RESUMO
Intratumor heterogeneity is a main cause of the dismal prognosis of glioblastoma (GBM). Yet, there remains a lack of a uniform assessment of the degree of heterogeneity. With a multiscale approach, we addressed the hypothesis that intratumor heterogeneity exists on different levels comprising traditional regional analyses, but also innovative methods including computer-assisted analysis of tumor morphology combined with epigenomic data. With this aim, 157 biopsies of 37 patients with therapy-naive IDH-wildtype GBM were analyzed regarding the intratumor variance of protein expression of glial marker GFAP, microglia marker Iba1 and proliferation marker Mib1. Hematoxylin and eosin stained slides were evaluated for tumor vascularization. For the estimation of pixel intensity and nuclear profiling, automated analysis was used. Additionally, DNA methylation profiling was conducted separately for the single biopsies. Scoring systems were established to integrate several parameters into one score for the four examined modalities of heterogeneity (regional, cellular, pixel-level and epigenomic). As a result, we could show that heterogeneity was detected in all four modalities. Furthermore, for the regional, cellular and epigenomic level, we confirmed the results of earlier studies stating that a higher degree of heterogeneity is associated with poorer overall survival. To integrate all modalities into one score, we designed a predictor of longer survival, which showed a highly significant separation regarding the OS. In conclusion, multiscale intratumor heterogeneity exists in glioblastoma and its degree has an impact on overall survival. In future studies, the implementation of a broadly feasible heterogeneity index should be considered.
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Neoplasias Encefálicas , Glioblastoma , Humanos , Glioblastoma/patologia , Neoplasias Encefálicas/patologia , PrognósticoRESUMO
BACKGROUND: H3K27-altered diffuse midline gliomas are uncommon central nervous system tumors with extremely poor prognoses. CASE PRESENTATION: We report the case of a 24-year-old man patient with multiple, inter alia osseous metastases who presented with back pain, hemi-hypoesthesia, and hemi-hyperhidrosis. The patient underwent combined radio-chemotherapy and demonstrated temporary improvement before deteriorating. CONCLUSIONS: H3K27-altered diffuse midline glioma presents an infrequent but crucial differential diagnosis and should be considered in cases with rapid neurological deterioration and multiple intracranial and intramedullary tumor lesions in children and young adults. Combined radio-chemotherapy delayed the neurological deterioration, but unfortunately, progression occurred three months after the diagnosis.
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Glioma , Neoplasias da Coluna Vertebral , Criança , Masculino , Adulto Jovem , Humanos , Adulto , Neoplasias da Coluna Vertebral/complicações , Neoplasias da Coluna Vertebral/diagnóstico por imagem , Diagnóstico Diferencial , Osso e Ossos , Protocolos de Quimioterapia Combinada AntineoplásicaRESUMO
BACKGROUND: For recurrent glioblastoma (GB) patients, several therapy options have been established over the last years such as more aggressive surgery, re-irradiation or chemotherapy. Age and the Karnofsky Performance Status Scale (KPSS) are used to make decisions for these patients as these are established as prognostic factors in the initial diagnosis of GB. This study's aim was to evaluate preoperative patient comorbidities by using the age-adjusted Charlson Comorbidity Index (ACCI) as a prognostic factor for recurrent GB patients. METHODS: In this retrospective analysis we could include 123 patients with surgery for primary recurrence of GB from January 2007 until December 2016 (43 females, 80 males, mean age 57 years (range 21-80 years)). Preoperative age, sex, ACCI, KPSS and adjuvant treatment regimes were recorded for each patient. Extent of resection (EOR) was recorded as a complete/incomplete resection of the contrast-enhancing tumor part. RESULTS: Median overall survival (OS) was 9.0 months (95% CI 7.1-10.9 months) after first re-resection. Preoperative KPSS > 80% (P < 0.001) and EOR (P = 0.013) were associated with significantly improved survival in univariate analysis. Including these factors in multivariate analysis, preoperative KPSS < 80 (HR 2.002 [95% CI: 1.246-3.216], P = 0.004) and EOR are the only significant prognostic factor (HR 1.611 [95% CI: 1.036-2.505], P = 0.034). ACCI was not shown as a prognostic factor in univariate and multivariate analyses. CONCLUSION: For patients with surgery for recurrent glioblastoma, the ACCI does not add further information about patient's prognosis besides the well-established KPSS and extent of resection.
