Yuichiro Machida

Relationship of aquaporin 1, 3, and 5 expression in lung cancer cells to cellular differentiation, invasive growth, and metastasis potential

An oncogenic capacity of aquaporins, transmembrane channels for water, was recently proposed. This study seeks to elucidate the involvement of aquaporin 1, 3, and 5 in the development and progression of lung cancer. Expression of aquaporin 1, 3, and 5 was examined by immunohistochemistry, Western blot, and laser-captured microdissection/real-time reverse transcription polymerase chain reaction in 160 lung cancers of various histologic subtypes; and its correlation with clinicopathological factors and survival was analyzed. Aquaporin 1, 3, and 5 were expressed in tumor cells in 71%, 40%, and 56% of lung cancers, respectively. Aquaporin expressions were frequent in adenocarcinomas, whereas aquaporin 1 and 5 were negative in squamous cell carcinomas. Bronchioloalveolar carcinoma cells exhibited an apicolateral aquaporin 1 and apicolateral or basolateral aquaporin 3 localization in nonmucinous type, and apical aquaporin 1 and 5 and basolateral aquaporin 3 expression in mucinous type, which corresponded to aquaporins expression of nonneoplastic lung tissue. Basolateral aquaporin 5 expression was acquired during tumorigenesis of nonmucinous bronchioloalveolar carcinoma. In contrast, invasive adenocarcinoma tumor cells overexpressed aquaporin 1 and 5 with loss of subcellular polarization and with an intracytoplasmic distribution. Overexpression of aquaporin 1 correlated with high postoperative adenocarcinoma metastasis ratios and unfavorable disease-free survival rates (P = .031). We conclude that expression patterns of aquaporin 1, 3, and 5 in lung cancer cells are mostly associated with cellular differentiation. However, the expression of aquaporin 1 and 5 is up-regulated in invading lung cancer cells, particularly in adenocarcinomas; and the overexpression of aquaporin 1 with loss of subcellular polarization is suggested to be involved in their invasive and metastatic potential.

Correlation between glucose transporter-1 expression and 18F-fluoro-2-deoxyglucose uptake on positron emission tomography in lung cancer

PurposeThe aim of this study was to determine if glucose transporter-1 (Glut1) expression correlates with 18F-FDG (18F-fluoro-2-deoxyglucose) uptake on positron emission tomography (PET) in lung cancer and to examine the similarities and differences between them.MethodsA total of 34 patients with resected primary lung cancers were investigated in this study. There were 17 adenocarcinomas, 12 squamous cell carcinomas, and 5 cancers of other cell types. Immunohistochemical Glut1 intensity was categorized into three groups: negative, positive, and strongly positive. Glut1 frequency was defined by the proportion of positive cells among all cancer cells, and it was graded on a semiquantitative scale as 0–100% in 10% increments. The data are expressed as the mean ± SD.ResultsMaximum standardized uptake values (SUVmax) were 4.8 ± 6.3 in “negative” Glut1 intensity cases, 4.7 ± 3.1 in “positive” Glut1 intensity cases, and 11.2 ± 5.2 in “strongly positive” Glut1 intensity cases. Although SUVmax correlated significantly with tumor size (correlation coefficient 0.58, P = 0.00033), Glut1 frequency did not correlate significantly with tumor size (correlation coefficient 0.18, P = 0.301). Cell type and cell differentiation correlated significantly with Glut1 expression and 18F-FDG uptake.ConclusionGlut1 expression correlates significantly with 18F-FDG uptake. There are similarities in cell differentiation and cell type between Glut1 expression and 18F-FDG uptake. 18F-FDG uptake correlates significantly with tumor size, but Glut1 expression does not.

Relationships between EGFR mutation status of lung cancer and preoperative factors - are they predictive?

