New prognostic factors and calculators for outcome prediction in patients with recurrent glioblastoma: A pooled analysis of EORTC Brain Tumour Group phase I and II clinical trials.

BACKGROUND: Prognostic models have been developed to predict survival of patients with newly diagnosed glioblastoma (GBM). To improve predictions, models should be updated with information at the recurrence. We performed a pooled analysis of European Organization for Research and Treatment of Cancer (EORTC) trials on recurrent glioblastoma to validate existing clinical prognostic factors, identify new markers, and derive new predictions for overall survival (OS) and progression free survival (PFS).¦METHODS: Data from 300 patients with recurrent GBM recruited in eight phase I or II trials conducted by the EORTC Brain Tumour Group were used to evaluate patient's age, sex, World Health Organisation (WHO) performance status (PS), presence of neurological deficits, disease history, use of steroids or anti-epileptics and disease characteristics to predict PFS and OS. Prognostic calculators were developed in patients initially treated by chemoradiation with temozolomide.¦RESULTS: Poor PS and more than one target lesion had a significant negative prognostic impact for both PFS and OS. Patients with large tumours measured by the maximum diameter of the largest lesion (⩾42mm) and treated with steroids at baseline had shorter OS. Tumours with predominant frontal location had better survival. Age and sex did not show independent prognostic values for PFS or OS.¦CONCLUSIONS: This analysis confirms performance status but not age as a major prognostic factor for PFS and OS in recurrent GBM. Patients with multiple and large lesions have an increased risk of death. With these data prognostic calculators with confidence intervals for both medians and fixed time probabilities of survival were derived.

Brain multimodality monitoring: an update.

PURPOSE OF REVIEW: An important goal of neurocritical care is the management of secondary brain injury (SBI), that is pathological events occurring after primary insult that add further burden to outcome. Brain oedema, cerebral ischemia, energy dysfunction, seizures and systemic insults are the main components of SBI. We here review recent data showing the clinical utility of brain multimodality monitoring (BMM) for the management of SBI. RECENT FINDINGS: Despite being recommended by international guidelines, standard intracranial pressure (ICP) monitoring may be insufficient to detect all episodes of SBI. ICP monitoring, combined with brain oxygen (PbtO(2)), cerebral microdialysis and regional cerebral blood flow, might help to target therapy (e.g. management of cerebral perfusion pressure, blood transfusion, glucose control) to patient-specific pathophysiology. Physiological parameters derived from BMM, including PbtO(2) and microdialysis lactate/pyruvate ratio, correlate with outcome and have recently been incorporated into neurocritical care guidelines. Advanced intracranial devices can be complemented by quantitative electroencephalography to monitor changes of brain function and nonconvulsive seizures. SUMMARY: BMM offers an on-line comprehensive scrutiny of the injured brain and is increasingly used for the management of SBI. Integration of monitored data using new informatics tools may help optimize therapy of brain-injured patients and quality of care.

Treatment of brain metastases from non-small cell lung cancer with whole-brain radiotherapy (wbrt) in combination with gefitinib (gft) or temozolomide (tmz): a randomized multicenter phase ii trial of the swiss group of clinical cancer research (sakk #70/03)

