Early prediction of treatment outcome for lenvatinib using 18F-FDG PET/CT in patients with unresectable or advanced thyroid carcinoma refractory to radioiodine treatment: a prospective, multicentre, non-randomised study.
Satoshi Takeuchi, Kenji Hirata, Keiichi Magota, Shiro Watanabe, Rika Moku, Akihiko Shiiya, Jun Taguchi, Shin Ariga, Tomohiro Goda, Yoshihito Ohhara, Takurou Noguchi, Yasushi Shimizu, Ichiro Kinoshita, Rio Honma, Yasushi Tsuji, Akihiro Homma, Hirotoshi Dosaka-Akita
EJNMMI research, 13, 1, 69, 69, 2023年07月17日, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND: Lenvatinib is widely used to treat unresectable and advanced thyroid carcinomas. We aimed to determine whether 18F-fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) performed 1 week after lenvatinib treatment initiation could predict treatment outcomes. RESULTS: This was a prospective, nonrandomised, multicentre study. Patients with pathologically confirmed differentiated thyroid carcinoma (DTC) and lesions refractory to radioiodine treatment were eligible for inclusion. Patients were treated with 24 mg lenvatinib as the initial dose and underwent PET/CT examination 1 week after treatment initiation. Contrast-enhanced CT was scheduled at least 4 weeks later as the gold standard for evaluation. The primary endpoint was to evaluate the discrimination power of maximum standardised uptake value (SUVmax) obtained by PET/CT compared to that obtained by contrast-enhanced CT. Evaluation was performed using the area under the receiver operating characteristic (ROC-AUC) curve. Twenty-one patients were included in this analysis. Receiver operating characteristic (ROC) curve analysis yielded an AUC of 0.714 for SUVmax after 1 week of lenvatinib treatment. The best cut-off value for the treatment response for SUVmax was 15.211. The sensitivity and specificity of this cut-off value were 0.583 and 0.857, respectively. The median progression-free survival was 26.3 months in patients with an under-cut-off value and 19.7 months in patients with an over-cut-off value (P = 0.078). CONCLUSIONS: The therapeutic effects of lenvatinib were detected earlier than those of CT because of decreased FDG uptake on PET/CT. PET/CT examination 1 week after the initiation of lenvatinib treatment may predict treatment outcomes in patients with DTC. TRIAL REGISTRATION: This trial was registered in the University Hospital Medical Information Network (UMIN) Clinical Trials Registry (number UMIN000022592) on 6 June, 2016.

切除不能/転移性PPGLにおける初回I-131MIBG治療による総糖代謝量の変化と予後の関係性の解析　　　　　　　　　　　　　　　
竹中 淳規, 渡邊 史郎, 安部 崇重, 土川 貴裕, 竹内 啓, 平田 健司, 木村 理奈, 若林 直人, 篠原 信雄, 工藤 與亮
核医学, 60, Suppl., S216, S216, (一社)日本核医学会, 2023年
日本語

EGFR inhibition in EGFR-mutant lung cancer cells perturbs innate immune signaling pathways in the tumor microenvironment.
Akihiko Shiiya, Takuro Noguchi, Utano Tomaru, Shin Ariga, Yuta Takashima, Yoshihito Ohhara, Jun Taguchi, Satoshi Takeuchi, Yasushi Shimizu, Ichiro Kinoshita, Tomonobu Koizumi, Yoshihiro Matsuno, Naofumi Shinagawa, Jun Sakakibara-Konishi, Hirotoshi Dosaka-Akita
Cancer science, 2022年12月18日, ［国際誌］
英語, 研究論文（学術雑誌）, Epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) elicit potent cell cycle arrest in EGFR-mutant non-small-cell lung cancer (NSCLC) cells. However, little is known about the mechanisms through which these drugs alter the tumor phenotype that contributes to the immune escape of EGFR-mutant cells. Using EGFR-mutant NSCLC cell lines and tissue samples from patients, we investigated the changes in immune checkpoints expressed in tumor cells following EGFR inhibition. Subsequently, we also analyzed the role of soluble factors from the dying tumor cells in the activation of immune signaling pathways involved in therapy resistance. Upon EGFR-TKI treatment, we found that EGFR-mutant cells upregulated the expression of innate immune checkpoint CD24 in vitro. We then analyzed biopsy samples from six patients who developed resistance to a first-generation EGFR-TKI without the acquired T790M mutation. Immunohistochemistry revealed that levels of tumor CD24 expression were increased upon treatment compared with those from pre-treatment samples. Monocyte-derived macrophages facilitated antibody-dependent cellular phagocytosis when EGFR-TKI-treated EGFR-mutant cells were incubated with anti-CD24 antibodies in vitro, suggesting that CD24 may be a therapeutical target for EGFR-mutant lung cancer. Moreover, EGFR inhibition accelerated the release of cell-free DNA (cfDNA) from dying tumor cells, which activated the type I interferon signaling pathways in human THP-1 monocytes in a stimulator of interferon genes-dependent manner. Our study indicates that EGFR inhibition in EGFR-mutant NSCLC cells fosters a tumor microenvironment associated with immune escape. Thus, CD24 targeted therapy and cfDNA monitoring may contribute to improved treatment outcomes in patients with EGFR-mutant NSCLC.

Expression of karyopherin alfa 2 and karyopherin beta 1 correlate with poor prognosis in gastric cancer.
Yoshihito Ohhara, Ichiro Kinoshita, Akira Suzuki, Makoto Imagawa, Jun Taguchi, Takuro Noguchi, Satoshi Takeuchi, Yasushi Shimizu, Hideyuki Seki, Junichi Suzuki, Hirotoshi Dosaka-Akita
Oncology, 2022年10月21日, ［国際誌］
英語, 研究論文（学術雑誌）, INTRODUCTION: Karyopherin alfa 2 (KPNA2) and karyopherin beta 1 (KPNB1), constitute nuclear transport protein complexes involved in nuclear import, and are significant in tumor progression. Although high KPNA2 expression was associated with poor prognosis in solid tumors, the relationship between KPNA2 and KPNB1 expression and their prognostic role in gastric cancer (GC) remains unclear. METHODS: Immunohistochemistry was used to correlate the expression of KPNA2 and KPNB1 with various features, including clinicopathologic characteristics in 130 patients with GC and survival in 94 patients with invasive lesions extending to the submucosa or deeper. RESULTS: High expression of KPNA2 and KPNB1 was found in 25% and 36% of the patients, respectively. Both were significantly related to tumor depth, lymph node metastasis, lymphatic invasion, venous invasion, and Ki-67 expression. KPNA2 expression was significantly related to that of KPNB1 (P < 0.001). Patients with high KPNB1 expression had poorer prognosis than those with low expression (P = 0.027), as was also observed in case of KPNA2 (P < 0.001). Patients with high expression of both KPNA2 and KPNB1 accounted for 18% and had a poorer prognosis than those with high expression of either and those with low expression of both (P = 0.001). Multivariate analysis revealed that high expression of both KPNA2 and KPNB1 was an independent prognostic factor in patients with GC (HR 3.46, 95% CI 1.64-2.73, P = 0.001). CONCLUSION: KPNA2 expression was correlated with KPNB1 expression, and high co-expression of KPNA2 and KPNB1 may represent a strong prognostic biomarker in GC.

Risk Factor Analysis for the Occurrence of Severe Adverse Effects in Eribulin Treatment.
Yoshitaka Saito, Yoh Takekuma, Takashi Takeshita, Takuro Noguchi, Satoshi Takeuchi, Yasushi Shimizu, Ichiro Kinoshita, Hirotoshi Dosaka-Akita, Mitsuru Sugawara
Anticancer research, 42, 7, 3693, 3700, 2022年07月, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND/AIM: Eribulin is an effective chemotherapeutic agent for the treatment of metastatic breast cancer and advanced or metastatic soft-tissue sarcomas. However, severe adverse effects (SAEs) occur in 30-40% of the patients, and significantly reduce the patients' quality of life and disturb the recommended treatment schedules. Neutropenia is the main cause of treatment suspension, delay, and/or dose reductions, also leading to relative dose intensity reduction. This study aimed to examine the risk factors for SAE occurrence after eribulin treatment. PATIENTS AND METHODS: Eighty patients with metastatic breast cancer or advanced or metastatic soft tissue sarcoma who received eribulin were retrospectively evaluated. Risk factors for SAE occurrence in the first cycle were primarily assessed. In addition, factors associated with SAE occurrence during all treatment cycles were evaluated. RESULTS: SAEs in the first cycle occurred in 45% of patients. The primary SAE was neutropenia (91.7%). The incidence of SAEs during all treatment cycles was 61.3%. Multivariate analyses suggested that lower baseline neutrophil and hemoglobin levels were risk factors for SAE occurrence and severe neutropenia incidence in the first cycle. An independent factor associated with SAE occurrence during all cycles was age ≥65 years and a tendency was confirmed for baseline anemia. CONCLUSION: Baseline neutropenia and anemia were risk factors for SAE occurrence during the first eribulin treatment cycle. Age ≥65 years was also associated with SAE occurrence during all treatment cycles. Patients with these risk factors should be carefully monitored for assessment and prophylaxis.

