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Purpose: MYD88 mutations, notably the recurrent gain-of-function L265P variant, are a distinguishing feature of activated B-cell like (ABC) diffuse large B-cell lymphoma (DLBCL), leading to constitutive NFκB pathway activation. The aim of this study was to examine the distinct genomic profiles of MYD88 -mutant DLBCL, notably according to the presence of the L265P or other non-L265P MYD88 variants. Experimental Design: A cohort of 361 DLBCL cases (94 MYD88 mutant and 267 MYD88 wild-type) was submitted to next-generation sequencing (NGS) focusing on 34 genes to analyze associated mutations and copy number variations, as well as gene expression profiling, and clinical and prognostic analyses. Results: Importantly, we highlighted different genomic profiles for MYD88 L265P and MYD88 non-L265P-mutant DLBCL, shedding light on their divergent backgrounds. Clustering analysis also segregated subgroups according to associated genetic alterations among patients with the same MYD88 mutation. We showed that associated CD79B and MYD88 L265P mutations act synergistically to increase NFκB pathway activation, although the majority of MYD88 L265P-mutant cases harbors downstream NFκB alterations, which can predict BTK inhibitor resistance. Finally, although the MYD88 L265P variant was not an independent prognostic factor in ABC DLBCL, associated CD79B mutations significantly improved the survival of MYD88 L265P-mutant ABC DLBCL in our cohort. Conclusions: This study highlights the relative heterogeneity of MYD88 -mutant DLBCL, adding to the field's knowledge of the theranostic importance of MYD88 mutations, but also of associated alterations, emphasizing the usefulness of genomic profiling to best stratify patients for targeted therapy. Clin Cancer Res; 23(9); 2232-44. ©2016 AACR ., (©2016 American Association for Cancer Research.)

Extensive research has demonstrated that dysregulation of costimulatory molecule expression plays a pivotal role in cancer biology. However, the impact of intratumoral CD70 on the initiation, progression, and immune response in diffuse large B-cell lymphoma (DLBCL) remains poorly understood. This study aims to elucidate the clinical significance of CD70 in DLBCL diagnosis and prognosis, as well as its relationship with the immune microenvironment. We first analyzed CD70 expression across various cancers, including DLBCL, using multiple online databases (TIMER, GEPIA, GENT2, TNMPlot, GSCA, and GEO). We then evaluated the clinical correlations and prognostic value of CD70 in DLBCL. Additionally, we investigated the functional role of CD70 in DLBCL cells. Genomic alterations of CD70 were analyzed using the cBioPortal online tool. Co-expression network analysis was performed to assess the biological functions associated with CD70. Furthermore, we utilized TIMER2.0 to examine the correlation between CD70 expression and immune cell infiltration. Our results revealed that CD70 expression was significantly upregulated in DLBCL tissues compared to matched normal tissues, and high CD70 expression was associated with poor clinical outcomes in DLBCL patients. In vitro experiments demonstrated that CD70 inhibition promotes apoptosis and induces G1 phase arrest in DLBCL cells. Genomic alteration analysis showed that patients with CD70 alterations exhibited worse overall survival compared to those without such alterations. Co-expression and functional enrichment analyses indicated that CD70 is functionally related to tumor necrosis factor receptor binding and the NF-κB signaling pathway. Moreover, we found that CD70 expression levels were negatively correlated with B cell and NK cell infiltration in DLBCL. In conclusion, this study suggests that CD70 is a potential diagnostic and therapeutic biomarker for DLBCL. Our findings provide valuable insights for the development of novel therapeutic strategies targeting CD70 in DLBCL treatment. [ABSTRACT FROM AUTHOR]

Diffuse large B-cell lymphoma (DLBCL) is characterized by high molecular and clinical heterogeneity. Autophagy, a lysosome-driven catabolic process devoted to macromolecular turnover, is fundamental in maintaining normal hematopoietic stem cells and progenitors homeostasis, and its dysregulation plays a critical role in the initiation and progression of hematological malignancies. One main regulator of autophagy is BECLIN-1, which may interact alternatively with either BCL-2, thus allowing apoptosis, or PI3KC3, thus promoting autophagy. The altered expression of BCL2 and BECN1 correlates with lymphoma outcomes, but whether this is associated with dysregulated cross-talk between autophagy and apoptosis remains to be elucidated. Analysis of the TCGA database revealed that BCL2 and BECN1 mRNA expression were inversely correlated in DLBCL patients. In representative DLBCL cell lines exposed to doxorubicin, the cells highly expressing BCL-2 were resistant, while the ones highly expressing BECLIN-1 were sensitive, and this correlated with low and high autophagy flux, respectively. Venetoclax targeting of BCL-2 increased while the spautin-1-mediated inhibition of BECLIN-1-dependent autophagy reversed doxorubicin sensitivity in the former and in the latter, respectively. By interrogating the TCGA DLBCL dataset, we found that BCL2 and BECN1 acted as negative and positive prognostic markers for DLBCL, respectively. The differentially expressed gene analysis in the respective cohorts revealed that BCL2 positively correlated with oncogenic pathways (e.g., glucose transport, HIF1A signaling, JAK-STAT signaling, PI3K-AKT-mTOR pathway) and negatively correlated with autophagy-related transcripts, while BECN1 showed the opposite trend. Notably, patients with high BECN1 expression displayed longer survival. Our data reveal, for the first time, that the modulation of BECLIN-1-dependent autophagy influences the prognosis of DLBCL patients and provide a mechanistic explanation supporting the therapeutic use of drugs that, by stimulating autophagy, can sensitize lymphoma cells to chemotherapy. [ABSTRACT FROM AUTHOR]

