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BACKGROUND: Checkpoint inhibitor-induced overlap syndrome ([OS] myocarditis, and myositis with or without myasthenia gravis) is rare but life-threatening. CASES PRESENTATION: Here we present a case series of four cancer patients that developed OS. High troponinemia raised the concern for myocarditis in all the cases. However, the predominant clinical feature differed among the cases. Two patients showed marked myocarditis with a shorter hospital stay. The other two patients had a prolonged ICU stay due to severe neuromuscular involvement secondary to myositis and myasthenia gravis. Treatment was based on steroids, plasmapheresis, intravenous immunoglobulin, and immunosuppressive biological agents. CONCLUSION: The management of respiratory failure is challenging, particularly in those patients with predominant MG. Along with intensive clinical monitoring, bedside respiratory mechanics can guide the decision-making process of selecting a respiratory support method, the timing of elective intubation and extubation.
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Miastenia Gravis , Miocardite , Miosite , Insuficiência Respiratória , Humanos , Inibidores de Checkpoint Imunológico , Imunossupressores , Síndrome , Insuficiência Respiratória/induzido quimicamente , Insuficiência Respiratória/terapiaRESUMO
INTRODUCTION/AIMS: Needle electromyography (EMG) is understood to be a relatively safe procedure based on clinical experience. There are no evidence-based guidelines for EMG procedures in thrombocytopenic patients. The purpose of this study was to determine whether there is an increased risk of bleeding complications associated with needle EMG in patients with thrombocytopenia. METHODS: This retrospective study included patients with a primary cancer and thrombocytopenia who underwent needle EMG between January 1, 2016 and October 30, 2020. Patients' medical records were reviewed for demographics; diagnoses; platelet counts within a 7-day period of EMG examination; concurrent use of anticoagulants or antiplatelet medications; number of sites sampled by needle EMG, including anatomical differentiation of paraspinal and both deep and superficial limb muscles; and associated complications not limited to bleeding within 30 days of EMG examination. RESULTS: The initial data search identified 198 patients with a documented diagnosis of thrombocytopenia; 124 met these criteria and were included in the study. A total of 1001 muscle sample sites were documented, with 111 sites in paraspinal muscles, 876 sites in superficial limb muscles, and 14 sites within deep limb muscles. Five patients were concurrently using therapeutic anticoagulation and 3 were using antiplatelet medications. There were no clinically significant complications, but five minor incidents were documented in the medical records within 30 days post-EMG examination. DISCUSSION: Our findings suggest that bleeding complications from standard needle EMG in oncology patients with documented thrombocytopenia are rare. Testing of high-risk muscles in this patient population appears to be safe.
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Neoplasias , Inibidores da Agregação Plaquetária , Anticoagulantes/efeitos adversos , Eletromiografia/efeitos adversos , Eletromiografia/métodos , Humanos , Neoplasias/complicações , Inibidores da Agregação Plaquetária/efeitos adversos , Estudos RetrospectivosRESUMO
JC virus, the cause of progressive multifocal leukoencephalopathy (PML), and the BK virus are genetically similar and share sequence homology in immunogenic proteins. We treated three immunosuppressed patients with PML with ex vivo-expanded, partially HLA-matched, third-party-produced, cryopreserved BK virus-specific T cells. The immunosuppression in these patients was due to the conditioning regimen for cord-blood transplantation in one patient, a myeloproliferative neoplasm treated with ruxolitinib in another, and acquired immunodeficiency syndrome in the third. After T-cell infusion in two of the patients, alleviation of the clinical signs and imaging features of PML was seen and JC virus in the cerebrospinal fluid (CSF) cleared. The other patient had a reduction in JC viral load and stabilization of symptoms that persisted until her death 8 months after the first infusion. Two of the patients had immune reconstitution syndrome. Donor-derived T cells were detected in the CSF after infusion. (Funded by the M.D. Anderson Cancer Center Moon Shots Program and the National Institutes of Health; ClinicalTrials.gov number, NCT02479698 .).
