RESUMO
BACKGROUND: High-grade gliomas have a poor prognosis and do not respond well to treatment. Effective cancer immune responses depend on functional immune cells, which are typically absent from the brain. This study aimed to evaluate the safety and activity of two adenoviral vectors expressing HSV1-TK (Ad-hCMV-TK) and Flt3L (Ad-hCMV-Flt3L) in patients with high-grade glioma. METHODS: In this dose-finding, first-in-human trial, treatment-naive adults aged 18-75 years with newly identified high-grade glioma that was evaluated per immunotherapy response assessment in neuro-oncology criteria, and a Karnofsky Performance Status score of 70 or more, underwent maximal safe resection followed by injections of adenoviral vectors expressing HSV1-TK and Flt3L into the tumour bed. The study was conducted at the University of Michigan Medical School, Michigan Medicine (Ann Arbor, MI, USA). The study included six escalating doses of viral particles with starting doses of 1×1010 Ad-hCMV-TK viral particles and 1×109 Ad-hCMV-Flt3L viral particles (cohort A), and then 1×1011 Ad-hCMV-TK viral particles and 1×109 Ad-hCMV-Flt3L viral particles (cohort B), 1×1010 Ad-hCMV-TK viral particles and 1×1010 Ad-hCMV-Flt3L viral particles (cohort C), 1×1011 Ad-hCMV-TK viral particles and 1×1010 Ad-hCMV-Flt3L viral particles (cohort D), 1×1010 Ad-hCMV-TK viral particles and 1×1011 Ad-hCMV-Flt3L viral particles (cohort E), and 1×1011 Ad-hCMV-TK viral particles and 1×1011 Ad-hCMV-Flt3L viral particles (cohort F) following a 3+3 design. Two 1 mL tuberculin syringes were used to deliver freehand a mix of Ad-hCMV-TK and Ad-hCMV-Flt3L vectors into the walls of the resection cavity with a total injection of 2 mL distributed as 0·1 mL per site across 20 locations. Subsequently, patients received two 14-day courses of valacyclovir (2 g orally, three times per day) at 1-3 days and 10-12 weeks after vector administration and standad upfront chemoradiotherapy. The primary endpoint was the maximum tolerated dose of Ad-hCMV-Flt3L and Ad-hCMV-TK. Overall survival was a secondary endpoint. Recruitment is complete and the trial is finished. The trial is registered with ClinicalTrials.gov, NCT01811992. FINDINGS: Between April 8, 2014, and March 13, 2019, 21 patients were assessed for eligibility and 18 patients with high-grade glioma were enrolled and included in the analysis (three patients in each of the six dose cohorts); eight patients were female and ten were male. Neuropathological examination identified 14 (78%) patients with glioblastoma, three (17%) with gliosarcoma, and one (6%) with anaplastic ependymoma. The treatment was well-tolerated, and no dose-limiting toxicity was observed. The maximum tolerated dose was not reached. The most common serious grade 3-4 adverse events across all treatment groups were wound infection (four events in two patients) and thromboembolic events (five events in four patients). One death due to an adverse event (respiratory failure) occurred but was not related to study treatment. No treatment-related deaths occurred during the study. Median overall survival was 21·3 months (95% CI 11·1-26·1). INTERPRETATION: The combination of two adenoviral vectors demonstrated safety and feasibility in patients with high-grade glioma and warrants further investigation in a phase 1b/2 clinical trial. FUNDING: Funded in part by Phase One Foundation, Los Angeles, CA, The Board of Governors at Cedars-Sinai Medical Center, Los Angeles, CA, and The Rogel Cancer Center at The University of Michigan.
