When trichoscopy enlightens clinics: more about discoid lupus

Composition as pattern

Abstract

I argue for patternism, a new answer to the question of when some objects compose a whole. None of the standard principles of composition comfortably capture our natural judgments, such as that my cat exists and my table exists, but there is nothing wholly composed of them. Patternism holds, very roughly, that some things compose a whole whenever together they form a "real pattern". Plausibly we are inclined to acknowledge the existence of my cat and my table but not of their fusion, because the first two have a kind of internal organizational coherence that their putative fusion lacks. Kolmogorov complexity theory supplies the needed rigorous sense of "internal organizational coherence".

Ecological and human health risks arising from exposure to metals in urban soils under different land use in Nigeria

Abstract

The concentrations of eight metals (Cd, Pb, Cr, Ni, Cu, Mn, Zn and Fe) were measured in soils under different land use in an urban environment of the Niger Delta in Nigeria. The aim was to provide information on the potential ecological and human health risks associated with human exposure to metals in these soils. The potential ecological risk due to metals in soils of these land use types falls in the range of low to moderate ecological risk with a significant contribution from Cd. The severity of the individual metals to ecological risk in these land use types followed the order Cd > Pb > Zn > Cu > Ni > Cr > Mn. The non-carcinogenic risk, expressed in terms of the hazard index (HI), arising through exposure to metals through oral, dermal and inhalation pathways, was greater than 1 for children in the majority of the land use types and less than 1 for adults for all land use types. This indicated that there are considerable non-cancer risks arising from childhood exposure to metals in soils of these land use types. The cancer risk values were within acceptable threshold values indicating a negligible cancer risk for both children and adults exposed to metals in these urban soils.

Impact of hand eczema on quality of life: metropolitan versus non-metropolitan areas

Summary

Background

An inverse relationship between disease severity and health-related quality of life (HR-QoL) in patients with hand eczema is well established, but modifying effects of demographic variables have been less well studied.

Objective

To identify the influence of metropolitan versus non-metropolitan residence on the relationship between disease severity and HR-QoL in patients with occupational hand eczema.

Methods

The city of Copenhagen and the rest of Zealand were defined as metropolitan and non-metropolitan areas, respectively. Participants were 773 persons with occupational hand eczema. A questionnaire on the severity of hand eczema and HR-QoL was sent to all participants.

Results

The odds for reporting moderate to high severity of occupational hand eczema were significantly lower in the metropolitan population than in the non-metropolitan population [odds ratio (OR): 0.42; 95%CI: 0.23–0.75], whereas low dermatology-related quality of life was more prevalent in metropolitan than in non-metropolitan patients (OR: 1.31; 95%CI: 0.83–2.05), indicating that hand eczema had a more pronounced negative effect in metropolitan patients, in spite of less severe eczema.

Conclusion

Our data indicate that area of residence has a modifying effect on the relationship between disease severity and HR-QoL, with a more negative impact on HR-QoL in metropolitan than in non-metropolitan areas. This information is important with respect to fully appreciating the burden of occupational hand eczema.

The CBTRUS story: providing accurate population-based statistics on brain and other central nervous system tumors for everyone

The Central Brain Tumor Registry of the United States (CBTRUS) was established to provide descriptive statistical data on all primary brain tumors. The following editorial describes some of the historical events that led to its establishment and its current role as the recognized "go-to" resource for researchers; clinicians and treatment facilities; federal and state agencies; manufacturers of medical drugs and devices; and organizations that provide education, emotional support, and guidance for brain tumor patients and their caregivers.

Highlights from the Literature

Corrigendum

Corrigendum to Beier et al. Multicenter pilot study of radiochemotherapy as first-line treatment for adults with medulloblastoma (NOA-07). Neuro Oncol (doi: https://doi.org/10.1093/neuonc/nox155) first published online 21 August 2017

Forthcoming Meetings

Simultaneous care in neuro-oncology

See the article by Philip et al on pp. 391–399.

A new practical and versatile mouse model of proneural glioblastoma

See the article by Rahme et al. on pp. 332–342.

