RESUMO
Epithelioid glioblastoma (eGBM) is a rare subtype of GBM. Given the update of the definition of GBM, the understanding of the molecular characteristics and prognosis of "true" adult eGBM remains limited. Herein, we retrospectively analyzed the clinicopathological data of 39 adult eGBM cases. Adult eGBM primarily affected females, with a male-to-female ratio of 1:2.3. The average age of diagnosis was 53 years, and the tumor affected the temporal lobe in 41% of cases (16/39, 41%). Microscopically, the tumors consisted mainly or entirely of epithelioid cells. Perivascular infiltration (10/39, 25.6%) and leptomeningeal dissemination (7/39, 17.9%) were not uncommon. BRAF V600E mutation was detected in 40.9% of cases (n = 9/22). Next-generation sequencing revealed that CDKN2A/B homogeneous deletion was the most frequently mutated gene (8/10, 80%), followed by TERT promoter mutation (7/10, 70%), Cyclin-dependent kinases 4 or 6 (CDK4/6) amplification (5/10, 50%) and BRAF V600E mutation (50%, 5/10). Notably, the incidence of ARID1B mutation in eGBM was 50% (5/10), representing the first report of such a mutation in this subtype of GBM. ARID1B was known to be a subunit of the SWI/SNF chromatin remodeler. Chromosome analysis showed a 7+/10- signature in 90% (9/10) cases. Adult eGBM carried a dismal prognosis compared to GBM with IDH and H3 wild-type (typical GBM) (OS: 13.89 vs 24.30 months; P = .003) and even typical GBM without MGMT promoter methylation (OS: 13.89 vs 22.08 months; P = .036). Based on these findings, it can be concluded that adult eGBM harbors a high frequency of the 7+/10- signature and alterations in the MAPK pathway, SWI/SNF complex and cyclin-related genes and portends an extremely poor prognosis.
Assuntos
Neoplasias Encefálicas , Metilases de Modificação do DNA , Glioblastoma , Mutação , Proteínas Proto-Oncogênicas B-raf , Fatores de Transcrição , Proteínas Supressoras de Tumor , Humanos , Glioblastoma/genética , Glioblastoma/patologia , Glioblastoma/mortalidade , Masculino , Feminino , Estudos Retrospectivos , Pessoa de Meia-Idade , Prognóstico , Adulto , Idoso , Fatores de Transcrição/genética , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/mortalidade , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Cromossômicas não Histona/genética , Telomerase/genética , Inibidor p16 de Quinase Dependente de Ciclina/genética , Quinase 4 Dependente de Ciclina/genética , Regiões Promotoras Genéticas/genética , Enzimas Reparadoras do DNA/genéticaRESUMO
OBJECTIVE: To explore the histopathological characteristics of paired recurrent gliomas and their clinical significance. METHODS: Glioma patients who received both primary surgery and reoperation when recurrence at Sun Yat-sen University Cancer Center from June 2001 to June 2019 were enrolled. Clinical and pathological characteristics were analyzed retrospectively, and histopathology of reoperation specimens was divided into three categories according to tumor cell activity and the degree of necrosis: active group, low-activity group, and necrosis group. RESULTS: A total of 89 patients were included in this study. The 2016 WHO grade of the first operation pathology and IDH1 status were related to survival time after the first operation, but there was no significant association with survival time after reoperation. The time interval between primary and reoperation was shorter for primary high-grade glioma and/or IDH1 wild-type tumor patients than for low-grade glioma and/or IDH1 mutant tumor patients (P < 0.001). Histopathological types of recurrent gliomas were analyzed, and 67 cases (75.3%) were classified into the active group, 14 (15.8%) into the low-activity group, and 8 (8.9%) into the necrosis group. The low-activity or necrosis group was associated with a higher radiotherapy dose and shorter operation interval. Further univariate and multivariate Cox survival analyses showed the histopathological patterns of recurrent gliomas to be related to survival time after reoperation. CONCLUSION: Primary WHO low grade or IDH1 mutant gliomas appeared survival benefit mainly on later recurrence, but was not a prognostic predictor following recurrence. Histopathological feature of recurrent glioma is related to previous treatment, including radiotherapy dosage and chemotherapy treatment, and is also an important independent prognostic factor for patients after reoperation.
Assuntos
Neoplasias Encefálicas , Glioma , Humanos , Estudos de Coortes , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/cirurgia , Neoplasias Encefálicas/metabolismo , Estudos Retrospectivos , Relevância Clínica , Glioma/genética , Glioma/cirurgia , Glioma/tratamento farmacológico , Prognóstico , Necrose , Isocitrato Desidrogenase/genética , Isocitrato Desidrogenase/metabolismo , MutaçãoRESUMO
Although there have been recent advances in the molecular pathology of ependymomas, little is known about the underlying molecular evolution during its development. Here, we assessed the clinical, pathological and molecular evolutionary process of ependymoma recurrence in a 9-year-old patient who had seven recurrences of supratentorial ependymoma and died from intracranial multiregional recurrences at the age of 19 years old. Whole-genome sequencing (WGS) of 7 tumor samples (1 primary and 6 subsequent recurrent tumors) was performed to elucidate the mutation landscape and identify potential driver mutations for tumor evolution. The genetic profiles of the seven tumor specimens showed significant heterogeneity and suggested a highly branched evolutionary pattern. The mutational signatures and chromothripsis changed with treatments. Strikingly, adhesion G protein-coupled receptor L3 (ADGRL3, also known as Latrophilins 3, LPNH3) was found to be consistently mutated during the entire disease process. However, Sanger sequencing of other 78 ependymoma patients who underwent surgery at our institution showed no genetic alteration of ADGRL3, as found in the present case. The mRNA levels of ADGRL3 were significantly lower in ependymomas (n = 36), as compared with normal brain tissue (n = 3). Grade III ependymomas had the lowest ADGRL3 expression. Moreover, ependymomas with lower mRNA level of ADGRL3 had shorter overall survival. Our findings, therefore, demonstrate a rare evolutionary process of ependymoma involving ADGRL3.
