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Amyloid-beta related angiitis (ABRA) is a rare central nervous system inflammatory and vasculitic process. It is seen in patients with cerebral amyloid angiopathy (CAA) and thought to be mediated by an autoimmune reaction against cerebrovascular ß-amyloid. We describe the case of a patient with ABRA with clinical information and brain imaging over a 10-year period. The patient was hospitalized in 2018 for altered mental status, paranoia and hallucinations. Her symptoms started in 2009 with an episode of vertigo and loss of consciousness. From 2011-2019, she had multiple episodes of transient focal neurological deficits with overall cumulative progressive decline in cognition and functional status. Retrospective and comparative reviews of brain magnetic resonance imaging (MRI) from 2009-2019 showed waxing and waning vasogenic cerebral edema with overall progression of white matter hyperintensities and peripheral micro-hemorrhages consistent with inflammatory CAA. Re-examination of a brain biopsy from 2009 showed ABRA, and immunostaining was positive for ß-amyloid. She was treated with intravenous steroids with minimal symptomatic improvement. She was lost to our follow-up after hospital discharge. We describe the temporal progression of ABRA through serial brain imaging over a 10-year period. To our knowledge, this is the longest published follow-up duration of ABRA. The patient in our case had severe cognitive impairment and disability despite treatment with steroids.
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INTRODUCTION: Glioblastoma (GBM) is heterogeneous and underlying genomic profiles influence evolution, resistance, and therapeutic responses. While extensive knowledge regarding genomic profiling of primary GBM exists, there remains a lack of understanding of genomic differences in recurrent GBM. METHODS: We used the FoundationOne® comprehensive genomic profiling assay (CGP) to analyze ten matched primary and recurrent GBM. Genomic alterations (GA) were compared to the cancer database Catalogue of Somatic Mutations in Cancer (COSMIC). RESULTS: All matched tumor pairs demonstrated differences in GA between the primary and recurrence including one resected without any intervening therapy. This suggests that time and/or therapeutic intervention contribute to GA. Although mutations were common to both the primary and recurrence, the percent reads varied substantially suggesting clonal expansions and contractions. For example, EGFR mutations were significantly expanded in three patients, and CNAs were increased in two patients at recurrence. Four genes that were commonly altered in both primary and recurrent GBM were more prevalent in our cohort than reported in COSMIC: CDKN2A (86% vs. 53%) and CDKN2B (86% vs. 54%) deletions, EGFR activating mutation (52% vs. 10%) or amplification (81% vs. 45%), and TERT mutation (95% vs. 51%). Lastly, PI3K pathway activating mutations were also commonly seen in our cohort (67%). CONCLUSIONS: CGP revealed that GA identified in GBM changed over time and with treatment. Mutations in TERT, CDKN2A/CDKN2B, EGFR, and PI3K pathway were commonly observed in both primary and recurrent GBM revealing their prognostic and therapeutic potential. This may have important implications for individualized therapies and needs further evaluation.
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Neoplasias Encefálicas/genética , Genótipo , Glioblastoma/genética , Mutação , Recidiva Local de Neoplasia/genética , Idoso , Neoplasias Encefálicas/patologia , Variações do Número de Cópias de DNA , Bases de Dados Genéticas , Feminino , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Glioblastoma/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/patologia , PrognósticoRESUMO
Multinodular and vacuolating neuronal tumor is a recently described seizure-associated entity with overlapping features of a malformative and neoplastic process. We report a case of multinodular and vacuolating neuronal tumor in a 29-year-old man with a history of recent headaches and complex partial seizures. Neuroimaging revealed a nonenhancing, T2 and T2 fluid-attenuated inversion recovery hyperintense multinodular lesion in the right temporal lobe. Lesional tissue demonstrated well-demarcated nodules of ganglioid cells with vacuolation of both the perikarya and the fibrillary neuropil-like background. The ganglioid cells showed weak cytoplasmic reactivity for synaptophysin and were nonreactive for neurofilament and chromogranin. CD34-positive stellate cells were present within the nodules. A 50-gene next-generation sequencing panel did not identify any somatic mutations in genomic DNA extracted from the tumor.
