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Localized or isolated neurofibromas are peripheral nerve sheath tumors. They are rare in the orbit and occur without a systemic neurofibromatosis. There are few cases of bilateral tumors reported but none affecting both supraorbital and infraorbital nerves. We report a 45-year-old female who presented an extraconal mass in the right orbit as an incidental finding in a head computer tomography, without ocular symptoms. Magnetic resonance image showed a well-defined oval mass in the right supraorbital and infraorbital nerves, of similar characteristics, as well as smaller masses in the left supraorbital and infraorbital nerves. A progressive increase in size of the left supraorbital and infraorbital tumor motivated their surgical excision. The histological result was compatible with a neurofibroma. These uncommon orbital tumors are slow growing and affect the sensory nerves of the trigeminal nerve. Neurofibromas usually present progressive symptoms due to the orbital mass, proptosis, or visual changes although not in this case. Surgical removal is the only definitive treatment.

The brain is endowed with a unique cellular composition and organization, embedded within a vascular network and isolated from the circulating blood by a specialized frontier, the so-called blood-brain barrier (BBB), which is necessary for its proper function. Recent reports have shown that increments in the permeability of the blood vessels facilitates the entry of toxic components and immune cells to the brain parenchyma and alters the phenotype of the supporting astrocytes. All of these might contribute to the progression of different pathologies such as brain cancers or neurodegenerative diseases. Although it is well known that BBB breakdown occurs due to pericyte malfunctioning or to the lack of stability of the blood vessels, its participation in the diverse neural diseases needs further elucidation. This review summarizes what it is known about BBB structure and function and how its instability might trigger or promote neuronal degeneration and glioma progression, with a special focus on the role of pericytes as key modulators of the vasculature. Moreover, we will discuss some recent reports that highlights the participation of the BBB alterations in glioma growth. This pan-disease analysis might shed some light into these otherwise untreatable diseases and help to design better therapeutic approaches. Work was supported by Ministerio de Economía y Competitividad and FEDER funds: PI13/01258 to AHL, by “Asociación Española contra el Cancer (AECC) grant: INVES192GARG to RG and by Ministerio de Ciencia, Innovación y Universidades and FEDER funds: RTI2018-093596 to PSG. Sí

Cocaine consumption is associated with a variety of clinical manifestations. Though cocaine intranasal inhalation always determines nasal mucosal damages, extensive septum perforations, and midline destructions-known as cocaine-induced midline destructive lesions (CIMDL)-affect only a limited fraction of patients. CIMDL is viewed as a cocaine-associated autoimmune phenomenon in which the presence of atypical anti-neutrophil cytoplasmic antibody (ANCA) promotes and/or defines the disease phenotype. A 51-year-old man presented with an intracranial tumor-like lesion by its space-occupying effect. CT also revealed the destruction of the nasal septum and skull base. A diagnosis of CIMDL was made in light of the patient's history as well as findings of the physical and endoscopic examinations, imaging studies, and laboratory testing. There was no evidence of other pathologies. Histopathological results from cerebral biopsy led us to consider the intracranial pathology as an extension of the CIMDL. CIMDL is the result of a necrotizing inflammatory tissue response triggered by cocaine abuse in a subset of predisposed patients. The reported case is the first CIMDL consistent with brain extension mimicking a tumor-like lesion. While the presence of atypical ANCA seems to promote and/or define the disease phenotype, the specific role of these and other circulating autoantibodies needs further investigation.

Exercise intolerance is the most common phenotype in McArdle disease. Fixed weakness can be present in advanced ages, mainly affecting the shoulder girdle.

Some phase 2 trials had reported encouraging progression-free survival with Bevacizumab in monotherapy or combined with chemotherapy in glioblastoma. However, phase 3 trials showed a significant improvement in progression free survival without a benefit in overall survival. To date, there are no predictive biomarker of response for Bevacizumab in glioblastoma. We used Immunochemical analysis on tumor samples and pretreatment and post-treatment perfusion-MRI to try to identify possible predictive angiogenesis-related biomarkers of response and survival in patients with glioblastoma treated with bevacizumab in the first recurrence. We analyzed histological parameters: vascular proliferation, mitotic number and Ki-67 index; molecular factors: MGMT promoter methylation, EGFR amplification and EGFR variant III; immunohistochemical: MET, Midkine, HIF1, VEGFA, VEGF-R2, CD44, Olig2, microvascular area and microvascular density; and radiological: rCBV. In the statistical analysis, no significant correlation of any histological, molecular, microvascular or radiological parameters could be demonstrated with the response rate, PFS or OS with bevacizumab treatment. Unfortunately, in this histopathological, molecular, immunohistochemical and neuroradiological study we did not find any predictive biomarker of response or survival benefit for Bevacizumab in glioblastoma.

Background and purpose Our objectives were: (1) compare dynamic susceptibility-weighted (DSC) and dynamic contrast-enhanced (DCE) permeability parameters, (2) evaluate diagnostic accuracy of DSC and DCE discriminating high- and low-grade tumors, (3) analyze relationship of permeability parameters with overall (OS) and progression-free survival (PFS) and (4) assess differences in high-grade tumors classified according to molecular biomarkers. Materials and methods 49 patients with histologically proved diffuse gliomas underwent DSC and DCE imaging. Parametric maps of cerebral blood volume (CBV), CBV-leakage corrected, volume transfer coefficient (Ktrans), fractional volume of the extravascular extracellular space (EES) (Ve), fractional blood plasma volume (Vp) and rate constant between EES and blood plasma (Kep) were calculated. High-grade gliomas were also classified according to isocitrate dehydrogenase (IDH), alpha-thalassemia/mental retardation syndrome X-linked (ATRX) and O6-methylguanine-dna-methyltransferase promoter methylation (MGMT) status. Results There is correlation between parameters leakage, Ktrans and Vp. ROC curve analysis showed significance in both Ktrans and Ve for glioma grading. Threshold value of 0.075 for Ve generated the best combination of sensitivity (80%) and specificity (75%) in tumor gradation. Leakage was the only permeability parameter related to OS (P = 0.006) and PFS (0.012); with prolonged survival for leakage values lower than 1.2. IDH-mutated high-grade tumors showed lower leakage and Ktrans values. High-grade tumors with loss of ATRX presented lower leakage and Vp values. Conclusions Both DSC and DCE permeability parameters serve as non-invasive method for glioma grading. Leakage was the unique permeability parameter related to survival and the best discriminating high-grade gliomas classified according to IDH and ATRX status.

