Expression of the progenitor marker NG2/CSPG4 predicts poor survival and resistance to ionising radiation in glioblastoma

Glioblastoma (GBM) is a highly aggressive brain tumour, where patients respond poorly to radiotherapy and exhibit dismal survival outcomes. The mechanisms of radioresistance are not completely understood. However, cancer cells with an immature stem-like phenotype are hypothesised to play a role in radioresistance. Since the progenitor marker neuron-glial-2 (NG2) has been shown to regulate several aspects of GBM progression in experimental systems, we hypothesised that its expression would influence the survival of GBM patients. Quantification of NG2 expression in 74 GBM biopsies from newly diagnosed and untreated patients revealed that 50% express high NG2 levels on tumour cells and associated vessels, being associated with significantly shorter survival. This effect was independent of age at diagnosis, treatment received and hypermethylation of the O6-methylguanine methyltransferase (MGMT) DNA repair gene promoter. NG2 was frequently co-expressed with nestin and vimentin but rarely with CD133 and the NG2 positive tumour cells harboured genetic aberrations typical for GBM. 2D proteomics of 11 randomly selected biopsies revealed upregulation of an antioxidant, peroxiredoxin-1 (PRDX-1), in the shortest surviving patients. Expression of PRDX-1 was associated with significantly reduced products of oxidative stress. Furthermore, NG2 expressing GBM cells showed resistance to ionising radiation (IR), rapidly recognised DNA damage and effectuated cell cycle checkpoint signalling. PRDX-1 knockdown transiently slowed tumour growth rates and sensitised them to IR in vivo. Our data establish NG2 as an important prognostic factor for GBM patient survival, by mediating resistance to radiotherapy through induction of ROS scavenging enzymes and preferential DNA damage signalling

Comprehensive geriatric assessment in 326 older women with early breast cancer

Background: One-third of new early breast cancer diagnoses occur in women over 70 years old. However, older women are less likely to receive radical curative treatments. This study prospectively evaluated a cohort of older women using a Comprehensive Geriatric Assessment (CGA) to determine whether fitness explained the apparent under-treatment in this patient group. Methods: In this multi-centre prospective study, patients aged >= 70 years with Stages I-III breast cancer underwent a pretreatment baseline CGA consisting of eight assessment tools. Patients were defined as 'fit' if they had normal score in seven out of eight of the assessment tools. 'High risk' patients were defined as those with grade 3, ER negative, HER2 positive, or node positive breast cancer. Results: Data on 326 patients were available for full analysis. The median age was 77 years. In all, 182 (56%) of the total population were defined as high risk, with 49%, 61% and 53% of those in the 70-74, 75-84 and >= 85 years age groups respectively having high risk tumours. A total of 301 patients had sufficient CGA records of whom 131 (44%) were reported as fit, with 34%, 54% and 12% of them in the 70-74, 75-84 and >= 85 years age groups respectively. More fit than unfit patients underwent primary breast surgery (100% vs 91%, P = 0.0002), axillary surgery (92% vs 84%, P = 0.0340), and adjuvant chemotherapy for high-risk disease (51% vs 20%, P = 0.0001). Rates of adjuvant radiotherapy after wide local excision were not significantly different (88% vs 90% respectively, P = 0.8195). Conclusions: In this study, all women >= 70 years deemed fit by CGA underwent primary surgery. Nearly 50% of fit women with high-risk disease did not receive adjuvant chemotherapy suggesting under treatment in this group

Technical-Induced Hemolysis in Patients with Respiratory Failure Supported with Veno-Venous ECMO – Prevalence and Risk Factors

The aim of the study was to explore the prevalence and risk factors for technical-induced hemolysis in adults supported with veno-venous extracorporeal membrane oxygenation (vvECMO) and to analyze the effect of hemolytic episodes on outcome. This was a retrospective, single-center study that included 318 adult patients (Regensburg ECMO Registry, 2009–2014) with acute respiratory failure treated with different modern miniaturized ECMO systems. Free plasma hemoglobin (fHb) was used as indicator for hemolysis. Throughout a cumulative support duration of 4,142 days on ECMO only 1.7% of the fHb levels were above a critical value of 500 mg/l. A grave rise in fHb indicated pumphead thrombosis (n = 8), while acute oxygenator thrombosis (n = 15) did not affect fHb. Replacement of the pumphead normalized fHb within two days. Neither pump or cannula type nor duration on the first system was associated with hemolysis. Multiple trauma, need for kidney replacement therapy, increased daily red blood cell transfusion requirements, and high blood flow (3.0–4.5 L/min) through small-sized cannulas significantly resulted in augmented blood cell trauma. Survivors were characterized by lower peak levels of fHb [90 (60, 142) mg/l] in comparison to non-survivors [148 (91, 256) mg/l, p≤0.001]. In conclusion, marked hemolysis is not common in vvECMO with modern devices. Clinically obvious hemolysis often is caused by pumphead thrombosis. High flow velocity through small cannulas may also cause technical-induced hemolysis. In patients who developed lung failure due to trauma, fHb was elevated independantly of ECMO. In our cohort, the occurance of hemolysis was associated with increased mortality