Details of a Researcher - Masuda, Kenta

Papers - Masuda, Kenta

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Epigenetics and genetics in endometrial cancer: new carcinogenic mechanisms and relationship with clinical practice.

Banno K, Kisu I, Yanokura M, Masuda K, Ueki A, Kobayashi Y, Susumu N, Aoki D

Epigenomics (Epigenomics) 4 ( 2 ) 147 - 62 2012.04

ISSN 1750-1911

Endometrial cancer is the seventh most common cancer worldwide among females. An increased incidence and a younger age of patients are also predicted to occur, and therefore elucidation of the pathological mechanisms is important. However, several aspects of the mechanism of carcinogenesis in the endometrium remain unclear. Associations with genetic mutations of cancer-related genes have been shown, but these do not provide a complete explanation. Therefore, epigenetic mechanisms have been examined. Silencing of genes by DNA hypermethylation, hereditary epimutation of DNA mismatch repair genes and regulation of gene expression by miRNAs may underlie carcinogenesis in endometrial cancer. New therapies include targeting epigenetic changes using histone deacetylase inhibitors. Some cases of endometrial cancer may also be hereditary. Thus, patients with Lynch syndrome which is a hereditary disease, have a higher risk for developing endometrial cancer than the general population. Identification of such disease-related genes may contribute to early detection and prevention of endometrial cancer. © 2012 Future Medicine Ltd.

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Narrow band imaging in gynecology: a new diagnostic approach with improved visual identification (Review).

Kisu I, Banno K, Tsuji K, Masuda K, Ueki A, Kobayashi Y, Yamagami W, Susumu N, Aoki D

International journal of oncology (International Journal of Oncology) 40 ( 2 ) 350 - 6 2012.02

ISSN 1019-6439

Narrow band imaging (NBI) is a new endoscopic technique in which images of mucosal microstructures and capillary structures are enhanced by shifting the light spectrum to a narrow band. Image-enhanced gastrointestinal endoscopy using NBI has improved the qualitative diagnosis of the grade and depth of invasion of an atypical lesion. NBI is currently not commonly used in gynecological endoscopy, but has recently been applied in laparoscopy and hysteroscopy. The utility of NBI for diagnosis of endometrial lesions and endometriosis has also been shown. In gynecological endoscopy, NBI provides enhanced images of mucosal microstructures and capillary structures and improves visual identification of lesions. Therefore, image-enhanced observation using NBI is likely to be useful for improved detection of lesions in endoscopic diagnosis. However, this technique remains experimental so far, and no study has demonstrated improved clinical outcome using this technique. In this review, we discuss the utility and potential applications of NBI in clinical practice in gynecology.

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Endometrial Cancer and Hypermethylation: Regulation of DNA and MicroRNA by Epigenetics.

Banno K, Kisu I, Yanokura M, Masuda K, Kobayashi Y, Ueki A, Tsuji K, Yamagami W, Nomura H, Susumu N, Aoki D

Biochemistry research international (Biochemistry Research International) 2012 738274 2012

ISSN 2090-2247

Endometrial cancer is the seventh most common cancer in women worldwide. Therefore elucidation of the pathogenesis and development of effective treatment for endometrial cancer are important. However, several aspects of the mechanism of carcinogenesis in the endometrium remain unclear. Associations with genetic variation and mutations of cancer-related genes have been shown, but these do not provide a complete explanation. Therefore, in recent years, epigenetic mechanisms that do not involve changes in DNA sequences have been examined. Studies aimed at detection of aberrant DNA hypermethylation in cancer cells present in microscopic amounts in vivo and application of the results to cancer diagnosis have also started. Breakdown of the DNA mismatch repair mechanism is thought to play a large role in the development of endometrial cancer, with changes in the expression of the hMLH1 gene being particularly important. Silencing of genes such as APC and CHFR, Sprouty 2, RASSF1A, GPR54, CDH1, and RSK4 by DNA hypermethylation, onset of Lynch syndrome due to hereditary epimutation of hMLH1 and hMSH2 mismatch repair genes, and regulation of gene expression by microRNAs may also underlie the carcinogenic mechanisms of endometrial cancer. Further understanding of these issues may permit development of new therapies. © Copyright 2012 Kouji Banno et al.

