Details of a Researcher - Iwata, Takashi

Papers - Iwata, Takashi

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Uterine cervical cancer associated with obstructed hemivagina and ipsilateral renal agenesis (OHVIRA) syndrome: A case report and review of the literature

Oka E., Chiyoda T., Iwata T., Yamagami W., Aoki D.

Gynecologic Oncology Reports (Gynecologic Oncology Reports) 34 100645 2020.11

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Tumor-infiltrating lymphocytes predict survival outcomes in patients with cervical cancer treated with concurrent chemoradiotherapy

Ohno A., Iwata T., Katoh Y., Taniguchi S., Tanaka K., Nishio H., Nakamura M., Morisada T., Chen G., Saito M., Yaguchi T., Kawakami Y., Aoki D.

Gynecologic Oncology (Gynecologic Oncology) 159 ( 2 ) 329 - 334 2020.11

ISSN 00908258

© 2020 Elsevier Inc. Objectives: To (i) identify correlations between selected immunogenic factors and clinicopathological characteristics, (ii) determine whether intratumoral abundance of various specific tumor-infiltrating lymphocytes (TILs) is a prognostic indicator in women with Stage II and III cervical cancer who undergo treatment with cisplatin-based concurrent chemoradiotherapy (CCRT), and (iii) investigate subtypes of FOXP3+ T cells in 15 fresh samples of cervical cancer. Methods: In this retrospective study, intratumoral lesions in colposcopic biopsies from 55 women with advanced cervical cancer who subsequently underwent CCRT at our institution were subjected to automatic immunological staining using the following six mouse monoclonal antibodies: anti-CD3, anti-CD4, anti-CD8, anti-CD20, anti-CD206, and anti-FOXP3. Associations between the findings on automatic scoring of the number of each type of TIL in each specimen and various clinicopathological characteristics were analyzed, as were associations between the abundance of various specific types of TIL and survival. Subtypes of FOXP3+ TILs in 15 additional fresh tumor samples were also investigated using flow cytometry. Results: Infiltration with CD8+ TILs was associated with pelvic lymph node metastasis. Abundant infiltration by CD3+, CD4+, CD8+, CD206+, and FOXP3+ TILs were statistically significant indicators of better progression-free and overall survival. Regarding subtypes of FOXP3+ TILs, non-Tregs (Fr-III) were found in all samples tested for this. Conclusions: The abundance of various specific intratumoral TILs may be prognostic indicators in patients with advanced cervical cancer undergoing CCRT.

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Clinical implications of next-generation sequencing-based panel tests for malignant ovarian tumors

Saotome K., Chiyoda T., Aimono E., Nakamura K., Tanishima S., Nohara S., Okada C., Hayashi H., Kuroda Y., Nomura H., Susumu N., Iwata T., Yamagami W., Kataoka F., Nishihara H., Aoki D.

Cancer Medicine (Cancer Medicine) 9 ( 20 ) 7407 - 7417 2020.10

ISSN 2045-7634

© 2020 The Authors. Cancer Medicine published by John Wiley & Sons Ltd. Precision medicine based on cancer genomics is being applied in clinical practice. However, patients do not always derive benefits from genomic testing. Here, we performed targeted amplicon exome sequencing-based panel tests, including 160 cancer-related genes (PleSSision-160), on 88 malignant ovarian tumors (high-grade serous carcinoma, 27; endometrioid carcinoma, 15; clear cell carcinoma, 30; mucinous carcinoma, 6; undifferentiated carcinoma, 4; and others, 6 (immature teratoma, 1; carcinosarcoma, 3; squamous cell carcinoma, 1; and mixed, 1)), to assess treatment strategies and useful biomarkers for malignant ovarian tumors. Overall, actionable gene variants were found in 90.9%, and druggable gene variants were found in 40.9% of the cases. Actionable BRCA1 and BRCA2 variants were found in 4.5% of each of the cases. ERBB2 amplification was found in 33.3% of mucinous carcinoma cases. Druggable hypermutation/ultramutation (tumor mutation burden ≥ 10 SNVs/Mbp) was found in 7.4% of high-grade serous carcinoma, 46.7% of endometrioid carcinoma, 10% of clear cell carcinoma, 0% of mucinous carcinoma, 25% of undifferentiated carcinoma, and 33.3% of the other cancer cases. Copy number alterations were significantly higher in high-grade serous carcinoma (P <.005) than in other histologic subtypes; some clear cell carcinoma showed high copy number alterations that were correlated with advanced stage (P <.05) and worse survival (P <.01). A high count of copy number alteration was associated with worse survival in all malignant ovarian tumors (P <.05). Our study shows that targeted agents can be detected in approximately 40% of malignant ovarian tumors via multigene panel testing, and copy number alteration count can be a useful marker to help assess risks in malignant ovarian tumor patients.