BACKGROUND: Patients with BM rarely survive .6 months and are commonly excluded from clinical trials. We aimed at improving outcome by exploring 2 combined modality regimens with at the time novel agents for which single-agent activity had been shown. METHODS: NSCLC patients with multiple BM were randomized to WBRT (10 × 3 Gy) and either GFT 250 mg p.o. daily or TMZ 75 mg/m2 p.o. daily ×21/28 days, starting on Day 1 of RT and to be continued until PD. Primary endpoint was overall survival, a Simon's optimal 2-stage design was based on assumptions for the 3-month survival rate. Cognitive functioning and quality of life were also evaluated. RESULTS: Fifty-nine patients (36 M, 23 F; 9 after prior chemo) were included. Median age was 61 years (range 46-82), WHO PS was 0 in 18 patients, 1 in 31 patients, and 2 in 10 patients. All but 1 patients had extracranial disease; 33 of 43 (TMZ) and 15 of 16 (GFT) had adenocarcinoma histology. GFT arm was closed early after stage 1 analysis when the prespecified 3-mo survival rate threshold (66%) was not reached, causes of death were not GFT related. Main causes of death were PD in the CNS 24%, systemic 41%, both 8%, and toxicity 10% [intestinal perforation (2 patients), pneumonia (2), pulmonary emboli (1), pneumonitis NOS (1), seizure (1)]. We summarize here other patients' characteristics for the 2 trial arms: TMZ (n ¼ 43)/GFT (n ¼ 16); median treatment duration: 1.6 /1.8 mo; Grade 3-4 toxicity: lymphopenia 5 patients (12%)/0; fatigue 8 patients (19%)/2 patients (13%). Survival data for TMZ/GFT arms: 3-month survival rate: 58.1% (95% CI 42.1-73)/62.5% (95% CI 35- 85); median OS: 4.9 months (95% CI 2.5-5.6)/6.3 months (95% CI 2.2- 14.6); median PFS: 1.8 months (95% CI 1.5-1.8)/1.8 (95% CI 1.1-3.9); median time to neurol. progr.: 8.0 months (95% CI 2.2-X)/4.8 (95% CI 3.9-10.5). In a model to predict survival time including the variables' age, PS, number of BM, global QL, total MMSE score, and subjective cognitive function, none of the variables accounted for a significant improvement in survival time. CONCLUSIONS: The combinations of WBRT with GFT or TMZ were feasible. However, in this unselected patient population, survival remains poor and a high rate of complication was observed. Four patients died as a result of high-dose corticosteroids. Preliminary evaluation of cognitive function andQL failed to show significant improvement. Indications and patient selection for palliative treatment should be revisited and careful monitoring and supportive care is required. Research and progress for this frequent clinical situation is urgently needed. Trial partly supported by AstraZeneca (Switzerland), Essex Chemie (Switzerland) and Swiss Federal Government.

Behavioral changes in brain-injured critical care adults with different levels of consciousness during nociceptive stimulation: an observational study.

PURPOSE: The primary objective of this study was to describe the frequency of behaviors observed during rest, a non-nociceptive procedure, and a nociceptive procedure in brain-injured intensive care unit (ICU) patients with different levels of consciousness (LOC). Second, it examined the inter-rater reliability and discriminant and concurrent validity of the behavioral checklist used. METHODS: The non-nociceptive procedure involved calling the patient and shaking his/her shoulder. The nociceptive procedure involved turning the patient. The frequency of behaviors was recorded using a behavioral checklist. RESULTS: Patients with absence of movement, or stereotyped flexion or extension responses to a nociceptive stimulus displayed more behaviors during turning (median 5.5, range 0-14) than patients with localized responses (median 4, range 0-10) or able to self-report their pain (median 4, range 0-10). Face flushing, clenched teeth, clenched fist, and tremor were more frequent in patients with absence of movement, or stereotyped responses to a nociceptive stimulus. The reliability of the checklist was supported by a high intra-class correlation coefficient (0.77-0.92), and the internal consistency was acceptable in all three groups (KR 20, 0.71-0.85). Discriminant validity was supported as significantly more behaviors were observed during nociceptive stimulation than at rest. Concurrent validity was confirmed as checklist scores were correlated to the patients' self-reports of pain (r s = 0.53; 95 % CI 0.21-0.75). CONCLUSION: Brain-injured patients reacted significantly more during a nociceptive stimulus and the number of observed behaviors was higher in patients with a stereotyped response.

Mild guanidinoacetate increase under partial guanidinoacetate methyltransferase deficiency strongly affects brain cell development.

