Details of a Researcher - Masuda, Kenta

Papers - Masuda, Kenta

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Japanese society for cancer of the colon and rectum (JSCCR) guidelines 2024 for the clinical practice of hereditary colorectal cancer.

Tanakaya K, Yamaguchi T, Hirata K, Yamada M, Kumamoto K, Akiyama Y, Ishimaru K, Okamoto K, Kawasaki Y, Komine K, Sakamoto A, Shigeyasu K, Shibata Y, Shimamoto Y, Shimodaira H, Sekine S, Takao A, Takao M, Takamizawa Y, Takeuchi Y, Tanabe N, Taniguchi F, Chino A, Cho H, Doi S, Nakajima T, Nakamori S, Nakayama Y, Nagasaki T, Hasumi H, Banno K, Hinoi T, Fujiyoshi K, Horimatsu T, Masuda K, Miguchi M, Mizuuchi Y, Miyakura Y, Mutoh M, Yoshioka T, Tanaka S, Sakamoto K, Sakamaki K, Itabashi M, Ishida H, Tomita N, Sugihara K, Ajioka Y, Japanese Society for Cancer of the Colon, Rectum

International journal of clinical oncology 2025.11

ISSN 1341-9625

Approximately 5% of all colorectal cancers have a strong genetic component and are classified as hereditary colorectal cancer (HCRC). Some of the unique features commonly seen in HCRC cases include early age of onset, synchronous/metachronous cancer occurrence, and multiple cancers in other organs. These characteristics require different management approaches, including diagnosis, treatment or surveillance, from those used in the management of sporadic colorectal cancer. Accurate diagnosis of HCRC is essential because it enables targeted surveillance and risk reduction strategies that improve patient outcomes. Recent genetic advances revealed several causative genes for polyposis and non-polyposis syndromes. The Japanese Society for Cancer of the Colon and Rectum (JSCCR) first published guidelines for the management of HCRC in 2012, with subsequent revisions every 4 years. The 2024 update to the JSCCR guidelines for HCRC was developed by meticulously reviewing evidence from systematic reviews and the consensus of the JSCCR HCRC Guidelines Committee, which includes representatives from patient advocacy groups for FAP and Lynch syndrome. These guidelines provide an up-to-date summary of HCRC, along with clinical recommendations for managing FAP and Lynch syndrome.

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Current Situation and Future Directions of Risk-reducing Salpingo-oophorectomy.

Kenta Masuda, Yusuke Kobayashi, Tomoko Seki, Tomoko Yoshihama, Kohei Nakamura, Yumiko Goto, Mamiko Yamada, Aiko Nagayama, Sayaka Uchida, Ikumi Ono, Kumiko Misu, Megumi Yokota, Wataru Yamagami

The Keio journal of medicine 74 ( 3 ) 138 - 145 2025.09

Lead author, Corresponding author, Accepted, ISSN 0022-9717

High-grade serous carcinoma (HGSC), the most aggressive subtype of epithelial ovarian cancer, is strongly associated with hereditary breast and ovarian cancer (HBOC) syndrome and is primarily linked to germline BRCA1/2 pathogenic variants (PVs). The cumulative risks of ovarian cancer by the age of 70 years are 40% and 18% for carriers of BRCA1 and BRCA2 PVs, respectively. Risk-reducing salpingo-oophorectomy (RRSO) is a recommended preventive strategy that reduces the risk of ovarian cancer by more than 80% and may improve overall survival. However, surgical menopause after RRSO poses several challenges, including infertility and hormonal deficiency. Although the use of hormone replacement therapy may alleviate symptoms, it requires careful consideration of breast cancer risk. Emerging strategies, such as prophylactic salpingectomy with delayed oophorectomy, are being investigated to balance cancer prevention and patient quality of life. Further research is required to refine personalized prevention and management approaches for HBOC-associated ovarian cancer.

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The Keio HBOC Center: A Model of Hereditary Breast and Ovarian Cancer Management.

Yusuke Kobayashi, Kenta Masuda, Tomoko Seki, Takeo Kosaka, Minoru Kitago, Ikumi Ono, Kumiko Misu, Arisa Ueki, Tomoko Yoshihama, Aiko Nagayama, Yota Yasumizu, Yumiko Goto, Kohei Nakamura, Mamiko Yamada, Megumi Yokota, Sayaka Uchida, Mari Takeuchi, Takeru Funakoshi, Wataru Yamagami

The Keio journal of medicine 74 ( 3 ) 124 - 129 2025.09

ISSN 0022-9717

The management of hereditary breast and ovarian cancer (HBOC) in Japan has changed drastically with the expansion of indications for poly ADP-ribose polymerase inhibitors, the increase in diagnostic opportunities with the spread of companion diagnoses, and partial insurance coverage of HBOC management. These circumstances require a response that is coordinated across the entire hospital rather than from individual departments. In April 2021, we established the HBOC Center, which is operated by nine departments: Obstetrics and Gynecology, Reproduction, Surgery (breast group, hepato-pancreato-biliary group), Urology, Dermatology, Neuropsychiatry, the Center for Medical Genetics, and the Cancer Center. In addition to discussions of individual cases, our monthly conferences have enabled us to establish indication criteria and appropriate items for surveillance, visualize the examination flow in the hospital, construct a patient database, and provide open lectures to educate the public. The future HBOC management system should not only fulfill the existing requirements for risk-reducing surgery and facility standards but also offer comprehensive and diversified attention based on the needs of patients and their family members.

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Pancreatic Cancer in Hereditary Breast and Ovarian Cancer Syndrome: Is Early Detection Possible?

Kodai Abe, Minoru Kitago, Yusuke Kobayashi, Kenta Masuda, Tomoko Seki, Mamiko Yamada, Yumiko Goto, Ikumi Ono, Kumiko Misu, Kohei Nakamura, Yuko Kitagawa

The Keio journal of medicine 74 ( 3 ) 146 - 150 2025.09

ISSN 0022-9717

A program of recruiting families with hereditary pancreatic cancer and hereditary breast and ovarian cancer (HBOC) syndrome as high-risk individuals for pancreatic cancer surveillance using magnetic resonance cholangiopancreatography (MRCP) and endoscopic ultrasound (EUS) has proven effective, resulting in the improvement of early detection rates and life expectancy. Given this, recent guidelines recommend pancreatic surveillance for patients with familial pancreatic cancer and pathological variants of ten genes, including BRCA1/2. In April 2021, our hospital established the HBOC Center, which is operated by nine departments, including obstetrics and gynecology, breast surgery, pancreatology, urology, medical genetics, dermatology, psychiatry and neurology, and oncology. Currently, MRCP or EUS is performed once or twice a year in 63 cases with pathogenic variants in 54 families. Although 4 cases (6.3%) revealed pancreatic microcysts or branched intraductal papillary mucinous neoplasms, no sign of pancreatic cancer was detected. Since January 2021, the germline BRCA1/2 test for companion diagnosis of pancreatic cancer has been covered by insurance, improving the accessibility of genetic testing among patients with pancreatic cancer. However, the BRCA1/2 positivity rate remains low at 1.3%, and its indication for use is very limited. The implementation of genetic testing, including BRCA1/2 analysis, is necessary for the prevention and early detection of pancreatic cancer in high-risk families.

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Exploring Breast Cancer Risk Management in HBOC Patients: Image Surveillance Versus Risk-reducing Surgery.

Tomoko Seki, Yusuke Kobayashi, Kenta Masuda, Kohei Nakamura, Mamiko Yamada, Yumiko Goto, Kumiko Misu, Ikumi Ono, Aiko Nagayama, Tetsu Hayashida, Yuko Kitagawa

The Keio journal of medicine 74 ( 3 ) 130 - 137 2025.09

ISSN 0022-9717

In Japan, the rising incidence of hereditary breast and ovarian cancer syndrome (HBOC) follows partial insurance coverage introduced in 2020. Compared with the general population (~11% lifetime risk), individuals with HBOC face a significantly higher lifetime risk of breast cancer (48%-76%), often presenting at younger ages. BRCA1 mutations are linked to triple-negative breast cancer, whereas BRCA2 mutations typically result in luminal-type disease. Key risk management strategies include surveillance and prophylactic surgery. Annual magnetic resonance imaging and mammography are recommended at younger ages than in the general population, despite concerns regarding contrast agents, radiation exposure, and examination-related burdens. Although risk-reducing mastectomy lowers breast cancer risk by over 90%, it remains underutilized because of cosmetic and psychological considerations. Nipple-sparing or skin-sparing mastectomy combined with immediate or delayed reconstruction offers a balance between risk reduction and postoperative outcomes, although safety and procedure details still warrant careful evaluation. Managing the high breast cancer risk associated with HBOC requires ongoing efforts to refine current strategies while minimizing patient burden.

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Clinical Sequence Revealed the Prevalence and Biological Significance of Somatic Pathogenic Variants in Thoracic Cancer: Implications for Germline Status.

Takahiro Fukushima, Kohei Nakamura, Hideki Terai, Keiko Ohgino, Ryutaro Kawano, Marin Ishikawa, Katsura Emoto, Hatsuyo Takaoka, Ayaka Saito, Fumimaro Ito, Shigenari Nukaga, Shinnosuke Ikemura, Ichiro Kawada, Kenta Masuda, Hiroyuki Yasuda, Hajime Okita, Keisuke Asakura, Kenzo Soejima, Kenjiro Kosaki, Hiroshi Nishihara, Koichi Fukunaga

Clinical lung cancer 26 ( 5 ) 407 - 419.e20 2025.07

ISSN 1525-7304

PURPOSE: Presumed germline pathogenic variants (PGPVs) are occasionally detected in thoracic cancer and their frequency and functional significance remain underexplored. We investigated the prevalence and biological significance of PGPVs identified in comprehensive genomic profiling (CGP) panels in patients with thoracic cancer. PATIENTS AND METHODS: Between January 2021 and August 2023, 204 patients with thoracic cancer were included in this study. A somatic cancer genomic profile system-FoundationOne CDx or an in-house system (Rapid-Neo)-was used for next-generation sequencing-based cancer gene panel tests. Potential PGPVs were identified by evaluating the variant allele frequency (VAF; cutoff > 10%) and pathogenicity based on ClinVar. RESULTS: PGPVs were detected at a frequency of 9.7% from cohort 1 and 8.1% from cohort 2 in thoracic cancer, based on real-world comprehensive genomic profiling panel testing. Copy number plot did not indicate any homologous recombination deficiency patterns in cases with BRCA1, BRCA2, and RAD51D pathogenic variants in thoracic cancer compared with those in hereditary breast and ovarian cancers. Only one hit of MSH6 pathogenic germline variant was observed for lung cancer tissue in the case of Lynch syndrome; therefore, high tumor mutational burden/microsatellite instability or mismatch repair deficiency was not observed, unlike that in endometrial cancer tissue in the same individual. CONCLUSION: This study underscores the importance of identifying PGPVs through CGP testing conducted in patients with thoracic cancer. Using frequency and functional analysis. Further investigation is warranted regarding the clinical significance of these PGPVs in managing patients with thoracic cancer and their families.

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LCN2-mediated ferroptosis resistance in tissue homeostasis and early-stage tumorigenesis of the fallopian tube epithelium.

Keiyo Imaeda, Tomohiro Tamura, Shimpei Nagai, Eiji Sugihara, Juntaro Yamasaki, Yuji Otsuki, Kohei Nakamura, Takashi Takeda, Kanako Nakamura, Yuya Nogami, Kosuke Tsuji, Tatsuyuki Chiyoda, Iori Kisu, Yusuke Kobayashi, Kouji Banno, Rui Yamaguchi, Kazuhiro Sakurada, Hideyuki Saya, Daisuke Aoki, Ahmed Ashour Ahmed, Osamu Nagano, Kenta Masuda, Wataru Yamagami

iScience 28 ( 6 ) 112654 - 112654 2025.06

Corresponding author, Accepted

While the fallopian tube epithelium (FTE) is known to be composed of various differentiated cells such as secretory and ciliated cells, the upstream regulatory mechanisms of cell differentiation that are essential for tissue homeostasis remain under investigation. In this study, we established human FTE organoids and identified quiescent cells within the early organoid formation by observing cellular proliferation heterogeneity. We also analyzed two single-cell transcriptomic data to trace the differentiation trajectory in human FTE, and found that the gene LCN2 serves as a marker gene of early stage of the trajectory. Genetically manipulated FTE organoids indicated that LCN2 inhibits ferroptosis and promotes cell survival under oxidative stress. In addition, the FTE organoids introduced p53 dysfunction, the common genetic characteristics of high-grade serous carcinoma, showed upregulated LCN2 expression and enhanced ferroptosis resistance. This study provides insights into the LCN2-mediated protective mechanism of human FTE quiescent cells and its potential role in tumorigenesis.

