Radiation-induced dimer formation of EGFR: implications for the radiosensitizing effect of cetuximab.

AIM: The purpose of this study was to investigate whether radiation induces ligand-independent dimerization of epidermal growth factor receptor (EGFR) and explore the possible role of radiation-induced receptor dimerization in the radiosensitizing effect of cetuximab. MATERIALS AND METHODS: The human vulvar squamous cell carcinoma cell line A431 was used. The dimerization and activation of EGFR were quantified using immunoprecipitation, a western blotting analysis, and a chemical cross-linking analysis with dithiobis-sulfosuccinimidyl propionate. RESULTS: Irradiation at a dose of 2 Gy induced the autophosphorylation of EGFR. Consistent with autophosphorylation, a 360-kDa polypeptide, corresponding to the size of the EGFR dimer, was detected in addition to an EGFR monomer. Radiation also induced hetero-dimerization between EGFR and HER2/neu. Cetuximab combined with radiation inhibited radiation-induced autophosphorylation of EGFR, and inhibited radiation-induced homo-dimerization of EGFR. However, cetuximab incompletely inhibited radiation-induced hetero-dimerization between EGFR and HER2. CONCLUSION: The results of this investigation suggest that radiation-induced homo- and/or hetero-dimerization between EGFR and/or HER2 might be involved in the radioresponse of cancer cells.

Clinical usefulness of CYFRA 21-1 for esophageal squamous cell carcinoma in radiation therapy.

AIM: The aim of this study was to examine the clinical usefulness of cytokeratin 19 fragments (CYFRA 21-1) compared with squamous cell carcinoma (SCC) antigen in patients with esophageal cancer treated with radiation therapy. METHODS: Fifty-one patients with stage I-IV esophageal cancer were evaluated. CYFRA 21-1 and SCC antigen serum levels were measured at the start and the end of radiation therapy. RESULTS: CYFRA 21-1 (> 3.5 ng/mL) and SCC antigen (> 1.5 ng/mL) before radiation therapy were elevated in 63% and 53% of the patients, respectively. The CYFRA 21-1 levels were significantly correlated with TNM stages, tumor depth and lymph node metastasis (P = 0.0003, P = 0.019 and P = 0.019, respectively), whereas no correlation was observed between SCC antigen and these factors. The values of CYFRA 21-1 in all patients who survived without recurrence were under the cutoff level at the end of treatment, but the values in all patients with locoregional recurrence were above the level. However, there was no significant correlation between SCC antigen level at the end of treatment and any clinical outcome. CONCLUSIONS: The results suggest that the evaluation of CYFRA 21-1 would be useful not only for assessment before radiation therapy but also for monitoring after radiation therapy in the treatment for esophageal cancer.

An eight-year survivor with multiple brain metastases of non-small cell lung cancer: an autopsy case.

BACKGROUND: Patients with brain metastases of non-small cell lung cancer (NSCLC) have a poor prognosis, so chemotherapy and best-supportive care are typically pursued as initial treatments. CASE REPORT: A 52-year-old man presented with symptoms of disorientation and disturbed consciousness as a result of multiple brain metastases. A histopathological examination revealed that the primary tumor was a large cell carcinoma located in the left upper lung. Whole brain irradiation (WBI) with a total dose of 50 Gy was immediately started. Since the brain tumors were successfully controlled, irradiation of the primary lung lesion with a total dose of 60 Gy was initiated 6 months after the WBI. Afterward, the patient was clinically free from lung cancer, but other cancers developed in the cecum and appendix and were surgically removed. He survived for more than 8 years after the WBI but eventually died of respiratory insufficiency caused by multiple lung metastases. The autopsy findings indicated that the lung lesions were metastatic adenocarcinomas from the appendiceal cancer, and the patient had remained disease-free from lung cancer. CONCLUSION: In view of the possibility of long-term survival in patients with stage IV NSCLC and brain metastasis, especially those with only intracranial metastases, careful consideration is be needed in the selection of treatment options.

Clinical outcomes of single-fraction stereotactic radiation therapy of lung tumors.

BACKGROUND: The objective of the current study was to investigate the effects and the morbidities of single-fraction stereotactic radiation therapy (SRT) for lung tumors. METHODS: A Microtron device was modified to deliver stereotactic irradiation under respiratory gating. Between August 1998 and December 2004, 59 malignant lung tumors (11 primary tumors, 48 metastases) that measured < 40 mm in greatest dimension were treated by single-fraction SRT. Nine tumors received a minimal dose of < 30 grays (Gy), and 50 tumors received a minimal dose of > or = 30 Gy. The macroscopic target volume ranged from 1 cc to 19 cc (mean, 5 cc). RESULTS: The 1-year and 2-year local progression-free rates (LPFRs) were 93% and 78%, respectively. The overall survival rate was 76.5% at 1 year and 41% at 2 years. Local regrowth of the irradiated tumor was a direct cause of death in two patients. Only the minimal radiation dose to the reference target volume tended to have an influence on the LPFR (P = 0.068). The 2-year LPFRs for patients who received irradiation doses of > or = 30 Gy and < 30 Gy were 83% and 52%, respectively. With regard to morbidities, Grade 3 respiratory symptoms (according to the Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer late radiation morbidity scoring scheme) were noted in one patient. CONCLUSIONS: The results from the current study suggested that single-fraction SRT was tolerable and was capable of attaining excellent local control in patients who had malignant lung tumors that measured < 4 cm in greatest dimension.

[Stereotactic hypofractionated radiotherapy of non-hepatic abdominal tumors].

PURPOSE: The clinical experiences of 12 patients with non-hepatic abdominal tumors who underwent stereotactic hypofractionated radiotherapy are presented. METHODS AND MATERIALS: Ten lesions were metastatic, one was a primary pancreatic cancer, and the remaining one was irradiated postoperatively for a positive margin of extrahepatic bile duct cancer. In one patient, single fractional stereotactic radiotherapy was employed, while the remaining 11 patients were treated with 3 fractions. Gross tumor volume of the 10 ranged from 2 cc to 32 cc (mean: 11 cc), and the minimal dose enclosing 95% of the planning target volume (D95) was between 28.6 Gy and 35 Gy. The minimal number of portals was 6. In 8 patients, radiotherapy was performed under respiratory gating. Mean follow-up time was 10 months (5-51 months). RESULTS: Local regrowth was seen in 9 months in only 1 of the 12 tumors, and the patient died of the disease. Four patients died because of tumor growth in other sites. The remaining 7 patients are alive without disease. As for morbidity, NCI-CTC grade 3 gastritis was seen in one patient, grade 2 gastritis in 2 patients, and grade 2 duodenitis in one patient. These patients all improved with non-surgical therapy. CONCLUSION: Stereotactic hypofractionated radiotherapy is effective for the treatment of selected non-hepatic abdominal tumors. However, the optimal radiation dose for tumor control and the tolerance dose of the gastrointestinal tract in hypofractionated irradiation must be studied further.