Effectiveness of prophylactic HPV vaccines against cervical abnormalities and HPV infection in Japan: The J-HERS 2021 multicenter study.

This study investigated the efficacy of the prophylactic human papillomavirus (HPV) vaccine, which was initiated between 2009 and 2013 in Japan. The study involved 1529 eligible women aged 16-39 years who visited 11 outpatient clinics in Japan for various reasons. These patients underwent HPV genotype analysis and a Pap test of cervical cell samples. A total of 299 women (19.6%) had received the prophylactic HPV vaccine (bivalent:quadrivalent vaccine ratio = 2:1). Of the 5062 participants in the Japanese Human Papillomavirus Disease Education and Research Survey (J-HERS 2011), which was conducted in the pre-vaccination era, 3236 eligible participants were included as controls. In this study (J-HERS 2021), the highest rate of HPV vaccination (53%) was observed in patients aged 22-27 years. Vaccinated individuals exhibited a 49% rate of protection against low-grade intraepithelial lesions (LSILs) and atypical squamous cells, not excluding high-grade squamous intraepithelial lesions (ASCH) or worse (LSIL/ASCH+), and a 100% rate of protection against high-grade squamous intraepithelial lesions (HSILs) or worse (HSIL+). Significant reductions in HPV16 (95%) and HPV18 (100%) infections were noted, but no differences were observed in HPV6 and HPV11 infections. The prevalences of HPV51 and HPV59 increased with vaccination, although these changes were not confirmed in the comparative study with J-HERS 2011. Comparing the prevaccination (J-HERS 2011) and postvaccination (J-HERS 2021) periods, 43%, 51%, 88%, and 62% reductions in HPV16, HPV18, HPV16/18, and HPV31/58 infection rates were observed, respectively. Similarly, 62% and 71% reductions in LSIL/ASCH+ and HSIL+ rates were noted, respectively. There were 88% and 87% reductions in LSIL/ASCH+ and HSIL+ rates in 16-21- and 28-33-year-old patients, respectively. Bivalent or quadrivalent vaccines provided 100% protection against high-grade squamous cell lesions (suggestive of CIN2 or CIN3) in young women aged <39 years at 9-12 years after initiation of Japan's first nationwide HPV vaccination program. Cross-protection against HPV31 and HPV58 is likely to occur, although some HPV-type replacements are inconsistent across vaccination regimens. This demonstrates the effectiveness of the HPV vaccine. However, continuous monitoring of cervical cancer and precancer is necessary in younger generations (born 1997-2007), who were rarely vaccinated due to the prolonged suspension of the vaccine recommendations in Japan.

Chemical Peeling Therapy Using Phenol for the Cervico-Vaginal Intraepithelial Neoplasia.

Objective: This study aimed to validate the use of liquid phenol-based chemical peeling therapy for cervical and vaginal intraepithelial neoplasia (CIN and VaIN, respectively), with the goal of circumventing obstetric complications associated with surgical treatment and to determine the factors associated with treatment resistance. Methods: A total of 483 eligible women diagnosed with CIN, VaIN, or both, participated in this study. Participants underwent phenol-based chemical peeling therapy every 4 weeks until disease clearance. Disease clearance was determined by negative Pap tests for four consecutive weeks or by colposcopy. HPV genotyping was conducted at the onset of the study and after disease clearance in select cases. Our preliminary analysis compared the recurrence and persistence rates between 294 individuals who received phenol-based chemical peeling therapy and 189 untreated patients. Results: At 2 years following diagnosis, persistent disease was observed in 18%, 60%, and 88% of untreated patients with CIN1-3, respectively, and <2% of patients with CIN who received phenol-based chemical peeling therapy. Among 483 participants, 10 immune-suppressed patients required multiple treatments to achieve disease clearance, and 7 were diagnosed with cervical cancer. Of the 466 participants, except those with cancer or immune suppression, the number of treatment sessions until CIN/VaIN clearance ranged from 2 to 42 (average: 9.2 sessions). In total, 43 participants (9.2%) underwent surgical treatment. Six patients (1.3%) experienced recurrence of CIN2 or worse, suggesting that treatment failed in 46 patients (9.9%). No obstetrical complications were noted among the 98 pregnancies following this therapy. Factors associated with resistance to this therapy include immune suppression, ages 35-39 years, higher-grade lesions, and multiple HPV-type infections. Conclusions: Phenol-based therapy is safe and effective for CINs and VaINs. Women aged < 35 years and with persistent CIN1 or CIN2 with a single HPV-type infection are suitable candidates for phenol-based chemical peeling therapy. However, this therapy requires multiple lengthy sessions.

