Objective
Spine injury is highly prevalent in patients with poly-trauma, but data on the co-occurrence of spine trauma in patients with traumatic brain injury (TBI) are scarce. In this study, we used ...the Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI) database to assess the prevalence, characteristics, and outcomes of patients with TBI and a concurrent traumatic spinal injury (TSI).
Methods
Data from the European multi-center CENTER-TBI study were analyzed. Adult patients with TBI (≥18 years) presenting with a concomitant, isolated TSI of at least serious severity (Abbreviated Injury Scale; AIS ≥3) were included. For outcome analysis, comparison groups of TBI patients with TSI and systemic injuries (non-isolated TSI) and without TSI were created using propensity score matching. Rates of mortality, unfavorable outcomes (Glasgow Outcome Scale Extended; GOSe < 5), and full recovery (GOSe 7–8) of all patients and separately for patients with only mild TBI (mTBI) were compared between groups at 6-month follow-up.
Results
A total of 164 (4%) of the 4,254 CENTER-TBI core study patients suffered from a concomitant isolated TSI. The median age was 53 interquartile range (IQR): 37–66 years and 71% of patients were men. mTBI was documented in 62% of cases, followed by severe TBI (26%), and spine injuries were mostly cervical (63%) or thoracic (31%). Surgical spine stabilization was performed in 19% of cases and 57% of patients were admitted to the ICU. Mortality at 6 months was 11% and only 36% of patients regained full recovery. There were no significant differences in the 6-month rates of mortality, unfavorable outcomes, or full recovery between TBI patients with and without concomitant isolated TSI. However, concomitant non-isolated TSI was associated with an unfavorable outcome and a higher mortality. In patients with mTBI, a negative association with full recovery could be observed for both concomitant isolated and non-isolated TSI.
Conclusion
Rates of mortality, unfavorable outcomes, and full recovery in TBI patients with and without concomitant, isolated TSIs were comparable after 6 months. However, in patients with mTBI, concomitant TSI was a negative predictor for a full recovery. These findings might indicate that patients with moderate to severe TBI do not necessarily exhibit worse outcomes when having a concomitant TSI, whereas patients with mTBI might be more affected.
Abstract
Background
Trauma-induced coagulopathy in patients with traumatic brain injury (TBI) is associated with high rates of complications, unfavourable outcomes and mortality. The mechanism of the ...development of TBI-associated coagulopathy is poorly understood.
Methods
This analysis, embedded in the prospective, multi-centred,
observational Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI) study, aimed to characterise the coagulopathy of TBI. Emphasis was placed on the acute phase following TBI, primary on subgroups of patients with abnormal coagulation profile within 4 h of admission, and the impact of pre-injury anticoagulant and/or antiplatelet therapy. In order to minimise confounding factors, patients with isolated TBI (iTBI) ( n = 598) were selected for this analysis.
Results
Haemostatic disorders were observed in approximately 20% of iTBI patients. In a subgroup analysis, patients with pre-injury anticoagulant and/or antiplatelet therapy had a twice exacerbated coagulation profile as likely as those without premedication. This was in turn associated with increased rates of mortality and unfavourable outcome post-injury. A multivariate analysis of iTBI patients without pre-injury anticoagulant therapy identified several independent risk factors for coagulopathy which were present at hospital admission. Glasgow Coma Scale (GCS) less than or equal to 8, base excess (BE) less than or equal to − 6, hypothermia and hypotension increased risk significantly.
Conclusion
Consideration of these factors enables early prediction and risk stratification of acute coagulopathy after TBI, thus guiding clinical management.
Data on the incidence of a hypercoagulable state in trauma, as measured by thromboelastometry (ROTEM), is limited and the prognostic value of hypercoagulability after trauma on outcome is unclear. We ...aimed to determine the incidence of hypercoagulability after trauma, and to assess whether early hypercoagulability has prognostic value on the occurrence of multiple organ failure (MOF) and mortality.
