Refinement of prognostication for IDH-mutant astrocytomas using DNA methylation-based classification.

The 2021 World Health Organization (WHO) grading system of isocitrate dehydrogenase (IDH)-mutant astrocytomas relies on histological features and the presence of homozygous deletion of the cyclin-dependent kinase inhibitor 2A and 2B (CDKN2A/B). DNA methylation profiling has become highly relevant in the diagnosis of central nervous system (CNS) tumors including gliomas, and it has been incorporated into routine clinical diagnostics in some countries. In this study, we, therefore, examined the value of DNA methylation-based classification for prognostication of patients with IDH-mutant astrocytomas. We analyzed histopathological diagnoses, genome-wide DNA methylation array data, and chromosomal copy number alteration profiles from a cohort of 385 adult-type IDH-mutant astrocytomas, including a local cohort of 127 cases and 258 cases from public repositories. Prognosis based on WHO 2021 CNS criteria (histological grade and CDKN2A/B homozygous deletion status), other relevant chromosomal/gene alterations in IDH-mutant astrocytomas and DNA methylation-based subclassification according to the molecular neuropathology classifier were assessed. We demonstrate that DNA methylation-based classification of IDH-mutant astrocytomas can be used to predict outcome of the patients equally well as WHO 2021 CNS criteria. In addition, methylation-based subclassification enabled the identification of IDH-mutant astrocytoma patients with poor survival among patients with grade 3 tumors and patients with grade 4 tumors with a more favorable outcome. In conclusion, DNA methylation-based subclassification adds prognostic information for IDH-mutant astrocytomas that can further refine the current WHO 2021 grading scheme for these patients.

Image-guided radiation therapy (IGRT) in prostate cancer in México, survey of SOMERA (Sociedad Mexicana de Radioterapeutas/Mexican Society of Radiation Oncologists) with recommendations on its implementation and process.

Background: Prostate cancer is one of the main tumors worldwide, its treatment is multidisciplinary, includes radiotherapy in all stages: curative, radical, adjuvant, salvage and palliative. Technological advances in planning systems, image acquisition and treatment equipment have allowed the delivery of higher doses limiting toxicity in healthy tissues, distributing radiation optimally and ensuring reproducibility of conditions. Image-guided radiotherapy (IGRT) is not standard in guidelines, only recommended with heterogeneity in its own process. Materials and methods: A survey was conducted to members of the Mexican Society of Radiation Oncologists (SOMERA), to know the current status and make recommendations about its implementation and use, taking into account existing resources. Results: Responses of 541 patients were evaluated, 85% belonged to the intermediate-high risk group, 65% received adjuvant or salvage radiotherapy (RT), 80% received intensity-modulated radiation therapy (IMRT) using doses up to 80 Gy/2 Gy. Cone beam computed tomography (CBCT) was performed on 506 (93.5%), (100% IMRT) and 90% at a periodicity of 3-5/week. 3D treatment with 42% portal images 1/week. Online correction strategies (36% changes before treatment), following a diet and bladder and rectal control. Evidence and recommendations are reviewed. Conclusions: IGRT should be performed in patients with prostate cancer. In Mexico, despite limitations in the distribution of human and technological resources, it is routinely applied. More information is still needed on clinical evidence of its benefits and the process should be implemented according to infrastructure, following institutional guidelines, recommending to report the initial experience that helps to standardize national conduct.

The clinical value of proneural, classical and mesenchymal protein signatures in WHO 2021 adult-type diffuse lower-grade gliomas.

