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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 Estimulação Elétrica , Glioblastoma , Humanos , Glioblastoma/tratamento farmacológico , Reposicionamento de Medicamentos , Reprogramação Metabólica , Temozolomida/farmacologia , Antineoplásicos/uso terapêutico , Neoplasias Encefálicas/tratamento farmacológico , Terapia CombinadaRESUMO
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 Hipofisárias , Adenoma/diagnóstico por imagem , Adenoma/patologia , Adenoma/cirurgia , Endoscopia/métodos , Humanos , Imageamento por Ressonância Magnética/métodos , Neoplasias Hipofisárias/diagnóstico por imagem , Neoplasias Hipofisárias/patologia , Neoplasias Hipofisárias/cirurgia , Estudos Retrospectivos , Resultado do TratamentoRESUMO
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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Realidade Aumentada , Drenagem , Humanos , Procedimentos Neurocirúrgicos , VentriculostomiaRESUMO
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/farmacologia , Neoplasias Encefálicas/tratamento farmacológico , Desoxiglucose/farmacologia , Metabolismo Energético/efeitos dos fármacos , Glioblastoma/tratamento farmacológico , Imidazóis/farmacologia , Piridinas/farmacologia , Pirimidinas/farmacologia , Animais , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patologia , Linhagem Celular Tumoral , Embrião de Galinha/efeitos dos fármacos , Glioblastoma/metabolismo , Glioblastoma/patologia , Glicólise/efeitos dos fármacos , Humanos , Fosforilação OxidativaRESUMO
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/cirurgia , Monitorização Neurofisiológica Intraoperatória/tendências , Imageamento por Ressonância Magnética/tendências , Neuroendoscopia/tendências , Neoplasias Hipofisárias/cirurgia , Osso Esfenoide/cirurgia , Adenoma/diagnóstico por imagem , Adulto , Idoso , Feminino , Seguimentos , Humanos , Monitorização Neurofisiológica Intraoperatória/métodos , Imageamento por Ressonância Magnética/métodos , Masculino , Pessoa de Meia-Idade , Neuroendoscopia/métodos , Neoplasias Hipofisárias/diagnóstico por imagem , Estudos Retrospectivos , Osso Esfenoide/diagnóstico por imagem , Fatores de Tempo , Resultado do Tratamento , Carga Tumoral/fisiologiaRESUMO
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 imagem , Adenoma/cirurgia , Endoscopia , Imageamento por Ressonância Magnética , Neoplasias Hipofisárias/diagnóstico por imagem , Neoplasias Hipofisárias/cirurgia , Adenoma/patologia , Adulto , Idoso , Feminino , Humanos , Modelos Logísticos , Masculino , Microcirurgia , Pessoa de Meia-Idade , Invasividade Neoplásica , Neoplasias Hipofisárias/patologia , Reoperação , Estudos Retrospectivos , Resultado do Tratamento , Carga Tumoral , Adulto JovemRESUMO
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.
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Benzodiazepinas/farmacologia , Adesão Celular/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Dacarbazina/análogos & derivados , Sinergismo Farmacológico , Glioblastoma/patologia , Antineoplásicos Alquilantes/farmacologia , Antipsicóticos/farmacologia , Apoptose/efeitos dos fármacos , Western Blotting , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patologia , Dacarbazina/farmacologia , Glioblastoma/tratamento farmacológico , Glioblastoma/metabolismo , Humanos , Olanzapina , Fosfoproteínas/metabolismo , Análise Serial de Proteínas , Temozolomida , Células Tumorais CultivadasRESUMO
INTRODUCTION: In low-grade glioma (LGG) surgery, intraoperative differentiation between tumor and most likely tumor-free brain tissue can be challenging. Intraoperative ultrasound can facilitate tumor resection. The aim of this study is to evaluate the accuracy of linear array ultrasound in comparison to conventional intraoperative ultrasound (cioUS) and intraoperative high-field MRI (iMRI). METHODS: We prospectively enrolled 13 patients harboring a LGG of WHO Grade II. After assumed near total removal, a resection control was performed using navigated cioUS, navigated lioUS, and iMRI. We harvested 30 navigated biopsies from the resection cavity and compared the histopathological findings with the respective imaging results. Spearman's rho was calculated to test for significant correlations. Sensitivity and specificity as well as receiver operating characteristics (ROC) were calculated to assess test performance of each imaging modality. RESULTS: Imaging results of lioUS correlated significantly (p < 0.009) with iMRI. Both iMRI and lioUS correlated significantly with final histopathological diagnosis (p < 0.006, p < 0.014). cioUS did not correlate with other imaging findings or with final diagnosis. The highest sensitivity for residual tumor detection was found in iMRI (83 %), followed by lioUS (79 %). The sensitivity of cioUS was only 21 %. Specificity was highest in cioUS (100 %), whereas iMRI and lioUS both achieved 67 %. ROC curves showed fair results for iMRI and lioUS and a poor result for cioUS. CONCLUSIONS: Intraoperative resection control in LGGs using lioUS reaches a degree of accuracy close to iMRI. Test results of lioUS are superior to cioUS. cioUS often fails to discriminate solid tumors from "normal" brain tissue during resection control. Only in lesions <10 cc cioUS does show good accuracy.
