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PURPOSE: This phase 1/2 study aimed to evaluate the safety and preliminary efficacy of combining disulfiram and copper (DSF/Cu) with radiation therapy (RT) and temozolomide (TMZ) in patients with newly diagnosed glioblastoma (GBM). METHODS AND MATERIALS: Patients received standard RT and TMZ with DSF (250-375 mg/d) and Cu, followed by adjuvant TMZ plus DSF (500 mg/d) and Cu. Pharmacokinetic analyses determined drug concentrations in plasma and tumors using high-performance liquid chromatography-mass spectrometry. RESULTS: Thirty-three patients, with a median follow-up of 26.0 months, were treated, including 12 IDH-mutant, 9 NF1-mutant, 3 BRAF-mutant, and 9 other IDH-wild-type cases. In the phase 1 arm, 18 patients were treated; dose-limiting toxicity probabilities were 10% (95% CI, 3%-29%) at 250 mg/d and 21% (95% CI, 7%-42%) at 375 mg/d. The phase 2 arm treated 15 additional patients at 250 mg/d. No significant difference in overall survival or progression-free survival was noted between IDH- and NF1-mutant cohorts compared with institutional counterparts treated without DSF/Cu. However, extended remission occurred in 3 BRAF-mutant patients. Diethyl-dithiocarbamate-copper, the proposed active metabolite of DSF/Cu, was detected in plasma but not in tumors. CONCLUSIONS: The maximum tolerated dose of DSF with RT and TMZ is 375 mg/d. DSF/Cu showed limited clinical efficacy for most patients. However, promising efficacy was observed in BRAF-mutant GBM, warranting further investigation.
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Sonobiopsy is an emerging technology that combines focused ultrasound (FUS) with microbubbles to enrich circulating brain disease-specific biomarkers for noninvasive molecular diagnosis of brain diseases. Here, we report the first-in-human prospective trial of sonobiopsy in high-grade glioma patients to evaluate its feasibility and safety in enriching plasma circulating tumor biomarkers. A nimble FUS device integrated with a clinical neuronavigation system was used to perform sonobiopsy following an established clinical workflow for neuronavigation. Analysis of blood samples collected before and after FUS sonication showed that sonobiopsy enriched plasma circulating tumor DNA (ctDNA), including a maximum increase of 1.6-fold for the mononucleosome cell-free DNA (cfDNA) fragments (120-280 bp), 1.9-fold for the patient-specific tumor variant ctDNA level, and 5.6-fold for the TERT mutation ctDNA level. Histological analysis of surgically resected tumors confirmed the safety of the procedure. Transcriptome analysis of sonicated and nonsonicated tumor tissues found that FUS sonication modulated cell physical structure-related genes. Only 2 out of 17,982 total detected genes related to the immune pathways were upregulated. These feasibility and safety data support the continued investigation of sonobiopsy for noninvasive molecular diagnosis of brain diseases.
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Introduction: Vaccination is the most effective mechanism to prevent severe COVID-19. However, breakthrough infections and subsequent transmission of SARS-CoV-2 remain a significant problem. Intranasal vaccination has the potential to be more effective in preventing disease and limiting transmission between individuals as it induces potent responses at mucosal sites. Methods: Utilizing a replication-deficient adenovirus serotype 5-vectored vaccine expressing the SARS-CoV-2 RBD (AdCOVID) in homozygous and heterozygous transgenic K18-hACE2, we investigated the impact of the route of administration on vaccine immunogenicity, SARS-CoV-2 transmission, and survival. Results: Mice vaccinated with AdCOVID via the intramuscular or intranasal route and subsequently challenged with SARS-CoV-2 showed that animals vaccinated intranasally had improved cellular and mucosal antibody responses. Additionally, intranasally vaccinated animals had significantly better viremic control, and protection from lethal infection compared to intramuscularly vaccinated animals. Notably, in a novel transmission model, intranasal vaccination reduced viral transmission to naïve co-housed mice compared to intramuscular vaccination. Discussion: Our data provide convincing evidence for the use of intranasal vaccination in protecting against SARS-CoV-2 infection and transmission.
