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BACKGROUND: Glioblastoma represents a brain tumor with a notoriously poor prognosis. First-line therapy may include adjunctive Tumor Treating Fields (TTFields) which are electric fields that are continuously delivered to the brain through non-invasive arrays. On a different note, CUSP9v3 represents a drug repurposing strategy that includes 9 repurposed drugs plus metronomic temozolomide. Here, we examined whether TTFields enhance the antineoplastic activity of CUSP9v3 against this disease. METHODS: We performed preclinical testing of a multimodal approach of TTFields and CUSP9v3 in different glioblastoma models. RESULTS: TTFields had predominantly synergistic inhibitory effects on the cell viability of glioblastoma cells and non-directed movement was significantly impaired when combined with CUSP9v3. TTFields plus CUSP9v3 significantly enhanced apoptosis, which was associated with a decreased mitochondrial outer membrane potential (MOMP), enhanced cleavage of effector caspase 3 and reduced expression of Bcl-2 and Mcl-1. Moreover, oxidative phosphorylation and expression of respiratory chain complexes I, III and IV was markedly reduced. CONCLUSION: TTFields strongly enhance the CUSP9v3-mediated anti-glioblastoma activity. TTFields are currently widely used for the treatment of glioblastoma patients and CUSP9v3 was shown to have a favorable safety profile in a phase Ib/IIa trial (NCT02770378) which facilitates transition of this multimodal approach to the clinical setting.
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Antineoplásicos , Neoplasias Encefálicas , Terapia por Estimulación Eléctrica , Glioblastoma , Humanos , Glioblastoma/tratamiento farmacológico , Reposicionamiento de Medicamentos , Reprogramación Metabólica , Temozolomida/farmacología , Antineoplásicos/uso terapéutico , Neoplasias Encefálicas/tratamiento farmacológico , Terapia CombinadaRESUMEN
PURPOSE: Screwed anterior lumbar interbody fusion (SALIF) alleviates the need for supplemental posterior fixation leading to reduction of perioperative morbidity. Specifically, elderly and multimorbid patients would benefit from shorter operative time and faster recovery but tend to have low bone mineral density (BMD). The current study aimed to compare loosening, defined as increase of ROM and NZ, of SALIF versus transforaminal lumbar interbody fusion (TLIF) under cyclic loading in cadaveric spines with reduced BMD. METHODS: Twelve human spines (L4-S2; 6 male 6 female donors; age 70.6 ± 19.6; trabecular BMD of L5 84.2 ± 24.4 mgHA/cm3, range 51-119 mgHA/cm3) were assigned to two groups. SALIF or TLIF were instrumented at L5/S1. Range of motion (ROM) and neutral zone (NZ) were assessed before and after axial cyclic loading (0-1150 N, 2000 cycles, 0.5 Hz) in flexion-extension (Flex-Ext), lateral bending, (LB), axial rotation (AR). RESULTS: ROM of the SALIF specimens increased significantly in all loading directions (p ≤ 0.041), except for left AR (p = 0.053), whereas for TLIF it increased significantly in left LB (p = 0.033) and Flex (p = 0.015). NZ of SALIF showed increase in Flex-Ext and LB, whereas NZ of TLIF did not increase significantly in any motion direction. CONCLUSIONS: Axial compression loading caused loosening of SALIF in Flex-Ext and LB, but not TLIF at L5/S1 in low BMD specimens. Nevertheless, Post-cyclic ROM and NZ of SALIF is comparable to TLIF. This suggests that, neither construct is optimal for the use in patients with reduced BMD.
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OBJECTIVE: One proposed method to improve sound localisation for bilateral cochlear implant (BiCI) users is to synchronise the automatic gain control (AGC) of both audio processors. In this study we tested whether AGC synchronisation in a dual-loop front-end processing scheme with a 3:1 compression ratio improves sound localisation acuity. DESIGN: Source identification in the frontal hemifield was tested in in an anechoic chamber as a function of (roving) presentation level. Three different methods of AGC synchronisation were compared to the standard unsynchronised approach. Both root mean square error (RMSE) and signed bias were calculated to evaluate sound localisation in the horizontal plane. STUDY SAMPLE: Six BiCI users. RESULTS: None of the three AGC synchronisation methods yielded significant improvements in either localisation error or bias, neither across presentation levels nor for individual presentation levels. For synchronised AGC, the pooled mean (standard deviation) localisation error of the three synchronisation methods was 24.7 (5.8) degrees RMSE, for unsynchronised AGC it was 27.4 (7.5) degrees. The localisation bias was 5.1 (5.5) degrees for synchronised AGC and 5.0 (3.8) for unsynchronised. CONCLUSIONS: These findings do not support the hypothesis that the tested AGC synchronisation configurations improves localisation acuity in bilateral users of MED-EL cochlear implants.