Summary: Approximately 20%–50% of patients with large B‐cell lymphoma (LBCL) experience poor outcomes. We aimed to evaluate the combined prognostic value of circulating tumour DNA (ctDNA) and total metabolic tumour volume (TMTV) in LBCL. This observational single‐centre study included 112 newly diagnosed LBCL patients, receiving R‐CHOP/R‐CHOP‐like chemotherapies. CtDNA load was calculated following next‐generation sequencing of cell‐free DNA (cfDNA) using a targeted 40‐gene lymphopanel. TMTV was measured using a fully automated artificial intelligence‐based method for lymphoma lesion segmentation. CtDNA was detected in cfDNA samples from 95 patients with a median concentration of 3.15 log haploid genome equivalents per mL. TMTV measurements were available for 102 patients. The median TMTV was 501 mL. High ctDNA load (>3.57 log hGE/mL) or high TMTV (>200 mL) were associated with shorter 1‐year PFS (44% vs. 83%, p < 0.001 and 64% vs. 97%, p = 0.002, respectively). When combined, three prognostic groups were identified. The shortest PFS was observed when both TMTV and ctDNA load were high (p < 0.001). Even with a short follow up, combining ctDNA load with TMTV improved the risk stratification of patients with aggressive LBCL. In the near future, very high‐risk patients could benefit from CAR T‐cell therapy or bispecific antibodies as first‐line treatments. [ABSTRACT FROM AUTHOR]

Multiple myeloma (MM) is an incurable hematological cancer with high spatial- and temporal-heterogeneity. Invasive single-point bone marrow sampling cannot capture the tumor heterogeneity and is difficult to repeat for serial assessments. Liquid biopsy is a technique for identifying and analyzing circulating MM cells and cell products produced by tumors and released into the circulation, allowing for the minimally invasive and comprehensive detection of disease burden and molecular alterations in MM and monitoring treatment response and disease progression. Furthermore, liquid biopsy can provide complementary information to conventional detection approaches and improve their prognostic values. This article reviewed the technologies and applications of liquid biopsy in MM. [ABSTRACT FROM AUTHOR]

Hyaluronic acid (HA) is a significant glycosaminoglycan component of the extracellular matrix, playing an essential role in cell localization and proliferation. However, high levels of HA may also correlate with multidrug resistance of tumor cells, an increased tendency to metastasize, or cancer progression, and thus represent a very unfavorable prognosis for cancer patients. The purpose of this review article is to summarize the results of studies describing the relationship between HA, the main ligand of the CD44 receptor, or other components of the HA signaling pathway. In addition, we review the course of selected female malignancies, i.e., breast, cervical, endometrial, and ovarian cancer, with the main focus on the mechanisms oriented to CD44. We also analyze reports on the beneficial use of HA-containing preparations in adjuvant therapy among patients with these types of cancer. Data from the literature suggest that HA and its family members may be critical prognostic biomarkers of selected malignancies among women. Nevertheless, the results of the available studies are inconclusive, and the actual clinical significance of HA expression analysis is still quite enigmatic. In our opinion, the HA-CD44 signaling pathway should be an attractive target for future research related to targeted therapy in gynecological cancers. [ABSTRACT FROM AUTHOR]

Background: Characterization of gene mutation profiles can provide new treatment options for patients with diffuse large B-cell lymphoma (DLBCL). However, this method is challenged by the limited source of tissue specimens, especially those of DLBCL patients at advanced stages. Therefore, in the current study, we aimed to describe the gene mutation landscape of DLBCL using circulating tumor DNA (ctDNA) samples obtained from patients' blood samples, as well as to explore the relationship between ctDNA mutations and the prognosis and treatment response of patients with newly diagnosed DLBCL. Methods: A total of 169 newly diagnosed Chinese DLBCL patients were included in this study, among which 85 patients were divided into a training set and 84 were assigned into a validation set. The mutation profile of a 59-gene panel was analyzed by targeted next generation sequencing (NGS) of the patients' ctDNA samples. Differences in clinical factors between patients with and without ctDNA mutations were analyzed. In addition, we also explored gene mutation frequencies between GCB and non-GCB subtypes, and the relationship between gene mutation status, clinical factors, mean VAF (variant allele frequencies) and the patients' overall survival (OS) and progression-free survival (PFS). Results: ctDNA mutations were detected in 64 (75.3%) patients of the training set and 67 (79.8%) patients of the validation set. The most commonly mutated genes in both sets were PCLO, PIM1, MYD88, TP53, KMT2D, CD79B, HIST1H1E and LRP1B, with mutation frequencies of >10%. Patients with detectable ctDNA mutations trended to present advanced Ann Arbor stages (III-IV), elevated LDH (lactate dehydrogenase) levels, shorter OS and PFS, and a lower complete response (CR) rate to the R-CHOP regimen compared with DLBCL patients without ctDNA mutations. In addition, mean VAF (≤4.94%) and PCLO mutations were associated with poor OS and PFS. Conclusion: We investigated the ctDNA mutation landscape in Chinese patients with newly diagnosed DLBCL and found that ctDNA could reflect tumor burden and patients with detectable ctDNA mutations trended to have shorter OS and PFS and a lower CR rate. [ABSTRACT FROM AUTHOR]

Diffuse large B‐cell lymphoma (DLBCL) is the most common lymphoma subtype, accounting for 30–40% of lymphoma diagnoses. Although aggressive, cure is achievable in approximately 60% of cases with primary chemoimmunotherapy, and in a further substantial minority by salvage therapy and autologous stem cell transplantation. Despite promising activity in early phase clinical trials, no intensified or novel treatment regimen has improved outcomes over R‐CHOP21 in randomised studies. However, there remain several areas of controversy including the most appropriate prognostic markers, central nervous system prophylaxis and the optimal treatment for patients with high‐risk disease. This position statement presents an evidence‐based synthesis of the literature for application in Australasian practice. [ABSTRACT FROM AUTHOR]

