RESUMO
INTRODUCTION: Recent studies have identified that glioblastoma IDH-wildtype consists of different molecular subgroups with distinct prognoses. In order to accurately describe and classify gliomas, the Visually AcceSAble Rembrandt Images (VASARI) system was developed. The goal of this study was to evaluate the VASARI characteristics in molecular subgroups of IDH-wildtype glioblastoma. METHODS: A retrospective analysis of glioblastoma IDH- wildtype with comprehensive next-generation sequencing and pre-operative and post-operative MRI was performed. VASARI characteristics and 205 genes were evaluated. Multiple comparison adjustment by the Bejamin-Hochberg false discovery rate (BH-FDR) was performed. A 1:3 propensity score match (PSM) with a Caliper of 0.2 was done. RESULTS: 178 patients with GBM IDH-WT met the inclusion criteria. 4q12 amplified patients (n = 20) were associated with cyst presence (30% vs. 12%, p = 0.042), decreased hemorrhage (35% vs. 62%, p = 0.028), and non-restricting/mixed (35%/60%) rather than restricting diffusion pattern (5%), meanwhile, 4q12 non-amplified patients had mostly restricting (47.4%) rather than a non-restricting/mixed diffusion pattern (28.4%/23.4%). This remained statistically significant after BH-FDR adjustment (p = 0.002). PSM by 4q12 amplification showed that diffusion characteristics continued to be significantly different. Among RB1-mutant patients, 96% had well-defined enhancing margins vs. 70.6% of RB1-WT (p = 0.018), however, this was not significant after BH-FDR or PSM. CONCLUSIONS: Patients with glioblastoma IDH-wildtype harboring 4q12 amplification rarely have restricting DWI patterns compared to their wildtype counterparts, in which this DWI pattern is present in ~ 50% of patients. This suggests that some phenotypic imaging characteristics can be identified among molecular subtypes of IDH-wildtype glioblastoma.
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Neoplasias Encefálicas , Glioblastoma , Glioma , Humanos , Glioblastoma/diagnóstico por imagem , Glioblastoma/genética , Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/genética , Estudos Retrospectivos , Glioma/genética , Prognóstico , Isocitrato Desidrogenase/genética , Mutação , Ubiquitina-Proteína Ligases/genética , Proteínas de Ligação a Retinoblastoma/genéticaRESUMO
PURPOSE: Genomic alterations are fundamental for molecular-guided therapy in patients with breast and lung cancer. However, the turn-around time of standard next-generation sequencing assays is a limiting factor in the timely delivery of genomic information for clinical decision-making. METHODS: In this study, we evaluated genomic alterations in 54 cerebrospinal fluid samples from 33 patients with metastatic lung cancer and metastatic breast cancer to the brain using the Oncomine Precision Assay on the Genexus sequencer. There were nine patients with samples collected at multiple time points. RESULTS: Cell-free total nucleic acids (cfTNA) were extracted from CSF (0.1-11.2 ng/µl). Median base coverage was 31,963× with cfDNA input ranging from 2 to 20 ng. Mutations were detected in 30/54 CSF samples. Nineteen (19/24) samples with no mutations detected had suboptimal DNA input (< 20 ng). The EGFR exon-19 deletion and PIK3CA mutations were detected in two patients with increasing mutant allele fraction over time, highlighting the potential of CSF-cfTNA analysis for monitoring patients. Moreover, the EGFR T790M mutation was detected in one patient with prior EGFR inhibitor treatment. Additionally, ESR1 D538G and ESR1::CCDC170 alterations, associated with endocrine therapy resistance, were detected in 2 mBC patients. The average TAT from cfTNA-to-results was < 24 h. CONCLUSION: In summary, our results indicate that CSF-cfTNA analysis with the Genexus-OPA can provide clinically relevant information in patients with brain metastases with short TAT.
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Ácidos Nucleicos Livres , Neoplasias Pulmonares , Humanos , Neoplasias Pulmonares/patologia , Ácidos Nucleicos Livres/líquido cefalorraquidiano , Mutação , Receptores ErbB/genética , Inibidores de Proteínas QuinasesRESUMO
Recurrent and anaplastic pleomorphic xanthoastrocytoma (r&aPXA) is a rare primary brain tumor that is challenging to treat. Two-thirds of PXA tumors harbor a BRAF gene mutation. BRAF inhibitors have been shown to improve tumor control. However, resistance to BRAF inhibition develops in most cases. Concurrent therapy with MEK inhibitors may improve tumor control and patient survival. In this study, we identified 5 patients diagnosed with BRAF-mutated PXA who received BRAF and MEK inhibitors over a 10-year interval at our institution. Patient records were evaluated, including treatments, adverse effects (AEs), outcomes, pathology, next-generation sequencing, and MRI. The median age was 22 years (range, 14-66 years), 60% male, and 60% anaplastic PXA. Median overall survival was 72 months (range, 19-112 months); 1 patient died of tumor-related hemorrhage while off therapy, and the other 4 experienced long-term disease control (21, 72, 98, and 112 months, respectively). Dual BRAF/MEK inhibitors were well tolerated, with only grade 1-2 AEs, including rash, neutropenia, fatigue, abdominal discomfort, and diarrhea. No grade 3-5 AEs were detected. A literature review was also performed of patients diagnosed with BRAF-mutated PXA and treated with BRAF and/or MEK inhibitors through August 2021, with a total of 32 cases identified. The median age was 29 years (range, 8-57 years) and the median PFS and OS were 8.5 months (range, 2-35 months) and 35 months (range, 10-80 months), respectively. The most common AEs were grade 1-2 fatigue and skin rash. Results of this case series and literature review indicate that dual-drug therapy with BRAF and MEK inhibitors for r&aPXA with BRAF V600E mutation may delay tumor progression without unexpected AEs.
