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BACKGROUND AND AIMS: Recent advances have introduced molecular subtyping of pancreatic cystic lesions (PCLs) as a possible amendment to the diagnostic algorithm. The study evaluated the feasibility and diagnostic accuracy of molecular analysis and subtyping of PCLs using the recently introduced EUS-guided through-the-needle-biopsy (TTNB) sampling. METHODS: We prospectively included 101 patients in the study who presented with PCLs >15 mm in the largest cross-section. EUS-guided TTNB samples were obtained by a micro-biopsy forceps introduced through a 19-gauge needle. The TTNB samples were analyzed by next-generation sequencing (NGS) for point mutations in tumor suppressors and oncogenes using a 51-gene customized hotspot panel. Sensitivity and specificity were calculated with the histologic diagnosis as reference. RESULTS: After initial microscopic evaluation of the samples, 91 patients had residual TTNB samples available for NGS. Of these, 49 harbored mutations, most frequently in KRAS and GNAS, reflecting an excess frequency of intraductal papillary mucinous neoplasms (IPMNs) in the study population. A sensitivity and specificity of 83.7% (95% confidence interval [CI], 70.3-92.7) and 81.8% (95% CI, 48.2-97.7), respectively, were demonstrated for the diagnosis of a mucinous cyst and 87.2% (95% CI, 74.2-95.2) and 84.6% (95% CI, 54.5-98.1) for the diagnosis of an IPMN. CONCLUSIONS: Thus, molecular analysis of TTNB samples by NGS has high sensitivity and specificity for diagnosing mucinous cysts and IPMNs. Although the procedure comes with a risk of adverse events of 9.9%, TTNB samples are a robust alternative to cyst fluid for a combined histologic and molecular diagnosis of PCLs. (Clinical trial registration number: NCT03578445.).
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Cisto Pancreático , Neoplasias Pancreáticas , Humanos , Líquido Cístico , Aspiração por Agulha Fina Guiada por Ultrassom Endoscópico/métodos , Sequenciamento de Nucleotídeos em Larga Escala , Pâncreas/patologia , Cisto Pancreático/diagnóstico , Cisto Pancreático/genética , Cisto Pancreático/patologia , Neoplasias Pancreáticas/diagnóstico , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patologiaRESUMO
Cerebrospinal fluid-based real-time quaking-induced conversion (CSF RT-QuIC) is currently the most prominent method for early detection of sporadic Creutzfeldt-Jakob disease (sCJD), the most common prion disease. CSF RT-QuIC delivers high sensitivity (>90%) and specificity (100%), which has been demonstrated by large ring-trial studies testing probable and definitive sCJD cohorts. Following the inclusion of CSF RT-QuIC in the revised European CJD Surveillance Network diagnostic criteria for sCJD, it has become a standard diagnostic procedure in many prion disease reference or surveillance centers around the world. In this study, we present the implementation of the second-generation CSF RT-QuIC (commonly known as Improved QuIC or IQ) at the Danish Reference Center for Prion Diseases (DRCPD). The method's sensitivity and specificity were evaluated and validated by analyzing 63 CSF samples. These 63 samples were also analyzed at the National CJD Research and Surveillance Unit (NCJDRSU), based at the University of Edinburgh, UK; analysis was carried out using the first generation or previous CSF RT-QuIC method (PQ). The sensitivity and specificity of PQ during tests at the NCJDRSU were 92% and 100%, respectively. Using these 63 CSF samples, the agreement between the two RT-QuIC generations at DRCPD and NCJDRSU prion laboratories was 100%.
