A randomized, single ascending dose safety, tolerability and pharmacokinetics study of NicaPlant® in aneurysmal subarachnoid hemorrhage patients undergoing clipping.

Introduction: Aneurysmal subarachnoid hemorrhage (aSAH) is associated with high morbidity and mortality. Post-hemorrhagic vasospasm with neurological deterioration is a major concern in this context. NicaPlant®, a modified release formulation of the calcium channel blocker nicardipine, has shown vasodilator efficacy preclinically and a similar formulation known as NPRI has shown anti-vasospasm activity in aSAH patients under compassionate use. Research question: The study aimed to assess pharmacokinetics and pharmacodynamics of NicaPlant® pellets to prevent vasospasm after clip ligation in aSAH. Material and methods: In this multicenter, controlled, randomized, dose escalation trial we assessed the safety and tolerability of NicaPlant®. aSAH patients treated by clipping were randomized to receive up to 13 NicaPlant® implants, similarly to the dose of NPRIs previous used, or standard of care treatment. Results: Ten patients across four dose groups were treated with NicaPlant® (3-13 implants) while four patients received standard of care. 45 non-serious and 13 serious adverse events were reported, 4 non-serious adverse events and 5 serious adverse events assessed a probable or possible causal relationship to the investigational medical product. Across the NicaPlant® groups there was 1 case of moderate vasospasm, while in the standard of care group there were 2 cases of severe vasospasm. Discussion and conclusion: The placement of NicaPlant® during clip ligation of a ruptured cerebral aneurysm raised no safety concern. The dose of 10 NicaPlant® implants was selected for further clinical studies.

Peritumoral ADC Values Correlate with the MGMT Methylation Status in Patients with Glioblastoma.

Different results have been reported concerning the relationship of the apparent diffusion coefficient (ADC) values and the status of methylation as the promoter gene for the enzyme methylguanine-DNA methyltransferase (MGMT) in patients with glioblastomas (GBs). The aim of this study was to investigate if there were correlations between the ADC values of the enhancing tumor and peritumoral areas of GBs and the MGMT methylation status. In this retrospective study, we included 42 patients with newly diagnosed unilocular GB with one MRI study prior to any treatment and histopathological data. After co-registration of ADC maps with T1-weighted sequences after contrast administration and dynamic susceptibility contrast (DSC) perfusion, we manually selected one region-of-interest (ROI) in the enhancing and perfused tumor and one ROI in the peritumoral white matter. Both ROIs were mirrored in the healthy hemisphere for normalization. In the peritumoral white matter, absolute and normalized ADC values were significantly higher in patients with MGMT-unmethylated tumors, as compared to patients with MGMT-methylated tumors (absolute values p = 0.002, normalized p = 0.0007). There were no significant differences in the enhancing tumor parts. The ADC values in the peritumoral region correlated with MGMT methylation status, confirmed by normalized ADC values. In contrast to other studies, we could not find a correlation between the ADC values or the normalized ADC values and the MGMT methylation status in the enhancing tumor parts.

Magnetic Resonance Spectroscopy in Diagnosis and Follow-Up of Gliomas: State-of-the-Art.

Preoperative grade prediction is important in diagnostics of glioma. Even more important can be follow-up after chemotherapy and radiotherapy of high grade gliomas. In this review we provide an overview of MR-spectroscopy (MRS), technical aspects, and different clinical scenarios in the diagnostics and follow-up of gliomas in pediatric and adult populations. Furthermore, we provide a recap of the current research utility and possible future strategies regarding proton- and phosphorous-MRS in glioma research.

An Update on Neurosurgical Management of Primary CNS Lymphoma in Immunocompetent Patients.

Primary central nervous system lymphomas (PCNSL) are rare CNS tumors that harbor a conspicuously longer diagnostic delay compared to other malignant brain tumors. The gold standard for diagnosis is stereotactic biopsy to acquire tissue for histopathological analysis and therefore neurosurgery plays a central role when reducing the diagnostic period is mandated. However, histopathological diagnosis could be complicated if the patient was preoperatively exposed to corticosteroids. Besides the histopathological result, diagnosis of a PCNSL also requires full diagnostic workup to exclude cerebral metastatic disease of a systemic lymphoma. Most reviews of PCNSL discuss recent advancements in systemic treatment options from an (neuro-)oncologic viewpoint, whereas our intention was to discuss the optimization of the diagnostic period and therefore describe current standards of imaging, summarizing the diagnostic workup, discussing the surgical workup and future diagnostic prospects as well as the influence of preoperative corticosteroid therapy to reduce the diagnostic delay of PCNSL patients.

