HPV self-sampling in CIN2+ detection: sensitivity and specificity of different RLU cut-off of HC2 in specimens from 786 women.

AIMS: Mortality for cervical cancer varies between the different regions of the world, with high rates in low-income countries where screening programmes are not present and organised. However, increasing screening coverage is still a priority in all countries: one way to do that is to base screening on self-sampled screening. The success of a self-sampling screening strategy depends on capacity to recruit unscreened women, on the performance and acceptability of the device and on the clinical performance of the high-risk human papillomavirus (HPV) test. METHODS: This study based on 786 enrolled women investigates the best cut-off value of Hybrid Capture 2 HPV test (HC2) for self-sampled specimens in terms of sensitivity and specificity. RESULTS: In this population, we found that the sensitivity and the specificity for cervical intraepithelial neoplasia grade 2 or more detection of HC2 performed on self-sampled specimens were 82.5% and 82.8%, respectively considering the relative light units (RLU) cut-off value of 1. Increasing the cut-off value the sensitivity decreases and the specificity raises and the best area under the curve for the RLU cut-off value is 1. CONCLUSIONS: Our results confirm that the cut-off value of 1 suggested by Qiagen for PreservCyt specimen is the best cut-off value also for self-sampled specimens.

Comparison of Onclarity Human Papillomavirus (HPV) Assay with Hybrid Capture II HPV DNA Assay for Detection of Cervical Intraepithelial Neoplasia Grade 2 and 3 Lesions.

Analytical and clinical performance validation is essential before introduction of a new human papillomavirus (HPV) assay into clinical practice. This study compares the new BD Onclarity HPV assay, which detects E6/E7 DNA from 14 high-risk HPV types, to the Hybrid Capture II (HC2) HPV DNA test, to concurrent cytology and histology results, in order to evaluate its performance in detecting high-grade cervical lesions. A population of 567 women, including 325 with ≥ASCUS (where ASCUS stands for atypical cells of undetermined significance) and any HC2 result and 242 with both negative cytology and negative HC2 results, were prospectively enrolled for the study. The overall agreement between Onclarity and HC2 was 94.6% (95% confidence intervals [CI], 92.3% to 96.2%). In this population with a high prevalence of disease, the relative sensitivities (versus adjudicated cervical intraepithelial neoplasia grades 2 and 3 [CIN2+] histology endpoints) of the Onclarity and HC2 tests were 95.2% (95% CI, 90.7% to 97.5%) and 96.9% (95% CI, 92.9% to 98.7%), respectively, and the relative specificities were 50.3% (95% CI, 43.2% to 57.4%) for BD and 40.8% (95% CI, 33.9%, 48.1%) for HC2. These results indicate that the BD Onclarity HPV assay has sensitivity comparable to that of the HC2 assay, with a trend to an increased specificity. Moreover, as Onclarity gives the chance to discriminate between the different genotypes, we calculated the genotype prevalence and the absolute risk of CIN2+: HPV 16 was the most prevalent genotype (19.8%) with an absolute risk of CIN2+ of 77.1%.

Self-sampling to increase participation in cervical cancer screening: an RCT comparing home mailing, distribution in pharmacies, and recall letter.

BACKGROUND: We performed a multicentre randomised controlled trial to evaluate the effect on participation in organised screening programmes of a self-sampling device mailed home or picked up at a pharmacy compared with the standard recall letter. METHODS: Women aged 30-64 non-responding to screening invitation were eligible. Response rate to first invitation ranged from 30% to 60% between centres. The control was the standard reminder letter to undergo the test used by the programme (Pap test in three centres and HPV DNA test in three other centres). Home mailing of the self-sampler was preceded by a letter with a leaflet about HPV. The analysis was intention-to-treat. RESULTS: In all, 14 041 women were randomised and recruited: 5012 in the control arm, 4516 to receive the self-sampler at home, and 4513 to pick up the self-sampler at a pharmacy. Participation was 11.9% in the control, 21.6% (relative participation: 1.75; 95% CI 1.60-1.93) in home, and 12.0% (relative participation: 0.96; 95% CI 0.86-1.07) in the pharmacy arms, respectively. The heterogeneity between centres was high (excess heterogeneity of that expected due to chance, i.e., I(2), 94.9% and 94.1% for home and pharmacy arm, respectively). The estimated impact on the overall coverage was +4.3% for home mail self-sampling compared with +2.2% for standard reminder. CONCLUSIONS: Home mailing of self-sampler proved to be an effective way to increase participation in screening programmes, even in those with HPV as primary testing. Picking up at pharmacies showed effects varying from centre to centre.

A phase-III prevention trial of low-dose tamoxifen in postmenopausal hormone replacement therapy users: the HOT study.