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Astrocitoma , Neoplasias Encefálicas , Adulto , Feminino , Humanos , Masculino , Adulto Jovem , Astrocitoma/tratamento farmacológico , Astrocitoma/genética , Neoplasias Encefálicas/patologia , Fadiga , Quinases de Proteína Quinase Ativadas por Mitógeno/genética , Quinases de Proteína Quinase Ativadas por Mitógeno/uso terapêutico , Mutação , Recidiva Local de Neoplasia , Inibidores de Proteínas Quinases/efeitos adversos , Proteínas Proto-Oncogênicas B-raf/genética , Adolescente , Pessoa de Meia-Idade , IdosoRESUMO
INTRODUCTION: Recurrent glioblastoma (rGBM) prognosis is dismal. In the absence of effective adjuvant treatments for rGBM, re-resections remain prominent in our arsenal. This study evaluates the impact of reoperation on post-progression survival (PPS) considering rGBM genetic makeup. METHODS: To assess the genetic heterogeneity and treatment-related changes (TRC) roles in re-operated or medically managed rGBMs, we compiled demographic, clinical, histopathological, and next-generation genetic sequencing (NGS) characteristics of these tumors from 01/2005 to 10/2019. Survival data and reoperation were analyzed using conventional and random survival forest analysis (RSF). RESULTS: Patients harboring CDKN2A/B loss (p = 0.017) and KDR mutations (p = 0.031) had notably shorter survival. Reoperation or bevacizumab were associated with longer PPS (11.2 vs. 7.4-months, p = 0.006; 13.1 vs 6.2, p < 0.001). Reoperated patients were younger, had better performance status and greater initial resection. In 136/273 (49%) rGBMs undergoing re-operation, CDKN2A/B loss (p = 0.03) and KDR mutations (p = 0.02) were associated with shorter survival. In IDH-WT rGBMs with NGS data (n = 166), reoperation resulted in 7.0-month longer survival (p = 0.004) than those managed medically. This reoperation benefit was independently identified by RSF analysis. Stratification analysis revealed that EGFR-mutant, CDKN2A/B-mutant, NF1-WT, and TP53-WT rGBM IDH-WT subgroups benefit most from reoperation (p = 0.03). Lastly, whether or not TRC was prominent at re-operation does not have any significant impact on PPS (10.5 vs. 11.5-months, p = 0.77). CONCLUSIONS: Maximal safe re-resection significantly lengthens PPS regardless of genetic makeup, but reoperations are especially beneficial for IDH-WT rGBMs with EGFR and CDKN2A/B mutations with TP53-WT, and NF1-WT. Histopathology at recurrence may be an imperfect gauge of disease severity at progression and the imaging progression may be more reflective of the prognosis.
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Neoplasias Encefálicas , Glioblastoma , Recidiva Local de Neoplasia , Reoperação , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/cirurgia , Receptores ErbB/genética , Variação Genética , Glioblastoma/genética , Glioblastoma/patologia , Glioblastoma/cirurgia , Humanos , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/cirurgia , Prognóstico , Análise de SobrevidaRESUMO
INTRODUCTION: We aimed to evaluate IDH1 p.R132H mutation and 2-hydroxyglutarate (2HG) in cerebrospinal fluid (CSF) as biomarkers for patients with IDH-mutant gliomas. METHODS: CSF was collected from patients with infiltrating glioma, and 2HG levels were measured by liquid chromatography-mass spectrometry. IDH1 p.R132H mutant allele frequency (MAF) in CSF-ctDNA was measured by digital droplet PCR (ddPCR). Tumor volume was measured from standard-of-care magnetic resonance images. RESULTS: The study included 48 patients, 6 with IDH-mutant and 42 with IDH-wildtype gliomas, and 57 samples, 9 from the patients with IDH-mutant and 48 from the patients with IDH-wildtype gliomas. ctDNA was detected in 7 of the 9 samples from patients with IDH-mutant glioma, and IDH1 p.R132H mutation was detected in 5 of the 7 samples. The MAF ranged from 0.3 to 39.95%. Total 2HG level, D-2HG level, and D/L-2HG ratio in CSF were significantly higher in patients with IDH-mutant gliomas than in patients with IDH-wildtype gliomas. D-2HG level and D/L-2HG ratio correlated with total tumor volume in patients with IDH-mutant gliomas but not in patients with IDH-wildtype gliomas. CONCLUSION: Our results suggest that detection of IDH1 p.R132H mutation by ddPCR and increased D-2HG level in CSF may help identify IDH-mutant gliomas. Our results also suggest that D-2HG level and D/L-2HG ratio correlate with tumor volume in patients with IDH-mutant gliomas. Further prospective studies with larger cohorts are needed to validate these findings.
