Lors de ma thèse, je me suis intéressée à la recherche d’altérations somatiques dans deux sarcomes : le sarcome histiocytaire (SH) et le dermatofibrosarcome protubérant (DP). Pour étudier ces cancers sur les plans moléculaire et thérapeutique le chien apparaît comme un modèle naturel unique. En effet, il développe spontanément des cancers homologues aux cancers humains avec de fortes prédispositions raciales. De plus, le chien partage notre environnement et est l’espèce la mieux suivie médicalement après l’Homme, ce qui en fait un modèle de tumeurs spontanées inégalable. Le SH est rare chez l’Homme, mais fréquent dans une race de chien en particulier : le bouvier bernois. Ce cancer a fait l’objet d’études antérieures dans l’équipe et dans ce contexte j’ai identifié des mutations somatiques récurrentes dans 102 cas de SH canin. Un gène de la voie MAPK a particulièrement retenu notre attention, je l’ai retrouvé muté dans 54 cas de SH canin, soit 53%. En collaboration avec le « groupe de travail des histiocytoses humaines », nous avons aussi montré la présence de mutations de ce gène dans 1 cas sur 16 cas de SH humain. Par la suite, j’ai (1) montré le rôle activateur de ces mutations de la voie MAPK dans le SH (2) ciblé cette voie de signalisation par 4 molécules inhibitrices sur 8 lignées cellulaires de SH canin, dont 7 développées dans l’équipe. J’ai alors montré que le tramétinib possédait le meilleur potentiel thérapeutique pour le SH, et l’équipe projette maintenant de tester cette molécule dans un essai préclinique chez le chien. En ce qui concerne le DP, c’est un fibrosarcome déjà bien décrit chez l’Homme mais dont le diagnostic n’est pas réalisé en médecine vétérinaire. J’ai pu mettre en évidence, dans un cas de DP canin, l’existence d’une fusion de gènes similaire à la fusion pathognomonique des DP humains. En effet, cette fusion implique les mêmes mécanismes : des points de cassures similaires, plaçant le gène PDGFB sous le contrôle du promoteur d’un gène de collagène, et a pour conséquence une surexpression du facteur de croissance PDGFB. Une thérapie ciblée étant utilisée pour les DP humains porteurs de cette fusion, nous supposons qu’elle pourrait l’être aussi pour les DP canins. Ainsi, ces travaux ont permis de mieux caractériser ces sarcomes sur le plan moléculaire et ouvrent des perspectives diagnostiques et thérapeutiques profitant à la recherche translationnelle à fois en médecine vétérinaire et humaine. / During my thesis I searched for somatic alterations in two sarcomas: histiocytic sarcoma (HS) and dermatofibrosarcoma protuberans (DP). To study these cancers on the molecular and therapeutic aspects, the dog appears as a unique natural model. Indeed, dogs spontaneously develop cancers that are homologous to human cancers with strong racial predispositions. In addition, dogs share our environment and it is the species with the best medical care after humans. HS is rare in humans, but frequent in a particular dog breed: Bernese mountain dog. This cancer has been the subject of previous studies in the team and in this context I identified recurrent somatic mutations in 102 cases of canine HS. A gene of the MAPK pathway has caught our attention, I found mutations in 53% of canine HS cases. In collaboration with the “working group on human histiocytosis”, we also showed the presence of mutations of this gene in 1 case out of 16 human cases of HS. Subsequently, I showed the activating role of these mutations in the MAPK pathway and I targeted this pathway by 4 inhibiting molecules on 8 canine HS cell lines, including 7 developed in the team. I then highlighted the trametinib with the best therapeutic potential for HS and the team now plans to test this molecule in preclinical assays in dogs. Regarding the DP, it is a fibrosarcoma already well described in humans but the diagnosis is not routinely made in veterinary medicine. In one case of canine DP, I was able to highlight the existence of a similar gene fusion to the pathognomonic fusion of the human DP. Indeed, this fusion involves the same mechanisms: similar breakpoints placing the PDGFB gene under the control of the promoter of a collagen gene, resulting in the overexpression of the growth factor PDGFB. A targeted therapy is available for human patients carrying this gene fusion; thus, we suppose it could also be used in therapy for canine DP. In conclusion, this work has further characterized these sarcomas at the molecular level and now opens diagnostic and therapeutic opportunities, benefiting to the translational research in both veterinary and human medicine.

