Genetic and phenotypic characterization of indolent T-cell lymphoproliferative disorders of the gastrointestinal tract.

Indolent T-cell lymphoproliferative disorders of the gastrointestinal tract are rare clonal T-cell diseases that more commonly occur in the intestines and have a protracted clinical course. Different immunophenotypic subsets have been described, but the molecular pathogenesis and cell of origin of these lymphocytic proliferations is poorly understood. Hence, we performed targeted next-generation sequencing and comprehensive immunophenotypic analysis of ten indolent T-cell lymphoproliferative disorders of the gastrointestinal tract, which comprised CD4 <sup>+</sup> (n=4), CD8 <sup>+</sup> (n=4), CD4 <sup>+</sup> /CD8 <sup>+</sup> (n=1) and CD4 <sup>-</sup> /CD8 <sup>-</sup> (n=1) cases. Genetic alterations, including recurrent mutations and novel rearrangements, were identified in 8/10 (80%) of these lymphoproliferative disorders. The CD4 <sup>+</sup> , CD4 <sup>+</sup> /CD8 <sup>+</sup> , and CD4 <sup>-</sup> /CD8 <sup>-</sup> cases harbored frequent alterations of JAK-STAT pathway genes (5/6, 82%); STAT3 mutations (n=3), SOCS1 deletion (n=1) and STAT3-JAK2 rearrangement (n=1), and 4/6 (67%) had concomitant mutations in epigenetic modifier genes (TET2, DNMT3A, KMT2D). Conversely, 2/4 (50%) of the CD8 <sup>+</sup> cases exhibited structural alterations involving the 3' untranslated region of the IL2 gene. Longitudinal genetic analysis revealed stable mutational profiles in 4/5 (80%) cases and acquisition of mutations in one case was a harbinger of disease transformation. The CD4 <sup>+</sup> and CD4 <sup>+</sup> /CD8 <sup>+</sup> lymphoproliferative disorders displayed heterogeneous Th1 (T-bet <sup>+</sup> ), Th2 (GATA3 <sup>+</sup> ) or hybrid Th1/Th2 (T-bet <sup>+</sup> /GATA3 <sup>+</sup> ) profiles, while the majority of CD8 <sup>+</sup> disorders and the CD4 <sup>-</sup> /CD8 <sup>-</sup> disease showed a type-2 polarized (GATA3 <sup>+</sup> ) effector T-cell (Tc2) phenotype. Additionally, CD103 expression was noted in 2/4 CD8 <sup>+</sup> cases. Our findings provide insights into the pathogenetic bases of indolent T-cell lymphoproliferative disorders of the gastrointestinal tract and confirm the heterogeneous nature of these diseases. Detection of shared and distinct genetic alterations of the JAK-STAT pathway in certain immunophenotypic subsets warrants further mechanistic studies to determine whether therapeutic targeting of this signaling cascade is efficacious for a proportion of patients with these recalcitrant diseases

Rearrangements of MYC gene facilitate risk stratification in diffuse large B-cell lymphoma patients treated with rituximab-CHOP

Contains fulltext : 136658.pdf (publisher's version ) (Closed access)In order to address the debatable prognostic role of MYC rearrangements in diffuse large B-cell lymphoma patients treated with rituximab, cyclophosphamide, hydroxydaunorubicin, vincristine, and prednisone, we evaluated MYC rearrangements by fluorescence in situ hybridization in 563 cases using break-apart probes and IGH/MYC dual-fusion probes. Concurrent BCL2 and BCL6 aberrations were also assessed. Data were correlated with clinicopathological variables and prognostic parameters. MYC rearrangements were observed in 39/432 evaluable cases (9%), including 4 rearrangements detectable only with the dual-fusion probes, 15 detectable only with the break-apart probes and 20 detectable with both dual-fusion probes and break-apart probes. MYC rearrangements correlated with germinal center B-cell origin (P=0.02), MYC protein expression (P=0.032), and larger tumor mass size (P=0.0003). Patients with MYC rearrangements were more likely to be treatment resistant (P<0.0001). All types of MYC rearrangements were associated with poorer disease-specific survival, that is, 20/39 dead, median disease-specific survival 42 months, compared with 98/393 dead among the non-rearranged cases, median disease-specific survival not reached (P=0.0002). Cases with MYC rearrangements that overexpressed MYC protein were at risk with respect to disease-specific survival independent of the International Prognostic Index (P=0.046 and P<0.001, respectively). Presence of concurrent BCL2 aberrations but not of BCL6 aberrations was prognostically additive. Radiotherapy seemed to diminish the prognostic effects of MYC rearrangements in diffuse large B-cell lymphoma patients since only 2/10 irradiated patients with MYC rearrangements died of/with disease, compared with 16/28 non-irradiated patients with MYC rearrangements. We conclude that MYC rearrangements add prognostic information for individual risk estimation and such cases might represent a distinct, biologically determined disease subgroup

