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Quality-adjusted life years are used in cost-effectiveness analyses (CEAs). To calculate QALYs, a "utility" (0-1) is used for each health state induced or prevented by the intervention. We aimed to estimate the impact of quality of life (QoL) assumptions (utilities and durations of health states) on CEAs of cervical cancer screening. To do so, 12 alternative sets of utility assumptions were retrieved from published cervical cancer screening CEAs. Two additional sets were based on empirical QoL data that were integrally obtained through two different measures (SF-6D and EQ-5D) from eight groups of women (total n = 3,087), from invitation for screening to diagnosis with cervical cancer. Per utility set we calculated the number of quality-adjusted days lost (QADL) for each relevant health state in cervical cancer screening, by multiplying the study-specific assumed disutilities (i.e., 1-utility) with study-specific durations of the loss in QoL, resulting in 14 "QADL-sets." With microsimulation model MISCAN we calculated cost-effectiveness of 342 alternative screening programs (varying in primary screening test [Human Papillomavirus (HPV) vs. cytology], starting ages, and screening interval) for each of the 14 QADL-sets. Utilities used in CEAs appeared to differ largely. We found that ten QADL-sets from the literature resulted in HPV and two in cytology as preferred primary test. The SF-6D empirical QADL-set resulted in cytology and the EQ-5D one in HPV as preferred primary test. In conclusion, assumed utilities and health state durations determine cost-effectiveness of cervical cancer screening. Also, the measure used to empirically assess utilities can be crucial for CEA conclusions.

Women treated for high-grade cervical intraepithelial neoplasia (CIN) are at risk of recurrent CIN Grade 2 or worse (rCIN2+). Currently, posttreatment monitoring is performed using cytology or cytology/high-risk (hr)HPV cotesting. This study aimed to evaluate the performance of p16/Ki-67 dual-stained cytology (p16/Ki-67) for posttreatment monitoring. Three hundred and twenty-three women treated for high-grade CIN in the SIMONATH study underwent close surveillance by cytology, hrHPV and DNA methylation marker testing up to 12 months posttreatment. Histological endpoints were ascertained by colposcopy with biopsy at 6 and/or 12 months. p16/Ki-67 dual-staining was performed on residual liquid-based cytology samples obtained at, or shortly before biopsy collection. Clinical performance estimates of cytology, hrHPV, p16/Ki-67 testing and combinations thereof for the detection of rCIN2+ were determined and compared to each other. Sensitivity of p16/Ki-67 for rCIN2+ (69.2%) was nonsignificantly lower than that of cytology (82.1%; ratio 0.84, 95% CI: 0.71-1.01), but significantly lower than that of hrHPV testing (84.6%; ratio 0.82, 95% CI: 0.68-0.99). Specificity of p16/Ki-67 for rCIN2+ (90.4%) was significantly higher compared to both cytology (70.8%; ratio 1.28, 95% CI: 1.19-1.37) and hrHPV testing (76.2%; ratio 1.19, 95% CI: 1.12-1.26). Overall, hrHPV testing showed very high sensitivity, along with a good specificity. When considering cotesting, combined p16/Ki-67/hrHPV testing showed rCIN2+ sensitivity comparable to cytology/hrHPV cotesting (87.2% vs. 89.7%; ratio 0.97, 95% CI: 0.92-1.03), but with significantly increased specificity (74.2% vs. 58.1%; ratio 1.28, 95% CI: 1.19-1.38). Thus, when considered in combination with hrHPV, p16/Ki-67 might be an attractive approach for surveillance of women treated for high-grade CIN.

Introduction. Recent studies have shown that CADM1/MAL-methylation testing detects high-grade CIN lesions with a high short-term progression risk for cervical cancer. Women treated for CIN2/3 are at risk of post-treatment disease, representing either persistent (incompletely treated) or incident (early onset) lesions. Here, we evaluated CADM1/MAL-methylation analysis as potential tool for detecting recurrent high-grade CIN lesions (rCIN2/3). Methods and materials. A multicenter prospective clinical cohort study was conducted among 364 women treated for CIN2/3. Cervical scrapes were taken prior to treatment, and six and 12 months post-treatment and tested for cytology, hrHPV (plus genotype) and CADM1/MAL-methylation. When at six months either of these tests was positive, a colposcopy-directed biopsy was obtained. At 12 months, all women underwent an exit-colposcopy with biopsy. In case of rCIN2/3, re-treatment was done. Results. We found 28 rCIN2 (7.7%) and 14 rCIN3 (3.8%), resulting in a total recurrence rate of 11.5%. All 14 women with rCIN3 and 15/28 (54%) with rCIN2 showed hrHPV type-persistence. Of these, 9/14 ( 64%) rCIN3 and 8/15 (53%) rCIN2 were CADM1/MAL-methylation positive. All incident rCIN2, characterized by hrHPV genotype-switch, were CADM1/MAL-methylation negative. All three carcinomas found after re-treatment were CADM1/MAL-methylation positive. CADM1/MAL-methylation positivity at both baseline and follow-up significantly increased the risk of >= rCIN3 (from 0.7% to 18.4%), and >= rCIN2 (from 82% to 36.8%), compared to a consistently CADM1/MAL-methylation negative result (p-value

Recently, DNA methylation analysis of FAM19A4 in cervical scrapes has been shown to adequately detect high-grade cervical intraepithelial neoplasia and cervical cancer (≥ CIN3) in high-risk HPV (hrHPV)-positive women. Here, we compared the clinical performance of FAM19A4 methylation analysis to cytology and HPV16/18 genotyping, separately and in combination, for ≥ CIN3 detection in hrHPV-positive women participating in a prospective observational multi-center cohort study. The study population comprised hrHPV-positive women aged 18-66 years, visiting a gynecological outpatient clinic. From these women, cervical scrapes and colposcopy-directed biopsies (for histological confirmation) were obtained. Cervical scrapes were analyzed for FAM19A4 gene promoter methylation, cytology and HPV16/18 genotyping. Methylation analysis was performed by quantitative methylation-specific PCR (qMSP). Sensitivities and specificities for ≥ CIN3 were compared between tests. Stratified analyses were performed for variables that potentially influence marker performance. Of all 508 hrHPV-positive women, the sensitivities for ≥ CIN3 of cytology, FAM19A4 methylation analysis, and cytology combined with HPV16/18 genotyping were 85.6, 75.6 and 92.2%, respectively, with corresponding specificities of 49.8, 71.1 and 29.4%, respectively. Both sensitivity and specificity of FAM19A4 methylation analysis were associated with age (p ≤ 0.001 each). In women ≥ 30 years (n = 287), ≥ CIN3 sensitivity of FAM19A4 methylation analysis was 88.3% (95%CI: 80.2-96.5) which was noninferior to that of cytology [85.5% (95%CI: 76.0-94.0)], at a significantly higher specificity [62.1% (95%CI: 55.8-68.4) compared to 47.6% (95%CI: 41.1-54.1)]. In conclusion, among hrHPV-positive women from an outpatient population aged ≥ 30 years, methylation analysis of FAM19A4 is an attractive marker for the identification of women with ≥ CIN3.

Background: Despite the introduction of Human papillomavirus (HPV) vaccination in national immunization programs (NIPs), vaccination rates in most countries remain relatively low. An understanding of the reasons underlying decisions about whether to vaccinate is essential in order to promote wider spread of HPV vaccination. This is particularly important in relation to policies seeking to address shortfalls in current HPV campaigns. The aim of this study was to explore prevailing perspectives concerning HPV vaccination among girls, boys, and parents, and so to identify potential determinants of HPV vaccination decisions in these groups. Method: Perspectives were explored using Q-methodology. Forty-seven girls, 39 boys, and 107 parents in the Netherlands were asked to rank a comprehensive set of 35 statements, assembled based on the health belief model (HBM), according to their agreement with them. By-person factor analysis was used to identify common patterns in these rankings, which were interpreted as perspectives on HPV vaccination. These perspectives were further interpreted and described using data collected with interviews and open-ended questions. Results: The analysis revealed four perspectives: "prevention is better than cure," "fear of unknown side effects," "lack of information and awareness," and "my body, my choice." The first two perspectives and corresponding determinants of HPV vaccination decisions were coherent and distinct; the third and fourth perspectives were more ambiguous and, to some extent, incoherent, involving doubt and lack of awareness and information (perspective 3), and overconfidence (perspective 4). Conclusions: Given the aim of publically funded vaccination programs to minimize the spread of HPV infection and HPV-related disease and the concerns about current uptake levels, our results indicate that focus should be placed on increasing awareness and knowledge, in particular among those in a modifiable phase.

