Ryo Konno

Human Papillomavirus Infection and Cervical Cancer Prevention in Japan and Korea

Cervical cancer is a common cancer among women in Japan and Korea. Implementation of national cervical cancer screening programs has led to a reduction in the incidence of cervical cancer in both countries. However, over the past decade, there has been a recent marked increase in cervical cancer incidence among young women in Japan. Human papillomavirus (HPV) is found in the majority of cervical cancers, and HPV-16 and 18 are the two most common types. The next most frequent HPV types in cervical cancer are 52, 58 and 33 for Japan and 52, 58, and 33 for Korea, varying slightly when compared to the worldwide distribution. Screening coverage for both countries remains a challenge. Current coverage is reported at 24% in Japan, with the lowest coverage in young Japanese women, and 41% in Korea. Cytology remains the predominant screening method. HPV DNA testing is widely used to triage women with abnormal cytology in Korea. HPV vaccines have been licensed in Korea, but not yet in Japan. In both countries cost is a substantial impediment to implementation and no national programs are currently planned or in place. Therefore, increased disease awareness and utilization of screening is the first priority for controlling cervical cancer.

Recommendations for Cervical Cancer Prevention in Asia Pacific

Asia Oceania includes countries from both the Asia Pacific region and Australasia, which cover very diverse geographical areas and populations as well as bearing 52% of the cervical cancer burden in the world. Human papillomavirus (HPV) genotype distribution in women with normal cytology varies between countries in this region, as well as with the distribution typically observed in worldwide estimates or in Western countries. HPV-16 remains the predominant oncogenic type for high-grade cervical dysplasia and cervical cancer across the region, and HPV-18 is generally among the five most common types. HPV-58 is commonly found in cervical cancer as well as in women with normal cytology, and HPV-31, 33 and 35 are relatively less frequent in these regions compared to the West. While screening programmes have been proposed and implemented in several populations, successful programmes are rather limited and the majority of countries still have no or minimal screening services. Prophylactic HPV vaccination will only be feasible when it becomes affordable, thus the current priority and the short-term goal for cervical cancer control is to identify feasible and effective screening measures, and to find the most effective way to combine vaccination with sustainable screening programmes. This Regional Report has carefully described the disease burden of HPV and cervical cancer and the current situations in cervical cancer prevention for many countries in the Asia Oceania region. These data identify the many challenges and opportunities to be considered for policy decisions for cervical cancer control. Furthermore, this report presents the results of advanced decision analytic models calibrated to countries in the region that provide early insight into what strategies are most promising and those likely to be cost-effective and affordable. It thus provides a synthesis of the available evidence-based scientific information, in the context of a significant and systematic international review, that is likely to be useful to governments and public health providers.

Inhibition of peritoneal dissemination of ovarian cancer by tyrosine kinase receptor inhibitor SU6668 (TSU‐68)

SU6668 (TSU‐68) is a small‐molecule synthetic inhibitor of the angiogenic related receptor tyrosine kinases Flk‐1/KDR, PDGFRβ, and FGFR1. Using a mouse model of peritoneally disseminated ovarian cancer, we investigated whether SU6668 inhibits peritoneal dissemination and prolongs survival time. BALB/c nude mice were intraperitoneally (i.p.) inoculated with SHIN‐3 (VEGF‐hypersecretory) or KOC‐2S (PDGF‐hypersecretory) ovarian serous adenocarcinoma cells with marked peritoneal dissemination ability. From the day after i.p. inoculation of tumor cells, SU6668 was orally administered 6 times weekly at a daily dose of 100 mg/kg or 400 mg/kg. The SU6668‐administered group and the vehicle‐administered control group were compared for the number of tumor vascular endothelial cells, weight of peritoneally disseminated tumors, amount of ascitic fluid and survival time. As a result, these 3 parameters were significantly smaller in the SHIN‐3‐inoculated, SU6668‐administered mice than in the control group (p = 0.03, p = 0.002, and p = 0.02, respectively). The mean survival time was significantly longer, at 58.1 ± 11.2 days, in the SU6668‐administered mice than that (34.5 ± 8.8 days) in the control group (p = 0.002). Similarly, in the KOC‐2S‐inoculated mice, the oral administration of SU6668 significantly reduced these 3 parameters (p = 0.04, p = 0.04, and p = 0.03, respectively), and significantly prolonged survival (16.6 ± 1.7 days vs. 11.0 ± 0.7 days, p = 0.008). Thus, the oral administration of SU6668 inhibited angiogenesis and peritoneal dissemination and prolonged survival in mice with peritoneally disseminated ovarian cancer. These effects were observed with both the VEGF‐ and PDGF‐hypersecretory cell lines. Our results suggest that molecular targeting with oral SU6668 will become a new therapeutic strategy targeting peritoneally disseminated ovarian cancer.

