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Background: Although more than 10 years have passed since HPV vaccination was implemented, first as an interim programme (Emergent vaccine promotion programme) in November 2010, followed by incorporating into the National Immunization Programme in April, 2013 and suspended in June 2013, limited studies have investigated the HPV vaccine effectiveness against high-grade cervical lesions in Japan., Methods: We collected the matched data of the results of cervical biopsy and history of vaccination from the Japan Cancer Society database. The subjects were women aged 20 to 29 years screened for cervical cancer between April, 2015 and March, 2017, and with information on HPV vaccination status. We estimated the relative risk of developing high-grade cervical lesions in vaccinated subjects using Poisson regression as compared to unvaccinated subjects., Results: Among the 34,281 women screened, 3770 (11.0%) were vaccinated. The prevalence of CIN2+ was statistically significantly lower in the vaccinated women as compared to the unvaccinated women (Vaccine Effectiveness (VE) =76%; RR = 0.24, 95% CI:0.10-0.60). High VE against CIN3+ was also observed (91%; RR = 0.09, 95% CI:0.00-0.42)., Conclusion: Women aged 20-29 years who received at least one dose of HPV vaccine had a significantly lower risk of high-grade cervical lesions than those not vaccinated. In Japan, HPV vaccination should be resumed in order to reduce the incidence of cervical cancer.

The effectiveness of HPV vaccine against HSIL+ (pathologically diagnosed CIN2+) in the first cohort in Japan was investigated in 22,743 women aged 20 to 29 years (parts of national cervical cancer screening program of FY [fiscal year] 2015, the Japan Cancer Society). Vaccinated women had a statistically significant 69% lower risk of HSIL+ as compared to the unvaccinated women; the crude relative risk estimate was 0.31 (95% CI: 0.11-0.83; p-value = 0.013) by normal approximation and 0.31 (95% CI: 0.08-0.80; p-value = 0.009) by the exact Poisson regression. The effect of age was not significant (chisq = 7.7 (df = 9), p-value = 0.569) and the estimate of relative risk remained essentially intact after adjustment for age. This study brings scientific evidence on the effectiveness of HPV vaccine on development of cervical high grade lesions., (Copyright © 2018 The Authors. Published by Elsevier Ltd.. All rights reserved.)

This study aimed to determine whether the cervical length increases over a period of six months, after the loop electrosurgical excision procedure (LEEP) for grade III cervical intraepithelial neoplasia (CIN), and to identify the factors associated with an increase in the cervical length. We retrospectively reviewed the medical records of 183 patients who underwent the LEEP between April 2011 and March 2014, at the Department of Gynaecology, Kyosai Hospital. Transvaginal ultrasonography was performed at two, three and six months after the LEEP, and the mean increase in the cervical length between two and three months, two and six months, and three and six months were 2.07, 5.23 and 2.92 mm, respectively. The increase in the cervical length was not associated with age, gravidity, parity and the width of CIN. In conclusion, the cervical length may increase gradually over a period of six months after the LEEP.

Aim: The aim of this study was to identify predictors of recurrent/residual disease for management after loop electrosurgical excisional procedure., Methods: We retrospectively reviewed 178 patients with cervical intraepithelial neoplasia grade 3 and microinvasive squamous cell carcinoma who underwent the loop electrosurgical excisional procedure between April 2011 and March 2014. Endocervical/ectocervical margin status, endocervical curettage (ECC) status, and maximum width of cervical intraepithelial neoplasia were assessed. Patients were followed up for 6-12 months., Results: Patients with endocervical margin involvement were significantly older and those with ectocervical margin involvement were significantly younger than patients with no margin involvement (P = 0.02 for both comparisons). ECC-positive patients were significantly older than ECC-negative patients (P = 0.049). There was a significant difference in the mean width of the cervical intraepithelial neoplasia between women with ectocervical involvement and those without ecto- or endocervical involvement (10.2 ± 3.1 mm vs 7.3 ± 3.5 mm, P = 0.0002). The odds ratios for possible recurrent/residual disease for endocervical involvement, ectocervical involvement, and ECC-positivity were 2.1 (0.5-8.4), 3.2 (1.3-7.9), and 6.8 (1.4-32.1), respectively. However, while most ECC-positive patients underwent a second surgery, most patients with ectocervical involvement did not need further treatment., Conclusion: Older age and ECC were significantly associated with endocervical margin involvement; younger age and width of cervical intraepithelial neoplasia were associated with ectocervical margin involvement. Ectocervical margin involvement significantly increased the risk of possible recurrent/residual disease; however, these patients might recover naturally. ECC-positivity significantly increased the risk of recurrent/residual disease., (© 2016 Japan Society of Obstetrics and Gynecology.)