Background: Despite multi-modality therapy, the majority of patients with metastatic or recurrent Ewing sarcoma (ES), the second most common pediatric bone malignancy, will die of their disease. ES tumors express aberrantly activated ETS transcription factors through translocations that fuse the EWS gene to ETS family genes FLI1 or ERG. The aberrant activation of ETS transcription factors promotes malignant transformation and proliferation. While, FLI1 or ERG cannot be readily targeted, there is an opportunity to deploy functional genomics screens, to develop novel therapeutic approaches by identifying targetable liabilities in EWS/FLI1 dependent tumors. Materials and Methods: We performed a near whole-genome pooled shRNA screen in a panel of five EWS/FLI1 dependent Ewing sarcoma cell lines and one EWS/ERG cell line to identify essential genes. Essential genes were defined as those genes whose loss resulted in reduced viability selectively in ES cells compared to non-Ewing cancer cell lines. Essential hits were subsequently validated with genomic knockdown and chemical inhibition in vitro, followed by validation of the on-target effect of chemical inhibition. Next, we determined the in vivo effects of small-molecule inhibition on survival and tumor growth in NOD scid gamma (NSG) mice with established subcutaneous ES xenografts. Results: Top hits in our screen that could be readily targeted by small-molecule inhibitors, and thus have potential for rapid clinical validation, were selected for further investigation. These hits included IKBKE, CCND1 and CDK4. IKBKΕ, a non-canonical IKK with an oncogenic role in breast cancer, was one of the top kinase hits in the screen. IKBKΕ shares significant homology to TBK1, another non-canonical IKK that is essential in k-RAS dependent lung cancer. We validated IKBKE through small-molecule inhibition of IKBKE/TBK1 and shRNA based knockdown. Ewing sarcoma cell lines are sensitive to low micromolar concentrations of two IKBKE/TBK1 inhibitors (CYT387 and MRT67307). Additionally, in a panel of ES cell lines, knockdown of IKBKE resulted in decreased growth and impaired colony formation. These observations, paired with impairment of NF-κB nuclear localization following CYT387 treatment suggests that non-canonical IKK mediated signaling may be essential in Ewing sarcoma. We further validated these results through inhibition of IKBKE/TBK1 in in vivo xenograft models treated with 100 mg/kg/day of CYT387. Treatment over the course of twenty-nine days resulted in a significant increase in survival (p-value = 0.0231) and a significant decrease (p-value = 0.036) in tumor size after fifteen days of treatment. CDK4 and CCND1 are highly expressed in Ewing sarcoma as compared to other tumor types. shRNA mediated knockdown of CDK4 and CCND1 resulted in impaired viability and anchorage independent growth. Furthermore, treatment of Ewing sarcoma cell lines with a highly selective CDK4/6 inhibitor, LEE011, resulted in decreased viability (IC50 range of 0.26-18.06 μM), potent G1 arrest in six of eight EWS/FLI1 containing Ewing sarcoma lines tested and apoptosis in a panel of four highly sensitive lines. Administration of 75 mg/kg/day and 250 mg/kg/day of LEE011 in NSG mice with Ewing xenografts resulted in significant impairment of tumor growth, (p-value <0.001 for both treatment arms), as compared to vehicle control. Conclusions: These studies suggest a role for the targeting of IKBKE and CDK 4/6 in Ewing sarcoma, findings with immediate clinical relevance for patients with this malignancy, because small-molecule inhibitors of these proteins have already entered clinical trial for other disease indications.