Analysis of estrogen receptor α and β in endometrial carcinomas : Correlation with ERβ and clinicopathologic findings in 45 cases

Estrogens play important roles in the pathogenesis of the great majority of endometrial endometrioid adenocarcinoma. Recently, a novel estrogen receptor (ER), ERβ, has been characterized, but little is known about the status of ERβ in endometrial carcinoma. We therefore examined expression of both ERa and ERβ in 45 cases of endometrioid endometrial adenocarcinoma using mRNA in situ hybridization, reverse transcription and polymerase chain reaction (RT-PCR), and immunohistochemistry. We also correlated the findings with various clinicopathologic parameters in these cases to examine their possible biologic significance. Accumulation of mRNA hybridization signals for both ERa and ERβ was detected predominantly in the cytoplasm of carcinoma cells, and to a lesser extent in some stromal cells. ERβ mRNA was detected in 16/45 cases (35.6%), and ERa mRNA hybridization signals were detected in 36/45 cases (80.0%). Among the 16 ERp positive cases, 15 cases also had ERa mRNA hybridization signals. In the cases that expressed both ERα and ERβ, ERa mRNA hybridization signals were more widely distributed than ERp mRNA. In 21 cases, carcinoma cells had ERa mRNA hybridization signals but not ERβ mRNA. There was a statistically significant positive correlation between the results of mRNA in situ hybridization and semiquantitative RT-PCR or immunohistochemistry for both ERa and ERβ. There were no significant correlations between ERβ mRNA expression and PR labeling index, Ki67 LI, age, or histologic grade. The results from our study indicate that ERβ is coexpressed with ERa, and that the estrogenic effects occur predominantly through ERa in endometrial carcinomas.

Identification of Human Papillomavirus Type 58 Lineages and the Distribution Worldwide

BACKGROUND Human papillomavirus type 58 (HPV-58) accounts for a much higher proportion of cervical cancers in East Asia than other types. A classification system of HPV-58, which is essential for molecular epidemiological study, is lacking. METHODS AND RESULTS This study analyzed the sequences of 401 isolates collected from 15 countries and cities. The 268 unique concatenated E6-E7-E2-E5-L1-LCR sequences that comprised 57% of the whole HPV-58 genome showed 4 distinct clusters. L1 and LCR produced tree topologies that best resembled the concatenated sequences and thus are the most appropriate surrogate regions for lineage classification. Moreover, short fragments from L1 (nucleotides 6014-6539) and LCR (nucleotides 7257-7429 and 7540-52) were found to contain sequence signatures informative for lineage identification. Lineage A was the most prevalent lineage across all regions. Lineage C was more frequent in Africa than elsewhere, whereas lineage D was more prevalent in Africa than in Asia. Among lineage A variants, sublineage A2 dominated in Africa, the Americas, and Europe, but not in Asia. Sublineage A1, which represents the prototype that originated from a patient with cancer, was rare worldwide except in Asia. CONCLUSIONS HPV-58 can be classified into 4 lineages that show some degree of ethnogeographic predilection in distribution. The evolutionary, epidemiological, and pathological characteristics of these lineages warrant further study.