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Up-regulation of Imp3 confers in vivo tumorigenicity on murine osteosarcoma cells.

Ueki A, Shimizu T, Masuda K, Yamaguchi SI, Ishikawa T, Sugihara E, Onishi N, Kuninaka S, Miyoshi K, Muto A, Toyama Y, Banno K, Aoki D, Saya H

PloS one (PLoS ONE) 7 ( 11 ) e50621 2012

Osteosarcoma is a high-grade malignant bone tumor that manifests ingravescent clinical behavior. The intrinsic events that confer malignant properties on osteosarcoma cells have remained unclear, however. We previously established two lines of mouse osteosarcoma cells: AX cells, which are able to form tumors in syngeneic mice, and AXT cells, which were derived from such tumors and acquired an increased tumorigenic capacity during tumor development. We have now identified Igf2 mRNA-binding protein3 (Imp3) as a key molecule responsible for this increased tumorigenicity of AXT cells in vivo. Imp3 is consistently up-regulated in tumors formed by AX cells, and its expression in these cells was found to confer malignant properties such as anchorage-independent growth, loss of contact inhibition, and escape from anoikis in vitro. The expression level of Imp3 also appeared directly related to tumorigenic ability in vivo which is the critical determination for tumor-initiating cells. The effect of Imp3 on tumorigenicity of osteosarcoma cells did not appear to be mediated through Igf2-dependent mechanism. Our results implicate Imp3 as a key regulator of stem-like tumorigenic characteristics in osteosarcoma cells and as a potential therapeutic target for this malignancy. © 2012 Ueki et al.

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Narrow band imaging hysteroscopy: a comparative study using randomized video images.

Kisu I, Banno K, Kobayashi Y, Ono A, Masuda K, Ueki A, Nomura H, Hirasawa A, Abe T, Kouyama K, Susumu N, Aoki D

International journal of oncology (International Journal of Oncology) 39 ( 5 ) 1057 - 62 2011.11

ISSN 1019-6439

Narrow band imaging (NBI) has been used in the gastrointestinal endoscopy field as a novel endoscopic imaging technique and has contributed to improved qualitative diagnosis and detection of lesions. However, there are only a few studies of use of NBI in the gynecology field. We applied NBI in flexible hysteroscopy at our outpatient clinic and evaluated the utility of NBI hysteroscopy for diagnosis of malignant endometrial lesions by comparison of the sensitivity and specificity between white light alone and white light+NBI using hysteroscopic video images. The subjects were 65 patients with a suspected endo-metrial lesion in the uterine cavity. These patients underwent flexible hysteroscopy using NBI in addition to conventional white light. Video images from 65 patients were edited into two groups, white light alone (WL group) and white light+NBI (NBI group) (130 images in total). Computerized block randomization of the order was then performed. Four raters independently diagnosed the images without use of other clinical information. Using the pathological diagnosis as the gold standard, we evaluated the sensitivity and specificity of diagnosis of atypical endometrial hyperplasia (AEH) or endometrial carcinoma compared between the WL and NBI groups. The sensitivity of diagnosis of AEH or endometrial carcinoma was numerically higher in the NBI group for all raters, and the average sensitivity was significantly higher in the NBI group compared to the WL group (78.6% vs. 63.7%, P<0.001). The specificity for each rater and the average specificity were comparable between the two groups. Compared to white light hysteroscopy, NBI hysteroscopy had a higher sensitivity for diagnosis of AEH or endometrial carcinoma without loss of specificity. This suggests that NBI hysteroscopy may be more useful than white light hysteroscopy for endoscopic diagnosis of malignant endometrial lesions.

