Tatsuya Yoshimasu

Overexpression of ADAM9 in Non-Small Cell Lung Cancer Correlates with Brain Metastasis

The “a disintegrin and metalloprotease” (ADAM) family contributes to regulation of the cell–cell and cell–matrix interactions that are critical determinants of malignancy. To determine the relationship between metastasis and ADAM proteins, we compared the mRNA levels of ADAM9, -10, -12, -15, and -17 in sublines of an EBC-1 lung cancer cell line that were highly metastatic to either brain or bone. ADAM9 mRNA levels were significantly higher in highly brain-metastatic sublines than in the parent or highly bone-metastatic sublines. To elucidate the role of ADAM9 in brain metastasis, we stably transfected A549 and EBC-1 cells with a full-length ADAM9 expression vector. Compared with mock-transfectants, ADAM9 overexpression resulted in increased invasive capacity in response to nerve growth factor, increased adhesion to brain tissue, and increased expression of integrin α3 and β1 subunits. Administration of the anti-β1 monoclonal antibody attenuated this increase in invasive and adhesive activity. Intravenous administration of ADAM9-overexpressing A549 cells to mice resulted in micrometastatic foci in the brain and multiple metastatic colonies in the lungs. In contrast, administration of parent and mock-transfected A549 cells to mice resulted in lung tumors without brain metastasis. These results suggest that ADAM9 overexpression enhances cell adhesion and invasion of non-small cell lung cancer cells via modulation of other adhesion molecules and changes in sensitivity to growth factors, thereby promoting metastatic capacity to the brain.

Increased expression of integrin α3β1 in highly brain metastatic subclone of a human non‐small cell lung cancer cell line

To clarify the roles of integrin and extracellular matrix (ECM) in the process of non‐small cell lung cancer (NSCLC) brain metastasis, we established an in vivo model of brain metastasis of human NSCLC cell line EBC‐1/original in athymic mice, and established highly brain metastatic subclone EBC‐1/brain and highly bone metastatic subclone EBC‐1/bone. Integrin expression of these subclones was evaluated by flow cytometry. In vitro cell attachment, migration and proliferation assays with ECMs were performed using these subclones. Expression of integrin α3 subunit was higher in EBC‐1/brain than in both EBC‐1/original and EBC‐1/bone. In vitro cell attachment, migration, and proliferation assays revealed that EBC‐1/brain had higher affinity and higher reactivity to laminin than EBC‐1/original and EBC‐1/bone. Blocking of integrin α3β1 significantly (P<0.05) decreased brain metastasis by EBC‐1/brain. Interaction of integrin α3β1 and laminin plays important roles in the process of brain metastasis of non‐small cell lung cancer.

A case of granulomatous mastitis mimicking breast carcinoma

A 58-year-old woman presenting with idiopathic granulomatous mastitis mimicking breast carcinoma is described. The mass was elastic, hard and painless, and located in the upper outer quadrant of the right breast. Fine needle aspiration cytology did not provide any diagnostic information. Mammography, ultrasonography and magnetic resonance imaging (MRI) strongly suggested malignancy. Excisional biopsy was performed for definitive diagnosis, and idiopathic granulomatous mastitis was demonstrated histopathologically. Neither wound complication nor recurrence has been identified in the patient, although corticosteroids were not used post operatively. We reviewed the literature, and found that our present case is rare in older patients, and that mammography, ultrasonography and MRI provide little information for differentiating between granulomatous mastitis and carcinoma.

Bisphosphonate therapy for bone metastases from Breast Cancer: Clinical results and a new therapeutic approach

BackgroundWe evaluated the usefulness of bisphosphonate (BIS) monotherapy, the safety of rapid infusion of BIS and the efficacy of BIS-sequential therapy for bone metastases from breast cancer.Patients and MethodsTwenty-nine patients with bone metastasis or invasion were treated with BIS monotherapy. Each BIS (pamidronate 30 mg, alendronate 10 mg, or incadronate 10 mg) was infused over 30 minutes every two weeks a median of 12 times.ResultsWith BIS therapy, five patients (17%) showed partial response of the bone lesions, and eighteen patients (64%) had pain relief. Of the nine patients treated with BIS-sequential therapy, one (11%) showed a partial response of the bone metastases, three (33%) had pain relief, and one (11%) showed a decrease in the serum tumor marker level.ConclusionBIS therapy is effective against bone metastases from breast cancer, and rapid infusion of BIS is both safe and convenient for patients. BIS-sequential therapy can be a unique therapeutic option in some cases.

Pamidronate-induced remission of pain associated with hypertrophic pulmonary osteoarthropathy in chemoendocrine therapy-refractory inoperable metastatic breast carcinoma.

We describe an extremely rare case of a woman with pulmonary metastatic disease from breast cancer, who presented with features of hypertrophic pulmonary osteoarthropathy (HPOA). Pain associated with HPOA may be extremely disabling and resistant to treatment. Treatment with pamidronate, an inhibitor of osteoclastic bone resorption, given every 2 weeks by i.v. drip infusion, led to rapid disappearance of uncontrolled pain caused by HPOA.

Analysis of the early postoperative serum carcinoembryonic antigen time-course as a prognostic tool for bronchogenic carcinoma.

The serum kinetics of carcinoembryonic antigen (CEA) after resection of lung carcinoma are not well characterized. Its prognostic implications remain unclear. This study was designed to clarify the correlation between postoperative CEA time‐course and patient prognosis.

