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PURPOSE: Patients with glioblastoma (GBM) have a dismal prognosis. Although the DNA alkylating agent temozolomide (TMZ) is the mainstay of chemotherapy, therapeutic resistance rapidly develops in patients. Base excision repair inhibitor TRC102 (methoxyamine) reverses TMZ resistance in preclinical glioma models. We aimed to investigate the efficacy and safety of oral TRC102+TMZ in recurrent GBM (rGBM). PATIENTS AND METHODS: A preregistered (NCT02395692), nonrandomized, multicenter, phase 2 clinical trial (BERT) was planned and conducted through the Adult Brain Tumor Consortium (ABTC-1402). Arm 1 included patients with bevacizumab-naïve GBM at the first recurrence, with the primary endpoint of response rates. If sufficient activity was identified, a second arm was planned for the bevacizumab-refractory patients. The secondary endpoints were overall survival (OS), progression-free survival (PFS), PFS at 6 months (PFS6), and toxicity. RESULTS: Arm 1 enrolled 19 patients with a median of two treatment cycles. Objective responses were not observed; hence, arm 2 did not open. The median OS was 11.1 months [95% confidence interval (CI), 8.2-17.9]. The median PFS was 1.9 months (95% CI, 1.8-3.7). The PFS6 was 10.5% (95% CI, 1.3%-33.1%). Most toxicities were grades 1 and 2, with two grade 3 lymphopenias and one grade 4 thrombocytopenia. Two patients with PFS ≥ 17 months and OS > 32 months were deemed "extended survivors." RNA sequencing of tumor tissue, obtained at diagnosis, demonstrated significantly enriched signatures of DNA damage response (DDR), chromosomal instability (CIN70, CIN25), and cellular proliferation (PCNA25) in "extended survivors." CONCLUSIONS: These findings confirm the safety and feasibility of TRC102+TMZ in patients with rGBM. They also warrant further evaluation of combination therapy in biomarker-enriched trials enrolling GBM patients with baseline hyperactivated DDR pathways.
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Neoplasias Encefálicas , Glioblastoma , Recurrencia Local de Neoplasia , Temozolomida , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/patología , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/mortalidad , Reparación por Escisión/efectos de los fármacos , Glioblastoma/tratamiento farmacológico , Glioblastoma/patología , Glioblastoma/genética , Glioblastoma/mortalidad , Hidroxilaminas/uso terapéutico , Hidroxilaminas/administración & dosificación , Recurrencia Local de Neoplasia/tratamiento farmacológico , Recurrencia Local de Neoplasia/patología , Pronóstico , Temozolomida/uso terapéutico , Temozolomida/administración & dosificaciónRESUMEN
OBJECTIVE: To investigate the incidence of corticotroph hyperplasia (CH) or lymphocyte infiltration in the pituitary of patients with obesity. METHODS: The pituitary and adrenal glands from 161 adult autopsies performed between 2010 and 2019 at our institution were reviewed. The clinical history, body mass index (BMI), and cause of death were recorded. Routine hematoxylin and eosin staining, reticulin staining, and immunohistochemical staining for adrenocorticotropic hormone, CD3, and CD20 were performed. The results were analyzed using the Fisher and chi-square statistics. Decedents were separated into 4 groups based on BMI (kg/m2): (1) lean (BMI, <25.0), (2) overweight (BMI, 25.0-29.9), (3) obesity class I (BMI, 30.0-34.9), and (4) obesity classes II to III (BMI, >34.9). RESULTS: CH/neoplasia was identified in 44 of 161 pituitary glands. Four (9.1%) of 53 lean patients had pituitary lesions, whereas 27.3% (12) of overweight, 22.7% (10) of obesity class I, and 40.9% (18) of obesity class II patients had hyperplasia (P < .0001). Small corticotroph tumors were identified in 15 patients; only 1 was a lean patient, and the tumor was associated with the Crooke hyaline change of nontumorous corticotrophs. The presence of CH and neoplasia was associated with adrenal cortical hyperplasia and lipid depletion. Microscopic foci of T and B lymphocytes were identified in the pituitaries of patients in each weight category; no independent association between BMI and lymphocyte inflammation was found. CONCLUSION: Our data indicate an association between CH/neoplasia and obesity. It remains unclear whether obesity is the cause or effect of adrenocorticotropic hormone and cortisol excess.
