In this lecture I will present an update on the activities of the European KCK (KidsCancerKinome) consortium. Nine European research centers devoted to molecular-biologic, pharmacologic and clinical studies of childhood cancers and two SMEs are engaged in the KidsCancerKinome consortium. The research centers already have an established collaboration for pre-clinical evaluation of anti-cancer compounds in the European ‘Innovative Therapies for Children with Cancer’ consortium (ITCC). The KidsCancerKinome consortium aims to perform a comprehensive analysis of the human protein kinase family in childhood tumors, as protein kinases are excellent targets for small inhibitory molecules designed for adult tumors, and many more of such drugs are currently in development. Six aggressive childhood tumors, killing ~2000 children in Europe annually, will be addressed, i.e Ewing sarcoma, osteosarcoma, rhabdomyosarcoma, neuroblastoma, medulloblastoma and ALL. The KCK consortium has generated gene expression profiles (Affy U133plus2 arrays) of >
500 tumor samples form those six tumortypes. We have performed extensive analyses of mRNa expression of human kinases. Examples of interesting expression patterns of the human kinome will be presented. Detailed analyses for the first 5 kinases for which targetted drugs are available, i.e. PI3K, IGF1R, AURKA+B, and CDK2 will be presented. Lentiviral shRNA mediated knockdown of kinase protein expression has been used in cell lines to validate those kinases as drug targets. Many novel kinase inhibitors are under development for adult oncology and KCK will test their in vitro activity against the tumor-driving kinases identified in this program. We are currently testing small molecule inhibitors for the first 5 kinases. For those kinases that have no small molecule inhibitors, a novel generation of siRNA based nucleic acid drugs (LNAs), produced by the Santaris company, will be applied and tested in vitro. Successful small molecule inhibitors and LNAs will be taken further to in vivo validation in established xenograft models of the six childhood tumor types. Pharmaco-kinetic studies of these drugs will finally prepare them.
An extra articular correction may be necessary in osteoarthritis with an important post traumatic or congenital deformity. In the last 5 years we performed 11 TKR associated with a tibial (9 cases) or a femoral Osteotomy (2 cases), in one time surgery. The average intra osseous deformity was 14°. The technical problems are different in varus and valgus knees. 1- Which type of osteotomy ? In varus knees with a tibial deformity (6 cases) we use a hight tibial valgus osteotomy with opening wedge. Pre operative planning with long standing X rays allows precise determination of the amount of correction needed. A rigide wire, driven up to the fibular head, is placed. A provisional wedge of the desired size (degree of correction) is maintened temporarily by a staple, which will be removed later. Once the correction has been performed and maintened, the standard instrumentation to implant the prosthesis is used. In valgus knees with a tibial deformity (2 cases) a hight tibial closing wedge osteotomy, and in valgus knees with a femoral deformity (2 cases), a low femoral closing wedge osteotomy, are used. In all cases a medial approach without any release and without fibular osteotomy is performed. 2- Which kind of prosthesis? Two degrees of constraint are possible in fonction of particular needs. Most of the time, a non-constrained PS articular implants will be used and when more constraint will be needed (in lateral instability), CCK-type articular surfaces will be choised. In all cases, a stem will have to be, associated with the osteotomy (tibial or femoral). Different diameters will allow a good press-fit and if necessary, an offset stem will be used. 3- Associated osteosynthesis or not? Stability provided by the press-fit stem may allow not to use an osteosynthesis in most than 50% of cases. If a doubt remains about stability, a small plate can bee added on the medial tibial side of the tibia. 4- Which immediate post-op follow-up? Full weight bearing will be immediate. A splint will be used only for walking during six weeks. A standard rehabilitation protocole will be followed. In our 11 patients with a short follow up (1 to 5 years) complications consisted in one hematom and one phlebitis. Post-operative alpha angle was 96° and beta angle 91°. TKR with an associated osteotomy seems to be a possible alternative when osteoarthritis is associated with an important extra articular deformity.