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ABSTRACT: BACKGROUND: Downstream activation through receptor tyrosine kinases (RTKs) plays important roles in carcinogenesis. In this study, we assessed the clinical involvement of Axl, an RTK, and its ligand, Gas6, in surgically treated lung adenocarcinoma. METHODS: Axl and Gas6 mRNA and protein expression levels were quantified using quantitative real-time polymerase chain reaction and immunohistochemistry, respectively, in completely resected lung adenocarcinoma tissues (n = 88) and were evaluated for correlation with clinicopathologic features and patient survival. RESULTS: Higher expressions of Axl mRNA/protein and Gas6 protein were significantly related to worse clinicopathological features and prognosis (5-year overall survival rates: Axl mRNA low: 72.3 %, high: 49.7 %, P = 0.047; Axl protein low: 77.5 %, high: 38.6 %, P < 0.001; and Gas6 protein low: 70.5 %, high: 48 %, P = 0.042). On the contrary, higher Gas6 mRNA expression was related to better clinicopathological features and prognosis (5-year overall survival rates: Gas6 mRNA low: 59.2 %, high: 81.8 %, P = 0.054). Multivariate analysis suggests that high Axl mRNA expression may be an independent factor for poor patient prognosis (P = 0.04). CONCLUSIONS: In lung adenocarcinoma, Axl and Gas6 expression levels were associated with tumor advancement and patient survival, thus rendering them as reliable biomarkers and potential targets for treatment of lung adenocarcinoma.
Annals of Surgical Oncology 12/2012; · 4.17 Impact Factor
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Jin Sakamoto,
Makoto Sonobe,
Masashi Kobayashi,
Masashi Ishikawa,
Ryutaro Kikuchi,
Daisuke Nakajima,
Tetsu Yamada, Ei Nakayama,
Tsuyoshi Takahashi,
Toshihiko Sato,
Fengshi Chen,
Toru Bando,
Hiroshi Date
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ABSTRACT: BACKGROUND: Postoperative recurrence in non-small cell lung cancer (NSCLC) reduces the life expectancy of patients. In this retrospective study, we investigated the prognostic factors in patients with postoperative brain metastases from surgical resected non-small cell lung cancer (NSCLC). METHODS: We conducted a retrospective chart review of patients who had undergone resection for NSCLC between April 2004 and February 2009 and found 65 had experienced postoperative brain metastases by March 2010. We reviewed these patients for clinicopathological information, treatments and responses to treatment, and overall survival. RESULTS: The 5-year survival rate after the diagnosis of brain metastases was 15.4 %. Significantly favorable prognostic factors for patients after a diagnosis of brain metastases included female gender, adenocarcinoma, a small number (1-3) of brain metastases, no extracranial metastasis at the diagnosis of brain metastases, radiation treatment (whole-brain radiation and/or stereotactic irradiation), and local treatment [stereotactic irradiation and/or surgical operation (craniotomy)]. Furthermore, in patients with only brain metastases as the postoperative initial recurrence, the favorable positive prognostic factors included a small number (1-3) of brain metastases, adjuvant chemotherapy, chemotherapy (including adjuvant and other chemotherapy and excluding epidermal growth factor receptor-tyrosine kinase inhibitors), and local treatment. CONCLUSIONS: Our study found that the foregoing clinical characteristics in postoperative brain metastases and the administration of treatment contributed to patient life expectancy.
International Journal of Clinical Oncology 12/2012; · 1.41 Impact Factor
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Masashi Ishikawa,
Ryo Miyahara,
Makoto Sonobe,
Marika Horiuchi,
Toshi Mennju, Ei Nakayama,
Masashi Kobayashi,
Ryutaro Kikuchi,
Jiro Kitamura,
Naoto Imamura,
Cheng-Long Huang,
Hiroshi Date
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ABSTRACT: The overexpression of receptor tyrosine kinase EphA2 has been reported in various cancers. In non-small cell lung cancer (NSCLC), a positive correlation has been reported between high EphA2 immunohistochemical staining level and poor prognosis. However, its ligand, ephrin-A1, is supposed to act as a tumor suppressor via the kinase activity of EphA2. Thus, the biphasic roles of this system are not fully elucidated. We retrospectively evaluated the expression levels of EphA2 and ephrin-A1 in surgically treated pathological (p-) stage I NSCLC tumor samples, and their relation to clinicopathologic features or postoperative prognoses.