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Obesidad Mórbida , Enfermedades de la Hipófisis , Neoplasias Hipofisarias , Adulto , Humanos , Corticotrofos/metabolismo , Corticotrofos/patología , Obesidad Mórbida/patología , Hiperplasia/patología , Sobrepeso/complicaciones , Sobrepeso/epidemiología , Hipófisis/patología , Hormona Adrenocorticotrópica/metabolismo , Enfermedades de la Hipófisis/complicaciones , Enfermedades de la Hipófisis/epidemiología , Neoplasias Hipofisarias/complicaciones , Neoplasias Hipofisarias/epidemiología , Neoplasias Hipofisarias/patología , Obesidad/complicaciones , Obesidad/epidemiologíaRESUMEN
Molecular subtypes of medulloblastoma [Sonic Hedgehog (SHH), Wingless/INT (WNT), Group 3, and Group 4] are defined by common patterns of gene expression. These differential gene expression patterns appear to result in different histomorphology and prognosis. Quantitative histomorphometry is a well-known method of computer-aided pathology image analysis. The hypotheses we sought to examine in this preliminary proof of concept study were whether computer extracted nuclear morphological features of medulloblastomas from digitized tissue slide images could independently: (1) distinguish between molecularly determined subgroups and (2) identify patterns within these subgroups that correspond with clinical outcome. Our dataset was composed of 46 medulloblastoma patients: 16 SHH (5 dead, 11 survived), 3 WNT (0 dead, 3 survived), 12 Group 3 (4 dead, 8 survived), and 15 were Group 4 (5 dead, 10 survived). A watershed-based thresholding scheme was used to automatically identify individual nuclei within digitized whole slide hematoxylin and eosin tissue images. Quantitative histomorphometric features corresponding to the texture (variation in pixel intensity), shape (variations in size, roundness), and architectural rearrangement (distances between, and number of connected neighbors) of nuclei were subsequently extracted. These features were ranked using feature selection schemes and these top-ranked features were then used to train machine-learning classifiers via threefold cross-validation to separate patients based on: (1) molecular subtype and (2) disease-specific outcomes within the individual molecular subtype groups. SHH and WNT tumors were separated from Groups 3 and 4 tumors with a maximum area under the receiver operating characteristic curve (AUC) of 0.7, survival within Group 3 tumors was predicted with an AUC of 0.92, and Group 3 and 4 patients were separated into high- and low-risk groups with p = 0.002. Model prediction was quantitatively compared with age, stage, and histological subtype using univariate and multivariate Cox hazard ratio models. Age was the most statistically significant variable for predicting survival in Group 3 and 4 tumors, but model predictions had the highest hazard ratio value. Quantitative nuclear histomorphometry can be used to study medulloblastoma genetic expression phenotypes as it may distinguish meaningful features of disease pathology.
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Infiltrating gliomas comprise the most common group of primary intraparenchymal brain tumors and present a level of complexity which requires careful integration of histopathology and molecular diagnostics for optimal therapy. To this end, the fourth edition of the World Health Organization (WHO) Classification of Tumors of the Central Nervous System (CNS) has been followed by a series of publications by cIMPACT-NOW (the Consortium to Inform Molecular and Practical Approaches to CNS Tumor Taxonomy) incorporating molecular signatures to propose updated diagnostic categories in anticipation of the upcoming fifth edition of CNS tumor classification. Integration of histopathology, immunophenotyping, and molecular findings is profoundly changing the practice of diagnostic surgical neuropathology and enabling a more personalized approach to treating patients with gliomas.
