Publications by authors named "Seiichi Kakegawa"

46 Publications

[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

Semi-comprehensive analysis of gene amplification in thymic malignant tumors using multiplex ligation-dependent probe amplification and fluorescence in situ hybridization.

Int J Clin Exp Pathol 2020 1;13(5):1035-1044. Epub 2020 May 1.

Department of Molecular and Cellular Pathology, Graduate School of Medical Science, Kanazawa University Ishikawa, Japan.

Research on the amplification of oncogenes in thymic malignant tumor is limited. In this study, we aimed to determine the gene amplification status of receptor tyrosine kinases and other cell regulator genes in thymic malignant tumors, with a view toward the future introduction of molecular targeted therapy. In addition, we examined the usefulness of multiplex, ligation-dependent probe amplification (MLPA) in the semi-comprehensive detection of these gene amplifications. The participants of this study were nine patients with thymic carcinoma and one patient with atypical carcinoid who underwent resection at our department from 1999 to 2016. Twenty-four oncogenes () were analyzed for amplification by MLPA. In cases where amplification by MLPA was suspected, confirmation was performed by fluorescence in situ hybridization (FISH). Immunostaining for detected oncoproteins and p53 were performed in cases with confirmed oncogene amplification. (2/10, 20%) and (1/10, 10%) amplifications were detected using MLPA and FISH. Immunostaining in both cases was positive. The -amplified tumor relapsed and spread rapidly after operation despite the use of post-operative chemo-radiotherapy. amplification may be involved in the carcinogenesis of thymic malignant tumors. In addition, amplification may be a concern in the increased malignancy.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7270679PMC
May 2020

[Thymoma Presenting Synchronously with a Mycosis Fungoides;Report of a Case].

Kyobu Geka 2020 Jun;73(6):466-470

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

A 65-year-old woman presented with mycosis fungoides and an anterior mediastinal tumor. Stage Ⅱa mycosis fungoides was treated with bath psoralen plus ultraviolet A, topical corticosteroids, and oral bexarotene. One month later, a surgical resection was performed for the anterior mediastinal tumor, which was a stage Ⅱ thymoma with membrane invasion. Furthermore, adjuvant radiotherapy was performed for anterior mediastinum. The mycosis fungoides lesion exacerbated after 3 months;thus, chemotherapies were performed. The patient died of respiratory insufficiency due to multiple pulmonary metastases of mycosis fungoides 1 year after the operation.
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June 2020

Comparison Between Stereotactic Radiotherapy and Sublobar Resection for Non-Small Cell Lung Cancer.

Ann Thorac Surg 2019 05 17;107(5):1544-1550. Epub 2018 Nov 17.

Department of Thoracic, Cardiovascular and General Surgery, Kanazawa University, Kanazawa, Japan.

Background: The aim of this study was to compare outcomes of primary treatment with stereotactic body radiation therapy (SBRT) versus sublobar resection (SLR) for clinical stage I non-small cell lung cancer (NSCLC) in patients with medical comorbidities.

Methods: Consecutive patients who underwent SBRT (n = 106) or SLR (100 wedge resection, 41 segmentectomy) because of medical comorbidities associated with stage I NSCLC were enrolled. Lesions located in the outer third of the lung field on computed tomography were defined as external, and others were defined as internal. A propensity score-matched analysis was also performed that compared SBRT and SLR results. Charts were reviewed to determine local tumor recurrence, disease-specific survival (DSS), and overall survival (OS).

Results: A propensity score-matched analysis, recurrence-free survival (RFS) became significant in favor of surgery (p = 0.036). For large nodules of greater than 2.0 cm in diameter, RFS was significantly better in the surgery group (p = 0.042). No significant differences in OS, DSS, or RFS were observed with small nodules of less than 2.0 cm in diameter. In the external group, a higher recurrence rate was seen for SBRT group. For internal group, there was no statistical difference between each treatment. Local recurrence rate was higher in the SBRT group (p = 0.0082) in the external group.

Conclusions: In a matched comparison of stage I NSCLC in patients with medical comorbidities, RFS was in favor of surgery comparing SBRT, but there were no significant differences in OS or DSS. The tumor size and tumor location should be considered before deciding whether to perform SBRT or surgery.
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http://dx.doi.org/10.1016/j.athoracsur.2018.10.015DOI Listing
May 2019

[Utility of Partial Splenic Embolization Prior to Lung Resection in Patients Demonstrating Platelet Transfusion Refractoriness Due to Hypersplenism].

Kyobu Geka 2017 Dec;70(13):1063-1067

General, Thoracic and Cardiovascular Surgery, Kanazawa University, Kanazawa, Japan.

It is often difficult to control perioperative bleeding in patients with liver cirrhosis and concurrent thrombocytopenia and coagulation factor deficiency. Partial splenic embolization (PSE), an auxiliary treatment strategy in management of liver cirrhosis and hepatocellular carcinoma, can not only increase platelets but also improve liver function. With advances in interventional radiology, PSE is a safer and more reliable procedure compared to a splenectomy. We present the case of a 69-year-old man diagnosed with left lung cancer, with thrombocytopenia, and hepatitis C virus-related cirrhosis. Although he was administered prophylactic platelet transfusion prior to operation, he was noted to be refractory to platelet transfusion. PSE was performed to improve his thrombocytopenia, following which we could safely perform left upper lobectomy of the lung and ND2a-1 lymph node dissection without any major bleeding. PSE is useful induction therapy to provide a wider choice of treatment options for patients with thrombocytopenia.
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December 2017

Mean Computed Tomography Value to Predict the Tumor Invasiveness in Clinical Stage IA Lung Cancer.

