Takeshi Ebara

Effect of radiation on the expression of E-cadherin and α-catenin and invasive capacity in human lung cancer cell line in vitro ☆

PURPOSE To investigate the effect of radiation on E-cadherin and alpha-catenin expression in a human lung cancer cell line, and also evaluate invasive capacity in the membrane invasion culture system using the Boyden Chamber. MATERIALS AND METHODS The immunoblot and immunofluorescence analyses were performed using the human lung cancer cell line A549 to examine altered expression of E-cadherin and alpha-catenin after irradiation. We also compared invasive capacity of untreated cells with that of irradiated cells. RESULTS Immunoblot analysis revealed that the expression of E-cadherin increased after irradiation. In a time-course analysis, the expression was increased 6 h after irradiation with 10 Gy and reached its peak level at 24 h, being 2.3 times the control value, whereas expression at 1 and 3 h after irradiation was almost equivalent to that of the control. A slight increase in expression was observed after irradiation of 2 Gy and the expression reached peak levels after 5 Gy. After fractionated irradiation, the increase in expression of both E-cadherin and alpha-catenin was observed, and the alteration of alpha-catenin was more prominent than that after a single irradiation of the same total dose. In the immunofluorescence study for E-cadherin antibody analyzed by confocal laser scanning microscopy, increased intensity in irradiated cells produced as a nondisrupted and continuous line at cell-cell contact sites. In an invasive assay, the number of migrated cells in irradiated cells after a dose of 5 and 10 Gy was reduced significantly compared to untreated cells. CONCLUSION The results indicate that irradiation of A549 increased the expression of E-cadherin, possibly preserving their functional property.

Long-term results of curative intraluminal high dose rate brachytherapy for endobronchial carcinoma

BackgroundThe treatment strategy of central lung tumors is not established. Intraluminal brachytherapy (ILBT) is widely used for palliative treatment of endobronchial tumors, however, it is also a promising option for curative treatment with limited data. This study evaluates the results after ILBT for endobronchial carcinoma.MethodSixteen-endobronchial carcinoma of 13 patients treated with ILBT in curative intent for 2000 to 2008 were retrospectively reviewed. ILBT using high dose rate 192 iridium thin wire system was performed with 5 Gy/fraction at mucosal surface. The patient age ranged from 57 to 82 years old with median 75 years old. The 16 lesions consisted of 13 central endobronchial cancers including 7 roentgenographically occult lung cancers and 3 of tracheal cancers. Of them, 10 lesions were treated with ILBT of median 20 Gy combined with external beam radiation therapy of median 45 Gy and 6 lesions were treated with ILBT alone of median 25 Gy.ResultsMedian follow-up time was 32.5 months. Two-year survival rate and local control rate were 92.3% and 86.2%, respectively. Local recurrences were observed in 2 lesions. Three patients died due to lung cancer (1 patient) and intercurrent disease (2 patients). Complications greater than grade 2 were not observed except for one grade 3 dyspnea.ConclusionsILBT combined with or without EBRT might be a curative treatment option in inoperable endobronchial carcinoma patients with tolerable complication.

Phase II study of oral S-1 and cisplatin with concurrent radiotherapy for locally advanced non-small-cell lung cancer

PURPOSE To determine the efficacy and safety of oral S-1 in combination with cisplatin and thoracic radiotherapy in patients with unresectable stage III non-small-cell lung cancer (NSCLC). METHODS AND MATERIALS S-1 (50mg/m(2)) was administered orally twice daily for 14 days, with cisplatin (40 mg/m(2)) on days 1 and 8 of each cycle every 3 weeks, for 2-4 cycles. Thoracic radiation therapy was administered in 2 Gy fractions five times weekly for a total dose of 60 Gy. The primary endpoint was the response rate, and secondary endpoints included progression-free survival, overall survival and safety. RESULTS Forty-one patients were enrolled in this study. The objective response rate was 87.8% (98% CI: 77.8-97.8%). The median progression-free survival was 467 days (15.4 months), and the median survival time was 904 days (29.7 months). The overall survival rates at 1- and 2-years were 85.7% and 52.9%, respectively. Hematological toxicities included grade 3/4 neutropenia (17%) and grade 3/4 leukopenia (27%). No grade 3 febrile neutropenia was detected, and grade 3/4 non-hematological toxicities were also mild. A grade 3 gastrointestinal hemorrhage was observed in one patient. CONCLUSIONS The combination of oral S-1 plus cisplatin with concurrent radiotherapy is a promising treatment with a high efficacy and lower toxicity in patients with locally advanced NSCLC.

