Improved early outcome prediction by MRI-based 3D tumor volume assessment in patients with CNS lymphomas.

BACKGROUND: Central nervous system lymphomas (CNSL) display remarkable clinical heterogeneity, yet accurate prediction of outcomes remains challenging. The IPCG criteria are widely used in routine practice for the assessment of treatment response. However, the value of the IPCG criteria for ultimate outcome prediction is largely unclear, mainly due to the uncertainty in delineating complete from partial responses during and after treatment. METHODS: We explored various MRI features including semi-automated 3D tumor volume measurements at different disease milestones and their association with survival in 93 CNSL patients undergoing curative-intent treatment. RESULTS: At diagnosis, patients with more than 3 lymphoma lesions, periventricular involvement, and high 3D tumor volumes showed significantly unfavorable PFS and OS. At first interim MRI during treatment, the IPCG criteria failed to discriminate outcomes in responding patients. Therefore, we randomized these patients into training and validation cohorts to investigate whether 3D tumor volumetry could improve outcome prediction. We identified a 3D tumor volume reduction of ≥97% as the optimal threshold for risk stratification (=3D early response, 3D_ER). Applied to the validation cohort, patients achieving 3D_ER had significantly superior outcomes. In multivariate analyses, 3D_ER was independently prognostic of PFS and OS. Finally, we leveraged prognostic information from 3D MRI features and circulating biomarkers to build a composite metric that further improved outcome prediction in CNSL. CONCLUSIONS: We developed semi-automated 3D tumor volume measurements as strong and independent early predictors of clinical outcomes in CNSL patients. These radiologic features could help improve risk stratification and help guide future treatment approaches.

Spinal adenosine A2a receptor activation elicits long-lasting phrenic motor facilitation.

Acute intermittent hypoxia elicits a form of spinal, brain-derived neurotrophic factor (BDNF)-dependent respiratory plasticity known as phrenic long-term facilitation. Ligands that activate G(s)-protein-coupled receptors, such as the adenosine 2a receptor, mimic the effects of neurotrophins in vitro by transactivating their high-affinity receptor tyrosine kinases, the Trk receptors. Thus, we hypothesized that A2a receptor agonists would elicit phrenic long-term facilitation by mimicking the effects of BDNF on TrkB receptors. Here we demonstrate that spinal A2a receptor agonists transactivate TrkB receptors in the rat cervical spinal cord near phrenic motoneurons, thus inducing long-lasting (hours) phrenic motor facilitation. A2a receptor activation increased phosphorylation and new synthesis of an immature TrkB protein, induced TrkB signaling through Akt, and strengthened synaptic pathways to phrenic motoneurons. RNA interference targeting TrkB mRNA demonstrated that new TrkB protein synthesis is necessary for A2a-induced phrenic motor facilitation. A2a receptor activation also increased breathing in unanesthetized rats, and improved breathing in rats with cervical spinal injuries. Thus, small, highly permeable drugs (such as adenosine receptor agonists) that transactivate TrkB receptors may provide an effective therapeutic strategy in the treatment of patients with ventilatory control disorders, such as obstructive sleep apnea, or respiratory insufficiency after spinal injury or during neurodegenerative diseases.

Zymogen activation and characterization of a major gelatin-cleavage activity localized to the sea urchin extraembryonic matrix.

The hyaline layer (HL) is an apically located extracellular matrix (ECM) which surrounds the sea urchin embryo from the time of fertilization until metamorphosis occurs. While gelatin-cleavage activities were absent from freshly prepared hyaline layers, a dynamic pattern of activities developed in layers incubated at 15 or 37 degrees C in Millipore-filtered sea water (MFSW). Cleavage activities at 90, 55, 41, and 32 kDa were evident following incubation at either temperature. The activation pathway leading to the appearance of these species was examined to determine the minimum salt conditions required for processing and to establish precursor-product relationships. In both qualitative and quantitative assays, the purified 55 kDa gelatinase activity was inhibited by 1,10-phenanthroline (a zinc-specific chelator) and ethylenebis (oxyethylenenitrilo) tetraacetic acid (EGTA). Calcium reconstituted the activity of the EGTA-inhibited enzyme with an apparent dissociation constant (calcium) of 1.2 mM. Developmental substrate gel analysis was performed using various stage embryos. The 55 and 32 kDa species comigrated with gelatin-cleavage activities present in sea urchin embryos. Collectively, the results reported here document a zymogen activation pathway which generates a 55 kDa, gelatin-cleaving activity within the extraembryonic HL. This species displayed characteristics of the matrix metalloproteinase class of ECM modifying enzymes.