Shigebumi Tanaka

l-type amino acid transporter 1 and CD98 expression in primary and metastatic sites of human neoplasms.

The significance of l‐type amino acid transporter (LAT) 1 expression remains unclear in the metastatic process of human neoplasms, whereas experimental studies have demonstrated that LAT1 is associated with the metastatic process of cancer cells. We compared the immunohistochemical expression of LAT1 and CD98 between the primary site and a concordant pulmonary metastatic site in 93 cancer patients, all of whom had undergone thoracotomy. LAT1, CD98, Ki‐67 labeling index, vascular endothelial growth factor (VEGF), CD31, and CD34 were analyzed by immunohistochemical staining in the resected tumors of 93 cancer patients: 45 colon cancers; nine breast cancers; eight head and neck cancers; 11 genital cancers; 14 soft‐tissue sarcomas; and six other cancers. The expression of these markers was significantly higher in the metastatic sites than in the primary sites. In total, the positive rates of LAT1, CD98, Ki‐67, VEGF, CD31, and CD34 were 40, 24, 56, 41, 45, and 39%, respectively, in the primary sites and 65, 45, 84, 67, 73, and 61%, respectively, in the metastatic sites. LAT1 expression was closely correlated with CD98 expression, angiogenesis, and cell proliferation. The association between LAT1 and CD98 expression was strongest in the primary and metastatic sites. The present study suggests that overexpression of LAT1 and CD98 has an important role to play in the metastatic process of variable human neoplasms. Moreover, LAT1 expression was significantly correlated with cell proliferation and angiogenesis. (Cancer Sci 2008; 99: 2380–2386)

Fluorine-18-α-Methyltyrosine Positron Emission Tomography for Diagnosis and Staging of Lung Cancer: A Clinicopathologic Study

Purpose:l-[3-18F]-α-Methyltyrosine ([18F]FMT) is an amino acid tracer for positron emission tomography (PET). We evaluated the diagnostic usefulness of [18F]FMT PET in non–small-cell lung cancer (NSCLC) patients. Tumor uptake of [18F]FMT was compared with that of 2-[18F]-fluoro-2-deoxy-d-glucose ([18F]FDG) and correlated with L-type amino acid transporter 1 (LAT1) expression. Experimental Design: Fifty NSCLC patients were enrolled in this study, and a pair of PET study with [18F]FMT and [18F]FDG was done. LAT1 expression and Ki-67 labeling index of the resected tumors were analyzed by immunohistochemical staining. Results: For the primary tumor detection, [18F]FMT PET exhibited a sensitivity of 90% whereas the sensitivity for [18F]FDG PET was 94%. For lymph node staging, the sensitivity and specificity of [18F]FMT PET were 57.8% and 100%, and those of [18F]FDG PET were 65.7% and 91%, respectively. The expression of LAT1 in squamous cell carcinoma and large cell carcinoma was significantly higher than that in adenocarcinoma. [18F]FMT uptake was also higher in squamous cell carcinoma and large cell carcinoma than in adenocarcinoma. Uptake of [18F]FMT in the tumor is closely correlated with LAT1 expression (ρ = 0.890). Conclusion: [18F]FMT PET had no false-positives in the detection of primary tumor and lymph node metastasis and could improve the diagnostic performance in NSCLC. Uptake of [18F]FMT correlated with the expression of LAT1 that showed a significant association with cellular proliferation.

FBXW7 Mediates Chemotherapeutic Sensitivity and Prognosis in NSCLCs

Non–small cell lung cancer (NSCLC) is a leading cause of cancer-related deaths worldwide. To improve the prognosis of patients with NSCLCs, new and validated therapeutic targets are critically needed. In this study, we focused on F-box and WD repeat domain containing-7 (FBXW7), an E3 ubiquitin ligase, that regulates the degradation of MCL1, Myc, cyclin E, and TOP2A. Importantly, loss of FBXW7 was associated with increased sensitivity of tumors to a class I–specific histone deacetylase (HDAC) inhibitor, MS-275. Immunohistochemical analysis revealed increased expression of FBXW7 targets, MCL1 and TOP2A, in NSCLC tumors with low expression of FBXW7. Moreover, clinical specimens exhibiting low FBXW7 expression presented with more progressive cancer and significantly shorter cancer-specific survival than patients with high FBXW7 expression. Mechanistic study of NSCLC cell lines with silenced FBXW7 revealed enhanced MS-275 sensitivity and taxol resistance. Interestingly, taxol resistance was eliminated by MS-275 treatment, suggesting the potential of HDAC inhibitors for the treatment of aggressive taxol-resistant NSCLCs that lack FBXW7. Implications: FBXW7 status impacts chemosensitivity and is a prognostic marker in NSCLCs. Visual Overview: http://mcr.aacrjournals.org/content/early/2013/12/19/1541-7786.MCR-13-0341/F1.large.jpg. Mol Cancer Res; 12(1); 32–37. ©2013 AACR.