BACKGROUND The epidermal growth factor receptor (EGFR) mutation status of lung cancer is important because it means that EGFR-tyrosine kinase inhibitor treatment is indicated. The purpose of this prospective study is to determine whether EGFR mutation status could be identified with reference to preoperative factors. MATERIALS AND METHODS One hundred-forty eight patients with lung cancer (111 adenocarcinomas, 25 squamous cell carcinomas and 12 other cell types) were enrolled in this study. The EGFR mutation status of each lung cancer was analyzed postoperatively. RESULTS There were 58 patients with mutant EGFR lung cancers (mutant LC) and 90 patients with wild-type EGFR lung cancers (wild-type LC). There were significant differences in gender, smoking status, maximum tumor diameter in chest CT, type of tumor shadow, clinical stage between mutant LC and wild-type LC. EGFR mutations were detected only in adenocarcinomas. Maximum standardized uptake value (SUVmax:3.66±4.53) in positron emission tomography-computed tomography of mutant LC was significantly lower than that (8.26±6.11) of wild-type LC (p<0.0001). Concerning type of tumor shadow, the percentage of mutant LC was 85.7% (6/7) in lung cancers with pure ground glass opacity (GGO), 65.3%(32/49) in lung cancers with mixed GGO and 21.7%(20/92) in lung cancers with solid shadow (p<0.0001). For the results of discriminant analysis, type of tumor shadow (p=0.00036) was most significantly associated with mutant EGFR. Tumor histology (p=0.0028), smoking status (p=0.0051) and maximum diameter of tumor shadow in chest CT (p=0.047) were also significantly associated with mutant EGFR. The accuracy for evaluating EGFR mutation status by discriminant analysis was 77.0% (114/148). CONCLUSIONS Mutant EGFR is significantly associated with lung cancer with pure or mixed GGO, adenocarcinoma, never-smoker, smaller tumor diameter in chest CT. Preoperatively, EGFR mutation status can be identified correctly in about 77 % of lung cancers.

Diagnostic Performance of Diffusion Weighted Imaging of Malignant and Benign Pulmonary Nodules and Masses: Comparison with Positron Emission Tomography

BACKGROUND Diffusion-weighted imaging (DWI) makes it possible to detect malignant tumors based on the diffusion of water molecules. However, it is uncertain whether DWI has advantages over FDG-PET for distinguishing malignant from benign pulmonary nodules and masses. MATERIALS AND METHODS One hundred- forty-three lung cancers, 17 metastatic lung tumors, and 29 benign pulmonary nodules and masses were assessed in this study. DWI and FDG-PET were performed. RESULTS The apparent diffusion coefficient (ADC) value (1.27 ± 0.35 ?10-3 mm2/sec) of malignant pulmonary nodules and masses was significantly lower than that (1.66 ± 0.58 ?10-3 mm2/sec) of benign pulmonary nodules and masses. The maximum standardized uptake value (SUV max: 7.47 ± 6.10) of malignant pulmonary nodules and masses were also significantly higher than that (3.89 ± 4.04) of benign nodules and masses. By using optimal cutoff values for ADC (1.44?10-3 mm2/sec) and for SUV max (3.43), which were determined with receiver operating characteristics curves (ROC curves), the sensitivity (80.0%) of DWI was significantly higher than that (70.0%) of FDG-PET. The specificity (65.5%) of DWI was equal to that (65.5%) of FDG-PET. The accuracy (77.8%) of DWI was not significantly higher than that (69.3%) of FDG- PET for pulmonary nodules and masses. As the percentage of bronchioloalveolar carcinoma (BAC) component in adenocarcinoma increased, the sensitivity of FDG-PET decreased. DWI could not help in the diagnosis of mucinous adenocarcinomas as malignant, and FDG-PET could help in the correct diagnosis of 5 out of 6 mucinous adenocarcinomas as malignant. CONCLUSIONS DWI has higher potential than PET in assessing pulmonary nodules and masses. Both diagnostic approaches have their specific strengths and weaknesses which are determined by the underlying pathology of pulmonary nodules and masses.

Diagnostic Performance of Diffusion-Weighted Imaging for Multiple Hilar and Mediastinal Lymph Nodes with FDG Accumulation.

