Abstract
High-precision radiotherapy (HPR) of recurrent high grade glioma (HGG) requires accurate spatial allocation of these infiltrative tumors. We investigated the impact of
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F-FET PET on tumor ...delineation and progression of recurrent HGG after HPR with carbon ions. T
1
contrast enhanced MRI and
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F-FET-PET scans of 26 HGG patients were fused with radiotherapy planning volumes. PET-positive (PET+) tumor volumes using different isocontours (I%) were systematically investigated and compared with MRI-derived gross tumor volumes (GTV). Standardized uptake ratios (SUR) were further correlated with GTV and tumor progression patterns. In grade IV glioma, SUR > 2.92 significantly correlated with poor median overall survival (6.5 vs 13.1 months, p = 0.00016). We found no reliable SUR cut-off criteria for definition of PET+ volumes. Overall conformity between PET and MRI-based contours was low, with maximum conformities between 0.42–0.51 at I40%. The maximum sensitivity and specificity for PET+ volumes outside of GTV predicting tumor progression were 0.16 (I40%) and 0.52 (I50%), respectively. In 75% of cases, FLAIR hyperintense area covered over 80% of PET+ volumes.
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F-FET-PET derived SUR has a prognostic impact in grade IV glioma. The value of substantial mismatches between MRI-based GTV and PET+ volumes to improve tumor delineation in radiotherapy awaits further validation in randomized prospective trials.
Abstract
Aims
Non-vitamin K oral anticoagulants are safe and effective for stroke prevention in patients with atrial fibrillation (AF). Data on the safety and efficacy of edoxaban in routine care are ...limited in Europe. We report 1-year outcomes in patients with AF treated with edoxaban in routine care.
Methods and results
ETNA-AF-Europe is a prospective, multicentre, post-authorization, observational study enrolling patients treated with edoxaban in 10 European countries, the design of which was agreed with the European Medicines Agency as part of edoxaban’s post-approval safety plan. Altogether 13 092 patients in 852 sites completed the 1-year follow-up mean age: 73.6 ± 9.5 years; 57% male, mean follow-up: 352 ± 49 days (median: 366 days). Most patients had associated comorbidities (mean CHA2DS2-VASc score: 3.1 ± 1.4). Stroke or systemic embolism was reported in 103 patients (annualized event rate: 0.82%/year), and major bleeding events were reported in 132 patients (1.05%/year). Rates of intracranial haemorrhage were low 30 patients (0.24%/year). Death occurred in 442 patients (3.50%/year); cardiovascular (CV) death occurred in 206 patients (1.63%/year). The approved dosing of edoxaban was chosen in 83%. All-cause and CV mortality were higher in patients receiving edoxaban 30 mg vs. 60 mg, in line with the higher age and more frequent comorbidities of the 30 mg group. Major bleeding was also numerically more common in patients receiving edoxaban 30 mg vs. 60 mg.
Conclusion
The rates of stroke, systemic embolism, and major bleeding are low in this large unselected cohort of high-risk AF patients routinely treated with edoxaban.
Hypoxic preconditioning provides protection against ischemic brain lesions in animal models of cerebral ischemia-hypoxia. To analyze the underlying molecular mechanisms, we developed an in vitro ...model of hypoxic neuroprotection in cerebellar granule neurons (CGN) by reducing the oxygen tension to 1-5% for 1-24 hr. Exposure to 5% O2 for 9 hr resulted in reduction of cell death after potassium deprivation, treatment with 100 microm glutamate, or 500 microm 3-nitroproprioninc acid (3-NP) by 46, 22, and 55%, respectively. Shorter (1 or 3 hr) or longer (>12 hr) intervals or pretreatment with lower oxygen tension failed to rescue CGN from death. In contrast, toxicity of four different chemotherapeutic drugs 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea, cisplatine, topotecane, and vincristine was unaffected by hypoxic preconditioning. The induction of protective effects was dependent on new protein synthesis. Protein levels of B-cell lymphoma protein-2 (BCL-2), BCL-x(L/S), heat shock protein 70/90, and BCL-2-associated death protein remained unaltered. CGN incubated at 5% O2 for 9 hr showed increased levels of the vascular endothelial growth factor (VEGF), the VEGF receptor-2 (VEGFR-2), phosphorylated Akt/protein kinase B (PKB), and extracellular signal-regulated kinase 1 (ERK1). Incubation with a neutralizing anti-VEGF antibody, a monoclonal antibody to VEGFR-2, wortmannin, or antisense-Akt/PKB, but not treatment with U0126, an ERK-inhibitor, reverted the resistance acquired by hypoxic preconditioning. Inhibition of VEGFR-2 blocked the activation of Akt/PKB. Finally, pretreatment with recombinant VEGF resulted in a hypoxia-resistant phenotype in the absence of hypoxic preconditioning. Our data are indicating a sequential requirement for VEGF/VEGFR-2 activation and Akt/PKB phosphorylation for neuronal survival mediated by hypoxic preconditioning and propose VEGF as a hypoxia-induced neurotrophic factor.
