Details of a Researcher - Iwata, Takashi

Papers - Iwata, Takashi

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Gastric-type adenocarcinoma of the uterine cervix: clinical features and future directions.

Nishio H, Matsuda R, Iwata T, Yamagami W

Japanese journal of clinical oncology 2024.02

ISSN 0368-2811

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Proposal for the optimal staging of extramammary Paget's disease: A retrospective analysis of 57 cases with distant metastasis.

Funakoshi T, Nakamura Y, Hirai I, Kobayashi K, Fukuda K, Iwata T

Experimental dermatology 33 ( 2 ) e15017 2024.02

ISSN 0906-6705

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SCD1 inhibition enhances the effector functions of CD8+ T cells via ACAT1-dependent reduction of esterified cholesterol

Sugi T., Katoh Y., Ikeda T., Seta D., Iwata T., Nishio H., Sugawara M., Kato D., Katoh K., Kawana K., Yaguchi T., Kawakami Y., Hirai S.

Cancer Science (Cancer Science) 115 ( 1 ) 48 - 58 2024.01

ISSN 13479032

We previously reported that the inhibition of stearoyl-CoA desaturase 1 (SCD1) enhances the antitumor function of CD8+ T cells indirectly via restoring production of DC recruiting chemokines by cancer cells and subsequent induction of antitumor CD8+ T cells. In this study, we investigated the molecular mechanism of direct enhancing effects of SCD1 inhibitors on CD8+ T cells. In vitro treatment of CD8+ T cells with SCD1 inhibitors enhanced IFN-γ production and cytotoxic activity of T cells along with decreased oleic acid and esterified cholesterol, which is generated by cholesterol esterase, acetyl-CoA acetyltransferase 1 (ACAT1), in CD8+ T cells. The addition of oleic acid or cholesteryl oleate reversed the enhanced functions of CD8+ T cells treated with SCD1 inhibitors. Systemic administration of SCD1 inhibitor to MCA205 tumor-bearing mice enhanced IFN-γ production of tumor-infiltrating CD8+ T cells, in which oleic acid and esterified cholesterol, but not cholesterol, were decreased. These results indicated that SCD1 suppressed effector functions of CD8+ T cells through the increased esterified cholesterol in an ACAT1-dependent manner, and SCD1 inhibition enhanced T cell activity directly through decreased esterified cholesterol. Finally, SCD1 inhibitors or ACAT1 inhibitors synergistically enhanced the antitumor effects of anti-PD-1 antibody therapy or CAR-T cell therapy in mouse tumor models. Therefore, the SCD1–ACAT1 axis is regulating effector functions of CD8+ T cells, and SCD1 inhibitors, and ACAT1 inhibitors are attractive drugs for cancer immunotherapy.

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Phase I and II randomized clinical trial of an oral therapeutic vaccine targeting human papillomavirus for treatment of cervical intraepithelial neoplasia 2 and 3.

Kawana K, Kobayashi O, Ikeda Y, Yahata H, Iwata T, Satoh T, Akiyama A, Maeda D, Hori-Hirose Y, Uemura Y, Nakayama-Hosoya K, Katoh K, Katoh Y, Nakajima T, Taguchi A, Komatsu A, Asai-Sato M, Tomita N, Kato K, Aoki D, Igimi S, Kawana-Tachikawa A, Schust DJ.

JNCI Cancer Spectr 7 ( 6 ) 2023.11

Accepted

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Human papillomavirus vaccine impact on invasive cervical cancer in Japan: Preliminary results from cancer statistics and the MINT study

Onuki M., Takahashi F., Iwata T., Nakazawa H., Yahata H., Kanao H., Horie K., Konnai K., Nio A., Takehara K., Kamiura S., Tsuda N., Takei Y., Shigeta S., Matsumura N., Yoshida H., Motohara T., Yamazaki H., Nakamura K., Hamanishi J., Tasaka N., Ishikawa M., Hirashima Y., Kudaka W., Mori-Uchino M., Kukimoto I., Fujii T., Watanabe Y., Noda K., Yoshikawa H., Yaegashi N., Matsumoto K.

Cancer Science (Cancer Science) 114 ( 11 ) 4426 - 4432 2023.11

ISSN 13479032

The first prophylactic vaccine against human papillomavirus (HPV) 16 and HPV18 was licensed in Japan in 2009. HPV vaccine effectiveness against high-grade cervical lesions has been demonstrated among young Japanese women, but evidence of its effects on invasive cervical cancer (ICC) is lacking. Using data from two different cancer registries, we compared recent trends of new ICC cases by age group using Poisson regression analysis. We also analyzed time trends in HPV16/18 prevalence among 1414 Japanese women aged <40 years newly diagnosed with ICC in the past decade. Based on the population-based cancer registry, the incidence of ICC among young women aged 20–29 years showed a significant decline from 3.6 to 2.8 per 100 000 women-years during 2016–2019, but no similar decline was observed for older age groups (p < 0.01). Similarly, using data from the gynecological cancer registry of the Japan Society of Obstetrics and Gynecology, the annual number of ICCs among women aged 20–29 years also decreased from 256 cases to 135 cases during 2011–2020 (p < 0.0001). Furthermore, a declining trend in HPV16/18 prevalence in ICC was observed only among women aged 20–29 years during 2017–2022 (90.5%–64.7%, p = 0.05; Cochran–Armitage trend test). This is the first report to suggest population-level effects of HPV vaccination on ICC in Japan. Although the declining trend in HPV16/18 prevalence among young women with ICC supports a causal linkage between vaccination and results from cancer registries, further studies are warranted to confirm that our findings are attributable to vaccination.

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Clinical availability and characteristics of multigene panel testing for recurrent/advanced gynecologic cancer

Kitazawa S., Chiyoda T., Nakamura K., Sakai K., Yoshihama T., Nishio H., Kobayashi Y., Iwata T., Banno K., Yamagami W., Nishihara H., Aoki D.

International Journal of Clinical Oncology (International Journal of Clinical Oncology) 28 ( 11 ) 1554 - 1562 2023.11

ISSN 13419625

Background: Japan’s health insurance covers multigene panel testing. This study aimed to determine the potential availability and utility of gene panel testing clinically in gynecologic oncology. Methods: We analyzed the characteristics of patients with gynecologic cancer who underwent gene panel testing using FoundationOne® CDx or OncoGuide™ NCC Oncopanel between November 2019 and October 2022. Results: Out of 102 patients analyzed, 32, 18, 43, 8, and 1 had cervical, endometrial, ovarian cancers, sarcoma, and vaginal cancer, respectively. Druggable gene alteration was found in 70 patients (68.6%; 21 with cervical cancer, 15 with endometrial cancer, 28 with ovarian cancer, 5 with sarcoma, and 1 with other). The most common druggable gene alteration was PIK3CA mutation (n = 21), followed by PTEN mutation (n = 12) and high tumor mutation burden (TMB-H) (n = 11). TMB-H was detected in 5 patients with cervical cancer, 5 with endometrial cancer, and 1 with endometrial stromal sarcoma. Eleven patients (10.8%) received molecularly targeted therapy according to their gene aberrations. Gene panel testing was mostly performed when the second-line treatment was ineffective. Of all 102 patients, 60 did not have recommended treatment, and 15 died or had worsened conditions before obtaining the test results. Conclusion: Through multigene panel testing, although many patients had druggable gene alterations, 10.8% of them received the recommended treatment. TMB-H was mainly observed in cervical/endometrial cancer, suggesting its potential as a therapeutic biomarker of immune checkpoint inhibitors. Furthermore, patients’ prognosis and performance status should be considered before performing the test.

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Intra-Patient Genomic Variations of Human Papillomavirus Type 31 in Cervical Cancer and Precancer

Kogure G., Tanaka K., Matsui T., Onuki M., Matsumoto K., Iwata T., Kukimoto I.

Viruses (Viruses) 15 ( 10 ) 2023.10

Human papillomavirus type 31 (HPV31) is detected less frequently in cervical cancer than two major causative types, HPV16 and HPV18. Here, we report a comprehensive analysis of HPV31 genome sequences in cervical lesions collected from Japanese women. Of 52 HPV31-positive cervical specimens analyzed by deep sequencing, 43 samples yielded complete genome sequences of around 7900 base pairs and 9 samples yielded partially deleted genome sequences. Phylogenetic analysis showed that HPV31 variant distribution was lineage A in 19 samples (36.5%), lineage B in 28 samples (53.8%), and lineage C in 5 samples (9.6%), indicating that lineage B variants are dominant among HPV31 infections in Japan. Deletions in the viral genome were found in the region from the E1 to L1 genes, but all the deleted genomes retained the E6/E7 genes. Among intra-patient nucleotide variations relative to a consensus genome sequence in each sample, C-to-T substitutions were most frequently detected, followed by T-to-C and C-to-A substitutions. High-frequency, intra-patient mutations (>10%) in cervical cancer samples were found in the E1, E2, and E7 genes, and all of them were nonsynonymous substitutions. The enrichment of high-frequency nonsynonymous substitutions strongly suggests that these intra-patient mutations are positively selected during the development of cervical cancer/precancer.

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Successful radiotherapy for recurrent obstructive pancreatitis secondary to pancreatic metastasis from cervical squamous-cell carcinoma

Nakajima Y., Iwasaki E., Kayashima A., Machida Y., Kawasaki S., Horibe M., Kawaida M., Masugi Y., Iwata T., Kanai T.

Clinical Journal of Gastroenterology (Clinical Journal of Gastroenterology) 16 ( 5 ) 755 - 760 2023.10

ISSN 18657257

Metastatic pancreatic cancer is a rare condition and cases of pancreatic metastasis from cervical cancer are infrequently reported. Furthermore, the incidence rates of pancreatic tumors as the cause of pancreatitis and of pancreatitis in patients with pancreatic tumors are similarly low. Pancreatitis may occur when a tumor obstructs the pancreatic duct. This condition may be difficult to manage and significantly reduces the quality of life because of severe abdominal pain. Here, we present a rare case of obstructive pancreatitis caused by pancreatic metastasis from cervical squamous-cell carcinoma, pathologically confirmed using endoscopic ultrasonography-guided fine-needle biopsy and treated with palliative irradiation to achieve rapid therapeutic relief. It is important to obtain appropriate tissue samples, confirm the pathological diagnosis, and compare the pathological findings with those of the primary tumor to select the appropriate treatment for obstructive pancreatitis caused by a metastatic pancreatic tumor.

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Serum Free Fatty Acid Changes Caused by High Expression of Stearoyl-CoA Desaturase 1 in Tumor Tissues Are Early Diagnostic Markers for Ovarian Cancer.

Katoh K, Katoh Y, Kubo A, Iida M, Ikeda Y, Iwata T, Nishio H, Sugawara M, Kato D, Suematsu M, Hirai S, Kawana K

Cancer research communications 3 ( 9 ) 1840 - 1852 2023.09

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難治性子宮頸癌に対する腫瘍浸潤リンパ球輸注療法

岩田卓, 野上侑哉, 西尾浩, 松井友哉, 菅原正貴, 陳冠良, 青木大輔

Japanese Journal of Gynecological Oncology (Japan Society of Gynecologic Oncology) 41 ( 2 ) 84 - 93 2023.04

ISSN 13478559

進行子宮頸癌は極めて難治性で，有効な新規治療法の開発が望まれている．腫瘍浸潤リンパ球輸注療法（TIL療法）は米国国立衛生研究所（NIH）で開発された養子免疫療法で，進行子宮頸癌において約20％の完全奏効（CR）が報告されている．注目すべき特徴はCRとなった症例では，その後の再発が低率で，治癒が期待できるとされていることである．また，免疫チェックポイント阻害薬の無効例であっても高い効果が報告されている．TIL療法の手順では，まず最初に患者自身の腫瘍を切除して浸潤リンパ球を抽出し，培養28日目に活性を有するリンパ球を選択する．このリンパ球をフィーダー細胞である健常人由来の末梢血単核球と共培養して14日で約1,000倍に増殖させ（急速拡大培養），骨髄抑制処置を行った患者に輸注する．輸注後は抗腫瘍効果を増強するためIL-2を8時間ごと5回投与する．我々は，2021年10月より先進医療の枠組みのもと，第3種再生医療として進行子宮頸癌症例を対象としたTIL療法の第2相臨床試験を実施している（jRCTc031200283）．先進医療と並行して前臨床試験を実施し，医師主導治験への導出を目指す．

子宮頸部高度異形成(CIN3)に対して円錐切除vs.レーザー照射(非切除)　円錐切除

岩田卓

アンチ・エイジング医学 19 ( 2 ) 156 - 159 2023.04

Evaluation of CD4+ cells infiltration as a prognostic factor in cervical intraepithelial neoplasia 2

Chen G., Iwata T., Sugawara M., Nishio H., Katoh Y., Kukimoto I., Aoki D.

Journal of Gynecologic Oncology (Journal of Gynecologic Oncology) 34 ( 1 ) e2 2023.01

ISSN 20050380

Objective: To identify candidate predictors for the prognosis of cervical intraepithelial neoplasia 2 (CIN2) lesions and evaluate the prognostic value of the local immune response. Methods: One hundred fifteen CIN2 patients were enrolled. The percentage of p16-, minichromosome maintenance complex component 2-or apolipoprotein B mRNA editing enzyme catalytic subunit 3G (APOBEC3G)-positive cells was determined immunohistochemically. Tumor-infiltrating lymphocytes (TILs) in intertumoral lesions were scored using an automated system. CIN3 disease progression and regression rates were estimated by the Kaplan–Meier method. A case-control study was conducted to screen CIN2 prognostic factors in 10 regression and 10 progression patients. Selected factors were examined in a cohort study to determine their prognostic value for CIN2. Results: Among all participants, the cumulative progression and regression rates at 60 months were 0.477 and 0.510, respectively. In the case-control study, p16-and APOBEC3G-positive cells were higher in the progression group (p=0.043, p=0.023). Additionally, CD4+ cell infiltration was enhanced in the regression group (p=0.023). The cohort study revealed a significantly increased progression rate in patients with elevated p16-positive cells (p<0.001), and increased CD4+ TIL infiltration was associated with better regression (p=0.011). Kaplan– Meier analysis according to human papillomavirus (HPV) positivity revealed a greater CIN3 development risk in HPV16-positive patients than in HPV16-negative cases. Finally, multivariate analysis identified HPV16 infection and CD4+ TIL infiltration as independent prognostic factors in CIN2 regression. Conclusion: CD4+ TIL infiltration in intertumoral lesions was related with CIN2 regression. Our findings suggest CD4+ TIL infiltration may be useful for the triage of CIN2 patients.

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当科で経験した子宮頸部胃型粘液性癌12例の検討

木村由実子, 西尾浩, 千代田達幸, 松井友哉, 岩田卓, 椎名美季, 大野あゆみ, 横田めぐみ, 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) 72 ( 1 ) 19 - 24 2023.01

Accepted, ISSN 2186-0599

子宮頸部胃型粘液性癌はハイリスクHPV感染との関連が低く稀な組織型であり,予後不良な疾患とされる.本研究では当科で経験した子宮頸部胃型粘液性癌について検討を行った.対象症例は12例であり,年齢の中央値は50歳(range:33～60歳),観察期間の中央値は16ヵ月(range:3～29ヵ月),臨床進行期(FIGO 2008)はIB1期6例,IB2期4例,IIB期1例,IVA期1例であった.初回治療として,手術を行った症例は12例中9例,同時化学放射線療法(concurrent chemoradiation therapy:CCRT)を行った症例は3例であった.手術を行った9症例のうち5例(56%)は術前の細胞診および組織診において浸潤癌の所見を認めなかった.12例中5例(42%)に再発を認め,うち4例は治療終了後12ヵ月以内に再発し,いずれも腹膜播種によるものであった.子宮頸部胃型粘液性癌は予後不良な組織型であり,治療後早期に再発する可能性を念頭に置き,慎重な経過観察を行う必要がある.(著者抄録)

Whole-genome analysis of human papillomavirus 67 isolated from Japanese women with cervical lesions

Kogure G., Onuki M., Hirose Y., Yamaguchi-Naka M., Mori S., Iwata T., Kondo K., Sekizawa A., Matsumoto K., Kukimoto I.

Virology Journal (Virology Journal) 19 ( 1 ) 157 2022.12

Background: Human papillomavirus (HPV) type 67 is phylogenetically classified into Alphapapillomavirus species 9 (alpha-9) together with other carcinogenic types (HPV16, 31, 33, 35, 52 and 58), but is the only alpha-9 type defined as possibly carcinogenic. This study aimed to determine whole-genome sequences of HPV67 isolated from Japanese women with cervical cancer or cervical intraepithelial neoplasia (CIN) to better understand the genetic basis of the oncogenic potential of HPV67. Methods: Total cellular DNA isolated from cervical exfoliated cells that were single positive for HPV67 (invasive cervical cancer, n = 2; CIN3, n = 6; CIN 2, n = 1; CIN1, n = 2; the normal cervix, n = 1) was subjected to PCR to amplify HPV67 DNA, followed by next generation sequencing to determine the complete viral genome sequences. Variant lineages/sublineages were assigned through viral whole-genome phylogenetic analysis. The transcriptional activity of the virus early promoter was assessed by luciferase reporter assays in cervical cancer cell lines. Results: Phylogenetic analyses of HPV67 genomes from Japan (n = 12) revealed that 11 belonged to lineage A (sublineage A1, n = 9; sublineage A2, n = 2) and one belonged to lineage B. All cancer cases contained sublineage A1 variants, and one of these contained an in-frame deletion in the E2 gene. The long control region of the HPV67 genome did not induce transcription from the virus early promoter in HeLa cells, but showed weak transcriptional activity in CaSki cells. Conclusions: The single detection of HPV67 in cervical cancer and precancer specimens strongly suggests the carcinogenic potential of this rare genotype. The phylogenetic analysis indicates a predominance of lineage A variants among HPV67 infections in Japan. Since only 23 complete genome sequences of HPV67 had been obtained until now, the newly determined genome sequences in this study are expected to contribute to further functional and evolutionary studies on the genetic diversity of HPV67.

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Pembrolizumab plus chemotherapy in Japanese patients with persistent, recurrent or metastatic cervical cancer: Results from KEYNOTE-826

Nishio S., Yonemori K., Usami T., Minobe S., Yunokawa M., Iwata T., Okamoto A., Aoki Y., Itamochi H., Takekuma M., Harano K., Yamamoto K., Maruko T., Ugai H., Tekin C., Colombo N., Fujiwara K., Hasegawa K., Ushijima K.

Cancer Science (Cancer Science) 113 ( 11 ) 3877 - 3887 2022.11

ISSN 13479032

Pembrolizumab plus chemotherapy with or without bevacizumab demonstrated prolonged progression-free survival (PFS) and overall survival (OS) versus chemotherapy in patients with persistent, recurrent, or metastatic cervical cancer in the phase 3, randomized, double-blind, placebo-controlled KEYNOTE-826 study. We report outcomes in patients enrolled in Japan. Patients received pembrolizumab 200 mg or placebo Q3W for up to 35 cycles plus chemotherapy (paclitaxel 175 mg/m2 + cisplatin 50 mg/m2 or carboplatin AUC 5) with or without bevacizumab 15 mg/kg. Dual primary endpoints were PFS per RECIST v1.1 by investigator assessment and OS in the global population; these were evaluated in patients with tumors with PD-L1 combined positive score (CPS) ≥1, all-comers, and PD-L1 CPS ≥10. Fifty-seven patients from Japan were randomized (pembrolizumab plus chemotherapy, n = 35; placebo plus chemotherapy, n = 22). Pembrolizumab plus chemotherapy improved PFS versus placebo plus chemotherapy in patients with PD-L1 CPS ≥1 (n = 51; hazard ratio [HR; 95% CI], 0.36 [0.16–0.77]), all-comers (n = 57; 0.45 [0.22–0.90]), and patients with PD-L1 CPS ≥10 (n = 25; 0.36 [0.12–1.07]). HRs (95% CI) for OS were 0.38 (0.14–1.01), 0.41 (0.17–1.00), and 0.37 (0.10–1.30), respectively. Incidence of grade 3–5 AEs was 94% in the pembrolizumab group and 100% in the placebo group. Consistent with findings in the global KEYNOTE-826 study, pembrolizumab plus chemotherapy with or without bevacizumab may prolong survival versus placebo plus chemotherapy with or without bevacizumab and had a manageable safety profile in Japanese patients with persistent, recurrent, or metastatic cervical cancer.

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がん微小環境における脂質代謝の制御は、抗腫瘍免疫応答を増強し、抗PD-1抗体の効果を増強する

加藤侑希, 谷口智憲, 岩田卓, 川名敬, 河上裕

Reproductive Immunology and Biology (日本生殖免疫学会) 37 ( 1-2 ) 23 - 31 2022.11

ISSN 1881-607X

抗PD-1/PD-L1阻害薬は、治療前に腫瘍抗原特異的なCD8陽性T細胞が腫瘍組織に浸潤している腫瘍(hot tumor)では、がん細胞などが発現するPD-L1によるエフェクターCD8陽性T細胞抑制の解除により、がん細胞を排除できる。しかし、多くの症例ではCD8陽性T細胞浸潤が少なく(cold tumor)、抗PD-1/PD-L1阻害薬単独投与の効果は限定的であり、この治療抵抗性機序を解明して治療効果を増強する方法の開発が期待されている。我々は、様々なヒトがんの網羅的遺伝子発現解析により、cold tumorの中には、脂肪酸不飽和化酵素であるStearoyl-CoA desaturase 1(SCD1)の高発現をはじめとする、脂質代謝異常が深く関与するサブタイプが存在することを見出した。そこで、本研究では、脂肪酸代謝の抗腫瘍免疫応答への関与及び、それを標的としたがん免疫療法の可能性を検討した。まず、各種マウスがん細胞株を移植したマウス腫瘍モデルを用いて、SCD1阻害剤投与により、抗腫瘍免疫応答を増強できるかを検討した。その結果、SCD1阻害剤投与群において、腫瘍内樹状細胞(DC)のCD80/CD86やCD83の発現上昇、およびその浸潤増加が認められた。更に、CD8陽性T細胞の腫瘍内浸潤数の増加も観察され、所属リンパ節及び腫瘍組織内で、腫瘍抗原特異的T細胞の誘導が増強された。腫瘍内浸潤CD8陽性T細胞におけるPD-1などの共刺激分子の発現もSCD1阻害剤投与群において増強されていたので、SCD1阻害剤と抗PD-1抗体の併用療法の効果を評価した。その結果、抗PD-1抗体単独投与ではほとんど効果を示さないがん細胞株においても、両薬の併用によって相乗的な抗腫瘍効果が観察され、完全奏効例も認められた。SCD1阻害剤のin vitroでの免疫細胞に対する効果を評価したところ、DC及びCD8陽性T細胞に直接作用し、その機能を増強することも明らかとなった。以上より、がん微小環境における脂質代謝の制御により、cold tumorをhot tumorに変え、免疫チェックポイント阻害薬の治療効果を向上させる可能性が示された。(著者抄録)

Regional differences in human papillomavirus type 52 prevalence among Japanese women with cervical intraepithelial neoplasia†

Kukimoto I., Onuki M., Yamamoto K., Yahata H., Aoki Y., Yokota H., Konnai K., Nio A., Takehara K., Kamiura S., Tsuda N., Takei Y., Shimada M., Nakai H., Yoshida H., Motohara T., Yamazaki H., Nakamura K., Okunomiya A., Tasaka N., Ishikawa M., Hirashima Y., Shimoji Y., Mori M., Iwata T., Takahashi F., Yoshikawa H., Yaegashi N., Matsumoto K.

Japanese journal of clinical oncology (Japanese journal of clinical oncology) 52 ( 10 ) 1242 - 1247 2022.10

ISSN 0368-2811

Although geographical differences in the distribution of human papillomavirus genotypes have been observed worldwide, no studies have reported on national differences in the prevalence of human papillomavirus types in Japan. Here, we report a cross-sectional study to explore regional differences in the prevalence of human papillomavirus types among Japanese women with cervical intraepithelial neoplasia or invasive cervical cancer. Using human papillomavirus genotyping data from the nationwide prospective study on human papillomavirus vaccine effectiveness, we compared the frequency of detection of 15 high-risk and two low-risk human papillomavirus types in each disease category between the women who visited hospitals located in eastern Japan and those who visited hospitals located in western Japan. The risk of cervical intraepithelial neoplasia progression was assessed by calculating a prevalence ratio of each human papillomavirus type for cervical intraepithelial neoplasia grade 2/3 versus grade 1. Among the human papillomavirus types studied, human papillomavirus 52 was detected significantly more frequently in western hospitals than in eastern hospitals in cervical intraepithelial neoplasia grade 1 patients, but was less frequent in cervical intraepithelial neoplasia grade 2/3. The prevalence of particular human papillomavirus types was not significantly different between patients in hospitals in eastern Japan and those in hospitals in western Japan for invasive cervical cancer. In both eastern and western hospitals, a higher risk of cervical intraepithelial neoplasia progression was observed in patients infected with human papillomavirus 16, 31 or 58. In contrast, there was a significantly higher prevalence of human papillomavirus 52 infection in women with cervical intraepithelial neoplasia grade 2/3 than in those with cervical intraepithelial neoplasia grade 1 in eastern hospitals (prevalence ratio, 1.93; 95% confidence interval, 1.48-2.58), but not in western hospitals (prevalence ratio, 1.03; 95% confidence interval, 0.83-1.30). Regional differences of human papillomavirus 52 prevalence in cervical intraepithelial neoplasia lesions may exist and emphasize the importance of continuous monitoring of human papillomavirus type prevalence throughout the country in order to accurately assess the efficacy of human papillomavirus vaccines.

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特集 AYA世代の女性ヘルスケア-対応と実際- Ⅳ.婦人科腫瘍・婦人科疾患への対策 1.子宮頸部病変の妊孕性温存手術

田中恒成, 岩田卓

産婦人科の実際 (金原出版) 71 ( 10 ) 1101 - 1105 2022.09

ISSN 05584728

Development of a prognostic prediction support system for cervical intraepithelial neoplasia using artificial intelligence-based diagnosis

Takahashi T., Matsuoka H., Sakurai R., Akatsuka J., Kobayashi Y., Nakamura M., Iwata T., Banno K., Matsuzaki M., Takayama J., Aoki D., Yamamoto Y., Tamiya G.

Journal of Gynecologic Oncology (Journal of Gynecologic Oncology) 33 ( 5 ) e57 2022.09

ISSN 20050380

Objective: Human papillomavirus subtypes are predictive indicators of cervical intraepithelial neoplasia (CIN) progression. While colposcopy is also an essential part of cervical cancer prevention, its accuracy and reproducibility are limited because of subjective evaluation. This study aimed to develop an artificial intelligence (AI) algorithm that can accurately detect the optimal lesion associated with prognosis using colposcopic images of CIN2 patients by utilizing objective AI diagnosis. Methods: We identified colposcopic findings associated with the prognosis of patients with CIN2. We developed a convolutional neural network that can automatically detect the rate of high-grade lesions in the uterovaginal area in 12 segments. We finally evaluated the detection accuracy of our AI algorithm compared with the scores by multiple gynecologic oncologists. Results: High-grade lesion occupancy in the uterovaginal area detected by senior colposcopists was significantly correlated with the prognosis of patients with CIN2. The detection rate for high-grade lesions in 12 segments of the uterovaginal area by the AI system was 62.1% for recall, and the overall correct response rate was 89.7%. Moreover, the percentage of high-grade lesions detected by the AI system was significantly correlated with the rate detected by multiple gynecologic senior oncologists (r=0.61). Conclusion: Our novel AI algorithm can accurately determine high-grade lesions associated with prognosis on colposcopic images, and these results provide an insight into the additional utility of colposcopy for the management of patients with CIN2.

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Risk assessment in the patients with uterine cervical cancer harboring intermediate risk factors after radical hysterectomy: a multicenter, retrospective analysis by the Japanese Gynecologic Oncology Group

Shigeta S., Shimada M., Tsuji K., Nagai T., Tanase Y., Matsuo K., Kamiura S., Iwata T., Yokota H., Mikami M.

International Journal of Clinical Oncology (International Journal of Clinical Oncology) 27 ( 9 ) 1507 - 1515 2022.09

ISSN 13419625

Background: Adjuvant therapy is usually considered for surgically treated patients with uterine cervical cancer harboring intermediate risk (IR) factors such as large tumor diameter, stromal invasion to the outer half, and lymphovascular space invasion (LVSI). However, the indications and types of adjuvant therapy for the IR group remain controversial. This study aimed to analyze the differences in patient outcomes in the IR group to provide novel insights for tailoring adjuvant therapy. Methods: Data from 6192 patients with cervical cancer who underwent radical hysterectomy at 116 institutions belonging to the Japanese Gynecologic Oncology Group were reviewed. Results: In total, 1688 patients were classified into the IR group, of whom 37.3% did not receive adjuvant therapy. Conversely, approximately equal proportions of the remaining patients received adjuvant radiotherapy, concurrent chemoradiotherapy, and chemotherapy. Patients with all three risk factors showed worse overall survival than those with one or two risk factors. In addition to LVSI, non-squamous cell carcinoma histology, and vaginal invasion were identified as independent risk factors for both recurrence and mortality in multivariate analyses. Tumor diameter greater than 40 mm and surgical center volume were identified as independent risk factors for recurrence. Stromal invasion to the outer half and ovarian metastasis were identified as independent risk factors for mortality. Conclusions: This study revealed the significant differences in prognosis in the IR group. The indications for adjuvant therapy should be further studied, focusing on conventional risk factors and other pathological findings.

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Climacteric symptoms in postoperative patients among endometrial cancer, cervical cancer, and ovarian cancer: a cross-sectional study

Horiba Y., Yoshino T., Yokota M., Iwata T., Watanabe K., Mimura M., Aoki D.

Supportive Care in Cancer (Supportive Care in Cancer) 30 ( 8 ) 6785 - 6793 2022.08

ISSN 09414355

Purpose: To date, no studies have assessed climacteric symptoms after hystero-adnexectomy for endometrial, cervical, or ovarian cancer. Thus, this study aimed to compare climacteric symptoms among patients who underwent surgery for these three cancer types. Methods: In this cross-sectional study, we interviewed patients who were registered at a menopausal outpatient clinic between January 1999 and July 2016 after undergoing total hysterectomy, intrapelvic only or intrapelvic plus para-aortic lymph node dissection, and bilateral adnexectomy performed via laparotomy as a cancer treatment. Climacteric symptoms were assessed using a patient-reported questionnaire covering core domains with five symptoms only at the initial consultation. Each symptom was graded from 0 (no symptoms) to 3 (severe symptoms). We evaluated the frequency of symptom severity according to the time elapsed since surgery and the cancer type. Results: The numbers of patients with endometrial, ovarian, and cervical cancer were 328, 90, and 107, respectively. Overall, climacteric symptoms were more severe in patients with cervical cancer than in those with endometrial or ovarian cancer; symptom severity decreased with increasing time since surgery. However, symptom severity did not decrease significantly over time in patients with cervical cancer even after > 5 years had elapsed since surgery. Conclusion: The climacteric symptoms were less severe in patients with endometrial or ovarian cancer with longer time elapsed since surgery but not in those with cervical cancer. Patients with cervical cancer may require more prompt interventions, including symptomatic treatment and longer follow-up period, than those with endometrial or ovarian cancer.