Molecular epidemiology of human papillomavirus 18 infections in Japanese Women

Yamaguchi-Naka M., Onuki M., Tenjimbayashi Y., Hirose Y., Tasaka N., Satoh T., Morisada T., Iwata T., Sekizawa A., Matsumoto K., Kukimoto I.

Infection, Genetics and Evolution (Infection, Genetics and Evolution) 83 104345 2020.09

ISSN 15671348

© 2020 Elsevier B.V. Among the oncogenic genotypes of human papillomavirus (HPV), HPV18 is the second most common type detected in cervical cancer worldwide and is primarily involved in the generation of cervical adenocarcinoma. Although HPV intra-type variants confer different risks of cervical carcinogenesis, there is little information on the genetic diversity of HPV18 compared to the most prevalent type, HPV16. In this study, we investigated the genetic variation of HPV18 in cervical specimens obtained from Japanese women with normal cervices or cervical cancers and precancers. Of the 101 HPV18-positive samples analyzed, viral whole genome amplification followed by next-generation sequencing led to the determination of viral complete genome sequences of 18 samples. Phylogenetic analysis of these HPV18 whole genome sequences identified a distinct variant cluster consisting of only Japanese samples (n = 7) belonging to sublineage A1. Viral genome sequences were also analyzed for the E6/E7 (n = 66) and E2 (n = 27) genes by Sanger sequencing. Phylogenetic analyses of these regions showed that the variant distribution among Japanese women was strongly biased toward sublineage A1 (72 of 87; 82.8%). No significant differences were observed in the prevalence of specific sublineages between cervical cancer/precancer cases and controls, and between squamous cell carcinoma and adenocarcinoma cases. These data contribute to our understanding of the genetic diversity of HPV18 in Japanese women.

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Human Papillomavirus (HPV) Genotyping Assay Suitable for Monitoring the Impact of the 9-Valent HPV Vaccine

Kukimoto Iwao, Matsumoto Koji, Takahashi Fumiaki, Iwata Takashi, Tanaka Kohsei, Yamaguchi-Naka Mayuko, Yamamoto Kasumi, Yahata Hideaki, Nakabayashi Makoto, Kato Hisamori, Tsuda Naotake, Onuki Mamiko, Yaegashi Nobuo, MINT Study II Group

The Tohoku Journal of Experimental Medicine (Tohoku University Medical Press) 251 ( 4 ) 287 - 294 2020.08

ISSN 00408727

<p>In Japan, a bivalent human papillomavirus (HPV) vaccine against carcinogenic HPV16/18 was licensed in 2009, and a quadrivalent vaccines against HPV16/18 and non-carcinogenic HPV6/11 was licensed in 2011. Recently, the next-generation 9-valent vaccine targeting HPV6/11/16/18/31/33/45/52/58 has been approved. Accurate HPV genotyping is essential for HPV vaccine research and surveillance. The Roche Linear Array (LA) has long been a standard assay for HPV genotyping, but its recent product discontinuation notice has urged us to introduce an alternative assay with comparable performance. In the present study, an in-house HPV genotyping assay that employs PCR with PGMY09/11 primers and reverse blotting hybridization (PGMY-CHUV) was compared with LA to assess genotype-specific agreement. A total of 100 cervical precancer specimens were subjected to both PGMY-CHUV and LA. For detection of genotypes included in the 9-valent vaccine, PGMY-CHUV completely agreed with LA for detection of HPV6, HPV11, HPV16, HPV18, HPV33 and HPV45, and showed near-complete agreement for HPV31 and HPV58 (98% and 99%, respectively). Moreover, PGMY-CHUV detected a significantly higher prevalence of HPV52 than LA (22% vs. 14%, P = 0.008 by McNemar’s exact test), with 92.0% overall agreement, 63.6% positive agreement and a kappa value of 0.73. Most (87.5%) of HPV52 discordant cases involved mixed infections with HPV35 or HPV58. In conclusion, while the two assays present equivalent data for assessing the effectiveness of the bivalent and quadrivalent vaccines, PGMY-CHUV is more suitable for evaluating the impact of the current 9-valent vaccine because of its superior detection of HPV52 in co-infection cases.</p>