Among cerebral creatine deficiency syndromes, guanidinoacetate methyltransferase (GAMT) deficiency can present the most severe symptoms, and is characterized by neurocognitive dysfunction due to creatine deficiency and accumulation of guanidinoacetate in the brain. So far, every patient was found with negligible GAMT activity. However, GAMT deficiency is thought under-diagnosed, in particular due to unforeseen mutations allowing sufficient residual activity avoiding creatine deficiency, but enough guanidinoacetate accumulation to be toxic. With poorly known GAA-specific neuropathological mechanisms, we developed an RNAi-induced partial GAMT deficiency in organotypic rat brain cell cultures. As expected, the 85% decrease of GAMT protein was insufficient to cause creatine deficiency, but generated guanidinoacetate accumulation causing axonal hypersprouting and decrease in natural apoptosis, followed by induction of non-apoptotic cell death. Specific guanidinoacetate-induced effects were completely prevented by creatine co-treatment. We show that guanidinoacetate accumulation without creatine deficiency is sufficient to affect CNS development, and suggest that additional partial GAMT deficiencies, which may not show the classical brain creatine deficiency, may be discovered through guanidinoacetate measurement.

Congenital hypogonadotropic hypogonadism with split hand/foot malformation: a clinical entity with a high frequency of FGFR1 mutations.

PURPOSE: Congenital hypogonadotropic hypogonadism (CHH) and split hand/foot malformation (SHFM) are two rare genetic conditions. Here we report a clinical entity comprising the two. METHODS: We identified patients with CHH and SHFM through international collaboration. Probands and available family members underwent phenotyping and screening for FGFR1 mutations. The impact of identified mutations was assessed by sequence- and structure-based predictions and/or functional assays. RESULTS: We identified eight probands with CHH with (n = 3; Kallmann syndrome) or without anosmia (n = 5) and SHFM, seven of whom (88%) harbor FGFR1 mutations. Of these seven, one individual is homozygous for p.V429E and six individuals are heterozygous for p.G348R, p.G485R, p.Q594*, p.E670A, p.V688L, or p.L712P. All mutations were predicted by in silico analysis to cause loss of function. Probands with FGFR1 mutations have severe gonadotropin-releasing hormone deficiency (absent puberty and/or cryptorchidism and/or micropenis). SHFM in both hands and feet was observed only in the patient with the homozygous p.V429E mutation; V429 maps to the fibroblast growth factor receptor substrate 2α binding domain of FGFR1, and functional studies of the p.V429E mutation demonstrated that it decreased recruitment and phosphorylation of fibroblast growth factor receptor substrate 2α to FGFR1, thereby resulting in reduced mitogen-activated protein kinase signaling. CONCLUSION: FGFR1 should be prioritized for genetic testing in patients with CHH and SHFM because the likelihood of a mutation increases from 10% in the general CHH population to 88% in these patients.Genet Med 17 8, 651-659.

Subthalamic (STN) Deep Brain Stimulation (DBS) in Parkinson's Disease (PD): Correlation Between the Location of the Stimulated Contacts and the Clinical Effects in 14 Patients

Objectives: To correlate the chronic stimulated electrode position on postoperative MRI with the clinical response obtained in PD patients. Material and Method: We retrospectively reviewed 14 consecutive parkinsonian patients who were selected for STN-DBS surgery. Coordinates were determined on an IR T2 MRI coronal section per pendicular to AC-PC plane 3 mm posterior to midcommissural point (MCP) and 12 mm lateral to the midline the inferior aspect of subthalamic region. A CRW stereotactic frame was used for the surgical procedure. A 3D IR T2 MRI was performed postoperatively to determine the location of the stimulated contact in each patient. The clinical results were assessed independently by the neurological team. Results: All but 2 patients had monopolar stimulation. The mean coordinates of the stimulated contacts were: AP ^ ÿ4:23G1:4, Lat ^ 1:12G0:15, Vert ^ ÿ4:1 G2:7 to the MCP. With a mean follow-up of 8 months, all stimulated patients had a significant clinical improvement (preop/postop «ON» UPDRS: 25:8G7:0= 23:3 G8:6; preop/postop «OFF» UPDRS: 50:2G11:4=26:0 G7:8), 60% of them without any antiparkinsonian drug. Conclusion: According to the stereotactic atlas of Schaltenbrand and Warren and the 3D shape of the STN, our results show that our targetting is accurate and almost all the stimulated contacts are comprised in the STN volume. This indicates that MRI is a safe, precise and reproducible procedure for targetting the STN. The location of the stimulated contact within the STN volume is a good predictor of the clinical results.

