2022/03/30 更新

写真a

ムコウヤマ ノブアキ
向山 宣昭
MUKOYAMA Nobuaki
所属
医学部附属病院 耳鼻いんこう科 助教
大学院担当
大学院医学系研究科
職名
助教

学位 1

  1. 医学博士 ( 2019年3月   名古屋大学 ) 

 

論文 22

  1. A Nationwide Survey on Digestive Reconstruction Following Pharyngolaryngectomy With Total Esophagectomy: A Multicenter Retrospective Study in Japan

    Okamura Akihiko, Watanabe Masayuki, Mukoyama Nobuaki, Ota Yoshihiro, Shiraishi Osamu, Shimbashi Wataru, Baba Yoshifumi, Matsui Hidetoshi, Shinomiya Hirotaka, Sugimura Keijiro, Morita Masaru, Sakai Makoto, Sato Hiroshi, Shibata Tomotaka, Nasu Motomi, Matsumoto Shuichi, Toh Yasushi, Shiotani Akihiro

    ANNALS OF GASTROENTEROLOGICAL SURGERY   6 巻 ( 1 ) 頁: 54 - 62   2022年1月

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    記述言語:日本語   出版者・発行元:Annals of Gastroenterological Surgery  

    Aim: Digestive reconstruction after pharyngolaryngectomy with total esophagectomy (PLTE) remains challenging, with the optimal method remaining unclear. The current study aimed to clarify the short-term outcomes after PLTE and determine the optimal digestive reconstruction method. Methods: Based on a nationwide survey of 151 patients who underwent PLTE, outcomes of digestive reconstruction methods are described. Results: Among digestive reconstruction methods, a simple gastric tube was most frequently used (37.1%), followed by gastric tube combined with free graft transfer (FGT) (35.1%), gastric tube with microvascular anastomosis (22.5%), and other procedures (5.3%). Intraoperative evaluation of microcirculation (IOEM) was utilized in 29 patients (19.2%). Among the included patients, 66.9% developed any-grade complications, 41.0% developed severe complications, and 23.8% developed digestive reconstruction-related complications (DRRCs; leakage or necrosis). Reoperation within 30 days for any complications and DRRCs was required in 13.9% and 8.6% of the patients, respectively. Mortality within 90 days was observed in 4.6%. Among the three major methods, gastric tube combined with FGT promoted the least DRRCs in the gastric tube (P =.005), although the overall incidence of DRRCs was comparable. The use of IOEM was significantly associated with a reduction of severe DRRCs (P =.005). Conclusions: Pharyngolaryngectomy with total esophagectomy is a high-risk surgery significantly associated with the occurrence of postoperative morbidity and mortality. Nonetheless, the addition of FGT can help prevent gastric tip complications, while IOEM can be an effective method for improving outcomes.

    DOI: 10.1002/ags3.12509

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  2. Surgical Strategy for Squamous Cell Carcinoma of the External Auditory Canal: Management of Locally Advanced Cases with Skull Base Involvement

    Goto S., Nishio N., Iwami K., Yoshida T., Maruo T., Mukoyama N., Tsuzuki H., Yokoi S., Wada A., Hiramatsu M., Hayashi Y., Kamei Y., Fujii M., Sone M., Fujimoto Y.

    Journal of Neurological Surgery, Part B: Skull Base     2022年

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    記述言語:日本語   出版者・発行元:Journal of Neurological Surgery, Part B: Skull Base  

    ObjectiveSurgical indications for advanced-stage squamous cell carcinoma (SCC) of the external auditory canal (EAC) are highly dependent on the skull base surgery team. The aim of this study was to evaluate the surgical outcomes in patients with SCC of the EAC and to clarify the surgical indication of far advanced cases using the T4 subclassification. MethodsPatients with SCC of the EAC who underwent curative treatment from 2002 to 2021 at our hospital were retrospectively reviewed. Clinical and surgical results, including operative data, overall survival (OS), and disease-specific survival (DSS), were analyzed. To clarify the surgical indication for advanced-stage tumors, we proposed the T4 subclassification. ResultsIn the 46 patients included in the study, 8 patients had T1 tumors, 10 had T2 tumor, 5 had T3 tumors, and 23 had T4 tumors. The 5-year DSS with T1, T2, T3, and T4 tumors were 100, 85.7, 100, and 61.7%, respectively. No prognostic impacts for margin status were found between the 5-year OS and DSS (p = 0.23 and 0.13, respectively). Patients with far-advanced-stage (T4b) tumors were significantly associated with shorter DSS than those with early-stage (T1/T2) and advanced-stage (T3/T4a) tumors (p = 0.007 and 0.03, respectively). ConclusionThe present study focused on patients with SCC of the EAC at a university hospital over a period of 20 years, especially with skull base involvement, and a T4 subclassification was proposed. Complete tumor resection in an en bloc fashion could help achieve a good survival rate even in patients with locally advanced tumors.

    DOI: 10.1055/a-1733-2585

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  3. S-1 facilitates canerpaturev (C-REV)-induced antitumor efficacy in a triple-negative breast cancer model

    Miyajima Noriyuki, Eissa Ibrahim Ragab, Abdelmoneim Mohamed, Naoe Yoshinori, Ichinose Toru, Matsumura Shigeru, Bustos-Villalobos Itzel, Mukoyama Nobuaki, Morimoto Daishi, Shibata Masahiro, Takeuchi Dai, Tsunoda Nobuyuki, Kikumori Toyone, Tanaka Maki, Kodera Yasuhiro, Kasuya Hideki

    NAGOYA JOURNAL OF MEDICAL SCIENCE   83 巻 ( 4 ) 頁: 683 - 696   2021年11月

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    記述言語:日本語   出版者・発行元:Nagoya Journal of Medical Science  