Striated muscle needs to maintain cellular homeostasis in adaptation to increases in physiological and metabolic demands. Failure to do so can result in rhabdomyolysis. The identification of novel genetic conditions associated with rhabdomyolysis helps to shed light on hitherto unrecognized homeostatic mechanisms. Here we report seven individuals in six families from different ethnic backgrounds with biallelic variants in MLIP, which encodes the muscular lamin A/C-interacting protein, MLIP. Patients presented with a consistent phenotype characterized by mild muscle weakness, exercise-induced muscle pain, variable susceptibility to episodes of rhabdomyolysis, and persistent basal elevated serum creatine kinase levels. The biallelic truncating variants were predicted to result in disruption of the nuclear localizing signal of MLIP. Additionally, reduced overall RNA expression levels of the predominant MLIP isoform were observed in patients’ skeletal muscle. Collectively, our data increase the understanding of the genetic landscape of rhabdomyolysis to now include MLIP as a novel disease gene in humans and solidifies MLIP’s role in normal and diseased skeletal muscle homeostasis.

Our goal was to analyze postmortem tissues of an adult patient with late-onset thymidine kinase 2 (TK2) deficiency who died of respiratory failure. Compared with control tissues, we found a low mtDNA content in the patient’s skeletal muscle, liver, kidney, small intestine, and particularly in the diaphragm, whereas heart and brain tissue showed normal mtDNA levels. mtDNA deletions were present in skeletal muscle and diaphragm. All tissues showed a low content of OXPHOS subunits, and this was especially evident in diaphragm, which also exhibited an abnormal protein profile, expression of non-muscular β-actin and loss of GAPDH and α-actin. MALDI-TOF/TOF mass spectrometry analysis demonstrated the loss of the enzyme fructose-bisphosphate aldolase, and enrichment for serum albumin in the patient’s diaphragm tissue. The TK2-deficient patient’s diaphragm showed a more profound loss of OXPHOS proteins, with lower levels of catalase, peroxiredoxin 6, cytosolic superoxide dismutase, p62 and the catalytic subunits of proteasome than diaphragms of ventilated controls. Strong overexpression of TK1 was observed in all tissues of the patient with diaphragm showing the highest levels. TK2 deficiency induces a more profound dysfunction of the diaphragm than of other tissues, which manifests as loss of OXPHOS and glycolytic proteins, sarcomeric components, antioxidants and overactivation of the TK1 salvage pathway that is not attributed to mechanical ventilation.

A 29-year-old man developed, since the age of 18, exercise intolerance and exercise-induced rhabdomyolysis, with myoglobinuria. Muscle biopsy showed ragged-red fibers. Multiple mitochondrial DNA deletions were detected. The previously reported pathogenic homozygous mutation c.323C>T (p.Thr108Met) in TK2 was identified. This case expands the phenotypic spectrum of TK2 deficiency and indicates that it should be considered in the differential diagnosis of episodic rhabdomyolysis and exercise intolerance, along with other metabolic and mitochondrial myopathies. Since a new treatment is under development, it is essential improving knowledge of the natural history of TK2 deficiency.

We present a 36-year-old female affected of ulcerative proctitis treated with rectal mesalazine and with no other pathological previous history...

[Background] TK2 gene encodes for mitochondrial thymidine kinase, which phosphorylates the pyrimidine nucleosides thymidine and deoxycytidine. Recessive mutations in the TK2 gene are responsible for the ‘myopathic form’ of the mitochondrial depletion/multiple deletions syndrome, with a wide spectrum of severity., [Methods] We describe 18 patients with mitochondrial myopathy due to mutations in the TK2 gene with absence of clinical symptoms until the age of 12., [Results] The mean age of onset was 31 years. The first symptom was muscle limb weakness in 10/18, eyelid ptosis in 6/18, and respiratory insufficiency in 2/18. All patients developed variable muscle weakness during the evolution of the disease. Half of patients presented difficulty in swallowing. All patients showed evidence of respiratory muscle weakness, with need for non-invasive Mechanical Ventilation in 12/18. Four patients had deceased, all of them due to respiratory insufficiency. We identified common radiological features in muscle magnetic resonance, where the most severely affected muscles were the gluteus maximus, semitendinosus and sartorius. On muscle biopsies typical signs of mitochondrial dysfunction were associated with dystrophic changes. All mutations identified were previously reported, being the most frequent the in-frame deletion p.Lys202del. All cases showed multiple mtDNA deletions but mtDNA depletion was present only in two patients., [Conclusions] The late-onset is the less frequent form of presentation of the TK2 deficiency and its natural history is not well known. Patients with late onset TK2 deficiency have a consistent and recognizable clinical phenotype and a poor prognosis, due to the high risk of early and progressive respiratory insufficiency., This work was supported by research grants of Plan Nacional de I + D + I and Instituto de Salud Carlos III (ISCIII), Subdirección General de Evaluación y Fomento de la Investigación Sanitaria”, project PI16–01843 (CP), PI16/00579 and CP09/00011 for CJM and the European Regional Development Fund (FEDER a way to achieve Europe). MAM has received funding from the Spanish ISCIII (grant PI 15/00431). A multicentric grant funded by the ISCIII (PMP15/00025 to MAM, RM, MO, CP).