Objective: This study aimed to review literature if therapeutic strategies in adenocarcinoma in situ of the cervix could lead to a more conservative approach. Methods: A review of the literature was conducted using a Medline search for articles published between 1966 and 2013. Results: Thirty-five studies showed that after a radical cone, 16.5% residual disease in the re-cone or uterus was found. After cone with positive margins, residual abnormalities were found in 49.3%. Thirty-seven studies showed 5% recurrence rate after conservative therapy (large loop excision transformation zone-cold knife conization. After conization with negative margins, the risk of recurrence was 3%. Conclusions: Adenocarcinoma in situ is a relatively rare premalignant but increasingly frequent lesion of the cervix. Although there is a risk of relapse (3%) with a chance of malignancy (

Objective Referral for colposcopy because of abnormal Pap test results is likely to be distressing, but the extent and duration of these effects are unknown. We aimed to fill this gap. Methods We conducted a prospective observational study at two departments of Obstetrics and Gynecology (an academic and a non-academic setting). Women referred for colposcopy completed questionnaires before colposcopy, and at 1, 3, and 6months afterwards. A reference group of 706 screen participants, aged 29–60years old, was included and completed questionnaires once. Main outcome measures were generic health-related quality of life (HRQoL), assessed through the EQ-5D and the SF-12 physical and mental scores (PCS-12 and MCS-12); anxiety as assessed by STAI-6, and screen-specific anxiety as assessed by the psychological consequences questionnaire (PCQ). Results 154 women responded to the questionnaire, of whom 132 were included in the analyses. Histological results were CIN 1 in 17/115 women (15%) and CIN 2+ in 62 (54%). In 36 women (31%) there was no histologically confirmed neoplasia. Before colposcopy physical HRQoL scores were similar or slightly better than in the reference group, while mental HRQoL (MSC-12) and (screen-specific) anxiety were worse (p Conclusions Referral for gynecological evaluation because of abnormal PAP-test results was distressing. Anxiety – and not the physical burden of management – seemed to be the most bothersome to women. For all CIN-grades, distress disappeared over six months following colposcopy, suggesting a reassuring effect of gynecological management.

Objective To review and characterise by clinical evaluation, immunohistochemistry and HPV typing a group of adenocarcinomas initially diagnosed with primary localisation in the cervix. Furthermore, to assess the prevalence and prognostic significance of HPV genotypes in a large series of HPV positive cervical adenocarcinomas (AC). Methods One hundred and seventy-one cases of adenocarcinomas (AC) with a primary localisation in the cervix and diagnosed between 1989 and 2008 in the region of Rotterdam, the Netherlands were retrieved. Slides and blocks were reviewed and immunohistochemically stained for CEA and vimentin. HPV testing for high-risk HPV (hrHPV) by PCR (GP5+/6+) and genotyping by reversed line blot were performed. Results In 113 of 171 patients HPV evaluation was possible. 101 were HPV-positive (89%) and 11 were HPV-negative (11%). The 5-year disease free survival was 80% in the HPV-positive group versus 74% in the HPV-negative group (ns). The distribution of HPV types was type 18 in 55 patients (54%), type 16 in 37 (37%), type 45 in 7 (7%), types 53 and 39 were found in 2 respective patients. 5-year overall-survival in patients with HPV-18 was not significantly worse than in patients with HPV-16 (81 versus 87%). Patients with HPV-45 had a worse 5-year survival, 57%. Conclusions AC is hrHPV related in most cases (89%) and HPV-18 is the most frequent type (54%). With the exception of HPV-45, HPV-positivity or type in endocervical AC has no significant influence on survival.

OBJECTIVES To provide an early risk assessment of extending screening intervals beyond five years for a human papillomavirus (HPV) based cervical screening programme in the Netherlands. DESIGN 14 year follow-up of a population based randomised cohort from the POBASCAM randomised trial. SETTING Organised cervical screening in the Netherlands, based on a programme of three screening rounds (each round done every five years). PARTICIPANTS 43 339 women aged 29-61 years with a negative HPV and/or negative cytology test participating in the POBASCAM trial. INTERVENTIONS Women randomly assigned to HPV and cytology co-testing (intervention) or cytology testing only (control), and managed accordingly. MAIN OUTCOME MEASURES Cumulative incidence of cervical cancer and cervical intraepithelial neoplasia (CIN) grade 3 or worse (CIN3+). Associations with age were expressed as incidence rate ratios. In HPV positive women, reductions in CIN3+ incidence after negative cytology, HPV type 16/18 genotyping, and/or repeat cytology were estimated. RESULTS The cumulative incidence of cervical cancer (0.09%) and CIN3+ (0.56%) among HPV negative women in the intervention group after three rounds of screening were similar to the cumulative among women with negative cytology in the control group after two rounds (0.09% and 0.69%, respectively). Cervical cancer and CIN3+ risk ratios were 0.97 (95% confidence interval 0.41 to 2.31, P=0.95) and 0.82 (0.62 to 1.09, P=0.17), respectively. CIN3+ incidence was 72.2% (95% confidence interval 61.6% to 79.9%, Pfive years) should be implemented with risk stratification.

Background: High-risk human papillomavirus (hrHPV)-positive women require triage to identify those with cervical high-grade intraepithelial neoplasia and cancer (>= CIN3 (cervical intraepithelial neoplasia grade 3)). FAM19A4 methylation analysis, which detects advanced CIN and cancer, is applicable to different sample types. However, studies comparing the performance of FAM19A4 methylation analysis in hrHPV-positive self-samples and paired physician-taken scrapes are lacking. Methods: We compared the performance of FAM19A4 methylation analysis (and/or HPV16/18 genotyping) in self-samples and paired physician-taken scrapes for >= CIN3 detection in hrHPV-positive women (n = 450,18-66 years). Results: Overall FAM19A4 methylation levels between sample types were significantly correlated, with strongest correlation in women with >= CIN3 (Spearman's rho 0.697, P= 30 years, >= CIN3 sensitivity of FAM19A4 methylation analysis was 78.4% in self-samples and 88.2% in scrapes (ratio 0.89; CI: 0.75-1.05). In women = CIN3 sensitivities were 37.5% and 45.8%, respectively (ratio 0.82; CI: 0.55-1.21). In both groups, >= CIN3 specificity of FAM19A4 methylation analysis was significantly higher in self-samples compared with scrapes. Conclusions: FAM19A4 methylation analysis in hrHPV-positive self-samples had a slightly lower sensitivity and a higher specificity for >= CIN3 compared with paired physician-taken scrapes. With a similarly good clinical performance in both sample types, combined FAM19A4 methylation analysis and HPV16/18 genotyping provides a feasible triage strategy for hrHPV-positive women, with direct applicability on self-samples.

Women who test positive for a high-risk type of the human papillomavirus (HPV) require triage testing to identify those women with cervical intraepithelial neoplasia grade 3 or cancer (>= CIN3). Although Pap cytology is considered an attractive triage test, its applicability is hampered by its subjective nature. This study prospectively compared the clinical performance of p16/Ki-67 dual-stained cytology to that of Pap cytology, with or without HPV16/18 genotyping, in high-risk HPV-positive women visiting gynecologic outpatient clinics (n=446 and age 18-66 years). From all women, cervical scrapes (for Pap cytology, HPV16/18 genotyping, and p16/Ki-67 dual-stained cytology) and colposcopy-directed biopsies were obtained. The sensitivity of p16/Ki-67 dual-stained cytology for >= CIN3 (93.8%) did neither differ significantly from that of Pap cytology (87.7%; ratio 1.07 and 95% confidence interval (CI): 0.97-1.18) nor from that of Pap cytology combined with HPV16/18 genotyping (95.1%; ratio 0.99 and 95% CI: 0.91-1.07). However, the specificity of p16/Ki-67 dual-stained cytology for >= CIN3 (51.2%) was significantly higher than that of Pap cytology (44.9%; ratio 1.14 and 95% CI: 1.01-1.29) and Pap cytology combined with HPV16/18 genotyping (25.8%; ratio 1.99 and 95% CI: 1.68-2.35). After exclusion of women who had been referred because of abnormal Pap cytology, the specificity of p16/Ki-67 dual-stained cytology for >= CIN3 (56.7%) remained the same, whereas that of Pap cytology (60.3%) increased substantially, resulting in a similar specificity of both assays (ratio 0.94 and 95% CI: 0.83-1.07) in this sub-cohort. In summary, p16/Ki-67 dual-stained cytology has a good clinical performance and is an interesting objective microscopy-based triage tool for high-risk HPV-positive women.

