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Innovations in cancer immunotherapy have resulted in the development of several novel immunotherapeutic strategies that can disrupt immunosuppression. One key advancement lies in immune checkpoint inhibitors (ICIs), which have shown significant clinical efficacy and increased survival rates in patients with various therapy-resistant cancers. This immune intervention consists of monoclonal antibodies directed against inhibitory receptors (e.g., PD-1) on cytotoxic CD8 T cells or against corresponding ligands (e.g., PD-L1/PD-L2) overexpressed on cancer cells and other cells in the tumor microenvironment (TME). However, not all cancer cells respond-there are still poor clinical responses, immune-related adverse effects, adaptive resistance, and vulnerability to ICIs in a subset of patients with cancer. This challenge showcases the heterogeneity of cancer, emphasizing the existence of additional immunoregulatory mechanisms in many patients. Therefore, it is essential to investigate PD-L1's interaction with other oncogenic genes and pathways to further advance targeted therapies and address resistance mechanisms. Accordingly, our aim was to investigate the mechanisms governing PD-L1 expression in tumor cells, given its correlation with immune evasion, to uncover novel mechanisms for decreasing PD-L1 expression and restoring anti-tumor immune responses. Numerous studies have demonstrated that the upregulation of Raf Kinase Inhibitor Protein (RKIP) in many cancers contributes to the suppression of key hyperactive pathways observed in malignant cells, alongside its broadening involvement in immune responses and the modulation of the TME. We, therefore, hypothesized that the role of PD-L1 in cancer immune surveillance may be inversely correlated with the low expression level of the tumor suppressor Raf Kinase Inhibitor Protein (RKIP) expression in cancer cells. This hypothesis was investigated and we found several signaling cross-talk pathways between the regulations of both RKIP and PD-L1 expressions. These pathways and regulatory factors include the MAPK and JAK/STAT pathways, GSK3ß, cytokines IFN-γ and IL-1ß, Sox2, and transcription factors YY1 and NFκB. The pathways that upregulated PD-L1 were inhibitory for RKIP expression and vice versa. Bioinformatic analyses in various human cancers demonstrated the inverse relationship between PD-L1 and RKIP expressions and their prognostic roles. Therefore, we suspect that the direct upregulation of RKIP and/or the use of targeted RKIP inducers in combination with ICIs could result in a more targeted anti-tumor immune response-addressing the therapeutic challenges related to PD-1/PD-L1 monotherapy alone.
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Antígeno B7-H1 , Neoplasias , Proteína de Ligação a Fosfatidiletanolamina , Humanos , Antígeno B7-H1/metabolismo , Neoplasias/imunologia , Neoplasias/terapia , Neoplasias/metabolismo , Neoplasias/tratamento farmacológico , Proteína de Ligação a Fosfatidiletanolamina/metabolismo , Proteína de Ligação a Fosfatidiletanolamina/genética , Microambiente Tumoral/imunologia , Evasão Tumoral/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Evasão da Resposta ImuneRESUMO
Importance: Cystic fibrosis (CF) is a multiorgan genetic disease with progressive upper and lower airway involvement. The effects of CF transmembrane conductance regulator (CFTR) modifier therapies on CF-related upper airway disease, specifically chronic rhinosinusitis (CRS), are not characterized. Objective: To determine the outcome of elexacaftor-tezacaftor-ivacaftor (ETI) on CRS as measured by changes in sinus computed tomography (CT) metrics and on clinical parameters in individuals with CF. Design, Setting, and Participants: This prospective longitudinal cohort study was conducted at the CF center of a tertiary care hospital between October 1, 2019, and July 31, 2021. A total of 64 participants with CF were included in the analysis. Intervention: Sinus CT was obtained within 1 month of initiation of ETI therapy (baseline), and within 1 month of 1 year of ETI therapy. Images were independently analyzed by pulmonology, radiology, and otolaryngology physicians, using the Lund-Mackay and Sheikh-Lind scoring