Craniopharyngiomas (CPs) are histologically benign tumors that are associated with high levels of morbidity. Two clinicopathological variants - adamantinomatous (ACP) and papillary (PCP) - have been described. They differ in their molecular features, whereby activating mutations in BRAF (V600E) and CTNNB1 genes characterize PCP and ACP, respectively. Recently, both variants have been shown to express elevated PD-L1 protein expression, but ACP also exhibited tumor cell-intrinsic PD-1 expression. In this study we analyze these molecular alterations in 52 cases with a long follow-up and examine their associations with immunohistochemical and clinical characteristics. ACPs comprise 73.1% of cases, while 21.2% are PCPs. Aberrant nuclear immunoreactivity for β-catenin was observed in all ACPs. BRAF p.V600E mutations were observed in 90.9% of PCPs. Only one ACP case featured both alterations. Both types of CP exhibited strong nuclear staining for p63 with diffuse and basal distribution. ACP and PCP consistently expressed PD-L1, most in a substantial percentage of tumor cells, with a distinctive spatial distribution of expression in each subtype; only ACP demonstrated PD-1 expression. There was no evidence of differences in clinical prognosis between ACPs and PCPs. The identification of hallmark molecular signatures in the two CP variants is useful for sub-categorization in routine histopathology reporting. It is also pertinent to personalized therapy and for the development of improved non-invasive therapeutic strategies in this disease.

Exclusion of brain metastases from clinical trials is a major cause of the limited therapeutic options for this growing population of cancer patients. Here, we report a medium-throughput drug-screening platform (METPlatform) based on organotypic cultures that allows to evaluate inhibitors against metastases growing in situ. By applying this approach to brain metastasis, we identified several hits from a library of FDA approved inhibitors and others being tested in clinical trials. A blood-brain barrier permeable HSP90 inhibitor showed high potency against mouse and human brain metastases at clinically relevant stages of the disease, including a novel model of local relapse after neurosurgery. Furthermore, in situ proteomic analysis applied to organotypic cultures with metastases treated with the chaperone inhibitor revealed novel biomarkers in human brain metastasis and actionable mechanisms of resistance. Our work validates METPlatform as a potent resource for metastasis research integrating drug-screening and unbiased omic approaches that is fully compatible with human samples. We envision that METPlatform could be established as a clinically relevant strategy to personalize the management of metastatic disease in the brain and elsewhere.SummarySystemic spread of cancer continues to be the key aspect associated with lethality. In this publication, Zhu et al. describes a drug-screening platform specifically designed to study vulnerabilities of metastasis when colonizing secondary organs and demonstrates its value in difficult-to-treat brain metastasis using new models and patient-derived samples.

Congenital myasthenic syndromes are clinically and genetically heterogeneous disorders characterized by a neuromuscular transmission defect. Mutations in novel genes have been described in recent years. Among these, MUSK gene mutations are extremely rare, with only 8 families identified worldwide to date. We report a Spanish case, a carrier of one known hetero-allelic missense mutation and one newly identified MUSK gene variant. Our patient presented with congenital onset ophthalmoplegia and palpebral ptosis associated with limb-girdle weakness and exercise intolerance without prominent fatigability, developed during his twenties. He was misdiagnosed as mitochondrial myopathy because of paraclinic and histologic findings, but detailed clinical examination prompted us to reassess him with repetitive stimulation technique, demonstrating decremental response and suggesting myasthenic syndrome. A genetic study confirmed the clinical diagnosis allowing us to started treatment with excellent clinical response.

Carey-Fineman-Ziter syndrome is a congenital myopathy associated with mutations in the MYMK gene. It is clinically defined by the combination of hypotonia, Moebius-Robin sequence, facial anomalies and motor delay. Historically it was considered a brainstem dysgenesis syndrome. We provide detailed information of a Spanish boy with compound heterozygous variants in MYMK gene. A muscle biopsy performed as a toddler only disclosed minimal changes, but muscle MRI showed severe fatty infiltration of gluteus muscles and to a lesser extent in adductors magnus, sartorius and soleus muscles. Clinical course is fairly static, but the identification of new well characterized genetic cases will help to delineate the complete phenotype.

[Background]: The cell cycle checkpoint G1/S, dependent on cyclin-dependent kinase (CDK) 4 amplification/overexpression and retinoblastoma phosphorylation, is altered in most anaplastic oligodendrogliomas (AOs). [Objective]: We aimed to evaluate the efficacy of palbociclib, an oral inhibitor of CDK4/6 with proven efficacy in breast cancer, in patients with AO. The primary endpoint was progression-free survival at 6 months. [Patients and Methods]: We conducted a multicenter, open-label, phase II trial evaluating the efficacy and safety of palbociclib in patients with AO who progressed on radiotherapy and chemotherapy with histologically and molecularly confirmed grade 3 oligodendroglioma and conserved retinoblastoma protein (pRb) expression by immunohistochemistry. Patients were treated with palbociclib (125 mg/day) for 3/1 weeks on/off. [Results]: Overall, 34 patients were enrolled across 10 hospitals in the Spanish Group of Neuro-Oncology (GEINO) study. The study was stopped early owing to the lack of efficacy, with 74% of evaluable patients progressing within 6 months, which was insufficient to consider palbociclib as an active drug in this population. Within the median follow-up of 12 months, the median progression-free survival was 2.8 months [95% confidence interval (CI) 2.6–3.1] and the median overall survival was 32.1 months (95% CI 5.1–59.2). There were no partial or complete responses; only 13 patients (38%) achieved stable disease as the best response. Palbociclib was well tolerated, with neutropenia (grade 3 or higher: 58.8%) and thrombocytopenia (grade 3 or higher: 14.7%) as the most common adverse events (AEs). Both AEs had no significant impact. [Conclusion]: Despite the good tolerance, palbociclib monotherapy did not show favorable efficacy against recurrent AO., Palbociclib was provided by Pfizer under a cooperative research agreement with the Spanish Group for Research in NeuroOncology (GEINO). Funding research was supported by Pfzer under the Investigator-Initiated Research Award, number WI174842.

The radiological diagnosis of glioma progression is still challenging. A 33-year-old woman diagnosed with a frontal tumor underwent awake craniotomy with total tumor resection. The diagnosis was IDH-mutated diffuse astrocytoma, WHO grade II. The patient did not receive additional radiotherapy or chemotherapy. Periodic MRI scans showed a T2/FLAIR nodular enlargement which appeared de novo and grew slowly and gradually until 4 years post surgery. The patient underwent a second craniotomy to completely resect the T2/FLAIR hyperintensity. In the histological and molecular study of the second resection, no tumor cells were identified. We could hypothesize that the reactive changes favored by surgery could explain the ongoing radiologic findings. .

