ERCC1 expression in aseptic loosening after total hip replacement.
ABSTRACT Particle-induced osteolysis is a major cause of aseptic loosening after total joint replacement. The purpose of the current study was to evaluate the DNA damage repair capacity of macrophages in patients with aseptic hip loosening by determination of ERCC1. Moreover, we wanted to elucidate if the potency of the DNA-repair mechanisms correlates with the survival of joint implants. For this purpose we compared the immunohistochemical ERCC1 expression in capsules and interface membranes of patients with loosening of a hip replacement in the first 10 years after implantation with those in patients with late loosening. In analogy with ERCC1 studies on cancer in humans we calculated the semi-quantitative H-score by multiplying the staining intensity with the proportion score of positive stained macrophages. The level of ERCC1 reaction in the specimens taken from patients with early aseptic loosening (mean H-score 0.57) was clearly lower in comparison with those from patients undergoing exchange hip arthroplasty later than 10 years after surgery (mean H-score 2.24). We determined an H-score for ERCC1 expression of 1 as a cutoff point giving a sensitivity and specificity of 100% for identification of early aseptic loosening after less than 10 years. In summary, lower levels of ERCC1 were found in patients with early aseptic loosening compared to patients with aseptic loosening later than 10 years.
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ABSTRACT: To assess the correlation of excision repair cross complementation group 1 (ERCC1) immunohistochemical expression with objective tumor response and cancer-specific survival in patients with locally advanced head and neck squamous cell carcinoma treated with cisplatin-based induction chemotherapy. The initial cohort was composed of 107 patients who were treated from 1992 to 1996 by an induction chemotherapy regimen for locally advanced head and neck squamous cell carcinoma. p53 mutations had previously been studied. Pretherapeutic biopsy samples from 96 patients with a known tumor response were available. Two independent observers blinded to clinical annotations evaluated ERCC1 immunohistochemical expression. Of 96 patients, 68 (71%; 95% confidence interval, 61-79%) had tumors that expressed ERCC1 intensively and diffusely. Using the logistic regression method, the 28 (29%) patients with tumors expressing ERCC1 at lower levels had a 4-fold greater odds of benefiting from an objective response to chemotherapy (odds ratio, 4.3; 95% confidence interval, 1.4-13.4; P = 0.01) compared with the group of 68 patients with high ERCC1 expression. ERCC1 and p53 status, but not their interaction, were independent predictors of tumor response. In a Cox proportional hazard model adjusted on age, TNM stage, tumor differentiation, and tumor localization, ERCC1 low expression was associated with a lower risk of cancer death (risk ratio, 0.42; 95% confidence interval, 0.20-0.90; P = 0.04) whereas p53 status had no prognostic value. Our results suggest that those patients characterized by low ERCC1 expression are more likely to benefit from cisplatin induction chemotherapy compared with patients with high ERCC1 expression.Clinical Cancer Research 08/2007; 13(13):3855-9. · 7.84 Impact Factor
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ABSTRACT: Particle-induced osteolysis is a major cause of aseptic loosening after total joint replacement. The purpose of the current study was to identify various apoptosis-related pathways in the cellular response to wear debris. Fas receptor, BAK and caspase-3 cleaved were evaluated immunohistochemically in capsules and interface membranes from patients with aseptic hip implant loosening. Moreover, we investigated local cellular proliferation, documented by the presence of Ki-67, to evaluate the proportion of apoptosis in relation to the proliferation in the different cells. We detected a strong expression of caspase-3 cleaved, Fas and BAK in macrophages, giant cells and T-lymphocytes. The fibroblasts showed caspase-3 cleaved and BAK, but no Fas staining. Demonstrated by Ki-67 staining, we found increased proliferation of macrophages and fibroblasts. Statistical analysis showed a significant positive correlation (p<0.001) between the above mentioned results and the presence of wear debris. The intensity of apoptosis and proliferation differed, depending on the extent of osteolysis. Overall, four different patterns of immunoreactivity were identified. We think, however, that in particle-induced osteolysis apoptosis is pathologically increased - a phenomenon also seen in other diseases. In these instances, the number and degree of apoptotic reactions are so great that the resulting cell remains cannot be completely removed. This leads to an increased excretion of fibrogenic mediators that could be responsible for increased proliferation of fibroblasts in spite of the increased apoptosis. Moreover, it leads to an increased excretion of cytokines which could be responsible for the activation of osteoclasts.Biomaterials 01/2008; 29(24-25):3444-50. · 7.60 Impact Factor
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ABSTRACT: Humans are exposed to metals from industry, the environment and from wear debris from worn orthopaedic joint replacements. Patients exposed to worn cobalt chrome hip replacements show an increase of chromosome aberrations in the bone marrow adjacent to the implant and an increase of chromosome translocations and aneuploidy in the peripheral blood. This study has tested whether particles of surgical cobalt chrome alloy are able to induce similar DNA damage and chromosome aberrations in human cells in vitro. Because increasingly young patients are receiving hip replacements it has also tested whether the response is altered at different cellular age in vitro. Primary human fibroblasts, were tested at different pre senescent population doublings (PD10 (young) and PD35 (older)) to particles of cobalt chrome alloy for up to 15 days. As in patients there was an increase of aneuploidy, chromosome translocations and DNA damage after exposure to the cobalt chrome particles in vitro. The overall level of DNA damage and numerical and structural aberrations was approximately the same in young and older cells. However, the cellular reaction to the DNA damage was different. Older cells showed a greater loss of viability and induction of senescence and a lesser rate of mitosis and cell growth than young cells. They showed less change in transcription, particularly of p38 and caspase 10 mRNA levels, than young cells. They showed more complex aneuploidy in association with unseparated or prematurely separated chromatids. This study suggests that at least part of the chromosome changes in patients with worn implants may be due to direct effects of the metal wear particles from the implant. It would be of interest to test whether the altered reaction of the human cells at different in vitro age might correspond with a different incidence of chromosome aberrations in patients at different ages.Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis 07/2007; 619(1-2):45-58. · 3.90 Impact Factor