Human papillomavirus (HPV) infections may result in benign hyperplasia, caused by low-risk HPV types, or (pre)malignant lesions caused by high-risk HPV types. The molecular basis of this difference in malignant potential is not completely understood. Here, we performed gene profiling of different HPV infected vulvar tissues (condylomata acuminata (n = 5), usual type vulvar intraepithelial neoplasia (uVIN) (n = 9)) and control samples (n = 14) using Affymetrix Human U133A plus 2 GeneChips. Data were analyzed using OmniViz (R), Partek (R) and Ingenuity (R) Software. Results were validated by real-time RT-PCR and immunostaining. Although similarities were observed between gene expression profiles of low- and high-risk HPV infected tissues (e.g., absence of estrogen receptor in condylomata and uVIN), high-risk HPV infected tissues showed more proliferation and displayed more DNA damage than tissues infected with low-risk HPV. These observations were confirmed by differential regulation of cell cycle checkpoints and by increased expression of DNA damage-biomarkers p53 and ?H2AX. Furthermore, FANCA, FANCD2, BRCA1 and RAD51, key players in the DNA damage response, were significantly upregulated (p < 0.05). In addition, we compared our results with publicly available gene expression profiles of various other HPV-induced cancers (vulva, cervix and head-and-neck). This showed p16INK4a was the most significant marker to detect a high-risk HPV infection, but no other markers could be found. In conclusion, this study provides insight into the molecular basis of low- and high-risk HPV infections and indicates two main pathways (cell cycle and DNA damage response) that are much stronger affected by high-risk HPV as compared to low-risk HPV.

Imiquimod has been shown to be an effective treatment for usual type vulvar intraepithelial neoplasia (uVIN). Since local inflammation and burning are common side effects, patients often use nonsteroidal anti-inflammatory drugs (NSAIDs). Our study investigated whether NSAID-use, which has been documented to inhibit the cell-mediated immune response, interferes with the outcome of imiquimod treatment. Monocyte-derived dendritic cells (moDCs) and Langerhans cells (moLCs) were cultured in the presence of NSAIDs. The expression of relevant surface markers (CD80, CD86, CD40, HLA-DR, CCR6 and CCR7), stimulatory function, and cytokine production were evaluated. Furthermore, we analyzed in uVIN patients whether frequent NSAID-use had an effect on the clinical response and on immunocompetent cell counts before and after imiquimod treatment. Although an effect was observed on the expression of moDC and moLC maturation markers, NSAIDs did not affect the ability of moDCs and moLCs to stimulate allogeneic T-cell proliferation, or the production of cytokines in an allogeneic T-cell stimulation assay. In agreement with this, in uVIN patients treated with imiquimod, no interference of frequent NSAID-use with clinical outcome was observed. However, we did notice that high CD1a(+) and CD207(+) cell counts in frequent NSAID-users before treatment seemed to predict a favourable response to imiquimod treatment. Our data indicate that NSAID-use does not seem to interfere with moDC and moLC function and does not interfere with immunomodulatory properties of imiquimod in uVIN patients. Therefore, NSAIDs can safely be used to reduce imiquimod side effects in uVIN patients during treatment.

ObjectiveThis study aimed to evaluate the treatment and follow-up in a large series of women with early cervical adenocarcinoma (AC), stages IA1 and IA2, and to perform an extensive review of the literature in an effort to ascertain whether conservative therapy is justified.MethodsRecords of 59 cases of microinvasive AC diagnosed between 1987 and 2006 in the Rotterdam district, the Netherlands, were retrieved. Clinical and pathological data were reviewed and analyzed. A mesh review of all relevant literature concerning stage IA1 and IA2 was performed.ResultsOf all patients, 33 had stage IA1 and 26 stage IA2 cervical AC. Also, 42 patients were treated conservatively (ie, conization or simple hysterectomy) and 17 patients were treated radically (ie, radical hysterectomy/trachelectomy with lymph node dissection). Recurrence occurred in 1 patient (1.7%) with stage IA1 disease (grade 1 adenocarcinoma, depth 1.4 mm, and width 3.8 mm, with lymph vascular space involvement [LVSI]) treated by vaginal hysterectomy. The mean follow-up was 79.9 months. From the literature, pooling all data from patients with stage IA1 and IA2 AC, the risk of recurrent disease was 1.5% after conservative therapy and 2.0% after radical therapy.ConclusionsExtensive treatment such as radical hysterectomy with pelvic lymph node dissection or trachelectomy does not prevent recurrent disease. Patients with microinvasive AC should be treated identically to patients with SCC. In stage IA1 and IA2 AC, we recommend conservative therapy (by conization). In cases with LVSI, an additional lymphadenectomy is advised. For patients with stage IA2 AC with LVSI, a trachelectomy/radical hysterectomy with lymph node dissection should be considered.

Objective. Recently we reported on the efficacy of imiquimod for treating vulvar intraepithelial neoplasia (VIN) in a placebo-controlled, double-blinded randomized clinical trial (RCT). Four weeks after treatment, a complete response was observed in 35% of patients and a partial response in 46%. All complete responders remained disease-free at 12 months follow-up. In the current investigations, we assessed long-term follow-up at least 5 years after the initial RCT. Methods. Twenty-four of 26 imiquimod-treated patients who had participated in the initial RCT were seen for follow-up. Primary endpoint was durability of clinical response to imiquimod assessed by naked eye vulvar examination and histology. Long-term clinical response was correlated to lesion size before start of the initial RCT. Secondary endpoints were mental health, global quality of life, body image and sexual function in relation with long-term clinical response. Results. Median follow-up period was 7.2 years (range 5.6-8.3 years). VIN recurred in one of nine complete responders. Of the initial partial responders, two became disease-free after additional imiquimod treatment. In the other partial responders, VIN recurred at least once after the initial RCT. In long-term complete responders, lesion size at study entry was smaller and these patients had a significantly better global quality of life at follow-up than patients with residual disease and/or recurrence after imiquimod treatment. Conclusions. In case of a complete response, imiquimod is effective in the long-term. Furthermore, patients with a long-term complete response had a significantly better global quality of life than patients who recurred after imiquimod treatment. (C) 2010 Elsevier Inc. All rights reserved.

We studied the health and economic effects of human papillomavirus (HPV) DNA testing in cervical screening using a simulation model. The key data source was a Dutch longitudinal screening trial. We compared cytological testing with repeat cytology (for borderline/mildly abnormal smears) to HPV testing with cytology triage (for HPV-positive smears), combination testing (combined HPV and cytology) and cytological testing with HPV triage (for borderline/mildly abnormal smears). We varied the screening interval from 5 to 10 years. The main outcome measures were the number of cervical cancer cases, the number of quality-adjusted life years (QALYs), and the incremental cost-effectiveness ratio (ICER). The base-case estimates were accompanied with ranges across 118 calibrated parameter settings (calibration criteria: cervical intraepithelial neoplasia 2/3, cancer and mortality rates). In comparison to 5-yearly cytology, 5-yearly HPV testing with cytology triage gave a reduction in the number of cancer cases of 23% (range, 9-27%). The reduction was 26% (range, 10-29%) for combination testing and 3% (range, -1 to 8%) for cytology with HPV triage. For strategies with primary HPV testing, the model also estimated a reduction in cancer cases when the screening interval was extended to 7.5 years. Five-yearly cytology with HPV triage and 5 to 7.5-yearly HPV testing with cytology triage were cost effective for the base-case settings and the majority of calibrated parameter settings (ICER below Dutch willingness-to-pay threshold of -20,000/QALY). Our model indicates that HPV testing with cytology triage is likely to be cost effective. An extension of the screening interval may be considered to control costs.

