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In this national population-based study of glioma, we present epidemiologic data on incidence, demographics, survival, clinical characteristics and symptoms, and evaluate the association of specific indicators with the grade of glioma. We included 1930 patients registered in the Danish Neuro-Oncology Registry (DNOR) from 2009 to 2014. DNOR is a large-scale national population-based database including all adult glioma patients in Denmark. The age-adjusted annual incidence of histologic verified glioma was 7.3 cases pr. 100,000 person-years. High-grade gliomas were present in 85% and low-grade glioma in 15%. The overall male:female ratio was 3:2 and the mean age at onset was 60 years. Data for WHO grade I, II, III and IV glioma showed several important differences regarding age and sex distribution and symptomatology at presentation. The mean age increased with the grade of glioma and males predominated in all grades. Focal deficits were the most frequent presenting symptom, but among patients with glioma, grade II epileptic seizures were the most frequent symptom. Headache was a rare mono-symptomatic onset symptom. At presentation, higher age, focal deficits and cognitive change for <3 months duration, and headache <1 month were significant independent indicators of high-grade gliomas. Younger age and epileptic seizures for more than 3 months were indicative for low-grade gliomas. Survival rates for glioma grade I–IV showed decreasing survival with increasing grade. Glioma grade I–IV showed high diversity regarding several demographic and clinical characteristics emphasizing the importance of individually tailored disease treatments and support.

Survival of glioblastoma patients varies and prognostic markers are important in the clinical setting. With digital pathology and improved immunohistochemical multiplexing becoming a part of daily diagnostics, we investigated the prognostic value of the Ki-67 labelling index (LI) in glioblastomas more precisely than previously by excluding proliferation in non-tumor cells from the analysis. We investigated the Ki-67 LI in a well-annotated population-based glioblastoma patient cohort (178 IDH-wildtype, 3 IDH-mutated). Ki-67 was identified in full tumor sections with automated digital image analysis and the contribution from non-tumor cells was excluded using quantitative double-immunohistochemistry. For comparison of the Ki-67 LI between WHO grades (II-IV), 9 IDH-mutated diffuse astrocytomas and 9 IDH-mutated anaplastic astrocytomas were stained. Median Ki-67 LI increased with increasing WHO grade (median 2.7%, 6.4% and 27.5%). There was no difference in median Ki-67 LI between IDH-mutated and IDH-wildtype glioblastomas ( p  = 0.9) and Ki-67 LI was not associated with survival in glioblastomas in neither univariate ( p  = 0.9) nor multivariate analysis including MGMT promoter methylation status and excluding IDH-mutated glioblastomas ( p  = 0.2). Ki-67 may be of value in the differential diagnostic setting, but it must not be over-interpreted in the clinico-pathological context.

Ipilimumab is a fully human monoclonal antibody that binds cytotoxic T-lymphocyte antigen 4 to enhance antitumour immunity. Our aim was to assess the use of ipilimumab after radiotherapy in patients with metastatic castration-resistant prostate cancer that progressed after docetaxel chemotherapy. We did a multicentre, randomised, double-blind, phase 3 trial in which men with at least one bone metastasis from castration-resistant prostate cancer that had progressed after docetaxel treatment were randomly assigned in a 1:1 ratio to receive bone-directed radiotherapy (8 Gy in one fraction) followed by either ipilimumab 10 mg/kg or placebo every 3 weeks for up to four doses. Non-progressing patients could continue to receive ipilimumab at 10 mg/kg or placebo as maintenance therapy every 3 months until disease progression, unacceptable toxic effect, or death. Patients were randomly assigned to either treatment group via a minimisation algorithm, and stratified by Eastern Cooperative Oncology Group performance status, alkaline phosphatase concentration, haemoglobin concentration, and investigator site. Patients and investigators were masked to treatment allocation. The primary endpoint was overall survival, assessed in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT00861614. From May 26, 2009, to Feb 15, 2012, 799 patients were randomly assigned (399 to ipilimumab and 400 to placebo), all of whom were included in the intention-to-treat analysis. Median overall survival was 11·2 months (95% CI 9·5–12·7) with ipilimumab and 10·0 months (8·3–11·0) with placebo (hazard ratio [HR] 0·85, 0·72–1·00; p=0·053). However, the assessment of the proportional hazards assumption showed that it was violated (p=0·0031). A piecewise hazard model showed that the HR changed over time: the HR for 0–5 months was 1·46 (95% CI 1·10–1·95), for 5–12 months was 0·65 (0·50–0·85), and beyond 12 months was 0·60 (0·43–0·86). The most common grade 3–4 adverse events were immune-related, occurring in 101 (26%) patients in the ipilimumab group and 11 (3%) of patients in the placebo group. The most frequent grade 3–4 adverse events included diarrhoea (64 [16%] of 393 patients in the ipilimumab group vs seven [2%] of 396 in the placebo group), fatigue (40 [11%] vs 35 [9%]), anaemia (40 [10%] vs 43 [11%]), and colitis (18 [5%] vs 0). Four (1%) deaths occurred because of toxic effects of the study drug, all in the ipilimumab group. Although there was no significant difference between the ipilimumab group and the placebo group in terms of overall survival in the primary analysis, there were signs of activity with the drug that warrant further investigation. Bristol-Myers Squibb.

