Faculty Profiles - SHIGEYASU Kunitoshi

Papers - SHIGEYASU Kunitoshi

Division display >> ／ All the affair displays 1 - 92 of about 92

ADAR1-high tumor-associated macrophages induce drug resistance and are therapeutic targets in colorectal cancer. International journal

Hibiki Umeda, Kunitoshi Shigeyasu, Toshiaki Takahashi, Kazuya Moriwake, Yoshitaka Kondo, Kazuhiro Yoshida, Sho Takeda, Shuya Yano, Yuki Matsumi, Hiroyuki Kishimoto, Tomokazu Fuji, Kazuya Yasui, Hideki Yamamoto, Kosei Takagi, Masashi Kayano, Hiroyuki Michiue, Keiichiro Nakamura, Yoshiko Mori, Fuminori Teraishi, Hiroshi Tazawa, Yuzo Umeda, Shunsuke Kagawa, Ajay Goel, Toshiyoshi Fujiwara

Molecular cancer 24 ( 1 ) 116 - 116 2025.4

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: Colorectal cancer (CRC) is considered the third most common type of cancer worldwide. Tumor-associated macrophages (TAMs) have been shown to promote drug resistance. Adenosine-to-inosine RNA-editing, as regulated by adenosine deaminase acting on RNA (ADAR), is a process that induces the posttranscriptional modification of critical oncogenes. The aim of this study is to determine whether the signals from cancer cells would induce RNA-editing in macrophages. METHODS: The effects of RNA-editing on phenotypes in macrophages were analyzed using clinical samples and in vitro and in vivo models. RESULTS: The intensity of the RNA-editing enzyme ADAR1 (Adenosine deaminase acting on RNA 1) in cancer and mononuclear cells indicated a strong positive correlation between the nucleus and cytoplasm. The ADAR1-positive mononuclear cells were positive for CD68 and CD163, a marker for M2 macrophages. Cancer cells transport pro-inflammatory cytokines or ADAR1 protein directly to macrophages via the exosomes, promoting RNA-editing in AZIN1 (Antizyme Inhibitor 1) and GLI1 (Glioma-Associated Oncogene Homolog 1) and resulting in M2 macrophage polarization. GLI1 RNA-editing in the macrophages induced by cancer cells promotes the secretion of SPP1, which is supplied to the cancer cells. This activates the NFκB pathway in cancer cells, promoting oxaliplatin resistance. When the JAK inhibitors were administered, oncogenic RNA-editing in the macrophages was suppressed. This altered the macrophage polarization from M2 to M1 and decreased oxaliplatin resistance in cancer cells. CONCLUSIONS: This study revealed that ADAR1-high TAMs are crucial in regulating drug resistance in CRC and that targeting ADAR1 in TAMs could be a promising treatment approach for overcoming drug resistance in CRC.

DOI： 10.1186/s12943-025-02312-y

Short-term Safety of Robot-assisted Rectal Surgery in Patients Aged ≥75 Years: A Single-center Retrospective Study. International journal

Fuminori Teraishi, Yusuke Yoshida, Ryohei Shoji, Nobuhiko Kanaya, Yuki Matsumi, Kunitoshi Shigeyasu, Yoshitaka Kondo, Shunsuke Kagawa, Toshiyoshi Fujiwara

Anticancer research 45 ( 3 ) 1291 - 1299 2025.3

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND/AIM: The aging population challenges surgical management of rectal cancer. This study evaluated the short-term safety of robot-assisted rectal surgery (RARS) in patients aged 75 years and older, examining perioperative complications and surgical outcomes in this vulnerable population. PATIENTS AND METHODS: A single-center retrospective cohort study was conducted at Okayama University Hospital from September 2020 to December 2024, including 109 patients undergoing RARS. Patients were divided into older (≥75 years, n=19) and non-older (<75 years, n=90) groups. Surgical procedures utilized the da Vinci Xi system, with comprehensive assessment of perioperative characteristics and complications using the Clavien-Dindo classification. RESULTS: The older group demonstrated significantly higher American Society of Anesthesiologists classification (89.5% ≥2 vs. 58.9% in non-older group, p=0.036). Postoperative complications were more frequent in the older group (8 vs. 18 cases, p=0.04), though severe complications were similar to those in the non-older group. Median postoperative hospital stay was longer in the older group (12 vs. 9 days, p=0.01), but this difference disappeared when excluding stoma cases. Critically, no postoperative mortality was observed within 30 days in either group. CONCLUSION: Robot-assisted rectal surgery appears safe for patients aged 75 years and older. While the older group experienced more complications, these were predominantly manageable. The findings suggest that careful patient selection and experienced surgical teams can successfully employ robotic techniques in older patients while maintaining oncological standards.

DOI： 10.21873/anticanres.17516

Tailoring Neoadjuvant Therapy for Rectal Cancer: A Single-center Study of Local Recurrence Patterns. International journal

Ryohei Shoji, Fuminori Teraishi, Yoshitaka Kondo, Yusuke Yoshida, Nobuhiko Kanaya, Yuki Matsumi, Kunitoshi Shigeyasu, Shunsuke Kagawa, Toshiyoshi Fujiwara

Anticancer research 45 ( 3 ) 1261 - 1271 2025.3

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND/AIM: Postoperative local recurrence remains an important issue in rectal cancer, and the optimal treatment strategy, surgical approach, and prognosis after treatment are yet to be addressed. PATIENTS AND METHODS: We reviewed 21 patients who underwent surgical resection at our department for postoperative pelvic local recurrence of rectal cancer between January 2013 and December 2022, and performed a retrospective analysis of outcomes in terms of preoperative treatment and surgical approach. RESULTS: Of the 21 patients, four (19%) were treated with upfront surgery (Upfront surgery group), 13 (62%) with chemotherapy (Chemotherapy group), and four (19%) with neoadjuvant chemoradiotherapy (NACRT; NACRT group). The surgical approach was open laparotomy (Open group) in 10 (47.6%) patients and minimally invasive surgery (MIS, MIS group) in 11 (52.4%). Seventeen (81.0%) had a negative resection margin (RM). Overall median postoperative survival was 71 months and median relapse-free survival was 6.2 months. The most common form of recurrence was pelvic local re-recurrence in seven patients (33.3%). By preoperative treatment type, the RM securement rate was higher in the Chemotherapy and NACRT groups than in the Upfront surgery group, and the postoperative recurrence rate was lowest in the NACRT group. By surgical approach, intraoperative blood loss and incidence of Clavien-Dindo Grade 3 or higher postoperative adverse events were both significantly lower in the MIS group than in the Open group. CONCLUSION: Surgical intervention for postoperative recurrence of rectal cancer results in good survival, but short relapse-free survival. NACRT can deter local re-recurrence after resection, and MIS may contribute to reducing complications.

DOI： 10.21873/anticanres.17513

Predictive marker for response to trifluridine/tipiracil plus bevacizumab in metastatic colorectal cancer patients. International journal

Toshiaki Takahashi, Kunitoshi Shigeyasu, Yoshitaka Kondo, Sho Takeda, Hibiki Umeda, Kazuya Moriwake, Masashi Kayano, Yuya Sakurai, Shunsuke Nakamura, Masafumi Takahashi, Kaori Nitta, Kazuhiro Yoshida, Yuki Matsumi, Hiroyuki Michiue, Hideki Yamamoto, Hiroyuki Kishimoto, Fuminori Teraishi, Ryohei Shoji, Nobuhiko Kanaya, Hajime Kashima, Yoshihiko Kakiuchi, Shinji Kuroda, Shunsuke Kagawa, Toshiyoshi Fujiwara

BMC cancer 25 ( 1 ) 1 - 1 2025.1

Language：English Publishing type：Research paper (scientific journal)

OBJECTIVE: Trifluridine/tipiracil (FTD/TPI) is one of the options for late-line treatment of colorectal cancer (CRC). However, the specific patient populations that would particularly benefit from it remain unclear. This study attempted to identify predictive markers of chemotherapy efficacy with trifluridine/tipiracil (FTD/TPI), focusing on the RNA-editing enzyme adenosine deaminase acting on RNA 1 (ADAR1) expression and neutrophil-lymphocyte ratio (NLR). METHODS: To assess the effectiveness of FTD/TPI in CRC patients, we retrospectively analyzed 72 CRC patients at Okayama University Hospital from 2014 to 2022. RESULTS: Adding bevacizumab to FTD/TPI resulted in a more prolonged progression-free survival (PFS), consistent with the SUNLIGHT study findings (p = 0.0028). Among the participants, those with a high NLR had a shorter PFS (p = 0.0395). Moreover, high ADAR1 expression was associated with longer PFS (p = 0.0151). In multivariate analysis, low ADAR1 (HR = 3.43, p = 0.01) and absence of bevacizumab (HR = 4.25, p = 0.01) were identified as factors shortening PFS. The high ADAR1 group demonstrated fewer cases of progressive disease and a higher proportion of stable disease than the low ADAR1 group (p = 0.0288). Low NLR and high ADAR1 were predictive markers of prolonged PFS in the bevacizumab-treated group (p = 0.0036). CONCLUSION: Low NLR and high ADAR1 were predictive markers for a positive response to the FTD/TPI plus bevacizumab regimen associated with prolonged PFS. The FTD/TPI plus bevacizumab regimen should be proactively implemented in the low NLR and high ADAR1 subgroups.

DOI： 10.1186/s12885-024-13370-8

ADAR1 could be a potential diagnostic target for intrauterine infection patients. International journal

Keiichiro Nakamura, Kunitoshi Shigeyasu, Thuy Ha Vu, Jota Maki, Kazuhiro Okamoto, Hisashi Masuyama

Scientific reports 14 ( 1 ) 29419 - 29419 2024.11

Language：English Publishing type：Research paper (scientific journal)

Intrauterine infection (IUI) is mainly an ascending infection in which vaginal and cervical pathogens ascend to the uterus and can affect the fetus. Until now, there is still no effective diagnostic biomarker for IUI, such as chorioamnionitis (CAM) and funisitis (FUN). Deoxyribonucleic acid (DNA)/Ribonucleic acid (RNA) editing molecules such as apolipoprotein-B mRNA-editing complex (APOBEC) 3 families and Adenosine deaminase family acting on RNA (ADAR)1 were examined in chorioamniotic membranes and umbilical cord of 83 patient samples. Furthermore, Ureaplasma parvum induced ADAR1 was investigated in human HTR-8/SVneo EVT cell line. ADAR1 had a significantly higher area under the curve (AUC) (0.721 and 0.745) than other APOBEC3s or cytokines in CAM and FUN patients. In vitro, ureaplasma parvum was demonstrated to activate ADAR1 (p = 0.025) and reduce RIG-I, IRF3, IFN-[Formula: see text], and IFN-β expression in EVT cell line (p = 0.005, p = 0.010, p < 0.001, and p = 0.018, respectively). High expression of ADAR1 was strongly associated with CAM and FUN patients (multivariate analyses; p = 0.035 and p = 0.002). ADAR1 could be a potential diagnostic target for IUI, such as CAM and FUN patients.

DOI： 10.1038/s41598-024-81097-4

Subjective global assessment for nutritional screening and its impact on surgical outcomes: A prospective study in older patients with colorectal cancer. International journal

Fuminori Teraishi, Yusuke Yoshida, Ryohei Shoji, Nobuhiko Kanaya, Yuki Matsumi, Kunitoshi Shigeyasu, Yoshitaka Kondo, Shunsuke Kagawa, Rie Tamura, Yoshikazu Matsuoka, Hiroshi Morimatsu, Toshiharu Mitsuhashi, Toshiyoshi Fujiwara

Langenbeck's archives of surgery 409 ( 1 ) 356 - 356 2024.11

Language：English Publishing type：Research paper (scientific journal)

PURPOSE: Our perioperative management center provides preoperative intervention and functional and nutritional assessments for colorectal cancer patients aged over 75 years. This study evaluated the associations of preoperative nutritional status with postoperative outcomes and prognosis in colorectal cancer patients aged 75 years or older. METHODS: This was a prospective, observational study of 71 colorectal cancer patients aged 75 years or older who underwent surgery between July 2020 and September 2022. The Subjective Global Assessment (SGA) was evaluated as a nutritional index. The patients were classified into three groups: SGA-A (well nourished), B (moderately malnourished), and C (severely malnourished), and the correlations with postoperative outcomes and prognosis were examined. RESULTS: The median age of the 71 patients (34 males, 37 females) was 78 (75-92) years, and their median body mass index (BMI) was 22.3 (13.4-31.9) kg/m2. Forty-eight patients had colon cancer, and 23 had rectal cancer. On the SGA, 28 patients were SGA-A, 25 SGA-B, and 18 SGA-C. The SGA-B/C group had significantly higher BMI (p < 0.01) and more ICU admissions (p = 0.02). The G8 score was significantly lower (p = 0.03) in the SGA-B/C group, suggesting coexisting functional decline. In terms of postoperative outcomes, the SGA-B/C group had a significantly longer postoperative hospital stay (p = 0.04). The 3-year OS rates for all stages were 100% in the SGA-A group and 49.7% in the SGA-B/C group (p = 0.03), while the 3-year OS rates for patients excluding Stage IV were 100% in the SGA-A group and 68.5% in the SGA-B/C group, not significantly different (p = 0.14). The 3-year RFS rate was 95.5% in the SGA-A group and 65.3% in the SGA-B/C group (p = 0.15). CONCLUSION: The SGA is a promising nutritional index associated with short-term outcomes in older patients undergoing colorectal cancer surgery. The SGA can be assessed in a few minutes during an outpatient visit, making it useful for routine clinical use.

DOI： 10.1007/s00423-024-03548-w

High risk of multiple gastric cancers in Japanese individuals with Lynch syndrome.

Nobuhiko Kanaya, Thijs A van Schaik, Hideki Aoki, Yumiko Sato, Fumitaka Taniguchi, Kunitoshi Shigeyasu, Kokichi Sugano, Kiwamu Akagi, Hideyuki Ishida, Kohji Tanakaya

Annals of gastroenterological surgery 8 ( 6 ) 1008 - 1016 2024.11

Language：English Publishing type：Research paper (scientific journal)

AIM: Lynch syndrome (LS) is a dominantly inherited syndrome characterized by an increased risk for LS associated tumors such as colorectal cancer (CRC) and gastric cancer (GC). However, the clinical benefit of surveillance for GC remains unclear while it has already been recommended for CRC. This study aimed to elucidate the clinical features of GC in Japanese individuals with LS, and the risk of developing multiple GCs to build regional-tailored surveillance programs in LS patients with GC. METHODS: Data on Japanese individuals with LS were retrospectively collected from a single institution. The clinical features of GC, including the cumulative risk of multiple GCs, were analyzed. RESULTS: Among 96 individuals with LS (MLH1/MSH2/MSH6, 75:20:1), 32 GC lesions were detected in 15 individuals with LS (male/female, 11:4). The median age at initial GC diagnosis was 52.7 y (range: 28-71). Histological examination revealed a predominance of intestinal type (19/24: 87.5%). Moreover, the majority of the GC lesions (82%) were determined to have high-frequency of microsatellite instability. The cumulative risk of individuals with LS developing GC at 70 y was 31.3% (MLH1 36.1%, MSH2 18.0%). Notably, the cumulative risk of individuals with LS developing metachronous and/or synchronous GCs at 0, 10 and 20 y after initial diagnosis of GC was 26.7%, 40.7%, and 59.4%, respectively. CONCLUSION: Due to a higher risk of developing multiple GCs, intensive surveillance might be especially recommended for Japanese individuals with LS associated initial GC.

DOI： 10.1002/ags3.12809

Apolipoprotein-B mRNA-editing complex 3B could be a new potential therapeutic target in endometriosis. International journal

Thuy Ha Vu, Keiichiro Nakamura, Kunitoshi Shigeyasu, Chiaki Kashino, Kazuhiro Okamoto, Kotaro Kubo, Yasuhiko Kamada, Hisashi Masuyama

Scientific reports 14 ( 1 ) 24968 - 24968 2024.10

Language：English Publishing type：Research paper (scientific journal)

This study investigated the correlation of Apolipoprotein-B mRNA-editing complex 3B (APOBEC3B) expression with hypoxia inducible factor 1α (HIF-1α), Kirsten rat sarcoma virus (KRAS) and phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) in endometriosis patients, and the inhibitory effects of APOBEC3B knockdown in a human endometriotic cell line. Here, APOBEC3B, HIF-1α, KRAS, and PIK3CA were examined in patients with and without endometriosis using reverse transcription polymerase chain reaction (RT-PCR). The apoptosis, cell proliferation, invasion, migration, and biological function of APOBEC3B knockdown were explored in 12Z immortalized human endometriotic cell line. We observed APOBEC3B, HIF-1α, KRAS and PIK3CA expressions were significantly higher in endometriosis patients (p < 0.001, p < 0.001, p = 0.029, p = 0.001). Knockdown of APOBEC3B increased apoptosis, which was 28.03% and 22.27% higher than in mock and control siRNA samples, respectively. APOBEC3B knockdown also decreased PIK3CA expression and increased Caspase 8 expression, suggesting a potential role in the regulation of apoptosis. Furthermore, knockdown of APOBEC3B significantly inhibited cell proliferation, invasion, and migration compared to mock and control siRNA. (Cell proliferation: mock: p < 0.001 and control siRNA: p = 0.049. Cell invasion: mock: p < 0.001 and control siRNA: p = 0.029. Cell migration: mock: p = 0.004, and control siRNA: p = 0.014). In conclusion, this study suggests that APOBEC3B may be a new potential therapeutic target for endometriosis.