Spirocerca lupi is a nematode that infects the dog’s oesophagus and promotes the formation of an inflammatory fibroblastic nodule that progresses to sarcoma in approximately 25% of cases. Differentiating neoplastic from non-neoplastic cases ante-mortally is challenging and has major therapeutic and prognostic implications. More importantly, spirocercosis-associated oesophageal sarcoma is an excellent and under-utilized spontaneous model of parasite-associated malignancy and the pathogenesis of the neoplastic transformation is poorly understood. The current study objective was to investigate potential clinical, clinicopathological, radiological and tissue biomarkers for the malignant transformation and an attempt to use these biomarkers to gain a deeper understanding of the pathogenesis of the neoplastic transformation. Our central hypothesis was that the parasite produces excretory product(s) which diverts the immune response from a T helper 1 (Th1) to Th2 cell response, typical of many nematode infections, and further to an immunoregulatory (immunosuppressive), FoxP3+ regulatory T cell-predominated response which then facilitates neoplastic transformation. The following parameters were studied and compared between cases with non-neoplastic and neoplastic spirocercosis: clinical presentation, haematology, serum albumin and globulin, thoracic radiology, haematoxylin-eosin (H&E) histology, Immunohistochemistry for expression of vascular endothelial growth factor (VEGF)-A, fibroblast growth factor (FGF), platelet-derived growth factor (PDGF), MAC387 (myeloid cells), CD3 (T cells), Pax5 (B cells) and FoxP3 (T regulatory cells) and plasma cytokine concentrations including IL-2, IL-4, IL-6, IL-8, IL-10, IL-18, GM-CSF and MCP-1. Hypertrophic osteopathy showed 100% specificity for neoplastic transformation but relatively poor sensitivity (40%). Female gender, anaemia, leukocytosis, thrombocytosis, spondylitis and bronchial displacement were significantly more common in neoplastic cases, but appeared in non-neoplastic cases as well. The H&E study revealed 2 stages in the non-neoplastic nodules: early inflammation, characterized by fibrocytes and abundant collagen, and a pre-neoplastic stage, characterized by activated fibroblasts and reduced collagen. The neoplastic cases were all sarcomas, primarily osteosarcoma with very aggressive features comparable to other appendicular osteosarcoma in the dog. The inflammation in spirocercosis is characterized by pockets of pus (MAC387+ cells) surrounded by organized lymphoid foci (CD3+ and to a lesser degree Pax5+ cells). There was no evidence of a local accumulation of FoxP3+ cells, unlike many previous studies which have reported an increase in Foxp3+ T cells in both malignancies and parasite infections. Interleukin-8 plasma concentration was higher in the neoplastic group compared to the non-neoplastic and the control groups. Interleukin-18 concentration was higher in the non-neoplastic group followed by the control group and finally the neoplastic group. As with most similar studies, no ideal biomarker with high sensitivity and specificity was identified. However, if examined together, a panel of the biomarkers that were identified more commonly in the neoplastic cases should substantially increase the index of suspicion for neoplastic transformation in a diagnosed spirocercosis case. The inflammatory response showed features of increased myeloid (innate) response and lymphocytic response with pro-inflammatory cytokines. This was not our initial hypothesis and the question remains whether the response is secondary to the worm infection, or to a symbiotic bacterium that is carried by the worm. The role of such a reaction in neoplastic transformation remains to be elucidated. / Thesis (PhD)--University of Pretoria, 2012. / Companion Animal Clinical Studies / unrestricted

This research covers the story of four persons from different backgrounds brought together by their faith in God, fellowship in the same church, residing in the same community and sharing the experience of living with HIV and AIDS: either as infected and/or affected individually. I am one of these persons due to the fact that I lost my sister to HIV and AIDS, thus I am affected. Though I only appear in the story as the researcher, it is my own loss that made it possible for me to empathise with my co-researchers. While one co-researcher was affected due to the fact that her husband was infected, became ill and died of HIV and AIDS-related sicknesses, the other two women were both infected by their husbands and at the same time were affected because they had to nurse the same husband who infected them. This was one of the cruelest moments in their lives but they forgave their husbands and cared for them