Bovine Aortic Arch: A Marker For The Development And Progression Of Thoracic Aortic Disease

This study investigated the relationship between congenital bovine arch (BA) variant and thoracic aortic aneurysm (TAA), thoracic aortic expansion rate, bicuspid aortic valve (BAV), and aortic complications. We hypothesized that BA would be significantly associated with the presence and progression of thoracic aortic disease. To determine prevalence of BA, we retrospectively reviewed thoracic CT and/or MRI scans of 616 patients with thoracic aortic disease and 844 patients without thoracic aortic disease (all from Yale-New Haven Hospital). In patients with thoracic aortic disease, we assessed accuracy of official radiology reports in citing BA, and reviewed all available hospital records to determine disease location, thoracic aortic growth rate, presence of bicuspid aortic valve (BAV), and prevalence of thoracic aortic dissection and rupture in patients with and without BA. BA was observed in 26.1% of patients with thoracic aortic disease and 16.4% of patients without thoracic aortic disease (P\u3c0.001). Radiology reports cited BA in only 16.1% of patients with aortic disease and concomitant BA. There was no association between BA and location of aortic disease, prevalence of dissection (P=0.39), or presence of BAV (P=0.68). Rate of aortic expansion was 0.29 cm/year in the BA group and 0.09 cm/year in the non-BA group (P=0.003). Mean age at initial aortic repair was 56.2 years in BA patients and 61.4 years in non-BA patients (P=0.0004). Our findings suggest that BA is indeed associated with both the development and progression of thoracic aortic disease, and support the following conclusions: 1) BA is significantly more common in patients with thoracic aortic disease than in the general population. 2) Radiologists often overlook BA. 3) BA is not significantly associated with BAV, aortic dissection, or disease at any particular location within the thoracic aorta. 4) BA is associated with elevated TAA growth rate and earlier repair

The influence of HLA genotype on the development of metal hypersensitivity following joint replacement

We thank Innovate UK Edge for providing funding to allow this research to be carried out.Background  Over five million joint replacements are performed across the world each year. Cobalt chrome (CoCr) components are used in most of these procedures. Some patients develop delayed type hypersensitivity (DTH) responses to CoCr implants, resulting in tissue damage and revision surgery. DTH is unpredictable and genetic links have yet to be definitively established. Methods At a single site, we carried out an initial investigation to identify HLA alleles associated with development of DTH following metal-on-metal hip arthroplasty. We then recruited patients from other centres to train and validate an algorithm incorporating patient age, gender, HLA genotype44 and blood metal concentrations to predict the development of DTH. Accuracy of the modelling was assessed using performance metrics including time dependent receiver operator curves. Results Using next generation sequencing, here we determine the HLA genotypes of 606 patients. 176 of these patients had experienced failure of their prostheses; the remaining 430 remain asymptomatic at a mean follow up of twelve years. We demonstrate that the development of DTH is associated with patient age, gender, the magnitude of metal exposure and the presence of certain HLA class II alleles. We show that the predictive algorithm developed from this investigation performs to an accuracy suitable for clinical use, with weighted mean survival probability errors of 1.8% and 3.1%53 for pre-operative and post-operative models respectively. Conclusions The development of DTH following joint replacement appears to be determined by the interaction between implant wear and a patient’s genotype. The algorithm described in this paper may improve implant selection and help direct patient surveillance following surgery. Further consideration should be given towards understanding patient specific responses to different biomaterials.Publisher PDFPeer reviewe

Comprehensive and Integrated Genomic Characterization of Adult Soft Tissue Sarcomas

Sarcomas are a broad family of mesenchymal malignancies exhibiting remarkable histologic diversity. We describe the multi-platform molecular landscape of 206 adult soft tissue sarcomas representing 6 major types. Along with novel insights into the biology of individual sarcoma types, we report three overarching findings: (1) unlike most epithelial malignancies, these sarcomas (excepting synovial sarcoma) are characterized predominantly by copy-number changes, with low mutational loads and only a few genes (, , ) highly recurrently mutated across sarcoma types; (2) within sarcoma types, genomic and regulomic diversity of driver pathways defines molecular subtypes associated with patient outcome; and (3) the immune microenvironment, inferred from DNA methylation and mRNA profiles, associates with outcome and may inform clinical trials of immune checkpoint inhibitors. Overall, this large-scale analysis reveals previously unappreciated sarcoma-type-specific changes in copy number, methylation, RNA, and protein, providing insights into refining sarcoma therapy and relationships to other cancer types

The influence of HLA genotype on the development of metal hypersensitivity following joint replacement

Background Over five million joint replacements are performed across the world each year. Cobalt chrome (CoCr) components are used in most of these procedures. Some patients develop delayed type hypersensitivity (DTH) responses to CoCr implants, resulting in tissue damage and revision surgery. DTH is unpredictable and genetic links have yet to be definitively established. Methods At a single site, we carried out an initial investigation to identify HLA alleles associated with development of DTH following metal-on-metal hip arthroplasty. We then recruited patients from other centres to train and validate an algorithm incorporating patient age, gender, HLA genotype44and blood metal concentrations to predict the development of DTH. Accuracy of the modelling was assessed using performance metrics including time dependent receiver operator curves.Results Using next generation sequencing, here we determine the HLA genotypes of 606 patients. 176 of these patients had experienced failure of their prostheses; the remaining 430 remain asymptomatic at a mean follow up of twelve years. We demonstrate that the development of DTH is associated with patient age, gender, the magnitude of metal exposure and the presence of certain HLA class II alleles. We show that the predictive algorithm developed from this investigation performs to an accuracy suitable for clinical use, with weighted mean survival probability errors of 1.8% and 3.1%53for pre-operative and post-operative models respectively.Conclusions The development of DTH following joint replacement appears to be determined by the interaction between implant wear and a patient’s genotype. The algorithm described in this paper may improve implant selection and help direct patient surveillance following surgery. Further consideration should be given towards understanding patient specific responses to different biomaterials

Comprehensive and Integrated Genomic Characterization of Adult Soft Tissue Sarcomas

Sarcomas are a broad family of mesenchymal malignancies exhibiting remarkable histologic diversity. We describe the multi-platform molecular landscape of 206 adult soft tissue sarcomas representing 6 major types. Along with novel insights into the biology of individual sarcoma types, we report three overarching findings: (1) unlike most epithelial malignancies, these sarcomas (excepting synovial sarcoma) are characterized predominantly by copy-number changes, with low mutational loads and only a few genes (, , ) highly recurrently mutated across sarcoma types; (2) within sarcoma types, genomic and regulomic diversity of driver pathways defines molecular subtypes associated with patient outcome; and (3) the immune microenvironment, inferred from DNA methylation and mRNA profiles, associates with outcome and may inform clinical trials of immune checkpoint inhibitors. Overall, this large-scale analysis reveals previously unappreciated sarcoma-type-specific changes in copy number, methylation, RNA, and protein, providing insights into refining sarcoma therapy and relationships to other cancer types