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DNA Tumoral Circulante , Glioma , Isocitrato Desidrogenase , Biomarcadores , Neoplasias Encefálicas/líquido cefalorraquidiano , Neoplasias Encefálicas/diagnóstico , DNA Tumoral Circulante/líquido cefalorraquidiano , Glioma/diagnóstico , Glutaratos , Humanos , Isocitrato Desidrogenase/líquido cefalorraquidiano , Isocitrato Desidrogenase/genética , Mutação , Estudos ProspectivosRESUMO
PURPOSE: Systemic chemotherapy including monotherapy with temozolomide (TMZ) or bevacizumab (BEV); two-drug combinations, such as irinotecan (IRI) and BEV, TMZ and BEV and a three-drug combination with TMZ, IRI and BEV (TIB) have been used in treating patients with progressive high-grade gliomas including glioblastoma (GBM). Most patients tolerated these regimens well with known side effects of hypertension, proteinuria, and reversible clinical myelosuppression (CM). However, organ- or system- specific toxicities from chemotherapy agents have never been examined by postmortem study. This is the largest cohort used to address this issue in glioma patients. METHODS: Postmortem tissues (from all major systems and organs) were prospectively collected and examined by standard institution autopsy and neuropathological procedures from 76 subjects, including gliomas (N = 68, 44/M, and 24/F) and brain metastases (N = 8, 5/M, and 3/F) between 2009 and 2019. Standard hematoxylin and eosin (H&E) were performed on all major organs including brain specimens. Electronic microscopic (EM) study was carried out on 14 selected subject's kidney samples per standard EM protocol. Medical records were reviewed with adverse events (AEs) analyzed and graded according to the Common Terminology Criteria for Adverse Events (CTCAE), version 4.03. A swimmer plot was utilized to visualize the timelines of patient history by treatment group. The binary logistic regression models were performed to explore any associations between treatment strategies and incident myelosuppression. RESULTS: Twenty-four glioma subjects were treated with TIB [median: 5.5 (range: 1-25) cycles] at tumor recurrence. Exposure to IRI significantly increased the frequency of CM (p = 0.05). No unexpected adverse events clinically, or permanent end-organ damage during postmortem examination was identified in glioma subjects who had received standard or prolonged duration of BEV, TMZ or TIB regimen-based chemotherapies except rare events of bone marrow suppression. The most common causes of death (COD) were tumor progression (63.2%, N = 43) followed by aspiration pneumonia (48.5%, N = 33) in glioma subjects. No COD was attributed to acute toxicity from TIB. The study also demonstrated that postmortem kidney specimen is unsuitable for studying renal ultrastructural pathological changes due to autolysis. CONCLUSION: There is no organ or system toxicity by postmortem examinations among glioma subjects who received BEV, TMZ or TIB regimen-based chemotherapies regardless of durations except for occasional bone marrow suppression and reversible myelosuppression clinically. IRI, but not the extended use of TMZ, significantly increased CM in recurrent glioma patients. COD most commonly resulted from glioma tumor progression with infiltration to brain stem and aspiration pneumonia.
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Neoplasias Encefálicas , Glioblastoma , Glioma , Pneumonia Aspirativa , Humanos , Temozolomida/uso terapêutico , Glioblastoma/terapia , Bevacizumab/uso terapêutico , Irinotecano/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Recidiva Local de Neoplasia/tratamento farmacológico , Neoplasias Encefálicas/terapia , Glioma/tratamento farmacológicoRESUMO
BACKGROUND: Despite surgical resection and chemoradiation, all patients with GBM invariably recur. Radiological imaging is limited in differentiating tumor recurrence (TR) from treatment-related changes (TRC); therefore, re-resection is often needed. Few studies have assessed the relationship between re-resection histopathology and overall survival (OS). We performed a large retrospective study to analyze the clinical significance of histopathology following re-resection and its influence on genomic sequencing results. METHODS: Clinical, radiographic, and histological information was compiled from 675 patients with GBM (2005-2017). 137-patients met the inclusion criteria. IDH1 p.R132H immunohistochemistry was performed in all patients. Next-generation sequencing interrogating 205 tumor-related genes was performed in 68-patients. Molecular alterations from initial and subsequent resections were compared in a subset of cases. RESULTS: There were no differences in OS (17.3-months TRC vs. 21-months TR, p = 0.881) and survival from progression (9.0 vs. 11.7-months, p = 0.778) between patients with TR and TRC on re-resection. TR patients were more likely to receive salvage radiotherapy (26% vs. 0%) and tumor-treating fields (25% vs. 5%,) after the 2nd surgery than the TRC group (p = < 0.045). There was no correlation between mutations and TRC. IDH status was not predictive of TRC. Fifteen-patients had sequencing results from multiple surgeries without evident differences in genomic alterations. CONCLUSIONS: Histopathologic findings following chemoradiation do not correlate with clinical outcomes. Such findings should be considered during patient management and clinical trial enrollment. Standardization of tissue sampling and interpretation following reoperation is urgently needed. Future work is required to understand the relationship between the mutation profile following TRC and outcomes.
