2019年, アメリカがん学会, The Best of the AACR Journals 2019　　　　　　　　　　　　　　　
野口 卓郎

2016年, アメリカがん学会, AACR-Aflac, Inc. Scholar-in-Training Award　　　　　　　　　　　　　　　
野口卓郎

2013年, 北海道医学会, Best Articles of the Year　　　　　　　　　　　　　　　
野口卓郎

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.

Notch pathway regulates osimertinib drug-tolerant persistence in EGFR-mutated non-small-cell lung cancer.
Hirofumi Takahashi, Jun Sakakibara-Konishi, Megumi Furuta, Tetsuaki Shoji, Kosuke Tsuji, Daisuke Morinaga, Eiki Kikuchi, Junko Kikuchi, Takuro Noguchi, Kanako C Hatanaka, Yutaka Hatanaka, Naofumi Shinagawa, Satoshi Konno
Cancer science, 2022年11月21日, ［国際誌］
英語, 研究論文（学術雑誌）, Osimertinib is a third-generation epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) that has shown marked antitumor activity in patients with EGFR-mutated non-small-cell lung cancer (NSCLC). However, these effects are transient and most patients develop resistance. Reversible drug-tolerant persister (DTP) cells are defined as a small subpopulation of cells with markedly reduced sensitivity and non-genetic acquired resistance to EGFR-TKIs. Notch is a transmembrane receptor that plays an important role in tumorigenesis. We previously reported that there is significant crosstalk between the Notch and EGFR pathways in NSCLC. Moreover, the Notch pathway is associated with resistance to previous-generation EGFR-TKIs. However, the role of Notch in osimertinib resistance is not fully understood. In this study, we evaluated whether Notch is involved in osimertinib resistance. We show that NOTCH1 and Notch target genes are upregulated in osimertinib DTP cells, and that the addition of a γ-secretase inhibitor (GSI), a Notch inhibitor, impairs drug-tolerant persistence in vitro and in vivo. Compared with osimertinib, combined GSI and osimertinib suppress phospho-ERK partly by enhancing DUSP1 expression. Furthermore, Notch1 and HES1 were upregulated after EGFR-TKI treatment in half of human EGFR-mutated NSCLC tumor tissues. These results suggest that the combination of GSI and osimertinib may be a potential therapy for EGFR-mutated NSCLC.

Clinical analysis of extrapulmonary neuroendocrine carcinoma: a retrospective and single institution experience.
Taiki Okumura, Takuro Noguchi, Nodoka Sekiguchi, Takashi Kobayashi, Shintaro Kanda, Koichi Ida, Tomonori Minagawa, Shigeo Tokumaru, Takeji Umemura, Tomonobu Koizumi
Chemotherapy, 2022年11月03日, ［国際誌］
英語, 研究論文（学術雑誌）, INTRODUCTION: Extrapulmonary neuroendocrine carcinoma (EPNEC) is a clinicopathological entity distinct from neuroendocrine carcinoma (NEC) of the lung. Here, we reviewed the clinical features, treatment modalities, and prognosis of EPNEC patients in a single-institution series. METHODS: We retrospectively reviewed the medical records of EPNEC patients, and examined the clinical profiles and treatment outcomes at our hospital between 2013 and 2021. RESULTS: Thirty-one EPNEC patients (21 men, 10 women) with a median age of 65 years were included. The primary sites were as follows: stomach (n = 7); rectum and bladder (n=3 each); prostate, esophagus, cervix and pancreas (n=2 each); maxillary sinus, parotid gland, gallbladder, anal canal, larynx, uterine body, ovary, appendix, anterior mediastinum, and unknown primary lesion (n = 1 each). Thirteen patients had locally advanced stage and 18 cases had distant metastases. Chemotherapy using platinum-combined CPT-11 or VP-16 was mainly performed. Various therapeutic modalities were used, especially in locally advanced cases. Ten patients underwent surgery, including initial surgery in 5 and conversion in 5 after chemotherapy. The response rate to initial chemotherapy was 56.5% and the median overall survival in all patients was 12.8 (95%CI: 9.6-34.5) months. Survival was significantly longer in patients with locally advanced (80.3 months) and receiving surgery (not reached) than in those with metastatic disease (9.9 months) and without surgery (9.6 months). Disscussion/Conclusion: EPNEC occurs in various organs and has poor prognosis. Long-term survival may be possible with surgical resection in cases with early-stage disease or tumor shrinkage due to chemotherapy.

EGFR変異陽性非小細胞肺癌におけるosimertinib耐性とNotch経路の関わり
高橋 宏典, 榊原 純, 古田 恵, 庄司 哲明, 辻 康介, 森永 大亮, 菊地 英毅, 菊地 順子, 野口 卓郎, 畑中 佳奈子, 畑中 豊, 品川 尚文, 今野 哲
肺癌, 62, 6, 715, 715, (NPO)日本肺癌学会, 2022年11月
日本語

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.

Response to lorlatinib on a patient with ALK-rearranged non-small cell lung cancer harboring 1151Tins mutation with uterine metastasis.
Takashi Kobayashi, Shintaro Kanda, Toshirou Fukushima, Takuro Noguchi, Nodoka Sekiguchi, Tomonobu Koizumi
Thoracic cancer, 12, 16, 2275, 2278, 2021年08月, ［国際誌］
英語, We describe a case of an anaplastic lymphoma kinase (ALK)-rearranged non-small cell lung cancer with development of uterine metastasis after crizotinib and alectinib treatment. Gene analysis from the tissue of uterine metastasis revealed the presence of 1151Tins, which was considered to be a crizotinib and alectinib resistance mutation. Subsequent therapy with the third-generation ALK inhibitor lorlatinib, but not ceritinib, showed antitumor activity for 1 year. The uterus is an uncommon site for metastasis from lung cancer, and our case indicated that serial gene analysis could provide new information about ALK inhibitor resistance.

Primary mediastinal germ cell tumors - A retrospective analysis of >30 years of experience in a single institution.
Tomonobu Koizumi, Shintaro Kanda, Ryo Nihonmatu, Daisuke Gomi, Nodoka Sekiguchi, Takuro Noguchi, Toshirou Fukushima, Takashi Kobayashi, Hiroshi Yamamoto, Tetsu Takeda
Thoracic cancer, 12, 6, 807, 813, 2021年03月, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND: This study was performed to clarify the treatment outcome of patients with primary mediastinal germ cell tumors (PMGCTs), focusing on the clinical manifestations and management during definitive therapy and long-term follow-up. METHODS: In this study, we retrospectively reviewed the medical records of patients with PMGCTs treated at Shinshu University School of Medicine, and examined the clinical profiles and treatment outcomes of 22 patients (mean age of 29 years) with primary mediastinal GCTs treated at our hospital between 1983 and 2019. RESULTS: Five patients were diagnosed with pure seminoma and 17 had nonseminomatous GCT. A total of 21 patients were treated with cisplatin-based chemotherapy and 15 patients (68.2%) underwent thoracic surgery after chemotherapy. Although all cases of nonseminomatous GCT were negative for tumor markers after cisplatin-based chemotherapy, two cases showed variable GCT cells and two had somatic components (angiosarcoma and rhabdomyosarcoma) in resected specimens. Three relapsed soon after surgery. Growing teratoma syndrome developed during chemotherapy in four cases. Urgent thoracic surgery was performed in three patients, but one case was inoperable. The calculated 10-year overall survival rates were 100% in mediastinal seminoma and 64.7% in NSGCT. During follow-up, second non-GCT malignancies developed in three patients (colon cancer, 190 months; thyroid cancer, 260 months; non-small cell lung cancer, 250 months after the initial chemotherapy) and one patient with primary mediastinal seminoma was associated with multiple type I endocrine tumors. CONCLUSIONS: Our experiences demonstrated that long-term survival and/or cure can be achieved with adequate chemotherapy followed by local surgical treatment even in patients with mediastinal GCTs. However, the clinical manifestations and biological behaviors during and/or after chemotherapy were complex and varied. In addition, the development of secondary malignancies should be taken into consideration for long-term follow-up. Clinicians should be aware of the various clinical features and secondary malignancies in primary mediastinal GCTs.