The levels of EphA2 and ephrin-A1 mRNA expression were quantified by real-time reverse-transcription polymerase chain reaction in tissue samples from p-stage I NSCLC patients who had undergone complete resection in our facility (n=195). They were divided into two (EphA2/ephrin-A1-Low and -High) groups based on the median expression level, and their respective clinicopathologic features and prognoses were analyzed. Furthermore, samples were stained immunohistochemically and classified into four groups according to their staining levels, and their prognoses analyzed.
Marked demographic differences were found between EphA2/ephrin-A1-Low and -High groups. Both EphA2-High and ephrin-A1-High groups had more females, no smoking history, adenocarcinoma histology, well-differentiated carcinomas, p-stage IA patients, and patients with EGFR gene mutations. Five-year overall survival rates of the EphA2-Low and the EphA2-High patient groups were 68.9% and 86.1%, respectively (P=0.017), and five-year disease-free survival rates were 69.9% and 83.2%, respectively (P=0.035). There were no statistical differences between ephrin-A1-Low and ephrin-A1-High groups concerning postoperative survival. Although showing smaller differences, the findings from the immunohistochemical analyses supported the above results.
Higher expression of EphA2 and ephrin-A1 was more related to the female sex, reduced smoking status, adenocarcinoma, well differentiated carcinomas, p-stage IA, and EGFR gene mutations. Higher EphA2 mRNA expression in p-stage I NSCLC patients was positively related to improved prognoses. These results may reflect a tumor suppressive role for the EphA2/ephrin-A1 system in a population of patients restricted to p-stage I NSCLC.
Lung cancer (Amsterdam, Netherlands) 01/2012; 76(3):431-8. · 3.14 Impact Factor
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ABSTRACT: The insulin-like growth factor 1 receptor (IGF1R) is widely expressed in normal tissues and many malignancies in humans. We investigated the clinical significance of the expression of the IGF1R gene in human lung adenocarcinoma.
A total of 238 patients with lung adenocarcinoma were investigated. Quantitative real-time reverse-transcription polymerase chain reaction (RT-PCR) assays were performed to evaluate the gene expression of IGF1R, and immunohistochemical staining was done to evaluate the protein expression of IGF1R.
Among the 238 patients with lung adenocarcinoma, 107 tumors (45.0%) were IGF1R-low and 131 tumors (55.0%) were IGF1R-high. The IGF1R gene expression ratio was significantly lower in moderately to poorly differentiated adenocarcinomas than in well-differentiated adenocarcinomas (P = 0.0388). Gene expression of IGF1R was significantly correlated with protein expression of IGF1R (r = 0.7163, P < 0.0001). Regarding patient survival, overall survival was significantly lower in patients with IGF1R-low tumors than in those with IGF1R-high tumors (63.2% versus 76.1% 5-year survival, P = 0.0188). Multivariate analysis using a Cox proportional-hazards model demonstrated that IGF1R gene status was a significant prognostic factor predicting overall survival of patients with lung adenocarcinoma (hazard ratio 1.800; P = 0.0321). Moreover, the disease-free survival rate was significantly lower in patients with IGF1R-low tumors than in those with IGF1R-high tumors (49.2% versus 64.6% 5-year survival, P = 0.0084).
The present study suggests the level of IGF1R expression to be a useful prognostic marker for patients with dedifferentiated lung adenocarcinoma.
Annals of Surgical Oncology 07/2011; 19 Suppl 3:S412-20. · 4.17 Impact Factor
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Makoto Sonobe,
Masashi Kobayashi,
Masashi Ishikawa,
Ryutaro Kikuchi, Ei Nakayama,
Tsuyoshi Takahashi,
Toshi Menju,
Kazumasa Takenaka,
Ryo Miyahara,
Cheng-Long Huang,
Kenichi Okubo,
Toru Bando,
Hiroshi Date
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ABSTRACT: Oncogenic gene mutations observed in lung adenocarcinomas, such as epidermal growth factor receptor (EGFR) and KRAS, have some predictive value for chemotherapeutic drugs or EGFR-tyrosine kinase inhibitors. However, the influence of these gene alterations on patients' prognosis remains controversial.
