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To determine the prevalence of underlying high-intermediate (high-IM) and high-risk endometrial cancer (EC) in patients with preoperative diagnosis of Endometrial intraepithelial neoplasia (EIN) and to assess the impact of the information retrieved from the sentinel lymph node (SLN) on adjuvant therapy.Retrospective cohort study of women undergoing hysterectomy, optional bilateral salpingo-oophorectomy (BSO) and lymph nodes assessment for EIN between December 2007 and August 2021.One hundred and sixty two (162) eligible patients were included, of whom 101 (62.3%) had a final diagnosis of EIN, while 61 (37.7%) were ultimately diagnosed with carcinoma. Out of 15 patients with high-IM to high-risk disease (9.25% of all EIN), 12 had grade 2-3 EC including 8 with50% myometrial invasion, 2 with serous subtype, 1 with cervical invasion and 2 with pelvic lymph nodes involvement. Of the 3 patients with grade 1 EC, one patient had disease involving the adnexa and 2 patients had tumor invading50% of the myometrium and with lymphovascular space invasion (LVSI). Ten patients received vaginal brachytherapy after surgery, 3 patients with extrauterine spread were treated with systemic chemotherapy followed by vaginal brachytherapy and pelvic external-beam radiotherapy and 2 patients with early-stage serous carcinoma received chemotherapy followed by vaginal brachytherapy.Information from SLN, even when negative, can be helpful in the management of patients with EC after preoperative EIN, as some patients are found to have high-IM to high-risk disease on final pathology. These patients would require either re-staging surgery or adjuvant external beam radiotherapy, both could be avoided by proper staging.

Gene expression values

Differential expression results

Supplementary Figure 1: Log-transformed Quantile-Quantile plots of the Univariate Survival Analysis p-values. P-values derived from the univariate survival analysis of the effects of each individual gene was plotted for each fold in which the analysis took place. The horizontal line at 2.52 represents -log(0.003), which was the cutoff for variable selection in the final modeling of survival in the test cohort. Supplementary Figure 2: Abridged representation of the FOXM1 regulatory network. See references [2-5]

Mutation list

Patient characteristics

Mutation list

Summary Background The quadrivalent human papillomavirus (HPV) vaccine was shown to prevent infections and lesions related to HPV6, 11, 16, and 18 in a randomised, placebo-controlled study in men aged 16–26 years. We assessed the incidences of external genital warts related to HPV6 or 11, and external genital lesions and anal dysplasia related to HPV6, 11, 16, or 18, over 10 years of follow-up. Methods The 3-year base study was an international, multicentre, double-blind, randomised, placebo-controlled trial done at 71 sites in 18 countries. Eligible participants were heterosexual men (aged 16–23 years) or men who have sex with men (MSM; aged 16–26 years). Men who had clinically detectable anogenital warts or genital lesions at screening that were suggestive of infection with non-HPV sexually transmitted diseases, or who had a history of such findings, were excluded. Eligible participants were randomly assigned (1:1) to receive three doses of either quadrivalent HPV vaccine or placebo on day 1, month 2, and month 6, administered as a 0·5-mL injection into the deltoid muscle. The 7-year, open-label, long-term follow-up extension study was done at 46 centres in 16 countries. Participants who received one or more doses of the quadrivalent HPV vaccine in the base study were eligible for enrolment into the long-term follow-up study (early vaccination group). Placebo recipients were offered the three-dose quadrivalent HPV vaccine at the end of the base study; those who received one or more quadrivalent HPV vaccine doses were eligible for enrolment into the long-term follow-up study (catch-up vaccination group). The primary efficacy endpoints were the incidence of external genital warts related to HPV6 or 11 and the incidence of external genital lesions related to HPV6, 11, 16, or 18 in all participants and the incidence of anal intraepithelial neoplasia (including anal warts and flat lesions) or anal cancer related to HPV6, 11, 16, or 18 in MSM only. The primary efficacy analysis was done in the per-protocol population for the early vaccination group, which included participants who received all three vaccine doses, were seronegative at day 1 and PCR-negative from day 1 through month 7 of the base study for the HPV type being analysed, had no protocol violations that could affect evaluation of vaccine efficacy, and had attended at least one visit during the long-term follow-up study. For the catch-up vaccination group, efficacy was assessed in the modified intention-to-treat population, which included participants who had received at least one vaccine dose, were seronegative and PCR-negative for HPV types analysed from day 1 of the base study to the final follow-up visit before receiving the quadrivalent HPV vaccine, and had at least one long-term follow-up visit. Safety was assessed in all randomised participants who received at least one vaccine dose. This study is registered with ClinicalTrials.gov , NCT00090285 . Findings Between Aug 10, 2010, and April 3, 2017, 1803 participants were enrolled in the long-term follow-up study, of whom 936 (827 heterosexual men and 109 MSM) were included in the early vaccination group and 867 (739 heterosexual men and 128 MSM) were included in the catch-up vaccination group. Participants in the early vaccination group were followed up for a median of 9·5 years (range 0·1–11·5) after receiving the third dose of the quadrivalent HPV vaccine, and participants in the catch-up vaccination group were followed up for a median of 4·7 years (0·0–6·6) after receiving the third dose. In early vaccine group participants during long-term follow-up compared with the placebo group in the base study, the incidence per 10 000 person-years of external genital warts related to HPV6 or 11 was 0·0 (95% CI 0·0–8·7) versus 137·3 (83·9–212·1), of external genital lesions related to HPV6, 11, 16, or 18 was 0·0 (0·0–7·7) versus 140·4 (89·0–210·7), and of anal intraepithelial neoplasia or anal cancer related to HPV6, 11, 16, or 18 in MSM only was 20·5 (0·5–114·4) versus 906·2 (553·5–1399·5). Compared with during the base study (ie, before quadrivalent HPV vaccine administration), during the long-term follow-up period, participants in the catch-up vaccination group had no new reported cases of external genital warts related to HPV6 or 11 (149·6 cases per 10 000 person-years [95% CI 101·6–212·3] vs 0 cases per 10 000 person-years [0·0–13·5]) or external genital lesions related to HPV6, 11, 16, or 18 (155·1 cases per 10 000 person-years [108·0–215·7] vs 0 cases per 10 000 person-years [0·0–10·2]), and a lower incidence of anal intraepithelial neoplasia or anal cancer related to HPV6, 11, 16, or 18 (886·0 cases per 10 000 person-years [583·9–1289·1] vs 101·3 cases per 10 000 person-years [32·9–236·3]). No vaccine-related serious adverse events were reported. Interpretation The quadrivalent HPV vaccine provides durable protection against anogenital disease related to HPV6, 11, 16, and 18. The results support quadrivalent HPV vaccination in men, including catch-up vaccination. Funding Merck Sharp & Dohme.