Suitability of Oral Rehydration Solution (ORS) for Use in the Cisplatin Short Hydration Method.
Yoshitaka Saito, Yoh Takekuma, Masaki Kobayashi, Naofumi Shinagawa, Takuro Noguchi, Satoshi Takeuchi, Yasushi Shimizu, Ichiro Kinoshita, Hirotoshi Dosaka-Akita, Mitsuru Sugawara
Anticancer research, 42, 6, 3185, 3193, 2022年06月, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND/AIM: Short hydration is a method to change partial intravenous hydration to oral to administer cisplatin (CDDP); however, the most suitable form of oral hydration is unknown. This study aimed to determine whether oral rehydration solution (ORS) affects CDDP-induced nephrotoxicity (CIN) and electrolyte imbalance. PATIENTS AND METHODS: Lung cancer patients (n=200) who had received CDDP-including regimens (CDDP dosage ≥75 mg/m2) were retrospectively evaluated. We used logistic analysis to evaluate whether ORS intake could be a preventive factor for CIN (≥grade 2 serum creatinine elevation). Moreover, incidence of CIN and electrolyte imbalance and the variation in serum creatinine and electrolyte levels were compared between ORS and non-ORS (control) patients. RESULTS: CIN occurred in 9.8% of ORS patients, and 7.5% of non-ORS patients (p=0.79). The variation in serum creatinine level was also similar in both groups. Multivariate analysis suggested that ORS intake does not affect CIN, although CIN was associated with the coadministration of non-steroidal anti-inflammatory drugs and the presence of diabetes mellitus. The variations in serum electrolyte levels did not differ, and incidence of hyponatremia, hypokalemia, and hypochloremia was also similar between the groups. Moreover, patients in ORS group experienced significantly more anorexia compared to controls, and approximately 40% of the patients were unable to continue ORS intake. CONCLUSION: ORS intake in CDDP short hydration regimens does not affect CIN and CDDP-induced electrolyte imbalance; however, its intake is associated with the incidence of anorexia suggesting that ORS should not be used for oral hydration.

Long-term survival after repetitive lymphadenectomy for nodal recurrence of pancreatic neuroendocrine neoplasms: a report of two cases.
Yuma Hane, Takahiro Tsuchikawa, Satoshi Takeuchi, Kimitaka Tanaka, Yoshitsugu Nakanishi, Toshimichi Asano, Takehiro Noji, Yo Kurashima, Yuma Ebihara, Soichi Murakami, Toru Nakamura, Keisuke Okamura, Toshiaki Shichinohe, Satoshi Hirano
Journal of surgical case reports, 2021, 10, rjab446, 2021年10月, ［国際誌］
英語, Pancreatic neuroendocrine neoplasms (PNENs) are rare, but their incidence has increased in recent years. Curative surgery is recommended in several global guidelines for resectable PNENs. Lymph node recurrence after R0 resection for PNENs is infrequent, and global guidelines recommend surgical resection for recurrence, if resectable. However, data on the prognosis after surgical resection for nodal recurrence of PNENs are limited. We herein report two cases in which long-term survival was achieved after repetitive lymphadenectomy for nodal recurrence of PNENs. In both cases, the pathological findings for primary PNEN showed well-differentiated neuroendocrine neoplasms and R0 resection was successfully performed. The Ki-67 index increased with each resection in both cases. Both patients showed long-term survival (10 and 14 years, respectively). Repetitive lymphadenectomy for nodal recurrence of PNENs may improve patient prognosis.

Severe hypertriglyceridemia induced by S-1: Subsequent case series of four patients and further review of the literature.
Yoshitaka Saito, Yoh Takekuma, Satoshi Takeuchi, Yoshito Komatsu, Mitsuru Sugawara
International journal of clinical pharmacology and therapeutics, 59, 12, 787, 793, 2021年09月10日, ［国際誌］
英語, 研究論文（学術雑誌）, OBJECTIVE: We previously reported a case where S-1, containing tegafur, gimeracil, and oteracil potassium, induced severe hypertriglyceridemia. After the case, we regularly monitored serum lipid levels and surprisingly observed an additional 4 cases within 1.5 years. We here report the treatment process. CASE REPORT: At least 3 patients exhibited hyperlipidemia at baseline; in 2 of them, this was caused by previous fluoropyrimidine treatment. One patient experienced grade 4 hypertriglyceridemia, and the other 3 grade 3 hypertriglyceridemia. One patient developed temporary serum triglyceride elevation during the S-1 administration period, and the 3 experienced persistent elevation. The severity of serum triglyceride level worsened with increasing administration and peaked in cycles 2 - 6. Fenofibrate 80 - 160 mg/day and S-1 dose reduction were effective, with some significantly and others gradually decreasing to grade 0 - 1. DISCUSSION: The summarized clinical features are as follows: (1) Severe hypertriglyceridemia tends to appear after several treatment cycles and worsens with increasing administration. (2) It tends to occur in patients with hyperlipidemia at baseline. (3) Patients previously affected with fluoropyrimidines-induced hypertriglyceridemia can experience S-1 symptoms. (4) In some cases, it might decrease after the S-1 suspension period. (5) Fibrates and S-1 dose reductions were effective. As the final fluoropyrimidine product is fluorouracil, its presence or that of its metabolizing enzymes and the genetic background of the patients might have affected the results. We should be aware of the risk of temporal and asymptomatic occurrence of S-1-induced hypertriglyceridemia for early detection with appropriate treatment.

Phase II trial of combination treatment with S-1/cetuximab in patients with platinum-ineligible recurrent and/or metastatic squamous cell carcinoma of the head and neck.
Jun Taguchi, Yasushi Shimizu, Shin Ariga, Tomohiro Goda, Yoshihito Ohhara, Rio Honma, Takuro Noguchi, Satoshi Takeuchi, Ichiro Kinoshita, Toraji Amano, Takatsugu Mizumachi, Satoshi Kano, Miki Takahara, Takahisa Abe, Akihiro Homma, Hirotoshi Dosaka-Akita
International journal of clinical oncology, 26, 1, 51, 58, 2021年01月, ［国内誌］
英語, 研究論文（学術雑誌）, BACKGROUND: The standard of care for first-line treatment of recurrent and/or metastatic squamous cell carcinoma of the head and neck (R/M SCCHN) in patients who cannot tolerate platinum-based regimens has not been clarified. We aimed to develop a new treatment regimen for patients with R/M SCCHN who are ineligible for platinum-based therapy, by evaluating the effects and safety of tegafur/gimeracil/oteracil (S-1) and cetuximab. METHODS: Platinum-ineligibility was defined as: elderly (aged ≥ 75 years), poor PS, comorbidity, platinum resistance and refusal to undergo platinum-based therapy. Patients received S-1 (80 mg/m2/day for 14 days followed by a seven-day break) and cetuximab (initial dose, 400 mg/m2, followed by 250 mg/m2 weekly) until disease progression or unacceptable toxicity. The primary endpoint was overall response rate (ORR). RESULTS: Between September 2014 and September 2018, we enrolled 23 patients. Among the 21 patients who were evaluable, 20 were male [median age, 69 years (range 49-82)]. The ORR was 9 (43%) of 21 patients [95% confidence interval (CI) 22-66]. One and eight patients achieved complete response (CR) and partial response (PR), respectively. The median overall survival (OS) was 13.7 months (95% CI 9.0-18.3) and progression-free survival (PFS) was 5.7 months (95% CI 3.1-8.2). Grade 3/4 adverse events included acneiform rash and skin reactions (33%), hypomagnesemia (19%), hand-foot syndrome (14%), fatigue (14%), mucositis (10%), and anorexia (10%). CONCLUSIONS: Combination treatment with S-1 and cetuximab was effective and tolerated well by patients with platinum-ineligible R/M SCCHN. Registered clinical trial number: UMIN000015123.

Prevalence, clinical course, and predictive factors of immune checkpoint inhibitor monotherapy-associated hepatitis in Japan.
Takashi Kitagataya, Goki Suda, Kazunori Nagashima, Takehiko Katsurada, Koji Yamamoto, Megumi Kimura, Osamu Maehara, Ren Yamada, Taku Shigesawa, Kazuharu Suzuki, Akihisa Nakamura, Masatsugu Ohara, Machiko Umemura, Naoki Kawagishi, Masato Nakai, Takuya Sho, Mitsuteru Natsuizaka, Kenichi Morikawa, Koji Ogawa, Shunsuke Ohnishi, Yoshito Komatsu, Hiroo Hata, Satoshi Takeuchi, Takashige Abe, Jun Sakakibara-Konishi, Takanori Teshima, Akihiro Homma, Naoya Sakamoto
Journal of gastroenterology and hepatology, 35, 10, 1782, 1788, 2020年10月, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND AND AIM: Immune checkpoint inhibitors (ICI) have revolutionized anti-malignancy therapy and thus have been increasingly used. Although ICI may cause immune-related adverse events (irAE) in various organs, including the liver, the prevalence and predictive factors of irAE have not been clarified. METHODS: In this retrospective study, consecutive patients who had malignancies and were treated with ICI without other chemotherapeutic agents at Hokkaido University Hospital between 2014 and 2019 were screened. Patients were excluded if they were < 20 years old and had insufficient clinical data. RESULTS: Of the 233 patients screened, 202 patients met the inclusion criteria and were included in the analysis. The patients were aged 25-92 years, and 60.9% were male. The patients received nivolumab (n = 137), pembrolizumab (n = 45), ipilimumab (n = 17), atezolizumab (n = 2), and avelumab (n = 1). The prevalence of any grade and grade ≥ 3 irAE hepatitis was 8.4% (17/202) and 4.0% (8/202), respectively. irAE hepatitis occurred at a median duration of 42 days in any grade and 36 days in grade ≥ 3 after ICI initiation. The clinical course of grade ≥ 3 irAE hepatitis was generally favorable; however, 50% required corticosteroid treatment and two patients required additional mycophenolate mofetil. Female sex and history of ICI treatment were significantly associated with the incidence of grade ≥ 3 irAE hepatitis. CONCLUSIONS: Grade ≥ 3 irAE hepatitis was observed in 4.0% of the patients who were treated with ICI. Female sex and history of ICI treatment were significantly associated with the incidence of grade ≥ 3 irAE hepatitis.