    Canerpaturev (C-REV) is a highly attenuated, replication-competent, mutant strain of oncolytic herpes simplex virus type 1 that may be an effective new cancer treatment option. S-1, an oral formulation containing the 5-fluorouracil (5-FU) prodrug tegafur and the two enzyme modulators gimeracil and oteracil, is used as a key chemotherapeutic agent for metastatic recurrent breast cancer. Although the antitumor effects of oncolytic viruses combined with 5-FU in vivo have been reported, the detailed mechanisms are unknown. Here, we investigated the antitumor mechanism of the combination of C-REV and S-1 in triple-negative breast cancer (TNBC) in the context of tumor immunity. The combined effect of C-REV and S-1 was evaluated in a bilateral tumor model of murine TNBC 4T1 in vivo. S-1 enhanced the TNBC growth inhibitory effects of C-REV, and decreased the number of tumor-infiltrating, myeloid-derived suppressor cells (MDSCs), which suppress both innate and adaptive immune responses. Moreover, C-REV alone and in combination with S-1 significantly increased the number of CD8+ T cells in the tumor and the production of interferon γ (IFNγ) from these cells. Our findings indicate that C-REV suppresses TNBC tumor growth by inducing the expansion of effector CD8+ T cell subsets in tumors in which S-1 can inhibit MDSC function. Our study suggests that MDSCs may be an important cellular target for breast cancer treatment. The combination of C-REV and S-1 is a new approach that might be directly translated into future clinical trials against TNBC.

    DOI: 10.18999/nagjms.83.4.683

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  4. Oncolytic herpes simplex virus HF10 (canerpaturev) promotes accumulation of CD8(+)PD-1(-) tumor-infiltrating T cells in PD-L1-enriched tumor microenvironment

    Eissa Ibrahim Ragab, Mukoyama Nobuaki, Abdelmoneim Mohamed, Naoe Yoshinori, Matsumura Shigeru, Bustos-Villalobos Itzel, Ichinose Toru, Miyajima Noriyuki, Morimoto Daishi, Tanaka Maki, Fujimoto Yasushi, Sone Michihiko, Kodera Yasuhiro, Kasuya Hideki

    INTERNATIONAL JOURNAL OF CANCER   149 巻 ( 1 ) 頁: 214 - 227   2021年7月

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    記述言語:日本語   出版者・発行元:International Journal of Cancer  

    Oncolytic viruses (OVs) remodel the tumor microenvironment by switching a “cold” tumor into a “hot” tumor with high CD8+ T-cell infiltration. CD8+ T-cell activity plays an essential role in the antitumor efficacy of OVs. However, the activity of T cells is impaired by the programmed cell death protein-1/programmed cell death-ligand 1 (PD-1/PD-L1) interaction. To date, it remains unclear why OVs alone have a significant antitumor activity even when PD-L1 expression persists on tumor or immune cells. In this study, we found that canerpaturev (C-REV) treatment significantly suppressed tumor growth, even though it induced a significant increase in PD-L1 expression in tumors in vivo as well as persistence of high PD-L1 expression on antigen-presenting cells (macrophage and dendritic cells [DCs]). Surprisingly, we observed that C-REV treatment increased the abundance of activated CD8+PD-1− tumor-infiltrating lymphocytes (TILs) in the tumor on both the injected and contralateral sides, although infiltration of CD8+PD-1high TILs into the tumor was observed in the control group. Moreover, the difference in PD-1 expression was observed only in tumors after treatment with C-REV, whereas most CD8+ T cells in the spleen, tumor-draining lymph nodes and blood were PD-1-negative, and this did not change after C-REV treatment. In addition, changes in expression of T-cell immunoglobulin and mucin-domain containing-3 and T-cell immune-receptor with Ig and ITIM domains were not observed on CD8+ TILs after C-REV treatment. Taken together, our findings may reveal mechanisms that allow OVs to trigger an antitumor immune response, irrespective of a PD-L1-enriched tumor microenvironment, by recruitment of CD8+PD-1− TILs.

    DOI: 10.1002/ijc.33550

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  5. Surgical Classification of Radical Temporal Bone Resection and Transcranial Tympanotomy: A Retrospective Study from the Neurosurgical Perspective

    Iwami Kenichiro, Fujii Masazumi, Nishio Naoki, Maruo Takashi, Yoshida Tadao, Mukoyama Nobuaki, Osuka Koji, Takanari Keisuke, Murotani Kenta, Kamei Yuzuru, Sone Michihiko, Fujimoto Yasushi, Saito Kiyoshi

    WORLD NEUROSURGERY   151 巻   頁: E192 - E207   2021年7月

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    記述言語:日本語   出版者・発行元:World Neurosurgery  

    Objective: To review the authors' surgical experience with radical temporal bone resection (TBR) with an emphasis on the classification of skull base osteotomy and transcranial tympanotomy (TCT) that is required for middle ear transection. Methods: We reviewed the records of 25 patients who underwent radical TBR at our facilities between 2011 and 2020. Results: The osteotomy line of radical TBR was divided into 3 segments: anterior (A), medial (M), and posterior (P). Each segment was further classified as follows: A1, through the glenoid fossa (1 patient); A2, in front of the glenoid fossa (23 patients); A3, through the greater wing of the sphenoid bone (1 patient); M1, through the middle ear (16 patients); M2, through the inner ear (9 patients); P1, through the mastoid (9 patients); and P2, through the posterior cranial fossa (16 patients). The M segment was significantly associated with operation time and intraoperative blood loss. In all patients with M1 osteotomy, TCT was performed; TCT was classified into superior and far posterior approaches. A superior approach was performed in all 16 patients, whereas the far posterior approach was performed in only 7 patients with both M1 and P2 osteotomy. Conclusions: Our newly proposed osteotomy classification of radical TBR is suitable for minute but clinically important adjustment of the osteotomy line. TCT is an indispensable technique for M1 osteotomy; our newly proposed classification expands our understanding of TCT and how to incorporate this technique into radical TBR.

