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Kohei Yokoi

Publications and source records attributed to Kohei Yokoi.

15 recordsLinked to original sources
PubMed2007

RhoB is frequently downregulated in non-small-cell lung cancer and resides in the 2p24 homozygous deletion region of a lung cancer cell line.

Identification of a homozygous deletion in cancer cells provides strong evidence for the location of a tumor suppressor gene (TSG). We analyzed the 2p24 homozygous deletion of a non-small-cell lung cancer (NSCLC) cell line, NCI-H2882, and found that the deletion size was 3.7 Mbp. Since RhoB, which has been suggested to be a candidate TSG, was located in this region, we analyzed RhoB for alterations in NSCLC. Although we found no mutations in 48 cell lines including 20 NSCLCs, a loss of heterozygosity (LOH) analysis in 128 primary NSCLCs showed that 25 of 62 informative samples had LOH at the RhoB locus. Northern blot analysis of 28 cell lines (including 15 NSCLCs) indicated that RhoB expression was downregulated in 27. We analyzed RhoB expression in 112 primary NSCLCs with immunohistochemistry and found no or a weak RhoB expression in 33 (42%) of 78 adenocarcinomas, whereas we found it in 29 (94%) of 31 squamous cell carcinomas. No or a weak expression of RhoB was more frequently observed in poorly- or moderately-differentiated adenocarcinomas than in well-differentiated ones (p = 0.0014). Furthermore, no or a weak expression of RhoB indicated a tendency to poor patient prognosis. Although hypermethylation was not found at the promoter region, the RhoB expression in NSCLC cell lines was induced by histone deacetylase inhibition, suggesting that RhoB downregulation may be due to histone modification. The present study demonstrates that RhoB expression is frequently downregulated in NSCLCs by multiple mechanisms, suggesting that RhoB is a candidate TSG for NSCLC.

Aged↗
PubMed2006

Establishment and characterization of four malignant pleural mesothelioma cell lines from Japanese patients.

Malignant pleural mesothelioma (MPM) is an asbestos-related malignancy that is highly resistant to current therapeutic modalities. We established four MPM cell lines (ACC-MESO-1, ACC-MESO-4, Y-MESO-8A and Y-MESO-8D) from Japanese patients, with the latter two from the same patient with biphasic-like characteristics of MPM, showing epithelial and sarcomatous phenotypes, respectively, in cell culture. These cells grew well in RPMI-1640 medium supplemented with 10% fetal bovine serum under 5% CO2. Mutation and expression analyses demonstrated that the tumor suppressor gene NF2, which is known to be one of the most frequently mutated in MPM, is mutated in ACC-MESO-1. We detected homozygous deletion of p16INK4A/p14ARF in all four MPM cell lines. However, mutations of other tumor suppressor genes, including TP53, and protooncogenes, including KRAS, NRAS, BRAF, EGFR and HER2, were not found in these cell lines. Polymerase chain reaction amplification of the simian virus 40 sequence did not detect any products. We also analyzed genetic alterations of six other MPM cell lines and confirmed frequent mutations of NF2 and p16INK4A/p14ARF. To characterize the biological differences between Y-MESO-8A and Y-MESO-8D, we carried out cDNA microarray analysis and detected genes that were differentially expressed in these two cell lines. Thus, our new MPM cell lines seem to be useful as new models for studying various aspects of the biology of human MPM as well as materials for the development of future therapies.

Adenocarcinoma↗
PubMed2006

EGFR point mutation in non-small cell lung cancer is occasionally accompanied by a second mutation or amplification.

