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In situ transgenesis methods such as viruses and electroporation can rapidly create somatic transgenic mice but lack control over copy number, zygosity, and locus specificity. Here we establish mosaic analysis by dual recombinase-mediated cassette exchange (MADR), which permits stable labeling of mutant cells expressing transgenic elements from precisely defined chromosomal loci. We provide a toolkit of MADR elements for combination labeling, inducible and reversible transgene manipulation, VCre recombinase expression, and transgenesis of human cells. Further, we demonstrate the versatility of MADR by creating glioma models with mixed reporter-identified zygosity or with "personalized" driver mutations from pediatric glioma. MADR is extensible to thousands of existing mouse lines, providing a flexible platform to democratize the generation of somatic mosaic mice. VIDEO ABSTRACT.
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Neoplasias Encefálicas/genética , Modelos Animais de Doenças , Marcação de Genes/métodos , Loci Gênicos/genética , Glioma/genética , Mutagênese Insercional/métodos , Transgenes/genética , Animais , Linhagem Celular Tumoral , Feminino , Células HEK293 , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Células-Tronco Neurais/metabolismo , Recombinases/metabolismo , TransfecçãoRESUMO
INTRODUCTION: Down syndrome (DS) is the most common multiple malformation syndrome in humans and is associated with an increased risk of childhood malignancy, particularly leukemia. Incidence of brain tumors in patients with DS is limited to sporadic cases. We report the first case of a RELA fusion-positive ependymoma in a 3-year-old boy with DS. CASE PRESENTATION: Imaging prompted by new left-sided hemiparesis demonstrated an 8-cm hemorrhagic right temporal-parietal mass. Subsequent image-complete resection confirmed a RELA fusion-positive anaplastic ependymoma with 90% OLIG2 staining. Postoperatively, the patient, unfortunately, experienced fatal recurrence and drop metastases with leptomeningeal involvement. CONCLUSION: To our knowledge, this is the first reported case of a confirmed RELA fusion-positive ependymoma in a child with DS. We discuss this finding in the context of intracranial tumors in children with DS, as well as the finding of 90% positive OLIG2 expression and its potential as a prognostic marker.
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Neoplasias Encefálicas , Síndrome de Down , Ependimoma , Glioma , Neoplasias Supratentoriais , Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/cirurgia , Criança , Pré-Escolar , Síndrome de Down/complicações , Ependimoma/complicações , Ependimoma/diagnóstico por imagem , Ependimoma/genética , Humanos , Masculino , Fator de Transcrição RelARESUMO
Extracellular vesicles (EVs) are membrane-enclosed particles that are released by virtually all cells from all living organisms. EVs shuttle biologically active cargo including protein, RNA, and DNA between cells. When shed by cancer cells, they function as potent intercellular messangers with important functional consequences. Cells produce a diverse spectrum of EVs, spanning from small vesicles of 40-150 nm in diameter, to large vesicles up to 10 µm in diameter. While this diversity was initially considered to be purely based on size, it is becoming evident that different classes of EVs, and different populations within one EV class may harbor distinct molecular cargo and play specific functions. Furthermore, there are considerable cell type-dependent differences in the cargo and function of shed EVs. This review focuses on the most recent proteomic studies that have attempted to capture the EV heterogeneity by directly comparing the protein composition of different EV classes and EV populations derived from the same cell source. Recent studies comparing protein composition of the same EV class(es) derived from different cell types are also summarized. Emerging approaches to study EV heterogeneity and their important implications for future studies are also discussed.
