RESUMEN
Cancer immunotherapy remains limited by poor antigenicity and a regulatory tumor microenvironment (TME). Here, we create "onion-like" multi-lamellar RNA lipid particle aggregates (LPAs) to substantially enhance the payload packaging and immunogenicity of tumor mRNA antigens. Unlike current mRNA vaccine designs that rely on payload packaging into nanoparticle cores for Toll-like receptor engagement in immune cells, systemically administered RNA-LPAs activate RIG-I in stromal cells, eliciting massive cytokine/chemokine response and dendritic cell/lymphocyte trafficking that provokes cancer immunogenicity and mediates rejection of both early- and late-stage murine tumor models. In client-owned canines with terminal gliomas, RNA-LPAs improved survivorship and reprogrammed the TME, which became "hot" within days of a single infusion. In a first-in-human trial, RNA-LPAs elicited rapid cytokine/chemokine release, immune activation/trafficking, tissue-confirmed pseudoprogression, and glioma-specific immune responses in glioblastoma patients. These data support RNA-LPAs as a new technology that simultaneously reprograms the TME while eliciting rapid and enduring cancer immunotherapy.
Asunto(s)
Inmunoterapia , Lípidos , ARN , Microambiente Tumoral , Animales , Perros , Femenino , Humanos , Ratones , Antígenos de Neoplasias/inmunología , Neoplasias Encefálicas/terapia , Neoplasias Encefálicas/inmunología , Vacunas contra el Cáncer/inmunología , Vacunas contra el Cáncer/uso terapéutico , Línea Celular Tumoral , Citocinas/metabolismo , Células Dendríticas/inmunología , Células Dendríticas/metabolismo , Glioblastoma/terapia , Glioblastoma/inmunología , Glioma/terapia , Glioma/inmunología , Inmunoterapia/métodos , Ratones Endogámicos C57BL , Neoplasias/terapia , Neoplasias/inmunología , ARN/química , ARN/uso terapéutico , ARN Mensajero/metabolismo , ARN Mensajero/genética , Lípidos/químicaRESUMEN
BACKGROUND: Patients with primary brain tumors (pPBTs) often exhibit heightened distress. This study assesses how symptoms of anxiety and depression change over time in pPBTs and identifies factors that may predict patients' symptom trajectories. METHODS: Ninety-nine adult pPBTs completed psychosocial assessments at neuro-oncology appointments over 6-18 months. Quality of life was assessed with the Functional Assessment of Cancer Therapy-Brain; symptoms of anxiety and depression were assessed with the Patient-Reported Outcomes Measurement Information System short forms. The prevalence of patients with clinically elevated symptoms and those who experienced clinically meaningful changes in symptoms throughout follow-up were examined. Linear mixed-effects models evaluated changes in symptoms over time at the group level, and latent class growth analysis (LCGA) evaluated changes in symptoms over time at the individual level. RESULTS: At enrollment, 51.5% and 32.3% of patients exhibited clinically elevated levels of anxiety and depression, respectively. Of patients with follow-up data (n = 74), 54.1% and 50% experienced clinically meaningful increases in anxiety and depression scores, respectively. There were no significant changes in anxiety or depression scores over time, but better physical, functional, and brain-cancer well-being predicted lower levels of anxiety and depression (p < 0.001). Five sub-groups of patients with distinct symptom trajectories emerged via LCGA. CONCLUSIONS: pPBTs commonly experience elevated symptoms of anxiety and depression that may fluctuate in clinically meaningful manners throughout the disease. Routine screening for elevated symptoms is needed to capture clinically meaningful changes and identify factors affecting symptoms to intervene on.
