Variation in medical management and neurosurgical treatment of patients with supratentorial spontaneous intracerebral haemorrhage.

INTRODUCTION: The role of surgery in spontaneous intracerebral haemorrhage (sICH) remains controversial. This leads to variation in the percentage of patients who are treated with surgery between countries. PATIENTS AND METHODS: We sent an online survey to all neurosurgeons (n = 140) and to a sample of neurologists (n = 378) in Dutch hospitals, with questions on management in supratentorial sICH in general, and on treatment in six patients, to explore current variation in medical and neurosurgical management. We assessed patient and haemorrhage characteristics influencing treatment decisions. RESULTS: Twenty-nine (21%) neurosurgeons and 92 (24%) neurologists responded. Prior to surgery, neurosurgeons would more frequently administer platelet-transfusion in patients on clopidogrel (64% versus 13%; p = 0.000) or acetylsalicylic acid (61% versus 11%; p = 0.000) than neurologists. In the cases, neurosurgeons and neurologists were similar in their choice for surgery as initial treatment (24% and 31%; p = 0.12), however variation existed amongst physicians in specific cases. Neurosurgeons preferred craniotomy with haematoma evacuation (74%) above minimally-invasive techniques (5%). Age, Glasgow Coma Scale score and ICH location were important factors influencing decisions on treatment for neurosurgeons and neurologists. 69% of neurosurgeons and 80% of neurologists would randomise patients in a trial evaluating the effect of minimally-invasive surgery on functional outcome. DISCUSSION: Our results reflect the lack of evidence about the right treatment strategy in patients with sICH. CONCLUSION: New high quality evidence is needed to guide treatment decisions for patients with ICH. The willingness to randomise patients into a clinical trial on minimally-invasive surgery, contributes to the feasibility of such studies in the future.

Preclinical evaluation of convection-enhanced delivery of liposomal doxorubicin to treat pediatric diffuse intrinsic pontine glioma and thalamic high-grade glioma.

OBJECTIVE Pediatric high-grade gliomas (pHGGs) including diffuse intrinsic pontine gliomas (DIPGs) are primary brain tumors with high mortality and morbidity. Because of their poor brain penetrance, systemic chemotherapy regimens have failed to deliver satisfactory results; however, convection-enhanced delivery (CED) may be an alternative mode of drug delivery. Anthracyclines are potent chemotherapeutics that have been successfully delivered via CED in preclinical supratentorial glioma models. This study aims to assess the potency of anthracyclines against DIPG and pHGG cell lines in vitro and to evaluate the efficacy of CED with anthracyclines in orthotopic pontine and thalamic tumor models. METHODS The sensitivity of primary pHGG cell lines to a range of anthracyclines was tested in vitro. Preclinical CED of free doxorubicin and pegylated liposomal doxorubicin (PLD) to the brainstem and thalamus of naïve nude mice was performed. The maximum tolerated dose (MTD) was determined based on the observation of clinical symptoms, and brains were analyzed after H & E staining. Efficacy of the MTD was tested in adult glioma E98-FM-DIPG and E98-FM-thalamus models and in the HSJD-DIPG-007-Fluc primary DIPG model. RESULTS Both pHGG and DIPG cells were sensitive to anthracyclines in vitro. Doxorubicin was selected for further preclinical evaluation. Convection-enhanced delivery of the MTD of free doxorubicin and PLD in the pons was 0.02 mg/ml, and the dose tolerated in the thalamus was 10 times higher (0.2 mg/ml). Free doxorubicin or PLD via CED was ineffective against E98-FM-DIPG or HSJD-DIPG-007-Fluc in the brainstem; however, when applied in the thalamus, 0.2 mg/ml of PLD slowed down tumor growth and increased survival in a subset of animals with small tumors. CONCLUSIONS Local delivery of doxorubicin to the brainstem causes severe toxicity, even at doxorubicin concentrations that are safe in the thalamus. As a consequence, the authors could not establish a therapeutic window for treating orthotopic brainstem tumors in mice. For tumors in the thalamus, therapeutic concentrations to slow down tumor growth could be reached. These data suggest that anatomical location determines the severity of toxicity after local delivery of therapeutic agents and that caution should be used when translating data from supratentorial CED studies to treat infratentorial tumors.

Time intervals from aneurysmal subarachnoid hemorrhage to treatment and factors contributing to delay.

