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Abstract Accurate circulating biomarkers have potential clinical applications in population screening, tumor subclassification, monitoring tumor status, and the delivery of individualized treatments resulting from tumor genotyping. Recently, significant progress has been made within this field in several cancer types, but despite the many potential benefits, currently there is no validated circulating biomarker test for patients with glioma. A number of circulating factors have been examined, including circulating tumor cells, cell-free DNA, microRNA, exosomes, and proteins from both peripheral blood and cerebrospinal fluid with variable results. In the following article, we provide a narrative review of the current evidence pertaining to circulating biomarkers in patients with glioma, including discussion of the advantages and challenges encountered with the current methods used for discovery. Additionally, the potential clinical applications are described with reference to the literature.

Predicting reduced health-related quality of life (HRQoL) after resection of a benign or low-grade brain tumour provides the opportunity for early intervention, and targeted expenditure of scarce supportive care resources. We aimed to develop, and evaluate the performance of, machine learning (ML) algorithms to predict HRQoL outcomes in this patient group. Using a large prospective dataset of HRQoL outcomes in patients surgically treated for low grade glioma, acoustic neuroma and meningioma, we investigated the capability of ML to predict a) HRQoL-impacting symptoms persisting between 12 and 60 months from tumour resection and b) a decline in global HRQoL by more than the minimum clinically important difference below a normative population mean within 12 and 60 months after resection. Ten-fold cross-validation was used to measure the area under the receiver operating characteristic curve (AUC), area under the precision-recall curve (PR-AUC), sensitivity, and specificity of models. Six ML algorithms were explored per outcome: Random Forest Classifier, Decision Tree Classifier, Logistic Regression, K Neighbours Classifier, Support Vector Machine, and Gradient Boosting Machine. The final cohort included 262 patients. Outcome measures for which AUC>0.9 were Appetite loss, Constipation, Nausea and vomiting, Diarrhoea, Dyspnoea and Fatigue. AUC was between 0.8 and 0.9 for global HRQoL and Financial difficulty. Pain and Insomnia achieved AUCs below 0.8. PR-AUCs were similar overall to the AUC of each respective classifier. ML algorithms based on routine demographic and perioperative data show promise in their ability to predict HRQoL outcomes in patients with low grade and benign brain tumours between 12 and 60 months after surgery.

To compare health-related quality of life (HRQoL) and symptom burden following meningioma resection in patients from two samples from Australia and India. This will add to the body of data on the longer-term consequences of living with a meningioma in two socio-economically and culturally different countries. The European Organisation for Research and Treatment of Cancer (EORTC) Core Quality of Life Questionnaire (QLQ-C30), Brain Neoplasm Module (QLQ-BN20) and the Hospital Anxiety and Depression Scale (HADS) were administered to 159 Australian and 92 Indian meningioma patients over 24 months postoperative. A linear mixed model analysis identified differences between groups over time. Australian patients reported better physical functioning in the early months after surgery (T1: mean diff: 19.8, p<0.001; T2: mean diff: 12.5, p = 0.016) whereas Indian patients reported better global HRQoL (mean: -20.3, p<0.001) and emotional functioning (mean diff:-15.6, p = 0.020) at 12-24 months. In general, Australian patients reported more sleep and fatigue symptoms while Indian patients reported more gastro-intestinal symptoms over the 2-year follow-up. Future uncertainty and symptoms common for brain tumour patients were consistently more commonly reported by patients in Australia than in India. No differences for depression and anxiety were identified. This is the first cross cultural study to directly compare postoperative HRQoL in meningioma patients. Some differences in HRQoL domains and symptom burden may be explained by culturally intrinsic reporting of symptoms, as well as higher care support from family members in India. Although there were differences in some HRQoL domains, clinically meaningful differences between the two samples were less common than perhaps expected. This may be due to an Indian sample with high literacy and financial resources to afford surgery and follow up care.

Glioblastoma is the most formidable of primary brain tumors, owing to its aggressive nature and the limited efficacy of the best available treatment, which comprises maximal safe surgical resection, radiotherapy, and alkylating chemotherapy. Most patients die within a year after diagnosis, which underscores the urgent need for innovative therapeutic strategies. Of interest, then, is an interim analysis in this issue of the Journal : Choi et al. 1 report the outcomes of treating three patients with a secreting chimeric antigen receptor (CAR) T cell (see Key Concepts). CAR T-cell technology has reshaped our therapeutic approach to combating hematologic cancers. It harnesses the . . .

