Diagnostic Accuracy of Neuroimaging to Delineate Diffuse Gliomas within the Brain: A Meta-Analysis.

BACKGROUND: Brain imaging in diffuse glioma is used for diagnosis, treatment planning, and follow-up. PURPOSE: In this meta-analysis, we address the diagnostic accuracy of imaging to delineate diffuse glioma. DATA SOURCES: We systematically searched studies of adults with diffuse gliomas and correlation of imaging with histopathology. STUDY SELECTION: Study inclusion was based on quality criteria. Individual patient data were used, if available. DATA ANALYSIS: A hierarchic summary receiver operating characteristic method was applied. Low- and high-grade gliomas were analyzed in subgroups. DATA SYNTHESIS: Sixty-one studies described 3532 samples in 1309 patients. The mean Standard for Reporting of Diagnostic Accuracy score (13/25) indicated suboptimal reporting quality. For diffuse gliomas as a whole, the diagnostic accuracy was best with T2-weighted imaging, measured as area under the curve, false-positive rate, true-positive rate, and diagnostic odds ratio of 95.6%, 3.3%, 82%, and 152. For low-grade gliomas, the diagnostic accuracy of T2-weighted imaging as a reference was 89.0%, 0.4%, 44.7%, and 205; and for high-grade gliomas, with T1-weighted gadolinium-enhanced MR imaging as a reference, it was 80.7%, 16.8%, 73.3%, and 14.8. In high-grade gliomas, MR spectroscopy (85.7%, 35.0%, 85.7%, and 12.4) and 11C methionine-PET (85.1%, 38.7%, 93.7%, and 26.6) performed better than the reference imaging. LIMITATIONS: True-negative samples were underrepresented in these data, so false-positive rates are probably less reliable than true-positive rates. Multimodality imaging data were unavailable. CONCLUSIONS: The diagnostic accuracy of commonly used imaging is better for delineation of low-grade gliomas than high-grade gliomas on the basis of limited evidence. Improvement is indicated from advanced techniques, such as MR spectroscopy and PET.

Prognostic value of the S100B protein in newly diagnosed and recurrent glioma patients: a serial analysis.

The S100B protein is associated with brain damage and a breached blood-brain barrier. A previous pilot study showed that high serum levels of S100B are associated with shorter survival in glioma patients. The aim of our study was to assess the prognostic value in terms of survival and longitudinal dynamics of serum S100B for patients with newly diagnosed and recurrent glioma. We obtained blood samples from patients with newly diagnosed and recurrent glioma before the start (baseline) and at fixed time-points during temozolomide chemotherapy. S100B-data were dichotomized according to the upper limit of the reference value of 0.1 µg/L. Overall survival (OS) was estimated with Kaplan-Meier curves and groups were compared with the log rank analysis. To correct for potential confounders a Cox regression analysis was used. We included 86 patients with newly-diagnosed and 27 patients with recurrent glioma. Most patients in both groups had baseline serum levels within normal limits. In the newly diagnosed patients we found no significant difference in OS between the group of patients with S100B levels >0.1 µg/L at baseline compared to those with <0.1 µg/L. In the patients with recurrent glioma we found a significantly shorter OS for patients with raised levels. In both groups, S100B values did not change significantly throughout the course of the disease. Serum S100B levels do not seem to have prognostic value in newly diagnosed glioma patients. In recurrent glioma patients S100B might be of value in terms of prognostication of survival.

Symptoms and medication management in the end of life phase of high-grade glioma patients.

