Complications of closing wedge high tibial osteotomies for unicompartmental osteoarthritis of the knee.

We systematically reviewed the published literature on the complications of closing wedge high tibial osteotomy for the treatment of unicompartmental osteoarthritis of the knee. Publications were identified using the Cochrane Library, MEDLINE, EMBASE and CINAHL databases up to February 2012. We assessed randomised (RCTs), controlled group clinical (CCTs) trials, case series in publications associated with closing wedge osteotomy of the tibia in patients with osteoarthritis of the knee and finally a Cochrane review. Many of these trials included comparative studies (opening wedge versus closing wedge) and there was heterogeneity in the studies that prevented pooling of the results.

The influence of expression of P-glycoprotein on the penetration of anticancer drugs through multicellular layers.

The success of chemotherapy in the treatment of solid tumours may be limited by cellular mechanisms leading to drug resistance and/or by the slow penetration of drugs through tissue, resulting in a steep concentration gradient from tumour blood vessels. One mechanism leading to the development of multidrug resistance is overexpression of the membrane-based export pump P-glycoprotein (P-gp). The relationship between expression of P-gp by constituent cells and the penetration of P-gp substrates through tissue was studied by comparing the penetration of P-gp substrates through multicellular layers derived from either wild-type or P-gp overexpressing cell lines. P-gp reversal agents were added to confirm the contribution of P-gp in influencing the penetration of its substrates. Our data indicate: 1) penetration of the P-gp substrates, 99mTc-sestaMIBI and 14C-doxorubicin, is greater through multicellular layers formed from P-gp overexpressing cell lines as compared with wild-type cells; 2) the addition of agents that inhibit the function of P-gp results in decreased penetration of these substrates through multicellular layers with P-gp expression. There was no effect of P-gp reversal agents on penetration of 14C-sucrose or of 3H-5-fluorouracil (non-substrate controls). Our data suggest that the administration of agents that inhibit the function of P-gp might have opposing effects on therapeutic index in solid tumours: increased sensitivity of perivascular tumour cells but decreased penetration of P-gp substrates to more distal cells. These effects may explain, in part, the limited therapeutic benefit for solid tumours that has accrued from use of agents that reverse the effects of P-gp.

Penetration of anticancer drugs through solid tissue: a factor that limits the effectiveness of chemotherapy for solid tumors.

Penetration of anticancer agents to cells distant from the vascular system is required for efficacy of cancer chemotherapy against solid tumors. Many solid tumors have a poorly formed blood vascular system with variable rates of blood flow and much larger intercapillary distances than those found in normal tissues. The requirement for drugs to penetrate several layers of tissue might pose a barrier to the effective treatment of solid tumors. Multicellular layers (approximately 200 microm thick) were grown in vitro on Teflon membranes from EMT6 murine and MCF7 human tumors and have been used to quantitate the penetration of four widely used anticancer drugs through solid tissue. The penetration of doxorubicin and mitoxantrone was limited and very slow (<10% of the rate of penetration through the Teflon membrane alone). The penetration of methotrexate and 5-FU was more rapid (approximately 30-50% of the rate of penetration through the Teflon membrane alone), but remains a substantial barrier to the effectiveness of these drugs. Strategies to improve the penetration of anticancer drugs through poorly vascularized tumor tissue have considerable potential to improve the outcome of chemotherapy for solid tumors.

Influence of cell concentration in limiting the therapeutic benefit of P-glycoprotein reversal agents.

Pharmacological reversal of multidrug resistance (MDR) has been demonstrated frequently in tissue culture, but there has been minimal evidence of therapeutic effectiveness for solid tumours of animals, or in clinical trials. The concentration of cells in solid tumours is approx. 10(9) cells/ml but typically 10(5)-10(6) cells/ml in tissue culture. We investigated, therefore, the influence of cell concentration in culture on the ability of verapamil and cyclosporin A to increase the sensitivity of MDR-expressing cells to doxorubicin. Our data indicate that: 1. the uptake of the MDR substrates, doxorubicin and 99mTc-SestaMIBI, and the toxicity of doxorubicin decrease at higher cell concentration; 2. the effect of reversal agents on uptake and cytotoxicity of MDR substrates decreases markedly at higher cell concentration; 3. cell concentration effects are not overcome by continuous replenishment of drug to maintain a stable extracellular concentration. Our results suggest one mechanism which may contribute to the failure to observe reversal of MDR in animals, or in patients bearing established solid tumours.