Details of a Researcher - Iwata, Takashi

Papers - Iwata, Takashi

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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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