Abstract

The Past, Present, Future of Cervical Arthroplasty

Seung Hwan Yoon

Ideally, cervical arthroplasty has been introduced to maintain cervical motion and potentially avoid or minimize adjacent-segment degeneration. If cervical arthroplasty would be successful, the long-term results of surgery for cervical disc disease may improve all the time. However, there have been reported associated problems; kyphosis after Bryan, heterotopic ossification induced motion limitation, no motion preservation even at index level and higher revision rate compared to ACDF in limited cases. Also, the risk of developing adjacent segment degeneration was equivalent at over 2 year follow up reports after both ACDF and cervical arthroplasty procedures in cervical degenerative disc disorders. Cervical disk arthroplasty, one of the emerging motion-sparing technologies, is currently undergoing evaluation in the many country as an alternative to arthrodesis for the treatment of cervical radiculopathy and myelopathy. There are many challenges when deciding between arthrodesis and arthroplasty. Prosthetic performance demands exacting implantation techniques to ensure correct placement, thus placing increasing demands on special instrumentation and surgical skills. It demands to understand the prosthetic lubrication, wear, and biologic effects and to be familiar with currently available information regarding kinematics, basic science, testing, and early clinical results. Fortunately, by too much research, a number of devices are either at the late stage of preclinical study or in the early stage of clinical trial, and the results maybe promising. New design device will be produced to replace totally or partially patient spinal disc largely dependent on the pathological entity in near future.

Moximed － KineSpring System: A New Way to Treat Medial Osteoarthritis

Gernot Willscheid, Casper Grim and Martin Engelhardt

Osteoarthritis (OA) of the knee is a major public health problem whose prevalence is expected to grow dramatically with the aging of the population and increasing rates of obesity. Besides this numerous studies have shown a correlation between load, disease progression and pain in medial osteoarthritic knees. Several unloading interventions such as weight loss, wedged insoles, knee braces, HTO, and joint distraction provide proof of concept.The goal is to expand upon these preliminary findings to develop and evaluate minimally invasive modalities that effectively alter the joint loading patterns and clinical course of this disease. To help restore normal joint loading conditions, the KineSpring System’s absorber component reduces loads on the medial knee during the stance phase of gait and remains passive during the swing phase of gait. It is implanted extra-capsular and extra-articular in the subcutaneous tissue alongside the medial aspect of the joint. There is no need to remove bone, ligament, or cartilage. This presentation showes a new way to treat medial osteoarthritis especially for middle aged patient or for patients that are not ideal for HTO or unicompartimental knee replacements.

Split Immunity: Immune Inhibition of Rat Gliomas by Subcutaneous Exposure to Unmodified Live Tumor Cells - 2012 Update

Ilan Volovitz, Yotvat Marmor, Meir Azulay, Arthur Machlenkin, Ofir Goldberger, Felix Mor, Shimon Slavin, Zvi Ram, Irun R. Cohen and Lea Eisenbach

Gliomas, which appear to grow uninhibited in the brain, almost never metastasize outside the CNS. The rare occurrences of extracranial metastasis are usually associated with an immune compromised status of the host. This observation raises the possibility that some gliomas might not grow outside the CNS due to an inherent immune response. We now report that the highly malignant F98 Fischer rat undifferentiated glioma, which grows aggressively in the brain, spontaneously regresses when injected live subcutaneously (sc). We found that this regression is immune-mediated and that it markedly enhances the survival, or cures rats challenged with the same tumor intracranially (ic) either before or after the sc live-cell inoculation. Adoptive transfer experiments showed the effect was immune-mediated, and that the CD8 T-cell fraction, which exhibited direct tumor cytotoxicity, was more effective than the CD4 T-cell fraction in mediating resistance to intracranial challenge of na?ve rats. The results in the F98 model were corroborated also in the Lewis rat CNS-1 astrocytoma model. In both tumor models the unprecedented survival results using live-cell immunization were significantly better than those achieved using immunization with irradiated cells. We propose here a location-based immunotherapeutic phenomenon we term ‘Split immunity’: a tumor that thrives in an immune privileged site may be inhibited by injecting live unmodified tumor cells in a site that is not privileged, generating protective immunity that spreads back to the privileged site. Split immunity could explain several long-standing paradoxes regarding the lack of overt extracranial metastasis in patients with primary brain tumors. (www.jimmunol.org/content/early/2011/10/12/jimmunol.1003946.full.pdf)