to the end. In order for my research to reach the holistic insight into these women’s stories, I used the postfoundationalist practical theology approach. The reason for this is that this approach is contextual and relevant to people’s everyday life. One does not have to import knowledge to try to solve problems emanating from a particular context, but one needs to engage the locals and from that engagement, people start to reflect positively on their problems. Other lessons learnt is that one needs more than just a religious experience to play a role in solving the problem of HIV and AIDS; one needs more of the other disciplines to work together. In places like Mozambique, HIV and AIDS is not regarded as one of the health problems, but is classified as an interdepartmental or multi-sectoral problem. This means that HIV and AIDS do not affect only the Health Department, but all the departments. As such, each department is expected to have its own HIV and AIDS budget. It is here that I propose the Multi Disciplinary Team (MDT) composed of professionals from different disciplines working together to help solve the problem at hand. HIV and AIDS also help us to revisit our own understanding of God. While some people see the pandemic as the punishment from God for promiscuity, the truth is that we are all created in His image and this loving God does not destroy His own creation through HIV and AIDS. In His loving care, He reaches out to the unreached and cares for all His people: whether they are infected with HIV and AIDS, cancer or just are as healthy as they could be. The process of this research has empowered and enabled me to contribute to those who are infected and affected to be resilient and to stand, having hope in the goodness of God, working with others to bring a lasting solution to those infected and affected. Being resilient helps one to reclaim the marred Image of God in oneself and to reflect that image to impact onto our communities. / Thesis (PhD)--University of Pretoria, 2011. / Practical Theology / unrestricted

No description available.

L'objectif de cette thèse menée dans le cadre de l'essai clinique ANRS 154 Lenakap a été d'étudier l'impact clinique et immunologique d'un traitement par lénalidomide dans la maladie de Kaposi liée au VIH (MK-VIH) et d'identifier de nouveaux biomarqueurs de la pathologie, notamment à travers l'étude du trio de chimiokine et récepteurs CXCL12/CXCR4-CXCR7. A l'heure actuelle aucun traitement curatif de la MK-VIH n'est disponible. Le lénalidomide, un immunomodulateur pléïotrope, ciblant différentes anomalies rencontrées dans la MK constitue une perspective thérapeutique dans cette indication. L'interprétation de la réponse clinique des patients au traitement au cours de l'essai clinique ANRS 154 Lenakap est difficile, notamment en raison de discordances entre les scores d'évaluation utilisés. Cependant, nos résultats ont montré une bonne tolérance du lénalidomide chez les patients inclus, infectés par le VIH et traités par antirétroviraux. Aucune interaction médicamenteuse pharmacologiquement ou cliniquement significative n'a été détectée chez les patients, ouvrant de nouvelles perspectives pour la prise en charge de ces derniers, y compris dans d'autres indications, tels que le myélome multiple et les syndromes myélodysplasiques. Nous avons également mis en évidence l'impact du TNF-α, de l'IFN-γ et de l'IL-10 dans la progression de la MK-VIH.L'ensemble des mécanismes physiopathologiques de la MK n'est pas encore élucidé et nous ne disposons actuellement d'aucun biomarqueur, de suivi d'évolution, ou de réponse au traitement dans cette indication. Des données de la littérature suggèrent une implication du trio CXCL12/CXCR4-CXCR7 dans la physiopathologie de la MK-VIH. Nos analyses immunohistochimiques et par immunofluorescence, couplées à la mise au point d'une technique de quantification sur lames numérisées ont permis de mettre en évidence la présence augmentée des protéines CXCL12/CXCR4-CXCR7 dans les lésions de MK. Les corrélations positives retrouvées entre les protéines du trio et la présence du virus sous forme latente, la prolifération cellulaire et à la présence du facteur de croissance VEGF, suggèrent de possibles effets autocrines et paracrines du trio à l'origine d'une propagation tissulaire du virus et d'effets prolifératif et pro-angiogénique dans le MK. Cette étude suggère pour la première fois le rôle de biomarqueur tissulaire, témoin du processus physiopathologique de la MK, pour le trio CXCL12/CXCR4-CXCR7. En revanche, CXCL12 ne semble pas être un biomarqueur plasmatique à la fois de la physiopathologie ou de la progression de la MK. Enfin, cette étude confirme l'état pro-inflammatoire des patients infectés par le VIH et rapporte une immunomodulation