OBJECTIVES: Accumulating evidence shows that mesenchymal transition of glioblastomas is associated with a more aggressive course of disease and therapy resistance. In WHO2021-defined adult-type diffuse gliomas of lower grade (dLGG), the transition of the tumor phenotype over time, has not been studied. Most efforts to correlate proneural, classical or mesenchymal phenotype with outcome in dLGG were made prior to the WHO 2021 classification. Here, we set out to investigate if phenotype predicted survival and tumor recurrence in a clinical cohort of dLGGs, re-classified according to the 2021 WHO criteria. METHODS: Using a TMA-based approach with five immunohistochemical markers (EGFR, p53, MERTK, CD44 and OLIG2), we investigated 183 primary and 49 recurrent tumors derived from patients with previously diagnosed dLGG. Of the 49 relapses, nine tumors recurred a second time, and one a third time. RESULTS: In total, 71.0% of all tumors could be subtyped. Proneural was most dominant in IDH-mut tumors (78.5%), mesenchymal more common among IDH-wt tumors (63.6%). There was a significant difference in survival between classical, proneural and mesenchymal phenotypes in the total cohort (p<0.001), but not after molecular stratification (IDH-mut: p = 0.220, IDH-wt: p = 0.623). Upon recurrence, proneural was retained in 66.7% of the proneural IDH-mut dLGGs (n = 21), whereas IDH-wt tumors (n = 10) mainly retained or gained mesenchymal phenotype. No significant difference in survival was found between IDH-mut gliomas remaining proneural and those shifting to mesenchymal phenotype (p = 0.347). CONCLUSION: Subtyping into classical, proneural and mesenchymal phenotypes by five immunohistochemical markers, was possible for the majority of tumors, but protein signatures did not correlate with patient survival in our WHO2021-stratified cohort. At recurrence, IDH-mut tumors mainly retained proneural, while IDH-wt tumors mostly retained or gained mesenchymal signatures. This phenotypic shift, associated with increased aggressiveness in glioblastoma, did not affect survival. Group sizes were, however, too small to draw any firm conclusions.

Stalled oligodendrocyte differentiation in IDH-mutant gliomas.

BACKGROUND: Roughly 50% of adult gliomas harbor isocitrate dehydrogenase (IDH) mutations. According to the 2021 WHO classification guideline, these gliomas are diagnosed as astrocytomas, harboring no 1p19q co-deletion, or oligodendrogliomas, harboring 1p19q co-deletion. Recent studies report that IDH-mutant gliomas share a common developmental hierarchy. However, the neural lineages and differentiation stages in IDH-mutant gliomas remain inadequately characterized. METHODS: Using bulk transcriptomes and single-cell transcriptomes, we identified genes enriched in IDH-mutant gliomas with or without 1p19q co-deletion, we also assessed the expression pattern of stage-specific signatures and key regulators of oligodendrocyte lineage differentiation. We compared the expression of oligodendrocyte lineage stage-specific markers between quiescent and proliferating malignant single cells. The gene expression profiles were validated using RNAscope analysis and myelin staining and were further substantiated using data of DNA methylation and single-cell ATAC-seq. As a control, we assessed the expression pattern of astrocyte lineage markers. RESULTS: Genes concordantly enriched in both subtypes of IDH-mutant gliomas are upregulated in oligodendrocyte progenitor cells (OPC). Signatures of early stages of oligodendrocyte lineage and key regulators of OPC specification and maintenance are enriched in all IDH-mutant gliomas. In contrast, signature of myelin-forming oligodendrocytes, myelination regulators, and myelin components are significantly down-regulated or absent in IDH-mutant gliomas. Further, single-cell transcriptomes of IDH-mutant gliomas are similar to OPC and differentiation-committed oligodendrocyte progenitors, but not to myelinating oligodendrocyte. Most IDH-mutant glioma cells are quiescent; quiescent cells and proliferating cells resemble the same differentiation stage of oligodendrocyte lineage. Mirroring the gene expression profiles along the oligodendrocyte lineage, analyses of DNA methylation and single-cell ATAC-seq data demonstrate that genes of myelination regulators and myelin components are hypermethylated and show inaccessible chromatin status, whereas regulators of OPC specification and maintenance are hypomethylated and show open chromatin status. Markers of astrocyte precursors are not enriched in IDH-mutant gliomas. CONCLUSIONS: Our studies show that despite differences in clinical manifestation and genomic alterations, all IDH-mutant gliomas resemble early stages of oligodendrocyte lineage and are stalled in oligodendrocyte differentiation due to blocked myelination program. These findings provide a framework to accommodate biological features and therapy development for IDH-mutant gliomas.

Longitudinal DNA methylation analysis of adult-type IDH-mutant gliomas.

Diffuse gliomas are the most prevalent malignant primary brain tumors in adults and remain incurable despite standard therapy. Tumor recurrence is currently inevitable, which contributes to a persistent high morbidity and mortality in these patients. In this study, we examined the genome-wide DNA methylation profiles of primary and recurrent adult-type IDH-mutant gliomas to elucidate DNA methylation changes associated with tumor progression (with or without malignant transformation). We analyzed DNA methylation profiles of 37 primary IDH-mutant gliomas and 42 paired recurrences using the DNA methylation EPIC beadChip array. DNA methylation-based classification reflected the tumor progression over time. We observed a methylation subtype switch in a proportion of IDH-mutant astrocytomas; the primary tumors were subclassified as low-grade astrocytomas, which progressed to high-grade astrocytomas in the recurrent tumors. The CNS WHO grade 4 IDH-mutant astrocytomas did not always resemble methylation subclasses of higher grades. The number of differentially methylated CpG sites increased over time, and astrocytomas accumulated more differentially methylated CpG sites than oligodendrogliomas during tumor progression. Few differentially methylated CpG sites were shared between patients. We demonstrated that DNA methylation profiles are mostly maintained during IDH-mutant glioma progression, but CpG site-specific methylation alterations can occur.

