Patients' and physicians' interpretation of chemotherapy-induced peripheral neurotoxicity.

To test if and how chemotherapy-induced peripheral neurotoxicity (CIPN) is perceived differently by patients and physicians, making assessment and interpretation challenging. We performed a secondary analysis of the CI-PeriNomS study which included 281 patients with stable CIPN. We tested: (a) the association between patients' perception of activity limitation in performing eight common tasks and neurological impairment and (b) how the responses to questions related to these daily activities are interpreted by the treating oncologist. To achieve this, we compared patients' perception of their activity limitation with neurological assessment and the oncologists' blind interpretation. Distribution of the scores attributed by oncologists to each daily life maximum limitation ("impossible") generated three groups: Group 1 included limitations oncologists attributed mainly to motor impairment; Group 2 ones mainly attributed to sensory impairment and Group 3 ones with uncertain motor and sensory impairment. Only a subset of questions showed a significant trend between severity in subjective limitation, reported by patients, and neurological impairment. In Group 1, neurological examination confirmed motor impairment in only 51%-65% of patients; 76%-78% of them also had vibration perception impairment. In Group 2, sensory impairment ranged from 84% to 100%; some degree of motor impairment occurred in 43%-56% of them. In Group 3 strength reduction was observed in 49%-50% and sensory perception was altered in up to 82%. Interpretation provided by the panel of experienced oncologists was inconsistent with the neurological impairment. These observations highlight the need of a core set of outcome measures for future CIPN trials.

Evaluation of the psychometric properties of the EORTC chemotherapy-induced peripheral neuropathy questionnaire (QLQ-CIPN20).

PURPOSE: To investigate the scale structure and psychometrics of the EORTC chemotherapy-induced peripheral neuropathy module (QLQ-CIPN20). METHODS: Using confirmatory factor analyses (CFA), we tested two hypothesized scale structure models of the QLQ-CIPN20 in 473 patients with non-small cell lung cancer, 281 patients with heterogeneous cancer diagnoses, and 500 patients with colorectal cancer. We also modeled the two hypothesized models as bi-factor models. These included a general factor, in addition to the specific domain factors. Additional models were investigated with exploratory factor analysis (EFA). Known groups validity was evaluated where justified. RESULTS: CFA could not confirm the two hypothesized models (Model 1: CFI < 0.926; TLI < 0.914; RMSEA > 0.077 and Model 2: CFI < 0.906; TLI < 0.887; RMSEA > 0.105) in any of the three samples. Including a general factor to these two hypothesized models to produce a bi-factor model also did not yield satisfactory results. Using EFA, we identified four different factor structures in the three samples that were unstable due to cross loadings of the items. When scoring the QLQ-CIPN20 as a simple, additive checklist evidence was found for known groups validity in the first two samples based on Common Toxicity Criteria (CTC-AE), and in the third sample based on exposure to CIPN-inducing chemotherapy. CONCLUSIONS: Neither CFA nor EFA yielded support for a stable subscale structure for the QLQ-CIPN20. Scoring the questionnaire as a simple additive checklist results in acceptable validity.

Seizure reduction is a prognostic marker in low-grade glioma patients treated with temozolomide.

We aimed to analyze the value of seizure reduction and radiological response as prognostic markers of survival in patients with low-grade glioma (LGG) treated with temozolomide (TMZ) chemotherapy. We retrospectively reviewed adult patients with a progressive LGG and uncontrolled epilepsy in two hospitals (VUmc Amsterdam; MCH The Hague), who received chemotherapy with TMZ between 2002 and 2014. End points were a ≥50 % seizure reduction and MRI response 6, 12 and 18 months (mo) after the start of TMZ, and their relation with progression-free survival (PFS) and overall survival (OS). We identified 53 patients who met the inclusion criteria. Seizure reduction was an independent prognostic factor for both PFS (HR 0.38; 95 % CI 0.19-0.73; p = 0.004) and OS (HR 0.39; 95 % CI 0.18-0.85; p = 0.018) after 6mo, adjusting for age and histopathological diagnosis, as well as after 12 and 18mo. Patients with an objective radiological response showed a better OS (median 87.5mo; 95 % CI 62.0-112.9) than patients without a response (median 34.4mo; 95 % CI 26.1-42.6; p = 0.046) after 12mo. However, after 6 and 18mo OS was similar in patients with and without a response on MRI. Seizure reduction is an early and consistent prognostic marker for survival after treatment with TMZ, that seems to precede the radiological response. Therefore, seizure reduction may serve as a surrogate marker for tumor response.