Background: When evaluating health-economics for cervical cancer prevention policies in Japan, it is important to use Japanese value settings. This study aimed to obtain preference-based measures (preference measures) for hypothesized health states among healthy Japanese women, and to examine differences between the EuroQol-5D (EQ-5D) and standard gamble (SG) instruments., Materials and Methods: The investigation was performed among female students at a nursing university. We used written hypothetical scenarios describing three grades of cervical intraepithelial neoplasia (CIN) and eight stages of cervical cancer, both at diagnosis and after medical intervention. Preference measures were evaluated using both EQ-5D and SG., Results: We received responses from 136 women. The mean number of respondents per stage was 24.6 (SD: 2.7). At diagnosis, average EQ-5D scores for CIN1, CIN2, CIN3, IA1, IA2, IB1, IB2, IIA, IIB, III, and IV stages were 0.84 (0.14), 0.78 (0.12), 0.73 (0.10), 0.78 (0.12), 0.72 (0.12), 0.63 (0.13), 0.64 (0.12), 0.68 (0.08), 0.62 (0.13), 0.55 (0.21), and 0.18 (0.24), respectively. Using one-way analysis of variance with the Tukey-Kramer method for multiple comparisons (each stage vs. CIN1), we found significant differences for IB1 and more advanced stages (p<0.05). After medical intervention, corresponding EQ-5D scores were 0.84 (0.12), 0.81 (0.12), 0.84 (0.12), 0.80 (0.15), 0.78 (0.11), 0.64 (0.15), 0.63 (0.15), 0.71 (0.15), 0.50 (0.17), 0.52 (0.17), 0.21 (0.28). The multiple comparisons identified significant differences for IB1 and more advanced stages, excepting IIA (p<0.05). SG evaluations were more variable and relatively higher than EQ-5D evaluations., Conclusions: We obtained preference measures for three grades of CIN1-3 and eight stages of cervical cancer. In combination with appropriate sensitivity analyses, these preference measures will provide a basis for an economic evaluation of cervical cancer prevention in Japan. We suggest that EQ-5D is appropriate for cost-utility analysis of this topic.

In this open, extended follow-up study (NCT00929526, Clinicaltrials.gov), we evaluated the human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine efficacy, immunogenicity and safety up to 4 years after first vaccination in Japanese women aged 20-25 years. In the initial randomized, double-blind study (NCT00316693), 1040 women received the study vaccine or hepatitis A control vaccine; 752 women were included in the follow-up study. In women from the according-to-protocol efficacy cohort (ATP-E), who were initially seronegative for the HPV type analyzed, no cervical intraepithelial neoplasia (CIN) grade 1 or greater (CIN1+) cases associated with HPV-16/18 were reported in the HPV group, while in the control group, 5 cases were identified in extended follow-up analyses (vaccine efficacy [VE] 100% [95% CI: -3.7-100]) and 8 cases in combined initial and follow-up studies analyses (VE 100% [42.2-100]). In the ATP-E, VE against CIN1+ and CIN2+ associated with high-risk HPV types reached 66.4% (21.6-87.1) and 83.0% (22.1-98.2) in extended follow-up analyses, and 63.4% (28.8-82.3) and 77.3% (30.4-94.4) in analyses of combined studies, respectively. During the 4-year period, protection against CIN1+ and CIN2+, irrespective of the HPV type, was 56.7% (32.8-72.6) and 54.9% (20.5-75.3) in women receiving ≥1 vaccine dose, regardless of baseline serostatus (total vaccinated cohort [TVC]) and 61.0% (11.8-84.2) and 73.9% (1.1-95.3) in women naïve to HPV infection at baseline (TVC-naïve), respectively. The high VE observed in Japanese women, accompanied by a sustained immune response and a clinically acceptable safety profile, support findings of large, international trials.