BACKGROUND It is sometimes difficult to assess patients who have multiple hilar and mediastinal lymph nodes (MHMLN) with FDG accumulation in PET-CT. Since it is uncertain whether diffusion-weighted magnetic resonance imaging (DWI) is useful in the assessment of such patients, its diagnostic performance was assessed. MATERIALS AND METHODS Twenty-three patients who had three or more stations of hilar and mediastinal lymph nodes with SUVmax of 3 or more in PET-CT were included in this study. RESULTS For diagnosis of disease, there were 20 malignancies (lung cancers 17, malignant lymphomas 2 and metastatic lung tumor 1), and 3 benign cases (sarcoidosis 2 and benign disease 1). For diagnosis of lymph nodes, there were 7 malignancies (metastasis of lung cancer 7 and malignant lymphoma 1) and 16 benign lymphadenopathies (pneumoconiosis/silicosis 7, sarcoidosis 4, benign disease 4, and atypical lymphocyte infiltration 1). The ADC value (1.57±0.29x10(-3) mm2/sec) of malignant MHMLN was significantly lower than that (1.99±0.24x10(-3) mm2/sec) of benign MHMLN (P=0.0437). However, the SUVmax was not significantly higher (10.0±7.34 as compared to 6.38±4.31) (P=0.15). The sensitivity (86%) by PET-CT was not significantly higher than that (71%) by DWI for malignant MHMLN (P=1.0). The specificity (100%) by DWI was significantly higher than that (31%) for benign MHMLN (P=0.0098). Furthermore, the accuracy (91%) with DWI was significantly higher than that (48%) with PET-CT for MHMLN (P=0.0129). CONCLUSIONS Evaluation by DWI for patients with MHMLN with FDG accumulation is useful for distinguishing benign from malignant conditions.

Do Japanese thoracic surgeons think that dissection of the pulmonary ligament is necessary after an upper lobectomy

It is uncertain whether the dissection of the pulmonary ligament is necessary in patients who undergo an upper lobectomy. A questionnaire was sent to the directors of Thoracic Surgery in 102 hospitals, asking whether dissection of the pulmonary ligament is performed in such patients, and the complications associated with dissecting or preserving the ligament. Seventy-eight directors (76%) returned the questionnaire. The preservation of the ligament is the current practice in 54 hospitals (69%), while 13 hospitals (17%) occasionally dissect, 9 hospitals (11%) regularly dissect, and 2 hospitals (3%) half dissect the ligament. Thirty directors experienced complications which were thought to be associated with dissecting the ligament: bronchial stenosis (21 directors), atelectasis (8), and bronchial obstruction (4). Twenty-six directors described complications thought to be associated with preserving the ligament: the pooling of pleural effusion (19 directors), insufficient expansion of lung (18), atelectasis (8), and empyema (7). Preservation of the ligament may therefore be useful in preventing bronchial stenosis and obstruction, while its dissection may be useful to prevent the pooling of pleural effusion.

Diffusion-weighted imaging (DWI) signal intensity and distribution represent the amount of cancer cells and their distribution in primary lung cancer

The aim of this study was to interpret diffusion-weighted imaging (DWI) signals in lung cancers. They were converted into several three-dimensional DWI signals patterns, which represent the degree of DWI signal intensity by height and the degree of distribution by area: flat, low elevation, irregular elevation, single-peak elevation, multiple-peak elevation, and nodular elevation. There were 39 adenocarcinomas and 21 squamous cell carcinomas. Three-dimensional DWI signals decreased significantly in order of cell differentiation. Tumor cellular densities were increased according to the increase in three-dimensional DWI signals. DWI signal intensity and distribution can represent the amount of cancer cells and their distribution in the carcinoma.

