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High-grade B-cell lymphoma with translocations involving MYC and BCL2 or BCL6, usually referred to as double hit lymphoma (DHL), is an aggressive hematological malignance with distinct genetic features and poor clinical prognosis. Current standard chemoimmunotherapy fails to confer satisfying outcomes and few targeted therapeutics are available for the treatment against DHL. Recently, the delineating of the genetic landscape in tumors has provided insight into both biology and targeted therapies. Therefore, it is essential to understand the altered signaling pathways of DHL to develop treatment strategies with better clinical benefits. Herein, we summarized the genetic alterations in the two DHL subtypes (DHL-BCL2 and DHL-BCL6). We further elucidate their implications on cellular processes, including anti-apoptosis, epigenetic regulations, B-cell receptor signaling, and immune escape. Ongoing and potential therapeutic strategies and targeted drugs steered by these alterations were reviewed accordingly. Based on these findings, we also discuss the therapeutic vulnerabilities that coincide with these genetic changes. We believe that the understanding of the DHL studies will provide insight into this disease and capacitate the finding of more effective treatment strategies. [ABSTRACT FROM AUTHOR]

Simple Summary: The peripheral nervous systems may be involved by several hematological diseases ranging from preneoplastic diseases to overt malignancies or paraneoplastic syndromes. In most cases, a monoclonal paraprotein plays a pivotal role in the damage of peripheral nervous systems through different mechanisms. For these reasons, the multidisciplinary approach between hematologist and neurologist is fundamental to correctly diagnose and treat monoclonal gammopathies of neurological significance. We reviewed the biologic, clinic and neurophysiological features, as well as tailored treatments of monoclonal gammopathies of neurological significance. Monoclonal gammopathy and peripheral neuropathy are common diseases of elderly patients, and almost 10% of patients with neuropathy of unknown cause have paraprotein. However, growing evidence suggests that several hematological malignancies synthesize and release monoclonal proteins that damage the peripheral nervous system through different mechanisms. The spectrum of the disease varies from mild to rapidly progressive symptoms, sometimes affecting not only sensory nerve fibers, but also motor and autonomic fibers. Therefore, a multidisciplinary approach, mainly between hematologists and neurologists, is recommended in order to establish the correct diagnosis of monoclonal gammopathy of neurological significance and to tailor therapy based on specific genetic mutations. In this review, we summarize the spectrum of monoclonal gammopathies of neurological significance, their distinctive clinical and neurophysiological phenotypes, the most relevant pathophysiological events and new therapeutic approaches. [ABSTRACT FROM AUTHOR]

Background: The clinical benefit of cusatuzumab, a CD70‐directed monoclonal antibody with enhanced effector functions, was investigated in patients with relapsed/refractory (R/R) cutaneous T‐cell lymphoma (CTCL). Methods: In this cohort expansion of the ARGX‐110‐1201 study, 27 patients with R/R CTCL received cusatuzumab at 1 (n = 11) or 5 mg/kg (n = 16) once every 3 weeks to investigate its safety, dose, and exploratory efficacy. The pharmacokinetics, immunogenicity, CD70 expression, and CD70/CD27 biology were also assessed. Results: The most common adverse events included infusion‐related reactions, pyrexia, and asthenia. Eighteen serious adverse events (grade 1‐3) were reported in 11 patients; 1 of these (vasculitis) was considered drug‐related. For 8 of the 11 patients receiving 1 mg/kg, anti‐drug antibodies (ADAs) affected the minimal concentration, and this resulted in undetectable cusatuzumab concentrations at the end of treatment and, in some cases, a loss of response. This effect was greatly reduced in the patients receiving 5 mg/kg. The overall response rate was 23%; this included 1 complete response and 5 partial responses (PRs) in 26 of the 27 evaluable patients. In addition, 9 patients achieved stable disease. The mean duration on cusatuzumab was 5.2 months, and the median duration was 2.5 months. Patients with Sézary syndrome (SS) achieved a 60% PR rate with a dosage of 5 mg/kg and a 33% PR rate with a dosage of 1 mg/kg; this resulted in an overall response rate of 50% for patients with SS at both doses. Conclusions: Cusatuzumab was well tolerated, and antitumor activity was observed at both 1 and 5 mg/kg in highly pretreated patients with R/R CTCL. The observed dose‐dependent effect on exposure supports the use of 5 mg/kg for future development. Cusatuzumab, a monoclonal antibody targeting CD70, is well tolerated and shows dose‐dependent evidence of antitumor activity in a heavily pretreated patient population with cutaneous T‐cell lymphoma. The overall response rate was 23% with increased efficacy in patients with Sézary syndrome, warranting further clinical development. [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]

