Publications by authors named "Tomoyuki Araya"

25 Publications

  • Page 1 of 1

Nivolumab-induced polymyalgia rheumatica in a patient with lung adenocarcinoma.

Am J Med Sci 2021 Apr 24. Epub 2021 Apr 24.

Department of Respiratory Medicine, Kanazawa University Hospital, Kanazawa, Ishikawa, Japan.

A 79-year-old woman was diagnosed with stage IV (cT1aN1M1, OSS) lung adenocarcinoma with bone metastasis of the right femur. She received nivolumab as a third-line treatment. She developed pain in the right shoulder, left wrist, right knee, and waist as well as a low-grade fever and morning stiffness, after five courses of nivolumab. After closer examination, she was diagnosed with polymyalgia rheumatica (PMR) precipitated by an immune-related adverse event. Nivolumab was discontinued, and oral prednisolone was started. Her arthralgia improved. Caution should be exercised regarding the development of PMR when polyarthralgia occurs during nivolumab treatment in patients with lung cancer.
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http://dx.doi.org/10.1016/j.amjms.2021.04.010DOI Listing
April 2021

Late-onset programmed cell death protein-1 inhibitor-induced pneumonitis after cessation of nivolumab or pembrolizumab in patients with advanced non-small cell lung cancer: a case series.

Transl Lung Cancer Res 2021 Mar;10(3):1576-1581

Respiratory Medicine, Kanazawa University Hospital, Ishikawa, Japan.

Awareness of the immune-related adverse event of programmed cell death protein-1 (PD-1) inhibitor-induced pneumonitis is important. Herein, we report the clinical course of 3 patients suspected to have PD-1 inhibitor-induced pneumonitis after cessation of PD-1 inhibitor treatment. In case 1, a 62-year-old man was diagnosed with stage IVA adenocarcinoma. Nivolumab monotherapy was prescribed as second-line therapy and later discontinued due to financial reasons. Seven months after the final administration of nivolumab, the patient developed what we diagnosed as nivolumab-induced pneumonitis. The patient was immediately prescribed prednisolone (1 mg/kg p.o. daily), and the pneumonitis resolved after 1.5 months. In case 2, a 68-year-old man was diagnosed with stage IVB squamous cell carcinoma. Nivolumab monotherapy was prescribed as fourth-line therapy. After the second administration of nivolumab, the patient developed what we diagnosed as nivolumab-induced pneumonitis; nivolumab was discontinued, and the patient was immediately prescribed prednisolone (1 mg/kg p.o. daily). Eight months after the final administration of nivolumab, the patient again developed nivolumab-induced pneumonitis. The pneumonitis resolved without additional medication. In case 3, a 69-year-old man was diagnosed with stage IVB adenocarcinoma. Pembrolizumab monotherapy was initiated as sixth-line therapy, and it was discontinued after 4 cycles due to disease progression. Four months after the final dose of pembrolizumab, the patient developed what we diagnosed as pembrolizumab-induced pneumonitis. The patient immediately received a high intravenous dose of methylprednisolone (1,000 mg per day for three days). The pneumonitis and respiratory failure progressed, and he died 8 weeks after the onset of the pneumonitis. We report pneumonitis after discontinuation of ICIs in 3 patients. We confirm that, although uncommon, PD-1 inhibitor-induced irAEs can develop after treatment discontinuation. Further accumulation of cases and clarification of the clinical features of patients with irAEs, such as the time of onset, imaging findings, and treatment outcomes are needed.
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http://dx.doi.org/10.21037/tlcr-20-582DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8044496PMC
March 2021

[Immunoglobulin G4( IgG4)-related Fibrosing Mediastinitis Localized in the Retrosternal Area:Report of a Case].

Kyobu Geka 2021 Apr;74(4):317-320

Department of Thoracic Surgery, Kanazawa Medical Center, Kanazawa, Japan.

An 84-year-old man was referred to our out-patient clinic with an elongated mass localized to the retrosternal area that was incidentally identified by computed tomography. On 18F-fluorodeoxyglucose-positron emission tomography, this lesion showed intense tracer uptake. Thus, a surgical biopsy under thoracoscopy was performed. Histological examination revealed dense fibrous tissue associated with inflammatory cell infiltration. The immunoglobulin (Ig) G4/IgG plasma cell ratio was over 90%. Serum IgG4 levels were normal. According to the Umehara criteria for IgG4-related disease, a final diagnosis of a "possible" IgG4-related fibrosing mediastinitis was made. Oral glucocorticoid treatment with 30 mg/day prednisolone reduced the mass.
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April 2021

Successful Treatment of Advanced Thymic Carcinoma with Carboplatin plus -Paclitaxel and Maintenance Monotherapy with -Paclitaxel: Two Case Reports.

Case Rep Oncol 2020 Sep-Dec;13(3):1506-1512. Epub 2020 Dec 17.

Department of Respiratory Medicine, Kanazawa University Hospital, Kanazawa, Japan.