Assuntos
Ependimoma , Adulto , Criança , Ependimoma/genética , Ependimoma/patologia , Ependimoma/cirurgia , Humanos , Mutação , RNA Mensageiro , Receptores Acoplados a Proteínas G/genética , Adulto JovemRESUMO
Hepatocellular carcinoma (HCC) is one of the most common human malignancies worldwide with very poor prognosis. Resistance to targeted therapeutic drugs such as sorafenib remains one of the major challenges in clinical treatment. In the present study, PARP1 was found to be highly expressed in human embryonic stem cells, but progressively decreased upon specified hepatic differentiation. Reactivation of PARP1 expression was also detected in HCC residual tumors after sorafenib treatment in xenograft mouse model, indicating the potential important roles of PARP1 in stem cell pluripotency and HCC sorafenib treatment resistance. Overexpression of PARP1 was frequently observed in HCC patients, and closely associated with poor clinical outcome. Treatment of Sorafenib induced activation of DNA damage repair signaling, which is highly active and essential for maintenance of stem cell pluripotency in HCC residual tumors. PARP inhibitor Olaparib extensively suppressed the DNA damage repair signaling, and significantly inhibited the global pluripotent transcriptional network. The repression of key pluripotent transcriptional factors and DNA damage repair signaling by Olaparib was mainly through CHD1L-mediated condensation of the chromatin structure at their promotor regions. The global reshaping of the pluripotent transcriptome by Olaparib might reinforce Sorafenib in eliminating HCC residual tumors and enhance therapeutic efficiency.
Assuntos
Carcinoma Hepatocelular/genética , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Neoplasias Hepáticas/genética , Ftalazinas/farmacologia , Piperazinas/farmacologia , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Transcriptoma , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/patologia , Cromatina/genética , Cromatina/metabolismo , Dano ao DNA , Células-Tronco Embrionárias , Perfilação da Expressão Gênica , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/patologia , Sorafenibe/farmacologiaRESUMO
BACKGROUND: Differential diagnosis of tumour recurrence (TuR) from treatment effects (TrE), mostly induced by radiotherapy and chemotherapy, is still difficult by using conventional computed tomography (CT) or magnetic resonance (MR) imaging. We have investigated the diagnostic performance of PET/CT with 3 tracers, 13N-NH3, 18F-FDOPA, and 18F-FDG, to identify TuR and TrE in glioma patients following treatment. METHODS: Forty-three patients with MR-suspected recurrent glioma were included. The maximum and mean standardized uptake values (SUVmax and SUVmean) of the lesion and the lesion-to-normal grey-matter cortex uptake (L/G) ratio were obtained from each tracer PET/CT. TuR or TrE was determined by histopathology or clinical MR follow-up for at least 6 months. RESULTS: In this cohort, 34 patients were confirmed to have TuR, and 9 patients met the diagnostic standard of TrE. The SUVmax and SUVmean of 13N-NH3 and 18F-FDOPA PET/CT at TuR lesions were significantly higher compared with normal brain tissue (13N-NH3 0.696 ± 0.558, 0.625 ± 0.507 vs 0.486 ± 0.413; 18F-FDOPA 0.455 ± 0.518, 0.415 ± 0.477 vs 0.194 ± 0.203; both P < 0.01), but there was no significant difference in 18F-FDG (6.918 ± 3.190, 6.016 ± 2.807 vs 6.356 ± 3.104, P = 0.290 and 0.493). L/G ratios of 13N-NH3 and 18F-FDOPA were significantly higher in TuR than in TrE group (13N-NH3, 1.573 ± 0.099 vs 1.025 ± 0.128, P = 0.008; 18F-FDOPA, 2.729 ± 0.131 vs 1.514 ± 0.141, P < 0.001). The sensitivity, specificity and AUC (area under the curve) by ROC (receiver operating characteristic) analysis were 57.7%, 100% and 0.803, for 13N-NH3; 84.6%, 100% and 0.938, for 18F-FDOPA; and 80.8%, 100%, and 0.952, for the combination, respectively. CONCLUSION: Our results suggest that although multiple tracer PET/CT may improve differential diagnosis efficacy, for glioma TuR from TrE, 18F-FDOPA PET-CT is the most reliable. The combination of 18F-FDOPA and 13N-NH3 does not increase the diagnostic efficiency, while 18F-FDG is not worthy for differential diagnosis of glioma TuR and TrE.