Histoculture drug response assay for gefitinib in non-small-cell lung cancer

ObjectiveThere are many predictive factors for gefitinib sensitivity, including epidermal growth factor receptor (EGFR) gene mutation, EGFR copy number, and k-ras mutation. To investigate all of them is too expensive. We evaluated the chemosensitivity for gefitinib in non-small-cell lung cancer (NSCLC) using a histoculture drug response assay (HDRA).MethodsSurgically resected fresh tumor specimens from 22 patients with NSCLC were used. There were 13 male and 9 female patients, ranging in age from 49 to 84 (average 70) years old. Sixteen patients (73%) were smokers. Sixteen adenocarcinomas, four squamous cell carcinomas, and two other histological types were included. Small pieces of viable cancer tissue were placed on the collagen gel and then cultured for 7 days in the presence of gefitinib.ResultsThe HDRA was successful in all specimens. A dose-response relation was observed between inhibition rates and gefitinib concentration (p = 0.016). The inhibition rate at 20 μg/ml (IR20) in adenocarcinoma without smoking (39.2% ± 35.1%, n = 6) was higher than that with smoking (2.2% ± 5.0%, n = 10, P = 0.001) and that of nonadenocarcinoma (16.9% ± 23.6%, n = 6, P = 0.09). Gene mutation analysis was performed in two of three adenocarcinomas without smoking, which showed especially high IR20 values, and sensitizing mutations were observed in these specimens. A cutoff inhibition rate of approximately 40%–50% appeared to be suitable for a concentration of 20 μg/ml.ConclusionHDRA appears to be applicable for evaluating sensitivity to gefitinib in NSCLC. It provides a convenient method for predicting the response to gefitinib in patients with NSCLC whose fresh tumor specimens are available.

Clinical efficacy of bisphosphonate therapy for bone metastasis from breast cancer

Bisphosphonates inhibit osteoclastic bone resorption and are being used as treatment for bone metastases from breast cancer. Intravenous bisphosphonate therapy can significantly reduce skeletal related events (SREs) when administered concurrently with chemotherapy or endocrine therapy. In addition, intravenous bisphosphonate monotherapy is also able to alleviate cancer induced bone pain, and to improve bone metastases in some patients. Oral bisphosphonates are not routinely used for the treatment of bone metastases due to their low bioavailability. However, minodronate, a bisphosphonate 100-fold more potent than pamidronate, is now in phase II clinical studies in Japan, and may alter the role of oral bisphosphonates in the treatment of bone metastasis from breast cancer. The ASCO guidelines recommend that patients with osteolytic bone metastases be treated not with bisphosphonate monotherapy, but with concurrent bisphosphonate and systemic therapy. In addition, it is also recommended that current standards of care for cancer pain, analgesics and radiotherapy, should not be replaced with bisphosphonate therapy.

Epidermal Growth Factor Receptor Mutations Are Associated with Docetaxel Sensitivity in Lung Cancer

Introduction: A recent large randomized controlled trial revealed that patients with lung cancer with epidermal growth factor receptor (EGFR) mutations had better prognoses when treated with the EGFR-tyrosine kinase inhibitor, gefitinib, than with cytotoxic chemotherapeutic agents. Lung cancer with EGFR mutations is highly sensitive to EGFR-tyrosine kinase inhibitors. The previous trial implied that EGFR mutations might be predictive of the response to cytotoxic chemotherapy. Methods: Forty-six tumor tissue specimens (32 adenocarcinomas and 14 nonadenocarcinomas) were obtained from patients with lung cancer who underwent surgical resection. EGFR mutations were detected using polymerase chain reaction-invader assay. A histoculture drug response assay was used as an in vitro drug sensitivity test. The inhibition rates of cisplatin, docetaxel (DOC), vinorelbine, and gemcitabine were measured. Results: Sensitizing EGFR mutations were detected in samples from 14 patients, all with adenocarcinomas. The inhibition rate of cisplatin in tumors with EGFR mutations (group M) was 34.8 ± 15.5%, which was significantly lower (p = 0.0153) than in wild-type tumors (group W; 46.6 ± 14.0%). The inhibition rate of DOC in group M (18.8 ± 13.4%) was also significantly lower (p = 0.0051) than in group W (35.4 ± 19.1%). There were no significant differences in inhibition rates of gemcitabine and vinorelbine between groups M and W. Inhibition rates of DOC were significantly lower in group M (p = 0.0256) than in group W (32.6 ± 18.4) in samples from patients with adenocarcinoma. Conclusion: The histoculture drug response assay indicated that lung cancers with EGFR mutations were less sensitive to DOC than EGFR wild-type tumors.

Intrapleural administration of a large amount of diluted fibrin glue for intractable pneumothorax. A clinical study based on 57 cases: including 2 unsuccessful cases.

OBJECTIVE Pleurodesis using chemical agents has been applied to high-risk patients with pneumothorax. This treatment, however, is sometimes unsuccessful in patients with intractable pneumothorax. We have developed intrapleural administration of diluted fibrin glue as an effective treatment for such patients. METHODS Fibrin glue was diluted 4-fold with saline and/or contrast media. Pleurodesis with a large amount of the diluted fibrin glue was performed in 55 high risk patients (57 cases, bil.2 patients) with intractable pneumothorax. RESULTS The air leaks were stopped by administration of the glue in all except 2 patients. During the follow-up period, a recurrence rate of 10.5% was observed. These recurrent pneumothoraces were successfully treated using the same procedure with no further recurrence. Pyrexia (12.3%) and chest discomfort (8.8%) were observed as side effects, and there was no occurrence of severe chest pain or thoracic empyema. CONCLUSIONS These results suggested that intrapleural administration of a large amount of diluted fibrin glue was an effective treatment for intractable pneumothoraces in high-risk patients.