Kiyohide Takahashi, Shuhei Miyagi, Miho Nishiyama and Tsutomu Shinohara : A Lobulated Mass with Extensive Ecchymosis in the Epigastrium., Internal Medicine, 2024.
Hiroto Yoneda, Atsushi Mitsuhashi, Aito Yoshida, Hirokazu Ogino, Satoshi Itakura, Thi Na Nguyen, Hiroshi Nokihara, Seidai Satou, Tsutomu Shinohara, Masaki Hanibuchi, Shinji Abe, K Mika Kaneko, Yukinari Kato and Yasuhiko Nishioka : Antipodoplanin antibody enhances the antitumor effects of CTLA-4 blockade against malignant mesothelioma by natural killer cells., Cancer Science, Vol.115, No.2, 357-368, 2023.
(Summary)
-f enhanced the antitumor effects of CTLA-4 blockade. Combination therapy with anti-PDPN Ab and anti-CTLA-4 Ab increased tumor-infiltrating natural killer (NK) cells. The depletion of NK cells inhibited the synergistic effects of PMab-1-mG
Eiji Takeuchi, Hirokazu Ogino, Kensuke Kondo, Yoshio Okano, Seiya Ichihara, Michihiro Kunishige, Naoki Kadota, Hisanori Machida, Nobuo Hatakeyama, Keishi Naruse, Hiroshi Nokihara, Tsutomu Shinohara and Yasuhiko Nishioka : An increased relative eosinophil count as a predictive dynamic biomarker in non-small cell lung cancer patients treated with immune checkpoint inhibitors., Journal of Thoracic Oncology, Vol.15, No.3, 248-257, 2023.
(Summary)
We retrospectively reviewed all 151 patients diagnosed with NSCLC and treated with ICI monotherapy and blood test data between March 2016 and August 2021 at National Hospital Organization Kochi Hospital and Tokushima University.
Yohei Yabuki, Masaki Hanibuchi, Eiji Takeuchi, Takashi Haku, Takanori Kanematsu, Naoki Nishimura, Yuko Toyoda, Atsushi Mitsuhashi, Kenji Otsuka, Seidai Satou, Hisatsugu Goto, Hiroto Yoneda, Hirokazu Ogino, Hiroshi Nokihara, Tsutomu Shinohara and Yasuhiko Nishioka : A multicenter, open-label, phase II trial of pemetrexed plus bevacizumab in elderly patients with previously untreated advanced or recurrent nonsquamous non-small cell lung cancer., Thoracic cancer, Vol.14, No.32, 3232-3239, 2023.
(Summary)
Combination chemotherapy with PEM plus Bev in elderly patients with previously untreated advanced non-squamous NSCLC exhibited favorable antitumor activity and tolerability, suggesting that a combination of PEM plus Bev might be a promising treatment option for this population.
Eiji Takeuchi, Kensuke Kondo, Yoshio Okano, Seiya Ichihara, Michihiro Kunishige, Naoki Kadota, Hisanori Machida, Nobuo Hatakeyama, Keishi Naruse, Hirokazu Ogino, Hiroshi Nokihara, Tsutomu Shinohara and Yasuhiko Nishioka : Pretreatment eosinophil counts as a predictive biomarker in non-small cell lung cancer patients treated with immune checkpoint inhibitors., Thoracic Cancer, Vol.14, No.30, 3042-3050, 2023.
(Summary)
We retrospectively reviewed all patients diagnosed with NSCLC and treated with ICI monotherapy between March 2016 and August 2021 at National Hospital Organization Kochi Hospital and Tokushima University.
Kenya Sumitomo, Shingo Ashida, Makoto Hiroi and Tsutomu Shinohara : Prostatic lymphangitis carcinomatosis with massive bilateral pleural effusion., The American Journal of the Medical Sciences, Vol.366, No.4, e62-e63, 2023.
Kenya Sumitomo, Taku Okamoto, Kaoru Arii, Manabu Matumoto and Tsutomu Shinohara : Slowly Expanding 18 F-FDG PET-Positive Irregular Opacities in the Lung Due to Diffuse Lymphoid Hyperplasia Preceding Rheumatoid Arthritis., Clinical Nuclear Medicine, Vol.48, No.6, 542-544, 2023.
(Summary)
Pulmonary diffuse lymphoid hyperplasia (DLH), a nonneoplastic lymphoproliferative disorder (LPD), is extremely rare, and no PET/CT findings have been reported for pulmonary DLH. We observed slowly expanding irregular opacities with 18 F-FDG accumulation (SUV max , 3.64) in the right lower lobe of a 51-year-old asymptomatic man. The patient underwent video-assisted thoracoscopic biopsy on suspicion of malignant lesions. Histologically, no neoplastic cells were present, and the lesion was consistent with DLH. Six months later, the patient developed rheumatoid arthritis. DLH should be considered in the differentiation of PET-positive irregular opacities, even in the absence of known immune abnormalities.
Atsushi Mitsuhashi, Kazuya Koyama, Hirokazu Ogino, Tania Afroj, Thi Na Nguyen, Hiroto Yoneda, Kenji Otsuka, Masamichi Sugimoto, Osamu Kondoh, Hiroshi Nokihara, Masaki Hanibuchi, Hiromitsu Takizawa, Tsutomu Shinohara and Yasuhiko Nishioka : Identification of fibrocyte cluster in tumors reveals the role in antitumor immunity by PD-L1 blockade., Cell Reports, Vol.42, No.3, 112162, 2023.
(Summary)
fibrocytes do not. Tumor-infiltrating fibrocytes acquire myofibroblast-like phenotypes through transforming growth factor β (TGF-β)/small mothers against decapentaplegic (SMAD) signaling. Thus, TGF-βR/SMAD inhibitor enhances the antitumor effects of dual VEGF and PD-L1 blockade by regulating fibrocyte differentiation. Fibrocytes are highlighted as regulators of the response to programmed death 1 (PD-1)/PD-L1 blockade.
Michihiro Kunishige, Seiya Ichihara, Naoki Kadota, Yoshio Okano, Hisanori Machida, Nobuo Hatakeyama, Keishi Naruse, Tsutomu Shinohara and Eiji Takeuchi : Non-small cell lung cancer with EGFR (L858R and E709X) and CNNB1 mutations responded to afatinib., Thoracic Cancer, Vol.14, No.4, 423-426, 2022.
(Summary)
Lung cancer with complex epidermal growth factor receptor (EGFR) and CTNNB1 comutations is rare, and the efficacy of tyrosine kinase inhibitors (TKIs) is generally poor. Here, we encountered a lung cancer patient with complex EGFR (L858R and E709X) and CTNNB1 comutations who successfully responded to afatinib. A 78-year-old woman visited our hospital with a cough and bloody sputum that had worsened over the past year. She had multiple mass shadows in both lungs and nodular shadows in the bronchi. The patient was diagnosed with lung adenocarcinoma cT4N3M1c stage IVB. A genetic analysis of the primary tumor using the Oncomine Dx target test multi-CDx system revealed positivity for EGFR (L858R and E709X) and CTNNB1 mutations. The expression of programmed death ligand 1 (22C3 clones) in tumor cells was negative by immunostaining. The patient was treated with afatinib as first-line therapy and achieved clinical improvement and a partial response and is continuing treatment 1 year later. Case reports of lung cancer patients with EGFR/CTNNB1 comutations are rare, and TKIs are not considered to be effective. We herein present the first case report of lung cancer with the co-occurrence of uncommon and complex EGFR (L858R and E709X) and CTNNB1 mutations that was successfully treated with afatinib.
Seiya Ichihara, Michihiro Kunishige, Naoki Kadota, Yoshio Okano, Hisanori Machida, Nobuo Hatakeyama, Keishi Naruse, Tsutomu Shinohara and Eiji Takeuchi : Late-onset acute type 1 diabetes mellitus 7 months after discontinuation of pembrolizumab against lung cancer., Thoracic Cancer, Vol.14, No.1, 81-84, 2022.
(Summary)
Immune-related adverse events (irAEs) occur in rare cases, even after the completion of immune checkpoint inhibitor (ICI) therapy. We encountered a lung cancer patient diagnosed with acute-onset type 1 diabetes mellitus (DM) 7 months after the cessation of ICI. A 68-year-old woman was referred to our hospital for chest abnormalities. She was diagnosed with lung adenocarcinoma cT4N2M1c, stage IVB. Immunostaining showed that the expression of programmed death ligand 1 in tumor cells was negative. A genetic analysis using the Oncomine Dx Target Test Multi-CDx System revealed that the primary tumor was positive for ERBB2. Combined immunotherapy with carboplatin, pemetrexed, and pembrolizumab was performed as first-line therapy, followed by maintenance therapy with pemetrexed plus pembrolizumab, which was successful. After the seventh course, maintenance therapy was stopped because only the primary tumor showed local enlargement. Local chest radiotherapy (66 Gy/33 Fr) was performed, and the patient was followed up. HbA1c was 4.9% 3 months after the completion of pembrolizumab, and dry mouth and polyuria occurred after 5 months. Seven months later, the patient developed diabetic ketoacidosis with a blood glucose of 348 mg/dL and an HbA1c of 11.3%. Antiglutamic acid decarboxylase antibodies were negative and urinary C-peptide was 9.3 μg/day. The patient was diagnosed with acute-onset type 1 diabetes and received insulin therapy. There has been no case report of type 1 diabetes diagnosed 7 months after the last administration of an ICI. These results indicate that irAE needs to be considered even after the cessation of ICI.
Miho Nishiyama, Kiyohide Takahashi, Shun Morizumi, Yoshinobu Takahashi, Shinichi Iwamura, Kenya Sumitomo, Seiichi Nakano and Tsutomu Shinohara : Transient and Recurrent Pulmonary Infiltrations Associated with Familial Mediterranean Fever., Internal Medicine, Vol.61, No.22, 3415-3419, 2022.
(Summary)
Chest symptoms and pleural effusion due to serositis in familial Mediterranean fever (FMF) are occasionally misdiagnosed as acute pneumonia. However, the actual pulmonary involvement of FMF is extremely rare. A 67-year-old man was referred to our hospital due to repeated and transient anterior chest pain. Chest images revealed a moderate amount of pericardial fluid, slight bilateral pleural effusion, and infiltrations in both lower lung lobes. Colchicine treatment without antibiotics rapidly improved these symptoms and findings. Pericarditis, pleurisy and the response to colchicine indicated FMF. FMF should be considered as a causative disease of pulmonary infiltrations, especially if it occurs repeatedly.