Circulating cell-free DNA (cfDNA) detection, a non-invasive method, appears promising for genetic analyses as well as quantitative assessment of tumor burden in patients with cancer. Although the analysis of cfDNA for clinical prognosis and monitoring disease burden in multiple myeloma (MM) has been recently studied, the results are unclear. In this meta-analysis, we explored the clinical significance of circulating cfDNA detection in patients with MM. We searched PubMed, Embase, and the Cochrane Library for eligible studies published up until July 25, 2021. Diagnostic accuracy variables were calculated and analyzed using Meta-Disc, and prognostic data were analyzed using Review Manager. Overall, seven studies comprising 235 myeloma patients met our inclusion criteria. The overall sensitivity and specificity of cfDNA to detect minimal residual disease (MRD) were 0.58 and 0.91, respectively. Moreover, higher levels of cfDNA were associated with worse progression-free survival as well as with poor overall survival. Our meta-analysis revealed that ctDNA detection has an obvious advantage in terms of MRD detection specificity, but it showed no superiority over bone marrow assessment in terms of MRD detection sensitivity, and higher levels of cfDNA were indicative of worse prognosis in patients with MM. cfDNA detection is a non-invasive method and thus shows promise as a good alternative to BM biopsies for monitoring clonal evolution and tumor burden so as to guide the treatment of patients with MM. [ABSTRACT FROM AUTHOR]

Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous entity, and cell surface cluster of differentiation (CD) 5 expression may represent a distinct subset. Here, we provide a narrative review of CD5+ DLBCL to understand its clinical implications. Between 5–10% of DLBCL express CD5, making it an uncommon subset. Studies have variably shown that CD5+ DLBCL may be associated with increased age, high lactate dehydrogenase, B symptoms, extra-nodal sites, higher International Prognostic Index score, and advanced stage. CD5+ DLBCLs are more likely to express Bcl-2, MYC, and MUM1; a large proportion exhibit an activated B-cell (ABC)-like phenotype. The balance of studies generally supports an independent prognostic value of CD5 in DLBCL While more aggressive first-line regimens have been advocated for CD5+ DLBCL, including dose-adjusted R-EPOCH and autologous stem cell transplant, evidence to support these approaches is lacking; further study is warranted to identify the optimal treatment strategy for this disease entity. [ABSTRACT FROM AUTHOR]

Background: Mounting studies have sought to identify novel mutation biomarkers having diagnostic and prognostic potentials. Nevertheless, the understanding of the mutated pathways related to development and prognosis of B-cell lymphoma is still lacking. We aimed to comprehensively analyze the mutation alterations in genes of canonical signaling pathways and their impacts on the clinic outcomes of patients with B-cell lymphoma. Methods: Circulating cell-free DNA (cfDNA) samples from 79 patients with B-cell lymphomas were used for targeted sequencing with a 560-gene panel for depicting mutation landscapes and identifying gene fusion events. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) functional enrichment analyses of mutated genes were performed. The associations of mutation status of genes and seven canonical oncogenic pathways with progression-free survival (PFS) were assessed using Kaplan-Meier test and multivariate Cox analysis. The variant allele frequencies (VAFs) of genes in TP53 and Hippo pathways in paired baseline and post-treatment samples from 18 B-cell lymphoma patients were compared. Finally, the associations of identified fusion genes, mutated genes, and pathways with treatment response were evaluated based on objective response rates (ORRs) comparisons of groups. Results: We identified 666 mutations from 262 genes in baseline cfDNAs from 79 B-cell lymphoma patients, and found some genes were preferentially mutated in our cohort such as GNAQ , GNAS , H3F3A , DNMT3A , HLA-A , and HLA-B. These frequently mutated genes were significantly associated with negative "regulation of gene expression, epigenetic" and virus infections such as cytomegalovirus, Epstein-Barr virus, human immunodeficiency virus 1 infections. We detected five fusion genes in at least two patients with B-cell lymphoma, and among them, TCF7L2 _ WT1 gene fusion was most frequently detected in 30.4% of patients (24 of 79 cases). SEPT6 _ TRIM33 gene fusion, mutated TP53 and Hippo pathways were significantly associated with poor PFS, and SEPT6 _ TRIM33 fusion gene and mutated TP53 pathway were independent prognostic factors for B-cell lymphoma. A decreased VAF of TP53 p.Y88C and LATS2 p.F972L was detected in patients with complete response to treatments. Moreover, a significant difference in ORR was observed in patients with NPM1_NR4A3 and SEPT6_TRIM33 fusions. Conclusions: SEPT6 _ TRIM33 gene fusion and mutated TP53 and Hippo pathways may serve as prognostic makers for B-cell lymphoma patients. [ABSTRACT FROM AUTHOR]

Keywords: mantle cell lymphoma; quadruple hits lymphoma; cytogenetic; diagnosis EN mantle cell lymphoma quadruple hits lymphoma cytogenetic diagnosis 634 637 4 11/18/21 20211115 NES 211115 B-cell lymphomas that concurrently carry I MYC i , I BCL2 i and/or I BCL6 i gene rearrangements - so-called double-hit or triple-hit lymphomas - are rare entities associated with poor prognosis. FISH study showed MYC/IGH (J), CCND1/IGH (K), BCL2/IGH (L), and BCL6 (M) gene translocations. Quadruple-hit pleomorphic mantle cell lymphoma with MYC, BCL2, BCL6, and CCND1 gene rearrangements The lymphoma cells have pleomorphic morphology (A) and express CD20 (B), BCL2 (C), BCL6 (D), cyclin D1 (E), MYC (F), CD21 (G), P53 (H), and with a high Ki67 proliferation rate (I). [Extracted from the article]

