To obtain baseline data for human papillomavirus (HPV) screening and vaccination in Japan, we analyzed HPV DNA data from 2282 Japanese women ( P ersistent infection with oncogenic human papillomaviruses (HPV), most commonly types 16 and 18, leads to cervical cancer, the second most common cancer in women worldwide.(1) Therefore, oncogenic HPV testing combined with cytology was approved for primary screening in the USA, because of sensitivity and cost-effectiveness.(2) In addition, HPV vaccines have been licensed in the USA, Australia, and European and other countries, because of their efficacy and safety. Clinical studies of HPV vaccines have demonstrated close to 100% protection against HPV16-and HPV18-related infections and diseases, (3)(4)(5) implying possible cross-protection against HPV45, HPV31, and HPV52.(4,5) Based on evidence from clinical trials, (3)(4)(5)(6)(7) these two tools targeting HPV (detection assay and vaccine) are becoming increasingly attractive for cervical cancer prevention worldwide. In Japan, however, HPV DNA testing is still unavailable in mass screening and no HPV vaccine has yet been licensed. Type-specific and age-related data of HPV prevalence, both for women with normal cytology and for women with cervical diseases, are prerequisites to make a well-judged decision about the future role of HPV screening and vaccination in cervical cancer prevention, but these data are missing in Japan. A meta-analysis of Japanese HPV studies provided representative data of HPV type distribution, but no information about age-specific prevalence.In the present study, we analyzed HPV DNA data from 2282 Japanese women to obtain the prevalence data of HPV among women across a broad age range. Our data may help provide models for further evaluating potential impact and cost effectiveness of HPV screening and vaccination in Japan. Materials and MethodsStudy subjects. Our study subjects consisted of 2282 Japanese women (1517 normal HPV detection and genotyping. Exfoliated cells from the ectocervix and endocervix were collected into a tube containing 1 mL PBS and stored at -30°C until DNA extraction. We detected HPV DNA in cervical samples by PCR-based methodology described previously.(9) In brief, total cellular DNA was extracted from cervical samples by a standard sodium dodecyl sulfateproteinase K procedure. HPV DNA was amplified by PCR using consensus primers (L1C1 and L1C2 + L1C2 M) for the HPV L1 region. Direct comparisons of HPV detection methodology have demonstrated that the sensitivity of our PCR assay is higher than that of PCR assays using MY09 and MY11 and GP17 and GP18 primers. (10,11) A reaction mixture without template DNA was included in every set of PCR runs as a negative control. Also, primers for a fragment of the β-actin gene were used as a control to rule out false-negative results for samples in which HPV DNA was not detected. To avoid contamination, we used disposable utensils and discarded them after a single use. We also used aliquoted reagents and maintained separate locations ...

Ovarian cancer, and clear cell carcinoma in particular, reportedly increases the risk of venous thromboembolism (VTE). However, the mechanisms remain unclear. Tissue factor (TF) supposedly represents a major factor in the procoagulant activities of cancer cells. The present study examined the involvement of TF expression in VTE for patients with ovarian cancer. Subjects comprised 32 consecutive patients (mean age 49.8 years) with histologically confirmed ovarian cancer. Presence of VTE was examined using a combination of clinical features, D-dimer levels and venous ultrasonography. Immunohistochemical analysis was used to evaluate TF expression into 4 degrees. Venous thromboembolism was identified in 10 of the 32 patients (31%), including five of the 11 patients with clear cell carcinoma. Tissue factor expression was detected in cancer tissues from 24 patients and displayed significant correlations with VTE development (P ¼ 0.0003), D-dimer concentration (P ¼ 0.003) and clear cell carcinoma (Po0.05). Multivariate analysis identified TF expression as an independent predictive factor of VTE development (Po0.05). Tissue factor (TF) expression is a possible determinant of VTE development in ovarian cancer. In particular, clear cell carcinoma may produce excessive levels of TF and is more likely to develop VTE.