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Neoplasias Encefálicas/cirurgia , Glioma/cirurgia , Imageamento por Ressonância Magnética/normas , Neuronavegação/normas , Ultrassonografia/normas , Adolescente , Adulto , Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/patologia , Feminino , Glioma/diagnóstico por imagem , Glioma/patologia , Humanos , Imageamento por Ressonância Magnética/métodos , Masculino , Pessoa de Meia-Idade , Neuronavegação/métodos , Sensibilidade e Especificidade , Ultrassonografia/métodos , Adulto JovemRESUMO
OBJECT: High-grade gliomas (HGGs) and metastasis (MET) are the most common intracranial lesions in neurosurgical routine. Both of them show an invasive growth pattern extending into neural tissue beyond the margins of contrast enhancement on MRI. These "undetected" areas might be the origin of early tumor recurrence. The aim of the present study was to evaluate whether 5-aminolevulinic acid (5-ALA) fluorescence provides an additional benefit in detection of invasive tumor compared with intraoperative MRI (iMRI). METHODS: The authors prospectively enrolled 45 patients harboring contrast-enhancing lesions, in whom gross-total resection was intended. All patients had surgery in which iMRI and 5-ALA-guided resection were used following a specific protocol. First, a typical white light tumor resection was performed. Then, spatial location of residual fluorescence was marked. After that, an iMRI was performed and residual uptake of contrast was marked. Navigated biopsy samples were taken from all marked areas and from additional sites according to the surgeon's judgment. Cross tables and receiver operating characteristic curves were calculated, assessing performance of the imaging methods for tumor detection alone and for combined detection of infiltration zone and solid tumor (pathological tissue). Also, correlations of histopathological findings with imaging results were tested using Spearman rho. RESULTS: Thirty-four patients with HGGs and 11 with METs were enrolled. Three patients harboring a MET showed no 5-ALA enhancement and were excluded; 127 histopathological samples were harvested in the remaining patients. In HGG, sensitivity for tumor detection was significantly higher (p < 0.001) in 5-ALA (0.85) than in iMRI (0.41). Specificity was significantly lower (p < 0.001) in 5-ALA (0.43) than in iMRI (0.70). For detection of pathological tissue, 5-ALA significantly exceeded iMRI in specificity (0.80 vs 0.60) and sensitivity (0.91 vs 0.66) (p < 0.001). Imaging results of iMRI and 5-ALA did not correlate significantly; only 5-ALA showed a significant correlation with final histopathological diagnosis of the specimen and with typical histopathological features of HGGs. In METs, sensitivity and specificity for tumor detection were equal in 5-ALA and iMRI. Both techniques showed high values for sensitivity (0.75) and specificity (0.80). The odds ratio for detection of tumor tissue was 12 for both techniques. Concerning pathological tissue, no statistically significant difference was found either. Imaging results of iMRI and 5-ALA correlated significantly (p < 0.022), as with final histopathological diagnosis in METs. CONCLUSIONS: In METs, due to the rate of nonenhancing lesions, the authors found no additional benefit of 5-ALA compared with iMRI. In HGG, imaging results of 5-ALA and iMRI are significantly different at the border zone; 5-ALA has a higher sensitivity and a lower specificity for tumor detection than Gd-DTPA-enhanced iMRI. For detection of infiltrating tumor at the border of the resection cavity, 5-ALA is superior to Gd-DTPA-enhanced iMRI concerning both sensitivity and specificity. Thus, use of 5-ALA in addition to iMRI might be beneficial to maximize extent of resection. Clinical synergistic effects will be evaluated in a prospective randomized trial.