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Malignant gliomas are still extremely difficult to treat because complete surgical resection is biologically not feasible due to the invasive nature of these diseases and the proximity of tumors to functionally sensitive areas. Moreover, adjuvant therapies are facing a strong therapeutic resistance since the central nervous system is a highly protected environment and the tumor cells display a vast intra-tumoral genetic and epigenetic variation. As a consequence, new therapeutics are urgently needed but the process of developing novel compounds that finally reach clinical application is highly time-consuming and expensive. Drug repurposing is an approach to facilitate and accelerate the discovery of new cancer treatments. In malignant glioma, like in other cancers, pre-existing physiological pathways that regulate cell growth, cell death or cell migration are dysregulated causing malignant transformation. A wide variety of drugs are clinically used to treat non-cancerous diseases interfering with these malignancy-associated pathways. Repurposed drugs have key advantages: They already have approval for clinical use by national regulatory authorities. Moreover, they are for the most part inexpensive and their side effect and safety profiles are well characterized. In this work, we provide an overview on current repurposing strategies for the treatment of malignant glioma.
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Antineoplásicos/uso terapéutico , Neoplasias Encefálicas/tratamiento farmacológico , Descubrimiento de Drogas , Reposicionamiento de Medicamentos/métodos , Glioma/tratamiento farmacológico , Animales , HumanosRESUMEN
INTRODUCTION: Intraoperative magnetic resonance imaging (iMRI) improves the intraoperative detection of adenoma remnants in transsphenoidal surgery. iMRI might be redundant in endoscopic pituitary surgery in non-invasive tumors (Knosp 0-2) due to a superior visualization of anatomical structures in the periphery of the sella turcica compared to the microscopic technique. We identified the anatomical location of tumor remnants in iMRI and evaluated risk factors for secondary resection after iMRI and hereby selected patients with pituitary adenomas who may benefit from iMRI-assisted resection. METHODS: We conducted a retrospective monocenter study of patients who underwent iMRI-assisted transsphenoidal surgical resection of pituitary adenomas at our department between 2012 and 2020. A total number of 190 consecutive iMRI-assisted transsphenoidal surgeries of pituitary adenomas graded as Knosp 0-2 were selected for analysis. Exclusion criteria were missing iMRI availability or pathologies other than adenomas. Of these 190 cases, 46.3% (N = 88) were treated with microscopic, 48.4% (N = 92) with endoscopic, and 5.3% (N = 10) with endoscopic-assisted technique. Volumetric measurement of preoperative, intraoperative, and postoperative tumor extension was performed. Demographic data, tumor characteristics, and MRI features were evaluated. Additionally, analysis of adenoma remnants identified by iMRI was performed. RESULTS: An additional resection after iMRI was performed in 16.3% (N = 31). iMRI helped to reach gross total resection (GTR) in 83.9% (26/31) of these cases. False-positive resection was found in 1 patient (0.5%). Multivariable logistic analysis identified tumor volume (OR = 1.2, p = 0.007) recurrence (OR = 11.3, p = 0.002) and microscopic technique (OR = 2.8, p = 0.029) as independent risk factors for additional resection. Simultaneously, the endoscopic technique was significantly associated with GTR as evaluated by iMRI (OR = 2.8, p = 0.011) and postoperative MRI (OR = 5.8, p = 0.027). The detailed analysis of adenoma remnants on iMRI revealed the suprasellar location in a diaphragm fold, penetrating tumor above the diaphragm, or undetected invasion of cavernous sinus as well as in case of microscopic resection tumor location outside the line of sight as the main reasons for incomplete resections. CONCLUSION: Tumor volume, recurrence, and microscopic technique were identified as independent predictors for additional resection in patients with Knosp 0-2 adenomas. iMRI might increase the extent of resection (EOR) safely even after the endoscopic visualization of the sella with very low risk for false-positive findings. Remnants of tumors hidden within the diaphragmic folds, intrathecally, or behind the infiltrated wall of cavernous sinus not recognized on preoperative MRI were the most common findings in iMRI.