Metachronous liver metastases after long-term follow-up of endoscopic resection for rectal neuroendocrine neoplasms: a report of three cases.
Yuma Hane, Takahiro Tsuchikawa, Kimitaka Tanaka, Yoshitsugu Nakanishi, Toshimichi Asano, Takehiro Noji, Yo Kurashima, Yuma Ebihara, Soichi Murakami, Toru Nakamura, Keisuke Okamura, Satoshi Takeuchi, Toshiaki Shichinohe, Satoshi Hirano
Surgical case reports, 6, 1, 22, 22, 2020年01月15日, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND: Rectal neuroendocrine neoplasms (NENs) are rare, but their incidence has increased in recent years. The metastasis rate is low in cases of a tumor diameter < 1 cm or depth of invasion lower than the submucosa; therefore, the European Neuroendocrine Tumor Society (ENETS) and the North American Neuroendocrine Tumor Society (NANETS) consensus guidelines recommend endoscopic resection. Since little has been reported on the long-term prognosis of endoscopic resection for rectal NEN, consensus is lacking regarding the follow-up period after endoscopic resection. CASE PRESENTATION: Here, we report three cases of metachronous liver metastasis after long-term follow-up of endoscopic mucosal resection (EMR) for rectal NEN. The pathological findings indicated a depth lower than the submucosa and complete radical resection in all cases and lymphovascular invasion in only one case. All three cases showed metachronous multiple liver metastases after 9-13 years of follow-up for EMR, despite achieving complete resection and without muscular invasion. CONCLUSIONS: Metachronous liver metastases may occur after long interval following endoscopic resection; thus, long-term follow-up is necessary after endoscopic resection for rectal NEN.

Late Onset of Non-islet Cell Tumor Hypoglycemia Managed via Multidisciplinary Treatment in a Patient with a Solitary Fibrous Tumor.
Takeuchi S, Goda T, Taguchi J, Douhata Y, Honma R, Ariga S, Ohhara Y, Shimizu Y, Kinoshita I, Fukuda I, Nagashima Y, Akita H
Internal medicine (Tokyo, Japan), 57, 16, 2431, 2436, 2018年08月, ［査読有り］, ［国内誌］
英語, 研究論文（学術雑誌）, Solitary fibrous tumor (SFT) is a rare subtype of soft tissue sarcoma (STS). We herein describe a case of late onset of non-islet cell tumor hypoglycemia (NICTH) that was managed via multidisciplinary treatment in a patient with SFT. A 67-year-old man previously diagnosed with SFT 4 years prior to this presentation and treated with several rounds of surgery, presented with massive tumors. Eighteen months following his prescribed chemotherapy, the patient developed hypoglycemia. He was diagnosed with NICTH, after confirming the presence of high molecular weight insulin-like growth factor-2. This case suggests that paraneoplastic syndrome can occur even in cases of rare cancers, such as STS.

Early prediction of lenvatinib treatment efficacy by using ¹⁸F-FDG PET/CT in patients with unresectable or advanced thyroid carcinoma that is refractory to radioiodine treatment: a protocol for a non-randomized single-arm multicenter observatio
Takeuchi S, Shiga T, Hirata K, Taguchi J, Magota K, Ariga S, Gouda T, Ohhara Y, Homma R, Shimizu Y, Kinoshita I, Tsuji Y, Homma A, Iijima H, Tamaki N, Dosaka-Akita H
BMJ open, 8, 8, e021001, 2018年08月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, INTRODUCTION: Lenvatinib, an oral molecular targeted drug, is used to treat patients with unresectable or advanced thyroid carcinoma that is refractory to radioiodine treatment. Effective methods for evaluating molecular targeted drugs are a critical unmet need owing to their expensive costs and unique adverse events. The aim of this study is to determine whether 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET)/CT at 1 week after commencing lenvatinib can predict treatment outcomes. DESIGN AND METHODS: This study is planned as a non-randomised single-arm multicentre study; patients with pathologically confirmed differentiated thyroid carcinoma (DTC) with lesions that are refractory to radioiodine treatment are eligible. The main exclusion criteria are medullary or anaplastic carcinoma, prior treatment with chemotherapy, poor general condition and thromboembolism-requiring treatment. Patients to be included in the study will be treated with lenvatinib and undergo FDG-PET/CT examination twice: before and 1 week after the initiation of treatment. Contrast-enhanced CT, the gold standard for evaluation, will be performed at least 4 weeks after the initiation of treatment. The primary objective is to evaluate the ability of the lesion maximum standard uptake value for FDG PET/CT performed 1 week after the initiation of treatment to predict outcomes compared with the response evaluation obtained via contrast-enhanced CT performed at least 4 weeks after the initiation of treatment. ETHICS AND DISSEMINATION: This study is conducted in accordance with the Declaration of Helsinki and has received ethical approval from the institutional review board of the Hokkaido University Hospital (approval number: 015-402). The results of this study will be disseminated through a presentation at a conference and the publication of the data in a peer-reviewed journal. The study will be implemented and reported in line with the SPIRIT statement. TRIAL REGISTRATION NUMBER: UMIN000022592.

Therapeutic activity of retroviral replicating vector-mediated prodrug activator gene therapy for pancreatic cancer.
Inoko K, Hiraoka K, Inagaki A, Takahashi M, Kushibiki T, Hontani K, Takano H, Sato S, Takeuchi S, Nakamura T, Tsuchikawa T, Shichinohe T, Gruber HE, Jolly DJ, Kasahara N, Hirano S
Cancer gene therapy, 25, 7-8, 184, 195, 2018年08月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Toca 511, a retroviral replicating vector (RRV) encoding the yeast cytosine deaminase (yCD) prodrug activator gene, which mediates conversion of the prodrug 5-fluorocytosine (5-FC) to the anticancer drug 5-fluorouracil (5-FU), is currently being evaluated in Phase II/III clinical trials for glioma, and showing highly promising evidence of therapeutic activity. Here we evaluated RRV-mediated prodrug activator gene therapy as a new therapeutic approach for pancreatic ductal adenocarcinoma (PDAC). RRV spread rapidly and conferred significant cytotoxicity with prodrug in a panel of PDAC cells. Efficient intratumoral replication and complete inhibition of tumor growth upon 5-FC administration were observed in both immunodeficient and immunocompetent subcutaneous PDAC models. Biodistribution of RRV was highly restricted in normal tissues, especially in immunocompetent hosts. Tumor growth inhibition by Toca 511 followed by 5-FC was also confirmed in the orthotopic PDAC model. This study provides the first proof-of-concept for application of Toca 511 and Toca FC (extended release 5-FC) to the treatment of human PDAC, and provided support for inclusion of PDAC in a Phase I study evaluating Toca 511 in various systemic malignancies, (NCT02576665), which has recently been initiated.

Pathological complete response of locally advanced colon cancer after preoperative radiotherapy: a case report and narrative review of the literature.
Sekiya S, Imamura K, Takeuchi S, Teramura K, Watanabe Y, Tamoto E, Takada M, Kinoshita Y, Anbo Y, Nakamura F, Kashimura N, Noguchi H, Miura K, Hirano S
Surgical case reports, 4, 1, 58, 58, 2018年06月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND: The oncological effectiveness of preoperative radiotherapy for locally advanced colon cancer is unclear. We report a case of pathological complete response in a patient with locally advanced ascending colon cancer after preoperative radiotherapy following failure of chemotherapy. CASE PRESENTATION: A 65-year-old Japanese woman presented with malaise and hematochezia. A computed tomography (CT) revealed a tumor in the ascending colon which seemed to infiltrate the adjacent structures. She was diagnosed with locally advanced ascending colon cancer stages T4b, N2a, M0, and IIIC. We selected modified FOLFOX6 with panitumumab as neoadjuvant chemotherapy. However, we discontinued the chemotherapy after the 8th cycle because of disease progression and severe adverse effects. The patient then underwent radiotherapy of 60 Gy in 30 fractions, resulting in significant tumor size reduction. One month after the radiotherapy, we performed a right hemicolectomy with multivisceral resection without complications. Histopathologically, we found no residual cancer cells in the resected specimen. The patient remains alive and has not required additional therapies for 24 months, as there are no signs of recurrence. CONCLUSIONS: The present case suggests that preoperative radiotherapy might be an effective treatment options for locally advanced colon cancer.

