Shoji Oura

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.

Expression of Bcl-2, but not Bax, correlates with estrogen receptor status and tumor proliferation in invasive breast carcinoma

Bcl‐2 and Bax have been demonstrated to be associated with apoptosis in breast carcinoma, and the ratio between Bax and Bcl‐2 seems to be an important determinant of cellular sensitivity to induction of apoptosis. However, little information is available on the relationship between Bcl‐2, Bax and the proliferative activity of breast carcinoma. The purpose of this study was to investigate the significance of apoptosis‐related genes bcl‐2 and Bax and their correlation with expression of p53, tumor proliferation defined by MIB‐1 expression and estrogen receptor status. Immunohistochemistry was performed to determine Bcl‐2, Bax, p53, estrogen receptor (ER) and MIB‐1 expression in paraffin‐embedded tissues of 177 invasive breast cancers. Expression of the anti‐apoptotic protein Bcl‐2 was not correlated with the pro‐apoptotic Bax. Bcl‐2 immunostaining displayed a negative correlation with increasing histologic grade, p53 and MIB‐1 (P< 0.0001, P< 0.05 and P< 0.0001, respectively) and a positive correlation with rising ER immunostaining (r = 0.305, P< 0.0001). Conversely, expression of the apoptosis‐promoting protein Bax did not correlate with increasing histologic grade, p53, MIB‐1 or ER status. Neither Bcl‐2 expression nor Bax expression correlated with age, menopausal status, tumor size, histologic type or axillary lymph node status. These results imply that Bcl‐2 is associated with good prognostic markers and the regulation of Bax is complex and does not necessarily correlate with mutant p53 status in breast cancers.

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.

Ipsilateral breast tumor recurrence (IBTR) in patients with operable breast cancer who undergo breast-conserving treatment after receiving neoadjuvant chemotherapy: risk factors of IBTR and validation of the MD Anderson Prognostic Index.

There is limited information about the risk factors for ipsilateral breast tumor recurrence (IBTR) after patients undergo breast‐conserving surgery plus radiotherapy (breast‐conserving treatment [BCT]) subsequent to neoadjuvant chemotherapy (NAC). The objective of the current study was to analyze these risk factors.

Fibroadenoma of the axillary accessory breast: diagnostic value of dynamic magnetic resonance imaging

Accessory breast is synonymous with polymastia or supernumerary breast tissue. An accessory breast without a nipple or areola is rare. We report a case of fibroadenoma of an accessory breast with no nipple or areola in a 41-year-old woman who presented with a right axillary mass associated with five small nodules in the normally situated breast. Magnetic resonance imaging (MRI) showed the accessory breast surrounding the tumor. We ignored the presence of the component surrounding the mass and made a preoperative diagnosis of an axillary mass of possible metastases from multiple breast cancers or breast cancer of unknown origin associated with multiple breast fibroadenomas. From a retrospective view, based on the histological results, MRI and dynamic MRI demonstrated a tiny component of breast-like tissue surrounding the axillary mass and an enhancement pattern typical of fibroadenoma for the axillary mass. For the later diagnosis of the axillary mass, the interpretation of whether the component of breast tissue surrounding the axillary mass was present is crucial. If the component exists, a tumor that originated from the accessory breast should be foremost in the differential diagnosis. Dynamic MRI appears to contribute to the diagnosis of fibroadenoma of an accessory breast before biopsy or surgical resection.

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.

MR-axillography oriented surgical sampling for assessment of nodal status in the selection of patients with breast cancer for axillary lymph nodes dissection

BackgroundWe have reported that magnetic resonance axillography (MR-axillography) is the best method for assessing lymph node size and representing the relation of the lymph node to normal anatomy.MethodsThe four largest nodes on MR-axillography were sampled in 62 consecutive patients with breast cancer undergoing axillary clearance. Axillary clearance yielded a mean of 17.0 (range 5–28) nodes.ResultsA method of preliminary sampling of four nodes in the axilla oriented by MR-axillography was assessed in all cases, 22 of whom were histologically node positive. Based on the sampled nodes, lymph node metastases were detected in 20 of 22 (91%) of the node-positive patients. Based on the sampled nodes, of the 19 patients with macrometastatic nodes, lymph node metastases were detected in all 19 (100%), but only in 1 of the 3 (33%) patients with only one micrometastatic node.ConclusionsThis experience indicates that sampling the four largest nodes by MR-axillography orientation accurately identifies patients with macrometaststic nodes. This result may be comparable to that of surgical sampling performed by the most skilled surgeons.

Intraductal spread of invasive breast carcinoma has a positive correlation with c-erb B-2 overexpression and vascular invasion.

Studies of the histologic characteristics and biologic behavior of the intraductal spread of breast carcinoma are critically important in that they may lead to the identification of a unique spread pattern rather than a noninvasive lesion.

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.