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Adenoma , Neoplasias Hipofisarias , Adenoma/diagnóstico por imagen , Adenoma/patología , Adenoma/cirugía , Endoscopía/métodos , Humanos , Imagen por Resonancia Magnética/métodos , Neoplasias Hipofisarias/diagnóstico por imagen , Neoplasias Hipofisarias/patología , Neoplasias Hipofisarias/cirugía , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
OBJECTIVE: Placement of a ventricular drain is one of the most common neurosurgical procedures. However, a higher rate of successful placements with this freehand procedure is desirable. The authors' objective was to develop a compact navigational augmented reality (AR)-based tool that does not require rigid patient head fixation, to support the surgeon during the operation. METHODS: Segmentation and tracking algorithms were developed. A commercially available Microsoft HoloLens AR headset in conjunction with Vuforia marker-based tracking was used to provide guidance for ventriculostomy in a custom-made 3D-printed head model. Eleven surgeons conducted a series of tests to place a total of 110 external ventricular drains under holographic guidance. The HoloLens was the sole active component; no rigid head fixation was necessary. CT was used to obtain puncture results and quantify success rates as well as precision of the suggested setup. RESULTS: In the proposed setup, the system worked reliably and performed well. The reported application showed an overall ventriculostomy success rate of 68.2%. The offset from the reference trajectory as displayed in the hologram was 5.2 ± 2.6 mm (mean ± standard deviation). A subgroup conducted a second series of punctures in which results and precision improved significantly. For most participants it was their first encounter with AR headset technology and the overall feedback was positive. CONCLUSIONS: To the authors' knowledge, this is the first report on marker-based, AR-guided ventriculostomy. The results from this first application are encouraging. The authors would expect good acceptance of this compact navigation device in a supposed clinical implementation and assume a steep learning curve in the application of this technique. To achieve this translation, further development of the marker system and implementation of the new hardware generation are planned. Further testing to address visuospatial issues is needed prior to application in humans.
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Realidad Aumentada , Drenaje , Humanos , Procedimientos Neuroquirúrgicos , VentriculostomíaRESUMEN
BACKGROUND: Dysregulation of the metabolome is a hallmark of primary brain malignancies. In this work we examined whether metabolic reprogramming through a multi-targeting approach causes enhanced anti-cancer activity in glioblastoma. METHODS: Preclinical testing of a combined treatment with ONC201/TIC10 and 2-Deoxyglucose was performed in established and primary-cultured glioblastoma cells. Extracellular flux analysis was used to determine real-time effects on OXPHOS and glycolysis. Respiratory chain complexes were analysed by western blotting. Biological effects on tumour formation were tested on the chorioallantoic membrane (CAM). RESULTS: ONC201/TIC10 impairs mitochondrial respiration accompanied by an increase of glycolysis. When combined with 2-Deoxyglucose, ONC201/TIC10 induces a state of energy depletion as outlined by a significant decrease in ATP levels and a hypo-phosphorylative state. As a result, synergistic anti-proliferative and anti-migratory effects were observed among a broad panel of different glioblastoma cells. In addition, this combinatorial approach significantly impaired tumour formation on the CAM. CONCLUSION: Treatment with ONC201/TIC10 and 2-Deoxyglucose results in a dual metabolic reprogramming of glioblastoma cells resulting in a synergistic anti-neoplastic activity. Given, that both agents penetrate the blood-brain barrier and have been used in clinical trials with a good safety profile warrants further clinical evaluation of this therapeutic strategy.
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Antineoplásicos/farmacología , Neoplasias Encefálicas/tratamiento farmacológico , Desoxiglucosa/farmacología , Metabolismo Energético/efectos de los fármacos , Glioblastoma/tratamiento farmacológico , Imidazoles/farmacología , Piridinas/farmacología , Pirimidinas/farmacología , Animales , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patología , Línea Celular Tumoral , Embrión de Pollo/efectos de los fármacos , Glioblastoma/metabolismo , Glioblastoma/patología , Glucólisis/efectos de los fármacos , Humanos , Fosforilación OxidativaRESUMEN
Cathepsin G (CatG) is responsible for several distinct immune processes of adaptive and innate immunity depending on extra- or intracellular occurrence of CatG. Recently, we established a method to detect CatG activity at the cell surface of natural killer cells by using the activity-based probe MARS116-Bt in flow cytometry. MARS116-Bt consists of biotin, spacer, amino acid sequence, and a phosphonate warhead which binds covalently to the serine amino acid residue within the active center of CatG. Herein, MARS116 was conjugated to 5(6)-carboxyfluorescein (FAM) in order to limit non-specific signal-to-noise ratio generally resulting from binding of fluorescein-labelled avidin (avidin-FAM) to biotinylated, intracellular proteins; since MARS116-Bt is incubated with avidin-FAM in a second labelling step. MARS116-FAM was capable to detect intracellular CatG activity, in contrast to the control compound MARS116*-FAM which lacks the functional phosphonate warhead crucial for binding to the active-site of CatG and contains a carboxyl group instead. Furthermore, intracellular CatG activity was determined in CD4+ T cells, CD8+ T cells as well as in T regulatory cell (Treg) subsets. Thus, MARS116-FAM is a convenient activity-based probe to detect intracellular CatG activity in a flow cytometry approach.