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Neoplasias Encefálicas , Depresión , Adulto , Humanos , Depresión/diagnóstico , Depresión/etiología , Depresión/epidemiología , Calidad de Vida , Ansiedad/diagnóstico , Ansiedad/etiología , Ansiedad/psicología , Prevalencia , Neoplasias Encefálicas/complicaciones , Neoplasias Encefálicas/diagnósticoRESUMEN
BACKGROUND: Electroanatomic mapping systems are increasingly used during ablations to decrease the need for fluoroscopy and therefore radiation exposure. For left-sided arrhythmias, transseptal puncture is a common procedure performed to gain access to the left side of the heart. We aimed to demonstrate the radiation exposure associated with transseptal puncture. METHODS: Data were retrospectively collected from the Catheter Ablation with Reduction or Elimination of Fluoroscopy registry. Patients with left-sided accessory pathway-mediated tachycardia, with a structurally normal heart, who had a transseptal puncture, and were under 22 years of age were included. Those with previous ablations, concurrent diagnostic or interventional catheterisation, and missing data for fluoroscopy use or procedural outcomes were excluded. Patients with a patent foramen ovale who did not have a transseptal puncture were selected as the control group using the same criteria. Procedural outcomes were compared between the two groups. RESULTS: There were 284 patients in the transseptal puncture group and 70 in the patent foramen ovale group. The transseptal puncture group had a significantly higher mean procedure time (158.8 versus 131.4 minutes, p = 0.002), rate of fluoroscopy use (38% versus 7%, p < 0.001), and mean fluoroscopy time (2.4 versus 0.6 minutes, p < 0.001). The acute success and complication rates were similar. CONCLUSIONS: Performing transseptal puncture remains a common reason to utilise fluoroscopy in the era of non-fluoroscopic ablation. Better tools are needed to make non-fluoroscopic transseptal puncture more feasible.
Asunto(s)
Ablación por Catéter , Foramen Oval Permeable , Exposición a la Radiación , Humanos , Estudios Retrospectivos , Resultado del Tratamiento , Punciones/métodos , Ablación por Catéter/métodosRESUMEN
PURPOSE: To determine whether participation in a clinical trial was associated with improved survival in patients with glioblastoma (GBM). METHODS: Following IRB approval, patients were identified using CPT and ICD codes. Data was collected using retrospective review of electronic medical records. When necessary, death data was obtained from online obituaries. Inverse propensity score matching was utilized to transform the two cohorts to comparable sets. Survival was compared using Kaplan-Meyer curves and Wilcoxon Rank Sum Test. RESULTS: In this cohort of 365 patients, 89 were enrolled in a clinical trial and 276 were not. Patients enrolled in clinical trials had a significantly higher mean baseline KPS score, higher proportion of surgical resections, and were more likely to receive temozolomide treatment than patients not enrolled in a clinical trial. After inverse propensity score matching, patients enrolled in a clinical trial lived significantly longer than those not enrolled (28.8 vs 22.2 months, p = 0.005). A potential confounder of this study is that patients not in a clinical trial had significantly fewer visits with neuro-oncologists than patients enrolled in a clinical trial (7 ± 8 vs 12 ± 9, p < 0. 0001). CONCLUSIONS: Clinical trials enroll patients with the most favorable prognostic features. Even when correcting for this bias, clinical trial enrollment is an independent predictor of increased survival regardless of treatment arm.
Asunto(s)
Neoplasias Encefálicas , Ensayos Clínicos como Asunto , Glioblastoma , Neoplasias Encefálicas/terapia , Estudios de Cohortes , Glioblastoma/terapia , Humanos , Pronóstico , TemozolomidaRESUMEN
BACKGROUND: Patients with CHD can be exposed to high levels of cumulative ionising radiation. Utilisation of electroanatomic mapping during catheter ablation leads to reduced radiation exposure in the general population but has not been well studied in patients with CHD. This study evaluated the radiation sparing benefit of using three-dimensional mapping in patients with CHD. METHODS: Data were retrospectively collected from the Catheter Ablation with Reduction or Elimination of Fluoroscopy multi-institutional registry. Patients with CHD were selected. Those with previous ablations, concurrent diagnostic or interventional catheterisation and unknown arrhythmogenic foci were excluded. The control cohort was matched for operating physician, arrhythmia mechanism, arrhythmia location, weight and age. The procedure time, rate of fluoroscopy use, fluoroscopy time, procedural success, complications, and distribution of procedures per year were compared between the two groups. RESULTS: Fifty-six patients with congenital heart disease and 56 matched patients without CHD were included. The mean total procedure time was significantly higher in patients with CHD (212.6 versus 169.5 minutes, p = 0.003). Their median total fluoroscopy time was 4.4 minutes (compared to 1.8 minutes), and their rate of fluoroscopy use was 23% (compared to 13%). The acute success and minor complication rates were similar and no major complications occurred. CONCLUSIONS: With the use of electroanatomic mapping during catheter ablation, fluoroscopy use can be reduced in patients with CHD. The majority of patients with CHD received zero fluoroscopy.