Assuntos
Antineoplásicos , Glioblastoma , Glioma , Adulto , Feminino , Humanos , Masculino , Quimiorradioterapia , Terapia Genética , Glioblastoma/genética , Glioblastoma/terapia , Glioma/genética , Glioma/terapia , Adolescente , Pessoa de Meia-Idade , IdosoRESUMO
BACKGROUND: Deep-brain stimulation is the surgical procedure of choice for patients with advanced Parkinson's disease. The globus pallidus interna and the subthalamic nucleus are accepted targets for this procedure. We compared 24-month outcomes for patients who had undergone bilateral stimulation of the globus pallidus interna (pallidal stimulation) or subthalamic nucleus (subthalamic stimulation). METHODS: At seven Veterans Affairs and six university hospitals, we randomly assigned 299 patients with idiopathic Parkinson's disease to undergo either pallidal stimulation (152 patients) or subthalamic stimulation (147 patients). The primary outcome was the change in motor function, as blindly assessed on the Unified Parkinson's Disease Rating Scale, part III (UPDRS-III), while patients were receiving stimulation but not receiving antiparkinsonian medication. Secondary outcomes included self-reported function, quality of life, neurocognitive function, and adverse events. RESULTS: Mean changes in the primary outcome did not differ significantly between the two study groups (P=0.50). There was also no significant difference in self-reported function. Patients undergoing subthalamic stimulation required a lower dose of dopaminergic agents than did those undergoing pallidal stimulation (P=0.02). One component of processing speed (visuomotor) declined more after subthalamic stimulation than after pallidal stimulation (P=0.03). The level of depression worsened after subthalamic stimulation and improved after pallidal stimulation (P=0.02). Serious adverse events occurred in 51% of patients undergoing pallidal stimulation and in 56% of those undergoing subthalamic stimulation, with no significant between-group differences at 24 months. CONCLUSIONS: Patients with Parkinson's disease had similar improvement in motor function after either pallidal or subthalamic stimulation. Nonmotor factors may reasonably be included in the selection of surgical target for deep-brain stimulation. (ClinicalTrials.gov numbers, NCT00056563 and NCT01076452.)
Assuntos
Terapia por Estimulação Elétrica/métodos , Globo Pálido , Destreza Motora , Doença de Parkinson/terapia , Núcleo Subtalâmico , Atividades Cotidianas , Idoso , Cognição , Terapia por Estimulação Elétrica/efeitos adversos , Terapia por Estimulação Elétrica/mortalidade , Feminino , Seguimentos , Humanos , Análise de Intenção de Tratamento , Masculino , Pessoa de Meia-Idade , Doença de Parkinson/mortalidade , Doença de Parkinson/fisiopatologia , Qualidade de Vida , Resultado do TratamentoRESUMO
BACKGROUND: The risk of suicide behaviours post-deep brain stimulation (DBS) surgery in Parkinson's disease (PD) remains controversial. We assessed if suicide ideation and behaviours are more common in PD patients (1) randomised to DBS surgery versus best medical therapy (BMT); and (2) randomised to subthalamic nucleus (STN) versus globus pallidus interna (GPi) DBS surgery. METHODS: In Phase 1 of the Veterans Affairs CSP 468 study, 255 PD patients were randomised to DBS surgery (n=121) or 6 months of BMT (n=134). For Phase 2, a total of 299 patients were randomised to STN (n=147) or GPi (n=152) DBS surgery. Patients were assessed serially with the Unified Parkinson's Disease Rating Scale Part I depression item, which queries for suicide ideation; additionally, both suicide behaviour adverse event data and proxy symptoms of increased suicide risk from the Parkinson's Disease Questionnaire (PDQ-39) and the Short Form Health Survey (SF-36) were collected. RESULTS: In Phase 1, no suicide behaviours were reported, and new-onset suicide ideation was rare (1.9% for DBS vs 0.9% for BMT; Fisher's exact p=0.61). Proxy symptoms of relevance to suicide ideation were similar in the two groups. Rates of suicide ideation at 6 months were similar for patients randomised to STN versus GPi DBS (1.5% vs 0.7%; Fisher's exact p=0.61), but several proxy symptoms were worse in the STN group. CONCLUSIONS: Results from the randomised, controlled phase of a DBS surgery study in PD patients do not support a direct association between DBS surgery and an increased risk for suicide ideation and behaviours.
Assuntos
Globo Pálido/fisiopatologia , Doença de Parkinson/psicologia , Doença de Parkinson/terapia , Núcleo Subtalâmico/fisiopatologia , Ideação Suicida , Tentativa de Suicídio/psicologia , Suicídio/psicologia , Idoso , Estimulação Encefálica Profunda , Transtorno Depressivo/diagnóstico , Transtorno Depressivo/fisiopatologia , Transtorno Depressivo/psicologia , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Doença de Parkinson/fisiopatologiaRESUMO
INTRODUCTION: Molecular classification has transformed the management of brain tumors by enabling more accurate prognostication and personalized treatment. Access to timely molecular diagnostic testing for brain tumor patients is limited, complicating surgical and adjuvant treatment and obstructing clinical trial enrollment. METHODS: By combining stimulated Raman histology (SRH), a rapid, label-free, non-consumptive, optical imaging method, and deep learning-based image classification, we are able to predict the molecular genetic features used by the World Health Organization (WHO) to define the adult-type diffuse glioma taxonomy, including IDH-1/2, 1p19q-codeletion, and ATRX loss. We developed a multimodal deep neural network training strategy that uses both SRH images and large-scale, public diffuse glioma genomic data (i.e. TCGA, CGGA, etc.) in order to achieve optimal molecular classification performance. RESULTS: One institution was used for model training (University of Michigan) and four institutions (NYU, UCSF, Medical University of Vienna, and University Hospital Cologne) were included for patient enrollment in the prospective testing cohort. Using our system, called DeepGlioma, we achieved an average molecular genetic classification accuracy of 93.2% and identified the correct diffuse glioma molecular subgroup with 91.5% accuracy within 2 minutes in the operating room. DeepGlioma outperformed conventional IDH1-R132H immunohistochemistry (94.2% versus 91.4% accuracy) as a first-line molecular diagnostic screening method for diffuse gliomas and can detect canonical and non-canonical IDH mutations. CONCLUSIONS: Our results demonstrate how artificial intelligence and optical histology can be used to provide a rapid and scalable alternative to wet lab methods for the molecular diagnosis of brain tumor patients during surgery.