Diffuse malignant mesothelioma of the pleura (MPM) is a highly aggressive tumour that typically is associated with short survival. CD70 and CD27 belong to the tumour necrosis factor (TNF) and the TNF receptor (TNFR) superfamily, respectively. Under physiological conditions, the tightly regulated interaction between CD70 and CD27 plays a co‐stimulatory role in promoting T‐cell expansion and differentiation through the NFκB pathway. Aberrantly high CD70 expression has been documented in haematological and solid malignancies in association with immune evasion in malignant cells. In this study, 172 well‐characterised primary diffuse MPM tumours including epithelioid (n = 145), biphasic (n = 15), and sarcomatoid (n = 12) histotypes were evaluated immunohistochemically for CD70, CD27, CD3, CD4, CD8, CD56, PDCD1 (PD‐1), and FOXP3 expression. Twenty per cent (34/172) of the mesothelioma cells expressed CD70 on the cell membrane. Overall survival was significantly decreased in the cohort of patients with CD70‐expressing tumour cells (p < 0.01). Patients with MPM containing a higher number of CD3+ (p < 0.01), CD4+ (p < 0.01), CD8+ (p < 0.01), or FOXP3+ (p < 0.01) tumour‐infiltrating lymphoid cells (TILs) showed significantly worse clinical outcomes. As potential independent risk factors for MPM patients, multivariate Cox proportional hazards regression analysis revealed CD70 expression on mesothelioma cells [hazard ratio (HR) 2.25; p = 0.010], higher FOXP3+ TILs (HR 2.81; p = 0.004), and higher CD3+ TIL accumulation (HR 6.12; p < 0.001). In contrast, as a potential independent favourable factor, higher CD27+ TIL accumulation (HR 0.48; p = 0.037) was identified. In vitro experiments and an immunodeficient mouse model revealed that CD70 enhances the invasiveness of MPM cells through MET–ERK axis activation. Further analyses in syngeneic mouse models demonstrated possible roles for CD70 in immune evasion. Collectively, these findings suggest that the CD70–CD27 pathway enhances the malignant phenotypes of MPM and diminishes anti‐tumor immune response in patients with these neoplasms. These markers might be useful in MPM for prognostic evaluations as well as targeted therapeutics. © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Background: Chronic Lymphocytic Leukemia (CLL) is the most frequent lymphoproliferative disorder in western countries and is characterized by a remarkable clinical heterogeneity. During the last decade, multiple genomic studies have identified a myriad of somatic events driving CLL proliferation and aggressivity. Nevertheless, and despite the mounting evidence of inherited risk for CLL development, the existence of germline variants associated with clinical outcomes has not been addressed in depth.Methods: Exome sequencing data from control leukocytes of CLL patients involved in the International Cancer Genome Consortium (ICGC) was used for genotyping. Cox regression was used to detect variants associated with clinical outcomes. Gene and pathways level associations were also calculated.Results: Single nucleotide polymorphisms in PPP4R2 and MAP3K4 were associated with earlier treatment need. A gene-level analysis evidenced a significant association of RIPK3 with both treatment need and survival. Furthermore, germline variability in pathways such as apoptosis, cell-cycle, pentose phosphate, GNα13 and Nitric oxide was associated with overall survival.Conclusion: Our results support the existence of inherited conditionants of CLL evolution and points towards genes and pathways that may results useful as biomarkers of disease outcome. More research is needed to validate these findings. [ABSTRACT FROM AUTHOR]

Summary: Hodgkin Lymphoma (HL) is an unusual B‐cell lymphoma because the malignant cells exist as a minority population in a densely cellular microenvironment. The microenvironment is comprised predominately of inflammatory and immune cells with fibrosis in some cases. There are multiple dysregulated signalling pathways that sustain HL within this microenvironment, such as the Nuclear factor‐κB and Janus kinase/signal transducers and activators of transcription pathways. Advances in genomic medicine have enabled a better characterisation of the rare tumour cells and improved our understanding of the signalling mechanisms that exist between the malignant cell and its microenvironment. Current therapy for HL produces excellent clinical outcomes in most younger patients. However, problems with current treatment approaches include poorer outcomes in the elderly, toxicity of highly‐effective combination chemotherapy regimens and relapse in high‐risk patients. Better understanding of disease biology aids in upfront prognostication of patients, defines new methods for treatment monitoring and assists in the recognition of novel targets for therapy. Biology‐driven therapies, including anti‐CD30 antibody conjugates, cellular immunotherapies and immune modulation, particularly with checkpoint inhibitors, have changed treatment algorithms for relapsed/refractory patients. Future challenges exist in incorporating immune‐based therapies earlier in treatment algorithms to reduce toxicity and prevent relapse for patients with HL. [ABSTRACT FROM AUTHOR]

Emerging biologic subsets and new prognostic markers are significantly and adversely affecting curability after standard chemoimmunotherapy for aggressive B-cell lymphomas. The identification of concurrent MYC and B-cell CLL/lymphoma 2 (BCL2) deregulation, whether at a genomic or protein level, has opened a new era of investigation within the most common subtype of aggressive B-cell lymphomas. Double-hit lymphoma (DHL), defined as a dual rearrangement of MYC and BCL2 and/or B-cell CLL/lymphoma 6 (BCL6) genes, is an uncommon subset accounting for 5% to 7% of all diffuse large B-cell lymphomas (DLBCLs), and long-term survivors are rare. Double-expressor lymphoma (DEL), defined as overexpression of MYC and BCL2 proteins not related to underlying chromosomal rearrangements, is not a distinct entity in the current World Health Organization classification but accounts for 20% to 30% of DLBCL cases and also has poor outcomes. There are many practical considerations related to identifying, determining the prognosis of, and managing DHL and DEL. [ABSTRACT FROM AUTHOR]