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mTOR-mediated p62/SQSTM1 stabilization confers a robust survival mechanism for ovarian cancer

Tomohiro Tamura, Shimpei Nagai, Kenta Masuda, Keiyo Imaeda, Eiji Sugihara, Juntaro Yamasaki, Miho Kawaida, Yuji Otsuki, Kentaro Suina, Hiroyuki Nobusue, Tomoko Akahane, Tatsuyuki Chiyoda, Iori Kisu, Yusuke Kobayashi, Kouji Banno, Kazuhiro Sakurada, Hajime Okita, Rui Yamaguchi, Ahmed Ashour Ahmed, Wataru Yamagami, Hideyuki Saya, Daisuke Aoki, Osamu Nagano

Cancer Letters (Elsevier BV) 616 217565 - 217565 2025.04

Corresponding author, Accepted, ISSN 0304-3835

Over 50 % of patients with high-grade serous carcinoma (HGSC) are homologous recombination proficient, making them refractory to platinum-based drugs and poly (ADP-ribose) polymerase (PARP) inhibitors. These patients often develop progressive resistance within 6 months after primary treatment and tend to die early, thus new therapies are urgently needed. In this study, we comprehensively investigated this tumor type by leveraging a combination of machine learning analysis of a large published dataset and newly developed genetically engineered HGSC organoid models from murine fallopian tubes. Aberrant activation of RAS/PI3K signaling was a signature of poor prognosis in BRCA1/2 wild-type ovarian cancer, and mTOR-induced elevated p62 expression was a robust marker of chemotherapy-induced mTOR-p62-NRF2 signal activation. mTOR inhibition with everolimus decreased p62 and enhanced sensitivity to conventional chemotherapy, indicating that p62 serves as an important biomarker for therapeutic intervention. Combination therapy with conventional chemotherapy and mTOR inhibitors is a promising therapeutic strategy for refractory HGSC, with p62 as a biomarker.

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BRCA1/2 reversion mutations in a pan‐cancer cohort

Kohei Nakamura, Hideyuki Hayashi, Ryutaro Kawano, Marin Ishikawa, Eriko Aimono, Takaaki Mizuno, Hajime Kuroda, Yasuyuki Kojima, Naoki Niikura, Aya Kawanishi, Kei Takeshita, Shinsuke Suzuki, Shinichi Ueno, Kosuke Okuwaki, Jiichiro Sasaki, Masatoshi Yamaguchi, Kenta Masuda, Tatsuyuki Chiyoda, Wataru Yamagami, Chihiro Okada, Sachio Nohara, Shigeki Tanishima, Hiroshi Nishihara

Cancer Science (Wiley) 115 ( 2 ) 635 - 647 2024.02

ISSN 1347-9032

Abstract

Tumor sensitivity to platinum (Pt)‐based chemotherapy and poly(adenosine diphosphate ribose) polymerase (PARP) inhibitors is increased by homologous recombination deficiency‐causing mutations; in particular, reversion mutations cause drug resistance by restoring protein function. Treatment response is predicted by breast cancer susceptibility gene 1/2 (BRCA1/2) mutations; however, BRCA1/2 reversion mutations have not been comprehensively studied in pan‐cancer cohorts. We aimed to characterize BRCA1/2 reversion mutations in a large pan‐cancer cohort of Japanese patients by retrospectively analyzing sequencing data for BRCA1/2 pathogenic/likely pathogenic mutations in 3738 patients with 32 cancer types. We identified somatic mutations in tumors or circulating cell‐free DNA that could restore the ORF of adverse alleles, including reversion mutations. We identified 12 (0.32%) patients with somatic BRCA1 (n = 3) and BRCA2 (n = 9) reversion mutations in breast (n = 4), ovarian/fallopian tube/peritoneal (n = 4), pancreatic (n = 2), prostate (n = 1), and gallbladder (n = 1) cancers. We identified 21 reversion events—BRCA1 (n = 3), BRCA2 (n = 18)—including eight pure deletions, one single‐nucleotide variant, six multinucleotide variants, and six deletion–insertions. Seven (33.3%) reversion deletions showed a microhomology length greater than 1 bp, suggesting microhomology‐mediated end‐join repair. Disease course data were obtained for all patients with reversion events: four patients acquired mutations after PARP‐inhibitor treatment failure, two showed somatic reversion mutations after disease progression, following Pt‐based treatment, five showed mutations after both treatments, one patient with pancreatic cancer and BRCA1 reversion mutations had no history of either treatment. Although reversion mutations commonly occur in BRCA‐associated cancers, our findings suggest that reversion mutations due to Pt‐chemotherapy might be correlated with BRCA1/2‐mediated tumorigenesis even in non‐BRCA‐associated histologies.

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Evaluation of the one-step nucleic acid amplification assay for detecting lymph node metastasis in patients with cervical and endometrial cancer: A multicenter prospective study.

Togami S, Tanimoto A, Yanazume S, Tokunaga H, Nagai T, Watanabe M, Yahata H, Asanoma K, Yamamoto H, Tanaka T, Ohmichi M, Yamada T, Todo Y, Yamada R, Kato H, Yamagami W, Masuda K, Kawaida M, Niikura H, Moriya T, Kobayashi H

Gynecologic oncology 170 70 - 76 2023.03

ISSN 0090-8258

Objective: This multicenter study aimed to evaluate the accuracy of the one-step nucleic acid amplification (OSNA) assay in diagnosing lymph node metastasis (LNM) in patients with cervical and endometrial cancers. Methods: Surgically removed LNs from patients with cervical and endometrial cancer were sectioned at 2-mm intervals along the short axis direction and alternately examined using the OSNA assay and conventional histopathological examination. Ultrastaging (200-μm LN sections) was performed for metastatic LNs using hematoxylin and eosin staining and immunostaining with an anti-CK19 antibody in cases where the OSNA assay and histopathological examination (performed using 2-mm LN sections) results showed discordance. Results: A total of 437 LNs from 133 patients were included; 61 patients (14%) showed metastasis by histopathological examination, with a concordance rate of 0.979 (95% confidence interval [CI]: 0.961–0.991) with the OSNA assay. The sensitivity and specificity of the OSNA assay were 0.918 (95% CI: 0.819–0.973) and 0.989 (95% CI: 0.973–0.997), respectively. Discordance between the two methods was observed in nine LNs (2.1%), and allocation bias of metastatic foci was identified as the major cause of discordance. Conclusions: The OSNA assay showed equally accurate detection of LN metastasis as the histopathological examination. We suggest that the OSNA assay may be a useful tool for the rapid intraoperative diagnosis of LN metastasis in patients with cervical and endometrial cancers.

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Current status of hereditary breast and ovarian cancer practice among gynecologic oncologists in Japan: a nationwide survey by the Japan Society of Gynecologic Oncology (JSGO).

Yusuke Kobayashi, Kenta Masuda, Akira Hiraswa, Kazuhiro Takehara, Hitoshi Tsuda, Yoh Watanabe, Katsutoshi Oda, Satoru Nagase, Masaki Mandai, Aikou Okamoto, Nobuo Yaegashi, Mikio Mikami, Takayuki Enomoto, Daisuke Aoki, Hidetaka Katabuchi

Journal of gynecologic oncology 33 ( 5 ) e61 2022.09

ISSN 2005-0380

OBJECTIVE: The practices pertaining to hereditary breast and ovarian cancer (HBOC) in Japan have been rapidly changing owing to the clinical development of poly(ADP-ribose) polymerase inhibitors, the increasing availability of companion diagnostics, and the broadened insurance coverage of HBOC management from April 2020. A questionnaire of gynecologic oncologists was conducted to understand the current status and to promote the widespread standardization of future HBOC management. METHODS: A Google Form questionnaire was administered to the members of the Japan Society of Gynecologic Oncology. The survey consisted of 25 questions in 4 categories: respondent demographics, HBOC management experience, insurance coverage of HBOC management, and educational opportunities related to HBOC. RESULTS: A total of 666 valid responses were received. Regarding the prevalence of HBOC practice, the majority of physicians responded in the negative and required human resources, information sharing and educational opportunities, and expanded insurance coverage to adopt and improve HBOC practice. Most physicians were not satisfied with the educational opportunities provided so far, and further expansion was desired. They remarked on the psychological burdens of many HBOC managements. Physicians reported these burdens could be alleviated by securing sufficient time to engage in HBOC management, creating easy-to-understand explanatory material for patients, collaboration with specialists in genetic medicine, and educational opportunities. CONCLUSION: Gynecologic oncologists in Japan are struggling to deal with psychological burdens in HBOC practice. To promote the clinical practice of HBOC management, there is an urgent need to strengthen human resources and improve educational opportunities, and expand insurance coverage for HBOC management.

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TP53 variants in p53 signatures and the clonality of STICs in RRSO samples.

Tomoko Akahane, Kenta Masuda, Akira Hirasawa, Yusuke Kobayashi, Arisa Ueki, Miho Kawaida, Kumiko Misu, Kohei Nakamura, Shimpei Nagai, Tatsuyuki Chiyoda, Wataru Yamagami, Shigenori Hayashi, Fumio Kataoka, Kouji Banno, Kokichi Sugano, Hajime Okita, Kenjiro Kosaki, Hiroshi Nishihara, Daisuke Aoki

Journal of gynecologic oncology 33 ( 4 ) e50 2022.07

Corresponding author, Accepted, ISSN 2005-0380

OBJECTIVE: Precursor lesions may be identified in fallopian tube tissue after risk-reducing salpingo-oophorectomy (RRSO) in patients with pathogenic variants of BRCA1/2. Serous tubal intraepithelial carcinoma (STIC) is considered a precursor of high-grade serous carcinoma, whereas the significance of the p53 signature remains unclear. In this study, we investigated the relationship between the p53 signature and the risk of ovarian cancer. METHODS: We analyzed the clinicopathological findings and conducted DNA sequencing for TP53 variants of p53 signatures and STIC lesions isolated using laser capture microdissection in 13 patients with pathogenic variants of BRCA1/2 who underwent RRSO and 17 control patients with the benign gynecologic disease. RESULTS: TP53 pathogenic variants were detected significantly higher in RRSO group than control (p<0.001). No difference in the frequency of p53 signatures were observed between groups (53.8% vs 29.4%; p=0.17). TP53 sequencing and next-generation sequencing analysis in a patient with STIC and occult cancer revealed 2 TP53 mutations causing different p53 staining for STICs and another TP53 mutation shared between STIC and occult cancer. CONCLUSION: The sequence analysis for TP53 revealed 2 types of p53 signatures, one with a risk of progression to STIC and ovarian cancer with pathological variants in TP53 and the other with a low risk of progression without pathological variants in TP53 as seen in control.

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SIK2 inhibition enhances PARP inhibitor activity synergistically in ovarian and triple-negative breast cancers.

