Takehiro Okumura

Biologic Correlation of 2-[18F]-Fluoro-2-Deoxy-D-Glucose Uptake on Positron Emission Tomography in Thymic Epithelial Tumors

PURPOSE The usefulness of 2-[(18)F]-fluoro-2-deoxy-D-glucose ([(18)F]FDG) positron emission tomography (PET) can help predict the grade of malignancy and staging in thymic epithelial tumors. However, no satisfactory biologic explanation exists for this phenomenon. The aim of this study was to investigate the underlying biologic mechanisms of [(18)F]FDG uptake. PATIENTS AND METHODS Forty-nine patients with thymic epithelial tumors who underwent [(18)F]FDG PET were included in this study. Tumor sections were stained by immunohistochemistry for glucose transporter 1 (GLUT1), glucose transporter 3 (GLUT3), hypoxia-inducible factor-1 alpha (HIF-1alpha), vascular endothelial growth factor (VEGF), microvessels (CD31 and CD34), cell cycle control marker (p53), and apoptosis marker (bcl-2). We also conducted an in vitro study of [(18)F]FDG uptake in a thymic tumor cell line. RESULTS There was a positive correlation between [(18)F]FDG uptake and GLUT1 (P < .0001), HIF-1alpha (P = .0036), VEGF (P < .0001), microvessel density (MVD; P < .0001), and p53 (P = .0002). GLUT3 and bcl-2 showed no positive correlation with [(18)F]FDG uptake. The expression of Glut1, HIF-1alpha, VEGF, CD31, CD34, and p53 was also significantly associated with the grade of malignancy and poor outcome in thymic epithelial tumors, whereas this relationship was not observed in GLUT3 and bcl-2. Our in vitro study demonstrated that upregulation of GLUT1 and HIF-1alpha was closely associated with [(18)F]FDG uptake into thymic tumor cell. CONCLUSION [(18)F]FDG uptake in thymic epithelial tumors is determined by the presence of glucose metabolism (GLUT1), hypoxia (HIF-1alpha), angiogenesis (VEGF and MVD), and cell cycle regulator (p53).

Utility of 18FDG-PET for differentiating the grade of malignancy in thymic epithelial tumors.

PURPOSE The objective of this study was to assess the value of (18)F-FDG PET in thymic epithelial tumors according to the WHO histologic classification and to evaluate its potential for differentiating the grade of malignancy in thymic epithelial tumors. MATERIALS AND METHODS Thirty-six patients with a thymic epithelial tumor who underwent (18)F-FDG PET examination before treatment were enrolled in the present study. The T/M ratio, which is the ratio of the peak standardized uptake value (SUV) of the tumor to the mean SUV of mediastinum, was compared in subgroups of a simplified WHO histological classification; low-risk thymoma (Types A, AB and B1), high-risk thymoma (Types B2 and B3), and thymic carcinoma. RESULTS Tumors included 15 low-risk thymomas, 10 high-risk thymomas and 11 thymic carcinomas. Upon visual inspection, all tumors showed (18)F-FDG accumulation and the mean T/M ratio in these three subgroups was 2.64, 4.29 and 8.90, respectively. The differences between the three subgroups were statistically significant (low-risk vs. high-risk: p=0.01, high-risk vs. thymic carcinoma: p=0.01). CONCLUSION A significant relationship was seen between (18)F-FDG PET accumulation and histologic subtype in thymic epithelial tumors when they were classified into three groups. PET may be useful for predicting the grade of malignancy in thymic epithelial tumors.

Surgical treatment for metastatic malignancies. Pulmonary metastasis: indications and outcomes.

Surgical resection is an important modality in the treatment of pulmonary metastases from various solid tumors. The criteria for pulmonary metastasectomy are as follows: (1) the patient must be a good risk for surgical intervention; (2) the primary malignancy is controlled; (3) there is no other, extrapulmonary, metastasis; and (4) the pulmonary lesions are thought to be completely resectable. The appropriate selection of candidates according to these criteria leads to an overall 5-year survival after pulmonary metastasectomy of about 30%–40%. However, most of the reported results are retrospective analyses, and the significance of pulmonary metastasectomy seems to vary according to the primary malignancy. To clarify the significance of surgical treatment for pulmonary metastases, we need further analysis of various prognostic factors, with special reference to each primary malignancy, as well as a multiinstitutional study, and randomized prospective studies, if possible.

