EGFR mutation status and prognosis for gefitinib treatment in Japanese lung cancer.
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Carcinoma, Non-Small-Cell Lung↗
Biomedical subjects
Yosuke Yamakawa
Publications and source records attributed to Yosuke Yamakawa.
Arg and DAP3 expression was correlated with human thymoma stage.
Thymoma is one of the most common solid tumors in the mediastinum. As there is no typical cell line for human thymoma, the development and use of molecular-based therapy for thymoma will require detailed molecular genetic analysis of patients' tissues. The recent reports showed that the gain of chromosome 1q regions was frequent in thymoma. We investigated the use of oligonucleotide arrays to monitor in vivo gene expression levels at chromosome 1q regions in the early- (stage I or II) and late-stage (stage IVa) thymoma tissues from patients. These in vivo gene expression profiles were verified by real-time quantitative reverse transcription polymerase chain reaction (RT-PCR) using LightCycler for 36 thymoma patients. Using both the methods, candidate genes were come up. These are Arg tyrosine kinase and death-associated protein 3 (DAP3), which are known as ionizing radiation resistance conferring proteins. The Arg/GAPDH mRNA level in stage IV thymoma (90.716 +/- 177.851) was significantly higher than in stage I thymoma (10.335 +/- 25.744, P = 0.0465). The DAP3/GAPDH mRNA level in stage IV thymoma (17.424 +/- 20.649) was significantly higher than in stage I thymoma (5.184 +/- 3.878, P = 0.0305). DAP3 expression was also correlated with the WHO classification. The combined use of oligonucleotide microarray and real-time RT-PCR analyses provided a candidate molecular marker surrounding the development and progression of thymoma correlated with chromosome 1q.
Apoptosis Regulatory Proteins↗
Histone deacetylase 1 mRNA expression in lung cancer.
Histone deacetylases (HDACs) play a crucial role in tumorigenesis, however, the expression status of HDACs in lung cancer tissues has not been reported. We have investigated that HIDAC 1 mRNA levels and other clinico-pathological data, including MTA 1 mRNA expression in lung cancer. The study included 102 lung cancer cases. The HDAC1 mRNA levels were quantified by real time reverse transcription-polymerase chain reaction (RT-PCR) using LightCycler (Roche Molecular Biochemicals, Mannheim, Germany). The HDAC1/GAPDH mRNA levels were not significantly different in tumor tissues from lung cancer (30.654 +/- 33.047) and adjacent non-malignant lung tissues (18.953 +/- 56.176 , P = 0.1827). No significant difference in HDAC1/GAPDH mRNA levels was found among age, gender, and lymph node metastasis. The HDAC1/GAPDH mRNA levels were significantly higher in stage III or IV lung cancer (50.929 +/- 120.433) than in stage I lung cancer (11.430 +/- 25.611, P = 0.0472). HDAC1/GAPDH mRNA levels were significantly higher in T3 or T4 lung carcinoma (54.326 +/- 127.018) than in T1 or T2 lung cancers (14.790 +/- 48.670, P = 0.1601). HDAC1/GAPDH mRNA levels were correlated with MTA1/GAPDH mRNA levels (y = 0.0106x + 2.5827 , P = 0.0352 ). HDAC1/GAPDH mRNA levels were also correlated with HDAC1 protein (P = 0.0484) expression by immunohistochemistry. Using the LightCycler RT-PCR assay, the HDAC1 gene expression might correlate with progression of lung cancers. However, further studies are needed to confirm the impact of HDAC1 for the molecular target of the lung cancer.
Adult↗
Thymidylate synthase and dihydropyrimidine dehydrogenase mRNA levels in thymoma.
PURPOSE: Thymoma is one of the most common solid tumors in the mediastinum. However, there is no definitive consensus regarding the optimal adjuvant chemotherapy for advanced thymoma. METHODS: To predict tumor sensitivity to 5-fluorouracil (5-FU) in thymoma, we investigated the mRNA levels of thymidylate synthase (TS), the key enzyme that catalyzes the methylation of deoxyuridine monophosphate, and correlates with the resistance of 5-FU and dihydropyrimidine dehydrogenase (DPD), which degrades 5-FU in thymoma. We used real-time quantitative reverse transcription-polymerase chain reaction (RT-PCR) using the LightCycler to monitor the TS and DPD gene expression levels in thymoma tissue specimens from patients, coamplified with glyceraldehyde-3-phosphate dehydrogenase (GAPDH) as an internal standard. RESULTS: In the resected tumor specimens, TS and DPD mRNA levels were 3.876 and 14.651, respectively. Both the TS and DPD mRNA levels were significantly higher in the tumor tissue specimens than in the normal adjacent thymus tissue specimens. No significant correlations were observed between the TS or DPD levels and other clinicopathological factors. CONCLUSIONS: The combined use of measurements of TS and DPD mRNA levels using real-time RT-PCR analyses may provide an indication of the selective cytoxicity of 5-FU on thymoma. In general, 5-FU itself is not considered to be a useful treatment for thymoma. The usufulness of DPD-inhibiting fluoropyrimidine (DIF) drugs for thymoma should therefore be further considered.