A standard chemotherapy regimen for advanced thymic carcinoma has not yet been established. We treated 2 cases of thymic carcinoma with carboplatin plus nanoparticle albumin-bound ()-paclitaxel, and -paclitaxel maintenance therapy. The first case was a 68-year-old female, admitted for dyspnea and left shoulder pain. Chest computed tomography (CT) showed a huge mass in the anterior mediastinum, pleural and pericardial effusions, and multiple lung metastases. Specimens obtained from the anterior mediastinal mass by CT-guided needle biopsy revealed squamous cell carcinoma of the thymus, which was in stage IVB. The patient was administered carboplatin plus -paclitaxel as first-line treatment. After 3 cycles of chemotherapy, a partial response was observed with marked shrinkage of the tumor. Following 6 cycles of chemotherapy, -paclitaxel maintenance therapy was initiated. Disease progression was seen 9.1 months after initiation of treatment. The patient experienced no serious adverse events. The second case was a 70-year-old male who had productive cough, dyspnea, and right-sided chest pain. Chest CT revealed a huge mass in the anterior mediastinum, pericardial effusion, and multiple lymphadenopathies. Specimens obtained from station 11s by endobronchial ultrasound-guided transbronchial needle aspiration revealed undifferentiated thymic carcinoma, which was in stage IVB. Six cycles of carboplatin plus -paclitaxel were administered, followed by 5 cycles of -paclitaxel for maintenance. A partial response was seen, which was sustained for more than 13 months. The patient experienced no serious adverse events. These cases show that chemotherapy with carboplatin plus -paclitaxel and -paclitaxel as maintenance therapy can be a useful regimen for advanced thymic carcinoma.
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http://dx.doi.org/10.1159/000510894DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7841741PMC
December 2020

Final Results from a Phase II Trial of Osimertinib for Elderly Patients with Epidermal Growth Factor Receptor t790m-Positive Non-Small Cell Lung Cancer That Progressed during Previous Treatment.

J Clin Med 2020 Jun 5;9(6). Epub 2020 Jun 5.

Department of Pulmonary Medicine, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan.

Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are used for treating EGFR-mutated lung cancer, and osimertinib is effective in cases that acquired T790M mutations after treatment with the first- and second-generation EGFR-TKIs. However, no study has evaluated its safety and efficacy in older patients. This phase II trial (jRCTs071180002) evaluated osimertinib in T790M mutation-positive Japanese patients who were ≥75 years old and had experienced relapse or progression after previous EGFR-TKI treatment. Our previous report that enrolled 36 patients showed the overall response rate (58.3%) and disease control rate (97.2%), while this report describes the results for the progression-free survival (PFS), overall survival (OS), and safety analyses. The median PFS was 11.9 months (95% confidence interval (CI): 7.9-17.5), and the median OS was 22.0 months (95% CI: 16.0 months-not reached). The most frequent adverse events were anemia/hypoalbuminemia (27 patients, 75.0%), thrombocytopenia (21 patients, 58.3%), and paronychia/anorexia/diarrhea/neutropenia (15 patients, 41.7%). Pneumonitis was observed in four patients (11.1%), including two patients (5.6%) with Grade 3-4 pneumonitis. These results suggest that osimertinib was relatively safe and effective for non-small cell lung cancer that acquired T790M mutations after previous EGFR-TKI treatment, even among patients who were ≥75 years old.
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http://dx.doi.org/10.3390/jcm9061762DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7356339PMC
June 2020

Real-World Efficacy of First-Line Pembrolizumab in Patients With Advanced or Recurrent Non-Small-Cell Lung Cancer and High PD-L1 Tumor Expression.

Clin Lung Cancer 2020 09 26;21(5):e366-e379. Epub 2020 Feb 26.

Department of Respiratory Medicine, Kanazawa University, Kanazawa, Japan.

Background: In clinical trials, first-line treatment with pembrolizumab improved overall survival (OS) in patients with advanced non-small-cell lung cancer (NSCLC) with a programmed death ligand 1 (PD-L1) tumor proportion score of ≥ 50%. However, data on the efficacy of this treatment between clinical trials and actual clinical practice are inconsistent.

Patients And Methods: Ninety-five patients with histologically diagnosed advanced or recurrent NSCLC and a PD-L1 tumor proportion score of ≥ 50% who received pembrolizumab as first-line treatment were consecutively enrolled onto this multicenter retrospective study from February 2017 to December 2018. Clinical data were collected from electronic medical records. We assessed the objective response rate, progression-free survival (PFS), OS, and immune-related adverse events (irAE), and determined their associations with clinical characteristics.

Results: The objective response rate was 40.0%. The median PFS was 6.1 months, and OS did not reach the median. Multivariate analyses revealed that nonadenocarcinoma histology (hazard ratio, 1.78; 95% confidence interval, 1.05-3.03; P = .015) and ≥ 3 metastatic sites (hazard ratio, 3.97; 95% confidence interval, 1.97-8.01; P < .001) were independently correlated with poor PFS. Patients with irAE and patients without interstitial lung disease had significantly longer PFS (14.0 and 4.9 months, respectively; P = .011) than patients without irAE or patients with interstitial lung disease.