Usefulness of Intraluminal Brachytherapy Combined With External Beam Radiation Therapy for Submucosal Esophageal Cancer: Long-Term Follow-Up Results

PURPOSE To assess the efficacy of radiation therapy (RT) by using intraluminal brachytherapy (IBT) combined with external beam RT (EBRT) for submucosal esophageal cancer. METHODS AND MATERIALS Between 1991 and 2005, 59 consecutive patients received definitive RT without chemotherapy. IBT was performed after patients completed EBRT as a booster therapy for 17 patients, using low-dose-rate Cs-137 sources until 1997, and for 19 patients, using high-dose-rate Ir-192 sources thereafter. The long-term outcomes were investigated with a median follow-up time of 61 months. RESULTS Logoregional recurrences and distant metastases were observed in 14 patients and in 2 patients in the lung, respectively, and 5 patients were rescued by salvage treatments. The 5-year logoregional control and cause-specific survival rates were 75% and 76%, respectively. The 5-year cause-specific survival rate in the EBRT group was 62%, whereas the corresponding rate in the IBT group was 86% (p = 0.04). Multivariate analysis revealed that IBT was the most powerful predictor of survival but did not reach a significant level (p = 0.07). There were five esophageal ulcers in the IBT group, but no ulcers developed with small fractions of 3 Gy. Grade 2 or higher cardiorespiratory complications developed in 2 patients (5.6%) in the IBT group and in 3 patients (13.0%) in the EBRT group. CONCLUSIONS Combining IBT with EBRT is suggested to be one of the preferable treatment modalities for medically inoperable submucosal esophageal cancer because of its preferable local control and survival probabilities, with appreciably less morbidity.

Intraoperative radiotherapy for resectable extrahepatic bile duct cancer

PURPOSE Through a retrospective study of intraoperative radiation therapy (IORT) in bile duct cancer, we hope to help clarify its clinical usefulness. METHODS AND MATERIALS Between 1976 and 1996, IORT was carried out in 35 patients with bile duct cancer at the Tokyo Metropolitan Komagome Hospital. Of the 35 patients, resection proved to be curative in 15. Intraoperative irradiation of 15-30 Gy (average 20.1 Gy) was delivered by electron beam in the 5- to 19-MeV energy ranges. Postoperative external-beam radiation therapy (EBRT) was also delivered in 16 patients. The EBRT was fractionated to 2 Gy/day, in principle, and was delivered at 8.8-54 Gy (average 40.4 Gy) by 10-MV X-rays. RESULTS The median survival in our patients was 19 months. The 1-year, 2-year, and 5-year survival rates were 57%, 43%, and 19%, respectively. Statistical analysis identified the following prognostic factors: performance status, curative surgical resection, lymph node metastasis, IORT dosage, and treatment period. Only 1 patient (3%) died within 30 days after surgery, and the incidence of late-onset complications was 21%. CONCLUSION The combination of IORT and EBRT is useful for patients with bile duct cancer who undergo noncurative resection or who have lymph node metastasis.

Rectal bleeding after high-dose-rate brachytherapy combined with hypofractionated external-beam radiotherapy for localized prostate cancer: the relationship between dose-volume histogram parameters and the occurrence rate.

PURPOSE To determine the predictive risk factors for Grade 2 or worse rectal bleeding after high-dose-rate brachytherapy (HDR-BT) combined with hypofractionated external-beam radiotherapy (EBRT) for prostate cancer using dose-volume histogram analysis. METHODS AND MATERIALS The records of 216 patients treated with HDR-BT combined with EBRT were analyzed. The treatment protocols for HDR-BT were 5 Gy × five times in 3 days or 7 Gy × three, 10.5 Gy × two, or 9 Gy × two in 2 days. The EBRT doses ranged from 45 to 51 Gy with a fractional dose of 3 Gy. RESULTS In 20 patients Grade 2 or worse rectal bleeding developed, and the cumulative incidence rate was 9% at 5 years. By converting the HDR-BT and EBRT radiation doses into biologic effective doses (BED), the BED(3) at rectal volumes of 5% and 10% in the patients who experienced bleeding were significantly higher than those in the remaining 196 patients. Univariate analysis showed that a higher rectal BED(3-5%) and the use of fewer needles in brachytherapy were correlated with the incidence of bleeding, but BED(3-5%) was found to be the only significant factor on multivariate analysis. CONCLUSIONS The radiation dose delivered to small rectal lesions as 5% is important for predicting Grade 2 or worse rectal bleeding after HDR-BT combined with EBRT for prostate cancer.

Phase I study of oral S-1 plus Cisplatin with concurrent radiotherapy for locally advanced non-small-cell lung cancer.