Activating mutations of EGFR are found frequently in a subgroup of patients with non-small cell lung cancer (NSCLC) and are highly correlated with the response to gefitinib and erlotinib. In the present study, we searched for mutations of EGFR, HER2 and KRAS in 264 resected primary NSCLC from Japanese patients and determined whether there is a correlation between genetic alterations of these genes and clinicopathological factors, together with 85 tumors that we reported previously. EGFR mutations were found in 102 of the total 349 tumors, and seven tumors had two missense mutations. Reverse transcription-polymerase chain reaction of EGFR and subsequent subcloning analyses identified that the double mutations occurred in the same allele. Furthermore, in 202 NSCLC analyzed by Southern blotting, we identified 11 tumors with gene amplification of EGFR, with eight tumors containing a mutation in EGFR. Sequence analysis detected only weak or no signals of the wild-type allele in the eight tumors, strongly suggesting that the mutated allele was amplified selectively. These findings indicate that a dual genetic change of EGFR can occur in the same allele either with a possible second-hit mutation or with amplification, which may imply a more selective growth advantage in a cancer cell. Meanwhile, HER2 mutations and amplifications were found in six of 349 tumors and three of 202 tumors, respectively, and KRAS mutations in 21 of 349 tumors. Mutations of the EGFR and HER2 genes were more frequently found in female never or light-smoking patients with adenocarcinoma, and there were no tumors that had two or more mutations simultaneously among EGFR, HER2 and KRAS. The current study further demonstrates that a double genetic event in EGFR can occasionally occur in lung cancer, thus providing new clues for understanding the involvement of epidermal growth factor receptor signaling cascades in the pathogenesis of NSCLC.

Adult↗
PubMed2005

Transcriptional silencing of secreted frizzled related protein 1 (SFRP 1) by promoter hypermethylation in non-small-cell lung cancer.

Secreted frizzled related protein 1 (SFRP 1) is an antagonist of the transmembrane frizzled receptor, a component of the Wnt signaling pathway, and has been suggested to be a candidate tumor suppressor in several human malignancies. Since SFRP 1 is located at chromosome 8 p 11, where lung cancers also exhibit frequent allelic loss, we hypothesized that the inactivation of SFRP 1 is also involved in lung carcinogenesis. To substantiate this, we performed mutational analysis of SFRP 1 for 29 non-small-cell lung cancer (NSCLC) and 25 small-cell lung cancer (SCLC) cell lines, and expression analysis for the same cell lines. Although somatic mutations were not detected in the coding sequence, downregulation of SFRP 1 was observed in 14 (48%) NSCLC and nine (36%) SCLC cell lines. We analysed epigenetic alteration of the SFRP 1 promoter region and detected hypermethylation in 15 (52%) of 29 NSCLC cell lines, two (8%) of 25 SCLC cell lines, and 44 (55%) of 80 primary lung tumors. By comparing the methylation status with SFRP 1 expression, we found a significant correlation between them. We also performed loss of heterozygosity (LOH) analysis and found that 15 (38%) of 40 informative surgical specimens had LOH in the SFRP 1 gene locus. Furthermore, we performed colony formation assay of two NSCLC cell lines (NCI-H 460 and NCI-H 2009) and found the reduction of colony formation with SFRP 1 transfection. In addition, we also detected that SFRP 1 inhibits the transcriptional activity of beta-catenin, which is thought to be a downstream molecule of SFRP 1, with luciferase reporter assay. Our current studies demonstrated that the SFRP 1 gene is frequently downregulated by promoter hypermethylation and suppresses tumor growth activity of lung cancer cells, which suggests that SFRP 1 is a candidate tumor suppressor gene for lung cancer.

Base Sequence↗
PubMed2005

Mutations of epidermal growth factor receptor of non-small cell lung cancer were associated with sensitivity to gefitinib in recurrence after surgery.

The epidermal growth factor receptor (EGFR) gene has recently been reported to be mutated in a subset of non-small cell lung cancers (NSCLC), with the mutations being correlated with the patients' drug sensitivity to gefitinib, an EGFR kinase inhibitor. In this study, we searched for EGFR mutations in patients with lung cancer using primary tumor specimens obtained at initial surgery and examined whether their recurrent tumors showed a response to gefitinib depending on the presence of the activating mutation. Among 12 lung cancers that were treated with gefitinib after recurrence, we found that all four tumors which showed a response to gefitinib had an activating mutation in EGFR, whereas none of the remaining eight tumors had a mutation. Southern blot analysis showed that two of the four responsive tumors had the EGFR gene amplification. We also examined another 73 NSCLC specimens (47 males and 26 females; 53 adenocarcinomas and 20 non-adenocarcinomas) which were not treated with gefitinib to determine whether NSCLCs with an EGFR mutation have different clinicopathological properties and/or unique genetic alterations of the other cancer-associated genes. We found that 13 (18%) of 73 tumors had a mutation of the EGFR gene, with the most being detected in female adenocarcinomas. Comparing the alterations in KRAS and P53 with the EGFR mutation, we found that 10 tumors with the KRAS mutation did not have an EGFR mutation, suggesting that each mutation occurs exclusively during the development of lung cancer. These results suggest that the mutation analysis of the EGFR gene using the specimens obtained at surgery might be useful in selecting the appropriate treatment(s) for recurrent lung cancer patients.