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Tisotumab vedotin in Japanese patients with recurrent/metastatic cervical cancer: Results from the innovaTV 206 study

Yonemori K., Kuboki Y., Hasegawa K., Iwata T., Kato H., Takehara K., Hirashima Y., Kato H., Passey C., Buchbjerg J.K., Harris J.R., Andreassen C., Nicacio L., Soumaoro I., Fujiwara K.

Cancer Science (Cancer Science) 113 ( 8 ) 2788 - 2797 2022.08

ISSN 13479032

New treatments, particularly second-line options, are needed to improve outcomes for patients with recurrent/metastatic cervical cancer (r/mCC). Tisotumab vedotin (TV) is an antibody–drug conjugate directed to tissue factor, a transmembrane protein commonly expressed in cancer cells, to deliver cytotoxic monomethyl auristatin E. This single-arm, open-label phase 1/2 trial evaluated the consistency of safety and efficacy outcomes of TV in Japanese patients with r/mCC to bridge the current findings with those reported in previous trials in non-Japanese patients in the United States and Europe. In part 1 (dose escalation; N = 6), patients with advanced solid tumors received TV 1.5 or 2.0 mg/kg once every 3 weeks to determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D). Part 2 (dose expansion; N = 17) evaluated the RP2D in r/mCC patients with 1–2 prior lines of therapy. In part 1, no dose-limiting toxicities were observed, the MTD was not reached, and TV 2.0 mg/kg was established as the RP2D. In part 2, the most common treatment-emergent adverse events were anemia (58.8%), nausea (58.8%), alopecia (47.1%), epistaxis (47.1%), and diarrhea (35.3%); adverse events of special interest were bleeding (76.5%), ocular events (35.3%), and peripheral neuropathy (17.6%), and were mostly grade 1/2. In part 2, confirmed objective response rate was 29.4%, median duration of response was 7.1 months, and median time to response was 1.2 months. In Japanese patients with r/mCC, TV demonstrated a manageable and tolerable safety, pharmacokinetics, and efficacy profile consistent with that observed in non-Japanese patients.

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Management and outcomes of hydronephrosis in patients with metastatic extramammary Paget’s disease: A retrospective analysis

Fusumae T., Fukuda K., Hirai I., Nakamura Y., Kobayashi K., Tanese K., Matsumoto K., Iwata T., Funakoshi T.

Journal of Dermatology (Journal of Dermatology) 49 ( 8 ) 787 - 791 2022.08

ISSN 03852407

Hydronephrosis in extramammary Paget’s disease (EMPD) with distant metastasis (metastatic EMPD) has been observed in medical practice; however, its prognosis remains unclear. Retrospective analyses were performed to assess the management and outcomes of hydronephrosis in metastatic EMPD. During a follow-up of 44 patients with metastatic EMPD, 13 (30%) developed hydronephrosis. Ten (77%) of the 13 patients with hydronephrosis had impaired renal function (estimated glomerular filtration rate: <60 ml/min/1.73 m2), and ureteral stents were placed in every patient with impaired renal function. The stent was placed successfully in all 10 patients, and their renal function recovered within a median period of 7 days. Importantly, each of these patients continued chemotherapy, and none of them experienced stent failure. The median overall survival time (OS) in patients with metastatic EMPD and hydronephrosis (n = 13) was 7.8 months. Treatment for hydronephrosis was not a significant factor for OS, and median OS in patients who underwent ureteral stent replacement (n = 10) was 14.7 months. Collectively, our results indicate that hydronephrosis is relatively common, and ureteral stent placement should be considered in cases of metastatic EMPD with hydronephrosis to maintain renal function and continue chemotherapy toward a better prognosis.

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Inhibition of stearoyl-CoA desaturase 1 (SCD1) enhances the antitumor T cell response through regulating β-catenin signaling in cancer cells and ER stress in T cells and synergizes with anti-PD-1 antibody

Katoh Y., Yaguchi T., Kubo A., Iwata T., Morii K., Kato D., Ohta S., Satomi R., Yamamoto Y., Oyamada Y., Ouchi K., Takahashi S., Ishioka C., Matoba R., Suematsu M., Kawakami Y.

Journal for ImmunoTherapy of Cancer (Journal for ImmunoTherapy of Cancer) 10 ( 7 ) 2022.07

Background Understanding the mechanisms of non-T cell inflamed tumor microenvironment (TME) and their modulation are important to improve cancer immunotherapies such as immune checkpoint inhibitors. The involvement of various immunometabolisms has recently been indicated in the formation of immunosuppressive TME. In this study, we investigated the immunological roles of stearoyl-CoA desaturase 1 (SCD1), which is essential for fatty acid metabolism, in the cancer immune response. Methods We investigated the roles of SCD1 by inhibition with the chemical inhibitor or genetic manipulation in antitumor T cell responses and the therapeutic effect of anti-programmed cell death protein 1 (anti-PD-1) antibody using various mouse tumor models, and their cellular and molecular mechanisms. The roles of SCD1 in human cancers were also investigated by gene expression analyses of colon cancer tissues and by evaluating the related free fatty acids in sera obtained from patients with non-small cell lung cancer who were treated with anti-PD-1 antibody. Results Systemic administration of a SCD1 inhibitor in mouse tumor models enhanced production of CCL4 by cancer cells through reduction of Wnt/β-catenin signaling and by CD8 + effector T cells through reduction of endoplasmic reticulum stress. It in turn promoted recruitment of dendritic cells (DCs) into the tumors and enhanced the subsequent induction and tumor accumulation of antitumor CD8 + T cells. SCD1 inhibitor was also found to directly stimulate DCs and CD8 + T cells. Administration of SCD1 inhibitor or SCD1 knockout in mice synergized with an anti-PD-1 antibody for its antitumor effects in mouse tumor models. High SCD1 expression was observed in one of the non-T cell-inflamed subtypes in human colon cancer, and serum SCD1 related fatty acids were correlated with response rates and prognosis of patients with non-small lung cancer following anti-PD-1 antibody treatment. Conclusions SCD1 expressed in cancer cells and immune cells causes immunoresistant conditions, and its inhibition augments antitumor T cells and therapeutic effects of anti-PD-1 antibody. Therefore, SCD1 is an attractive target for the development of new diagnostic and therapeutic strategies to improve current cancer immunotherapies including immune checkpoint inhibitors.

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子宮頸部上皮内病変(CIN)に対してレーザー蒸散術後に子宮頸がんと診断された18例の検討

田中郁百, 西尾浩, 岩田卓, 大野あゆみ, 谷本慧子, 横田めぐみ, 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) 71 ( 3 ) 447 - 451 2022.07

ISSN 2186-0599

子宮頸部上皮内病変(CIN)へのレーザー蒸散術は、切除検体の病理診断が行われないため症例ごとに手術適応を十分に検討し術後の経過観察を慎重に行う必要がある。今回当科でCIN2もしくはCIN3と診断され蒸散術を行った1469例のうち、術後に子宮頸がんを認めた症例について検討を行った。蒸散術後の経過観察中に子宮頸がんと診断された症例は1469例中18例(1.2%)で、臨床進行期分類(FIGO 2008)はIA1期8例、IB1期10例であった。子宮頸がん診断までの中央値は11ヵ月(3～72.6ヵ月)で、15例(83%)は術後18ヵ月以内に診断されていた。治療はIA1期の6例は円錐切除術のみ、2例で円錐切除術後に拡大単純子宮全摘出術、IB1期の10例は広汎子宮全摘出術を行った。いずれも再発を認めていない。CINに対する蒸散術後は浸潤がんが発生する可能性を念頭におき慎重に経過観察する必要がある。(著者抄録)

Clinical course of a Japanese girl with Leber congenital amaurosis associated with a novel nonsense pathogenic variant in NMNAT1: a case report and mini review.

Kayazawa T, Kuniyoshi K, Hatsukawa Y, Fujinami K, Yoshitake K, Tsunoda K, Shimojo H, Iwata T, Kusaka S

Ophthalmic genetics 43 ( 3 ) 400 - 408 2022.06

ISSN 1381-6810

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Ancient Evolutionary History of Human Papillomavirus Type 16, 18 and 58 Variants Prevalent Exclusively in Japan

Tanaka K., Kogure G., Onuki M., Matsumoto K., Iwata T., Aoki D., Kukimoto I.

Viruses (Viruses) 14 ( 3 ) 2022.03

Human papillomavirus (HPV) is a sexually transmitted virus with an approximately 8-kilo base DNA genome, which establishes long-term persistent infection in anogenital tissues. High levels of genetic variations, including viral genotypes and intra-type variants, have been described for HPV genomes, together with geographical differences in the distribution of genotypes and variants. Here, by employing a maximum likelihood method, we performed phylogenetic analyses of the complete genome sequences of HPV16, HPV18 and HPV58 available from GenBank (n = 627, 146 and 157, respectively). We found several characteristic clusters that exclusively contain HPV genomes from Japan: two for HPV16 (sublineages A4 and A5), one for HPV18 (sublineage A1) and two for HPV58 (sublineages A1 and A2). Bayesian phylogenetic analyses of concatenated viral gene sequences showed that divergence of the most recent common ancestor of these Japan-specific clades was estimated to have occurred ~98,000 years before present (YBP) for HPV16 A4, ~39,000 YBP for HPV16 A5, ~38,000 YBP for HPV18 A1, ~26,000 for HPV58 A1 and ~25,000 YBP for HPV58 A2. This estimated timeframe for the divergence of the Japan-specific clades suggests that the introduction of these HPV variants into the Japanese archipelago dates back to at least ~25,000 YBP and provides a scenario of virus co-migration with ancestral Japanese populations from continental Asia during the Upper Paleolithic period.

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Changes in HPV16/18 Prevalence among Unvaccinated Women with Cervical Intraepithelial Neoplasia in Japan: Assessment of Herd Effects following the HPV Vaccination Program.

Onuki M, Yamamoto K, Yahata H, Kanao H, Horie K, Konnai K, Nio A, Takehara K, Kamiura S, Tsuda N, Takei Y, Shigeta S, Nakai H, Yoshida H, Motohara T, Kato T, Nakamura K, Hamanishi J, Tasaka N, Ishikawa M, Kado N, Taira Y, Mori M, Iwata T, Takahashi F, Kukimoto I, Yoshikawa H, Yaegashi N, Matsumoto K, For The Mint Study Group

Vaccines (Vaccines) 10 ( 2 ) 2022.01

ISSN 2076-393X

Since the human papillomavirus (HPV) vaccination program for Japanese girls aged 12–16 years began in 2010, vaccination uptake has been low in women born before 1993 but high (approximately 70%) in those born during 1994–1999. We previously compared the prevalence of vaccine types HPV16 and HPV18 in cervical intraepithelial neoplasia grade 1–3 (CIN1–3) or adenocarcinoma in situ (AIS) between vaccinated and unvaccinated cohorts and found direct protection effects among vaccinated women in Japan. In this study, we focused on changes in HPV16/18 prevalence among “unvaccinated” cohorts with CIN/AIS. We analyzed HPV16/18 prevalence among 5051 unvaccinated women aged <40 years, newly diagnosed with CIN/AIS during 2012–2021 for time trends. Declining trends in HPV16/18 prevalence over 9 years were observed in CIN1 (36.0–10.0%, Ptrend = 0.03) and CIN2–3/AIS (62.5–36.4%, Ptrend = 0.07) among women aged <25 years. HPV16/18 prevalence in CIN1 and CIN2–3/AIS diagnosed at age 20–24 years was lower in 1994–1999 birth cohorts compared with 1988–1993 birth cohorts (4.5% vs. 25.7% for CIN1 and 40.0% vs. 58.1% for CIN2–3/AIS, both p = 0.04). Significant reduction in HPV16/18 prevalence among young unvaccinated women with CIN1 and CIN2–3/AIS suggests herd effects of HPV vaccination in Japan.

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Human papillomavirus vaccine effectiveness by age at first vaccination among Japanese women.

Onuki M, Yamamoto K, Yahata H, Kanao H, Yokota H, Kato H, Shimamoto K, Takehara K, Kamiura S, Tsuda N, Takei Y, Shigeta S, Matsumura N, Yoshida H, Motohara T, Watari H, Nakamura K, Ueda A, Tasaka N, Ishikawa M, Hirashima Y, Kudaka W, Taguchi A, Iwata T, Takahashi F, Kukimoto I, Yoshikawa H, Yaegashi N, Matsumoto K, MINT Study Group.

Cancer science (Cancer Science) 113 ( 4 ) 1428 - 1434 2022.01

ISSN 1347-9032

In Japan, the National Immunization Program against human papillomavirus (HPV) targets girls aged 12-16 years, and catch-up vaccination is recommended for young women up to age 26 years. Because HPV infection rates increase soon after sexual debut, we evaluated HPV vaccine effectiveness by age at first vaccination. Along with vaccination history, HPV genotyping results from 5795 women younger than 40 years diagnosed with cervical intraepithelial neoplasia grade 2-3 (CIN2-3), adenocarcinoma in situ (AIS), or invasive cervical cancer were analyzed. The attribution of vaccine-targeted types HPV16 or HPV18 to CIN2-3/AIS was 47.0% for unvaccinated women (n = 4297), but 0.0%, 13.0%, 35.7%, and 39.6% for women vaccinated at ages 12-15 years (n = 36), 16-18 years (n = 23), 19–22 years (n = 14), and older than 22 years (n = 91), respectively, indicating the greater effectiveness of HPV vaccination among those initiating vaccination at age 18 years or younger (P <.001). This finding was supported by age at first sexual intercourse; among women with CIN2-3/AIS, only 9.2% were sexually active by age 14 years, but the percentage quickly increased to 47.2% by age 16 and 77.1% by age 18. Additionally, the HPV16/18 prevalence in CIN2-3/AIS was 0.0%, 12.5%, and 40.0% for women vaccinated before (n = 16), within 3 years (n = 8), and more than 3 years after (n = 15) first intercourse, respectively (P =.004). In conclusion, our data appear to support routine HPV vaccination for girls aged 12-14 years and catch-up vaccination for adolescents aged 18 years and younger in Japan.

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Transcription factor homeobox d9 drives the malignant phenotype of hpv18-positive cervical cancer cells via binding to the viral early promoter

Hayashi S., Iwata T., Imagawa R., Sugawara M., Chen G., Tanimoto S., Sugawara Y., Tanaka I., Matsui T., Nishio H., Nakamura M., Katoh Y., Mori S., Kukimoto I., Aoki D.

Cancers (Cancers) 13 ( 18 ) 2021.09

ISSN 2072-6694

Persistent infections with two types of human papillomaviruses (HPV), HPV16 and HPV18, are the most common cause of cervical cancer (CC). Two viral early genes, E6 and E7, are associated with tumor development, and expressions of E6 and E7 are primarily regulated by a single viral promoter: P97 in HPV16 and P105 in HPV18. We previously demonstrated that the homeobox D9 (HOXD9) transcription factor is responsible for the malignancy of HPV16-positive CC cell lines via binding to the P97 promoter. Here, we investigated whether HOXD9 is also involved in the regulation of the P105 promoter using two HPV18-positive CC cell lines, SKG-I and HeLa. Following the HOXD9 knockdown, cell viability was significantly reduced, and E6 expression was suppressed and was accompanied by increased protein levels of P53, while mRNA levels of TP53 did not change. E7 expression was also downregulated and, while mRNA levels of RB1 and E2F were unchanged, mRNA levels of E2F-target genes, MCM2 and PCNA, were decreased, which indicates that the HOXD9 knockdown downregulates E7 expression, thus leading to an inactivation of E2F and the cell-cycle arrest. Chromatin immunoprecipitation and promoter reporter assays confirmed that HOXD9 is directly associated with the P105 promoter. Collectively, our results reveal that HOXD9 drives the HPV18 early promoter activity to promote proliferation and immortalization of the CC cells.

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A randomized phase II/III trial of conventional paclitaxel and carboplatin with or without bevacizumab versus dose-dense paclitaxel and carboplatin with or without bevacizumab, in stage IVB, recurrent, or persistent cervical carcinoma (JCOG1311): Primary analysis

Ishikawa M., Shibata T., Iwata T., Nishio S., Takada T., Suzuki S., Horie K., Kudaka W., Kagabu M., Tanikawa M., Kitagawa R., Takekuma M., Kobayashi H., Yaegashi N.

Gynecologic Oncology (Gynecologic Oncology) 162 ( 2 ) 292 - 298 2021.08

ISSN 00908258

Objective: To assess the efficacy and safety of dose-dense weekly paclitaxel plus carboplatin (ddTC) with or without bevacizumab compared to conventional, tri-weekly paclitaxel plus carboplatin (cTC) with or without bevacizumab, in metastatic or recurrent cervical carcinoma not amenable to curative local therapy. Methods: Patients were randomly assigned to either the cTC or ddTC arm. The cTC regimen was paclitaxel 175 mg/m2 and carboplatin at an area under the curve (AUC) of 5 on day 1. The ddTC regimen was paclitaxel 80 mg/m2 on day 1, 8, 15 and carboplatin at AUC of 5 on day 1. Both cTC and ddTC treatments were repeated every 3 weeks for up to 9 cycles. After bevacizumab was approved in Japan, patients in both arms received bevacizumab 15 mg/kg if not contraindicated. The primary endpoint of phase II part was response rate (RR). If the RR of ddTC+bevacizumab was found to be at least 5% better than to cTC + bevacizumab, the study would proceed to phase III part, which had overall survival as its primary endpoint. Clinical trial information: jRCTs031180007. Results: In total, 122 patients were randomly assigned to either the cTC arm (cTC + bevacizumab: 32; cTC:29) or the ddTC arm (ddTC+bevacizumab: 30; ddTC:31). The RR for patients on cTC + bevacizumab was 67.9%, and for patients on ddTC+bevacizumab 60.7%, cTC: 55.2%, and ddTC: 50.0%. Conclusions: The study did not meet the primary endpoint of phase II portion. Dose-dense, weekly paclitaxel plus carboplatin is not promising for metastatic or recurrent cervical carcinoma.

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Adoptive cell therapy using tumor-infiltrating lymphocytes for melanoma refractory to immune-checkpoint inhibitors

Hirai I., Funakoshi T., Kamijuku H., Fukuda K., Mori M., Sakurai M., Koda Y., Kato J., Mori T., Watanabe N., Noji S., Yaguchi T., Iwata T., Ohta S., Fujita T., Tanosaki R., Handa M., Okamoto S., Amagai M., Kawakami Y.

Cancer Science (Cancer Science) 112 ( 8 ) 3163 - 3172 2021.08

ISSN 13479032

To evaluate the feasibility of adoptive cell therapy (ACT) using ex vivo-expanded tumor-infiltrating lymphocytes (TILs) in Japanese patients with melanoma who failed immune-checkpoint inhibitor therapy, an open-label, single-arm, pilot study was conducted. We investigated the immunological and genetic factors of the pretreatment tumor and expanded TILs that may be associated with the clinical response. The treatment protocol comprised preparation of TIL culture, lympho-depleting non-myeloablative preconditioning with cyclophosphamide and fludarabine, TIL infusion, and intravenous administration of low-dose IL-2. Three patients of clinical subtypes mucosal, superficial spreading, and acral melanoma underwent TIL-ACT. Most severe adverse events, including fever and leukopenia, were manageable with the supportive regimen specified in the protocol, suggesting that the TIL-ACT regimen is suitable for Japanese patients with melanoma. One patient showed a short-term partial response, one relatively long-stable disease, and one experienced disease progression. Whole-exome and transcriptional sequencing of isolated tumor cells and immunohistochemical analyses before TIL-ACT revealed various immunostimulatory factors, including a high tumor mutation burden and immune cell-recruiting chemokines, as well as various immunosuppressive factors including TGF-β, VEGF, Wnt/β-catenin, and MAPK signaling and epithelial-to-mesenchymal transition, which might influence the efficacy of TIL-ACT. Our results imply mechanisms for the antitumor effect of and resistance to TIL-ACT. Further studies of immune-resistant mechanisms of TIL-ACT are warranted. This study is registered with the UMIN Clinical Trial Registry (UMIN 000011431).

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特集婦人科がん機能温存治療のすべて子宮頸がん　子宮頸部円錐切除術

岩田卓

産科と婦人科 ((株)診断と治療社) 88 ( 7 ) 812 - 817 2021.07

ISSN 03869792

Nucleosome positioning on episomal human papillomavirus dna in cultured cells

Murakami I., Iwata T., Morisada T., Tanaka K., Aoki D.

Pathogens (Pathogens) 10 ( 6 ) 2021.06

ISSN 2076-0817

Several human papillomaviruses (HPV) are associated with the development of cervical carcinoma. HPV DNA synthesis is increased during the differentiation of infected host keratinocytes as they migrate from the basal layer of the epithelium to the spinous layer, but the molecular mechanism is unclear. Nucleosome positioning affects various cellular processes such as DNA replication and repair by permitting the access of transcription factors to promoters to initiate transcription. In this study, nucleosome positioning on virus chromatin was investigated in normal immortalized keratinocytes (NIKS) stably transfected with HPV16 or HPV18 genomes to determine if there is an association with the viral life cycle. Micrococcal nuclease-treated DNA analyzed by Southern blotting using probes against HPV16 and HPV18 and quantified by nucleosome scanning analysis using real-time PCR revealed mononucleosomal-sized fragments of 140–200 base pairs that varied in their location within the viral genome according to whether the cells were undergoing proliferation or differentiation. Notably, changes in the regions around nucleotide 110 in proliferating and differentiating host cells were common to HPV16 and HPV18. Our findings suggest that changes in nucleosome positions on viral DNA during host cell differentiation is an important regulatory event in the viral life cycle.

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増刊号産婦人科患者説明ガイド-納得・満足を引き出すために婦人科疾患 Q1　子宮腟部びらんと言われました.どんな病気ですか?

岩田卓

臨床婦人科産科 (株式会社医学書院) 75 ( 4 ) 297 - 298 2021.04

ISSN 0386-9865

The validity of the subsequent pregnancy index score for fertility-sparing trachelectomy in early-stage cervical cancer.

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

Fertility and sterility (Fertility and Sterility) 115 ( 5 ) 1250 - 1258 2021.02

ISSN 0015-0282

Objective: To evaluate timing and a prediction model for pregnancy in early-stage cervical cancer patients who underwent fertility-sparing trachelectomy. Design: Retrospective cohort. Setting: Academic multicenter. Patient(s): Women ages <45 years with clinical stage I–II cervical cancer were enrolled between 2009 and 2013 (n = 393). Intervention(s): Planned fertility-sparing trachelectomy. Main Outcome Measure(s): Cumulative incidences and clinicopathological characteristics of those who developed subsequent pregnancy were examined. Result(s): There were 77 (21.6%) women who had subsequent pregnancies after fertility-sparing trachelectomy with 1-, 2-, and 5-year cumulative pregnancy rates of 2.8%, 6.2%, and 17.4%, respectively. The median time to develop subsequent pregnancy was 3.2 years. In a competing risk analysis, women had a higher risk of recurrent cancer than conception during the first 11 months postsurgery. On multivariable analysis, younger age, being married, and postoperative reproductive treatment were independently associated with an increased chance of developing a subsequent pregnancy. The subsequent pregnancy index (SPI) score to predict the likelihood of having pregnancy was proposed, and it was calculated based on age, marital status, and reproductive treatment (2, 2, and 4 points, respectively). Women with a higher SPI score had significantly higher subsequent pregnancy rates (5-year pregnancy rate; the score was 3 in 4.7% of cases; 4 to 5 in 11.3%; 6 to 7 in 27.4%; and 8 in 50.8%), but they had similar recurrence rates (5.0%). Conclusion(s): The SPI score proposed in our study is useful in predicting subsequent pregnancy in women with early-stage cervical cancer undergoing fertility-sparing trachelectomy.

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子宮頸癌の治療　子宮頸癌の手術

岩田　卓

日本産科婦人科学会雑誌 72 ( 12 ) 1688 - 1693 2020.12

Accepted

Outcomes in patients with extramammary Paget disease with brain metastasis: A retrospective analysis.

Fusumae T, Fukuda K, Hirai I, Nakamura Y, Tanese K, Iwata T, Funakoshi T

Journal of the American Academy of Dermatology (Journal of the American Academy of Dermatology) 83 ( 6 ) 1832 - 1834 2020.12

ISSN 0190-9622

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Current status of cancer immunotherapy for gynecologic malignancies.

Nishio H, Iwata T, Aoki D

Japanese journal of clinical oncology (Japanese journal of clinical oncology) 51 ( 2 ) 167 - 172 2020.11

ISSN 0368-2811

Recent cancer immunotherapy development with immune checkpoint inhibitors has shown durable clinical responses in a wide variety of tumor types. These drugs targeting programmed cell death 1, its ligand programmed death ligand 1 and cytotoxic T cell lymphocyte-associated antigen 4 have revolutionized the field of cancer treatment. It is of significant interest in optimizing the immunotherapy for cancer patients beyond the conventional treatments such as surgery, chemotherapy and radiation. Many clinical trials evaluating the safety and efficacy of various combined regimens with immune checkpoint inhibitors have been reported and are in progress. Among gynecologic malignancy, endometrial cancers have distinct subtypes with microsatellite instability-high status and polymerase ɛ mutation. These types have been shown to immunogenic tumors and appropriated candidate for immune checkpoint inhibitors. Also, recurrent cervical cancer showed a promising objective response with single anti-PD1 Ab treatment. Despite their definite outcome and considerable potential of immunotherapy, not all patients received a survival benefit and further understanding of human tumor immunology is essential to improve this type of therapy. In this review, we have summarized the updated results of clinical trials of cancer immunotherapy for gynecologic malignancies and discussed the future perspectives.

High Levels of Within-Host Variations of Human Papillomavirus 16 E1/E2 Genes in Invasive Cervical Cancer

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

Frontiers in Microbiology (Frontiers in Microbiology) 11 596334 2020.11

© Copyright © 2020 Hirose, Yamaguchi-Naka, Onuki, Tenjimbayashi, Tasaka, Satoh, Tanaka, Iwata, Sekizawa, Matsumoto and Kukimoto. Human papillomavirus type 16 (HPV16) is the most common HPV genotype found in invasive cervical cancer (ICC). Recent comprehensive genomics studies of HPV16 have revealed that a large number of minor nucleotide variations in the viral genome are present in each infected woman; however, it remains unclear whether such within-host variations of HPV16 are linked to cervical carcinogenesis. Here, by employing next-generation sequencing approaches, we explored the mutational profiles of the HPV16 genome within individual clinical specimens from ICC (n = 31) and normal cervix (n = 21) in greater detail. A total of 367 minor nucleotide variations (167 from ICC and 200 from the normal cervix) were detected throughout the viral genome in both groups, while nucleotide variations at high frequencies (>10% abundance in relative read counts in a single sample) were more prevalent in ICC (10 in ICC versus 1 in normal). Among the high-level variations found in ICC, six were located in the E1/E2 genes, and all of them were non-synonymous substitutions (Q142K, M207I, and L262V for E1; D153Y, R302T, and T357A for E2). In vitro functional analyses of these E1/E2 variants revealed that E1/M207I, E2/D153Y, and E2/R302T had reduced abilities to support viral replication, and that E2/D153Y and E2/R302T failed to suppress the viral early promoter. These results imply that some within-host variations of E1/E2 present at high levels in ICC may be positively selected for and contribute to cervical cancer development through dysfunction or de-stabilization of viral replication/transcription proteins.

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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

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.

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)

有害事象によりベバシズマブ投与を中止した婦人科がん症例の検討

大野, あゆみ, 千代田, 達幸, 野村, 弘行, 同前, 愛, 早乙女, 啓子, 冨永, 英一郎, 岩田, 卓, 山上, 亘, 片岡, 史夫, 平沢, 晃, 田中, 守 and 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) 67 ( 3 ) 396 - 400 2018.07

ISSN 2186-0599

ベバシズマブは婦人科がんにおいて日常的に用いられる分子標的薬となっているが、特有の有害事象により投与継続が困難となるケースを経験する。そこで本研究ではベバシズマブ投与中止の原因となった重篤な有害事象と臨床的背景を明らかにすることを目的とした。ベバシズマブ併用化学療法を2013年12月から開始した上皮性卵巣癌、卵管癌、腹膜癌(以下卵巣癌)48例および2017年1月から開始した子宮頸癌12例の計60例について後方視的に有害事象とその発現時期を検討した。卵巣癌は初発投与19例、再発投与29例の計48例、子宮頸癌は初発投与1例、再発投与11例の計12例を組み入れた。卵巣癌の年齢中央値は54歳(37〜76歳)、ベバシズマブ投与サイクル数中央値は15回(1〜68回)であった。子宮頸癌の年齢中央値は50歳(33〜68歳)、ベバシズマブ投与サイクル数中央値は5.5回(1〜10回)であった。卵巣癌48例中有害事象による投与中止例は4例あり、内訳は高度蛋白尿・ネフローゼ2例(4.2%)、腸炎1例(2.08%)、血栓塞栓症1例(2.08%)であった。子宮頸癌12例中有害事象による投与中止例は3例あり、全例血栓塞栓症(25%)であった。血液毒性、高血圧による投与中止例は認めず、出血および消化管穿孔、瘻孔は認めなかった。有害事象の発現時期について高度蛋白尿・ネフローゼは17、23サイクル終了時、血栓塞栓症はそれぞれ1、1、2、8サイクル終了時に認めた。高度蛋白尿・ネフローゼは投与数を重ねてから出現し、血栓塞栓症は投与開始後早期に認めた。検討した症例数は少ないものの、子宮頸癌では卵巣癌に比較して血栓塞栓症を多く認める可能性が示唆され、今後症例の蓄積が必要である。(著者抄録)

Within-Host Variations of Human Papillomavirus Reveal APOBEC Signature Mutagenesis in the Viral Genome

Hirose, Y., Onuki, M., Tenjimbayashi, Y., Mori, S., Ishii, Y., Takeuchi, T., Tasaka, N., Satoh, T., Morisada, T., Iwata, T., Miyamoto, S., Matsumoto, K., Sekizawa, A. and Kukimoto, I.