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Neoplasias Encefálicas , Neoplasias del Sistema Nervioso Central , Glioma , Adulto , Neoplasias Encefálicas/diagnóstico , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/terapia , Sistema Nervioso Central , Glioma/diagnóstico , Glioma/genética , Glioma/terapia , Humanos , NeuropatologíaRESUMEN
OBJECTIVES: Although glioblastoma (GBM) is rare in the pediatric population, it is the most common cause of death among children with central nervous system neoplasms. Recent molecular profiling of these neoplasms has demonstrated distinct differences in comparison to their adult counterparts. Moreover, many pediatric GBMs occur within the context of cancer predisposition syndromes, such as constitutional mismatch repair deficiency syndrome (CMMRD). Children with CMMRD who develop GBM exhibit a high tumor mutational burden and may benefit from treatment with immune checkpoint inhibitors. METHODS: We performed next-generation sequencing and immunohistochemistry for mismatch repair proteins in our cohort of pediatric and adult GBMs to further characterize the molecular profiles of these groups. RESULTS: We examined a total of 11 pediatric and 11 adult GBMs. Pediatric patients had a higher number of alterations compared to their adult counterparts. They also had a higher frequency of alterations in the mismatch repair genes, which can be detected by immunohistochemistry (IHC). We also identified one pediatric patient with CMMRD syndrome. CONCLUSIONS: Our study highlighted the distinct molecular differences between pediatric and adult GBM. We also demonstrated that pediatric patients have a higher frequency of alterations in the mismatch repair genes, which may render them susceptible to treatment with immune checkpoint inhibitors. These alterations can be detected using routine IHC and should be performed on all pediatric GBM.
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Biomarcadores de Tumor/análisis , Neoplasias Encefálicas/genética , Reparación de la Incompatibilidad de ADN/genética , Perfilación de la Expresión Génica/métodos , Glioblastoma/genética , Adolescente , Adulto , Neoplasias Encefálicas/diagnóstico , Niño , Preescolar , Neoplasias Colorrectales/diagnóstico , Neoplasias Colorrectales/genética , Femenino , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Humanos , Inmunohistoquímica , Masculino , Persona de Mediana Edad , Síndromes Neoplásicos Hereditarios/diagnóstico , Síndromes Neoplásicos Hereditarios/genética , Análisis de Secuencia de ADN/métodos , Transcriptoma , Adulto JovenRESUMEN
BACKGROUND: Improving the care of patients with glioblastoma (GB) requires accurate and reliable predictors of patient prognosis. Unfortunately, while protein markers are an effective readout of cellular function, proteomics has been underutilized in GB prognostic marker discovery. METHODS: For this study, GB patients were prospectively recruited and proteomics discovery using liquid chromatography-mass spectrometry analysis (LC-MS/MS) was performed for 27 patients including 13 short-term survivors (STS) (≤10 months) and 14 long-term survivors (LTS) (≥18 months). RESULTS: Proteomics discovery identified 11 941 peptides in 2495 unique proteins, with 469 proteins exhibiting significant dysregulation when comparing STS to LTS. We verified the differential abundance of 67 out of these 469 proteins in a small previously published independent dataset. Proteins involved in axon guidance were upregulated in STS compared to LTS, while those involved in p53 signaling were upregulated in LTS. We also assessed the correlation between LS MS/MS data with RNAseq data from the same discovery patients and found a low correlation between protein abundance and mRNA expression. Finally, using LC-MS/MS on a set of 18 samples from 6 patients, we quantified the intratumoral heterogeneity of more than 2256 proteins in the multisample dataset. CONCLUSIONS: These proteomic datasets and noted protein variations present a beneficial resource for better predicting patient outcome and investigating potential therapeutic targets.