Human papillomavirus (HPV) 58 accounts for a notable proportion of cervical cancers in East Asia and parts of Latin America, but it is uncommon elsewhere. The reason for such ethnogeographical predilection is unknown. In our study, nucleotide sequences of E6 and E7 genes of 401 HPV58 isolates collected from 15 countries/cities across four continents were examined. Phylogenetic relationship, geographical distribution and risk association of nucleotide sequence variations were analyzed. We found that the E6 genes of HPV58 variants were more conserved than E7. Thus, E6 is a more appropriate target for type-specific detection, whereas E7 is more appropriate for strain differentiation. The frequency of sequence variation varied geographically. Africa had significantly more isolates with E6-367A (D86E) but significantly less isolates with E6-203G, -245G, -367C (prototype-like) than other regions (p ≤ 0.003). E7-632T, -760A (T20I, G63S) was more frequently found in Asia, and E7-793G (T74A) was more frequent in Africa (p < 0.001). Variants with T20I and G63S substitutions at E7 conferred a significantly higher risk for cervical intraepithelial neoplasia grade III and invasive cervical cancer compared to other HPV58 variants (odds ratio = 4.44, p = 0.007). In conclusion, T20I and/or G63S substitution(s) at E7 of HPV58 is/are associated with a higher risk for cervical neoplasia. These substitutions are more commonly found in Asia and the Americas, which may account for the higher disease attribution of HPV58 in these areas., (Copyright © 2012 UICC.)

Efficacy, immunogenicity and tolerability of the human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine were evaluated in Japanese women aged 20-25 years, for which results have been reported previously. We analyzed the baseline data from that study and report the prevalence rates of HPV infection in young healthy Japanese women. One thousand and the forty Japanese women aged 20-25 years were enrolled in a phase II, double-blind, controlled, randomized, multicenter study. At study entry, cervical specimens were collected from the women and tested by line probe assay for 25 HPV-types and by HPV-16/18-specific polymerase chain reaction. The most frequently detected HPV-type in baseline cervical specimens was HPV-52 (8.1%), followed by HPV-16 (6.5%), HPV-51 (4.5%), HPV-18 (4.0%) and HPV-31 (3.8%). The proportion of HPV DNA-positive women increased with severity of cytological abnormalities: 26.1% (237/908) in normal cytology, 93.3% (70/75) in low-grade squamous intraepithelial lesion and 100% (7/7) in high-grade squamous intraepithelial lesion. The relative contribution of HPV-16 and HPV-18 was 4.1 and 3.0% for normal cytology cases, and 20.0 and 16.0% in low-grade squamous intraepithelial lesion, respectively. HPV-16 was found in four of seven high-grade squamous intraepithelial lesion cases (57.1%) and five of the six cervical intraepithelial neoplasia 2+ cases (83.3%). Multiple and single HPV infections were observed in 13.5% (140/1039) and 20.7% (215/1039) of all women, respectively. The HPV prevalence rates in Japanese women aged 20-25 years underline the importance of HPV vaccination at a young age and this report should be useful for monitoring changes in HPV prevalence after widespread HPV vaccination in Japanese women., (© 2011 Japanese Cancer Association and GlaxoSmithKline Biologicals.)