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Técnicas Biosensibles/métodos , Catepsina G/sangre , Citometría de Flujo/métodos , Fluoresceínas/química , HumanosRESUMEN
OBJECTIVE: Half of all newly diagnosed patients with glioblastoma are > 65 years still with a poor prognosis. Preserving quality of life is of high importance. However, patient reported outcome (PRO) data in this patient group is rare. The aim was to compare health-related quality of life (HRQoL) and distress between elderly and younger patients with high-grade glioma (HGG). METHODS: We used baseline data of a prospective study where HGG patients were enrolled from 4 hospitals. Distress was measured using the distress thermometer (DT), HRQoL using the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Core Questionnaire (QLQ-C30) plus brain module (BN20). We compared distress and HRQoL by age (≥ 65 vs. < 65 years), gender, performance score, and time since diagnosis using multivariate linear and logistic regressions. RESULTS: A total of n = 93 (30%) out of n = 309 patients were ≥ 65 years (mean 70 years, range 65-86 years). Mean DT score of elderly patients (5.2, SD 2.6) was comparable with younger patients (4.9, SD 2.6). Elderly patients reported significantly lower global health (GHS, mean elderly vs. younger; 50.8 vs. 60.5, p = 0.003), worse physical (56.8 vs. 73.3, p < 0.001) and lower cognitive functioning (51.1 vs. 63.2, p = 0.002), worse fatigue (52.5 vs. 43.5, p = 0.042), and worse motor dysfunction (34.9 vs. 23.6, p = 0.030). KPS and not age was consistently associated with HRQoL. CONCLUSION: Physical functioning was significantly reduced in the elderly compared with younger HGG patients, and at the same time, emotional functioning and DT scores were comparable. KPS shows a greater association with HRQoL than with calendric age in HGG patients reflecting the particular importance for adequate assessment of HRQoL and general condition in elderly patients.
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Neoplasias Encefálicas/psicología , Glioblastoma/psicología , Factores de Edad , Anciano , Anciano de 80 o más Años , Neoplasias Encefálicas/patología , Disfunción Cognitiva/patología , Disfunción Cognitiva/psicología , Fatiga/patología , Fatiga/psicología , Femenino , Glioblastoma/patología , Humanos , Masculino , Clasificación del Tumor , Estudios Prospectivos , Calidad de Vida , Encuestas y CuestionariosRESUMEN
OBJECTIVE: Many innovations have been introduced into pituitary surgery in the quest to maximize the extent of tumor resection. Because of the deep and narrow surgical corridor as well as the heterogeneity of confronted pathologies, anatomical orientation and identification of the target tissue can become difficult. Intraoperative MRI (iMRI) may have the potential to increase extent of resection (EOR) in transsphenoidal pituitary surgery. Furthermore, it may simplify anatomical orientation and risk assessment in difficult cases. Here, the authors evaluated the additional value of iMRI for the resection of pituitary adenomas performed in the past 10 years in their department. METHODS: They performed a retrospective single-center analysis of patients treated for pituitary adenoma in their department after the introduction of iMRI between 2008 and 2018. Of 495 transsphenoidal approaches, 300 consecutive MRI-assisted surgeries for pituitary adenomas encompassing 294 patients were selected for further analysis. Microscopic, endoscopic, or endoscope-assisted microscopic transsphenoidal approaches were distinguished. EOR as well as additional resection following iMRI was evaluated via detailed volumetric analysis. Patients were stratified according to the Knosp adenoma classification. Furthermore, demographic data, clinical symptoms, endocrine outcome, and complications were evaluated. Univariable and multivariable Cox regression analyses of progression-free survival (PFS) were performed. RESULTS: Pituitary adenomas classified as Knosp grades 0-2 were found in 60.3% of cases (n = 181). The most common tumors were nonfunctioning adenomas (75%). Continued resection following iMRI significantly increased EOR (7.5%, p < 0.001) and the proportion of gross-total resections (GTRs) in transsphenoidal pituitary surgery (54% vs 68.3%, p < 0.001). Additional resection after iMRI was performed in 37% of cases. Only in the subgroup of patients with Knosp grades 0-2 adenomas treated with the microsurgical technique was additional resection significantly more common than in the endoscopic group (p = 0.039). Residual tumor volume, Knosp grade, and age were confirmed as independent predictors of PFS (p < 0.001, p = 0.021, and p = 0.029, respectively) in a multivariable Cox regression analysis. Improvement of visual field deficits was documented in 78.6% of patients whose optic apparatus had been affected preoperatively. Revision surgery was done in 7.3% of cases; in 5.6% of cases, it was performed for cerebrospinal fluid fistula. CONCLUSIONS: In this series, iMRI led to the detection of a resectable tumor remnant in a high proportion of patients, resulting in a greater EOR and higher proportion of GTRs after continued resection in microsurgical and endoscopic transsphenoidal resection of pituitary adenomas. The volume of residual tumor was the most important predictor of PFS. Given the study data, the authors postulated that every bit of removed tumor serves the patient and increases their chances of a favorable outcome.
