Tom J. Snijders

Valproic acid for the treatment of malignant gliomas: review of the preclinical rationale and published clinical results.

Introduction: Glioblastoma multiforme is the most common and aggressive primary brain tumor. Valproate has been used as an anti-epileptic drug and mood stabilizer for decades. Recently, it was found to inhibit the proliferation of various cancers including glioblastoma multiforme. Areas covered: We provide a comprehensive review of the mechanisms of action of valproate in gliomas, of its potential side effects and of the published clinical results obtained with this drug in glioblastomas. Valproate inhibits a subset of histone deacetylases and cellular kinases, and affects gene transcription through histone hyperacetylation, DNA hypomethylation and the modulation of several transcription factors. As a result, VPA induces differentiation of glioma cells, can prevent their invasion in surrounding tissues and may inhibit tumor angiogenesis. VPA can also inhibit DNA repair, thereby potentiating cytotoxic treatments such as chemotherapies or radiation therapy. Based on these mechanisms and case reports of glioblastoma remissions following VPA treatment, several clinical studies currently assess the therapeutic potential of VPA in glioma therapy. Expert opinion: The combination of VPA treatment with chemotherapy and radiotherapy in glioblastoma appears a rational option that deserves well-designed prospective clinical trials that assess the efficacy and the molecular characteristics of the responding tumors in these patients.

Myeloid sarcoma presenting as a recurrent, multifocal nerve root entrapment syndrome

Background Myeloid sarcoma is an extramedullary manifestation of haematologic malignancy, most commonly acute myeloid leukemia (AML), which can cause neurological symptoms. Case description A 45-year-old male with a history of AML presented with a lumbosacral nerve root entrapment syndrome followed by cauda equina compression, but without systemic signs of AML recurrence. MRI showed a mass compressing the spinal cord at level L5–S2. After surgically removing the tumour pathologic examination yielded a myeloid sarcoma. Combined chemotherapy and radiation therapy followed. Five months later the patient developed a thoracal (Th10–Th11) radiculopathy due to a relapse of the myeloid sarcoma, followed by C8-Th1-radiculopathy caused by leptomeningeal spread. Conclusion This case forms the first description of recurrent, multifocal and progressive radiculopathy due to myeloid sarcoma. This diagnosis should be considered in patients with radiculopathy with previous haematological malignancy and/or signs or symptoms of such disease; the absence of systemic disease activity does not rule out myeloid sarcoma.

Prognostic relevance of epilepsy at presentation in glioblastoma patients.

BACKGROUND Epileptogenic glioblastomas are thought to convey a favorable prognosis, either due to early diagnosis or potential antitumor effects of antiepileptic drugs. We investigated the relationship between survival and epilepsy at presentation, early diagnosis, and antiepileptic drug therapy in glioblastoma patients. METHODS Multivariable Cox regression was applied to survival data of 647 consecutive patients diagnosed with de novo glioblastoma between 2005 and 2013 in order to investigate the association between epilepsy and survival in glioblastoma patients. In addition, we quantified the association between survival and valproic acid (VPA) treatment. RESULTS Epilepsy correlated positively with survival (HR: 0.75 (95% CI: 0.61-0.92), P < .01). This effect is independent of age, sex, performance status, type of surgery, adjuvant therapy, tumor location, and tumor volume, suggesting that this positive correlation cannot be attributed solely to early diagnosis. For patients who presented with epilepsy, the use of the antiepileptic drug VPA did not associate with survival when compared with patients who did not receive VPA treatment. CONCLUSION Epilepsy is an independent prognostic factor for longer survival in glioblastoma patients. This prognostic effect is not solely explained by early diagnosis, and survival is not associated with VPA treatment.

Current treatment of low grade gliomas

Low grade gliomas affect predominantly young adults, and have a relatively favorable prognosis compared to grade III and grade IV gliomas. The challenge for an optimal management of these patients is to find the balance between an optimal survival and the preservation of neurological function including cognition. Because all medical treatments may induce side effects, in young and nearly asymptomatic patients the choices can be difficult. This review summarizes the current strategies: a watch-and-wait policy, surgery, chemotherapy, and radiotherapy.

Relevance of Physical Fitness Levels and Exercise-related Beliefs for Self-reported and Experimental Pain in Fibromyalgia: An Explorative Study

Background:It has been suggested that low physical fitness is a contributor to pain in fibromyalgia and that exercise-related beliefs play a role in the persistence of this association. Yet the association between physical fitness and pain is hardly explored in detail. Objectives:The aim of this exploratory study in patients with fibromyalgia was to investigate the association of physical fitness levels with self-reported and experimental pain as well as with pain catastrophizing and activity-avoidance beliefs. Methods:Physical fitness of 18 patients with fibromyalgia was examined using maximal ergocycling and the 6-minute walking test (6MWT). Pain intensity was assessed using self-report scales and quantitative sensory testing. Results:A reduced walking distance on the 6MWT was correlated with more severe self-reported pain on the Fibromyalgia Impact Questionnaire (r = −0.52, P < 0.05). Recovery of heart rate after ergocycling was correlated with cold pain thresholds (r = 0.70, P < 0.01), pressure pain thresholds (r = −0.70, P < 0.01), and heat wind-up (r = 0.66, P < 0.05). Activity-avoidance beliefs correlated with a lower peak VO2 on the cycle test (r = −0.52, P < 0.05), a shorter distance on the 6MWT (r = −0.56, P < 0.05), and more severe self-reported pain (r = 0.61, P < 0.05), reflecting that patients with activity-avoidance beliefs were less physically fit and experienced more severe pain. Conclusions:The results demonstrate some associations between physical fitness and pain in fibromyalgia and point to the importance of activity avoidance. Although the causal directionality of the associations needs substantiation in clinical research, the findings support the notion that low fitness and activity-avoidance beliefs should be targeted while treating pain in fibromyalgia.