During the end of life (EOL) phase of high-grade glioma (HGG) patients, care is primarily aimed at reducing symptom burden while maintaining quality of life as long as possible. In this study, we evaluated the prevalence of symptoms and medication management in HGG patients during the EOL phase. We analyzed disease-specific symptoms, general EOL symptoms, symptom frequency, and medication use at 3 months and 1 week before death in a cohort of 178 HGG patients, based on questionnaires completed by physicians responsible for EOL care. In addition, information on patient's perceived quality of care (QOC) was derived from 87 questionnaires completed by patient's relatives. Somnolence, focal neurological deficits and cognitive disturbances were the most prevalent symptoms during the EOL phase. Overall, disease-specific symptoms occurred more often than general EOL symptoms at both 3 months and 1 week before death. Somnolence and/or dysphagia were present in 81 % of patients whose medication was withdrawn and 96 % of patients in whom antiepileptic drugs (AEDs) were withdrawn. One week before death, 65.9 % of patients with high symptom frequency experienced good QOC, compared to 87.5 % of patients with low symptom frequency (p = 0.032). Disease-specific symptoms are the main concern in EOL care for HGG patients. Somnolence and dysphagia may hamper the regular oral administration of drugs, and particularly AEDs, during the EOL phase. High symptom frequency at 1 week before death negatively affects patient's perceived QOC.

End of life care in high-grade glioma patients in three European countries: a comparative study.

Exploring cross-national differences is useful to evaluate whether different patterns of end of life (EOL) care meet patient's specific needs. This study aimed to (1) compare EOL care processes for high-grade glioma (HGG) patients in three European countries, (2) explore differences in perceived quality of care (QOC), and (3) identify aspects of good QOC in the EOL phase. We analyzed 207 questionnaires from relatives of deceased HGG patients, using a similar retrospective study design in three countries [The Netherlands (n = 83), Austria (n = 72) and the UK (n = 52)], and examined four subthemes: (1) organization of EOL care, (2) treatment preferences, (3) experiences with EOL care, (4) perceived QOC. Three months before death 75 % of patients were at home. In all countries, on average, 50 % were transferred to a hospital at least once and received effective symptom treatment during the last 3 months. In The Netherlands, Austria and UK, respectively, patients most often died at home (60 %), in a hospital (41 %) or hospice (41 %) (p < 0.001). Advance directives were present in 46 % of Dutch, 36 % of British and 6 % of Austrian patients (p < 0.001). Fifty-three percent of patients experienced good QOC, irrespective of country. Dying at the preferred place, satisfaction with information provided and effective symptom treatment were independently associated with good QOC. There are various cross-national differences in organization and experiences with EOL care for HGG, but patient's perceived QOC is similar in the three countries. As symptom treatment was considered effective in only half of HGG patients, and independently predicted good QOC, this particularly needs further improvement in all countries.

Central neurotoxicity of standard treatment in patients with newly-diagnosed high-grade glioma: a prospective longitudinal study.

Following tumor resection, the majority of high-grade glioma (HGG) patients are treated with a combined modality regimen of radiotherapy and temozolomide. As a result of the tumor itself or as treatment-related neurotoxic side-effects, these patients may experience cognitive deficits. Additionally, radiological abnormalities expressed as white matter hyperintensities (WMH) and cerebral atrophy (CA) can develop. In this study, these functional and morphological parameters are evaluated, and their relation is investigated. After surgery, HGG patients underwent chemo-irradiation for six weeks, followed by six cycles of temozolomide. Assessments were performed before chemo-irradiation, post-concomitantly, after the third and sixth adjuvant cycle, and 3 and 7 months after treatment. Degree of WMH and CA was scored on MRI. Patients' neuropsychological performance was compared to healthy matched controls, yielding six cognitive domain z-scores. Development or progression of pre-existing WMH and CA during follow-up was observed in 36 and 45 % of the patients (n = 39) respectively. Cognitive functioning remained stable or improved in 70 % of the patients and deteriorated in 30 % of the patients (n = 33). Of the cognitive decliners, 80 % had tumor progression within 4 months thereafter. No clear association between cognitive functioning and WMH or CA was found. Central neurotoxic effects of combined modality treatment in HGG patients expressed by radiological abnormalities are encountered in approximately 40 % of patients. However, functional impact as indexed by cognitive functioning was found to be limited. Furthermore, development or progression of pre-existing WMH and CA does not consistently result in functional impairment as measured by cognitive tests.