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Vírus BK/imunologia , Terapia Baseada em Transplante de Células e Tecidos , Leucoencefalopatia Multifocal Progressiva/terapia , Linfócitos T/transplante , Adulto , Idoso , Encéfalo/diagnóstico por imagem , Terapia Baseada em Transplante de Células e Tecidos/efeitos adversos , Feminino , Humanos , Síndrome Inflamatória da Reconstituição Imune , Hospedeiro Imunocomprometido , Infusões Parenterais , Vírus JC , Leucoencefalopatia Multifocal Progressiva/diagnóstico por imagem , Leucoencefalopatia Multifocal Progressiva/virologia , Imageamento por Ressonância Magnética , Masculino , Linfócitos T/imunologia , Transplante Homólogo , Carga ViralRESUMO
INTRODUCTION: Paraneoplastic cerebellar degeneration (PCD) is a rare set of neurological disorders arising from tumor-associated autoimmunity against antigens within the cerebellum. Anti-Purkinje cell cytoplasmic antibody 1 (PCA-1), or anti-Yo, is the most commonly linked antibody and is classically associated with breast and ovarian cancers. METHODS: Medical records of patients at our institution who developed PCA-1 associated PCD were reviewed. Clinical information, including cancer history, cancer-directed treatment, and serum and CSF titers of PCA-1 antibody were extracted. CASES: We report a series of cases of PCA-1 associated PCD in patients with known breast or ovarian cancer diagnosis not receiving immunotherapy. These cases highlight aspects of PCA-1 paraneoplastic syndrome such as triggering by cytotoxic chemotherapy or surgery, the possibility of tumor recurrence and the association with development of a second cancer. DISCUSSION: Diagnosis of the syndrome requires neurological workup with lumbar puncture (LP) with cerebrospinal fluids (CSF) studies, serum and CSF paraneoplastic antibody panel, and neuroimaging. Inpatient admission for prompt workup and initiation of treatment is recommended. Treatment most commonly includes immunosuppression with corticosteroids, plasmapheresis, and/or intravenous immune globulin (IVIG); however, we postulate that other immune modulating treatments may warrant consideration. CONCLUSION: These cases highlight the need for early recognition of the syndrome in patients receiving nonimmune based chemotherapy, for prompt workup and treatment.
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Neoplasias Ovarianas , Degeneração Paraneoplásica Cerebelar , Anticorpos Antineoplásicos , Antígenos de Neoplasias , Autoanticorpos , Cerebelo , Feminino , Humanos , Recidiva Local de Neoplasia , Neoplasias Ovarianas/complicações , Neoplasias Ovarianas/terapia , Degeneração Paraneoplásica Cerebelar/etiologia , Degeneração Paraneoplásica Cerebelar/terapiaRESUMO
Immunotherapy has revolutionized treatment of cancer over the past two decades. The antitumor effects of immunotherapy approaches are at the expense of growing spectrum of immune-related adverse events (irAEs) due to cross-reactivity between the tumor and normal host tissue. These adverse events can happen in any organ and range from mild to severe and even life-threatening conditions. While neurological irAEs associated with immune checkpoint inhibitors (CPIs) are rare, they pose a significant challenge in management as the clinical phenotypes are heterogenous and frequently necessitate cessation of therapy and systemic immune suppression and lead to transient functional decline. On the other hand, immune effector cell-associated neurotoxicity (ICANS) is common, frequently occurs in conjunction with cytokine release syndrome (CRS), and poses a significant clinical challenge to the development and widespread use of these effective therapies. Early recognition of these neurological syndromes, timely diagnosis, and thoughtful management are key for further clinical development of these effective therapies in cancer patients. Here, we describe clinical phenotypes of CPI-induced neurological complications and ICANS and discuss steps in clinical monitoring, diagnosis, and effective management.
