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Background: Activating and inhibitory receptors of natural killer (NK) cells such as NKp, NKG2, or CLEC are highly relevant to cold tumors including glioblastoma (GBM). Here, we aimed to characterize the expression of these receptors in GBM to gain insight into their potential role as modulators of the intratumoral microenvironment., Methods: We performed a transcriptomic analysis of several NK receptors with a focus on the activating receptor encoded by KLRC2, NKG2C, among bulk and single-cell RNA sequencing GBM data sets. We also evaluated the effects of KLRC2-overexpressing GL261 cells in mice treated with or without programmed cell death protein-1 (PD-1) monoclonal antibody (mAb). Finally, we analyzed samples from two clinical trials evaluating PD-1 mAb effects in patients with GBM to determine the potential of NKG2C to serve as a biomarker of response., Results: We observed significant expression of several inhibitory NK receptors on GBM-infiltrating NK and T cells, which contrasts with the strong expression of KLRC2 on tumor cells, mainly at the infiltrative margin. Neoplastic KLRC2 expression was associated with a reduction in the number of myeloid-derived suppressor cells and with a higher level of tumor-resident lymphocytes. A stronger antitumor activity after PD-1 mAb treatment was observed in NKG2C high -expressing tumors both in mouse models and patients with GBM whereas the expression of inhibitory NK receptors showed an inverse association., Conclusions: This study explored the role of neoplastic NKG2C/ KLRC2 expression in shaping the immune profile of GBM and suggests that it is a predictive biomarker for positive responses to immune checkpoint inhibitor treatment in patients with GBM. Future studies could further validate this finding in prospective trials., Competing Interests: Competing interests: MER-R reports personal fees from BMS and grants from Highlight-Therapeutics and Roche outside the submitted work. She also has received speaker’s bureau honoraria from BMS and ROCHE. The rest of the authors declare that they have no competing interests., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: We previously reported that tumor 3D volume growth rate (3DVGR) classification could help in the assessment of drug activity in patients with meningioma using 3 main classes and a total of 5 subclasses: class 1: decrease; 2: stabilization or severe slowdown; 3: progression. The EORTC-BTG-1320 clinical trial was a randomized phase II trial evaluating the efficacy of trabectedin for recurrent WHO 2 or 3 meningioma. Our objective was to evaluate the discriminative value of 3DVGR classification in the EORTC-BTG-1320., Methods: All patients with at least 1 available MRI before trial inclusion were included. 3D volume was evaluated on consecutive MRI until progression. 2D imaging response was centrally assessed by MRI modified Macdonald criteria. Clinical benefit was defined as neurological or functional status improvement or steroid decrease or discontinuation., Results: Sixteen patients with a median age of 58.5 years were included. Best 3DVGR classes were: 1, 2A, 3A, and 3B in 2 (16.7%), 4 (33.3%), 2 (16.7%), and 4 (33.3%) patients, respectively. All patients with progression-free survival longer than 6 months had best 3DVGR class 1 or 2. 3DVGR classes 1 and 2 (combined) had a median overall survival of 34.7 months versus 7.2 months for class 3 (P = .061). All class 1 patients (2/2), 75% of class 2 patients (3/4), and only 10% of class 3 patients (1/10) had clinical benefit., Conclusions: Tumor 3DVGR classification may be helpful to identify early signals of treatment activity in meningioma clinical trials., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Importance: Dysregulated metabolism is a hallmark of renal cell carcinoma (RCC). Glutaminase is a key enzyme that fuels tumor growth by converting glutamine to glutamate. Telaglenastat is an investigational, first-in-class, selective, oral glutaminase inhibitor that blocks glutamine utilization and downstream pathways. Preclinically, telaglenastat synergized with cabozantinib, a VEGFR2/MET/AXL inhibitor, in RCC models., Objective: To compare the efficacy and safety of telaglenastat plus cabozantinib (Tela + Cabo) vs placebo plus cabozantinib (Pbo + Cabo)., Design, Setting, and Participants: CANTATA was a randomized, placebo-controlled, double-blind, pivotal trial conducted at sites in the US, Europe, Australia, and New Zealand. Eligible patients had metastatic clear-cell RCC following progression on 1 to 2 prior lines of therapy, including 1 or more antiangiogenic therapies or nivolumab plus ipilimumab. The data cutoff date was August 31, 2020. Data analysis was performed from December 2020 to February 2021., Interventions: Patients were randomized 1:1 to receive oral cabozantinib (60 mg daily) with either telaglenastat (800 mg twice daily) or placebo until disease progression or unacceptable toxicity., Main Outcomes and Measures: The primary end point was progression-free survival (Response Evaluation Criteria in Solid Tumors version 1.1) assessed by blinded independent radiology review., Results: A total of 444 patients were randomized: 221 to Tela + Cabo (median [range] age, 61 [21-81] years; 47 [21%] women and 174 [79%] men) and 223 to Pbo + Cabo (median [range] age, 62 [29-83] years; 68 [30%] women and 155 [70%] men). A total of 276 (62%) patients had received prior immune checkpoint inhibitors, including 128 with prior nivolumab plus ipilimumab, 93 of whom had not received prior antiangiogenic therapy. Median progression-free survival was 9.2 months for Tela + Cabo vs 9.3 months for Pbo + Cabo (HR, 0.94; 95% CI, 0.74-1.21; P = .65). Overall response rates were 31% (69 of 221) with Tela + Cabo vs 28% (62 of 223) with Pbo + Cabo. Treatment-emergent adverse event (TEAE) rates were similar between arms. Grade 3 to 4 TEAEs occurred in 160 patients (71%) with Tela + Cabo and 172 patients (79%) with Pbo + Cabo and included hypertension (38 patients [17%] vs 40 patients [18%]) and diarrhea (34 patients [15%] vs 29 patients [13%]). Cabozantinib was discontinued due to AEs in 23 patients (10%) receiving Tela + Cabo and 33 patients (15%) receiving Pbo + Cabo., Conclusions and Relevance: In this randomized clinical trial, telaglenastat did not improve the efficacy of cabozantinib in metastatic RCC. Tela + Cabo was well tolerated with AEs consistent with the known risks of both agents., Trial Registration: ClinicalTrials.gov Identifier: NCT03428217.