N Kadota, N Nakahira, M Miyauchi, K Naruse, E Takeuchi and Tsutomu Shinohara : Usefulness of bronchoalveolar lavage (BAL) in the diagnosis of pulmonary alveolar proteinosis., QJM : Monthly Journal of the Association of Physicians, Vol.115, No.11, 767-768, 2022.
T Na Nguyen, Atsushi Mitsuhashi, Hirokazu Ogino, Hiroyuki Kozai, Hiroto Yoneda, Tania Afroj, Seidai Satou, Hiroshi Nokihara, Tsutomu Shinohara and Yasuhiko Nishioka : S-1 eliminates MDSCs and enhances the efficacy of PD-1 blockade via regulation of tumor-derived Bv8 and S100A8 in thoracic tumor., Cancer Science, Vol.114, No.2, 384-398, 2022.
(Summary)
Myeloid-derived suppressor cells (MDSCs) have been known to play a pivotal role in the induction of immune tolerance, which limits the benefits of immune checkpoint inhibitors (ICIs). Recent studies revealed that several chemotherapeutic agents decreased tumor-infiltrating MDSCs. Therefore, combination therapy with cytotoxic chemotherapeutic agents and ICIs was approved for first-line treatment for lung cancer. However, the impact of chemotherapeutic agents on MDSCs and an optimal partner of ICIs has not been fully investigated in thoracic tumors, including lung cancer and malignant pleural mesothelioma. In the present study, we found that treatment with 5-FU and its oral formulation, S-1, suppressed tumor progression and inhibited the accumulation of MDSCs in thoracic tumor-bearing mice. Tumor-infiltrating T cells and dendritic cells were significantly expanded in S-1-treated mice. 5-FU suppressed the ability of tumor cells to recruit MDSCs, while it did not suppress the survival and differentiation of mouse MDSCs in vitro. We also revealed that 5-FU or S-1 significantly downregulated the expression of tumor-derived Bv8 and S100A8. The knockdown of Bv8 or S100A8 in tumor cells suppressed tumor growth and MDSC recruitment in vivo. Furthermore, in comparison with pemetrexed, administration of S-1 improved the synergistic therapeutic efficacy of anti-PD-1 antibodies with or without carboplatin. Our findings revealed a novel mechanism wherein S-1 primed a favorable tumor microenvironment to provide the rationale for combination therapy with S-1 and ICIs as the optimal therapy for thoracic cancer.
Junki Terada, Yuko Toyoda, Eiji Takeuchi, Nobuyuki Tanida, Satoshi Ito, Kenji Yorita, Hisashi Matsuoka, Hiroki Bando, Yutaka Morita, Yuri Okamoto and Tsutomu Shinohara : Surgical resection combined with perioperative chemotherapy for a patient with locally recurrent, previously stage IV thymic small-cell carcinoma: A case report., Thoracic Cancer, Vol.13, No.23, 3415-3419, 2022.
(Summary)
An 83-year-old Japanese man visited our hospital with dyspnea and general fatigue. Computed tomography (CT) revealed a tumor in the anterior mediastinum, bilateral pleural effusion, pericardial fluid, and multiple liver nodules. We performed a CT-guided tumor biopsy, and the patient was diagnosed with thymic small-cell carcinoma, Masaoka-Koga stage classification IVb. The patient received four cycles of carboplatin and etoposide, and all lesions disappeared on CT. However, after 6 months, CT revealed a recurrent tumor in the anterior mediastinum. After one cycle of rechallenge chemotherapy, we performed extended total thymectomy followed by another three cycles of chemotherapy. More than 2.5 years after the last chemotherapy session, the patient's carcinoma did not recur. Thus, this case suggests that salvage surgery may be a treatment option for local recurrence of thymic carcinoma after complete remission with chemotherapy, even in patients with stage IV cancer.
(Keyword)
male / Humans / Aged, 80 and over / Thymoma / Thymus Neoplasms / Thymectomy / Carboplatin / Carcinoma / Carcinoma, Small Cell
K Nakagoshi, T Yaguchi, K Takahashi, Shun Morizumi, M Nishiyama, Y Takahashi, S Iwamura, Kenya Sumitomo and Tsutomu Shinohara : Pulmonary nocardiosis caused by Nocardia pneumoniae mimicking non-tuberculous mycobacterial disease., QJM : Monthly Journal of the Association of Physicians, Vol.115, No.9, 625-626, 2022.
Hiroyuki Hino, Shizuka Shinohara, Yoshio Okano, Keishi Naruse, Eiji Takeuchi, Shoji Sakiyama and Tsutomu Shinohara : Solitary Ground-Glass Nodule Mimicking Lung Cancer due to Focal Progression of Usual Interstitial Pneumonia., International Journal of Surgical Pathology, 2022.
(Summary)
Idiopathic pulmonary fibrosis is often associated with lung cancer, but early malignant lesions mixed with fibrous lesions are not always easy to diagnose. A 78-year-old woman was referred to our hospital due to a ground-glass nodule in the left upper lobe detected on chest high resolution computed tomography during follow-up of chronic idiopathic interstitial pneumonia. Pathological examination of the resected specimen revealed that the ground-glass nodule was locally progressed usual interstitial pneumonia (UIP). It should be noted that focal progression of UIP may occur and present with ground-glass nodule mimicking lung cancer, even if lesions in other areas remain unchanged. Moreover, in such cases, recognition of nodular lesions by the gross findings on the pleural surface and palpation during surgical resection are difficult and require precise marking.
Eiji Takeuchi, Kensuke Kondo, Yoshio Okano, Michihiro Kunishige, Yoshihiro Kondo, Naoki Kadota, Hisanori Machida, Nobuo Hatakeyama, Keishi Naruse, Hirokazu Ogino, Hiroshi Nokihara, Tsutomu Shinohara and Yasuhiko Nishioka : Early mortality factors in immune checkpoint inhibitor monotherapy for advanced or metastatic non-small cell lung cancer., Journal of Cancer Research and Clinical Oncology, Vol.45, 101893, 2022.
(Summary)
Immune checkpoint inhibitors (ICI) are a promising treatment, but may cause hyperprogressive disease and early death. The present study investigated early mortality factors in ICI monotherapy for lung cancer.
Maho Suzukawa, Ken Ohta, Yuma Fukutomi, Hiroya Hashimoto, Takeo Endo, Masahiro Abe, Yosuke Kamide, Makoto Yoshida, Yoshihiro Kikuchi, Toshiyuki Kita, Kenji Chibana, Yasushi Tanimoto, Kentaro Hyodo, Shohei Takata, Toshiya Inui, Masahide Yasui, Yoshinori Harada, Toshio Sato, Yumi Sakakibara, Yoshiaki Minakata, Yoshikazu Inoue, Shinji Tamaki, Tsutomu Shinohara, Kazutaka Takami, Motofumi Tsubakihara, Masahide Oki, Kentaro Wakamatsu, Masahide Horiba, Gen Ideura, Koko Hidaka, M Akiko Saito, Nobuyuki Kobayashi and Masami Taniguchi : Classifications of moderate to severe asthma phenotypes in Japan and analysis of serum biomarkers: A Nationwide Cohort Study in Japan (NHOM Asthma Study)., Allergology International, Vol.72, No.1, 63-74, 2022.
(Summary)
, body mass index (BMI), and hypertension were the phenotype-classifying variables determined by tree analysis that assigned 79.5% to the appropriate cluster. Among the cytokines measured, IL-1RA, YKL40/CHI3L1, IP-10/CXCL10, RANTES/CCL5, and TIMP-1 were useful biomarkers for classifying GINA 4, 5 phenotypes.
Yoshio Okano, Takashi Yamasaki, Ryuichiro Imai, Hiroyasu Okazaki, Yuji Higuchi and Tsutomu Shinohara : Cardiopulmonary arrest due to bronchoscopy-induced Takotsubo syndrome in a patient with antineutrophil cytoplasmic autoantibody-associated lung disease: a case report., Journal of Rural Medicine, Vol.17, No.3, 181-183, 2022.
(Summary)
This case indicates that bronchoscopy can cause severe TTS, especially in patients with systemic inflammation.
Mika Takashima, Kozo Kagawa, Toru Sawada, Hiroyuki Hino, Keishi Naruse, Eiji Takeuchi, Shoji Sakiyama and Tsutomu Shinohara : Type A thymoma: a rare cause of neoplastic cardiac tamponade with long-term survival., BMC Pulmonary Medicine, Vol.22, No.1, 2022.
(Summary)
This case indicates that neoplastic cardiac tamponade, even in elderly patients, should not necessarily be regarded as a terminal cancer and requires a systematic investigation for underlying causes.
Nobuo Hatakeyama, Hiroyuki Hino, Eiji Takeuch, Shoji Sakiyama and Tsutomu Shinohara : An 18 F-FDG-PET-Positive Mucoid Impaction With Ring Enhancement on CT Mimicking Lung Cancer., Clinical Nuclear Medicine, Vol.47, No.10, 904-905, 2022.
(Summary)
We encountered a case of an 18 F-FDG PET-positive solitary nodule with ring enhancement on CT mimicking lung cancer in the left S6 region of an 80-year-old woman. Since transbronchial biopsy by endobronchial ultrasonography with a guide sheath could not obtain sufficient material, despite the guide sheath being placed within the lesion, the patient underwent thoracoscopic partial left S6 resection. The nodule was diagnosed as acquired cystic bronchiectasis and mucoid impaction associated with chronic inflammation. The ring-shaped enhancement and the 18 F-FDG uptake may reflect angiogenesis in the cystic wall and accumulation of viable inflammatory cells in the wall and inner space, respectively.
Adult cases of type 2 congenital pulmonary airway malformation (CPAM) are extremely rare, and no PET/CT findings have been reported for CPAM. We encountered a case of 18FDG PET-positive CPAM mimicking lung cancer in a 45-year-old asymptomatic man. CT revealed a large cavitary mass in the left lower lobe. SUVmax measured by 18FDG PET was 3.5. The patient underwent video-assisted thoracoscopic lobectomy on suspicion of CPAM with/or lung cancer. Histologically, no neoplastic cells were present, and the lesion was consistent with type 2 CPAM. An adenomatoid proliferative pattern and granulomatous lesions may have contributed to a PET/CT false-positive result.