Fluoroscopy-assisted thoracoscopic surgery after computed tomography-guided bronchoscopic barium marking

BACKGROUND Small lesions of the peripheral lung have been detected more frequently with the recent prevalence of computed tomography (CT). Identification of these lesions is indispensable for wedge resection performed by video-assisted thoracic surgery. Previous reports of marking techniques showed some failure and complications. We have developed a new marking technique and herein describe the efficacy of this technique: fluoroscopy-assisted thoracoscopic surgery after computed tomography-guided bronchoscopic barium marking. METHODS Twenty patients underwent this procedure for 21 small peripheral pulmonary lesions approximately 10 mm in size. RESULTS All the lesions were successfully marked and identified during fluoroscopy-assisted thoracoscopy. They were resected with sufficient margins. There were no complications related to this procedure. The pathologic examination of these 21 lesions revealed primary lung cancer in 14, atypical adenomatous hyperplasia in four, a metastatic tumor in one, and a benign tumor in two. CONCLUSIONS This procedure is both a reliable and minimally invasive technique in thoracoscopic wedge resection for small peripheral pulmonary lesions.

Correlation Between 18F-FDG Uptake on PET and Molecular Biology in Metastatic Pulmonary Tumors

18F-FDG PET can help in predicting therapeutic response and outcome in patients with metastatic pulmonary tumors. However, no satisfactory biologic explanation exists for this phenomenon. The aim of this study was to investigate the underlying biologic mechanisms of 18F-FDG uptake in metastatic pulmonary tumors. Methods: One hundred forty-six patients with metastatic pulmonary tumors who underwent 18F-FDG PET before treatment were included in this study. Tumor sections were stained by immunohistochemistry for glucose transporter 1 (Glut1), glucose transporter 3 (Glut3), hexokinase I, hypoxia-inducible factor-1α (HIF-1α), vascular endothelial growth factor (VEGF), and microvessel density determined by CD34. 18F-FDG uptake and the expression of these biomarkers were correlated in primary lung cancer and benign pulmonary lesions. Results: 18F-FDG uptake in metastatic pulmonary tumors correlated significantly with the expression of Glut1 (γ = 0.4579, P < 0.0001), HIF-1α (γ = 0.3654, P < 0.0001), hexokinase I (γ = 0.3921, P < 0.0001), VEGF (γ = 0.5528, P < 0.0001), and CD34 (γ = 0.2342, P = 0.0044). 18F-FDG uptake in metastatic pulmonary tumors was significantly lower than in primary lung cancer but higher than in benign pulmonary lesions. High uptake of 18F-FDG was significantly associated with poor outcome after pulmonary metastasectomy. In patients with metastatic pulmonary tumors, 18F-FDG uptake and the expression of Glut1, HIF-1α, and VEGF were significantly higher in adenocarcinoma and squamous cell carcinoma than in sarcoma. 18F-FDG uptake was significantly correlated with tumor size (P < 0.0001), but there was no significant relationship between tumor size and the expression of these biomarkers. Conclusion: The amount of 18F-FDG uptake in metastatic pulmonary tumors is determined by the presence of glucose metabolism (Glut1), phosphorylation of glucose (hexokinase I), hypoxia (HIF-1α), and angiogenesis (VEGF and microvessel density).