Human papillomavirus genotype contribution to cervical cancer and precancer: Implications for screening and vaccination in Japan

Onuki M., Matsumoto K., Iwata T., Yamamoto K., Aoki Y., Maenohara S., Tsuda N., Kamiura S., Takehara K., Horie K., Tasaka N., Yahata H., Takei Y., Aoki Y., Kato H., Motohara T., Nakamura K., Ishikawa M., Kato T., Yoshida H., Matsumura N., Nakai H., Shigeta S., Takahashi F., Noda K., Yaegashi N., Yoshikawa H.

Cancer Science (Cancer Science) 111 ( 7 ) 2546 - 2557 2020.07

ISSN 13479032

© 2020 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association. To obtain baseline data for cervical cancer prevention in Japan, we analyzed human papillomavirus (HPV) data from 5045 Japanese women aged less than 40 years and diagnosed with cervical abnormalities at 21 hospitals during 2012-2017. These included cervical intraepithelial neoplasia grade 1 (CIN1, n = 573), CIN2-3 (n = 3219), adenocarcinoma in situ (AIS, n = 123), and invasive cervical cancer (ICC, n = 1130). The Roche Linear Array was used for HPV genotyping. The HPV type-specific relative contributions (RCs) were estimated by adding multiple infections to single types in accordance with proportional weighting attributions. Based on the comparison of type-specific RCs between CIN1 and CIN2-3/AIS/ICC (CIN2+), RC ratios were calculated to estimate type-specific risks for progression to CIN2+. Human papillomavirus DNA was detected in 85.5% of CIN1, 95.7% of CIN2-3/AIS, and 91.2% of ICC. Multiple infections decreased with disease severity: 42.9% in CIN1, 40.4% in CIN2-3/AIS, and 23.7% in ICC (P <.0001). The relative risk for progression to CIN2+ was highest for HPV16 (RC ratio 3.78, 95% confidence interval [CI] 3.01-4.98), followed by HPV31 (2.51, 1.54-5.24), HPV18 (2.43, 1.59-4.32), HPV35 (1.56, 0.43-8.36), HPV33 (1.01, 0.49-3.31), HPV52 (0.99, 0.76-1.33), and HPV58 (0.97, 0.75-1.32). The relative risk of disease progression was 1.87 (95% CI, 1.71-2.05) for HPV16/18/31/33/35/45/52/58, but only 0.17 (95% CI, 0.14-0.22) for HPV39/51/56/59/66/68. Human papillomavirus 16/18/31/33/45/52/58/6/11 included in a 9-valent vaccine contributed to 89.7% (95% CI, 88.7-90.7) of CIN2-3/AIS and 93.8% (95% CI, 92.4-95.3) of ICC. In conclusion, our data support the Japanese guidelines that recommend discriminating HPV16/18/31/33/35/45/52/58 genotypes for CIN management. The 9-valent vaccine is estimated to provide over 90% protection against ICC in young Japanese women.

更年期症状を契機に診断された甲状腺機能異常の2例

平田桃, 横田めぐみ, 谷本慧子, 仲村勝, 山上亘, 森定徹, 片岡史夫, 岩田卓, 阪埜浩司, 田中守, 青木大輔

東京産科婦人科学会会誌 ((一社)東京産科婦人科学会) 69 ( 3 ) 575 - 580 2020.07

ISSN 2186-0599

更年期障害を疑われ受診したが、甲状腺疾患を認めた2症例につき報告する。症例1:52歳、0妊0産。子宮頸部腺癌IB1期に対し広汎子宮全摘出術および両側付属器摘出術後である。冷え、関節痛を主訴に受診し、採血でTSH高値を認め精査にて潜在性甲状腺機能低下症の診断となった。症例2:65歳。1妊1産。ほてり、動悸を主訴に受診した。変動するTSHを認め、精査の結果、橋本病に合併した無痛性甲状腺炎の診断となった。甲状腺機能異常は亢進症/低下症ともに症状が更年期障害と類似していることから鑑別疾患の一つとして念頭に置くことが重要である。(著者抄録)