The prevalence of human papillomavirus (HPV) genotypes in relation to age was investigated by the polymerase chain reaction (PCR) method in cytologically normal smears from 4 different groups of women. Group A consisted of young women from a district population, aged 15-34 years, using oral contraceptives and visiting general practitioners for a check-up (n = 156); group B were asymptomatic women, aged 35-55, in a district population participating in a triennial screening program for cervical cancer (n = 1555); group C and D consisted of women, seen at the gynecological outpatient department for a wide spectrum of gynecological complaints or for control of their hormonal contraception, aged 15-34 years (n = 2320), and aged 35-55 years (n = 1826) respectively. An HPV (all types) prevalence of 14.1%, 4.1%, 13.9% and 6.6% and an HPV 16/18 prevalence of 3.8%, 0.9%, 3.3% and 1.5% were found in groups A, B, C and D respectively. Statistically significant differences (p value < 0.001) in HPV prevalence were found between women aged 15-34 years and women aged 35-55 years in the district population and in the hospital population. No statistically significant differences in HPV 16/18 were observed after age-matching between women in corresponding age-classes of both populations. In a 5-year interval analysis a strong age-dependent relationship was demonstrated, with a maximum between 20 and 24 years. After the age of 35 a constant level of 1-2% HPV 16/18 was observed. These results indicate that genital HPV infections are age-dependent and suggest that HPV infections at young age can be transient. The implications of these findings in the context of cervical cancer screening are discussed.

Ovarian small-cell carcinoma of the hypercalcemic type is a rare and highly malignant tumor. In two thirds of the patients, the tumor is associated with asymptomatic paraneoplastic hypercalcemia. The diagnosis may be impeded; the tumor must be distinguished from other tumors with similar features.This tumor occurs predominantly in young women and is merely lethal. The 1-year survival is solely 50%, with an overall 5-year survival rate of approximately 10%. It is believed that the empirical treatment characterized by combination of radical surgery, chemotherapy, and radiotherapy results in the most favorable outcome in terms of survival. However, the outcome remains extremely poor despite this aggressive approach.Alternatively, these poor survival rates may justify a less aggressive fertility sparing approach without compromising the outcome. Such an approach is illustrated by a case report involving a patient with ovarian small-cell carcinoma of the hypercalcemic type, FIGO stage IIIC. A fertility-sparing approach was used, consisting of conservative surgery followed by induction chemotherapy, interval debulking surgery, and local radiotherapy. During follow-up of 60 months, there was no evidence of disease and the normal menstrual cycle resumed.In addition to this case report, histopathological features, different therapeutic modalities, and outcome of ovarian small-cell carcinoma of the hypercalcemic type is reviewed. This report suggests that a fertility-sparing approach may be just as feasible as the generally applied aggressive approach.

Cervical cancer develops from precancerous high-grade cervical intraepithelial neoplasia (CIN) harboring a transforming infection with high-risk human papillomavirus, which is characterized by p16INK4a overexpression. Once such a lesion has developed, progression toward an invasive squamous cell carcinoma (SCC) may take one or more decades, underlining the heterogeneity of these lesions in terms of duration of existence and progression risk. We performed array-based comparative genomic hybridization (array CGH) on 46 p16INK4a immunopositive CIN2/3 lesions to determine whether this heterogeneity is reflected in their chromosomal profiles. Chromosomal profiles of CIN2/3 lesions were related to those of invasive cervical SCC and promoter methylation of CADM1, a tumor suppressor gene known to be functionally involved in the tumorigenic phenotype of cervical cancer cells. Frequent alterations found in CIN2/3 lesions included gains located at chromosome 1, 3, 7, and 20 and losses located at 4, 11, 16, 17, and 19. Unsupervised hierarchical clustering identified two subsets of CIN2/3 lesions, chromosomal profiles of one of which closely resembled invasive SCCs. Gains of 1, 3q, and 20 were characteristic for CIN2/3 lesions with chromosomal signatures resembling carcinomas. In addition, dense promoter methylation of the CADM1 gene was significantly more frequent in these CIN2/3 lesions (P = 0.004). No chromosomal alterations were detected in six CIN1 lesions, five of which were completely p16INK4a immunonegative. These findings suggest that biomarkers associated with gains at chromosomes 1, 3q, and 20 are potential hallmarks of advanced p16INK4a-positive CIN2/3 lesions with a high short-term risk of progression. [Cancer Res 2009;69(2):647–55]

A novel approach for primary prevention of cervical cancer has become available by the discovery of efficient prophylactic human papillomavirus (HPV) vaccines based on virus-like particles. This review elaborates on the progress in the field of prophylactic HPV vaccination achieved in the past decade, provides indications for prophylactic HPV vaccination, and discusses the impact on public health and the current secondary prevention system. In summary, with current vaccines, effective prevention and control of cervical cancer within the next decades requires an integrated vaccination-screening approach, including routine prophylactic vaccination to young women and adapted cervical screening for older women (or =30 years).

Usual type VIN is a premalignant disorder caused by persistent HPV infection. High prevalence of VIN in immuno-suppressed women suggests that a good innate and adaptive immune response is important for defense against HPV. Here, we explored expression levels of chemokines and related these to the presence or absence of immuno-competent cells (dendritic and T-cells) in affected (HPV-positive VIN) and non-affected (HPV-negative) vulvar tissues from the same patients. Combining microarray data with quantitative real-time RT-PCR, it was observed that several important chemokines were differentially expressed between VIN and control samples (up-regulation of IL8, CXCL10, CCL20 and CCL22 and down-regulation of CXCL12, CCL21 and CCL14). Furthermore, an increased number of mature dendritic cells (CD208+) seemed to be bottled up in the dermis, and although a T-cell response (increased CD4+ and CD8+ cells) was observed in VIN, a much larger response is required to clear the infection. In summary, it seems that most mature dendritic cells do not receive the proper chemokine signal for migration and will stay in the dermis, not able to present viral antigen to naive T-cells in the lymph node. Consequently the adaptive immune response diminishes, resulting in a persistent HPV infection with increased risk for neoplasia.

Genital infection with human papillomavirus (HPV) is usually transient, as the immune system is capable of eliminating the virus. When immunity “fails” and the infection persists, vulvar intraepithelial neoplasia (VIN) may develop. In this study, we examined the distribution of inflammatory cells in 51 patients with HPV-associated usual-type VIN and in 19 healthy controls. Frozen vulvar tissue samples were tested for the presence of HPV-DNA, and immunohistochemical staining for the markers CD1a, CD207, CD208, CD123/CD11c, CD94, CD4, CD8, and CD25/HLA-DR was performed. Cells were counted in both the epidermis and dermis over at least 2 mm of basal membrane length. In the epidermis of VIN patients, CD1a+ and CD207+ (Langerin) dendritic cells (DC) and CD8+ T cells were significantly lower than in controls, whereas the number of CD123+/CD11c− plasmacytoid DCs (pDC) was significantly increased. No significant changes were observed for CD208+ DCs, CD94+ natural killer (NK) cells, CD4+ T cells, and CD25+/HLA-DR+ regulatory T cells. In the dermis of VIN patients, elevated numbers of CD208+, CD123+/CD11c−, CD94+, CD4+, CD8+, and CD25+/HLA-DR+ cells were observed when compared with healthy controls. The numbers of CD1a+ and CD207+ DCs were not different between groups. In summary, high-risk HPV–related usual-type VIN lesions are characterized by an immunosuppressive state in the epidermis, showing a reduction of immature myeloid DCs (mDC) and CD8+ T cells. In the dermis, inflammatory activation is reflected by the influx of mature mDCs and pDCs, NK cells, and T cells, suggesting that the cellular immune response on viral HPV infection occurs in the dermis of VIN patients. [Cancer Res 2008;68(16):6617–22]

BACKGROUND: Alternatives to surgery are needed for the treatment of vulvar intraepithelial neoplasia. We investigated the effectiveness of imiquimod 5% cream, a topical immune-response modulator, for the treatment of this condition. METHODS: Fifty-two patients with grade 2 or 3 vulvar intraepithelial neoplasia were randomly assigned to receive either imiquimod or placebo, applied twice weekly for 16 weeks. The primary outcome was a reduction of more than 25% in lesion size at 20 weeks. Secondary outcomes were histologic regression, clearance of human papillomavirus (HPV) from the lesion, changes in immune cells in the epidermis and dermis of the vulva, relief of symptoms, improvement of quality of life, and durability of response. Reduction in lesion size was classified as complete response (elimination), strong partial response (76 to 99% reduction), weak partial response (26 to 75% reduction), or no response (