Challenges of developing small-molecule kinase inhibitors for brain tumors and the need for emphasis on free drug levels

Abstract

Despite biological rationale and significant clinical study, the pursuit of small-molecule kinase inhibitors for the treatment of brain cancers has had very limited success. This Advance-in-Brief discusses the need for drugs to achieve free brain penetration to engage their targets where CNS tumors reside. This need to achieve free, as opposed to total, drug concentrations in the brain may be a contributing factor to why so many small-molecule kinase inhibitors have not realized success in the neuro-oncology setting. For kinase targets of interest for brain cancer, either the vast majority of small-molecule inhibitors have data suggesting that free brain penetration would be limited or there are inadequate data to suggest that free brain penetration could be expected. Therefore, kinase targets of interest in the treatment of brain cancers may be inadequately assessed due to a lack of freely brain-penetrant inhibitors available for clinical study. Encouraging recent drug discovery efforts that focused on achieving free brain penetration for cancers in the CNS are highlighted. Still, further efforts are needed to enable thorough clinical evaluation of biological hypotheses.

Visual and semiquantitative 11C-methionine PET: an independent prognostic factor for survival of newly diagnosed and treatment-naïve gliomas

Abstract

Background

Few data exist regarding the prognostic value of L-[S-methyl-¹¹C]methionine (MET) PET for treatment-naïve gliomas.

Methods

A total of 160 glioma patients (89 men, 71 women; mean age: 45, range 18–84 y) underwent a MET PET prior to any therapy. The PET scans were evaluated visually and semiquantitatively by tumor-to-background (T/N) ratio thresholds chosen by analysis of receiver operating characteristics. Additionally, isocitrate dehydrogenase 1–R132H (IDH1-R132H) immunohistochemistry was performed. Survival analysis was done using Kaplan–Meier estimates and the Cox proportional hazards model.

Results

Significantly shorter mean survival times (7.2 vs 8.6 y; P = 0.024) were seen in patients with amino acid avid gliomas (n = 137) compared with visually negative tumors (n = 33) in MET PET. T/N ratio thresholds of 2.1 and 3.5 were significantly associated with survival (10.3 vs 7 vs 4.3 y; P < 0.001). Mean survival differed significantly using the median T/N ratio of 2.4 as cutoff, independent of histopathology (P < 0.01; mean survival: 10.2 ± 0.8 y vs 5.5 ± 0.6 y). In the subgroup of 142 glioma patients characterized by IDH1-R132H status, METT/N ratio demonstrated a significant prognostic impact in IDH1-R132H wildtype astrocytomas and glioblastoma (P = 0.001). Additionally, multivariate testing revealed semiquantitative MET PET as an independent prognostic parameter for treatment-naïve glioma patients without (P = 0.031) and with IDH1-R132H characterization of gliomas (P = 0.024; odds ratio 1.57).

Conclusion

This retrospective analysis demonstrates the value of MET PET as a prognostic parameter on survival in treatment-naïve glioma patients.

Metabolic heterogeneity and plasticity of glioma stem cells in a mouse glioblastoma model

Abstract

Background

Glioblastomas have been shown to rely on glycolysis as an energy source. However, recent evidence suggests that at least a subset of glioma cells with stem cell–like properties can thrive on oxidative phosphorylation. It remains unclear whether both metabolic phenotypes support tumor propagation, if they are independent, and how stable they are. The present study investigated these questions with the use of isogenic murine glioma stem cells (GSCs).

Methods

GSCs were established from tumors formed by Ink4a/Arf–null, H-Ras^V12-expressing glioma-initiating cells that differed in extracellular acidification potential. Metabolic characteristics of GSCs were determined by measurement of glucose, oxygen, and glutamine uptake, ATP content, and lactate production. Effects of metabolic inhibitors and changes in oxygen or nutrient availability on lactate production and tumorsphere growth were also determined.

Results

GSCs were found either to consume more glucose and produce more lactate or to consume more oxygen and maintain a higher ATP content depending on the metabolic characteristics of the tumor cells of origin. The latter, mitochondrial-type GSCs increased lactate production after treatment with the oxidative phosphorylation inhibitor oligomycin or phenformin. Exposure to hypoxia also increased lactate production and expression of glycolysis-related enzymes and metabolites in mitochondrial-type GSCs in a reversible manner.

