Telomerase reverse transcriptase (TERT) activity is up-regulated in several types of tumors including glioblastoma (GBM). In the present study, 128 primary glioblastoma patients were examined for ...single nucleotide polymorphisms of TERT in blood and in 92 cases for TERT promoter mutations in tumors. TERT promoter mutations were observed in 86% of the tumors and of these, C228T (-124 bp upstream start codon) was detected in 75% and C250T (-146 bp) in 25% of cases. TERT promoter mutations were associated with shorter overall survival (11 vs. 20 months p = 0.002 and 12 vs. 20, p = 0.04 for C228T and C250T, respectively). The minor alleles of rs2736100 and rs10069690 SNP's, located in intron 2 and the promotor regions, respectively, were associated with an increased risk of developing GBM (p = 0.004 and 0.001). GBM patients having both TERT promoter mutations and being homozygous carriers of the rs2853669 C-allele displayed significantly shorter overall survival than those with the wild type allele. The rs2853669 SNP is located in a putative Ets2 binding site in the promoter (-246 bp upstream start codon) close to the C228T and C250T mutation hot spots. Interleukin-6 (IL-6) expression regulated by TERT promoter status and polymorphism, what leads us to think that TERT and IL-6 plays a significant role in GBM, where specific SNPs increase the risk of developing GBM while the rs2853669 SNP and specific mutations in the TERT promoter of the tumor lead to shorter survival.
Venous thromboembolism (VTE) is a common problem among patients with glioblastoma multiforme (GBM) and with some other cancers. Here, we evaluated genetic and non-genetic potential risk factors for ...VTE among GBM patients.
A cohort of 139 patients treated with concomitant radiotherapy and temozolomide were included in the study. Next generation sequencing and genotyping approaches were applied to assess genetic risk factors in the haemostatic system. Clinical data including surgery, reoperation as well as blood group and patient information such as age and gender were available from patient records. Logistic regression analysis was performed to asses VTE risk.
In the study 47 patients (34%) were diagnosed for VTE during the course of their disease. When genetic and non-genetic potential risk factors were evaluated, only B blood group was found to be significantly associated with VTE incidence (odds ratio OR = 6.91; confidence interval CI = 2.19–24.14; P = 0.001). In contrast, A and O blood groups did not correlate with VTE risk. Frontal lobe tumor location also seemed to slightly increase VTE risk compared to other brain sites (OR = 3.14; CI = 1.1–10.7) although the significance level was at borderline (P = 0.05). Current study identified B blood group as the component in non-O blood groups that is responsible for increased VTE risk.
In conclusion, these results suggest for the first time that B blood group is predictive for VTE incidence among patients with glioblastoma, information that may be potentially valuable when selecting GBM patients who are at risk for VTE for anticoagulant prophylaxis.
•Thrombosis is a major problem in patients with high grade glioblastoma tumors (GBM).•We investigated several potential thrombosis risk factors in 139 GBM patients.•B blood group but not A or O blood groups significantly increased thrombosis risk.•GBM patients with B blood group could benefit from thrombosis prophylaxis.
We sought to analyse the androgen receptor (AR) in glioblastoma (GBM) due to the location of the AR gene on chromosome X, often reported with shorter survival and higher prevalence of GBM among ...males. Copy number (CN) and mRNA expression of AR were tested with droplet digital PCR in 91 fresh‐frozen GBM samples and 170 formalin‐fixed, paraffin‐embedded samples collected at Linköping University Hospital. The fresh‐frozen cohort was also subjected to pyrosequencing methylation analysis of 17 CpG sites in the AR promoter. Additionally, the gene expression of AR was analysed in the fresh‐frozen cohort and The Cancer Genome Atlas (TCGA) cohort of isocitrate dehydrogenase wild‐type primary GBM (135 females and 219 males). The association of AR expression and overall survival (OS) was tested with Kaplan–Meier log rank analysis after dichotomisation by maximally selected rank statistics. We found that AR CN alterations were more common in female GBM. AR gene expression correlated with methylation levels of different CpG sites in males and females but there was no difference in expression between sexes. Survival analysis of TCGA cohort revealed the opposite effect of AR overexpression on OS of males and females, with high AR expression correlating with shorter OS in females and longer OS in males. Additional gene set enrichment analysis showed that AR expression correlated with DNA repair response, especially in the male group. In summary, we found that high AR gene expression in GBM exhibits sex‐dependent effects on patient survival, which, for males, is linked to DNA repair response.
Glioblastoma (GBM) is more common among males; however, the reason for sex differences remains largely unknown. Through molecular analyses of androgen receptor (AR) in GBM samples, we found that AR is commonly expressed in tumours of both sexes, but copy number alterations of the gene coding for AR are more frequent in females. Additionally, high AR expression correlates with worse survival among females but better survival among males.
