The impact of concurrent temozolomide with adjuvant radiation and IDH mutation status among patients with anaplastic astrocytoma

This study assesses the controversial role of temozolomide (TMZ) concurrent with adjuvant radiation (RT) in patients with anaplastic astrocytoma (AA). The impact of isocitrate dehydrogenase (IDH) status on therapy and outcomes is also examined. All adult patients diagnosed with AA from 2001 to 2011 and treated with standard doses of adjuvant RT were identified retrospectively for clinical data extraction. IDH status was determined by IDH1-R132H immunostain and sequencing for other mutations in IDH1/IDH2. Cumulative survival probabilities were estimated using the Kaplan-Meier method. Cox proportional hazards regression models were fit for univariable/multivariable analyses. 136 patients had received concurrent TMZ while 29 had not. Of these, IDH status was determined on 114 and 27 patients, respectively. On univariable analysis, improved five-year survival was independently associated with concurrent TMZ (46.2 vs. 29.3 %, p = 0.02) and IDH mutation (78.9 vs. 22.0 %, p < 0.001). IDH mutation was additionally associated with a greater likelihood of extensive resection possibly secondary to a more favorable tumor location. Gross total/subtotal resections also led to improved survival when compared to biopsy alone on univariable analysis. On multivariable analysis, the association with five-year survival persisted for both concurrent TMZ and IDH mutation, but not with extent of surgery. Both IDH mutation and concurrent TMZ are associated with improved five-year survival in patients with AA who are receiving adjuvant RT. Secondarily, the association between five-year survival and extent of resection is lost on multivariable analysis. This suggests a possible association between IDH mutation, tumor location and consequent resectability.     

Osteopontin: a new role for a familiar actor

Our understanding of the events that occur in cancer progression has been enhanced by the use of cell lines in vitro. Changes in gene expression, induction of signalling, and cell motility can all be investigated in this setting. However, other aspects of progression can be revealed only in vivo, especially the interactions of tumour cells with host cells and organ systems. In one such in vivo model, described by McAllister and colleagues, it proved possible to establish a novel function of an already well-characterised protein, osteopontin, adding to its attractiveness as a target in cancer therapy.     

PROTEIN KINASE C AND TRANSMITTER RELEASE

1. Protein kinase C (PKC) is an important second messenger-activated enzyme. In noradrenergic nerves it appears to be tonically activated by diacylglycerol (DAG) to facilitate transmitter release and the steps in this involve activation of phospholipase C, generation of DAG and activation of PKC. It is suggested that the subsequent facilitation of transmitter release is due to the phosphorylation of proteins involved in the release process distal to Ca²⁺entry, presumably those involved in vesicle dynamics. 2. There are differences between central noradrenergic neurons and sympathetic nerves. In central neurons PKC appears to be tonically active and its inhibition results in a decrease in noradrenaline release under most, if not all, conditions. 3. In sympathetic nerves PKC inhibitors only decrease transmitter release during high-frequency stimulation and not during low-frequency stimulation. At high frequency there is a gradual increase in the effect of PKC inhibitors on transmitter release during the first 15 s of a stimulation train. It is suggested that this is due to a progressive rise in intracellular Ca²⁺ and a consequent activation of PKC. 4. Activation of PKC by phorbol esters produces a large enhancement in action potential-evoked noradrenaline release in both the central nervous system and in peripheral tissues. The structural requirements of the phorbol esters for maximal effect suggest that the phorbol esters must access the interior of the nerve terminal to activate PKC and the neural membrane acts as a barrier for highly lipophilic phorbol esters, thereby reducing their activity. Activation of PKC represents one of the most powerful ways to enhance transmitter release and may have therapeutic potential.     

Adherence of human polymorphonuclear leukocytes to endothelial monolayers: effects of temperature, divalent cations, and chemotactic factors on the strength of adherence measured with a new centrifugation assay

Polymorphonuclear leukocytes (PMNs) adhere to endothelial cells at sites of acute inflammation. To examine this phenomenon in vitro, we have developed a new assay to measure adherence of PMNs to cultured endothelial cells. Human PMNs were labeled with 111indium-oxine and incubated in microtiter wells with monolayers of either human umbilical vein or bovine aortic endothelial cells. Following incubation, the wells were sealed, inverted, and centrifuged at varying speeds. Results are expressed as the percentage of PMNs added initially that remained attached to the monolayers after being subjected to dislodgment forces (ie, relative centrifugal forces) ranging from 1 to 1,200 g. Adherence of PMNs to endothelial monolayers was temperature dependent, dependent on the concentration of extracellular Mg2+ (but not Ca2+), and enhanced significantly by the chemotactic peptides, N-formyl-methionyl-leucyl- phenylalanine (fMLP) and human C5a. It was found that fMLP and C5a not only increased the number of PMNs that adhered to endothelial cells, but also increased the strength of adherence.     