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Vesículas Extracelulares/metabolismo , Proteômica/métodos , Exossomos/metabolismo , HumanosRESUMO
PURPOSE: Parasellar plasmacytomas are rare tumors localized to the sellar region arising from plasma cells. Knowledge of clinical, imaging, surgical, and pathological characteristics is limited to single case reports. METHODS: A retrospective analysis of five primary cases was conducted, followed by systematic review of English language articles using PubMed in accordance with PRISMA guidelines. RESULTS: Five primary case patients include four men and one woman, ages 60-77, followed up to 3 years. A systematic review identified 65 additional patients, of whom 65% presented with cranial nerve palsies and 15% with hypopituitarism. Sixteen percent had history of known multiple myeloma (MM) while 37% were diagnosed concurrently with MM on presentation of parasellar plasmacytoma. Imaging showed median tumor size of 38 mm (range, 4-70 mm), with MRI intensity similar to that of other sellar masses. Surgical biopsy with immunohistochemical studies confirmed plasmacytoma diagnosis. Eighty-one percent underwent parasellar radiotherapy, and chemotherapy initiated in 59% of the 69 patients with MM. Overall survival rate was 74% at follow-up (median 12 months), with 18% having parasellar recurrences and 38% progressing to systemic MM after presentation of a solitary plasmacytoma (median 3 months). CONCLUSIONS: Parasellar plasmacytomas are rare tumors that should be considered in the differential diagnosis for lesions involving the sella and arising from the clivus, especially when cranial nerve paresis is apparent, even in the absence of known MM. Although recurrence rates for parasellar plasmacytoma is low, patients should be monitored for progression to MM. Treatment depends on the presence of systemic disease at diagnosis.
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Plasmocitoma/metabolismo , Idoso , Feminino , Humanos , Masculino , Mieloma Múltiplo/metabolismo , Estudos RetrospectivosRESUMO
Cancer cell secretion of TGF-ß is a potent mechanism for immune evasion. However, little is known about how central nervous system tumors guard against immune eradication. We sought to determine the impact of T-cell TGF-ß signaling blockade on progression of medulloblastoma (MB), the most common pediatric brain tumor. Genetic abrogation of T-cell TGF-ß signaling mitigated tumor progression in the smoothened A1 (SmoA1) transgenic MB mouse. T regulatory cells were nearly abolished and antitumor immunity was mediated by CD8 cytotoxic T lymphocytes. To define the CD8 T-cell subpopulation responsible, primed CD8 T cells were adoptively transferred into tumor-bearing immunocompromised SmoA1 recipients. This led to generation of CD8(+)/killer cell lectin-like receptor G1 high (KLRG1(hi))/IL-7R(lo) short-lived effector cells that expressed granzyme B at the tumor. These results identify a cellular immune mechanism whereby TGF-ß signaling blockade licenses the T-cell repertoire to kill pediatric brain tumor cells.
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Linfócitos T CD8-Positivos/metabolismo , Transdução de Sinais , Fator de Crescimento Transformador beta/metabolismo , Animais , Comportamento Animal , Linfócitos T CD8-Positivos/citologia , Diferenciação Celular , Citometria de Fluxo , Camundongos , Camundongos Endogâmicos C57BLRESUMO
Alzheimer's disease (AD) is hallmarked by amyloid plaques, neurofibrillary tangles, and widespread cortical neuronal loss (Selkoe, 2001). The "amyloid cascade hypothesis" posits that cerebral amyloid sets neurotoxic events into motion that precipitate Alzheimer dementia (Hardy and Allsop, 1991). Yet, faithful recapitulation of all AD features in widely used transgenic (Tg) mice engineered to overproduce Aß peptides has been elusive. We have developed a Tg rat model (line TgF344-AD) expressing mutant human amyloid precursor protein (APPsw) and presenilin 1 (PS1ΔE9) genes, each independent causes of early-onset familial AD. TgF344-AD rats manifest age-dependent cerebral amyloidosis that precedes tauopathy, gliosis, apoptotic loss of neurons in the cerebral cortex and hippocampus, and cognitive disturbance. These results demonstrate progressive neurodegeneration of the Alzheimer type in these animals. The TgF344-AD rat fills a critical need for a next-generation animal model to enable basic and translational AD research.