    DOI: 10.1016/j.wneu.2021.04.002

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  6. C-REV Retains High Infectivity Regardless of the Expression Levels of cGAS and STING in Cultured Pancreatic Cancer Cells

    Morimoto Daishi, Matsumura Shigeru, Bustos-Villalobos Itzel, Sibal Patricia Angela, Ichinose Toru, Naoe Yoshinori, Eissa Ibrahim Ragab, Abdelmoneim Mohamed, Mukoyama Nobuaki, Miyajima Noriyuki, Tanaka Maki, Kodera Yasuhiro, Kasuya Hideki

    CELLS   10 巻 ( 6 )   2021年6月

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    記述言語:日本語   出版者・発行元:Cells  

    Oncolytic virus (OV) therapy is widely considered as a major breakthrough in anti-cancer treatments. In our previous study, the efficacy and safety of using C-REV for anti-cancer therapy in patients during stage I clinical trial was reported. The stimulator of interferon genes (STING)– TBK1–IRF3–IFN pathway is known to act as the central cellular host defense against viral infection. Recent reports have linked low expression levels of cGAS and STING in cancer cells to poor prognosis among patients. Moreover, downregulation of cGAS and STING has been linked to higher susceptibility to OV infection among several cancer cell lines. In this paper, we show that there is little correlation between levels of cGAS/STING expression and susceptibility to C-REV among human pancreatic cancer cell lines. Despite having a responsive STING pathway, BxPC-3 cells are highly susceptible to C-REV infection. Upon pre-activation of the STING pathway, BxPc-3 cells exhibited resistance to C-REV infection. However, without pre-activation, C-REV completely suppressed the STING pathway in BxPC-3 cells. Additionally, despite harboring defects in the STING pathway, other high-grade cancer cell lines, such as Capan-2, PANC-1 and MiaPaCa-2, still exhibited low susceptibility to C-REV infection. Furthermore, overexpression of STING in MiaPaCa-2 cells altered susceptibility to a limited extent. Taken together, our data suggest that the cGAS– STING pathway plays a minor role in the susceptibility of pancreatic cancer cell lines to C-REV infection.

    DOI: 10.3390/cells10061502

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  7. Safety and feasibility of fat injection therapy with adipose-derived stem cells in a rabbit hypoglossal nerve paralysis model: A pilot study

    Wada Akihisa, Nishio Naoki, Yokoi Sayaka, Tsuzuki Hidenori, Mukoyama Nobuaki, Maruo Takashi, Hiramatsu Mariko, Yamamoto Tokunori, Goto Momokazu, Fujimoto Yasushi, Sone Michihiko

    AURIS NASUS LARYNX   48 巻 ( 2 ) 頁: 274 - 280   2021年4月

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    記述言語:日本語   出版者・発行元:Auris Nasus Larynx  

    Objective: The aim of this study is to establish a unilateral tongue atrophy model by cutting the hypoglossal nerve and to evaluate the safety and feasibility of a fat injection of adipose-derived stem cells (ADSCs) to restore swallowing function. Methods: A total of 12 rabbits were randomized to three groups; the ADSCs+fat group (n=4), the fat group (n=4) and the control group (n=4). All rabbits were treated with denervation of the left hypoglossal nerve and their conditions including body weight and food intake were checked during follow-up periods (8 weeks). At 4 weeks after the transection of the nerve, rabbits received the injection therapy into the denervated side of the tongue with 1.0mL fat tissue premixed with 0.5mL ADSCs in the ADSCs+fat group, 1.0mL fat tissue premixed with 0.5mL PBS in the fat group and 1.5mL PBS in the control group. Rabbits were euthanized 8 weeks post-treatment and resected tongues were collected, formalin-fixed and paraffin embedded. To evaluate the change of the intrinsic muscles of the tongue, muscle fibers around the treatment area was analyzed by evaluating 5 consecutive hematoxylin-eosin slides per rabbit. Results: Food intake did not decrease upon nerve denervation, and none of the rabbits displayed adverse effect such as aspiration, surgical wound dehiscence or infection. No significant body weight changes were found between the three groups at 4 and 8 weeks after nerve transection (p>0.05). In the control group, the denervated side of tongue had significantly smaller muscle fiber areas and diameters compared to the non-denervated side (p<0.05). The ADSCs+fat group demonstrated a larger area of inferior longitudinal muscle fibers compared to the control and the fat groups (582±312µm2 vs. 405±220µm2 and 413±226µm2; p<0.05). A significant thicker lesser diameter of inferior longitudinal muscle fibers was found in the ADSCs+fat group compared to the control and the fat groups (24±8µm vs. 20±6µm and 20±7µm; p<0.05). Conclusion: The rabbit tongue atrophy model was found suitable for the assessment of muscle change after nerve transection. Fat injection therapy with ADSCs demonstrated great potential to prevent the muscle atrophy after denervation and to promote the muscle regeneration around the injection area.

    DOI: 10.1016/j.anl.2020.08.003

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  8. Feasibility of virtual surgical simulation in the head and neck region for soft tissue reconstruction using free flap: a comparison of preoperative and postoperative volume measurement

    Yokoi S., Nishio N., Fujimoto Y., Fujii M., Iwami K., Hayashi Y., Takanari K., Hiramatsu M., Maruo T., Mukoyama N., Tsuzuki H., Wada A., Kamei Y., Sone M.

    INTERNATIONAL JOURNAL OF ORAL AND MAXILLOFACIAL SURGERY   50 巻 ( 3 ) 頁: 316 - 322   2021年3月

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    記述言語:日本語   出版者・発行元:International Journal of Oral and Maxillofacial Surgery  

    In the head and neck region, preoperative evaluation of the free flap volume is challenging. The current study validated preoperative three-dimensional (3D) virtual surgical simulation for soft tissue reconstruction by assessing flap volume and evaluated fat and muscle volume changes at follow-up in 13 head and neck cancer patients undergoing anterolateral craniofacial resection. Patients received 3D virtual surgical simulation, and the volume of the planned defects was estimated by surgical simulation. Following en bloc resection of the tumor, the defect in the skull base was covered using a rectus abdominis myocutaneous flap. Following surgery, computed tomography scans were acquired at day 1 and at 6 and 12 months. Virtual planned defect was on average 227 ml (range, 154–315) and was 10% smaller than the actual flap volume in patients without skin involvement of the tumor. Between day 1 and 12 months post-surgery, the volume of fat and muscle tissue in the free flap dropped by 9% and 58%, respectively. Our results indicate that 3D virtual surgical simulation provides essential information in determining the accurate volume of the required free flap for surgical defect repair and may thus help improve surgical planning and functional and esthetic outcome.

