Glioma patient-reported outcomes: patients and clinicians.

INTRODUCTION: Routine assessment of patient-reported outcomes (PROs) in oncology has shown to improve the quality of the delivered care and to prolong survival. However, for successful implementation of routine assessment of PROs, more knowledge on their usability in clinical practice is needed. OBJECTIVE: This study aimed to cross-sectionally assess the perspective of patients and clinicians on the practicality of routinely measuring PROs in clinical practice for glioma patients. METHODS: Semistructured interviews were conducted evaluating the role of healthcare professionals (HCP) in discussing results of PRO measures (PROMs), and the preferred topics, methods and frequency of PRO assessment. Glioma patients, their proxies and HCPs involved in the treatment of glioma patients from eight centres in the Netherlands were included. RESULTS: Twenty-four patients, 16 proxies and 35 HCPs were interviewed. The majority of patients, proxies and HCPs (92%, 81% and 80%, respectively) were willing to discuss PRO results during consultations. Although HCPs prefer that results are discussed with the nurse specialist, only one-third of patients/proxies agreed. Functioning of daily life was considered important in all three groups. Most participants indicated that discussion of PROM results should take place during standard follow-up visits, and completed at home about 1 week in advance. On group level, there was no preference for administration of questionnaires on paper or digitally. Lastly, all centres had staff available to send questionnaires on paper. CONCLUSION: This study shows that routine assessment of PROs is desired by patients, proxies and HCP's in neuro-oncological care in Dutch hospitals.

A pilot randomized controlled trial of exercise to improve cognitive performance in patients with stable glioma: a proof of concept.

BACKGROUND: Patients with glioma often suffer from cognitive deficits. Physical exercise has been effective in ameliorating cognitive deficits in older adults and neurological patients. This pilot randomized controlled trial (RCT) explored the possible impact of an exercise intervention, designed to improve cognitive functioning in glioma patients, regarding cognitive test performance and patient-reported outcomes (PROs). METHODS: Thirty-four clinically stable patients with World Health Organization grades II/III glioma were randomized to a home-based remotely coached exercise group or an active control group. Patients exercised 3 times per week for 20-45 minutes, with moderate to vigorous intensity, during 6 months. At baseline and immediate follow-up, cognitive performance and PROs were assessed with neuropsychological tests and questionnaires, respectively. Linear regression analyses were used to estimate effect sizes of potential between-group differences in cognitive performance and PROs at 6 months. RESULTS: The exercise group (n = 21) had small- to medium-sized better follow-up scores than the control group (n = 11) on several measures of attention and information processing speed, verbal memory, and executive function, whereas the control group showed a slightly better score on a measure of sustained selective attention. The exercise group also demonstrated small- to medium-sized better outcomes on measures of self-reported cognitive symptoms, fatigue, sleep, mood, and mental health-related quality of life. CONCLUSIONS: This small exploratory RCT in glioma patients provides a proof of concept with respect to improvement of cognitive functioning and PROs after aerobic exercise, and warrants larger exercise trials in brain tumor patients.

[Meningitis due to infection with Borrelia hispanica]. / Meningitis door een infectie met Borrelia hispanica.

BACKGROUND Tick-borne relapsing fever is a disease that is caused by infection with a Borrelia bacterium, and is transmitted by ticks. This infectious disease is characterised by relapsing episodes of high fever, often accompanied by aspecific symptoms. CASE DESCRIPTION We describe the history of a 20-year-old woman who developed recurrent episodes of fever with headache and vomiting after a holiday in Morocco. Additional examination showed pleiocytosis in the cerebrospinal fluid, which was initially suggestive of viral meningitis. However, Borrelia spp. were isolated from a 16S-rRNA-PCR-test which led to the diagnosis 'tick-borne relapsing fever'. The patient was treated with intravenous ceftriaxone for two weeks, after which time her symptoms gradually improved. CONCLUSION Prompt antibiotic treatment of tick-borne relapsing fever can prevent a serious course of the disease. For this reason, in patients with recurrent episodes of fever, it is important to consider this diagnosis if they have recently made a trip to Africa, America or the Middle East.

