Publications by authors named "Maurilio Ponzoni"

294 Publications

Genetic and Phenotypic Attributes of Splenic Marginal Zone Lymphoma.

Blood 2021 Oct 15. Epub 2021 Oct 15.

University of Milan & Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.

Splenic marginal zone B-cell lymphoma (SMZL) is a heterogeneous clinico-biological entity. The clinical course is variable, multiple genes are mutated with no unifying mechanism, essential regulatory pathways and surrounding microenvironments are diverse. We sought to clarify the heterogeneity of SMZL by resolving different subgroups and their underlying genomic abnormalities, pathway signatures and microenvironment compositions to uncover biomarkers and therapeutic vulnerabilities. We studied 303 SMZL spleen samples collected through the IELSG46 multicenter, international study (NCT02945319) by using a multiplatform approach. We carried out genetic and phenotypic analyses, defined self-organized signatures, validated the findings in independent primary tumor meta-data and in genetically modified mouse models, and determined correlations with outcome data. We identified two prominent genetic clusters in SMZL, termed NNK (58% of cases, harboring NF-κB, NOTCH and KLF2 modules) and DMT (32% of cases, with DNA-damage response, MAPK and TLR modules). Genetic aberrations in multiple genes as well as cytogenetic and immunogenetic features distinguished NNK- from DMT-SMZLs. These genetic clusters not only have distinct underpinning biology, as judged by differences in gene-expression signatures, but also different outcome, with inferior survival in NNK-SMZLs. Digital cytometry and in situ profiling segregated two basic types of SMZL immune microenvironments termed immune-suppressive SMZL (50% of cases, associated with inflammatory cells and immune checkpoint activation) and immune-silent SMZL (50% of cases, associated with an immune-excluded phenotype) with distinct mutational and clinical connotations. In summary, we propose a nosology of SMZL that can implement its classification and also aid in the development of rationally targeted treatments.
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http://dx.doi.org/10.1182/blood.2021012386DOI Listing
October 2021

Implications of recent molecular achievements in early diagnosis and precision treatments for primary CNS lymphoma.

Expert Opin Ther Targets 2021 Oct 26:1-12. Epub 2021 Oct 26.

Lymphoma Unit, Department of Onco-Hematology, IRCCS San Raffaele Scientific Institute, Milan, Italy.

Primary diffuse large B-cell lymphoma (DLBCL) of the central nervous system (PCNSL) represents a relevant challenge in onco-hematology. PCNSL has specific molecular profile and biological characteristics that distinguish it from systemic DLBCL. Several translational studies have allowed for significant improvement in the knowledge about its genomic and molecular profile. High-dose-methotrexate-based chemotherapy followed whole-brain irradiation or autologous stem cell transplantation is the most commonly used therapeutic approach in PCNSL patients. This work provides an overview of the new biomarkers of PCNSL, focusing on their potential diagnostic, predictive and prognostic role. Publications in English language, peer-reviewed, high-quality international journals, were identified on PubMed. Early diagnosis, a better antitumor response definition and recognition of new effective treatments are important research fields aiming to improve PCNSL outcome and management. The acquisition of new molecular and genomic knowledge in PCNSL has allowed for the attainment of promising diagnostic and prognostic tools as well as the development of clinical trials with new therapeutic approaches beyond chemotherapy agents, which have demonstrated activity in refractory/relapsed PCNSL and deserve to be investigated in first-line therapy.
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http://dx.doi.org/10.1080/14728222.2021.1988927DOI Listing
October 2021

Genomic complexity is associated with epigenetic regulator mutations and poor prognosis in diffuse large B-cell lymphoma.

Oncoimmunology 2021 20;10(1):1928365. Epub 2021 Jul 20.

Department of Hematology and Oncology, Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou, China.

Diffuse large B-cell lymphoma (DLBCL) is the most common type of lymphoma with high mutation burdens but a low response rate to immune checkpoint inhibitors. In this study, we performed targeted next-generation sequencing and fluorescent multiplex immunohistochemistry, and investigated the clinical significance and immunological effect of mutation numbers in 424 DLBCL patients treated with standard immunochemotherapy. We found that and nonsynonymous mutations (MUT) were significantly associated with increased nonsynonymous mutation numbers, and that high mutation numbers (MUT) were associated with significantly poorer clinical outcome in germinal center B-cell-like DLBCL with wild-type . To understand the underlying mechanisms, we identified a gene-expression profiling signature and the association of MUT with decreased T cells in DLBCL patients with wild-type . On the other hand, in overall cohort, MUT was associated with lower PD-1 expression in T cells and PD-L1 expression in macrophages, suggesting a positive role of MUT in immune responses. Analysis in a whole-exome sequencing dataset of 304 patients deposited by Chapuy et al. validated the correlation of MUT- with genomic complexity and the significantly poorer survival associated with higher numbers of genomic single nucleotide variants in activated B-cell-like DLBCL with wild-type . Together, these results suggest that KMT2D inactivation or epigenetic dysregulation has a role in driving DLBCL genomic instability, and that genomic complexity has adverse impact on clinical outcome in DLBCL patients with wild-type treated with standard immunochemotherapy. The oncoimmune data in this study have important implications for biomarker and therapeutic studies in DLBCL.
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http://dx.doi.org/10.1080/2162402X.2021.1928365DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8293967PMC
October 2021

Oncogene-induced senescence in hematopoietic progenitors features myeloid restricted hematopoiesis, chronic inflammation and histiocytosis.

Nat Commun 2021 07 27;12(1):4559. Epub 2021 Jul 27.

San Raffaele Telethon Institute for Gene Therapy, IRCCS San Raffaele Scientific Institute, Milan, Italy.