[Associations between Maternal Postpartum Depression and Psychosocial Factors Including Marital Relationship and Social Support].

OBJECTIVES: We aimed to investigate the psychosocial factors for postpartum depression as indicated by a high score of the Edinburgh Postnatal Depression Scale (EPDS), including marital relationship and social support. Relevant factors for antenatal depression were also analyzed. METHODS: Thirty-five wife-and-husband pairs who visited University Hospital A for the wife's antenatal health check-up participated in a questionnaire survey using the Japanese version of the EPDS. Social support from the wife's husband, kins, and others including friends at the third trimester of pregnancy and 1 month after birth was assessed. The Marital Love Scale (MLS) was also used, and two marital relationship questions were asked regarding the husband's and wife's considerate actions toward each other during pregnancy. Binary logistic regression analysis was conducted to determine adjusted associations between higher EPDS scores (≥5 for postpartum depression and ≥7 for antenatal depression) and indicators for social support and marital relationships. RESULTS: The most relevant factor for higher postpartum EPDS scores was a higher antenatal EPDS score, followed by the couple's poor communication skills (the wife did not feel any appreciation from her husband) during pregnancy and no support from the wife's husband during the postpartum period. The wife's poor marital communication skills and the husband's low MLS scores during pregnancy were associated (borderline significance) with the wife's higher antenatal EPDS scores. CONCLUSIONS: A good marital relationship before birth and support by the husband after birth may be important for preventing postpartum depression.

Determination of human papillomavirus type in archival tissue specimens of invasive cervical cancer using molecular mapping and E6/E7-based polymerase chain reaction.

In our previous study, an L1-based human papillomavirus (HPV) test using liquid-based cytology revealed that some invasive cervical cancers (ICC) exhibited multiple HPV types or harbored no HPV DNA. Here, molecular mapping of formalin-fixed paraffin-embedded cancer tissue specimens from the same patients were conducted to confirm these observations. Among 377 ICC cases, 73 eligible specimens (9 positive for multiple HPV types, 16 negative for HPV, and 48 positive for a single HPV type from the previous study) were reexamined by manual microdissection of cancer lesions, then subjected to HPV genotyping using the uniplex E6/E7 polymerase-chain-reaction method to detect all high-risk and potentially high-risk HPV types. The HPV typing results were confirmed in 52 of 73 cancer cases; among the 21 remaining cases, 15 were discordant and 6 were partially concordant. In total, 8 of 16 (50%) HPV-negative samples became positive; 6 were positive for HPV16 and 2 were positive for HPV67. Moreover, two samples previously positive for HPV6 and HPV53 were negative for HPV. All nine cancers with multiple HPV types were found to harbor only a single HPV type. In total, 63 cancer tissues exhibited a single HPV type. HPV16 and HPV18 were detected in squamous cell carcinoma (SCC) and adenocarcinoma (ADC). Alpha-5 (HPV82), -6 (HPV56), and -9 (HPV31/52/67) HPV types were detected in SCC, whereas Alpha-7 (HPV59/68) types were detected in ADC and adenosquamous carcinoma (ADSCC). These findings suggested that the different HPV types induced different histological cancers. Furthermore, all SCCs and 10 of 11 usual-type ADCs were positive for high-risk HPV types, supporting the use of HPV screening for the detection of these cancers and associated premalignant lesions. HPV16 is likely to remain undetected in some cervical cancer tissues because of low viral-copy-numbers. Putative high-risk HPV types (e.g., HPV67 and HPV82) might be high risk in Japan.

A retrospective study of immunotherapy using the cell wall skeleton of Mycobacterium bovis Bacillus Calmette-Guérin (BCG-CWS) for cervical cancer.