妊娠中期に卵巣癌と診断し、手術療法と化学療法治療後に生児を得られた1例

田中邦生, 長谷川慶太, 吉村拓馬, 大石真希, 大谷利光, 池ノ上学, 春日義史, 落合大吾, 岩田卓, 宮越敬, 田中守, 青木大輔

東京産科婦人科学会会誌 ((一社)東京産科婦人科学会) 69 ( 2 ) 387 - 391 2020.04

ISSN 2186-0599

緒言:卵巣癌合併妊娠は1万から5万例に1例と頻度が低く、対応に一定の見解はない。今回我々は妊娠中期に卵巣癌を診断され、手術療法と化学療法を行い生児を得られた症例を経験した。症例:44歳、1妊0産。妊娠16週時に卵巣癌を疑われ、妊娠18週時に右付属器摘出術、左卵巣腫瘍摘出術、大網生検を施行した。右卵巣原発の高異型度漿液性癌IIIC期の診断にて術後パクリタキセルとカルボプラチン(TC)併用療法を4サイクル施行し、妊娠35週5日時に選択的帝王切開術とinterval debulking surgeryを同時に施行した。2118gの女児を娩出し、術後TC療法を2サイクル施行した。術後母体は再発を認めず、児の発育も良好である。結論:卵巣癌合併妊娠に対して、予め分娩時期を想定した管理・治療を行ったことで母児ともに合併症なく手術療法と化学療法を行うことができた。(著者抄録)

Differential expression of human papillomavirus 16-, 18-, 52-, and 58-derived transcripts in cervical intraepithelial neoplasia

Baba S., Taguchi A., Kawata A., Hara K., Eguchi S., Mori M., Adachi K., Mori S., Iwata T., Mitsuhashi A., Maeda D., Komatsu A., Nagamatsu T., Oda K., Kukimoto I., Osuga Y., Fujii T., Kawana K.

Virology Journal (Virology Journal) 17 ( 1 ) 32 2020.03

© 2020 The Author(s). Background: Human papillomavirus (HPV) infection is a primary cause of cervical cancer. Although epidemiologic study revealed that carcinogenic risk differs according to HPV genotypes, the expression patterns of HPV-derived transcripts and their dependence on HPV genotypes have not yet been fully elucidated. Methods: In this study, 382 patients with abnormal cervical cytology were enrolled to assess the associations between HPV-derived transcripts and cervical intraepithelial neoplasia (CIN) grades and/or HPV genotypes. Specifically, four HPV-derived transcripts, namely, oncogenes E6 and E6*, E1^E4, and viral capsid protein L1 in four major HPV genotypes-HPV 16, 18, 52, and 58-were investigated. Results: The detection rate of E6/E6*increased with CIN progression, whereas there was no significant change in the detection rate of E1^E4 or L1 among CIN grades. In addition, we found that L1 gene expression was HPV type-dependent. Almost all HPV 52-positive specimens, approximately 50% of HPV 58-positive specimens, around 33% of HPV 16-positive specimens, and only one HPV18-positive specimen expressed L1. Conclusions: We demonstrated that HPV-derived transcripts are HPV genotype-dependent. Especially, expression patterns of L1 gene expression might reflect HPV genotype-dependent patterns of carcinogenesis.

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GPC1 specific CAR-T cells eradicate established solid tumor without adverse effects and synergize with anti-PD-1 ab

Kato D., Yaguchi T., Iwata T., Katoh Y., Morii K., Tsubota K., Takise Y., Tamiya M., Kamada H., Akiba H., Tsumoto K., Serada S., Naka T., Nishimura R., Nakagawa T., Kawakami Y.

eLife (eLife) 9 2020.03

© Kato et al. Current xenogeneic mouse models cannot evaluate on-target off-tumor adverse effect, hindering the development of chimeric antigen receptor (CAR) T cell therapies for solid tumors, due to limited human/mouse cross-reactivity of antibodies used in CAR and sever graft-versus-host disease induced by administered human T cells. We have evaluated safety and antitumor efficacy of CAR-T cells targeting glypican-1 (GPC1) overexpressed in various solid tumors. GPC1-specific human and murine CAR-T cells generated from our original anti-human/mouse GPC1 antibody showed strong antitumor effects in xenogeneic and syngeneic mouse models, respectively. Importantly, the murine CAR-T cells enhanced endogenous T cell responses against a non-GPC1 tumor antigen through the mechanism of antigen-spreading and showed synergistic antitumor effects with anti-PD-1 antibody without any adverse effects in syngeneic models. Our study shows the potential of GPC1 as a CAR-T cell target for solid tumors and the importance of syngeneic and xenogeneic models for evaluating their safety and efficacy.