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Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/metabolismo , Córtex Cerebral/patologia , Transtornos Cognitivos/patologia , Hipocampo/patologia , Degeneração Neural/patologia , Placa Amiloide/patologia , Tauopatias/patologia , Fatores Etários , Doença de Alzheimer/complicações , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Precursor de Proteína beta-Amiloide/genética , Animais , Comportamento Animal , Angiopatia Amiloide Cerebral , Córtex Cerebral/metabolismo , Transtornos Cognitivos/complicações , Transtornos Cognitivos/genética , Transtornos Cognitivos/metabolismo , Modelos Animais de Doenças , Feminino , Gliose/genética , Gliose/patologia , Hipocampo/metabolismo , Humanos , Masculino , Degeneração Neural/genética , Degeneração Neural/metabolismo , Placa Amiloide/genética , Presenilina-1/genética , Ratos , Ratos Endogâmicos F344 , Ratos Transgênicos , Tauopatias/metabolismo , Proteínas tau/metabolismoRESUMO
Spinocerebellar ataxia 13 (SCA13) is an autosomal dominant disease resulting from mutations in KCNC3 (Kv3.3), a voltage-gated potassium channel. The KCNC3(R420H) mutation was first identified as causative for SCA13 in a four-generation Filipino kindred with over 20 affected individuals. Electrophysiological analyses in oocytes previously showed that this mutation did not lead to a functional channel and displayed a dominant negative phenotype. In an effort to identify the molecular basis of this allelic form of SCA13, we first determined that human KCNC3(WT) and KCNC3(R420H) display disparate post-translational modifications, and the mutant protein has reduced complex glycan adducts. Immunohistochemical analyses demonstrated that KCNC3(R420H) was not properly trafficking to the plasma membrane and surface biotinylation demonstrated that KCNC3(R420H) exhibited only 24% as much surface expression as KCNC3(WT). KCNC3(R420H) trafficked through the ER but was retained in the Golgi. KCNC3(R420H) expression results in altered Golgi and cellular morphology. Electron microscopy of KCNC3(R420H) localization further supports retention in the Golgi. These results are specific to the KCNC3(R420H) allele and provide new insight into the molecular basis of disease manifestation in SCA13.
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Arginina/genética , Histidina/genética , Líquido Intracelular/metabolismo , Mutação/genética , Canais de Potássio Shaw/genética , Degenerações Espinocerebelares/genética , Animais , Animais Geneticamente Modificados , Biotinilação , Células COS , Caderinas/metabolismo , Chlorocebus aethiops , Citoplasma/genética , Citoplasma/metabolismo , Drosophila , Proteínas de Drosophila/genética , Retículo Endoplasmático/metabolismo , Feminino , Humanos , Masculino , Oócitos , Processamento de Proteína Pós-Traducional , Transporte Proteico , Ataxias Espinocerebelares/congênito , Degenerações Espinocerebelares/metabolismo , TransfecçãoRESUMO
OBJECTIVE: Pituicytomas are rare neoplasms that typically present as solid, noninfiltrative tumors occupying the sella and/or suprasellar space for which there is no consensus on optimal surgical management. We aimed to define a preferred surgical strategy for these tumors based on our clinical experience and comprehensive review of the world literature. DESIGN: Case series and review of the literature. METHODS: We documented the clinical, radiographic, and surgical findings of three patients with pituicytoma treated at our institution, as well as complications and long-term outcomes. A comprehensive review of the medical literature identified all cases of pituicytoma for which data regarding surgical approach, outcome and complications could be extracted. We compared our results with published data. RESULTS: All three cases at our institution achieved gross total removal. Two patients underwent an expanded endoscopic endonasal transsphenoidal and transplanum (EETS-TP) approach, while one tumor was removed via craniotomy. Post-operatively all patients developed pan-hypopitutarism. The patient undergoing craniotomy suffered profound visual loss but no other neurological complications were noted. A literature review identified 67 reported cases of pituicytoma. Surgical data was available in 60 cases. Surgical approach was documented in 57 patients. Sixty-three surgeries were performed in which approach and extent of resection was available. Gross total removal was obtained in 33 % of craniotomies, 42 % of transsphenoidal procedures, and 100 % of expanded transsphenoidal procedures. Neurological complications including visual loss, hemiparesis and cranial nerve palsies were reported after craniotomy, but not after transsphenoidal approaches. Overall EETS-TP approaches were associated with the highest rate of gross total removal and no visual or neurological complications. CONCLUSIONS: EETS-TP surgery is the preferred strategy for surgical removal of pituicytoma. EETS-TP and transsphenoidal approaches are associated with higher rates of gross total removal and lower rates of neurological complications than craniotomy. Gross total removal should be the intended goal of surgery.