Local polymorphic delta activity in cortical lesions causes global decreases in functional connectivity.

Increasing evidence from neuroimaging and modeling studies suggests that local lesions can give rise to global network changes in the human brain. These changes are often attributed to the disconnection of the lesioned areas. However, damaged brain areas may still be active, although the activity is altered. Here, we hypothesize that empirically observed global decreases in functional connectivity in patients with brain lesions can be explained by specific alterations of local neural activity that are the result of damaged tissue. We simulated local polymorphic delta activity (PDA), which typically characterizes EEG/MEG recordings of patients with cerebral lesions, in a realistic model of human brain activity. 78 neural masses were coupled according to the human structural brain network. Lesions were created by altering the parameters of individual neural masses in order to create PDA (i.e. simulating acute focal brain damage); combining this PDA with weakening of structural connections (i.e. simulating brain tumors), and fully deleting structural connections (i.e. simulating a full resection). Not only structural disconnection but also PDA in itself caused a global decrease in functional connectivity, similar to the observed alterations in MEG recordings of patients with PDA due to brain lesions. Interestingly, connectivity between regions that were not lesioned directly also changed. The impact of PDA depended on the network characteristics of the lesioned region in the structural connectome. This study shows for the first time that locally disturbed neural activity, i.e. PDA, may explain altered functional connectivity between remote areas, even when structural connections are unaffected. We suggest that focal brain lesions and the corresponding altered neural activity should be considered in the framework of the full functionally interacting brain network, implying that the impact of lesions reaches far beyond focal damage.

Neurocognitive functioning and health-related quality of life in patients with radiologically suspected meningiomas.

Few data are available concerning the neurocognitive outcome and health-related quality of life (HRQOL) following neurosurgery in meningioma patients, and even less is known about neurocognitive functioning and HRQOL in untreated patients with stable lesions. The present study aims at quantifying the nature and extent of neurocognitive deficits and HRQOL in suspected WHO grade I meningioma patients who have not received surgery and/or radiotherapy and compare outcome to that of healthy controls. Neurocognitive functioning was assessed by using a standardized test battery in 21 radiologically suspected WHO grade I meningioma patients with a wait-and-scan approach. HRQOL was assessed with the MOS SF-36 questionnaire. These patients were matched for age, sex, and education with 21 healthy controls. Associations between neurocognitive functioning on the one hand and HRQOL and tumor characteristics on the other were determined. Compared to healthy controls, meningioma patients had lower psychomotor speed (p = 0.011) and working memory capacity (p = 0.034) and furthermore attained lower levels of self-perceived general health and vitality. Neurocognitive functioning in untreated patients was not related to tumor volume, edema or tumor lateralization. No correlations were found between psychomotor speed or working memory and HRQOL. Untreated meningioma patients with stable lesions have limitations in neurocognitive functioning and HRQOL. In deciding upon a treatment strategy these reductions in functioning should be taken into consideration and communicated with the patient.

Local MEG networks: the missing link between protein expression and epilepsy in glioma patients?

Connectivity and network analysis in neuroscience has been applied to multiple spatial scales, but the links between these different scales have rarely been investigated. In tumor-related epilepsy, altered network topology is related to behavior, but the molecular basis of these observations is unknown. We elucidate the associations between microscopic features of brain tumors, local network topology, and functional patient status. We hypothesize that expression of proteins related to tumor-related epilepsy is directly correlated with network characteristics of the tumor area. Glioma patients underwent magnetoencephalography, and functional network topology of the tumor area was used to predict tissue protein expression patterns of tumor tissue collected during neurosurgery. Protein expression and network topology were interdependent; in particular between-module connectivity was selectively associated with two epilepsy-related proteins. Total number of seizures was related to both the role of the tumor area in the functional network and to protein expression. Importantly, classification of protein expression was predicted by between-module connectivity with up to 100% accuracy. Thus, network topology may serve as an intermediate level between molecular features of tumor tissue and symptomatology in brain tumor patients, and can potentially be used as a non-invasive marker for microscopic tissue characteristics.