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Neoplasias , Síndromes Neurotóxicas , Humanos , Fatores Imunológicos , Imunoterapia/efeitos adversos , Neoplasias/tratamento farmacológico , Síndromes Neurotóxicas/etiologia , Síndromes Neurotóxicas/terapiaRESUMO
PURPOSE OF REVIEW: This review provides clinical characterization and approach to management of neurotoxicities associated with checkpoint inhibitor therapy and chimeric antigen receptor T cell (CAR T cell) therapy. RECENT FINDINGS: Immuno-oncology has revolutionized cancer treatment. The immunomodulatory effect of these treatments extends beyond the targeted cancers; however, with a range of immune-mediated toxicities being associated with these therapies. Both the peripheral and central nervous system are vulnerable to these toxicities, with several distinct clinical syndromes strongly associated with specific immunotherapies. Neurologic immune-related adverse events are significant sequelae of both checkpoint inhibitors and CAR T cell therapy. In addition to clinical characterization of these syndromes, an understanding of the biologic underpinnings of these sequelae is essential. This will facilitate identification of patients at risk of these toxicities, develop treatments to prevent them and identify more effective clinical treatment when they occur.
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Neoplasias , Síndromes Neurotóxicas , Humanos , Imunoterapia/efeitos adversos , Neoplasias/terapiaRESUMO
OBJECTIVE: B vitamins are essential for the functioning of the nervous system. Vitamin B1 (thiamine) deficiency is associated with neuropsychiatric syndromes such as Wernicke's encephalopathy (WE), which, if untreated, has an estimated mortality of 17-20%. Although the prevalence of thiamine deficiency in the general population is difficult to estimate, it is being increasingly recognized in oncology, especially in the inpatient setting. We describe three cases of thiamine deficiency (TD) in the outpatient psychiatric oncology setting. METHOD: Retrospective chart review of three adult patients, who were seen in the psychiatric oncology clinic and found to have TD on laboratory testing, was done. Patient, disease, and thiamine treatment-related information were obtained, and descriptive statistics were used to analyze the data. RESULTS: The average age was 59 years, mean body mass index (BMI) was 22.00 ± 4.58 (mean ± SD), and mean thiamine level was 59.10 ± 7.69 that ranged from 45 to 68 nmol/L (normal thiamine level reference: 70-180 nmol/L). None of the patients had brain imaging nor cerebrospinal fluid analysis. Risk factors such as unbalanced nutrition, prior GI surgery, renal disease, and chemotherapy were noted. SIGNIFICANCE OF RESULTS: TD can have a multifactorial etiology in oncology. Identification of TD in both inpatient and outpatient setting is important. Our report highlights how early identification of TD in the outpatient setting can help prevent further clinical progression.
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Oncologia/métodos , Serviços de Saúde Mental/estatística & dados numéricos , Deficiência de Tiamina/complicações , Idoso , Instituições de Assistência Ambulatorial/organização & administração , Instituições de Assistência Ambulatorial/estatística & dados numéricos , Índice de Massa Corporal , Feminino , Humanos , Masculino , Oncologia/estatística & dados numéricos , Transtornos Mentais/psicologia , Transtornos Mentais/terapia , Pessoa de Meia-Idade , Pacientes Ambulatoriais/estatística & dados numéricos , Prevalência , Estudos Retrospectivos , Fatores de Risco , Deficiência de Tiamina/psicologiaRESUMO
High-frequency oscillations in local field potentials recorded with intracranial EEG are putative biomarkers of seizure onset zones in epileptic brain. However, localized 80-500 Hz oscillations can also be recorded from normal and non-epileptic cerebral structures. When defined only by rate or frequency, physiological high-frequency oscillations are indistinguishable from pathological ones, which limit their application in epilepsy presurgical planning. We hypothesized that pathological high-frequency oscillations occur in a repetitive fashion with a similar waveform morphology that specifically indicates seizure onset zones. We investigated the waveform patterns of automatically detected high-frequency oscillations in 13 epilepsy patients and five control subjects, with an average of 73 subdural and intracerebral electrodes recorded per patient. The repetitive oscillatory waveforms were identified by using a pipeline of unsupervised machine learning techniques and were then correlated with independently clinician-defined seizure onset zones. Consistently in all patients, the stereotypical high-frequency oscillations with the highest degree of waveform similarity were localized within the seizure onset zones only, whereas the channels generating high-frequency oscillations embedded in random waveforms were found in the functional regions independent from the epileptogenic locations. The repetitive waveform pattern was more evident in fast ripples compared to ripples, suggesting a potential association between waveform repetition and the underlying pathological network. Our findings provided a new tool for the interpretation of pathological high-frequency oscillations that can be efficiently applied to distinguish seizure onset zones from functionally important sites, which is a critical step towards the translation of these signature events into valid clinical biomarkers.awx374media15721572971001.