Only a subset of cervical precursor lesions progress to cervical cancer and because of the lack of the predictive markers, it cannot be ascertained which lesions will progress or not. To estimate the risk of disease progression associated with human papillomavirus (HPV) genotypes, we followed 570 Japanese women with cytological LSIL (low-grade squamous intraepithelial lesion) and histological CIN (cervical intraepithelial neoplasia) grade 1-2 lesions (479 CIN 1; 91 CIN 2) at 3 to 4 month intervals for a mean follow-up period of 39.1 months. At entry, we detected HPV DNA in cervical samples by polymerase chain reaction-based methodology. Over the period of follow-up period, 46 lesions progressed to CIN 3 while 362 regressed to normal cytology. Women with multiple HPV infections were more likely to have persistent lesions (hazard ratio [HR] for regression, 0.65; 95% confidence interval [CI], 0.42-1.02; p 5 0.07); however, multiple infections did not increase the risk of progression (HR for progression, 1.04; 95% CI, 0.37-2.94; p 5 0.94). After adjusting for CIN grade and women's age, HRs for progression to CIN 3 (vs. women with low-risk types or negative for HPV DNA) varied markedly by HPV genotype: type 16 (11.1, 95% CI: 1.39-88.3); 18 (14.1, 0.65-306); 31 (24.7, 2.51-243); 33 (20.3, 1.78-231); 35 (13.7, 0.75-251); 52 (11.6, 1.45-93.3); 58 (8.85, 1.01-77.6); other high-risk types (4.04, 0.47-34.7). HPV 45 was not detected in our study subjects. The cumulative probability of CIN 3 within 5 years was 20.5% for HPV 16, 18, 31, 33, 35, 52 and 58; 6.0% for other high-risk types; 1.7% for low-risk types (p 5 0.0001). In conclusion, type-specific HPV testing for women with LSIL/CIN 1-2 lesions is useful for identifying populations at increased or decreased risk of disease progression.Cervical cancer remains the second most common cancer in women worldwide, with nearly 500,000 women developing the disease every year.1 The marked decline in incidence rates of cervical cancer in developed countries is attributed to the development of cytology screening programs that detect women with precursor lesions. However, cancer prevention eventually requires the eradication of such precursor lesions. Vaccination against human papillomavirus (HPV) types 16 and 18 prevents new infection; however, it has no therapeutic effect on women with abnormal Pap results. 2Most low-grade cervical lesions are known to regress spontaneously, whereas only a small fraction progress to cervical cancer.3-7 However, we cannot predict which lesions will regress or progress. Recommendations by the American Society for Colposcopy and Cervical Pathology (ASCCP) suggest that women with cervical intraepithelial neoplasia grade 2 (CIN 2) should be treated. 8 However, there is risk of overtreatment, as 40-60% of CIN 2 lesions spontaneously regress

Venous thromboembolism (VTE) such as deep-vein thrombosis (DVT) and pulmonary thromboembolism (PTE) often occurs after surgery and rarely occurs even before surgery in patients with ovarian cancer. It is well known that levels of plasma D-dimer (DD) before treatment in most ovarian cancer patients are increased. This study therefore examined whether increased levels of DD are associated with presence of VTE before treatment of ovarian cancer. Between November 2004 and March 2007, DD levels prior to initial treatment were measured in 72 consecutive patients with presumed epithelial ovarian cancer (final diagnosis: epithelial ovarian cancer, n ¼ 60; and epithelial ovarian borderline malignancy, n ¼ 12). Venous ultrasound imaging (VUI) of the lower extremity was conducted for all patients except for two patients in whom DVT was detected by pelvic computed tomography (CT). When DVT was found, pulmonary scintigraphy was subsequently performed to ascertain presence of PTE. D-dimer levels were above the cut-off value (0.5 mg ml À1 ) in 65 of 72 patients (90.2%). Venous ultrasound imaging or CT revealed DVT in 18 of 72 patients (25.0%) and pulmonary scintigraphy found PTE in 8 patients (11.1%). All patients with VTE were asymptomatic when VTE was found. D-dimer levels were associated with incidence of VTE (0 -1.4 mg ml À1 ; 0 of 26 (0%), 1.5 -7.4 mg ml À1 ; 9 of 30 (30%) and X7.5 mg ml À1 ; 9 of 16 (56.3%), P for trend ¼ 0.0003). However, even if 1.5 mg ml À1 was used as a cut-off value, this had low specificity and positive predictive value (47.2, 38.3%), though it had high sensitivity and negative predictive value (100, 100%). Therefore, ovarian cancer patients with DD level X1.5 mg ml À1 should be examined using VUI to detect silent DVT. Patients with VTE underwent preventive managements including anticoagulant therapy before initial treatment, chemotherapy or surgery, and after surgery. There was no clinical onset of postoperative VTE in all 72 patients. Measurement of DD levels and subsequent ultrasonography revealed that silent or subclinical VTE frequently occurs before surgery in ovarian cancer. The usefulness of preoperative assessment of VTE needs further confirmation in randomised controlled trials.

