OBJECTIVEThe aim of this study was to compare sensitivity and specificity between the novel threshold and amplitude criteria for motor evoked potentials (MEPs) monitoring after transcranial ...electrical stimulation (TES) during surgery for supratentorial lesions in the same patient cohort.METHODSOne hundred twenty-six patients were included. All procedures were performed under general anesthesia. Craniotomies did not expose motor cortex, so that direct mapping was less suitable. After TES, MEPs were recorded bilaterally from abductor pollicis brevis (APB), from orbicularis oris (OO), and/or from tibialis anterior (TA). The percentage increase in the threshold level was assessed and considered significant if it exceeded by more than 20% on the affected side the percentage increase on the unaffected side. Amplitude on the affected side was measured with a stimulus intensity of 150% of the threshold level set for each muscle.RESULTSEighteen of 126 patients showed a significant change in the threshold level as well as an amplitude reduction of more than 50% in MEPs recorded from APB, and 15 of the patients had postoperative deterioration of motor function of the arm (temporary in 8 cases and permanent in 7 true-positive and false-negative results). Recording from TA was performed in 66 patients; 4 developed postoperative deterioration of motor function of the leg (temporary in 3 cases and permanent in 1), and showed a significant change in the threshold level, and an amplitude reduction of more than 50% occurred in 1 patient. An amplitude reduction of more than 50% occurred in another 10 patients, without a significant change in the threshold level or postoperative deterioration. Recording from OO was performed in 61 patients; 3 developed postoperative deterioration of motor function of facial muscles (temporary in 2 cases and permanent in 1) and had a significant change in the threshold level, and 2 of the patients had an amplitude reduction of more than 50%. Another 6 patients had an amplitude reduction of more than 50% but no significant change in the threshold level or postoperative deterioration.Sensitivity of the threshold criterion was 100% when MEPs were recorded from APB, OO, or TA, and its specificity was 97%, 100%, and 100%, respectively. Sensitivity of the amplitude criterion was 100%, 67%, and 25%, with a specificity of 97%, 90%, and 84%, respectively.CONCLUSIONSThe threshold criterion was comparable to the amplitude criterion with a stimulus intensity set at 150% of the threshold level regarding sensitivity and specificity when recording MEPs from APB, and superior to it when recording from TA or OO.
Immunotherapeutic treatment strategies for glioblastoma (GBM) are under investigation in clinical trials. However, our understanding of the immune phenotype of GBM-infiltrating T cells ...(tumor-infiltrating lymphocytes; TILs) and changes during disease progression is limited. Deeper insight is urgently needed to therapeutically overcome tumor-induced immune exhaustion.
We used flow cytometry and cytokine assays to profile TILs and peripheral blood lymphocytes (PBLs) from patients with GBM, comparing newly diagnosed or recurrent GBM to long-term survivors (LTS) and healthy donors. TCR sequencing was performed on paired samples of newly diagnosed and recurrent GBM.
We identified a clear immune signature of exhaustion and clonal restriction in the TILs of patients with GBM. Exhaustion of CD8
TILs was defined by an increased prevalence of PD-1
, CD39
, Tim-3
, CD45RO
, HLA-DR
marker expression, and exhibition of an effector-/transitional memory differentiation phenotype, whereas KLRG1 and CD57 were underrepresented. Immune signatures were similar in primary and recurrent tumors; however, restricted TCR repertoire clonality and a more activated memory phenotype were observed in TILs from recurrent tumors. Moreover, a reduced cytokine response to PHA stimulation in the blood compartment indicates a dysfunctional peripheral T-cell response in patients with GBM. LTS displayed a distinct profile, with abundant naïve and less exhausted CD8
T cells.
TILs and PBLs exhibit contrasting immune profiles, with a distinct exhaustion signature present in TILs. While the exhaustion profiles of primary and recurrent GBM are comparable, TCR sequencing demonstrated a contracted repertoire in recurrent GBM, concomitant with an increased frequency of activated memory T cells in recurrent tumors.
.
Preclinical data indicate anti-invasive activity of APG101, a CD95 ligand (CD95L)-binding fusion protein, in glioblastoma.
Patients (N = 91) with glioblastoma at first or second progression were ...randomized 1:2 between second radiotherapy (rRT; 36 Gy; five times 2 Gy per week) or rRT+APG101 (400 mg weekly i.v.). Patient characteristics N = 84 (26 patients rRT, 58 patients rRT+APG101) were balanced.