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Síndrome de Creutzfeldt-Jakob , Doenças Priônicas , Príons , Humanos , Síndrome de Creutzfeldt-Jakob/diagnóstico , Doenças Priônicas/diagnóstico , Sensibilidade e Especificidade , DinamarcaRESUMO
Atypical teratoid/rhabdoid tumor (ATRT) is an aggressive central nervous system tumor characterized by loss of SMARCB1/INI1 protein expression and comprises three distinct molecular groups, ATRT-TYR, ATRT-MYC and ATRT-SHH. ATRT-SHH represents the largest molecular group and is heterogeneous with regard to age, tumor location and epigenetic profile. We, therefore, aimed to investigate if heterogeneity within ATRT-SHH might also have biological and clinical importance. Consensus clustering of DNA methylation profiles and confirmatory t-SNE analysis of 65 ATRT-SHH yielded three robust molecular subgroups, i.e., SHH-1A, SHH-1B and SHH-2. These subgroups differed by median age of onset (SHH-1A: 18 months, SHH-1B: 107 months, SHH-2: 13 months) and tumor location (SHH-1A: 88% supratentorial; SHH-1B: 85% supratentorial; SHH-2: 93% infratentorial, often extending to the pineal region). Subgroups showed comparable SMARCB1 mutational profiles, but pathogenic/likely pathogenic SMARCB1 germline variants were over-represented in SHH-2 (63%) as compared to SHH-1A (20%) and SHH-1B (0%). Protein expression of proneural marker ASCL1 (enriched in SHH-1B) and glial markers OLIG2 and GFAP (absent in SHH-2) as well as global mRNA expression patterns differed, but all subgroups were characterized by overexpression of SHH as well as Notch pathway members. In a Drosophila model, knockdown of Snr1 (the fly homologue of SMARCB1) in hedgehog activated cells not only altered hedgehog signaling, but also caused aberrant Notch signaling and formation of tumor-like structures. Finally, on survival analysis, molecular subgroup and age of onset (but not ASCL1 staining status) were independently associated with overall survival, older patients (> 3 years) harboring SHH-1B experiencing relatively favorable outcome. In conclusion, ATRT-SHH comprises three subgroups characterized by SHH and Notch pathway activation, but divergent molecular and clinical features. Our data suggest that molecular subgrouping of ATRT-SHH has prognostic relevance and might aid to stratify patients within future clinical trials.
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Neoplasias do Sistema Nervoso Central , Neoplasias Neuroepiteliomatosas , Tumor Rabdoide , Teratoma , Neoplasias do Sistema Nervoso Central/genética , Metilação de DNA , Proteínas Hedgehog/genética , Proteínas Hedgehog/metabolismo , Humanos , Neoplasias Neuroepiteliomatosas/genética , Prognóstico , Tumor Rabdoide/genética , Proteína SMARCB1/genética , Proteína SMARCB1/metabolismo , Teratoma/genéticaRESUMO
We report a case of sudden death in a 31-year-old male diagnosed at autopsy with clinical undiagnosed acromegaly. The purpose of this report is to underline the importance of health professionals reacting to phenotypic acromegaly, such as acral enlargement and/or unexplained hypertension, including a range of severe comorbidities, to avoid a fatal outcome. Recent studies have shown that the increased mortality seen in acromegaly patients can be reversed with modern treatment aimed at normalizing GH and IGF-I levels. One year before death, the presented case was diagnosed with hypertension, but was otherwise described as healthy. The forensic autopsy, including post-mortem CT, showed phenotypic facial and body characteristics for acromegaly, general visceromegaly, and a pituitary tumor. The cause of death was heart failure due to end-stage acromegalic cardiopathy. Because the disease is slowly progressive, the individual himself, and the people close to him, might not have considered the acromegaly-related facial changes as abnormal.
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Acromegalia , Insuficiência Cardíaca , Hormônio do Crescimento Humano , Adulto , Morte Súbita/etiologia , Humanos , MasculinoRESUMO
Patients undergoing cerebral revascularization surgery have a relatively high incidence of wound complications. We report a case of heterotopic epithelialization of the dura presenting as a non-healing scalp wound after an extracranial-intracranial (EC-IC) arterial bypass. The scalp wound was revised twice without healing. During the third revision, epithelial tissue was found growing on the dura and was removed. After the epithelial tissue was removed, the wound healed without further complications. This case illustrates the importance of thoroughly examining a non-healing wound to find the cause.
