Prognostic Value of ADAMTS Proteases and Their Substrates in Epithelial Ovarian Cancer

Background: ADAMTS are metalloproteases with disintegrin and thrombospondin motifs. They are secreted proteases playing a role in biological processes such as inflammation, angiogenesis, and urogenital development. ADAMTS have specific substrates, such as the proteoglycans (PG) versican, aggrecan, and brevican. Despite data indicating a role of ADAMTS in tumor invasion and metastases, effects played by these molecules in cancer progression are still controversial. In ovarian cancer, the importance of ADAMTS gene mutations was recently described and related to chemotherapy outcome. Objective: To analyze protein levels of ADAMTS-1, -4, and -5, and TIMP-3 in human ovarian cancer classified as benign, borderline, or malignant. We also assessed the expression of the ADAMTS substrates aggrecan, brevican, and versican in these neoplasms. Correlations between overall survival and protein expression were performed. Methods: Tumors were classified according to the WHO Classification of Tumors of Female Reproductive Organs. Protein and PG expression was studied by immunohistochemistry. Differences in labeling were analyzed by percent measurements of stained areas. Results: ADAMTS-1, ADAMTS-5, and its tissue inhibitor TIMP-3 are increased in borderline and malignant tumors compared to benign neoplasms. Aggrecan and versican levels were increased in malignant subtypes compared to benign ovarian cancer. Higher ADAMTS-1, TIMP-3, and versican expression was associated with a shorter overall survival. Conclusions: Comparison of protease, TIMP-3, and substrate expression showed that in malignant tumors all ADAMTS and TIMP-3 expression levels were significantly raised compared to the substrates studied.

Sentinel node biopsy in breast cancer: results in a large series

Sentinel lymph node biopsy (SLNB) is an appropriate method for the evaluation of axillary status in cases of early breast cancer. We report our experience in treating cases evaluated using SLNB. We analyzed a total of 1192 cases assessed by means of SLNB from July 1999 to December 2007. SLNB processing was successfully completed in 1154 cases with the use of blue dye or radiolabeled 99mTc-Dextran-500, or both. Of these 1154 patients, 857 were N0(i-) (no regional lymph node metastasis, negative immunohistochemistry, IHC), 96 were N0(i+) (no regional lymph node metastasis histologically, positive IHC, no IHC cluster greater than 0.2 mm) and 201 were N1mi (greater than 0.2 mm, none greater than 2.0 mm). Most of the tumors (70 percent) were invasive ductal carcinomas and tumors were staged as T1 in 770 patients (65 percent). A total of 274 patients underwent SLNB and axillary dissections up to April 2003. The inclusion criteria were tumor size equal to or less than 3 cm in diameter, no clinically palpable axillary lymph nodes, no neoadjuvant therapy. In 19 cases, the SLN could not be identified intraoperatively. A false-negative rate of 11 percent and a negative predictive value of 88.2 percent were obtained for the 255 assessable patients. The overall concordance between SLNB and axillary lymph node status was 92 percent. SLNB sensitivity for nodes was 81 percent and specificity was 100 percent. The higher sensitivity, specificity, accuracy, and lower false-negative rates of SLNB suggest that this method may be an appropriate alternative to total axillary dissection in early breast cancer patients.

Expression of E-cadherin, Snail and Hakai in epithelial cells isolated from the primary tumor and from peritumoral tissue of invasive ductal breast carcinomas

Epithelial intercellular cohesion, mainly mediated by E-cadherin (CDH1) expression and function, may be deregulated during cancer cell invasion of adjacent tissues and lymphatic and vascular channels. CDH1 expression is down-modulated in invasive lobular breast carcinomas but its regulation in invasive ductal carcinomas (IDC) is less clear. CDH1 expression is repressed by transcription factors such as Snail (SNAI1) and its product is degraded after Hakai ubiquitination. We compared CDH1, SNAI1 and HAKAI mRNA expression in IDC and paired adjacent normal breast tissue and evaluated its relation with node metastasis and circulating tumor cells. Matched tumor/peritumoral and blood samples were collected from 30 patients with early IDC. Epithelial cells from each compartment (tumor/peritumoral) were recovered by an immunomagnetic method and gene expression was determined by real time RT-PCR. There were no differences in CDH1, SNAI1 and HAKAI mRNA expression between tumor and corresponding peritumoral samples and no differential tumoral gene expression according to nodal involvement. Another 30 patients with a long-term follow-up (at least 5 years) and a differential prognosis (good or poor, as defined by breast cancer death) had E-cadherin and Snail protein detected by immunohistochemistry in tumor samples. In this group, E-cadherin-positive expression, but not Snail, may be associated with a better prognosis. This is the first report simultaneously analyzing CDH1, SNAI1 and HAKAI mRNA expression in matched tumor and peritumoral samples from patients with IDC. However, no clear pattern of their expression could distinguish the invasive tumor compartment from its adjacent normal tissue.

Tumores de células germinativas intracranianos na infância: avaliação de 14 casos / Primary intracranial germ cell tumors in children: evaluation of fourteen cases

This study evaluates the diagnosis, therapy and survival of 14 patients with primary intracranial germ cell tumors during the period from 1991 to 2001. There were 11 males and 3 females. Mean age was 12.2 years old (20 days-18 years). On admission, the most common symptoms were headache (10/14), vomiting (6/14) and visual (6/14). The tumor was in pineal and hypothalamic region in 10 cases, suprasellar in 3 cases, and in the cerebral parenchyma in 1 case. Histologically there were 1 embryonal carcinoma, 5 germinomas, 2 mature teratomas, 1 immature teratoma and 5 mixed germ cell tumors. Treatment differed among the patients according to the type of tumor. Three patients died after tumor progression or relapse and one patient died from another condition. The remaining patients are alive and without disease.

Este estudo avalia o diagnóstico, a terapia e a sobrevida de 14 pacientes com tumor de células germinativas intracraniano durante o período entre 1991 e 2001. Onze pacientes eram do sexo masculino e três do feminino. A média de idade do grupo foi 12,5 anos (20 dias-18 anos). Na admissão, os mais comuns sintomas foram cefaléia (10/14), vômitos (6/14) e visuais (6/14). Os tumores estavam localizados em região hipotalâmica/hipofisária em 10 casos, suprasselar em 3 casos e intraparenquimatosa em 1 caso. Histologicamente, havia 1 caso de carcinoma embrionário, 5 de germinomas, 2 de teratoma maduro, 1 de teratoma imaturo e 5 de tumores mistos. O tratamento foi variável, dependendo da histologia da lesão. Três pacientes morreram após a progressão tumoral ou recidiva e um paciente morreu devido causa não relacionada ao tumor. Os demais estão vivos e sem doença.