    DOI: 10.1016/j.ijom.2020.07.025

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  9. 当院における気管切開術の現状と問題点

    横井 麻衣, 平松 真理子, 向山 宣昭, 藤本 保志, 曾根 三千彦

    日本気管食道科学会会報   72 巻 ( 1 ) 頁: 10 - 15   2021年2月

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    記述言語:日本語   出版者・発行元:特定非営利活動法人 日本気管食道科学会  

    <p>経皮的気管切開術(PDT)は外科的気管切開術(ST)と比べて手術時間が短く簡便でありICU等のベッドサイドで施行される例が増えている。当院におけるSTとPDTについて比較検討すると,STが157例,PDTは25例施行されており,抜管困難による気管切開術を選択する症例が最も多かった。合併症は創部感染12例,術後出血6例,チューブ閉塞8例,交換困難4例,気道肉芽5例であり,創部感染率はSTの方が高かった。術後出血と交換困難については,それぞれPDT術後の出血が持続し処置に難渋した症例と,穿刺時の輪状軟骨前壁損傷による交換困難を生じた症例を経験した。当院におけるPDTは主科(他科)が行う傾向がある。われわれが経験した術後治療に難渋した2症例は,ともに最初の穿刺場所が問題点と考えられ,穿刺前に体表からメルクマールとなる甲状軟骨,輪状軟骨などがわかりにくい症例はSTの方が安全である可能性が示唆される。また,安全性を高めるためには,適応を十分に考慮する必要がある。</p>

    DOI: 10.2468/jbes.72.10

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  10. Investigation of parotid gland cancer surgery that preserved the facial nerve

    Hamabata R., Mukoyama N., Nishio N., Maruo T., Hiramatsu M., Yokoi S., Sone M., Fujimoto Y.

    Japanese Journal of Head and Neck Cancer   47 巻 ( 3 ) 頁: 316 - 321   2021年

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    記述言語:日本語   出版者・発行元:Japanese Journal of Head and Neck Cancer  

    Summary There are few reports on the transition and prognosis of postoperative facial nerve paralysis in patients undergoing parotid gland cancer surgery that preserves the facial nerve. The treatment policy for parotid gland cancer in our department is, in principle, combined resection of the facial nerve and one-stage reconstruction of the nerve if there is facial nerve paralysis before surgery, and preservation of the nerve if there is no paralysis regardless of histological type. We examined 31 cases of parotid gland cancer surgery that preserved the facial nerve over the past 15 years. The median observation period was 60 months. Total resection was performed in 24 cases, and lobectomy was performed in 7 cases. The average score of postoperative facial nerve paralysis was 24 points, and the median score was 27 points. The transition of postoperative facial nerve paralysis, although there were cases of transient complete paralysis, eventually recovered to an average of 39.5 points. The recovery period was 6 months after surgery in many cases. The treatment results were good, with 5-year overall survival rate, 5-year disease-free survival rate, and local control rate of 96.0%, 89.5%, and 93.5%, respectively. In cases of parotid gland cancer without facial nerve paralysis, treatment results are considered to be guaranteed even if the nerve is preserved regardless of the pathological type.

    DOI: 10.5981/jjhnc.47.316

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  11. Prospective Evaluation of Health-Related Quality of Life in Patients Undergoing Anterolateral Craniofacial Resection with Orbital Exenteration

    Mukoyama Nobuaki, Nishio Naoki, Kimura Hiroyuki, Kishi Shinichi, Tokura Tatsuya, Kimura Hiroki, Hiramatsu Mariko, Maruo Takashi, Tsuzuki Hidenori, Fujii Masazumi, Iwami Kenichiro, Takanari Keisuke, Kamei Yuzuru, Ozaki Norio, Sone Michihiko, Fujimoto Yasushi

    JOURNAL OF NEUROLOGICAL SURGERY PART B-SKULL BASE   81 巻 ( 05 ) 頁: 585 - 593   2020年10月

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    記述言語:日本語   出版者・発行元:Journal of Neurological Surgery, Part B: Skull Base  

    Objective  This study was aimed to evaluate health-related quality of life in patients undergoing anterolateral craniofacial resection (AL-CFR) with orbital exenteration (OE) for malignant skull base tumors and to investigate the effects of early psychiatric intervention. Design  Present study is a prospective, observational study. Setting  The study took place at the hospital department. Participants  Twenty-six consecutive patients were selected who underwent AL-CFR with OE at our hospital between 2005 and 2015. Main Outcome Measures  Health-related quality of life was assessed preoperatively and 3, 6, 12, and 24 months after surgery using the Hospital Anxiety and Depression Scale (HADS) and medical outcomes study 8-items Short Form health survey (SF-8). In all cases, psychiatric intervention was organized by the consultation liaison psychiatry team preoperatively and postoperatively. Results  Ten (38.0%) of the 26 patients died and 16 (62.0%) were alive and disease-free at the end of the study. The 3-year overall and disease-free survival rates were 64.9% and 53.3%, respectively. Twenty-one patients (80.8%) developed psychiatric complications after surgery and needed treatment with psychotropic medication. Before surgery, 28% of patients had HADS scores ≥8 for anxiety and 20% had scores ≥8 for depression. Seven of the eight items in the SF-8 were significantly lower than those for the general Japanese population. However, scores for all the SF-8 items gradually improved during postoperative follow-up, reaching approximately 50 points, which is the national standard value, at 2 years after surgery. Conclusions  Craniofacial resection with OE was feasible and well tolerated in patients with malignant skull base tumors who received early psychiatric intervention to decrease the considerable psychological impact of this procedure.