CCR4-positive peripheral T-cell lymphoma presenting as eosinophilic pneumonia and developing from prolonged pustular psoriasis.
Nodoka Sekiguchi, Masamichi Komatsu, Takashi Ichiyama, Aya Kobayashi, Daisuke Gomi, Toshirou Fukushima, Takashi Kobayashi, Takuro Noguchi, Hideyuki Nakazawa, Naoko Asano, Fumihiro Ishida, Tomonobu Koizumi
The Journal of international medical research, 49, 2, 300060521996165, 300060521996165, 2021年02月, ［国際誌］
英語, 研究論文（学術雑誌）, A 29-year-old woman with chronic, prolonged pustular psoriasis was admitted to our hospital because of high-grade fever and a systemic skin rash. General examination revealed a whole-body skin rash and superficial lymphadenopathy. Peripheral blood examination showed unclassified cells positive for CD3, CD4, and T-cell receptor αβ, and negative for CD20 and CD56. Soon after administration, she developed acute respiratory failure and required artificial ventilation. Bronchoalveolar lavage fluid showed increased numbers of eosinophils and abnormal lymphocytes of the same phenotype in peripheral blood and skin. She was diagnosed with eosinophilic pneumonia, and her respiratory failure was improved by corticosteroid therapy. Based on the histological findings of skin, lymph node, and bone marrow biopsies, a diagnosis of peripheral T-cell lymphoma not otherwise specified (PTCL-NOS), with positivity for CC chemokine receptor 4 was made. She received chemotherapy followed by allogeneic stem cell transplantation, which resulted in complete remission of her PTCL-NOS. She remained alive and disease-free 6 years later. This is the first reported case of PTCL-NOS developing during the clinical course of pustular psoriasis. The clinical manifestations of PTCL-NOS are complex, but an accurate diagnosis and appropriate therapy may produce a good clinical outcome in patients with PTCL-NOS.

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.

Newly emerged immunogenic neoantigens in established tumors enable hosts to regain immunosurveillance in a T-cell-dependent manner.
Tomoaki Muramatsu, Takuro Noguchi, Daisuke Sugiyama, Yoshie Kanada, Kaori Fujimaki, Sachiko Ito, Momokazu Gotoh, Hiroyoshi Nishikawa
International immunology, 33, 1, 39, 48, 2021年01月01日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Tumor neoantigens derived from genetic alterations are potential T-cell targets for antitumor immunity. However, tumors develop immune escape mechanisms including loss of preexisting neoantigens and/or impairment of T-cell responses during tumor development and progression. Here, we addressed whether newly emerged immunogenic neoantigens in established tumors enabled hosts to inhibit tumor growth via controlling immune escape mechanisms. Using a doxycycline-driven gene expression system, we generated murine MC38, CT26 (colorectal cancer) and B16 (melanoma) cell lines with inducible expression of model immunogenic neoantigens such as chicken ovalbumin and human NY-ESO-1. A model neoantigen was induced by doxycycline administration in the tumors once tumors became palpable. Tumor growth was significantly inhibited upon induction of the neoantigen and this inhibition was abrogated in nude mice lacking T cells and in mice deprived of CD8+ T cells, indicating the critical role of CD8+ T cells in tumor regression. In addition, PD-1/PD-L1 blockade further augmented the antitumor immune response, resulting in a far stronger inhibition of tumor growth. Accordingly, newly emerged tumor neoantigen-specific CD8+ T cells with enhanced effector functions were significantly increased in mice treated with PD-1/PD-L1 blockade. We propose that a newly emerged neoantigen is sufficient to inhibit tumor growth via preventing immune escape in a T-cell-dependent manner. Our results imply that induction of immunogenic tumor neoantigens is a novel strategy to overcome the resistance to immune checkpoint blockade therapy.

Experiences of trastuzumab plus paclitaxel combination therapy in metastatic human epidermal growth factor receptor 2-positive extramammary Paget's disease: Four cases and a review.
Nodoka Sekiguchi, Sae Kubota, Takuro Noguchi, Toshirou Fukushima, Takashi Kobayashi, Shintaro Kanda, Tomonobu Koizumi, Tomomi Miyake, Takushi Shirai, Ryuhei Okuyama
The Journal of dermatology, 2020年07月24日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Tumor cells in extramammary Paget's disease sometimes overexpress human epidermal growth factor receptor 2 (HER2). Several case reports indicated successful response to HER2 inhibitor in patients with HER2-positive metastatic extramammary Paget's disease. However, these were single-case reports, and most cases were evaluated only by immunohistochemistry and treated with HER2 inhibitor monotherapy. Here, we report cases of HER2-positive metastatic extramammary Paget's disease identified by both immunohistochemistry and in situ hybridization, and the patients were treated with HER2 inhibitor (trastuzumab) and paclitaxel combination chemotherapy. Partial response was observed in one case. The case was positive on both immunohistochemistry (3+) and in situ hybridization (HER2/chromosome 17 centromere, ≥2.0). Our observations suggest that HER2 should be checked in patients with advanced and/or metastatic extramammary Paget's disease, and that therapy with HER2 blockers should be considered as an option for treatment of HER2-positive extramammary Paget's disease, especially in cases positive for both HER2 gene amplification and overexpression.

Giant paratesticular liposarcoma with lung metastases: a case report and review of the literature.
Takuro Noguchi, Toshirou Fukushima, Hiroaki Hara, Nodoka Sekiguchi, Takashi Kobayashi, Takesumi Ozawa, Daisuke Gomi, Tomonobu Koizumi
Journal of medical case reports, 14, 1, 86, 86, 2020年07月02日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND: Due to its rarity, little is known about the clinical presentations and responses to systemic chemotherapies in advanced and/or metastatic cases of paratesticular liposarcoma. CASE PRESENTATION: Here, we report the case of a 75-year-old Japanese man with giant paratesticular liposarcoma. Imaging studies revealed a 26 cm tumor in his right scrotum and lung metastases at presentation. He underwent radical orchiectomy followed by systemic chemotherapies. Pathological findings of the resected primary tumor confirmed a dedifferentiated liposarcoma. He then started chemotherapy treatment with gemcitabine plus docetaxel. His disease status was stable for 1 year. Eribulin was used for second-line chemotherapy. He had a relapse at 5 months after eliburin and died at 22 months after diagnosis. CONCLUSION: Early diagnosis and curative radical surgery are important for treatment of paratesticular liposarcoma. However, a giant paratesticular liposarcoma could cause metastases, and systemic chemotherapy may be helpful for prolonging survival in patients with metastatic paratesticular liposarcoma.