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Neoplasias Encefálicas , Glioblastoma , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias Encefálicas/epidemiologia , Neoplasias Encefálicas/terapia , Comorbidade , Feminino , Glioblastoma/epidemiologia , Glioblastoma/cirurgia , Humanos , Avaliação de Estado de Karnofsky , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Adulto JovemRESUMO
Although a pathophysiological impact remains difficult to prove in individual patient care, a patent foramen ovale (PFO) is currently considered of high relevance for secondary prophylaxis in selected patients with cryptogenic ischemic stroke. By quantification of histological clot composition, we aimed to enhance pathophysiological understanding of PFO attributable ischemic strokes. Retrospectively, we evaluated all cerebral clots retrieved by mechanical thrombectomy for acute ischemic stroke treatment between 2011 and 2021 at our comprehensive stroke care center. Inclusion criteria applied were cryptogenic stroke, age (≤60 years), and PFO status according to transesophageal echocardiography, resulting in a study population of 58 patients. Relative clot composition was calculated using orbit image analysis to define the ratio of main histologic components (fibrin/platelets (F/P), red blood cell count (RBC), leukocytes). Cryptogenic stroke patients with PFO (PFO+, n = 20) displayed a significantly higher percentage of RBC (0.57 ± 0.17; p = 0.002) and lower percentage of F/P (0.38 ± 0.15; p = 0.003) compared to patients without PFO (PFO-, n = 38) (RBC: 0.41 ± 0.21; F/P: 0.52 ± 0.20). In conclusion, histologic clot composition in cryptogenic stroke varies depending on the presence of a PFO. Our findings histologically support the concept that a PFO may be of pathophysiological relevance in cryptogenic ischemic stroke.
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Forame Oval Patente , AVC Isquêmico , Acidente Vascular Cerebral , Trombose , Ecocardiografia Transesofagiana/métodos , Forame Oval Patente/complicações , Forame Oval Patente/diagnóstico por imagem , Humanos , AVC Isquêmico/diagnóstico por imagem , AVC Isquêmico/etiologia , Pessoa de Meia-Idade , Estudos Retrospectivos , Acidente Vascular Cerebral/complicações , Acidente Vascular Cerebral/etiologia , Trombose/complicaçõesRESUMO
OBJECTIVE: The number of diagnosed fatal encephalitis cases in humans caused by the classical Borna disease virus (BoDV-1) has been increasing, ever since it was proved that BoDV-1 can cause human infections. However, awareness of this entity is low, and a specific imaging pattern has not yet been identified. We therefore provide the first comprehensive description of the morphology of human BoDV-1 encephalitis, with histopathological verification of imaging abnormalities. METHODS: In an institutional review board-approved multicenter study, we carried out a retrospective analysis of 55 magnetic resonance imaging (MRI) examinations of 19 patients with confirmed BoDV-1 encephalitis. Fifty brain regions were analyzed systematically (T1w, T2w, T2*w, T1w + Gd, and DWI), in order to discern a specific pattern of inflammation. Histopathological analysis of 25 locations in one patient served as correlation for MRI abnormalities. RESULTS: Baseline imaging, acquired at a mean of 11 ± 10 days after symptom onset, in addition to follow-up scans of 16 patients, revealed characteristic T2 hyperintensities with a predilection for the head of the caudate nucleus, insula, and cortical spread to the limbic system, whereas the occipital lobes and cerebellar hemispheres were unaffected. This gradient was confirmed by histology. Nine patients (47.4%) developed T1 hyperintensities of the basal ganglia, corresponding to accumulated lipid phagocytes on histology and typical for late-stage necrosis. INTERPRETATION: BoDV-1 encephalitis shows a distinct pattern of inflammation in both the early and late stages of the disease. Its appearance can mimic sporadic Creutzfeldt-Jakob disease on MRI and should be considered a differential diagnosis in the case of atypical clinical presentation. ANN NEUROL 2020;88:723-735.