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Ablación por Catéter , Exposición a la Radiación , Humanos , Mapeo del Potencial de Superficie Corporal/métodos , Estudios Retrospectivos , Resultado del Tratamiento , Exposición a la Radiación/prevención & control , Fluoroscopía/métodos , Ablación por Catéter/métodos , Arritmias Cardíacas/epidemiologíaRESUMEN
INTRODUCTION: Glioblastoma is a very aggressive cancer with dismal prognosis despite standard of care including surgical resection, radiation therapy, and chemotherapy. There is interest in applying immunotherapy to glioblastoma as this modality has demonstrated remarkable improvements in the management of several solid tumors including melanoma, renal cell carcinoma, and non-small cell lung cancer. This review aims to provide an overview of the current state of glioblastoma immunotherapy. METHODS: Literature search was performed on PubMed between 1961 and 2020. RESULTS: Initial clinical trials of checkpoint inhibitors and vaccine therapy for glioblastoma have largely been disappointing for both primary and recurrent glioblastoma. This failure has been attributed to glioblastoma's highly immunosuppressive environment and multiple mechanisms of therapy resistance including high tumor heterogeneity, low mutational burden, systemic immunosuppression, and local immune dysfunction. CONCLUSIONS: Current clinical trials are exploring combination therapy and novel treatment strategies beyond immune checkpoint therapies and vaccine therapy such as CAR T cells. There is also an effort to establish synergy between immunotherapy and current standard of care. Furthermore, recent advances in personalized neoantigen vaccines suggest a shift towards personalized, patient-specific GBM treatment.
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Neoplasias Encefálicas , Glioblastoma , Neoplasias Encefálicas/terapia , Carcinoma de Pulmón de Células no Pequeñas , Glioblastoma/terapia , Humanos , Inmunoterapia , Neoplasias Pulmonares , Recurrencia Local de NeoplasiaRESUMEN
OPINION STATEMENT: Laser interstitial thermal therapy (LITT) is a minimally invasive treatment option for brain tumors including glioblastoma, other primary central nervous system (CNS) neoplasms, metastases, and radiation necrosis. LITT employs a fiber optic coupled laser delivery probe stabilized via stereotaxis to deliver thermal energy that induces coagulative necrosis in tumors to achieve effective cytoreduction. LITT complements surgical resection, radiation treatment, tumor treating fields, and systemic therapy, especially in patients who are high risk for surgical resection due to tumor location in eloquent regions or poor functional status. These factors must be balanced with the increased rate of cerebral edema post LITT compared to surgical resection. LITT has also been shown to induce transient disruption of the blood-brain barrier (BBB), especially in the peritumoral region, which allows for enhanced CNS delivery of anti-neoplastic agents, thus greatly expanding the armamentarium against brain tumors to include highly effective anti-neoplastic agents that have poor BBB penetration. In addition, hyperthermia-induced immunogenic cell death is another secondary side effect of LITT that opens up immunotherapy as an attractive adjuvant treatment for brain tumors. Numerous large studies have demonstrated the safety and efficacy of LITT against various CNS tumors and as the literature continues to grow on this novel technique so will its indications.
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Neoplasias Encefálicas/cirugía , Glioblastoma/cirugía , Terapia por Láser/métodos , Traumatismos por Radiación/cirugía , Antineoplásicos/uso terapéutico , Barrera Hematoencefálica/metabolismo , Neoplasias Encefálicas/patología , Neoplasias Encefálicas/secundario , Quimioterapia Adyuvante , Glioblastoma/patología , Humanos , Técnicas EstereotáxicasRESUMEN
BACKGROUND: Catheter ablation is a safe and effective therapy for the treatment of supraventricular tachycardia in children. Current improvements in technology have allowed progressive reduction in radiation exposure associated with the procedure. To assess the impact of three-dimensional mapping, we compared acute procedural results collected from the Catheter Ablation with Reduction or Elimination of Fluoroscopy registry to published results from the Prospective Assessment after Pediatric Cardiac Ablation study. METHODS: Inclusion and exclusion criteria from the Prospective Assessment after Pediatric Cardiac Ablation study were used as guidelines to select patient data from the Catheter Ablation with Reduction or Elimination of Fluoroscopy registry to compare acute procedural outcomes between cohorts. Outcomes assessed include procedural and fluoroscopy exposure times, success rates of procedure, and complications. RESULTS: In 786 ablation procedures, targeting 498 accessory pathways and 288 atrioventricular nodal reentrant tachycardia substrates, average procedural time (156.5 versus 206.7 minutes, p < 0.01), and fluoroscopy time (1.2 versus 38.3 minutes, p < 0.01) were significantly shorter in the study group. Success rates for the various substrates were similar except for manifest accessory pathways which had a significantly higher success rate in the study group (96.4% versus 93.0%, p < 0.01). Major complication rates were significantly lower in the study group (0.3% versus 1.6%, p < 0.01). CONCLUSIONS: In a large, multicentre study, three-dimensional systems show favourable improvements in clinical outcomes in children undergoing catheter ablation of supraventricular tachycardia compared to the traditional fluoroscopic approach. Further improvements are anticipated as technology advances.