This was a prospective observational cohort study in trauma patients who met the highest trauma level team activation. Hypercoagulability was defined as a G value of ≥ 11.7 dynes/cm(2) and hypocoagulability as a G value of <5.0 dynes/cm(2). ROTEM was performed on admission and 24 hours later.
A total of 1,010 patients were enrolled and 948 patients were analyzed. Median age was 38 (interquartile range (IQR) 26 to 53), 77% were male and median injury severity score was 13 (IQR 8 to 25). On admission, 7% of the patients were hypercoagulable and 8% were hypocoagulable. Altogether, 10% of patients showed hypercoagulability within the first 24 hours of trauma. Hypocoagulability, but not hypercoagulability, was associated with higher sequential organ failure assessment scores, indicating more severe MOF. Mortality in patients with hypercoagulability was 0%, compared to 7% in normocoagulable and 24% in hypocoagulable patients (P <0.001). EXTEM CT, alpha and G were predictors for occurrence of MOF and mortality.
The incidence of a hypercoagulable state after trauma is 10% up to 24 hours after admission, which is broadly comparable to the rate of hypocoagulability. Further work in larger studies should define the clinical consequences of identifying hypercoagulability and a possible role for very early, targeted use of anticoagulants.
Background Trauma-induced coagulopathy in traumatic brain injury (TBI) remains associated with high rates of complications, unfavorable outcomes, and mortality. The underlying mechanisms are largely ...unknown. Embedded in the prospective multinational Collaborative European Neurotrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI) study, coagulation profiles beyond standard conventional coagulation assays were assessed in patients with isolated TBI within the very early hours of injury. Methods Results from blood samples (citrate/EDTA) obtained on hospital admission were matched with clinical and routine laboratory data of patients with TBI captured in the CENTER-TBI central database. To minimize confounding factors, patients with strictly isolated TBI (iTBI) (n = 88) were selected and stratified for coagulopathy by routine international normalized ratio (INR): (1) INR < 1.2 and (2) INR ≥ 1.2. An INR > 1.2 has been well adopted over time as a threshold to define trauma-related coagulopathy in general trauma populations. The following parameters were evaluated: quick’s value, activated partial thromboplastin time, fibrinogen, thrombin time, antithrombin, coagulation factor activity of factors V, VIII, IX, and XIII, protein C and S, plasminogen, D-dimer, fibrinolysis-regulating parameters (thrombin activatable fibrinolysis inhibitor, plasminogen activator inhibitor 1, antiplasmin), thrombin generation, and fibrin monomers. Results Patients with iTBI with INR ≥ 1.2 (n = 16) had a high incidence of progressive intracranial hemorrhage associated with increased mortality and unfavorable outcome compared with patients with INR < 1.2 (n = 72). Activity of coagulation factors V, VIII, IX, and XIII dropped on average by 15–20% between the groups whereas protein C and S levels dropped by 20%. With an elevated INR, thrombin generation decreased, as reflected by lower peak height and endogenous thrombin potential (ETP), whereas the amount of fibrin monomers increased. Plasminogen activity significantly decreased from 89% in patients with INR < 1.2 to 76% in patients with INR ≥ 1.2. Moreover, D-dimer levels significantly increased from a mean of 943 mg/L in patients with INR < 1.2 to 1,301 mg/L in patients with INR ≥ 1.2. Conclusions This more in-depth analysis beyond routine conventional coagulation assays suggests a counterbalanced regulation of coagulation and fibrinolysis in patients with iTBI with hemostatic abnormalities. We observed distinct patterns involving key pathways of the highly complex and dynamic coagulation system that offer windows of opportunity for further research. Whether the changes observed on factor levels may be relevant and explain the worse outcome or the more severe brain injuries by themselves remains speculative.