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Neoplasias Hipofisárias/cirurgia , Craniotomia , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias Hipofisárias/diagnósticoRESUMO
Neuronal ceroid lipofuscinosis (NCL), type 6 (CLN6) is a neurodegenerative disorder associated with progressive neurodegeneration leading to dementia, seizures, and retinopathy. CLN6 encodes a resident-ER protein involved in trafficking lysosomal proteins to the Golgi. CLN6p deficiency results in lysosomal dysfunction and deposition of storage material comprised of Nile Red + lipids/proteolipids that include subunit C of the mitochondrial ATP synthase (SUBC). White matter involvement has been recently noted in several CLN6 animal models and several CLN6 subjects had neuroimaging was consistent with leukodystrophy. CLN6 patient-derived induced pluripotent stem cells (IPSCs) were generated from several of these subjects. IPSCs were differentiated into oligodendroglia or neurons using well-established small-molecule protocols. A doxycycline-inducible transgenic system expressing neurogenin-2 (the I3N-system) was also used to generate clonal IPSC-lines (I3N-IPSCs) that could be rapidly differentiated into neurons (I3N-neurons). All CLN6 IPSC-derived neural cell lines developed significant storage material, CLN6-I3N-neuron lines revealed significant Nile Red + and SUBC + storage within three and seven days of neuronal induction, respectively. CLN6-I3N-neurons had decreased tripeptidyl peptidase-1 activity, increased Golgi area, along with increased LAMP1 + in cell bodies and neurites. SUBC + signal co-localized with LAMP1 + signal. Bulk-transcriptomic evaluation of control- and CLN6-I3N-neurons identified >1300 differentially-expressed genes (DEGs) with Gene Ontogeny (GO) Enrichment and Canonical Pathway Analyses having significant changes in lysosomal, axonal, synaptic, and neuronal-apoptotic gene pathways. These findings indicate that CLN6-IPSCs and CLN6-I3N-IPSCs are appropriate cellular models for this disorder. These I3N-neuron models may be particularly valuable for developing therapeutic interventions with high-throughput drug screening assays and/or gene therapy.
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Metilação de DNA/genética , Ventrículos Laterais/patologia , Mutação/genética , Neoplasias Neuroepiteliomatosas/genética , Neoplasias Neuroepiteliomatosas/patologia , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/genética , Septo Pelúcido/patologia , Adulto , Criança , Metilases de Modificação do DNA/genética , Enzimas Reparadoras do DNA/genética , Feminino , Glioma/genética , Glioma/metabolismo , Glioma/patologia , Humanos , Ventrículos Laterais/diagnóstico por imagem , Lisina/genética , Imageamento por Ressonância Magnética , Masculino , Neoplasias Neuroepiteliomatosas/diagnóstico por imagem , Septo Pelúcido/diagnóstico por imagem , Proteínas Supressoras de Tumor/genética , Adulto JovemRESUMO
PURPOSE: Hemangiopericytoma (HPC) is a rare tumor of the central nervous system. Primary spinal occurrence of this tumor is extremely uncommon and cases involving the intramedullary spinal cord are even more rare. The purpose of this study was to explore the clinical features, surgical strategies, outcome and pathology in a consecutive series of patients treated at a single institution. METHODS: The authors performed a retrospective review of the clinicopathological characteristics of four patients with a pathological diagnosis of spinal HPC. RESULTS: Four cases with intradural as well as intra/extra-medullary components were identified. Gross total resection with no recurrence at the operative site was achieved in the majority of patients with a spinal HPC. One patient had significant recurrence and eventually, succumbed to the disease. CONCLUSION: Increased awareness of these tumors' capability to occur intradurally and intramedullarly can help surgeons accurately diagnose and choose an effective plan of care. Gross total resection of hemangiopericytomas is the mainstay of treatment and should be pursued if feasible. Histopathology is essential to the diagnosis.