Antiepileptic drug treatment in the end-of-life phase of glioma patients: a feasibility study.

BACKGROUND: During the end-of-life (EOL) phase of glioma patients, a rapid deterioration in neurological functioning may interfere with the oral intake of antiepileptic drugs (AEDs). We aimed to assess the feasibility of non-oral AED treatment in an out-of-hospital setting according to an expert-based guideline. METHODS: Glioma patients with a history of epilepsy, in whom further antitumor therapy was considered to be no longer meaningful, were recruited at two Dutch hospitals. As soon as swallowing difficulties developed, the patient's caregiver administered prophylactic treatment with buccal clonazepam. Acute seizures were treated with intranasal midazolam. We evaluated the adherence to the study medication, seizure prevalence, and caregiver's satisfaction. RESULTS: Of the 34 patients who were approached, 25 gave consent to participate and 23 had died at the end of the study. Thirteen of 19 patients (68.4 %) who had developed swallowing difficulties showed adherence to the study protocol. Thirteen patients used prophylactic buccal clonazepam, of which eight patients remained seizure-free until death. Six patients received treatment with intranasal midazolam at least once. In all patients, seizure control was reached. None of the patients needed to be transferred to the hospital due to recurrent seizures. All caregivers were to some degree satisfied with the use of the study medication. CONCLUSIONS: Our results demonstrate that it is feasible to treat seizures with a combination of non-oral benzodiazepines in the EOL phase of glioma patients, as it seems to provide an important level of comfort among caregivers to be able to manage seizures at home.

Platinum-induced neurotoxicity and preventive strategies: past, present, and future.

Neurotoxicity is a burdensome side effect of platinum-based chemotherapy that prevents administration of the full efficacious dosage and often leads to treatment withdrawal. Peripheral sensory neurotoxicity varies from paresthesia in fingers to ataxic gait, which might be transient or irreversible. Because the number of patients being treated with these neurotoxic agents is still increasing, the need for understanding the pathogenesis of this dramatic side effect is critical. Platinum derivatives, such as cisplatin and carboplatin, harm mainly peripheral nerves and dorsal root ganglia neurons, possibly because of progressive DNA-adduct accumulation and inhibition of DNA repair pathways (e.g., extracellular signal-regulated kinase 1/2, c-Jun N-terminal kinase/stress-activated protein kinase, and p38 mitogen-activated protein kinass), which finally mediate apoptosis. Oxaliplatin, with a completely different pharmacokinetic profile, may also alter calcium-sensitive voltage-gated sodium channel kinetics through a calcium ion immobilization by oxalate residue as a calcium chelator and cause acute neurotoxicity. Polymorphisms in several genes, such as voltage-gated sodium channel genes or genes affecting the activity of pivotal metal transporters (e.g., organic cation transporters, organic cation/carnitine transporters, and some metal transporters, such as the copper transporters, and multidrug resistance-associated proteins), can also influence drug neurotoxicity and treatment response. However, most pharmacogenetics studies need to be elucidated by robust evidence. There are supportive reports about the effectiveness of several neuroprotective agents (e.g., vitamin E, glutathione, amifostine, xaliproden, and venlafaxine), but dose adjustment and/or drug withdrawal seem to be the most frequently used methods in the management of platinum-induced peripheral neurotoxicity. To develop alternative options in the treatment of platinum-induced neuropathy, studies on in vitro models and appropriate trials planning should be integrated into the future design of neuroprotective strategies to find the best patient-oriented solution.

Seizure reduction in a low-grade glioma: more than a beneficial side effect of temozolomide.