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Neoplasias del Oído/diagnóstico , Células Endoteliales/patología , Tumor del Glomo Yugular/diagnóstico , Tumor del Glomo Timpánico/diagnóstico , Paraganglioma/diagnóstico , Adulto , Recuento de Células , Muerte Celular , Progresión de la Enfermedad , Neoplasias del Oído/metabolismo , Neoplasias del Oído/patología , Células Endoteliales/metabolismo , Células Endoteliales/fisiología , Tumor del Glomo Yugular/metabolismo , Tumor del Glomo Yugular/patología , Tumor del Glomo Timpánico/metabolismo , Tumor del Glomo Timpánico/patología , Humanos , Inmunohistoquímica , Imagen por Resonancia Magnética , Masculino , Recurrencia Local de Neoplasia/diagnóstico , Recurrencia Local de Neoplasia/metabolismo , Recurrencia Local de Neoplasia/patología , Degeneración Nerviosa , Paraganglioma/metabolismo , Paraganglioma/patología , Adulto JovenRESUMEN
Sclerosing polycystic adenosis (SPA) is a rare benign salivary gland lesion that usually arises from the parotid gland. SPA was originally interpreted to be a non-neoplastic alteration analogous to fibrocystic changes of the breast, but now there is uncertainty about whether it may represent a neoplasm. SPA often contains intraductal proliferations with an appearance similar to ductal neoplasia of the breast, and one study reported X-chromosome inactivation using polymorphisms of the human androgen receptor (Skalova et al., in AJSP 30:939-944, 2006). We investigated the genetics of SPA through targeted next generation sequencing (NGS). Four cases of SPA were retrieved from the authors' consultation files. A custom, targeted NGS panel including 1425 cancer-related genes was performed on all cases, followed by immunohistochemistry for PTEN. All four cases developed in females, ranging from 40 to 69 years (mean 52.5 years), affecting the parotid (n = 3) and submandibular glands (n = 1). All cases exhibited characteristic histologic features of SPA: well-circumscribed lesions with fibrosis and an admixture of ducts, myoepithelial cells and acinar cells, the latter containing brightly eosinophilic intracytoplasmic granules. Two cases had intraductal apocrine epithelial proliferations. By targeted NGS, loss-of-function mutations in PTEN were revealed in all 4 cases. In addition, 2 of 4 cases harbored PIK3CA mutations and 2 of 4 possessed PIK3R1 alterations; one case lacked both PIK3CA and PIK3R1 mutations. PTEN expression by immunohistochemistry was lost in the ductal and acinar elements but not the myoepithelial cells in all cases. SPA is characterized by genetic alterations in the PI3K pathway, with PTEN mutations seen most frequently. This molecular profile is similar to salivary duct carcinoma and the apocrine variant of intraductal carcinoma (i.e., salivary duct carcinoma-in situ). PI3K pathway alterations were found in cases both with and without intraductal apocrine proliferations, and PTEN immunohistochemistry suggested that the ductal and acinar cells, but not myoepithelial cells, were affected. Taken together, these findings strongly support that SPA is a neoplasm, more correctly named "sclerosing polycystic adenoma." The salivary duct carcinoma-like genetic alterations, coupled with the fact that the surrounding myoepithelial cells appear to be non-neoplastic, suggest a close relationship between SPA and apocrine intraductal carcinoma.
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Adenoma/patología , Fosfatidilinositol 3-Quinasas/genética , Neoplasias de las Glándulas Salivales/patología , Adenoma/genética , Adulto , Anciano , Femenino , Humanos , Persona de Mediana Edad , Mutación , Fosfohidrolasa PTEN/genética , Neoplasias de las Glándulas Salivales/genética , Transducción de Señal/fisiologíaRESUMEN
Glioma is recognized to be a highly heterogeneous CNS malignancy, whose diverse cellular composition and cellular interactions have not been well characterized. To gain new clinical- and biological-insights into the genetically-bifurcated IDH1 mutant (mt) vs wildtype (wt) forms of glioma, we integrated data from protein, genomic and MR imaging from 20 treatment-naïve glioma cases and 16 recurrent GBM cases. Multiplexed immunofluorescence (MxIF) was used to generate single cell data for 43 protein markers representing all cancer hallmarks, Genomic sequencing (exome and RNA (normal and tumor) and magnetic resonance imaging (MRI) quantitative features (protocols were T1-post, FLAIR and ADC) from whole tumor, peritumoral edema and enhancing core vs equivalent normal region were also collected from patients. Based on MxIF analysis, 85,767 cells (glioma cases) and 56,304 cells (GBM cases) were used to generate cell-level data for 24 biomarkers. K-means clustering was used to generate 7 distinct groups of cells with divergent biomarker profiles and deconvolution was used to assign RNA data into three classes. Spatial and molecular heterogeneity metrics were generated for the cell data. All features were compared between IDH mt and IDHwt patients and were finally combined to provide a holistic/integrated comparison. Protein expression by hallmark was generally lower in the IDHmt vs wt patients. Molecular and spatial heterogeneity scores for angiogenesis and cell invasion also differed between IDHmt and wt gliomas irrespective of prior treatment and tumor grade; these differences also persisted in the MR imaging features of peritumoral edema and contrast enhancement volumes. A coherent picture of enhanced angiogenesis in IDHwt tumors was derived from multiple platforms (genomic, proteomic and imaging) and scales from individual proteins to cell clusters and heterogeneity, as well as bulk tumor RNA and imaging features. Longer overall survival for IDH1mt glioma patients may reflect mutation-driven alterations in cellular, molecular, and spatial heterogeneity which manifest in discernable radiological manifestations.
