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Supplementary Figure from A Novel EGFRvIII T-Cell Bispecific Antibody for the Treatment of Glioblastoma

Supplementary Data from Activity and Resistance of a Brain-Permeable Paradox Breaker BRAF Inhibitor in Melanoma Brain Metastasis

The therapeutic benefit of approved BRAF and MEK inhibitors (BRAFi/MEKi) in patients with brain metastatic BRAF V600E/K–mutated melanoma is limited and transient. Resistance largely occurs through the restoration of MAPK signaling via paradoxical BRAF activation, highlighting the need for more effective therapeutic options. Aiming to address this clinical challenge, we characterized the activity of a potent, brain-penetrant paradox breaker BRAFi (compound 1a, C1a) as first-line therapy and following progression upon treatment with approved BRAFi and BRAFi/MEKi therapies. C1a activity was evaluated in vitro and in vivo in melanoma cell lines and patient-derived models of BRAF V600E–mutant melanoma brain metastases following relapse after treatment with BRAFi/MEKi. C1a showed superior efficacy compared with approved BRAFi in both subcutaneous and brain metastatic models. Importantly, C1a manifested potent and prolonged antitumor activity even in models that progressed on BRAFi/MEKi treatment. Analysis of mechanisms of resistance to C1a revealed MAPK reactivation under drug treatment as the predominant resistance-driving event in both subcutaneous and intracranial tumors. Specifically, BRAF kinase domain duplication was identified as a frequently occurring driver of resistance to C1a. Combination therapies of C1a and anti–PD-1 antibody proved to significantly reduce disease recurrence. Collectively, these preclinical studies validate the outstanding antitumor activity of C1a in brain metastasis, support clinical investigation of this agent in patients pretreated with BRAFi/MEKi, unveil genetic drivers of tumor escape from C1a, and identify a combinatorial treatment that achieves long-lasting responses.Significance:A brain-penetrant BRAF inhibitor demonstrates potent activity in brain metastatic melanoma, even upon relapse following standard BRAF inhibitor therapy, supporting further investigation into its clinical utility.

Purpose of review The molecular characterization of central nervous system (CNS) malignancies is crucial for obtaining the correct diagnosis and prognosis, and to guide the optimal therapeutic approach. However, obtaining surgical specimens can be challenging because of the anatomical location of the tumour and may limit the correct characterization of these malignancies. Recently, it has been shown that the cerebrospinal fluid (CSF) circulating tumour DNA (ctDNA) can be used as a liquid biopsy to characterize and monitor CNS malignancies and here we review its implications and advances. Recent findings In the last 5 years, several groups including ours have shown that ctDNA is highly present in the CSF, in larger amounts than in plasma, and that ctDNA can be sequenced to provide information about the diagnosis and prognosis of brain malignancies. Furthermore, the analysis of CSF ctDNA has allowed the selection of optimal therapeutic approaches monitoring response to treatment and tracking tumour evolution, providing crucial information about the molecular changes during tumour progression. Summary Here, we review the recent discoveries and data relative to CSF ctDNA and discuss how CSF ctDNA can be used as a liquid biopsy to facilitate and complement the clinical management of patients with CNS malignancies.

T-cell bispecific antibodies (TCB) are engineered molecules that bind both the T-cell receptor and tumor-specific antigens. Epidermal growth factor receptor variant III (EGFRvIII) mutation is a common event in glioblastoma (GBM) and is characterized by the deletion of exons 2–7, resulting in a constitutively active receptor that promotes cell proliferation, angiogenesis, and invasion. EGFRvIII is expressed on the surface of tumor cells and is not expressed in normal tissues, making EGFRvIII an ideal neoantigen target for TCBs. We designed and developed a novel 2+1 EGFRvIII-TCB with optimal pharmacologic characteristics and potent antitumor activity. EGFRvIII-TCB showed specificity for EGFRvIII and promoted tumor cell killing as well as T-cell activation and cytokine secretion only in patient-derived models expressing EGFRvIII. Moreover, EGFRvIII-TCB promoted T-cell recruitment into intracranial tumors. EGFRvIII-TCB induced tumor regression in GBM animal models, including humanized orthotopic GBM patient-derived xenograft models. Our results warrant the clinical testing of EGFRvIII-TCB for the treatment of EGFRvIII-expressing GBMs.

The therapeutic benefit of approved BRAF and MEK inhibitors (BRAFi/MEKi) in patients with brain metastatic BRAF V600E/K–mutated melanoma is limited and transient. Resistance largely occurs through the restoration of MAPK signaling via paradoxical BRAF activation, highlighting the need for more effective therapeutic options. Aiming to address this clinical challenge, we characterized the activity of a potent, brain-penetrant paradox breaker BRAFi (compound 1a, C1a) as first-line therapy and following progression upon treatment with approved BRAFi and BRAFi/MEKi therapies. C1a activity was evaluated in vitro and in vivo in melanoma cell lines and patient-derived models of BRAF V600E–mutant melanoma brain metastases following relapse after treatment with BRAFi/MEKi. C1a showed superior efficacy compared with approved BRAFi in both subcutaneous and brain metastatic models. Importantly, C1a manifested potent and prolonged antitumor activity even in models that progressed on BRAFi/MEKi treatment. Analysis of mechanisms of resistance to C1a revealed MAPK reactivation under drug treatment as the predominant resistance-driving event in both subcutaneous and intracranial tumors. Specifically, BRAF kinase domain duplication was identified as a frequently occurring driver of resistance to C1a. Combination therapies of C1a and anti–PD-1 antibody proved to significantly reduce disease recurrence. Collectively, these preclinical studies validate the outstanding antitumor activity of C1a in brain metastasis, support clinical investigation of this agent in patients pretreated with BRAFi/MEKi, unveil genetic drivers of tumor escape from C1a, and identify a combinatorial treatment that achieves long-lasting responses. Significance: A brain-penetrant BRAF inhibitor demonstrates potent activity in brain metastatic melanoma, even upon relapse following standard BRAF inhibitor therapy, supporting further investigation into its clinical utility.

Glioblastoma multiforme (GBM) is the most aggressive brain tumor with poor prognosis to most patients. Immunotherapy of GBM is a potentially beneficial treatment option, whose optimal implementation may depend on familiarity with tumor specific antigens, presented as HLA peptides by the GBM cells. Furthermore, early detection of GBM, such as by a routine blood test, may improve survival, even with the current treatment modalities. This study includes large-scale analyses of the HLA peptidome (immunopeptidome) of the plasma-soluble HLA molecules (sHLA) of 142 plasma samples, and the membranal HLA of GBM tumors of 10 of these patients' tumor samples. Tumor samples were fresh-frozen immediately after surgery and the plasma samples were collected before, and at multiple visits after surgery. In total, this HLA peptidome analysis involved 52 different HLA allotypes and resulted in the identification of more than 35,000 different HLA peptides. Strong correlations were observed in the signal intensities and in the repertoires of identified peptides between the tumors and plasma-soluble HLA peptidomes of the individual patients, whereas low correlations were observed between these HLA peptidomes and the tumors' proteomes. HLA peptides derived from Cancer/Testis Antigens (CTAs) were selected based on their presence among the HLA peptidomes of the patients and absence of expression of their source genes from any healthy and essential human tissues, except from immune-privileged sites. Additionally, peptides were selected as potential biomarkers if their levels in the plasma-sHLA peptidome were significantly reduced after the removal of tumor mass. The CTAs identified among the analyzed HLA peptidomes provide new opportunities for personalized immunotherapy and for early diagnosis of GBM.