systems. Percent predicted forced expiratory volume in 1 second (ppFEV1), body mass index (BMI), and microbiologic data collected at initiation of ETI therapy and 3-month intervals for 1 year were also measured. Main Outcomes and Measures: The study hypothesis was that ETI therapy will improve CRS as measured by changes in sinus CT at initiation and 1 year after ETI therapy and clinical parameters in individuals with CF. Results: Among the 64 participants (39 [60.9%] female; median age, 18.5 [IQR, 16.0-28.5] years; 64 [100%] White), improvement in CRS was noted by improvements in sinus CT scans using both sinus CT scoring systems after 1 year of ETI therapy. The reduction in the median total score using the Lund-Mackay sinus CT scoring system (from 5.8 [IQR, 5.0-7.0] to 3.3 [IQR, 2.6-4.2]) and the Sheikh-Lind scoring system (from 3.8 [IQR, 3.0-5.0] to 2.2 [IQR, 2.0-2.5]) was noted. Increases in ppFEV1 and BMI were also observed by 3 months of ETI therapy with persistent improvement through 1 year of treatment. Similarly, after 1 year of ETI therapy, participants with CF had reductions in positivity for Pseudomonas aeruginosa and Staphylococcus aureus in oropharyngeal cultures. Conclusion and Relevance: This cohort study found that use of ETI therapy was associated with improved CRS outcomes in participants with CF as quantified by improved sinus CT scans measured by 2 radiographic scoring systems and was also associated with improved clinical outcomes. Despite improvement in CT scan scores, most people with CF continue to have scores that indicate severe sinus disease.
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Fibrose Cística , Feminino , Humanos , Adolescente , Masculino , Fibrose Cística/tratamento farmacológico , Estudos de Coortes , Estudos Longitudinais , Estudos Prospectivos , Regulador de Condutância Transmembrana em Fibrose Cística/genética , MutaçãoRESUMO
The pediatric spine undergoes complex stages of development and growth, resulting in highly age-dependent physiology and variable susceptibility to certain pathologies. Optimal radiologic evaluation requires image acquisition tailored to the clinical history and an interpretive approach that accounts for demographic variations. In this article, the author discusses the diagnostic approach to pediatric spine masses, beginning with a discussion of normal anatomy and variants, clinical evaluation, and imaging techniques and protocols. The author then covers the major etiologies, imaging appearances, and mimics of pediatric spine masses in the following categories: congenital malformations, genetic syndromes, intramedullary, intradural, epidural, bone, and paraspinal lesions.
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Neoplasias da Coluna Vertebral , Coluna Vertebral , Criança , Humanos , Síndrome , Coluna Vertebral/diagnóstico por imagem , Coluna Vertebral/patologia , Neoplasias da Coluna Vertebral/diagnóstico por imagem , Neoplasias da Coluna Vertebral/patologia , Imageamento por Ressonância Magnética/métodosRESUMO
This article focuses on clinical applications of arterial spin labeling (ASL) and is part of a wider effort from the International Society for Magnetic Resonance in Medicine (ISMRM) Perfusion Study Group to update and expand on the recommendations provided in the 2015 ASL consensus paper. Although the 2015 consensus paper provided general guidelines for clinical applications of ASL MRI, there was a lack of guidance on disease-specific parameters. Since that time, the clinical availability and clinical demand for ASL MRI has increased. This position paper provides guidance on using ASL in specific clinical scenarios, including acute ischemic stroke and steno-occlusive disease, arteriovenous malformations and fistulas, brain tumors, neurodegenerative disease, seizures/epilepsy, and pediatric neuroradiology applications, focusing on disease-specific considerations for sequence optimization and interpretation. We present several neuroradiological applications in which ASL provides unique information essential for making the diagnosis. This guidance is intended for anyone interested in using ASL in a routine clinical setting (i.e., on a single-subject basis rather than in cohort studies) building on the previous ASL consensus review.