Shizuka Shinohara, Shun Morizumi, Kenya Sumitomo and Tsutomu Shinohara : Angioedema of the Eyelids Induced by a Ketoprofen Adhesive Patch., Internal Medicine, Vol.61, No.5, 2022.
Kenya Sumitomo, Shun Morizumi, Kiyohide Takahashi, Miho Nishiyama, Hidenobu Takahashi, Shinichi Iwamura, Kenichi Maeda and Tsutomu Shinohara : A Case of Arc-welders' Pneumoconiosis Improved by Reduction of Dust Exposure, The Journal of the Japanese Society of Internal Medicine, Vol.111, No.2, 296-302, 2022.
Yoshihiro Kondo, Michihiro Kunishige, Naoki Kadota, Yoshio Okano, Hisanori Machida, Nobuo Hatakeyama, Keishi Naruse, Tsutomu Shinohara and Eiji Takeuchi : A single dose of pembrolizumab treatment causing a profound and durable response in lung cancer., Thoracic Cancer, Vol.13, No.4, 648-652, 2022.
(Summary)
Profound and durable responses to a single dose of pembrolizumab in lung cancer are rare. We encountered a non-small cell lung cancer patient showing a deep and durable response with a single dose of pembrolizumab. A 79-year-old man reported bloody sputum for several weeks and visited a general physician. A chest x-ray revealed a tumor shadow in the right middle lung field at that time, and the patient was referred to our hospital. He was diagnosed with adenocarcinoma of the lung by transbronchial biopsy. The expression of programmed death ligand 1 in tumor cells was 100% by immunostaining. Based on the above, immunotherapy with pembrolizumab was performed as first-line therapy. Cancer cells had significantly shrunk at the end of the first cycle. The patient had grade-3 immune-related hepatitis at the end of the first cycle. Pembrolizumab treatment was stopped and prednisolone (80 mg/body) was initiated. Subsequently, liver function normalized, and prednisolone was tapered and discontinued. Since then, no tumor recurrence has been detected for 1.5 years without treatment. There have been few reports of profound and durable responses to a single dose of pembrolizumab in lung cancer. The results indicate that a single dose of pembrolizumab alone may be sufficient to cause durable response and serious immune-related adverse events in some cases.
Yoshio Okano, Michihiro Kunishige, Yoshihiro Kondo, Naoki Kadota, Atsushi Morishita, Keishi Naruse, Hisanori Machida, Nobuo Hatakeyama, Hiroyuki Hino, Tsutomu Shinohara, Shoji Sakiyama and Eiji Takeuchi : Dramatic response to immunochemotherapy followed by salvage surgery in an elderly lung cancer patient., Thoracic Cancer, Vol.13, No.3, 510-513, 2021.
(Summary)
F-fluorodeoxyglucose (FDG) on FDG-positron emission tomography/computed tomography before chemotherapy almost disappeared after pembrolizumab-based immunochemotherapy, left upper lobectomy and lymph node dissection were performed. No cancer cells were pathologically detected from the resected tissue. Therefore, ICIs combined with chemotherapy may enable inoperable advanced lung cancer patients to undergo surgery and achieve a complete response.
Hisanori Machida, Keishi Naruse and Tsutomu Shinohara : Multiple tumors on the pleura with pleural effusion mimicking malignant mesothelioma., European Journal of Internal Medicine, Vol.95, 95-96, 2021.
Atsushi Mitsuhashi, Kensuke Kondoh, Kazuki Horikawa, Kazuya Koyama, Thi Na Nguyen, Tania Afroj, Hiroto Yoneda, Kenji Otsuka, Hirokazu Ogino, Hiroshi Nokihara, Tsutomu Shinohara and Yasuhiko Nishioka : Programmed death (PD)-1/PD-ligand 1 blockade mediates antiangiogenic effects by tumor-derived CXCL10/11 as a potential predictive biomarker., Cancer Science, Vol.112, No.12, 4853-4866, 2021.
(Summary)
Immune checkpoint inhibitor (ICI) programmed death (PD)-1/PD-ligand 1 (PD-L1) blockade has been approved for various cancers. However, the underlying antitumor mechanisms mediated by ICIs and the predictive biomarkers remain unclear. We report the effects of anti-PD-L1/PD-1 Ab in tumor angiogenesis. In syngeneic mouse models, anti-PD-L1 Ab inhibited tumor angiogenesis and induces net-like hypoxia only in ICI-sensitive cell lines. In tumor tissue and serum of ICI-sensitive cell line-bearing mice, interferon-γ (IFN-γ) inducible angiostatic chemokines CXCL10/11 were upregulated by PD-L1 blockade. In vitro, CXCL10/11 gene upregulation by IFN-γ stimulation in tumor cell lines correlated with the sensitivity of PD-L1 blockade. The CXCL10/11 receptor CXCR3-neutralizing Ab or CXCL11 silencing in tumor cells inhibited the antiangiogenic effect of PD-L1 blockade in vivo. In pretreatment serum of lung carcinoma patients receiving anti-PD-1 Ab, the concentration of CXCL10/11 significantly correlated with the clinical outcome. Our results indicate the antiangiogenic function of PD-1/PD-L1 blockade and identify tumor-derived CXCL10/11 as a potential circulating biomarker of therapeutic sensitivity.
Kenya Sumitomo, Shun Morizumi, Kiyohide Takahashi, Masaaki Kimura, Hirofumi Koda, Yuko Toyoda and Tsutomu Shinohara : Human metapneumovirus-associated community-acquired pneumonia in adults during the first wave of COVID-19., Journal of Rural Medicine, Vol.16, No.4, 263-269, 2021.
(Summary)
hMPV infection may be considered in the differential diagnosis of COVID-19 and CAP in Japan under the preventive measures for SARS-CoV-2 infection, at least during the epidemic season of hMPV infection.
Takashige Taoka, Tsutomu Shinohara, Nobuo Hatakeyama, Sachiko Iwamura, Yoshiro Murase, Satoshi Mitarai and Fumitaka Ogushi : Mycobacterium Shinjukuense Pulmonary Disease Progressed to Pleuritis after Iatrogenic Pneumothorax: A Case Report., Journal of Clinical Tuberculosis and Other Mycobacterial Diseases, Vol.19, 2020.
(Summary)
infection should be considered in the differential diagnosis of mycobacterial pulmonary disease with effusion.
Reina Ohji, Tsutomu Shinohara, Hiroshi Ohji, Nobuo Hatakeyama, Sachiko Iwamura and Fumitaka Ogushi : Pulmonary tuberculosis misdiagnosed as extensively drug-resistant tuberculosis due to selection of a nontuberculous mycobacterial colony from a preculture dish used for a drug-susceptibility test., Respiratory Investigation, Vol.58, No.3, 216-219, 2020.
(Summary)
Drug-susceptibility test (DST) is important for tuberculosis care; however, there are several pitfalls with the procedure. A 70-year-old woman was diagnosed with extensively drug-resistant tuberculosis based on the result of a DST using microdilution method. Because she had no history of medication for tuberculosis and the sputum acid-fast bacillus smear test turned negative during standard treatment, identification of the strain used for DST was performed. Consequently, the strain was found to be M. intracellulare. It was assumed that a colony of M. intracellulare that had existed in the preculture solid medium was selected and used for the DST.
Takeshi Imakura, Yuko Toyoda, Seidai Satou, Kazuya Koyama, Haruka Nishimura, Kozo Kagawa, Naoki Takahashi, Nobuhito Naito, Kojin Murakami, Hiroshi Kawano, Masahiko Azuma, Tsutomu Shinohara and Yasuhiko Nishioka : Distinct improvement of pulmonary function, ground-glass opacity, hypoxia and physical findings in an idiopathic pulmonary fibrosis patient after pirfenidone treatment : a case report with a review of the literature., The Journal of Medical Investigation : JMI, Vol.67, No.3.4, 358-361, 2020.
(Summary)
Background : Pirfenidone (PFD), an anti-fibrosis drug for idiopathic pulmonary fibrosis (IPF), suppresses disease progression and delays decline of forced vital capacity. However, this drug rarely makes marked improvement of pulmonary function, chest high-resolution computed tomography (HRCT) findings and hypoxia. Case presentation : A 59 year-old-man, who was a former smoker and had a history of alcoholic liver cirrhosis, developed exertional dyspnea and was referred to our hospital. HRCT showed honeycomb changes with surrounding ground-glass opacity (GGO) in a predominantly basal and subpleural distribution. He was diagnosed with IPF and the treatment with PFD was started. At 16 months after the start of treatment, the predicted forced vital capacity value markedly improved from 82.9% to 98.6%. His resting-state partial pressure of arterial oxygen while breathing room air increased from a minimum of 54.7 mmHg (at 2 months treatment) to 72.5 mmHg. The GGO observed at diagnosis disappeared in HRCT. But after 32 months of treatment, his general condition got worse gradually, and he died from chronic progression of IPF after 48 months of treatment. Conclusion : Our case suggests that a complication of chronic liver disease and the existence of GGO may be characteristics of super-responder to PFD treatment for IPF patients. J. Med. Invest. 67 : 358-361, August, 2020.
Naoki Kadota, Tsutomu Shinohara, Hiroyuki Hino, Yuichiro Goda, Yoshiro Murase, Satoshi Mitarai and Fumitaka Ogushi : Mycobacterium abscessus ssp. abscessus infection progressing to empyema from vertebral osteomyelitis in an immunocompetent patient without pulmonary disease: a case report., BMC Pulmonary Medicine, Vol.19, No.1, 2019.
(Summary)
VO of the thoracic spine due to non-tuberculous mycobacterial infection should be considered as a cause of pleuritis or empyema without pulmonary disease, especially in patients with back pain.
Naoki Kadota, Tsutomu Shinohara, Keishi Naruse, Hiroyuki Hino and Fumitaka Ogushi : A lobulated mass in the left lower lobe: not what it seems., Thorax, Vol.74, No.5, 519-520, 2019.
Hiroshi Ohji, Tsutomu Shinohara, Naoki Kadota, Yoshio Okano, Keishi Naruse, Yoshihito Iwahara and Fumitaka Ogushi : Pneumocystis jirovecii pneumonia in an HIV-infected patient mimicking acute eosinophilic pneumonia: a case report with a review of the literature., Journal of Thoracic Disease, Vol.10, No.11, E774-E778, 2018.