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Adenoma/cirugía , Monitorización Neurofisiológica Intraoperatoria/tendencias , Imagen por Resonancia Magnética/tendencias , Neuroendoscopía/tendencias , Neoplasias Hipofisarias/cirugía , Hueso Esfenoides/cirugía , Adenoma/diagnóstico por imagen , Adulto , Anciano , Femenino , Estudios de Seguimiento , Humanos , Monitorización Neurofisiológica Intraoperatoria/métodos , Imagen por Resonancia Magnética/métodos , Masculino , Persona de Mediana Edad , Neuroendoscopía/métodos , Neoplasias Hipofisarias/diagnóstico por imagen , Estudios Retrospectivos , Hueso Esfenoides/diagnóstico por imagen , Factores de Tiempo , Resultado del Tratamiento , Carga Tumoral/fisiologíaRESUMEN
PURPOSE: Fluorescence guided surgery by 5-aminolevulinic acid (5-ALA) and intraoperative MRI (iMRI) are currently the most important intraoperative imaging techniques in high grade glioma (HGG) surgery. Few comparative studies exist for these techniques. This review aims to systematically compare 5-ALA and iMRI assisted surgery based on the current literature and discuss the potential impact of a combined use of both techniques. METHODS: A systematic literature search based on preferred reporting items for systematic reviews and meta-analysis was performed concerning accuracy of tumor detection; extent of resection; neurological deficits (ND); Quality of life (QoL); usability and combined use of both techniques. Original clinical articles on HGG published until March 31st were screened. RESULTS: 169 publications were screened, 81 were eligible and 22 were finally included in the review using. Overall, there is evidence that both imaging techniques improve gross total resection rate in non-eloquent lesions. Imaging results do not correlate at the border zone of a HGG. 5-ALA and contrast-enhanced iMRI seem to have a supplementary effect in tumor detection. Overall, both imaging techniques alone or combined do not seem to increase rate of permanent ND or decrease QoL in HGG surgery when used with intraoperative monitoring/mapping. CONCLUSION: Based on the currently available literature no superiority of one technique over the other can be found in the most important outcome parameters. Based on the available information a combined use of 5-ALA and iMRI seems very promising to achieve a resection beyond gadolinium-enhancement. However, only low quality of evidence exists for this approach.
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Ácido Aminolevulínico , Neoplasias Encefálicas/cirugía , Glioma/cirugía , Imagen por Resonancia Magnética Intervencional , Imagen Óptica , Cirugía Asistida por Computador , Neoplasias Encefálicas/diagnóstico por imagen , Neoplasias Encefálicas/patología , Colorantes Fluorescentes , Glioma/diagnóstico por imagen , Glioma/patología , Humanos , Imagen Óptica/métodosRESUMEN
The use of intraoperative MRI (iMRI) increases extent of resection in transsphenoidal pituitary surgery. Microsurgical and endoscopic techniques have been established as equal and standard surgical methods. The object of the current study was to evaluate the additional value of iMRI for resection of invasive pituitary adenomas. We conducted a retrospective monocenter study of all consecutive patients treated with invasive pituitary adenomas graded as Knosp III-IV at our department after the introduction of iMRI in 2008. Out of 315 transsphenoidal surgeries for pituitary adenomas, 111 met the criteria for analysis. Patients treated with endoscopic or microsurgical technique were included. iMRI was performed at surgeons' discretion, when maximal safe resection was assumed. Detailed volumetric tumor analysis using semiautomatic segmentation software (Brainlab Elements) before surgery, during surgery, and after surgery was performed. Additionally, demographic data, additional resection, endocrinological outcome as well as complications were evaluated. Postoperative tumor volume as measured in the follow-up MRI 3 months after surgery was significantly lower compared with intraoperative tumor volume (p < 0.001). The difference was statistically significant for both surgical techniques (p < 0.001). No significant difference was found between both techniques in intraoperative and postoperative tumor volume (p = 0.395 and p = 0.329 respectively). Additional tumor resection was performed in 56 cases (50.5%). We found no significant difference between microsurgical and endoscopic techniques regarding additional resection after iMRI (p = 0.512). New diagnosed permanent diabetes insipidus was found in 10 patients (10.5%, 10/95). New hypopituitarism was seen in 22.1% (21/95) cases and according to multivariate logistic regression was significantly associated with microsurgical technique (p = 0.035). Visual improvement was achieved in 76.8% (N = 53/69, p < 0.001) of patients with visual impairment before surgery. Revision surgery as the consequence of cerebrospinal fistula was performed in eight cases (7.2%). Meningitis was documented in three patients (2.7%). One patient died as a consequence of intraoperative vascular injury. Intraoperative MRI after maximal safe resection significantly improves the overall extent of resection in invasive pituitary adenomas independent of the surgical technique employed. Simultaneously, iMRI-assisted transsphenoidal surgery results in excellent visual recovery with low-risk profile for surgical complications for both endoscopic as well as microsurgical technique. Endoscopic technique might be related to the lower incidence of new hypopituitarism after surgery.