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Mapeamento Encefálico , Córtex Cerebral/fisiopatologia , Epilepsias Parciais/patologia , Adolescente , Adulto , Criança , Pré-Escolar , Eletrodos Implantados , Eletroencefalografia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , PeriodicidadeRESUMO
OBJECTIVE: Obstructive sleep apnea (OSA) is accompanied by brain changes in areas that regulate autonomic, cognitive, and mood functions, which were initially examined by Gaussian-based diffusion tensor imaging measures, but can be better assessed with non-Gaussian measures. We aimed to evaluate axonal and myelin changes in OSA using axial (AK) and radial kurtosis (RK) measures. MATERIALS AND METHODS: We acquired diffusion kurtosis imaging data from 22 OSA and 26 controls; AK and RK maps were calculated, normalized, smoothed, and compared between groups using analysis of covariance. RESULTS: Increased AK, indicating axonal changes, emerged in the insula, hippocampus, amygdala, dorsolateral pons, and cerebellar peduncles and showed more axonal injury over previously identified damage. Higher RK, showing myelin changes, appeared in the hippocampus, amygdala, temporal and frontal lobes, insula, midline pons, and cerebellar peduncles and showed more widespread myelin damage over previously identified injury. CONCLUSIONS: Axial kurtosis and RK measures showed widespread changes over Gaussian-based techniques, suggesting a more sensitive nature of kurtoses to injury.
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Axônios , Imagem de Tensor de Difusão/métodos , Bainha de Mielina , Apneia Obstrutiva do Sono/diagnóstico por imagem , Encéfalo/diagnóstico por imagem , Encéfalo/fisiopatologia , Mapeamento Encefálico/métodos , Estudos Transversais , Imagem de Difusão por Ressonância Magnética/métodos , Feminino , Humanos , Processamento de Imagem Assistida por Computador/métodos , Masculino , Pessoa de Meia-Idade , Reprodutibilidade dos Testes , Apneia Obstrutiva do Sono/fisiopatologiaRESUMO
Obstructive sleep apnea (OSA) is characterized by recurrent upper airway blockage, with continued diaphragmatic efforts to breathe during sleep. Brain structural changes in OSA appear in various regions, including white matter sites that mediate autonomic, mood, cognitive, and respiratory control. However, the relationships between brain white matter changes and disease severity in OSA are unclear. This study examines associations between an index of tissue integrity, magnetization transfer (MT) ratio values (which show MT between free and proton pools associated with tissue membranes and macromolecules), and disease severity (apnea-hypopnea index [AHI]) in OSA subjects. We collected whole-brain MT imaging data from 19 newly diagnosed, treatment-naïve OSA subjects (50.4 ± 8.6 years of age, 13 males, AHI 39.7 ± 24.3 events/hr], using a 3.0-Tesla MRI scanner. With these data, whole-brain MT ratio maps were calculated, normalized to common space, smoothed, and correlated with AHI scores by using partial correlation analyses (covariates, age and gender; P < 0.005). Multiple brain sites in OSA subjects, including superior and inferior frontal regions, ventral medial prefrontal cortex and nearby white matter, midfrontal white matter, insula, cingulate and cingulum bundle, internal and external capsules, caudate nuclei and putamen, basal forebrain, hypothalamus, corpus callosum, and temporal regions, showed principally lateralized negative correlations (P < 0.005). These regions showed significant correlations even with correction for multiple comparisons (cluster-level, family-wise error, P < 0.05), except for a few superior frontal areas. Predominantly negative correlations emerged between local MT values and OSA disease severity, indicating potential usefulness of MT imaging for examining the OSA condition. These findings indicate that OSA severity plays a significant role in white matter injury. © 2016 Wiley Periodicals, Inc.
