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.

Clinical Trial on the Safety and Tolerability of Personalized Cancer Vaccines Using Human Platelet Lysate-Induced Antigen-Presenting Cells.

Research and development of personalized cancer vaccines as precision medicine are ongoing. We predicted human leukocyte antigen (HLA)-compatible cancer antigen candidate peptides based on patient-specific cancer genomic profiles and performed a Phase I clinical trial for the safety and tolerability of cancer vaccines with human platelet lysate-induced antigen-presenting cells (HPL-APCs) from peripheral monocytes. Among the five enrolled patients, two patients completed six doses per course (2-3 × 107 cells per dose), and an interim analysis was performed based on the immune response. An immune response was detected by enzyme-linked immunosorbent spot (ELISpot) assays to HLA-A*33:03-matched KRASWT, HLA-DRB1*09:01-compliant KRASWT or G12D, or HLA-A*31:01-matched SMAD4WT, and HLA-DRB1*04:01-matched SMAD4G365D peptides in two completed cases, respectively. Moreover, SMAD4WT-specific CD8+ effector memory T cells were amplified. However, an attenuation of the acquired immune response was observed 6 months after one course of cancer vaccination as the disease progressed. This study confirmed the safety and tolerability of HPL-APCs in advanced and recurrent cancers refractory to standard therapy and is the first clinical report to demonstrate the immunoinducibility of personalized cancer vaccines using HPL-APCs. Phase II clinical trials to determine immune responses with optimized adjuvant drugs and continued administration are expected to demonstrate efficacy.

Ingestion of taxifolin-rich foods affects brain activity, mental fatigue, and the whole blood transcriptome in healthy young adults: a randomized, double-blind, placebo-controlled, crossover study.

The antioxidant properties of polyphenols, which are found in most plants, have been shown to be useful for maintaining health, including enhancing brain function and alleviating stress. We aimed to investigate the effect of a single intake of taxifolin-containing foods on cognitive task performance and whole blood gene expression in healthy young adults. This study was a randomized, placebo-controlled, double-blind, crossover trial in which healthy young adults were administered a single dose of either a placebo or food containing taxifolin. Cognitive tests (serial 3s, serial 7s, and rapid visual information processing) to examine brain activity and visual analog scale questionnaires to analyze mental fatigue were applied. The set of tests was repeated four times. The findings showed that taxifolin intake improved calculation abilities and reduced mental fatigue. An analysis of whole blood gene expression before and after the test revealed that the expression of foreign substance removal-related genes increased following the ingestion of taxifolin and that most differentially expressed genes were enriched in granulocytes. Taxifolin intake was shown to affect the brain activity of healthy young adults and demonstrated an antifatigue effect, thereby reducing subjective fatigue. A single intake of taxifolin may enhance the removal of foreign substances by strengthening the innate immune system and suppressing the occurrence of injury.

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.

Expansion of Human Papillomavirus-Specific T Cells in Periphery and Cervix in a Therapeutic Vaccine Recipient Whose Cervical High-Grade Squamous Intraepithelial Lesion Regressed.

Advances in high-throughput sequencing have revolutionized the manner with which we can study T cell responses. We describe a woman who received a human papillomavirus (HPV) therapeutic vaccine called PepCan, and experienced complete resolution of her cervical high-grade squamous intraepithelial lesion. By performing bulk T cell receptor (TCR) ß deep sequencing of peripheral blood mononuclear cells before and after 4 vaccinations, 70 putatively vaccine-specific clonotypes were identified for being significantly increased using a beta-binomial model. In order to verify the vaccine-specificity of these clonotypes, T cells with specificity to a region, HPV 16 E6 91-115, previously identified to be vaccine-induced using an interferon-γ enzyme-linked immunospot assay, were sorted and analyzed using single-cell RNA-seq and TCR sequencing. HPV specificity in 60 of the 70 clonotypes identified to be vaccine-specific was demonstrated. TCR ß bulk sequencing of the cervical liquid-based cytology samples and cervical formalin-fixed paraffin-embedded samples before and after 4 vaccinations demonstrated the presence of these HPV-specific T cells in the cervix. Combining traditional and cutting-edge immunomonitoring techniques enabled us to demonstrate expansion of HPV-antigen specific T cells not only in the periphery but also in the cervix. Such an approach should be useful as a novel approach to assess vaccine-specific responses in various anatomical areas.