Genetics and pharmacogenomics of diffuse gliomas.

Rapidly evolving techniques for analysis of the genome provide new opportunities for cancer therapy. For diffuse gliomas this has resulted in molecular markers with potential for personalized therapy. Some drugs that utilize pharmacogenomics are currently being tested in clinical trials. In melanoma, lung-, breast-, gastric- and colorectal carcinoma several molecular markers are already being clinically implemented for diagnosis and treatment. These insights can serve as a background for the promise and limitations that pharmacogenomics has for diffuse gliomas. Better molecular characterization of diffuse gliomas, including analysis of the molecular underpinnings of drug efficacy in clinical trials, is urgently needed. We foresee exciting developments in the upcoming years with clinical benefit for the patients.

Connectivity in MEG resting-state networks increases after resective surgery for low-grade glioma and correlates with improved cognitive performance.

PURPOSE: Low-grade glioma (LGG) patients often have cognitive deficits. Several disease- and treatment related factors affect cognitive processing. Cognitive outcome of resective surgery is unpredictable, both for improvement and deterioration, especially for complex domains such as attention and executive functioning. MEG analysis of resting-state networks (RSNs) is a good candidate for presurgical prediction of cognitive outcome. In this study, we explore the relation between alterations in connectivity of RSNs and changes in cognitive processing after resective surgery, as a stepping stone to ultimately predict postsurgical cognitive outcome. METHODS: Ten patients with LGG were included, who had no adjuvant therapy. MEG recording and neuropsychological assessment were obtained before and after resective surgery. MEG data were recorded during a no-task eyes-closed condition, and projected to the anatomical space of the AAL atlas. Alterations in functional connectivity, as characterized by the phase lag index (PLI), within the default mode network (DMN), executive control network (ECN), and left- and right-sided frontoparietal networks (FPN) were compared to cognitive changes. RESULTS: Lower alpha band DMN connectivity was increased after surgery, and this increase was related to improved verbal memory functioning. Similarly, right FPN connectivity was increased after resection in the upper alpha band, which correlated with improved attention, working memory and executive functioning. DISCUSSION: Increased alpha band RSN functional connectivity in MEG recordings correlates with improved cognitive outcome after resective surgery. The mechanisms resulting in functional connectivity alterations after resection remain to be elucidated. Importantly, our findings indicate that connectivity of MEG RSNs may be used for presurgical prediction of cognitive outcome in future studies.

Synaptic vesicle protein 2A predicts response to levetiracetam in patients with glioma.

OBJECTIVES: To correlate SV2A expression in surgically removed tumor and peritumoral tissue of glioma patients with epilepsy with the clinical response to levetiracetam in a prospective cohort. METHODS: Forty glioma patients with epilepsy were recruited. All patients had undergone surgery and were on levetiracetam monotherapy. Clinical characteristics were documented. Follow-up visits were scheduled at 3 and 6 months. Patients who responded to levetiracetam were compared to those who did not respond. Expression of SV2A was determined by means of immunohistochemistry in the surgically removed tumor and peritumoral tissue. Optical density (OD) was used to measure SV2A expression. RESULTS: In total, 34 patients were eligible for analysis. Patients with a good response to treatment had significantly stronger SV2A expression as demonstrated by OD in tumor tissue (mean 44.5, SD 17.3) as well as in peritumoral tissue (mean 67.5, SD 7.8) than patients who did not show such a response (mean 8.1, SD 7.7, p < 0.01 and 45.6, SD 11.2, p < 0.01). SV2A expression predicted efficacy of levetiracetam monotherapy with an accuracy of 91%. CONCLUSIONS: Our results suggest that expression of SV2A in tumor and peritumoral tissue is correlated to the clinical response to levetiracetam and predicts levetiracetam efficacy.