Conclusions

Both glycolytic and mitochondrial-type energy production can sustain tumor propagation by isogenic GSCs. Whereas both phenotypes can be independent and stable, cells that rely on oxidative phosphorylation can also switch to a more glycolytic phenotype in response to metabolic stress, suggesting that plasticity is a further characteristic of GSC metabolism.

Long-term exposure to ambient air pollution and incidence of brain tumor: the European Study of Cohorts for Air Pollution Effects (ESCAPE)

Abstract

Background

Epidemiological evidence on the association between ambient air pollution and brain tumor risk is sparse and inconsistent.

Methods

In 12 cohorts from 6 European countries, individual estimates of annual mean air pollution levels at the baseline residence were estimated by standardized land-use regression models developed within the ESCAPE and TRANSPHORM projects: particulate matter (PM) ≤2.5, ≤10, and 2.5–10 μm in diameter (PM_2.5, PM₁₀, and PM_coarse), PM_2.5 absorbance, nitrogen oxides (NO₂ and NO_x) and elemental composition of PM. We estimated cohort-specific associations of air pollutant concentrations and traffic intensity with total, malignant, and nonmalignant brain tumor, in separate Cox regression models, adjusting for risk factors, and pooled cohort-specific estimates using random-effects meta-analyses.

Results

Of 282194 subjects from 12 cohorts, 466 developed malignant brain tumors during 12 years of follow-up. Six of the cohorts also had data on nonmalignant brain tumor, where among 106786 subjects, 366 developed brain tumor: 176 nonmalignant and 190 malignant. We found a positive, statistically nonsignificant association between malignant brain tumor and PM_2.5 absorbance (hazard ratio and 95% CI: 1.67; 0.89–3.14 per 10^–5/m³), and weak positive or null associations with the other pollutants. Hazard ratio for PM_2.5 absorbance (1.01; 0.38–2.71 per 10^–5/m³) and all other pollutants were lower for nonmalignant than for malignant brain tumors.

Conclusion

We found suggestive evidence of an association between long-term exposure to PM_2.5 absorbance indicating traffic-related air pollution and malignant brain tumors, and no association with overall or nonmalignant brain tumors.

Loss of host-derived osteopontin creates a glioblastoma-promoting microenvironment

Abstract

Background

Microglia and periphery-derived monocytes infiltrate human and mouse glioblastoma and their density is positively correlated with malignancy. Using microarray and RNA sequencing, we have previously shown that glioblastoma-associated microglia/monocytes (GAMs) express osteopontin/SPP1.

Methods

We used quantitative reverse transcriptase PCR, immunofluorescence stainings, western blot, and flow cytometry to identify the various sources of osteopontin (OPN) expression in human and mouse glioblastoma. We implanted wild type GL261 glioblastoma cells, which do not express significant levels of OPN, into wild type and OPN^−/− mice to investigate the role of microenvironment-derived OPN on glioblastoma progression.

Results

Our data indicate that GAMs are the predominant source of OPN in both human and mouse glioblastoma and express only the secreted form of OPN. Loss of microenvironment-derived OPN enhanced tumor progression. Staining by Ki67 and terminal deoxynucleotidyl transferase deoxyuridine triphosphate nick end labeling showed no difference in overall cell proliferation but a decreased apoptosis rate in tumors in OPN^−/− mice. CD31 staining showed a significantly decreased number of microvessels in tumors in OPN^−/− mice, accompanied by reduced coverage of vessels with platelet derived growth factor receptor β⁺ pericytes. Flow cytometry analysis revealed a significant increase of CD11b⁺/CD45^low microglia but not of CD11b⁺/CD45^high macrophages/monocytes in tumors in OPN^−/− mice. Sorted CD11b⁺ cells from wild type and OPN^−/− naïve brains and tumors did not show a significant difference in the expression pattern of activation marker genes.

Conclusion

Our results show that in tested human and mouse glioblastoma samples, OPN is predominantly expressed and secreted by GAMs and that, in contrast to OPN expression in the tumor cells per se, loss of stroma-derived OPN creates a glioblastoma-promoting microenvironment.

Molecular differences in IDH wildtype glioblastoma according to MGMT promoter methylation

Abstract

Background

O⁶-methylguanine-DNA-methyltransferase (MGMT) promoter methylation status is a predictive biomarker in glioblastoma. We investigated whether this marker furthermore defines a molecularly distinct tumor subtype with clinically different outcome.