We previously showed that silencing of TSLC1 recently renamed CADM1, is functionally involved in high-risk HPV-mediated cervical carcinogenesis. CADM1 silencing often results from promoter methylation. Here, we determined the extent of CADM1 promoter methylation in cervical (pre)malignant lesions and its relation to anchorage-independent growth and gene silencing to select a CADM1-based methylation marker for identification of women at risk of cervical cancer. Methylation-specific PCRs targeting three regions within the CADM1 promoter were performed on high-risk HPV-containing cell lines, PBMCs, normal cervical smears, and (pre)malignant lesions. CADM1 protein expression in cervical tissues was analysed by immunohistochemistry. All statistical tests were two-sided. Density of methylation was associated with the degree of anchorage-independent growth and CADM1 gene silencing in vitro. In cervical squamous lesions, methylation frequency and density increased with severity of disease. Dense methylation (defined as >= 2 methylated regions) increased from 5% in normal cervical samples to 30% in CIN3 lesions and 83% in squamous cell carcinomas (SCCs) and was significantly associated with decreased CADM1 protein expression (p < 0.00005). The frequency of dense methylation was significantly higher in >= CIN3 compared with = CIN3. Copyright (c) 2008 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Background: Differentiated vulvar intraepithelial neoplasia (VIN) is presumed to be the precursor of invasive squamous cell carcinoma (SCC) of the vulva. It is commonly assumed that differentiated VIN is related to lichen sclerosus (LS). However, evidence for this is limited to a small number of studies describing epithelial alterations adjacent to vulvar SCC. Aim: To study the histology and human papillomavirus (HPV) status in patients with a history of both LS and VIN without coexistent SCC. Methods: Original biopsy specimens and surgical specimens of patients retrieved from the pathology files were revised for the presence of LS, VIN and (early) invasive SCC, specifically focused on the two different types of VIN: differentiated and undifferentiated. Thereafter, VIN lesions were tested for the presence of HPV DNA. Results: Twenty-seven patients fulfilled the criteria for LS and VIN without SCC. In all 27 patients, LS was found to be related to undifferentiated VIN. Grading yielded the following results: VIN 1 (n = 10), VIN 2 (n = 11) and VIN 3 (n = 6). Additionally, VIN lesions from 26 patients could be tested for the presence of HPV DNA. HPV DNA, predominantly type 16, was present in 8 (31%) of them. Seven of these eight patients had VIN 2 or 3. During follow-up, three patients progressed to (early) invasive carcinoma. In two of these patients, differentiated VIN was observed overlying early invasive SCC. Conclusions: VIN related to LS without coexisting SCC is likely to be undifferentiated, in contrast to what was previously thought. HPV DNA was demonstrated in 31% of the lesions, and was strongly related to high-grade VIN.

The conventional direct referral to colposcopy of persistent borderline or mildly dyskaryotic (BMD) smears in cervical cancer screening leads to considerable unnecessary referrals and associated anxiety and costs. This may be improved by including testing for oncogenic human papillomavirus (HPV) in the triage. We assessed costs and side effects (referrals, treatments and time in follow-up) for 3 possible HPV triage strategies (immediate HPV testing, a 6-month delay in HPV testing, a 2-stage combination of both) and compared them with the conventional strategy. The assessments are based on recent Dutch data from various national databases and trials. We estimated that the referral rate could be reduced by 49, 58 and 58% with immediate, delayed and 2-stage HPV testing, respectively. As a consequence, the average length of follow-up, as well as average costs, also decrease. Therefore, we advocate including HPV testing before referring to colposcopy. Among the 3 HPV strategies, analysis of additional aspects favors implementation of immediate HPV testing.

Vulvar intraepithelial neoplasia (VIN) is a premalignant disorder caused by human papillomaviruses. Basic knowledge about the molecular pathogenesis of VIN is sparse. Therefore, we have analyzed the gene expression profile of 9 VIN samples in comparison to 10 control samples by using genome wide Affymetrix Human U133A plus2 GeneChips. Results were validated by quantitative real-time RT-PCR analysis and immunostaining of a few representative genes (TACSTD1, CCNE2, AR and ESR1). Significance analysis of microarrays (SAM) showed that 1,497 genes were differentially expressed in VIN compared to controls. By analyzing the biological processes affected by the observed differences, we found that VIN appears to be a highly proliferative disease; many cyclins (CCNA, CCNB and CCNE) and almost all prereplication complex proteins are upregulated. Thereby, VIN does not seem to depend for its proliferation on paracrine or endocrine signals. Many receptors (for example ESR1 and AR) and ligands are downregulated. Furthermore, although VIN is not an invasive disease, the inhibition of expression of a marked number of cell-cell adhesion molecules seems to indicate development towards invasion. Upon reviewing apoptosis and angiogenesis, it was observed that these processes have not become significantly disregulated in VIN. In conclusion: although VIN is still a premalignant disease, it already displays several hallmarks of cancer.

Objective To study diagnostic and therapeutic strategies, outcomes, and follow-up in a large series of women with adenocarcinoma in situ (AIS) of the uterine cervix and investigate if human papillomavirus (HPV) typing among women with negative cytology reports would have helped with early AIS detection. Materials and Methods Records of 132 AIS cases diagnosed between 1989 and 2012 were retrieved. Clinical and pathological data were reviewed and analyzed. Results Mean age at diagnosis was 37 years. Seventy-two percent (n = 95) of all patients were asymptomatic; diagnosis was established using cytology and biopsy. Primary treatment for 124 patents was cold knife cone or loop electrosurgical excision procedure (LEEP). Positive margins were found in 18% of those women treated with CKC versus 40% in those treated with LEEP. The mean follow-up time was 62 months (range, 2-217 months; median, 46 months). Three recurrences were found after conservative treatment in 86 patients. High-risk HPV (hrHPV) positivity was detected in 115 (96%) of 120 patients, with HPV-18 being the most commonly occurring subtype (51%). Conclusions There is a small risk of relapse after conservative therapy with cold knife cone or LEEP when resection margins are negative in women with AIS. Patients should be given the options of hysterectomy or conservative therapy with strict follow-up.

In the Netherlands 2% of cervical smears in the cervical cancer screening program are read as borderline or mildly dyskaryotic cytology (BMD smear). Only in about 10% of these women a high-grade CIN lesion (CIN II-III) is present; therefore referral is for the majority unnecessary. In our study triage with high-risk HPV (hrHPV) testing was used to identify women at risk for development of high-grade CIN lesions after a repeat BMD smear. A "wait-and-see" period was incorporated allowing clearance of HPV and regression of the lesion. Women with a low-grade lesion, irrespective of their HPV status, were monitored at 12 months; women with a high-grade lesion were monitored at 6 and 12 months. Fifty-one of the 105 women (49%) were hrHPV negative at baseline; none of them showed progression of the lesion within the first year of follow-up (NPV 100%). High-grade CIN was present in 1 patient who was HPV negative at baseline (2%); she demonstrated regression after 12 months. Nineteen of the hrHPV positive women (35%) demonstrated a high-grade CIN lesion at baseline and 3 cleared hrHPV after 6 months, with a subsequent regression of CIN. Ten women remained hrHPV positive with persistence of high-grade CIN and were eventually treated. At baseline, 35 hrHPV positive women demonstrated a low-grade lesion, 19 remained hrHPV positive after 12 months and 5 developed high-grade CIN. Sixteen out of the 35 cleared the hrHPV infection without progression of the lesion. In conclusion, triage, using hrHPV testing for women with persistent BMD cytology, can select women who are not at risk for development of high-grade CIN. We recommend return to the screening program without referral for colposcopic examination if hrHPV is absent. For hrHPV positive women, a repeat hrHPV test after another 6 months is suggested. Referral is only required if persistence of hrHPV is established.

Objective. Recently, gene expression profiling techniques have been used on several human cancers to classify tumor subgroups with a specific biological behavior, which were previously undetected by the conventional histopathologic staging systems. In the current study, the clinical usefulness and prognostic value of gene expression profiling in human endometrial carcinomas were studied. Methods. A macro cDNA array, containing cDNAs of 588 genes selected from different areas of cancer research, was used to generate gene expression profiles of tumor tissue samples. The gene expression profiles of 12 endometrial cancers, 3 benign (e.g. noncancer) endometrial tissue samples and 3 myometrial tissue samples, taken from human surgical specimen, were compared. Results. The efficacy to generate a gene expression profile of these tissue samples was 77%. The RNA samples could be randomly taken from the tissue samples and were highly reproducible. Cluster analysis of gene expression profiles of the different samples showed that the benign endometrial and the myometrial samples clustered separately from the tumor samples, indicating that the gene expression profiles were tissue specific and not patient specific. Cluster analysis of the tumor samples revealed two distinct tumor clusters. Ranking of the tumors in the two clusters showed high similarity with the histopathologic classification [International Federation of Gynecology and Obstetrics (FIGO) grading]. Conclusion. Classification of endometrial tumors on basis of their gene expression profiles showed similarity with the FIGO grading system.