Evaluation of DNA extraction protocols from liquid-based cytology specimens for studying cervical microbiota.

Cervical microbiota (CM) are considered an important factor affecting the progression of cervical intraepithelial neoplasia (CIN) and are implicated in the persistence of human papillomavirus (HPV). Collection of liquid-based cytology (LBC) samples is routine for cervical cancer screening and HPV genotyping and can be used for long-term cytological biobanking. We sought to determine whether it is possible to access microbial DNA from LBC specimens, and compared the performance of four different extraction protocols: (ZymoBIOMICS DNA Miniprep Kit; QIAamp PowerFecal Pro DNA Kit; QIAamp DNA Mini Kit; and IndiSpin Pathogen Kit) and their ability to capture the diversity of CM from LBC specimens. LBC specimens from 20 patients (stored for 716 ± 105 days) with CIN values of 2 or 3 were each aliquoted for each of the four kits. Loss of microbial diversity due to long-term LBC storage could not be assessed due to lack of fresh LBC samples. Comparisons with other types of cervical sampling were not performed. We observed that all DNA extraction kits provided equivalent accessibility to the cervical microbial DNA within stored LBC samples. Approximately 80% microbial genera were shared among all DNA extraction protocols. Potential kit contaminants were observed as well. Variation between individuals was a significantly greater influence on the observed microbial composition than was the method of DNA extraction. We also observed that HPV16 was significantly associated with community types that were not dominated by Lactobacillus iners.

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.

Epidemiological guideline influence on the therapeutic trend and patient outcome of uterine cervical cancer in Japan: Japan society of gynecologic oncology guideline evaluation committee project.

OBJECTIVE: The Japan Society of Gynecologic Oncology published its first clinical guidelines for uterine cervical cancer in 2007 which has been revised twice in 2011 and 2017. The aim of this study was to investigate the influence of the first guideline publication on the therapeutic trend and patient outcome by analyzing uterine cervical cancer cases registered to the cancer registry organized by the Japan Society of Obstetrics and Gynecology. METHODS: Data of uterine cervical cancer cases registered to the cancer registry from 2000 to 2012 were provided. Epidemiological and clinical trend were analyzed by the Chi-squared test with subsequent standardized residual analysis. Overall survival among the patients registered between 2004 and 2009 was analyzed using the Fine and Gray competing risk model. RESULTS: 68,707 cases were registered during the study period. A trend analysis revealed that the guideline publication may have led to a decrease in neoadjuvant chemotherapy in parallel with an increase in radiation therapy mainly in stage II and III patients undergoing primary treatment. A survival analysis indicated that the introduction of the guideline may have improved overall survival among stage III uterine cervical cancer patients, even though a significant difference was not observed in all of the cases. CONCLUSIONS: This study demonstrated the potential influence of the guideline publication on the clinical trend and patient outcome. As this is the first assessment of the guideline for uterine cervical cancer in Japan, continuous evaluation is necessary to further comprehend the significance of this guideline.

Changes in the Clinicopathological Demographics of Vulvar Cancer in Japan: Increasing Oldest-Old, Stage Shifting, and Decreasing Cohort-Level Survival †.

