Age at menarche is not an independent risk factor for high-risk human papillomavirus infections and cervical intraepithelial neoplasia.

Data are controversial as to the role of menarche age as a risk factor of high-risk human papillomavirus (HR-HPV) infections. The objective of this study was to analyse the risk estimates for age at menarche as determinant of cervical intraepithelial neoplasia (CIN) and HR-HPV infections. A cohort of 3187 women were stratified into three groups according to their age at menarche: (i) women <13 years of age; (ii) those between 13 and 14 years and (iii) women >15 years of age. These groups were analysed for predictors of (a) HR-HPV, (b) high-grade CIN and (c) outcome of HR-HPV and cytological abnormalities during prospective follow-up. All the three groups had identical prevalence of HR-HPV, Papanicolaou smear abnormalities and CIN grades. In contrast to menarche age itself, the time from menarche to the first intercourse (TMI), to the first pregnancy (TMP) and to the first delivery (TMD) were all significant (P = 0.0001) predictors of HR-HPV (but not CIN2) in univariate analysis, but lost their significance in a multivariate model. Outcome of cervical disease and HR-HPV infection was unrelated to menarche age, the latter and the three intervals being not predictors of CIN2 in a multivariate model. In conclusion, age at menarche and the intervals between menarche and (i) onset of sexual activity, (ii) first pregnancy and iii) first delivery, are not independent predictors of HR-HPV infections and CIN2 in multivariate analysis.

Dose-reduced first cycle of chemotherapy for prevention of life-threatening acute complications in nonseminomatous germ cell tumor patients with ultra high tumor markers and/or poor performance status.

PURPOSE: Patients with metastatic nonseminomatous germ cell tumors (mNSGCT) and a high tumor burden or a poor performance status at initial diagnosis are at risk from potentially life-threatening early complications during or after the first chemotherapy cycle. The outcomes with dose-reduced first cycle of chemotherapy in this population of patients are not well established. METHODS: We performed a retrospective analysis of patients with mNSGCT and International Germ Cell Cancer Collaborative Group (IGCCCG) poor risk features. All patients received cisplatin and etoposide-based combinations as first-line treatment. Ultra high tumor marker levels were defined as α-fetoprotein ≥ 100,000 ng/ml or human chorionic gonadotropin ≥ 200,000 mIU/ml. Before 2005, the first treatment cycle was administered at a full dose in our center. After 2005, we used an abbreviated course of cisplatin and etoposide (EP) for the first cycle, followed by subsequent full-dose administration. RESULTS: From 1987 to 2012, 265 patients with poor risk features according to IGCCCG received first-line chemotherapy. Among them, 63 out of 265 (24%) patients had ultra high tumor marker levels and/or ECOG performance status of 3-4. Dose reduction of the first chemotherapy cycle was associated with a significant decrease of life-threatening complications from 76 to 44% (p = 0.01), but not with the overall survival (HR 0.99, 95% CI 0.44-2.26). CONCLUSIONS: Dose reduction of the first EP cycle by 40-60% in the subgroup of poor risk patients with ultra high tumor marker levels and/or ECOG performance status 3-4 is associated with significantly lowered acute complication rates but not with overall survival.

Cell cycle regulators p105, p107, Rb2/p130, E2F4, p21CIP1/WAF1, cyclin A in predicting cervical intraepithelial neoplasia, high-risk human papillomavirus infections and their outcome in women screened in three new independent states of the former Soviet Union.