Glioblastoma (GBM) is the most common malignant adult primary brain tumor. Despite its high lethality, a small proportion of patients have a relatively long overall survival (OS). Here we report a study of a series of 74 GBM samples from 29 long-term survivors ([LTS] OS ≥36 months) and 45 non-LTS. Using next-generation sequencing, we analyzed genetic alterations in the genes most frequently altered in gliomas. Approximately 20% of LTS had a mutation in the IDH1 or IDH2 (IDH) genes, denoting the relevance of this molecular prognostic factor. A new molecular group of GBMs harbored alterations in ATRX or DAXX genes in the absence of driver IDH or H3F3A mutations. These patients tended to have a slightly better prognosis, to be younger at diagnosis, and to present frontal or temporal tumors, and, morphologically, to present giant tumor cells. A significant fraction of LTS GBM patients had tumors with 1 or more alterations in the relevant GBM signaling pathways (RTK/PI3K, TP53 and RB1). In these patients, the PDGFRA alteration is suggested to be a favorable molecular factor. Our findings here are relevant for developing future targeted therapies and for identifying molecular prognostic factors in GBM patients.

Background and objective The use of histological degeneration scores in surgically-treated herniated lumbar discs is not common in clinical practice and its use has been primarily restricted to research. The objective of this study is to evaluate if there is an association between a higher grade of histological degeneration when compared with clinical or radiological parameters. Patients and method Retrospective consecutive analysis of 122 patients who underwent single-segment lumbar disc herniation surgery. Clinical information was available on all patients, while the histological study and preoperative magnetic resonance imaging were also retrieved for 75 patients. Clinical variables included age, duration of symptoms, neurological deficits, or affected deep tendon reflex . The preoperative magnetic resonance imaging was evaluated using Modic and Pfirrmann scores for the affected segment by 2 independent observers. Histological degeneration was evaluated using Weiler's score; the presence of inflammatory infiltrates and neovascularization , not included in the score, were also studied. Correlation and chi-square tests were used to assess the association between histological variables and clinical or radiological variables. Interobserver agreement was also evaluated for the MRI variables using weighted kappa. Results No statistically significant correlation was found between histological variables (histological degeneration score, inflammatory infiltrates or neovascularization) and clinical or radiological variables. Interobserver agreement for radiological scores resulted in a kappa of 0.79 for the Pfirrmann scale and 0.65 for the Modic scale, both statistically significant. Conclusions In our series of patients, we could not demonstrate any correlation between the degree of histological degeneration or the presence of inflammatory infiltrates when compared with radiological degeneration scales or clinical variables such as the patient's age or duration of symptoms.

BACKGROUND AND PURPOSE: Multifocal glioblastomas (ie, glioblastomas with multiple foci, unconnected in postcontrast pretreatment T1-weighted images) represent a challenge in clinical practice due to their poor prognosis. We wished to obtain imaging biomarkers with prognostic value that have not been found previously. MATERIALS AND METHODS: A retrospective review of 1155 patients with glioblastomas from 10 local institutions during 2006–2017 provided 97 patients satisfying the inclusion criteria of the study and classified as having multifocal glioblastomas. Tumors were segmented and morphologic features were computed using different methodologies: 1) measured on the largest focus, 2) aggregating the different foci as a whole, and 3) recording the extreme value obtained for each focus. Kaplan-Meier, Cox proportional hazards, correlations, and Harrell concordance indices (c-indices) were used for the statistical analysis. RESULTS: Age (P < .001, hazard ratio = 2.11, c-index = 0.705), surgery (P < .001, hazard ratio = 2.04, c-index = 0.712), contrast-enhancing rim width (P < .001, hazard ratio = 2.15, c-index = 0.704), and surface regularity (P = .021, hazard ratio = 1.66, c-index = 0.639) measured on the largest focus were significant independent predictors of survival. Maximum contrast-enhancing rim width (P = .002, hazard ratio = 2.05, c-index = 0.668) and minimal surface regularity (P = .036, hazard ratio = 1.64, c-index = 0.600) were also significant. A multivariate model using age, surgery, and contrast-enhancing rim width measured on the largest foci classified multifocal glioblastomas into groups with different outcomes (P < .001, hazard ratio = 3.00, c-index = 0.853, median survival difference = 10.55 months). Moreover, quartiles with the highest and lowest individual prognostic scores based on the focus with the largest volume and surgery were identified as extreme groups in terms of survival (P < .001, hazard ratio = 18.67, c-index = 0.967). CONCLUSIONS: A prognostic model incorporating imaging findings on pretreatment postcontrast T1-weighted MRI classified patients with glioblastoma into different prognostic groups.