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Revascularização Cerebral/efeitos adversos , Craniotomia/efeitos adversos , Complicações Pós-Operatórias/patologia , Couro Cabeludo/cirurgia , Cicatrização , Dura-Máter/cirurgia , Feminino , Humanos , Pessoa de Meia-IdadeRESUMO
INTRODUCTION: Autoimmune hypophysitis is a rare disease of the pituitary, which may affect vision by inflammation and compression of the optic chiasm. However, intrachiasmatic abscess formation has not been previously reported. METHODS: In this study, we report a case of a 29-year-old female with bitemporal hemianopia due to a cystic intrasellar tumor. The patient underwent surgical decompression of the lesion, which was found to be an intrachiasmatic abscess. RESULTS: The histologic findings were consistent with IgG4 hypophysitis. CONCLUSION: This rare clinical presentation suggests that in case of a disproportionate degree of visual impairment in relation to the size of the lesion, suspicion should lead to an intrachiasmatic lesion.
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Hipofisite Autoimune/diagnóstico por imagem , Abscesso Encefálico/diagnóstico por imagem , Quiasma Óptico/diagnóstico por imagem , Adulto , Hipofisite Autoimune/complicações , Hipofisite Autoimune/patologia , Hipofisite Autoimune/cirurgia , Abscesso Encefálico/complicações , Abscesso Encefálico/patologia , Abscesso Encefálico/cirurgia , Descompressão Cirúrgica , Feminino , Hemianopsia/etiologia , Humanos , Imageamento por Ressonância Magnética , Procedimentos Neurocirúrgicos , Quiasma Óptico/cirurgiaRESUMO
Variably protease-sensitive prionopathy (VPSPr) is a recently characterised rare subtype of sporadic prion disease, mainly affecting individuals with valine homozygosity at codon 129 in the prion protein gene, with only seven methionine homozygote cases reported to date. This case presents clinical, neuropathological and biochemical features of the eighth VPSPr case worldwide with methionine homozygosity at codon 129 and compares the features with the formerly presented cases.The patient, a woman in her 70s, presented with cognitive decline, impaired balance and frequent falls. Medical history and clinical presentation were suggestive of a rapidly progressive dementia disorder. MRI showed bilateral thalamic hyperintensity. Cerebrospinal fluid real-time quaking-induced conversion was negative, and the electroencephalogram was unremarkable. The diagnosis was established through post-mortem pathological examinations. VPSPr should be suspected in rapidly progressive dementia lacking typical features or paraclinical results of protein misfolding diseases.
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Síndrome de Creutzfeldt-Jakob , Demência , Doenças Priônicas , Príons , Feminino , Humanos , Príons/genética , Príons/metabolismo , Proteínas Priônicas/genética , Proteínas Priônicas/metabolismo , Metionina/genética , Metionina/metabolismo , Homozigoto , Encéfalo/patologia , Doenças Priônicas/genética , Doenças Priônicas/metabolismo , Doenças Priônicas/patologia , Demência/genética , Racemetionina/metabolismo , Códon/genética , Códon/metabolismo , Peptídeo Hidrolases/genética , Peptídeo Hidrolases/metabolismo , Síndrome de Creutzfeldt-Jakob/patologiaRESUMO
This case report presents two patients who were diagnosed with non-systemic vasculitic neuropathy (NSVN). The phenotypes were atypical: 1) slowly progressive neuropathy and 2) plexopathy in contrast to the classic NSVN phenotype: painful, asymmetric with subacute progression. Both patients had remarkable responses to the immunosuppressants prednisolone and rituximab, and the cases highlight the importance to consider NSVN as a differential diagnosis of patients with neuropathy of unknown aetiology, as treatment can be initiated to avoid irreversible nerve damage.
