Complications, compliance, and undertreatment do not explain the relationship between cognition and survival in diffuse glioma patients.

Background: Cognitive deficits occur in all different grades of glioma. In a recent study, we found these deficits to be independently, and possibly causally, related to survival in diffuse gliomas. In this study, we investigated whether the relationship between cognition and survival was mediated by three different factors: undertreatment, complications of treatment, and compliance. We hypothesized that patients with cognitive impairment may undergo less intensive treatment, be less compliant, and suffer more from complications, resulting in shortened survival for cognitively impaired patients. Methods: In a retrospective cohort study of patients undergoing awake craniotomy between operative neuropsychological assessments in five cognitive domains. We used Structural Equation Modeling to perform mediation analyses. Mediation analyses are analyses to evaluate whether a variable is a factor in the causal chain, referred to as an intermediate factor. Results: In total 254 patients were included, of whom 111 patients were LGG patients and 143 were HGG patients. The most frequently impaired domain was memory (37.8% ≤-2 SD) in HGG and attention and executive functioning in LGG (33.3≤-1.5 SD). We confirmed the significant association between different cognitive domains and survival. These associations could not be explained by one of the aforementioned intermediate factors. Conclusions: This suggests that other mechanisms should be involved in the relation between cognition and survival. Hypothetically, cognitive functioning can act as a marker for diffuse infiltration of the tumor or cognitive functioning and survival could be determined by overlapping germline and somatic tumoral molecular-genetic factors.

Tumor-related molecular determinants of neurocognitive deficits in patients with diffuse glioma.

BACKGROUND: Cognitive impairment is a common and debilitating symptom in patients with diffuse glioma, and is the result of multiple factors. We hypothesized that molecular tumor characteristics influence neurocognitive functioning (NCF), and aimed to identify tumor-related markers of NCF in diffuse glioma patients. METHODS: We examined the relation between cognitive performance (executive function, memory, and psychomotor speed) and intratumoral expression levels of molecular markers in treatment-naive patients with diffuse glioma. We performed a single-center study in a consecutive cohort, through a two-step design: (1) hypothesis-free differential expression and gene set enrichment analysis to identify candidate oncogenetic markers for cognitive impairment. Nineteen molecular markers of interest were derived from this set of genes, as well as from prior knowledge; (2) correlation of cognitive performance to intratumoral expression levels of these nineteen molecular markers, measured with immunohistochemistry. RESULTS: From 708 included patients with immunohistochemical data, we performed an in-depth analysis of neuropsychological data in 197, and differential expression analysis in 65 patients. After correcting for tumor volume and location, we found significant associations between expression levels of CD3 and IDH-1 and psychomotor speed; between IDH-1, ATRX, NLGN3, BDNF, CK2Beta, EAAT1, GAT-3, SRF, and memory performance; and between IDH-1, P-STAT5b, NLGN3, CK2Beta, and executive functioning. P-STAT5b, CD163, CD3, and Semaphorin-3A were independently associated after further correction for histopathological grade. CONCLUSION: Molecular characteristics of glioma can be independent determinants of patients' cognitive functioning. This suggests that besides tumor volume, location, and histological grade, variations in glioma biology influence cognitive performance through mechanisms that include perturbation of neuronal communication. These results pave the way towards targeted cognition improving therapies in neuro-oncology.

Added Value of Cognition in the Prediction of Survival in Low and High Grade Glioma.

Background: Diffuse gliomas, which are at WHO grade II-IV, are progressive primary brain tumors with great variability in prognosis. Our aim was to investigate whether pre-operative cognitive functioning is of added value in survival prediction in these patients. Methods: In a retrospective cohort study of patients undergoing awake craniotomy between 2010 and 2019 we performed pre-operative neuropsychological assessments in five cognitive domains. Their added prognostic value on top of known prognostic factors was assessed in two patient groups [low- (LGG) and high-grade gliomas (HGG]). We compared Cox proportional hazards regression models with and without the cognitive domain by means of loglikelihood ratios tests (LRT), discriminative performance measures (by AUC), and risk classification [by Integrated Discrimination Index (IDI)]. Results: We included 109 LGG and 145 HGG patients with a median survival time of 1,490 and 511 days, respectively. The domain memory had a significant added prognostic value in HGG as indicated by an LRT (p-value = 0.018). The cumulative AUC for HGG with memory included was.78 (SD = 0.017) and without cognition 0.77 (SD = 0.018), IDI was 0.043 (0.000-0.102). In LGG none of the cognitive domains added prognostic value. Conclusions: Our findings indicated that memory deficits, which were revealed with the neuropsychological examination, were of additional prognostic value in HGG to other well-known predictors of survival.