EGFR遺伝子変異とEGFRチロシンキナーゼ阻害薬(EGFR-TKI)に対する反応が異なる肺3重癌の1例　　　　　　　　　　　　　　　
合田 智宏, 木下 一郎, 堂畑 雄一, 有賀 伸, 田口 純, 本間 理央, 竹内 啓, 清水 康, 秋田 弘俊, 品川 尚文, 樋田 泰浩, 加賀 基知三
肺癌, 57, 7, 915, 915, (NPO)日本肺癌学会, 2017年12月, ［査読有り］
日本語

Molecular targeting of cell-permeable peptide inhibits pancreatic ductal adenocarcinoma cell proliferation.
Sato S, Nakamura T, Katagiri T, Tsuchikawa T, Kushibiki T, Hontani K, Takahashi M, Inoko K, Takano H, Abe H, Takeuchi S, Ono M, Kuwabara S, Umemoto K, Suzuki T, Sato O, Nakamura Y, Hirano S
Oncotarget, 8, 69, 113662, 113672, 2017年12月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Background: Chromosome 16 open reading frame 74 (C16orf74) is highly expressed in pancreatic ductal adenocarcinoma (PDAC) and is involved in cancer cell proliferation and invasion through binding to calcineurin (CN). Therefore, C16orf74 is a good target for the development of a PDAC treatment. A cell-permeable dominant-negative (DN) peptide that can inhibit the C16orf74/CN interaction was designed to examine whether this peptide can inhibit PDAC cell proliferation in vitro and in vivo. Method: TheDN-C16orf74 peptide, which corresponds to the portion of C16orf74 that interacts with CN, was synthesized, and we assessed its anti-tumor activity in proliferation assays with human PDAC cells and the underlying molecular signaling pathway. Using an orthotopic xenograft model of PDAC, we treated mice intraperitoneally with phosphate-buffered saline (PBS), control peptide, or DN-C16orf74 and analyzed the tumor-suppressive effects. Result: DN-C16orf74 inhibited the binding of C16orf74 to CN in an immunoprecipitation assay. DN-C16orf74 suppressed PDAC cell proliferation, and the level of suppression depended on the expression levels of C16orf74 in vitro. DN-C16orf74 also exhibited anti-tumor effects in orthotopic xenograft model. Furthermore, the tumor-suppressive effect was associated with inhibition of the phosphorylation of Akt and mTOR. Conclusion: The cell-permeable peptide DN-C16orf74 has a strong anti-tumor effect against PDAC in vitro and in vivo.

Refining prognosis in patients with hepatocellular carcinoma through incorporation of metabolic imaging biomarkers
Satoshi Takeuchi, Eric M. Rohren, Reham Abdel-Wahab, Lianchun Xiao, Jeffrey S. Morris, Homer A. Macapinlac, Manal M. Hassan, Ahmed O. Kaseb
EUROPEAN JOURNAL OF NUCLEAR MEDICINE AND MOLECULAR IMAGING, 44, 6, 969, 978, SPRINGER, 2017年06月, ［査読有り］
英語, 研究論文（学術雑誌）, F-18-fluorodeoxyglucose positron emission tomopraphy/computed tomography (FDGPET/CT) has been proven to be useful for imaging many types of cancer; however, its role is not well defined in hepatocellular carcinoma (HCC). We assessed the prognostic value of metabolic imaging biomarkers as established by baseline pretreatment FDG PET/CT in patients with HCC.
We retrospectively analyzed the records of patients with HCC who underwent FDG PET/CT before initial treatment from May 2013 through May 2014. Four PET/CT parameters were measured: maximum standardized uptake value (SUVmax), total lesion glycolysis (TLG), metabolic tumor volume (MTV), and tumor-to-normal-liver SUV ratio (TNR). Optimal cut-off values for the PET/CT parameters to stratify patients in terms of overall survival (OS) were determined. Multivariate analysis was performed to determine whether the PET/CT parameters could add to the prognostic value of the Cancer of the Liver Italian Program (CLIP) scoring system and the Barcelona-Clinic Liver Cancer (BCLC) staging system.
The analysis included 56 patients. Univariate analysis of the association between OS and continuous variables, including the PET/CT parameters SUVmax, TLG, tumor size, total bilirubin level, and alkaline phosphatase level were significant predictors of OS. SUVmax ae 11.7, TLG ae 1,341, MTV ae 230 mL, and TNR ae 4.8 were identified as cut-off values. Multivariate analysis revealed that SUVmax ae 11.7 and TNR ae 4.8 were independent factors predicting a poor prognosis in both the CLIP scoring system and the BCLC staging system, as was TLG in the BCLC staging system.
Pretreatment FDG PET/CT in patients with HCC can add to the prognostic value of standard clinical measures. Incorporation of imaging biomarkers derived from FDG PET/CT into HCC staging systems should be considered.

Premedication with intravenous magnesium has a protective effect against cisplatin-induced nephrotoxicity
Yoshitaka Saito, Masaki Kobayashi, Takehiro Yamada, Kumiko Kasashi, Rio Honma, Satoshi Takeuchi, Yasushi Shimizu, Ichiro Kinoshita, Hirotoshi Dosaka-Akita, Ken Iseki
SUPPORTIVE CARE IN CANCER, 25, 2, 481, 487, SPRINGER, 2017年02月, ［査読有り］
英語, 研究論文（学術雑誌）, Magnesium supplementation is an effective protective method against cisplatin-induced nephrotoxicity (CIN); however, there are few reports regarding the mechanism of its nephroprotective effect. The aim of this study was to determine whether premedication with intravenous magnesium prevents CIN and to determine the relationship between its nephroprotective effect and serum magnesium level.Fifty-eight patients with head and neck cancer who received cisplatin, docetaxel, and 5-fluorouracil (DCF) were retrospectively investigated. Grade 2 or more serum creatinine elevation was defined as CIN. The incidence of CIN was compared between a magnesium sulfate (20 mEq, 2.46 g) premedication group and a non-magnesium group during the first cycle and in all cycles.CIN did not occur in any patients receiving magnesium premedication but did occur in 5 of 29 patients during the first cycle and in 6 patients during all subsequent cycles in patients who did not receive magnesium premedication. Furthermore, the variation of creatinine clearance was significantly worse in the non-magnesium group than in the magnesium premedication group from baseline. There was no difference in adverse effects or response rate between the two groups. Univariate analysis suggested that magnesium premedication significantly reduced the risk of CIN. On the other hand, serum magnesium depletion was seen in both groups to equal degrees despite supplementation.Intravenous magnesium premedication has a protective effect on cisplatin-induced nephrotoxicity without the influence on the serum magnesium level. Magnesium premedication is a simple nephroprotective method that does not influence other adverse effects or rate of response to chemotherapy.

Identification of novel serum autoantibodies against EID3 in non-functional pancreatic neuroendocrine tumors
Koji Hontani, Takahiro Tsuchikawa, Takaki Hiwasa, Toru Nakamura, Takashi Ueno, Toshihiro Kushibiki, Mizuna Takahashi, Kazuho Inoko, Hironobu Takano, Satoshi Takeuchi, Hirotoshi Dosaka-Akita, Masaki Kuwatani, Naoya Sakamoto, Yutaka Hatanaka, Tomoko Mitsuhashi, Hideaki Shimada, Toshiaki Shichinohe, Satoshi Hirano
Oncotarget, 8, 63, 106206, 106221, Impact Journals LLC, 2017年, ［査読有り］
英語, 研究論文（学術雑誌）, Pancreatic neuroendocrine tumors (pNETs) are relatively rare heterogenous tumors, comprising only 1-2% of all pancreatic neoplasms. The majority of pNETs are non-functional tumors (NF-pNETs) that do not produce hormones, and as such, do not cause any hormone-related symptoms. As a result, these tumors are often diagnosed at an advanced stage because patients do not present with specific symptoms. Although tumor markers are used to help diagnosis and predict some types of cancers, chromogranin A, a widely used tumor marker of pNETs, has significant limitations. To identify novel NF-pNET-associated antigens, we performed serological identification of antigens by recombinant cDNA expression cloning (SEREX) and identified five tumor antigens (phosphatase and tensin homolog, EP300-interacting inhibitor of differentiation 3 [EID3], EH domain-containing protein 1, galactosidebinding soluble 9, and BRCA1-associated protein). Further analysis using the AlphaLISA® immunoassay to compare serum antibody levels revealed that antibody levels against the EID3 antigen was significantly higher in the patient group than in the healthy donor group (n = 25, both groups). In addition, higher serum anti-EID3 antibody levels in NF-pNET patients correlated with shorter disease-free survival. The AUC calculated by ROC analysis was 0.784 with moderate diagnostic accuracy. In conclusion, serum anti-EID3 antibody levels may be useful as a tumor marker for prediction of tumor recurrence in NF-pNETs.

Intravenous magnesium premedication has prophylactic efficacy against cisplatin-induced nephrotoxicity without an influence on serum magnesium level.　　　　　　　　　　　　　　　
Saito Y, Kobayashi M, Yamada T, Kasashi K, Honma R, Takeuchi S, Shimizu Y, Kinoshita I, Dosaka-Akita H, Iseki K
Support Care Cancer., 25, 481, 487, 2017年, ［査読有り］

Role of targeted therapy in metastatic colorectal cancer
Yoshihito Ohhara, Naoki Fukuda, Satoshi Takeuchi, Rio Honma, Yasushi Shimizu, Ichiro Kinoshita, Hirotoshi Dosaka-Akita
WORLD JOURNAL OF GASTROINTESTINAL ONCOLOGY, 8, 9, 642, 655, BAISHIDENG PUBLISHING GROUP INC, 2016年09月, ［査読有り］
英語, Colorectal cancer (CRC) is a significant cause of cancer-related morbidity and mortality all over the world. Improvements of cytotoxic and biologic agents have prolonged the survival in metastatic CRC (mCRC), with a median overall survival of approximately 2 years and more in the past two decades. The biologic agents that have proven clinical benefits in mCRC mainly target vascular endothelial growth factor (VEGF) and epidermal growth factor receptor (EGFR). In particular, bevacizumab targeting VEGF and cetuximab and panitumumab targeting EGFR have demonstrated significant survival benefits in combination with cytotoxic chemotherapy in the first-line, second-line, or salvage setting. Aflibercept, ramucirumab, and regorafenib are also used in second-line or salvage therapy. Recent retrospective analyses have shown that KRAS or NRAS mutations were negative predictive markers for anti-EGFR therapy. Based on the evidence from large randomized clinical trials, personalized therapy is necessary for patients with mCRC according to their tumor biology and characteristics. The aim of this paper was to summarize the results of the major randomized clinical trials and highlight the benefits of the molecular targeted agents in patients with mCRC.