Assuntos
Neoplasias Encefálicas/diagnóstico por imagem , Glioma/diagnóstico por imagem , Recidiva Local de Neoplasia/diagnóstico por imagem , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada/métodos , Compostos Radiofarmacêuticos/farmacocinética , Adolescente , Adulto , Idoso , Amônia/farmacocinética , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/terapia , Di-Hidroxifenilalanina/análogos & derivados , Di-Hidroxifenilalanina/farmacocinética , Progressão da Doença , Feminino , Radioisótopos de Flúor/farmacocinética , Fluordesoxiglucose F18/farmacocinética , Glioma/metabolismo , Glioma/terapia , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/metabolismo , Radioisótopos de Nitrogênio/farmacocinética , Curva ROC , Sensibilidade e Especificidade , Resultado do Tratamento , Adulto JovemRESUMO
Various scoring systems have been proposed to predict the postoperative prognosis of colorectal liver metastasis (CRLM), including the clinical risk score (CRS), the immunoscore and so on. Recently, histopathological growth patterns (HGPs) have been recognized. However, the correlation between HGPs and the immunoscore, and their prognostic values in patients with CRLM after liver resection remain undetermined. In this study, HGPs were retrospectively evaluated in H&E-stained slides from 166 CRLM patients. The immunoscore was calculated according to the densities of immunostained CD3 + and CD8 + cells. A risk score combining HGPs, the immunoscore and the CRS was defined and divided patients into the low-, medium- and high-risk group. Our results showed that the densities of CD3 + and CD8 + cells were higher in the desmoplastic HGP (dHGP) group than in the non-dHGP group, and the proportion of high immunoscores was also higher in the dHGP group (51.9% vs. 33.0%, respectively, P = 0.020). Patients with the dHGP had significantly longer relapse-free survival (RFS) and overall survival (OS) than those with the non-HGP. The low-risk group showed significantly higher 2-year RFS and 5-year OS rates than the other two groups (RFS: 76.2%, 43.7% and 33.1%, respectively; P < 0.001; OS: 89.7%, 54.4% and 33.3%, respectively; P < 0.001). In conclusion, the dHGP correlates with relatively high immunoscores, predicting a favorable prognosis independent of the immunoscore and CRS. A novel risk score combining HGPs, the immunoscore and the CRS may be used for the stratification of CRLM patients' survival.
Assuntos
Neoplasias Colorretais/cirurgia , Hepatectomia , Neoplasias Hepáticas/cirurgia , Fígado/patologia , Recidiva Local de Neoplasia/epidemiologia , Adulto , Idoso , Linfócitos T CD8-Positivos/imunologia , Neoplasias Colorretais/imunologia , Neoplasias Colorretais/mortalidade , Neoplasias Colorretais/patologia , Intervalo Livre de Doença , Estudos de Viabilidade , Feminino , Seguimentos , Humanos , Fígado/citologia , Fígado/imunologia , Fígado/cirurgia , Neoplasias Hepáticas/imunologia , Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas/secundário , Linfócitos do Interstício Tumoral/imunologia , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/imunologia , Período Pós-Operatório , Prognóstico , Estudos Retrospectivos , Medição de Risco/métodos , Taxa de SobrevidaRESUMO
BACKGROUND: Gliomas represent the largest class of primary central nervous system neoplasms, many subtypes of which exhibit poor prognoses. Surgery followed by radiotherapy and chemotherapy has been used as a standard strategy but yielded unsatisfactory improvements in patient survival outcomes. The S-phase kinase protein 2 (Skp2), a critical component of the E3-ligase SCF complex, has been documented in tumorigenesis in various cancer types but its role in glioma has yet to be fully clarified. In this study, we investigated the function of Skp2 in the proliferation, stem cell maintenance, and drug sensitivity to temozolomide (TMZ) of glioma. METHODS: To investigate the role of Skp2 in the prognosis of patients with glioma, we first analyzed data in databases TCGA and GTEx. To further clarify the effect of Skp2 on glioma cell proliferation, we suppressed its level in glioblastoma (GBM) cell lines through knockdown and small molecule inhibitors (lovastatin and SZL-P1-41). We then detected cell growth, colony formation, sphere formation, drug sensitivity, and in vivo tumor formation in xenograft mice model. RESULTS: Skp2 mRNA level was higher in both low-grade glioma and GBM than normal brain tissues. The knockdown of Skp2 increased cell sensitivity to TMZ, decreased cell proliferation and tumorigenesis. In addition, Skp2 level was found increased upon stem cells enriching, while the knockdown of Skp2 led to reduced sphere numbers. Downregulation of Skp2 also induced senescence. Repurposing of lovastatin and novel compound SZL-P1-41 suppressed Skp2 effectively, and enhanced glioma cell sensitivity to TMZ in vitro and in vivo. CONCLUSION: Our data demonstrated that Skp2 modulated glioma cell proliferation in vitro and in vivo, stem cell maintenance, and cell sensitivity to TMZ, which indicated that Skp2 could be a potential target for long-term treatment.