Background: Temozolomide (TMZ) is an oral alkylating agent active against gliomas with a favorable toxicity profile. It is part of the standard of care in the management of glioblastoma (GBM), and is commonly used in low-grade gliomas (LGG). In-silico mathematical models can potentially be used to personalize treatments and to accelerate the discovery of optimal drug delivery schemes., Methods: Agent-based mathematical models fed with either mouse or patient data were developed for the in-silico studies. The experimental test beds used to confirm the results were: mouse glioma models obtained by retroviral expression of EGFR-wt/EGFR-vIII in primary progenitors from p16/p19 ko mice and grown in-vitro and in-vivo in orthotopic allografts, and human GBM U251 cells immobilized in alginate microfibers. The patient data used to parametrize the model were obtained from the TCGA/TCIA databases and the TOG clinical study., Results: Slow-growth "virtual" murine GBMs benefited from increasing TMZ dose separation in-silico . In line with the simulation results, improved survival, reduced toxicity, lower expression of resistance factors, and reduction of the tumor mesenchymal component were observed in experimental models subject to long-cycle treatment, particularly in slowly growing tumors. Tissue analysis after long-cycle TMZ treatments revealed epigenetically driven changes in tumor phenotype, which could explain the reduction in GBM growth speed. In-silico trials provided support for implementation methods in human patients., Conclusions: In-silico simulations, in-vitro and in-vivo studies show that TMZ administration schedules with increased time between doses may reduce toxicity, delay the appearance of resistances and lead to survival benefits mediated by changes in the tumor phenotype in slowly-growing GBMs., (© The Author(s) 2022. Published by Oxford University Press, the Society for Neuro-Oncology and the European Association of Neuro-Oncology.)

Bone metastases are very common complications associated with certain types of cancers that frequently negatively impact the quality of life and functional status of patients; thus, early detection is necessary for the implementation of immediate therapeutic measures to reduce the risk of skeletal complications and improve survival and quality of life. There is no consensus or universal standard approach for the detection of bone metastases in cancer patients based on imaging. Endorsed by the Spanish Society of Medical Oncology (SEOM), the Spanish Society of Medical Radiology (SERAM), and the Spanish Society of Nuclear Medicine and Molecular Imaging (SEMNIM) a group of experts met to discuss and provide an up-to-date review of our current understanding of the biological mechanisms through which tumors spread to the bone and describe the imaging methods available to diagnose bone metastasis and monitor their response to oncological treatment, focusing on patients with breast and prostate cancer. According to current available data, the use of next-generation imaging techniques, including whole-body diffusion-weighted MRI, PET/CT, and PET/MRI with novel radiopharmaceuticals, is recommended instead of the classical combination of CT and bone scan in detection, staging and response assessment of bone metastases from prostate and breast cancer.Clinical trial registration: Not applicable., (© 2022. The Author(s).)