DNA methylation profiling improves routine diagnosis of paediatric central nervous system tumours: A prospective population-based study.

AIMS: Paediatric brain tumours are rare, and establishing a precise diagnosis can be challenging. Analysis of DNA methylation profiles has been shown to be a reliable method to classify central nervous system (CNS) tumours with high accuracy. We aimed to prospectively analyse CNS tumours diagnosed in Sweden, to assess the clinical impact of adding DNA methylation-based classification to standard paediatric brain tumour diagnostics in an unselected cohort. METHODS: All CNS tumours diagnosed in children (0-18 years) during 2017-2020 were eligible for inclusion provided sufficient tumour material was available. Tumours were analysed using genome-wide DNA methylation profiling and classified by the MNP brain tumour classifier. The initial histopathological diagnosis was compared with the DNA methylation-based classification. For incongruent results, a blinded re-evaluation was performed by an experienced neuropathologist. RESULTS: Two hundred forty tumours with a histopathology-based diagnosis were profiled. A high-confidence methylation score of 0.84 or more was reached in 78% of the cases. In 69%, the histopathological diagnosis was confirmed, and for some of these also refined, 6% were incongruent, and the re-evaluation favoured the methylation-based classification. In the remaining 3% of cases, the methylation class was non-contributory. The change in diagnosis would have had a direct impact on the clinical management in 5% of all patients. CONCLUSIONS: Integrating DNA methylation-based tumour classification into routine clinical analysis improves diagnostics and provides molecular information that is important for treatment decisions. The results from methylation profiling should be interpreted in the context of clinical and histopathological information.

Stemness and clinical features in relation to the subventricular zone in diffuse lower-grade glioma: an exploratory study.

Background: The subventricular zone (SVZ) of the human brain is a site of adult stem cell proliferation and a microenvironment for neural stem cells (NSCs). It has been suggested that NSCs in the SVZ are potential cells of origin containing driver mutations of glioblastoma, but their role in the origin of diffuse lower-grade gliomas (dLGGs) is not much studied. Methods: We included 188 patients ≥18 years with IDH-mutated dLGG (WHO grades 2-3) histologically diagnosed between 2007 and 2020. Tissue microarrays of tumor samples for patients between 2007 and 2016 were used for immunodetection of Nestin, SOX2, SOX9, KLF4, NANOG, CD133 cMYC, and Ki67. DNA methylation profile was used for stemness index (mDNAsi). Tumor contact with the SVZ was assessed and the distance was computed. Results: Overall, 70.2% of the dLGG had SVZ contact. Tumors with SVZ contact were larger (102.4 vs 30.9 mL, P < .01), the patients were older (44.3 vs 40.4 years, P = .04) and more often had symptoms related to increased intracranial pressure (31.8% vs 7.1%, P < .01). The expression of SOX2, SOX9, Nestin, and Ki67 showed intersample variability, but no difference was found between tumors with or without SVZ contact, nor with the actual distance to the SVZ. mDNAsi was similar between groups (P = .42). Conclusions: We found no statistical relationship between proximity with the SVZ and mDNAsi or expression of SOX2, SOX9, Nestin, and Ki67 in IDH-mutated dLGG. Our data suggest that the potential impact of SVZ on IDH-mutated dLGG is probably not associated with a more stemness-like tumor profile.

[Social determinants of access to the explicit guarantees health program implemented in Chile]. / Determinantes sociales que influyen en el acceso en Chile al Plan GES, según CASEN 2017.