BACKGROUND: The growth-controlling functions of the high-risk human papillomaviruses (HPV) depend on their ability to interact with several cellular proteins, including the key regulatory proteins of the cell cycle. We have examined the value of cell cycle regulatory proteins as predictors of the intermediate end point markers in cervical carcinogenesis: (a) grade of cervical intraepithelial neoplasia (CIN), (b) high-risk HPV type, (c) clearance/persistence of high-risk HPV, and (d) disease outcome in women participating in a multicenter follow-up study in three New Independent States countries. METHODS: Totally, 232 biopsy samples tested high-risk HPV-positive and/or Papanicolaou smear-positive women were immunohistochemically stained for the following cell cycle markers: p105, p107, p130, E2F4, p21(CIP1/WAF1/SDI1), cyclin A, and Ki-67. In addition, apoptotic index (AI) and mitotic index (MI) were determined in H&E-stained sections. Prospective follow-up data were available to disclose the clinical and virological outcome of the lesions. RESULTS: The expression of Ki-67, p21(CIP1/WAF1/SDI1), and cyclin A and AI and MI values were markedly increased in high-grade lesions, but only MI was an independent predictor of CIN3 in multivariate analysis. Cyclin A was the only independent predictor of high-risk HPV (odds ratio, 1.09; 95% confidence interval, 1.01-1.18; P = 0.021), exceeding the predictive power of CIN grade and high-grade squamous intraepithelial lesion Papanicolaou smears. None of these markers provided any useful predictive information as to the clinical and virological outcomes during the follow-up. Highly significant correlations (P = 0.0001) were found between AI and MI as well as between MI and cyclin A, Ki-67 and p21(CIP1/WAF1/SDI1), Ki-67 and cyclin A, and p21(CIP1/WAF1/SDI1) and cyclin A followed by that between p105 and cyclin A (P = 0.001) and p105 and p130 (P = 0.002). CONCLUSIONS: All tested factors related to cell cycle were increased, but only MI and cyclin A was an independent predictor of CIN3 and high-risk HPV carriage, respectively.

Oral contraceptives are not an independent risk factor for cervical intraepithelial neoplasia or high-risk human papillomavirus infections.

BACKGROUND: Oral contraception (OC) has been proclaimed by the IARC as a risk factor of cervical cancer (CC), on prolonged use by high-risk human papillomavirus (HPV) positive women. However, the available data are far from complete, and more evidence is necessary on the potential confounding effects of sexual behavior and HPV infection. The aim of the present was study to analyse the risk estimates for OC users in order to develop several intermediate end-point markers in cervical carcinogenesis. PATIENTS AND METHODS: A cohort of 3,187 women, enrolled in a multi-center screening trial in three New Independent States (NIS) of the former Soviet Union (the NIS Cohort Study), was stratified into three groups according to their contraception modes: i) non-users of contraception, ii) non-OC users and iii) OC users. These groups were analysed forpredictors of three outcome measures: a) exposure to HR-HPV; b) progression to high-grade cervical intraepithelial neoplasia (CIN2/3 and HSIL); and c) persistence/clearance of HR-HPV and cytological abnormalities during a prospective follow-up. RESULTS: All three groups had an identical prevalence of HR-HPV (HCII and PCR), Pap smear abnormalities and CIN histology, but differed significantly (p=0.0001) with regard to all key variables of sexual behaviour, known as risk factors for CC. Predictors of HR-HPV, CIN2/3 and HSIL were different in the three groups, reflecting these different sexual preferences. Use of OC was not a significant predictor of CIN2/3 or HSIL in HPV-positive or HPV-negative women. Outcomes of cervical disease and HR-HPV infection were unrelated to contraception. In a multivariate regression model mode of contraception was of no predictive value for either HR-HPV or high-grade CIN. CONCLUSION: Sexual behaviour is different among OC users, non-OC users and in nonusers of contraception; these risk factors predispose women to HR-HPV, high-grade CIN, and determine the outcome of their cervical disease/HR-HPV infection. The use of OC is not an independent risk factor for any of these intermediate end-point markers of cervical carcinogenesis. Failure to record these epidemiological data inevitably leads to erroneous conclusions about the role of OC as an independent risk factor of cervical cancer.

Smoking is an independent risk factor for oncogenic human papillomavirus (HPV) infections but not for high-grade CIN.