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Neoplasias Encefálicas/patologia , Convulsões/etiologia , Lobo Temporal/patologia , Adulto , Neoplasias Encefálicas/complicações , Neoplasias Encefálicas/diagnóstico por imagem , Humanos , Imageamento por Ressonância Magnética , Masculino , Lobo Temporal/diagnóstico por imagemRESUMO
There is little data on why glioblastomas (GBM) hemorrhage and how it may affect patient outcomes. The aim of this study was to investigate the mechanisms of hemorrhage in glioblastoma by examining molecular and genetic features by immunohistochemistry (IHC) and mRNA expression profiles in association with imaging and clinical outcomes. An observational retrospective cohort analysis was performed on 43 FFPE GBM tissue samples. MR images were assessed for the presence of hemorrhage and extent of resection. Specimens were examined for CD34 and CD105 expression using IHC. Tumor mRNA expression profiles were analyzed for 92 genes related to angiogenesis and vascularity. Forty-three specimens were analyzed, and 20 showed signs of hemorrhage, 23 did not. The average OS for patients with GBM with hemorrhage was 19.12 months (95% CI 10.39-27.84), versus 13.85 months (95% CI 8.85-18.85) in those without hemorrhage (p > 0.05). Tumors that hemorrhaged had higher IHC staining for CD34 and CD105. mRNA expression analysis revealed tumor hemorrhage was associated with increased expression of HIF1α and MDK, and decreased expression of F3. Hemorrhage in GBM was not associated with worsened OS. Increased expression of angiogenic factors and increased CD34 and CD105 IHC staining in tumors with hemorrhage suggests that increased hypoxia-induced angiogenesis and vessel density may play a role in glioblastoma hemorrhage. Characterizing tumors that are prone to hemorrhage and mechanisms behind the development of these hemorrhages may provide insights that can lead to the development of targeted, individualized therapies for glioblastoma.
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Neoplasias Encefálicas/irrigação sanguínea , Neoplasias Encefálicas/metabolismo , Glioblastoma/irrigação sanguínea , Glioblastoma/metabolismo , Neovascularização Patológica/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Antígenos CD34/metabolismo , Neoplasias Encefálicas/diagnóstico , Endoglina/metabolismo , Feminino , Glioblastoma/diagnóstico , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , RNA Mensageiro/metabolismo , Estudos RetrospectivosRESUMO
A seven-year-old male underwent surgical resection and chemoradiation for average risk medulloblastoma; twelve years later, the presence of a necrotic and infiltrative mass in the same area and invading the brainstem prompted a subtotal resection. Pathology was indicative of glioblastoma. He was then treated with concurrent temozolomide and using biologically effective dose calculations for gross residual tumor tissue in the brainstem as well as brainstem tolerance, a radiotherapy dose of 3750 cGy was chosen, fractionated in twice-daily fractions of 125 cGy each. The gross tumor volume was expanded with a 5 mm margin to the planning target volume, which was also judiciously subtracted from the normal brainstem. He completed his radiotherapy course with subsequent imaging free of residual tumor and continued adjuvant temozolomide and remains under follow-up surveillance. This case underscores the rarity of metachronous medulloblastoma and glioblastoma, of which only five known cases heretofore have been described. We discuss the technicalities of radiotherapy planning in this patient, including common hurdles for radiation oncologists in similar patients.
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Members of the four-member C-terminal EPS15-Homology Domain-containing (EHD) protein family play crucial roles in endocytic recycling of cell surface receptors from endosomes to the plasma membrane. In this study, we show that Ehd1 gene knockout in mice on a predominantly B6 background is embryonic lethal. Ehd1-null embryos die at mid-gestation with a failure to complete key developmental processes including neural tube closure, axial turning and patterning of the neural tube. We found that Ehd1-null embryos display short and stubby cilia on the developing neuroepithelium at embryonic day 9.5 (E9.5). Loss of EHD1 also deregulates the ciliary SHH signaling with Ehd1-null embryos displaying features indicative of increased SHH signaling, including a significant downregulation in the formation of the GLI3 repressor and increase in the ventral neuronal markers specified by SHH. Using Ehd1-null MEFS we found that EHD1 protein co-localizes with the SHH receptor Smoothened in the primary cilia upon ligand stimulation. Under the same conditions, EHD1 was shown to co-traffic with Smoothened into the developing primary cilia and we identify EHD1 as a direct binding partner of Smoothened. Overall, our studies identify the endocytic recycling regulator EHD1 as a novel regulator of the primary cilium-associated trafficking of Smoothened and Hedgehog signaling.