The immune checkpoint molecule CD70 and its receptor CD27 are aberrantly expressed in many hematological and solid malignancies. Dysregulation of the CD70-CD27 axis within the tumor and its microenvironment is associated with tumor progression and immunosuppression. This is in contrast to physiological conditions, where tightly controlled expression of CD70 and CD27 plays a role in co-stimulation in immune responses. In hematological malignancies, cancer cells co-express CD70 and CD27 promoting stemness, proliferation and survival of malignancy. In solid tumors, only expression of CD70 is present on the tumor cells which can facilitate immune evasion through CD27 expression in the tumor microenvironment. The discovery of these tumor promoting and immunosuppressive effects of the CD70-CD27 axis has unfolded a novel target in the field of oncology, CD70. In this review, we thoroughly discuss current insights into expression patterns and the role of the CD70-CD27 axis in hematological and solid malignancies, its effect on the tumor microenvironment and (pre)clinical therapeutic strategies. [ABSTRACT FROM AUTHOR]

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Purpose of Review: Genomic analyses have immensely advanced our conception of the heterogeneity of diffuse large B cell lymphoma (DLBCL), resulting in subgroups with distinct molecular profiles. In this review, we summarize our current knowledge of the biology of DLBCL complexity and discuss the potential implications for precision medicine. Recent Findings: During the last two decades, gene expression profiling, copy number analysis, and high throughput sequencing enabled the identification of molecular subclasses of DLBCL that are biologically and clinically meaningful. The resulting classifications provided novel prospects of diagnosis, prognostication, and therapeutic strategies for this aggressive disease. Summary: The molecular characterization of DLBCL offers unprecedented insights into the biology of these lymphomas that can guide precision medicine. The knowledge of the molecular setup of an individual DLBCL patients enables prognostication of patients and will be useful to stratify patients in clinical trials. Future direction should focus to implement the molecular classifications of DLBCL in the clinical practice to evaluate their significance and scope using real-world data. [ABSTRACT FROM AUTHOR]

Nectins are immunoglobulin-like cell adhesion molecules constituting a family with four members, nectin-1, nectin-2, nectin-3, and nectin-4. In the brain, nectin-2 as well as nectin-1 and nectin-3 are expressed whereas nectin-4 is hardly expressed. In the nervous system, physiological functions of nectin-1 and nectin-3, such as synapse formation, mossy fiber trajectory regulation, interneurite affinity, contextual fear memory formation, and stress-related mental disorders, have been revealed. Nectin-2 is ubiquitously expressed in non-neuronal tissues and various nectin-2 functions in non-nervous systems have been extensively investigated, but nectin-2 functions in the brain have not been revealed until recently. Recent findings have revealed that nectin-2 is expressed in the specific areas of the brain and plays important roles, such as homeostasis of astrocytes and neurons and the formation of synapses. Moreover, a single nucleotide polymorphism in the human NECTIN2 gene is associated with Alzheimer's disease. We here summarize recent progress in our understanding of nectin-2 functions in the brain. [ABSTRACT FROM AUTHOR]

