Key Points• Translocations between PD-L1 and the IGH locus represent a genetic mechanism of PD-L1 overexpression in DLBCL.• Genetic alterations in the PD-L1/PDL-2 locus are mainly associated with the non-GCB subtype of DLBCL.Diffuse large B-cell lymphoma (DLBCL) is one of the most common and aggressive types of B-cell lymphoma. Deregulation of proto-oncogene expression after a translocation, most notably to the immunoglobulin heavy-chain locus (IGH), is one of the hallmarks of DLBCL. Using whole-genome sequencing analysis, we have identified the PD-L1/PD-L2 locus as a recurrent translocation partner for IGH in DLBCL. PIM1 and TP63 were also identified as novel translocation partners for PD-L1/PD-L2. Fluorescence in situ hybridization was furthermore used to rapidly screen an expanded DLBCL cohort. Collectively, a subset of samples was found to be affected by gains (12%), amplifications (3%), and translocations (4%) of the PD-L1/PD-L2 locus. RNA sequencing data coupled with immunohistochemistry revealed that these cytogenetic alterations correlated with increased expression of PD-L1 but not of PD-L2. Moreover, cytogenetic alterations affecting the PD-L1/PD-L2 locus were more frequently observed in the non-germinal center B cell-like (non-GCB) subtype of DLBCL. These findings demonstrate the genetic basis of PD-L1 overexpression in DLBCL and suggest that treatments targeting the PD-1-PD-L1/PD-L2 axis might benefit DLBCL patients, especially those belonging to the more aggressive non-GCB subtype. (Blood. 2016;127(24):3026-3034)

Wearable devices may provide a promising alternative solution for measuring RV. However, more robust studies in non-stationary conditions are needed using appropriate methodology in terms of number of subjects involved, acquisition and analysis techniques implied.

Key Points Sequencing of Chinese DLBCL reveals novel mutation targets and highlights additional/alternative tumorigenic pathways in these tumors. DTX1 is frequently mutated in Chinese DLBCL and deleterious mutations in this gene contribute to the activation of the Notch pathway.

In view of their superior soft tissue contrast compared to computed tomography, magnetic resonance images are commonly involved in stereotactic radiosurgery/radiotherapy applications for target delineation purposes. It is known, however, that magnetic resonance images are geometrically distorted, thus deteriorating dose delivery accuracy. The present work focuses on the assessment of geometric distortion inherent in magnetic resonance images used in stereotactic radiosurgery/radiotherapy treatment planning and attempts to quantitively evaluate the consequent impact on dose delivery. The geometric distortions for 3 clinical magnetic resonance protocols (at both 1.5 and 3.0 T) used for stereotactic radiosurgery/radiotherapy treatment planning were evaluated using a recently proposed phantom and methodology. Areas of increased distortion were identified at the edges of the imaged volume which was comparable to a brain scan. Although mean absolute distortion did not exceed 0.5 mm on any spatial axis, maximum detected control point disposition reached 2 mm. In an effort to establish what could be considered as acceptable geometric uncertainty, highly conformal plans were utilized to irradiate targets of different diameters (5-50 mm). The targets were mispositioned by 0.5 up to 3 mm, and dose–volume histograms and plan quality indices clinically used for plan evaluation and acceptance were derived and used to investigate the effect of geometrical uncertainty (distortion) on dose delivery accuracy and plan quality. The latter was found to be strongly dependent on target size. For targets less than 20 mm in diameter, a spatial disposition of the order of 1 mm could significantly affect (>5%) plan acceptance/quality indices. For targets with diameter greater than 2 cm, the corresponding disposition was found greater than 1.5 mm. Overall results of this work suggest that efficacy of stereotactic radiosurgery/radiotherapy applications could be compromised in case of very small targets lying distant from the scanner’s isocenter (eg, the periphery of the brain).

Mutations in DNA damage response and repair genes correlate with genomic instability in diffuse large B cell lymphomas.

BackgroundEpstein-Barr virus (EBV) encodes six nuclear transformation-associated proteins that induce extensive changes in cellular gene expression and signaling and induce B-cell transformation. The role of HIF1A in EBV-induced B-cell immortalization has not been previously studied.Methods and FindingsUsing Western blotting and Q-PCR, we found that HIF1A protein is stabilized in EBV-transformed lymphoblastoid cells. Western blotting, GST pulldown assays, and immunoprecipitation showed that EBV-encoded nuclear antigens EBNA-5 and EBNA-3 bind to prolylhydroxylases 1 and 2, respectively, thus inhibiting HIF1A hydroxylation and degradation. Immunostaining and Q-PCR showed that the stabilized HIF1A translocates to the nucleus, forms a heterodimer with ARNT, and transactivates several genes involved in aerobic glycolysis. Using biochemical assays and Q-PCR, we also found that lymphoblastoid cells produce high levels of lactate, lactate dehydrogenase and pyruvate.ConclusionsOur data suggest that activation of the aerobic glycolytic pathway, corresponding to the Warburg effect, occurs in EBV-transformed lymphoblastoid cells, in contrast to mitogen-activated B-cells.

Background/Aim: Recently, indocyanine green (ICG) fluorescence imaging has been used for the identification of the parathyroid glands (PG) during thyroid and parathyroid surgery. However, an overall consensus on the optimal technique, the dosage, the timing of the ICG administration and finally its interpretation and clinical usefulness is still lacking evidence. The aim of this review is to investigate the use of ICG angiography during thyroidectomy and/or parathyroidectomy for identification as well as for the perfusion integrity of the parathyroid glands. Materials and Methods: The PubMed database was systematically searched for publications regarding intraoperative ICG imaging in patients that undergo thyroidectomy or parathyroidectomy. Results: Eighteen publications reporting on 612 patients, namely 71 parathyroidectomy and 541 thyroidectomy patients met the inclusion criteria. Eleven publications reported the use of ICG 23 This article is freely accessible online.

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