Streptococcus intermedius
occasionally causes brain abscesses that can be life-threatening, requiring prompt antibiotic and neurosurgical treatment. The source is often dental, and it may spread to ...the eye or the brain parenchyma. We report the case of a 34-year-old man with signs of apical periodontitis, endophthalmitis, and multiple brain abscesses caused by
Streptococcus intermedius
. Initial treatment with meropenem and vancomycin was unsuccessful due to subtherapeutic concentrations, despite recommended dosages. Adequate concentrations could be reached only after increasing the dose of meropenem to 16 g/day and vancomycin to 1.5 g × 4. The patient exhibited high creatinine clearance consistent with augmented renal clearance, although iohexol and cystatin C clearances were normal. Plasma free vancomycin clearance followed that of creatinine. A one-day dose of trimethoprim–sulfamethoxazole led to an increase in serum creatinine and a decrease in both creatinine and urea clearances. These results indicate that increased tubular secretion of the drugs was the cause of suboptimal antibiotic treatment. The patient eventually recovered, but his left eye needed enucleation. Our case illustrates that augmented renal clearance can jeopardize the treatment of serious bacterial infections and that high doses of antibiotics are needed to achieve therapeutic concentrations in such cases. The mechanisms for regulation of kidney tubular transporters of creatinine, urea, vancomycin, and meropenem in critically ill patients are discussed.
Biological causes of sex disparity seen in the prevalence of cancer, including glioblastoma (GBM), remain poorly understood. One of the considered aspects is the involvement of the sex chromosomes, ...especially loss of chromosome Y (LOY).
Tumors from 105 isocitrate dehydrogenase (IDH) wild type male GBM patients were tested with droplet digital PCR for copy number changes of ten genes on chromosome Y. Decreased gene expression, a proxy of gene loss, was then analyzed in 225 IDH wild type GBM derived from TCGA and overall survival in both cohorts was tested with Kaplan-Meier log-rank analysis and maximally selected rank statistics for cut-off determination.
LOY was associated with significantly shorter overall survival (7 vs. 14.6 months,
= 0.0016), and among investigated individual genes survival correlated most prominently with loss of the sex-determining region Y gene (SRY) (10.8 vs. 14.8 months,
= 0.0031). Gene set enrichment analysis revealed that epidermal growth factor receptor, platelet-derived growth factor receptor, and MYC proto-oncogene signaling pathways are associated with low SRY expression.
Our data show that deletions and reduced gene expression of chromosome Y genes, especially SRY, are associated with reduced survival of male GBM patients and connected to major susceptibility pathways of gliomagenesis.
Purpose
Fluorescence-guided surgery applying 5-aminolevulinic acid (5-ALA) in high-grade gliomas is an established method in adults. In children, results have so far been ambiguous. The aim of this ...study was to investigate 5-ALA-induced fluorescence in pediatric brain tumors by using the surgical microscope and a spectroscopic hand-held probe.
Methods
Fourteen randomly selected children (age 4–17) with newly MRI-verified brain tumors were included. No selection was based on the suspected diagnosis prior to surgery. All patients received 5-ALA (20 mg /kg) either orally or via a gastric tube prior to surgery. Intratumoral fluorescence was detected with the microscope and the probe. Moreover, fluorescence in the skin of the forearm was measured. Histopathology samples revealed seven low-grade gliomas, four medulloblastomas, one diffuse intrinsic pontine glioma, one glioblastoma and one atypical meningioma. Blood samples were analyzed, and potential clinical side effects were monitored.
Results
Microscopically, vague fluorescence was visible in two patients. Intratumoral fluorescence could be detected in five patients with the probe, including the two patients with vague microscopic fluorescence. Three of the oldest children had PpIX fluorescence in the skin. Nine children did not show any fluorescence in the tumor or in the skin. No clinical side effects or laboratory adverse events were observed.
Conclusion
Fluorescence could not be used to guide surgery in this study, neither with the surgical microscope nor with the hand-held probe. In nine children, no fluorescence was discerned and children with noticeable fluorescence were all older than nine years. 5-ALA was considered safe to apply in children.
Stereotactic neurosurgical brain biopsies are afflicted with risks of inconclusive results and hemorrhage. Such complications can necessitate repeated trajectories and prolong surgical time.
To ...develop and introduce a 1-insertion stereotactic biopsy kit with direct intraoperative optical feedback and to evaluate its applicability in 3 clinical cases.
An in-house forward-looking probe with optical fibers was designed to fit the outer cannula of a side-cutting biopsy kit. A small aperture was made at the tip of the outer cannula and the edges aligned with the optical probe inside. Stereotactic biopsies were performed using the Leksell Stereotactic System. Optical signals were measured in millimeter steps along the preplanned trajectory during the insertion. At the region with the highest 5-aminolevulinic acid (5-ALA)-induced fluorescence, the probe was replaced by the inner cannula, and tissue samples were taken. The waiting time for pathology diagnosis was noted.
