Terje Sundstrøm

Five-year incidence of surgery for idiopathic normal pressure hydrocephalus in Norway

Objectives –  We have previously determined the incidence and prevalence of idiopathic normal pressure hydrocephalus (iNPH) in the county of Vestfold in Norway. This study aimed at determining the incidence of surgeries for iNPH.

Prehospital use of cervical collars in trauma patients: a critical review.

The cervical collar has been routinely used for trauma patients for more than 30 years and is a hallmark of state-of-the-art prehospital trauma care. However, the existing evidence for this practice is limited: Randomized, controlled trials are largely missing, and there are uncertain effects on mortality, neurological injury, and spinal stability. Even more concerning, there is a growing body of evidence and opinion against the use of collars. It has been argued that collars cause more harm than good, and that we should simply stop using them. In this critical review, we discuss the pros and cons of collar use in trauma patients and reflect on how we can move our clinical practice forward. Conclusively, we propose a safe, effective strategy for prehospital spinal immobilization that does not include routine use of collars.

Multimodal imaging enables early detection and characterization of changes in tumor permeability of brain metastases

Our goal was to develop strategies to quantify the accumulation of model therapeutics in small brain metastases using multimodal imaging, in order to enhance the potential for successful treatment. Human melanoma cells were injected into the left cardiac ventricle of immunodeficient mice. Bioluminescent, MR and PET imaging were applied to evaluate the limits of detection and potential for contrast agent extravasation in small brain metastases. A pharmacokinetic model was applied to estimate vascular permeability. Bioluminescent imaging after injecting d-luciferin (molecular weight (MW) 320 D) suggested that tumor cell extravasation had already occurred at week 1, which was confirmed by histology. 7T T1w MRI at week 4 was able to detect non-leaky 100 μm sized lesions and leaky tumors with diameters down to 200 μm after contrast injection at week 5. PET imaging showed that (18)F-FLT (MW 244 Da) accumulated in the brain at week 4. Gadolinium-based MRI tracers (MW 559 Da and 2.066 kDa) extravasated after 5 weeks (tumor diameter 600 μm), and the lower MW agent cleared more rapidly from the tumor (mean apparent permeabilities 2.27 × 10(-5)cm/s versus 1.12 × 10(-5)cm/s). PET imaging further demonstrated tumor permeability to (64)Cu-BSA (MW 65.55 kDa) at week 6 (tumor diameter 700 μm). In conclusion, high field T1w MRI without contrast may improve the detection limit of small brain metastases, allowing for earlier diagnosis of patients, although the smallest lesions detected with T1w MRI were permeable only to d-luciferin and the amphipathic small molecule (18)F-FLT. Different-sized MR and PET contrast agents demonstrated the gradual increase in leakiness of the blood tumor barrier during metastatic progression, which could guide clinicians in choosing tailored treatment strategies.

A Novel, Diffusely Infiltrative Xenograft Model of Human Anaplastic Oligodendroglioma with Mutations in FUBP1, CIC, and IDH1

Oligodendroglioma poses a biological conundrum for malignant adult human gliomas: it is a tumor type that is universally incurable for patients, and yet, only a few of the human tumors have been established as cell populations in vitro or as intracranial xenografts in vivo. Their survival, thus, may emerge only within a specific environmental context. To determine the fate of human oligodendroglioma in an experimental model, we studied the development of an anaplastic tumor after intracranial implantation into enhanced green fluorescent protein (eGFP) positive NOD/SCID mice. Remarkably after nearly nine months, the tumor not only engrafted, but it also retained classic histological and genetic features of human oligodendroglioma, in particular cells with a clear cytoplasm, showing an infiltrative growth pattern, and harboring mutations of IDH1 (R132H) and of the tumor suppressor genes, FUBP1 and CIC. The xenografts were highly invasive, exhibiting a distinct migration and growth pattern around neurons, especially in the hippocampus, and following white matter tracts of the corpus callosum with tumor cells accumulating around established vasculature. Although tumors exhibited a high growth fraction in vivo, neither cells from the original patient tumor nor the xenograft exhibited significant growth in vitro over a six-month period. This glioma xenograft is the first to display a pure oligodendroglioma histology and expression of R132H. The unexpected property, that the cells fail to grow in vitro even after passage through the mouse, allows us to uniquely investigate the relationship of this oligodendroglioma with the in vivo microenvironment.