Simple Summary The optimal treatment and management of patients with brain cancer depend on the molecular characteristics of their tumour. Since the tumour changes with time, it is, therefore, essential to characterise the tumour of each patient at the exact time of selecting the most suitable therapeutic strategy. However, obtaining a tumour biopsy for its characterisation is a risky and invasive procedure and, sometimes, not even feasible, leading to a lack of information about the tumour. These challenges can be overcome by using a liquid biopsy of cerebrospinal fluid. Brain cancer cells release DNA into the cerebrospinal fluid, and the analysis of the cell-free circulating tumour DNA can reveal the genetic profile of brain cancer in a relatively noninvasive manner. In this review, we revise the recent results in this field that show how circulating tumour DNA in cerebrospinal fluid can provide diagnostic and prognostic information, identify potential therapeutic targets, monitor the tumour response or resistance to treatment, and help to identify tumour relapse. Abstract The correct characterisation of central nervous system (CNS) malignancies is crucial for accurate diagnosis and prognosis and also the identification of actionable genomic alterations that can guide the therapeutic strategy. Surgical biopsies are performed to characterise the tumour; however, these procedures are invasive and are not always feasible for all patients. Moreover, they only provide a static snapshot and can miss tumour heterogeneity. Currently, monitoring of CNS cancer is performed by conventional imaging techniques and, in some cases, cytology analysis of the cerebrospinal fluid (CSF); however, these techniques have limited sensitivity. To overcome these limitations, a liquid biopsy of the CSF can be used to obtain information about the tumour in a less invasive manner. The CSF is a source of cell-free circulating tumour DNA (ctDNA), and the analysis of this biomarker can characterise and monitor brain cancer. Recent studies have shown that ctDNA is more abundant in the CSF than plasma for CNS malignancies and that it can be sequenced to reveal tumour heterogeneity and provide diagnostic and prognostic information. Furthermore, analysis of longitudinal samples can aid patient monitoring by detecting residual disease or even tracking tumour evolution at relapse and, therefore, tailoring the therapeutic strategy. In this review, we provide an overview of the potential clinical applications of the analysis of CSF ctDNA and the challenges that need to be overcome in order to translate research findings into a tool for clinical practice.

Brain metastases are the most common tumor of the brain with a dismal prognosis. A fraction of patients with brain metastasis benefit from treatment with immune checkpoint inhibitors (ICI) and the degree and phenotype of the immune cell infiltration has been used to predict response to ICI. However, the anatomical location of brain lesions limits access to tumor material to characterize the immune phenotype. Here, we characterize immune cells present in brain lesions and matched cerebrospinal fluid (CSF) using single-cell RNA sequencing combined with T cell receptor genotyping. Tumor immune infiltration and specifically CD8+ T cell infiltration can be discerned through the analysis of the CSF. Consistently, identical T cell receptor clonotypes are detected in brain lesions and CSF, confirming cell exchange between these compartments. The analysis of immune cells of the CSF can provide a non-invasive alternative to predict the response to ICI, as well as identify the T cell receptor clonotypes present in brain metastasis., The use of CSF for diagnosis of metastatic brain tumors could be of clinical and patient benefit. Here the authors undertake a single-cell RNA analysis of CSF and brain to determine whether the phenotype in the CSF is reflective of the phenotype in the tumor.

XPO1; BTK; Sistema immunitari innat XPO1; BTK; Sistema inmune innato XPO1; BTK; Innate immune system Background Patients diagnosed with primary central nervous system lymphoma (PCNSL) often face dismal outcomes due to the limited availability of therapeutic options. PCNSL cells frequently have deregulated B-cell receptor (BCR) signaling, but clinical responses to its inhibition using ibrutinib have been brief. In this regard, blocking nuclear export by using selinexor, which covalently binds to XPO1, can also inhibit BCR signaling. Selinexor crosses the blood–brain barrier and was recently shown to have clinical activity in a patient with refractory diffuse large B-cell lymphoma in the CNS. We studied selinexor alone or in combination with ibrutinib in pre-clinical mouse models of PCNSL. Methods Orthotopic xenograft models were established by injecting lymphoma cells into the brain parenchyma of athymic mice. Tumor growth was monitored by bioluminescence. Malignant cells and macrophages were studied by immunohistochemistry and flow cytometry. Results Selinexor blocked tumor growth and prolonged survival in a bioluminescent mouse model, while its combination with ibrutinib further increased survival. CNS lymphoma in mice was infiltrated by tumor-promoting M2-like macrophages expressing PD-1 and SIRPα. Interestingly, treatment with selinexor and ibrutinib favored an anti-tumoral immune response by shifting polarization toward inflammatory M1-like and diminishing PD-1 and SIRPα expression in the remaining tumor-promoting M2-like macrophages. Conclusions These data highlight the pathogenic role of the innate immune microenvironment in PCNSL and provide pre-clinical evidence for the development of selinexor and ibrutinib as a new promising therapeutic option with cytotoxic and immunomodulatory potential. This work was supported by research funding from the Instituto de Salud Carlos III, Fondo de Investigaciones Sanitarias (PI17/00950, M.C., PI17/00943, F.B, PI18/01392, P.A., PI16/01278, J.S) cofinanced by the European Regional Development Fund (ERDF); Fundación Asociación Española Contra el Cáncer (M.C. and P.A.) and Gilead Fellowships (GLD16/00144, GLD18/00047, F.B). M.C. holds a contract from Ministerio de Ciencia, Innovación y Universidades (RYC-2012-12018). S.B. is the recipient of a postdoctoral fellowship from Fundación Alfonso Martin Escudero.

Introduction: Mild traumatic brain injury brain injury (mTBI) has traditionally been considered to cause no significant brain damage since symptoms spontaneously remit after a few days. However, this idea is facing increasing scrutiny. The purpose of this study is to demonstrate the presence of early cognitive alterations in a series of patients with mTBI and to link these findings to different markers of brain damage. Methods: We conducted a prospective study of a consecutive series of patients with mTBI who were evaluated over a 12-month period. Forty-one (3.7%) of the 1144 included patients had experienced a concussion. Patients underwent a routine clinical evaluation and a brain computed tomography (CT) scan and were also administered a standardised test for post-concussion symptoms within the first 24 h of mTBI and also 1-2 weeks later. The second assessment also included a neuropsychological test battery. The results of these studies were compared to those of a control group of 28 healthy volunteers with similar characteristics. Twenty patients underwent a magnetic resonance imaging (MRI) scan. Results: Verbal memory and learning were the cognitive functions most affected by mTBI. Seven out of the 20 patients with normal CT findings displayed structural alterations on MR images, which were compatible with diffuse axonal injury in two cases. Conclusions: Results from this pilot study suggest that early cognitive alterations and structural brain lesions affect a considerable percentage of patients with post-concussion syndrome following mTBI. Resumen: Introducción: Los traumatismos craneoencefálicos leves (TCE-L) han sido tradicionalmente considerados acontecimientos sin repercusiones cerebrales significativas, cuya sintomatología remite espontáneamente en unos días. Sin embargo, estos hechos son cada vez más cuestionados. Este estudio pretende objetivar la existencia de alteraciones cognitivas precoces en una serie de pacientes con TCE-L y relacionar los hallazgos con distintos marcadores de lesión cerebral. Métodos: Estudio prospectivo de una cohorte de pacientes con un TCE-L valorados de forma consecutiva durante 12 meses. De un total de 1.144 pacientes, se seleccionó a 41 (3,7%) que habían presentado una conmoción cerebral. Además de la valoración clínica habitual y de la práctica de una tomografía computarizada (TC) cerebral, los pacientes fueron estudiados mediante un test estandarizado para síntomas posconmocionales en las primeras 24 h después del TCE-L y al cabo de 1-2 semanas y, coincidiendo con la segunda valoración, mediante una batería neuropsicológica. Los resultados se compararon con los de un grupo de 28 voluntarios sanos de características parecidas. En 20 pacientes se practicó una resonancia magnética (RM) craneal. Resultados: En este análisis exploratorio, la memoria y el aprendizaje verbal fueron las funciones cognitivas más afectadas después del TCE-L. Siete de los 20 pacientes con TC cerebral normal presentaron alteraciones estructurales visibles por RM, que en dos casos fueron compatibles con la presencia de lesión axonal difusa. Conclusiones: Los resultados de este estudio piloto sugieren la presencia de alteraciones cognitivas precoces y lesiones cerebrales estructurales en un porcentaje no despreciable de pacientes que han presentado una conmoción cerebral recuperada después de un TCE-L. Keywords: Mild traumatic brain injury, Neuropsychological alterations, Diffuse axonal injury, Sport Concussion Assessment Tool 2, Susceptibility-weighted imaging, Post-concussion syndrome, Palabras clave: Traumatismo craneoencefálico leve, Déficits neuropsicológicos, Lesión axonal difusa, Sport Concussion Assessment Tool 2, Susceptibility weighted imaging, Síndrome posconmocional