In the management of aneurysmal subarachnoid hemorrhage (aSAH), aneurysm treatment as early as feasible is mandatory to minimize the risk of a rebleed and may thus improve outcome. We assessed the different time intervals from the first symptoms of aSAH to start of aneurysm treatment in an effort to identify which factors contribute mostly to a delay in time to treatment. In 278 aSAH patients, time intervals between the different steps from initial hemorrhage to aneurysm treatment were retrospectively reviewed, and delaying factors were determined. Half of the patients presented to a hospital within 115 min (IQR 60-431). The median (IQR) interval from hemorrhage to diagnosis was 169 min (96-513), and from diagnosis to treatment 1,057 min (416-1,428), or 17.6 h. Aneurysm treatment started within 24 h in 76 % of treated patients. Independent factors predicting delay to treatment were primary presentation at a referring hospital and admission to the treatment center later in the day. Delay in treatment was not independently related to poor outcome. The interval to aneurysm treatment might be improved upon by immediate and direct transport to the treatment center combined with optimization of in-hospital logistics, following the 'time-is-brain' concept so successfully adopted in the treatment of ischemic stroke.

Slowing of M1 oscillations in brain tumor patients in resting state and during movement.

OBJECTIVE: Brain tumors may severely disrupt the structure and function of the brain. While abnormal low-frequency activity can be found around tumor borders, disrupted structural connectivity may also impinge on neural activity in distant brain regions and other frequency bands. We investigated how glioma in patients with normal motor functioning affects activity in primary motor areas (M1). METHODS: Using magnetoencephalography in 12 patients with unilateral glioma located around the central sulcus, we studied activity in bilateral M1s in resting state and during movement with focus on motor-related mu (8-12Hz) and beta rhythms (15-30Hz). Principal component analysis served to test for differences in spectral content. RESULTS: A shift was found towards lower frequencies for M1 in the tumor hemisphere compared to M1 in the healthy hemisphere, caused by an increase in mu and decrease in beta power. This pattern was observed both in resting state and during movement. CONCLUSIONS: This 'slowing' of brain oscillations in M1 resembles findings in patients with monohemispheric stroke and Parkinson's disease. A loss of intra-cortical connectivity may account for these findings, possibly supplemented by tumor-induced changes in neurotransmitter systems. SIGNIFICANCE: Motor functioning may be unaffected by a spectral shift of mu and beta oscillations.

In silico analysis of kinase expression identifies WEE1 as a gatekeeper against mitotic catastrophe in glioblastoma.

Kinases execute pivotal cellular functions and are therefore widely investigated as potential targets in anticancer treatment. Here we analyze the kinase gene expression profiles of various tumor types and reveal the wee1 kinase to be overexpressed in glioblastomas. We demonstrate that WEE1 is a major regulator of the G(2) checkpoint in glioblastoma cells. Inhibition of WEE1 by siRNA or small molecular compound in cells exposed to DNA damaging agents results in abrogation of the G(2) arrest, premature termination of DNA repair, and cell death. Importantly, we show that the small-molecule inhibitor of WEE1 sensitizes glioblastoma to ionizing radiation in vivo. Our results suggest that inhibition of WEE1 kinase holds potential as a therapeutic approach in treatment of glioblastoma.

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.

Tumour control by whole brain irradiation of anti-VEGF-treated mice bearing intracerebral glioma.

AIM OF THE STUDY: Tumour angiogenesis and invasion are key features of glioblastoma multiforme (GBM). Angiogenesis inhibitors increase progression-free survival (PFS) of recurrent GBM patients. VEGF inhibition controls the bulk tumour growth by inhibition of angiogenesis, but does not inhibit the invasive tumour component. We investigated if invasive tumour growth can be controlled by combining anti-VEGF treatment with irradiation of tumour plus surrounding brain in an orthotopic murine model for GBM. METHODS AND MATERIALS: GBM cell line U251-NG2 was inoculated through a guide screw in the right frontal lobe of 53 athymic nude mice. Pegaptanib (a slow-releasing aptamer against VEGF) was injected in the tumour bed either or not followed by irradiation treatment with implanted I-125 seeds. Pegaptanib and/or irradiation were compared with sham-treated controls, resulting in four groups of 10-15 mice each. After 6 weeks of treatment, histological analysis was performed on all brains. RESULTS: VEGF inhibition by locally deposited pegaptanib decreased tumour blood vessel density, and increased tumour hypoxia. Pegaptanib treatment still allowed the formation of tumour satellites. Irradiation decreased tumour size and suppressed formation of satellites. Combined pegaptanib plus irradiation further increased PFS. Tumour size directly correlated with PFS. CONCLUDING STATEMENT: The anti-tumour effects of local VEGF inhibition are partially circumvented by the formation of invasive tumour satellites. Additional irradiation is effective in slowing down proliferation of these invasive tumour components.