Measurements took 5 to 10 minutes, and the surgeon received direct visual feedback of intraoperative 5-ALA fluorescence, microcirculation, and tissue gray-whiteness. The 5-ALA fluorescence corroborated with the pathological findings which had waiting times of 45, 50, and 75 minutes. Because only 1 trajectory was required and the patient could be prepared for the end of surgery immediately after sampling, this shortened the total surgical time.
A 1-insertion stereotactic biopsy procedure with real-time optical guidance has been presented and successfully evaluated in 3 clinical cases. The method can be modified for frameless navigation and thus has great potential to improve safety and diagnostic yield for both frameless and frame-based neurosurgical biopsy procedures.
Objectives
Seizures as presenting symptom of glioblastoma (GBM) are known to predict prolonged survival, whereas the clinical impact of other initial symptoms is less known. Our main objective was to ...evaluate the influence of different presenting symptoms on survival in a clinical setting. We also assessed lead times, tumour size and localization.
Methods
Medical records of 189 GBM patients were reviewed regarding the first medical appointment, presenting symptom/s, date of diagnostic radiology and survival. Tumour size, localization and treatment data were retrieved. Overall survival was calculated using Kaplan‐Meier and Mann‐Whitney U test. Cox regression was used for risk estimation.
Results
Cognitive impairment as the initial symptom was often misinterpreted in primary health care leading to a delayed diagnosis. Initial global symptoms (66% of all patients) were associated with reduced survival compared to no global symptoms (median 8.4 months vs. 12.6 months). Those with the most common cognitive dysfunctions: change of behaviour, memory impairment and/or disorientation had a reduced median survival to 6.4 months. In contrast, seizures (32%) were associated with longer survival (median 11.2 months vs. 8.3 months). Global symptoms were associated with larger tumours than seizures, but tumour size had no linear association with survival. The setting of the first medical appointment was evenly distributed between primary health care and emergency units.
Conclusion
Patients with GBM presenting with cognitive symptoms are challenging to identify, have larger tumours and reduced survival. In contrast, epileptic seizures as the first symptom are associated with longer survival and smaller tumours.
Objectives
The median survival in glioblastoma (GBM) patients used to be less than 1 year. Surgical removal of the tumor with subsequent concomitant radiation/temozolomide (the Stupp regimen) has ...been shown to prolong survival. The Stupp protocol was implemented in the county of Jönköping in 2006.
The purpose of this study was to examine if the Stupp treatment has prolonged overall survival, in an unselected patient cohort with histologically verified GBM.
Material and Method
This study includes all patients from the county of Jönköping, with a diagnosis of GBM from January 2001 to December 2012. Patients were divided into 2 cohorts, 2001‐2005 and 2006‐2012, that is before and after implementation of the Stupp regimen. By reviewing the medical case notes, the dates of the histological diagnosis and of death were identified. The median and mean overall survival and Kaplan‐Meier survival analysis were calculated and compared between the 2 cohorts.
Results
The mean survival was 110 days longer in the cohort treated according to the Stupp regimen. Four patients in the 2006‐2012 cohort and 1 patient in the 2001‐2005 cohort are still alive. When comparing survival in patients with radical surgery vs biopsy, those that underwent radical surgery survived longer. The significance was slightly greater in the 2001‐2005 cohort (mean 163 vs 344 days, P < .001) than in the 2006‐2012 cohort (mean 220 vs 397 days, P = .02).
Conclusion
Survival significantly improved after the implementation of the Stupp regimen in the study region of Sweden.
Do I want to know it all? Malmström, Annika; Åkesson, Lisa; Milos, Peter ...
Supportive care in cancer,
2021, Letnik:
29, Številka:
6
Journal Article
Recenzirano
Odprti dostop
Purpose Glioma patients have poor prognosis. The amount of detail of disease-related information patients wish to receive is not known. The aim of this study was to explore glioma patients ...experiences and preferences regarding receiving information on diagnosis and prognosis. Methods Semi-structured interviews were performed with patients diagnosed with glioma. The interviews were analysed by qualitative content analysis without predefined categories by two independent coders. Results Ten women and 15 men, with newly diagnosed grade II-IV glioma, age 25-76 years, were interviewed. Participants experience on diagnosis communication was either indirect, meaning they found out their diagnosis unintentionally, e.g., from their electronic health record (EHR) instead of from their doctor, this causing anxiety and feelings of abandonment, insufficiently tailored: lacking in many aspects or individualised and compassionate. Participants generally wanted to know "the truth" about diagnosis and prognosis, but what they meant varied; some desired full honest information to allow for autonomous choices, others preferred general information without details, and some wanted no bad news at all, only positive information. Participants disclosed vulnerability after receiving their diagnosis, being cast into the unknown. They expressed a need for better everyday practical information to help create some control. Supportive staff could reduce participants distress. Conclusion There is a need to further develop and implement individually tailored information to glioma patients, both in consultations and patient-accessed EHR systems, which should have safe guards for sensitive information. Not all patients want to know it all, one size does not fit all.
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