Ann Thorac Surg 2017 Jul 19;104(1):261-266. Epub 2017 Apr 19.

Department of Thoracic, Cardiovascular and General Surgery, Kanazawa University, Kanazawa, Japan.

Background: The purpose of this study was to validate the ability of the mean computed tomography (m-CT) value to predict tumor invasiveness and recurrence, and further, to compare with other measurements such as consolidation/tumor ratio and solid tumor size.

Methods: A retrospective study was conducted of 494 patients with clinical stage IA lung cancer who had peripherally located lung adenocarcinoma. Receiver operating characteristic curve analysis was used to compare the ability to predict tumor invasiveness and recurrence between m-CT value, consolidation/tumor ratio, and tumor size. Multiple logistic regression analyses were performed to determine the independent variables for the prediction of pathologic, less invasive lung cancer. Disease-free survival was measured from the date of the operation until any recurrence.

Results: The m-CT values were 643.6 ± 9.4 Hounsfield units in the noninvasive cancer group and 365.9 ± 11.4 Hounsfield units in the invasive cancer group (p < 0.0001). The invasive cancer group was strongly associated with a high CT attenuation value, high consolidation/tumor ratio, large solid tumor size, large tumor size, and high standardized uptake value. Multiple logistic analyses, including the preoperatively determined variables, revealed that standardized uptake value and m-CT are independent predictive factors of less invasive lung cancer. In addition, the hazard ratio of the m-CT value was higher than that of the standardized uptake value value.

Conclusions: The evaluation of m-CT value is useful in predicting less invasive lung cancer. The m-CT value can potentially determine operative procedure, particularly limited resection for peripheral lung adenocarcinoma.
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http://dx.doi.org/10.1016/j.athoracsur.2017.01.060DOI Listing
July 2017

[Congenital Bronchial Atresia Requiring Differentiation from Intralobar Sequestration].

Kyobu Geka 2017 Mar;70(3):169-173

Department of General, Thoracic and Cardiovascular Surgery, Kanazawa University, Kanazawa, Japan.

We reported a case of bronchial atresia requiring differentiation from the intralobar sequestration. A 42-year-old man was referred to our institution with suspicion of intralobar sequestration, based on a 3-dimensional computed tomography (CT) angiography that showed abnormal blood vessels from the right inferior phrenic artery flowing into the right lower lobe. CT revealed a lesion between S9 and S10 wherein there were refluxed blood vessels from A9 without an accompanying bronchus, with polycysts and emphysematous changes. Ventilation-perfusion scintigraphy revealed a reduction in uptake in the same sites. He was diagnosed as congenital bronchial atresia preoperatively, and we performed a right basal segmentectomy. Pathological examination confirmed the bronchiectasis and emphysematous changes in the lung parenchyma, but malignant findings were not confirmed.
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March 2017

[A Recurrent Case of Thymic Adenocarcinoma Effectively Treated with S-1 Over a Long-Term Period].

Gan To Kagaku Ryoho 2017 Mar;44(3):239-242

Dept. of Thoracic, Cardiovascular and General Surgery, Kanazawa University.

A 61-year-old woman with an abnormal radiograph shadow in her anterior mediastinum was admitted to our hospital and underwent an extended thymectomy. The pathological diagnosis of the tumor was a non-papillary adenocarcinoma of the thymus in pathological stage IV b using the Masaoka classification owing to mediastinal lymph node metastasis. We found parasternal lymph node metastases 5 months after her first operation, and subsequently, she underwent surgery and adjuvant radiotherapy. We found systemic lymph node metastases and metastatic lesions in distant organs, including her lungs, brain, and kidney 27 months after her first operation. Systemic chemotherapy, such as carboplatin plus paclitaxel and an ADOC regimen were not very effective, so we performed immunohistochemical staining of the primary thymic adenocarcinoma. The levels of both thymidylate synthase and dihydropyrimidine dehydrogenase were low; therefore, we started S-1 100mg/body (2 weeks of administration, 1 week of withdrawal)31 months after her first operation. She entered complete remission 6 months after the initiation of S-1. We surgically resected her solitary lung metastasis 13 months after initiation of S-1, and then continued the S-1 treatment. There was no recurrence for more than 2 years after the lung surgery. We believe that when the expression levels of thymidylate synthase or dihydropyrimidine dehydrogenase are low in cases of recurrent thymic adenocarcinoma, S-1 may be able to induce an effective response.
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March 2017

[Lung Segmentectomy Using Video-assisted Thoracic Surgery for Lung Cancer in a Patient with Situs Inversus Totalis].

Kyobu Geka 2016 Jul;69(7):521-4

Department of Thoracic Surgery, Nishigunma National Hospital, Shibukawa, Japan.

The case was 83-year-old man who had complete situs inversus, and was pointed out to have peripheral adenocarcinoma with the size of 1.8 cm at the left upper lobe( S3). Because of severe emphysema and other multiple comorbidities, left S3 segmentectomy with hilar lymph node sampling was performed using video-assisted thoracic surgery (VATS). Preoperatively, the simulation of operation was performed using the 3 dimension computed tomography images of pulmonary arteriovenous and bronchus (3DCTAB). Postoperative course was uneventful. 3DCTAB was thought to be useful in understanding the anatomical location of pulmonary arteriovenous and bronchus directly, and in performing segmentectomy in the case of situs inversus like this.
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July 2016

Prognostic potential of the MDM2 309T>G polymorphism in stage I lung adenocarcinoma.

Cancer Med 2016 08 26;5(8):1791-801. Epub 2016 May 26.

Department of Thoracic and Visceral Organ Surgery, Gunma University Graduate School of Medicine, Maebashi, Gunma, 371-8511, Japan.

