Summary This guideline provides recommendations for diagnostic and therapeutic procedures for patients with malignant gliomas. We differentiate evidence-based standards from reasonable options or ...non-evidence-based measures that should no longer be considered. The recommendations herein should provide a framework and assurance for the choice of diagnostic procedures and therapeutic measures and aim to reduce complications from unnecessary treatment and cost. The guideline contributes to a critical appreciation of concurrent drugs with a focus on the controlled use of anticonvulsants and steroids. It should serve as a guideline for all professionals involved in the diagnostics and care of glioma patients and also as a source of knowledge for insurance companies and other institutions involved in the cost regulation of cancer care in Europe. Implementation of the recommendations summarised here will need interdisciplinary structures of care for patients with brain tumours and structured processes of diagnostic and therapeutic procedures.
BACKGROUND:Surgical removal of intra-axial brain tumors aims at maximal tumor resection while preserving function. The potential benefit of awake craniotomy over craniotomy under general anesthesia ...(GA) for motor preservation is yet unknown.
OBJECTIVE:To compare the clinical outcomes of patients who underwent surgery for perirolandic tumors while either awake or under GA.
METHODS:Between 2004 and 2015, 1126 patients underwent surgical resection of newly diagnosed intra-axial tumors in a single institution. Data from 85 patients (44 awake, 41 GA) with full dataset who underwent resections for perirolandic tumors were retrospectively analyzed.
RESULTS:Identification of the motor cortex required significantly higher stimulation thresholds in anesthetized patients (9.1 ± 4 vs 6.2 ± 2.7 mA for awake patients, P = .0008). There was no group difference in the subcortical threshold for motor response used to assess the proximity of the lesion to the corticospinal (pyramidal) tract. High-grade gliomas were the most commonly treated pathology. The extent of resection and residual tumor volume were not different between groups. Postoperative motor deficits were more common in the anesthetized patients at 1 wk (P = .046), but no difference between the groups was detected at 3 mo. Patients in the GA group had a longer mean length of hospitalization (10.3 vs 6.7 d for the awake group, P = .003).
CONCLUSION:Awake craniotomy results in a better early postoperative motor outcome and shorter hospitalization compared with patients who underwent the same surgery under GA. The finding of higher cortical thresholds for the identification of the motor cortex in anesthetized patients may suggest an inhibitory effect of anesthetic agents on motor function.
Summary Background Besides the use of temozolomide and radiotherapy for patients with favourable methylation status, little progress has been made in the treatment of adult glioblastoma. Local ...control of the disease by complete removal increases time to progression and survival. We assessed the efficacy and safety of a locally applied adenovirus-mediated gene therapy with a prodrug converting enzyme (herpes-simplex-virus thymidine kinase; sitimagene ceradenovec) followed by intravenous ganciclovir in patients with newly diagnosed resectable glioblastoma. Methods For this international, open-label, randomised, parallel group multicentre phase 3 clinical trial, we recruited patients from 38 sites in Europe. Patients were eligible if they were aged 18–70 years, had newly diagnosed supratentorial glioblastoma multiforme amenable to complete resection, and had a Karnofsky score of 70 or more at screening. We used a computer-generated randomisation sequence to allocate patients in a one-to-one ratio (with block sizes of four) to receive either surgical resection of the tumour and intraoperative perilesional injection of sitimagene ceradenovec (1 × 1012 viral particles) followed by ganciclovir (postoperatively, 5 mg/kg intravenously twice a day) in addition to standard care or resection and standard care alone. Temozolomide, not being standard in all participating countries at the time of the study, was allowed at the discretion of the treating physician. The primary endpoint was a composite of time to death or re-intervention, adjusted for temozolamide use, assessed by intention-to-treat (ITT) analysis. This trial is registered with EudraCT, number 2004-000464-28. Findings Between Nov 3, 2005, and April 16, 2007, 250 patients were recruited and randomly allocated: 124 to the experimental group and 126 to the standard care group, of whom 119 and 117 patients, respectively, were included in the ITT analyses. Median time to death or re-intervention was