BACKGROUND: In Chile, an eventual implementation of a plan with universal health coverage is a challenge. The already implemented explicit health guarantees plan (GES) could be a benchmark. For this reason, it is important to obtain information about the results of its implementation. AIM: To identify the social determinants of health that influence the access to GES. MATERIAL AND METHODS: The National Socioeconomic Characterization Survey performed in 2017 was used as a data source. The beneficiaries of 20 diseases covered by GES and inquired in the survey were considered for the present study. RESULTS: People with the higher probability of access to GES plan belong to the lowest income quintiles, are nationals, live in the central-southern metropolitan Santiago, have lower education, have a public health insurance program (FONASA) and are aged mostly over 60 years. The diseases with the highest probability of access to the program are primary arterial hypertension, type 1 and type 2 diabetes mellitus, acute myocardial infarction, moderate and severe bronchial asthma, breast cancer, colon cancer, and bipolar disorder. CONCLUSIONS: The access probability to the GES program is in line with the epidemiological profile of the Chilean population, and with a greater social vulnerability.

DNA methylation alterations across time and space in paediatric brain tumours.

DNA methylation is increasingly used for tumour classification and has expanded upon the > 100 currently known brain tumour entities. A correct diagnosis is the basis for suitable treatment for patients with brain tumours, which is the leading cause of cancer-related death in children. DNA methylation profiling is required for diagnosis of certain tumours, and used clinically for paediatric brain tumours in several countries. We therefore evaluated if the methylation-based classification is robust in different locations of the same tumour, and determined how the methylation pattern changed over time to relapse. We sampled 3-7 spatially separated biopsies per patient, and collected samples from paired primary and relapse brain tumours from children. Altogether, 121 samples from 46 paediatric patients with brain tumours were profiled with EPIC methylation arrays. The methylation-based classification was mainly homogeneous for all included tumour types that were successfully classified, which is promising for clinical diagnostics. There were indications of multiple subclasses within tumours and switches in the relapse setting, but not confirmed as the classification scores were below the threshold. Site-specific methylation alterations did occur within the tumours and varied significantly between tumour types for the temporal samples, and as a trend in spatial samples. More alterations were present in high-grade tumours compared to low-grade, and significantly more alterations with longer relapse times. The alterations in the spatial and temporal samples were significantly depleted in CpG islands, exons and transcription start sites, while enriched in OpenSea and regions not affiliated with a gene, suggesting a random location of the alterations in less conserved regions. In conclusion, more DNA methylation changes accumulated over time and more alterations occurred in high-grade tumours. The alterations mainly occurred in regions without gene affiliation, and did not affect the methylation-based classification, which largely remained homogeneous in paediatric brain tumours.

Spatial heterogeneity in DNA methylation and chromosomal alterations in diffuse gliomas and meningiomas.

Adult-type diffuse gliomas and meningiomas are the most common primary intracranial tumors of the central nervous system. DNA methylation profiling is a novel diagnostic technique increasingly used also in the clinic. Although molecular heterogeneity is well described in these tumors, DNA methylation heterogeneity is less studied. We therefore investigated the intratumor genetic and epigenetic heterogeneity in diffuse gliomas and meningiomas, with focus on potential clinical implications. We further investigated tumor purity as a source for heterogeneity in the tumors. We analyzed genome-wide DNA methylation profiles generated from 126 spatially separated tumor biopsies from 39 diffuse gliomas and meningiomas. Moreover, we evaluated five methods for measurement of tumor purity and investigated intratumor heterogeneity by assessing DNA methylation-based classification, chromosomal copy number alterations and molecular markers. Our results demonstrated homogeneous methylation-based classification of IDH-mutant gliomas and further corroborates subtype heterogeneity in glioblastoma IDH-wildtype and high-grade meningioma patients after excluding samples with low tumor purity. We detected a large number of differentially methylated CpG sites within diffuse gliomas and meningiomas, particularly in tumors of higher grades. The presence of CDKN2A/B homozygous deletion differed in one out of two patients with IDH-mutant astrocytomas, CNS WHO grade 4. We conclude that diffuse gliomas and high-grade meningiomas are characterized by intratumor heterogeneity, which should be considered in clinical diagnostics and in the assessment of methylation-based and molecular markers.

Determinantes sociales que influyen en el acceso en Chile al Plan GES, según CASEN 2017 / Social determinants of access to the explicit guarantees health program implemented in Chile

BACKGROUND: In Chile, an eventual implementation of a plan with universal health coverage is a challenge. The already implemented explicit health guarantees plan (GES) could be a benchmark. For this reason, it is important to obtain information about the results of its implementation. AIM: To identify the social determinants of health that influence the access to GES. MATERIAL AND METHODS: The National Socioeconomic Characterization Survey performed in 2017 was used as a data source. The beneficiaries of 20 diseases covered by GES and inquired in the survey were considered for the present study. RESULTS: People with the higher probability of access to GES plan belong to the lowest income quintiles, are nationals, live in the central-southern metropolitan Santiago, have lower education, have a public health insurance program (FONASA) and are aged mostly over 60 years. The diseases with the highest probability of access to the program are primary arterial hypertension, type 1 and type 2 diabetes mellitus, acute myocardial infarction, moderate and severe bronchial asthma, breast cancer, colon cancer, and bipolar disorder. CONCLUSIONS: The access probability to the GES program is in line with the epidemiological profile of the Chilean population, and with a greater social vulnerability.