Significance of Malignant Peritoneal Cytology on the Survival of Women with Early-Stage Cervical Cancer: A Japanese Gynecologic Oncology Group Study.

Matsuo K, Shimada M, Matsuzaki S, Machida H, Nagase Y, Saito T, Kamiura S, Iwata T, Sugiyama T, Mikami M

Journal of clinical medicine (Journal of Clinical Medicine) 8 ( 11 ) 2019.11

This study examined the association between peritoneal cytology and survival in early-stage cervical cancer. This is a nationwide multicenter retrospective study, examining consecutive women with clinical stage IB1-IIB cervical cancer who underwent radical hysterectomy with available peritoneal cytology results from 2004–2008. Propensity score inverse probability of treatment weighting was used to assess the impact of malignant peritoneal cytology on survival. Among 1409 analyzed cases, 88 (6.2%) had malignant peritoneal cytology. On weighted models, malignant peritoneal cytology was associated with decreased disease-free survival (hazard ratio (HR) 1.78, 95% confidence interval (CI) 1.36–2.32) and overall survival (OS, HR 1.93, 95% CI 1.44–2.59). On sensitivity analyses, malignant peritoneal cytology was associated with decreased OS in adenocarcinoma/adenosquamous carcinoma, high-risk early-stage disease and those who received concurrent chemo-radiotherapy. However, among women who received postoperative systemic chemotherapy, malignant peritoneal cytology was not associated with OS (HR 1.21, 95% CI 0.72–2.04). A systematic review, including our results, showed that malignant peritoneal cytology was associated with decreased OS (HR 4.03, 95% CI 1.81–8.99) and increased recurrence in squamous carcinoma (odds ratio 1.89, 95% CI 1.05–3.39) and adenocarcinoma (odds ratio 4.30, 95% CI 2.30–8.02). In conclusion, the presence of malignant cells in peritoneal cytology is associated with decreased survival in early-stage cervical cancer. The possible benefit of systemic chemotherapy in this subgroup merits further investigation.

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妊娠中　子宮頸部円錐切除術　妊娠への配慮

仲村勝, 岩田卓, 宮越敬, 田中守, 青木大輔

周産期医学 49 ( 11 ) 1453 - 1455 2019.11

Accepted

Transcription factor homeobox D9 is involved in the malignant phenotype of cervical cancer through direct binding to the human papillomavirus oncogene promoter

Hirao N., Iwata T., Tanaka K., Nishio H., Nakamura M., Morisada T., Morii K., Maruyama N., Katoh Y., Yaguchi T., Ohta S., Kukimoto I., Aoki D., Kawakami Y.

Gynecologic Oncology (Gynecologic Oncology) 155 ( 2 ) 340 - 348 2019.11

ISSN 00908258

© 2019 Elsevier Inc. Objective: To determine the involvement of homeobox D9 (HOXD9) in the survival, proliferation, and metastasis of cervical cancer cells through regulating the expression of human papillomavirus (HPV) 16 E6/E7 genes using the P97 promoter. Methods: One hundred cases of cervical cancer (CC), CC cell lines SKG-I, SKG-II, SKG-IIIa, SKG-IIIb, HeLa, and SiHa, and a human tumor xenograft mouse model were used to examine the roles of HOXD9 in CC. Knockdown experiments employed RNA interference of HOXD9. qPCR, functional assays, western blotting, DNA microarray, and luciferase and ChIP assays were applied for assessments. Results: All CC cell lines expressed HOXD9 mRNA and protein. In uterine CC, HOXD9 gene expression was significantly higher than in normal cervical tissues. A positive correlation of lymphovascular space invasion and lymph node metastasis with high levels of HOXD9 expression was found in patient samples. HOXD9-knockdown cells in the mouse xenograft model only formed small or no tumors. Knockdown of HOXD9 markedly reduced CC cell proliferation, migration and invasion, induced apoptosis, increased P53 protein expression, and suppressed HPV E6/E7 expression by directly binding to the P97 promoter of HPV16 E6/E7 genes. A positive correlation between HOXD9 and HPV16 E6 expression was found in CC patients. Conclusions: HOXD9 promotes HPV16 E6 and E7 expression by direct binding to the P97 promoter, which enhances proliferation, migration, and metastasis of CCr cells. Our results suggest that HOXD9 could be a prognostic biomarker and potential therapeutic target in CC.