Late neurocognitive sequelae in patients with WHO grade I meningioma.

BACKGROUND: Information on neurocognitive outcome following treatment of benign meningiomas is virtually lacking. This is remarkable considering that survival in these patients is the most favourable of all intracranial tumours. The aim of the present study was therefore to document the extent and nature of neurocognitive deficits in patients with World Health Organization (WHO) grade I meningioma after treatment. METHODS: 89 patients with WHO grade I meningioma who underwent surgery with or without adjuvant radiotherapy were individually matched to 89 healthy controls for age, sex and educational level. Neurocognitive functioning of patients was assessed at least 1 year following treatment and compared with that of healthy controls using the Student's t test. Additionally, associations between tumour characteristics (size, lateralisation and localisation), treatment characteristics (radiotherapy) and epilepsy burden (based on seizure frequency and antiepileptic drug use) and neurocognitive functioning were investigated. RESULTS: Compared with healthy controls, patients with meningioma showed significant impairments in executive functioning (p<0.001), verbal memory (p<0.001), information processing capacity (p = 0.001), psychomotor speed (p = 0.001) and working memory (p = 0.006). Patients with skull base meningiomas performed significantly lower on three out of six neurocognitive domains compared with convexity meningiomas. Left-sided as opposed to right-sided meningiomas were related to verbal memory deficits. A higher epilepsy burden was significantly associated with lower executive functioning which primarily could be attributed to antiepileptic drug use. No significant associations were established between neurocognitive status and radiotherapy or tumour volume. CONCLUSIONS: Meningioma patients are characterised by long term deficits in neurocognitive functioning that can partly be attributed to the use of antiepileptic drugs and tumour location but not to the use of radiotherapy.

The influence of low-grade glioma on resting state oscillatory brain activity: a magnetoencephalography study.

PURPOSE: In the present MEG-study, power spectral analysis of oscillatory brain activity was used to compare resting state brain activity in both low-grade glioma (LGG) patients and healthy controls. We hypothesized that LGG patients show local as well as diffuse slowing of resting state brain activity compared to healthy controls and that particularly global slowing correlates with neurocognitive dysfunction. PATIENT AND METHODS: Resting state MEG recordings were obtained from 17 LGG patients and 17 age-, sex-, and education-matched healthy controls. Relative spectral power was calculated in the delta, theta, upper and lower alpha, beta, and gamma frequency band. A battery of standardized neurocognitive tests measuring 6 neurocognitive domains was administered. RESULTS: LGG patients showed a slowing of the resting state brain activity when compared to healthy controls. Decrease in relative power was mainly found in the gamma frequency band in the bilateral frontocentral MEG regions, whereas an increase in relative power was found in the theta frequency band in the left parietal region. An increase of the relative power in the theta and lower alpha band correlated with impaired executive functioning, information processing, and working memory. CONCLUSION: LGG patients are characterized by global slowing of their resting state brain activity and this slowing phenomenon correlates with the observed neurocognitive deficits.

Acquired encephaloceles and epilepsy in osteopetrosis.

Osteopetrosis is a condition in which there is a defect in bone resorption by osteoclasts. With thickening of the skull and skull base, the cranial capacity becomes compromised and skull foramina gradually occlude, resulting in a wide range of neurological symptoms and signs. We present a case of autosomal dominant osteopetrosis with temporal lobe epilepsy and nasal obstruction due to acquired bifrontal encephaloceles associated with a decreased intracranial capacity. Neurosurgical reconstruction of the frontal skull base alleviated the symptoms of epilepsy and nasal obstruction.

The development of an EORTC quality of life questionnaire to assess chemotherapy-induced peripheral neuropathy: the QLQ-CIPN20.

