Treatment of knee articular cartilage defects: surgical strategies, results and analysis of factors determining the clinical outcome

Articular cartilage lesions, with their inherent limited healing potential, are hard to treat and remain a challenging problem for orthopedic surgeons. Despite the development of several treatment strategies, the real potential of each procedure in terms of clinical benefit and effects on the joint degeneration processes is not clear. Aim of this PhD project was to evaluate the results, both in terms of clinical and imaging improvement, of new promising procedures developed to address the challenging cartilage pathology. Several studies have been followed in parallel and completed over the 3-year PhD, and are reported in detail in the following pages. In particular, the studies have been focused on the evaluation of the treatment indications of a scaffold based autologous chondrocyte implantation procedure, documenting its results for the classic indication of focal traumatic lesions, as well as its use for the treatment of more challenging patients, older, with degenerative lesions, or even as salvage procedure for more advanced stages of articular degeneration. The second field of study involved the analysis of the results obtained treating lesions of the articular surface with a new biomimetic osteochondral scaffold, which showed promise for the treatment of defects where the entire osteochondral unit is involved. Finally, a new minimally invasive procedure based on the use of growth factors derived from autologous platelets has been explored, showing results and underlining indicatios for the treatment of cartilage lesions and different stages of joint degeneration. These studies shed some light on the potential of the evaluated procedures, underlining good results as well as limits, they give some indications on the most appropriate candidates for their application, and document the current knowledge on cartilage treatment procedures suggesting the limitations that need to be addressed by future studies to improve the management of cartilage lesions.

Microenvironment and prognostic factors in bone tumors: IDH mutations in chondrosarcoma

Microenvironment in bone tumors is a dynamic entity composed of cells from different origins (immune cells, stromal cells, mesenchymal stem cells, endothelial cells, pericytes) and vascular structures surrounded by a matrix of different nature (bone, cartilage, myxoid). Interactions between cancer cells and tumor microenvironment (TME) are complex and can change as tumor progress, but are also crucial in determining response to cancer therapies. Chondrosarcoma is the second most frequent bone cancer in adult age, but its treatment still represents a challenge, for the intrinsic resistance to conventional chemotherapy and radiation therapy. This resistance is mainly due to pathological features, as dense matrix, scarce mitoses and poor vascularization, sustained by biological mechanisms only partially delucidated. Somatic mutation in the Krebs cycle enzyme isocytrate dehydrogenase (IDH) have been described in gliomas, acute myeloid leukemia, cholangiocarcinoma, melanoma, colorectal, prostate cancer, thyroid carcinoma and other cancers. In mesenchymal tumors IDH mutations are present in about 50% of central chondrosarcoma. IDH mutations are an early event in chondrosarcoma-genesis, and contribute to the acquisition of malignancy through the block of cellular differentiation, hypoxia induction through HIF stabilization, DNA methylation and alteration of cellular red-ox balance. While in gliomas IDH mutations confers a good prognosis, in chondrosarcoma IDH prognostic role is controversial in different reported series. First aim of this project is to define the prevalence and the prognostic role of IDH mutation in high grade central conventional chondrosarcoma patients treated at Istituto Ortopedico Rizzoli. Second aim is the critical revision of scientific literature to understand better how a genomic event in cancer cell can trigger alteration in the TME, through immune infiltrate reshaping, angiogenesis induction, metabolic and methylation rewiring. Third aim is to screen other sarcoma histotypes for the presence of IDH mutation.