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1.
Acta Neuropathol Commun ; 12(1): 117, 2024 Jul 16.
Artículo en Inglés | MEDLINE | ID: mdl-39014393

RESUMEN

Papillary tumor of the pineal region (PTPR) is an uncommon tumor of the pineal region with distinctive histopathologic and molecular characteristics. Experience is limited with respect to its molecular heterogeneity and clinical characteristics. Here, we describe 39 new cases and combine these with 37 previously published cases for a cohort of 76 PTPR's, all confirmed by methylation profiling. As previously reported, two main methylation groups were identified (PTPR-A and PTPR-B). In our analysis we extended the subtyping into three subtypes: PTPR-A, PTPR-B1 and PTPR-B2 supported by DNA methylation profile and genomic copy number variations. Frequent loss of chromosome 3 or 14 was found in PTPR-B1 tumors but not in PTPR-B2. Examination of clinical outcome showed that nearly half (14/30, 47%) of examined patients experienced tumor progression with significant difference among the subtypes (p value = 0.046). Our analysis extends the understanding of this uncommon but distinct neuroepithelial tumor by describing its molecular heterogeneity and clinical outcomes, including its tendency towards tumor recurrence.


Asunto(s)
Metilación de ADN , Glándula Pineal , Pinealoma , Humanos , Masculino , Femenino , Adulto , Persona de Mediana Edad , Pinealoma/genética , Pinealoma/patología , Adolescente , Adulto Joven , Niño , Glándula Pineal/patología , Anciano , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patología , Preescolar , Variaciones en el Número de Copia de ADN
2.
Cell Rep ; 43(6): 114284, 2024 Jun 25.
Artículo en Inglés | MEDLINE | ID: mdl-38814785

RESUMEN

Nuclear envelope (NE) ruptures are emerging observations in Lamin-related dilated cardiomyopathy, an adult-onset disease caused by loss-of-function mutations in Lamin A/C, a nuclear lamina component. Here, we test a prevailing hypothesis that NE ruptures trigger the pathological cGAS-STING cytosolic DNA-sensing pathway using a mouse model of Lamin cardiomyopathy. The reduction of Lamin A/C in cardio-myocyte of adult mice causes pervasive NE ruptures in cardiomyocytes, preceding inflammatory transcription, fibrosis, and fatal dilated cardiomyopathy. NE ruptures are followed by DNA damage accumulation without causing immediate cardiomyocyte death. However, cGAS-STING-dependent inflammatory signaling remains inactive. Deleting cGas or Sting does not rescue cardiomyopathy in the mouse model. The lack of cGAS-STING activation is likely due to the near absence of cGAS expression in adult cardiomyocytes at baseline. Instead, extracellular matrix (ECM) signaling is activated and predicted to initiate pro-inflammatory communication from Lamin-reduced cardiomyocytes to fibroblasts. Our work nominates ECM signaling, not cGAS-STING, as a potential inflammatory contributor in Lamin cardiomyopathy.


Asunto(s)
Matriz Extracelular , Proteínas de la Membrana , Miocitos Cardíacos , Membrana Nuclear , Nucleotidiltransferasas , Transducción de Señal , Animales , Nucleotidiltransferasas/metabolismo , Nucleotidiltransferasas/genética , Proteínas de la Membrana/metabolismo , Proteínas de la Membrana/genética , Ratones , Membrana Nuclear/metabolismo , Matriz Extracelular/metabolismo , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/patología , Lamina Tipo A/metabolismo , Lamina Tipo A/genética , Cardiomiopatías/metabolismo , Cardiomiopatías/patología , Modelos Animales de Enfermedad , Ratones Endogámicos C57BL , Cardiomiopatía Dilatada/patología , Cardiomiopatía Dilatada/metabolismo , Cardiomiopatía Dilatada/genética , Daño del ADN
3.
J Stroke Cerebrovasc Dis ; 33(7): 107699, 2024 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-38552890