Predicting disease progression in high-grade glioma with neuropsychological parameters: the value of personalized longitudinal assessment.

PURPOSE: Progressive disease in patients with high-grade glioma may be reflected in cognitive decline. However, the cognitive functions most sensitive to progression may differ between patients. We investigated whether decline on a personalized selection of tests predicted progressive disease according to RANO criteria in high-grade glioma patients. METHODS: Starting one day before surgery, patients underwent neuropsychological assessment every three months during standard treatment and clinical follow-up. We first made a personalized selection of three tests that showed the highest Reliable Change Index (RCI) values, i.e., most positive change, at the first post-surgical assessment for each patient. In subsequent follow up, a decline of RCI ≤ - 1 on at least two of the three tests in the selection was considered cognitive decline. We performed a discrete Cox proportional hazards model including a time-dependent coefficient cognitive decline (vs. stability) and covariate age to predict progressive disease. RESULTS: Twenty five patients were included. Cognitive decline on the personalized test selection preceded or had occurred by the time progression was established in 9/15 patients with RANO confirmed progressive disease (60%). Decline was absent in 8/10 patients (80%) with stable disease during participation. The independent hazard ratio for progression in case of cognitive decline was 5.05 (p < 0.01) compared to stable performance. CONCLUSIONS: Using only three patient-specific neuropsychological tests, we found a fivefold increased chance of disease progression in case of cognitive decline as compared to stable performance. Brief, patient-tailored cognitive assessment may be a noninvasive addition to disease monitoring without overburdening patients and clinical care.

Internet-based guided self-help for glioma patients with depressive symptoms: a randomized controlled trial.

Depressive symptoms are common in glioma patients, and can negatively affect health-related quality of life (HRQOL). We performed a nation-wide randomized controlled trial to evaluate the effects of an online guided self-help intervention for depressive symptoms in adult glioma patients. Glioma patients with depressive symptoms were randomized to a 5-week online course based on problem-solving therapy, or a waiting list control group. After having received the intervention, the glioma patient groups combined were compared with patients with cancer outside the central nervous system (non-CNS cancer controls), who also received the intervention. Sample size calculations yielded 63 participants to be recruited per arm. The primary outcome [depressive symptoms (CES-D)] and secondary outcomes [fatigue (Checklist Individual Strength (CIS)) and HRQOL (Short Form-36)], were assessed online at baseline, post-intervention, and 3 and 12 months follow-up. In total, 89 glioma patients (intervention N = 45; waiting list N = 44) and 26 non-CNS cancer controls were included, of whom 35 and 54% completed the intervention, respectively. Recruitment could not be extended beyond 3.5 years due to funding. On depression, no statistically significant differences between the groups were found. Fatigue decreased post-treatment in the glioma intervention group compared with the waiting list group (p = 0.054, d = 0.306). At 12 months, the physical component summary (HRQOL) remained stable in glioma patients, while scores improved in non-CNS cancer controls (p = 0.035, d = 0.883). In this underpowered study, no evidence for the effectiveness of online guided self-help for depression or HRQOL in glioma patients was found, but it may improve fatigue. Trial registration Netherlands Trial Register NTR3223.

Molecular classification of anaplastic oligodendroglioma using next-generation sequencing: a report of the prospective randomized EORTC Brain Tumor Group 26951 phase III trial.