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Doenças do Sistema Nervoso Periférico , Vasculite , Humanos , Vasculite/diagnóstico , Tempo para o Tratamento , Doenças do Sistema Nervoso Periférico/diagnóstico , Doenças do Sistema Nervoso Periférico/terapia , Dor , PrednisolonaRESUMO
Purpose: To present the clinical and histopathological characteristics of a rare case of ductal carcinoma in situ ex pleomorphic adenoma in the lacrimal gland. Observations: A 73-years-old Caucasian female presented with complaints of double vision and pain in the left eye region. Clinical examination revealed ptosis and exophthalmos of the left eye as well as diplopia on downward gaze. Magnetic resonance imaging of the left orbit demonstrated a 17 × 22 mm homogeneous tumor in the left lacrimal fossa. The tumor was excised in toto. Histopathological examination revealed a pleomorphic adenoma with ductal structures with benign looking epithelial cells, surrounded by myoepithelial cells. Tumor areas with cribriform architecture consisting of ductal structures with abnormal luminal epithelial cells and intact myoepithelial cell layer were also present. The surgical margins were clear. All luminal and myoepithelial cells were positive for cytokeratin 7, the luminal cells in the cribriform areas were positive for human epidermal growth factor 2 and androgen receptor. The myoepithelial cells were positive for cytokeratin 5, calponin and focally for glial fibrillar acid protein. The findings were diagnostic for ductal carcinoma in situ ex pleomorphic adenoma. Next generation sequencing Oncomine Comprehensive Assay mutation analysis found mutations in the BRCA2 (p.K3326*), BAP1 (p.S395*), and TP53 (p.E285K) genes in the ductal carcinoma in situ and BRCA2 (p.C9976A) in the pleomorphic adenoma part. Conclusion and importance: To our knowledge, this tumor is only the second described ductal carcinoma in situ ex pleomorphic adenoma of the lacrimal gland.
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AIMS: To evaluate whether the use of intra-arterial methylene blue injection improves lymph node yield, and to determine whether a higher lymph node count results in upstaging in colorectal cancer. METHOD AND RESULTS: We performed a retrospective study of colorectal cancer specimens (n = 234) 1 year after implementation of the method. All colorectal cancer specimens from the previous year served as our control group. Data concerning tumour characteristics, lymph node count, number of positive lymph nodes and success of methylene injection had been prospectively collected in accordance with the department's ongoing registration. The method was easy to implement and perform with a high rate of success (86%). The number of identified lymph nodes was highly significantly improved in the study group (P < 0.0001). In resections with pT1/T2 tumours, we demonstrated a significant increase in the number of resection specimens containing positive lymph nodes, with an increase in pN1 resections from 9.4% in the control group to 26.7% in the study group (P = 0.04). CONCLUSIONS: THE methylene blue technique significantly improves lymph node identification in colorectal cancer specimens, and the improved lymph node identification leads to upstaging of International Union Against Cancer (UICC) pT1/pT2 cancers.
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Neoplasias Colorretais/patologia , Metástase Linfática/patologia , Azul de Metileno/administração & dosagem , Estadiamento de Neoplasias/métodos , Idoso , Idoso de 80 Anos ou mais , Neoplasias Colorretais/secundário , Corantes/administração & dosagem , Feminino , Humanos , Injeções Intralesionais , Excisão de Linfonodo , Linfonodos/patologia , Masculino , Pessoa de Meia-Idade , Estudos RetrospectivosRESUMO
Background: Neurological complications during and after SARS-CoV-2 infection have been frequently described. The detection of either SARS-CoV-2 RNA or specific antibodies against SARS-CoV-2 in cerebrospinal fluid in the context of concomitant neurological manifestations indicates neuroinfection. Methods and Results: This is a retrospective descriptive analysis of cerebrospinal fluids and serum samples from 2 hospitalized patients and autopsy findings from 2 patients who died at home. Samples were analysed by 3 independent enzyme-linked immunosorbent assays. Specific antibodies against SARS-CoV-2 were detected in cerebrospinal fluids and paired serum in all 4 cases. Levels of antibodies in cerebrospinal fluids were highest in samples from a deceased man with critical progression of COVID-19 and detectable SARS-CoV-2 viral RNA in cerebrospinal fluid, serum, 4 brain biopsies and 15 additional tissue samples, though immunohistochemical staining for SARS-CoV-2 in brain tissue did not detect the virus. Conclusion: Detection of SARS-CoV-2 antibodies in paired serum and cerebrospinal fluid may support the presence of SARS-CoV-2 neuroinflammatory disease in patients with COVID-19 and neurological manifestations.