Automated tracking of nanoparticle-labeled melanoma cells improves the predictive power of a brain metastasis model

Biologic and therapeutic advances in melanoma brain metastasis are hampered by the paucity of reproducible and predictive animal models. In this work, we developed a robust model of brain metastasis that empowers quantitative tracking of cellular dissemination and tumor progression. Human melanoma cells labeled with superparamagnetic iron oxide nanoparticles (SPION) were injected into the left cardiac ventricle of mice and visualized by MRI. We showed that SPION exposure did not affect viability, growth, or migration in multiple cell lines across several in vitro assays. Moreover, labeling did not impose changes in cell-cycle distribution or apoptosis. In vivo, several SPION-positive cell lines displayed similar cerebral imaging and histologic features. MRI-based automated quantification of labeled cells in the brain showed a sigmoid association between metastasis frequency and doses of inoculated cells. Validation of this fully automated quantification showed a strong correlation with manual signal registration (r(2) = 0.921, P < 0.001) and incidence of brain metastases (r(2) = 0.708, P < 0.001). Metastasis formation resembled the pattern seen in humans and was unaffected by SPION labeling (histology; tumor count, P = 0.686; survival, P = 0.547). In summary, we present here a highly reproducible animal model that can improve the predictive value of mechanistic and therapeutic studies of melanoma brain metastasis.

SEVERE TRAUMATIC BRAIN INJURY IN NORWAY: IMPACT OF AGE ON OUTCOME

OBJECTIVE The aim of this study was to investigate the influence of age on mortality and 3-month outcome in a Norwegian cohort of patients with severe traumatic brain injury (TBI). METHODS Norwegian residents ≥ 16 years of age who were admitted with a severe TBI to the countrys 4 major trauma centres in 2009 and 2010 were included, as were adults (16- 64 years) and elderly patients (≥ 65 years). RESULTS Half of the adult subjects and 84% of the elderly subjects were injured by falls. One-third of the adults and half of the elderly subjects were admitted to a local hospital before being transported to a regional trauma hospital. Subdural haematomas were more frequent in the elderly subjects. One-quarter of adults and two-thirds of the elderly subjects died within 3 months. At 3 months, 41% of the adult survivors were still in-patients, mainly in rehabilitation units (92%). Of the surviving elderly subjects, 14% were in-patients and none were in rehabilitation units. There was no difference in functional level for survivors at the 3-month follow-up. CONCLUSION Old age is associated with fall-induced severe TBI and high mortality rates. Less intensive treatment strategies were applied to elderly patients in the present study despite high rates of haemorrhage. Few surviving elderly patients received rehabilitation at 3 months post-injury.

What is the Pressure in Chronic Subdural Hematomas? A Prospective, Population-Based Study

Surgery for chronic subdural hematoma (CSDH) is performed to relieve brain displacement and high intracranial pressure (ICP). However, the intraoperative impression is often that the pressure inside the CSDH is low, despite marked clinical symptoms. We wanted to quantify the CSDH pressure and relate this to radiological and clinical characteristics. This prospective, population-based study of unilateral CSDHs was conducted over a 3-year period. CSDHs that were secondary to other conditions, re-operations, or CSDHs requiring other procedures than burr hole craniostomy under local anesthesia were excluded. Subdural pressure registration was performed via a simple manometric technique, and full compliance with a standardized protocol was mandatory. Sixty patients were included (mean age 76.2 years; for men, 77.4, and for women, 72.9). The mean pressure in the CSDHs was 15.2 cm H(2)O (range, 0-40) with no gender difference. Men had significantly larger volumes (mean 158.1 vs. 103.2 cm(3)) and midline shifts (mean 1.04 vs. 0.68 cm) than did women. Large hematomas with large midline shifts had higher pressures and more often required repeat surgery. With a patients increasing age, the volumes and midline shifts seemed to become larger, whereas the pressures became lower. We did not find an association between repeat surgery and pressure or age. Our results are generally in line with those of previous studies reporting quantitative pressure registrations. However, there are important disparities regarding methodology, not least when comparing with various subjective scales that are widely used in clinical practice. A mean subdural pressure of 15.2 cm H(2)O is probably within the range of a normal ICP.