DNA methylation profiling for molecular classification of adult diffuse lower-grade gliomas.

BACKGROUND: DNA methylation profiling has facilitated and improved the classification of a wide variety of tumors of the central nervous system. In this study, we investigated the potential utility of DNA methylation profiling to achieve molecular diagnosis in adult primary diffuse lower-grade glioma (dLGG) according to WHO 2016 classification system. We also evaluated whether methylation profiling could provide improved molecular characterization and identify prognostic differences beyond the classical histological WHO grade together with IDH mutation status and 1p/19q codeletion status. All patients diagnosed with dLGG in the period 2007-2016 from the Västra Götaland region in Sweden were assessed for inclusion in the study. RESULTS: A total of 166 dLGG cases were subjected for genome-wide DNA methylation analysis. Of these, 126 (76%) were assigned a defined diagnostic methylation class with a class prediction score ≥ 0.84 and subclass score ≥ 0.50. The assigned methylation classes were highly associated with their IDH mutation status and 1p/19q codeletion status. IDH-wildtype gliomas were further divided into subgroups with distinct molecular features. CONCLUSION: The stratification of the patients by methylation profiling was as effective as the integrated WHO 2016 molecular reclassification at predicting the clinical outcome of the patients. Our study shows that DNA methylation profiling is a reliable and robust approach for the classification of dLGG into molecular defined subgroups, providing accurate detection of molecular markers according to WHO 2016 classification.

WHO Grade Loses Its Prognostic Value in Molecularly Defined Diffuse Lower-Grade Gliomas.

BACKGROUND: While molecular insights to diffuse lower-grade glioma (dLGG) have improved the basis for prognostication, most established clinical prognostic factors come from the pre-molecular era. For instance, WHO grade as a predictor for survival in dLGG with isocitrate dehydrogenase (IDH) mutation has recently been questioned. We studied the prognostic role of WHO grade in molecularly defined subgroups and evaluated earlier used prognostic factors in the current molecular setting. MATERIAL AND METHODS: A total of 253 adults with morphological dLGG, consecutively included between 2007 and 2018, were assessed. IDH mutations, codeletion of chromosomal arms 1p/19q, and cyclin-dependent kinase inhibitor 2A/B (CDKN2A/B) deletions were analyzed. RESULTS: There was no survival benefit for patients with WHO grade 2 over grade 3 IDH-mut dLGG after exclusion of tumors with known CDKN2A/B homozygous deletion (n=157) (log-rank p=0.97). This was true also after stratification for oncological postoperative treatment and when astrocytomas and oligodendrogliomas were analyzed separately. In IDH-mut astrocytomas, residual tumor volume after surgery was an independent prognostic factor for survival (HR 1.02; 95% CI 1.01-1.03; p=0.003), but not in oligodendrogliomas (HR 1.02; 95% CI 1.00-1.03; p=0.15). Preoperative tumor size was an independent predictor in both astrocytomas (HR 1.03; 95% CI 1.00-1.05; p=0.02) and oligodendrogliomas (HR 1.05; 95% CI 1.01-1.09; p=0.01). Age was not a significant prognostic factor in multivariable analyses (astrocytomas p=0.64, oligodendrogliomas p=0.08). CONCLUSION: Our findings suggest that WHO grade is not a robust prognostic factor in molecularly well-defined dLGG. Preoperative tumor size remained a prognostic factor in both IDH-mut astrocytomas and oligodendrogliomas in our cohort, whereas residual tumor volume predicted prognosis in IDH-mut astrocytomas only. The age cutoffs for determining high risk in patients with IDH-mut dLGG from the pre-molecular era are not supported by our results.

Hepatic hydatidosis that debuts with a direct rupture to the pleural cavity.

We present the case of a patient with pain in the right hypochondrium, dyspnea, deterioration of his general condition and a positive anti-Echinoccocus antibodies test. Ultrasound and thoraco-abdominal computed tomography (CT) demonstrated a complex hepatic cystic lesion with a transdiaphragmatic fistulous tract trajectory, directed to the pleural space. The lesion was compatible with a complicated hydatid cyst with direct rupture to the pleural cavity. Treatment with albendazole prior to surgery was started.