Cognitive impairments are independently associated with shorter survival in diffuse glioma patients.

BACKGROUND: Diffuse gliomas (WHO grade II-IV) are progressive primary brain tumors with great variability in prognosis. Cognitive deficits are of important prognostic value for survival in diffuse gliomas. Until now, few studies focused on domain-specific neuropsychological assessment and rather used MMSE as a measure for cognitive functioning. Additionally, these studies did not take WHO 2016 diagnosis into account. We performed a retrospective cohort study with the aim to investigate the independent relationship between cognitive functioning and survival in treatment-naive patients undergoing awake surgery for a diffuse glioma. METHODS: In patients undergoing awake craniotomy between 2010 and 2017, we performed pre-operative neuropsychological assessments in five cognitive domains, with special attention for the domains executive functioning and memory. We evaluated the independent relation between these domains and survival, in a Cox proportional hazards model that included state-of-the-art integrated histomolecular ('layered' or WHO-2016) classification of the gliomas and other known prognostic factors. RESULTS: We included 197 patients. Cognitive impairments (Z-values ≦ - 2.0) were most frequent in the domains memory (18.3%) and executive functioning (25.9%). Impairments in executive functioning and memory were significantly correlated with survival, even after correcting for the possible confounders. Analyses with the domains language, psychomotor speed, and visuospatial functioning yielded no significant results. Extensive domain-specific neuropsychological assessment was more strongly correlated to survival than MMSE. CONCLUSION: Cognitive functioning is independently related to survival in diffuse glioma patients. Possible mechanisms underlying this relationship include the notion of cognitive functioning as a marker for diffuse infiltration of the tumor and the option that cognitive functioning and survival are determined by overlapping genetic pathways and biomarkers.

Neurocognitive changes after awake surgery in glioma patients: a retrospective cohort study.

PURPOSE: Deficits in neurocognitive functioning (NCF) frequently occur in glioma patients. Both treatment and the tumor itself contribute to these deficits. In order to minimize the harmful effects of surgery, an increasing number of patients undergo awake craniotomy. To investigate whether we can indeed preserve cognitive functioning after state-of-the art awake surgery and to identify factors determining postoperative NCF, we performed a retrospective cohort study. METHODS: In diffuse glioma (WHO grade 2-4) patients undergoing awake craniotomy, we studied neurocognitive functioning both pre-operatively and 3-6 months postoperatively. Evaluation covered five neurocognitive domains. We performed analysis of data on group and individual level and evaluated the value of patient-, tumor- and treatment-related factors for predicting change in NCF, using linear and logistic regression analysis. RESULTS: We included 168 consecutive patients. Mean NCF-scores of psychomotor speed and visuospatial functioning significantly deteriorated after surgery. The percentage of serious neurocognitive impairments (- 2 standard deviations) increased significantly for psychomotor speed only. Tumor involvement in the left thalamus predicted a postoperative decline in NCF for the domains overall-NCF, executive functioning and psychomotor speed. An IDH-wildtype status predicted decline for overall-NCF and executive functioning. CONCLUSIONS: In all cognitive domains, except for psychomotor speed, cognitive functioning can be preserved after awake surgery. The domain of psychomotor speed seems to be most vulnerable to the effects of surgery and early postoperative therapies. Cognitive performance after glioma surgery is associated with a combination of structural and biomolecular effects from the tumor, including IDH-status and left thalamic involvement.

Tumor-related neurocognitive dysfunction in patients with diffuse glioma: a retrospective cohort study prior to antitumor treatment.