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Neoplasias Encefálicas , Glioma , Adulto , Humanos , Inteligência Artificial , Estudos Prospectivos , Glioma/diagnóstico por imagem , Glioma/genética , Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/genética , Imuno-Histoquímica , Isocitrato Desidrogenase/genética , Mutação/genéticaRESUMO
Molecular classification has transformed the management of brain tumors by enabling more accurate prognostication and personalized treatment. However, timely molecular diagnostic testing for patients with brain tumors is limited, complicating surgical and adjuvant treatment and obstructing clinical trial enrollment. In this study, we developed DeepGlioma, a rapid (<90 seconds), artificial-intelligence-based diagnostic screening system to streamline the molecular diagnosis of diffuse gliomas. DeepGlioma is trained using a multimodal dataset that includes stimulated Raman histology (SRH); a rapid, label-free, non-consumptive, optical imaging method; and large-scale, public genomic data. In a prospective, multicenter, international testing cohort of patients with diffuse glioma (n = 153) who underwent real-time SRH imaging, we demonstrate that DeepGlioma can predict the molecular alterations used by the World Health Organization to define the adult-type diffuse glioma taxonomy (IDH mutation, 1p19q co-deletion and ATRX mutation), achieving a mean molecular classification accuracy of 93.3 ± 1.6%. Our results represent how artificial intelligence and optical histology can be used to provide a rapid and scalable adjunct to wet lab methods for the molecular screening of patients with diffuse glioma.
Assuntos
Neoplasias Encefálicas , Glioma , Adulto , Humanos , Inteligência Artificial , Estudos Prospectivos , Glioma/diagnóstico por imagem , Glioma/genética , Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/genética , Mutação , Isocitrato Desidrogenase/genética , Imagem Óptica , InteligênciaRESUMO
PURPOSE: Glioblastoma(GBM) is a lethal disease characterized by inevitable recurrence. Here we investigate the molecular pathways mediating resistance, with the goal of identifying novel therapeutic opportunities. EXPERIMENTAL DESIGN: We developed a longitudinal in vivo recurrence model utilizing patient-derived explants to produce paired specimens(pre- and post-recurrence) following temozolomide(TMZ) and radiation(IR). These specimens were evaluated for treatment response and to identify gene expression pathways driving treatment resistance. Findings were clinically validated using spatial transcriptomics of human GBMs. RESULTS: These studies reveal in replicate cohorts, a gene expression profile characterized by upregulation of mesenchymal and stem-like genes at recurrence. Analyses of clinical databases revealed significant association of this transcriptional profile with worse overall survival and upregulation at recurrence. Notably, gene expression analyses identified upregulation of TGFß signaling, and more than one-hundred-fold increase in THY1 levels at recurrence. Furthermore, THY1-positive cells represented <10% of cells in treatment-naïve tumors, compared to 75-96% in recurrent tumors. We then isolated THY1-positive cells from treatment-naïve patient samples and determined that they were inherently resistant to chemoradiation in orthotopic models. Additionally, using image-guided biopsies from treatment-naïve human GBM, we conducted spatial transcriptomic analyses. This revealed rare THY1+ regions characterized by mesenchymal/stem-like gene expression, analogous to our recurrent mouse model, which co-localized with macrophages within the perivascular niche. We then inhibited TGFBRI activity in vivo which decreased mesenchymal/stem-like protein levels, including THY1, and restored sensitivity to TMZ/IR in recurrent tumors. CONCLUSIONS: These findings reveal that GBM recurrence may result from tumor repopulation by pre-existing, therapy-resistant, THY1-positive, mesenchymal cells within the perivascular niche.