Asunto(s)
Ablación por Catéter , Taquicardia Supraventricular , Niño , Fluoroscopía , Humanos , Estudios Prospectivos , Taquicardia Supraventricular/cirugía , Resultado del TratamientoRESUMEN
OBJECTIVE: Neurosurgical education in the US has changed significantly as a consequence of the novel coronavirus (COVID-19) pandemic. Institutional social distancing requirements have resulted in many neurosurgical programs utilizing video conferencing for educational activities. However, it is unclear how or if these practices should continue after the pandemic. The objective of this study was to characterize virtual education in neurosurgery and understand how it should be utilized after COVID-19. METHODS: A 24-question, 3-part online survey was administered anonymously to all 117 US neurosurgical residency programs from May 15, 2020, to June 15, 2020. Questions pertained to the current use of virtual conferencing, preferences over traditional conferences, and future inclinations. The Likert scale (1 = strongly disagree, 3 = neutral, 5 = strongly agree) was used. Comparisons were calculated using the Mann-Whitney U-test. Statistical significance was set at 0.05. RESULTS: One-hundred eight responses were recorded. Overall, 38 respondents (35.2%) were attendings and 70 (64.8%) were trainees. Forty-one respondents (38.0%) indicated attending 5-6 conferences per week and 70 (64.8%) attend national virtual conferences. When considering different conference types, there was no overall preference (scores < 3) for virtual conferences over traditional conferences. In regard to future use, respondents strongly agreed that they would continue the practice at some capacity after the pandemic (median score 5). Overall, respondents agreed that virtual conferences would partially replace traditional conferences (median score 4), whereas they strongly disagreed with the complete replacement of traditional conferences (median score 1). The most common choices for the partial replacement of tradition conferences were case conferences (59/108, 55%) and board preparation (64/108, 59%). Lastly, there was a significant difference in scores for continued use of virtual conferencing in those who attend nationally sponsored conferences (median score 5, n = 70) and those who do not (median score 4, n = 38; U = 1762.50, z = 2.97, r = 0.29, p = 0.003). CONCLUSIONS: Virtual conferences will likely remain an integral part of neurosurgical education after the COVID-19 pandemic has abated. Across the country, residents and faculty report a preference for continued use of virtual conferencing, especially virtual case conferences and board preparation. Some traditional conferences may even be replaced with virtual conferences, in particular those that are more didactic. Furthermore, nationally sponsored virtual conferences have a positive effect on the preferences for continued use of virtual conferences.
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COVID-19/epidemiología , Educación a Distancia/normas , Internado y Residencia/normas , Procedimientos Neuroquirúrgicos/educación , Encuestas y Cuestionarios , Telecomunicaciones/normas , Adulto , Anciano , Educación a Distancia/métodos , Femenino , Humanos , Internado y Residencia/métodos , Masculino , Persona de Mediana Edad , Procedimientos Neuroquirúrgicos/métodos , Procedimientos Neuroquirúrgicos/normasRESUMEN
Translation of nanoparticles (NPs) into human clinical trials for patients with refractory cancers has lagged due to unknown biologic reactivities of novel NP designs. To overcome these limitations, simple well-characterized mRNA lipid-NPs have been developed as cancer immunotherapeutic vaccines. While the preponderance of RNA lipid-NPs encoding for tumor-associated antigens or neoepitopes have been designed to target lymphoid organs, they remain encumbered by the profound intratumoral and systemic immunosuppression that may stymie an activated T cell response. Herein, we show that systemic localization of untargeted tumor RNA (derived from whole transcriptome) encapsulated in lipid-NPs, with excess positive charge, primes the peripheral and intratumoral milieu for response to immunotherapy. In immunologically resistant tumor models, these RNA-NPs activate the preponderance of systemic and intratumoral myeloid cells (characterized by coexpression of PD-L1 and CD86). Addition of immune checkpoint inhibitors (ICIs) (to animals primed with RNA-NPs) augments peripheral/intratumoral PD-1+CD8+ cells and mediates synergistic antitumor efficacy in settings where ICIs alone do not confer therapeutic benefit. These synergistic effects are mediated by type I interferon released from plasmacytoid dendritic cells (pDCs). In translational studies, personalized mRNA-NPs were safe and active in a client-owned canine with a spontaneous malignant glioma. In summary, we demonstrate widespread immune activation from tumor loaded RNA-NPs concomitant with inducible PD-L1 expression that can be therapeutically exploited. While immunotherapy remains effective for only a subset of cancer patients, combination therapy with systemic immunomodulating RNA-NPs may broaden its therapeutic potency.