A Rare Distant Metastasis of Papillary Cystadenocarcinoma Arising from Maxillary Gingiva
Fumihiro Nishimaki, Takahiko Gibo, Keita Tsukada, Takuro Noguchi, Toshirou Fukushima, Takashi Kobayashi, Nodoka Sekiguchi, Takesumi Ozawa, Tomonobu Koizumi
Case Reports in Oncology, 13, 2, 683, 688, S. Karger AG, 2020年06月16日
研究論文（学術雑誌）, Papillary cystadenocarcinoma is an uncommon disease with low-grade histological and clinical features. Although the tumor has the potential to produce regional lymph node metastasis, there have been no reports of cases with distant metastasis. We describe a case of papillary cystadenocarcinoma arising from the maxilla that developed pulmonary metastasis 3 years after radical surgery of the primary tumor and regional lymph node. The histological findings were confirmed on resected specimens of the pulmonary nodule and a pathological diagnosis of a metastatic lesion derived from papillary cystadenocarcinoma was made. To our knowledge, this is the first report of the development of pulmonary metastasis in a patient with papillary cystadenocarcinoma. The present case suggests that papillary cystadenocarcinoma has the potential to produce lung metastasis in the clinical course. Based on our experience, we emphasize that long-term follow-up and/or careful examination are necessary in patients with cystadenocarcinoma, especially in patients with lymph node metastasis during the initial surgical therapy.

National incidence and initial therapy for thymic carcinoma in Japan: based on analysis of hospital-based cancer registry data, 2009-2015.
Tomonobu Koizumi, Kengo Otsuki, Yuriko Tanaka, Takuro Noguchi, Toshirou Fukushuima, Takashi Kobayashi, Takesumi Ozawa, Nodoka Sekiguchi, Kazutoshi Hamanaka
Japanese journal of clinical oncology, 50, 4, 434, 439, 2020年04月07日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND: Although thymic carcinoma is a rare epithelial neoplasm that tends to be aggressive and metastasize widely, its incidence in Japan remains unclear. This study was to examine the incidence and initial treatment of thymic carcinoma in the Japanese population using data from a hospital-based cancer registry. METHODS: Using data from the national database of hospital-based cancer registries, we examined the incidence and initial treatment of thymic carcinoma diagnosed and treated in designated and non-designated cancer care hospitals between 2009 and 2015. Based on Japanese population estimates, we calculated the incidence rate of thymic cancer in Japan. RESULTS: A total of 2587 thymic carcinoma cases were diagnosed between 1 January 2009 and 31 December 2015. These patients consisted of 1705 (66%) men and 882 (34%) women, with a median age of 65.5 years (range, 16-96 years). The number and proportion of thymic carcinoma to all registered cancer cases per year increased each year. The incidence rate was estimated to be 0.29/100000 during the observation period, with an annual onset incidence of 0.38/100000 in 2015. Almost half of all cases of thymic carcinoma were treated surgically, while the others were treated with non-surgical therapy consisting of chemotherapy with or without radiotherapy. CONCLUSIONS: We estimated the incidence rate of thymic carcinoma in Japan based on the designated cancer care hospital-based cancer registry. The half of all patients with thymic carcinoma was unfit for multimodality therapy, including thoracic surgery.

Posterior mediastinal ganglioneuroblastoma in an adolescent: A case report and review.
Nodoka Sekiguchi, Takuro Noguchi, Toshirou Fukushima, Takashi Kobayashi, Takesumi Ozawa, Yoshinori Sato, Tetsu Takeda, Kazuo Yoshida, Tomonobu Koizumi
Thoracic cancer, 11, 2, 451, 455, 2020年02月, ［査読有り］, ［国際誌］
英語, Ganglioneuroblastoma is an uncommon malignant tumor of the sympathetic nervous system, which is considered a disease of children with the majority of cases in patients less than four years old and it rarely occurs in adults. We encountered a very unusual case of a posterior mediastinal ganglioneuroblastoma that developed in a 17-year-old male adolescent who underwent successful excision of the mediastinal mass and remained stable postoperatively. However, he developed lumbago one year after the surgery. Radiographic findings revealed osteolytic lesions in the lumbar vertebra and histological analysis confirmed bone metastasis of ganglioneuroblastoma. Here, we report the clinical course and present a review of the literature regarding adolescent and adult onset mediastinal ganglioneuroblastoma.

Intra-oesophageal invasion of thymoma.
Ozawa M, Fukushima T, Noguchi T, Kobayashi T, Sekiguchi N, Koizumi T
Respirology case reports, 7, 8, e00485, 2019年11月, ［査読有り］

Targeted therapy with trastuzumab for epidermal growth factor receptor 2 (HER2)-positive advanced salivary duct carcinoma: A case report.
Gibo T, Sekiguchi N, Gomi D, Noguchi T, Fukushima T, Kobayashi T, Ozawa T, Yamada SI, Koizumi T
Molecular and clinical oncology, 11, 2, 111, 115, 2019年08月, ［査読有り］

[What Are Patients' Expectations from Palliative Chemotherapy ?]
Takeuchi N, Koike K, Yoshida S, Sekiguchi N, Noguchi T
Gan to kagaku ryoho. Cancer & chemotherapy, 46, 8, 1275, 1279, 2019年08月, ［査読有り］

ACTH-producing thymic neuroendocrine tumor initially presenting as psychosis: A case report and literature review.
Okumura T, Takayama S, Nishio SI, Miyakoshi T, Noguchi T, Kobayashi T, Fukushima T, Sekiguchi N, Otsuki T, Komatsu M, Koizumi T
Thoracic cancer, 10, 7, 1648, 1653, 2019年07月, ［査読有り］

[Desensitization Therapy for Osimertinib in Patients Who Developed Toxic Erythema - Two Case Reports].
Hiroaki Watanabe, Akira Mimura, Toshiro Fukushima, Takuro Noguchi, Takesumi Ozawa, Takashi Kobayashi, Nodoka Sekiguchi, Shigeru Ohmori, Tomonobu Koizumi
Gan to kagaku ryoho. Cancer & chemotherapy, 46, 5, 961, 963, 2019年05月, ［査読有り］, ［国内誌］
日本語, 研究論文（学術雑誌）, We encountered 2 cases of T790M-positive non-small cell lung cancer in patients who developed toxic erythema within a week after initiation of osimertinib(80mg/day)therapy. Since osimertinib was regarded as the suspected drug, we adminis- tered desensitization therapy for osimertinib at an initial dose of 10mg/day. During the process of dose escalation, slight eruption and flare were observed, but we were able to provide appropriate treatment. Osimertinib therapy was continued and conferred tumor reduction in both cases. We report the clinical course and suggest that desensitization therapy is an alternative therapy for patients who present with drug-induced allergic reaction.

Late and Rapid Relapse in Mediastinum from Testicular Germ Cell Tumor Stage I Over 13 Years after Surgery.
Fukushima T, Noguchi T, Kobayashi T, Sekiguchi N, Ozawa T, Koizumi T, Tamada H
Case reports in oncology, 12, 2, 500, 505, 2019年05月, ［査読有り］

A Case of Unresectable Pulmonary Artery Intimal Sarcoma with Prolonged Survival by Chemotherapy
Noguchi Takuro, Gomi Daisuke, Fukushima Toshirou, Ozawa Takesumi, Kobayashi Takashi, Sekiguchi Nodoka, Mamiya Keiko, Koizumi Tomonobu
CASE REPORTS IN ONCOLOGY, 12, 1, 192, 198, 2019年, ［査読有り］

High-Dimensional Analysis Delineates Myeloid and Lymphoid Compartment Remodeling during Successful Immune-Checkpoint Cancer Therapy.
Matthew M Gubin, Ekaterina Esaulova, Jeffrey P Ward, Olga N Malkova, Daniele Runci, Pamela Wong, Takuro Noguchi, Cora D Arthur, Wei Meng, Elise Alspach, Ruan F V Medrano, Catrina Fronick, Michael Fehlings, Evan W Newell, Robert S Fulton, Kathleen C F Sheehan, Stephen T Oh, Robert D Schreiber, Maxim N Artyomov
Cell, 175, 5, 1443, 1443, 2018年11月15日, ［国際誌］
英語

