Old and new concepts in histopathological characterization of familial breast cancer.

BRCA1- and BRCA2-deficient cells display genomic instability due to impaired DNA repair and may subsequently be predisposed to malignant transformation. Cancers arising in BRCA1 gene mutation carriers differ substantially from sporadic breast cancers of age-matched controls in their histopathological appearance. BRCA1-related breast cancers have been morphologically associated with poorly differentiated and medullary types, exhibiting triple negativity and 'basal phenotype'. There are different types of mutations listed in Breast Cancer Information Core professional databases and most of them are small insertions or deletions. Moreover, the search for more pathological alterations has led to identification of missense mutations, intronic variant sequences and unclassified variants, reporting an unclear role in breast cancer susceptibility. We review the latest evidence regarding analysis of various mutations in BRCA1/2 genes and low-risk breast cancer susceptibility genes. Preliminary data from our laboratories indicate that biomarkers for invasiveness may lead to better characterization of familial breast cancers. Multivariate regression analysis has allowed us to select the best combination of markers to predict familial or hereditary breast cancers. We found that a marker signature comprising human epidermal growth factor receptor 2 (HER2) negativity, Na(+)/H(+) exchanger regulatory factor 1 (NHERF1) negativity and BRCA1 positivity (designated 'triple-biomarker' signature) is frequently associated with familial breast cancer and promises to be a reliable test in its molecular characterization.

Efficient in vivo microRNA targeting of liver metastasis.

Targeting oncogenic microRNAs (miRNAs) is emerging as a promising strategy for cancer therapy. In this study, we provide proof of principle for the safety and efficacy of miRNA targeting against metastatic tumors. We tested the impact of targeting miR-182, a pro-metastatic miRNA frequently overexpressed in melanoma, the in vitro silencing of which represses invasion and induces apoptosis. Specifically, we assessed the effect of anti-miR-182 oligonucleotides synthesized with 2' sugar modifications and a phosphorothioate backbone in a mouse model of melanoma liver metastasis. Luciferase imaging showed that mice treated with anti-miR-182 had a lower burden of liver metastases compared with control. We confirmed that miR-182 levels were effectively downregulated in the tumors of anti-miR-treated mice compared with tumors of control-treated mice, both in the liver and in the spleen. This effect was accompanied by an upregulation of multiple miR-182 direct targets. Transcriptional profiling of tumors treated with anti-miR-182 or with control oligonucleotides revealed an enrichment of genes controlling survival, adhesion and migration modulated in response to anti-miR-182 treatment. These data indicate that in vivo administration of anti-miRs allows for efficient miRNA targeting and concomitant upregulation of miRNA-controlled genes. Our results demonstrate that the use of anti-miR-182 is a promising therapeutic strategy for metastatic melanoma and provide a solid basis for testing similar strategies in human metastatic tumors.

Liposarcoma in the bone marrow: a terminal event.

We report a case of metastatic liposarcoma in the bone marrow with a rapidly fatal course. In view of the poor prognosis and paucity of clinical and imaging findings in patients with high-grade liposarcoma that is metastatic to bone marrow, we propose that bone marrow examination should be performed during the patient's initial evaluation as well as follow-up examinations.

Papillary fibroelastoma of the heart: report of two cases and review of the literature.

Papillary fibroelastoma is the most common primary cardiac valvular tumor. Historically, papillary fibroelastoma was an incidental autopsy finding, deemed to have no clinical significance. More recently, reports of symptomatic cases of papillary fibroelastoma with complications such as myocardial infarction and stroke have led papillary fibroelastoma to be considered a potentially dangerous lesion. We report 2 cases of symptomatic papillary fibroelastoma, both of which presented with a stroke. Both patients underwent uneventful open-heart surgery. The literature is reviewed, with a compilation of 79 cases.

Concurrent malakoplakia and papillary urothelial carcinoma of the urinary bladder.

A case of malakoplakia and papillary urothelial carcinoma of the urinary bladder is reported. In this case, malakoplakia was an incidental finding in a biopsy of the urinary bladder of a 74-yr old female, who presented with hematuria. The biopsy showed a low-grade papillary urothelial carcinoma in close association with malakoplakia. This is a rare association of these lesions.