DOI： 10.1038/s41598-024-76589-2

Primary ileal myeloid sarcoma presenting with bowel obstruction: a case report. International journal

Hitoshi Minagi, Nobuhiko Kanaya, Yoshitaka Kondo, Yoshihiko Kakiuchi, Shinji Kuroda, Ryohei Shoji, Hajime Kashima, Yuki Matsumi, Satoru Kikuchi, Kunitoshi Shigeyasu, Fuminori Teraishi, Shunsuke Kagawa, Toshiyoshi Fujiwara

Surgical case reports 10 ( 1 ) 229 - 229 2024.10

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: Myeloid sarcoma (MS) is an extramedullary tumor constituted by myeloid blasts or immature myeloid cells. It frequently occurs in conjunction with acute myeloid leukemia (AML); however, it can exceptionally manifest in patients without leukemia. Here, we present a rare case of primary MS originating in the small bowel without evidence of bone marrow involvement. CASE REPRESENTATION: A 33 year-old female with no relevant medical history was admitted to our hospital with recurrent abdominal pain. Computed tomography (CT) revealed bowel obstruction due to thickening of the ileum wall, which was suspected to be an ileal tumor. Initially, ectopic endometriosis was suspected because of abdominal pain associated with the menstrual cycle and changes observed on a follow-up CT scan. The lesion could not be detected by double-balloon endoscopy. Despite conservative treatment, the obstruction persisted, and laparoscopic partial ileal resection was performed, which revealed extensive involvement of the ileum and mesentery. Additionally, the mesentery of the resected ileum was extremely thickened. Histopathological and immunohistochemical examinations of the surgical specimen indicated ileal MS. Bone marrow aspiration after discharge was negative for cytological findings of leukemia, leading to a final diagnosis of primary ileal MS. Her postoperative course was uneventful, and she is currently undergoing systemic chemotherapy tailored to AML at another hospital. CONCLUSIONS: Even though MS of the small bowel is rare and may not be considered preoperatively, similar surgical treatment to that of other small bowel malignancies can ensure proper postoperative diagnosis and appropriate chemotherapy. Given the potential need for chemotherapy, ensuring surgical safety that allows for its rapid initiation is critical.

DOI： 10.1186/s40792-024-02030-5

Overcoming immunotherapy resistance and inducing abscopal effects with boron neutron immunotherapy (B-NIT). Reviewed International journal

Takuya Fujimoto, Osamu Yamasaki, Noriyuki Kanehira, Hirokazu Matsushita, Yoshinori Sakurai, Naoya Kenmotsu, Ryo Mizuta, Natsuko Kondo, Takushi Takata, Mizuki Kitamatsu, Kazuyo Igawa, Atsushi Fujimura, Yoshihiro Otani, Makoto Shirakawa, Kunitoshi Shigeyasu, Fuminori Teraishi, Yosuke Togashi, Minoru Suzuki, Toshiyoshi Fujiwara, Hiroyuki Michiue

Cancer science 115 ( 10 ) 3231 - 3247 2024.8

Language：English Publishing type：Research paper (scientific journal)

Immune checkpoint inhibitors (ICIs) are effective against many advanced malignancies. However, many patients are nonresponders to immunotherapy, and overcoming this resistance to treatment is important. Boron neutron capture therapy (BNCT) is a local chemoradiation therapy with the combination of boron drugs that accumulate selectively in cancer and the neutron irradiation of the cancer site. Here, we report the first boron neutron immunotherapy (B-NIT), combining BNCT and ICI immunotherapy, which was performed on a radioresistant and immunotherapy-resistant advanced-stage B16F10 melanoma mouse model. The BNCT group showed localized tumor suppression, but the anti-PD-1 antibody immunotherapy group did not show tumor suppression. Only the B-NIT group showed strong tumor growth inhibition at both BNCT-treated and shielded distant sites. Intratumoral CD8+ T-cell infiltration and serum high mobility group box 1 (HMGB1) levels were higher in the B-NIT group. Analysis of CD8+ T cells in tumor-infiltrating lymphocytes (TILs) showed that CD62L- CD44+ effector memory T cells and CD69+ early-activated T cells were predominantly increased in the B-NIT group. Administration of CD8-depleting mAb to the B-NIT group completely suppressed the augmented therapeutic effects. This indicated that B-NIT has a potent immune-induced abscopal effect, directly destroying tumors with BNCT, inducing antigen-spreading effects, and protecting normal tissue. B-NIT, immunotherapy combined with BNCT, is the first treatment to overcome immunotherapy resistance in malignant melanoma. In the future, as its therapeutic efficacy is demonstrated not only in melanoma but also in other immunotherapy-resistant malignancies, B-NIT can become a new treatment candidate for advanced-stage cancers.

DOI： 10.1111/cas.16298

The adenosine deaminase family acting on RNA 1 can be a useful diagnostic biomarker in chorioamnionitis. International journal

Keiichiro Nakamura, Kunitoshi Shigeyasu, Jota Maki, Eriko Eto, Hisashi Masuyama

Placenta 153 53 - 58 2024.8

Language：English Publishing type：Research paper (scientific journal)

INTRODUCTION: Chorioamnionitis (CAM) involves infection and inflammation of the chorion and amniotic membrane, but there are still no effective diagnostic biomarkers for CAM. METHODS: We investigated the correlation between RNA editing enzyme Adenosine deaminase family acting on RNA 1 (ADAR1) and CAM in chorion and amniotic membrane specimens derived from premature rupture of the membrane (PROM), CAM (pathologically diagnosed), and clinical CAM (clinically diagnosed) patients using reverse transcription polymerase chain reaction (RT-PCR). RESULTS: ADAR1 was upregulated in the chorion and amniotic membrane specimens of CAM and clinical CAM patients (p < 0.001 and p = 0.005). ADAR1 had a significantly higher area under the curve (AUC) (0.735 and 0.828) than markers of inflammation characteristics in diagnosing CAM and clinical CAM patients. ADAR1 also had significantly higher AUC (0.701 and 0.837) than clinical characteristics for CAM and clinical CAM patients. DISCUSSION: ADAR1 can be a useful diagnostic biomarker in CAM patients.

DOI： 10.1016/j.placenta.2024.05.133

BRAF-mutant microsatellite-stable rectal cancer with acquired KRAS mutation leading to drug resistance in liver metastasis. International journal

Kunitoshi Shigeyasu, Hideki Yamamoto, Toshiaki Takahashi, Kazuya Moriwake, Masashi Kayano, Sho Takeda, Yuki Matsumi, Yuzo Umeda, Yoshitaka Kondo, Fuminori Teraishi, Kazuya Yasui, Tomokazu Fuji, Shunsuke Kagawa, Toshiyoshi Fujiwara

International cancer conference journal 13 ( 3 ) 189 - 192 2024.7

Language：English Publishing type：Research paper (scientific journal)

BRAF-mutant microsatellite-stable colorectal cancer (CRC), metastasized to distant sites, is associated with a poor prognosis. However, the BEACON CRC regimen, comprising a BRAF inhibitor, MEK inhibitor, and anti-EGFR antibody, offered a prolonged prognosis. Nonetheless, resistance to this regimen may occur, as observed in our reported case of CRC, where a KRAS mutation was identified in addition to the BRAF V600E mutation. Here, we present a case of 74-year-old woman with rectal cancer (pT4bN1bM0 Stage IIIc) harboring the BRAF V600E mutation. After resection of the primary tumor and during adjuvant chemotherapy using CAPOX (capecitabine and oxaliplatin), liver and lung metastases became apparent, and a companion diagnosis test revealed the presence of a BRAF V600E mutation. The new lesions were deemed resistant to the CAPOX regimen, and we decided to introduce encorafenib and cetuximab. After resection of liver metastases, encorafenib and cetuximab were reintroduced, but a new lesion appeared in hepatic S7, indicating resistance to the encorafenib and cetuximab regimen. The resistant liver metastasis was subsequently resected. To elucidate the resistance mechanism, we conducted a comprehensive analysis using the FoundationOne CDx cancer gene panel test, revealing the presence of a KRAS Q61H mutation alongside the BRAF V600E mutation. Subsequent liquid biopsy after liver recurrence confirmed the persistence of the KRAS Q61H mutation. Our results highlight the significance of cancer genome profiling tests (CGP tests) and liquid biopsies in guiding treatment strategies for BRAF-mutant colorectal cancer. Therefore, CGP testing offers valuable information for treatment, even if it does not lead to new drug administrations.

DOI： 10.1007/s13691-024-00678-2

最先端医療の今潰瘍性大腸炎におけるRNA編集の意義と臨床応用

近藤喜太, 金谷信彦, 高橋一剛, 重安邦俊, 藤原俊義

Medical Science Digest 50 ( 7 ) 402 - 403 2024.6

BNCT pancreatic cancer treatment strategy with glucose-conjugated boron drug. International journal

Takuya Fujimoto, Fuminori Teraishi, Noriyuki Kanehira, Tomoyuki Tajima, Yoshinori Sakurai, Natsuko Kondo, Masahiro Yamagami, Atsushi Kuwada, Akira Morihara, Mizuki Kitamatsu, Atsushi Fujimura, Minoru Suzuki, Yutaka Takaguchi, Kunitoshi Shigeyasu, Toshiyoshi Fujiwara, Hiroyuki Michiue

Biomaterials 309 122605 - 122605 2024.5

Language：English Publishing type：Research paper (scientific journal)

Multidisciplinary therapy centered on radical surgery for resectable pancreatic cancer is expected to prolong prognosis, but relies on CA19-9 biomarker levels to determine treatment strategy. Boron neutron capture therapy (BNCT) is a chemoradiotherapy using tumor hyperaccumulator boron drugs and neutron irradiation. The purpose of this study is to investigate novel boron drug agents for BNCT for pancreatic cancer. Bioinformatics was used to evaluate the uptake of current boron amino acid (BPA) drugs for BNCT into pancreatic cancer. The expression of the amino acid transporter LAT1, a BPA uptake transporter, was low in pancreatic cancer and even lower in high CA19-9 pancreatic cancer. In contrast, the glucose transporter was high in high CA19-9 pancreatic cancers and inversely correlated with LAT1 expression. Considering the low EPR effect in pancreatic cancer, we synthesized a small molecule Glucose-BSH, which is boron BSH bound to glucose, and confirmed its specific uptake in pancreatic cancer. uptake of Glucose-BSH was confirmed in an environment compatible with the tumor microenvironment. The therapeutic efficacy and safety of Glucose-BSH by therapeutic neutron irradiation were confirmed with BNCT. We report Glucose-BSH boron drug discovery study of a Precision Medicine BNCT with application to high CA19-9 pancreatic cancer.

DOI： 10.1016/j.biomaterials.2024.122605

【微小環境から読み解く胆膵癌】胆道癌制御性T細胞による肝内胆管癌の免疫微小環境の制御

吉田一博, 楳田祐三, 重安邦俊, 藤智和, 安井和也, 高木弘誠, 藤原俊義

肝胆膵 88 ( 5 ) 619 - 624 2024.5

Adenosine Deaminase Family Acting on RNA 1 (ADAR1) May Be a De Novo Target for Endometriosis Treatment. International journal

Thuy Ha Vu, Keiichiro Nakamura, Kunitoshi Shigeyasu, Kotaro Kubo, Chiaki Kashino, Hisashi Masuyama

In vivo (Athens, Greece) 38 ( 2 ) 683 - 690 2024

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND/AIM: Adenosine deaminase family acting on RNA 1 (ADAR1) expression was examined to determine its correlation with endometriosis. The biological functions and inhibitory effects of ADAR1 knockdown were investigated in a human endometriotic cell line. MATERIALS AND METHODS: ADAR1 was examined in patients with and without endometriosis using reverse transcription polymerase chain reaction (RT-PCR), and the apoptotic expression of ADAR1 small interfering RNA (siRNA) was confirmed using flow cytometry. The biological functions and inhibitory effects of ADAR1 knockdown were investigated using RT-PCR in a 12Z immortalized human endometriotic cell line. RESULTS: ADAR1 expression was significantly higher in patients with endometriosis than in those without (p<0.001). ADAR1 siRNA increased early and late apoptosis, compared to the mock (24.83%) and control (19.96%) cells. ADAR1 knockdown led to apoptosis through MDA5, RIG-I, IRF3, IRF7, caspase 3, caspase 7, and caspase 8 expression in the cell lines. CONCLUSION: ADAR1 is a potential novel therapeutic target in endometriosis.

DOI： 10.21873/invivo.13489

Clinical Impact of Prehabilitation on Elective Laparoscopic Surgery in Frail Octogenarians With Colorectal Cancer. International journal

Fuminori Teraishi, Kunitoshi Shigeyasu, Yoshitaka Kondo, Shunsuke Kagawa, Rie Tamura, Yoshikazu Matsuoka, Hiroshi Morimatsu, Toshiyoshi Fujiwara

Anticancer research 43 ( 12 ) 5597 - 5604 2023.12

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND/AIM: The aim of the present study was to clarify the clinical impact of prehabilitation by the perioperative management center (PERIO) at our hospital in severely frail octogenarians with colorectal cancer. PATIENTS AND METHODS: We compared the clinicopathological characteristics of octogenarians who underwent surgery for colorectal cancer before the establishment of PERIO intervention (Control group) with those who received prehabilitation (PERIO group). All patients were classified as American Society of Anesthesiologists (ASA) class 3 or higher. The primary outcome was the incidence of postoperative complications. RESULTS: There were 21 patients in the Control group and 19 patients in the PERIO group. Operative time was significantly longer in the PERIO group (Control group, 200 min vs. PERIO group, 230 min; p=0.03) and blood loss was significantly higher in the PERIO group (Control group, 5 ml vs. PERIO group, 30 ml; p=0.02). Postoperative complications occurred in 10 patients (47.6%) in the Control group and 3 patients (15.8%) in the PERIO group and were significantly lower in the PERIO group (p=0.03). Postoperative hospital stay was 13 days (range=7-31 days) in the Control group and 11 days (range=8-70 days) in the PERIO group (p=0.39). The rate of discharge directly to home was 81% in the Control group and 93.3% in the PERIO group (p=0.29). CONCLUSION: In frail octogenarians with colorectal cancer of ASA class 3 or higher, the incidence of postoperative complications was significantly lower after PERIO intervention.

DOI： 10.21873/anticanres.16762

Dual antiplatelet therapy inhibits neutrophil extracellular traps to reduce liver micrometastases of intrahepatic cholangiocarcinoma. International journal

Masashi Yoshimoto, Shunsuke Kagawa, Hiroki Kajioka, Atsuki Taniguchi, Shinji Kuroda, Satoru Kikuchi, Yoshihiko Kakiuchi, Tomohiko Yagi, Shohei Nogi, Fuminori Teraishi, Kunitoshi Shigeyasu, Ryuichi Yoshida, Yuzo Umeda, Kazuhiro Noma, Hiroshi Tazawa, Toshiyoshi Fujiwara

Cancer letters 567 216260 - 216260 2023.7

Language：English Publishing type：Research paper (scientific journal)

The involvement of neutrophil extracellular traps (NETs) in cancer metastasis is being clarified, but the relationship between intrahepatic cholangiocarcinoma (iCCA) and NETs remains unclear. The presence of NETs was verified by multiple fluorescence staining in clinically resected specimens of iCCA. Human neutrophils were co-cultured with iCCA cells to observe NET induction and changes in cellular characteristics. Binding of platelets to iCCA cells and its mechanism were also examined, and their effects on NETs were analyzed in vitro and in in vivo mouse models. NETs were present in the tumor periphery of resected iCCAs. NETs promoted the motility and migration ability of iCCA cells in vitro. Although iCCA cells alone had a weak NET-inducing ability, the binding of platelets to iCCA cells via P-selectin promoted NET induction. Based on these results, antiplatelet drugs were applied to these cocultures in vitro and inhibited the binding of platelets to iCCA cells and the induction of NETs. Fluorescently labeled iCCA cells were injected into the spleen of mice, resulting in the formation of liver micrometastases coexisting with platelets and NETs. These mice were treated with dual antiplatelet therapy (DAPT) consisting of aspirin and ticagrelor, which dramatically reduced micrometastases. These results suggest that potent antiplatelet therapy prevents micrometastases of iCCA cells by inhibiting platelet activation and NET production, and it may contribute to a novel therapeutic strategy.