Conclusion: The outcome of patients receiving first-line pembrolizumab treatment was worse in those with nonadenocarcinoma and with a large number of metastatic sites. Patients with irAE and without interstitial lung disease had a more favorable outcome.
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http://dx.doi.org/10.1016/j.cllc.2020.02.017DOI Listing
September 2020

Efficacy and Safety of Nivolumab in Patients with Advanced Non-small-cell Lung Cancer and Poor Performance Status.

J Cancer 2019 19;10(10):2139-2144. Epub 2019 May 19.

Department of Pharmacy, National Hospital Organization Kanazawa Medical Center.

: Nivolumab efficacy in patients with non-small-cell lung cancer (NSCLC) and performance status (PS) of 2-4 is unclear. We aimed to compare survival, treatment efficacy, and safety in patients with NSCLC with poor PS who received nivolumab plus best supportive care (BSC) with those in patients who received BSC alone in a palliative care unit (PCU). : This retrospective study included 99 consecutive patients with NSCLC who received nivolumab plus BSC or BSC alone between December 2015 and March 2018. : In total, 43 patients with PS of 0-1 (good PS group) and 20 patients with PS of 2-4 (poor PS group) received nivolumab plus BSC; the remaining 36 patients received BSC alone in the PCU (PC group). Median overall survival was 32 days [95% confidence interval (CI), 21-43] in the poor PS group and 31 days (95% CI, 25-37) in the PC group (hazard ratio, 0.653; 95% CI, 0.368-1.158; P = 0.137). Moreover, median overall survival in patients with PS of 3 or 4 among the poor PS group was not significantly longer than that in the PC group (HR, 1.235; 95% CI, 0.646-2.360; P = 0.516). The frequency of severe pneumonitis in the poor PS group was significantly higher than that in the good PS group (25% vs. 2%, P = 0.010). : Survival benefit of nivolumab in patients with NSCLC with poor PS, especially 3 or 4, was not confirmed. Further studies with larger numbers of patients are required to confirm our results.
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http://dx.doi.org/10.7150/jca.31217DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6584408PMC
May 2019

Real-World Evidence of Safety and Efficacy of Carboplatin plus Nanoparticle Albumin-Bound Paclitaxel in Patients with Advanced Non-Small-Cell Lung Cancer and Preexisting Interstitial Lung Disease: A Retrospective Study.

Can Respir J 2019 20;2019:5315903. Epub 2019 Mar 20.

Department of Respiratory Medicine, Cellular Transplantation Biology, Kanazawa University Graduate School of Medical Sciences, 13-1 Takara-Machi, Kanazawa 920-8641, Japan.

Background: Standard chemotherapy for advanced non-small-cell lung cancer (NSCLC) with preexisting interstitial lung disease (ILD) has not yet been established. Although a combination of carboplatin and paclitaxel is most frequently used for patients with advanced NSCLC and ILD, the safety and efficacy of carboplatin plus nanoparticle albumin-bound paclitaxel (nab-paclitaxel) are yet to be elucidated.

Objectives: This study aimed to evaluate the safety and efficacy of carboplatin plus nab-paclitaxel for advanced NSCLC with ILD.

Methods: This retrospective study included nine patients with advanced NSCLC and ILD who received carboplatin plus nab-paclitaxel as first-line chemotherapy at the National Hospital Organization Kanazawa Medical Center between April 2013 and December 2017. The ILD-GAP index was used to evaluate mortality risk of baseline ILD.

Results: A usual interstitial pneumonia (UIP) pattern of ILD was observed in five (55.6%) patients on their baseline high-resolution computed tomography (HRCT) scans. The median ILD-GAP index was 4 (range, 1-5), and six (66.7%) patients had ILD-GAP index ≥4. We observed no ILD exacerbations or chemotherapy-related deaths. The overall response and disease control rates were 77.8% (95% CI, 40.0-97.2) and 88.9% (95% CI, 51.8-97.2), respectively. The median progression-free survival and overall survival were 5.8 months (95% CI, 2.1-7.7) and 8.0 months (95% CI, 2.6-16.8), respectively.

Conclusions: Carboplatin plus nab-paclitaxel showed favorable safety and efficacy in patients who had advanced NSCLC and ILD with a high risk of mortality. Prospective studies are required to further confirm these results.
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http://dx.doi.org/10.1155/2019/5315903DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6446117PMC
December 2019

Clinicopathological features of immunoglobulin G4-related pleural lesions and diagnostic utility of pleural effusion cytology.

Cytopathology 2019 05 8;30(3):285-294. Epub 2018 Nov 8.

Department Thoracic surgery of National Hospital Organization, Kanazawa Medical Center, Kanazawa, Japan.

Objective: Immunoglobulin (Ig)G4-related disease is a recently described systemic immune-mediated fibro-inflammatory disease that frequently occurs in tumorous form. Herein, we elucidated the clinicopathological and cytological characteristics of IgG4-related pleural lesions (PLs).

Patients And Methods: Among 22 patients with fibro-inflammatory PLs of idiopathic aetiology, eight cases were diagnosed as IgG4-PL and the remaining 14 as non-IgG4-PL according to comprehensive diagnostic criteria for IgG4-related disease. Cell block examination of pleural effusion (CBPE) was performed in five patients with IgG4-PL and in six with non-IgG4-PL. Both groups were compared in terms of clinical presentation, laboratory data, histopathological features of resected pleura, and cytological features of pleural effusion (PE).