The blood-brain barrier (BBB) defines the physiological function of the brain. Its disruption is common in multiple neuropathological diseases. Accumulating evidence suggest that BBB alterations occur in early stages of neurodegenerative diseases, being associated with neuronal loss processes. The vascular abnormalities and BBB leakage characterize the progression of gliomas, however it is unclear their correlation with the neurodegeneration observed in such tumors. Methods: To establish the different gene signatures we have performed an in-silico analysis using glioma data sets and we have validated the results in a cohort of 26 gliomas (high and low grade) and 7 controls from non-tumor donors. We have also used patient-derived xenografts (PDXs) to correlate the degree of BBB disruption (measured by IgG extravasation immunofluorescence staining) with the neuronal loss (evaluated by NeuN immunofluorescence staining) and with the motor impairment (assessed by a rotarod test). Results: We measured the expression of a series of signatures associated with different biological processes, relevant for glioma development. The “Synapse” and the “BBB dysfunction” signatures were inversely correlated during glioma development. Thus, the most aggressive tumors were associated with BBB breakdown and neuronal dysfunction. These phenotypes correlate with the mesenchymal subtype of gliomas and with a shorter survival. The vascular normalization induced by the isocitrate dehydrogenase 1 (IDH1) mutations rescued the neuronal loss, reducing the motor impairment and increasing the overall survival of PDX-bearing mice. Conclusions: Our data demonstrate that vascular normalization can revert the neuronal loss and the aggressiveness in those tumors, which is linked to the appearance of motor dysfunction symptoms. Overall, we propose that disruption of the BBB is associated with neurodegeneration in glioma patients. These results could help us to understand the progression of this pathology as well as other neurodegenerative diseases and therefore to improve their therapeutic approaches. Citation Format: Pablo Mata-Martínez, Berta Segura-Collar, Maria Garranzo-Asensio, Juan M. Sepúlveda-Sánchez, Aurelio Hernández-Lain, Pilar Sánchez-Gómez, Ricardo Gargini. Blood-brain barrier dysfunction leads to neuronal loss in glioma pathology [abstract]. In: Proceedings of the AACR Virtual Special Conference on the Evolving Tumor Microenvironment in Cancer Progression: Mechanisms and Emerging Therapeutic Opportunities; in association with the Tumor Microenvironment (TME) Working Group; 2021 Jan 11-12. Philadelphia (PA): AACR; Cancer Res 2021;81(5 Suppl):Abstract nr PO013.

A 29-year-old man, born from consanguineous parents, started with toe walking and frequent falls during his second year of life. He developed weakness in lower limbs during the first decade that subsequently extended to upper limbs. On examination, the patient had weakness in proximal muscles of all four limbs and in the tibialis anterior muscle. In addition, he had bilateral Achilles and patellar contractures, bilateral scapular winging, asymmetric calves and a positive Beevor sign, an upward movement of the umbilicus on contraction of rectus femoris due to weakness in the lower part. The muscle biopsy showed dystrophic changes and lobulated fibers. Genetic analysis through a next-generation sequencing panel of genes related to neuromuscular disorders revealed a novel homozygous nonsense mutation (p.Tyr85*) in the TCAP gene. Subsequent western blot assay showed a complete telethonin deficiency. Our observation expands the phenotypic spectrum of TCAP mutations and indicates that telethonin deficiency should be considered in the differential diagnosis of patients presenting with asymmetric calves and early joint retractions.

Calf pseudohypertrophy due to radiculopathy is an exceptional phenomenon rarely described. We report a 67 year old woman with a previous history of lumbar disc surgery consulting by progressive increase for more than a year of evolution painless right calf associated loss of strength. Electromyographic findings showed chronic S1 radiculopathy and radiologically was appreciated in the medial gastrocnemius and soleus rights substitution of normal muscle tissue by adipose tissue without evidence of myopathy or sarcomatous degeneration.

BACKGROUND Despite some evidence for the adoption of endoscopic transnasal trans-sphenoidal surgery (ETSS) for pituitary adenomas, the advantages of this technique over the traditional approach have not been robustly confirmed. OBJECTIVE To compare ETSS with the microscopic sublabial trans-septal trans-sphenoidal surgery (MTSS) for pituitary adenomas. METHODS We retrospectively reviewed 2 cohorts of ETSS and MTSS performed at our institution from 1995 to 2017. Patient characteristics, surgical data, and outcomes were recorded prospectively. We performed a univariate and multivariable analysis to determine the best surgical approach. To improve the quality of the results, we matched the distribution of patient characteristics between groups by propensity score (PS) method. RESULTS A total of 187 procedures (90 MTSS, 97 ETSS) were reviewed. We found better results in the ETSS group in terms of gross total resection (P = .002) and hormone-excess secretion control (P = .014). There was also a lower incidence of cerebrospinal fluid leakage (P = .039), transitory diabetes insipidus (P = .028), and postoperative hypopituitarism (P = .045), as well as a shorter hospital length of stay (P

The diagnosis of brain metastasis involves high morbidity and mortality and remains an unmet clinical need in spite of being the most common tumor in the brain. Exclusion of these cancer patients from clinical trials is a major cause of their limited therapeutic options. In this study, we report a novel drug-screening platform (METPlatform) based on organotypic cultures which allows identifying effective anti-metastasis agents in the presence of the organ microenvironment. We have applied this approach to clinically relevant stages of brain metastasis using both experimental models and human tumor tissue (by performing patient-derived organotypic cultures). We identified heat shock protein 90 (HSP90) as a promising therapeutic target for brain metastasis. Debio-0932, a blood-brain barrier permeable HSP90 inhibitor, shows high potency against mouse and human brain metastases from melanoma, lung and breast adenocarcinoma with distinct oncogenomic profiles at clinically relevant stages of the disease, including a novel model of local relapse after neurosurgery. Furthermore, we have also used METPlatform to perform unbiased proteomics of brain metastases in situ. By applying this analysis to brain metastases treated with the chaperone inhibitor, we uncovered non-canonical clients of HSP90 as potential novel mediators of brain metastasis and actionable mechanisms of resistance driven by autophagy. Combined therapy using HSP90 and autophagy inhibitors showed synergistic effects compared to sublethal concentrations of each monotherapy, demonstrating the potential of METPlatform to design and test rationale combination therapies to target metastasis more effectively. In conclusion, our work validates METPlatform as a potent resource for metastasis research integrating drug-screening and unbiased omic approaches that is fully compatible with human samples and questions the rationale of excluding patients with brain metastasis from clinical trials. We envision that METPlatform will be established as a clinically relevant strategy to personalize the management of metastatic disease in the brain and elsewhere.

Introduction: Sarcoglycanopathies (LGMD 2C 2F) are a subgroup of limb-girdle muscular dystrophies (LGMD), caused by mutations in sarcoglycan genes. They usually have a childhood onset and rapidly progressive course with loss of ability to walk over 12–16 years. Methods : Next generation sequencing (NGS) targeted gene panel was performed in three adult patients with progressive muscle weakness in which routine muscle histology and immunohistochemistry were not diagnostic. Results: Genetic analysis revealed homozygous or compound heterozygous mutations in SGCA gene and Western Blot demonstrated protein reduction confirming the diagnosis of α-sarcoglicanopathy. Discussion: Our cases evidence that the diagnosis of mild forms of alfa sarcoglicanopathy could be a challenge and suggest the possibility that they could be underdiagnosed. The use of Next generation Sequencing targeted gene panels is very helpful in the diagnosis of these patients.