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Adenoma/diagnóstico por imagen , Adenoma/cirugía , Endoscopía , Imagen por Resonancia Magnética , Neoplasias Hipofisarias/diagnóstico por imagen , Neoplasias Hipofisarias/cirugía , Adenoma/patología , Adulto , Anciano , Femenino , Humanos , Modelos Logísticos , Masculino , Microcirugia , Persona de Mediana Edad , Invasividad Neoplásica , Neoplasias Hipofisarias/patología , Reoperación , Estudios Retrospectivos , Resultado del Tratamiento , Carga Tumoral , Adulto JovenRESUMEN
The aim of our study was to compare depicted pre-, intra-, and postoperative tumor volume of met-PET, perfusion-weighed MRI (PWI), and Gd-DTPA MRI. Further, to assess their sensitivity and specificity in correlation with histopathological specimen. Inclusion criteria of the prospective study were histological confirmed glioblastoma (GB), age > 18, and eligible for gross total resection (GTR). Met-PET was performed before and after surgery. Gd-DTPA MRI and PWI were performed before, during, and after surgery. A combined 5-aminolevulinic acid (5-ALA) and iMRI-guided surgery was performed. Volumetric analysis was evaluated for all imaging modalities except for 5-ALA. A total of 59 navigated biopsies were taken. Sensitivity and specificity were calculated for Gd-DTPA MRI, PWI, met-PET, and 5-ALA according to the histology of specimen. Met-PET depicted significantly larger tumor volume before surgery (p = 0.01) compared to PWI and Gd-DTPI MRI. We found no significant difference in tumor volume between met-PET and PWI after surgery (p = 0.059). Both PWI and met-PET showed significantly larger tumor volume after surgery when compared to Gd-DTPA (p = 0.018 and p = 0.003, respectively). Intraoperative PWI reading was impaired in 33.3% due to artifacts. Met-PET showed the highest sensitivity for detection of GB with 95%. The lowest sensitivity was found with Gd-DTPA MRI (50%), while 5-ALA and intraoperative PWI showed similar results (69 and 67%). Met-Pet is the imaging modality with the highest sensitivity to detect a residual tumor in GB. Intraoperative PWI seems to have a synergistic effect to Gd-DTPA and 5-ALA. However, its value may be limited by artifacts. Both pre- and intraoperative PWI cannot substitute met-PET in tumor detection.
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Neoplasias Encefálicas/diagnóstico por imagen , Glioblastoma/diagnóstico por imagen , Imagen por Resonancia Magnética , Tomografía de Emisión de Positrones , Adulto , Anciano , Ácido Aminolevulínico , Neoplasias Encefálicas/patología , Neoplasias Encefálicas/cirugía , Femenino , Gadolinio DTPA , Glioblastoma/patología , Glioblastoma/cirugía , Humanos , Masculino , Metionina , Persona de Mediana Edad , Neoplasia Residual , Fármacos Fotosensibilizantes , Estudios Prospectivos , Radiofármacos , Sensibilidad y Especificidad , Carga TumoralRESUMEN
Cerebral vasospasm (CV) and delayed cerebral ischemia (DCI) are major factors that limit good outcome in patients with spontaneous subarachnoid hemorrhage (SAH). Continuous therapy with intra-arterial calcium channel blockers has been introduced as a new step in the invasive treatment cascade of CV and DCI. Sedation is routinely necessary for this procedure. We report about the feasibility to apply this therapy in awake compliant patients without intubation and sedation. Out of 67 patients with invasive endovascular treatment of cerebral vasospasm due to spontaneous SAH, 5 patients underwent continuous superselective intracarotid nimodipine therapy without intubation and sedation. Complications, neurological improvement, and outcome at discharge were summarized. Very good outcome was achieved in all 5 patients. The Barthel scale was 100 and the modified Rankin scale 0-1 in all cases at discharge. We found no severe complications and excellent neurological monitoring was possible in all cases due to patients' alert status. Symptoms of DCI resolved within 24 h in all 5 cases. We could demonstrate the feasibility and safety of selective intracarotid arterial nimodipine treatment in awake, compliant patients with spontaneous SAH and symptomatic CV and DCI. Using this method, an excellent monitoring of neurological function as well as early detection of other complications is possible. It might be an important step in the risk reduction of invasive CV therapy to improve the outcome with CV and DCI after SAH in selected patients.