Purpose: FGFR genomic alterations (amplification, mutations, and/or fusions) occur in ∼8% of gliomas, particularly FGFR1 and FGFR3. We conducted a multicenter open-label, single-arm, phase II study of a selective FGFR1-3 inhibitor, infigratinib (BGJ398), in patients with FGFR-altered recurrent gliomas., Patients and Methods: Adults with recurrent/progressive gliomas harboring FGFR alterations received oral infigratinib 125 mg on days 1 to 21 of 28-day cycles. The primary endpoint was investigator-assessed 6-month progression-free survival (PFS) rate by Response Assessment in Neuro-Oncology criteria. Comprehensive genomic profiling was performed on available pretreatment archival tissue to explore additional molecular correlations with efficacy., Results: Among 26 patients, the 6-month PFS rate was 16.0% [95% confidence interval (CI), 5.0-32.5], median PFS was 1.7 months (95% CI, 1.1-2.8), and objective response rate was 3.8%. However, 4 patients had durable disease control lasting longer than 1 year. Among these, 3 had tumors harboring activating point mutations at analogous positions of FGFR1 (K656E; n = 2) or FGFR3 (K650E; n = 1) in pretreatment tissue; an FGFR3-TACC3 fusion was detected in the other. Hyperphosphatemia was the most frequently reported treatment-related adverse event (all-grade, 76.9%; grade 3, 3.8%) and is a known on-target toxicity of FGFR inhibitors., Conclusions: FGFR inhibitor monotherapy with infigratinib had limited efficacy in a population of patients with recurrent gliomas and different FGFR genetic alterations, but durable disease control lasting more than 1 year was observed in patients with tumors harboring FGFR1 or FGFR3 point mutations or FGFR3-TACC3 fusions. A follow-up study with refined biomarker inclusion criteria and centralized FGFR testing is warranted., (©2022 The Authors; Published by the American Association for Cancer Research.)

Background: MET-signaling and midkine (ALK ligand) promote glioma cell maintenance and resistance against anticancer therapies. ALK and c-MET inhibition with crizotinib have a preclinical therapeutic rationale to be tested in newly diagnosed GBM., Methods: Eligible patients received crizotinib with standard radiotherapy (RT)/temozolomide (TMZ) followed by maintenance with crizotinib. The primary objective was to determine the recommended phase 2 dose (RP2D) in a 3 + 3 dose escalation (DE) strategy and safety evaluation in the expansion cohort (EC). Secondary objectives included progression-free (PFS) and overall survival (OS) and exploratory biomarker analysis., Results: The study enrolled 38 patients. The median age was 52 years (33-76), 44% were male, 44% were MGMT methylated, and three patients had IDH1/2 mutation. In DE, DLTs were reported in 1/6 in the second cohort (250 mg/QD), declaring 250 mg/QD of crizotinib as the RP2D for the EC. In the EC, 9/25 patients (32%) presented grade ≥3 adverse events. The median follow up was 18.7 months (m) and the median PFS was 10.7 m (95% CI, 7.7-13.8), with a 6 m PFS and 12 m PFS of 71.5% and 38.8%, respectively. At the time of this analysis, 1 died without progression and 24 had progressed. The median OS was 22.6 m (95% CI, 14.1-31.1) with a 24 m OS of 44.5%. Molecular biomarkers showed no correlation with efficacy., Conclusions: The addition of crizotinib to standard RT and TMZ for newly diagnosed GBM was safe and the efficacy was encouraging, warranting prospective validation in an adequately powered, randomized controlled study.

Glioblastomas (GBMs) are the most frequent and highly aggressive brain tumors, being resistant to all cytotoxic and molecularly targeted agents tested so far. There is, therefore, an urgent need to find novel therapeutic approaches and/or alternative targets to bring treatment options to patients. Here, we first show that GBMs express high levels of N-MYC protein, a transcription factor involved in normal brain development. A novel stapled peptide designed to specifically target N-MYC protein monomer, IDP-410, is able to impair the formation of N-MYC/MAX complex and reduce the stability of N-MYC itself. As a result, the viability of GBM cells is compromised. Moreover, the efficacy is found dependent on the levels of expression of N-MYC. Finally, we demonstrate that IDP-410 reduces GBM growth in vivo when administered systemically, both in subcutaneous and intracranial xenografts, reducing the vascularization of the tumors, highlighting a potential relationship between the function of N-MYC and the expression of mesenchymal/angiogenic genes. Overall, our results strengthen the view of N-MYC as a therapeutic target in GBM and strongly suggest that IDP-410 could be further developed to become a first-in-class inhibitor of N-MYC protein, affecting not only tumor cell proliferation and survival, but also the interplay between GBM cells and their microenvironment., (© 2022. The American Society for Experimental NeuroTherapeutics, Inc.)