J Virol (Journal of Virology) 92 ( 12 ) 2018.06

ISSN 1098-5514

Persistent infection with oncogenic human papillomaviruses (HPVs) causes cervical cancer, accompanied by the accumulation of somatic mutations into the host genome. There are concomitant genetic changes in the HPV genome during viral infection; however, their relevance to cervical carcinogenesis is poorly understood. Here, we explored within-host genetic diversity of HPV by performing deep-sequencing analyses of viral whole-genome sequences in clinical specimens. The whole genomes of HPV types 16, 52, and 58 were amplified by type-specific PCR from total cellular DNA of cervical exfoliated cells collected from patients with cervical intraepithelial neoplasia (CIN) and invasive cervical cancer (ICC) and were deep sequenced. After constructing a reference viral genome sequence for each specimen, nucleotide positions showing changes with >0.5% frequencies compared to the reference sequence were determined for individual samples. In total, 1,052 positions of nucleotide variations were detected in HPV genomes from 151 samples (CIN1, n = 56; CIN2/3, n = 68; ICC, n = 27), with various numbers per sample. Overall, C-to-T and C-to-A substitutions were the dominant changes observed across all histological grades. While C-to-T transitions were predominantly detected in CIN1, their prevalence was decreased in CIN2/3 and fell below that of C-to-A transversions in ICC. Analysis of the trinucleotide context encompassing substituted bases revealed that TpCpN, a preferred target sequence for cellular APOBEC cytosine deaminases, was a primary site for C-to-T substitutions in the HPV genome. These results strongly imply that the APOBEC proteins are drivers of HPV genome mutation, particularly in CIN1 lesions.IMPORTANCE HPVs exhibit surprisingly high levels of genetic diversity, including a large repertoire of minor genomic variants in each viral genotype. Here, by conducting deep-sequencing analyses, we show for the first time a comprehensive snapshot of the within-host genetic diversity of high-risk HPVs during cervical carcinogenesis. Quasispecies harboring minor nucleotide variations in viral whole-genome sequences were extensively observed across different grades of CIN and cervical cancer. Among the within-host variations, C-to-T transitions, a characteristic change mediated by cellular APOBEC cytosine deaminases, were predominantly detected throughout the whole viral genome, most strikingly in low-grade CIN lesions. The results strongly suggest that within-host variations of the HPV genome are primarily generated through the interaction with host cell DNA-editing enzymes and that such within-host variability is an evolutionary source of the genetic diversity of HPVs.

Liquid-based cytology versus conventional cytology for detection of uterine cervical lesions: a prospective observational study

Nishio, H., Iwata, T., Nomura, H., Morisada, T., Takeshima, N., Takano, H., Sasaki, H., Nakatani, E., Teramukai, S. and Aoki, D.

Jpn J Clin Oncol (Japanese Journal of Clinical Oncology) 48 ( 6 ) 522 - 528 2018.06

ISSN 1465-3621

Objective: Liquid-based cytology (LBC) and conventional cytology (CS) are routine diagnostic techniques in cervical cytology, but few studies have compared their diagnostic performances with each other and with histologic diagnosis. This study aimed to compare the diagnostic performances of these techniques in subjects with abnormal cervical cytology of atypical cells of undetermined significance (ASC-US) or worse. Methods: A total of 312 patients diagnosed with ASC-US or worse were enrolled in this prospective study in Japan from 2013 to 2014. LBC and CS samples were prepared by a split-sampling technique and evaluated blindly. The results were classified using the Bethesda System 2001. Colposcopy and biopsy were conducted simultaneously or within 4 weeks of cytology-specimen collection in all cases. Diagnostic performance was calculated in terms of sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) for detection of CIN2 or worse, with a cut-off ASC-US or worse. Results: There was one unsatisfactory CS sample and the remaining 311 cases were evaluated. The sensitivities of LBC and CS were 100.0% and 98.8%, specificities were 17.2% and 23.8%, PPVs were 56.1% and 57.9% and NPVs were 100.0% and 94.7%, respectively. LBC had slightly higher sensitivity and NPV for detection of CIN2, but there was no significant difference between the two methods. Conclusions: There was no significant difference in the diagnostic performances of LBC and CS in patients with ASC-US or worse. LBC may therefore be an alternative approach to CS for cervical cancer screening.

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Postoperative chemotherapy for node-positive cervical cancer: Results of a multicenter phase II trial (JGOG1067)

Matoda, M., Takeshima, N., Michimae, H., Iwata, T., Yokota, H., Torii, Y., Yamamoto, Y., Takehara, K., Nishio, S., Takano, H., Mizuno, M., Takahashi, Y., Takei, Y., Hasegawa, T., Mikami, M., Enomoto, T., Aoki, D. and Sugiyama, T.

Gynecol Oncol 149 ( 3 ) 513 - 519 2018.06

ISSN 1095-6859

OBJECTIVE: This multicenter phase II Japanese Gynecologic Oncology Group study (JGOG1067) was designed to evaluate the efficacy and safety of postoperative chemotherapy in patients with node-positive cervical cancer. METHODS: Patients with stage IB-IIA squamous cervical cancer who underwent radical hysterectomy and were confirmed to have pelvic lymph node metastasis were eligible for this study. The patients postoperatively received irinotecan (CPT-11; 60mg/m(2) intravenously on days 1 and 8) and nedaplatin (NDP; 80mg/m(2) intravenously on day 1). Chemotherapy administration commenced within 6weeks after surgery and was repeated every 28days for up to 5cycles. The primary endpoint of this study was the 2-year recurrence-free survival (RFS) rate. The secondary endpoints were the 5-year overall survival (OS) rate, 5-year RFS rate, and adverse events such as complications of chemotherapy and lower-limb edema. RESULTS: Sixty-two patients were analyzed according to our protocol, among whom 55 (88.7%) completed 5cycles of scheduled treatment. The median follow-up period was 66.1months (range, 16.8-96.6months). The 2-year and 5-year RFS rates were 87.1% (95% confidence interval [CI]: 75.9-99.3) and 77.2% (95% CI: 64.5-85.8), respectively. Fourteen patients (22.5%) experienced recurrence during the follow-up period, 8 of whom died of the disease. The 5-year OS rate in this study was 86.5% (95% CI: 74.8-93.0). Only 9.7% of the patients experienced lymphedema in their legs. CONCLUSION: Postoperative chemotherapy without radiotherapy was found to be very effective in high-risk patients with node-positive cervical cancer.

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女性が健康で輝き続ける社会へ〜子宮頸がん克服へ向けて〜子宮頸がん検診における精度管理について

森定, 徹, 雑賀, 公美子, 河野, 加奈子, 齊藤, 英子, 田中, 恒成, 佐伯, 直彦, 仲村, 勝, 岩田, 卓, 田中, 京子, 斎藤, 博 and 青木, 大輔

関東連合産科婦人科学会誌 55 ( 2 ) 198 - 199 2018.05

ISSN 2186-0610

【エキスパートに聞く　合併症妊娠のすべて-妊娠前からのトータルケア】子宮頸癌

田中, 京子, 岩田, 卓 and 青木, 大輔

産科と婦人科 85 ( 5 ) 562 - 565 2018.05

ISSN 0386-9792

近年子宮頸癌の若年発症例が増加傾向で、晩婚化や未婚の増加、妊娠・出産年齢の高年齢化などに伴い、妊孕性温存の考慮や妊娠の合併など診断、治療に苦慮することがある。妊娠合併子宮頸癌の治療について「子宮頸癌治療ガイドライン(2017年版)」では臨床進行期にあわせて治療方針が推奨されているが、妊娠継続を強く希望された場合には胎児の週数、頸癌の進行期などを考慮し症例ごとに十分なインフォームド・コンセントが必要となる。胎児娩出の時期については胎児予後と母体予後について十分検討しなければならない。(著者抄録)

遺伝性乳癌卵巣癌症候群に対するリスク低減卵管卵巣摘出後の漢方療法に関する検討

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 and 青木, 大輔

産婦人科漢方研究のあゆみ (産婦人科漢方研究会) ( 35 ) 189 - 191 2018.04

ISSN 0913-865X

遺伝性乳癌卵巣癌症候群(hereditary breast and ovarian cancer syndrome:HBOC)は、BRCA1またはBRCA2(BRCA1/2)の生殖細胞系列変異(病的バリアント)が原因であり、家系内に乳癌や卵巣癌(卵管癌・腹膜癌含む)などが好発する。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%以上であり、現時点ではリスク低減卵管卵巣摘出術(risk-reducing salpingo-oophorectomy:RRSO)が卵巣癌発症リスクを減少させ全死亡率の低下を可能とすることから、最も確実な癌予防法とされている。しかしながら閉経前のRRSOは医原性の卵巣欠落症状を惹起するため、その術後の管理が重要である。本検討では当院でRRSOを施行した症例における術後の女性QOL管理について検討した。2008年から2016年までに当院にてRRSOを施行した8例を調査対象として、RRSO後の卵巣欠落症状の有無・血清脂質・骨密度検査について検討した。特に卵巣欠落症状に対する漢方薬を含めた介入につき後方視的に検討した。8例のうち7例が継続的に当院女性健康維持外来に受診をしており、7例全例(100%)で介入を施行されていた。術後に薬物治療を必要とする卵巣欠落症状を呈したのは5例(71%)で、いずれも術後に漢方治療を行っていた。なお6例で乳癌の既往があった。BRCA1/2遺伝子変異保持者に対するRRSOはわが国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ET療法が困難な例が存在し、症例によっては漢方療法が有効であると考えられた。(著者抄録)

Identifying a candidate population for ovarian conservation in young women with clinical stage IB-IIB cervical cancer

Matsuo, K., Shimada, M., Yamaguchi, S., Kanao, H., Nakanishi, T., Saito, T., Kamiura, S., Iwata, T., Mikami, M. and Sugiyama, T.

Int J Cancer (International Journal of Cancer) 142 ( 5 ) 1022 - 1032 2018.03

ISSN 1097-0215

This study seeks to identify risk factors associated with ovarian metastasis and to characterize a population with minimum risk of ovarian metastasis in young women with stage IB-IIB cervical cancer. This was a nation-wide multicenter retrospective study in Japan examining consecutive cases of surgically-treated women with clinical stage IB-IIB cervical cancer who had oophorectomy at radical hysterectomy (n = 5,697). Multivariable analysis was performed to identify independent risk factors for ovarian metastasis. Ovarian metastasis was seen in 70 (1.2%, 95% confidence interval 0.9-1.5) cases. In the entire cohort, adenocarcinoma, lympho-vascular space invasion, uterine corpus tumor invasion, and pelvic/para-aortic nodal metastases remained independent risk factors for ovarian metastasis (all, adjusted-p < 0.05). In a sensitivity analysis of 3,165 women aged <50 years (ovarian metastasis, 1.0%), adenocarcinoma, parametrial tumor involvement, uterine corpus tumor involvement, and pelvic/para-aortic nodal metastases remained independent risk factors for ovarian metastasis (all, adjusted-P < 0.05). In the absence of these five risk factors (representing 46.1% of women aged <50 years), the incidence of ovarian metastasis was 0.14%. With the presence of adenocarcinoma alone (representing 18.9% of women aged <50 years), the incidence of ovarian metastasis was 0.17% and was not associated with increased risk of ovarian metastasis compared to the subgroup without any risk factors (p = 0.87). In conclusion, nearly two thirds of women aged <50 years with clinical stage IB-IIB cervical cancer had no risk factor for ovarian metastasis or had adenocarcinoma alone: these subgroups had ovarian metastasis rates of around 0.1% and may be a candidate population for ovarian conservation at surgical treatment.

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合併増大号　今月の臨床産婦人科感染症の診断・管理─その秘訣とピットフォール HPV感染症 HPV検査の活用法

村上功, 岩田卓, 森定徹, 青木大輔

臨床婦人科産科 (株式会社医学書院) 72 ( 1 ) 150 - 157 2018.01

ISSN 0386-9865

Postoperative chemotherapy for node-positive cervical cancer :Results of a multicenter phase II trial (JGOG1067)

Iwata Takashi

Gynecologic Oncology 2018.01

Joint Work

【産婦人科感染症の診断・管理-その秘訣とピットフォール】HPV感染症 HPV検査の活用法

村上, 功, 岩田, 卓, 森定, 徹 and 青木, 大輔

臨床婦人科産科 72 ( 1 ) 150 - 157 2018.01

ISSN 0386-9865

HPV検査は,ハイリスクHPV一括検査とHPVタイピング検査に大別される.おのおのの特性および適応についての理解が必要である.HPV検査を取り入れた検診のメリットは,病変の発見感度の向上と検診間隔を延長できる可能性である.ただし特異度の問題,検診のマネジメント面での問題など,解決すべき問題点が存在する.子宮頸がん検診は一般市民に対してより一層の啓発活動や受診推進が必要である.さらに,検診手法の合理化や検診間隔の適正化についての検討も急務である.(著者抄録)

Prognostic factors and optimal therapy for stages I-II neuroendocrine carcinomas of the uterine cervix: A multi-center retrospective study

Ishikawa, M., Kasamatsu, T., Tsuda, H., Fukunaga, M., Sakamoto, A., Kaku, T., Nakanishi, T., Hasumi, Y., Iwata, T., Baba, T., Nogawa, T., Kudaka, W., Kaneda, H., Ono, S., Saito, F., Taniguchi, Y., Okada, S., Mizuno, M., Onda, T. and Yaegashi, N.

Gynecol Oncol (Gynecologic Oncology) 148 ( 1 ) 139 - 146 2018.01

ISSN 1095-6859

PURPOSE: We aimed to determine appropriate treatment guidelines for patients with stages I-II high-grade neuroendocrine carcinomas (HGNEC) of the uterine cervix in a multicenter retrospective study. PATIENTS AND METHODS: We reviewed the clinicopathological features and prognoses of 93 patients with HGNEC of International Federation of Gynecology and Obstetrics (FIGO) stages I and II. All patients were diagnosed with HGNEC by central pathological review. RESULTS: The median overall survival (OS) and disease-free survival (DFS) were 111.3months and 47.4months, respectively. Eighty-eight patients underwent radical surgery, and five had definitive radiotherapy. The hazard ratio (HR) for death after definitive radiotherapy to death after radical surgery was 4.74 (95% confidence interval [CI], 1.01-15.90). Of the surgery group, 18 received neoadjuvant chemotherapy. Pathological prognostic factors and optimal adjuvant therapies were evaluated for the 70 patients. Forty-one patients received adjuvant chemotherapy with etoposide-platinum (EP) or irinotecan-platinum (CPT-P). Multivariate analyses identified the invasion of lymphovascular spaces as a significant prognostic factor for both OS and DFS. Pelvic lymph node metastasis was also a prognostic factor for DFS. Adjuvant chemotherapy with an EP or CPT-P regimen appeared to improve DFS (HR=0.27, 95% CI, 0.10-0.69). A trend toward improved OS was also observed, but was not statistically significant (HR=0.39, 95% CI, 0.15-1.01). CONCLUSION: Radical surgery followed by adjuvant chemotherapy with an EP or CPT-P regimen was optimal treatment for stages I and II HGNEC of the uterine cervix.

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Involvement of local renin-angiotensin system in immunosuppression of tumor microenvironment

Nakamura, K., Yaguchi, T., Ohmura, G., Kobayashi, A., Kawamura, N., Iwata, T., Kiniwa, Y., Okuyama, R. and Kawakami, Y.

Cancer Sci (Cancer Science) 109 ( 1 ) 54 - 64 2018.01

ISSN 1349-7006

To improve current cancer immunotherapies, strategies to modulate various immunosuppressive cells including myeloid derived suppressor cells (MDSC) which were shown to be negative factors in immune-checkpoint blockade therapy, need to be developed. In the present study, we evaluated the role of the local renin-angiotensin system (RAS) in the tumor immune-microenvironment using murine models bearing tumor cell lines in which RAS was not involved in their proliferation and angiogenetic ability. Giving angiotensin II receptor blockers (ARB) to C57BL/6 mice bearing murine colon cancer cell line MC38 resulted in significant enhancement of tumor antigen gp70 specific T cells. ARB administration did not change the numbers of CD11b(+) myeloid cells in tumors, but significantly reduced their T-cell inhibitory ability along with decreased production of various immunosuppressive factors including interleukin (IL)-6, IL-10, vascular endothelial growth factor (VEGF), and arginase by CD11b(+) cells in tumors. ARB also decreased expression of immunosuppressive factors such as chemokine ligand 12 and nitric oxide synthase 2 in cancer-associated fibroblasts (CAF). Last, combination of ARB and anti-programmed death-ligand 1 (PD-L1) antibodies resulted in significant augmentation of anti-tumor effects in a CD8(+) T cell-dependent way. These results showed that RAS is involved in the generation of an immunosuppressive tumor microenvironment caused by myeloid cells and fibroblasts, other than the previously shown proliferative and angiogenetic properties of cancer cells and macrophages, and that ARB can transform the immunosuppressive properties of MDSC and CAF and could be used in combination with PD-1/PD-L1 immune-checkpoint blockade therapy.

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Human PBMC-transferred murine MHC class I/II-deficient NOG mice enable long-term evaluation of human immune responses

Yaguchi, T., Kobayashi, A., Inozume, T., Morii, K., Nagumo, H., Nishio, H., Iwata, T., Ka, Y., Katano, I., Ito, R., Ito, M. and Kawakami, Y.

Cell Mol Immunol (Cellular and Molecular Immunology) 15 ( 11 ) 953 - 962 2017.11

ISSN 2042-0226

Immunodeficient mice engrafted with human peripheral blood cells are promising tools for in vivo analysis of human patient individual immune responses. However, when human peripheral blood mononuclear cells (PBMCs) are transferred into NOG (NOD/Shi-scid, IL-2rg(null)) mice, severe graft versus host disease (GVHD) hinders long term detailed analysis. Administration of human PBMCs into newly developed murine MHC class I- and class II-deficient NOG (NOG-dKO; NOG- Iab, B2m-double-knockout) mice showed sufficient engraftment of human immune cells with little sign of GVHD. Immunization with influenza vaccine resulted in an increase in influenza-specific human IgG Ab, indicating induction of antigen-specific B cells in the NOG-dKO mice. Immunization with human dendritic cells pulsed with HLA-A2 restricted cytomegalovirus peptide induced specific cytotoxic T cells, indicating the induction of antigen-specific T cells in the NOG-dKO mice. Adoptive cell therapies (ACTs) using melanoma antigen recognized by T cells (MART-1)-specific TCR-transduced activated T cells showed strong tumor growth inhibition in NOG-dKO mice without any sign of GVHD accompanied by preferential expansion of the transferred MART-1-specific T cells. ACTs using cultured human melanoma infiltrating T cells also showed anti-tumor effects against autologous melanoma cells in NOG-dKO mice, in which changes in human cancer phenotypes by immune intervention, such as increased CD271 expression, could be evaluated. Therefore, NOG-dKO mice are useful tools for more detailed analysis of both the induction and effector phases of T-cell and B-cell responses for a longer period than regular NOG mice.Cellular & Molecular Immunology advance online publication, 20 November 2017; doi:10.1038/cmi.2017.106.

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Early impact of the Japanese immunization program implemented before the HPV vaccination crisis

Matsumoto, K., Yaegashi, N., Iwata, T., Yamamoto, K., Nagashima, M., Saito, T., Ushijima, K., Takahashi, F., Noda, K. and Yoshikawa, H.

Int J Cancer 141 ( 8 ) 1704 - 1706 2017.10

ISSN 1097-0215

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CITRUS, cervical cancer screening trial by randomization of HPV testing intervention for upcoming screening: Design, methods and baseline data of 18,471 women

Morisada, T., Teramoto, K., Takano, H., Sakamoto, I., Nishio, H., Iwata, T., Hashi, A., Katoh, R., Okamoto, A., Sasaki, H., Nakatani, E., Teramukai, S. and Aoki, D.

Cancer Epidemiol 50 ( Pt A ) 60 - 67 2017.10

ISSN 1877-783X

BACKGROUND: To assess the efficacy of screening with concurrent liquid-based cytology and human papillomavirus (HPV) testing for primary cervical cancer screening, we initiated a randomized trial entitled CervIcal cancer screening Trial by Randomization of HPV testing intervention for Upcoming Screening (CITRUS). METHODS: Between June 2013 and March 2015, women aged 30-64 years of age who participated in a regular cervical cancer screening program (every 2 years) were invited to enrollment of our study. After giving their informed consent, 18,402 women were randomly assigned to liquid-based cytology as the control group (n=9145) or to HPV DNA testing with liquid-based cytology as the intervention group (n=9257). We subsequently compared the incidence rate of cervical intraepithelial neoplasia (CIN), the rate of false positive tests and the rate of overdiagnosis, as well as assessing the risks and benefits of receiving screening for women in both groups. The primary outcome of our study was the incidence of cervical intraepithelial neoplasia grade 3 or worse (CIN3+) during the study period of around 6 years. RESULTS: In the control group, 97.9% of women were NILM, and 2.06% ASC-US or worse (ASC-US+). In the intervention group, 87.13% of women were NILM/HPV negative, 0.72% ASC-US/HPV negative, 10.34% NILM/HPV positive, 0.69% ASC-US/HPV positive, 0.90% worse than ASC-US/either HPV. Positive HPV testing was not linearly related to age in our study. CONCLUSIONS: Insights from CITRUS will provide future prospects for cervical cancer screening focused on the use of HPV testing in Japan. CLINICAL TRIAL REGISTRATION NUMBER: NCT01895517, UMIN000010843, TRIUC1312.

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【知らなきゃ困る　産婦人科小手術】 (第2章)小手術の実際とコツ　子宮頸部　子宮頸部レーザー蒸散術

岩田, 卓

産科と婦人科 84 ( Suppl. ) 149 - 153 2017.03

ISSN 0386-9792

A new marker, insulinoma-associated protein 1 (INSM1), for high-grade neuroendocrine carcinoma of the uterine cervix: Analysis of 37 cases

Kuji, S., Watanabe, R., Sato, Y., Iwata, T., Hirashima, Y., Takekuma, M., Ito, I., Abe, M., Nagashio, R., Omae, K., Aoki, D. and Kameya, T.

Gynecol Oncol 144 ( 2 ) 384 - 390 2017.02

ISSN 1095-6859

OBJECTIVE: High-grade neuroendocrine carcinoma of uterine cervix (HGNCUC) has been recognized as a highly malignant tumor. Therapeutic strategy specific to neuroendocrine (NE) tumors needs to be considered, but some cases wouldn't allow simple final diagnoses. Insulinoma-associated protein 1 (INSM1), which is a zinc-finger transcription factor related to NE differentiation, is frequently expressed in NE tumors. We investigated the association between INSM1 and HGNCUC, and the possibility of INSM1 as a useful NE marker. METHODS: Thirty-seven cases of formalin-fixed and paraffin-embedded HGNCUCs were evaluated immunohistochemically for conventional NE markers and INSM1. We also surveyed polymerase chain reactions and examined the frequency and the genotype of human papillomavirus (HPV) infections. RESULTS: In HGNCUC, chromogranin A, synaptophysin and neural cell adhesion molecule (NCAM) were expressed in 86%, 86% and 68%, respectively. In addition, INSM1 was detected in 95%. Positivity for INSM1 was clearly evaluated histologically, because the intensity of nuclear staining on positive cells was high and nonspecific reactions were minimal. In uni- and multivariate analyses of prognostic factors on stage I and II surgical cases, the association between INSM1 expression and prognosis was insignificant. We confirmed 72% of 29 examined cases had high risk HPV infections (type 16, 14%; type 18, 86%). CONCLUSIONS: This study has clarified that INSM1 is closely related to the development of HGNCUC, and a useful new NE marker in conducting its correct and rapid diagnosis.

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Whole-genome analysis of human papillomavirus genotypes 52 and 58 isolated from Japanese women with cervical intraepithelial neoplasia and invasive cervical cancer

Tenjimbayashi, Y., Onuki, M., Hirose, Y., Mori, S., Ishii, Y., Takeuchi, T., Tasaka, N., Satoh, T., Morisada, T., Iwata, T., Miyamoto, S., Matsumoto, K., Sekizawa, A. and Kukimoto, I.

Infect Agent Cancer 12 44 2017

ISSN 1750-9378

BACKGROUND: Human papillomavirus genotypes 52 and 58 (HPV52/58) are frequently detected in patients with cervical intraepithelial neoplasia (CIN) and invasive cervical cancer (ICC) in East Asian countries including Japan. As with other HPV genotypes, HPV52/58 consist of multiple lineages of genetic variants harboring less than 10% differences between complete genome sequences of the same HPV genotype. However, site variations of nucleotide and amino acid sequences across the viral whole-genome have not been fully examined for HPV52/58. The aim of this study was to investigate genetic variations of HPV52/58 prevalent among Japanese women by analyzing the viral whole-genome sequences. METHODS: The entire genomic region of HPV52/58 was amplified by long-range PCR with total cellular DNA extracted from cervical exfoliated cells isolated from Japanese patients with CIN or ICC. The amplified DNA was subjected to next generation sequencing to determine the complete viral genome sequences. Phylogenetic analyses were performed with the whole-genome sequences to assign variant lineages/sublineages to the HPV52/58 isolates. The variability in amino acid sequences of viral proteins was assessed by calculating the Shannon entropy scores at individual amino acid positions of HPV proteins. RESULTS: Among 52 isolates of HPV52 (CIN1, n = 20; CIN2/3, n = 21; ICC, n = 11), 50 isolates belonged to lineage B (sublineage B2) and two isolates belonged to lineage A (sublineage A1). Among 48 isolates of HPV58 (CIN1, n = 21; CIN2/3, n = 19; ICC, n = 8), 47 isolates belonged to lineage A (sublineages A1/A2/A3) and one isolate belonged to lineage C. Single nucleotide polymorphisms specific for individual variant lineages were determined throughout the viral genome based on multiple sequence alignments of the Japanese HPV52/58 isolates and reference HPV52/58 genomes. Entropy analyses revealed that the E1 protein was relatively variable among the HPV52 isolates, whereas the E7, E4, and L2 proteins showed some variations among the HPV58 isolates. CONCLUSIONS: Among the HPV52/58-positive specimens from Japanese women with CIN/ICC, the variant distributions were strongly biased toward lineage B for HPV52 and lineage A for HPV58 across histological categories. Different patterns of amino acid variations were observed in HPV52 and HPV58 across the viral whole-genome.

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Prospects for personalized combination immunotherapy for solid tumors based on adoptive cell therapies and immune checkpoint blockade therapies

Kato, D., Yaguchi, T., Iwata, T., Morii, K., Nakagawa, T., Nishimura, R. and Kawakami, Y.

Nihon Rinsho Meneki Gakkai Kaishi 40 ( 1 ) 68 - 77 2017

ISSN 1349-7413

Immune checkpoint blockade (ICB) and adoptive cell therapies (ACT) with antigen-receptor gene-engineered T cells have been shown to be successful for a limited number of patients with solid tumors. Responders to ICB therapy typically have T cell-inflamed tumors. Thus, it is important to develop strategies that convert non-T cell-inflamed tumors to T cell-inflamed tumors. Although chimeric antigen receptor transduced T (CAR-T) cell therapy targeting hematological malignancies demonstrated durable clinical responses, the success of gene-engineered T cell therapies in solid tumors is hampered by a lack of unique antigens, antigen loss in cancer cells, and the immune-suppressive tumor microenvironment (TME) of solid tumors. However, gene-engineered T cells possess strong killing activity and cytokine production capacity, which can induce antigen spreading and modulate the TME of non-T cell-inflamed tumors seen in non-responders to ICB therapy. Immune responses against cancer are highly heterogeneous, not only between tumor types, but also within a patient or between different patients with the same type of cancer, indicating that personalized immunotherapy should be employed, based on the immune status of the individual patient. Here, we offer our perspective for personalized combination immunotherapy for solid tumors based on ACT and ICB therapies.

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【妊孕性温存】各種がんと生殖機能温存　子宮頸がん

田中, 京子, 仲村, 勝, 森定, 徹, 岩田, 卓 and 青木, 大輔

HORMONE FRONTIER IN GYNECOLOGY 2016.12

わが国において子宮頸がんの罹患患者数は近年漸増傾向で、特に20〜30歳代の若年者の罹患数が年々増加傾向にあり、妊孕性温存希望の子宮頸がん症例が増加している。子宮頸部上皮内がんから臨床進行期IA1期で脈管侵襲や断端陽性などのリスクがない症例では円錐切除術のみで温存が可能であるが、IA2期以上はリンパ節郭清を含む子宮全摘出術の手術が推奨されている。近年、初期の浸潤子宮頸がんに対する妊孕性温存治療として広汎性子宮頸部摘出術が行われており、本稿では、子宮頸がんに対する妊孕性温存術式としての子宮頸部円錐切除術および広汎性子宮頸部摘出術について述べる。(著者抄録)

【機能温存と撲滅を目的とした子宮頸がんの診療ストラテジー】早期子宮頸癌に対する機能温存手術としての腹式広汎性子宮頸部摘出術

田中, 京子, 仲村, 勝, 森定, 徹, 岩田, 卓 and 青木, 大輔

産婦人科の実際 65 ( 11 ) 1547 - 1550 2016.10

ISSN 0558-4728

Comparison of methods using paraffin-embedded tissues and exfoliated cervical cells to evaluate human papillomavirus genotype attribution

Torii, Y., Fujii, T., Kukimoto, I., Saito, M., Iwata, T., Takahashi, H., Ichikawa, R., Kawai, S., Otani, S. and Aoki, D.

Cancer Sci 107 ( 10 ) 1520 - 1526 2016.10

ISSN 1349-7006

Monitoring the attribution of human papillomavirus (HPV) genotypes to cervical precancerous lesions is essential in assessing the efficacy of HPV vaccines. To resolve the lack of studies comparing the HPV genotyping procedures used to estimate HPV genotype attribution, we undertook a retrospective cross-sectional study to determine the appropriate genotyping procedures for evaluating the potential efficacy of HPV vaccines. Three procedures, including two different genotyping methods, Clinichip HPV test (C-Chip) and modified GP5+/6+ PCR coupled to fluorescent bead sorter detection (MGP), using exfoliated cervical cells (C-Chip and C-MGP, respectively) or formalin-fixed paraffin-embedded tissues (F-MGP), were compared. The overall agreement in detecting high-risk HPV was 88.5-92.1% among the three procedures, and genotype-specific agreement was 83.9-100% for all pairwise comparisons. In cervical intraepithelial neoplasia grade 2/3 specimens, HPV16/18 attribution estimated with the hierarchical attribution method was consistent among the procedures: 52.3% (45/86) for C-Chip, 54.7% (47/86) for C-MGP, and 52.3% (45/86) for F-MGP (P = 0.81). HPV16/18/31/33/45/52/58 hierarchical attribution was 88.4% (76/86) with C-Chip, 86.0% (74/86) with C-MGP, and 83.7% (72/86) with F-MGP (P = 0.49). In cervical intraepithelial neoplasia grade 3 specimens, the corresponding hierarchical attribution was 96.4% (53/55) with C-Chip, 89.1% (49/55) with C-MGP, and 94.5% (52/55) with F-MGP (P = 0.27). Although F-MGP is theoretically a reliable method for determining HPV genotype attribution, it is acceptable to use C-Chip or C-MGP, coupled to the hierarchical attribution formula to correct the bias of multiple infections. These approaches using exfoliated cervical cells are practical for monitoring the efficacy of HPV vaccines.