BACKGROUND: Recent evidence implicates smoking as a risk factor for cervical cancer (CC), but the confounding from high-risk human papillomavirus (HPV) infections is not clear. OBJECTIVES: To analyse the role of smoking as an independent predictor of CIN2+ and HR-HPV infections in a population-based prospective (NIS, New Independent States of former Soviet Union) cohort study. STUDY DESIGN AND METHODS: A cohort of 3,187 women was stratified into three groups according to their smoking status: (i) women who never smoked; (ii) those smoking in the past; and (iii) women who are current smokers. These groups were analysed for predictors of (a) HR-HPV; (b) high-grade CIN, and (c) outcome of HR-HPV infections and cytological abnormalities during prospective follow-up (n = 854). RESULTS: The three groups were significantly different in all major indicators or risk sexual behaviour (or history) implicating strong confounding. There was no increase in HSIL/LSIL/ASC-US cytology or CIN1+/CIN2+/CIN3+ among current smokers. Only few predictors of HR-HPV and CIN2+ were common to all three groups, indicating strong interference of the smoking status. There was no difference in outcomes of cervical disease or HR-HPV infections between the three groups. In multivariate model, being current smoker was one of the five independent predictors of HR-HPV (P = 0.014), with adjusted OR = 1.52 (95%CI 1.09-2.14). In addition to age, HR-HPV was the only independent predictor of CIN2+ in multivariate model (OR = 14.8; 95%CI 1.72-127.31). CONCLUSIONS: These data indicate that cigarette smoking is not an independent risk factor of CIN2+, but the increased risk ascribed to smoking is mediated by acquisition of HR-HPV, of which current smoking was an independent predictor in multivariate model.

Acquisition of high-risk human papillomavirus infections and pap smear abnormalities among women in the New Independent States of the Former Soviet Union.

The rates of acquisition and the times of incident high-risk (HR) human papillomavirus (HPV) infections and Pap smear abnormalities and their predictive factors were analyzed in women participating in a multicenter screening study in three countries of the New Independent States of the former Soviet Union. The 423 patients were prospectively monitored for a mean of 21.6 months. At the baseline, 118 women were HR HPV DNA negative (Hybrid Capture II assay) and Pap smear negative (group 1), 184 were HPV DNA positive and Pap smear negative (group 2), and 121 were HPV DNA negative and Pap smear positive (group 3). The time to the acquisition of an incident abnormal Pap smear (19.4 months) was significantly longer in group 1 than in group 2 (9.2 months) (P = 0.0001). The times of acquisition of incident HR HPV infection were 16.6 and 11.0 months in group 1 and group 3, respectively (P = 0.006). The monthly rates of acquisition of incident HR HPV infections were very similar in group 1 (1.0%) and group 3 (0.8%), whereas the rate of acquisition of an abnormal Pap smear was significantly higher in group 2 (3.1%) than in group 1 (1.5%) (P = 0.0001). The acquisition of HR HPV infection (but not a positive Pap smear result) was significantly (P = 0.0001) age dependent. The only significant independent (P = 0.001) predictor of the incidence of an abnormal Pap smear result was a high HR HPV load of >20 relative light units/control value (CO) (rate ratio, 2.050; 95% confidence interval, 1.343 to 3.129). Independent predictors of incident HR HPV infection were patient category (a sexually transmitted disease) and ever having been pregnant. The time of acquisition of HR HPV infection was 3 months shorter than that of an abnormal Pap smear. At the baseline the high load of a particular HR HPV type is the single most important predictor of an incident Pap smear abnormality, whereas young age and having a sexually transmitted disease predict incident HR HPV infections.

Sexual habits and human papillomavirus infection among females in three New Independent States of the former Soviet Union.

