Prognostic factors to predict postoperative survival in patients with recurrent glioblastoma.

Background: There are no generally accepted criteria for selecting patients with recurrent glioblastoma for surgery. This retrospective study in a Danish population-based cohort aimed to identify prognostic factors affecting postoperative survival after repeated surgery for recurrent glioblastoma and to test if the preoperative New Scale for Recurrent Glioblastoma Surgery (NSGS) developed by Park CK et al could assist in the selection of patients for repeat glioblastoma surgery. Methods: Clinical data from 66 patients with recurrent glioblastoma and repeated surgery were analyzed. Kaplan-Meier plots were produced to illustrate survival in each of the three NSGS prognostic groups, and Cox proportional hazard regression was used to identify prognostic variables. Multivariable analysis was used to identify differences in survival in the three prognostic groups. Results: Six variables significantly affected postoperative survival: preoperative Karnofsky Performance Status (KPS) < 70 (p = 0.002), decreased KPS after second surgery (p = 0.012), ependymal involvement (p = 0.002), tumor volume â‰§ 50 cm3 (p = 0.021), age (p = 0.033) and Ki-67 (p = 0.005). Retrospective application of the criteria previously published by Park CK et al showed that median postoperative survival for the three prognostic groups was 390 days (0 points), 279 days (1 point), and 80 days (2 points), respectively. Conclusion: Several prognostic variables to predict postoperative survival in patients with recurrent glioblastoma were identified and should be considered when selecting patient for repeat surgery. The NSGS scoring system was useful as there were significant differences in postoperative survival between its three prognostic groups.

Fluorescein-guided resection of cerebral metastases is associated with greater tumor resection.

BACKGROUND: Sodium fluorescein (fluorescein) crosses a disrupted blood-brain barrier similarly to gadolinium contrast in contrast-enhancing cerebral tumors. When exposed to light with 560 nm wavelength during surgery, fluorescein emits a yellow-green fluorescent light that can be visualized through an operating microscope equipped with an appropriate emission filter. The distribution of the fluorescence correlates with the contrast on a gadolinium contrast-enhanced MRI. OBJECTIVE: The objective of this single-center retrospective study was to investigate if the use of fluorescein would increase the extent of resection and to examine if fluorescein guided resection influences postoperative neurological status. METHODS: During the study period from August 2014 to August 2018, 117 patients were operated for cerebral metastases. Of these, 56 operations were guided by fluorescein and 61 by traditional white light. All patients had an early postoperative MRI within 72 h after surgery. RESULTS: The use of fluorescein increased the extent of resection in patients with cerebral metastases. The use of fluorescein was not associated with increased postoperative sequelae or neurological damage regardless of underlying primary cancer. CONCLUSION: Fluorescein is a helpful supplement in the neurosurgical treatment of cerebral metastases.

Comparison of 5-aminolevulinic acid and sodium fluorescein for intraoperative tumor visualization in patients with high-grade gliomas: a single-center retrospective study.

OBJECTIVE: Maximal safe resection is an important surgical goal in the treatment for high-grade gliomas. Fluorescent dyes help the surgeon to distinguish malignant tissue from healthy. The aims of this study were 1) to compare the 2 fluorescent dyes 5-aminolevulinic acid (5-ALA) and sodium fluorescein (fluorescein) regarding extent of resection, progression-free survival, and overall survival; and 2) to assess the influence of other risk factors on clinical outcome and screen for potential disadvantages of the dyes. METHODS: A total of 209 patients with high-grade gliomas were included in this retrospective study. Resections were performed in the period from 2012 to 2017 using 5-ALA or fluorescein. Extent of resection was assessed as the difference in tumor volume between early postoperative and preoperative MRI studies. Tumor progression-free survival and overall survival were analyzed using an adjusted Cox proportional hazards model. RESULTS: One hundred fifty-eight patients were operated on with 5-ALA and 51 with fluorescein. The median duration of follow-up was 46.7 and 21.2 months, respectively. Covariables were evenly distributed. There was no statistically significant difference in volumetrically assessed median extent of resection (96.9% for 5-ALA vs 97.4% for fluorescein, p = 0.46) or the percentage of patients with residual tumor volume less than 0.175 cm3 (29.5% for 5-ALA vs 36.2% for fluorescein, p = 0.39). The median overall survival was 14.8 months for the 5-ALA group and 19.7 months for the fluorescein group (p = 0.06). The median adjusted progression-free survival was 8.7 months for the 5-ALA group and 9.2 months for the fluorescein group (p = 0.03). CONCLUSIONS: Fluorescein can be used as a viable alternative to 5-ALA for intraoperative fluorescent guidance in brain tumor surgery. Comparative, prospective, and randomized studies are much needed.