Results: PE was the most common (six patients, 75%) clinical presentation of IgG4-PL. IgG4-PL comparatively showed significantly more frequent concomitant allergic disease (P = .021), higher serum IgE levels (P = .012), higher adenosine deaminase levels in pleural fluid (P = .005), and rare spontaneous recovery without treatment (P = .046). The IgG4-PL group was histologically characterised by thicker fibrous pleura, storiform fibrosis, and infiltration of regulatory T cells, eosinophils and basophils. Using CBPE, IgG4-PL was cytologically distinct with numerous IgG4+ cells and eosinophils. The cytology of CBPE positively correlated with the histology of pleural tissue in the number of IgG4+ cells and eosinophils (R = .769 and .803, respectively).

Conclusion: IgG4-PL frequently presents with PE and is histologically and cytologically characterised by abundant infiltration of IgG4+ cells and eosinophils. We believe that CBPE with immunohistochemistry/special staining could assist in the auxiliary diagnosis of IgG4-PL.
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http://dx.doi.org/10.1111/cyt.12641DOI Listing
May 2019

IgG4-Related Pleuritis With No Other Organ Involvement.

Am J Med Sci 2018 11 9;356(5):487-491. Epub 2018 May 9.

Department of Respiratory Medicine, Cellular Transplantation Biology, Kanazawa University Graduate School of Medicine, Kanazawa, Japan.

A 65-year-old man was admitted for productive cough and dyspnea. Bilateral pleural effusions were observed on chest X-ray. Although the bilateral pleural effusions were exudative with an increased number of lymphocytes, bacterial culture and polymerase chain reaction analysis for Mycobacterium tuberculosis were negative. Immunological examinations showed high levels of immunoglobulin G4 (IgG4) in both serum and pleural effusion fluid. Pathologic evaluation of a left pleural biopsy specimen using hematoxylin and eosin staining and immunohistochemical staining showed fibrosis-associated lymphoplasmacytic infiltration, 50 IgG4-positive plasma cells per high-power field, and an IgG4/IgG ratio of 40%. Thus, a diagnosis of IgG4-related pleuritis without other systemic manifestations was established. The bilateral pleural effusion improved following corticosteroid therapy. This is a rare case of IgG4-related pleuritis with no other organ involvement.
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http://dx.doi.org/10.1016/j.amjms.2018.05.004DOI Listing
November 2018

(18)F-FDG uptake predicts diagnostic yield of transbronchial biopsy in peripheral lung cancer.

Lung Cancer 2014 Jul 4;85(1):47-52. Epub 2014 Apr 4.

Third Department of Internal Medicine, Faculty of Medical Sciences, University of Fukui, 23-3 Matsuokashimoaizuki, Eiheiji-cho, Fukui 910-1193, Japan.

Objectives: Recent advances in endobronchial ultrasonography with a guide sheath (EBUS-GS) have enabled better visualization of distal airways, while virtual bronchoscopic navigation (VBN) has been shown useful as a guide to navigate the bronchoscope. However, indications for utilizing VBN and EBUS-GS are not always clear. To clarify indications for a bronchoscopic examination using VBN and EBUS-GS, we evaluated factors that predict the diagnostic yield of a transbronchial biopsy (TBB) procedure for peripheral lung cancer (PLC) lesions.

Methods: We retrospectively reviewed the charts of 194 patients with 201 PLC lesions (≤3cm mean diameter), and analyzed the association of diagnostic yield of TBB with [(18)F]-fluoro-2-deoxy-d-glucose ((18)F-FDG) positron emission tomography and chest computed tomography (CT) findings.

Results: The diagnostic yield of TBB using VBN and EBUS-GS was 66.7%. High maximum standardized uptake value (SUVmax), positive bronchus sign, and ground-glass opacity component shown on CT were all significant predictors of diagnostic yield, while multivariate analysis showed only high (18)F-FDG uptake (SUVmax ≥2.8) and positive bronchus sign as significant predictors. Diagnostic yield was higher for PLC lesions with high (18)F-FDG uptake (SUVmax ≥2.8) and positive bronchus sign (84.6%) than for those with SUVmax <2.8 and negative bronchus sign (33.3%). High (18)F-FDG uptake was also correlated with tumor invasiveness.

Conclusions: High (18)F-FDG uptake predicted the diagnostic yield of TBB using VBN and EBUS-GS for PLC lesions. (18)F-FDG uptake and bronchus sign may indicate for the accurate application of bronchoscopy with those modalities for diagnosing PLC.
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http://dx.doi.org/10.1016/j.lungcan.2014.03.025DOI Listing
July 2014

Successful treatment with a combination of electrocautery using wire snares and gefitinib in patients with EGFR-mutant lung cancer and central airway obstruction.

Intern Med 2013 ;52(20):2331-5

Department of Respiratory Medicine, Ishikawa Prefectural Central Hospital, Japan.