BACKGROUND: To examine trends in the clinicopathological characteristics of vulvar cancer in Japan. METHODS: This is a nationwide retrospective study examining consecutive women with vulvar cancer between 2001 and 2010 in Japan (n = 1061). Temporal trends in demographics, tumor characteristics, and survival were assessed by cohort-level analysis. The National Cancer Institute's Surveillance, Epidemiology, and End Result Program was used for external validation (n = 10,154). RESULTS: The number of oldest-old women aged ≥80 years significantly increased (from 18.0% in 2001 to 30.6% in 2010; 70.5% relative increase) in the study period. A stage shift was observed, with stage I disease decreasing from 43.0% to 34.0% (21.0% relative decrease), and tumors with distant metastases increasing from 23.2% to 35.6% (53.3% relative increase, p < 0.05). The number of women who underwent surgical treatment decreased from 84.0% to 69.7% (17.0% relative decrease), whereas utilization of radiotherapy increased from 34.4% to 43.2% (25.7% relative increase) over time (p < 0.05). In the cohort-level analysis, the five-year survival rates significantly decreased from 2001 to 2010 (p < 0.05), specifically, 66.9% to 51.0% for progression-free survival (23.7% relative decrease), 79.5% to 67.9% for cause-specific survival (14.6% relative decrease), and 74.9% to 62.3% for overall survival (16.9% relative decrease). In the patient-level analysis, oldest-old women were less likely to undergo surgical treatment and were independently associated with decreased survival (p < 0.05). In the US cohort, the number of oldest-old women (25.2% to 27.8%) and the five-year cause-specific survival rate (81.8% to 79.9%) remained unchanged during the study period (p > 0.05). CONCLUSION: Demographics and outcomes of vulvar cancer in Japan significantly changed during the study period. An increasing oldest-old population and a stage shift to more metastatic disease resulted in a cohort-level decrease in survival rates.

The promise of combining cancer vaccine and checkpoint blockade for treating HPV-related cancer.

Human papillomavirus (HPV)-associated intraepithelial neoplasia or cancers are ideal candidates for cancer immunotherapy since HPV oncoproteins, such as E6 and E7 proteins of high-risk HPVs, could be utilized as foreign antigens. In HPV-associated cancers as well as nonviral cancers, the cancer cells may evade host immunity through the expression of immune checkpoint molecules, downregulation of human leukocyte antigen, and activation of immune regulatory cells. Because of these immune suppressive mechanisms, HPV therapeutic vaccines have shown little efficacy against HPV-associated cancers, although they have shown efficacy in treating HPV-associated intraepithelial neoplasias. Recently, checkpoint blockade emerged as a promising new treatment for solid cancers; however, these therapies have shown only modest efficacy against HPV-associated cancers. Here we reviewed literature analyzing a combinatory therapy using an immune checkpoint inhibitor and an HPV therapeutic vaccine for treating HPV-associated cancers to compensate for shortfalls of each monotherapy. Complimentary modes of T cell activation would be deployed; as vaccines would directly stimulate the T cells, while checkpoint inhibitors would do so by releasing inhibition. Some promising studies using animal models and early human clinical trials raised a possibility that such combinations may be efficacious in regressing HPV-associated cancers. Epitope spreading (the phenomenon in which non-targeted antigens become new targets of immune response) may play a critical role mechanistically. Currently ongoing studies will shed light as to whether such combination therapy would indeed be a promising new treatment paradigm. Current and future studies must also determine the adverse effect profile of such a combination treatment.

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.

Association between 18F-fluorodeoxyglucose-PET/CT and histological grade of uterine endometrial carcinoma.