Background: High-risk human papillomavirus (HR-HPV) testing has become a preferred cervical cancer screening strategy in some countries due to its superior sensitivity over cytology-based methods for identifying cervical intraepithelial neoplasia of grade 2 or worse (CIN2+). Improved sensitivity has been accompanied by reductions in specificity and concerns regarding overscreening and overtreatment of women with transient or nonprogressing HR-HPV infections. Triage of HR-HPV+ women to colposcopy is, thus, warranted for appropriate management and treatment.Methods: Using data from the Canadian Cervical Cancer Screening Trial (CCCaST), we compared the performance of cytology and HR-HPV strategies to detect CIN2+ among HR-HPV+ women (age, 30–69 years). Colposcopy referral rates and performance gains from adding other HR-HPV genotypes to HPV16/18+ triage were also evaluated.Results: A strategy referring all women HPV16/18+ and HPV16/18−, but with atypical squamous cells of undetermined significance or worse cytology (ASC-US+) had the highest sensitivity [82.5%; 95% confidence interval (CI), 70.9%–91.0%] but yielded the highest colposcopy referral rate. HPV16/18+ triage was the next most sensitive strategy (64.1%; 95% CI, 51.1%–75.7%). Low-grade squamous intraepithelial lesion or worse cytology (LSIL+) triage yielded a low sensitivity (32.8%; 95% CI, 21.9%–45.4%) but had the most favorable specificity (93.6%; 95% CI, 91.0%–95.6%), positive predictive value (41.5%; 95% CI, 28.1%–55.9%), and colposcopy referral rate of strategies examined. HPV viral load triage strategies did not perform optimally overall. Inclusion of HR-HPV genotypes 31 and 52 to HPV16/18+ triage provided the highest sensitivities.Conclusion: Concerns surrounding HPV-based screening can be effectively mitigated via triage.Impact: Balancing the benefits of HPV-based primary cervical screening with informed management recommendations for HR-HPV+ women may decide the success of its widening utilization. Cancer Epidemiol Biomarkers Prev; 26(6); 923–9. ©2017 AACR.

Supplemental Table 1. Performance of Triage Strategies for the Detection of CIN3+ Among HR-HPV+ Women. Supplemental Table 2. Performance of Additional Triage Strategies for the Detection of CIN2+ Among HR-HPV+ Women.

Sporadic somatic inactivation of genes such as PTEN within histologically normal endometrium (latent precancers) is an early step in endometrial carcinogenesis. We have used clone-specific mutations of PTEN to determine the fate of latent precancers over time in women who do (high risk) and do not (low risk) develop endometrial neoplasia. PTEN immunohistochemistry was performed on 45 occurrences of endometrial neoplasia and their paired antecedent benign biopsies, along with age matched sample pairs from 167 patients who did not develop a neoplasm. When PTEN-deficient cells were present at both time points, DNA sequencing was performed to determine whether they were single or multiple independent events. Loss of PTEN protein in isolated glands was common in the initial normal biopsies of high- and low-risk groups (42% and 27%, respectively, P = 0.066). Protein-deficient glands have a tendency to disappear over time in low-risk women (P = 0.047) and, even when “persistent,” are infrequently (19%, 3/16) confirmed to be the same clone. Similarly, only a small proportion (6.7%, 1/15) of latent precancers seen in high-risk women are the direct progenitors of subsequent neoplasia. There is a high rate of latent precancer turnover in both low- and high-risk patients, with rare long-term persistence of unique clones, which may or may not progress to a histologic lesion. The temporal dynamics of clonal emergence, persistence, and involution are sufficiently complex that in the individual patient, the presence of a latent precancer has an unknown contribution to long-term cancer risk. Cancer Res; 74(10); 2796–802. ©2014 AACR.

PDF file - 14KB, Supplementary Table 1. Mutation List for Pairmax paired protein null samples n = 31.

A demonstration project of primary human papillomavirus (HPV) testing was initiated in 2011 among more than 23,000 women attending routine cervical cancer screening. We examined the additional diagnostic performance of HPV genotyping for detecting disease in women with abnormal cytology.Women aged 30 to 65 years were originally screened for HPV using Hybrid Capture II test. Women with positive results were triaged using conventional cytology, and those with atypical squamous cells of undetermined significance or worse (≥ASC-US) were referred to colposcopy. We retrospectively genotyped (Roche cobas 4800 HPV system [Roche Molecular Systems Inc, Pleasanton, CA]) cervical specimens that were HPV + with Hybrid Capture II test and extracted women's medical history postbaseline screening. We calculated positive predictive values (PPVs) and 95% confidence intervals (CIs) of triage tests to detect histologically confirmed cervical intraepithelial neoplasia of grade 2 or worse (CIN2 + ) within the first year of follow-up among women positive for HPV16, HPV18, and HPV16 and/or HPV18 as well as among those negative for HPVs 16 and 18.Of 1,396 HPV-positive women, 1,092 (78%) were classified as normal, 136 (10%) had CIN1, 80 (6%) had CIN2, 81 (6%) had CIN3, and 7 women had cancer throughout the entire follow-up period. Seventy CIN2 + cases were detected within the first year of follow-up. The PPV for detecting CIN2 + was 20.9% (63/239; 95% CI = 16.4-25.9) for ASC-US + cytology. In women with ASC-US + , PPVs were 31.2% (24/77; 95% CI = 21.1-42.7) for HPV16 + , 27.8% (5/18; 95% CI = 9.7-53.5) for HPV18 + , 30.8% (28/91; 95% CI = 21.5-41.3) for HPV16 + and/or HPV18 + women, and 16.6% (35/211; 95% CI = 11.8-22.3) in women testing negative for HPVs 16 and 18.Partial genotyping as an additional triage strategy to cytology can markedly improve clinical diagnostic performance.

