ObjectiveTo determine the impact of elevated neuroendocrine serum markers on treatment outcome in patients with metastatic castration-resistant prostate cancer (mCRPC) undergoing treatment with abiraterone in a post-chemotherapy setting. Patients and MethodChromogranin A (CGa) and neurone-specific enolase (NSE) were determined in serum drawn before treatment with abiraterone from 45 patients with mCRPC. Outcome measures were overall survival (OS), prostate-specific antigen (PSA) response defined by a PSA level decline of ≥50%, PSA progression-free survival (PSA-PFS), and clinical or radiographic PFS. ResultsThe CGa and NSE serum levels did not correlate (P = 0.6). Patients were stratified in to low-(nine patients), intermediate- (18) or high-risk (18) groups according to elevation of none, one, or both neuroendocrine markers, respectively. The risk groups correlated with decreasing median OS (median OS not reached vs 15.3 vs 6.6 months; P < 0.001), decreasing median clinical or radiographic PFS (8.3 vs 4.4 vs 2.7 months; P = 0.001) and decreasing median PSA-PFS (12.0 vs 3.2 vs 2.7 months; P = 0.012). In multivariate Cox regression analysis the combination of CGa and NSE (≥1 marker positive vs both markers negative) remained significant predictors of OS, clinical or radiographic PFS, and PSA-PFS. We did not observe a correlation with PSA response (63% vs 35% vs 31%; P = 0.2). ConclusionChromogranin A and NSE did not predict PSA response in patients with mCRPC treated with abiraterone. However, we observed a correlation with shorter PSA-PFS, clinical or radiographic PFS, and OS. This might be due to an elevated risk of developing resistance under abiraterone treatment related to neuroendocrine differentiation.

No abstract

BACKGROUND Trauma-induced coagulopathy (TIC) substantially contributes to mortality in bleeding trauma patients. OBJECTIVE The aim of the study was to administer fibrinogen concentrate in the prehospital setting to improve blood clot stability in trauma patients bleeding or presumed to bleed. DESIGN A prospective, randomised, placebo-controlled, double-blinded, international clinical trial. SETTING This emergency care trial was conducted in 12 Helicopter Emergency Medical Services (HEMS) and Emergency Doctors’ vehicles (NEF or NAW) and four trauma centres in Austria, Germany and Czech Republic between 2011 and 2015. PATIENTS A total of 53 evaluable trauma patients aged at least 18 years with major bleeding and in need of volume therapy were included, of whom 28 received fibrinogen concentrate and 25 received placebo. INTERVENTIONS Patients were allocated to receive either fibrinogen concentrate or placebo prehospital at the scene or during transportation to the study centre. MAIN OUTCOME MEASURES Primary outcome was the assessment of clot stability as reflected by maximum clot firmness in the FIBTEM assay (FIBTEM MCF) before and after administration of the study drug. RESULTS Median FIBTEM MCF decreased in the placebo group between baseline (before administration of study treatment) and admission to the Emergency Department, from a median of 12.5 [IQR 10.5 to 14] mm to 11 [9.5 to 13] mm ( P = 0.0226), but increased in the FC Group from 13 [11 to 15] mm to 15 [13.5 to 17] mm ( P = 0.0062). The median between-group difference in the change in FIBTEM MCF was 5 [3 to 7] mm ( P < 0.0001). Median fibrinogen plasma concentrations in the fibrinogen concentrate Group were kept above the recommended critical threshold of 2.0 g l −1 throughout the observation period. CONCLUSION Early fibrinogen concentrate administration is feasible in the complex and time-sensitive environment of prehospital trauma care. It protects against early fibrinogen depletion, and promotes rapid blood clot initiation and clot stability. TRIAL REGISTRY NUMBERS EudraCT: 2010-022923-31 and ClinicalTrials.gov: NCT01475344.