RESUMEN

BACKGROUND: Radiation treatment for diseases of the brain can result in hemorrhagic adverse radiation effects. The underlying pathologic substrate of brain bleeding after irradiation has not been elucidated, nor potential associations with induced somatic mutations. METHODS: We retrospectively reviewed our department's pathology database over 5 years and identified 5 biopsy specimens (4 patients) for hemorrhagic lesions after brain irradiation. Tissues with active malignancy were excluded. Samples were characterized using H&E, Perl's Prussian Blue, and Masson's Trichrome; immunostaining for B-cells (anti-CD20), T-cells (anti-CD3), endothelium (anti-CD31), macrophages (anti-CD163), α-smooth muscle actin, and TUNEL. DNA analysis was done by two panels of next-generation sequencing for somatic mutations associated with known cerebrovascular anomalies. RESULTS: One lesion involved hemorrhagic expansion among multifocal microbleeds that had developed after craniospinal irradiation for distant medulloblastoma treatment. Three bleeds arose in the bed of focally irradiated arteriovenous malformations (AVM) after confirmed obliteration. A fifth specimen involved the radiation field distinct from an irradiated AVM bed. From these, 2 patterns of hemorrhagic vascular pathology were identified: encapsulated hematomas and cavernous-like malformations. All lesions included telangiectasias with dysmorphic endothelium, consistent with primordial cavernous malformations with an associated inflammatory response. DNA analysis demonstrated genetic variants in PIK3CA and/or PTEN genes but excluded mutations in CCM genes. CONCLUSIONS: Despite pathologic heterogeneity, brain bleeding after irradiation is uniformly associated with primordial cavernous-like telangiectasias and disruption of genes implicated in dysangiogenesis but not genes implicated as causative of cerebral cavernous malformations. This may implicate a novel signaling axis as an area for future study.


Asunto(s)
Mutación , Traumatismos por Radiación , Adulto , Femenino , Humanos , Masculino , Persona de Mediana Edad , Adulto Joven , Biopsia , Hemorragia Cerebral/genética , Hemorragia Cerebral/etiología , Hemorragia Cerebral/patología , Fosfatidilinositol 3-Quinasa Clase I/genética , Irradiación Craneana/efectos adversos , Bases de Datos Factuales , Análisis Mutacional de ADN , Predisposición Genética a la Enfermedad , Secuenciación de Nucleótidos de Alto Rendimiento , Malformaciones Arteriovenosas Intracraneales/genética , Malformaciones Arteriovenosas Intracraneales/radioterapia , Malformaciones Arteriovenosas Intracraneales/patología , Hemorragias Intracraneales/genética , Hemorragias Intracraneales/etiología , Hemorragias Intracraneales/patología , Fenotipo , Fosfohidrolasa PTEN/genética , Traumatismos por Radiación/genética , Traumatismos por Radiación/patología , Traumatismos por Radiación/etiología , Estudios Retrospectivos , Factores de Riesgo
4.
Neurooncol Adv ; 6(1): vdae014, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38420615

RESUMEN

Background: A significant unmet need exists for the treatment of glioblastoma, IDH-wildtype (GBM). Preclinical work shows that acetazolamide sensitizes GBM to temozolomide (TMZ) by overcoming TMZ resistance due to BCL-3-dependent upregulation of carbonic anhydrase. Acetazolamide is Food and Drug Administration-approved for the treatment of altitude sickness. Drug repurposing enables the application of drugs to diseases beyond initial indications. This multi-institutional, open-label, phase I trial examined a combination of acetazolamide and TMZ in patients with MGMT promoter-methylated high-grade glioma. Methods: A total of 24 patients (GBM, IDH-wildtype = 22; Grade 4 astrocytoma, IDH-mutant = 1; Grade 3 astrocytoma, IDH-mutant = 1) were accrued over 17 months. All patients received oral acetazolamide (250 mg BID for 7 days increased to 500 mg BID for Days 8-21 of each 28-day cycle) during the adjuvant phase of TMZ for up to 6 cycles. Results: No patient had a dose-limiting toxicity. Adverse events were consistent with known sequelae of acetazolamide and TMZ. In the 23 WHO Grade 4 patients, the median overall survival (OS) was 30.1 months and the median progression-free survival was 16.0 months. The 2-year OS was 60.9%. In total 37% of the study population had high BCL-3 staining and trended toward shorter OS (17.2 months vs N.R., P = .06). Conclusions: The addition of acetazolamide is safe and tolerable in GBM patients receiving standard TMZ. Survival results compare favorably to historical data from randomized trials in patients with MGMT promoter-methylated GBM and support examination of acetazolamide in a randomized trial. BCL-3 expression is a potential biomarker for prognosis in GBM or for patients more likely to benefit from TMZ.