Mycobacterium bovis Bacillus Calmette-Guérin (BCG) has the potential to promote adaptive immunity. We sought to examine the synergistic effect of BCG-CWS vaccination on cervical cancer patients undergoing standard treatments including surgery, chemotherapy, and/or radiation. We retrospectively analyzed 103 patients (13 cases administered with BCG-CWS vaccine and 90 controls without BCG-CWS) who underwent a standard treatment for cervical cancer from 2005 to 2021. The BCG-CWS group underwent repeated intradermal injections of the BCG-CWS vaccine before or immediately after the standard therapy start from 2011 to 2018. The vaccination was repeated weekly for 1 month, and then every 4 weeks thereafter. The effectiveness of the BCG-CWS vaccination on cervical cancer treatment was evaluated by determining the hazard ratios of overall survival between the BCG-CWS group and the control group with multivariate analysis using the Cox model. Hazard ratios between 2 groups were determined after adjustment by clinical parameters including surgery, chemotherapy, radiation, age, clinical stage, presence of human papillomavirus, and pathology. Long-term follow-up revealed a significantly better prognosis (hazard ratio: 0.2108, P = .008 by the Cox model) for patients with cervical cancer in the BCG-CWS group compared to patients in the control group. Among patients with advanced cancer worse than stage IB2, some completely cleared the disease, whereas the others showed long-term survival with recurrence. BCG-CWS therapy appears to be an effective immune adjuvant therapy for cervical cancer, although randomized control studies are needed to confirm this. We also need to clarify the underlying mechanisms slowing the progression of cervical cancer in those receiving this vaccination. This study sheds light on the potential of immunostimulatory drugs such as BCG-CWS and suggests the important role of immunity for cancer elimination in combination therapy.

HPV Genotyping by Molecular Mapping of Tissue Samples in Vaginal Squamous Intraepithelial Neoplasia (VaIN) and Vaginal Squamous Cell Carcinoma (VaSCC).

HPV genotypes were determined in 63 vaginal squamous intraepithelial neoplasia (VaIN) and 7 vaginal squamous cell carcinomas (VaSCC). Of these, 37 cases had VaIN alone, and 26 cases had both VaIN and cervical intraepithelial neoplasia (CIN) or condyloma. HPV typing was performed in scraped cells by Genosearch-31 (GS-31) and in the archived tissues by uniplex E6/E7 PCR. In a total of 49 VaIN1, 17 VaIN2/3, and 7 VaSCC tissues, the prevalence of HPV was 91.2% in VaIN (VaIN1: 87.8%, VaIN2/3: 100%) and 85.7% in VaSCC. Comparing HPV results in scraped cell and tissue, 46.2% of high-risk (HR) types and 68.1% of any HPV types that had been identified in cell samples were not present in corresponding tissues. HPV types in VaIN and CIN lesions differed in 92.3% (24/26) of cases with multiple lesions. These results suggest that there are many preclinical HPV infections in the vagina or the cervix, and VaIN and CIN are independently developed. The manual microdissection procedure of tissue revealed one HPV type in one lesion. Seventeen HPV types, including high-risk (HR), possible high-risk (pHR), and low-risk (LR), were identified in 43 VaIN1 lesions. In higher grade lesions, six HR (HPV16, 18, 51, 52, 56, 58), one pHR (HPV66), and one LR (HPV42) HPV types were identified in 17 VaIN2/3, and six HPV types, including HPV16, 45, 58, and 68 (HR), and HPV53 and 67 (pHR), were detected in each case of VaSCC. The vagina appears to be the reservoir for any mucosal HPV type, and HR- or pHR-HPV types are causative agents for vaginal malignancies.

Comparison of Aptima and hybrid capture-2 HPV tests and Pap test in the referral population in Japan.

The Aptima human papillomavirus (HPV) test (APTIMA) detects E6-E7 mRNA in abnormal cells in the uterine cervix. To investigate the accuracy of APTIMA for cervical cancer screening in Japan, 423 subjects, mostly referrals with abnormal cytology or being followed up for cervical intraepithelial neoplasia (CIN)1, were screened using two HPV tests, hybrid capture 2 (HC2) and APTIMA, and by the Pap test. Colposcopy was conducted in all subjects with a positive result in either test type. HPV genotyping was performed by Genosearch-31. A result of atypical squamous cells-undetermined significance (ASC-US) or worse on the HC2 test (ASC-US-HC2), and low-grade squamous intraepithelial lesion (LSIL) or worse (LSIL+) on the Pap test, was regarded as positive. APTIMA (97.5%) was more sensitive than LSIL+ (85.1%) for detecting CIN2 or worse (CIN2+) (McNemar test; p = .0003), and more sensitive (98.6%) than ASC-US-HC2 (92.7%) for detecting CIN3+. APTIMA and HC2 had similar sensitivities. HPV genotyping revealed that CIN2/3 with high-risk HPV (HR-HPV) was overlooked in five cases by ASC-US-HC2, and in four cases by HC2, while no such lesions were missed by APTIMA. Thus, APTIMA might be superior to HC2 for primary HPV screening in Japan. One cancer case positive for HPV67 (potentially high risk, [pHR]) was overlooked by Pap test and both HPV tests, suggesting a need for a new HPV test able to detect pHR-HPV types.