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Infecciones por Adenoviridae , Vacunas contra el Adenovirus , COVID-19 , Vacunas , Animales , Ratones , Adenoviridae/genética , SARS-CoV-2 , COVID-19/prevención & control , Vacunación , Animales Modificados GenéticamenteRESUMEN
Sonobiopsy is an emerging technology that combines focused ultrasound (FUS) with microbubbles to enrich circulating brain disease-specific biomarkers for noninvasive molecular diagnosis of brain diseases. Here, we report the first-in-human prospective trial of sonobiopsy in glioblastoma patients to evaluate its feasibility and safety in enriching circulating tumor biomarkers. A nimble FUS device integrated with a clinical neuronavigation system was used to perform sonobiopsy following an established clinical workflow for neuronavigation. Analysis of blood samples collected before and after FUS sonication showed enhanced plasma circulating tumor biomarker levels. Histological analysis of surgically resected tumors confirmed the safety of the procedure. Transcriptome analysis of sonicated and unsonicated tumor tissues found that FUS sonication modulated cell physical structure-related genes but evoked minimal inflammatory response. These feasibility and safety data support the continued investigation of sonobiopsy for noninvasive molecular diagnosis of brain diseases.
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An international consensus report in 2019 recommended a classification system for limbic-predominant age-related TDP-43 encephalopathy neuropathologic changes (LATE-NC). The suggested neuropathologic staging system and nomenclature have proven useful for autopsy practice and dementia research. However, some issues remain unresolved, such as cases with unusual features that do not fit with current diagnostic categories. The goal of this report is to update the neuropathologic criteria for the diagnosis and staging of LATE-NC, based primarily on published data. We provide practical suggestions about how to integrate available genetic information and comorbid pathologies [e.g., Alzheimer's disease neuropathologic changes (ADNC) and Lewy body disease]. We also describe recent research findings that have enabled more precise guidance on how to differentiate LATE-NC from other subtypes of TDP-43 pathology [e.g., frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS)], and how to render diagnoses in unusual situations in which TDP-43 pathology does not follow the staging scheme proposed in 2019. Specific recommendations are also made on when not to apply this diagnostic term based on current knowledge. Neuroanatomical regions of interest in LATE-NC are described in detail and the implications for TDP-43 immunohistochemical results are specified more precisely. We also highlight questions that remain unresolved and areas needing additional study. In summary, the current work lays out a number of recommendations to improve the precision of LATE-NC staging based on published reports and diagnostic experience.
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Enfermedad de Alzheimer , Esclerosis Amiotrófica Lateral , Demencia Frontotemporal , Humanos , Enfermedad de Alzheimer/patología , Demencia Frontotemporal/patología , Esclerosis Amiotrófica Lateral/patología , Proteínas de Unión al ADN/genéticaRESUMEN
Glioblastoma (GBM) is the most common primary malignant brain tumor in adults. Prior studies examining the mutational landscape of GBM revealed recurrent alterations in genes that regulate the same growth control pathways. To this regard, ~ 40% of GBM harbor EGFR alterations, whereas BRAF variants are rare. Existing data suggests that gain-of-function mutations in these genes are mutually exclusive. This study was designed to explore the clinical, pathological, and molecular differences between EGFR- and BRAF-mutated GBM. We reviewed retrospective clinical data from 89 GBM patients referred for molecular testing between November 2012 and December 2015. Differences in tumor mutational profile, location, histology, and survival outcomes were compared in patients with EGFR- versus BRAF-mutated tumors, and microarray data from The Cancer Genome Atlas was used to assess differential gene expression between the groups. Individuals with BRAF-mutant tumors were typically younger and survived longer relative to those with EGFR-mutant tumors, even in the absence of targeted treatments. BRAF-mutant tumors lacked distinct histomorphology but exhibited unique localization in the brain, typically arising adjacent to the lateral ventricles. Compared to EGFR- and IDH1-mutant tumors, BRAF-mutant tumors showed increased expression of genes related to a trophoblast-like phenotype, specifically HLA-G and pregnancy specific glycoproteins, that have been implicated in invasion and immune evasion. Taken together, these observations suggest a distinct clinical presentation, brain location, and gene expression profile for BRAF-mutant tumors. Pending further study, this may prove useful in the stratification and management of GBM.