ObjectiveConsidering that epilepsy is common, and knowledge is lacking on its role especially for the prognosis of high-grade gliomas, the objective of this study was to investigate the association between epilepsy prior to glioma diagnosis and survival among glioma patients.MethodsIn a nationwide population-based cohort study, we included 3763 adult glioma patients diagnosed between 2009 and 2018 according to the Danish Neuro-Oncology Registry. Information on epilepsy was redeemed through Danish Neuro-Oncology Registry, National Patient Registry, and National Prescription Registry. Cox proportional hazard models with 95% confidence intervals (CIs) were applied to examine hazard ratios (HRs) for the association between epilepsy (< 1 year prior to glioma including epilepsy at onset; 1–10 years prior to glioma; no prior epilepsy) and risk of death, and whether it differed according to tumor grade and size, performance status, and treatment modalities.ResultsA 32% decreased risk of death in patients with epilepsy within 1 year prior to glioma compared to no prior epilepsy was found (HR = 0.68; CI 0.63–0.75). A favorable prognosis was seen for epilepsy in all glioma grades: II (HR = 0.55; CI 0.39–0.77), III (HR = 0.59; CI 0.48–0.73), and IV (HR = 0.85; CI 0.77–0.94).ConclusionsPatients with epilepsy within 1 year prior to glioma diagnosis had significant survival benefits compared to patients with no prior epilepsy. This association was significant for both low-grade gliomas (grade II) and high-grade gliomas (grade III and IV). Survival benefits in glioma patients with epilepsy at onset are possibly primarily attributable to tumor-specific histopathology, molecular biomarkers, and early diagnosis.

Background and purpose: Venous thromboembolism (VTE) is a cause of increased morbidity and risk of death. Studies report VTE in up to 30% of glioma patients but the results vary. The VTE risk is relevant when evaluating prophylaxis to avoid unnecessary bleeding or overdiagnosis. This study examines the VTE incidence in patients with glioma WHO grade 2-4, and when VTE occurred, risk factors, and overall survival (OS) for patients with WHO grade 4. Materials and methods: In total 3,630 patients with WHO grade 2 (п = 230), grade 3 (п = 317), and grade 4 (п = 3,083) gliomas from 2010 to 2018 were identified using the Danish Neuro-Oncology Registry. VTE diagnoses and time of death were obtained from Statistics Denmark. Results and interpretation: The VTE incidence was 5.2, 6.3, and 6.8% in patients with WHO grade 2, 3, and 4 gliomas, respectively. The VTE incidence rate was highest during the first 3 months after the diagnosis with 53 events. Increasing age (HR 1.03, 95%C| 1.01-1.04), male sex (HR 1.47, 95%C| 1.09-1.99), poor регformance status (HR 1.57, 95%CI 1.10-2.25), and post-operative long-course radiochemotherapy (HR 2.10, 95%C| 1.19-3.72) were predictors of VTE in patients with glioma WHO grade 4. There was no difference in OS comparing patients having VTE to those without (p = 0.068). In conclusion, patients with glioma WHO grade 2-4 were at high risk of VTE, especially the first 3 months after diagnosis. Increasing age, male sex, poor performance status, and long-course radiochemotherapy were associated with increased risk of VTE in patients with glioma WHO grade 4.