Activating mutations in the BRAF-MAPK pathway have been reported in histiocytoses, hematological inflammatory neoplasms characterized by multi-organ dissemination of pro-inflammatory myeloid cells. Here, we generate a humanized mouse model of transplantation of human hematopoietic stem and progenitor cells (HSPCs) expressing the activated form of BRAF (BRAF). All mice transplanted with BRAF-expressing HSPCs succumb to bone marrow failure, displaying myeloid-restricted hematopoiesis and multi-organ dissemination of aberrant mononuclear phagocytes. At the basis of this aggressive phenotype, we uncover the engagement of a senescence program, characterized by DNA damage response activation and a senescence-associated secretory phenotype, which affects also non-mutated bystander cells. Mechanistically, we identify TNFα as a key determinant of paracrine senescence and myeloid-restricted hematopoiesis and show that its inhibition dampens inflammation, delays disease onset and rescues hematopoietic defects in bystander cells. Our work establishes that senescence in the human hematopoietic system links oncogene-activation to the systemic inflammation observed in histiocytic neoplasms.
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http://dx.doi.org/10.1038/s41467-021-24876-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8316479PMC
July 2021

CD4+ T cells sustain aggressive chronic lymphocytic leukemia in Eμ-TCL1 mice through a CD40L-independent mechanism.

Blood Adv 2021 07;5(14):2817-2828

Cellular Immunology Unit, Division of Immunology, Transplantation, and Infectious Diseases.

Chronic lymphocytic leukemia (CLL) is caused by the progressive accumulation of mature CD5+ B cells in secondary lymphoid organs. In vitro data suggest that CD4+ T lymphocytes also sustain survival and proliferation of CLL clones through CD40L/CD40 interactions. In vivo data in animal models are conflicting. To clarify this clinically relevant biological issue, we generated genetically modified Eμ-TCL1 mice lacking CD4+ T cells (TCL1+/+AB0), CD40 (TCL1+/+CD40-/-), or CD8+ T cells (TCL1+/+TAP-/-), and we monitored the appearance and progression of a disease that mimics aggressive human CLL by flow cytometry and immunohistochemical analyses. Findings were confirmed by adoptive transfer of leukemic cells into mice lacking CD4+ T cells or CD40L or mice treated with antibodies depleting CD4 T cells or blocking CD40L/CD40 interactions. CLL clones did not proliferate in mice lacking or depleted of CD4+ T cells, thus confirming that CD4+ T cells are essential for CLL development. By contrast, CD8+ T cells exerted an antitumor activity, as indicated by the accelerated disease progression in TCL1+/+TAP-/- mice. Antigen specificity of CD4+ T cells was marginal for CLL development, because CLL clones efficiently proliferated in transgenic mice whose CD4 T cells had a T-cell receptor with CLL-unrelated specificities. Leukemic clones also proliferated when transferred into wild-type mice treated with monoclonal antibodies blocking CD40 or into CD40L-/- mice, and TCL1+/+CD40-/- mice developed frank CLL. Our data demonstrate that CD8+ T cells restrain CLL progression, whereas CD4+ T cells support the growth of leukemic clones in TCL1 mice through CD40-independent and apparently noncognate mechanisms.
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http://dx.doi.org/10.1182/bloodadvances.2020003795DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8341348PMC
July 2021

Publisher Correction: HMGA1-pseudogene7 transgenic mice develop B cell lymphomas.

Sci Rep 2021 Jun 11;11(1):12741. Epub 2021 Jun 11.

Istituto di Endocrinologia ed Oncologia Sperimentale - CNR c/o Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università degli Studi di Napoli "Federico II", Naples, Italy.

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http://dx.doi.org/10.1038/s41598-021-92173-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8196011PMC
June 2021

Burkitt lymphoma with a granulomatous reaction: an M1/Th1-polarised microenvironment is associated with controlled growth and spontaneous regression.

Histopathology 2021 May 5. Epub 2021 May 5.

Department of Medical Biotechnologies, University of Siena, Siena, Italy.

Aims: Burkitt lymphoma (BL) is an aggressive B-cell lymphoma that, in some instances, may show a granulomatous reaction associated with a favourable prognosis and occasional spontaneous regression. In the present study, we aimed to define the tumour microenvironment (TME) in four such cases, two of which regressed spontaneously.

Methods And Results: All cases showed aggregates of tumour cells with the typical morphology, molecular cytogenetics and immunophenotype of BL surrounded by a florid epithelioid granulomatous reaction. All four cases were Epstein-Barr virus (EBV)-positive with type I latency. Investigation of the TME showed similar features in all four cases. The analysis revealed a proinflammatory response triggered by Th1 lymphocytes and M1 polarised macrophages encircling the neoplastic cells with a peculiar topographic distribution.

Conclusions: Our data provide an in-vivo picture of the role that specific immune cell subsets might play during the early phase of BL, which may be capable of maintaining the tumour in a self-limited state or inducing its regression. These novel results may provide insights into new potential therapeutic avenues in EBV-positive BL patients in the era of cellular immunotherapy.
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http://dx.doi.org/10.1111/his.14391DOI Listing
May 2021

MYD88 L265P mutation and interleukin-10 detection in cerebrospinal fluid are highly specific discriminating markers in patients with primary central nervous system lymphoma: results from a prospective study.

Br J Haematol 2021 05 23;193(3):497-505. Epub 2021 Feb 23.

Pathology Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy.

Reliable biomarkers are needed to avoid diagnostic delay and its devastating effects in patients with primary central nervous system (CNS) lymphoma (PCNSL). We analysed the discriminating sensitivity and specificity of myeloid differentiation primary response (88) (MYD88) L265P mutation (mut-MYD88) and interleukin-10 (IL-10) in cerebrospinal fluid (CSF) of both patients with newly diagnosed (n = 36) and relapsed (n = 27) PCNSL and 162 controls (118 CNS disorders and 44 extra-CNS lymphomas). The concordance of MYD88 mutational status between tumour tissue and CSF sample and the source of ILs in PCNSL tissues were also investigated. Mut-MYD88 was assessed by TaqMan-based polymerase chain reaction. IL-6 and IL-10 messenger RNA (mRNA) was assessed on PCNSL biopsies using RNAscope technology. IL levels in CSF were assessed by enzyme-linked immunosorbent assay. Mut-MYD88 was detected in 15/17 (88%) PCNSL biopsies, with an 82% concordance in paired tissue-CSF samples. IL-10 mRNA was detected in lymphomatous B cells in most PCNSL; expression of IL-6 transcripts was negligible. In CSF samples, mut-MYD88 and high IL-10 levels were detected, respectively, in 72% and 88% of patients with newly diagnosed PCNSL and in 1% of controls; conversely, IL-6 showed a low discriminating sensitivity and specificity. Combined analysis of MYD88 and IL-10 exhibits a sensitivity and specificity to distinguish PCNSL of 94% and 98% respectively. Similar figures were recorded in patients with relapsed PCNSL. In conclusion, high detection rates of mut-MYD88 and IL-10 in CSF reflect, respectively, the MYD88 mutational status and synthesis of this IL in PCNSL tissue. These biomarkers exhibit a very high sensitivity and specificity in detecting PCNSL both at initial diagnosis and relapse. Implications of these findings in patients with lesions unsuitable for biopsy deserve to be investigated.
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http://dx.doi.org/10.1111/bjh.17357DOI Listing
May 2021

Treating life-threatening TAFRO syndrome with interleukin-1 inhibition.

