Details of a Researcher - Iwata, Takashi

Papers - Iwata, Takashi

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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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