Our study attempts to establish the relationship between telomerase activity and allelic imbalance (AI) on chromosomes 3p and 6 in high-risk HPV-containing cervical lesions. These chromosomes were implicated previously in telomerase regulation in HPV containing immortalized cells and cervical cancer cells. Allelotyping and telomerase analysis were carried out on 28 high-grade cervical lesions (CIN III: n = 20; cervical carcinomas: n = 8), using 23 microsatellite markers on 3p, 6p and 6q. Clear telomerase activity was found in 17 of 28 lesions (61%). Allelic imbalance frequency at 6q14-22 was significantly higher in lesions with detectable telomerase activity, compared to lesions without telomerase activity (p = 0.02). No association was found between telomerase activity and AI at any of the remaining regions studied on 3p and chromosome 6. In addition, in telomerase positive passages of the HPV 16 immortalized cell line FK16A, shown recently to be responsive to chromosome 6 mediated telomerase repression, AI was found in the overlapping region of 6q14-27. These data suggest that 6q14-22 may contain 1 or more genes involved in telomerase deregulation and immortalization during cervical carcinogenesis.

We followed 353 women referred with abnormal cervical cytology in a non-intervention cohort study. In 91 pregnant women we compared high-risk human papilloma virus rates in the subsequent trimesters and postpartum in comparison to 262 non-pregnant women. High-risk human papilloma virus clearance was compared with 179 high-risk human papilloma virus positive non-pregnant women. Our main questions were: (1) do high-risk human papilloma virus rates change during pregnancy?; and (2) is there any difference between high-risk human papilloma virus clearance in pregnant and non-pregnant women? Women were monitored 3–4 monthly by cytology, colposcopy, and high-risk human papilloma virus testing. The median follow-up time was 33 months (range 3–74). Non-pregnant women showed prevalence rates of high-risk human papilloma virus of 64, 57, 53, and 50%, respectively, in four subsequent 3-months periods since the start of the study. These high-risk human papilloma virus rates were higher than in the three trimesters of pregnancy, and during the first 3 months postpartum, i.e. 50, 44, 45, and 31%, respectively. Postpartum only, this difference was statistically significant (P=0.004). Paired comparisons of high-risk human papilloma virus prevalence rates of the different trimesters with the postpartum rate showed (McNemar test) decreased rates: first trimester: 18% (P=0.02), second trimester: 13% (P=0.02) and third trimester: 23% (P

The relation between human papillomavirus type 16 (HPV 16) viral load in cervical scrapes and development of high-grade cervical intraepithelial neoplasia (CIN II or III) was studied in a nested case-control study of women with normal cytology (group A) and in a cohort of women with abnormal cytology (group B). HPV 16 DNA load was determined using a quantitative real-time PCR assay. In group A, case women (women with CIN II/III, n = 12) had a significantly higher viral load than control women (women with CIN ≤ I, n = 47). This resulted in an increased relative risk of women with the 50% highest viral load for development of CIN II/III (OR 7.7; CI 1.6–33). In group B, women with CIN II/III (n = 38) had a significantly higher viral load than women with CIN ≤ I (n = 25). Women with the 50% highest viral load had an increased relative risk of CIN II/III (OR 3.2; CI 1.1–9.3) and a decreased chance of both viral clearance and cytologic regression. Our data suggest that in women with normal cytology an increased HPV 16 load confers an increased risk of developing a CIN lesion. A sustained high viral load is subsequently informative for progression to a high-grade CIN lesion. © 2002 Wiley-Liss, Inc.

Item does not contain fulltext OBJECTIVE: Women treated for high-grade cervical disease (cervical intraepithelial neoplasia grade 2 or grade 3 [CIN2/3]) face a significant risk of developing post-treatment disease. Therefore, in most European countries, they are monitored by cytologic testing at 6, 12, and 24 months after treatment. Although testing for high-risk types of the human papillomavirus (hrHPV) in the follow-up seems to be a valuable supplementary method, its use is not yet fully explored. METHODS: Besides reviewing the literature, we completed a long-term follow-up study describing the cumulative risk for CIN2/3 or cancer (CIN2+) of different hrHPV and cytology test results after treatment. CONCLUSIONS: High-risk HPV testing improves the sensitivity to detect posttreatment CIN2/3 (relative sensitivity=1.15, 95% confidence interval [CI]=1.06-1.25), but the highest sensitivity (95%, 95% CI=91%-98%) is reached by performing cotesting (both cytology and hrHPV). The CIN2+ risk after a single negative cotesting result taken 6 months after treatments was similar to the risk after 3 consecutive negative cytologic test results (5-y CIN2+ risk being 3.0% [95% CI=1.5%-6.1%] and 2.9% [95% CI=1.2%-7.1%], respectively). Women who test negative for cotesting at both 6 and 24 months after treatment have a minimal risk of developing CIN3+ in the next 5 years (0.0%, 95% CI=0.0%-3.0%). RECOMMENDATIONS: We propose a new posttreatment surveillance protocol, consisting of combined testing with both cytology and hrHPV at 6 and 24 months after treatment. After 2 negative cotesting results, women should be retested after 5 years.

Background: To generate knowledge about potential improvements to human papillomavirus (HPV) vaccination information and organization strategies, we assessed how aspects of HPV vaccination are associated with parents' preferences for their daughters' uptake, and which trade-offs parents are willing to make between these aspects. Methods: A discrete choice experiment (DCE) was conducted among parents with a daughter aged 10-12 years. Panel mixed logit regression models were used to determine parents' preferences for vaccination. Trade-offs were quantified between four vaccination programme aspects: degree of protection against cervical cancer, duration of protection, risk of serious side-effects, and age of vaccination. Results: Total response rate was 302/983 (31%). All aspects influenced respondents' preferences for HPV vaccination (p < 0.05). Respondents preferred vaccination at age 14 years instead of at a younger age. Respondents were willing to trade-off 11% of the degree of protection to obtain life-time protection instead of 25 years. To obtain a vaccination with a risk of serious side-effects of 1/750,000 instead of 1/150,000, respondents were willing to trade-off 21%. Conclusions: Uptake may rise if the age ranges for free HPV vaccinations are broadened. Based on the trade-offs parents were willing to make, we conclude that uptake would increase if new evidence indicated outcomes are better than are currently understood, particularly for degree and duration of protection.

Objective To study colposcopic performance in diagnosing high-grade cervical intraepithelial neoplasia or cervical cancer (CIN2+ and CIN3+) using colposcopic characteristics and high-risk human papillomavirus (hrHPV) genotyping. Design Cross-sectional multicentre study. Setting Two colposcopy clinics in The Netherlands and Spain. Population Six hundred and ten women aged 17 years and older referred for colposcopy because of abnormal cytology. Methods A cervical smear was obtained. Colposcopists identified the worst lesion, graded their impression and scored the colposcopic characteristics of the lesions. Up to four biopsies were collected, including one biopsy from visually normal tissue. Main outcome measures CIN2+ and CIN3+, positive for HPV16 or other high-risk HPV types (non-16 hrHPV-positive). Results The mean age in HPV16-positive CIN2+ women was 35.1 years compared with 39.1 years in women with other hrHPV types (P = 0.002). Sensitivity for colposcopy to detect CIN2+ was 87.9% (95%CI 83.2–91.5), using colposcopic cut-off of ‘any abnormality’. The remaining CIN2+ were found by a biopsy from visually normal tissue or endocervical curettage (ECC). Detection of CIN2+ by lesion-targeted biopsies was not different between HPV16-positive women [119/135; 88.1% (95%CI 81.2–92.9)] and non-16 hrHPV-positive women [100/115; 87.0% (95%CI 79.1–92.3); P = 0.776]. In multivariate analysis, ‘acetowhitening’ [odds ratio (OR) 1.91, 95%CI 1.56–3.17], ‘time of appearance’ (OR 1.95, 95%CI 1.21–3.15) and ‘lesion >25% of visible cervix’ (OR 2.25, 95%CI 1.44–3.51) were associated with CIN2+. Conclusions In this population following European screening practice, HPV16-related CIN2+ lesions were detected at younger age and showed similar colposcopic impression as non-16 hrHPV high-grade lesions. There was no relationship between any of the colposcopic characteristics and HPV16 status.