particulière chez les patients MK-VIH avec des taux plasmatiques de TNF-alpha, IL-6, IFN-gamma et IL-10 augmentés, peut-être à l'origine du développement et de la progression de la maladie. / The objective of my PhD works, conducted as part of the clinical trial ANRS 154 Lenakap, was to evaluate the clinical and immunological impact of lenalidomide in patients with HIV-associated Kaposi's sarcoma (AIDS-KS) and to identify new biomarkers of disease, particularly through the study of the trio CXCL12/CXCR4-CXCR7 So far, no cure for the AIDS-KS is available. Lenalidomide, an oral immunomodulating agent targeting various anomalies observed in KS is a therapeutic perspective in this indication. Evaluation of clinical response to treatment in the ANRS 154 Lenakap clinical trial was difficult, especially because of discrepancies observed between assessments scores used to evaluate this parameter. However, lenalidomide was well tolerated in patients infected with HIV and treated with antiretroviral drugs. We detected no pharmacologically or clinically significant drug interactions between lénalidomide and antiretroviral drugs, opening new perspectives for the treatment of HIV-positive patients, including other indications such as multiple myeloma and myelodysplastic syndromes. We also highlighted the impact of TNF-alpha, IFN-gamma and IL-10 in the progression of AIDS-KS. All pathophysiological mechanisms of KS are not yet elucidated, and so far, no biomarker is available to monitor evolution, or response to treatment in this indication. Some data suggest an involvement of the trio CXCL12/CXCR4-CXCR7 in the pathophysiology of KS. Our immunohistochemical and immunofluorescence analysis, coupled to a technique for quantification of digitized slides, have allowed us to demonstrate the over-expression of CXCL12, CXCR4 and CXCR7 proteins in KS cutaneous lesions. Moreover, we reported for the first time the simultaneous in situ up-regulation of CXCL12, CXCR4 and CXCR7 in AIDS- and classic-KS. These deregulations correlated with lesion severity, latent viral load, proliferation and angiogenesis. This suggests a possible autocrine and paracrine effects of the trio leading to the virus propagation, the cells proliferation and the angiogenic process observed in KS. Our results further indicate that the trio could be used in KS rather as a histologic than a circulating biomarker. Finally, this study confirms the pro-inflammatory state of HIV-infected patients and highlights a specific immune modulation in AIDS-KS patients with increased TNF-α, IL-6, IFN-γ and IL-10 plasma levels. This microenvironment may participate in the disease progression.

Kaposi's sarcoma herpesvirus (KSHV) is a cancer-causing virus, primarily affecting AIDS patients. KSHV is found in 3-10% of the U.S. population and can cause a range of cancers in the highly immunosuppressed; these cancers include Kaposi's sarcoma, pleural effusion lymphoma (PEL) and multicentric Castleman's disease (MCD). The current techniques for treating these cancers are relatively ineffective, largely due to their inefficiency at targeting tumors formed by the infection. One protein produced by KSHV, the viral homolog of interleukin-6 (vIL-6), is thought to play a major role in tumor development post-infection. Here a novel animal model is implemented to study the ways vIL-6 affects tumor development through growth factors and other cytokines within infected highly immune-deficient Rag2-/-γc-/- mice. Mice were subcutaneously injected with one of three types of cells: B cells infected with a wild-type (WT) KSHV, B cells infected with mutant KSHV without the gene for viral interleukin 6, and a negative control of uninfected B cells. After allowing time for tumors to develop the mice were sacrificed and the tumors assessed. Analysis of the physical properties of the tumors, as well as markers expressed by the tumors, were used to help determine whether vIL-6 could be an appropriate target when treating these cancers. In this study vIL-6 was seen to influence certain B cell markers (CD30), as well as onset of tumors (with no significant increase in overall tumor mass, but with marginally statistically significant increase in tumor number). This indicates that although vIL-6 could play a small role as a target for cancer, further investigation into the relationship of CD30 in these types of cancers needs to be explored. It was also found that the KSHV viral-infection decreases the development of tumors compared with uninfected immortalized B cells (BJAB). Not only would results from this experiment help develop new treatments, and change the lives of those suffering with cancers induced by KSHV, but they would provide a foundation for future studies with these types of cancers.