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Invasive intraductal papillary mucinous neoplasms (inv-IPMNs) have a better prognosis than regular pancreatic ductal adenocarcinoma (PDAC), but no association with status of surgical margins and microscopic infiltration patterns has previously been described. The aim of this study is to review patterns of invasion and the predictive value of clinical guidelines in terms of rates of resection of high-grade dysplasia (HGD) and cancer among intraductal papillary mucinous neoplasms (IPMNs). Consecutively, resected IPMNs between 2011 and 2017 were analyzed. Data were obtained from a prospectively maintained database. A total of 132 patients were identified. Out of these, 38 patients with inv-IPMNs, initially identified as solid lesions suspicious of cancer, were compared with a control group of 101 patients with ordinary PDAC. Lower rates of vascular invasion, perineural invasion, lymph node metastasis, advanced T stage, and R1 status were characteristic of the inv-IPMNs in addition to better overall survival (OS) for a low tumor stage. Furthermore, as novel findings, the PDACs presented with resection margin involvement of 3 or more positive margins (31.3% vs. 9.5%, p = 0.044), associated with poor OS. Of the patients presenting as pT3, the inv-IPMN less often invaded more than one extrapancreatic anatomical structure (40.1% vs. 63.9%, p = 0.03). Regarding the predictive value of clinical guidelines, the frequency of resected HGD in IPMNs with high-risk stigmata (n = 54) and IPMNs with worrisome features was 30.7%, and the frequency of invasive carcinoma was 5.7%. In conclusion, we report a low resection rate of high-risk IPMNs and present novel findings describing inv-IPMNs as a less infiltrative phenotype compared with regular PDAC.
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Carcinoma Ductal Pancreático/patologia , Neoplasias Intraductais Pancreáticas/patologia , Neoplasias Pancreáticas/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Ductal Pancreático/mortalidade , Carcinoma Ductal Pancreático/cirurgia , Bases de Dados Factuais , Feminino , Humanos , Masculino , Margens de Excisão , Pessoa de Meia-Idade , Gradação de Tumores , Invasividade Neoplásica , Pancreatectomia , Neoplasias Intraductais Pancreáticas/mortalidade , Neoplasias Intraductais Pancreáticas/cirurgia , Neoplasias Pancreáticas/mortalidade , Neoplasias Pancreáticas/cirurgia , Pancreaticoduodenectomia , Fenótipo , Estudos Retrospectivos , Medição de Risco , Fatores de Risco , Resultado do TratamentoRESUMO
In the present manuscript, we report the clinical presentation and challenging diagnostic work-up of a sporadic Creutzfeldt-Jakob disease patient with confirmed VV1 subtype and heterozygous 1-octapeptide repeat deletion in the prion protein gene. The described patient was a 58-year-old woman. Interestingly, most of the reported patients with the VV1 subtype to date are men with an average age of 44 years at disease onset. The patient was observed clinically from symptoms onset until her death 22 months later. This report describes the patient's insidious clinical evolution and the paraclinical examinations and pathology reports gathered at different time points of disease progression. Unfortunately, the absence of typical clinical and paraclinical features of classic sporadic Creutzfeldt-Jakob disease made the brain biopsy surgery necessary. This case report illustrates the diagnostic difficulties posed by the phenotypic heterogeneity of sporadic Creutzfeldt-Jakob disease and urges clinicians to consider this diagnosis even in patients who do not fulfil the typical clinical disease criteria. Furthermore, it highlights the need for real-time quaking-induced conversion method adaptation for detection of rare sporadic Creutzfeldt-Jakob disease subtypes with certain prion protein gene variants.