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AVC Isquêmico , Doenças Neurodegenerativas , Humanos , Criança , Angiografia por Ressonância Magnética/métodos , Imageamento por Ressonância Magnética/métodos , Neuroimagem/métodos , Marcadores de Spin , Perfusão , Circulação CerebrovascularRESUMO
OBJECTIVE: Large vestibular aqueduct (LVA) is the most common inner ear dysplasia identified in patients with hearing loss. Our objective was to systematically quantify LVA morphologies and correlate imaging findings with established audiometric outcomes. STUDY DESIGN: Retrospective review. SETTING: Tertiary referral center. PATIENTS: Patients with large vestibular aqueduct identified radiographically, with or without hearing loss. INTERVENTIONS: Diagnostic only. MAIN OUTCOME MEASURES: Vestibular aqueduct (VA) width at midpoint, width at external aperture, and length were measured on cross-sectional imaging. Morphology was classified as type I (borderline), type II (tubular), or type III (funneled). Audiometric endpoints included air/bone conduction, pure tone averages, and air-bone gaps at 250 and 500 Hz. Statistical associations were evaluated using linear regression models, adjusted for age at first audiogram and sex. RESULTS: One hundred seventeen patients (197 ears) were included, with mean age at first audiogram of 22.2 years (standard deviation, 21.7 yr). Imaging features associated with poor audiometric outcomes were increasing VA width at midpoint and external aperture, decreasing VA length, dilated extraosseous endolymphatic sac, cochleovestibular malformations, and increasing VA type (III > II > I). CONCLUSIONS: Quantitative LVA measurements and a standardized morphologic classification system aid in prediction of early audiometric endpoints.
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Surdez , Perda Auditiva Neurossensorial , Perda Auditiva , Aqueduto Vestibular , Humanos , Perda Auditiva Neurossensorial/diagnóstico por imagem , Aqueduto Vestibular/diagnóstico por imagem , Aqueduto Vestibular/anormalidades , Audiometria , Audição , Estudos Retrospectivos , Audiometria de Tons PurosRESUMO
Zero echo-time (ZTE) MRI is a novel imaging technique that utilizes ultrafast readouts to capture signal from short-T2 tissues. Additional sequence advantages include rapid imaging times, silent scanning, and artifact resistance. A robust application of this technology is imaging of cortical bone without the use of ionizing radiation, thus representing a viable alternative to CT for both rapid screening and "one-stop-shop" MRI. Although ZTE is increasingly used in musculoskeletal and body imaging, neuroimaging applications have historically been limited by complex anatomy and pathology. In this article, we review the imaging physics of ZTE including pulse sequence options, practical limitations, and image reconstruction. We then discuss optimization of settings for ZTE bone neuroimaging including acquisition, processing, segmentation, synthetic CT generation, and artifacts. Finally, we examine clinical utility of ZTE in the head and neck with imaging examples including malformations, trauma, tumors, and interventional procedures.
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Processamento de Imagem Assistida por Computador , Imageamento por Ressonância Magnética , Artefatos , Cabeça/diagnóstico por imagem , Humanos , Processamento de Imagem Assistida por Computador/métodos , Imageamento por Ressonância Magnética/métodos , Pescoço/diagnóstico por imagemRESUMO
The use of standardized imaging protocols is paramount in order to facilitate comparable, reproducible images and, consequently, to optimize patient care. Standardized MR protocols are lacking when studying head and neck pathologies in the pediatric population. We propose an international, multicenter consensus paper focused on providing the best combination of acquisition time/technical requirements and image quality. Distinct protocols for different regions of the head and neck and, in some cases, for specific pathologies or clinical indications are recommended. This white paper is endorsed by several international scientific societies and it is the result of discussion, in consensus, among experts in pediatric head and neck imaging.
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Neoplasias de Cabeça e Pescoço , Cabeça , Criança , Consenso , Cabeça/diagnóstico por imagem , Humanos , Imageamento por Ressonância Magnética/métodos , Pescoço/diagnóstico por imagemRESUMO
Arterial spin labeling (ASL) is a powerful noncontrast MRI technique for evaluation of cerebral blood flow (CBF). A key parameter in single-delay ASL is the choice of postlabel delay (PLD), which refers to the timing between the labeling of arterial free water and measurement of flow into the brain. Multidelay ASL (MDASL) utilizes several PLDs to improve the accuracy of CBF calculations using arterial transit time (ATT) correction. This approach is particularly helpful in situations where ATT is unknown, including young subjects and slow-flow conditions. In this article, we discuss the technical considerations for MDASL, including labeling techniques, quantitative metrics, and technical artefacts. We then provide a practical summary of key clinical applications with real-life imaging examples in the pediatric brain, including stroke, vasculopathy, hypoxic-ischemic injury, epilepsy, migraine, tumor, infection, and metabolic disease.