Progression-free survival at 6 months (PFS-6) rates were 3.8% 95% confidence interval (CI), 0.1-19.6 for rRT and 20.7% (95% CI, 11.2-33.4) for rRT+APG101 (P = 0.048). Median PFS was 2.5 (95% CI, 2.3-3.8) months and 4.5 (95% CI, 3.7-5.4) months with a hazard ratio (HR) of 0.49 (95% CI, 0.27-0.88; P = 0.0162) adjusted for tumor size. Cox regression analysis adjusted for tumor size revealed a HR of 0.60 (95% CI, 0.36-1.01; P = 0.0559) for rRT+APG101 for death of any cause. Lower methylation levels at CpG2 in the CD95L promoter in the tumor conferred a stronger risk reduction (HR, 0.19; 95% CI, 0.06-0.58) for treatment with APG101, suggesting a potential biomarker.
CD95 pathway inhibition in combination with rRT is an innovative concept with clinical efficacy. It warrants further clinical development. CD95L promoter methylation in the tumor may be developed as a biomarker.
Purpose: Expression of the receptor tyrosine kinase c-Met and its ligand scatter factor/hepatocyte growth factor (SF/HGF) are strongly
increased in glioblastomas, where they promote tumor ...proliferation, migration, invasion, and angiogenesis. We used a novel
one-armed anti-c-Met antibody to inhibit glioblastoma growth in vivo .
Experimental Design: U87 glioblastoma cells (c-Met and SF/HGF positive) or G55 glioblastoma cells (c-Met positive and SF/HGF negative) were used
to generate intracranial orthotopic xenografts in nude mice. The one-armed 5D5 (OA-5D5) anti-c-Met antibody was infused intratumorally
using osmotic minipumps. Following treatment, tumor volumes were measured and tumors were analyzed histologically for extracellular
matrix (ECM) components and proteases relevant to tumor invasion. Microarray analyses were done to determine the effect of
the antibody on invasion-related genes.
Results: U87 tumor growth, strongly driven by SF/HGF, was inhibited >95% with OA-5D5 treatment. In contrast, G55 tumors, which are
not SF/HGF driven, did not respond to OA-5D5, suggesting that the antibody can have efficacy in SF/HGF-activated tumors. In
OA-5D5-treated U87 tumors, cell proliferation was reduced >75%, microvessel density was reduced >90%, and apoptosis was increased
>60%. Furthermore, OA-5D5 treatment decreased tumor cell density >2-fold, with a consequent increase in ECM deposition and
increased immunoreactivity for laminin, fibronectin, and tenascin. Microarray studies showed no incresae in these ECM factors,
rather down-regulation of urokinase-type plasminogen activator and matrix metalloproteinase 16 in glioblastoma cells treated
with OA-5D5.
Conclusions: Local treatment with OA-5D5 can almost completely inhibit intracerebral glioblastoma growth when SF/HGF is driving tumor
growth. The mechanisms of tumor inhibition include antiproliferative, antiangiogenic, and proapoptotic effects.
OBJECTIVE Warning criteria for monitoring of motor evoked potentials (MEP) after direct cortical stimulation during surgery for supratentorial tumors have been well described. However, little is ...known about the value of MEP after transcranial electrical stimulation (TES) in predicting postoperative motor deficit when monitoring threshold level. The authors aimed to evaluate the feasibility and value of this method in glioma surgery by using a new approach for interpreting changes in threshold level involving contra- and ipsilateral MEP. METHODS Between November 2013 and December 2014, 93 patients underwent TES-MEP monitoring during resection of gliomas located close to central motor pathways but not involving the primary motor cortex. The MEP were elicited by transcranial repetitive anodal train stimulation. Bilateral MEP were continuously evaluated to assess percentage increase of threshold level (minimum voltage needed to evoke a stable motor response from each of the muscles being monitored) from the baseline set before dural opening. An increase in threshold level on the contralateral side (facial, arm, or leg muscles contralateral to the affected hemisphere) of more than 20% beyond the percentage increase on the ipsilateral side (facial, arm, or leg muscles ipsilateral to the affected hemisphere) was considered a significant alteration. Recorded alterations were subsequently correlated with postoperative neurological deterioration and MRI findings. RESULTS TES-MEP could be elicited in all patients, including those with recurrent glioma (31 patients) and preoperative paresis (20 patients). Five of 73 patients without preoperative paresis showed a significant increase in threshold level, and all of them developed new paresis postoperatively (transient in 4 patients and permanent in 1 patient). Eight of 20 patients with preoperative paresis showed a significant increase in threshold level, and all of them developed postoperative neurological deterioration (transient in 4 patients and permanent in 4 patients). In 80 patients no significant change in threshold level was detected, and none of them showed postoperative neurological deterioration. The specificity and sensitivity in this series were estimated at 100%. Postoperative MRI revealed gross-total tumor resection in 56 of 82 patients (68%) in whom complete tumor resection was attainable; territorial ischemia was detected in 4 patients. CONCLUSIONS The novel threshold criterion has made TES-MEP a useful method for predicting postoperative motor deficit in patients who undergo glioma surgery, and has been feasible in patients with preoperative paresis as well as in patients with recurrent glioma. Including contra- and ipsilateral changes in threshold level has led to a high sensitivity and specificity.