Purpose: A novel, selective, next-generation transforming growth factor beta (TGFβ) receptor type-1 small molecule inhibitor, LY3200882, demonstrated promising preclinical data. This first-in-human trial evaluated safety, tolerability, recommended phase II dose (RP2D), pharmacokinetics, pharmacodynamics, and preliminary antitumor activity of LY3200882 as monotherapy or with other anticancer agents in patients with advanced cancer., Patients and Methods: This phase I multicenter study of oral LY3200882 (NCT02937272) comprised dose escalation, monotherapy expansion in grade 4 glioma, and combination therapy in solid tumors (LY3200882 and PD-L1 inhibitor LY3300054), pancreatic cancer (LY3200882, gemcitabine, and nab-paclitaxel), and head and neck squamous cell cancer (LY3200882, cisplatin, and radiation)., Results: Overall, 139 patients with advanced cancer were treated. The majority (93.5%) of patients experienced ≥1 treatment-emergent adverse events (TEAE), with 39.6% LY3200882-related. Grade 3 LY3200882-related toxicities were only observed in combination therapy arms. One patient in the pancreatic cancer arm experienced cardiovascular toxicity. The LY3200882 monotherapy RP2Ds were established in two schedules: 50 mg twice a day 2-weeks-on/2-weeks-off and 35 mg twice a day 3-weeks-on/1-week-off. Four patients with grade 4 glioma had durable Revised Assessment in Neuro Oncology (RANO) partial responses (PR) with LY3200882 monotherapy ( n = 3) or LY3200882-LY3300054 combination therapy ( n = 1). In treatment-naïve patients with advanced pancreatic cancer, 6 of 12 patients achieved Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 PR and 3 of 12 patients demonstrated stable disease, for an overall 75% disease-control rate with the combination of LY3200882, gemcitabine, and nab-paclitaxel., Conclusions: LY3200882 as monotherapy and combination therapy was safe and well tolerated with preliminary antitumor activity observed in pancreatic cancer. Further studies to evaluate the efficacy of LY3200882 with gemcitabine and nab-paclitaxel in advanced pancreatic cancer are warranted., (©2021 The Authors; Published by the American Association for Cancer Research.)

Introduction: The SARS-CoV-2 pandemic has generated a mortality rate 10times higher than normal influenza according to the World Health Organization (WHO), yet they do not mention palliative care in their action guidelines on maintaining essential health services during this crisis. The aim of this study was to analyse the death process of patients who died from SARS-CoV-2 at the Hospital Costa del Sol., Material and Methods: Descriptive cross-sectional study of the period in which all patients who died of SARS-CoV-2 from February to April 2020 were analysed. Sociodemographic characteristics, sample characterization and a set of variables related to the death process were collected in the death event., Results: A total of 16 deaths were recorded out of a total of 103 admissions positive for SARS-CoV-2. Limitation of therapeutic effort was decided in 68.8% of the patients, and admission to the intensive care unit was refused in 56.3%. Support devices had not been removed in any of the cases on the day of death, 43.8% had palliative sedation, and 18.8% were in induced coma., Conclusions: Quality standards were maintained in the death process in patients who died from SARS-CoV-2, although there were aspects that could be improved. Palliative care is an essential component of the response to SARS-CoV-2 that must be incorporated into all health care settings., (Copyright © 2021 FECA. Publicado por Elsevier España, S.L.U. All rights reserved.)

The extraordinary plasticity of glioma cells allows them to contribute to different cellular compartments in tumor vessels, reinforcing the vascular architecture. It was recently revealed that targeting glioma-derived pericytes, which represent a big percentage of the mural cell population in aggressive tumors, increases the permeability of the vessels and improves the efficiency of chemotherapy. However, the molecular determinants of this transdifferentiation process have not been elucidated. Here we show that mutations in EGFR stimulate the capacity of glioma cells to function as pericytes in a BMX- (bone marrow and X-linked) and SOX9-dependent manner. Subsequent activation of platelet-derived growth factor receptor beta in the vessel walls of EGFR-mutant gliomas stabilized the vasculature and facilitated the recruitment of immune cells. These changes in the tumor microenvironment conferred a growth advantage to the tumors but also rendered them sensitive to pericyte-targeting molecules such as ibrutinib or sunitinib. In the absence of EGFR mutations, high-grade gliomas were enriched in blood vessels, but showed a highly disrupted blood-brain barrier due to the decreased BMX/SOX9 activation and pericyte coverage, which led to poor oxygenation, necrosis, and hypoxia. Overall, these findings identify EGFR mutations as key regulators of the glioma-to-pericyte transdifferentiation, highlighting the intricate relationship between the tumor cells and their vascular and immune milieu. Our results lay the foundations for a vascular-dependent stratification of gliomas and suggest different therapeutic vulnerabilities determined by the genetic status of EGFR . SIGNIFICANCE: This study identifies the EGFR-related mechanisms that govern the capacity of glioma cells to transdifferentiate into pericytes, regulating the vascular and immune phenotypes of the tumors. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/81/8/2142/F1.large.jpg., (©2021 American Association for Cancer Research.)