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Cílios/genética , Cílios/metabolismo , Proteínas Hedgehog/metabolismo , Morfogênese , Tubo Neural/embriologia , Tubo Neural/metabolismo , Transdução de Sinais , Proteínas de Transporte Vesicular/genética , Animais , Cílios/patologia , Desenvolvimento Embrionário/genética , Feminino , Fibroblastos/metabolismo , Deleção de Genes , Expressão Gênica , Genes Letais , Patrimônio Genético , Genótipo , Masculino , Camundongos , Camundongos Knockout , Morfogênese/genética , Família Multigênica , Ligação Proteica , Transporte Proteico , Receptor Smoothened/metabolismoAssuntos
Neoplasias Encefálicas/diagnóstico , Complicações do Diabetes , Lobo Frontal/patologia , Lipoma/diagnóstico , Biomarcadores/líquido cefalorraquidiano , Neoplasias Encefálicas/complicações , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/fisiopatologia , Criança , Diabetes Mellitus/patologia , Diagnóstico Diferencial , Feminino , Lobo Frontal/cirurgia , Humanos , Lipoma/complicações , Lipoma/patologia , Lipoma/fisiopatologia , Imageamento por Ressonância Magnética , Convulsões/complicações , Convulsões/tratamento farmacológico , Convulsões/patologia , Convulsões/fisiopatologia , Tomografia Computadorizada por Raios XRESUMO
PURPOSE: Atypical teratoid rhabdoid tumors (ATRTs) arise from the central nervous system largely in the pediatric population. They portend a very poor prognosis with few long-term survivors. We describe a series of five cases at our institution. METHODS: We conducted a retrospective chart review and clinical follow-up. RESULTS: Three patients underwent chemoradiation after surgical resection; the two patients whose caretakers declined this therapy passed away soon after diagnosis. Chemoradiation included intravenous and intrathecal chemotherapy as well as intensity-modulated radiotherapy after resection. Of the patients receiving chemoradiation, two patients had infratentorial tumors, two had gross residual tumor after resection, and two were under the age of 3 years. The three patients receiving trimodality therapy remain clinically and symptomatically disease-free with follow-up times of 44, 46, and 55 months. Two of the patients have mild neuropsychiatric sequelae after therapy. CONCLUSIONS: Long-term, high-volume trials of ATRT are currently not published. We offer experience in successful long-term survival of this tumor treated with chemoradiotherapy.
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Neoplasias do Sistema Nervoso Central/tratamento farmacológico , Quimiorradioterapia/métodos , Tumor Rabdoide/tratamento farmacológico , Sobreviventes , Teratoma/tratamento farmacológico , Adolescente , Criança , Pré-Escolar , Intervalo Livre de Doença , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Estudos RetrospectivosRESUMO
BACKGROUND: Peripheral artery disease (PAD), which affects an estimated 27 million people in Europe and North America, is caused by atherosclerotic plaques that limit blood flow to the legs. Chronic, repeated ischemia in the lower leg muscles of PAD patients is associated with loss of normal myofiber morphology and myofiber degradation. In this study, we tested the hypothesis that myofiber morphometrics of PAD calf muscle are significantly different from normal calf muscle and correlate with reduced calf muscle strength and walking performance. METHODS: Gastrocnemius biopsies were collected from 154 PAD patients (Fontaine stage II) and 85 control subjects. Morphometric parameters of gastrocnemius fibers were determined and evaluated for associations with walking distances and calf muscle strength. RESULTS: Compared with control myofibers, PAD myofiber cross-sectional area, major and minor axes, equivalent diameter, perimeter, solidity, and density were significantly decreased (P < 0.005), whereas roundness was significantly increased (P < 0.005). Myofiber morphometric parameters correlated with walking distances and calf muscle strength. Multiple regression analyses demonstrated myofiber cross-sectional area, roundness, and solidity as the best predictors of calf muscle strength and 6-min walking distance, whereas cross-sectional area was the main predictor of maximum walking distance. CONCLUSIONS: Myofiber morphometrics of PAD gastrocnemius differ significantly from those of control muscle and predict calf muscle strength and walking distances of the PAD patients. Morphometric parameters of gastrocnemius myofibers may serve as objective criteria for diagnosis, staging, and treatment of PAD.