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Neoplasias Encefálicas/genética , Receptores ErbB/genética , Glioblastoma/genética , Proteínas Proto-Oncogénicas B-raf/genética , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Neoplasias Encefálicas/patología , Niño , Femenino , Perfilación de la Expresión Génica , Genes MHC Clase I/genética , Glioblastoma/patología , Humanos , Masculino , Persona de Mediana Edad , Mutación , Estudios RetrospectivosRESUMEN
INTRODUCTION: Malignant Peripheral Nerve Sheath Tumors (MPNSTs) are a rare type of soft tissue sarcoma. While these tumors often metastasize, intracranial metastases of MPNSTs have only been rarely noted. METHODS: Using Pubmed, Google Scholar, and Science Direct we conducted a systematic review of the literature to identify all reported cases of MPNSTs with metastases to the brain since the inception of these databases through January 2020. Data were extracted and data analysis was completed using python statistical packages. RESULTS: Only 26 cases (including present study) of MPNSTs resulting in intracranial metastases have been reported in the literature. Eight of these 26 cases occurred in patients who were previously diagnosed with Neurofibromatosis Type 1 (NF1). Additionally, one patient had been previously diagnosed with Neurofibromatosis Type 2 (NF2). The average reported time from diagnosis of a MPNST to the time of diagnosis with intracranial metastasis was 36 months, with a median time of 14 months. The average reported survival time for patients after being diagnosed with intracranial metastasis was 5.9 months. The cases that utilized a combination of therapeutic intervention including surgical resection, radiotherapy and chemotherapy saw the greatest improvement of survival times. CONCLUSION: MPNSTs with brain metastases are extremely rare and have a poor prognosis with a 6 months median survival after metastasis. While combination therapy is indicated, further studies on treatment are needed to determine survival benefits. Early and effective initial diagnosis of MPNST before brain metastases occurs is likely to give the best chance of increased overall survival.
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Neoplasias Encefálicas/diagnóstico , Neoplasias Encefálicas/secundario , Neurofibromatosis 1/complicaciones , Neurofibromatosis 1/patología , Neurofibrosarcoma/diagnóstico , Neurofibrosarcoma/secundario , Adulto , Humanos , Imagen por Resonancia Magnética , Masculino , Neurofibromatosis 1/diagnóstico por imagen , Tomografía de Emisión de PositronesRESUMEN
Supernumerary ectopic ovaries are very rare, with fewer than 40 cases of isolated supernumerary ovaries reported in the literature since their discovery in 1864. Tumors arising in ectopic ovaries are also extremely rare, with only a handful of reports in the literature. Given the rarity of this combination of findings, we report a case of a 68-yr-old woman incidentally found to have a 4.7 cm solid retroperitoneal mass adjacent to the liver, diagnosed as a benign Brenner tumor arising in a supernumerary ectopic ovary. To our knowledge, there has been only one previously reported case of Brenner tumor arising in this unusual setting.
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Tumor de Brenner/diagnóstico , Neoplasias Ováricas/diagnóstico , Anciano , Tumor de Brenner/patología , Femenino , Humanos , Neoplasias Ováricas/patología , Ovario/patologíaRESUMEN
Sellar region lesions include a broad range of benign and malignant neoplastic as well as non-neoplastic entities, many of which are newly described or have recently revised nomenclature. In contrast to other intracranial sites, imaging features are relatively less specific, and the need for histopathological diagnosis is of paramount importance. This review will describe pituitary adenomas, inflammatory lesions, and tumors unique to the region (craniopharyngioma) as well as tumors which may occur in but are not exclusively localized to the sellar location (schwannoma, metastasis, etc.).