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Safety and efficacy of mucosal immunotherapy using human papillomavirus (HPV) type 16 E7-expressing Lactobacillus-based vaccine for the treatment of high-grade squamous intraepithelial lesion (HSIL): the study protocol of a randomized placebo-controlled clinical trial (MILACLE study)

Ikeda Y, Uemura Y, Asai-Sato M, Nakao T, Nakajima T, Iwata T, Akiyama A, Satoh T, Yahata H, Kato K, Maeda D, Aoki D, Kawana K.

Jpn J Clin Oncol 49 ( 9 ) 887 - 890 2019.09

Research paper (scientific journal)

A Clinical Trial to Verify the Efficiency of the LC-1000 Exfoliative Cell Analyzer as a New Method of Cervical Cancer Screening

Nakamura M., Ueda M., Iwata T., Kiguchi K., Mikami Y., Kakuma T., Aoki D.

Acta Cytologica (Acta Cytologica) 63 ( 5 ) 391 - 400 2019.08

ISSN 00015547

© 2019 S. Karger AG, Basel. All rights reserved. Objective: The exfoliative cell analyzer, LC-1000 (Sysmex Corporation, Japan), is a medical device that presents the cell proliferation index and 23 research parameters as indicators of cellular proliferative potential. The objective was to evaluate the clinical usability of qualitative assessment by LC-1000 compared with cytology, the human papillomavirus (HPV) test, and histology as gold standard. Study Design: Women that visited 3 sites between July 2015 and March 2017 were registered. The primary endpoint in this study was the comparison between LC-1000 measurement and HPV test for sensitivity and specificity for cervical intraepithelial neoplasia 2+ (CIN2+). A tree model algorithm was newly constructed by a statistical method and its relationship with histological results was evaluated. Results: The sensitivity and specificity of LC-1000 were 78.3 and 74.1%, while those of the HPV test were 94.7 and 85.4%, respectively. A tree model comprising five categories was constructed. The proportion of advanced lesions was higher with the change in the rank classification results from 1 to 5. The positive predictive values of CIN2+ in the categories 4 and 5 were high. Despite the small number of subjects, cancer was undetected in categories 1 and 2. In addition, the comparison with follow-up results in 19 women assessed as CIN1 showed that the rate of progression in the categories 3-5 was 50% (7/14); progression in the categories 1 and 2 was 0% (0/5). Conclusions: LC-1000 may be useful for cervical cancer screening as an index to qualitatively evaluate CIN and cancer based on the changes in characteristics of cells.

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Local anatomy around terminal ureter related to the anterior leaf of the vesicouterine ligament in radical hysterectomy

Nakamura M., Tanaka K., Hayashi S., Morisada T., Iwata T., Imanishi N., Aoki D.

European Journal of Obstetrics Gynecology and Reproductive Biology (European Journal of Obstetrics Gynecology and Reproductive Biology) 235 66 - 70 2019.04

ISSN 03012115

© 2019 Elsevier B.V. Objectives: Radical hysterectomy is performed for invasive cervical cancer. In this surgery, separation of the anterior leaf and posterior leaves of the vesicouterine ligament (VUL) is important. We studied the local anatomy of the anterior leaf of the VUL, especially the branches of the umbilical artery from the view point of surgery and cadaver dissection. Study Design: We observed the cervicovesical blood vessels and the connective tissue layer continued from umbilical artery and searched for the origin of the cervicovesical blood vessels in radical hysterectomy. We also dissected a formalin-fixed female cadaver, and observed the same points. Results: After separation of the connective tissue of urinary bladder from the cervical fascia, we could discern the outline of the distal ureter near the ureterovesical junction. We separate the connective tissue of the so-called anterior leaf of the VUL enwrapping the ureter gently, and then the ureter with the connective tissue is completely rolled out laterally. We identified a cervicovesical vessel crossing over the ureter. We looked for the central side of the cervicovesical vessel and found that cervicovesical vessel was a branch of the superior vesical artery. And, during cadaver dissection, we found that the connective tissue and the branches of the superior vesical artery were similarly observed. Conclusions: We found the precise anatomy of the connective tissue layer from umbilical artery to urinary bladder and the superior vesical artery. Our procedure based on the precise anatomy obtained in this study is reasonable anatomically as a method for separation of the vesicouterine ligament during radical hysterectomy.