Pulmonary function after pulmonary resection by posterior thoracotomy, anterior thoracotomy or video-assisted surgery

OBJECTIVE Predicted postoperative forced expiratory volume in 1s (ppoFEV1) is estimated in lung cancer patients before pulmonary resection, as well as the clinical stage. This study aims to evaluate ppoFEV1 and ppo-vital capacity (ppoVC) on postoperative day 7 (POD7) and to compare the results following video-assisted thoracic surgery (VATS) and open thoracotomy procedures. METHODS Of the 155 patients who underwent pulmonary resection, 70 had VATS; 30 had muscle-sparing thoracotomy (anterior limiting thoracotomy (AL)); and 55 had postero-lateral thoracotomy (PL). VC and FEV1 were measured on POD7 and compared with the VC and FEV1 before surgery using analysis of covariance (ANCOVA). The ratio of the actual- and the ppoVC and FEV1 was evaluated to identify factors associated with variations in postoperative residual VC/FEV1. RESULTS There were significant differences by analysis of covariance (ANCOVA) in the VC/FEV1 among the three surgical approaches. In the VATS group, the VC ratio and the FEV1 ratio were 96.5% and 94.7%, respectively; they were significantly higher in the VATS group than in the thoracotomy group (AL: 90.4% and 90.1%, respectively; PL: 87.4% and 87.6%, respectively). Non-chronic obstructive pulmonary disease (COPD) and upper lobectomy were also associated with a low VC ratio and FEV1 ratio. CONCLUSION Predicted postoperative pulmonary function might be overestimated in COPD patients or in those undergoing VATS or lower lobectomy.

Immunohistochemical analysis of phosphorylated epidermal growth factor receptor might provide a surrogate marker of EGFR mutation

PURPOSE Overexpression of EGFR is found in several malignancies including lung cancers. Recently, EGFR mutation has been shown to correlate with responsiveness to tyrosine kinase inhibitors (TKI). Although antibodies against phophorylated EGFR have been used in vitro, phosphorylated EGFR has yet not been examined well in resected non-small cell lung cancers (NSCLCs). EXPERIMENTAL DESIGN We studied the immunohistochemistry of anti-EGFR and phosphorylated EGFR in 97 resected NSCLCs, examined the relationship with EGFR mutation, and performed quantitative RT-PCR of the EGFR gene in the TaqMan assay. RESULT EGFR mutation was seen in 27% of 97 NSCLCs and 37% of 70 adenocarcinomas. EGFR was stained in 60% of 97 NSCLCs. Phosphorylation of tyrosine 845 (pY845) and 1068 (pY1068) was positive in 49% and 48%, respectively. The observed correlation with EGFR mutation and pY845 or pY1068 was statistically significant (P=0.0001 for pY845, P<0.0001 for pY1068, chi square test), although phospho-EGFR status was not associated with a particular mutation type. pY1068-positive tumors also correlated with female, light smoker, and adenocarcinoma histology, but not with mRNA expression. Moreover, patients with pY1068-positive tumors showed prolonged survival (P=0.0093, log-rank test). CONCLUSION It is possible that immunohistochemistry of phosphorylated EGFR can substitute for EGFR mutation analysis. Further investigation is necessary to determine whether phospho-EGFR immunohistochemistry predicts response to TKIs and survival benefit.

Successful Management of a Large Bronchopleural Fistula After Lobectomy: Report of a Case

The development of bronchopleural fistula after pulmonary resection is a well-known complication associated with a high mortality rate. We herein describe the successful management of a bronchopleural fistula using a rib and intercostal muscle in a patient with a large stump opening of 25 mm in diameter. A flap with rib and intercostal muscle is useful for large bronchopleural fistulas to avoid airway stenosis.

Successful resection of a glomus tumor of the trachea

Extracutaneous glomus tumors are uncommon, and their occurrence in the trachea is rare. We present a case of a surgically resected glomus tumor of the trachea in a 56-year-old woman who presented with worsening dyspnea and cough. Bronchoscopy and computed tomography showed a polypoid tumor arising from the posterior membrane of the lower trachea just above the carina; the tracheal lumen was approximately 80% occluded. The patient underwent successful tracheal sleeve resection with primary reconstruction. The histological characteristics and immunohistochemical profile were typical for this tumor. The clinicopathological features of this unusual neoplasm are discussed, and the literature is reviewed.

