides., Conclusions: Good to excellent reproducibility of p16/Ki-67 dual-stain cytology was observed with almost identical clinical performance of novice evaluators compared with reference evaluations. The current findings suggest that p16/Ki-67 dual-stain evaluation can be implemented in routine cytology practice with limited training., (© 2014 American Cancer Society.)

Objective: Kaiser Permanente Northern California (KPNC) introduced 3-year Pap and human papillomavirus DNA cotesting for cervical cancer screening in women 30 years or older in 2003 to 2004. Patient and provider willingness to extend screening intervals and the impact on annual cervical cancer incidence after interval extension are evaluated., Materials and Methods: Age-adjusted cervical cancer rates and screening intervals were calculated from KPNC Regional Laboratory databases and Northern California Cancer Registry from 2000 to 2009., Results: The median screening interval between negative cotests was 36 months compared to the 16 months after a negative Pap test alone before the implementation of cotesting. The age-adjusted invasive cancer rate was 6.5 per 100,000 women in 2000 and 6.3 in 2009; there was no difference in the rates of cervical cancer in women 30 years or older from 2000 to 2009 (p(trend) = .7)., Conclusions: Patients and providers were compliant with the extension of screening intervals with cotesting. Cervical cancer rates remained constant during the 10-year study period despite extending screening intervals after a negative cotest.

Objective: This study aimed to characterize the 24-month risk of cervical intraepithelial neoplasia grade 2 or worse (CIN 2+) and grade 3 or worse (CIN 3+) in women with low-risk cytological finding and CIN 1 on endocervical curettage (ECC)., Materials and Methods: Cervical screening tests and cervical biopsy results from Kaiser Permanente Northern California were reviewed for years 2004 to 2008. Women with index cytological result of atypical squamous cells of undetermined significance or low-grade squamous intraepithelial lesion who underwent excisional procedure within 24 months of CIN 1 diagnosis were grouped by ECC status. A third cohort comprised women with ECC-CIN 1 followed up without excisional procedure. The 24-month cumulative incidence of CIN 2+ and CIN 3+ was calculated for each cohort., Results: Excisional procedures were performed in 224 women; 54 had ECC-CIN 1 with ectocervical biopsy CIN 1 or less, and 170 had ectocervical CIN 1 with negative ECC finding. The 24-month risk of CIN 2+ was lower in the ECC-CIN 1 cohort compared with the ECC-negative (ectocervical CIN 1) cohort (24.1 vs 44.7%, p = .018) and nonsignificantly lower for CIN 3+ (7.4% vs 14.1%, p = .23). Among 203 women with ECC-CIN 1 followed up without excisional procedure but with follow-up ECC at a median of 21.7 months from index ECC, CIN 2 was found in 21 (10.3%, 95% CI = 6.7%-15.6%), and CIN 3 was found in 3 (1.5%, 95% CI = 0.4%-4.6%)., Conclusions: A diagnosis of CIN 1 on ECC preceded by atypical squamous cells of undetermined significance or low-grade squamous intraepithelial lesion does not increase the risk of CIN 2+ compared with women with ectocervical CIN 1 and negative ECC. The risk of CIN 2+ in women followed up without excisional procedure is sufficiently low that it is reasonable to offer conservative management similar to that for ectocervical CIN 1.