The clinical significance of the T2-FLAIR mismatch sign in grade II and III gliomas: a population-based study.

BACKGROUND: The T2-FLAIR mismatch sign is an imaging finding highly suggestive of isocitrate dehydrogenase mutated (IDH-mut) 1p19q non-codeleted (non-codel) gliomas (astrocytomas). In previous studies, it has shown excellent specificity but limited sensitivity for IDH-mut astrocytomas. Whether the mismatch sign is a marker of a clinically relevant subtype of IDH-mut astrocytomas is unknown. METHODS: We included histopathologically verified supratentorial lower-grade gliomas (LGG) WHO grade II-III retrospectively during the period 2010-2016. In the period 2017-2018, patients with suspected LGG radiologically were prospectively included, and in this cohort other diagnoses than glioma could occur. Clinical, radiological and molecular data were collected. For clinical evaluation we included all patients with IDH-mut astrocytomas. In the 2010-2016 cohort DNA methylation analysis with Infinium MethylationEPIC BeadChip (Illumina) was performed for patients with an IDH-mut astrocytoma with available tissue. We aimed to examine the association of the T2-FLAIR mismatch sign with clinical factors and outcomes. Additionally, we evaluated the diagnostic reliability of the mismatch sign and its relation to methylation profiles. RESULTS: Out of 215 patients with LGG, 135 had known IDH-mutation and 1p19q codeletion status. Fifty patients had an IDH-mut astrocytoma and 12 of these (24.0%) showed a mismatch sign. The sensitivity and specificity of the mismatch sign for IDH-mut detection were 26.4 and 97.6%, respectively. There were no differences between patients with an IDH-mut astrocytoma with or without mismatch sign when grouped according to T2-FLAIR mismatch sign with respect to baseline characteristics, clinical outcomes and methylation profiles. The overall interrater agreement between neuroradiologist and clinical neurosurgeons for the T2-FLAIR mismatch sign was significant when all 215 MRI examination assessed (κ = 0.77, p < 0.001, N = 215). CONCLUSION: The T2-FLAIR mismatch sign in patients with an IDH-mut astrocytoma is not associated with clinical presentation or outcome. It seems unlikely that the IDH-mut astrocytomas with mismatch sign represent a specific subentity. Finally, we have validated that the T2-FLAIR mismatch sign is a reliable and specific marker of IDH-mut astrocytomas.

Intratumor DNA methylation heterogeneity in glioblastoma: implications for DNA methylation-based classification.

BACKGROUND: A feature of glioblastoma (GBM) is cellular and molecular heterogeneity, both within and between tumors. This variability causes a risk for sampling bias and potential tumor escape from future targeted therapy. Heterogeneous intratumor gene expression in GBM is well documented, but little is known regarding the epigenetic heterogeneity. Variability in DNA methylation within tumors would have implications for diagnostics, as methylation can be used for tumor classification, subtyping, and determination of the clinically used biomarker O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation. We therefore aimed to profile the intratumor DNA methylation heterogeneity in GBM and its effect on diagnostic properties. METHODS: Three to 4 spatially separated biopsies per tumor were collected from 12 GBM patients. We performed genome-wide DNA methylation analysis and investigated intratumor variation. RESULTS: All samples were classified as GBM isocitrate dehydrogenase (IDH) wild type (wt)/mutated by methylation profiling, but the subclass differed within 5 tumors. Some GBM samples exhibited higher DNA methylation differences within tumors than between, and many cytosine-phosphate-guanine (CpG) sites (mean: 17 000) had different methylation levels within the tumors. MGMT methylation status differed in IDH mutated patients (1/1). CONCLUSIONS: We demonstrated that intratumor DNA methylation heterogeneity is a feature of GBM. Although all biopsies were classified as GBM IDH wt/mutated by methylation analysis, the assigned subclass differed in samples from the same patient. The observed heterogeneity within tumors is important to consider for methylation-based biomarkers and future improvements in stratification of GBM patients.