BACKGROUND: Seizures are a common symptom in patients with low-grade glioma (LGG), negatively influencing quality of life, if uncontrolled. Besides antiepileptic drugs, antitumour treatment might contribute to a reduction in seizure frequency. The aim of this study was to determine the effect of temozolomide (TMZ) chemotherapy on seizure frequency, to identify factors associated with post-treatment seizure reduction and to analyse the prognostic value of seizure reduction for survival. METHODS: We retrospectively reviewed adult patients with supratentorial LGG and epilepsy who received chemotherapy with TMZ as initial treatment or for progressive disease in two hospitals (VUmc Amsterdam; MCH The Hague) between 2002 and 2012. RESULTS: We identified 104 patients with LGG with epilepsy who had received TMZ. Uncontrolled epilepsy in the 3 months preceding chemotherapy was present in 66 of 104 (63.5%) patients. A ≥ 50% reduction in seizure frequency after 6 months occurred in 29 of 66 (43.9%) patients. Focal symptoms at presentation (OR 6.55; 95% CI 1.45 to 32.77; p = 0.015) appeared to be positively associated with seizure reduction. Seizure reduction was an independent prognostic factor for progression-free survival (HR 0.32; 95% CI 0.15 to 0.66; p = 0.002) and overall survival (HR 0.33; 95% CI 0.14 to 0.79; p = 0.013), along with a histological diagnosis of oligodendroglioma (HR 0.38; 95% CI 0.17 to 0.86; p = 0.021). Objective responses on MRI were similar for patients with and without seizure reduction. CONCLUSIONS: TMZ may contribute to an important reduction in seizure frequency in patients with LGG. Seizure reduction following TMZ treatment has prognostic significance and may serve as an important clinical outcome measure in patients with LGG.

Measuring health-related quality of life in high-grade glioma patients at the end of life using a proxy-reported retrospective questionnaire.

To develop, validate, and report on the use of a retrospective proxy-reported questionnaire measuring health-related quality of life (HRQoL) in the end-of-life (EOL) phase of high-grade glioma (HGG) patients. Items relevant for the defined construct were selected using existing questionnaires, topics identified as important in literature, and expert opinion (experienced neuro-oncologists and EOL experts). Psychometric properties, content validity and internal consistency, were determined and the questionnaire was subsequently adapted. Proxy-reported HRQoL data of HGG patients in the EOL, including changes over time, were analyzed. Twenty-nine items were selected covering seven domains; physical comfort, physical and cognitive functioning, psychological, social and spiritual well-being, and overall quality of life. Relatives of 83 deceased HGG patients completed the questionnaire. Content validity was assessed to be adequate. Internal consistency in the domains varied from reasonable to good. Two items were excluded due to poor psychometric properties. Symptom burden increased (p < 0.01), except for nausea (p = 0.058), as death approached. Cognitive, physical and psychological functioning deteriorated over time (all p < 0.01). Acceptance of disease seemed to increase slightly towards death, but this was not significant (p = 0.058). Participating in social activities and family life was rated as poor (≤ 50), whereas received support from their social environment and dying with dignity were rated as good (>50). Overall quality of life was rated as poor, mean (SD) of 29 (26). Measuring HRQoL at the EOL of HGG patients with a retrospective, proxy-reported questionnaire was feasible, yielding a validated instrument. HRQoL was reported as poor and deteriorated as death approached.

Withdrawal of antiepileptic drugs in glioma patients after long-term seizure freedom: design of a prospective observational study.

BACKGROUND: Epilepsy is common in patients with a glioma. Antiepileptic drugs (AEDs) are the mainstay of epilepsy treatment, but may cause side effects and may negatively impact neurocognitive functioning and quality of life. Besides antiepileptic drugs, anti-tumour treatment, which currently consists of surgery, radiotherapy and/or chemotherapy, may contribute to seizure control as well. In glioma patients with seizure freedom after anti-tumour therapy the question emerges whether AEDs should be continued, particularly in the case where anti-tumour treatment has been successful. We propose to explore the possibility of AED withdrawal in glioma patients with long-term seizure freedom after anti-tumour therapy and without signs of tumour progression. METHODS/DESIGN: We initiate a prospective, observational study exploring the decision-making process on the withdrawal or continuation of AEDs in low-grade and anaplastic glioma patients with stable disease and prolonged seizure freedom after anti-tumour treatment, and the effects of AED withdrawal or continuation on seizure freedom. We recruit participants through the outpatient clinics of three tertiary referral centers for brain tumour patients in The Netherlands. The patient and the treating physician make a shared decision to either withdraw or continue AED treatment. Over a one-year period, we aim to include 100 glioma patients. We expect approximately half of the participants to be willing to withdraw AEDs. The primary outcome measures are: 1) the outcome of the shared-decision making on AED withdrawal or continuation, and decision related arguments, and 2) seizure freedom at 12 months and 24 months of follow-up. We will also evaluate seizure type and frequency in case of seizure recurrence, as well as neurological symptoms, adverse effects related to AED treatment or withdrawal, other anti-tumour treatments and tumour progression. DISCUSSION: This study addresses two issues that are currently unexplored. First, it will explore the willingness to withdraw AEDs in glioma patients, and second, it will assess the risk of seizure recurrence in case AEDs are withdrawn in this specific patient population. This study aims to contribute to a more tailored AED treatment, and prevent unnecessary and potentially harmful use of AEDs in glioma patients.