RESUMO
BACKGROUND: MRI is one of the most important techniques to assess the treatment response of gliomas. However, differentiating tumor recurrence (TuR) from treatment effects (TrE) remains challenging. PURPOSE: To compare the diagnostic performance of MR diffusion-weighted imaging (DWI), arterial spin labeling (ASL), proton MR spectroscopy (MRS), and amide proton transfer (APT) imaging in differentiating between TuR and TrE in posttreatment glioma patients. STUDY TYPE: Prospective. POPULATION: Thirty patients with suspected tumor progression. FIELD STRENGTH/SEQUENCE: DWI, ASL, proton MRS, and APT imaging were performed at 3T MR. ASSESSMENT: MR indices, including ADC, relative cerebral blood flow (rCBF), ratios of Cho/Cr, Cho/NAA, and NAA/Cr and APT-weighted (APTw) effect were obtained from DWI, ASL, proton MRS, and APT imaging, respectively. Indices were measured in the contralateral normal-appearing white matter and lesions defined on the Gd-enhanced T1 w image. TuR or TrE was either determined histologically or clinically from longitudinal MRI follow-up for at least 6 months. STATISTICAL TESTS: The diagnostic performance of the indices was evaluated using Student's t-test, receiver operating characteristic (ROC) curve, and multivariate logistic regression analyses. RESULTS: Among the 30 patients, 16 were diagnosed as having TuR and the rest having TrE. The recurrent tumors showed a significantly higher APTw effect (1.56 ± 1.14%) and rCBF (1.44 ± 0.61) compared with lesions representing treatment effects (-0.44 ± 1.34% and 0.72 ± 0.25, respectively, with P < 0.001). The areas under the curve (AUCs) were 0.87 and 0.90 for APTw and rCBF, respectively, in differentiating between TuR and TrE. Combining APTw and rCBF achieved a higher AUC of 0.93. MRS index ratios of Cho/Cr (P = 0.25), Cho/NAA (P = 0.16), and NAA/Cr (P = 0.86) and ADC (P = 0.37) showed no significant differences between TuR and TrE lesions, with AUCs lower than 0.70. DATA CONCLUSION: Compared with DWI and MRS, ASL and APT imaging techniques showed better diagnostic capability in distinguishing TuR from TrE. LEVEL OF EVIDENCE: 1 Technical Efficacy: Stage 4 J. Magn. Reson. Imaging 2020;51:1154-1161.
Assuntos
Neoplasias Encefálicas , Glioma , Imageamento por Ressonância Magnética Multiparamétrica , Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/terapia , Imagem de Difusão por Ressonância Magnética , Glioma/diagnóstico por imagem , Glioma/terapia , Humanos , Imageamento por Ressonância Magnética , Recidiva Local de Neoplasia , Estudos ProspectivosRESUMO
BACKGROUND: Ependymal tumors are pathologically defined intrinsic neoplasms originating in the intracranial compartments or the spinal cord that affect both children and adults. The recently integrated classification of ependymomas based on both histological and molecular characteristics is capable of subgrouping patients with various prognoses. However, the application of histological and molecular markers in Chinese patients with ependymomas has rarely been reported. We aimed to demonstrate the significance of histological characteristics, the v-relavian reticuloendotheliosis viral oncogene homolog A (RELA) fusions and other molecular features in ependymal tumors. METHODS: We reviewed the histological characteristics of ependymal tumors using conventional pathological slides and investigate the RELA fusions and Cylclin D1 (CCND1) amplification by Fluorescence in situ hybridization (FISH) and trimethylation of histone 3 lysine 27 (H3K27me3) expression by immunohistochemistry (IHC) methods. SPSS software was used to analyze the data. RESULTS: We demonstrated that hypercellularity, atypia, microvascular proliferation, necrosis, mitosis, and an elevated Ki-67 index, were tightly associated with an advanced tumor grade. Tumor location, necrosis, mitosis and the Ki-67 index were related to the survival of the ependymomas, but Ki67 was the only independent prognostic factor. Additionally, RELA fusions, mostly presented in pediatric grade III intracranial ependymomas, indicated decreased survival times of patients, and closely related to the patients' age, tumor grade, cellularity, cellular atypia, necrosis and Ki67 index in the intracranial ependymal tumors, whereas reduction of H3K27me3 predicted the worse prognosis in ependymal tumors. CONCLUSIONS: Histological and molecular features facilitate tumor grading and prognostic predictions for ependymal tumors in Chinese patients.
Assuntos
Neoplasias Encefálicas/patologia , Ependimoma/patologia , Histonas/análise , Antígeno Ki-67/análise , Neoplasias da Medula Espinal/patologia , Fator de Transcrição RelA/análise , Adolescente , Adulto , Biomarcadores Tumorais/análise , Neoplasias Encefálicas/cirurgia , Criança , China , Ciclina D1/análise , Ependimoma/cirurgia , Feminino , Seguimentos , Humanos , Imuno-Histoquímica , Hibridização in Situ Fluorescente , Estimativa de Kaplan-Meier , Masculino , Necrose , Gradação de Tumores , Prognóstico , Neoplasias da Medula Espinal/cirurgia , Adulto JovemRESUMO
PURPOSE: We aim to investigate the impacts of extent of resection and adjuvant radiotherapy on survival of high-grade meningiomas (WHO grade II-III) according to modern diagnosis and management. METHODS: Patients with high-grade meningiomas were identified in the Surveillance Epidemiology and End Results (SEER) database between 2000 and 2015 and used for survival analysis. Propensity score matching (PSM) was conducted to reduce selection bias. Another 92 patients from Sun Yat-sen University Cancer Center (SYSUCC) were used for validation. RESULTS: 530 patients were enrolled from SEER. Patients with gross total resection (GTR) had no significantly different overall survival (OS) compared with those with subtotal resection (STR), even after performing PSM between these two groups. Multivariable analysis found that age ≥ 65 years (HR 2.22, P < 0.001), tumor diameter > 6 cm (HR 1.59, P = 0.004) and grade III tumor (HR 4.31, P < 0.001) were associated with worse OS. Stratification analysis showed that adjuvant radiotherapy conferred significantly improved OS for grade III meningiomas, but not for grade II meningiomas, regardless of resection extent. In SYSUCC cohort, resection extent was also not significantly associated with OS. However, patients with GTR (Simpson grade I-III) had distinctly increased progression-free survival (PFS) than those with STR (P < 0.001). Additionally, for grade II meningiomas after GTR, radiotherapy was unable to improve OS and PFS. CONCLUSION: On modern management of high-grade meningiomas, GTR does not improve OS, but seems to be associated with increased PFS. Radiotherapy is reasonable as a supplement for treating grade III meningiomas, whereas its effect for grade II meningiomas remains uncertain and needs further validation by prospective study.