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Ácido Aminolevulínico , Neoplasias Encefálicas/diagnóstico , Gadolínio DTPA , Glioblastoma/diagnóstico , Imageamento por Ressonância Magnética/métodos , Neuronavegação/métodos , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/cirurgia , Meios de Contraste , Feminino , Corantes Fluorescentes , Glioblastoma/patologia , Glioblastoma/cirurgia , Humanos , Masculino , Pessoa de Meia-Idade , Monitorização Intraoperatória/métodos , Estudos ProspectivosRESUMO
BACKGROUND: A new-onset adrenocortical insufficiency (NAI) is the most critical postoperative endocrinological complication after transsphenoidal surgery for macroadenomas. Because of increased mortality risk, arginine vasopressin deficiency (AVP-D) is also a relevant postoperative complication. This study aimed to identify easy-to-acquire magnet resonance imaging (MRI) aspects of the pituitary stalk to predict these insufficiencies after transsphenoidal surgery. METHODS: Pituitary stalk morphology was reviewed intraoperatively and three months postoperatively in the MRIs of 48 transsphenoidal surgeries for macroadenomas. NAI was validated in endocrinological follow-up controls 10-14 months post-surgery. RESULTS: Intraoperative pituitary stalk diameters were 0.5 mm larger in patients who developed NAI and AVP-D. The odds ratio was 29 for NAI and 6 for AVP-D in binary regression analysis. A value of 2.9 mm was identified as the optimal cut-off for the minimal pituitary stalk diameter regarding NAI, with a high specificity of 89%. There was no difference in pituitary stalk diameter regarding these insufficiencies three months post-surgery. CONCLUSIONS: We identified an increased pituitary stalk diameter in intraoperative MRIs as a predictive factor of NAI and AVP-D after transsphenoidal surgery. These findings might improve the early detection of NAI and, thus, optimal management. However, validating these retrospective findings in prospective studies is obligatory.
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BACKGROUND: Ventriculostomy (VST) is a frequent neurosurgical procedure. Freehand catheter placement represents the standard current practice. However, multiple attempts are often required. We present augmented reality (AR) headset guided VST with in-house developed head models. We conducted a proof of concept study in which we tested AR-guided as well as freehand VST. Repeated AR punctures were conducted to investigate if a learning curve can be derived. METHODS: Five custom-made 3D-printed head models, each holding an anatomically different ventricular system, were filled with agarose gel. Eleven surgeons placed two AR-guided as well as two freehand ventricular drains per head. A subgroup of four surgeons did a total of three series of AR-guided punctures each to test for a learning curve. A Microsoft HoloLens served as the hardware platform. The marker-based tracking did not require rigid head fixation. Catheter tip position was evaluated in computed tomography scans. RESULTS: Marker-tracking, image segmentation, and holographic display worked satisfactorily. In freehand VST, a success rate of 72.7% was achieved, which was higher than under AR guidance (68.2%, difference not statistically significant). Repeated AR-guided punctures increased the success rate from 65 to 95%. We assume a steep learning curve as repeated AR-guided punctures led to an increase in successful attempts. Overall user experience showed positive feedback. CONCLUSIONS: We achieved promising results that encourage the continued development and technical improvement. However, several more developmental steps have to be taken before an application in humans can be considered. In the future, AR headset-based holograms have the potential to serve as a compact navigational help inside and outside the operating room.