5.
Int J Gynecol Pathol ; 43(1): 90-96, 2024 Jan 01.
Artículo en Inglés | MEDLINE | ID: mdl-37046379

RESUMEN

Immature neuroectodermal tissue can be found in the ovary as part of an immature teratoma or as part of a teratoma with malignant neuroectodermal transformation. Such lesions may closely resemble central nervous system tumors, but their biologic similarity is unclear. We describe an 18-yr-old female who presented with abdominal pain caused by an ovarian mass with widespread metastases. Histology showed a primitive, high-grade tumor arising in the background of a mature teratoma. The tumor was SOX10 positive, with focal expression of GFAP, S100, NSE, and synaptophysin. Molecular analysis demonstrated co-amplification of PDGFRA and KIT , alterations common in high-grade gliomas. By whole-genome methylation profiling, it clustered into the "diffuse pediatric-type high-grade glioma, RTK1 subtype, subclass c" group. Despite progressing through 2 lines of chemotherapy with widespread metastatic disease, she achieved an excellent response to chemotherapy directed toward aggressive germ cell tumors. This case emphasizes the importance of immunohistochemical, genomic, and epigenetic analyses to accurately classify these exceedingly rare tumors and determine the optimal therapy.


Asunto(s)
Glioma , Neoplasias de Células Germinales y Embrionarias , Neoplasias Ováricas , Teratoma , Humanos , Femenino , Niño , Neoplasias Ováricas/genética , Neoplasias Ováricas/patología , Teratoma/complicaciones , Teratoma/genética , Glioma/complicaciones , Glioma/genética
7.
bioRxiv ; 2023 Aug 28.
Artículo en Inglés | MEDLINE | ID: mdl-37693381

RESUMEN

Mutations in the nuclear Lamin A/C gene (LMNA) cause diverse degenerative disorders, including malignant dilated cardiomyopathy in adults. A prevailing hypothesis postulates that LMNA mutations cause nuclear envelope ruptures that trigger pathogenic inflammatory signaling via the cGAS-STING cytosolic DNA-sensing pathway. Here, we provide evidence against this hypothesis, using a mouse model of LMNA-related cardiomyopathy that mimics Lamin A/C protein reduction observed in patient cardiomyocytes. We observed that pervasive nuclear envelope ruptures preceded the onset of cardiac transcriptional modulation and dilated cardiomyopathy. Nuclear ruptures activated DNA damage response without causing immediate cardiomyocyte death. However, cGAS-STING downstream cytokine genes remained inactive in the mutant cardiomyocytes. Deleting cGas or Sting did not alleviate cardiomyopathy. Instead, extracellular matrix signaling was predicted to emanate from Lamin A/C-reduced cardiomyocytes to communicate with fibroblasts in the heart. These findings suggest that cGAS-STING is not a major pathogenetic contributor to LMNA-related dilated cardiomyopathy in adult humans.