High-Dimensional Analysis Delineates Myeloid and Lymphoid Compartment Remodeling during Successful Immune-Checkpoint Cancer Therapy.
Matthew M Gubin, Ekaterina Esaulova, Jeffrey P Ward, Olga N Malkova, Daniele Runci, Pamela Wong, Takuro Noguchi, Cora D Arthur, Wei Meng, Elise Alspach, Ruan F V Medrano, Catrina Fronick, Michael Fehlings, Evan W Newell, Robert S Fulton, Kathleen C F Sheehan, Stephen T Oh, Robert D Schreiber, Maxim N Artyomov
Cell, 175, 4, 1014, 1030, 2018年11月01日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Although current immune-checkpoint therapy (ICT) mainly targets lymphoid cells, it is associated with a broader remodeling of the tumor micro-environment. Here, using complementary forms of high-dimensional profiling, we define differences across all hematopoietic cells from syngeneic mouse tumors during unrestrained tumor growth or effective ICT. Unbiased assessment of gene expression of tumor-infiltrating cells by single-cell RNA sequencing (scRNAseq) and longitudinal assessment of cellular protein expression by mass cytometry (CyTOF) revealed significant remodeling of both the lymphoid and myeloid intratumoral compartments. Surprisingly, we observed multiple subpopulations of monocytes/macrophages, distinguishable by the markers CD206, CX3CR1, CD1d, and iNOS, that change over time during ICT in a manner partially dependent on IFNγ. Our data support the hypothesis that this macrophage polarization/activation results from effects on circulatory monocytes and early macrophages entering tumors, rather than on pre-polarized mature intratumoral macrophages.

Chemotherapy for advanced and metastatic thymic carcinoma　　　　　　　　　　　　　　　
Noguchi T, Koizumi T
Mediastinum, 2, 52, 2018年08月, ［査読有り］, ［招待有り］
英語

Temporally Distinct PD-L1 Expression by Tumor and Host Cells Contributes to Immune Escape.
Takuro Noguchi, Jeffrey P Ward, Matthew M Gubin, Cora D Arthur, Sang Hun Lee, Jasreet Hundal, Mark J Selby, Robert F Graziano, Elaine R Mardis, Alan J Korman, Robert D Schreiber
Cancer immunology research, 5, 2, 106, 117, AMER ASSOC CANCER RESEARCH, 2017年02月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Antibody blockade of programmed death-1 (PD-1) or its ligand, PD-L1, has led to unprecedented therapeutic responses in certain tumor-bearing individuals, but PD-L1 expression's prognostic value in stratifying cancer patients for such treatment remains unclear. Reports conflict on the significance of correlations between PD-L1 on tumor cells and positive clinical outcomes to PD-1/PD-L1 blockade. We investigated this issue using genomically related, clonal subsets from the same methylcholanthrene-induced sarcoma: a highly immunogenic subset that is spontaneously eliminated in vivo by adaptive immunity and a less immunogenic subset that forms tumors in immunocompetent mice, but is sensitive to PD-1/PD-L1 blockade therapy. Using CRISPR/Cas9-induced loss-of-function approaches and overexpression gain-of-function techniques, we confirmed that PD-L1 on tumor cells is key to promoting tumor escape. In addition, the capacity of PD-L1 to suppress antitumor responses was inversely proportional to tumor cell antigenicity. PD-L1 expression on host cells, particularly tumor-associated macrophages (TAM), was also important for tumor immune escape. We demonstrated that induction of PD-L1 on tumor cells was IFNγ-dependent and transient, but PD-L1 induction on TAMs was of greater magnitude, only partially IFNγ dependent, and was stable over time. Thus, PD-L1 expression on either tumor cells or host immune cells could lead to tumor escape from immune control, indicating that total PD-L1 expression in the immediate tumor microenvironment may represent a more accurate biomarker for predicting response to PD-1/PD-L1 blockade therapy, compared with monitoring PD-L1 expression on tumor cells alone. Cancer Immunol Res; 5(2); 106-17. ©2017 AACR.

Tumor-specific mutant antigens in cancer immunotherapy
Gubin Matthew M, Ward Jeffrey P, Noguchi Takuro, Zhang Xiuli, Arthur Cora, Krebber Willem-Jan, Mulder Gwenn E, Melief Cornelis J. M, Gillanders William E, Artyomov Maxim, Mardis Elaine R, Schreiber Robert D
CANCER IMMUNOLOGY RESEARCH, 4, 11, 2016年11月, ［査読有り］

Metabolic Competition in the Tumor Microenvironment Is a Driver of Cancer Progression
Chih-Hao Chang, Jing Qiu, David O'Sullivan, Michael D. Buck, Takuro Noguchi, Jonathan D. Curtis, Qiongyu Chen, Mariel Gindin, Matthew M. Gubin, Gerritje J. W. van der Windt, Elena Tonc, Robert D. Schreiber, Edward J. Pearce, Erika L. Pearce
CELL, 162, 6, 1229, 1241, CELL PRESS, 2015年09月, ［査読有り］
英語, 研究論文（学術雑誌）, Failure of T cells to protect against cancer is thought to result from lack of antigen recognition, chronic activation, and/or suppression by other cells. Using a mouse sarcoma model, we show that glucose consumption by tumors metabolically restricts T cells, leading to their dampened mTOR activity, glycolytic capacity, and IFN-g production, thereby allowing tumor progression. We show that enhancing glycolysis in an antigenic "regressor'' tumor is sufficient to override the protective ability of T cells to control tumor growth. We also show that checkpoint blockade antibodies against CTLA-4, PD-1, and PD-L1, which are used clinically, restore glucose in tumor microenvironment, permitting T cell glycolysis and IFN-gamma production. Furthermore, we found that blocking PD-L1 directly on tumors dampens glycolysis by inhibiting mTOR activity and decreasing expression of glycolysis enzymes, reflecting a role for PD-L1 in tumor glucose utilization. Our results establish that tumor-imposed metabolic restrictions can mediate T cell hyporesponsiveness during cancer.

Checkpoint blockade cancer immunotherapy targets tumour-specific mutant antigens
Matthew M. Gubin, Xiuli Zhang, Heiko Schuster, Etienne Caron, Jeffrey P. Ward, Takuro Noguchi, Yulia Ivanova, Jasreet Hundal, Cora D. Arthur, Willem-Jan Krebber, Gwenn E. Mulder, Mireille Toebes, Matthew D. Vesely, Samuel S. K. Lam, Alan J. Korman, James P. Allison, Gordon J. Freeman, Arlene H. Sharpe, Erika L. Pearce, Ton N. Schumacher, Ruedi Aebersold, Hans-Georg Rammensee, Cornelis J. M. Melief, Elaine R. Mardis, William E. Gillanders, Maxim N. Artyomov, Robert D. Schreiber
NATURE, 515, 7528, 577, +, NATURE PUBLISHING GROUP, 2014年11月, ［査読有り］
英語, 研究論文（学術雑誌）, The immune system influences the fate of developing cancers by not only functioning as a tumour promoter that facilitates cellular transformation, promotes tumour growth and sculpts tumour cell immunogenicity(1-6), but also as an extrinsic tumour suppressor that either destroys developing tumours or restrains their expansion(1,2,7). Yet, clinically apparent cancers still arise in immunocompetent individuals in part as a consequence of cancer-induced immunosuppression. In many individuals, immunosuppression is mediated by cytotoxic T-lymphocyte associated antigen-4 (CTLA-4) and programmed death-1 (PD -1), two immunomodulatory receptors expressed on T cells(8,9). Monoclonal-antibody-based therapies targeting CTLA-4 and/or PD-1 (checkpoint blockade) have yielded significant clinical benefits including durable responses to patients with different malignancies(10-13). However, little is known about the identity of the tumour antigens that function as the targets of T cells activated by checkpoint blockade immunotherapy and whether these antigens can be used to generate vaccines that are highly tumour-specific. Here we use genomics and bioinformatics approaches to identify tumour-specific mutant proteins as a major class of T-cell rejection antigens following anti-PD-1 and/or anti-CTLA-4 therapy of mice bearing progressively growing sarcomas, and we show that therapeutic synthetic long-peptide vaccines incorporating these mutant epitopes induce tumour rejection comparably to checkpoint blockade immunotherapy. Although mutant tumour-antigen-specific T cells are present in progressively growing tumours, they are reactivated following treatment with anti-PD-1 and/or anti-CTLA-4 and display some overlapping but mostly treatment-specific transcriptional profiles, rendering them capable of mediating tumour rejection. These results reveal that tumour-specific mutant antigens are not only important targets of checkpoint blockade therapy, but they can also be used to develop personalized cancer-specific vaccines and to probe the mechanistic