Astrocytic brain tumors are the most frequent primary brain tumors. Treatment with radio- and chemotherapy has increased survival making prognostic biomarkers increasingly important. The aim of the present study was to investigate the expression and prognostic value of transferrin receptor-1 (TfR1) as well as ferritin heavy (FTH) and light (FTL) chain in astrocytic brain tumors. A cohort of 111 astrocytic brain tumors (grade II-IV) was stained immunohistochemically with antibodies against TfR1, FTH, and FTL and scored semi-quantitatively. Double-immunofluorescence stainings were established to determine the phenotype of cells expressing these markers. We found that TfR1, FTH, and FTL were expressed by tumor cells in all grades. TfR1 increased with grade (p<0.001), but was not associated with prognosis in the individual grades. FTH and FTL were expressed by tumor cells and cells with microglial/macrophage morphology. Neither FTH nor FTL increased with malignancy grade, but low FTH expression by both tumor cells (p = 0.03) and microglia/macrophages (p = 0.01) correlated with shorter survival in patients anaplastic astrocytoma. FTL-positive microglia/macrophages were frequent in glioblastomas, and high FTL levels correlated with shorter survival in the whole cohort (p = 0.01) and in patients with anaplastic astrocytoma (p = 0.02). Double-immunofluorescence showed that TfR1, FTH, and FTL were co-expressed to a limited extent with the stem cell-related marker CD133. FTH and FTL were also co-expressed by IBA-1-positive microglia/macrophages. In conclusion, TfR1 was highly expressed in glioblastomas and associated with shorter survival in the whole cohort, but not in the individual malignancy grades. Low levels of FTH-positive tumor cells and microglia/macrophages were associated with poor survival in anaplastic astrocytomas, while high amounts of FTL-positive microglia/macrophages had a negative prognostic value. The results suggest that regulation of the iron metabolism in astrocytic brain tumors is complex involving both autocrine and paracrine signaling.

BackgroundAs many glioblastoma patients are in a poor condition they are unable to undergo the full treatment documented in clinical trials. We aimed to examine the survival and its relationship to clinical characteristics and treatment in a nationwide population of glioblastoma patients in Denmark.MethodsWe included prospectively recorded clinical data from 1364 adult patients with histologically verified glioblastoma from the Danish Neuro-Oncology Registry, 2009–2014.ResultsThe age standardized incidence rate was 6.3/100,000 person-years for males and 3.9 for females and the median age was 66 years. The median overall survival was 11.2 months. There was an independently significant prognostic effect of age, performance status, cognitive symptoms, tumor diameter, multifocality, crossing midline, and contrast enhancement. For partial and total resection compared to biopsy only, the adjusted risk of dying was reduced by 43% (HR [CI] 0.57 [0.48–0.68]) and 51% (0.49 [0.40–0.60]), respectively. For patients receiving a partial and full radiochemotherapy regimen compared to no postsurgical treatment, the risk reduction was 56% (HR [CI] 0.44 [0.37–0.53]) and 70% (0.30 [0.25–0.35]), respectively. The full radiochemotherapy regimen was only allocated to 50% of the patients, 29% among the oldest (70+ years) and 60% among the younger (18–69 years).ConclusionsGlioblastoma patients had a poor overall survival but with several specific independent prognostic factors. Extensive cancer treatment was associated with an increasing survival in all age groups, but only half of the patients were sufficiently fit for a full regimen of postoperative combined radiochemotherapy.