Background: A phase 2 double-blind, controlled, randomized multicenter study with human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine is ongoing in healthy Japanese women aged 20 to 25 years. We assessed the vaccine efficacy in the event-triggered analysis., Methods: Japanese women aged 20 to 25 years were randomly assigned to receive either HPV-16/18 AS04-adjuvanted (n = 519) or hepatitis A (n = 521) vaccine at 0, 1, and 6 months. The women were assessed for virological and cytological end points associated with HPV-16/18 in cervical specimens and for the vaccine safety and immunogenicity., Results: The mean length of follow-up for women in the primary analysis for efficacy at the time of a prespecified event-triggered interim analysis was 13.6 months after the first vaccination. Vaccine efficacy against HPV-16/18 persistent infections (6-month definition) in the according-to-protocol cohort for efficacy was 100% (99% confidence interval, 20.5-100, P = 0.0037). At 6 months after the third dose of vaccine, geometric mean titers against HPV-16 and HPV-18 were 2899.3 and 1352.2 enzyme-linked immunosorbent assay units per milliliter, respectively, that is, 97- and 60-fold higher than geometric mean titers observed after natural infection. There were no clinically meaningful differences in safety between the HPV and control group., Conclusions: The HPV-16/18 AS04-adjuvanted vaccine was as efficacious in Japan as in other countries and was generally safe and highly immunogenic in Japanese women.

Introduction: The incidence of cervical cancer (CC) is high in Japan and is further increasing among women younger than 30 years. This burden could be reduced by the implementation of a CC vaccine, but its cost-effectiveness is unknown., Methods: We quantified the clinical impact and assessed the cost-effectiveness of adding CC vaccination at age 12 to the current screening in place in Japan with a lifetime Markov model adapted to the Japanese setting. Transition probabilities and utility values were obtained from public databases. Direct costs for treatment and screening were estimated using Japanese medical fees. Annual costs and benefits were discounted at 3%. Sensitivity analyses were conducted on the age at vaccination, the vaccine characteristics, the discount rates, the proportion of human papillomavirus types 16/18 in cancer, and the screening coverage., Results: Vaccinating a 12-year-old cohort was predicted to reduce CC incidence and deaths from CC by 73%. These clinical effects were associated with an incremental cost-effectiveness ratio of yen1.8 million per quality-adjusted life year gained. The incremental cost-effectiveness ratio of vaccinating all 10- to 45-year-old women was yen2.8 million per quality-adjusted life year, still below the threshold value., Conclusions: The implementation of a CC vaccination in Japan could reduce the CC burden in a very cost-effective manner for women up to 45 years.

The Harmonic Scalpel((R)) (HS) is a new surgical tool that cuts and coagulates by converting electrical energy into ultrasonic mechanical vibrations. The purpose of our study was to compare HS conization and the loop electrosurgical excision procedure (LEEP) for cervical intraepithelial neoplasia (CIN) with respect to both clinical and pathological features. Fifty-one consecutive women conservatively treated (29 with LEEP and 22 with HS conization) for CIN III were retrospectively reviewed. The background of the patients was similar. Operative time, intra- and postoperative blood loss were not significantly different. With HS conization all specimens were removed in one piece, but with LEEP the median number of specimens obtained per patient was 3.3 (p<0.0001) with a maximum of 5. The depth of thermal artifacts at the endocervical margin was significantly less with HS conization (0.20 mm) than with LEEP (0.30 mm; p = 0.0006). This new method produced an ideal-shaped specimen without increasing complications and thermal artifacts compared with LEEP.