DOI： 10.1016/j.canlet.2023.216260

Locally Advanced Rectal Cancer Invading the Gluteus Maximus Muscle Completely Responded to Total Neoadjuvant Therapy.

Masaki Sakamoto, Fuminori Teraishi, Kunitoshi Shigeyasu, Shunsuke Kagawa, Toshiyoshi Fujiwara

Acta medica Okayama 77 ( 2 ) 209 - 213 2023.4

Language：English

A 70-year-old male with anal pain and fever was diagnosed with rectal cancer perforation and abscess in the right gluteus maximus (GM) muscle. He underwent a transverse colon colostomy followed by preoperative capecitabine+oxaliplatin. Some local control was achieved but a residual abscess was observed in the right GM muscle. To secure circumferential resection margin by tumor reduction, he received chemoradiotherapy as total neoadjuvant therapy (TNT) and underwent laparoscopic abdominoperineal resection, D3 lymph node dissection, combined coccyx resection, and partial resection of the right GM muscle. The skin defect and pelvic dead space were filled with a right lateral vastus lateral great muscle flap. Histopathologically, the resected specimen showed no tumor cells in the primary tumor or lymph nodes, indicating a pathological complete response (pCR). This case suggests that TNT might improve the R0 resection and pCR rates and overall survival.

DOI： 10.18926/AMO/65152

ADAR1 has an oncogenic function and can be a prognostic factor in cervical cancer. International journal

Keiichiro Nakamura, Kunitoshi Shigeyasu, Kazuhiro Okamoto, Hirofumi Matsuoka, Hisashi Masuyama

Scientific reports 13 ( 1 ) 4720 - 4720 2023.3

Language：English Publishing type：Research paper (scientific journal)

Adenosine deaminase acting on RNA 1 (ADAR1), a recently described epigenetic modifier, is believed to play a critical oncogenic role in human cancers. However, its functional role and clinical significance in cervical cancer (CC) remain unclear. ADAR1 knockdown was performed to investigate its oncogenic functions in SiHa (HPV16), HeLa (HPV18), and Yumoto (non-HPV) CC cell lines. Cytoplasmic and nuclear ADAR1 expression were examined to clarify their correlation with clinicopathological parameters and prognosis in patients with CC. This resulted in increased apoptosis and necroptosis in HPV16 -type SiHa, HPV18-type HeLa, and non-HPV-type Yumoto CC cell lines. Progression-free survival (PFS) rates of patients exhibiting high cytoplasmic and nuclear ADAR1 expression were poorer than those in the other groups (P = 0.016). Multivariate analysis indicated that the combination of higher cytoplasmic and nuclear ADAR1 expression was an independent predictor of prognosis in patients with CC (P = 0.017). ADAR1 could be a potential therapeutic target for HPV-positive or HPV-negative CC. The combination of cytoplasmic and nuclear ADAR1 comprises a better prognostic factor for CC.

DOI： 10.1038/s41598-023-30452-y

ADAR1 is a promising risk stratification biomarker of remnant liver recurrence after hepatic metastasectomy for colorectal cancer. International journal

Nanako Hata, Kunitoshi Shigeyasu, Yuzo Umeda, Shuya Yano, Sho Takeda, Kazuhiro Yoshida, Tomokazu Fuji, Ryuichi Yoshida, Kazuya Yasui, Hibiki Umeda, Toshiaki Takahashi, Yoshitaka Kondo, Hiroyuki Kishimoto, Yoshiko Mori, Fuminori Teraishi, Hideki Yamamoto, Hiroyuki Michiue, Keiichiro Nakamura, Hiroshi Tazawa, Toshiyoshi Fujiwara

Scientific reports 13 ( 1 ) 2078 - 2078 2023.2

Language：English Publishing type：Research paper (scientific journal)

Adenosine-to-inosine RNA editing is a process mediated by adenosine deaminases that act on the RNA (ADAR) gene family. It has been discovered recently as an epigenetic modification dysregulated in human cancers. However, the clinical significance of RNA editing in patients with liver metastasis from colorectal cancer (CRC) remains unclear. The current study aimed to systematically and comprehensively investigate the significance of adenosine deaminase acting on RNA 1 (ADAR1) expression status in 83 liver metastatic tissue samples collected from 36 patients with CRC. The ADAR1 expression level was significantly elevated in liver metastatic tissue samples obtained from patients with right-sided, synchronous, or RAS mutant-type CRC. ADAR1-high liver metastasis was significantly correlated with remnant liver recurrence after hepatic metastasectomy. A high ADAR1 expression was a predictive factor of remnant liver recurrence (area under the curve = 0.72). Results showed that the ADAR1 expression level could be a clinically relevant predictive indicator of remnant liver recurrence. Patients with liver metastases who have a high ADAR1 expression requires adjuvant chemotherapy after hepatic metastasectomy.

DOI： 10.1038/s41598-023-29397-z

A Case Report of Non-typical Annular Pancreas Diagnosed during Laparoscopic Gastric Surgery.

Toshiaki Takahashi, Yoshihiko Kakiuchi, Satoru Kikuch, Shinji Kuroda, Sho Takeda, Kunitoshi Shigeyasu, Yoshitaka Kondo, Fuminori Teraishi, Shunsuke Kagawa, Toshiyoshi Fujiwara

Acta medica Okayama 77 ( 1 ) 91 - 95 2023.2

Language：English

An annular pancreas is a rare anomaly of the pancreas, defined as pancreatic tissue that totally or partly encircles the duodenum, usually the descending portion. A 76-year-old man who was diagnosed with gastric cancer cT3N0M0 Stage IIB underwent laparoscopic distal gastrectomy with D2 lymph node dissection. Intraoperatively, the dorsal half of the duodenal bulb was seen to be half surrounded by the pancreas, and a non-typical annular pancreas was diagnosed. Because of the risk to the pancreas, it was considered impossible to perform anastomosis by a linear stapler as in the usual laparoscopic procedure. Therefore, we performed laparoscopically assisted distal gastrectomy and Billroth-I reconstruction using a circular stapler, and the surgery was completed without difficulties. His postoperative course was good despite the development of a pancreatic fistula, which was an International Study Group for Pancreas Fistula biochemical leak. Some APs can be diagnosed preoperatively, but the rarer subtypes such as ours are more difficult to visualize on imaging. In gastrectomy, it is both oncologically important and technically challenging to perform lymph node dissection around the pancreas. In this case with an especially proximal pancreas, a circular stapler was considered better suited for gastroduodenal anastomosis and required a broader field than that afforded by laparoscopy. A case of non-typical annular pancreas diagnosed during laparoscopic gastric surgery is described.

DOI： 10.18926/AMO/64368

RNA editing is a valuable biomarker for predicting carcinogenesis in ulcerative colitis. International journal

Kazutaka Takahashi, Kunitoshi Shigeyasu, Yoshitaka Kondo, Kazuyoshi Gotoh, Shuya Yano, Yuzo Umeda, Toshihiro Inokuchi, Caiming Xu, Kazuhiro Yoshida, Hibiki Umeda, Toshiaki Takahashi, Sho Takeda, Ryuichi Yoshida, Fuminori Teraishi, Hiroyuki Kishimoto, Yoshiko Mori, Kazuhiro Noma, Yoshinaga Okugawa, Sakiko Hiraoka, Hiroyuki Michiue, Hiroshi Tazawa, Osamu Matsushita, Ajay Goel, Toshiyoshi Fujiwara

Journal of Crohn's & colitis 17 ( 5 ) 754 - 766 2022.12

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND AND AIMS: Ulcerative colitis (UC) can develop colitis-associated colorectal neoplasm (CAN). Adenine-to-inosine RNA editing, which is regulated by adenosine deaminase acting on RNA (ADAR), induces the posttranscriptional modification of critical oncogenes, including antizyme inhibitor 1 (AZIN1), leading to colorectal carcinogenesis. Therefore, we hypothesized that ADAR1 might be involved in the development of CAN in UC. METHODS: We systematically analyzed a cohort of 139 UC cases (40 acute phase, 73 remission phase, 26 CAN). The degree of inflammation was evaluated using the Mayo endoscopic score (MES). RESULTS: The type 1 IFN-related inflammation pathway was upregulated in the rectum of active UC, rectum of UC-CAN, and tumor site of UC-CAN patients. ADAR1 expression was upregulated in the entire colon of CAN cases, while it was down-regulated in non-CAN MES0 cases. ADAR1 expression in the rectum predicted the development of CAN better than p53 or β-catenin, with an area under the curve of 0.93. The high expression of ADAR1 and high AZIN1 RNA editing in UC was triggered by type 1 IFN stimulation from UC-specific microbiomes, such as Fusobacterium in vitro analyses. The induction of AZIN1 RNA editing by ADAR1, whose expression is promoted by Fusobacterium, may induce carcinogenesis in UC. CONCLUSIONS: The risk of CAN can be evaluated by assessing ADAR1 expression in the rectum of MES0 UC patients, freeing UC patients from unnecessary colonoscopy and reducing their physical burden. RNA editing may be involved in UC carcinogenesis, and may be used to facilitate the prevention and treatment of CAN in UC.

DOI： 10.1093/ecco-jcc/jjac186

Dysregulated DNA methylation in the pathogenesis of Fabry disease. International journal

Jin-Song Shen, Uthra Balaji, Kunitoshi Shigeyasu, Yoshinaga Okugawa, Siamak Jabbarzadeh-Tabrizi, Taniqua S Day, Erland Arning, John Marshall, Seng H Cheng, Jinghua Gu, Raphael Schiffmann, Teodoro Bottiglieri, Ajay Goel

Molecular genetics and metabolism reports 33 100919 - 100919 2022.12

Language：English Publishing type：Research paper (scientific journal)

Fabry disease is an X-linked lysosomal storage disorder caused by a deficiency of α-galactosidase A and subsequent accumulation of glycosphingolipids with terminal α-D-galactosyl residues. The molecular process through which this abnormal metabolism of glycosphingolipids causes multisystem dysfunction in Fabry disease is not fully understood. We sought to determine whether dysregulated DNA methylation plays a role in the development of this disease. In the present study, using isogenic cellular models derived from Fabry patient endothelial cells, we tested whether manipulation of α-galactosidase A activity and glycosphingolipid metabolism affects DNA methylation. Bisulfite pyrosequencing revealed that changes in α-galactosidase A activity were associated with significantly altered DNA methylation in the androgen receptor promoter, and this effect was highly CpG loci-specific. Methylation array studies showed that α-galactosidase A activity and glycosphingolipid levels were associated with differential methylation of numerous CpG sites throughout the genome. We identified 15 signaling pathways that may be susceptible to methylation alterations in Fabry disease. By incorporating RNA sequencing data, we identified 21 genes that have both differential mRNA expression and methylation. Upregulated expression of collagen type IV alpha 1 and alpha 2 genes correlated with decreased methylation of these two genes. Methionine levels were elevated in Fabry patient cells and Fabry mouse tissues, suggesting that a perturbed methionine cycle contributes to the observed dysregulated methylation patterns. In conclusion, this study provides evidence that α-galactosidase A deficiency and glycosphingolipid storage may affect DNA methylation homeostasis and highlights the importance of epigenetics in the pathogenesis of Fabry disease and, possibly, of other lysosomal storage disorders.

DOI： 10.1016/j.ymgmr.2022.100919

Clinical features of biliary tract cancer in Japanese individuals with Lynch syndrome. International journal

Nobuhiko Kanaya, Hideki Aoki, Toshiaki Morito, Fumitaka Taniguchi, Kunitoshi Shigeyasu, Chieko Tamura, Kokichi Sugano, Kiwamu Akagi, Hideyuki Ishida, Kohji Tanakaya

Journal of gastrointestinal oncology 13 ( 5 ) 2532 - 2538 2022.10

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: Biliary tract cancer (BTC) is a Lynch syndrome (LS)-associated cancer with a high mortality rate. This study aimed to clarify the clinical features of BTC in individuals with LS and to discuss its management. METHODS: We obtained data from genetically verified Japanese individuals with LS who were diagnosed at a single institution, between January 2003 and April 2021. Moreover, 21 individuals with sporadic BTC (n=15) and LS associated BTC (n=6) underwent microsatellite instability (MSI) testing. RESULTS: Among 92 individuals with LS, 6 individuals with MLH1 variants developed BTCs (10 lesions, male/female, 2:1). The median age at diagnosis of initial BTC was 69 years (range, 34-78 years). Histological examination revealed a predominance of differentiated adenocarcinoma (89%). Then, 2 individuals had multiple BTCs. All available 7 BTC lesions showed high-frequency of microsatellite instability (MSI-H). MLH1 carriers showed a 7.2% cumulative risk of BTC development at an age of 70 years. Five of the six individuals died of BTC. CONCLUSIONS: MSI analysis could facilitate LS identification in individuals with BTC. Surveillance for BTC should be considered for MLH1 carriers in Japan.

DOI： 10.21037/jgo-22-165

RNA editing facilitates the enhanced production of neoantigens during the simultaneous administration of oxaliplatin and radiotherapy in colorectal cancer. International journal

Yasuhiro Komatsu, Kunitoshi Shigeyasu, Shuya Yano, Sho Takeda, Kazutaka Takahashi, Nanako Hata, Hibiki Umeda, Kazuhiro Yoshida, Yoshiko Mori, Kazuya Yasui, Ryuichi Yoshida, Yoshitaka Kondo, Hiroyuki Kishimoto, Fuminori Teraishi, Yuzo Umeda, Shunsuke Kagawa, Hiroyuki Michiue, Hiroshi Tazawa, Ajay Goel, Toshiyoshi Fujiwara

Scientific reports 12 ( 1 ) 13540 - 13540 2022.8

Language：English Publishing type：Research paper (scientific journal)

Most cases of colorectal cancers (CRCs) are microsatellite stable (MSS), which frequently demonstrate lower response rates to immune checkpoint inhibitors (ICIs). RNA editing produces neoantigens by altering amino acid sequences. In this study, RNA editing was induced artificially by chemoradiation therapy (CRT) to generate neoantigens in MSS CRCs. Altogether, 543 CRC specimens were systematically analyzed, and the expression pattern of ADAR1 was investigated. In vitro and in vivo experiments were also performed. The RNA editing enzyme ADAR1 was upregulated in microsatellite instability-high CRCs, leading to their high affinity for ICIs. Although ADAR1 expression was low in MSS CRC, CRT including oxaliplatin (OX) treatment upregulated RNA editing levels by inducing ADAR1. Immunohistochemistry analyses showed the upregulation of ADAR1 in patients with CRC treated with CAPOX (capecitabine + OX) radiation therapy relative to ADAR1 expression in patients with CRC treated only by surgery (p < 0.001). Compared with other regimens, CRT with OX effectively induced RNA editing in MSS CRC cell lines (HT29 and Caco2, p < 0.001) via the induction of type 1 interferon-triggered ADAR1 expression. CRT with OX promoted the RNA editing of cyclin I, a neoantigen candidate. Neoantigens can be artificially induced by RNA editing via an OX-CRT regimen. CRT can promote proteomic diversity via RNA editing.

DOI： 10.1038/s41598-022-17773-0

ADAR1 and AZIN1 RNA editing function as an oncogene and contributes to immortalization in endometrial cancer. International journal

Keiichiro Nakamura, Kunitoshi Shigeyasu, Kazuhiro Okamoto, Hirofumi Matsuoka, Hisashi Masuyama

Gynecologic oncology 166 ( 2 ) 326 - 333 2022.6

Language：English Publishing type：Research paper (scientific journal)

OBJECTIVE: Adenosine-to-inosine (A-to-I) RNA editing is a recently described epigenetic modification, which is believed to constitute a key oncogenic mechanism in human cancers. However, its functional role and clinical significance in endometrial cancer (EC) remain unclear. METHODS: Adenosine Deaminase family Acting on RNA1 (ADAR1) expression and Antizyme inhibitor 1 (AZIN1) RNA editing were examined to clarify the correlation with clinicopathological parameters and prognosis in EC patients. The biological functions and inhibitory effects of ADAR1 knockdown were investigated in JHUCS-1 and TU-ECS-1 EC cell lines. RESULTS: ADAR1 showed significant association with worse histology (P = 0.006), and lymph vascular space involvement (P = 0.049) in EC. The level of AZIN1 RNA editing was also significantly associated with worse histology (P = 0.012). ADAR1 expression was significantly correlated with AZIN1 RNA editing level (R = 0.729, R2 = 0.547, P < 0.001). Multivariate analysis indicated that higher ADAR1 expression along with AZIN1 RNA editing is an independent predictor of prognosis in EC patients (P = 0.015). Knockdown of ADAR1 led to increased MDA-5, RIG-I, PKR, and IRF-7 expression, which in turn resulted in increased levels of Bak and apoptosis in EC cells. CONCLUSIONS: High ADAR1 expression along with AZIN1 RNA editing could be a predictor of worse prognosis in EC. ADAR1 could be a potential therapeutic target in EC patients.