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Encefalite Viral/patologia , Infecções por Mononegavirales/patologia , Adolescente , Adulto , Idoso , Bornaviridae , Encéfalo/patologia , Criança , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Fenótipo , Estudos Retrospectivos , Adulto JovemRESUMO
Exposure of the anterior skull base is challenging due to strategic structures. The interhemispheric approach (IHA) has turned out to be a feasible technique. We report our experience with IHAs in patients with extraaxial lesions (EAL). We performed a retrospective chart review at a tertiary neurosurgical center between April 2009 and March 2020. We included patients with resection of EAL through IHAs concentrating on surgical technique, complete resection rate, postoperative outcome, and complications. Seventy-four patients resected by an IHA were included: 49 (66.2%) frontal (FIA), nine (12.1%) parietooccipital (PIA), and 16 (21.6%) frontobasal IHAs (FBIAs). Median age at time of surgery was 59 years (range 16-88 years), 47 (63.5%) female and 27 (36.5%) male. Complete resection rate was 83.8% (FIA 89.8%, PIA 55.6%, FBIA 81.3%). Rate of new minor deficits was 17.6%, rate of major deficits 5.4%, total rate 23.0%. 51 (68.9%) WHO°I meningiomas, ten (13.5%) WHO°II meningiomas, two (2.7%) WHO°III meningiomas, nine (12.2%) metastases, one (1.4%) sarcoma, and one (1.4%) local adenocarcinoma were resected. Total complication rate was 27.0%. Rate of major complications requiring intervention was 9.6%. Mean follow-up was 34.2 (± 33.2) months. In patients with lesions of the interhemispheric fissure, overall morbidity and complications are comparatively high. Extensions of IHAs with potential even higher morbidity are not necessary though; we support the use of standardized IHAs. Our findings suggest regular usage of relatively feasible IHAs for a satisfying outcome. Invasive, complicated, or contralateral trajectories were not needed.
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Neoplasias Meníngeas , Meningioma , Neoplasias da Base do Crânio , Feminino , Humanos , Masculino , Neoplasias Meníngeas/cirurgia , Meningioma/cirurgia , Procedimentos Neurocirúrgicos , Estudos Retrospectivos , Neoplasias da Base do Crânio/cirurgia , Resultado do TratamentoRESUMO
Machine Learning (ML) has evolved beyond being a specialized technique exclusively used by computer scientists. Besides the general ease of use, automated pipelines allow for training sophisticated ML models with minimal knowledge of computer science. In recent years, Automated ML (AutoML) frameworks have become serious competitors for specialized ML models and have even been able to outperform the latter for specific tasks. Moreover, this success is not limited to simple tasks but also complex ones, like tumor segmentation in histopathological tissue, a very time-consuming task requiring years of expertise by medical professionals. Regarding medical image segmentation, the leading AutoML frameworks are nnU-Net and deepflash2. In this work, we begin to compare those two frameworks in the area of histopathological image segmentation. This use case proves especially challenging, as tumor and healthy tissue are often not clearly distinguishable by hard borders but rather through heterogeneous transitions. A dataset of 103 whole-slide images from 56 glioblastoma patients was used for the evaluation. Training and evaluation were run on a notebook with consumer hardware, determining the suitability of the frameworks for their application in clinical scenarios rather than high-performance scenarios in research labs.