Adult↗
Flow-cytometric diagnosis of thymoma using needle biopsy specimens.
INTRODUCTION: Thymoma is a neoplasm of thymic epithelial cells which is characteristically associated with a large number of non-neoplastic T lymphocytes. These T cells are induced by epithelial cells and show a unique phenotype of CD4(+)8(+) double positive (DP), when studied by flow cytometry. This DP phenotype can be used as one of the diagnostic criteria to indicate a thymoma. The preoperative diagnosis of thymoma and other thymic tumors is an important problem because the treatment differs according to the diagnosis. METHODS: A flow-cytometric analysis of needle biopsy specimens was performed on ten thymic tumors. The results were then compared with the findings of a histological diagnosis using conventional hematoxylin-eosin (H&E) staining. RESULTS: Six cases with high frequencies of DP cells were diagnosed as thymoma by a flow-cytometric analysis, and were confirmed by a histological analysis of the resected specimen. Flow cytometry did not suggest a thymoma in the other four cases with few DP cells. The final diagnoses of the resected specimen of these four cases were: one thymic carcinoma, one malignant lymphoma, and two germ-cell tumors. The accuracy and specificity of diagnosis of thymoma using a fluorescence-activated cell sorting analysis from needle biopsy specimens were 6/6 (100%). On the other hand, the specificity of H&E staining from needle biopsy specimens for the diagnosis of thymoma was 6/6 (100%), but the accuracy was only 6/9 (66.7%). DISCUSSION: Flow cytometry can be applied to needle biopsy specimens and thus is considered to offer useful information for the preoperative diagnosis of thymic tumors.
Adult↗
Multicystic mesothelial cyst of the mediastinum: report of a case.
We report the rare case of a multicystic mesothelial cyst of the mediastinum. A 43-year-old man was referred to our department after a routine chest X-ray showed an anterior mediastinum mass. The lesion was resected by thoracoscopy, which revealed multicystic, thin-walled tense masses arising in the anterior mediastinum. The cysts were not adherent to the pericardium or to the thymus of the right lobe. Immunohistochemistry revealed that the cyst was lined with a layer of mesothelial cells and there were no malignant foci. The lining cells were positive for keratin and negative for the lymphocyte marker. These findings were consistent with a diagnosis of multicystic mesothelial cyst.
Adult↗
Elevated serum epidermal growth factor receptor level is correlated with lymph node metastasis in lung cancer.
BACKGROUND: Using an enzyme immunoassay for epidermal growth factor receptor (EGFR), we investigated whether serum EGFR levels could be used as predictors of the development and extent of lung cancer. METHODS: The study included 106 lung cancer patients and 16 patients with nonmalignant thoracic disease. Serum samples were collected before clinical treatment. RESULTS: There was no difference between serum EGFR levels in patients with lung cancer (21.275 +/- 22.035 fm/ml) in comparison with those in nonmalignant-disease controls (22.630 +/- 7.330 fm/ml; P = 0.8083). However, lung cancer patients with lymph node metastasis (23.515 +/- 20.065 fm/ml) had significantly higher EGFR levels compared with those in patients without lymph node metastasis (16.390 +/- 10.970 fm/ml; P = 0.0228). The serum EGFR levels were similar in samples from lung cancer patients with various pathological subtypes. There was no difference in the prognosis between the lung cancer group with normal EGFR levels (<850 ng/ml) and the group with elevated EGFR levels (>850 ng/ml). CONCLUSION: Serum EGFR levels may serve as a marker that can be used as an indicator of lymph node metastasis in lung cancer. However, there was no difference between levels in patients with lung cancer and those in nonmalignant-disease controls, indicating that the measurement of serum EGFR levels was of limited value in the detection of lung cancer.
Aged↗
Hrad17 expression in thymoma.