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Enfermedades de la Hipófisis/diagnóstico , Neoplasias Hipofisarias/diagnóstico , Adenoma/diagnóstico , Adenoma/patología , Quistes del Sistema Nervioso Central/diagnóstico , Quistes del Sistema Nervioso Central/patología , Craneofaringioma/diagnóstico , Craneofaringioma/patología , Diagnóstico Diferencial , Humanos , Hipofisitis/diagnóstico , Hipofisitis/patología , Enfermedad Relacionada con Inmunoglobulina G4/diagnóstico , Enfermedad Relacionada con Inmunoglobulina G4/patología , Enfermedades de la Hipófisis/patología , Hipófisis/patología , Neoplasias Hipofisarias/patologíaRESUMEN
Primary hepatic lymphomas (PHLs) are exceedingly rare. Many reported cases are associated with various viral serologies, and some viruses may be implicated in lymphomagenesis through emerging, though as-of-yet uncertain, mechanisms. A review of the literature reveals previously reported cases of PHL, some of which support the potential roles of the hepatitis B and C viruses (HBV and HCV) in the development of PHL. We describe an exceptional case of primary hepatic high-grade B-cell lymphoma, discovered at autopsy, in a patient whose clinical history is significant for coinfection with both HBV and HCV. Additionally, attempts at cytogenetic testing of formalin-fixed, paraffin-embedded (FFPE) autopsy tissues, which we performed approximately ten years after the original autopsy, led us to question the utility of older tissue blocks in molecular and some immunohistochemical assays.
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Meningiomas are among the most common tumors of the adult central nervous system (CNS). They are classified by the World Health Organization into three pathologic grades with increasing severity: grade I are benign with favorable treatment outcomes and low recurrence rates while grade III display malignant behavior and poor progression-free survival. Previous studies have shown that inactivation of NF-2 is the most common genetic event in high-grade meningioma; however, there is dearth of molecular data to distinguish grade II (AM-II) from the even more aggressive grade III (AM-III). As part of a routine diagnostic workup, 19 AM-II and 5 AM-III were submitted for targeted sequencing on a panel of twenty-four genes relevant to CNS tumors. The data generated during the course of clinical care was collected and re-analyzed with the aim of identifying molecular features to distinguish AM-II and AM-III. Our cases contained several well-characterized, potentially actionable mutations, but we did not find any novel, recurrent sequence variants. Copy number variations were common in both AM-II and AM-III; chr22q loss was the most prevalent followed in decreasing frequency by losses of chr1p, chr14q, and chr10. In particular, chr10 loss was noted in 4 of 5 AM-III cases but none of the AM-II cases. This suggests that chr10 loss may serve as a diagnostic and perhaps a prognostic marker to differentiate AM-II from AM-III. If confirmed in larger studies, our finding could further aid the classification of meningioma.
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Meningioma/genética , Adolescente , Adulto , Anciano , Niño , Variaciones en el Número de Copia de ADN , Femenino , Humanos , Masculino , Meningioma/patología , Persona de Mediana Edad , Mutación PuntualRESUMEN
Zika virus (ZIKV) has gained worldwide attention since it emerged, and a global effort is underway to understand the correlates of protection and develop diagnostics to identify rates of infection. As new therapeutics and vaccine approaches are evaluated in clinical trials, additional effort is focused on identifying the adaptive immune correlates of protection against ZIKV disease. To aid in this endeavor we have begun to dissect the role of CD4+T cells in the protection against neuroinvasive ZIKV disease. We have identified an important role for CD4+T cells in protection, demonstrating that in the absence of CD4+T cells mice have more severe neurological sequela and significant increases in viral titers in the central nervous system (CNS). The transfer of CD4+T cells from ZIKV immune mice protect type I interferon receptor deficient animals from a lethal challenge; showing that the CD4+T cell response is necessary and sufficient for control of ZIKV disease. Using a peptide library spanning the complete ZIKV polyprotein, we identified both ZIKV-encoded CD4+T cell epitopes that initiate immune responses, and ZIKV specific CD4+T cell receptors that recognize these epitopes. Within the ZIKV antigen-specific TCRß repertoire, we uncovered a high degree of diversity both in response to a single epitope and among different mice responding to a CD4+T cell epitope. Overall this study identifies a novel role for polyfunctional and polyclonal CD4+T cells in providing protection against ZIKV infection and highlights the need for vaccines to develop robust CD4+T cell responses to prevent ZIKV neuroinvasion and limit replication within the CNS.