Frameless stereotactic neuronavigated biopsy: A retrospective study of morbidity, diagnostic yield, and the potential of fluorescence: A single-center clinical investigation.

OBJECTIVE: The primary objective of this retrospective study was to evaluate the diagnostic yield and morbidity/mortality associated with frameless stereotactic neuronavigated intracranial biopsies with and without the use of fluorescein. PATIENTS AND METHODS: Patient cases from January 2007 to December 2017 were identified using the ICD-10 procedure code AAG00. Relevant clinical data, including histological diagnosis, were collected retrospectively from the electronic patient charts and independently reviewed by two authors. RESULTS: 111 biopsies obtained from 103 patients were identified. Of these, 109 biopsies yielded a diagnosis and resulted in a diagnostic yield of 98.2%. Fluorescein was used in 13 biopsies (11.7%). Twelve patients (10.8%) experienced postoperative complications, and the mortality attributed to the surgery was 1.8%. In 12.6% of cases, the biopsies showed inflammation or nonspecific reactive changes. No statistically significant differences were observed in diagnostic yield or number and severity of complications according to whether intraoperative histological examination was used or not. CONCLUSION: Although direct comparisons between studies are difficult due to lack of consensus about the definition of diagnostic yield, the present study reports a similar diagnostic yield to other studies. Intraoperative histopathological analysis appeared to give little extra benefit.

Patterns of cerebral tissue oxygen tension and cytoplasmic redox state in bacterial meningitis.

BACKGROUND: Compromised cerebral energy metabolism is common in patients with bacterial meningitis. In this study, simultaneous measurements of cerebral oxygen tension and lactate/pyruvate ratio were compared to explore whether disturbed energy metabolism was usually caused by insufficient tissue oxygenation or compromised oxidative metabolism of pyruvate indicating mitochondrial dysfunction. SUBJECT AND METHODS: Ten consecutive patients with severe streptococcus meningitis were included in this prospective cohort study. Intracranial pressure, brain tissue oxygen tension (PbtO2 ), and energy metabolism (intracerebral microdialysis) were continuously monitored in nine patients. A cerebral lactate/pyruvate (LP) ratio <30 was considered indicating normal oxidative metabolism, LP ratio >30 simultaneously with pyruvate below lower normal level (70 µmol/L) was interpreted as biochemical indication of ischemia, and LP ratio >30 simultaneously with a normal or increased level of pyruvate was interpreted as mitochondrial dysfunction. The biochemical variables were compared with PbtO2 simultaneously monitored within the same cerebral region. RESULTS: In two cases, the LP ratio was normal during the whole study period and the simultaneously monitored PbtO2 was 18 ± 6 mm Hg. In six cases, interpreted as mitochondrial dysfunction, the simultaneously monitored PbtO2 was 20 ± 6 mm Hg and without correlation with the LP ratio. In one patient, exhibiting a pattern interpreted as ischemia, PbtO2 decreased below 10 mm Hg and a correlation between LP and PbtO2 was observed. CONCLUSION: This study demonstrated that compromised cerebral energy metabolism, evidenced by increased LP ratio, was common in patients with severe bacterial meningitis while not related to insufficient tissue oxygenation.

Use of intracranial pressure monitoring in bacterial meningitis: a 10-year follow up on outcome and intracranial pressure versus head CT scans.