OBJECTIVES: We used palindromic polymerase chain reaction-driven complementary deoxyribonucleic acid differential display to identify and isolate a gene, the human homolog of the Schizosaccharomyces pombe checkpoint gene rad17 (Hrad17), from colon cancer tissue. The loss of checkpoint control in mammalian cells results in genomic instability, leading to the amplification, rearrangement, or loss of chromosomes--events associated with tumor progression. We hypothesized that the Hrad17 may be expressed in thymoma, especially in invasive thymoma. We attempted to determine the influence of Hrad17 expression on clinicopathological features for patients with thymoma who had undergone surgery. METHODS: Expression of Hrad17 messenger ribonucleic acid (RNA) was evaluated by reverse transcription-polymerase chain reaction using a LightCycler in 38 thymomas and 10 adjacent histologically normal thymus samples from patients for whom follow-up data was available. RESULTS: Hrad17 transcripts were detected in all 38 tumor samples (8.789 +/- 7.337) at levels significantly higher than those in normal thymus samples (1.908 +/- 2.267, p < 0.0001). No relationship was seen between Hrad17 gene expression and age, gender, or pathological thymoma subtypes. Hrad17 mRNA expression in invasive thymomas (stage II-IV, 10.067 +/- 5.293) was significantly higher than that in stage I thymomas (5.193 +/- 4.485, p = 0.0168). Immunohistochemistry showed that Hrad17 protein was highly expressed in invasive thymoma tumor tissue but not within the normal thymus tissue. CONCLUSIONS: Hrad17 was highly expressed in invasive thymoma.
Cell Cycle Proteins↗
Expression of matrix metalloproteinases 2 and 7 in tumor cells correlates with the World Health Organization classification subtype and clinical stage of thymic epithelial tumors.
To investigate the roles of matrix metalloproteinases (MMPs) in thymic epithelial tumors, we examined the expression of MMP-2, -7, and -9; membrane-type 1 (MT1)-MMP; and tissue inhibitor of metalloproteinase-2 (TIMP-2) in 57 tumors by immunohistochemistry and in selected 15 cases by in situ hybridization. The tumors consisted of 5 type A, 12 type AB, 11 type B1, 11 type B2, 9 type B3, and 9 type C thymomas according to the World Health Organization histologic classification system and of 22 stage I, 13 stage II, 8 stage III, and 14 stage IV thymomas according to the Masaoka staging system. In the positive cases, MMPs and TIMP-2 were expressed in both tumor cells and stromal cells. The cellular localization of MMPs detected by immunohistochemistry was almost identical with that of the mRNA signals detected by in situ hybridization. MMP-2 and MMP-7 were predominantly expressed in type B3 thymoma and type C thymoma, respectively. Expression of MT1-MMP and TIMP-2 correlated with that of MMP-2, indicating a proteolytic activation of the latter. MMP-9 was prominent in type B2 thymoma. Expression in tumor cells of MMP-2 or MMP-7 was also correlated with clinical stage. The present study suggests that certain MMPs may play an important role in the tumor progression of different subtypes of thymic epithelial tumors and that MMP-2 and MMP-7 may contribute to the tumor aggressiveness and malignant potential.
Adult↗
Saber-sheath malacic trachea remodeled and fixed into a normal shape by long-term placement and then removal of gianturco wire stent.
We report the case of a 59-year-old man who presented with major dyspnea due to saber-sheath malacic trachea associated with chronic pulmonary obstructive disease. The placement of a temporary tracheal stent alleviated his dyspnea very well; hence the stent was replaced with a Gianturco wire stent (Cook Cardiology, Bloomington, IN). However, this required removal due to wire-stent-related complications 2 years after the replacement. Surprisingly the trachea had been remodeled to a normal shape resulting in comfortable, functional respiratory status. A review of the literature reveals our case to be the first report of curing saber-sheath malacic trachea without leaving any prostheses or other foreign materials.
Bronchoscopy↗
Gelatinolytic activity of matrix metalloproteinase in lung cancer studied using film in situ zymography stamp method.
In this study, we investigated activity of matrix metalloproteinase (MMP) of lung cancer by newly developed film in situ zymography (FIZ) stamp method, which allows visual localization of gelatinolytic activity within the cut surface of a tumor. We performed FIZ stamp method and conventional gelatin zymography in 39 resected specimen of lung cancer. The degree of gelatinolytic activity was scored (FIZ score) and correlated with the clinicopathological factors of the tumor. FIZ score of normal lung was very low. Lung cancer tissue had consistently higher FIZ score than the matched normal lung tissue. There were statistically significant differences in the FIZ score according to the pathological stage (P = 0.0015), nodal status (P = 0.0007) and lymphatic invasion (P = 0.0004). Direct correlation was observed between the FIZ score and MMP-2 activity (rho = 0.568, P = 0.0030) as quantitated using conventional gelatin zymography. MMP-2 may play an important role in the lymphatic invasion of lung cancer. FIZ stamp method may be a simple and useful diagnostic aid for the presence of cancer cells in the resected specimen.