longer in the experimental group (308 days, 95% CI 283–373) than in the control group (268 days, 210–313; hazard ratio HR 1·53, 95% CI 1·13–2·07; p=0·006). In a subgroup of patients with non-methylated MGMT , the HR was 1·72 (95% CI 1·15–2·56; p=0·008). However, there was no difference between groups in terms of overall survival (median 497 days, 95% CI 369–574 for the experimental group vs 452 days, 95% CI 437–558 for the control group; HR 1·18, 95% CI 0·86–1·61, p=0·31). More patients in the experimental group had one or more treatment-related adverse events those in the control group (88 71% vs 51 43%). The most common grade 3–4 adverse events were hemiparesis (eight in the experimental group vs three in the control group) and aphasia (six vs two). Interpretation Our findings suggest that use of sitimagene ceradenovec and ganciclovir after resection can increase time to death or re-intervention in patients with newly diagnosed supratentorial glioblastoma multiforme, although the intervention did not improve overall survival. Locally delivered gene therapy for glioblastoma should be further developed, especially for patients who are unlikely to respond to standard chemotherapy. Funding Ark Therapeutics Ltd.
Awake craniotomy for removal of intraaxial tumors within or adjacent to eloquent brain regions is a well-established procedure. However, awake craniotomy failures have not been well characterized. In ...the present study, the authors aimed to analyze and assess the incidence and causes for failed awake craniotomy.
The database of awake craniotomies performed at Tel Aviv Medical Center between 2003 and 2010 was reviewed. Awake craniotomy was considered a failure if conversion to general anesthesia was required, or if adequate mapping or monitoring could not have been achieved.
Of 488 patients undergoing awake craniotomy, 424 were identified as having complete medical, operative, and anesthesiology records. The awake craniotomies performed in 27 (6.4%) of these 424 patients were considered failures. The main causes of failure were lack of intraoperative communication with the patient (n = 18 4.2%) and/or intraoperative seizures (n = 9 2.1%). Preoperative mixed dysphasia (p < 0.001) and treatment with phenytoin (p = 0.0019) were related to failure due to lack of communication. History of seizures (p = 0.03) and treatment with multiple antiepileptic drugs (p = 0.0012) were found to be related to failure due to intraoperative seizures. Compared with the successful awake craniotomy group, a significantly lower rate of gross-total resection was achieved (83% vs 54%, p = 0.008), there was a higher incidence of short-term speech deterioration postoperatively (6.1% vs 23.5%, p = 0.0017) as well as at 3 months postoperatively (2.3% vs 15.4%, p = 0.0002), and the hospitalization period was longer (4.9 ± 6.2 days vs 8.0 ± 10.1 days, p < 0.001). Significantly more major complications occurred in the failure group (4 14.8% of 27) than in the successful group (16 4% of 397) (p = 0.037).
Failures of awake craniotomy were associated with a lower incidence of gross-total resection and increased postoperative morbidity. The majority of awake craniotomy failures were preventable by adequate patient selection and avoiding side effects of drugs administered during surgery.
Gliadel occasionally induces edema following its implantation. We aimed to correlate such post-surgical radiological changes to its efficacy and subsequent survival. Fifty-six patients with recurrent ...high grade glioma were treated between 2005 and 2016 with Gliadel implantation. Volumetric measurements of MRI features, including FLAIR abnormalities, tumor bulk (volume of gadolinium enhancement on T1) and resection cavity volumes over time were conducted. To assess dynamics over time, linear regression trendlines for each of these were calculated and examined to correlate with survival. Median follow-up after resection was 21.5 months. Median survival post-Gliadel implantation and overall survival since diagnosis were 12 months and 22 months, respectively. A subgroup of patients (n = 6) with a transient increase in FLAIR changes volume over time survived significantly longer post-Gliadel compared to those who did not demonstrate such change (36 vs 12 months, p = .03). Positive trends, representing overall growth in volume over time, of tumor bulk and resection cavity predicted survival in multivariate analyses (hazard ratios 7.9 and 84, p = .003 and .002, respectively). Increase in tumor bulk and resection cavity over time were associated with decreased survival, while transient FLAIR increase was a favorable prognostic factor. This may represent a transient inflammatory process in the tumor, possibly stemming from a presumed immune-mediated anti-tumor response.
