Clasificación de los trastornos del sueño

Sleep disorders are frequent processes, both as a symptom associated with other diseases and as independent disorders. However, only in the last 4 decades has Sleep medicine gained its position among the medical specialties. In fact, it was only in these years that significant advances were obtained in the study of the etiology and treatment of these disorders. Similarly, the different classifications have been evolving over the years. First, they were based upon the clinical symptom; later on, more emphasis was given to the diseases. Finally, in 2005, the new classification was once again based on the symptoms. More than 90 disorders are listed in this latest classification, and an attempt is made to include the symptoms and the diseases of sleep, as well as those in which sleep disorders are fundamental. It is essential to have a clear idea of this complete classification of sleep disorders in order to deal with these patients appropriately

Síndrome CLIPPERS. A propósito de un caso

Presentamos el caso de un varón de 44 años, con antecedentes personales de linfohistiocitosis hemofagocítica primaria (portador homocigótico de mutación Ala91Val), resuelta tras esplenectomía. Presenta un cuadro de inicio brusco y curso progresivo, de 2 meses de evolución, de sensación de adormecimiento y hormigueo en ambas plantas de los pies, rigidez en las piernas que se desencadena con la actividad física y sensación de inestabilidad. Además, desde hace 48 h, asocia adormecimiento y hormigueo de ambas palmas. Niega antecedentes epidemiológicos de interés

18F-FDG-PET Imaging Patterns in Autoimmune Encephalitis: Impact of Image Analysis on the Results

Brain positron emission tomography imaging with 18Fluorine-fluorodeoxyglucose (FDG-PET) has demonstrated utility in suspected autoimmune encephalitis. Visual and/or assisted image reading is not well established to evaluate hypometabolism/hypermetabolism. We retrospectively evaluated patients with autoimmune encephalitis between 2003 and 2018. Patients underwent EEG, brain magnetic resonance imaging (MRI), cerebrospinal fluid (CSF) sampling and autoantibodies testing. Individual FDG-PET images were evaluated by standard visual reading and assisted by voxel-based analyses, compared to a normal database. For the latter, three different methods were performed: two based on statistical surface projections (Siemens syngo.via Database Comparison, and 3D-SSP Neurostat) and one based on statistical parametric mapping (SPM12). Hypometabolic and hypermetabolic findings were grouped to identify specific patterns. We found six cases with definite diagnosis of autoimmune encephalitis. Two cases had anti-LGI1, one had anti-NMDA-R and two anti-CASPR2 antibodies, and one was seronegative. 18F-FDG-PET metabolic abnormalities were present in all cases, regardless of the method of analysis. Medial–temporal and extra-limbic hypermetabolism were more clearly depicted by voxel-based analyses. We found autoantibody-specific patterns in line with the literature. Statistical surface projection (SSP) methods (Neurostat and syngo.via Database Comparison) were more sensitive and localized larger hypermetabolic areas. As it may lead to comparable and accurate results, visual analysis of FDG-PET studies for the diagnosis of autoimmune encephalitis benefits from voxel-based analysis, beyond the approach based on MRI, CSF sample and EEG

Factors associated with a higher rate of distant failure after primary treatment for glioblastoma

Our purpose was to analyze the pattern of failure in glioblastoma (GBM) patients at first recurrence after radiotherapy and temozolomide and its relationship with different factors. From 77 consecutive GBM patients treated at our institution with fluorescence guided surgery and standard radiochemotherapy, 58 first recurrences were identified and included in a retrospective review. Clinical data including age, Karnofsky performance score, preoperative tumor volume and location, extend of resection, MGMT promoter methylation status, time to progression (PFS), overall survival (OS) and adjuvant therapies were reviewed for every patient. Recurrent tumor location respect the original lesion was the end point of the study. The recurrence pattern was local only in 65.5% of patients and non-local in 34.5%. The univariate and multivariate analysis showed that greater preoperative tumor volume in T1 gadolinium enhanced sequences, was the only variable with statistical signification (p < 0.001) for increased rate of non-local recurrences, although patients with MGMT methylation and complete resection of enhancing tumor presented non-local recurrences more frequently. PFS was longer in patients with non-local recurrences (13.8 vs. 6.4 months; p = 0.019, log-rank). However, OS was not significantly different in both groups (24.0 non-local vs. 19.3 local; p = 0.9). Rate of non-local recurrences in our series of patients treated with fluorescence guided surgery and standard radiochemotherapy was higher than previously published in GBM, especially in patients with longer PFS. Greater preoperative enhancing tumor volume was associated with increased rate of non-local recurrences

Hypofractionated radiation therapy and temozolomide in patients with glioblastoma and poor prognostic factors. A prospective, single-institution experience