Gene Expression Profiling of the Rat Endometriosis Model

To investigate the molecular mechanism of endometriosis, gene expression profiling was analyzed in a rat endometriosis model.

Geographical distribution and oncogenic risk association of human papillomavirus type 58 E6 and E7 sequence variations.

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.

Smooth muscle metaplasia and innervation in interstitium of endometriotic lesions related to pain.

OBJECTIVE To investigate the pathogenesis of endometriotic pain. DESIGN Retrospective nonrandomized immunohistochemical study. SETTING A university hospital, Department of Gynecology. PATIENT(S) Twenty human endometriotic specimens were selected from different lesions including ovarian endometrioma, peritoneal lesion, and deep infiltrating lesion. Premenopausal women with histologically diagnosed endometriosis were selected (mean age 39 years; range, 25-53 years). The chief complaint was dysmenorrhea, dyschezia, and dyspareunia. A rat endometriosis model was induced in 10 SLC-Sprague-Dawley rats (8 weeks old) by surgical autotransplantation of the uterus. INTERVENTION(S) Immunohistochemical staining of endometriotic specimens for alpha-smooth muscle actin (ASMA), neural cell adhesion molecule (NCAM), and nerve growth factor (NGF) expression. MAIN OUTCOME MEASURE(S) Comparison of the immunoreactive staining of ASMA, NCAM, and NGF expression in human endometriosis and a rat endometriosis model. RESULT(S) Morphological analysis revealed thick interstitium in both human and rat endometriotic lesions. The major components of fibrotic interstitium are smooth muscle cells, stained by anti-ASMA antibody, and nerve cells, stained by anti-NCAM antibody. Inflammatory cells are also present (e.g., macrophages and lymphocytes) as revealed by anti-NGF antibody staining. CONCLUSION(S) These results suggest that the contraction of smooth muscle cells and the hyperalgia derived from innervation in the interstitial area is related to pain in endometriosis.

The correlation between the response to progestogen treatment and the expression of progesterone receptor B and 17β-hydroxysteroid dehydrogenase type 2 in human endometrial carcinoma

objective  In situ metabolism and synthesis of oestrogens are considered to play important roles in the pathogenesis and development of human endometrial endometrioid adenocarcinoma. Approximately 3–5% of patients with these neoplasms are under age 40, some of whom have been treated with progestogen alone as a primary therapy for both atypical endometrial hyperplasia and adenocarcinoma in order to preserve their fertility. Medroxyprogesterone acetate (MPA) has been used extensively in the treatment of both breast and endometrial disorders as an endocrine therapy. However, details of the alterations of in situ oestrogen metabolism following progestogen treatment have yet to be fully elucidated.

Role of immunoreactions and mast cells in pathogenesis of human endometriosis-morphologic study and gene expression analysis-

Study objectivesTo investigate the pathophysiology of human endometriosis, we examined by morphological and molecular biological methods.MethodsSamples of ovarian endometriosis and normal ovarian tissues were obtained laparoscopically after informed consent. A morphological study by toluidine blue staining, immunohistochemistry of c-kit and electron microscopy demonstrated the localization of mast cells in the stromal lesions of endometriosis. Oligonucleotide microarrays were used for gene expression analysis.ResultsInfiltration of numerous mast cells and development of fibrosis was observed throughout the stromal lesions. Gene expression analysis by oligonucleotide microarrays indicated inflammatory immunoreactions in the lesions. Expressions of the FCERlG and PGDS, which are considered to be mast cell-specific genes, were upregulated in the ovarian endometriotic lesions as compared to the normal ovarian tissues. Furthermore, expressions of genes associated with immunological inflammation, such as IL-8, GRO1, GRO2, CXCR4, MCP1, and those related to tissue remodeling (MMP, COLAA2, and COL5A2) were also higher in endometriotic lesions than in the normal ovarian tissue.ConclusionsThus it is likely that mast cells and their related inflammatory immunoreactions via chemokines play important roles in producing fibrosis and adhesions in endometriotic lesions.