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Linfocitos T CD4-Positivos/inmunología , Infección por el Virus Zika/inmunología , Infección por el Virus Zika/prevención & control , Traslado Adoptivo , Secuencia de Aminoácidos , Animales , Antígenos Virales/genética , Antígenos Virales/inmunología , Sistema Nervioso Central/inmunología , Sistema Nervioso Central/virología , Modelos Animales de Enfermedad , Epítopos de Linfocito T/genética , Epítopos de Linfocito T/inmunología , Genes Codificadores de la Cadena beta de los Receptores de Linfocito T , Humanos , Inmunidad Celular , Hígado/inmunología , Hígado/virología , Depleción Linfocítica , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Receptor de Interferón alfa y beta/deficiencia , Receptor de Interferón alfa y beta/genética , Receptor de Interferón alfa y beta/inmunología , Vacunas Virales/inmunología , Replicación Viral/inmunología , Virus Zika/genética , Virus Zika/inmunología , Virus Zika/patogenicidad , Infección por el Virus Zika/genéticaRESUMEN
Cutaneous spindle cell malignancy is associated with a broad differential diagnosis, particularly in the absence of a known primary melanocytic lesion. We present an unusually challenging patient who presented with clinical symptoms involving cranial nerves VII and VIII and a parotid-region mass, which was S100-positive while lacking in melanocytic pigment and markers. Over a year after resection of the parotid mass, both a cutaneous primary lentigo maligna melanoma and a metastatic CP angle melanoma were diagnosed in the same patient, prompting reconsideration of the diagnosis in the original parotid-region mass. Next-generation sequencing of a panel of cancer-associated genes demonstrated 19 identical, clinically significant mutations as well as a high tumor mutation burden in both the parotid-region and CP angle tumors, indicating a metastatic relationship between the two and a melanocytic identity of the parotid-region tumor.
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Encéfalo/patología , Linfocitos T CD8-positivos/patología , Linfoma Cutáneo de Células T/patología , Esclerosis Múltiple/patología , Convulsiones/patología , Anciano , Encéfalo/diagnóstico por imagen , Femenino , Humanos , Linfoma Cutáneo de Células T/complicaciones , Esclerosis Múltiple/complicaciones , Convulsiones/complicacionesRESUMEN
OBJECTIVE: To determine whether specific patterns of [18F]-AV-1451 tau-PET retention are observed in patients with autopsy-proven sporadic Creutzfeldt-Jakob disease (CJD). METHODS: In vivo [18F]-AV-1451 PET neuroimaging was performed in 5 patients with sporadic CJD (median age, 66 years [63-74]), and results were compared to cognitively normal (CN) persons (n = 44; median age, 68 years [63-74]) and to participants with very mild Alzheimer disease (AD) dementia (n = 8; median age, 77 years [63-90]). Autopsy was completed in all patients with CJD, confirming the clinical diagnosis and permitting characterization of AD neuropathologic change (ADNC). RESULTS: All patients with CJD presented with rapidly progressive dementia, typical magnetic resonance brain imaging changes, and elevated CSF total tau (median = 6,519; range = 1,528-13,240 pg/mL). Death occurred within 9 months of symptom onset, with a median 1 month (0.2-3.3) interval from [18F]-AV-1451 PET to autopsy. No unique pattern of [18F]-AV-1451 retention was observed on visual inspection. Summary standardized uptake value ratios in patients with CJD (1.17, 1.08-1.36) were indistinguishable from CN persons (1.14, 0.84-1.54; p = 0.6), and well below those of participants with AD (2.23, 1.60-3.04; p ≤ 0.01). [18F]-AV-1451 retention in patients with CJD and CN persons was similar in brain areas frequently affected in AD and CJD. Neuropathologic analysis confirmed the clinical diagnosis in all patients with CJD. Four patients with CJD also had low-level ADNC (A1B1C0); one patient had intermediate-level ADNC (A2B2C1/2). CONCLUSION: Increased [18F]-AV-1451 retention was not observed in patients with rapidly progressive dementia due to sporadic CJD. The [18F]-AV-1451 PET tracer maintains good specificity for paired helical tau filaments associated with AD dementia.