Correspondence between neurophysiological and clinical measurements of chemotherapy-induced peripheral neuropathy: secondary analysis of data from the CI-PeriNomS study.

Chemotherapy-induced peripheral neuropathy (CIPN) lacks standardized clinical measurement. The objective of the current secondary analysis was to examine data from the CIPN Outcomes Standardization (CI-PeriNomS) study for associations between clinical examinations and neurophysiological abnormalities. Logistic regression estimated the strength of associations of vibration, pin, and monofilament examinations with lower limb sensory and motor amplitudes. Examinations were classified as normal (0), moderately abnormal (1), or severely abnormal (2). Among 218 participants, those with class 1 upper extremity (UE) and classes 1 or 2 lower extremity (LE) monofilament abnormality were 2.79 (95% confidence interval [CI]: 1.28-6.07), 3.49 (95%CI: 1.61-7.55), and 4.42 (95%CI: 1.35-14.46) times more likely to have abnormal sural nerve amplitudes, respectively, compared to individuals with normal examinations. Likewise, those with class 2 UE and classes 1 or 2 LE vibration abnormality were 8.65 (95%CI: 1.81-41.42), 2.54 (95%CI: 1.19-5.41), and 7.47 (95%CI: 2.49-22.40) times more likely to have abnormal sural nerve amplitudes, respectively, compared to participants with normal examinations. Abnormalities in vibration and monofilament examinations are associated with abnormal sural nerve amplitudes and are useful in identifying CIPN.

Parsonage-Turner syndrome following post-exposure prophylaxis.

BACKGROUND: The 'Parsonage-Turner syndrome' (PTS) is a rare but distinct disorder with an abrupt onset of shoulder pain, followed by weakness and atrophy of the upper extremity musculature, and a slow recovery requiring months to years. To our best knowledge, this is the first case describing symptoms and signs of PTS following the administration of a post-exposure prophylaxis (PEP) regimen against possible human immunodeficiency virus (HIV) and hepatitis B virus (HBV) infection. CASE PRESENTATION: A 25-year-old Caucasian man presented with pain and unilateral scapular winging following PEP against possible HIV and HBV infection. Although atrophy and weakness were observed for the right supraspinatus muscle, a full range of motion was achievable. Neurological examination, plain radiography of the right shoulder and electromyography showed no additional abnormalities. The patient was diagnosed with post-vaccination PTS and treated non-operatively. During the following 15 months the scapular winging receded and full muscle strength was regained. CONCLUSION: Parsonage-Turner syndrome is a rare clinical diagnosis. The precise pathophysiological mechanism of PTS remains unclear, but it seems to involve an interaction between genetic predisposition, mechanical vulnerability and an autoimmune trigger. An immunological event, such as - in this case - a vaccination as part of PEP treatment, can trigger the onset of PTS. The clinical presentation is distinctive with acute severe pain followed by patchy paresis, atrophy and sensory symptoms that persist for months to years. No currently available tests can provide a definite confirmation or exclusion of PTS. Routine blood examination, electromyography (EMG), and computed tomography (CT) or magnetic resonance imaging (MRI) serve mainly to exclude other disorders. The recovery can be quite lengthy, non-operative treatment is the accepted practice. Supplementary administration of oral prednisolone could shorten the duration of pain. Although the outcome is typically preferable, a substantial amount of patients are left with some residual paresis and functional impairment.

Health-related quality of life of significant others of patients with malignant CNS versus non-CNS tumors: a comparative study.

