RESUMEN
Given the marginal penetration of most drugs across the blood-brain barrier, the efficacy of various agents remains limited for glioblastoma (GBM). Here we employ low-intensity pulsed ultrasound (LIPU) and intravenously administered microbubbles (MB) to open the blood-brain barrier and increase the concentration of liposomal doxorubicin and PD-1 blocking antibodies (aPD-1). We report results on a cohort of 4 GBM patients and preclinical models treated with this approach. LIPU/MB increases the concentration of doxorubicin by 2-fold and 3.9-fold in the human and murine brains two days after sonication, respectively. Similarly, LIPU/MB-mediated blood-brain barrier disruption leads to a 6-fold and a 2-fold increase in aPD-1 concentrations in murine brains and peritumoral brain regions from GBM patients treated with pembrolizumab, respectively. Doxorubicin and aPD-1 delivered with LIPU/MB upregulate major histocompatibility complex (MHC) class I and II in tumor cells. Increased brain concentrations of doxorubicin achieved by LIPU/MB elicit IFN-γ and MHC class I expression in microglia and macrophages. Doxorubicin and aPD-1 delivered with LIPU/MB results in the long-term survival of most glioma-bearing mice, which rely on myeloid cells and lymphocytes for their efficacy. Overall, this translational study supports the utility of LIPU/MB to potentiate the antitumoral activities of doxorubicin and aPD-1 for GBM.
Asunto(s)
Barrera Hematoencefálica , Neoplasias Encefálicas , Doxorrubicina , Microburbujas , Receptor de Muerte Celular Programada 1 , Doxorrubicina/farmacología , Doxorrubicina/administración & dosificación , Doxorrubicina/uso terapéutico , Doxorrubicina/análogos & derivados , Animales , Humanos , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Receptor de Muerte Celular Programada 1/metabolismo , Ratones , Barrera Hematoencefálica/metabolismo , Barrera Hematoencefálica/efectos de los fármacos , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/inmunología , Neoplasias Encefálicas/patología , Línea Celular Tumoral , Glioma/tratamiento farmacológico , Glioma/inmunología , Glioma/patología , Encéfalo/metabolismo , Encéfalo/efectos de los fármacos , Femenino , Sistemas de Liberación de Medicamentos , Ondas Ultrasónicas , Glioblastoma/tratamiento farmacológico , Glioblastoma/inmunología , Glioblastoma/patología , Masculino , Microglía/efectos de los fármacos , Microglía/metabolismo , Ratones Endogámicos C57BL , Anticuerpos Monoclonales Humanizados/uso terapéutico , Anticuerpos Monoclonales Humanizados/administración & dosificación , Anticuerpos Monoclonales Humanizados/farmacología , Inhibidores de Puntos de Control Inmunológico/farmacología , Inhibidores de Puntos de Control Inmunológico/administración & dosificación , PolietilenglicolesRESUMEN
OBJECTIVE: Neurosurgery is one of the most competitive specialties, and navigating the match process is often challenging for aspiring applicants. Here, we analyze insights from the National Resident Matching Program Director Surveys, illustrating evolving trends in applicant selection for interviews and for the ranking process, and providing a comparison with other specialties. METHODS: We evaluated 7 surveys administered from 2012 to 2022. Six biennial surveys reported on factors influencing interview and ranking processes, while all 7 surveys included data about the program director (PD)'s attitude toward United States Medical Licensing Examination (USMLE) test scores. RESULTS: The response rate of PDs decreased over the years. The most cited factor for interviews included specialty-specific recommendation letters (95%), USMLE Step 1 scores (91%), and interest in research (78%). A recent decline in emphasis on USMLE Step 1 scores coincided with a growing reliance on USMLE Step 2 scores. Award in basic science held significant esteem to a subset of programs. Personal characteristics dominated for ranking, with faculty interaction (89%), interpersonal skills (89%), and house staff interaction (85%) being the most important. Yet, PDs reported a difficulty in assessing interpersonal skills through virtual interviews. CONCLUSIONS: Our analysis revealed the pervasive importance of specialized endorsements and academic achievements when screening applicants for the interview process. A shift in emphasis toward the USMLE Step 2 became apparent. Personal characteristics, on the other hand, seemed crucial to make a match and rank high among the pool of interviewed applicants. We uncovered difficulties in assessing these characteristics through virtual interviews.