A case of a non-traumatic giant aneurysm of the middle meningeal artery is presented in a 59-year-old patient with a history of liver transplantation, liver cirrhosis and hepatocarcinoma, chronic renal disease, hypertension and chronic bronchitis who presented with tonic-clonic seizures. CT and MRI showed a lesion suggestive of metastasis without ruling out a glial type tumor. He was operated through a left FT craniotomy. During the surgery there was an arterial hemorrhage. The histological sample oriented toward an aneurysmal origin that was confirmed with ARM and angiography. A second intervention allowed the removal of a giant middle meningeal aneurysm partially thrombosed. Aneurysms of the middle meningeal artery are rare and generally present a traumatic history. No case of giant aneurysm has been found in the medical literature.

Cancer response to immunotherapy depends on the infiltration of CD8+ T cells and the presence of tumor-associated macrophages within tumors. Still, little is known about the determinants of these factors. We show that LIF assumes a crucial role in the regulation of CD8+ T cell tumor infiltration, while promoting the presence of protumoral tumor-associated macrophages. We observe that the blockade of LIF in tumors expressing high levels of LIF decreases CD206, CD163 and CCL2 and induces CXCL9 expression in tumor-associated macrophages. The blockade of LIF releases the epigenetic silencing of CXCL9 triggering CD8+ T cell tumor infiltration. The combination of LIF neutralizing antibodies with the inhibition of the PD1 immune checkpoint promotes tumor regression, immunological memory and an increase in overall survival., LIF is a pleiotropic cytokine that promotes an immunosuppressive microenvironment and has critical functions in embryonic development. Here, the authors show that LIF regulates CD8+ T cell tumor infiltration in cancer by repressing CXCL19 and promoting the presence of protumoral macrophages and thatLIF inhibition, via neutralizing antibodies, promotes T cell infiltration and synergizes with immune checkpoint inhbitors resulting in tumor regression and immunological memory.

Malignant transformation in tumors is a complex process requiring accumulation of numerous oncogenic abnormalities. Brain tumors show considerable phenotypic and genetic heterogeneity. In a series comprising diffuse infiltrating astrocytomas (DIA) and reactive gliosis, we investigated the main factors associated with signaling pathways. We assessed expression levels and their association with tumor progression and survival. We studied 19 grade II astrocytomas, 25 anaplastic astrocytomas (grade III), 60 glioblastomas (grade IV), and 15 cases of reactive gliosis. Epidermal growth factor receptor (EGFR), pMAPK, 4E‐BP1, p4E‐BP1, pS6, eIF4E, and peIF4E expression levels were evaluated using immunohistochemistry. Expression levels were semiquantitatively evaluated using a histoscore. Immunohistochemistry and PCR were used for IDH1 mutations. Statistical analysis was based on the following tests: chi‐square, Student's t, Pearson correlation, Spearman's rho, and Mann–Whitney; ROC and Kaplan–Meier curves were constructed. A significant increase was observed between grades for expression of total and phosphorylated 4E‐BP1 and for eIF4E, Ki67, EGFR, and cyclin D1. Although expression of EGFR, eIF4E, and Ki67 correlated with survival, only peIF4E was an independent predictor of survival in the multivariate analysis. Combining the evaluation of different proteins enables us to generate helpful diagnostic nomograms. In conclusion, cell signaling pathways are activated in DIAs; peIF4E is an independent prognostic factor and a promising therapeutic target. Joint analysis of the expression of 4E‐BP1 and peIF4E could be helpful in the diagnosis of glioblastoma multiforme in small biopsy samples.

Introduction Tumor-associated status epilepticus (TASE) follows a relatively benign course compared with SE in the general population. Little, however, is known about associated prognostic factors. Methods We conducted a prospective, observational study of all cases of TASE treated at a tertiary hospital in Barcelona, Spain between May 2011 and May 2019. We collected data on tumor and SE characteristics and baseline functional status and analyzed associations with outcomes at discharge and 1-year follow-up. Results Eighty-two patients were studied; 58.5% (n = 48) had an aggressive tumor (glioblastoma or brain metastasis). Fifty-one patients (62.2%) had a favorable outcome at discharge compared with just 30 patients (25.8%) at 1-year follow-up. Fourteen patients (17.1%) died during hospitalization. Lateralized period discharges (LPDs) on the baseline electroencephalography (EEG), presence of metastasis, and SE severity were significantly associated with a worse outcome at discharge. The independent predictors of poor prognosis at 1-year follow-up were SE duration of at least 21 h, an aggressive brain tumor, and a nonsurgical treatment before SE onset. Lateralized period discharges, super-refractory SE, and an aggressive tumor type were independently associated with increased mortality. Conclusions Status epilepticus duration is the main modifiable factor associated with poor prognosis at 1-year follow-up. Accordingly, patients with TASE, like those with SE of any etiology, should receive early, aggressive treatment.

Patients with glioblastoma currently do not sufficiently benefit from recent breakthroughs in cancer treatment that use checkpoint inhibitors1,2. For treatments using checkpoint inhibitors to be successful, a high mutational load and responses to neoepitopes are thought to be essential3. There is limited intratumoural infiltration of immune cells4 in glioblastoma and these tumours contain only 30–50 non-synonymous mutations5. Exploitation of the full repertoire of tumour antigens—that is, both unmutated antigens and neoepitopes—may offer more effective immunotherapies, especially for tumours with a low mutational load. Here, in the phase I trial GAPVAC-101 of the Glioma Actively Personalized Vaccine Consortium (GAPVAC), we integrated highly individualized vaccinations with both types of tumour antigens into standard care to optimally exploit the limited target space for patients with newly diagnosed glioblastoma. Fifteen patients with glioblastomas positive for human leukocyte antigen (HLA)-A*02:01 or HLA-A*24:02 were treated with a vaccine (APVAC1) derived from a premanufactured library of unmutated antigens followed by treatment with APVAC2, which preferentially targeted neoepitopes. Personalization was based on mutations and analyses of the transcriptomes and immunopeptidomes of the individual tumours. The GAPVAC approach was feasible and vaccines that had poly-ICLC (polyriboinosinic-polyribocytidylic acid-poly-l-lysine carboxymethylcellulose) and granulocyte–macrophage colony-stimulating factor as adjuvants displayed favourable safety and strong immunogenicity. Unmutated APVAC1 antigens elicited sustained responses of central memory CD8+ T cells. APVAC2 induced predominantly CD4+ T cell responses of T helper 1 type against predicted neoepitopes.