Cognition is a key component in health-related quality of life (HRQoL) and is currently incorporated as a major parameter of outcome assessment in patients treated for brain tumors. The effect of ...surgery on cognition and HRQoL remains debatable. The authors investigated the impact of resection of low-grade gliomas (LGGs) on cognition and the correlation with various histopathological markers.
A retrospective analysis of patients with LGG who underwent craniotomy for tumor resection at a single institution between 2010 and 2014 was conducted. Of 192 who underwent resective surgery for LGG during this period, 49 had complete pre- and postoperative neurocognitive evaluations and were included in the analysis. These patients completed a full battery of neurocognitive tests (memory, language, attention and working memory, visuomotor organization, and executive functions) pre- and postoperatively. Tumor and surgical characteristics were analyzed, including volumetric measurements and histopathological markers (IDH, p53, GFAP).
Postoperatively, significant improvement was found in memory and executive functions. A subgroup analysis of patients with dominant-side tumors, most of whom underwent intraoperative awake mapping, revealed significant improvement in the same domains. Patients whose tumors were on the nondominant side displayed significant improvement only in memory functions. Positive staining for p53 testing was associated with improved language function and greater extent of resection in dominant-side tumors. GFAP positivity was associated with improved memory in patients whose tumors were on the nondominant side. No correlation was found between cognitive outcome and preoperative tumor volume, residual volume, extent of resection, or IDH1 status.
Resection of LGG significantly improves memory and executive function and thus is likely to improve functional outcome in addition to providing oncological benefit. GFAP and pP53 positivity could possibly be associated with improved cognitive outcome. These data support early, aggressive, surgical treatment of LGG.
Glioblastoma (GB) is a highly invasive type of brain cancer exhibiting poor prognosis. As such, its microenvironment plays a crucial role in its progression. Among the brain stromal cells, the ...microglia were shown to facilitate GB invasion and immunosuppression. However, the reciprocal mechanisms by which GB cells alter microglia/macrophages behavior are not fully understood. We propose that these mechanisms involve adhesion molecules such as the Selectins family. These proteins are involved in immune modulation and cancer immunity. We show that P-selectin mediates microglia-enhanced GB proliferation and invasion by altering microglia/macrophages activation state. We demonstrate these findings by pharmacological and molecular inhibition of P-selectin which leads to reduced tumor growth and increased survival in GB mouse models. Our work sheds light on tumor-associated microglia/macrophage function and the mechanisms by which GB cells suppress the immune system and invade the brain, paving the way to exploit P-selectin as a target for GB therapy.