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Glioblastoma , Humanos , Glioblastoma/diagnóstico por imagem , Neoplasias Encefálicas/diagnóstico por imagem , Aprendizado de Máquina , Interpretação de Imagem Assistida por Computador/métodos , Redes Neurais de ComputaçãoRESUMO
ABSTRACTBorna disease virus 1 (BoDV-1) was just recently shown to cause predominantly fatal encephalitis in humans. Despite its rarity, bornavirus encephalitis (BVE) can be considered a model disease for encephalitic infections caused by neurotropic viruses and understanding its pathomechanism is of utmost relevance. Aim of this study was to compare the extent and distribution pattern of cerebral inflammation with the clinical course of disease, and individual therapeutic procedures. For this, autoptic brain material from seven patients with fatal BVE was included in this study. Tissue was stained immunohistochemically for pan-lymphocytic marker CD45, the nucleoprotein of BoDV-1, as well as glial marker GFAP and microglial marker Iba1. Sections were digitalized and counted for CD45-positive and BoDV-1-positive cells. For GFAP and Iba1, a semiquantitative score was determined. Furthermore, detailed information about the individual clinical course and therapy were retrieved and summarized in a standardized way. Analysis of the distribution of lymphocytes shows interindividual patterns. In contrast, when looking at the BoDV-1-positive glial cells and neurons, a massive viral involvement in the brain stem was noticeable. Three of the seven patients received early high-dose steroids, which led to a significantly lower lymphocytic infiltration of the central nervous tissue and a longer survival compared to the patients who were treated with steroids later in the course of disease. This study highlights the potential importance of early high-dose immunosuppressive therapy in BVE. Our findings hint at a promising treatment option which should be corroborated in future observational or prospective therapy studies.ABBREVIATIONS: BoDV-1: Borna disease virus 1; BVE: bornavirus encephalitis; Cb: cerebellum; CNS: central nervous system; FL: frontal lobe; GFAP: glial fibrillary acid protein; Hc: hippocampus; Iba1: ionized calcium-binding adapter molecule 1; Iba1act: general activation of microglial cells; Iba1nod: formation of microglial nodules; IL: insula; Me: mesencephalon; Mo: medulla oblongata; OL: occipital lobe; pASS: per average of 10 screenshots; patearly: patients treated with early high dose steroid shot; patlate: patients treated with late or none high dose steroid shot; Po: pons; So: stria olfactoria; Str: striatum.
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Encéfalo , Humanos , Masculino , Feminino , Encéfalo/virologia , Encéfalo/imunologia , Doença de Borna/tratamento farmacológico , Doença de Borna/virologia , Linfócitos/imunologia , Proteínas dos Microfilamentos/metabolismo , Antígenos Comuns de Leucócito/metabolismo , Proteína Glial Fibrilar Ácida/metabolismo , Proteínas de Ligação ao Cálcio/metabolismo , Terapia de Imunossupressão , Vírus da Doença de Borna/fisiologia , Encefalite Viral/tratamento farmacológico , Encefalite Viral/virologia , Encefalite Viral/imunologia , Neuroglia/virologia , Neuroglia/metabolismoRESUMO
BACKGROUND: Nowadays, there is no method to quantitatively characterize the material composition of acute ischemic stroke thrombi prior to intervention, but dual-energy CT (DE-CT) offers imaging-based multimaterial decomposition. We retrospectively investigated the material composition of thrombi ex vivo using DE-CT with histological analysis as a reference. METHODS: Clots of 70 patients with acute ischemic stroke were extracted by mechanical thrombectomy and scanned ex vivo in formalin-filled tubes with DE-CT. Multimaterial decomposition in the three components, i.e., red blood cells (RBC), white blood cells (WBC), and fibrin/platelets (F/P), was performed and compared to histology (hematoxylin/eosin