Antibody-based therapy in colorectal cancer
Takuro Noguchi, Gerd Ritter, Hiroyoshi Nishikawa
IMMUNOTHERAPY, 5, 5, 533, 545, FUTURE MEDICINE LTD, 2013年05月, ［査読有り］
英語, Treatment in patients with nonresectable and resectable colorectal cancer at the advanced stage is challenging, therefore intensive strategies such as chemotherapy, signaling inhibitors and monoclonal antibodies (mAbs) to control the disease are required. mAbs are particularly promising tools owing to their target specificities and strong antitumor activities through multiple mechanisms, as shown by rituximab in B-cell non-Hodgkin's lymphoma and trastuzumab in breast cancer. Three mAbs (cetuximab, bevacizumab and panitumumab) have been approved for the treatment of colorectal cancer in the USA and many other mAbs are being tested in clinical trials. The potential of antibody therapy is associated with several mechanisms including interference of vital signaling pathways targeted by the antibody and immune cytotoxicity selectively directed against tumor cells by tumor-bound antibody through the Fc portion of the antibody, such as antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity. Moreover, recent experimental findings have shown that immune complexes formed by therapeutic mAbs with tumor-released antigens could augment the induction of tumor-specific cytotoxic CD8(+) T cells through activation of APCs. In addition, antibodies targeting immune checkpoints on hematopoietic cells have recently opened a new avenue for the treatment of cancer. In this review, we focus on mAb treatment in colorectal cancer and its immunological aspects.

Establishment of animal models to analyze the kinetics and distribution of human tumor antigen-specific CD8⁺ T cells.
Muraoka D, Nishikawa H, Noguchi T, Wang L, Harada N, Sato E, Luescher I, Nakayama E, Kato T, Shiku H
Vaccine, 31, 17, 2110, 2118, ELSEVIER SCI LTD, 2013年04月, ［査読有り］
英語, 研究論文（学術雑誌）, Many patients develop tumor antigen-specific T cell responses detectable in peripheral blood mononuclear cells (PBMCs) following cancer vaccine. However, measurable tumor regression is observed in a limited number of patients receiving cancer vaccines. There is a need to re-evaluate systemically the immune responses induced by cancer vaccines. Here, we established animal models targeting two human cancer/testis antigens, NY-ESO-1 and MAGE-A4. Cytotoxic T lymphocyte (CTL) epitopes of these antigens were investigated by immunizing BALB/c mice with plasmids encoding the entire sequences of NY-ESO-1 or MAGE-A4. CD8(+) T cells specific for NY-ESO-1 or MAGE-A4 were able to be detected by ELISPOT assays using antigen presenting cells pulsed with overlapping peptides covering the whole protein, indicating the high immunogenicity of these antigens in mice. Truncation of these peptides revealed that NY-ESO-1-specific CD8(+) T cells recognized D-d-restricted 8mer peptides, NY-ESO-1(81-88). MAGE-A4-specific CD8(+) T cells recognized D-d-restricted 9mer peptides, MAGE-A4(265-273). MHC/peptide tetramers allowed us to analyze the kinetics and distribution of the antigen-specific immune responses, and we found that stronger antigen-specific CD8(+) T cell responses were required for more effective anti-tumor activity. Taken together, these animal models are valuable for evaluation of immune responses and optimization of the efficacy of cancer vaccines. (C) 2013 Elsevier Ltd. All rights reserved.

A novel human-derived antibody against NY-ESO-1 improves the efficacy of chemotherapy
Anurag Gupta, Natko Nuber, Christoph Esslinger, Mareike Wittenbrink, Martin Treder, Alexandro Landshammer, Takuro Noguchi, Marcus Kelly, Sacha Gnjatic, Erika Ritter, Lotta von Boehmer, Hiroyoshi Nishikawa, Hiroshi Shiku, Lloyd Old, Gerd Ritter, Alexander Knuth, Maries van den Broek
Cancer Immunity, 13, 1, 3, 2013年, ［査読有り］
英語, 研究論文（学術雑誌）, We investigated whether antibodies against intracellular tumor-associated antigens support tumor-specific immunity when administered together with a treatment that destroys the tumor. We propose that released antigens form immune complexes with the antibodies, which are then efficiently taken up by dendritic cells. We cloned the first human monoclonal antibodies against the Cancer/ Testis (CT) antigen, NY-ESO-1. We tested whether the monoclonal anti-NY-ESO-1 antibody (12D7) facilitates cross-presentation of a NY-ESO-1-derived epitope by dendritic cells to human CD8+ T cells, and whether this results in the maturation of dendritic cells in vitro. We investigated the efficacy of 12D7 in combination with chemotherapy using BALB/c mice bearing syngeneic CT26 tumors that express intracellular NY-ESO-1. Human dendritic cells that were incubated with NY-ESO-1:12D7 immune complexes efficiently stimulated NY-ESO-1157-165/HLA-A2-specific human CD8+ T cells to produce interferon-γ, whereas NY-ESO-1 alone did not. Furthermore, the incubation of dendritic cells with NY-ESO-1:12D7 immune complexes resulted in the maturation of dendritic cells. Treatment of BALB/c mice that bear CT26/NY-ESO-1 tumors with 5-fluorouracil (5-FU) plus 12D7 was significantly more effective than chemotherapy alone. We propose systemic injection of monoclonal antibodies (mAbs) against tumor-associated antigens plus a treatment that promotes the local release of those antigens resulting in immune complex formation as a novel therapeutic modality for cancer. © 2013 by Maries van den Broek.

Intracellular Tumor-Associated Antigens Represent Effective Targets for Passive Immunotherapy
Takuro Noguchi, Takuma Kato, Linan Wang, Yuka Maeda, Hiroaki Ikeda, Eiichi Sato, Alexander Knuth, Sacha Gnjatic, Gerd Ritter, Shimon Sakaguchi, Lloyd J. Old, Hiroshi Shiku, Hiroyoshi Nishikawa
CANCER RESEARCH, 72, 7, 1672, 1682, AMER ASSOC CANCER RESEARCH, 2012年04月, ［査読有り］
英語, 研究論文（学術雑誌）, Monoclonal antibody (mAb) therapy against tumor antigens expressed on the tumor surface is associated with clinical benefit. However, many tumor antigens are intracellular molecules that generally would not be considered suitable targets for mAbtherapy. In this study, we provide evidence challenging this view through an investigation of the efficacy of mAb directed against NY-ESO-1, a widely expressed immunogen in human tumors that is expressed intracellularly rather than on the surface of cells. On their own, NY-ESO-1 mAb could neither augment antigen-specific CD8(+) T-cell induction nor cause tumor eradication. To facilitate mAb access to intracellular target molecules, we combined anti-NY-ESO-1 mAb with anticancer drugs to accentuate the release of intracellular NY-ESO-1 from dying tumor cells. Strikingly, combination therapy induced a strong antitumor effect that was accompanied by the development of NY-ESO-1-specific effector/memory CD8(+) T cells that were not elicited by single treatments alone. The combinatorial effect was also associated with upregulation of maturation markers on dendritic cells, consistent with the organization of an effective antitumor T-cell response. Administration of Fc-depleted F(ab) mAb or combination treatment in Fc gamma receptor-deficient host mice abolished the therapeutic effect. Together, our findings show that intracellular tumor antigens can be captured by mAbs and engaged in an efficient induction of CD8(+) T-cell responses, greatly expanding the possible use of mAb for passive cancer immunotherapy. Cancer Res; 72(7); 1672-82. (C)2012 AACR.