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Mapeamento Encefálico , Encéfalo/diagnóstico por imagem , Apneia Obstrutiva do Sono/patologia , Substância Branca/diagnóstico por imagem , Adulto , Sintomas Afetivos/diagnóstico por imagem , Sintomas Afetivos/etiologia , Estudos Transversais , Feminino , Humanos , Processamento de Imagem Assistida por Computador , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Testes Neuropsicológicos , Polissonografia , Escalas de Graduação Psiquiátrica , Apneia Obstrutiva do Sono/complicações , Apneia Obstrutiva do Sono/diagnóstico por imagemRESUMO
Posterior reversible encephalopathy syndrome (PRES) is a clinico-radiologic entity. Its management and outcome in the oncology population is limited because it is still difficult to identify despite an increasingly recognized occurrence. This is the largest retrospective study of PRES in cancer patients reported from a single institution. We explore the clinical manifestations and radiologic features to comprehensively assess PRES in order to prevent permanent neurologic deficits and mortality. We retrospectively identified 69 patients with cancer who developed PRES at MDACC between 01/2006 to 06/2012. Clinical and radiographic data were abstracted from their records and reviewed for our analysis. Mean age at PRES onset was 52 ± 17.8 years. Fifty-two (75 %; p < 0.001) patients were women. Most common diagnoses were leukemia (30 %) and lymphoma (12 %). Forty-eight (70 %) patients were treated with chemotherapy, 21 (30 %) bone marrow transplant and 14 (20 %) tacrolimus. Most common clinical presentation was seizures (67 %). PRES was associated with hypertension in 62 (90 %) patients. On brain MRI, 33 (44 %) patients had some evidence of hemorrhage, 22 (73 %) of these were thrombocytopenic. Thirty-five (51 %) patients fully recovered and 19 (28 %) had permanent neurological deficits. Morbidity and mortality were associated with continuation with offending agent, thrombocytopenia, variations in mean arterial pressure ≥20 mmHg, electrographic seizures at onset, atypical MRI pattern and delay in diagnostic imaging (7.4 ± 4.8 days vs. 1.9 ± 1.8 days; p = 0.031) as half of them did not receive a prompt intervention. Special attention should be given to patients who present with high-risk factors in order to prevent development of PRES or decrease patient morbidity and mortality. Management of PRES should be guided by the radiographic findings. Overall, early recognition, discontinuation of the offending agents, correction of thrombocytopenia and blood pressure control are still the main strategies to manage PRES.
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Neoplasias/complicações , Síndrome da Leucoencefalopatia Posterior/complicações , Adulto , Idoso , Antineoplásicos/uso terapêutico , Antineoplásicos/toxicidade , Encéfalo/diagnóstico por imagem , Feminino , Humanos , Estimativa de Kaplan-Meier , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Neoplasias/diagnóstico por imagem , Neoplasias/fisiopatologia , Neoplasias/terapia , Síndrome da Leucoencefalopatia Posterior/diagnóstico por imagem , Síndrome da Leucoencefalopatia Posterior/fisiopatologia , Síndrome da Leucoencefalopatia Posterior/terapia , Estudos Retrospectivos , Fatores de Risco , Convulsões/complicações , Convulsões/diagnóstico por imagem , Convulsões/fisiopatologia , Convulsões/terapiaRESUMO
Immune checkpoint inhibitor (ICI) mediated encephalitides are increasingly being recognized in the literature, but atypical cases may be missed or misdiagnosed. Recent efforts are directed to identify biomarkers to help elucidate early diagnosis and treatment. Herein, we describe two cases of antibody negative ICI-mediated encephalitis with elevated serum Neurofilament light chain (sNfL) levels. Practical Implication: Baseline and longitudinal measurements of serum neurofilament light chains can help determine treatment strategies and prognosis in patients with suspected immune checkpoint inhibitor encephalitis.
