Synovial sarcoma is a soft tissue malignancy with a poor prognosis; many patients will die from this disease within 10 years of diagnosis, despite treatment. Gene expression profiling and immunohistochemistry studies have identified oncogenes that are highly expressed in synovial sarcoma. Included in this group are receptor tyrosine kinases such as epidermal growth factor receptor, insulin-like growth factor receptor 1, fibroblast growth factor receptor 3, KIT, and HER2. Inhibitors of these growth-promoting receptors are likely to inhibit proliferation of synovial sarcoma; however, the effect of receptor tyrosine kinase inhibitors on synovial sarcoma is largely unknown. We assessed the ability of the following receptor tyrosine kinase inhibitors to halt proliferation and induce apoptosis in synovial sarcoma monolayer and three dimensional spheroid in vitro models: gefitinib (Iressa), NVP-AEW541, imatinib mesylate (Gleevec), SU5402, trastuzumab (Herceptin), and 17-allylamino-17-demethoxygeldanamycin (17-AAG). Gefitinib, NVP-AEW541, and imatinib inhibited proliferation only at relatively high concentrations, which are not clinically applicable. 17-AAG, which destabilizes multiple receptor tyrosine kinases and other oncoproteins through heat shock protein 90 inhibition, prevented proliferation and induced apoptosis in synovial sarcoma monolayer models at concentrations achievable in human serum. 17-AAG treatment was also associated with receptor tyrosine kinase degradation and induction of apoptosis in synovial sarcoma spheroid models. 17-AAG was more effective than doxorubicin, particularly in the spheroid models. Here we provide in vitro evidence that 17-AAG, a clinically applicable drug with known pharmacology and limited toxicity, inhibits synovial sarcoma proliferation by inducing apoptosis, and thus has potential as a systemic therapy for this disease.Synovial sarcoma accounts for f7% to 10% of soft tissue malignancies and is associated with significant morbidity and mortality (1). Approximately 50% of patients will die from metastatic disease within 10 years of diagnosis despite treatment; the efficacy of conventional chemotherapeutics is controversial, although a recent report has suggested that combination doxorubicin/ifosfamide therapy offers a modest survival advantage in advanced cases (2,3).A translocation between SYT on chromosome 18 and SSX1 or SSX2 on chromosome X is characteristic of synovial sarcoma and is the only apparent cytogenetic abnormality in one third of cases (4). The biological roles of SYT and SSX are poorly understood; studies suggest that SYT functions as a transcriptional activator and SSX as a transcriptional repressor (4), although neither binds DNA directly. This implies that the SYT-SSX fusion protein combines these opposing activities and contributes to the pathogenesis of synovial sarcoma by dysregulating transcriptional patterns (4, 5). Expression profiling studies have identified a number of genes that are highly expressed in synovial sarcoma, including known oncog...
ObjectiveTo describe the characteristics and outcomes in adult and pediatric patients diagnosed with myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) at the two major referral centers in the Mountain West of the United States, a geographic area encompassing roughly 15% of the land mass of the continental US.BackgroundSince the development of commercial assays, MOGAD has become increasingly recognized as an etiologic diagnosis for several CNS demyelinating phenotypes, yet the epidemiological characteristics, relapse rates and outcomes of large populations are not well-describedDesign/MethodsA retrospective chart review for patients within the health systems at the University of Utah and the University of Colorado, and affiliated children's hospitals, was conducted. To identify MOGAD patients, we queried the ICD10 codes corresponding to demyelinating disease of CNS, neuromyelitis optic spectrum disease, optic neuritis, transverse myelitis, and acute disseminated encephalomyelitis. These patients were then cross matched against antibody testing results and existing research databases at each institution. Search dates included 1/1/2016-12/1/2021 to encompass the period of commercially available MOG IgG testing. Patients were cross referenced with a list of positive MOG IgG assays at each institution.ResultsWe describe the characteristics of over 50 patients (adults and children) with MOGAD, including age of onset, gender, symptoms at onset, associated autoimmunity, antibody titers, response to therapies and relapse rates.ConclusionsThis is a comprehensive characterization of a diverse population of pediatric and adult MOGAD patients seen at the two major referral hospitals in the Mountain West. The treatment regimens and outcomes in this population may inform approaches to current management and future clinical trials.