Assuntos
Neoplasias Encefálicas , Glioblastoma , Animais , Camundongos , Humanos , Glioblastoma/metabolismo , Linhagem Celular Tumoral , Neoplasias Encefálicas/patologia , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/tratamento farmacológico , Temozolomida/farmacologia , Resistencia a Medicamentos Antineoplásicos/genética , Antineoplásicos Alquilantes/farmacologiaRESUMO
Aims: Targeting tumor metabolism may improve the outcomes for patients with glioblastoma (GBM). To further preclinical efforts targeting metabolism in GBM, we tested the hypothesis that brain tumors can be stratified into distinct metabolic groups with different patient outcomes. Therefore, to determine if tumor metabolites relate to patient survival, we profiled the metabolomes of human gliomas and correlated metabolic information with clinical data. Results: We found that isocitrate dehydrogenase-wildtype (IDHwt) GBMs are metabolically distinguishable from IDH mutated (IDHmut) astrocytomas and oligodendrogliomas. Survival of patients with IDHmut gliomas was expectedly more favorable than those with IDHwt GBM, and metabolic signatures can stratify IDHwt GBMs subtypes with varying prognoses. Patients whose GBMs were enriched in amino acids had improved survival, while those whose tumors were enriched for nucleotides, redox molecules, and lipid metabolites fared more poorly. These findings were recapitulated in validation cohorts using both metabolomic and transcriptomic data. Innovation: Our results suggest the existence of metabolic subtypes of GBM with differing prognoses, and further support the concept that metabolism may drive the aggressiveness of human gliomas. Conclusions: Our data show that metabolic signatures of human gliomas can inform patient survival. These findings may be used clinically to tailor novel metabolically targeted agents for GBM patients with different metabolic phenotypes. Antioxid. Redox Signal. 39, 942-956.
Assuntos
Astrocitoma , Neoplasias Encefálicas , Glioblastoma , Glioma , Humanos , Mutação , Glioma/genética , Glioma/metabolismo , Astrocitoma/genética , Astrocitoma/metabolismo , Astrocitoma/patologia , Glioblastoma/genética , Glioblastoma/metabolismo , Glioblastoma/patologia , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo , Isocitrato Desidrogenase/genética , Isocitrato Desidrogenase/metabolismoRESUMO
Conventional histopathology with hematoxylin & eosin (H&E) has been the gold standard for histopathological diagnosis of a wide range of diseases. However, it is not performed in vivo and requires thin tissue sections obtained after tissue biopsy, which carries risk, particularly in the central nervous system. Here we describe the development of an alternative, multicolored way to visualize tissue in real-time through the use of coherent Raman imaging (CRI), without the use of dyes. CRI relies on intrinsic chemical contrast based on vibrational properties of molecules and intrinsic optical sectioning by nonlinear excitation. We demonstrate that multicolor images originating from CH(2) and CH(3) vibrations of lipids and protein, as well as two-photon absorption of hemoglobin, can be obtained with subcellular resolution from fresh tissue. These stain-free histopathological images show resolutions similar to those obtained by conventional techniques, but do not require tissue fixation, sectioning or staining of the tissue analyzed.
Assuntos
Rastreamento de Células/métodos , Técnicas de Preparação Histocitológica , Análise Espectral Raman/métodos , Tomografia de Coerência Óptica/métodos , Animais , Neoplasias Encefálicas/patologia , Linhagem Celular Tumoral , Doenças Desmielinizantes/patologia , Modelos Animais de Doenças , Hemoglobinas/química , Humanos , Lipídeos/química , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Nus , Proteínas/química , Coloração e Rotulagem , Acidente Vascular Cerebral/patologia , Tomografia de Coerência Óptica/instrumentaçãoRESUMO
Delineation of tumor margins is a critical and challenging objective during brain cancer surgery. A tumor-targeting deep-blue nanoparticle-based visible contrast agent is described, which, for the first time, offers in vivo tumor-specific visible color staining. This technology thus enables color-guided tumor resection in real time, with no need for extra equipment or special lighting conditions. The visual contrast agent consists of polyacrylamide nanoparticles covalently linked to Coomassie Blue molecules (for nonleachable blue color contrast), which are surface-conjugated with polyethylene glycol and F3 peptides for efficient in vivo circulation and tumor targeting, respectively.