Background Short-term medical mission (STMM) providers supplement healthcare delivery and education in low- and middle-income countries (LMIC). Despite numerous providers working in this space, the views of volunteers who contribute their time and skills to these programs are rarely sought. Method A qualitative study of 24 volunteers for Pangea Global Health Education (Pangea) was undertaken using semi-structured interviews to better understand their perspectives on program design and delivery, personal and professional outcomes of their volunteer experiences and the resulting implications for STMM program design. An inductive thematic analysis of their responses was completed. Social constructionist theory was utilised to contextualise themes and implications for program design. Results Participants highlighted the importance of co-creation with local learners and staff, the necessity to understand clinical context and the importance of relating to culture in the advancement of patient care. They reported personal growth, including a better understanding of others, and identifying commonalities between people. Professionally, participants reported learning from their colleagues, including new medical content, as well as refining their teaching practices. They also reported learning from those they taught and respecting the resourcefulness of medical and nursing staff working in LMIC. Conclusion STMM providers may benefit from co-creation with their learners in the development of health professional education programs. A deep understanding of local context and culture provides for a richer learning environment and enables sustainable long-term program delivery. Utilising a social constructionist framework enables a better understanding of cultural barriers, which inhibit group learning, including the tendency to maintain hierarchical divides; addressing these will allow for optimised patient care.

Purpose Molecular biomarkers are important for classifying intracranial gliomas, prompting research into correlating imaging with genotype (“radiogenomics”). A limitation of the existing radiogenomics literature is the paucity of studies specifically characterizing grade 2–3 gliomas into the three key molecular subtypes. Our study investigated the accuracy of multiple different conventional MRI features for genotype prediction. Methods Grade 2–3 gliomas diagnosed between 2007 and 2013 were identified. Two neuroradiologists independently assessed nine conventional MRI features. Features with better inter-observer agreement (κ ≥ 0.6) proceeded to consensus assessment. MRI features were correlated with genotype, classified as IDH-mutant and 1p/19q-codeleted (IDH mut /1p19q codel ), IDH-mutant and 1p/19q-intact (IDH mut /1p19q int ), or IDH-wildtype (IDH wt ). For IDH wt tumors, additional molecular markers of glioblastoma were noted. Results One hundred nineteen patients were included. T2-FLAIR mismatch (stratified as > 50%, 25–50%, or < 25%) was the most predictive feature across genotypes (p < 0.001). All 30 tumors with > 50% mismatch were IDH mut /1p19q int , and all seven with 25–50% mismatch. Well-defined margins correlated with IDH mut /1p19q int status on univariate analysis (p < 0.001), but this related to correlation with T2-FLAIR mismatch; there was no longer an association when considering only tumors with < 25% mismatch (p = 0.386). Enhancement (p = 0.001), necrosis (p = 0.002), and hemorrhage (p = 0.027) correlated with IDH wt status (especially “molecular glioblastoma”). Calcification correlated with IDH mut /1p19q codel status (p = 0.003). A simple, step-wise algorithm incorporating these features, when present, correctly predicted genotype with a positive predictive value 91.8%. Conclusion T2-FLAIR mismatch strongly predicts IDH mut /1p19q int even with a lower threshold of ≥ 25% mismatch and outweighs other features. Secondary features include enhancement, necrosis and hemorrhage (predicting IDH wt , especially “molecular glioblastoma”), and calcification (predicting IDH mut /1p19q codel ).

Studies looking at the benefit of surgery at first relapse (second surgery) for recurrent glioblastoma were confounded by including patients with varying grades of glioma, performance status and extent of resection. This case–controlled study aims to remove these confounders to assess the survival impact of second surgery in recurrent glioblastoma. Retrospective data on patients with glioblastoma recurrence at two tertiary Australian hospitals from July 2009 to April 2015 was reviewed. Patients who had surgery at recurrence were matched with those who did not undergo surgery at recurrence, based on the extent of their initial resection and age. Overall survival (OS1 assessed from initial diagnosis and OS2 from the date of recurrence) as well as functional outcomes after resection were analysed. There were 120 patients (60 in each institution); median age at diagnosis was 56 years. Median OS1 was 14 months (95% CI 11.5–15.7) versus 22 months (95% CI 18–25) in patients who did not undergo second surgery and those with surgery at recurrence. OS2 was improved by second surgery (4.7 vs 9.6, HR 0.52, 95% CI 0.38–0.72, P < 0.001), and by chemotherapy, given at recurrence, (HR 0.47, 95% CI 0.24–0.92, P = 0.03). After second surgery, 80% did not require rehabilitation and 61% were independently mobile. Second surgery for recurrent glioblastoma was associated with a survival advantage. Chemotherapy independent of surgery, also improved survival. Functional outcomes were encouraging. More research is required in the era of improved surgical techniques and new antineoplastic therapies.