Eur J Intern Med 2021 05 17;87:121-123. Epub 2021 Feb 17.

Università Vita-Salute San Raffaele, IRCCS San Raffaele Scientific Institute, Milan, Italy; Unit of Immunology, Rheumatology, Allergy and Rare Diseases (UnIRAR); IRCCS San Raffaele Scientific Institute, Milan, Italy.

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http://dx.doi.org/10.1016/j.ejim.2021.02.006DOI Listing
May 2021

A Rare Case of Castleman Disease Presenting as an Ovarian Tumor.

Int J Gynecol Pathol 2021 Jul;40(4):379-382

Castleman disease (CD) is a rare lymphoproliferative disorder of unknown etiology. Its most common location is the mediastinum, but many other sites have been reported. We report a case of primary CD of the ovary, a rare localization with only 2 cases including the present case described in the world literature to date. A 58-yr-old woman who initially presented with abdominal pain underwent computed tomography scan which showed bilateral well-circumscribed solid adnexal masses. Because an ovarian bilateral tumor was suspected the patient was treated with a hysterectomy and bilateral salpingo-oophorectomy and the histopathologic examination confirmed the diagnosis of CD hyaline-vascular type of the right ovary associated with a contralateral fibroma. Three years after surgery the patient is alive and well and shows no signs of recurrent disease. The occurrence of this rare presentation of CD is the subject of this report. The problems of differential diagnosis with the most frequent lesions of the female pelvis are also discussed.
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http://dx.doi.org/10.1097/PGP.0000000000000721DOI Listing
July 2021

Aggressive B-cell Lymphoma with MYC/TP53 Dual Alterations Displays Distinct Clinicopathobiological Features and Response to Novel Targeted Agents.

Mol Cancer Res 2021 02 5;19(2):249-260. Epub 2020 Nov 5.

Duke University Medical Center, Division of Hematopathology and Department of Pathology, Durham, North Carolina.

Diffuse large B-cell lymphoma (DLBCL) is the major type of aggressive B-cell lymphoma. High-grade B-cell lymphoma (HGBCL) with / double-hit (DH) represents a distinct entity with dismal prognosis after standard immunochemotherapy in the current WHO lymphoma classification. However, whether mutation synergizes with MYC abnormalities ( rearrangement and/or Myc protein overexpression) contributing to HGBCL-like biology and prognosis is not well investigated. In this study, patients with DLBCL with MYC/TP53 abnormalities demonstrated poor clinical outcome, high-grade morphology, and distinct gene expression signatures. To identify more effective therapies for this distinctive DLBCL subset, novel MYC/TP53/BCL-2-targeted agents were investigated in DLBCL cells with MYC/TP53 dual alterations or HGBCL-/-DH. A BET inhibitor INCB057643 effectively inhibited cell viability and induced apoptosis in DLBCL/HGBCL cells regardless of // status. Combining INCB057643 with a MDM2-p53 inhibitor DS3032b significantly enhanced the cytotoxic effects in HGBCL-DH without mutation, while combining with the BCL-2 inhibitor venetoclax displayed potent therapeutic synergy in DLBCL/HGBCL cells with and without concurrent mutation. Reverse-phase protein arrays revealed the synergistic molecular actions by INCB057643, DS3032b and venetoclax to induce cell-cycle arrest and apoptosis and to inhibit AKT/MEK/ERK/mTOR pathways, as well as potential drug resistance mechanisms mediated by upregulation of Mcl-1 and RAS/RAF/MEK/ERK pathways. In summary, these findings support subclassification of DLBCL/HGBCL with dual MYC/TP53 alterations, which demonstrates distinct pathobiologic features and dismal survival with standard therapy, therefore requiring additional targeted therapies. IMPLICATIONS: The clinical and pharmacologic studies suggest recognizing DLBCL with concomitant mutation and MYC abnormalities as a distinctive entity necessary for precision oncology practice. VISUAL OVERVIEW: http://mcr.aacrjournals.org/content/molcanres/19/2/249/F1.large.jpg.
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http://dx.doi.org/10.1158/1541-7786.MCR-20-0466DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8092941PMC
February 2021

XPO1 expression worsens the prognosis of unfavorable DLBCL that can be effectively targeted by selinexor in the absence of mutant p53.

J Hematol Oncol 2020 11 4;13(1):148. Epub 2020 Nov 4.

Division of Hematopathology, Department of Pathology, Duke University Medical Center, Durham, NC, 27710, USA.

The XPO1 inhibitor selinexor was recently approved in relapsed/refractory DLBCL patients but only demonstrated modest anti-DLBCL efficacy, prompting us to investigate the prognostic effect of XPO1 in DLBCL patients and the rational combination therapies in high-risk DLBCL. High XPO1 expression (XPO1) showed significant adverse prognostic impact in 544 studied DLBCL patients, especially in those with BCL2 overexpression. Therapeutic study in 30 DLBCL cell lines with various molecular and genetic background found robust cytotoxicity of selinexor, especially in cells with BCL2-rearranged (BCL2-R) DLBCL or high-grade B-cell lymphoma with MYC/BCL2 double-hit (HGBCL-DH). However, expression of mutant (Mut) p53 significantly reduced the cytotoxicity of selinexor in overall cell lines and the BCL2-R and HGBCL-DH subsets, consistent with the favorable impact of XPO1 observed in Mut-p53-expressing patients. The therapeutic effect of selinexor in HGBCL-DH cells was significantly enhanced when combined with a BET inhibitor INCB057643, overcoming the drug resistance in Mut-p53-expressing cells. Collectively, these data suggest that XPO1 worsens the survival of DLBCL patients with unfavorable prognostic factors such as BCL2 overexpression and double-hit, in line with the higher efficacy of selinexor demonstrated in BCL2-R DLBCL and HGBCL-DH cell lines. Expression of Mut-p53 confers resistance to selinexor treatment, which can be overcome by combined INCB057643 treatment in HGBCL-DH cells. This study provides insight into the XPO1 significance and selinexor efficacy in DLBCL, important for developing combination therapy for relapsed/refractory DLBCL and HGBCL-DH.
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http://dx.doi.org/10.1186/s13045-020-00982-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7641823PMC
November 2020

Intra-tumour heterogeneity of diffuse large B-cell lymphoma involves the induction of diversified stroma-tumour interfaces.

