Details of a Researcher - Iwata, Takashi

Papers - Iwata, Takashi

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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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