Adenocarcinoma↗
PubMed2005

Catamenial pneumothorax in a pregnant patient.

We report the case of a 29-year-old woman who experienced recurrence of catamenial pneumothorax during pregnancy. Pneumothorax unrelated to the hormonal cycle occurred by pulmonary endometriosis. Thoracoscopic resection of cystic lesions and pleurodesis effectively controlled the pneumothorax.

Adult↗
PubMed2005

Risk of pleural recurrence after needle biopsy in patients with resected early stage lung cancer.

BACKGROUND: Concerning the complications resulting from percutaneous needle biopsy (PNB), although cases of tumor seeding into the needle track have occasionally been reported, there were only two cases of pleural recurrences to date. The aim of this study was to elucidate the real risk of pleural recurrence after needle biopsy in patients with resected early stage lung cancer. METHODS: Between 1986 and 2000, 335 patients with stage I nonsmall cell lung cancer underwent complete resection of the lung tumor. We retrospectively reviewed their medical records and investigated the relationship between the diagnostic methods used and the cancer recurrence patterns. RESULTS: Preoperative diagnoses were obtained for 290 patients; 220 were diagnosed by bronchoscopy and 66 by PNB. Among the patients without a preoperative diagnosis, 27 were diagnosed by intraoperative needle biopsy and 14 by wedge resection of the lung. Tumors diagnosed by needle biopsy including PNB and intraoperative needle biopsy were smaller and showed less vessel invasion than those diagnosed by other methods (p < 0.01). After surgical resection, 9 patients had pleural recurrence and 1 patient, needle track implantation. Seven of these 10 patients were diagnosed by needle biopsy using 18G cutting type needle. Pleural recurrence or needle track implantation was observed for 8.6% of the patients who underwent a needle biopsy, whereas it was 0.9% for patients who were examined using other diagnostic modalities (p = 0.0009). CONCLUSIONS: Needle biopsy especially using a cutting-type biopsy needle can cause a pleural recurrence in addition to needle track implantation.

Adult↗
PubMed2004

Objective definition and measurement method of ground-glass opacity for planning limited resection in patients with clinical stage IA adenocarcinoma of the lung.

OBJECTIVE: The standard operation for patients with stage IA lung adenocarcinoma is considered to be a lobectomy. Recently, some researchers have reported that patients with tumors showing greater proportions of ground-glass opacity (GGO) at computed tomography (CT) could be candidates for limited resection, because of its less aggressive nature. However, the lack of a precise definition or standard measuring method of GGO prevents its general use as an index for planning limited resection. Therefore, we attempted to define GGO based on CT number and measured it more objectively. METHODS: Between 1998 and 2001, 90 patients with clinical stage IA adenocarcinoma, who underwent standard or intentional limited resection and whose images of chest high-resolution CT were preserved in Digital Imaging and Communications in Medicine (DICOM) format, constituted the study population. The tumor shadow seen on the solid window (WL, -160HU; WW, 2HU) was regarded as the central solid area of the tumor seen on the lung window, and GGO was defined as the whole tumor area with the exception of the central solid area. Each area was measured using Scion Image (Scion Corp., Frederick, MD). We analyzed the relationship between the proportion of GGO and both of pathologic findings and recurrence. RESULTS: Among the 90 tumors, 31 (34.4%) were calculated to have a GGO area greater than or equal to 50%. Of these, 27 (87%) tumors were bronchioloalveolar carcinoma. Lymphatic and vascular invasions, or nodal involvement were found only in patients with a smaller proportion of GGO (<50%) (P < 0.05). During the follow-up period (median 36 months), recurrences occurred in eight patients who were diagnosed as having tumors showing smaller proportion of GGO (<50%). CONCLUSIONS: Tumors with a greater proportion of GGO measured by our method are thought to have a less invasive nature. Our objective measuring method of GGO could be useful for future multicenter trials to elucidate the value of limited resection for clinical stage IA adenocarcinoma based on the proportion of GGO.