OBJECTIVE: The incidence of endometrial adenocarcinoma of the uterine corpus has increased in Japan. This study aimed to clarify the relationships between this type of cancer and various data provided by 18F-fluorodeoxyglucose (FDG) accumulation in positron emission tomography/computed tomography (PET/CT). MATERIALS AND METHODS: The study cohort thus comprised 27 patients with endometrial adenocarcinoma who had undergone PET/CT examinations from April 2008 to March 2015. All patients provided informed consent at our hospital. Data from 27 patients with endometrial adenocarcinoma (Grades 1-3) were retrospectively analyzed to determine the relationships between the maximum standardized uptake value (SUVmax), histological grading, tumor size, and rate of positivity for glucose transporter 1, hexokinase II, and glucose-6-phosphatase-α (G6Pase-α). RESULTS: SUVmax values differed significantly between patients with Grade 1 (G1) and Grade 2 (G2) or higher cancer (P = 0.031). For G1 cancer, a negative correlation was found between SUVmax and G6Pase-α (R = -0.475, P = 0.046). The regression coefficient for G6Pase-α was -0.125 (95% CI: -0.165 to -0.084) and the P-value 0.008; thus this difference was significant. CONCLUSION: PET/CT is a useful test for discriminating between G1 and G2 or higher cancer in patients with endometrial adenocarcinoma of the uterine corpus. In addition, the negative correlation identified between SUVmax and G6Pase-α activity in patients with well-differentiated endometrial cancer may be a novel finding.

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.

Impact of institutional accreditation by the Japan Society of Gynecologic Oncology on the treatment and survival of women with cervical cancer.

OBJECTIVE: The Japan Society of Gynecologic Oncology (JSGO) initiated a nation-wide training system for the education and certification for gynecologic oncologists in 2005. To assess the impact of the quality of the JSGO-accredited institutions, JSGO undertook an analysis of the Uterine Cervical Cancer Registry of the Japan Society of Obstetrics and Gynecology (JSOG) to determine the effectiveness of the JSGO-accredited institutions on the treatment and survival of women with cervical cancer. METHODS: The effectiveness of 119 JSGO-accredited institutions and 125 non-JSGO-accredited institutions on the treatment and survival of women with cervical cancer were compared by analyzing the tumor characteristics, treatment patterns, and survival outcomes of women with stage T1B-T4 cervical cancer utilizing the data in the JSOG nation-wide registry for cervical cancer (2006-2009). RESULTS: A total of 14,185 eligible women were identified: 10,920 (77.0%) cases for 119 JSGO-accredited institutions and 3,265 (23.0%) cases for 125 non-accredited institutions. A multivariate analysis showed that age, stage, histology type, and treatment pattern were independently associated with mortality. Moreover, women who received treatment at the JSGO-accredited institutions had a significantly decreased mortality risk compared to non-accredited institutions (adjusted hazard ratio [aHR]=0.843; 95% confidence interval [CI]=0.784-0.905). Similar findings on multivariate analysis were seen among subset of women who received surgery alone (aHR=0.552; 95% CI=0.393-0.775) and among women who received radiotherapy (aHR=0.845; 95% CI=0.766-0.931). CONCLUSION: Successful implementation of gynecologic oncology accrediting institution was associated with improved survival outcome of women with cervical cancer in Japan.

Fully sialylated alpha-chain of complement 4-binding protein (A2160): a novel prognostic marker for epithelial ovarian carcinoma.

PURPOSE: Fully sialylated alpha-chain of complement 4-binding protein (A2160) is a member of the glycoprotein family and has recently been identified as a diagnostic biomarker for epithelial ovarian cancer. This study examined the utility of A2160 as a prognostic biomarker for this disease. METHODS: This is a retrospective analysis of prospectively collected plasma samples from 93 women with stage I-IV epithelial ovarian cancer who underwent primary cytoreductive surgery between 2009 and 2014. Pretreatment A2160 levels were correlated to clinico-pathological factors and survival outcome. RESULTS: Women with advanced-stage disease had significantly higher 2160 levels compared to those with early stage disease (stage I-II versus III-IV, median 2.17-2.70 versus 5.31-8.70 U/mL, P < 0.01). Women with high-grade serous ovarian carcinoma had higher A2160 levels compared to other histologies (6.60 versus 3.01 U/mL, P = 0.05). Women who had suboptimal cytoreduction had significantly higher A2160 levels than those who achieved optimal/complete cytoreduction (7.02 versus 2.30-3.17 U/mL, P < 0.01). On univariable analysis, higher A2160 levels were significantly associated with decreased progression-free survival (64-100 versus 1-33%ile, 5-year rates 53.4 versus 78.9%, P = 0.029). After controlling for age, CA-125 level, cytoreductive status, histology, and stage, higher A2160 levels remained an independent prognostic factor for decreased progression-free survival (adjusted-hazard ratio (HR) 2.48, 95% confidence interval (CI) 1.01-6.11, P = 0.049). Similarly, higher A2160 levels were independently associated with decreased cause-specific survival on multivariable analysis (adjusted-HR 3.07, 95% CI 1.19-7.93, P = 0.021). CONCLUSION: Our study suggests that A2160 may be a useful prognostic biomarker for epithelial ovarian cancer, and higher pretreatment levels of A2160 predicts poor survival outcome.