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Symptoms and effects of physical factors in Japanese middle-aged women

Yokota, M., Makita, K., Hirasawa, A., Iwata, T. and Aoki, D.

Menopause 23 ( 9 ) 974 - 83 2016.09

ISSN 1530-0374

OBJECTIVE: The aim of the study was to clarify the prevalence and severity rates of symptoms and investigate whether symptoms varied in relation to body mass index (BMI). METHODS: The study group composed of 1,969 women, aged 40 to 60 years, who presented at our department from 1993 through 2014. The participation rate was 98%. The presence or absence of symptoms was evaluated by having the participants complete the Keio Questionnaire, a self-administered questionnaire. To allow the results to be compared according to ovarian function, serum levels of follicle-stimulating hormone and estradiol were measured. Participants were classified into three groups according to BMI: underweight, normal weight, and overweight. Symptoms were also compared among these subgroups. RESULTS: The most common symptom was general fatigue. Vasomotor symptoms differed significantly between pre- and postmenopause status. When symptoms were analyzed according to BMI, the severity rates of the following symptoms were significantly higher in the overweight group than in the normal weight and underweight groups: hot flushes, sweats, joint pain, numbness, and incontinence. On the contrary, the underweight group had significantly higher severities of cold constitution, nervousness, and wrinkled skin than did the other groups. In addition, an increase in BMI was associated with an increased severity of vasomotor symptoms. CONCLUSIONS: The prevalence and severities of shoulder stiffness, considered a characteristic symptom in Japanese women, were high. Increased BMI was shown to be associated with a higher severity of vasomotor symptoms, joint pain, nervousness, and urinary symptoms.

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Neoadjuvant chemotherapy for locally advanced cervical cancer

Iwata, T., Miyauchi, A., Suga, Y., Nishio, H., Nakamura, M., Ohno, A., Hirao, N., Morisada, T., Tanaka, K., Ueyama, H., Watari, H. and Aoki, D.

Chin J Cancer Res 28 ( 2 ) 235 - 40 2016.04

ISSN 1000-9604

Neoadjuvant chemotherapy followed by surgery (NCS) has not been fully evaluated clinically. Currently, the main regimen of neoadjuvant chemotherapy (NAC) used in NCS includes cisplatin. The antitumor effects of NAC reduce lymph node metastasis and the tumor diameter in patients prior to surgery, and this can reduce the number of high risk patients who require postoperative radiation therapy. Many randomized controlled trials (RCTs) have examined the long-term prognosis of NCS compared to primary surgery, but the utility of NCS remains uncertain. The advent of concurrent chemoradiotherapy (CCRT) has markedly improved the outcome of radiotherapy (RT), and CCRT is now used as a standard method in many cases of advanced bulky cervical cancer. NCS gives a better treatment outcome than radiation therapy alone, but it is important to verify that NCS gives a similar or better outcome compared to CCRT.

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妊娠を契機に発見された浸潤子宮頸癌症例の検討

菅, 裕佳子, 西尾, 浩, 宮内, 安澄, 春日, 義史, 仲村, 勝, 森定, 徹, 岩田, 卓, 田中, 京子, 宮越, 敬, 田中, 守 and 青木, 大輔

関東連合産科婦人科学会誌 53 ( 1 ) 139 - 145 2016.03

ISSN 2186-0610

妊娠を契機に発見される子宮頸癌は子宮頸癌全体の2〜3%とされる.しかし,これらについての臨床的な取り扱いは明確でない.本研究では当院で治療を行った妊娠を契機に発見された浸潤子宮頸癌症例15例について診療録をもとに後方視的に検討を行った.全症例の内訳は,臨床進行期IB1期14例,IIB期1例,組織型は,扁平上皮癌10例,腺癌5例であった.診断の契機となった子宮頸部細胞診で細胞診異常が確認された時期は13例(87%)が1st trimesterであった.これに続き子宮頸部組織診または円錐切除術によって確定診断された時期は8例(53.3%)が1st trimester,7例(46.7%)が2nd trimesterであった.妊娠転帰は11例が妊娠を継続せず,速やかに広汎子宮全摘出術を行い,4例は本人希望により妊娠継続し,予定帝王切開術と広汎子宮全摘出術を同時に行った.この妊娠非継続例,継続例の2群間において妊娠初期子宮頸部細胞診,確定診断,広汎子宮全摘出術の各施行時期について解析を行った.その結果,それぞれの中央値は,非継続例では妊娠6週,12週,17週で,継続例では妊娠10週,18週,32週となり,細胞診施行時期は2群間で有意な差は認めず,確定診断については妊娠継続例で遅い傾向を認めた.妊娠初期スクリーニング検査で細胞診異常を認めた際には速やかな対応が重要であると考えられた.(著者抄録)

30歳未満で診断された浸潤子宮頸癌21例の検討

大石, 真希, 仲村, 勝, 國富, 晴子, 西尾, 浩, 森定, 徹, 岩田, 卓, 田中, 京子, 冨永, 英一郎, 田中, 守 and 青木, 大輔

東京産科婦人科学会会誌 65 ( 1 ) 12 - 16 2016.01

ISSN 2186-0599

本邦における若年層の子宮頸癌罹患者数は増加傾向にあることから、当院における30歳未満の子宮頸癌患者の臨床的特徴を検討した。2013年1月から2014年12月までの期間に30歳未満で治療を行った浸潤子宮頸癌症例を対象とし、診療録を元に後方視的検討を行った。浸潤子宮頸癌症例は237例あり、そのうち、30歳未満は21例であった。臨床進行期はI期20例、III期1例であり、組織型は扁平上皮癌が15例、腺癌が4例、腺扁平上皮癌が1例、すりガラス細胞癌が1例であった。診断の契機は、検診発見群は12例(57%)であり、その割合は30歳以上と同程度であった。外来発見群の腫瘍径は、30歳未満では30歳以上と比較して小さい傾向を認めた。妊孕性温存治療が可能であった症例は48%と低かった。検診発見群の方が妊孕性温存治療の可能性が高く、妊孕性温存が課題となる若年者における子宮頸がん検診の受診が望まれる。(著者抄録)

Pregnancy Outcomes After Abdominal Radical Trachelectomy for Early-Stage Cervical Cancer: A 13-Year Experience in a Single Tertiary-Care Center

Kasuga, Y., Nishio, H., Miyakoshi, K., Sato, S., Sugiyama, J., Matsumoto, T., Tanaka, K., Ochiai, D., Minegishi, K., Hamatani, T., Iwata, T., Morisada, T., Nakamura, M., Fujii, T., Kuji, N., Aoki, D. and Tanaka, M.

Int J Gynecol Cancer 26 ( 1 ) 163 - 168 2016.01

Joint Work, ISSN 1525-1438

To investigate pregnancy outcomes in women after abdominal radical trachelectomy (RT) for early-stage cervical cancer.|The patients' background, fertility, and pregnancy outcomes were reviewed in a total of 61 pregnancies in 48 of 172 women who underwent abdominal RT at Keio University Hospital between September 2002 and December 2013.|There were 5 women with stage IA1, 2 with stage IA2, and 41 with stage IB1. Histological types were as follows: squamous cell carcinoma (n = 36), adenocarcinoma (n = 10), and adenosquamous cell carcinoma (n = 2). The pregnancy rate of women attempting to conceive after abdominal RT was 44% (48/109). The mean ± SD duration from abdominal RT to conception was 3.1 ± 1.9 years. Of 61 pregnancies, 42 pregnancies were achieved by fertility treatment (in vitro fertilization-embryo transfer, 39; intrauterine insemination, 3). After excluding one pregnancy without detailed clinical information, there were 42 live births (5 in 22-27 weeks, 11 in 28-33weeks, 20 in 34-36 weeks, and 6 in 37-38 weeks), 13 miscarriages, and 5 ongoing pregnancies. While there were 10 first trimester miscarriages, 3 pregnancies ended in the second trimester owing to chorioamnionitis. The mean gestational age at birth was 33 weeks of pregnancy. Thirty-seven neonates were appropriate-for-date, and one was small-for-date. Six pregnancies exhibited massive bleeding from the residual cervix in the late pregnancy. Preterm birth less than 34 weeks of pregnancy was related to premature rupture of the membrane (P < 0.05). Chorioamnionitis was evident in 9 of 11 pregnancies with preterm premature rupture of the membrane followed by birth at less than 34 weeks of pregnancy. No parturients exhibited lochiometra and endometritis postpartum.|Abdominal RT provided favorable pregnancy outcomes, and fertility treatment could be advantageous to conception. Massive bleeding from the residual cervix as well as ascending infection might be characteristic features during pregnancy after abdominal RT.

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Human Papillomavirus Test for Triage of Japanese Women With Low-Grade Squamous Intraepithelial Lesions

Iwata, T., Hasegawa, T., Ochiai, K., Takizawa, K., Umezawa, S., Kuramoto, H., Ohmura, M., Kubushiro, K., Arai, H., Sakamoto, M., Motoyama, T., Watanabe, K. and Aoki, D.

Reprod Sci 22 ( 12 ) 1509 - 15 2015.12

ISSN 1933-7205

We evaluated high-risk human papillomavirus (HR-HPV) DNA testing for high-grade cervical intraepithelial neoplasia (CIN) lesions by cobas HPV test and diagnostic HPV16/18 genotyping in Japanese women with low-grade squamous intraepithelial lesions. Of 357 patients, HR-HPV positivity prevalence was 75.6%, and 21.3% had grade 2 or higher CIN lesions (CIN2+), with the highest prevalence at 30 to 34 years. Negative predictive values of HR-HPV for CIN2+ in our patients were 93.1% (any age) and 94.9% (40-50 years). Absolute risk for CIN2+ in HR-HPV positive and HPV16/18 positive individuals was 25.9 and 35.1, respectively. Relative risk for CIN2+ lesions was 5.1 for HPV16/18 positive versus HR-HPV negative, and 3.8 for HR-HPV positive versus HR-HPV negative women. Predictive values of CIN2+ positive were higher for HPV16/18 positive women (any age) than 12 other HPV positive-genotypes, and highest (50%) at 40-50 years. The HPV16/18 genotyping might prevent women (>40 years) at risk of high-grade CIN lesions from undergoing unnecessary colposcopy/overtreatment of nonprogressive lesions.

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Human leukocyte antigen class II DRB1*1302 allele protects against cervical cancer: At which step of multistage carcinogenesis?

Matsumoto, K., Maeda, H., Oki, A., Takatsuka, N., Yasugi, T., Furuta, R., Hirata, R., Mitsuhashi, A., Kawana, K., Fujii, T., Iwata, T., Hirai, Y., Yokoyama, M., Yaegashi, N., Watanabe, Y., Nagai, Y., Yoshikawa, H. and Group, Japan HPV and Cervical Cancer (JHACC) Study

Cancer Sci 106 ( 10 ) 1448 - 54 2015.10

ISSN 1349-7006

We investigated the role of human leukocyte antigen (HLA) class II alleles in multistage cervical carcinogenesis. Cross-sectional analysis for HLA association with cervical cancer included 1253 Japanese women: normal cytology (NL, n = 341), cervical intraepithelial neoplasia grade 1 (CIN1, n = 505), CIN grade 2 or 3 (CIN2/3, n = 96), or invasive cervical cancer (ICC, n = 311). The HLA class II allele frequencies were compared by Fisher's exact test or the χ(2) -test. The Bonferroni adjustment corrected for multiple comparisons. Among the study subjects, 454 women with low-grade squamous intraepithelial lesion cytology were prospectively monitored by cytology and colposcopy every 3-4 months to analyze cumulative risk of CIN3 within the next 10 years in relation to HLA class II alleles. HLA class II DRB1*1302 allele frequency was similar between women with NL (11.7%) and CIN1 (11.9%), but significantly decreased to 5.2% for CIN2/3 and 5.8% for ICC (P = 0.0003). Correction for multiple testing did not change this finding. In women with low-grade squamous intraepithelial lesion cytology, the cumulative risk of CIN3 diagnosed within 10 years was significantly reduced among DRB1*1302-positive women (3.2% vs. 23.7%, P = 0.03). In conclusion, the two different types of analysis in this single study showed the protective effect of the DRB1*1302 allele against progression from CIN1 to CIN2/3.

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Intratumoral CD8+ lymphocyte infiltration as a prognostic factor and its relationship with cyclooxygenase 2 expression and microsatellite instability in endometrial cancer

Suemori Tomohiro, Susumu Nobuyuki, Iwata Takashi, Banno Kouji, Yamagami Wataru, Hirasawa Akira, Sugano Kokichi, Matsumoto Eri, Aoki Daisuke

International Journal of Gynecological Cancer 25 ( 7 ) 1165 - 1172 2015.09

ISSN 1048-891X

Objective Microsatellite instability (MSI) is caused by a defective DNA mismatch repair system. Colorectal cancer in MSI-positive patients is characterized by an increased number of tumor-infiltrating lymphocytes. On the other hand, it has recently been reported that cyclooxygenase 2 (COX-2) suppresses antitumor immunity. The objectives of the present study were to clarify the relationships among MSI status, COX-2 expression, and antitumor immune status and to verify impact of these factors on the prognosis of endometrial cancer. Methods The data of 123 patients with endometrial cancer were analyzed. The numbers of tumor-infiltrating CD8+ T lymphocytes within cancer cell nests (TILs), as a representative of the antitumor immunity, and COX-2 expression levels in the tumor cells were analyzed by immunohistochemical staining. Microsatellite instability was evaluated by polymerase chain reaction analysis for 11 markers. Fisher exact probability test, Kaplan-Meier method, and proportional hazards analysis were used for the statistical analyses. Results The MSI-positive tumors showed significantly higher grades (G2 or G3) and significantly larger numbers of TILs than did the MSI-negative tumors. The COX-2-high group showed significantly fewer TILs than did the COX-2-low group. Multivariate analysis identified a low number of TILs (<10), positive lymph node involvement, and high tumor malignancy grade as factors independently associated with poor prognosis. The prognosis was significantly poorer in the patients with MSI-positive tumors with high COX-2 expression than in those with MSI-positive tumors showing low COX-2 expression. Conclusions The number of TILs, which was increased by MSI and decreased by COX-2 expression, was associated with a poorer prognosis in patients with endometrial cancer. We also propose that COX-2 may block MSI-activated TILs in the tumor microenvironment.

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Polymorphisms of estrogen metabolism-related genes ESR1, UGT2B17, and UGT1A1 are not associated with osteoporosis in surgically menopausal Japanese women

Yokota, M., Hirasawa, A., Makita, K., Akahane, T., Sakai, K., Makabe, T., Horiba, Y., Yamagami, W., Ogawa, M., Iwata, T., Yanamoto, S., Deshimaru, R., Banno, K., Susumu, N. and Aoki, D.

Prz Menopauzalny 14 ( 3 ) 161 - 7 2015.09

ISSN 1643-8876

Bilateral salpingo-oophorectomy (BSO) is a risk factor for osteoporosis. Previous studies have reported an association between genetic polymorphisms and the risk of developing osteoporosis. However, the relationship between osteoporosis and genetic polymorphisms in Japanese women treated with BSO is not well understood. To improve the quality of life for post-BSO patients, it is important to determine the genetic factors that influence their risk for osteoporosis. The aim of this study was to investigate the association between gene variations of estrogen metabolism-related genes and osteoporosis in surgically menopausal patients, which may improve their quality of life.|This study included 203 menopausal women treated with BSO because of gynecologic disorders. One hundred and twenty-six women with artificial (surgical) menopause, who had undergone BSO in the premenopausal period, were compared with 77 women with natural menopause, who had undergone BSO in the postmenopausal period. The women were tested for bone mineral density to diagnose osteoporosis. Polymorphisms of estrogen receptor 1 (ESR1) and UDP-glucuronosyl transferase (UGT) genes UGT2B17 and UGT1A1 were analyzed, and their association with bone mass and osteoporosis was statistically evaluated.|No significant association was found between osteoporosis and polymorphisms in ESR1, UGT2B17, or UGT1A1 in both groups, suggesting that BSO might be a more significant physiological factor in influencing bone mass density compared to genetic variations.|These results suggest that the ESR1, UGT2B17, and UGT1A1 polymorphisms are not genetic factors affecting osteoporosis in postmenopausal Japanese women.

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婦人科手術と後腹膜解剖　CT画像より得られた膀胱側腔、直腸側腔の画像情報をもとに考察した広汎子宮全摘出術

仲村勝, 西尾浩, 森定徹, 岩田卓, 田中京子, 今西宣晶, 陣崎雅弘, 相磯貞和, 藤井多久磨, 青木大輔

産婦人科手術 ( 26 ) 71 - 78 2015.06

ISSN 0915-8375

未固定遺体のマルチスライスCTで得た0.3125mmスライス幅の連続断層画像を、三次元構築ソフトにて3D再構築を行うことで、系統解剖では理解が難しかった解剖構造を示すことができた。3Dモデルでは基靱帯、膀胱側腔、直腸側腔が確認でき、実際の手術風景と近似していた。第2仙椎の高さでは、直腸側腔が後腹膜と骨盤側壁の間に見られ、第2仙骨神経前枝が直腸側腔の深部にあり、直腸側腔深部の扱いに注意が必要と考えられた。第3仙椎の高さでは、基靱帯が内腸骨血管と子宮との間にあり、基靱帯の腹側に膀胱側腔、背側に直腸側腔を認めた。第4仙椎の高さでは、膀胱側腔は豊富な脂肪組織を含み、内閉鎖筋と基靱帯の間に示され、直腸側腔は内腸骨血管と仙骨子宮靱帯との間に示された。骨盤神経叢は直腸側腔の底部と仙骨子宮靱帯のすぐ外側に認めた。恥骨の高さでは、膀胱側腔の外側、背側に内閉鎖筋と肛門挙筋が存在し、膀胱側腔は尿道近くまで展開していた。

Effects of chemotherapy on patients with recurrent cervical cancer previously treated with concurrent chemoradiotherapy: a retrospective multicenter survey in Japan

Tokunaga, H., Nakanishi, T., Iwata, T., Aoki, D., Saito, T., Nagase, S., Takahashi, F., Yaegashi, N. and Watanabe, Y.

International Journal of Clinical Oncology 20 ( 3 ) 561 - 565 2015.06

ISSN 1341-9625

Predictive factors of the efficacy of chemotherapy for Japanese patients with recurrent cervical cancer who have been previously treated with concurrent chemoradiotherapy (CCRT) are currently unknown, and hence we aimed to investigate this. We retrospectively studied the prognostic outcomes of patients with recurrent cervical cancer treated with CCRT between 2002 and 2010 at four medical facilities. A total of 64 patients were included in this study. Forty-two patients received definitive CCRT and 22 patients received postoperative adjuvant CCRT, with 55 receiving platinum-based combination chemotherapy and nine receiving single-agent chemotherapy. The overall response rate (ORR) was 12.5 %, with one complete response. The median survival period was 12 months. The ORR and overall survival rate did not differ significantly according to recurrence site, post-CCRT interval, or chemotherapy regimen. None of the factors analyzed in this study were identified as positive predictive factors for the efficacy of chemotherapy in patients with recurrent cervical cancer after CCRT. Based on the results of previous studies, in order to improve long-term prognosis in recurrent cases, adjuvant chemotherapy should be considered as a potential treatment option for selected patients, especially as postoperative adjuvant therapy.

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Aberrant myosin 1b expression promotes cell migration and lymph node metastasis of HNSCC

Ohmura Gaku, Tsujikawa Takahiro, Yaguchi Tomonori, Kawamura Naoshi, Mikami Shuji, Sugiyama Juri, Nakamura Kenta, Kobayashi Asuka, Iwata Takashi, Nakano Hiroshi, Shimada Taketoshi, Hisa Yasuo, Kawakami Yutaka

Molecular Cancer Research 13 ( 4 ) 721 - 731 2015.04

ISSN 1541-7786

Lymph node metastasis is the major clinicopathologic feature associated with poor prognosis in patients with head and neck squamous cell carcinoma (HNSCC). Here, web-based bioinformatics meta-analysis was performed to elucidate the molecular mechanism of lymph node metastasis of human HNSCC. Preferential upregulation of Myosin 1b (MYO1B) transcript in HNSCC datasets was identified. Myo1b mRNA was highly expressed in human HNSCC cells and patient tissue specimens compared with their normal counterparts as shown by quantitative PCR (qPCR) analyses. Immunohistochemistry (IHC)-detected Myo1b expression was significantly correlated with lymph node metastases in patients with oral cancer of the tongue. HNSCC with high expression of Myo1b and chemokine receptor 4 (CCR4), another metastasis-associated molecule, was strongly associated with lymph node metastasis. RNA interference (RNAi) of Myo1b in HNSCC cells, SAS and HSC4, significantly inhibited migratory and invasive abilities through decreased large protrusion formation of cell membranes. Finally, Myo1b knockdown in SAS cells significantly inhibited in vivo cervical lymph nodemetastases in a cervical lymph node metastatic mouse model system. Implications: Myo1b is functionally involved in lymph node metastasis of human HNSCC through enhanced cancer cell motility and is an attractive target for new diagnostic and therapeutic strategies for patients with HNSCC. Mol Cancer Res; 13(4); 721-31.

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Cytokine profile in cervical mucosa of Japanese patients with cervical intraepithelial neoplasia

Iwata Takashi, Fujii Takuma, Morii Kenji, Saito Miyuki, Sugiyama Juri, Nishio Hiroshi, Morisada Tohru, Tanaka Kyoko, Yaguchi Tomonori, Kawakami Yutaka, Aoki Daisuke

International Journal of Clinical Oncology 20 ( 1 ) 126 - 133 2015.02

ISSN 1341-9625

BACKGROUND: Immune responses in the uterine cervix are considered to play an important role in persistent human papillomavirus (HPV) infection and carcinogenesis, but many aspects of the mechanism are still unclear. The goal of this study was to measure cytokines to analyze immune responses in patients with cervical intraepithelial neoplasia (CIN).MATERIALS AND METHODS: The levels of 17 cytokines (IL-1β, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-10, IL-12, IL-13, IL-17, G-CSF, GM-CSF, INF-γ, MCP-1, MIP-1β, and TNFα) in cervical mucus were simultaneously measured using a multiplex immunoassay in 52 high-grade squamous intraepithelial lesion (HSIL) cases and overproduction of IL-1β, IL-8, and MIP-1β was identified. The levels of these 3 cytokines were measured in 130 patients with or without CIN lesions using enzyme-linked immunosorbent assay. The associations of the cytokine levels with the cytology, infecting HPV type, and status of cigarette smoking were investigated.RESULTS: IL-1β and IL-8 levels were associated with the cytology, and these levels were higher in HSIL cases than in NILM (negative for intraepithelial lesion and malignancy) and LSIL (low-grade squamous intraepithelial lesion) cases (P = 0.005, P = 0.001, respectively). The MIP-1β level was significantly lower in smokers (P = 0.018) and high-risk (HR)-HPV-infected patients (P = 0.021).CONCLUSIONS: Enhanced expression of IL-1β and IL-8 indicates that Th2 inflammatory responses become stronger in the local uterine cervical region with the progression of CIN lesions, and a decrease in the MIP-1β level may be advantageous for immunoescape of HPV. Cigarette smoking may further facilitate persistent HPV infection.

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Performance of p16INK4a/Ki-67 immunocytochemistry for identifying CIN2+ in atypical squamous cells of undetermined significance and low-grade squamous intraepithelial lesion specimens: a Japanese Gynecologic Oncology Group study

Fujii, T., Saito, M., Hasegawa, T., Iwata, T., Kuramoto, H., Kubushiro, K., Ohmura, M., Ochiai, K., Arai, H., Sakamoto, M., Motoyama, T. and Aoki, D.

Int J Clin Oncol 20 ( 1 ) 134 - 42 2015.02

ISSN 1437-7772

p16(INK4a) immunohistochemistry has revealed a high rate of positivity in cervical intraepithelial neoplasia grade 2 (CIN2) and more severe conditions (CIN2+). The Lower Anogenital Squamous Terminology Standardization project proposed p16(INK4a) immunohistochemistry as an ancillary test for CIN. Immunocytochemistry involving dual staining for p16(INK4a) and Ki-67 in the triage of atypical squamous cells of undetermined significance (ASCUS) and low-grade squamous intraepithelial lesions (LSIL) is reported to be useful in the identification of CIN2+. However, it is unclear whether p16(INK4a)/Ki-67 immunocytochemistry is of practical relevance for the triage of ASCUS and LSIL in the Japanese screening system.|From 427 women fulfilling the eligibility criteria, 188 ASCUS and 239 LSIL specimens were analyzed. The accuracy of p16(INK4a)/Ki-67 immunocytochemistry and genotyping of high-risk human papillomaviruses (HPVs) in detecting CIN2+ were compared.|p16(INK4a)/Ki-67 immunocytochemistry was positive in 33.5 % (63/188) of ASCUS, and 36.8 % (88/239) of LSIL specimens. The sensitivity and specificity of p16(INK4a)/Ki-67 immunocytochemistry was 87.3 % (95 % confidence interval 78.0-93.8 %) and 76.4 % (71.6-80.8 %), respectively. The positive and negative predictive values were 45.7 % (37.6-54.0 %) and 96.4 % (93.4-98.3 %), respectively; positive and negative likelihood ratios were 3.71 and 0.17, respectively. Using the McNemar test, p16(INK4a)/Ki-67 immunocytochemistry showed equivalent sensitivity but higher specificity than the HPV genotyping test|Compared with high-risk HPV genotyping, p16(INK4a)/Ki-67 immunocytochemistry was a more accurate triage test for identifying CIN2+ in ASCUS and LSIL specimens.

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【ゲノム時代の婦人科がん診療を展望する-がんの個性に応じたpersonalizationへの道】　子宮頸がん若年子宮頸がんに対する妊孕能温存手術の個別化

西尾浩, 田中京子, 岩田卓, 青木大輔

臨床婦人科産科 69 ( 1 ) 53 - 58 2015

ISSN 0386-9865

Monitoring the impact of a national HPV vaccination program in Japan (MINT Study)

Matsumoto Koji, Yaegashi Nobuo, Iwata Takashi, Ariyoshi Kazuya, Fujiwara Kiyoshi, Shiroyama Yuko, Usami Tomoka, Kawano Yoshiaki, Horie Koji, Kawano Kouichiro, Noda Kiichiro, Yoshikawa Hiroyuki

Japanese Journal of Clinical Oncology 44 ( 10 ) 1000 - 1003 2014.10

ISSN 0368-2811

We have developed a collaborative hospital-based approach to monitoring the impact of a human papillomavirus vaccine on cervical cancer, its precursor lesions and human papillomavirus type-specific prevalence in Japan. The monitoring will be conducted for a total period of 21 years on women aged <40 who are newly diagnosed with invasive cervical cancer, cervical intraepithelial neoplasia or adenocarcinoma in situ at 21 participating institutes. Women are monitored to determine their vaccine history and will be human papillomavirus-genotyped each year. The primary endpoint is the human papillomavirus16/human papillomavirus18-positive rate in women aged 16-25 who are diagnosed with invasive cervical cancer, cervical intraepithelial neoplasia grade 2/3 and adenocarcinoma in situ. The major secondary endpoints are the number of women aged <40 who are diagnosed with invasive cervical cancer, cervical intraepithelial neoplasia grade 2/3 and adenocarcinoma in situ, the human papillomavirus type-specific prevalence, and the number of deaths from invasive cervical cancer in women aged <40. Long-term surveillance for human papillomavirus-associated cervical diseases in young females is important for the development of future strategies for cervical cancer prevention in Japan.

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Human papillomavirus genotype distribution in cervical intraepithelial neoplasia grade 2/3 and invasive cervical cancer in Japanese women

Azuma Yukari, Kusumoto-Matsuo Rika, Takeuchi Fumihiko, Uenoyama Asami, Kondo Kazunari, Tsunoda Hajime, Nagasaka Kazunori, Kawana Kei, Morisada Tohru, Iwata Takashi, Aoki Daisuke, Kukimoto Iwao

Japanese Journal of Clinical Oncology 44 ( 10 ) 910 - 917 2014.10

OBJECTIVE: Human papillomavirus vaccines are being introduced worldwide and are expected to reduce the incidence of cervical cancer. Here we report a cross-sectional study using a validated human papillomavirus genotyping method to reveal the human papillomavirus prevalence and genotype distribution in Japanese women with cervical intraepithelial neoplasia Grade 2/3 and invasive cervical cancer.METHODS: Cervical exfoliated cells were collected from 647 patients with abnormal cervical histology (cervical intraepithelial neoplasia Grade 2, n = 164; cervical intraepithelial neoplasia Grade 3, n = 334; and invasive cervical cancer, n = 149), and subjected to the PGMY-PCR-based genotyping assay. The association between human papillomavirus infection and lesion severity was calculated using a prevalence ratio.RESULTS: Overall, the prevalence of human papillomavirus deoxyribonucleic acid was 96.3% in cervical intraepithelial neoplasia Grade 2, 98.8% in cervical intraepithelial neoplasia Grade 3 and 88.0% in invasive cervical cancer (97.8% in squamous cell carcinoma and 71.4% in adenocarcinoma). The three most prevalent types were as follows: human papillomavirus 16 (29.3%), human papillomavirus 52 (27.4%) and human papillomavirus 58 (22.0%) in cervical intraepithelial neoplasia Grade 2; human papillomavirus 16 (44.9%), human papillomavirus 52 (26.0%) and human papillomavirus 58 (17.4%) in cervical intraepithelial neoplasia Grade 3; and human papillomavirus 16 (47.7%), human papillomavirus 18 (23.5%) and human papillomavirus 52 (8.7%) in invasive cervical cancer. The prevalence ratio of human papillomavirus 16 was significantly higher in cervical intraepithelial neoplasia Grade 3 compared with cervical intraepithelial neoplasia Grade 2 (prevalence ratio, 1.62; 95% confidence interval, 1.26-2.13) and in squamous cell carcinoma compared with cervical intraepithelial neoplasia Grade 3 (prevalence ratio, 1.55; 95% confidence interval, 1.25-1.87). Multiple infections decreased from cervical intraepithelial neoplasia Grade 2/3 (38.4/29.6%) to invasive cervical cancer (14.1%), whereas co-infections with human papillomavirus 16/52/58 were found in cervical intraepithelial neoplasia Grade 2/3.CONCLUSIONS: The results of this study provide pre-vaccination era baseline data on human papillomavirus type distribution in Japanese women and serve as a reliable basis for monitoring the future impact of human papillomavirus vaccination in Japan.

