Takaomi Suzuma

Biallelic inactivation of retinoic acid receptor β2 gene by epigenetic change in breast cancer

A growing body of evidence supports the hypotheses that retinoic acid receptor beta2 (RAR beta2) is a tumor suppressor gene. Although the loss of RAR beta2 expression has been reported in many malignant tumors, including breast cancer, the molecular mechanism is still poorly understood. We hypothesized that loss of RAR beta2 activity could result from multiple factors, including epigenetic modification and loss of heterozygosity (LOH). Using methylation-specific polymerase chain reaction and LOH analysis, we found that biallelic inactivation via epigenetic changes of both maternal and paternal alleles, or epigenetic modification of one allele combined with genetic loss of the remaining allele, could completely suppress RAR beta2 expression in breast cancer. Thus, it is possible that substantial numbers of human cancers arise through suppressor gene silencing via epigenetic mechanisms that inactivate both alleles. Because of this, chromatin-remodeling drugs may provide a novel strategy for cancer prevention and treatment.

Evaluation of axillary lymph node status in breast cancer with MRI

BackgroundWe performed a retrospective study to establish the optimal radiological criteria for axillary lymph node metastases from breast cancer by measuring all dissected nodes, and to determine whether magnetic resonance imaging (MRI) could reliably reveal axillary involvement.MethodsPathological findings and MRI scans of 202 patients with invasive breast cancer were re-viewed. The long- and short-axis dimensions of all level I and II lymph nodes were measured micro-scopically, and then the long-to-short axis (L/S) ratio of each node was calculated. These parameters were compared with pathological nodal status to define radiological criteria for axillary involvement. MRI was carried out using T1-weighted spin-eho sequences in the coronal and sagittal planes. On MRI, every detected lymph node was measured and the shape of the nodal cortex was also examined. Then the diagnostic ability of MRI was assessed using these morphologic criteria.ResultsOn histopathological examinations of 4043 dissected lymph nodes, a long-axis dimension of 10 mm or larger combined with a long-to-short axis ratio of less than 1.6 was the most accurate criteria for predicting lymph node metastases. On MRI, eccentric cortical hypertrophy was seen in only metas-tatic axillae. When these morphologic features were used as criteria for malignancy, MRI had a sensi-tivity of 79%, a specificity of 93%, and an accuracy of 88%. In 16 of 17 false-negative axillae, MRI showed normally sized lymph nodes (<10 mm).ConclusionOur study indicates that MRI is a useful diagnostic method for the evaluation of axillary nodal status, but is limited in the detection of small metastatic lymph nodes.

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.

Expression of Bcl-2 but not Bax or p53 correlates with in vitro resistance to a series of anticancer drugs in breast carcinoma

Programmed cell death is an important determinant of the response to chemotherapy. Among the factors controlling this process, a significant role is played by bcl-2, bax and p53. The in vitro chemosensitivity of the 177 breast carcinomas was assessed by the histoculture drug response assay (HDRA) using mitomycin C (MMC), 5-fluorouracil (5-Fu), adriamycin (ADM), cisplatin (CDDP), and cyclophosphamide (CPA). The susceptibility of Bcl-2-negative tumors to all the drugs killing was significantly higher than that of Bcl-2-positive tumors. No relationship between Bax or p53 immunoreactivity and sensitivity for any of anticancer drugs studied was demonstrated. Immunohistochemical results regarding Bcl-2 are promising in the evaluation of the sensitivity of cancer cells to a series of anticancer drugs and might be therapeutically useful as an indicator of response to adjuvant chemotherapy for breast cancer.

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.

Correlation between nuclear grade and biological prognostic variables in invasive Breast Cancer

BackgroundGrading of carcinomas is an estimation of differentiation. Nuclear grading is the cytological evaluation of tumor nuclei in comparison with the nuclei of normal mammary epithelial cells. Because nuclear grading does not involve an assessment of the growth pattern of the tumor, it applies not only to invasive ductal carcinoma but also to other subtypes of breast carcinoma.MethodsA total of 215 primary breast carcinomas obtained from the Affiliated Kihoku Hospital of Wakayama Medical College were enrolled in our present study. Nuclear grade was evaluated according to the criteria of the National Surgical Adjuvant Study of Breast Cancer (NSAS-B) protocol. Immuno-histochemistry was also performed to determine Bcl-2, p53, c-erbB-2, estrogen receptor (ER) and MIB-1 expression in paraffin-embedded tissues for all cases.ResultsThirty-two (14.9%) of the patients were graded as 1,124 (57.7%) as 2, and 59 (27.4%) as 3. Nuclear grade displayed a negative correlation with Bcl-2 expression (r=0.308, p<0.0001), and a positive correlation with c-erbB-2 overexpression (r= 0.172, p=0.01 17) and tumor proliferative index labeling by MIB-1 (r=0.485, p<0.0001).ConclusionsThese results imply that nuclear grade is related to the characteristics of tumor biology, indicating that the morphology and biology of breast cancer are tightly linked. Our present results also suggest that adding the nuclear grade to the pathological diagnosis of invasive breast carcinoma may be clinically useful for predicting tumor behavior, for example aggressiveness, and for prognostication.

Magnetic resonance axillography for preoperative diagnosis of the axillopectoral muscle (langer’s axillary arch): a case report

The axillary arch of Langer is the most common muscular variation in the axilla. Recognition of anatomic variations is important for surgeons to perform safe axillary surgery. We describe a case of a woman with breast cancer, in whom sentinel lymph node biopsy was successfully performed and the presence of this anomaly preoperatively diagnosed by magnetic resonance axillography.

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.

Allelic loss of chromosome 3p24 correlates with tumor progression rather than with retinoic acid receptor β2 expression in breast carcinoma

A tumor suppressor gene, retinoic acid receptor (RAR) β2, has been mapped to chromosome 3p24, a region where loss of heterozygosity (LOH) has been observed commonly in carcinomas of various tumor tissues. RAR β2 expression is reduced or lost in many malignant tumors including breast cancer, however, whether LOH accounts for the loss of expression of RAR β2 in breast cancer is unknown. We, therefore, assessed LOH on chromosome band 3p24 to correlate it with RAR β2 expression and other established prognostic parameters in 52 breast carcinomas. Based on three microsatellites, D3S 1283, D3S 1293 and D3S 1286, all of the tumors were informative, of these, 12 (23%) exhibited LOH. RAR β2 expression was lost in 42% (19/45) of these samples. We found that LOH on chromosome band 3p24 was not correlated with loss of RAR β2, but correlated with higher histological grade, p53-positivity, and loss of estrogen and progesterone receptors. Our findings suggest that LOH of the RAR β2 gene does not account for the frequent loss of RAR β2 expression in breast cancer but the genomic structural alteration at or close to the RAR β2 gene locus are likely to be associated with tumor progression and/or loss of hormonal dependency.