Tsutomu Shinohara, Shoutaro Tsuji, Yoshio Okano, Hisanori Machida, Nobuo Hatakeyama and Fumitaka Ogushi : Elevated Levels of Intelectin-1, a Pathogen-binding Lectin, in the BAL Fluid of Patients with Chronic Eosinophilic Pneumonia and Hypersensitivity Pneumonitis., Internal Medicine, Vol.57, No.24, 3507-3514, 2018.
(Summary)
Objective Human intelectin-1 (hITLN-1) binds to galactofuranosyl residues, which are present in the microbial cell wall, but which are absent in mammalian tissues, and has been suggested to play an immunological role against microorganisms. However, the involvement of hITLN-1 in the pathogenesis of diffuse pulmonary diseases remains unknown. The aim of this study was to compare the hITLN-1 concentrations in the bronchoalveolar lavage (BAL) fluid of patients with diffuse pulmonary diseases. Methods The cell components and concentrations of hITLN-1 were analyzed in the BAL fluid of 8 patients with idiopathic chronic eosinophilic pneumonia (ICEP), 3 patients with drug-induced eosinophilic pneumonia, 4 patients with hypersensitivity pneumonitis (HP), 11 patients with sarcoidosis, 9 patients with cryptogenic organizing pneumonia, and 5 patients with idiopathic fibrosing interstitial pneumonia (fibrosing nonspecific interstitial pneumonia or usual interstitial pneumonia). Results The hITLN-1 concentrations in the BAL fluid of patients with ICEP and HP were higher than in those with other diseases. In the ICEP group, no significant difference was observed in the hITLN-1 concentrations of patients with or without a history of bronchial asthma. Conclusion The results of the present study suggest that hITLN-1 may be involved in the pathogenesis of ICEP and HP, and that an increase in the hITLN-1 concentration in the BAL fluid may represent a new biomarker for these diseases.
Nobuaki Shime, Nobuyuki Saito, Miya Bokui, Naoki Sakane, Mitsuhiro Kamimura, Tsutomu Shinohara, Tadashi Kosaka, Hisashi Ishikura and Atsuko Kobayashi : Clinical outcomes after initial treatment of methicillin-resistant Staphylococcus aureus infections., Infection and Drug Resistance, Vol.11, 1073-1081, 2018.
(Summary)
In this observational study reflecting real-world conditions, vancomycin was associated with higher 30-day mortality and incidence of kidney dysfunction than other anti-MRSA agents. The significance of the differences observed among antimicrobials other than vancomycin is uncertain.
Naoki Takahashi, Kazuya Tsuji, Hiroyuki Tamiya, Tsutomu Shinohara, Naoto Kuroda and Eiji Takeuchi : Goodpasture's disease in a patient with advanced lung cancer treated with nivolumab: An autopsy case report., Lung Cancer, Vol.122, 22-24, 2018.
(Summary)
Nivolumab, an anti-programmed death-1 immune checkpoint inhibitor (ICI), is now widely used to treat numerous cancers. Although most adverse effects related to ICIs are controllable, fulminant immune-related adverse events can occur. A 74-year-old patient with non-small-cell lung cancer was treated with nivolumab as a second-line treatment. After 8 cycles, acute kidney injury with macroscopic hematuria appeared, followed by diffuse ground-glass opacities with hemoptysis. Since the clinical course suggested Goodpasture's disease, methylprednisolone pulse therapy and plasma exchange were started. Later, it was confirmed that the serum anti-glomerular basement membrane antibody was positive. However, the patient died 35 days after admission due to respiratory failure, and an autopsy showed crescentic glomerulonephritis and massive alveolar hemorrhage which were compatible with Goodpasture's disease. Our case provides a possible link between nivolumab and lethal Goodpasture's disease.
Tsutomu Shinohara, Keishi Naruse, Norihiko Hamada, Takashi Yamasaki, Nobuo Hatakeyama and Fumitaka Ogushi : Fan-shaped ground-glass opacity (GGO) as a premonitory sign of pulmonary infarction: a case report., Journal of Thoracic Disease, Vol.10, No.1, E55-E58, 2018.
(Summary)
Radiological findings of pulmonary infarction have been well characterized mainly in established infarction. However, the early course CT appearance of patients who develop pulmonary infarction has not yet been fully elucidated. A 50-year-old female with a history of postmenopausal hormone replacement therapy (HRT) presented with dry cough and high-resolution computed tomography (HRCT) findings of fan-shaped segmental ground-glass opacity (GGO) in the right lower lobe. As the parenchymal density in the GGO gradually enlarged over a period of 4 weeks in spite of antibiotic treatment, the patient was referred to our hospital on clinical suspicion of bronchioloalveolar cell carcinoma. However, the pathological findings of a transbronchial biopsy of the lesion were compatible with pulmonary infarction. After an endoscopic examination, the typical CT appearance of established pulmonary infarction was observed. Moreover, enhanced CT detected an intraluminal filling defect in the right lower lobe artery suggesting peripheral pulmonary emboli. Our case was a peripheral pulmonary infarction probably induced by HRT, and suggested that fan-shaped GGO may be a premonitory sign of pulmonary infarction.
Naoki Kadota, Tsutomu Shinohara, Keishi Naruse and Nobuo Hatakeyama : Solitary costal plasmacytoma mimicking lung cancer metastasis., Clinical Case Reports, Vol.5, No.10, 1724-1725, 2017.
(Summary)
A clinical diagnosis of metastatic bone tumors is usually based on radiological findings without bone biopsy. Plasmacytoma can present as a single osteolytic lesion as described in this case. Early bone biopsy should be considered in unusual clinical settings for a differential diagnosis of primary bone tumors.
Yoshihito Iwahara, Tsutomu Shinohara, Keishi Naruse and Yukihisa Komatsu : Non-Hodgkin's lymphoma involving a femur bone and bilateral adrenal glands alone with adrenal insufficiency., BMJ Case Reports, Vol.2017, 2017.
(Summary)
Primary bone lymphoma and primary adrenal lymphoma are rare clinicopathological entities of non-Hodgkin's lymphoma (NHL). We present the first case of diffuse large B-cell lymphoma with the involvement of a single bone and both adrenal glands alone with adrenal insufficiency. As primary extranodal NHL may have other unusual extranodal lesions, which may present unexplained clinical findings, patients with primary extranodal NHL require careful systemic examination, even when lymphadenopathy is absent.
Shu Harada, Tsutomu Shinohara, Keishi Naruse and Hisanori Machida : Diffuse 18F-fluorodeoxyglucose accumulation in the bone marrow of a patient with haemophagocytic lymphohistiocytosis due to Hodgkin lymphoma., BMJ Case Reports, Vol.2016, 2016.
Yoshio Okano, Tsutomu Shinohara, Shino Imanishi, Naoki Takahashi, Nobuhito Naito, Takanari Taoka, Naoki Kadota and Fumitaka Ogushi : Miliary pulmonary nodules due to Mycobacterium xenopi in a steroid-induced immunocompromised patient successfully treated with chemotherapy: a case report., BMC Pulmonary Medicine, Vol.16, No.1, 2016.
(Summary)
Even when clinical and radiological disease manifestations are similar to those of miliary tuberculosis, M. xenopi infection should be considered in the differential diagnosis of miliary nodules.
Naoki Takahashi, Tsutomu Shinohara, Rie Oi, Muneyuki Ota, Shinichi Toriumi and Fumitaka Ogushi : Acute respiratory distress syndrome caused by Mycoplasma pneumoniae without elevated pulmonary vascular permeability: a case report., Journal of Thoracic Disease, Vol.8, No.5, E319-24, 2016.
(Summary)
Sporadic patients with acute respiratory distress syndrome (ARDS) caused by Mycoplasma pneumoniae have been reported. However, knowledge about the pathophysiology and pharmacological treatment of this condition is insufficient. Moreover, the pulmonary vascular permeability in ARDS related to M. pneumoniae infection has not been reported. We report a case of ARDS caused by Mycoplasma pneumoniae without elevated pulmonary vascular permeability, which was successfully treated using low-dose short-term hydrocortisone, suggesting that pulmonary infiltration in ARDS caused by Mycoplasma pneumoniae does not match the criteria of permeability edema observed in typical ARDS.
Nobuhito Naito, Tsutomu Shinohara, Hisanori Machida, Hiroyuki Hino, Keishi Naruse and Fumitaka Ogushi : Kikuchi-Fujimoto disease associated with community acquired pneumonia showing intrathoratic lymphadenopathy without cervical lesions., SpringerPlus, Vol.4, 2015.
(Summary)
KFD should be considered in the differential diagnosis of massive mediastinal and hilar lymphadenopathy, even when there are no superficial lesions. In addition, we need to bear in mind that unexpected disorders occasionally coexist with common diseases.
A case of primary gingival tuberculosis in a 71-year-old Japanese woman is herein presented. A serous saliva culture was positive for tuberculosis, and we recognized that the origin of the tuberculosis infection was the gingiva based on the genetic identification in gingival biopsy tissue. The definitive diagnosis was facilitated by the genetic identification, a useful modern tool for diagnosing infectious diseases. The location and clinical presentation of this lesion were unusual, which underlines the importance of considering tuberculosis in the differential diagnosis of oral lesions that affect the gingiva.
Maiko Kamei, Tsutomu Shinohara, Kotaro Kasahara, Takahira Kuno, Keishi Naruse and Hironobu Watanabe : Extensive rhabdomyosarcomatous differentiation in recurrent low-grade urothelial carcinoma of the bladder after transurethral resection: a case report., Journal of Medical Case Reports, Vol.9, 2015.
(Summary)
Urothelial carcinoma of the urinary bladder with extensive rhabdomyosarcomatous differentiation is rare, but it should be considered in the differential diagnosis even when urothelial carcinoma coexisting with a rhabdomyosarcomatous component is low-grade and non-invasive.
Kensaku KASHIMA, Hiroshi YAMASAKI, Mitsugu KAWAMURA, Yasumichi TSUDA, Satoru OOGIKU, Takuya MINED, Masaru MABUCHI and Tsutomu Shinohara : Relationship between Standing Balance and Walking Independence of Elderly Inpatients: Examination of the Weight-bearing Ratio and One-leg Standing Time, Rigakuryoho Kagaku, Vol.30, No.4, 509-512, 2015.
Tsutomu Shinohara, Naoki Kadota, Hiroyuki Hino, Keishi Naruse, Yuji Ohtsuki and Fumitaka Ogushi : Improvement in idiopathic nonspecific interstitial pneumonia after smoking cessation., Respiratory Medicine Case Reports, Vol.14, 7-9, 2014.