Extrapleural hematoma as a complication following thoracotomy for pulmonary lobectomy.
Takuro Noguchi, Yasuhiro Hida, Kichizo Kaga, Masaya Kawada, Hiroto Niizeki, Satoshi Kondo
General thoracic and cardiovascular surgery, 59, 1, 57, 60, 2011年01月, ［査読有り］, ［国内誌］
英語, 研究論文（学術雑誌）, Extrapleural hematoma as a complication following thoracic surgery is rare. We report a case of an extrapleural hematoma following pleural lobectomy that resolved completely with nonsurgical treatment. A 63-year-old woman underwent left lower lobectomy for lung cancer through a left posterolateral thoracotomy. She had been prescribed the anticoagulant cilostazol to increase her heart rate for atrioventricular dissociation. Preoperatively, it was stopped, and a temporary pacemaker was placed to counteract bradycardia via the right jugular vein without complication. The chest tube was removed, and cilostazol was resumed on the third postoperative day. On day 7, she suddenly experienced left shoulder pain followed by hypotension, tachycardia, and anemia. Enhanced computed tomography (CT) revealed an extrapleural hematoma rather than a hemothorax. She became symptomatic after rapid infusion. The hematoma resolved without an invasive intervention. The CT results 189 days after the onset showed almost complete regression of the hematoma.

Peptide Vaccine Induces Enhanced Tumor Growth Associated with Apoptosis Induction in CD8(+) T Cells
Daisuke Muraoka, Takuma Kato, Linan Wang, Yuka Maeda, Takuro Noguchi, Naozumi Harada, Kazuyoshi Takeda, Hideo Yagita, Philippe Guillaume, Immanuel Luescher, Lloyd J. Old, Hiroshi Shiku, Hiroyoshi Nishikawa
JOURNAL OF IMMUNOLOGY, 185, 6, 3768, 3776, AMER ASSOC IMMUNOLOGISTS, 2010年09月, ［査読有り］
英語, 研究論文（学術雑誌）, CD8(+) CTLs play a critical role in antitumor immunity. However, vaccination with synthetic peptide containing CTL epitopes has not been generally effective in inducing protective antitumor immunity. In this study, we addressed the detailed mechanism(s) involved in this failure using a new tumor model of BALB/c transplanted tumors expressing NY-ESO-1, an extensively studied human cancer/testis Ag. Whereas peptide immunization with an H2-D-d-restricted CTL epitope derived from NY-ESO-1 (NY-ESO-1 p81-88) induced NY-ESO-1(81-88)-specific CD8(+) T cells in draining lymph nodes and spleens, tumor growth was significantly enhanced. Single-cell analysis of specific CD8(+) T cells revealed that peptide immunization caused apoptosis of > 80% of NY-ESO-1(81-88)-specific CD8(+) T cells at tumor sites and repetitive immunization further diminished the number of specific CD8(+) T cells. This phenomenon was associated with elevated surface expression of Fas and programmed death-1. When peptide vaccination was combined with an adjuvant, a TLR9 ligand CpG, the elevated Fas and programmed death-1 expression and apoptosis induction were not observed, and vaccine with peptide and CpG was associated with strong tumor growth inhibition. Selection of appropriate adjuvants is essential for development of effective cancer vaccines, with protection of effector T cells from peptide vaccine-induced apoptosis being a prime objective. The Journal of Immunology, 2010, 185: 3768-3776.

Minimally Invasive Esophagectomy for Cancer Patients with Low Pulmonary Function
Takuro Noguchi, Toshiaki Shichinohe, Satoshi Hirano, Satoshi Kondo
HEPATO-GASTROENTEROLOGY, 57, 101, 768, 771, H G E UPDATE MEDICAL PUBLISHING S A, 2010年07月, ［査読有り］
英語, 研究論文（学術雑誌）, Background/Aims: The aim of the study is to assess postoperative pulmonary complications after minimally invasive esophagectomy for cancer patients with severe preoperative pulmonary dysfunction.
Methodology: From 2004 to 2007, 37 patients underwent minimally invasive esophagectomy for esophageal cancer in our department. This procedure included hand-assisted thoracoscopic surgery and mediastinoscope-assisted transhiatal esophagectomy. The preoperative pulmonary function was evaluated using spirometry based on the Global Initiative for Chronic Obstructive Lung Disease system. Five of them had severe preoperative pulmonary dysfunction.
Results: Two of these patients developed aspiration pneumonia after the operation, which was successfully treated with antibiotics. The operating time, the incidence of postoperative pulmonary complication, and the duration of hospital stay were comparable for these five patients and those without preoperative pulmonary dysfunction.
Conclusion: Minimally invasive esophagectomy can be safely performed for esophageal cancer patients with severe preoperative pulmonary dysfunction.

Two Distinct Mechanisms of Augmented Antitumor Activity by Modulation of Immunostimulatory/Inhibitory Signals
Jun Mitsui, Hiroyoshi Nishikawa, Daisuke Muraoka, Linan Wang, Takuro Noguchi, Eiichi Sato, Satoshi Kondo, James P. Allison, Shimon Sakaguchi, Lloyd J. Old, Takuma Kato, Hiroshi Shiku
CLINICAL CANCER RESEARCH, 16, 10, 2781, 2791, AMER ASSOC CANCER RESEARCH, 2010年05月, ［査読有り］
英語, 研究論文（学術雑誌）, Purpose: Blockade of CTL-associated antigen-4 (CTLA-4), an inhibitory immunomodulatory molecule on T cells, has been shown to enhance T-cell responses and induce tumor rejection, and a number of clinical trials with anti-CTLA-4 blocking monoclonal antibody (mAb) are under way. However, accumulating evidence indicates that anti-CTLA-4 mAb increases the number of CD4(+)CD25(+)Foxp3(+) regulatory T cells (Treg) and that anti-CTLA4 mAb alone is often insufficient to reject established tumors in mice and humans. Thus, finding maneuvers to control Tregs and other immunosuppressive mechanisms remains a critical challenge.
Experimental Design: The potential to enhance antitumor immune responses by combining anti-CTLA-4 mAb with anti-glucocorticoid-induced tumor necrosis factor receptor family related gene (GITR) mAb, a costimulatory molecule that abrogates directly/indirectly Treg-mediated immune suppression or anti-CD25 mAb that depletes Tregs was analyzed with two tumor models, CT26 (a murine colon carcinoma cell line) and CMS5a (a murine fibrosarcoma cell line).
Results: Anti-CTLA-4/anti-GITR mAb combination treatment exhibited far stronger antitumor effects compared with either antibody alone. This strong antitumor effect was attributed to (a) increased numbers of CD8(+) T cells infiltrating tumor sites in anti-CTLA-4 mAb-treated mice and (b) increased cytokine secretion and Treg resistance of tumor-specific CD8(+) T cells with strongly upregulated CD25 expression in anti-GITR mAb-treated mice, indicating distinct quantitative/qualitative changes induced by modulating CTLA-4 and GITR signaling.
Conclusions: This study shows that combined treatment with different immune modulators can augment antitumor immune responses and provides justification for exploring anti-CTLA-4/anti-GITR mAb combination treatment in the clinic. Clin Cancer Res; 16(10); 2781-91. (C) 2010 AACR.