The Lower Anogenital Squamous Terminology (LAST) Project recommends the use of p16 immunohistochemistry as an adjunct to morphologic assessment of cervical biopsies according to a specific set of criteria. We analyzed the effect of adjunctive p16 according to LAST criteria in a US-based diagnostic utility study involving 70 surgical pathologists providing a total of 38,500 reads on cervical biopsies. Compared with the results obtained using hematoxylin and eosin-stained slides only, including p16-stained slides per LAST criteria increased sensitivity and specificity for diagnosing histologic high-grade squamous intraepithelial lesions across all cases by 8.1% (95% confidence interval [95% CI], 6.5-9.7; P

Objectives To evaluate the efficacy of a carrageenan-based lubricant gel in reducing the risk of genital human papillomavirus (HPV) infections in women. Methods We conducted a planned interim analysis of a randomized, double-blind, placebo-controlled, phase 2B trial. Women aged 18 years and older were randomly assigned (1:1) to a carrageenan-based gel or a placebo gel to be self-applied every other day for the first month and before and after each intercourse during follow-up. Assessments were performed at 0.5, 1, 3, 6, 9 and 12 months. The primary outcome was incidence of a new infection by an HPV type that was not present at baseline. Intention-to-treat analyses were performed. Results Between January 2013 and June 2017, a total of 280 participants were randomly assigned to the carrageenan (n = 141) or the placebo (n = 139) arm. All participants were included in safety analyses, but three (1%) were excluded from efficacy analyses (HPV results unavailable for two participants in the carrageenan and one participant in the placebo arm). The median follow-up time was 9.2 months (interquartile range, 1.9–13.2 months). A total of 59 (42%) of 139 participants in the carrageenan arm and 78 (57%) of 138 participants in the placebo arm became infected by at least one new HPV type (hazard ratio = 0.64, 95% confidence interval = 0.45–0.89, p 0.009). A total of 62 (44%) of 141 participants in the carrageenan arm versus 43 (31%) of 139 participants in the placebo arm reported an adverse event (p 0.02), none of which was deemed related to the gels. Conclusions Our trial's interim analysis suggests that using a carrageenan-based lubricant gel can reduce the risk of genital HPV infections in women.

Objective To evaluate if the prognostic value of lymphovascular space invasion (LVSI) is different in endometrial cancer patients with negative lymph nodes following sentinel lymph node (SLN) mapping or lymph node dissection (LND) as staging procedure. Material and methods A retrospective study of 510 patients diagnosed with endometrial carcinoma in our institution between 2007 and 2014. We excluded patients that were diagnosed with positive nodes (Stage IIIc). We compared patients' characteristics and survival outcomes as function of their LVSI status (positive LVSI vs negative LVSI subgroups) in each cohort separately. Results 413 patients met the inclusion criteria, out of whom 239 underwent SLN and 174 patients underwent LND only. In the SLN group, life table analysis showed 5-year OS and PFS of 80% and 72% in patients with LVSI compared to 96%, and 93% without LVSI. Same trend was observed among patients with LND with 5-year OS and PFS of 74% and 64% in patients with LVSI compared to 97%, and 90% without LVSI. On multivariable analysis, adjusted for age, FIGO stage, grade and maximal tumor size, the favorable survival of negative LVSI remained only in the LND cohort (SLN cohort: HR 1.2, CI [0.3–4.0], P = 0.8 and HR 1.7, CI [0.7–4.3], p = 0.2 for OS and PFS, respectively; LND cohort: HR 3.1, CI [1.4–6.5], p Conclusions The prognostic value of LVSI disappears when patients undergo staging with SLN and are found to have negative nodes in contrast to those who have undergone LND. Future studies should confirm our observation on patients with negative sentinel nodes, and plan on tailoring adjuvant treatment to this specific subgroup.

The diagnosis of squamous intraepithelial lesions in cervical tissue specimens is subject to substantial variability. Adjunctive immunohistochemical (IHC) staining for p16 has been shown to add objective biomarker information to morphologic interpretation of hematoxylin and eosin (HE)-stained tissues. In the CERvical Tissue AdjunctIve aNalysis (CERTAIN) study, we systematically analyzed the impact of adjunctive p16 IHC on the accuracy (agreement with reference pathology results) of diagnosing cervical intraepithelial neoplasia of grade 2 or worse (CIN2+) in the United States. Eleven hundred cervical biopsies were divided into 4 sets of 275 cases by stratified randomization. All HE slides from each set were interpreted by 17 to 18 individual surgical pathologists, for a total of 19,250 reads by 70 surgical pathologists. After a wash-out period and blinding to original results, cases were re-read by the same pathologists using HE+p16-stained slides. Using expert consensus diagnoses on HE+p16 as reference, adjunctive p16 IHC use significantly improved diagnostic agreement of surgical pathologists by 4.7% (95% confidence interval [CI], 3.9, 5.4; P0.0001). This improvement was driven by an increase of 11.5% (95% CI, 9.3, 13.5; P0.0001) in sensitivity and an increase of 3.0% (95% CI, 2.2, 3.7; P0.0001) in specificity. Diagnostic performance was significantly increased as well when expert consensus diagnoses established on HE only was used as reference. Furthermore, interobserver reliability improved significantly from moderate (HE: κ=0.58) to substantial (HE+p16: κ=0.73; P0.0001). Adjunctive use of p16 IHC provides more accurate and reproducible diagnostic results in the interpretation of cervical biopsies, ensuring that more patients are treated correctly without treating more patients.

Objective: Evaluation of the impact of lower uterine segment involvement (LUSI) in type II endometrial cancer, and mutational profile of uterine papillary serous carcinomas (UPSC). Methods: Retrospective cohort study comparing patients with type II endometrial cancer with LUSI to patients without LUSI. Genes commonly implicated in carcinogenesis were analyzed in a subgroup of 42 patients with UPSC using next generation sequencing. Results: 83 patients with type II endometrial cancer were included in the study, of these, LUSI was diagnosed in 31.3%. During a median follow-up of 45.5 months, patients with LUSI developed more local and distant recurrences (local: 19.2% vs. 3.5%, P = .03; distant: 50% vs. 17.5%, P = .004) and progression events (73.1% vs. 26.3%, P

Background Sentinel lymph node (SLN) mapping has emerged as a promising solution to the ongoing debate regarding lymphadenectomy in the initial surgical management of endometrial cancer. Currently, little is known about its possible impact on location of disease recurrence compared to systematic lymphadenectomy. Methods In this retrospective study, 472 consecutive patients with endometrial cancer who underwent either SLN mapping (SLN cohort, n =275) or systematic lymphadenectomy (LND cohort, n =197) from sequential, non-overlapping historical time points were compared. Clinical characteristics were extracted from a prospectively gathered electronic database. Both overall and pelvic sidewall recurrence free survival (RFS) were evaluated at 48-month post-operative follow-up. Results No significant difference in overall RFS could be identified between the cohorts at 48months (HR 0.74, 95% CI 0.43–1.28, p =0.29). However, the SLN cohort had improved pelvic sidewall RFS compared to the LND cohort (HR 0.32, 95% CI 0.14–0.74, p =0.007). The pelvic sidewall recurrences accounted for 30% of recurrences in the SLN cohort (8 out of 26 recurrences) compared to 71.4% in the LND cohort (20 out of 28 recurrences). Conclusions SLN mapping may enable more efficient detection of the LNs at greatest risk of metastasis and help to guide adjuvant therapy, which in turn seems to decrease the risk of pelvic sidewall recurrences.