It is often assumed that brain tumor patients' significant others (SOs: partners, other family members or close friends) may face greater stress than those of patients with malignancies not involving the central nervous system (CNS), due to progressive changes in neurological and cognitive functioning. We compared health-related quality of life (HRQOL) of SOs of patients with high-grade glioma (HGG) and low-grade glioma (LGG) with that of SOs of patients with non-CNS tumors with similar prognosis and at a similar phase in the disease trajectory (i.e. non-small cell lung cancer (NSCLC) and low-grade hematological malignancies (NHL/CLL), respectively). HRQOL of SOs and patients was assessed using the Short Form-36 (SF-36) Health Survey. Patients' neurological functioning was indexed and they underwent comprehensive neurocognitive testing. SOs of 213 LGG patients, 99 NHL/CLL patients, 55 HGG patients and 29 NSCLC patients participated. The SOs of LGG and NHL/CLL patients reported similar levels of HRQOL. SOs of HGG patients reported significantly lower mental health scores (MCS; p = 0.041) and social functioning (p = 0.028) than those of NSCLC patients. Mental health scores (MCS) of HGG and NSCLC patients were associated significantly with the mental health of their SOs (p = 0.013 and p < 0.001, respectively). Surprisingly, HGG patients' cognitive and neurological functioning were not predictive of SOs' mental health at the multivariate level. SOs of patients with highly malignant CNS tumors in the acute phase are at increased risk of compromised HRQOL compared to those of patients with systemic tumors without CNS involvement and a comparable life expectancy.

Frequency and burden of potentially treatable symptoms in glioma patients with stable disease.

Background & aims: Glioma patients experience a multitude of symptoms that negatively affect their health-related quality of life. Symptoms vary greatly across disease phases, and the patients' stable phase might be particularly suitable for assessing and treating symptoms. Identifying symptoms and patients' needs is a first step toward improving patient care. In glioma patients with stable disease, we assessed the frequency and burden of patient-reported symptoms, examined how these symptoms co-occur, and also determined whether patients would consider treatment to ameliorate specific symptoms. Methods: In this retrospective study, patients rated the frequency and burden of seventeen symptoms on a seven-point Likert scale and stated whether they would consider treatment for these symptoms. Correlations between frequency, burden, and considering treatment were evaluated with Kendall's Tau correlation coefficients. Based on partial correlations between symptom frequencies we visualized the symptoms as a network. Results: Fifty-two glioma patients with stable disease were included (31 WHO grade II/III, 21 WHO grade IV). The top five symptoms were fatigue, memory problems, reduced physical fitness, concentration problems, and drowsiness. Fatigue had the highest median frequency (4.5, interquartile range 2.5). Over half of the patients experienced three or more symptoms simultaneously and associations between all symptoms were depicted as a network. Overall, 35% of patients would consider treatment for at least one symptom. The wish to undergo symptom treatment correlated only moderately with symptom frequency and burden (range of correlations 0.24-0.57 and 0.28-0.61, respectively). Conclusion: Glioma patients with stable disease experience multiple symptoms with a consequently high symptom burden. Despite the high prevalence of symptoms, the inclination for symptom management interventions was relatively low. The most frequent and burdensome symptoms and the way they are interrelated could serve as a roadmap for future research on symptom management in these patients.

MRI and thallium-201 SPECT in the prediction of survival in glioma.

INTRODUCTION: This paper aims to study the value of MRI and Thallium 201 ((201)Tl) single-photon emission computed tomography (SPECT) in the prediction of overall survival (OS) in glioma patients treated with temozolomide (TMZ) and to evaluate timing of radiological follow-up. METHODS: We included patients treated with TMZ chemoradiotherapy for newly diagnosed glioblastoma multiforme (GBM) and with TMZ for recurrent glioma. MRIs and (201)Tl SPECTs were obtained at regular intervals. The value of both imaging modalities in predicting OS was examined using Cox regression analyses. RESULTS: Altogether, 138 MRIs and 113 (201)Tl SPECTs in 46 patients were performed. Both imaging modalities were strongly related to OS (P ≤ 0.02). In newly diagnosed GBM patients, the last follow-up MRI (i.e., after six adjuvant TMZ courses) and SPECT (i.e., after three adjuvant TMZ courses) were the strongest predictors of OS (P = 0.01). In recurrent glioma patients, baseline measurements appeared to be the most predictive of OS (P < 0.01). The addition of one imaging modality to the other did not contribute to the prediction of OS. CONCLUSIONS: Both MRI and (201)Tl SPECT are valuable in the prediction of OS. It is adequate to restrict to one of both modalities in the radiological follow-up during treatment. In the primary GBM setting, MRI after six adjuvant TMZ courses contributes significantly to the prediction of survival. In the recurrent glioma setting, baseline MRI appears to be a powerful predictor of survival, whereas follow-up MRIs during TMZ seem to be of little additional value.