BACKGROUND:Glioblastoma is the most common and aggressive primary brain tumor. Despite current treatment, recurrence is inevitable. There are no clear guidelines for treatment of recurrent glioblastoma. OBJECTIVE:To investigate factors at initial surgery predictive of reoperation, and the prognostic variables associated with survival, including reoperation for recurrence. METHODS:A retrospective cohort study was performed, including adult patients diagnosed with glioblastoma between January 2010 and December 2013. Student t test and Fisher exact test compared continuous and categorical variables between reoperation and nonreoperation groups. Univariable and Cox regression multivariable analysis was performed. RESULTS:In a cohort of 204 patients with de novo glioblastoma, 49 (24%) received reoperation at recurrence. The median overall survival in the reoperation group was 20.1 months compared with 9.0 months in the nonreoperation group (P = .001). Reoperation was associated with longer overall survival in our total population (hazard ratio, 0.646; 95% confidence interval, 0.543-0.922; P = .016) but subject to selection bias. Subgroup analyses excluding patients unlikely to be considered for reoperation suggested a much less significant effect of reoperation on survival, which warrants further study with larger cohorts. Factors at initial surgery predictive for reoperation were younger age, smaller tumor size, initial extent of resection ≥50%, shorter inpatient stay, and maximal initial adjuvant therapy. When unfavorable patient characteristics are excluded, reoperation is not an independent predictor of survival. CONCLUSION:Patients undergoing reoperation have favorable prognostic characteristics, which may be responsible for the survival difference observed. We recommend that a large clinical registry be developed to better aid consistent and homogenous data collection. ABBREVIATIONS:ECOG, Eastern Cooperative Oncology GroupEOR, extent of resectionIDH-1, isocitrate dehydrogenase 1IP, inpatientMGMT, O-methylguanine methyltransferaseOS, overall survivalPFS, progression-free survivalRMH, Royal Melbourne Hospital

Glioblastomas are highly aggressive and deadly brain tumours, with a median survival time of 14–18 months post-diagnosis. Current treatment modalities are limited and only modestly increase survival time. Effective therapeutic alternatives are urgently needed. The purinergic P2X7 receptor (P2X7R) is activated within the glioblastoma microenvironment and evidence suggests it contributes to tumour growth. Studies have implicated P2X7R involvement in a range of neoplasms, including glioblastomas, although the roles of P2X7R in the tumour milieu remain unclear. Here, we report a trophic, tumour-promoting role of P2X7R activation in both patient-derived primary glioblastoma cultures and the U251 human glioblastoma cell line, and demonstrate its inhibition reduces tumour growth in vitro. Primary glioblastoma and U251 cell cultures were treated with the specific P2X7R antagonist, AZ10606120 (AZ), for 72 h. The effects of AZ treatment were also compared to cells treated with the current first-line chemotherapeutic drug, temozolomide (TMZ), and a combination of both AZ and TMZ. P2X7R antagonism by AZ significantly depleted glioblastoma cell numbers compared to untreated cells, in both primary glioblastoma and U251 cultures. Notably, AZ treatment was more effective at tumour cell killing than TMZ. No synergistic effect between AZ and TMZ was observed. AZ treatment also significantly increased lactate dehydrogenase release in primary glioblastoma cultures, suggesting AZ-induced cellular cytotoxicity. Our results reveal a trophic role of P2X7R in glioblastoma. Importantly, these data highlight the potential for P2X7R inhibition as a novel and effective alternative therapeutic approach for patients with lethal glioblastomas.

Patients with brain tumours are motivated to participate in clinical trials involving repeat tissue sampling. Normalising the use of neoadjuvant and staged surgical trials necessitates collaboration among patients, regulatory agencies, and researchers. Initial and repetitive tissue sampling plays a crucial role in enhancing our understanding of resistance mechanisms and vulnerabilities in brain tumour therapy. Standardising biopsy techniques and ensuring technical uniformity across institutions are vital for effective interinstitutional collaboration. Although liquid biopsy technologies hold promise, they are not yet ready to replace tissue analysis. Clear communication about the risks and benefits of biopsies is essential, particularly regarding potential postoperative deficits. Changes in mindset and neurosurgical culture are imperative to achieve much needed breakthroughs in the development of new, effective therapies for brain tumours.