    DOI: 10.1055/s-0039-1694010

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  12. 気管切開術─安全な管理を導けるコツはなにか

    藤本 保志, 横井 麻衣, 平松 真理子, 向山 宣昭, 丸尾 貴志, 曾根 三千彦

    日本気管食道科学会会報   71 巻 ( 2 ) 頁: 82 - 82   2020年4月

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    記述言語:日本語   出版者・発行元:特定非営利活動法人 日本気管食道科学会  

    DOI: 10.2468/jbes.71.82

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  13. Diagnosis of cervical lymph node metastases in head and neck cancer with ultrasonic measurement of lymph node volume

    Nishio Naoki, Fujimoto Yasushi, Hiramatsu Mariko, Maruo Takashi, Tsuzuki Hidenori, Mukoyama Nobuaki, Yokoi Sayaka, Wada Akihisa, Furukawa Madoka Kaneko, Furukawa Masaki, Sone Michihiko

    AURIS NASUS LARYNX   46 巻 ( 6 ) 頁: 889 - 895   2019年12月

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    記述言語:日本語   出版者・発行元:Auris Nasus Larynx  

    Objective: The purpose of this study was to evaluate the usefulness of ultrasound (US) volume measurement of the cervical lymph nodes for diagnosing nodal metastasis in patients with head and neck cancer using a node-by-node comparison. Methods: Thirty-four consecutive patients with head and neck cancer from one tertiary university hospital were prospectively enrolled from 2012 to 2017. Patients with histologically proven squamous cell primary tumors in the head and neck region scheduled to undergo a therapeutic neck dissection were eligible. For each patient, 1–4 target lymph nodes were selected from the planned neck dissection levels. Lymph nodes with thickness >20 mm or in a cluster were excluded. Node-by-node comparisons between the pre-operative US assessment, the post-operative actual measurements and histopathological results were performed for all target lymph nodes. Quantitative measurements, such as three diameters, ratios of the three diameters and volume were analyzed in this study. Lymph node volume was calculated using the ellipsoid formula. Results: Patients comprised 28 men and 6 women with a mean age of 60.0 years (range, 29–80 years) at the time of surgery. In total, 67 target lymph nodes were analyzed in this study and the thickness ranged from 3.9 to 20.0 mm (mean 8.0 mm). There was a strong correlation between the US volume and post-operative actual volume (ρ = 0.87, p < 0.01). The US volume measured 2156 ± 2156 mm3 for the tumor positive nodes, which was significantly greater than the US volume of 512 ± 315 mm3 for tumor negative nodes (p < 0.01). Significant differences between tumor positive and tumor negative nodes were found in five variables (volume, thickness, major axis, minor axis and ratio of minor axis to thickness) for total lymph nodes. To identify predictors of lymph node metastasis, ROC curves of the US variables of target lymph nodes were compared, of which 4 variables were considered acceptable for predicting the lymph node metastasis: volume (AUC 0.86), thickness (AUC 0.86), major axis (AUC 0.79), and minor axis (AUC 0.79) for total lymph nodes. The optimal cut-off level for US volume in total lymph nodes was found to be 1242 mm3, whereby a 62% sensitivity and 98% specificity was reached (likelihood ratio: 25.2). Conclusion: Pre-operative ultrasonic volume measurement of the cervical lymph nodes was useful for early detection of cervical nodal metastasis in head and neck cancer.

    DOI: 10.1016/j.anl.2019.02.003

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  14. Combination of Cetuximab and Oncolytic Virus Canerpaturev Synergistically Inhibits Human Colorectal Cancer Growth

    Wu Zhiwen, Ichinose Toru, Naoe Yoshinori, Matsumura Shigeru, Villalobos Itzel Bustos, Eissa Ibrahim Ragab, Yamada Suguru, Miyajima Noriyuki, Morimoto Daishi, Mukoyama Nobuaki, Nishikawa Yoko, Koide Yusuke, Kodera Yasuhiro, Tanaka Maki, Kasuya Hideki

    MOLECULAR THERAPY-ONCOLYTICS   13 巻   頁: 107 - 115   2019年6月

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    記述言語:日本語   出版者・発行元:Molecular Therapy - Oncolytics  

    The naturally occurring oncolytic herpes simplex virus canerpaturev (C-REV), formerly HF10, proved its therapeutic efficacy and safety in multiple clinical trials against melanoma, pancreatic, breast, and head and neck cancers. Meanwhile, patients with colorectal cancer, which has increased in prevalence in recent decades, continue to have poor prognosis and morbidity. Combination therapy has better response rates than monotherapy. Hence, we investigated the antitumor efficacy of cetuximab, a widely used anti-epidermal growth factor receptor (EGFR) monoclonal antibody, and C-REV, either alone or in combination, in vitro and in an in vivo human colorectal xenograft model. In human colorectal cancer cell lines with different levels of EGFR expression (HT-29, WiDr, and CW2), C-REV exhibited cytotoxic effects in a time- and dose-dependent manner, irrespective of EGFR expression. Moreover, cetuximab had no effect on viral replication in vitro. Combining cetuximab and C-REV induced a synergistic antitumor effect in HT-29 tumor xenograft models by promoting the distribution of C-REV throughout the tumor and suppressing angiogenesis. Application of cetuximab prior to C-REV yielded better tumor regression than administration of the drug after the virus. Thus, cetuximab represents an ideal virus-associated agent for antitumor therapy, and combination therapy represents a promising antitumor strategy for human colorectal cancer.

    DOI: 10.1016/j.omto.2019.04.004

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  15. The Current Status and Future Prospects of Oncolytic Viruses in Clinical Trials against Melanoma, Glioma, Pancreatic, and Breast Cancers

    Eissa Ibrahim Ragab, Bustos-Villalobos Itzel, Ichinose Toru, Matsumura Shigeru, Naoe Yoshinori, Miyajima Noriyuki, Morimoto Daishi, Mukoyama Nobuaki, Wu Zhiwen, Tanaka Maki, Hasegawa Hitoki, Sumigama Seiji, Aleksic Branko, Kodera Yasuhiro, Kasuya Hideki

    CANCERS   10 巻 ( 10 )   2018年10月

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    記述言語:日本語   出版者・発行元:Cancers  