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Síndrome de Creutzfeldt-Jakob/diagnóstico , Síndrome de Creutzfeldt-Jakob/genética , Proteínas Priônicas/genética , Progressão da Doença , Feminino , Humanos , Pessoa de Meia-Idade , Técnicas de Diagnóstico Molecular , Polimorfismo Genético , Príons/genéticaRESUMO
AIMS: Intraductal papillary mucinous neoplasms (IPMNs) may be precursor lesions of pancreatic cancer. The path towards malignancy is associated with mutations in tumour suppressor-and oncogenes that may serve as biomarkers during diagnostic investigation. A novel micro forceps has made it possible to obtain biopsies from the cyst wall for analysis by next generation sequencing (NGS), providing an opportunity for early detection and intervention. However, the impact of spatial tumour heterogeneity on the representability of the biopsies has not been determined. The primary aim is to characterise the impact of molecular heterogeneity of the luminal cyst wall on tissue sampling strategies with small biopsies. METHODS: We performed NGS and immunohistochemical phenotyping on 18 resected IPMNs with varying degrees of dysplasia and for a subset, concomitant carcinoma, using a commercially available NGS-panel of 51 oncogenes. We simulated endoscopic biopsies by performing punch biopsies (PBs) of the cyst wall from resected specimens. RESULTS: In total, 127 NGS analyses were performed. Concomitant KRAS and GNAS was a common feature of the IPMNs. Mutations in KRAS and GNAS were associated with low-grade dysplasia whereas alterations in TP53, SMAD4, CDKN2A and PIK3CA were associated with high-grade dysplasia and/or carcinoma. The mutational analysis of the PBs from the cyst wall was compared with the whole lesion. No difference was detected between PBs and whole lesions when the cumulated mutational profile in increasing order of randomly performed PBs was compared. CONCLUSIONS: Small IPMN biopsies from the cyst wall are adequate to yield a molecular diagnosis.
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OBJECTIVES: To address the diagnostic accuracy of endoscopic ultrasound guided through-the-needle-biopsies (TTNBs) and simultaneously obtained cytology samples from pancreatic cysts compared to the final histopathological diagnosis of the surgical specimen, and to give an overview of ancillary tests performed on TTNBs. METHODS: A literature search was conducted in MEDLINE, Embase and Scopus. Studies were included in the meta-analysis, if they had data for TTNB, cytology and a surgical specimen of pancreatic cysts as reference standard. The assessment of the risk of bias and quality of the included studies was conducted using the modified QUADAS-2 tool. RESULTS: Ten studies with 99 patients were included in the meta-analysis. Data regarding study design and clinicopathological features were extracted systematically. For TTNB, pooled sensitivity was 0.86 (95 % CI 0.62-0.96), specificity 0.95 (95 % CI 0.79-0.99) and area under the curve (AUC) 0.86 for the diagnosis of a mucinous cyst and pooled sensitivity was 0.78 (95 % CI 0.61-0.89), specificity 0.99 (95 % CI 0.90-0.99) and AUC 0.92 for the diagnosis of a high-risk cyst. For a specific diagnosis, pooled sensitivity was 0.69 (95 % CI 0.50-0.83), specificity 0.47 (95 % CI 0.28-0.68) and AUC 0.49. For cytology performed simultaneously, pooled sensitivity was 0.46 (95 % CI 0.35-0.57), specificity 0.90 (95 % CI 0.46-0.99) and AUC 0.64 for the diagnosis of mucinous cysts, and pooled sensitivity was 0.38 (95 % CI 0.23-0.55), specificity 0.99 (95 % CI 0.90-0.99) and AUC 0.84 for the diagnosis of a high-risk cyst. For a specific diagnosis, pooled sensitivity was 0.29 (95 % CI 0.21-0.39), specificity 0.45 (95 % CI 0.25-0.66) and AUC 0.30. Furthermore, immunohistochemical stains can be useful to establish the specific cyst subtype. CONCLUSIONS: TTNBs have a higher sensitivity and specificity than cytology for the diagnosis of mucinous cyst and high- risk cysts of the pancreas.