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Glioma/tratamiento farmacológico , Inmunoterapia , Lípidos/administración & dosificación , Nanopartículas/administración & dosificación , Medicina de Precisión , Animales , Antígeno B7-2/antagonistas & inhibidores , Antígeno B7-2/genética , Antígeno B7-2/inmunología , Antígeno B7-H1/antagonistas & inhibidores , Antígeno B7-H1/genética , Antígeno B7-H1/inmunología , Linfocitos T CD8-positivos/efectos de los fármacos , Linfocitos T CD8-positivos/inmunología , Vacunas contra el Cáncer/inmunología , Vacunas contra el Cáncer/uso terapéutico , Células Dendríticas/inmunología , Modelos Animales de Enfermedad , Perros , Glioma/inmunología , Glioma/patología , Glioma/veterinaria , Humanos , Lípidos/química , Lípidos/inmunología , Activación de Linfocitos/inmunología , Nanopartículas/química , ARN Neoplásico/química , ARN Neoplásico/genética , ARN Neoplásico/inmunología , Transcriptoma/genéticaRESUMEN
Glioblastoma (GBM) generates a varied immune response and understanding the immune microenvironment may lead to novel immunotherapy treatments modalities. The goal of this study was to evaluate the expression of immunologic markers of potential clinical significance in primary versus recurrent GBM and assess the relationship between these markers and molecular characteristics of GBM. Human GBM samples were evaluated and analyzed with immunohistochemistry for multiple immunobiologic markers (CD3, CD8, FoxP3, CD68, CD163, PD1, PDL1, CTLA4, CD70). Immunoreactivity was analyzed using Aperio software. Degree of strong positive immunoreactivity within the tumor was compared to patient and tumor characteristics including age, gender, MGMT promoter methylation status, and ATRX, p53, and IDH1 mutation status. Additionally, the TCGA database was used to perform similar analysis of these factors in GBM using RNA-seq by expectation-maximization. Using odds ratios, IDH1 mutated GBM had statistically significant decreased expression of CD163 and CD70 and a trend for decreased PD1, CTLA4, and Foxp3. ATRX-mutated GBMs exhibited statistically significant increased CD3 immunoreactivity, while those with p53 mutations were found to have significantly increased CTLA4 immunoreactivity. The odds of having strong CD8 and CD68 reactivity was significantly less in MGMT methylated tumors. No significant difference was identified in any immune marker between the primary and recurrent GBM, nor was a significant change in immunoreactivity identified among age intervals. TCGA analysis corroborated findings related to the differential immune profile of IDH1 mutant, p53 mutant, and MGMT unmethylated tumors. Immunobiologic markers have greater association with the molecular characteristics of the tumor than with primary/recurrent status or age.