One-third of lung cancer patients present with life-threatening central airway obstruction (CAO). Two elderly patients were referred to our institution with symptoms caused by CAO. In each case, thoracic computed tomography and a bronchoscopic examination revealed a tumor obstructing the central airway. The tumors were resected endoscopically, and the patients' respiratory and performance status remarkably improved. Both patients were diagnosed with an advanced stage of lung adenocarcinoma harboring epidermal growth factor receptor (EGFR) mutations. They received gefitinib monotherapy, with partial responses sustained for more than 12 months. Combination therapy with endoscopic tumor resection and gefitinib is beneficial in patients with EGFR-mutant lung cancer and CAO.
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http://dx.doi.org/10.2169/internalmedicine.52.0557DOI Listing
May 2014

Usefulness of transesophageal bronchoscopic ultrasound-guided fine-needle aspiration in the pathologic and molecular diagnosis of lung cancer lesions adjacent to the esophagus.

J Bronchology Interv Pulmonol 2013 Apr;20(2):121-6

Department of Respiratory Medicine, Ishikawa Prefectural Central Hospital, Kanazawa University Graduate School of Medical Science, Kanazawa, Japan.

Background: The discovery of driver oncogenes has increased the need to obtain a sufficient amount of tissue specimens for lung cancer diagnosis. Although endoscopic ultrasound (with bronchoscope)-guided fine-needle aspiration (EUS-B-FNA) is reportedly a feasible and well-tolerated modality, additional advantages of EUS-B-FNA are yet to be thoroughly investigated. The purpose of this study was to evaluate the ability of EUS-B-FNA to obtain sufficient tissue specimens for pathologic and molecular diagnoses of lung cancer.

Methods: Among lung cancer patients who were diagnosed between December 2010 and December 2012 in our institute, patients who underwent EUS-B-FNA to diagnose lung cancer were enrolled (n=26). EUS-B-FNA was performed when bronchoscopic diagnosis was impossible or difficult to obtain sufficient samples. Epidermal growth factor receptor (EGFR) mutations and echinoderm microtubule-associated protein-like 4 and the anaplastic lymphoma kinase (EML4-ALK) fusion gene were evaluated using EUS-B-FNA samples of non-small cell lung cancer.

Results: EUS-B-FNA was performed on 28 lesions in 26 patients. Among the target lesions, 23 were mediastinal lymph nodes including nodal stations 2L, 4L, 7, 8, and 10L. The remaining 5 were intrapulmonary lesions. EUS-B-FNAs were completed without complications in all the patients. The diagnostic yield of EUS-B-FNA in diagnosing lung cancer was 100% (26/26). Additional diagnostic gain of EUS-B-FNA was 69.2% (18/26) as compared to bronchoscopy alone. EGFR mutations and EML4-ALK fusion gene could be evaluated in all patients with non-small cell lung cancer (n=20) using EUS-B-FNA samples. One case with EGFR mutation and 1 case with ALK fusion gene were diagnosed. Six non-small cell carcinomas were also diagnosed by bronchoscopy, but all bronchoscopic samples were insufficient to evaluate mutation analyses.

Conclusions: EUS-B-FNA is a practical and feasible method to obtain abundant tumorous tissue samples for pathologic diagnosis and molecular analysis, particularly when the target lesions are inaccessible by other modalities because of their locations or because of the patient's poor physical condition.
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http://dx.doi.org/10.1097/LBR.0b013e31829182a0DOI Listing
April 2013

Antitumor effects of inductive hyperthermia using magnetic ferucarbotran nanoparticles on human lung cancer xenografts in nude mice.

Onco Targets Ther 2013 24;6:237-42. Epub 2013 Mar 24.

Department of Respiratory Medicine, Cellular Transplantation Biology, Kanazawa University Graduate School of Medical Science, Kanazawa, Japan.

Background: The effects of inductive hyperthermia on lung cancer have yet to be fully investigated. Magnetic nanoparticles used in inductive hyperthermia are made-to-order and expensive. This study was performed to investigate the use of ferucarbotran in inductive hyperthermia and to clarify whether inductive hyperthermia using ferucarbotran promotes antitumor effects in vivo using a lung cancer cell line.

Methods: We injected A549 cells subcutaneously into the right thighs of BALB/c nu/nu nude mice. Forty mice with A549 xenografts were then classified into three groups. Group 1 was the control group. All mice in groups 2 and 3 had ferucarbotran injected into their tumors, and mice in group 3 were then subjected to alternating magnetic field irradiation. We evaluated tumor temperature during the hyperthermic procedure, the time course of tumor growth, histologic findings in tumors after hyperthermic treatment, and adverse events.

Results: Intratumor temperature rose rapidly and was maintained at 43°C-45°C for 20 minutes in an alternating magnetic field. Tumor volumes in groups 1 and 2 increased exponentially, but tumor growth in group 3 was significantly suppressed. No severe adverse events were observed. Histologic findings for the tumors in group 3 revealed mainly necrosis.

Conclusion: Inductive hyperthermia using ferucarbotran is a beneficial and promising approach in the treatment of lung cancer. Ferucarbotran is a novel tool for further development of inductive hyperthermia.
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http://dx.doi.org/10.2147/OTT.S42815DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3615880PMC
April 2013

Successful treatment with erlotinib of severe neutropenia induced by gefitinib in a patient with advanced non-small cell lung cancer.