Assuntos
Neoplasias Meníngeas/mortalidade , Meningioma/mortalidade , Procedimentos Neurocirúrgicos/mortalidade , Radioterapia Adjuvante/mortalidade , Adolescente , Adulto , Idoso , Estudos de Coortes , Terapia Combinada , Gerenciamento Clínico , Feminino , Seguimentos , Humanos , Masculino , Neoplasias Meníngeas/patologia , Neoplasias Meníngeas/terapia , Meningioma/patologia , Meningioma/terapia , Pessoa de Meia-Idade , Gradação de Tumores , Taxa de Sobrevida , Adulto JovemRESUMO
BACKGROUND: Surgical procedures are critical in making a conclusive histopathological diagnosis of primary central nervous system lymphoma (PCNSL), which typically presents contrast-enhancing lesions in magnetic resonance imaging (MRI). The fluorescein sodium-guided technique could enhance tumor visibility. We reported a series of patients with PCNSL underwent fluorescein sodium-guided surgical procedures. PATIENTS AND METHODS: 12 patients clinically considered brain tumors underwent fluorescein sodium-guided surgery in Sun Yat-sen University Cancer Center from March 2016 to July 2017. The age of 4 female and 8 male patients ranges from 39 to 62 years. In 4 patients, corticosteroid had been prescribed before surgery due to intracranial hypertension. After injection of low dose of sodium fluorescein (3-5 mg/kg), the lesions with strong fluorescence staining were identified as the target area for biopsy or resection. RESULTS: Based on the targeted tissues with bright and homogenous fluorescence staining, all 12 patients were conclusively diagnosed as B cell non-Hodgkin's lymphoma (diffuse large cell). The specificity of the specimens sent for frozen section was 86.4% (19/22). No fluorescein sodium associated side effects were observed. CONCLUSION: Fluorescein sodium guided surgery is an effective and safe tool in biopsy or tumor resection in patients suspicious for PCNSL with preoperative MRI presented contrast-enhanced homogenous lesions. Such technique might still be considered in those patients who have been pretreated with corticosteroid.
Assuntos
Neoplasias Encefálicas/cirurgia , Meios de Contraste , Fluoresceína , Biópsia Guiada por Imagem , Linfoma/cirurgia , Cirurgia Assistida por Computador , Adulto , Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/patologia , Feminino , Humanos , Linfoma/diagnóstico por imagem , Linfoma/patologia , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Procedimentos NeurocirúrgicosRESUMO
UNLABELLED: High-grade tumors with poor differentiation usually show phenotypic resemblance to their developmental ancestral cells. Cancer cells that gain lineage precursor cell properties usually hijack developmental signaling pathways to promote tumor malignant progression. However, the molecular mechanisms underlying this process remain unclear. In this study, the chromatin remodeler chromodomain-helicase-DNA-binding-protein 1-like (CHD1L) was found closely associated with liver development and hepatocellular carcinoma (HCC) tumor differentiation. Expression of CHD1L decreased during hepatocyte maturation and increased progressively from well-differentiated HCCs to poorly differentiated HCCs. Chromatin immunoprecipitation followed by high-throughput deep sequencing found that CHD1L could bind to the genomic sequences of genes related to development. Bioinformatics-aided network analysis indicated that CHD1L-binding targets might form networks associated with developmental transcription factor activation and histone modification. Overexpression of CHD1L conferred ancestral precursor-like properties of HCC cells both in vitro and in vivo. Inhibition of CHD1L reversed tumor differentiation and sensitized HCC cells to sorafenib treatment. Mechanism studies revealed that overexpression of CHD1L could maintain an active "open chromatin" configuration at promoter regions of estrogen-related receptor-beta and transcription factor 4, both of which are important regulators of HCC self-renewal and differentiation. In addition, we found a significant correlation of CHD1L with developmental transcriptional factors and lineage differentiation markers in clinical HCC patients. CONCLUSION: Genomic amplification of chromatin remodeler CHD1L might drive dedifferentiation of HCC toward an ancestral lineage through opening chromatin for key developmental transcriptional factors; further inhibition of CHD1L might "downgrade" poorly differentiated HCCs and provide novel therapeutic strategies.