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Whole-genome analysis of human papillomavirus type 16 prevalent in japanesewomen with or without cervical lesions

Hirose Y., Onuki M., Tenjimbayashi Y., Yamaguchi-Naka M., Mori S., Tasaka N., Satoh T., Morisada T., Iwata T., Kiyono T., Mimura T., Sekizawa A., Matsumoto K., Kukimoto I.

Viruses (Viruses) 11 ( 4 ) 2019.04

© 2019 by the authors. Licensee MDPI, Basel, Switzerland. Recent large-scale genomics studies of human papillomaviruses (HPVs) have shown a high level of genomic variability of HPV16, the most prevalent genotype in HPV-associated malignancies, and provided new insights into the biological and clinical relevance of its genetic variations in cervical cancer development. Here, we performed deep sequencing analyses of the viral genome to explore genetic variations of HPV16 that are prevalent in Japan. A total of 100 complete genome sequences of HPV16 were determined from cervical specimens collected from Japanese women with cervical intraepithelial neoplasia and invasive cervical cancer, or without cervical malignancies. Phylogenetic analyses revealed the variant distribution in the Japanese HPV16 isolates; overall, lineage A was the most prevalent (94.0%), in which sublineage A4 was dominant (52.0%), followed by sublineage A1 (21.0%). The relative risk of sublineage A4 for cervical cancer development was significantly higher compared to sublineages A1/A2/A3 (odds ratio = 6.72, 95% confidence interval = 1.78–28.9). Interestingly, a novel cluster of variants that branched from A1/A2/A3 was observed for the Japanese HPV16 isolates, indicating that unique HPV16 variants are prevalent among Japanese women.

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Fertility-sparing trachelectomy for early-stage cervical cancer: A proposal of an ideal candidate

Machida H., Iwata T., Okugawa K., Matsuo K., Saito T., Tanaka K., Morishige K., Kobayashi H., Yoshino K., Tokunaga H., Ikeda T., Shozu M., Yaegashi N., Enomoto T., Mikami M.

Gynecologic Oncology (Gynecologic Oncology) 156 ( 2 ) 341 - 348 2019

ISSN 00908258

© 2019 Elsevier Inc. Objective: To propose an ideal patient candidate with early-stage cervical cancer for undergoing fertility-sparing trachelectomy. Methods: This nationwide, multicenter, retrospective study was conducted by the Japan Society of Obstetrics and Gynecology involving women aged <45 years with clinical stage I-II cervical cancer who had planned fertility-sparing trachelectomy and pelvic lymphadenectomy between 2009 and 2013 (n = 393). Ideal candidates were defined to have a tumor size of ≤2 cm, no lymph node metastasis, no deep stromal invasion, and no high-risk histology (n = 284, 69.6%). Less-ideal candidates were defined to have any one of these four characteristics (n = 109, 30.4%). Propensity score inverse probability of treatment weighting was used to assess survival outcomes. Results: Less-ideal candidates were more likely to undergo hysterectomy conversion (22.9% versus 3.2%), receive postoperative radiotherapy (11.9% versus 0.4%), or chemotherapy (32.1% versus 3.2%) compared with ideal candidates (all, P < 0.05). The weighted model revealed that among those who underwent trachelectomy (ideal candidates, n = 275 and less-ideal candidates, n = 84), less-ideal candidates had significantly decreased disease-free survival (5-year rates: 85.5% versus 95.5%; HR 3.93, 95% CI 1.99–7.74; P < 0.001) and cause-specific survival (92.5% versus 98.6%; HR 5.47, 95% CI 1.68–17.8, P = 0.001) compared with ideal candidates. Similarly, less-ideal candidates were significantly associated with decreased disease-free survival compared with ideal candidates among those who were young age, had small tumors or squamous histology, and underwent surgery alone (all, P < 0.05). Conclusion: Less-ideal candidates had approximately four-fold higher recurrence risk and cancer mortality compared with ideal candidates. Ideal candidates for fertility-sparing trachelectomy for early-stage cervical cancer proposed in our study may be useful as the future framework for developing guidelines for fertility-sparing trachelectomy in Japan.

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Reduction in HPV16/18 prevalence among young women with high-grade cervical lesions following the Japanese HPV vaccination program

Matsumoto K., Yaegashi N., Iwata T., Yamamoto K., Aoki Y., Okadome M., Ushijima K., Kamiura S., Takehara K., Horie K., Tasaka N., Sonoda K., Takei Y., Aoki Y., Konnai K., Katabuchi H., Nakamura K., Ishikawa M., Watari H., Yoshida H., Matsumura N., Nakai H., Shigeta S., Takahashi F., Noda K., Yoshikawa H.