Lung Cancer 2013 Jun 13;80(3):344-6. Epub 2013 Mar 13.

Department of Respiratory Medicine, Ishikawa Prefectural Central Hospital, 2-1 Kuratsuki-Higashi, Kanazawa 920-8530, Japan.

Neutropenia is a rare side effect of gefitinib and was scarcely reported in many large-scale randomized phase III trials using gefitinib monotherapy as first-line treatment. A 77-year-old female was referred to our institution due to abnormal shadow of the right lung, diagnosed by CT scan and biopsy histopathology as adenocarcinoma of the lung (cT3N1M1b). Mutation analysis with PCR-Invader assay of tumor DNA samples revealed short in-frame deletion in exon 19. Based on the diagnosis, first-line treatment was initiated using oral gefitinib (250 mg, daily). During the initial 27 days of gefitinib therapy, the only side effect was a mild skin rash. After 28 days, there was marked tumor shrinkage, indicative of a partial response to gefitinib; however, grade 4 neutropenia was also detected. The patient was switched to the oral erlotinib monotherapy (150 mg/day) as second-line chemotherapy with careful monitoring of neutropenia. Discontinuation of the gefitinib, without the need for granulocyte colony-stimulating factor support, was successful in allowing the neutrophils and leukocytes counts to recover to normal by day 47. The patient continued oral erlotinib for more than 9 months and there has been no evidence of neutropenia, leukopenia, or disease progression. Clinicians should be aware that gefitinib-induced neutropenia in patients with non-small cell lung cancer can be treated successful by switching to erlotinib.
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http://dx.doi.org/10.1016/j.lungcan.2013.02.014DOI Listing
June 2013

Expression, purification, and analyses of glycosylation and disulfide bonds of Stereum purpureum endopolygalacturonase I in Pichia pastoris.

Protein Expr Purif 2009 May 4;65(1):15-22. Epub 2009 Jan 4.

Faculty of Agriculture and Life Science, Hirosaki University, 3 Bunkyo-cho, Aomori Prefecture, Hirosaki 036-8561, Japan.

We have succeeded in the expression of Stereum purpureum endopolygalacturonase I (EndoPG I) using the Pichia expression system and in purification of the three kinds of recombinant EndoPG I, which have one to three sugar chains by using CM52 column chromatography. The sugar chains which were added to EndoPG I were the M8, M9, and/or M10 high-mannose type. The results of LC-MS analysis showed that recombinant EndoPG Is were randomly glycosylated at four N-glycosylation sites. From the thermal denaturation curves of the recombinant enzymes, it was suggested that EndoPG I differing in thermal stability was included in the sample after purification. Therefore, we investigated the disulfide bonds of recombinant EndoPG I by LC-MS analysis. As a result, peptides without a second or third disulfide bond were detected. This result is the first indicating that there are incomplete enzymes in terms of disulfide bonds in the Pichia expression system.
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http://dx.doi.org/10.1016/j.pep.2008.12.014DOI Listing
May 2009

Eosinophilic pneumonia and thoracic metastases as an initial manifestation of prostatic carcinoma.

Intern Med 2008 1;47(15):1419-23. Epub 2008 Aug 1.

Respiratory Medicine, Cellular Transplantation Biology, Kanazawa University Graduate School of Medical Science.

We herein report an 80-year-old man with prostatic carcinoma who developed eosinophilic pneumonia and intrathoracic metastases. He presented with shortness of breath, cough, and fever as a chief complaint. Chest X-ray and computed tomography showed bilateral pulmonary nodules, intrathoracic lymphadenopathy, and right-sided consolidation. Positron emission tomography (PET) using (18)F-fluorodeoxyglucose (FDG) showed poor uptake in these nodules and lymph nodes. The patient subsequently received a pelvic computed tomography scan, which revealed a massively enlarged prostate. The serum prostate specific antigen level was elevated to 4,181.2 ng/mL, and a transrectal biopsy revealed prostatic adenocarcinoma. Based on the morphological and immunohistochemical findings, the nodules in the lung and the lymph nodes were diagnosed as secondary neoplasm from the prostate. As for right-sided consolidation, remarkable bronchoalvelar lavage fluid eosinophilia was detected, that was compatible with eosinophilic pneumonia. Eosinophilic pneumonia in this case disappeared and has not recurred by treatment of prostatic carcinoma and steroid therapy for a week, and was regarded to be tumor-associated. Although prostatic carcinoma with an initial manifestation of intrathoracic metastases and eosinophilic pneumonia is uncommon, physicians should suspect the condition. In addition, we should also keep in mind that prostatic carcinoma sometimes shows poor uptake in FDG-PET. PET: Positron emission tomography, FDG: (18)F-flouorodeoxyglucose.
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http://dx.doi.org/10.2169/internalmedicine.47.1124DOI Listing
October 2008

Sputum eosinophilia, airway hyperresponsiveness and airway narrowing in young adults with former asthma.

Allergol Int 2008 Sep;57(3):211-7

Respiratory Medicine, Cellular Transplantation Biology, Kanazawa University Graduate School of Medicine, Ishikawa, Japan.