The key role of calreticulin in immunomodulation induced by chemotherapeutic agents.
Yamamura Y, Tsuchikawa T, Miyauchi K, Takeuchi S, Wada M, Kuwatani T, Kyogoku N, Kuroda A, Maki T, Shichinohe T, Hirano S
International journal of clinical oncology, 20, 2, 386, 394, 2015年04月, ［査読有り］, ［国内誌］
英語, 研究論文（学術雑誌）, BACKGROUND: It has recently been shown that certain chemotherapeutic agents can improve host immune responses. The present study aimed to demonstrate the mechanism by which chemotherapeutic agents modify the tumor microenvironment and induce tumor-specific immune responses. METHODS: Three mouse cancer cell lines [CT26 mouse colon cancer cells, B16 melanoma cells and Lewis lung carcinoma (LLC)], 5 human carcinoma cell lines (human esophageal squamous cell carcinoma cell lines TE8 and HEC46 and the human pancreatic carcinoma cell lines PK-9, AsPC-1 and SUIT-2) and 5 chemotherapeutic agents [mitoxantrone (MIT), mitomycin C(MMC), 5-fluorouracil (5FU), camptothecin (CPT-11) and cisplatin (CDDP)] that are frequently used in a clinical setting for cancer treatment were utilized to investigate the surface expression level of calreticulin and HLA class I after exposure to chemotherapeutic agents. RESULTS: Increased calreticulin (CRT) expression on the surface of mouse cell lines and, moreover, increased surface expression levels of both CRT and HLA class I in all human cell lines were observed in cells treated by the chemotherapeutic agents as compared with non-treated cells. The surface expression level of CRT was significantly correlated with the HLA class I expression level in all human cell lines. CONCLUSIONS: In conclusion, chemotherapeutic drugs can improve the immunogenicity of cancer cells in a cell-specific manner through the mechanism of translocation of CRT.

Expression of Fucosyltransferase 8 Is Associated with an Unfavorable Clinical Outcome in Non-Small Cell Lung Cancers.
Honma R, Kinoshita I, Miyoshi E, Tomaru U, Matsuno Y, Shimizu Y, Takeuchi S, Kobayashi Y, Kaga K, Taniguchi N, Dosaka-Akita H
Oncology, 88, 5, 298, 308, 2015年04月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, UNLABELLED: Objecitive: Fucosyltransferase 8 (FUT8), the only enzyme responsible for the core α1,6-fucosylation of asparagine-linked oligosaccharides of glycoproteins, is a vital enzyme in cancer development and progression. We examined FUT8 expression in non-small cell lung cancers (NSCLCs) to analyze its clinical significance. We also examined the expression of guanosine diphosphate-mannose-4,6-dehydratase (GMD), which is imperative for the synthesis of fucosylated oligosaccharides. METHODS: Using immunohistochemistry, we evaluated the expression of FUT8 and GMD in relation to patient survival and prognosis in potentially curatively resected NSCLCs. RESULTS: High expression of FUT8 was found in 67 of 129 NSCLCs (51.9%) and was significantly found in non-squamous cell carcinomas (p = 0.008). High expression of FUT8 was associated with poor survival (p = 0.03) and was also a significant and independent unfavorable prognostic factor in patients with potentially curatively resected NSCLCs (p = 0.047). High expression of GMD was significantly associated with high FUT8 expression (p = 0.04). CONCLUSIONS: High expression of FUT8 is associated with an unfavorable clinical outcome in patients with potentially curatively resected NSCLCs, suggesting that FUT8 can be a prognostic factor. The analysis of FUT8 expression and its core fucosylated products may provide new insights for the therapeutic targets of NSCLCs.

Impact of ¹⁸F-FDG PET/CT on the management of adrenocortical carcinoma: analysis of 106 patients.
Takeuchi S, Balachandran A, Habra MA, Phan AT, Bassett RL Jr, Macapinlac HA, Chuang HH
European journal of nuclear medicine and molecular imaging, 41, 11, 2066, 2073, SPRINGER, 2014年11月, ［査読有り］
英語, 研究論文（学術雑誌）, Purpose Adrenocortical carcinoma (ACC) is a rare and aggressive malignancy. Limited data are available about on value of F-18-FDG PET/CT in ACC. We evaluated the impact of PET/CT on the management of ACC.
Methods We performed a retrospective review in patients with ACC who had undergone PET/CT. The impact of PET/CT on the management plan was evaluated by comparing the findings on PET/CT to the findings on contrast-enhanced CT. The sensitivity, specificity, and accuracy of each form of imaging were calculated. The correlations between PET/CT parameters, including maximum standardized uptake value (SUVmax), total lesion glycolysis, and decline in SUVmax after chemotherapy, and clinical outcome were evaluated.
Results Included in the analysis were 106 patients with 180 PET/CT scans. Of the 106 patients, 7 underwent PET/CT only for initial staging, 84 underwent PET/CT only for restaging, and 15 underwent PET/CT for both initial staging and restaging. PET/CT changed the management plan in 1 of 22 patients (5 %) at initial staging and 9 of 99 patients (9 %) at restaging. In 5 of the patients in whom PET/CT changed the management plan, PET/CT showed response to chemotherapy but contrast-enhanced CT showed stable disease. Sensitivity, specificity, and accuracy were 100 %, 100 %, and 100 % for PET/CT at initial staging; 92.6 %, 100 %, and 96.4 % for CT at initial staging; 98.4 %, 100 %, and 99.5 % for PET/CT at restaging; and 96.8 %, 98.6 %, and 98.0 % for CT at restaging, respectively. No PET/CT parameters were associated with survival at either initial diagnosis or recurrence.
Conclusion PET/CT findings could substantially change the management plan in a small proportion of patients with ACC. Although lesion detection was similar between PET/CT and CT, PET/CT may be preferred for chemotherapeutic response assessment because it may predict response before anatomic changes are detected on CT.

Expression of α1,6-fucosyltransferase is associated with prognosis and histology in non-small cell lung cancers　　　　　　　　　　　　　　　
Honma R, Kinoshita I, Miyoshi E, Tomaru U, Matsuno Y, Shimizu Y, Takeuchi S, Kobayashi Y, Kaga K, Taniguchi N, Akita DH
2014年10月, ［査読有り］
英語, 研究論文（学術雑誌）

Impact of initial PET/CT staging in terms of clinical stage, management plan, and prognosis in 592 patients with non-small-cell lung cancer
Satoshi Takeuchi, Benjapa Khiewvan, Patricia S. Fox, Stephen G. Swisher, Eric M. Rohren, Roland L. Bassett, Homer A. Macapinlac
EUROPEAN JOURNAL OF NUCLEAR MEDICINE AND MOLECULAR IMAGING, 41, 5, 906, 914, SPRINGER, 2014年05月, ［査読有り］
英語, 研究論文（学術雑誌）, Our objective was to determine the impact of initial F-18-FDG PET/CT (PET/CT) staging on clinical stage and the management plan and the prognostic value of PET/CT in patients with non-small-cell lung cancer (NSCLC).
We retrospectively reviewed the records of 592 patients with NSCLC who were referred to The University of Texas MD Anderson Cancer Center during 2002/2011 and had both PET/CT and conventional CT for initial staging. Clinical stages and management plans were compared between PET/CT and CT. The impact of PET/CT on management plans was considered medium/high when PET/CT changed the planned treatment modality or treatment intent. PET/CT and CT stages were compared with all-cause mortality and survival rates. We also assessed potential prognostic factors for progression-free survival (PFS) and overall survival (OS).
PET/CT changed the stage in 170 patients (28.7 %; 16.4 % upstaged, 12.3 % downstaged). PET/CT had a medium/high impact on the management plan in 220 patients (37.2 %). PFS and OS were significantly worse in patients with upstaged disease than in patients with no change in stage (median PFS 29.0 vs. 53.8 months, P < 0.001; median OS:64.7 vs. 115.9 months, P = 0.006). PFS and OS were significantly worse in patients with medium/high impact of PET/CT than in patients with no/low impact of PET/CT (median PFS 24.7 vs. 60.6 months, P < 0.001; median OS 64.7 vs. 115.9 months, P < 0.001). In multivariate analysis, a medium/high impact of PET/CT was an independent predictor of worse PFS (hazard ratio, HR, 1.73; 95 % CI 1.30 - 2.29; P = 0.0002) and OS (HR 1.84; 95 % CI 1.26 - 2.69; P = 0.002).
Initial PET/CT staging not only impacts stage and management plan but also has prognostic value.