The prevalence of VAIN, CIN, and related HPV genotypes in Japanese women with abnormal cytology.

Vaginal intraepithelial neoplasia (VAIN) is often found by chance. We investigated the prevalence of VAIN and related human papillomavirus (HPV) types in comparison with cervical intraepithelial neoplasia (CIN). This study enrolled 648 women who were referred to the outpatient clinic of Kanazawa Medical University Hospital for abnormal cytology from January 2009 to January 2019. HPV genotypes were determined using Genosearch-31 + 4, which can detect 35 different HPV types. Colposcopy was performed at the first visit by an experienced gynecological oncologist. Among 611 subjects with squamous cell lesions, 107 (17.5%) VAIN cases were identified, and 67 (11.0%) women had both VAIN and CIN. Ultimately, 72 VAIN1, 15 VAIN2/3, 203 CIN1, 249 CIN2/3, 32 cervical squamous cell carcinomas (SCC), and one vaginal SCC (Vag-SCC) were identified. The prevalences of VAIN1, VAIN2/3, and Vag-SCC were 35.5%, 6.0%, and 3.1% of equivalent cervical lesions, respectively. The VAIN patients were older than the CIN patients (P = .002). About half of the VAIN cases were diagnosed during the follow-up. Multiple HPV infections were found in 42.9% of the VAIN and CIN patients. HPV52, 16, 51, 53, and 56 were the most common types in VAIN, whereas HPV16, 52, 58, 51, and 31 predominated in CIN. HPV18 was rare in VAIN, HPV58 was more common in CIN than in VAIN, and HPV53 and HPV73 were more common in VAIN. In conclusion, VAIN1 was identified more frequently than we expected. Various HPV types were identified in the vagina, which is likely a reservoir for HPV.

Single type infection of human papillomavirus as a cause for high-grade cervical intraepithelial neoplasia and invasive cancer in Japan.

To elucidate oncogenic human papilloma virus (HPV) types in Japan, HPV genotyping was performed in 1526 cervical intraepithelial neoplasia (CIN) and 371 invasive cervical cancer (ICC) patients with the novel Genosearch-31+5 HPV test. The HPV-positive rates were 89.3% and 90.8% in CIN and ICC. Regarding single-type infections, 13 internationally recognized high-risk (13HR) types excluding HPV 35, and probably HR HPV 53, 67, 69, and 70 were identified in ICC, suggesting that all these types may be oncogenic. HPV16 and 18 were identified in both SCC and adenocarcinoma (ADC). HPV HPV52, 31 and 58 (alpha-9) were predominantly detected in SCC, whereas HPV 18, 45, 39 and 59 (alpha-7) were in ADC. The prevalence of HPV 18 in SCC significantly decreased with increasing age of patients, whereas the opposite trend was observed in the other HR types. HPV18 is likely to induce SCC rapidly. All ICC cases aged 20-29 were positive for HPV 16 or 18, suggesting that present HPV 16, 18 vaccines may be quite effective to prevent ICC in young women.

Malignant Transformation of an Ovarian Endometrioma during Endometriosis Treatment: A Case Report.

Dienogest (DNG) is considered to be effective against ovarian endometrioma (OMA). We report a rare case of OMA transformation to ovarian cancer during long-term endometriosis treatment with a periodic administration of a gonadotropin-releasing hormone agonist (Gn-RH agonist) and DNG. The patient was a 41-year-old Japanese woman. OMA and adenomyosis of the uterus were revealed via computed tomography. Consequently, she underwent conservative treatment without undergoing surgery because her overall status was poor. She received cyclic therapy (Gn-RH agonist and DNG) for approximately eight years. However, she reported lumbago and underwent close medical examination at our hospital after about eight years of treatment. Under the suspicion of malignant transformation, she underwent surgery. The pathological diagnosis was clear cell carcinoma of the right ovary (stage 2B). After surgery, she received six courses of chemotherapy (conventional TC). No evidence of disease was observed after chemotherapy. Our findings suggest that malignant transformation of OMA can occur during DNG treatment. Since the delayed detection of ovarian cancer greatly affects the prognosis, women older than 40 with OMA are encouraged to undergo regular check-ups every few months.