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Extremidades/fisiopatologia , Claudicação Intermitente/patologia , Fibras Musculares Esqueléticas/patologia , Idoso , Feminino , Humanos , Claudicação Intermitente/fisiopatologia , Masculino , Pessoa de Meia-Idade , Força MuscularRESUMO
Patients with peripheral artery disease (PAD) develop a myopathy in their ischemic lower extremities, which is characterized by myofiber degeneration, mitochondrial dysfunction and impaired limb function. Desmin, a protein of the cytoskeleton, is central to maintenance of the structure, shape and function of the myofiber and its organelles, especially the mitochondria, and to translation of sarcomere contraction into muscle contraction. In this study, we investigated the hypothesis that disruption of the desmin network occurs in gastrocnemius myofibers of PAD patients and correlates with altered myofiber morphology, mitochondrial dysfunction, and impaired limb function. Using fluorescence microscopy, we evaluated desmin organization and quantified myofiber content in the gastrocnemius of PAD and control patients. Desmin was highly disorganized in PAD but not control muscles and myofiber content was increased significantly in PAD compared to control muscles. By qPCR, we found that desmin gene transcripts were increased in the gastrocnemius of PAD patients as compared with control patients. Increased desmin and desmin gene transcripts in PAD muscles correlated with altered myofiber morphology, decreased mitochondrial respiration, reduced calf muscle strength and decreased walking performance. In conclusion, our studies identified disruption of the desmin system in gastrocnemius myofibers as an index of the myopathy and limitation of muscle function in patients with PAD.
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Desmina/metabolismo , Mitocôndrias/metabolismo , Fibras Musculares Esqueléticas/metabolismo , Músculo Esquelético/metabolismo , Doença Arterial Periférica/metabolismo , Idoso , Estudos de Casos e Controles , Contagem de Células , Humanos , Extremidade Inferior , Pessoa de Meia-Idade , Fibras Musculares Esqueléticas/patologia , Músculo Esquelético/patologia , Músculo Esquelético/fisiopatologia , Doença Arterial Periférica/patologia , Doença Arterial Periférica/fisiopatologia , CaminhadaRESUMO
BACKGROUND: Peripheral artery disease (PAD), a manifestation of systemic atherosclerosis that produces blockages in the arteries supplying the legs, affects approximately 5% of Americans. We have previously, demonstrated that a myopathy characterized by myofiber oxidative damage and degeneration is central to PAD pathophysiology. OBJECTIVES: In this study, we hypothesized that increased oxidative damage in the myofibers of the gastrocnemius of PAD patients is myofiber-type selective and correlates with reduced myofiber size. METHODS: Needle biopsies were taken from the gastrocnemius of 53 PAD patients (28 with early PAD and 25 with advanced PAD) and 25 controls. Carbonyl groups (marker of oxidative damage), were quantified in myofibers of slide-mounted tissue, by quantitative fluorescence microscopy. Myofiber cross-sectional area was determined from sarcolemma labeled with wheat germ agglutinin. The tissues were also labeled for myosin I and II, permitting quantification of oxidative damage to and relative frequency of the different myofiber Types (Type I, Type II and mixed Type I/II myofibers). We compared PAD patients in early (N=28) vs. advanced (N=25) disease stage for selective, myofiber oxidative damage and altered morphometrics. RESULTS: The carbonyl content of gastrocnemius myofibers was higher in PAD patients compared to control subjects, for all three myofiber types (p<0.05). In PAD patients carbonyl content was higher (p<0.05) in Type II and I/II fibers compared to Type I fibers. Furthermore, the relative frequency and cross-sectional area of Type II fibers were lower, while the relative frequencies and cross-sectional area of Type I and Type I/II fibers were higher, in PAD compared to control gastrocnemius (p<0.05). Lastly, the type II-selective oxidative damage increased and myofiber size decreased as the disease progressed from the early to advanced stage. CONCLUSIONS: Our data confirm increased myofiber oxidative damage and reduced myofiber size in PAD gastrocnemius and demonstrate that the damage is selective for type II myofibers and is worse in the most advanced stage of PAD.