Keywords: primary cutaneous B-cell lymphomas; work-up; computerized tomography; positron emission tomography; bone marrow biopsy EN primary cutaneous B-cell lymphomas work-up computerized tomography positron emission tomography bone marrow biopsy 1 3 3 06/26/20 20200623 NES 200623 Primary cutaneous lymphomas (PCLs) are a heterogeneous group of extranodal non-Hodgkin lymphomas, limited to the skin, with no evidence of extracutaneous disease at the time of diagnosis. In particular, rearrangements of the MYC gene detected by FISH are present in a considerable percentage of patients with PCLCL-LT (32%) and patients exhibiting MYC rearrangement showed an inferior disease-specific survival and disease-free survival ([5]). Moreover, PCFCL patients with a positive bone marrow had a significantly worse prognosis when compared with patients without bone marrow involvement (5-year disease specific survival 63 vs. 95%). [Extracted from the article]

Purpose This study evaluated the predictive significance of total metabolic tumour volume (TMTV) measured on baseline FDG PET/CT and its value in addition to gene expression profiling using a new method of gene analysis (rapid reverse transcriptase multiplex ligation-dependent probe amplification assay, RT-MLPA) in patients with diffuse large B-cell lymphoma treated with R-CHOP or R-CHOP-like chemotherapies. Methods The analysis included 114 patients. TMTV was measured using a 41% SUVmax threshold and tumours were classified into GCB or ABC subtypes according to the RT-MLPA assay. Results The median follow-up was 40 months. the 5-year progression-free survival (PFS) was 54% and the 5-year overall survival (OS) was 62%. The optimal TMTV cut-off value was 261 cm³. In 59 patients with a high TMTV the 5-year PFS and OS were 37% and 39%, respectively, in comparison with 72% and 83%, respectively, in 55 patients with a low TMTV (p = 0.0002 for PFS, p < 0.0001 for OS). ABC status was significantly associated with a worse prognosis. TMTV combined with molecular data identified three groups with very different outcomes: (1) patients with a low TMTV whatever their phenotype (n = 55), (2) patients with a high TMTV and GCB phenotype (n = 33), and (3) patients with a high TMTV and ABC phenotype (n = 26). In the three groups, 5-year PFS rates were 72%, 51% and 17% (p < 0.0001), and 5-year OS rates were 83%, 55% and 17% (p < 0.0001), respectively. In multivariate analysis, TMTV, ABC/GCB phenotype and International Prognostic Index were independent predictive factors for both PFS and OS (p < 0.05 for both). Conclusions This integrated risk model could lead to more accurate selection of patients that would allow better individualization of therapy. [ABSTRACT FROM AUTHOR]

Background: The International Prognostic Index (IPI) scoring system is the most widely used prognostic tool for diffuse large B-cell lymphoma (DLBCL); however, it fails to consistently identify patients with poor outcomes. This retrospective study was undertaken to confirm the clinical value of a new prognostic score and compare it with the IPI. Methods: The aim of this single-center study was to confirm the clinical value of a new prognostic score and its association with various clinical features, disease progression, and death in 70 patients with DLBCL who had undergone at least 6 cycles of chemotherapy. Results: The IPI and the new prognostic index were both associated with 3-year mortality (p ≤ 0.032); however, only the new prognostic index was associated with 3-year progression (p ≤ 0.036). Multivariate analysis showed that the new prognostic index was associated with 3-year progression but not overall survival. The new prognostic score also distinguished 3-year progression-free survival and overall survival in the low- and low-intermediate-risk groups as well as in the low-intermediate- and high-intermediate-risk groups. Conclusions: The new prognostic score represents a comprehensive prognostic model superior to the IPI. Prospective studies are necessary to explore whether treatment strategies may be adjusted using this new prognostic score. [ABSTRACT FROM AUTHOR]

With the introduction of next-generation sequencing, the genetic landscape of the complex group of B-cell lymphoid malignancies has rapidly been unravelled in recent years. This has provided important information about recurrent genetic events and identified key pathways deregulated in each lymphoma subtype. In parallel, there has been intense search and development of novel types of targeted therapy that 'hit' central mechanisms in lymphoma pathobiology, such as BTK, PI3K or BCL2 inhibitors. In this review, we will outline the current view of the genetic landscape of selected entities: follicular lymphoma, diffuse large B-cell lymphoma, mantle cell lymphoma, chronic lymphocytic leukaemia and marginal zone lymphoma. We will detail recurrent alterations affecting important signalling pathways, that is the B-cell receptor/NF-κB pathway, NOTCH signalling, JAK-STAT signalling, p53/DNA damage response, apoptosis and cell cycle regulation, as well as other perhaps unexpected cellular processes, such as immune regulation, cell migration, epigenetic regulation and RNA processing. Whilst many of these pathways/processes are commonly altered in different lymphoid tumors, albeit at varying frequencies, others are preferentially targeted in selected B-cell malignancies. Some of these genetic lesions are either involved in disease ontogeny or linked to the evolution of each disease and/or specific clinicobiological features, and some of them have been demonstrated to have prognostic and even predictive impact. Future work is especially needed to understand the therapy-resistant disease, particularly in patients treated with targeted therapy, and to identify novel targets and therapeutic strategies in order to realize true precision medicine in this clinically heterogeneous patient group. [ABSTRACT FROM AUTHOR]