Assuntos
Neoplasias Encefálicas/patologia , Cirurgia Geral , Hidrogéis , Nanopartículas , Corantes de Rosanilina/química , Humanos , Espectroscopia de Ressonância Magnética , Espectrometria de Massas , Células Tumorais Cultivadas , Recursos HumanosRESUMO
OBJECT: Anterior temporal lobectomy (ATL) and selective amygdalohippocampectomy (SelAH) are the preferred surgical approaches for the treatment of medically refractory epilepsy involving the nondominant and dominant temporal lobes, respectively. Both techniques provide access to mesial structures-with the ATL providing a wider surgical corridor than SelAH. Because the extent of mesial temporal resection potentially impacts seizure outcome, the authors examined mesial resection volumes, seizure outcomes, and neuropsychiatric test scores in patients undergoing either ATL or transcortical SelAH at a single institution. METHODS: A retrospective study was conducted in 96 patients with medically refractory mesial temporal lobe epilepsy. Fifty-one patients who had nondominant temporal lobe epilepsy underwent standard ATL, and 45 patients with language-dominant temporal lobe epilepsy underwent transcortical SelAH. Volumetric MRI analysis was used to quantify the mesial resection in both groups. In addition, the authors examined seizure outcomes and the change in neuropsychiatric test scores. RESULTS: Seizure-free outcome in the entire patient cohort was 94% at a mean follow-up of 44 months. There was no significant difference in the seizure outcome between the 2 groups. The extent of resection of the mesial structures following ATL was slightly higher than for SelAH (98% vs. 91%, p < 0.0001). The change in neuropsychiatric test scores largely reflected the side of surgery, but overall IQ and memory function did not change significantly in either group. CONCLUSIONS: Transcortical SelAH provides adequate access to the mesial structures, and allows for a resection that is nearly as extensive as that achieved with standard ATL. Seizure outcomes and neuropsychiatric sequelae are similar in both procedures.
Assuntos
Tonsila do Cerebelo/cirurgia , Lobectomia Temporal Anterior/efeitos adversos , Epilepsia do Lobo Temporal/cirurgia , Hipocampo/cirurgia , Convulsões/etiologia , Análise de Variância , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Estudos Longitudinais , Imageamento por Ressonância Magnética , Masculino , Estudos Retrospectivos , Resultado do TratamentoRESUMO
The purpose of this report is to chronicle a 2-decade period of educational innovation and improvement, as well as governance reform, across the specialty of neurological surgery. Neurological surgery educational and professional governance systems have evolved substantially over the past 2 decades with the goal of improving training outcomes, patient safety, and the quality of US neurosurgical care. Innovations during this period have included the following: creating a consensus national curriculum; standardizing the length and structure of neurosurgical training; introducing educational outcomes milestones and required case minimums; establishing national skills, safety, and professionalism courses; systematically accrediting subspecialty fellowships; expanding professional development for educators; promoting training in research; and coordinating policy and strategy through the cooperation of national stakeholder organizations. A series of education summits held between 2007 and 2009 restructured some aspects of neurosurgical residency training. Since 2010, ongoing meetings of the One Neurosurgery Summit have provided strategic coordination for specialty definition, neurosurgical education, public policy, and governance. The Summit now includes leadership representatives from the Society of Neurological Surgeons, the American Association of Neurological Surgeons, the Congress of Neurological Surgeons, the American Board of Neurological Surgery, the Review Committee for Neurological Surgery of the Accreditation Council for Graduate Medical Education, the American Academy of Neurological Surgery, and the AANS/CNS Joint Washington Committee. Together, these organizations have increased the effectiveness and efficiency of the specialty of neurosurgery in advancing educational best practices, aligning policymaking, and coordinating strategic planning in order to meet the highest standards of professionalism and promote public health.
Assuntos
Internato e Residência , Neurocirurgia , Educação de Pós-Graduação em Medicina , Bolsas de Estudo , Humanos , Neurocirurgiões/educação , Neurocirurgia/educação , Estados UnidosRESUMO
The evaluation of candidate optical contrast agents for brain tumor delineation in ex vivo models may not accurately predict their activity in vivo. This study describes an in vivo model system designed to assess optical contrast agents for brain tumor delineation. The brain tumor window (BTW) model was created by performing biparietal craniectomies on 8-week-old Sprague-Dawley rats, injecting 9L glioma cells into the cortex and bonding a cover slip to the cranial defect with cyanoacrylate glue. Tumor growth was followed serially and occurred in an exponential fashion. Once tumors on the cortical surface achieved a 1mm radius, intravenous contrast agents were injected while the appearance of the cortical surface was recorded. Computerized image analysis was used to quantitatively evaluate visible differences between tumor and normal brain. Tumor margins became readily apparent following contrast administration in the BTW model. Based on red component intensity, tumor delineation improved fourfold at 50 min post-contrast administration in the BTW model (P<0.002). In summary, window placement overlying an implanted glioma is technically possible and well tolerated in the rat. The BTW model is a valid system for assessing the in vivo activity of optical contrast agents.
