Faculty Profiles - SHIGEYASU Kunitoshi

Papers - SHIGEYASU Kunitoshi

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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

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