Conization, as a surgical treatment for cervical intraepithelial neoplasm (CIN), is a good method that preserves reproductive functions. Technological developments have introduced a wide variety of energy sources for surgical procedures. Traditional cold knife conization has been replaced by laser conization and by the loop electrosurgical excisional procedure (LEEP). However, laser conization and LEEP have some disadvantages. Laser conization requires expensive equipment. LEEP induces electrocautery artifacts and cannot excise the cervical tissue as a single-piece, because of the various extensions and depths of lesion, so that evaluation of the margins is sometimes not possible. Laser conization and LEEP both generate smoke. The presence of smoke is not only inconvenient, but also dangerous. Harmonic Scalpel (HS), ultrasonic cutting and coagulation system, is a new surgical tool that cuts and coagulates using ultrasonic mechanical vibrations. Eleven women with CIN III underwent conization using HS. HS eliminated the major disadvantages of electrosurgery and laser surgery. No complications during conization were observed. Postoperative hemorrhage was noted in only one patient. Histological diagnosis was not affected by heat or ultrasound. This surgical method using HS is characterized by negligible bleeding, a good visual field not obscured by smoke and resection of an ideal shape that fits the size of the lesion. It is concluded that this method overcomes most problems associated with conization using conventional methods.

Objective: To study a possible etiologic relationship between the prognosis of uterine cervical dysplasia, association of type-specific human papillomavirus (HPV) DNA and cytologic features characteristic of HPV infection., Study Design: Two hundred thirteen cases of uterine cervical dysplasia were selected in which follow-up survey for more than two years was possible. Frequency of the presence of HPV DNA in the DNA samples was determined by polymerase chain reaction. The cervical scrapings were also examined microscopically for the frequencies of cells with cytologic features characteristic of HPV infection., Results: HPV was positive in 98 cases (46.0%). The high-risk type of HPV was detected at almost the same frequencies in both progressive and regressive states of dysplasia. Cytologic features were more evident in cells infected with the low-risk type of HPV., Conclusion: Involvement of an as-yet-unknown factor or factors coupled with infection with the high-risk type of HPV is implicated in the progression of uterine cervical dysplasia. Cytologic features characteristic of HPV infection may serve as a diagnostic marker for a favorable prognosis in dysplasia.

Objective: To evaluate the clinical significance of human papillomavirus (HPV) type, grade of cervical intraepithelial neoplasia (CIN) and age on the progression of CIN., Study Design: Clinical follow-up data, histopathologic diagnosis, polymerase chain reaction (PCR) and HPV DNA typing were available on 194 patients, 119 with CIN 2/moderate dysplasia and 75 with CIN 3/severe dysplasia., Results: HPV 16 was observed most frequently (47.0%) in progressed CIN, while HPV-negative cases (57.7%) were most frequently regressed. HPV positivity (P = .0466), especially HPV 16 positivity (P = .0104), was significantly more frequent than HPV negativity in the progression group. The rate of CIN progression was higher with HPV (50.5%) than without HPV (35.4%). Of the CIN cases with HPV 16, 56.5% progressed, while 30.8% of the CIN cases with HPV 6 and/or 11 and 35.4% of the CIN cases without HPV progressed. The probability of progression was 1.87-fold higher in the HPV-positive group than that in the HPV-negative group (P = .03). Multiple logistic regression analysis revealed that HPV (odds ratio 2.23, P = .0103) and grade of the lesion (odds ratio 3.30, P = .0002) in the initial biopsy strongly and independently correlated with progression of CIN., Conclusion: HPV status and histologic grade are independent predictive risk factors for progression and may be useful in the management of CIN.

We examined infection in the tissue of cervical dysplasia of human papillomavirus (HPV) 52b, which we recently isolated from cervical cancer. To screen a lot of samples, we used an assay system with an HPV DNA typing kit containing an HPV 33 probe that cross-hybridizes with HPV 52b DNA. DNA samples from 123 patients with cervical dysplasia were first screened with this kit. Sixteen of these appeared to be positive, and they were subjected to Southern blot hybridization with the HPV 52b probe under highly stringent conditions. Of the 16 samples, two were found to have HPV 52b genome DNA. Our results, together with the fact that HPV 52b was isolated from cervical cancer, seem to support the notion that HPV 52b infection is closely associated with the onset of cervical cancer.