BACKGROUND: On a global scale, the New Independent States (NIS) of the former Soviet Union have an intermediate incidence of cervical cancer, the main etiologic factor of which is human papillomavirus (HPV), a major sexually transmitted disease (STD). Recently, the prevalence of all STDs has exploded in these countries. GOAL: The goal of this study was to examine the sexual habits and HPV prevalence among females in three NIS countries. STUDY DESIGN: In this multinational (European Community-funded) trial, a series of 3,175 consecutive female patients were examined for HPV status (by Hybrid Capture II) at six clinics in Russia, Belarus, and Latvia. A meticulous survey of their sexual habits and other potential risk factors of HPV infections was made by structured questionnaire. RESULTS: Three categories of patients were examined: those attending STD clinics (n=722), gynecological patients (n=761), and those who participated in cervical cancer screening (n=1,692). These three categories were significantly differentiated by a large number of key variables, including the HPV detection rate (44.9% of STD patients, 39.8% of gynecological patients, and 24.5% of those who were screened). A wide variety sexual habits of these subjects were predictors of the HPV status in univariate analysis. Binary logistic regression analysis found that six different variables remained as independent predictors of HPV status. Patient category (STD) and (young) age were two highly significant predictors of increased risk (P<0.0001), whereas having a nonsmoking partner and having zero or one partner during the past 2 years were significant protective factors (P=0.004 and P=0.007, respectively). CONCLUSION: The results of this study indicate that women and girls in these NIS countries are conservative in many key characteristics of "high-risk" sexual behavior, such as age at onset of sexual activity, number of partners, and casual sex partners. HPV-positive and HPV-negative groups are clearly distinguished by the same variables identified as the key risk factors of HPV infection and cervical intraepithelial neoplasia in Western countries.

Human papillomavirus testing and conventional pap smear cytology as optional screening tools of women at different risks for cervical cancer in the countries of the former soviet union.

OBJECTIVES: Human papillomavirus (HPV) infection is a sexually transmitted disease (STD) and the single most important etiological agent of cervical cancer. In parallel with the increase of STDs and because of the lack of any organized cancer screening in the new independent states of the former Soviet Union, the incidence and mortality rates of cervical cancer are rapidly rising. This is the first report from an ongoing European Commission-funded (INCO-Copernicus Program) cross-sectional and cohort study (focused on the key issues of this major health problem in the new independent states) analyzing the performance of the HPV DNA (Hybrid Capture II) test as a potential screening tool for cervical cancer in these countries. MATERIALS AND METHODS: A series of 3,175 women (screening, gynecological, or STD patients) from six clinics in Russia, Belarus, and Latvia received routine cytology and HPV testing with Hybrid Capture II (HCII). All women with HPV-positive results or abnormalities in cytology were subjected to colposcopy and biopsy. The sensitivity, specificity, receiver operating characteristics, as well as positive (PPV) and negative predicting values (NPV), were determined for HCII and quality-controlled cytology in detecting significant pathology (cervical intraepithelial neoplasia [CIN] 3 and cancer). RESULTS: Significant pathology was strongly associated with high-grade cytology (odds ratio [OR] = 8.5; 95% confidence interval [CI] = 4.1-17.8; chi-square, p < .0001). Pap smear cytology detected high-grade lesions with a sensitivity of 64.0% (44.8-83.2), specificity of 89.1% (84.5-93.7), PPV of 44.4% (28.8-61.0), and NPV of 94.8% (91.2-98.4). Of the 3,086 samples analyzed by HCII, 33.0% were positive for oncogenic HPV types, with a wide variation (from 23% to 45%) between the three patient groups (p < .0001). The presence of high-grade cytology was significantly associated with HCII positivity at all cutoff levels (OR = 14.4; 95% CI = 8.4-24.5; chi-square, p < .0001; 1 pg/mL threshold). In the receiver operating characteristics curve, the HCII cutoff point most closely balancing sensitivity (83.1%) and specificity (75.6%) was 2 pg/mL. The presence of high-grade histology was associated with HCII positivity (cutoff 1 pg/mL; OR = 4.8; 95% CI = 0.7-34.2;p = .047). At the cutoff (1 pg/mL), sensitivity of the HCII test was 96.6% (90.0-100), specificity was 15.9% (10.6-21.2), PPV was 15.1% (9.9-20.3), and NPV was 96.8% (90.3-100). Changing the cutoff significantly affected sensitivity at 20 pg/mL and NPV at 500 pg/mL. CONCLUSIONS: HCII assay is a sensitive tool in detecting significant pathology, but less specific than the Pap test. A negative HCII test practically precludes high-grade CIN (NPV, >95%). Because the performance characteristics of the HCII test depend on the prevalence of HPV and CIN in the study population, the cost-benefit issues in different settings will be the limiting factor for the application of this test as a screening tool.