Lung cancer screening and its efficacy

The efficacy of lung cancer screening should not be evaluated by the survival rate of lung cancer patients but by lung cancer mortality in a certain population because the survival rate can be greatly affected by several types of bias. Randomized controlled trials that were conducted during the 1970s and 1980s in Europe and the United States failed to prove the efficacy of lung cancer screening in decreasing the mortality rate; but recently the results of case-control studies in Japan have revealed that undergoing currently available screening decreases the risk of lung cancer deaths by 30%–60%. A system is now being created in Japan whereby the guidelines regarding cancer screening will continue to be updated. The preliminary reports concerning lung cancer screening using thoracic computed tomography revealed that not only the detection rate of lung cancer but also the survival rate of detected lung cancer patients were surprisingly high. However, the presence of some potential bias in these studies cannot be ignored; therefore, it is still unknown whether there is actual efficacy. Several randomized controlled trials are presently in progress overseas, but the interim results were not favorable. A randomized controlled trial should therefore immediately be started in Japan as well.

Diffusion Weighted Imaging Can Distinguish Benign from Malignant Mediastinal Tumors and Mass Lesions: Comparison with Positron Emission Tomography.

BACKGROUND Diffusion-weighted magnetic resonance imaging (DWI) makes it possible to detect malignant tumors based on the diffusion of water molecules. It is uncertain whether DWI is more useful than positron emission tomography-computed tomography (PET-CT) for distinguishing benign from malignant mediastinal tumors and mass lesions. MATERIALS AND METHODS Sixteen malignant mediastinal tumors (thymomas 7, thymic cancers 3, malignant lymphomas 3, malignant germ cell tumors 2, and thymic carcinoid 1) and 12 benign mediastinal tumors or mass lesions were assessed in this study. DWI and PET-CT were performed before biopsy or surgery. RESULTS The apparent diffusion coefficient (ADC) value (1.51±0.46x10(-3) mm2/sec) of malignant mediastinal tumors was significantly lower than that (2.96±0.86x10(-3) mm2/sec) of benign mediastinal tumors and mass lesions (P<0.0001). Maximum standardized uptake value (SUVmax) (11.30±11.22) of malignant mediastinal tumors was significantly higher than that (2.53±3.92) of benign mediastinal tumors and mass lesions (P=0.0159). Using the optimal cutoff value (OCV) 2.21x10(-3) mm2/sec for ADC and 2.93 for SUVmax, the sensitivity (100%) by DWI was not significantly higher than that (93.8%) by PET-CT for malignant mediastinal tumors. The specificity (83.3%) by DWI was not significantly higher than that (66.7%) for benign mediastinal tumors and mass lesions. The accuracy (92.9%) by DWI was not significantly higher than that (82.1%) by PET-CT for mediastinal tumors and mass lesions. CONCLUSIONS There was no significant difference between diagnostic capability of DWI and that of PET-CT for distinguishing mediastinal tumors and mass lesions. DWI is useful in distinguishing benign from malignant mediastinal tumors and mass lesions.

Recurrence and Metastasis of Lung Cancer Demonstrate Decreased Diffusion on Diffusion-Weighted Magnetic Resonance Imaging

BACKGROUND Diffusion-weighted magnetic resonance imaging (DWI) is reported to be useful for detecting malignant lesions. The purpose of this study is to clarify characteristics of imaging, detection rate and sensitivity of DWI for recurrence or metastasis of lung cancer. METHODS A total of 36 lung cancer patients with recurrence or metastasis were enrolled in this study. While 16 patients underwent magnetic resonance imaging (MRI), computed tomography (CT) and positron emission tomography-computed tomography (PET-CT), 17 underwent MRI and CT, and 3 underwent MRI and PET-CT. RESULTS Each recurrence or metastasis showed decreased diffusion, which was easily recognized in DWI. The detection rate for recurrence or metastasis was 100% (36/36) in DWI, 89% (17/19) in PET-CT and 82% (27/33) in CT. Detection rate of DWI was significantly higher than that of CT (p=0.0244) but not significantly higher than that of PET-CT (p=0.22). When the optimal cutoff value of the apparent diffusion coefficient value was set as 1.70?10-3 mm2/sec, the sensitivity of DWI for diagnosing recurrence or metastasis of lung cancer was 95.6%. CONCLUSIONS DWI is useful for detection of recurrence and metastasis of lung cancer.