Prospective validation of a new imaging scorecard to assess leptomeningeal metastasis: A joint EORTC BTG and RANO effort.

BACKGROUND: Validation of the 2016 RANO MRI scorecard for leptomeningeal metastasis failed for multiple reasons. Accordingly, this joint EORTC Brain Tumor Group and RANO effort sought to prospectively validate a revised MRI scorecard for response assessment in leptomeningeal metastasis. METHODS: Coded paired cerebrospinal MRI of 20 patients with leptomeningeal metastases from solid cancers at baseline and follow-up after treatment and instructions for assessment were provided via the EORTC imaging platform. The Kappa coefficient was used to evaluate the interobserver pairwise agreement. RESULTS: Thirty-five raters participated, including 9 neuroradiologists, 17 neurologists, 4 radiation oncologists, 3 neurosurgeons, and 2 medical oncologists. Among single leptomeningeal metastases-related imaging findings at baseline, the best median concordance was noted for hydrocephalus (Kappa = 0.63), and the worst median concordance for spinal linear enhancing disease (Kappa = 0.46). The median concordance of raters for the overall response assessment was moderate (Kappa = 0.44). Notably, the interobserver agreement for the presence of parenchymal brain metastases at baseline was fair (Kappa = 0.29) and virtually absent for their response to treatment. 394 of 700 ratings (20 patients x 35 raters, 56%) were fully completed. In 308 of 394 fully completed ratings (78%), the overall response assessment perfectly matched the summary interpretation of the single ratings as proposed in the scorecard instructions. CONCLUSION: This study confirms the principle utility of the new scorecard, but also indicates the need for training of MRI assessment with a dedicated reviewer panel in clinical trials. Electronic case report forms with "blocking options" may be required to enforce completeness and quality of scoring.

A multidisciplinary neuro-oncological triage panel reduces the time to referral and treatment for patients with a brain tumor.

BACKGROUND: Regional collaboration and appropriate referral management are crucial in neuro-oncological care. Lack of electronic access to medical records across health care organizations impedes interhospital consultation and may lead to incomplete and delayed referrals. To improve referral management, we have established a multidisciplinary neuro-oncological triage panel (NOTP) with digital image exchange and determined the effects on lead times, costs, and time investment. METHODS: A prospective cohort study was conducted from February 2019 to March 2020. All newly diagnosed patients referred to Brain Tumor Center Amsterdam were analyzed according to referral pathway: (1) standard referral (SR), (2) NOTP. The primary outcome was lead time, defined as time-to-referral, time-to-treatment, and total time (median days [interquartile range]). Secondary outcomes were costs and time investment. RESULTS: In total, 225 patients were included, of whom 153 had SR and 72 NOTP referral. Patients discussed in the NOTP were referred more frequently for first neurosurgical consultation (44.7% vs 28.8%) or combined neurological and neurosurgical consultation (12.8% vs 2.5%, P = .002). Time-to-referral was reduced for NOTP referral compared to SR (1 [0.25-4] vs 6 [1.5-10] days, P < .001). Total time decreased from 27 [14-48] days for the standard group to 15 [12-38.25] days for the NOTP group (P = .040). Costs and time investment were comparable for both groups. CONCLUSION: Implementation of digital referral to a multidisciplinary NOTP is feasible and leads to more swift patient-tailored referrals at comparable costs and time investment as SR. This quality improvement initiative has the potential to improve collaboration and coordination of multidisciplinary care in the field of neuro-oncology.

Cognitive functioning in glioblastoma patients during radiotherapy and temozolomide treatment: initial findings.