Background: Pneumatosis intestinalis (PI) is a rare entity which refers to the presence of gas within the wall of the small bowel or colon which is a radiographic sign. The etiology and clinical presentation are variable. Patients with PI may present either with chronic mild non-specific symptoms or with acute abdominal pain with peritonitis. Some cases of intestinal pneumatosis have been reported as adverse events of new oncological treatments such as targeted therapies that are widely used in multiple tumors., Case Presentation: A 59-year-old caucasian female with radioactive iodine-refractory metastatic thyroid papillary carcinoma with BRAF V600E mutation was treated with dabrafenib and trametinib as a compassionate use. After 4 months treatment, positron emission tomography-computed tomography (PET-CT) showed PI. At the time of diagnosis, the patient was asymptomatic without signs of peritonitis. The initial treatment was conservative and no specific treatment for PI was needed. Unfortunately, after dabrafenib-trametinib withdrawal, the patient developed tumor progression with significant clinical worsening., Conclusions: This case report is, in our knowledge, the first description of PI in a patient treated with dabrafenib-trametinib. Conservative treatment is feasible if there are no abdominal symptoms.

Background: Gliomas remain refractory to all attempted treatments, including those using immune checkpoint inhibitors. The characterization of the tumor (immune) microenvironment has been recognized as an important challenge to explain this lack of response and to improve the therapy of glial tumors., Methods: We designed a prospective analysis of the immune cells of gliomas by flow cytometry. Tumors with or without isocitrate dehydrogenase 1/2 ( IDH1/2 ) mutations were included in the study. The genetic profile and the presence of different molecular and cellular features of the gliomas were analyzed in parallel. The findings were validated in syngeneic mouse models., Results: We observed that few immune cells infiltrate mutant IDH1/2 gliomas whereas the immune content of IDH1/2 wild-type tumors was more heterogeneous. Some of them contained an important immune infiltrate, particularly enriched in myeloid cells with immunosuppressive features, but others were more similar to mutant IDH1/2 gliomas, with few immune cells and a less immunosuppressive profile. Notably, we observed a direct correlation between the percentage of leukocytes and the presence of vascular alterations, which were associated with a reduced expression of Tau, a microtubule-binding protein that controls the formation of tumor vessels in gliomas. Furthermore, overexpression of Tau was able to reduce the immune content in orthotopic allografts of GL261 cells, delaying tumor growth., Conclusions: We have confirmed the reduced infiltration of immune cells in IDH1/2 mutant gliomas. By contrast, in IDH1/2 wild-type gliomas, we have found a direct correlation between the presence of vascular alterations and the entrance of leukocytes into the tumors. Interestingly, high levels of Tau inversely correlated with the vascular and the immune content of gliomas. Altogether, our results could be exploited for the design of more successful clinical trials with immunomodulatory molecules.

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., Trial Registration: This study is registered with ClinicalTrials.gov, identifier NCT0253032 (retrospectively registered on 21 August 2015).

Gliomas that express the mutated isoforms of isocitrate dehydrogenase 1/2 (IDH1/2) have better prognosis than wild-type (wt) IDH1/2 gliomas. However, how these mutant (mut) proteins affect the tumor microenvironment is still a pending question. Here, we describe that the transcription of microtubule-associated protein TAU ( MAPT ), a gene that has been classically associated with neurodegenerative diseases, is epigenetically controlled by the balance between wt and mut IDH1/2 in mouse and human gliomas. In IDH1/2 mut tumors, we found high expression of TAU that decreased with tumor progression. Furthermore, MAPT was almost absent from tumors with epidermal growth factor receptor ( EGFR ) mutations, whereas its trancription negatively correlated with overall survival in gliomas carrying wt or amplified (amp) EGFR We demonstrated that the overexpression of TAU, through the stabilization of microtubules, impaired the mesenchymal/pericyte-like transformation of glioma cells by blocking EGFR, nuclear factor kappa-light-chain-enhancer of activated B (NF-κB) and the transcriptional coactivator with PDZ-binding motif (TAZ). Our data also showed that mut EGFR induced a constitutive activation of this pathway, which was no longer sensitive to TAU. By inhibiting the transdifferentiation capacity of EGFRamp/wt tumor cells, TAU protein inhibited angiogenesis and favored vascular normalization, decreasing glioma aggressiveness and increasing their sensitivity to chemotherapy., (Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

Background: 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., Methods: 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., Results: 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., Conclusion: 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.