Chemotherapy-induced peripheral neuropathy (CIPN) is a common phenomenon, often resulting in serious limitations in daily functioning and compromised quality of life. Currently available toxicity grading systems typically use a combination of clinical and paraclinical parameters and relies on the judgment of clinicians and/or nurses. However, because many of the symptoms of CIPN are subjective in nature, it is only logical that an assessment of CIPN be based, at least in part, on patient self-report data. We report on the development of a patient self-report questionnaire, the CIPN20, intended to supplement the core quality of life questionnaire of the European Organization for Research and Treatment of Cancer (EORTC). Following EORTC guidelines, relevant CIPN-related issues were identified from a literature survey and interviews with health professionals (n=15) and patients (n=112). The resulting 20-item questionnaire was pre-tested in three languages and four countries and is currently being examined in a large, international clinical trial. The EORTC CIPN20 should provide valuable information on CIPN-related symptoms and functional limitations of patients exposed to potentially neurotoxic chemotherapeutic and/or neuroprotective agents.

Dose-related vincristine-induced peripheral neuropathy with unexpected off-therapy worsening.

This study describes the natural course of vincristine-induced peripheral neuropathy in patients with lymphoma (n = 114) receiving vincristine in two different dose intensities. Neuropathic changes were observed in both dose intensity groups, but the higher dose intensity group reported significantly more symptoms during therapy, whereas neurologic signs were significantly more prominent after a cumulative dose of 12 mg vincristine. Furthermore, off-therapy worsening of symptoms (24%) and signs (30%) occurred unexpectedly.

The relevance of intraventricular chemotherapy for leptomeningeal metastasis in breast cancer: a randomised study.

To assess the benefit of intraventricular chemotherapy, patients with leptomeningeal metastasis (LM) from breast cancer were randomised to treatment including intraventricular (IT) chemotherapy (n=17) or to non-intrathecal (non-IT) treatment (n=18). Appropriate systemic therapy and involved field radiation therapy (RT) were given in both arms. Intention-to-treat analysis showed neurological improvement or stabilisation in 59% of the IT and in 67% of the non-IT group, with median time to progression of 23 weeks (IT) and 24 weeks (non-IT). Median survival of IT patients was 18.3 weeks and 30.3 weeks for non-IT patients (difference 12.9 weeks; 95% Confidence Interval (CI) -5.5 to +34.3 weeks; P=0.32). Neurological complications of treatment occurred in 47% (IT) vs 6% (non-IT) (P=0.0072). In conclusion, standard systemic chemotherapy with involved field RT for LM from breast cancer is feasible. Addition of intraventricular chemotherapy does not lead to survival benefit or improved neurological response, and is associated with an increased risk of neurotoxicity.

[Impaired cognitive functioning in low-grade glioma patients: relationship to tumor localisation, radiotherapy and the use of anticonvulsants]. / Verminderd cognitief functioneren van patiënten met een laaggradig glioom: samenhang met de tumorlokalisatie, de bestraling en het gebruik van anti-epileptica.

OBJECTIVE: To determine the effects of radiotherapy and other medical interventions on cognitive functioning in patients with a low-grade glioma (LGG). DESIGN: Cross-sectional study. METHOD: A total of 195 LGG patients, of whom 104 had received radiotherapy 1-22 years previously, were compared to 100 patients with a low-grade haematological malignancy and 195 healthy controls. The analysis was aimed at differentiating between the effects of the tumour (disease duration, lateralisation) and treatment effects (neurosurgery, radiotherapy, use of anticonvulsants) on cognitive function and the relative risk of cognitive disability. RESULTS: LGG patients had lower performance levels in all cognitive domains than haematological patients and performed even worse when they were compared to healthy controls. Radiotherapy was associated with poorer cognitive functioning; however, cognitive disability was found only in patients receiving fractional doses exceeding 2 Gy. The use of anticonvulsants was strongly associated with disorders in the area of attention and planning functions. CONCLUSION: In this study, the tumour itself was the most damaging factor with respect to cognitive function and radiotherapy was associated with cognitive disability only if elevated fractional doses were used. Epilepsy or the use of anticonvulsants was also associated with diminished cognitive functioning.