We assessed a possible role for high-risk human papillomavirus (HPV) testing in the policy after treatment for cervical intraepithelial neoplasia (CIN) 2 or 3 (moderate to severe dysplasia). According to the Dutch guidelines follow-up after treatment consists of cervical cytology at 6, 12 and 24 months. Colposcopy is only performed in case of abnormal cervical cytology. In this observational study 184 women treated for CIN 2 or 3 were prospectively monitored by cervical cytology and high-risk HPV testing 3, 6, 9, 12 and 24 months after treatment. Post-treatment CIN 2/3 was present in 29 women (15.8%). A positive high-risk HPV test 6 months after treatment was more predictive for post-treatment CIN 2/3 than abnormal cervical cytology (sensitivity 90% and 62% respectively, with similar specificity). At 6 months the negative predictive value of a high-risk HPV negative, normal smear, was 99%. Largely overlapping, partly different groups of women with post-treatment CIN 2/3 were identified by HPV testing and cervical cytology. Based on these results we advocate to include high-risk HPV testing in monitoring women initially treated for CIN 2/3. In case of a high-risk HPV positive test or abnormal cervical cytology, colposcopy is indicated. All women should be tested at 6 and 24 months after treatment and only referred to the population-based cervical cancer screening programme when the tests are negative on both visits. © 2001 Cancer Research Campaign http://www.bjcancer.com

This study aimed to assess the role of specific human papillomavirus type 16 (HPV-16) variants, in combination with p53 codon 72 polymorphism genotypes, in cervical carcinogenesis. An initial sequence analysis of HPV-16 long control, E6 and E7 regions of 53 well-defined cervical samples containing HPV-16 revealed that a T to G transition at nucleotide position 350 within the E6 open reading frame was the most common variation, the frequency of which seemed to decrease with increasing severity of the lesion. Therefore, a total of 246 cervical samples of residents of The Netherlands was specifically analysed for HPV-16 350G/T variants and/or p53 codon 72 genotypes. These comprised HPV-negative normal cervical scrapes (n=40), normal cervical scrapes containing HPV-16 (n=46), scrapes containing HPV-16 from women with abnormal cervical cytology participating in a non-intervention follow-up study without (n=38) and with (n=51) a histologically proven cervical intraepithelial neoplasia (CIN) III lesion at the end of the study, and cervical squamous cell carcinomas (n=71). Neither specific HPV-16 350G/T variants nor specific p53 genotypes were associated with a higher risk of developing CIN III or cervical cancer. However, HPV-16 350T variants were significantly over-represented in p53 Arg homozygous women with cervical cancer. This suggests that, in p53 Arg/Arg women, infection with HPV-16 350T variants confers a higher risk of cervical cancer.

T-helper (Th) cell-dependent IL-2 production and plasma IgG responses to virus-like particles consisting of the human papillomavirus type 16 (HPV-16) major capsid protein L1 (L1-VLP) were determined in patients with cytological evidence of cervical intraepithelial neoplasia (CIN) participating in a non-intervention prospective cohort study. IgG responses were associated with HPV-16 persistence and high-grade CIN lesions, while high frequencies of Th responses were observed in patients with both virus clearance and virus persistence, irrespective of CIN grade. The IgG response was found in conjunction with an IL-2 response to L1-VLP in 87% of the patients. Recognition of the HPV-16 L1 Th epitope (amino acids 311-335) was found to be more closely associated than recognition of L1-VLP as a whole to HPV exposure and CIN development. Among the HPV-16+ patients included in this study, those showing a Th response to amino acids 311-335 were more likely to carry the HLA DRB1*11/DQB1*0301 haplotype, while those showing an IgG response to L1-VLP were more likely to carry DRB1*0101/DQB1*0501. However, neither cell-mediated nor humoral immune responses against HPV-16 L1 appear to be sufficient for the natural control of HPV infection and CIN development.

High-risk human papillomavirus (HPV) infection plays an important role in cervical intra-epithelial neoplasia (CIN), but HPV infection alone is not sufficient for progression to cervical cancer. Several lines of evidence suggest that cellular immune surveillance is important in the control of HPV infection and the development of CIN. The presentation to T cells of target viral peptides in the context of HLA molecules is influenced by the genetic polymorphisms of both HPV and HLA and thereby influences the host immune response and clinical outcome of HPV infection. HLA class I and II polymorphism in susceptibility for HPV 16 infection, development and progression of CIN was analyzed in a group of 118 patients participating in a prospective study of women with initial abnormal cytology. Patients were stratified according to HPV status and course of the disease. HLA-B*44 frequency was increased in the small group of patients with a lesion that showed clinical progression during follow-up [OR = 9.0 (4.6-17.5), p = 0.007]. HLA-DRB1*07 frequency was increased among HPV 16-positive patients compared with patients who were negative for all HPV types [OR = 5.9 (3.0-11.3), p = 0.02]. Our results are consistent with the immunogenetic factors associated with disease progression being different from those associated with susceptibility to HPV 16 infection. Sequencing of the HPV 16 E6 and E7 open reading frames of a subset of these patients (n = 40) showed the frequency of HPV 16 variants to be similar to other studies. However, there was no significant correlation between variant incidence and disease progression or viral persistence and no significant correlation with any HLA allele. It appears that multiple HLA types can influence HPV 16-associated cervical dysplasia but the role of HPV 16 variants in disease progression and susceptibility in relation to HLA polymorphism remains unclear.

Distribution of the photosensitizer Foscant (meta-tetrahydroxyphenylchlorin, mTHPC), after i.v. or i.p. injection, was investigated in Wag/Rij rats bearing i.p. tumours. These results were compared with the efficacy of mTHPC-mediated photodynamic therapy for illumination intervals of 4 hr to 3 days. For the distribution experiments a single tumour (CC531 colon carcinoma) was implanted intra-abdominally in a fat pad, or a cell suspension (1 3 106 CC531 cells) was injected into the peritoneal cavity, which results in a dissemination of tumour nodules on the peritoneum. 14 C-mTHPC was not selectively taken up in the single-tumour model after i.v. or i.p. injection, but higher concentrations were achieved for i.p. administration. For this tumour model the concentration ratios between tumour and normal tissue never exceeded a value of 3. In the disseminated-tumour model, an uptake of up to 40% of the injected dose was found per gram tumour at 4 hr after an i.p. injection and this resulted in very high (G14) concentration ratios of tumour to normal tissues. Low uptake was found after the i.v. injection route (1% of the injected dose per gram tumour) with lower tumour/normal tissue ratios (F8). The efficacy of i.p. photodynamic therapy (IPPDT) was evaluated using the single-tumour model only. The lower abdomen was illuminated at 4 hr to 3 days after mTHPC, and tumour size was repeatedly measured via a small laparoscopy. Significant delay in tumour regrowth was achieved for 6 J · cm 22 at 1 day after i.v., or at 4 hr after i.p. mTHPC (p values 0.019 and 0.045 respectively). Response to PDT, of tumours implanted in the fat pad, was not greater for i.p. administration of the photosensitizer and there was a poor correlation between times of maximum drug uptake in tumours and optimal illumination times for PDT efficacy. Int. J. Cancer 73:230‐235, 1997. r 1997 Wiley-Liss, Inc. The treatment of ovarian cancer presents a serious oncologic challenge because of the poor overall 5-year survival of 32%. Ovarian cancer tends to disseminate in the peritoneal cavity, and the local and superficial nature of this dissemination makes the application of local therapy, such as photodynamic therapy (PDT), attractive. PDT is an anti-cancer therapy in which a photosensitizer is administered systemically or topically and excited by light of a wavelength corresponding to an absorption peak of the photosensitizer. Light of wavelengths used to excite currently available photosensitizers penetrates less than 1 cm into tissue, and therefore toxicity (both normal tissue and tumour) is limited to a fixed depth. Because of the superficial character of the treatment and the lack of systemic toxicity (photosensitizers are non-toxic until excited by illumination), PDT would appear to be suitable for the treatment of

BACKGROUND The biologic rationale for combining cisplatin with locoregional hyperthermia (HT) relates to the potentiating effect of HT on cisplatin cytotoxicity. METHODS Patients with recurrent cervical carcinoma, who had a pelvic recurrence after radiotherapy, were treated with weekly cycles of locoregional HT (using the 70-megahertz, 4 antenna-phased array system for 1 hour and cisplatin, 50 mg/m2 intravenously [i.v.], for a maximum of 12 cycles.) RESULTS Twenty-three patients were entered in this study. A total of 169 cycles were given. Responses were observed in 12 of 23 patients, a response rate of 52% (95% confidence interval, 31-73%). Salvage surgery became possible in 3 of 12 responding patients, whose tumors were previously considered unresectable. The median duration of response was 9.5+ months, the median overall survival was 8+ months, and the 1-year survival was 42%. No correlation was found between treatment outcome and clinical parameters such as age, weight, performance status, and histology. Thermal parameters such as T20, T50, and T90 were higher in responding patients, but were not significantly different from nonresponding patients. Overall toxicity was moderate. Subcutaneous fatty necrosis due to HT occurred in 10% of the cycles, whereas 2 patients developed skin burns. Squamous cell carcinoma antigen proved to be a valuable tool for the evaluation of response and detection of progression. CONCLUSIONS Weekly locoregional HT and cisplatin, 50 mg/m2 i.v., for a maximum of 12 cycles was effective treatment in patients with a previously irradiated recurrent carcinoma of the uterine cervix. Cancer 1997; 79:935-43. © 1997 American Cancer Society.