Usefulness of the maximum standardized uptake value for the diagnosis and staging of patients with cervical cancer undergoing positron emission tomography/computed tomography.

Cervical cancer recently has become more common among younger women in Japan. Diagnosing early-stage cancer is straightforward using cervical cytodiagnosis and histological diagnosis. However, postmenopausal endophytic cervical cancer and skip lesions in cervical adenocarcinoma are difficult to detect. We compared the maximum standardized uptake value (SUVmax) of 18F-fluorodeoxy-glucose positron emission tomography/computed tomography (PET/CT) for primary staging of cervical cancer and evaluated the relationship of the imaging findings to prognosis.This was a retrospective study of 38 patients with cervical cancer who underwent PET/CT. Patients were grouped according to disease stage, and the mean SUVmax, overall survival, and progression-free survival (PFS) were evaluated.The mean SUVmax was significantly different between patients with stage ≤I and ≥II diseases among those with squamous (P > .001) and glandular (P = .023) lesions. With an SUVmax of receiver operating characteristic curves as the optimal cutoff value, the log-rank test for PFS revealed a statistically significant difference between the 2 disease stages (P = .020 and P = .016, respectively).SUVmax is useful to differentiate between stage ≤I and ≥II cervical cancer. SUVmax may be useful for the prognostic evaluation of disease recurrence in patients with cervical cancer.

Utility of 18F-fluorodeoxyglucose-positron emission tomography in the differential diagnosis of benign and malignant gynaecological tumours.

INTRODUCTION: Positron emission tomography/computed tomography (PET/CT) involving 18F-fluorodeoxyglucose (FDG) is widely used for systemic cancer and recurrence diagnosis. However, the differential diagnosis of benign and malignant gynaecological tumours according to FDG accumulation is unclear. This study aimed to investigate the intensity of FDG uptake/metabolic activity for the differential diagnosis of benign and malignant gynaecological tumours. METHODS: This study included seven patients with physiological phenomena, 34 with benign tumours, 13 with borderline malignant tumours and 119 with malignant tumours who underwent 18F-FDG PET/CT. We assessed the maximum standardized uptake value (SUVmax) and determined its utility in the diagnosis of benign and malignant tumours using a receiver operating characteristic (ROC) curve analysis. RESULTS: Among the 63 patients with ovarian tumours, the mean SUVmax of 22 patients with benign ovarian tumours was 2.48 and the mean SUVmax of 41 patients with malignant ovarian tumours was 10.98 (P < 0.001). In the ROC curve analysis, the area under the curve (AUC) was 0.977, with a 95% confidence interval of 0.947-1.000. With a cut-off value of 3.97 for the optimal SUVmax, the sensitivity and specificity were 95.1% and 86.4%, respectively. In addition, the AUC was 0.911 (95% CI: 0.768-1.000) for the assessment of uterine myomas and sarcomas. With a cut-off value of 10.62 for the optimal SUVmax, the sensitivity and specificity were 91.7% and 86.7% respectively. CONCLUSIONS: The SUVmax value helps differentiate benign and malignant ovarian tumours, as well as uterine myomas and uterine sarcomas.

Comparison of the digene hybrid capture 2 and Roche cobas 4800 HPV tests for detection of CIN2+ in a referral population in Japan.

To examine validity of the hybrid capture-2 and cobas 4800 HPV tests, 396 women including 188 women visiting for cancer screening, and 208 referral cases were examined with both HPV tests and the liquid-based cervical Pap test. Concordant results between the HPV assays were observed in 333 cases (coincident rates; 84.1%, kappa value; 0.682). The sensitivity for CIN2+ was 98.6% (69/70) and 82.9% (58/70) for HC2 and cobas 4800 (McNemar's test; P = 0.0026). The sensitivity for CIN3+ was 97.2% (35/36) and 83.3% (30/36) (Not significant, P = 0.0736). The specificities for CIN2+ or CIN3+ did not differ between the tests. The HPV16, 52, 18, 31, and 58 were the most common types in CIN2+ cases. Reasonable sensitivity for HPV52, and cross-hybridization with some probable high-risk HPV type such as HPV82 explain the higher sensitivity of HC2 than cobas 4800 in detection of CIN2+ in a referral population in Japan.