Background: 30-80% of outgrown asthma subjects develop symptoms again later in life. We investigated inflammation and function of lower airway in adolescents with former asthma.

Methods: 326 never-smoking young adults (mean age 24.0 years) were interviewed with special emphasis on history of asthma. Diagnosis of asthma was based on GINA guidelines. Former asthma subjects consisted of ones with a history of physician-diagnosed childhood asthma, who had been free of asthma symptoms without the use of medication for at least 10 years prior to the study. Provocative concentration of methacholine causing a 20% fall in forced expiratory volume in 1 second (FEV(1))(PC(20)) and eosinophil percentage in induced sputum were measured.

Results: 31 subjects were former asthma subjects (FBA), 11 subjects were current asthma subjects (CBA) and 284 subjects had no history of asthma (non-BA). PC(20) and FEV(1)/FVC ratio were significantly lower in the FBA group than in the non-BA group (P < 0.01). Maximal mid-expiratory flow (MMF) was significantly lower in the FBA group than in the non-BA group (P < 0.05). Sputum eosinophil percentage was significantly increased in the FBA group compared with the non-BA group (P < 0.01). PC(20) was significantly lower in the CBA group than in the FBA and non-BA groups (P < 0.01). FEV(1), FEV(1)/FVC ratio and MMF were significantly lower in the CBA group than in the FBA group (P < 0.05, P < 0.05 and P < 0.05, respectively) and the non-BA group (P < 0.01, P < 0.01 and P < 0.05, respectively). Sputum eosinophils were significantly higher in the CBA group than in the FBA and non-BA groups (P < 0.01).

Conclusions: This study shows that subjects with long-term outgrown asthma continue to have airway eosinophilic inflammation, airway hyperresponsiveness and airway narrowing.
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http://dx.doi.org/10.2332/allergolint.O-06-461DOI Listing
September 2008

[Early stage pulmonary alveolar proteinosis detected by chest CT scan in a medical examination].

Nihon Kokyuki Gakkai Zasshi 2007 Mar;45(3):277-81

The Division of Respiratory Medicine, Kanazawa Municipal Hospital.

We report a case of pulmonary proteinosis detected at an early stage and followed up on chest CT. A 49-year-old man underwent detailed examinations because of abnormal shadows on chest CT taken on a routine medical examination. The chest CT revealed almost symmetrical ground glass opacities (GGOs) in both lungs with thickened alveolar septa. We could not make a definitive diagnosis even with bronchoalveolar lavage and transbronchial lung biopsy, but after about half a year, the GGOs increased. VATS-biopsy demonstrated alveoli filled with PAS-positive granular materials, and we made a diagnosis of pulmonary alveolar proteinosis. This case was found at an early stage and we were then able to follow up the disease.
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March 2007

[A case of advanced large cell lung carcinoma for whom fourth-line chemotherapy of cisplatin and gemcitabine proved effective for the first time].

Gan To Kagaku Ryoho 2007 Feb;34(2):217-9

Respiratory Medicine, Cellular Transplantation Biology, Kanazawa University Graduate School of Medicine.

Case: A 56-year-old Japanese man who was suffering from dry cough and right neck mass visited our hospital. Chest X-ray revealed a lung mass shadow in the lower left lung field. We diagnosed it as an advanced large cell carcinoma after conducting transbronchial lung biopsy and neck lymphnode biopsy. A right neck mass enlarged after three chemotherapy regimens of carboplatin and vinorelbine for first-line, docetaxel for second-line, and TS-1 and cisplatin for third-line. Finally, cisplatin (80 mg/m(2), day 1) and gemcitabine (800 mg/m(2), day 1, 8) were administered as fourth-line therapy. Partial response was observed after completing four chemotherapy cycles.

Conclusion: In this case, the fourth-line chemotherapy, consisting of cisplatin and gemcitabine, proved effective for refractory NSCLC. Further research should be conducted regarding third-line chemotherapy for NSCLC patients with good performance status.
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February 2007

Bi-weekly administration of gemcitabine plus vinorelbine in elderly patients with advanced non-small-cell lung cancer: multicenter phase II trial.

Lung Cancer 2007 Jun 14;56(3):371-6. Epub 2007 Feb 14.

Respiratory Medicine, Kanazawa University Hospital, Takara-machi 13-1, Kanazawa 920-8641, Japan.

Purpose: Gemcitabine (GEM) and vinorelbine (VNR) have demonstrated activity as a first-line treatment in elderly patients with advanced non-small-cell lung cancer (NSCLC). We conducted a multicenter phase II trial to evaluate the efficacy and toxicity of bi-weekly administration of GEM plus VNR in elderly patients with advanced NSCLC.

Patients And Methods: Forty-six chemotherapy-naive elderly (age: >or=70 years) NSCLC patients were enrolled. Patients were eligible if they had histologically or cytologically confirmed unresectable NSCLC with measurable and/or assessable disease. Patients received GEM (1000 mg/m2) and VNR (25 mg/m2) every 2 weeks.