Opinion statement: Hairy cell leukemia variant (HCL-V) is a rare B cell lymphoproliferative disorder with a clinical-pathological distinction from the classic form of hairy cell leukemia (HCL-C). HCL-V is more aggressive in nature, has a higher tendency to be refractory to conventional purine analog pharmacotherapies, and leads to a poorer prognosis. Hence, these differing features bring paramount importance to the diagnosis and management of HCL-V. While there is no genetic mutation diagnostic of HCL-V, genetic profiling efforts have identified potential therapeutic targets (i.e., MAP2K1, KDM6A, CREBBP, ARID1A, CCND3, U2AF1, KMT2C) and yielded prognostic markers (i.e., IGHV4-34 rearrangements). To date, combination chemoimmunotherapies, such as cladribine and rituximab, have shown the best results in HCL-V. Future directions include targeted therapies such as moxetumomab pasudotox, ibrutinib, trametinib, and binimetinib and potentially anti-CD22 chimeric antigen receptor T cell therapy. The purpose of this review is to provide an outline of the diagnostic approach and an update on the therapeutic advancements in HCL-V. [ABSTRACT FROM AUTHOR]

MYC rearrangements (MYCr) occur in several B-cell neoplasms and impact disease progression and overall survival. We used whole genome sequencing (WGS) and whole transcriptome sequencing (WTS) to analyze and compare MYCr in different B-cell neoplasms. The MYCr features of cases with plasma cell myeloma (PCM) (n = 88) showed distinct characteristics compared to cases with mature B-cell lymphomas (n = 62, including Burkitt lymphoma (BL), diffuse large B-cell lymphoma (DLBCL) and high grade lymphoma with MYC and BCL2 and/or BCL6 rearrangements (HGBL)): they were more complex and showed a wider variety of translocation partners and breakpoints. Additionally, unlike B-cell lymphomas, they showed no evidence of activation-induced deaminase (AID) involvement in the formation of MYCr with immunoglobolin heavy chain (IGH), indicating a different mechanism of origin. The different MYCr characteristics resulted in poor MYCr detection rates by fluorescence in situ hybridization of only 50% in PCM, compared to 94% in lymphoma. [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: Diffuse large B-cell lymphoma (DLBCL) is the most frequent lymphoid neoplasm among adults,and approximately 30–40% of patients will experience relapse while 5–10% will suffer from primary refractory disease caused by different mechanisms, including treatment-induced resistance. For refractory and relapsed DLBCL (rrDLBCL) patients, early detection and understanding of the mechanisms controlling treatment resistance are of great importance to guide therapy decisions. Here, we have focused on genetic variations in immune surveillance genes in diagnostic DLBCL (dDLBCL) and rrDLBCL patients to elaborate on the suitability of new promising immunotherapies. Methods: Biopsies from 30 dDLBCL patients who did not progress or relapse during follow up and 17 rrDLBCL patients with refractory disease or who relapsed during follow up were analyzed by whole-exome sequencing, including matched individual germline samples to include only somatic genetic variants in downstream analysis of a curated list of 58 genes involved in major immune surveillance pathways. Results: More than 70% of both dDLBCLs and rrDLBCLs harbored alterations in immune surveillance genes, but rrDLBCL tumor samples have a lower number of genes affected compared to dDLBCL tumor samples. Increased gene mutation frequencies in rrDLBCLs were observed in more than half of the affected immune surveillance genes than dDLBCLs. Conclusion: Genetic variants in the antigen-presenting genes affect a higher number of rrDLBCL patients supporting an important role for these genes in tumor progression and development of refractory disease and relapse. [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]

Summary: The Hodgkin lymphoma (HL) genomic landscape is hardly known due to the scarcity of tumour cells in the tissue. Liquid biopsy employing circulating tumour DNA (ctDNA) can emerge as an alternative tool for non‐invasive genotyping. By using a custom next generation sequencing (NGS) panel in combination with unique molecule identifiers, we aimed to identify somatic variants in the ctDNA of 60 HL at diagnosis. A total of 277 variants were detected in 36 of the 49 samples (73·5%) with a good quality ctDNA sample. The median number of variants detected per patient was five (range 1–23) with a median variant allele frequency of 4·2% (0·84–28%). Genotyping revealed somatic variants in the following genes: SOCS1 (28%), IGLL5 (26%), TNFAIP3 (23%), GNA13 (23%), STAT6 (21%) and B2M (19%). Moreover, several poor prognosis features (high LDH, low serum albumin, B‐symptoms, IPI ≥ 3 or at an advanced stage) were related to significantly higher amounts of ctDNA. Variant detection in ctDNA by NGS is a feasible approach to depict the genetic features of HL patients at diagnosis. Our data favour the implementation of liquid biopsy genotyping for the routine evaluation of HL 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]