Zhen Lu, Weiqun Mao, Hailing Yang, Janice M Santiago-O'Farrill, Philip J Rask, Jayanta Mondal, Hu Chen, Cristina Ivan, Xiuping Liu, Chang-Gong Liu, Yuanxin Xi, Kenta Masuda, Eli M Carrami, Meng Chen, Yitao Tang, Lan Pang, David S Lakomy, George A Calin, Han Liang, Ahmed A Ahmed, Hariprasad Vankayalapati, Robert C Bast Jr

The Journal of clinical investigation 132 ( 11 ) 2022.06

ISSN 00219738

Poly(ADP-ribose) polymerase inhibitors (PARP inhibitors) have had an increasing role in the treatment of ovarian and breast cancers. PARP inhibitors are selectively active in cells with homologous recombination DNA repair deficiency caused by mutations in BRCA1/2 and other DNA repair pathway genes. Cancers with homologous recombination DNA repair proficiency respond poorly to PARP inhibitors. Cancers that initially respond to PARP inhibitors eventually develop drug resistance. We have identified salt-inducible kinase 2 (SIK2) inhibitors, ARN3236 and ARN3261, which decreased DNA double-strand break (DSB) repair functions and produced synthetic lethality with multiple PARP inhibitors in both homologous recombination DNA repair deficiency and proficiency cancer cells. SIK2 is required for centrosome splitting and PI3K activation and regulates cancer cell proliferation, metastasis, and sensitivity to chemotherapy. Here, we showed that SIK2 inhibitors sensitized ovarian and triple-negative breast cancer (TNBC) cells and xenografts to PARP inhibitors. SIK2 inhibitors decreased PARP enzyme activity and phosphorylation of class-IIa histone deacetylases (HDAC4/5/7). Furthermore, SIK2 inhibitors abolished class-IIa HDAC4/5/7-associated transcriptional activity of myocyte enhancer factor-2D (MEF2D), decreasing MEF2D binding to regulatory regions with high chromatin accessibility in FANCD2, EXO1, and XRCC4 genes, resulting in repression of their functions in the DNA DSB repair pathway. The combination of PARP inhibitors and SIK2 inhibitors provides a therapeutic strategy to enhance PARP inhibitor sensitivity for ovarian cancer and TNBC.

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MEK inhibition suppresses metastatic progression of KRAS-mutated gastric cancer.

Juntaro Yamasaki, Yuki Hirata, Yuji Otsuki, Kentaro Suina, Yoshiyuki Saito, Kenta Masuda, Shogo Okazaki, Takatsugu Ishimoto, Hideyuki Saya, Osamu Nagano

Cancer science (Cancer Science) 113 ( 3 ) 916 - 925 2021.12

ISSN 1347-9032

Metastatic progression of tumors is driven by genetic alterations and tumor-stroma interaction. To elucidate the mechanism underlying the oncogene-induced gastric tumor progression, we have developed an organoid-based model of gastric cancer from GAstric Neoplasia (GAN) mice, which express Wnt1 and the enzymes COX2 and microsomal prostaglandin E synthase 1 in the stomach. Both p53 knockout (GAN-p53KO) organoids and KRASG12V -expressing GAN-p53KO (GAN-KP) organoids were generated by genetic manipulation of GAN mouse-derived tumor (GAN wild-type [WT]) organoids. In contrast with GAN-WT and GAN-p53KO organoids, which manifested Wnt addiction, GAN-KP organoids showed a Wnt-independent phenotype and the ability to proliferate without formation of a Wnt-regulated three-dimensional epithelial architecture. After transplantation in syngeneic mouse stomach, GAN-p53KO cells formed only small tumors, whereas GAN-KP cells gave rise to invasive tumors associated with the development of hypoxia as well as to liver metastasis. Spatial transcriptomics analysis suggested that hypoxia signaling contributes to the metastatic progression of GAN-KP tumors. In particular, such analysis identified a cluster of stromal cells located at the tumor invasive front that expressed genes related to hypoxia signaling, angiogenesis, and cell migration. These cells were also positive for phosphorylated extracellular signal-regulated kinase (ERK), suggesting that mitogen-activated protein kinase (MAPK) signaling promotes development of both tumor and microenvironment. The MEK (MAPK kinase) inhibitor trametinib suppressed the development of GAN-KP gastric tumors, formation of a hypoxic microenvironment, tumor angiogenesis, and liver metastasis. Our findings therefore establish a rationale for application of trametinib to suppress metastatic progression of KRAS-mutated gastric cancer.

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Meningitis caused by Listeria monocytogenes in a locally advanced cervical cancer patient with pyometra: A case report.

Matoba Y, Nishio H, Sekiguchi K, Uno S, Masuda K, Hiramatsu M, Takahashi M, Oishi M, Uwamino Y, Uchida S, Daté Y, Morisada T, Banno K, Nakahara J, Aoki D

Gynecologic oncology reports (Gynecologic Oncology Reports) 37 100799 2021.08

Locally advanced cervical cancer occasionally induces pyometra, but there have been no reports of meningitis where pyometra is the cause of infection. Here, we report a case of Listeria monocytogenes meningitis related to pyometra during concurrent chemoradiotherapy (CCRT) in a cervical cancer patient. The patient, a 77-year-old woman, was diagnosed with Stage IIB (FIGO 2018) cervical adenocarcinoma, and CCRT was initiated. Pyometra was exacerbated during CCRT, and after her first brachytherapy, she presented at our hospital with fever and decreased consciousness level. After admission to the Intensive Care Unit, the patient lost consciousness and experienced frequent seizures; tracheal intubation was required. Whole-body computed tomography revealed pyometra; therefore, transvaginal removal of the abscess was performed. Laboratory tests and vital signs indicated septic shock, and meropenem was administered. L. monocytogenes was detected in the abscess from the uterine cavity and the blood cultures on the third day of hospitalization. A lumbar puncture was performed on the same day to investigate whether the patient had meningitis. A FilmArray meningitis/encephalitis panel test of the spinal fluid revealed L. monocytogenes. After the diagnosis of meningitis with L. monocytogenes, ampicillin and gentamicin were started, and the blood test results gradually improved. Five months after the initial episode, her consciousness recovered, however she still received mechanical ventilatory support. L. monocytogenes infections can occur in patients undergoing chemotherapy, even without the use of steroids or immunosuppressive agents. In cases with pyometra, intrauterine manipulation can increase the risk of severe infection.

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Adipocyte-like signature in ovarian cancer minimal residual disease identifies metabolic vulnerabilities of tumor-initiating cells.

Artibani M, Masuda K, Hu Z, Rauher PC, Mallett G, Wietek N, Morotti M, Chong K, KaramiNejadRanjbar M, Zois CE, Dhar S, El-Sahhar S, Campo L, Blagden SP, Damato S, Pathiraja PN, Nicum S, Gleeson F, Laios A, Alsaadi A, Santana Gonzalez L, Motohara T, Albukhari A, Lu Z, Bast RC Jr, Harris AL, Ejsing CS, Klemm RW, Yau C, Sauka-Spengler T, Ahmed AA

JCI insight (American Society for Clinical Investigation) 6 ( 11 ) 2021.06

Research paper (scientific journal), Joint Work, Accepted

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Prevalence of disease-causing genes in Japanese patients with BRCA1/2-wildtype hereditary breast and ovarian cancer syndrome

Kaneyasu T., Mori S., Yamauchi H., Ohsumi S., Ohno S., Aoki D., Baba S., Kawano J., Miki Y., Matsumoto N., Nagasaki M., Yoshida R., Akashi-Tanaka S., Iwase T., Kitagawa D., Masuda K., Hirasawa A., Arai M., Takei J., Ide Y., Gotoh O., Yaguchi N., Nishi M., Kaneko K., Matsuyama Y., Okawa M., Suzuki M., Nezu A., Yokoyama S., Amino S., Inuzuka M., Noda T., Nakamura S.

npj Breast Cancer (npj Breast Cancer) 6 ( 1 ) 25 - 25 2020.12

Research paper (scientific journal), Joint Work

© 2020, The Author(s). Panel sequencing of susceptibility genes for hereditary breast and ovarian cancer (HBOC) syndrome has uncovered numerous germline variants; however, their pathogenic relevance and ethnic diversity remain unclear. Here, we examined the prevalence of germline variants among 568 Japanese patients with BRCA1/2-wildtype HBOC syndrome and a strong family history. Pathogenic or likely pathogenic variants were identified on 12 causal genes for 37 cases (6.5%), with recurrence for 4 SNVs/indels and 1 CNV. Comparisons with non-cancer east-Asian populations and European familial breast cancer cohorts revealed significant enrichment of PALB2, BARD1, and BLM mutations. Younger onset was associated with but not predictive of these mutations. Significant somatic loss-of-function alterations were confirmed on the wildtype alleles of genes with germline mutations, including PALB2 additional somatic truncations. This study highlights Japanese-associated germline mutations among patients with BRCA1/2 wildtype HBOC syndrome and a strong family history, and provides evidence for the medical care of this high-risk population.

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Retrospective evaluation of risk-reducing salpingo-oophorectomy for BRCA1/2 pathogenic variant carriers among a cohort study in a single institution.

Kobayashi Y, Hirasawa A, Chiyoda T, Ueki A, Masuda K, Misu K, Kawaida M, Hayashi S, Kataoka F, Banno K, Kosaki K, Aoki D

Japanese journal of clinical oncology (Japanese journal of clinical oncology) 51 ( 2 ) 213 - 217 2020.10

Research paper (scientific journal), Joint Work, ISSN 0368-2811

© The Author(s) 2020. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permission@oup.com. BACKGROUND: Risk-reducing salpingo-oophorectomy is performed for the primary prevention of ovarian cancer in patients with hereditary breast-ovarian cancer syndrome. We performed risk-reducing salpingo-oophorectomy for the first time in Japan in 2008, and we experienced 20 cases of risk-reducing salpingo-oophorectomy through 2019. In the past, the use of risk-reducing salpingo-oophorectomy in Japan was restricted because it was not covered by a Japanese National Health Insurance. Since April 2020, risk-reducing salpingo-oophorectomy has been covered by insurance for patients with breast-ovarian cancer syndrome and pre-existing breast cancer, and this surgery is expected to become more widely implemented in Japan. METHODS: To contribute to the widespread use of risk-reducing salpingo-oophorectomy in the future, we retrospectively reviewed 20 cases of risk-reducing salpingo-oophorectomy at our hospital cohort study to clarify the issues in its implementation. RESULTS: The variant genes for which risk-reducing salpingo-oophorectomy was indicated were BRCA1 and BRCA2 in 13 (65%) and 7 patients (35%), respectively. The median age at which risk-reducing salpingo-oophorectomy was performed was 49 years (range, 38-58), 13 patients (65%) had gone through menopause, and 16 patients (80%) had a history of breast cancer. Of the five patients (25%) with vasomotor symptoms, four received Chinese medicine, and only one received hormone replacement therapy. Occult cancer was detected in the removed ovaries in two patients (10%), although no postoperative peritoneal carcinogenesis has been observed to date. CONCLUSIONS: Women who paid for risk-reducing salpingo-oophorectomy out of pocket were older than the recommended age at which the procedure should be performed, and this may explain the higher rate of occult cancers than previously reported. We need to perform risk-reducing salpingo-oophorectomy at the recommended age to ensure that the procedure is effective for primary prevention.

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Cowden syndrome complicated by schizophrenia: A first clinical report

Kobayashi Y., Takeda T., Kunitomi H., Ueki A., Misu K., Kowashi A., Takahashi T., Anko M., Watanabe K., Masuda K., Uchida T., Tominaga E., Banno K., Kosaki K., Aoki D.

European Journal of Medical Genetics (European Journal of Medical Genetics) 63 ( 8 ) 103959 2020.08

ISSN 17697212

© 2020 Elsevier Masson SAS Patients with Cowden syndrome exhibit mucocutaneous lesions, hamartomatous polyposis of the gastrointestinal tract, and macrocephaly, often complicated by malignant tumors, such as breast, thyroid, and uterine cancers. Autism spectrum and epilepsy have been known as neuropsychiatric symptoms associated with Cowden syndrome; however, to the best of our knowledge, there is no report on cases complicated by schizophrenia. Here, we report a first case of Cowden syndrome complicated by schizophrenia. A 49-year-old Japanese woman started experiencing auditory hallucinations in her teens. She had left breast cancer at the age of 34 years, and right breast cancer at the age of 37 years, all of which were surgically treated. She was also being treated by oral medications for Hashimoto's disease. On consulting her previous doctor for abnormal uterine bleeding that lasted for a year, she was diagnosed with endometrial cancer. However, immediately before surgery, her auditory hallucinations and paranoid delusions became severe, and she was referred to our hospital for detailed examination and treatment. No abnormalities were found on head MRI, and she was diagnosed with schizophrenia on the basis of neuropsychiatric examination findings. After her psychiatric symptoms were controlled by 2 mg of risperidone, she underwent surgery for endometrial cancer. Although there was no apparent family history, physical findings including macrocephaly and papillomatous skin lesions together with her past medical history of multiple malignant tumors suggested Cowden syndrome. Postoperatively, genetic testing revealed a pathogenic variant c.655C > T; p. Gln219* (NM_000314.4) in PTEN, leading to the confirmation of the diagnosis of Cowden syndrome.