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Neoplasias Encefálicas/patologia , Glioblastoma/patologia , Recidiva Local de Neoplasia/patologia , Lesões por Radiação/patologia , Adulto , Idoso , Encéfalo/efeitos dos fármacos , Encéfalo/patologia , Encéfalo/efeitos da radiação , Neoplasias Encefálicas/terapia , Quimiorradioterapia/efeitos adversos , Feminino , Glioblastoma/terapia , Humanos , Masculino , Pessoa de Meia-Idade , Estudos RetrospectivosRESUMO
INTRODUCTION: Optimal treatment for recurrent glioblastoma isocitrate dehydrogenase 1 and 2 wild-type (rGBM IDH-WT) is not standardized, resulting in multiple therapeutic approaches. A phase III clinical trial showed that tumor treating fields (TTFields) monotherapy provided comparable survival benefits to physician's chemotherapy choice in rGBM. However, patients did not equally benefit from TTFields, highlighting the importance of identifying predictive biomarkers of TTFields efficacy. METHODS: A retrospective review of an institutional database with 530 patients with infiltrating gliomas was performed. Patients with IDH-WT rGBM receiving TTFields at first recurrence were included. Tumors were evaluated by next-generation sequencing for mutations in 205 cancer-related genes. Post-progression survival (PPS) was examined using the log-rank test and multivariate Cox-regression analysis. RESULTS: 149 rGBM patients were identified of which 29 (19%) were treated with TTFields. No significant difference in median PPS was observed between rGBM patients who received versus did not receive TTFields (13.9 versus 10.9 months, p = 0.068). However, within the TTFields-treated group (n = 29), PPS was improved in PTEN-mutant (n = 14) versus PTEN-WT (n = 15) rGBM, (22.2 versus 11.6 months, p = 0.017). Within the PTEN-mutant group (n = 70, 47%), patients treated with TTFields (n = 14) had longer median PPS (22.2 versus 9.3 months, p = 0.005). No PPS benefit was observed in PTEN-WT patients receiving TTFields (n = 79, 53%). CONCLUSIONS: TTFields therapy conferred a significant PPS benefit in PTEN-mutant rGBM. Understanding the molecular mechanisms underpinning the differences in response to TTFields therapy could help elucidate the mechanism of action of TTFields and identify the rGBM patients most likely to benefit from this therapeutic option.
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Neoplasias Encefálicas , Glioblastoma , PTEN Fosfo-Hidrolase/genética , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/terapia , Doença Crônica , Glioblastoma/genética , Glioblastoma/terapia , Humanos , Mutação , Recidiva , Estudos RetrospectivosRESUMO
INTRODUCTION: Despite aggressive treatment, glioblastoma invariably recurs. The optimal treatment for recurrent glioblastoma (rGBM) is not well defined. Stereotactic radiosurgery (SRS) for rGBM has demonstrated favorable outcomes for selected patients; however, its efficacy in molecular GBM subtypes is unknown. We sought to identify genetic alterations that predict response/outcomes from SRS in rGBM-IDH-wild-type (IDH-WT). METHODS: rGBM-IDH-WT patients undergoing SRS at first recurrence and tested by next-generation sequencing (NGS) were reviewed (2009-2018). Demographic, clinical, and molecular characteristics were evaluated. NGS interrogating 205-genes was performed. Primary outcome was survival from GK-SRS assessed by Kaplan-Meier method and multivariable Cox proportional-hazards. RESULTS: Sixty-three lesions (43-patients) were treated at 1st recurrence. Median age was 61-years. All patients were treated with resection and chemoradiotherapy. Median time from diagnosis to 1st recurrence was 8.7-months. Median cumulative volume was 2.895 cm3 and SRS median marginal dose was 18 Gy (median isodose-54%). Bevacizumab was administered in 81.4% patients. PFS from SRS was 12.9-months. Survival from SRS was 18.2-months. PTEN-mutant patients had a longer PFS (p = 0.049) and survival from SRS (p = 0.013) in multivariable analysis. Although no statistically significant PTEN-mutants patients had higher frequency of radiation necrosis (21.4% vs. 3.4%) and lower in-field recurrence (28.6% vs. 37.9%) compared to PTEN-WT patients. CONCLUSIONS: SRS is a safe and effective treatment option for selected rGBM-IDH-WT patients following first recurrence. rGBM-IDH-WT harboring PTEN-mutation have improved survival with salvage SRS compared to PTEN-WT patients. PTEN may be used as a molecular biomarker to identify a subset of rGBM patients who may benefit the most from SRS.