We retrospectively analyzed the tumors of 180 patients with completely resected pathological stage I-III lung adenocarcinoma which harbored either KRAS codon 12 mutation or EGFR gene mutations within exons 18-21 to investigate the impact of these gene mutations on the patients' survival. Gene mutations were detected by established methods.
Of 180 patients, 32 had KRAS codon 12 mutations (KRAS group), 148 had EGFR mutations within exon 18-21 (EGFR group). Pathological stage and operation mode were independent factors for disease-free survival. However, the EGFR group had better overall survival than the KRAS group (P = 0.0271). Cox proportional hazard model revealed pathological stage (P = 0.0001) and presence of EGFR gene mutations (P = 0.0408) were independent factors for overall survival. In survival after tumor recurrence, the EGFR group had a better median survival time (46.7 months) after recurrence than the KRAS group (26.0 months).
In patients with completely resected lung adenocarcinomas, KRAS and EGFR gene mutation status of tumors was not associated with disease-free survival. However, the presence of an EGFR gene mutation boded well for the patient's overall survival, and thus patients with EGFR mutations have a better prognosis than those with KRAS mutations.
Annals of Surgical Oncology 05/2011; 19 Suppl 3:S347-54. · 4.17 Impact Factor
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Tsuyoshi Takahashi,
Makoto Sonobe,
Masashi Kobayashi,
Akihiko Yoshizawa,
Toshi Menju, Ei Nakayama,
Nobuya Mino,
Shotaro Iwakiri,
Kiyoshi Sato,
Ryo Miyahara,
Kenichi Okubo,
Toshiaki Manabe,
Hiroshi Date
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ABSTRACT: A fusion gene between echinoderm microtubule-associated protein-like 4 (EML4) and the anaplastic lymphoma kinase (ALK) has recently been identified in nonsmall-cell lung cancers (NSCLCs). We screened for EML4-ALK fusion genes and examined the clinicopathological and genetic characteristics of fusion-harboring NSCLC tumors.
We examined 313 NSCLC samples from patients who underwent resection at our hospital between May 2001 and July 2005. We screened for the fusion genes using reverse-transcription polymerase chain reaction (RT-PCR) assay and confirmed the results with direct sequencing. We also examined mutations in the epidermal growth factor receptor (EGFR), KRAS, and ERBB2 genes.
Five EML4-ALK fusion genes were detected (four from 111 female samples and one from 202 male samples; 1.6% overall). All five genes were found in adenocarcinomas and accounted for 2.4% of the 211 adenocarcinoma samples. One EML4-ALK fusion was variant 1, and two were variant 3. In addition, we also found two new fusion variants. Patients with fusion-positive tumors were nonsmokers or light smokers. Among the 211 adenocarcinomas, mutations in EGFR, KRAS, and ERBB2 were detected in 105, 29, and 7 tumors, respectively. Interestingly, all of the fusion-positive NSCLCs had no mutations within these genes.
EML4-ALK fusion genes were observed predominantly in adenocarcinomas, in female or nonsmoking populations. Additionally, the EML4-ALK fusions were mutually exclusive with mutations in the EGFR, KRAS, and ERBB2 genes.
Annals of Surgical Oncology 03/2010; 17(3):889-97. · 4.17 Impact Factor
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Tsuyoshi Takahashi,
Makoto Sonobe,
Toshi Menju, Ei Nakayama,
Nobuya Mino,
Shotaro Iwakiri,
Shinjiro Nagai,
Kiyoshi Sato,
Ryo Miyahara,
Kenichi Okubo,
Toshiki Hirata,
Hiroshi Date,
Hiromi Wada
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ABSTRACT: Mutations in Kelch-like ECH-associated protein 1 (Keap1) have been reported to protect tumor cells from chemotherapeutic agents. However, their prognostic significance in nonsmall cell lung cancer (NSCLC) is still unclear. In this study, we examined the effect of Keap1 gene mutations on survival and disease-free interval using resected primary NSCLC tissue.