Cancer genomics has evolved over the years from understanding the pathogenesis of cancer to screening the future possibilities of cancer occurrence. Understanding the genetic profile of tumors holds a prognostic as well as a predictive value in this era of therapeutic surveillance, molecular remission, and precision medicine. Identifying molecular markers in tumors is the current standard of approach, and requires an efficient combination of an accessible sample type and a profoundly sensitive technique. Liquid biopsy or cell-free DNA has evolved as a novel sample type with promising results in recent years. Although cell-free DNA has significant role in various cancer types, this review focuses on its application in Non-Hodgkin's Lymphoma. Beginning with the current concept and clinical relevance of minimal residual disease in Non-Hodgkin's lymphoma, we discuss the literature on circulating DNA and its evolving application in the realm of cutting-edge technology. [ABSTRACT FROM AUTHOR]

Abstract: The mechanical traits of cancer include abnormally high solid stress as well as drastic and spatially heterogeneous changes in intrinsic mechanical tissue properties. Whereas solid stress elicits mechanosensory signals promoting tumor progression, mechanical heterogeneity is conducive to cell unjamming and metastatic spread. This reductionist view of tumorigenesis and malignant transformation provides a generalized framework for understanding the physical principles of tumor aggressiveness and harnessing them as novel in vivo imaging markers. Magnetic resonance elastography is an emerging imaging technology for depicting the viscoelastic properties of biological soft tissues and clinically characterizing tumors in terms of their biomechanical properties. This review article presents recent technical developments, basic results, and clinical applications of magnetic resonance elastography in patients with malignant tumors., Competing Interests: Conflicts of interest and sources of funding: J.G., L.J.S., and I.S. received funding from the German Research Foundation (DFG) CRC1340. J.G. and I.S. received funding from the DFG GRK2260 BIOQIC. J.G. and I.S. hold patents related to MRE and are shareholder of Time Harmonic Elastography Applications and Devices. L.J.S. and K.H.H are fellows of the BIH Clinician Scientist Program funded by the Charité– Universitätsmedizin Berlin and the Berlin Institute of Health., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

We report a case of IVL with CNS symptoms alone, in which liquid biopsies of both plasma and cerebrospinal fluid (CSF) were diagnostically useful. Our case suggests that liquid biopsies of the CSF produce negative results in IVL because of the exclusive growth of tumor cells within blood vessel lumens. Further investigation of the diagnostic role of liquid biopsies of plasma and CSF in IVL is warranted. [Extracted from the article]

We next re-hybridized the type B metaphases with the I IGL i break-apart probe and found that telomeric I IGL i was translocated to der(8)t(8;22), creating the I MYC i I IGL i fusion signal with the telomeric signal of the two tandem I MYC i signals. We first investigated the I MYC i and I IGH i status in the two karyotypes using the I MYC i I IGH i dual fusion (DF) probe. As t(8;14) and t(8;22) were found to involve I MYC i on the distinct chromosome 8 homologue, distinguished by the presence [t(8;22)] or absence [t(8;14)] of an extra copy of I MYC i , it is likely that the two 8q24/ I MYC i translocations developed independently in t(14;18)-bearing primary lymphoma cells. [Extracted from the article]

Since the 2016 WHO update, progress has been made in understanding the biology of Burkitt lymphoma (BL) and the concept of high-grade B-cell lymphomas (HGBCL) that allows some degree of refinement. The summary presented here reviews in detail the discussions of the Clinical Advisory Committee and expands upon the newly published 2022 International Consensus Classification for lymphoid malignancies (Campo et al. Blood, 2022). BL remains the prototypic HGBCL and diagnostic criteria are largely unchanged. HGBCL with MYC and BCL2 and HGBCL with MYC and BCL6 rearrangements are now separated to reflect biologic and pathologic differences. HGBCL, NOS remains a diagnosis of exclusion that should be used only in rare cases. FISH strategies for diffuse large B-cell lymphoma (DLBCL) and HGBCL are discussed in detail for these diseases. Advances in integrative analysis of mutations, structural abnormalities, copy number, and gene expression signatures allow a more nuanced view of the heterogeneity of DLBCL, NOS as well as definitions of HGBCL and point to where the future may be headed for classification of these diseases., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