Glioblastoma (GBM) is the most common and devastating primary brain tumor. The presence of cancer stem cells (CSCs) has been linked to their therapy resistance. Molecular and cellular components of the tumor microenvironment also play a fundamental role in the aggressiveness of these tumors. In particular, high levels of hypoxia and reactive oxygen species participate in several aspects of GBM biology. Moreover, GBM contains a large number of macrophages, which normally behave as immunosuppressive tumor-supportive cells. In fact, the presence of both, hypoxia and M2-like macrophages, correlates with malignancy and poor prognosis in gliomas. Antioxidant agents, as nutritional supplements, might have antitumor activity. Ocoxin® oral solution (OOS), in particular, has anti-inflammatory and antioxidant properties, as well as antitumor properties in several neoplasia, without known side effects. Here, we describe how OOS affects stem cell properties in certain GBMs, slowing down their tumor growth. In parallel, OOS has a direct effect on macrophage polarization in vitro and in vivo , inhibiting the protumoral features of M2 macrophages. Therefore, OOS could be a feasible candidate to be used in combination therapies during GBM treatment because it can target the highly resilient CSCs as well as their supportive immune microenvironment, without adding toxicity to conventional treatments., Competing Interests: The authors declare that this work was partially supported by Catalysis S.L. ES is a current employee of Catalysis S.L. The authors declare that there are no other nonfinancial competing interests.

The conflict of interest declaration was published incorrectly in the original version.

Objectives: To identify gaps in patient safety during intra-hospital transfers., Material and Methods: A working group was set up and patient transfers carried out in the different healthcare areas of a hospital were identified. Using the Modal Failure and Effects Analysis (FMEA), the risks of each failure mode identified were quantified using the Risk Prioritisation Index (RPI) and establishing improvement measures for all RPIs with scores greater than 100., Results: There were 31 critical points that could lead to failures / deficiencies in 20 types of transfers. A total of 35 safety improvement measures were proposed for the transfers in the different areas analysed., Conclusions: The use of FMEA has made it possible to objectify the risks for patient safety during internal hospital transfers by providing information to prioritise improvement strategies., (Copyright © 2018 FECA. Publicado por Elsevier España, S.L.U. All rights reserved.)

The goal of this article is to provide recommendations about the management of kidney cancer. Based on pathologic and molecular features, several kidney cancer variants were described. Nephron-sparing techniques are the gold standard of localized disease. After a randomized trial, sunitinib could be considered in adjuvant treatment in high-risk patients. Patients with advanced disease constitute a heterogeneous population. Prognostic classification should be considered. Both sunitinib and pazopanib are the standard options for first-line systemic therapy in advanced renal cell carcinoma. Based on the results of two randomized trials, both nivolumab and cabozantinib should be considered the standard for second and further lines of therapy. Response evaluation for present therapies is a challenge.

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.

Aim: To assess motivation to quit smoking in patients admitted to an acute care hospital, determine predictors of readiness to change, and identify a risk group that requires targeted motivational interviewing., Methods: A cross-sectional descriptive study. A retrospective study was performed on the medical records of 248 patients aged >18 years with smoking habits admitted to the medical and surgery units of a district hospital between May 2014 and April 2015. The data collected included sociodemographic data, data on respiratory function, number of cigarettes smoked per day, motivation to quit smoking, patient-reported readiness to quit, history of respiratory diseases and previous admissions., Results: The Richmond test revealed that 54% of patients (n=134) were poorly motivated to quit smoking vs. 11.74% (n=29) who reported to be highly motivated. The group of patients who reported to be willing to receive support (n=77) was prevailingly composed of men (p=.009) admitted to a medical care unit (p=.026) -mainly the Unit of Cardiology (51%)- who smoked 11/29 cigarettes/day (p=.015). Dyspnoea at admission, a history of respiratory disease and previous admissions for respiratory problems were not predictors of readiness to quit., Conclusions: This study identifies a risk group of patients with respiratory disease, low motivation to quit smoking and poor readiness to receive smoke cessation support, that should be the target of motivational approaches to behavior change., (Copyright © 2016 Elsevier España, S.L.U. All rights reserved.)

The original version of this article unfortunately contained a mistake. Figure 3 was incorrect.

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 Author(s) 2017. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com)

[This corrects the article DOI: 10.3892/ol.2017.5988.].

The present observational, multicenter, retrospective study investigated the efficacy and tolerability of lacosamide in controlling secondary epileptic seizures in patients with brain tumors in Spain. Data from the medical records of patients ≥18 years of age with brain tumors, who had received at least one dose of lacosamide for seizure management between July 2013 and November 2013, were collected. The primary and secondary objectives of the present study were to assess the effectiveness and tolerability of lacosamide. Data from 39 patients (mean age, 54.1 years; 66.7% male) were collected, where the two main reasons for initiation of lacosamide treatment were the lack of efficacy of other antiepileptic drugs (in 76.9% of patients) and the presence of adverse events (12.8%) associated with other antiepileptic drugs. At the initiation of treatment, patients received a mean lacosamide dose of 138.5±68.3 mg/day. At 6 months, lacosamide had significantly reduced the mean number of seizures from 26.4 (standard deviation [SD], 50.4) seizures for the 6 months prior to lacosamide initiation to a mean of 9.4 (SD, 22.8) seizures during the 6 months subsequent to lacosamide initiation; P<0.001. Lacosamide was generally well tolerated; of the 25 patients who had complete safety data available at a 6-month follow-up, 3 patients (12%) reported an adverse event, including dizziness, asthenia, instability and irritability. The present retrospective analysis suggested that lacosamide is an effective and well-tolerated treatment in patients experiencing seizures due to brain tumors. Additional prospective studies with a larger patient population and randomized trial design are warranted.