Utility of F-18-FDG PET/CT in follow-up of patients with low-grade serous carcinoma of the ovary
Satoshi Takeuchi, Martin Lucchini, Kathleen M. Schmeler, Robert L. Coleman, David M. Gershenson, Mark F. Munsell, Homer A. Macapinlac, Pedro T. Ramirez
GYNECOLOGIC ONCOLOGY, 133, 1, 100, 104, ACADEMIC PRESS INC ELSEVIER SCIENCE, 2014年04月, ［査読有り］
英語, 研究論文（学術雑誌）, Objective. Ovarian low-grade serous carcinoma (LGSC) is a rare and indolent tumor. The utility of F-18-FDG PET/CT in monitoring patients with LGSC has not been established. We assessed the accuracy and clinical impact of F-18-FDG PET/CT in patients with ovarian LGSC after initial treatment.
Methods. A retrospective analysis was performed on patients with ovarian LGSC who had undergone F-18-FDG PET/CT scans during follow-up after primary treatment The impact of F-18-FDG PET/CT on the management plan was assessed. The sensitivity, specificity, and accuracy of F-18-FDG PET/CT findings in the detection of recurrence were calculated. Total lesion glycolysis (TLG) was determined to assess metabolic activity of tumors. Potential prognostic factors for disease-free and overall survival after recurrence were assessed.
Results. Forty-eight patients were included in the analysis, 39 with recurrent disease and 9 without recurrence. A total of 91 F-18-FDG PET/CT scans were performed, and 30% of these (27191) had an impact on the management plan. Sensitivity, specificity, and accuracy in the detection of LGSC recurrence were 94%, 100%, and 97%, respectively, for F-18-FDG PET/CT; 89%, 95%, and 93%,respectively, for CT; and 68%, 89%, and 73%, respectively, for serum CA-125. There was no significant difference in sensitivity between PET/CT and CT. Survival after recurrence was poorer in patients with a TLG value greater than 67.7 g.
Conclusions. F-18-FDG PET/CT may provide useful information during the follow-up of patients with LGSC after initial treatment TLG may be a predictor of survival after recurrence. (C) 2014 Elsevier Inc. All rights reserved.

Assessment of early changes in 3H-fluorothymidine uptake after treatment with gefitinib in human tumor xenograft in comparison with Ki-67 and phospho-EGFR expression.
Zhao S, Kuge Y, Zhao Y, Takeuchi S, Hirata K, Takei T, Shiga T, Dosaka-Akita H, Tamaki N
BMC cancer, 13, 525, 525, Biomed central, 2013年11月06日, ［査読有り］
英語, 研究論文（その他学術会議資料等）, Background: The purpose of this study was to evaluate whether early changes in 3'-deoxy-3'-H-3-fluorothymidine (H-3-FLT) uptake can reflect the antiproliferative effect of gefitinib in a human tumor xenograft, in comparison with the histopathological markers, Ki-67 and phosphorylated EGFR (phospho-EGFR). Methods: An EGFR-dependent human tumor xenograft model (A431) was established in female BALB/c athymic mice, which were divided into three groups: one control group and two treatment groups. Mice in the treatment groups were orally administered a partial regression dose (100 mg/kg/day) or the maximum tolerated dose of gefitinib (200 mg/kg/day), once daily for 2 days. Mice in the control group were administered the vehicle (0.1% Tween 80). Tumor size was measured before and 3 days after the start of treatment. Biodistribution of H-3-FLT and F-18-FDG (%ID/g/kg) was examined 3 days after the start of the treatment. Tumor cell proliferative activity with Ki-67 was determined. Immunohistochemical staining of EGFR and measurement of phospho-EGFR were also performed. Results: High expression levels of EGFR and Ki-67 were observed in the A431 tumor. After the treatment with 100 and 200 mg/kg gefitinib, the uptake levels of H-3-FLT in the tumor were significantly reduced to 67% and 61% of the control value, respectively (0.39 +/- 0.09, 0.36 +/- 0.06, 0.59 +/- 0.11% ID/g/kg for 100 mg/kg, 200 mg/kg, and control groups, respectively; p < 0.01 vs. control), but those of F-18-FDG were not. After the treatment with 100 and 200 mg/kg gefitinib, the expression levels of Ki-67 in the tumor were markedly decreased (4.6 +/- 2.4%, 6.2 +/- 1.8%,and 10.4 +/- 5.7% for 100 mg/kg, 200 mg/kg, and control groups, respectively, p < 0.01 vs. control). The expression levels of the phospho-EGFR protein also significantly decreased (29% and 21% of the control value for 100, and 200 mg/kg, respectively p < 0.01 vs. control). There was no statistically significant difference in tumor size between pre- and post-treatments in each group. Conclusion: In our animal model, H-3-FLT uptake levels significantly decreased after the treatment with two different doses of gefitinib before a significant change in tumor size was observed. These results were confirmed by the immunohistochemical staining of Ki-67 and phospho-EGFR protein immunoassay. Thus, it was indicated that early changes in H-3-FLT uptake may reflect the antiproliferative effect of gefitinib in a mouse model of a human epidermoid cancer.

北海道大学病院における上咽頭癌の治療―10年間(2000~2010)のまとめ―
土屋和彦, 安田耕一, 西川由記子, 木下留美子, 鬼丸力也, 原田慶一, 井上哲也, 加藤徳雄, 清水伸一, 白土博樹, 西岡健, 鈴木恵士郎, 田口大志, 長谷川雅一, 折舘伸彦, 本間明宏, 鈴木清護, 畠山博充, 加納里志, 水町貴諭, 坂下智博, 福田諭, 竹内啓, 田口純
耳鼻咽喉科展望, 56, 補冊2, 174, 175, 耳鼻咽喉科展望会, 2013年05月05日
日本語

F-18-Fluorothymidine PET/CT as an early predictor of tumor response to treatment with cetuximab in human lung cancer xenografts
Satoshi Takeuchi, Songji Zhao, Yuji Kuge, Yan Zhao, Ken-Ichi Nishijima, Toshiyuki Hatano, Yasushi Shimizu, Ichiro Kinoshita, Nagara Tamaki, Hirotoshi Dosaka-Akita
ONCOLOGY REPORTS, 26, 3, 725, 730, SPANDIDOS PUBL LTD, 2011年09月, ［査読有り］
英語, 研究論文（学術雑誌）, We investigated whether F-18-fluorothymidine-positron-emission tomography/computed tomography (F-18-FLT-PET/CT) is useful for the evaluation of the very early response to anti-epidermal growth factor receptor (EGFR) antibody cetuximab therapy in human lung cancer xenografts. A human tumor xenograft model was established with a human non-small cell lung cancer cell line. The mice were randomly assigned to four groups: tumor growth follow-up, ex vivo study, PET/CT imaging and non-treated control. Mice were administered saline as control or cetuximab on day 1. An immunohistochemical study with Ki-67 was performed. Tumor volume treated with cetuximab was kept significantly smaller than control after day 8, although there was no difference on day 3. On day 3, F-18-FLT distribution was higher in the tumor than in other tissues, and was significantly decreased by treatment with cetuximab. On PET/CT imaging, F-18-FLT distribution in the tumor was clearly visualized, and the maximum standardized uptake value (SUV) was significantly decreased after treatment with cetuximab (p<0.01). Ki-67 expression was also significantly decreased on day 3 (p=0.01). These results suggest that F-18-FLT-PET/CT can be a useful predictor to determine the response to molecular targeted drugs such as cetuxima.b at an earlier time point than the change of tumor size.

A case of high-grade neuroendocrine carcinoma that improved with bevacizumab plus modified FOLFOX6 as the fourth-line chemotherapy
Satoshi Takeuchi, Rio Honma, Jun Taguchi, Toraji Amano, Yasushi Shimizu, Ichiro Kinoshita, Kanako Kubota, Yoshihiro Matsuno, Hirotoshi Dosaka-Akita
Case Reports in Oncology, 4, 2, 260, 266, 2011年05月, ［査読有り］
英語, 研究論文（学術雑誌）, High-grade neuroendocrine carcinoma differs from usual neuroendocrine carcinoma, and its prognosis is dismal. In this case report, a case of high-grade neuroendocrine carcinoma that improved with bevacizumab plus modified FOLFOX6 as the fourth-line chemotherapy is presented. A 29-year-old male with a huge liver tumor was diagnosed with high-grade neuroendocrine carcinoma originating from the liver. Multiple liver and bone metastases were found one month after surgery. He was treated with three chemotherapy regimens used for the management of small-cell lung cancer with extensive disease. However, none of them could be maintained because of tumor progression. He was then treated with bevacizumab plus modified FOLFOX6 as the fourth-line regimen. Dramatic tumor shrinkage was obtained, and a partial response was achieved. This case suggests that high-grade neuroendocrine carcinoma can be treated with bevacizumab in combination with cytotoxic chemotherapy. Copyright © 2011 S. Karger AG, Basel.