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Encéfalo/diagnóstico por imagen , Carbolinas , Síndrome de Creutzfeldt-Jakob/diagnóstico por imagen , Tomografía de Emisión de Positrones , Radiofármacos , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/líquido cefalorraquídeo , Enfermedad de Alzheimer/diagnóstico por imagen , Enfermedad de Alzheimer/patología , Encéfalo/patología , Síndrome de Creutzfeldt-Jakob/líquido cefalorraquídeo , Síndrome de Creutzfeldt-Jakob/patología , Diagnóstico Diferencial , Femenino , Humanos , Estudios Longitudinales , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Estudios ProspectivosAsunto(s)
Infarto Cerebral/diagnóstico , Linfoma de Células T/diagnóstico , Encéfalo/diagnóstico por imagen , Encéfalo/patología , Infarto Cerebral/complicaciones , Infarto Cerebral/patología , Femenino , Humanos , Linfoma de Células T/complicaciones , Linfoma de Células T/patología , Persona de Mediana Edad , Células T Asesinas Naturales/patologíaRESUMEN
Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide, and tobacco is one of the most common factors for HNSCC of the oral cavity. We have previously observed that bitter melon (Momordica charantia) extract (BME) exerts antiproliferative activity against several cancers including HNSCC. In this study, we investigated the preventive role of BME in 4-nitroquinoline 1-oxide (4-NQO) carcinogen-induced HNSCC. We observed that BME feeding significantly reduced the incidence of 4-NQO-induced oral cancer in a mouse model. Histologic analysis suggested control 4-NQO-treated mouse tongues showed neoplastic changes ranging from moderate dysplasia to invasive squamous cell carcinoma, whereas no significant dysplasia was observed in the BME-fed mouse tongues. We also examined the global transcriptome changes in normal versus carcinogen-induced tongue cancer tissues, and following BME feeding. Gene ontology and pathway analyses revealed a signature of biological processes including "immune system process" that is significantly dysregulated in 4-NQO-induced oral cancer. We identified elevated expression of proinflammatory genes, s100a9, IL23a, IL1ß and immune checkpoint gene PDCD1/PD1, during oral cancer development. Interestingly, BME treatment significantly reduced their expression. Enhancement of MMP9 ("ossification" pathway) was noted during carcinogenesis, which was reduced in BME-fed mouse tongue tissues. Our study demonstrates the preventive effect of BME in 4-NQO-induced carcinogenesis. Identification of pathways involved in carcinogen-induced oral cancer provides useful information for prevention strategies. Together, our data strongly suggest the potential clinical benefits of BME as a chemopreventive agent in the control or delay of carcinogen-induced HNSCC development and progression. Cancer Prev Res; 11(4); 191-202. ©2017 AACRSee related editorial by Rao, p. 185.
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4-Nitroquinolina-1-Óxido/toxicidad , Carcinoma de Células Escamosas/prevención & control , Modelos Animales de Enfermedad , Fenómenos del Sistema Inmunológico/efectos de los fármacos , Momordica charantia/química , Neoplasias de la Boca/prevención & control , Extractos Vegetales/farmacología , Animales , Apoptosis , Carcinógenos/toxicidad , Carcinoma de Células Escamosas/inducido químicamente , Carcinoma de Células Escamosas/patología , Proliferación Celular , Ratones , Ratones Endogámicos C57BL , Ratones SCID , Neoplasias de la Boca/inducido químicamente , Neoplasias de la Boca/inmunología , Neoplasias de la Boca/patología , Células Tumorales CultivadasRESUMEN
Diffuse leptomeningeal glioneuronal tumor, a recent addition to the World Health Organization classification system, typically presents in the pediatric population with signs and symptoms related to elevated intracranial pressure and imaging characteristics that may mimic infectious etiologies. The tumor is usually low grade and tends to harbor BRAF rearrangement/duplication in up to 75% of cases, BRAF V600E mutation in a smaller subset of cases, and loss of chromosomal arm 1p in approximately 50%-60% of cases, with ~20% of those showing loss of both 1p and 19q (codeletion). We report here 2 contrasting cases of diffuse leptomeningeal glioneuronal tumors, one with typical low-grade features and an indolent, although not benign, course, in which the disease is currently successfully managed by chemotherapy, and a second case with unusually high-grade features on initial presentation, including frank anaplasia and elevated mitotic index, in which the disease showed an initial response to chemoradiation but ultimately was fatal.