BACKGROUND: Postmenopausal hormone replacement therapy (HRT) relieves menopausal symptoms and may decrease mortality in recently postmenopausal women, but increases breast cancer risk. Low-dose tamoxifen has shown retained activity in phase-II studies. METHODS: We conducted a phase-III trial in 1884 recently postmenopausal women on HRT who were randomly assigned to either tamoxifen, 5 mg/day, or placebo for 5 years. The primary end point was breast cancer incidence. RESULTS: After 6.2 ± 1.9 years mean follow-up, there were 24 breast cancers on placebo and 19 on tamoxifen (risk ratio, RR, 0.80; 95% CI 0.44-1.46). Tamoxifen showed favorable trends in luminal-A tumors (RR, 0.32; 95% CI 0.12-0.86), in HRT users <5 years (RR, 0.35; 95% CI 0.15-0.82) and in women completing at least 12 months of treatment (RR, 0.49; 95% CI 0.23-1.02). Serious adverse events did not differ between placebo and tamoxifen, including, respectively, coronary heart syndrome (6 versus 4), cerebrovascular events (2 versus 5), VTE (2 versus 5) and uterine cancers (3 versus 1). Vasomotor symptoms were 50% more frequent on tamoxifen. CONCLUSIONS: The addition of low-dose tamoxifen to HRT did not significantly reduce breast cancer risk and increased climacteric symptoms in recently postmenopausal women. However, we noted beneficial trends in some subgroups which may deserve a larger study.

Comparison of HE4, CA125 and ROMA algorithm in women with a pelvic mass: correlation with pathological outcome.

OBJECTIVE: The quality of first surgery is one of the most important prognostic factors in ovarian cancer patients. Pre-surgical distinction of benign and malignant pelvic mass plays a critical role in ovarian cancer management and survival. The aim of this study was to evaluate the clinical performance of ROMA algorithm and of CA125 and HE4 in the triage of patients with a pelvic mass undergoing surgery, in order to discriminate benign from malignant disease. METHODS: Three hundred and forty-nine pre- and post-menopausal women, aged 18 years or older undergoing surgery because of a pelvic mass were enrolled: serum concentrations of CA125 and HE4 were determined and ROMA was calculated for each sample. RESULTS: Median serum CA125 and HE4 levels were higher in patients with EOC compared to subjects with benign disease (p<0.0001). The resultant accuracy (using Receiver Operating Characteristics, ROC Area) values for HE4, CA125 and ROMA showed a good performance ranging from 89.8% for CA125 in pre-menopausal patients to 93.3% for ROMA in post-menopausal patients: AUC for ROMA resulted significantly higher in comparison to CA125 alone (93.3% vs 90.3%, p=0.0018) in post menopausal patients. A sub-analysis considering the 40 patients with endometrioid disease showed the highest accuracy of HE4 in these patients. CONCLUSIONS: Data presented confirm the accuracy of HE4 and of the ROMA algorithm in the distinction of ovarian carcinoma from benign disease, with a trend towards better performance for ROMA than for CA125 alone, statistically significant in postmenopausal patients.

"Low-grade positivity" of HPV viral load after atypical squamous cells of undetermined significance (ASC-US) cytology identifies women at low-risk for cervical intraepithelial neoplasia grade 2 and 3.

The correlation between high-risk HPV-DNA viral load, expressed as relative light units (RLU) values obtained from the Hybrid Capture 2 (HC2) test, and the prevalence of CIN2/CIN3 was investigated and statistically analyzed in 614 ASC-US consecutive cases. Cases were categorized into three groups according to RLU values: "low-grade positivity", "intermediate positivity" and "high-grade positivity", and the prevalence of CIN2/CIN3 was evaluated in the single groups and compared among them. CIN/CIN3 rates demonstrated a significant (p < 0.001) increase with a direct correlation with increasing RLU values: 4.6% (RLU from 1.0 to 10.0), 9.1% (RLU from 11.0 to 100.0) and 32.2% (RLU > 100.0) respectively. The prevalence of CIN2/CIN3 between the group with RLU < 10.0 (4.6%) and the group with RLU > 10 (24.2%) showed statistical significance (p = 0.0002). Increasing hrHPV viral load significantly correlates with increasing prevalence of CIN2/CIN3 in ASC-US cases.

HPV-DNA testing for cervical cancer precursors: from evidence to clinical practice.