8.
Neurol Clin Pract ; 13(5): e200182, 2023 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-37664132

RESUMEN

Purpose of Review: Tumor-like brain lesions are rare and commonly suggest a neoplastic etiology. Failure to rapidly identify non-neoplastic causes can lead to increased morbidity and mortality. In this review, we describe 10 patients who presented with atypical, non-neoplastic tumor-like brain lesions in which brain biopsy was essential for a correct diagnosis and treatment. Recent Findings: There has been increasing recognition of autoimmune conditions affecting the nervous system, and many of those diseases can cause tumor-like brain lesions. Currently available reports of non-neoplastic tumor-like brain lesions are scarce. Most case series focus on tumefactive demyelinating lesions, and a comprehensive review including other neuroimmunological conditions such as CNS vasculitis, neurosarcoidosis, histiocytic and infectious etiologies is lacking. Summary: We review the literature on tumor-like brain lesions intending to increase the awareness and differential diagnosis of non-neoplastic brain tumor mimics. We advocate for earlier brain biopsies, which, in our case series, significantly changed diagnosis, management, and outcomes.

9.
Acta Neuropathol ; 145(1): 71-82, 2023 01.
Artículo en Inglés | MEDLINE | ID: mdl-36271929

RESUMEN

High-grade astrocytoma with piloid features (HGAP) is a recently recognized glioma type whose classification is dependent on its global epigenetic signature. HGAP is characterized by alterations in the mitogen-activated protein kinase (MAPK) pathway, often co-occurring with CDKN2A/B homozygous deletion and/or ATRX mutation. Experience with HGAP is limited and to better understand this tumor type, we evaluated an expanded cohort of patients (n = 144) with these tumors, as defined by DNA methylation array testing, with a subset additionally evaluated by next-generation sequencing (NGS). Among evaluable cases, we confirmed the high prevalence CDKN2A/B homozygous deletion, and/or ATRX mutations/loss in this tumor type, along with a subset showing NF1 alterations. Five of 93 (5.4%) cases sequenced harbored TP53 mutations and RNA fusion analysis identified a single tumor containing an NTRK2 gene fusion, neither of which have been previously reported in HGAP. Clustering analysis revealed the presence of three distinct HGAP subtypes (or groups = g) based on whole-genome DNA methylation patterns, which we provisionally designated as gNF1 (n = 18), g1 (n = 72), and g2 (n = 54) (median ages 43.5 years, 47 years, and 32 years, respectively). Subtype gNF1 is notable for enrichment with patients with Neurofibromatosis Type 1 (33.3%, p = 0.0008), confinement to the posterior fossa, hypermethylation in the NF1 enhancer region, a trend towards decreased progression-free survival (p = 0.0579), RNA processing pathway dysregulation, and elevated non-neoplastic glia and neuron cell content (p < 0.0001 and p < 0.0001, respectively). Overall, our expanded cohort broadens the genetic, epigenetic, and clinical phenotype of HGAP and provides evidence for distinct epigenetic subtypes in this tumor type.


Asunto(s)
Astrocitoma , Neoplasias Encefálicas , Neurofibromatosis 1 , Humanos , Neurofibromatosis 1/genética , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patología , Homocigoto , Eliminación de Secuencia , Astrocitoma/genética , Astrocitoma/patología , Mutación/genética , Metilación de ADN/genética
10.
Front Neurol ; 13: 826676, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-35309588

RESUMEN

Several variants of the TANK-Binding Kinase 1 (TBK1) gene have been associated with frontotemporal dementia - amyotrophic lateral sclerosis (FTD-ALS) spectrum diseases. Corticobasal syndrome (CBS) is characterized by asymmetric limb rigidity, dystonia or myoclonus, in association with speech or limb apraxia, cortical sensory deficit, and/or alien limb. It can result from a variety of underlying pathologies and although typically sporadic, it has been occasionally associated with MAPT and GRN variants. We describe here the proband of a family with multiple occurrences of FTD-ALS spectrum disease who developed an isolated right-sided primary asymmetric akinetic-rigid syndrome and subsequent speech and cognitive dysfunction associated with contralateral anterior temporal lobe atrophy on MRI and corresponding hypometabolism by FDG-PET. Genetic testing revealed a novel Lys694del variant of the TBK1 gene and Type A TDP-43 pathology in a predominantly frontotemporal distribution contralateral to the affected side. To our knowledge this is the first report of CBS as the initial expression of a TBK1 variant. This case emphasizes the importance of considering TBK1 genetic screening in patients with CBS, as this may be an underrepresented population on the spectrum of genetic FTD-ALS.