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Glioma/genética , Isocitrato Deshidrogenasa/genética , Adulto , Anciano , Biomarcadores de Tumor/genética , Neoplasias Encefálicas/patología , Estudios de Casos y Controles , Femenino , Técnica del Anticuerpo Fluorescente/métodos , Heterogeneidad Genética , Humanos , Isocitrato Deshidrogenasa/metabolismo , Imagen por Resonancia Magnética/métodos , Masculino , Persona de Mediana Edad , Mutación , Clasificación del Tumor , Proteómica , Análisis de Secuencia de ARN/métodos , Análisis de la Célula Individual , Secuenciación del Exoma/métodosRESUMEN
An integrated approach has been adopted by the World Health Organization (WHO) for diagnosing brain tumors. This approach relies on the molecular characterization of biopsied tissue in conjunction with standard histology. Diffuse gliomas (grade II to grade IV malignant brain tumors) have a wide range in overall survival, from months for the worst cases of glioblastoma (GBM) to years for lower grade astrocytic and oligodendroglial tumors. We previously identified a change in the cell adhesion molecule PTPmu in brain tumors that results in the generation of proteolytic fragments. We developed agents to detect this cell surface-associated biomarker of the tumor microenvironment. In the current study, we evaluated the PTPmu biomarker in tissue microarrays and individual tumor samples of adolescent and young adult (n = 25) and adult (n = 69) glioma populations using a fluorescent histochemical reagent, SBK4-TR, that recognizes the PTPmu biomarker. We correlated staining with clinical data and found that high levels of the PTPmu biomarker correlate with increased survival of glioma patients, including those with GBM. Patients with high PTPmu live for 48 months on average, whereas PTPmu low patients live only 22 months. PTPmu high staining indicates a doubling of patient survival. Use of the agent to detect the PTPmu biomarker would allow differentiation of glioma patients with distinct survival outcomes and would complement current molecular approaches used in glioma prognosis.
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Biomarcadores de Tumor/metabolismo , Neoplasias Encefálicas/metabolismo , Glioma/metabolismo , Proteínas Tirosina Fosfatasas Clase 2 Similares a Receptores/metabolismo , Adolescente , Adulto , Neoplasias Encefálicas/patología , Femenino , Glioma/patología , Humanos , Masculino , Pronóstico , Microambiente TumoralRESUMEN
Astroblastoma (AB) is a rare CNS tumor demonstrating abundant astroblastomatous pseudorosettes. Its molecular features have not been comprehensively studied and its status as a tumor entity is controversial. We analyzed a cohort of 27 histologically-defined ABs using DNA methylation profiling, copy number analysis, FISH and site-directed sequencing. Most cases demonstrated mutually exclusive MN1 rearrangements (n = 10) or BRAFV600E mutations (n = 7). Two additional cases harbored RELA rearrangements. Other cases lacked these specific genetic alterations (n = 8). By DNA methylation profiling, tumors with MN1 or RELA rearrangement clustered with high-grade neuroepithelial tumor with MN1 alteration (HGNET-MN1) and RELA-fusion ependymoma, respectively. In contrast, BRAFV600E-mutant tumors grouped with pleomorphic xanthoastrocytoma (PXA). Six additional tumors clustered with either supratentorial pilocytic astrocytoma and ganglioglioma (LGG-PA/GG-ST), normal or reactive cerebrum, or with no defined DNA methylation class. While certain histologic features favored one genetic group over another, no group could be reliably distinguished by histopathology alone. Survival analysis between genetic AB subtypes was limited by sample size, but showed that MN1-rearranged AB tumors were characterized by better overall survival compared to other genetic subtypes, in fact, significantly better than BRAFV600E-mutant tumors (P = 0.013). Our data confirm that histologically-defined ABs are molecularly heterogeneous and do not represent a single entity. They rather encompass several low- to higher-grade glial tumors including neuroepithelial tumors with MN1 rearrangement, PXA-like tumors, RELA ependymomas, and possibly yet uncharacterized lesions. Genetic subtyping of tumors exhibiting AB histology, particularly determination of MN1 and BRAFV600E status, is necessary for important prognostic and possible treatment implications.