Effectiveness of Tc-99m MIBI scintigraphy in diagnosing lung cancer

The use of Tc-99m hexakis 2-methoxy isobutyl isonitrile (MIBI) scintigraphy for qualitative diagnosis was examined. A total of 36 lesions from 31 patients with respiratory disease (19 lesions from 19 primary lung cancer patients, 8 lesions from 3 metastatic lung cancer patients and 10 lesions from benign lung disease patients) were examined. Positive results were seen in 89.4% of the primary lung cancer lesions, 50.0% of the metastatic lung cancer lesions, and 20.0% of the benign lung disease lesions. The positive rate of 77.7% for malignant lung cancer was significantly higher (P<0.01) than that for benign lung cancer. In particular, for lesions with a tumor diameter of 1.0 cm or more, the positive rate for malignant lung cancer lesions (95.2%) was significantly higher (P<0.001) than that for benign lung disease lesions (25.0%). These results thus indicate Tc-99m MIBI scintigraphy to be useful for qualitative diagnosis of lung peripheral coin lesions with a diameter of 1.0 cm or more.

Video-Assisted Thoracoscopic Surgery after Preoperative CT-Guided Lipiodol Marking of Small or Impalpable Pulmonary Nodules.

PURPOSE Small pulmonary lesions that include ground-glass attenuation have been increasingly discovered because of progressive imaging diagnostic technologies. Despite the detection of such small lesions, sometimes it is quite difficult to localize them because of their size or considerable depth from the visceral pleura. In the present study, we examined the usefulness of computed tomography-guided lipiodol marking for thoracoscopic resection of impalpable pulmonary nodules. METHODS Fifty-six patients with an undiagnosed peripheral lesion(s) of the lung who had undergone preoperative computed tomography-guided lipiodol marking followed by video-assisted thoracoscopic surgery were studied. RESULTS All of the nodules were successfully marked by computed tomography-guided lipiodol marking, and all except for one case were localized by means of intraoperative fluoroscopy as clear spots. With regard to complications, pneumothorax occurred in 21 patients (37.5%), and only one patient required transient drainage. Although hemorrhaging in the lung parenchyma and hemosputum occurred in nine patients (16.1%) and one patient (1.8%), respectively, no patients were in serious condition. No intra- or postoperative mortality or morbidity was observed. CONCLUSION Preoperative computed tomography-guided lipiodol marking of small or impalpable pulmonary nodules is a safe and useful procedure for thoracoscopic resection of the lung.

Preoperative 18F-Fluorodeoxyglucose Positron Emission Tomography can Predict the Tumor Malignancy of Small Peripheral Lung Cancer

PURPOSE Recent advances in image diagnostic technology have enhanced the discovery of peripheral small size lung cancers. Here, we examined the utility of 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) for the evaluation of grade of tumor malignant potency. METHODS Seventy-nine patients with peripheral small lung cancers (≤2 cm) who underwent surgical resections and preoperative FDG-PET were enrolled. The correlations between the maximum standardized uptake value (SUVmax) and various clinicopathological features related to tumor invasiveness, nodal metastasis, and recurrence were analyzed. RESULTS The median SUVmax of all tumors was 2.4 (range, 0-16.1). The SUVmax was significantly higher in patients with vascular invasion (5.6 ± 3.5 vs. 2.4 ± 2.4; P <0.0001), lymphatic invasion (4.9 ± 3.7 vs. 2.7 ± 2.6; P = 0.0029), lymph node metastasis (6.1 ± 4.4 vs. 3.0 ± 2.7; P = 0.0022), and recurrences (5.8 ± 3.3 vs. 3.1 ± 3.1; P = 0.0219). Patients with SUVmax ≥2.5 had a significantly higher incidence rate of vascular invasion (56% vs. 7%; P <0.0001), lymphatic invasion (51% vs. 15%; P = 0.0006), lymph node metastasis (26% vs. 3%; P = 0.0033), and recurrence (18% vs. 3%; P = 0.0289). The patients with SUVmax ≥1.5 also had a significantly higher incidence of vascular invasion, lymphatic invasion, lymph node metastasis, and recurrence. It is particularly worth noting that patients with SUVmax <1.5 had no vascular invasion, lymph node metastasis, or recurrence. CONCLUSION Preoperative SUVmax of peripheral small lung cancers were significantly associated with tumor malignancy.