We retrospectively analyzed the tumors from 79 patients with completely resected pathological Stage I-II NSCLC for the presence of Keap1 gene mutations and examined the prognosis of the patients.
Keap1 gene mutations were detected in four patients (5.1%). The postoperative 5-year survival rate for patients with Keap1 mutations was significantly lower than those without a mutation (25% vs. 76%, P = 0.038). The postoperative 5-year disease-free survival rate for patients with a mutant Keap1 tumor was slightly lower than for patients with Keap1 wild-type tumors (25% vs. 66%, P = 0.057).
Keap1 gene mutations are likely to be associated with a worse prognosis and lower postoperative disease-free survival rates in pathological Stage I-II NSCLC.
Journal of Surgical Oncology 03/2010; 101(6):500-6. · 2.10 Impact Factor
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Nobuya Mino MD,
PhD Ryo Miyahara MD,
Ei Nakayama MD,
Tsuyoshi Takahashi MD,
Ayuko Takahashi MD,
PhD Shotaro Iwakiri MD,
PhD Makoto Sonobe MD,
PhD Kenichi Okubo MD,
PhD Toshiki Hirata MD,
PhD Atsuko Sehara MD, [......],
Ryo Miyahara, Ei Nakayama,
Tsuyoshi Takahashi,
Ayuko Takahashi,
Shotaro Iwakiri,
Makoto Sonobe,
Kenichi Okubo,
Toshiki Hirata,
Atsuko Sehara,
Hiroshi Date
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ABSTRACT: Background and ObjectivesA disintegrin and metalloprotease 12 (ADAM12) has multiple domains and functions, and it plays important roles in the development of cancer. We conducted a retrospective study to determine whether the expression of the membrane type of ADAM12 (ADAM12-L) could be a prognostic factor in resected pathological (p-) stage I lung adenocarcinoma.MethodsADAM12-L mRNA expression was quantified by a reverse-transcription polymerase chain reaction in tissue samples from 84 completely resected p-stage I lung adenocarcinoma patients. The patients were divided into ADAM12-L-Low and ADAM12-L-High groups, and correlations with clinicopathologic features were obtained.ResultsFive-year survival rates of the ADAM12-L-Low and ADAM12-L-High groups were 95.1% and 71.9%, respectively. The postoperative prognosis for the ADAM12-L-High group was significantly poorer than for the ADAM12-L-Low group (P = 0.006). Multivariate analysis confirmed that high expression of ADAM12-L was an independent factor for poor prognosis (P = 0.007, hazard ratio 8.288). The ADAM12-L-High group was less differentiated and had a significantly higher rate of cancer recurrence.ConclusionsADAM12-L mRNA expression is an independent prognostic factor in resected p-stage I lung adenocarcinoma, and is significantly correlated with tumor differentiation stage and postoperative cancer recurrence. J. Surg. Oncol. 2009;100:267–272. © 2009 Wiley-Liss, Inc.
Journal of Surgical Oncology 08/2009; 100(3):267 - 272. · 2.10 Impact Factor
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Ryutaro Shirakawa,
Shuya Fukai,
Mitsunori Kawato,
Tomohito Higashi,
Hirokazu Kondo,
Tomoyuki Ikeda, Ei Nakayama,
Katsuya Okawa,
Osamu Nureki,
Takeshi Kimura,
Toru Kita,
Hisanori Horiuchi
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ABSTRACT: The small GTPases RalA and RalB are multifunctional proteins regulating a variety of cellular processes. Like other GTPases, the activity of Ral is regulated by the opposing effects of guanine nucleotide exchange factors (GEFs) and GTPase-activating proteins (GAPs). Although several RalGEFs have been identified and characterized, the molecular identity of RalGAP remains unknown. Here, we report the first molecular identification of RalGAPs, which we have named RalGAP1 and RalGAP2. They are large heterodimeric complexes, each consisting of a catalytic alpha1 or alpha2 subunit and a common beta subunit. These RalGAP complexes share structural and catalytic similarities with the tuberous sclerosis tumor suppressor complex, which acts as a GAP for Rheb. In vitro GTPase assays revealed that recombinant RalGAP1 accelerates the GTP hydrolysis rate of RalA by 280,000-fold. Heterodimerization was required for this GAP activity. In PC12 cells, knockdown of the beta subunit led to sustained Ral activation upon epidermal growth factor stimulation, indicating that the RalGAPs identified here are critical for efficient termination of Ral activation induced by extracellular stimuli. Our identification of RalGAPs will enable further understanding of Ral signaling in many biological and pathological processes.