Adenocarcinoma↗
PubMed2004

Pulmonary metastases from uterine malignancies: results of surgical resection in 133 patients.

OBJECTIVE: The long-term results of the surgical treatment for patients with pulmonary metastases from uterine malignancies were clarified. METHODS: A total of 133 patients who underwent pulmonary metastasectomy for uterine malignancies were enrolled in the Metastatic Lung Tumor Study Group of Japan between March 1984 and February 2002. These patients constituted the study population, and their clinical, pathologic, and prognostic data were retrospectively analyzed. RESULTS: The morbidity and mortality rates related to the operation were minimal (1% and 1%, respectively). The 5- and 10-year survivals after the surgical resection in all cases were 54.6% and 44.9%, respectively. The 5-year survivals for each histologic type were estimated to be 46.8% for squamous cell carcinoma (n = 58), 40.3% for cervical adenocarcinoma (n = 13), 75.7% for endometrial adenocarcinoma (n = 23), 86.5% for choriocarcinoma (n = 16), and 37.9% for leiomyosarcoma (n = 11). In the univariate analysis, the following were shown to be associated with poor survival: primary tumor in the cervix, short disease-free interval (<12 months), large number of resected metastases (> or =4), and large tumor size (> or =3 cm). After mutual adjustment, short disease-free interval (<12 months) alone was related to risk of death (hazard ratio = 2.26, 95% confidence interval = 1.06-4.78) for 105 patients, excluding patients with choriocarcinoma and miscellaneous histologic types. CONCLUSION: Pulmonary metastasectomy for uterine malignancies is a safe and acceptable treatment to improve survival. Patients with a disease-free interval of 12 months or more are good candidates for this treatment if there is adequate control of the primary tumor without extrapulmonary metastasis.

Adenocarcinoma↗
PubMed2004

[Extrapleural pneumonectomy for thoracic malignancies].

Extrapleural pneumonectomy has been used by thoracic surgeons in the treatment of malignant pleural mesothelioma as well as other pleural diseases, such as tuberculous empyema. Recently, this operative procedure has been also sporadically applied for the treatment of carcinomatous pleuritis of lung cancer and/or invasive thymoma in some institutions. We performed this operation in 24 patients with thoracic malignancy: 15 patients with carcinomatous pleuritis of primary lung adenocarcinoma (6 patients with T4N0 disease, 2 with T4N1, and 7 with T4N2), 3 patients with stage IV a thymoma, and 6 patients with malignant pleural mesothelioma (2 patients with stage II disease, 3 with stage III, and 1 with stage IV). All patients survived the operation and were discharged from the hospital. Major complications were intrathoracic hemorrhage and empyema in 2 patients each. The median survival time and 5-year survival rate of lung cancer patients were 34 months and 45.5%, respectively. All patients with thymoma are alive now without disease 9 to 133 months after operation. All patients with malignant pleural mesothelioma except 1, who lately underwent this treatment, died of disease from 15 to 27 months after surgery. Our results indicate that carefully selected patients with carcinomatous pleuritis of lung cancer and thymoma may be candidates for extrapleural pneumonectomy for cure. Nevertheless, the ultimate value of this surgical treatment should be ascertained in a prospective study with a large number of patients.

Adult↗
PubMed2002

A prematurely terminated phase III trial of intraoperative intrapleural hypotonic cisplatin treatment in patients with resected non-small cell lung cancer with positive pleural lavage cytology: the incidence of carcinomatous pleuritis after surgical intervention.