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積極的な手術後にTC療法を行いえた卵巣原発癌肉腫の一例

長谷川明俊, 渡邉豊治, 飯田玲, 福永朝子, 増田健太, 芥川秀之, 榊原嘉彦, 青野一則, 秋葉靖雄, 小西康博

関東連合産科婦人科学会誌 ((一社)関東連合産科婦人科学会) 48 ( 4 ) 445 - 450 2011.11

ISSN 2186-0610

卵巣原発癌肉腫の好発年齢は60歳代で,頻度は全卵巣悪性腫瘍のうち約1%とまれである.診断時はすでにFIGO stage IIIないしIVであることが多く,他の上皮性癌と比べてプラチナ抵抗性であり,予後は不良とされている.今回,我々は積極的な手術療法とTC(パクリタキセル+カルボプラチン)療法を施行した卵巣原発癌肉腫(FIGO stage IIIc)の症例を報告する.症例は81歳,2回経妊2回経産.腹部膨満感を主訴に前医受診したところ卵巣腫瘍を認め,当院に紹介.CT,MRI検査にて20cmの卵巣腫瘍と両側の水腎症を認めた.CA125は58U/ml,CEAは7.6ng/mlと軽度上昇していた.卵巣癌と診断し手術を施行.骨盤内を占拠する小児頭大の卵巣腫瘍を認め,腫瘤は小腸とS状結腸に癒着していた.また癌性腹膜炎の状態で播種巣は大きなもので4cm大であった.術中迅速病理検査にて卵巣癌(扁平上皮癌)と診断.術式はcytoreductive surgery(ATH+BSO+OMT+腹膜播種巣除去)を施行した.高齢で輸血療法を必要とした長時間の手術となったためリンパ節郭清は余儀なく省略することとなった.術後病理結果より卵巣癌肉腫,pT3cNXMX,FIGO stage IIIcと診断した.術後にTC療法を6クール施行した.しかしTC療法を終えて5か月経過してから再燃(イレウス,腎後性腎不全)となり初診から15か月後に永眠となった.(著者抄録)

Carcinoma of the Lower Uterine Segment (LUS): Clinicopathological Characteristics and Association with Lynch Syndrome.

Masuda K, Banno K, Yanokura M, Kobayashi Y, Kisu I, Ueki A, Ono A, Nomura H, Hirasawa A, Susumu N, Aoki D

Current genomics (Current Genomics) 12 ( 1 ) 25 - 9 2011.03

ISSN 1389-2029

Endometrial cancer arises from the uterine body and fundus in many cases, but can also originate from the lower region of the uterine body through the upper region of the cervix. Such tumors are referred to as carcinoma of the lower uterine segment (LUS) or isthmus, and account for 3-6.3% of all cases of endometrial cancer. This relatively low incidence has permitted performance of only small-scale studies, but the clinical and pathological characteristics of carcinoma of the LUS in all these reports have differed from those of other endometrial cancers. Generally, endometrial cancer is classified into estrogen-dependent endometrioid adenocarcinoma (designated as type I), and non-endometrioid types that are less associated with estrogen and include poorly differentiated adenocarcinoma (type II). In some reports, carcinoma of the LUS has been found to have type II characteristics. Carcinoma of the LUS has also been associated with Lynch syndrome, a hereditary disease with frequent development of colorectal, endometrial, and ovarian cancers. Lynch syndrome is thought to be induced by mismatch repair gene mutation. The frequency of Lynch syndrome in cases of general endometrial cancer is 1-2%. In contrast, the frequency in patients with carcinoma of the LUS is much higher, with up to 29% of cases diagnosable with Lynch syndrome and a high frequency of hMSH2 mutation found in one study. This suggests that further investigation of the clinical and pathological characteristics of carcinoma of the LUS and the association with Lynch syndrome is required through performance of a large-scale survey. © 2011 Bentham Science Publishers Ltd.

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Flexible hysteroscopy with narrow band imaging (NBI) for endoscopic diagnosis of malignant endometrial lesions.