Objective: To characterize the antecedent screening of women 65 years of age and older diagnosed with cervical cancer., Methods: Screening histories of women 65 years of age and older who were diagnosed with cervical cancer between 2003 and 2008 were examined utilizing the organization's databases and the regional Cancer Registry. Stopping screening was recommended at age 65 for members who had either 3 consecutive negative Paps or a single negative Pap plus HPV test ("cotest")., Results: From 2003 through 2008 there were 56 Kaiser Permanente Northern California members 65 years of age and older diagnosed with cervical cancer. During the same time period there were 1,323,100 woman-years of membership in women age 65 and older. The risk of invasive cancer among women age 65 and older was 4.2/100,000/year in 2003-2008. 33 of 56 (59%) had one or more Pap smears prior to diagnosis. Of the 33, 14 women (25%) had 3 consecutive negative Pap smears prior to diagnosis. Three of 46,401 women with 1 or more negative cotests at age 65 and older were subsequently diagnosed with invasive cancer during 132,639 women-years of follow-up (2.3/100,000/year)., Conclusions: Most cervical cancers diagnosed at age 65 and older occur in women who have not met our criteria for stopping screening. A few cancers will continue to occur at age 65 and older despite multiple negative tests, as is true in other age groups. We currently have no evidence that these cancers would be prevented with continued screening at ages 65 and older., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Background: The human papillomavirus (HPV) Persistence and Progression Cohort is a natural history study of carcinogenic HPV positive women. Here, we present the HPV genotypes found in first ∼500 cases of cervical intraepithelial neoplasia grade 3 (CIN3) or more severe disease (CIN3+) diagnosed at the study baseline., Methods: Women aged 30 and older were screened for cervical cancer using Pap smears and tested for carcinogenic HPV using Hybrid Capture 2 (HC2; Qiagen). We randomly selected women who tested HPV positive and were diagnosed with CIN3+ (n = 448) or without CIN3+ (

Objective: To explore the effect of screening history on the risk of cervical precancer and cancer after an human papillomavirus (HPV)-positive test., Methods: A large health maintenance organization introduced cytology and HPV cotesting into routine clinical practice in 2003. We selected women aged 30 and older who tested HPV positive, cytology negative between January 2006 and December 2008 who had any clinical follow-up documented before January 2010 (n=26,799). The 1-year and 4-year cumulative incidence rates and rate ratios for cervical intraepithelial neoplasia grade 2 or higher (CIN 2+) with 95% confidence intervals (95% CIs) were calculated as estimates of absolute risk and relative risk, respectively. Results were stratified on immediate past HPV test and Pap results., Results: Without consideration of past screening round, the 1-year and 4-year cumulative incidence rates for CIN 2+ after an HPV-positive, Pap-negative result were 2.83 (95% CI 2.55-3.12) and 7.89 (95% CI 7.00-8.78). However, risks varied substantially by past screening result. For example, the 4-year risk of CIN2+ was greater for women who had a past HPV-positive, Pap-negative result (cumulative incidence rate=11.79, 95% CI 10.22-13.36) compared with those who had HPV-negative, Pap-negative result (cumulative incidence rate=4.56, 95% CI 3.43-5.69; cumulative incidence rate ratio=2.59, 95% CI 2.30-2.87)., Conclusion: Because cervical precancer is associated with persistent HPV infection, the risk associated with an HPV-positive test can vary significantly depending on the immediate past screening round. Optimizing screening programs will require knowledge of screening history.

Objective: To characterize the 6- and 18-month cumulative risk of cervical intraepithelial neoplasia grade 2 or worse (CIN 2+) and grade 3 or worse (CIN 3+) in women aged 30 years and older after a low-grade squamous intraepithelial lesion (LSIL) cytology and high-risk human papillomavirus (HPV)-negative screening result in routine clinical practice., Materials and Methods: Comprehensive quality assurance databases of screening test and biopsy results from the Regional Laboratory of the Kaiser Permanente Northern California Health Plan were reviewed. All women aged 30 years and older with LSIL cytology were sorted by high-risk HPV status. Associated biopsy results were tabulated, and the corresponding risks of CIN 2+ and CIN 3+ diagnosed within 18 months after LSIL cytology were calculated overall and by decade of age., Results: During the 6-year period, from 2003 to 2008, 4,113 LSIL cases were interpreted in women aged 30 years and older for which corresponding high-risk HPV and biopsy results were available. The proportion of women with LSIL testing positive for HPV declined with age, from 89% in the group aged 30 to 39 years to 76% in women older than 50 years (p < .001). Of 622 women with HPV-negative LSIL cytology, there was no case of cancer detected at colposcopy occurring within 6 months of the screening test. The 18-month risks of CIN 2+ and CIN 3+ were 3.5% and 1.4%, respectively., Conclusions: The risk of CIN 3+ is sufficiently low in women aged 30 years and older with high-risk HPV-negative LSIL that 1 year follow-up rather than immediate colposcopy should be considered when it occurs in routine clinical practice.