BACKGROUND: Histopathological diagnosis of diffuse gliomas is subject to interobserver variation and correlates modestly with major prognostic and predictive molecular abnormalities. We investigated a series of patients with locally diagnosed anaplastic oligodendroglial tumors included in the EORTC phase III trial 26951 on procarbazine/lomustine/vincristine (PCV) chemotherapy to explore the diagnostic, prognostic, and predictive value of targeted next-generation sequencing (NGS) in diffuse glioma and to assess the prognostic impact of FUBP1 and CIC mutations. METHODS: Mostly formalin-fixed paraffin-embedded samples were tested with targeted NGS for mutations in ATRX, TP53, IDH1, IDH2, CIC, FUBP1, PI3KC, TERT, EGFR, H3F3A, BRAF, PTEN, and NOTCH and for copy number alterations of chromosomes 1p, 19q, 10q, and 7. TERT mutations were also assessed, with PCR. RESULTS: Material was available from 139 cases, in 6 of which results were uninformative. One hundred twenty-six tumors could be classified: 20 as type II (IDH mutation [mut], "astrocytoma"), 49 as type I (1p/19q codeletion, "oligodendroglioma"), 55 as type III (7+/10q- or TERTmut and 1p/19q intact, "glioblastoma"), and 2 as childhood glioblastoma (H3F3Amut), leaving 7 unclassified (total 91% classified). Molecular classification was of clear prognostic significance and correlated better with outcome than did classical histopathology. In 1p/19q codeleted tumors, outcome was not affected by CIC and FUBP1 mutations. MGMT promoter methylation remained the most predictive factor for survival benefit of PCV chemotherapy. CONCLUSION: Targeted NGS allows a clinically relevant classification of diffuse glioma into groups with very different outcomes. The diagnosis of diffuse glioma should be primarily based on a molecular classification, with the histopathological grade added to it. Future discussion should primarily aim at establishing the minimum requirements for molecular classification of diffuse glioma.

CT within 6 hours of headache onset to rule out subarachnoid hemorrhage in nonacademic hospitals.

OBJECTIVE: To investigate whether staff radiologists working in nonacademic hospitals can adequately rule out subarachnoid hemorrhage (SAH) on head CT <6 hours after headache onset. METHODS: In a multicenter, retrospective study, we studied a consecutive series of patients presenting with acute headache to 11 nonacademic hospitals. Inclusion criteria were (1) normal level of consciousness without focal deficits, (2) head CT <6 hours after headache onset and reported negative for the presence of SAH by a staff radiologist, and (3) subsequent CSF spectrophotometry. Two neuroradiologists and one stroke neurologist from 2 academic tertiary care centers independently reviewed admission CTs of patients with CSF results that were considered positive for presence of bilirubin according to local criteria. We investigated the negative predictive value for detection of SAH by staff radiologists in nonacademic hospitals on head CT in patients scanned <6 hours after onset of acute headache. RESULTS: Of 760 included patients, CSF analysis was considered positive for bilirubin in 52 patients (7%). Independent review of these patients' CTs identified one patient (1/52; 2%) with a perimesencephalic nonaneurysmal SAH. Negative predictive value for detection of subarachnoid blood by staff radiologists working in a nonacademic hospital was 99.9% (95% confidence interval 99.3%-100.0%). CONCLUSIONS: Our results support a change of practice wherein a lumbar puncture can be withheld in patients with a head CT scan performed <6 hours after headache onset and reported negative for the presence of SAH by a staff radiologist in the described nonacademic setting.

[Meningitis after a mouse bite]. / Meningitis na muizenbeet.

BACKGROUND: Infection with the lymphocytic choriomeningitis virus is a human zoonosis caused by a rodent-borne arenavirus and is often seen in autumn and winter when mice retreat into houses. Infection in humans is acquired after inhalation of aerosols or direct contact with excreta of an infected rodent. CASE DESCRIPTION: A 37-year-old woman was referred to St. Elisabeth hospital in Tilburg, Netherlands, complaining of severe progressive headache, nausea and vomiting. Three weeks before presentation a mouse had bitten her finger. On neurological examination there were no abnormalities. Cerebrospinal fluid investigations indicated viral meningitis. Immunofluorescence serological testing confirmed the diagnosis of lymphocytic choriomeningitis. CONCLUSION: Infection by lymphocytic choriomeningitis virus after contact with rodents can cause viral meningitis. The acquired form of the disease is known to be self-limiting in immunocompetent patients.