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Neoplasias Encefálicas/inmunología , Glioblastoma/inmunología , Adulto , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Encéfalo/inmunología , Encéfalo/patología , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/mortalidad , Neoplasias Encefálicas/patología , Antígenos CD8/metabolismo , Metilación de ADN , Metilasas de Modificación del ADN/genética , Metilasas de Modificación del ADN/metabolismo , Enzimas Reparadoras del ADN/genética , Enzimas Reparadoras del ADN/metabolismo , Femenino , Glioblastoma/genética , Glioblastoma/mortalidad , Glioblastoma/patología , Humanos , Isocitrato Deshidrogenasa/genética , Linfocitos Infiltrantes de Tumor/inmunología , Linfocitos Infiltrantes de Tumor/patología , Masculino , Persona de Mediana Edad , Mutación , Clasificación del Tumor , Recurrencia , Proteína p53 Supresora de Tumor/genética , Proteínas Supresoras de Tumor/genética , Proteínas Supresoras de Tumor/metabolismo , Proteína Nuclear Ligada al Cromosoma X/genéticaRESUMEN
INTRODUCTION: The emergence of advanced in vivo neuroimaging methods has redefined the understanding of brain function with a shift from traditional localizationist models to more complex and widely distributed neural networks. In human language processing, the traditional localizationist models of Wernicke and Broca have fallen out of favor for a dual-stream processing system involving complex networks organized over vast areas of the dominant hemisphere. The current review explores the cortical function and white matter connections of human language processing, as well as their relevance to surgical planning. METHODS: We performed a systematic review of the literature with narrative data analysis. RESULTS: Although there is significant heterogeneity in the literature over the past century of exploration, modern evidence provides new insight into the true cortical function and white matter anatomy of human language. Intraoperative data and postoperative outcome studies confirm a widely distributed language network extending far beyond the traditional cortical areas of Wernicke and Broca. CONCLUSIONS: The anatomic distribution of language networks, based on current theories, is explored to present a modern and clinically relevant interpretation of language function. Within this framework, we present current knowledge regarding the known effects of damage to both cortical and subcortical components of these language networks. Ideally, we hope this framework will provide a common language for which to base future clinical studies in human language function.
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Mapeo Encefálico/métodos , Desarrollo del Lenguaje , Neuroimagen/métodos , HumanosRESUMEN
BACKGROUND: Despite the conformity of stereotactic radiosurgery (SRS) treatment, there are concerns about the risk of malignancy. OBJECTIVE: We compared the number of cancer cases observed after treatment in a group of SRS patients to the number of cancer cases that would be expected in an age- and gender-matched group. METHODS: We collected data from the University of Florida SRS database for patients treated for meningiomas, intracranial schwannomas, arteriovenous malformations (AVMs), trigeminal neuralgia, pituitary adenomas, cavernous angiomas, and metastases. We used the Florida Cancer Data System (FCDS) to determine the actual cancer rates for SRS-treated patients, and we compared these to the cancer rates in similar groups of non-SRS-treated patients based on rates available from the SEER (surveillance epidemiology and end results) database. RESULTS: A total of 2,369 patients were analyzed. Of these, 862 were patients with metastases who were analyzed only to ensure the sensitivity of using the FCDS to determine malignancy rates. The results for patients with more than 5 years of follow-up are reported. Without the metastases patients, a total of 627 patients had more than 5 years of follow-up data. Follow-up in patient-years was 1,711 for the meningioma patients, 1,851 for the schwannoma patients, 1,407 for the AVM patients and 338 for patients with a diagnosis of 'other'. The observed cancer rate in the meningioma patients was 3.96% compared to the expected rate of 10% (binomial 95% confidence interval, CI = 1.85-7.94). The observed cancer rate in the schwannoma patients was 4.93% compared to the expected rate of 12.5% (95% CI = 2.61-8.89). The observed cancer rate in the AVM patients was 3.64% compared to the expected rate of 4.43% (95% CI = 1.49-8.10). The observed cancer rate in patients treated for other diagnoses (e.g. pituitary adenoma or trigeminal neuralgia) was 0% compared to the expected rate of 6.36% (95% CI = 0-11.7). CONCLUSIONS: In a large population of SRS-treated patients, there was no increased risk of malignancy compared to the general population.