Changes in Brain Energy and Membrane Metabolism in Glioblastoma following Chemoradiation.

Brain parenchyma infiltration with glioblastoma (GB) cannot be entirely visualized by conventional magnetic resonance imaging (MRI). The aim of this study was to investigate changes in the energy and membrane metabolism measured with phosphorous MR spectroscopy (31P-MRS) in the presumably "normal-appearing" brain following chemoradiation therapy (CRT) in GB patients in comparison to healthy controls. Twenty (seven female, thirteen male) GB patients underwent a 31P-MRS scan prior to surgery (baseline) and after three months of standard CRT (follow-up examination. The regions of interest "contrast-enhancing (CE) tumor" (if present), "adjacent to the (former) tumor", "ipsilateral distant" hemisphere, and "contralateral" hemisphere were compared, differentiating between patients with stable (SD) and progressive disease (PD). Metabolite ratios PCr/ATP, Pi/ATP, PCr/Pi, PME/PDE, PME/PCr, and PDE/ATP were investigated. In PD, energy and membrane metabolism in CE tumor areas have a tendency to "normalize" under therapy. In different "normal-appearing" brain areas of GB patients, the energy and membrane metabolism either "normalized" or were "disturbed", in comparison to baseline or controls. Differences were also detected between patients with SD and PD. 31P-MRS might contribute as an additional imaging biomarker for outcome measurement, which remains to be investigated in a larger cohort.

Phosphorous Magnetic Resonance Spectroscopy and Molecular Markers in IDH1 Wild Type Glioblastoma.

The World Health Organisation's (WHO) classification of brain tumors requires consideration of both histological appearance and molecular characteristics. Possible differences in brain energy metabolism could be important in designing future therapeutic strategies. Forty-three patients with primary, isocitrate dehydrogenase 1 (IDH1) wild type glioblastomas (GBMs) were included in this study. Pre-operative standard MRI was obtained with additional phosphorous magnetic resonance spectroscopy (31-P-MRS) imaging. Following microsurgical resection of the tumors, biopsy specimens underwent neuropathological diagnostics including standard molecular diagnosis. The spectroscopy results were correlated with epidermal growth factor (EGFR) and O6-Methylguanine-DNA methyltransferase (MGMT) status. EGFR amplified tumors had significantly lower phosphocreatine (PCr) to adenosine triphosphate (ATP)-PCr/ATP and PCr to inorganic phosphate (Pi)-PCr/Pi ratios, and higher Pi/ATP and phosphomonoesters (PME) to phosphodiesters (PDE)-PME/PDE ratio than those without the amplification. Patients with MGMT-methylated tumors had significantly higher cerebral magnesium (Mg) values and PME/PDE ratio, while their PCr/ATP and PCr/Pi ratios were lower than in patients without the methylation. In survival analysis, not-EGFR-amplified, MGMT-methylated GBMs showed the longest survival. This group had lower PCr/Pi ratio when compared to MGMT-methylated, EGFR-amplified group. PCr/Pi ratio was lower also when compared to the MGMT-unmethylated, EGFR not-amplified group, while PCr/ATP ratio was lower than all other examined groups. Differences in energy metabolism in various molecular subtypes of wild-type-GBMs could be important information in future precision medicine approach.

Phosphorous Magnetic Resonance Spectroscopy to Detect Regional Differences of Energy and Membrane Metabolism in Naïve Glioblastoma Multiforme.

Background: Glioblastoma multiforme (GBM) is a highly malignant primary brain tumor with infiltration of, on conventional imaging, normal-appearing brain parenchyma. Phosphorus magnetic resonance spectroscopy (31P-MRS) enables the investigation of different energy and membrane metabolites. The aim of this study is to investigate regional differences of 31P-metabolites in GBM brains. Methods: In this study, we investigated 32 patients (13 female and 19 male; mean age 63 years) with naïve GBM using 31P-MRS and conventional MRI. Contrast-enhancing (CE), T2-hyperintense, adjacent and distant ipsilateral areas of the contralateral brain and the brains of age- and gender-matched healthy volunteers were assessed. Moreover, the 31P-MRS results were correlated with quantitative diffusion parameters. Results: Several metabolite ratios between the energy-dependent metabolites and/or the membrane metabolites differed significantly between the CE areas, the T2-hyperintense areas, the more distant areas, and even the brains of healthy volunteers. pH values and Mg2+ concentrations were highest in visible tumor areas and decreased with distance from them. These results are in accordance with the literature and correlated with quantitative diffusion parameters. Conclusions: This pilot study shows that 31P-MRS is feasible to show regional differences of energy and membrane metabolism in brains with naïve GBM, particularly between the different "normal-appearing" regions and between the contralateral hemisphere and healthy controls. Differences between various genetic mutations or clinical applicability for follow-up monitoring have to be assessed in a larger cohort.