BACKGROUND: The aim of this study was to evaluate the clinical outcome of patients with severe bacterial meningitis where intracranial pressure (ICP) monitoring has been performed. METHODS: A retrospective observational study including patients admitted 1st. January 2005 to 31st. December 2014. Thirty nine patients age 18-89 years were included. All the patients received intensive care with mechanical ventilation, ICP monitoring, sedation, antibiotics and corticosteroids according to current guidelines. Clinical outcome was defined as death during hospitalization or survival at hospital discharge. RESULTS: The most common pathogen was Streptococcus pneumoniae (26; 67%). Thirteen patients died (33%) and neurologic impairment was noted in twenty two (84.6%) surviving patients. In S. pneumoniae cases patients with adverse outcome were significantly older (p = 0.0024) and immunosuppressed (p = 0.034). Lower mean-cerebral perfusion pressure (CPP) was found to correlate with adverse outcome (p = 0.005). Cerebrospinal fluid (CSF) was drained in fourteen patients. Increased ICP (>20 mmHg) was observed in twenty four patients. No significant correlation was found between measured ICP and head CT scans with signs of elevated ICP. CONCLUSIONS: Patients with severe meningitis should be admitted to intensive care units and evaluated for ICP monitoring regardless of head CT findings.

Shift of microRNA profile upon orthotopic xenografting of glioblastoma spheroid cultures.

Glioblastomas always recur despite surgery, radiotherapy and chemotherapy. A key player in the therapeutic resistance may be immature tumor cells with stem-like properties (TSCs) escaping conventional treatment. A group of promising molecular targets are microRNAs (miRs). miRs are small non-coding RNAs exerting post-transcriptional regulation of gene expression. In this study we aimed to identify over-expressed TSC-related miRs potentially amenable for therapeutic targeting. We used non-differentiated glioblastoma spheroid cultures (GSCs) containing TSCs and compared these to xenografts using a NanoString nCounter platform. This revealed 19 over-expressed miRs in the non-differentiated GSCs. Additionally, non-differentiated GSCs were compared to neural stem cells (NSCs) using a microarray platform. This revealed four significantly over-expressed miRs in the non-differentiated GSCs in comparison to the NSCs. The three most over-expressed miRs in the non-differentiated GSCs compared to xenografts were miR-126, -137 and -128. KEGG pathway analysis suggested the main biological function of these over-expressed miRs to be cell-cycle arrest and diminished proliferation. To functionally validate the profiling results suggesting association of these miRs with stem-like properties, experimental over-expression of miR-128 was performed. A consecutive limiting dilution assay confirmed a significantly elevated spheroid formation in the miR-128 over-expressing cells. This may provide potential therapeutic targets for anti-miRs to identify novel treatment options for GBM patients.

Convection-enhanced delivery of an anti-miR is well-tolerated, preserves anti-miR stability and causes efficient target de-repression: a proof of concept.

Over-expressed microRNAs (miRs) are promising new targets in glioblastoma (GBM) therapy. Inhibition of over-expressed miRs has been shown to diminish GBM proliferation, invasion and angiogenesis, indicating a significant therapeutic potential. However, the methods utilized for miR inhibition have had low translational potential. In clinical trials convection-enhanced delivery (CED) has been applied for local delivery of compounds in the brain. The aim of this study was to determine if safe and efficient miR inhibition was possible by CED of an anti-miR. We used a highly invasive GBM orthotopic xenograft model and targeted a well-validated miR, let-7a, with a 2'-O-methoxyethyl anti-miR with a combined phosphodiester/phosphorothioate backbone to establish an initial proof of concept. In vitro, anti-let-7a was delivered unassisted to the patient-derived T87 glioblastoma spheroid culture. In vivo, anti-let-7a or saline were administered by CED into orthotopic T87-derived tumors. After 1 month of infusion, tumors were removed and tumor mRNA levels of the target-gene High-mobility group AT-hook 2 (HMGA2) were determined. In vitro, 5 days inhibition was superior to 1 day at de-repressing the let-7a target HMGA2 and the inhibition was stable for 24 h. In vivo, anti-miR integrity was preserved in the pumps and no animals showed signs of severe adverse effects attributable to the anti-miR treatment. HMGA2 tumor level was significantly de-repressed in the anti-miR treated animals. The results showed-as an initial proof of concept-that miRs can be efficiently inhibited using CED delivery of anti-miR. The next step is to apply CED for anti-miR delivery focusing on key oncogenic miRs.

Estimation of Tumor Volumes by 11C-MeAIB and 18F-FDG PET in an Orthotopic Glioblastoma Rat Model.