Highlights • Preoperative diagnosis of endometrioid carcinoma is common in finally diagnosed serous endometrial cancer. • Endometrioid preoperative sample is associated with better outcome in women finally diagnosed with serous uterine cancer. • Endometrioid preoperative sample is reflected in the mutational profile of final pathology., The aim of this study was to evaluate the impact of discordant endometrial sampling on the prognosis of patients finally diagnosed with uterine papillary serous carcinoma (UPSC) and to analyze UPSC mutational profile. Retrospective cohort study comparing outcomes of patients post-operatively diagnosed with UPSC and preoperatively diagnosed with endometrioid endometrial cancer (EEC) or UPSC. Genes commonly implicated in carcinogenesis were analyzed in a subgroup of 40 patients post-operatively diagnosed with UPSC, using next generation sequencing. 61 patients with UPSC on post-surgical, final pathology were included in the study. Prior to surgery, 15 were diagnosed with EEC (discordant) and 46 were correctly diagnosed with UPSC (concordant). After a median follow-up of 41.6 months [5.4–106.7], a preoperative diagnosis of EEC was associated with better 3-year progression-free survival (100% vs. 60.9%, P = 0.003) and longer disease free interval (63.5 versus 15 months, P = 0.026) compared to patients with an initial diagnosis of UPSC. Patients with a concordant diagnosis of UPSC were 5 times more likely to progress or die compared to those with a discordant EEC diagnosis (P = 0.02, P = 0.03, respectively), and their tumors were associated with higher rates of TP53 (88.9% vs. 61.5%, P = 0.04), and a lower rate of PTEN (14.8% vs. 38.5%, P = 0.09) and ARID1A (3.7% vs. 23.1%, P = 0.05) mutations. A pre-surgical diagnosis of EEC is associated with improved prognosis in patients with UPSC. Some histologically defined UPSC tumors contain endometrioid-like molecular characteristics that may confer a survival advantage, suggesting a possible need for molecular approaches to better stratify patients into risk groups.

Large-scale genomic studies have detailed the molecular landscape of tumors from patients with high-grade serous ovarian cancers (HGSC) who underwent primary debulking surgery and correlated the identified subgroups to survival. In recent years, there is increased use of neoadjuvant chemotherapy (NACT) for patients with HGSC and while abundant data exist for patients who underwent primary debulking, little data are available on the cancer cells remaining after NACT that could lead to recurrences. We aimed to analyze gene expression profiles of NACT-treated HGSC tumor samples, and correlate them to treatment response and outcome. Tumor samples were collected from patients with stage III or IV HGSC (NACT cohort, N = 57) at the time of surgery and diagnosis (biopsy samples N = 8). Tumor content was validated by histologic examination and bioinformatics. Gene expression analysis was performed using a tailored NanoString-based assay, while sequencing was performed using MiSeq. A cross-validated survival classifier revealed patient clusters with either a “Better” or “Worse” prognostic outcome. The association with overall survival remained significant after controlling for clinical variables, and differential gene expression, gene set enrichment analyses, and the appropriate survival models were used to assess the associations between alterations in gene expression in cancer cells remaining after NACT and outcome. Pathway-based analysis of the differentially expressed genes revealed comparatively high levels of cell cycle and DNA repair gene expression in the poor outcome group. Implications: Our work suggests mRNA expression patterns in key genes following NACT may reflect response to treatment and outcome in patient with HGSC.

The histopathological classification of a disease should reflect both current concepts of its pathogenesis as well as its clinical behavior. Over the last 50 years our understanding of the pathobiology and behavior of cervical cancer precursors has evolved considerably. As a result, the terminology used to classify preinvasive lesions of the cervix has frequently changed.40 Although these changes in nomenclature and the resulting lack of a uniform terminology have been an ongoing source of confusion to both gynecologists and pathologists, each change has actually reduced the number of specific pathological categories and has made clinical decision-making more straightforward.

The Canadian Cervical Cancer Screening Trial was a randomized controlled trial comparing the performance of human papillomavirus (HPV) testing and Papanicolaou cytology to detect cervical intraepithelial neoplasia of grades 2 or worse (CIN2+) among women aged 30–69 years attending routine cervical cancer screening in Montreal and St. John's, Canada (n = 10,154). We examined screening and prognostic values of enrollment cytologic and HPV testing results. Extended follow-up data were available for St. John's participants (n = 5,754; 501,682.6 person-months). HPV testing detected more CIN2+ than cytology during protocol-defined (82.9 vs. 44.4%) and extended (54.2 vs. 19.3%) follow-up periods, respectively. Three-year risks ranged from 0.87% (95% CI: 0.37–2.05) for HPV-/Pap- women to 35.77% (95% CI: 25.88–48.04) for HPV+/Pap+ women. Genotype-specific risks ranged from 0.90% (95% CI: 0.40–2.01) to 43.84% (95% CI: 32.42–57.24) among HPV− and HPV16+ women, respectively, exceeding those associated with Pap+ or HPV+ results taken individually or jointly. Ten-year risks ranged from 1.15% (95% CI: 0.60–2.19) for HPV−/Pap− women to 26.05% (95% CI: 15.34–42.13) for HPV+/Pap+ women and genotype-specific risks ranged from 1.13% (95% CI: 0.59–2.14) to 32.78% (95% CI: 21.15–48.51) among women testing HPV− and HPV16+, respectively. Abnormal cytology stratified risks most meaningfully for HPV+ women. Primary HPV testing every 3 years provided a similar or greater level of reassurance against disease risks as currently recommended screening strategies. HPV-based cervical screening may allow for greater disease detection than cytology-based screening and permit safe extensions of screening intervals; genotype-specific testing could provide further improvement in the positive predictive value of such screening.