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Monitoring the impact of a national HPV vaccination program in Japan (MINT Study): rationale, design and methods

Matsumoto, K., Yaegashi, N., Iwata, T., Ariyoshi, K., Fujiwara, K., Shiroyama, Y., Usami, T., Kawano, Y., Horie, K., Kawano, K., Noda, K., Yoshikawa, H. and Group, MINT Study

Jpn J Clin Oncol 44 ( 10 ) 1000 - 3 2014.10

ISSN 1465-3621

We have developed a collaborative hospital-based approach to monitoring the impact of a human papillomavirus vaccine on cervical cancer, its precursor lesions and human papillomavirus type-specific prevalence in Japan. The monitoring will be conducted for a total period of 21 years on women aged <40 who are newly diagnosed with invasive cervical cancer, cervical intraepithelial neoplasia or adenocarcinoma in situ at 21 participating institutes. Women are monitored to determine their vaccine history and will be human papillomavirus-genotyped each year. The primary endpoint is the human papillomavirus16/human papillomavirus18-positive rate in women aged 16-25 who are diagnosed with invasive cervical cancer, cervical intraepithelial neoplasia grade 2/3 and adenocarcinoma in situ. The major secondary endpoints are the number of women aged <40 who are diagnosed with invasive cervical cancer, cervical intraepithelial neoplasia grade 2/3 and adenocarcinoma in situ, the human papillomavirus type-specific prevalence, and the number of deaths from invasive cervical cancer in women aged <40. Long-term surveillance for human papillomavirus-associated cervical diseases in young females is important for the development of future strategies for cervical cancer prevention in Japan.

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Human papillomavirus genotype distribution in cervical intraepithelial neoplasia grade 2/3 and invasive cervical cancer in Japanese women

Azuma, Y., Kusumoto-Matsuo, R., Takeuchi, F., Uenoyama, A., Kondo, K., Tsunoda, H., Nagasaka, K., Kawana, K., Morisada, T., Iwata, T., Aoki, D. and Kukimoto, I.

Jpn J Clin Oncol 44 ( 10 ) 910 - 7 2014.10

ISSN 1465-3621

Human papillomavirus vaccines are being introduced worldwide and are expected to reduce the incidence of cervical cancer. Here we report a cross-sectional study using a validated human papillomavirus genotyping method to reveal the human papillomavirus prevalence and genotype distribution in Japanese women with cervical intraepithelial neoplasia Grade 2/3 and invasive cervical cancer.|Cervical exfoliated cells were collected from 647 patients with abnormal cervical histology (cervical intraepithelial neoplasia Grade 2, n = 164; cervical intraepithelial neoplasia Grade 3, n = 334; and invasive cervical cancer, n = 149), and subjected to the PGMY-PCR-based genotyping assay. The association between human papillomavirus infection and lesion severity was calculated using a prevalence ratio.|Overall, the prevalence of human papillomavirus deoxyribonucleic acid was 96.3% in cervical intraepithelial neoplasia Grade 2, 98.8% in cervical intraepithelial neoplasia Grade 3 and 88.0% in invasive cervical cancer (97.8% in squamous cell carcinoma and 71.4% in adenocarcinoma). The three most prevalent types were as follows: human papillomavirus 16 (29.3%), human papillomavirus 52 (27.4%) and human papillomavirus 58 (22.0%) in cervical intraepithelial neoplasia Grade 2; human papillomavirus 16 (44.9%), human papillomavirus 52 (26.0%) and human papillomavirus 58 (17.4%) in cervical intraepithelial neoplasia Grade 3; and human papillomavirus 16 (47.7%), human papillomavirus 18 (23.5%) and human papillomavirus 52 (8.7%) in invasive cervical cancer. The prevalence ratio of human papillomavirus 16 was significantly higher in cervical intraepithelial neoplasia Grade 3 compared with cervical intraepithelial neoplasia Grade 2 (prevalence ratio, 1.62; 95% confidence interval, 1.26-2.13) and in squamous cell carcinoma compared with cervical intraepithelial neoplasia Grade 3 (prevalence ratio, 1.55; 95% confidence interval, 1.25-1.87). Multiple infections decreased from cervical intraepithelial neoplasia Grade 2/3 (38.4/29.6%) to invasive cervical cancer (14.1%), whereas co-infections with human papillomavirus 16/52/58 were found in cervical intraepithelial neoplasia Grade 2/3.|The results of this study provide pre-vaccination era baseline data on human papillomavirus type distribution in Japanese women and serve as a reliable basis for monitoring the future impact of human papillomavirus vaccination in Japan.

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Candidate biomarkers for cervical cancer treatment: Potential for clinical practice (Review)

Iida, M., Banno, K., Yanokura, M., Nakamura, K., Adachi, M., Nogami, Y., Umene, K., Masuda, K., Kisu, I., Iwata, T., Tanaka, K. and Aoki, D.

Mol Clin Oncol 2 ( 5 ) 647 - 655 2014.09

ISSN 2049-9450

Cervical cancer ranks high among the causes of female cancer mortalities and is an important disease in developing and developed countries. Current diagnosis of cervical cancer depends on colposcopy, pathological diagnosis and preoperative diagnosis using methods, including magnetic resonance imaging and computed tomography. Advanced cervical cancer has a poor prognosis. The tumor marker squamous cell carcinoma is conventionally used for screening, but recent studies have revealed the mechanisms of carcinogenesis and the factors associated with a poor prognosis in cervical cancer. These include epigenetic biomarkers, with the methylation level of the checkpoint with forkhead and ring finger gene being potentially useful for predicting the malignancy of cervical cancer and sensitivity to treatment with paclitaxel. The extent of methylation of the Werner DNA helicase gene is also useful for determining sensitivity to an anticancer agent, CPT-11. In addition to epigenetic changes, the expression levels of hypoxia-inducible factor 1α subunit, epidermal growth factor receptor and cyclooxygenase-2 have been reported as possible biomarkers in cervical cancer. Novel prognostic factors, including angiogenic factors, fragile histidine triad, thymidylate synthase, glucose-related protein 58 and mucin antigens, have also been described, and hemoglobin and platelets may also be significant prognostic biomarkers. Utilization of these biomarkers may facilitate personalized treatment and improved outcomes in cervical cancer.

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子宮頸部円錐切除術後の出血に関する検討

渡邊, 慶子, 西尾, 浩, 冨永, 英一郎, 岩田, 卓, 杉山, 重里, 森定, 徹, 田中, 京子, 吉村, 泰典 and 青木, 大輔

東京産科婦人科学会会誌 63 ( 3 ) 394 - 399 2014.07

ISSN 2186-0599

子宮頸部円錐切除術は主に診断の確定のために行われ、異形成・上皮内癌の場合は治療法ともなりうる侵襲の少ない術式であるが、術後出血を認める例が少なくない。そこで今回、円錐切除術後の出血に関する検討を後方視的に行った。2012年1月から12月に当科での施行症例は228例であり、年齢・手術時間の中央値は39歳、22分であった。手術後に止血処置を要した症例(止血群)は21例(9.2%)、術後日数(中央値)は13日であった。このうち、4例で縫合止血を要し、17例では止血剤散布とガーゼ圧迫での止血が可能であった。年齢・手術時間は、止血群と非止血群で有意差を認めなかったが、止血群で年齢が高い傾向を認めた。使用器具や出産経験による出血の頻度に違いは認めなかった。子宮頸部円錐切除術は、術後1〜2週間を中心に約1割の症例で止血処置を要するため、出血に関する情報提供を行う必要がある。(著者抄録)

Immunosuppression through constitutively activated NF-κB signalling in human ovarian cancer and its reversal by an NF-κB inhibitor

Nishio H., Yaguchi T., Sugiyama J., Sumimoto H., Umezawa K., Iwata T., Susumu N., Fujii T., Kawamura N., Kobayashi A., Park J., Aoki D., Kawakami Y.

British Journal of Cancer 110 ( 12 ) 2965 - 2974 2014.06

ISSN 0007-0920

Background:Although T-cell immunity is thought to be involved in the prognosis of epithelial ovarian cancer (EOC) patients, immunosuppressive conditions hamper antitumour immune responses. Thus, their mechanisms and overcoming strategies need to be investigated.Methods:The role of NF-κB in human EOC cells and macrophages was evaluated by in vitro production of immunosuppressive IL-6 and IL-8 by EOC cells and in vivo analysis of immune responses in nude mice implanted with human EOC cells using an NF-κB inhibitor DHMEQ.Results:In EOC patients, increased plasma IL-6, IL-8, and arginase were observed. The NF-κB inhibitor DHMEQ inhibited the production of IL-6 and IL-8 by EOC cell lines. Immunosuppression of human DCs and macrophages by culture supernatant of EOC cells was reversed with the pretreatment of DHMEQ. Administration of DHMEQ to nude mice implanted with human EOC resulted in the restoration of T-cell stimulatory activity of murine DCs along with the reduction of tumour accumulation and arginase expression of MDSCs. Nuclear factor-κB inhibition in tumour-bearing mice also enhanced antitumour effects of transferred murine naive T cells.Conclusions:NF-κB is involved in the immunosuppression induced by human EOC, and its inhibitor may restore antitumour immune responses, indicating that NF-κB is an attractive target for EOC treatment. © 2014 Cancer Research UK.

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Immunosuppression through constitutively activated NF-κB signalling in human ovarian cancer and its reversal by an NF-κB inhibitor

Nishio, H., Yaguchi, T., Sugiyama, J., Sumimoto, H., Umezawa, K., Iwata, T., Susumu, N., Fujii, T., Kawamura, N., Kobayashi, A., Park, J., Aoki, D. and Kawakami, Y.

Br J Cancer 110 ( 12 ) 2965 - 74 2014.06

ISSN 1532-1827

Although T-cell immunity is thought to be involved in the prognosis of epithelial ovarian cancer (EOC) patients, immunosuppressive conditions hamper antitumour immune responses. Thus, their mechanisms and overcoming strategies need to be investigated.|The role of NF-κB in human EOC cells and macrophages was evaluated by in vitro production of immunosuppressive IL-6 and IL-8 by EOC cells and in vivo analysis of immune responses in nude mice implanted with human EOC cells using an NF-κB inhibitor DHMEQ.|In EOC patients, increased plasma IL-6, IL-8, and arginase were observed. The NF-κB inhibitor DHMEQ inhibited the production of IL-6 and IL-8 by EOC cell lines. Immunosuppression of human DCs and macrophages by culture supernatant of EOC cells was reversed with the pretreatment of DHMEQ. Administration of DHMEQ to nude mice implanted with human EOC resulted in the restoration of T-cell stimulatory activity of murine DCs along with the reduction of tumour accumulation and arginase expression of MDSCs. Nuclear factor-κB inhibition in tumour-bearing mice also enhanced antitumour effects of transferred murine naive T cells.|NF-κB is involved in the immunosuppression induced by human EOC, and its inhibitor may restore antitumour immune responses, indicating that NF-κB is an attractive target for EOC treatment.

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Application of microRNA in the treatment and diagnosis of cervical cancer

Banno Kouji, Iida Miho, Yanokura Megumi, Kisu Iori, Nakamura Kanako, Adachi Masataka, Iwata Takashi, Tanaka Kyoko, Aoki Daisuke

129 - 137 2014.02

MicroRNAs (miRNAs) are small non-coding RNA molecules of 20-23 nucleotides that regulate gene expression by binding to complementary mRNA sequences. Aberrant miRNA expression is implicated in carcinogenesis and malignancy of cancer. miRNAs involved in carcinogenesis are broadly classified into oncogenic and tumor suppressor miRNAs, and overexpression of oncogenic miRNAs and decreased expression of tumor suppressor miRNAs are found in cancer cells. Recent studies using miRNAs with different expression patterns between normal and cancer tissues have proposed use of miRNAs as biomarkers for cancer diagnosis and as treatment targets. In cervical cancer, miRNAs may be useful for onset detection, diagnosis and treatment. Here, we review the potential clinical applications of miRNAs for diagnosis and as a therapeutic strategy in cervical cancer.

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当院健康維持外来における慢性頭痛に対する呉茱萸湯の検討

堀場, 裕子, 吉野, 鉄大, 牧田, 和也, 横田, めぐみ, 岩田, 卓, 青木, 大輔 and 吉村, 泰典

産婦人科漢方研究のあゆみ ( 31 ) 89 - 93 2014

ISSN 0913-865X

2000年4月〜2012年12月に健康維持外来受診した初診患者で、頭痛に対して呉茱萸湯エキス製剤が処方された有経・閉経68例を抽出し、これらのうち初診時の症状に対する問診票への記載が確認できた40例の回答状況の相違について検討した。その結果、1)40例中、有効は32例、無効は8例であった。また、片頭痛と診断されたのは有効例では12例、無効例では1例であり、両群間の平均年齢・BMI・閉経例の割合は有意差は認められなかった。2)問診票の項目で有意差が認められた項目は「動悸」「意欲がわかない」「腟の痒み」であった。3)呉茱萸湯の投与目標としての「頭痛」「嘔気」「手足の冷え」「肩こり」は有効例と無効例においてどちらも有意差は認められなかった。4)重症度別で比較すると「動悸」は有効例では重症度2と3が合計37%であったのに対し、無効例では重症度2と3は認められなかった。一方、「意欲がわかない」は有効例では症状ありが70%であったのに対し、無効例では47%であった。更に「腟の痒み」は有効例では症状なしと重症度1しか認めず、無効例では重症度2が25%であった。以上より、「動悸」「意欲がわかない」は呉茱萸湯の奏功例を見分ける指標となり得ることが示唆された。

MicroRNA in cervical cancer

Banno Kouji, Iida Miho, Yanokura Megumi, Kisu Iori, Iwata Takashi, Tominaga Eiichiro, Tanaka Kyoko, Aoki Daisuke

The Scientific World Journal 2014 2014

Cervical cancer is a female-specific disease with a high incidence and mortality. MicroRNAs (miRNAs) are implicated in posttranscriptional regulation of gene expression and in the pathogenic mechanisms of cancer, suggesting their importance in diagnosis and treatment. miRNAs may have roles in the pathogenesis of cervical cancer based on the increases or decreases in several specific miRNAs found in patients with this disease. The miRNAs implicated in cervical cancer are miR-21, miR-126, and miR-143, and clinical application of these miRNAs for diagnosis and treatment is under investigation. Methods for diagnosis of cervical cancer include analysis of changes in the levels of specific miRNAs in serum and determination of aberrant hypermethylation of miRNAs. Supplementation of miR-143 or inhibition of miR-21 activity in vivo may be therapeutic strategy for cervical cancer. Previous approaches to development of siRNA as a drug have provided information for establishment of therapy based on these approaches, and an anti-miR-21 inhibitor has been developed. miRNAs also have effects on drug resistance and may be useful in combination therapy with other drugs. © 2014 Kouji Banno et al.

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MicroRNA in cervical cancer: OncomiRs and tumor suppressor miRs in diagnosis and treatment

Banno, K., Iida, M., Yanokura, M., Kisu, I., Iwata, T., Tominaga, E., Tanaka, K. and Aoki, D.

ScientificWorldJournal 2014 178075 2014

ISSN 1537-744X

Cervical cancer is a female-specific disease with a high incidence and mortality. MicroRNAs (miRNAs) are implicated in posttranscriptional regulation of gene expression and in the pathogenic mechanisms of cancer, suggesting their importance in diagnosis and treatment. miRNAs may have roles in the pathogenesis of cervical cancer based on the increases or decreases in several specific miRNAs found in patients with this disease. The miRNAs implicated in cervical cancer are miR-21, miR-126, and miR-143, and clinical application of these miRNAs for diagnosis and treatment is under investigation. Methods for diagnosis of cervical cancer include analysis of changes in the levels of specific miRNAs in serum and determination of aberrant hypermethylation of miRNAs. Supplementation of miR-143 or inhibition of miR-21 activity in vivo may be therapeutic strategy for cervical cancer. Previous approaches to development of siRNA as a drug have provided information for establishment of therapy based on these approaches, and an anti-miR-21 inhibitor has been developed. miRNAs also have effects on drug resistance and may be useful in combination therapy with other drugs.

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Repair of the threatened feminine identity: experience of women with cervical cancer undergoing fertility preservation surgery

Komatsu, H., Yagasaki, K., Shoda, R., Chung, Y., Iwata, T., Sugiyama, J. and Fujii, T.

Cancer Nurs 37 ( 1 ) 75 - 82 2014

ISSN 1538-9804

Fertility preservation is important for women of reproductive age with cervical cancer. The underlying reasons behind suboptimal reproductive results after successful fertility-preserving surgery have not yet been fully revealed.|The objective of this study was to explore the experience of fertility preservation with radical trachelectomy from the perspective of women with cervical cancer.|We conducted interviews with women with cervical cancer who underwent radical trachelectomy using a Grounded Theory methodology with a theoretical framework of symbolic interactionism.|Our findings articulate a process in which feminine identity is first threatened by a diagnosis of cancer, then repaired by fertility preservation with radical trachelectomy, and finally reconstructed after the surgery, through interactions with self, others, and external events in women with cervical cancer. Feeling incomplete as a woman because of the loss of the uterus was a critical factor in the women's feeling that their feminine identity was threatened. Thus, fertility preservation was significant for these women. The meaning of fertility preservation varied among the women, and their life perspectives were therefore distinct after the surgery.|Women with cervical cancer who undergo radical trachelectomy experience an identity transformation process, and child bearing is not the only expected outcome of fertility preservation.|Nurses should coordinate care through the cancer trajectory. Understanding the identity transformation process helps nurses to assess patients' needs and provide appropriate individual care.

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【がん免疫療法の最前線】がん免疫病態の細胞分子機構

河上, 裕, 杉山, 重里, 西尾, 浩, 岩田, 卓 and 青木, 大輔

産科と婦人科 81 ( 2 ) 145 - 150 2014

ISSN 0386-9792

【がん免疫療法の最前線】細胞傷害性T細胞を用いた免疫療法

岩田, 卓, 杉山, 重里, 西尾, 浩, 平尾, 薫丸 and 青木, 大輔

産科と婦人科 81 ( 2 ) 151 - 156 2014

ISSN 0386-9792

【産婦人科手術Up to Date】 (第2章)婦人科　子宮頸癌　子宮頸癌における妊孕性温存術式

田中, 京子, 杉山, 重里, 西尾, 浩, 森定, 徹, 岩田, 卓 and 青木, 大輔

産科と婦人科 81 ( Suppl. ) 109 - 113 2014

ISSN 0386-9792

Methylation of human papillomavirus-52 and -58 is a candidate biomarker in cervical neoplasia

Murakami, I., Fujii, T., Dan, K., Saito, M., Ohno, A., Iwata, T. and Aoki, D.

J Clin Virol 58 ( 1 ) 149 - 54 2013.09

ISSN 1873-5967

Previous studies of human papillomavirus (HPV)16/18 genome methylation have concluded that methylation status of the L1 gene might act as a biomarker for cervical intraepithelial neoplasia (CIN).|We investigated the correlation between methylation status in the L1 gene and the long control region (LCR) of HPV52/58 and CIN.|Exfoliated cervical cells were taken from 54 HPV52-positive and 41 HPV58-positive women. The HPV genome was examined using bisulfite modification, polymerase chain reaction amplification, and sequencing.|The CpGs were unmethylated or hypomethylated in the HPV52/58 LCR. In contrast, the methylation status of the HPV52 L1 gene was correlated with the severity of cervical neoplasia, with average percentages of 15%, 34%, and 52% for cervicitis/CIN1, CIN2, and CIN3, respectively (P<0.05). Methylation status of the HPV52 L1 gene was also correlated with the prognosis of CIN1/2, with median percentages of 15% and 35% for regression and persistence/progression, respectively (P<0.05). The methylation status of the HPV58 L1 gene was correlated with the severity of cervical neoplasia, with average percentages of 12%, 38%, and 61% for cervicitis/CIN1, CIN2, and CIN3, respectively (P<0.05).|The increased methylation at the CpG sites in the HPV52/58 L1 gene was correlated with the severity of cervical neoplasia, similar to HPV16/18 in previous studies. These data suggest that HPV methylation status of the L1 gene is a candidate biomarker of CIN for detecting CIN2 and CIN3.

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Methylation of human papillomavirus-52 and -58 is a candidate biomarker in cervical neoplasia

Murakami Isao, Fujii Takuma, Dan Katsuaki, Saito Miyuki, Ohno Akiko, Iwata Takashi, Aoki Daisuke

Journal of Clinical Virology 58 ( 1 ) 149 - 154 2013.09

ISSN 1386-6532

Background: Previous studies of human papillomavirus (HPV)16/18 genome methylation have concluded that methylation status of the L1 gene might act as a biomarker for cervical intraepithelial neoplasia (CIN). Objectives: We investigated the correlation between methylation status in the L1 gene and the long control region (LCR) of HPV52/58 and CIN. Study design: Exfoliated cervical cells were taken from 54 HPV52-positive and 41 HPV58-positive women. The HPV genome was examined using bisulfite modification, polymerase chain reaction amplification, and sequencing. Results: The CpGs were unmethylated or hypomethylated in the HPV52/58 LCR. In contrast, the methylation status of the HPV52 L1 gene was correlated with the severity of cervical neoplasia, with average percentages of 15%, 34%, and 52% for cervicitis/CIN1, CIN2, and CIN3, respectively ( P<. 0.05). Methylation status of the HPV52 L1 gene was also correlated with the prognosis of CIN1/2, with median percentages of 15% and 35% for regression and persistence/progression, respectively ( P<. 0.05). The methylation status of the HPV58 L1 gene was correlated with the severity of cervical neoplasia, with average percentages of 12%, 38%, and 61% for cervicitis/CIN1, CIN2, and CIN3, respectively ( P<. 0.05). Conclusions: The increased methylation at the CpG sites in the HPV52/58 L1 gene was correlated with the severity of cervical neoplasia, similar to HPV16/18 in previous studies. These data suggest that HPV methylation status of the L1 gene is a candidate biomarker of CIN for detecting CIN2 and CIN3. © 2013 Elsevier B.V.

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p16(INK4a) immunohistochemistry is a promising biomarker to predict the outcome of low grade cervical intraepithelial neoplasia: comparison study with HPV genotyping

Nishio, S., Fujii, T., Nishio, H., Kameyama, K., Saito, M., Iwata, T., Kubushiro, K. and Aoki, D.

J Gynecol Oncol 24 ( 3 ) 215 - 21 2013.07

ISSN 2005-0380

In cervical intraepithelial neoplasia (CIN), p16(INK4a) immunohistochemistry has been reported to be a useful diagnostic biomarker. However, limited information is available about the association between the p16(INK4a) immunohistochemistry and the outcomes of CIN. Here, we report p16(INK4a) immunohistochemistry as an effective biomarker to predict the outcomes of CIN.|p16(INK4a) immunohistochemistry was performed in patients with CIN from January 2000 to August 2009. Among these patients, we have performed a retrospective analysis of the medical records to evaluate the outcome of CIN 1-2 and performed statistical analysis to determine the correlation between p16(INK4a) expression and the outcomes. We also performed HPV genotyping and analyzed the relation between the infecting human papillomavirus (HPV) genotype and the outcomes.|A total of 244 patients, including 82 with CIN 1, 60 with CIN 2, and 102 with CIN 3, were examined. The rate of p16(INK4a) overexpression increased with increasing CIN grade, 20.7% for CIN 1, 80.0% for CIN 2, and 89.2% for CIN 3, with significant differences between CIN 1 and CIN 2-3 group. In the 131 CIN 1-2 patients, the progression rate was significantly higher for the patients showing p16(INK4a) overexpression than for those not showing p16(INK4a) overexpression (p=0.005); the regression rate was also found to be significantly lower for the patients showing p16(INK4a) overexpression (p=0.003). High-risk HPV genotypes were detected in 73 patients (73.7%). Both progression and regression rates were not significantly different between the high-risk HPV-positive and HPV-negative groups (p=0.401 and p=0.381, respectively).|p16(INK4a) overexpression was correlated with the outcome of CIN 1-2, and p16(INK4a) is considered to be a superior biomarker for predicting the outcome of CIN 1-2 compared with HPV genotyping.

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Reproductive and obstetric outcomes after radical abdominal trachelectomy for early-stage cervical cancer in a series of 31 pregnancies.

Nishio Hiroshi, Fujii Takuma, Sugiyama Juri, Kuji Naoaki, Tanaka Mamoru, Hamatani Toshio, Miyakoshi Kei, Minegishi Kazuhiro, Tsuda Hiroshi, Iwata Takashi, Tanaka Kyoko, Fukuchi Takeshi, Takehara Yuji, Yoshimura Yasunori, Aoki Daisuke

Human reproduction (Oxford, England) 28 ( 7 ) 1793 - 1798 2013.07

What are the reproductive and obstetric outcomes in patients undergoing radical abdominal trachelectomy (RAT) for early-stage cervical cancer? When RAT was performed before a pregnancy achieved with fertility treatments, pregnancy rate of 36.2% was obtained and 71.4% of these women gave birth at ≥ 32 weeks of gestation. Reproductive and obstetric outcomes after radical vaginal trachelectomy (RVT) are well documented; however, these outcomes after RAT have not been well studied. This is a retrospective cohort study of patients at a single institution who underwent RAT and became pregnant. Reproductive and obstetric outcomes of 114 patients who had undergone RAT from September 2002 to December 2010 were investigated. Women of reproductive age with early-stage cervical cancer who wished to preserve their fertility were documented. Patients' median age was 33 years (25-40 years). A total of 31 pregnancies were achieved in 25 patients and 6 patients had 2 pregnancies. Eighteen of 25 patients (72.0%) had infertility problems; 17 patients conceived with IVF-embryo transfer and 1 patient with intrauterine insemination. The pregnancy rate among patients who wished to conceive was 36.2% (25/69). Among 31 pregnancies in 25 patients, 4 patients had first trimester miscarriage and 1 patient had second trimester miscarriage. Excluding the five patients who miscarried and the five ongoing pregnancies, all the 21 patients had deliveries by Cesarean section. Four patients had a preterm birth in the second trimester and 17 patients delivered in the third trimester. Of the 17 pregnancies that reached the third trimester, 2 (11.8%) were preterm births between 29 and 32 weeks, 11 (64.7%) were delivered between 32 and 37 weeks and 4 (23.5%) at ≥ 37 weeks of gestation. Because of the retrospective data collection, not all pregnancies may have been recorded. Prospective multicenter studies are needed to determine if the results shown in this retrospective cohort can be generalized to all patients with early-stage cervical cancer who wish to undergo the fertility-sparing RAT procedure.

Reproductive and obstetric outcomes after radical abdominal trachelectomy for early-stage cervical cancer in a series of 31 pregnancies

Nishio, H., Fujii, T., Sugiyama, J., Kuji, N., Tanaka, M., Hamatani, T., Miyakoshi, K., Minegishi, K., Tsuda, H., Iwata, T., Tanaka, K., Fukuchi, T., Takehara, Y., Yoshimura, Y. and Aoki, D.

Hum Reprod 28 ( 7 ) 1793 - 8 2013.07

ISSN 1460-2350

What are the reproductive and obstetric outcomes in patients undergoing radical abdominal trachelectomy (RAT) for early-stage cervical cancer?|When RAT was performed before a pregnancy achieved with fertility treatments, pregnancy rate of 36.2% was obtained and 71.4% of these women gave birth at ≥ 32 weeks of gestation.|Reproductive and obstetric outcomes after radical vaginal trachelectomy (RVT) are well documented; however, these outcomes after RAT have not been well studied.|This is a retrospective cohort study of patients at a single institution who underwent RAT and became pregnant. Reproductive and obstetric outcomes of 114 patients who had undergone RAT from September 2002 to December 2010 were investigated.|Women of reproductive age with early-stage cervical cancer who wished to preserve their fertility were documented.|Patients' median age was 33 years (25-40 years). A total of 31 pregnancies were achieved in 25 patients and 6 patients had 2 pregnancies. Eighteen of 25 patients (72.0%) had infertility problems; 17 patients conceived with IVF-embryo transfer and 1 patient with intrauterine insemination. The pregnancy rate among patients who wished to conceive was 36.2% (25/69). Among 31 pregnancies in 25 patients, 4 patients had first trimester miscarriage and 1 patient had second trimester miscarriage. Excluding the five patients who miscarried and the five ongoing pregnancies, all the 21 patients had deliveries by Cesarean section. Four patients had a preterm birth in the second trimester and 17 patients delivered in the third trimester. Of the 17 pregnancies that reached the third trimester, 2 (11.8%) were preterm births between 29 and 32 weeks, 11 (64.7%) were delivered between 32 and 37 weeks and 4 (23.5%) at ≥ 37 weeks of gestation.|Because of the retrospective data collection, not all pregnancies may have been recorded.|Prospective multicenter studies are needed to determine if the results shown in this retrospective cohort can be generalized to all patients with early-stage cervical cancer who wish to undergo the fertility-sparing RAT procedure.