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Neoplasias Encefálicas/cirugía , Malformaciones Arteriovenosas Intracraneales/cirugía , Neoplasias Inducidas por Radiación/etiología , Radiocirugia/efectos adversos , Neuralgia del Trigémino/cirugía , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Persona de Mediana Edad , Aceleradores de Partículas , Radiocirugia/instrumentación , Estudios Retrospectivos , Riesgo , Resultado del Tratamiento , Adulto JovenRESUMEN
BACKGROUND: Immune checkpoint inhibitors (ICIs) have shown growing promise in the treatment of brain metastases, especially combined with stereotactic radiosurgery (SRS). The combination of ICIs with SRS has been studied for efficacy as well as increasing radiation necrosis risks. In this review, we compare clinical outcomes of radiation necrosis, intracranial control, and overall survival between patients with brain metastases treated with either SRS alone or SRS-ICI combination therapy. METHODS: A literature search of PubMed, Scopus, Embase, Web of Science, and Cochrane was performed in May 2023 for articles comparing the safety and efficacy of SRS/ICI versus SRS-alone for treating brain metastases. RESULTS: The search criteria identified 1961 articles, of which 48 met inclusion criteria. Combination therapy with SRS and ICI does not lead to significant increases in incidence of radiation necrosis either radiographically or symptomatically. Overall, no difference was found in intracranial control between SRS-alone and SRS-ICI combination therapy. Combination therapy is associated with increased median overall survival. Notably, some comparative studies observed decreased neurologic deaths, challenging presumptions that improved survival is due to greater systemic control. The literature supports SRS-ICI administration within 4 weeks of another for survival but remains inconclusive, requiring further study for other outcome measures. CONCLUSIONS: Combination SRS-ICI therapy is associated with significant overall survival benefit for patients with brain metastases without significantly increasing radiation necrosis risks compared to SRS alone. Although intracranial control rates appear to be similar between the 2 groups, timing of treatment delivery may improve control rates and demands further study attention.
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Neoplasias Encefálicas , Radiocirugia , Humanos , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Radiocirugia/efectos adversos , Terapia Combinada , Neoplasias Encefálicas/radioterapia , Necrosis , Estudios RetrospectivosRESUMEN
Myelodysplastic neoplasms (MDS) define clonal hematopoietic malignancies characterized by heterogeneous mutational and clinical spectra typically seen in the elderly. Curative treatment entails allogeneic hematopoietic stem cell transplant, which is often not a feasible option due to older age and significant comorbidities. Immunotherapy has the cytotoxic capacity to elicit tumor-specific killing with long-term immunological memory. While a number of platforms have emerged, therapeutic vaccination presents as an appealing strategy for MDS given its promising safety profile and amenability for commercialization. Several preclinical and clinical trials have investigated the efficacy of vaccines in MDS; these include peptide vaccines targeting tumor antigens, whole cell-based vaccines and dendritic cell-based vaccines. These therapeutic vaccines have shown acceptable safety profiles, but consistent clinical responses remain elusive despite robust immunological reactions. Combining vaccines with immunotherapeutic agents holds promise and requires further investigation. Herein, we highlight therapeutic vaccine trials while reviewing challenges and future directions of successful vaccination strategies in MDS.
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Neoplasias Hematológicas , Síndromes Mielodisplásicos , Vacunas , Anciano , Humanos , Síndromes Mielodisplásicos/terapia , Inmunoterapia , VacunaciónRESUMEN
OBJECTIVE: The objective of this study was to determine risk factors predictive of external ventricular drain (EVD)-related hemorrhage and the association of such hemorrhages with mortality, discharge disposition, length of stay (LOS), and total cost. METHODS: After Institutional Review Board approval, data was collected retrospectively for adult patients requiring EVD placement from 2015 to 2018 at the authors' institution. Collected data included demographic patient information, peri-procedural factors, and relevant post-procedural measures. Computerized tomography (CT) images and associated radiologic reports were independently reviewed, identifying hemorrhages accompanying EVD placement. RESULTS: From this 487-patient sample, 85 (17.5â¯%) patients had hemorrhages, including asymptomatic hemorrhages identified on imaging alone. A univariable analysis of patient parameters in the overall cohort was performed to identify possible predictors of hemorrhage. Age (p = 0.002), Charlson Comorbidity Index (CCI) (p < 0.001), platelet count (p = 0.002), presence of uremia (p = 0.035), and the number of times the EVD was replaced (p < 0.001) were associated with hemorrhage in univariable models. The experience of the resident surgeon based on post-graduate year (PGY level) and the number of attempts/passes needed for EVD placement were not associated with hemorrhage risk. Significant predictor of hemorrhage confirmed in a multivariable analysis only included the number of times the EVD was replaced (OR = 2.78, adjusted p < 0.001). Outcomes between EVD-related hemorrhage versus no hemorrhage groups, including mortality, discharge disposition, LOS, and cost, were compared. EVD-related hemorrhage was found to be associated with increased mortality (OR = 3.58, adjusted p < 0.001) and decreased likelihood of discharge home (OR = 0.13, adjusted p = 0.030) in the associated multivariable regressions. CONCLUSION: The number of times an EVD was replaced was associated with EVD-related hemorrhage outcome. EVD-related hemorrhage is associated with increased mortality and a decreased likelihood of being discharged home.