Results: The objective response rate of this treatment was 22.7% (95% confidence interval (CI), 10.3-35.1%), median survival time was 310 days, and median time to progression was 133 days. The one-year survival rate was 40.9% (95% CI, 26.3-55.4%), and most adverse events were mild. Only three (6.8%) patients needed to omit GEM because of grade 4 neutropenia or due to physician judgment. No patients suffered treatment-related death.

Conclusions: Bi-weekly administration of GEM plus VNR in elderly patients was an effective, feasible and well-tolerated treatment schedule.
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http://dx.doi.org/10.1016/j.lungcan.2007.01.001DOI Listing
June 2007

A phase II study of combination chemotherapy with docetaxel and carboplatin for patients with advanced or metastatic non-small cell lung cancer.

Anticancer Res 2006 Sep-Oct;26(5B):3723-8

Respiratory Medicine, Kanazawa University Hospital, Takara-machi 13-1, Kanazawa, Ishikawa, Japan.

Background: The aim of this phase II study was to evaluate the efficacy of combination chemotherapy consisting of docetaxel and carboplatin in patients with inoperable non-small cell lung cancer (NSCLC).

Patients And Methods: For this multicenter phase II study, the eligibility criteria included histologically or cytologically proven inoperable NSCLC, measurable lesions, Eastern Cooperative Oncology Group performance status (PS) 0-2, adequate organ and bone marrow functions, and written informed consent. Patients received 60 mg/m2 of docetaxel and carboplatin (target AUC 5.5) on day 1 every 3 weeks until disease progression. The primary end-point of this study was response rate and the secondary end-points were toxicities, time to progression and overall survival.

Results: A total of 40 patients were enrolled and 39 patients were eligible. A complete response and partial response were observed in 1 and 13 patients, respectively. An objective response rate was 35.9% (95% confidential interval [CI] 20.8-51.0%). The median time to progression was 5.2 months and the median overall survival was 12.0 months. The 1- and 2-year survival rates were 53.8% and 25.1%, respectively. The major toxicities were leukocytopenia and neutropenia. Grade 3 or 4 thrombocytopenia was rare and non-hematological toxicities were generally mild. Grade 3 non-hematological toxicities were observed in 6 patients (2 with nausea and vomiting, 1 with diarrhea, 1 with elevated transaminase levels, 1 with allergic reaction and 1 with edema). No grade 4 non-hematological toxicities were observed.

Conclusion: Docetaxel and carboplatin combination chemotherapy was well tolerated and active in Japanese patients with advanced or metastatic NSCLC.
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December 2006

Design, synthesis, and enzymatic property of a sulfur-substituted analogue of trigalacturonic acid.

Bioorg Med Chem Lett 2005 Nov;15(22):4932-5

Faculty of Agriculture and Lifescience, Hirosaki University, 3-Bunkyo-cho, Hirosaki 036-8561, Japan.

A sulfur-substituted analogue of trigalacturonic acid (3) was synthesized. The synthesis features the application of 3-cyano-3-(tert-butyldimethylsilyl)oxypropylthioether (CSP) as a novel protective group for thiols. This analogue was designed with the expectation that it would be a stable analogous substrate for endo-polygalacturonase isolated from Stereum purpureum based on computer modeling experiments. Surface plasmon resonance experiments revealed that 3 forms a stable complex with the target enzyme.
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http://dx.doi.org/10.1016/j.bmcl.2005.08.019DOI Listing
November 2005

Expression, purification, and crystallization of endopolygalacturonase from a pathogenic fungus, Stereum purpureum, in Escherichia coli.

Protein Expr Purif 2005 Dec 1;44(2):130-5. Epub 2005 Jul 1.

Kinetic Crystallography Research Team, Membrane Dynamics Research Group, RIKEN, Harima Institute at SPring-8, 1-1-1 Kouto, Mikazuki-cho, Sayo-gun, Hyogo 679-5148, Japan.

Endopolygalacturonases (EC 3.2.1.15) catalyze random hydrolysis of the alpha-1,4 glycosidic linkages in polygalacturonic acid, a component of pectin. Previously, we reported crystal structures of endogenously produced Stereum purprureum endopolygalacturonase I (endoPG I), both in its native form and complexed with its product, galacturonate. However, the substrate-binding mechanism of endoPG I is still unclear, because crystals have not yet been obtained with a substrate analog, or with mutant enzymes that can bind substrates. We describe here an expression system using Escherichia coli and a purification method to prepare functionally active endoPG I for such mutation and crystallographic studies. Expression in E. coli strain Origami (DE3) provided a soluble and active enzyme with proper disulfide bond formation, whereas the enzyme expressed in BL21 (DE3) was localized in inclusion bodies. A sufficient amount of recombinant endoPG I produced by Origami (DE3) was purified by a single-step procedure using cation exchange chromatography. The specific activity of recombinant endoPG I was equivalent to that of the enzyme produced by S. purpureum. Recombinant endoPG I was crystallized under the same conditions as those used for the native enzyme produced by S. purpureum. The crystals diffracted beyond 1.0 A resolution with synchrotron radiation.
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http://dx.doi.org/10.1016/j.pep.2005.06.001DOI Listing
December 2005