Fluctuations in oxygen tension during tissue remodeling impose a major metabolic challenge in human tumors. Stem-like tumor cells in glioblastoma, the most common malignant brain tumor, possess ...extraordinary metabolic flexibility, enabling them to initiate growth even under non-permissive conditions. We identified a reciprocal metabolic switch between the pentose phosphate pathway (PPP) and glycolysis in glioblastoma stem-like (GS) cells. Expression of PPP enzymes is upregulated by acute oxygenation but downregulated by hypoxia, whereas glycolysis enzymes, particularly those of the preparatory phase, are regulated inversely. Glucose flux through the PPP is reduced under hypoxia in favor of flux through glycolysis. PPP enzyme expression is elevated in human glioblastomas compared to normal brain, especially in highly proliferative tumor regions, whereas expression of parallel preparatory phase glycolysis enzymes is reduced in glioblastomas, except for strong upregulation in severely hypoxic regions. Hypoxia stimulates GS cell migration but reduces proliferation, whereas oxygenation has opposite effects, linking the metabolic switch to the “go or grow” potential of the cells. Our findings extend Warburg’s observation that tumor cells predominantly utilize glycolysis for energy production, by suggesting that PPP activity is elevated in rapidly proliferating tumor cells but suppressed by acute severe hypoxic stress, favoring glycolysis and migration to protect cells against hypoxic cell damage.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Peripheral metastases of glioblastoma (GBM) are very rare despite the ability of GBM cells to pass through the blood-brain barrier and be disseminated through the peripheral blood. Here, we describe ...a detailed genetic and immunological characterization of a GBM metastasis in the skeleton, which occurred during anti-PD-1 immune checkpoint therapy. We performed whole genome sequencing (WGS) and 850 K methylation profiling of the primary and recurrent intracranial GBM as well as one of the bone metastases. Copy number alterations (CNA) and mutational profiles were compared to known genomic alterations in the TCGA data base. In addition, immunophenotyping of the peripheral blood was performed. The patient who was primarily diagnosed with IDH-wildtype GBM. After the resection of the first recurrence, progressive intracranial re-growth was again detected, and chemotherapy was replaced by PD-1 checkpoint inhibition, which led to a complete intracranial remission. Two months later MR-imaging revealed multiple osseous lesions. Biopsy confirmed the GBM origin of the skeleton metastases. Immunophenotyping reflected the effective activation of a peripheral T-cell response, with, however, increase of regulatory T cells during disease progression. WGS sequencing demonstrated distinct genomic alterations of the GBM metastasis, with gains along chromosomes 3 and 9 and losses along chromosome 4, 10, and 11. Mutational analysis showed mutations in potentially immunologically relevant regions. Additionally, we correlated tumour-infiltrating lymphocyte and microglia presence to the occurrence of circulating tumour cells (CTCs) in a larger cohort and found a decreased infiltration of cytotoxic T cells in patients positive for CTCs. This study exemplifies that the tumour microenvironment may dictate the response to immune checkpoint therapy. In addition, our study highlights the fact that despite an effective control of intracranial GBM, certain tumour clones have the ability to evade the tumour-specific T-cell response and cause progression even outside of the CNS.