Cervical cancer (CC) morbidity and mortality have decreased in the United States, but they remain high among black women. We assessed racial disparities in CC mortality, accounting for socioeconomic status (SES). We linked data from the 1988 to 2007 Surveillance Epidemiology and End Results (SEER) database to the US Census. Additional SES information was obtained through linkage with Area Resource Files. We used the Kaplan-Meier method for estimating probabilities following CC diagnosis and Cox proportional hazards regression to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for CC mortality by race. The models were incrementally adjusted for marital status, registry, period, stage, age at diagnosis, histology, treatment, household income, poverty and unemployment rates. We stratified the analyses by disease stage and American state. A total of 44,554 women with CC were identified. Compared to white women, black women had a higher risk of dying from CC; crude and adjusted HRs were 1.41 (CI: 1.34-1.48) and 1.09 (CI: 1.03-1.15), respectively. Corresponding estimates for Hispanic women were 0.85 (CI: 0.80-0.89) and 0.75 (CI: 0.71-0.80). Black women diagnosed at late disease stages had a higher risk of CC death, whereas Hispanic women diagnosed at early and late stages had significantly lower risks. Black CC patients in California experienced poorer survival relative to white women. Conversely, longer CC survival was seen among Hispanic women in California, Georgia and Utah. While crude estimates indicated an increased CC death risk among black women, risks diminished upon adjustment for clinical and sociodemographic characteristics.

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).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.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.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.CLINICALTRIALS.GOV,: NCT00092521 and NCT00092534.

Background and aims With the debate over extent of lymphadenectomy in endometrial cancer, sentinel lymph node (SLN) mapping may provide a focused approach to evaluate the most relevant lymph nodes (LN) while minimizing the complications. We evaluated SLN mapping using filtered technetium 99 , indocyanine green (ICG), and blue dye. Methods Prospective evaluation of 100 patients who underwent SLN mapping by using submucosal and deep stromal cervical injections of technetium 99 , ICG, and blue dye as part of the staging for endometrial cancer. Results 286 SLNs were mapped (2.9 per patient) in 92% of patients. The bilateral detection rate was 76%. ICG had a significantly higher SLN detection rate than blue dye in both overall (87% vs 71%, respectively; p=0.005) and bilateral (65% vs 43%, respectively; p=0.002) detection, but similar SLN detection rates compared to technetium 99 in both overall (87% vs 88%, respectively; p=0.83) and bilateral (65% vs 71%, respectively; p=0.36) detection. In eight cases, the SLN was in the para-aortic area and in 14 cases in the pre-sacral, hypogastric vein, or parametrial area. In nine cases, the SLN was positive for metastasis, and in seven cases the SLN was the only positive node. One SLN was falsely negative. No complications or anaphylactic reactions occurred. Conclusion Intra-operative SLN mapping using cervical injection is feasible in patients with endometrial cancer and yields adequate detection rates. It allows mapping of SLNs in areas (pre-sacral, hypogastric vein, parametrial) not routinely sampled. Given the poorer performance of blue dye, surgeons may omit its use if a combination of ICG and technetium 99 is used.

Background Primary analyses of a study in young women aged 16–26 years showed efficacy of the nine-valent human papillomavirus (9vHPV; HPV 6, 11, 16, 18, 31, 33, 45, 52, and 58) vaccine against infections and disease related to HPV 31, 33, 45, 52, and 58, and non-inferior HPV 6, 11, 16, and 18 antibody responses when compared with quadrivalent HPV (qHPV; HPV 6, 11, 16, and 18) vaccine. We aimed to report efficacy of the 9vHPV vaccine for up to 6 years following first administration and antibody responses over 5 years. Methods We undertook this randomised, double-blind, efficacy, immunogenicity, and safety study of the 9vHPV vaccine study at 105 study sites in 18 countries. Women aged 16–26 years old who were healthy, with no history of abnormal cervical cytology, no previous abnormal cervical biopsy results, and no more than four lifetime sexual partners were randomly assigned (1:1) by central randomisation and block sizes of 2 and 2 to receive three intramuscular injections over 6 months of 9vHPV or qHPV (control) vaccine. All participants, study investigators, and study site personnel, laboratory staff, members of the sponsor's study team, and members of the adjudication pathology panel were masked to vaccination groups. The primary outcomes were incidence of high-grade cervical disease (cervical intraepithelial neoplasia grade 2 or 3, adenocarcinoma in situ, invasive cervical carcinoma), vulvar disease (vulvar intraepithelial neoplasia grade 2/3, vulvar cancer), and vaginal disease (vaginal intraepithelial neoplasia grade 2/3, vaginal cancer) related to HPV 31, 33, 45, 52, and 58 and non-inferiority (excluding a decrease of 1·5 times) of anti-HPV 6, 11, 16, and 18 geometric mean titres (GMT). Tissue samples were adjudicated for histopathology diagnosis and tested for HPV DNA. Serum antibody responses were assessed by competitive Luminex immunoassay. The primary evaluation of efficacy was a superiority analysis in the per-protocol efficacy population, supportive efficacy was analysed in the modified intention-to-treat population, and the primary evaluation of immunogenicity was a non-inferiority analysis. The trial is registered with ClinicalTrials.gov, number NCT00543543. Findings Between Sept 26, 2007, and Dec 18, 2009, we recruited and randomly assigned 14 215 participants to receive 9vHPV (n=7106) or qHPV (n=7109) vaccine. In the per-protocol population, the incidence of high-grade cervical, vulvar and vaginal disease related to HPV 31, 33, 45, 52, and 58 was 0·5 cases per 10 000 person-years in the 9vHPV and 19·0 cases per 10 000 person-years in the qHPV groups, representing 97·4% efficacy (95% CI 85·0–99·9). HPV 6, 11, 16, and 18 GMTs were non-inferior in the 9vHPV versus qHPV group from month 1 to 3 years after vaccination. No clinically meaningful differences in serious adverse events were noted between the study groups. 11 participants died during the study follow-up period (six in the 9vHPV vaccine group and five in the qHPV vaccine group); none of the deaths were considered vaccine-related. Interpretation The 9vHPV vaccine prevents infection, cytological abnormalities, high-grade lesions, and cervical procedures related to HPV 31, 33, 45, 52, and 58. Both the 9vHPV vaccine and qHPV vaccine had a similar immunogenicity profile with respect to HPV 6, 11, 16, and 18. Vaccine efficacy was sustained for up to 6 years. The 9vHPV vaccine could potentially provide broader coverage and prevent 90% of cervical cancer cases worldwide. Funding Merck and Co, Inc. © 2017 Elsevier Ltd

Background Metformin has been associated with reduced cancer risk. The mechanisms underlying this cancer protective effect remain unknown. Methods "Window of opportunity" study of metformin in women with operable endometrial cancer (EC). Eleven newly diagnosed, untreated, non-diabetic patients with EC received metformin 500mg tid from diagnostic biopsy to surgery. Fasting plasma insulin, insulin-like growth factor 1 (IGF-1), insulin-like growth factor binding protein 1 (IGFBP-1) and insulin-like growth factor binding protein 7 (IGFBP-7) measurements were taken before and after metformin treatment. Ki-67, pAMPK, and pS6 immunohistochemistry staining was performed on the endometrial cancer before and after metformin treatment and was compared to a control group of 10 women with EC who did not receive metformin. Results Metformin was administered for a mean of 36.6days. None of the patients suffered side effects requiring withdrawal from the study. The study group comprised 8 patients with endometrioid EC, and 3 non-endometrioid EC, with a mean follow-up time of 57months. Mean plasma insulin ( p =0.0005), IGF-1 ( p =0.001), and IGFBP-7 ( p =0.0098) were significantly reduced after metformin treatment. A clear reduction in ki-67 and pS6 expression was observed by both conventional light microscope analysis and digital image analysis with a significant mean reduction in percentage of cells staining for ki-67 (9.7%, P =0.02) and pS6 (31%, P =0.03). In the non-treated control group expression was similar between the biopsy and the surgical specimens. Conclusions This pilot trial presents biological evidence consistent with anti-proliferative effects of metformin in women with EC in the clinical setting.