The aim of this study was to evaluate cognitive functioning in newly-diagnosed glioblastoma multiforme (GBM) patients during treatment with radiotherapy (RT) plus concomitant and adjuvant temozolomide (TMZ). Cognitive assessment took place following surgery, but prior to the start of RT (baseline), after 6 weeks of RT and concomitant TMZ (1st follow-up), and after three cycles of adjuvant TMZ (2nd follow-up). Standardized cognitive summary measures and delta scores for six cognitive domains were calculated at the individual level. Cognitive functioning of progression-free GBM patients was compared to that of matched healthy controls. Analyses were performed on a group of 13 GBM patients that were progression-free during follow-up. The results showed that the majority of patients had deficits in multiple cognitive domains at baseline. Between baseline and 1st follow-up, four patients improved in one cognitive domain, four patients deteriorated in one domain, one patient improved in one domain and deteriorated in another, and four patients remained stable in all six domains. Between 1st and 2nd follow-up, the majority of patients (11) remained stable in all six cognitive domains, whereas one patient declined in one domain, and one patient showed a deterioration in two domains. Overall, between baseline and 2nd follow-up, three patients improved in one cognitive domain, two patients deteriorated in two domains, one patient improved in one domain and deteriorated in another, and seven patients remained stable in all six cognitive domains. In conclusion, preceding treatment, the majority of GBM patients show clear-cut deficits in cognitive functioning. In the course of the first 6 months of their disease, however, progression-free GBM patients undergoing radiotherapy plus concomitant and adjuvant temozolomide treatment do not deteriorate in cognitive functioning.

Cognitive and radiological effects of radiotherapy in patients with low-grade glioma: long-term follow-up.

BACKGROUND: Our previous study on cognitive functioning among 195 patients with low-grade glioma (LGG) a mean of 6 years after diagnosis suggested that the tumour itself, rather than the radiotherapy used to treat it, has the most deleterious effect on cognitive functioning; only high fraction dose radiotherapy (>2 Gy) resulted in significant added cognitive deterioration. The present study assesses the radiological and cognitive abnormalities in survivors of LGG at a mean of 12 years after first diagnosis. METHODS: Patients who have had stable disease since the first assessment were invited for follow-up cognitive assessment (letter-digit substitution test, concept shifting test, Stroop colour-word test, visual verbal learning test, memory comparison test, and categoric word fluency). Compound scores in six cognitive domains (attention, executive functioning, verbal memory, working memory, psychomotor functioning, and information processing speed) were calculated to detect differences between patients who had radiotherapy and patients who did not have radiotherapy. White-matter hyperintensities and global cortical atrophy were rated on MRI scans. FINDINGS: 65 patients completed neuropsychological follow-up at a mean of 12 years (range 6-28 years). 32 (49%) patients had received radiotherapy (three had fraction doses >2 Gy). The patients who had radiotherapy had more deficits that affected attentional functioning at the second follow-up, regardless of fraction dose, than those who did not have radiotherapy (-1.6 [SD 2.4] vs -0.1 [1.3], p=0.003; mean difference 1.4, 95% CI 0.5-2.4). The patients who had radiotherapy also did worse in measures of executive functioning (-2.0 [3.7] vs -0.5 [1.2], p=0.03; mean difference 1.5, 0.2-2.9) and information processing speed (-2.0 [3.7] vs -0.6 [1.5], p=0.05; mean difference 0.8, 0.009-1.6]) between the two assessments. Furthermore, attentional functioning deteriorated significantly between the first and second assessments in patients who had radiotherapy (p=0.25). In total, 17 (53%) patients who had radiotherapy developed cognitive disabilities deficits in at least five of 18 neuropsychological test parameters compared with four (27%) patients who were radiotherapy naive. White-matter hyperintensities and global cortical atrophy were associated with worse cognitive functioning in several domains. INTERPRETATION: Long-term survivors of LGG who did not have radiotherapy had stable radiological and cognitive status. By contrast, patients with low-grade glioma who received radiotherapy showed a progressive decline in attentional functioning, even those who received fraction doses that are regarded as safe (

Health-related quality of life of long-term high-grade glioma survivors.