    Oncolytic viral therapy has been accepted as a standard immunotherapy since talimogene laherparepvec (T-VEC, Imlygic®) was approved by the Food and Drug Administration (FDA) and European Medicines Agency (EMA) for melanoma treatment in 2015. Various oncolytic viruses (OVs), such as HF10 (Canerpaturev—C-REV) and CVA21 (CAVATAK), are now actively being developed in phase II as monotherapies, or in combination with immune checkpoint inhibitors against melanoma. Moreover, in glioma, several OVs have clearly demonstrated both safety and a promising efficacy in the phase I clinical trials. Additionally, the safety of several OVs, such as pelareorep (Reolysin®), proved their safety and efficacy in combination with paclitaxel in breast cancer patients, but the outcomes of OVs as monotherapy against breast cancer have not provided a clear therapeutic strategy for OVs. The clinical trials of OVs against pancreatic cancer have not yet demonstrated efficacy as either monotherapy or as part of combination therapy. However, there are several oncolytic viruses that have successfully proved their efficacy in different preclinical models. In this review, we mainly focused on the oncolytic viruses that transitioned into clinical trials against melanoma, glioma, pancreatic, and breast cancers. Hence, we described the current status and future prospects of OVs clinical trials against melanoma, glioma, pancreatic, and breast cancers.

    DOI: 10.3390/cancers10100356

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  16. Pathological tumor volume predicts survival outcomes in oral squamous cell carcinoma

    Mukoyama Nobuaki, Suzuki Hidenori, Hanai Nobuhiro, Sone Michihiko, Hasegawa Yasuhisa

    ONCOLOGY LETTERS   16 巻 ( 2 ) 頁: 2471 - 2477   2018年8月

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    記述言語:日本語   出版者・発行元:Oncology Letters  

    The present study examined whether the pathological tumor volume (PTV) was correlated with the survival outcomes in patients with oral squamous cell carcinoma (SCC) and clinical lymph node metastasis. Forty-seven patients who underwent radical surgery without preoperative treatment were enrolled. The PTV of the primary tumor, which was surgically resected without preoperative treatment, was calculated based on the diameters in three dimensions. A survival analysis was performed using a Cox proportional hazards model. A PTV of ≥18 cm3 was significantly correlated with shorter overall survival (P<0.01) and local recurrence-free survival (P<0.01) in a univariate analysis. A multivariate analysis with adjustment for the pathological stage (stage I-II/III-IV), primary site (tongue/others) and positive surgical margin and/or extracap-sular extension (absent/present) showed that a PTV of ≥18 cm3 was significantly correlated with shorter overall survival (P<0.01) and local recurrence-free survival (P<0.01). The present findings suggested that PTV in oral SCC provides a prognostic parameter that may predict shorter or longer overall and local recurrence-free survival.

    DOI: 10.3892/ol.2018.8951

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  17. Maxillary sinus carcinoma outcomes over 60 years: experience at a single institution

    Nishio Naoki, Fujimoto Yasushi, Hiramatsu Mariko, Maruo Takashi, Tsuzuki Hidenori, Mukoyama Nobuaki, Shimono Mariko, Sone Michihiko, Kawabe Yoshitaka, Saito Kiyoshi, Fujii Masazumi, Nakashima Tsutomu

    NAGOYA JOURNAL OF MEDICAL SCIENCE   80 巻 ( 1 ) 頁: 91 - 98   2018年2月

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    記述言語:日本語   出版者・発行元:Nagoya Journal of Medical Science  

    Advances in the diagnosis and treatment of patients with maxillary sinus carcinoma have improved patient prognosis. This study investigated changes in demographic and clinical characteristics, treatment methods, and outcomes of patients with maxillary sinus carcinomas during three different 10-year periods spanning 60 years at our university hospital. Of the 233 patients with maxillary sinus carcinomas managed at Nagoya University Hospital, 135 were treated between 1951 and 1960 (first period), 35 between 1981 and 1990 (second period), and 63 between 2003 and 2012 (third period). Patient age, sex, TN classifications, treatment methods, and survival rates were compared among patients treated during these time periods. Of the 135, 35, and 63 patients with maxillary sinus carcinomas treated during these time periods, 86 (63.7%), 21 (51.4%), and 48 (76.2%), respectively, were men; 14 (10.4%), six (17.1%), and 14 (22.2%), respectively, were aged ≥70 years; and 135 (100%), 28 (80.0%), and 43 (68.3%), respectively, were treated surgically. The 5-year overall survival rates in patients treated during the first, second, and third periods were 29.7%, 44.3%, and 57.5%, respectively. These findings indicated that advances in the diagnosis and treatment of patients with maxillary sinus carcinoma, including computed tomography and craniofacial resection, have contributed to improvements in patient survival rates.

    DOI: 10.18999/nagjms.80.1.91

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  18. Peak of Standardized Uptake Value in Oral Cancer Predicts Survival Adjusting for Pathological Stage

    Suzuki Hidenori, Tamaki Tsuneo, Nishio Masami, Beppu Shintaro, Mukoyama Nobuaki, Hanai Nobuhiro, Nishikawa Daisuke, Koide Yusuke, Hasegawa Yasuhisa

    IN VIVO   32 巻 ( 5 ) 頁: 1193 - 1198   2018年

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    記述言語:日本語   出版者・発行元:In Vivo  

    Background/Aim: To predict survival outcomes of different patients with the same stage of disease is difficult. The possible correlation between 18F-fluorodeoxyglucose (18F-FDG) uptake parameters and survival outcomes was investigated in oral squamous cell carcinoma patients by multivariate analysis adjusted for the pathological stage according to the 8th edition of the tumor-node-metastasis (TNM) classification of the Union for International Cancer Contro. Patients and Methods: 18F-FDG-uptake parameters of 28 patients were assessed by positron emission tomography with computed tomography (PET/CT). Results: A peak of standardized uptake value of primary tumor (p-SUVpeak) of ≥14.1 was significantly correlated with shorter overall survival by univariate and multivariate analyses adjusted for the pathological TNM stage. A p-SUVpeak of ≥14.1 was significantly associated with shorter local recurrence-free survival and disease-free survival. Conclusion: A higher p-SUVpeak on pretreatment 18F-FDG-PET/CT is a prognostic parameter of identifying lower survival outcomes.

    DOI: 10.21873/invivo.11363

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  19. A case of large ectopic hamartomatous thymoma of the neck

    Yokoi S., Nishio N., Fujimoto Y., Mukoyama N., Kinoshita W., Sone M.

