Taeko Nagao

Matrix metalloproteinase inhibitor MMI-166 inhibits lymphogenous metastasis in an orthotopically implanted model of lung cancer

Matrix metalloproteinases (MMP) are considered to be critically involved in tumor invasion and the metastasis of various cancers. MMI-166 is a selective inhibitor of matrix metalloproteinase (MMP-2, MMP-9, and MMP-14). The purpose of this study was to evaluate the effects of MMI-166 on both the growth of the implanted tumor and the lymph node metastasis of the mediastinum and prolonging the life span, using an orthotopic implantation model of the Ma44-3 cancer cell line. We examined the anti-invasive effect of MMI-166 in lung cancer cell lines using an in vitro invasion assay. Next, we examined the anticancer effect of MMI-166 in vivo. MMI-166 (200 mg/kg body weight) or a vehicle was administered orally to the orthotopically implanted lung cancer model. MMI-166 dose-dependently inhibited the invasion of cancer cell lines with expressions of MMP-2 and/or MMP-9 in vitro. In vivo, MMI-166 significantly inhibited mediastinal lymph node metastasis in this orthotopic model (weight of the mediastinum: control, 0.089 ± 0.009 versus MMI-166, 0.069 ± 0.008 mg; P = 0.005; metastatic area: control, 93,495 ± 55,747 versus MMI-166, 22,747 ± 17,478 pixels; P = 0.045). MMI-166 prolonged the life span by 6 days in median survival time in the orthotopically implanted model (P = 0.039). These results showed that MMI-166 could possibly inhibit lymph node metastasis and prolong the life span in lung cancer patients.

The time since last menstrual period is important as a clinical predictor for non-steroidal aromatase inhibitor-related arthralgia.

BackgroundThe clinical predictors of aromatase inhibitor-related arthralgia (AIA), a drug-related adverse reaction of aromatase inhibitors (AIs), remain unclear.MethodsAIA was prospectively surveyed every 4 months in 328 postmenopausal breast cancer patients administered a non-steroidal AI (anastrozole). Various clinicopathological parameters were recorded and analyzed (chi-square test, Fishers exact test and logistic regression analysis).ResultsThe mean observation period was 39.9 months. AIA manifested in 114 patients (34.8%), with peaks of onset at 4 (33.7%) and 8 months (11.4%) after starting AI administration. Some cases manifested even after 13 months. AIA tended to occur in younger patients (incidences of 46.3%, 37.4% and 28.0% for ages of < 55, 55-65 and > 65 years, respectively (p = 0.063)) and decreased significantly with the age at menarche (53.3%, 35.3% and 15.4% for < 12, 12-15 and > 15 years, respectively (p = 0.036)). The incidences were 45.1%, 46.3 and 25.1% for the time since the last menstrual period (LMP) < 5 years, 5-10 years and > 10 years, being significantly lower at > 10 years (p < 0.001). In logistic regression analysis, the AIA incidence was significantly lower in the time since LMP > 10-year group versus the < 5-year group (odds ratio 0.44, p = 0.002), but the age at menarche showed no association. AIA manifested significantly earlier (≤ 6 months) as the time since LMP became shorter (< 5 years).ConclusionAIA tends to manifest early after starting AI, but some cases show delayed onset. The incidence was significantly lower in patients with a duration of > 10 years since LMP. When the time since LMP was short, the onset of AIA was significantly earlier after starting AI administration.

Current status of breast cancer screening in the world

The mortality associated with breast cancer is decreasing in Europe and the United States. There are various reasons for these trends, including an increase in detection of early-stage breast cancers due to increased use of mammographic screening and the establishment of standardized systemic treatments based on evidence-based medicine. However, in Japanese women, both the morbidity and the mortality of breast cancer are increasing. In this manuscript, we describe the current status of mammographic screening in Europe and the United States, and the status of breast cancer screening in Japan. Quality control systems are also introduced, and the need for practical measures, such as implementation of quality control systems aimed at improving the cancer screening rate (with a target of 50%) and population-based screening (organized screening), based on the Cancer Control Act, is described. Current countermeasures for dense breasts in women in their 40s, both overseas and in Japan, are also described, together with discussions of the diagnostic capability of digital mammography, the usefulness of screening combined with computer-aided diagnosis, and the current status of screening using MRI in Europe and the United States.