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.

Effect of MG132, a proteasome inhibitor, on the expression of growth related oncogene protein-alpha in human umbilical vein endothelial cells.

Growth related oncogene protein-alpha (GRO-alpha) is a member of C-X-C chemokine and plays an important role in inflammatory responses. Expression of GRO gene family is regulated by a number of factors at both transcriptional and posttranscriptional levels. In the present study, we have addressed the possible regulation of GRO-alpha expression by ubiquitin-proteasome system. Cultures of human umbilical vein endothelial cells were treated with a proteasome inhibitor, MG132, and the levels of GRO-alpha mRNA were analyzed by reverse transcription-polymerase chain reaction or northern blotting. Levels of GRO-alpha protein in the cell-conditioned medium were determined by enzyme-linked immunosorbent assay. MG132 alone increased the levels of GRO-alpha mRNA and protein; however, it did not affect the GRO-alpha mRNA induced by lipopolysaccharide (LPS) and inhibited the LPS-induced decrease in IkappaB levels. Other proteasome inhibitors, MG115 and lactacystin, also induced the expression of GRO-alpha mRNA. MG132 induced the phosphorylation of p38 MAPK, MEK and JNK. Pretreatment of the cells with SB203580, an inhibitor of p38 MAPK, suppressed the MG132-induced GRO-alpha expression, but pretreatment of the cells with U0126, PD98059 or SP600125, inhibitors of MEK1/2 or JNK, did not influence the effect of MG132. We conclude that MG132 upregulates GRO-alpha expression in vascular endothelial cells, at least in part, through the activation of p38 MAPK.

15-Deoxy-D12,14-prostaglandin J2 inhibits CX3CL1/fractalkine expression in human endothelial cells.

Peroxisome proliferator-activated receptor-gamma (PPAR-gamma)is a member of nuclear hormone receptor superfamily, and is knownto play a role in various biological processes including inflammatoryresponses and adipocyte differentiation. CX3CL1/fractalkineis a potent agonist for chemotaxis and adhesion of monocytes and lymphocytes. Endothelial cells produce fractalkine when stimulated with cytokinessuch as interleukin-1 (IL-1), tumour necrosis factor-alpha andinterferon-gamma (IFN-gamma). We herein report that 15-deoxy-n12,14 -prostaglandinJ2 (15d-PGJ2), a PPAR-gamma agonist,inhibits the expression of fractalkine induced by IFN-gamma orIL-1beta in human endothelial cells. Agonist for PPAR-alpha (WY14643)or PPAR-gamma (ciglitazone) did not inhibit the cytokine-inducedfractalkine expression, and the effect of 15d-PGJ2 maybe independent of PPAR. 15-Deoxy-D12,14 prostaglandinJ2 also inhibited the adhesion of blood mononuclear cellsto endothelial monolayers treated with IFN-gamma or IL-1beta. The data suggest that 15d-PGJ2 regulates inflammatoryreactions, at least in part, through the inhibition of fractalkineexpression and leucocyte traffic through the endothelium.