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Aspiração por Agulha Fina Guiada por Ultrassom Endoscópico , Neoplasias Císticas, Mucinosas e Serosas/patologia , Cisto Pancreático/patologia , Neoplasias Pancreáticas/patologia , Pseudocisto Pancreático/patologia , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias Císticas, Mucinosas e Serosas/cirurgia , Cisto Pancreático/cirurgia , Neoplasias Pancreáticas/cirurgia , Pseudocisto Pancreático/cirurgia , Valor Preditivo dos Testes , Reprodutibilidade dos TestesRESUMO
Glioblastomas (GBM) are heterogeneous highly vascular brain tumors exploiting the unique microenvironment in the brain to resist treatment and anti-tumor responses. Anti-angiogenic agents, immunotherapy, and targeted therapy have been studied extensively in GBM patients over a number of decades with minimal success. Despite maximal efforts, prognosis remains dismal with an overall survival of approximately 15 months.Bevacizumab, a humanized anti-vascular endothelial growth factor (VEGF) antibody, underwent accelerated approval by the U.S. Food and Drug Administration in 2009 for the treatment of recurrent GBM based on promising preclinical and early clinical studies. Unfortunately, subsequent clinical trials did not find overall survival benefit. Pursuing pleiotropic targets and leaning toward multitarget strategies may be a key to more effective therapeutic intervention in GBM, but preclinical evaluation requires careful consideration of model choices. In this study, we discuss bevacizumab resistance, dual targeting of pro-angiogenic modulators VEGF and YKL-40 in the context of brain tumor microenvironment, and how model choice impacts study conclusions and its translational significance.
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Bevacizumab/administração & dosagem , Neoplasias Encefálicas/tratamento farmacológico , Proteína 1 Semelhante à Quitinase-3/antagonistas & inibidores , Sistemas de Liberação de Medicamentos/métodos , Glioblastoma/tratamento farmacológico , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores , Animais , Antineoplásicos Imunológicos/administração & dosagem , Neoplasias Encefálicas/metabolismo , Proteína 1 Semelhante à Quitinase-3/metabolismo , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/fisiologia , Glioblastoma/metabolismo , Humanos , Camundongos , Camundongos Endogâmicos NOD , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/fisiologia , Fator A de Crescimento do Endotélio Vascular/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto/métodosRESUMO
OBJECTIVE: To systematically describe central (CNS) and peripheral (PNS) nervous system complications in hospitalized COVID-19 patients. METHODS: We conducted a prospective, consecutive, observational study of adult patients from a tertiary referral center with confirmed COVID-19. All patients were screened daily for neurological and neuropsychiatric symptoms during admission and discharge. Three-month follow-up data were collected using electronic health records. We classified complications as caused by SARS-CoV-2 neurotropism, immune-mediated or critical illness-related. RESULTS: From April to September 2020, we enrolled 61 consecutively admitted COVID-19 patients, 35 (57%) of whom required intensive care (ICU) management for respiratory failure. Forty-one CNS/PNS complications were identified in 28 of 61 (45.9%) patients and were more frequent in ICU compared to non-ICU patients. The most common CNS complication was encephalopathy (n = 19, 31.1%), which was severe in 13 patients (GCS ≤ 12), including 8 with akinetic mutism. Length of ICU admission was independently associated with encephalopathy (OR = 1.22). Other CNS complications included ischemic stroke, a biopsy-proven acute necrotizing encephalitis, and transverse myelitis. The most common PNS complication was critical illness polyneuromyopathy (13.1%), with prolonged ICU stay as independent predictor (OR = 1.14). Treatment-related PNS complications included meralgia paresthetica. Of 41 complications in total, 3 were para/post-infectious, 34 were secondary to critical illness or other causes, and 4 remained unresolved. Cerebrospinal fluid was negative for SARS-CoV-2 RNA in all 5 patients investigated. CONCLUSION: CNS and PNS complications were common in hospitalized COVID-19 patients, particularly in the ICU, and often attributable to critical illness. When COVID-19 was the primary cause for neurological disease, no signs of viral neurotropism were detected, but laboratory changes suggested autoimmune-mediated mechanisms.