Le Sarcome d'Ewing est un cancer pédiatrique rare, principalement dû à l'expression de l'oncogène de jonction EWS-Fli1, et dont les traitements médicamenteux ont peu évolué au cours des dernières décennies. Nous nous intéressons à une nouvelle approche thérapeutique utilisant des siRNA, ciblant spécifiquement l'oncogène EWS-Fli1, et permettant l'inhibition de la croissance tumorale. Durant mon travail de thèse, j'ai utilisé des nanocristaux de diamant issus soit de détonation (DND), soit de synthèse haute pression-haute température (NDHPHT) pour vectoriser les siRNA, accrochés par interaction électrostatique. Pour ce faire, les NDs ont été rendus cationiques par différentes méthodes: (i) hydrogénation assistée par plasma, (ii) par recuit thermique, ou (iii) par traitement chimique pour les DNDs, ou (iv) greffage covalent d'un polymère cationique sur des NDHPHT (COP-NDHPHT).Mes travaux ont comporté deux axes: (i) étude in vitro des complexes ND:siRNA (caractérisations physico-chimiques des NDs et étude de l'efficacité d'inhibition de l'oncogène par les complexes); (ii) distribution tissulaire de COP-NDHPHT, injectés dans des souris, grâce à des NDHPHT fluorescents, contenant des défauts azote-lacune. Pour les détecter individuellement dans des coupes d'organes de souris portant une tumeur xénogreffée sous-cutanée, nous avons développé un système d'imagerie en épifluorescence à grande ouverture numérique, et résolu en temps afin de rejeter l'autofluorescence tissulaire (de durée de vie plus courte que celle des NDs). Nous avons quantifié le nombre, l'état d'agrégation et la localisation cellulaire de ces vecteurs (grâce à un marquage histopathologique imagé simultanément) 24h après injection. Les NDs ont été clairement détectés dans les différents organes, dont la tumeur, ouvrant la voie à un contrôle de la progression tumorale grâce au siRNA. / Ewing Sarcoma is a rare pediatric cancer, caused in the majority of the cases by the expression of the fusion oncogene EWS-Fli1. Current treatments have not much evolved over the past decades. We are investigating a new therapy based on siRNA specifically targeting the oncogene and inhibiting the tumor growth. During my PhD thesis, I have tested different types of synthetic nanodiamonds (ND) used to vectorize siRNA electrostatically bound at their surface: ND produced by detonation (DND) or by High Pressure-High Temperature synthesis (NDHPTH). Their surfaces have been cationized by various processes: (i) plasma or (ii) thermal hydrogenation, (ii) chemical treatment, or (iv) covalent grafting of a copolymer (COP-NDHPHT).My PhD work included two main axis: (i) in vitro study of ND:siRNA complexes (NDs physico-chemical characterization and oncogene inhibition efficacy by the complexes); (ii) tissue distribution of COP-NDHPHT, injected into mice, using fluorescent NDHPHT containing nitrogen-vacancy defects. To detect them individually in sections of mouse organs carrying a subcutaneous xenograft tumor, we developed an epifluorescence imaging system with large numerical aperture and resolved in time to reject tissue autofluorescence (of a shorter lifetime than NDs). We quantified the number, the aggregation state and the cell localization (thanks to simultaneous histopathological imaging) of these vectors 24 hours after injection. NDs have been clearly detected in different organs, including the tumor, paving the way for tumor progression control with siRNA.