The role of seizures and antiepileptic treatments associated with glioblastoma is a current topic of discussion. The objective of this study is to characterize and establish implications of epilepsy associated with glioblastoma.We retrospectively analyzed the medical history, focused on epileptic features of 134 histologically diagnosed glioblastoma over a period of 4 years.The sample group had an average age of 56 years and 66% were male. Complete tumor resection was performed in 66% and 64.2% received further radio-oncologic treatment. The average survival rate was 12.4 months and 11.5% survived to 5 years. Epileptic seizures were the presentation symptom in 27% of cases and 51% suffered seizures during the disease, 26% become drug-resistant. Focal evolving to a bilateral convulsive seizures were the most frequent type. Epileptic seizures at presentation independently predicted longer survival (p0.001). Furthermore, a history of epilepsy or seizures during disease improved survival. Late onset seizures, recurrences or status epilepticus during the course of the disease indicated tumor progression or the final stages of life. Prophylactic antiepileptic drugs did not prevent seizures. Similarly, there was no difference in survival between patients who did not use antiepileptic drugs and those using valproate or levetiracetam. Patients under 60 years, full oncologic treatment and secondary glioblastomas were factors that improved survival (p0.001).Previous history of epilepsy or the onset of seizures as a presentation symptom in glioblastomas predict longer survival. Half of patients have seizures during the course of the disease. Antiepileptic drugs alone do not increase survival in glioblastoma patients.

Objective [11C] methionine (MET) positron-emission tomography (PET) is a useful diagnostic and therapeutic tool in neuro-oncology. The aim of this study was to evaluate the relationship between MET uptake and the histopathological grade in both primary brain tumours and brain metastases. A secondary goal was to assess the relationship between MET uptake and patients’ survival after surgery. Methods We reviewed a consecutive series of 43 PET studies performed at our institution. Out of the 43 patients studied, 35 harboured primary brain tumours (3 grade I, 12 grade II, 7 grade III and 13 grade IV) and 8 patients had brain metastases. We measured the tumour/cortex ratio (T/C ratio) on each PET study and we investigated the correlations among the tracer uptake, tumour grade, tumour type, MRI parameters and outcome. Results The mean T/C ratio was 1.8 ± 0.9 for benign lesions and low grade gliomas (grade I and II) and 2.7 ± 1 for high grade gliomas (grade III and IV). In brain metastases it was 2.5 ± 0.7, with a significant difference in MET uptake between low and high grades gliomas (P = 0.03). There was no statistically significant difference among all different histologic types. We found that both contrast enhancement and perfusion studies correlate with MET uptake in brain tumours. Moreover, in Kaplan–Meier curves, the T/C ratio adversely affects long term survival in patients with brain tumours (P = 0.01). Conclusions MET PET appears to be useful in diagnosis and evaluation of potential malignancy in brain tumours. MET uptake is also related with the overall survival in patients with brain tumours. Nevertheless, further studies are needed in order to define its possible clinical implications in identifying patients at high risk of tumour progression or resistance to therapy.

This paper describes a method to grade gliomas examined by magnetic resonance imaging. It is a preliminary study focused only on the features extracted from susceptibility-weighted images. The proposed method involves fusion of classifiers based on decision trees designed using fuzzy techniques. The favorable results indicate that the fuzzy approach may be of particular value for grading gliomas.

Purpose: Diffuse gliomas are the most common primary tumor of the brain and include different subtypes with diverse prognosis. The genomic characterization of diffuse gliomas facilitates their molecular diagnosis. The anatomical localization of diffuse gliomas complicates access to tumor specimens for diagnosis, in some cases incurring high-risk surgical procedures and stereotactic biopsies. Recently, cell-free circulating tumor DNA (ctDNA) has been identified in the cerebrospinal fluid (CSF) of patients with brain malignancies. Experimental Design: We performed an analysis of IDH1, IDH2, TP53, TERT, ATRX, H3F3A, and HIST1H3B gene mutations in two tumor cohorts from The Cancer Genome Atlas (TCGA) including 648 diffuse gliomas. We also performed targeted exome sequencing and droplet digital PCR (ddPCR) analysis of these seven genes in 20 clinical tumor specimens and CSF from glioma patients and performed a histopathologic characterization of the tumors. Results: Analysis of the mutational status of the IDH1, IDH2, TP53, TERT, ATRX, H3F3A, and HIST1H3B genes allowed the classification of 79% of the 648 diffuse gliomas analyzed, into IDH-wild-type glioblastoma, IDH-mutant glioblastoma/diffuse astrocytoma and oligodendroglioma, each subtype exhibiting diverse median overall survival (1.1, 6.7, and 11.2 years, respectively). We developed a sequencing platform to simultaneously and rapidly genotype these seven genes in CSF ctDNA allowing the subclassification of diffuse gliomas. Conclusions: The genomic analysis of IDH1, IDH2, TP53, ATRX, TERT, H3F3A, and HIST1H3B gene mutations in CSF ctDNA facilitates the diagnosis of diffuse gliomas in a timely manner to support the surgical and clinical management of these patients. Clin Cancer Res; 24(12); 2812–9. ©2018 AACR.

A case of a non-traumatic giant aneurysm of the middle meningeal artery is presented in a 59-year-old patient with a history of liver transplantation, liver cirrhosis and hepatocarcinoma, chronic renal disease, hypertension and chronic bronchitis who presented with tonic-clonic seizures. CT and MRI showed a lesion suggestive of metastasis without ruling out a glial type tumor. He was operated through a left FT craniotomy. During the surgery there was an arterial hemorrhage. The histological sample oriented toward an aneurysmal origin that was confirmed with ARM and angiography. A second intervention allowed the removal of a giant middle meningeal aneurysm partially thrombosed. Aneurysms of the middle meningeal artery are rare and generally present a traumatic history. No case of giant aneurysm has been found in the medical literature.

Objectives Lacosamide is an antiepileptic drug (AED), which has proven to be effective to control seizures, including acute conditions such as status epilepticus. The aim of this study is to describe the clinical experience with lacosamide in neuro-oncological patients. Materials and methods Multicenter retrospective study in patients with cancer-related seizures, who received lacosamide as an add-on therapy. Results Forty-eight patients with benign and malignant tumors, including primary brain tumors, lymphomas, systemic cancer with central nervous system involvement, or paraneoplastic encephalitis, were included. Lacosamide was effective in the control of chronic seizures in patients with either benign or malignant tumors. The success rate was greater in malignant tumors, and drug-resistant epilepsies were more likely associated with benign tumors. Adverse events occurred in nearly 70% of patients, particularly in acute conditions and associated with the concomitant use of radio-/chemotherapy. Lacosamide-related adverse events were more likely somnolence and dizziness, which usually resolved after dose adjustment. After starting lacosamide, nearly half of the patients discontinued one of the baseline AEDs and decreased or discontinued dexamethasone. Fifteen patients with status epilepticus were treated with intravenous lacosamide, and 73% of them had their condition resolved without serious drug-related adverse events. Conclusion Lacosamide is an AED to consider in cases of cancer-related seizures. Lacosamide pharmacodynamics and pharmacokinetics allow the achievement of responder rates over 50% with no serious adverse effects, amelioration of side effects from other AEDs or radio-/chemotherapy, and no significant drug interactions. Furthermore, the intravenous formulation shows clear benefits in acute conditions such as status epilepticus.