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Isquemia Encefálica/tratamiento farmacológico , Bloqueadores de los Canales de Calcio/administración & dosificación , Nimodipina/administración & dosificación , Hemorragia Subaracnoidea/complicaciones , Vasoespasmo Intracraneal/tratamiento farmacológico , Anciano , Isquemia Encefálica/etiología , Arterias Carótidas , Estudios de Factibilidad , Femenino , Humanos , Infusiones Intraarteriales , Masculino , Persona de Mediana Edad , Resultado del Tratamiento , Vasoespasmo Intracraneal/etiología , VigiliaRESUMEN
The objective of the present study is to assess the influence of extent of resection (EoR), use of intraoperative imaging, and awake surgery on health-related quality of life (HRQoL) in high-grade glioma (HGG) patients in a prospective multicenter study. We analyzed 170 surgeries of patients suffering from a HGG. During the first year after resection, HRQoL was evaluated using the European Organization of Research and Treatment of Cancer Core Questionnaire C30 and Brain Neoplasm 20 questionnaires. We assessed the influence of EoR; awake surgery; and use of 5-aminolevulinic acid (5-ALA), intraoperative MRI (iMRI), and their combination on sum scores for function and symptoms as well as several neurological single items. In mixed-model analyses, adjustments for age, Karnofsky performance status (KPS), and eloquent location were performed. In the mixed model, EoR generally did not significantly influence HRQoL (p = 0.10). Yet, patients receiving subtotal resection (STR) vs. patients with biopsy showed significantly better QoL and role and cognitive functions (p = 0.04, p = 0.02, and p < 0.01, respectively). The combination of iMRI and 5-ALA reached the highest EoR (95%) followed by iMRI alone (94%), 5-ALA alone (74%), and no imaging (73%). Thereby, neurological symptoms were lowest and functioning score highest after combined use of iMRI and 5-ALA, without reaching significance (p = 0.59). Despite lower scores in emotional function (59 vs. 46, p = 0.24), no significant impact of awake surgery on HRQoL was found (p = 0.70). In HGG patients, STR compared to biopsy was significantly associated with better HRQoL and fewer neurological symptoms in this series. An escalated use of intraoperative imaging increased EoR with stable or slightly better HRQoL and fewer neurological symptoms. Based on HRQoL, awake surgery was a well-tolerated and safe method in our series.
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Neoplasias Encefálicas/cirugía , Glioma/cirugía , Calidad de Vida , Adulto , Anciano , Ácido Aminolevulínico/uso terapéutico , Biopsia , Neoplasias Encefálicas/patología , Cognición , Estudios Transversales , Femenino , Glioma/patología , Humanos , Estado de Ejecución de Karnofsky , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Monitoreo Intraoperatorio , Evaluación del Resultado de la Atención al Paciente , Fármacos Fotosensibilizantes/uso terapéutico , Estudios Prospectivos , Encuestas y Cuestionarios , VigiliaRESUMEN
One major obstacle in cancer therapy is chemoresistance leading to tumor recurrence and metastasis. Cancer stem cells, in particular glioblastoma stem cells, are highly resistant to chemotherapy, radiation, and immune recognition. In case of immune recognition, several survival mechanisms including, regulation of autophagy, proteases, and cell surface major histocompatibility complex class I molecules, are found in glioblastoma stem cells. In different pathways, cathepsins play a crucial role in processing functional proteins that are necessary for several processes and proper cell function. Consequently, strategies targeting these pathways in glioblastoma stem cells are promising approaches to interfere with tumor cell survival and will be discussed in this review.
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Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patología , Catepsinas/metabolismo , Glioblastoma/metabolismo , Glioblastoma/patología , Células Madre Neoplásicas/metabolismo , Células Madre Neoplásicas/patología , Animales , Autofagia , Humanos , ProteolisisRESUMEN
The sulfone dapsone is an old antibiotic used for the treatment of mycobacterial and protozoal infections. We postulated before that dapsone might possess biological activity exceeding its anti-infectious properties and that it could potentially be repurposed for the treatment of glioma. To test this hypothesis, we treated established and primary cultured glioma cells with dapsone or several dapsone analogues which we previously synthesized (D2-D5) and determined effects on proliferation, anchorage-independent growth and migration. While dapsone and its synthetic analogues D2-D5 displayed only modest anti-proliferative activity, important neoplastic features such as anchorage-independent growth, clonogenic survival and directed migration were significantly inhibited by dapsone treatment. Moreover, dapsone analogues D3, D4 and D5 yielded even enhanced anti-glioma activity against different pro-neoplastic features. Overall these data suggest that dapsone provides activity against glioma which can be further enhanced by molecular modifications. These compounds could potentially serve as a therapeutic adjunct to the treatment of gliomas in a repurposing approach.