Biologic correlates of 18F-FDG uptake on PET in pulmonary pleomorphic carcinoma

BACKGROUND Pulmonary pleomorphic carcinoma is a rare epithelial tumor, and little is also known about the information on the usefulness of 2-[¹⁸F]-fluoro-2-deoxy-d-glucose (¹⁸F-FDG) positron emission tomography (PET). Therefore, we conducted the study including the underlying biologic analysis of ¹⁸F-FDG uptake. METHODS Fifteen patients with pulmonary pleomorphic carcinoma who underwent ¹⁸F-FDG PET before treatment were included in this study. Tumor sections were stained by immunohistochemistry for glucose transporter 1 (Glut1); glucose transporter 3 (Glut3); hypoxia-inducible factor-1 alpha (HIF-1α); cell proliferation (Ki-67 labeling index); vascular endothelial growth factor (VEGF); microvessels (CD34); cell cycle control marker (p53); and apoptosis marker (bcl-2). These parameters were correlated with a control group of patients with other non-small cell lung cancer (NSCLC) (n=33). RESULTS The maximal standardized uptake value (SUV(max)) of the primary tumors in 15 patients ranged from 6.1 to 26.8 (median 19.3). There were positive correlation between ¹⁸F-FDG uptake and Glut1 (p=0.0016), Glut3 (p=0.0080), VEGF (p=0.0048), and microvessel density (MVD) (p=0.0005). HIF-1α, p53 and bcl-2 showed no positive correlation with ¹⁸F-FDG uptake. ¹⁸F-FDG uptake, Glut1, Glut3, HIF-1α, VEGF and Ki-67 were significantly higher in patients with pulmonary pleomorphic carcinoma than those with other NSCLC. CONCLUSION ¹⁸F-FDG uptake in pulmonary pleomorphic carcinoma is closely associated with the presence of glucose metabolism (Glut1 and Glut3) and angiogenesis (VEGF and MVD). The relationship between ¹⁸F-FDG uptake and these biomarkers may lead to a more rational use of PET scan in pulmonary pleomorphic carcinoma.

Recurrence of mediastinal node cancer after lobe-specific systematic nodal dissection for non-small-cell lung cancer.

OBJECTIVES The standard surgical treatment for patients with non-small-cell lung cancer (NSCLC) is lobectomy with systematic nodal dissection (SND). Lobe-specific patterns of nodal metastases have been recognized, and lobe-specific SND (L-SND) has been reported. We performed L-SND depending on patient-related factors, such as age or the presence of diabetes or respiratory dysfunction, or in the context of specific tumour-related factors, such as the presence of a tumour with a wide area of ground-glass opacity. METHODS Between September 2002 and December 2008, 335 consecutive patients with clinical and intraoperative N0 NSCLC underwent curative lobectomies at Shizuoka Cancer Center Hospital. Among these 335 patients, 206 underwent SND (Group A) and 129 underwent L-SND. Of the 129 patients undergoing L-SND, 98 underwent L-SND due to patient-related factors (Group B) and 31 underwent L-SND due to tumour-related factors (Group C). RESULTS There were no significant differences in morbidity or blood loss between patients undergoing SND or L-SND, but there was a significant difference in the mean operative times. The 5-year disease-free survival (5-DFS) and 5-year overall survival (5-OS) of patients in Group C were 100%. Although the patients in Group B showed no significant difference in 5-DFS and 5-OS compared with Group A, patients in Group B had significantly more initial recurrence of mediastinal node cancer than did the Group A patients (P = 0.0050). CONCLUSIONS The recurrence of mediastinal node cancer in patients undergoing L-SND was significantly greater than that in those undergoing SND.

Expression of 4F2hc (CD98) in pulmonary neuroendocrine tumors

4F2hc (CD98) has been associated with tumor growth, and is highly expressed in various tumors. The aim of this study was to evaluate the clinicopathological significance of 4F2hc expression in pulmonary neuroendocrine (NE) tumors. Surgically-resected patient tumors including 16 large cell neuroendocrine carcinoma (LCNEC), 12 small cell lung cancer (SCLC), 1 atypical carcinoid (AC) and 5 typical carcinoid (TC) samples were included in this study. Tumor sections were immunohistochemically stained for 4F2hc (CD98), glucose transporter 1 (Glut1) and 3 (Glut3), hypoxia-inducible factor-1α (HIF-1α), hexokinase I, vascular endothelial growth factor (VEGF), microvessel density (CD34), epidermal growth factor receptor (EGFR), Akt/mammalian target of rapamycin (mTOR) signaling pathway (p-Akt, p-mTOR and p-S6K) and for a cell cycle regulator (p53). 4F2hc was overexpressed in 0% of the pulmonary carcinoids (TCs and ACs), 62.5% of the LCNECs and 50.0% of the SCLCs. A positive 4F2hc expression was significantly associated with age, histology and Glut1 expression. Moreover, a significant correlation was found between 4F2hc expression, and Glut1, HIF-1α, p-Akt, p-mTOR and p-S6K. The expression of 4F2hc was also significantly associated with poor overall survival. The expression of 4F2hc expression tended to increase from low-grade to high-grade pulmonary NE tumors. Our results suggest that 4F2hc may play a significant role in tumor progression, hypoxic conditions and poor outcome in patients with pulmonary NE tumors.