In medical refractory temporal lobe epilepsy (TLE), the epileptogenic zone can be difficult to identify and therefore difficult to treat, especially in the absence of clear MRI pathologies and ...specific results from presurgical evaluation. Invasive monitoring with stereo-electroencephalography (sEEG) is a tool for a better determination of the epileptogenic zone. Here, we investigate the impact of sEEG on decision-making in temporal lobe epilepsy surgery. We reviewed patients with TLE who underwent further investigation with sEEG in our epilepsy unit. We examined specifically how sEEG findings influenced our decision regarding indication for a surgical procedure and resection volume. From 2013 to 2017, we performed 152 temporal resections in epilepsy patients. Twenty-one of these patients were designated for further preoperative investigation with sEEG due to incongruent findings in presurgical evaluation. Six patients were implanted bitemporally. In five cases, the hypothesis for the epileptogenic zone and localization had to be changed due to sEEG findings and resulted in a different tailored resection than intended. In three cases, sEEG findings led to the cancelation of the originally intended temporal resection as the epileptogenic zone was not definable or bilateral. In another three cases, the prognosis for reduction of seizures postoperatively had to be reduced due to the sEEG findings. However, the resection was performed after interdisciplinary discussion and informed consent of the patient. The examination by sEEG led to a change of plan for further treatment in 13 patients (61.9%) suffering TLE in total. Invasive monitoring with sEEG electrodes had a strong impact on decision-making for further treatment in patients suffering from temporal lobe epilepsy with incongruent findings in presurgical examination designated for epilepsy surgery. This applies to resection volumes as well as to prediction of seizure outcome.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Summary
Objective
Selective amygdalohippocampectomy (sAHE) is a well‐established treatment for temporal lobe epilepsy, commonly with favorable neuropsychological outcome. Yet, it is still unknown if ...subsequent resection of the anteromesial temporal lobe (AMTLR), when necessary, deteriorates neuropsychological performance in this selected group of patients. Thus, we evaluated the clinical and neuropsychological data of patients who, due to insufficient seizure control after sAHE, received a subsequent ipsilateral AMTLR and compared these findings with patients who did not receive a second resection (control group).
Methods
Patients’ characteristics and neuropsychological data were assessed and analyzed in the reoperated as well as in the control group at each step of treatment. Experienced neuropsychologists conducted the standardized examination focusing on verbal, figural and working memory, speech fluency and attention. Preoperative diagnostics included further continuous video‐electroencephalography monitoring, high‐resolution magnetic resonance imaging and functional transcranial Doppler sonography.
Results
Eighty patients having received sAHE in our center from 11/2007 to 02/2013 were included in this study. Seventeen of these patients underwent subsequent AMTLR. Thirteen of these were available for follow‐up after the second surgery and twelve had a comprehensive neuropsychological testing at all three steps. Analyzing the neuropsychological data revealed no significant differences compared with controls. On the individual level, the data demonstrated that improvement in a subdomain was more frequent than decline, if the performance had already deteriorated after the first procedure. Seizure control improved significantly (p < 0.001) in all patients after subsequent AMTLR resulting in seven patients being seizure‐free at follow‐up.
Significance
Subsequent AMTLR following sAHE can be a safe procedure to improve seizure outcome in selected patients. In our series the risk for further neuropsychological deterioration after the second procedure was low. The neuropsychological performance after the sAHE can be a valuable criterion to advise patients who are eligible for a second surgery on their risk of further cognitive decline.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Purpose: Major shortcomings of traditional mouse models based on xenografted human glioblastoma cell lines are that tumor cells do
not invade and that genetic alterations, such as amplification of ...the epidermal growth factor receptor ( EGFR ) gene, are not maintained. Such models are thus of limited value for preclinical studies. We established a highly invasive
model to evaluate the effect of antibodies against EGFR (cetuximab) and vascular endothelial growth factor receptor-2 (antibody
DC101).
Experimental Design: After short-term culture, glioblastoma spheroids were implanted into the brains of nude mice. Animals were treated either
i.c. with cetuximab or i.p. with DC101. Tumor burden was determined histologically using image analysis of 36 different landmark
points on serial brain sections.
Results: Invasive xenografts were obtained from nine different glioblastomas. Three of seven cases treated with cetuximab responded
with significant tumor growth inhibition, whereas four did not. All responsive tumors were derived from glioblastomas exhibiting
EGFR amplification and expression of the truncated EGFRvIII variant, which were maintained in the xenografts. All nonresponsive
tumors lacked EGFR amplification and EGFRvIII expression. The proportion of apoptotic cells was increased, whereas proliferation and invasion
were decreased in responsive tumors. None of four xenograft cases treated with DC101 responded to treatment, and the diffusely
invading tumors grew independent of angiogenesis.
Conclusions: Inhibition of glioblastoma growth and invasion can be achieved using i.c. delivery of an anti-EGFR antibody, but tumor response
depends on the presence of amplified and/or mutated EGFR. Antiangiogenic treatment with DC101 is not effective against diffusely
invading tumors.
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