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Hemangiopericitoma/cirurgia , Neoplasias da Medula Espinal/cirurgia , Adulto , Feminino , Hemangiopericitoma/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Procedimentos Neurocirúrgicos , Estudos Retrospectivos , Neoplasias da Medula Espinal/patologiaRESUMO
Glioblastoma (GBM) is the most common malignant brain tumor. Less than 1% of patients survive longer than 10 years. A 77-year-old woman was diagnosed with MGMT-methylated GBM in 2009. The patient received cilengitide as part of the CENTRIC clinical trial in conjunction with standard radiation and chemotherapy. Though the study was halted in 2013, our patient received cilengitide until 2016 with no radiographic evidence of recurrence thus far. This is the oldest reported GBM patient with greater than 10-year survival. Her exceptional response may have been influenced by MGMT promoter methylation status and PTEN expression.
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Neoplasias Encefálicas , Glioblastoma , Feminino , Humanos , Criança , Glioblastoma/diagnóstico por imagem , Glioblastoma/tratamento farmacológico , Glioblastoma/genética , Temozolomida/uso terapêutico , Dacarbazina/uso terapêutico , Metilases de Modificação do DNA/genética , Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/genética , Metilação de DNA , Enzimas Reparadoras do DNA/genética , PrognósticoRESUMO
BACKGROUND: Intracranial solitary fibrous tumors (SFTs), formerly known as hemangiopericytomas, are rare, aggressive mesenchymal extra-axial tumors typically treated via resection, often with preoperative embolization and postoperative radiation and/or antiangiogenic therapy. Although surgery confers a significant survival benefit, local recurrence and distant metastasis are not uncommon and may occur in a delayed fashion. OBSERVATIONS: The authors describe the case of a 29-year-old male who initially presented with headache, visual disturbance, and ataxia, and was found to have a large right tentorial lesion with mass effect on surrounding structures. He underwent tumor embolization and resection with gross total resection achieved and pathology consistent with World Health Organization grade 2 hemangiopericytoma. The patient recovered well, but 6 years later presented with low back pain and lower extremity radiculopathy and was found to have metastatic disease within the L4 vertebral body causing moderate central canal stenosis. This was successfully treated with tumor embolization followed by spinal decompression and posterolateral instrumented fusion. Metastasis of intracranial SFT to vertebral bone is exceedingly rare. To our knowledge this is only the 16th reported case. LESSONS: Serial surveillance for metastatic disease is imperative in patients with intracranial SFTs given their propensity and unpredictable time course for distant spread.
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Background: Meningiomas are the most common primary intracranial tumor with increasing incidence. Stereotactic Radiosurgery Gamma Knife (SRS-GK) is a commonly used modality for neoadjuvant and adjuvant treatment of these tumors and is often necessary for long-term disease control, particularly for the World Health Organization grade II/III meningiomas. While there is strong evidence to support the use of SRS-GK for meningioma, there exists a risk of secondary malignancy that is not well understood. We report a case of glioblastoma (GBM) that arose near the bed of a meningioma previously treated with SRS-GK and discuss other cases of GBM that emerged at a site of meningioma reported in the literature. Case Description: A 79-year-old female with a history of a blood-clotting disorder presented to the hospital with sudden facial sensory disturbances. On magnetic resonance imaging (MRI), a homogeneously enhancing lesion was observed in the right temporal lobe, consistent with a meningioma. Following 2 years of surveillance, the patient underwent SRS-GK for enlargement of the lesion. The patient later presented with headache and gait instability 12 years following SRS-GK. MRI revealed a large ring-enhancing lesion with surrounding edema histologically confirmed to be a GBM. At 9 months following initial tumor resection and a combination of radiotherapy and temozolomide, the patient was neurologically intact. Conclusion: There is a very small risk of meningioma to GBM conversion following SRS. Although SRS-GK poses a risk of secondary malignancy, there are some reported cases that underwent malignant transformation without SRS-GK. This suggests that SRS-GK is not the only factor in transformation and is a reasonable therapeutic modality to consider utilizing. Patients and their families should be appropriately counseled on the potential risks of radiation therapy, even for benign lesions like a meningioma.