Background. The Canadian Women's HIV Study (CWHS) enrolled human immunodeficiency virus (HIV)-positive and high-risk HIV-negative women in a longitudinal cohort. This analysis considered the effects of HIV and highly active antiretroviral therapy (HAART) on HPV persistence and cervical squamous intraepithelial lesions (SILs). Methods. Longitudinal cytopathologic and HPV DNA results were analyzed using multistate models. States of cervical SIL were defined as absent, present, and treatment; HPV states were defined as negative or positive. Demographic variables and markers of sexual activity were considered predictors. Results were calculated on the basis of transition probabilities and reported as hazard ratios (HRs). Results. The CWHS followed 750 HIV-positive and 323 HIV-negative women during 1993-2002. A total of 467 and 456 women were included in the longitudinal cervical cytopathologic and HPV DNA analyses, respectively. HIV-positive women had increased prevalence (46.6% vs 28.7%; P

Since being introduced in the 1940s, cervical cytology - despite its limitations - has had unequivocal success in reducing cervical cancer burden in many countries. However, we now know that infection with human papillomavirus (HPV) is a necessary cause of cervical cancer and there is overwhelming evidence from large-scale clinical trials, feasibility studies and real-world experience that supports the introduction of molecular testing for HPV as the primary technology in cervical cancer screening (i.e., "HPV primary screening"). While questions remain about the most appropriate age groups for screening, screening interval and triage approach, these should not be considered barriers to implementation. Many countries are in various stages of adopting HPV primary screening, whereas others have not taken any major steps towards introduction of this approach. As a group of clinical experts and researchers in cervical cancer prevention from across Canada, we have jointly authored this comprehensive examination of the evidence to implement HPV primary screening. Our intention is to create a common understanding among policy makers, agencies, clinicians, researchers and other stakeholders about the evidence concerning HPV primary screening to catalyze the adoption of this improved approach to cervical cancer prevention. With the first cohort of vaccinated girls now turning 21, the age when routine screening typically begins, there is increased urgency to introduce HPV primary screening, whose performance may be less adversely affected compared with cervical cytology as a consequence of reduced lesion prevalence post-vaccination.

Substantial evidence exists to support the introduction of molecular testing for human papillomavirus (HPV) as the primary technology in cervical cancer screening. While HPV testing is much more sensitive than cytology for detection of high-grade precancerous lesions, it is less specific. To improve efficiency, it is therefore recommended that a specific test (like cytology) be used in triaging HPV positive women to colposcopy. A number of studies have been conducted that support the use of cytology alone or in conjunction with HPV genotyping for triage. The decision to incorporate genotyping also depends on the commercial HPV test that is selected since not all tests provide results for certain individual high-risk types. Regardless of whether policy officials decide to adopt a triage approach that incorporates genotyping, the use of liquid based cytology (LBC) may also improve screening performance by reducing diagnostic delays. With LBC, the same cell suspension from a single collection may be used for HPV testing and a smear can be immediately prepared if HPV status is positive. This was a critical lesson from a community based demonstration project in Montreal (VASCAR study), where conventional cytology exists and specimen co-collection was not permitted for ethical reasons, requiring HPV positive women to return for an additional screening visit prior to colposcopy.

Background: High-risk human papillomavirus (HR-HPV) testing has become a preferred cervical cancer screening strategy in some countries due to its superior sensitivity over cytology-based methods for identifying cervical intraepithelial neoplasia of grade 2 or worse (CIN2+). Improved sensitivity has been accompanied by reductions in specificity and concerns regarding overscreening and overtreatment of women with transient or nonprogressing HR-HPV infections. Triage of HR-HPV+ women to colposcopy is, thus, warranted for appropriate management and treatment. Methods: Using data from the Canadian Cervical Cancer Screening Trial (CCCaST), we compared the performance of cytology and HR-HPV strategies to detect CIN2+ among HR-HPV+ women (age, 30–69 years). Colposcopy referral rates and performance gains from adding other HR-HPV genotypes to HPV16/18+ triage were also evaluated. Results: A strategy referring all women HPV16/18+ and HPV16/18−, but with atypical squamous cells of undetermined significance or worse cytology (ASC-US+) had the highest sensitivity [82.5%; 95% confidence interval (CI), 70.9%–91.0%] but yielded the highest colposcopy referral rate. HPV16/18+ triage was the next most sensitive strategy (64.1%; 95% CI, 51.1%–75.7%). Low-grade squamous intraepithelial lesion or worse cytology (LSIL+) triage yielded a low sensitivity (32.8%; 95% CI, 21.9%–45.4%) but had the most favorable specificity (93.6%; 95% CI, 91.0%–95.6%), positive predictive value (41.5%; 95% CI, 28.1%–55.9%), and colposcopy referral rate of strategies examined. HPV viral load triage strategies did not perform optimally overall. Inclusion of HR-HPV genotypes 31 and 52 to HPV16/18+ triage provided the highest sensitivities. Conclusion: Concerns surrounding HPV-based screening can be effectively mitigated via triage. Impact: Balancing the benefits of HPV-based primary cervical screening with informed management recommendations for HR-HPV+ women may decide the success of its widening utilization. Cancer Epidemiol Biomarkers Prev; 26(6); 923–9. ©2017 AACR.