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This paper presents a fully automated pipeline using a sparse convolutional autoencoder for quality control (QC) of affine registrations in large-scale T1-weighted (T1w) and T2-weighted (T2w) magnetic resonance imaging (MRI) studies. Here, a customized 3D convolutional encoder-decoder (autoencoder) framework is proposed and the network is trained in a fully unsupervised manner. For cross-validating the proposed model, we used 1000 correctly aligned MRI images of the human connectome project young adult (HCP-YA) dataset. We proposed that the quality of the registration is proportional to the reconstruction error of the autoencoder. Further, to make this method applicable to unseen datasets, we have proposed dataset-specific optimal threshold calculation (using the reconstruction error) from ROC analysis that requires a subset of the correctly aligned and artificially generated misalignments specific to that dataset. The calculated optimum threshold is used for testing the quality of remaining affine registrations from the corresponding datasets. The proposed framework was tested on four unseen datasets from autism brain imaging data exchange (ABIDE I, 215 subjects), information eXtraction from images (IXI, 577 subjects), Open Access Series of Imaging Studies (OASIS4, 646 subjects), and "Food and Brain" study (77 subjects). The framework has achieved excellent performance for T1w and T2w affine registrations with an accuracy of 100% for HCP-YA. Further, we evaluated the generality of the model on four unseen datasets and obtained accuracies of 81.81% for ABIDE I (only T1w), 93.45% (T1w) and 81.75% (T2w) for OASIS4, and 92.59% for "Food and Brain" study (only T1w) and in the range 88-97% for IXI (for both T1w and T2w and stratified concerning scanner vendor and magnetic field strengths). Moreover, the real failures from "Food and Brain" and OASIS4 datasets were detected with sensitivities of 100% and 80% for T1w and T2w, respectively. In addition, AUCs of > 0.88 in all scenarios were obtained during threshold calculation on the four test sets.
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OBJECTIVE: Patients with low-grade glioma (LGG) in eloquent regions often present with seizures, and findings on detailed neuropsychological testing are often abnormal. This study evaluated the association between cortical excitability, seizures, and cognitive function in patients with LGG. METHODS: LGG patients who underwent transcranial magnetic stimulation (TMS) from January 2021 to December 2022 were studied. Cortical excitability was measured using the resting motor thresholds (RMTs) of the upper and lower extremities. Early postoperative seizures served as the seizure endpoint. Neuropsychological assessment was completed prior to surgery contemporaneous with the TMS studies. RESULTS: A total of 31 patients were analyzed for seizure outcome. Median (interquartile range [IQR]) upper-extremity RMT was 39% (34%-46%) of maximum stimulator output, and the median (IQR) lower-extremity RMT was 69% (51%-79%). Lower-extremity RMT was higher in patients with early postoperative seizures, especially in those with motor region tumors (p = 0.02); however, RMT was not associated with seizures at presentation or long-term seizure control. A total of 26 patients completed neuropsychological assessment. There were significant negative correlations between upper-extremity RMT and psychomotor processing speed (Wechsler Adult Intelligence Scale-Fourth Edition [WAIS-IV] Processing Speed Index r = -0.42, p = 0.031; WAIS-IV Coding r = -0.41, p = 0.036; WAIS-IV Symbol Search r = -0.39, p = 0.048), executive function (Trail Making Test Part B r = -0.41, p = 0.036), and hand dexterity (Grooved Pegboard Test r = -0.50, p = 0.047). CONCLUSIONS: RMT was positively correlated with early postoperative seizure risk and negatively correlated with psychomotor processing speed, executive function, and hand dexterity. These findings support the theory of local and regional resting oscillatory network dysfunction from a glioma-brain network.