staining) as reference. Attenuation and effective Z values were assessed, and histological composition was compared to stroke etiology according to the Trial of ORG 10172 in Acute Stroke Treatment (TOAST) criteria. RESULTS: Histological and imaging analysis showed the following correlation coefficients for RBC (r = 0.527, p < 0.001), WBC (r = 0.305, p = 0.020), and F/P (r = 0.525, p < 0.001). RBC-rich thrombi presented higher clot attenuation in Hounsfield units than F/P-rich thrombi (51 HU versus 42 HU, p < 0.01). In histological analysis, cardioembolic clots showed less RBC (40% versus 56%, p = 0.053) and more F/P (53% versus 36%, p = 0.024), similar to cryptogenic clots containing less RBC (34% versus 56%, p = 0.006) and more F/P (58% versus 36%, p = 0.003) than non-cardioembolic strokes. No difference was assessed for the mean WBC portions in all TOAST groups. CONCLUSIONS: DE-CT has the potential to quantitatively characterize the material composition of ischemic stroke thrombi. RELEVANCE STATEMENT: Using DE-CT, the composition of ischemic stroke thrombi can be determined. Knowledge of histological composition prior to intervention offers the opportunity to define personalized treatment strategies for each patient to accomplish faster recanalization and better clinical outcomes. KEY POINTS: ⢠Acute ischemic stroke clots present different recanalization success according to histological composition. ⢠Currently, no method can determine clot composition prior to intervention. ⢠DE-CT allows quantitative material decomposition of thrombi ex vivo in red blood cells, white blood cells, and fibrin/platelets. ⢠Histological clot composition differs between stroke etiology. ⢠Insights into the histological composition in situ offer personalized treatment strategies.
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AVC Isquêmico , Acidente Vascular Cerebral , Trombose , Humanos , Fibrina/análise , Estudos Retrospectivos , Acidente Vascular Cerebral/diagnóstico por imagem , Acidente Vascular Cerebral/patologia , Acidente Vascular Cerebral/terapia , Trombose/diagnóstico por imagem , Trombose/patologia , Trombose/terapia , Tomografia Computadorizada por Raios X/métodosRESUMO
BACKGROUND: The aim of this clinical trial was to compare Fluorescein-stained intraoperative confocal laser endomicroscopy (CLE) of intracranial lesions and evaluation by a neuropathologist with routine intraoperative frozen section (FS) assessment by neuropathology. METHODS: In this phase II noninferiority, prospective, multicenter, nonrandomized, off-label clinical trial (EudraCT: 2019-004512-58), patients above the age of 18 years with any intracranial lesion scheduled for elective resection were included. The diagnostic accuracies of both CLE and FS referenced with the final histopathological diagnosis were statistically compared in a noninferiority analysis, representing the primary endpoint. Secondary endpoints included the safety of the technique and time expedited for CLE and FS. RESULTS: A total of 210 patients were included by 3 participating sites between November 2020 and June 2022. Most common entities were high-grade gliomas (37.9%), metastases (24.1%), and meningiomas (22.7%). A total of 6 serious adverse events in 4 (2%) patients were recorded. For the primary endpoint, the diagnostic accuracy for CLE was inferior with 0.87 versus 0.91 for FS, resulting in a difference of 0.04 (95% confidence interval -0.10; 0.02; P = .367). The median time expedited until intraoperative diagnosis was 3 minutes for CLE and 27 minutes for FS, with a mean difference of 27.5 minutes (standard deviation 14.5; P < .001). CONCLUSIONS: CLE allowed for a safe and time-effective intraoperative histological diagnosis with a diagnostic accuracy of 87% across all intracranial entities included. The technique achieved histological assessments in real time with a 10-fold reduction of processing time compared to FS, which may invariably impact surgical strategy on the fly.