Progressive multifocal leukoencephalopathy rarely occurs in patients with multiple myeloma. Intracranial central nervous system invasion is also an uncommon event in multiple myeloma, occurring in less than 1% of cases. We describe herein an exceptional case of coexisting progressive multifocal leukoencephalopathy and intraparenchymal central nervous system myeloma infiltration. A 73-year-old woman with relapsed multiple myeloma was treated with 15 cycles of lenalidomide and dexamethasone, but therapy had to be stopped because of a hip fracture after a fall. During hospitalization, the patient developed progressive multifocal leukoencephalopathy caused by John Cunningham virus, and a prominent intra-parenchymal CD138-positive infiltrate was detected. VDJ rearrangements of the immunoglobulin heavy chain gene and the mutational profile of plasma cells in bone marrow at the time of diagnosis and in brain biopsy after progression were analyzed by next generation sequencing, showing genetic differences between medullary and extramedullary myeloma cells. The role of long-term treatment with lenalidomide and dexamethasone in the development progressive multifocal leukoencephalopathy or intraparenchymal central nervous system myeloma infiltration remains unknown. However, our results suggest that both events may have arisen as a consequence of treatment-related immunosuppression. Thus, an appropriate clinical approach compatible with the simultaneous treatment of progressive multifocal leukoencephalopathy and multiple myeloma should be developed.

Diffuse infiltrating low-grade gliomas include oligodendrogliomas and astrocytomas, and account for about 5% of all primary brain tumors. Treatment strategies for these low-grade gliomas in adults have recently changed. The 2016 World Health Organization (WHO) classification has updated the definition of these tumors to include their molecular characterization, including the presence of isocitrate dehydrogenase (IDH) mutation and 1p/19p codeletion. In this new classification, the histologic subtype of grade II-mixed oligoastrocytoma has also been eliminated. The precise optimal management of patients with low-grade glioma after resection remains to be determined. The risk–benefit ratio of adjuvant treatment must be weighed for each individual.

The SEOM/GEINO clinical guidelines provide recommendations for radiological, and molecular diagnosis, treatment and follow-up of adult patients with anaplastic gliomas (AG). We followed the 2016 WHO classification which specifies the major diagnostic/prognostic and predictive value of IDH1/IDH2 missense mutations and 1p/19q codeletions in AG. The diagnosis of anaplastic oligoastrocytoma is discouraged. Surgery, radiotherapy and chemotherapy with PCV or TMZ are the first-line standard of care for AG with slight modifications according to molecular variables. A multidisciplinary team is highly recommended in the management of these tumors.

Background Mutations in the LAMA2 gene cause autosomal recessive laminin α2 related congenital muscular dystrophy. In patients with partial laminin α2 deficiency the phenotype is usually milder than in those with absent protein. Apart from the typical white matter abnormalities, there is an increased risk of cerebral complications such as epilepsy and mental retardation, despite a structurally normal brain. Methods/results We present a patient with primary partial laminin α2 deficiency due to a homozygous novel LAMA2 missense mutation who developed West syndrome in his first year of life. To our knowledge, this combination has not previously been reported. A 5 year-old boy exhibited global hypotonia with generalized muscle weakness from birth. At 8 months of age he presented infantile spasms and an EEG finding of hypsarrhythmia. Seizures were controlled in a few weeks with intramuscular synthetic ACTH, followed by valproic acid. Two years later antiepileptic medication was withdrawn. He achieved unsupported walking at the age of 4, but his cognitive status corresponded to a 2 year-old child. Epilepsy has not recurred and brain MRI showed the typical white matter abnormalities without associated neuronal migration defects. Conclusion This report widens the clinical spectrum of cerebral manifestations related with mutations in LAMA2. The beginning of a severe epileptic encephalopathy modifies the natural history of the disease.

McArdle disease is a metabolic myopathy that presents with exercise intolerance and episodic rhabdomyolysis. Excessive muscle recruitment has also been shown to be present during strenuous exercise, suggesting decreased power output. These findings could potentially be explained by either impaired contractility, decreased fiber size, or altered fiber type proportion. However, there is a paucity of data on the morphological features seen on muscle histology. Methods We examined muscle biopsies of patients with McArdle disease from a Spanish cohort and compared the findings with healthy controls. Results We found no significant difference in the fiber type proportion or mean fiber size between McArdle patients and controls in the biceps brachii or vastus lateralis muscles. Conclusions No alterations in muscle fiber type proportion or size were found on muscle histology of patients with McArdle disease. Future research should focus on assessment of muscle fiber contractility to investigate the functional impairment. Muscle Nerve 55: 916–918, 2017 Sin financiación 2.496 JCR (2017) Q3, 106/197 Clinical Neurology, 168/261 Neurosciences 1.072 SJR (2017) Q2, 112/378 Neurology (clinical), 75/191 Physiology, 43/107 Physiology (medical); Q3, 57/92 Cellular and Molecular Neuroscience No data IDR 2017 UEM

Diffuse infiltrating low-grade gliomas include oligodendrogliomas and astrocytomas, and account for about 5% of all primary brain tumors. Treatment strategies for these low-grade gliomas in adults have recently changed. The 2016 World Health Organization (WHO) classification has updated the definition of these tumors to include their molecular characterization, including the presence of isocitrate dehydrogenase (IDH) mutation and 1p/19p codeletion. In this new classification, the histologic subtype of grade II-mixed oligoastrocytoma has also been eliminated. The precise optimal management of patients with low-grade glioma after resection remains to be determined. The risk-benefit ratio of adjuvant treatment must be weighed for each individual.

Enteroviruses are a common cause of aseptic meningitis and mild infections in childhood. However, in immunocompromised patients they may cause severe neurologic conditions such as encephalitis or polio-like paralysis. Acknowledgment: The authors thank the patient and his family.