Dear Sir,Recently, pooled IARC studies 1,2 and meta-analyses 3,4 have showed that at least 13 human papillomavirus (HPV) types, including types 16,18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59 and 68, are commonly associated with invasive cervical cancer (ICC). Based on HPV type prevalence data from these studies, current HPV vaccines against only HPV16/18 are considered to prevent a majority (>70%) of cervical cancer worldwide. 5,6 However, HPV data in East Asia have not been fully evaluated in previous pooled and meta-analyses. The present study thus focused on HPV type prevalence in Japan. We performed a meta-analysis of published data to obtain the representative results, and investigated HPV type prevalence and type-specific risks for cervical carcinogenesis in Japan. Furthermore, obtained data were compared with those in China, Korea and other regions.Source articles presenting HPV prevalence data among Japanese women were identified from National Library of Medicine (PubMed). For the meta-analysis, the following inclusion criteria were considered: (i) Studies were published between 1995 and 2005. (ii) Studies had to use PCR-based assays to identify at least 16 strains of HPV6,11,16,18, 31, 33, 35, 39, 45, 51, 52, 53, 56, 58, 59 and 68. (iii) Studies had to include at least 20 HPV-positive women with squamous intraepithelial lesion (SIL), cervical intraepithelial neoplasia (CIN) or ICC. When data or data subsets from an identical study had been published in more than one article, only the publication with the largest sample size was included. However, data from different studies conducted by the same study group were included. Overall, a total of 14 Japanese studies were identified for the present study. [7][8][9][10][11][12][13][14][15][16][17][18][19][20] For some articles, additional typespecific data were obtained from the authors. 11,12,20 HPV type prevalence data were collected separately for squamous cell carcinoma (SCC) and for adeno-and adenosquamous carcinoma (ADC). Where histological data were not reported, ICC cases were classified as unspecified carcinoma (UC). On the basis of the pooled analysis of IARC studies, 2 HPV types were separated into 2 groups. High-risk HPVs considered as carcinogenic or probably carcinogenic included HPV16,18,26, 31, 33, 35, 39, 45, 51, 52, 53, 56, 58, 59, 66, 68, 73 and 82; all other HPV types were classified as low-risk types. To evaluate HPV genotype-specific risks for progression from LSIL (low grade SIL) to HSIL (high grade SIL) or more, prevalence ratios [(HSIL 1 ICC):LSIL] and 95% confidence intervals were calculated after adjusting for study area, specimen used for HPV DNA testing, and PCR primers. Logistic regression model was used for statistical adjustment, and the analysis was carried out using JMP 6.0J statistics package (SAS Institute, Cary, NC, USA). The p-values obtained in all tests were considered significant at <0.05.This analysis included 7,262 Japanese women (4,941 normal cytology, 475 LSIL, 720 HSIL and 1,126 ICC) from 14 Japanese HPV studie...