Aberrant methylation of tumour-related genes in thymic epithelial tumours

BACKGROUND Thymoma is an uncommon neoplasm derived from epithelial cells of the thymus. Few studies have addressed the genetic alterations that occur in the tumourigenesis of thymoma. METHODS We examined aberrant DNA methylation of DAP-K, p-16, MGMT and HPP1 genes in 26 thymomas and 6 thymic carcinoma to clarify the association between aberrant DNA methylation and clinicopathological features. RESULTS Fifteen (47%) of 32 thymic epithelial tumours showed aberrant methylation. Aberrant methylation was more frequent in thymic carcinoma (86%) than in thymoma (29%). Moreover, the frequency of tumours with methylation of multiple genes in thymic carcinoma was higher than in thymoma (60% vs 20%). In thymoma, the frequency of tumour methylation, including the type A tumour component (28%), was lower than that of tumours with type B tumour component (42%). MGMT methylation was detected in 23% of thymoma and in 83% of thymic carcinoma. The frequency of methylation of the MGMT gene in both tumours was high compared with the other 3 genes. CONCLUSIONS Aberrant DNA methylation was more frequent in thymic carcinoma than in thymoma, and the frequency of DNA methylation in thymic epithelial tumours is roughly parallel to their malignant behaviour.

Serum estradiol should be monitored not only during the peri-menopausal period but also the post-menopausal period at the time of aromatase inhibitor administration

BackgroundAromatase inhibitor (AI) therapy is being extensively used as postoperative adjuvant therapy in patients with hormone receptor-positive postmenopausal breast cancer. On the other hand, it has been reported that ovarian function was restored when AI was administered to patients who had undergone chemical menopause with chemotherapy or tamoxifen. However, there have been no reports of comprehensive monitoring of estradiol (E2) in breast cancer patients with ordinary menopause who were being administered AI.Patients and MethodsBeginning in March 2008, regular monitoring of the serum levels of E2, luteinizing hormone (LH) and follicle-stimulating hormone (FSH) was performed for 66 postmenopausal breast cancer patients who had been started on AI therapy. For this study, we chose anastrozole as the AI. The assays of those hormones were outsourced to a commercial clinical laboratory.ResultsIn 4 of the 66 patients the serum E2 level was decreased at 3 months but had then increased at 6 months, while in 2 other patients E2 was decreased at both 3 and 6 months but had increased at 9 months.ConclusionThe results indicate that, in some breast cancer patients with ordinary menopause, E2 rebounds following AI therapy. In the future, E2 monitoring should be performed for a larger number of patients being administered AI therapy.Trial registrationOur trial registration number is 19-11-1211.

A case of matrix-producing carcinoma of the breast

BackgroundMatrix-producing carcinoma (MPC) of the breast is one variant type of metaplastic carcinoma. The cellular origin of MPC remains unclear. It has been suggested the tumor cells in MPC have the combined characteristics of both epithelial cells and mesenchymal cells. Several reports suggested that the tumor cells in MPC might originate from the myoepithelial cells, but others suggested the origin was basal-like cells.Case presentationThe patient was a 42-year-old Japanese female. A tumor of about 2 cm in diameter was noted in the right breast. CT revealed the circumference of the tumor to have a ring-like structure, and fine needle aspiration cytology indicated suspicion for malignancy. Breast-conserving surgery was performed. Histopathological studies showed carcinoma cells, having cuboidal to oval-shaped nucleus, were proliferating in cord-like and sheet-like structures in the periphery. In the central areas of the tumor, myxoedematous area was observed with cartilaginous matrix and necrosis. The diagnosis was a matrix-producing carcinoma. Immunohistochemical findings showed the tumor cells had the characteristics of both epithelial cells and mesenchymal cells, while being negative for estrogen receptor, progesterone receptor, Her2, myoepithelial cell markers and basal cell markers.ConclusionThe findings for our present patient and many of the other MPC patients reported in the published literature indicate that this breast cancer has the properties of both epithelial cells and mesenchymal cells. In addition, there is a possibility that matrix-producing tumor cells of our present patient may have a feature of undifferentiated cells.