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The surgical treatment of recurrent adenomas can be challenging. Intraoperative magnetic resonance imaging (iMRI) can improve the orientation and increase the safe extent of resection. We conducted a quantitative and qualitative retrospective analysis of recurrent adenomas treated by endoscopic or microscopic iMRI-assisted transsphenoidal surgery. A total number of 59 resections were selected. Detailed volumetric measurements, tumor characteristics, and MRI features of intraoperative remnants were evaluated. Intraoperative MRI increased the gross total resection (GTR) rate from 33.9% to 49.2%. Common locations of tumor remnants after iMRI were the clivus, the wall of the cavernous sinus or the perforation of the diaphragm. Increasing tumor volume and the microscopic technique were significantly associated with further resection after iMRI in the univariate analysis (p = 0.004, OR 1.6; p = 0.009, OR 4.4). Only the increasing tumor volume was an independent predictor for further resection (p = 0.007, OR 1.5). A significantly higher proportion of GTRs was achieved with the endoscopic technique (p = 0.001). Patients with a large recurrent pituitary adenoma who underwent microscopic transsphenoidal resection were the most likely to benefit from iMRI regarding the extent of resection. Occult invasions of the cavernous sinus and/or the clivus were the most common findings leading to further resection of tumor remnants after iMRI.
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Adenoma , Neoplasias Hipofisárias , Adenoma/diagnóstico por imagem , Adenoma/cirurgia , Endoscopia/métodos , Humanos , Imageamento por Ressonância Magnética/métodos , Neoplasias Hipofisárias/diagnóstico por imagem , Neoplasias Hipofisárias/cirurgia , Estudos RetrospectivosRESUMO
PURPOSE: Anti-apoptotic and pro-migratory phenotypes are hallmarks of neoplastic diseases, including primary brain malignancies. In this work, we examined whether reprogramming of the apoptotic and migratory machineries through a multi-targeting approach would induce enhanced cell death and enhanced inhibition of the migratory capacity of glioblastoma cells. METHODS: Preclinical testing and molecular analyses of combined inhibition of Bcl-2/Bcl-xL and RAC1 were performed in established, primary cultured and stem-like glioblastoma cell systems. RESULTS: We found that the combined inhibition of Bcl-2/Bcl-xL and RAC1 resulted in synergistic pro-apoptotic and anti-migratory effects in a broad range of different glioblastoma cells. At the molecular level, we found that RAC1 inhibition led to a decreased expression of the deubiquitinase Usp9X, followed by a decreased stability of Mcl-1. We also found that the combined inhibition led to a significantly decreased migratory activity and that tumor formation of glioblastoma cells on chorion allantoic membranes of chicken embryos was markedly impaired following the combined inhibition. CONCLUSIONS: Our data indicate that concomitant inhibition of RAC1 and Bcl-2/Bcl-xL induces pro-apoptotic and anti-migratory glioblastoma phenotypes as well as synergistic anti-neoplastic activities. The clinical efficacy of this inhibitory therapeutic strategy warrants further evaluation.