BACKGROUND: The prognosis of patients with resected non-small cell lung cancer without carcinomatous pleuritis whose intrapleural cancer cells were detected by means of a cytologic examination of pleural lavage fluid obtained immediately after a thoracotomy has been reported to be poor. METHODS: The Japan Clinical Oncology Group conducted a phase III trial for a 3-year period starting from October 1994 to determine whether intraoperative intrapleural hypotonic cisplatin treatment could effectively control pleural disease and thereby prolong the survival of these patients. The patients were randomized to receive either intraoperative intrapleural hypotonic cisplatin treatment or no treatment before closure of the open thorax. The intraoperative intrapleural hypotonic cisplatin treatment consisted of exposing the entire thorax to cisplatin (50 microg/mL) in distilled water for 15 minutes. RESULTS: Because of the slow registration pace, the study was prematurely terminated in January 1998. During the 41-month period from the start of the registration, 49 patients were entered into the study, and all were eligible. Twenty-five and 24 patients were randomly assigned to the treatment and control groups, respectively. No statistically significant difference in the overall survival and disease-free survival between the 2 groups was observed. However, the appearance of carcinomatous pleuritis was suppressed by the hypotonic cisplatin treatment (42% of the control group vs 8% of the treatment group, P =.008). CONCLUSIONS: Although the randomized trial was prematurely terminated, the intraoperative intrapleural hypotonic cisplatin treatment was found to effectively suppress the appearance of carcinomatous pleuritis in resected patients who demonstrated a positive pleural lavage cytology finding.

Aged↗
PubMed2002

Proportion of ground-glass opacity on high-resolution computed tomography in clinical T1 N0 M0 adenocarcinoma of the lung: A predictor of lymph node metastasis.

OBJECTIVE: In patients with clinical T1 N0 M0 lung adenocarcinoma, we investigated whether the proportion of ground-glass opacity area measured on high-resolution computed tomography was valuable for predicting the existence of lymph node metastasis, lymphatic invasion, or vascular invasion. METHODS: Between 1994 and 1999, 111 patients with clinical stage IA adenocarcinoma underwent surgical resection of the lung at our hospital. Of these, 96 patients received high-resolution computed tomography of the chest, and they constituted the study population. The tumors were semiquantitatively classified into 5 groups on the basis of the proportion of ground-glass opacity area to whole tumor shadow on high-resolution computed tomography: group I, 0%; group II, 1% to 25%; group III, 26% to 50%; group IV, 51% to 75%; and group V, 76% to 100%. Correlations of computed tomographic findings, pathologic results of lymph node metastasis and lymphatic and vascular invasion, and the histologic subtype according to the new World Health Organization classification were examined. We also investigated the characteristics of the patients with ground-glass opacity areas on high-resolution computed tomography and their value for predicting lymph node metastasis. RESULTS: Among the 96 patients, 15 (15.6%) had mediastinal lymph node metastases, and 3 (3.1%) had hilar node metastases. Regarding the proportion of the ground-glass opacity area of the tumors, 15 (15.6%) tumors were classified as group V, 11 (11.5%) as group IV, 9 (9.3%) as group III, 22 (22.9%) as group II, and 39 (40.6%) as group I, respectively. Of the 18 patients with lymph node metastases, no patients were found in groups IV and V, 2 (22.2%) were found in group III, 4 (18.2%) were found in group II, and 12 (30.8%) were found in group I (trend P =. 003), respectively. Twenty-six patients classified into groups IV and V also showed neither lymphatic invasion nor recurrence. All the smaller tumors (< or =2.0 cm) in group IV or V were histologically proved to be bronchioloalveolar carcinoma. Adjusted for smoking status and other characteristics, patients without ground-glass opacity on high-resolution computed tomography had a significantly increased risk of concurrent lymph node metastasis compared with those with ground-glass opacity. CONCLUSION: In patients with clinical T1 N0 M0 adenocarcinoma, the proportion of ground-glass opacity area on thin-section computed tomography scans was a strong predictor for tumor aggressiveness and thus could be a useful index for planning limited surgical resection for these patients.

Adenocarcinoma↗