Background: Myxopapillary ependimoma (MPE) is a benign slow-growing tumor, and it has been designated histologically as a Grade I neoplasm according to the 2016 World Health Organization classification. Despite the benign character, dissemination and metastasis have occasionally been reported. The retrograde dissemination to other levels of the neuraxis is extremely rare, being more frequent to the intracranial compartment. Case Description: We hereby present a case of medullary metastasis of cauda equina MPE, with a history of having undergone a subtotal resection and postoperative adjuvant radiotherapy. The patient presents complaints of night dorsal pain attributable to intradural metastasis twenty-one years after the first surgical intervention. Conclusion: The case reported highlights the importance of long follow-up in patients with MPE, since the possibility of secondary seeding to distant craniospinal sites or local spinal sites after surgery, and radiotherapy should be considered in metastatic disease.

Resumen: Introducción: La exploración de las pupilas constituye una parte fundamental de la exploración neurológica. El tamaño y la reactividad a la luz de ambas pupilas deben registrarse de forma individual y periódica, dado que una alteración en estos parámetros puede constituir el único signo detectable de deterioro neurológico en determinados pacientes. Sin embargo, existe una gran variabilidad intra-observadores e inter-observadores al analizar estos parámetros, debido a la influencia de una serie de factores tales como la variabilidad en la luz ambiental, la agudeza visual y experiencia del propio observador, intensidad del estímulo luminoso y el método utilizado para dirigir este estímulo.En los últimos años las cámaras digitales han incorporado dispositivos de infrarrojos que han permitido desarrollar equipos digitales portátiles y de fácil manejo, que permiten realizar estudios repetidos y no invasivos del tamaño y reactividad pupilar a la luz con un método objetivo, accesible y económico. Desarrollo: El objetivo de esta revisión es describir los fundamentos de la pupilometría por infrarrojos y discutir sus posibles aplicaciones en la monitorización del paciente neurocrítico. En esta revisión también se incluyen una serie de recomendaciones metodológicas a considerar en la exploración de las pupilas. Conclusiones: La posibilidad de evaluar los cambios en la reactividad pupilar de forma precoz, objetiva y quasi-continua aporta un nuevo método de monitorización no invasivo que podría mejorar el factor predictivo del deterioro neurológico y monitorizar el estado neurológico a la cabecera del paciente, evitando así exámenes innecesarios y permitiendo intervenciones terapéuticas precoces. Abstract: Introduction: Pupil assessment is a fundamental part of the neurological examination. Size and reactivity to light of each pupil should be recorded periodically since changes in these parameters may represent the only detectable sign of neurological deterioration in some patients. However, there is great intraobserver and interobserver variability in pupil examination due to the influence of many factors, such as the difference in ambient lighting, the visual acuity and experience of the examiner, the intensity of the luminous stimulus, and the method used to direct this stimulus.In recent years, digital cameras have incorporated infrared devices allowing the development of user-friendly portable devices that permit repeated, non-invasive examinations of pupil size and its reactivity to light with an objective, accessible and inexpensive method. Development: The purpose of this review is to describe the fundamentals of infrared pupillometry and discuss potential applications in the monitoring of neurocritical patients. We also present some recommendations in the routine assessment of pupils in neurocritical patients. Conclusions: The possibility of evaluating the changes in pupil reactivity in an early, objective and almost continuous way provides a new non-invasive monitoring method. This method could improve the predictive factor of neurological deterioration and the bedside monitoring of the neurological state of the patient, avoiding unnecessary examinations and enabling early therapeutic intervention. Palabras clave: Neuromonitorización, Neuroworsening, Pupilas, Pupilometría infrarroja, Pupilómetro, Valoración pupilar, Keywords: Infrared pupillometry, Neuro-monitoring, Neuro-deterioration, Pupillometer, Pupil assessment, Pupils

Introduction: Pupil assessment is a fundamental part of the neurological examination. Size and reactivity to light of each pupil should be recorded periodically since changes in these parameters may represent the only detectable sign of neurological deterioration in some patients. However, there is great intraobserver and interobserver variability in pupil examination due to the influence of many factors, such as the difference in ambient lighting, the visual acuity and experience of the examiner, the intensity of the luminous stimulus, and the method used to direct this stimulus.In recent years, digital cameras have incorporated infrared devices allowing the development of user-friendly portable devices that permit repeated, non-invasive examinations of pupil size and its reactivity to light with an objective, accessible and inexpensive method. Development: The purpose of this review is to describe the fundamentals of infrared pupillometry and discuss potential applications in the monitoring of neurocritical patients. We also present some recommendations in the routine assessment of pupils in neurocritical patients. Conclusions: The possibility of evaluating the changes in pupil reactivity in an early, objective and almost continuous way provides a new non-invasive monitoring method. This method could improve the predictive factor of neurological deterioration and the bedside monitoring of the neurological state of the patient, avoiding unnecessary examinations and enabling early therapeutic intervention. Resumen: Introducción: La exploración de las pupilas constituye una parte fundamental de la exploración neurológica. El tamaño y la reactividad a la luz de ambas pupilas deben registrarse de forma individual y periódica, dado que una alteración en estos parámetros puede constituir el único signo detectable de deterioro neurológico en determinados pacientes. Sin embargo, existe una gran variabilidad intra-observadores e inter-observadores al analizar estos parámetros, debido a la influencia de una serie de factores tales como la variabilidad en la luz ambiental, la agudeza visual y experiencia del propio observador, intensidad del estímulo luminoso y el método utilizado para dirigir este estímulo.En los últimos años las cámaras digitales han incorporado dispositivos de infrarrojos que han permitido desarrollar equipos digitales portátiles y de fácil manejo, que permiten realizar estudios repetidos y no invasivos del tamaño y reactividad pupilar a la luz con un método objetivo, accesible y económico. Desarrollo: El objetivo de esta revisión es describir los fundamentos de la pupilometría por infrarrojos y discutir sus posibles aplicaciones en la monitorización del paciente neurocrítico. En esta revisión también se incluyen una serie de recomendaciones metodológicas a considerar en la exploración de las pupilas. Conclusiones: La posibilidad de evaluar los cambios en la reactividad pupilar de forma precoz, objetiva y quasi-continua aporta un nuevo método de monitorización no invasivo que podría mejorar el factor predictivo del deterioro neurológico y monitorizar el estado neurológico a la cabecera del paciente, evitando así exámenes innecesarios y permitiendo intervenciones terapéuticas precoces. Keywords: Infrared pupillometry, Neuro-monitoring, Neuro-deterioration, Pupillometer, Pupil assessment, Pupils, Palabras clave: Neuromonitorización, Neuroworsening, Pupilas, Pupilometría infrarroja, Pupilómetro, Valoración pupilar