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Compostos de Anilina/farmacologia , Proteínas Reguladoras de Apoptose/antagonistas & inibidores , Apoptose/efeitos dos fármacos , Proteína de Sequência 1 de Leucemia de Células Mieloides/metabolismo , Sulfonamidas/farmacologia , Ubiquitina Tiolesterase/metabolismo , Proteínas rac1 de Ligação ao GTP/antagonistas & inibidores , Antineoplásicos/farmacologia , Apoptose/genética , Proteínas Reguladoras de Apoptose/genética , Proteínas Reguladoras de Apoptose/metabolismo , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patologia , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Movimento Celular/genética , Regulação para Baixo/efeitos dos fármacos , Glioblastoma/genética , Glioblastoma/metabolismo , Glioblastoma/patologia , Humanos , Proteína de Sequência 1 de Leucemia de Células Mieloides/genética , Proteínas Proto-Oncogênicas c-bcl-2/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Interferência de RNA , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Ubiquitina Tiolesterase/genética , Proteína bcl-X/antagonistas & inibidores , Proteína bcl-X/genética , Proteína bcl-X/metabolismo , Proteínas rac1 de Ligação ao GTP/genética , Proteínas rac1 de Ligação ao GTP/metabolismoRESUMO
BACKGROUND AND PURPOSE: Drug repurposing represents a promising approach to safely accelerate the clinical application of therapeutics with anti-cancer activity. In this study, we examined whether inhibition of the anti-apoptotic Bcl-2 family proteins Bcl-2 and Bcl-xL enhances the biological effects of the repurposed CUSP9 regimen in an in vitro setting of glioblastoma. EXPERIMENTAL APPROACH: We applied 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide assays to assess cellular proliferation. Annexin V/propidium iodide and tetramethylrhodamine, ethyl ester staining were used to examine apoptosis. Western blotting, RT-PCR, and specific knockdown experiments using siRNA were employed to examine molecular mechanisms of action. KEY RESULTS: Bcl-2/Bcl-xL inhibition exerted synergistic anti-proliferative effects across established, primary cultured, and stem-like glioblastoma cells when combined with CUSP9 which had been reduced to only one tenth of its proposed original concentration (CUSP9-LD). The combination treatment also led to enhanced apoptosis with loss of mitochondrial membrane potential and activation of caspases. On the molecular level, CUSP9-LD counteracted ABT263-mediated up-regulation of Mcl-1. Silencing of Mcl-1 enhanced ABT263-mediated apoptosis which indicates that down-regulation of Mcl-1 is crucial for the induction of cell death by the combination treatment. CONCLUSION AND IMPLICATIONS: These data suggest that Bcl-2/Bcl-xL inhibition enhances the susceptibility of glioblastoma cells towards CUSP9, allowing dramatic dose reduction and potentially decreased toxicity when applied clinically. A clinical trial involving the original CUSP doses (CUSP9v3) is currently ongoing in our institution (NCT02770378). The Bcl-2/Bcl-xL inhibitor ABT263 is in clinical trials and might represent a valuable adjunct to the original CUSP.
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Compostos de Anilina/farmacologia , Antineoplásicos/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Neoplasias Encefálicas/tratamento farmacológico , Glioblastoma/tratamento farmacológico , Proteínas Proto-Oncogênicas c-bcl-2/antagonistas & inibidores , Sulfonamidas/farmacologia , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Reposicionamento de Medicamentos , Sinergismo Farmacológico , Humanos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Proteína de Sequência 1 de Leucemia de Células Mieloides/genética , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , RNA Interferente PequenoRESUMO
OBJECTIVES: The aim of this paper was to demonstrate the long-term results following microsurgery in a single surgeon's continuous series of patients with Cushing disease (CD), to assess the influence of changes in surgical procedures, and to compare the results with those of other treatment modalities. In particular, preoperative diagnosis, tumor size, results of histological examination, and complications were considered. METHODS: Between 1971 and 2004, 426 patients suffering from newly diagnosed CD underwent primary surgery. Pre-operative measures included clinical examination, endocrinological workup (testing of the hypothalamic-pituitary-adrenal axis, and 2- and 8-mg dexamethasone overnight suppression tests), sellar imaging (polytomography, computed tomography, and magnetic resonance [MR] imaging), and in patients with negative results on imaging studies, inferior petrosal sinus sampling. Follow-up examinations consisting of endocrinological workup, and imaging took place 1 week and 3 months after surgery and then at yearly intervals. RESULTS: During microsurgery as first treatment, the adenoma finding rate was 86.6%. After selective adenomectomy, the remission rate was 75.9%, and this rate showed no improvement over the years. The best results were achieved in microadenomas confirmed on MR imaging or histopathological investigation. The recurrence rate (15%) and the complication rate (5.9%) declined over the years. If no adenoma was found, exploration of the sella turcica was performed in 45.6%, hypophysectomy in 3.5%, and hemihypophysectomy in 50.9% of these patients, leading to an early remission in 37.9%. In case of persistence or recurrence, further treatment (repeated operation, adrenalectomy, radio-therapy, or medical treatment) was used to control the disease. CONCLUSIONS: Microsurgery remains the treatment of first choice in CD, even though no improvement in remission rates was observed over the years, because complication or remission rates for other treatment options are comparable or worse.