Kisu I, Banno K, Kobayashi Y, Ono A, Masuda K, Ueki A, Nomura H, Hirasawa A, Abe T, Kouyama K, Susumu N, Aoki D

International journal of oncology (International Journal of Oncology) 38 ( 3 ) 613 - 8 2011.03

ISSN 1019-6439

Narrow band imaging (NBI) for detection of blood vessels and microstructures on the mucosal surface is used in gastrointestinal endoscopy since it can improve qualitative diagnosis and detection of lesion. However, there are no studies on flexible hysteroscopy using NBI. We performed flexible hysteroscopy with NBI for outpatients to investigate the sensitivity and specificity of endoscopic diagnosis of malignant endometrial lesions. Of patients who attended our hospital for suspected lesions in the uterine cavity between April 2009 and May 2010, 104 subjects underwent hysteroscopy with NBI, in addition to white light. Using the pathological diagnosis as the gold-standard, we evaluated the sensitivity and specificity of NBI hysteroscopy for detecting atypical endometrial hyperplasia (AEH) or carcinoma. The results were also compared with historical data (n=209) for conventional hysteroscopy using white light only in 2008. The sensitivities were 97.2% [95% confidence interval (95% CI): 90.3-99.7%] and 82.6% (95% CI: 74.4-89.0%) for NBI hysteroscopy and conventional hysteroscopy, respectively. The 95% CIs for the two methods did not overlap and the sensitivity of lesion detection was higher with NBI hysteroscopy. Specificities were comparable, 90.6% (95% CI: 75.0-98.0%) and 85.1% (95% CI: 76.3-91.6%) between the methods. NBI hysteroscopy has increased sensitivity for detection of atypical endometrial hyperplasia (AEH) or carcinoma. A comparison with historical data suggested that NBI may be useful for diagnosis of malignant endometrial lesions. As far as we are aware, this is the first evaluation of flexible hysteroscopy with NBI for diagnosis of malignant endometrial lesions.

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Relationship between DNA Mismatch Repair Deficiency and Endometrial Cancer.

Masuda K, Banno K, Yanokura M, Kobayashi Y, Kisu I, Ueki A, Ono A, Asahara N, Nomura H, Hirasawa A, Susumu N, Aoki D

Molecular biology international 2011 256063 2011

ISSN 2090-2182

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待機療法にてhCG陰性化後も血腫が遺残し、腹腔鏡下手術を行った陳旧性卵管妊娠の一例

渡邉豊治, 福永朝子, 増田健太, 芥川秀之, 榊原嘉彦, 長谷川明俊, 青野一則, 秋葉靖雄, 小西康博

日本産科婦人科内視鏡学会雑誌 ((一社)日本産科婦人科内視鏡学会) 26 ( 2 ) 410 - 413 2010.12

ISSN 1884-9938

21歳女。急性腹症にて救急搬送され、子宮外妊娠の疑いで入院管理となった。経腟エコーで骨盤腔に血液と思われる液体貯留と凝血塊を認めたが、子宮内、付属器にGSは認めず、生化学検査で異常はなく血中hCG値は328IU/lと比較的低値を示した。疼痛は軽減傾向にあったため待機療法後に外来管理とし、4日後に下腹部痛にて再入院となったが、画像所見などに変化はなく、血中hCG値は更に低下していた。経過観察後に再度外来管理とし、基礎体温が低温相となったことを確認した。約半月後に行ったCTでは56×41mm大の内部不均一な血腫様腫瘤を子宮前方に認め、内容は内膜症性嚢胞様であった。その後、月経が再開し、基礎体温は2相性となったものの腫瘤は縮小せず、MRIでは膀胱子宮窩に38×62mm大の腫瘤を認め、診断的・治療的腹腔鏡手術を施行した。腫瘤は大網に覆われ、可動性良好で、右卵管、特に卵管采と付着しているように見え、色素通水で腫瘤より色素が流出したことから、腫瘤は卵管そのものと判明した。卵管子宮側と卵管采が側面で癒着し、腫瘤と卵管采との間で卵管が切断されている状態であったため、腫瘤と卵管采を摘出し、卵管開口術を施行した。病理組織所見で変性した絨毛を確認した。