EBioMedicine 2020 Nov 20;61:103055. Epub 2020 Oct 20.

Tumor Immunology Unit, University of Palermo, Palermo, Italy; Tumor and Microenvironment Histopathology Unit, IFOM, FIRC Institute of Molecular Oncology, Milan, Italy. Electronic address:

Background: Intra-tumour heterogeneity in lymphoid malignancies encompasses selection of genetic events and epigenetic regulation of transcriptional programs. Clonal-related neoplastic cell populations are unsteadily subjected to immune editing and metabolic adaptations within different tissue microenvironments. How tissue-specific mesenchymal cells impact on the diversification of aggressive lymphoma clones is still unknown.

Methods: Combining in situ quantitative immunophenotypical analyses and RNA sequencing we investigated the intra-tumour heterogeneity and the specific mesenchymal modifications that are associated with A20 diffuse large B-cell lymphoma (DLBCL) cells seeding of different tissue microenvironments. Furthermore, we characterized features of lymphoma-associated stromatogenesis in human DLBCL samples using Digital Spatial Profiling, and established their relationship with prognostically relevant variables, such as MYC.

Findings: We found that the tissue microenvironment casts a relevant influence over A20 transcriptional landscape also impacting on Myc and DNA damage response programs. Extending the investigation to mice deficient for the matricellular protein SPARC, a stromal prognostic factor in human DLBCL, we demonstrated a different immune imprint on A20 cells according to stromal Sparc proficiency. Through Digital Spatial Profiling of 87 immune and stromal genes on human nodal DLBCL regions characterized by different mesenchymal composition, we demonstrate intra-lesional heterogeneity arising from diversified mesenchymal contextures and impacting on the stromal and immune milieu.

Interpretation: Our study provides experimental evidence that stromal microenvironment generates topological determinants of intra-tumour heterogeneity in DLBCL involving key transcriptional pathways such as Myc expression, damage response programs and immune checkpoints.

Funding: This study has been supported by the Italian Foundation for Cancer Research (AIRC) (grants 15999 and 22145 to C. Tripodo) and by the University of Palermo.
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http://dx.doi.org/10.1016/j.ebiom.2020.103055DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7581880PMC
November 2020

A dose-dense short-term therapy for human immunodeficiency virus/acquired immunodeficiency syndrome patients with high-risk Burkitt lymphoma or high-grade B-cell lymphoma: safety and efficacy results of the "CARMEN" phase II trial.

Br J Haematol 2021 01 21;192(1):119-128. Epub 2020 Oct 21.

Division of Hematology, Ospedali Civili di Brescia, Brescia, Italy.

A few prospective trials in HIV-positive patients with Burkitt lymphoma (BL) or high-grade B-cell lymphoma (HGBL) have been reported. Investigated therapies have shown good efficacy but relevant safety problems, with high rates of interruptions, severe mucositis, septic complications, and fungal infections. Here, we report the results of a multicentre phase II trial addressing a new dose-dense, short-term therapy aimed at maintaining efficacy and improving tolerability. The experimental programme included a 36-day polychemotherapy induction followed by high-dose cytarabine-based consolidation and response-tailored BEAM (carmustine, etoposide, cyatarabine, and melphalan)- conditioned autologous stem cell transplantation (ASCT). This therapy would be considered active if ≥11 complete remissions (CR) after induction (primary endpoint) were recorded among 20 assessable patients. HIV-positive adults (median age 42, range 26-58; 16 males) with untreated BL (n = 16), HGBL (n = 3) or double-hit lymphoma (n = 1) were enrolled. All patients had high-risk features, with meningeal and bone marrow infiltration in five and nine patients respectively. The experimental programme was safe and active in a multicentre setting, with only two episodes of grade 4 non-haematological toxicity (hepatotoxicity and mucositis), and no cases of systemic fungal infections; two patients died of toxicity (bacterial infections). Response after induction (median duration: 47 days; interquartile range 41-54), was complete in 13 patients and partial in five [overall response rate = 90%; 95% confidence interval (CI) = 77-100]. All responders received consolidation, and five required autologous stem cell transplant. At a median follow-up of 55 (41-89) months, 14 patients are relapse-free and 15 are alive, with a five-year progression-free survival and an overall survival of 70% (95% CI = 60-80%) and 75% (95% CI = 66-84) respectively. No patient with cerebrospinal fluid (CSF)/meningeal lymphoma experienced central nervous system recurrence. With respect to previously reported regimens, this programme was delivered in a shorter period, and achieved the main goal of maintaining efficacy and improving tolerability.
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http://dx.doi.org/10.1111/bjh.17188DOI Listing
January 2021

A Spatially Resolved Dark- versus Light-Zone Microenvironment Signature Subdivides Germinal Center-Related Aggressive B Cell Lymphomas.

iScience 2020 Oct 16;23(10):101562. Epub 2020 Sep 16.

Hematopathology Unit, European Institute of Oncology, Milan, Italy.

We applied digital spatial profiling for 87 immune and stromal genes to lymph node germinal center (GC) dark- and light-zone (DZ/LZ) regions of interest to obtain a differential signature of these two distinct microenvironments. The spatially resolved 53-genes signature, comprising key genes of the DZ mutational machinery and LZ immune and mesenchymal milieu, was applied to the transcriptomes of 543 GC-related diffuse large B cell lymphomas and double-hit (DH) lymphomas. According to the DZ/LZ signature, the GC-related lymphomas were sub-classified into two clusters. The subgroups differed in the distribution of DH cases and survival, with most DH displaying a distinct DZ-like profile. The clustering analysis was also performed using a 25-genes signature composed of genes positively enriched in the non-B, stromal sub-compartments, for the first time achieving DZ/LZ discrimination based on stromal/immune features. The report offers new insight into the GC microenvironment, hinting at a DZ microenvironment of origin in DH lymphomas.
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http://dx.doi.org/10.1016/j.isci.2020.101562DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7522121PMC
October 2020

ATR addiction in multiple myeloma: synthetic lethal approaches exploiting established therapies.