Assuntos
Carcinoma Hepatocelular/patologia , Linhagem da Célula , Cromatina/fisiologia , DNA Helicases/fisiologia , Proteínas de Ligação a DNA/fisiologia , Neoplasias Hepáticas/patologia , Fatores de Transcrição/fisiologia , Animais , Carcinoma Hepatocelular/tratamento farmacológico , Diferenciação Celular , Cromatina/química , Sequenciamento de Nucleotídeos em Larga Escala , Neoplasias Hepáticas/tratamento farmacológico , Camundongos , Camundongos Endogâmicos C57BL , Niacinamida/análogos & derivados , Niacinamida/farmacologia , Compostos de Fenilureia/farmacologia , Receptores de Estrogênio/fisiologia , SorafenibeRESUMO
BACKGROUND: Alveolar soft part sarcoma (ASPS) is a relatively rare malignant tumor and early diagnosis and appropriate treatment for ASPS are essential for a good prognosis. PURPOSE: To retrospectively review the clinical presentation and computed tomography (CT) and magnetic resonance imaging (MRI) findings of ASPS so as to improve the accuracy of imaging diagnosis. MATERIAL AND METHODS: Fourteen patients with pathologically proven ASPS were enrolled. Their clinical and imaging findings were retrospectively reviewed. RESULTS: The median age of the patients was 29 years (range, 13-37 years). Most tumors were located in the soft tissues of the trunk and lower limbs. The median maximal diameter of the masses was 91 mm. Thirteen masses presented with ovoid or irregular shapes. Eleven masses had less clear boundaries. Compared with the adjacent muscles, the masses were isodense or hypodense on CT, hypo-, iso-, or hyperintense on T1-weighted images, and heterogeneous hyperintense on T2-weighted images. Intense enhancement was seen after contrast agent administration, with prominent intra- or peri-tumoral feeders on CT or flow voids on MRI. By the end of the last follow-up, 13 patients had distant metastasis and three patients had local recurrence. CONCLUSION: ASPS should be included in the differential diagnosis when a bulky, heterogeneous soft tissue mass in the trunk and the lower limbs with intense enhancement after contrast administration and prominent intra- or peri-tumoral feeders on CT or flow voids on MRI is seen, particularly in young patients.
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Imageamento por Ressonância Magnética , Sarcoma Alveolar de Partes Moles/diagnóstico por imagem , Sarcoma Alveolar de Partes Moles/patologia , Tomografia Computadorizada por Raios X , Adolescente , Adulto , Diagnóstico Diferencial , Feminino , Humanos , Perna (Membro)/diagnóstico por imagem , Perna (Membro)/patologia , Masculino , Radiografia Torácica , Reprodutibilidade dos Testes , Estudos Retrospectivos , Tórax/patologia , Adulto JovemRESUMO
BACKGROUND: Perineural invasion (PNI) is correlated with adverse survival in several malignancies, but its significance in esophageal squamous cell carcinoma (ESCC) remains to be clearly defined. The objective of this study was to determine the association between PNI status and clinical outcomes. METHODS: We retrospectively evaluated the PNI of 433 patients with ESCC treated with surgery between 2000 and 2007 at a single academic center. The resulting data were analyzed using Spearman's rank correlation, the Kaplan-Meier method, Cox proportional hazards regression modeling and Harrell's concordance index (C-index). RESULTS: PNI was identified in 209 of the 433 (47.7%) cases of ESCC. The correlation analysis demonstrated that PNI in ESCC was significantly correlated with tumor differentiation, infiltration depth, pN classification and stage (P < 0.05). The five-year overall survival rate was 0.570 for PNI-negative tumors versus 0.326 for PNI-positive tumors. Patients with PNI-negative tumors exhibited a 1.7-fold increase in five-year recurrence-free survival compared with patients with PNI-positive tumors (0.531 v 0.305, respectively; P < 0.0001). In the subset of patients with node-negative disease, PNI was evaluated as a prognostic predictor as well (P < 0.05). In the multivariate analysis, PNI was an independent prognostic factor for overall survival (P = 0.027). The C-index estimate for the combined model (PNI, gender and pN status) was a significant improvement on the C-index estimate of the clinicopathologic model alone (0.739 v 0.706, respectively). CONCLUSIONS: PNI can function as an independent prognostic factor of outcomes in ESCC patients, and the PNI status in primary ESCC specimens should be considered for therapy stratification.