How often is thunderclap headache caused by the reversible cerebral vasoconstriction syndrome?

BACKGROUND: Thunderclap headache (TCH) has a broad differential diagnosis that includes the reversible cerebral vasoconstriction syndrome (RCVS). It is believed to be caused by a dysregulation of vascular tone, which leads to reversible and segmental vasoconstriction and may cause permanent neurological deficits. One of the remaining mysteries is the incidence of the syndrome in a general hospital setting. METHODS: We recruited consecutive patients with TCH without evidence of aneurysmal subarachnoid hemorrhage on immediate computed tomography-scanning from the emergency room in a period of 12 months. Only those patients with an acute and severe onset of the pain were recruited; the peak of the pain had to be reached in less than 1 minute (verbal analog scale >8/10), and the minimum duration of the pain had to be 6 hours. All patients underwent lumbar puncture, magnetic resonance angiography, and serial transcranial Doppler sonography. RESULTS: Thirty-four patients fulfilled the inclusion criteria; 3 of those were diagnosed with the RCVS (8.8%; 95%confidence interval 3-23). CONCLUSIONS: We found the incidence of RCVS to be 8.8% (95% confidence interval 3-23) (3 patients) in patients presenting with TCH without evidence for severe illness. We believe that RCVS is an under recognized condition, and there fore additional imaging should be performed in every patient with TCH.

[Intracranial hypotension syndrome following manipulation of the cervical spine]. / Liquorhypotensiesyndroom na cervicale manipulatie.

BACKGROUND: Chiropractic interventions such as manipulation of the cervical spine can incidentally lead to severe neurological complications. CASE DESCRIPTION: A 63-year-old female patient presented at the Neurology outpatient clinic with a five-week history of severe postural headache, tinnitus and nausea. The onset of these symptoms was concurrent with chiropractic manipulation of the cervical spine because of cervical pain. Cranial MRI showed findings characteristic for intracranial hypotension syndrome. Cervical MRI revealed a large posterior dural tear at the level of Ci-ii. Following unsuccessful conservative therapy, the patient underwent a lumbar epidural blood patch after which she recovered rapidly. CONCLUSION: Manipulation of the cervical spine can cause a dural tear and subsequently an intracranial hypotension syndrome. Postural headaches directly after spinal manipulation should therefore be a reason to suspect this complication. If conservative management fails, an epidural blood patch may be performed.

Health-related quality of life and cognitive functioning in long-term anaplastic oligodendroglioma and oligoastrocytoma survivors.

Overall survival of patients with anaplastic oligodendroglial tumors has been improved due to the addition of procarbazine, lomustine and vincristine (PCV) chemotherapy to radiotherapy (RT), especially in 1p/19q-codeleted tumors. With improved survival, quality of survival becomes pivotal. We evaluated cognitive functioning and health-related quality of life (HRQOL) in a cohort of long-term anaplastic oligodendroglioma survivors. Thirty-two out of 37 long-term survivors included in European Organisation for Research and Treatment of Cancer (EORTC) study 26951 in the Netherlands and France participated. Cognition was assessed using neuropsychological tests for 6 domains, and HRQOL with the EORTC Quality of Life Questionnaire (EORTC QLQ-C30) and Brain Cancer Module (EORTC QLQ-BN20). Fatigue and mood were evaluated. Results were compared to healthy controls and to patients' own HRQOL 2.5 years following initial treatment. At the time of assessment, median survival for the patients was 147 months, 27 were still progression-free since initial treatment. Of progression-free patients, 26% were not, and 30% were severely cognitively impaired; 41% were employed and 81% could live independently. Patients' HRQOL was worse compared to controls, but similar to 2.5 years after initial treatment. Initial treatment (RT versus RT + PCV) was not correlated with cognition or HRQOL. In conclusion, cognitive functioning in long-term anaplastic oligodendroglioma survivors is variable. However, most patients function independently. In progression-free patients, HRQOL is relatively stable during the disease course. In this small sample, no effect of the addition of PCV on cognition or HRQOL was identified.