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COVID-19 , Acidente Vascular Cerebral , Adulto , Seguimentos , Humanos , Sistema Nervoso Periférico , Estudos Prospectivos , RNA Viral , SARS-CoV-2RESUMO
Until recently, diagnostics of brain tumors were almost solely based on morphology and immunohistochemical stainings for relatively unspecific lineage markers. Although certain molecular markers have been known for longer than a decade (combined loss of chromosome 1p and 19q in oligodendrogliomas), molecular biomarkers were not included in the WHO scheme until 2016. Now, the classification of diffuse gliomas rests on an integration of morphology and molecular results. Also, for many other central nervous system tumor entities, specific diagnostic, prognostic and predictive biomarkers have been detected and continue to emerge. Previously, we considered brain tumors with similar histology to represent a single disease entity. We now realize that histologically identical tumors might show alterations in different molecular pathways, and often represent separate diseases with different natural history and response to treatment. Hence, knowledge about specific biomarkers is of great importance for individualized treatment and follow-up. In this paper we review the biomarkers that we currently use in the diagnostic work-up of brain tumors.
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Biomarcadores Tumorais , Neoplasias Encefálicas/diagnóstico , Astrocitoma/diagnóstico , Astrocitoma/genética , Neoplasias Encefálicas/genética , Ependimoma/diagnóstico , Ependimoma/genética , Glioma/diagnóstico , Glioma/genética , Humanos , Meduloblastoma/diagnóstico , Meduloblastoma/genética , Meningioma/diagnóstico , Meningioma/genética , Mutação , Oligodendroglioma/diagnóstico , Oligodendroglioma/genética , Tumor Rabdoide/diagnóstico , Tumor Rabdoide/genéticaRESUMO
Octapeptide repeat insertions (OPRI) found in the prion protein gene (PRNP) constitute a subgroup of pathogenic mutations linked to inherited prion diseases, a hallmark of which is a misfolded prion protein. The number of repeats in OPRI has been associated with different disease phenotypes. However, due to the rarity of the cases and heterogenous disease manifestations, the recognition and classification of these variants has been difficult. Here, we report the first Danish family, the fifth worldwide, carrying a novel 8-OPRI with a unique sequence of the additional 8 inserts: R1-R2-R2-R3-R2-R2-R2a-R2-R3g-R2-R2-R3-R4. The mutation was found on the allele coding for methionine at codon 129 in the PRNP gene. The clinical exome sequencing revealed that no other dementia-associated genes harbored pathogenic alterations. Mutation carriers had onset of symptoms in their early thirties, but disease duration varied from 5 to 11 years. Progressive dementia with psychiatric and motor symptoms were the most prominent clinical features. Clinical, pathological, and genetic characteristics of other 4 reported families with 8-OPRI were reviewed and compared with the findings in the Danish family.
Assuntos
Repetições de Microssatélites/genética , Doenças Priônicas/genética , Proteínas Priônicas/genética , Adulto , Idade de Início , Alelos , Demência/genética , Demência/psicologia , Progressão da Doença , Família , Feminino , Heterozigoto , Humanos , Masculino , Transtornos Mentais/genética , Transtornos Mentais/psicologia , Pessoa de Meia-Idade , Transtornos dos Movimentos/genética , Transtornos dos Movimentos/psicologia , Mutação/genética , Linhagem , Doenças Priônicas/psicologiaRESUMO
This is the first report of presumed sporadic Creutzfeldt-Jakob disease (sCJD) and Gerstmann-Sträussler-Scheinker disease (GSS) with the prion protein gene c.305C>T mutation (p.P102L) occurring in one family. The father and son were affected with GSS and the mother had a rapidly progressive form of CJD. Diagnosis of genetic, variant, and iatrogenic CJD was ruled out based on the mother's clinical history, genetic tests, and biochemical investigations, all of which supported the diagnosis of sCJD. However, given the low incidence of sCJD and GSS, their co-occurrence in one family is extraordinary and challenging. Thus, a hypothesis for the transmission of infectious prion proteins (PrPSc) via microchimerism was proposed and investigated. DNA from 15 different brain regions and plasma samples of the CJD patient was subjected to PCR and shallow sequencing for detection of a male sex-determining chromosome Y (chr. Y). However, no trace of chr. Y was found. A long CJD incubation period or presumed small concentrations of chr. Y may explain the obtained results. Further studies of CJD and GSS animal models with controlled genetic and proteomic features are needed to determine whether maternal CJD triggered via microchimerism by a GSS fetus might present a new PrPSc transmission route.