No abstract

R e s e a R c h a R t i c l e5. Group 2 correlated with high STAT3 expression (i.e., STAT3 activation). (G) GSEA showed a significantly different distribution of the STAT3 activation-associated genes, with group 1 being negatively correlated (NES, -1.97; P < 0.001). Figure 1A; supplemental material available online with this article; doi:10.1172/JCI69094DS1). Gene set enrichment analysis (GSEA) showed a significantly different distribution of the STAT3 activation-associated genes among the hierarchical clustering-defined gene expression groups (normalized enrichment score [NES], -1.97; nominal P < 0.001; Figure 1G). In addition, mining the public repository Oncomine (www.oncomine. org) showed that STAT3 target genes were elevated in MM versus control tissue (Supplemental Figure 1B). Furthermore, we found the STAT3 signaling gene expression pattern to be associated with low bone disease, the MMSET groups, and the presence of a gain of the 1q21 locus, whereas we identified an inverse correlation with hyperdiploid disease (Supplemental Figure 1, C-E). Thus, STAT3 phosphorylation and target gene activation seems to be a major hallmark of a large subgroup of human MM. Constitutive GP130 signaling induces myeloma formation in a murine BM transduction-transplantation model. To test whether constitutive activation of GP130 signaling enables B cells to proliferate independently of cytokine stimulation, the IL-3-dependent Analysis of the malignant plasma cells revealed a t(12;15) translocation involving c-Myc (16). While Eμ-Myc transgenic mice (in which MYC expression is under control of the Eμ enhancer) develop aggressive pro-/pre-B cell lymphomas early in life (17), activationinduced deaminase-dependent expression of MYC in germinal center B cells leads to a high incidence of MM with a median survival of approximately 2 years (4). Transgenic mice expressing abnormally high levels of XBP-1, a protein involved in the terminal differentiation of B cells, develop monoclonal gammopathy of undetermined significance (MGUS), and some develop MM later in life (18). The Journal of Clinical Investigation R e s e a R c h a R t i c l e5In the present study, we showed that constitutive activation of GP130/JAK/STAT3 signal transduction in a retroviral murine BM transduction-transplantation model was sufficient to induce or facilitate MM development in mice. This model was characterized by very high penetrance and relatively short latency. Importantly, constitutive GP130 activation efficiently cooperated with MYC overexpression by driving cell growth and differentiation of malignant plasma cells. Our data indicate that constitutive GP130 signal transduction is a critical early step in myelomagenesis. Results STAT3 phosphorylation and target gene activation is a hallmark of human MM.Activation of the IL-6/IL-6R/GP130 complex is crucial for survival and proliferation of human myeloma (6,11,13), and the JAK/STAT3 pathway is a major target downstream of IL-6R/GP130 signaling (8,14). We therefore evaluated a series of BM biopsies from pati...

No abstract

PurposeTo assess the prognostic value of FDG PET/CT compared to the tumor markers S100B and melanoma inhibitory activity (MIA) in patients with high risk melanoma.MethodsRetrospective study in 125 consecutive patients with high risk melanoma that underwent FDG PET/CT for re-staging. Diagnostic accuracy and prognostic value was determined for FDG PET/CT as well as for S100B and MIA. As standard of reference, cytological, histological, PET/CT or MRI follow-up findings as well as clinical follow-up were used.ResultsOf 125 patients, FDG PET/CT was positive in 62 patients. 37 (29.6%) patients had elevated S100B (>100 pg/ml) and 24 (20.2%) had elevated MIA (>10 pg/ml) values. Overall specificities for FDG PET/CT, S100B and MIA were 96.8% (95% CI, 89.1% to 99.1%), 85.7% (75.0% to 92.3%), and 95.2% (86.9% to 98.4%), corresponding sensitivities were 96.8% (89.0% to 99.1%), 45.2% (33.4% to 55.5%), and 36.1% (25.2% to 48.6%), respectively. The negative predictive values (NPV) for PET/CT, S100B, and MIA were 96.8% (89.1% to 99.1%), 61.4% (50.9% to 70.9%), and 60.6% (50.8% to 69.7%). The positive predictive values (PPV) were 96.7% (89.0% to 99.1%), 75.7% (59.9% to 86.6%), and 88.0% (70.0% to 95.8%). Patients with elevated S100B- or MIA values or PET/CT positive findings showed a significantly (p<0.001 each, univariate Cox regression models) higher risk of melanoma associated death which was increased 4.2-, 6.5- or 17.2-fold, respectively.ConclusionPET/CT has a higher prognostic power in the assessment of cancer-associated mortality in melanoma patients compared with S100 and MIA.

No abstract