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Encéfalo , Circulação Cerebrovascular , Artefatos , Encéfalo/irrigação sanguínea , Encéfalo/diagnóstico por imagem , Circulação Cerebrovascular/fisiologia , Criança , Humanos , Imageamento por Ressonância Magnética/métodos , Marcadores de SpinRESUMO
Closed spinal dysraphism (SD) is a type of neural tube defect originating during early embryonic development whereby the neural tissue of the spinal defect remains covered by skin, often coinciding with markers of cutaneous stigmata. It is hypothesized that these events are caused by multifactorial processes, including genetic and environmental causes. We present an infant with a unique congenital midline lesion associated with a closed SD. Through comprehensive molecular profiling of the intraspinal lesion and contiguous skin lesion, an internal tandem duplication (ITD) of the kinase domain of the fibroblast growth factor receptor 1 (FGFR1) gene was found. This ITD variant is somatic mosaic in nature as supported by a diminished variant allele frequency in the lesional tissue and by its absence in peripheral blood. FGFR1 ITD results in constitutive activation of the receptor tyrosine kinase to promote cell growth, differentiation, and survival through RAS/MAPK signaling. Identification of FGFR1 ITD outside of central nervous system tumors is exceedingly rare, and this report broadens the phenotypic spectrum of somatic mosaic FGFR1-related disease.
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Neoplasias do Sistema Nervoso Central , Defeitos do Tubo Neural , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos , Humanos , Lactente , Defeitos do Tubo Neural/genética , Defeitos do Tubo Neural/metabolismo , Fenótipo , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/genética , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/metabolismo , Transdução de SinaisRESUMO
Infantile Krabbe disease (IKD) can be treated with hematopoietic cell transplantation (HCT) if done during the first weeks of life before symptoms develop. To facilitate this, newborn screening (NBS) has been instituted in 8 US states. An application to add IKD to the recommended NBS panel is currently under review. In this report, the outcomes of newborns with IKD diagnosed through NBS and treated with HCT are presented. The unique challenges associated with NBS for this disease are discussed, including opportunities for earlier diagnosis and streamlining treatment referrals. This is a retrospective review of six infants with IKD detected by NBS who were referred for HCT. The timing from diagnosis to HCT was examined, and both HCT and neurodevelopmental outcomes are described. Neurologic testing before HCT revealed evidence of active IKD in all infants. All underwent HCT between 24 and 40 days of age, were successfully engrafted, and are alive 30 to 58 months later (median, 47.5 months). All are gaining developmental milestones albeit at a slower pace than unaffected age-matched peers. Gross motor function is most notably affected. NBS for these patients enabled early access to HCT, the only currently available treatment of infants with IKD. All children are alive and have derived developmental and neurologic benefits from timely HCT. Long-term follow up is ongoing. Optimization of HCT and further development of emerging therapies, all of which must be delivered early in life, are expected to further improve outcomes of infants with IKD.
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Transplante de Células-Tronco Hematopoéticas , Leucodistrofia de Células Globoides , Criança , Pré-Escolar , Humanos , Lactente , Recém-Nascido , Leucodistrofia de Células Globoides/diagnóstico , Leucodistrofia de Células Globoides/terapia , Estudos Longitudinais , Triagem NeonatalRESUMO
Neck masses commonly present in children and several potential diagnostic and management pathways exist, though with a paucity of evidence-based recommendations. The purpose of this article is to evaluate the current literature and utilization of various diagnostic imaging modalities , with a review of imaging features and management pearls for pediatric neck masses. A comprehensive understanding and practical imaging workflow will guide optimal patient workup and management.
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Diagnóstico por Imagem/métodos , Neoplasias de Cabeça e Pescoço/diagnóstico por imagem , Doenças Linfáticas/diagnóstico por imagem , Doenças da Boca/diagnóstico por imagem , Doenças Respiratórias/diagnóstico por imagem , Doenças da Glândula Tireoide/diagnóstico por imagem , Adolescente , Criança , Pré-Escolar , Diagnóstico Diferencial , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Pescoço/anormalidades , Pescoço/diagnóstico por imagem , Guias de Prática Clínica como AssuntoRESUMO
Cerebral cavernous malformations (CCM) may present in sporadic or familial forms, with different cutaneous manifestations including deep blue nodules, capillary malformations, and hyperkeratotic cutaneous capillary venous malformations (HCCVM). We report the case of an infant with a KRIT1-positive HCCVM associated with familial CCM. Moreover, histopathology showed positive immunohistochemical stain with GLUT1, further expanding the differential diagnosis of GLUT1-positive vascular anomalies.