Cancer Science (Cancer Science) 110 ( 12 ) 3811 - 3820 2019

ISSN 13479032

© 2019 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association. The Japanese government began a human papillomavirus (HPV) vaccination program for girls aged 12-16 years in 2010 but withdrew its recommendation in 2013 because of potential adverse effects, leading to drastically reduced vaccination uptake. To evaluate population-level effects of HPV vaccination, women younger than 40 years of age newly diagnosed with cervical intraepithelial neoplasia grade 1-3 (CIN1-3), adenocarcinoma in situ (AIS), or invasive cervical cancer (ICC) have been registered at 21 participating institutes each year since 2012. A total of 7709 women were registered during 2012-2017, of which 5045 were HPV genotyped. Declining trends in prevalence of vaccine types HPV16 and HPV18 during a 6-year period were observed in CIN1 (50.0% to 0.0%, Ptrend <.0001) and CIN2-3/AIS (83.3% to 45.0%, Ptrend =.07) only among women younger than 25 years of age. Overall, HPV vaccination reduced the proportion of HPV16/18-attributable CIN2-3/AIS from 47.7% to 33.0% (P =.003): from 43.5% to 12.5% as routine vaccination (P =.08) and from 47.8% to 36.7% as catch-up vaccination (P =.04). The HPV16/18 prevalence in CIN2-3/AIS cases was significantly reduced among female individuals who received their first vaccination at age 20 years or younger (P =.02). We could not evaluate vaccination effects on ICC owing to low incidence of ICC among women aged less than 25 years. We found HPV vaccination to be effective in protecting against HPV16/18-positive CIN/AIS in Japan; however, our data did not support catch-up vaccination for women older than 20 years. Older adolescents who skipped routine vaccination due to the government’s suspension of its vaccine recommendation could benefit from receiving catch-up vaccination before age 20 years.

遺伝性乳癌卵巣癌に対するリスク低減卵管卵巣摘出後のQOLに関する検討

谷本, 慧子, 平沢, 晃, 牧田, 和也, 岩田, 卓, 堀場, 裕子, 横田, めぐみ, 小川, 真里子, 弟子丸, 亮太, 柳本, 茂久, 高松, 潔 and 青木, 大輔

日本女性医学学会雑誌 ((一社)日本女性医学学会) 26 ( 1 ) 45 - 47 2018.11

ISSN 2185-8861

遺伝性乳癌卵巣癌(hereditary breast cancer ovarian cancer syndrome、HBOC)は、BRCA1またはBRCA2(BRCA1/2)の生殖細胞系列病的変異(バクアント)が原因であり、家系内に乳癌・卵巣癌・卵管癌・腹膜癌などが好発し、BRCA1/2遺伝子変異保持者では70歳までに卵巣癌発症例が40%以上であると報告されている。BRCA1/2遺伝子変異保持者に対するマネージメントとして、リスク低減卵管卵巣摘出術(risk reduction salpingo-oophorectomy、RRSO)は卵巣癌や卵管癌の発症リスクを減少させ、全死亡率を低下することも報告されているが、閉経前の両側卵巣摘出術は医原性の卵巣欠落症状を惹起するため、その管理が重要である。本検討では、当院でRRSOを施行した8症例を対象に、RRSO後の諸症状より女性QOLについて後方視的に検討した。8例のうち6例で乳癌の既往があった。術後に薬物治療を必要とする卵巣欠落症状を呈した症例は3例で漢方治療を行っていた。またRRSO後早期に脂質異常症を発症した例もあった。BRCA1/2遺伝子変異保持者に対するRRSOは本邦の実臨床に導入されてきているが、RRSO実施例では短期的には卵巣欠落症状、長期的には脂質異常症や骨粗鬆症などを発症してQOL低下をもたらす可能性が高い。海外の各種ガイドラインでは術後卵巣欠落症状に対するホルモン補充療法(HRT)が提唱されているものの、乳癌既往例などではHRTが禁忌な例が存在し、症例には漢方療法が有効である。RRSO後はがんサーベイランスとともに、女性医学の観点から将来的なQOLに関係する項目を経時的に追跡することが重要である。(著者抄録)

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