RESUMEN
PURPOSE: We aimed to investigate surgical outcomes in octogenarians with subaxial cervical spine injuries and determine the predictors of complications and mortality. METHODS: Eligible for inclusion were all patients surgically treated between 2006 and 2018, with either anterior or posterior fixation for subaxial spine injuries. A cohort of octogenarians was identified and matched 1:1 to a corresponding cohort of younger adults. Primary outcomes were perioperative complications and mortality. RESULTS: Fifty-four patients were included in each of the octogenarian and younger groups (median age: 84.0 vs. 38.5). While the risks for surgical complications, including dural tears and wound infections, were similar between groups, the risks of postoperative medical complications, including respiratory or urinary tract infections, were significantly higher among the elderly (p < 0.05). Additionally, there were no differences in operative time (p = 0.625) or estimated blood loss (p = 0.403) between groups. The 30 and 90-day mortality rates were significantly higher among the elderly (p = 0.004 and p < 0.001). These differences were due to comorbidities in the octogenarian cohort as they were revoked when propensity score matching was performed to account for the differences in American Society of Anesthesiology (ASA) grade. Multivariable logistic regression revealed age and ASA score to be independent predictors of complications and the 90-day mortality, respectively. CONCLUSIONS: Octogenarians with comorbidities were more susceptible to postoperative complications, explaining the increased short-term mortality in this group. However, octogenarians without comorbidities had similar outcomes compared to the younger patients, indicating that overall health, including comorbidities, rather than chronological age should be considered in surgical decision-making.
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Vértebras Cervicales , Complicaciones Posoperatorias , Humanos , Masculino , Femenino , Anciano de 80 o más Años , Vértebras Cervicales/cirugía , Vértebras Cervicales/lesiones , Complicaciones Posoperatorias/epidemiología , Complicaciones Posoperatorias/etiología , Adulto , Resultado del Tratamiento , Estudios de Cohortes , Traumatismos Vertebrales/cirugía , Persona de Mediana Edad , Anciano , Estudios RetrospectivosRESUMEN
We recently discovered a putative paclitaxel response predictive biomarker for glioblastoma and breast cancer using the whole genome CRISPR knockout screen. The biomarker candidate was validated in two independent breast cancer patient cohorts that received taxane treatment. To further evaluate the potential application of this biomarker in the clinic for patients with glioblastoma, a prospective validation in cohorts of patients with glioblastoma is essential and will be performed as part of our ongoing phase II clinical trial (NCT04528680). The validation of novel biomarkers of susceptibility to therapy is critical to elucidate the efficacy signal of therapeutic agents. This is especially important in the context of glioblastoma, where therapeutic benefit is variable and unpredictable, leading to negative trials, yet the outcome of subset of patients has outperformed expectations.
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Neoplasias de la Mama , Glioblastoma , Femenino , Humanos , Biomarcadores , Mama , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/genética , Paclitaxel/uso terapéutico , Ensayos Clínicos Fase II como AsuntoRESUMEN
PURPOSE: We recently reported on clinical trials for patients with recurrent glioblastoma where low-intensity pulsed ultrasound and microbubbles (LIPU/MB) improved paclitaxel or carboplatin delivery into the brain. Here, we report variable local tumor control with paclitaxel at the maximal/target dose in our phase I trial (NCT04528680). To address this, we investigated the combination of paclitaxel with carboplatin in preclinical glioma models. EXPERIMENTAL DESIGN: We performed MRI-based analysis to evaluate disease control in patients from our trial. We studied the cytotoxicity of paclitaxel and carboplatin against 11 human glioma lines as monotherapy and in combination at concentrations derived from human intraoperative studies. Synergy was assessed with the Loewe model and the survival benefit evaluated in two xenografts. We examined the effects on cell cycle progression, DNA damage, and apoptosis. RESULTS: Patients treated with paclitaxel and LIPU/MB exhibited variable local tumor control, which correlated with overall survival. We observed limited cross-resistance to paclitaxel and carboplatin in glioma lines, with almost a third of them being exclusively susceptible to one drug. This combination led to susceptibility of 81% of lines and synergy in 55% of them. The combination proved more efficacious in two intracranial xenografts when administered with LIPU/MB, leading to complementary effects on cell cycle arrest. CONCLUSIONS: Combining paclitaxel and carboplatin in gliomas may be more efficacious than monotherapy, as in other cancers, due to synergy and independent susceptibility to each drug. These results form the basis for an ongoing phase II trial (NCT04528680) where we investigate this combination with LIPU/MB.