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Adenoma Hipofisário Secretor de ACT/cirurgia , Adenoma/cirurgia , Microcirurgia , Hipersecreção Hipofisária de ACTH/cirurgia , Adenoma Hipofisário Secretor de ACT/complicações , Adenoma Hipofisário Secretor de ACT/diagnóstico , Adenoma/complicações , Adenoma/diagnóstico , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Competência Clínica , Estudos de Coortes , Feminino , Humanos , Hipofisectomia , Masculino , Pessoa de Meia-Idade , Hipersecreção Hipofisária de ACTH/diagnóstico , Hipersecreção Hipofisária de ACTH/etiologia , Estudos Retrospectivos , Fatores de Tempo , Resultado do TratamentoRESUMO
OBJECTIVES: At present, there is no standard therapy approved for recurrent glioblastoma (rGB). In particular, the counselling of patients with an unmethylated O6-methylguanine-DNA methyltransferase (MGMT) promoter GB remains a challenge. Our aim was to compare the overall survival (OS) and progression free survival (PFS) in patients treated surgically and non-surgically at the time of GB recurrence. This was evaluated with particular reference to the impact of recurrent surgery for patients with unmethylated MGMT promoter rGB. PATIENTS AND METHODS: The clinical and radiological data from 127 consecutive cases of rGB was retrospectively identified and evaluated. The PFS and OS from cohorts of surgically and non-surgically treated patients at time of GB recurrence were compared using Kaplan Meier estimations and Log-Rank tests. Multivariate Cox regression analysis included the major influencing variables (surgical resection, MGMT promoter methylation status, Karnofsky performance scale (KPS), age, eloquent tumor location) to analyze the survival benefit. Subgroup analysis of cases depending on the MGMT promoter methylation status was performed. RESULTS: Multiple Cox regression analysis revealed inferior OS (pâ¯=â¯0.029, ORâ¯=â¯1.731, CI 95% 1.059-2.829) of patients treated non-surgically (14 vs. 31 months). MGMT promoter methylation and age were related to longer OS (pâ¯<â¯0.001, OR 2.683, CI 95% 1.631-4.414 and pâ¯=â¯0.009, ORâ¯=â¯1.029, CI95% 1.007-0.052 respectively). Gross total resection (GTR) in comparison to subtotal resection (STR) lead to a median OS of 39 months vs. 22 months and a PFS of seven vs. four months respectively. In the subgroup of cases with unmethylated MGMT promoter rGB, those who underwent GTR survived significantly longer (OS: 31 months) than patients who underwent STR (OS: 15 months, pâ¯=â¯0.024). PFS was six vs. four months after GTR and STR respectively. CONCLUSION: Surgical management for recurrent glioblastoma appears to be a safe procedure which results in longer OS in comparison to non-surgical management. GTR may be of particular benefit to patients with unmethylated MGMT promoter rGB.
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Neoplasias Encefálicas/cirurgia , Metilação de DNA/genética , Metilases de Modificação do DNA/metabolismo , Enzimas Reparadoras do DNA/metabolismo , Tomada de Decisões , Glioblastoma/cirurgia , Recidiva Local de Neoplasia/cirurgia , Proteínas Supressoras de Tumor/metabolismo , Adulto , Idoso , Antineoplásicos Alquilantes/uso terapêutico , Biomarcadores Tumorais/genética , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patologia , Metilases de Modificação do DNA/genética , Enzimas Reparadoras do DNA/genética , Dacarbazina/uso terapêutico , Intervalo Livre de Doença , Feminino , Glioblastoma/metabolismo , Glioblastoma/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/metabolismo , Recidiva Local de Neoplasia/patologia , Regiões Promotoras Genéticas , Proteínas Supressoras de Tumor/genéticaRESUMO
OBJECTIVEThe gold standard for evaluation of ventriculoperitoneal (VP) shunt position, dislocation, or disconnection is conventional radiography. Yet, assessment with this modality can be challenging because of low image quality and can result in repetitive radiation exposure with high fluctuation in the radiation dose. Recently, CT-based radiation doses have been significantly reduced by using low-dose protocols. Thus, whole-body low-dose CT (LDCT) has become applicable for routine use in VP shunt evaluation. The authors here compared image quality and approximate radiation dose between radiography and LDCT in patients with implanted VP shunt systems.METHODSVentriculoperitoneal shunt systems have been investigated with LDCT scanning at the authors' department