Clinical neurophysiology in disorders of consciousness: brain function monitoring in the ICU and beyond.

Over the past two decades, electrophysiology has undergone unprecedented changes thanks to technical improvements, which simplify measurement and analysis and allow more compact data storage. This book covers in detail the spectrum of electrophysiology applications in patients with disorders of consciousness. Its content spans from clinical aspects of the management of subjects in the intensive care unit, including EEG, evoked potentials and related implications in terms of prognosis and patient management to research applications in subjects with ongoing consciousness impairment. While the first section provides up-to-date information for the interested clinician, the second part highlights the latest developments in this exciting field. The book comprehensively combines clinical and research information related to neurophysiology in disorder-of- consciousness patients, making it an easily accessible reference for neuro-ICU specialists, epileptologists and clinical neurophysiologists as well as researchers utilizing EEG and event-related potentials.

Brain metastasis as initial presentation of papillary adenocarcinoma of the lung: case report

The authors describe the case of a 33-year-old patient with history of seizures alone without any previous symptom, being diagnosed with brain metastases from primary papillary adenocarcinoma of the lung. Emphasis is given to the diagnostic investigation for brain metastasis and prognostic evaluation of papillary adenocarcinoma of the lung, and a brief literature review on such diseases is performed.

Performance of 18F-FET versus 18F-FDG-PET for the diagnosis and grading of brain tumors: systematic review and meta-analysis.

BACKGROUND: For the past decade (18)F-fluoro-ethyl-l-tyrosine (FET) and (18)F-fluoro-deoxy-glucose (FDG) positron emission tomography (PET) have been used for the assessment of patients with brain tumor. However, direct comparison studies reported only limited numbers of patients. Our purpose was to compare the diagnostic performance of FET and FDG-PET. METHODS: We examined studies published between January 1995 and January 2015 in the PubMed database. To be included the study should: (i) use FET and FDG-PET for the assessment of patients with isolated brain lesion and (ii) use histology as the gold standard. Analysis was performed on a per patient basis. Study quality was assessed with STARD and QUADAS criteria. RESULTS: Five studies (119 patients) were included. For the diagnosis of brain tumor, FET-PET demonstrated a pooled sensitivity of 0.94 (95% CI: 0.79-0.98) and pooled specificity of 0.88 (95% CI: 0.37-0.99), with an area under the curve of 0.96 (95% CI: 0.94-0.97), a positive likelihood ratio (LR+) of 8.1 (95% CI: 0.8-80.6), and a negative likelihood ratio (LR-) of 0.07 (95% CI: 0.02-0.30), while FDG-PET demonstrated a sensitivity of 0.38 (95% CI: 0.27-0.50) and specificity of 0.86 (95% CI: 0.31-0.99), with an area under the curve of 0.40 (95% CI: 0.36-0.44), an LR+ of 2.7 (95% CI: 0.3-27.8), and an LR- of 0.72 (95% CI: 0.47-1.11). Target-to-background ratios of either FDG or FET, however, allow distinction between low- and high-grade gliomas (P > .11). CONCLUSIONS: For brain tumor diagnosis, FET-PET performed much better than FDG and should be preferred when assessing a new isolated brain tumor. For glioma grading, however, both tracers showed similar performances.