Effect of virucidal heat treatment on proteins in human factor VIII concentrates

Intermediate-purity and fibrinogen-poor factor VIII concentrates were heated in the lyophilized state at 60 degrees C for up to 72 hours to inactivate blood-borne viruses. The effect of heat treatment on factor VIII, von Willebrand factor (vWf), and other proteins present in the concentrates (albumin, fibrinogen, fibronectin, IgG, and IgM) was evaluated. Heat-induced protein aggregation, particularly of fibrinogen and fibronectin, occurred within 48 hours in the intermediate-purity concentrates and correlated well with decreased solubility of these products. Heated fibrinogen-poor concentrates were readily soluble and did not show protein aggregation even after 72 hours at 60 degrees C. Neither concentrate developed detectable neoantigens when tested against antisera to whole human plasma and to heated and unheated concentrates. Aggregation of the vWf molecule, detected by altered mobility in crossed immunoelectrophoresis and multimeric analysis in SDS agarose gels, occurred in heated intermediate-purity concentrates but not in fibrinogen-poor concentrates. Thus, higher-purity factor VIII concentrates withstand heat treatment better than concentrates that contain greater levels of contaminating proteins, particularly fibrinogen.     

Predicting Deletion of Chromosomal Arms 1p/19q in Low-Grade Gliomas from MR Images Using Machine Intelligence

Several studies have linked codeletion of chromosome arms 1p/19q in low-grade gliomas (LGG) with positive response to treatment and longer progression-free survival. Hence, predicting 1p/19q status is crucial for effective treatment planning of LGG. In this study, we predict the 1p/19q status from MR images using convolutional neural networks (CNN), which could be a non-invasive alternative to surgical biopsy and histopathological analysis. Our method consists of three main steps: image registration, tumor segmentation, and classification of 1p/19q status using CNN. We included a total of 159 LGG with 3 image slices each who had biopsy-proven 1p/19q status (57 non-deleted and 102 codeleted) and preoperative postcontrast-T1 (T1C) and T2 images. We divided our data into training, validation, and test sets. The training data was balanced for equal class probability and was then augmented with iterations of random translational shift, rotation, and horizontal and vertical flips to increase the size of the training set. We shuffled and augmented the training data to counter overfitting in each epoch. Finally, we evaluated several configurations of a multi-scale CNN architecture until training and validation accuracies became consistent. The results of the best performing configuration on the unseen test set were 93.3% (sensitivity), 82.22% (specificity), and 87.7% (accuracy). Multi-scale CNN with their self-learning capability provides promising results for predicting 1p/19q status non-invasively based on T1C and T2 images. Predicting 1p/19q status non-invasively from MR images would allow selecting effective treatment strategies for LGG patients without the need for surgical biopsy.     

Changes in cartilage and bone metabolism identified by serum markers in early osteoarthritis of the knee joint

Serum concentrations of two extracellular matrix molecules were determined over a 3 yr period in individuals with chronic knee pain to investigate whether sequential serum measurements of cartilage- and bone-derived molecular fragments reflect early stages of osteoarthritis (OA) of the knee joints. Thirty-eight individuals with chronic knee pain (> 3 months at inclusion) with or without radiographic evidence of knee joint OA at the 3 yr follow-up radiographic examination were studied. Serum concentrations of cartilage oligomeric matrix protein (COMP) and bone sialoprotein (BSP) increased significantly (P < 0.001) in the 23 individuals with radiographic OA at follow-up, while remaining unchanged in the 15 individuals with normal radiographs at follow-up. The baseline concentrations of the two variables did not differ between the groups. These findings suggest that pathological processes in cartilage and subchondral bone coincide in OA, and appear to be reflected by circulating levels of macromolecules released from cartilage and bone. Changes in serum levels of COMP and BSP are potential tools in studies of knee joint OA in subjects with chronic knee pain.