DOI： 10.1016/j.ygyno.2022.05.026

Tumor-targeted fluorescence labeling systems for cancer diagnosis and treatment. International journal

Hiroshi Tazawa, Kunitoshi Shigeyasu, Kazuhiro Noma, Shunsuke Kagawa, Fuminori Sakurai, Hiroyuki Mizuguchi, Hisataka Kobayashi, Takeshi Imamura, Toshiyoshi Fujiwara

Cancer science 113 ( 6 ) 1919 - 1929 2022.6

Language：English Publishing type：Research paper (scientific journal)

Conventional imaging techniques are available for clinical identification of tumor sites. However, detecting metastatic tumor cells that are spreading from primary tumor sites using conventional imaging techniques remains difficult. In contrast, fluorescence-based labeling systems are useful tools for detecting tumor cells at the single-cell level in cancer research. The ability to detect fluorescent-labeled tumor cells enables investigations of the biodistribution of tumor cells for the diagnosis and treatment of cancer. For example, the presence of fluorescent tumor cells in the peripheral blood of cancer patients is a predictive biomarker for early diagnosis of distant metastasis. The elimination of fluorescent tumor cells without damaging normal tissues is ideal for minimally invasive treatment of cancer. To capture fluorescent tumor cells within normal tissues, however, tumor-specific activated target molecules are needed. This review focuses on recent advances in tumor-targeted fluorescence labeling systems, in which indirect reporter labeling using tumor-specific promoters is applied to fluorescence labeling of tumor cells for the diagnosis and treatment of cancer. Telomerase promoter-dependent fluorescence labeling using replication-competent viral vectors produces fluorescent proteins that can be used to detect and eliminate telomerase-positive tumor cells. Tissue-specific promoter-dependent fluorescence labeling enables identification of specific tumor cells. Vimentin promoter-dependent fluorescence labeling is a useful tool for identifying tumor cells that undergo epithelial-mesenchymal transition (EMT). The evaluation of tumor cells undergoing EMT is important for accurately assessing metastatic potential. Thus, tumor-targeted fluorescence labeling systems represent novel platforms that enable the capture of tumor cells for the diagnosis and treatment of cancer.

DOI： 10.1111/cas.15369

Regulatory T cells induce a suppressive immune milieu and promote lymph node metastasis in intrahepatic cholangiocarcinoma. International journal

Daisuke Konishi, Yuzo Umeda, Kazuhiro Yoshida, Kunitoshi Shigeyasu, Shuya Yano, Tomohiro Toji, Sho Takeda, Ryuichi Yoshida, Kazuya Yasui, Tomokazu Fuji, Kazuyuki Matsumoto, Hiroyuki Kishimoto, Hiroyuki Michiue, Fuminori Teraishi, Hironari Kato, Hiroshi Tazawa, Hiroyuki Yanai, Takahito Yagi, Ajay Goel, Toshiyoshi Fujiwara

British journal of cancer 127 ( 4 ) 757 - 765 2022.5

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: Emerging evidence indicates that immunogenicity plays an important role in intrahepatic cholangiocarcinoma (ICC). Herein, we systematically evaluated the clinical relevance of immunogenicity in ICC. METHODS: Highly immunogenic ICCs identified in the public dataset and the Cancer Immunome Atlas (TCIA) were assessed to determine the prognostic impact of immunogenicity in ICC and key components after curative resection. We also investigated the clinical relevance of the immune milieu in ICC. RESULTS: Using the Gene Expression Omnibus dataset 89749 and TCIA, we identified CD8+/forkhead box P3 (FoxP3)+ tumour-infiltrating lymphocytes (TILs), T-cell immunoglobulin and mucin domain 3 (TIM-3) and human leukocyte antigen-A (HLA-A) in highly immunogenic ICCs. Immunohistochemical analysis of the in-house cohort showed that intratumoral FoxP3+ TILs correlated with CD8+ TILs (P = 0.045, Fisher's exact test) and that high FoxP3+/CD8+ ratio (FCR) was an important marker for poor survival (P < 0.001, log-rank test). Furthermore, the FCR was higher in tumour-free lymph nodes in ICCs with lymph node metastases than in those without lymph node metastases (P = 0.003, Mann-Whitney U test). CONCLUSIONS: FCR should be considered an important biomarker that represents the immune environment of ICC based on its potentially important role in tumour progression, especially lymph node metastasis.

DOI： 10.1038/s41416-022-01838-y

Anorectal leiomyoma with GLUT1 overexpression mimicking malignancy on FDG-PET/CT. International journal

Fuminori Teraishi, Kunitoshi Shigeyasu, Shunsuke Kagawa, Toshiyoshi Fujiwara

Journal of surgical case reports 2022 ( 5 ) rjac101 2022.5

Language：English

A 43-year-old female underwent pelvic magnetic resonance imaging for uterine myoma that incidentally revealed a 4.6 × 2.8 cm soft tissue mass in the anorectal region. Rectal endoscopy showed a submucosal tumor just above the anal canal. Fluorodeoxyglucose-positron emission tomography/computed tomography (FDG-PET/CT) revealed an anorectal tumor with very high FDG uptake. Aspiration cytology and needle biopsy were inconclusive, and the patient underwent trans-perineal tumor resection. The excised tumor was a 4.6 × 3.5 × 2.7 cm gray-white bifurcated nodular tumor. Light microscopy revealed fenestrated growth of poorly dysmorphic short spindle-shaped cells with eosinophilic sporophytes. Immunohistochemical staining was positive for αSMA and desmin, negative for CD117 (KIT) and S100, and the patient was diagnosed with benign leiomyoma. Tumor cells were also positive for glucose transporter-1 (GLUT1) immunohistochemically. It is important to keep in mind that FDG-PET/CT may show false-positive results even in benign anal leiomyoma for various reasons, including GLUT1 overexpression.

DOI： 10.1093/jscr/rjac101

Association between Advanced T Stage and Thick Rectus Abdominis Muscle and Outlet Obstruction and High-Output Stoma after Ileostomy in Patients with Rectal Cancer

Yasuhiro Komatsu, Kunitoshi Shigeyasu, Sho Takeda, Yoshiko Mori, Kazutaka Takahashi, Nanako Hata, Kokichi Miyamoto, Hibiki Umeda, Yoshihiko Kakiuchi, Satoru Kikuchi, Shuya Yano, Shinji Kuroda, Yoshitaka Kondo, Hiroyuki Kishimoto, Fuminori Teraishi, Masahiko Nishizaki, Shunsuke Kagawa, Toshiyoshi Fujiwara

International Surgery 106 ( 3 ) 102 - 111 2022

Publishing type：Research paper (scientific journal)

Objective: This study aimed to identify factors associated with outlet obstruction and high-output stoma (HOS) after ileostomy creation. Summary of background data: Ileostomy creation is effective in preventing leakage among patients undergoing low anterior resection for rectal cancer. However, major complications such as outlet obstruction and HOS can occur after surgery. Moreover, these complications cannot be prevented. Methods: This retrospective study included 34 patients with rectal cancer who underwent low anterior resection and ileostomy creation at Okayama University Hospital from January 2015 to December 2018. Then, the risk factors associated with outlet obstruction and HOS were analyzed. Results: Of 34 patients, 7 (21%) experienced outlet obstruction. In a multivariate logistic regression analysis, advanced T stage (P ¼ 0.10), ileostomy with a short horizontal diameter (P ¼ 0.01), and thick rectus abdominis (RA) muscle (P ¼ 0.0005) were considered independent risk factors for outlet obstruction. There was a significant correlation between outlet obstruction and HOS (P ¼ 0.03). Meanwhile, the independent risk factors of HOS were advanced T stage (P ¼ 0.03) and thick RA muscle (P ¼ 0.04). Conclusions: Thick RA muscle and advanced T stage were the common risk factors of outlet obstruction and HOS. Therefore, in high-risk patients, these complications can be prevented by choosing an appropriate ileostomy location according to RA muscle thickness and by preventing tubing into the ileostomy.

DOI： 10.9738/INTSURG-D-21-00012.1

A Case of a Transwoman with Colorectal Cancer after Flap Vaginoplasty

Shiho Watanabe, Fuminori Teraishi, Sari Fujimoto, Toshiyuki Watanabe, Sho Takeda, Shuhei Narita, Koya Yamashita, Kunitoshi Shigeyasu, Shunsuke Kagawa, Yuzaburo Namba, Yoshihiro Kimata

Journal of Plastic and Reconstructive Surgery 2022

Immuno-hyperthermia effected by antibody-conjugated nanoparticles selectively targets and eradicates individual cancer cells. International journal

Tetsuya Kagawa, Yuki Matsumi, Hiromichi Aono, Toshiaki Ohara, Hiroshi Tazawa, Kunitoshi Shigeyasu, Shuya Yano, Sho Takeda, Yasuhiro Komatsu, Robert M Hoffman, Toshiyoshi Fujiwara, Hiroyuki Kishimoto

Cell cycle (Georgetown, Tex.) 20 ( 13 ) 1 - 11 2021.6

Language：English Publishing type：Research paper (scientific journal) Publisher：TAYLOR & FRANCIS INC

Hyperthermia has been used for cancer therapy for along period of time, but has shown limited clinical efficacy. Induction-heating hyperthermia using the combination of magnetic nanoparticles (MNPs) and an alternating magnetic field (AMF), termed magnetic hyperthermia (MHT), has previously shown efficacy in an orthotopic mouse model of disseminated gastric cancer. In the present study, superparamagnetic iron oxide nanoparticles (SPIONs), atype of MNP, were conjugated with an anti-HER2 antibody, trastuzumab and termed anti-HER2-antibody-linked SPION nanoparticles (anti-HER2 SPIONs). Anti-HER2 SPIONs selectively targeted HER2-expressing cancer cells co-cultured along with normal fibroblasts and HER2-negative cancer cells and caused apoptosis only in the HER2-expressing individual cancer cells. The results of the present study show proof-of-concept of anovel hyperthermia technology, immuno-MHT for selective cancer therapy, that targets individual cancer cells.AbbreviationsAMF:alternating magnetic fieldDDW:double distilled waterDMEM:Dulbecco's Modified Eagle's Mediumf:frequencyFBS:fetal bovine serumFITC:Fluorescein isothiocyanateGFP:green fluorescent proteinH:amplitudeHsp:heat shock proteinMHT:magnetic hyperthermiaMNPs:magnetic nanoparticlesPI:propidium iodideRFP:red fluorescent proteinSPION:superparamagnetic iron oxide (Fe3O4) nanoparticle.

DOI： 10.1080/15384101.2021.1915604

Hyperthermia generated by magnetic nanoparticles for effective treatment of disseminated peritoneal cancer in an orthotopic nude-mouse model. International journal

Yuki Matsumi, Tetsuya Kagawa, Shuya Yano, Hiroshi Tazawa, Kunitoshi Shigeyasu, Sho Takeda, Toshiaki Ohara, Hiromichi Aono, Robert M Hoffman, Toshiyoshi Fujiwara, Hiroyuki Kishimoto

Cell cycle (Georgetown, Tex.) 20 ( 12 ) 1 - 12 2021.6

Language：English Publishing type：Research paper (scientific journal) Publisher：TAYLOR & FRANCIS INC

Magnetic hyperthermia (MHT), which combines magnetic nanoparticles (MNPs) with an alternating magnetic field (AMF), holds promise as a cancer therapy. There have been many studies about hyperthermia, most of which have been performed by direct injection of MNPs into tumor tissues. However, there have been no reports of treating peritoneal disseminated disease with MHT to date. In the present study, we treated peritoneal metastasis of gastric cancer with MHT using superparamagnetic iron oxide (Fe3O4) nanoparticle (SPION) coated with carboxydextran as an MNP, in an orthotopic mouse model mimicking early peritoneal disseminated disease of gastric cancer. SPIONs of an optimal size were intraperitoneally administered, and an AMF (390 kHz, 28 kAm-1) was applied for 10 minutes, four times every three days. Three weeks after the first MHT treatment, the peritoneal metastases were significantly inhibited compared with the AMF-alone group or the untreated-control group. The results of the present study show that MHT can be applied as a new treatment option for disseminated peritoneal gastric cancer.Abbreviations: AMF: alternating magnetic field; Cy1: cytology-positive; DMEM: Dulbecco's Modified Eagle's Medium; FBS: fetal bovine serum; H&E: hematoxylin and eosin; HIPEC: hyperthermic intraperitoneal chemotherapy; MEM: Minimum Essential Medium; MHT: magnetic hyperthermia; MNPs: magnetic nanoparticles; P0: macroscopic peritoneal dissemination; RFP: red fluorescent protein; SPION: superparamagnetic iron oxide (Fe3O4) nanoparticle.

DOI： 10.1080/15384101.2021.1919441

Clinical and epigenetic features of colorectal cancer patients with somatic POLE proofreading mutations. International journal

Takashi Kawai, Akihiro Nyuya, Yoshiko Mori, Takehiro Tanaka, Hiroaki Tanioka, Kazuya Yasui, Toshiaki Toshima, Fumitaka Taniguchi, Kunitoshi Shigeyasu, Yuzo Umeda, Toshiyoshi Fujiwara, Makoto Okawaki, Yoshiyuki Yamaguchi, Ajay Goel, Takeshi Nagasaka

Clinical epigenetics 13 ( 1 ) 117 - 117 2021.5

Language：English Publishing type：Research paper (scientific journal) Publisher：BMC

BACKGROUND: Mutations in the POLE gene result in an ultra-hypermutated phenotype in colorectal cancer (CRC); however, the molecular characterisation of epigenetic alterations remains unclear. We examined the genetic and epigenetic profiles of POLE-mutant CRC to elucidate the clinicopathological features of the associated genetic and epigenetic alterations. RESULTS: Tumour tissues (1,013) obtained from a cohort of patients with CRC were analysed to determine associations between the proofreading domain mutations of POLE with various clinicopathological variables, microsatellite instability (MSI) status, BRAF and KRAS mutations, and the methylation status of key regions of MLH1, MGMT, and SFRP2 promoters by calculating the methylation scores (range 0-6). Only four cases (0.4%) exhibited pathogenic POLE hotspot mutations (two p.P286R [c.857C > G], one p.V411L [c.1231G > C], and p.S459F [c.1376C > T] each), which were mutually exclusive to BRAF and KRAS mutations and MSI. CRC patients were divided into four subgroups: patients with POLE mutations (POLE, 0.4%, n = 4), patients with both MSI and extensive methylation in MLH1 (MSI-M, 2.9%, n = 29), patients with MSI but no extensive methylation in MLH1 (MSI-U, 3.6%, n = 36), and patients without MSI (non-MSI, 93.2%, n = 944). The POLE group was younger at diagnosis (median 52 years, P < 0.0001), with frequent right-sided tumour localisation (frequency of tumours located in the right colon was 100%, 93.1%, 36.1%, and 29.9% in POLE, MSI-M, MSI-U, and non-MSI, respectively; P < 0.0001), and was diagnosed at an earlier stage (frequency of stages I-II was 100%, 72.4%, 77.8%, and 46.6% in POLE, MSI-M, MSI-U, and non-MSI, respectively, P < 0.0001). The mean methylation score in POLE was not different from that in MSI-U and non-MSI, but the methylation signature was distinct from that of the other subgroups. Additionally, although the examined number of POLE-mutant tumours was small, the number of CD8-positive cells increased in tumours with partial methylation in the MLH1 gene. CONCLUSIONS: CRC patients with POLE proofreading mutations are rare. Such mutations are observed in younger individuals, and tumours are primarily located in the right colon. Diagnosis occurs at an earlier stage, and distinct epigenetic alterations may be associated with CD8 cell infiltration.

