Familial breast cancer: characteristics and outcome of BRCA 1–2 positive and negative cases

BACKGROUND: The clinical and pathological characteristics and the clinical course of patients with breast cancer and BRCA 1–2 mutation are poorly known. METHODS: From 1997, patients with breast cancer and a family history of breast or ovarian cancer were offered BRCA testing. The clinical and pathological features of patients with known BRCA status were retrospectively assessed and comparisons were made between cancers arising in BRCA positive and BRCA wild type (WT) patients respectively. Type of treatment, pattern of relapse, event (local relapse, contralateral breast cancer, metastases) free and overall survival were also compared in the two groups. Out of the 210 patients tested, 125 had been treated and followed-up at our Institution and were evaluated in this study. RESULTS: BRCA positive patients tended to be more often premenopausal (79% vs 65%) and to have positive lymphnodes (63% vs 49%), poorly differentiated tumours (76% vs 40% – p = 0.002 at univariate analysis, not significant at multivariate analysis) and negative estrogen receptors (43% vs 29%). Treatment was not different in the two groups. In the 86 BRCA-WT patients, the first event was a local relapse in 3 (3%), metachronous contralateral breast cancer in 7 (8%) and distant metastases in 16 (19%). In the 39 BRCA positive patients, the corresponding figures were 3 (8%), 8 (21%) and 3 (8%). There was no difference in event free survival, with a median of 180 months in both groups of patients. At 20 years, projected survival was 85% for BRCA positive patients and 55% for BRCA-WT, but this difference was not statistically significant. CONCLUSION: Although BRCA positive patients have more frequently negative prognostic factors, their prognosis appears to be equal to or better than in patients with BRCA-WT

Thymidylate synthetase mRNA levels are increased in liver metastases of colorectal cancer patients resistant to fluoropyrimidine-based chemotherapy

BACKGROUND: Fluoropyrimidines such as 5-fluorouracil (5-FU) and 5-fluoro-2'deoxyuridine (FUDR) are among the most effective chemotherapeutic agents for treatment of metastatic colorectal cancer (CRC). Increased expression of thymidylate synthetase (TS) in CRC metastases has been proposed to be an important mechanism of resistance to fluoropyrimidine-based chemotherapy. METHODS: The present study investigated whether TS mRNA levels in liver metastases of 20 CRC patients before treatment with FUDR by hepatic arterial infusion (HAI) correlated with frequency of clinical response or survival duration. RESULTS: Median survival duration of patients with TS mRNA levels above and below the median was 15 and 18 months, respectively (p > 0.05). Clinical response was achieved in 40% of patients with low TS mRNA levels, but in only 20% of patients with high TS mRNA levels (p = 0.01). TS mRNA levels were also measured for liver metastases of 7 of the patients that did not achieve a clinical response. A statistically significant increase in expression of TS mRNA was observed for liver metastases resistant to chemotherapy (21 ± 14) in comparison to liver metastases of the same patients before chemotherapy (8 ± 4) (p = 0.03). CONCLUSION: This is the first report to demonstrate increased TS expression in liver metastases from CRC patients resistant to fluoropyrimidine based chemotherapy. These findings are consistent with previous studies indicating that increased TS expression is associated with resistance to fluoropyrimidine-based chemotherapy

Activation of Infiltrating Cytotoxic T Lymphocytes and Lymphoma Cell Apoptotic Rates in Gastric MALT Lymphomas : Differences between High-Grade and Low-Grade Cases

In this study, we have characterized infiltrating T lymphocytes from 13 low-grade and 17 high-grade primary gastric MALT lymphomas by immunohistochemistry, with particular regard to the presence, activation, and topographic distribution of cytotoxic effectors. Although the prevalence of CD4+ and CD8+ cells was similar in low- and high-grade lymphomas, higher numbers of TIA-1+ cytotoxic effectors were found in this latter group of cases (11.6 versus 7.8%; P = 0.004). Activation of CD8+ cytotoxic T lymphocytes (CTLs) was significantly more pronounced in high- than in low-grade lymphomas, as shown by immunostaining for perforin (8.7 versus 4.0%; P = 0.001) and granzyme-B (GrB) (8.7% versus 3.0%; P < 0.0001). Of note, CD20/GrB double labeling showed that high-grade lymphomas carried a markedly higher content (about ninefold) of activated CTLs relative to the number of CD20+ lymphoma B cells (0.081 ± 0.076 versus 0.009 ± 0.011; P < 0.0001). Moreover, high-grade lymphomas showed significantly increased apoptotic rates compared to low-grade cases (5.3 and 1.1% of terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL)-positive cells, respectively; P < 0.0001). In the whole series, the percentage of GrB+ cells and the GrB+/CD20+ ratio showed a strong linear correlation with the number of TUNEL-labeled cells. These findings, together with the frequent colocalization of CTLs and TUNEL+ neoplastic cells, suggested that apoptotic death of lymphoma cells may be due at least in part to the killing by cytotoxic effectors. Our results are consistent with the occurrence of host antitumor cell-mediated immune responses in gastric MALT lymphomas. Moreover, the finding of stronger cytotoxic responses in high- than in low-grade cases is of potential usefulness in the design of more effective therapeutic strategies for the management of these disorders

Templated Synthesis of Copper(II) Azacyclam Complexes Using Urea as a Locking Fragment and Their Metal-Enhanced Binding Tendencies towards Anions

Copper(II) azacyclam complexes were obtained through a metal-templated procedure involving the pertinent open-chain tetramine, formaldehyde and a phenylurea derivative as a locking fragment. Both metal complexes can establish interactions with anions through the metal centre and the amide NH group. Equilibrium studies in DMSO by a spectrophotometric titration technique were carried out to assess the affinity of the complexes towards anions. While the NH group of an amide model compound and the metal centre of the plain CuII(azacyclam)2+ complex do not interact at all with anions, the new complexes establish strong interactions with oxo anions, profiting from a pronounced cooperative effect. In particular, 1) they form stable 1:1 and 1:2 complexes with H2PO4- ions in a stepwise mode with both hydrogen-bonding and metal–ligand interactions, and 2) in the presence of CH3COO-, they undergo deprotonation of the amido NH group and thus profit from axial coordination of the partially negatively charged carbonyl oxygen atom in a scorpionate binding mode

ACTIVATION BY POINT MUTATION OF KI-RAS GENE OCCURRING IN TRANSFECTED HUMAN NORMAL DNA

A mutation-activated human Ki-ras gene was detected in NIH 3T3 cells transfected with high molecular weight DNA extracted from peripheral blood leukocytes of a healthy blood donor. A deoxyguanosine at position 35 of the first exon was substituted by deoxythymidine. Nevertheless, cloning and sequencing of seven independent Ki-ras first exons, isolated from the same human genomic DNA used to transfect NIH 3T3 cells, failed to reveal the expected point mutation. Since transfected DNA is susceptible to mutagenesis in mammalian cells, we hypothesize that a base substitution occurred during the transfection assay