Aim: To assess pain management in patients hospitalized with a non-oncological disease and evaluate factors involved in pain assessment., Methods: A descriptive, cross-sectional study. We reviewed pain episodes documented in the medical records of 105 patients aged>18 years admitted to the medical units of a regional hospital between September and December 2014. Reports of pain episodes were evaluated by assessing 22 variables related to pain management quality criteria., Results: A total of 184 reports were reviewed. Pain was measured using the visual analogue scale (VAS) in 70.1% of patients (n=129); pain was reassessed in 44.3% (n=54) of patients. Pain reassessment was significantly more frequent in patients aged<70 years, as compared to older patients (53.1 vs. 26.8%, respectively; p=0.01). Pain was more frequently considered to be unrelated to the cause of admission in women as compared to men (50 vs. 25.7% p=0.027). Pain was identified in the patient care plan as a collaborative problem by the nurse for 21.1% of the patients., Conclusions: Some aspects of pain management should be improved, especially those regarding pain description and reassessment. The age and sex of patients significantly influence the approach of pain., (Copyright © 2015 Elsevier España, S.L.U. All rights reserved.)

Aim: To examine the perceptions and beliefs of doctors and nurses, and the barriers and facilitators they must address as regards the right to die with dignity in an acute-care hospital, and to consider the applicability of the provisions of Law 2/2010 of 8 April in this respect., Method: A qualitative descriptive study, based on the focus group technique, using discourse analysis of the views of doctors and nurses responsible for the health care of terminal cancer and non-cancer patients in an acute-care hospital., Results: The results obtained show that there are diverse obstacles to assure the rights of terminal patients, and to ensure the proper performance of their duties by healthcare professionals and institutions. The nature and impact of these difficulties depend on the characteristics of the patients and their families, the health workers involved, the organisation of health care, and cultural factors., Conclusions: The study highlights the need to improve the process of communication with patients and their families, to facilitate shared decision making and to establish measures to clarify issues such as palliative sedation and treatment limitation. It is necessary to improve the applicability of the law on living wills and dignified death in non-cancer specialist areas. Further training is needed regarding ethical, spiritual and anthropological aspects of care in these situations., (Copyright © 2013 Elsevier España, S.L. All rights reserved.)

Background: In Andalusia, Spain, a legislative framework was put in place in 2010 to guarantee dignity in dying and quality of care in the last phase of life., Aim: The aim of this study was to determine whether health professionals have incorporated the requirements of this legislation into their clinical practice and whether there have been improvements in decision-making procedures affecting the quality of dying in hospitals., Methods: A cross-sectional analysis was carried out in an acute hospital in Andalusia, Spain. Clinical records of patients who died in the Costa del Sol Hospital were evaluated before and after the new legislative framework was introduced. Participants were all the patients aged over 18 years (n=398) who died in 2009 (n=216) or 2011 (n=182) of oncological disease or non-oncological chronic disease. Bivariate analyses evaluated differences between the two periods and associations among the patients' characteristics and the context of care., Results: Provision of information on measures to facilitate comfort and the relief of physical suffering increased from 15.7% to 22.0%, although this was not significant. There was a significant increase in the number of patients who received joint counselling in this regard from doctors and nurses, from 0% in 2009 to 7.1% in 2011., Conclusions: The minimal changes found 1 year after the implementation of the framework confirm that culture change is a lengthy, difficult task that cannot be achieved through laws alone.

Introduction: There are very few studies on the aetiology of temporal lobe epilepsy (TLE) in childhood. The purpose of the present study is to analyse the data of 61 children diagnosed with TLE, in order to describe the aetiology of TLE in children seen in a neuropaedriatic clinic. We also discuss the currently proposed classification., Patients and Methods: A retrospective analysis was carried out on patients diagnosed with TLE. Patients consisted of 61 children less than 15 years old., Results: Patients were classified into three groups: Group 1 (symptomatic temporal lobe epilepsy) consisted of 25 patients (40.98 %) with any temporal lesion on neuroimaging (tumours, malformations or infections) or significant history; Group 2 (Mesial temporal sclerosis) consisted of 17 patients (27.86 %), a history of simple and complex febrile seizure were common in this group; and Group 3 (Cryptogenic epilepsy) consisted of 19 patients (31.15 %) with no abnormalities on neuroimaging or significant history., Conclusion: To our knowledge, this is the largest paediatric series of childhood new-onset TLE assessed only by MRI in the literature. We have modified the previous aetiological classification in order to make the groups more realistic.