Background: Hypofractionated radiation therapy is a feasible and safe treatment option in elderly and frail patients with glioblastoma. The aim of this study was to evaluate the effectiveness of hypofractionated radiation therapy with concurrent temozolomide in terms of feasibility and disease control in primary glioblastoma patients with poor prognostic factors other than advanced age, such as post-surgical neurological complications, high tumor burden, unresectable or multifocal lesions, and potential low treatment compliance due to social factors or rapidly progressive disease. Material and methods: GTV included the surgical cavity plus disease visible in T1WI-MRI, FLAIR-MRI and in the MET-uptake. The CTV was defined as the GTV plus 1.5-2 cm margin; the PTV was the CTV+0.3 cm margin. Forty, fourty-five, and fifty grays in 15 fractions were prescribed to 95% of PTV, CTV, and GTV, respectively. Treatment was delivered using IMRT or the VMAT technique. Simultaneously, 75 mg/m2/day of temozolomide were administered. Results: Between January 2010 and November 2017, we treated a total of 17 patients. The median age at diagnosis was 68-years; median KPS was 50-70%. MGMT-methylation status was negative in 5 patients, and 8 patients were IDH-wildtype. Eight of 18 patients were younger than 65-years. Median tumor volume was 26.95cc; median PTV volume was 322cc. Four lesions were unresectable; 6 patients underwent complete surgical resection. Median residual volume was 1.14cc. Progression-free survival was 60% at 6 months, 33% at 1-year and 13% at 2-years (median OS = 7 months). No acute grade 3-5 toxicities were documented. Symptomatic grade 3 radiation necrosis was observed in one patient. Conclusions: Patients with poor clinical factors other than advanced age can be selected for hypofractionated radiotherapy. The OS and PFS rates obtained in our series are similar to those in patients treated with standard fractionation, assuring good treatment adherence, low rates of toxicity and probable improved cost-effectiveness

The oncolytic virus Delta-24-RGD elicits an antitumor effect in pediatric glioma and DIPG mouse models

Pediatric high-grade glioma (pHGG) and diffuse intrinsic pontine gliomas (DIPGs) are aggressive pediatric brain tumors in desperate need of a curative treatment. Oncolytic virotherapy is emerging as a solid therapeutic approach. Delta-24-RGD is a replication competent adenovirus engineered to replicate in tumor cells with an aberrant RB pathway. This virus has proven to be safe and effective in adult gliomas. Here we report that the administration of Delta-24-RGD is safe in mice and results in a significant increase in survival in immunodeficient and immunocompetent models of pHGG and DIPGs. Our results show that the Delta-24-RGD antiglioma effect is mediated by the oncolytic effect and the immune response elicited against the tumor. Altogether, our data highlight the potential of this virus as treatment for patients with these tumors. Of clinical significance, these data have led to the start of a phase I/II clinical trial at our institution for newly diagnosed DIPG (NCT03178032)

Oncolytic virotherapy for the treatment of pediatric brainstem gliomas

Diffuse intrinsic pontine glioma (DIPG) is the most frequent brainstem glioma and the most lethal brain tumor in childhood. Despite transient benefit with radiotherapy, the prognosis of children with this disease remains dismal with severe neurological morbidity and median survival less than 12 months. Oncolytic immunovirotherapy is emerging as a potential therapeutic approach in neuro-oncology. The oncolytic adenovirus Delta-24-RGD has shown efficacy in adult patients with recurrent GBM. Our group has demonstrated that Delta-24-RGD has oncolytic activity and triggers immune response in preclinical models of DIPG, and has a synergistic effect with radiotherapy in animal models of this disease. In this scenario, we conducted a first-in-human phase 1 clinical trial to evaluate the safety and efficacy of intratumoral injection of Delta-24-RGD in pediatric patients with newly diagnosed DIPG prior to standard radiotherapy. The study confirmed the feasibility of this treatment with an acceptable safety profile and encouraging efficacy results. Correlative analyses showed a biological activity from Delta-24-RGD in DIPG. Further advanced trials are needed to validate these results. Meanwhile, plenty of opportunities to increase the potential contribution of oncolytic viruses in the management of devastating tumors with no current effective treatment such as DIPG need to be explored and exploited

Immuno-virotherapy for glioblastoma: Characterization of Delta 24-ACT in combination with different immunomodulators as therapeutic approach

The tumor microenvironment of glioblastoma is extremely immunosuppressive due to high amount of myeloid cells leading to low levels of lymphocytes. This immunosuppressive scenario makes difficult the development of curative therapies for this devastating tumor. Our group has engineered Delta-24-ACT, an oncolytic adenovirus armed with the costimulatory ligand 4-1BBL which is capable to trigger the activation of T cells and thereby, increasing the antitumor response. Since, monotherapies have not elicited survival benefit in glioblastoma, in this project; we evaluated the antitumor effect of Delta-24-ACT combined with different modulators of the immune system (targeting both lymphoid and myeloid cell populations). Delta-24-ACT was able to infect and kill murine (GL261-5 and CT-2A) and human (U87-MG and U251-MG) glioma cell lines, while maintaining its replication in the latter. Of importance, after infection with Delta-24-ACT, the 4-1BBL not only was detected on the membrane of glioma cells but also it was able to stimulate CD8 T cells in vitro. These data suggested its potential to trigger an effective immune response. Furthermore, in vivo, Delta-24-ACT significantly increased the median survival and led to long-term survivors in three different orthotopic glioma models. However, the virus did not generate antiglioma memory immune response. In order to improve the survival and to generate immune memory, we combined the virus with different immune modulating approaches (dendritic cell vaccination, IDO inhibitor, macrophages inhibitor etc). However, no differences in survival benefit were observed when compared to Delta-24-ACT. Since Delta-24-ACT treatment led to the expression of higher levels of PD-1 in T cells, we combined Delta-24-ACT with an anti-PD-L1 antibody. This combination not only alleviated the exhaustion phenotype showed by the T-cells but in addition, resulted in an increase survival and the acquisition of antiglioma memory immune response. In summary, our data demonstrated that Delta-24-ACT exerts a potent antitumor response in vitro and in vivo. Moreover, the different proposed combination strategies induce survival benefit in mice as a result of the recruitment of immune cell populations modulating the immunosuppressive tumor microenvironment of gliomas. Of importance, Delta-24-ACT in combination with PD-L1 blockade displayed the best therapeutic effect