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Neoplasias Encefálicas/genética , Glioblastoma/genética , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/terapia , PTEN Fosfo-Hidrolase/genética , Radiocirurgia/métodos , Adulto , Idoso , Neoplasias Encefálicas/terapia , Feminino , Glioblastoma/terapia , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Estudos Retrospectivos , Terapia de Salvação/métodosRESUMO
PURPOSE OF REVIEW: IDH-mutant low-grade gliomas (LGG) have emerged as a distinct clinical and molecular entity with unique treatment considerations. Here, we review updates in IDH-mutant LGG diagnosis and classification, imaging biomarkers, therapies, and neurocognitive and patient-reported outcomes. RECENT FINDINGS: CDKN2A/B homozygous deletion in IDH-mutant astrocytoma is associated with shorter survival, similar to WHO grade 4. The T2-FLAIR mismatch, a highly specific but insensitive sign, is diagnostic of IDH-mutant astrocytoma. Maximal safe resection is currently indicated in all LGG cases. Radiotherapy with subsequent PCV (procarbazine, lomustine, vincristine) provides longer overall survival compared to radiotherapy alone. Temozolomide in place of PCV is reasonable, but high-level evidence is still lacking. LGG adjuvant treatment has important quality of life and neurocognitive side effects that should be considered. Although incurable, IDH-mutant LGG have a favorable survival compared to IDH-WT glioma. Recent advances in molecular-based classification, imaging, and targeted therapies will hopefully improve survival and quality of life.
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Neoplasias Encefálicas/patologia , Cromossomos Humanos Par 1/genética , Glioma/patologia , Isocitrato Desidrogenase/genética , Neoplasias Encefálicas/classificação , Neoplasias Encefálicas/genética , Análise Mutacional de DNA/métodos , Glioma/classificação , Glioma/genética , Humanos , Gradação de TumoresRESUMO
AIM: Glioblastomas (GBMs) and diffuse intrinsic pontine gliomas (DIPGs) are infiltrating gliomas with poor prognosis. CXCR4 has been linked to glioma cell invasion, survival, proliferation, and angiogenesis. This study aimed to evaluate the expression of CXCR4 in molecular subtypes of adult and pediatric infiltrating gliomas. MATERIALS AND METHODS: We evaluated the expression of CXCR4 in 21 DIPGs and 44 adult infiltrating gliomas (25 GBM, 8 astrocytomas, and 11 oligodendrogliomas) by immunohistochemistry. Mutations in 315 cancer genes and rearrangements in 28 genes were evaluated by next-generation sequencing. RESULTS: CXCR4 was expressed in -DIPGs and adult infiltrating gliomas in tumor cells (28.6% and 5.6%, respectively) and endothelial cells (14.3% and 19.4%?, respectively). In adult gliomas, there was a correlation between CXCR4 expression and mutations in EGFR, PIK3CA, TERT promoter, and CDKN2A/B loss. In contrast, CXCR4 expression was not detected in IDH1/IDH2 mutant gliomas. These associations were confirmed using The Cancer Genome Atlas (TCGA) database. CONCLUSION: CXCR4 is expressed in a subset of DIPGs and GBMs, but it is not expressed in astrocytomas or oligodendrogliomas. CXCR4 expression is variable and it is influenced by tumor genomic alterations. It is important to consider CXCR4 expression in clinical trials that evaluate the efficacy of CXCR4 inhibitors in the treatment of gliomas.
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Glioblastoma , Glioma , Oligodendroglioma , Biomarcadores Tumorais/genética , Criança , Células Endoteliais , Glioma/genética , Humanos , Receptores CXCR4/genéticaRESUMO
BACKGROUND AND PURPOSE: Delayed neurological deficits are a devastating consequence of subarachnoid hemorrhage (SAH), which affects about 30% of surviving patients. Although a very serious concern, delayed deficits are understudied in experimental SAH models; it is not known whether rodents recapitulate the delayed clinical decline seen in SAH patients. We hypothesized that mice with SAH develop delayed functional deficits and that microthrombi and infarction correlate with delayed decline. METHODS: Adult C57BL/6J mice of both sexes were subjected to endovascular perforation to induce SAH. Mice were allowed to survive for up to 1 week post-ictus and behavioral performance was assessed daily. Postmortem microthrombi, large artery diameters (to assess vasospasm), and infarct volume were measured. These measures were analyzed for differences between SAH mice that developed delayed deficits and SAH mice that did not get delayed deficits. Correlation analyses were performed to identify which measures correlated with delayed neurological deficits, sex, and infarction. RESULTS: Twenty-three percent of males and 47% of females developed delayed deficits 3 to 6 days post-SAH. Female mice subjected to SAH had a significantly higher incidence of delayed deficits than male mice with SAH. Mice that developed delayed deficits had significantly more microthrombi and larger infarct volumes than SAH mice that did not get delayed deficits. Microthrombi positively correlated with infarct volume, and both microthrombi and infarction correlated with delayed functional deficits. Vasospasm did not correlate with either infarction delayed functional deficits. CONCLUSIONS: We discovered that delayed functional deficits occur in mice following SAH. Sex differences were seen in the prevalence of delayed deficits. The mechanism by which microthrombi cause delayed deficits may be via formation of infarcts.