Assuntos
Carcinoma de Células Escamosas/patologia , Neoplasias Esofágicas/patologia , Nervos Periféricos/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma de Células Escamosas/mortalidade , Progressão da Doença , Intervalo Livre de Doença , Neoplasias Esofágicas/mortalidade , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Invasividade Neoplásica , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Fatores de Risco , Fatores de TempoRESUMO
OBJECTIVES: The appropriate adjuvant therapy for patients with endometrial carcinoma with solitary adnexal involvement is unclear. We conducted a retrospective single-institution study to evaluate the outcome and efficacy of adjuvant chemotherapy alone in this population. METHODS: All patients with endometrial carcinoma who received primary surgical treatment between January 1999 and May 2010 were reviewed. The patients who were diagnosed with stage IIIA disease based only on isolated adnexal involvement and treated with surgical procedures followed by adjuvant chemotherapy alone were included. Demographic, clinicopathologic, treatment and outcome data were collected. Recurrence and survival were analyzed. RESULTS: Among 1453 reviewed patients, 67 patients were identified. The median age was 48 years. All patients were treated with platinum-based adjuvant chemotherapy, with the majority (36/67, 53.7%) receiving paclitaxel plus carboplatin. The total number of cycles of chemotherapy administered was 305 (median four cycles/person). Most of the chemotherapy related toxicities were mild or moderate. The median follow-up time was 76 months. Eight patients experienced recurrence. The majority of initial relapses were distant (7/8, 87.5%), characterized by liver metastases (3/8, 37.5%). The 5-year disease-free survival (DFS) and overall survival (OS) rates were 89.6% and 91.9%, respectively. Multivariate analysis confirmed that grade 3 tumor was an independent predictor of worse DFS and OS (HR=5.19, P=0.048; HR=6.55, P=0.037, respectively). CONCLUSION: Patients with stage IIIA endometrial carcinoma with solitary adnexal involvement have favorable outcomes. Adjuvant chemotherapy alone may be effective and feasible for these patients.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias do Endométrio/tratamento farmacológico , Neoplasias do Endométrio/patologia , Anexos Uterinos/patologia , Adulto , Idoso , Quimioterapia Adjuvante , Feminino , Humanos , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Compostos Organoplatínicos/administração & dosagem , Estudos Retrospectivos , Resultado do TratamentoRESUMO
Isocitrate dehydrogenase (IDH)-mutant astrocytoma with microvascular proliferation, necrosis, CDKN2A/B homozygous deletion, or any combination of these features corresponds to World Health Organization grade 4 according to current criteria. However, the prognostic significance of CDKN2A hemizygous deletion in IDH-mutant astrocytoma is not well established. We undertook a comprehensive study that included assessments of histological and genetic approaches to prognosis for these tumors. Samples from a cohort of 114 patients with extended observation were subjected to histological review and molecular analysis. CDKN2A (9p21) deletion was detected by fluorescence in situ hybridization. Overall survival (OS) was calculated via Kaplan-Meier estimation using the log-rank test. Histological grade, Ki-67 index, and the extent of surgical resection correlated with the OS of IDH-mutant astrocytoma patients. Both CDKN2A homozygous deletion and hemizygous deletion were detectable. Patients with CDKN2A homozygous-deletion tumors had the poorest OS; those with CDKN2A hemizygous-deletion tumors had an intermediate OS (p < .001). We then established a novel grading system that combined CDKN2A homozygous and hemizygous deletions with histological grade; the combined grading system was an independent prognostic factor for IDH-mutant astrocytomas. We conclude that CDKN2A homozygous and hemizygous deletion should be combined in a grading system for IDH-mutant astrocytomas.
Assuntos
Astrocitoma , Neoplasias Encefálicas , Humanos , Isocitrato Desidrogenase/genética , Homozigoto , Hibridização in Situ Fluorescente , Neoplasias Encefálicas/patologia , Mutação/genética , Deleção de Sequência , Astrocitoma/patologia , Prognóstico , Inibidor p16 de Quinase Dependente de Ciclina/genéticaRESUMO
Astroblastoma is an extremely rare central nervous system tumor characterized by astroblastic pseudorosettes and vascular hyalinization. Despite these histologic hallmarks, its morphology can vary, occasionally resembling other central nervous system tumors such as ependymoma. A novel tumor entity, astroblastoma, meningioma 1 (MN1)-altered, has been identified, featuring MN1 gene rearrangements typically involving BEN-domain containing 2 (BEND2) as a fusion partner. Most astroblastomas arise in the cerebral hemisphere. Here, we report 4 cases of spinal cord astroblastoma in female patients, all showing Ewing sarcoma RNA-binding protein 1 fusion with BEND2, rather than MN1. These tumors displayed growth patterns akin to traditional intracranial astroblastomas, with three cases demonstrating high-grade histology, including elevated mitotic activity and necrosis. Interestingly, some cases exhibited positive staining for pan-cytokeratin and hormone receptors. DNA methylation profiling clustered three of the four cases with the reference "AB_EWSR," whereas one case exhibited an independent methylation signature near the reference methylation group "AB_EWSR" and "pleomorphic xanthoastrocytoma." Together with the existing literature, we summarized a total of eleven cases, which predominantly affected children and young adults with female predilection. Eight of 10 patients experienced recurrence, underscoring the aggressive nature of this disease. We suggest recognizing a new molecular subgroup of spinal astroblastoma and recommend testing newly diagnosed infratentorial astroblastomas for Ewing sarcoma RNA-binding protein 1-BEND2 fusion.