IgG reactivity against the immunodominant region aa6-35 of Human Papillomavirus (HPV) type-16 E7 was determined in a peptide-based ELISA in a cohort study of women with initial mild to moderate cervical dyskaryosis. On the basis of HPV DNA patterns, as determined by PCR in cervical smears prior to IgG testing, HPV-16-positive patients were grouped as having either a cleared, a fluctuating, or a persistent HPV-16 infection. In a cross-sectional study at the start of serological follow-up, positive IgG reactivities were found more often in the total group of HPV-16-positive patients (20.0%) than in patients consistently typed as HPV-negative over a period of at least 12 months prior to testing (3.1%, p < 0.04). The highest proportion of positive responders was found in patients with a cleared HPV-16 infection (29.4%). Also, IgG reactivities found in HPV-16 clearance patients were significantly higher than in patients with a persistent infection (p < 0.008). In a subsequent longitudinal study over a period of up to 27 months, consistently positive reactivities were observed in patients with cleared viral infections who showed seroreactivity in the cross-sectional study, while mostly negative reactivities were found in patients with viral persistence. HPV-16 E7-specific IgG subclass responses were determined in a selection of 19 CIN and 11 HPV-16-positive cervical carcinoma (CeCa) patients with positive E7-specific IgG responses. IgG2 was predominant in the CIN patients, suggesting the presence of IFNgamma (Th1) at the site of HPV infection. In the CeCa patients IgG1 and IgG2 were produced equally, possibly indicating a rise in Th2 cytokines. Our data suggest that HPV-16 E7 IgG reactivity in a subset of CIN patients with viral clearance may result from successful Th1 responses.

The purpose of this work was to study intraobserver and interobserver variation in the interpretation of colposcopic images of cervical intraepithelial neoplasia (CIN). Twenty-three experienced colposcopists were asked to assess colposcopic images presented on slides and to select the biopsy site. Eleven cases were independently interpreted twice with an interval of 2-3 months by all observers. No information about the cytological classification was available. In each case the "majority assessment" was considered as the standard, being "no CIN" in 2 cases, CIN I in 4 cases, CIN II in 3 cases, and CIN III in 2 cases. Intraobserver concordance was 66.7%, the kappa value was 0.54. Interobserver agreement was found to be 52.4 and 51.0% in the first and second sessions, respectively, while the mean kappa values were 0.41 and 0.33, respectively. In selecting the site for biopsy, 77.4% of all observers agreed while the same site was selected in 85.3% of cases by the individual colposcopist in the two sessions. Overall, CIN I and II interpretations revealed lower levels of agreement than no CIN or CIN III interpretations. It is concluded that observer variability in interpreting colposcopic images and selecting the site for biopsy is in the same range as observer variation in other subjective diagnostic tests such as cytology and histopathology. This variation should be taken into account in the colposcopical management of patients with abnormal cytology.

Background. The clinical value of pretreatment serum concentrations of cytokeratin 19 fragments, measured by Cyfra 21-1, was compared with tissue polypeptide antigen (TPA) and squamous cell carcinoma antigen (SCC-Ag) in 78 patients with squamous cell cervical cancer. Methods. Serum levels were compared with tumor stage, size, lymph node status, parametrial involvement, and prognostic data. The clinical performance of the different tests was evaluated by their receiver operating characteristic (ROC) curves. Results. Serum levels of all markers were related significantly to tumor stage and size. Elevated serum levels of these markers were not found to be predictive for the presence of lymph node metastases. In contrast, a positive relation was found between quantitative serum Cyfra 21-1, TPA, and SCC-Ag levels and the presence of either lymph node metastases or parametrial involvement (i.e., extracervical disease). An elevated, i.e. positive, serum Cyfra 21-1 level was related significantly to the presence of extracervical disease (P = 0.020). The clinical performance of each serum marker in predicting lymph node metastases or parametrial involvement appeared to be similar as expressed by their ROC curves. In the univariate analysis, Cyfra 21-1, TPA, and SCC-Ag showed prognostic value with respect to disease free interval and survival. Elevated serum levels were associated with a poor prognosis. However, after adjusting for tumor stage and size, none of these markers remained statistically significant. Conclusions. Cyfra 21-1 may be of additional value in assessing stage of disease, tumor size, and the presence of extracervical disease in patients with cervical cancer. Determining its value during follow-up warrants further study.

BACKGROUND: Many studies have examined the short-term value of high-risk human papillomavirus (hrHPV) testing in predicting cumulative risk of cervical intraepithelial neoplasia grade 3 or cancer (CIN3+). This study focuses on long-term CIN3+ risk after initial wait and see policy. METHODS: A total of 342 women with abnormal cytology of borderline/mild dyskaryosis (BMD) or worse (>BMD), included between 1990 and 1992, were followed-up by cytology and hrHPV testing until 1996 and monitored by cytology thereafter. Primary endpoint was cumulative CIN3+ risk by December 2009. RESULTS: Women with BMD had a 5-year CIN3+ risk of 22.5% (95% confidence interval (CI) 17.0-29.1) and of 0.7% (0.1-4.5) in the subsequent 5 years. High-risk human papillomavirus-negative women with BMD had a 5-year risk of BMD had a 5-year risk of 45.1% (36.4-54.1) and of 3.5% (0.9-12.2) in the subsequent 5 years CONCLUSION: Women with BMD have an elevated CIN3+ risk for 5 years only; afterwards their risk is similar to the general population. High-risk human papillomavirus-negative women with BMD may return to regular screening directly. All other women with >= BMD should be referred for additional testing and/or colposcopy. British Journal of Cancer (2012) 106, 817-825. doi:10.1038/bjc.2012.5 www.bjcancer.com Published online 14 February 2012 (C) 2012 Cancer Research UK

Objective Currently, women treated for high-grade cervical intraepithelial neoplasia (CIN 2/3) are followed-up by cytology to monitor them for residual and recurrent (post-treatment) disease. This systematic review and meta-analysis determine the test performance of testing for high-risk types of the human papillomavirus (hrHPV), cytology and co-testing (combined hrHPV testing and cytology) in predicting high-grade post-treatment disease (CIN2+). Methods Studies that compared at least two of three post-treatment surveillance methods, and were published between January 2003 and May 2011, were identified through a bibliographic database search (PubMed, Embase.com and Wiley/Cochrane Library). Identification of relevant studies was conducted independently by two reviewers with a multi-step process. The reference standard used to diagnose post-treatment disease was histologically confirmed CIN2+. Sensitivity, specificity, diagnostic odds ratios and relative sensitivity and specificity were calculated for each study. Pooled estimates were calculated using a random effects model if heterogeneity among studies was significant, otherwise by using a fixed effects model. Estimates were reported with 95% confidence intervals (95%CI). Results Out of 2410 potentially relevant citations, 8 publications, incorporating 1513 treated women, were included. Pooled sensitivities were 0.79 (95%CI 0.72–0.85) for cytology, 0.92 (0.87–0.96) for hrHPV testing, and 0.95 (0.91–0.98) for co-testing. HrHPV testing was more sensitive than cytology to predict post-treatment CIN2+ (relative sensitivity 1.15; 95%CI 1.06–1.25). Pooled specificities were 0.81 (95%CI 0.74–0.86) for cytology, 0.76 (0.67–0.84) for hrHPV testing and 0.67 (0.60–0.74) for co-testing. HrHPV testing and cytology had a similar specificity (relative specificity 0.95, 95%CI 0.88–1.02). Conclusions This review indicates that the hrHPV test should be included in post-treatment testing 6months after treatment, because hrHPV testing has a higher sensitivity than cytology in detecting high-grade post-treatment disease and has a similar specificity.