The brain microenvironment imposes a particularly intense selective pressure on metastasis-initiating cells, but successful metastases bypass this control through mechanisms that are poorly understood. Reactive astrocytes are key components of this microenvironment that confine brain metastasis without infiltrating the lesion. Here, we describe that brain metastatic cells induce and maintain the co-option of a pro-metastatic program driven by signal transducer and activator of transcription 3 (STAT3) in a subpopulation of reactive astrocytes surrounding metastatic lesions. These reactive astrocytes benefit metastatic cells by their modulatory effect on the innate and acquired immune system. In patients, active STAT3 in reactive astrocytes correlates with reduced survival from diagnosis of intracranial metastases. Blocking STAT3 signaling in reactive astrocytes reduces experimental brain metastasis from different primary tumor sources, even at advanced stages of colonization. We also show that a safe and orally bioavailable treatment that inhibits STAT3 exhibits significant antitumor effects in patients with advanced systemic disease that included brain metastasis. Responses to this therapy were notable in the central nervous system, where several complete responses were achieved. Given that brain metastasis causes substantial morbidity and mortality, our results identify a novel treatment for increasing survival in patients with secondary brain tumors. Reactive astrocytes expressing STAT3 support the metastatic growth of tumor cells colonizing the brain and can be pharmacologically targeted to improve the clinical management of patients with secondary brain tumors.

Background We conducted a multicenter, 2-stage, open-label, phase II trial to assess the efficacy and safety of dacomitinib in adult patients with recurrent glioblastoma (GB) and epidermal growth factor receptor gene (EGFR) amplification with or without variant III (EGFRvIII) deletion. Methods Patients with first recurrence were enrolled in 2 cohorts. Cohort A included patients with EGFR gene amplification without EGFRvIII mutation. Cohort B included patients with EGFR gene amplification and EGFRvIII mutation. Dacomitinib was administered (45 mg/day) until disease progression/unacceptable adverse events (AEs). Primary endpoint was progression-free survival (PFS; RANO criteria) at 6 months (PFS6). Results Thirty patients in Cohort A and 19 in Cohort B were enrolled. Median age was 59 years (range 39-81), 65.3% were male, and Eastern Cooperative Oncology Group Performance Status 0/1/2 were 10.2%/65.3%/24.5%, respectively. PFS6 was 10.6% (Cohort A: 13.3%; Cohort B: 5.9%) with a median PFS of 2.7 months (Cohort A: 2.7 mo; Cohort B: 2.6 mo). Four patients were progression free at 6 months and 3 patients were so at 12 months. Median overall survival was 7.4 months (Cohort A: 7.8 mo; Cohort B: 6.7 mo). The best overall response included 1 complete response and 2 partial responses (4.1%). Stable disease was observed in 12 patients (24.5%: eight in Cohort A and four in Cohort B). Diarrhea and rash were the most common AEs; 20 (40.8%) patients experienced grade 3-4 drug-related AEs. Conclusions Dacomitinib has a limited single-agent activity in recurrent GB with EGFR amplification. The detailed molecular characterization of the 4 patients with response in this trial can be useful to select patients who could benefit from dacomitinib.

The diagnosis of brain metastasis involves high morbidity and mortality and remains as an unmet clinical need in spite of being the most common tumor in the brain. Brain metastasis affects between 10-30% of cancer patients with 200.000 new cases yearly only in the US. Increasing evidences point out the relevance of the microenvironment to understand the biology of brain colonization by metastatic cells, however translation strategies targeting it are lacking. We have identified altered signaling pathways in pro-metastatic reactive astrocytes (RA), and translated that into a novel therapeutic application for brain metastasis. Specifically we have identified a subpopulation of RA characterized by activated STAT3 pathway (pSTAT3+). This subpopulation is located in the vicinity of metastatic lesions intermingled with pSTAT3- RA in several experimental models and in 89% of human brain metastases independently of the primary tumor source. The pro-metastatic behaviour of RA is regulated by the activation of the STAT3 pathway, which modulates the immune system locally promoting the survival of cancer cells. Specifically the secretome of pSTAT3+ RA decreases the anti-tumor activity of CD8+ T cells as well as promotes the expansion of the pro-tumor population of CD74+ microglia/macrophage, which infiltrates metastasis cores. Interestingly, the immunosuppressive nature of pSTAT3+ RA is linked to the acquisition of stem cell-like properties, which might reflect the misuse of brain responses to injury instigated by the presence of cancer cells. Genetic and pharmacologic approaches targeting STAT3 in RA impair the progression of brain metastasis, even at advanced stages of the disease. Moreover, a safe and orally bioavailable STAT3 inhibitor reduced brain metastasis in 75% of 18 stage IV lung adenocarcinoma patients with established brain metastases, improving the outcome of the disease by increasing patient survival from 4 to 15 months. Besides increasing therapeutic opportunities for patients with brain metastasis, we have described for the first time the role of reactive astrocytes as regulators of local immunosuppression in brain metastasis as well as the importance of uncovering the heterogeneity within the metastasis-associated microenvironment. Citation Format: Neibla Priego, Lucía Zhu, Catia Monteiro, Manon Mulders, David Wasilewski, Wendy Bindeman, Laura Doglio, Elena Martínez-Saez, Santiago Ramón y Cajal, Coral Fustero-Torre, Elena Piñeiro-Yáñez, Aurelio Hernández-Laín, Valeria Poli, Javier A. Menéndez, Ricardo Soffietti, Joaquim Bosch-Barrera, Manuel Valiente. Stat3 labels a subpopulation of reactive astrocytes required for brain metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2746.