•Histological comparison of bone composition and cut marks on human, pig and goat ribs.•Juvenile age of non-human influences the shape of cut marks.•Stress fractures occurred perpendicular to the cut ...marks along lamellae and cement lines.•Cut marks on ribs always affected entheses of intercostal muscles.•Cut mark proportions are similar between human and pig ribs.
Cut marks provide essential knowledge to interpret which and how tools were used, both in archaeological and forensic context. Lots of studies focused on experimentally produced cut marks on animal models to develop methods for stabbing incidents. However, animal models are criticized to be morphologically different in comparison to human bones.
This study analyzed the bone composition and experimentally obtained cut marks done on ribs from humans, pigs and goats. Methods included a qualitative description of differences between the species and a quantitative analysis of the cut mark proportions in histological thin sections and micro CT scans.
The results indicated that especially the cortical bone of non-human ribs was different in comparison to human bone tissue as they were more robust and usually juvenile. Plexiform bone dominates and remodeled lamellar bone is rarely visible. The knife impact tends to create debris inside the cut mark and stress fractures along lamellae and cement lines perpendicular to the cut mark.
Moreover, entheses of the intercostal muscles are always affected by the incision. Pig ribs were shown to be better suited as a model for sharp force trauma than goat ribs in comparison to humans. Though, plexiform bone and non-remodeled bone made it not quite ideal. We suggested to use bone material from animals used for breeding instead of meat production as they are slaughtered at higher ages.
Genetically engineered mouse models have the potential to unravel fundamental biological processes and provide mechanistic insights into the pathogenesis of human diseases. We have previously ...observed that germline genetic variation at the TULP4 locus influences clinical characteristics in patients with myeloproliferative neoplasms. To elucidate the role of TULP4 in pathological and physiological processes in vivo, we generated a Tulp4 knockout mouse model. Systemic Tulp4 deficiency exerted a strong impact on embryonic development in both Tulp4 homozygous null (Tulp4−/−) and heterozygous (Tulp4+/−) knockout mice, the former exhibiting perinatal lethality. High‐resolution episcopic microscopy (HREM) of day 14.5 embryos allowed for the identification of multiple developmental defects in Tulp4−/− mice, including severe heart defects. Moreover, in Tulp4+/− embryos HREM revealed abnormalities of several organ systems, which per se do not affect prenatal or postnatal survival. In adult Tulp4+/− mice, extensive examinations of hematopoietic and cardiovascular features, involving histopathological surveys of multiple tissues as well as blood counts and immunophenotyping, did not provide evidence for anomalies as observed in corresponding embryos. Finally, evaluating a potential obesity‐related phenotype as reported for other TULP family members revealed a trend for increased body weight of Tulp4+/− mice.
Research Highlights
To study the role of the TULP4 gene in vivo, we generated a Tulp4 knockout mouse model.
Correlative analyses involving HREM revealed a strong impact of Tulp4 deficiency on murine embryonic development.
Classical histopathologic analyses in conjunction with high‐resolution episcopic microscopy (HREM) allowed for the identification of phenotypic abnormalities in a novel Tulp4 knockout mouse model.
This retrospective, multicenter study aimed to reveal risk predictors for mortality in the intensive care unit (ICU) as well as survival after ICU discharge in patients with acute myeloid leukemia ...(AML) requiring treatment in the ICU.
Multivariate analysis of data for 187 adults with AML treated in the ICU in one institution revealed the following as independent prognostic factors for death in the ICU: arterial oxygen partial pressure below 72 mmHg, active AML and systemic inflammatory response syndrome upon ICU admission, and need for hemodialysis and mechanical ventilation in the ICU. Based on these variables, we developed an ICU mortality score and validated the score in an independent cohort of 264 patients treated in the ICU in three additional tertiary hospitals. Compared with the Simplified Acute Physiology Score (SAPS) II, the Logistic Organ Dysfunction (LOD) score, and the Sequential Organ Failure Assessment (SOFA) score, our score yielded a better prediction of ICU mortality in the receiver operator characteristics (ROC) analysis (AUC = 0.913 vs. AUC = 0.710 SAPS II, AUC = 0.708 LOD, and 0.770 SOFA in the training cohort; AUC = 0.841 for the developed score vs. AUC = 0.730 SAPSII, AUC = 0.773 LOD, and 0.783 SOFA in the validation cohort). Factors predicting decreased survival after ICU discharge were as follows: relapse or refractory disease, previous allogeneic stem cell transplantation, time between hospital admission and ICU admission, time spent in ICU, impaired diuresis, Glasgow Coma Scale <8 and hematocrit of ≥25% at ICU admission. Based on these factors, an ICU survival score was created and used for risk stratification into three risk groups. This stratification discriminated distinct survival rates after ICU discharge.