Background: Studies on the serum concentration of hyaluronic acid (HA) in newly diagnosed patients with acute myeloid leukemia (AML), B-acute lymphoblastic leukemia (BALL), and mantle-cell lymphoma (MCL) are scarce. In this study, we focused on investigating whether HA could serve as a possible prognostic marker in patients with AML, B-ALL, and MCL. Methods: The serum concentration of HA was measured in a total of 51 patients with newly diagnosed AML, B-ALL, and MCL. Venous blood was collected 1 day before the initiation of chemotherapy (D0), on day 16 of the first cycle of chemotherapy (D16), and on D30. Results: The serum HA concentration on D0 in patients with AML, B-ALL, and MCL was higher than in the control group. For all types of hematological malignancy, on D0, serum HA values of nonsurvivors were higher than in survivors. Moreover, patients in relapse had higher levels of serum HA than patients in remission. A strong positive correlation between serum HA and ferritin, â 2-microglobulin, and lactate dehydroge-nase was found. Conclusion: Serum HA may serve as a possible prognostic marker for AML, B-ALL, and MCL patients, especially on D0. Prospective case-control studies on larger populations may provide further information. [ABSTRACT FROM AUTHOR]

Low molecular weight hyaluronan (LMW-HA), a degradation fragment of the extracellular matrix component hyaluronan (HA), has been proven to play a crucial role in cancer progression. However, no systematic clinical study of breast cancer has been performed to correlate LMW-HA levels with metastasis. In the present study, we analyzed 176 serum specimens and found for the first time that the serum LMW-HA (but not total HA) level significantly correlated with lymph node metastasis, suggesting that serum LMW-HA represents a better prognostic indicator of breast cancer progression than HA. Similarly, we found that breast cancer cell lines displaying higher invasive potential had a higher LMW-HA concentration than less-invasive cell lines. This higher LMW-HA level was accompanied by the overexpression of hyaluronan synthase (HAS2) and hyaluronidase (both HYAL1 and HYAL2). Of great importance, decreasing LMW-HA production significantly inhibited breast cancer cell migration and invasion. Overall, our results suggest that during cancer progression, cancer cells may actively remodel their microenvironment via an autocrine/paracrine-like process, resulting in elevated LMW-HA levels, which in turn may facilitate cancer progression by promoting the migration and invasion of cancer cells. Therefore, cancer-associated LMW-HA may be a more promising molecular biomarker than total HA for detecting metastasis and may have further applications in breast cancer treatment [ABSTRACT FROM AUTHOR]

Background The main cause of death of breast cancer patients is not the primary tumor itself but the metastatic disease. Identifying breast cancer-specific signatures for metastasis and learning more about the nature of the genes involved in the metastatic process would 1) improve our understanding of the mechanisms of cancer progression and 2) reveal new therapeutic targets. Previous studies showed that the transcriptional regulator megakaryoblastic leukemia-1 (Mkl1) induces tenascin-C expression in normal and transformed mammary epithelial cells. Tenascin-C is known to be expressed in metastatic niches, is highly induced in cancer stroma and promotes breast cancer metastasis to the lung. Methods Using HC11 mammary epithelial cells overexpressing different Mkl1 constructs, we devised a subtractive transcript profiling screen to identify the mechanism by which Mkl1 induces a gene set co-regulated with tenascin-C. We performed computational analysis of the Mkl1 target genes and used cell biological experiments to confirm the effect of these gene products on cell behavior. To analyze whether this gene set is prognostic of accelerated cancer progression in human patients, we used the bioinformatics tool GOBO that allowed us to investigate a large breast tumor data set linked to patient data. Results We discovered a breast cancer-specific set of genes including tenascin-C, which is regulated by Mkl1 in a SAP domain-dependent, serum response factor-independent manner and is strongly implicated in cell proliferation, cell motility and cancer. Downregulation of this set of transcripts by overexpression of Mkl1 lacking the SAP domain inhibited cell growth and cell migration. Many of these genes are direct Mkl1 targets since their promoter-reporter constructs were induced by Mkl1 in a SAP domain-dependent manner. Transcripts, most strongly reduced in the absence of the SAP domain were mechanoresponsive. Finally, expression of this gene set is associated with high-proliferative poor-outcome classes in human breast cancer and a strongly reduced survival rate for patients independent of tumor grade. Conclusions This study highlights a crucial role for the transcriptional regulator Mkl1 and its SAP domain during breast cancer progression. We identified a novel gene set that correlates with bad prognosis and thus may help in deciding the rigor of therapy. [ABSTRACT FROM AUTHOR]

Summary The PRDM16 (1p36) gene is rearranged in acute myeloid leukaemia (AML) and myelodysplastic syndrome (MDS) with t(1;3)(p36;q21), sharing characteristics with AML and MDS with MECOM (3q26.2) translocations. We used fluorescence in situ hybridization to study 39 haematological malignancies with translocations involving PRDM16 to assess the precise breakpoint on 1p36 and the identity of the partner locus. Reverse-transcription polymerase chain reaction (PCR) was performed in selected cases in order to confirm the partner locus. PRDM16 expression studies were performed on bone marrow samples of patients, normal controls and CD34+ cells using TaqMan real-time quantitative PCR. PRDM16 was rearranged with the RPN1 (3q21) locus in 30 cases and with other loci in nine cases. The diagnosis was AML or MDS in most cases, except for two cases of lymphoid proliferation. We identified novel translocation partners of PRDM16, including the transcription factors ETV6 and IKZF1. Translocations involving PRDM16 lead to its overexpression irrespective of the consequence of the rearrangement (fusion gene or promoter swap). Survival data suggest that patients with AML/MDS and PRDM16 translocations have a poor prognosis despite a simple karyotype and a median age of 65 years. There seems to be an over-representation of late-onset therapy-related myeloid malignancies. [ABSTRACT FROM AUTHOR]