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Fibras Musculares Esqueléticas/metabolismo , Fibras Musculares Esqueléticas/patologia , Estresse Oxidativo , Doença Arterial Periférica/metabolismo , Doença Arterial Periférica/patologia , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
Epstein-Barr virus-associated smooth muscle tumors (EBV-SMTs) are rare lesions that occur in immunocompromised patients. Dural involvement appears to be less common in organ transplant recipients than in HIV patients. Due to the paucity of reported cases following organ transplantation, the natural history of these lesions is unclear. We describe an 8-year-old female who presented with adrenal, small bowel, and intracranial tumors 6 years following renal transplantation. Histopathological analysis revealed a highly cellular, mitotically active, smooth muscle neoplasm without necrosis. The tumor stained diffusely for smooth muscle actin and myosin. In situ hybridization for EBV-encoded RNA was diffusely positive. Following gross total resection, antiviral therapy, and a reduction in immunosuppression, the patient is tumor-free at 3 years follow-up. In patients with compromised immune systems, it is important to recognize this unique form of SMT because, even when there are multiple lesions, the prognosis may be excellent.
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Infecções por Vírus Epstein-Barr/patologia , Herpesvirus Humano 4/isolamento & purificação , Neoplasias Musculares/virologia , Músculo Liso/patologia , Criança , Feminino , Humanos , Hospedeiro Imunocomprometido , Transplante de Rim , Neoplasias Musculares/patologia , Neoplasias Musculares/cirurgia , Músculo Liso/cirurgia , Resultado do TratamentoRESUMO
We report the fourth case of an intracranial malignant triton tumor not associated with a cranial nerve in a 26-year-old male with a clinical history of neurofibromatosis type 1. The patient was found unresponsive and displayed confusion, lethargy, hyperreflexia, and dysconjugate eye movements upon arrival at the emergency room. MRI revealed a large bifrontal mass. Biopsy demonstrated a high-grade spindle cell tumor with focal areas of rhabdomyoblasts that stained positive for desmin, myogenin, and muscle-specific actin. Electron microscopy showed skeletal muscle differentiation. Based on the clinical history of NF1 and the pathologic results, a diagnosis of malignant triton tumor was made. The differential diagnosis, immunohistochemistry, molecular genetics, and treatment of malignant triton tumor are reviewed.
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Neoplasias Encefálicas/diagnóstico , Lobo Frontal , Neoplasias de Bainha Neural/diagnóstico , Neurofibromatose 1/complicações , Adulto , Biomarcadores Tumorais/análise , Neoplasias Encefálicas/etiologia , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/terapia , Terapia Combinada , Diagnóstico , Evolução Fatal , Humanos , Imuno-Histoquímica , Imageamento por Ressonância Magnética , Masculino , Técnicas de Diagnóstico Molecular , Neoplasias de Bainha Neural/etiologia , Neoplasias de Bainha Neural/patologia , Neoplasias de Bainha Neural/terapiaRESUMO
BACKGROUND: Peripheral arterial disease (PAD) is characterized by myofiber degeneration and loss of function in muscles of the lower limbs. Human enterovirus (HEV) infection has been implicated in the pathogenesis of a number of muscle diseases. However, its association with PAD has not been studied. In this study, we tested the hypothesis that infectious HEV is present in skeletal muscle of patients with PAD and is associated with severity of disease. METHODS AND RESULTS: Gastrocnemius biopsies from 37 patients with PAD and 14 controls were examined for the presence of HEV RNA, viral capsid protein, viral RNA copy number, and viral infectivity. HEV RNA was detected in 54% of the biopsies from patients with PAD but was not detected in muscle biopsies from control patients. This difference in prevalence among PAD and control patients was significant at P<0.001. Viral RNA copy numbers were increased significantly at the later stages of disease; Fontaine Stage IV (10(5.50) copies/mg muscle wet weight, at P<0.005) and Stage III (10(4.87) copies/mg, at P<0.010) compared to Stage II (10(2.50) copies/mg). Viral replication was confirmed by the presence of the negative-strand of viral RNA in all specimens positive for HEV RNA. Cultures of HeLa and human skeletal muscle cells treated with muscle homogenates showed HEV replication and the presence of HEV capsid protein. CONCLUSION: Our data identified infectious HEV in the gastrocnemius of PAD patients but not in controls. Viral copy number and prevalence of infection were higher in the later stages of disease. Our data point to the need for further studies to determine the contribution of HEV infection to the pathophysiology of PAD.