Haematologica 2020 10 1;105(10):2440-2447. Epub 2020 Oct 1.

IRCCS San Raffaele Scientific Institute, Milan, Italy.

Therapeutic strategies designed to tinker with cancer cell DNA damage response have led to the widespread use of PARP inhibitors for BRCA1/2-mutated cancers. In the haematological cancer multiple myeloma, we sought to identify analogous synthetic lethality mechanisms that could be leveraged upon established cancer treatments. The combination of ATR inhibition using the compound VX-970 with a drug eliciting interstrand cross-links, melphalan, was tested in in vitro, ex vivo, and most notably in vivo models. Cell proliferation, induction of apoptosis, tumor growth and animal survival were assessed. The combination of ATM inhibition with a drug triggering double strand breaks, doxorucibin, was also probed. We found that ATR inhibition is strongly synergistic with melphalan, even in resistant cells. The combination was dramatically effective in targeting myeloma primary patient cells and cell lines reducing cell proliferation and inducing apoptosis. The combination therapy significantly reduced tumor burden and prolonged survival in animal models. Conversely, ATM inhibition only marginally impacted on myeloma cell survival, even in combination with doxorucibin at high doses. These results indicate that myeloma cells extensively rely on ATR, but not on ATM, for DNA repair. Our findings posit that adding an ATR inhibitor such as VX-970 to established therapeutic regimens may provide a remarkably broad benefit to myeloma patients.
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http://dx.doi.org/10.3324/haematol.2018.215210DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7556682PMC
October 2020

Clinical Experience in a Large Cohort of Patients with Vitreoretinal Lymphoma in a Single Center.

Ocul Immunol Inflamm 2021 Apr 26;29(3):472-478. Epub 2020 Aug 26.

Department of Ophthalmology, IRCCS San Raffaele Scientific Institute, Milan, Italy.

: To report our five-year experience on vitreoretinal lymphoma (VRL) as a single-center tertiary hospital. : The ophthalmic, cytopathology, and onco-hematologic records of patients with VRL consecutively seen from 2014 to 2019 were reviewed. : Fifty-nine eyes of 31 patients with large B-cell VRL were included. Eighty-one percent has developed central nervous system lymphoma at the end of follow-up. Several different imaging findings were noted, including vitritis, leopard spot appearance, Bruch's membrane/RPE infiltrations, and ellipsoid zone disruption. A variable combination of MYD88-L265P mutation in the aqueous and/or in the vitreous and positive cytology/histology allowed to reach a definite diagnosis in all the patients. Therapies included intravitreal injections of methotrexate and rituximab, systemic chemotherapy, pan-encephalic radiotherapy, and hematopoietic stem cell transplantation. : No definite guidelines exist for VRL management. It is crucial to collect as much data as possible from tertiary referral hospitals, which suitably manage a conspicuous number of VRL patients.
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http://dx.doi.org/10.1080/09273948.2020.1787460DOI Listing
April 2021

Improving the antitumor activity of R-CHOP with NGR-hTNF in primary CNS lymphoma: final results of a phase 2 trial.

Blood Adv 2020 08;4(15):3648-3658

Università Vita-Salute San Raffaele, Milan, Italy.

Rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) is the standard treatment of diffuse large B-cell lymphoma (DLBCL). Primary DLBCL of the central nervous system (CNS) (primary central nervous system lymphoma [PCNSL]) is an exception because of the low CNS bioavailability of related drugs. NGR-human tumor necrosis factor (NGR-hTNF) targets CD13+ vessels, enhances vascular permeability and CNS access of anticancer drugs, and provides the rationale for the treatment of PCNSL with R-CHOP. Herein, we report activity and safety of R-CHOP preceded by NGR-hTNF in patients with PCNSL relapsed/refractory to high-dose methotrexate-based chemotherapy enrolled in a phase 2 trial. Overall response rate (ORR) was the primary endpoint. A sample size of 28 patients was considered necessary to demonstrate improvement from 30% to 50% ORR. NGR-hTNF/R-CHOP would be declared active if ≥12 responses were recorded. Treatment was well tolerated; there were no cases of unexpected toxicities, dose reductions or interruptions. NGR-hTNF/R-CHOP was active, with confirmed tumor response in 21 patients (75%; 95% confidence interval, 59%-91%), which was complete in 11. Seventeen of the 21 patients with response to treatment received consolidation (ASCT, WBRT, and/or lenalidomide maintenance). At a median follow-up of 21 (range, 14-31) months, 5 patients remained relapse-free and 6 were alive. The activity of NGR-hTNF/R-CHOP is in line with the expression of CD13 in both pericytes and endothelial cells of tumor vessels. High plasma levels of chromogranin A, an NGR-hTNF inhibitor, were associated with proton pump inhibitor use and a lower remission rate, suggesting that these drugs should be avoided during TNF-based therapy. Further research on this innovative approach to CNS lymphomas is warranted. The trial was registered as EudraCT: 2014-001532-11.
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http://dx.doi.org/10.1182/bloodadvances.2020002270DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7422104PMC
August 2020

Mantle cell lymphoma.

Crit Rev Oncol Hematol 2020 Sep 4;153:103038. Epub 2020 Jul 4.

Medizinische Klinik III der Universität München-Grosshadern, München, Germany.