No I MYC i rearrangement involving an IG light chain was found in the GF-type pattern, which may be consistent with I IGL/MYC i and I IGK/MYC i rearrangements involving breakpoints located 3' of I MYC i [[11]]. Cases with I MYC/IGH i fusion identified in the absence of a I MYC i rearrangement by the I MYC i BAP probe were excluded from this study, but have been described by King, et al. [[10]]. I MYC i rearrangements in DLBCL and HGBL may involve one of many different partner genes, including the immunoglobulin (IG) heavy chain locus, the kappa or lambda light chain locus, or a non-IG locus. [Extracted from the article]

Tumors contain various stromal cells that support cancer progression. Some types of cancer, such as scirrhous gastric cancer, are characterized by large areas of fibrosis accompanied by cancer-associated fibroblasts (CAFs). Asporin (ASPN) is a small leucine-rich proteoglycan highly expressed in CAFs of various tumors. ASPN accelerates CAF migration and invasion, resulting in CAF-led cancer cell invasion. In addition, ASPN further upregulated the expression of genes specific to a characteristic subgroup of fibroblasts in tumors. These cells were preferentially located at the tumor periphery and could be generated by a unique mechanism involving the CAF-mediated education of normal fibroblasts (CEFs). In this review, we at first describe recent findings regarding the function of ASPN in the tumor microenvironment, as well as the mechanism involved in the generation of CEFs. CAFs are derived from heterogeneous origins besides resident normal fibroblasts. Among them, CAFs derived from mesothelial cells (mesothelial cell-derived CAF [MC-CAFs]) play pivotal roles in peritoneal carcinomatosis. We observed that MC-CAFs on the surfaces of organs also participate in tumor formation by infiltrating into the parenchyma, promoting local invasion by gastric cancers. This review also highlights the potential functions of macrophages in the formation of MC-CAFs in gastric cancers, by transfer the contents of cancer cell-derived extracellular vesicles., (© 2022 Japanese Society of Pathology and John Wiley & Sons Australia, Ltd.)

Relapsed or refractory diffuse large B-cell lymphoma (DLBCL) cases have a poor outcome. Here we analysed clinico-biological features in 373 DLBCL patients homogeneously treated with rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone (R-CHOP), in order to identify variables associated with early failure to treatment (EF), defined as primary refractoriness or relapse within 12 months from diagnosis. In addition to clinical features, mutational status of 106 genes was studied by targeted next-generation sequencing in 111 cases, copy number alterations in 87, and gene expression profile (GEP) in 39. Ninety-seven cases (26%) were identified as EF and showed significantly shorter overall survival (OS). Patients with B symptoms, advanced stage, high levels of serum lactate dehydrogenase (LDH) or β2-microglobulin, low lymphocyte/monocyte ratio and higher Revised International Prognostic Index (R-IPI) scores, as well as those with BCL2 rearrangements more frequently showed EF, with R-IPI being the most important in logistic regression. Mutations in NOTCH2, gains in 5p15·33 (TERT), 12q13 (CDK2), 12q14·1 (CDK4) and 12q15 (MDM2) showed predictive importance for EF independently from R-IPI. GEP studies showed that EF cases were significantly enriched in sets related to cell cycle regulation and inflammatory response, while cases in response showed over-representation of gene sets related to extra-cellular matrix and tumour microenvironment., (© 2021 British Society for Haematology and John Wiley & Sons Ltd.)