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長期的なホットフラッシュに三物黄ごん湯が有効であった1例

堀場, 裕子, 牧田, 和也, 横田, めぐみ, 岩田, 卓, 青木, 大輔 and 吉村, 泰典

産婦人科漢方研究のあゆみ ( 30 ) 30 - 33 2013

ISSN 0913-865X

59歳女性。46歳時に子宮筋腫の術前診断にて単純子宮全摘術を施行された。摘出標本の病理組織学的所見では低分化型子宮肉腫で、高用量黄体ホルモン療法を施行され、再発や転移は認められなかった。しかし今回、50歳頃からホットフラッシュが出現、59歳頃からは全身倦怠感も感じるようになり、漢方治療を希望して健康維持の外来受診となった。初診時、漢方医学的所見から病態はお血が主体と考え、桂枝茯苓丸エキス製剤(7.5g/日、食前服用)を処方したところ、2週間後の再診時には便通が軽度軽快したのみであったが、処方は4週間継続された。一方、両親の介護が始まったことでイライラが増強したため、加味逍遙散エキス製剤(7.5g/日、食前服用)を追加したが、ホットフラッシュは明らかな変化なく、腹診所見から柴胡加竜骨牡蠣湯エキス製剤(6.0g/日)を処方するも、こちらも変化はみられなかった。以後、再度の問診にてホットフラッシュと同時に起こる手足のほてりと発汗を認めたことから三物黄ごん湯エキス製剤(7.5g/日、食前服用)を処方した結果、2週間経過でホットフラッシュの回数は軽減、1ヵ月後には日常生活で気にならなくなった。

P16^INK4a immunohistochemistry is a promising biomarker to predict the outcome of low grade cervical intraepithelial neoplasia

Nishio Sakiko, Fujii Takuma, Nishio Hiroshi, Kameyama Kaori, Saito Miyuki, Iwata Takashi, Kubushiro Kaneyuki, Aoki Daisuke

Journal of Gynecologic Oncology 24 ( 3 ) 215 - 221 2013

ISSN 2005-0380

Objective: In cervical intraepithelial neoplasia (CIN), p16^INK4a immunohistochemistry has been reported to be a useful diagnostic biomarker. However, limited information is available about the association between the p16^INK4a immunohistochemistry and the outcomes of CIN. Here, we report p16^INK4a immunohistochemistry as an effective biomarker to predict the outcomes of CIN. Methods: p16^INK4a immunohistochemistry was performed in patients with CIN from January 2000 to August 2009. Among these patients, we have performed a retrospective analysis of the medical records to evaluate the outcome of CIN 1-2 and performed statistical analysis to determine the correlation between p16^INK4a expression and the outcomes. We also performed HPV genotyping and analyzed the relation between the infecting human papillomavirus (HPV) genotype and the outcomes. Results: A total of 244 patients, including 82 with CIN 1, 60 with CIN 2, and 102 with CIN 3, were examined. The rate of p16^INK4a overexpression increased with increasing CIN grade, 20.7% for CIN 1, 80.0% for CIN 2, and 89.2% for CIN 3, with significant differences between CIN 1 and CIN 2-3 group. In the 131 CIN 1-2 patients, the progression rate was significantly higher for the patients showing p16^INK4a overexpression than for those not showing p16^INK4a overexpression (p=0.005); the regression rate was also found to be significantly lower for the patients showing p16^INK4a overexpression (p=0.003). High-risk HPV genotypes were detected in 73 patients (73.7%). Both progression and regression rates were not significantly different between the high-risk HPV-positive and HPV-negative groups (p=0.401 and p=0.381, respectively). Conclusion: p16^INK4a overexpression was correlated with the outcome of CIN 1-2, and p16^INK4a is considered to be a superior biomarker for predicting the outcome of CIN 1-2 compared with HPV genotyping. © 2013. Asian Society of Gynecologic Oncology, Korean Society of Gynecologic Oncology.

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【らくらく理解!見方・読み方・読む視点　保存版:産科の検査値まるごと大図鑑】子宮頸部細胞診

岩田, 卓

ペリネイタルケア 32 ( 6 ) 532 - 534 2013

ISSN 0910-8718

【婦人科がん手術の基本手技を学ぶ】広汎性子宮頸部摘出術における妊孕能向上への工夫

藤井, 多久磨, 田中, 京子, 廣瀬, 茂道, 岩田, 卓, 杉山, 重里 and 青木, 大輔

産婦人科手術 ( 24 ) 37 - 42 2013

ISSN 0915-8375

Cancer-testis antigen BORIS is a novel prognostic marker for patients with esophageal cancer

Okabayashi, K., Fujita, T., Miyazaki, J., Okada, T., Iwata, T., Hirao, N., Noji, S., Tsukamoto, N., Goshima, N., Hasegawa, H., Takeuchi, H., Ueda, M., Kitagawa, Y. and Kawakami, Y.

Cancer Sci 103 ( 9 ) 1617 - 24 2012.09

ISSN 1349-7006

Esophageal squamous cell cancer (ESCC) is one of the most common lethal tumors in the world, and development of new diagnostic and therapeutic methods is needed. In this study, cancer-testis antigen, BORIS, was isolated by functional cDNA expression cloning using screening technique with serum IgG Abs from ESCC patients. BORIS was previously reported to show cancer-testis antigen like expression, but its immunogenicity has remained unclear in cancer patients. BORIS was considered to be an immunogenic antigen capable of inducing IgG Abs in patients with various cancers, including four of 11 ESCC patients. Immunohistochemical study showed that the BORIS protein was expressed in 28 of 50 (56%) ESCC tissues. The BORIS expression was significantly associated with lymph node metastasis in ESCC patients with pT1 disease (P = 0.036). Furthermore, the patients with BORIS-positive tumors had a poor overall survival (5-year survival rate: BORIS-negative 70.0% vs BORIS-positive 29.9%, log-rank P = 0.028) in Kaplan-Meier survival analysis and log-rank test. Multivariate Cox proportional hazard model demonstrated that BORIS expression was an independent poor prognostic factor (hazard ratio = 4.158 [95% confidence interval 1.494-11.57], P = 0.006). Downregulation of BORIS with specific siRNAs resulted in decreased cell proliferation and invasion ability of ESCC cell lines. BORIS may be a useful biomarker for prognostic diagnosis of ESCC patients and a potential target for treatment including by BORIS-specific immunotherapy and molecular target therapy.

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Cancer-testis antigen BORIS is a novel prognostic marker for patients with esophageal cancer

Okabayashi Koji, Fujita Tomonobu, Miyazaki Junichiro, Okada Tsutomu, Iwata Takashi, Hirao Nobumaru, Noji Shinobu, Tsukamoto Nobuo, Goshima Naoki, Hasegawa Hirotoshi, Takeuchi Hiroya, Ueda Masakazu, Kitagawa Yuko, Kawakami Yutaka

Cancer Science 103 ( 9 ) 1617 - 1624 2012.09

ISSN 1347-9032

Esophageal squamous cell cancer (ESCC) is one of the most common lethal tumors in the world, and development of new diagnostic and therapeutic methods is needed. In this study, cancer-testis antigen, BORIS, was isolated by functional cDNA expression cloning using screening technique with serum IgG Abs from ESCC patients. BORIS was previously reported to show cancer-testis antigen like expression, but its immunogenicity has remained unclear in cancer patients. BORIS was considered to be an immunogenic antigen capable of inducing IgG Abs in patients with various cancers, including four of 11 ESCC patients. Immunohistochemical study showed that the BORIS protein was expressed in 28 of 50 (56%) ESCC tissues. The BORIS expression was significantly associated with lymph node metastasis in ESCC patients with pT1 disease (P = 0.036). Furthermore, the patients with BORIS-positive tumors had a poor overall survival (5-year survival rate: BORIS-negative 70.0% vs BORIS-positive 29.9%, log-rank P = 0.028) in Kaplan-Meier survival analysis and log-rank test. Multivariate Cox proportional hazard model demonstrated that BORIS expression was an independent poor prognostic factor (hazard ratio = 4.158 [95% confidence interval 1.494-11.57], P = 0.006). Downregulation of BORIS with specific siRNAs resulted in decreased cell proliferation and invasion ability of ESCC cell lines. BORIS may be a useful biomarker for prognostic diagnosis of ESCC patients and a potential target for treatment including by BORIS-specific immunotherapy and molecular target therapy. © 2012 Japanese Cancer Association.

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Tumor volume and lymphovascular space invasion as a prognostic factor in early invasive adenocarcinoma of the cervix

Murakami, I., Fujii, T., Kameyama, K., Iwata, T., Saito, M., Kubushiro, K. and Aoki, D.

J Gynecol Oncol 23 ( 3 ) 153 - 8 2012.07

ISSN 2005-0399

The aim of this study was to investigate the risk and recurrence of early invasive adenocarcinoma of the cervix, and to determine whether non-radical methods of management could be performed.|The medical and histopathological records of 50 patients with early invasive adenocarcinoma of the cervix treated at Keio University Hospital between 1993 and 2005 were reviewed, and compared with the literature.|The median follow-up period was 64.3 months. The depth of stromal invasion was ≤3 mm in 33 cases and >3 mm, but ≤5 mm in 17 cases. The horizontal spread was ≤7 mm in 25 cases and >7 mm in 25 cases. One of the 33 cases that had tumor volumes of ≤500 mm(3), and three of the 17 cases with tumor volumes of >500 mm(3) were positive for lymph node metastasis. When our data were combined with previously reported results, statistically significant differences were observed between the tumor volume and the frequency of pelvic lymph node metastasis/the rate of recurrence (p<0.0001). The frequency of pelvic lymph node metastases was significantly higher in the lymphovascular space invasion (LVSI)-positive group than in the LVSI-negative group (p=0.02). No adnexal metastasis or parametrial involvement was noted.|Assessment of the depth of stromal invasion, tumor volume, and LVSI is critical for selecting an appropriate therapeutic modality. Non-radical methods of management are considered suitable for patients with LVSI-negative adenocarcinoma of the cervix exhibiting a stromal invasion depth of ≤5 mm and a tumor volume of ≤500 mm(3).

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Tumor volume and lymphovascular space invasion as a prognostic factor in early invasive adenocarcinoma of the cervix

Murakami Isao, Fujii Takuma, Kameyama Kaori, Iwata Takashi, Saito Miyuki, Kubushiro Kaneyuki, Aoki Daisuke

Journal of Gynecologic Oncology 23 ( 3 ) 153 - 158 2012.06

ISSN 2005-0380

Objective: The aim of this study was to investigate the risk and recurrence of early invasive adenocarcinoma of the cervix, and to determine whether non-radical methods of management could be performed. Methods: The medical and histopathological records of 50 patients with early invasive adenocarcinoma of the cervix treated at Keio University Hospital between 1993 and 2005 were reviewed, and compared with the literature. Results: The median follow-up period was 64.3 months. The depth of stromal invasion was ≤3 mm in 33 cases and >3 mm, but ≤5 mm in 17 cases. The horizontal spread was ≤7 mm in 25 cases and >7 mm in 25 cases. One of the 33 cases that had tumor volumes of ≤500 mm ³, and three of the 17 cases with tumor volumes of >500 mm ³ were positive for lymph node metastasis. When our data were combined with previously reported results, statistically significant differences were observed between the tumor volume and the frequency of pelvic lymph node metastasis/the rate of recurrence (p<0.0001). The frequency of pelvic lymph node metastases was significantly higher in the lymphovascular space invasion (LVSI)-positive group than in the LVSI-negative group (p=0.02). No adnexal metastasis or parametrial involvement was noted. Conclusion: Assessment of the depth of stromal invasion, tumor volume, and LVSI is critical for selecting an appropriate therapeutic modality. Non-radical methods of management are considered suitable for patients with LVSI-negative adenocarcinoma of the cervix exhibiting a stromal invasion depth of ≤5 mm and a tumor volume of ≤500 mm ³. © 2012. Asian Society of Gynecologic Oncology, Korean Society of Gynecologic Oncology.

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”大建中湯”の長期内服が深部静脈血栓症発症後の下肢痛に有効であった1例

堀場, 裕子, 牧田, 和也, 横田, めぐみ, 岩田, 卓, 青木, 大輔 and 吉村, 泰典

産婦人科漢方研究のあゆみ ( 29 ) 50 - 53 2012

ISSN 0913-865X

53歳女性。27歳時に胞状奇胎にて子宮内容掻爬術を2回施行され、34歳時には単純子宮全摘術+肺部分切除術が予定されていたが、術前に深部静脈血栓症が判明し、IVCフィルター挿入後に手術施行となった。今回、腹部膨満の自覚ほか、冷えの増悪と便秘が出現して紹介来院となった。漢方医学的所見では顔面蒼白で、体格は中程度、舌は白色・湿潤・歯痕ありで、脈は沈・遅であった。以上、これらを踏まえ、全身の冷えと腹部膨満を目標に大建中湯エキス顆粒(15g/日)の処方を行ったところ、内服開始4週間で冷えと腹部膨満の軽減を自覚、更に1ヵ月経過で腹部膨満はほとんど消失した。しかし、内服開始3ヵ月経過で冷えは軽減し熟眠できるようになったが、内服を中止すると腹部膨満と便秘が出現するため、本人の希望で現在も同処方を内服継続中である。以上、大建中湯の長期内服は腸閉塞の発症予防とともに患者のQOLの改善に有用であり、身近で簡便に使用できる漢方製剤の一つと考えられた。

【婦人科悪性腫瘍の診断治療アップデート】子宮頸がん　子宮頸癌の進行期分類と治療方針

岩田, 卓 and 青木, 大輔

産婦人科の実際 61 ( 3 ) 301 - 308 2012

ISSN 0558-4728

【生殖医療と周辺領域との関わり】腫瘍　子宮頸癌の治療と生殖医療の役割

藤井, 多久磨, 西尾, 浩, 杉山, 樹里, 岩田, 卓 and 青木, 大輔

産科と婦人科 78 ( 3 ) 332 - 336 2011

ISSN 0386-9792

【症例の比較で学ぶ画像診断　婦人科・泌尿生殖器領域50選】子宮頸部　子宮頸癌術後の病変

秋田, あやの, 秋田, 大宇, 奥田, 茂男 and 岩田, 卓

画像診断 31 ( 4 ) s48 - s51 2011

ISSN 0285-0524

【症例の比較で学ぶ画像診断　婦人科・泌尿生殖器領域50選】子宮頸部　頸部の嚢胞性病変

秋田, あやの, 秋田, 大宇, 奥田, 茂男 and 岩田, 卓

画像診断 31 ( 4 ) s44 - s47 2011

ISSN 0285-0524

【症例の比較で学ぶ画像診断　婦人科・泌尿生殖器領域50選】子宮頸部　頸管内に下垂した体部病変

秋田, あやの, 秋田, 大宇, 奥田, 茂男 and 岩田, 卓

画像診断 31 ( 4 ) s40 - s43 2011

ISSN 0285-0524

【症例の比較で学ぶ画像診断　婦人科・泌尿生殖器領域50選】子宮頸部　頸部の腫瘤性病変

秋田, あやの, 秋田, 大宇, 奥田, 茂男 and 岩田, 卓

画像診断 31 ( 4 ) s36 - s39 2011

ISSN 0285-0524

【婦人科がん妊孕性・卵巣機能温存治療と妊娠・分娩】子宮頸癌に対する広汎性子宮頸部摘出術

西尾, 浩, 藤井, 多久磨, 杉山, 重里, 仲村, 勝, 岩田, 卓 and 青木, 大輔

産婦人科の実際 60 ( 2 ) 155 - 160 2011

ISSN 0558-4728

機能温存手術　広汎性子宮頸部摘出術におけるneo-cervix形成の工夫

田中, 京子, 藤井, 多久磨, 杉山, 重里, 西尾, 浩, 岩田, 卓 and 青木, 大輔

産婦人科手術 ( 22 ) 101 - 105 2011

ISSN 0915-8375

Digital colposcopy for the diagnosis of cervical adenocarcinoma using a narrow band imaging system

Fujii, T., Nakamura, M., Kameyama, K., Saito, M., Nishio, H., Ohno, A., Hirao, N., Iwata, T., Tsukazaki, K. and Aoki, D.

Int J Gynecol Cancer 20 ( 4 ) 605 - 10 2010.05

ISSN 1525-1438

Although the colposcopic features of cervical glandular disease and cervical adenocarcinoma are not widely well known, unique microvascular patterns are reportedly useful for identifying such diseases. The narrow band imaging (NBI) system used in endoscopy can be used to obtain high-contrast vascular images. Therefore, we examined the utility of NBI colposcopy and compared the results with those of conventional colposcopy.|Twenty-one patients with adenocarcinoma in situ or early invasive adenocarcinomas were examined using digital NBI colposcopy, and the photo records were compared with those of conventional colposcopy. The histological examination and immunohistochemistry with anti-CD31 antibody confirmed the microvascular pattern.|Digital NBI colposcopy depicted the fine vascular texture on the surface of the cervix more clearly than conventional colposcopy. The vascular pattern was depicted in 86% (18/21) of glandular disease cases. The characteristic fine vascular patterns were critical for identifying cervical glandular diseases.|Digital NBI colposcopy was useful for identifying early cervical adenocarcinoma as well as adenocarcinoma in situ. This system yields cervical glandular disease-related colposcopic findings that may be useful for both clinical and educational purposes.

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Digital colposcopy for the diagnosis of cervical adenocarcinoma using a narrow band imaging system

Fujii Takuma, Nakamura Masaru, Kameyama Kaori, Saito Miyuki, Nishio Hiroshi, Ohno Akiko, Hirao Nobumaru, Iwata Takashi, Tsukazaki Katsumi, Aoki Daisuke

International Journal of Gynecological Cancer 20 ( 4 ) 605 - 610 2010.05

ISSN 1048-891X

Introduction: Although the colposcopic features of cervical glandular disease and cervical adenocarcinoma are not widely well known, unique microvascular patterns are reportedly useful for identifying such diseases. The narrow band imaging (NBI) system used in endoscopy can be used to obtain high-contrast vascular images. Therefore, we examined the utility of NBI colposcopy and compared the results with those of conventional colposcopy. Methods: Twenty-one patients with adenocarinoma in situ or early invasive adenocarci-nomas were examined using digital NBI colposcopy, and the photo records were compared with those of conventional colposcopy. The histological examination and immunohisto-chemistry with anti-CD31 antibody confirmed the microvascular pattern. Results: Digital NBI colposcopy depicted the fine vascular texture on the surface of the cervix more clearly than conventional colposcopy. The vascular pattern was depicted in 86% (18/21) of glandular disease cases. The characteristic fine vascular patterns were critical for identifying cervical glandular diseases. Conclusions: Digital NBI colposcopy was useful for identifying early cervical adeno-carcinoma as well as adenocarcinoma in situ. This system yields cervical glandular disease-related colposcopic findings that may be useful for both clinical and educational purposes.

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Abdominal Radical Trachelectomy as a Fertility-Sparing Procedure in Women With Early Stage Cervical Cancer in a Series of 61 Women COMMENT

Nishio, H., Fujii, T., Kameyama, K., Susumu, N., Nakamura, M., Iwata, T. and Aoki, D.

Obstetrical & Gynecological Survey 65 ( 1 ) 19 - 20 2010.01

ISSN 0029-7828

Although vaginal radical trachelectomy is an effective treatment for early stage cervical cancer and has an acceptable live birth rate, there are concerns over its oncological safety and possible-surgical injury with this radical procedure. Moreover, most gynecologists have difficulty performing this unfamiliar procedure and require special training. Many of these problems can be overcome with the use of abdominal radical trachelectomy. The abdominal approach provides adequate resection of the parametrial and vaginal tissue and does not require special training. Only a few case studies have investigated abdominal radical trachelectomy. This retrospective study presents follow-up data and reviews a series of cases conducted in Japanese women with early stage cervical cancer who had undergone elective abdominal radical trachelectomy and pelvic lymphadenectomy between 2002 and 2008. The aim of the study was to assess the effectiveness and safety of the abdominal approach in this population. A total of 61 patients at a median age of 33 years (range, 26-44 years) were followed up for a median 27 months (range, 1-67 months). There were 6 recurrences (9.8%, 6/61); 1 occurred in a patient with adenocarcinoma. None of the other 5 recurrences were found in cases with a primary tumor diameter of <20 mm. Twenty-nine (47.5%) of the 61 patients attempted to conceive and 4 (13.8%) were successful. Of the 4 live births, 2 were preterm, the remaining 2 were full term. The rates of serious intraoperative and postoperative complications were similar to those reported in the literature for standard radical hysterectomy and lymphadenectomy. The investigators conclude from these findings that an abdominal radical trachelectomy is an effective and relatively safe procedure in selected patients and may be an acceptable treatment option for young women with early stage cervical cancer.

Abdominal radical trachelectomy as a fertility-sparing procedure in women with early stage cervical cancer in a series of 61 women

Nishio Hiroshi, Fujii Takuma, Kameyama Kaori, Susumu Nobuyuki, Nakamura Masaru, Iwata Takashi, Aoki Daisuke

Obstetrical and Gynecological Survey 65 ( 1 ) 19 - 20 2010.01

ISSN 0029-7828

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閉経前両側卵巣摘出例における骨密度とFRAXの特徴に関する検討

堀場, 裕子, 平沢, 晃, 牧田, 和也, 松村, 聡子, 小川, 真里子, 岩田, 卓, 弟子丸, 亮太, 柳本, 茂久 and 青木, 大輔

Osteoporosis Japan 18 ( 3 ) 461 - 465 2010

ISSN 0919-6307

1979年〜2009年に大学病院産婦人科で44歳以下で両側卵巣摘出術を受けた51例(卵摘群)、健康維持外来受診中で、有経、自然閉経後卵巣摘出を含めた323例(対照群)を対象に2008年に開発したFRAXを用い、骨折リスクを算出し、閉経前両側卵巣摘出という因子がFRAXに与える影響について検討した。卵摘群では骨量正常が45例、骨量減少が6例、骨粗鬆症例は認めなかった。一方、対照群では骨量正常が238例、骨量減少が59例、骨粗鬆症が26例であった。卵摘群と対照群の骨密度を比較すると、卵摘群においてYAM値90%未満の例が31.8%に認められ、両群間に有意差を認めず、平均値の比較でも対照群と有意差を認めなかった。卵摘群における骨量減少6例は共に低BMIで、うち2例ではBMIが16以下であった。61歳例のFRAX値は9.7で他の5例に比べ高値であった。卵摘群における骨正常例ではL2-4YAMと大腿骨骨密度が骨量減少例と比べ有意に高値であった。

【妊孕能の可能性と限界を考える】子宮頸癌と生殖機能温存治療の実際

西尾, 浩, 藤井, 多久磨, 青海, 咲子, 仲村, 勝, 岩田, 卓 and 青木, 大輔

産婦人科の実際 59 ( 5 ) 777 - 782 2010

ISSN 0558-4728

【婦人科がんに関する最近の話題】広汎性子宮頸部摘出術後の妊孕能

仲村, 勝, 藤井, 多久磨, 西尾, 浩, 岩田, 卓, 高松, 潔 and 青木, 大輔

産科と婦人科 77 ( 9 ) 1089 - 1093 2010

ISSN 0386-9792

【妊娠を考慮した子宮頸部初期病変への対応】広汎性子宮頸部摘出術(radical trachelectomy)

仲村, 勝, 藤井, 多久磨, 西尾, 浩, 岩田, 卓 and 青木, 大輔

産科と婦人科 77 ( 4 ) 439 - 443 2010

ISSN 0386-9792

【知っておきたい婦人科がんのリスク】子宮頸がんリスクに関する環境因子

藤井, 多久磨, 岩田, 卓, 平尾, 薫丸, 齋藤, 深雪 and 青木, 大輔

産科と婦人科 77 ( 1 ) 45 - 48 2010

ISSN 0386-9792

【産婦人科診療　pros and cons】婦人科腫瘍　CIN局所療法の選択とその適応について

藤井, 多久磨, 西尾, 浩, 平尾, 薫丸, 岩田, 卓 and 青木, 大輔

産婦人科の実際 59 ( 3 ) 473 - 478 2010

ISSN 0558-4728

Abdominal radical trachelectomy as a fertility-sparing procedure in women with early-stage cervical cancer in a series of 61 women

Nishio, H., Fujii, T., Kameyama, K., Susumu, N., Nakamura, M., Iwata, T. and Aoki, D.

Gynecol Oncol 115 ( 1 ) 51 - 5 2009.10

ISSN 1095-6859

This retrospective study was conducted as a review of a series of women who had undergone abdominal radical trachelectomy and pelvic lymphadenectomy for early-stage cervical cancer.|We performed a retrospective review of patients who had undergone an abdominal radical trachelectomy. Data regarding tumor size and histology, surgical complications, recurrences, pregnancies and live births were collected and were presented as a percentage of the total number of cases.|A total of 61 women were followed up for a median of 27 months (range: one month--79 months). There were six recurrences (9.8%); none of the recurrences occurred in patients with a tumor diameter of <20 mm except in one case with adenocarcinoma. Twenty-nine women attempted to conceive; four of these women were successful. All four of these women had live births: two had preterm deliveries, and the remaining two had full-term deliveries. The cumulative pregnancy rate among the women who attempted to conceive was 13.8% (4/29).|Among selected women with early-stage cervical cancer, especially those with a tumor diameter of <20 mm, abdominal radical trachelectomy and pelvic lymphadenectomy is a fertility-sparing treatment option, even though the cumulative conception rate was not particularly high compared with that for women who had undergone a vaginal radical trachelectomy.

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Abdominal radical trachelectomy as a fertility-sparing procedure in women with early-stage cervical cancer in a series of 61 women

Nishio Hiroshi, Fujii Takuma, Kameyama Kaori, Susumu Nobuyuki, Nakamura Masaru, Iwata Takashi, Aoki Daisuke

Gynecologic Oncology 115 ( 1 ) 51 - 55 2009.10

ISSN 0090-8258

Objective: This retrospective study was conducted as a review of a series of women who had undergone abdominal radical trachelectomy and pelvic lymphadenectomy for early-stage cervical cancer. Methods: We performed a retrospective review of patients who had undergone an abdominal radical trachelectomy. Data regarding tumor size and histology, surgical complications, recurrences, pregnancies and live births were collected and were presented as a percentage of the total number of cases. Results: A total of 61 women were followed up for a median of 27 months (range: one month - 79 months). There were six recurrences (9.8%); none of the recurrences occurred in patients with a tumor diameter of < 20 mm except in one case with adenocarcinoma. Twenty-nine women attempted to conceive; four of these women were successful. All four of these women had live births: two had preterm deliveries, and the remaining two had full-term deliveries. The cumulative pregnancy rate among the women who attempted to conceive was 13.8% (4/29). Conclusion: Among selected women with early-stage cervical cancer, especially those with a tumor diameter of < 20 mm, abdominal radical trachelectomy and pelvic lymphadenectomy is a fertility-sparing treatment option, even though the cumulative conception rate was not particularly high compared with that for women who had undergone a vaginal radical trachelectomy. © 2009 Elsevier Inc. All rights reserved.

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当科更年期外来における更年期不定愁訴に対する漢方薬の使用状況について　8年前の調査結果との比較検討

牧田, 和也, 堀場, 裕子, 平沢, 晃, 岩田, 卓, 片岡, 史夫, 冨永, 英一郎, 堀口, 文, 青木, 大輔 and 吉村, 泰典

産婦人科漢方研究のあゆみ ( 26 ) 44 - 47 2009

ISSN 0913-865X

2006年1月〜2007年12月に更年期外来を3ヵ月以上継続通院した671例を抽出し、治療内容について外来カルテを中心に追跡調査し、2000年外来で行った同様調査結果と比較検討した。125例(18.6%)は特に継続的な薬物治療は行わず、血液検査や骨密度測定を定期的に施行している経過観察例、残り546例(81.4%)は継続的な薬物治療が行われていた。ホルモン補充療法(HRT)継続施行例は128例(19.1%)、漢方薬のみ使用例は54例(8.5%)であった。漢方薬の内訳は8年前の調査では桂枝茯苓丸の使用頻度が最も高く、加味逍遙散、牛車腎気丸、芍薬甘草湯の順であったが、今回調査でも使用頻度は桂枝茯苓丸が最も高く、以下加味逍遙散と共に慢性頭痛に対する呉茱萸湯、釣藤散使用例が急増していた。8年前調査では使用漢方薬の種類は10種類程度であったが今回調査では23種類に及んでいた。

【婦人科的基礎疾患を合併する妊娠・分娩の対応とその問題点】子宮頸癌合併妊娠

岩田, 卓, 西尾, 浩, 藤井, 多久磨 and 青木, 大輔

産婦人科の実際 58 ( 7 ) 999 - 1004 2009

ISSN 0558-4728

【産婦人科手術療法マニュアル】婦人科手術　悪性　子宮頸部円錐切除術

岩田, 卓, 藤井, 多久磨, 塚崎, 克己 and 青木, 大輔

産科と婦人科 76 ( Suppl. ) 217 - 223 2009

ISSN 0386-9792

卵巣腫瘍で腹腔鏡下手術を施行し、境界悪性腫瘍と診断された症例の術前MRI評価について

西尾, 浩, 藤井, 多久磨, 奥田, 茂男, 亀山, 香織, 大野, 暁子, 仲村, 勝, 岩田, 卓 and 青木, 大輔

日本産科婦人科内視鏡学会雑誌 25 ( 1 ) 246 - 251 2009

ISSN 1884-9938

良性卵巣腫瘍の術前診断で腹腔鏡下卵巣腫瘍摘出術および付属器切除術を施行し、術後病理検査で境界悪性腫瘍と診断された15例を対象に、術前MRI所見を後方視的に検討した。その結果、術前MRIで境界悪性腫瘍を含めた悪性腫瘍の可能性を示唆する所見を認めた症例は6例(40%)で、腫瘍内の一部に造影効果を認める充実部分が存在する(4例)、もしくは20cm以上の腫瘍径(2例)などの所見があった。その他の9例では悪性腫瘍を示唆する所見は指摘できなかった。また、術後に粘液性境界悪性腫瘍と診断された10例のうち8例(80%)は単房性腫瘍であり、そのうち6例(60%)はT1強調画像、T2強調画像ともに高信号を呈する内膜症性嚢胞と診断されていた。術後の臨床経過については、いずれの症例においても観察期間(平均36ヵ月)に再発所見を認めていない。

【QOLを考慮した婦人科がん治療】【妊孕能温存】　広汎性子宮頸部摘出術の適応と限界

西尾, 浩, 藤井, 多久磨, 仲村, 勝, 岩田, 卓 and 青木, 大輔

臨床婦人科産科 63 ( 12 ) 1495 - 1499 2009

ISSN 0386-9865

【子宮疾患・子宮内膜症の臨床　基礎・臨床研究のアップデート】腫瘍性疾患　頸部腫瘍　子宮頸上皮内癌

塚崎, 克己, 岩田, 卓, 藤井, 多久磨 and 青木, 大輔

日本臨床 67 ( 増刊5 子宮疾患・子宮内膜症の臨床 ) 200 - 205 2009

ISSN 0047-1852

産婦人科領域における最新の手術広汎性子宮頸部摘出術の適応と今後の課題

藤井, 多久磨, 西尾, 浩, 仲村, 勝, 岩田, 卓, 青木, 大輔 and 吉村, 泰典

日本産科婦人科学会東京地方部会会誌 58 ( 3 ) 295 - 296 2009

ISSN 0288-5751

広汎性子宮頸部摘出術は子宮頸部早期浸潤癌に対し、最近注目を集めている手術法である。この術式は安全性の確認が行われている段階で、長期予後は明らかとなっていない。我々の施設で施行された症例検討では腫瘍径が小さい扁平上皮癌では比較的安全と考えられる。一方、腫瘍径が大きいものや腺癌ではリスクが低くないことから注意を要する。この手術を施行するには患者への十分な情報提供が必要なことから、当面は限られた施設で適応規準を整備して施行することが手術を受ける患者にとって一番のメリットであると考えている。(著者抄録)

Ancillary testing of liquid-based cytology specimens for identification of patients at high risk of cervical cancer

Fujii, T., Saito, M., Iwata, T., Hirao, N., Nishio, H., Ohno, A., Tsukazaki, K., Mukai, M., Kameyama, K. and Aoki, D.