Osimertinibの早期中毒性皮疹出現症例に減感作再投与療法を試みた2例
渡辺 宏晃, 三村 享, 福嶋 敏郎, 野口 卓郎, 小沢 岳澄, 小林 孝至, 関口 和, 大森 栄, 小泉 知展, 癌と化学療法, 46, 5, 961, 963, 2019年05月
osimertinib投与早期に重篤な中毒性紅斑性皮疹を認め、投与を断念せざるを得なかった患者に対し減感作療法を行うことで再度投与を継続できた2症例を経験した。症例1:患者は60歳、女性。右上葉原発性肺腺がん[pT2aN2M0、stage IIIA、EGFR(Del19)遺伝子変異陽性]の術後再発例。afatinibによる一次治療後に多発肺転移および胸腺播種を認め、再生検でT790Mが陽性であった。osimertinibによる治療(80mg/day)を開始したが、服用開始10日目から紅斑や発熱などの全身症状が出現し、中毒性皮疹と診断されosimertinib治療が中止となった。osimertinibによる減感作療法を施行し、その後軽度の発赤の発現を認めたが、osimertinib 80mg/dayまで増量し、内服継続可能であった。症例2:患者は94歳、女性。EGFR(Del19)遺伝子変異陽性肺腺がん(cT4aN1M1b、stage IV)、多発肺、脳、肝転移および胸膜播種の患者。gefitinibによる一次治療を開始したが再発。liquid biopsyでT790M陽性と診断され、osimertinibによる治療が開始された。内服3日目にそう痒感を伴う全身の浮腫性紅斑が出現したため、osimertinibが中止された。osimertinibによる減感作療法を開始し、grade 2の皮疹が出現したが、抗ヒスタミン薬内服で軽快し、osimertinib 80mg/dayの服用を継続できた。両患者ともに良好な腫瘍縮小効果が認められ、osimertinibによる減感作療法はosimertinib不耐となった患者に有効な再投与法であると考えられた。(著者抄録), (株)癌と化学療法社, 日本語

抗体について教えてください　　　　　　　　　　　　　　　
野口 卓郎, Immuno-Oncology Frontier, 1, 1, 34, 35, 2015年01月
(株)メディカルレビュー社, 日本語

細胞内腫瘍抗原に対する新規抗体療法の開発
野口 卓郎, 加藤 琢磨, 王 立楠, 池田 裕明, 佐藤 永一, KNUTH Alexander, GNJATIC Sacha, RITTER Gerd, 坂口 志文, OLD Lloyd, 宮本 正樹, 平野 聡, 珠玖 洋, 西川 博嘉, 北海道醫學雜誌 = Acta medica Hokkaidonensia, 88, 1, 2013年01月01日
日本語

RS-308 肝切除を伴う胆嚢癌手術術式の検討(要望演題20 胆嚢癌に必要な肝切除とは,第63回日本消化器外科学会総会)
野口 卓郎, 平野 聡, 田中 栄一, 七戸 俊明, 鈴木 温, 佐川 憲明, 橋田 秀明, 近藤 哲, 日本消化器外科学会雑誌, 41, 7, 1135, 1135, 2008年07月01日
一般社団法人日本消化器外科学会, 日本語

RS-332 肝切除術における自動縫合器の応用 : グリソン処理に用いた場合の有用性と問題点(要望演題21-3 自動縫合器の使用法 肝・胆・膵,第63回日本消化器外科学会総会)
新垣 雅人, 田中 栄一, 野口 卓郎, 加藤 健太郎, 橋田 秀明, 佐川 憲明, 鈴木 温, 七戸 俊明, 平野 聡, 近藤 哲, 日本消化器外科学会雑誌, 41, 7, 1138, 1138, 2008年07月01日
一般社団法人日本消化器外科学会, 日本語

DP-001-6 IPMNに対する周囲臓器を温存した膵実質のみの切除 : Parenchymal Pancreatectomy(第108回日本外科学会定期学術集会)
田中 栄一, 平野 聡, 鈴木 温, 佐川 憲明, 市村 龍之助, 橋田 秀明, 鈴置 真人, 野口 卓郎, 近藤 哲, 日本外科学会雑誌, 109, 2, 347, 347, 2008年04月25日
一般社団法人日本外科学会, 日本語

DP-099-6 StageIII・IV胆嚢癌に対する外科的治療戦略(第108回日本外科学会定期学術集会)
橋田 秀明, 野口 卓郎, 市村 龍之助, 鈴置 真人, 佐川 憲明, 鈴木 温, 七戸 俊明, 田中 栄一, 平野 聡, 近藤 哲, 日本外科学会雑誌, 109, 2, 543, 543, 2008年04月25日
一般社団法人日本外科学会, 日本語

24年間の経過をたどり巨大嚢胞を形成した甲状腺乳頭癌の1例
野口 卓郎, 高橋 弘昌, 高橋 将人, 細田 充主, 佐々木 彩実, 藤堂 省, 日本臨床外科学会雑誌, 68, 1, 27, 30, 2007年01月
症例は70歳,男性.1982年,前頸部に約11×6cm大の腫瘤を認め,当科を初診し,針生検にて甲状腺乳頭癌,T3N3M0(現取扱い規約上T4aN1bM0)と診断された.術後の永久気管瘻がほぼ不可避との説明を受け,手術を拒否し,以降外来を受診していなかった.2006年4月,前頸部に突出する皮下腫瘤からの淡血性液の噴出を認め,当科を受診し即日入院となった.全身状態は良好であり,直ちに腫瘤穿刺により嚢胞液500mlを吸引したが,翌日には元の大きさに戻り緊急手術の方針となった.甲状腺峡部から左葉にかけて約11×15cm大の嚢胞性腫瘤を認め,皮下にも進展していた.可及的に気管浸潤部を剥離し甲状腺峡部左葉切除術施行した.術後,嗄声,誤飲なく経過は良好で,第7病日に頸部ドレーン抜去後,滲出液等貯留なく,第12病日に退院となった.24年間の自然経過により巨大嚢胞を形成した甲状腺乳頭癌の1切除例を経験したので報告する.(著者抄録), 日本臨床外科学会, 日本語

多血症を伴う末梢型肺腫瘤影を呈した肺梗塞の1切除例
野口 卓郎, 鈴木 雅行, 朝田 政克, 伊藤 清高, 橋本 正人, 日本呼吸器外科学会雑誌, 20, 7, 914, 918, 2006年11月
症例は38歳、男性。じん肺検診で、胸部CT上左肺S8に約1cm大の結節影を認めた。CTで腫瘤の辺縁は比較的明瞭で周囲に淡い浸潤影を伴っていた。喀痰細胞診、CTガイド下穿刺細胞診では悪性の所見は認めなかったが、画像所見上悪性の可能性が否定できないことから、胸腔鏡下肺部分切除を施行した。胸腔鏡下では腫瘍の位置が同定できず、小開胸を追加、用手的に同定し、肺部分切除を施行した。標本を術中迅速病理診に提出し、肺梗塞疑いの所見を得たため、それ以上の胸腔内操作を追加せず手術終了とした。本症例は多血症を合併しており、肺梗塞との因果関係が推測された。肺梗塞により腫瘤影を呈したまれな症例を経験したので報告する。(著者抄録), (NPO)日本呼吸器外科学会, 日本語