Lymphomas encompass a diverse group of malignant lymphoid neoplasms. Over recent years much scientific effort has been undertaken to identify and understand molecular changes in lymphomas, resulting in a wide range of genetic alterations that have been reported across all types of lymphomas. As many of these changes are now incorporated into the World Health Organization's defined criteria for the diagnostic evaluation of patients with lymphoid neoplasms, their accurate identification is crucial. Even if many alterations are not routinely evaluated in daily clinical practice, they may still have implications in risk stratification, treatment, prognosis or disease monitoring. Moreover, some alterations can be used for targeted treatment. Therefore, these advances in lymphoma molecular diagnostics in some cases have led to changes in treatment algorithms. Here, we give an overview of and discuss advances in molecular techniques in current clinical practice, as well as highlight some of them in a clinical context. [ABSTRACT FROM AUTHOR]

Simple Summary: CYCLON is a nuclear protein, which has been associated with disease progression and treatment resistance in DLBCL, the most common form of aggressive B-cell lymphoma, but also represents a predictive factor of refractory disease and relapse for immuno-chemotherapy-treated DLBCL patients. The molecular mechanisms related to this unstructured protein remain largely uncharacterized. Here, we performed a mass-spectrometry-based identification of the CYCLON protein interactome that suggested it could exert nucleolar functions related to cell proliferation. Among the CYCLON oncogenic network, we performed an immunohistochemical evaluation of the multi-functional nucleolar protein NPM1 in a DLBCL cohort and showed that CYCLON/NPM1 concomitant expression delineates a poor prognosis subgroup of patients. Multivariate survival analyses demonstrated that specific sub-cellular localizations of CYCLON and NPM1 represent independent novel predictors specifically associated with refractory DLBCL. R-CHOP immuno-chemotherapy significantly improved clinical management of diffuse large B-cell lymphoma (DLBCL). However, 30–40% of DLBCL patients still present a refractory disease or relapse. Most of the prognostic markers identified to date fail to accurately stratify high-risk DLBCL patients. We have previously shown that the nuclear protein CYCLON is associated with DLBCL disease progression and resistance to anti-CD20 immunotherapy in preclinical models. We also recently reported that it also represents a potent predictor of refractory disease and relapse in a retrospective DLBCL cohort. However, only sparse data are available to predict the potential biological role of CYCLON and how it might exert its adverse effects on lymphoma cells. Here, we characterized the protein interaction network of CYCLON, connecting this protein to the nucleolus, RNA processing, MYC signaling and cell cycle progression. Among this network, NPM1, a nucleolar multi-functional protein frequently deregulated in cancer, emerged as another potential target related to treatment resistance in DLBCL. Immunohistochemistry evaluation of CYCLON and NPM1 revealed that their co-expression is strongly related to inferior prognosis in DLBCL. More specifically, alternative sub-cellular localizations of the proteins (extra-nucleolar CYCLON and pan-cellular NPM1) represent independent predictive factors specifically associated to R-CHOP refractory DLBCL patients, which could allow them to be orientated towards risk-adapted or novel targeted therapies. [ABSTRACT FROM AUTHOR]

Background: DLBCL represent a heterogeneous group of aggressive diseases. High grade B-cell lymphomas (HGBCL) were recently individualized from DLBCL as a discrete diagnostic entity due to their worse prognosis. Currently, although most patients are successfully treated with RCHOP regimens, 1/3 will either not respond or ultimately relapse. Alterations in histone modifying enzymes have emerged as the most common alterations in DLBCL, but their role as prognostic biomarkers is controversial. We aimed to ascertain the prognostic value of EZH2 immunoexpression in RCHOP-treated DLBCL and HGBCL. Results: We performed a retrospective cohort study including 125 patients with RCHOP-treated DLBCL or HGBCL. EZH2 expression levels did not differ between diagnostic groups or between DLBCL-NOS molecular groups. We found no associations between EZH2 expression levels and outcome, including in the subgroup analysis (GC versus non-GC). Nonetheless, EZH2/BCL2 co-expression was significantly associated with worse outcome (event free survival and overall survival). Conclusion: Although EZH2 mutations are almost exclusively found in GC-DLBCL, we found similar EZH2 expression levels in both DLBCL-NOS molecular groups, suggesting non-mutational mechanisms of EZH2 deregulation. These findings suggest that the use of EZH2 antagonists might be extended to non-GC DLBCL patients with clinical benefit. EZH2/BCL2 co-expression was associated with a worse outcome. [ABSTRACT FROM AUTHOR]

B-cell lymphomas/leukemias with simultaneous t(14;18)(q32;q21) and MYC rearrangements have recently been shown to constitute a separate diagnostic entity, presenting with a rapid clinical course and a very poor prognosis. We describe the establishment of an Epstein–Barr virus negative cell line, designated U-2973, from a male patient with a de novo aggressive B-cell lymphoma/leukemia and very high peripheral blast cell count. Flow cytometry of bone marrow cells and U-2973 displayed a mature B-cell phenotype, and immunostaining showed expression of MYC and BCL2. IG gene rearrangement data were consistent with a lymphoid neoplasm of germinal centre derivation. Cytogenetic studies using conventional G-banding, fluorescent in situ hybridization, spectral karyotyping and single nucleotide polymorphism array demonstrated a complex karyotype with both a t(14;18) and double translocations between MYC and a non- IG gene partner located at chromosome 12p12.1. [ABSTRACT FROM AUTHOR]