Methods

We analyzed copy number variation (CNV) and methylation profiles of 1095 primary and 92 progressive isocitrate dehydrogenase wildtype glioblastomas, including paired samples from 49 patients. DNA mutation data from 182 glioblastoma samples of The Cancer Genome Atlas (TCGA) and RNA expression from 107 TCGA and 55 Chinese Glioma Genome Atlas samples were analyzed.

Results

Among untreated glioblastomas, MGMT promoter methylated (mMGMT) and unmethylated (uMGMT) tumors did not show different CNV or specific gene mutations, but a higher mutation count in mMGMT tumors. We identified 3 methylation clusters. Cluster 1 showed the highest average methylation and was enriched for mMGMT tumors. Seventeen genes including gastrulation brain homeobox 2 (GBX2) were found to be hypermethylated and downregulated on the mRNA level in mMGMT tumors. In progressive glioblastomas, platelet derived growth factor receptor alpha (PDGFRA) and GLI2 amplifications were enriched in mMGMT tumors. Methylated MGMT tumors gain PDGFRA amplification of PDGFRA, whereas uMGMT tumors with amplified PDGFRA frequently lose this amplification upon progression. Glioblastoma patients surviving <6 months and with mMGMT harbored less frequent epidermal growth factor receptor (EGFR) amplifications, more frequent TP53 mutations, and a higher tumor necrosis factor–nuclear factor-kappaB (TNF-NFκB) pathway activation compared with patients surviving >12 months.

Conclusions

MGMT promoter methylation status does not define a molecularly distinct glioblastoma subpopulation among untreated tumors. Progressive mMGMT glioblastomas and mMGMT tumors of patients with short survival tend to have more unfavorable molecular profiles.

Multicenter pilot study of radiochemotherapy as first-line treatment for adults with medulloblastoma (NOA-07)

Abstract

Background

Medulloblastoma in adult patients is rare, with 0.6 cases per million. Prognosis depends on clinical factors and medulloblastoma entity. No prospective data on the feasibility of radiochemotherapy exist. The German Neuro-Oncology Working Group (NOA) performed a prospective descriptive multicenter single-arm phase II trial to evaluate feasibility and toxicity of radio-polychemotherapy.

Methods

The NOA-07 trial combined craniospinal irradiation with vincristine, followed by 8 cycles of cisplatin, lomustine, and vincristine. Adverse events, imaging and progression patterns, histological and genetic markers, health-related quality of life (HRQoL), and cognition were evaluated. Primary endpoint was the rate of toxicity-related treatment terminations after 4 chemotherapy cycles, and the toxicity profile. The feasibility goal was reached if at least 45% of patients received at least 4 cycles of maintenance chemotherapy.

Results

Thirty patients were evaluable. Each 50% showed classic and desmoplastic/nodular histology. Sixty-seven percent were classified into the sonic hedgehog (SHH) subgroup without TP53 alterations, 13% in wingless (WNT), and 17% in non-WNT/non-SHH. Four cycles of chemotherapy were feasible in the majority (n = 21; 70.0%). Hematological side effects and polyneuropathy were prevalent toxicities. During the active treatment period, HRQoL and verbal fluency improved significantly. The 3-year event-free survival rate was 66.6% at the time of databank lock.

Conclusions

Radio-polychemotherapy did lead to considerable toxicity and a high amount of dose reductions throughout the first 4 chemotherapy cycles that may affect efficacy. Thus, we propose frequent patient surveillance using this regimen. Modifications of the regimen may increase feasibility of radio-polychemotherapy of adult patients with medulloblastoma.

Mesenchymal stem cells as natural biofactories for exosomes carrying miR-124a in the treatment of gliomas

Abstract

Background

MicroRNAs (miRs) are promising new therapeutics for glioblastoma. However, which miRs are most effective against glioblastomas and how these miRs should be delivered are major unanswered problems.

Methods

To identify potent antiglioma miRs, we selected 8 miRs based on a literature search and screened them against a panel of glioma stem cell (GSC) lines, representing all of the glioblastoma subtypes defined by The Cancer Genome Atlas. To address delivery, we tested the hypothesis that ex vivo cultured bone marrow–derived mesenchymal stem cells (MSCs) can package miRs into exosomes and that these engineered exosomes can systemically deliver antiglioma miRs to glioblastomas.