The MDM2 protein plays an important role in the regulation of cell proliferation and apoptosis via ubiquitination and proteasome-mediated degradation of p53. The genetic polymorphism rs2279744 (c.309T>G) of the MDM2 gene is reportedly associated with susceptibility and/or prognosis in various cancers. In this study, we investigated the risk factors for worse survival in patients with lung adenocarcinoma (AC). We examined the association between c.309T>G and the prognosis of lung cancer by retrospectively reviewing 453 lung cancer patients. We studied both, clinicopathological and genetic characteristics, including the c.309T>G, p53 Arg72Pro, EGFR, KRAS, and p53 mutations. Associations between these factors and survival outcome were analyzed using Cox proportional hazards models. The frequencies of MDM2 polymorphisms were T/T, 20.8%; T/G, 48.6%, and G/G, 30.7%. The overall survival (OS) of AC patients with pathological stage I disease and the MDM2 T/T genotype was significantly shorter than that of those with the T/G or G/G genotypes (P = 0.02). Multivariate analysis revealed that the MDM2 T/T genotype was an independent, significant prognostic factor (hazard ratio [HR] = 2.23; 95% confidence interval [CI]: 1.07-4.65; P = 0.03). The MDM2 T/T genotype was predictive of poorer survival in a Japanese population. Genotyping for this polymorphism might predict the clinical outcomes of stage I AC patients.
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http://dx.doi.org/10.1002/cam4.750DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4884639PMC
August 2016

Prospective Analysis of Oncogenic Driver Mutations and Environmental Factors: Japan Molecular Epidemiology for Lung Cancer Study.

J Clin Oncol 2016 07 9;34(19):2247-57. Epub 2016 May 9.

Tomoya Kawaguchi, Akihiro Tamiya, Shigeki Shimizu, Shun-ichi Isa, and Akihide Matsumura, National Hospital Organization Kinki-chuo Chest Medical Center; Tomoya Kawaguchi and Naoki Yoshimoto, Osaka City University, Osaka; Yasuhiro Koh, Seiichi Kakegawa, Masakuni Serizawa, Akihito Kubo, and Hideo Saka, National Hospital Organization Nagoya Medical Center; Masahiko Ando, Nagoya University, Nagoya; Yasuhiro Koh, Wakayama Medical University, Wakayama; Yasuhiro Koh and Masakuni Serizawa, Shizuoka Cancer Center Research Institute, Shizuoka; Norimasa Ito, National Hospital Organization Matsue Medical Center, Matsue; Sadanori Takeo, National Hospital Organization Kyushu Medical Center; Yukito Ichinose, National Kyushu Cancer Center, Fukuoka; Hirofumi Adachi, National Hospital Organization Hokkaido Cancer Center, Hokkaido; Tsutomu Tagawa, National Hospital Organization Nagasaki Medical Center, Omura; Seiichi Kakegawa, National Hospital Organization Nishigunma National Hospital, Shibukawa; Motohiro Yamashita, National Hospital Organization Shikoku Cancer Center, Matsuyama; Kazuhiko Kataoka, National Hospital Organization Iwakuni Clinical Center, Iwakuni; Yukiyasu Takeuchi, National Hospital Organization Toneyama National Hospital, Toyonaka; Shigeki Shimizu, Hyogo Medical Collage, Hyogo; and Akihito Kubo, Aichi Medical University School of Medicine, Aichi, Japan.

Purpose: Oncogenic driver mutations are critical for lung cancer development and serve as therapeutic targets. However, their associations with environmental factors are not fully understood. We aimed to elucidate the relationship between tumor developmental biology and exposure to environmental factors.

Patients And Methods: This was a prospective, multicenter, molecular epidemiology study. Eligible patients were those with newly diagnosed stages I to IIIB non-small-cell lung cancer (NSCLC) who underwent surgery. The tumors were examined for somatic mutations in 72 cancer-associated genes by targeted deep sequencing, estrogen receptor β (ERβ) expression using immunohistochemical staining, and infection with any of 37 types of human papillomavirus (HPV) using a polymerase chain reaction-based microarray system. Detailed information on patient demographics and environmental factors was obtained from a comprehensive questionnaire.

Results: From July 2012 to December 2013, 957 patients were enrolled, and molecular analyses were performed on 876 samples (from 441 ever- and 435 never-smokers). Oncogenic driver mutations in P53 and KRAS increased proportionally with smoking status, whereas mutations in EGFR and SMAD4 decreased. KRAS mutations in smokers and SMAD4 mutations were observed more frequently in proportion to body mass index. TP53 and NFE2L2 mutations were observed more frequently in advanced NSCLC stages. As for never-smokers, no environmental factors were significantly associated with mutational changes. EGFR mutations and TP53 mutations were observed more frequently in women and in men, respectively. Mutations in these two genes were also potentially associated with ERβ expression. Only three patients (0.3%) were HPV positive.

Conclusion: The mutational spectrum is associated with smoking, body mass index, and other environmental factors, as well as with ERβ expression. Little association was observed between HPV and NSCLC.
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http://dx.doi.org/10.1200/JCO.2015.64.2322DOI Listing
July 2016

Prognostic significance of aromatase and estrogen receptor beta expression in EGFR wild-type lung adenocarcinoma.

Am J Transl Res 2016 15;8(1):81-97. Epub 2016 Jan 15.

Department of Thoracic and Visceral Organ Surgery, Graduate School of Medicine, Gunma University 3-39-22 Showa-machi, Maebashi, Gunma 371-8511, Japan.

Objectives: Based on recent findings of aromatase and estrogen receptor beta (ERβ) expression in non-small-cell lung cancer, we assessed the clinicopathological and prognostic significance of aromatase and ERβ expression and their relationship to epidermal growth factor receptor (EGFR) mutation in lung adenocarcinoma.