Evaluación del desempeño del APACHE II y SAPS III, en una unidad de cuidados intensivos / Performance evaluation of APACHE II and SAPS III in an intensive care unit / Avaliação de desempenho do APACHE II e SAPS III, em unidade de terapia intensiva

RESUMEN Objetivo El objetivo principal de este trabajo, fue validar y comparar la capacidad predictiva de mortalidad de los indicadores de gravedad APACHE II (Acute Physiology and Chronic Health Evaluation, Score II) y SAPS III (Simplified Acute Physiology, Score III) en una muestra de pacientes admitidos en la Unidad de Cuidados Intensivos Adulto (UCI) del Hospital de Curicó, entre los años 2011 y 2013. Materiales y Métodos Estudio analítico, observacional de cohorte histórica de casos consecutivos desde la admisión a la UCI hasta el egreso hospitalario. Para el análisis, se usó el Modelo de Regresión Logística Binaria. De un total de 1 042 pacientes ingresados a la UCI, se incluyó a 793 pacientes sobrevivientes, y a 249 pacientes fallecidos, que representaban el 76,1% y 23,9% respectivamente, del total. Resultados El SAPS III presenta mejor capacidad predictiva que el APACHE II, según el área bajo la curva de características operativas del receptor 0,81 y 0,80 respectivamente. La sensibilidad para el modelo SAPS III es 0,95 y para APACHE II es 0,93. El índice de especificidad es 0,3 para el SAPS III y 0,4 para el APACHE II, con probabilidad superior a 0,5. Conclusión Los indicadores de predicción de mortalidad en UCI; APACHE II y SAPS III tienen una buena capacidad predictiva general, pero ambos indicadores presentan una baja especificidad.(AU)

ABSTRACT Objective The main objective of this work was to validate and compare the predictive capacity of mortality of the severity score systems APACHE II (Acute Physiology and Chronic Health Evaluation, Score II) and SAPS III (Simplified Acute Physiology, Score III) in a sample of patients admitted to the Adult Intensive Care Unit (ICU) of the Hospital de Curicó between 2011 and 2013. Materials and Methods Analytical, observational, retrospective cohort study of consecutive cases since admission to the ICU until hospital discharge. A binary logistic regression model was used for the analysis. Out of 1 042 patients admitted to the ICU, 793 surviving patients and 249 deceased patients were included, representing 76.1% and 23.9%, respectively, of the total sample. Results The SAPS III score has a better predictive capacity than the APACHE II, according to the area under the curve and the receiver operating characteristic curve: 0.81 and 0.80, respectively. Sensitivity for the SAPS III model was 0.95 and for APACHE II was 0.93. The specificity index was 0.3 for SAPS III and 0.4 for APACHE II, with a probability above 0.5. Conclusion APACHE II and SAPS III, as ICU mortality prediction indicators, have a good predictive power but low specificity.(AU)

RESUMO Objetivo O objetivo principal deste trabalho foi validar e comparar a capacidade preditiva de mortalidade dos sistemas de escore de gravidade APACHE II (Fisiologia Aguda e Avaliação Crônica de Saúde, Escore II) e SAPS III (Fisiologia Aguda Simplificada, Escore III) em uma amostra de pacientes internado na Unidade de Terapia Intensiva Adulto (UTI) do Hospital de Curicó entre 2011 e 2013. Materiais e métodos Estudo de coorte analítico, observacional e retrospectivo de casos consecutivos desde a admissão na UTI até a alta hospitalar. Um modelo de regressão logística binária foi usado para a análise. Dos 1.042 pacientes admitidos na UTI, foram incluídos 793 pacientes sobreviventes e 249 falecidos, representando 76,1% e 23,9%, respectivamente, do total da amostra. Resultados O escore SAPS III tem melhor capacidade preditiva do que o APACHE II, de acordo com a área sob a curva e a curva de característica de operação do receptor: 0,81 e 0,80, respectivamente. A sensibilidade para o modelo SAPS III foi de 0,95 e para APACHE II foi de 0,93. O índice de especificidade foi de 0,3 para SAPS III e 0,4 para APACHE II, com probabilidade superior a 0,5. Conclusão APACHE II e SAPS III, como indicadores de predição de mortalidade em UTI, apresentam bom poder preditivo, mas baixa especificidade.(AU)

Co-sleeping versus sleep training: publications with advice for parents / Colecho versus entrenamiento del sueño: publicaciones con consejos para padres

Abstract Introduction: Sleep patterns in infants is one of the main issues regarding children upbringing and has different positions in publications. Objective: To analyze 63 publications with parenting advice on sleep in infants to subsequently characterize them in terms of their position on co-sleeping and sleep training. Materials and methods: Publications issued in the past two decades, available for purchase and/or reference in Chile. 63 publications, including parenting advice books and 32 web sites, were identified. Results: 65% of the analyzed publications favored some form co-sleeping; 76% mentioned sleep training, expressing a tendency to defend and/or accept the strategy known as 'positive routines' rather than 'cry it out methods'. Conclusions: Chilean parents are confronted with contradictory information. The current debate on the regulation of infant sleep is also seen in Ibero-America, although expert opinion differs from that found in Anglo-Saxon samples.