Ewing-like sarcomas (ELS) are a heterogenous group of neoplasms that typically occur in the bone and soft tissue of pediatric and young adult patients. ELS share various degrees of morphological, immunohistochemical, molecular, and clinical similarity with Ewing sarcomas. However, these tumors lack the pathognomonic molecular hallmark of Ewing sarcoma, which is defined as translocation between a gene of the RNA-binding TET family (EWSR1 or FUS) with a gene of the ETS-transcription family (FLI1, ERG, ETV1, ETV4, or FEV). Accurate classification and distinction from classical Ewing sarcomas is important for patient management. A subset of ELS harboring the BCOR-CCNB3 fusion has been described recently – the majority of which that have been reported to date are bone-based tumors, though there have been cases of discrete soft tissue-based tumors. We herein present a case of ELS harboring the BCOR-CCNB3 translocation occurring in a pediatric patient presenting with a large abdominal mass discovered on chest CT after failed outpatient treatment for pneumonia with effusion. This patient was a 14-year-old Caucasian boy with a past medical history significant for obesity and three episodes of pneumonia since 6-years-old. Imaging showed a large heterogeneous mass at the posterior left upper quadrant of the abdomen protruding through the posterior aspect of the left hemidiaphragm causing atelectasis. The mass abuts the inferior leftward aspect of the descending thoracic aorta and also protrudes between the 11th and 12th posterior lateral left rib. Pathology revealed this mass to be an Ewing-like sarcoma with a BCOR-CCNB3 fusion. Patient was treated with chemotherapy and radiation. This case demonstrates the importance of determining an accurate diagnosis to provide specific management.

Most cardiac tumors are metastatic tumors, which are 20–40 times more common than primary tumors of the heart. Most primary tumors of the heart are benign, with atrial myxomas being the most common. Primary cardiac tumors are extremely rare with an incidence of less than 0.1 percent. Virtually all types of sarcomas have been reported in the heart as isolated case reports. We present a rare case of biatrial high-grade osteosarcoma. A fifty-four-year-old Hispanic female presented with shortness of breath and was cyanotic on the exam while visiting Mexico. Due to abnormal chest x-ray, echocardiogram concerning for bilateral atrial myoma she was referred to a cardiothoracic surgeon. She underwent bi atrial intracardiac tumor resection in Mexico. Several months prior to her resection she noted numbness on the side of the face that was evaluated by her physicians in the United States with a Brain MRI and carotid Ultrasound/Doppler that was unrevealing. She also remembered an episode of uncontrolled hypertension two years prior to surgery requiring admission to a local hospital in East Tennessee with cardiology evaluation that did not include an echocardiogram. Surgical pathology showed extensive undifferentiated spindle cell proliferation with multifocal osteoid production and foci of osseocartilaginous differentiation. There was prominent necrosis and moderately high mitotic rate (10-19/HPF). Tumor cells were positive for SatB2 and negative for vascular, muscular, or neural markers. This is consistent with a primary cardiac high-grade osteosarcoma. These occur very rarely, usually in the atria, and behave aggressively. Post resection staging PET-CT showed hypermetabolic mixed lytic and sclerotic lesion of T10 concerning for metastasis disease. She received approximately 6 cycles of adriamycin and ifosfamide chemotherapy. Adriamycin was discontinued due to left ventricular dysfunction with an ejection fraction of 30-35%, multiple segmental abnormalities, diffuse left ventricular hypokinesis, and moderate to severe mitral valve regurgitation. Despite intracardiac tumor, resection, concern for metastatic disease, chemotherapy, and systolic dysfunction patient is asymptomatic and does have robust performance status. A follow-up PET-CT five months after cessation of treatment reveals no significant evidence of uptake other than abnormalities in the T10 vertebra. A repeat echocardiogram continues to reveal a depressed ejection fraction of 35%. The patient is completely asymptomatic, seemingly fit with an ECOG performance status of 0-1. Osteosarcomas are aggressive with a high incidence of recurrence and metastasis. Fewer than 50 cases of primary cardiac osteosarcomas have been reported in the literature. Currently, it is postulated that they arise from undifferentiated mesenchymal stem cells in the endocardium that transform into active osteoblasts. Even though complete resection can be achieved in some cases, long-term results are usually poor. No standard therapy has been established due to the tumor's low incidence rate and lack of clinical trial data. Our case highlights the importance of evaluating common symptoms thoroughly since it may be a harbinger of rare and serious disorders. This case reflects the heterogeneous nature of sarcoma histology, the consequent tumor biology and hence varied clinical course and prognosis.