Guideline for the diagnosis, treatment and response criteria for Bing-Neel syndrome

Bing Neel syndrome is a rare disease manifestation of Waldenström’s macroglobulinemia that results from infiltration of the central nervous system by malignant lymphoplasmacytic cells. In this guideline we describe the clinical symptoms, as well as the appropriate laboratory and radiological studies, that can aid in the diagnosis. The presentation of Bing Neel syndrome may be very diverse, and includes headaches, cognitive deficits, paresis, and psychiatric symptoms. The syndrome can present in patients with known Waldenström’s macroglobulinemia, even in the absence of systemic progression, but also in previously undiagnosed patients. Diagnostic work-up should include cerebral spinal fluid analysis with multiparameter flow cytometry to establish B-cell clonality, protein electrophoresis and immunofixation for the detection and classification of a monoclonal protein as well as molecular diagnostic testing for immunoglobulin gene rearrangement and mutated MYD88. MRI of the brain and spinal cord is also essential. The second challenge is to expand our knowledge of prognosis and treatment outcome. Prospective clinical trials on Bing Neel syndrome patients that employ uniform treatment along with appropriate laboratory cerebral spinal fluid assessments and standardized MRI protocols will be invaluable, constituting a significant step forward in delineating treatment outcome for this intriguing disease manifestation.

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.

Prognosis and therapy of tumor-related versus non-tumor-related status epilepticus: a systematic review and meta-analysis.

BackgroundStatus epilepticus (SE) is a medical emergency with high mortality rates. Of all SE’s, 7% are caused by a brain tumor. Clinical guidelines on the management of SE do not make a distinction between tumor-related SE and SE due to other causes. However, pathophysiological research points towards specific mechanisms of epilepsy in brain tumors. We investigated whether clinical features support a distinct profile of tumor-related SE by looking at measures of severity and response to treatment.MethodsSystematic review of the literature and meta-analysis of studies on adult SE that report separate data for tumor-related SE and non-tumor-related SE on the following outcomes: short-term mortality, long-term morbidity, duration of SE, and efficacy of anticonvulsant intervention.ResultsFourteen studies on outcome of SE were included. Tumor-related SE was associated with higher mortality than non-tumor-related SE (17.2% versus 11.2%, RR 1.53, 95%-CI 1.24-1.90). After exclusion of patients with hypoxic-ischemic encephalopathy (a group with a known poor prognosis) from the non-tumor-group, the difference in mortality increased (17.2% versus 6.6%; RR 2.78, 95%-CI 2.21 – 3.47). Regarding long-term morbidity and duration of SE there were insufficient data. We did not find studies that systematically compared effects of therapy for SE between tumor- and non-tumor-related SE.ConclusionsBased on – mostly retrospective – available studies, short-term mortality seems higher in tumor-related SE than in SE due to other causes. Further studies on the outcome and efficacy of different therapeutic regimens in tumor-related SE are needed, to clarify whether tumor-related SE should be regarded as a distinct clinical entity.

Preventing inflammation inhibits biopsy-mediated changes in tumor cell behavior

Although biopsies and tumor resection are prognostically beneficial for glioblastomas (GBM), potential negative effects have also been suggested. Here, using retrospective study of patients and intravital imaging of mice, we identify some of these negative aspects, including stimulation of proliferation and migration of non-resected tumor cells, and provide a strategy to prevent these adverse effects. By repeated high-resolution intravital microscopy, we show that biopsy-like injury in GBM induces migration and proliferation of tumor cells through chemokine (C-C motif) ligand 2 (CCL-2)-dependent recruitment of macrophages. Blocking macrophage recruitment or administrating dexamethasone, a commonly used glucocorticoid to prevent brain edema in GBM patients, suppressed the observed inflammatory response and subsequent tumor growth upon biopsy both in mice and in multifocal GBM patients. Taken together, our study suggests that inhibiting CCL-2-dependent recruitment of macrophages may further increase the clinical benefits from surgical and biopsy procedures.

Diagnostic markers for CNS lymphoma in blood and cerebrospinal fluid: a systematic review

Diagnosing central nervous system (CNS) lymphoma remains a challenge. Most patients have to undergo brain biopsy to obtain tissue for diagnosis, with associated risks of serious complications. Diagnostic markers in blood or cerebrospinal fluid (CSF) could facilitate early diagnosis with low complication rates. We performed a systematic literature search for studies on markers in blood or cerebrospinal fluid for the diagnosis CNS lymphoma and assessed the methodological quality of studies with the Quality Assessment of Diagnostic Accuracy Studies tool (QUADAS‐2). We evaluated diagnostic value of the markers at a given threshold, as well as differences between mean or median levels in patients versus control groups. Twenty‐five studies were included, reporting diagnostic value for 18 markers in CSF (microRNAs ‐21, ‐19b, and ‐92a, RNU2‐1f, CXCL13, interleukins ‐6, ‐8, and ‐10, soluble interleukin‐2‐receptor, soluble CD19, soluble CD27, tumour necrosis factor‐alfa, beta‐2‐microglobulin, antithrombin III, soluble transmembrane activator and calcium modulator and cyclophilin ligand interactor, soluble B cell maturation antigen, neopterin and osteopontin) and three markers in blood (microRNA‐21 soluble CD27, and beta‐2‐microglobulin). All studies were at considerable risk of bias and there were concerns regarding the applicability of 15 studies. CXCL‐13, beta‐2‐microglobulin and neopterin have the highest potential in diagnosing CNS lymphoma, but further study is still needed before they can be used in clinical practice.