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The Repertoire of Serous Ovarian Cancer Non-genetic Heterogeneity Revealed by Single-Cell Sequencing of Normal Fallopian Tube Epithelial Cells.

Hu Z, Artibani M, Alsaadi A, Wietek N, Morotti M, Shi T, Zhong Z, Santana Gonzalez L, El-Sahhar S, KaramiNejadRanjbar M, Mallett G, Feng Y, Masuda K, Zheng Y, Chong K, Damato S, Dhar S, Campo L, Garruto Campanile R, Soleymani Majd H, Rai V, Maldonado-Perez D, Jones S, Cerundolo V, Sauka-Spengler T, Yau C, Ahmed AA

Cancer cell (Cancer Cell) 37 ( 2 ) 226 - 242.e7 2020.02

Research paper (scientific journal), Joint Work, Accepted, ISSN 1535-6108

The inter-differentiation between cell states promotes cancer cell survival under stress and fosters non-genetic heterogeneity (NGH). NGH is, therefore, a surrogate of tumor resilience but its quantification is confounded by genetic heterogeneity. Here we show that NGH in serous ovarian cancer (SOC) can be accurately measured when informed by the molecular signatures of the normal fallopian tube epithelium (FTE) cells, the cells of origin of SOC. Surveying the transcriptomes of ∼6,000 FTE cells, predominantly from non-ovarian cancer patients, identified 6 FTE subtypes. We used subtype signatures to deconvolute SOC expression data and found substantial intra-tumor NGH. Importantly, NGH-based stratification of ∼1,700 tumors robustly correlated with survival. Our findings lay the foundation for accurate prognostic and therapeutic stratification of SOC. Using single-cell RNA sequencing, Hu et al. identify six subtypes of fallopian tube epithelium (FTE) cells in normal human fallopian tube tissues. The FTE cellular subtypes reveal intra-tumoral heterogeneity in serous ovarian cancer (SOC) and define SOC subtypes that correlate with patient prognosis.

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An evolving story of the metastatic voyage of ovarian cancer cells: cellular and molecular orchestration of the adipose-rich metastatic microenvironment.

Motohara T, Masuda K, Morotti M, Zheng Y, El-Sahhar S, Chong KY, Wietek N, Alsaadi A, Karaminejadranjbar M, Hu Z, Artibani M, Gonzalez LS, Katabuchi H, Saya H, Ahmed AA

Oncogene (Oncogene) 38 ( 16 ) 2885 - 2898 2019.04

Joint Work, Accepted, ISSN 09509232

© 2018, The Author(s). Metastasis is a complex multistep process that involves critical interactions between cancer cells and a variety of stromal components in the tumor microenvironment, which profoundly influence the different aspects of the metastatic cascade and organ tropism of disseminating cancer cells. Ovarian cancer is the most lethal gynecological malignancy and is characterized by peritoneal disseminated metastasis. Evidence has demonstrated that ovarian cancer possesses specific metastatic tropism for the adipose-rich omentum, which has a pivotal role in the creation of the metastatic tumor microenvironment in the intraperitoneal cavity. Considering the distinct biology of ovarian cancer metastasis, the elucidation of the cellular and molecular mechanisms underlying the reciprocal interplay between ovarian cancer cells and surrounding stromal cell types in the adipose-rich metastatic microenvironment will provide further insights into the development of novel therapeutic approaches for patients with advanced ovarian cancer. Herein, we review the biological mechanisms that regulate the highly orchestrated crosstalk between ovarian cancer cells and various cancer-associated stromal cells in the metastatic tumor microenvironment with regard to the omentum by illustrating how different stromal cells concertedly contribute to the development of ovarian cancer metastasis and metastatic tropism for the omentum.

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Tuning microtubule dynamics to enhance cancer therapy by modulating FER-mediated CRMP2 phosphorylation.

Zheng Y, Sethi R, Mangala LS, Taylor C, Goldsmith J, Wang M, Masuda K, Karaminejadranjbar M, Mannion D, Miranda F, Herrero-Gonzalez S, Hellner K, Chen F, Alsaadi A, Albukhari A, Fotso DC, Yau C, Jiang D, Pradeep S, Rodriguez-Aguayo C, Lopez-Berestein G, Knapp S, Gray NS, Campo L, Myers KA, Dhar S, Ferguson D, Bast RC Jr, Sood AK, von Delft F, Ahmed AA

Nature communications (Nature Communications) 9 ( 1 ) 476 2018.12

Joint Work, Accepted

© 2018 The Author(s). Though used widely in cancer therapy, paclitaxel only elicits a response in a fraction of patients. A strong determinant of paclitaxel tumor response is the state of microtubule dynamic instability. However, whether the manipulation of this physiological process can be controlled to enhance paclitaxel response has not been tested. Here, we show a previously unrecognized role of the microtubule-associated protein CRMP2 in inducing microtubule bundling through its carboxy terminus. This activity is significantly decreased when the FER tyrosine kinase phosphorylates CRMP2 at Y479 and Y499. The crystal structures of wild-type CRMP2 and CRMP2-Y479E reveal how mimicking phosphorylation prevents tetramerization of CRMP2. Depletion of FER or reducing its catalytic activity using sub-therapeutic doses of inhibitors increases paclitaxel-induced microtubule stability and cytotoxicity in ovarian cancer cells and in vivo. This work provides a rationale for inhibiting FER-mediated CRMP2 phosphorylation to enhance paclitaxel on-target activity for cancer therapy.

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Aberrant chromatin remodeling in gynecological cancer.

Okawa R, Banno K, Iida M, Yanokura M, Takeda T, Iijima M, Kunitomi-Irie H, Nakamura K, Adachi M, Umene K, Nogami Y, Masuda K, Kobayashi Y, Tominaga E, Aoki D

Oncology letters (Oncology Letters) 14 ( 5 ) 5107 - 5113 2017.11

ISSN 1792-1074

© 2017, Spandidos Publications. All rights reserved. Epigenetic regulatory mechanisms are a current focus in studies investigating cancer. Chromatin remodeling alters chromatin structure and regulates gene expression, and aberrant chromatin remodeling is involved in carcinogenesis. AT-rich interactive domain-containing protein 1A (ARID1A) and SWItch/sucrose non-fermentable-related, matrix-associated, actin-dependent regulator of chromatin, subfamily a, member 4 are remodeling factors that are mutated in numerous types of cancer. In gynecological cancer, ARID1A mutations have been identified in 46-57% of clear cell carcinoma and 30% of endometrioid carcinoma. Mutations of chromodomain helicase, DNA-binding protein 4 have been detected in 17-21% of endometrial serous cancer, and mutations of ARID1A and mixed-lineage leukemia 3 occur in 36 and 27% of uterine carcinosarcoma, respectively. These data suggest that aberrant chromatin remodeling is a potential cause of cancer, and have led to the development of novel proteins targeting these processes. Additional accumulation of information on the mechanisms of chromatin remodeling and markers for these events may promote personalized anticancer therapies.

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Drug repositioning of mevalonate pathway inhibitors as antitumor agents for ovarian cancer.

Kobayashi Y, Kashima H, Rahmanto YS, Banno K, Yu Y, Matoba Y, Watanabe K, Iijima M, Takeda T, Kunitomi H, Iida M, Adachi M, Nakamura K, Tsuji K, Masuda K, Nomura H, Tominaga E, Aoki D

Oncotarget (Oncotarget) 8 ( 42 ) 72147 - 72156 2017.09

© 2018 Oncotarget. All rights reserved. Drug repositioning is an alternative strategy redirecting existing drugs for new disease. We have previously reported an antitumor effect of statins, antidyslipidemic drugs, on ovarian cancer in vitro and in vivo. In this study, we investigated the antitumor effects of other mevalonate pathway inhibitors and the mechanism of the antitumor effect from a metabolic perspective. The effects of inhibitors of the mevalonate pathway on tumor cell growth were evaluated in vitro. Bisphosphonates that inhibit this pathway are commonly used as antiosteoporotic drugs, and antitumor effects of the bisphosphonate were examined in vitro and in vivo. Metabolites in SKOV3 ovarian cancer cells were analyzed before and after lovastatin treatment, using capillary electrophoresis-mass spectrometry. All mevalonate pathway inhibitors showed concentration-dependent inhibitory effects on tumor cell growth. Particularly marked effects were obtained with inhibitors of farnesyltransferase and geranylgeranyltransferase. The bisphosphonate was also shown to have an antitumor effect in vivo. The expression of autophagy marker LC3A/3B was increased in cells after treatment. In metabolomics analysis, lovastatin treatment increased the metabolites involved in the tricarboxylic acid cycle while reducing the metabolites associated with glycolysis. Also it decreased glutathione and resulted to work with chemotherapeutic agents synergistically. Inhibition at any point in the mevalonate pathway, and especially of farnesyl pyrophosphate and geranylgeranyl pyrophosphate, suppresses growth of ovarian cancer cells. Inhibition of this pathway may induce autophagy, cause a shift to activation of the tricarboxylic acid cycle and enhance susceptibility to chemotherapy. Drug repositioning targeting mevalonate pathway for ovarian cancer deserves consideration for clinical application.

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Clinical utility of a self-administered questionnaire for assessment of hereditary gynecologic cancer.

Masuda K, Hirasawa A, Irie-Kunitomi H, Akahane T, Ueki A, Kobayashi Y, Yamagami W, Nomura H, Kataoka F, Tominaga E, Banno K, Susumu N, Aoki D

Japanese journal of clinical oncology (Japanese Journal of Clinical Oncology) 47 ( 5 ) 401 - 406 2017.05

ISSN 0368-2811

© The Author 2017. Published by Oxford University Press. All rights reserved. Background: A patient's medical history and familial cancer history are important information for assessing the risk of hereditary cancer. We have generated a self-administered questionnaire for patients with gynecologic cancer. This pilot study analyzed the usefulness of this questionnaire and the rates of patients that meet the Society of Gynecologic Oncology criteria in ovarian cancer and endometrial cancer patients.Method: Ovarian or endometrial cancer patients were recruited for this study. After informed consent was obtained, participants completed the questionnaire. Genetic risks were assessed from the data of each patient's questionnaire by Society of Gynecologic Oncology guideline. Clinical and pathological findings were compared between the genetic risk groups.Results: A total of 105 patients were identified with ovarian cancer and 56 patients with endometrial cancer eligible for this study. According to the Society of Gynecologic Oncology guideline, of the 105 ovarian cancer patients, 25 patients (23%) had a 20-25% risk and three patients (2.9%) had a 5-10% risk of hereditary breast and ovarian cancer syndrome. A further 22 patients (21%) had a 5-10% risk of Lynch syndrome. Two patients (1.9%) met the Amsterdam criteria II. Of 56 endometrial cancer patients, 24 patients (42.9%) had a 5-10% risk of Lynch syndrome. The endometrial cancer patients with genetic risk of Lynch syndrome were younger (mean age: 47.79) at diagnosis compared to patients without a genetic risk of Lynch syndrome (mean age: 57.91).Conclusions: In this study, we were able to show that the newly designed questionnaire is a useful tool for evaluating cancer family history along with Society of Gynecologic Oncology criteria or Amsterdam criteria II. When considering the risk of Lynch syndrome for a patient with ovarian cancer, it is important to collect a second and third relative's family history.