(Summary)
Although cigarette smoking has been recognized as a risk factor for the development of several interstitial lung diseases, the relationship between smoking and nonspecific interstitial pneumonia (NSIP) has not yet been fully elucidated. We here present a case of fibrotic NSIP with mild emphysema in an elderly male with normal pulmonary function, whose symptoms, serum KL-6 level, and high-resolution computed tomography findings of interstitial changes markedly improved without medication following the cessation of smoking. Our case suggests that smoking may be an etiological factor in some patients with NSIP and that early smoking cessation before a clinically detectable decline in pulmonary function may be critical for smokers with idiopathic NSIP.
Yuki Tsukazaki, Tsutomu Shinohara, Kumiko Tanaka, Keishi Naruse, Yoshihito Iwahara and Shuji Inoue : Hepatosplenic Hodgkin lymphoma without lymphadenopathy following reversible methotrexate-associated lymphoproliferative disorder., Modern Rheumatology, Vol.27, No.2, 372-375, 2014.
(Summary)
Lymphoproliferative disorders (LPDs) occur more frequently in rheumatoid arthritis (RA) patients treated with immunosuppressive agents than in the non-RA population. However, the various forms of disease progression have not yet been elucidated in detail. We encountered a case of Epstein-Barr virus (EBV)-positive atypical polymorphous LPD in the cervical and intraabdominal lymph nodes with hepatosplenomegaly in an 88-year-old female with RA who had taken infliximab and methotrexate (MTX) for six years. Although spontaneous remission occurred following the withdrawal of infliximab and MTX, reversible LPD evolved into hepatosplenic Hodgkin lymphoma without lymphadenopathy presenting as a cholestatic febrile illness. Our findings suggest that the recurrent lesions of MTX-associated LPDs may not always coincide with the primary lesion and may present unexplained findings based on various extranodal diseases.
Makoto Tobiume, Tsutomu Shinohara, Takahira Kuno, Shinji Mukai, Keishi Naruse, Nobuo Hatakeyama and Fumitaka Ogushi : BCG-induced pneumonitis with lymphocytic pleurisy in the absence of elevated KL-6., BMC Pulmonary Medicine, Vol.14, 2014.
(Summary)
We speculate that the pathogenesis of our case may be a hypersensitive reaction to the proteic component of BCG entering the lung and pleural space, which is different from the etiology of the common type of HP.
(Keyword)
Adjuvants, Immunologic / Aged, 80 and over / BCG Vaccine / Carcinoma, Renal Cell / female / Humans / Kidney Neoplasms / T lymphocytes / Pleurisy / Pneumonia
Mika Takashima, Tsutomu Shinohara, Atsushi Morishita, Keishi Naruse, Hiroyuki Hino and Fumitaka Ogushi : Thallium-201-scintigraphy-positive recurrent pulmonary hyalinising granuloma with elevated IgG4., The International Journal of Tuberculosis and Lung Disease, Vol.18, No.1, 125-126, 2014.
Mami Inayama, Tsutomu Shinohara, Mitsuteru Yoshida, Hiroyuki Hino, Nobuo Hatakeyama and Fumitaka Ogushi : Bronchopleural fistula following M. abscessus infection 11 years after lobectomy for lung cancer., SpringerPlus, Vol.2, No.1, 2013.
(Summary)
Bronchopleural fistula (BPF) is a potentially fatal complication of lung cancer resection surgery that occurs during the healing process of the bronchial stump. However, the vulnerability of the healed surgical wound to overlapping acquired airway destruction has not yet been determined in detail. We herein present a case of fatal BPF following Mycobacterium abscessus (M. abscessus) infection, which occurred 11 years after right upper lobectomy for lung cancer. The findings of the present study suggest that patients with M. abscessus pulmonary disease in which airway destruction is progressing towards the bronchial stump of previous lobectomy should be considered for early completion pneumonectomy to prevent fatal BPF.
Mari Kogiso, Tsutomu Shinohara, Kathleen C Dorey and Yoshimi Shibata : Cholera toxin induces a shift from inactive to active cyclooxygenase 2 in alveolar macrophages activated by Mycobacterium bovis BCG., Infection and Immunity, Vol.81, No.1, 373-380, 2012.
(Summary)
Intranasal vaccination stimulates formation of cyclooxygenases (COX) and release of prostaglandin E(2) (PGE(2)) by lung cells, including alveolar macrophages. PGE(2) plays complex pro- or anti-inflammatory roles in facilitating mucosal immune responses, but the relative contributions of COX-1 and COX-2 remain unclear. Previously, we found that Mycobacterium bovis BCG, a human tuberculosis vaccine, stimulated increased release of PGE(2) by macrophages activated in vitro; in contrast, intranasal BCG activated no PGE(2) release in the lungs, because COX-1 and COX-2 in alveolar macrophages were subcellularly dissociated from the nuclear envelope (NE) and catalytically inactive. This study tested the hypothesis that intranasal administration of BCG with cholera toxin (CT), a mucosal vaccine component, would shift the inactive, NE-dissociated COX-1/COX-2 to active, NE-associated forms. The results showed increased PGE(2) release in the lungs and NE-associated COX-2 in the majority of COX-2(+) macrophages. These COX-2(+) macrophages were the primary source of PGE(2) release in the lungs, since there was only slight enhancement of NE-associated COX-1 and there was no change in COX-1/COX-2 levels in alveolar epithelial cells following treatment with CT and/or BCG. To further understand the effect of CT, we investigated the timing of BCG versus CT administration for in vivo and in vitro macrophage activations. When CT followed BCG treatment, macrophages in vitro had elevated COX-2-mediated PGE(2) release, but macrophages in vivo exhibited less activation of NE-associated COX-2. Our results indicate that inclusion of CT in the intranasal BCG vaccination enhances COX-2-mediated PGE(2) release by alveolar macrophages and further suggest that the effect of CT in vivo is mediated by other lung cells.
Mari Kogiso, Tsutomu Shinohara, Kathleen C Dorey and Yoshimi Shibata : Role of PPARγ in COX-2 activation in mycobacterial pulmonary inflammation., Inflammation, Vol.35, No.5, 1685-1695, 2012.
(Summary)
Preliminary studies show that intranasal (i.n.) administration of BCG in mice induces M1 activation of alveolar macrophages (M) that increase TNF-α production and cyclooxygenase-2 (COX-2) expression but reduce constitutive peroxisome proliferator-activated receptor gamma (PPARγ) expression. However, COX-2 is catalytically inactive for prostaglandin E(2) release, unlike COX-2 that is active in M1 activation in vitro by BCG. In this study, we determined the role of PPARγ for BCG-induced M1 activation in vivo and in vitro. We found that treatment of mice with GW9662, a PPARγ antagonist, prior to i.n. BCG, partially restored PPARγ expression, and decreased TNF-α production and COX-2 expression. But COX-2 was still inactive. The decreased effects on TNF-α and COX-2 were also observed when alveolar M were treated in vitro with GW9662/BCG, but COX-2 was still active. Our results indicate that PPARγ upregulates M1 activation of alveolar M, but inactive COX-2 formation is independent of PPARγ in mycobacterial pulmonary inflammation.
Takahira Kuno, Tsutomu Shinohara, Kotaro Kasahara, Aoi Matsuoka, Yukihisa Komatsu, Keishi Naruse and Hironobu Watanabe : Extragonadal seminoma presenting as a large mass in the pelvic cavity without c-kit-activating mutations., Japanese Journal of Clinical Oncology, Vol.42, No.7, 650-653, 2012.
(Summary)
Extragonadal germ cell tumors are relatively rare tumors, which usually occur in the mediastinum or retroperitoneum. In this report, we present a case of primary seminoma arising in the pelvic cavity. A 58-year-old man with urinary retention and abdominal distension was admitted to our hospital. Computed tomography and magnetic resonance imaging demonstrated a large mass in the pelvic cavity. Histological examination of the specimens obtained by open biopsy revealed seminomatous malignant cells. Immunohistochemical studies detected vimentin, placental alkaline phosphatase and c-kit. Taking these results together with the patient's other clinical manifestations, this case was diagnosed as extragonadal seminoma without c-kit-activating mutations, and chemotherapy followed by radiation therapy was successful. Primary seminoma in the pelvic cavity is extremely rare, but should be considered a cause of pelvic mass formation.
Hisanori MACHIDA, Tsutomu Shinohara, Nobuo HATAKEYAMA, Yoshio OKANO, Mayuri Nakano, Makoto Tobiume, Yoshihito IWAHARA and Fumitaka OGUSHI : Exacerbation of cranial nerurological symptoms by platelet transfusion before the diagnosis of thrombotic thrombocytopenic purpura, The Japanese Journal of Clinical Hematology, Vol.53, No.1, 105-109, 2012.
Hisanori Machida, Tsutomu Shinohara, Nobuo Hatakeyama, Yoshio Okano, Hiroyuki Hino and Fumitaka Ogushi : A Case of Lung Aspergilloma in Which Endobronchial Watanabe Spigot (EWS) Was Not Effective for Hemoptysis, The Journal of the Japan Society for Respiratory Endoscopy, Vol.34, No.3, 262-266, 2012.
Hisanori Machida, Tsutomu Shinohara, Nobuo Hatakeyama, Yoshio Okano, Mayuri Nakano, Makoto Tobiume, Keishi Naruse, Yoshihito Iwahara and Fumitaka Ogushi : CD5-positive diffuse large B cell lymphoma infiltrating the central nervous system presenting Guillain-Barré-like syndrome after chemotherapy., Journal of Clinical and Experimental Hematopathology, Vol.52, No.3, 199-204, 2012.
(Summary)
An 83-year-old woman was admitted to our hospital with abdominal pain. Examination revealed mediastinal lymphoadenopathy, hepatosplenomegaly, and infiltration of abnormal cells into the bone marrow with hemophagocytosis, and CD5-positive diffuse large B cell lymphoma was diagnosed. Chemotherapy was administered and progressive weakness of the limbs, resembling a Guillain-Barré-like syndrome, subsequently appeared. Cerebrospinal fluid examination indicated lymphoma cell infiltration. Although immune globulin and steroid therapies were not effective, intrathecal injection of methotrexate, predonisolone, and cytarabine improved these symptoms. Subsequent to chemotherapy, cell surface antigen changes were observed in the cerebrospinal fluid relative to those in bone marrow.