Abstract
Background: Methionine aminopeptidase (MetAP) 2 is one of the two eukaryotic enzymes responsible for cleaving the N-terminal methionine from newly synthesized polypeptides to allow further ...post-translational modifications such as myristoylation to take place. The enzyme is the target of the anti-angiogenic natural product, fumagillin and so is believed to play a role in angiogenesis. Fumagillin analogues have shown activity in several disease models including oncology, inflammation and obesity indicating MetAP2 is a promising target in a number of indications. The semi-synthetic fumagillin analogue, TNP470, has shown activity in a Phase I/II cancer trial, suggesting that MetAP2 is a good oncology target. Here we describe the discovery, optimization and anti-tumor activity of fragment-derived MetAP2 inhibitors. Results: We identified fragment hits to MetAP2 using our fragment-based screening approach, Pyramid™. These were optimized by structure-based drug design to novel, potent lead compounds with sub-100 nM potency against the isolated MetAP2 enzyme. The two most advanced compounds inhibited proliferation of HUVECs with potencies of 130 nM and 300 nM. Levels of the MetAP2 substrate, Met-14-3-3, were shown to increase on treatment of HUVECs with these compounds indicating that Met-14-3-3 was not being processed and hence MetAP2 was being inhibited. The compounds also inhibited HUVEC tubule formation demonstrating their anti-angiogenic properties. The two lead compounds were further tested in vivo. Both compounds were well tolerated at doses up to 200 mg/kg bid. Levels of Met-14-3-3 were seen to increase in the thymus and spleen (where high expression of MetAP2 has been reported) of mice treated with the compounds, indicating again that MetAP2 was being inhibited in these tissues. Compound 1 was tested in a mouse HCT116 xenograft model. Mice were subcutaneously inoculated with HCT116 cells and oral dosing at 200 mg/kg bid started one day later. Tumor growth was inhibited in treated mice compared with control and growth inhibition was greater in Compound 1 treated mice (T/C 46%) compared with mice treated with 30 mg/kg TNP470 subcutaneously q2d (T/C 61%). Conclusions: The compounds described here are novel small-molecule inhibitors of MetAP2. Their promising tumor growth inhibitory properties merit their testing in further tumor models and potentially other indications.
Citation Format: {Authors}. {Abstract title} abstract. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2315. doi:1538-7445.AM2012-2315
Paniati talks about the ITE e-Community. One of the biggest benefits of being an ITE member is access to the ITE e-Community, ITE's internal social media network. The e-Community provides a place to ...share with all ITE members through the All Member Forum, or a narrower interest area through the more than 87 available forums. More than 12,800 of ITE's 16,000 members are registered for one or more forum. Most choose to get a daily feed that summarizes posts from the last 24 hours and lands in your inbox in the early morning.
Abstract We report a single centre’s experience of the diagnosis and management of an uncommon form of type 2 von Willebrand disease (VWD) in members of two unrelated families. The affected patients ...presented with mild to moderate bleeding phenotypes and accompanying MCMDM-1 VWD bleeding assessment tool scores of 5 or less. Genetic analysis in both families confirmed a missense mutation in exon 30 of the von Willebrand factor (VWF) gene, a single base substitution T>A at nucleotide 5282 which led to change at codon 1761 from methionine to lysine (M1761K). This mutation lies within the A3 domain of the VWF protein, a region that is important for collagen binding. All affected patients were found to have normal coagulation profiles, normal VWF multimers and normal VWF assays except the VWF collagen-binding (VWF: CB) assay levels, which were significantly reduced. Desmopressin effected a good response in all treated patients, with a 3- to 5-fold rise of VWF:CB levels. However, there was variability in the degree to which VWF:CB levels remained elevated. Surgical procedures, including the delivery of one patient, were able to be managed with either desmopressin and/or tranexamic acid alone, with little need for recourse to VWF factor concentrate therapy.