Results of Phosphorus Magnetic Resonance Spectroscopy for Brain Metastases Correlate with Histopathologic Results.

BACKGROUND: Brain metastases (BMs) are classically well-circumscribed lesions. Still, the amount of edema in these neoplasms suggests either mechanisms of infiltration or defense. A better understanding of the mechanisms within the edema of BMs seems reasonable to preoperatively identify areas of potential infiltration and resect them. BMs represent tumors with high energy demand and cell turnover; therefore, they qualify for preoperative investigation with phosphorus-31 magnetic resonance spectroscopy (31PMRS), which reveals information about those characteristics. METHODS: Ten patients with BMs were included in this trial. All underwent preoperative standard magnetic resonance imaging with additional 31PMRS. In all patients, 1 voxel within the contrast-enhancing tumor (CE+), 1 voxel at the border (including CE+ areas and surrounding T2-hyperintensive [T2+] areas), and 1 distant voxel purely including T2+ areas were determined by a neuroradiologist and a neurosurgeon. A frameless stereotactic biopsy was performed after craniotomy. Subsequently, the metabolites of the 31PMRS were analyzed and compared with the histopathologic results. RESULTS: Ratios, reflecting resynthesis (CE+/border/T2+: 1.109 ± 0.192/1.112 ± 0.158/1.083 ± 0.097), hydrolysis (0.303 ± 0.089/0.360 ± 0.122/0.321 ± 0.089), energy demand (4.227 ± 2.35/3.453 ± 1.284/3.599 ± 0.833), and membrane turnover (1.239 ± 0.2611/3.453 ± 1.284/3.599 ± 0.283) were calculated and compared intraindividually with a voxel from the contralateral side (resynthesis/hydrolysis/energy demand/membrane turnover: 1.063 ± 0.085/0.335 ± 0.073/3.317 ± 0.7573/0.784 ± 0.186), respectively. Resynthesis showed a trend toward higher ratios in CE+ and border biopsies without reaching statistical significances. This trend was also seen concerning energy demand. Membrane turnover was significantly higher in CE+, border zone, and also in the T2+ areas compared with controls (P > 0.001). CONCLUSIONS: 31PMRS in BMs provides information on metabolic changes in tumor and surrounding edema. There is proof of enhanced metabolism in tissue without histologic tumor manifestation.

Structured Evaluation of Glioma Patients by an Occupational Therapist-Is Our Clinical Examination Enough?

BACKGROUND: Preservation of neurologic function is mandatory when offering a surgical intervention to patients with low-grade gliomas (LGGs), given that the goal of any treatment is the patient's return to their normal everyday life. OBJECTIVE: To determine whether a structured evaluation by an occupational therapist can reveal deficits that might be overseen in routine clinical examination of patients with a surgically treated LGG. METHODS: A total of 20 patients with radiographically suspected LGG were examined in a standardized fashion at 3 stages: preoperatively, postoperatively, and 3 months thereafter. Results were analyzed descriptively. RESULTS: A total of 19 patients (95%) showed no postoperative motor deficit; one suffered from akinesia due to supplementary motor area involvement and demonstrated a transient deficit with manifestation on the first postoperative day. Patients with eloquent LGGs, involving speech (n = 6, 30%), exhibited different transient speech disturbances according to the location of the lesion. Structured testing revealed a postoperative worsening of movement mirroring (upper extremity) and finger discrimination (sensory) in 5 of 20 patients (25%). Force meter evaluation of the upper extremity was decreased significantly postoperatively for the affected hemisphere, even though motor deficits were absent in most patients. The action research arm test detected deterioration in more than one half of the patients postoperatively. Patients recovered from these deficits within the first 3 months. CONCLUSIONS: Routine clinical examination and neuropsychological evaluation fail to detect mild deficits in sensory function, reactivity, and apraxia, which may have a serious impact on patients' ability to return to their normal lives and work.