(Keyword)
Aged, 80 and over / Antigens, Neoplasm / Antineoplastic Combined Chemotherapy Protocols / CD5 Antigens / Cell Movement / neuronal damage of central nervous system / Cytarabine / female / Guillain-Barre Syndrome / Humans / Immunoglobulins, Intravenous / Lymphoma, Large B-Cell, Diffuse / Methotrexate / Prednisolone / Steroids
We describe a patient with acute myeloid leukemia with myelodysplasia-related changes (AML-MRC) that clinically resembled acute promyelocytic leukemia (APL). The karyotype of his leukemic cells was 46, XY, del (3) (q?) and did not include a chromosomal translocation involving the retinoic acid receptor-α gene. However, retinoic acid syndrome developed, and partial remission was achieved after treatment with all-trans retinoic acid (ATRA) followed by chemotherapy. Our case might provide new insights into the mechanism of the growth inhibitory effect of ATRA on APL-like cells.
Mami Inayama, Tsutomu Shinohara, Hiroyuki Hino, Mitsuteru Yoshida and Fumitaka Ogushi : Chylothorax caused by acupuncture., Internal Medicine, Vol.50, No.20, 2375-2377, 2011.
(Summary)
Chylothorax, the accumulation of fatty fluid within the chest cavity, is associated with multiple etiologies including surgical injuries. A rare complication of acupuncture in a 37-year-old woman who developed left pneumothorax and pleural fluid collection after acupuncture was performed on the neck and upper back is described. Chest tube drainage resulted in complete lung expansion, and analysis of the milky fluid revealed chyle leakage. Conservative treatment with a diet low in lipids and rich in medium-chain triacylglycerols allowed extubation. Acupuncture-induced thoracic duct injury, although extremely rare, should be considered as a cause of chylothorax.
We here report a rare case of a patient with IgD-lambda-positive multiple myeloma presenting with FDG-PET/CT negative bone marrow involvement. A 72-year-old man was admitted to our hospital for evaluation of a paravertebral tumor of the chest. Thoracotomy was performed and a histopathological evaluation of resected intrathoracic tumor demonstrated a plasmacytic neoplasma. Initially we thought that this case was a solitary plasmacytoma because there were no positive findings on postoperative FDG-PET/CT. However, bone marrow aspiration study demonstrated massive infiltration of myeloma cells (72%). It is necessary to recognize that IgD-lambda type myeloma cells may not be sufficiently metabolically active to form high uptake on FDG-PET/CT.
(Keyword)
Aged / Bone Marrow / Diagnosis, Differential / Fluorodeoxyglucose F18 / Humans / Immunoglobulin D / magnetic resonance imaging / male / Monoclonal Gammopathy of Undetermined Significance / Multiple Myeloma / Plasmacytoma / Positron-Emission Tomography / Radiopharmaceuticals / Tomography, X-Ray Computed
Hisanori MACHIDA, Tsutomu Shinohara, Nobuo HATAKEYAMA, Mami INAYAMA, Emiko HOSOKAWA and Fumitaka OGUSHI : Two cases of drug-induced intrathoracic lesions caused by mesalazine in patients with ulcerative colitis, The journal of the Japanese Respiratory Society, Vol.49, No.7, 538-542, 2011.
Mari Kogiso, Akihito Nishiyama, Tsutomu Shinohara, Masataka Nakamura, Emiko Mizoguchi, Yoshinori Misawa, Elisabeth Guinet, Mahyar Nouri-Shirazi, Kathleen C Dorey, Ann Ruth Henriksen and Yoshimi Shibata : Chitin particles induce size-dependent but carbohydrate-independent innate eosinophilia., Journal of Leukocyte Biology, Vol.90, No.1, 167-176, 2011.
(Summary)
Murine M that phagocytose CMP develop into M1; this response depends on the size and the chemical composition of the particles. In contrast, recent studies concluded that chitin particles induce M2 and eosinophil migration, promoting acquired Th2 immune responses against chitin-containing microbes or allergens. This study examined whether these apparently inconsistent responses to chitin could be induced by variation in the size and chemical composition of the chitin particles. We compared the responses of M with CMP, LCB, and Sephadex G-100 beads (>40 μm). Beads were given i.p. to WT mice and to mice deficient in a CRTH2, a receptor for the eosinophil chemoattractant PGD(2). In contrast to the M1 activation induced by CMP, i.p. administration of LCB or Sephadex beads induced within 24 h a CRTH2-dependent peritoneal eosinophilia, as well as CRTH2-independent activation of peritoneal M that expressed Arg I, an M2 phenotype. LCB-induced M exhibited elevated Arg I and a surface MR, reduced surface TLR2 levels, and no change in the levels of CHI3L1 or IL-10 production. Our results indicate that the effects of chitin in vivo are highly dependent on particle size and that large, nonphagocytosable beads, independent of their chemical composition, induce innate eosinophilia and activate M expressing several M2, but not M1, phenotypes.
Shoutaro Tsuji, Makiko Yamashita, R Donald Hoffman, Akihito Nishiyama, Tsutomu Shinohara, Takashi Ohtsu and Yoshimi Shibata : Capture of heat-killed Mycobacterium bovis bacillus Calmette-Guérin by intelectin-1 deposited on cell surfaces., Glycobiology, Vol.19, No.5, 518-526, 2009.
(Summary)
Intelectin is an extracellular animal lectin found in chordata. Although human and mouse intelectin-1 recognize galactofuranosyl residues included in cell walls of various microorganisms, the physiological function of mammalian intelectin had been unclear. In this study, we found that human intelectin-1 was a serum protein and bound to Mycobacterium bovis bacillus Calmette-Guérin (BCG). Human intelectin-1-binding to BCG was inhibited by Ca(2+)-depletion, galactofuranosyl disaccharide, ribose, or xylose, and was dependent on the trimeric structure of human intelectin-1. Although monomeric, mouse intelectin-1 bound to BCG, with its C-terminal region contributing to efficient binding. Human intelectin-1-transfected cells not only secreted intelectin-1 into culture supernatant but also expressed intelectin-1 on the cell surface. The cell surface intelectin-1 was not a glycosylphosphatidylinositol-anchored membrane protein. Intelectin-1-transfected cells captured BCG more than untransfected cells, and the BCG adherence was inhibited by an inhibitory saccharide of intelectin-1. Intelectin-1-preincubated cells took up BCG more than untreated cells, but the adhesion of intelectin-1-bound BCG was the same as that of untreated BCG. Mouse macrophages phagocytosed BCG more efficiently in medium containing mouse intelectin-1 than in control medium. These results indicate that intelectin is a host defense lectin that assists phagocytic clearance of microorganisms.
Tsutomu Shinohara, Traci Pantuso, Shizuka Shinohara, Mari Kogiso, N Quentin Myrvik, Ann Ruth Henriksen and Yoshimi Shibata : Persistent inactivation of macrophage cyclooxygenase-2 in mycobacterial pulmonary inflammation., American Journal of Respiratory Cell and Molecular Biology, Vol.41, No.2, 146-154, 2008.
(Summary)
The induction of cyclooxygenase-2 (COX-2) in tissue macrophages (MØ) increases prostaglandin E(2) (PGE(2)) release, potentially down-regulating granulomatous inflammation. In response to Mycobacteria, local MØ express COX-2, which is either nuclear envelope (NE)-associated or NE-dissociated. Persistent mycobacterial pulmonary inflammation is characterized by alveolar MØ expressing NE-dissociated (inactive) COX-2 without release of PGE(2). In this study, we examined COX-2 in alveolar MØ after intranasal exposure to heat-killed Mycobacterium bovis BCG (HK-BCG). After administration, whole lungs of C57Bl/6 mice were lavaged with saline; COX-2 expression and PGE(2) release by alveolar MØ and tumor necrosis factor (TNF)-alpha and nitric oxide levels in the lung lavage were monitored. Normal alveolar MØ had undetectable levels of COX-2 on Western blots. However, 1 day after intranasal administration, almost all alveolar MØ had phagocytosed HK-BCG and expressed NE-dissociated COX-2 without any increase in the release of PGE(2). At 28 days after intranasal administration, 68% of alveolar MØ still contained both BCG and the NE-dissociated form of COX-2. NE-associated (active) COX-2 was not observed in alveolar MØ. In contrast, 7 days after intraperitoneal injection of HK-BCG, peritoneal MØ containing HK-BCG were no longer detected. At 28 days after intranasal administration, TNF-alpha and nitrite levels in the lung lavage fluid were significantly higher than those in controls. Our results indicate that mycobacterial pulmonary inflammation is associated with suppressed PGE(2) production by alveolar MØ, with expression of COX-2 dissociated from the NE.
Akihito Nishiyama, Tsutomu Shinohara, Traci Pantuso, Shoutaro Tsuji, Makiko Yamashita, Shizuka Shinohara, N Quentin Myrvik, Ann Ruth Henriksen and Yoshimi Shibata : Depletion of cellular cholesterol enhances macrophage MAPK activation by chitin microparticles but not by heat-killed Mycobacterium bovis BCG., American Journal of Physiology, Cell Physiology, Vol.295, No.2, C341-9, 2008.
(Summary)
When macrophages phagocytose chitin (N-acetyl-d-glucosamine polymer) microparticles, mitogen-activated protein kinases (MAPK) are immediately activated, followed by the release of Th1 cytokines, but not IL-10. To determine whether phagocytosis and macrophage activation in response to chitin microparticles are dependent on membrane cholesterol, RAW264.7 macrophages were treated with methyl-beta-cytodextrin (MBCD) and stimulated with chitin. These results were compared with the corresponding effects of bacterial components including heat-killed (HK) Mycobacterium bovis bacillus Calmette-Guèrin (BCG) and an oligodeoxynucleotide (ODN) of bacterial DNA (CpG-ODN). The MBCD treatment did not alter chitin binding or the phagocytosis of chitin particles 20 min after stimulation. At the same time, however, chitin-induced phosphorylation of cellular MAPK was accelerated and enhanced in an MBCD dose-dependent manner. The increased phosphorylation was also observed for chitin phagosome-associated p38 and ERK1/2. In contrast, CpG-ODN and HK-BCG induced activation of MAPK in MBCD-treated cells at levels comparable to, or only slightly more than, those of control cells. We also found that MBCD treatment enhanced the production of tumor necrosis factor-alpha (TNF-alpha) and the expression of cyclooxygenase-2 (COX-2) in response to chitin microparticles. In neither MBCD- nor saline-treated macrophages, did chitin particles induce detectable IL-10 mRNA synthesis. CpG-ODN induced TNF-alpha production, and COX-2 expression were less sensitive to MBCD treatment. Among the agonists studied, our results indicate that macrophage activation by chitin microparticles was most sensitive to cholesterol depletion, suggesting that membrane structures integrated by cholesterol are important for physiological regulation of chitin microparticle-induced cellular activation.