The Canadian Cervical Cancer Screening Trial was a randomized controlled trial comparing the performance of human papillomavirus (HPV) testing and Papanicolaou cytology to detect cervical intraepithelial neoplasia of grades 2 or worse (CIN2+) among women aged 30-69 years attending routine cervical cancer screening in Montreal and St. John's, Canada (n = 10,154). We examined screening and prognostic values of enrollment cytologic and HPV testing results. Extended follow-up data were available for St. John's participants (n = 5,754; 501,682.6 person-months). HPV testing detected more CIN2+ than cytology during protocol-defined (82.9 vs. 44.4%) and extended (54.2 vs. 19.3%) follow-up periods, respectively. Three-year risks ranged from 0.87% (95% CI: 0.37-2.05) for HPV-/Pap- women to 35.77% (95% CI: 25.88-48.04) for HPV+/Pap+ women. Genotype-specific risks ranged from 0.90% (95% CI: 0.40-2.01) to 43.84% (95% CI: 32.42-57.24) among HPV- and HPV16+ women, respectively, exceeding those associated with Pap+ or HPV+ results taken individually or jointly. Ten-year risks ranged from 1.15% (95% CI: 0.60-2.19) for HPV-/Pap- women to 26.05% (95% CI: 15.34-42.13) for HPV+/Pap+ women and genotype-specific risks ranged from 1.13% (95% CI: 0.59-2.14) to 32.78% (95% CI: 21.15-48.51) among women testing HPV- and HPV16+, respectively. Abnormal cytology stratified risks most meaningfully for HPV+ women. Primary HPV testing every 3 years provided a similar or greater level of reassurance against disease risks as currently recommended screening strategies. HPV-based cervical screening may allow for greater disease detection than cytology-based screening and permit safe extensions of screening intervals; genotype-specific testing could provide further improvement in the positive predictive value of such screening.

The burden of anogenital warts will be a determining factor when making decisions about the type of human papillomavirus (HPV) vaccine to be used (bivalent or quadrivalent) and whether to vaccinate males. We conducted a multicenter prospective study to (1) describe the impact of anogenital warts on quality of life and (2) estimate the quality-adjusted life-years (QALYs) lost due to anogenital warts.Between September 2006 and February 2008, 272 patients with a first or recurrent episode of anogenital warts were recruited from the clinical practices of 42 physicians across Canada. Quality of life was measured at recruitment, and 2 and 6 months later with the EuroQol, Short Form-12, short Spielberg State-Trait Anxiety Inventory, and HPV impact profile. The duration of an episode and QALYs lost due to anogenital warts were estimated among 51 incident cases recruited within 90 days of disease onset.Anogenital warts had a significant impact on the quality of life. This negative impact was similar for first and recurrent episodes, and lasted as long as lesions persisted. Anogenital warts had the greatest negative impact on usual activities, pain/discomfort, and anxiety/depression, and on self-image, sexual activity, and partner issues and possible transmission. The median duration of a first anogenital wart episode amongst incident cases was 125 days and resulted in QALYs lost of 0.017 to 0.041, which is equivalent to 6 to 15 days of healthy life lost.The burden of anogenital warts is substantial and should be considered by physicians and public health officials when making recommendations about HPV vaccination..

Background Data on the impact of abnormal cervical smear results on health-related quality of life (HrQoL) are scarce. We aimed to (i) prospectively assess the HrQoL of women who were informed of an abnormal smear result; (ii) identify predictors of greater negative psychosocial impact of an abnormal result; and (iii) prospectively estimate the quality-adjusted life-years (QALYs) lost following an abnormal result. Methods Between 08/2006 and 08/2008, 492 women with an abnormal result and 460 women with a normal result, frequency matched for age and clinic, were recruited across Canada. HrQoL was measured at recruitment and 4 and 12 weeks later with the EuroQol, Short Form-12, short Spielberg State-Trait Anxiety Inventory (STAI) and HPV Impact Profile. Three blocks of potential predictors of higher psychosocial impact were tested by hierarchical modeling: (i) socio-demographics; (ii) sexual activity; and (iii) smear result severity, communication, and understanding. Results Receiving an abnormal result significantly increased anxiety (STAI mean difference between both groups = 8.3). Initial anxiety decreased over time for the majority of women. However, 35% of women had clinically meaningful anxiety at 12 weeks (i.e. STAI scores ≥0.5 standard deviation of the controls). These women reported a lower socio-economic level, did not completely understand the information about their result and perceived themselves at higher risk of cancer. QALY lost following an abnormal result were between 0.007 and 0.009. Conclusions Receiving an abnormal smear has a statistically significant and clinically meaningful negative impact on mental health. However, this negative impact subsides after 12 weeks for the majority of women. Copyright © 2011 John Wiley & Sons, Ltd.

We present a hitherto unreported case of vulvar phyllodes tumor which displayed morphologically malignant stroma including rhabdomyosarcomatous cellular elements. Clinically, the 61-year-old patient is free of recurrence 1 year after wide local excision.

Up to 20% of women having a cytology smear showing atypical squamous cells of undetermined significance (ASC-US) and infected with high-risk human papillomavirus (HR HPV) have high-grade cervical intraepithelial neoplasia (CIN 2/3). Results obtained with the Amplicor HPV and Hybrid Capture 2 (HC-2) assays for HR HPV DNA detection in women referred to colposcopy for an ASC-US smear were compared. Cervical samples in PreservCyt were tested for the presence of 13 HR HPV types with HC-2, with Amplicor at three cutoffs for positivity (0.2, 1.0, and 1.5 optical density units), and for 36 genotypes with the Linear Array (LA). Of 396 eligible women, 316 did not have CIN, 47 had CIN 1, 29 had CIN 2/3, and 4 had CIN of unknown grade. HR HPV was detected in 129 (32.6%) and 164 (41.4%) samples with HC-2 and Amplicor HPV (cutoff, 0.2), respectively ( P = 0.01). Overall, 112 specimens were positive and 215 were negative with the HC-2 and Amplicor HPV assays (agreement of 82.6%; 95% confidence interval [CI], 78.5 to 86.0). The clinical sensitivity and specificity of Amplicor HPV at cutoffs of 0.2, 1.0 and 1.5 and of HC-2 for detection of CIN 2/3 were 89.7% (95% CI, 72.8 to 97.2) and 62.5% (95% CI, 57.5 to 52.4), 89.7% (95% CI, 72.8 to 97.2) and 64.5% (95% CI, 59.4 to 69.2), 89.7% (95% CI, 72.8 to 97.2) and 64.7% (95% CI, 59.7 to 69.5), and 93.1% (95% CI, 77.0 to 99.2) and 72.2% (95% CI, 67.4 to 76.5), respectively. Both HR HPV detection tests identified women with ASC-US who would benefit the most from colposcopy. Women with persistent HR HPV infection need further investigation despite a first normal colposcopy.