    Practica Oto-Rhino-Laryngologica   111 巻 ( 9 ) 頁: 645 - 649   2018年

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    記述言語:日本語   出版者・発行元:Practica Oto-Rhino-Laryngologica  

    An ectopic hamartomatous thymoma (EHT) is an extremely rare benign soft tumor most commonly occurring in the lower neck region, that can be difficult to differentiate (preoperatively) from malignant tumors. We report a case of EHT of the neck diagnosed in a 42-year-old man. The patient presented with a 10-year history of a tumor in the lower neck region that had rapidly increased in size over the previous 3 years. Fine-needle aspiration biopsy findings suggested lipoma. As the clinical findings and CT/MRI images indicated the possibility of a malignant tumor, an open biopsy was performed. The biopsy revealed EHT and resection of the tumor was performed. Although there were slight adhesions between the tumor and mediastinum, the tumor had not invaded the thymus or thyroid, and could be successfully resected. Histopathological examination of the tumor revealed the characteristic features of EHT, including spindle cells, epithelial cells, and fat tissue mixed. The postoperative course was uneventful, and there was no evidence of recurrence during the 18-month follow up period. When encountering lesions in the lower neck, it is important to consider EHT in the differential diagnosis.

    DOI: 10.5631/jibirin.111.645

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  20. Computed Tomographic Assessment of Autologous Fat Injection Augmentation for Vocal Fold Paralysis

    Nishio Naoki, Fujimoto Yasushi, Hiramatsu Mariko, Maruo Takashi, Suga Kenji, Tsuzuki Hidenori, Mukoyama Nobuaki, Shimono Mariko, Toriyama Kazuhiro, Takanari Keisuke, Kamei Yuzuru, Sone Michihiko

    LARYNGOSCOPE INVESTIGATIVE OTOLARYNGOLOGY   2 巻 ( 6 ) 頁: 459 - 465   2017年12月

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    記述言語:日本語   出版者・発行元:Laryngoscope Investigative Otolaryngology  

    Objective: To perform a quantitative computed tomography (CT) assessment of short- and long-term outcomes of autologous fat injection augmentation in patients with unilateral vocal fold paralysis. Study Design: Retrospective case series. Methods: Twelve patients who had undergone autologous fat injection augmentation for unilateral vocal fold paralysis in our hospital between 2011 and 2015 were enrolled in this study. The autologous fat for injection was acquired from periumbilical subcutaneous tissue and was injected orally using a special-purpose laryngeal injection needle. To evaluate the injected fat at the follow-up assessments, CT was performed at several times after surgery in clinical practice. All thin-section CT images were transferred to a workstation, and the volume of the injected fat was calculated. Results: Patients comprised 6 men and 6 women with a mean age at the time of surgery of 62.9 years (range, 46–82 years). The actual injected fat volume was 1.1–2.5 ml (mean, 1.6 ml). In seven patients assessed by CT two days after surgery, the average residual rate of the injected fat was 63.9%. The mean residual rates of the injected fat were 30.0% at 3 months, 33.7% at 6 months, 29.2% at 12 months, and 32.0% at 24 months. Conclusions: Although the injected fat volume decreased within the first three months and the residual rate of the injected fat was 30.0% at three months after injection, the residual fat volume remained at the same level for 24 months after injection. Level of Evidence: 4.

    DOI: 10.1002/lio2.125

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  21. Genomic Signature of the Natural Oncolytic Herpes Simplex Virus HF10 and Its Therapeutic Role in Preclinical and Clinical Trials.

    Eissa IR, Naoe Y, Bustos-Villalobos I, Ichinose T, Tanaka M, Zhiwen W, Mukoyama N, Morimoto T, Miyajima N, Hitoki H, Sumigama S, Aleksic B, Kodera Y, Kasuya H

    Frontiers in oncology   7 巻 ( JUL ) 頁: 149   2017年

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    記述言語:英語   出版者・発行元:Frontiers in Oncology  

    Oncolytic viruses (OVs) are opening new possibilities in cancer therapy with their unique mechanism of selective replication within tumor cells and triggering of antitumor immune responses. HF10 is an oncolytic herpes simplex virus-1 with a unique genomic structure that has non-engineered deletions and insertions accompanied by frame-shift mutations, in contrast to the majority of engineered OVs. At the genetic level, HF10 naturally lacks the expression of UL43, UL49.5, UL55, UL56, and latency-associated transcripts, and overexpresses UL53 and UL54. In preclinical studies, HF10 replicated efficiently within tumor cells with extensive cytolytic effects and induced increased numbers of activated CD4+ and CD8+ T cells and natural killer cells within the tumor, leading to a significant reduction in tumor growth and prolonged survival rates. Investigator-initiated clinical studies of HF10 have been completed in recurrent breast carcinoma, head and neck cancer, and unresectable pancreatic cancer in Japan. Phase I trials were subsequently completed in refractory superficial cancers and melanoma in the United States. HF10 has been demonstrated to have a high safety margin with low frequency of adverse effects in all treated patients. Interestingly, HF10 antigens were detected in pancreatic carcinoma over 300 days after treatment with infiltration of CD4+ and CD8+ T cells, which enhanced the immune response. To date, preliminary results from a Phase II trial have indicated that HF10 in combination with ipilimumab (anti-CTLA-4) is safe and well tolerated, with high antitumor efficacy. Improvement of the effect of ipilimumab was observed in patients with stage IIIb, IIIc, or IV unresectable or metastatic melanoma. This review provides a concise description of the genomic functional organization of HF10 compared with talimogene laherparepvec. Furthermore, this review focuses on HF10 in cancer treatment as monotherapy as well as in combination therapy through a concise description of all preclinical and clinical data. In addition, we will address approaches for future directions in HF10 studies as cancer therapy.