Resumen: Introducción: Los traumatismos craneoencefálicos leves (TCE-L) han sido tradicionalmente considerados acontecimientos sin repercusiones cerebrales significativas, cuya sintomatología remite espontáneamente en unos días. Sin embargo, estos hechos son cada vez más cuestionados. Este estudio pretende objetivar la existencia de alteraciones cognitivas precoces en una serie de pacientes con TCE-L y relacionar los hallazgos con distintos marcadores de lesión cerebral. Métodos: Estudio prospectivo de una cohorte de pacientes con un TCE-L valorados de forma consecutiva durante 12 meses. De un total de 1.144 pacientes, se seleccionó a 41 (3,7%) que habían presentado una conmoción cerebral. Además de la valoración clínica habitual y de la práctica de una tomografía computarizada (TC) cerebral, los pacientes fueron estudiados mediante un test estandarizado para síntomas posconmocionales en las primeras 24 h después del TCE-L y al cabo de 1-2 semanas y, coincidiendo con la segunda valoración, mediante una batería neuropsicológica. Los resultados se compararon con los de un grupo de 28 voluntarios sanos de características parecidas. En 20 pacientes se practicó una resonancia magnética (RM) craneal. Resultados: En este análisis exploratorio, la memoria y el aprendizaje verbal fueron las funciones cognitivas más afectadas después del TCE-L. Siete de los 20 pacientes con TC cerebral normal presentaron alteraciones estructurales visibles por RM, que en 2 casos fueron compatibles con la presencia de lesión axonal difusa. Conclusiones: Los resultados de este estudio piloto sugieren la presencia de alteraciones cognitivas precoces y lesiones cerebrales estructurales en un porcentaje no despreciable de pacientes que han presentado una conmoción cerebral recuperada después de un TCE-L. Abstract: Introduction: Mild traumatic brain injury (mTBI) has traditionally been considered to cause no significant brain damage since symptoms spontaneously remit after a few days. However, this idea is facing increasing scrutiny. The purpose of this study is to demonstrate the presence of early cognitive alterations in a series of patients with mTBI and to link these findings to different markers of brain damage. Methods: We conducted a prospective study of a consecutive series of patients with mTBI who were evaluated over a 12-month period. Forty-one (3.7%) of the 1144 included patients had experienced a concussion. Patients underwent a routine clinical evaluation and a brain computed tomography (CT) scan, and were also administered a standardised test for post-concussion symptoms within the first 24 hours of mTBI and also 1 to 2 weeks later. The second assessment also included a neuropsychological test battery. The results of these studies were compared to those of a control group of 28 healthy volunteers with similar characteristics. Twenty patients underwent an MRI scan. Results: Verbal memory and learning were the cognitive functions most affected by mTBI. Seven out of the 20 patients with normal CT findings displayed structural alterations on MR images, which were compatible with diffuse axonal injury in 2 cases. Conclusions: Results from this pilot study suggest that early cognitive alterations and structural brain lesions affect a considerable percentage of patients with post-concussion syndrome following mTBI. Palabras clave: Traumatismo craneoencefálico leve, Déficits neuropsicológicos, Lesión axonal difusa, Sport Concussion Assessment Tool 2, Susceptibility weighted imaging, Síndrome posconmocional, Keywords: Mild traumatic brain injury, Neuropsychological alterations, Diffuse axonal injury, Sport Concussion Assessment Tool 2, Susceptibility-weighted imaging, Post-concussion syndrome

Combined pleomorphic xanthoastrocytoma (PXA) and ganglioglioma (GG) is an extremely rare tumor, with fewer than 20 cases reported. The authors report a case of combined PXA-GG in an 18-year-old man with a history of seizures. The tumor showed necrosis and the BRAF V600E mutation on histological examination, with no evidence of tumor recurrence 1 year after gross-total resection. The BRAF V600E mutation was present, which suggests that both cell lineages may share a common cellular origin.

Cancer immunotherapy to gliomas has so far failed to show encouraging results, as gliomas are rarely mutated and show various mechanisms of immune escape. To improve therapy to these type of cancer, the Glioma Actively Personalized Vaccine Consortium (GAPVAC) integrated a highly personalized peptide vaccine approach into glioblastoma standard of care treatment combining neoepitope and nonmutated tumor antigens to exploit the full repertoire of tumor antigens. In this phase I clinical trial fifteen patients received two different types of personalized peptide vaccines (APVAC1 and APVAC2), that were selected based on transcriptome, immunopeptidome and mutational analysis of the patient’s individual tumors. While APVAC1 vaccines were composed of nonmutated tumor antigens selected in a warehouse-based approach, APVAC2 vaccines primarily targeted neoepitopes. Both vaccines were used in combination with poly-ICLC and GM-CSF as adjuvants and demonstrated expected safety profile and outstanding Immunogenicity. Immunomonitoring of APVAC1 peptides was carried out using a combinatorial ex vivo Class I 2D multimer (2DMM) and Class II intracellular cytokine staining (ICS) assay with an outstanding sensitivity to detect even one peptide-specific cell in one million of CD4 or CD8 T-cells. Nonmutated APVAC1 class I peptides showed induction of persistent CD8 T-cell responses, mainly consisting of a highly favorable central memory phenotype (CM). Furthermore, APVAC1 class II peptides demonstrated induction of polyfunctional CD4 T-cells predominantly of a type 1 T helper cell (TH1) phenotype. Notably, an APVAC1 class II specific T-cell response was detected in tumor-infiltrating lymphocyte (TIL) fraction obtained from resection of one patient. On the other side, immune responses to APVAC2 peptides were analyzed using a pan-ICS assay including a single in vitro sensitization step to analyze a broad array of cytokines produced by CD4 T helper (TH) cells and CD8 CTLs in parallel. APVAC2 peptides showed excellent immunogenicity and induced potent and multifunctional CD4 T-cell responses, mostly of a TH1 phenotype that often concurred with CTL responses. Furthermore, the induction of APVAC1-specific CD8 memory cells, as a marker for the potency of the vaccine-induced immune responses, reversely correlated with the baseline frequencies of regulatory T-cells (Treg). Taken together, actively personalized peptide vaccines (APVACs) were highly immunogenic and induced sustained responses of a highly favorable CD4 and CD8 T-cell phenotype. The vaccination showed the expected safety profile and the approach was feasible, even in this highly individualized setting. Therefore, the APVAC vaccination approach clearly represents a step forward on the path to bring the benefit of immunotherapy to glioblastoma patients. Citation Format: Alexander Ulges, Norbert Hilf, Wolfgang Wick, Michael Platten, Pierre-Yves Dietrich, Katrin Frenzel, Arie Admon, Sjoerd S.H. van der Burg, Andreas von Deimling, Per thor Straten, Cecile Gouttefangeas, Judith R. Kroep, Francisco Martínez-Ricarte, Hideo Okada, Christian H. Ottensmeier, Berta Ponsati, Hans S. Poulsen, Stefan Stevanovic, Ghazaleh Tabatabai, Hans-Georg Rammensee, Ugur Sahin, Dominik Maurer, Regina Mendrzyk. Immunomonitoring for actively personalized peptide vaccines (APVACs) during immunotherapeutic treatment of glioblastoma [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr A020.

SummaryGlioma-initiating cells (GICs), also called glioma stem cells, are responsible for tumor initiation, relapse, and therapeutic resistance. Here, we show that TGF-β inhibitors, currently under clinical development, target the GIC compartment in human glioblastoma (GBM) patients. Using patient-derived specimens, we have determined the gene responses to TGF-β inhibition, which include inhibitors of DNA-binding protein (Id)-1 and -3 transcription factors. We have identified a cell population enriched for GICs that expresses high levels of CD44 and Id1 and tend to be located in a perivascular niche. The inhibition of the TGF-β pathway decreases the CD44high/Id1high GIC population through the repression of Id1 and Id3 levels, therefore inhibiting the capacity of cells to initiate tumors. High CD44 and Id1 levels confer poor prognosis in GBM patients.