The objective of this study was to compare the health-related quality of life (HRQOL) of long-term to short-term high-grade glioma (HGG) survivors, determine the prognostic value of HRQOL for overall survival, and determine the effect of tumor recurrence on HRQOL for long-term survivors. Following baseline assessment (after surgery, before radiotherapy), self-perceived HRQOL (using the Medical Outcomes Study Short Form 36 [SF-36]) and brain tumor-specific symptoms (using the 20-item Brain Cancer Module) were assessed every 4 months until 16 months after histological diagnosis. Kaplan-Meier survival analysis and the Cox proportional hazards model were performed to estimate overall survival of patients with impaired scores on the aggregated SF-36 higher-order summary scores measuring physical functioning on a physical component scale and on a mental component scale (MCS). Sixteen patients with a short-term survival (baseline and 4-month follow-up) and 16 with a long-term survival (follow-up until 16 months after diagnosis) were selected out of 68 initially recruited HGG patients. At baseline, the short-term and long-term survivors did not differ in their HRQOL. Between baseline and the 4-month follow-up, HRQOL of short-term survivors deteriorated, whereas the long-term survivors improved to a level comparable to healthy controls. Patients with impaired mental functioning (MCS) at baseline had a shorter median survival than patients with normal functioning. After accounting for differences in patient and tumor characteristics, however, mental functioning was not independently related to poorer overall survival. Not surprisingly, in the group of long-term survivors, the five patients with recurrence had a more compromised HRQOL at the 16-month follow-up compared to the 11 patients without recurrence. We concluded that baseline HRQOL is not related to duration of survival and that long-term survivors show improvement of HRQOL to a level comparable to that of the healthy.

The RANO Leptomeningeal Metastasis Group proposal to assess response to treatment: lack of feasibility and clinical utility and a revised proposal.

BACKGROUND: A scorecard to evaluate magnetic resonance imaging (MRI) findings during the course of leptomeningeal metastases (LM) has been proposed by the Response Assessment in Neuro-Oncology (RANO) group. METHODS: To explore the feasibility of the Leptomeningeal Assessment in Neuro-Oncology (LANO) scorecard, cerebrospinal MRIs of 22 patients with LM from solid tumors were scored by 10 neuro-oncologists and 9 neuroradiologists at baseline and at follow-up after treatment. Raters were blinded for clinical data including treatment. Agreement between raters of single items was evaluated using a Krippendorff alpha coefficient. Agreement between numerical parameters such as scores for changes between baseline and follow-up and total scores was evaluated by determining the intraclass coefficient of correlation. RESULTS: Most raters experienced problems with the instructions of the scorecard. No acceptable alpha concordance coefficient was obtained for the rating of single items at baseline or follow-up. The most concordant ratings were obtained for spinal nodules. The concordances were worst for brain linear leptomeningeal enhancement and cranial nerve enhancement. Discordance was less prominent among neuroradiologists than among neuro-oncologists. High variability was also observed for evaluating changes between baseline and follow-up and for total scores. CONCLUSIONS: Assessing response of LM by MRI remains challenging. Central imaging review is therefore indispensable for clinical trials. Based on the present results, we propose a new, simplified scorecard that will require validation using a similar approach as pursued here. The main challenges are to define measurable versus nonmeasurable (target) lesions and measures of change that allow assessment of response.

Synchronized brain activity and neurocognitive function in patients with low-grade glioma: a magnetoencephalography study.

We investigated the mechanisms underlying neurocognitive dysfunction in patients with low-grade glioma (LGG) by relating functional connectivity revealed by magnetoencephalography to neurocognitive function. We administered a battery of standardized neurocognitive tests measuring six neurocognitive domains to a group of 17 LGG patients and 17 healthy controls, matched for age, sex, and educational level. Magnetoencephalography recordings were conducted during an eyes-closed "resting state," and synchronization likelihood (a measure of statistical correlation between signals) was computed from the delta to gamma frequency bands to assess functional connectivity between different brain areas. We found that, compared with healthy controls, LGG patients performed more poorly in psychomotor function, attention, information processing, and working memory. LGG patients also had significantly higher long-distance synchronization scores in the delta, theta, and lower gamma frequency bands than did controls. In contrast, patients displayed a decline in synchronization likelihood in the lower alpha frequency band. Within the delta, theta, and lower and upper gamma bands, increasing short- and long-distance connectivity was associated with poorer neurocognitive functioning. In summary, LGG patients showed a complex overall pattern of differences in functional resting-state connectivity compared with healthy controls. The significant correlations between neurocognitive performance and functional connectivity in various frequencies and across multiple brain areas suggest that the observed neurocognitive deficits in these patients can possibly be attributed to differences in functional connectivity due to tumor and/or treatment.