Generation and Characterization of Knockout Mice and Analysis of Patient Material Demonstrates a Role for Tissue Inhibitor of Metalloproteinases 4 (Timp4) in the Cardiovascular System and Tumor Metastasis

This thesis focuses on tissue inhibitor of metalloproteinases 4 (TIMP4) which is the newest member of a small gene and protein family of four closely related endogenous inhibitors of extracellular matrix (ECM) degrading enzymes. Existing data on TIMP4 suggested that it exhibits a more restricted expression pattern than the other TIMPs with high expression levels in heart, brain, ovary and skeletal muscle. These observations and the fact that the ECM is of special importance to provide the cardiovascular system with structural strength combined with elasticity and distensibility, prompted the present molecular biologic investigation on TIMP4. In the first part of the study the murine Timp4 gene was cloned and characterized in detail. The structure of murine Timp4 genomic locus resembles that in other species and of the other Timps. The highest Timp4 expression was detected in heart, ovary and brain. As the expression pattern of Timp4 gives only limited information about its role in physiology and pathology, Timp4 knockout mice were generated next. The analysis of Timp4 knockout mice revealed that Timp4 deficiency has no obvious effect on the development, growth or fertility of mice. Therefore, Timp4 deficient mice were challenged using available cardiovascular models, i.e. experimental cardiac pressure overload and myocardial infarction. In the former model, Timp4 deficiency was found to be compensated by Timp2 overexpression, whereas in the myocardial infarct model, Timp4 deficiency resulted in increased mortality due to increased susceptibility for cardiac rupture. In the wound healing model, Timp4 deficiency was shown to result in transient retardation of re-epithelialization of cutaneous wounds. Melanoma tumor growth was similar in Timp4 deficient and control mice. Despite of this, lung metastasis of melanoma cells was significantly increased in Timp4 null mice. In an attempt to translate the current findings to patient material, TIMP4 expression was studied in human specimens representing different inflammatory cardiovascular pathologies, i.e. giant cell arteritis, atherosclerotic coronary arteries and heart allografts exhibiting signs of chronic rejection. The results showed that cardiovascular expression of TIMP4 is elevated particularly in areas exhibiting inflammation. The results of the present studies suggest that TIMP4 has a special role in the regulation of tissue repair processes in the heart, and also in healing wounds and metastases. Furthermore, evidence is provided suggesting the usefulness of TIMP4 as a novel systemic marker for vascular inflammation.

Critical elements underpinning the emergence of the medical game ecosystem: gamifying traumatic brain injury rehabilitation in Finland

The healthcare sector is currently in the verge of a reform and thus, the medical game research provide an interesting area of research. The aim of this study is to explore the critical elements underpinning the emergence of the medical game ecosystem with three sub-objectives: (1) to seek who are the key actors involved in the medical game ecosystem and identify their needs, (2) to scrutinise what types of resources are required in medical game development and what types of relationships are needed to secure those resources, and (3) to identify the existing institutions (‘the rules of the game’) affecting the emergence of the medical game ecosystem. The theoretical background consists of service ecosystems literature. The empirical study conducted is based on the semi-structured theme interviews of 25 experts in three relevant fields: games and technology, health and funding. The data was analysed through a theoretical framework that was designed based upon service ecosystems literature. The study proposes that the key actors are divided into five groups: medical game companies, customers, funders, regulatory parties and complementors. Their needs are linked to improving patient motivation and enhancing the healthcare processes resulting in lower costs. Several types of resources, especially skills and knowledge, are required to create a medical game. To gain access to those resources, medical game companies need to build complex networks of relationships. Proficiency in managing those value networks is crucial. In addition, the company should take into account the underlying institutions in the healthcare sector affecting the medical game ecosystem. Three crucial institutions were identified: validation, lack of innovation supporting structures in healthcare and the rising consumerisation. Based on the findings, medical games cannot be made in isolation. A developmental trajectory model of the emerging medical game ecosystem was created based on the empirical data. The relevancy of relationships and resources is dependent on the trajectory that the medical game company at that time resides. Furthermore, creating an official and documented database for clinically valdated medical games was proposed to establish the medical game market and ensure an adequate status for the effective medical games. Finally, ecosystems approach provides interesting future opportunities for research on medical game ecosystems.