Follicular lymphoma (FL) is a common subtype of low grade B-cell non-Hodgkin lymphoma (NHL). Although this form of lymphoma often pursues an indolent course, in some cases it may behave in a more aggressive manner. Clinical and histological parameters have been shown to correlate with an adverse prognosis but a number of cytogenetic abnormalities may also be associated with aggressive disease. Although, the t(14;18) in itself does not affect outcome in cases of FL, secondary abnormalities that occur in a complex polyploid karyotype may identify cases with a poor prognosis. It is unusual to find both t(14;18) and C-MYC translocation in the same tumour; those cases in which it has been described include examples of high-grade B-cell NHL (either de novo or transformed FL) or B-cell acute lymphoblastic lymphoma. In this report, three cases of FL are described in which both t(14;18) and a C-MYC translocation were identified at presentation. We also summarize four further cases from the literature. This is a small series but one which raises the possibility that the presence of a C-MYC translocations at presentation may identify a particularly aggressive subtype of FL. Further studies are required to investigate the true incidence of this aberration, the impact on C-MYC regulation, clinical course and response to treatment. [ABSTRACT FROM AUTHOR]

Malignant mesothelioma is a rare malignancy of the body cavities with dismal prognosis. It has been a diagnostic dilemma for years with many clinical and pathological mimics. Discovery of a reliable tumour marker will definitely be of value in screening individuals with a history of asbestos exposure, diagnosis, treatment and follow up of malignant mesothelioma. Many tumour markers have been studied and speculatively associated with the malignant mesothelioma, but much still needs to be proven. [ABSTRACT FROM AUTHOR]

The serum levels of hyaluronic acid (sHA) were measured using an affinoimmunoenzymatic assay in patients with distal (n = 16) and proximal (n = 15) progressive systemic sclerosis (PSS) and in 31 controls. The severity of PSS was evaluated using a standardized organ-involvement score. The mean sHA was significantly higher in the patients with PSS than in controls (means ±SD: 80±43.4 μg/1 vs. 42.3±19.1 μg/1, P <0.001). sHA was significantly higher in patients with proximal PSS than in patients with distal PSS (106.4±44.6 μg/1 vs. 55.4±23.8 μg/1, P <0.001). A positive correlation was found between sHA and the disease score (r=0.67, P <0.001). sHA was also correlated with lung diffusion capacity for carbon monoxide (r=0.70, P <0.001), but only in those patients who had abnormal lung function, and therefore presumably had lung PSS involvement. We suggest that sHA could be an indicator of the degree of systemic involvement in PSS. Its prognostic value and possible use in the follow up of patients with PSS remain to be clarified. [ABSTRACT FROM AUTHOR]

The metabolic tumour volume (MTV) is an independent prognostic indicator in diffuse large B-cell lymphoma (DLBCL). However, its measurement is not standardised and is subject to wide variations depending on the method used. This study aimed to compare the reproducibility of MTV measurement as well as the thresholds obtained for each method and their prognostic values. The baseline MTV was measured in 239 consecutive patients treated at Henri Becquerel Centre by two blinded evaluators. Eight methods were compared: 3 absolute (SUV (standardised uptake value) ≥ 2.5; SUV≥ liver SUVmax; SUV≥ PERCIST SUV), 1 percentage SUV threshold method (SUV ≥ 41% SUVmax) and 4 adaptive methods (Daisne, Nestle, Fitting, Black). The intraclass correlation coefficients were excellent, from 0.91 to 0.96, for the absolute SUV methods, Black and Nestle methods, and good for 41% SUVmax, Fitting and Daisne methods (0.82 to 0.88), with a significantly lower variability with absolute methods compared to 41% SUVmax (p < 0.04). Thresholds were found to be specific to each segmentation method and ranged from 295 to 552 cm3. There was a strong correlation between the MTV and patient prognosis regardless of the segmentation method used (p = 0.001 for PFS and OS). The largest inter-observer cut-off variability was observed in the 41% SUVmax method, which resulted in more inter-observer disagreements in the classification of patients between high and low MTV groups. MTV measurements based on absolute SUV criteria were found to be significantly more reproducible than those based on 41% SUVmax criteria. The threshold was specific for each of eight segmentation methods, but all predicted prognosis. [ABSTRACT FROM AUTHOR]

Background: Recently, copy number alteration (CNA) of 9p24.1 were demonstrated in 10% of diffuse large b-cell lymphoma (DLBCL), with gene expression and mutation profiles that were similar to those of primary mediastinal large B-cell lymphoma (PMBCL). However, their CNA-based profile and clinical impact still remain unclear.Methods: Multiplex ligation-dependent probe amplification were employed to investigate the prevalence of JAK2/PD-L2 amplification in DLBCL and their CNA-based pattern of driver genes. The clinical outcome and characteristics were also analyzed.Results: Using unsupervised hierarchical clustering, a small group of DLBCL (10.5%, 8/76) was clustered together with PMBCL as Cluster_2, demonstrating amplification of JAK2 (100%,8/8) and PD-L2 (75.0%,6/8). This subgroups of DLBCL demonstrated significant higher expression of PD-L1 than those with MYD88 L265P mutation(p = 0.024). And they exhibited dismal OS and PFS as compared with DLBCL_others(p = 0.003 and 0.001, respectively), which is similar to DLBCL with MYD88 L265P mutation.Conclusions: DLBCL with amplification of JAK2/PD-L2 exhibits CNA pattern that is similar to PMBCL, and demonstrates unfavorable clinical outcome that resembles those with MYD88 L265P mutation. It is essential to identify this subgroup of DLBCL who may acquire more benefits from the JAK2 and PD-L1 signaling inhibition. [ABSTRACT FROM AUTHOR]