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Hemangioma Cavernoso do Sistema Nervoso Central , Dermatopatias Vasculares , Malformações Vasculares , Capilares/anormalidades , Capilares/patologia , Transportador de Glucose Tipo 1 , Hemangioma Cavernoso do Sistema Nervoso Central/complicações , Humanos , Proteína KRIT1 , Dermatopatias Vasculares/patologia , Malformações Vasculares/diagnóstico , Malformações Vasculares/patologiaRESUMO
Introduction: Medulloblastoma (MB) is a malignant, heterogenous brain tumor. Advances in molecular profiling have led to identifying four molecular subgroups of MB (WNT, SHH, Group 3, Group 4), each with distinct clinical behaviors. We hypothesize that (1) aggressive MB tumors, growing heterogeneously, induce pronounced local structural deformations in the surrounding parenchyma, and (b) these local deformations as captured on Gadolinium (Gd)-enhanced-T1w MRI are independently associated with molecular subgroups, as well as overall survival in MB patients. Methods: In this work, a total of 88 MB studies from 2 institutions were analyzed. Following tumor delineation, Gd-T1w scan for every patient was registered to a normal age-specific T1w-MRI template via deformable registration. Following patient-atlas registration, local structural deformations in the brain parenchyma were obtained for every patient by computing statistics from deformation magnitudes obtained from every 5mm annular region, 0 < d < 60 mm, where d is the distance from the tumor infiltrating edge. Results: Multi-class comparison via ANOVA yielded significant differences between deformation magnitudes obtained for Group 3, Group 4, and SHH molecular subgroups, observed up to 60-mm outside the tumor edge. Additionally, Kaplan-Meier survival analysis showed that the local deformation statistics, combined with the current clinical risk-stratification approaches (molecular subgroup information and Chang's classification), could identify significant differences between high-risk and low-risk survival groups, achieving better performance results than using any of these approaches individually. Discussion: These preliminary findings suggest there exists significant association of our tumor-induced deformation descriptor with overall survival in MB, and that there could be an added value in using the proposed radiomic descriptor along with the current risk classification approaches, towards more reliable risk assessment in pediatric MB.
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Arterial spin labeling (ASL) is a powerful noncontrast magnetic resonance imaging (MRI) technique that enables quantitative evaluation of brain perfusion. To optimize the clinical and research utilization of ASL, radiologists and physicists must understand the technical considerations and age-related variations in normal and disease states. We discuss advanced applications of ASL across the lifespan, with example cases from children and adults covering a wide variety of pathologies. Through literature review and illustrated clinical cases, we highlight the subtleties as well as pitfalls of ASL interpretation. First, we review basic physical principles, techniques, and artifacts. This is followed by a discussion of normal perfusion variants based on age and physiology. The three major categories of perfusion abnormalities-hypoperfusion, hyperperfusion, and mixed patterns-are covered with an emphasis on clinical interpretation and relationship to the disease process. Major etiologies of hypoperfusion include large artery, small artery, and venous disease; other vascular conditions; global hypoxic-ischemic injury; and neurodegeneration. Hyperperfusion is characteristic of vascular malformations and tumors. Mixed perfusion patterns can be seen with epilepsy, migraine, trauma, infection/inflammation, and toxic-metabolic encephalopathy. LEVEL OF EVIDENCE: 4 TECHNICAL EFFICACY STAGE: 3.
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Encefalopatias , Circulação Cerebrovascular , Adulto , Artérias , Encefalopatias/diagnóstico por imagem , Circulação Cerebrovascular/fisiologia , Criança , Humanos , Angiografia por Ressonância Magnética/métodos , Imageamento por Ressonância Magnética/métodos , Marcadores de SpinRESUMO
Noncontrast magnetic resonance imaging techniques for measuring brain perfusion include arterial spin labeling (ASL) and intravoxel incoherent motion (IVIM). These techniques provide noninvasive and repeatable assessment of cerebral blood flow or cerebral blood volume without the need for intravenous contrast. This article discusses the technical aspects of ASL and IVIM with a focus on normal physiologic variations, technical parameters, and artifacts. Multiple pediatric clinical applications are presented, including tumors, stroke, vasculopathy, vascular malformations, epilepsy, migraine, trauma, and inflammation.