MCL is a well-characterized generally aggressive lymphoma with a poor prognosis. However, patients with a more indolent disease have been reported in whom the initiation of therapy can be delayed without any consequence for the survival. In 2017 the World Health Organization updated the classification of MCL describing two main subtypes with specific molecular characteristics and clinical features, classical and indolent leukaemic nonnodal MCL. Recent research results suggested an improving outcome of this neoplasm. The addition of rituximab to conventional chemotherapy has increased overall response rates, but it did not improve overall survival compared to chemotherapy alone. The use of intensive frontline therapies including rituximab and consolidation with autologous stem cell transplantation ameliorated response rate and prolonged progression-free survival in young fit patients, but any impact on survival remains to be proven. Furthermore, the optimal timing, cytoreductive regimen and conditioning regimen, and the clinical implications of achieving a disease remission even at molecular level remain to be elucidated. The development of targeted therapies as the consequence of better understanding of pathogenetic pathways in MCL might improve the outcome of conventional chemotherapy and spare the toxicity of intense therapy in most patients. Cases not eligible for intensive regimens, may be considered for less demanding therapies, such as the combination of rituximab either with CHOP or with purine analogues, or bendamustine. Allogeneic SCT can be an effective option for relapsed disease in patients who are fit enough and have a compatible donor. Maintenance rituximab may be considered after response to immunochemotherapy as the first-line strategy in a wide range of patients. Finally, since the optimal approach to the management of MCL is still evolving, it is critical that these patients are enrolled in clinical trials to identify the better treatment options.
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http://dx.doi.org/10.1016/j.critrevonc.2020.103038DOI Listing
September 2020

Three-dimensional co-culture model of chronic lymphocytic leukemia bone marrow microenvironment predicts patient-specific response to mobilizing agents.

Haematologica 2021 09 1;106(9):2334-2344. Epub 2021 Sep 1.

IRCCS, Ospedale San Raffaele, Division of Experimental Oncology, Milan Italy.

Chronic Lymphocytic Leukemia (CLL) cells disseminate into supportive tissue microenvironments. To investigate the mechanisms involved in leukemic cell tissue retention we developed a 3D bone marrow (BM) microenvironment that recreates CLL - BM-stromal cells interactions inside a scaffold within a bioreactor. Our system allows the parallel analysis of CLL cells retained inside the scaffold and those released in the presence/absence of pharmacological agents, mimicking tissue and circulating cell compartments, respectively. CLL cells can be retained within the scaffold only in the presence of microenvironmental elements, which through direct contact down-regulate the expression of HS1 cytoskeletal protein in CLL cells. Consist with this, the expression of HS1 was lower in CLL cells obtained from patients' BM versus CLL cells circulating in the PB. Moreover, we demonstrate that CLL cells with inactive-HS1, impaired cytoskeletal activity and a more aggressive phenotype are more likely retained within the scaffold despite the presence of Ibrutinib, whose mobilizing effect is mainly exerted on those with active-HS1, ensuing dynamic cytoskeletal activity. This differential effect would not otherwise be assessable in a traditional 2D system and may underlie a distinctive resistance of single CLL clones. Notably, CLL cells mobilized in the peripheral blood of patients during Ibrutinib therapy exhibited activated HS1, underscoring that our model reliably mirrors the in vivo situation. The 3D model described herein is suitable to reproduce and identify critical CLL-BM interactions, opening the way to pathophysiological studies and the evaluation of novel targeted therapies in an individualized manner.
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http://dx.doi.org/10.3324/haematol.2020.248112DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8409046PMC
September 2021

A refined cell-of-origin classifier with targeted NGS and artificial intelligence shows robust predictive value in DLBCL.

Blood Adv 2020 07;4(14):3391-3404

Division of Hematopathology and Department of Pathology, Duke University Medical Center, Durham, NC.

Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous entity of B-cell lymphoma. Cell-of-origin (COO) classification of DLBCL is required in routine practice by the World Health Organization classification for biological and therapeutic insights. Genetic subtypes uncovered recently are based on distinct genetic alterations in DLBCL, which are different from the COO subtypes defined by gene expression signatures of normal B cells retained in DLBCL. We hypothesize that classifiers incorporating both genome-wide gene-expression and pathogenetic variables can improve the therapeutic significance of DLBCL classification. To develop such refined classifiers, we performed targeted RNA sequencing (RNA-Seq) with a commercially available next-generation sequencing (NGS) platform in a large cohort of 418 DLBCLs. Genetic and transcriptional data obtained by RNA-Seq in a single run were explored by state-of-the-art artificial intelligence (AI) to develop a NGS-COO classifier for COO assignment and NGS survival models for clinical outcome prediction. The NGS-COO model built through applying AI in the training set was robust, showing high concordance with COO classification by either Affymetrix GeneChip microarray or the NanoString Lymph2Cx assay in 2 validation sets. Although the NGS-COO model was not trained for clinical outcome, the activated B-cell-like compared with the germinal-center B-cell-like subtype had significantly poorer survival. The NGS survival models stratified 30% high-risk patients in the validation set with poor survival as in the training set. These results demonstrate that targeted RNA-Seq coupled with AI deep learning techniques provides reproducible, efficient, and affordable assays for clinical application. The clinical grade assays and NGS models integrating both genetic and transcriptional factors developed in this study may eventually support precision medicine in DLBCL.
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http://dx.doi.org/10.1182/bloodadvances.2020001949DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7391158PMC
July 2020

Role of ETS1 in the Transcriptional Network of Diffuse Large B Cell Lymphoma of the Activated B Cell-Like Type.

Cancers (Basel) 2020 Jul 15;12(7). Epub 2020 Jul 15.

Institute of Oncology Research, Faculty of Biomedical Sciences, USI, 6500 Bellinzona, Switzerland.

Diffuse large B cell lymphoma (DLBCL) is a heterogenous disease that has been distinguished into at least two major molecular entities, the germinal center-like B cell (GCB) DLBCL and activated-like B cell (ABC) DLBCL, based on transcriptome expression profiling. A recurrent ch11q24.3 gain is observed in roughly a fourth of DLBCL cases resulting in the overexpression of two ETS transcription factor family members, ETS1 and FLI1. Here, we knocked down ETS1 expression by siRNA and analyzed expression changes integrating them with ChIP-seq data to identify genes directly regulated by ETS1. ETS1 silencing affected expression of genes involved in B cell signaling activation, B cell differentiation, cell cycle, and immune processes. Integration of RNA-Seq (RNA sequencing) data and ChIP-Seq (chromatin immunoprecipitation sequencing) identified 97 genes as bona fide, positively regulated direct targets of ETS1 in ABC-DLBCL. Among these was the Fc receptor for IgM, FCMR (also known as FAIM3 or Toso), which showed higher expression in ABC- than GCB-DLBCL clinical specimens. These findings show that ETS1 is contributing to the lymphomagenesis in a subset of DLBCL and identifies FCMR as a novel target of ETS1, predominantly expressed in ABC-DLBCL.
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http://dx.doi.org/10.3390/cancers12071912DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7409072PMC
July 2020

EZN-2208 treatment suppresses chronic lymphocytic leukaemia by interfering with environmental protection and increases response to fludarabine.