DOI： 10.1186/s13148-021-01104-7

SMAD4 Germline Pathogenic Variant-Related Gastric Juvenile Polyposis with Adenocarcinoma Treated with Laparoscopic Total Gastrectomy: A Case Report International journal

Yuya Sakurai, Satoru Kikuchi, Kunitoshi Shigeyasu, Yoshihiko Kakiuchi, Takehiro Tanaka, Hibiki Umeda, Masaki Sakamoto, Sho Takeda, Shuya Yano, Mashu Futagawa, Fumino Kato, Reimi Sogawa, Hideki Yamamoto, Shinji Kuroda, Yoshitaka Kondo, Fuminori Teraishi, Hiroyuki Kishimoto, Masahiko Nishizaki, Shunsuke Kagawa, Akira Hirasawa, Toshiyoshi Fujiwara

American Journal of Case Reports 22 e932241 2021.5

Language：English Publishing type：Research paper (scientific journal) Publisher：International Scientific Information, Inc.

Objective: Rare diseaseBackground: Juvenile polyposis syndrome is an uncommon, autosomal-dominant hereditary disease that is distinguished by multiple polyps in the stomach or intestinal tract. It is associated with a high risk of malignancy. Pathogenic variants in SMAD4 or BMPR1A account for 40% of all cases.Case Report: A 49-year-old woman underwent esophagogastroduodenoscopy because of exacerbation of anemia. She had numerous erythematous polyps in most parts of her stomach. Based on biopsy findings, juvenile polyposis syndrome (JPS) was suspected morphologically, but there was no evidence of malignancy. Colonoscopy showed stemmed hyperplastic polyps and an adenoma; video capsule endoscopy revealed no lesions in the small intestine. After preoperative surveillance, laparoscopic total gastrectomy with D1 lymph node dissection was performed to prevent malignant transformation. The pathological diagnosis was juvenile polyp-like polyposis with adenocarcinoma. In addition, a germline pathogenic variant in the SMAD4 gene was detected with genetic testing.Conclusions: JPS can be diagnosed with endoscopy and genetic testing. Further, appropriate surgical management may prevent cancer-related death in patients with this condition.

DOI： 10.12659/ajcr.932241

Long-term Survival with a Rare Advanced Primary Gastrointestinal Malignant Melanoma Treated with Laparoscopic Surgery/Immune Checkpoint Inhibitor.

Motochika Endo, Shuya Yano, Hiroaki Asano, Sho Takeda, Yuki Hamada, Yoshitaka Kondo, Shinji Kuroda, Kunitoshi Shigeyasu, Satoru Kikuchi, Takehiro Tanaka, Fuminori Teraishi, Masahiko Nishizaki, Shunsuke Kagawa, Toshiyoshi Fujiwara

Acta medica Okayama 75 ( 2 ) 231 - 238 2021.4

Language：English Publishing type：Research paper (scientific journal) Publisher：OKAYAMA UNIV MED SCHOOL

Targeted therapies for malignant melanoma have improved patients' prognoses. A primary gastrointestinal malignant melanoma is very rare, with no standard treatment strategy. We treated a 78-year-old Japanese female with advanced primary gastrointestinal melanoma of the descending colon and gallbladder. We administered a multidisciplinary treatment: surgical resection of the descending colon and gallbladder tumors, resection of the metastatic lymph nodes behind the pancreas head, and immune checkpoint antibody-blockade therapy (nivolumab) for ~4 years. PET/CT demonstrated no recurrent lesion for > 3 years. Multidisciplinary therapies (e.g., surgery, chemotherapy, radiotherapy, target therapy, and immune checkpoint antibody-blockade therapy) can successfully treat primary gastrointestinal malignant melanoma.

DOI： 10.18926/AMO/61906

Perspective and prospective of RNA editing in colorectal cancer microenvironment

Sho Takeda, Kunitoshi Shigeyasu, Yasuhiro Komatsu, Kazutaka Takahashi, Nanako Hata, Kazuhiro Yoshida, Shuya Yano, Yoshitaka Kondo, Fuminori Teraishi, Yuzo Umeda, Hiroshi Tazawa, Shunsuke Kagawa, Toshiyoshi Fujiwara

CANCER SCIENCE 112 481 - 481 2021.2

Reversible EMT-MET biosensor-mediated imaging visualizes inducible resistance to chemotherapy with hybrid E/M phase

Naoki Mimura, Shuya Yano, Hiroshi Tazawa, Takeshi Ieda, Daiki Okabayashi, Kunitoshi Shigeyasu, Sho Takeda, Kazuhiro Yoshida, Fuminori Teraishi, Yuzo Umeda, Shunsuke Kagawa, Toshiyoshi Fujiwara

CANCER SCIENCE 112 193 - 193 2021.2

RNA editing activated by chemoradiation therapy artificially generates neoantigen in colorectal cancer

Yasuhiro Komatsu, Kunitoshi Shigeyasu, Sho Takeda, Kazutaka Takahashi, Nanako Hata, Kazuhiro Yoshida, Shuya Yano, Toshiaki Ohara, Kazuhiro Noma, Yuzo Umeda, Shinji Kuroda, Yoshitaka Kondo, Fuminori Teraishi, Hiroshi Tazawa, Shunsuke Kagawa, Toshiyoshi Fujiwara

CANCER SCIENCE 112 336 - 336 2021.2

The PVT1 lncRNA is a novel epigenetic enhancer of MYC, and a promising risk-stratification biomarker in colorectal cancer. International journal

Kunitoshi Shigeyasu, Shusuke Toden, Tsuyoshi Ozawa, Takatoshi Matsuyama, Takeshi Nagasaka, Toshiaki Ishikawa, Debashis Sahoo, Pradipta Ghosh, Hiroyuki Uetake, Toshiyoshi Fujiwara, Ajay Goel

Molecular cancer 19 ( 1 ) 155 - 155 2020.11

Language：English Publishing type：Research paper (scientific journal) Publisher：BMC

Accumulating evidence suggests that dysregulation of transcriptional enhancers plays a significant role in cancer pathogenesis. Herein, we performed a genome-wide discovery of enhancer elements in colorectal cancer (CRC). We identified PVT1 locus as a previously unrecognized transcriptional regulator in CRC with a significantly high enhancer activity, which ultimately was responsible for regulating the expression of MYC oncogene. High expression of the PVT1 long-non-coding RNA (lncRNA) transcribed from the PVT1 locus was associated with poor survival among patients with stage II and III CRCs (p < 0.05). Aberrant methylation of the PVT1 locus inversely correlated with the reduced expression of the corresponding the PVT1 lncRNA, as well as MYC gene expression. Bioinformatic analyses of CRC-transcriptomes revealed that the PVT1 locus may also broadly impact the expression and function of other key genes within two key CRC-associated signaling pathways - the TGFβ/SMAD and Wnt/β-Catenin pathways. We conclude that the PVT1 is a novel oncogenic enhancer of MYC and its activity is controlled through epigenetic regulation mediated through aberrant methylation in CRC. Our findings also suggest that the PVT1 lncRNA expression is a promising prognostic biomarker and a potential therapeutic target in CRC.

DOI： 10.1186/s12943-020-01277-4

Case Report : A case of synchronous double cancer of the lung and rectum markedly responded to pembrolizumab

82 ( 2 ) 186 - 190 2020.2

Visualization of epithelial-mesenchymal transition in an inflammatory microenvironment-colorectal cancer network. Reviewed International journal

Takeshi Ieda, Hiroshi Tazawa, Hiroki Okabayashi, Shuya Yano, Kunitoshi Shigeyasu, Shinji Kuroda, Toshiaki Ohara, Kazuhiro Noma, Hiroyuki Kishimoto, Masahiko Nishizaki, Shunsuke Kagawa, Yasuhiro Shirakawa, Takashi Saitou, Takeshi Imamura, Toshiyoshi Fujiwara

Scientific reports 9 ( 1 ) 16378 - 16378 2019.11

Language：English Publishing type：Research paper (scientific journal) Publisher：NATURE PUBLISHING GROUP

Epithelial-mesenchymal transition (EMT) is a biological process by which epithelial cells acquire mesenchymal characteristics. In malignant tumors, EMT is crucial for acquisition of a mesenchymal phenotype with invasive and metastatic properties, leading to tumor progression. An inflammatory microenvironment is thought to be responsible for the development and progression of colorectal cancer (CRC); however, the precise role of inflammatory microenvironments in EMT-related CRC progression remains unclear. Here, we show the spatiotemporal visualization of CRC cells undergoing EMT using a fluorescence-guided EMT imaging system in which the mesenchymal vimentin promoter drives red fluorescent protein (RFP) expression. An inflammatory microenvironment including TNF-α, IL-1β, and cytokine-secreting inflammatory macrophages induced RFP expression in association with the EMT phenotype in CRC cells. In vivo experiments further demonstrated the distribution of RFP-positive CRC cells in rectal and metastatic tumors. Our data suggest that the EMT imaging system described here is a powerful tool for monitoring EMT in inflammatory microenvironment-CRC networks.

DOI： 10.1038/s41598-019-52816-z

Activation of AZIN1 RNA editing facilitates and promotes invasive potential of cancer associated fibroblasts in colorectal cancer

Sho Takeda, Kunitoshi Shigeyasu, Yoshinaga Okugawa, Kazuhiro Yoshida, Yoshiko Mori, Shuya Yano, Kazuhiro Noma, Yuzo Umeda, Yoshitaka Kondo, Hiroyuki Kishimoto, Fuminori Teraishi, Hiroshi Tazawa, Shunsuke Kagawa, Ajay Goel, Toshiyoshi Fujiwara

CANCER RESEARCH 79 ( 13 ) 2019.7

Clinicopathological features of breast cancer in Japanese female patients with Lynch syndrome. Reviewed

Nobuhiko Kanaya, Kohji Tanakaya, Rie Yamasaki, Takashi Arata, Kunitoshi Shigeyasu, Hideki Aoki, Toshiaki Morito, Hiromi Sanaii, Kiwamu Akagi, Toshiyoshi Fujiwara

Breast cancer (Tokyo, Japan) 26 ( 3 ) 359 - 364 2019.5

Language：English Publishing type：Research paper (scientific journal) Publisher：SPRINGER JAPAN KK

BACKGROUND: Lynch syndrome (LS) is a predominantly inherited syndrome caused by a pathological germline mutation in one of the mismatch repair (MMR) genes. Whether breast cancer (BC) is one of the LS-associated tumors is controversial. The aim of this retrospective cohort study was to evaluate the clinical features of BC in Japanese patients with LS. METHODS: Of 38 mutation carriers, 4 females with BC were examined in this study. RESULTS: Two of the four patients had multiple BC. Their median age at the diagnosis of BC was 63 (range, 47-84) years. The TNM (6th revision) stages of the six BCs were as follows: stage I, 33% (2/6); stage IIA, 50% (3/6); and stage IIB, 17% (1/6). Histological examination revealed four scirrhous, one papillotubular, and one medullary carcinoma. The positive ratios for estrogen receptor (ER), progesterone receptor (PgR), and human epidermal growth receptor 2 (HER2) were 83.3% (5/6), 83.3% (5/6), and 16.7% (1/6), respectively. Two of the three specimens showed MSI-H and one showed MSS. These MSI-H BCs had tumor-infiltrating lymphocytes. Two of the three specimens showed an absence of MLH1 and PMS2 proteins on immunohistochemistry. The cumulative risks for a person with LS to develop BC were 4.35% at the age of 50 years, 8.70% at 60 years, and 21.5% at 70 years. CONCLUSIONS: Our study results showed BC in Japanese females with LS to be an MSI-H tumor, which was ER and PgR positive and HER2 negative.

DOI： 10.1007/s12282-018-0931-z

Cancer stem cell-associated miRNAs serve as prognostic biomarkers in colorectal cancer. Reviewed International journal

Shusuke Toden, Shigeyasu Kunitoshi, Jacob Cardenas, Jinghua Gu, Elizabeth Hutchins, Kendall Van Keuren-Jensen, Hiroyuki Uetake, Yuji Toiyama, Ajay Goel

JCI insight 4 ( 6 ) 2019.3

Language：English Publishing type：Research paper (scientific journal) Publisher：AMER SOC CLINICAL INVESTIGATION INC

Chemoresistance in cancer is linked to a subset of cancer cells termed "cancer stem cells" (CSCs), and in particular, those expressing the CD44 variant appear to represent a more aggressive disease phenotype. Herein, we demonstrate that CD44v6 represents a CSC population with increased resistance to chemotherapeutic agents, and its high expression is frequently associated with poor overall survival (OS) and disease-free survival (DFS) in patients with colorectal cancer (CRC). CD44v6+ cells showed elevated resistance to chemotherapeutic drugs and significantly high tumor initiation capacity. Inhibition of CD44v6 resulted in the attenuation of self-renewal capacity and resensitization to chemotherapeutic agents. Of note, miRNA profiling of CD44v6+ spheroid-derived CSCs identified a unique panel of miRNAs indicative of high self-renewal capacity. In particular, miR-1246 was overexpressed in CD44v6+ cells, and associated with poor OS and DFS in CRC patients. We demonstrate that CD44v6+ CSCs induced chemoresistance and enhance tumorigenicity in CRC cells, and this was in part orchestrated by a distinct panel of miRNAs with dysregulated profiles. These findings suggest that specific miRNAs could serve as therapeutic targets as well as promising prognostic biomarkers in patients with colorectal neoplasia.

DOI： 10.1172/jci.insight.125294

Activation of AZIN1 RNA editing is a novel mechanism that promotes invasive potential of cancer-associated fibroblasts in colorectal cancer. Reviewed International journal

Sho Takeda, Kunitoshi Shigeyasu, Yoshinaga Okugawa, Kazuhiro Yoshida, Yoshiko Mori, Shuya Yano, Kazuhiro Noma, Yuzo Umeda, Yoshitaka Kondo, Hiroyuki Kishimoto, Fuminori Teraishi, Takeshi Nagasaka, Hiroshi Tazawa, Shunsuke Kagawa, Toshiyoshi Fujiwara, Ajay Goel

Cancer letters 444 127 - 135 2019.3

Language：English Publishing type：Research paper (scientific journal) Publisher：ELSEVIER IRELAND LTD

Adenosine-to-inosine (A-to-I) RNA editing is a recently described epigenetic modification, which is believed to constitute a key oncogenic mechanism in human cancers. However, its functional role in cancer-associated fibroblasts (CAFs) within the tumor microenvironment (TME) and its clinical significance remains unclear. Herein, we systematically analyzed a large cohort of 627 colorectal cancer (CRC) specimens, and investigated the expression pattern of ADAR1 and its biological significance on the antizyme inhibitor 1 (AZIN1) RNA editing levels. Both ADAR1 expression and AZIN1 RNA editing levels were significantly elevated in CRC tissues vs. normal mucosa, and these findings correlated with the increased expression of mesenchymal markers, Vimentin (ρ = 0.44) and Fibroblast activation protein (ρ = 0.38). Intriguingly, ADAR1 expression was specifically upregulated in both cancer cells and fibroblasts from cancerous lesions. Conditioned medium from cancer cells led to induction of ADAR1 expression and activation of AZIN1 RNA editing in fibroblasts (p < 0.05). Additionally, edited AZIN1 enhanced the invasive potential of fibroblasts. In conclusion, we provide novel evidence that hyper-editing of AZIN1 enhances the invasive potential of CAFs within the TME in colon and is an important predictor of tumor invasiveness in CRC.