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Excitabilidade Cortical , Glioma , Adulto , Humanos , Glioma/cirurgia , Encéfalo , Convulsões/etiologia , Estimulação Magnética Transcraniana , Excitabilidade Cortical/fisiologia , Potencial Evocado Motor/fisiologiaRESUMO
Aim: Neurofilament light chain (NfL) is a nonspecific sensitive biomarker of axonal damage.Methods: This case series identified cancer patients with neurological complications who had serum NfL measurements and paired these results to outcomes.Results: NfL serum levels were available in 15 patients with hematological malignancies or solid tumors. The neurological complications studied were immune effector cell-associated neurotoxicity syndrome, immune checkpoint inhibitor-related encephalopathy, anoxic brain injury, Guillain-Barre syndrome, hemophagocytic lymphohistiocytosis, transverse myelitis, paraneoplastic syndrome, central nervous system demyelinating disorder and chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids. All patients but one with serum NfL >900 pg/ml died during hospitalization.Conclusion: Serum NfL levels consistently corresponded to death, disease severity or recovery in this series.
[Box: see text].
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Neoplasias , Proteínas de Neurofilamentos , Humanos , Masculino , Feminino , Pessoa de Meia-Idade , Proteínas de Neurofilamentos/sangue , Neoplasias/sangue , Neoplasias/complicações , Idoso , Adulto , Doenças do Sistema Nervoso/sangue , Doenças do Sistema Nervoso/etiologia , Biomarcadores/sangueRESUMO
Immune checkpoint therapies (ICT) can induce life-threatening immune-related adverse events, including myocarditis and myositis, which are rare but often concurrent. The molecular pathways and immune subsets underlying these toxicities remain poorly understood. To address this need, we performed single-cell RNA sequencing of heart and skeletal muscle biopsies obtained from living patients with cancers treated with ICTs and admitted to the hospital with myocarditis and/or myositis (overlapping myocarditis plus myositis, n = 10; myocarditis-only, n = 1) or ICT-exposed patients ruled out for toxicity utilized as controls (n = 9). All biopsies were obtained within 96 hours of clinical presentation. Analyses of 58,523 cells revealed CD8+ T cells with a cytotoxic phenotype expressing activation/exhaustion markers in both myocarditis and myositis. Furthermore, the analyses identified a population of myeloid cells expressing tissue-resident signatures and FcγRIIIa (CD16a), which is known to bind IgG and regulate complement activation. Immunohistochemistry of affected cardiac and skeletal muscle tissues revealed protein expression of pan-IgG and complement product C4d, which were associated with the presence of high-titer serum autoantibodies against muscle antigens in a subset of patients. We further identified a population of inflammatory IL1B+TNF+ myeloid cells specifically enriched in myocarditis and associated with greater toxicity severity and poorer clinical outcomes. These results provide insight into the myeloid subsets present in human immune-related myocarditis and myositis tissues and nominate new targets for investigation into rational treatments to overcome these high-mortality toxicities. See related Spotlight by Fankhauser et al., p. 954.
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Miocardite , Miosite , Humanos , Miocardite/imunologia , Miosite/imunologia , Masculino , Feminino , Pessoa de Meia-Idade , Inibidores de Checkpoint Imunológico/efeitos adversos , Inibidores de Checkpoint Imunológico/uso terapêutico , Idoso , Neoplasias/imunologia , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Adulto , Receptores de IgG/metabolismo , Músculo Esquelético/imunologia , Músculo Esquelético/metabolismo , Músculo Esquelético/patologia , Análise de Célula ÚnicaRESUMO
Background: Electrocorticography (ECoG) language mapping is often performed extraoperatively, frequently involves offline processing, and relationships with direct cortical stimulation (DCS) remain variable. We sought to determine the feasibility and preliminary utility of an intraoperative language mapping approach guided by real-time visualization of electrocorticograms. Methods: A patient with astrocytoma underwent awake craniotomy with intraoperative language mapping, utilizing a dual iPad stimulus presentation system coupled to a real-time neural signal processing platform capable of both ECoG recording and delivery of DCS. Gamma band modulations in response to 4 language tasks at each electrode were visualized in real-time. Next, DCS was conducted for each neighboring electrode pair during language tasks. Results: All language tasks resulted in strongest heat map activation at an electrode pair in the anterior to mid superior temporal gyrus. Consistent speech arrest during DCS was observed for Object and Action naming tasks at these same electrodes, indicating good correspondence with ECoG heat map recordings. This region corresponded well with posterior language representation via preoperative functional MRI. Conclusions: Intraoperative real-time visualization of language task-based ECoG gamma band modulation is feasible and may help identify targets for DCS. If validated, this may improve the efficiency and accuracy of intraoperative language mapping.
