Prognostic role of KRAS and BRAF in stage II and III resected colon cancer: results of the translational study on the PETACC-3, EORTC 40993, SAKK 60-00 trial.

PURPOSE: Mutations within the KRAS proto-oncogene have predictive value but are of uncertain prognostic value in the treatment of advanced colorectal cancer. We took advantage of PETACC-3, an adjuvant trial with 3,278 patients with stage II to III colon cancer, to evaluate the prognostic value of KRAS and BRAF tumor mutation status in this setting. PATIENTS AND METHODS: Formalin-fixed paraffin-embedded tissue blocks (n = 1,564) were prospectively collected and DNA was extracted from tissue sections from 1,404 cases. Planned analysis of KRAS exon 2 and BRAF exon 15 mutations was performed by allele-specific real-time polymerase chain reaction. Survival analyses were based on univariate and multivariate proportional hazard regression models. RESULTS: KRAS and BRAF tumor mutation rates were 37.0% and 7.9%, respectively, and were not significantly different according to tumor stage. In a multivariate analysis containing stage, tumor site, nodal status, sex, age, grade, and microsatellite instability (MSI) status, KRAS mutation was associated with grade (P = .0016), while BRAF mutation was significantly associated with female sex (P = .017), and highly significantly associated with right-sided tumors, older age, high grade, and MSI-high tumors (all P < 10(-4)). In univariate and multivariate analysis, KRAS mutations did not have a major prognostic value regarding relapse-free survival (RFS) or overall survival (OS). BRAF mutation was not prognostic for RFS, but was for OS, particularly in patients with MSI-low (MSI-L) and stable (MSI-S) tumors (hazard ratio, 2.2; 95% CI, 1.4 to 3.4; P = .0003). CONCLUSION: In stage II-III colon cancer, the KRAS mutation status does not have major prognostic value. BRAF is prognostic for OS in MS-L/S tumors.

Behavior of nuclear matrix proteins during camptothecin-induced apoptosis in HL-60 human leukemia cells.

In this study we focused our attention on the behavior of four nuclear matrix proteins during the various stages of apoptosis in the HL-60 cell line exposed to the DNA topoisomerase I inhibitor, camptothecin. We have examined the following antigens by immunocytochemical techniques: (i) the 180-kDa nucleolar isoform of DNA topoisomerase II; (ii) a 126-kDa polypeptide of nuclear bodies; (iii) a 125-kDa protein; and (iv) a 160-kDa polypeptide which are known to be components of the matrix inner network. Indirect immunofluorescence experiments were performed to follow these nuclear matrix antigens during apoptosis. Moreover, the ultrastructural localization of both 125- and 160-kDa proteins was investigated by electron microscope immunocytochemistry with gold-conjugated secondary antibodies. While the antibody to the nucleolar isoform of DNA topoisomerase II gave a fluorescent pattern that was well-maintained until the late phases of apoptosis, the other three nuclear antigens showed marked modifications in their distribution. A common feature, particularly evident for 125- and 160-kDa proteins, was their absence from cap-shaped chromatin marginations, whereas they were present in the areas of remaining decondensed chromatin. The 126-kDa polypeptide concentrated progressively in an irregular mass at the opposite side of the crescentic caps and then broke up in fine spots. The 125- and 160-kDa proteins localized in the nucleolus and precisely within certain granules which are known to appear in the nucleolar area after camptothecin administration. These results show that, in addition to the well-known chromatin changes, nuclear organization undergoes other rearrangements during the apoptotic process.

Catalogue d'une vente aux enchères publiques pour cause de départ de M. Tuite,... d'environ 60 tableaux... / [expert] Febvre

[Vente. Art. 1859-05-18 - 1859-05-19. Paris]

Phenotyping of 60 cultured human gliomas and 34 other neuroectodermal tumors by means of monoclonal antibodies against glioma, melanoma and HLA-DR antigens.

The reactivity spectrum of three monoclonal antibodies (Mabs) to human malignant glioma, five Mabs to melanomas and one Mab anti-HLA-DR was investigated by an indirect antibody binding radioimmunoassay on a panel of cells derived from 60 glioma lines, including 47 malignant astrocytomas, 11 low-grade astrocytomas and two malignant ependymomas as well on cells from 12 melanoma, three neuroblastoma, three medulloblastoma, two schwannoma, two retinoblastoma, two choroïd plexus papilloma, ten meningioma and 12 unrelated tumor lines. The anti-glioma Mabs BF7 and GE2 reacted preferentially with gliomas, while the anti-glioma Mab CG12 reacted with gliomas, melanomas, neuroblastomas and medulloblastomas. The five anti-melanoma Mabs reacted with gliomas, neuroblastomas and medulloblastomas. The anti-HLA-DR Mab D1-12 reacted with gliomas, melanomas and some meningiomas. On the basis of the data presented, we describe three different antigenic systems; the first one is glioma-associated, the second one is related to differentiation antigens expressed on cells derived from the neuroectoderm and the third is represented by HLA-DR antigens which are expressed not only on B-lymphoblastoid cells but also on melanomas and gliomas.

Prospective association of the SHARE-operationalized frailty phenotype with adverse health outcomes: evidence from 60+ community-dwelling Europeans living in 11 countries.

BACKGROUND: Among the many definitions of frailty, the frailty phenotype defined by Fried et al. is one of few constructs that has been repeatedly validated: first in the Cardiovascular Health Study (CHS) and subsequently in other large cohorts in the North America. In Europe, the Survey of Health, Aging and Retirement in Europe (SHARE) is a gold mine of individual, economic and health information that can provide insight into better understanding of frailty across diverse population settings. A recent adaptation of the original five CHS-frailty criteria was proposed to make use of SHARE data and measure frailty in the European population. To test the validity of the SHARE operationalized frailty phenotype, this study aims to evaluate its prospective association with adverse health outcomes. METHODS: Data are from 11,015 community-dwelling men and women aged 60+ participating in wave 1 and 2 of the Survey of Health, Aging and Retirement in Europe, a population-based survey. Multivariate logistic regression analyses were used to assess the 2-year follow up effect of SHARE-operationalized frailty phenotype on the incidence of disability (disability-free at baseline) and on worsening disability and morbidity, adjusting for age, sex, income and baseline morbidity and disability. RESULTS: At 2-year follow up, frail individuals were at increased risk for: developing mobility (OR 3.07, 95% CI, 1.02-9.36), IADL (OR 5.52, 95% CI, 3.76-8.10) and BADL (OR 5.13, 95% CI, 3.53-7.44) disability; worsening mobility (OR 2.94, 95% CI, 2.19- 3.93) IADL (OR 4.43, 95% CI, 3.19-6.15) and BADL disability (OR 4.53, 95% CI, 3.14-6.54); and worsening morbidity (OR 1.77, 95% CI, 1.35-2.32). These associations were significant even among the prefrail, but with a lower magnitude of effect. CONCLUSIONS: The SHARE-operationalized frailty phenotype is significantly associated with all tested health outcomes independent of baseline morbidity and disability in community-dwelling men and women aged 60 and older living in Europe. The robustness of results validate the use of this phenotype in the SHARE survey for future research on frailty in Europe.