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Glioblastoma , Glioma , Humanos , Carboplatino , Paclitaxel , Glioblastoma/tratamiento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Recurrencia Local de Neoplasia/tratamiento farmacológico , Glioma/tratamiento farmacológicoRESUMEN
PURPOSE: Evidence suggests that MAPK pathway activation, as measured by ERK1/2 phosphorylation (p-ERK), predicts overall survival (OS) in patients with recurrent glioblastoma receiving anti-PD-1 therapy. We aimed to validate these findings in independent cohorts. EXPERIMENTAL DESIGN: In a 24-patient clinical trial on recurrent glioblastoma and high-grade gliomas, we examined the link between p-ERK levels and OS. Patients received intravenous nivolumab, followed by maximal safe resection and an intracerebral injection of either ipilimumab alone or combined with nivolumab. Biweekly adjuvant nivolumab was then administered up to five times (NCT03233152). Using REporting recommendations for tumor MARKER prognostic studies (REMARK) criteria, we conducted independent analyses for p-ERK quantification and statistical evaluations. Additional comparative analysis included prior cohorts, totaling 65 patients. Cox proportional hazards models and meta-analysis were employed to assess p-ERK as a predictive biomarker after immunotherapy. RESULTS: Lower median p-ERK+ cell density was observed compared with prior studies, likely due to variable tissue processing across cohorts. Nonetheless, high p-ERK was associated with prolonged OS, particularly in isocitrate dehydrogenase wild-type glioblastomas (P = 0.036). Median OS for high and low p-ERK patients were 55.6 and 30 weeks, respectively. Multivariable analysis reinforced p-ERK's significance in survival prediction (P = 0.011). Upon p-ERK normalization across cohorts (n = 65), meta-analysis supported the survival benefit of elevated tumor p-ERK levels (P = 0.0424). CONCLUSIONS: This study strengthens the role of p-ERK as a predictive biomarker for OS in patients with glioblastoma on immune checkpoint blockade. Future research should focus on further validation in prospective trials and the standardization of preanalytical variables influencing p-ERK quantification.
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Glioblastoma , Humanos , Glioblastoma/tratamiento farmacológico , Glioblastoma/patología , Antígeno CTLA-4 , Nivolumab/uso terapéutico , Receptor de Muerte Celular Programada 1 , Fosforilación , Sistema de Señalización de MAP Quinasas , Estudios Prospectivos , Recurrencia Local de Neoplasia/tratamiento farmacológico , Ipilimumab/uso terapéutico , Adyuvantes Inmunológicos/uso terapéutico , InmunoterapiaRESUMEN
Traumatic brain injury (TBI) is a leading cause of morbidity and mortality. The innate and adaptive immune responses play an important role in the pathogenesis of TBI. Gamma-delta (γδ) T cells have been shown to affect brain immunopathology in multiple different conditions, however, their role in acute and chronic TBI is largely unknown. Here, we show that γδ T cells affect the pathophysiology of TBI as early as one day and up to one year following injury in a mouse model. TCRδ-/- mice are characterized by reduced inflammation in acute TBI and improved neurocognitive functions in chronic TBI. We find that the Vγ1 and Vγ4 γδ T cell subsets play opposing roles in TBI. Vγ4 γδ T cells infiltrate the brain and secrete IFN-γ and IL-17 that activate microglia and induce neuroinflammation. Vγ1 γδ T cells, however, secrete TGF-ß that maintains microglial homeostasis and dampens TBI upon infiltrating the brain. These findings provide new insights on the role of different γδ T cell subsets after brain injury and lay down the principles for the development of targeted γδ T-cell-based therapy for TBI.