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Drenaje , Humanos , Masculino , Femenino , Factores de Riesgo , Persona de Mediana Edad , Drenaje/efectos adversos , Anciano , Estudios Retrospectivos , Tiempo de Internación , Adulto , Ventriculostomía/efectos adversos , Resultado del Tratamiento , Anciano de 80 o más AñosRESUMEN
BACKGROUND: Normal pressure hydrocephalus can be treated with ventriculoperitoneal shunt (VPS) placement, but no broadly implemented indication for VPS exists. METHODS: Our protocol consists of physical therapy and occupational therapy practitioners administering validated tests of gait, balance, and cognition before and after lumbar drain placement. Specific tests include: Timed "Up & Go", Tinetti Gait and Balance Assessment, Berg Balance Scale, Mini Mental Status Exam, Trail Making Test Part B, and the Rey Auditory and Visual Learning Test. Minimal clinically important difference values for each test were determined from literature review. A retrospective review of patients treated under this protocol was performed. The primary outcomes were candidacy for VPS based on the protocol and patient-reported symptomatic improvement after VPS placement. RESULTS: A total of 48/75 (64%) patients received VPS. A total of 43/48 (89.6%) of those shunted reported improved symptoms at 6-week follow-up. However, 10/22 (45.5%) reported worsening symptoms at 1-year follow-up. The mean Tinetti score significantly increased after lumbar drain in patients who improved with VPS compared to the no shunt group (4.27 vs. -0.48, P < 0.001). A total of 6/33 (18%) patients with postoperative imaging had a subdural fluid collection identified and 3/49 (6%) had other complications, including 1 seizure, 1 intracerebral hemorrhage, and 1 stroke. CONCLUSIONS: Standardized assessment of gait, balance, and cognition before and after temporary cerebrospinal fluid diversion identifies patients with normal pressure hydrocephalus likely to benefit from VPS placement with a low complication rate. One year after VPS, approximately one half of patients had symptoms recurrence.
Asunto(s)
Hidrocéfalo Normotenso , Selección de Paciente , Derivación Ventriculoperitoneal , Humanos , Hidrocéfalo Normotenso/cirugía , Derivación Ventriculoperitoneal/métodos , Femenino , Masculino , Anciano , Estudios Retrospectivos , Persona de Mediana Edad , Anciano de 80 o más Años , Equilibrio Postural/fisiología , Resultado del Tratamiento , Protocolos ClínicosRESUMEN
OBJECTIVE: Neurosurgery has remained relatively homogeneous in terms of racial and gender diversity, trailing behind national demographics. Less than 5% of practicing neurosurgeons in the United States identify as Black/African American (AA). Research and academic productivity are highly emphasized within the field and are crucial for career advancement at academic institutions. They also serve as important avenues for mentorship and recruitment of diverse trainees and medical students. This study aimed to summarize the academic accomplishments of AA neurosurgeons by assessing publication quantity, h-index, and federal grant funding. METHODS: One hundred thirteen neurosurgery residency training programs accredited by the Accreditation Council for Graduate Medical Education in 2022 were included in this study. The American Society of Black Neurosurgeons registry was reviewed to analyze the academic metrics of self-identified Black or AA academic neurosurgeons. Data on the academic rank, leadership position, publication quantity, h-index, and race of neurosurgical faculty in the US were obtained from publicly available information and program websites. RESULTS: Fifty-five AA and 1393 non-AA neurosurgeons were identified. Sixty percent of AA neurosurgeons were fewer than 10 years out from residency training, compared to 37.4% of non-AA neurosurgeons (p = 0.001). AA neurosurgeons had a median 32 (IQR 9, 85) publications compared to 52 (IQR 22, 122) for non-AA neurosurgeons (p = 0.019). AA neurosurgeons had a median h-index of 12 (IQR 5, 24) compared to 16 (IQR 9, 31) for non-AA colleagues (p = 0.02). Following stratification by academic rank, these trends did not persist. No statistically significant differences in the median amounts of awarded National Institutes of Health funding (p = 0.194) or level of professorship attained (p = 0.07) were observed between the two cohorts. CONCLUSIONS: Racial disparities between AA and non-AA neurosurgeons exist in publication quantity and h-index overall but not when these groups are stratified by academic rank. Given that AA neurosurgeons comprise more junior faculty, it is expected that their academic accomplishments will increase as more enter academic practice and current neurosurgeons advance into more senior positions.