BACKGROUND: Impairments in neurocognitive functioning (NCF) frequently occur in glioma patients. Both the tumor and its treatment contribute to these impairments. We aimed to quantify NCF in glioma patients before treatment and to investigate which factors influence NCF. METHODS: We performed a retrospective cohort study in diffuse glioma patients according to STROBE (Strengthening the Reporting of Observational Studies in Epidemiology) criteria. All patients had undergone neuropsychological assessment as part of routine clinical care, before awake surgery. We studied "overall NCF" and NCF in 5 neurocognitive domains separately. For "overall NCF" and per domain, we performed analyses at 2 different levels of outcome measures: (1) group level: mean cognitive functioning of the study sample, and (2) individual level: the percentage of impaired patients. We performed multivariable logistic regression analyses to investigate which factors were associated with the occurrence of cognitive impairments. RESULTS: From our cohort of glioma patients (2010-2016), 168 patients met all the inclusion criteria. All cognitive domains were significantly affected at the group level. The percentages of neurocognitive impairments (-2SD) were highest for Executive Functioning, Psychomotor Speed, and Memory (26.5%, 23.2%, and 19.3%, respectively). Patients with high-grade glioma were affected more severely than patients with low-grade glioma. Tumor volume, isocitrate dehydrogenase status, WHO grade, and histology were associated with the occurrence of domain-specific impairments. CONCLUSIONS: Cognitive impairment occurs in the majority of treatment-naive glioma patients. The domains Executive Functioning, Speed, and Memory are involved most frequently. These impairments in NCF are explained not only by tumor location and volume, but also by other (biological) mechanisms.

Tumor-related neurocognitive dysfunction in patients with diffuse glioma: a systematic review of neurocognitive functioning prior to anti-tumor treatment.

Deficits in neurocognitive functioning (NCF) frequently occur in glioma patients. Both treatment and the tumor itself contribute to these deficits. Data about the role of the tumor are scarce, because NCF has mostly been studied postoperatively. We aimed to summarize data on pre-treatment NCF in glioma patients and to determine the overall and domain-specific prevalence of neurocognitive dysfunction. We searched PubMed and Embase according to PRISMA-P protocol for studies that evaluated pre-treatment NCF in glioma patients (1995-November 2016) and extracted information about NCF. We performed analysis of data for two main outcome measures; mean cognitive functioning of the study sample (at group level) and the percentage of impaired patients (at individual level). We included 23 studies. Most studies were small observational prospective cohort studies. In 11 (47.5%) studies, patient selection was based on tumor location. NCF was analyzed at the group level in 14 studies, of which 13 (92.9%) found decreased NCF at group level, compared to normative data or matched controls. The proportion of individuals with decreased NCF was reported in 15 studies. NCF was impaired (in any domain) in 62.6% of the individuals (median; interquartile range 31.0-79.0). Cognitive impairments were more common in patients with high-grade glioma than with low-grade glioma (OR 2.50; 95% CI 1.71-3.66). Cognitive impairment occurs in the majority of treatment-naive glioma patients, suggesting that neurocognitive dysfunction is related to the tumor. However, the literature about pre-treatment NCF in glioma patients is characterized by small-scale studies and strong heterogeneity in patient selection, resulting in high risk of bias.

[A score for rating instability in spinal metastases and the usefulness of conservative measures for instability]. / Instabiliteit bij spinale metastasen: objectieve score en nut van conservatieve maatregelen.

Spinal instability in patients with spinal metastatic disease plays a role in the selection of surgical intervention. The classic 'three-column model' used in traumatology to assess the stability of the spinal column is not always applicable to spinal metastatic disease. The recently introduced Spinal Instability Neoplastic Score (SINS) is the first instrument that can be used to classify instability in spinal metastatic disease. Utilisation of the SINS by the medical community could lead to more uniformity, which could prevent a delay in the treatment of patients with spinal instability. Only a select group of patients with spinal instability due to metastatic disease is eligible for spinal surgery. Other patients are often prescribed bed rest or other conservative treatment. The usefulness of such treatments, however, has not been adequately substantiated.