PURPOSE To determine the maximum tolerated dose (MTD) and recommended dose (RD) of S-1 in combination with cisplatin and thoracic radiotherapy in patients with unresectable Stage III non-small-cell lung cancer (NSCLC). METHODS AND MATERIALS S-1 was administered orally twice daily for 14 days and cisplatin on Days 1 and 8 of each cycle; this was repeated every 3 weeks. Doses of each drug were planned as follows: level 0, 50/40; level 1, 60/40; level 2, 70/40; level 3, 80/40 (S-1 [mg/m(-2)/day(-1)]/cisplatin [mg/m(-2)/day(-1)]). Thoracic radiation therapy was administered in 2 Gy fractions five times weekly to a total dose of 60 Gy. RESULTS Ten patients were enrolled in this study. All patients received 60 Gy of thoracic radiotherapy and 7 (70%) patients received four cycles of chemotherapy. At level 1, 2 of 3 patients experienced a delay exceeding 10 days in the cisplatin administration of Day 29. Grade 4 neutropenia and Grade 3 fever occurred in 1 and 1 patients, respectively. Nonhematologic toxicities were mild. None developed >or=Grade 3 esophagitis or lung toxicity. At level 0, 2 of 7 patients developed dose-limiting toxicity. Thus, level 1 was considered the MTD and Level 0 was selected as the RD. Objective responses were seen in all patients. CONCLUSIONS The RD is the level 0 dose, and this regimen is a feasible and well-tolerated regimen for the treatment of patients with Stage III NSCLC.

Change in E-cadherin expression after X-ray irradiation of a human cancer cell line in vitro and in vivo

PURPOSE To investigate changes in E-cadherin expression after X-ray irradiation of a human cancer cell line in vitro and in vivo. METHODS AND MATERIALS E-cadherin expression on a human squamous cell carcinoma of the thyroid gland (T-SCC cell), which was established in our laboratory, at 24 h after graded single doses of irradiation and at 7 successive times after 10-Gy irradiation were investigated in vitro by immunoblot analysis with the monoclonal antibody to human E-cadherin. The changes in E-cadherin expression caused by irradiation of T-SCC tumors that were transplanted into athymic nude mice were also determined in vivo by immunohistochemical staining and immunoblot analysis in a similar fashion to that in vitro. RESULTS In vitro studies revealed that E-cadherin expression had increased significantly on T-SCC cells at 24 h after irradiation with doses of 2 to 10 Gy and that, in a time-course analysis, the expression had increased significantly at 3 to 72 h after irradiation compared with an unirradiated control cell, although it was not observed at 1 h after irradiation. In in vivo studies, a significant increase in E-cadherin expression was observed at 24 h after irradiation with 5 and 10 Gy by immunohistochemical staining and time-course studies demonstrated that E-cadherin increased temporarily at 12 to 24 h after 10-Gy irradiation; however, immunoblot analysis did not show alteration of E-cadherin expression by irradiation. CONCLUSION X-ray irradiation upregulated E-cadherin expression on T-SCC cells in vitro and in vivo.

Primary mediastinal synovial sarcoma: a report of 2 cases.

Synovial sarcoma is the third most common histological type of extremity soft tissue sarcoma. However, primary mediastinal synovial sarcoma is extremely rare. We present 2 cases of unresectable primary mediastinal synovial sarcoma. The radiographic imaging of our present cases was characteristic of a heterogeneously enhancing mass. They were treated with radiotherapy and chemotherapy. However, there was complete obstruction of esophagus resulting from progressive diseases. The radiographic findings and treatment were discussed.

A seven-year disease-free survivor of malignant pleural mesothelioma treated with hyperthermia and chemotherapy: a case report

IntroductionMalignant pleural mesothelioma was once a rare finding but its incidence is increasing worldwide, most likely because of widespread exposure to asbestos. Although complete surgical resection is considered the only curative treatment, the results of surgery have shown a median survival time of only one year. In inoperable cases, chemotherapy, radiotherapy, and a combination of both have been considered as palliative therapy. Therefore, outcomes for inoperable cases have been poor. Here, we report the case of a long-term survivor treated with hyperthermia and chemotherapy.Case presentationA 61-year-old Japanese man with a performance status of 1 due to chest pain was referred to our hospital. He had a history of asbestos exposure for approximately five years. A computed tomography scan showed diffuse extensive right pleural thickening with small nodular lesions, and video-assisted thoracoscopy revealed tumor invasion of the ipsilateral chest wall muscles. The histopathologic findings were consistent with a diagnosis of malignant pleural mesothelioma (sarcomatoid type). The tumor was diagnosed as being stage cT3N0M0. Our patient refused any invasive therapies including surgery and radiotherapy, and was therefore treated with hyperthermia and systemic chemotherapy with agents such as cisplatin and irinotecan. He underwent three hyperthermia sessions and a single course of chemotherapy without any severe complications. One month after treatment, a follow-up computed tomography scan showed no definitive abnormality in the thoracic space. Our patient has subsequently survived without any evident disease for more than seven years.ConclusionsThe combination of hyperthermia and chemotherapy may be a novel and safe therapeutic option for malignant pleural mesothelioma, and can be considered for patients ineligible for radical treatment. Further clinical studies of the combination of hyperthermia and chemotherapy are needed to confirm the effects of this treatment on malignant pleural mesothelioma.