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Comportamento Animal , Infarto Cerebral/etiologia , Trombose Intracraniana/etiologia , Hemorragia Subaracnóidea/complicações , Hemorragia Subaracnóidea/patologia , Animais , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BLRESUMO
INTRODUCTION: Glioblastomas (GBMs) usually occur as a solitary lesion; however, about 0.5-35% present with multiple lesions (M-GBM). The genetic landscape of GBMs have been thoroughly investigated; nevertheless, differences between M-GBM and single-foci GBM (S-GBM) remains unclear. The present study aimed to determine differences in clinical and molecular characteristics between M-GBM and S-GBM. METHODS: A retrospective review of multifocal/multicentric infiltrative gliomas (M-IG) from our institutional database was performed. Demographics, clinical, radiological, and genetic features were obtained and compared between M-GBM IDH-wild type (IDH-WT) vs 193 S-GBM IDH-WT. Mutations were examined by a targeted next-generation sequencing assay interrogating 315 genes. RESULTS: 33M-IG were identified from which 94% were diagnosed as M-GBM IDH-WT, the remaining 6% were diagnosed as astrocytomas IDH-mutant. M-GBM and S-GBM comparison revealed that EGFR alterations were more frequent in M-GBM (65% vs 42% p = 0.019). Furthermore, concomitant EGFR/PTEN alterations were more common in M-GBM vs. S-GBM (36% vs 19%) as well as compared to TCGA (21%). No statistically significant differences in overall survival were observed between M-GBM and S-GBM; however, within the M-GBM cohort, patients harboring KDR alterations had a worse survival (KDR-altered 6.7 vs KDR-WT 16.6 months, p = 0.038). CONCLUSIONS: The results of the present study demonstrate that M-GBM genetically resembles S-GBM, however, M-GBM harbor higher frequency of EGFR alterations and co-occurrence of EGFR/PTEN alterations, which may account for their highly malignant and invasive phenotype. Further study of genetic alterations including differences between multifocal and multicentric GBMs are warranted, which may identify potential targets for this aggressive tumor.
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Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Glioblastoma/genética , Glioblastoma/patologia , Idoso , Feminino , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Estudos RetrospectivosRESUMO
INTRODUCTION: Recently, the term "Diffuse glioma, BRAF V600E-mutant" has been recommended for IDH-wildtype gliomas with BRAF p.V600E mutation and without CDKN2A/B deletion. However, additional alterations in gliomas that coexist with BRAF-mutations are poorly defined. METHODS: We analyzed next-generation sequencing results in 315 cancer-associated genes for 372 gliomas from our institution (2010 to 2017). In addition, we reviewed IDH-WT gliomas with mutation and copy-number alterations available in cBioPortal, to further characterize BRAF-mutant gliomas. RESULTS: Seventeen (4.6%) showed BRAF mutations. Tumor types included 8 glioblastomas, 2 epithelioid glioblastomas (E-GBM), 2 pleomorphic xanthoastrocytomas (PXA), 1 anaplastic oligodendroglioma, 1 diffuse astrocytoma, and 3 pilocytic astrocytomas. Fifty-three percent (53%) of cases exhibited BRAF-alterations other than p.V600E. The majority of the tumors were localized in the temporal lobe (52.9%). In addition to BRAF mutations, glioblastomas showed concomitant mutations in TP53 (3/8), CDKN2A/B-loss (6/8), TERT-promoter (6/8), and/or PTEN (5/8). Both E-GBMs and PXAs showed CDKN2A/B-loss and BRAF p.V600E with absence of TERTp, TP53, and PTEN mutations. Similar findings were observed in BRAF-mutant infiltrating gliomas from cBioPortal. CONCLUSIONS: Knowledge of additional alterations that co-occur with BRAF-mutations in gliomas may improve diagnosis and help identify patients that could benefit from targeted therapies. Furthermore, we provide examples of two patients whose tumors responded to BRAF pathway inhibitors, arguing in favor of these therapies in patients with BRAF-mutant gliomas.
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Biomarcadores Tumorais/genética , Neoplasias Encefálicas/diagnóstico , Glioblastoma/diagnóstico , Mutação , Proteínas Proto-Oncogênicas B-raf/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Criança , Pré-Escolar , Feminino , Seguimentos , Glioblastoma/genética , Glioblastoma/patologia , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Adulto JovemRESUMO
INTRODUCTION: We report 2 cases of medulloblastoma maturing into gangliocytoma after receiving multimodal therapy. Here we present 2 cases of diagnosed medulloblastoma which on re-resection were noted to be gangliocytoma without heterogeneity, which is an extremely rare occurrence. CASE PRESENTATION: The first patient, an 11-year-old boy diagnosed with high-risk (non-WNT, non-SHH) medulloblastoma, was treated with near-total surgical resection followed by craniospinal radiation therapy with weekly vincristine. He then received maintenance chemotherapy with vincristine, cyclophosphamide, and cisplatin. On surveillance MR imaging studies residual tumor in the lateral aspect of the tumor bed was noted to be slowly growing, eliciting gross-total resection of the residual tumor. Histopathology showed benign gangliocytoma without residual medulloblastoma. The second patient, a 3-year-old girl, was diagnosed with medulloblastoma, desmoplastic nodular variant. She was initially treated with gross total resection and chemotherapy with etoposide, carboplatin, and high-dose methotrexate. At 4 months off therapy, she was noted to have local recurrence along the resection cavity. Second-line therapy was started with irinotecan and temozolomide, but MRI assessment during treatment showed further disease progression. She then received craniospinal radiation. Eleven months off therapy, further radiographic progression was noted, and the patient underwent second-look surgery, with pathology showing gangliocytoma and treatment-related gliosis. DISCUSSION/CONCLUSION: The maturation of medulloblastoma into a ganglion cell-rich lesion is very rare, with few well-characterized previous reports. Given the rare nature of this entity, it would be of great value to understand the process of posttreatment maturation and the genetic and treatment factors which contribute to this phenomenon.