11.
Acta Neuropathol ; 143(3): 403-414, 2022 03.
Artículo en Inglés | MEDLINE | ID: mdl-35103816

RESUMEN

Tumors of the central nervous system (CNS) often display a wide morphologic spectrum that has, until recently, been the sole basis for tumor classification. The introduction of the integrated histomolecular diagnostic approach in CNS tumors has facilitated a classification system that is increasingly data-driven and with improved alignment to clinical outcome. Here, we report a previously uncharacterized glioma type (n = 31) using unsupervised clustering analysis of DNA methylation array data from approximately 14,000 CNS tumor samples. Histologic examination revealed circumscribed growth and morphologic similarities to pleomorphic xanthoastrocytoma (PXA), astroblastoma, ependymoma, polymorphous neuroepithelial tumor of the young (PLNTY), and IDH-wildtype glioblastoma (GBM). Median age (46.5 years) was significantly older than other circumscribed gliomas and younger than GBM. Dimensionality reduction with uniform manifold approximation and projection (UMAP) and hierarchical clustering confirmed a methylation signature distinct from known tumor types and methylation classes. DNA sequencing revealed recurrent mutations in TP53 (57%), RB1 (26%), NF1 (26%), and NF2 (14%). BRAF V600E mutations were detected in 3/27 sequenced cases (12%). Copy number analysis showed increased whole chromosome aneuploidy with recurrent loss of chromosome 13 (28/31 cases, 90%). CDKN2A/B deletion (2/31, 6%) and MGMT promoter methylation (1/31, 3%) were notably rare events. Most tumors showed features of a high-grade glioma, yet survival data showed significantly better overall survival compared to GBM (p < 0.0001). In summary, we describe a previously uncharacterized glioma of adults identified by a distinct DNA methylation signature and recurrent loss of chromosome 13.


Asunto(s)
Astrocitoma , Neoplasias Encefálicas , Glioma , Monosomía , Mutación , Proteína p53 Supresora de Tumor , Astrocitoma/genética , Astrocitoma/patología , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patología , Cromosomas Humanos Par 13 , Humanos , Persona de Mediana Edad , Mutación/genética , Proteína p53 Supresora de Tumor/genética
12.
Am J Clin Pathol ; 158(1): 96-104, 2022 07 01.
Artículo en Inglés | MEDLINE | ID: mdl-35195717

RESUMEN

OBJECTIVES: Tissue carryovers are contaminants of surgical pathology cases in which extraneous tissue is incorporated into tissue blocks. Carryovers occur most frequently at the grossing or embedding stations, but little is published about them. We sought to analyze their transmission during transit to the histology lab. METHODS: Cassettes of friable donor tissue were mixed with cassettes of spongy recipient tissue in formalin-filled containers and agitated by shipment via pneumatic tube. The tissue cassettes were processed, embedded as blocks, and cut as usual. Liquid samples were prepared from the submission containers as well as from workstation submission containers and histology tissue processor waste. RESULTS: A high rate of contamination (14.9%) was observed under these artificial conditions. Friable donor tissue, including urothelium and colorectal adenocarcinoma, were promiscuous contaminants, as were placental villi. Fluid from submission containers showed viable tumor cells and fragments, which were also present in workstation submission containers and in tissue processor waste fluid. CONCLUSIONS: This study implicates liquid transport media as a possible avenue of contamination during submission and transportation of tissue cassettes for histologic processing. Attention should be given to the friability of submitted tissue and physical agitation of the cassettes in transit. Such contaminants may be present in the fluid in tissue submission bins and in tissue processor fluid.