    DOI: 10.3389/fonc.2017.00149

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  22. 口腔咽頭癌手術症例における気管切開の検討

    都築 秀典, 藤本 保志, 平松 真理子, 西尾 直樹, 向山 宣昭, 曾根 三千彦

    日本気管食道科学会会報   68 巻 ( 2 ) 頁: 166 - 166   2017年

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    記述言語:日本語   出版者・発行元:特定非営利活動法人 日本気管食道科学会  

    DOI: 10.2468/jbes.68.166

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▼全件表示

科研費 1

  1. 強力な免疫チェックポイント分子阻害能を有する新たな腫瘍溶解性ウイルスの開発

    研究課題/研究課題番号:20K16438  2020年4月 - 2022年3月

    科学研究費助成事業  若手研究

    向山 宣昭

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    担当区分:研究代表者 

    配分額:4160000円 ( 直接経費:3200000円 、 間接経費:960000円 )

    本研究は、T細胞の機能を抑制する免疫チェックポイント分子を阻害する新たな腫瘍溶解性ウイルスの開発を目的とする。具体的には、腫瘍溶解性単純ヘルペスウイルスであるC-REVに、PD-L1に対する抗PD-L1抗体の一本鎖抗体(single chain Fv;scFv)ならびにPD-1細胞外領域(PD-1(1-239))を産生させることにより、ウイルスが腫瘍に感染、破壊するだけでなく、PD-1/PD-L1結合を阻害する新規ウイルスを作製する。
    腫瘍溶解性ウイルスは腫瘍特異的に感染し、腫瘍を崩壊する。さらに、破壊された腫瘍が癌抗原を放出することにより癌免疫応答を惹起する。本研究は、T細胞 の機能を抑制する免疫チェックポイント分子を阻害する新たな腫瘍溶解性ウイルスの開発を目的とする。本研究の独創的な点は、腫瘍溶解性ウイルスに免疫 チェックポイント分子であるPD-L1に対する抗PD-L1 scFvのみならず、PD-L1に結合するPD-1の細胞外領域(PD-1(1-239))を発現させ、免疫チェックポイント分 子の結合を強く抑制することにより、腫瘍内特異的に免疫チェックポイントを阻害すると共に、腫瘍溶解性ウイルスが直接腫瘍を溶解し、腫瘍特異的なリンパ球 を誘導することにより抗腫瘍免疫をより強固にすることにある。
    今年度は、抗PD-L1 scFvおよびPD-1の細胞外領域発現C-REV(C-REVαPD-L1-PD-1(1-239))を作製した。抗マウスPD-L1 scFvの塩基配列はGenBankより入手し、人工遺伝子合成により作成した。活性化マウスT細胞からRNAを抽出、逆転写酵素によりcDNAを作成し、PCR法にてPD-1(1-239)を増幅した。PCR産物をTAクローニングし、塩基配列をシークエンスにより確認した。さらに2A配列を含むprimerを作成し、overlap PCR法にてPD-L1-2A-PD-1(1-239)を作成した。この遺伝子をHSV1 UL43領域に相同組み換えで組み込むためのTarget vectorに挿入した。Lipofectamin3000 を用いてVero細胞にC-REVのゲノムDNAと上記のベクターをトランスフェクションし、相同遺伝子組み換えによりUL43に抗PD-L1 scFvとPD-1細胞外領域(PD-1(1- 239))を発現するC-REVの作製を試みた。
    抗PD-L1 scFvおよびPD-1の細胞外領域発現C-REV(C-REVαPD-L1-PD-1(1-239))を作製:抗マウスPD-L1 scFvの塩基配列はGenBankより入手し(KF041825)、人工遺伝子合成により作成した。活性化マウスT細胞からRNAを抽出、逆転写酵素によりcDNAを作成し、PCR法にてPD-1(1-239)を増幅した。PCR産物をTAクローニングし、塩基配列をシークエンスにより確認した。さらに2A配列を含むprimerを作成し、overlap PCR法にてPD-L1-2A-PD-1(1-239)を作成した。PCR産物をTAクローニングし、塩基配列をシークエンスにより確認した。この遺伝子をHSV1 UL43領域に相同組み換えで組み込むためのTarget vectorに挿入した。Lipofectamin3000を用いてVero細胞にC-REVのゲノムDNAと上記のベクターをトランスフェクションし、相同遺伝子組み換えによりUL43に抗PD-L1 scFvとPD-1細胞外領域(PD-1(1-239))を発現するC-REVの作製を試みた。Target vectorはGFPを発現することから、GFP発現を指標に細胞を採取し、ウイルス感染細胞を得た。ウイルス感染細胞からウイルスを得て、さらにVero細胞に感染させた。現在、得られたウイルスのVero細胞への感染を繰り返すことにより、高純度のウイルスを得ることを試みている。
    抗PD-L1 scFvならびPD-1の細胞外領域のPD-1/PD-L1結合阻害、および殺細胞効果の検討:
    In vitroでPD-L1発現細胞と活性化T細胞を共培養し、そこにC-REVαPD-L1-PD-1(1-239)感染細胞の培養上清を加え培養する。FACSを用いて活性化T細胞を検出し、抗PD-L1 scFvならびPD-1の細胞外領域のPD-1/PD-L1結合阻害活性を調べる。さらに、C-REVまたはC-REVαPD-L1-PD-1(1-239)を1, 0.1, 0.01 MOIでSCC7細胞に感染させ、経時的に培養上清中のウイルス力価を測定し、ウイルス増殖能を調べる。また、SCC7細胞を96 well plateに播き、C-REVまたはC-REVαPD-L1-PD-1(1-239)を1, 0.1, 0.01 MOIで感染させ、経時的にMTT assayにより細胞の生存率を調べ、殺細胞能力を確認する。
    In vivoでの抗腫瘍効果を調べるために、マウス扁平上皮癌細胞株SCC7をマウス皮下に2つ移植する。7日後、一方の腫瘍にMock (PBS)、C-REVαPD-L1-PD-1(1-239)、または親株C-REVを腫瘍内に注射する(3日おきに3回)。継時的に腫瘍サイズとマウス体重を測定し、治療効果を明らかにする。
    抗腫瘍効果発現機序解析として、T細胞、癌随伴マクロファージ、樹状細胞(DC)ならびに免疫抑制性機能を有する骨髄由来抑制細胞の腫瘍への浸潤を調べ、腫瘍環境の変化を確認する。