Materials And Methods: We evaluated 150 resected primary lung adenocarcinoma specimens. Expression of aromatase, ERα, ERβ, progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) was evaluated by immunostaining, and EGFR and KRAS mutations were analyzed. Overall survival (OS) and recurrence-free survival (RFS) were calculated using the Kaplan-Meier method.

Results: Expression of aromatase, ERα, ERβ, PR, and HER2 was detected in 88.0%, 1.3%, 79.3%, 2.7%, and 39.3% of specimens, respectively. In patients with EGFR wild-type lung adenocarcinoma, high aromatase expression was an independent predictor of poor OS (hazard ratio [HR]=2.638; 95% confidence interval [CI], 1.173-5.936; P=.019) and RFS (HR=2.505; 95% CI, 1.154-5.434; P=.020). Positive ERβ expression was also an independent predictor of poor RFS (HR=4.013; 95% CI, 1.219-13.207; P=.022). Furthermore, high aromatase expression was a significant predictor of poor survival only in females (OS, P=.010; RFS, P=.007), whereas positive ERβ expression was an important predictor of poor survival only in males (OS, P=.073; RFS, P=.051). No prognostic significance was observed in patients with EGFR mutations.

Conclusions: Our findings suggest that EGFR wild-type lung adenocarcinoma is an estrogen-dependent carcinoma, and aromatase expression and ERβ expression are potent prognostic markers for EGFR wild-type lung adenocarcinoma.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4759418PMC
April 2016

Risk factors associated with recurrence of surgically resected node-positive non-small cell lung cancer.

Surg Today 2016 Oct 19;46(10):1196-208. Epub 2016 Jan 19.

Department of Thoracic and Visceral Organ Surgery, Gunma University Graduate School of Medicine, Maebashi, Gunma, Japan.

Purpose: The aim of this study was to identify risk factors for recurrence in non-small cell lung cancer (NSCLC) patients with lymph node metastases after surgical resection.

Methods: We reviewed 66 consecutive patients with surgically resected NSCLC who had pathologically proven positive lymph nodes (pN1 or pN2). All patients underwent a preoperative 2-[(18)F]-fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET) evaluation. We analyzed the recurrence-free survival (RFS) and recurrence-free proportion (RFP) according to the clinicopathological factors.

Results: A total of 27 patients were pathologically N1 and 39 were N2. The 5-year overall survival rate and the RFS rate were 47.2 and 27.7 %, respectively. The cut-off values for the SUVmax of the tumor and the lymph node ratio (LNR) were determined to be 6.5 and 0.12, respectively, using a receiver operating characteristics curve analysis. Both univariate and multivariate analyses revealed three significant independent factors for RFS: namely, the SUVmax of the tumor, the LNR, and the use of adjuvant chemotherapy. Only the SUVmax was an independent significant predictor of the RFP.

Conclusions: Both the SUVmax and the LNR can serve as prognostic factors for patients with pN + NSCLC. Our study suggests that the LNR could be a stronger prognostic factor than the N classification of the TNM system and the SUVmax may predict recurrence in node-positive NSCLC patients.
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http://dx.doi.org/10.1007/s00595-015-1301-5DOI Listing
October 2016

Impact of the Deletion Polymorphism on Survival Among Patients With Completely Resected Non-Small-Cell Lung Carcinoma.

J Glob Oncol 2016 Feb 23;2(1):15-25. Epub 2015 Dec 23.

, , , , , , , , , , and , Gunma University Graduate School of Medicine, Maebashi, Gunma; and , National Hospital Organization Nishi-Gunma Hospital, Shibukawa, Gunma; and , , and , Maebashi Red Cross Hospital, Maebashi, Gunma, Japan.

Purpose: A deletion polymorphism of the gene has been reported to be a prognostic factor for patients with non-small-cell lung cancer (NSCLC) treated with epidermal growth factor receptor-tyrosine kinase inhibitors in the Asian population. We investigated the impact of the deletion polymorphism on survival among patients with completely resected NSCLC.

Patients And Methods: The polymorphism was detected by polymerase chain reaction analysis. We measured overall survival (OS) and recurrence-free survival rates in 411 patients and postrecurrence survival (PRS) in 94 patients who experienced recurrence and received additional anticancer therapy.

Results: The deletion polymorphism was detected in 61 patients (14.8%). OS rates were significantly lower for patients with the deletion polymorphism than for those with the wild-type sequence. On multivariable analysis, the deletion polymorphism was identified as an independent prognostic factor for OS (hazard ratio, 1.98; 95% CI, 1.17 to 3.36; = .011). Among the 94 patients who experienced recurrence and were treated with anticancer therapy, patients with the deletion polymorphism showed significantly poorer PRS than those with the wild-type sequence (median, 9.8 months 26.9 months, respectively; < .001). Multivariable analysis revealed that the deletion polymorphism was an independent predictor of PRS (hazard ratio, 3.36; 95% CI, 1.75 to 6.47; < .001). This trend remained apparent in subgroup analyses stratified by status, histology, and therapeutic modality.

Conclusion: The deletion polymorphism is a novel indicator of shortened PRS among patients with recurrent NSCLC treated with anticancer therapy in the Asian population.
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http://dx.doi.org/10.1200/JGO.2015.000638DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5497739PMC
February 2016

Ultra-Sensitive Detection of the Pretreatment EGFR T790M Mutation in Non-Small Cell Lung Cancer Patients with an EGFR-Activating Mutation Using Droplet Digital PCR.