Simple Summary: Monitoring the response to treatment in hematologic malignancies is essential in defining the best way to optimize patient management. In general, achieving a deeper response has been shown to lead to a better prognosis, and the techniques used to study the minimal residual disease (MRD) are becoming more precise. The use of liquid biopsies, that is, analyzing the presence of alterations in nucleic acids, usually in peripheral blood or other biological fluids, is being studied and optimized with increasingly innovative molecular techniques, such as next-generation sequencing (NGS) in the monitoring of the MRD, avoiding, in many cases, more invasive tests in different hematological neoplasms. Currently, liquid biopsies are not standardized for the MRD monitoring, but there is increasing evidence of its correlation with other techniques to measure responses to treatments and patient outcomes. The study of cell-free DNA (cfDNA) and other peripheral blood components (known as "liquid biopsies") is promising, and has been investigated especially in solid tumors. Nevertheless, it is increasingly showing a greater utility in the diagnosis, prognosis, and response to treatment of hematological malignancies; in the future, it could prevent invasive techniques, such as bone marrow (BM) biopsies. Most of the studies about this topic have focused on B-cell lymphoid malignancies; some of them have shown that cfDNA can be used as a novel way for the diagnosis and minimal residual monitoring of B-cell lymphomas, using techniques such as next-generation sequencing (NGS). In myelodysplastic syndromes, multiple myeloma, or chronic lymphocytic leukemia, liquid biopsies may allow for an interesting genomic representation of the tumor clones affecting different lesions (spatial heterogeneity). In acute leukemias, it can be helpful in the monitoring of the early treatment response and the prediction of treatment failure. In chronic lymphocytic leukemia, the evaluation of cfDNA permits the definition of clonal evolution and drug resistance in real time. However, there are limitations, such as the difficulty in obtaining sufficient circulating tumor DNA for achieving a high sensitivity to assess the minimal residual disease, or the lack of standardization of the method, and clinical studies, to confirm its prognostic impact. This review focuses on the clinical applications of cfDNA on the minimal residual disease in hematological malignancies. [ABSTRACT FROM AUTHOR]

Simple Summary: Hairy cell leukemia (HCL) is a rare B cell neoplasm that accounts for 2% of B-cell lymphomas. The diagnosis was based on the presence of abnormal lymphoid cells that expressed CD103, CD123, CD25 and CD11c. The aim of this retrospective study was to describe the immunophenotypic profile of HCL and HCL-like disorders using 13 markers and to assess the added value of immunophenotypic row data and unsupervised analysis. We confirmed that the immunological profile alone is not sufficient and that morphologic, phenotypic and molecular data need to be integrated. Hairy cell leukemia (HCL) is characterized by abnormal villous lymphoid cells that express CD103, CD123, CD25 and CD11c. HCL-like disorders, including hairy cell leukemia variant (vHCL) and splenic diffuse red pulp lymphoma (SDRPL), have similar morphologic criteria and a distinct phenotypic and genetic profile. We investigated the immunophenotypic features of a large cohort of 82 patients: 68 classical HCL, 5 vHCL/SDRPL and 9 HCL-like NOS. The HCL immunophenotype was heterogeneous: positive CD5 expression in 7/68 (10%), CD10 in 12/68 (18%), CD38 in 24/67 (36%), CD23 in 22/68 (32%) and CD43 in 19/65 (31%) patients. CD26 was expressed in 35/36 (97%) of HCL patients, none of vHCL/SDRPL and one of seven HCL-like NOS (14%). When adding CD26 to the immunologic HCL scoring system (one point for CD103, CD123, CD25, CD11c and CD26), the specificity was improved, increasing from 78.6% to 100%. We used unsupervised analysis of flow cytometry raw data (median fluorescence, percentage of expression) and the mutational profile of BRAF, MAP2K1 and KLF2. The analysis showed good separation between HCL and vHCL/SDRPL. The HCL score is not sufficient, and the use of unsupervised analysis could be promising to achieve a distinction between HCL and HCL-like disorders. However, these preliminary results have to be confirmed in a further study with a higher number of patients. [ABSTRACT FROM AUTHOR]