腹腔鏡下子宮筋腫核出術時に偶然発見された高分化型乳頭状中皮腫の一例

長谷川明俊, 渡邉豊治, 飯田玲, 福永朝子, 増田健太, 芥川秀之, 榊原嘉彦, 青野一則, 秋葉靖雄, 小西康博

日本産科婦人科内視鏡学会雑誌 ((一社)日本産科婦人科内視鏡学会) 26 ( 2 ) 575 - 579 2010.12

ISSN 1884-9938

37歳女。下腹部痛・発熱を主訴とした。子宮と右付属器に圧痛を認め、超音波では子宮後壁に3個の漿膜下筋腫、子宮右壁に変性を伴った子宮筋腫、他にも小さな筋腫と腹水を認めた。右付属器炎と子宮筋腫変性の合併による腹痛と診断し、抗生剤と消炎鎮痛剤により症状は軽快したが、不妊症を伴う子宮筋腫であったため腹腔鏡下子宮筋腫核出術を施行した。術中、子宮後壁漿膜・直腸表面・ダグラス窩・膀胱子宮窩腹膜に5〜10mmの乳頭状腫瘤を多数認め、大網にも20mm大の乳頭状腫瘤を認めたため、可及的にcytoreductionを行った。病理診断で腹水細胞診は陰性、子宮筋腫と思われた腫瘤は良性の平滑筋腫であった。腹膜腫瘤は軽度の異型を呈し、カルレチニン、サイトケラチン5/6、D2-40はすべて陽性であったため、高分化型乳頭状中皮腫と病理診断した。術後8ヵ月経過してadjuvant therapyなしで無症状である。

MicroRNA and endometrial cancer: Roles of small RNAs in human tumors and clinical applications (Review)

Yanokura M., Banno K., Kobayashi Y., Kisu I., Ueki A., Ono A., Masuda K., Nomura H., Hirasawa A., Susumu N., Aoki D.

Oncology Letters (Oncology Letters) 1 ( 6 ) 935 - 940 2010.11

ISSN 17921074

MicroRNAs (miRNAs) are small non-coding RNAs of approximately 22 base pairs that regulate the expression of genes by targeting messenger RNA with complementarity with the miRNA base sequence. Regulation of gene expression by miRNAs is crucial in cellular development and differentiation, and recent studies suggest a relationship between human diseases and the breakdown of gene silencing mechanisms induced by miRNA abnormalities. In particular, abnormal miRNA expression has been detected in various types of cancer and the target genes have been identified. These results indicate that miRNAs act in a manner equivalent to oncogenes or tumor suppressors. miRNAs may also serve as diagnostic biomarkers and therapeutic targets. In this review, we introduce the latest findings on miRNAs in human endometrial cancer, a common malignancy, and discuss the potential of miRNAs as biomarkers and targets for molecular therapy.

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当院での腹腔鏡下手術において開腹手術へ移行した3症例

増田健太, 秋葉靖雄, 飯田玲, 福永朝子, 芥川秀之, 榊原嘉彦, 長谷川明俊, 青野一則, 渡邉豊治, 小西康博

日本産科婦人科学会神奈川地方部会会誌 (神奈川産科婦人科学会) 46 ( 2 ) 108 - 112 2010.01

ISSN 0910-2485

症例1(32歳、0経妊0経産)。子宮筋腫の増大傾向で、著者らの施設へ紹介受診となった。超音波およびMRIでは子宮体底部に4個の筋腫核が認められ、術中、正常筋層と腫瘤の境界が不明瞭のため、開腹術に移行した。摘出した6個中4個がadenomatoid tumorと診断された。症例2(46歳、2経妊2経産)。31歳時に左卵管妊娠、33歳時に右卵巣皮様嚢胞腫で開腹術の既往があった。今回、健診で左卵巣腫大を指摘され、著者らの施設へ紹介受診となった。超音波とMRIでは左卵巣に6cm大の腫瘤が認められた。術中、腫瘍周囲の癒着が強固で破裂の可能性があり、開腹術に移行して未破裂のまま摘出したところ、左卵巣皮様嚢胞腫と診断された。症例3(37歳、0経妊0経産)。前医で右内膜症性嚢胞の穿刺吸引後にアルコール固定術を受けるも、再発にて、著者らの施設へ紹介受診となった。超音波とMRIでは13cm大の多房性嚢胞性病変が認められ、術中は骨盤底と後腹膜との癒着が剥離困難であった。そのため、開腹術に移行したところ、凝血塊を伴った内膜症性嚢胞であった。

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