Assuntos
Neoplasias Encefálicas/patologia , Meios de Contraste , Glioma/patologia , Monitorização Intraoperatória/métodos , Corantes de Rosanilina , Animais , Mapeamento Encefálico , Neoplasias Encefálicas/cirurgia , Linhagem Celular Tumoral , Modelos Animais de Doenças , Progressão da Doença , Glioma/cirurgia , Processamento de Imagem Assistida por Computador/métodos , Imageamento por Ressonância Magnética/métodos , Ratos , Ratos Sprague-Dawley , Corantes de Rosanilina/administração & dosagemRESUMO
OBJECTIVE: The purpose of this study was to assess for peri-operative factors associated with brain shift following craniotomy for subdural grid electrode placement. METHODS: A retrospective analysis of cases operated at a single institution was undertaken, examining 63 consecutive patients undergoing craniotomy for subdural grid placement for seizure monitoring between 2001 and 2007. Peri-operative records were reviewed in order to assess for intraoperative employment of osmotic duiresis. Postoperative MRI scans were analyzed for shift of the midline and brain displacement. RESULTS: One patient was excluded due to gross hemispheric atrophy confounding the midline, and four patients were excluded due to lack of available imaging. Hence 58 patients were radiographically reviewed. The employment of osmotic diuresis during grid placement appeared to be the most significant peri-operative factor influencing brain shift. Osmotic diuresis was administered in only 14 patients. Midline shift of the third ventricle was greater in the osmotic diuresis group (2.3 ± 0.3 mm vs. 1.5 ± 0.2 mm, p = 0.037). Moreover, the volume of shifted brain was significantly higher in the osmotic diuresis group (7.9 ± 0.5 cm(3) vs. 4.7 ± 0.5 cm(3), p = 0.003). There was no significant difference in the rates of neurological complications between patients who received osmotic diuresis and those who did not. CONCLUSION: Employment of osmotic diuresis during grid placement appears to be associated with a paradoxical increase in the volume of shifted brain. This may be due to a combination of the resultant "sagging" of the brain and the pressure exerted by the grid, suggesting that osmotic diuresis might not improve mass effect as intended when employed within this context.
Assuntos
Encéfalo/efeitos dos fármacos , Encéfalo/patologia , Craniotomia , Diuréticos Osmóticos/efeitos adversos , Eletrodos Implantados , Eletroencefalografia , Epilepsia/diagnóstico , Imageamento por Ressonância Magnética , Manitol/efeitos adversos , Adolescente , Adulto , Mapeamento Encefálico , Diuréticos Osmóticos/administração & dosagem , Epilepsia/fisiopatologia , Feminino , Humanos , Masculino , Manitol/administração & dosagem , Pessoa de Meia-Idade , Tamanho do Órgão/efeitos dos fármacos , Estudos Retrospectivos , Espaço Subdural , Terceiro Ventrículo/efeitos dos fármacos , Terceiro Ventrículo/patologia , Adulto JovemRESUMO
BACKGROUND: Preprocedure diffusion tensor magnetic resonance imaging (MRI) may predict the response of trigeminal neuralgia (TN) patients to Gamma Knife (Elekta AB) and microvascular decompression (MVD). OBJECTIVE: To test this hypothesis using pontine-segment diffusion tensor MRI radial diffusivity (RD), a known biomarker for demyelination, to predict TN recurrence following MVD. METHODS: RD from the pontine segment of the trigeminal tract was extracted in a semiautomated and blinded fashion and normalized to background pontine RD. Following validation against published results, the relationship of normalized RD to symptom duration (DS) was measured. Both parameters were then introduced into machine-learning classifiers to group patient outcomes as TN remission or recurrence. Performance was evaluated in an observational study with leave-one-out cross-validation to calculate accuracy, sensitivity, specificity, and receiver operating characteristic curves. RESULTS: The study population included 22 patients with TN type 1 (TN1). There was a negative correlation of normalized RD and preoperative symptom duration (P = .035, R2 = .20). When pontine-segment RD and DS were included as input variables, 2 classifiers predicted pain-free remission versus eventual recurrence with 85% accuracy, 83% sensitivity, and 86% specificity (leave-one-out cross-validation; P = .029) in a cohort of 13 patients undergoing MVD. CONCLUSION: Pontine-segment RD and DS accurately predict MVD outcomes in TN1 and provide further evidence that diffusion tensor MRI contains prognostic information. Use of a classifier may allow more accurate risk stratification for neurosurgeons and patients considering MVD as a treatment for TN1. These findings provide further insight into the relationship of pontine microstructure, represented by RD, and the pathophysiology of TN.