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Encéfalo , Imageamento por Ressonância Magnética , Encéfalo/diagnóstico por imagem , Criança , Imagem de Difusão por Ressonância Magnética , Humanos , Movimento (Física) , Perfusão , Marcadores de SpinRESUMO
Ultrasonography (US) is the first-line imaging modality for screening neonates and young infants with suspected spinal abnormalities. Whether performed for a suspicious congenital skin lesion, such as a lumbosacral tract or lipomatous mass, or abnormal neurological findings, US can help define spinal anatomy, characterize congenital spine malformations, and direct further work-up and management. The purpose of this article is to review the diagnostic imaging approach to infant spine US, including technique and indications, normal anatomy and variants with a focus on embryological origins, and classification and diagnosis of congenital spine malformations.
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Lipoma , Imageamento por Ressonância Magnética , Humanos , Lactente , Recém-Nascido , Coluna Vertebral/diagnóstico por imagem , UltrassonografiaRESUMO
Phosphatase and tensin homologue (PTEN) regulates cell growth and survival through inhibition of the mammalian target of rapamycin (MTOR) signalling pathway. Germline genetic variation of PTEN is associated with autism, macrocephaly and PTEN hamartoma tumour syndromes. The effect of developmental PTEN somatic mutations on nervous system phenotypes is not well understood, although brain somatic mosaicism of MTOR pathway genes is an emerging cause of cortical dysplasia and epilepsy in the paediatric population. Here we report two somatic variants of PTEN affecting a single patient presenting with intractable epilepsy and hemimegalencephaly that varied in clinical severity throughout the left cerebral hemisphere. High-throughput sequencing analysis of affected brain tissue identified two somatic variants in PTEN. The first variant was present in multiple cell lineages throughout the entire hemisphere and associated with mild cerebral overgrowth. The second variant was restricted to posterior brain regions and affected the opposite PTEN allele, resulting in a segmental region of more severe malformation, and the only neurons in which it was found by single-nuclei RNA-sequencing had a unique disease-related expression profile. This study reveals brain mosaicism of PTEN as a disease mechanism of hemimegalencephaly and furthermore demonstrates the varying effects of single- or bi-allelic disruption of PTEN on cortical phenotypes.
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Córtex Cerebral/diagnóstico por imagem , Variação Genética/genética , Hemimegalencefalia/diagnóstico por imagem , Hemimegalencefalia/genética , Mutação/genética , PTEN Fosfo-Hidrolase/genética , Córtex Cerebral/cirurgia , Hemimegalencefalia/cirurgia , Humanos , Lactente , MasculinoRESUMO
PURPOSE: We investigated the hypothesis that increasing fMRI temporal resolution using a multiband (MB) gradient echo-echo planar imaging (GRE-EPI) pulse sequence provides fMRI language maps of higher statistical quality than those acquired with a traditional GRE-EPI sequence. METHODS: This prospective study enrolled 29 consecutive patients receiving language fMRI prior to a potential brain resection for tumor, AVM, or epilepsy. A 4-min rhyming task was performed at 3.0 Tesla with a traditional GRE-EPI pulse sequence (TR = 2000, TE = 30, matrix = 64/100%, slice = 4/0, FOV = 24, slices = 30, time points = 120) and an additional MB GRE-EPI pulse sequence with an acceleration factor of 6 (TR = 333, TE = 30, matrix 64/100%, slice = 4/0, FOV = 24, time points = 720). Spatially filtered t statistical maps were generated. Volumes of interest (VOIs) were drawn around activations at Broca's, dorsolateral prefrontal cortex, Wernicke's, and the visual word form areas. The t value maxima were measured for the overall brain and each of the VOIs. A paired t test was performed for the corresponding traditional and MB GRE-EPI measurements. RESULTS: The mean age of subjects was 42.6 years old (18-75). Sixty-two percent were male. The average overall brain t statistic maxima for the MB pulse sequence (t = 15.4) was higher than for the traditional pulse sequence (t = 9.3, p = < .0001). This also held true for Broca's area (p < 0.0001), Wernicke's area (p < .0001), dorsolateral prefrontal cortex (p < .0001), and the visual word form area (p < .0001). CONCLUSION: A MB GRE-EPI fMRI pulse sequence employing high temporal resolution provides clinical fMRI language maps of greater statistical significance than those obtained with a traditional GRE-EPI sequence.