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Neoplasias Cerebelares , Ganglioneuroma , Meduloblastoma , Neoplasias Cerebelares/diagnóstico por imagem , Neoplasias Cerebelares/terapia , Criança , Pré-Escolar , Terapia Combinada , Feminino , Ganglioneuroma/diagnóstico por imagem , Ganglioneuroma/cirurgia , Humanos , Masculino , Meduloblastoma/diagnóstico por imagem , Meduloblastoma/terapia , Recidiva Local de Neoplasia , VincristinaRESUMO
Superficial/cutaneous malignant peripheral nerve sheath tumor is a rare soft tissue neoplasm that shares morphological, immunohistochemical, and molecular features with spindle/desmoplastic melanoma. We aimed to identify a methylome signature to distinguish these two entities. We analyzed 15 cases of spindle/desmoplastic melanoma and 15 cases of cutaneous malignant peripheral nerve sheath tumor in 23 men and 7 women. DNA from formalin-fixed, paraffin-embedded tissues was extracted and processed using the Illumina Infinium Methylation EPIC array interrogating 866,562 CpG sites. Using a home-grown informatics pipeline, we identified differentially methylated positions between the two entities. Functional network analysis for enrichment signatures was performed using DAVID tools. Identified differentially methylated positions were compared with the Cancer Genome Atlas's cutaneous melanoma dataset and a recently published malignant peripheral nerve sheath tumor dataset to assess the specificity of the identified signature. Unsupervised hierarchical clustering showed different patterns of methylation in cutaneous malignant peripheral nerve sheath tumor and spindle/desmoplastic melanoma. Two probes, cg20783223 and cg13332552, colocalized in the promoter region of BCAT1 and miR-2504. Pathway analysis highlighted enrichment in a subset of genes involved in breast and gastric cancer centered on BCAT1 and downstream activated genes in the mTOR pathway. Our study identifies BCAT1 as a novel methylome signature distinguishing spindle/desmoplastic melanoma from cutaneous malignant peripheral nerve sheath tumor.
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Biomarcadores Tumorais/genética , Melanoma/genética , MicroRNAs/genética , Neurofibrossarcoma/genética , Neoplasias Cutâneas/genética , Neoplasias de Tecidos Moles/genética , Transaminases/genética , Adulto , Idoso , Metilação de DNA , Diagnóstico Diferencial , Feminino , Humanos , Masculino , Melanoma/diagnóstico , Pessoa de Meia-Idade , Neurofibrossarcoma/diagnóstico , Neoplasias Cutâneas/diagnóstico , Neoplasias de Tecidos Moles/diagnóstico , Adulto Jovem , Melanoma Maligno CutâneoRESUMO
PURPOSE OF REVIEW: Cerebral radiation necrosis (CRN) is a major dose-limiting adverse event of radiotherapy. The incidence rate of RN varies with the radiotherapy modality, total dose, dose fractionation, and the nature of the lesion being targeted. In addition to these known and controllable features, there is a stochastic component to the occurrence of CRN-the genetic profile of the host or the lesion and their role in the development of CRN. RECENT FINDINGS: Recent studies provide some insight into the genetic mechanisms underlying radiation-induced brain injury. In addition to these incompletely understood host factors, the diagnostic criteria for CRN using structural and functional imaging are also not clear, though multiple structural and functional imaging modalities exist, a combination of which may prove to be the ideal diagnostic imaging approach. As the utilization of novel molecular therapies and immunotherapy increases, the incidence of CNR is expected to increase and its diagnosis will become more challenging. Tissue biopsies can be insensitive and suffer from sampling biases and procedural risks. Liquid biopsies represent a promising, accurate, and non-invasive diagnostic strategy, though this modality is currently in its infancy. A better understanding of the pathogenesis of CRN will expand and optimize the diagnosis and management of CRN by better utilizing existing treatment options including bevacizumab, pentoxifylline, hyperbaric oxygen therapy, and laser interstitial thermal therapy.