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Neoplasias Encefálicas/genética , Reordenamiento Génico/genética , Genómica/métodos , Neoplasias Neuroepiteliales/genética , Proteínas Proto-Oncogénicas B-raf/genética , Transactivadores/genética , Proteínas Supresoras de Tumor/genética , Adolescente , Adulto , Anciano , Neoplasias Encefálicas/mortalidad , Neoplasias Encefálicas/patología , Niño , Preescolar , Estudios de Cohortes , Femenino , Humanos , Masculino , Persona de Mediana Edad , Neoplasias Neuroepiteliales/mortalidad , Neoplasias Neuroepiteliales/patología , Pronóstico , Tasa de Supervivencia/tendencias , Adulto JovenAsunto(s)
Neoplasias del Sistema Nervioso Central , Linfoma de Células B Grandes Difuso , Anciano , Neoplasias del Sistema Nervioso Central/diagnóstico por imagen , Neoplasias del Sistema Nervioso Central/terapia , Femenino , Humanos , Linfoma de Células B Grandes Difuso/diagnóstico por imagen , Linfoma de Células B Grandes Difuso/terapia , Masculino , Persona de Mediana Edad , Neoplasias Primarias Secundarias/diagnóstico por imagen , Neoplasias Primarias Secundarias/terapia , Estudios RetrospectivosRESUMEN
Background: The Cooperative Human Tissue Network, Midwestern Division, is a National Cancer Institute-funded program that provides quality research biospecimens to qualified investigators. Consented human tissues are procured according to researcher specifications for weight (size) and preservation type; weights of samples in significant demand and limited supply are negotiated. Weights of procured tissues are entered into a dedicated biospecimen database. This study seeks to provide guidance for acceptable tissue weights for researchers. Methods: Tissue weights by year and anatomic site were retrieved from the database for primary malignant tissues. The total number of tissues included was 5141. Statistical evaluation of data included the number of tissues for each year, anatomic site as well as minimum, maximum, average weights, standard deviation, and standard error. Anatomic sites with few tissues were excluded. Results: "Stock price" type graphs were constructed to show an average as "volume" with both full weight ranges and range that accommodated 80% of tissues. Average weight and number of sample trends varied by anatomic site. Tissues fell into four weight groups; 10 and 90 percentile boundaries were calculated for each. Smallest average research tissue weights for middle 80% were recorded for prostate and oropharynx (140 mg). Second weight group included tonsil, thyroid, breast, oral cavity, larynx, pancreas, salivary gland, skin, tongue, lung, and parotid (265 mg). The third group included stomach, cervix, colon, esophagus, endometrium, bone, brain, bladder, small bowel, uterus, liver, kidney lymph node, adrenal, and ovary (513 mg). The fourth and heaviest weight group included soft tissue tumors and spleen (1201 mg). Conclusions: Since tissue weights are not usually included in recommendations for research tissue procurement or for frozen tissues stored in biorepositories, we offer this data as a practical guide to researcher acceptable tissue weights for selected sites based on a 3-year researcher request and acceptance history.