The large amount of literature published over the last two decades on human papillomavirus (HPV)-DNA testing has definitely demonstrated the association between high-risk viral genotypes (hrHPV) and cervical cancer. Moreover, hrHPV-DNA testing has shown excellent performance in several clinical applications, from screening settings to the follow-up of treated patients, compared to conventional cytology or colposcopy options. On the other hand, when a huge number of reports are published on the same subject in a relatively short period of time, with many variations in settings, study designs and applications, the result is often confusion and decreased comprehension by readers. In daily office practice, several different situations (in symptomatic or asymptomatic women) can be positively managed by the correct use of hrHPV-DNA testing. Validated hrHPV-DNA testing and, specifically, the HC2® assay, due to its excellent sensitivity and negative predictive value together with optimal reproducibility, currently represent a powerful tool in the clinician's hands to optimally manage several situations related to HPV infection and the potential development of cervical cancer.

Human papillomavirus viral load expressed as relative light units (RLU) correlates with the presence and grade of preneoplastic lesions of the uterine cervix in atypical squamous cells of undetermined significance (ASCUS) cytology.

Human papillomavirus (HPV) testing is more sensitive and has higher negative predictive value (NPV) than the Pap test for the detection of cervical intraepithelial neoplasia (CIN) in patients with atypical squamous cells of undetermined significance (ASCUS) cytology, but has low specificity, leading to high referral rates to second-level triage. Our goal was to identify the prognostic significance of HPV viral load figures. We evaluated whether a correlation between viral load, expressed as relative light units/cutoff (RLU/CO), and the severity of cervical lesions existed in 614 ASCUS cases. Hybrid Capture 2 (HC2®) RLU/CO values, categorised into five classes, were correlated to clinical outcomes and statistically analysed. A significant correlation (p < 0.0001) was observed between increasing RLU values and the prevalence of high-grade CIN (CIN2/CIN3). The mean RLU values for negative, low-grade and high-grade lesions were 68.1, 172.5 and 1,020.0 RLU/CO, respectively (p < 0.0001). CIN2/CIN3 ranged from 4% for 0 < RLU/CO values ≤ 1, to 5% for 1 < RLU/CO values ≤ 10, to 9% for 10 < RLU/CO values ≤ 100, to 23% for 100 < RLU/CO values ≤ 1,000 and to 48% when RLU/CO values were >1,000 (p < 0.05). The HPV viral load in ASCUS cases significantly correlates with the severity of cervical cancer precursors. These data may have prognostic value, as they significantly correlate with the probability of a CIN2+ .

Progestin intrauterine device and GnRH analogue for uterus-sparing treatment of endometrial precancers and well-differentiated early endometrial carcinoma in young women.

BACKGROUND: To test the efficacy of levonorgestrel-release intrauterine device (LNG-IUD) plus gonadotropin-releasing hormone (GnRH) for treating women aged <40 years with atypical endometrial hyperplasia (AEH) or presumed International Federation of Gynecology and Obstetrics stage IA limited to the endometrium, well differentiated (G1), endometrioid endometrial cancer (EC), who wish to preserve their fertility. PATIENTS AND METHODS: A prospective observational study was conducted. Treatment consisted on the insertion of an LNG-IUD for 1 year plus GnRH analogue for 6 months. RESULTS: From January 1996 to June 2009, 20 and 14 patients with AEH and EC, respectively, were studied. Complete response rate was 95% in patients with AEH and 57.1% in women with EC-G1. A progression of the disease was observed in one (5%) and in four patients (28%) with AEH and EC, respectively. Four of 20 patients with AEH and 2 of 14 with EC-G1 experienced recurrences. The average relapse time was 36 months (range: 16-62 months). All of them were alive without evidence of disease at the last follow-up, mean: 29 months (range: 4-102 months). Nine women achieved 11 spontaneous pregnancies. CONCLUSIONS: The combined treatment showed effectiveness in a substantial proportion of patients with AEH and EC. Close follow-up during and after treatment is crucial.

Resource use and cost analysis of managing abnormal Pap smears: a retrospective study in five countries.

OBJECTIVE: To evaluate and compare treatment patterns and related resource use and costs in women with abnormal cervical smears in five countries. METHODS: Data from patient charts were collected for a minimum of 24 months, starting from the first recorded abnormal cervical smear. Costs, from the public health perspective, were calculated based on country-specific unit costs per procedure and expressed in euros. RESULTS: A total of 3,380 patient charts were reviewed. Subjects with suspected or detectable cervical cancer were excluded from the analysis (n = 380). A significant age difference of 1.8-2.6 years was observed between the lowest and highest severity of cytological and histological types (p < 0.05). The correlation between cytology and histology results was weak overall (35.8%) and varied widely between countries (ranging from 48% for Australia to 29.7% for the UK). As expected, countries with an organised screening programme (UK, Australia) diagnosed and initiated treatment at earlier disease stages. These countries demonstrated a much lower and narrower cost band for more advanced histological types. In contrast, other countries (Germany, Italy, Spain) followed an opportunistic screening programme in which advanced disease was diagnosed and treated at much higher and more varied costs. Histological, not cytological, results were the main factor underlying the cost differences per type. CONCLUSION: Costs and treatment patterns in women with abnormal cervical smears differ among countries due to the type of screening programme (organised versus opportunistic) and, consequently, the histological type. These results need to be taken into consideration when designing cost-effectiveness studies which include cervical cancer screening data.