硝子化した虫垂壁を表在性に進展した早期虫垂粘液嚢胞腺癌の1例 早期虫垂癌の治療方針の検討
野口 卓郎, 鈴木 康弘, 高橋 基夫, 近藤 哲, 日本外科系連合学会誌, 31, 2, 209, 213, 2006年04月
症例は71歳,男性.自覚症状はなし.腹部CTで骨盤内嚢胞性病変認め,下部消化管内視鏡を施行し,盲腸が壁外から圧排される像を認めたが,組織診は得られなかった.虫垂粘液嚢胞腺腫,または癌の診断で,手術を行った.下腹部正中切開にてアプローチし,虫垂の腫大を認めたが,播種病変,腹水,リンパ節腫大を認めず虫垂切除のみ施行した.術後病理診断は,高分化型粘液嚢胞腺癌であった.全層硝子化した壁に対して癌を表在性に認め,深達度は大部分でm相当と診断され,リンパ管侵襲,脈管侵襲陰性のため,追加切除せず経過観察の方針とした.術後12ヵ月経過し,無再発生存中である(著者抄録), 日本外科系連合学会, 日本語

画像上肉腫様変化も疑った大腸脂肪腫の1例
野口 卓郎, 鈴木 康弘, 高橋 基夫, 近藤 哲, 日本外科系連合学会誌, 30, 5, 771, 774, 2005年10月
症例は47歳女性.腹痛,下血に対して大腸内視鏡を施行し,S状結腸に粘膜下腫瘍を認めた.生検で悪性所見は認めなかった.大腸脂肪腫と考えられたが,表面にびらんを伴っており,CTで内部が不均一であったことから肉腫様変化も疑われた.大きさから内視鏡的切除は困難と考え,リンパ節郭清を伴う結腸切除術を施行した.術後病理診断は大腸脂肪腫で,表面のびらんは細菌感染によるものであり,内部不均一なCT像は高度炎症による線維性隔壁の増生であることが示された.非典型所見を示す大腸脂肪腫を経験したので報告した(著者抄録), 日本外科系連合学会, 日本語

早期胃癌に対する完全腹腔鏡下幽門側胃切除,再建と左副腎同時切除の経験
野口 卓郎, 奥芝 俊一, 手術, 59, 9, 1363, 1366, 2005年08月
78歳男.検診で体下部大彎後壁に約2cm大の隆起病変を認め,内視鏡的粘膜切除術(EMR)を施行した.病理検査で,胃癌と確診された.EMR施行3ヵ月後に同部位に隆起病変を認めた.生検を施行し,EMR後の胃癌再発と診断した.同時期に,CT上左副腎腫瘍も指摘された.胃癌EMR施行後の遺残再発癌と診断した.深達度は内視鏡所見,および,EMR検体病理所見から,SM1と診断し,腹腔鏡下幽門側胃切除,Billroth I法再建の方針とした.術後1日目より,病室内での歩行が可能で,術後3日目には病棟内の歩行が可能になった.経口摂取に関しては,術後4日目から水分摂取を開始とし,術後7日目には全粥7割程度の摂食が可能となった.合併症なく経過し,術後13日目に退院した, 金原出版(株), 日本語

漿膜浸潤を疑う胃印環細胞癌に対し,開腹術に先行した腹腔鏡検査で腹膜播種を評価した1例
野口 卓郎, 奥芝 俊一, 北城 秀司, 森川 利昭, 近藤 哲, 加藤 紘之, 北海道外科雑誌, 50, 1, 19, 22, 2005年06月
52歳女.患者は貧血を指摘され,上部消化器内視鏡にて胃体上部大彎後壁に陥凹性病変を認めた.癌の進展度については陥凹面よりも広範に進行しており,深達度MPが疑われる胃印環細胞癌と診断された.漿膜層への微小浸潤の可能性を考慮し,腹膜播種に関して精査が必要と考え,開腹術に先行して腹腔鏡検査を施行した.その結果,細胞診ではCY0と診断された.胃全摘,脾摘,D2郭清を施行したところ,病理では腫瘍の進展範囲は1.0cm×4.0cmで,組織学的には粘膜層に印環細胞を認め,腫瘍細胞は散在性に漿膜下まで達していた.CAM5.2染色でも,腫瘍細胞は散在性に漿膜下に浸潤していた.術後はTS-1を内服し,16ヵ月が経過現在,再発は認められていない, 北海道外科学会, 日本語

がんと免疫　　　　　　　　　　　　　　　
信州大学医学部附属病院

肺癌免疫療法におけるメモリー型T細胞・樹状細胞クロストークの解明
科学研究費助成事業
2023年04月01日 - 2026年03月31日
野口 卓郎
日本学術振興会, 基盤研究(C), 北海道大学, 23K07617

宿主免疫抑制性分子を標的とした新規肺癌免疫療法の開発　　　　　　　　　　　　　　　
橋渡し研究プログラム・研究開発シーズA
2023年04月 - 2024年03月
日本医療研究開発機構(AMED), 研究代表者

切除不能進行肺癌に対する免疫抑制経路Ｘの標的検証　　　　　　　　　　　　　　　
創薬ブースター
2024年 - 2024年
日本医療研究開発機構(AMED), 研究代表者, DNW-24006

がん患者末梢血浮遊DNAの全身性炎症反応への役割の解明
科学研究費助成事業 若手研究
2019年04月01日 - 2022年03月31日
野口 卓郎
1）腫瘍細胞死により腫瘍細胞から放出されるcfDNAの腫瘍微小環境への影響を検証するin vitro実験系を確立した。ヒトEGFR変異陽性非小細胞肺癌細胞株を、EGFR変異を標的とした分子標的薬であるEGFRチロシンキナーゼ阻害薬で治療すると、培養上清中のcfDNA濃度が有意に上昇することを明らかとした。次に、このcfDNAの自然免疫系への影響を解析するために、IRFレポーターヒト単球細胞株を得た。このヒト単球細胞株は、腫瘍細胞由来cfDNAを取り込むことにより、IRFレポーターシグナルを誘導した。一方で、このヒト単球細胞株のSTINGをノックアウトした場合、腫瘍細胞由来cfDNAの取り込みにより観察されたIRFレポーターシグナルは消失した。これら結果は、腫瘍由来cfDNAはSTING依存性に自然免疫経路に関与することを示唆する。
2）EGFRチロシンキナーゼ阻害薬治療下のEGFR変異陽性非小細胞肺癌患者血漿中におけるcfDNA濃度の解析を行った。興味深いことに、治療効果を認める患者において、cfDNAの濃度は治療後有意に低下していた。In vitroの結果ではEGFR変異陽性肺癌細胞周囲のcfDNA濃度は治療により上昇することが示されたことから、EGFR変異陽性肺癌患者における腫瘍微小環境と末梢循環系におけるcfDNAの代謝には異なった制御機構が備わっている可能性が示唆された。
3）健常人末梢血からCD14陽性細胞由来マクロファージの分化誘導実験系を確立した。従来型で提唱されるM1/M2マクロファージに加え、そのサイトカインの組み合わせにより誘導される形質変化を評価することが可能となった。
日本学術振興会, 若手研究, 北海道大学, 19K16827

肺癌に対するメモリー型抗腫瘍T細胞誘導治療薬の開発　　　　　　　　　　　　　　　
橋渡し研究プログラム・研究開発シーズA
2021年04月 - 2022年03月
日本医療研究開発機構(AMED), 研究代表者

非小細胞肺癌に対するシアロ糖タンパク質を標的とした新規がん免疫治療の開発　　　　　　　　　　　　　　　
2020年 - 2020年
公益財団法人 秋山記念生命科学振興財団, 研究代表者