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Neoplasias Encefálicas , Fluoresceína , Secções Congeladas , Microscopia Confocal , Humanos , Neoplasias Encefálicas/cirurgia , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/diagnóstico por imagem , Masculino , Microscopia Confocal/métodos , Feminino , Pessoa de Meia-Idade , Estudos Prospectivos , Secções Congeladas/métodos , Idoso , Adulto , Seguimentos , Adulto Jovem , Prognóstico , Idoso de 80 Anos ou maisRESUMO
BACKGROUND: Inflammatory demyelinating diseases of the central nervous system, such as multiple sclerosis, are significant sources of morbidity in young adults despite therapeutic advances. Current murine models of remyelination have limited applicability due to the low white matter content of their brains, which restricts the spatial resolution of diagnostic imaging. Large animal models might be more suitable but pose significant technological, ethical and logistical challenges. METHODS: We induced targeted cerebral demyelinating lesions by serially repeated injections of lysophosphatidylcholine in the minipig brain. Lesions were amenable to follow-up using the same clinical imaging modalities (3T magnetic resonance imaging, 11C-PIB positron emission tomography) and standard histopathology protocols as for human diagnostics (myelin, glia and neuronal cell markers), as well as electron microscopy (EM), to compare against biopsy data from two patients. FINDINGS: We demonstrate controlled, clinically unapparent, reversible and multimodally trackable brain white matter demyelination in a large animal model. De-/remyelination dynamics were slower than reported for rodent models and paralleled by a degree of secondary axonal pathology. Regression modelling of ultrastructural parameters (g-ratio, axon thickness) predicted EM features of cerebral de- and remyelination in human data. INTERPRETATION: We validated our minipig model of demyelinating brain diseases by employing human diagnostic tools and comparing it with biopsy data from patients with cerebral demyelination. FUNDING: This work was supported by the DFG under Germany's Excellence Strategy within the framework of the Munich Cluster for Systems Neurology (EXC 2145 SyNergy, ID 390857198) and TRR 274/1 2020, 408885537 (projects B03 and Z01).
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Doenças Desmielinizantes , Esclerose Múltipla , Substância Branca , Suínos , Humanos , Animais , Camundongos , Doenças Desmielinizantes/diagnóstico por imagem , Doenças Desmielinizantes/patologia , Cuprizona , Porco Miniatura , Esclerose Múltipla/diagnóstico por imagem , Esclerose Múltipla/patologia , Bainha de Mielina/patologia , Substância Branca/patologia , Microscopia Eletrônica , Modelos Animais de DoençasRESUMO
Medulloblastomas (MBs) are malignant pediatric brain tumors that are molecularly and clinically heterogenous. The application of omics technologies-mainly studying nucleic acids-has significantly improved MB classification and stratification, but treatment options are still unsatisfactory. The proteome and their N-glycans hold the potential to discover clinically relevant phenotypes and targetable pathways. We compile a harmonized proteome dataset of 167 MBs and integrate findings with DNA methylome, transcriptome and N-glycome data. We show six proteome MB subtypes, that can be assigned to two main molecular programs: transcription/translation (pSHHt, pWNT and pG3myc), and synapses/immunological processes (pSHHs, pG3 and pG4). Multiomic analysis reveals different conservation levels of proteome features across MB subtypes at the DNA methylome level. Aggressive pGroup3myc MBs and favorable pWNT MBs are most similar in cluster hierarchies concerning overall proteome patterns but show different protein abundances of the vincristine resistance-associated multiprotein complex TriC/CCT and of N-glycan turnover-associated factors. The N-glycome reflects proteome subtypes and complex-bisecting N-glycans characterize pGroup3myc tumors. Our results shed light on targetable alterations in MB and set a foundation for potential immunotherapies targeting glycan structures.