Journal of Biological Chemistry 07/2009; 284(32):21580-8. · 4.77 Impact Factor
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Nobuya Mino,
Ryo Miyahara, Ei Nakayama,
Tsuyoshi Takahashi,
Ayuko Takahashi,
Shotaro Iwakiri,
Makoto Sonobe,
Kenichi Okubo,
Toshiki Hirata,
Atsuko Sehara,
Hiroshi Date
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ABSTRACT: A disintegrin and metalloprotease 12 (ADAM12) has multiple domains and functions, and it plays important roles in the development of cancer. We conducted a retrospective study to determine whether the expression of the membrane type of ADAM12 (ADAM12-L) could be a prognostic factor in resected pathological (p-) stage I lung adenocarcinoma.
ADAM12-L mRNA expression was quantified by a reverse-transcription polymerase chain reaction in tissue samples from 84 completely resected p-stage I lung adenocarcinoma patients. The patients were divided into ADAM12-L-Low and ADAM12-L-High groups, and correlations with clinicopathologic features were obtained.
Five-year survival rates of the ADAM12-L-Low and ADAM12-L-High groups were 95.1% and 71.9%, respectively. The postoperative prognosis for the ADAM12-L-High group was significantly poorer than for the ADAM12-L-Low group (P = 0.006). Multivariate analysis confirmed that high expression of ADAM12-L was an independent factor for poor prognosis (P = 0.007, hazard ratio 8.288). The ADAM12-L-High group was less differentiated and had a significantly higher rate of cancer recurrence.
ADAM12-L mRNA expression is an independent prognostic factor in resected p-stage I lung adenocarcinoma, and is significantly correlated with tumor differentiation stage and postoperative cancer recurrence.
Journal of Surgical Oncology 07/2009; 100(3):267-72. · 2.10 Impact Factor
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ABSTRACT: An 89-year-old woman with dyspnea and disturbed consciousness due to hypoventilation was admitted to our hospital. Chest radiography showed no abnormal shadow, but she was intubated for deteriorated hypoventilation. Bronchoscopy demonstrated obstruction of the left main bronchus at the carina. Computed tomography (CT) showed neither a mass lesion in the mediastinum nor an aortic aneurysm, but compression of the airway by the ascending aorta was observed. It was thought that the patient's thin thoracic cage was unable to support the weight of the ascending aorta, which consequently compressed the left main bronchus. After inserting stents into both main bronchi, the patient's consciousness improved, and respirator support was withdrawn. In aged, bedridden, thin patients with hypopnea or recurrent airway infection, CT and bronchoscopy should be performed to investigate airway patency.
General Thoracic and Cardiovascular Surgery 03/2009; 57(2):108-10.
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ABSTRACT: Intrathoracic schwannomas are solitary in general. We report a rare case of intrathoracic multiple schwannomas arising from a single intercostal nerve. A 27-year-old man was admitted with multiple tumors, along with the fourth intercostal nerve in the posterior chest wall. Thoracoscopic surgical exploration found a small tumor at 2 cm distal to the main tumors, which had not been detected preoperatively. All these tumors were completely resected en bloc and were diagnosed as schwannomas of the fourth intercostal nerve.
The Annals of thoracic surgery 08/2008; 86(2):660-1. · 3.74 Impact Factor
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ABSTRACT: We report two cases of lung abscesses treated with percutaneous drainage. A 69-year-old man with diabetes mellitus was admitted to our hospital because of fever. Chest radiograph and chest CT scan demonstrated a lung abscess adjacent to the chest wall in right S10. Antibiotics did not achieve an adequate response. A drainage catheter was inserted percutaneously. We washed the abscess cavity daily using 1% povidone iodine saline. There was a clear improvement on the chest radiograph. A 74-year-old man with cerebral infarct was admitted to our hospital because of persistent cough and fever. Chest radiograph and chest CT scan demonstrated a lung abscess adjacent to the chest wall in left S10. Antibiotics did not achieve an adequate response. A drainage catheter was inserted percutaneously. We washed the abscess cavity daily using 1% povidone iodine saline. There was a clear improvement on the chest radiograph. We think that percutaneous drainage is a very useful method to treat lung abscesses in which antibiotics do not achieve an adequate response.
