Reduced Risk of Revision with Computer-Guided Versus Non-Computer-Guided THA: An Analysis of Manufacturer-Specific Data from the National Joint Registry of England, Wales, Northern Ireland and the Isle of Man.

Computer-assisted total hip arthroplasty (THA) is known to improve implantation precision, but clinical data demonstrating an improvement in survivorship and patient-reported outcome measures (PROMs) are lacking. Our aim was to compare the risk of revision, PROMs, and patient satisfaction between cohorts who underwent THA with and without the use of computer guidance. METHODS: We used the data set and linked PROM data of the National Joint Registry of England, Wales, Northern Ireland and the Isle of Man. Our sample included THAs performed for osteoarthritis using cementless acetabular components from a single manufacturer (cementless and hybrid THAs). An additional analysis was performed limiting the sample size to cementless-only THAs. The primary end point was revision (any component) for any reason. Kaplan-Meier survivorship analysis and an adjusted Cox proportional-hazards model were used. RESULTS: There were 41,683 non-computer-guided and 871 (2%) computer-guided cases included in our analysis of the cementless and hybrid group. There were 943 revisions in the non-computer-guided group and 7 in the computer-guided group. The cumulative revision rate at 10 years was 3.88% (95% confidence interval [CI]: 3.59% to 4.18%) for the non-computer-guided group and 1.06% (95% CI: 0.45% to 2.76%) for the computer-guided group. The Cox proportional-hazards model yielded a hazard ratio of 0.45 (95% CI: 0.21 to 0.96; p = 0.038). In the analysis of the cementless-only group, the cumulative revision rate at 10 years was 3.99% (95% CI: 3.62% to 4.38%) and 1.20% (95% CI: 0.52% to 3.12%) for the 2 groups, respectively. The Cox proportional-hazards model yielded a hazard ratio of 0.47 (95% CI: 0.22 to 1.01; p = 0.053). There was no significant difference in the 6-month Oxford Hip Score, the EuroQol-5 Dimension (EQ-5D) and EQ-VAS (Visual Analogue Scale) scores, and patient-reported success rates. Patient satisfaction (single-item satisfaction outcome measure) was higher in the computer-guided group, but this finding was limited by a reduced number of responses. CONCLUSIONS: In our analysis, the use of computer-guided surgery was associated with a lower rate of revision at mean follow-up of 5.6 years. This finding was upheld when the sample was restricted to cementless-only THAs. Causality cannot be inferred in view of the observational nature of the study, and additional studies are recommended to validate these findings. LEVEL OF EVIDENCE: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.

The cyclin-dependent kinase inhibitor, p21(WAF1), promotes angiogenesis by repressing gene transcription of thioredoxin-binding protein 2 in cancer cells.

The cyclin-dependent kinase inhibitor, p21(WAF1), induces cell-cycle arrest and can act as a tumor suppressor. However, increasing evidence indicates that p21(WAF1) can also increase resistance to some anticancer therapies and thus promote tumor growth. The mechanisms explaining this paradox have not been explained. We found that conditioned media from MCF-7 breast cancer cells transfected with a p21(WAF1)-specific small interfering RNA (siRNA) significantly reduced endothelial cell migration, invasion and vascular sprouting. Liquid chromatography/mass spectrometry analysis of the conditioned media revealed that p21(WAF1) knockdown significantly reduced secretion of thioredoxin (Trx), a redox protein known to promote tumor angiogenesis. p21(WAF1) knockdown decreased Trx enzymatic activity in cancer cells, by effects on the expression levels of intracellular thioredoxin-binding protein 2 (TBP2), known to bind and inactivate Trx. Consistent with these findings, media from cancer cells transfected with TBP2 siRNA promoted endothelial cell invasion and blocked the anti-angiogenic effect of p21(WAF1) siRNA. Addition of Trx siRNA blocked the pro-angiogenic effects of TBP2 siRNA. Chromatin immunoprecipitation assays showed p21(WAF1) bound TBP2 gene promoter. Taken together, our data suggests that p21(WAF1) can induce Trx secretion and angiogenesis in cancer cells, by direct transcriptional repression of the TBP2 promoter.

Enhancing the anti-angiogenic action of histone deacetylase inhibitors.

BACKGROUND: Histone deacetylase inhibitors (HDACIs) have many effects on cancer cells, such as growth inhibition, induction of cell death, differentiation, and anti-angiogenesis, all with a wide therapeutic index. However, clinical trials demonstrate that HDACIs are more likely to be effective when used in combination with other anticancer agents. Moreover, the molecular basis for the anti-cancer action of HDACIs is still unknown. In this study, we compared different combinations of HDACIs and anti-cancer agents with anti-angiogenic effects, and analysed their mechanism of action. RESULTS: Trichostatin A (TSA) and alpha-interferon (IFNalpha) were the most effective combination across a range of different cancer cell lines, while normal non-malignant cells did not respond in the same manner to the combination therapy. There was a close correlation between absence of basal p21WAF1 expression and response to TSA and IFNalpha treatment. Moreover, inhibition of p21WAF1 expression in a p21WAF1-expressing breast cancer cell line by a specific siRNA increased the cytotoxic effects of TSA and IFNalpha. In vitro assays of endothelial cell function showed that TSA and IFNalpha decreased endothelial cell migration, invasion, and capillary tubule formation, without affecting endothelial cell viability. TSA and IFNalpha co-operatively inhibited gene expression of some pro-angiogenic factors: vascular endothelial growth factor, hypoxia-inducible factor 1alpha and matrix metalloproteinase 9, in neuroblastoma cells under hypoxic conditions. Combination TSA and IFNalpha therapy markedly reduced tumour angiogenesis in neuroblastoma-bearing transgenic mice. CONCLUSION: Our results indicate that combination TSA and IFNalpha therapy has potent co-operative cytotoxic and anti-angiogenic activity. High basal p21WAF1 expression appears to be acting as a resistance factor to the combination therapy.

Histone deacetylase inhibitors: multifunctional anticancer agents.

Acetylation and deacetylation of chromatin histone protein by histone deacetylase (HDAC) alters chromatin structure and dynamically affects transcriptional regulation. Many lines of evidence indicate that histone hypo-acetylation induces repression of tumour suppressor gene expression. Small molecule inhibitors of HDAC (HDACI) are highly effective in up-regulating tumour suppressor gene expression, reducing tumour growth and inducing programmed cell death in vitro and in cancer patients in phase I and II clinical trials. HDACI-induced growth inhibition and cytotoxicity have been attributed to acetylation of both histone and non-histone proteins. Less studied, but equally important, is the role of HDAC and HDACI on other components of the malignant phenotype: tumour initiation and progression. In this review, we summarise evidence indicating that the in vivo anti-cancer efficacy of HDACIs is at least in part dependent on suppression of cancer cell migration, invasion, metastasis, blood supply, and angiogenesis. As histone hypo-acetylation is involved in the tumourigenesis of various haematological and solid malignancies, the clinical use of HDACIs in patients at high risk of cancer or with precancerous conditions warrants further investigation.