Adenocarcinoma↗
Cten mRNA expression was correlated with tumor progression in lung cancers.
Cten is a recently isolated gene, which has homology with tensin suggesting that it is a focal adhesion molecule. Tensin family proteins play an important role in cell motility. We attempted to determine the influence of cten expression on clinicopathological features in patients with lung cancer who had undergone surgery. Expression of cten messenger RNA was evaluated by reverse transcription-polymerase chain reaction (RT-PCR) in 89 lung carcinomas and adjacent histological normal lung samples using LightCycler. Cten/glyceraldehyde-3-phosphate dehydrogenase (GAPDH) mRNA expression was not significantly different between lung cancer tissue (1.479+/-2.060) and normal lung tissue (1.528+/-1.592, P=0.8267). There was no relationship between cten/GAPDH expression and age, gender or N-status. However, tumor/normal ratio (T/N ratio) of cten/GAPDH expression was significantly higher in stage II-IV lung cancer (3.113+/-6.493) when compared with stage I lung cancer (1.237+/-1.820, P=0.0316). T/N ratio of cten/GAPDH expression was significantly higher in T4 lung cancer (4.612+/-9.726) when compared with T1 lung cancer (0.896+/-0.860, P=0.0252), and T2 lung cancer (1.636+/-2.066, P=0.0470), respectively. Thus cten/GAPDH mRNA expression has been correlated with evidence of tumor progression in terms of T and overall stage of lung cancer. Alternatively, cell motility or migration might play a role in progression of lung cancer.
Carcinoma, Non-Small-Cell Lung↗
Gene expression analysis of human thymoma correlates with tumor stage.
Thymoma is one of the most common solid tumors in the mediastinum. The recent development of high-density oligonucleotide arrays provides a unique opportunity to generate gene expression profiles of cells from various stages of tumor progression as it occurs in actual neoplastic tissues. We used oligonucleotide arrays to monitor in vivo gene expression levels in early- (stage I or II) and late- (stage IVa) stage thymoma tissues in 36 patients. These in vivo gene expression profiles were verified by real-time quantitative RT-PCR using LightCycler. Using both methods, 2 candidate genes were identified that were more highly expressed in advanced-stage thymomas. One was a well-known gene, c-JUN, and another was an unknown gene, AL050002. AL050002 expression, but not c-JUN expression, was also correlated with the WHO classification (type B3 vs. type B1, B2 or AB). The combined use of oligonucleotide microarray and real-time RT-PCR analyses provides a powerful new approach to elucidate the in vivo molecular events correlated with tumor stage of thymoma.
DNA, Complementary↗
The expression of Bcl-2 family proteins (Bcl-2, Bcl-x, Bax, Bak and Bim) in human lymphocytes.
Bcl-2 family proteins regulate programmed cell death, and may play an important role in the selection of lymphocytes. We investigated the expression of Bcl-2, Bcl-x, Bax, Bak and Bim in human lymphocytes using flow-cytometry. Bcl-2 was down-regulated in CD4(+)8(+) (DP) thymocytes and CD19(+)38(+) tonsillar lymphocytes (GC B cells). Among DP thymocytes, cells co-expressing CD69 up-regulated Bcl-2, suggesting that the role of Bcl-2 is promoting survival of positively selected DP cells. Unexpectedly, the expression level of Bcl-x was higher in DP cells than in Single Positive (SP) cells and in CD69(+) DP thymocytes it was lower than in CD69(+) DP thymocytes. Expression of Bim was low in DP thymocytes but high in a subset of GC B cells. Bim and Bax were expressed more highly in SP than in DP thymocytes. Among peripheral blood lymphocytes (PBL), CD8(+) T cells expressed an approximately ten-fold higher level of Bcl-x than CD4(+) T cells while both subsets expressed similar levels of Bcl-2. Bak expression was low and Bim expression was absent in PBL. These results suggest that not only Bcl-2 but other members of the Bcl-2 family are involved in T cell development in the thymus and affinity maturation of B cells in the germinal center.
Adult↗
Ets-1 gene expression in patients with thymoma.