Datenherrschaft – an Ethically Justified Solution to the Problem of Ownership of Patient Information

Patient information systems are crucial components for the modern healthcare and medicine. It is obvious that without them the healthcare cannot function properly – one can try to imagine how brain surgery could be done without using information systems to gather and show information needed for an operation. Thus, it can be stated that digital information is irremovable part of modern healthcare. However, the legal ownership of patient information lacks a coherent and justified basis. The whole issue itself is actually bypassed by controlling pa- tient information with different laws and regulations how patient information can be used and by whom. Nonetheless, the issue itself – who owns the patient in- formation – is commonly missed or bypassed. This dissertation show the problems if the legislation of patient information ownership is not clear. Without clear legislation, the outcome can be unexpected like it seems to be in Finland, Sweden and United Kingdom: the lack of clear regulation has come up with unwanted consequences because of problematic Eu- ropean Union database directive implementation in those countries. The legal ownership is actually granted to the creators of databases which contains the pa- tient information, and this is not a desirable situation. In healthcare and medicine, we are dealing with issues such as life, health and information which are very sensitive and in many cases very personal. Thus, this dissertation leans on four philosophical theories form Locke, Kant, Heidegger and Rawls to have an ethically justified basis for regulating the patient infor- mation in a proper way. Because of the problems of property and ownership in the context of information, a new concept is needed and presented to replace the concept of owning, that concept being Datenherrschaft (eng. mastery over in- formation). Datenherrschaft seems to be suitable for regulating patient infor- mation because its core is the protection of one’s right over information and this aligns with the work of the philosophers whose theories are used in the work. The philosophical argumentation of this study shows that Datenherrschaft granted to the patients is ethically acceptable. It supports the view that patient should be controlling the patient information about themselves unless there are such specific circumstance that justifies the authorities to use patient information to protect other people’s basic rights. Thus, if the patients would be legally grant- ed Datenherrschaft over patient information we would endorse patients as indi- viduals who have their own and personal experience of their own life and have a strong stance against any unjustified paternalism in healthcare. Keywords: patient information, ownership, Datenherrschaft, ethics, Locke, Kant, Heidegger, Rawls

Critical elements underpinning the emergence of the medical game ecosystem:gamifying traumatic brain injury rehabilitation in Finland

The healthcare sector is currently in the verge of a reform and thus, the medical game research provide an interesting area of research. The aim of this study is to explore the critical elements underpinning the emergence of the medical game ecosystem with three sub-objectives: (1) to seek who are the key actors involved in the medical game ecosystem and identify their needs, (2) to scrutinise what types of resources are required in medical game development and what types of relationships are needed to secure those resources, and (3) to identify the existing institutions (‘the rules of the game’) affecting the emergence of the medical game ecosystem. The theoretical background consists of service ecosystems literature. The empirical study conducted is based on the semi-structured theme interviews of 25 experts in three relevant fields: games and technology, health and funding. The data was analysed through a theoretical framework that was designed based upon service ecosystems literature. The study proposes that the key actors are divided into five groups: medical game companies, customers, funders, regulatory parties and complementors. Their needs are linked to improving patient motivation and enhancing the healthcare processes resulting in lower costs. Several types of resources, especially skills and knowledge, are required to create a medical game. To gain access to those resources, medical game companies need to build complex networks of relationships. Proficiency in managing those value networks is crucial. In addition, the company should take into account the underlying institutions in the healthcare sector affecting the medical game ecosystem. Three crucial institutions were identified: validation, lack of innovation supporting structures in healthcare and the rising consumerisation. Based on the findings, medical games cannot be made in isolation. A developmental trajectory model of the emerging medical game ecosystem was created based on the empirical data. The relevancy of relationships and resources is dependent on the trajectory that the medical game company at that time resides. Furthermore, creating an official and documented database for clinically validated medical games was proposed to establish the medical game market and ensure an adequate status for the effective medical games. Finally, ecosystems approach provides interesting future opportunities for research on medical game ecosystems

Nature of crossmodal plasticity in the blind brain and interplay with sight restoration

Thèse réalisée en cotutelle avec l'Université catholique de Louvain.