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Infecções por Enterovirus/epidemiologia , Enterovirus/isolamento & purificação , Músculo Esquelético/virologia , Doença Arterial Periférica/epidemiologia , Idoso , Biópsia , Proteínas do Capsídeo/isolamento & purificação , Estudos de Casos e Controles , Enterovirus/genética , Enterovirus/crescimento & desenvolvimento , Infecções por Enterovirus/diagnóstico , Infecções por Enterovirus/virologia , Feminino , Células HeLa , Humanos , Iowa/epidemiologia , Masculino , Pessoa de Meia-Idade , Nebraska/epidemiologia , Doença Arterial Periférica/diagnóstico , Doença Arterial Periférica/virologia , Prevalência , RNA Viral/isolamento & purificação , Fatores de Risco , Índice de Gravidade de Doença , Carga Viral , Replicação ViralRESUMO
Peripheral arterial disease (PAD), which affects ~10 million Americans, is characterized by atherosclerosis of the noncoronary arteries. PAD produces a progressive accumulation of ischemic injury to the legs, manifested as a gradual degradation of gastrocnemius histology. In this study, we evaluated the hypothesis that quantitative morphological parameters of gastrocnemius myofibers change in a consistent manner during the progression of PAD, provide an objective grading of muscle degeneration in the ischemic limb, and correlate to a clinical stage of PAD. Biopsies were collected with a Bergström needle from PAD patients with claudication (n = 18) and critical limb ischemia (CLI; n = 19) and control patients (n = 19). Myofiber sarcolemmas and myosin heavy chains were labeled for fluorescence detection and quantitative analysis of morphometric variables, including area, roundness, perimeter, equivalent diameter, major and minor axes, solidity, and fiber density. The muscle specimens were separated into training and validation data sets for development of a discriminant model for categorizing muscle samples on the basis of disease severity. The parameters for this model included standard deviation of roundness, standard deviation of solidity of myofibers, and fiber density. For the validation data set, the discriminant model accurately identified control (80.0% accuracy), claudicating (77.7% accuracy), and CLI (88.8% accuracy) patients, with an overall classification accuracy of 82.1%. Myofiber morphometry provided a discriminant model that establishes a correlation between PAD progression and advancing muscle degeneration. This model effectively separated PAD and control patients and provided a grading of muscle degeneration within clinical stages of PAD.
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Músculo Esquelético/patologia , Doença Arterial Periférica/patologia , Idoso , Algoritmos , Biópsia , Análise Discriminante , Progressão da Doença , Feminino , Corantes Fluorescentes , Humanos , Processamento de Imagem Assistida por Computador , Modelos Lineares , Masculino , Microscopia de Fluorescência , Pessoa de Meia-Idade , Modelos Biológicos , Fibras Musculares Esqueléticas/patologia , Miosinas/metabolismo , Sarcolema/patologiaRESUMO
Autophagic vacuolar cardiomyopathy is an underrecognized, but potentially fatal, complication of treatment with chloroquine (CQ) and its derivative hydroxychloroquine (HCQ), which are used as therapy for malaria and common connective tissue disorders. Currently, the diagnosis of autophagic vacuolar cardiomyopathy is established through an endomyocardial biopsy and requires electron microscopy, which is not widely available and has a significant potential for sampling error. Recently, we have reported that immunohistochemistry for autophagic markers LC3 and p62 can replace electron microscopy in the diagnosis of HCQ-induced and colchicine-induced autophagic vacuolar skeletal myopathies. In the current study, we use 3 cases of CQ-induced or HCQ-induced cardiomyopathy and 1 HCQ-treated control case to show that the same two markers can be used to diagnose autophagic vacuolar cardiomyopathies by light microscopy. CQ-induced or HCQ-induced autophagic vacuolar cardiomyopathy is not universally fatal, but successful treatment requires early detection. By lowering the barriers to diagnosis, the application of these immunohistochemical markers will decrease the number of misdiagnosed patients, thus increasing the likelihood of favorable clinical outcomes.