Bilateral male breast cancer with male potential hypogonadism

BackgroundMale breast cancer is a comparatively rare disease, and simultaneous bilateral male breast cancer is considered to be an extremely rare event. Risk factors are said to be genetic factors and hormonal abnormalities due to obesity or testicular diseases.Case presentationThe patient was a 47-year-old Japanese male. His family had no history of female breast cancer. This patient also had hypospadias and hormonal examination indicated the presence of primary testicular potential hypogonadism, and these hormonal abnormalities seemed to be present since childhood or the fetal period. The bilateral breast cancer developed in this man at a comparatively young age, and histopathological studies of multiple sections showed that there was almost no normal epithelial cell in the ducts, while the ducts were almost completely filled with breast cancer cells.ConclusionIt is thought that male breast cancer is caused by an imbalance between estrogen and testosterone. We cannot rule out the possibility that the breast cancer developed due to the effect of the slight elevation of estrogen over a long period of time, but the actual causative factors in this patient were unable to be definitively identified. In the future, we hope to further elucidate the causes of male breast cancer.

Joint Symptoms, Aromatase Inhibitor-Related Adverse Reactions, Are Indirectly Associated with Decreased Serum Estradiol

Background. Joint symptoms (JSs) are problematic adverse drug reactions (ADRs) of aromatase inhibitors (AIs). Involvement of decreased serum estradiol (SE) has been suggested. Patients and Methods. 104 postmenopausal breast cancer patients administered an AI were prospectively investigated regarding various clinical parameters, JS and hot flashes as ADRs, and the SE level. Results. JS manifested in 31.7% of patients and hot flashes in 18.3%. Chi-square testing showed a significantly higher incidence of JS in several patient strata: <55 years old, decreased SE, and elevated total cholesterol (TC). In univariate analysis, JS correlated significantly with a pre-AI % YAM of ≥80%, decreased SE, and elevated TC. Eight (7.7%) patients maintained SE at ≥5 pg/mL for >6 consecutive months, with no JS. In chi-square testing, hot flashes showed a significantly higher incidence in patients <55 years old. Conclusion. AI-ADRs occurred more readily in younger patients. Decreased SE may be indirectly involved in JS.

Therapy for multiple primary lung cancers

We considered 33 patients to have a multiple primary lung cancer (MPLC) at our hospital from January 1986 to August 2001. We used the criteria of Martini and Melamed for MPLC. Sixteen patients developed metachronous cancer within 0.8 to 9.4 years of the first operation (mean 4.2 years), while 17 patients had synchronous cancers. The most common histologic pair was squamous cell carcinoma-squamous cell carcinoma (45%). The next was adenocarcinoma-adenocarcinoma (21%). Stage I lesions occupied 80% of all lesions. Nine patients underwent lobectomy, while 9 patients underwent surgery including a limited operation. Eleven patients had non-surgical local treatment including photodynamic therapy (PDT), brachytherapy, and radiation therapy. Five-year survival for patients with synchronous and metachronous disease from second operation was 36.1% and 40.1%, respectively. Survival of patients including only stage I non-small cell lung cancer (NSCLC) lesions was significantly better compared with those including stage II or III NSCLC and SCLC lesions (p = 0.002). Therefore it is very important to perform close follow-up surveillance for early detection of cancer.