Clin Cancer Res 2015 Aug 16;21(15):3552-60. Epub 2015 Apr 16.

Department of Respiratory Medicine and Medical Oncology, National Hospital Organization Nagoya Medical Center, Aichi, Japan. Third Department of Internal Medicine, Wakayama Medical University, Kimiidera, Wakayama, Japan. Drug Discovery and Development Division, Shizuoka Cancer Center Research Institute, Shizuoka, Japan.

Purpose: The resistance to the EGFR tyrosine kinase inhibitors (TKI) is a major concern in non-small cell lung cancer (NSCLC) treatment. T790M mutation in EGFR accounts for nearly 50% of the acquired resistance to EGFR-TKIs. Earlier studies suggested that T790M mutation was also detected in TKI-naïve NSCLCs in a small cohort. Here, we use an ultra-sensitive droplet digital PCR (ddPCR) technique to address the incidence and clinical significance of pretreatment T790M in a larger cohort.

Experimental Design: ddPCR was established as follows: wild-type or T790M mutation-containing DNA fragments were cloned into plasmids. Candidate threshold was identified using wild-type plasmid, normal human genomic DNA, and human A549 cell line DNA, which expresses wild type. Surgically resected tumor tissues from 373 NSCLC patients with EGFR-activating mutations were then examined for the presence of T790M using ddPCR.

Results: Our data revealed a linear performance for this ddPCR method (R(2) = 0.998) with an analytical sensitivity of approximately 0.001%. The overall incidence of the pretreatment T790M mutation was 79.9% (298/373), and the frequency ranged from 0.009% to 26.9%. The T790M mutation was detected more frequently in patients with a larger tumor size (P = 0.019) and those with common EGFR-activating mutations (P = 0.022), as compared with the others.

Conclusions: The ultra-sensitive ddPCR assay revealed that pretreatment T790M was found in the majority of NSCLC patients with EGFR-activating mutations. ddPCR should be utilized for detailed assessment of the impact of the low frequency pretreatment T790M mutation on treatment with EGFR-TKIs.
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http://dx.doi.org/10.1158/1078-0432.CCR-14-2151DOI Listing
August 2015

An analysis of variations in the bronchovascular pattern of the right upper lobe using three-dimensional CT angiography and bronchography.

Gen Thorac Cardiovasc Surg 2015 Jun 28;63(6):354-60. Epub 2015 Feb 28.

Department of Thoracic and Visceral Organ Surgery, Gunma University Graduate School of Medicine, 3-39-22 Showa-machi, Maebashi, Gunma, 371-8511, Japan.

Objectives: General thoracic surgeons must be familiar with anatomical variations in the pulmonary bronchi and vessels. We analyzed variations in the bronchovascular pattern of the right upper lung lobe using three-dimensional CT angiography and bronchography and then compared our results with those of previous reports.

Methods: We reviewed anatomical variations in the right upper pulmonary bronchus and vessels of 263 patients using 3DCT angiography and bronchography images obtained using a 64-channel multidetector CT and workstation running volume-rendering reconstruction software.

Results: Variations in the pulmonary vein were classified into four types: the "anterior-plus-central vein type" was the most common, noted in 219 cases (83.2 %). The "anterior vein type" was evident in 23 cases (8.8 %), a significantly lower incidence than in previous reports (p < 0.001). Also, the branching patterns of the segmental arteries of the pulmonary artery differed partially from those noted in previous reports. Furthermore, we identified some new variations. The "B(1)- or B(2)-defective branch type" bronchus was noted in 19 cases (7.2 %), which was a higher prevalence than that in previous reports.

Conclusion: We explored the bronchovascular pattern and the frequency of variations in the right upper lobe using a large number of 3DCT images. The incidences of variations differed, sometimes significantly, from those noted by previous reports. Moreover, we report some new branching variations. Our data can be used by thoracic surgeons to perform safe and precise lung resections.
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http://dx.doi.org/10.1007/s11748-015-0531-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4454828PMC
June 2015

Single-nucleotide polymorphism (c.309T>G) in the gene and lung cancer risk.

Biomed Rep 2014 Sep 26;2(5):719-724. Epub 2014 Jun 26.

Department of Thoracic and Visceral Organ Surgery, Gunma University Graduate School of Medicine, Maebashi, Gunma 371-8511, Japan.

Murine double minute 2 (MDM2) is a negative regulator of p53. A single-nucleotide polymorphism (SNP) (rs2279744: c.309T>G) in the promoter region of the gene has been shown to result in higher levels of MDM2 RNA and protein. Regarding the contribution of c.309T>G in the gene to the lung cancer risk, previous studies are conflicting. In order to evaluate the association between c.309T>G and the lung cancer risk, a case-control study was performed. The genotypes were determined in 762 lung cancer patients and in 700 cancer-free control subjects using the Smart Amplification Process. Statistical adjustment was performed for gender, age and pack-years of smoking. The distributions of c.309T>G (T/T, T/G, G/G) were 20.1, 49.7, 30.2% in the case group and 21.7, 47.9, 30.4% in the healthy-control group. There were no overall associations between the genotypes and the risk of lung cancer [T/G genotype: Adjusted odds ratio (AOR), 1.30; 95% confidence interval (CI), 0.88-1.93; and G/G genotype: AOR, 1.18; 95% CI, 0.78-1.80]. The subgroup analysis of gender, histology, smoking status and epidermal growth factor receptor mutation status also indicated that there was no association with lung cancer. Additionally, the genotypes did not have an effect on the age at the time of diagnosis of lung cancer (P=0.25). In conclusion, the G allele frequency in the lung cancer cases was 0.551, which was similar to other studies. The results of the present study suggest that the c.309T>G is not significantly associated with lung cancer.
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http://dx.doi.org/10.3892/br.2014.305DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4106610PMC
September 2014

[Current surgical treatment of primary chest wall tumor].