Genetic Variants Associated with Age-related Traits and Diseases in the Sardinian Population

David Schlessinger and Goncalo Abecasis

Age-related diseases are “complex traits,” influenced by many genes and environmental factors. Simplifying genetic studies, Sardinia provides a population that grew from an original cohort 10,000 years ago to a modern population of 1,500,000, and is relatively homogeneous but with excellent coverage of European genetic variation. Over 12 years the SardiNIA project has reported analyses in a group of 7,000 participants in a cluster of 4 towns, with comparable numbers of males and females aged 14 to 102, to find genetic factors affecting >300 quantitative traits. Participants repeat visits every 3 years to provide longitudinal information about diagnostic/prognostic value of findings. In >90 publications, genome-wide association studies have reported on anthropometric, blood chemistry, personality, pro-inflammatory molecules and cytokines, and recently, immune system cell traits (see Abstract of Francesco Cucca). Many of the genetic variants associated with traits are also risk factors for disease － for example, variants affecting both cholesterol and coronary artery disease. Based on sequencing of DNA and RNA of participants’ lymphocytes, an enriched catalogue of non-coding RNA and coding gene variants provides further power to discriminate “causal” variants and mechanisms at loci identified by GWAS; analyses often reveal more than one associated variant in the same gene and thus account for an increasing fraction of heritability. In a direct assessment for a disease phenotype closely related to possible clinical intervention, variants in the transcription factor BCL11A were shown to prolong the formation of fetal hemoglobin － and thus alleviate thalassemia and sickle cell disease.

Finding Genetic Factors in the Sardinian Population for Both Levels of Immune Cells and Molecules, and Correlated Autoimmune Disease Pathogenesis

Francesco Cucca, Goncalo Abecasis and David Schlessinger

Genome-Wide Association Scans (GWAS) have greatly expanded our understanding of the genes involved in autoimmunity. Major challenges now are to increase the spectrum of disease loci, to reduce the associated variants at each locus to the causal change -the “fine mapping” stage?and to link genes and variants with function to explain pathogenesis. To meet these challenges, we have started 3 integrated initiatives in the founder, autoimmunity-prone Sardinian population. In one initiative, whole genome sequencing of >2,000 Sardinians yielded over 17,600,000 variants for marker imputation in association testing. In a second initiative, we assembled cohorts of ~3,000 Sardinian multiple sclerosis cases, ~2,000 diabetes Type 1 cases, and ~4,000 controls, and performed a sequencing based genome-wide association study (GWAS), finding some new disease loci and refining known ones to likely candidate causal variants. The third initiative was designed to profile comprehensively the inherited phenotypic structure of the human immune system in ~3,500 of the ~7,000 volunteers of the SardiNIA cohort longitudinal study (see Abstract of David Schlessinger) to identify variants by sequencing- based GWAS that regulate the levels of different immune cell types and soluble molecules, and relate them to autoimmune disease risk alleles. Several variants associated at P < 10^－8 were found, with some of them overlapping known autoimmune disease risk variants. Taken together, the 3 approaches can thus relate specific immune phenotypes to disease risk, providing an entr?e to functional studies of steps in pathogenesis.