Open Biol 2020 05 13;10(5):190262. Epub 2020 May 13.

Division of Experimental Oncology, IRCCS San Raffaele Scientific Institute, Milan, Italy.

The transcription factor HIF-1α is overexpressed in chronic lymphocytic leukaemia (CLL), where it promotes leukaemia progression by favouring the interaction of leukaemic cells with protective tissue microenvironments. Here, we tested the hypothesis that a pharmacological compound previously shown to inhibit HIF-1α may act as a chemosensitizer by interrupting protective microenvironmental interactions and exposing CLL cells to fludarabine-induced cytotoxicity. We found that the camptothecin-11 analogue EZN-2208 sensitizes CLL cells to fludarabine-induced apoptosis in cytoprotective cultures; EZN-2208 improves fludarabine responses, especially in early phases of leukaemia expansion, and exerts significant anti-leukaemia activity, thus suggesting that this or similar compounds may be considered as effective CLL therapeutic approaches.
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http://dx.doi.org/10.1098/rsob.190262DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7276525PMC
May 2020

Long-lasting efficacy and safety of lenalidomide maintenance in patients with relapsed diffuse large B-cell lymphoma who are not eligible for or failed autologous transplantation.

Hematol Oncol 2020 Aug 5;38(3):257-265. Epub 2020 May 5.

Vita-Salute San Raffaele University, Milan, Italy.

We report final results of a phase II trial addressing efficacy and feasibility of lenalidomide maintenance in patients with chemosensitive relapse of diffuse large B-cell lymphoma (DLBCL) not eligible for or failed after autologous stem cell transplantation (ASCT). Patients with relapsed DLBCL who achieved at least a partial response to salvage chemoimmunotherapy were enrolled and treated with lenalidomide 25 mg/day for 21 of 28 days for 2 years or until progression or unacceptable toxicity. Primary endpoint was 1-year PFS. Forty-six of 48 enrolled patients were assessable. Most patients had IPI ≥2, advanced stage and extranodal disease before the salvage treatment that led to trial registration; 28 (61%) patients were older than 70 years. Lenalidomide was well tolerated. With the exception of neutropenia, grade-4 toxicities occurred in <1% of courses. Three patients died of complications during maintenance and three died due to second cancers at 32 to 64 months. There were 13 SAEs recorded in 12 patients; all these patients but two recovered. Lenalidomide was interrupted due to toxicity in other 6 patients, and 25 patients required dose reduction (transient in 21). At 1 year from registration, 31 patients were progression free. After a median follow-up of 65 (range 39-124) months, 22 patients remain progression free, with a 5-year PFS of 48% ± 7%. The duration of response to lenalidomide was longer than response to prior treatment in 30 (65%) patients. Benefit was observed both in de novo and transformed DLBCL, germinal-center-B-cell and nongerminal-center-B-cell subtypes. Twenty-six patients are alive (5-year OS 62% ± 7%). With the limitations of a nonrandomized design, these long-term results suggest that lenalidomide maintenance might bring benefit to patients with chemosensitive relapse of DLBCL not eligible for or failed after ASCT. Lenalidomide was associated with durable disease control and was well tolerated in this elderly population. Further investigations on immunomodulatory drugs as maintenance in these high-risk patients are warranted.
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http://dx.doi.org/10.1002/hon.2742DOI Listing
August 2020

Hematopoietic stem cell function in β-thalassemia is impaired and is rescued by targeting the bone marrow niche.

Blood 2020 07;136(5):610-622

San Raffaele-Telethon Institute for Gene Therapy (SR-TIGET), Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) San Raffaele Scientific Institute, Milan, Italy.

Hematopoietic stem cells (HSCs) are regulated by signals from the bone marrow (BM) niche that tune hematopoiesis at steady state and in hematologic disorders. To understand HSC-niche interactions in altered nonmalignant homeostasis, we selected β-thalassemia, a hemoglobin disorder, as a paradigm. In this severe congenital anemia, alterations secondary to the primary hemoglobin defect have a potential impact on HSC-niche cross talk. We report that HSCs in thalassemic mice (th3) have an impaired function, caused by the interaction with an altered BM niche. The HSC self-renewal defect is rescued after cell transplantation into a normal microenvironment, thus proving the active role of the BM stroma. Consistent with the common finding of osteoporosis in patients, we found reduced bone deposition with decreased levels of parathyroid hormone (PTH), which is a key regulator of bone metabolism but also of HSC activity. In vivo activation of PTH signaling through the reestablished Jagged1 and osteopontin levels correlated with the rescue of the functional pool of th3 HSCs by correcting HSC-niche cross talk. Reduced HSC quiescence was confirmed in thalassemic patients, along with altered features of the BM stromal niche. Our findings reveal a defect in HSCs in β-thalassemia induced by an altered BM microenvironment and provide novel and relevant insight for improving transplantation and gene therapy approaches.
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http://dx.doi.org/10.1182/blood.2019002721DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7547533PMC
July 2020

HMGA1-pseudogene7 transgenic mice develop B cell lymphomas.

Sci Rep 2020 04 27;10(1):7057. Epub 2020 Apr 27.

Istituto di Endocrinologia ed Oncologia Sperimentale - CNR c/o Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università degli Studi di Napoli "Federico II", Naples, Italy.

We have recently identified and characterized two pseudogenes (HMGA1P6 and HMGA1P7) of the HMGA1 gene, which has a critical role in malignant cell transformation and cancer progression. HMGA1P6 and HMGAP17 act as microRNA decoy for HMGA1 and other cancer-related genes upregulating their protein levels. We have previously shown that they are upregulated in several human carcinomas, and their expression positively correlates with a poor prognosis and an advanced cancer stage. To evaluate in vivo oncogenic activity of HMGA1 pseudogenes, we have generated a HMGA1P7 transgenic mouse line overexpressing this pseudogene. By a mean age of 12 months, about 50% of the transgenic mice developed splenomegaly and accumulation of lymphoid cells in several body compartments. For these mice FACS and immunohistochemical analyses suggested the diagnosis of B-cell lymphoma that was further supported by clonality analyses and RNA expression profile of the pathological tissues of the HMGA1P7 transgenic tissues. Therefore, these results clearly demonstrate the oncogenic activity of HMGA1 pseudogenes in vivo.
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http://dx.doi.org/10.1038/s41598-020-62974-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7184748PMC
April 2020

Treatment of MALT lymphoma of the conjunctiva with intralesional rituximab supplemented with autologous serum.