Asunto(s)
Neoplasias , Placenta , Femenino , Formaldehído , Humanos , Adhesión en Parafina , Embarazo , Manejo de Especímenes , Fijación del Tejido
13.
Hum Pathol ; 121: 56-64, 2022 03.
Artículo en Inglés | MEDLINE | ID: mdl-35016891

RESUMEN

Limited tissue in biopsies of malignant bone lesions can preclude definitive subclassification, especially when cellular or matrix elements are sparse, absent, or confounding. It is uncertain whether immunohistochemistry for SOX9 (marker of chondrogenesis) and SATB2 (marker of osteoblastic differentiation) may be discriminatory tools toward osteosarcoma and chondrosarcoma. This study interrogated the preresection biopsies of a cohort of osteosarcoma and chondrosarcoma with SATB2 and SOX9 in tandem, to assess their value as diagnostic adjuncts as well as their concordance with the final resection diagnoses. SATB2 was expressed more frequently in osteosarcoma (46/53, 86%) than in chondrosarcoma (9/18, 50%); SOX9 was expressed in high frequencies in both osteosarcoma (52/53, 98%) and chondrosarcoma (17/18, 94%), and SATB2 and SOX9 were coexpressed in both osteosarcoma (46/53, 89%) and chondrosarcoma (8/18, 44%). There exists significant overlap in the expression of SATB2 and SOX9 in osteosarcoma and chondrosarcoma. These markers are not expressed in a distribution that is unique enough for application toward this particular diagnostic differential.


Asunto(s)
Neoplasias Óseas , Condrosarcoma , Proteínas de Unión a la Región de Fijación a la Matriz , Osteosarcoma , Biomarcadores de Tumor/análisis , Biopsia , Neoplasias Óseas/diagnóstico , Neoplasias Óseas/genética , Neoplasias Óseas/metabolismo , Condrosarcoma/patología , Humanos , Inmunohistoquímica , Osteosarcoma/patología , Factor de Transcripción SOX9 , Factores de Transcripción/metabolismo
14.
Int J Surg Pathol ; 30(3): 317-325, 2022 May.
Artículo en Inglés | MEDLINE | ID: mdl-34657504

RESUMEN

Background: Desmoplastic small round cell tumors (DSRCT) are malignant neoplasms of young males arising most commonly in the abdominopelvic cavity, with a subset originating from extra-abdominal soft tissues. As either primary or metastatic lesions, they are rare in intraosseous sites. Case Presentation: We describe the fifth report of primary DSRCT of bone. A healthy 18-year old male presented with a blastic, 17 cm lesion within the left distal femur, suspicious for osteosarcoma or Ewing sarcoma. Subsequent biopsy revealed nests of small round blue cells infiltrating through a desmoplastic stroma. These cells were diffusely positive for epithelial markers, with paranuclear staining for desmin and focal reactivity with NSE. Break-apart FISH revealed a rearrangement in EWSR1, and RNA fusion panel confirmed WT1 as its partner in the pathognomonic t(11;22)(p13;q12) rearrangement. PET/CT showed widespread metastatic disease to visceral and bony sites. Conclusions: Due to their rarity as well as clinicopathologic and immunomorphologic overlap, primary intraosseous DSRCT can create diagnostic challenges with the more frequently encountered tumors of bone.


Asunto(s)
Tumor Desmoplásico de Células Pequeñas Redondas , Biopsia , Tumor Desmoplásico de Células Pequeñas Redondas/diagnóstico , Tumor Desmoplásico de Células Pequeñas Redondas/genética , Tumor Desmoplásico de Células Pequeñas Redondas/patología , Fémur/patología , Humanos , Masculino , Proteínas de Fusión Oncogénica/genética , Tomografía Computarizada por Tomografía de Emisión de Positrones
17.
J Immunother Cancer ; 9(7)2021 07.
Artículo en Inglés | MEDLINE | ID: mdl-34272305