Neurofibromatosis Type 1-like Syndrome Or Legius Syndrome: An Update

Eric Legius

Multiple caf?-au-lait spots are the hallmark of Von Recklinghausen disease or neurofibromatosis type 1. In 2007 our group reported that some individuals with multiple caf?-au-lait spots have a heterozygous mutation in the SPRED1 gene and have neurofibromatosis type 1-like syndrome or Legius syndrome. It is estimated that about 1?4% of individuals with multiple caf?-au-lait spots have a heterozygous SPRED1 mutation. Mutational data on SPRED1 and clinical data from 146 patients are tabulated in an online database (http://www.lovd.nl/SPRED1). The SPRED1 gene was identified in 2001 and codes for a protein that downregulates the RAS-MAPKinase pathway similar to neurofibromin, the protein encoded by the NF1 gene. Individuals with Legius syndrome have multiple caf?-au-lait spots with or without freckling, but they do not show the typical NF1 associated tumors such as neurofibromas or optic pathway gliomas. Neurofibromatosis type 1 associated bone abnormalities and Lisch nodules are also not reported in patients with Legius syndrome. It was however shown that children with Legius syndrome have a higher incidence of learning disabilities and attention deficit disorder compared to the general population. Mice with a homozygous knock-out of the Spred1 gene show similar learning deficits and decreased synaptic plasticity in hippocampal neurons as seen in Nf1 heterozygous mice, underlining the importance of the RAS-MAPKinase pathway for learning and memory. Recently a specific binding between neurofibromin and SPRED1 was demonstrated. SPRED1 seems to be important to recruit neurofibromin to the plasma membrane.

The Pancreas in Diabetes

Peter C. Butler

The pancreas is composed of the exocrine and endocrine compartment, the former being ~98% of the organ. In individuals with type 1 and type 2 diabetes the exocrine pancres is decreased in size, has an increased risk of pancreatitis and pancreatic cancer. The islets in type 1 diabetes are largely but not always devoid of beta cells and in type 2 diabetes islets are ~60% deficient in beta cells. In both type 1 and type 2 diabetes there is increased beta cell apoptosis that appears to be ongoing over a long period. It is possible that the chemokines released by processes related to beta cell apoptosis in type 1 and 2 diabetes may drive regeneration programs comparable to those in ulcerative colitis. If so, then it would be predicted that there is a stem niche in the pancreas that may be chronically stimulated in both type 1 and 2 diabetes. The possible role of such a stem cell niche in the link between diabetes and pancreatic cancer, and the role of drugs used for treatment of type 2 diabetes will be discussed.

Autologous T Cells as a Personalized Treatment for Patients with Cancer

Steven Rosenberg

The adoptive transfer of anti-tumor T cells can mediate regression of established metastatic cancers in patients. In a series of three sequential clinical trials we treated patients with metastatic melanoma using autologous tumor infiltrating lymphocytes (TIL) selected for anti-tumor activity. These cells were adoptively transferred to patients following the administration of a lymphodepleting regimen of cyclophosphamide and fludarabine with or without whole body irradiation. In three pilot trials objective response rates of 49%?72% (RECIST criteria) were observed. Twenty of 93 patients (22%) achieved a complete tumor regression of widespread cancer and 19 of these 20 patients have ongoing complete responses at 59 to 104 months. Significant correlations with the incidence of patient response were seen with persistence of the infused transferred cells at one month, longer telomeres of the transferred cells, and the percent and number of CD27+ infused cells. There was no evidence of T regulatory cells in the infused samples, though there was an inverse correlation between the likelihood of objective clinical response and reconstitution with Foxp3+ CD4+ T cells in the peripheral circulation at 1 week. New techniques utilizing exomic sequencing have been used to identify multiple mutated antigens recognized by TIL.Because melanomas are the only histologic type of cancer that readily gives rise to TIL with demonstrable anti-tumor activity, we have begun a series of clinical trials using the transduction of genes encoding cytokines or anti-tumor T cell receptors (TCR) into normal peripheral lymphocytes for use in adoptive cell transfer. Anti-tumor TCRs have been identified that recognize the MART-1 and gp100 melanoma/melanocyte antigens and 30% of melanoma patients receiving autologous cells transduced with genes encoding these TCRs showed an objective response. Autologous cells transduced with genes encoding the anti-NY-ESO-1 TCR cancer-testes antigen mediated objective clinical responses in 80% of patients with synovial cell sarcoma and 50% of patients with melanoma. Patients with B cell lymphomas exhibited an 80% objective regression rate using cells transduced with a CD19 chimeric antibody TCR. The cellular and molecular mechanisms of T cell destruction of cancers are under active investigation. These studies demonstrate the power and potential of adoptive T cell immunotherapy to mediate the regression of established metastatic cancers in humans.