UNLABELLED: Brain tumor volume assessment is a major challenge. Molecular imaging using PET may be a promising option because it reflects the biologically active cells. We compared the agreement between PET- and histology-derived tumor volumes in an orthotopic glioblastoma rat model with a noninfiltrating (U87MG) and an infiltrating (T87) tumor phenotype using 2 different radiotracers, 2 different image reconstruction algorithms, parametric imaging, and 2 different image segmentation techniques. METHODS: Rats with U87MG- and T87-derived glioblastomas were continuously scanned with PET for 1 h starting immediately after the injection of 11C-methylaminoisobutyric acid (11C-MeAIB). One hour later, 18F-FDG was injected, followed by a 3-h dynamic PET scan. Images were reconstructed using 2-dimensional ordered-subsets expectation maximization and 3-dimensional maximum a posteriori probability (MAP3D) algorithms. In addition, a parametric image, encompassing the entire tumor kinetics in a single image, was calculated on the basis of the 11C-MeAIB images. All reconstructed images were segmented by fixed thresholding of maximum voxel intensity (VImax) and mean background intensity. The agreement between PET- and histology-derived tumor volumes and intra- and interobserver agreement of the PET-derived volumes were evaluated using Bland-Altman plots. RESULTS: By PET, the mean U87MG tumor volume was 35.0 mm3 using 18F-FDG and 34.1 mm3 with 11C-MeAIB, compared with 33.7 mm3 by histology. Corresponding T87 tumor volumes were 122.1 mm3 using 18F-FDG, 118.3 mm3 with 11C-MeAIB, and 125.4 mm3 by histology. None of these volumes were significantly different. The best agreement between PET- and histology-derived U87MG tumor volumes was achieved with 11C-MeAIB, MAP3D reconstruction, and fixed thresholding of VImax. The intra- and interobserver agreement was high using this method. For T87 tumors, the best agreement between PET- and histology-derived volumes was obtained using 18F-FDG, MAP3D reconstruction, and fixed thresholding of mean background intensity. The agreement using 11C-MeAIB, parametric imaging, and fixed thresholding of VImax was slightly inferior, but the intra- and interobserver agreement was clearly superior. CONCLUSION: Estimation of tumor volume by PET of noninfiltrating brain tumors was accurate and reproducible. In contrast, tumor volume estimation by PET of infiltrating brain tumors was difficult and hard to reproduce. On the basis of our results, PET evaluation of highly infiltrating brain tumors should be further developed.

Comparison between cerebral tissue oxygen tension and energy metabolism in experimental subdural hematoma.

BACKGROUND: An experimental swine model (n = 7) simulating an acute subdural hematoma (ASDH) was employed (1) to explore the relation between the brain tissue oxygenation (PbtO(2)) and the regional cerebral energy metabolism as obtained by microdialysis, and (2) to define the lowest level of PbtO(2) compatible with intact energy metabolism. METHODS: ASDH was produced by infusion of 7 ml of autologous blood (infusion rate 0.5 ml/min) by a catheter placed subdurally. PbtO(2) and microdialysis probes were placed symmetrically in the injured ("bad-side") and non-injured ("good-side") hemispheres. Intracranial pressure (ICP) was monitored in the "good-side." RESULTS: ICP, cerebral perfusion pressure (CPP), PbtO(2), glucose, lactate, pyruvate, lactate-pyruvate ratio (LP ratio), glutamate, and glycerol were recorded at baseline (60 min) and post trauma (360 min). After the creation of the ASDH, PbtO(2) decreased significantly in both the hemispheres (P < 0.001). No significant difference was found between the sides post trauma. The LP ratio, glutamate, and glycerol in the "bad-side" increased significantly over the "good-side" where the values remained within the normal limits. A PbtO(2) value below approximately 25 mmHg was found to be associated with disturbed energy metabolism in the "bad-side" but not in the "good-side." No correlation was found between the LP ratio and PbtO(2) in either hemisphere. CONCLUSIONS: PbtO(2) monitoring accurately describes tissue oxygenation but does not disclose whether the oxygen delivery is sufficient for maintaining cerebral energy metabolism. Accordingly, it may not be possible to define a threshold level for PbtO(2) below which energy failure and permanent tissue damage occurs.