OBJECTIVES: The Ets-1 protooncogene transcription factor is involved in several cellular functions, including the activation of several proteases, and reportedly plays an important role in carcinoma invasion and metastasis. We hypothesize that Ets-1 mRNA expression could be a predictor of thymoma development and invasion. METHODS: Subjects were 37 patients with thymoma whose mRNA expression was quantified by real-time reverse-transcription polymerase chain reaction (RT-PCR) using LightCycler, a microvolume multisample fluorimeter. RESULTS: No significant difference was found in Ets-1 mRNA expression for gender, age, or pathological subtype. Ets-1 mRNA expression in tumor tissues from stage II-IV thymoma (25.311 +/- 42.336) was more elevated than in that from stage I thymoma (2.097 +/- 4.492) (p = 0.0374). Ets-1 mRNA expression may thus serve as a marker of higher thymoma stages. CONCLUSIONS: With use of the Light Cycler RT-PCR assay, Ets-1 expression may play an important role in the extension and progression of thymoma as in other cancers. Further study and longer follow-up are, however, needed to confirm the Ets-1 impact on biological tumor behavior.
Adult↗
Elevated serum pro-MMP2 levels in patients with stage IV thymoma.
PURPOSE: There is increasing evidence that matrix metalloproteinases (MMPs) play important roles in tumor invasion and metastasis. Using a one-step sandwich enzyme immunoassay, we investigated whether serum pro-MMP2 levels could be predictors of the development and extension of thymoma. METHODS: The subjects of this study were 33 patients with thymoma and 26 patients with nonmalignant thoracic disease. RESULTS: Serum pro-MMP2 levels were elevated in patients with stage IV thymoma (938.6+/-80.2ng/ml) compared with those in the controls (P = 0.03). Patients with stage IVb thymoma had significantly higher serum pro-MMP2 levels than patients with other stages, being 1088.7+/-440ng/ml in stage IVb, 686.0+/-74.0ng/ml in stage I (P = 0.01), 685.8+/-48.6ng/ml in stage II (P = 0.01), and 691.7+/-74.0 ng/ml in stage III (P = 0.02). Serum pro-MMP2 levels were elevated in patients with polygonal cell type thymoma compared with those with mixed cell type thymoma, being 823.1+/-55.5ng/ml vs 613.6+/-59.9ng/ml, respectively (P = 0.04). Using the reference limit of 850ng/ml (mean +/- 2SD) set from analyses in the control group, all patients who had pro-MMP2 levels below the cutoff level survived. On the other hand, four of nine patients who had an elevated pro-MMP2 level died from recurrence. CONCLUSION: Serum pro-MMP2 levels may serve as a marker that could be used as an indicator of distant metastases in thymoma. Elevated pro-MMP2 levels may be correlated with poor survival.
Biomarkers, Tumor↗
Elevated serum pro-mMP2 levels in patients with advanced lung cancer are not suitable as a prognostic marker.
Using the one-step sandwich enzyme immunoassay for pro-MMP2, we investigated whether the serum pro-MMP2 levels could be used as predictors of the development and extension of lung cancer. The study included 52 lung cancer patients and 26 nonmalignant thoracic disease patients. Serum samples were collected before clinical treatment. The serum pro-MMP2 levels were found to be elevated in patients with lung cancer (1006.3+/-37.4 ng/ml) in comparison with nonmalignant controls (767.7+/-41.6 ng/ml) (P = 0.0002). In addition, stage IIIb lung cancer patients (1167.2+/-124.2 ng/ml) had significantly higher pro-MMP2 levels compared with stage I patients (936.0+/-44.8 ng/ml, P = 0.0431). The serum pro-MMP2 levels were similar in the samples between the pathological subtypes. As a result, the serum pro-MMP2 levels may serve as a marker that can be used as a diagnostic indicator of higher stages in lung cancer. There was no difference in the prognosis between the group with normal pro-MMP2 levels (<850 ng/ml) and the group of elevated pro-MMP2 levels (>850 ng/ml), thus indicating that serum analyses of the pro-MMP2 levels were of limited value in the prognosis of lung cancer.
Biomarkers, Tumor↗
Sclerosing hemangioma with metastases to multiple nodal stations.
We present a case of a large pulmonary sclerosing hemangioma with metastases to multiple lymph nodal stations and suspected contralateral pulmonary metastasis. Four cases (including the present) have been reported to have lymph node metastasis, and all had large tumors exceeding 3.5 cm in diameter. Accordingly, resection of sclerosing hemangioma is advisable while the tumor is small. Even in cases with a large sclerosing hemangioma, lymph node metastasis may be uncommon. However lymph node dissection may be necessary to detect lymph node metastasis in selected cases.
Aged↗