DOI： 10.1016/j.canlet.2018.12.009

Dysregulated DNA methylation in the pathogenesis of Fabry disease

Jin-Song Shen, Kunitoshi Shigeyasu, Yoshinaga Okugawa, Uthra Balaji, Jinyan Chan, Jinghua Gu, Taniqua Day, Siamak Jabbarzadeh-Tabrizi, Raphael Schiffmann, Ajay Goel

MOLECULAR GENETICS AND METABOLISM 126 ( 2 ) S134 - S134 2019.2

Multiple gastrointestinal stromal tumors of the small intestine in a patient with neurofibromatosis type 1: a case report

Mori Yoshiko, Fujiwara Toshiyoshi, Shigeyasu Kunitoshi, Yoshioka Takahiro, Nagasaka Takeshi, Haraga Junko, Kagawa Shunsuke, Teraishi Fuminori, Toyooka Shinichi, Hirasawa Akira

JOURNAL OF FAMILIAL TUMORS 19 ( 2 ) 77 - 82 2019

Language：Japanese Publisher：The Japanese Society for Familial Tumors

Neurofibromatosis type 1 (NF1) is a complex autosomal dominant disorder caused by germline variants in the NF1 tumor suppressor gene characterized by multiple caféau lait spots and cutaneous neurofibromas. Therefore, NF1 predisposes patients to benign and malignant tumor development. We report a 54-year-old NF1 male with multiple gastrointestinal stromal tumors (GIST) in the small intestine. We resected a part of the small intestine with larger tumors, but left the part with small tumors to avoid short bowel syndrome. Histological examination revealed spindle cells with eosinophilic cytoplasm. The tumors were positive for KIT on immunopathological examination. They were smaller than 3.5 cm and their mitotic activity was less than 5/50 in high-power fields. We left 17 GIST that were smaller than 10 mm, but no progression has been detected to date. (<250 words)

DOI： 10.18976/jsft.19.2_77

Enhanced AZIN1 RNA editing and overexpression of its regulatory enzyme ADAR1 are important prognostic biomarkers in gastric cancer. Reviewed International journal

Yoshinaga Okugawa, Yuji Toiyama, Kunitoshi Shigeyasu, Akira Yamamoto, Tsunehiko Shigemori, Chengzeng Yin, Takashi Ichikawa, Hiromi Yasuda, Hiroyuki Fujikawa, Shigeyuki Yoshiyama, Junichiro Hiro, Masaki Ohi, Toshimitsu Araki, Masato Kusunoki, Ajay Goel

Journal of translational medicine 16 ( 1 ) 366 - 366 2018.12

Language：English Publishing type：Research paper (scientific journal) Publisher：BMC

BACKGROUND: Adenosine-to-inosine (A-to-I) RNA editing is catalyzed by adenosine deaminases acting on RNA (ADAR) enzymes. Recent evidence suggests that RNA editing of antizyme inhibitor 1 (AZIN1) RNA is emerging as a key epigenetic alteration underlying cancer pathogenesis. METHODS: We evaluated AZIN1 RNA editing levels, and the expression of its regulator, ADAR1, in 280 gastric tissues from 140 patients, using a RNA editing site-specific quantitative polymerase chain reaction assays. We also analyzed the clinical significance of these results as disease biomarkers in gastric cancer (GC) patients. RESULTS: Both AZIN1 RNA editing levels and ADAR1 expression were significantly elevated in GC tissues compared with matched normal mucosa (P < 0.0001, 0.0008, respectively); and AZIN1 RNA editing was positively correlated with ADAR1 expression. Elevated expression of ADAR1 significantly correlated with poor overall survival (P = 0.034), while hyper-edited AZIN1 emerged as an independent prognostic factor for OS and disease-free survival in GC patients [odds ratio (OR):1.98, 95% CI 1.17-3.35, P = 0.011, OR: 4.55, 95% CI 2.12-9.78, P = 0.0001, respectively]. Increased AZIN1 RNA editing and ADAR1 over-expression were significantly correlated with key clinicopathological factors, such as advanced T stage, presence of lymph node metastasis, distant metastasis, and higher TNM stages in GC patients. Logistic regression analysis revealed that hyper-editing status of AZIN1 RNA was an independent risk factor for lymph node metastasis in GC patients [hazard ratio (HR):3.03, 95% CI 1.19-7.71, P = 0.02]. CONCLUSIONS: AZIN1 RNA editing levels may be an important prognostic biomarker in GC patients, and may serve as a key clinical decision-making tool for determining preoperative treatment strategies in GC patients.

DOI： 10.1186/s12967-018-1740-z

Visualization of epithelial-mesenchymal transition in inflammatory microenvironment-colorectal cancer crosstalk

Hiroshi Tazawa, Takeshi Ieda, Shuya Yano, Kunitoshi Shigeyasu, Shinji Kuroda, Toshiaki Ohara, Kazuhiro Noma, Hiroyuki Kishimoto, Masahiko Nishizaki, Shunsuke Kagawa, Takashi Saitou, Takeshi Imamura, Toshiyoshi Fujiwara

CANCER SCIENCE 109 669 - 669 2018.12

Integrated fluorescent cytology with nano-biologics in peritoneally disseminated gastric cancer. Reviewed International journal

Megumi Watanabe, Shunsuke Kagawa, Kazuya Kuwada, Yuuri Hashimoto, Kunitoshi Shigeyasu, Michihiro Ishida, Shuichi Sakamoto, Atene Ito, Satoru Kikuchi, Shinji Kuroda, Hiroyuki Kishimoto, Shuta Tomida, Ryuichi Yoshida, Hiroshi Tazawa, Yasuo Urata, Toshiyoshi Fujiwara

Cancer science 109 ( 10 ) 3263 - 3271 2018.10

Language：English Publishing type：Research paper (scientific journal) Publisher：WILEY

Gastric cancer patients positive for peritoneal cytology are at increased risk of tumor recurrence, but although a certain proportion of cytology-positive patients relapse rapidly with aggressive progression, others survive longer with conventional chemotherapies. This heterogeneity makes it difficult to stratify patients for more intensive therapy and poses a substantial challenge for the implementation of precision medicine. We developed a new approach to identify biologically malignant subpopulations in cytology-positive gastric cancer patients, using a green fluorescent protein (GFP)-expressing attenuated adenovirus in which the telomerase promoter regulates viral replication (TelomeScan, OBP-401). The fluorescence emitted from TelomeScan-positive cells was successfully quantified using a multi-mode microplate reader. We then analyzed clinical peritoneal washes obtained from 68 gastric cancer patients and found that patients positive for TelomeScan had a significantly worse prognosis. In 21 cytology-positive patients, the median survival time of those who were TelomeScan positive (235 days) was significantly shorter than that for those who were TelomeScan negative (671 days; P = 0.0062). This fluorescent virus-guided cytology detects biologically malignant cancer cells from the peritoneal washes of gastric cancer patients and may thus be useful for both therapy stratification and precision medicine approaches based on genetic profiling of disseminated cells.

DOI： 10.1111/cas.13760

AZIN1 RNA editing confers cancer stemness and enhances oncogenic potential in colorectal cancer. Reviewed International journal

Kunitoshi Shigeyasu, Yoshinaga Okugawa, Shusuke Toden, Jinsei Miyoshi, Yuji Toiyama, Takeshi Nagasaka, Naoki Takahashi, Masato Kusunoki, Tetsuji Takayama, Yasuhide Yamada, Toshiyoshi Fujiwara, Leilei Chen, Ajay Goel

JCI insight 3 ( 12 ) 2018.6

Language：English Publishing type：Research paper (scientific journal) Publisher：AMER SOC CLINICAL INVESTIGATION INC

Adenosine-to-inosine (A-to-I) RNA editing, a process mediated by adenosine deaminases that act on the RNA (ADAR) gene family, is a recently discovered epigenetic modification dysregulated in human cancers. However, the clinical significance and the functional role of RNA editing in colorectal cancer (CRC) remain unclear. We have systematically and comprehensively investigated the significance of the expression status of ADAR1 and of the RNA editing levels of antizyme inhibitor 1 (AZIN1), one of the most frequently edited genes in cancers, in 392 colorectal tissues from multiple independent CRC patient cohorts. Both ADAR1 expression and AZIN1 RNA editing levels were significantly elevated in CRC tissues when compared with corresponding normal mucosa. High levels of AZIN1 RNA editing emerged as a prognostic factor for overall survival and disease-free survival and were an independent risk factor for lymph node and distant metastasis. Furthermore, elevated AZIN1 editing identified high-risk stage II CRC patients. Mechanistically, edited AZIN1 enhances stemness and appears to drive the metastatic processes. We have demonstrated that edited AZIN1 functions as an oncogene and a potential therapeutic target in CRC. Moreover, AZIN1 RNA editing status could be used as a clinically relevant prognostic indicator in CRC patients.

DOI： 10.1172/jci.insight.99976

A multi-institution phase II study of docetaxel and S-1 in combination with trastuzumab for HER2-positive advanced gastric cancer (DASH study). Reviewed International journal

Shunsuke Kagawa, Atsushi Muraoka, Takeshi Kambara, Hiroshi Nakayama, Ryosuke Hamano, Norimitsu Tanaka, Kazuhiro Noma, Kohji Tanakaya, Hiroyuki Kishimoto, Kunitoshi Shigeyasu, Shinji Kuroda, Satoru Kikuchi, Kazuya Kuwada, Masahiko Nishizaki, Yasuhiro Shirakawa, Toshiyoshi Fujiwara

Cancer chemotherapy and pharmacology 81 ( 2 ) 387 - 392 2018.2

Language：English Publishing type：Research paper (scientific journal) Publisher：Springer Verlag

BACKGROUND: Trastuzumab when combined with fluoropyrimidine and cisplatin was proven to improve survival in patients with human epidermal growth factor receptor 2 (HER2)-positive gastric cancer (GC) in the ToGA study. The safety and efficacy of trastuzumab in combination with docetaxel and S-1 have not yet been evaluated. METHODS: This study was a multicenter, phase II study. Patients with chemotherapy-naïve HER2-positive advanced or metastatic GC were eligible. Trastuzumab was administered intravenously on day 1 of the first cycle at 8 and 6 mg/kg in subsequent cycles. Docetaxel was administered intravenously at 40 mg/m2 on day 1 of each cycle. S-1 was administered at a dosage based on body surface area for 14 days in a 3-weekly cycle. The primary endpoint was progression-free survival (PFS). RESULTS: A total of 23 patients were enrolled. Median PFS was 6.7 months (95% CI 4.1-10.1). The response rate (RR) was 39.1%. Median overall survival (OS) and time to treatment failure (TTF) were 17.5 and 4.4 months, respectively. Major grade 3-4 adverse events were neutropenia (39.1%), leukopenia (30.4%), and febrile neutropenia (8.7%). CONCLUSION: Trastuzumab in combination with docetaxel and S-1 showed effective antitumor activity and manageable toxicities as first-line treatment for patients with HER2-positive GC.

DOI： 10.1007/s00280-017-3505-4

alpha-Galactosidase A activity modulates DNA methylation of androgen receptor promoter in Fabry disease endothelial cells

Jin-Song Shen, Kunitoshi Shigeyasu, Yoshinaga Okugawa, Taniqua Day, Raphael Schiffmann, Ajay Goel

MOLECULAR GENETICS AND METABOLISM 123 ( 2 ) S130 - S131 2018.2

Novel evidence for AZIN1 RNA editing-mediated oncogenic role in colorectal cancer

Kunitoshi Shigeyasu, Sho Takeda, Yoshinaga Okugawa, Yuji Toiyama, Takeshi Nagasaka, Hiroshi Tazawa, Shunsuke Kagawa, Ajay Goel, Toshiyoshi Fujiwara

CANCER SCIENCE 109 529 - 529 2018.1

SNORA21 - An Oncogenic Small Nucleolar RNA, with a Prognostic Biomarker Potential in Human Colorectal Cancer. Reviewed International journal

Kazuhiro Yoshida, Shusuke Toden, Wenhao Weng, Kunitoshi Shigeyasu, Jinsei Miyoshi, Jacob Turner, Takeshi Nagasaka, Yanlei Ma, Tetsuji Takayama, Toshiyoshi Fujiwara, Ajay Goel

EBioMedicine 22 68 - 77 2017.8

Language：English Publishing type：Research paper (scientific journal) Publisher：ELSEVIER SCIENCE BV

BACKGROUND: Emerging evidence indicates that small nucleolar RNAs (snoRNAs) play a central role in oncogenesis. Herein, we systematically evaluated expression profiles of snoRNAs in colorectal cancer (CRC) and investigated their clinical and functional role in this malignancy. METHODS: We compared expression levels of snoRNAs between cancer and normal tissues using publicly available datasets and identified the most differentially expressed and commonly upregulated snoRNAs in CRC. These results were examined in 489 colorectal tissues to assess their clinical significance, followed by a series of in vitro and in vivo experiments to evaluate the functional role of candidate snoRNAs. RESULTS: Using multiple RNA profiling datasets, we identified consistent overexpression of SNORA21 in CRC. In the clinical validation cohorts, the expression level of SNORA21 was upregulated in colorectal adenomas and cancers. Furthermore, elevated SNORA21 emerged as an independent factor for predicting poor survival. Both in vitro and in vivo experiments revealed that CRISPR/Cas9-mediated inhibition of SNORA21 expression resulted in decreased cell proliferation and invasion through modulation of multiple cancer related pathways. CONCLUSIONS: We systematically identified SNORA21 as a key oncogenic snoRNA in CRC, which plays an important role in cancer progression, and might serve as an important prognostic biomarker in CRC.

DOI： 10.1016/j.ebiom.2017.07.009

Gene expression profiles in BRAF V600E mutant colorectal cancer and association with SFRP2 methylation status

Kazuya Yasui, Takeshi Nagasaka, Toshiaki Toshima, Takashi Kawai, Kunitoshi Shigeyasu, Yoshiko Mori, Junko Haraga, Keiichiro Nakamura, Yuzo Umeda, Hiroshi Tazawa, Ajay Goel, Toshiyoshi Fujiwara

CANCER RESEARCH 77 2017.7

Novel findings for the clinical significance of RNA editing status of AZIN1 and ADAR 1 and 2 expression levels in gastric cancer patients

Yoshinaga Okugawa, Yuji Toiyama, Kunitoshi Shigeyasu, Takashi Ichikawa, Satoshi Oki, Koichiro Mori, Yuka Nagano, Hiromi Yasuda, Shigeyuki Yoshiyama, Masaki Ohi, Koji Tanaka, Yasuhiro Inoue, Toshimitsu Araki, Yasuhiko Mohri, Motoyoshi Tanaka, Chikao Miki, Ajay Goel, Masato Kusunoki

CANCER RESEARCH 77 2017.7

Novel evidence for AZIN1 RNA editing-mediated oncogenic role in colorectal cancer

Kunitoshi Shigeyasu, Shusuke Toden, Yoshinaga Okugawa, Jinsei Miyoshi, Takeshi Nagasaka, Toshiyoshi Fujiwara, Leilei Chen, Ajay Goel

CANCER RESEARCH 77 2017.7

Ovarian metastasectomy in colorectal cancer may improve the clinical outcomes of patients with metastatic colorectal cancer regardless of BRAF or KRAS mutational profiles

Mori Yoshiko, Nagasaka Takeshi, Tanioka Hiroaki, Nyuya Akihiro, Kawai Takashi, Toshima Toshiaki, Yasui Kazuya, Shigeyasu Kunitoshi, Kishimoto Hiroyuki, Umeda Yuzo, Fujiwara Toshiyoshi

ANNALS OF ONCOLOGY 28 2017.6

Emerging Role of MicroRNAs as Liquid Biopsy Biomarkers in Gastrointestinal Cancers. Reviewed International journal

Kunitoshi Shigeyasu, Shusuke Toden, Timothy J Zumwalt, Yoshinaga Okugawa, Ajay Goel

Clinical cancer research : an official journal of the American Association for Cancer Research 23 ( 10 ) 2391 - 2399 2017.5

Language：English Publishing type：Research paper (scientific journal) Publisher：AMER ASSOC CANCER RESEARCH

Cancer has emerged as a leading cause of mortality worldwide, claiming more than 8 million lives annually. Gastrointestinal cancers account for about 35% of these mortalities. Recent advances in diagnostic and treatment strategies have reduced mortality among patients with gastrointestinal cancer, yet a significant number of patients still develop late-stage cancer, where treatment options are inadequate. Emerging interests in "liquid biopsies" have encouraged investigators to identify and develop clinically relevant noninvasive genomic and epigenomic signatures that can be exploited as biomarkers capable of detecting premalignant and early-stage cancers. In this context, microRNAs (miRNA), which are small, noncoding RNAs that are frequently dysregulated in cancers, have emerged as promising entities for such diagnostic purposes. Even though the future looks promising, current approaches for detecting miRNAs in blood and other biofluids remain inadequate. This review summarizes existing efforts to exploit circulating miRNAs as cancer biomarkers and evaluates their potential and challenges as liquid biopsy-based biomarkers for gastrointestinal cancers. Clin Cancer Res; 23(10); 2391-9. ©2017 AACR.

DOI： 10.1158/1078-0432.CCR-16-1676

Exportin-5 Functions as an Oncogene and a Potential Therapeutic Target in Colorectal Cancer. Reviewed International journal

Kunitoshi Shigeyasu, Yoshinaga Okugawa, Shusuke Toden, C Richard Boland, Ajay Goel

Clinical cancer research : an official journal of the American Association for Cancer Research 23 ( 5 ) 1312 - 1322 2017.3

Language：English Publishing type：Research paper (scientific journal) Publisher：AMER ASSOC CANCER RESEARCH

Purpose: Dysregulated expression of miRNAs has emerged as a hallmark feature in human cancers. Exportin-5 (XPO5), a karyopherin family member, is a key protein responsible for transporting precursor miRNAs from the nucleus to the cytoplasm. Although XPO5 is one of the key regulators of miRNA biogenesis, its functional role and potential clinical significance in colorectal cancer remains unclear.Experimental Design: The expression levels of XPO5 were initially assessed in three genomic datasets, followed by determination and validation of the relationship between XPO5 expression and clinicopathologic features in two independent colorectal cancer patient cohorts. A functional characterization of XPO5 in colorectal cancer was examined by targeted gene silencing in colorectal cancer cell lines and a xenograft animal model.Results: XPO5 is upregulated, both at mRNA and protein levels, in colorectal cancers compared with normal tissues. High XPO5 expression is associated with worse clinicopathologic features and poor survival in colorectal cancer patient cohorts. The siRNA knockdown of XPO5 resulted in reduced cellular proliferation, attenuated invasion, induction of G1-S cell-cycle arrest, and downregulation of key oncogenic miRNAs in colorectal cancer cells. These findings were confirmed in a xenograft animal model, wherein silencing of XPO5 resulted in the attenuation of tumor growth.Conclusions: XPO5 acts like an oncogene in colorectal cancer by regulating the expression of miRNAs and may be a potential therapeutic target in colorectal cancer. Clin Cancer Res; 23(5); 1312-22. ©2016 AACR.