Simple Summary: The pathogenetic mechanisms and peculiar tropism of primary CNS lymphoma (PCNSL) of the central nervous system (CNS) have been the subject of debate for decades. Hypothesis-driven targeted molecular studies have revealed that PCNSLs derived from self-/polyreactive B cells that have escaped developmental control mechanisms. The early acquisition of activating mutations targeting the B cell receptor pathway provides a survival advantage. The failure of the germinal center (GC) reaction and its checkpoints increases tumor B cell affinity for the CNS. During this faulty GC reaction, PCNSL tumor cells acquire further oncogenic alterations converging on the Toll-like receptor, B cell receptor, and NF-κB pathway. These activated pathways sustain proliferation. Concomitantly, cells become unable to complete terminal B cell differentiation, becoming trapped within the vicious cycle of the GC reaction as low-affinity IgM+ B cells related to memory cells. Primary lymphoma of the central nervous system (PCNSL, CNS) is a specific diffuse large B cell lymphoma (DLBCL) entity confined to the CNS. Key to its pathogenesis is a failure of B cell differentiation and a lack of appropriate control at differentiation stages before entrance and within the germinal center (GC). Self-/polyreactive B cells rescued from apoptosis by MYD88 and/or CD79B mutations accumulate a high load of somatic mutations in their rearranged immunoglobulin (IG) genes, with ongoing somatic hypermutation (SHM). Furthermore, the targeting of oncogenes by aberrant SHM (e.g., PIM1, PAX5, RHOH, MYC, BTG2, KLHL14, SUSD2), translocations of the IG and BCL6 genes, and genomic instability (e.g., gains of 18q21; losses of 9p21, 8q12, 6q21) occur in these cells in the course of their malignant transformation. Activated Toll-like receptor, B cell receptor (BCR), and NF-κB signaling pathways foster lymphoma cell proliferation. Hence, tumor cells are arrested in a late B cell differentiation stage, corresponding to late GC exit B cells, which are genetically related to IgM+ memory cells. Paradoxically, the GC reaction increases self-/polyreactivity, yielding increased tumor BCR reactivity for multiple CNS proteins, which likely contributes to CNS tropism of the lymphoma. The loss of MHC class I antigen expression supports tumor cell immune escape. Thus, specific and unique interactions of the tumor cells with resident CNS cells determine the hallmarks of PCNSL. [ABSTRACT FROM AUTHOR]

Simple Summary: Exportin-1 is a nuclear transport protein that is overexpressed in cancer cells and associated with inferior outcomes across a range of malignancies. Selinexor is a novel FDA-approved inhibitor of Exportin-1 (XPO1). Although significant research has focused on integration of selinexor into the treatment regimens of adult cancers, it is increasingly recognized that XPO1-directed therapy may be effective as part of management of childhood cancers. We therefore summarize the history of, and latest knowledge about, the function and therapeutic inhibition of XPO1 as it relates to childhood cancer pathogenesis and treatment. Overexpression of Exportin-1 (XPO1), a key regulator of nuclear-to-cytoplasmic transport, is associated with inferior patient outcomes across a range of adult malignancies. Targeting XPO1 with selinexor has demonstrated promising results in clinical trials, leading to FDA approval of its use for multiple relapsed/refractory cancers. However, XPO1 biology and selinexor sensitivity in childhood cancer is only recently being explored. In this review, we will focus on the differential biology of childhood and adult cancers as it relates to XPO1 and key cargo proteins. We will further explore the current state of pre-clinical and clinical development of XPO1 inhibitors in childhood cancers. Finally, we will outline potentially promising future therapeutic strategies for, as well as potential challenges to, integrating XPO1 inhibition to improve outcomes for children with cancer. [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]

Growing evidence now suggests that circulating tumour DNA (ctDNA) has great potential as a non-invasive biomarker for disease monitoring, since ctDNA carries tumour-specific modifications. In particular, monitoring ctDNA has important implications for identifying patients with haematological malignancies at clinical risk of disease progression. We hereby describe three patients with B-cell non-Hodgkin lymphoma and investigate the clinical value of sequential ctDNA profiling for the early detection of tumour relapse. Somatic mutations in diagnostic tumour biopsy samples of these three patients were identified by applying high-throughput next-generation sequencing. Droplet digital PCR probes and primers were designed and tested for each hotspot mutation. Serial ctDNA analysis was subsequently conducted among these three patients. We found that the longitudinal monitoring of plasma ctDNA could predict for at least one month in advance compared with flow cytometry, cytology and conventional imaging modalities. Therefore, our results support liquid biopsy based on ctDNA as a non-invasive complementary modality to other detection methods for detecting early relapse and contribute to more precise management for non-Hodgkin lymphoma patients. [ABSTRACT FROM AUTHOR]