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Genome-wide analysis of gynecologic cancer: The Cancer Genome Atlas in ovarian and endometrial cancer.

Iijima M, Banno K, Okawa R, Yanokura M, Iida M, Takeda T, Kunitomi-Irie H, Adachi M, Nakamura K, Umene K, Nogami Y, Masuda K, Tominaga E, Aoki D

Oncology letters (Oncology Letters) 13 ( 3 ) 1063 - 1070 2017.03

ISSN 1792-1074

© 2017, Spandidos Publications. All rights reserved. Cancer typically develops due to genetic abnormalities, but a single gene abnormality cannot completely account for the onset of cancer. The Cancer Genome Atlas (CGA) project was conducted for the cross-sectional genome-wide analysis of numerous genetic abnormalities in various types of cancer. This approach has facilitated the identification of novel AT-rich interaction domain 1A gene mutations in ovarian clear cell carcinoma, frequent tumor protein 53 (TP53) gene mutations in high-grade ovarian serous carcinoma, and Kirsten rat sarcoma and B-rapidly accelerated fibrosarcoma proto-oncogene, serine/threonine kinase gene mutations in low-grade ovarian serous carcinoma. Genome-wide analysis of endometrial cancers has led to the establishment of four subgroups: Polymerase ultramutated, microsatellite instability hypermutated, genome copy-number low and genome copy-number high. These results may facilitate the improvement of the prediction of patient prognosis and therapeutic sensitivity in various types of gynecologic cancer. The enhanced use of currently available therapeutic agents and the development of novel drugs may be facilitated by the novel classification of ovarian cancer based on TP53 mutations, the efficacy of poly (ADP-ribose) polymerase inhibitors for tumors with breast cancer 1/2 mutations and the effect of phosphoinositide-3-kinase (PI3K)/mammalian target of rapamycin inhibitors for tumors with mutations in the PI3K/protein kinase B signaling pathway. Important results have been revealed by genome-wide analyses; however, the pathogenic underlying mechanisms of gynecologic cancer will require further studies and multilateral evaluation using epigenetic, transcriptomic and proteomic analyses, in addition to genomic analysis.

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Carcinoma of the lower uterine segment diagnosed with Lynch syndrome based on MSH6 germline mutation: A case report.

Adachi M, Banno K, Masuda K, Yanokura M, Iijima M, Takeda T, Kunitomi H, Kobayashi Y, Yamagami W, Hirasawa A, Kameyama K, Sugano K, Aoki D

The journal of obstetrics and gynaecology research (Journal of Obstetrics and Gynaecology Research) 43 ( 2 ) 416 - 420 2017.02

ISSN 1341-8076

© 2016 Japan Society of Obstetrics and Gynecology Endometrial cancer in the lower uterine segment (LUS) is associated with Lynch syndrome with MLH1 or MSH2 germline mutation. Here, we report a case of carcinoma of the LUS diagnosed with Lynch syndrome based on MSH6 germline mutation in a 46-year-old woman with abnormal vaginal bleeding. She had had rectal cancer at age 39 with a family history of colon cancer (father, 75 years), pancreatic cancer (paternal grandmother, 74 years), and colon cancer (maternal grandmother, 85 years). Magnetic resonance imaging showed a tumor in the LUS. Endometrial biopsy revealed endometrioid adenocarcinoma G1. As her cancer history met the revised Bethesda criteria, we examined microsatellite instability and the result was negative, but loss of the MSH6 expression was detected by immunohistochemistry. Genetic testing revealed deleterious germline mutation of MSH6, which was compatible with Lynch syndrome. To our knowledge, this is the first case of endometrial carcinoma of the LUS with MSH6 germline mutation.

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Methylation Analysis of DNA Mismatch Repair Genes Using DNA Derived from the Peripheral Blood of Patients with Endometrial Cancer: Epimutation in Endometrial Carcinogenesis.

Takeda T, Banno K, Yanokura M, Adachi M, Iijima M, Kunitomi H, Nakamura K, Iida M, Nogami Y, Umene K, Masuda K, Kobayashi Y, Yamagami W, Hirasawa A, Tominaga E, Susumu N, Aoki D

Genes (Genes) 7 ( 10 ) 2016.10

© 2016 by the authors; licensee MDPI, Basel, Switzerland. Germline mutation of DNA mismatch repair (MMR) genes is a cause of Lynch syndrome. Methylation of MutL homolog 1 (MLH1) and MutS homolog 2 (MSH2) has been detected in peripheral blood cells of patients with colorectal cancer. This methylation is referred to as epimutation. Methylation of these genes has not been studied in an unselected series of endometrial cancer cases. Therefore, we examined methylation of MLH1, MSH2, and MSH6 promoter regions of peripheral blood cells in 206 patients with endometrial cancer using a methylation-specific polymerase chain reaction (MSP). Germline mutation of MMR genes, microsatellite instability (MSI), and immunohistochemistry (IHC) were also analyzed in each case with epimutation. MLH1 epimutation was detected in a single patient out of a total of 206 (0.49%) —1 out of 58 (1.72%) with an onset age of less than 50 years. The patient with MLH1 epimutation showed high level MSI (MSI-H), loss of MLH1 expression and had developed endometrial cancer at 46 years old, complicated with colorectal cancer. No case had epimutation of MSH2 or MSH6. The MLH1 epimutation detected in a patient with endometrial cancer may be a cause of endometrial carcinogenesis. This result indicates that it is important to check epimutation in patients with endometrial cancer without a germline mutation of MMR genes.

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ARID1A gene mutation in ovarian and endometrial cancers (Review).

Takeda T, Banno K, Okawa R, Yanokura M, Iijima M, Irie-Kunitomi H, Nakamura K, Iida M, Adachi M, Umene K, Nogami Y, Masuda K, Kobayashi Y, Tominaga E, Aoki D

Oncology reports (Oncology Reports) 35 ( 2 ) 607 - 13 2016.02

ISSN 1021-335X

The ATrich interacting domaincontaining protein 1A gene (ARID1A) encodes ARID1A, a member of the SWI/SNF chromatin remodeling complex. Mutation of ARID1A induces changes in expression of multiple genes (CDKN1A, SMAD3, MLH1 and PIK3IP1) via chromatin remodeling dysfunction, contributes to carcinogenesis, and has been shown to cause transformation of cells in association with the PI3K/AKT pathway. Information on ARID1A has emerged from comprehensive genome wide analyses with next generation sequencers. ARID1A mutations have been found in various types of cancer and occur at high frequency in endometriosis associated ovarian cancer including clear cell adenocarcinoma and endometrioid adenocarcinoma, and also occur at endometrial cancer especially in endometrioid adenocarcinoma. It has also been suggested that ARID1A mutation occurs at the early stage of canceration from endometriosis to endometriosis associated carcinoma in ovarian cancer and also from atypical endometrial hyperplasia to endometrioid adenocarcinoma in endometrial cancer. Therefore, development of a screening method that can detect mutations of ARID1A and activation of the PI3K/AKT pathway might enable early diagnosis of endometriosis associated ovarian cancers and endometrial cancers. Important results may also emerge from a current clinical trial examining a multidrug regimen of temsirolimus a small molecule inhibitor of the PI3K/AKT pathway for treatment of advanced ovarian clear cell adenocarcinoma with ARID1A mutation and PI3K/AKT pathway activation. Also administration of sorafenib, a multikinase inhibitor, can inhibit cancer proliferation with PIK3CA mutation and resistance to mTOR inhibitors and GSK126, a molecular targeted drug can inhibit proliferation of ARID1A mutated ovarian clear cell adenocarcinoma cells by targeting and inhibiting EZH2. Further studies are needed to determine the mechanism of chromatin remodeling dysregulation initiated by ARID1A mutation, to develop methods for early diagnosis to investigate new cancer therapy targeting ARID1A, and to examine the involvement of ARID1A mutations in development survival and progression of cancer cells.

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Metformin: A candidate for the treatment of gynecological tumors based on drug repositioning.

Irie H, Banno K, Yanokura M, Iida M, Adachi M, Nakamura K, Umene K, Nogami Y, Masuda K, Kobayashi Y, Tominaga E, Aoki D

Oncology letters (Oncology Letters) 11 ( 2 ) 1287 - 1293 2016.02

ISSN 1792-1074

© 2016, Spandidos Publications. All rights reserved. Metformin is a first-line drug used for the treatment of type 2 diabetes. Recently, metformin has been reported to reduce the carcinogenic risk and inhibit tumor cell growth in glioma and breast cancer. The anticancer action of metformin involves the enhancement of phosphorylation of liver kinase B1, activation of adenosine monophosphate-activated protein kinase and inhibition of mammalian target of rapamycin, which reduces cell growth. Metformin is anticipated to exert antitumor effects in gynecological cancer, and its efficacy for the treatment of endometrial, breast and ovarian cancer has been suggested in preclinical studies and clinical trials. Although the effect of metformin on cervical cancer remains to be examined in clinical trials, its antitumor effects have been reported in preclinical studies. Thus, the use of metformin for the treatment of gynecological cancer may become a successful example of drug repositioning, following establishment of the drug's antitumor effects, risk evaluation, screening and validation of efficacy.

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Characterization of the STK11 splicing variant as a normal splicing isomer in a patient with Peutz-Jeghers syndrome harboring genomic deletion of the STK11 gene.

Masuda K, Kobayashi Y, Kimura T, Umene K, Misu K, Nomura H, Hirasawa A, Banno K, Kosaki K, Aoki D, Sugano K

Human genome variation (Human Genome Variation) 3 16002 2016

© 2016 The Japan Society of Human Genetics. We report a STK11 splicing variant comprising a 131-bp insertion that is derived from intron 1, which has previously been reported to possess potent pathogenicity the same variant was detected in a Peutz-Jeghers syndrome patient harboring a genomic deletion in the vicinity of exon 1 of the STK11 gene, which indicated that this variant was derived from the wild-type allele. We also found the same variant in other normal subjects. This variant corresponds to the predicted transcript variant of STK11 (XM-011528209), which is derived from the genomic sequence of Chr19 (NT-011295.12). Therefore, we concluded that the splicing variant was not pathogenic.

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Aurora kinase A has a significant role as a therapeutic target and clinical biomarker in endometrial cancer.

Umene K, Yanokura M, Banno K, Irie H, Adachi M, Iida M, Nakamura K, Nogami Y, Masuda K, Kobayashi Y, Tominaga E, Aoki D

International journal of oncology (International Journal of Oncology) 46 ( 4 ) 1498 - 506 2015.04

ISSN 1019-6439

aurora kinase a (aurKa) regulates the cell cycle checkpoint and maintains genomic integrity. aurKa is overexpressed in various malignant tumors and its upregulation induces chromosomal instability, which leads to aneuploidy and cell transformation. to investigate the role of aurKa in endometrial cancer, we evaluated the association of immunohistochemical expression of aurKa with clinicopathological factors. furthermore, we examined the effects of aurKa inhibition by transfected sirna in Hec-1B cells on colony-forming ability, invasion and migration capacity, and chemosensitivity. immunohistochemical staining showed that overexpression of AURKA was significantly associated with tumor grade (P<0.05) and poor histologic differentiation (P<0.05). the recurrence rate also tended to be high in cases with overexpression of aurKa (P<0.1) and these cases also had a tendency for shorter disease-free survival (DfS) (P<0.1). aurKa inhibition in endometrial cancer cell lines significantly decreased cell growth, invasion and migration (P<0.05), and increased chemosensitivity to paclitaxel. We also evaluated the efficacy of a combination of AURKA siRNA and paclitaxel against subcutaneous tumors formed in a nude mouse. After treatment, the tumor volume shrank significantly compared to treatment with paclitaxel only (P<0.05). to our knowledge, this is the first study in endometrial carcinoma to show a correlation between overexpression of aurKa and tumor grade, histological type and sensitivity to paclitaxel. aurKa is a promising therapeutic target in endometrial cancer and the combination therapy with aurKa inhibitors and paclitaxel could be effective for endometrial cancer that is resistant to conventional treatment and has a poor prognosis.

