Purpose: Carbonic anhydrase IX (CA IX) is a hypoxia-inducible enzyme, which is associated with neoplastic growth. Ectopic CA IX expression has been observed in several tumors, whose normal counterparts do not express this enzyme. Normal human brain tissue shows only slight or no expression of CA IX. Experimental Design: We describe CA IX expression in human diffusely infiltrating astrocytomas. The association of CA IX is evaluated with clinicopathologic and molecular factors including cell proliferation and apoptosis as well as the expression of p53 and epidermal growth factor receptor. Results: CA IX immunopositivity was observed in 284 cases of 362 (78%) tumors.The positive areas were often located in close proximity to necrotic regions (P < 0.001). The CA IX immunoreactivity showed strong association with tumor malignancy grades (P < 0.0001). CA IX showed no association with p53 expression nor did it correlate with epidermal growth factor receptorâ mplification, apoptosis, or cell proliferation. CA IX intensity had significant prognostic value in univariate (P=0.0011, log-rank test) and multivariate survival analysis (P = 0.038, Cox analysis). Conclusions: CA IX expression is common in diffusely infiltrating high-grade astrocytomas. Our results suggest that CA IX is a useful biomarker for predicting poor prognosis of astrocytic tumors. It may also be a promising target molecule for the improvement of therapeutic interventions in astrocytomas.

Estrogens have an important role in the development and progression of breast cancer. 17␤-Hydroxysteroid dehydrogenase type 1 (17HSD1), type 2 (17HSD2), and type 5 (17HSD5) are associated with sex steroid metabolism in normal and cancerous breast tissue. The mRNA expressions of the 17HSD1, 17HSD2, and 17HSD5 enzymes were analyzed in 794 breast carcinoma specimens by using tissue microarrays and normal histologic sections. The results were correlated with the estrogen receptor ␣ (ER-␣) and ␤ (ER-␤), progesterone receptor, Ki67, and c-erbB-2 expressions analyzed by immunohistochemical techniques and with the Tumor-Node-Metastasis classification, tumor grade, disease-free interval, and survival of the patients. Signals for 17HSD1 mRNA were detected in 16%, 17HSD2 in 25%, and 17HSD5 in 65% of the breast cancer specimens. No association between the 17HSD1, 17HSD2, and 17HSD5 expressions was detected. A significant association was observed between ER-␣ and ER-␤ (P ‫؍‬ 0.02; odds ratio, 1.96) expressions. There was also a significant inverse association between ER-␣ and 17HSD1 (P ‫؍‬ 0.04; odds ratio, 0.53), as well as ER-␣ and 17HSD5 (P ‫؍‬ 0.001; odds ratio, 0.35). Patients with tumors expressing 17HSD1 mRNA or protein had significantly shorter overall and disease-free survival than the other patients (P ‫؍‬ 0.0010 and 0.0134, log rank). The expression of 17HSD5 was significantly higher in breast tumor specimens than in normal tissue (P ‫؍‬ 0.033; odds ratio, 5.56). The group with 17HSD5 overexpression had a worse prognosis than the other patients (P ‫؍‬ 0.0146). ER-␣ also associated with survival (P ‫؍‬ 0.045). Cox multivariate analyses showed that 17HSD1 mRNA, tumor size, and ER-␣ had independent prognostic significance.

Our data confirm the important role of VEGF in bone healing. We show for the first time that adenoviral VEGF-A gene transfer may modify bone defect healing in a rodent model.

No abstract

The p53 tumor suppressor gene is commonly mutated in human hepatocellular carcinoma (HCC). The most frequent mutation in HCC in populations exposed to a high dietary intake of aflatoxin B1 (AFB1) is an AGGarg-->AGTser missense mutation in codon 249 of the p53 gene. We analyzed HCCs from Monterrey, Mexico, for the codon 249ser hotspot mutation. We also analyzed the serum AFB1-albumin adduct levels of the donors and family members to measure the current AFB1 exposure in this population. Moreover, the presence of hepatitis B and/or C viral infection (HBV or HCV) was analyzed serologically in the patients. Tumor cells were microdissected from tissue sections and exon 7 p53 sequences were amplified by polymerase chain reaction from genomic DNA and sequenced directly. The serological tests for anti-p53 antibodies, HBV or HCV were done by ELISA. Immunohistochemical analysis of p53 protein was done using a polyclonal rabbit antiserum (CM-1). Eight of 21 cases were positive by p53 immunohistochemistry. Of the 16 cases sequenced for exon 7 of p53 three codon 249 AGGarg-->AGTser mutations were found. Serum antibodies recognizing p53 protein were found in one of 18 patients. Positive serology for HBV and/or HCV was found in 12 of 20 cases. The serum AFB1-albumin adduct levels in this population ranged from 0.54 to 4.64 pmol aflatoxin/mg albumin. These results indicate that dietary AFB1 and hepatitis viruses are etiological agents in the molecular pathogenesis of HCC in this geographic region of Mexico.