since 2015. A consecutive series of 57 patients (70 investigations) treated between 2015 and 2016 was retrospectively assessed. A historical patient cohort that had been evaluated with radiography was compared with the LDCT patients in terms of radiation dose and image quality. Three independent observers evaluated projection of the valve pressure level and correct intraperitoneal position, as well as complete shunt projection, using a Likert-type scale of 1-5, where 1 indicated "not assessable" and 5 meant "assessable with high accuracy." Descriptive statistics and the Mann-Whitney U-test were used for analysis.RESULTSTwenty-seven radiographs (38.6%) and 43 LDCT scans (61.4%) were analyzed. The median dose-length product (DLP) of the LDCT scans was 100 mGy·cm (range 59.9-183 mGy·cm). The median total dose-area product (DAP) of the radiographic images was 3177 mGy·cm2 (range 641-13,833 mGy·cm2). The estimated effective dose (EED) was significantly lower with the LDCT scan (p < 0.001). The median EED was 4.93 and 1.90 mSv for radiographs and LDCT, respectively. Significantly better identification of the abdominal position of the distal shunt catheter was achieved with LDCT (p < 0.001). Simultaneously, significantly improved visualization of the entire shunt system was realized with this technique (p < 0.001). On the contrary, identification of the valve settings was significantly worse with LDCT (p < 0.001).CONCLUSIONSWhole-body LDCT scanning allows good visualization of the distal catheter after VP shunt placement. Despite the fact that only a rough estimation of effective doses is possible in a direct comparison of LDCT and radiography, the data showed that shunt assessment via LDCT does not lead to greater radiation exposure. Thus, especially in difficult anatomical conditions, as in patients who have undergone multiple intraabdominal surgeries, have a high BMI, or are immobile, the use of LDCT shunt evaluation has high clinical value. Further data are needed to determine the value of LDCT for the evaluation of complications or radiation dose in pediatric patients.
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Tomografia Computadorizada por Raios X/métodos , Derivação Ventriculoperitoneal , Imagem Corporal Total/métodos , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Doses de Radiação , Estudos Retrospectivos , Adulto JovemRESUMO
BACKGROUND: The routine use of intraoperative magnetic resonance imaging (iMRI) helps to achieve gross total resection in transsphenoidal pituitary surgery. We compared the added value of iMRI for extent of resection in endoscopic versus microsurgical transsphenoidal adenomectomy. METHODS: A total of 96 patients with pituitary adenoma were included. Twenty-eight consecutive patients underwent endoscopic transsphenoidal tumor resection. For comparison, we used a historic cohort of 68 consecutive patients treated microsurgically. We evaluated the additional resection after conducting iMRI using intraoperative and late postoperative volumetric tumor analysis 3 months after surgery. Demographic data, clinical symptoms, and complications as well as pituitary function were evaluated. RESULTS: We found significantly fewer additional resections after conducting iMRI in the endoscopic group (P = 0.042). The difference was even more profound in Knosp grade 0-2 adenomas (P = 0.029). There was no significant difference in Knosp grade 3-4 adenomas (P = 0.520). The endoscopic approach was associated with smaller intraoperative tumor volume (P = 0.023). No significant difference was found between both techniques in postoperative tumor volume (P = 0.228). Satisfactory results of pituitary function were significantly more often associated with an endoscopic approach in the multiple regression analysis (P = 0.007; odds ratio, 17.614; confidence interval 95%, 2.164-143.396). CONCLUSIONS: With the endoscopic approach, significantly more tumor volume reduction was achieved before conducting iMRI, decreasing the need for further resection. This finding was even more pronounced in adenomas graded Knosp 0-2. In the case of extensive and invasive adenomas with infiltration of cavernous sinus and suprasellar or parasellar extension, additional tumor resection and increase in the extent of resection was achieved with iMRI in both groups. The endoscopic approach seems to result in better endocrine outcomes, especially in Knosp grade 0-2 pituitary adenomas.
