Update on the management of elderly patients with glioblastoma: a narrative review.

Glioblastoma in the elderly (>65 years of age) is associated with shorter overall survival (OS) than in younger patients. Best practice recommendations for elderly patients, especially those with borderline or poor performance status, remain a subject of debate amongst clinicians despite recent randomized trials. This review provides an updated evidence-based summary to inform the modern management of elderly patients with glioblastoma. Based on evidence from the CE.6 randomized controlled trial, hypofractionated radiation therapy administered over a three-week course (40 Gy in 15 fractions) concomitantly with temozolomide (TMZ) followed by adjuvant TMZ has been found to be superior to radiation therapy alone with mean OS of 9.3 vs. 7.6 months and progression-free survival (PFS) of 5.3 vs. 3.9 months. This regimen should be offered to newly-diagnosed elderly patients with glioblastoma with preserved functional status, and was not associated with a negative impact on health-related quality of life (QOL). Management of elderly patients with glioblastoma can be challenging and requires a patient-centered strategy. Personalized decisions accounting for clinical, psychosocial, molecular and treatment factors are critical for realistic decision making. The importance of discussing goals-of-care with patients and their caregivers early in the disease trajectory, and establishing capacity for decision-making and advanced care planning, is also reviewed.

Blood-Brain Barrier Opening in Primary Brain Tumors with Non-invasive MR-Guided Focused Ultrasound: A Clinical Safety and Feasibility Study.

The blood-brain barrier (BBB) has long limited therapeutic access to brain tumor and peritumoral tissue. In animals, MR-guided focused ultrasound (MRgFUS) with intravenously injected microbubbles can temporarily and repeatedly disrupt the BBB in a targeted fashion, without open surgery. Our objective is to demonstrate safety and feasibility of MRgFUS BBB opening with systemically administered chemotherapy in patients with glioma in a phase I, single-arm, open-label study. Five patients with previously confirmed or suspected high-grade glioma based on imaging underwent the MRgFUS in conjunction with administration of chemotherapy (n = 1 liposomal doxorubicin, n = 4 temozolomide) one day prior to their scheduled surgical resection. Samples of "sonicated" and "unsonicated" tissue were measured for the chemotherapy by liquid-chromatography-mass spectrometry. Complete follow-up was three months. The procedure was well-tolerated, with no adverse clinical or radiologic events related to the procedure. The BBB within the target volume showed radiographic evidence of opening with an immediate 15-50% increased contrast enhancement on T1-weighted MRI, and resolution approximately 20 hours after. Biochemical analysis of sonicated versus unsonicated tissue suggest chemotherapy delivery is feasible. In this study, we demonstrated transient BBB opening in tumor and peritumor tissue using non-invasive low-intensity MRgFUS with systemically administered chemotherapy was safe and feasible. The characterization of therapeutic delivery and clinical response to this treatment paradigm requires further investigation.

Incidence of Dural Venous Sinus Thrombosis in Patients with Glioblastoma and Its Implications.

OBJECTIVE: Glioblastoma (GBM) is associated with increased risk of developing dural venous sinus thrombosis (DVST), which often goes undiagnosed as symptoms are readily attributed to tumor. The purpose of this study was to investigate the incidence of DVST, potential predictive features on imaging, complications, its effect on survival, and time of greatest risk for developing DVST. METHODS: A retrospective search of patients with GBM who had surgery followed by chemotherapy and/or radiation therapy between 2009 and 2015 at our institution was performed. Magnetic resonance imaging studies of the brain were reviewed on volumetric postgadolinium T1-weighted sequences for DVST. Tumors were characterized using the Visually Accessible REMBRANDT (Repository for Molecular Brain Neoplasia Data) Images classification, and identified thromboses were tracked for propagation, regression, or resolution. Statistical analyses were directed at identifying clinical predictors and survival differences between the DVST and no-DVST groups. RESULTS: In total, 163 cases totaling 1637 scans, were reviewed; 12 patients (7.4%) developed DVST, of whom 11 presented with thrombus before any treatment. Tumor invasion of dural sinuses and greater T1/fluid-attenuated inversion recovery ratios were significantly associated with thrombus development (P = 0.02 and P = 0.02, respectively). In patients who developed DVST, thrombosis was more likely to develop ipsilateral to tumor side (P = 0.01) and was associated with a greater likelihood of developing extracranial venous thromboembolism (P = 0.012). There were no venous infarcts and no significant difference in survival between groups (P = 0.83). CONCLUSIONS: Patients with GBM have increased risk of developing DVST, independent of surgical treatment or chemoradiation. DVST presence does not affect survival. Tumor invasion of dural sinuses and greater T1/fluid-attenuated inversion recovery ratio on preoperative imaging were the most significant predictors of DVST development.

Hypoxia Detection in Infiltrative Astrocytoma: Ferumoxytol-based Quantitative BOLD MRI with Intraoperative and Histologic Validation.