BACKGROUND: There is a need for treatment personalization as every cancer is molecularly unique. In addition glioblastoma (GB) are immunologically regarded as resistant, cold tumor with few targetable antigens available from mutations, thus demanding new personalized immunotherapies. So far outside Neuro-Oncology, T cells orchestrate impressive anti-tumor effects with checkpoint inhibitors, but also vaccines. METHODS: The GAPVAC consortium established an immunotherapy, for which personalized selection of 2 peptide-based actively personalized vaccines (APVAC) per patient for treatment of newly diagnosed GB was based not only on whole-exome sequencing but also on human leukocyte antigen (HLA)-ligandome analyses providing insight into the actual presentation of relevant epitopes in the tumor. GAPVAC-101 (NCT02149225) enrolled 16 patients in a European phase I feasibility, safety and immunogenicity trial integrated into standard of care. For APVAC1, up to 7 peptides were selected from a trial specific warehouse based on individual biomarker data. Vaccination (i.d.) with GM-CSF and poly-ICLC in 15 patients started with the 1st adjuvant cycle of temozolomide (TMZ). For APVAC2, analyses revealed a median of 36 somatic, non-synonymous mutations in the patients tumors. From the 4th TMZ cycle, 11 patients received APVAC2 with usually 2 de novo antigens per patient selected according to mutation, actual or putative HLA presentation and immunogenicity. Overall 20 APVAC2 antigens incl. 14 mutated were vaccinated. RESULTS: Adverse events were largely reversible injection site reactions and two anaphylactic reactions and one increase in cerebral edema. Short, non-mutated APVAC1 antigens induced sustained CD8 responses with memory phenotype. Mutated APVAC2 antigens induced predominantly CD4 responses of favorable TH1 type. Median PFS and OS were 14.2 and 29 months from diagnosis, respectively, in patients that received 1 APVAC vaccination (N=15). CONCLUSION: Overall, GAPVAC displayed expected safety profiles and high biological activity indicating further development.

BACKGROUND: There is a need for treatment personalization as every cancer is molecularly unique. In addition glioblastoma (GB) are immunologically regarded as resistant, “cold” tumor with few targetable antigens available from mutations, thus demanding new personalized immunotherapies. So far outside Neuro-Oncology, T cells orchestrate impressive anti-tumor effects with checkpoint inhibitors, but also vaccines. MATERIAL AND METHODS: The GAPVAC consortium established an immunotherapy, for which personalized selection of 2 peptide-based actively personalized vaccines (APVAC) per patient for treatment of newly diagnosed GB was based not only on whole-exome sequencing but also on human leukocyte antigen (HLA)-ligandome analyses providing insight into the actual presentation of relevant epitopes in the tumor. GAPVAC-101 (NCT02149225) enrolled 16 patients in a European phase I feasibility, safety and immunogenicity trial integrated into standard of care. For APVAC1, up to 7 peptides were selected from a trial specific warehouse based on individual biomarker data. Vaccination (i.d.) with GM-CSF and poly-ICLC in 15 patients started with the 1(st) adjuvant cycle of temozolomide (TMZ). For APVAC2, analyses revealed a median of 36 somatic, non-synonymous mutations in the patients’ tumors. From the 4(th) TMZ cycle, 11 patients received APVAC2 with usually 2 de novo antigens per patient selected according to mutation, actual or putative HLA presentation and immunogenicity. Overall 20 APVAC2 antigens incl. 14 mutated were vaccinated. RESULTS: Adverse events were largely reversible injection site reactions and two anaphylactic reactions and one increase in cerebral edema. Short, non-mutated APVAC1 antigens induced sustained CD8 responses with memory phenotype. Mutated APVAC2 antigens induced predominantly CD4 responses of favorable TH1 type. Median PFS and OS were 14.2 and 29 months from diagnosis, respectively, in patients that received ≥1 APVAC vaccination (N=15). CONCLUSION: Overall, GAPVAC displayed expected safety profiles and high biological activity indicating further development.

2000Background: The need for treatment personalization is obvious as every cancer is molecularly unique. In addition glioblastoma (GB) are immunologically regarded as resistant, “cold” tumor with f...

Resumen Introduccion A pesar de los avances cientificos y tecnicos de los ultimos anos, la hemorragia subaracnoidea aneurismatica (HSAa) sigue presentando una alta morbilidad y mortalidad. Este hecho, junto con los impresionantes resultados de la craneotomia descompresiva primaria (CDP) en el infarto maligno de la arteria cerebral media sugiere la posibilidad que la CDP sea una alternativa terapeutica a considerar en algunos pacientes con una HSAa. Presentamos nuestra experiencia de un estudio piloto en el que se utilizo la CDP en pacientes con HSAa en mal grado neurologico y hematoma intracerebral asociado. Pacientes y metodos Entre el 1 de marzo de 2002 y el 31 de abril de 2008, se trataron 342 pacientes con HSAa en nuestro hospital. De estos, 64 tenian una puntuacion de 4 o 5 de la escala de la WFNS (World Federation of Neurosurgical Societies). En el presente estudio prospectivo se analizan 11 pacientes en los que se realizo una CDP durante la misma cirugia de clipaje o/y evacuacion del hematoma asociado. Resultados En tres pacientes la CDP se realizo despues del tratamiento endovascular del aneurisma debido a la necesidad de evacuar el hematoma asociado. En los ocho pacientes restantes, la CDP se realizo durante el clipaje y la evacuacion del hematoma asociado. La evaluacion de los resultados de estos once pacientes se llevo a cabo al ano de la cirugia mediante la escala de resultados de Glasgow. La CDP fue eficaz en el control de presion intracraneal en los pacientes que sobrevivieron. Seis pacientes sobrevivieron, cuatro de ellos con un buen resultado neurologico. Sin embargo, dos de estos seis pacientes tuvieron un resultado desfavorable. De los cinco pacientes que no sobrevivieron, un paciente murio a causa de un hematoma subgalealepidural diferido como complicacion de la CDP, y los restantes cuatro pacientes fallecieron a causa de una hipertension intracraneal refractaria. Conclusiones La CDP puede ser una alternativa terapeutica en un grupo seleccionado de pacientes con HSAa con mal grado neurologico. Sin embargo, en la actualidad hay una falta de evidencia para apoyar unas recomendaciones claras para su uso.

Object Continuous intracranial pressure (ICP) monitoring using an epidural sensor is a common technique used in selected neurosurgical patients. The aim of this study was to assess the safety and accuracy of the Neurodur-P epidural sensor in the clinical setting. Methods The zero drift, as well as the medical and technical complications, of using the Neurodur-P sensor placed in the epidural space was evaluated in 106 patients with hydrocephalus of varying causes or with suspected intracranial hypertension. Results The median duration of ICP monitoring was 8 days (interquartile range [IQR] 6–12 days). In 78 (73.6%) of the 106 patients the pressure reading was recorded at sensor removal. No zero drift was observed in 28 sensors. The median drift was 0 mm Hg with an IQR of −1 to 1 mm Hg. No significant differences were found between patients monitored for ≤ 5 days and those monitored for > 5 days (t = 535, p = 0.100). No correlation was found between zero drift and monitoring time (r = 0.153, p = 0.181). Of the 83 patients with a follow-up computed tomography scan, 3 showed a < 1 ml collection of blood at the catheter tip. No clinical infections could be attributed to the devices. Only 1 sensor malfunctioned. Conclusions Continuous ICP monitoring using the Neurodur-P sensor is safe, reliable, and easy to perform. At present, using this device is the authors' standard method for the long-term monitoring of patients with alterations in complex cerebrospinal fluid dynamics or with implanted shunts.