DOI： 10.1158/1078-0432.CCR-16-1023

H19 Noncoding RNA, an Independent Prognostic Factor, Regulates Essential Rb-E2F and CDK8-β-Catenin Signaling in Colorectal Cancer. Reviewed International journal

Masahisa Ohtsuka, Hui Ling, Cristina Ivan, Martin Pichler, Daisuke Matsushita, Matthew Goblirsch, Verena Stiegelbauer, Kunitoshi Shigeyasu, Xinna Zhang, Meng Chen, Fnu Vidhu, Geoffrey A Bartholomeusz, Yuji Toiyama, Masato Kusunoki, Yuichiro Doki, Masaki Mori, Shumei Song, Jillian R Gunther, Sunil Krishnan, Ondrej Slaby, Ajay Goel, Jaffer A Ajani, Milan Radovich, George A Calin

EBioMedicine 13 113 - 124 2016.11

Language：English Publishing type：Research paper (scientific journal) Publisher：ELSEVIER SCIENCE BV

The clinical significance of long noncoding RNAs (lncRNAs) in colorectal cancer (CRC) remains largely unexplored. Here, we analyzed a large panel of lncRNA candidates with The Cancer Genome Atlas (TCGA) CRC dataset, and identified H19 as the most significant lncRNA associated with CRC patient survival. We further validated such association in two independent CRC cohorts. H19 silencing blocked G1-S transition, reduced cell proliferation, and inhibited cell migration. We profiled gene expression changes to gain mechanism insight of H19 function. Transcriptome data analysis revealed not only previously identified mechanisms such as Let-7 regulation by H19, but also RB1-E2F1 function and β-catenin activity as essential upstream regulators mediating H19 function. Our experimental data showed that H19 affects phosphorylation of RB1 protein by regulating gene expression of CDK4 and CCND1. We further demonstrated that reduced CDK8 expression underlies changes of β-catenin activity, and identified that H19 interacts with macroH2A, an essential regulator of CDK8 gene transcription. However, the relevance of H19-macroH2A interaction in CDK8 regulation remains to be experimentally determined. We further explored the clinical relevance of above mechanisms in clinical samples, and showed that combined analysis of H19 with its targets improved prognostic value of H19 in CRC.

DOI： 10.1016/j.ebiom.2016.10.026

Expansion of epigenetic alterations in EFEMP1 promoter predicts malignant formation in pancreatobiliary intraductal papillary mucinous neoplasms. Reviewed International journal

Kazuhiro Yoshida, Takeshi Nagasaka, Yuzo Umeda, Takehiro Tanaka, Keisuke Kimura, Fumitaka Taniguchi, Tomokazu Fuji, Kunitoshi Shigeyasu, Yoshiko Mori, Hiroyuki Yanai, Takahito Yagi, Ajay Goel, Toshiyoshi Fujiwara

Journal of cancer research and clinical oncology 142 ( 7 ) 1557 - 69 2016.7

Language：English Publishing type：Research paper (scientific journal) Publisher：SPRINGER

PURPOSE: Although limited understanding exists for the presence of specific genetic mutations and aberrantly methylated genes in pancreatobiliary intraductal papillary mucinous neoplasms (IPMNs), the fundamental understanding of the dynamics of methylation expansion across CpG dinucleotides in specific gene promoters during carcinogenesis remains unexplored. Expansion of DNA methylation in some gene promoter regions, such as EFEMP1, one of the fibulin family, with tumor progression has been reported in several malignancies. We hypothesized that DNA hypermethylation in EFEMP1 promoter would expand with the tumor grade of IPMN. METHODS: A sample of 65 IPMNs and 30 normal pancreatic tissues was analyzed. IPMNs were divided into the following three subsets according to pathological findings: 31 with low-grade dysplasia (low grade), 11 with high-grade dysplasia (high grade), and 23 with associated invasive carcinoma (invasive Ca). Mutations in the KRAS or GNAS genes were analyzed by Sanger sequencing, and methylation status of two discrete regions within the EFEMP1 promoter, namely region 1 and region 2, was analyzed by bisulfite sequencing and fluorescent high-sensitive assay for bisulfite DNA (Hi-SA). Expression status of EFEMP1 was investigated by immunohistochemistry (IHC). RESULTS: KRAS mutations were detected in 39, 55, and 70 % of low-grade, high-grade, and invasive Ca, respectively. GNAS mutations were observed in 32, 55, and 22 % of low-grade, high-grade, and invasive Ca, respectively. The methylation of individual regions (region 1 or 2) in the EFEMP1 promoter was observed in 84, 91, and 87 % of low-grade, high-grade, and invasive Ca, respectively. However, simultaneous methylation of both regions (extensive methylation) was exclusively detected in 35 % of invasive Ca (p = 0.001) and five of eight IPMNs (63 %) with extensive methylation, whereas 20 of 57 (35.1 %) tumors of unmethylation or partial methylation of the EFEMP1 promoter region showed weak staining EFEMP1 in extracellular matrix (p = 0.422). In addition, extensive EFEMP1 methylation was particularly present in malignant tumors without GNAS mutations and associated with disease-free survival of patients with IPMNs (p < 0.0001). CONCLUSIONS: Extensive methylation of the EFEMP1 gene promoter can discriminate invasive from benign IPMNs with superior accuracy owing to their stepwise accumulation of tumor progression.

DOI： 10.1007/s00432-016-2164-x

The ATP6V1C2 (a vacuolar-ATPase gene) is a novel early prognosticator for colorectal cancer

Timothy J. Zumwalt, Kunitoshi Shigeyasu, Wenhao Weng, Yoshinaga Okugawa, Jinsei Miyoshi, Ajay Goel

CANCER RESEARCH 76 2016.7

Genome-wide enhancer analysis identifies PVT1 as an oncogenic enhancer of MYC

Kunitoshi Shigeyasu, Shusuke Toden, Takeshi Nagasaka, Toshiyoshi Fujiwara, C. Richard Boland, Ajay Goel

CANCER RESEARCH 76 2016.7

Exportin-5 Is an Oncogene and a Potential Prognostic Marker in Colorectal Cancer

Kunitoshi Shigeyasu, Shusuke Toden, C. R. Boland, Ajay Goel

GASTROENTEROLOGY 150 ( 4 ) S1013 - S1013 2016.4

MGMT Inactivation Arrest Tumor Growth and Serves As a Promising Predictive Biomarker for Treatment Response in Colorectal Cancer

Yoshiko Mori, Takeshi Nagasaka, Hiroshi Tazawa, Yuzo Umeda, Kunitoshi Shigeyasu, Kazuhiro Yoshida, Ajay Goel, Toshiyoshi Fujiwara

GASTROENTEROLOGY 150 ( 4 ) S1013 - S1013 2016.4

A microRNA Network Mediates Chemoresistance in Colorectal Cancer Stem Cells

Shusuke Toden, Kunitoshi Shigeyasu, Yoshinaga Okugawa, Wenhao Weng, C. R. Boland, Ajay Goel

GASTROENTEROLOGY 150 ( 4 ) S104 - S104 2016.4

Curcumin Inhibits Polycomb Repressive Complex 2 through lncRNA-PVT1 and Enhances Gemcitabine Sensitivity in Chemoresistant Pancreatic Cancer

Kazuhiro Yoshida, Shusuke Toden, Wenhao Weng, Kunitoshi Shigeyasu, Haiyong Han, Carlos Becerra, C. R. Boland, Ajay Goel

GASTROENTEROLOGY 150 ( 4 ) S624 - S624 2016.4

Gasdermin C Is Upregulated by Inactivation of Transforming Growth Factor β Receptor Type II in the Presence of Mutated Apc, Promoting Colorectal Cancer Proliferation. Reviewed International journal

Masashi Miguchi, Takao Hinoi, Manabu Shimomura, Tomohiro Adachi, Yasufumi Saito, Hiroaki Niitsu, Masatoshi Kochi, Haruki Sada, Yusuke Sotomaru, Tsuneo Ikenoue, Kunitoshi Shigeyasu, Kohji Tanakaya, Yasuhiko Kitadai, Kazuhiro Sentani, Naohide Oue, Wataru Yasui, Hideki Ohdan

PloS one 11 ( 11 ) e0166422 2016

Language：English Publishing type：Research paper (scientific journal) Publisher：PUBLIC LIBRARY SCIENCE

Mutations in TGFBR2, a component of the transforming growth factor (TGF)-β signaling pathway, occur in high-frequency microsatellite instability (MSI-H) colorectal cancer (CRC). In mouse models, Tgfbr2 inactivation in the intestinal epithelium accelerates the development of malignant intestinal tumors in combination with disruption of the Wnt-β-catenin pathway. However, no studies have further identified the genes influenced by TGFBR2 inactivation following disruption of the Wnt-β-catenin pathway. We previously described CDX2P-G19Cre;Apcflox/flox mice, which is stochastically null for Apc in the colon epithelium. In this study, we generated CDX2P-G19Cre;Apcflox/flox;Tgfbr2flox/flox mice, with simultaneous loss of Apc and Tgfbr2. These mice developed tumors, including adenocarcinoma in the proximal colon. We compared gene expression profiles between tumors of the two types of mice using microarray analysis. Our results showed that the expression of the murine homolog of GSDMC was significantly upregulated by 9.25-fold in tumors of CDX2P-G19Cre;Apcflox/flox;Tgfbr2flox/flox mice compared with those of CDX2P-G19Cre;Apcflox/flox mice. We then investigated the role of GSDMC in regulating CRC tumorigenesis. The silencing of GSDMC led to a significant reduction in the proliferation and tumorigenesis of CRC cell lines, whereas the overexpression of GSDMC enhanced cell proliferation. These results suggested that GSDMC functioned as an oncogene, promoting cell proliferation in colorectal carcinogenesis. In conclusion, combined inactivation of both Apc and Tgfbr2 in the colon epithelium of a CRC mouse model promoted development of adenocarcinoma in the proximal colon. Moreover, GSDMC was upregulated by TGFBR2 mutation in CRC and promoted tumor cell proliferation in CRC carcinogenesis, suggesting that GSDMC may be a promising therapeutic target.

DOI： 10.1371/journal.pone.0166422

The generation of colorectal cancer mouse model based on microsatellite instability and the identification of transforming growth factor-beta signal target Reviewed

Miguchi Masashi, Hinoi Takao, Shimomura Manabu, Adachi Tomohiro, Saito Yasufumi, Niitsu Hiroaki, Kochi Masatoshi, Sotomaru Yusuke, Ijichi Hideaki, Ikenoue Tsuneo, Shigeyasu Kunitoshi, Tanakaya Kohji, Sentani Kazuhiro, Oue Naohide, Yasui Wataru, Ohdan Hideki

CANCER RESEARCH 75 2015.8

Fluorescence virus-guided capturing system of human colorectal circulating tumour cells for non-invasive companion diagnostics. Reviewed International journal

Kunitoshi Shigeyasu, Hiroshi Tazawa, Yuuri Hashimoto, Yoshiko Mori, Masahiko Nishizaki, Hiroyuki Kishimoto, Takeshi Nagasaka, Shinji Kuroda, Yasuo Urata, Ajay Goel, Shunsuke Kagawa, Toshiyoshi Fujiwara

Gut 64 ( 4 ) 627 - 35 2015.4

Language：English Publishing type：Research paper (scientific journal) Publisher：BMJ PUBLISHING GROUP

BACKGROUND: Molecular-based companion diagnostic tests are being used with increasing frequency to predict their clinical response to various drugs, particularly for molecularly targeted drugs. However, invasive procedures are typically required to obtain tissues for this analysis. Circulating tumour cells (CTCs) are novel biomarkers that can be used for the prediction of disease progression and are also important surrogate sources of cancer cells. Because current CTC detection strategies mainly depend on epithelial cell-surface markers, the presence of heterogeneous populations of CTCs with epithelial and/or mesenchymal characteristics may pose obstacles to the detection of CTCs. METHODS: We developed a new approach to capture live CTCs among millions of peripheral blood leukocytes using a green fluorescent protein (GFP)-expressing attenuated adenovirus, in which the telomerase promoter regulates viral replication (OBP-401, TelomeScan). RESULTS: Our biological capturing system can image epithelial and mesenchymal tumour cells with telomerase activities as GFP-positive cells. After sorting, direct sequencing or mutation-specific PCR can precisely detect different mutations in KRAS, BRAF and KIT genes in epithelial, mesenchymal or epithelial-mesenchymal transition-induced CTCs, and in clinical blood samples from patients with colorectal cancer. CONCLUSIONS: This fluorescence virus-guided viable CTC capturing method provides a non-invasive alternative to tissue biopsy or surgical resection of primary tumours for companion diagnostics.

DOI： 10.1136/gutjnl-2014-306957

TMCO3-A Novel Na+/H+ Transporter Protein With a Promising Potential As a Prognostic Biomarker in Colorectal Cancer

Kunitoshi Shigeyasu, Yoshinaga Okugawa, Shusuke Toden, Ajay Goel

GASTROENTEROLOGY 148 ( 4 ) S353 - S353 2015.4

Clinical Significance of MLH1 Methylation and CpG Island Methylator Phenotype as Prognostic Markers in Patients with Gastric Cancer. Reviewed International journal

Kunitoshi Shigeyasu, Takeshi Nagasaka, Yoshiko Mori, Naosuke Yokomichi, Takashi Kawai, Tomokazu Fuji, Keisuke Kimura, Yuzo Umeda, Shunsuke Kagawa, Ajay Goel, Toshiyoshi Fujiwara

PloS one 10 ( 6 ) e0130409 2015

Language：English Publishing type：Research paper (scientific journal) Publisher：PUBLIC LIBRARY SCIENCE

BACKGROUND: To improve the outcome of patients suffering from gastric cancer, a better understanding of underlying genetic and epigenetic events in this malignancy is required. Although CpG island methylator phenotype (CIMP) and microsatellite instability (MSI) have been shown to play pivotal roles in gastric cancer pathogenesis, the clinical significance of these events on survival outcomes in patients with gastric cancer remains unknown. METHODS: This study included a patient cohort with pathologically confirmed gastric cancer who had surgical resections. A cohort of 68 gastric cancers was analyzed. CIMP and MSI statuses were determined by analyzing promoter CpG island methylation status of 28 genes/loci, and genomic instability at 10 microsatellite markers, respectively. A Cox's proportional hazards model was performed for multivariate analysis including age, stage, tumor differentiation, KRAS mutation status, and combined CIMP/MLH1 methylation status in relation to overall survival (OS). RESULTS: By multivariate analysis, longer OS was significantly correlated with lower pathologic stage (P = 0.0088), better tumor differentiation (P = 0.0267) and CIMP-high and MLH1 3' methylated status (P = 0.0312). Stratification of CIMP status with regards to MLH1 methylation status further enabled prediction of gastric cancer prognosis. CONCLUSIONS: CIMP and/or MLH1 methylation status may have a potential to be prognostic biomarkers for patients with gastric cancer.

DOI： 10.1371/journal.pone.0130409

Molecular diagnosis and therapy for occult peritoneal metastasis in gastric cancer patients. Reviewed International journal

Shunsuke Kagawa, Kunitoshi Shigeyasu, Michihiro Ishida, Megumi Watanabe, Hiroshi Tazawa, Takeshi Nagasaka, Yasuhiro Shirakawa, Toshiyoshi Fujiwara

World journal of gastroenterology 20 ( 47 ) 17796 - 803 2014.12

Language：English Publishing type：Research paper (scientific journal) Publisher：BAISHIDENG PUBLISHING GROUP INC

To apply an individualized oncological approach to gastric cancer patients, the accurate diagnosis of disease entities is required. Peritoneal metastasis is the most frequent mode of metastasis in gastric cancer, and the tumor-node-metastasis classification includes cytological detection of intraperitoneal cancer cells as part of the staging process, denoting metastatic disease. The accuracy of cytological diagnosis leaves room for improvement; therefore, highly sensitive molecular diagnostics, such as an enzyme immunoassay, reverse transcription polymerase chain reaction, and virus-guided imaging, have been developed to detect minute cancer cells in the peritoneal cavity. Molecular targeting therapy has also been spun off from basic research in the past decade. Although conventional cytology is still the mainstay, novel approaches could serve as practical complementary diagnostics to cytology in near future.