Blood Adv 2020 03;4(6):1013-1019

Ophthalmology Unit, and.

Patients with indolent conjunctival lymphomas exhibit good prognosis, with exceptional cases of dissemination, and are suitable candidates for intralesional therapies. We report the first prospective phase 2 trial using intralesional rituximab supplemented with autologous serum in adults with relapsed/refractory indolent CD20+ lymphoma of the conjunctiva (NCT01514344). Patients received 4 weekly intralesional injections of rituximab, followed by 6 monthly injections; 500 μL of autologous serum was added to rituximab in patients with lymphoma unresponsive to weekly doses. Safety, activity, and antitumor effect of autologous serum were investigated. Twenty patients with mucosa-associated lymphoid tissue (MALT)-type lymphoma were enrolled. Tolerability was excellent, with only 3 mild local reactions. After weekly injections, 11 patients achieved tumor regression, 8 had stable disease, and 1 experienced progressive disease; 9 patients received autologous serum, with response improvement in 4 cases (3 complete responses, 1 partial response). At the end of treatment, 12 patients achieved a complete remission, and 1 achieved a partial response, with an overall response rate of 65% (95% confidence interval, 45-85). At a median follow-up of 42 months (range, 10-78), 12 patients remain relapse free, with 5-year progression-free survival and time-to-next-treatment rates of 59% ± 11% and 69% ± 11%, respectively. Three patients with local relapse were retreated with intralesional rituximab and serum; 2 achieved a complete response that lasted 25+ and 38+ months. Thus, intralesional rituximab is a safe and active therapy in patients with relapsed conjunctival MALT lymphoma. The addition of autologous serum improves response in some cases. Retreatment of local relapses can result in a second durable remission.
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http://dx.doi.org/10.1182/bloodadvances.2020001459DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7094013PMC
March 2020

Correction to: Update on lymphoproliferative disorders of the gastrointestinal tract: disease spectrum from indolent lymphoproliferations to aggressive lymphomas.

Virchows Arch 2020 May;476(5):793

Department of Cellular Pathology, SIHMDS, Barts Health NHS Trust and Centre for Haemato-Oncology, Barts Cancer Institute, London, UK.

This erratum is meant to address the error in which the names of one of the authors of the manuscript, was incorrect. Author assumes full responsibility for this error.
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http://dx.doi.org/10.1007/s00428-020-02772-1DOI Listing
May 2020

Lymphomas arising in immune-privileged sites: insights into biology, diagnosis, and pathogenesis.

Virchows Arch 2020 May 20;476(5):647-665. Epub 2019 Dec 20.

Department of Pathology, Massachusetts General Hospital and Harvard Medical School, 55 Fruit Street, Boston, MA, 02114, USA.

Session 2 of the 2018 European Association of Hematopathology/Society for Hematopathology Workshop focused on lymphomas arising in immune-privileged sites: both lymphomas arising in the traditionally described "immune sanctuary" sites of the central nervous system (CNS) and testes, as well as those arising at sites of local immune privilege. Primary CNS large B cell lymphoma and primary testicular large B cell lymphoma were discussed, and the biology of these unique tumors was highlighted by several cases showing the classic mutation profile including MYD88 L265P and CD79B. The tendency of these tumors to involve both the CNS and testis was also reinforced by several cases. Four cases of low-grade B cell lymphomas (LGBCL) of the CNS were discussed. Two were classic Bing-Neel syndrome associated with LPL, and two were LGBCL with plasmacytic differentiation and amyloid deposition without systemic disease. Rare examples of systemic T and NK cell lymphomas involving the CNS were also discussed. Several cases of breast implant-associated anaplastic large cell lymphoma (BI-ALCL) were submitted showing the typical clinicopathologic features. These cases were discussed along with a case with analogous features arising in a patient with a gastric band implant, as well as large B cell lymphomas arising alongside foreign materials. Finally, large B cell lymphomas arising in effusions or localized sites of chronic inflammation (fibrin-associated diffuse large B cell lymphoma [DLBCL] and DLBCL associated with chronic inflammation) were described. The pathogenesis of all of these lymphomas is believed to be related to decreased immune surveillance, either innate to the physiology of the organ or acquired at a local site.
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http://dx.doi.org/10.1007/s00428-019-02698-3DOI Listing
May 2020

The clinico-pathological spectrum of primary cutaneous lymphoma other than mycosis fungoides/Sezary syndrome.

Virchows Arch 2020 May 28;476(5):683-699. Epub 2019 Nov 28.

Department of Pathology, Queen Elizabeth University Hospital, Level 3, Laboratory Medicine Building, 1345 Govan Rd, Glasgow, G51 4TF, Scotland.

The major aim of Session 1 of the 2018 European Association of Hematopathology/Society for Hematopathology Workshop was to collect examples of cutaneous lymphomas, excluding mycosis fungoides/Sezary syndrome, as defined in the current WHO classification of tumours of the haemetopoietic and lymphoid tissues. Overall 42 cases were submitted. These were considered in four main categories: primary cutaneous B cell lymphomas (12 cases), primary cutaneous T cell lymphomas/lymphoproliferations with CD8+/cytotoxic phenotype (12 cases), primary cutaneous CD30-positive lymphoproliferative disorders (15 cases) and primary cutaneous T cell lymphomas/leukaemias with CD4+ phenotype (4 cases). Using these cases as examples, we were able to present the full spectrum of cutaneous lymphoproliferations (excluding mycosis fungoides/Sezary syndrome), including examples of rare, provisional and new entities as listed in the 2017 update of the WHO classification. The findings are summarized in this report with emphasis on differential diagnostic considerations and the importance of clinico-pathological correlation for final subtyping. In presenting these findings we hope to raise awareness of this enigmatic group of neoplasms and to further our understanding of these rare disease entities.
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http://dx.doi.org/10.1007/s00428-019-02713-7DOI Listing
May 2020
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