Kyobu Geka 2014 Jan;67(1):9-14

Department of Chest Surgery, Nishi-gunma Hospital, Shibukawa, Japan.

Primary chest wall tumor is relatively rare. According to the annual report by The Japanese Association for Thoracic Surgery in 2012, 447 primary chest wall tumors were resected in 2010. It was only 0.66% of the total number of operations in general thoracic surgery in Japan. From January 1992 to December 2012, 3,022 cases in general thoracic surgery were operated in our department. Of these, 30 patients (1%) with primary chest wall tumor were surgically treated. We retrospectively reviewed the medical records of them and investigated the details of this tumor. The patients group included 11 males and 19 females, with a mean age 57.6 years (range, 16 to 79 years). The majority of these patients were referred to us because of radiographical abnormalities on chest X-ray( 56.7%) or clinical symptoms( 33.3%). The operative procedure was tumor extirpation in 25 cases and chest wall resection in 5 cases. Histologically, 23 cases (76.7%) were benign tumors, 7 cases (23.3%) were malignant tumors. Malignant tumors included aggressive and poor prognostic cases such as malignant fibrous histiocytoma or malignant peripheral nerve sheath tumor, on the other hand, extremely rare tumor with low grade malignancy such as parachordoma arising from the chest wall soft tissue was included. In conclusion, although, the standard therapy for malignant primary chest wall tumors has not been established, aggressive surgical resection remains the treatment of choice and to provide an accurate diagnosis.
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January 2014

Postrecurrence survival of surgically resected pulmonary adenocarcinoma patients according to and mutation status.

Mol Clin Oncol 2014 Mar 31;2(2):187-196. Epub 2013 Dec 31.

Department of Thoracic and Visceral Organ Surgery, Gunma University Graduate School of Medicine, Maebashi, Gunma 371-8511, Japan.

The aim of this study was to investigate the prognosis of pulmonary adenocarcinoma patients following postoperative recurrence, according to epidermal growth factor receptor () and Kirsten rat sarcoma 2 viral oncogene homolog () gene mutation status and recurrence site. In total 58 adenocarcinoma patients with recurrence following surgical resection were retrospectively evaluated between 2002 and 2011. The patients were divided into groups according to the presence or absence of and mutations and the clinicopathological characteristics, recurrence sites and postrecurrence survival were compared. and mutations were detected in 26 (45%) and 11 patients (19%), respectively. Initial recurrence was distant in 25 (43%), local in 17 (29%) and both distant and local in 16 cases (28%). In -mutant (+) cases, bilateral/contralateral lung recurrence was a frequent finding. + cases exhibited significantly better outcomes compared to + and -- (wild-type) cases. The 2-year post-recurrence survival rates were 81, 18 and 47% in +, + and wild-type cases, respectively. The patients with distant organ recurrence exhibited significantly worse survival compared with those without distant recurrence in wild-type, but not in the + cases or the entire cohort. Multivariate analysis revealed that mutations and a number of recurrent lesions were the only statistically significant independent predictors of postrecurrence prognosis. Our results indicated distinct survival differences in recurrent adenocarcinoma patients according to driver mutations. Patients with -mutated tumors exhibited increased survival, regardless of recurrence at distant sites, whereas patients with -mutated adenocarcinoma exhibited poor outcome following postoperative recurrence. Therefore, the assessment of driver mutations is essential for predicting postrecurrence survival following surgical resection.
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http://dx.doi.org/10.3892/mco.2013.237DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3917770PMC
March 2014

Rapid detection of SNP (c.309T>G) in the MDM2 gene by the Duplex SmartAmp method.

PLoS One 2013 2;8(4):e60151. Epub 2013 Apr 2.

Division of Thoracic and Visceral Organ Surgery, Gunma University Graduate School of Medicine, Maebashi, Gunma, Japan.

Background: Genetic polymorphisms in the human MDM2 gene are suggested to be a tumor susceptibility marker and a prognostic factor for cancer. It has been reported that a single nucleotide polymorphism (SNP) c.309T>G in the MDM2 gene attenuates the tumor suppressor activity of p53 and accelerates tumor formation in humans.

Methodology: In this study, to detect the SNP c.309T>G in the MDM2 gene, we have developed a new SNP detection method, named "Duplex SmartAmp," which enabled us to simultaneously detect both 309T and 309G alleles in one tube. To develop this new method, we introduced new primers i.e., nBP and oBPs, as well as two different fluorescent dyes that separately detect those genetic polymorphisms.

Results And Conclusions: By the Duplex SmartAmp method, the genetic polymorphisms of the MDM2 gene were detected directly from a small amount of genomic DNA or blood samples. We used 96 genomic DNA and 24 blood samples to validate the Duplex SmartAmp by comparison with results of the conventional PCR-RFLP method; consequently, the Duplex SmartAmp results agreed totally with those of the PCR-RFLP method. Thus, the new SNP detection method is considered useful for detecting the SNP c.309T>G in the MDM2 gene so as to judge cancer susceptibility against some cellular stress in the clinical setting, and also to handle a large number of samples and enable rapid clinical diagnosis.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0060151PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3614994PMC
October 2013

Pericardium reconstruction with the starfish heart positioner after extended thymectomy with combined left side pericardium resection.

Ann Thorac Surg 2012 Dec;94(6):2136-8

Department of Thoracic and Visceral Organ Surgery, Gunma University Graduate School of Medicine, and Department of General Thoracic Surgery, Maebashi Red Cross Hospital, Gunma, Japan.