Assuntos
Cirurgia de Descompressão Microvascular , Neuralgia do Trigêmeo , Algoritmos , Imagem de Tensor de Difusão , Humanos , Projetos Piloto , Recidiva , Resultado do Tratamento , Nervo Trigêmeo/cirurgia , Neuralgia do Trigêmeo/diagnóstico por imagem , Neuralgia do Trigêmeo/cirurgiaRESUMO
BACKGROUND: Detection of glioma recurrence remains a challenge in modern neuro-oncology. Noninvasive radiographic imaging is unable to definitively differentiate true recurrence versus pseudoprogression. Even in biopsied tissue, it can be challenging to differentiate recurrent tumor and treatment effect. We hypothesized that intraoperative stimulated Raman histology (SRH) and deep neural networks can be used to improve the intraoperative detection of glioma recurrence. METHODS: We used fiber laser-based SRH, a label-free, nonconsumptive, high-resolution microscopy method (<60 sec per 1â ×â 1 mm2) to image a cohort of patients (n =â 35) with suspected recurrent gliomas who underwent biopsy or resection. The SRH images were then used to train a convolutional neural network (CNN) and develop an inference algorithm to detect viable recurrent glioma. Following network training, the performance of the CNN was tested for diagnostic accuracy in a retrospective cohort (n =â 48). RESULTS: Using patch-level CNN predictions, the inference algorithm returns a single Bernoulli distribution for the probability of tumor recurrence for each surgical specimen or patient. The external SRH validation dataset consisted of 48 patients (recurrent, 30; pseudoprogression, 18), and we achieved a diagnostic accuracy of 95.8%. CONCLUSION: SRH with CNN-based diagnosis can be used to improve the intraoperative detection of glioma recurrence in near-real time. Our results provide insight into how optical imaging and computer vision can be combined to augment conventional diagnostic methods and improve the quality of specimen sampling at glioma recurrence.
Assuntos
Neoplasias Encefálicas , Glioma , Algoritmos , Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/cirurgia , Glioma/diagnóstico por imagem , Glioma/cirurgia , Humanos , Redes Neurais de Computação , Estudos RetrospectivosRESUMO
Catatonia is a psychomotor and behavioral syndrome associated with mood disorders, psychotic disorders, neurological disease, and general medical conditions. Catatonia has also been described as a manifestation of partial onset seizures. We describe a case of catatonia following successful epilepsy surgery. A 38-year-old patient with congenital hydrocephalus and left hippocampal sclerosis underwent selective left amygdalohippocampectomy for medically refractory seizures. Three days after surgery, she became progressively less interactive. Verbal output was dramatically reduced. She exhibited waxy flexibility, stupor, mutism, posturing, rigidity, negativism, and grimacing. Video/EEG monitoring showed no evidence of ongoing seizure activity. She was treated with high-dose benzodiazepines for presumed catatonia, but the behavioral pattern did not resolve. Subsequently the patient underwent a full course of electroconvulsive therapy. Catatonia resolved over the ensuing 3 weeks. Following discharge from the hospital, the patient's global functioning returned to the premorbid level, and she has been seizure free for more than 4 years.
Assuntos
Lobectomia Temporal Anterior/efeitos adversos , Catatonia/etiologia , Catatonia/terapia , Eletroconvulsoterapia , Adulto , Eletroencefalografia , Epilepsia do Lobo Temporal/cirurgia , Feminino , Humanos , Imageamento por Ressonância Magnética , Testes NeuropsicológicosRESUMO
Intraoperative diagnosis is essential for providing safe and effective care during cancer surgery1. The existing workflow for intraoperative diagnosis based on hematoxylin and eosin staining of processed tissue is time, resource and labor intensive2,3. Moreover, interpretation of intraoperative histologic images is dependent on a contracting, unevenly distributed, pathology workforce4. In the present study, we report a parallel workflow that combines stimulated Raman histology (SRH)5-7, a label-free optical imaging method and deep convolutional neural networks (CNNs) to predict diagnosis at the bedside in near real-time in an automated fashion. Specifically, our CNNs, trained on over 2.5 million SRH images, predict brain tumor diagnosis in the operating room in under 150 s, an order of magnitude faster than conventional techniques (for example, 20-30 min)2. In a multicenter, prospective clinical trial (n = 278), we demonstrated that CNN-based diagnosis of SRH images was noninferior to pathologist-based interpretation of conventional histologic images (overall accuracy, 94.6% versus 93.9%). Our CNNs learned a hierarchy of recognizable histologic feature representations to classify the major histopathologic classes of brain tumors. In addition, we implemented a semantic segmentation method to identify tumor-infiltrated diagnostic regions within SRH images. These results demonstrate how intraoperative cancer diagnosis can be streamlined, creating a complementary pathway for tissue diagnosis that is independent of a traditional pathology laboratory.