An Automated and Robust Tumours Detection and Segmentation Framework for Whole-Body PET-CT Studies

A dual-modality positron emission tomography – computed tomography (PET-CT) is one of widely used medical imaging system. It combines functional (from PET) with anatomical (from CT) information, in a co-aligned space, provides advantages on diagnosing with several types of cancers. The most unique benefit of PET is to noninvasively visualise metabolic information such as glucose metabolism, through administrating radioactive tracer into the human body and quantitatively assess treatment response by analysing tumours metabolism. PET response criterion in solid tumour (PERCIST) is a widely accepted approach of assessing metabolic response of malignant tumours. It suggests placing volume of interest (VOI) reference on the liver structure (or the descending aorta structure if the liver is diseased, e.g. liver cancer) of the PET image to measure average of pixel variations. VOI references are then used to derive a PERCIST-based thresholding value, where the structures’ metabolism comprising of higher than the threshold will be considered as tumours. However, the delineation of VOI reference on the low resolution and poor signal-to-noise ratio (SNR) PET image is a difficult, time consuming and subjective task; in particular, for the small descending aorta structure. In addition, the global threshold does not provide accurate delineation of the tumour structure on PET. In this study, we propose a fully automatic tumours detection and segmentation framework for whole-body PET-CT studies based on PERCIST. We used multi-atlas based approach to segment PERCIST recommended VOI reference and to detect tumours. Then we used cellular automata with anisotropic diffusion filter (CA-ADF) based algorithm for accurate tumour segmentation on PET. In our evaluation, both clinical and simulation results presented that our proposed framework was able to detect and segment all the tumours with high accuracy, which demonstrated the reliability and robustnes

Prognostic impact of concurrent MYC and BCL6 rearrangements and expression in de novo diffuse large B-cell lymphoma

Double-hit B-cell lymphoma is a common designation for a group of tumors characterized by concurrent translocations of MYC and BCL2, BCL6, or other genes. The prognosis of concurrent MYC and BCL6 translocations is not well known. In this study, we assessed rearrangements and expression of MYC, BCL2 and BCL6 in 898 patients with de novo diffuse large B-cell lymphoma treated with standard chemotherapy (cyclophosphamide, doxorubicin, vincristine, and prednisone plus rituximab). Neither BCL6 translocation alone (more frequent in activated B-cell like diffuse large B-cell lymphoma) nor in combination with MYC translocation (observed in 2.0% of diffuse large B-cell lymphoma) predicted poorer survival in diffuse large B-cell lymphoma patients. Diffuse large B-cell lymphoma patients with MYC/BCL6 co-expression did have significantly poorer survival, however, MYC/BCL6 co-expression had no effect on prognosis in the absence of MYC/BCL2 co-expression, and had no additive impact in MYC+/BCL2+ cases. The isolated MYC+/BCL6+/BCL2- subset, more frequent in germinal center B-cell like diffuse large B-cell lymphoma, had significantly better survival compared with the isolated MYC+/BCL2+/BCL6- subset (more frequent in activated B-cell like diffuse large B-cell lymphoma). In summary, diffuse large B-cell lymphoma patients with either MYC/BCL6 rearrangements or MYC/BCL6 co-expression did not always have poorer prognosis; MYC expression levels should be evaluated simultaneously; and double-hit B-cell lymphoma needs to be refined based on the specific genetic abnormalities present in these tumors