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Idioma , Imageamento por Ressonância Magnética , Adulto , Mapeamento Encefálico , Imagem Ecoplanar , Humanos , Masculino , Estudos ProspectivosRESUMO
BACKGROUND: Endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) is a sensitive and specific tool in the risk stratification of pancreatic lesions, including cysts. The sensitivity and specificity of EUS-FNA has been shown to improve when cytology is combined with next-generation sequencing (NGS). Ideally, fresh cyst fluid is used for NGS. In this pilot study, we explore the possibility of sequencing DNA derived from residual alcohol-fixed pancreatic aspirates. METHODS: Residual cytologic fixatives (n = 42) from 39 patients who underwent EUS-FNA for pancreatic lesions were collected along with demographics, imaging, and laboratory studies. Samples were designated as nonneoplastic/nonmucinous benign (NB), mucinous cyst (MC), pancreatic ductal adenocarcinoma (PDAC), or well-differentiated neuroendocrine tumor (NET) on the basis of cytopathologic evaluation and sequenced on the Oncomine platform (ThermoFisher Scientific, Waltham, Massachusetts). RESULTS: Ten of 14 (71.4%) MCs exhibited clinically significant variants, including KRAS, GNAS, and TP53. Ten of 15 (66.7%) PDACs had KRAS alterations, and 9 of 15 (60%) showed variants in TP53. No variants were detected in any NETs. Only 1 of 9 (11.1%) NB aspirates showed variants in KRAS and MAP2K. Sequencing of formalin-fixed, paraffin-embedded tissue revealed variants identical to those detected in fixative-derived DNA in 4 of 5 cases (80%). CONCLUSION: Residual DNA from alcohol-fixed aspirates are an underutilized source for NGS. Sequencing residual fixative-derived DNA has the potential to be integrated into the workup of pancreatic aspirates, possibly impacting management.
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Biomarcadores Tumorais/genética , Carcinoma Ductal Pancreático/diagnóstico , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Mutação , Tumores Neuroendócrinos/diagnóstico , Cisto Pancreático/diagnóstico , Neoplasias Pancreáticas/diagnóstico , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/cirurgia , Técnicas Citológicas , Aspiração por Agulha Fina Guiada por Ultrassom Endoscópico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Tumores Neuroendócrinos/genética , Tumores Neuroendócrinos/cirurgia , Cisto Pancreático/genética , Cisto Pancreático/cirurgia , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/cirurgia , Projetos Piloto , Prognóstico , Manejo de Espécimes , Adulto JovemRESUMO
Mitochondria play a variety of roles in the cell, far beyond their widely recognized role in ATP generation. One such role is the regulation and sequestration of calcium, which is done with the help of the mitochondrial calcium uniporter (MCU) and its regulators, MICU1 and MICU2. Genetic variations in MICU1 and MICU2 have been reported to cause myopathy, developmental disability and neurological symptoms typical of mitochondrial disorders. The symptoms of MICU1/2 deficiency have generally been attributed to calcium regulation in the metabolic and biochemical roles of mitochondria. Here, we report a female child with heterozygous MICU1 variants and multiple congenital brain malformations on MRI. Specifically, she shows anterior perisylvian polymicrogyria, dysmorphic basal ganglia, and cerebellar dysplasia in addition to white matter abnormalities. These novel findings suggest that MICU1 is necessary for proper neurodevelopment through a variety of potential mechanisms, including calcium-mediated regulation of the neuronal cytoskeleton, Miro1-MCU complex-mediated mitochondrial movement, or enhancing ATP production. This case provides new insight into the molecular pathogenesis of MCU dysfunction and may represent a novel diagnostic feature of calcium-based mitochondrial disease.