ObjectiveTo investigate the mechanisms by which neurons take up paraneoplastic and other antibodies.BackgroundOur laboratory has previously demonstrated that neurons can take up both normal and paraneoplastic IgGs and that paraneoplastic autoantibodies such as anti-Yo and anti-Hu can bind to their intracellular target antigens to produce neuronal death. In this study we investigated how neuronal antibody uptake occurs.Design/MethodsWe first compared neuronal uptake of normal and paraneoplastic Fab fragments with that of normal IgG Fc fragments or whole paraneoplastic IgGs. To determine whether neurons expressed receptors capable of binding the Fc portion of the IgG molecule, paraformaldehyde-fixed mouse and rat brains sections were probed with antibodies for the three major types of Fc receptors: FcγRI (CD64), FcγRII, (CD32) and FcγRIII (CD16). Neuronal uptake of antineuronal IgGs was compared between wild type mice and knockout mice lacking the FcγRI receptor. We also investigated whether neuronal IgG uptake could be blocked by normal IgG.ResultsNeurons incorporated the Fc fragment of normal IgG but not the Fab fragment. Intact paraneoplastic IgGs were taken up by neurons, but immunospecific Fab fragments were excluded. Neurons throughout cerebrum, cerebellum, and brainstem showed immunolabeling for FcγRI, but only rare neurons expressed FcγRII or FcγRIII. Uptake of paraneoplastic IgG and neuronal death were not observed in cultures from FcγRI knockout mice but were extensive in cultures from wild type controls. Paraneoplastic antibody uptake could be inhibited by normal IgG.ConclusionsNeuronal uptake of normal and paraneoplastic IgGs requires the interaction of the Fc portion of the IgG molecule with previously uncharacterized neuronal FcγRI receptors. Our study provides a mechanism through which antibodies reactive with intracellular neuronal proteins could gain access to their target antigens to cause neuronal injury and neurological disease. The observation that neuronal antibody uptake can be blocked by normal IgG has possible implications for patient treatment.
ObjectiveDescribe a case of NMDAR encephalitis in a young Latino male patient, additionally the factors resulting in delayed preventative and diagnostic medical care, which contributed to the development of a preventable case of NMDAR encephalitis.BackgroundAdolescent undocumented immigrants in the United States face a history of prejudice and bias that perpetuates disparities and stigmas related to their healthcare. The lack of culturally informed practices among healthcare workers can create multiple lost opportunities to deliver standard of care practices, including routine testicular exams. The treatment of NMDAR encephalitis with immunotherapy, and resection of culpable tumors when present, can be lifesaving. Recognition of the germ cell tumor association has also renewed awareness of the importance of screening for such tumors.Design/MethodsN/A.ResultsCase: A 25-year-old male who immigrated from Mexico to the U.S. at age 13 presented to the hospital for concern of status epilepticus. His past medical history included atypical developmental delay beginning in late teenage years. A large abdominal mass was identified on imaging as a stage IIIC (pT1bN0M1bS2) NSGCT (70% teratoma/30% seminoma) tumor arising from an unresected, undescended left testicle. Autonomic instability in the setting of this malignancy prompted an evaluation for, and diagnosis of, NMDAR encephalitis. His course was complicated by altered mental status, seizures, sympathetic storming, and orofacial dystonia. After tumor resection, and initiation of immune therapy, the patient showed a remarkable recovery.ConclusionsThis patient's preventive healthcare was impacted at multiple timepoints by changing political policies and a lack of culturally informed practices that unpredictably disrupted reliable access to medical care. Recognition of care gaps allows us to expand our differential diagnoses, and enact a comprehensive approach to fill in gaps. Effective communication, incorporating focused discussions within culturally sensitive frameworks, requires ongoing education for clinicians regarding the populations they serve to prevent disease and minimize health care disparities.
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