Resumen Introducción. Uno de los temas centrales en la crianza de los hijos, y que se sabe tiene muchas posiciones diferentes en las publicaciones, es el sueño en los bebés. Objetivo. Describir las diferentes posiciones de las publicaciones que ofrecen asesoramiento a los padres chilenos sobre el sueño en bebés durante las últimas dos décadas. Materiales y métodos. Se seleccionaron 63 publicaciones disponibles para su compra o de referencia en Chile de las dos últimas décadas, las cuales dan consejos a los padres en relación al sueño de los bebés. Estas publicaciones se analizaron para luego caracterizarlas en relación a las posiciones de colecho y entrenamiento del sueño. Resultados. Se encontró que el 65% de las publicaciones analizadas aconseja, de alguna forma, el colecho y el 76% menciona el entrenamiento del sueño, expresando una tendencia a defender o aceptar la estrategia conocida como "rutinas positivas" en lugar del "dejar llorar". Conclusiones. Los padres chilenos se enfrentan con información contradictoria: existe un debate sobre la regulación del sueño infantil en Iberoamérica y la opinión de los expertos difiere de la encontrada en muestras anglosajonas.

Solid lipid nanoparticles for delivery of Calendula officinalis extract.

Solid lipid nanoparticles (SLN) composed of long-chain fatty acids (palmitic acid, stearic acid or arachidic acid), Epikuron 200 (purified phosphatidylcholine), and bile salts (cholate, taurocholate or taurodeoxycholate) have been prepared by dilution of a microemulsion. A total of five different systems were prepared, and characterized by photon correlation spectroscopy, transmission electron microscopy, differential scanning calorimetry, and infrared spectroscopy. The SLN formulation showing optimal properties (lowest size and polydispersity index and highest zeta potential) was obtained with stearic acid and taurodeoxycholate as cosurfactant. This formulation was loaded with Calendula officinalis extract, a natural compound used on ophthalmic formulations given its anti-inflammatory, emollient, and wound repairing activity. Calendula-loaded SLN preparations were characterized in order to determine loading capacity and entrapment efficiency. In vitro cytotoxicity and wound healing efficacy of Calendula-loaded SLN compared to that of a free plant extract were evaluated on a conjunctival epithelium cell line WKD. Our results suggest that this SLN formulation is a safe and solvent-free Calendula extract delivery system which could provide a controlled therapeutic alternative for reducing disease-related symptoms and improving epithelium repair in ocular surface.

The PLGA implant as an antimitotic delivery system after experimental trabeculectomy.

PURPOSE: To investigate the effect of poly (lactic-co-glycolic acid) (PLGA) implants loaded with mitomycin C (MMC) and with different adjuvant treatments after glaucoma filtration surgery (GFS), in comparison to standard treatments. METHODS: Forty-two New Zealand White rabbits underwent bilateral GFS and received different treatments: topical MMC (group 1); topical 5-fluorouracil (5-FU; group 2); PLGA implant (group 3); MMC-loaded and -coated PLGA implant (group 4); MMC-loaded and 5-FU-coated PLGA implant (group 5); subconjunctival bevacizumab (group 6); MMC-loaded PLGA implant and subconjunctival bevacizumab (group 7); and no treatment (right eye of all animals; control group). Intraocular pressure (IOP) and filtering bleb were evaluated on different days after GFS. Histology was performed to examine the conjunctiva, sclerotomy, filtering bleb, and persistence of the implant. RESULTS: The best hypotensive results were achieved in the MMC-loaded and -coated PLGA implant group, which presented the lowest IOP values on days 1, 5, 7, 14, and 28 after GFS. Excluding the implant groups, in which the bleb could not be properly measured, bleb survival was superior to controls in groups 1, 2 and lower in group 6. Group 7 presented greater extension, height, and vascularization of the bleb. Epithelial thinning and lymphoplasmacytic infiltrate were observed in groups 1, 2, 4, 5, and 7. The rates of closure of the sclerotomy and bleb were 100% and 76%, respectively, and implant persistence was 95%. CONCLUSIONS: MMC-loaded and -coated implants have optimal surgical results, followed by topical MMC application. In this experimental model, bevacizumab could interact with MMC.