Molecular crosstalk between tumour and brain parenchyma instructs histopathological features in glioblastoma

The histopathological and molecular heterogeneity of glioblastomas represents a major obstacle for effective therapies. Glioblastomas do not develop autonomously, but evolve in a unique environment that adapts to the growing tumour mass and contributes to the malignancy of these neoplasms. Here, we show that patient-derived glioblastoma xenografts generated in the mouse brain from organotypic spheroids reproducibly give rise to three different histological phenotypes: (i) a highly invasive phenotype with an apparent normal brain vasculature, (ii) a highly angiogenic phenotype displaying microvascular proliferation and necrosis and (iii) an intermediate phenotype combining features of invasion and vessel abnormalities. These phenotypic differences were visible during early phases of tumour development suggesting an early instructive role of tumour cells on the brain parenchyma. Conversely, we found that tumour-instructed stromal cells differentially influenced tumour cell proliferation and migration in vitro, indicating a reciprocal crosstalk between neoplastic and non-neoplastic cells. We did not detect any transdifferentiation of tumour cells into endothelial cells. Cell type-specific transcriptomic analysis of tumour and endothelial cells revealed a strong phenotype-specific molecular conversion between the two cell types, suggesting co-evolution of tumour and endothelial cells. Integrative bioinformatic analysis confirmed the reciprocal crosstalk between tumour and microenvironment and suggested a key role for TGFβ1 and extracellular matrix proteins as major interaction modules that shape glioblastoma progression. These data provide novel insight into tumour-host interactions and identify novel stroma-specific targets that may play a role in combinatorial treatment strategies against glioblastoma.

Organisation of traumatic head injury management in the Nordic countries

Objective: The aim of this study is to map and evaluate the available resources and the premises of traumatic head injury management in the Nordic countries, before the implementation of a Nordic adaption of the Brain Trauma Foundation guidelines for prehospital management. Methods: The study is a synthesis of two cross-sectional surveys. Questionnaires were used to collect data on the annual number of acute head injury operations, the infrastructure, the level of education, the use of trauma protocols and the management of traumatic head injury at Nordic hospitals. Results: The proportion of acute head injury operations performed outside a neurosurgical department was 0% in Denmark, 16% in Finland, 19% in Norway and 33% in Sweden. Eighty-four per cent of Nordic hospitals had written protocols for the assessment and treatment of trauma patients and 78% had regular training in trauma management; 67% had specific protocols for the treatment of traumatic head injury. Computed tomography (CT) was available in 93% of the hospitals, and 59% of the hospitals could link CT scans to the regional neurosurgical department. Conclusions: Most Nordic hospitals are well prepared to manage patients with acute traumatic head injury. A substantial proportion of the operations are performed at local and central hospitals without neurosurgical expertise, despite an efficient pre and interhospital transport system. The Nordic adaption of the Brain Trauma Foundation guidelines recommends that this practice is terminated.

Melanoma brain metastasis is independent of lactate dehydrogenase A expression

BACKGROUND The key metabolic enzyme lactate dehydrogenase A (LDHA) is overexpressed in many cancers, and several preclinical studies have shown encouraging results of targeted inhibition. However, the mechanistic importance of LDHA in melanoma is largely unknown and hitherto unexplored in brain metastasis. METHODS We investigated the spatial, temporal, and functional features of LDHA expression in melanoma brain metastasis across multiple in vitro assays, in a robust and predictive animal model employing MRI and PET imaging, and in a unique cohort of 80 operated patients. We further assessed the genomic and proteomic landscapes of LDHA in different cancers, particularly melanomas. RESULTS LDHA expression was especially strong in early and small brain metastases in vivo and related to intratumoral hypoxia in late and large brain metastases in vivo and in patients. However, LDHA expression in human brain metastases was not associated with the number of tumors, BRAF(V600E) status, or survival. Moreover, LDHA depletion by small hairpin RNA interference did not affect cell proliferation or 3D tumorsphere growth in vitro or brain metastasis formation or survival in vivo. Integrated analyses of the genomic and proteomic landscapes of LDHA indicated that LDHA is present but not imperative for tumor progression within the CNS, or predictive of survival in melanoma patients. CONCLUSIONS In a large patient cohort and in a robust animal model, we show that although LDHA expression varies biphasically during melanoma brain metastasis formation, tumor progression and survival seem to be functionally independent of LDHA.