Virchows Arch 453 ( 6 ) 545 - 55 2008.12

ISSN 0945-6317

Integration of human papillomavirus DNAs into the host genome is crucial to the development of cervical cancer. Overexpression of the P16 protein has been reported in cervical intraepithelial neoplasia (CIN) as well as cervical cancer. Such molecular biomarkers have been utilized for ancillary testing of liquid-based cytology specimens; however, their clinical application remains controversial. To detect CIN 2 or more advanced lesions, 153 liquid-based cytology (LBC) specimens were investigated to determine the physical status of the human papillomavirus (HPV) DNA by in situ hybridization (ISH) and to detect overexpression of the P16 protein by immunocytochemistry combined with HPV genotyping by polymerase chain reaction. The combination of ISH, P16 immunocytochemistry, and LBC showed high sensitivity (89.3%) as well as high specificity (92.6%). We confirmed the usefulness of P16 immunocytochemistry combined with ISH and HPV genotyping as ancillary molecular-biological tests of LBC specimens for identifying patients at high risk of cervical cancer.

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Ancillary testing of liquid-based cytology specimens for identification of patients at high risk of cervical cancer

Fujii Takuma, Saito Miyuki, Iwata Takashi, Hirao Nobumaru, Nishio Hiroshi, Ohno Akiko, Tsukazaki Katsumi, Mukai Makio, Kameyama Kaori, Aoki Daisuke

Virchows Archiv 453 ( 6 ) 545 - 555 2008.12

ISSN 0945-6317

Integration of human papillomavirus DNAs into the host genome is crucial to the development of cervical cancer. Overexpression of the P16 protein has been reported in cervical intraepithelial neoplasia (CIN) as well as cervical cancer. Such molecular biomarkers have been utilized for ancillary testing of liquid-based cytology specimens; however, their clinical application remains controversial. To detect CIN 2 or more advanced lesions, 153 liquid-based cytology (LBC) specimens were investigated to determine the physical status of the human papillomavirus (HPV) DNA by in situ hybridization (ISH) and to detect overexpression of the P16 protein by immunocytochemistry combined with HPV genotyping by polymerase chain reaction. The combination of ISH, P16 immunocytochemistry, and LBC showed high sensitivity (89.3%) as well as high specificity (92.6%). We confirmed the usefulness of P16 immunocytochemistry combined with ISH and HPV genotyping as ancillary molecular-biological tests of LBC specimens for identifying patients at high risk of cervical cancer. © 2008 Springer-Verlag.

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子宮体がん術後患者における骨密度の特徴に関する検討

平沢, 晃, 牧田, 和也, 堀場, 裕子, 弟子丸, 亮太, 柳本, 茂久, 野村, 弘行, 片岡, 史夫, 岩田, 卓, 冨永, 英一郎, 阪埜, 浩司, 進, 伸幸, 堀口, 文 and 青木, 大輔

Osteoporosis Japan 16 ( 3 ) 429 - 431 2008

ISSN 0919-6307

産婦人科で初回治療として両側卵巣摘出術を伴う手術療法を施行した子宮体癌(体癌群)132例、健康維持外来を受診した非担癌自然閉経症例(対照群)224例、計356例を対象に、子宮体癌術後患者における骨代謝の特徴について自然閉経例と比較検討した。体癌群においては骨粗鬆症/骨量減少と診断できた症例は132例中35例(27%)で、対照群では224例中90例(40%)で、体癌群では骨量正常例が有意に多かった。また卵巣摘出時の閉経の有無によって骨粗鬆症/骨量減少の発生頻度に有意差を認めなかった。検討結果から、子宮体癌例は卵巣摘出を施行しているにも拘わらず、骨粗鬆症/骨量減少の高危険群とはいいがたいことが判明した。しかし、近年、若年発症例が増加していることから長期的フォローアップが必要と思われた。

Dendritic cell based personalized immunotherapy based on cancer antigen research

Kawakami, Y., Fujita, T., Kudo, C., Sakurai, T., Udagawa, M., Yaguchi, T., Hasegawa, G., Hayashi, E., Ueda, Y., Iwata, T., Wang, Q., Okada, S., Tsukamoto, N., Matsuzaki, Y. and Sumimoto, H.

Front Biosci 13 1952 - 8 2008

ISSN 1093-9946

Human tumor antigens were identified using various immunological and genetic methods, and immune responses to the identified antigens were evaluated in cancer patients. Autologous tumor specific unique antigens derived from genetic alterations in cancer cells were isolated from patients with favorable prognosis after immunotherapy, indicating that they are attractive targets for immunotherapy. Immunogenicity of shared antigens was found to differ among patients due to antigen expression in cancer cells and patients' immunoreactivity. These observations suggest that personalization may be applied for cancer immunotherapy. We therefore developed intratumoral DC administration protocols that are able to induce immune responses to both unique and shared tumor antigens expressed in each individual cancer. By combining cryoablative tumor pretreatment and TLR stimulated DC, the anti-tumor effect of the intratumoral DC administration was significantly augmented in a murine tumor model. This improved protocol enhanced systemic induction of anti-tumor CD8+ CTL, and was able to regress relatively large remote untreated tumors. In clinical trials, systemic immune induction was observed by intratumoral DC administration following cryoablative tumor treatment, although anti-tumor effects are relatively weak, indicating that additional interventions are required for more effective immunotherapy.

【妊娠中に発見された悪性腫瘍の取り扱い】子宮頸癌I a期に対する円錐切除術

西尾, 浩, 藤井, 多久磨, 仲村, 勝, 村上, 功, 岩田, 卓, 大野, 暁子, 塚崎, 克己 and 青木, 大輔

産婦人科の実際 57 ( 4 ) 633 - 637 2008

ISSN 0558-4728

【婦人科がん診療のリスクマネージメント】手術の問題点　広汎性子宮頸部摘出術

仲村, 勝, 藤井, 多久磨, 西尾, 浩, 岩田, 卓 and 青木, 大輔

産婦人科の実際 57 ( 11 ) 1734 - 1740 2008

ISSN 0558-4728

Epigenetic inactivation of the CHFR gene in cervical cancer contributes to sensitivity to taxanes

Banno, K., Yanokura, M., Kawaguchi, M., Kuwabara, Y., Akiyoshi, J., Kobayashi, Y., Iwata, T., Hirasawa, A., Fujii, T., Susumu, N., Tsukazaki, K. and Aoki, D.

Int J Oncol 31 ( 4 ) 713 - 20 2007.10

ISSN 1019-6439

A relationship between inactivation of mitotic checkpoint genes and sensitivity of cancer cells to anticancer agents has been reported. We investigated the effect of epigenetic inactivation by aberrant hypermethylation of the mitotic checkpoint gene CHFR (checkpoint with forkhead and ring finger) on the sensitivity of cervical cancer cells to taxanes. Methylation-specific PCR (MSP) of cervical smears showed aberrant methylation of CHFR in 12.3% (2/14) of adenocarcinoma specimens. In contrast, aberrant DNA methylation was not detected in normal cervical cells or squamous cell carcinoma cells. Aberrant methylation of CHFR was also analyzed in 6 human cervical carcinoma-derived cell lines and was observed in SKG-IIIb and HeLa cells. These cell lines showed high sensitivity to taxanes, but became taxane-resistant upon treatment with 5-azacytidine. Furthermore, suppression of CHFR expression in siRNA-transfected SKG-IIIa cells caused increased sensitivity to taxanes. In conclusion, aberrant methylation of the CHFR gene may be useful as a molecular marker for selection of therapy for patients with cervical adenocarcinoma with a poor prognosis, and may also suggest a new therapeutic strategy of targeting CHFR in cervical cancer. To our knowledge, this study is the first to examine epigenetic inactivation by aberrant hypermethylation of CHFR in cervical cancer.

Epigenetic inactivation of the CHFR gene in cervical cancer contributes to sensitivity to taxanes

Banno Kouji, Yanokura Megumi, Kawaguchi Makiko, Kuwabara Yoshiko, Akiyoshi Jyunko, Kobayashi Yusuke, Iwata Takashi, Hirasawa Akira, Fujii Takuma, Susumu Nobuyuki, Tsukazaki Kastumi, Aoki Daisuke

International Journal of Oncology 31 ( 4 ) 713 - 720 2007.10

ISSN 1019-6439

A relationship between inactivation of mitotic checkpoint genes and sensitivity of cancer cells to anticancer agents has been reported. We investigated the effect of epigenetic inactivation by aberrant hypermethylation of the mitotic checkpoint gene CHFR (checkpoint with forkhead and ring finger) on the sensitivity of cervical cancer cells to taxanes. Methylation-specific PCR (MSP) of cervical smears showed aberrant methylation of CHFR in 12.3% (2/14) of adenocarcinoma specimens. In contrast, aberrant DNA methylation was not detected in normal cervical cells or squamous cell carcinoma cells. Aberrant methylation of CHFR was also analyzed in 6 human cervical carcinoma-derived cell lines and was observed in SKG-IIIb and HeLa cells. These cell lines showed high sensitivity to taxanes, but became taxane-resistant upon treatment with 5-azacytidine. Furthermore, suppression of CHFR expression in siRNA-transfected SKG-IIIa cells caused increased sensitivity to taxanes. In conclusion, aberrant methylation of the CHFR gene may be useful as a molecular marker for selection of therapy for patients with cervical adenocarcinoma with a poor prognosis, and may also suggest a new therapeutic strategy of targeting CHFR in cervical cancer. To our knowledge, this study is the first to examine epigenetic inactivation by aberrant hypermethylation of CHFR in cervical cancer.

莢膜細胞腫に合併した子宮体癌の1例

青海, 咲子, 岩田, 卓, 飯塚, 真, 小川, 誠司, 味八木, 寿子, 山上, 聖子, 松本, 直, 上野, 和典, 片岡, 史夫, 山下, 博, 新井, 宏治 and 廣瀬, 茂道

日本産科婦人科学会東京地方部会会誌 2007

症例は71歳、3経妊2経産。不正出血を主訴に来院した。内診では子宮は正常大、両側付属器を触知せず、経腟超音波断層法で内膜肥厚を認めた。頸部細胞診、内膜細胞診ともにclass II、内膜組織診は単純型子宮内膜増殖症であった。6ヵ月後の再検でも同様の結果であったため、その時点での治療は必要ないと判断し、患者希望で他院での定期検査とした。2年後に再度不正出血があり紹介受診となった。受診時、内膜細胞診はclass II、内膜組織診は単純型子宮内膜増殖症であり、右付属器に充実性腫瘍を認めたため、臨床経過よりエストロゲン産生腫瘍に伴う子宮内膜増殖症の可能性を考え、単純子宮全摘術・両側付属器切除術を行った。術後病理組織診断は莢膜細胞腫および子宮体癌I a期であった。閉経後にエストロゲン高値および充実性卵巣腫瘍認める場合、エストロゲン産生腫瘍の可能性および子宮内膜癌の併発を念頭に置く必要がある。

【誤診しやすい腫瘍・類腫瘍】 Peritoneal inclusion cyst　嚢胞性卵巣腫瘍との鑑別

岩田, 卓, 山下, 博, 新井, 宏治 and 青木, 大輔

産科と婦人科 74 ( 6 ) 676 - 683 2007

ISSN 0386-9792

【女性と生活習慣病】がん

岩田, 卓, 新井, 宏治 and 青木, 大輔

HORMONE FRONTIER IN GYNECOLOGY 14 ( 1 ) 59 - 64 2007

ISSN 1340-220X

肥満者ではインスリンやIGF-1(insulin-like growth factor-1)などの細胞増殖因子の分泌が増加し、子宮内膜がんをはじめ乳がん、大腸がん、腎がんなどの発がん要因となる。中でも子宮内膜組織においては閉経前と閉経後で機序は異なるものの、エストロゲンによる増殖刺激が肥満により亢進するため、特にがん化の関連が強い。一方、乳がんについては閉経後肥満女性での発がんの危険率は増加するが、閉経前肥満女性では逆に低下するとされている。本稿では肥満者における子宮内膜がんと乳がんの発がん機序を中心に、婦人科がんを生活習慣病の視点から解説する。(著者抄録)

【婦人科悪性腫瘍の術前診断(がんの局在、局所的および遠隔転移)のピットホール】子宮頸部0期がん・初期がんの診断に円錐切除は有用か　有用なので比較的に適応範囲を広くしている

岩田, 卓, 藤井, 多久磨, 平尾, 薫丸 and 青木, 大輔

産婦人科の世界 59 ( 8 ) 679 - 684 2007

ISSN 0386-9873

右付属器切除術後に月経困難症が発症した単角孤立性副角子宮の1例

山上, 聖子, 林, 茂徳, 岩田, 卓, 青海, 咲子, 飯塚, 真, 小川, 誠司, 味八木, 寿子, 松本, 直, 上野, 和典, 片岡, 史夫, 山下, 博, 新井, 宏治 and 廣瀬, 茂道

日本産科婦人科学会東京地方部会会誌 56 ( 3 ) 315 - 318 2007

ISSN 0288-5751

右付属器切除術後に月経困難症が増悪し、双角子宮との鑑別が困難であった単角孤立性副角子宮の症例を経験したので報告する。症例は41歳女性、1経妊1経産。右下腹部痛を主訴に来院し、MRIにて右チョコレート嚢腫と双角子宮を認めた。右卵巣嚢腫に対して右付属器切除術を行い術後病理組織診断では、内膜症性嚢胞であった。術後月経困難症状の増悪を認めたため、MRIを再度撮影したところ、子宮右側に内膜症性嚢胞の再発を疑わせる腫瘤を認めた。内膜症の根治目的で単純子宮全摘出術、腫瘍摘出術、左付属器切除術を施行、術後病理組織検査により腫瘍は内膜症性病変ではなく、孤立性副角の診断となった。本患者の子宮は双角子宮ではなく孤立性副角子宮であり、右付属器切除術の際の卵管切除のために月経血の流出を妨げ、子宮留血腫を形成し症状の増悪を引き起こしたと考えられた。子宮奇形の症例では、術前診断をより適確にする必要があると考えられた。(著者抄録)

A novel cancer testis antigen that is frequently expressed in pancreatic, lung, and endometrial cancers

Okada Takaho, Akada Masanori, Fujita Tomonobu, Iwata Takashi, Goto Yasufumi, Kido Kenji, Okada Tsutomu, Matsuzaki Yuriko, Kobayashi Kouichi, Matsuno Seiki, Sunamura Makoto, Kawakami Yutaka

Clinical Cancer Research 12 ( 1 ) 191 - 197 2006.01

ISSN 1078-0432

Purpose: To isolate cancer testis antigens that are expressed in pancreatic cancers and may be useful in clinical applications. Experimental Design: To efficiently isolate cancer testis antigens, a testis cDNA library was immunoscreened (SEREX) with serum from a patient with pancreatic ductal adenocarcinoma. The expression of isolated antigens in various cancer cell lines and tissues was evaluated by reverse transcription-PCR and Northern blot analyses. The immunogenicity of the antigen in cancer patients was evaluated by detection of the IgG antibody in sera from patients with various cancers. Results: Of the three clones isolated through screening of a total of 2 × 10⁶ cDNA library clones, one clone (KU-CT-1) was found to be expressed in various cancers but only in testis among normal tissues, indicating that it was a novel cancer testis antigen. The KU-CT-1 gene is located on chromosome 10p12 and produces two splice variants, which encode proteins of 397 and 872 amino acids, respectively. KU-CT-1 was expressed in pancreatic cancer tissues (3 of 9, 33%), lung cancer tissues (9 of 24, 38%), and endometrial cancer tissues (7 of 11, 64%). Specific serum IgG antibodies were detected in 3 of 20 pancreatic cancer patients, 2 of 12 endometrial cancer patients, 1 of 18 colon cancer patients, and 1 of 10 prostate cancer patients but not detected in 30 healthy individuals. Conclusions: KU-CT-1 is a new cancer testis antigen that is expressed in pancreatic, lung, and endometrial cancers and may be useful for diagnosis and immunotherapy for patients with various cancers. © 2006 American Association for Cancer Research.

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A novel cancer testis antigen that is frequently expressed in pancreatic, lung, and endometrial cancers

Okada, T., Akada, M., Fujita, T., Iwata, T., Goto, Y., Kido, K., Matsuzaki, Y., Kobayashi, K., Matsuno, S., Sunamura, M. and Kawakami, Y.

Clin Cancer Res 12 ( 1 ) 191 - 7 2006.01

ISSN 1078-0432

To isolate cancer testis antigens that are expressed in pancreatic cancers and may be useful in clinical applications.|To efficiently isolate cancer testis antigens, a testis cDNA library was immunoscreened (SEREX) with serum from a patient with pancreatic ductal adenocarcinoma. The expression of isolated antigens in various cancer cell lines and tissues was evaluated by reverse transcription-PCR and Northern blot analyses. The immunogenicity of the antigen in cancer patients was evaluated by detection of the IgG antibody in sera from patients with various cancers.|Of the three clones isolated through screening of a total of 2 x 10(6) cDNA library clones, one clone (KU-CT-1) was found to be expressed in various cancers but only in testis among normal tissues, indicating that it was a novel cancer testis antigen. The KU-CT-1 gene is located on chromosome 10p12 and produces two splice variants, which encode proteins of 397 and 872 amino acids, respectively. KU-CT-1 was expressed in pancreatic cancer tissues (3 of 9, 33%), lung cancer tissues (9 of 24, 38%), and endometrial cancer tissues (7 of 11, 64%). Specific serum IgG antibodies were detected in 3 of 20 pancreatic cancer patients, 2 of 12 endometrial cancer patients, 1 of 18 colon cancer patients, and 1 of 10 prostate cancer patients but not detected in 30 healthy individuals.|KU-CT-1 is a new cancer testis antigen that is expressed in pancreatic, lung, and endometrial cancers and may be useful for diagnosis and immunotherapy for patients with various cancers.

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結節性硬化症に関連する子宮組織奇形　大量出血にて発症した1例

利安, 隆史, 水沼, 仁孝, 加藤, 弘毅, 菅原, 俊祐, 白石, 悟, 末盛, 友浩, 岩田, 卓 and 西川, 眞史

臨床放射線 51 ( 10 ) 1241 - 1245 2006

ISSN 0009-9252

31歳女。不正性器出血持続、大量性器出血で緊急入院となった。貧血に対し輸血が施行され、.経腟エコーで右卵巣腫瘍が疑われ、MRが施行された。骨盤内には子宮と一塊となった内部構造不均一な腫瘤病変を認めた。子宮後面には異常な腔があり、内部には出血信号を示す液体貯留が存在した。CTでは非常に血流に富み内部不均一な骨盤内腫瘤、大量の腹腔内出血、骨盤内右側には高濃度血腫を認めた。造影で腫瘍腹側は強く濃染され、腫瘍左側に造影剤の血管外漏出が疑われた。経皮的塞栓術施行のため血管造影を施行、骨盤血管造影を行うと右内腸骨動脈が欠損し、代わりに左内腸骨が代償性に拡張していた。左子宮動脈をジェルフォーム細片、ボルテックスコイル2本で塞栓した。

【婦人科がん治療周辺領域の進歩】細胞診断　子宮頸がん検診におけるHPV検査の有用性

岩田, 卓, 藤井, 多久磨, 平尾, 薫丸, 斎藤, 深雪, 仲村, 勝, 大野, 暁子, 石川, 光也, 塚崎, 克己 and 青木, 大輔

産婦人科の世界 58 ( 12 ) 1111 - 1118 2006

ISSN 0386-9873

最近、当院で経験した絨毛性疾患の2例

飯塚, 真, 岩田, 卓, 青海, 咲子, 小川, 誠司, 山上, 聖子, 味八木, 寿子, 松本, 直, 上野, 和典, 片岡, 史夫, 山下, 博 and 新井, 宏治

日本産科婦人科学会東京地方部会会誌 55 ( 4 ) 448 - 453 2006

ISSN 0288-5751

我々が経験した臨床的絨毛癌および臨床的侵入奇胎の症例を報告する。症例1は39歳0経妊0経産。胞状奇胎の掻爬術後、経過順調型であったが術後8ヵ月目に血中hCGβ値が再上昇した。子宮に病巣はなく、肺に病巣を認めたため絨毛癌診断スコアにより臨床的絨毛癌と診断し、さらにWHO予後スコアによって低リスク症例と判定した。当初、アクチノマイシンDの単剤投与を行ったが、治療期間中にhCGβ値が上昇したため、EMA療法に変更し寛解となった。しかし寛解後8ヵ月で血中hCGβ値の再上昇認め、EMA療法を再開して再度寛解となった時点で肺病巣切除と子宮全摘術を行った。症例2は34歳0経妊0経産。胞状奇胎の掻爬術後、4週目に血中hCGβ値が上昇した。子宮筋層に原発巣を認め、同時に肺転移巣と思われる腫瘤を認めた。絨毛癌診断スコアにより臨床的侵入奇胎と診断し、WHO予後スコアによって中等度リスク症例と判定した。MAC療法を行って寛解となった。絨毛性疾患の治療にあたってはその厳密な診断および治療の選択が重要であると考えられた。(著者抄録)

Immune responses to DNA mismatch repair enzymes hMSH2 and hPMS1 in patients with pancreatic cancer, dermatomyositis and polymyositis

Okada Takaho, Noji Shinobu, Goto Yasufumi, Iwata Takashi, Fujita Tomonobu, Okada Tsutomu, Matsuzaki Yuriko, Kuwana Masataka, Hirakata Michito, Horii Akira, Matsuno Seiki, Sunamura Makoto, Kawakami Yutaka

International Journal of Cancer 116 ( 6 ) 925 - 933 2005.10

ISSN 0020-7136

To identify tumor antigens useful for diagnosis and immunotherapy of patients with pancreatic ductal adenocarcinoma, we applied a SEREX approach with a cDNA library made from 5 pancreatic cancer cell lines and sera obtained from 8 patients with pancreatic cancer, and isolated total 32 genes, including 14 previously characterized genes and 18 genes with unknown functions. Among these isolated antigens, serum IgG antibodies for 2 isolated DNA mismatch repair enzymes, Homo sapiens mutS homolog 2 (HMSH2) and Homo sapiens postmeiotic segregation increased 1 (hPMS1), were detected in patients with pancreatic ductal adenocarcinoma and dermatomyositis (DM), and polymyositis (PM), but not in sera from healthy individuals. Immunohistochemical study demonstrated that hMSH2 and hPMS1 were over-expressed in pancreatic ductal adenocarcinoma compared to normal pancreatic ducts. These results suggested that hMSH2 and hPMS1 may be useful as CD4+ helper T cell antigens for immunotherapy of pancreatic cancer patients and that serum IgG antibodies may be useful for diagnosis of patients with pancreatic ductal adenocarcinoma and DM/PM. © 2005 Wiley-Liss, Inc.

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Immune responses to DNA mismatch repair enzymes hMSH2 and hPMS1 in patients with pancreatic cancer, dermatomyositis and polymyositis

Okada, T., Noji, S., Goto, Y., Iwata, T., Fujita, T., Matsuzaki, Y., Kuwana, M., Hirakata, M., Horii, A., Matsuno, S., Sunamura, M. and Kawakami, Y.

Int J Cancer 116 ( 6 ) 925 - 33 2005.10

ISSN 0020-7136

To identify tumor antigens useful for diagnosis and immunotherapy of patients with pancreatic ductal adenocarcinoma, we applied a SEREX approach with a cDNA library made from 5 pancreatic cancer cell lines and sera obtained from 8 patients with pancreatic cancer, and isolated total 32 genes, including 14 previously characterized genes and 18 genes with unknown functions. Among these isolated antigens, serum IgG antibodies for 2 isolated DNA mismatch repair enzymes, Homo sapiens mutS homolog 2 (hMSH2) and Homo sapiens postmeiotic segregation increased 1 (hPMS1), were detected in patients with pancreatic ductal adenocarcinoma and dermatomyositis (DM), and polymyositis (PM), but not in sera from healthy individuals. Immunohistochemical study demonstrated that hMSH2 and hPMS1 were over-expressed in pancreatic ductal adenocarcinoma compared to normal pancreatic ducts. These results suggested that hMSH2 and hPMS1 may be useful as CD4+ helper T cell antigens for immunotherapy of pancreatic cancer patients and that serum IgG antibodies may be useful for diagnosis of patients with pancreatic ductal adenocarcinoma and DM/PM.

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Frequent immune responses to a cancer/testis antigen, CAGE, in patients with microsatellite instability - Positive endometrial cancer

Iwata Takashi, Fujita Tomonobu, Hirao Nobumaru, Matsuzaki Yuriko, Okada Tsutomu, Mochimaru Hiroshi, Susumu Nobuyuki, Matsumoto Eri, Sugano Kokichi, Yamashita Naohide, Nozawa Shiro, Kawakami Yutaka

Clinical Cancer Research 11 ( 10 ) 3949 - 3957 2005.05

ISSN 1078-0432

Purpose: Identification of cancer/testis antigens useful for diagnosis or immunotherapy of cancers was attempted by cDNA expression cloning with patients' sera (SEREX). Experimental Design: cDNA expression libraries made from testis or endometrial cancer cell lines were screened using sera from patients with endometrial cancer or melanoma patients immunized with dendritic cells pulsed with autologous tumor lysates. Tissue-specific expression by RT-PCR and immunogenicity by Western blotting of the bacterial recombinant antigen with sera from cancer patients were evaluated. Results: A cancer/testis antigen, CAGE, was isolated by two independently performed SEREX. CAGE was expressed in various cancer cell lines including endometrial cancer, colon cancer, and melanoma in 7 of 10 endometrial cancer tissues and in 1 of 3 atypical endometrial hyperplasia, but not in normal tissues including the endometrium and testis. The protein expression on cancer cells was confirmed by Western blot analysis with the recombinant CAGE protein, anti-CAGE IgG antibody was detected in sera from 5 of 45 endometrial cancer, 2 of 24 melanoma, and 2 of 33 colon cancer patients, but not in sera from healthy individuals. By ELISA analysis, anti-CAGE antibody was detected in 12 of 45 endometrial cancer, 2 of 20 melanoma, and 4 of 33 colon cancer patients. Intriguingly, anti-CAGE antibody was highly positive in 7 of the 13 (53.8%) microsatellite instability (MSI)-H patients with endometrial cancer, but negative in 20 non-MSI-H patients (P = 0.001). Conclusion: CAGE may be useful for immunotherapy and diagnosis of various cancers particularly MSI-positive endometrial cancer. © 2005 American Association for Cancer Research.

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Frequent immune responses to a cancer/testis antigen, CAGE, in patients with microsatellite instability-positive endometrial cancer

Iwata, T., Fujita, T., Hirao, N., Matsuzaki, Y., Okada, T., Mochimaru, H., Susumu, N., Matsumoto, E., Sugano, K., Yamashita, N., Nozawa, S. and Kawakami, Y.

Clin Cancer Res 11 ( 10 ) 3949 - 57 2005.05

ISSN 1078-0432

Identification of cancer/testis antigens useful for diagnosis or immunotherapy of cancers was attempted by cDNA expression cloning with patients' sera (SEREX).|cDNA expression libraries made from testis or endometrial cancer cell lines were screened using sera from patients with endometrial cancer or melanoma patients immunized with dendritic cells pulsed with autologous tum or lysates. Tissue-specific expression by RT-PCR and immunogenicity by Western blotting of the bacterial recombinant antigen with sera from cancer patients were evaluated.|A cancer/testis antigen, CAGE, was isolated by two independently performed SEREX. CAGE was expressed in various cancer cell lines including endometrial cancer, colon cancer, and melanoma in 7 of 10 endometrial cancer tissues and in 1 of 3 atypical endometrial hyperplasia, but not in normal tissues including the endometrium and testis. The protein expression on cancer cells was confirmed by Western blot analysis with the recombinant CAGE protein, anti-CAGE IgG antibody was detected in sera from 5 of 45 endometrial cancer, 2 of 24 melanoma, and 2 of 33 colon cancer patients, but not in sera from healthy individuals. By ELISA analysis, anti-CAGE antibody was detected in 12 of 45 endometrial cancer, 2 of 20 melanoma, and 4 of 33 colon cancer patients. Intriguingly, anti-CAGE antibody was highly positive in 7 of the 13 (53.8%) microsatellite instability (MSI)-H patients with endometrial cancer, but negative in 20 non-MSI-H patients (P = 0.001).|CAGE may be useful for immunotherapy and diagnosis of various cancers particularly MSI-positive endometrial cancer.

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ICSI後の月経中にDICにいたった子宮腺筋症の一例

末盛, 友浩, 浅井, 哲, 加藤, 直子, 佐藤, 健二, 岩田, 卓 and 白石, 悟

栃木県産婦人科医報 32 ( 1 ) 33 - 35 2005

【研修医のための身体所見のとり方】　産婦人科的診察について

岩田, 卓, 久布白, 兼行 and 野澤, 志朗

診断と治療 93 ( 4 ) 523 - 528 2005

ISSN 0370-999X

子宮原発の脂肪肉腫類似腫瘍の一例

浅井, 哲, 櫻井, 友義, 末盛, 友浩, 加藤, 直子, 佐藤, 健二, 岩田, 卓, 郡山, 智, 白石, 悟 and 西川, 眞史

栃木県産婦人科医報 32 ( 1 ) 26 - 29 2005

症例は71歳,3経妊3経産,閉経50歳.他院にて子宮癌検診時に超音波断断層法で高輝度な子宮腫瘍を指摘され,当院を紹介受診した.特に自覚症状はなかった.骨盤MRIではT1およびT2強調画像にて高信号を呈していたが,一部低信号領域が混在する不整な像を認める腫瘍であった.また脂肪抑制像では信号が抑制されたことから脂肪性腫瘍であると推測した.以上より子宮平滑筋脂肪腫を考えたが,内部不均一な画像より鑑別診断として子宮肉腫も否定できず,腹式単純子宮全摘出術および両側付属器切除術を行った.摘出標本での腫瘍部は割面像が境界明瞭な黄色の結節で,一部に灰白色を呈し,特に肉眼的変性像は認めなかった.病理組織学的には脂肪成分が分化型脂肪肉腫に類似していたが,平滑筋成分には悪性と断定しうる所見は認められなかった.子宮原発の脂肪肉腫は極めて発生頻度が少なく,病理診断は非常に困難であったため,最終診断として「子宮原発の分化型脂肪肉腫類似の脂肪成分を有する平滑筋性腫瘍」との表現とした(著者抄録)

Dominant human papillomavirus 16 infection in cervical neoplasia in young Japanese women; study of 881 outpatients

Masumoto, N., Fujii, T., Ishikawa, M., Mukai, M., Ono, A., Iwata, T., Kubushiro, K. and Nozawa, S.