¹⁸F‐Fluorothymidine(FLT)による抗EGFR抗体薬の早期治療効果予測　　　　　　　　　　　　　　　
竹内啓, 趙松吉, 趙松吉, 久下裕司, 趙莞, 西嶋剣一, 波多野利行, 清水康, 木下一郎, 玉木長良, 秋田弘俊
日本臨床腫瘍学会学術集会プログラム・抄録集, 9th, 367, 2011年
英語, 研究論文（その他学術会議資料等）

ヒト癌移植マウスにおける抗EGFR抗体(Cetuximab)による分子標的療法:¹⁸F‐FMISOを用いた早期治療効果評価　　　　　　　　　　　　　　　
趙松吉, 久下裕司, 趙芫, 竹内啓, 村上正紘, 李花, 西嶋剣一, 竹井俊樹, 秋田弘俊, 玉木長良
核医学, 48, 3, 335, 2011年
英語, 研究論文（その他学術会議資料等）

ヒト癌細胞移植マウスにおける抗EGFR抗体(cetuximab)による分子標的療法:FLTを用いた早期治療効果評価　　　　　　　　　　　　　　　
竹内啓, 趙松吉, 久下祐司, 趙莞, 西嶋剣一, 波多野利行, 清水康, 木下一郎, 玉木長良, 秋田弘俊
日本臨床腫瘍学会学術集会プログラム・抄録集, 8th, 188, 2010年
英語, 研究論文（その他学術会議資料等）

肉芽腫・腫瘍の鑑別診断におけるdynamic ¹¹C‐MET‐PETの有用性:小動物用PETを用いた基礎的検討　　　　　　　　　　　　　　　
趙松吉, 久下裕司, 伊敏, 趙芫, 竹内啓, 波多野利行, 鈴木幸太郎, 孫田惠一, 西嶋剣一, 小華和柾志, 玉木長良
核医学, 46, 3, S271, 2009年
英語, 研究論文（その他学術会議資料等）

ヒト癌細胞移植マウスにおける抗VEGF抗体(Bevacizumab)による分子標的療法:FLTを用いた早期治療効果評価　　　　　　　　　　　　　　　
趙松吉, 久下裕司, 趙芫, 竹内啓, 波多野利行, 西嶋剣一, 木下一郎, 秋田弘毅, 玉木長良
核医学, 46, 3, S260-S261, 2009年
英語, 研究論文（その他学術会議資料等）

A retrospective study of definitive chemoradiotherapy for elderly patients with esophageal cancer
Satoshi Takeuchi, Atsushi Htsu, Toshihiko Doi, Takashi Kojima, Keiko Minashi, Kiyomi Mera, Tomonori Yano, Makoto Tahara, Manabu Muto, Keiji Nihei
AMERICAN JOURNAL OF CLINICAL ONCOLOGY-CANCER CLINICAL TRIALS, 30, 6, 607, 611, LIPPINCOTT WILLIAMS & WILKINS, 2007年12月, ［査読有り］
英語, 研究論文（学術雑誌）, Objective: The efficacy and safety of definitive chemoradiotherapy (CRT) for elderly patients with esophageal cancer have not been fully elucidated yet. We conducted a retrospective comparison of the outcomes of CRT between elderly and nonelderly patients with Stage II-III (non-T4) esophageal cancer.
Methods: There were 33 elderly (aged over 71) patients and 145 nonelderly (aged under 70) patients who fulfilled the selection criteria. The treatment consisted of the continuous infusion of fluorouracil (5-FU) and the intravenous infusion of cisplatin (CDDP) combined with 60 Gy of radiation.
Results: Although the CR rate was almost identical between the 2 groups (63.6% vs. 63.4%, respectively), the recurrence rate after CR was higher in the elderly patients group than in the nonelderly patients group (47.6% vs. 33.7%, P = 0.32). The elderly patient group showed a significantly inferior survival in comparison to the nonelderly patient group with a median survival time (14.7 months vs. 35.1 months, P = 0.01). Discontinuations at the end of CRT were more frequent in the elderly patient group than in the nonelderly patients (57.6% vs. 17.3%, P = 0.01). In addition, over Grade 3 hematologic adverse events were more frequently observed in elderly patients than in nonelderly patients. There were no obvious differences in patients who died of causes other than primary disease.
Conclusion: This retrospective analysis revealed a significantly inferior efficacy even in selected elderly patients. Although improving the dose intensity of CRT should be desirable even in elderly patients, it seems to be difficult because of more substantial toxicity in elderly patients.

Feasibility of oxaliplatin and infusional fluorouracil/leucovorin (FOLFOX4) for Japanese patients with unresectable metastatic colorectal cancer
Nozomu Fuse, Toshihiko Doi, Atsushi Ohtsu, Satoshi Takeuchi, Takashi Kojima, Keisei Taku, Makoto Tahara, Manabu Muto, Masahiro Asaka, Shigeaki Yoshida
JAPANESE JOURNAL OF CLINICAL ONCOLOGY, 37, 6, 434, 439, OXFORD UNIV PRESS, 2007年06月, ［査読有り］
英語, 研究論文（学術雑誌）, Background: A combination of oxaliplatin and infusional fluorouracil/leucovorin (FOLFOX4) is one of the standard regimens for palliative and adjuvant chemotherapy for colorectal cancer. However, the feasibility of FOLFOX4 for Japanese patients has not been determined. We conducted this prospective study to evaluate the feasibility of FOLFOX4.
Methods: Previously treated or untreated patients with unresectable metastatic colorectal cancer were enrolled. The primary endpoint was the rate of completion which was defined as completion of the first 4 cycles with relative dose-intensity of oxaliplatin of 80% or higher.
Results: Of the 32 enrolled patients, 31 received FOLFOX4. Twenty-four patients (75%) had received prior chemotherapy. The rate of completion of the first four cycles was 87% (27/31; 95% Cl, 70.2-96.4%). With the median number of cycles of nine (range, 1-26), grade 3 or 4 hematological toxicity and non-hematological toxicity were seen in 12 (39%) and 5 (16%) patients, respectively. Grade 1 or 2 sensory neuropathy was seen in 28 patients (90%), but no grade 3 or 4 neuropathy was seen. Grade 1 or 2 allergic reaction was seen in five patients (16%). One patient developed fatal interstitial pneumonitis and died of respiratory failure. Objective response rate was 28.6% (6/21; 95% Cl, 11.352.2%) in the patients with measurable lesions. Median progression-free survival was 6.5 months (95% Cl, 4.6-8.5 months) in all patients.
Conclusions: The completion rate of the first four cycles was as high as expected with manageable toxicity, although fatal pneumonitis developed in one case. FOLFOX4 is feasible for Japanese patients.

New feeding management for percutaneous endoscopic gastrostomy (PEG) using semi-solid food with a new device, the 'CP-PEG connector'
Santa Hattori, Manabu Muto, Tomonori Yano, Keiko Minashi, Makoto Tahara, Takashi Kojima, Naomi Kiyota, Satoshi Takeuchi, Yasumasa Ezoe, Fumio Ito, Atsushi Ohtsu, Shigeaki Yoshida
GASTROINTESTINAL ENDOSCOPY, 65, 5, AB170, AB170, MOSBY-ELSEVIER, 2007年04月, ［査読有り］
英語

免疫チェックポイント阻害薬投与中に発症した大腸炎の2例　　　　　　　　　　　　　　　
長島 一哲, 桂田 武彦, 小田切 信介, 山梨 香菜, 木下 賢治, 村中 徹人, 秦 洋郎, 竹内 啓, 本間 理央, 合田 智宏, 三橋 智子, 小松 嘉人, 坂本 直哉, 日本癌治療学会学術集会抄録集, 55回, O23, 2, 2017年10月
(一社)日本癌治療学会, 日本語

がんクリニカルシークエンスの臨床運用 北海道大学病院での取り組み
天野 虎次, 西原 広史, 林 秀幸, 木下 一郎, 清水 康, 大原 克仁, 本間 理央, 竹内 啓, 佐藤 典宏, 秋田 弘俊, 日本内科学会雑誌, 106, Suppl., 193, 193, 2017年02月
(一社)日本内科学会, 日本語

Silica promotes anchorage independent growth of human bronchial cells via activation of NF-(e)over-capB1 p50
Motoo Katabami, Ichiro Kinoshita, Yasushi Shimizu, Satoshi Takeuchi, Hirotoshi Dosaka-Akita, CANCER RESEARCH, 76, 2016年07月
AMER ASSOC CANCER RESEARCH, 英語, 研究発表ペーパー・要旨（国際会議）

Locally advanced head and neck squamous cell carcinomas treated with TPF(docetaxel, cisplatin, 5-FU) induction chemotherapy
Jun Taguchi, Yasushi Shimizu, Ichiro Kinoshita, Rio Honma, Satoshi Takeuchi, Kazuhiko Tsuchiya, Hiroki Shirato, Akihiro Homma, Satoshi Fukuda, Hirotoshi Akita, ANNALS OF ONCOLOGY, 26, 90, 90, 2015年11月
OXFORD UNIV PRESS, 英語, 研究発表ペーパー・要旨（国際会議）

RETROSPECTIVE ANALYSIS OF CHEMOTHERAPY FOR EXTRAPULMONARY NEUROENDOCRINE CARCINOMAS (EPNEC)
Jun Taguchi, Ichiro Kinoshita, Naoki Fukuda, Shin Ariga, Tomohiro Goda, Rio Honma, Toraji Amano, Satoshi Takeuchi, Yasushi Shimizu, Hirotoshi Akita, ANNALS OF ONCOLOGY, 25, 2014年10月
OXFORD UNIV PRESS, 英語, 研究発表ペーパー・要旨（国際会議）

当科で導入化学療法を施行した頭頚部局所進行扁平上皮癌症例の治療成績
天野虎次, 田口純, 木下一郎, 合田智宏, 本間理央, 竹内啓, 清水康, 安田耕一, 土屋和彦, 白土博樹, 本間明宏, 福田諭, 秋田弘俊, 日本癌治療学会学術集会(CD-ROM), 50th, ROMBUNNO.PS2-008, 2012年
日本語