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Neoplasias Meníngeas/patología , Neuroglía/patología , Neuronas/patología , Biomarcadores de Tumor/análisis , Biomarcadores de Tumor/genética , Niño , Deleción Cromosómica , Cromosomas Humanos Par 1 , Cromosomas Humanos Par 19 , Imagen de Difusión por Resonancia Magnética , Resultado Fatal , Duplicación de Gen , Reordenamiento Génico , Predisposición Genética a la Enfermedad , Humanos , Inmunohistoquímica , Masculino , Neoplasias Meníngeas/diagnóstico por imagen , Neoplasias Meníngeas/genética , Neoplasias Meníngeas/terapia , Índice Mitótico , Técnicas de Diagnóstico Molecular , Mutación , Clasificación del Tumor , Neuroglía/química , Neuronas/química , Fenotipo , Proteínas Proto-Oncogénicas B-raf/genética , Resultado del TratamientoRESUMEN
OBJECTIVE Many patients with medically intractable epilepsy have mesial temporal sclerosis (MTS), which significantly affects their quality of life. The surgical excision of MTS lesions can result in marked improvement or even complete resolution of the epileptic episodes. Reliable radiological diagnosis of MTS is a clinical challenge. The purpose of this study was to evaluate the utility of volumetric mapping of the hippocampi for the identification of MTS in a case-controlled series of pediatric patients who underwent resection for medically refractory epilepsy, using pathology as a gold standard. METHODS A cohort of 57 pediatric patients who underwent resection for medically intractable epilepsy between 2005 and 2015 was evaluated. On pathological investigation, this group included 24 patients with MTS and 33 patients with non-MTS findings. Retrospective quantitative volumetric measurements of the hippocampi were acquired for 37 of these 57 patients. Two neuroradiologists with more than 10 years of experience who were blinded to the patients' MTS status performed the retrospective review of MR images. To produce the volumetric data, MR scans were parcellated and segmented using the FreeSurfer software suite. Hippocampal regions of interest were compared against an age-weighted local regression curve generated with data from the pediatric normal cohort. Standard deviations and percentiles of specific subjects were calculated. The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were determined for the original clinical read and the expert readers. Receiver operating characteristic curves were generated for the methods of classification to compare results from the readers with the authors' results, and an optimal threshold was determined. From that threshold the sensitivity, specificity, PPV, and NPV were calculated for the volumetric analysis. RESULTS With the use of quantitative volumetry, a sensitivity of 72%, a specificity of 95%, a PPV of 93%, an NPV of 78%, and an area under the curve of 0.84 were obtained using a percentage difference of normalized hippocampal volume. The resulting specificity (95%) and PPV (93%) are superior to the original clinical read and to Reader A and Reader B's findings (range for specificity 74%-86% and for PPV 64%-71%). The sensitivity (72%) and NPV (78%) are comparable to Reader A's findings (73% and 81%, respectively) and are better than those of the original clinical read and of Reader B (sensitivity 45% and 63% and NPV 71% and 70%, respectively). CONCLUSIONS Volumetric measurement of the hippocampi outperforms expert readers in specificity and PPV, and it demonstrates comparable to superior sensitivity and NPV. Volumetric measurements can complement anatomical imaging for the identification of MTS, much like a computer-aided detection tool would. The implementation of this approach in the daily clinical workflow could significantly improve diagnostic accuracy.