MGMT-STP27 methylation status as predictive marker for response to PCV in anaplastic Oligodendrogliomas and Oligoastrocytomas. A report from EORTC study 26951.

PURPOSE: The long-term follow-up results from the EORTC-26951 trial showed that the addition of procarbazine, CCNU, and vincristine (PCV) after radiotherapy increases survival in anaplastic oligodendrogliomas/oligoastrocytomas (AOD/AOA). However, some patients appeared to benefit more from PCV treatment than others. EXPERIMENTAL DESIGN: We conducted genome-wide methylation profiling of 115 samples included in the EORTC-26951 trial and extracted the CpG island hypermethylated phenotype (CIMP) and MGMT promoter methylation (MGMT-STP27) status. RESULTS: We first show that methylation profiling can be conducted on archival tissues with a performance that is similar to snap-frozen tissue samples. We then conducted methylation profiling on EORTC-26951 clinical trial samples. Univariate analysis indicated that CIMP+ or MGMT-STP27 methylated tumors had an improved survival compared with CIMP- and/or MGMT-STP27 unmethylated tumors [median overall survival (OS), 1.05 vs. 6.46 years and 1.06 vs. 3.8 years, both P < 0.0001 for CIMP and MGMT-STP27 status, respectively]. Multivariable analysis indicates that CIMP and MGMT-STP27 are significant prognostic factors for survival in presence of age, sex, performance score, and review diagnosis in the model. CIMP+ and MGMT-STP27 methylated tumors showed a clear benefit from adjuvant PCV chemotherapy: the median OS of CIMP+ samples in the RT and RT-PCV arms was 3.27 and 9.51 years, respectively (P = 0.0033); for MGMT-STP27 methylated samples, it was 1.98 and 8.65 years. There was no such benefit for CIMP- or for MGMT-STP27 unmethylated tumors. MGMT-STP27 status remained significant in an interaction test (P = 0.003). Statistical analysis of microarray (SAM) identified 259 novel CpGs associated with treatment response. CONCLUSIONS: MGMT-STP27 may be used to guide treatment decisions in this tumor type.

New clinical, pathological and molecular prognostic models and calculators in patients with locally diagnosed anaplastic oligodendroglioma or oligoastrocytoma. A prognostic factor analysis of European Organisation for Research and Treatment of Cancer Brain Tumour Group Study 26951.

BACKGROUND: The prognosis of patients with anaplastic oligodendrogliomas (AOD) and oligoastrocytomas (AOA) is variable. Biomarkers might be helpful to identify more homogeneous disease subtypes and improve therapeutic index. The aim of this study is to develop new clinical, pathological and molecular prognostic models for locally diagnosed anaplastic gliomas with oligodendroglial features (AOD or AOA). METHODS: Data from 368 patients with AOD or AOA recruited in The European Organisation for Research and Treatment of Cancer (EORTC) trial 26951 on adjuvant PCV (Procarbazine, CCNU, Vincristine) chemotherapy in anaplastic oligodendroglial tumours were used to develop multifactor models to predict progression free survival (PFS) and overall survival (OS). Different models were compared by their percentage of explained variation (PEV). Prognostic calculators were derived from these new models. RESULTS: Treatment (for PFS only), younger age, confirmed absence of residual tumour on imaging, frontal location, good World Health Organisation (WHO) performance status, absence of endothelial abnormalities and/or necrosis, 1p/19q codeletion and Isocitrate dehydrogenase 1 (IDH1) mutation were independent factors that predicted better PFS and OS. CONCLUSIONS: We identified important prognostic factors for AOD and AOA and showed that molecular markers added a major contribution to clinical and pathological factors in explaining PFS and OS. With a positive predictive value of 92% for PFS and 94% for OS, our models allow physicians to precisely identify high risk patients and aid in making therapeutic decisions.

Identification of drug-related problems by a clinical pharmacist in addition to computerized alerts.