We describe the use of the Starfish 2 heart positioning device as an aid to pericardium reconstruction after en bloc resection of mediastinal tumors of the left pericardium by use of median sternotomy with anterolateral thoracotomy. The Starfish device, which is a tool for off-pump coronary artery procedures, allows excellent cardiac positioning and hemodynamic stability during pericardium reconstruction through a median sternotomy with anterolateral thoracotomy.
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http://dx.doi.org/10.1016/j.athoracsur.2012.06.069DOI Listing
December 2012

Establishment of a human lung cancer cell line with high metastatic potential to multiple organs: gene expression associated with metastatic potential in human lung cancer.

Oncol Rep 2012 Nov 21;28(5):1727-35. Epub 2012 Aug 21.

Department of Thoracic and Visceral Organ Surgery, Gunma University Graduate School of Medicine, Gunma 371-8511, Japan.

Convenient and reliable multiple organ metastasis model systems might contribute to understanding the mechanism(s) of metastasis of lung cancer, which may lead to overcoming metastasis and improvement in the treatment outcome of lung cancer. We isolated a highly metastatic subline, PC14HM, from the human pulmonary adenocarcinoma cell line, PC14, using an in vivo selection method. The expression of 34,580 genes was compared between PC14HM and parental PC14 by cDNA microarray analysis. Among the differentially expressed genes, expression of four genes in human lung cancer tissues and adjacent normal lung tissues were compared using real-time reverse transcription polymerase chain reaction. Although BALB/c nude mice inoculated with parental PC14 cells had few metastases, almost all mice inoculated with PC14HM cells developed metastases in multiple organs, including the lung, bone and adrenal gland, the same progression seen in human lung cancer. cDNA microarray analysis revealed that 981 genes were differentially (more than 3-fold) expressed between the two cell lines. Functional classification revealed that many of those genes were associated with cell growth, cell communication, development and transcription. Expression of three upregulated genes (HRB-2, HS3ST3A1 and RAB7) was higher in human cancer tissue compared to normal lung tissue, while expression of EDG1, which was downregulated, was lower in the cancer tissue compared to the normal lung. These results suggest that the newly established PC14HM cell line may provide a mouse model of widespread metastasis of lung cancer. This model system may provide insights into the key genetic determinants of widespread metastasis of lung cancer.
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http://dx.doi.org/10.3892/or.2012.1972DOI Listing
November 2012

An immunoglobulin G4-related disease mimicking postoperative lung cancer recurrence.

Mod Rheumatol 2012 Sep 5;22(5):787-90. Epub 2012 Jan 5.

Department of Thoracic and Visceral Organ Surgery, Gunma University Graduate School of Medicine, 3-39-15 Showa-machi, Maebashi, Gunma 371-8511, Japan.

A postoperative lung cancer patient presented with lymphadenopathy, pleural thickening, and 18F-fluorodeoxyglucose (FDG) uptake on a positron emission tomography-computed tomography (PET-CT) scan. Lung cancer recurrence was initially suspected, but bilateral submandibular masses with 18F-FDG uptake indicated the possibility of a systemic disease, such as Mikulicz's disease. High serum immunoglobulin G4 (IgG4) and IgG4-positive plasma cell infiltration in the submandibular glands led to the diagnosis of IgG4-related disease. After systemic steroid therapy, 18F-FDG uptake decreased in both the submandibular glands and the suspected recurrent lesions.
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http://dx.doi.org/10.1007/s10165-011-0580-yDOI Listing
September 2012

[High-grade fetal adenocarcinoma of the lung; report of a case].

Kyobu Geka 2011 Nov;64(12):1122-5

Department of Thoracic Surgery, Nishigunma National Hospital, Shibukawa, Japan.

82-year-old man was admitted with an abnormal shadow on the chest roentgenogram. Computed tomography showed a 2.8 x 2.4 cm solid tumor in S3 of the left lung. Transbronchial lung biopsy revealed adenocarcinoma and a left upper lobectomy (ND2a-1) was performed. The tumor consisted mainly of tall columnar clear cells, and no morules were found. Immunohistochemically, the tumor was positive for alpha-fetoprotein (AFP) and p53. Accordingly, we made the histological diagnosis of high-grade fetal adenocarcinoma of the lung, pT2N0M0, stage IB. The patient was not received adjuvant therapy and has been doing well without any tumor recurrence for 3 months postoperatively.
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November 2011

A case of primary angiosarcoma of the lung presenting as a hemorrhagic bronchial tumor.

Ann Thorac Cardiovasc Surg 2012 9;18(4):347-51. Epub 2011 Dec 9.

Department of Thoracic Surgery, National Hospital Organization Nishigunma National Hospital, Shibukawa, Gunma, Japan.

Pulmonary angiosarcomas are usually secondary tumors, and only a few primary cases have been reported. Effective strategies for treating this tumor have not been established, and the prognosis of affected individuals is generally very poor. We report a case of primary angiosarcoma presenting as a hemorrhagic solitary nodule at the bifurcation of the left main bronchus, followed for two years before surgery. Bronchial arteriography revealed a tumor stain sign, and racemose hemangioma of the bronchial artery was excluded. The hemoptysis was not controlled by repeated bronchial artery embolization, and the patient underwent left pneumonectomy with routine mediastinal lymph node dissection. Histopathologically, the excised tissue revealed a highly-cellular growth of atypical spindle cells with a storiform pattern. These atypical cells showed relatively low mitotic activity; the MIB-1 index was 10%. The tumor was diagnosed as a primary angiosarcoma of the lung by the following immunohistological findings: positivity for factor VIII-related antigen and CD31. One year after resection, the patient remains well without signs of recurrence.
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http://dx.doi.org/10.5761/atcs.cr.11.01716DOI Listing
August 2013

Correlation between computed tomography findings and epidermal growth factor receptor and KRAS gene mutations in patients with pulmonary adenocarcinoma.