Brain tumors in eloquent areas: A European multicenter survey of intraoperative mapping techniques, intraoperative seizures occurrence, and antiepileptic drug prophylaxis.

Intraoperative mapping and monitoring techniques for eloquent area tumors are routinely used world wide. Very few data are available regarding mapping and monitoring methods and preferences, intraoperative seizures occurrence and perioperative antiepileptic drug management. A questionnaire was sent to 20 European centers with experience in intraoperative mapping or neurophysiological monitoring for the treatment of eloquent area tumors. Fifteen centers returned the completed questionnaires. Data was available on 2098 patients. 863 patients (41.1%) were operated on through awake surgery and intraoperative mapping, while 1235 patients (58.8%) received asleep surgery and intraoperative electrophysiological monitoring or mapping. There was great heterogeneity between centers with some totally AW oriented (up to 100%) and other almost totally ASL oriented (up to 92%) (31% SD). For awake surgery, 79.9% centers preferred an asleep-awake-asleep anesthesia protocol. Only 53.3% of the centers used ECoG or transcutaneous EEG. The incidence of intraoperative seizures varied significantly between centers, ranging from 2.5% to 54% (p < 0.001). It there appears to be a statistically significant link between the mastery of mapping technique and the risk of intraoperative seizures. Moreover, history of preoperative seizures can significantly increase the risk of intraoperative seizures (p < 0.001). Intraoperative seizures occurrence was similar in patients with or without perioperative drugs (12% vs. 12%, p = 0.2). This is the first European survey to assess intraoperative functional mapping and monitoring protocols and the management of peri- and intraoperative seizures. This data can help identify specific aspects that need to be investigated in prospective and controlled studies.

Disseminated Intravascular Coagulation in Secondary Glioblastoma due to Excessive Intraoperative Bleeding: Case Report and Review of the Literature.

BACKGROUND: Disseminated intravascular coagulation (DIC) describes a pathologic activation of coagulation mechanisms, leading to thrombi in various organs with contribution to multiple organ failure. In clinical practice, diagnosis of DIC can often be made by laboratory values, including prolonged coagulation times, thrombocytopenia, or high levels of fibrin degradation products. DIC is frequently observed after neurotrauma, but rarely occurs in patients with primary brain tumors. There are only few case reports of DIC in patients with primary brain tumors, all sharing the highly elevated mortality. We report the case of a young patient presenting with secondary glioblastoma, who developed multiorgan failure induced by DIC after extensive intraoperative bleeding. CASE DESCRIPTION: A 30-year-old patient was admitted in poor general condition with insomnia, severe headache, and vomiting. She had undergone surgery for secondary glioblastoma twice. Magnetic resonance imaging revealed a left temporoparietal mass lesion with indication for resection. Surgery then was complicated by diffuse intraoperative bleeding due to a high content of microvascular proliferation as shown in the histopathologic workup. Subsequently, an uncontrollable multiorgan failure developed, causing the patient's death 4 days after surgery. CONCLUSIONS: Although a rare complication, excessive intraoperative bleeding, especially in surgery for brain tumors located next to the ventricular system, DIC should be kept in mind as a possible diagnosis.

Correlation between degenerative spine disease and bone marrow density: a retrospective investigation.

BACKGROUND: Spondylosis leads to an overestimation of bone mineral density (BMD) with dual-energy x-ray absorptiometry (DXA) but not with quantitative computed tomography (QCT). The correlation between degenerative changes of the spine and QCT-BMD was therefore investigated for the first time. METHODS: One hundred thirty-four patients (66 female and 68 male) with a mean age of 49.0 ± 14.6 years (range: 19-88 years) who received a CT scan and QCT-BMD measurements of spine and hip were evaluated retrospectively. The occurrence and severity of spondylosis, osteochondrosis, and spondylarthrosis and the height of the vertebral bodies were assessed. RESULTS: A negative correlation was found between spinal BMD and number of spondylophytes (ρ = -0.35; p < 0.01), disc heights (r = -0.33; p < 0.01), number of discal air inclusions (ρ = -0.34; p < 0.01), the number of Schmorl nodules (ρ = -0.25; p < 0.01), the number (ρ = -0.219; p < 0.05) and the degree (ρ = -0.220; p < 0.05) of spondylarthrosis. Spinal and hip BMD correlated moderately, but the latter did not correlate with degenerative changes of the spine. In linear regression models age, osteochondrosis and spondylarthrosis were factors influencing spinal BMD. CONCLUSION: Degenerative spinal changes may be associated with reduced regional spinal mineralization. This knowledge could lead to a modification of treatment of degenerative spine disease with early treatment of osteopenia to prevent secondary fractures.