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Encéfalo/patologia , Lesões por Radiação/diagnóstico , Lesões por Radiação/patologia , Bevacizumab/uso terapêutico , Encéfalo/diagnóstico por imagem , Neoplasias Encefálicas/diagnóstico , Neoplasias Encefálicas/patologia , Diagnóstico Diferencial , Humanos , Incidência , Terapia a Laser , Biópsia Líquida , Imageamento por Ressonância Magnética , Necrose , Lesões por Radiação/epidemiologia , Lesões por Radiação/terapia , Fatores de RiscoRESUMO
BRAF p.V600E mutations are detected in greater than 50% of pediatric Langerhans cell histiocytosis (LCH) lesions. However, the use of mutation-specific BRAF V600E immunohistochemistry (IHC) as a surrogate for molecular testing in pediatric LCH is unknown. We tested the mutation-specific BRAF V600E monoclonal antibody (clone VE1) in formalin-fixed, paraffin-embedded LCH samples from 26 pediatric patients (14 males and 12 females, ages 7 mo-17 y) using allele-specific real-time polymerase chain reaction (PCR) with a limit of detection of 0.5% as the comparative gold standard. BRAF VE1 staining was scored for both intensity (0-3+) and percentage of immunoreactive tumor cells (0%-100%). BRAF VE1 immunoreactivity was determined using both lenient (≥1+, ≥1%) and stringent (≥2+, ≥10%) scoring criteria. Using lenient-scoring criteria, we found that the sensitivity and specificity of IHC compared with allele-specific real-time PCR were 100.0% and 18.2%, respectively. The poor specificity of lenient IHC analysis was attributable to weak, 1+ staining in both BRAF-mutated and wild-type LCH. Using stringent-scoring criteria, we found that specificity improved to 100.0% at the expense of sensitivity that decreased to 80.0%. Stringent scoring generated 3 false-negative results, but in all cases, neoplastic tissue comprised less than 5% of the stained section and/or the specimen was decalcified. In conclusion, highly sensitive molecular assays remain the gold standard for BRAF mutation analysis in LCH paraffin-embedded lesions. To avoid false-positive results, unequivocal VE1 staining of 2+ intensity in greater than or equal to 10% neoplastic histiocytes is required. However, negative VE1 results require additional studies to exclude false-negatives, and stringent-scoring criteria may not be optimal for scant or decalcified specimens.
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Histiocitose de Células de Langerhans/enzimologia , Mutação , Proteínas Proto-Oncogênicas B-raf/genética , Adolescente , Criança , Pré-Escolar , Feminino , Humanos , Imuno-Histoquímica , Lactente , MasculinoRESUMO
PURPOSE: Primary central nervous system lymphoma (PCNSL) is a non-Hodgkin lymphoma that affects the central nervous system (CNS). Although previous studies have reported the most common mutated genes in PCNSL, including MYD88 and CD79b, our understanding of genetic characterizations in primary CNS lymphomas is limited. The aim of this study was to perform a retrospective analysis investigating the most frequent mutation types, and their frequency, in PCNSL. METHODS: Fifteen patients with a diagnosis of PCNSL from our institution were analyzed for mutations in 406 genes and rearrangements in 31 genes by next generation sequencing (NGS). RESULTS: Missense mutations were identified as the most common mutation type (32%) followed by frame shift mutations (23%). The highest mutation rate was reported in the MYD88 (33.3%), CDKN2A/B (33.3%), and TP53 (26.7%) genes. Intermediate tumor mutation burden (TMB) and high TMB was detected in 13.3% and 26.7% of PCNSL, respectively. The most frequent gene rearrangement involved the IGH-BCL6 genes (20%). CONCLUSIONS: This study shows the most common genetic alterations in PCNSL as determined by a commercial next generation sequencing assay. MYD88 and CD79b are frequently mutated in PCNSL, IGH-BCL6 is the most frequent gene rearrangement and approximately 1/4 of cases show a high TMB. Mutations in multiple genes, in addition to high TMB and gene rearrangements, highlights the complex molecular heterogeneity of PCNSL. Knowledge about genetic alterations in PCNSL can inform the development of novel targets for diagnosis and treatment.
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Neoplasias do Sistema Nervoso Central/genética , Linfoma/genética , Mutação , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Mutação da Fase de Leitura , Predisposição Genética para Doença , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , Pessoa de Meia-Idade , Mutação de Sentido Incorreto , Estudos Retrospectivos , Adulto JovemRESUMO
Reactive angioendotheliomatosis (RAE) is a rare cutaneous vascular disorder characterized by intravascular hyperplasia of endothelial cells, sometimes with a vascular proliferation. Intravascular histiocytosis (IH) is a similar vascular disorder characterized by the presence of dilated vessels containing aggregates of mononuclear histiocytes (macrophages) within their lumina. Although their pathogenesis remains uncertain, there has been speculation about the possible relationship between IH and RAE. We report a case of coexistence of RAE and IH in a patient who underwent a wide reexcision of a metastatic malignant melanoma. The excision specimen did not show any residual melanoma but exhibited an intravascular collection of CD-68-positive histiocytes admixed with CD-31-positive endothelial cells and fibrin surrounded by D2-40-positive vascular wall. The presence of intravascular cells initially raised concern of intravascular invasion by melanoma. As there was no clinical lesion and immunohistochemical stains for melanocytic makers were negative, we interpret this as an incidental finding. Knowledge of this benign vascular disorder is important because the histologic changes may be mistaken for intravascular invasion of a malignant neoplasm.