Asunto(s)
Antibacterianos/uso terapéutico , Dapsona/química , Dapsona/farmacología , Glioma/tratamiento farmacológico , Humanos , Interleucina-8/metabolismo , Leucotrieno B4/antagonistas & inhibidores , Receptores de Formil Péptido/efectos de los fármacosRESUMEN
The association between health-related quality of life (HRQoL), psychosocial distress, and supportive care is in the focus of patient-centered neuro-oncology. We investigated the relationship between the aforementioned in glioma-patients to evaluate the association of these instruments and determine cut-off values for suitable HRQoL scales indicating a potential need for intervention. In an observational multi-center study, outpatients completed the Distress Thermometer (DT), EORTC Quality of Life Questionnaire (EORTC-QLQ-C30/BN20, HRQoL), and Supportive-Care-Needs-Survey-SF34-G (SCNS). Based on nine EORTC-function and selected -symptom scales items of the questionnaires were matched. Convergent validity of related single items and scores across the instruments was estimated. EORTC cut-off values were calculated. Data of 167 patients were analyzed. The strongest correlation of EORTC-QLQ-C30 and DT was found for cognitive function (cogf), global health status (GHS), emotional (emof), role function (rolef), future uncertainty (FU), fatigue, and between EORTC-QLQ-C30 and SCNS for FU, emof, rolef (r = |0.4-0.7|; p < 0.01). EORTC cut-off values of <54.2 (GHS/QoL) and <62.5 (emof) predicted a DT ≥ 6 (AUC 0.79, 0.85, p < 0.01). EORTC cut-off values of <70.8 (emof) and <52.8 (FU) predicted the need for supportive care (AUC 0.78, 0.85; p < 0.01). Worse EORTC-C30 scores correlate with higher DT and SCNS scores. With this exploratory assessment, cut-off values for EORTC-C30 subscores to predict distress and pathological SCNS-scores could be determined, which could influence patients' referral to further treatment. However, further prospective clinical trials are needed to confirm the clinical relevance of these cut-off values.
Asunto(s)
Neoplasias Encefálicas/complicaciones , Glioma/complicaciones , Necesidades y Demandas de Servicios de Salud , Calidad de Vida/psicología , Estrés Psicológico/etiología , Estrés Psicológico/enfermería , Adulto , Anciano , Neoplasias Encefálicas/psicología , Femenino , Glioma/psicología , Estado de Salud , Humanos , Masculino , Persona de Mediana Edad , Pacientes Ambulatorios , Psicometría , Apoyo Social , Estadística como Asunto , Encuestas y CuestionariosRESUMEN
To mount an adaptive immune response, MHC I molecules present antigenic peptides to CTLs. Transcriptional reduction of MHC I molecules is a strategy of immune evasion, which impairs the detection of infected or tumorous cells by CTLs. Natural killer (NK) cells, on the other hand, eliminate target cells specifically in the absence of MHC I. Consequently, infected or tumorous cells partly retain their MHC I at the cell surface to avoid NK recognition. However, it remains unclear which protease degrades MHC I molecules and how these cells maintain a limited set of MHC I at the cell surface. Here, we demonstrate that cathepsin G (CatG), a serine protease, found in the endocytic compartment of APCs and, to a lesser extent, CatD and CatS proteolytically degrade MHC I molecules. Inhibition of CatG boosted MHC I expression at the cell surface of primary human immune cells. In contrast, human glioblastoma cells do not harbor active CatG and might have lost the ability to proteolytically degrade MHC I during tumorigenesis to avoid NK-mediated killing. Overexpression of CatG in glioblastoma cells resulted in a rapid and efficient MHC I degradation. In conclusion, CatG is an essential protease for regulating MHC I molecules and thus modulation of CatG activity might present a new avenue for therapeutic intervention.
Asunto(s)
Neoplasias Encefálicas/inmunología , Catepsina G/fisiología , Glioblastoma/inmunología , Antígenos de Histocompatibilidad Clase I/metabolismo , Línea Celular Tumoral , Antígenos de Histocompatibilidad Clase I/análisis , Humanos , ProteolisisRESUMEN
The poor prognosis of patients with glioblastoma fuels the search for more effective therapeutic compounds. We previously hypothesised that the neuroleptic olanzapine may enhance antineoplastic effects of temozolomide the standard chemotherapeutic agent used in this disease. This study tested this hypothesis. The anti-proliferative effect of olanzapine was examined by MTT assays and cell count analysis. Soft-agar assays were performed to examine colony-forming ability. In addition, the inhibitory effect of olanzapine on the migratory capacity of U87MG and A172 cells was analyzed by Transwell(®) assays. Moreover, staining for annexin V/propidium iodide or carboxyfluorescein succinimidyl ester was performed prior to flow cytometric analysis in order to better understand the subjacent cellular mechanism. Our initial hypothesis that olanzapine may enhance temozolomide's anti-tumor activity could be confirmed in U87MG and A172 glioblastoma cell lines. Moreover, treatment with olanzapine alone resulted in a marked anti-proliferative effect on U87MG, A172 and two glioma stem-like cells with IC50 values ranging from 25 to 79.9 µM. In U87MG cells, anchorage-independent growth was dose-dependently inhibited. In A172 cells, migration was also shown to be inhibited in a dose-dependent manner. In addition, olanzapine was shown to exert a cell line-dependent pleomorphism with respect to the induction of apoptosis, necrosis and/or cytostasis. Our data show that the neuroleptic olanzapine enhances the anti-tumor activity of temozolomide against glioblastoma cell lines. Moreover, this is the first study to show that olanzapine provides on its own anti-cancer activity in glioblastoma and thus may have potential for repurposing.