Cell-free circulating tumour DNA (ctDNA) in plasma has been shown to be informative of the genomic alterations present in tumours and has been used to monitor tumour progression and response to treatments. However, patients with brain tumours do not present with or present with low amounts of ctDNA in plasma precluding the genomic characterization of brain cancer through plasma ctDNA. Here we show that ctDNA derived from central nervous system tumours is more abundantly present in the cerebrospinal fluid (CSF) than in plasma. Massively parallel sequencing of CSF ctDNA more comprehensively characterizes the genomic alterations of brain tumours than plasma, allowing the identification of actionable brain tumour somatic mutations. We show that CSF ctDNA levels longitudinally fluctuate in time and follow the changes in brain tumour burden providing biomarkers to monitor brain malignancies. Moreover, CSF ctDNA is shown to facilitate and complement the diagnosis of leptomeningeal carcinomatosis., DNA circulating in the plasma of cancer patients carries features of the primary tumour, however such DNA is found in low levels in brain cancer patients. Here, the authors show that circulating tumour DNA can be detected in the cerebral spinal fluid of cancer patients and that this better recapitulates the primary tumour compared to DNA from the plasma.

Introduction In children, deviations from the normal range of head circumference (HC) have traditionally been related with CSF dynamics abnormalities. In adults, this neglected parameter is helpful in the diagnosis and understanding of the pathophysiology of some CSF abnormalities. It has been demonstrated that HC is related to height. Because humans have increased in stature dramatically during the last 50 years, pediatric charts for head growth physiology and normal HC values in adults should be reevaluated. Objectives The main aim of the present study was to assess HC in a series of 270 normal healthy Spanish adults and to determine any differences between sexes and age groups. A secondary aim was to discuss the relevance of this parameter in the management of hydrocephalus in adult people. Methods HC measurements were taken using a measuring tape placed over the greatest frontal and occipital protuberances. The reference interval and the upper and lower thresholds for HC were calculated by 3 different methods: normal distribution, the non-parametrical percentile method, and the “robust method”. Results The results were consistent and showed that Spanish adult men with a HC greater than 60 cm, and Spanish adult women with a HC greater than 58 cm should be considered macrocephalic. Microcephaly should be considered when HC is 53.6 cm in men and 51.3 cm in women. Adult age groups of either sex do not present any statistically significant differences in HC. Conclusions HC obtained in Spanish adult people are greater than those reported in the classical Nellhaus graphs in both men and women aged 18. These findings should be considered in the management of hydrocephalus in adults today.

The results of the multicentre, randomized, controlled trial to test the effectiveness of decompressive craniectomy in adults with traumatic brain injury and high intracranial pressure (Decompressive Craniectomy, DECRA) were published in 2011. DECRA concluded that decompressive craniectomy decreased intracranial pressure (ICP) but was associated with more unfavourable outcomes. Our review aims to put the DECRA trial into context, comment on its findings and discuss whether we should include decompressive craniectomy in our clinical armamentarium.The key message that DECRA conveys is that decompressive craniectomy significantly lowers ICP and shortens the length of the stay in the ICU. However, neither mortality nor unfavourable outcome was reduced when adjusting the significant baseline covariates.The claim that decompressive craniectomy increases unfavourable outcome is overstated and not supported by the data presented in DECRA. We believe it premature to change clinical practice. Given the dismal outcome in these patients, it is reasonable to include this technique as a last resort in any type of protocol-driven management when conventional therapeutic measures have failed to control ICP, the presence of operable masses has been ruled out and the patient may still have a chance of a functional outcome. The main lesson to be learned from this study is that an upper threshold for ICP must be used as a cut-off for selecting decompressive craniectomy candidates.

The Glioma Actively Personalized Vaccine Consortium (GAPVAC; funded by the European Union Framework 7 Program) aims at treating newly diagnosed glioblastoma (GB) patients with two distinct actively personalized vaccines (APVACs). Resected tumor material is analyzed for multiple biomarkers to characterize the tumor in depth and to enable the design of APVACs tailored to each individual patient: Tumor-specific mutations, the HLA peptidome and gene expression profile are assessed by next-generation sequencing, mass spectrometry and RNA microarray analysis, respectively. Further, the patient-individual immune status is investigated by assessment of leukapheresis samples utilizing an in vitro immunogenicity platform. Data are integrated to define two distinct APVACs for each patient: APVAC1 is composed of up to ten peptides selected from a pre-manufactured “warehouse”. The warehouse contains 59 HLA class I-binding and three class II-binding tumor-associated peptides frequently over-presented in GB. APVAC2 is composed of one or two peptides that are de novo synthesized for a given patient and preferentially represent mutation-bearing neo-epitopes. After a preparation phase in which the warehouse was generated and setup of APVAC selection and manufacturing processes took place, the GAPVAC-101 phase I clinical trial was initiated. Primary endpoints of the study are assessment of safety, feasibility of APVAC manufacturing and biological activity. The trial is conducted at six European centers and recruits HLA-A*02:01 or A*24:02-positive patients with newly diagnosed GB after gross total resection. Patients receive APVAC1 and APVAC2 vaccinations plus immunomodulators (poly-ICLC and GM-CSF) three and six months post study enrolment, respectively, and concurrent to maintenance temozolomide (TMZ). As of November 2015, 11 patients have been enrolled, of whom six already received APVAC vaccines. Composition and manufacturing are ongoing for four patients. All APVACs were generated in time without ultimate failures. APVAC1 vaccines differ substantially with 31 out of 59 warehouse peptides have been selected at least once, indicating the need for personalization due to tumor heterogeneity even for non-mutated epitopes. In patients’ tumor samples an average of 40 non-synonymous mutations (including known driver mutations) were identified. Injection site reactions were the most frequent toxicities so far. One brain edema (Grade 3) and one allergic reaction (Grade 4)were observed, both potentially related to the vaccinations. First data on biological activity of APVACs and updated clinical data will be presented at the Annual Meeting. In conclusion, the GAPVAC concept has been successfully translated into the clinics and so far demonstrated to be safe and feasible with its level of personalization matching the observed tumor heterogeneity. Citation Format: Norbert Hilf, Katrin Frenzel, Sabrina Kuttruff-Coqui, Sandra Heesch, Sebastian Kreiter, Arie Admon, Valesca Bukur, Sjoerd van der Burg, Cecile Gouttefangeas, Judith R. Kroep, Marij Schoenmaekers-Welters, Jordi Piro, Berta Ponsati, Hans Skovgaard Poulsen, Ulrik Lassen, Francisco Martinez-Ricarte, Jordi Rodon, Juan Sahuquillo, Monika Stieglbauer, Stefan Stevanovic, Per thor Straten, Marco Skardelly, Ghazaleh Tabatabai, Michael Platten, David Capper, Andreas von Deimling, Valérie Dutoit, Hideho Okada, Christian Ottensmeier, Randi Kristina Feist, Jens Fritsche, Karoline Laske, Peter Lewandrowski, Martin Löwer, Regina Mendryzk, Miriam Meyer, Carsten Reinhardt, Bernhard Rössler, Anna Paruzynski, Nina Pawlowski, Colette Song, Stevermann Lea, Toni Weinschenk, Christoph Huber, Hans-Georg Rammensee, Pierre-Yves Dietrich, Wick Wolfgang, Ugur Sahin, Harpreet Singh-Jasuja. GAPVAC-101 phase I trial: First data of an innovative actively personalized peptide vaccination trial in patients with newly diagnosed glioblastoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2654.