Assuntos
Neoplasias Encefálicas/diagnóstico , Sistemas Computacionais , Monitorização Intraoperatória , Redes Neurais de Computação , Análise Espectral Raman , Algoritmos , Neoplasias Encefálicas/diagnóstico por imagem , Ensaios Clínicos como Assunto , Aprendizado Profundo , Humanos , Processamento de Imagem Assistida por Computador , ProbabilidadeRESUMO
Many countries worldwide are digitizing patients' medical records. What impact will these electronic health records have upon medical education? This debate examines the threats and opportunities.
Assuntos
Educação Médica/métodos , Sistemas Computadorizados de Registros Médicos , Documentação/métodos , Humanos , Prontuários Médicos , Relações Médico-Paciente , Estados UnidosRESUMO
CONTEXT: Deep brain stimulation is an accepted treatment for advanced Parkinson disease (PD), although there are few randomized trials comparing treatments, and most studies exclude older patients. OBJECTIVE: To compare 6-month outcomes for patients with PD who received deep brain stimulation or best medical therapy. DESIGN, SETTING, AND PATIENTS: Randomized controlled trial of patients who received either deep brain stimulation or best medical therapy, stratified by study site and patient age (< 70 years vs > or = 70 years) at 7 Veterans Affairs and 6 university hospitals between May 2002 and October 2005. A total of 255 patients with PD (Hoehn and Yahr stage > or = 2 while not taking medications) were enrolled; 25% were aged 70 years or older. The final 6-month follow-up visit occurred in May 2006. INTERVENTION: Bilateral deep brain stimulation of the subthalamic nucleus (n = 60) or globus pallidus (n = 61). Patients receiving best medical therapy (n = 134) were actively managed by movement disorder neurologists. MAIN OUTCOME MEASURES: The primary outcome was time spent in the "on" state (good motor control with unimpeded motor function) without troubling dyskinesia, using motor diaries. Other outcomes included motor function, quality of life, neurocognitive function, and adverse events. RESULTS: Patients who received deep brain stimulation gained a mean of 4.6 h/d of on time without troubling dyskinesia compared with 0 h/d for patients who received best medical therapy (between group mean difference, 4.5 h/d [95% CI, 3.7-5.4 h/d]; P < .001). Motor function improved significantly (P < .001) with deep brain stimulation vs best medical therapy, such that 71% of deep brain stimulation patients and 32% of best medical therapy patients experienced clinically meaningful motor function improvements (> or = 5 points). Compared with the best medical therapy group, the deep brain stimulation group experienced significant improvements in the summary measure of quality of life and on 7 of 8 PD quality-of-life scores (P < .001). Neurocognitive testing revealed small decrements in some areas of information processing for patients receiving deep brain stimulation vs best medical therapy. At least 1 serious adverse event occurred in 49 deep brain stimulation patients and 15 best medical therapy patients (P < .001), including 39 adverse events related to the surgical procedure and 1 death secondary to cerebral hemorrhage. CONCLUSION: In this randomized controlled trial of patients with advanced PD, deep brain stimulation was more effective than best medical therapy in improving on time without troubling dyskinesias, motor function, and quality of life at 6 months, but was associated with an increased risk of serious adverse events. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00056563.
Assuntos
Estimulação Encefálica Profunda , Doença de Parkinson/terapia , Idoso , Cognição , Estimulação Encefálica Profunda/efeitos adversos , Feminino , Globo Pálido , Humanos , Masculino , Pessoa de Meia-Idade , Destreza Motora , Qualidade de Vida , Núcleo SubtalâmicoRESUMO
In this surgical video, the operative technique is presented for awake implantation of a thoracic paddle electrode for spinal cord stimulation. In the first stage, a laminotomy is performed with the patient under conscious sedation. Once the paddle is in optimal position, the patient is tested intraoperatively to confirm adequate coverage and absence of untoward side effects. This paddle electrode is used for the trial period. If the patient derives satisfactory pain relief during the trial, they are returned for the second stage implantation of pulse generator, without moving the initial paddle electrode now already placed in an optimal location. Particular attention in this video is provided toward the optimal positioning and technique for the awake laminotomy to ensure patient comfort and reliability during testing, the use of extension leads tunneled opposite the planned pulse generator site, and the method of removing extension leads to preserve the placement of the initial paddle electrode.