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Bancos de Tejidos , Obtención de Tejidos y Órganos/métodos , Femenino , Humanos , Masculino , Tamaño de los Órganos , Bancos de Tejidos/normas , Bancos de Tejidos/provisión & distribución , Obtención de Tejidos y Órganos/normas , Estados UnidosRESUMEN
BACKGROUND: Astroblastomas (ABs) are rare glial tumors showing overlapping features with astrocytomas, ependymomas, and sometimes other glial neoplasms, and may be challenging to diagnose. METHODS: We examined clinical, histopathological, and molecular features in 28 archival formalin-fixed, paraffin-embedded AB cases and performed survival analyses using Cox proportional hazards and Kaplan-Meier methods. RESULTS: Unlike ependymomas and angiocentric gliomas, ABs demonstrate abundant distinctive astroblastic pseudorosettes and are usually Olig2 immunopositive. They also frequently exhibit rhabdoid cells, multinucleated cells, and eosinophilic granular material. They retain immunoreactivity to alpha thalassemia/mental retardation syndrome X-linked, are immunonegative to isocitrate dehydrogenase-1 R132H mutation, and only occasionally show MGMT promoter hypermethylation differentiating them from many diffuse gliomas. Like pleomorphic xanthoastrocytoma, ganglioglioma, supratentorial pilocytic astrocytoma, and other predominantly cortical-based glial tumors, ABs often harbor the BRAFV600E mutation, present in 38% of cases tested (n = 21), further distinguishing those tumors from ependymomas and angiocentric gliomas. Factors correlating with longer patient survival included age less than 30 years, female gender, absent BRAFV600E , and mitotic index less than 5 mitoses/10 high-power fields; however, only the latter was significant by Cox and Kaplan-Meier analyses (n = 24; P = .024 and .012, respectively). This mitotic cutoff is therefore currently the best criterion to stratify tumors into low-grade ABs and higher-grade anaplastic ABs. CONCLUSIONS: In addition to their own characteristic histological features, ABs share some molecular and histological findings with other, possibly ontologically related, cortical-based gliomas of mostly children and young adults. Importantly, the presence of BRAFV600E mutations in a subset of ABs suggests potential clinical utility of targeted anti-BRAF therapy.
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Biomarcadores de Tumor/genética , Neoplasias Encefálicas/patología , Corteza Cerebral/patología , Mutación/genética , Neoplasias Neuroepiteliales/patología , Proteínas Proto-Oncogénicas B-raf/genética , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Neoplasias Encefálicas/genética , Corteza Cerebral/metabolismo , Niño , Preescolar , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Clasificación del Tumor , Neoplasias Neuroepiteliales/genética , Pronóstico , Tasa de Supervivencia , Adulto JovenRESUMEN
The growth of precision medicine has made access to biobanks with high-quality, well-annotated neuro-oncology biospecimens critical. Developing and maintaining neuro-oncology biobanks is best accomplished through multidisciplinary collaboration between clinicians and researchers. Balancing the needs and leveraging the skills of all stakeholders in this multidisciplinary effort is of utmost importance. Collaboration with a multidisciplinary team of clinicians, health care team members, and institutions, as well as patients and their families, is essential for access to participants in order to obtain informed consent, collect samples under strict standard operating procedures, and accurate and relevant clinical annotation. Once a neuro-oncology biobank is established, development and implementation of policies related to governance and distribution of biospecimens (both within and outside the institution) is of critical importance for sustainability. Proper implementation of a governance process helps to ensure that the biospecimens and data can be utilized in research with the largest potential benefit. New NIH and peer-reviewed journal policies related to public sharing of 'omic' data generated from stored biospecimens create new ethical challenges that must be addressed in developing informed consents, protocols, and standard operating procedures. In addition, diversification of sources of funding for the biobanks is needed for long-term sustainability.