Introduction: With relative frequency epilepsy and migraine are associated in a same patient. Some times it is difficult to distinguish an attack of others. Reason why it would be of utility to have a treatment effective in both pathologies. It is tried to study in patients with this comorbidity, how of effective it is a drug indicated in the two pathologies, as it is topiramate., Patients and Methods: An observational, longitudinal and prospective study is made, where 15 patients are recruited with this association, and which they were treated with topiramate. They are revaluated at three and six months of treatment., Results: Significant differences are obtained (p < 0.05) in all the studied variables (severity and duration of the migraine attacks and frequency of the migraine and epileptic attacks), with a medium dose of 100 mg/day of topiramate, at the end of the study. Not serious adverse effects were observed., Conclusions: Topiramate in monotherapy seems to be a suitable treatment in patients who undergo epileptic and migrainous attacks jointly.

Introduction: 5% of patients with sarcoidosis are affected by neurological complications, of which myopathy is one of the least frequent. We report the clinical course and therapeutic response of two patients with sarcoid myopathy., Case Reports: We observed two females aged 63 and 55 who were previously diagnosed with sarcoidosis, which in one case was cutaneous and ophthalmic and in the other pulmonary. Both were asymptomatic from a systemic point of view when they visited the Neurology department. Both patients developed chronic myopathy (with a history of 9 months and 6 years), which was predominantly proximal, painful and both of them had normal or slightly high levels of creatine phosphokinase. The EMG was clearly myopathic in the two patients. A muscle biopsy showed a mononuclear-cell infiltrate with the formation of non-caseating granulomas. Both patients were treated with prednisone, although the therapeutic response was different in each case. One of the patients showed an important improvement in just a few days, while in the other case the disease remained stable, despite adding, first, azathioprine and later methotrexate to the treatment., Conclusions: Sarcoidosis can cause chronic, predominantly proximal, myopathy, and chiefly affects females over 50 years of age. The therapeutic response to steroids and immunosuppressants varies from case to case.

Introduction: Subacute sclerosing panencephalitis is a disease affecting the central nervous system that is produced by persistent infection by a defective measles virus. This disease is very infrequent and its incidence has gone down even further in western countries since the introduction of generalised measles vaccinations. Onset of the disease is usually during infancy or adolescence. Reports of cases beginning during adulthood are scarce., Case Report: We describe the case of a 30-year-old female with a slowly progressive subacute clinical picture consisting in behavioural disorders, with defrontalisation, cortico-subcortical cognitive impairment, long tract signs and visual disorders, which led the patient into a vegetative state. Four years after the onset of symptoms the patient died. The different electroencephalogram recordings performed did not show any periodic activity and magnetic resonance imaging of the head revealed cerebral atrophy with hyperintense lesions in T2 sequences in white matter. The histological study of the brain showed a chronic inflammatory infiltration with neuronal loss and demyelination, as well as intranuclear inclusions and neurofibrillary degeneration., Conclusions: The appearance of subacute sclerosing panencephalitis in adulthood is exceptional. Diagnosis requires a high degree of clinical suspicion, above all in the absence of typical symptoms, such as myoclonias or periodic complexes in EEG recordings.

Aims: In the search for new, potentially treatable, vascular risk factors, one of the most recent to be put forward is the presence of increased total homocysteine (tHc) levels in blood plasma and this has also given rise to a large amount of literature and controversy. The origin of this hypothesis lies in the observation that patients with congenital disorders affecting homocysteine (Hc) metabolism suffered from early atherosclerosis. In this paper we analyse the studies that have been published about Hc and cerebrovascular disease (CVD)., Development: An important number of retrospective case control studies have found a strong dose dependent link between levels of Hc in plasma and cerebrovascular, heart and peripheral thromboembolic disease. Yet the prospective studies that have been published to date note only a weak or inexistent link between homocysteine and CVD. Moreover, some observations question the causal relationship between hyperhomocysteinemia and atherothrombosis and account for the findings in the retrospective studies as being a result of the rise in Hc following a stroke or its increasing because of classical vascular risk factors. In any case, knowing that the ingestion of folic acid, vitamin B12 and pyridoxine lowers tHc levels in plasma has led to clinical trails being set up that evaluate the effects of this treatment on vascular risk., Conclusion: The relation between Hc levels in plasma and CVD is open to controversy. New studies and the findings of clinical studies with vitamin therapy will allow this relation to be fully explained in coming years.