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Clinicopathologic analysis with immunohistochemistry for DNA mismatch repair protein expression in synchronous primary endometrial and ovarian cancers.

Kobayashi Y, Nakamura K, Nomura H, Banno K, Irie H, Adachi M, Iida M, Umene K, Nogami Y, Masuda K, Kisu I, Ueki A, Yamagami W, Kataoka F, Hirasawa A, Tominaga E, Susumu N, Aoki D

International journal of gynecological cancer : official journal of the International Gynecological Cancer Society (International Journal of Gynecological Cancer) 25 ( 3 ) 440 - 6 2015.03

ISSN 1048-891X

Copyright © 2015 by IGCS and ESGO. Objective: Synchronous primary endometrial and ovarian cancers have been an important topic in clinical medicine because it is sometimes difficult to distinguish whether there are 2 primary tumors or a single primary tumor and an associated metastasis. In addition, although these tumors are recommended for either immunohistochemistry for DNA mismatch repair (MMR) proteins or a microsatellite instability test in the Bethesda guidelines as Lynch syndrome-associated cancers, few studies have completed these analyses. In this study, we characterized the clinicopathologic features and the expression pattern of MMR proteins in synchronous primary endometrial and ovarian cancers. Methods: Clinicopathologic features and the expression pattern of MMR proteins (MLH1, MSH2, and MSH6) were characterized and analyzed in 32 synchronous primary endometrial and ovarian cancers. Results: Most synchronous cancers are endometrioid type (endometrioid/endometrioid) (n = 24, 75%), grade 1 (n = 19, 59.4%), and diagnosed as stage I (n = 15, 46.9%) in both endometrium and ovary. It is worth mentioning that 75% of the patients (n = 24) had endometriosis,which was more common (n = 21, 87.5%) in endometrioid/endometrioid cancers, whereas only 3 cases (37.5%) were of different histology (P = 0.018). Loss of expression of at least 1MMR protein was observed in 17 (53.1%) of the endometrial tumors and in 10 (31.3%) of ovarian tumors. Only 4 cases (12.5%) that had specific MMR protein loss showed the same type of loss for both endometrial and ovarian tumors, in which 3 of the cases were losses in MLH1. One case showed concordant MSH6 protein loss, although the cases did not meet the Amsterdam criteria II. Conclusions: These results suggest that most synchronous primary endometrial ovarian cancers are not hereditary cancers caused by germ line mutations but rather sporadic cancers.

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Risk-reducing surgery in hereditary gynecological cancer: Clinical applications in Lynch syndrome and hereditary breast and ovarian cancer.

Adachi M, Banno K, Yanokura M, Iida M, Nakamura K, Nogami Y, Umene K, Masuda K, Kisu I, Ueki A, Hirasawa A, Tominaga E, Aoki D

Molecular and clinical oncology 3 ( 2 ) 267 - 273 2015.03

ISSN 2049-9450

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Drug repositioning for gynecologic tumors: a new therapeutic strategy for cancer.

Banno K, Iida M, Yanokura M, Irie H, Masuda K, Kobayashi Y, Tominaga E, Aoki D

TheScientificWorldJournal (Scientific World Journal) 2015 341362 2015

ISSN 2356-6140

© 2015 Kouji Banno et al. The goals of drug repositioning are to find a new pharmacological effect of a drug for which human safety and pharmacokinetics are established and to expand the therapeutic range of the drug to another disease. Such drug discovery can be performed at low cost and in the short term based on the results of previous clinical trials. New drugs for gynecologic tumors may be found by drug repositioning. For example, PPAR ligands may be effective against ovarian cancer, since PPAR activation eliminates COX-2 expression, arrests the cell cycle, and induces apoptosis. Metformin, an antidiabetic drug, is effective for endometrial cancer through inhibition of the PI3K-Akt-mTOR pathway by activating LKB1-AMPK and reduction of insulin and insulin-like growth factor-1 due to AMPK activation. COX-2 inhibitors for cervical cancer may also be examples of drug repositioning. PGE2 is induced in the arachidonate cascade by COX-2. PGE2 maintains high expression of COX-2 and induces angiogenic factors including VEGF and bFGF, causing carcinogenesis. COX-2 inhibitors suppress these actions and inhibit carcinogenesis. Combination therapy using drugs found by drug repositioning and current anticancer drugs may increase efficacy and reduce adverse drug reactions. Thus, drug repositioning may become a key approach for gynecologic cancer in drug discovery.

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MicroRNAS in endometrial cancer: recent advances and potential clinical applications.

Yanokura M, Banno K, Iida M, Irie H, Umene K, Masuda K, Kobayashi Y, Tominaga E, Aoki D

EXCLI journal (EXCLI Journal) 14 190 - 8 2015

© Leibniz Research Centre for Working Environment and Human Factors. All rights reserved. Endometrial cancer is a common malignant gynecological tumor, but there are few biomarkers that are useful for early and accurate diagnosis and few treatments other than surgery. However, use of microRNAs (miRNAs) that induces gene downregulation in cells may permit effective and minimally invasive diagnosis and treatment. In endometrial cancer cells, expression levels of miRNAs including miR-185, miR-210 and miR-423 are upregulat-ed and those of miR-let7e, miR-30c and miR-221 are downregulated compared to normal tissues, and these miRNAs are involved in carcinogenesis, invasion and metastasis. miRNAs with expression changes such as miR-181b, miR-324-3p and miR-518b may be used as prognostic biomarkers and transfection of miR-152 may inhibit cancer growth. However, most current studies of miRNAs are at a basic level and further work is needed to establish clinical applications targeting miRNAs.

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LATS1 and LATS2 phosphorylate CDC26 to modulate assembly of the tetratricopeptide repeat subcomplex of APC/C.

Masuda K, Chiyoda T, Sugiyama N, Segura-Cabrera A, Kabe Y, Ueki A, Banno K, Suematsu M, Aoki D, Ishihama Y, Saya H, Kuninaka S

PloS one (PLoS ONE) 10 ( 2 ) e0118662 2015

© 2015 Masuda et al. In budding yeast, the Mitotic Exit Network (MEN) regulates anaphase promoting complex/cyclosome (APC/C) via the Dbf2-Cdc14 signaling cascade. Dbf2 kinase phosphorylates and activates Cdc14 phosphatase, which removes the inhibitory phosphorylation of the APC/C cofactor Cdh1. Although each component of the MEN was highly conserved during evolution, there is presently no evidence supporting direct phosphorylation of CDC14 by large tumor suppressor kinase 1 (LATS1), the human counterpart of Dbf2; hence, it is unclear how LATS1 regulates APC/C. Here, we demonstrate that LATS1 phosphorylates the Thr7 (T7) residue of the APC/C component CDC26 directly. Nocodazole-induced phosphorylation of T7 was reduced by knockdown of LATS1 and LATS2 in HeLa cells, indicating that both of these kinases contribute to the phosphorylation of CDC26 in vivo. The T7 residue of CDC26 is critical for its interaction with APC6, a tetratricopeptide repeat-containing subunit of APC/C, and mutation of this residue to Asp (T7D) reduced the interaction of CDC26 with APC6. Replacement of endogenous CDC26 in HeLa cells with exogenous phosphor-mimic T7D-mutated CDC26 increased the elution size of APC/C subunits in a gel filtration assay, implying a change in the APC/C assembly upon phosphorylation of CDC26. Furthermore, T7D-mutated CDC26 promoted the ubiquitination of polo-like kinase 1, a well-known substrate of APC/C. Overall, these results suggest that LATS1/2 are novel kinases involved in APC/C phosphorylation and indicate a direct regulatory link between LATS1/2 and APC/C.

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Features of ovarian cancer in Lynch syndrome (Review).

Nakamura K, Banno K, Yanokura M, Iida M, Adachi M, Masuda K, Ueki A, Kobayashi Y, Nomura H, Hirasawa A, Tominaga E, Aoki D

Molecular and clinical oncology 2 ( 6 ) 909 - 916 2014.11

ISSN 2049-9450

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

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

Molecular and clinical oncology 2 ( 5 ) 647 - 655 2014.09

ISSN 2049-9450

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Carcinogenic mechanisms of endometrial cancer: involvement of genetics and epigenetics.

Banno K, Yanokura M, Iida M, Masuda K, Aoki D

The journal of obstetrics and gynaecology research (Journal of Obstetrics and Gynaecology Research) 40 ( 8 ) 1957 - 67 2014.08

ISSN 1341-8076

Endometrial cancer is increasing worldwide and the number of patients with this disease is likely to continue to grow, including younger patients. Many endometrial cancers show estrogen-dependent proliferation, but the carcinogenic mechanisms are unknown or not completely explained beyond mutations of single oncogenes and tumor suppressor genes. Possible carcinogenic mechanisms include imbalance between endometrial proliferation by unopposed estrogen and the mismatch repair (MMR) system; hypermethylation of the MMR gene hMLH1; mutation of PTEN, β-catenin and K-ras genes in type I endometrial cancer and of HER-2/neu and p53 genes in type II endometrial cancer; hypermethylation of SPRY2, RASSF1A, RSK4, CHFR and CDH1; and methylation of tumor suppressor microRNAs, including miR-124, miR-126, miR-137, miR-491, miR-129-2 and miR-152. Thus, it is likely that the carcinogenic mechanisms of endometrial cancer involve both genetic and epigenetic changes. Mutations and methylation of MMR genes induce various oncogenic changes that cause carcinogenesis, and both MMR mutation in germ cells and methylation patterns may be inherited over generations and cause familial tumorigenesis. Determination of the detailed carcinogenic mechanisms will be useful for prevention and diagnosis of endometrial cancer, risk assessment, and development of new treatment strategies targeting MMR genes. © 2014 The Authors. Journal of Obstetrics and Gynaecology Research © 2014 Japan Society of Obstetrics and Gynecology.

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Glycan profiling of gestational choriocarcinoma using a lectin microarray.

Kobayashi Y, Masuda K, Banno K, Kobayashi N, Umene K, Nogami Y, Tsuji K, Ueki A, Nomura H, Sato K, Tominaga E, Shimizu T, Saya H, Aoki D

Oncology reports (Oncology Reports) 31 ( 3 ) 1121 - 6 2014.03

ISSN 1021-335X

Glycosylation is an important post-translational modification, in which attachment of glycans to proteins has effects on biological functions and carcinogenesis. Analysis of human chorionic gonadotropin, a glycoprotein hormone produced by placental trophoblasts and trophoblastic tumors, has contributed to the diagnosis and treatment of trophoblastic disease, resulting in reduced incidence and mortality. However, alterations of the glycan structure itself in choriocarcinoma have not been characterized. We established a new choriocarcinoma cell line, induced choriocarcinoma cell-1 (iC3-1), which mimics the clinical pathohistology in vivo, to examine the tumorigenesis and pathogenesis of choriocarcinoma. In this study, the alterations of glycan structures in the development of choriocarcinoma were examined by performance of comprehensive glycan profiling in clinical samples and in iC3-1 cells using a conventional microarray and the recently introduced lectin microarray. Microarray comparison showed significant upregulation of several characteristic glycogenes in the iC3-1 cells as compared to the parental HTR8/SVneo cells. The lectin array showed increased α-2-6-sialic acid, Galβ1-4GlcNAc, GlcNAcβ1-3GalNAc, and decreased α-1-6 core fucose, high mannose, GalNacβ1-4Gal, GALNAc (Tn antigen) and Galβ-3Gal in choriocarcinoma tissue compared to normal villi. This is the first report of a lectin array analysis in choriocarcinoma and provides useful information for understanding of the disease.

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A tumor of the uterine cervix with a complex histology in a Peutz-Jeghers syndrome patient with genomic deletion of the STK11 exon 1 region.