Background: Limited evidence existed on the comparative effectiveness of decompressive craniectomy (DC) versus craniotomy for evacuation of traumatic acute subdural hematoma (ASDH) until the recently ...published randomised clinical trial RESCUE-ASDH. In this study, that ran concurrently, we aimed to determine current practice patterns and compare outcomes of primary DC versus craniotomy. Methods: We conducted an analysis of centre treatment preference within the prospective, multicentre, observational Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury (known as CENTER-TBI) and NeuroTraumatology Quality Registry (known as Net-QuRe) studies, which enrolled patients throughout Europe and Israel (2014–2020). We included patients with an ASDH who underwent acute neurosurgical evacuation. Patients with severe pre-existing neurological disorders were excluded. In an instrumental variable analysis, we compared outcomes between centres according to treatment preference, measured by the case-mix adjusted proportion DC per centre. The primary outcome was functional outcome rated by the 6-months Glasgow Outcome Scale Extended, estimated with ordinal regression as a common odds ratio (OR), adjusted for prespecified confounders. Variation in centre preference was quantified with the median odds ratio (MOR). CENTER-TBI is registered with ClinicalTrials.gov, number NCT02210221, and the Resource Identification Portal (Research Resource Identifier SCR_015582). Findings: Between December 19, 2014 and December 17, 2017, 4559 patients with traumatic brain injury were enrolled in CENTER-TBI of whom 336 (7%) underwent acute surgery for ASDH evacuation; 91 (27%) underwent DC and 245 (63%) craniotomy. The proportion primary DC within total acute surgery cases ranged from 6 to 67% with an interquartile range (IQR) of 12–26% among 46 centres; the odds of receiving a DC for prognostically similar patients in one centre versus another randomly selected centre were trebled (adjusted median odds ratio 2.7, p < 0.0001). Higher centre preference for DC over craniotomy was not associated with better functional outcome (adjusted common odds ratio (OR) per 14% IQR increase more DC in a centre = 0.9 95% CI 0.7–1.1, n = 200). Primary DC was associated with more follow-on surgeries and complications secondary cranial surgery 27% vs. 18%; shunts 11 vs. 5%; and similar odds of in-hospital mortality (adjusted OR per 14% IQR more primary DC 1.3 95% CI (1.0–3.4), n = 200). Interpretation: We found substantial practice variation in the employment of DC over craniotomy for ASDH. This variation in treatment strategy did not result in different functional outcome. These findings suggest that primary DC should be restricted to salvageable patients in whom immediate replacement of the bone flap is not possible due to intraoperative brain swelling. Funding: Hersenstichting Nederland for the Dutch NeuroTraumatology Quality Registry and the European Union Seventh Framework Program.
Abstract
Background: Mutations in BRAF are found in approximately 50% of melanomas. Vemurafenib, the selective mutant BRAF inhibitor, is an effective treatment in this disease but is limited by the ...onset of resistance. A number of mechanisms of resistance to RAF inhibitors have been described, including alternative mechanisms for activating the MEK-ERK and AKT pathways. HSP90 inhibitors affect clients in both these pathways and so it has been suggested that HSP90 inhibition is a potential mechanism for overcoming resistance to RAF inhibitors in melanoma. Results: AT13387 is a fragment-derived, potent HSP90 inhibitor, which is currently being evaluated in clinical trials. AT13387 inhibited cell proliferation in a range of melanoma cell lines, including cell lines with different mechanisms of resistance to vemurafenib (See Table). AT13387 treatment of melanoma cell lines resulted in the induction of HSP70, a marker of HSP90 inhibition, and depletion of HSP90 client proteins including BRAF and AKT. The levels of phospho-ERK, phospho-AKT and phospho-S6 were also depleted in both vemurafenib-sensitive (A375) and vemurafenib-resistant (A2058) lines indicating that the MEK-ERK and AKT signaling pathways were both inhibited. This demonstrates that vemurafenib resistance mediated by upregulation of the AKT pathway can be overcome by HSP90 inhibition. In vivo, AT13387 significantly inhibited growth of an A375 melanoma xenograft. Client proteins, including BRAF, CRAF and AKT were depleted in xenograft tissue and the MEK-ERK and AKT signaling pathways were again inhibited. Conclusions: These results demonstrate the activity of AT13387 in both vemurafenib-sensitive and -resistant models and show that HSP90 inhibition results in downregulation of signaling pathways that may be activated as a result of resistance to RAF inhibitors. These data support further clinical evaluation of AT13387 in melanoma.
Citation Format: {Authors}. {Abstract title} abstract. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2772. doi:1538-7445.AM2012-2772
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