Background:Preserving reproductive function in young patients with early endometrial cancer is an accepted concept today. The safety and feasibility of long-term conservative treatment, allowing more than 1 pregnancy, remain to be ascertained.Methods:This study was a retrospective chart review of a 27 women with endometrioid adenocarcinoma of the endometrium, who were treated conservatively at 2 tertiary-care institutions. Treatment comprised oral high-dose progestins with or without a levonorgestrel-releasing intrauterine device. Endometrial biopsy was repeated every 2 to 3 months.Results:Over 7.8 to 412 months (median, 57.4 months), tumors regressed completely in 24 (89%) of 27 patients and partially in 2 patients, with 79% responding within 1 to 17 months. Of the complete responders, 15 (62%) of 24 had a recurrence; 4 underwent hysterectomy, and 11 underwent subsequent progestational treatment. All 11 responded, and 3 subsequently conceived. After 2 to 4 years, 5 patients again had a recurrence, of whom 3 underwent hysterectomy. Overall, 2 patients developed ovarian adenocarcinoma. All patients are currently disease-free. Conception occurred in 14 (51.8%) of 27 patients, in 5 more than once. There were 17 live births, and 2 patients are pregnant.Conclusions:According to our data, prolonged progestational therapy for early-stage endometrial adenocarcinoma, allowing women to conceive, is feasible and apparently does not alter clinical outcome. Patients should be advised of the high recurrence rate and possible concomitant ovarian malignancy.

Although oncogenic human papillomavirus (HPV) infections have been established as the necessary cause of cervical cancer, most HPV infections are transient and rarely progress to squamous cervical lesions. The activity of HPV is tightly associated with epithelial cell differentiation; therefore, regulators of differentiation, such as retinoic acid (RA), have been considered targets for the prevention of HPV-associated squamous intraepithelial lesion (SIL) development. The purpose of this study was to determine the association between circulating RA and early events in cervical carcinogenesis, specifically type-specific HPV clearance and SIL detection. Archived blood samples from 643 women participating in the Ludwig-McGill Cohort in São Paulo, Brazil, were analyzed by high-pressure liquid chromatography for three RA isomers (all-trans, 13-cis, and 9-cis-RA). A type-specific HPV clearance event was defined as two consecutive visits negative for an HPV type during follow-up for 364 HPV-positive women. Among the 643 women in this analysis, 78 were diagnosed with incident SIL. The probability of clearing an oncogenic HPV infection was not significantly different across RA isomer quartiles. There was a suggestion that increasing all-trans-RA increased the rate of nononcogenic HPV clearance (P-trend = 0.05). There was no association observed between serum RA levels and incident SIL. Our results suggest that elevated circulating RA isomer levels do not increase the rate of HPV clearance or reduce the risk of incident SIL. The role of RA in the inhibition of HPV-induced carcinogenesis, as shown in vitro, lacks confirmatory evidence within epidemiologic studies among women. Cancer Prev Res; 3(8); 1007–14. ©2010 AACR.

We used modeling approaches to estimate the impact of human papillomavirus (HPV) vaccination on the performance of Pap cytology screening under different assumptions of lesion prevalence and expected changes in sensitivity and specificity likely to prevail post-vaccination. A major driver of the efficiency and costs of screening, the positive predictive value will be severely affected if Pap cytology continues to serve as the primary screening test in the post-vaccination era. Molecular-based screening with an HPV DNA test followed by Pap triage of HPV-positive cases has the potential for circumventing this problem. As a primary screening test, HPV testing can improve the overall quality of screening programs, thus allowing for increased testing intervals that would lower program costs with acceptable safety. Cytology should be reserved for the more labor-efficient task of triaging HPV-positive cases, a situation in which case loads would be "enriched" with smears containing relevant abnormalities. HPV followed by Pap strategy can also serve a secondary role in post-vaccination surveillance.

Background The association between human papillomavirus (HPV) viral load and high-grade squamous intraepithelial lesion (HSIL) of the uterine cervix has been demonstrated for high-risk HPV-16 but has not been investigated for low-risk HPV types. Objective To determine the association between the presence of low-grade SIL (LSIL) and viral load of low-risk HPV type 6. Study design 107 HPV-6-positive cytobrush samples collected from 90 women (67 without SIL, 11 with LSIL, 5 with HSIL, 6 with SIL of unknown grade and 1 with a smear with LSIL and a normal colposcopy) were analyzed for their content of HPV-6 DNA. Methods HPV-6 E6 and E2 DNA loads were measured in the cytobrush samples with two real-time PCR assays. HPV-6 integration was confirmed with restriction-site PCR. Results HPV-6 DNA in cervical samples ranged from 1.8 × 10 2 to 4.25 × 10 8 copies per μg of cellular DNA. HPV-6 E6 DNA loads were higher in women with LSIL, with or without co-infection with high-risk HPV types, than in women without SIL ( p = 0.03). HPV-6 loads greater than 8.76 × 10 6 copies per μg DNA, corresponding to the mean HPV-6 load measured in women with LSIL, were more frequently detected in these women with LSIL than in women without LSIL, controlling for age (odds ratio 13.5, 95% confidence interval 1.1–172.4). Although 10 samples generated HPV-6 E6/E2 ratios above 2, there was no evidence of integration of HPV-6 by restriction-site PCR. Conclusion Samples from women with LSIL contained higher HPV-6 loads than women without SIL. HPV-6 DNA was not integrated into cellular DNA in these samples.

Background Persistent HPV-16 infection is a marker for risk of progression to high-grade cervical lesions. The predictive value of HPV-16 viral loads for persistent HPV-16 infection was assessed longitudinally in a cohort of 1055 sexually active women. Methods HPV-16 viral loads were measured with real-time PCR targeting the E6 gene in 948 genital specimens collected from 139 women (100 HIV-seropositive, 39 HIV-seronegative). Results Forty of 139 participants were classified as having persistent HPV-16 infection (lasting more than 12 months) and 27 women had transient infection. CD4 counts were negatively correlated with HPV-16 loads ( R = −0.29, p = 0.02). In multivariate analysis controlling for age, HIV, race and CD4 counts, peak HPV-16 viral loads (odds ratio (OR) 1.3, 95% confidence interval (CI) 1.0–1.7) and CD4 cell counts (OR 2.0, 95% CI 1.1–3.6) were associated with persistence of HPV-16 infection. Women with ≥10 7 HPV-16 copies/μg cellular DNA were infected for a longer period of time than women with a lower viral load after controlling for age, CD4 count and HIV status ( p = 0.01). Conclusion Higher HPV-16 viral loads were predictive of persistence of HPV-16 infection, a marker risk for potential progression to high-grade pre-cancerous and cancerous lesions of the cervix.