Kobayashi Y, Masuda K, Kimura T, Nomura H, Hirasawa A, Banno K, Susumu N, Sugano K, Aoki D

Future oncology (London, England) (Future Oncology) 10 ( 2 ) 171 - 7 2014.02

ISSN 1479-6694

Patients with Peutz-Jeghers syndrome (PJS) have a risk of complicating malignant tumors, including cancer of the uterine cervix. Mutations in the STK11 gene have been identified as being responsible for PJS. However, the genotype-phenotype correlation in PJS is poorly understood, especially with respect to malignant tumors. Here, we report a detailed analysis of a case of a cervical tumor in a PJS patient showing a large genomic deletion in exon 1 of STK11 without human papillomavirus infection. Histological examination revealed a complex histology consisting of three components: lobular endocervical gland hyperplasia (LEGH), minimal deviation adenocarcinoma (MDA) and mucinous adenocarcinoma. Immunohistochemistry for STK11 was positive in the LEGH and MDA components, while that of the mucinous adenocarcinoma stained very faintly. These findings support a close relationship among LEGH, MDA and mucinous adenocarcinoma and imply that inactivation of STK11 may occur during progression from MDA to mucinous adenocarcinoma. © 2014 Future Medicine Ltd.

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Application of FDG-PET in cervical cancer and endometrial cancer: utility and future prospects.

Nogami Y, Iida M, Banno K, Kisu I, Adachi M, Nakamura K, Umene K, Masuda K, Tominaga E, Tanaka K, Aoki D

Anticancer research (Anticancer Research) 34 ( 2 ) 585 - 92 2014.02

ISSN 0250-7005

© 2014, International Institute of Anticancer Research. All rights reserved. Positron-emission tomography (PET), a diagnostic imaging technique using an agent labeled with a positron-emitting radionuclide, may facilitate improved diagnosis and treatment in gynecological fields. A combined PET/computerized tomography (CT) scan can identify the precise anatomical location of a lesion based on accumulation of 18F-fluoro-D-glucose (FDG). FDG-PET and PET/CT have been used for detecting metastatic lesions and predicting prognosis in uterine cancer. PET has higher reliability in diagnosing lymph node metastases of uterine cancer than CT or MRI, and is considered most useful among non-invasive diagnostic imaging methods. Accumulation of FDG in lesions is indicative of a poor prognosis. Due to its limited spatial resolution, PET is not suitable has lower utility for detecting small lesions, and is not suitable for early-stage screening, and diagnosing primary lesions. Further improvements in diagnostic technology, including PET/MRI, investigation of new positron tracers, and analysis of data from various combinations of tracers are likely to make PET particularly useful for diagnosis and therapeutic strategy planning.

Family history and BRCA1/BRCA2 status among Japanese ovarian cancer patients and occult cancer in a BRCA1 mutant case.

Hirasawa A, Masuda K, Akahane T, Ueki A, Yokota M, Tsuruta T, Nomura H, Kataoka F, Tominaga E, Banno K, Makita K, Susumu N, Sugano K, Kosaki K, Kameyama K, Aoki D

Japanese journal of clinical oncology (Japanese Journal of Clinical Oncology) 44 ( 1 ) 49 - 56 2014.01

ISSN 0368-2811

Background: This study aimed to examine family history among Japanese ovarian cancer patients and to investigate the TP53 status of fallopian tube epithelial and ovarian cancer cells in a Japanese BRCA1 mutant case that may be associated with the transformed state in hereditary ovarian cancer. Methods: One hundred and two primary ovarian cancer patients were retrospectively evaluated in this cross-sectional study. The family history of cancer was determined in probands. In a BRCA1 mutant case, p53 immunostaining and direct sequencing, followed by laser-capture microdissection, were performed for the fallopian tube, considered the origin of ovarian cancer. Results: Nine of 102 (8.8%) families were regarded as having hereditary breast-ovarian cancer syndrome, two families (2.0%) were diagnosed with Lynch syndrome and six patients harbored BRCA1 or BRCA2 mutations. One case underwent risk-reductive salpingooophorectomy as a BRCA1 mutant carrier was retrospectively diagnosed as occult cancer. Common TP53 mutations were detected in cancer and fallopian tube epithelial cells in the case. Conclusions: Here, we integrate family cancer history and histology in ovarian cancer cases as well as TP53 status in a BRCA1 mutant case into a discussion regarding carcinogenesis in a Japanese population. The TP53 status for the BRCA1 mutant case examined here supports the recently proposed theory that ovarian cancer develops because of BRCA1 or BRCA2 inactivation and/or TP53 mutations. © The Author 2013. Published by Oxford University Press. All rights reserved.

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Application of microRNA in diagnosis and treatment of ovarian cancer.

Banno K, Yanokura M, Iida M, Adachi M, Nakamura K, Nogami Y, Umene K, Masuda K, Kisu I, Nomura H, Kataoka F, Tominaga E, Aoki D

BioMed research international (BioMed Research International) 2014 232817 2014

ISSN 2314-6133

Ovarian cancer has a poor prognosis because early detection is difficult and recurrent ovarian cancer is usually drug-resistant. The morbidity and mortality of ovarian cancer are high worldwide and new methods of diagnosis and therapy are needed. MicroRNAs (miRNAs) are posttranscriptional regulators of gene expression that are involved in carcinogenesis, metastasis, and invasion. Thus, miRNAs are likely to be useful as diagnostic and prognostic biomarkers and for cancer therapy. Many miRNAs have altered expression in ovarian cancer compared to normal ovarian tissues and these changes may be useful for diagnosis and treatment. For example, deficiencies of enzymes including Dicer and Drosha that are required for miRNA biogenesis may be adverse prognostic factors; miRNAs such as miR-214 and miR-31, which are involved in drug resistance, and the miR-200 family, which is implicated in metastasis, may serve as biomarkers; and transfection of downregulated miRNAs and inhibition of upregulated miRNAs may be effective for treatment of ovarian cancer. Chemotherapy targeting epigenetic mechanisms associated with miRNAs may also be effective to reverse gene silencing. © 2014 Kouji Banno et al.

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Indocyanine green fluorescence imaging in the pregnant cynomolgus macaque: childbearing is supported by a unilateral uterine artery and vein alone?

Kisu I, Banno K, Yanokura M, Nogami Y, Umene K, Tsuji K, Masuda K, Ueki A, Kobayashi Y, Aoki D

Archives of gynecology and obstetrics (Archives of Gynecology and Obstetrics) 288 ( 6 ) 1309 - 15 2013.12

ISSN 0932-0067

Purpose: Uterine blood flow is required for the maintenance of uterine viability in pregnancy and delivery, but it is unknown how many vessels are necessary for maintenance of uterine viability. The objective of this study was to examine whether unilateral uterine vessels provide sufficient nutrition in pregnancy in a cynomolgus macaque and to evaluate hemodynamics of pregnant uterus by indocyanine green (ICG) fluorescence imaging. Methods: A cynomolgus macaque with uterine blood flow maintained by the right uterine artery and vein alone was made pregnant. Hemodynamics of the uterus in the third trimester was evaluated by ICG fluorescence imaging. Results: Pregnancy was maintained with the right uterine artery and vein. An appropriate-for-date infant was delivered by Cesarean section. ICG fluorescence imaging showed that the uterine body was imaged from the right side to the center; furthermore, collateral circulation was present from the right uterine artery toward the left uterine artery, with expanded blood flow to the left uterine body. Conclusion: Pregnancy and delivery were achieved in a cynomolgus macaque with a unilateral right uterine artery and vein. Blood flow to the side without the artery was complemented by vascularization of collateral circulation to the uterine artery. © 2013 Springer-Verlag Berlin Heidelberg.

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Hereditary gynecological tumors associated with Peutz-Jeghers syndrome (Review).

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

Oncology letters (Oncology Letters) 6 ( 5 ) 1184 - 1188 2013.11

ISSN 1792-1074

Peutz-Jeghers syndrome (PJS) is an autosomal dominant disease that is characterized by gastrointestinal hamartomatous polyposis and mucocutaneous melanin spots. The tumor suppressor gene, STK11/LKB1, which is located on chromosome 19p13.3, has been reported to be responsible for this condition. PJS is complicated by benign and malignant tumors of various organs and complications from rare diseases, including sex cord tumor with annular tubules (SCTAT) and minimal deviation adenocarcinoma (MDA), which have also recently attracted attention in the field of gynecology. Among the total MDA cases, 10% are complications of PJS, and mutations in the STK11 gene are closely associated with the development and prognosis of MDA. Furthermore, a new type of uterine cervical tumor, lobular endocervical glandular hyperplasia (LEGH), has been identified and has been predicted to be a precancerous lesion of MDA. The first case of LEGH induced by a germline STK11 mutation has also been described. A high risk of endometrial cancer in PJS has also been reported. These developments suggest that PJS is an important syndrome of hereditary gynecological tumors that requires further study.

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Current status of molecular-targeted drugs for endometrial cancer (Review).

Nogami Y, Banno K, Kisu I, Yanokura M, Umene K, Masuda K, Kobayashi Y, Yamagami W, Nomura H, Tominaga E, Susumu N, Aoki D

Molecular and clinical oncology 1 ( 5 ) 799 - 804 2013.09

ISSN 2049-9450

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Candidate biomarkers for genetic and clinicopathological diagnosis of endometrial cancer.

Banno K, Nogami Y, Kisu I, Yanokura M, Umene K, Masuda K, Kobayashi Y, Yamagami W, Susumu N, Aoki D

International journal of molecular sciences (International Journal of Molecular Sciences) 14 ( 6 ) 12123 - 37 2013.06

ISSN 16616596

The recent increase in the frequency of endometrial cancer has emphasized the need for accurate diagnosis and improved treatment. The current diagnosis is still based on conventional pathological indicators, such as clinical stage, tumor differentiation, invasion depth and vascular invasion. However, the genetic mechanisms underlying endometrial cancer have gradually been determined, due to developments in molecular biology, leading to the possibility of new methods of diagnosis and treatment planning. New candidate biomarkers for endometrial cancer include those for molecular epigenetic mutations, such as microRNAs. These biomarkers may permit earlier detection of endometrial cancer and prediction of outcomes and are likely to contribute to future personalized therapy for endometrial cancer. © 2013 by the authors; licensee MDPI, Basel, Switzerland.

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Aurora kinase inhibitors: Potential molecular-targeted drugs for gynecologic malignant tumors.

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

Biomedical reports 1 ( 3 ) 335 - 340 2013.05

ISSN 2049-9434

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Preoperative and intraoperative assessment of myometrial invasion in endometrial cancer: comparison of magnetic resonance imaging and frozen sections.

Kisu I, Banno K, Lin LY, Ueno A, Abe T, Kouyama K, Okuda S, Masugi Y, Umene K, Nogami Y, Tsuji K, Masuda K, Ueki A, Kobayashi Y, Yamagami W, Susumu N, Aoki D

Acta obstetricia et gynecologica Scandinavica (Acta Obstetricia et Gynecologica Scandinavica) 92 ( 5 ) 525 - 35 2013.05

ISSN 0001-6349

Objective To compare the diagnostic characteristics of the evaluation of myometrial invasion (MI) retrospectively between preoperative magnetic resonance imaging (MRI) and intraoperative frozen sections. Design A retrospective study. Setting University hospital. Sample 201 women diagnosed with endometrial carcinoma. Methods All women underwent preoperative MRI and 111 of them also underwent intraoperative frozen section assessment. The final pathological evaluation was used as the definitive diagnosis. Main outcome measures In women who underwent MRI and frozen sections (n = 111), the accuracies of detection of MI and of deep invasion (defined as ≥50% invasion) were compared. Results The accuracy, sensitivity, and specificity of MRI for detection of MI were 65.8, 58.8, and 88.5%, and those in frozen sections were 90.1, 90.6, and 88.5%, respectively. The accuracy and sensitivity of frozen sections were significantly higher (p < 0.001, p < 0.001), whereas the specificity of the two methods did not differ (p = 1.000). The accuracy, sensitivity, and specificity of MRI for detection of deep invasion were 83.8, 69.2, and 88.2%, and those of frozen sections were 93.7, 73.1, and 100.0%, respectively. The accuracy and specificity of frozen sections were significantly higher (p = 0.007 and p < 0.001, respectively), whereas sensitivity did not show a significant difference (p = 0.999). Conclusion In assessment of MI, the accuracy of frozen sections was significantly higher than that of MRI. Since the diagnostic characteristics differ between two methods, additional intraoperative frozen sections are recommended for more accurate assessment of MI when MRI is negative for the presence of any MI or positive for the presence of deep invasion. © 2012 The Authors Acta Obstetricia et Gynecologica Scandinavica © 2012 Nordic Federation of Societies of Obstetrics and Gynecology.