PurposeIn the Rehabilitation of Prostate Cancer (RePCa) study, the intervention reduced early adverse effects in prostate cancer 6 months after radiotherapy. This 3-year follow-up study assesses late adverse effects, evaluates rehabilitative long-term effects and identifies patients who benefit the most.DesignRePCa was a randomized clinical trial with multidisciplinary rehabilitation (n = 79) or usual care (n = 82). The intervention during the first 6 months consisted of consultations by nurses and physiotherapists focusing on psychosocial support and physical activity, respectively. Here we report the 3-year follow-up. Data consisted of disease-specific quality of life (EPIC-26), general quality of life (SF-12) and pelvic floor strength measured by electromyography.ResultsOne hundred forty-three patients (92%) responded. The primary outcome urinary irritative sum-score was no longer significantly different between groups. In patients with moderate-severe urinary problems at baseline, we observed a significant long-term effect on the urinary irritative sum-score in favour of the intervention (+ 13.4 points P = .014). More patients had moderate-severe bowel problems in the control group (n = 10; 14%) compared to the intervention group (n = 2; 3%) (P = .016). Pelvic floor strength deteriorated significantly in both groups.ConclusionThe short-term rehabilitation was beneficial but of limited benefit in the long term for all patients. A significant and clinically relevant effect was found in irradiated prostate cancer patients with moderate-severe urinary problems at baseline. In both groups, pelvic floor strength was weakened during follow-up.Impact for cancer survivorsPrior research showed patients benefit from early rehabilitation. Identification of patients with moderate-severe urinary problems followed by a focused rehabilitation during the first 6 months after radiotherapy results in long-term improvement. Radiated patients have to be aware of their pelvic floor strength.Implications for Cancer SurvivorsPatients can be informed that they benefit from early rehabilitation, and they cannot expect larger changes in adverse effects within the first years, but they have to be aware of their pelvic floor strength. Future rehabilitation studies could be applied mainly to patients with assessed rehabilitation needs after radiotherapy and intensified with long-term follow-up.

High-grade gliomas are some of the most lethal forms of human cancer, and new clinical biomarkers and therapeutic targets are highly needed. MicroRNAs (miRNAs), a group of short noncoding RNAs, hold great potential as new biomarkers and targets as they are commonly deregulated in a variety of diseases including gliomas. MicroRNA-21 (miR-21) is the most consistently overexpressed miRNA in several cancers including gliomas and is therefore very promising as a useful clinical biomarker and therapeutic target. To better understand the role of miR-21 in gliomas, paraffin-embedded glioma tissue samples from 193 patients with grade I, II, III, and IV tumors were analyzed by in situ hybridization (ISH) using LNA-DNA chimeric probes. We found miR-21 expression in tumor cells and tumor-associated blood vessels, whereas no expression was seen in adjacent normal brain parenchyma. Using advanced image analysis we obtained quantitative estimates reflecting the miR-21 expression levels in each of these compartments. The miR-21 levels correlated significantly with grade [ p  = 0.027, r s  = 0.161, 95 % confidence interval (CI), 0.015–0.301] with the highest levels measured in glioblastomas. Only tumor cell miR-21 was associated with poor prognosis when adjusting for known clinical parameters (age, grade, and sex) in a multivariate analysis [ p  = 0.049, hazard ratio (HR) = 1.545, 95 % CI, 1.002–2.381]. In conclusion, we have shown that miR-21 is located in both tumor cells and tumor blood vessels and that its level in the tumor cell compartment holds unfavorable prognostic value in gliomas.

High-grade gliomas have an aggressive clinical course and new clinical biomarkers and therapeutic targets are highly needed. WEE1 is a regulator of the G2 checkpoint in glioblastoma (GBM) cells. Inhibition of this kinase has, in experimental glioma studies, been suggested to enhance sensitivity to irradiation and temozolomide. However, expression level and prognostic potential of WEE1 protein in gliomas remain uninvestigated. In this study, glioma samples from 235 patients across all four WHO grades were analyzed by immunohistochemistry. Using image analysis, we calculated the area fraction of WEE1 positive nuclei. We found that WEE1 protein was localized in tumor cell nuclei and expressed in all glioma types and grades. Although WEE1 protein levels are higher in GBMs (mean 24.5 %) relative to grade III (mean 14,0 %, p  < 0.05) and grade II (mean 6.8 %, p  < 0.001) gliomas, high WEE1 protein was associated with better survival in GBMs ( p  = 0.002). This was confirmed in multivariate analysis (HR 0.60, p  = 0.003) even when adjusted for MGMT status (HR 0.60, p  = 0.005). In conclusion, we report a nuclear expression of WEE1 protein in all glioma grades and types. The WEE1 positive nuclear area was correlated with malignancy grade but it was inversely associated with prognosis in GBM. Although WEE1 is a frequently occurring protein and has been proposed as a novel target in GBM, the role of WEE1 in glioma patient survival appears to be connected to the MGMT status and is more complex than previously anticipated.