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Temporal arteritis peaks during the eighth decade, affecting patients with frequent comorbidities who are especially prone to adverse effects of corticosteroid therapy. Perivascular inflammation involving small periadventitial vessels is not uncommon in otherwise normal temporal artery biopsies (TABs). As ischemic events occur in patients with non-temporal artery--based inflammation, it has been recommended that any vascular inflammation within TABs be treated with corticosteroids. We sought to determine whether such patients are at increased risk for temporal arteritis-like adverse events compared with age-matched controls devoid of inflammatory infiltrates. TABs without transmural temporal arteritic damage accessioned between 2002 and 2012 were reviewed for inflammation (>15 perivascular lymphocytes) involving small blood vessels and/or temporal artery adventitia. Of 343 TABs, 278 (81%) were negative for transmural arteritis. Inflammation involving small vessels and/or temporal artery adventitia was present in 56 cases (20%). Age-matched controls were available for 39 cases. With a mean follow-up of 5 years (range, 1-11 years), 6/39 (15%) of patients developed stroke or cardiovascular events or died compared with 7/39 (18%) of age-matched controls. None of the patients with study-positive TAB had documented steroid therapy before or after TAB. Our results demonstrate that patients with inflammation involving only small vessels or temporal artery adventitia are not at increased risk for temporal arteritis-like adverse events, and suggest that the risks of protracted corticosteroid therapy in this elderly population likely exceed any potential benefits. We advise against diagnosing vasculitis in the absence of temporal arteritic damage.
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Arteritis de Células Gigantes/patología , Inflamación/patología , Arterias Temporales/patología , Corticoesteroides/efectos adversos , Adventicia/patología , Anciano , Anciano de 80 o más Años , Biopsia , Estudios de Casos y Controles , Reacciones Falso Positivas , Femenino , Arteritis de Células Gigantes/tratamiento farmacológico , Humanos , Inflamación/tratamiento farmacológico , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Pronóstico , Factores de Riesgo , Arterias Temporales/efectos de los fármacos , Factores de TiempoRESUMEN
Many cancers feature cellular hierarchies that are driven by tumor-initiating cancer stem cells (CSC) and rely on complex interactions with the tumor microenvironment. Standard cell culture conditions fail to recapitulate the original tumor architecture or microenvironmental gradients and are not designed to retain the cellular heterogeneity of parental tumors. Here, we describe a three-dimensional culture system that supports the long-term growth and expansion of tumor organoids derived directly from glioblastoma specimens, including patient-derived primary cultures, xenografts, genetically engineered glioma models, or patient samples. Organoids derived from multiple regions of patient tumors retain selective tumorigenic potential. Furthermore, organoids could be established directly from brain metastases not typically amenable to in vitro culture. Once formed, tumor organoids grew for months and displayed regional heterogeneity with a rapidly dividing outer region of SOX2(+), OLIG2(+), and TLX(+) cells surrounding a hypoxic core of primarily non-stem senescent cells and diffuse, quiescent CSCs. Notably, non-stem cells within organoids were sensitive to radiotherapy, whereas adjacent CSCs were radioresistant. Orthotopic transplantation of patient-derived organoids resulted in tumors displaying histologic features, including single-cell invasiveness, that were more representative of the parental tumor compared with those formed from patient-derived sphere cultures. In conclusion, we present a new ex vivo model in which phenotypically diverse stem and non-stem glioblastoma cell populations can be simultaneously cultured to explore new facets of microenvironmental influences and CSC biology. Cancer Res; 76(8); 2465-77. ©2016 AACR.
Asunto(s)
Neoplasias Encefálicas/patología , Hipoxia de la Célula , Glioblastoma/patología , Células Madre Neoplásicas/patología , Organoides/patología , Animales , Xenoinjertos , Humanos , RatonesRESUMEN
MRI-negative anterior cingulate epilepsy is a rare entity. Herein, we describe a case of MRI and functional imaging-negative intractable frontal lobe epilepsy in which, initially, secondary bilateral synchrony of surface and intracranial EEG and non-lateralizing semiology rendered identification of the epileptogenic zone difficult. A staged bilateral stereotactic EEG exploration revealed a very focal, putative ictal onset zone in the right anterior cingulate gyrus, as evidenced by interictal and ictal high-frequency oscillations (at 250Hz) and induction of seizures from the same electrode contacts by 50-Hz low-intensity cortical stimulation. This was subsequently confirmed by ILAE class 1 outcome following resection of the ictal onset and irritative zones. Histopathological examination revealed focal cortical dysplasia type 1b (ILAE Commission, 2011) as the cause of epilepsy. The importance of anatomo-electro-clinical correlation is illustrated in this case in which semiological and electrophysiological features pointed to the anatomical localization of a challenging, MRI-negative epilepsy.