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Extracellular adenosine is produced from ATP by CD39 and CD73, and can modulate tumor development by acting on cancer cells or immune cells. Adenosine metabolism has been poorly studied in uveal melanoma. We studied the protein levels of CD39 and CD73 in a small, well described cohort of patients with uveal melanoma. Our results show a high variability in the levels of the two proteins, both in positivity and in intensity. Our results suggest that similar studies on larger cohorts could determine the clinical value and the druggability of these enzymes in the given clinical setting.Supplemental data for this article is available online at http://dx.doi.org/10.1080/15257770.2022.2032738.

After analyzing treatment patterns in chronic lymphocytic leukemia (CLL) (objective 1), we investigated the relative effectiveness of ibrutinib versus other commonly used treatments (objective 2) in patients with treatment-naïve and relapsed/refractory CLL, comparing patient-level data from two randomized registration trials with two real-world databases. Hazard ratios (HR) and 95% confidence intervals (CIs) were estimated using a multivariate Cox proportional hazards model, adjusted for differences in baseline characteristics. Rituximab-containing regimens were often prescribed in clinical practice. The most frequently prescribed regimens were fludarabine + cyclophosphamide + rituximab (FCR, 29.3%), bendamustine + rituximab (BR, 17.7%), and other rituximab-containing regimens (22.0%) in the treatment-naïve setting (n = 604), other non-FCR/BR rituximab-containing regimens (38.7%) and non-rituximab-containing regimens (28.5%) in the relapsed/refractory setting (n = 945). Adjusted HRs (95% CI) for progression-free survival (PFS) and overall survival (OS), respectively, with ibrutinib versus real-world regimens were 0.23 (0.14-0.37; p < 0.0001) and 0.40 (0.22-0.76; p = 0.0048) in the treatment-naïve setting, and 0.21 (0.16-0.27; p < 0.0001) and 0.29 (0.21-0.41; p < 0.0001) in the relapsed/refractory setting. When comparing real-world use of ibrutinib (n = 53) versus other real-world regimens in relapsed/refractory CLL (objective 3), adjusted HRs (95% CI) were 0.37 (0.22-0.63; p = 0.0003) for PFS and 0.53 (0.27-1.03; p < 0.0624) for OS. This adjusted analysis, based on nonrandomized patient data, suggests ibrutinib to be more effective than other commonly used regimens for CLL.

B-cell prolymphocytic leukemia (B-PLL) is a rare hematological disorder whose underlying oncogenic mechanisms are poorly understood. Our cytogenetic and molecular assessments of 34 patients with B-PLL revealed several disease-specific features and potential therapeutic targets. The karyotype was complex (≥3 abnormalities) in 73% of the patients and highly complex (≥5 abnormalities) in 45%. The most frequent chromosomal aberrations were translocations involving MYC [t(MYC)] (62%), deletion (del)17p (38%), trisomy (tri)18 (30%), del13q (29%), tri3 (24%), tri12 (24%), and del8p (23%). Twenty-six (76%) of the 34 patients exhibited an MYC aberration, resulting from mutually exclusive translocations or gains. Whole-exome sequencing revealed frequent mutations in TP53, MYD88, BCOR, MYC, SF3B1, SETD2, CHD2, CXCR4, and BCLAF1. The majority of B-PLL used the IGHV3 or IGHV4 subgroups (89%) and displayed significantly mutated IGHV genes (79%). We identified 3 distinct cytogenetic risk groups: low risk (no MYC aberration), intermediate risk (MYC aberration but no del17p), and high risk (MYC aberration and del17p) (P = .0006). In vitro drug response profiling revealed that the combination of a B-cell receptor or BCL2 inhibitor with OTX015 (a bromodomain and extra-terminal motif inhibitor targeting MYC) was associated with significantly lower viability of B-PLL cells harboring a t(MYC). We concluded that cytogenetic analysis is a useful diagnostic and prognostic tool in B-PLL. Targeting MYC may be a useful treatment option in this disease., (© 2019 by The American Society of Hematology.)