RESUMEN

BACKGROUND: Tumor-infiltrating CD8+ T cells and neoantigens are predictors of a favorable prognosis and response to immunotherapy with checkpoint inhibitors in many types of adult cancer, but little is known about their role in pediatric malignancies. Here, we analyzed the prognostic strength of T cell-inflamed gene expression and neoantigen load in high-risk neuroblastoma. We also compared transcriptional programs in T cell-inflamed and non-T cell-inflamed high-risk neuroblastomas to investigate possible mechanisms of immune exclusion. METHODS: A defined T cell-inflamed gene expression signature was used to categorize high-risk neuroblastomas in the Therapeutically Applicable Research to Generate Effective Treatments (TARGET) program (n=123), and the Gabriella Miller Kids First (GMKF) program (n=48) into T cell-inflamed, non-T cell-inflamed, and intermediate groups. Associations between the T cell-inflamed and non-T cell-inflamed group, MYCN amplification, and survival were analyzed by Cox proportional hazards models. Additional survival analysis was conducted after integrating neoantigen load predicted from somatic mutations. Pathways activated in non-T cell-inflamed relative to T cell-inflamed tumors were analyzed using causal network analysis. RESULTS: Patients with T cell-inflamed high-risk tumors showed improved overall survival compared with those with non-T cell-inflamed tumors (p<0.05), independent of MYCN amplification status, in both TARGET and GMKF cohorts. Higher neoantigen load was also associated with better event-free and overall survival (p<0.005) and was independent of the T cell-inflamed signature. Activation of MYCN, ASCL1, SOX11, and KMT2A transcriptional programs was inversely correlated with the T cell-inflamed signature in both cohorts. CONCLUSIONS: Our results indicate that tumors from children with high-risk neuroblastoma harboring a strong T cell-inflamed signature have a more favorable clinical outcome, and neoantigen load is a prognosis predictor, independent of T cell inflammation. Strategies to target SOX11 and other signaling pathways associated with non-T cell-inflamed tumors should be pursued as potential immune-potentiating interventions.


Asunto(s)
Inmunoterapia/métodos , Neuroblastoma/inmunología , Microambiente Tumoral/inmunología , Estudios de Cohortes , Femenino , Humanos , Masculino , Neuroblastoma/mortalidad , Pronóstico , Factores de Riesgo , Análisis de Supervivencia
18.
Am J Clin Pathol ; 156(6): 1007-1018, 2021 Nov 08.
Artículo en Inglés | MEDLINE | ID: mdl-34180985

RESUMEN

OBJECTIVES: Large gene panel next-generation sequencing (NGS) is a powerful tool capable of generating predictive data on cancer prognosis and response to specific therapeutic interventions. The utility of large panel NGS data on tumor classification, however, may be underappreciated because of a workflow that often circumvents the surgical pathologist. We sought to describe cases in which NGS data lead to an unanticipated change in tumor classification and to discuss current workflow practices of NGS testing that limit its use as a diagnostic adjunct. METHODS: We performed a retrospective review to identify cases in which NGS testing uncovered data that led to a revision of the initial pathologic diagnosis that an outside or in-house pathologist had made. RESULTS: Nine cases are presented in which NGS data provided insights that led to a revision of the original pathologic diagnosis. Distinctive molecular signatures, mutational signatures, fusions, or identification of viral sequencing provided the critical evidence on which these tumors were reclassified. CONCLUSIONS: The current workflow of NGS testing should always include the surgical pathologist as an active partner to ensure that the molecular results are fully reflected in the final diagnosis. In some instances, active participation by the surgical pathologist may require amendment of previously issued pathology reports.