DOI： 10.3748/wjg.v20.i47.17796

Spontaneous rupture of a hepatic angiomyolipoma: Report of a case. Reviewed

Hideki Aoki, Takashi Arata, Toshiaki Morihiro, Nobuhiko Kanaya, Sho Takeda, Kenta Sui, Kunitoshi Shigeyasu, Koh Katsuda, Kohji Tanakaya, Hitoshi Takeuchi

Clinical journal of gastroenterology 7 ( 5 ) 429 - 33 2014.10

Language：English Publishing type：Research paper (scientific journal) Publisher：Springer-Verlag Tokyo

A 70-year-old female experienced sudden onset of back pain on the right side and was admitted to our hospital in December 2010. Abdominal computed tomography revealed an S7 hepatic mass measuring 7 cm in diameter accompanied by a subcapsular hematoma. Emergency angiography confirmed the diagnosis of a ruptured hepatic mass, and hemostasis was carried out by embolization of A8 and A7 of the liver. A right hepatic lobectomy was carried out 39 days following transarterial embolization. Although almost all aspects of the tumor were necrotic, residual tumor cells stained positive for HMB-45, and negative for α-SMA, S-100, CD 34, c-kit, CAM 5.2, and hepatocytes. The MIB-1 index was 2 %. Pathological diagnosis was hepatic angiomyolipoma (HAML). The patient has shown no signs of recurrence at 42 months following surgery. Here, we report on this case of spontaneous HAML rupture and discuss therapeutic strategies for HAML and ruptured hepatic tumors.

DOI： 10.1007/s12328-014-0517-z

Early detection of metachronous bile duct cancer in Lynch syndrome: report of a case. Reviewed

Kunitoshi Shigeyasu, Kohji Tanakaya, Takeshi Nagasaka, Hideki Aoki, Toshiyoshi Fujiwara, Kokichi Sugano, Hideki Ishikawa, Teruhiko Yoshida, Yoshihiro Moriya, Yoichi Furukawa, Ajay Goel, Hitoshi Takeuchi

Surgery today 44 ( 10 ) 1975 - 81 2014.10

Language：English Publishing type：Research paper (scientific journal) Publisher：SPRINGER

Lynch syndrome is an autosomal dominant disease associated with a high incidence of colorectal, endometrial, stomach, ovarian, pancreatic, ureter and renal pelvis, bile duct and brain tumors. The syndrome can also include sebaceous gland adenomas and keratoacanthomas, and carcinoma of the small bowel. The lifetime risk for bile duct cancer in patients with Lynch syndrome is approximately 2 %. The present report describes a case of Lynch syndrome with metachronous bile duct cancer diagnosed at an early stage. The patient was a 73-year-old Japanese male who underwent a successful left lobectomy of the liver, and there was no sign of recurrence for 2 years postoperative. However, this patient harbored a germline mutation in MLH1, which prompted diagnostic examinations for noncolorectal tumors when a periodic surveillance blood examination showed abnormal values of hepatobiliary enzymes. Although most patients with bile duct cancer are diagnosed at an advanced stage, the bile duct cancer was diagnosed at an early stage in the present patient due to the observation of the gene mutation and the preceding liver tumor. This case illustrates the importance of continuous surveillance for extracolonic tumors, including bile duct cancer, in patients with Lynch syndrome.

DOI： 10.1007/s00595-013-0669-3

Tumor-Infiltrating Lymphocytes Can Be Used to Screen for Lynch Syndrome-A Case Report Reviewed

田中屋宏爾, 金谷信彦, 重安邦俊, 國友知義, 青木秀樹, 竹内仁司, 山崎理恵

癌と化学療法 41 ( 12 ) 1602 - 4 2014

Language：Japanese Publishing type：Research paper (scientific journal) Publisher：Japanese Journal of Cancer and Chemotherapy Publishers Inc.

Lynch syndrome is an inherited syndrome associated with the development of colorectal and various other cancers. A 65- year-old male underwent a laparoscopic-assisted right hemi-colectomy for ascending colon cancer (cStage II). Histologically, his tumor was diagnosed as a poorly differentiated adenocarcinoma. Lymphocytic reactions, such as tumor-infiltrating lymphocytes (TIL), and Crohn's-like reactions, were observed. Genetic testing revealed the presence of a pathogenic mutation in the MLH1. In the Lynch syndrome, the most frequently observed findings include the accumulation of mutations, and an early onset of familial colon cancer. Although the case presented here did not show the typical clinical findings of Lynch syndrome, histological examination of the lymphocytic reactions proved useful for screening for Lynch syndrome. Herein, we establish the important role of the pathologist in alerting the clinician to the possibility of Lynch syndrome when the findings of TIL and Crohn's-like reactions are detected.

A Case of Gastric Cancer Developed after Pylorus-Preserving Gastrectomy in a Patient with Lynch Syndrome Reviewed

金谷信彦, 田中屋宏爾, 重安邦俊, 國友知義, 山崎理恵, 青木秀樹, 竹内仁司

癌と化学療法 41 ( 12 ) 2264 - 5 2014

Language：Japanese Publishing type：Research paper (scientific journal) Publisher：Japanese Journal of Cancer and Chemotherapy Publishers Inc.

Lynch syndrome is an inherited autosomal dominant disorder caused by germ-line mutation of mismatch repair genes, in which a malignant tumor develops at a young age in the colon, endometrium, stomach, or other tissues. A 54-year-old patient with gastric cancer received pylorus-preserving gastrectomy, and a genetic examination confirmed a pathological variation of the MLH1 gene. Five years after surgery, an upper gastrointestinal endoscopy revealed a residual 0 -IIa+IIc gastric tumor approximately 2 cm in size extending from the anastomotic site to the lesser curvature side of the stomach. The remaining stomach was completely removed. The final diagnosis was T1b (SM) N1M0, StageIB gastric cancer. Microsatellite instability was positive, and we attributed the cancer to Lynch syndrome. In Lynch syndrome, the risk of multicentric gastric cancer is higher than normal, and for the initial therapy, preventive total gastrectomy should be considered as an option.

Advanced hepatocellular carcinoma with lymph node metastases showing epithelial to mesenchymal transition effectively treated with systemic chemotherapy: Report of a case. Reviewed International journal

Hiroshi Sadamori, Takahito Yagi, Kunitoshi Shigeyasu, Yuzo Umeda, Masahiro Sugihara, Naosuke Yokomichi, Toshiaki Ohara, Naoshi Nishida, Takeshi Nagasaka, Ajay Goel, Toshiyoshi Fujiwara

Hepatology research : the official journal of the Japan Society of Hepatology 43 ( 12 ) 1368 - 73 2013.12

Language：English Publishing type：Research paper (scientific journal) Publisher：WILEY

We present a case in which combination chemotherapy was used to successfully treat hepatocellular carcinoma (HCC) with rapid progression of lymph node (LN) metastases after liver resection. In addition, epithelial to mesenchymal transition (EMT) markers were examined immunohistochemically. A 43-year-old man who had been diagnosed with HCC showed an enlarged LN near the hepatic artery proper. After extended left lobectomy with lymphadenectomy in the hepatoduodenal ligament, he experienced rapid progression of metastases to the para-aortic and mediastinal LN. Partial remission was achieved after induction and maintenance of combination chemotherapy using etoposide, carboplatin, epirubicin and 5-fluorouracil. As a consequence of this treatment, the patient survived 10 months. Immunohistochemical studies demonstrated that HCC cells in the metastatic LN showed low expression of E-cadherin and high expression of N-cadherin and vimentin, indicating EMT. Combination chemotherapy may prove effective for patients with HCC accompanied by LN metastases that show features of EMT.

DOI： 10.1111/hepr.12080

MGMT Methylation As a Novel Biomarker for the Identification of Stage III Colorectal Cancers At High-Risk of Disease Recurrence Following Curative Surgery Reviewed

Yoshiko Mori, Takeshi Nagasaka, Hiroshi Tazawa, Yuzo Umeda, Tatsuya Morikawa, Nobuhito Kubota, Kazuhiro Yoshida, Yuko Takehara, Naosuke Yokomichi, Kiyoto Takehara, Kunitoshi Shigeyasu, Akihiro Nyuya, Rikiya Shiwaku, Manabu Suno, Naoshi Nishida, Toshiyoshi Fujiwara, Ajay Goel

GASTROENTEROLOGY 144 ( 5 ) S85 - S85 2013.5

Accumulation of Epigenetic Alteration Could Predict Malignant Formation in Intraductal Papillary Mucinous Neoplasm (IPMN) Reviewed

Kazuhiro Yoshida, Takeshi Nagasaka, Yuzo Umeda, Naosuke Yokomichi, Yoshiko Mori, Nobuhito Kubota, Tatsuya Morikawa, Yuko Takehara, Kiyoto Takehara, Kunitoshi Shigeyasu, Akihiro Nyuya, Rikiya Shiwaku, Manabu Suno, Naoshi Nishida, Toshiyoshi Fujiwara, Ajay Goel

GASTROENTEROLOGY 144 ( 5 ) S98 - S98 2013.5

Genetic and Epigenetic Alterations in the Netrin-1 Receptors, UNC5c and DCC, Constitutes a Previously Unrecognized Pathway in Gastric Cancer Progression Reviewed

Nobuhito Kubota, Takeshi Nagasaka, Keisuke Toda, Yoshiko Mori, Tatsuya Morikawa, Yuzo Umeda, Naosuke Yokomichi, Kazuhiro Yoshida, Yuko Takehara, Kiyoto Takehara, Akihiro Nyuya, Rikiya Shiwaku, Kunitoshi Shigeyasu, Manabu Suno, Naoshi Nishida, Toshiyoshi Fujiwara, Ajay Goel

GASTROENTEROLOGY 144 ( 5 ) S527 - S527 2013.5

Cytokeratin 19 Staining Is a Novel, Predictive Biomarker for Extra-Hepatic Metastasis in Hepatocellular Carcinoma Reviewed

Naosuke Yokomichi, Takeshi Nagasaka, Naoshi Nishida, Yuzo Umeda, Yoshiko Mori, Tatsuya Morikawa, Nobuhito Kubota, Kazuhiro Yoshida, Yuko Takehara, Kiyoto Takehara, Kunitoshi Shigeyasu, Akihiro Nyuya, Rikiya Shiwaku, Manabu Suno, Toshiyoshi Fujiwara, Ajay Goel

GASTROENTEROLOGY 144 ( 5 ) S719 - S720 2013.5

Fecal DNA Methylation Assay for the Identification of a Multiple Gastrointestinal Cancers Including Pancreatic Caner Reviewed

Tatsuya Morikawa, Takeshi Nagasaka, Kazuhiro Yoshida, Yoshiko Mori, Nobuhito Kubota, Yuko Takehara, Naosuke Yokomichi, Naoshi Nishida, Kiyoto Takehara, Kunitoshi Shigeyasu, Akihiro Nyuya, Rikiya Shiwaku, Manabu Suno, Toshiyoshi Fujiwara, Ajay Goel

GASTROENTEROLOGY 144 ( 5 ) S601 - S602 2013.5

Multicenter phase II study of S-1 and docetaxel combination chemotherapy for advanced or recurrent gastric cancer patients with peritoneal dissemination. Reviewed International journal

Kunitoshi Shigeyasu, Shunsuke Kagawa, Futoshi Uno, Masahiko Nishizaki, Hiroyuki Kishimoto, Akira Gochi, Toshikazu Kimura, Takaomi Takahata, Yasuyuki Nonaka, Motoki Ninomiya, Toshiyoshi Fujiwara

Cancer chemotherapy and pharmacology 71 ( 4 ) 937 - 43 2013.4

Language：English Publishing type：Research paper (scientific journal) Publisher：SPRINGER

PURPOSE: Peritoneal dissemination is the most frequent and life-threatening mode of metastasis and recurrence in patients with gastric cancer. A multicenter phase II study was designed to evaluate the efficacy and tolerability of S-1 and docetaxel combination chemotherapy regimen for the treatment of advanced or recurrent gastric cancer patients with peritoneal dissemination. METHODS: Nineteen patients with histologically confirmed unresectable or recurrent gastric cancer with peritoneal dissemination were enrolled. Oral S-1 at 80 mg/m(2)/day was administered twice daily for 2 weeks, followed by 1 drug-free week. Docetaxel infusion at 40 mg/m(2) was performed on day 1, simultaneous with S-1 administration. The primary endpoints were overall survival (OS) and time to progression (TTP). The secondary endpoints were the response rates and safety status. RESULTS: Patients received a median of 4 cycles of the S-1 and docetaxel regimen (range 1-43). The disease control rate was 73.7 % (14/19). Median overall survival was 459 days (15.3 months), while median time to progression was 212 days (7.1 months). Neutropenia was the most common type of toxicity (n = 7, 36.8 %). CONCLUSIONS: Combination chemotherapy with S-1 and docetaxel is a tolerable and effective treatment for advanced or recurrent gastric cancer patients with peritoneal dissemination.

DOI： 10.1007/s00280-013-2086-0

A highly sensitive detection system of genetic alterations in circulating tumor cells using a telomerase-specific replication-competent adenovirus

Kunitoshi Shigeyasu, Yuuri Hashimoto, Tatsuya Morikawa, Yoshiko Mori, Dong-Sheng Sun, Shunsuke Kagawa, Futoshi Uno, Hiroshi Tazawa, Takeshi Nagasaka, Satoru Kyo, Hiroyuki Mizuguchi, Yasuo Urata, Toshiyoshi Fujiwara

CANCER RESEARCH 72 2012.4

Expansion of CpG methylation in the SFRP2 promoter region during colorectal tumorigenesis. Reviewed

Masanori Takeda, Takeshi Nagasaka, Sun Dong-Sheng, Hiroyuki Nishie, Tetsuhiro Oka, Eiji Yamada, Yoshiko Mori, Kunitoshi Shigeyasu, Tatsuya Morikawa, Satoshi Mizobuchi, Toshiyoshi Fujiwara

Acta medica Okayama 65 ( 3 ) 169 - 77 2011.6

Language：English Publishing type：Research paper (scientific journal) Publisher：OKAYAMA UNIV MED SCHOOL

Secreted frizzled-related protein 2, (SFRP2) is a Wnt inhibitor whose promoter CpGs were recently found to be methylated at high frequency in colorectal cancers (CRCs). We hypothesized that the pattern of SFRP2 methylation may differ throughout the promoter during progressive tumorigenesis. Using combined bisulfite restriction analysis (COBRA), two methylation-sensitive regions (Regions A and B) of the SFRP2 promoter were investigated in 569 specimens of colorectal tissue:222 CRCs, 103 adenomatous polyps (APs), 208 normal colonic mucosa from CRC patients (N-Cs), and 36 normal colonic mucosa from subjects with no evidence of colorectal neoplasia at colonoscopy (N-Ns). Extensive (including both Regions A and B) and partial (either Region A or B) SFRP2 methylation levels were found in 61.7% and 24.8% of CRCs, 8.7% and 37.9% of APs, 3.9% and 39.9% of N-Cs, and 0% and 30.6% of N-Ns, respectively. Extensive methylation of the SFRP2 promoter was present primarily in CRCs, while partial methylation was common in APs. Whereas APs with the KRAS mutant showed no correlation to any pattern of SFRP2 methylation, extensive methylation of the SFRP2 promoter was significantly associated with KRAS mutant CRCs (p＜.0001), suggesting that genetic alteration in the RAS-RAF pathway might precede the spread of CpG methylation through the SFRP2 promoter, which is observed in over 60% of advanced colorectal tumors.

DOI： 10.18926/AMO/46628

当院における肝癌治療の変遷

竹内仁司, 重安邦俊, 大原利章, 荒田尚, 村田宏, 金澤卓, 中川仁志, 田中屋宏爾, 金川泰一朗, 安井義政, 大田剛由, 詫間義隆, 牧野泰裕

山口県医学会誌 ( 41 ) 170 - 170 2007.3

医師個人の技術評価におけるPOSSUM scoring systemの有用性

竹内仁司, 安井義政, 金川泰一朗, 田中屋宏爾, 中川仁志, 金澤卓, 村田宏, 荒田尚, 大原利章, 重安邦俊, 愛洲尚哉

日本外科学会雑誌 108 ( 臨増2 ) 715 - 715 2007.3

　 PREV - NEXT 　

1