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Experience of risk-reducing salpingo-oophorectomy for a BRCA1 mutation carrier and establishment of a system performing a preventive surgery for hereditary breast and ovarian cancer syndrome in Japan: our challenges for the future.

Hirasawa A, Masuda K, Akahane T, Tsuruta T, Banno K, Makita K, Susumu N, Jinno H, Kitagawa Y, Sugano K, Kosaki K, Aoki D

Japanese journal of clinical oncology (Japanese Journal of Clinical Oncology) 43 ( 5 ) 515 - 9 2013.05

ISSN 0368-2811

Background: Risk-reducing salpingo-oophorectomy is currently regarded as the most certain primary method for preventing ovarian cancer among BRCA1/2 mutation carriers with hereditary breast and ovarian cancer syndrome. However, risk-reducing salpingo-oophorectomy has rarely been performed in Japan. Methods: We developed the first system in Japan for performing risk-reducing salpingooophorectomy for BRCA1/2 mutation carriers at our university hospital in 2008. Results: The indication for risk-reducing salpingo-oophorectomy for patients with hereditary breast/ovarian cancer syndrome is currently limited in Japan. This situation may be because of the limited number of genetic counseling units, the limited number of facilities that can perform BRCA1/2 genetic testing and the fact that prophylactic surgery is not covered by health insurance in Japan. Conclusions: Recent treatment guidelines for breast cancer in Japan recommended riskreducing salpingo-oophorectomy for BRCA1/2 mutation carriers. Risk-reducing salpingooophorectomy should be performed in the framework of the standard therapeutic modality for BRCA1/2 mutation carriers in the near future. © The Author 2013. Published by Oxford University Press. All rights reserved.

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New candidate therapeutic agents for endometrial cancer: potential for clinical practice (review).

Umene K, Banno K, Kisu I, Yanokura M, Nogami Y, Tsuji K, Masuda K, Ueki A, Kobayashi Y, Yamagami W, Tominaga E, Susumu N, Aoki D

Oncology reports (Oncology Reports) 29 ( 3 ) 855 - 60 2013.03

ISSN 1021-335X

Cases of endometrial cancer have increased in recent years, but the prognosis of patients with this disease has also been improved by combined modality therapy with surgery, radiotherapy and chemotherapy. However, the development of new therapy is required from the perspectives of conservation of fertility and efficacy for recurrent and intractable cancer. New candidate therapeutic agents for endometrial cancer include fourth-generation progestins for inhibition of growth and differentiation of endometrial glands; metformin for reduction of hTERT expression in the endometrium and inhibition of the mTOR pathway by activation of AMPK, with consequent inhibition of the cell cycle; mTOR inhibitors for supressing growth of cancer cells by G1 cell cycle arrest; microRNAs involved in the molecular mechanisms of oncogenesis and progression; and HDAC inhibitors that block the growth of cancer cells by transcriptional elevation of tumor-suppressor genes, cell cycle arrest and induction of apoptosis. In this study, we review the background and early clinical evidence for these agents as new therapeutic candidates for endometrial cancer.

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Gene expression profile of a newly established choriocarcinoma cell line, iC3-1, compared to existing choriocarcinoma cell lines and normal placenta

Kobayashi Y., Banno K., Shimizu T., Ueki A., Tsuji K., Masuda K., Kisu I., Nomura H., Tominaga E., Nagano O., Saya H., Aoki D.

Placenta (Placenta) 34 ( 2 ) 110 - 118 2013.02

ISSN 01434004

Gestational choriocarcinoma is a malignant trophoblastic tumor that usually occurs in the uterus after pregnancy. The tumor is curable with advanced chemotherapy, but the molecular mechanism of choriocarcinoma tumorigenesis remains unclear. This is partly because the low incidence makes it difficult to obtain clinical samples for investigation and because an appropriate choriocarcinoma cell model to study the tumorigenesis has not been developed. We have established a new choriocarcinoma cell line, induced choriocarcinoma cell-1 (iC3-1), that possesses unique characteristics compared to other choriocarcinoma cell lines, including production of tumors that consist of the two types of cells commonly found in choriocarcinoma and mimicking of the clinical pathology. Existing trophoblast cell lines utilized in previous choriocarcinoma studies have had significantly dissimilar gene expression profiles. Therefore, it is important to choose an appropriate cell line for a particular study based on the characteristics of the cell line. In this study, to clarify the genetic characteristics of iC3-1 and to explore the tumorigenesis mechanism, we examined the gene profile of iC3-1 compared to those of existing cell lines and normal placental tissue. Bioinformatics analysis showed that several characteristic genes, IGF1R, CHFR, MUC3A, TAF7, PARK7, CDC123 and PSMD8, were significantly upregulated in iC 3-1 compared to BeWo and JEG3 cells. Interestingly, HAS2, CD44 and S100P were significantly upregulated in iC3-1 compared to parental HTR8/SVneo cells and normal third trimester placenta. Choriocarcinoma samples also showed immunoreactivity to HAS2, CD44 and S100. In summary, the gene expression profile of iC3-1 suggests that studies using this cell line can make an important contribution to improved understanding of choriocarcinoma tumorigenesis. © 2012 Elsevier Ltd. All rights reserved.

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The APC/C activator Cdh1 regulates the G2/M transition during differentiation of placental trophoblast stem cells.

Naoe H, Chiyoda T, Ishizawa J, Masuda K, Saya H, Kuninaka S

Biochemical and biophysical research communications (Biochemical and Biophysical Research Communications) 430 ( 2 ) 757 - 62 2013.01

ISSN 0006-291X

Differentiation of placental trophoblast stem (TS) cells to trophoblast giant (TG) cells is accompanied by transition from a mitotic cell cycle to an endocycle. Here, we report that Cdh1, a regulator of the anaphase-promoting complex/cyclosome (APC/C), negatively regulates mitotic entry upon the mitotic/endocycle transition. TS cells derived from homozygous Cdh1 gene-trapped (Cdh1GT/GT) murine embryos accumulated mitotic cyclins and precociously entered mitosis after induction of TS cell differentiation, indicating that Cdh1 is required for the switch from mitosis to the endocycle. Furthermore, the Cdh1GT/GT TS cells and placenta showed aberrant expression of placental differentiation markers. These data highlight an important role of Cdh1 in the G2/M transition during placental differentiation. © 2012 Elsevier Inc.

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Aberrant DNA Methylation in Endometrial Cancer

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

Epigenetics in Human Disease (Epigenetics in Human Disease) 471 - 480 2012.12

ISSN 9780123884152

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Relationship of lower uterine segment cancer with Lynch syndrome: a novel case with an hMLH1 germline mutation.

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

Oncology reports (Oncology Reports) 28 ( 5 ) 1537 - 43 2012.11

ISSN 1021-335X

Lynch syndrome is a genetic disease that often develops in patients with endometrial cancer and is caused by abnormal DNA mismatch repair (MMR) genes. In the United States, it was recently reported that the prevalence of Lynch syndrome with an hMSH2 mutation in patients with endometrial cancer in the lower uterine segment (LUS) is much greater than that in patients with endometrial cancer, although no such reports have been published in Asia. In this study, we examined the correlation between endometrial cancer in LUS and abnormalities in MMR genes. We examined 625 patients, who were diagnosed with endometrial cancer and underwent a hysterectomy. Nine patients (1.4%) had cancer based on pathological confirmation of a tumor in the lower part of the uterus and no cancer in the upper part. These cases were compared with 27 cases of sporadic endometrial (non-LUS) cancer. The age and BMI of the patients with LUS cancer were significantly lower than those of the patients with non-LUS cancer. No differences were observed in the pathological characteristics. The microsatellite instability (MSI)-positive rates were similar. Immunohistochemistry showed a decreased expression of hMLH1 and hMSH6 in patients with LUS cancer. In contrast with earlier reports from the United States, hMSH2 was expressed in all the cases. Of the 2 patients with LUS cancer who exhibited high MSI, 1 patient showed abnormal methylation of hMLH1, while the other patient was diagnosed with Lynch syndrome with a mutation in the hMLH1 gene. This is the second report on the relationship of LUS cancer and Lynch syndrome, and the first to describe an Asian patient with LUS cancer with Lynch syndrome induced by an hMLH1 mutation.

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Epimutation and cancer: a new carcinogenic mechanism of Lynch syndrome (Review).

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

International journal of oncology (International Journal of Oncology) 41 ( 3 ) 793 - 7 2012.09

ISSN 1019-6439

Epimutation is defined as abnormal transcriptional repression of active genes and/or abnormal activation of usually repressed genes caused by errors in epigenetic gene repression. Epimutation arises in somatic cells and the germline, and constitutional epimutation may also occur. Epimutation is the first step of tumorigenesis and can be a direct cause of carcinogenesis. Cancers associated with epimutation include Lynch syndrome (hereditary non-polyposis colorectal cancer, HNPCC), chronic lymphocytic leukemia, breast cancer and ovarian cancer. Epimutation has been shown for many tumor suppressor genes, including RB, VHL, hMLH1, APC and BRCA1, in sporadic cancers. Methylation has recently been shown in DNA from normal tissues and peripheral blood in cases of sporadic colorectal cancer and many studies show constitutive epimutation in cancers. Epimutation of DNA mismatch repair (MMR) genes (BRCA1, hMLH1 and hMSH2) involved in development familial cancers has also been found. These results have led to a focus on epimutation as a novel oncogenic mechanism.

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Biomarkers in endometrial cancer: Possible clinical applications (Review).

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

Oncology letters (Oncology Letters) 3 ( 6 ) 1175 - 1180 2012.06

ISSN 1792-1074

The number of cases of endometrial cancer has shown a tendency to increase in recent years. Endometrial cancer originates from the endometrium and is classified, based on the development mechanism, into types 1 and 2, which are responsive and non-responsive to estrogen, respectively, and have significantly different gene expression profiles. Studies of genes with abnormal expression in endometrial cancer have identified multiple oncogenes, tumor suppressors, mismatch repair genes, apoptosis-associated genes, levels of hormone receptors and DNA ploidy and aneuploidy as biomarkers of endometrial cancer. The use of these molecules and genes may facilitate accurate diagnosis and prognostic prediction and contribute to individualized treatment. Trials of drugs which target these biomarkers and searches for new biomarkers using cDNA microarrays and RT-qPCR are ongoing and it is likely that these findings can be translated to clinical use.

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Progestin therapy for endometrial cancer: the potential of fourth-generation progestin (review).

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

International journal of oncology (International Journal of Oncology) 40 ( 6 ) 1755 - 62 2012.06

ISSN 1019-6439

Progestin preparations are made of synthetic progesterone and have often been used for hormone therapy in gynecological patients with endometriosis or endometrial cancer. Hormone therapy using progestin is considered to be one of the effective means of treatment particularly when dealing with endometrial cancer (an estrogen-dependent tumor). Numerous reports have been published concerning its efficacy in advanced or recurrent cases of atypical endometrial hyperplasia or endometrial cancer. Dienogest has been developed as a fourth-generation progestin for hormone therapy for endometriosis that can be used with high safety for long periods of time. In Japan, dienogest has been recommended as a first-line drug for endometriosis-associated pain. However, its antitumor activity has also been attracting close attention following a report that this drug suppressed the proliferation in vitro of endometrial cancer-derived cell lines which failed to respond to other progestins such as medroxyprogesterine acetate (MPA). The mechanism for antitumor activity of dienogest is considered to differ from the mechanism for antitumor activity of conventional progestin preparations used for treatment of endometrial cancer. This drug is expected to be clinically applicable as a new drug for the treatment of endometrial cancer.

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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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