Nihon Kokyūki Gakkai zasshi = the journal of the Japanese Respiratory Society. 09/2007; 45(8):631-5.
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ABSTRACT: A 69-year-old man had an abnormal shadow on chest X-ray and bronchoscopic examination showed that left B4 was completely occluded by a tumor. A non-pulsatile polypoid nodule was also found in right B'. The tumor in the left B4 was diagnosed as carcinoid, but the nodule in right B' was suspected to be hemangioma and biopsy was not performed. Bronchial arteriography revealed hypervascularization with dilated vessels distributing to the lingular lobe and convoluted and a dilated bronchial artery extending to the right upper lobe. From these findings, we diagnosed racemose hemangioma of the bronchial artery of the right upper lobe. After bronchial artery embolization of the right and left bronchial arteries, he underwent segmentectomy of the lingula and was discharged without complications. Two months after the operation, bronchoscopic examination showed that the racemose hemangioma had shrunk and the swelling in the surrounding mucosa had decreased. If a submucosal small nodule is observed during bronchoscopy, biopsy should be performed after bronchial arteriography, and if the nodule is diagnosed as racemose hemangioma, bronchial artery embolization should be performed.
Nihon Kokyūki Gakkai zasshi = the journal of the Japanese Respiratory Society. 05/2007; 45(4):333-6.
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ABSTRACT: A 44-year-old man was admitted to our hospital because of brain metastasis and intrapulmonary exacerbation of lung adenocarcinoma. Systemic chemotherapy (PAC + CBDCA) was administered, but neurological symptoms (muscle weakness of limbs and disorientation) appeared. Lumbar puncture and enhanced MRI of lumber vertebrae revealed meningeal carcinomatosis. MTX 20 mg/week (+ Ara-C 40 mg/week) was injected into the meningeal space. There was a clear improvement in the neurological symptoms, but it did not last long. Meningeal injection was performed 7 times. Whole-brain and whole-marrow radiation along with systemic chemotherapy gave a marked improvement in the symptoms and in the metastatic shadow on the chest CT scan.
Nihon Kokyūki Gakkai zasshi = the journal of the Japanese Respiratory Society. 04/2007; 45(3):267-71.
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ABSTRACT: A 17-year-old woman was admitted to our institution because of tracheal stenosis. She had undergone tracheostomy after a traffic accident, but the stenosis had persisted. Chest computed tomography showed retrosternal dislocation of the right sternoclavicular joint and compression of the trachea by the medial head of the right clavicle. To relieve the tracheal compression, 3 cm of the medial head of the clavicle was resected. The dyspnea disappeared completely, allowing closure of the tracheostomy. Posterior dislocation of the sternoclavicular joint and tracheal stenosis due to compression by the dislocated clavicle is rare.
The Annals of thoracic surgery 03/2007; 83(2):685-7. · 3.74 Impact Factor
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ABSTRACT: Two cases of asymptomatic pulmonary infarction were diagnosed by open lung biopsy with video-assisted thoracic surgery (VATS). Case 1: A pulmonary nodule in right S8b was pointed out in a 62-year-old man undergoing hemodialysis on chest x-ray film and CT. Case 2: A 50-year-old woman had undergone left mastectomy for mammary cancer 3 years previously and total hip replacement 1 year before. Chest X-ray film and CT revealed a pulmonary nodule in the left lower lung field and it was suspected to be metastasis of the mammary cancer. Both cases underwent open lung biopsy by VATS, and asymptomatic pulmonary infarction was revealed. When chest X-ray film shows a nodule in the lower-peripheral lung field in patients with risk factors, pulmonary infarction should be considered.
Nihon Kokyūki Gakkai zasshi = the journal of the Japanese Respiratory Society. 03/2007; 45(2):170-3.