Oncol Rep 2011 Nov 2;26(5):1205-11. Epub 2011 Aug 2.

Department of Thoracic and Visceral Organ Surgery, Gunma University Graduate School of Medicine, 3-39-15 Showa-machi, Maebashi, Gunma 371-8511, Japan.

We examined the correlation between computed tomography (CT) findings and the incidence of epidermal growth factor receptor (EGFR) and KRAS mutations in lung adenocarcinoma. We analyzed the tumors of 136 patients with surgically resected primary lung adenocarcinoma. CT scans were evaluated for the presence of ground grass opacity (GGO), spiculation and the maximum diameter of the tumor was measured. SMart Amplification Process (ver. 2) was used to detect the presence of EGFR and KRAS mutations. EGFR and KRAS mutations were found in 56 (41.1%) and 25 (18.4%) of the 136 cases, respectively. Although no significant association was found between GGO and EGFR mutations (p=0.07), the EGFR mutation occurred more frequently in male patients with GGO than in those without GGO (p=0.04). The KRAS mutation occurred more frequently in patients whose tumor diameter was ≥ 31 mm than in those whose tumor diameter was <30 mm (p=0.003). Evaluation of CT findings may be helpful for determining the presence of EGFR and KRAS mutations, particularly when it is not possible to obtain a tumor specimen.
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http://dx.doi.org/10.3892/or.2011.1412DOI Listing
November 2011

Clinical screening assay for EGFR exon 19 mutations using PNA-clamp smart amplification process version 2 in lung adenocarcinoma.

Oncol Rep 2011 Nov 15;26(5):1213-9. Epub 2011 Jul 15.

Department of Clinical Pharmacology, Gunma University Graduate School of Medicine, 3-39-22 Showa-machi, Maebashi 371-8511, Japan.

The presence of EGFR mutations is correlated with a positive therapeutic response to tyrosine kinase inhibitors; therefore, the accurate detection of EGFR mutations is crucial when deciding appropriate therapeutic strategies. Recently, the rapid and sensitive assay smart amplification process version 2 (SmartAmp2) was developed. However, this method can only detect one type of mutation in EGFR exon 19; therefore, we applied the PNA technology to the SmartAmp2 assay to develop PNA-clamp SmartAmp2 for the detection of many types of deletions in EGFR exon 19, in a single reaction. This new assay was evaluated using 172 clinical samples. Thirty-nine (22.7%) samples were found to have deletions by PNA-clamp SmartAmp2; whereas 30 (17.4%) and 38 (22.1%) tumors were found to have deletions by direct sequencing and PNA-enriched sequencing, respectively. Three cases, in which we detected mutations with PNA-clamp SmartAmp2, but not with direct sequencing, were treated with gefitinib, and all cases showed a partial therapeutic response. Using clinical samples, we demonstrated that PNA-clamp SmartAmp2 can detect various types of mutations in EGFR exon 19 in a relatively short time and with high sensitivity. This method detected small amounts of mutant DNA and identified patients for whom clinical information was previously unavailable from other tests. This test may contribute to the administration of efficient therapeutic strategies.
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http://dx.doi.org/10.3892/or.2011.1391DOI Listing
November 2011

Oncogenic KRAS-induced interleukin-8 overexpression promotes cell growth and migration and contributes to aggressive phenotypes of non-small cell lung cancer.

Int J Cancer 2012 Apr 3;130(8):1733-44. Epub 2011 Aug 3.

Department of Medicine and Molecular Science, Gunma University Graduate School of Medicine, 3-39-15 Showa-machi, Maebashi, Gunma, Japan.

The CXC chemokine interleukin-8 (IL-8) is an angiogenic growth factor that is overexpressed in various cancers, including non-small cell lung cancer (NSCLC). Previously, IL-8 was shown as a transcriptional target of RAS signaling, raising the possibility of its role in oncogenic KRAS-driven NSCLC. Using microarray analysis, we identified IL-8 as the most downregulated gene by shRNA-mediated KRAS knockdown in NCI-H1792 NSCLC cells where IL-8 is overexpressed. NSCLC cell lines harboring KRAS or EGFR mutations overexpressed IL-8, while IL-8 levels were more prominent in KRAS mutants compared to EGFR mutants. IL-8 expression was downregulated by shRNA-mediated KRAS knockdown in KRAS mutants or by treatment with EGFR tyrosine kinase inhibitors and EGFR siRNAs in EGFR mutants. In our analysis of the relationship of IL-8 expression with clinical parameters and mutation status of KRAS or EGFR in 89 NSCLC surgical specimens, IL-8 expression was shown to be significantly higher in NSCLCs of males, smokers, and elderly patients and those with pleural involvement and KRAS mutated adenocarcinomas. In KRAS mutant cells, the MEK inhibitor markedly decreased IL-8 expression, while the p38 inhibitor increased IL-8 expression. Attenuation of IL-8 function by siRNAs or a neutralizing antibody inhibited cell proliferation and migration of KRAS mutant/IL-8 overexpressing NSCLC cells. These results indicate that activating mutations of KRAS or EGFR upregulate IL-8 expression in NSCLC; IL-8 is highly expressed in NSCLCs from males, smokers, elderly patients, NSCLCs with pleural involvement, and KRAS-mutated adenocarcinomas; and IL-8 plays a role in cell growth and migration in oncogenic KRAS-driven NSCLC.
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http://dx.doi.org/10.1002/ijc.26164DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3374723PMC
April 2012