RESUMO
Perioperative chemotherapy is the standard treatment for locally advanced gastric or gastro-esophageal junction cancer, and the addition of programmed cell death 1 (PD-1) inhibitor is under investigation. In this randomized, open-label, phase 2 study (NEOSUMMIT-01), patients with resectable gastric or gastro-esophageal junction cancer clinically staged as cT3-4aN + M0 were randomized (1:1) to receive either three preoperative and five postoperative 3-week cycles of SOX/XELOX (chemotherapy group, n = 54) or PD-1 inhibitor toripalimab plus SOX/XELOX, followed by toripalimab monotherapy for up to 6 months (toripalimab plus chemotherapy group, n = 54). The primary endpoint was pathological complete response or near-complete response rate (tumor regression grade (TRG) 0/1). The results showed that patients in the toripalimab plus chemotherapy group achieved a higher proportion of TRG 0/1 than those in the chemotherapy group (44.4% (24 of 54, 95% confidence interval (CI): 30.9%-58.6%) versus 20.4% (11 of 54, 95% CI: 10.6%-33.5%)), and the risk difference of TRG 0/1 between toripalimab plus chemotherapy group and chemotherapy group was 22.7% (95% CI: 5.8%-39.6%; P = 0.009), meeting a prespecified endpoint. In addition, a higher pathological complete response rate (ypT0N0) was observed in the toripalimab plus chemotherapy group (22.2% (12 of 54, 95% CI: 12.0%-35.6%) versus 7.4% (4 of 54, 95% CI: 2.1%-17.9%); P = 0.030), and surgical morbidity (11.8% in the toripalimab plus chemotherapy group versus 13.5% in the chemotherapy group) and mortality (1.9% versus 0%), and treatment-related grade 3-4 adverse events (35.2% versus 29.6%) were comparable between the treatment groups. In conclusion, the addition of toripalimab to chemotherapy significantly increased the proportion of patients achieving TRG 0/1 compared to chemotherapy alone and showed a manageable safety profile. ClinicalTrials.gov registration: NCT04250948 .
Assuntos
Adenocarcinoma , Neoplasias Esofágicas , Neoplasias Gástricas , Humanos , Adenocarcinoma/patologia , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/cirurgia , Neoplasias Gástricas/patologia , Anticorpos Monoclonais Humanizados/efeitos adversos , Neoplasias Esofágicas/tratamento farmacológico , Neoplasias Esofágicas/cirurgia , Neoplasias Esofágicas/patologia , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversosRESUMO
BACKGROUND: MicroRNAs (miRNAs) have been documented as playing important roles in cancer development. In this study, we investigated the role of miR-124 in breast cancer and clarified the regulation of flotillin-1 (FLOT1) by miR-124. METHODS: The expression levels of miR-124 were examined in breast cancer cell lines and patient specimens using quantitative reverse transcription-PCR. The clinicopathological significance of the resultant data was later analyzed. Next, we explored the function of miR-124 to determine its potential roles on cancer cell growth and migration in vitro. A luciferase reporter assay was conducted to confirm the target gene of miR-124, and the results were validated in cell lines and patient specimens. RESULTS: We found that miR-124 expression was significantly downregulated in breast cancer cell lines and patient specimen compared with normal cell lines and paired adjacent normal tissues (P < 0.0001), respectively. MiR-124 was also associated with tumor node metastasis (TNM) stage (P = 0.0007) and lymph node metastasis (P = 0.0004). In breast cancer cell lines, the ectopic expression of miR-124 inhibited cell growth and migration in vitro. Moreover, we identified the FLOT1 gene as a novel direct target of miR-124, and miR-124 ectopic expression significantly inhibited FLOT1. Luciferase assays confirmed that miR-124 could directly bind to the 3' untranslated region of FLOT1 and suppress translation. Moreover, FLOT1 was widely upregulated, and inversely correlated with miR-124 in breast cancer tissues. Consistent with the effect of miR-124, the knockdown of FLOT1 significantly inhibited breast cancer cell growth and migration. We also observed that the rescue expression of FLOT1 partially restored the effects of miR-124. CONCLUSIONS: Our study demonstrated that miR-124 might be a tumor suppressor in breast cancer via the regulation of FLOT1. This microRNA could serve as a potential diagnostic marker and therapeutic target for breast cancer.
Assuntos
Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Proteínas de Membrana/genética , MicroRNAs/genética , Adulto , Neoplasias da Mama/metabolismo , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Proteínas de Membrana/metabolismo , MicroRNAs/metabolismo , Pessoa de Meia-IdadeRESUMO
Autophagy is an evolutionarily conserved process that involves lysosomal degradations of cellular organelles. Microtubule-associated protein 1 light chain 3A (LC3A), an autophagic gene, is differentially expressed in human cancers. However, the relationship between LC3A expression and hepatocellular carcinoma (HCC) has not been investigated. Tissue microarray-based immunohistochemistry was used to examine the expression patterns of LC3A in HCC. The resulting data were analyzed using receiver operating characteristic curves, Spearman's rank correlation, Kaplan-Meier plots and Cox proportional hazards regression modeling. Two distinct patterns of LC3A expression were observed in HCC: "stone-like" structuring and diffuse cytoplasmic expression. High levels of LC3A expression were more frequently observed in HCC tissues compared to the adjacent non-tumorous tissue. Correlation analyses indicated that high expression of the "stone-like" LC3A was correlated with greater levels of serum AFP, poorer tumor differentiation and the presence of vascular invasion. Kaplan-Meier survival analysis showed a significant association between high expression of the "stone-like" LC3A and unfavorable prognosis (P<0.001). Importantly, multivariate analysis (P<0.05) identified the "stone-like" expression of LC3A in HCC as an independent prognostic factor. Collectively, our data provide compelling evidence that "stone-like" expression of LC3A plays an important role in HCC progression and may act as a biomarker of prognosis for patients with HCC.