Results

Of the screened miRs, we identified miR-124a as the most effective antiglioma agent against GSCs. We then transduced MSCs with lentivirus vectors containing miR-124a and isolated vesicles from the medium. Electron microscopy, western blotting, and Nanosight proved that the isolated vesicles were exosomes. Quantitative PCR documented that these exosomes contained high levels of miR-124a, which was not present in control exosomes. In vitro treatment of GSCs with exosomes containing miR-124a (Exo-miR124) resulted in a significant reduction in viability and clonogenicity of GSCs compared with controls. In vivo treatment of mice harboring intracranial GSC267 with systemically delivered Exo-miR124 resulted in 50% of animals living long term. No evidence of tumor was present on histological analysis of the survivors. Mechanistic studies showed that miR-124a acts by silencing Forkhead box (FOX)A2, resulting in aberrant intracellular lipid accumulation.

Conclusion

MSCs can be used as natural biofactories to produce Exo-miR124, which is an effective antiglioma agent worthy of further clinical evaluation.

A proposed framework of supportive and palliative care for people with high-grade glioma

Abstract

Background

Patients with malignant high-grade glioma (HGG) have significant supportive and palliative care needs, yet few tailored guidelines exist to inform practice. This study sought to develop an HGG framework of supportive and palliative care informed by needs reported by patients, families, and health care professionals (HCPs).

Methods

This study integrates a mixed-methods research program involving: (i) exploring experiences through systematic literature review and qualitative study (10 patients, 23 carers, and 36 HCPs); and (ii) an epidemiological cohort study (N = 1821) describing care of cases of HGG in Victoria, Australia using linked hospital datasets. Recommendations based on these studies were developed by a multidisciplinary advisory committee for a framework of supportive and palliative care based on the findings of (i) and (ii).

Results

Key principles guiding framework development were that care: (i) aligns with patient/family caregiver needs according to illness transition points; (ii) involves continuous monitoring of patient/family caregiver needs; (iii) be proactive in response to anticipated concerns; (iv) includes routine bereavement support; and (v) involves appropriate partnership with patients/families. Framework components and resulting activities designed to address unmet needs were enacted at illness transition points and included coordination, repeated assessment, staged information provision according to the illness transition, proactive responses and referral systems, and specific regular inquiry of patients' and family caregivers' concerns.

Conclusion

This evidence-based, collaborative framework of supportive and palliative care provides an approach for patients with HGG that is responsive, relevant, and sustainable. This conceptual framework requires evaluation in robust clinical trials.

Clinical characteristics associated with postoperative seizure control in adult low-grade gliomas: a systematic review and meta-analysis

Abstract

Background

Epilepsy is the most common symptom in patients with supratentorial low-grade gliomas (LGGs), which adversely affects the patient's quality of life. Poor seizure control with anti-epileptic therapy is an indication for surgery in these patients. Recent studies have sought to identify predictors of postoperative seizure control after surgical resection of LGG; gross total resection was shown to be a significant predictor in this respect. However, the prognostic value of other factors is not clear.

Methods

We performed a systematic review and meta-analysis of 23 studies with a combined study population of 2641 patients with LGG, in order to identify potential factors associated with favorable postoperative seizure control. Data were extracted on age and sex of patient, tumor location, tumor histology, type of seizure, seizure duration, extent of resection, and imaging characteristics.

Results

Patients ≥45 years of age achieved better postoperative seizure control (risk ratio [RR], 0.89; 95% CI, 0.81–0.99). Focal seizures were associated with poor seizure control (RR, 1.32; 95% CI, 1.18–1.49) compared with generalized seizures (RR, 0.77; 95% CI, 0.68–0.87). Prolonged history of seizures (≥1 y) had a negative impact on postoperative seizure control (RR, 1.22; 95% CI, 1.10–1.34). Gross total resection was superior to subtotal resection with respect to postoperative seizure control (RR, 0.68; 95% CI, 0.63–0.73).

Conclusions

This systematic review and meta-analysis identified predictors of postoperative seizure control in patients undergoing surgical resection of LGGs. Our results provide a reference for clinical treatment of LGG-related epilepsy.