Aneuploidy and prognosis of non-small-cell lung cancer: a meta-analysis of published data

In lung cancer, DNA content abnormalities have been described as a heterogeneous spectrum of impaired tumour cell DNA histogram patterns. They are merged into the common term of aneuploidy and probably reflect a high genotypic instability. In non-small-cell lung cancer, the negative effect of aneuploidy has been a subject of controversy inasmuch as studies aimed at determining the survival–DNA content relationship have reported conflicting results. We made a meta-analysis of published studies aimed at determining the prognostic effect of aneuploidy in surgically resected non-small-cell lung cancer. 35 trials have been identified in the literature. A comprehensive collection of data has been constructed taking into account the following parameters: quality of specimen, DNA content assessment method, aneuploidy definition, histology and stage grouping, quality of surgical resection and demographic characteristics of the analysed population. Among the 4033 assessable patients, 2626 suffered from non-small-cell lung cancer with aneuploid DNA content (overall frequency of aneuploidy: 0.65; 95% CI: (0.64–0.67)). The DerSimonian and Laird method was used to estimate the size effects and the Peto and Yusuf method was used in order to generate the odds ratios (OR) of reduction in risk of death for patients affected by a nearly diploid (non-aneuploid) non-small-cell lung cancer. Survivals following surgical resection, from 1 to 5 years, were chosen as the end-points of our meta-analysis. Patients suffering from a nearly diploid tumour benefited from a significant reduction in risk of death at 1, 2, 3 and 4 years with respective OR: 0.51, 0.51, 0.45 and 0.67 (P< 10−4for each end-point). 5 years after resection, the reduction of death was of lesser magnitude: OR: 0.87 (P = 0.08). The test for overall statistical heterogeneity was conventionally significant (P< 0.01) for all 5 end-points, however. None of the recorded characteristics of the studies could explain this phenomenon precluding a subset analysis. Therefore, the DerSimonian and Laird method was applied inasmuch as this method allows a correction for heterogeneity. This method demonstrated an increase in survival at 1, 2, 3, 4 and 5 years for patients with diploid tumours with respective size effects of 0.11, 0.15, 0.20, 0.20 and 0.21 (value taking into account the correction for heterogeneity;P< 10−4for each end-point). Patients who benefit from a surgical resection for non-small-cell lung cancer with aneuploid DNA content prove to have a higher risk of death. This negative prognostic factor decreases the probability of survival by 11% at one year, a negative effect deteriorating up to 21% at 5 years following surgery. © 2001 Cancer Research Campaign http://www.bjcancer.co

Standars e controlli in citometria a flusso

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Il trattamento del carcinoma mammario: problemi risolti e da risolvere.

PROGRESSI IN CHIRURGIA, VOL. II N°2, PAG. 9 - 15; 199

Radioresistance in a tumour cell line correlates with radiation inducible Ku 70/80 end-binding activity

PURPOSE: The aims of the present study were to better understand the role of Ku80, which is involved in double-strand break repair in mammalian cells in themechanism of radiation resistance and to verify the possibility of increasingcell radiosensitivity by targeted inhibition of Ku autoantigen 80 (Ku 80).MATERIALS AND METHODS: Western blot and electrophoretic mobility shift assay (EMSA) were performed on the human bladder carcinoma cell line RT112(radioresistant) and on the human colorectal carcinoma cell line SW48(radiosensitive) to assess the expression levels of DNA-dependent protein kinase(DNA-PK) components and the DNA-binding activity of the Ku 70/80 heterodimerafter exposure to radiation, respectively. Ku 80 silencing was carried out withthe use of small interfering RNA (siRNA). RESULTS: Greater differences in theDNA-binding activity of Ku 70/80 and Ku 80 phosphorylation level were observed inRT112 as compared to SW48 after X-ray treatment. There is no correlation betweenKu expression and DNA-binding activity at lower doses. A significant increase innuclear Ku 80 expression was observed one hour after the exposure, only at thehigher doses, while the DNA-PK catalytic subunits (DNA-PKcs) and Ku 70 levels didnot change significantly. Inhibition of Ku 80 expression by siRNA inducedradiosensitivity in the RT112 cell line. CONCLUSIONS: Our data demonstrate thatin a bladder tumour cell line up-regulation of Ku end-binding activity withoutany marked change in Ku expression underlie radiation resistance