Early detection of cancer: ideas for a debate.

Even if the overall number of cancer is increasing, the mortality has started to decrease in the Western World. The role of early detection in this decrease is a matter of debate. To assess its impact on mortality it is important to distinguish between diagnosis of cancer in symptomatic patients, and early detection in asymptomatic individuals who may self-refer or who may be offered ad hoc or systematic screening. The policies for early detection and screening vary greatly between European countries, despite many similarities in their cancer burden, and this partly reflects the uncertainties surrounding asymptomatic testing for cancer. A Task Force of European expert, held in Azzate (VA), Italy, established to address these issues, acknowledged the need for more research in the field of individual risk assessment since general statistics are more and more perceived as inadequate to design personal early detection plans. The group also recognised that combinations of early detection and screening will enforce the effectiveness of new treatments in curbing mortality curves, although policies will vary with different cancers.

Detection of sentinel nodes by lymphoscintigraphy and gamma probe guided surgery in vulvar neoplasia.

BACKGROUND: Pathologic lymph node status is the most important prognostic factor in vulvar cancer; however, complete inguinofemoral node dissection is associated with significant morbidity. Intraoperative lymphoscintigraphy associated with gamma detecting probe-guided surgery has proved to be reliable in the detection of sentinel node (SN) involvement in melanoma and breast cancer patients. The present study evaluates the feasibility of the surgical identification of inguinal sentinel nodes using lymphoscintigraphy and a gamma detecting probe in patients with early vulvar cancer. METHODS: Technetium-99-labeled colloid human albumin was administered perilesionally in 44 patients. Twenty patients had T1 and 23 had T2 invasive epidermoid vulvar cancer; one patient had a lower-third vaginal cancer. An intraoperative gamma detecting probe was used to identify SNs during surgery. Complete inguinofemoral node dissection was subsequently performed. SNs underwent separate pathologic evaluation. RESULTS: A total of 77 groins were dissected in 44 patients. SNs were identified in all the studied groins. Thirteen cases had positive nodes: the SN was positive in all of them; in 10 cases the SN was the only positive node. Thirty-one patients showed negative SNs: all of them were negative for lymph node metastasis. CONCLUSIONS: Lymphoscintigraphy and SN biopsy under gamma detecting probe guidance proved to be an easy and reliable method for detection of SNs in early vulvar cancer. If these preliminary data will be confirmed, the technique would represent a real progress towards less aggressive treatment in patients with vulvar cancer.

Combined Pap smear, cervicography and HPV DNA testing in the detection of cervical intraepithelial neoplasia and cancer.

OBJECTIVE: The sensitivity of the Pap smear (PAP) continues to be the subject of debate. During the past several years, cervicography (CER) and HPV DNA testing have been suggested as optional tools in the screening of cervical cancer precursors. STUDY DESIGN: The performance characteristics of PAP, CER and HPV DNA testing (hybrid capture test [HCT]) in all potential combinations were evaluated in a series of 1,030 women (aged 16-70, median, 33), subjected to colposcopy (COLPO) as the reference tool. RESULTS: Of the 992 evaluable cases, 402/992 (41%) had positive COLPO (i.e., an abnormal transformation zone). Of them, 298 women underwent directed punch biopsy, while of the COLPO negative patients, 18/93 positive by at least one of the three tests had endocervical curettage. Of the 402 COLPO positive women, 146 (36%) remained negative on all tests, whereas 256 (64%) had at least one positive test. There were 84 cervical intraepithelial neoplasia (CIN) 2 and 3 lesions and 6 invasive carcinomas. Of the former, 10 were detected by PAP alone, 4 by CER alone and 3 by HCT alone. Three of the 6 carcinomas were HCT negative. The predictive value (PPV) of a positive test was 45% for PAP, 51% for CER and 48% for HCT. The combinations of PAP with CER (for PAP negative cases) and PAP with HCT were more sensitive for CIN 2 and 3 (95% and 94%, respectively) as compared with PAP alone but were associated with a significant decrease in specificity (44% and 46% vs. 57%, respectively). However, both combinations retained a PPV (43%) similar to that of PAP alone (45%). CONCLUSION: The potential combinations of PAP with CER and with HCT were more sensitive in detecting CIN 2 and 3 as compared with PAP alone and retained a PPV similar to that of PAP.