Asunto(s)
Secuenciación de Nucleótidos de Alto Rendimiento , Neoplasias , Humanos , Mutación , Neoplasias/diagnóstico , Neoplasias/genética , Estudios Retrospectivos , Flujo de Trabajo
19.
Muscle Nerve ; 64(2): 219-224, 2021 08.
Artículo en Inglés | MEDLINE | ID: mdl-34037996

RESUMEN

INTRODUCTION/AIMS: We studied a patient with a congenital myasthenic syndrome (CMS) caused by a dominant mutation in the synaptotagmin 2 gene (SYT2) and compared the clinical features of this patient with those of a previously described patient with a recessive mutation in the same gene. METHODS: We performed electrodiagnostic (EDX) studies, genetic studies, muscle biopsy, microelectrode recordings and electron microscopy (EM). RESULTS: Both patients presented with muscle weakness and bulbar deficits, which were worse in the recessive form. EDX studies showed presynaptic failure, which was more prominent in the recessive form. Microelectrode studies in the dominant form showed a marked reduction of the quantal content, which increased linearly with higher frequencies of nerve stimulation. The MEPP frequencies were normal at rest but increased markedly with higher frequencies of nerve stimulation. The EM demonstrated overdeveloped postsynaptic folding, and abundant endosomes, multivesicular bodies and degenerative lamellar bodies inside small nerve terminals. DISCUSSION: The recessive form of CMS caused by a SYT2 mutation showed far more severe clinical manifestations than the dominant form. The pathogenesis of the dominant form likely involves a dominant-negative effect due to disruption of the dual function of synaptotagmin as a Ca2+ -sensor and modulator of synaptic vesicle exocytosis.


Asunto(s)
Mutación/genética , Síndromes Miasténicos Congénitos/genética , Unión Neuromuscular/genética , Sinaptotagmina II/genética , Adulto , Preescolar , Femenino , Humanos , Síndrome Miasténico de Lambert-Eaton/genética , Síndrome Miasténico de Lambert-Eaton/fisiopatología , Masculino , Debilidad Muscular/genética , Debilidad Muscular/fisiopatología , Síndromes Miasténicos Congénitos/diagnóstico , Unión Neuromuscular/fisiopatología
20.
J Pathol Clin Res ; 7(5): 459-470, 2021 09.
Artículo en Inglés | MEDLINE | ID: mdl-33960723

RESUMEN

Autopsies of patients who have died from COVID-19 have been crucial in delineating patterns of injury associated with SARS-CoV-2 infection. Despite their utility, comprehensive autopsy studies are somewhat lacking relative to the global burden of disease, and very few comprehensive studies contextualize the findings to other fatal viral infections. We developed a novel autopsy protocol in order to perform postmortem examinations on victims of COVID-19 and herein describe detailed clinical information, gross findings, and histologic features observed in the first 16 complete COVID-19 autopsies. We also critically evaluated the role of ancillary studies used to establish a diagnosis of COVID-19 at autopsy, including immunohistochemistry (IHC), in situ hybridization (ISH), and electron microscopy (EM). IHC and ISH targeting SARS-CoV-2 were comparable in terms of the location and number of infected cells in lung tissue; however, nonspecific staining of bacteria was seen occasionally with IHC. EM was unrevealing in blindly sampled tissues. We then compared the clinical and histologic features present in this series to six archival cases of fatal seasonal influenza and six archival cases of pandemic influenza from the fourth wave of the 'Spanish Flu' in the winter of 1920. In addition to routine histology, the inflammatory infiltrates in the lungs of COVID-19 and seasonal influenza victims were compared using quantitative IHC. Our results demonstrate that the clinical and histologic features of COVID-19 are similar to those seen in fatal cases of influenza, and the two diseases tend to overlap histologically. There was no significant difference in the composition of the inflammatory infiltrate in COVID-19 and influenza at sites of acute lung injury at the time of autopsy. Our study underscores the relatively nonspecific clinical features and pathologic changes shared between severe cases of COVID-19 and influenza, while also providing important caveats to ancillary methods of viral detection.


Asunto(s)
COVID-19/patología , Gripe Humana/patología , Pandemias , SARS-CoV-2/fisiología , Anciano , Autopsia , COVID-19/diagnóstico , COVID-19/virología , Femenino , Humanos , Inmunohistoquímica , Hibridación in Situ , Gripe Humana/diagnóstico , Gripe Humana/virología , Pulmón/patología , Pulmón/virología , Masculino , Estaciones del Año
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