Fumitaka OGUSHI and Tsutomu Shinohara : Meaning of Pulmonary Function Test in Physical Checkup, Japanese Journal of National Medical Services, Vol.62, No.9, 477-481, 2008.
Makiko Yamashita, Tsutomu Shinohara, Shoutaro Tsuji, N Quentin Myrvik, Akihito Nishiyama, Ann Ruth Henriksen and Yoshimi Shibata : Catalytically inactive cyclooxygenase 2 and absence of prostaglandin E2 biosynthesis in murine peritoneal macrophages following in vivo phagocytosis of heat-killed Mycobacterium bovis bacillus Calmette-Guérin., The Journal of Immunology, Vol.179, No.10, 7072-7078, 2007.
(Summary)
Over 25 years ago, it was observed that peritoneal macrophages (Mphi) isolated from mice given heat-killed Mycobacterium bovis bacillus Calmette-Guérin (HK-BCG) i.p. did not release PGE(2). However, when peritoneal Mphi from untreated mice are treated with HK-BCG in vitro, cyclooxygenase 2 (COX-2), a rate-limiting enzyme for PGE(2) biosynthesis, is expressed and the release of PGE(2) is increased. The present study of peritoneal Mphi obtained from C57BL/6 mice and treated either in vitro or in vivo with HK-BCG was undertaken to further characterize the cellular responses that result in suppression of PGE(2) release. The results indicate that Mphi treated with HK-BCG in vivo express constitutive COX-1 and inducible COX-2 that are catalytically inactive, are localized subcellularly in the cytoplasm, and are not associated with the nuclear envelope (NE). In contrast, Mphi treated in vitro express catalytically active COX-1 and COX-2 that are localized in the NE and diffusely in the cytoplasm. Thus, for local Mphi activated in vivo by HK-BCG, the results indicate that COX-1 and COX-2 dissociated from the NE are catalytically inactive, which accounts for the lack of PGE(2) production by local Mphi activated in vivo with HK-BCG. Our studies further indicate that the formation of catalytically inactive COX-2 is associated with in vivo phagocytosis of HK-BCG, and is not dependent on extracellular mediators produced by in vivo HK-BCG treatment. This attenuation of PGE(2) production may enhance Mphi-mediated innate and Th1-acquired immune responses against intracellular infections which are suppressed by PGE(2).
Shoutaro Tsuji, Makiko Yamashita, Akihito Nishiyama, Tsutomu Shinohara, Zhongwei Li, N Quentin Myrvik, R Donald Hoffman, Ann Ruth Henriksen and Yoshimi Shibata : Differential structure and activity between human and mouse intelectin-1: human intelectin-1 is a disulfide-linked trimer, whereas mouse homologue is a monomer., Glycobiology, Vol.17, No.10, 1045-1051, 2007.
(Summary)
Human intelectin-1 (hITLN-1) is a 120-kDa lectin recognizing galactofuranosyl residues found in cell walls of various microorganisms but not in mammalian tissues. Although mouse intelectin-1 (mITLN-1) has been identified previously, its biochemical properties and functional characteristics have not been studied. Therefore, we have compared structures and saccharide-binding specificities of hITLN-1 and mITLN-1 using recombinant proteins produced by mammalian cells. Recombinant hITLN-1 is a trimer, disulfide-linked through Cys-31 and Cys-48, and N-glycosylated at Asn-163. Despite 84.9% amino acid identity to hITLN-1, recombinant and intestinal mITLN-1 are unglycosylated 30-kDa monomers. Recombinant hITLN-1, as well as recombinant and intestinal mITLN-1 were purified by Ca(2+)-dependent adsorption to galactose-Sepharose. In competitive binding studies, hITLN-1 was eluted from galactose-Sepharose by 100 mM 2-deoxygalactose, a galactofuranosyl disaccharide, d-xylose, and both d- and l-ribose. In contrast, mITLN-1 was partially eluted by the galactofuranosyl disaccharide, and only minimally by the other saccharides indicating that the two intelectins have different saccharide-binding specificities. When the N- and C-terminal regions of hITLN-1 were replaced, respectively, with those of mITLN-1, galactose-Sepharose binding was associated with the C-terminal regions. Finally, hITLN-1 binding to galactose-Sepharose was not affected by the substitution of the Cys residues in the N-terminal region that are necessary for oligomer formation, nor was it affected by the removal of the N-linked oligosaccharide at Asn-163. Although both hITLN-1 and mITLN-1 recognize galactofuranosyl residues, our comparative studies, taken together, demonstrate that these intelectins have different quaternary structures and saccharide-binding specificities.
Masaki Hanibuchi, Chiyuki Furukawa and Tsutomu Shinohara : Squamous Cell Carcinoma of the Lung in a 17-year-old Boy, Japanese Journal of Lung Cancer, Vol.47, No.4, 337-341, 2007.
(Keyword)
Lung cancer / Lung cancer in the young / Poorly differentiated squamous cell carcinoma / 肺癌 / 若年者肺癌 / 低分化型扁平上皮癌
Chiyuki Furukawa, Masaki Hanibuchi, Tsutomu Shinohara, Hisashi Ishikura and Suguru Kimura : A Case of Pulmonary Epithelioid Hemangioendothelioma, Japanese Journal of Lung Cancer, Vol.46, No.7, 811-815, 2006.
Riyo Ogura, Yoshikazu Hiasa, Shinobu Hosokawa, Tsutomu Shinohara, Haruo Kondou and Yoshiyuki Fujii : Gemcitabine reduced the size of tumor and improved QOL in a case of malignant pericardial mesothelioma, Heart, Vol.36, No.9, 647-652, 2004.
Masaki Hanibuchi, 島田 玲香, Yasuhiko Nishioka, Tsutomu Shinohara and Saburo Sone : 三尖弁感染症心内膜炎および化膿性脊椎炎に併発した敗血症性肺塞栓症の1例(症例報告), The journal of the Japanese Respiratory Society, Vol.41, No.5, 365-369, 2003.
107.
Tsutomu Shinohara, Naoki Nishimura, Masaki Hanibuchi, Hiroshi Nokihara, Toyokazu Miki, Hirofumi Hamada and Saburo Sone : Transduction of KAI1/CD82 cDNA promotes hematogenous spread of human lung-cancer cells in natural killer cell-depleted SCID mice, International Journal of Cancer, Vol.94, No.1, 16-23, 2001.
(Summary)
KAI1, which is identical to CD82, was initially identified as a metastasis-suppressor gene for human prostate cancer, and its expression is reported to be a favorable prognostic factor for operable human lung cancer. In this study, we examined the functional role of KAI1/CD82 in the late phase of metastatic spread of human lung-cancer cells. For this, KAI1/CD82 cDNA was introduced into KAI1/CD82 low-expressing human lung-cancer cell lines, SBC-3 and PC-14, and then the metastatic potential of the transformants was analyzed by i.v. inoculation of KAI1/CD82-transduced cells, SBC-3/KAI1 and PC-14/KAI1, into NK cell-depleted SCID mice. Contrary to our expectations, KAI1/CD82 gene transfer promoted multiorgan metastasis of i.v.-inoculated human lung-cancer cells, while s.c. tumor growth was unaffected. Cancer cells from metastatic tumors of NK cell-depleted SCID mice injected i.v. with SBC-3/KAI1 expressed appreciable cell-surface KAI1/CD82, and cells not expressing KAI1/CD82 (revertants) were not detected in the tumors. Our findings indicate that under conditions where the host's natural cytotoxicity is suppressed, KAI1/CD82 may enhance the formation of tumors by circulating lung-cancer cells at metastatic sites.
Naoki Nishimura, Yasuhiko Nishioka, Tsutomu Shinohara, Hirohisa Ogawa, Sayaka Yamamoto, Kenji Tani and Saburo Sone : Novel centrifugal method for simple and highly efficient adenovirus-mediated green fluorescence protein gene transduction into human monocyte-derived dendritic cells, Journal of Immunological Methods, Vol.253, No.1-2, 113-124, 2001.
(Summary)
Dendritic cells (DC) are professional antigen-presenting cells in the immune system. Gene transduction of DC with tumor-associated antigen (TAA) or other genes that enhance the immune reaction has been considered theoretically useful for DC-based immunotherapy. However, gene transduction of DC generated from human peripheral blood monocytes has been difficult due to its low efficiency, even when adenoviral vector was used at high multiplicity of infection (MOI). In the present study, we examined the effect of centrifugal force to enhance efficiency of adenovirus-mediated gene transduction into human monocyte-derived DC at various rotor speeds at various temperatures for various times. We judged the transduction efficiency using enhanced green fluorescence protein (EGFP)-expressing adenoviral vector, and the best condition for centrifugal transduction was determined as 2000 x g at 37 degrees C for 2 h at an MOI of 10 or greater. At an MOI of 50 without centrifugation, the gene transduction efficiency was about 66% and mean fluorescence intensity (MFI) of EGFP expression was about 150 (at 37 degrees C for 2 h). With centrifugal transduction (2000 x g at an MOI of 50 at 37 degrees C for 2 h), 86% or more DC were gene-modified, and especially, MFI of EGFP expression was highly enhanced (MFI: about 3100 or greater). Centrifugally gene-transduced DC were not damaged and were thoroughly functional as measured by mixed lymphocyte reaction (MLR). The centrifugal method was also applicable to human monocytes and K562 cells. The centrifugal transduction method with adenoviral vector might be helpful for the generation of gene-modified DC.
Naoki Nishimura, Yasuhiko Nishioka, Tsutomu Shinohara and Saburo Sone : Enhanced efficiency by centrifugal manipulation of adenovirus-mediated interleukin 12 gene transduction into human monocyte-derived dendritic cells., Human Gene Therapy, Vol.12, No.4, 333-346, 2001.