当院で施行した頭頚部局所進行扁平上皮癌に対するDCF(docetaxel,cisplatin,5‐FU)導入化学療法の検討
田口純, 天野虎次, 木下一郎, 合田智宏, 本間理央, 竹内啓, 清水康, 安田耕一, 土屋和彦, 鬼丸力也, 本間明宏, 福田諭, 秋田弘俊, 日本臨床腫瘍学会学術集会プログラム・抄録集, 10th, 179-180, 2012年
日本語

18F-FLUOROTHYMIDINE (18F-FLT) AS EARLY PREDICTOR OF TUMOR RESPONSE FOR ANTI-EPIDERMAL GROWTH FACTOR RECEPTOR ANTIBODY IN HUMAN LUNG CANCER XENOGRAFT
Satoshi Takeuchi, Songji Zhao, Yuji Kuge, Yan Zhao, Ken-Ichi Nishijima, Yasushi Shimizu, Ichiro Kinoshita, Nagara Tamaki, Hirotoshi Dosaka-Akita, JOURNAL OF THORACIC ONCOLOGY, 6, 6, S781, S781, 2011年06月
LIPPINCOTT WILLIAMS & WILKINS, 英語, 研究発表ペーパー・要旨（国際会議）

18F-Fluorothymidine PET at earlier time-point than the evaluation of tumor size for anti-epidermal growth factor receptor antibody in human lung cancer xenograft
Satoshi Takeuchi, Songji Zhao, Yuji Kuge, Yan Zhao, Ken-ichi Nishijima, Yasushi Shimizu, Ichiro Kinoshita, Nagara Tamaki, Hirotoshi Dosaka-Akita, CANCER RESEARCH, 71, 2011年04月
AMER ASSOC CANCER RESEARCH, 英語, 研究発表ペーパー・要旨（国際会議）

切除不能結腸直腸癌に対するBevacizumabの安全性及び有用性を検討するレトロスペクティブ調査(HGCSG0801)全症例のアップデート
小松嘉人, 結城敏志, 奥田博介, 畑中一映, 曽我部進, 宮城島拓人, 加藤貴司, 細川歩, 月岡雄治, 中村路夫, 高野眞寿, 内田多久實, 福島拓, 竹内啓, 浅香正博, 日本臨床腫瘍学会学術集会プログラム・抄録集, 9th, 303, 2011年
日本語

切除不能大腸癌に対するBevacizumab使用に関する調査(HGCSG0801)年齢別の解析
小松嘉人, 結城敏志, 久須美貴哉, 細川正夫, 高木智史, 畑中一映, 成瀬宏仁, 中積宏之, 竹内啓, 加藤寛士, 横山仁, 細川歩, 目黒高志, 堀田彰一, 浅香正博, 日本癌治療学会誌, 45, 2, 712, 2010年09月21日
日本語

切除不能結腸直腸癌に対するセツキシマブ使用例のレトロスペクティブ調査(HGCSG0901)　　　　　　　　　　　　　　　
畑中 一映, 結城 敏志, 中積 宏之, 辻 靖, 成瀬 宏仁, 棟方 正樹, 小川 浩平, 新谷 直昭, 佐藤 康史, 加藤 貴司, 中村 路夫, 伊東 重豪, 竹内 啓, 浅香 正博, 小松 嘉人, 日本癌治療学会誌, 45, 2, 507, 507, 2010年09月
(一社)日本癌治療学会, 日本語

癌分子標的治療--歩みと今後(2)カテゴリー別 癌分子標的治療薬(2)抗IGF-1R治療薬
竹内 啓, 秋田 弘俊, ザリバーキャンサージャーナル, 2, 2, 140, 144, 2010年06月
メディカルレビュー社, 日本語

ヒト癌移植マウスにおける抗EGFR抗体(Cetuximab)による分子標的療法 18F-FLT PETを用いた早期治療効果評価　　　　　　　　　　　　　　　
趙 松吉, 竹内 啓, 久下 裕司, 趙 芫, 波多野 利行, 李 花, 西嶋 剣一, 木下 一郎, 秋田 弘俊, 玉木 長良, JSMI Report, 3, 2, 117, 117, 2010年05月
日本分子イメージング学会, 日本語

F-18-Fluorothymidine (F-18-FLT) as tumor response predictor for anti-epidermal growth factor receptor antibody in human lung cancer xenograft
Satoshi Takeuchi, Songji Zhao, Yuji Kuge, Yan Zhao, Ken-ichi Nishijima, Toshiyuki Hatano, Yasushi Shimizu, Ichiro Kinoshita, Nagara Tamaki, Hirotoshi Dosaka-Akita, CANCER RESEARCH, 70, 2010年04月
AMER ASSOC CANCER RESEARCH, 英語, 研究発表ペーパー・要旨（国際会議）

Bevacizumabの有用性を検討するレトロスペクティブ調査(HGCSG0801)―FOLFIRI+BVの解析
竹内啓, 結城敏志, 中積宏之, 天野虎次, 林秀幸, 畑中一映, 加藤貴司, 目黒高志, 上畠寧子, 武藤修一, 久須美貴哉, 月岡雄治, 渡辺豊, 浅香正博, 小松嘉人, 日本癌治療学会誌, 44, 2, 419, 2009年09月14日
日本語

ヒト癌細胞移植マウスにおける抗EGFR抗体(Cetuximab)による分子標的療法 FLTを用いた早期治療効果評価　　　　　　　　　　　　　　　
竹内 啓, 趙 松吉, 久下 裕司, 趙 芫, 波多野 利行, 西嶋 剣一, 清水 康, 木下 一郎, 秋田 弘俊, 玉木 長良, 核医学, 46, 3, 316, 316, 2009年09月
(一社)日本核医学会, 日本語

Feasibility study of a new percutaneous endoscopic gastrostomy (PEG) procedure, the "Direct IDEAL PEG", in patients with advanced head and neck cancer or esophageal cancer
Tomonori Yano, Manabu Mute, Keiko Minashi, Naomi Kiyota, Takashi Kojima, Satoshi Takeuchi, Makoto Tahara, Kazuhiro Kaneko, Atsushi Ohtsu, GASTROINTESTINAL ENDOSCOPY, 67, 5, AB190, AB191, 2008年04月
MOSBY-ELSEVIER, 英語, 研究発表ペーパー・要旨（国際会議）

血管新生阻害薬の作用機序と臨床開発--抗VEGF抗体・VEGFtrap・VEGF-TKIなど (特集 肺癌分子標的療法--最近の展開)
竹内 啓, 秋田 弘俊, 最新医学, 63, 1, 45, 50, 2008年01月
最新医学社, 日本語

半導体PETと深層学習を利用したFDG PETからの腫瘍血流・代謝の同時定量
科学研究費助成事業
2020年04月01日 - 2023年03月31日
平田 健司, 竹内 啓, 真鍋 治, 久下 裕司
F-18 fluorodeoxyglucose (FDG)はブドウ糖類似体であり、体内に投与してからポジトロン断層法(PET)で撮影することにより、体内の糖代謝の多寡を画像化できる。原理的には、FDGを投与した直後から連続PET撮影した画像は血流の情報を含む。血流成分を抽出する試みは過去にも行われてきたが、PETの空間分解能の低さによるarterial input function (AIF)取得の困難さ等のため、臨床的に使用されるレベルには至っていない。腫瘍の血流にはdrug deliveryや治療効果判定に関する重要な情報が含まれていると考えられる。そこで本研究では新技術を導入することで、FDGによる腫瘍の糖代謝・血流の同時定量を目指した。今回申請者らが用いる新技術は、ハードウェアとしては高い空間分解能を持つ半導体PETであり、ソフトウェアとしては機械学習の一種であるdeep neural network (DNN)である。高い空間分解能は小さい血管からのAIF取得に役立ち、DNNはコンパートメントモデル・フリーで直接血流を予測するregressorとなりうる。腫瘍血流はO-15標識水のPETによる測定値をgold standardとする。1回のFDG PET撮影で患者負担の増加なしに糖代謝と同時に腫瘍血流が定量することを目指している。2年目である2021年度も新規の前向き臨床試験の立ち上げには到達できなかったが、PETのAI解析に向けて不足するエビデンスを固めるため、O-15標識水やFDGによる後ろ向き研究やファントム実験、画像診断レポートと画像とを組み合わせる研究等を行った。とくにO-15標識水に関しては、PET撮影した肺画像をUCLAの研究者とともに解析し、肺血流の定量値を得ることに成功し、腫瘍血流定量につながる成果が得られた。
日本学術振興会, 基盤研究(C), 北海道大学, 20K08015

低酸素腫瘍に対する新たな治療戦略の構築
科学研究費助成事業
2018年04月01日 - 2021年03月31日
志賀 哲, 安井 博宣, 竹内 啓, 久下 裕司, 趙 松吉
「エリブリンが腫瘍の低酸素状態を改善するか？」「化学療法や放射線治療の効果をどの程度改善するか？」「その結果、予後を改善するのか？」の3つの疑問に対し、動物実験および臨床試験を計画した。
ヒト乳癌細胞を移植した動物実験では、1）エリブリンは腫瘍の低酸素状態を改善し、2）放射線治療後の腫瘍の成長を有意に遅らせ、3）生存率を有意に向上させる事を示す事ができた。また、エリブリンが用量依存的に腫瘍の酸素化を改善し、投与後7日後の酸素化が最大であった事が解った。
ヒトでの試験は特定臨床試験を予定していたが、POC取得はできなかった。
日本学術振興会, 基盤研究(B), 18H02757