DNA methylation patterns delineate clinically relevant subgroups of meningioma. We previously established the six meningioma methylation classes (MC) benign 1–3, intermediate A and B, and malignant. ...Here, we set out to identify subgroup-specific mutational patterns and gene regulation. Whole genome sequencing was performed on 62 samples across all MCs and WHO grades from 62 patients with matched blood control, including 40 sporadic meningiomas and 22 meningiomas arising after radiation (Mrad). RNA sequencing was added for 18 of these cases and chromatin-immunoprecipitation for histone H3 lysine 27 acetylation (H3K27ac) followed by sequencing (ChIP-seq) for 16 samples. Besides the known mutations in meningioma, structural variants were found as the mechanism of
NF2
inactivation in a small subset (5%) of sporadic meningiomas, similar to previous reports for Mrad. Aberrations of
DMD
were found to be enriched in MCs with
NF2
mutations, and
DMD
was among the most differentially upregulated genes in
NF2
mutant compared to
NF2
wild-type cases. The mutational signature AC3, which has been associated with defects in homologous recombination repair (HRR), was detected in both sporadic meningioma and Mrad, but widely distributed across the genome in sporadic cases and enriched near genomic breakpoints in Mrad. Compared to the other MCs, the number of single nucleotide variants matching the AC3 pattern was significantly higher in the malignant MC, which also exhibited higher genomic instability, determined by the numbers of both large segments affected by copy number alterations and breakpoints between large segments. ChIP-seq analysis for H3K27ac revealed a specific activation of genes regulated by the transcription factor FOXM1 in the malignant MC. This analysis also revealed a super enhancer near the
HOXD
gene cluster in this MC, which, together with general upregulation of
HOX
genes in the malignant MC, indicates a role of
HOX
genes in meningioma aggressiveness. This data elucidates the biological mechanisms rendering different epigenetic subgroups of meningiomas, and suggests leveraging HRR as a novel therapeutic target.
Background
The extent of tumor resection (EOTR) calculated by enhanced T1 changes in glioblastomas has been previously reported to predict survival. However, fluid-attenuated inversion recovery ...(FLAIR) volume may better represent tumor burden. In this study, we report the first assessment of the dynamics of FLAIR volume changes over time as a predictive variable for post-resection overall survival (OS).
Methods
Contemporary data from 103 consecutive patients with complete imaging and clinical data who underwent resection of newly diagnosed glioblastoma followed by the Stupp protocol between 2010 and 2013 were analyzed. Clinical, radiographic, and outcome parameters were retrieved for each patient, including magnetic resonance imaging (MRI)-based volumetric tumor analysis before, immediately after, and 3 months post-surgery.
Results
OS rate was 17.6 months. A significant incremental OS advantage was noted, with as little as 85 % T1-weighted gadolinium-enhanced (T1Gd)-EOTR measured on contrast-enhanced MRI. Pre- and immediate postoperative FLAIR-based EOTR was not predictive of OS; however, abnormal FLAIR volume measured 3 months post-surgery correlated significantly with outcome when FLAIR residual tumor volume (RTV) was <19.3 cm
3
and <46 % of baseline volume (
p
< 0.0001 for both). Age and isocitrate dehydrogenase (IDH)-1 mutation were predictive of OS (
p
< 0.0001, Cox proportional hazards).
Conclusions
OS correlated with the immediate postoperative T1Gd-EOTR measured by enhanced T1 MRI, but not by FLAIR volume. Diminished abnormal FLAIR volume at 3 months post-surgery was associated with OS benefit when FLAIR-RTV was <19.3 cm
3
or <46 % of baseline. These threshold values provide a new radiological variable that can be used for prediction of OS in patients with glioblastoma immediately after completion of standard chemoradiation.
Direct cortical stimulation (DCS) is considered the gold-standard for functional cortical mapping during awake surgery for brain tumor resection. DCS is performed by stimulating one local cortical ...area at a time. We present a feasibility study using an intra-operative technique aimed at improving our ability to map brain functions which rely on activity in distributed cortical regions. Following standard DCS, Multi-Site Stimulation (MSS) was performed in 15 patients by applying simultaneous cortical stimulations at multiple locations. Language functioning was chosen as a case-cognitive domain due to its relatively well-known cortical organization. MSS, performed at sites that did not produce disruption when applied in a single stimulation point, revealed additional language dysfunction in 73% of the patients. Functional regions identified by this technique were presumed to be significant to language circuitry and were spared during surgery. No new neurological deficits were observed in any of the patients following surgery. Though the neuro-electrical effects of MSS need further investigation, this feasibility study may provide a first step towards sophistication of intra-operative cortical mapping.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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