Expression of thymidylate synthase, orotate phosphoribosyltransferase and dihydropyrimidine dehydrogenase in thymic epithelial tumors

BACKGROUND It remains unclear whether thymidylate synthase (TS), orotate phosphoribosyltransferase (OPRT) and dihydropyrimidine dehydrogenase (DPD) expressions are associated with the pathogenesis of thymic epithelial tumors. Therefore, we investigated the expression of TS, OPRT and DPD in thymic epithelial tumors. PATIENTS AND METHODS Fifty-six patients with thymic epithelial tumors were included in this study. Tumors sections were stained by immunohistochemistry for TS, OPRT, DPD, microvessel density (MVD) determined by CD34, and p53. We also conducted in vitro study of TS, OPRT and DPD expression using thymic carcinoma, thymic tumor and thymic fibroblast cell lines. RESULTS TS, OPRT and DPD were expressed in 61%, 48% and 41%, respectively. High grade malignancy is significantly associated with higher expression of TS, OPRT and DPD in thymic epithelial tumors. These biomarkers were closely associated with p53 and MVD, and the overexpression of TS and DPD was a prognostic marker for predicting poor outcome in univariate analysis. Our in vitro study showed that marked overexpression of TS and OPRT was observed in thymic carcinoma cells, but not in thymic tumor cells, or thymic fibroblast cells. CONCLUSIONS The expression of TS, OPRT and DPD was closely related to the grade of malignancy in thymic epithelial tumors. A positive expression of TS, DPD and OPRT might be an important factor in predicting the effectiveness of 5-FU based chemotherapy in this disease.

18F-FDG uptake on PET in primary mediastinal non-thymic neoplasm: A clinicopathological study

BACKGROUND The usefulness of 2-[(18)F]-fluoro-2-deoxy-D-glucose ((18)F-FDG) positron emission tomography (PET) has been investigated in thymic epithelial tumors. However, little is known about PET imaging of (18)F-FDG in primary non-thymic mediastinal neoplasms. The aim of this study is to explore the clinicopathological significance of (18)F-FDG PET in primary mediastinal (non-thymic) neoplasms. METHODS Twenty-one patients with mediastinal neoplasms who underwent (18)F-FDG PET before treatment were included in this study. Tumor sections were stained by immunohistochemistry for glucose transporter 1 (Glut1); glucose transporter 3 (Glut3); hypoxia-inducible factor-1 alpha (HIF-1α); hexokinase I; vascular endothelial growth factor (VEGF); microvessels (CD34); epidermal growth factor receptor (EGFR); Akt/mTOR signaling pathway (p-Akt and p-mTOR); cell cycle control (p53). RESULTS Seventeen of 21 patients were imaged on PET system using (18)F-FDG, but 4 patients with a histology of cyst showed nothing abnormal in PET scans. The histology of the resected tumors was as follows: 6 schwannoma, 3 teratoma, 4 cyst, 3 sarcoma, 1 undifferentiated carcinoma, 1 seminoma, 1 mediastinal goiter, 1 ganglioneuroma, and 1 Hodgkin lymphoma. (18)F-FDG uptake was significantly correlated with Glut1, HIF-1α, EGFR, p-Akt and p-S6K. These biomarkers were highly expressed in schwannoma, teratoma and high grade malignancies, whereas all patients with cyst and ganglioneuroma had no positive expression of these biomarkers. High uptake of (18)F-FDG was significant associated with Glut1, VEGF, EGFR, p-Akt, p-S6K and tumor maximal size. CONCLUSION The amount of (18)F-FDG uptake in primary mediastinal non-thymic neoplasms is determined by the presence of glucose metabolism (Glut1), hypoxia (HIF-1α) and upstream components of HIF-1α (EGFR, p-Akt and p-S6K).