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Meduloblastoma , Polissacarídeos , Proteoma , Meduloblastoma/metabolismo , Meduloblastoma/genética , Humanos , Polissacarídeos/metabolismo , Proteoma/metabolismo , Neoplasias Cerebelares/metabolismo , Neoplasias Cerebelares/genética , Metilação de DNA , Transcriptoma , Criança , Proteômica/métodos , Feminino , Regulação Neoplásica da Expressão Gênica , Masculino , Pré-Escolar , Perfilação da Expressão Gênica/métodosRESUMO
Temozolomide (TMZ) is standard treatment for glioblastoma (GBM); nonetheless, resistance and tumor recurrence are still major problems. In addition to its association with recurrent GBM and TMZ resistance, ALDH1A3 has a role in autophagy-dependent ferroptosis activation. In this study, we treated TMZ-resistant LN229 human GBM cells with the ferroptosis inducer RSL3. Remarkably, TMZ-resistant LN229 clones were also resistant to ferroptosis induction, although lipid peroxidation was induced by RSL3. By using Western blotting, we were able to determine that ALDH1A3 was down-regulated in TMZ-resistant LN229 cells. Most intriguingly, the cell viability results showed that only those clones that up-regulated ALDH1A3 after TMZ withdrawal became re-sensitized to ferroptosis induction. The recovery of ALDH1A3 expression appeared to be regulated by EGFR-dependent PI3K pathway activation since Akt was activated only in ALDH1A3 high clones. Blocking the EGFR signaling pathway with the EGFR inhibitor AG1498 decreased the expression of ALDH1A3. These findings shed light on the potential application of RSL3 in the treatment of glioblastoma relapse.
Assuntos
Ferroptose , Glioblastoma , Humanos , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos , Receptores ErbB/metabolismo , Glioblastoma/tratamento farmacológico , Glioblastoma/genética , Glioblastoma/metabolismo , Recidiva Local de Neoplasia , Fosfatidilinositol 3-Quinases , Temozolomida/farmacologiaRESUMO
BACKGROUND: Around the world, the emergency brought about by the COVID-19 pandemic forced medical schools to create numerous e-learning supplements to provide instruction during this crisis. The question now is to determine a way in which to capitalize on this momentum of digitization and harness the medical e-learning content created for the future. We have analyzed the transition of a pathology course to an emergency remote education online course and, in the second step, applied a flipped classroom approach including research skills training. METHODS: In the summer semester of 2020, the pathology course at the Technical University of Munich was completely converted to an asynchronous online course. Its content was adapted in winter 2021 and incorporated into a flipped classroom concept in which research skills were taught at the same time. RESULTS: Screencasts and lecture recordings were the most popular asynchronous teaching formats. Students reported developing a higher interest in pathology and research through group work. The amount of content was very challenging for some students. CONCLUSION: Flipped classroom formats are a viable option when using pre-existing content. We recommend checking such content for technical and didactic quality and optimizing it if necessary. Content on research skills can be combined very well with clinical teaching content.
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Parkinson's disease (PD), multiple system atrophy (MSA), and dementia with Lewy bodies (DLB) are neurodegenerative disorders with alpha-synuclein (α-syn) aggregation pathology. Different strains of α-syn with unique properties are suggested to cause distinct clinical and pathological manifestations resulting in PD, MSA, or DLB. To study individual α-syn spreading patterns, we injected α-syn fibrils amplified from brain homogenates of two MSA patients and two PD patients into the brains of C57BI6/J mice. Antibody staining against pS129-α-syn showed that α-syn fibrils amplified from the brain homogenates of the four different patients caused different levels of α-syn spreading. The strongest α-syn pathology was triggered by α-syn fibrils of one of the two MSA patients, followed by comparable pS129-α-syn induction by the second MSA and one PD patient material. Histological analysis using an antibody against Iba1 further showed that the formation of pS129-α-syn is associated with increased microglia activation. In contrast, no differences in dopaminergic neuron numbers or co-localization of α-syn in oligodendrocytes were observed between the different groups. Our data support the spreading of α-syn pathology in MSA, while at the same time pointing to spreading heterogeneity between different patients potentially driven by individual patient immanent factors.