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Atypical choroid plexus papilloma (aCPP) is very rarely seen in adults. Here, we present the case of a 47-year-old male with several months of headache, nausea, dizziness, and imbalance who was found to have an enhancing mass of the fourth ventricle with imaging findings suggestive of likely ependymoma. The patient underwent suboccipital craniotomy with C1 laminectomy and telovelar approach for gross-total resection of the lesion, with final pathology demonstrating WHO grade II aCPP. Subsequent genomic analysis showed a biologically relevant TERT mutation, as well as several variants of unknown significance. We conclude that aCPP is a rare, benign entity diagnosed by tissue sample that is potentially curative with surgical resection and may harbor targetable genetic mutations.
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BACKGROUND: Predictive markers of aggressive pituitary tumors have not been consistently demonstrated. Dural invasion and invasion-associated proteins, including matrix metalloproteinase-9 (MMP9) and cofilin, have been proposed to predict aggressive behavior and recurrence, but findings to date have been inconsistent. OBJECTIVE: To assess whether microscopic dural invasion predicts aggressive pituitary adenoma behavior and whether MMP9 and cofilin expression correlates with pathological and clinical invasion markers. METHODS: We retrospectively studied 328 consecutive pituitary mass resections by a single neurosurgeon at a single center; 254 were adenomas, and 98 had dural biopsies sent for routine pathological evaluation. Assessments included clinical features, postoperative course, and immunochemical expression of MMP9, cofilin, and phospho-cofilin. Recurrence was evaluated in those with at least 12 months of postoperative follow-up. RESULTS: Dural invasion was evident in 48% of biopsy specimens and was associated with male sex, larger tumors, suprasellar extension and sphenoid sinus invasion, cranial nerve palsies, and hypogonadism. Recurrence rates and the expression of MMP9, cofilin, and phospho-cofilin did not differ between those with and without dural invasion. However, differential expression of phospho-cofilin was associated with growth hormone deficiency and compressive pituitary mass effects. CONCLUSION: Dural invasion is associated with larger tumors, suprasellar and sphenoid sinus invasion, and pituitary failure but is not predictive of a more aggressive postoperative course. Routine dural biopsy is therefore of limited benefit in predicting postoperative recurrences. Cofilin expression may be an adjunctive biomarker of invasion in recurrent tumors, but MMP9 expression does not predict tumor behavior.
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Adenoma , Neoplasias Hipofisárias , Fatores de Despolimerização de Actina , Adenoma/patologia , Biomarcadores , Humanos , Masculino , Metaloproteinase 9 da Matriz , Neoplasias Hipofisárias/patologia , Estudos RetrospectivosRESUMO
Intrathecal methotrexate (IT MTX) resulting in severe adverse events including life-threatening cerebral edema is not well described. We report a rare case of death in a 37-year-old BRCA1+ woman with metastatic triple-negative breast cancer status post mastectomy following administration of IT MTX for leptomeningeal carcinomatosis. Within the 24 hours after intraoperative IT MTX delivery, she developed neurologically devastating diffuse cerebral edema leading to uncal and cerebellar tonsillar herniation. This case report highlights a rare but devastating side effect of IT MTX.