According to the World Health Organization (WHO) classification, the nosology of B-cell neoplasms integrates clinical, morphological, phenotypic, and genetic data. In this retrospective analysis, we identified 18 patients with isolated neoplastic lymphocytosis that could not be accurately classified within the WHO classification. Most of them were asymptomatic at the time of diagnosis and the evolution was relatively indolent, as only five patients required treatment after a median follow-up of 48 months. The neoplastic B-cells expressed CD5 in most cases, but the Royal Marsden Hospital score was strictly below 3. Trisomy 12 was the most frequent cytogenetic abnormality. High-throughput sequencing highlighted mutations found in both chronic lymphocytic leukemia (CLL) and marginal zone lymphoma (MZL). Similarly, the immunoglobulin heavy chain variable region repertoire was distinct from those reported in CLL or MZL. However, as treatment choice is dependent on the correct classification of the lymphoproliferative disorder, a histological diagnosis should be performed in case patients need to be treated., Competing Interests: The authors declare no conflicts of interest.

In splenic marginal zone lymphoma (SMZL), specific and functional Toll-like Receptor (TLR) patterns have been recently described, suggesting their involvement in tumoral proliferation. Splenic diffuse red pulp lymphoma with villous lymphocytes (SDRPL) is close to but distinct from SMZL, justifying here the comparison of TLR patterns and functionality in both entities. Distinct TLR profiles were observed in both lymphoma subtypes. SDRPL B cells showed higher expression of TLR7 and to a lesser degree TLR9, in comparison to SMZL B cells. In both entities, TLR7 and TLR9 pathways appeared functional, as shown by IL-6 production upon TLR7 and TLR9 agonists stimulations. Interestingly, circulating SDRPL, but not SMZL B cells, constitutively expressed CD86. In addition, stimulation with both TLR7 and TLR9 agonists significantly increased CD80 expression in circulating SDRPL but not SMZL B cells. Finally, TLR7 and TLR9 stimulations had no impact on proliferation and apoptosis of SMZL or SDRPL B cells. In conclusion, SMZL and SDRPL may derive from different splenic memory B cells with specific immunological features that can be used as diagnosis markers in the peripheral blood., Competing Interests: CONFLICTS OF INTEREST The authors declare no conflicts of interest.

Splenic diffuse red pulp lymphoma is an indolent small B-cell lymphoma recognized as a provisional entity in the World Health Organization 2008 classification. Its precise relationship to other related splenic B-cell lymphomas with frequent leukemic involvement or other lymphoproliferative disorders remains undetermined. We performed whole-exome sequencing to explore the genetic landscape of ten cases of splenic diffuse red pulp lymphoma using paired tumor and normal samples. A selection of 109 somatic mutations was then evaluated in a cohort including 42 samples of splenic diffuse red pulp lymphoma and compared to those identified in 46 samples of splenic marginal zone lymphoma and eight samples of hairy-cell leukemia. Recurrent mutations or losses in BCOR (the gene encoding the BCL6 corepressor) - frameshift (n=3), nonsense (n=2), splicing site (n=1), and copy number loss (n=4) - were identified in 10/42 samples of splenic diffuse red pulp lymphoma (24%), whereas only one frameshift mutation was identified in 46 cases of splenic marginal zone lymphoma (2%). Inversely, KLF2 , TNFAIP3 and MYD88 , common mutations in splenic marginal zone lymphoma, were rare (one KLF2 mutant in 42 samples; 2%) or absent ( TNFAIP3 and MYD88 ) in splenic diffuse red pulp lymphoma. These findings define an original genetic profile of splenic diffuse red pulp lymphoma and suggest that the mechanisms of pathogenesis of this lymphoma are distinct from those of splenic marginal zone lymphoma and hairy-cell leukemia., (Copyright© 2017 Ferrata Storti Foundation.)