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Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Antimaláricos/efeitos adversos , Autofagia/efeitos dos fármacos , Cardiomiopatias , Hidroxicloroquina/efeitos adversos , Proteínas Associadas aos Microtúbulos/metabolismo , Adulto , Idoso , Biomarcadores/metabolismo , Cardiomiopatias/induzido quimicamente , Cardiomiopatias/diagnóstico , Cardiomiopatias/metabolismo , Cloroquina/efeitos adversos , Erros de Diagnóstico/prevenção & controle , Evolução Fatal , Feminino , Humanos , Pessoa de Meia-Idade , Proteína Sequestossoma-1 , Vacúolos/efeitos dos fármacos , Vacúolos/ultraestruturaRESUMO
Mixed neuronal-glial tumors are rare and challenging to subclassify. One recently recognized variant, papillary glioneuronal tumor (PGNT), is characterized by prominent pseudopapillary structures and glioneuronal elements. We identified a novel translocation, t(9;17)(q31;q24), as the sole karyotypic anomaly in two PGNTs. A fluorescence in situ hybridization (FISH)-based positional cloning strategy revealed SLC44A1, a member of the choline transporter-like protein family, and PRKCA, a protein kinase C family member of serine/threonine-specific protein kinases, as the 9q31 and 17q24 breakpoint candidate genes, respectively. Reverse transcription-polymerase chain reaction (RT-PCR) analysis using a forward primer from SLC44A1 exon 5 and a reverse primer from PRKCA exon 10 confirmed the presence of a SLC44A1-PRKCA fusion product in both tumors. Sequencing of each chimeric transcript uncovered an identical fusion cDNA junction occurring between SLC44A1 exon 15 and PRKCA exon 9. A dual-color breakpoint-spanning probe set custom-designed for interphase cell recognition of the translocation event identified the fusion in a third PGNT. These results suggest that the t(9;17)(q31;q24) with the resultant novel fusion oncogene SLC44A1-PRKCA is the defining molecular feature of PGNT that may be responsible for its pathogenesis. The FISH and RT-PCR assays developed in this study can serve as valuable diagnostic adjuncts for this rare disease entity.
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Antígenos CD/genética , Neoplasias Encefálicas/genética , Carcinoma Papilar/genética , Fusão Oncogênica , Proteínas de Transporte de Cátions Orgânicos/genética , Proteína Quinase C-alfa/genética , Adolescente , Adulto , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/cirurgia , Carcinoma Papilar/patologia , Carcinoma Papilar/cirurgia , Criança , Citogenética , Feminino , Lobo Frontal/patologia , Lobo Frontal/cirurgia , Humanos , Hibridização in Situ Fluorescente , Masculino , Lobo Parietal/patologia , Lobo Parietal/cirurgia , Lobo Temporal/patologia , Lobo Temporal/cirurgiaRESUMO
Friedreich's ataxia (FRDA) affects very young persons. In a large series, the mean ages of onset and death were 11 and 38 years, respectively. The clinical spectrum of FRDA has expanded after genetic confirmation of the mutation became a routine laboratory test. The main cause of death in juvenile-onset FRDA is cardiomyopathy whereas patients with late-onset are more likely to succumb to neurological disability or an intercurrent illness. Many patients with early onset now survive for 20 years or longer. This study made a systematic comparison of the neuropathology in 14 patients with juvenile onset and long survival, and five patients with late onset and long survival. Mean ages of onset (± standard deviation) were 10 ± 5 and 28 ± 13 years, respectively. Disease durations were 33 ± 11 and 47 ± 11 years, respectively. Cross-sectional areas of the thoracic spinal cord were greatly reduced from the normal state but did not differ between the two groups. Similarly, the neurons of dorsal root ganglia were significantly reduced in size in both juvenile- and late-onset cases of FRDA. The dentate nucleus showed severe loss of neurons as well as modification and destruction of corticonuclear terminals in all FRDA patients. Delayed atrophy of the dentate nucleus is the likely cause of the ataxic phenotype of FRDA in late-onset cases, but the reason for the delay is unknown. Frataxin levels in the dentate nucleus of two patients with late onset were similar to those of seven patients with juvenile onset.
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Ataxia de Friedreich/patologia , Sistema Nervoso/patologia , Adolescente , Adulto , Idade de Início , Idoso , Anatomia Transversal , Tamanho Celular , Núcleos Cerebelares/metabolismo , Núcleos Cerebelares/patologia , Criança , Pré-Escolar , Ensaio de Imunoadsorção Enzimática , Feminino , Gânglios Espinais/patologia , Humanos , Imuno-Histoquímica , Proteínas de Ligação ao Ferro/metabolismo , Masculino , Pessoa de Meia-Idade , Neurônios/patologia , Medula Espinal/patologia , Sobrevida , Adulto Jovem , FrataxinaRESUMO
A 62-year-old woman with no known psychiatric illness had a 1.5-year history of progressive personality and language changes, leading to a loss of functional independence. Laboratory results revealed elevated autoimmune antibodies. She did not improve on high-dose steroid therapy and continued to deteriorate to her death, 2.5 years after symptom onset.