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Automated classification of blood cells from microscopic images is an interesting research area owing to advancements of efficient neural network models. The existing deep learning methods rely on large data for network training and generating such large data could be time-consuming. Further, explainability is required via class activation mapping for better understanding of the model predictions. Therefore, we developed a Siamese twin network (STN) model based on contrastive learning that trains on relatively few images for the classification of healthy peripheral blood cells using EfficientNet-B3 as the base model. Hence, in this study, a total of 17,092 publicly accessible cell histology images were analyzed from which 6% were used for STN training, 6% for few-shot validation, and the rest 88% for few-shot testing. The proposed architecture demonstrates percent accuracies of 97.00, 98.78, 94.59, 95.70, 98.86, 97.09, 99.71, and 96.30 during 8-way 5-shot testing for the classification of basophils, eosinophils, immature granulocytes, erythroblasts, lymphocytes, monocytes, platelets, and neutrophils, respectively. Further, we propose a novel class activation mapping scheme that highlights the important regions in the test image for the STN model interpretability. Overall, the proposed framework could be used for a fully automated self-exploratory classification of healthy peripheral blood cells. The whole proposed framework demonstrates the Siamese twin network training and 8-way k-shot testing. The values indicate the amount of dissimilarity.
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Gêmeos Unidos , Humanos , Células Sanguíneas , Redes Neurais de Computação , DescansoRESUMO
Lung and colon cancers are among the leading causes of human mortality and morbidity. Early diagnostic work up of these diseases include radiography, ultrasound, magnetic resonance imaging, and computed tomography. Certain blood tumor markers for carcinoma lung and colon also aid in the diagnosis. Despite the lab and diagnostic imaging, histopathology remains the gold standard, which provides cell-level images of tissue under examination. To read these images, a histopathologist spends a large amount of time. Furthermore, using conventional diagnostic methods involve high-end equipment as well. This leads to limited number of patients getting final diagnosis and early treatment. In addition, there are chances of inter-observer errors. In recent years, deep learning has shown promising results in the medical field. This has helped in early diagnosis and treatment according to severity of disease. With the help of EffcientNetV2 models that have been cross-validated and tested fivefold, we propose an automated method for detecting lung (lung adenocarcinoma, lung benign, and lung squamous cell carcinoma) and colon (colon adenocarcinoma and colon benign) cancer subtypes from LC25000 histopathology images. A state-of-the-art deep learning architecture based on the principles of compound scaling and progressive learning, EffcientNetV2 large, medium, and small models. An accuracy of 99.97%, AUC of 99.99%, F1-score of 99.97%, balanced accuracy of 99.97%, and Matthew's correlation coefficient of 99.96% were obtained on the test set using the EffcientNetV2-L model for the 5-class classification of lung and colon cancers, outperforming the existing methods. Using gradCAM, we created visual saliency maps to precisely locate the vital regions in the histopathology images from the test set where the models put more attention during cancer subtype predictions. This visual saliency maps may potentially assist pathologists to design better treatment strategies. Therefore, it is possible to use the proposed pipeline in clinical settings for fully automated lung and colon cancer detection from histopathology images with explainability.