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Adenoma/diagnóstico por imagem , Adenoma/cirurgia , Endoscopia/métodos , Microcirurgia/métodos , Neoplasias Hipofisárias/diagnóstico por imagem , Neoplasias Hipofisárias/cirurgia , Osso Esfenoide/cirurgia , Adolescente , Adulto , Idoso , Criança , Estudos de Coortes , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Nariz/cirurgia , Osso Esfenoide/diagnóstico por imagem , Resultado do Tratamento , Adulto JovemRESUMO
BACKGROUND: The presence of residual tumor is crucial in decision-making for low-grade gliomas (LGGs), because patients older than 40 years of age with residual tumor are considered for adjuvant treatment. There are hints that early postoperative fluid-attenuated inversion recovery (FLAIR) and T2 (within 48 hours) may overestimate residual tumor volume in LGG. Intraoperative magnetic resonance imaging (MRI) without subsequent resection or ultra-early postoperative MRI may assess the amount of residual tumor more adequately. To evaluate the utility of postoperative imaging in LGG, we volumetrically analyzed intraoperative, early, and late (3-4 months after surgery) postoperative MRIs of LGGs. PATIENTS AND METHODS: A total of 33 patients with LGG were assessed retrospectively. Residual tumor was defined as signal-enhanced tissue in T2 and FLAIR. Volumetric assessment was performed with intraoperative, early, and late postoperative T2/FLAIR via Brainlab-iPlan 3.0. Wilcoxon and χ(2) tests were used for statistical analysis. RESULTS: A significant difference of FLAIR/T2 abnormalities was found in intraoperative and early postoperative MRIs (FLAIR mean volume = 5.433 cm(3), T2 mean volume = 3.374 cm(3) vs. FLAIR mean volume = 14.090 cm(3), P = 0.002, T2 mean volume = 7.597 cm(3), P = 0.006). There was no significant difference between intraoperative and late postoperative FLAIR/T2 abnormalities (late postoperative FLAIR/T2 mean volume = 5.560 cm(3) and 2.370 cm(3), P = 0.520, P = 0.398), whereas a significant difference was detected between early and late postoperative images (FLAIR, P < 0.0001; T2, P < 0.00001). CONCLUSION: Intraoperative MRI without further resection or ultra-early postoperative MRI seems to reflect the actual volume of residual tumor in LGG more precisely compared with early postoperative MRI and therefore seems to be more useful regarding decisions for adjuvant therapy.
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Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/cirurgia , Glioma/diagnóstico por imagem , Glioma/cirurgia , Imageamento por Ressonância Magnética/métodos , Cirurgia Assistida por Computador/métodos , Adolescente , Adulto , Neoplasias Encefálicas/patologia , Criança , Feminino , Glioma/patologia , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Neoplasia Residual , Variações Dependentes do Observador , Prognóstico , Reprodutibilidade dos Testes , Estudos Retrospectivos , Sensibilidade e Especificidade , Resultado do Tratamento , Carga Tumoral , Adulto JovemRESUMO
BACKGROUND: Glioblastoma multiforme (GBM), a common primary malignant brain tumor, rarely disseminates beyond the central nervous system and has a very bad prognosis. The current study aimed at the analysis of immunological control in individual patients with GBM. METHODS: Immune phenotypes and plasma biomarkers of GBM patients were determined at the time of diagnosis using flow cytometry and ELISA, respectively. RESULTS: Using descriptive statistics, we found that immune anomalies were distinct in individual patients. Defined marker profiles proved highly relevant for survival. A remarkable relation between activated NK cells and improved survival in GBM patients was in contrast to increased CD39 and IL-10 in patients with a detrimental course and very short survival. Recursive partitioning analysis (RPA) and Cox proportional hazards models substantiated the relevance of absolute numbers of CD8 cells and low numbers of CD39 cells for better survival. CONCLUSIONS: Defined alterations of the immune system may guide the course of disease in patients with GBM and may be prognostically valuable for longitudinal studies or can be applied for immune intervention.