Dual Anti-angiogenic Chemotherapy with Temozolomide and Celecoxib in Selected Patients with Malignant Glioma Not Eligible for Standard Treatment.

AIM: Due to their high rate of neo-angiogenesis, malignant gliomas may qualify for treatment with anti-angiogenic substances. We report on a series of patients with malignant glioma not eligible for standard postoperative combined radiochemotherapy due to decreased health status. PATIENTS AND METHODS: A total of nine patients with malignant glioma, postoperatively presenting with a Karnofsky performance score (KPS) below 70, were treated with standalone metronomic low-dose chemotherapy with temozolomide and celecoxib (cyclo-oxygenase-2 inhibitor). Overall survival was defined as the primary end-point and the functional status (KPS) and time to progression as secondary end-points of our analysis. RESULTS: The median KPS after surgery was 60. Treatment achieved a decrease in tumor and edema volume and, more importantly, preserved the functional status defined as the ability to care for self (KPS 70%) until disease progression. No notable side-effects were recorded. CONCLUSION: In patients with decreased general condition (KPS <70), not eligible for standard treatment, anti-angiogenic therapy offers a reasonable alternative approach. Our results indicate prolonged survival and preserved quality of life in comparison to best supportive care.

Distance to the neurooncological center: a negative prognostic factor in patients with glioblastoma multiforme. An epidemiological study.

BACKGROUND: Regardless of current multimodal treatment strategies, the prognosis of patients harboring glioblastoma multiforme (GBM) is still dismal. The introduction of concomitant radiochemotherapy and adjuvant cyclic temozolomide has significantly improved the overall survival, compared to postoperative radiotherapy-alone. Furthermore this regimen shows a lower toxicity profile compared to previous nitrosourea-based chemotherapy and can easily be applied on an outpatient basis, thus potentially facilitating chemotherapy in rural and more remote areas. The distance to the oncological center has been shown to be a negative prognostic parameter in other types of cancer. Therefore, we aimed to investigate whether the introduction of temozolomide as the standard regimen in the treatment of GBM has influenced the administration of chemotherapy and the prognosis of patients depending on the distance to our neurooncological center. PATIENTS AND METHODS: A total of 208 patients diagnosed with GBM (M:F=1.4:1), surgically resected between 1990 and 2009, thus covering the pre-temozolomide and the temozolomide-era, were included retrospectively in this analysis. The distance from the patients' residences to the neurooncological center was determined and statistical analysis was performed to assess its influence on overall survival and administration of adjuvant treatment (radiotherapy-only, nitrosourea-based chemotherapy and adjuvant temozolomide). RESULTS: Overall, 41.3% of the cohort underwent subtotal surgical resection, whereas a gross total resection was accomplished in 57.2%. The median distance to the neurooncological center was 75 km (range=1-870 km). Postoperatively, 68 patients (32.7%) received concomitant and adjuvant radiochemotherapy with temozolomide, 31 (14.9%) were treated with nitrosourea other than the Procarbazin, Lomustin, Vincristin (PCV), 34 (16.3%) with PCV, and 71 patients (34.1%) had radiotherapy-alone. The distance to the neurooncological center had a significant influence on overall survival for the whole cohort (p=0.027) and patients with increasing distances, were significantly less often treated with chemotherapy (p=0.05). With the introduction of temozolomide this relation was lost (overall survival, temozolomide and other agents: p=0.685/p=0.007; administration of adjuvant chemotherapy in the temozolomide-era/whole cohort: p=0.612/p=0.05). CONCLUSION: The distance to the neurooncological center negatively-influenced the prognosis of patients with GBM. Patients were less often treated with adjuvant chemotherapy in the pre-temozolomide era with increasing distance to the neurooncological center. Although the introduction of temozolomide as the standard chemotherapeutic agent in GBM treatment changed this fact, the influence of the distance to the specialized center should be kept in mind as a prognostic factor for this disease.