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This study evaluates the potential of time-resolved laser induced fluorescence spectroscopy (TR-LIFS) as intra-operative tool for the delineation of brain tumor from normal brain. Forty two patients undergoing glioma (WHO grade I-IV) surgery were enrolled in this study. A TR-LIFS prototype apparatus (gated detection, fast digitizer) was used to induce in-vivo fluorescence using a pulsed N2 laser (337 nm excitation, 0.7 ns pulse width) and to record the time-resolved spectrum (360-550 nm range, 10 nm interval). The sites of TR-LIFS measurement were validated by conventional histopathology (H&E staining). Parameters derived from the TR-LIFS data including intensity values and time-resolved intensity decay features (average fluorescence lifetime and Laguerre coefficients values) were used for tissue characterization and classification. 71 areas of tumor and normal brain were analyzed. Several parameters allowed for the differentiation of distinct tissue types. For example, normal cortex (N=35) and normal white matter (N=12) exhibit a longer-lasting fluorescence emission at 390 nm (τ390=2.12±0.10 ns) when compared with 460 nm (τ460=1.16±0.08 ns). High grade glioma (grades III and IV) samples (N=17) demonstrate emission peaks at 460 nm, with large variation at 390 nm while low grade glioma (I and II) samples (N=7) demonstrated a peak fluorescence emission at 460 nm. A linear discriminant algorithm allowed for the classification of low-grade gliomas with 100% sensitivity and 98% specificity. High-grade glioma demonstrated a high degree of heterogeneity thus reducing the discrimination accuracy of these tumors to 47% sensitivity and 94% specificity. Current findings demonstrate that TR-LIFS holds the potential to diagnose brain tumors intra-operatively and to provide a valuable tool for aiding the neurosurgeon-neuropathologist team in to rapidly distinguish between tumor and normal brain during surgery.
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Neoplasias Encefálicas/patologia , Glioma/patologia , Interpretação de Imagem Assistida por Computador/métodos , Espectrometria de Fluorescência/métodos , Neoplasias Encefálicas/cirurgia , Glioma/cirurgia , Humanos , Sensibilidade e Especificidade , Espectrometria de Fluorescência/instrumentaçãoRESUMO
AIMS: Pseudosarcomatous reactive myofibroblastic proliferations have been described following surgery or trauma at a variety of anatomical sites. These types of reactions have not been previously described at injection sites. Here we evaluated prevalence, morphologic patterns and clinical resolution of such lesions. METHODS AND RESULTS: We analyzed 266 surgical resection specimens obtained during the definitive treatment of piriformis syndrome. Three cases showed exuberant reactive fibroblastic/myofibroblastic intramuscular proliferations, mimicking a sarcoma. In all three cases the surgeries were found to be preceded by local injections of cortisone and bupivacaine. Clinical follow-up revealed no uncontrolled growth. CONCLUSIONS: As the clinical history of injections is often not provided, it is important to be aware of this pitfall when reviewing skeletal muscle resections for entrapment syndromes.
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Músculo Esquelético/patologia , Miosite/patologia , Síndrome do Músculo Piriforme/patologia , Sarcoma/diagnóstico , Adulto , Diagnóstico Diferencial , Feminino , Humanos , Injeções Intramusculares/efeitos adversos , Masculino , Pessoa de Meia-Idade , Músculo Esquelético/lesões , Miosite/etiologia , Síndrome do Músculo Piriforme/etiologiaRESUMO
As commonly encountered, pituitary adenomas are invariably benign. We therefore studied protective pituitary proliferative mechanisms. Pituitary tumor transforming gene (Pttg) deletion results in pituitary p21 induction and abrogates tumor development in Rb(+/-)Pttg(-/-) mice. p21 disruption restores attenuated Rb(+/-)Pttg(-/-) pituitary proliferation rates and enables high penetrance of pituitary, but not thyroid, tumor growth in triple mutant animals (88% of Rb(+/-) and 72% of Rb(+/-)Pttg(-/-)p21(-/-) vs. 30% of Rb(+/-)Pttg(-/-) mice developed pituitary tumors, P < 0.001). p21 deletion also accelerated S-phase entry and enhanced transformation rates in triple mutant MEFs. Intranuclear p21 accumulates in Pttg-null aneuploid GH-secreting cells, and GH(3) rat pituitary tumor cells overexpressing PTTG also exhibited increased levels of mRNA for both p21 (18-fold, P < 0.01) and ATM (9-fold, P < 0.01). PTTG is abundantly expressed in human pituitary tumors, and in 23 of 26 GH-producing pituitary adenomas with high PTTG levels, senescence was evidenced by increased p21 and SA-beta-galactosidase. Thus, either deletion or overexpression of Pttg promotes pituitary cell aneuploidy and p53/p21-dependent senescence, particularly in GH-secreting cells. Aneuploid pituitary cell p21 may constrain pituitary tumor growth, thus accounting for the very low incidence of pituitary carcinomas.