2038 Background: The pRB-dependent cell cycle checkpoint is altered in the vast majority of anaplastic oligodendrogliomas (AO), either by homozygous deletion or by hypermethylation of CDKN2A and/or CDKN2B, or by amplification and/or overexpression of CDK4. Palbociclib is an oral inhibitor of CDK4 and 6 that has already been shown to be highly active in breast cancer. Methods: We conducted a multicenter, open-label, phase II trial evaluating efficacy and safety of Palbociclib in patients with AO that progressed to radiotherapy and more than one chemotherapy regimen containing Temozolomide and/or Lomustine. Inclusion criteria included: histologically and molecularly confirmed grade III oligodendroglioma (WHO 2016 classification, IDH1/2 mutation and 1p/19 codeletion were mandatory), recurrence after radiotherapy and 1 or 2 chemotherapy regimens and conserved RB protein expression by immunohistochemistry (IHC). Patients were treated with Palbociclib 125 mg/daily 3 weeks on/1off. The primary objective of the study was progression-free survival at 6 months (6M-PFS). Results: Between October 2015 and September 2018, 34 patients were enrolled across ten hospitals. The study was stopped early secondary to lack of efficacy, with 74% of evaluable patients progressing within 6 months. Number of patients alive and free from progression at 6 months after the enrollment was 9 (26%) out of the first 34 patients, below the minimum number required (18 out of 40) to consider Palbociclib as an active drug in this population. With a median follow-up of 11.2 months, the median PFS was 3 months (95% CI: 2.5-3.5 months). Median overall survival (OS) was 23.1 months (95% CI: 17.2-25 months). There were no partial or complete responses and only 11 patients (32%) achieved stable disease as best response. Palbociclib was well tolerated with neutropenia (Grade 3 or 4: 40%) and thrombocytopenia (Grade 3 or 4: 15%) as the most common adverse effects (AEs). Both AEs had no significant impact since there were no episodes of febrile neutropenia or bleeding. Conclusions: Despite the good tolerance and drug exposure, Palbociclib monotherapy did not show favorable activity in recurrent AO. Clinical trial information: NCT02530320.

2030 Background: Gliomas harboring mutations in IDH1/2 show a higher overall survival time than “wild type” (wt) tumors. Although the clinical aspects are well described, little is known about the underlying mechanisms by which these mutations generate such a difference in the clinical course. Our group has recently described that IDH1/2 mutations induce a distinct vascular phenotype in the tumors, with less blood-brain barrier (BBB) leakage than the IDH1/2 wt gliomas (In Press, DOI:10.1101/541326). Methods: Prospective study analyzing a cohort of 20 patients with primary gliomas resected in one institution. Samples were obtained in the first surgery and 12 IDHmut and 8 IDHwt gliomas were included. Immune infiltration was analysed by flow cytometry and vasculature by inmunohistochemistry. For molecular biology studies, western blots were performed with Mini-PROTEAN system. Proteins were visible by enhanced chemoluminescence. Results: We show that the immune component also differentiates these two pathologies. There is significantly less immune infiltration in IDH1/2 mutant gliomas. Within the CD45 subset, IDH1/2 mutant gliomas have a reduced proportion of T lymphocytes with a different T cell exhaustion profile and an increased proportion of CD11b+ cells in comparison to IDH1/2 wt cases. Myeloid compartment distribution is also different in these two types of tumors, showing an augmented proportion of the M2 (CD206+) and the neutrophil subsets in IDH1/2 wt gliomas. Moreover, a higher proportion of CD45 PDL1+ was present in the IDH1/2 wt tumors samples. The analysis of the vasculature showed an increase density and the lumen size of the vessels of the IDH1/2 wt compared to the IDH1/2 mutant gliomas which correlate with changes in the immune profile. The biochemical analysis showed that there is an increment in EGFR and PDGFR activity in the IDH wt gliomas that is related with more vascular aberrations and higher CD45 infiltrate. This suggests that EGFR and PDGFR are the key regulators of the tumor microenvironment. Conclusions: To understand the matching between the immune infiltration and vasculogenesis is relevant for interpreting data coming from the clinical trials with checkpoints inhibitors. At the time abstract submission survival analysis is not yet available due to the short time of follow-up but in May 2019, the number of expected events for analysis will be reached.

Multiple sclerosis (MS) is a demyelinating disease of the central nervous system, characterized by focal neurological dysfunction with a relapsing and remitting course. Tumor-like presentation of MS (or “tumefactive”/“pseudotumoral” presentation) has been described before with a certain frequency; it consists of a large single plaque (>2 cm) with presence of edema and mass effect and it is hard to distinguish from a brain tumor. However, we present a very rare case of a 53-year-old woman with a right temporal mass that turned out to be a MS plaque, who deteriorated within hours (brain herniation with loss of consciousness and unilateral mydriasis) and required an emergency craniotomy. We also present a review of the literature. It appears that only 4 cases of emergency craniotomy/craniectomy required in a patient with a tumor-like MS plaque have been reported before.

In glioblastoma, tumor progression appears to be triggered by expression of VEGF, a regulator of blood vessel permeability. Bevacizumab is a monoclonal antibody that inhibits angiogenesis by clearing circulating VEGF, resulting in a decline in the contrast-enhancing tumor, which does not always correlate with treatment response. Our objectives were: (1) to evaluate whether changes in DSC perfusion MRI-derived leakage could predict survival in recurrent glioblastoma, and (2) to estimate whether leakage at baseline was related to treatment outcome. We retrospectively analyzed DSC perfusion MRI in 24 recurrent glioblastomas treated with bevacizumab as second line chemotherapy. Leakage at baseline and changes in maximum leakage between baseline and the first follow-up after treatment were selected for quantitative analysis. Survival univariate analysis was made constructing survival curves using Kaplan–Meier method and comparing subgroups by log rank probability test. Leakage reduction at 8 weeks after initiation of bevacizumab treatment had a significant influence on overall survival (OS) and progression-free survival (PFS). Median OS and PFS were 2.4 and 2.8 months longer for patients with leakage reduction at the first follow-up. Higher leakage at baseline was associated with leakage reduction after treatment. Odds ratio of treatment response was 9 for patients with maximum leakage at baseline >5. Leakage decrease may predict OS and PFS in recurrent glioblastomas treated with bevacizumab. Leakage reduction postulates as a potential biomarker for treatment response evaluation. Leakage at baseline seems to predict response to treatment, but was not independently associated with survival.