Gynecol Oncol 94 ( 2 ) 509 - 14 2004.08

ISSN 0090-8258

Human papillomavirus (HPV) infection is reported to be related to carcinogenesis in the uterine cervix. In Japan, screening for cervical cancer by cytology is performed in women over 30 years old. The purpose of this study was to determine whether there is an association between patient age and cervical neoplasia or HPV infection in Japanese women.|Specimens from 881 randomly selected patients who came to our clinic were tested for HPV DNA by using Hybrid Capture II, whereas specimens from a 204-patient randomly selected subset diagnosed with cervical neoplasia were tested for HPV DNA by using polymerase chain reaction (PCR). HPV typing was performed in all the PCR-positive cases.|The HPV-positive rate in the 20- to 29-year-old patients (29.0% in the normal cytology/histology group and 85.5% in the abnormal group) was higher than in the 30- to 59-year-old patients, and the rate declined until age 60 when age increased. While HPV 18, HPV 52, other HPV types, and HPV types as a whole were frequently detected in 30- to 49-year-old patients, HPV 16 was detected more frequently in the younger group than the other HPV types (P = 0.03). Among the HPV 16-positive patients with cervical neoplasia, the proportion of cervical intraepithelial neoplasia (CIN) 3 cases was high (44%) in the 20- to 29-year-old group.|Screening for cervical neoplasia by cytology should also be performed in women under 30 years old in Japan. The HPV typing could be a tool to strictly follow-up younger women who were diagnosed with CIN.

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Association of HNPCC and endometrial cancers

Banno Kouji, Susumu Nobuyuld, Yanokura Megumi, Hirao Takeshi, Iwata Takashi, Hirasawa Akira, Aoki Daisuke, Sugano Kokichi, Nozawa Shiro

International Journal of Clinical Oncology 9 ( 4 ) 262 - 269 2004.08

ISSN 1341-9625

Hereditary nonpolyposis colorectal cancer (HNPCC) is among the representative familial cancers that are autosomally dominant inherited disorders. Because endometrial cancers develop at high rates in women with HNPCC, it is suggested that some endometrial cancers are familial cancers that are induced by mutations of the DNA mismatch repair (MMR) genes, as in HNPCC. To understand the clinical pathology of familial endometrial cancers that are associated with HNPCC, we surveyed the family histories of 385 patients with endometrial cancer and found that 0.5% of endometrial cancers met the new diagnostic criteria of HNPCC. From molecular and biological analyses, we found microsatellite instability in 30.8% of endometrial cancers and germline mutations of MMR genes in 8.3%. These results suggest a close relationship of MMR gene mutations to the development of endometrial cancers. For a better understanding of the clinical pathology of HNPCC-associated familial endometrial cancers, it is critical for gynecologists to perform a large multicenter study, including detailed family histories.

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Dominant human papillomavirus 16 infection in cervical neoplasia in young Japanese women; study of 881 outpatients

Masumoto Nobuo, Fujii Takuma, Ishikawa Mitsuya, Mukai Makio, Ono Akiko, Iwata Takashi, Kubushiro Kaneyuki, Nozawa Shiro

Gynecologic Oncology 94 ( 2 ) 509 - 514 2004.08

ISSN 0090-8258

Objective. Human papillomavirus (HPV) infection is reported to be related to carcinogenesis in the uterine cervix. In Japan, screening for cervical cancer by cytology is performed in women over 30 years old. The purpose of this study was to determine whether there is an association between patient age and cervical neoplasia or HPV infection in Japanese women. Methods. Specimens from 881 randomly selected patients who came to our clinic were tested for HPV DNA by using Hybrid Capture II, whereas specimens from a 204-patient randomly selected subset diagnosed with cervical neoplasia were tested for HPV DNA by using polymerase chain reaction (PCR). HPV typing was performed in all the PCR-positive cases. Results. The HPV-positive rate in the 20- to 29-year-old patients (29.0% in the normal cytology/histology group and 85.5% in the abnormal group) was higher than in the 30- to 59-year-old patients, and the rate declined until age 60 when age increased. While HPV 18, HPV 52, other HPV types, and HPV types as a whole were frequently detected in 30- to 49-year-old patients, HPV 16 was detected more frequently in the younger group than the other HPV types (P = 0.03). Among the HPV 16-positive patients with cervical neoplasia, the proportion of cervical intraepithelial neoplasia (CIN) 3 cases was high (44%) in the 20- to 29-year-old group. Conclusions. Screening for cervical neoplasia by cytology should also be performed in women under 30 years old in Japan. The HPV typing could be a tool to strictly follow-up younger women who were diagnosed with CIN. © 2004 Elsevier Inc. All rights reserved.

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Association of HNPCC and endometrial cancers

Banno, K., Susumu, N., Yanokura, M., Hirao, T., Iwata, T., Hirasawa, A., Aoki, D., Sugano, K. and Nozawa, S.

Int J Clin Oncol 9 ( 4 ) 262 - 9 2004.08

ISSN 1341-9625

Hereditary nonpolyposis colorectal cancer (HNPCC) is among the representative familial cancers that are autosomally dominant inherited disorders. Because endometrial cancers develop at high rates in women with HNPCC, it is suggested that some endometrial cancers are familial cancers that are induced by mutations of the DNA mismatch repair (MMR) genes, as in HNPCC. To understand the clinical pathology of familial endometrial cancers that are associated with HNPCC, we surveyed the family histories of 385 patients with endometrial cancer and found that 0.5% of endometrial cancers met the new diagnostic criteria of HNPCC. From molecular and biological analyses, we found microsatellite instability in 30.8% of endometrial cancers and germline mutations of MMR genes in 8.3%. These results suggest a close relationship of MMR gene mutations to the development of endometrial cancers. For a better understanding of the clinical pathology of HNPCC-associated familial endometrial cancers, it is critical for gynecologists to perform a large multicenter study, including detailed family histories.

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【子宮頸癌・子宮体癌・卵巣癌の診断と治療　最新の研究動向】　子宮頸癌　子宮頸癌の治療　手術概論

久布白, 兼行, 岩田, 卓 and 野澤, 志朗

日本臨床 62 ( 増刊10 子宮頚癌・子宮体癌・卵巣癌の診断と治療 ) 134 - 140 2004

ISSN 0047-1852

Surgical treatment for cervical cancer

Kubushiro Kaneyuki, Iwata Takashi, Nozawa Shiro

Nippon rinsho. Japanese journal of clinical medicine 62 Suppl 10 134 - 140 2004

ISSN 0047-1852

腫瘍マーカー　婦人科分野の腫瘍マーカー

岩田, 卓, 塚崎, 克己 and 野澤, 志朗

Drug Delivery System 19 ( 2 ) 133 - 135 2004

ISSN 0913-5006

p16^INK4a overexpression and human papillomavirus infection in small cell carcinoma of the uterine cervix

Masumoto Nobuo, Fujii Takuma, Ishikawa Mitsuya, Saito Miyuki, Iwata Takashi, Fukuchi Takeshi, Susumu Nobuyuki, Mukai Makio, Kubushiro Kaneyuki, Tsukazaki Katsumi, Nozawa Shiro

Human Pathology 34 ( 8 ) 778 - 783 2003.09

ISSN 0046-8177

Carcinogenesis of cervical cancer has been investigated, and p16 ^INK4a overexpression in squamous cell carcinoma of the cervix has been reported as a result of infection by human papillomavirus (HPV) (eg, HPV 16), and the consequence of the retinoblastoma (Rb) protein inactivation by HPV E7 protein. However, to our knowledge, there have been no studies on the relation between p16^INK4a overexpression associated with HPV and small cell carcinoma of the cervix, which behaves more aggressively clinically than squamous cell carcinoma. The purpose of this study was to determine whether p16^INK4a is overexpressed in small cell carcinoma, and if p16^INK4a is overexpressed, the types of HPV that are related to this cancer. We reviewed 10 cases of small cell carcinoma and examined them for p16^INK4a overexpression by immunohistochemistry. We also performed HPV typing with polymerase chain reaction (PCR)-sequencing analysis and in situ hybridization and found that p16^INK4a was overexpressed in every case. PCR-sequencing analyses revealed that all cases were HPV-positive and that 9 cases were positive for HPV 18. Five of the 9 cases positive for HPV 18 were also positive by in situ hybridization and yielded a punctate signal, considered to represent the integrated form. In conclusion, p16^INK4a was overexpressed and HPV 18 was frequently detected in an integrated form in small cell carcinoma. Therefore, inactivation of Rb protein by HPV 18 E7 protein may be associated with carcinogenesis of small cell carcinoma the same as inactivation of Rb protein by HPV 16 E7 protein is associated with carcinogenesis of squamous cell carcinoma. © 2003 Elsevier Inc. All rights reserved.

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P16 overexpression and human papillomavirus infection in small cell carcinoma of the uterine cervix

Masumoto, N., Fujii, T., Ishikawa, M., Saito, M., Iwata, T., Fukuchi, T., Susumu, N., Mukai, M., Kubushiro, K., Tsukazaki, K. and Nozawa, S.

Hum Pathol 34 ( 8 ) 778 - 83 2003.08

ISSN 0046-8177

Carcinogenesis of cervical cancer has been investigated, and p16(INK4a) overexpression in squamous cell carcinoma of the cervix has been reported as a result of infection by human papillomavirus (HPV) (eg, HPV 16), and the consequence of the retinoblastoma (Rb) protein inactivation by HPV E7 protein. However, to our knowledge, there have been no studies on the relation between p16(INK4a) overexpression associated with HPV and small cell carcinoma of the cervix, which behaves more aggressively clinically than squamous cell carcinoma. The purpose of this study was to determine whether p16(INK4a) is overexpressed in small cell carcinoma, and if p16(INK4a) is overexpressed, the types of HPV that are related to this cancer. We reviewed 10 cases of small cell carcinoma and examined them for p16(INK4a) overexpression by immunohistochemistry. We also performed HPV typing with polymerase chain reaction (PCR)-sequencing analysis and in situ hybridization and found that p16(INK4a) was overexpressed in every case. PCR-sequencing analyses revealed that all cases were HPV-positive and that 9 cases were positive for HPV 18. Five of the 9 cases positive for HPV 18 were also positive by in situ hybridization and yielded a punctate signal, considered to represent the integrated form. In conclusion, p16(INK4a) was overexpressed and HPV 18 was frequently detected in an integrated form in small cell carcinoma. Therefore, inactivation of Rb protein by HPV 18 E7 protein may be associated with carcinogenesis of small cell carcinoma the same as inactivation of Rb protein by HPV 16 E7 protein is associated with carcinogenesis of squamous cell carcinoma.

P16^INK4aoverexpression and human papillomavirus infection in small cell carcinoma of the uterine cervix

Masumoto Nobuo， Fujii Takuma， Ishikawa Mitsuya， Saito Miyuki， Iwata Takashi， Fukuchi Takeshi， Susumu Nobuyuki， Mukai Makio， Kubushiro Kaneyuki， Tsukazaki Katsumi， Nozawa Shiro

Human Pathology 34 ( 8 ) 778-783 2003.08

Research paper (scientific journal), Joint Work

遺伝性子宮内膜癌とは−特にDNAミスマッチ修復遺伝子について

阪埜浩司，進　伸幸，矢野倉恵，平尾　健，岩田　卓，平沢　晃，青木大輔，野澤志朗

産婦人科の世界 55 ( 8 ) 863-870 2003.08

Research paper (scientific journal), Joint Work

Papanicolaou tests and molecular analyses using new fluid-based specimen collection technology in 3000 Japanese women

Masumoto N., Fujii T., Ishikawa M., Mukai M., Saito M., Iwata T., Fukuchi T., Kubushiro K., Tsukazaki K., Nozawa S.

British Journal of Cancer 88 ( 12 ) 1883 - 1888 2003.06

ISSN 0007-0920

A fluid-based Papanicolaou test has been established to improve sample collection and preparation. This study was the first largescale investigation in Japan to examine the feasibility of using fluid-based Papanicolaou specimens to detect human papillomavirus (HPV) using Hybrid Capture II and polymerase chain reaction (PCR). Three thousand patients who visited Keio University Hospital between October 2000 and February 2001 were enrolled in the study. The results of the fluid-based Papanicolaou tests corresponded well with those of conventional Papanicolaou smears (96.8% concordance). The sensitivities of cervical neoplasia detection using the fluid-based Papanicolaou test (73.9%) and Hybrid Capture II (76.3%, P=0.55) were not significantly different. Among the cervical intraepithelial neoplasia 3 and squamous cell carcinoma specimens, HPV 16 and HPV 52 were predominantly detected using the PCR method. Although some DNA samples extracted from the fluid-based specimens were degradaded, PCR and direct sequencing could be performed without difficulty even after 1 year of specimen storage. We conclude that fluid-based Papanicolaou specimens can be applied to investigate HPV infection. © 2003 Cancer Research UK.

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Papanicolaou tests and molecular analyses using new fluid-based specimen collection technology in 3000 Japanese women

Masumoto, N., Fujii, T., Ishikawa, M., Mukai, M., Saito, M., Iwata, T., Fukuchi, T., Kubushiro, K., Tsukazaki, K. and Nozawa, S.

Br J Cancer 88 ( 12 ) 1883 - 8 2003.06

ISSN 0007-0920

A fluid-based Papanicolaou test has been established to improve sample collection and preparation. This study was the first large-scale investigation in Japan to examine the feasibility of using fluid-based Papanicolaou specimens to detect human papillomavirus (HPV) using Hybrid Capture II and polymerase chain reaction (PCR). Three thousand patients who visited Keio University Hospital between October 2000 and February 2001 were enrolled in the study. The results of the fluid-based Papanicolaou tests corresponded well with those of conventional Papanicolaou smears (96.8% concordance). The sensitivities of cervical neoplasia detection using the fluid-based Papanicolaou test (73.9%) and Hybrid Capture II (76.3%, P=0.55) were not significantly different. Among the cervical intraepithelial neoplasia 3 and squamous cell carcinoma specimens, HPV 16 and HPV 52 were predominantly detected using the PCR method. Although some DNA samples extracted from the fluid-based specimens were degradaded, PCR and direct sequencing could be performed without difficulty even after 1 year of specimen storage. We conclude that fluid-based Papanicolaou specimens can be applied to investigate HPV infection.

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Papanicolaou tests and molecular analyses using new fluid-based specimen collection technology in 3000 Japanese women

Masumoto Nobuo， Fujii Takuma， Ishikawa Mitsuya，　Mukai Makio， Saito Miyuki， Iwata Takashi， Fukuchi Takeshi， Kubushiro Kaneyuki， Tsukazaki Katsumi， Nozawa Shiro

British Journal of Cancer 88 1883-1888 2003.06

Research paper (scientific journal), Joint Work

HNPCCの診療と研究遺伝性非腺腫症性大腸癌(HNPCC)と子宮内膜癌

阪埜浩司，進　伸幸，平尾　健，岩田　卓，平沢　晃，青木大輔，野澤志朗

家族性腫瘍 3 ( 2 ) 62-67 2003.05

Research paper (scientific journal), Joint Work

子宮体癌におけるMicrosatellite Instability(MSI)の検出に免疫組織化学は有用か?

進, 伸幸, 青木, 大輔, 阪埜, 浩司, 平尾, 健, 平沢, 晃, 岩田, 卓, 鈴木, 直, 菅野, 康吉, 向井, 万起男 and 野澤, 志朗

日本婦人科腫瘍学会雑誌 21 ( 3 ) 208 2003

ISSN 1347-8559

【HNPCCの診療と研究】　遺伝性非腺腫症性大腸癌(HNPCC)と子宮内膜癌

阪埜, 浩司, 進, 伸幸, 平尾, 健, 岩田, 卓, 平沢, 晃, 青木, 大輔 and 野澤, 志朗

家族性腫瘍 3 ( 2 ) 62 - 67 2003

ISSN 1346-1052

【子宮内膜癌のライフサイエンス'03】　遺伝性子宮内膜癌とは　特にDNAミスマッチ修復遺伝子について

阪埜, 浩司, 進, 伸幸, 矢野倉, 恵, 平尾, 健, 岩田, 卓, 平沢, 晃, 青木, 大輔 and 野澤, 志朗

産婦人科の世界 55 ( 8 ) 863 - 870 2003

ISSN 0386-9873

子宮体癌におけるMicrosatellite Instabilityと薬剤感受性試験によるcisplatin感受性との関連

進, 伸幸, 青木, 大輔, 阪埜, 浩司, 平尾, 健, 岩田, 卓, 平沢, 晃, 金杉, 優, 鈴木, 直, 菅野, 康吉, 宇田川, 康博, 吉村, 泰典 and 野澤, 志朗

日本産科婦人科学会雑誌 55 ( 2 ) 186 2003

ISSN 0300-9165

子宮内膜癌におけるマイクロサテライト不安定性とhMLH1蛋白発現低下との関連

阪埜, 浩司, 進, 伸幸, 平沢, 晃, 金杉, 優, 岩田, 卓, 鈴木, 直, 青木, 大輔, 菅野, 康吉, 吉村, 泰典 and 野澤, 志朗

日本産科婦人科学会雑誌 54 ( 2 ) 325 2002

ISSN 0300-9165

子宮内膜癌におけるマイクロサテライト不安定性とhMLH1蛋白発現低下との関連

阪埜, 浩司, 進, 伸幸, 平沢, 晃, 金杉, 優, 岩田, 卓, 青木, 大輔, 菅野, 康吉 and 野澤, 志朗

家族性腫瘍 2 ( 2 ) A43 2002

ISSN 1346-1052

【頸管無力症と頸管縫縮術】　頸管縫縮術の適応と問題点　円錐切除術後妊娠における適応と問題点

岩田, 卓, 塚崎, 克己, 久布白, 兼行 and 野澤, 志朗

臨床婦人科産科 56 ( 7 ) 858 - 861 2002

ISSN 0386-9865

子宮頸部円錐切除術における妊孕能温存

Kubushiro Kaneyuki，Masumoto Nobuo，Iwata Takashi，Tsukazaki Katsumi，Nozawa Shirou

産科と婦人科 68 ( 8 ) 1024-1030 2001.08

Research paper (scientific journal), Joint Work

I_a期FIGO分類とその取り扱い

Kubushiro Kaneyuki，Iwata Takashi，Tsukazaki Katsumi，Nozawa Shirou

産婦人科治療 82 ( 2 ) 109-114 2001.02

Research paper (scientific journal), Joint Work

【産婦人科手術での妊孕能温存の工夫】　子宮頸部円錐切除術における妊孕能温存

久布白, 兼行, 舛本, 暢生, 岩田, 卓, 塚崎, 克己 and 野澤, 志朗

産科と婦人科 68 ( 8 ) 1024 - 1030 2001

ISSN 0386-9792

近年,女性のライフスタイルの変化に伴って,子宮頸部上皮内癌や微小浸潤扁平上皮癌に対する治療的円錐切除術の症例が増加している.妊娠中に上皮内癌が発見された症例については,待機的に管理して分娩後治療する方法があるが,妊娠初期であれば手術時の出血や術後の流早産に十分に留意しながら,非妊娠時と同様に安全に円錐切除術を行うことが可能と考えられる.又,円錐切除術後に妊娠した症例では,早産率が高い傾向にあることから,慎重な妊娠管理が必要である

「子宮頸癌Ia2期の診断と治療―保存的治療は可能か？」当科における子宮頸癌Ia2期症例の臨床病理学的検討とその治療

Kubushiro Kaneyuki，Yamashita Hiroshi，Nakagawa Hiroyuki，Iwata Takashi，Takehara Kyouko，Fukuchi Takeshi，Fujii Takuma，Tsukazaki Katsumi，Nozawa Shirou

第39回子宮癌研究会誌 21-26 2001

Research paper (scientific journal), Joint Work

【頸癌診療の最前線】　Ia期FIGO分類とその取り扱い

久布白, 兼行, 岩田, 卓, 塚崎, 克己 and 野澤, 志朗

産婦人科治療 82 ( 2 ) 169 - 174 2001

ISSN 0558-471X

1997年に日本産婦人科学会で採用された子宮頸癌臨床進行期分類Ia期では,オリジナルのFIGO分類では明確ではなかった「浸潤の測定起点」及び「病変の広がり」について明確にしたこと,又,腺癌についてはIa1及びIa2期の細分類は行われないといった我が国での取り決めがある.Ia1,Ia2期症例における病理学的検討の結果では,Ia2期はIa1期に比べ骨盤リンパ節転移,脈管侵襲,癒合浸潤の頻度はいずれも高率であった.Ia1期については治療として円錐切除術が可能と考えられる.一方,Ia2期については子宮摘出前に診断する為には円錐切除術が必要であり,縮小手術として骨盤リンパ節郭清を含めた準広汎子宮全摘術が選択可能と考えられる

Gonadotropin-releasing hormone analogue therapy for peritoneal inclusion cysts after gynecological surgery

Nozawa, S., Iwata, T., Yamashita, H., Banno, K., Kubushiro, K., Aoki, R. and Tsukazaki, K.

J Obstet Gynaecol Res 26 ( 6 ) 389 - 93 2000.12

ISSN 1341-8076

The purpose of this report is to estimate the effectiveness of gonadotropin-releasing hormone analogue (Gn-RHa) therapy for peritoneal inclusion cysts.|Patients who had cystic masses that developed after gynecological surgery and were strongly suspected of being peritoneal inclusion cysts based on the results of ultrasound, magnetic resonance imaging (MRI), and tumor marker studies, were treated with a Gn-RHa (buserelin acetate or leuprorelin acetate). Buserelin acetate was administered at a dose of 900 microg/day, and leuprorelin acetate at a dose of 3.75 mg/month. Ultrasonography was performed in the outpatient clinic every 2 weeks after the start of administration to measure the diameter of cysts.|We treated 8 patients with peritoneal inclusion cysts conservatively with a Gn-RHa. The cysts resolved in 7 of the patients. Two of them developed a recurrence, but further Gn-RHa therapy was followed by complete resolution of the cysts in one patient and we resume Gn-RHa therapy to the other patient. The peritoneal inclusion cysts failed to shrink in only one patient.|It is suggested that Gn-RHa therapy is effective in some cases of peritoneal inclusion cysts.

Gonadotropin-releasing hormone analogue therapy for peritoneal inclusion cysts after Gynecological Surgery

Nozawa Shiro, Iwata Takashi, Yamashita Hiroshi, Banno Koji, Kubushiro Kaneyuki, Aoki Rui, Tsukazaki Katsumi

Journal of Obstetrics and Gynaecology Research 26 ( 6 ) 389-393 2000.12

Research paper (scientific journal), Joint Work

「子宮頚癌I_a2期の診断と治療―保存的治療は可能か？」当科における子宮頚癌I_a2期症例の臨床病理学的検討とその治療

Kubushiro Kaneyuki，Yamashita Hiroshi，Nakagawa Hiroyuki，Iwata Takashi，Takehara Kyouko，Fukuchi Takeshi，Fujii Takuma，Tsukazaki Katsumi，Nozawa Shirou

産科と婦人科 67 ( 9 ) 1131-1136 2000.09

Research paper (scientific journal), Joint Work

多様な組織像を示す卵巣腺線維腫（境界悪性）及び子宮内膜異型増殖症を伴った卵巣明細胞腺癌の1例

Iwata Takashi，Nakabayashi Akira，Tei Chisei，Fukuchi Takeshi，Mukai Makio，Mikami Mikio

日本婦人科腫瘍学会雑誌 17 ( 1 ) 73-77 2000.05

Research paper (scientific journal), Joint Work

子宮頸癌腫瘍に対するレーザー療法

Fukuchi Takeshi, Iwata Takashi, Yamashita Hiroshi, Kubushiro Kaneyuki, Tsukazaki Katsumi, Nozawa Shiro

日本レーザー医学会誌 21 ( 1 ) 45-52 2000.03

Research paper (scientific journal), Joint Work

【産婦人科とレーザー】　子宮頸部腫瘍に対するレーザー療法

福地, 剛, 岩田, 卓, 山下, 博, 久布白, 兼行, 塚崎, 克己 and 野澤, 志朗

日本レーザー医学会誌 21 ( 1 ) 45 - 52 2000

ISSN 0288-6200

子宮頸癌Ia2期の診断と治療　保存的治療は可能か?　当科における子宮頸癌Ia2期症例の臨床病理学的検討とその治療

久布白, 兼行, 山下, 博, 中川, 博之, 岩田, 卓, 竹原, 京子, 福地, 剛, 藤井, 多久磨, 塚崎, 克己 and 野澤, 志朗

産科と婦人科 67 ( 9 ) 1131 - 1136 2000

ISSN 0386-9792

旧FIGO分類Ia期307例,Ib期331例を新FIGO分類で再分類したところ,301例がIa1期,116例がIa2期に各々相当した.骨盤リンパ節転移はIa1期では認められなかったのに対し,Ia2期では1例に見られた.脈管侵襲や癒合浸潤は,Ia2期ではIa1期に比べ有意に高率であった.再発はIa1期,Ia2期いずれにも認められなかった.Ia2期に相当する症例に対して必ずしも広汎子宮全摘術は必要ではなく,骨盤リンパ節郭清を含めた準広汎子宮全摘術を選択可能と考えた

低悪性度子宮内膜間質肉腫の4例

前田, 太郎, 岩田, 卓, 弟子丸, 亮太, 阪埜, 浩司, 福地, 剛, 進, 伸幸, 久布白, 兼行, 青木, 大輔, 塚崎, 克己, 吉村, 泰典, 野澤, 志朗 and 向井, 万起男

日本産科婦人科学会東京地方部会会誌 49 ( 3 ) 293 - 298 2000

ISSN 0288-5751

当科において1999年5月から2000年2月迄の間に低悪性度子宮内膜間質肉腫と診断された4例を経験した.発症年齢は31歳から41歳,いずれも閉経前の女性.4例のうち1例は卵巣癌との合併であり,術後にTJ療法を行った.他の3例は子宮筋腫の診断で初回手術を受け,術後に本腫瘍と診断されたが,腫瘍組織の免疫特殊染色結果でPR(Progesterone receptor)が陽性であったため,medroxyprogesterone acetate(MPA)療法を行っており現在のところ再発は認めていない

多彩な組織像を示す卵巣腺線維腫（境界悪性）及び子宮内膜異型増殖症を伴った卵巣明細胞癌の1例

Iwata Takashi, Nakabayashi Akira, Tei Chisei, Fukuchi Takeshi, Mukai Makio, Mikami Mikio

日本婦人科腫瘍学会雑誌 17 ( 1 ) 73-77 1999.06

Research paper (scientific journal), Joint Work

当科における妊娠中のレーザー円錐切除術

Takehara Kyoko，Tsukazaki Katsumi，Kubushiro Kaneyuki，Iwata Takasi，Nakagawa Hiroyuki，Yamashita Hiroshi，Takamatsu Kiyoshi，Yoshimura Yasunori，Nozawa Shiro

産婦人科手術 10 27-32 1999.05

Research paper (scientific journal), Joint Work

産科手術　当科における妊娠中のレーザー円錐切除術

竹原, 京子, 塚崎, 克己, 久布白, 兼行, 岩田, 卓, 中川, 博之, 山下, 博, 高松, 潔, 吉村, 泰典 and 野澤, 志朗

産婦人科手術 ( 10 ) 27 - 32 1999

ISSN 0915-8375

多様な組織像を示す卵巣腺線維腫(境界悪性)及び子宮内膜異型増殖症を伴った卵巣明細胞腺癌の1例

岩田, 卓, 中林, 章, 鄭, 智誠, 福地, 剛, 向井, 萬起男 and 三上, 幹男

日本婦人科腫瘍学会雑誌 17 ( 1 ) 73 - 77 1999

ISSN 1347-8559

国立埼玉病院産婦人科における重複癌症例の検討

岩田, 卓, 三上, 幹男, 中林, 章, 鄭, 智誠 and 新井, 宏治

日本産科婦人科学会埼玉地方部会会誌 28 25 - 29 1998

ISSN 0911-6281

婦人科悪性腫瘍癌患者740例のうち,27例に重複癌例が発見された.発生頻度は子宮頸癌で9/423,子宮体癌で10/134,卵巣癌で13/183.婦人科臓器以外の癌との重複癌症例では乳癌の12例,消化器癌の6例が多く,乳癌が最多であった.2親等以内に癌罹患者を有するものを家族歴陽性とすると,子宮頸癌で44.4%,子宮体癌で55.5%,卵巣癌で46.1%.重複癌が共に婦人科癌であった症例では,家族歴陽性は33.3%で比較的低値であったのに対し,乳癌との重複癌症例では81.6%と非常に高い値を示した

子宮癌根治術後の膀胱機能障害に関する検討

三上, 幹男, 中林, 章, 岩田, 卓, 鄭, 智誠 and 新井, 宏治

日本産科婦人科学会埼玉地方部会会誌 28 111 - 114 1998

ISSN 0911-6281

子宮癌根治術後の膀胱機能障害を軽減するために著者等は子宮頸癌Ib期と子宮体癌II期の手術可能症例には,神経染色剤にて骨盤神経を染色し直視下に神経を温存する広汎骨盤神経温存子宮全摘出術を施行している.著者等に行っている神経温存術症例の術後膀胱機能障害の程度を広汎神経非温存術後例と比較検討したところ,明らかに膀胱機能障害の程度は軽減されていることが明らかになった

子宮体部に発生した癌肉腫の2例

竹原, 京子, 平澤, 晃, 三上, 幹男, 岩田, 卓, 中林, 章, 林, 博隆 and 新井, 宏治

日本産科婦人科学会埼玉地方部会会誌 28 76 - 80 1998

ISSN 0911-6281

1)正所性の癌肉腫2例を報告した. 2)うち1例は内膜細胞診にて非上皮成分と腺癌細胞を疑わせる上皮性悪性細胞を認め,内膜細胞診が診断に有効であった. 3)組織学的所見として,腺癌部分と多彩な形態を示す肉腫部分を認め各種免疫染色により正所性の癌肉腫と診断した. 4)中高年,特に閉経後に婦人の出血では子宮体癌の中でも本腫瘍の可能性も念頭において診断を進める必要がある

虫垂原発転移性卵巣癌の1例

中林, 章, 岩田, 卓, 鄭, 智誠, 福地, 剛, 三上, 幹男 and 新井, 宏治

日本産科婦人科学会埼玉地方部会会誌 28 8 - 11 1998

ISSN 0911-6281

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