BACKGROUND: Both clinical pharmacists and computerized physician order entry systems with clinical decision support (CPOE/CDSS) can reduce drug-related problems (DRPs). However, the contribution of a clinical pharmacist in addition to CPOE/CDSS has not been established in a prospective study. OBJECTIVE: To determine which DRPs can be identified by a clinical pharmacist in a setting with routine use of CPOE/CDSS. SETTING: Two surgical and two neurological wards in St. Elisabeth hospital, a 600-bed teaching hospital in the Netherlands. METHODS: In this observational prospective follow-up study a clinical pharmacist reviewed the pharmacotherapy of patients admitted to surgical and neurological wards to identify DRPs (i.e. medication errors and adverse drug events) and discussed the relevance of identified problems and interventions to resolve these with the responsible physician. Acceptance of the proposed interventions and the presence of alerts in CPOE/CDSS were assessed. Primary outcome was the proportion of DRPs identified by the clinical pharmacist that also triggered a CPOE/CDSS alert. Differences between the DRPs that generated an alert and those that did not were expressed as relative risks or analyzed with Chi square statistics or Mann-Whitney U tests. MAIN OUTCOME MEASURE: The proportion of drug-related problems identified by the clinical pharmacist that also generated an alert in the CPOE/CDSS. RESULTS: During 1206 medication reviews, 442 potential DRPs were identified; 286 (65 %) DRPs were considered relevant and 247 (56 %) of the proposed interventions were accepted. A CPOE/CDSS alert was generated for 35 (8 %) of the DRPs the clinical pharmacist identified. The only difference between problems that triggered an alert and those that did not was the class of the DRP (indication 23 vs. 36 %, effectiveness 23 vs. 13 %, safety 23 vs. 10 % and pharmaceutical care issues 31 vs. 42 %, p = 0.02). CPOE/CDSS triggered 623 additional alerts that were handled during routine pharmacy service. CONCLUSIONS: As most DRPs identified by a clinical pharmacist were not detected in daily clinical practice by CPOE/CDSS, a clinical pharmacist contributes to reducing DRPs. The sensitivity of CPOE/CDSS to detect certain classes of problems should be optimized.

Adjuvant procarbazine, lomustine, and vincristine chemotherapy in newly diagnosed anaplastic oligodendroglioma: long-term follow-up of EORTC brain tumor group study 26951.

PURPOSE: Anaplastic oligodendroglioma are chemotherapy-sensitive tumors. We now present the long-term follow-up findings of a randomized phase III study on the addition of six cycles of procarbazine, lomustine, and vincristine (PCV) chemotherapy to radiotherapy (RT). PATIENTS AND METHODS: Adult patients with newly diagnosed anaplastic oligodendroglial tumors were randomly assigned to either 59.4 Gy of RT or the same RT followed by six cycles of adjuvant PCV. An exploratory analysis of the correlation between 1p/19q status and survival was part of the study. Retrospectively, the methylation status of the methyl-guanine methyl transferase gene promoter and the mutational status of the isocitrate dehydrogenase (IDH) gene were determined. The primary end points were overall survival (OS) and progression-free survival based on intent-to-treat analysis. RESULTS: A total of 368 patients were enrolled. With a median follow-up of 140 months, OS in the RT/PCV arm was significantly longer (42.3 v 30.6 months in the RT arm, hazard ratio [HR], 0.75; 95% CI, 0.60 to 0.95). In the 80 patients with a 1p/19q codeletion, OS was increased, with a trend toward more benefit from adjuvant PCV (OS not reached in the RT/PCV group v 112 months in the RT group; HR, 0.56; 95% CI, 0.31 to 1.03). IDH mutational status was also of prognostic significance. CONCLUSION: The addition of six cycles of PCV after 59.4 Gy of RT increases both OS and PFS in anaplastic oligodendroglial tumors. 1p/19q-codeleted tumors derive more benefit from adjuvant PCV compared with non-1p/19q-deleted tumors.