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Atrofia de Múltiplos Sistemas , Doença de Parkinson , Sinucleinopatias , Animais , Camundongos , alfa-Sinucleína/metabolismo , Anticorpos , Encéfalo/patologia , Atrofia de Múltiplos Sistemas/patologia , Doença de Parkinson/patologia , Sinucleinopatias/patologiaRESUMO
The fatal clinical course of human glioblastoma (GBM) despite aggressive adjuvant therapies is due to high rates of recurrent tumor growth driven by tumor cells with stem-cell characteristics (glioma stem cells, GSCs). The aldehyde dehydrogenase 1 (ALDH1) family of enzymes has been shown to be a biomarker for GSCs, and ALDH1 seems to be involved in the biological processes causing therapy resistance. Ferroptosis is a recently discovered cell death mechanism, that depends on iron overload and lipid peroxidation, and it could, therefore, be a potential therapeutic target in various cancer types. Since both ALDH1 and ferroptosis interact with lipid peroxidation (LPO), we aimed to investigate a possible connection between ALDH1 and ferroptosis. Here, we show that RSL3-induced LPO and ferroptotic cell death revealed RSL3-sensitive and -resistant malignant glioma cell lines. Most interestingly, RSL3 sensitivity correlates with ALDH1a3 expression; only high ALDH1a3-expressing cells seem to be sensitive to ferroptosis induction. In accordance, inhibition of ALDH1a3 enzymatic activity by chemical inhibition or genetic knockout protects tumor cells from RSL3-induced ferroptotic cell death. Both RSL-3-dependent binding of ALDH1a3 to LC3B and autophagic downregulation of ferritin could be completely blocked by ALDH inhibition. Therefore, ALDH1a3 seems to be involved in ferroptosis through the essential release of iron by ferritinophagy. Our results also indicate that ferroptosis induction might be a particularly interesting clinical approach for targeting the highly aggressive cell population of GSC.
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Ferroptose , Glioblastoma , Humanos , Família Aldeído Desidrogenase 1 , Autofagia , Ferroptose/genética , Glioblastoma/genética , Glioblastoma/metabolismo , Glioma/metabolismo , Recidiva Local de NeoplasiaRESUMO
This study reports a large single-center series of primary bone tumors of the spine (PBTs). We aimed to review the concepts for management, as this kind of tumor represents a very rare entity, and also propose a new treatment algorithm. Retrospective analysis revealed 92 patients receiving surgery for PBTs from 2007 to 2019 at our center. They were analyzed based on surgical management and the course of the disease. A total of 145 surgical procedures were performed (50 cervical, 46 thoracic, 28 lumbar, and 21 sacral). Complete tumor resection was achieved in 65%, of which 22% showed tumor recurrence during follow-up (mean time to recurrence 334 days). The five-year mortality rate was significantly lower after complete resection (3% versus 25% after subtotal resection). Most of the patients improved in their symptoms through surgery. Regarding the tumor entity, the most common PBTs were vertebral hemangiomas (20%), osteoid osteomas (15%), and chordomas (16%). The Enneking graduation system showed a good correlation with the risk of recurrence and mortality. Complete resection in PBTs increased survival rates and remains the method of choice. Thus, quality of life-especially with a higher extent of resection-should be considered.
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Background: JC virus reactivation causing progressive multifocal leukoencephalopathy (PML) occurs preferentially in human immunodeficiency virus (HIV) positive individuals or patients suffering from hematologic neoplasms due to impaired viral control. Reactivation in patients suffering from solid malignancies is rarely described in published literature. Case Presentation: Here we describe a case of PML in a male patient suffering from esophageal cancer who underwent neoadjuvant radiochemotherapy and surgical resection in curative intent resulting in complete tumor remission. The radiochemotherapy regimen contained carboplatin and paclitaxel (CROSS protocol). Since therapy onset, the patient presented with persistent and progredient leukopenia and lymphopenia in absence of otherwise known risk factors for PML. Symptom onset, which comprised aphasia, word finding disorder, and paresis, was apparent 7 months after therapy initiation. There was no relief in symptoms despite standard of care PML directed supportive therapy. The patient died two months after therapy onset. Conclusion: PML is a very rare event in solid tumors without obvious states of immununosuppression and thus harbors the risk of unawareness. The reported patient suffered from lymphopenia, associated with systemic therapy, but was an otherwise immunocompetent individual. In case of neurologic impairment in patients suffering from leukopenia, PML must be considered - even in the absence of hematologic neoplasia or HIV infection.