(Summary)
Transduction of dendritic cells (DCs) with genes encoding tumor-associated antigen or with other genes that enhance immune reaction has been theorized to be potentially useful for enhancing the efficiency of DC-based immunotherapy. However, gene transduction of DCs generated from human peripheral blood monocytes has been of limited use because of the low efficiency. Here, we report that the efficiency of in vitro adenovirus-mediated gene transduction into human monocyte-derived DCs can be dramatically enhanced by centrifugation. The best conditions for centrifugal gene transduction were determined to be as follows: 2000 x g at 37 degrees C for 2 hr at a multiplicity of infection (MOI) of 10 or greater. By this centrifugal method, approximately 88 and 70% of DCs were gene transducible at an MOI of 50 and 10, respectively. Functional analysis showed that DCs transduced with human interleukin 12 (IL-12)-expressing adenoviral vector under the optimal conditions of centrifugation stably produced IL-12 protein at high levels (8.1 ng/10(6) cells/48 hr). IL-12 gene-modified DCs (DC/IL-12) displayed a more mature phenotype than nontransduced DCs, as judged by decreased expression of CD1a and increased expression of CD83, B7.1 (CD80), B7.2 (CD86), and MHC class I and II molecules. DC/IL-12 showed a high phagocytic ability similar to nontransduced DCs and were significantly superior to control DCs in the stimulation of autologous and allogeneic T lymphocyte responses. The centrifugal transduction method with adenoviral vector might be useful for efficient generation of gene-modified DCs because it is very simple, highly efficient, reproducible, and not cytopathic. IL-12 gene-modified human DCs may be therapeutically useful as a good adjuvant in DC-based immunotherapy.
Saburo Sone, Tsutomu Shinohara, Yasuhiko Nishioka and Seiji Yano : Symposium on molecular pathogenesis of respiratory diseases and its clinical implication. 4. Molecular pathogenesis of lung cancer and its molecular targeted therapy, Internal Medicine, Vol.40, No.2, 167-170, 2001.
Takanori Kanematsu, 大串 文隆, Hirohisa Ogawa, Yasuhiko Nishioka, Tsutomu Shinohara, Hiroaki Yanagawa and Saburo Sone : 嚢胞状変化を呈した肺サルコイドーシスの1例, The journal of the Japanese Respiratory Society, Vol.39, No.2, 117-121, 2001.
112.
Naoki Nishimura, Yasuhiko Nishioka, Tsutomu Shinohara, Kenji Tani and Saburo Sone : Down-regulation by a new anti-inflammatory compound, FR167653, of differentiation and maturation of human monocytes and bone marrow CD34(+) cells to dendritic cells, International Journal of Immunopharmacology, Vol.22, No.7, 501-514, 2000.
113.
Prahlad Parajuli, Seiji Yano, Masaki Hanibuchi, Hiroshi Nokihara, Tsutomu Shinohara and Saburo Sone : Effect of clarythromycin on the distant metastases of human lung cancer cells in SCID mice, The Journal of Medical Investigation : JMI, Vol.44, No.3-4, 205-210, 1998.
(Summary)
Recently, the use of macrolides is suggested to be therapeutically effective in prolonging the survival of patients with inoperable non-small cell lung cancer. The purpose of this study was to examine therapeutic effects of a macrolide, clarythromycin (CAM) on the metastastic developments of two different human non-small cell lung cancers (squamous cell lung carcinoma RERF-LC-AI, and adenocarcinoma PC-14) in severe combined immunodeficient (SCID) mice depleted or undepleted of natural killer (NK) cells, respectively. CAM, injected subcutaneously at doses of 5 and 10 mg/kg body weight/day from day 7 to 41 after i.v. inoculation of human lung cancer cells, was not effective in inhibiting their distant organ metastases in SCID mice. CAM at concentrations of less than 10 micrograms/ml did not have a direct influence on the proliferation of these tumor cells in vitro. Although CAM alone was not effective in augmenting NK activity, it augmented the IL-2-induced killer (LAK) activity against Daudi cells in vitro. These results suggest that CAM alone may not be enough to control the spread of non-small cell lung cancer in the patient with T cell dysfunction.
(Tokushima University Institutional Repository: 110668, PubMed: 9597810)
114.
Seiji Yano, Hiroshi Nokihara, Masaki Hanibuchi, Prahlad Parajuli, Tsutomu Shinohara, Tetsuya Kawano and Saburo Sone : Model of malignant pleural effusion of human lung adenocarcinoma in SCID mice, Oncology Research, Vol.9, No.11-12, 573-579, 1997.
(Summary)
Malignant pleural effusion (PE) is a frequent problem in lung cancer. In this study, we established a model of malignant PE of human adenocarcinoma cells, PC-14, in SCID mice. Intravenously injected PC-14 cells formed colonies in the lungs as early as week 4 after tumor inoculation, and produced bloody PE in all recipient SCID mice by week 8. Pretreatment of SCID mice with anti-mouse IL-2 receptor beta chain antibody (TM-beta 1) to deplete natural killer (NK) cells markedly promoted the production of bloody PE and metastases to multiple organs, such as the lungs, liver, kidneys, and lymph nodes 4 weeks after tumor inoculation. Histological studies indicated that PC-14 cells formed colonies in the lungs, and then invaded the pleura and spread to the pleural cavity. To establish cell lines with a high potential to produce PE, we harvested PE, expanded the tumor cells in vitro, and injected them into SCID mice again. By four in vivo selection cycles in this way we obtained PC-14-PM4 cells, which produce lung metastases and PE earlier than PC-14 cells. The survival of SCID mice inoculated with PC-14-PM4 cells was significantly shorter than that of mice inoculated with PC-14 cells. The expressions of adhesion molecules, such as CD44, CD49d, ICAM-1, and MHC class I, on PC-14-PM4 cells tended to increase compared with PC-14 cells. These changes of adhesion molecules seem to be one of possible mechanisms involved in higher metastatic potential of PC-14-PM4 cells. PE models with PC-14 and PC-14-PM4 cells should be useful for biological and preclinical studies on malignant PE produced by human lung cancer.
Saburo Sone, Takashi Tsuruo, S Sato, Seiji Yano, Yasuhiko Nishioka and Tsutomu Shinohara : Transduction of the macrophage colony-stimulating factor gene into human multidrug resistant cancer cells: enhanced therapeutic efficacy of monoclonal anti-P-glycoprotein antibody in nude mice, Japanese Journal of Cancer Research, Vol.87, No.7, 757-764, 1996.
(Summary)
To develop a therapeutic modality for overcoming multidrug-resistant (MDR) cancer with anti-MDR1 antibody, we examined the effect of macrophage colony-stimulating factor (M-CSF) gene transfection into MDR AD10 cells on therapy of MDR cancer with anti-MDR1 antibody (MRK17) in nude mice. MDR human ovarian cancer (AD10) cells were transduced with the human M-CSF gene inserted into an expression vector to establish gene-modified cells capable of producing low (ML-AD10), intermediate (MM-AD10) nd high (MH-AD10) amounts of M-CSF. Systemic administration of MRK17 resulted in significant dose-dependent inhibition of subcutaneous growth of ML-AD10 tumors. In contrast, systemic administration of recombinant M-CSF in combination with MRK17 did not augment the therapeutic efficacy of MRK17 alone, but rather promoted the growth of the parent AD10 cells. To test the efficacy of in vivo M-CSF gene therapy combined with antibody, we mixed the parent AD10 cells with MH-AD10 cells producing a large amount of M-CSF, and inoculated the mixed cells subcutaneously. Treatment with MRK17 inhibited growth of the mixed cells more than that of the parent cells alone. Thus, combined therapy with anti-MDR1 mAb and M-CSF gene modification of MDR cancer cells may provide a new immunotherapeutic modality for overcoming MDR in humans.
Hiroaki Yanagawa, Saburo Sone, Y Takahashi, Takashi Haku, Seiji Yano, Tsutomu Shinohara and Takeshi Ogura : Serum levels of interleukin 6 in patients with lung cancer, Journal of Japan Association of Breast Cancer Screening, Vol.71, 1095-1098, 1995.
117.
E Shimizu, Tsutomu Shinohara, N Mori, J Yokota, K Tani, Keisuke Izumi, A Obashi and T Ogura : Loss of heterozygosity on chromosome arm 17p in small cell lung carcinomas, but not in neurofibromas, in a patient with von Recklinghausen neurofibromatosis., Cancer, Vol.71, No.3, 725-728, 1993.
(Summary)
The formation of SCLC may result from several genetic alterations, including inactivation of tumor-suppressor gene on chromosome 17p, most likely P53, although it still is unknown whether or not a mutation of the NF1 gene on 17q was involved in the development of SCLC in this patient.
Tsutomu Shinohara, Shun Morizumi and Kenya Sumitomo : Varying clinical presentations of nontuberculous mycobacterial disease : Similar to but different from tuberculosis., The Journal of Medical Investigation : JMI, Vol.68, No.3.4, 220-227, Aug. 2021.
(Summary)
The incidence rate of pulmonary nontuberculous mycobacterial disease (PNTMD) in Japan is the highest among major industrialized nations. Although the typical clinical course and radiological manifestations of PNTMD are different from those of pulmonary tuberculosis (TB), confusion about these mycobacterial diseases leads to a diagnostic pitfall. Diagnostic challenges include the coexistence of Mycobacterium tuberculosis (MTB) and nontuberculous mycobacteria (NTM), false positives for NTM in MTB nucleic acid amplification tests, microbial substitution, and abnormal radiological manifestations caused by NTM. Features of extrapulmonary NTM diseases, such as pleurisy, vertebral osteomyelitis, and disseminated disease, are different from the corresponding tuberculous diseases. Moreover, the immunological background of the patient (status of human immunodeficiency virus infection with or without antiviral therapy, continuation or discontinuation of immunosuppressive therapy, use of immune checkpoint inhibitor, pregnancy and delivery, etc.) influences the pathophysiology of mycobacterial diseases. This review describes the varying clinical presentations of NTM disease with emphasis on the differences from TB. J. Med. Invest. 68 : 220-227, August, 2021.
Saburo Sone, Tsutomu Shinohara, Yasuhiko Nishioka and Seiji Yano : 呼吸器疾患の分子病態と臨床, The Journal of the Japanese Society of Internal Medicine, Vol.89, No.9, 97-124, Sep. 2000.
Proceeding of International Conference:
1.
N. Nishimura, Yasuhiko Nishioka, Tsutomu Shinohara and Saburo Sone : Centrifugal enhancement of adenovirus-mediated gene transduction into human dendritic cells, American society for gene therapy(ASGT), Denver, Jun. 2000.