Purpose To validate ferumoxytol-based quantitative blood oxygenation level-dependent (BOLD) MRI for mapping oxygenation of human infiltrative astrocytomas by using intraoperative measurement of tissue oxygen tension and histologic staining. Materials and Methods Fifteen patients with infiltrative astrocytomas were recruited into this prospective multicenter study between July 2014 and December 2016. Prior to treatment, participants underwent preoperative quantitative BOLD MRI with ferumoxytol to generate tissue oxygen saturation (StO2) maps. Two intratumoral sites were identified, one with low StO2 and one with high StO2. Neuronavigation was used to locate sites intraoperatively for insertion of oxygen-sensing probes to measure local tissue oxygen tension (PtO2). Biopsies from both sites were taken and stained for markers of hypoxia (hypoxia-inducible factor 1α, carbonic anhydrase IX) and neoangiogenesis (vascular endothelial growth factor, endoglin [CD105]). Spearman correlation and nonparametric sign-rank tests were used to analyze data. Results Ten patients with median age of 58.5 years (interquartile range, 25 years; four men and six women) completed the study. Because there is no linear relationship between StO2 and PtO2, the ratios of low to high StO2 versus low to high PtO2 in each patient were compared and a significant correlation was found (r = 0.73; P = .01). Pathologic analyses revealed differences between carbonic anhydrase IX (P = .03) for sites of low StO2 versus high StO2. CD105 displayed a similar trend but was not significant (P = .09). Conclusion Ferumoxytol-based quantitative blood oxygenation level-dependent MRI can potentially be used as a noninvasive surrogate for oxygenation mapping in infiltrative astrocytomas. This technique can potentially be integrated in treatment planning for aggressive targeting of hypoxic areas in tumors.

Optimal Therapies for Newly Diagnosed Elderly Patients with Glioblastoma.

OPINION STATEMENT: Newly diagnosed elderly patients (age > 65-70 years) with glioblastoma should be treated with a patient-centred approach by a multi-disciplinary team. Chronological age alone should not be considered as a contraindication to treatment with maximal safe surgical resection. A 3-week course of adjuvant radiation and chemotherapy is appropriate in selected elderly patients with favourable Karnofsky performance status (KPS) who cannot tolerate a longer 6-week course of fractionated radiotherapy. The presence or absence of 06-methylguanine-DNA methyltransferase (MGMT) promoter methylation can be used to guide clinical decision-making as both prognostic and predictive biomarkers. This review provides an update and summary of the available evidence for treating newly diagnosed elderly patients with glioblastoma.

Circadian motor activity affected by stimulant medication in children with attention-deficit/hyperactivity disorder.

Attention-deficit/hyperactivity disorder (ADHD) is a highly prevalent disorder occurring in approximately 3-5% of school-aged children. The core symptoms of ADHD are effectively treated with stimulant medications such as methylphenidate; however, there are also negative side effects, including insomnia. It has been suggested that administration of stimulant medication may alter the timing or regularity of circadian motor activity levels. This study aimed to investigate the impact of stimulant medication on the strength and timing of circadian rhythms in 16 stimulant medication-naïve children with ADHD. Participants were monitored for changes in motor activity during a 3-week blinded placebo-controlled medication trial to examine the impact of immediate-release methylphenidate hydrochloride. Motor activity was measured by actigraphy, and 24-h activity profiles were analysed using cosinor analyses to identify measurable changes in circadian rhythms. The children in this sample demonstrated significant increases in motor activity during the sleep-onset latency period. They also showed a significant reduction in relative circadian amplitude and a phase-delay in the timing of the daily rhythm. Clinicians and parents of children being treated with stimulant medication for ADHD should be aware that stimulant medication may cause disruption of sleep/circadian rhythms. Behavioural strategies to improve sleep may be useful for children experiencing these negative effects from medication.

Acute impact of immediate release methylphenidate administered three times a day on sleep in children with attention-deficit/hyperactivity disorder.

OBJECTIVE: To determine the impact of immediate release Ritalin, given three times a day, on sleep quality and quantity in medication-naïve, newly diagnosed children with attention-deficit/hyperactivity disorder (ADHD). METHODS: Children (aged 6-12) rigorously diagnosed with ADHD (n = 21) underwent multiple measurement assessments (i.e., actigraphy, sleep diary, and questionnaires) during a 1-week baseline and then during a 3-week blinded randomized medication trial. RESULTS: Although the medication was effective in reducing ADHD symptoms, analyses of actigraphy and sleep diary data found statistically and clinically significant changes in the children's total sleep time and sleep onset latency in the medication compared to the no medication conditions. No effects on sleep were found based on the sleep questionnaire. CONCLUSIONS: Physicians and parents are encouraged to closely monitor children's sleep when treating ADHD with stimulant medication.