Our data emphasize that although individual risks differ widely depending on the patient and disease status, a substantial portion of critically ill patients with AML benefit from intensive care.
Non-vitamin K antagonist (VKA) oral anticoagulants (NOACs) have substantially improved anticoagulation therapy for prevention of stroke and systemic embolism in patients with atrial fibrillation ...(AF). The available routine care data have demonstrated the safety of different NOACs; however, such data for edoxaban are scarce. Here, we report baseline characteristics of 13,638 edoxaban-treated patients with AF enrolled between November 2016 and February 2018.
ETNA-AF-Europe is a multinational, multi-centre, post-authorisation, observational study conducted in 825 sites in 10 European countries. Patients will be followed up for four years.
Overall, 13,980 patients were enrolled of which 342 patients were excluded from the analysis. Mean patient age was 73.6 years with an average creatinine clearance of 69.4 mL/min. 56.6% were male. The calculated CHA
DS
-VASc and HAS-BLED mean scores were 3.1 and 2.6, respectively. Overall, 3.3, 14.6 and 82.0% of patients had low (CHA
DS
-VASc = 0), intermediate (CHA
DS
-VASc = 1) and high (CHA
DS
-VASc≥2) risks of stroke, respectively. High-risk patients (those with prior stroke, prior major bleeding, prior intracranial bleed or CHA
DS
-VASc ≥4) comprised 38.4% of the overall population. For 75.1% of patients edoxaban was their first anticoagulant prescription, whilst 16.9% switched from a VKA and 8.0% from another NOAC. A total of 23.4% of patients in ETNA-AF-Europe received the reduced dose of edoxaban 30 mg. Overall, 83.8% of patients received an edoxaban dose in line with the criteria outlined in the label.
Edoxaban was predominantly initiated in older, often anticoagulation-naïve, unselected European patients with AF, with a good overall adherence to the approved label.
NCT02944019; Date of registration: October 24, 2016.
Infiltration of monocytes into the arterial wall is an early cellular event in atherogenesis. Recent evidence shows that C-reactive protein (CRP) is deposited in the arterial intima at sites of ...atherogenesis. In this study, we demonstrate that CRP deposition precedes the appearance of monocytes in early atherosclerotic lesions. CRP is chemotactic for freshly isolated human blood monocytes. A specific CRP receptor is demonstrated on monocytes in vitro as well as in vivo, and blockage of the receptor by use of a monoclonal anti-receptor antibody completely abolishes CRP-induced chemotaxis. CRP may play a major role in the recruitment of monocytes during atherogenesis.
Two distinct receptors for vascular endothelial growth factor (VEGF), the tyrosine kinase receptors Flt-1 and Flk-1/KDR, have been described. In this study we show that monocytes, in contrast to ...endothelium, express only the VEGF receptor Flt-1, and that this receptor specifically binds also the VEGF homolog placenta growth factor (PlGF). Both VEGF and PlGF stimulate tissue factor production and chemotaxis in monocytes at equivalent doses. In contrast, endothelial cells expressing both the Flt-1 and the Flk-1/KDR receptors produce more tissue factor upon stimulation with VEGF than after stimulation with PlGF. Neutralizing antibodies to the KDR receptor reduce the VEGF-stimulated tissue factor induction in endothelial cells to levels obtained by stimulation with PlGF alone, but do not affect PlGF-induced tissue factor induction in endothelial cells nor the VEGF-dependent tissue factor production in monocytes. These findings strongly suggest Flt-1 as a functional receptor for VEGF and PlGF in monocytes and endothelial cells and identify this receptor as a mediator of monocyte recruitment and procoagulant activity.
There is increasing evidence that complement activation may play a role in atherogenesis. Complement proteins have been demonstrated to be present in early atherosclerotic lesions of animals and ...humans, and cholesterol-induced atherosclerotic lesion formation is reduced in complement-deficient animals. Potential complement activators in atherosclerotic lesions are now a subject matter of debate. C-reactive protein (CRP) is an acute-phase protein that is involved in inflammatory processes in numerous ways. It binds to lipoproteins and activates the complement system via the classic pathway. In this study we have investigated early atherosclerotic lesions of human coronary arteries by means of immunohistochemical staining. We demonstrate here that CRP deposits in the arterial wall in early atherosclerotic lesions with 2 predominant manifestations. First, there is a diffuse rather than a focal deposition in the deep fibroelastic layer and in the fibromuscular layer of the intima adjacent to the media. In this location, CRP frequently colocalizes with the terminal complement complex. Second, the majority of foam cells below the endothelium show positive staining for CRP. In this location, no colocalization with the terminal complement proteins can be observed. Our data suggest that CRP may promote atherosclerotic lesion formation by activating the complement system and being involved in foam cell formation.
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